Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
1
Sodium Borohydride Digest
Copyright: October 2003
Rohm and Haas…
Quality, Service and Innovation in Borohydride Products
Rohm and Haas (formerly Metal Hydrides Inc.) broke ground on the world’s first large-scale sodium borohydride plant in
1956, making possible the widespread use of this important chemical. Four and a half decades later, we have two world-class plants
(USA and NL), a wide variety of product forms (Powder, Granular, Caplets, Aqueous Solutions and Organic Solutions) and a
worldwide comprehensive customer support. While we are proud of our role as innovator in the sodium borohydride market, we
understand that continued success depends on giving our customers the tools they need to move from concept to finished product.
The Sodium Borohydride Digest is an important part of our efforts to help users understand the wide utility of sodium
borohydride reductions in organic Organic Synthesis. For example, sodium borohydride has long been the reagent of choice for
reducing aldehydes and ketones to alcohols. It has also become well known for situations where selective reductions are needed.
However, many organic chemist may be less familiar with the facts that successful reduction are also possible with acid chlorides,
imines, esters, carboxylic acids, unsaturated cyclic quaternary compounds and many other functional groups.
The Digest is designed to allow readers to survey the entire spectrum of sodium borohydride chemistry and to obtain more
details on reactions of interest. Illustrations of reductive chemistry are followed wherever possible, by the corresponding Chemical
Abstracts references, which are collected at the end of each section. In addition when ever possible reference to Alembic will be
sited. The Alembic is a publication that intends to highlight one specific chemical topic with possible interest for Organic Synthesis
on industrial scale.
*For Online Consulting Only
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
2
In addition, the Sodium Borohydride Digest is a guide to sodium borohydride’s relative position among reducing reagents.
We include table showing common functional groups and their general reducibility by sodium borohydride, sodium borohydride
derivatives and by some analogous aluminohydride reducing agents. Within the market of chemical reducing agents in organic
synthesis, NaBH4 is the primary reductant used on industrial scale, with a estimated (equivalent) market share greater than 50%.
Some of the benefits of using borohydride chemistry include :
- the least expensive metal hydride commercially available (on a hydride equivalent basis)
- safe with regards to storage and use & handling
- industrial implementation requires no or limited equipment investment
- ease of work-up (water soluble boron salts)
- ubiquitous solvents such as water and methanol are typically employed
- unique and versatile as a hydride reducing agent for both chemo- and diastereo-selectivity
Rohm and Haas welcomes request for additional information and will gladly provide technical assistance to those interested
in developing or optimizing sodium borohydride applications. Our research and technical service groups can provide assistance by
telephone or, if appropriate, by visiting your facility. We can furnish technical literature on a wide variety of applications. Finally,
Rohm and Haas, as a subscriber to the Responsible Care® Codes, is committed to the safe use of our products. We have wide variety
of information and presentations on safety and handling.
John Yamamoto, Ph.D
Editor
Rohm and Haas Company
Synthesis & ProcessApplications
*For Online Consulting Only
Rohm and Haas : the Sodium Borohydride Digest
Please feel free to send us your questions via venpure@rohmhaas.com, or contact one of our offices
in America:
Rohm and Haas Company
Borohydride Applications
60 Willow Street
Phone: 1-978-557-1832
Fax: 1-978-557-1879
in Asia:
Rohm and Haas China, Inc.
23rd Floor, Hitech Plaza
No. 488 S. Wu Ning Road
Shanghai, China
Phone: +86 21 6230 6366
Fax: +86 21 6230 6377
Updated information can be found at : http://www.hydridesolutions.com/
*For Online Consulting Only
3
press <CTRL>-F for Searching
in Europe:
Rohm and Haas France S.A.
la tour de Lyon
185, rue de Bercy
F-75579 Paris
Phone: +33-1 4002 5210
Fax : +33-1 4002 5441
:
4
press <CTRL>-F for Searching
Rohm and Haas : the Sodium Borohydride Digest
TABLE OF CONTENTS
I. Properties
A. Physical and Thermodynamic
B. Solubility
C. Stability
II. Organic Reductions
A. Theory
B. Practice
C. Carbonyl groups
Aldehydes
Ketones
Acids
Amides
Anhydrides
Acid Halides
Esters
Enol Esters
Imides
Lactone
D. Carbon-Nitrogen Compounds
Reductive Amination
Azides
Deamination
Diazonium Salts
*For Online Consulting Only
Page #
6
7
9
14
16
28
28
35
51
55
57
59
63
71
72
74
77
82
85
86
Heterocyclic C=N Bonds
Hydrazones
Imines
Nitriles
Nitro
Nitroso
Oximes
Quaternary Compounds
E. Miscellaneous Organic Reductions
Carbonium Ions
Reductive Cleavage
Reductive Cyclization
Dehalogenantions
Demercurations
Double bonds
Epoxides
Organo Calcogen Compounds
Ozonides
Peroxides and Hydroperoxide
III. Inorganic Applications
A. Inorganic Reductions
Metal Cation Reduction
Metal Anion Reduction
B. Organometallic
C. NaBH4 Derivatives
87
92
97
98
101
105
107
110
114
116
119
122
125
128
133
135
140
141
143
143
145
155
160
Rohm and Haas : the Sodium Borohydride Digest
Sodium Cyanoborohydride
160
Polymer Bound borohydrides
161
Other Solid Supports
162
NaBH2S3 Lanacett’s Reagent
162
NaBH(OR)3 Sodium Hydridotrialkoxyborates
163
NaBH4 Polyamine Polymer
163
Lithium Borohydride
164
Potassium Borohydride
164
Calcium Borohydride
164
Zinc Borohydride
164
Mixed Hydrides
165
Esters and Acids
165
Acetals and Ketals
165
166
Hydroboration with NaBH4
Other Derivatives
167
IV/ Analytical Procedures
A. Assay Methods
179
Trace Methods for Borohydrides 180
NaBH4 AssayHydrogen Evolution Method 182
Iodate Method
185
Trace NaBH4 AssayHydrogen evolution 188
Iodate Method
191
NBC Method
193
*For Online Consulting Only
5
press <CTRL>-F for Searching
Crystal Violet Method
195
V. Availability
VI. Personal Protective Equipment
VII. First Aid
VIII. Reactivity
IX. Fire Fighting/ Flammability
X. Spill And Waste Disposal
XI. Toxicity
XII. Storage And Handling
XIII. Shipping
198
199
200
202
204
205
207
208
210
Rohm and Haas : the Sodium Borohydride Digest
I. PROPERTIES
A. Physical and Thermodynamic Properties
These properties are listed in the following two
tables. Infrared and Raman spectra of both sodium and
potassium borohydrides have been reported (1).
Table I Selected Physical Properties of Sodium
Borohydride
Properties
Formula
NaBH4
Molecular Weight
37.84
Purity
>98.5%
Color
White
Crystalline
Form Face Centered cubic
(anhydrous)
a= 6.15 Å
(dihydrate)Exists
below 36.5 oC
Melting Point
505 oC (10 atms H2)
Decomposes
above
400 oC In Vacuum
Thermal Stability
Will not ignite above
400 oC on a hot plate
Ignites from free flame
in air, Burning quietly
Density
1.074g/cm3
Apparent Bulk Density 5lb/gal
*For Online Consulting Only
6
press <CTRL>-F for Searching
Table II Thermodynamic Properties of Sodium Borohydride
Function Value
Ref
Free Energies of Formation
Heat of Formation
Entropy
Heat Capacity
Free Energy of Ionization
NaBH4(s)= Na+ + BH4-
Borohydride ion BH4- (aq.)
Free Energy of Formation
Heat of Formation
Entropy
Hydrolysis
BH4- + H+ + 3 H2O (liq)=
H3BO3 + 4 H2(g)
Oxidation
BH4- + 8 OH- = B(OH)4- + 4
H2O + 8e-
∆Fo298
∆Ho298
So
Co p
∆Fo298
-30.1
kcal/mol
-45.53
kcal/mol
+24.26
cal/omol
+20.67
cal/omol
-5660 cal/mol
3
2
5
3
4
∆Fo298
∆Ho298
So298
+28.6
kcal/mol
+12.4
kcal/mol
+25.5
cal/omol
4
4
4
∆Fo298
∆Fo298
Eo298
-88.8
kcal/mol
-228.9
kcal/mol
+1.24 V
4
4
4
press <CTRL>-F for Searching
Rohm and Haas : the Sodium Borohydride Digest
gm. NaBH4 in 100g saturated
solution
B. Solubility
1. Water
The solubility of sodium borohydride in water,
the most commonly used solvent, has been accurately
measured at the different temperatures by Jensen (6).
The data presented in the following graph shows the
equilibrium temperature of the two crystal forms NaBH4
and NaBH4•2 H2O. The curve below 36.4oC represents
the solubility of the dihydrate, and above 36.4oC, the
solubility of anhydrous NaBH4.
55
50
45
40
35
30
25
0
20
40
60
Temperature o C
Figure 1. The solubility of sodium borohydride in water
at different temperatures.
*For Online Consulting Only
7
2. Nonaqueous Solvents
The solubility of sodium borohydride in different
solvents has been determined accurately at different
temperatures for many alcohols, amines, and glycol ethers. In
general, sodium borohydride is soluble in polar compounds
containing a hydroxyl or amine group. A point to note is the
glycol ethers differ from most solvent in that their ability to
solubilize sodium borohydride decreases as solvent
temperature increases. See table III.
Rohm and Haas : the Sodium Borohydride Digest
Table III NaBH4 Solubility in Various Solvents
(g/100g of solvent)
Solvent
Water
Liquid Ammonia
Methylamine
Ethylamine
N-Propylamine
Iso-Propylamine
N-Butylamine
Cyclohexylamine
Morpholine
Aniline
Pyridine
Monoethanolamine
Ethylenediamine
Methanol
Ethanol
Temp(oC)
0
25
60
25
-22.0
17
28
28
28
28
25
75
75
25
75
25
75
20
20
Solubility
25.0
55.0
88.5
104.0
27.6
20.9
9.6
6
4.9
1.8
1.4
2.5
0.6
3.1
3.4
7.7
22.0
16.4 (reacts)
4.0 (reacts
slowly)
Iso- Propanol
Tert-Butanol
25
60
25
*For Online Consulting Only
0.37
0.88
0.11
8
press <CTRL>-F for Searching
2-Ethylhexanol
Tetrahydrofurfuryl
Alcohol
Ethylene glycol
dimethyl ether
Diethylene glycol
dimethyl ether
Triethylene glycol
dimethyl ether
Tetraethylene glycol
dimethyl ether
Dimethylformamide
Dimethylacetamide
Dimethylsulfoxide
Acetonitrile
Tetrahydrofuran
60
25
20
0
20
0
25
45
75
0
25
50
100
0
25
50
75
100
20
20
25
28
20
01.8
0.01
14.0 (reacts
slowly
2.6
0.8
1.7
5.5
8.0
0.0
8.4
8.7
8.5
6.7
8.7
9.1
8.4
8.5
4.2
18.0
14.0
5.8
2.0
0.1
Rohm and Haas : the Sodium Borohydride Digest
3. Non-Solvents
In cases where sodium borohydride is not
soluble, traces amounts of water or low molecular
weight alcohols can be added to the organic solvent to
effect reduction. In general, two moles of water are
needed for every mole of sodium borohydride. This
procedure has proven effective with very high
molecular weight alcohols. In some cases, however, an
organic borohydride such as tetraethylammonium
borohydride will be more effective because of its greater
solubility. The use of NaBH4 on solid supports such as
silica gel, alumina, and zeolites in nonpolar solvents has
been published (See section IIIC).
C. Stability
Sodium borohydride is very stable thermally.
It decomposes slowly at temperatures above 400oC in
vacuum or under a hydrogen atmosphere. Sodium
borohydride absorbs water rapidly from moist air to
form the dihydrate complex, which decomposes slowly
forming
hydrogen
and
sodium
metaborate.
Decomposition in air is therefore a function of both
temperature and humidity. Generally higher reaction
temperatures favor borohydride reductive chemistries.
*For Online Consulting Only
press <CTRL>-F for Searching
9
1. Aqueous Solutions
The stability of sodium borohydride in water is dependent
upon the temperature and the pH. Increasing the temperature
and lowering the pH accelerates the hydrolysis reaction.
NaBH4 + 4 H2O Æ NaB(OH)4 + 4 H2
As the borohydrides are alkaline, the higher the concentration,
the more stable the resulting solutions. See Table IV.
Table IV pH of Solutions of NaBH4 at 24oC
Concentration of
pH
NaBH4
1.000M
10.48 ± 0.02
0.100M
10.05 ± 0.02
0.010M
9.56 ± 0.02
The kinetics of the hydrolysis reaction has been studied by
Gardiner and Collat (7,8), Wang and Jolly (9), and by Kreevoy
(10,12). The reaction is pseudo-first order and is subject to
general acid catalysis. First order kinetics also applies in
strongly alkaline solution (13).
The decomposition rate of aqueous NaBH4 solutions can be
estimated conveniently (14) using equation
Log10t1/2(mins)= pH-(0.034T-1.92)
where t1/2 is the half-life in minutes and T is the
temperature (kelvin scale). Table V. numerically shows
the relationship between pH and the half-life of NaBH4
at 25 oC in an aqueous solution.
Table V: pH Vs Half life of SBH
pH
NaBH4 Half life
4.0
0.0037 sec.
5.0
0.037 sec
5.5
0.12 sec
6.0
0.37 sec
7.0
3.7 sec.
8.0
36.8 sec.
9.0
6.1 mins
10.0
61.4 mins
11.0
10.2 hours
12.0
4.3 days
13.0
42.6 days
14.0
426.2 days
The hydrolysis of sodium borohydride in water causes a
rise in pH value, and the rate of decomposition therefore
decreases. For example, a 0.01 M solution of NaBH4 has
an initial pH of 9. 6 that changes during hydrolysis to
9.9.
*For Online Consulting Only
10
press <CTRL>-F for Searching
(a) Effect of pH
It is obvious, therefore, that the addition of sodium
hydroxide will stabilize aqueous sodium borohydride
solutions. This was demonstrated by Jensen (6) over a pH
range of 12.9 to 13.8 (calc.)
At higher pH values there is essentially no decomposition
during storage.
100
98
% NaBH4
Rohm and Haas : the Sodium Borohydride Digest
96
0.10 N NaOH
0.25 N NaOH
1.00N NaOH
94
92
90
88
86
0
50
100
150
Time (hours)
Figure 2. Effect of pH on stability of NaBH4 solutions.
(b) Effect of Temperature
If the temperature is increased, the stability decreases
as shown in Fig.1. This can be compensated for, by adding
more caustic or increasing the sodium borohydride
concentration.
press <CTRL>-F for Searching
Rohm and Haas : the Sodium Borohydride Digest
11
a rate of only 5x10-6% per day at 21oC and at 4x10-5% per day
at 54oC.
100
% NaBH4
90
80
24.0 oC
47.0o C
70
60
50
40
0
50
100
3. Tetraglyme solutions (Venpure OGS)
Venpure OGS is a tetraglyme solution of 8.5 % sodium
borohydride. This solution is to be used when sodium
borohydride is needed in an aprotic solvent. The stability of
the sodium borohydride in this solvent is very good, no
decomposition of the NaBH4 occurs after 336 hour at either 24
or 60 oC.
Time (hour)
Figure 3. Stability of an alkaline solution (1.00 N
NaOH) of sodium borohydride (0.10 M NaBH4) at 24o C
and 46o C
(c) Effect of catalysts
Noble metals, copper, nickel and cobalt borides
(15-23) catalyze the hydrolysis of the borohydride ion;
the catalyst is frequently formed by borohydride
reduction of the corresponding metal salts in solution.
2. Aqueous solutions (VenPure)
VenPure Solution is a stabilized water solution of
sodium borohydride in caustic soda. Such a solution
containing 12% NaBH4 and 40% NaOH, decomposes at
*For Online Consulting Only
4. Alcohol Solutions.
NaBH4 is unstable in acidic alcohols (e.g. phenol) and low
molecular weight primary alcohols such as methanol, ethanol
and ethylene glycol due to solvolysis but is stable in secondary
and tertiary alcohols such as isopropanol, t-butanol and 2ethylhexanol, even at elevated temperatures (24,25). It reacts
with higher molecular weight primary alcohols.
The instability in lower alcohols can be overcome by the
addition of base, as in aqueous solutions. For example, Jensen
(6) has reported that ethanol only 5.7% of the sodium
borohydride is lost in 144 hours at 24oC in the presence of 2 N
sodium hydroxide. Studies undertake at Rohm and Haas have
demonstrated that the addition of as little as 0.01 N MeONa to
a methanol solution or 0.01N NaOEt to an Ethanol solution of
Rohm and Haas : the Sodium Borohydride Digest
sodium borohydride can substantially suppress the
hydrolysis of NaBH4 as shown in the graphs below.
80
No NaOMe
added
0.010 N
NaOMe
60
40
20
30
% NaBH4 Consumed
% NaBH4 consumed
100
25
20
0.001 NaOEt
15
0.1 NaOEt
10
No NaOEt
5
0
0
0
0
10
20
30
2
Time, Hours
40
Time (minutes)
Figure 4. Effect of the addition of NaOMe on solvolysis
of NaBH4 in methanol over a short period of time.
12
press <CTRL>-F for Searching
Figure 5. Effect of the addition of NaOEt on the solvolysis of
sodium borohydride in ethanol at 30 oC.
100
80
0.1N NaOMe 30
oC
60
40
0.1N at 50 oC
20
0
0
200
Ti m e ( M i nu t e s)
Figure 6. Effect of Temperature on the solvolysis of NaBH4 in
methanol with NaOMe.
*For Online Consulting Only
Rohm and Haas : the Sodium Borohydride Digest
3
2,5
2
1,5
1
0,5
0
0.01NaOEt at 50°C
0.01NaOEt at 30°C
0
0,5
1
Ti m e ( ho ur s)
Figure 7. Effect of Temperature on the solvolysis of
SBH in ethanol with NaOEt.
5. Other Solvents
The stability of sodium borohydride solutions
in organic solvents is dependent upon the amount of
hydrolysis that can occur. In solvents such as Glymes,
DMAC, NMP, pyridine and dioxane, where there is no
chance of hydrolysis, sodium borohydride is stable
indefinitely. As soon as water is present in significant
amounts, hydrolysis can occur and affect the stability.
While dilute solutions of NaBH4 in dimethlyformamide
(DMF) have been used many times without incident, a
violent exothermic reaction was reported (26) involving
*For Online Consulting Only
press <CTRL>-F for Searching
13
a saturated (4.7M) solution and resulting in spontaneous
ignition of the flammable gases evolved.
Laboratory
investigation at Rohm and Haas showed that after a
temperature-dependent induction period, a runaway reaction
occurs in concentrated (>2M) NaBH4-DMF solutions in which
DMF is reduced to trimethyl amine. The reaction is
accelerated by small amounts of carboxylic acids. Formic acid
is known to be present in commercial DMF in ppm quantities
as a result of slight hydrolysis. Dimethylacetamide (DMAC),
which is also a good solvent for NaBH4, does not react
violently with NaBH4 under similar conditions.
In view of the above findings, we strongly advise
caution in working with NaBH4 in DMF. We recommend
substitution of dimethylacetamide as safer solvent especially if
the use of concentrated solutions or elevated temperatures is
contemplated.
D
O
D
R
δ-
O
R
W
W
δ+
Least reactive
Most reactive
Because of this, any substituent that increases the
fractional positive charge on the carbonyl carbon atom
will increase the rate of reduction. If the fractional
positive charge is decreased by substituents, then the
rate is slowed. Jensen (6), for example, has shown that
the rate of reduction for substituted benzaldehyde
derivatives is as shown in Figure 8.
In this case, the inductive effect leading to a greater
positive charge is overcome by the resonance effect.
100
90
80
70
% Reduction
II. ORGANIC REDUCTIONS
A. Theory
The rate of addition of sodium borohydride to a
ketoneic carbon is directly related to the magnitude of
the charge on that carbon.
O
14
press <CTRL>-F for Searching
Rohm and Haas : the Sodium Borohydride Digest
Benzaldehyde
60
Salicyladehyde
50
m-hydroxybenzaldehyde
40
p-hydroxybenzaldehyde
b-Resorcylaldehyde
30
20
10
0
0
50
100
Time (minutes)
Figure 8. Rate of reduction of benzaldehyde and a few
hydroxybenzaldehydes.
With perfluoro compounds, however, the inductive effect is
clearly shown, and it has been demonstrated (27) that
fluorinated esters are reducible by NaBH4 in nonaqueous
systems in good yield.
R-CF2-COOEt Æ R-CF2CH2-OH
The presence of metal ions, either as a catalyst (28, 29), or to
form other more powerful or stereo selective borohydrides,
and solvents (24) can influence reductions with NaBH4.
*For Online Consulting Only
Rohm and Haas : the Sodium Borohydride Digest
The mechanism of borohydride reductions of aldehydes
or ketones in the presence of alcohols was initially
thought to proceed by a stepwise hydride ion transfer to
the carbonyl carbon, resulting in formation of a
tetraalkoxyborate containing the substrate being
reduced. Subsequent hydrolysis of the complex, during
work up, generated the product alcohol.
The first model to predict the stereoselectivity of
hydride reductions of carbonyl groups was proposed by cram
in 1952 (35-36). This model proposed that the hydride atom
attacks the carbonyl group form the direction of the smallest
substituent as shown in figure 10.
O
R
R
R
In any case, kinetic studies show that the first
step in the process must be rate controlling.
*For Online Consulting Only
NaBH4
+
OH
O
+
Various aspects of the relatively few
mechanistic studies reported in ensuing years served
only to cloud the issue. These included solvent and
cation effects (24,25), Kinetic observations (30) that
suggested
complete
disproportionation
of
alkoxyborohydride intermediates to regenerate BH4- as
the actual reducing agent, and questions on the origin of
stereoselectivity. Detailed studies by Wigfield (31-34)
indicate that during carbonyl reductions in alcohol
solvents, the alkoxyborate anion intermediate contains
the solvent alkoxy rather than that of the product.
(Figure 9) Isotope studies show that disproportionation
of the intermediate back to BH4- does not occur.
15
press <CTRL>-F for Searching
R
H
K1
O
H
H
B
R'
H
H
R'OH
Figure 9
H
R
R
K2
+
NaBH3OR'
H103o
H
O
R
M
HO
S
P,L
H
O
H-
R
M
S
M
P,L
cation adds steric bulk to the molecule, which will increase the
specificity of the attack of the hydride.
HR
S
P,L
R
R
M
16
press <CTRL>-F for Searching
Rohm and Haas : the Sodium Borohydride Digest
O
S
M
L
S
Metal
R
M
H
OH
L
OH
S
P,L
Figure 10
In 1968 Felkin improved on Cram's model by
proposing that the bulkiest substituent could also be the
most electron-withdrawing group regardless of steric
size. (37) These new conclusions were later
substantiated by the theoretical calculations of Ahn. (3840) The theoretical calculations also showed that the
hydride attacking the carbonyl group approaches at a
103o angle instead of 90o.
Another model set forth by Cram in 1952
proposed that substrates containing a chelating group in
the α or β position will chelate with a metal cation to
form a five or six membered ring. (41) The chelating
*For Online Consulting Only
See the section on ketones for further details.
B. Practice
Sodium borohydride is an attractive reducing agent
for organic substrates because of its convenience as well as its
selectivity and efficiency. The general techniques of its use
are by now well known to the practitioners of organic
synthesis, who also knows that modifications are sometimes
dictated by the properties (solubility, thermal stability, pH
sensitivity) of the materials being reduced. Nevertheless, a few
comments are in order, to ensure the reagent’s effective use.
Part of the convenience associated with sodium
borohydride reductions lies in the fact that, unlike most other
complex hydrides, it is not necessary to exclude moisture and
atmospheric oxygen from the reaction mixture. While some of
Rohm and Haas : the Sodium Borohydride Digest
the borohydride will be consumed by reaction with any
water present, this will not have any adverse effect on
the desired reduction, provided that sufficient
borohydride is present. This is the main reason why
hydride reductions customarily use a slight excess of
reducing agent.
The selection of a solvent for a NaBH4
reduction can influence the results. Water and lower
alcohols are most commonly used, but the solubility
characteristics of the material being reduced may dictate
selection of a different solvent (see Table III for NaBH4
solubility information.) It is important to note that
while the literature containing numerous references to
borohydride reductions in methanol, NaBH4 is not
stable in this solvent, especially at elevated
temperatures. Interaction of NaBH4 and methanol,
analogous to hydrolysis, takes place readily unless the
reducing agent solution is stabilized by the addition of
alkali. Ethanol and isopropanol, in which NaBH4 is less
soluble, are preferable because of their much slower
rates of solvolytic reaction with NaBH4. Water is a
good solvent for NaBH4 and is recommended for watersoluble compounds. As is true with methanol, however,
addition of alkali to stabilize the borohydride solution
may be warranted.
*For Online Consulting Only
press <CTRL>-F for Searching
17
In simple ketone reductions, as well as in many other
cases, the order of addition has no effect on the course of the
reaction and the yields obtained. The conversion in complex
hydride reductions is analogous to that of Grignard reactions in
that addition of substrate to the reducing solution is considered
the normal method. This order of addition is used even with
alkali-sensitive compounds, such as aldehydes or
aminoketones, since only a small amount of starting material at
a time is subjected to the alkaline conditions of the reducing
agent and this is rapidly reduced.
After completing the reduction reaction, destruction of
any unreacted borohydride is recommended before attempting
product isolation or workup. This can be accomplished by
addition of excess acetone that rapidly consumes borohydride.
Alternatively, dilute aqueous base or dilute mineral acids can
be added for the same purpose. Note that concentrated acids
must never be used because of the potential for formation of
hazardous boranes, which may also cause undesired reduction
of other functional groups present. Provision should be made
to vent safely any hydrogen gas formed during destruction of
unreacted borohydride. See section VI for additional details.
1) Phase Transfer Catalysis
This general discussion of the practical aspects of
applying sodium borohydride as a reducing agent would not be
complete without mentioning the increasing use of phase
Rohm and Haas : the Sodium Borohydride Digest
transfer catalysis (PTC) as a means of overcoming
solvent incompatibilities between the borohydride and
the substrate to be reduces (42-45). Quaternary
ammonium salts, such as tetrbutylammonium ion, are
the most commonly used catalysts. In fact, preformed
tetrabutyl ammonium borohydride has also been used
for reductions in aprotic solvents such as ethylene
chloride (38). Crepitates (39) and chiral functional
polymers (40-43) have also been applied in PTC
reductions with sodium borohydride. Continuing
interest in stereospecific reductions has resulted in the
use of chiral quaternary ammonium salts as phase
transfer catalysts. Asymmetric induction has been
demonstrated to occur when ephedrinium salts are used
in PTC reductions with sodium borohydride (44-46).
2) Chemically Modified Borohydride Anion
Modifying the chemo and/or enantio-selective
reductive properties of NaBH4 with the addition of
either an organic or inorganic modifier has opened areas
of reductive chemistry that were normally considered
inaccessible to NaBH4. Two classes of reagent that
have been used to modify sodium borohydride are
carboxylic acids (55-56), chiral alcohols (57), sugars
(58-62), tartaric acid (63) and lactic acid (64-65).
*For Online Consulting Only
press <CTRL>-F for Searching
18
The reaction of carboxylic acids with NaBH4 forms
either mono or tris-substituted acyloxyborohydrides, which
have unique reactive properties depending on the quantity of
acid, added to the reaction. The true strength of this system is
realized with the reduction of nitrogen containing organic
molecules such as immines, oximes, enamines, iminium salts
and heterocyclic compounds. Reductive aminations can be
done efficiently using this system. Two reviews exploring the
vast chemistry of this methodology has been published
recently (55-56).
Finally, chiral alcohols have been added to the NaBH4
reducing system to induce selective enantiomeric reduction of
organic functional groups. This selectivity is induced by
asymmetric induction. Chiral alcohols such as amino alcohols,
sugars and tartaric acid have been used to accomplish these
selective reductions (55-65).
3) Changing of the Cation
Many different metal salts have been used with
sodium borohydride to form new more powerful and selective
reducing reagents. The most common metals to be added are
LiCl (66), ZnCl2 (67-79), TiCl4(80-82), Ti(Isopropoxide)4 (8385), Cp2TiCl2 (87), CeCl3 (88-89), CaCl2 (90-92) and
lanthanide salts (93). The use of these metal salts to modify
the chemo, stereoslectivity and the reductive strength of the
NaBH4 towards organic functional groups have been and are
press <CTRL>-F for Searching
Rohm and Haas : the Sodium Borohydride Digest
currently being studied. A review has recently been
written on this subject.
4) Modification of the substrate.
Recently cynuric acid (94) and BOP (95) have
been added to solutions of carboxylic acids prior to
treatment with sodium borohydride, to help the
reduction of carboxylic acid groups under mild
conditions. This methodology makes it possible to
convert amino acid to amino achohols under very mild
conditions.
Cl
Cl
O
R
+
OH
Cl
N
NMM, DME
N
N
Cl
3h, RT
O
R
N
NaBH4, H2O
N
N
Cl
0 oC
R
OH
Cyclodextrin have recently been used as an
additive to help induce stereoselectrive reduction of
carbonyl groups. This reagent works by forming an
inclusion complex with the substrate to be reduced in
such a way as to allow the addition of hydride to the
functional group from one direction only (96-101).
19
5) Co-catalyst:
The use of catalysts to increase the chemo and stereo
selectivity of sodium borohydride has been demonstrated
recently. Adiminato Co(II) complexes have reduced ketones
as well as carboxyamides and imines functional groups
stereoselectively (102-106). Other inorganic and organic
catalysts have been reported (107).
6) Supported borohydrides
The impregnation of organic and inorganic polymers
such as ion exchange resins, zeolites, silica gel, alumina or
aluminophosphates with sodium borohydride or derivative has
been used to stereoselectively and chemoselectively reduce
organic functional groups. Depending on the nature of the
support, the type of borohydride reagent used and the type of
co-reagent are used, different chemo and stereoselectivities can
be achieved. These reductive systems have advantages such as
with the exchange resins, the spent borohydride are easily
separated from the product by filtration and with silica gel and
alumina reactions can be done in aprotic solvents such as
hexane.
7) In situ or ex situ production of diborane.
Diborane, B2H6 can be synthesized directly from
borohydride in high yields using many different reagents.
Reagents that can accomplish this transform are H2SO4 (108-
*For Online Consulting Only
Rohm and Haas : the Sodium Borohydride Digest
111), I2 (112-120), Me3SiCl (121-122), TiCl4 (123-124),
BF3 (125-128) and others. These reaction can be done
either in situ where the compound to be reduced and the
reagents to generate diborane are placed in to the same
reaction flask or the diborane which is a gas at room
temperature can be transferred from the diborane
generation flask to a new flask which contains the
molecule to be reduced. Both of these methods are a
very economical way of generating diborane. Diborane
will form stable complexes with Lewis bases such as
ethers, thioethers, and amines to form borane Lewis acid
base complexes. The chemistry of these complexes has
been published and is outside of the scope of this digest.
Precaution: Diborane is a highly toxic gas at room
temperature and should be handled with appropriate
care.
8) Enantioselective reduction using sodium
borohydrides
Normally
alkali
and
alkaline
earth
borohydrides by them self cannot enantioselectively
reduce organic functional groups. There are a few
exceptions to this rule where the alkali or alkaline earth
cation complexes with the compound in such a manner
as to stericlly direct the approach of the borohydride to
*For Online Consulting Only
press <CTRL>-F for Searching
20
the functional group to be reduced therefore forming only one
conformer. (129)
Another method that works on the premise of
controlling the steric availability of functional group to the
reducing agent is the use of molecules that associates with the
substrate in such a manner as to sterically direct the
borohydride to react with only one face of the reducible
functional group. A prime example of this technique is
cyclodextrin. The molecule of interest can enter the cavity of
the cyclodextrin molecule and due to steric restraints imposed
by the cyclodextrin molecule only one face of the reducible
functional group is accessible to the borohydride reducing
agent. (130-131)
Enantioselective reductions can be achieved using
sodium borohydride by adding chiral modifying reagents such
as enantiomerically pure; chiral alcohols, chiral carboxylic
acids, sugars, tartaric acids and other chiral organic
compounds to the borohydride prior to reaction with the
substrate. These reagents have been shown to give high ee’s.
(55-65)
Chiral transition metal catalyst such as the cobalt
catalyst developed by Yamada et al. can catalytically reduce
functional groups such as ketones, imines and oximes by using
the sodium borohydride as a source of hydride. (102-106)
Many borane based chiral reducing reagents and
catalyst that are formed from and use diborane as a source of
Rohm and Haas : the Sodium Borohydride Digest
hydrides are synthesized from borohydrides (see above).
Many reviews using these reagents have been published.
(132-138)
9) Chemoselectivity
As a general rule the reactivity of sodium
borohydride towards organic functional groups at room
temperature is as follows:
Easily reduced
Aldehydes>> Ketones> Acid Chlorides = Imines =
>C=N+<
Moderately reduced
Esters, Epoxides, Lactones
Difficult to reduce:
Carboxylic Acids, Amides, Imides, Carbinol, Nitrile,
Nitro Dehalogenantion, Tosylehydrazone,
Hydroboration and C-Calcogen Bond Cleavage
The selectivity of sodium borohydride can be
attributed to the inherent reductive strength of sodium
borohydride itself. This reductive strength can be
modified by adding co-reagents that either transforms or
modify the boron hydride bond or by changing the
kinetic properties of the reductive system, such as
temperature or time of reaction.
*For Online Consulting Only
press <CTRL>-F for Searching
21
Modifiers which increase the reductive strength of
sodium borohydride by decreasing the bond strength between
boron and hydrogen while the borohydride keeps all four of
it’s hydrides are metal salts such as LiCl, ZnCl2, CaCl2, AlCl3 ,
N(Bu)4 and others. (66-82, 90-92)
Sodium borohydride can be transformed into a
stronger reducing agent by adding modifiers that cause the
sodium borohydride to loss between 1 and three hydrogens to
form NaBH3OR or NaBH(OR)3. These modifiers are usually
small molecular weight alcohols and carboxylic acids. (55-56)
Another method of increasing the reductive strength
of sodium borohydride is to increase the temperature of the
reaction. This accomplishes two things it increases the rate of
the reaction and also adds energy to system to overcome the ∆
G of the reaction.
These different methods of increasing the reactivity of
sodium borohydride can be and are usually used in
combination to accomplish many reductions that are not
possible with sodium borohydride alone.
Rohm and Haas : the Sodium Borohydride Digest
References:
1) Davis, W.D.; Mason, L.S.; Stegeman, G J. Am.
Chem. Soc. 1949, 71, 2774; Chem. Abstr. 43,
7805d
2) Douglas, T.; Harman, A.W. J. Res. Nat. Bur. Std.
1958, 60, 117; Chem. Abstr, 52, 10704I
3) Stockmayer, W.H.; Rice, D.W.; Stephanson, C.C.
J. Am. Chem. Soc. 1955, 77, 1980; Chem. Abstr, 49,
9361d
4) Johnston, H.L.; Hallet, N.C., J. Am. Chem. Soc.
1953, 75, 1467; Chem. Abstr, 47, 10331e
5) Havery, K.B.; McQuaker, N.R. Can. J. Chem.
1971, 49, 3272
6) Jensen, E.H. "A Study on Sodium Borohydride",
NytNordisk Forlag Amold Busck, Copenhagen
1954- (Out of Print)
7) Gardiner, J.A.; Collat, J.W. J. Am. Chem. Soc.
1965, 87, 1692; Chem. Abstr, 62, 13899b.
8) Gardiner, J.A.; Collat, J.W. Inorg. Chem. 1965, 4,
1208; Chem. Abstr, 63, 6610e
9) Wang, F.T.; Jolly, W.L. Inorg. Chem. 1972, 11,
1933; Chem. Abstr, 77, 93285z
10) Levine, L.A.; Kreevoy, M.M. J. Am. Chem. Soc.
1972, 94, 3346; Chem. Abstr, 77, 10408t
11) Kreevoy, M.M.; Hutchins, J.E.C. J. Am. Chem. Soc.
1972, 94, 6731; Chem. Abstr, 77, 118776a
*For Online Consulting Only
press <CTRL>-F for Searching
22
12) Abts, L.M.; Langland, J.T. Kreevoy, M.M., J. Am. Chem.
Soc. 1975, 97, 3181; Chem. Abstr, 83, 121307c
13) Prokopcikas, A Salkauskiene, J. Zh. Fiz. Khuim. 1970,
44, 2941; Chem Abstr, 74, 46077m
14) Mochalov, K.N.; Khain, V.S.; Gil'manshin, G.G.; KInetika
I Kataliz 1965, 6, 541, Chem. Abstr, 63, 17202b
15) Paul, R.E.; Buisson, P.J.; Joseph, N.M. Ind. Eng. Chem.
1952, 44, 1006, Chem. Abstr, 46, 9960e
16) Schlesinger, H.I. et. al. J. Am. Chem. Soc. 1953, 75, 215;
Chem Abstr, 47, 3742e
17) Levy, A; Brown, J.B.; Lyons, C.J. Ind. Eng. Chem. 1960,
52, 211; Chem. Abstr, 56, 4360h
18) Brown, H.C.; Brown, C.A. J. Am. Chem. Soc. 1962, 84,
1493; Chem. Abstr, 57, 111b
19) Prokocikas, A.; Valsiuniene, J; Kimtiene, D. Liet. TSR
Mokslu Akad. Darb, Ser. B 1970, 27; Chem. Abstr, 75,
10760k
20) Prokocikas, A.; Salkauskiene, J. Liet. TSR Mokslu Akad.
Darb, Ser. B 1971, 3; Chem. Abstr, 74, 146745w
21) Prokocikas, A.; Valsiuniene, J Liet. TSR Mokslu Akad.
Darb, Ser. B 1971, 13 Chem. Abstr, 75, 10767t
22) Holbrook, K.A.; Twist, P.J. J. Chem. Soc. A 1971, 890;
Chem. Abstr, 74, 116413u
23) Kaufman, C.M.; Sen, B. J. Chem. Soc. Dalton Trans.
1985, 307; Chem. Abstr, 102, 17327q
Rohm and Haas : the Sodium Borohydride Digest
24) Brown, H.C.; Ichikawa, K.J. J. Am. Chem. Soc.
1961, 83, 4372; Chem. Abstr, 56, 7117c
25) Brown, H.C.; Mead, E.J.; Subba Roa, B.C. J. Am.
Chem. Soc. 1955, 77, 6209; Chem. Abstr, 50, 8529h
26) Chem. and Eng. News, p 4 Spet 24, 1979
27) French 1,573,705 1969, Chem. Abstr. 72,
1000089q
28) Vicek, A.A.; Rusina, A Proc. Chem. Soc. 1961,
161; Chem. Abstr, 56, 7186I
29) Neilson, T; Wood, H.C.S.; Wylie, A.G. J. Chem.
Soc. 1962, 371; Chem. Abstr, 56, 15391b
30) Rickborn, B; Wuesthoff, M.R. J. Am. Chem. Soc.
1970. 92, 6894; Chem. Abstr, 73, 31417y
31) Wigfield, D.C.; Gowland, F.W. Tetrahedron Lett.
1976, 3373; Chem. Abstr, 86, 71391q
32) Wigfield, D.C.; Gowland, F.W. J. Org. Chem.
1977, 42, 1108; Chem. Abstr. 86, 12047b
33) Wigfield, D.C.; Gowland, F.W. Can. J. Chem.
1987, 56, 786; Chem. Abstr. 87, 133739r
34) Wigfield, D.C. Tetrahedron 1979, 35, 449
35) Cram, D.J.; Wilson D.R. J. Am. Chem. Soc. 1963,
85, 1245
36) Cram, D.J.; Greene, F.D. J. Am. Chem. Soc. 1953,
75, 6004
37) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron
Lett. 1968, 18, 2199
*For Online Consulting Only
press <CTRL>-F for Searching
38)
39)
40)
41)
42)
43)
44)
45)
46)
47)
48)
49)
23
Anh, N.T. Top. Curr. Chem. 1980, 88, 145
Ahn, N.T.; Eisenstein, O. Nouv. J. Chem. 1977, 1, 61
Ahn, N.T.; Eisenstein, O. Tetrahedron Lett. 1976, 3, 155
Cram, D.J.; Elhafez F.A.A. J. Am. Chem. Soc. 1952, 74,
5828
Louis-Andre, O; Gelbard, G. Tetrahedron Lett. 1985, 26,
831; Chem. Abstr. 103, 37624c
Lamaty, G.; Riviere, M.H.; Roque, J.P. Bull. Soc. Chim.
Fr. 1983, 33; Chem. Abstr. 95, 80246j
D'Incan, E.; Loupy, A. Tetrahedron 1981, 37, 1171;
Chem. Abstr. 95, 80246j
Julia, S.; Ginebreda, A.; Guixer, J; Masama, J.; Tomaas,
A.; Colonna, S. J. Chem. Soc., Perkin Trans 1, 1981, 574,
Chem. Abstr. 94, 191536c
Raber, D.J.; Guida, W.C.; Schoenberger, D.C.
Tetrahedron Lett. 1981, 22, 5107; Chem. Abstr. 96,
162074m
Montanari, F.; Rundo, P. J. Org. Chem. 1981, 46, 2125;
Chem. Abstr. 94, 191216y
D'Antone, S.; Penco, M.; Solaro, R. Reactive Polymers
1985, 3, 107; Chem. Abstr. 103, 88267w
Kondo, S.; Nakanishi, M.; Tsuda, K. J. Polymer Sci.;
Polymer Chem. Ed. 1985, 23, 581; Chem. Abstr. 103,
36794w
Rohm and Haas : the Sodium Borohydride Digest
50) D'Antone, S.; Solaro, R.; Penco, M.; Chiellini, E.
Conv. Ital. Sci. Macrmol., [atti], 6th 1983, 2, 318;
Chem. Abstr. 101, 56147z
51) Kondo, S.; Nakanishi, M.; Yamane, K.; Horibe, A.;
Tsuda, K. J. Appl. Poly. Sci. 1986, 32, 4255; Chem.
Abstr. 105, 191638h
52) Masse, J.P.; Parayre, E.R. J. Chem. Soc. Chem.
Commun. 1976, 438; Chem. Abstr. 85, 192270h
53) Horner,L.; Brich, W. Liebigs Ann. Chem. 1978,
710; Chem. Abstr. 89, 128818c
54) Kinishi, R.; Nakajima, Y.; Oba, J.; Inouye, Y.
Agric. Biol. Chem. 1978, 42, 869; Chem. Abstr. 89,
106932h
55) Gribble, G.W. Chem. Soc. Review 1998, 27, 395
56) Gribble, G.W. ACS Symposium Series 1996, 641,
167
57) Yamada, S.; Mori, Y.; Morimatsu, K.; Ishizu, Y.;
Ozaki, Y.; Yoshioka, R.; Nakatani, T.; Seko, H. J.
Org. Chem. 1996, 61, 8586
58) Sharma, L. Indian. J. Chem. 1997, 36B, 796
59) Sharma, L.; Singh, S. Indian J. Chem. 1994, 33B,
1183
60) Zhdanov, V.A.; Alekseev, Y.E.; Korol, E.L.;
Sudareva, T.P.; Alekseeva, V.G. Russ. J. Gen.
Chem. 1993, 63, 1045
*For Online Consulting Only
press <CTRL>-F for Searching
24
61) Morrison, J.D.; Gradbois, E.R.; Howard, S.I. J. Org.
Chem. 1980, 45, 4229
62) Hirao, A.; Nakahama, S.; Mochizuki, H.; Itsuno, S.;
Yamazaki, N. J. Org. Chem. 1980, 45, 4231
63) Yatagai, M.; Ohnuki, T. J. Chem. Soc. Perkin Trans. 1
1990, 1826
64) Bianch, G.; Achilli, F.; Gamba, A.; Vercesi, D. J. Chem.
Soc. Perkin Trans 1 1988, 417
65) Yatagai, M; Ohnuki, T. J. Chem. Soc. Perkin Trans. 1
1990, 1826
66) Wong, S.S.; Paddon-Row, M. N. J. Chem. Soc. Chem.
Commun. 1990, 546
67) Zhang, H.C.; Costanzo, M.J.; Maryanoff, B.E.
Tetrahedron Lett. 1994, 35, 4891
68) Helm, R.F.; Ralph, J. J. Wood Chem. Tech. 1993, 13, 593
69) Narasimhan, S.; Madhavan, S.; Prasad, K.G. Synth.
Commun. 1997, 27, 385
70) Narasimhan, S.; Madhavan, S.; Balakumar, R.;
Swarnalakshmi, S. Synth. Commun. 1997, 27, 391
71) Bhattacharyya, S. Organometallic 1996, 15, 1065
72) Bhattacharyya, S.; Chatterjee, A.; Williamson, J.S. Synth.
Commun. 1997, 27, 4265
73) Bhattacharyya, S. Synth. Commun. 1995, 25, 2061
74) Narasimhan, S.; Madhavan, S.; Prasad, K.G. J. Org.
Chem. 1995, 60, 5314
Rohm and Haas : the Sodium Borohydride Digest
75) Kim, S.; Oh, C.H.; Ko, J.S.; Ahn, K.H.; Kim, Y.J.
J. Org. Chem. 1985, 50, 1927
76) Ranu, B.C.; Jana, U.; Sarkaar, A. Synth. Commun.
1998, 28, 485
77) Narasimhan, S.; Madhavan, S.; Prasad, K.G. Synth.
Commun. 1996, 26, 703
78) Ranu, B.C.; Sarkar, A.; Chakraborty, R. J. Org.
Chem. 1994, 59, 4114
79) Bhattacharyya, S.; Chatterjee, A.; Duttachowdhury,
S.K. J. Chem. Soc. Perkin Tran. 1 1994, 1
80) Liu, Y.; Schwartz, J. Tetrahedron 1995, 51, 4471
81) Liu, Y.; Schwartz, J. J. Org. Chem. 1994, 59, 940
82) Dosa, P.; Kronish,I; McCallum, J.; Schwartz, J.;
Barden, M.C. J. Org. Chem. 1996, 61, 4886
83) Bhattacharyya S. J. Org. Chem. 1995, 60, 4928
84) Bhattacharyya S. Tetrahedron Lett. 1994, 35, 2401
85) Armstrong, J.D.; Wolfe, C.N.; Keller, J.L.; Lynch,
J.; Bhupathy, M.; Volante, R.P. Tetrahedron Lett.
1997, 1531
86) Barden, M.C.; Schwartz, J. J. Org.Chem. 1995, 60,
5963
87) Barros, M.T.; Alves, C.M.; Santos, A.G.; Godinho,
L.S.; Maycock, C.D. Tetrahedron. Lett. 1995, 36,
2321
*For Online Consulting Only
press <CTRL>-F for Searching
25
88) Masaguer, C.F.; Bleriot, Y.; Charlwood, J.; Winchester,
B.G.; Fleet, G.W.J. Tetrahedron, 1997, 55, 15147
89) Taniguchi, M.; Fujii, H.; Oshima, K.; Utimoto, K.
Tetrahedron, 1995, 51, 679
90) Teixeira, L.H.; Barreriro, E.J.; Fraga, C.A.M. Synth.
Commun. 1997, 27, 3241
91) Narasimhan, S.; Ganeshwar, K.; Madhavan, S.
Tetrahedron Lett. 1995, 36, 1141
92) Molander, G.A. Chem. Rev. 1992, 92, 29
93) Falorni, M.; Porcheddu, A.; Taddei, M. Tetrahedron. Lett.
1999, 40, 4395
94) McGeary, R.P. Tetrahedron Lett. 1998, 39, 3319
95) Ravichandran, R.; Divakar, S. J. Mol. Catal. A. 1999, 137,
31
96) Pichumani, K.; Velusamy P.; Srinivasan, C. Tetrahedron,
1994, 45, 12979
97) Goldberg, Y.; Abele, E.; Rubina, K.; Popelis, Y;
Shimanska, M. Chem. Heterocyclic Comp. 1993, 29, 1399
98) Fornasier, R.; Lucchini, V.; Scrimm, P.; Tonellato, U. J.
Org. Chem. 1986, 51, 1769
99) Sakuraba, H.; Inomata,N. Tanaka, Y. J.Org. Chem. 1989,
54, 3482
100) Fornasier, R.; Reniero, F.; Scrimm, P.; Tonellato, U. J.
Org. Chem. 1985, 50, 3209
101) Nagata, T.; Sugi, K.D.: Yamamda, T.; Mukaiyama, T.
Synlett. 1996, 1076
Rohm and Haas : the Sodium Borohydride Digest
102) Sugi, K.D.; Nagata, T.; Yamamda, T.;
Mukaiyama, T. Chem. Lett. 1997, 493
103) Sugi, K.D.; Nagata, T.; Yamamda, T.;
Mukaiyama, T. Chem. Lett. 1996, 737
104) Sugi, K.D.; Nagata, T.; Yamamda, T.;
Mukaiyama, T. Chem. Lett. 1996, 1081
105) T. Mukaiyama, T. Nagata, K. Yorozu, T.
Yamada Angew. Chem. Int. Ed. Engl., 1995, 34,
2145
106) Itsuno, S. Organic Reactions 1998, 52, 395
107) Vyskocil, S.; Smrcina, M.; Hanus, V.; Polasek,
H.; Kocovsky, P. J. Org. Chem. 1998, 63, 7738
108) Abiko, A.; Masamiune, S. Tetrahedron Lett.
1992, 33, 5517
109) Verardo, G.; Giumanini, A.G.; Strazzolini, P.;
Poiana, M. Synthesis 1993, 121
110) Verardo, G.; Giumanini, A.G.; Strazzolini, P.
Synth. Commun. 1994, 24, 609
111) Prasa, A.S.B.; Kanth, J.V.b.; Periasamy, M.
Tetrahedron, 1992, 48, 4623
112) K. Drauz et al. (Degussa); US Pat 5585500, 17
Dec. 1996
113) Prasa, A.S.B.; Kanth, J.V.b.; Periasamy, M.
Tetrahedron, 1992, 48, 4623
114) Barby, D.; Champagne, P. Synth. Commun.
1995, 25, 3503
*For Online Consulting Only
press <CTRL>-F for Searching
26
115) Das, B.; Kashinatham, A.; Madhusudhan, P.
Tetrahedron Lett. 1998, 39, 677
116) Prasa, A.S.B.; Kanth, J.V.B.; Periasamy, M.
Tetrahedron, 1992, 48, 4623
117) J. V. B. Kanth and M. Periasamy, J.Org. Chem. 1991,
56, 5964
118) J. W. Simek et al., J. Chem. Ed. 1997, 74, 107
119) A. I. Meyers, K. Drauz et al., J. Org. Chem. 1993, 58,
3568
120) Giannis, A.; Sandoff, K. Angew. Chem. Int. Ed. Engl..
1989, 28, 218
121) Dharanipragada, R.; Alarcon, A.; Hruby, V. J. Org.
Prep. Prac. Int. 1991, 23, 396
122) Kabno, S.; Tanaka, Y.; Sugino, E.; Hibino, S. Synthesis
1980, 695
123) Barney, C.L.; Huber, E.W.; McCarthy, J.R. Tetrahedron
Lett. 1990, 31, 5547
124) Boesten, W.H.; Schepers, C.H.M.; Roberts, M.J.A. EPO
322982 A2 1989
125) Tone, H.; Nishi, T.; Oikawa, Y.; Hikota, M.;
Yonemitsu, O. Tetraherdron Lett. 1987, 28, 4569
126) Taber, D.F.; Houze, J.B. J. Org. Chem. 1994, 59, 4004
127) Sengupta, S.; Sahu, D.P.; Chatterjee, S.K. Indian J.
Chem. 1994, 33b, 285
128) Bott, S.G.; Marchand, A.P.; Bolin, J.; Xing, D.;
Talafuse, L.K. J. Chem. Crystallgraphy 1995, 25, 657
Rohm and Haas : the Sodium Borohydride Digest
129) Fornasier, R.; Reniero, F.; Scrimin, P.;
Tomellato, U. J. Org. Chem. 1985, 50, 3209
130) Gol’dberg, Y.; Abele, E.; Rubina, K.; Popelis, Y.;
Shimanska, M. Chem. Hetero. Compounds 1993,
29, 1399
131) Pelter, A.; Smith, K.; Borwn, H.C. Borane
Reagents” 1988, acedemic press London
132) Abdel-Mgid, A.F. ACS Symposium Series 1996,
vol 641
133) Corey, E.J. Helal, C.J. Angew. Chem. Int. Ed.
1998, 37, 1986
134) Midland, M.M. Chem. Rev. 1989, 89, 1553
135) Brown, H.C.; Jadhav, P.K.; Mandal, A.K.
Tetrahedron 1981, 37, 3547
136) Pelter, A.; Smith, K. Comprehensive Organic
Chemistry 1973, 3, 695
137) Ager, D.J.; Prakash, I.; Schaad, D.R. Chem. Rev.
1996, 96, 835
*For Online Consulting Only
press <CTRL>-F for Searching
27
Rohm and Haas : the Sodium Borohydride Digest
C. Carbonyl Coumpounds
ALDEHYDES
Alembic 18, 32, 48, 50, 52, 55, 58
The use of NaBH4 for the reduction of
aldehydes to the corresponding primary alcohol is well
known. The reductions proceed rapidly, and in most
cases quantitatively in water, lower alcohols, amines
and a variety of other organic solvents :
4 RCHO + NaBH4 Æ NaB(OCH2R)4 Æ 4 RCH2OH
Jensen (1) has shown that NaBH4 can quantitatively
reduce the following aldehydes in a water/dioxane
solvent system within two minutes at room temperature.
Formaldehyde
Acetaldehyde
Paraformaldehyde
propionaldehyde
butylradehyde
isobutyraldehyde
isovaleraldehyde
4- chlorobenzaldehyde
Crotonaldehyde
anisaldehyde
Aldol
benzaldehyde
phenylacetaldehyde
4-tolualdehyde
naphthaldehyde
2-ethoxybenaldehyde
2-chlorobenzaldehyde
hexanal
methacrylaldehyde
glyceraldehyde
*For Online Consulting Only
press <CTRL>-F for Searching
28
While NaBH4 can reduce nearly all aldehydes the
reduction rate depends upon the concentration of the solvent
used and the reaction temperature. Reduction is generally
rapid and quantitative in aqueous media.
Kinetic studies of carbonyl compounds reduction in
water DMSO and water/DMSO mixtures indicate that the
reaction obeyed second order kinetics and that the rate
constants increased with increasing water contents (2). Room
temperature reductions of aldehydes (and ketones) in twophase systems, i.e. Et2O/aq. NaBH4, have resulted in excellent
yields of the corresponding alcohol (3). Water-soluble bisulfite
adducts of aldehydes can be formed to facilitate NaBH4
reduction in aqueous media (4).
Electron-Withdrawing substituents that increase the fractional
positive charge on the carbonyl carbon accelerate the reduction
rate while electron- donating substituents have the opposite
effect.
This high reactivity with NaBH4 enables one to
selectively reduce aldehydes in the presence of other
functional groups that are reducible under more vigorous
reaction conditions. For example, the reactivity of aldehydes
with NaBH4 is considerably greater than that of ketones.
Because of this difference in reactivity of the two carbonyl
groups, it is possible to carry out the selective reduction of
press <CTRL>-F for Searching
Rohm and Haas : the Sodium Borohydride Digest
aldehyde groups in the presence of keto groups,
providing a micromethod for distinguishing between
these two types of carbonyl compounds (5). Luche
demonstrated an example of the reverse selectivity, that
the use of 1 mole equivalence of CeCl3 will retard the
reduction of an aldehyde group in the presents of both
cyclic and acyclic ketone. (6)
Competitive reaction studies of aldehydeketone mixtures with NaBH4 have demonstrated the
enhanced reactivity with both aliphatic and aromatic
aldehydes with respect to the corresponding ketone (7).
The addition of thiol compounds can further enhance
the selectivity (8). The selectivity of NaBH4 for
aldehydes over ketones was utilized to reduce aldehydic
substituents on benzopyranopuyridines to the
corresponding alkanols without affecting the keto group
(9) and the synthesis of hycanthone (10).
O
NH(CH2)2NEt2
O
NH(CH2)2NEt2
NaBH4
C
H
O
*For Online Consulting Only
H
C
OH
H
29
NaBH4 reduction of aldehydes has been used as a “blocking”
technique to prevent Schiff base staining in histology work
(11).
Chemoselective reduction of aldehydes in the
presence of ketones is greatly enhanced by employing
acyloxyborohydrides formed from sodium borohydride and a
lower aliphatic carboxylic acid, as reported by Gribble and
coworkers. The reagent, e.g. NaBH(OAc)3, can either be
formed in situ or prepared separately before use (12). The
corresponding tetrabutylammonium salt, Bu4NBH(OAc)3 that
can be made readily at room temperature, has also been
reported (13).
Rohm and Haas : the Sodium Borohydride Digest
The specificity of NaBH4 for carbonyl groups makes it
possible to reduce aldehydes in the presence of the
following functional groups:
Functional group
carbonyl
ester
lactone
lactam
imide
acetate
nitrile
nitro
amine oxide
olefin
epoxy
tosyl ester
haloalkyl or aryl
thiocarbonyl
amide
acetylenes
References
14,15
16-21
22-24
25
26-27
22,28
17,24,29
30. 31
32
17,18,27,32-36,
28,34
38
18,39-41
40
42
43-48
Because of its selectivity and rapidity in
aldehyde reductions, NaBH4 has been used extensively
in the synthesis of steroids (37), carbohydrate
derivatives (49-53), insecticides (54,55), perfume
*For Online Consulting Only
press <CTRL>-F for Searching
30
ingredients (56-58), in the reduction of Vitamin A aldehyde
(59) and in the production of other pharmaceuticals such as
dihydrostreptomycin (60-63), antihypertensives (65), antiviral
(66) and antithrombotic (67) drugs. The mild reaction
conditions employed in NaBH4 reduction of aldehydes favor
retention of stereochemical configuration (65,68).
In some instances, lactones can be formed during
NaBH4 reduction of aldehydes located α or β to carboxylate
groups (69,70). Similarly, ozonolysis of unsaturated ketones
followed by NaBH4 reduction can lead to formation of δlactones (71).
Periodate cleavage of vicinyl diols followed by
NaBH4 reduction of the resulting dialdehyde has been utilized
to characterize polysaccharides and in the preparation of
lividomycin B derivatives (72). A related cleavage/reduction
reaction, ozonolysis followed by NaBH4 reduction, was
employed in the total synthesis of camptothecin from acridine
(73).
The use of aprotic solvents such as hexane as a
reaction solvent for the sodium borohydride reduction of
aldehydes has recently been demonstrated. Either aromatic or
aliphatic aldehydes were combined with hexane in the presents
of silica gel and sodium borohydride to give the corresponding
alcohols in high yield. (74)
The use of tetraalkyl ammonium chloride (75) or
crown ethers for the reduction of aldehydes with sodium
Rohm and Haas : the Sodium Borohydride Digest
borohydride in phase transfer catalysis systems is a well
established technique. (76) (Alembic 52, 55) Recently
polyethylene gycol has been used as a phase transfer
reagent in the reduction aldehydes with sodium
borohydride. This methodology has the advantage over
previous phase transfer reagent in that PEG is relatively
cheap reagent in comparison to traditional phase
transfer reagents such as crown ethers, polyethers or
onium salts. (77). (Alembic 56)
A very important technique for the reduction of
aldehydes with sodium borohydride is the impregnation
of solid supports such as polymer (78), ion exchange
resins (78, 79) (Alembic 52) and zeolite (80) with
borohydrides. (Alembic 58)
Many different metal
borohydrides such as Zn (77, 81) and Cu (79) have also
been used in cooperation with solid supports to achieve
high yield reductions of aldehydes to alcohols and
alkanes.
Polymeric zinc borohydride with organic
nitrogen compounds will reduce aldehydes selectively.
(82)
References:
1) Jensen, E.H. “A Study on Sodium Borohydride”,
Ny Nordisk, Forlag, Arnold Busck, Copenhagen
1954 (out of Print.)
*For Online Consulting Only
press <CTRL>-F for Searching
31
2) Adams, C.; Gold, V.; Reuben, D.M.E.; J. Chem. Soc.,
Perkin 2 1977, 1466; Chem. Abstr. 88, 36933n
3) Chung, J.S. Tackan Hwahak Heochi 1974, 18, 363; Chem.
Abstr. 82, 111712w
4) Jpn. Kokai, 74117,458 1974; Chem. Abstr. 83, 976v
5) Critchley, J.P.; Friend, J.; Swain, T. Chem. and Ind. 1958,
598; Chem. Abstr. 53, 983c
6) Luche, J.L.; Gemal, J.A. J. Amer. Chem. Soc. 1979, 101,
5848
7) Sell, C.S. Aust. J. Chem. 1975, 28, 1383; Chem. Abstr. 83,
163088n
8) Maki, Y. Terahedron Lett. 1977, 263; Chem. Abstr. 87,
22620a
9) Jpn. Kokai, 7652,199, 1976; Chem. Abstr. 85, 192694d
10) Laidlaw, G.M.; Collins, J.C.; Archer, S.; Rosi, D.;
Schulenberg, J.W. J. Org. Chem. 1973, 38, 1743; Chem.
Abstr. 78, 159373f
11) Lillie, R.D.; Pizzolato, P. Stain Technology 1973, 47, 13;
Chem. Abstr. 76, 32058k
12) Gribble, G.W.; Feerguson, D.C. J. Chem. Soc. Chem.
Commun. 1975, 535; Chem. Abstr. 83, 131278h
13) Nutaitis, C.F.; Bribble, G.W. Tetrahedron Lett. 1983, 24,
4287; Chem. Abstr. 49, 3075g
14) Brown, J.J.; Newbold, G.T. J. Chem. Soc. 1953, 3648;
Chem. Abstr. 49,3075g
Rohm and Haas : the Sodium Borohydride Digest
15) Stutz, E.; Deuel, H. Helv. Chim. Acta 1956, 39,
2126; Chem. Abstr. 51,50334b
16) Morrison, A.L.; Long, R.F. J. Chem. Soc. 1958,
211; Chem. Abstr. 52,11035h
17) Remers, W.A.; Roth, R.H.; Wweiss, M.J.J. Am.
Chem. Soc. 1964, 86, 4612; Chem. Abstr. 61,
1604d
18) Sciaky, R.; Mancini, F. Tetrahedron Lett. 1965,
137; Chem. Abstr. 62, 10475g
19) Brit. I,266,093 1972; Chem. Abstr. 76, 153599w
20) De Koning, H.; Subramaanian-Erhart, K.E.C. Syn.
Commun. 1973, 3,25; Chem. Abstr 78,135587c
21) Grieco, P.A.; Nishizawa, M.; Oguri, R.; Burke,
S.D.; Marinovic, N. J. Am. Chem. Soc. 1977, 99,
5773; Chem. Abstr. 87, 184712j
22) Golab, T.; Trabert, C.H.; Jaeger, H.; Reichstein, T.
Helv. Chim. Acta 1959, 42, 2418; Chem. Abstr. 55,
27407a
23) Chernobai, V.T.; Kolesnikov, D.G. Proc. Acad. Sci.
USSr (Engl. Trans.) 1959, 127, Chem. Abstr.
53,20696c
24) Ger. Offen. 2,142,842; Chem. Abstr. 77, 48245a
25) Fall, H.H.; Petering, H.G.; J. Am. Chem. Soc. 1956,
78, 377; Chem. Abstr. 50, 13038i
26) Schoeberl, A; Pape, C.V. Chem. Ber. 1965, 98,
1688; Chem. Abstr. 63, 4383c
*For Online Consulting Only
press <CTRL>-F for Searching
32
27) Danishefsky, S.; McKee, R.; Singn, R.K. J. Am. Chem.
Soc. 1977, 99, 4783; Chem. Abstr. 87, 184743v
28) Moreau, S.; Cacan, M.; Lablanche-Combier, A.; J. Org.
Chem. 1977, 42, 2632; Chem. Abstr. 87, 65069s
29) Milijkovic, D.; Petrovic, J. J. Org. Chem. 1977, 42, 2101;
Chem. Abstr. 87, 23595h
30) Schechter, H.; Ley, D.E.; Zeldin, H. J. Am. Chem. Soc.
1952, 74, 3664; Chem Abstr. 47, 5885c
31) Salgado, A.; Huybrechts, T.; De Buyck, L.; Czombos, J.;
Tkachev, A.; De Kimpe, N. Synth. Commun. 1999, 29, 5763
32) Dirlam, J.P.; McFarland, J.W. J. Org. Chem. 1977, 42,
1360; Chem. Abstr. 86, 155694z
33) Eldelson, J. Et. Al. J. Am. Chem. Soc. 1959, 81, 5150;
Chem. Abstr. 54, 7548b
34) Klein, E.; Rojahn, W.; Henneberg, D. Tetrahedron 1964,
20, 2025; Chem. Abstr. 61, 14716h
35) Ger. Ofen. 2,513,996 1976; Chem. Abstr. 86, 16353d
36) Ger. Offen. 2,559,433 1976; Chem. Abstr. 86, 55066g
37) U.S. 4,544,555 1985; Chem. Abstr. 105, 43157k
38) Dale, W.J.; Hennis, H.E.; J. Am. Chem. Soc. 1956, 78,
2543; Che. Abstr. 51, 1080a
39) Brink, M. Acta Chem. Scand. 1965, 19, 255; Chem. Abstr.
62, 14544d
40) Hull, R.; Van der Brock, P.J.; Swain, M.L. J. Chem. Soc.
Perkin 1 1975, 2271; Chem. Abstr. 84, 89960t
Rohm and Haas : the Sodium Borohydride Digest
41) Ger. Offen. 2,064,106 1972; Chem. Abstr. 77,
101126r
42) Fr. Demande 2,260,332 1971; Chem Abstr. 84,
89999n
43) Ger. Offen. 2,065,014 1971; Chem. Abstr. 76,
59435t
44) Jpn. 72,03,342 1972; Chem. Abstr. 76, 126766s
45) Jpn. 73,32,108 1973; Chem. Abstr. 80, 47827s
46) Jpn. 74 13 778 1974; Chem. Abstr. 81, 151982v
47) Jpn. Kokai 75 25, 539 1975; Chem. Abstr. 83,
131442g
48) Parry, R.J.; Kunitani, M.G. J. Am. Chem. Soc.
1976, 98, 4024; Chem. Abstr. 85, 89917e
49) Wolfrom, M.L.; Anno, K. J. Am. Chem. Soc. 1952,
74, 5583; Chem. Abstr. 101, 73033b
50) Morin, C. Carbohydr. Res. 1984, 128, 345;
Chem.Abstr. 101, 73033b
51) Sinhabau, A.K.; Barle, R.l.; Pochopin, N.;
Borchardt, R.T. J. Am. Chem. Soc. 1985, 107, 7628;
Chem. Abstr. 013, 209794b
52) Usuki, S.; Nagai, Y Anal. Biochem. 1986, 152;
Chem. Abstr. 014, 48213q
53) Williams, A.G.; Withers,S.E.
J. Microbiol.
Methods 1986, 4, 277; Chem. Abstr. 105, 75147y
54) Eur. Pat. Appl. 50,857 1982; Chem. Abstr. 97,
144560h
*For Online Consulting Only
press <CTRL>-F for Searching
55)
56)
57)
58)
59)
60)
61)
62)
63)
64)
65)
66)
67)
68)
69)
70)
33
Ger. Offen. 3,402,483 1984; Chem. Abstr. 102, 24273s
Eur. Pat. Appl. 53, 716 1982; Chem. Abstr. 97, 216516y
U.S. 4,521,634 1985; Chem. Abstr. 104, 6053g
Eur. Pat. Appl. 184, 7078 1986; Chem. Abstr. 105,
178244g
Brit. 778,753 1957; Chem. Abstr. 52,2077I
U.S. 3,397,197, 1968; corresponds to Brit 1,063,450
1967; Chem. Abstr. 68, 22212b
Kaplan, M.A.; Fardig, O.B.; Hopper, I.R. J. Am. Chem.
Soc. 1954, 76, 5161; Chem. Abstr 49, 20876I
U.S. 2,790,792 1957; Chem. Abstr. 51, 15561d
U.S.; 2,945,850 1960; Chem. Abstr. 54, 23211I
Jpn. Kokai Tokkyo Koho 83, 140,032 1983; Chem. Abstr.
100, 22323t
Arigoni, D.; Battagila, R.; Akhtar, M.; Smith, T. J. Chem.,
Chem. Commun. 1975, 185; Chem. Abstr. 83, 2961b
U.S. 5,233,041 1993
U.S. 5,767,269 1998
Jpn. Kokai Tokkyo Koho 85, 146,840 1985; Chem. Abstr.
104, 33760s
Spry, D.O. J. Org. Chem. 1975, 40, 2411; Chem. Abstr.
83, 97171f
Bowen, D.H.; Cloke, C.; Harrison, D.M.; MacMillan, J.
H. J. Chem. Soc., Perkin 1 1975, 83; Chem. Abstr. 82,
140326d
Rohm and Haas : the Sodium Borohydride Digest
71) Chavdarian, C.G.; Heathcock, C.H. J. Org. Chem.
1975, 40, 2970; Chem. Abstr. 83, 179317x
72) Jpn. 76,11,611 1976; Chem. Abstr. 86, 5774r
73) Corey, E.J.; Crouse, D.N.; Anderson, J.E. J. Org.
Chem. 1975, 40, 2140; Chem. Abstr. 83, 79450s
74) Yakabe, S.; Hirano, M.; Morimoto, T. Synth.
Commun. 1999, 29, 295
75) Stark, C.M.; Liotta, C.L.; Halpern, M. Phase
Transfer Catalysis: Fundamentals, Applications
and industrial Perspectives; Chapman and Hall;
New York, 1994
76) Blanton, J.R. Synth. Commun. 1997, 27, 2093
77) Tamami, N.; Goudarzian, N.; Kiasat, A.R. Eur.
Polym. J. 1997, 33, 977
78) Bandgar, B.P.; Kshirsagar, .N.; Wadgaonkar, P.P.
Synth. Commun. 1995, 25, 941
79) Sim, T.B.; Yoon, N.M. Bull. Chem. Soc. Jpn. 1997,
70, 1101
80) Sreekumar, R.; Padmakumar, R.; Rugmini, P.
Tetrahedran Lett. 1998, 39, 5151
81) Tamami, B.; Lakouraj, M.M. Synth. Commun.
1995, 25, 1089
82) Firouzabadi, F.; Zeynizadeh, B. Bull. Chem. Soc.
Jpn. 1997, 155
*For Online Consulting Only
press <CTRL>-F for Searching
34
Rohm and Haas : the Sodium Borohydride Digest
KETONES
Alembic: 7, 18, 21, 26, 31, 48, 50, 52, 55, 58, 62
Under normal conditions, NaBH4 reduces
ketones at a slower rate than aldehydes. While in most
cases aldehydes undergo reactions within a few minutes,
the reduction of ketones usually takes 30-90 minutes. A
few examples of ketones that are reduced at least 90 %
at room temperature are:
Time required for 90 % Reduction
Ketone
(min)
Acetone
40
3-hydroxy-2-butanone
2
acetophenone
100
benzophenone
130
benzoin
6
cyclopentanone
90
cyclohexanone
4
2-methylcyclohexanone
7
menthone
90
isatin
2
furoin
12
As indicated in the table, α-substituents which
increase the fractional positive charge on the carbonyl
*For Online Consulting Only
press <CTRL>-F for Searching
35
carbon enhance the rate of BH4- attack. Of course, many other
factors play a part in the rate of reduction. Ring strain and
steric effects are also important. Five and six membered cyclic
ketones are reduced much more rapidly than more highly
strained cyclic(1-4) ketones. The influence of steric effects
has been correlated with reduction rates(5).
Physico-chemical factors in ketone reductions by NaBH4 are
reported by other investigators for unbranched aliphatic
ketones (6), cycloalkyl phenyl ketones (7), substituted
acetophenones (8), and substituted fluorenones (9,10). The
heats of reduction for simple ketones are reported (11).
The mechanism and kinetics of ketone reduction by
sodium borohydride have been topics of extensive study in
recent years, particularly in view of the striking stereochemical
control that can be achieved with sodium borohydride.
(Alembic 11, 24)
Wigfield et. al. (12-18), in a series of elegant studies,
have provided a better insight into the mechanisms and
transition state in this reaction and a rationale for prediction of
stereodirection.
It has generally been assumed that the product of ketone
reduction is a tetraalkoxyborate formed according to the
equation:
4 R2C=O + BH4- Æ (R2CHO)4B-
Rohm and Haas : the Sodium Borohydride Digest
However, Wigfield has clearly shown (12,13) that
during ketone reduction in alcoholic solvents, the
alcohol plays a crucial role, and that the alkoxy groups
are derived from the solvent and not the ketone. Further
work (18) using mixtures of NaBH4 and NaBD4 in
ketone reductions demonstrated that disproportionation
of the monoalkoxy borohydride intermediate does not
occur, thus raising doubts as to the validity of the
previously proposed (19) completely disproportionation
mechanism.
Similarly, the evidence for solvent
participation and the determination (6) of a kinetic order
of 3/2 with respect to 2-propanol in reduction would
rule out 4 center and 6 center transition states which
have been advocated in the literature, and favor a linear
acyclic transition state (20,21) which is product-like in
nature. Thus, a stepwise mechanism as previously
proposed (22,23), but modified to incorporate the
solvent alkoxy group (12,13) has been suggested (18).
BH4- + >C=O Æ (RO)BH3- + >CHOH
(RO)BH3- + >C=O Æ (RO)2BH2- + >CHOH
(RO)2BH2- + >C=O Æ (RO)3BH- + >CHOH
(RO)3BH- + >C=O Æ (RO)4B- + >CHOH
Measurements of activation parameters in
cyclohexanone reductions (15,16) have led to a simple
*For Online Consulting Only
36
press <CTRL>-F for Searching
formula for calculating and predicting stereochemical product
ratios (17). Additional work by Wigfield and other on the
kinetics of ketone reduction (24-27), transition state analysis
(28-32), and steric effects (33-36) have contributed greatly to
the current understanding and utility of NaBH4 reductions in
organic synthesis.
While the rate of ketone reduction is influenced by
the solvent, ketone reductions are routinely conducted in a
wide variety of organic media as well as in water.
Comparative reduction rates for acetone in three solvents are
shown below (37)
Rate of acetone Reduction in
Water, Ethanol and Isopropanol at 0 oC
Solvent
Water
Ethanol
Isopropanol
k2x104
(L mol-1 sec-1)
93
97
15.1
Rohm and Haas : the Sodium Borohydride Digest
37
press <CTRL>-F for Searching
Among the many classes of solvents used for
sodium borohydride reductions of ketone are:
Alkanes
Sulfoxides
Aromatics
Amines
Alcohols
Carboxylic Acids
Ethers
Nitroalkanes
Nitriles
Phosphoramides
Amides
Water
Halocarbons
Rate of Reduction of Acetone with Increasing Temperature in
Isopropanol
Phase Transfer Catalysis techniques have been
applied successfully to the reduction of ketones with
sodium borohydride. (Alembic 55, 56) Several authors
(38,40, 40a) have described the asymmetric reductions
of ketones using ephedrinium bromides as
stereoregulating phase transfer agents. Others have
employed lecithin (41), crown ethers (42), and
phosphonium salts on silica gel (43) as phase transfer
catalysts for ketone reductions. Tetrabutylammonium
salts are common phase transfer catalysts (44).
Microemulsions have also been used as an alternative to
phase transfer catalysis (45).
Reduction rate is also influenced by temperature as
demonstrated by the following data:
Raising the temperature from 0o C to 35o C in isopropanol
increases the rate sufficiently so reduction can be
accomplished as rapidly in isopropanol at 35o C as in water at
0o C.
NaBH4 reduces a wide variety of aliphatic, alicyclic,
aromatic and heterocyclic ketones to their secondary alcohol.
Thioketones reduced to thiols. Diketones are reduced to diols
(46,47); this effect has recently been used in the synthesis of
cyclophanes (48).
This reduction of quinones to
hydroquinones was first published in 1949 (49) and rapidly
followed by similar reports (50-53). Sodium borohydride has
been used in ketone reductions raging from conversion of
anthraquinones to anthracenes (54), to the synthesis of codeine
(54), the preparation of vitamin A esters (56), quinuclidines
(57), and prostaglandins (58-60).
*For Online Consulting Only
Temperature oC
0
15
25
35
k2 x104
(L mol-1 sec-1)
15.1
36.1
63
105.0
Rohm and Haas : the Sodium Borohydride Digest
This remarkable utility is the result of the ease
of handling and use of NaBH4, its selectivity for ketones
and its stereospecificity.
The value of selective
reduction with sodium borohydride becomes obvious in
compounds containing other functional groups, such as
amido (61,62), epoxy (63-65), mercapto (66-67),
carboxyl lactone (68), nitrile (69-70), nitro (71), ester
(72-73) and many unsaturated CC bonds (74-78). This
property has been utilized in the synthesis of
tetracyclines (79,80) and prostaglandins (58-60, 81,82).
Ketone reductions have recently been employed in the
stereospecific conversion of carbonyl compounds to
olefins, by NaBH4 reduction of ketophosphonamides
(83) and in transposition of ketones via reduction of
nitro ketones (84), e.g., cholestan-3-one to the 2-one.
The recent growth in importance of aminoalcohols,
resulting from the synthesis of chloramphenicol
analogues and phenothiazines, is an example of the
general utility of NaBH4. These are readily available by
reduction of the corresponding amino ketone (85-91).
The selectivity of NaBH4 is also used
beneficially in converting keto acids to hydroxyacids
(92-95). The sodium salt of the acid is used because the
borohydrides are decomposed by organic acids. The
reduction of γ− and δ- keto acids and esters leads
directly to lactone formation (96-101). Normally,
*For Online Consulting Only
38
press <CTRL>-F for Searching
unsaturated keto acids give the unsaturated hydroxy-acids
(102-104).
O
O
OH
NaBH4
O
Ph
O
Ph
Similarly, ketoesters are reduced to the hydroxyester
(105-107) and unsaturated ketoesters to unsaturated
hydroxyesters (108,109).
In the case of diketones, diols (110-112) or
ketoalcohols (113-116) can be obtained with NaBH4,
depending on the reactivity of the two carbonyl groups.
Complete reduction to the diol has been employed in the
synthesis of cyclophanes (117).
A variety of additives or cation modifications have been
employed to enhance the selectivity or reactivity of sodium
borohydride in ketone reductions. Luche (118-121) has
demonstrated that lanthanides promote the selective 1,2
reduction of conjugated enones to form the allylic alcohol.
The use of PdCl2-NaBH4 to enhance selectivity in the
reduction of oxonaphthoic acids has been reported (122). This
area of chemistry has been topic of a review article. (123)
Rohm and Haas : the Sodium Borohydride Digest
Enhanced stereo- and chemoselectivity has
been achieved by the use of the cations such as zinc
(124-136), titanium (137- 142), zirconium (143,144),
lanthanide metals (123,145), Copper (146-148) and
calcium (149-156), chiral alcohols (157), chiral
carboxylic acids (158-165), sugars (166-170) and
macrocyclic ligands such as cyclodexstan (171-180).
(Alembic 17, 21, 26, 33, 57, 53)
The importance of ketone reduction with
NaBH4 is shown by its innumerable applications in
many fields of organic chemistry. Some of the diverse
applications where the chemo- and stereoselectivity of
sodium borohydride have been utilized in ketone
reduction are tabulated below.
*For Online Consulting Only
39
press <CTRL>-F for Searching
Class of compounds
Steroid ketones
Amino ketones
Prostaglandines
Menthanones
CNS suppressants
Synthetic juvenile hormones
Gibberellic acids
Antibiotics
Artificial flavors and coloring
Triterpenoids
Flavanoids
Adamantanone
Methadones
Epoxy ketones
Polymeric ketones
Antiinflammatories
Beta-Blockers
Antiulcer compounds
Antihypertensives
Fungicides/herbicides
Anti HIV
Antipsychotic
Anti viral
Taxol
ref
181-187
85-91
58-60,
188-192
193
194- 197
198- 201
201, 202
203-210
211- 214
113, 215
216- 218
219- 221
222- 224
225
226 -228
229- 231
232- 234
235, 236
237- 239
240- 143
244- 247
248
249
250
Rohm and Haas : the Sodium Borohydride Digest
One of the most important applications of
sodium borohydride is the stereospecific and selective
reduction of steroid ketones. Meteos (251) has
established the following sequence for the reactivity of
NaBH4 for most of the ketones in the steroid molecule:
∆5-3Keto > ∆8(14)-3 keto > 3 keto A/B cis > 3 Keto A/B
trans > 6 keto > 7 keto > ∆4-3 keto > 12 keto > 17 keto
> 20 keto >11 keto
Due to the differences in the reactivity of the keto
groups in the individual positions of the steroid ring,
certain keto groups can be reduced simply and
selectively by using stoichiometric quantities of
borohydride or by blocking individual positions.
In steroid chemistry and in prostaglandin
synthesis (252), it has been possible to reduce the keto
group with zinc borohydride made from ZnCl2 and
NaBH4 without attacking activated olefinic bonds.
Recently the addition of a catalytic amount of a
Co (II) complex has shown very good yields and
enantiomeric excess for the synthesis of chiral alcohols
from the reduction of ketones. (253- 255)
The use of nonpolar solvents such as hexane
are normally not considered for use with sodium
borohydride reductions of ketones because of the
solubility of SBH in this solvent. A unquie solution to
this problem is the use of solid supports such as silica
*For Online Consulting Only
press <CTRL>-F for Searching
40
gel (256, 257) or alumina (258- 260) which helps to catalyze
the reduction of ketones in hexanes.
Luche has demonstrated that ketones can be reduced
selectively in the presence of aldehydes by using NaBH4 with
CeCl3 (261).
References:
1) Brown, H.C.; Ichikawa, K. Tetrahedron 1957, 1, 221;
Chem. Abstr. 52, 274g
2) Brown, H.C.; Bernheimer, R.; Morgan, K.J. J. Am. Chem.
Soc. 1965, 87, 1280; Chem. Abstr. 62, 12996a
3) Brown, H.C.; et. al. J. Am. Chem. Soc. 1967, 89, 370;
Chem. Abstr. 66, 56915f
4) Brown, H.C.; Muzzia, J. J. Am. Chem. Soc. 1966, 88,
2811; Chem. Abstr. 65, 3712h
5) Mueller, P; Perberger, J.C. Helv. Chim. Acta 1976, 59, 59,
1880; Chem. Abstr. 85, 176715f
6) Geneste, P.; Lamaty, G.; Vidal, B.C.R. Acad. Sci. Paris,
Ser. C 1968, 226, 1387; Chem. Abstr. 69, 76160x
7) Sun, S.F.; Neidig, P.R. J. Org. Chem. 1969, 34, 1854;
Chem. Abstr. 71, 38066e
8) Bowden, K.; Hardy, M. Tetrahedron 1966, 22, 1169;
Chem. Abstr. 65, 587a
9) Warren, K.D.; Yandle, J.R. J. Chem. Soc. 1965, 5518;
Chem. Abstr. 63, 17823a
Rohm and Haas : the Sodium Borohydride Digest
10) Warren, K.D.; Yandle, J.R. J. Chem. Soc. 1965,
4049; Chem. Abstr. 63, 6810a
11) Davis, R.E.; Carter, J. Tetrahedron 1966, 22, 495;
Chem. Abstr. 64, 12525g
12) Wigfield, D.C.; Gowland, F.W. Tetrahedron Lett.
1976, 3373; Chem. Abstr. 86, 71391q
13) Wigfield, D.C.; Gowland, F.W. J. Org. Chem.
1976, 41, 2396; Chem. Abstr. 86, 120471bc
14) Wigfield, D.C.; Gowland, F.W. Tetrahedron Lett.
1976, 3377; Chem. Abstr. 86, 71347e
15) Wigfield, D.C.; Phelps, D.J. J. Am. Chem. Soc.
1974, 96, 543; Chem. Abstr. 80, 81887w
16) Wigfield, D.C.; Phelps, D.J. J. Org. Chem. 1976,
41, 2396; Chem. Abstr. 85, 45775c
17) Wigfield, D.C. Can. J. Chem. 1977, 55, 646; Chem.
Abstr. 87, 133739r See also Wipke, W.T.; Gund, P.
J. Am. Chem. Soc. 1976, 98, 8107; Chem. Abstr.
86, 4841y
18) Wigfield, D.C.; Gowland, F.W Can. J. Chem. 1978,
56, 786; Chem. Abstr. 89, 5680u
19) Rickborn, B.; Wuesthoff, M.R. J. Am. Chem. Soc.
1970, 92, 6894; Chem. Abstr. 74, 31417y
20) Wigfield, D.C.; Gowland, F.W. Tetrahedron Lett.
1979, 2209; Chem. Abstr. 92, 5827j
21) Burnet, R.D.; Kirk, D.N. J. Chem. Soc., Perkin 2
1976, 1523; Chem. Abstr. 86, 105635q
*For Online Consulting Only
press <CTRL>-F for Searching
41
22) Garrett, E.R.; Lyttle, D.A. J. Am. Chem. Soc. 1953, 75,
6051; Chem. Abstr. 49, 6982g
23) Brown, H.C.; Wheeler, O.H.; Ichikawa, K. Tetrahedron
1957, 1, 214; Chem. Abstr. 52, 274c
24) Wigfield, D.C.; Phelps, D.J. J. Chem. Soc, Perkin 2 1972,
680; Chem. Abstr. 76, 12619m
25) Krishnan, K.; Chandrasekaran, J. Indian J. Chem. Sec B.
1982, 21B, 595; Chem. Abstr. 98, 34038g
26) Cockerill, A.F.; Rackham, D.M. J. Chem. Soc, Perkin 2
1972, 2076; Chem. Abstr. 78, 15303k
27) Nanjappan, P.; Dhanadapani, C.; Natarajan, K.;
Ramalingam, K. Indian J. Chem. Sec B 1984, 23B, 623;
Chem. Abstr. 101, 229565q
28) Perberger, J.C.; Mueller, P. J. Am. Chem. Soc. 1977, 99,
6316; Chem. Abstr 87, 200601e
29) Wigfield, D.C.; Feiner, S.; Phelps, D.J. J. Org. Chem.
1975, 40, 2533; Chem. Abstr. 83, 131025y
30) Wigfield, D.C.; Phelps, D.J. Can. J. Chem. 1972, 50, 388;
Chem. Abstr. 76, 112413n
31) Durand, R.; Geneste, P.; Lamaty, G.; Roque, J.P.
Tetrahedron Lett. 1977, 199; Chem. Abstr 87, 5170m
32) Pasto, D.J.; Lepeska, B. J. Am. Chem. Soc. 1976, 98,
1091; Chem. Abstr. 84, 134874f
33) El-Semman, E.; Geiger, H. Justus Liebigs Ann. Chem.
1975, 75; Chem. Abstr. 82, 138943j
Rohm and Haas : the Sodium Borohydride Digest
34) Moreau, G. Bull. Soc. Chim. Fr. 1972, 2814; Chem.
Abstr. 78, 15339b
35) Wigfield, D.C.; Buchanan, G.W.; Ashley, C.A.;
Feiner, S. Can. J. Chem. 1976, 54, 3536; Chem.
Abstr. 86, 105786q
36) Boyer, B.; Lamaty, G.; Roque, J.P.; Geneste, P.
Recl. Trav. Chim. Pays-Bas 1974, 93, 260; Chem.
Abstr. 86, 105786q
37) Brown, H.C.; Ichikawa, K. J. Am. Chem. Soc. 1961,
83, 4372; Chem. Abstr. 56, 7117c
38) Colonna, S.; Formasier, R. Synthesis 1975, 531;
Chem. Abstr. 83, 178474j
39) Balcells, J.; Colonna, S.; Fornasier, R. Synthesis
1976, 266; Chem. Abstr. 85, 5305t
40) Masse, J.P.; Parayre, E.R. J. Chem. Soc., Chem.
Commun. 1976, 438; Chem. Abstr. 85, 192270h
41) Doiuchi, T.; Minoura, Y. Isr. J. Chem. 1977, 15,
84; Chem., Abstr. 87, 200492v
42) Landini, D.; Maia, A.M.; Montanari, F.; Pirisi, M
Gazz. Chim. Ital. 1975, 105, 863,; Chem. Abstr. 86,
120278u
43) Tundo, P. J. Chem. Soc. Chem. Commun. 1977,
641; Chem. Abstr. 88, 111115c
44) Lamaty, G.; Riviere, M.H.; Roque, J.P. Bull, Soc.
Chim. Fr. 1983, 33; Chem. Abstr. 99, 21730x
*For Online Consulting Only
press <CTRL>-F for Searching
42
45) Jaeger, D.A.; Ward, M.D.; Martin, C.A. Tetrahedron
1984, 40, 2691; Chem. Abstr. 102, 61879q
46) Brooke, D.G.; Smith, J.C. J. Chem. Soc. 1957, 2732;
Chem. Abstr. 51, 16311h
47) Kannan, R. Et. al. Indian J. Chem. 1967, 5, 84; Chem.
Abstr. 67, 43380z
48) Hylton, T.; Boekelheide, V. J. Am. Chem. Soc. 1968, 90,
6887; Chem. Abstr. 70, 28706d
49) Chalkin, S.W.; Brown, W.G. J. Am. Chem. Soc. 1949, 71,
122; Chem. Abstr. 43, 2570d
50) Lindberg, B.; Paju, J. Svensk. Kem. Tidskir. 1953, 65, 9;
Chem. Abstr. 47, 12133d
51) Nakanishi, K.; Kakisawa, H.; Hirata, Y. J. Am. Chem. Soc.
1955, 77, 3169; Chem. Abstr. 50, 3376b
52) Etienne, A.; Lepage, Y. Compt. Rend. 1955, 240, 1233;
Chem. Abstr. 50, 5605b
53) Moriconi, E.J.; Wallenberger, F.T.; O’Connor, W.F. J.
Org. Chem. 1959, 24, 86
54) Criswell, T.R.; Klanderman, B.H. J. Org. Chem. 1974, 39,
770; Chem. Abstr. 80, 108239a
55) Czech. 167,107 1977; Chem. Abstr. 87, 58532a
56) U.S.4,022,807 1977; Chem. Abstr. 87, 117976k
57) Ger. Offen. 2,650,876 1977; Chem. Abstr. 87, 152163q
58) U.S. 3,736,335 1973; Corresponds to Ger. Offen.
2,130,654 1971; Chem. Abstr. 76, 140041h
Rohm and Haas : the Sodium Borohydride Digest
59) Jpn. Kokai Tokkyo Koho 84, 134, 787 1984; Chem.
Abstr. 102, 45692t
60) Eur. Pat. Appl. 171,992 1986; Chem. Abstr. 102,
12115r
61) Brutcher, F.V.; Vanderwerff, W.D. J. Org. Chem.
1958, 23, 146; Chem. Abstr. 52, 18370h
62) Soai, K.; Hasegawa, H.J. J. Chem. Soc. Perkin 1
1985, 769; Chem. Abstr. 103, 70915w
63) Woodward, R.B. et. al. J. Am. Chem. Soc. 1956, 78,
3087; Chem. Abstr. 50, 14732c
64) Jpn. Kokai Tokkyo Koho 80 36,448 1980; Chem.
Abstr. 93, 186616d
65) Taniguchi, M.; Fujii, H.; Oshima, K.; Utimoto, K.
Tetrahedron, 1995, 51, 679
66) Overberger, C.G.; Lebovits, A. J. Am. Chem. Soc.
1956, 77, 3675; Chem. Abstr. 50, 3282e
67) Overberger, C.G.; Lebovits, A. J. Am. Chem.
Soc.1956, 78, 4792; Chem. Abstr. 51, 1896a
68) Dauben, W.G.; Hance, P.D.; Hayes, W.K. J. Am.
Chem. Soc. 1955, 77, 4609; Chem. Abstr. 50, 6387a
69) Nickon, A.; Fieser, L.F. J. Am. Chem. Soc. 1952,
74, 5566; Chem. Abstr. 48, 1380I
70) Clive, D.L.J.; Beaulieu, P.L.; Set, L. J. Org. Chem.
1984, 49, 11313; Chem. Abstr. 100, 138634z
71) Hodges, R.; Raphael, R.A. J. Chem. Soc. 1960, 50;
Chem. Abstr. 54, 8757b
*For Online Consulting Only
press <CTRL>-F for Searching
43
72) Adams, J.L.; Chen, T.M.; Metcalf, B.W. J.Org. Chem.
1985, 50, 2730; Chem. Abstr. 103, 123295c
73) Hassine, B. B.; Gorsane, M.; Pecher, J.; Martin, R.H. Bull.
Soc. Chem. Belg. 1985, 94, 597; Chem. Abstr. 105,
152672v
74) Eastman, R.H.; Freeman, S.K. J. Am. Chem. Soc. 1955,
77, 6642; Chem. Abstr. 50, 3247a
75) Fornasier, R.; Lucchini, V.; Scimin, P.; Tonellato, U. J.
Org. Chem. 1986, 51, 1769
76) Takahashi, T.; Miyazawa, M.; Tsuji, J. Tetrahedron. Lett.
1985, 26, 5139
77) Baluenga, J.; Fananas, J.F.; Sanz, R.; Garcia, F.; Carcia,
N. Tetrahedron Lett. 1999, 40, 4735
78) Arase, A.; Hoshi, M.; Yamaki, T.; Nakanishi, H. J. Chem.
Soc., Chem. Commun. 1994, 855
79) Boothe, J.H.; et. al. J. Am. Chem.Soc. 1959, 81, 1006;
Chem. Abstr. 53, 14071b
80) Woordward, R.B. et. al. J. Am. Chem. Soc. 1962, 84,
3222; Chem. Abstr. 57, 12399g
81) Corey, E.J. Et. al. J. Am. Chem. Soc. 1968, 90, 3245;
Chem. Abstr. 69, 33514x
82) Schneider, W.P. J. Chem. Soc., Chem. Commun. 1969,
304; Chem. Abstr. 70, 114673x
83) Corey, E.J.; Kwiatkowski, G.T. J. Am. Chem. Soc. 1968,
90, 6816; Chem. Abstr. 70, 19487f
Rohm and Haas : the Sodium Borohydride Digest
84) Hassner, A.; Larkin, J.M.; Bowd, J.E. J. Org.
Chem. 1968, 33, 1733; Chem. Abstr. 69, 3074n
85) Hermann, E.C.; Kreuchunas, A. J. Am. Chem. Soc.
1952, 74, 5168; Chem. Abstr. 48, 1329h
86) Huebner, C.F.; Diassi, P.A.; Scholz, C.R. J. Org.
Chem. 1953, 18, 21; Chem. Abstr. 48, 1329h
87) Jpn. Kokai Tokkai 76141,829 1976; Chem. Abstr.
87, 68415r
88) U.S. 4,192,805 1980; Chem. Abstr. 93, 46170d
89) Jpn Kokai Tokkyo Koho 86 78,754 1986; Chem.
Abstr. 105, 133651w
90) Taylor, E.C.; Loux, H.M. Chem. And Ind. 1954,
1585
91) Weisenborn, F.L.; Applegate, H.E. J. Am. Chem.
Soc. 1956, 78, 2021; Chem. Abstr. 50, 13969d
92) Wiltktop, B.; Patchett, A.A. J. Am. Chem. Soc.
1957, 79, 185; Chem. Abstr. 51, 6596b
93) Wagner, A.F. et. al. J. Am. Chem. Soc. 1955,
77,5140; Chem.Abstr. 50, 8456h
94) Drake, N.L. Tueminier, W.B. J. Am. Chem. Soc.
1955, 77, 1204; Chem. Abstr. 50, 1705c
95) Cava, M.P.; Van Meter, J.P. J. Org. Chem. 1969,
34, 538; Chem. Abstr. 70, 10628k
96) Bates, H.A.; Deng, P.N. J. Org. Chem. 1983, 48,
4478; Chem. Abstr. 99, 212331c
*For Online Consulting Only
press <CTRL>-F for Searching
44
97) Newman, M.S.; Dhawan, B. Khanna, V.K;. J. Org. Chem.
1986, 51, 1613; Chem. Abstr. 104, 206875p
98) Grieco, P.A.; Ferrino, S.; Vidari, G. J. Am. Chem. Soc.
1980, 102, 7586; Chem. Abstr. 94, 15535t
99) Lange G.L.; Lee, M. Tetrahedron Lett. 1985, 26, 6163;
Chem. Abstr. 105, 60340g
100) Cordier, Et. Al. Compt. Rend. 1954, 238, 2004
101) Cordier, P.; Hathout W. Compt. Rend. 1956, 242, 2956;
Chem. Abstr. 51, 286h
102) Ames, R.G.; Davey, W.J.; J. Chem. Soc. 1956, 3001;
Chem. Abstr. 51, 2642b
103) Zorbach, W.W. J. Am. Chem. Soc. 1953, 75, 6344;
Chem. Abstr. 49, 7580h
104) Cope, A.C.; Wood. G.W.; J. Am. Chem. Soc. 1957, 79,
3885; Chem. Abstr. 51, 17736g
105) Zang, H.C. ; Costanzo, M.J.; Maryanoff, B.E.
Tetrahedron Lett. 1994, 4891
106) Minckler, L.S.; Hussey, A.S.; Baker, R.H. J. Am. Chem.
Soc. 1956, 78, 1009; Chem. Abstr. 50, 12936h
107) Crombie, L.; Grittin, B.P. J. Chem. Soc. 1958, 4435;
Chem. Abstr. 53, 10022d
108) Feit, P.W. Chem. Ber. 1960, 93, 116; Chem. Abstr. 54,
9872e
109) Silverman, I.R.; Daub, G.H.; Vander Jagt, D.L. J. Org.
Chem. 1985, 50, 5550; Chem. Abstr. 104, 33954
Rohm and Haas : the Sodium Borohydride Digest
110) Juaristi, E.; Valle, L.; Valenzuela, B.A.; Aguilar,
M.A. J. Am. Chem. Soc. 1986, 108, 2000; Chem.
Abstr. 104, 149021f
111) Southwick, P.L.; Cremer, S.E.; J. Org. Chem.
1959, 24, 753; Chem. Abstr. 54, 611d
112) U.S. 3,217,718 1965; Chem. Abstr. 64, 5466c
113) Kolaczkowki, L.; Reusch, W. J. Org. Chem. 1985,
50, 4766; Chem. Abstr. 104, 6047h
114) Ishihara, M.; Tsuneya, T.; Shiota, H.; Shiga, M;
Nakastu, K. J. Org. Chem. 1986, 51, 491; Chem.
Abstr. 104, 87329b
115) Hylton, T.; Boekelheide, V. J. Am. Chem. Soc.
1968, 90, 6887; Chem. Abstr. 70, 28706d
116) Luche, J.L. J. Am. Chem. Soc. 1978, 100, 2226;
Chem. Abstr. 88, 190173w
117) Gemal, A.L.; Luche, J.L. J. Am. Chem. Soc. 1981,
103, 5459; Chem. Abstr. 95, 13173y
118) Wender, P.A.; Holt, D.A. J. Am. Chem. Soc. 1985,
107, 7771; Chem. Abstr. 104, 69029z
119) Marchand, A.P.; LaRoe, W.D.; et.al. J.Org. Chem.
1986, 51, 1622
120) Greeves, N.; Warren, S.; Tetrahedron Lett. 1986,
27, 259; Chem. Abstr. 105, 2267702z
121) Yamaguchi, H.; Numata; Marui, T.; Arimoto, M;
Takeda, H.; Yakugaku Zasshi 1975, 95, 477;
Chem. Abstr. 83, 147410
*For Online Consulting Only
press <CTRL>-F for Searching
45
122) Molander, G.A. Chem. Rev. 1992, 92, 29
123) Zhang, H.C.; Costanzo, M.J.; Maryanoff, B.E.
Tetrahedron Lett. 1994, 35, 4891
124) Helm, R.F.; Ralph, J. J. Wood Chem. Tech. 1993, 13, 593
125) Narasimhan, S.; Madhavan, S.; Prasad, K.G. Synth.
Commun. 1997, 27, 385
126) Narasimhan, S.; Madhavan, S.; Balakumar, R.;
Swarnalakshmi, S. Synth. Commun. 1997, 27, 391
127) Bhattacharyya, S. Organometallic 1996, 15, 1065
128) Bhattacharyya, S.; Chatterjee, A.; Williamson, J.S. Synth.
Commun. 1997, 27, 4265
129) Bhattacharyya, S. Synth. Commun. 1995, 25, 2061
130) Narasimhan, S.; Madhavan, S.; Prasad, K.G. J. Org.
Chem. 1995, 60, 5314
131) Kim, S.; Oh, C.H.; Ko, J.S.; Ahn, K.H.; Kim, Y.J. J. Org.
Chem. 1985, 50, 1927
132) Ranu, B.C.; Jana, U.; Sarkaar, A. Synth. Commun. 1998,
28, 485
133) Narasimhan, S.; Madhavan, S.; Prasad, K.G. Synth.
Commun. 1996, 26, 703
134) Ranu, B.C.; Sarkar, A.; Chakraborty, R. J. Org. Chem.
1994, 59, 4114
135) Bhattacharyya, S.; Chatterjee, A.; Duttachowdhury, S.K.
J. Chem. Soc. Perkin Tran. 1 1994, 1
136) Liu, Y.; Schwartz, J. Tetrahedron 1995, 51, 4471
137) Liu, Y.; Schwartz, J. J. Org. Chem. 1994, 59, 940
Rohm and Haas : the Sodium Borohydride Digest
138) Dosa, P.; Kronish,I; McCallum, J.; Schwartz, J.;
Barden, M.C. J. Org. Chem. 1996, 61, 4886
139) Bhattacharyya S. J. Org. Chem. 1995, 60, 4928
140) Bhattacharyya S. Tetrahedron Lett. 1994, 35, 2401
141) Armstrong, J.D.; Wolfe, C.N.; Keller, J.L.; Lynch,
J.; Bhupathy, M.; Volante, R.P. Tetrahedron Lett.
1997, 1531
142) Itsuno, S.; Sakurai, Y.; Shimizu, K.; Ito, K. J.
Chem. Soc. Perkin Trans 1 1990, 1859
143) Itsuno, S.; Sakurai, Y.; Ito, K. Synthesis 1988, 995
144) Barros, M.T.; Alves, C.M.; Santos, A.G.;
Godinho, L.S.; Maycock, C.D. Tetrahedron. Lett.
1995, 36, 2321
145) Masaguer, C.F.; Bleriot, Y.; Charlwood, J.;
Winchester, B.G.; Fleet, G.W.J. Tetrahedron,
1997, 55, 15147
146) Drouin, J.; Gauthier, S.; Patricola, O.; Lanteri, P.;
Longeray, R. Synlett 1993, 791
147) Patel, H.V.; Vyas, K.A.; Pandey, S.P.; Fernandes,
P.S. Org. Prep. Proc. Int. 1995, 27, 81
148) Rao, S.H.; Siva, P. Synth. Commun. 1994, 24, 549
149) Taniguchi, M.; Fujii, H.; Oshima, K.; Utimoto, K.
Tetrahedron, 1995, 51, 679
150) Teixeira, L.H.; Barreriro, E.J.; Fraga, C.A.M.
Synth. Commun. 1997, 27, 3241
*For Online Consulting Only
press <CTRL>-F for Searching
46
151) Narasimhan, S.; Ganeshwar, K.; Madhavan, S.
Tetrahedron Lett. 1995, 36, 1141
152) Hisa, M.T.S.; Chu, F.S. Experientai 1977, 33, 1132;
Chem. Abstr. 88, 5068p
153) Yoon, N.M.; Kang, J. Taehan Hwahak Hoechi 1975, 19,
360; Chem. Abstr. 84, 73602s
154) Tai C,-H.; Zhong, C.-P. K’Ohseuh T'ung Pau 1977, 22,
89; Chem. Abstr. 87, 67928y
155) Ito, Y.; Katsuki, T.; Yamaguchi, M. Tetrahedron Lett.
1984, 25, 6015; Chem. Abstr. 102, 220683q
156) Takahashi, T.; Miyazawa, M.; Tsuji, J. Tetrahedron Lett.
1985, 26, 5139; Chem. Abstr. 105, 60281p
157) Maiti, D.K.; Bhattacharya, P.K. Synth. Commun. 1998,
28, 99
158) Yamada, S.; Mori, Y.; Morimatsu, K.; Ishizu, Y.; Ozaki,
Y.; Yoshioka, R.; Nakatani, T.; Seko, H. J. Org. Chem.
1996, 61, 8586
159) Yatagai, M.; Ohnuki, T. J. Chem. Soc. Perkin Trans. 1
1990, 1826
160) Bianch, G.; Achilli, F.; Gamba, A.; Vercesi, D. J. Chem.
Soc. Perkin Trans 1 1988, 417
161) U.S. 4,943, 652 1990
162) U.S. 5,041,651 1991
163) U.S. 5,144,039 1992
164) U.S. 4,614,806 1986
165) U.S. 4,727,183 1988
Rohm and Haas : the Sodium Borohydride Digest
166) Sharma, L. Indian. J. Chem. 1997, 36B, 796
167) Sharma, L.; Singh, S. Indian J. Chem. 1994, 33B,
1183
168) Hirao, A.; Nakahama, S.; Mochizuki, H.; Itsuno,
S.; Yamazaki, N. J. Org. Chem. 1980, 45, 4231
169) Zhdanov, V.A.; Alekseev, Y.E.; Korol, E.L.;
Sudareva, T.P.; Alekseeva, V.G. Russ. J. Gen.
Chem. 1993, 63, 1045
170) Morrison, J.D.; Gradbois, E.R.; Howard, S.I. J.
Org. Chem. 1980, 45, 4229
171) Masuda, T.; Koida, K. Bull. Chem. Soc. Japn.
1973, 46, 2259; Chem. Abstr. 80, 120058y
172) Pierre, J.L.; Handel, H. Tetrahedron Lett. 1974,
2317; Chem. Abstr. 82, 57162b
173) Handel, H.; Pierre, J.L Tetrahedron 1975, 31, 997;
Chem. Abstr. 83, 78152j
174) Handel, H.; Pierre, J.L Tetrahedron Lett. 1976,
2029; Chem. Abstr. 85, 176568k
175) Ravichandran, R.; Divakar, S. J. Mol. Catal. A.
1999, 137, 31
176) Pichumani, K.; Velusamy P.; Srinivasan, C.
Tetrahedron, 1994, 45, 12979
177) Goldberg, Y.; Abele, E.; Rubina, K.; Popelis, Y;
Shimanska, M. Chem. Heterocyclic Comp. 1993,
29, 1399
*For Online Consulting Only
press <CTRL>-F for Searching
47
178) Fornasier, R.; Lucchini, V.; Scrimm, P.; Tonellato, U. J.
Org. Chem. 1986, 51, 1769
179) Sakuraba, H.; Inomata,N. Tanaka, Y. J.Org. Chem. 1989,
54, 3482
180) Fornasier, R.; Reniero, F.; Scrimm, P.; Tonellato, U. J.
Org. Chem. 1985, 50, 3209
181) Garrett, E.R.; Lyttle, D.A. J. Am. Chem. Soc. 1953, 75,
6051; Chem. Abstr. 49, 6982g
182) Dauben, W.G.; Blanz, E.J.; Jui, J. J. Am. Chem. Soc.
1953, 75, 6051, chem. Abstr. 51, 1223I
183) Wheeler, O.H.; Mateos, J.L. Can. J. Chem. 1958, 36,
1049; Chem. Abstr. 53, 2283g
184) Wheeler, O.H.; Mateos, J.L. Can. J. Chem. 1958, 36,
1431; Chem. Abstr. 53, 7241b
185) Hajos, A.; Fuchs, O. Acta, Chim. Acad. Sci. Hung. 1959,
21, 137; Chem. Abstr.54, 19764a
186) Takahashi, T.; Yamada, H.; Tsuji, J.; J. Am. Chem. Soc.
1981, 103, 5259; Chem. Abstr. 95, 169594u
187) Jpn. Kokai Tokkoyo Koho 82, 116,096, 1982; Chem.
Abstr. 98, 16938w
188) Bagli, J.F.; Bogri, T. J. Org. Chem. 1972, 37, 2132;
Chem. Abstr. 77, 74851q
189) Bundy, G.L.; Danials, E.G.; Lincoln, F.H.; Pike, J.E. J.
Am. Chem. Soc. 1972, 9, 1223; Chem. Abstr. 76,
124429k
Rohm and Haas : the Sodium Borohydride Digest
190) Mirjang, M.; Dorn, C.R. J. Org. Chem. 1972, 37,
1818; Chem. Abstr. 77, 34022p
191) Barros, M. T.; Alves, C.M.; Santos, A.G.;
Godinho, L.S.; Maycok, C.D. Tetrahedron Lett.
1995, 36, 2321; Chem. Abstr. 123 9179
192) U.S. 4,739,078 1988
193) Tadwalker, V.R.; Narayanaswamy, M.; Rao, A.S.
Inidian J. Chem. 1972, 9, 1223; Chem. Abstr. 76,
85932x
193) Daum, S.J.; Martini, C.M.; Kullnig, R.K.; Clarke,
R.L. J. Org. Chem. 1972, 37, 1665; Chem. Abstr.
77, 34736z
194) Belg. 901, 127 1985; Chem. Abstr. 103, 71329v
195) Eur. Pat. Appl. 138, 716 1985; Chem. Abstr. 103,
32295m
196) Avramova, P.; Ilarionov, T.; Dryanovska, L.
Pharmazie 1985, 40, 579; Chem. Abstr. 105,
133629k
197) Loew, P.; Johnson, W.S. J. Am. Chem. Soc. 1971,
93, 3766; Chem. Abstr. 75, 88398t
198) Faulkner, D.J.; Perterson, M.R. J. Am. Chem. Soc.
1971, 93, 3766; Chem. Abstr. 75, 88397s
199) Czech. 195,530 1982; Chem. Abstr. 98, 88962x
200) Chojecka-Koryn, E.; Sobotka, W. Pol. J. Chem.
1981, 55, 1241; Chem. Abstr. 99, 38656a
*For Online Consulting Only
press <CTRL>-F for Searching
48
201) Corey, E.J.; Carney, R.L. J. Am. Chem. Soc. 1971, 93,
7318; Chem. Abstr. 76, 46327j
202) Ger (east) 156,707 1982; Chem. Abstr. 99, 5878w
203) Barton, D.H.; Halpern, B.; Porter, Q.N.; Collins, D.J. J.
Chem. Soc (C), 1971, 2166; Chem. Abstr. 75, 48755a
204) Yoshimoto, A.; Matsuzawa, Y. et. al. J. Antibiot. 1984,
37, 920; Chcem. Abstr. 101, 192369a
205) Iida, H.; Yamazaki, N.; Kibayashi, C. J. Org. Chem.
1986, 51, 1069; Chem. Abstr. 104, 168240t
206) U.S. 4,465,674 1984; Chem. Abstr. 101, 230951u
207) Ulibarri, G.; Nadler, W.; Skrydstrup, T.; Audrain, H.;
Chiaroni, A.; Riche, C.; Grierson, D.S. J Org. Chem.
1995, 60, 2753; Chem. Abstr. 124 30187
208) U.S. 5,869,449 1999
209) U.S. 5,648,456 1997
210) U.S. 5,869,449 1999
211) Ger. Offen. 2,035,901 1971; Chem. Abstr. 75, 35259s
212) U.S. 3,558,712 1971; Chem. Abstr. 74, 100242b
213) U.S. 4,269,862 1981; Chem.Abstr. 95, 95775e
214) Jpn. Kokai Tokkyo Koho 82 28,079 1982; Chem. Abstr.
96, 218067f
215) Nasipuri, D.; Mukherjee, P.R.; Pakrashi, C.S.; Datta, S.;
Ghosh-Dastidar, P.P. J. Chem. Soc. Perkin 1 1976, 321;
Chem. Abstr. 84, 105838s
216) Grouiller, A.; Pacheco, H.C. R. Acad. Sci., Ser. C 1971,
272, 2085; Chem. Abstr 75, 75584a
Rohm and Haas : the Sodium Borohydride Digest
217) Stafford, H.A.; Lester, H.H. Plant Physiol. 1985,
78, 791; Chem. Abstr. 103, 157434n
218) Takahashi, H.; Kubota, Y.; Iguchi, M.; Onda, M.
Chem. Pharm. Bull. 1985, 33, 3134; Chem. Abstr.
105, 226273q
219) Murray, R.K.; Babiak, K.A.; Morgan, T.K. J. Org.
Chem. 1975, 40, 2463; Chem. Abstr. 83, 131183y
220) Subramaniam, R.; Fort, R.C. J. Org. Chem. 1984,
49, 2891; Chem. Abstr. 101, 71942y
221) Cheung, C.K.; Tseng, L.T.; Lin, M.H.; Srivastava,
S.; Lenoble, W. J. J. Am. Chem. Soc. 1986, 108,
1598; Chem. Abstr. 104, 14801r
222) Haller, R.; Ruemmler, R. Arch. Pharm. 1973, 306,
510; Chem. Abstr. 79, 125679r
223) Haller, R.; Ruemmler, R. Arch. Pharm. 1973, 306,
408; Chem. Abstr. 79, 77938a
224) Haller, R.; Ruemmler, R. Arch. Pharm. 1973, 306,
431; Chem. Abstr. 79, 77917t
225) Weissenberg, M. J. Chem. Soc. Perkin 1 1978,
568; Chem. Abstr. 89, 147130p
226) Merle-Aubry, L.; Merele, Y. Selegny, E.
Macromol. Chem. 1973, 172, 115; Chem. Abstr.
80, 60366k
227) Pieta, P.G.; Cavallo, P.F.; Takahashi, K.;
Marchall, G.R. J. Org. Chem. 1974, 39, 44; Chem.
Abstr. 80, 96353t
*For Online Consulting Only
press <CTRL>-F for Searching
49
228) Orlowski, R.C.; Walter, R.; Winkler, D. J. Org. Chem.
1976, 41, 3701; Chem. Abstr. 85, 177951s
229) PCT int. appl. 83, 02,613 1983; Chem. Abstr. 99,
175755w
230) Ger. Offen. 3,440,503 1985; Chem. Abstr. 104, 129660k
231) Eur. Pat. Appl. 189, 142 1986; Chem. Abstr. 105,
190651v
232) Willard, A. K.; Smith, R.L.; Cragoe, E.J. J. Org. Chem.
1981, 46, 3846; Chem. Abstr. 96, 52244j
233) U.S. 4,558,129 1985; Chem. Abstr. 104, 186449x
234) U.S. 4,330,554 1982; Chem. Abstr. 97, 144756b
235) Aristoff, P.A.; Johnson, P.D.; Harrison, A.W. J. Am.
Chem. Soc. 1985, 107, 7967; Chem. Abstr. 104, 68650h
236) U.S. 4,304,790 1981; Chem. Abstr. 96, 142440z
237) U.S. 4,474,778 1984; Chem. Abstr. 102, 78746s
238) Eur. Pat. Appl. 145,494 1985; Chem. Abstr. 104, 68892p
239) Can. 1,208,647 1986; Chem. Abstr 105, 208894p
240) U.S.; 4,486218 1984; Chem. Abstr. 103, 22594u
241) Jpn. Kokai Tokkyo Koho 84, 122,469 1984; Chem.
Abstr. 102, 62090n
242) U.S. 4,547,582 1985; Chem. Abstr. 104, 148534p
243) U.S. 5,489,697 1996
244) U.S. 5,869,324 1999
245) U.S. 5,847,164 1998
246) U.S. 8,874,591 1999
247) U.S. 5,658,916 1997
Rohm and Haas : the Sodium Borohydride Digest
248) U.S. 5,476,931 1995
249) U.S. 5,856,532 1999
250) Mateos, J.L. J. Org. Chem. 1959, 24, 2034; Chem.
Abstr. 54, 12199d
251) Corey, E.J.; Albonico, S.M.; Koelliker, U.; Schaaf,
T.K.; Varma, R. K. J. Am. Chem. Soc. 1971, 93,
1491; Chem. Abstr. 74, 141053j
253) Nagata, T.; Sugi, K.D.: Yamamda, T.; Mukaiyama,
T. Synlett. 1996, 1076
254) Sugi, K.D.; Nagata, T.; Yamamda, T.;
Mukaiyama, T. Chem. Lett. 1996, 737
255) T. Mukaiyama, T. Nagata, K. Yorozu, T. Yamada
Angew. Chem. Int. Ed. Engl., 1995, 34, 2145
256) Ranu, B.C.; Das, A.R. J. Org. Chem. 1991, 56,
4796
257) Yakabe, S.; Hirano, M.; Morimoto, T. Synth.
Commun. 1999, 29, 295
258) Yakabe, S.; Hirano, M.; Morimoto, T. Can J.
Chem. 1998, 76, 1916
259) Yakabe, S.; Hirno, M.; Clark, J.H.; Morimoto, T.
J. Chem. Research (S) 1998, 322
260) Varma, R.S.; Saini, R.K. Tetrahedron Lett. 1997,
38, 4337
261) Luche, J.L.; Germal, A.L. J. Am. Chem. Soc.
1979, 79, 5848
*For Online Consulting Only
press <CTRL>-F for Searching
50
Rohm and Haas : the Sodium Borohydride Digest
CARBOXYLIC ACIDS
Alembic: 48, 49, 55, 61, 62
Carboxylic acids are not normally reduced with
sodium borohydride in protic solvents. However, there
are a few techniques that permit the direct borohydride
reduction of carboxylic acids or their easily prepared
derivatives.
A number of aromatic and aliphatic carboxylic
acids (and esters) have been reduced to their
corresponding alcohol using sodium borohydride at high
temperatures (300o C) in the presence or absence of any
solvent (1,2).
C5H11COOH + NaBH4 Æ C6H13OH
Using a 0.25 mole equivalent of borohydride to acid, the
hexyl caproate was obtained.
Enol esters derived from the reaction of
carboxylic acids with N-ethyl-5-phenylisoxazolium-3’sulfoxate can be reduced with sodium borohydride in
water to the alcohols (3).
A series of perfluorinated acids were reduced
to the alcohols with NaBH4 (4):
*For Online Consulting Only
51
press <CTRL>-F for Searching
O
OH
NaBH4
O
H
H
O
OH
CF3
CF3
Carboxylic acids can be reacted with ethyl
chloroformate to form the mixed anhydrides, in situ, which are
then reduced in aqueous tetrahydrofuran to the corresponding
alcohols (5).
R
O
R
+
OH Cl
O
O NaBH4
OEt
O
O
OH
R
H
H
EtO
Other reagents such as cyanuric chloride, tosyl chloride and
BOP (6, 7, 8) have reduced amino acids to their corresponding
chiral alcohol in high yield. This technique is very cost
effective as well as very mild. One problem with this
methodology is that all carboxylic acid and alcohol groups will
react with these reagents. Therefore all hydroxy group that are
not to be reduced must be protected prier to treatment.
This technique has been applied in a number of
syntheses of complex materials (9- 13)
The
reductive
system
of
NaBH4/metal
chloride/diglyme is effective for reducing carboxylic acids.
Rohm and Haas : the Sodium Borohydride Digest
AlCl3 has been used successfully, but will also reduce
other functional groups if they are present (14,15).
Zinc borohydride will reduce both aliphatic
and aromatic carboxylic acids under reflux conditions in
THF in high yields, amino acids have also been reduced
to chiral amino alcohols with this methodology. (16,17)
Cuprous halide/NaBH4/diglyme gives a
reducing system which is specific for carboxylic acids
while TeCl4 or ThCl4 renders it specific for reduction of
esters and acids (18). Zirconium tetrachloride with
sodium borohydride will also reduce carboxylic acids to
their corresponding alcohols. (19)
NaBH4 has been used with TiCl4 to reduce
both a carboxylic acid to the alcohol and a nitro group
to the amine, in a single step, during the synthesis of the
alkaloid ismine (20). Ti(OiPr)3 with Sodium
borohydride also reduces aliphatic and
aromatic
carboxylic acids as well as amino acids to their
corresponding alcohol in high yields. (21)
Reagents such as I2, Me3SiCl, BF3, MeSO2OH
and H2SO4 are combined with borohydrides to form
borane, which is a very active component for the
reduction
of
carboxylic
acids.(22-28)
These
combinations of reagents have reduced both aliphatic
and aromatic carboxylic acid as well as amino acids to
their corresponding alcohols.
*For Online Consulting Only
press <CTRL>-F for Searching
52
Thioacids are also rapidly reduced to high yields of
the thiol, with small amounts of alcohols, by the system
AlCl3/NaBH4/diglyme (29).
Sodium borohydride alone normally does not reduce
carboxylic acid but the addition of triphenylborate reduces
both aromatic and aliphatic acids.(30) Other reagents which
can be used are dimethyl sulfate (31). The addition of trifluoro
acetic acid and catechol to sodium borohydride in THF at
room temperature will reduce both aliphatic and aromatic
carboxylic acids. (32)
The combination of Amberlist-15, LiCl and sodium
borohydride in methanol will reduce amino acids in high
yields. (33) Borohydride exchange resins with chloroformate
have reduced both aliphatic and aromatic carboxylic groups at
RT. (34)
References:
1) Nose, A.; Kudo, T. Yakugaku Zasshi 1976, 96, 1401;
Chem. Abstr. 86, 139533y
2) Yang, C.; Pittman, C.U. Synthetic Commun. 1998, 28,
2027
3) Hall, P.L.; Perfeti, R.B. J. Org. Chem. 1974, 39, 11;
Chem. Abstr. 80, 96354
4) U.S. 3,752,847 1973; Chem.Abstr. 79, 91611v
5) Ishizumi, K.; Koga, K.; Yamada, S. Chem. Pharm. Bull.
1968, 16, 492; Chem. Abstr. 69, 58805g
Rohm and Haas : the Sodium Borohydride Digest
6) Faloprni, M; Porcheddu, A.; Taddei, M.
Tettrahedron Lett. 1999, 40, 4395
7) Kokotos, G.; Noula, C. J. Org. Chem. 1996, 6994
8) McGreary, R.P. Tetrahedron Lett. 1998, 39, 3319
9) Ger. Offen. ,007,366 1981; Chem. Abstr. 95,
2033633t
10) Jpn. Tokkoyo Koho 83 33,866 1983; Chem. Abstr.
100, 68730b
11) Olsen, R.K.; Ramasamy, K.; Emery, T J. Org.
Chem. 1984, 49, 3527; Chem. Abstr. 101, 131063z
12) Jpn. Kokai Tokkyo Koho 85, 174,769 1985; Chem.
Abstr. 104, 88456c
13) U.S. 4,760,196 1988
14) Brown, H.C.; Subba Rao, B.C. J. Am. Chem. Soc.
1955, 77, 3164; Chem. Abstr. 50, 3995c
15) Blawood, R.K.; Hess, G.B.; Larrabee, C.E.;
Pilgrim, F.J. J. Am. Chem. Soc. 1958, 80, 6244;
Chem. Abstr. 53, 11373e
16) Narasimhan, S.; Madhavan, S.; Prasad, K.G. J.
Org. Chem. 1995, 60, 5314
17) Narasimhan, S.; Madhavan, S.; Prasad, K.G. Synth.
Commun. 1996, 26, 703
18) Subba Rao, B.C.; Thakar, G.P. J. Sci. Indust. Res.
1961, 20b, 317
19) Itsuno, S.; Sukurai, Y.; Ito, K. Synthesis 1988, 995
*For Online Consulting Only
press <CTRL>-F for Searching
53
20) Prabhakar, S.; Lobo, AM.; Marques, M.M.; Tavares, M.R.
J Chem. Research (s) 1985, 394; Chem. Abstr. 104,
225068u
21) Ravikumar, K.S.; Chanderasekaran, S. J. Org. Chem.
1996, 61, 826
22) Prasa, A.S.B.; Kanth, J.V.b.; Periasamy, M. Tetrahedron
1992, 48, 4623
23) Giannis, A.; Sandoff, K. Angew. Chem. Int. Ed. Engl.
1989, 28, 218
24) Sengupta, S.; Sahu, D.P.; Chatterjee, S.K. Indian J. Chem.
1994, 33b, 285
25) Wann, S.R.; Thorsen, P.T.; Kreevoy, M.M. J. Org. Chem.
1981, 46, 2579
26) Boesten, W.H.; Schepers, C.H.M.; Roberts, M.J.A. EPO
322982 A2 1989
27) Abiko, A.; Masamiune, S. Tetrahedron Lett. 1992, 33,
5517
28) U.S. 5,744,611 1998
29) Heasly, G.E. J. Org. Chem. 1971, 36, 3235; Chem. Abstr.
13524f
30) Yoon, N.M.; Chho, B.T.; Yoo, J.U.; Kim, G.P.. J. Korean
Chem. Soc. 1983, 27, 434
31) Cho, B.T.; Yoon, N.M. Bull. Korean Chem. Soc. 1982, 3,
149
32) Suseele, Y.; Periasamy, M. Tetrahedron 1992, 42, 371
33) Anand, R.C.; Vimal Tetrahedron Lett. 1998, 39, 917
Rohm and Haas : the Sodium Borohydride Digest
34) Bandger, B.P.; Modhave, R.K.; Wadgaonkar, P.P.;
Sande, A.R. J. Chem. Soc., Perkin Trans 1 1996,
1993
*For Online Consulting Only
press <CTRL>-F for Searching
54
Rohm and Haas : the Sodium Borohydride Digest
AMIDES
Alembic: 9, 47, 50, 61, 62
Amides were once considered to be not reducible
by NaBH4. Attempts to reduce primary amides in
boiling diglyme led to the formation of nitriles with
the elimination of water (1). In refluxing pyridine,
primary amides form the nitrile, secondary amides
do not react and tertiary amides are slowly reduced
to amine (2,3). When catalyzed by salts of
transition metals, such as cobalt, nickel and
zirconium, NaBH4 has been shown to reduce
primary and secondary amides to the amine. (4, 5)
Zn(BH4)2 can reduce both aromatic and aliphatic
amides to amines in high yields in refluxing THF.
(6) A cobalt complex recently developed will
reduce amides using NaBH4 as the hydride source
(7)
A number of useful techniques to accomplish
amides reductions are now known. These include
reduction with TiCl4/NaBH4 (8,9) reduction with
Bu4NBH4 in dichloromethane (10), reduction with
NaBH4 via imino derivatives using POCl3 (11), and
reduction via thioamides and (alkylthio)
methyleniminium salts (12).
The asymmetric
reduction of pyruvamides has also been reported
*For Online Consulting Only
press <CTRL>-F for Searching
55
(13), using NaBH4 in conjunction with chiral amines.
1o, 2o and 3o aromatic and aliphatic amides are
reduced using a combination of NaBH4 with reagents such
as I2, Me3SiCl, BF3, MeSO2OH and R2SeBr2 at RT. (14,
15, 16, 17, 18) These combination of reagents form
borane in-situ which is the ingredient which reduce the
amide group. B(OPh)3 is another reagent that is used
catalytically with NaBH4 to reduce amides in high
yields.(19)
The reduction of amides with NaBH4 in ether solvents
is accomplished by the addition of 1 molar equivalent
(based on NaBH4) of glacial acetic acid to the stirred
amide-NaBH4-solvent mixture. For the preparation of
tertiary amines from disubstituted amides, trifluoroacetic
is substituted for acetic acid (20,21). A very similar
technique where DMSO was the solvent gave good yields
of a wide variety of primary, secondary and tertiary
amines (22).
The activation of NaBH4 with ethanedithiol or
benzenethiol in boiling THF permitted the reduction of
certain amides and imides to the corresponding amines
(23).
It has recently been shown that cyclic secondary amides
can be selectively reduced to an alcohol in the presence of
tertiary amide by chemically activating the secondary
amine with BOC or Cbz. (24)
Rohm and Haas : the Sodium Borohydride Digest
References:
1) Elzey, S.E. Jr.; Mack, C.H.; Connick, W.J. Jr. J.
Org. Chem. 1967, 32, 846; Chem. Abstr. 67, 2860n
2) Kikugawa, Y.; Ikegami, S.; Yamada, S. Chem.
Pharm. Bull 1969, 17, 98; Chem. Abstr. 70, 97491
3) Saito, I.; Kiugawa, Y.; Yamada, S. Chem. Pharm.
Bull. 1970, 18, 1731; Chem. Abstr. 73, 110093x
4) Satoh, T.; Suzuki, S.; Suzuki, Y.; Miyaji, Y.; Imai,
Z. Tetrahedron Lett. 1969, 4555; Chem. Abstr.94,
1499e
5) Itsuno, S.; Sukurai, Y.; Ito, K. Synthesis 1988, 995
6) Narasimhan, S.; Madhavan, S.; Balakumar, R.;
Swarnalakshmi, S. Synth. Commun. 1997, 27, 391
7) Yamada, T.; Ohtsauka, Y.; Ikeno, T. Chem. Lett.
1998, 1129
8) Kano, S.; Tanaka, Y.; Sugino, E.; Hibino, S.
Synthesis 1980, 695; Chem. Abstr. 94, 14599e
9) Jp. Okai Tokkyo Koho 80, 162, 756 1980; Chem.
Abstr. 95, 62023e
10) Wakamatu, T.; Inaki, H.; Ogawa, A.; Watanabe, M.
Ban, Y. Heterocycles 1980, 14, 1437; Chem. Abstr.
94, 3027a
11) Kuehne, M.E. Shannon, P.J. J. Org. Chem. 1977,
42, 2082; Chem. Abstr. 87, 22928g
12) Raucher, S.; Klein, P. Tetrahedron Lett. 1980, 21,
4061; Chem. Abstr. 94, 156223b
*For Online Consulting Only
press <CTRL>-F for Searching
56
13) Munegumi, T.; Harada, K. Bull Chem. Soc. Jpn. 1983, 56,
298; Chem. Abstr. 99, 53287z
14) Prasa, A.S.B.; Kanth, J.V.b.; Periasamy, M. Tetrahedron,
1992, 48, 4623
15) Giannis, A.; Sandoff, K. Angew. Chem. Int. Ed. Engl.
1989, 28, 218
16) Sengupta, S.; Sahu, D.P.; Chatterjee, S.K. Indian J. Chem.
1994, 33b, 285
17) Wann, S.R.; Thorsen, P.T.; Kreevoy, M.M. J. Org. Chem.
1981, 46, 2579
18) Akabori, S.; Takanohashi, Y. J. Chem. Soc.; Perkin Trans
1, 1991, 479
19) Yoon, N.M.; Chho, B.T.; Yoo, J.U.; Kim, G.P.. J. Korean
Chem. Soc. 1983, 27, 434
20) Umino, N.; Iwakuma, T.; Itoh, N. Tetrahedron Lett. 1976,
763; Chem. Abstr. 85, 20719z
21) Malawska, B.; Gorczyca, M. Pol. J. Chem. 1985, 59, 811;
Chem. Abstr. 105, 226250e
22) Thorsen, P.T.; Kreevoy, M.M. J. Org. Chem. 1981, 46,
2579; Chem. Abstr. 95, 5881j
23) Maki, Y.; Kikuchi, K.; Sugiyama, H.; Seto, S. Chem. Ind.
1976, 322; Chem. Abstr. 85, 62767u
24) Lee, B.H.; Clothier M.F. Tetrahedron Lett. 1999, 40, 643
Rohm and Haas : the Sodium Borohydride Digest
ACID ANHYDRIDES
Alembic: 50
Because of their chemical nature, acid
anhydrides cannot be reduced by borohydride in
aqueous solvents. Early literature reports only a
few instances of carboxylic anhydrides reductions
with NaBH4 in ether solvents, The products being
either lactones (1-4), diols (5), or alcohols (6).
Cyclic anhydrides are readily reduced by
NaBH4 to γ and δ-lactones in very good yields (713) to form antibiotics, (14) growth factors (15) and
β-amino acids (16,17) . Additional reports of the
use of NaBH4 for reducing anhydrides have
appeared in the literature (18- 21)
Mixed carboxylic-diphenylphosphoric acid and
diphenylphosphorochloridate in the presence of
triethylamine, were reduced with excess NaBH4 to
the corresponding primary alcohols in fair yield.
Nitro, ester, amides groups and conjugated double
bonds were not affected (22).
The NaBH4/TiCl4 (4:1) system in diglyme has
been reported to reduce acid anhydrides to diols
(23).
*For Online Consulting Only
press <CTRL>-F for Searching
57
The reduction of a series of substituted phthalic
anhydrides to phthalides with sodium borohydride has
been reported (24). Preferential reduction of the carbonyl
function adjacent to the 3- substituent was observed. In
the 4- substituted analogous, selectivity of reduction was
found only when, the substituent is electron donating.
Acid anhydrides formed from amino acids and isobutyl
chloroformate are reducible with sodium borohydride to
form chiral amino alcohols in high yields. (25,26)
References:
1) Vaughn, W.R.; Goetschel, C.T.; Goodow, M.H.; Warren,
C.L. J. Am. Chem. Soc. 1963, 85, 2282; Chem. Abstr. 59,
6443c
2) Cross, B.E.; Galt, R.H.B.; Hanson, J.R. J. Chem. Soc.
1963, 5052; Chem. Abstr. 60, 566f
3) Birckelbaw, M.E.; LeQuesne, P.W.; Wocholski, C.K. J.
Org. Chem. 1970, 35, 588; Chem. Abstr. 72, 100989j
4) Longlois, N.; Gastambide, B. C. Acad. Sci. Paris, Ser, C
1967, 264, 1878; Chem. Abstr. 67, 90956b
5) Longlois, N.; Gastambide, B. C. Helv. Chim. Acta 1968,
51. 2048; Chem. Abstr. 70, 29097t
6) Perron, Y.G. et. al. J. Med. Chem. 1964, 7, 483; Chem.
Abstr. 61, 5631a
7) Bailey, D.M.; Johnson, R.E. J. Org. Chem. 1970, 35,
3574; Chem. Abstr. 73, 120261q
Rohm and Haas : the Sodium Borohydride Digest
8) Jefford, C.W.; Wang, J. Tetrahedron Lett. 1993, 34,
1111
9) Jefford, C.W.; Wang, J.B.; Lu, Z.H. Tetrahedron
Lett. 1993, 34, 7557
10) Patterson, J.W. J. Org. Chem. 1995, 60, 560
11) Kinoshita, Y.; Watanabe, H.; Kitahara, T.; Mori, K.
Synlett. 1995, 186
12) Patterson, J.W. J. Org. Chem. 1995, 60, 560
13) Miki, Y.; Hachiken, H. Synlett 1993, 333
14) Roa, A.V.R.; Reddy, D.R.; Annapurna, G.S.;
Deshpande, V.H. Tetrahedron Lett. 1987, 28, 451
15) Roa, A.V.R.; Reddy, R.G. Tetrahedron Lett. 1992,
33, 4061
16) Jefford, C.W.; Wang, J. Tetrahedron Lett. 1993, 34,
1111
17) Jefford, C.W.; Wang, J.B.; Lu, Z.H. Tetrahedron
Lett. 1993, 34, 7557
18) Brooks, C.J.W.; Ekhato, I.V. J. Chem. Soc., Chem.
Commun. 1982, 943; Chem. Abstr. 98, 34839u
19) U.S. 4,473,700 1984; Chem. Abstr. 102, 9487w
20) Jpn. Kokai Tokkyo Koho 85,156,691 1985; Chem.
Abstr. 104, 207262y
21) Zhidkova, T.A. et. al. Khim. 1985, 21, 1653;
Chem. Abstr. 105, 43108v
*For Online Consulting Only
press <CTRL>-F for Searching
58
22) Koizumi, T.; Yamamoto, N.; Yoshii, E. Chem. Pharm.
Bull. 1973, 21, 312; Chem. Abstr. 78, 135830b
23) Subba Roa, B.C. Curr. Sci. 1961, 30, 218; Chem. Abstr.
56, 3326c
24) McAlees, A.J.; Mc Crindle, R.; Sneddon, D. J. Chem.
Soc., Perkin Trans 1 1977, 2038; Chem. Abstr. 88, 50432e
25) Rodriques, M.; Llinares, M.; Doulut, S. Heitz, A.;
Martinez, J. Tetrahedron Lett. 1991, 32, 923
26) Ho, M.; Chung, J.K.K.; Tang, N. Tetrahedron Lett. 1993,
34, 6513
59
press <CTRL>-F for Searching
Rohm and Haas : the Sodium Borohydride Digest
ACID HALIDES
Cl
Alembic: 50, 58
O
NaBH4
N
NaBH4 reduction of acids chlorides in inert
solvents (generally ethers) is a generally accepted
synthetic procedure (1-6). NaBH4 reduction of various
acid chlorides from hydantoic peptides has been report
(7).
R
O
N
O
NaBH4
O
H
N
Cl
HO
O
N
H
O
OEt
O
O
O
This reduction has been applied to synthesis of oxazoles
having anti-inflammatory activity (8).
O
Cl
O
N
Ar
Cl
NaBH4
O
N
Ar
H
H
O
The following acid chloride reductions have been
reported:
*For Online Consulting Only
OH
Cl NaBH4
(OC)3Fe
OH
(10)
OEt
H
H
H
H
NaBH4
OH
H
(9)
O
Cl
O
OH
N
H
N
O
R
H
H
H
(OC)3Fe
OH
H
H
H
(11)
press <CTRL>-F for Searching
Rohm and Haas : the Sodium Borohydride Digest
O
O
NaBH4
(12)
HO
HO
Cl
O
HO
H
H
The
reduction
of
acid
chlorides
with
tetrabutylammonium borohydride in dichloromethane
provides instantaneous reactions and nearly quantitative
yields (13). Similar reactions of quaternary
borohydrides in binary solvents or the use of NaBH4
with a phase transfer catalyst, have been reported (14).
Phosphonium borohydride can reduce acid chlorides to
alcohols in high yields in aprotic solvents at RT. (15)
The Luche method, using CeCl3 with NaBH4,
has been applied to the reduction of conjugated
unsaturated acid chlorides to the corresponding
unsaturated alcohol (16).
NaBH4 reduces acid chlorides to aldehydes in
good yield in the presence of cadmium chloride and
DMF (17,18). The reagent bis-(triphenylphosphine)
copper (1) borohydride, easily prepared from NaBH4,
also gives high yields of aldehydes from acid chlorides
(19-22). Reduction to aldehydes by NaBH4 without
added metal salts has been studied (23). Careful control
of the ratio of NaBH4 to acid chloride, operation at –
*For Online Consulting Only
60
70oC in dimethylformamide-tetrahydrofuran solvent and strict
attention to the method of quenching the reaction minimized
overreduction to the alcohol. Aromatic and aliphatic acid
chlorides are reduced to alcohols with SBH in MeOH.(24)
Acid chlorides can be reduced to aldehydes with SBH in the
presence of pyridine as a borane scavenger to stop over
reduction to the alcohol. (25)
Zinc borohydride can reduce acid chlorides to their
corresponding alcohols in high yield in ether type solvents.
(26,27) The addition of organic nitrogen containing bases such
as DABCO and pyrazine have been added to zinc borohydride
to reduce acid chlorides to alcohols (28,29)
The addition of titanium tetraisopropoxide to NaBH4
has been shown to reduce acid chlorides to alcohols in 5 to 10
mins. (30) Cyanoborohydride has also been shown to reduce
acid chloride to alcohols in high yields. (31)
References:
1) Chaikin, S.W.; Brown, W.G. J. Am. Chem. Soc. 1949, 71,
122; Chem. Abstr. 43, 2570d
2) Walton, E. Et. Al. J. Am. Chem. Soc. 1955, 77, 5144;
Chem. Abst. 50, 8452h
3) Tomita, M; Hirai, K. J. Pharm. Soc. Japan. 1958, 78, 798;
Chem. Abstr. 52, 1875g
4) Vecchi, A.; Melone, G. J. Org. Chem. 1959, 24, 109;
Chem. Abstr. 54, 6627f
Rohm and Haas : the Sodium Borohydride Digest
5) Endres, G.F.; Epstein, J. J. Org. Chem. 1959, 24,
1497; Chem. Abstr. 54, 4379h
6) Sato, S.; Ono, Y.; Tatsumi, S.; Wakamatsu, H.;
Nippon Kagaku Zasshi 1971, 92, 178; Chem.
Abstra. 76, 33755x
7) Wessey, F. Schloegl, K.; Korger, G. Nature 1952,
169, 708; Chem. Abstr. 47, 2700f
8) Brit. 1,139,940 1969; Chem. Abstr. 70, 106494z
9) Ger, Offen. 2,237,832 1973; Chem. Abstr. 78,
111342t
10) Hudrilik, P.F.; Rudnik, L.R.; Korzenowski, S.H. J.
Am. Chem. Soc. 1973, 95, 6848; Chem. Abstr. 80,
3149t
11) Berens, G. et. al. J. Am. Chem. Soc. 1975, 97, 7076;
Chem. Abstr. 83, 206405h
12) Paul, K.G.; Johnson, F.; Favara, D.; J. Am. Chem.
Soc. 1976, 41, 690; Chem. Abstr. 84, 135153g
13) Raber, D.J. Guida, W.C. J. Org. Chem. 1976, 41,
690; Chem. Abstr. 84, 88901n
14) Brit. Pat. Appl 2,1544 1985; Chem. Abstr. 104,
168107e
15) Firouazbadi, H.; Adibi, M. Synth. Commun. 1996,
26, 2429
16) Lakshmy, K.V.; Mehta, P.G.; Seth, J.P.; Trivedi,
G.K. Org. Prep. Proced. Int. 1985, 17, 251; Chem
Abstr. 104, 88199w
*For Online Consulting Only
press <CTRL>-F for Searching
61
17) Johnstone, R.A.W.; Telford, R. J. Chem. Soc., Chem.
Commun. 1978, 354; Chem. Abstr. 89, 16547t
18) U.S. 4,211,727 1980; Chem. Abstr. 93, 203401b
19) Fleet, G.W.; Fller, C.J. Harding, P.J.C. Tetrahedron Lett.
1978, 1437; Chem Abstr. 89, 108495s
20) Barlett, P.A.; Johnson, C.R. J. Am. Chem. Soc. 1985, 107,
7792; Chem. Abstr. 104, 50753j
21) Sorrell, T.N.; Pearlman, P.S. J. Org. Chem. 1980, 45,
3449
22) Paquette, LA.; Teleha, C.A.; Taylor, R.T.; Maynard, G.D.;
Rogers, R.D.; Gallucci, J.C.; Springer, J.P. J. am. Chem.
Soc. 1990, 112, 265
23) 23)Babler, J.H.; Invergo, B.J. Tetrahedron Lett. 1981, 21,
11; Chem. Abstr. 94, 174230f
24) Kang, S.K.; Lee., D.H. Bull. Korean Chem. Soc. 1988, 9,
402
25) Babler, J.H. Synth. Commun. 1982, 12, 839
26) Kim, S.; Oh, C.H.; Ko, J.S.; Ahn, K.H.; Kim, Y.J. J. Org.
Chem. 1985, 50, 1927
27) Kotsuki, H.; Ushio, Y.; Yoshimura, N.; Ochi, M. Bull.
Chem. Soc. Jpn. 1988, 61, 2684
28) Firouzabadi, H.; Zeynizadeh, B. Bull. Chem. Soc. Jpn.
1997, 70, 155
29) Tamami, B.; Lakouraj, M.M. Synth. Commun. 1995, 25,
3089
Rohm and Haas : the Sodium Borohydride Digest
30) Ravikumar, K.S.; Chanderasekaran, S. J. Org.
Chem. 1996, 61, 826
31) Hui, B.C Inorg. Chem. 1980, 19, 3185
*For Online Consulting Only
press <CTRL>-F for Searching
62
Rohm and Haas : the Sodium Borohydride Digest
ESTERS
Alembic: 10, 36, 48, 50, 55, 57, 60, 61
Traditionally the reduction of simple aliphatic
esters with sodium borohydride in protolytic solvents is
extremely slow and therefore not practical for industrial
processes. In aprotic solvents such as dichloromethane,
the reduction of ethyl laurate with the soluble
tetrabutylammonium borohydride is only 25% complete
after 4 days at 25oC (1).
In comparison
tetrabutylammonium borohydride in CCl3H at reflux
temperatures will reduce aliphatic esters to alcohols in
70 % yields after 5h (2).
A large number of “activated” esters can be
reduced directly with sodium borohydride in protolytic
solvents. Electron withdrawing groups alpha to the
ester carbonyl group increase the positive charge on the
carbonyl carbon making it much more susceptible to
attack by the borohydride ion (3).
Examples of electron withdrawing groups and
their borohydride reduction products are:
Hydroxyl-Sugar EstersÆ Primary alcohols (4-7).
and Lactones
*For Online Consulting Only
63
press <CTRL>-F for Searching
OH
O
O
NaBH4
O
OEt
O
O
H
pH 2-3
H
In the case of ket-esters, both keto and ester groups are
reduced to give a diol (8-11).
The reduction of alpha-amino esters gives optically active
alpha amino alcohols (12,13). Alpha chloroamines also
activate esters for borohydride reduction (14).
NH3+ClOCH3
NaBH4
O
NH3+ClH
H
OH
Amido and thioamido groups residing on the carbon next to
ester group activates the ester group so that it can be reduced
with sodium borohydride at R.T. (15)
Alpha epoxy esters are reduced to epoxy alcohols (16,17) in
the presence of nitrile groups.
O
O
H
OCH3 NaBH4
O
H
Similarly, the following reduction in anhydrous solvents using
potassium borohydride has been reported (21).
EtO2C(CF2)3CO2EtÆ HOC(CF2)3COH
OH
Very rapid reductions of alpha-chloroesters to their
corresponding alcohols have been reported as part of the
amine ester study mentioned above (12,18). Similarly,
the following reduction is reported (19).
OCH3
H
O
Cl
N
HO
NaBH4
H
Cl
CH3
N
N
Processes have been patented (22,23) for the
reduction of perfluoroesters and acids with NaBH4 to the
corresponding alcohol.
Cyano- Like the halogens, the alpha-cyano group is a
powerful electron withdrawing group and activates
borohydride reduction of the ester group as illustrated below:
(24- 26)
OCH3
N
A series of fluoronitroesters have been reduced to the
corresponding alcohols with sodium borohydride in
water (20).
R
O2N
O
OR NaBH4
H2O
*For Online Consulting Only
F
OH
O
CH3
O
F
64
press <CTRL>-F for Searching
Rohm and Haas : the Sodium Borohydride Digest
N
H
H
OH
O
N
H
H
(24)
Ph
Ph
Ph
CN
R
O2N
NaBH4
Ph
O
NaBH4
Ph
diglyme
OEt 15-20 oC Ph
CN
(25)
H
H
HO
press <CTRL>-F for Searching
Rohm and Haas : the Sodium Borohydride Digest
R
CN
R
NaBH4
R
OEt EtOH
R
O
H
CN NaBH4 R
H
OEt
H
CN
H (26)
H
H
R
O
HO
The ester groups of a series of triglycerides
from virgin olive oil can be selectively reduced with
sodium borohydride to form their corresponding
alcohols in high yields. (27)
Miscellaneous: Examples of other activated esters,
which have been reduced with sodium borohydride, are
(28-30)
O
OH
O
OCH3 NaBH4 H
H3CO
OH
H
H
H
(28)
EtOH
O
OCH3
NH2
N
H2N
N
HO
NaBH4
NH2
H
H
NH2
N
H2N
(29)
N
NH2
N-Acyldipeptide ester Æ Amino Alcohol (30)
*For Online Consulting Only
65
The acyl groups in lecithin and monogalactosyl diglycerides
were reduced by sodium borohydride to fatty alcohols with no
detectable reduction or isomerization of double bonds in 94
and 64% yield, respectively (31) Changing the alcohol portion
of the ester group can facilitate the borohydride reduction of
the ester. It has been reported (32) that the reduction of esters
of alcohols more electronegative than methyl, such as phenol
and other acidic alcohols, can increase reduction rates by 300fold.
Another technique that is effective to reduce esters is
to modify the cation associated with the borohydride anion.
Lithium borohydride will reduce most esters quite easily (33).
The enhanced reduction effect of the lithium ion is
greatest in solvents of low dielectric constants. In such
solvents, the reaction presumably proceeds through the ionpair (Li+BH4-) rather than through the completely dissociated
ions. Magnesium borohydride and calcium borohydride
probably behave in a similar manner. The reactions of sodium
or potassium borohydride with lithium chloride, magnesium
chloride or calcium chloride in tetrahydrofuran, diglyme or
ethanol give the corresponding lithium, magnesium or calcium
borohydrides by metathesis. Reducing systems based on these
reactions can be used for ester reductions by in situ preparative
techniques without removal of the by-product alkali metal
chloride (34-41 ). Olefins have been demonstrated to increases
the reactivity of calcium borohydride towards the reduction of
Rohm and Haas : the Sodium Borohydride Digest
esters group.(42) This technique works for reducing
aromatic and aliphatic esters to alcohols.
The addition of olefins to Zn(BH4)2 also increase the
reactivity of the Zn(BH4)2 towards the reduction of
esters.(43) Other catalyst which have demonstrated to
increase reactivity of metal borohydride towards the
reduction of esters are trialkyl borates and amines. (4446)
Clear diglyme solutions of aluminum chloride and
sodium borohydride (molar ratio 1:3) easily reduce
esters to alcohols, but other functional groups and
double bonds are also reduced (47-48).
A study on the effect of metal halides on the
reducing properties of sodium borohydride in aprotic
solvents has been published (49). Cuprous halide gave a
reagent specific for the reduction of carboxylic acids,
and TeCl4or ThCl4 gave systems specific for the
reduction of esters and acids. Zirconium tetrahalides
produced a very strong reducing system that attacked all
functional groups including reduction of nitro groups at
room temperature. An extensive evaluation of cation
and solvent effects on the borohydride reduction of
carboxylic esters has been published (50).
It is also possible to modify the BH4- anion to
greatly enhance its reactivity. Many esters have been
reduced with large excesses of sodium borohydride in
*For Online Consulting Only
66
press <CTRL>-F for Searching
refluxing methanol (51-52). It is believed now that the active
reducing species was sodium trimethoxyborohydride which
was formed in situ.
Sodium acetanilidoborohydride has been synthesized
by the reaction of acetamilide (or benzanilide) in α-picoline.
This reagent reduced methyl esters in good yields without
affecting other functional groups (amide, nitro and isopropyl
ester) (53-54).
O
H3C
N
H
O
Ph
+
NaBH4
H3C
BH3-Na+
+ H2
N
Ph
Another system involves refluxing sodium borohydride with
ethanedithiol in dry THF along with the ester has been
described (55-56). Benzoate and aliphatic esters were reduced
and methyl cinnamate was reduced to 3-phenyl propanol.
A large number of aliphatic and aromatic acids and
esters have been reduced by sodium borohydride in the
presence or absence of a solvent at high temperatures.
Reductions using 1 equivalent of NaBH4 gave the
corresponding alcohols (57).
Rohm and Haas : the Sodium Borohydride Digest
A novel approach to ester reductions is the
slow addition of methanol to a refluxing mixture of the
ester and NaBH4 in tert-butanol or tetrahydrofuran (5859), resulting chemoselectively in high yields of
primary alcohols. This system has been applied
successfully to the preparation of N-protected amino
alcohols and N-protected peptide alcohols.
NaBH4 in diglyme at elevated temperatures
reduces aromatic ester to alcohols while at RT no
reaction occurs. (60) Both aromatic and aliphatic esters
are reduced to alcohols with NaBH4 in water or a 1:1
mixture of water and dioxane at RT. ( 61)
Sodium borohydride when combined with
reagents such as Me3SiCl or I2 form borane BH3, which
will reduce both aromatic and aliphatic esters
chemoselectively. (62-63)
Esters can be converted to aldehydes by
oxidizing the borate ester intermediate formed from the
reduction of esters with calcium borohydride ( 64).
*For Online Consulting Only
press <CTRL>-F for Searching
67
References:
1) Raber, D.J.; Guida, W.C. J. Org. Chem. 1976, 41 690;
Chem. Abstr. 84 880n
2) Narasimhan, S.; Swarnlakshmi, S.; Balakumar, R.;
Velmathi, S. Synlett. 1998. 1321
3) Schenker, E. "Newer Methods of Preparative Organic
Chemisty", Vol IV, 1968, 196, Verlang, Chemie,
Weinheim
4) Wolfrom, M.L.; Anno, K. J. Am. Chem. Soc. 1952, 74,
5583; Chem. Abstr. 8, 134e
5) Wolfrom, M.L.; Wood, H.B. J. Am. Chem. Soc. 1951, 73,
2933; Chem. Abstr. 46, 3961a
6) Barton, D.H.R. et. al. J. Chem. Soc. Perkin Trans. 1 1975,
2069; Chem. Abstr. 84, 31342b
7) Ger. Offern. 2,911,377, 1980; Chem. Abstr. 94, 121935h
8) Heymann, H.; Fiesser, L.F. J. Am. Chem. Soc. 1951, 73,
5252; Chem. Abstr. 47, 592d
9) Leonard, N.J.; Conrow, K.; Fulmer, R.W. J. Org. Chem.
1957, 22, 1445; Chem. Abstr. 52, 8134c
10) Soai, K.; Oyamada, H. Synthesis 1984, 605; Chem. Abstr.
101, 229944n
11) Brown, G.R.; Foubister, A.J. J. Chem. Soc., Chem.
Commun. 1985, 455; Chem. Abstr. 103, 122724e
12) Seki, H. et. al. Chem. Pharm. Bull. 1965, 13, 995; Chem.
Abstr. 63, 14971d
Rohm and Haas : the Sodium Borohydride Digest
13) Mandal, S.B.; Achari, B.; Chattopadyay, S.
Tetrahedron Lett. 1992, 33, 1647
14) Macmillan, J.G. et. al. J. Am. Chem. Soc. 1976, 98,
246; Chem. Abstr. 84, 90114b
15) Roy, A.; Bar, N.C.; Achari, B.; Mandal, S.B. Indian
J. Chem. 1998, 37b, 644
16) Corsano, S.; Pncetelli, G. J. Chem. Soc., Chem.
Commun. 1971, 1106; Chem. Abstr. 75, 151935h
17) Mauger, J.; Robert, A. J. Chem. Soc.; Chem.
Commun. 1986, 395
18) Seki, H.; Koga, K.; Yamada, S. Chem. Pharm. Bull.
1967, 15, 1948; Chem. Abstr. 69, 107039w
19) Beyereman, H.C.; Maat, L.; Noordam, A; Van Zon,
A. Recl. Trav. Chim. Pays-Bas 1977, 96, 222;
Chem. Abstr. 88, 70328p
20) U.S. 3,783,144 1974; Chem. Abstr 80, 70328p
21) Dobina, K.A. et. al. Zh. Prikl. Khim. 1973, 46, 678;
Chem. Abstr. 79, 4911b
22) French 1,573,705 1969; Chem.Absr. 72, 100009q
23) Jpn. Kokai Tokkyo Koho 83 85,832 1983; Chem.
Abstr. 99,104774r
24) Paul, R.; Williams, R.P.; Cohen, E. J.Org. Chem.
1975, 40, 1653; Chem. Abstr. 83, 192471n
25) Meschino, J.A.; Bond, C.H.; J. Org. Chem. 1963,
28, 3129; Chem. Abstr. 59, 15280f
*For Online Consulting Only
press <CTRL>-F for Searching
68
26) Marshall, J.A.; Caroll, R.D. J. Org. Chem. 1965, 30, 2748;
Chem. Abstr. 63, 11387d
27) Giumanini, A.G.; Tubaro, F. J. Prakt. Chemie. Band
1990, 332, 755
28) Span. 41324 1976; Chem. Abstr. 86, 106401x
29) Wong, J.; Brown, M.S.; Matsumoto, K.; Oesterlin, R.;
Rapoport, H. J. Am. Chem. Soc. 1971, 93, 4633; Chem.
Avstr. 86, 106401x
30) Yonemitsu, O.; Hamada, .; Kanaoka, Y. Tetrahedron Lett.
1968, 3575; Chem. Abstr. 69, 87454x
31) Nichols, B.W.; Safford, R. Chem. Phys. Lipids 1973, 11,
222 Chem. Abstr. 80, 47412
32) Takahashi, S.; Cohen, L.A. J. Org. Chem. 1970, 35, 1505;
Chem. Abstr. 73, 3270f
33) Nystrom, R.F.; Chaikin, S.W.; Brown, W.G. J. Am. Chem.
Soc. 1949, 71, 3245; Chem. Abstr. 44, 1017e
34) Paul, R.; Joseph, N. Bull. Soc. Chim. France 1952, 550;
Chem. Abstr. 47, 32651
35) Kollonitsch, J. Fuchs, O.; Gabor, V Nature 1955, 175,
346; Chem. Abstr. 50, 1774d
36) Brown, H.C.; Mead, E.J.; Subba Rao, B.C.; J. Am. Chem.
Soc. 1955, 77, 6209; Chem. Abstr. 50, 8529h
37) Jpn. Kokai Tokkyo Koho 80, 133,369, 1980; Chem.
Abstr. 94, 174915h
38) U.S.; 4512,991 1985; Chem. Abstr. 103, 71338x
Rohm and Haas : the Sodium Borohydride Digest
39) Jpn. Kokai, Tokkyo Koho 85, 178,845 1985; Chem.
Abstr. 104 88116s
40) Brisse, F.; Durocher, G. et.al. J. Am. Chem. Soc.
1986, 108, 6579
41) Dieks, H.; Senge, M.O.; Kirste, B.; Kurreck, H. J.
Org. Chem. 1997, 62, 8666
42) Narasimhan, S.; Prasad, G.; Madhavan, S. Synth.
Commun. 1995, 25, 1689
43) Narashhan, S.; Madhavan,S.; Prasad, K. Synth.
Commun. 1997, 27, 385
44) Brown, H.C.; Narasimhan, S. J. Org. Chem. 1982,
47, 1604
45) Yamakawa, T. Masaki, M.; Nohira, H. Bull. Chem.
Soc. Jpn. 1991, 64, 2730
46) Ranu, B.C.; Basu, M.K. Tetrahedron Lett. 1991,
32, 3243
47) Brown, H.C.; Subba Rao J. Am. Chem. Soc. 1956,
78, 2582; Chem. Abstr. 51, 1077c
48) U.S. 4,842,775 1989
49) Subba Rao, B.C.; Thakar, G.P.; J. Sci. Industr. Res.
1961, 0b, 317; Chem. Abstr. 56, 6881h
50) Brown, H.C.; Narasimhan, S; Choi, Y.M. J. Org.
Chem. 1982, 47, 4702; Chem. Abstr. 97, 197647y
51) Brown, M.S.; Rapoport, H. J. Org. Chem. 1963, 28,
3261; Chem. Abstr. 60, 2924d
*For Online Consulting Only
press <CTRL>-F for Searching
69
52) Zanka, A.; Ohmori, H.; Okamoto, T. Synlett 1999, 10,
1636
53) Kikugawa, Y. Chem. Lett. 1975, 1029; Chem. Abstr. 83,
192759n
54) Kikugawa, Y. Chem. Pharm. Bull. 1976, 24, 1059; Chem.
Abstr. 85, 108365s
55) Maki, Y.; Kikuchi, K.; Sugiyama, H. Set, S. Tetrahedron
Lett. 1975, 3295; Chem. Abstr. 83, 192758m
56) Guida, W.C.; Entreken, E.E.; Guida, A.R.; J Org. Chem.
1984, 40, 3024; Chem. Abstr. 101, 72355w
57) Nose, A.; Kudo, T.; Yakugaku Zasshi 1976, 96, 1401;
Chem. Abstr. 86, 139533v
58) Soai, K.; Oyamada, H.; Takase,M.; Ookawa, A. Bull.
Chem. Soc. Jpn. 1984, 57, 1948; Chem. Abstr. 101,
230087s
59) Soai, K.; Oyamada, H.; Takase, M. Bull. Chem. Soc. Jpn.
1984, 57, 2327; Chem. Abstr. 101, 192464c
60) Yang, C.; Pittman, C.U. Synthetic Commun. 1998, 28,
2027
61) Binco, A.; Passacantilli, P. Righi, G. Synth. Commun.
1988, 18, 1765
62) Prasa, A.S.B.; Kanth, J.V.b.; Periasamy, M. Tetrahedron,
1992, 48, 4623
63) Giannis, A.; Sandhoff, K. Angew. Chem. Int. Ed. Engl.
1989, 28, 218
Rohm and Haas : the Sodium Borohydride Digest
64) Narasimhan, S.; Ganeshwar, K.; Madhavan, S.
Synth. Commun. 1995, 25, 1689
*For Online Consulting Only
press <CTRL>-F for Searching
70
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
71
ENOL ESTERS
In mixed solvent systems containing water, NaBH4
reduces enol esters to the alcohol. The enol ester is first
hydrolyzed to the ketone, which is reduced by the
borohydride:
NaBH4
H2O
Aco
HO
HO
Cholestenone has been reduced to cholesterol in good
yield via the enol ester route (1). Enol ester reductions
are applied most frequently in steroid synthesis (2-6).
*For Online Consulting Only
References:
1) Belleau, B.; Gallagher, T.F. J. Am. Chem. Soc. 1951, 73,
4458; Chem. Abstr. 47, 138I
2) Kurath, P.; Capezzuto, M. J. Am. Chem. Soc. 1956, 78,
3527; Chem. Abstr. 51, 1229h
3) Djerassi, C. et. al. J. Am. Chem. Soc. 1958, 80, 2596;
Chem. Abstr. 52, 20262a
4) Smith, S.H.; Turner, A.B. J. Chem. Soc. Perkin 1 1975,
1751; Chem. Abstr. 84 5241y
5) Gruenke, L.D.; Craig, J.C. J. Labeled Compd.
Radiopharm. 1979, 16, 495; Chem. Abstr. 92, 59077h
6) Fendrich, G.; Abeles, R.H. Biochemistry 1982, 21, 6685;
Chem. Abstr. 98, 2166f
72
press <CTRL>-F for Searching
Rohm and Haas : the Sodium Borohydride Digest
O
IMIDES
While broadly definitive papers on the imide
reductions by NaBH4 have not appeared in the literature,
many specific reductions have been described and the
products obtained vary with starting imide. In some
cases, carbonyl reductions accompanied by ring opening
are obtained. For example, several cyclic imides have
been reduced by sodium borohydride in methanol as
shown below(1).
R
HO
O
Me
N
Ph
R
NaBH4
O
Me
R
H
N
Ph
H
N
Ph
O
Me
HO
O
Examples of reduction of substituted succinimides,
glutarimides and 3-nitrophthalimide by sodium
borohydride in isopropanol have also been reported
(2,3). The acid catalyzed borohydride reduction of
imides also has been described (4-6).
*For Online Consulting Only
N CH
3
Me
N CH (84%)
3
Me
O
OH
NaBH4
OH
(16%)
O
N CH
3
Me
O
Tetrahydrothalimide derivatives have been reduced with
sodium borohydride in ethanol (7). Various other imide
reductions are cited in the literature (8-15).
Imidic ethers have been reduced with the system
NaBH4/SnCl4 dietherate in gylme at 0 oC (16).
H
OEt
NH
NaBH4
H
NH2
SnCl4
Stereoselective reduction of imides to hydroxy lactam
can
be
achieved
by
reacting
imides
with
tetramethylammonium triacetoxy borohydride, NaBH4 with
magnesium perchlorate and NaBH4 with CeCl3. (17-19)
Rohm and Haas : the Sodium Borohydride Digest
Cyclic Imides can be deoxygenated to form
cyclic amines in high yields using NaBH4 with I2 or
H2SO4. (20)
References:
1) Ohki, S. et. al Yakugaku Zasshi 1973, 93, 841;
Chem. Abstr. 79, 91872f
2) Watanabe, T.; Hamaguchi, F.; Ohki, S. Yakugaku
Zasshi 1973, 93, 845; Chem. Abstr. 79, 78328p
3) Watanabe T. Hamaguchi, F.; Ohki, S.; Chem.
Pharm. Bull. 1972, 20, 2123; Chem. Abstr. 78,
4058h
4) Wijnberg, J.; Speckamp, W. Tetrahedron 1975, 31,
1437; Chem. Abstr. 84, 59813e
5) Wijnberg, J.; Speckamp, W. Tetrahedron 1975, 31,
4035; Chem. Abstr. 84, 74482q
6) Hubert, J.C.; Wijnberg, J.; Speckamp, W.
Tetrahedron 1975, 31, 1437; Chem. Abstr. 83,
147364u
7) Zielinski, T.; Esztajn, J.Jatczak, M. Rocz. Chem.
1975, 49, 1671; Chem. Abstr. 84, 150433s
8) Iida, H.; Takahaski, K.; Kikuchi, T; Heterocycles
1976, 4, 1497; Chem. Abstr. 86, 29596k
9) Newman, H. J. Org. Chem. 1974, 39, 100; Chem.
Abstr. 80, 95165w
*For Online Consulting Only
press <CTRL>-F for Searching
73
10) Martin, M.G.; Ganem, B. Tetrahedron Lett. 1984, 25,
2093; Chem. Abstr. 101, 131057a
11) Burnett, D.A.; Choi, J.-K., hart, D.J.; Tsai, Y.M. J. Am.
Chem. Soc. 1984, 106, 8201; Chem. Abstr. 012, 79186w
12) Trehan, I.R.; Kad, G.L.; Rani, S.; Bala, R. Inidian J.
Chem, Sec B 1985, 24B, 659; Chem. Abstr. 104, 225089b
13) Ger. Offen. 3,446,303 1986; Chem. Abstr. 105, 153331v
14) Koot, W.J.; VanGinkel, R.; Kraneburg, M.; Hiemstra, H.;
Louwier, S.; Moolemaar, M.J.; Speckamp, W.N.
Tetrahedron Lett. 1991, 32, 401
15) Leban, J.J.; Colson, K.L. J. Org. Chem. 1996, 61, 228
16) Tsuda, Y.; Sano, T.; Watanabe, H. Synthesis 1977, 652;
Chem. Abstr. 88, 36668e
17) Miller, S.A.; Chamberlin, A.R. J. Org. Chem. 1989, 54,
2502
18) Konopikova, M.; Fisera, L.; Pronayova, N.; Ertl, P.
Liebigs, Amn. Chem. 1993, 1047
19) Deprez, P.; Royer, J.; Husson, H.P. Tetrahedron 1993, 49,
3781
20) U.S. 5585500 1996
74
press <CTRL>-F for Searching
Rohm and Haas : the Sodium Borohydride Digest
Glycidic lactones Æ glycidol loactols (10)
LACTONES
Alembic: 50
O
Sodium borohydride has been used extensively
for the reduction of lactones mainly in the synthesis of
complex organic fine chemicals and pharmaceuticals.
Reductions are best carried out in water, alcohols or
mixtures of these solvents. Yields are generally
acceptable but may require use of an excess of sodium
borohydride. Lactones that resist reduction with sodium
borohydride in protic solvents usually can be reduced
with NaBH4 and AlCl3 in diglyme (1).
But recently it has been demonstrated that
sodium borohydride in MeOH can reduce lactones (2)
No definitive study of borohydride reduction of
lactones has been published. Nevertheless, the
application is well established (3-5). Some selected
examples are:
R
O
O NaBH4
X
R
R
polysaccharides loactones Æ aldose (6-9)
*For Online Consulting Only
O
O
O
O
N
O
OH
OH
H3C
NaBH4
H3C
H3C
(11)
HN
Ph
Ph
Lithocarpic lactone
H
H
O
O
X
O
H3C
O
O
R
O
NaBH4
O
PGF2
H
H
H
NaBH4
HO
HO
H
press <CTRL>-F for Searching
Rohm and Haas : the Sodium Borohydride Digest
O
O
O
O
NaBH4
O
O
(13)
HO
HO
Aflatoxins B1 and B2
O
OH
O
O
OH
O
NaBH4
O
(14)
O
O
O
OCH3
OCH3
Production of N-(dihydroxyalkyl) uracils
O
O
N
O
O
N
N
O
NaBH4
HO
O
N
(15,16)
HO
The use of lanthanide metal salts with sodium
borohydride has been shown to reduce lactone
efficiently. (17) Stereoselective reduction of a lactone
to α-hydroxy cyclic ether has been accomplished by
*For Online Consulting Only
75
using cyclodextrans as a template. (18) Sodium borohydride
has been shown to also convert lactones to α-hydroxy cyclic
ether in high yield (19)
References:
1) 1)Brown, H.C.; Subba Rao, B.C.; J. Am. Chem. Soc.
1956, 78, 2582; Chem. Abstr. 51, 1077c
2) Di Nardo, C.; Jerancic, L.O. de Lederkremer, R.M.;
Varela, O. J. Org. Chem. 1996, 61, 4007
3) Hsu, C.T.; Wang, N.Y.; Latimer, L.H.; Shih, C.J. J. Am.
Chem. Soc. 1983, 105, 593; Chem. Abstr. 98, 107052u
4) Kametani, T.; Tsubuki, M.; Furuyama, H.; Honda, T.J. J.
chem. Soc. Perkin 1 1985, 557; Chem. Abstr. 103, 6604s
5) Jpn. Kokai Tokkyo Koho 85,224,684 1985; Chem. Abstr.
104, 109358q
6) Wolfrom, M.L.; Wood, H.B. J. Am. Chem. Soc. 1951; 73;
2933; Chem. Abstr. 46, 3961a
7) Wolfom, M.L.; Anno, K. J. Am. Chem. Soc. 1952, 74,
5583; Chem. Abstr. 48, 134e
8) Frush, H.L.; Isbell, H.S. J. Am. Chem. Soc. 1956, 78,
2844; Chem. Abstr. 14533h
9) Shenai, V.A.; Sdudan, R.K. J. Appl. Polym. Sci. 1972, 16,
545; Chem. Abstr. 76, 155353k
10) Corsano, S.; Piancatelli, G. J. Chem. Soc., Chem.
Commun. 1971, 1106; Chem. Abstr. 75, 151935h
Rohm and Haas : the Sodium Borohydride Digest
11) Truitt, P.; Chakravarty, J. J. Org. Chem. 1970, 35,
864; Chem. Abstr. 72, 100568w
12) Hui, W.H.; Moon, L.M.; Lee, L.C. J. Chem. Soc.,
Perkin Trans 1 1975, 617; Chem. Avstr. 83,
10489u
13) Woodward, R.B. et. al. J. Am. Chem. Soc. 1973, 95,
6853; Chem. Abstr. 809, 3140h
14) Ashoor, S.H.; Chu, F.S. J. Assoc. Off. Anal. Chem.
1975, 58, 492; Chem. Abstr. 83, 109529u
15) Brit. 1,393,863 1975; Chem. Abstr. 84, 4991f
16) Hillers, S.; Zhuk, R.A.; Berzina,A.; Kaulina, L.
Khim. Geterotsikl. Soedin. 1975, 694; Chem. Abstr.
83, 114332d
17) Masaguer, C.F.; Bleriot, Y.; Charlwood, J.;
Winchester, B.G.; Fleet, G.W.J. Tetrahedron 1997,
44, 15147
18) Pitchumani, K.; Velusamy, P.; Srinivsan, C.
Tetrahedron 1994, 50, 12979
19) Wu, H.J.; Tsai, S..; Chern, J.H.; Lin, H.C. J. Org.
Chem. 1997, 62, 6367
*For Online Consulting Only
press <CTRL>-F for Searching
76
77
press <CTRL>-F for Searching
Rohm and Haas : the Sodium Borohydride Digest
D. Carbon Nitrogen Compounds
N
REDUCTIVE AMINATION
Alembic: 6, 7, 28, 52, 55
The little known reaction of N-ethylation of
amines by a combination of formaldehyde and sodium
borohydride involves the sequential treatment of a
primary or secondary amine with the reagents.
It is analogous to the Eschweiler-Clarke
reaction, except that reduction of the imine or
immonium intermediate with sodium borohydride
occurs at room temperature, instead of requiring reflux
conditions on the steam bath.
This reaction has found most frequent us in
alkaloid synthesis, to convert cyclic amines to their Nmethyl derivatives, the tetrahydroisoquinoline nucleus
being the most common substrate (1-5)
NaBH4
N
H CH2=O
N
CH3
Closely related structures in aporphines have also been
methylated with fomaldeyde- NaBH4 (6,7).
*For Online Consulting Only
N
H
NaBH4
CH3
CH2=O
Two additional references (8,9) report the methylation of
tetrahydropteridines in similar fashion. These are especially
noteworthy because the pteridine nucleus is selectively
methylated at the N-5 position.
H
H
N
N
H
N
NaBH4
N CH2=O
N
N
N
N
CH3
The utility of this reaction is by no means limited to
heterocyclic amines. Conversions to methyl tertiary amino
substituents in steroid systems have been reported (10-12).
Numerous other systems (13) have been described including
dibenzoxepis (14), Biological species (15), Amnonucleosides
Rohm and Haas : the Sodium Borohydride Digest
(16) and β-alkanolamines- via the readily formed
oxazolidins (17).
The methylation reaction has been applied to
organometallic specifically α-ferrocenylethylamine (18)
and α-ferrocenylbenzylamine (19).
Alkylation using NaBH4 in the presence of
lower aliphatic carboxylic acids have been investigate
extensively by Gribble (20-24) and exploited by others
(25-33). Giumanini has shown that the combination of
carboxylic acid and sodium borohydride can N-alkylate
hydrazides in high yields. (34)
Formaldehyde can be replaced by a number of
reagents in this reaction, e.g. ClCOOMe (to give NCOOMe) (35,36), other aldehydes (37) and aryl halides
(38).
Sodium cyanoborohydride has become a
popular alternative reducing agent for reductive
alkylations. (39-48)
Metal modifiers such as TiCl4, Ti(OiPr)4 and
ZnCl2 with borohydrides can reductively aminate
ketones and aldehydes to form 2o and 3o amines.(49-58)
The use of aprotic solvents such as hexane as a reaction
medium with solid supports such as silica gel and clays
for the reductive amination of aldehydes and ketones by
borohydride have been demonstrated to be highly
efficient.(59,60) Borohydride exchange resins can also
*For Online Consulting Only
press <CTRL>-F for Searching
78
induce reductive amination of aldehydes and ketones in high
yields in methanolic solutions. (61,62)
Reductive amination of ketones and aldehydes can be
accomplished in high yields using sodium borohydride with
sulfuric acid.(63-67).
References:
1) Konda, M.; Ohishi, T.; Yamada, S. Chem. Pahrm. Bull.
1977, 25, 69; Chem. Abstr. 86, 171684f
2) Kupchan, S.M.; Leipa, A.;J. Baxter, R.L.; Hintz, H.P. J.
Org. Chem. 1973, 38, 1846; Chem. Abstr. 790, 5482z
3) Dwama-Badu, D. et al. Experientia 1975, 31, 1251;
Chem. Abstr. 84, 90377q
4) Teitel, S.; O’Brian, J.P. Heterocycles 1974, 2, 625; Chem.
Bastr. 84, 90377q
5) Cava, M.P.; Noguchi, I; Buck, K.T. J. Org. Chem. 1973,
38, 2394; Chem. Absytr. 79, 42715y
6) Kupchan, S.M.; Dhingra, O.P.; Kim, C.K.; Kanewaran, V.
J. Org. Chem. 1976, 41, 4047; Chem. Abstr. 86, 72937j
7) Kametani, T. Et. Al. J. Chem. Soc. C 1971, 1032; Chem.
Abstr. 74, 142122t
8) Gupta, V.S.; Huennekens,F.M. Ach. Biochem. Biophys.
1967, 120, 712; Chem. Abstr. 67, 100112q
9) Whiteley, J.M.; Drais, J.H.; Huennekens, F.M. Arch.
Biochem. Biophys. 1969, 133, 436; Chem. Abstr. 71,
101824t
Rohm and Haas : the Sodium Borohydride Digest
10) Cava, A.; Poiter, P.; LeMen, J. Bull. Soc. Chim.
France 1965, 2502; Chem. Abstr. 63, 16409a
11) Husson, H.P.; Potier, P.; LeMen, J. Bull. Soc.
Chim. France 1966, 948; Chem. Abstr. 65, 2328d
12) Sondengam, B.L.
Hemo, J.H.; Charles, G.
Tetrahedron. Lett. 1973, 261; Chem. Abstr. 78,
124800r
13) Ger. Offen. 3,405,334 1985; Chem. Abstr. 104,
129795h
14) Bickelhaupt, F.; Stach, K.; Thiel, M. Monatsh.
1965, 95, 485; Chem. Abstr. 61, 5575h
15) Chovath, B.; Duraj, J; Sedlak, J. Neoplasma 1985,
32, 393; Chem. Abstr. 104, 105457y
16) Morr, M.; Ernest, L. J. Chem. Res. (S) 1981, 90;
Chem. Abstr. 95, 98193z
17) Saavedra, J.E. J. Org. Chem. 1985, 50, 2271;
Chem. Abstr. 103, 22139z
18) Gokel, G. et. al. Angew. Chem. Int. Ed. Engl. 1970,
9, 64; Chem. Abstr. 72, 6707d
19) Allenmark, S; Kalen, K Tetrahedron Lett. 1975,
3175; Chem. Abstr. 83, 206401d
20) Gribble, G.N.; Jasinski, J.M.; Pellicone, J.T.;
Panetta, J.A. Synthesis 1978, 766; Chem. Abstr. 72,
67071d
21) Gribble, G.N.; Wright, S.W.; Hetercycles 1982, 19,
229; Chem. Abstr. 96, 162482t
*For Online Consulting Only
press <CTRL>-F for Searching
79
22) Gribble, G.N.; Nutaitis, C.F.; Leese, R.M. Heterocycles
1984, 22, 379; Chem. Abstr. 102, 38296t
23) Gribble, G.W. ACS. Semposium Series 1996, 641, 167
24) Gribble, G.W. Chemical Soc. Reviews 1998, 27, 395
25) U.S. 4,378,368 1983; Chem. Abstr. 99, 16566u
26) Eur. Pat. Appl. 122,831 1984; Chem. Abstr. 102, 77872e
27) Ramajulu, J.M.; Joulle, M.M. Synth. Commun. 1996, 26,
1379
28) Pegorier, L.; Petit, Y.; Larcheveque, M. J. Chem. Soc.,
Chem. Commun. 1994, 633
29) Abdel-Magid, A.F.; Carson, K.G.; Harris, B.D.;
Maryanoff, C.A.; Shah, R.D. J. Org. Chem. 1996, 61,
3849
30) Yang, L.X. Hofer, K.G. Tetrahedron Lett. 1996, 37, 6081
31) Yang, Z.; Bradshaw, J.S.; Zhang, X.X.; Savage, P.B.;
Kralowiak, K.E.; Dalley, N.K.; Su, N.; Bronson, R.T.;
Izatt, R.M. J. Org. Chem. 1999, 64, 3162
32) Ramanjulu, J.M.; Joullie, M.M. Synth. Commun. 1996, 26,
1379
33) Abdel-Magid, A.F.; Marynoff, C.A.; Carson, K.G.
Tetrahedron Lett. 1990, 31, 5595
34) Verardo, G.; Toniutti, N.; Giumanini, A.G. Can. J. Chem.
1998, 76, 1180
35) Tsuchiya, T.; Kurita, J.; Snieckus, V. J. Org. Chem. 1977,
42, 1856
Rohm and Haas : the Sodium Borohydride Digest
36) Fowler, F.W. J. Org. Chem. 1972, 37, 1321; Chem.
Abstr. 77, 19494a
37) Eur. Pat. Appl. 112,606 1984; Chem. Abstr. 101,
231039q
38) Kutey, J.P.; Greenhouse, R.; Ridaura, V.E. J. Am.
Chem. Soc. 1974, 96, 7364; Chem. Abstr. 82,
16672z
39) Harding, K.E.; Clements, K.S. J. Org. Chem. 1984,
49, 3870; Chem. Abstr. 101, 171542m
40) Keck, G.E.; Enholm, E.J. J. Org. Chem. 1985, 50,
146; Chem. Abstr. 102, 45160t
41) Eur. Pat. Appl. 155,079 1985; Chem. Abstr. 104,
168094y
42) Ger. Offen. 3,507,019 1986; Chem.Abstr. 105,
227237t
43) Zhao, H.; Mootoo, D.R. J. Org. Chem. 1996, 61,
6762
44) Szardening, A.K.; Burkoth, T.S.; Look, G.C.;
Cambell, D.A. J. Org. Chem. 1996, 61, 6720
45) Saavedra, O.M.; Martin, O.R. J. Org. Chem. 1996,
61, 6987
46) Boga, C.; Manescalchi, F.; Savoia, D.; Tetrahedron
1994, 50, 4709
47) Barney, C.L.; Huber, E.W.; McCarthy, J.R.
Tetrahedron Lett. 1990, 31, 5547
*For Online Consulting Only
press <CTRL>-F for Searching
80
48) Manescalchi, F.; Nardi, A.R.; Savoia, D. Tetrahedron
Lett. 1994, 35, 2775
49) Bhattacharyya, S. J. Org. Chem. 1995, 60, 4928
50) Bhattacharyya, S. Tetrahedron Lett. 1994, 35, 2401
51) Neidigh, K.A.; Avery, M.A.; Williamson, J.S.;
Bhattacharyya, S. J. Chem. Soc., Perkin Trans. 1 1988,
2527
52) Armstrong, J.D.; Wolfe, C.N.; Keller, J.L.; Lynch, J.L.;
Bhupathy, M.; Volante, R.P.; 53) DeVita, R.J.
Tetrahedron Lett. 1997, 38, 1531
53) Bhattacharya, S.; Chatterjee, A.; Williamson, J.S. Synlett
1995, 1079
54) Bhattacharyya, S. Synth. Commun. 1995, 25, 2061
55) Bhattacharyya, S.; Chatterjee, A.; Williamson, J.S. Synth.
Commun. 1997, 27, 4265
56) Bhattachryya, S.; Chatterjee, A.; Duttaachowdhury, S.K.
J. Chem. Soc. Perkin. Trans. 1 1994, 1
57) Kim, S.; Oh, C.H.; Ko, J.S.; Ahn, K.H.; Kim, Y.J. J. Org.
Chem. 1985, 50, 1927
58) Ranu, B.C.; Majee, A.; Sarkar, A. J. Org. Chem. 1998, 63,
370
59) Varma, R.S.; Dahiya, R. Tetrahedron, 1998, 54, 6293
60) Nah, J.H.; Kim, S.Y.; Yoon, N.M. Bull. Korean, Chem.
Soc. 1998, 19, 269
61) Yoon, N.M.; Kim, E.G.; Son, H.S.; Choi, J. Synth.
Commun. 1993, 23, 1595
Rohm and Haas : the Sodium Borohydride Digest
62) Verardo, G.; Giumanini, A.G.; Strazzolini, P.;
Poiana, M. Synthesis 1993, 121
63) Verardo, G.; Giumanini, A.G.; Strazzolini, P.
Synth. Commun. 1994, 24, 609
64) Vyskocil, S.; Smrcina, M.; Hanus, V.; Polasek, H.;
Kocovsky, P. J. Org. Chem. 1998, 63, 7738
65) Giumanini, A.G.; Verardo, G. Gei, M.H.; Lassiani,
L. J. Labelled Compd. Radiopharm. 1987, 24, 255
66) Verardo, G.; Giumanini, A.G. Strazzolini, P.;
Poiana, M. Synthesis 1991, 6, 447
*For Online Consulting Only
press <CTRL>-F for Searching
81
AZIDES
Alembic: 50, 52, 55, 58
N3
O
Ac
*For Online Consulting Only
O
H
H
X
N
Ac
O
H
H
H
H
NH2
OH
O
O2N
OH
N3
NH
NaBH4
O2N
OH
NH
Cl2HC
Cl2HC
O
O
This reduction has been applied to chloramphenicol synthesis
(7).
"RR'N
S
N
X
NaBH4
H
N3
OH
N
HO
H
OH
CH3
CH3
O
NaBH4
O
N
HO
NH2
X
HN
HN
Highest yields were achieved when caustic was added to
stabilize the borohydride in an aqueous dioxane solvent
system.
The conversion of azides to amines by
conventional methods cannot be employed if sulfur is
present in the compound. NaBH4 in isopropanol is
effective if no other easily
reducible group is present, and is useful for acidsensitive compounds (2-6).
N
O
O
Acyl and aromatic azides (but not
monofunctional aliphatic azides) are reduced to the
corresponding primary amine as reported by Boyer and
Elizer (1).
4 RN3 + NaBH4 Æ 4 RNH2
R = acyl, aryl or sulfonly group.
X
82
press <CTRL>-F for Searching
Rohm and Haas : the Sodium Borohydride Digest
O
N3
"RR'N
S
NaBH4
CH3
N
CH3
O
HO
H
H
Rohm and Haas : the Sodium Borohydride Digest
And to the acyl azides of N-substituted, 6aminopenicilanic acids, to give the corresponding
penicillanyl alcohols (8).
It has been used in the synthesis of
antidepressant aryloxyphenylpropylamines (9) and
antigenic glycopeptides (10).
Azide reductions with bis(triphenylphosphine)
copper (1) borohydride (11) and with NaBH4 under
phase transfer conditions (12,13) have also been
reported.
Alky and aromatic azides can be reduced to
amines with transition metals and sodium borohydride
under mild reaction conditions. (14,15, 16) Some of
these reactions are also catalytic.
Zinc borohydride
formed in situ or complexed with DABCO can reduce
alkyl and aromatic azides to amines in high yield.
(17,18)
Reaction of sodium borohydride with 1,3
dithiolethane forms a reactive species which will reduce
azides easily.(19) Methanol is another reagent when
added to a solution of sodium borohydride will reduce
both aromatic and aliphatic azides. (20,21) Trifluoro
actic acid with sodium borohydride will n-alkylate azide
groups. (22)
Borohydride exchange resin with and with out
nickel acetate in methanol at RT will reduce aromatic
*For Online Consulting Only
press <CTRL>-F for Searching
83
and aliphatic azides to their corresponding primary amine in
high yields. (23,24)
References:
1) Boyer, J.H.; Ellzey, S.E. J. Org. Chem. 1958, 23, 127;
Chem. Abstr. 52, 18276f
2) Smith, P.A.; Hall, J.H.; Kan, R.O. J. Am. Chem. Soc.
1962, 84, 485; Chem. Abstr. 56,14129g
3) Woodward, R.W. et. al. J. Med. Chem. 1970, 13, 979;
Chem. Abstr. 73, 87769m
4) Verheyden, J.P.H.; Wanger, D.; Moffatt, J.G. J. Org.
Chem. 1971, 36, 250; Chem. Abstr. 74, 54139y
5) Sztaricskai, F.; Pelyvas, I.; Bognar, R.; Tamas, J. Acta,
Chim, Hung. 1983, 112, 275; Chem. Abst. 99, 2212852y
6) Kirk, D.N.; Wilson, M.A.; J. Chem. Soc. (C) 1971, 414;
Chem. Abstr. 74, 112291e
7) Ehrart, G.; Siedel, W.; Nahm, H. Chem. Ber. 1957, 90,
2088; Chem. Abstr. 53, 276h
8) Perron, Y.G. et. al. J. Med. Chem. 1964, 7, 483; Chem.
Abstr. 61, 5631a
9) U.S. 4,313,896 1982; Chem. Abstr. 96, 142447g
10) Ferrari, B.; Pavai, A.A. Tetrahedron 1985, 41, 1939;
Chem. Abstr. 103, 160841y
11) Clarke, S.J.; Fleet, G.W.; Irving, E.WM. J. Chem. Res. (s)
1981, 17; Chem. Abstr. 94, 208452x
Rohm and Haas : the Sodium Borohydride Digest
12) Rolla, F. J. Org. Chem. 1982, 47, 4327; Chem.
Abstr. 97, 161849b
13) Vlassa, M.; Kezdi, M. Pol. J. Chem. 1984, 58, 611;
Chem. Abstr. 103, 87759w
14) Rao, H.S.P.; Siva, P. Synth. Commun. 1994, 24,
549
15) Rao, H.S.P.; Reddy, K.S.; Turnbull, K.; Borchers,
V. Synth. Commun. 1992, 22, 1339
16) Tschaen, D.M.; Abramson, L.; Cai, D.; Desmond,
R.; Dolling, U.H.; Frey, L.; Karadty, S.; Shi, Y.ZJ.;
Verhoeven, T.R. J. Org. Chem. 1995, 60, 4324
17) Ranu, B.; Sarkar, A.; Chakraborty, R. J. Org.
Chem. 1994, 59, 4114; Chem. Abstr. 121 82111
18) Firouzabadi, H.; Adibi, M.; Zeynizadeh, B. Synth.
Commun. 1998, 28, 1257
19) Pei, Y.; Wickham, B.O.S. Tetrahedron Lett. 1993,
34, 7509
20) Soai, K.; Yokoyama, S.; Ookawa, A. Synthesis
1987, 48
21) Krein, D.M.; Sullivan, P.J.; Turnbull, K.
Tetrahedron Lett. 1996, 7213
22) U.S. 5,012,000 1991
23) Yoon, N.M.; Choi, J.; Shon, Y.S. Synth. Commun.
1993, 23, 3047
24) Kabalka, G.W.; Wadgonkar, P.P.; Chatla, N. Synth.
Commun. 1990, 20, 293
*For Online Consulting Only
press <CTRL>-F for Searching
84
Rohm and Haas : the Sodium Borohydride Digest
REDUCTIVE DEAMINATION
The alkaline cleavage of compounds of the
type RN(NO)ONH2 with NaBH4 has been reported (1)
to give the hydrocarbon RH. The reaction proceeds via
an
intermediate
cabonium
ion,
similar
to
dehalogenantion with NaBH4.
In hexameylphosphoraide, N,N-disulfonimides
of primary amines, e.g. RN(SO2C6H4Me-p)2 where R=
decyl, or 2,5-Me2C4H3CH2 are reduced to the
hydrocarbon RH by NaBH4 in good yield.
Other deamination, e.g. of amidines (3), have
been reported.
References:
1) Kimse, W.; Shuette, H. Liegig, Ann. Chem. 1968,
718, 86; Chem. Abstr. 70, 36855s
2) Hutchns, R.O.; Cistone, F.; Goldsmith, B.;
Heuman, P. J. Org. Chem. 1975, 40, 2018; Chem.
Abstr. 83, 58333r
3) Okamoto, Y.; Kinoshita, T. Chem. Pharm. Bull
1981, 29, 1165; Chem. Abstr. 95, 97752u
*For Online Consulting Only
press <CTRL>-F for Searching
85
press <CTRL>-F for Searching
Rohm and Haas : the Sodium Borohydride Digest
DIAZONIUM SALTS
NaBH4 has been reported to reduce diazonium
fluoroborates in high yields (1,2) using either methanol
or dimethylformamide as solvent. This is a reliable
means of replacing diazonium groups by hydrogen, and
thus of removing from aromatic rings groups easily
converted to the diazonium salts, such as nitro, amino,
and carbonyl groups.
R
N2+ BF4NaBH4
H
R
The use of a solvent that does not interact with
borohydride, such as higher alcohols, amines and glycol
ethers, is preferred.
Phenyldiimine (R-N=NH) has been suggested
to be the intermediate in the NaBH4 reduction of
benzenadiazonium salts, and under anaerobic conditions
has been detected in this reaction (3,4)
Diazonium groups can be reduced to their
corresponding hydrazine efficiently with sodium
borohydride or borohydride exchange resins. (5,6)
*For Online Consulting Only
86
References:
1) Hendrickson, J.B. J. Am. Chem. Soc. 1961, 83, 1251;
Chem. Abstr. 55, 13345c
2) Xu, G; Shi, X; Liu, M. Lanzhou Daxue Xueao, Ziran
Kexueban 1983, 19, 112; Chem. Abstr. 99, 21739g
3) Traylor, T.G.; McKenna, C.E. J. Am. Chem. Soc. 1971,
93, 2323; Chem. Abstr. 75, 5372f
4) Koenig, E.; Musso, H; Zahorszky, U.I. Angew Chem, Int.
Ed. Engl. 1972, 11, 45; Chem. Abstr. 76, 85126h
5) Bandgar, B. P.; Thite, C. S. Synth. Commun. 1997, 27,
635-639; Chem. Abstr. 126211857
6) HU 50108, 1989; Chem. Abstr. 113 5904
Rohm and Haas : the Sodium Borohydride Digest
HETEROCYCLIC C=N BONDS
Alembic: 7,12
Numerous examples of heterocyclic C=N
reductions by NaBH4 have appeared in the literature in
the last 20 years. NaBH4 has found wide application in
this area, mainly because the work-up is much easier
and the products are of high purity.
NaBH4 selectively reduces the C=N bond in a number
of heterocycles, such as 7-aminofurazone[3,4-d]
pyrimidines (1).
87
press <CTRL>-F for Searching
RO2C
RO2C
CO2R
CO2R
NaBH4
N
N
H
CO2R
RO2C
N
H
Quinoxalines (3),
O
N
NH
N
N
N
Ph
R
H
N
NaBH4
AcOH, 5oC
R
N
H
O
N
N
Pyracrimycin A (4),
3,5 substituted pyridines (2).
H
N
H
NaBH4
CONH2
N
H
H
H
CONH2
in which neither the C=C bond nor the amide group is reduced.
*For Online Consulting Only
88
press <CTRL>-F for Searching
Rohm and Haas : the Sodium Borohydride Digest
NaBH4 is also a versatile reagent for
heterocyclic C=N bond reduction in alkaloid synthesis,
e.g., in the synthesis of veracintine (5),
RO
RO
N* HCl
RO
Me
NaBH4
OH
HO
N
RO
OH
HO
CO2Me
CO2Me
Me
N
Reserpine (7,8) and analogs (9-11), and dihydrovasicnone
Me
Me
Me
HO
Tetrahydroisoquiniline derivatives (6).
NaBH4
N
H
N
N
N
Me
N
H
O
O
NaBH4
HO
H
In which the either group is unreactive (12).
Other areas of application also involve the synthesis
of vitamins, e.g. pteridine derivatives (13,14) and
tetrahydrofolic acid (15),
O
H2N
O
N
HN
Cl
N
N
N
HN
NaBH4
H2N
N
N
H
*For Online Consulting Only
H
Cl
Rohm and Haas : the Sodium Borohydride Digest
Amino acids (16)
HO
HO
N
CO2H
H
and pyrines (17, 18)
Recent applications include the conversion of
pyrroline carboxylates to proline (19), the reduction of
benzoxazepines (20), stereoselective synthesis of cis
tetrahydropyrimidines (21) and N-norreticuline (22),
and the formation of tetrahydrocarbolines (23) and
dihydrondoloquinazolines (24).
Sodium borohydride with carboxylic acid
forms trialkoxyborohydrides which have been
demonstrated to be a general method to
chemoselectively reduce cyclic imines to cyclic amines.
(25-36)
Sodium borohydride with NiCl2 have also been
used to reduce cyclic imine to their corresponding
amines. (37)
*For Online Consulting Only
press <CTRL>-F for Searching
89
References:
1) Maki, Y. Chem. Pharm. Bull. 1976, 24, 234; Chem. Abstr.
84, 180161u
2) Booker, E.; Eisner, U. J. Chem. Soc., Perkin Trans 1
1975, 929; Chem. Abstr. 83, 79041j
3) Rao, K.V.; Jackman, D. J. Heterocycl. Chem. 1973, 10,
213; Chem. Abstr. 79, 18669r
4) Coronelli, C.; Vigevani, A.; Cavalleri, B.; Gallo, G.G. J.
Antibiot. 1971, 24, 495; Chem. Abstr. 76, 140387a
5) Vassova, A Voticky, Z.; Tomko, J.; Ahond, A. Collect.
Czech. Chem. Commun. 1976, 41, 2964; Chem. Abstr. 86,
90128a
6) Dornyei, G.; Szantay, C. Acta Chim. Acad. Sci. Hung.
1976, 89, 161; Chem. Abstr. 86, 29595j
7) Woodward, R.B. et. al. J. Am. Chem. Soc. 1956, 78, 2023;
Chem. Abstr. 50, 13967b
8) Woodward, R.B. et. al. Tetrahedron, 1958, 2, 1; Chem.
Abstr. 52, 11870f
9) Velluz, L. et. al. Bull. Soc. Chim. France 1958, 673;
Chem. Abstr. 52, 18478d
10) Protiva, M.; Novak, L. Naturwiss. 1959, 46, 579; Chem.
Abstr. 54, 6775I
11) Protiva, M.; Ernest, I. Naturwiss. 1960, 47, 156; Chem.
Abstr. 54, 19746e
Rohm and Haas : the Sodium Borohydride Digest
12) Zharekeev,
B.K.;
Telezhenetskaya,
M.V.;
Khashimov, K.; Tunusov, S.Y. Khim, Prir. Soedin.
1974, 679; Chem. Abstr. 82, 73290x
13) Taylor, E.C.; Kobylecki, R. J. Org. Chem. 1978,
43, 680; Chem. Abstr. 88, 89628y
14) Pendergast, W.; Hall, W.R. J. Org. Chem. 1985, 50,
388; Chem. Abstr. 102, 78834u
15) Boyle, P.H.; Keating, M.T.; J. Chem. Soc. Chem.
Commun. 1974, 375; Chem. Abstr. 81, 105452z
16) Ramaswamy, S.G.; Adams, E. J. Org. Chem. 1977,
42, 3440; Chem. Abstr. 87, 184925f
17) Maki, Y.; Suzuki, M.; Ozeki, K. Tetrahedron Lett.
1976, 1199; Chem. Abstr. 85, 94314j
18) Beisler,J.A.; Abbai, M.M.; Driscoll, J.S. U.S. Pat.
Appl. 712, 854 (Aug. 8, 1976); Chem. Abstr. 87,
62862n
19) Smith, R.J. Enzyme 1984, 31, 115; Chem. Abstr.
101, 2755c
20) Levkovskaya, L.G.; Sazanov, N.V. et. al. Khim.
Geterotsiki. Soedin. 1985, 122; Chem. Abstr. 103,
37460w
21) Cho, H.; Shima, K. et. al. J. Org. Chem. 1985, 50,
4227; Chem. Abstr. 103, 178228p
22) Hung. Teljes 30,591 1984; Chem. Abstr. 101,
152163x
*For Online Consulting Only
press <CTRL>-F for Searching
90
23) Nakamura, T.; Ishida, A.; Irie, K.; Oshishi, T. Chem.
Pharm. Bull. 1984, 32, 2859; Chem. Abstr. 102, 6239
24) U.S.S.R. 816,116 1985; Chem. Abstr. 105, 208906u
25) Viagante, B.A.; Ozols, Y.Y.; Durbur, G. Y. Khim. Geter.
Soed. 1991, 1680
26) Carling R.W.; Leeson, P.D.; Moseley, A.M.; Baker, R.;
Foster, A.C.; Grimwood, S.; Kemp, J.A. Marshall, G.R. J.
Med. Chem. 1992, 35, 1942
27) Brown, D.W.; Mahon, M.F.; Hihan, A.; Sainbury, M. J.
Chem. Soc. Perkin Trans. 1 1995, 3117
28) Yadagiri, B.; Lown, J.W. Synth. Commun. 1990, 20, 175
29) Bock, M.G.; DiPardo, R.M.; Rittle, K.E.; Evans, B.E.;
Freidinger, R.M.; Veber, D.F.; Chang, R.S.L.; Chen, T.;
Keegen, M.E.; Lotti, V.J. J. Med.. Chem. 1986, 29, 1941
30) Ishii, H.; Ishikawa, T.; Ichikawas, Y.; Sakamoto, M.;
Ishikawa, M.; Takahashi, T. Chem. Pharm. Bull. Jpn.
1984, 32, 2984
31) Uchida, M.; Chihiro, M.; Morita, S.; Yamashita, H.;
Yamasaki, K.; Kanbe, T.; Yabuuchi, Y.; Nakagawa, K.
Chem. Pharm. Bull Jpn. 1990, 38, 534
32) Bergman, J.; Tilstam, U.; Tonroos, K.W. J. Chem. Soc.,
Perkin Trans. 1 1987, 519
33) Moody, C.J.; Warrellow, G.J. Tetrahedron Lett. 1987, 28,
6089
34) Bleicher, L.S.; Cosford, N.D.P.; Herbaut, A.; McCallum,
J.S.; McDonald, I.A. J. Org. Chem. 1998, 63, 1109
Rohm and Haas : the Sodium Borohydride Digest
35) Evans, B.E., et. al. J. Med. Chem. 1987, 30, 1229
36) Orito, K.; Miyazawa, M.; Kanbayashi, R.; Tokuda,
M.; Suginome, H. J. Org. Chem. 1999, 64, 6583
37) Roberts, D.; Jopule, J.A.; Bos, M.A.; Alvarez, M. J.
Org. Chem. 1997, 62, 568
*For Online Consulting Only
press <CTRL>-F for Searching
91
92
press <CTRL>-F for Searching
Rohm and Haas : the Sodium Borohydride Digest
HYDRAZONES
Alembic 12
The reduction of hydrazones (R-CH=NNHR')
to either hydrocarbon or hydrazides has been reported.
(1-3) Tris 2,4-methanoprotoadamantane is synthesized
by reducing the tosylhydrazone derivative in EtOH(4).
p-Tosyl hydrazone of conjugated olefinic or aromatic
carbonyl compounds (e.g. carvone) undergo elimination
reaction in preference to reduction with NaBH4, NaOR or
K2CO3 in methanol to yield methyl ethers instead of
hydrocarbon (11).
NNHTs
NaBH4
OMe
NaBH4
MeOH
N
NH
Ts
This has also been applied to the synthesis of 1-methyl1-dihalomethyl cyclohexane derivatives (5).
A number of hydrazides have been prepared by
The
NaBH4 reduction of the hydrazones (6,9).
hydrazones C=N bond is selectively reduced e.g. in the
synthesis of 3,4,5-trimethxybenzol hydrazides (10) .
MeO
MeO
O
N
H
N
R
NaBH4
MeO
MeO
R'
MeO
*For Online Consulting Only
O
H
N
H
MeO
N
R
R'
H
The hydrocarbon can, however, be obtained by changing
solvents (12).
Recent applications include the synthesis of
phoracatholide (13) and steroid derivatives (14,15) and the
labeling of glycoproteins (16).
Zinc cyanoborohydride can reduce hydrazones to
hydrocarbons in high yields. (17,18) A mechanistic study on
the reductive pathway of cyanoborohydride has been
completed. (19)
Bis-triphenyl phosphine copper (I) borohydride can
reduce hydrazones to alkanes in high yields.(20) Sodium
Rohm and Haas : the Sodium Borohydride Digest
borohydride in the presence of CeCl3 in MeOH at RT
will also reduce hydrazones to alkanes in high yield.
(21)
Acetoxy borohydrides have also been
demonstrated to reduce hydroazones to alkanes (22)
References:
1) Kabalka, G.W.; Baker, J.D. J. Org. Chem. 1975,
40, 1834
2) Kabalka, G.W.; Summer, S.T. J. Org. Chem. 1981,
46, 1217
3) Eycken, E.V.D.; Wilde, H.D.; Deprez, L.;
Wandewalle, M. Tetrahedron Lett. 1987, 28, 4759
4) Sasaki T.; Eguchi, S.; Hirako, Y. J. Org. Chem.
1977, 42, 2981; Chem. Abstr. 87, 117621r
5) Wenkert, E.; Wovkulick, P.; Pellicciari, P.;
Ceccherelli, P. J. Org. Chem. 1977, 42, 1105;
Chem. Abtr. 86, 120829z
6) Claudi, F.; Grifantini, M.; Guilni, U.; Martelli, S.;
Natalini, P.J. Pharm. Sci. 1977, 66, 1355; Chem.
Abstr. 87, 167827h
7) Mazone, G.; Arrigo-Reina, R.; Amico-Roxas, M.
Farmaco, E.D. Sci. 1976, 31, 517; Chem. Abstr. 85,
142768k
8) Ger. Offen. 2,305,972 1973; Chem. Abstr. 79,
115602w
*For Online Consulting Only
press <CTRL>-F for Searching
93
9) Vartanyan, S.A.; Vartanyan, R.S. et. al. Khim. Farm. Zh.
1985, 19, 821; Chem. Abstr. 105, 42705a
10) Mazzone, G.; Arrigo, R.R. Boll. Sedute Accad. Gioenia
Sci. Natur. Catania 1971, 41, 1755; Chem. Abstr. 78,
15733a
11) Grandi, R.; Marchesini, A.; Pagnonic, U.M.; Trave, R. J.
Org. Chem. 1976, 41, 1755; Chem. Abstr. 84, 180401x
12) Silvestri, M.G.; Bednarski, P.J.; Kho, E. J. Org. Chem.
1985, 50, 2798; Chem. Abstr. 103, 54313t
13) Mahanjan, R.J.; DeAraujo, H.C. Synthesis 1981, 46, 2786;
Chem. Abstr. 94, 208686b
14) Iida, T.; Chang, F.C. J. Org. Chem. 1981, 46, 2786;
Chem. Abstr. 95, 25399m
15) Iida, T.; Tamura, R.; Matumoto, T.; Chang, F.C. Synthesis
1984, 957; Chem. Abstr. 102, 221092h
16) Estep, T.N.; Miller, T.J. Anal. Biochem. 1985, 157, 100;
Chem. Abstr. 105, 168335y
17) Kim, S.; Oh, C.H.; Ko, J.S.; Ahn, K.H.; Kim, Y.J. J. Org.
Chem. 1985, 50, 1927
18) Paquette, L.A.; Wang, T.Z.; Vo, N.H. J. Am. Chem. Soc.
1993, 115, 1677
19) Miller, V.P.; Yang, D.Y.; Weigel, T.M.; Han, O.; Liu,
H.W. J. Org. Chem. 1989, 54, 4175
20) Fleet, G.W.J.; Harding, P.J.C. Tetrahedron Letter. 1980,
4031
Rohm and Haas : the Sodium Borohydride Digest
21) Fleet, G.W.J.; Harding, P.J.C.; Whitcombe, M.J.
Tetrahedron Lett. 1980, 21, 4031
22) Maryanoff, B.E.; McComsey, D.F.; Nortey, S.O. J.
Org. Chem. 1981, 46, 255
*For Online Consulting Only
press <CTRL>-F for Searching
94
95
press <CTRL>-F for Searching
Rohm and Haas : the Sodium Borohydride Digest
IMINES
Alembic 23, 33, 43, 62
NH2
H
R
NaBH4 readily reduces imines to their
corresponding secondary amines in good yield under
mild condition (1-6).
O
+
O
H
N
NO2 NaBH
4
N
R
AcOH
Me
H
R
N
HO
NO2
Me
Me
Allylic imines have been reduced to allylic amines in
high yield with sodium borohydride.(7,8)
A large number of Schiff bases have also been reduced
to the amine utilizing NaBH4 (9-12).
R
R
CO2H
N
R'
H
C
CO2H
H
NaBH4
R"
N
H
H
R'
R"
This type of reduction has been shown to provide the
most sensitive method of determining amino acids (13)
The amino acids are condensed with pyridoxal under
alkaline condition to form the Schiff base,
*For Online Consulting Only
OH
OH
OH
Me
H
O
H
HO
Cl
Cl
R
N
N
which is then reduced to the pyridoxylamino acid with sodium
borohydride. The individual acids are separated by column
chromatography, followed by radiochemical determination. In
this way, quantities of amino acids as small as 10-12 mmol can
be detected.
The selective reduction of imines has made NaBH4 a versatile
reagent n the synthesis of antibacterial such as
alkylaminoerythromycins
(14),
fungicides
(15),
8aminogibbanes (16), N-alkyamino pivalates (17) and
antiinflammatory hydroxybenzylamines (18).
Sodium cyanoborohydride is also used frequently for
imine reductions (19-23). Zinc borohydride can reduce imines
to secondary amines in high yields (24-26)
Rohm and Haas : the Sodium Borohydride Digest
Triacetoxy borohydride have been shown to
reduce imines formed from the reductive amination of
aldehydes and ketones with amines.(27)
Stereospecific reduction of imines has been reported
(28-30), including the chiral synthesis of doxpicomine
(31), in which an imine is reduced with 88%
enantiomeric excess. Sodium borohydride with amino
acids have been shown to steroselctively reduce imines
in high ee.(32) Stereoselctive reduction of imines can be
accomplished catalytically with a cobalt catalyst. (33)
Zinc
borohydride
can
also
reduce
imines
steroselectively.(34)
References:
1) Haire, M.J. J. Org. Chem. 1977, 42, 3446; Chem.
Abstr. 87, 183524n
2) Zhang, Z.; Martell, A.E.; Motekataitis, R.J.; Fu, L.
Tetrahedron. Lett. 1999, 40, 4615
3) Effenberger, F.; Jager, J. J. Org. Chem. 1997, 62,
3867
4) Froelich, O,.; Desos, P.; Bonin, M.; Quirion, J.C.;
Hussan, H.P J. Org. Chem. 1996, 61, 6700
5) Roberts, D.; Jopule, J.A.; Bos, M.A.; Alvarez, M.
J. Org. Chem. 1997, 62, 568
6) Krepski, L.R.; Jensen, K.M.; Heilmann, S.M.;
Rasmussen, J.K. Synthesis 1986, 301
*For Online Consulting Only
press <CTRL>-F for Searching
96
7) Shin, W.S.; Lee, K.; Oh, D.Y. Tetrahedron Lett. 1995, 36,
281
8) De Kimpe, N.; Stanoeva, E.; Verhe, R.; Schamp, N.
Synthesis 1988, 587
9) Lakhani, B.B.; Merchant, J.R. J. Inst. Chem. 1977, 49,
172; Chem. Abstr. 87, 167668g
10) Ger. Offen. 3,034,664 1982; Chem. Abstr. 97, 55815c
11) U.S. 4,454,226 1984; Chem. Abstr. 101, 70879w
12) Merrettt, M.; Stammers, D.K.; White, R.D.; Wootton, R.;
Kneen, G. Biochem. J. 1986, 239, 387; Chem. Abstr. 105,
218622n
13) Lustenberger, N.; Lange, H.; Hempel, K. Angew. Chem.
Int. Ed. Engl. 1972, 11, 227; Chem. Abstr. 76, 148553x
14) Ger. Offen 2,606,662 1977; Chem. Abstr. 88, 23335u
15) Eur. Pat. Appl. 129,433 1984; Chem. Abstr. 103,6367s
16) Hung, P.D.; Adam, G.J. Prakt. Chem. 1984, 326, 253;
Chem. Abstr. 101, 38694w
17) Coatwes, R.M.; Cummins, C.H. J. Org. Chem. 1986, 51,
1383; Chem. Abstr. 104, 186037m
18) U.S. 4,578,290 1986; Chem. Abstr. 105, 97344n
19) Oveman, L.E.; Mendelson, L.T.; Jacobsen, E.J. J. Am.
Chem. Soc. 1983, 105, 6629; Chem. Abstr. 99, 176116a
20) Borne, R.F.; Fifer, E.K.; Waters, I.W. J. Med. Chem.
1984, 27, 1271; Chem. Abstr. 101, 1306113s
21) W.S. 4,537,885 1985; Chem. Abstr. 104, 155969n
22) S. Aferican 83 08,227 1985; Chem. Abstr. 105, 114934z
Rohm and Haas : the Sodium Borohydride Digest
23) Cox, E.D.; Hamaker, L.K.; Li, J.; Yu, P.;
Czerwinski, K.M.; Deng, L.; Bennett, D.W.; Cook,
J.M.; Watson, W.H.; Krawiec, M. J. Org. Chem.
1997, 62, 44
24) Ranu, B.C.; Sarkar, A.; Majee, A. J. Org. Chem.
1997, 62, 1841
25) Uneyama, K.; Hao, J.A.; Amii, H. Tetrahedron
Lett. 1998, 39, 4079
26) Kotsuki, H.; Yoshimura, N.; Kadota, I.; Ushio, Y.;
Ochi, M. Synlett, 1990, 401
27) Ryglowski, A.; Kafarski, P. Tetrahedron 1996, 52,
10685
28) Wrobel, J.E.; Ganem, B. Tetrahedron Lett. 1981,
22, 3447; Chem. Abstr. 96, 51861w
29) Czarnocki, Z; Mieczko, J.B. Pol. J. Chem. 1995,
69, 1447; Chem. Abstr. 124 9059
30) Zhu, J.Z.; Quirion, J.C.; Husson, H.P. Tetrahedron
Lett. 1989, 30, 5137
31) Farkas, E.; Sunman, C.J. J. Org. Chem. 1985, 50,
1110; Chem. Abstr. 102, 149194y
32) Hajipour, A.R.; Hantehzadeh, M. J. Org. Chem.
1999 64, 8475
33) Sugi, K.D.; Nagata, T.; Yamamda, T.; Mukaiyama,
T. Chem. Lett. 1997, 493
*For Online Consulting Only
press <CTRL>-F for Searching
97
34) Jackson, W.R.; Jacobs, H.A.; Matthews, B.R.; Jayatilake,
G.S.; Watson, K.G. Tetrahedron. Lett. 1990, 31, 1447
press <CTRL>-F for Searching
Rohm and Haas : the Sodium Borohydride Digest
NITRILES
Alembic 50, 55, 60
Examples of nitrile reduction by NaBH4 are
limited to few heterocyclic compounds in which the –
CN groups are activated by the heteroatom ring, e.g.,
the indole derivative (1) and some pyridine, quinoline
(2) and napthalene (3) derivatives.
Ph
H
Ph
C
H
N
NH2
NaBH4
N
H
N
H
Recently, NaBH4 has been reported to reduce
effectively a number of aromatic nitriles to the amines
in the presence of trifluoroacetic acid (4,5). The active
species
is
believed
to
be
sodium
trifluoroacetoxyborohydride, was first formed by
reacting an equimolar CF3COOH with NaBH4 in THF
for 10 mins at 20 oC.
In a series of studies involving nitrogenase
reactions, Schrauzer has reported the NaBH4 reduction
of isocyanide (6) and cyanides (7), catalyzed by
*For Online Consulting Only
98
molybdenum complexes, to the amines and a number of other
products. The CN groups are activated by coordinating to a
metal atom rendering the carbon center more electropositive
and therefore, more easily attacked by BH4-. Similarly,
perfuoroalkylnitirle are reduced to the amines (8).
In the presence of a catalyst, e.g. Raney nickel, nickel
or cobalt boride the nitrile groups can be effectively reduced,
and this approach has found extensive applications in the
reduction of aromatic nitrile compounds (9), alkaloids (10),
amino acids and their derivatives (11), and biogenic
polyamines derivatives (12). The combination of CoCl2 and
sodium borohydride produces a reductive system that converts
nitriles to either alkanes or amines.(13,14)
Reaction of nitrile groups with girngard reagents to
form imine groups, which are subsequently selectively reduced
with zinc borohydride or sodium borohydride with trimethyl
silane chloride have been demonstrated.(15,16)
Lithium or sodium borohydride with trimethylsilane
chloride have reduced nitrile groups to amines in high
yields.(17)
Borohydride exchange resin spiked with copper
sulfate in MeOH at RT can reduce aromatic and aliphatic
nitriles to their corresponding amines.(18) Lithium
borohydride in a solvent mixture of MeOH and diglyme has
demonstrated the same reactivity but at only moderate yields
of the desired amine.(19)
Rohm and Haas : the Sodium Borohydride Digest
Nitriles can be removed as a cyanide group to
leave an alkane group by using sodium borohydride or
cyanoborohydride in low molecular weight alcohols at
both RT and at elevated temperatures.(20-26) zinc
borohydride has also shown similar reactively towards
nitrile groups.(27)
Publications include a patent on selective
nitrile reduction (28), and a proposed mechanism and
optimized procedure for cobalt boride catalyzed nitrile
reduction have been reported. (29).
References:
1) Rusinova, V.N. et. al. Khim. Geterotsikl. Soedin.
1974, 211; Chem. Abstr. 81, 37455a
2) Kikugawa, Y.; Kuramoto, M.; Saito, I.; Yamada, S.
Chem. Pharm. Bull. 1973, 21, 1927; Chem. Abstr.
79, 145754q
3) Jpn. Kokai Tokkyo Koho 85, 100,542 1985; Chem.
Abstr. 103, 123196w
4) Umino, N.; Iwaakuma, T.; Itoh, N. Tetrahedron
Lett. 1976, 2875; Chem. Abstr. 86, 16375m
5) Beugelmans, R.; Singh, .P.; Bois-Choussy, M.;
Chastanet, J.; Zhu, J. J. Org. Chem. 1994, 59, 5535
6) Schrauzer, G.N.; Doemeny, R.A.; Kiefer, G.W.;
Frazier,R.H. J. Am. Chem. Soc. 1972, 94, 3604;
Chem. Abstr. 77, 15965g
*For Online Consulting Only
press <CTRL>-F for Searching
99
7) Schrauzer, G.N.; Doemeny, R.A.; Kiefer, G.W.;
Frazier,R.H. J. Am. Chem. Soc. 1972, 94, 7378; Chem.
Abstr. 77, 161531d
8) Ellzey, S.E.; Wittman, J.S.; Connick, W.J. J. Org. Chem.
1965, 30, 3945; Chem. Abstr. 64, 6490b
9) Wade, R.C.; Holah, .G.; Hughes, A.N.; Hui, B.C. Catal.
Rev. Sci. Eng. 1976, 14, 211; Chem. Abstr. 86, 22275w
10) Harayama, T.; Ohtani, M.; Oki, M.; Inubushi, Y. Chem.
Pharm. Bull. 1975, 23, 1511; Chem. Abstr. 83, 131793x
11) Mezo, I.; Havanek, M.; Tepan, I.; Benes, J.; Tanaces, B.
Acta. Chim. Acas. Sci. Hung. 1975, 23, 1511; Chem.
Abstr. 83, 59244z
12) Ger. Offen. 3,506,330 1985; Chem. Abstr. 104, 168275h
13) Williams, J.P.; Laurewnt, D.R.; Friedrich, D.; Pinard, E.;
Roden, B.A.; Paquette, L.A. J. Am. Chem. Soc. 1994, 116,
4689
14) Backvall, J.E.; Plobeck, N.A. J. Org. Chem. 1990, 55,
4528
15) Kotsuki, H.; Yoshimura, N.; Kadota, I.; Ushio, Y.; Ochi,
M. Synthesis 1990, 401
16) Urabe, H.; Aoyama, Y.; Sato, F. J. Org. Chem. 1992, 57,
5056
17) Giannis, A.; Snadhoff, K. Angew. Chem. Int. Ed. Engl.
1989, 28, 218
18) Sim, T.B.; Yoon, N.M. Bull. Chem. Soc. Jpn. 1997, 70,
1101
Rohm and Haas : the Sodium Borohydride Digest
19)
20)
21)
22)
23)
24)
25)
26)
27)
28)
29)
Soai, K.; Ookawa, A. J. Org. Chem. 1986, 51, 4000
Mitch, C.H. Tetrahedron Lett. 1988, 29, 6831
Hui, B.C Inorg. Chem. 1980, 19, 3185
Guerrier, L.; Royer, J.; Grierson, D.S.; Husson,
H.P. J. Am. Chem. Soc. 1983, 105, 7754
Yue, C.; Royer, J.; .; Husson, H.P. J. Org. Chem.
1990, 55, 1140
Grierson, D.S.; Royer, J.; Gruerrier, L.; Husson,
H.P. J. Org. Chem. 1986, 51, 4475
Marco, J.L.; Royer, J.; Husson, H.P. Synth.
Commun. 1987, 17, 669
Polniaszek, R.P.; Belmont, S.E. J. Org. Chem.
1990, 55, 4688
Vidal, L.; Royer, J.; Husson, H.P. Tetrahedron Lett.
1995, 36, 2991
PCT Int. Appl. 85, 00,605 1985; Chem. Abstr. 104,
110018k
Osby, J.O.; Heinzman, S.W.; Ganem, B. J. Am.
Chem. Soc. 1986, 108, 67; Chem. Abstr. 104,
50458s
*For Online Consulting Only
press <CTRL>-F for Searching
100
Rohm and Haas : the Sodium Borohydride Digest
NITRO COMPOUNDS
Alembic: 4, 6, 9, 48, 51, 52, 61
Under normal conditions, NaBH4 does not
reduce the nitro group, except in a few aromatic nitro
compounds. For example, nitroanthraquinones are
reduced to the corresponding amines in 65 to 100 %
yield (1) in H2O, alcohols, aqueous DMF and THF.
Reduction to the amine has also been reported for the 2carbenthoxyindole derivatives (2).
Ordinarily, aliphatic nitro compounds are not reactive
with NaBH4, and the reduction of nitrobenzene
generally results in a number of products, e.g. azo,
azoxy, hydrazo derivatives and aniline (3,4).
In the presence of thiols, NaBH4 reduces nitro groups to
amine, hydroxylamines, azo and azoxy compounds, and
the activity is attributed to the thiolate derivatives (5).
A number of transition metal complexes have
been reported to catalyze the borohydride reduction of
nitro compounds, e.g., PdCl2(N-methylpyrrolidinone)2
(6), K2Ni(CN)4 (7), NiX2P2(8), and Co(NH3)6 3+ (9),
MoO3 (10).
NaBH4 can also convert a number of aromatic
nitro compounds to the amines in the presence of
palladium on charcoal (11-16). Cobalt and nickel
borides, generated from Co(II) and Ni(II) salts and
*For Online Consulting Only
press <CTRL>-F for Searching
101
NaBH4 are extremely effective in catalyzing the reduction of
nitro compounds to amines (17-20).
It has been reported that copper (I) acetate will reduce
aromatic nitro compounds in ethanol. (21) Other copper (I)
complex such as CuBr•SMe2 in methanol at RT have also been
demonstrated to reduce aromatic nitro compounds in the
presence of halides, alkoxides and amines. (22) Potassium
borohydride with CuCl will reduce aromatic nitro compounds
to amines at RT. (23)
Aromatic nitro groups can also be selectively reduced
to amino compounds by sulfurated sodium borohydride,
NaBH2S3, prepared by the reaction between sulfur and NaBH4
in dry THF (24,25)
Sato has found (26) that SnCl2•2 H2O and NaBH4 in
ethanol reduces aromatic nitro compounds selectively in the
presence of other functional groups, such as ester, chloro,
nitrile and olefinic bonds.
Bismuth trichloride or SbCl3 with either sodium or
potassium borohydride will reduce both aromatic and aliphatic
nitro compounds to their corresponding amine in the presence
of nitrile, chloride amine, hydroxy and alkoxy groups at
elevated temperatures.( 27,28,29,30) The use of bismuth
trichloride as a catalytic crosscoupling reagent of two aromatic
nitro molecules to a azobenzene compound at RT has been
demonstrated.
This reaction will not effect ester, nitrile,
chloride, hydroxy and alkoxy groups. (31)
Rohm and Haas : the Sodium Borohydride Digest
The addition of selenium metal to sodium
borohydride to form a Lancette type reagent that
reduces aromatic nitro compounds to aromatic amines.
(32)
Sodium borohydride with catalytic amounts of
sodium methoxide will reduce nitro groups on
imidazoles, pyrazoles or pyridine rings at RT. (33)
α−β unsaturated nitroalkenes can be reduced to
a ketone group with NaBH4 and hydrogen peroxide at
RT. Under these reaction conditions will not effect
acetal, ester or olefinic groups. (34)
Sodium borohydride with ammonium sulfate in
ethanol will reduce aromatic nitro compounds in less
then an hour. This methodology is chemoselective and
will not reduce nitrile, ester, carboxylic acid, halide and
olefinic groups. (35 )
Borohydride exchange resins spiked with Ni
acetate will reduce aliphatic and aromatic nitro
compounds at RT in MeOH. (36)
The nickel complexes anchored to a polymer
backbone with NaBH4 can reduce nitrobenzene to
analine. (37).
It has been demonstrated that sodium
borohydride in refluxing diglyme can reduce
nitrobenzene to analine in quantitative yields if
*For Online Consulting Only
press <CTRL>-F for Searching
102
ammonium chloride is added to the reaction as a proton
donor.(38)
References:
1) Morley, J.O. Synthesis 1976, 8, 528; Chem. Abstr. 85,
177120v
2) Nantko-Namirski, P.; Ozdowska, Z. Acta Pol Pharm.
1975, 32, 273; Chem. Abstr. 84, 17065g
3) Panson, G.S.; Weill, C.E. J. Org. Chem. 1956, 21, 803;
Chem. Abstr. 51, 7320a
4) Nose, A.; Kudo, T. Yakugaku Zasshi 1977, 97, 116;
Chem. Abstr. 86, 170979u
5) Maki, Y.; Sugiyama, H.; Kikucki, K.; Seto, S. Chem. Lett.
1975, 1093; Chem. Abstr. 83, 192711r
6) Nazarova, N.M.; Opyttsev, Y.A.; Shcherbakova, S.I.;
Freidlin, L. K. Izv. Akad. Nauk SSSR, Ser. Khim. 1975,
2589; Chem. Abstr. 84, 43501r
7) Hanaya, K.; Kudo, H.; Hara, T.; Fujita, N.; Iwase, A.
Yamagata Daigaku Kiyo Shizen Kagaku 1974, 8, 397;
Chem. Abstr. 81, 169229q
8) Hanaaya, K.; Fujita, N.; Kudoi, H. Chem. Ind. 1973, 794;
Chem. Abstr. 79, 125994q
9) Arai, Y. et. al. Nippon Kagaku Kaishi 1972, 194; Chem.
Abstr. 76, 85484c
10) Yanada, K.; Yanada, R.; Meguri, H. Tetrahedron Lett.
1992, 1463
Rohm and Haas : the Sodium Borohydride Digest
11) Neilson, T.; Wood, H.C.S.; Wylie, A.G. J. Chem.
Soc. 1962, 371; Chem. Abstr. 56, 15391b
12) Hahn, R.C.; Johnson, R.P. J. Am. Chem. Soc. 1977,
99, 1508; Chem. Abstr. 86, 170495h
13) Billing, M.J.; Baker, E.W. Chem. Ind. 1969, 654;
Chem. Abstr. 71, 22123k
14) Coutts, R.T.; El-Hawari, A.M. Can. J. Chem. 1975,
53, 3637; Chem. Absrt. 84, 105464s
15) Numazawa, M.;Kimura, K. Steriods 1983, 41, 675;
Chem. Abstr. 100, 68583f
16) Walker, T.E.; Matheny, C.; Storm, C.B.; Hayden,
H. J. Org. Chem. 1986, 51, 1175; Chem. Abstr.
104, 168804e
17) Wade, R.C.; Holah, D.G.; Hughes, A.N.; Hui, B.C.
Catal. Rev. Sci. Eng. 1976, 14, 211; Chem. Abstr.
86, 22275w
18) Nose, A.; Kudo, T. Chem. Pharm. Bull. 1981, 29,
1159; Chem. Abstr. 95, 132421j
19) Ger. Offen. 3,309,493 1984; Chem. Abstr. 102,
95892d
20) Osby, J.O.; Ganem, B. Tetrahedron Lett. 1986, 27,
1205; Chem. Abstr. 105, 23917e
21) Drouin, J.; Gauthier, S.; Patricola, O.; Lanteri, P.;
Longeray, R. Synlett 1993, 791
22) Patel, H.V.; Vayas, K.A. Org. Prep. Proc. Int.
1995, 27, 81
*For Online Consulting Only
press <CTRL>-F for Searching
103
23) He, Y.; Zhao, H.; Pan, X.; Wang, S. Synth. Commun.
1989, 19, 3047
24) Lalancette, J.M.; Brindle, J.R. Can. J. Chem. 1971, 49,
Chem. Abstr. 151488q
25) Jpn. Kokai Tokkyo Koho 85, 152, 497 1985; Chem.
Abstr. 104, 69119d
26) Satoh, T.; Mitsuo, N.; Nishiki, M; Inoue, Y.; Ooi, Y.
Chem. Pharm. Bull. 1981, 29, 1443; Chem. Abstr. 95,
97224y
27) Ren, P.; Pan, S.F.; Dong, T.W.; Wu, S.H. Chin. Chem.
Lett. 1995, 6, 553; Chem. Abstr 123 313453
28) Ren, P.; Pan, S.F.; Dong, T.W.; Wu, S.H. Synth. Commun.
1995, 25, 3799
29) Borah, H.N.; Prajapati, D.; Sandhu, J.S. J. Chem. Res. (s)
1994, 228
30) Pan, S.F.; Ren, P.D.; Dong, T.W. Chinese Chem. Lett.
1996, 7, 981
31) Ren, P.; Pan, S.; Dong, T.; Wu, S. Synth. Commun. 1996,
26, 3903
32) Shao, J.G.; Wang, L.C.; Zheng, M.; Zhong, Q. Chinese
Chem Lett. 1997, 8, 683
33) Suwinski, J.; Wagner, P.; Holt, E.M. Tetrahedron 1996,
52, 9541
34) Ballini, R.; Bosica, G. Synthesis 1994, 723
35) Gohain, S.; Prajapati, D.; Sandhu, J.S. Chem. Lett. 1995,
72
Rohm and Haas : the Sodium Borohydride Digest
36) Yoon, N.M.; Choi, J. Synlett 1993, 135
37) Loubinoux, B.; Chanot, J.J.; Caubere, P. J.
Organomet. Chem. 1975, 88, C4; Chem. Abstr. 83,
27763b
38) Yang, C.M.; Pittman, Jr. C.U. Synth. Commun.
1998, 28, 2027
*For Online Consulting Only
press <CTRL>-F for Searching
104
NaBH4
The conversion of the nitroso group to the
hydroxylamine has been reported with NaBH4 in the
absence of a catalyst (1).
N
OH
Transition metal complexes also catalyze the
reduction, e.g. bis(dimethylglyoximato)cobalt(2), or
palladium on charcoal (3,4).
O
N
N
N
N
47 %
NaBH4
NO
Co(DMGH)2
NH2
*For Online Consulting Only
Pd/C
NO
NaBH4
H
NMe2
NMe2
NITROSO COMPOUNDS
ON
105
press <CTRL>-F for Searching
Rohm and Haas : the Sodium Borohydride Digest
41 %
12 %
NH2
Nitroso reduction to the corresponding amine has
been reported in the case of the anticancer drug methyl CCNU,
in which a nitrourea is reduced to a semicarbazide by NaBH4
(5).
The reduction of nitrosamine Æ amine can be
accomplished in high yields using borohydride exchange
resins spiked with CuI- sulfate in methanol at 0oC. (6)
References:
1) Patrick, T.B.; Schield, J.A.; Kirchner, D.G. J. Org. Chem.
1974, 39, 1758; Chem. Abstr. 81, 25235r
2) Green, M.; Swinden, G. Inorg. Chim. Acta. 1971, 5, 49;
Chem. Abstr. 75, 34882c
3) Neilson, T.; Wood, H.C.S.; Wylie, A.G. J. Chem. Soc.
1962, 371; Chem. Abstr. 56, 15391b
4) Goodman, M.M.; Knapp, F.F. J. Org. Chem. 1982, 47,
3004; Chem. Abstr. 97, 38614u
5) Caddy, B.; Idowu, O.R. Analyst 1982, 107, 550; Chem.
Abstr. 97, 103741z
Rohm and Haas : the Sodium Borohydride Digest
6) Lee, S.Y.; Sim, T.B.; Yoon, N.M. Bull. Korean
Chem. Soc. 1997, 18, 1127
*For Online Consulting Only
press <CTRL>-F for Searching
106
OXIMES
Alembic 8, 50
The reduction of oximes may give amines,
hydroxylamines or alcohols. Thus, ketoximes are
reduced to the primary amines (1).
O
N
R
OH
OH
NaBH4
Me
H
N H
R
S
NOH
S
NHBz HO
S
NaBH4
OH
NHBz
S
OH
*For Online Consulting Only
O
NaBH4
N
R' R"CO2H
N
OH
O
OH
OH
Me
NHBz
Partial reduction of an oxime may also afford a
hydroxylamine; this can be achieved effectively by using
NaBH4 in carboxylic acid (4).
R
Reductive hydrolysis of oximes generally
produces the corresponding alcohols (2,3).
NHBz HO
107
press <CTRL>-F for Searching
Rohm and Haas : the Sodium Borohydride Digest
HO
R
HO
NaBH4
N
R"
R'
N
R"
R"CO2H
The reaction appears to be general for aldoximes and
ketoximes, except for bezophenone oxime and bibenzyl
ketoxime, among a number of compounds studied.
An interesting report shows that NaBH4 absorbed on
Al2O3 or silica gel effectively reduces oximes to
hydroxylamines in benzene (5).
Sulfurated sodium borohydride, NaBH2S3 (6-8) and
NaBH4 in the presence of NiCl2 or MoO3 (9) have been used to
reduce oximes to the amine. Sodium cyanoborohydride is
often used to reduce oximes to hydroxylamines (10-12).
Rohm and Haas : the Sodium Borohydride Digest
Borohydride exchange resins spiked with
nickel acetate have reduced aromatic oximes to amines
in MeOH at RT. (13)
Borane produced by the reaction of sodium
borohydride with I2 or H2SO4 in THF at 0o C to reduce
o-acyl oximes to amines. (14,15)
Metal complexes such as ZrCl4, FeCl3 and
SnCl4 have been shown to reduce asymmetric o-oximes
to amines in high yields under mild reaction conditions.
(16,17)
Lithium borohydride as been shown to reduce
oximes to hydroxy amines at RT in THF. (18) While
amino oximes have been reduced to amino nitriles in
refluxing acetonitrile. (19)
References:
1) Seelkopt, C. Rev. Fac. Farm. Univ. Los Andes
1974, 15, 157; Chem. Abstr. 83, 78998q
2) Mikhno, S.D.; et. al. Zh. Org. Khim. 1977, 13, 175;
Chem. Abstr. 86, 171291a
3) Nazir, M.; Kreiser, W.; Inhoffen, H.H. Synthesis
1977, 466; Chem. Abstr. 87, 133228y
4) Gribble, G.W.; Leiby, R.W.; Sheehan, M.N.
Synthesis 1977, 856; Chem. Abstr. 88, 89018z
5) Ciurdaru, V.; Hodosan, F. Rev. Roum. Chim. 1977,
22, 1027; Chem. Abstr. 87, 201881h
*For Online Consulting Only
press <CTRL>-F for Searching
108
6) Lalancette, J.M.; Brindle, J.R. Can. J. Chem. 1970, 48,
735; Chem. Abstr. 72, 110402b
7) Jpn. Kokai Tokkyo Koho 79 119,485 1979; Chem. Abstr.
92, 128979t
8) Jpn. Kokai Tokkyo Koho 81, 122,386 1981; Chem. Abstr.
96, 122832a
9) Ipaktschi, J. Chem. Ber. 1984, 117, 856; Chem. Abstr.
101, 22611f
10) Baldwin, J.WE.; Kruse, L.I.; Cha, J.K. J. Am. Chem. Soc.
1981, 103, 942; Chem. Abstr. 94, 121385d
11) U.S. 4,312,887 1982; Chem. Abstr. 96, 142446f
12) Tsuchiya, T.; Nakano, M.; Torii, T.; Suzuki, Y.;
Umezawa, S. Carbohydrate. Res. 1985, 136, 195; Chem.
Abstr. 103, 123834c
13) Badgar, B.P.; Nikat, S.M.; Wadgaonkar, P.P. Synth.
Commun. 1995, 25, 863
14) Barby, D.; Champagne, P. Synth. Commun. 1995, 25,
3503
15) U.S. 5,200,561 1993
16) Itsuno, S.; Sakurai, Y.; Shimizu, K.; Ito, K. J. Chem. Soc.,
Perkin Trans. 1 1990, 1859
17) Itsuno, S.; Sakurai, Y.; Shimizu, K.; Ito, K. J. Chem. Soc.,
Perkin Trans. 1 1989, 1548
18) Cho, B.T.; Seong, S.Y. Bull. Korean Chem. Soc. 1988, 9,
322
Rohm and Haas : the Sodium Borohydride Digest
19) Petukhov, P.A.; Tkachev, A.V. Tetrahedron 1997,
53, 2535
*For Online Consulting Only
press <CTRL>-F for Searching
109
Rohm and Haas : the Sodium Borohydride Digest
QUATERNARY COMPOUNDS
Alembic: 15, 28
A wide variety of cyclic quaternary ammonium
salts containing >C=N+< unsaturations have been
reduced with NaBH4, including pyridinum (1-7)
pyrazinium (8,9), pyrazolium (10,11), isoquinolinium
(12,13,14), quinolium (15,16), pyroliumum (17),
Pyoladine (18), oxazolium(19,20,21), thiazolium
(22,23), and indoloquinolizium (24,25) in these the
>C=N+< is effectively hydrogenated to the amine. One
of the most interesting reactions of this type is the
complete reduction of quaternized 4-aminopyridines to
the 4-aminopiperidines (26), and the reduction of
oxidopyrazinium iodides to 1-hydroxypiperazines (8),
OH
O
N
Me
Me
N+
N
Me
Me
Similar results are reported for ternary oxonium salts,
e.g., substituted are reported for tenary oxonium salts, e.g. 2substituted 1,3-benzoathiolylium salts (27), and pyrylium salts
(28,29).
R
R
NaBH4
N+
N
R
R
a reduction impossible to carry out by catalytic
hydrogenantion.
*For Online Consulting Only
O
O
+
NaBH4
N
NaBH4
NH2
NH2
110
press <CTRL>-F for Searching
R'
R'
R
O
R'
Thiopyrylium salts (solfonium compounds) (30) are
reduced in a similar manner.
Rohm and Haas : the Sodium Borohydride Digest
NO2
S
S
+
NaBH4
S
NO2
S
Even nitrilium salts (-C+N-R), by way of imino ester [C(OR’)=N-R], are reduced in good yield to the
secondary amine (31).
Iminium
salts
have
been
reduced
stereoselectively with sodium borohydride. (32,33,34)
Trimethyl propogyl ammonium iodide can be reduced
with sodium borohydride to an alkene and isopropyl
alcohol in high yield (35)
Nickel (II) chloride with sodium borohydride
can reduce quartarnary ammonium salts in high yields
(36).
*For Online Consulting Only
press <CTRL>-F for Searching
111
Alkaloids have been synthesized by reducing quarternary
ammonium salts with sodium borohydride. (37)
References:
1) Knaus, E.E.; Redda, K. J. Heterocycl. Chem. 1976, 13,
1237; Chem. Abstr. 86, 155471d
2) Boulton, A.J.; Epsztajn, J.; Katritzky A.R.; Nie, P.
Tetrahedron Lett. 1976, 2689; Chem. Abstr. 86, 55248t
3) Lyle, R.E.; Krueger, W.E; Gunn, V.E. J. Org. Chem.
1983, 48, 3574; Chem. Abstr. 99, 139723a
4) Gessner, W.; Brossi, A.; Chen, R.S.; Fritz, R.R.; Abell,
C.W. Helv. Chim. Acta 1984, 67, 2037; Chem. Abstr.
102, 166584t
5) Jpn. Kokai Tokkyo Koho 85, 228,460 1985; Chem. Abstr.
104, 148756n
6) Park, K.K.; Han, D.; Shin, D. Bull. Korean Chem. Soc.
1986, 7, 201
7) Burge, J.R.; Prey, P.A. J. Org. Chem. 1996, 61, 530
8) Ohta, A.; Matsunaga, M.; Iwata, N.; Watanabe, T.
Heterocycles 1977, 8, 351; Chem. Abstr. 88, 74373n
9) Bryce, M.R.; Eaves, J.G.; Parker, D.; Howard, J.A.K.;
Johnson, O. J. Chem. Soc., Perkin Trans 2 1985, 433;
Chem. Abstr. 103, 5770f
10) Omar, N.M.; Bayomi, S.M. Egypt. J. Pharm. Sci. 1975,
16, 49; Chem. Abstr. 87, 682226e
Rohm and Haas : the Sodium Borohydride Digest
11) Elguero, J.; Jacquier, R.; Mignonac-Mondon, S.
Bull. Soc. Chim. Fr. 1972, 2807; Chem. Bastr. 78,
29668v
12) Kasmetani, RT.; Okawara, T. J. Chem. Soc. Perkin
Trans. 1 1977, 579; Chem. Abstr. 87, 39710c
13) Sigh, H.; Kumar, K.S. J. Chem. Sci. 1975, 1, 18;
Chem. Abstr. 85, 192683z
14) Ger. Offen. 3,244,594 1984; Chem. Abstr. 101,
151766j
15) Sharma, N.D.; Goyal, V.K.; Joshi, B.C. Croat.
Chem. Acta 1976, 48, 317; Chem. Abstr. 86,
106326b
16) Verma, P.N.; Sharma, N.D.; Goyal, V.K.; Joshi,
B.C. Acta Cienc. Indica Chem. 1980, 6, 213; Chem.
Abstr. 95, 80686c
17) Zoltewicz, J.A.; Dill, C.D.; Abboud, K.A. J. Org.
Chem. 1997, 62, 6760
18) Seeman, J. Synthesis 1977, 498; Chem. Abstr. 87,
151934e
19) Zoretic, P.A.; Branchaud,B.; Sinha, N.D. J. Org.
Chem. 1977, 42, 3201; Chem. Abstr. 87, 151923a
20) Leed, A.R.; Boettger, S.D.; Ganem, B. J. Org.
Chem. 1980, 45, 1098; Chem. Abstr. 92, 198143q
21) Alberola, A.; Gonzalez,A.M.; Laguna, M.A.;
Pulido, F. J. Synthesis 1982, 1067; Chem. Abstr.
98, 179256m
*For Online Consulting Only
press <CTRL>-F for Searching
112
22) Hori, M.; Kataoka, T.; Shimizu, H.; Imai, Y. Fujimura, H.
Yakugaku Zasshi 1975, 95, 634; Chem. Abstr. 83,
193149a
23) Calrke, G.M.; Sykes, P. J. Chem. Soc. (C) 1967, 1269;
Chem. Abstr. 67, 72972z
24) Oehl, R.; Lenzer, G.; Rosenmund, P. Chem. Ber. 1976,
109, 705; Chem. Abstr. 84, 121687x
25) Hung. Teljes 27,692 1983; Chem. Abstr. 100, 192140y
26) Walker, G.N. J. Org. Chem. 1961, 26,2740; Chem. Abstr.
55, 27301I
27) Degani, I; Fichi, R J. Chem. Soc., Perkin Trans 1 1976,
323; Chem. Abstr. 84, 121361m
28) Safieddine, A.; Royer,J.; Dreux, J. Bull. Soc. Chim. Fr.
1972, 2510; Chem. Abstr. 77, 151294q
29) Muljiani, Z; Talik, B.D. Indian J. Chem. 1969, 7, 28;
Chem. Abstr. 70, 87449v
30) Iddon, B.; Suschitzky, H.; Taylor, D.S.; Chippendale, K.E.
J. Chem. Soc., Perkin Trans 1 1974, 2500; Chem. Abstr.
82, 111966g
31) Borch, R.F. J. Org. Chem. 1969, 34, 627; Chem. Abstr.
70, 106088v
32) Poliaszek, R.P.; Kaufman, C.R. J. Am. Chem. Soc. 1989,
111, 4849
33) Sassaman, Tetrahedron, 1996, 52, 10835
34) Pewarson, W.; Fang, W.K. J. Org. Chem. 1995, 60, 4960;
Chem. Abstr. 123 313721
Rohm and Haas : the Sodium Borohydride Digest
35) Gupton, J.T., Layman, W.J. J. Org. Chem. 1987,
52, 3683
36) Roberts, D.; Jopule, J.A.; Bos, M.A.; Alvarez, M. J.
Org. Chem. 1997, 62, 568
*For Online Consulting Only
press <CTRL>-F for Searching
113
(including several cyclopropenyl derivatives) (7-14) as well as
the synthesis of specific isotopically labeled compounds:
E. Miscellaneous Organic Reductions
CARBONIUM IONS
H
Alembic: 6
C+
A variety of carbonium ions (R3C+) including
aryl carbonium (1-6). Cyclopropenium (7-10), vinyl
carbonium (>C=C-R2) (11-13) and heteroatoms
stabilized carbonium ions (14-18) have been reduced
with sodium borohydride to the parent hydrocarbons
(R3CH):
(C6H5)3C+Cl- + NaBH4 Æ(C6H5)3CH
H
C+
R'
H
NaBH4
C
H
H+
C
C
H
R'
R
R'
"R
ClO4-
NaBH4
R
R'
"R
R
H
C
H
H
C
R
This reduction has been useful for preparation
of specific pharmacologically interesting molecules
*For Online Consulting Only
114
press <CTRL>-F for Searching
Rohm and Haas : the Sodium Borohydride Digest
R'
ClO4R
H
NaBT4
C
R'
T
R
Via reduction of carbonium ion intermediates, several
workers have been able to trap these intermediates thus
substantiating specific reaction paths (11).
In systems where other nucleophiles are absent,
intensely colored carbonium ions such as malachite green (2)
and crystal violet (19) are rapidly reduced allowing their use
for determination of low concentrations of sodium
borohydride.
References:
1) Olkah, G.A. Svobada, J.J. J. Am. Chem. Soc. 1973, 95,
3794; Chem. Abstr. 97, 31150j
2) Bunton, C.A.; Huang, S.K.; Paik, C.H. J. Am. Chem. Soc.
1975, 97, 6262; Chem. Abstr. 83, 192173s
3) Bunton, C.A.; Huang, S.K.; Paik, C.H Tetrahedron Lett.
1976, 1445; Chem. Abstr. 85, 108063s
4) Gribble, G.W.; Leese, R.M.; Evan, B.E. Synthesis 1977,
172; Chem. Abstr. 86, 170986u
Rohm and Haas : the Sodium Borohydride Digest
5) Fry, A.J. et. al. Tetrahedron Lett. 1976, 4803;
Chem. Abstr. 87, 5056d
6) Buton, C.A.; Carrasco, N. Watts, W.E. J. Chem.
Soc., Chem. Commun. 1977, 529; Chem. Abstr. 87,
200400p
7) U.S. 3,654,324 1972; Chem. Abstr. 76, 153229a
8) Pawlowski, N.E.; Lee D.J.; Sinnhuber, R.O. J. Org.
Chem. 1972, 37, 3245; Chem. Abstr. 77, 164069
9) U.S. 3,699,146 1972; Chem. Abstr. 78, 57859b
10) Mata-Segreda, K.J.F.; Schowen, R.L. J. Org.
Chem. 1981, 46, 644; Chem. Abstr. 94, 833332z
11) Wigfield, D.C.; Feiner, S.; Taymaz, K. Tetrahedron
Lett. 1972, 895; Chem. Abstr. 76, 126140h
12) Hrazdina, G. Phytochemistry 1972, 11, 3491;
Chem. Abstr. 78, 43208b
13) Creary, X. J. Org. Chem. 1976, 41, 3734; Chem.
Abstr. 85, 176498n
14) Greenberg, S.; Moffatt, J.G. J. Am. Chem. Soc.
1973, 95, 4016; Chem. Abstr. 79, 42796a
15) Wudl, F. et. al. J. Org. Chem. 1974, 39, 3608;
Chem. Abstr. 82, 16720po
16) Stahl, I. Chem. Ber. 1985, 118, 3166; Chem. Abstr.
103, 215243n
17) Hirai, K.; Sugimoto, H.; Ishiba, T. J. Org. Chem.
1977, 42, 1543; Chem. Abstr. 86, 188865p
*For Online Consulting Only
press <CTRL>-F for Searching
115
18) Tobia, D.; Rickborn, B. J. Org. Chem. 1986, 51, 3849;
Chem. Abstr. 105, 208214s
19) Rudie, C.N.; Demko, P.R. J. Am. Oil Chem. Soc. 1979,
56, 520; Chem. Abstr. 90, 214801u
O
REDUCTIVE CLEAVAGES
X
R"
Y
NaBH4
EtOH
R'
R"
X
H
H
N
R
N
OH
R
N
H2N
OH
N
N
N
N
H2N
HO
CH3 N
H
(2)
N
N
H
N
H
N
HO
H
NaBH4
(3)
Reductive cleavages of imides (4-6) and decyanation
(7,8) have been reported:
O
O
R
O
NH
O
*For Online Consulting Only
O
NaBH4
X or Y = NR2, OR, SR
Reductive cleavage of one of the two alkylidene
carbonheteroatom bonds is generally effected in this
reduction. In many of the examples reported, the
functional groups containing the heteroatoms are part of
the same molecule (1), allowing for ring opening under
mild conditions, so as not to effect other functional
groups in the compound.
H
N
Sodium borohydride reductive cleavages or
hydride displacements, are known in several classes of
compounds. The most commonly employed reaction
involves the reductive cleavage of N, N’- N,O-, O,O’-,
N,S- linked alkylidene compounds:
R'
116
press <CTRL>-F for Searching
Rohm and Haas : the Sodium Borohydride Digest
NH2
NaBH4
(5)
R
O
O
press <CTRL>-F for Searching
Rohm and Haas : the Sodium Borohydride Digest
N
Ph
NaBH4
N
Ph
CN
(7)
H
Reductive cleavage with NaBH4 is a commonly used
method in the study of glycoproteins and related
compounds (9,12). IT has frequently been applied to
ring opening reactions of barituric acids (13,14), furans
(15,16), pyrans (17), oxazines (18), benzothiazoles (19)
and cyclic α-nitroketones (20). It also finds uses in
cleaving side chains of azeidine compounds (21,22).
Cyanoborohydride has been used to reductively
cleave N-O bonds (23) , while lithium borohydride (24)
and sodium borohydride (25) have been used to cleave
C-N bonds in high yields. Silicon oxygen bonds have
been reductively cleaved with tetrabutyl ammonium
borohydride (26) and C-O have been reduced to a
methyl and hydoxy group with sodium borohydride.
(27)
Sulfur Nitrogen bounds have been reductively
cleaved to form amine and thioketone groups. (28)
*For Online Consulting Only
117
References:
1) Shimizu, K.; Ito, K.; Sekiya, M. Chem. Pharm. Bull. 1974,
22, 1256; Chem. Abstr. 81, 120403c
2) U.S. 3,983,118 1976
3) U.S. 3,714,186 1973; Chem. Asbstr. 82, 170620m
4) Rautio, M. Farm. Aikak. 1974, 83, 131; Chem. Abstr. 82,
170620m
5) Parker, W.L.; Johnson, F. J. Org. Chem. 1973, 38, 2489;
Chem. Abstr. 79, 53201d
6) Jpn. Kokai Tokkyo Koho 84, 161,3445 1984; Chem.
Abstr. 102, 149102s
7) Jpn. 74 19,243 1974; Chem. Abstr. 82, 97816z
8) Takahashi, K.; Kurita, H.; Ogura, K.; Ida, H. J. Org.
Chem. 1985, 50, 4368; Chem.Abstr. 103, 178145j
9) Liao, M.J.; Huang, K.S.; Khorana, H.G. J. Biol. Chem.
1984, 259, 4200; Chem. Abstr. 100, 187575h
10) Sahimamura, M.; Inoue, Y., S. Arch. Biochem.. Biophys.
1984, 232, 699; Chem. Abstr. 101, 106875h
11) Ud-Din, N.; Jeanloz, R.W. et. al. J. Biol. Chem. 1986,
261, 1992; Chem. Abstr. 104, 166504h
12) Mawhinney, T.P. J. Chromatog. 1986, 351, 91; Chem.
Abstr. 104, 65133f
13) Rautio, M. Acta Chem. Scand. Ser. B. 1979, B33, 770;
Chem. Abstr. 93, 71685h
14) Rautio, M.; Heeso, A.; Rahkamaa, E. Arch. Pharm.
(weinheim) 1981, 314, 622; Chem. Abstr. 95, 114299w
Rohm and Haas : the Sodium Borohydride Digest
15) Jpn. Kokai Tokkyo Koho 79,109,972 1979; Chem.
Abstr. 92, 164251h
16) Eur. Pat. Appl. 153, 890 1985; Chem. Abstr. 104,
224716s
17) U.S. 4,199,515 1980; Chem. Abstr. 93, 95129f
18) Marco, J.L. Royer, J.; Husson, H.P. Tetrahedron
Lett. 1985, 26, 6345; Chem. Abstr. 105, 78464k
19) Liso, G.; Trapani, G.; Reho, A.; Latofa, A.
Synthesis 1985, 288; Chem. Abstr. 104, 88471d
20) U.S. 4,554,387 1985; Chem.Abstr. 104, 185986h
21) Eur. Pat. Appl. 62,876 1982; Chem. Abstr. 98,
107072e
22) Ger. Offen. 3,229,439 1983; Chem. Abstr. 99,
5435z
23) Wade, P.A.; Tao, J.A.; Bereznak, J.F.; Yuan, C.K.
Tetrahedron Lett. 1989, 30, 5969
24) Gupta, R.B.; Franck, R.W. J. Am. Chem. Soc. 1989,
111, 7668
25) Barluenga, J.; Kouznetsov, V.; Rubio, E.; Tomas,
M. Tetrahedron Lett. 1993, 34, 1981
26) Micouin, L.; Quirion, J.C.; Husson, H.P.
Tetrahedron Lett. 1996, 37, 849
27) Firouzabadi, H.; Afsharifar, G.R Synth. Commun.
1996, 26, 1065
28) Kim, H.K..; Lee, Y.Y.; Kim, K.; Kim, J.H. Bull.
Korean Chem. Soc. 1994, 15, 273
*For Online Consulting Only
press <CTRL>-F for Searching
118
119
press <CTRL>-F for Searching
Rohm and Haas : the Sodium Borohydride Digest
have been prepared by NaBH4 reductive cyclization of imines
(13-16).
REDUCTIVE CYCLIZATION
Several interesting reductive cyclization
involving sodium borohydride have been reported. For
instance, NaBH4 reduction of beta and gamma keto
(aldehydro) esters (or acids) yields lactone derivatives
in good yields (1-8):
R"
R"
NR'
N
O
CCl3
O
R
NaBH4
R
O
O
O
Reduction of aromatic beta and gamma keto acids leads
directly to lactone formation (9-12).
N
N
In contrast to the above, where only sodium
borohydride was employed to effect the reductive cyclization,
Coutts has used NaBH4 catalyzed by palladized charcoal to
prepare heterocyclic hydroamic acids, such as quinolones and
hydroxyquinolones (17,18) from o-nitro esters,
O
O
O
H
H
OH
R'
NaBH4
CN
R'
R'
OH NaBH4
R
"R
O
O
R
Similarly, quinazoline derivatives, many
showing anti-inflammatory and analgesic activities,
*For Online Consulting Only
CN
"R
NO2
NaBH4
CO2Et Pd/C
N
H
N
OH
O
CN
O
press <CTRL>-F for Searching
Rohm and Haas : the Sodium Borohydride Digest
and bezothiazine hydroamic acids and their lactams
from a-(o-nitrophenylthio) esters, acids and cinnamates
(19-21)
S
R'
"R CO R
2
NO2
R'
NaBH4
S
Pd/C
N
R"
O
OH
Recent
publications
include
reductive
cyclization of gamma imino compounds (22,23)
photocatalyzed NaBH4 cyclizations (24-27) and even
cyclization to form epoxides (28,29)
Organic compounds containing alkenes and
halides, tin trichlorides or hydrazones are reductively
cyclized with sodium borohydride or cyanoborohydride
to from cyclic hydrocarbons. (30,31,32 )
Cyclic amines can be formed by the reductive
amination/cyclization of ketones with amines or azides
with borohydrides.(33,34) The five membered rings
contained in Protocin C and D can be synthesized the
same methodology. (35). It has been demonstrated that
imines and O-mesty groups can be reductively cycilized
to form cyclic amines in high yields with NaBH in
MeOH (36). Other functional groups that have been
*For Online Consulting Only
120
used to form cyclic amines are amides and aldehydes. (37,38).
References:
1) Brownbridge, P.; Warren, S. J. Chem. Soc., Chem.
Commun. 1977, 465; Chem. Abstr. 88, 37213q
2) U.S. 4,031,113 1977; Chem. Abstr. 87, 135031c
3) Spry, D.O. J. Org. Chem. 1975, 40, 2411; Chem. Abstr.
83, 97171f
4) Jpn. Kokai Tokkyo Koho 83 13,572 1983; Chem. Abstr.
99, 38365e
5) Bates, H.A.; Deng, P-N. J. Org. Chem. 1983, 48, 4479;
Chem. Abstr. 99, 212331c
6) Jpn. Kokai Tokkyo Koho 83, 154,572 1983; Chem. Abstr.
100, 66612r
7) Rao, A.V.R.; Sreenivasan, N.; Reddy, D.R.; Deshpande,
V.H. Tetrahedron Lett. 1987, 27, 455
8) Lange, G.L.; Organ, M.G. J. Org. Chem. 1996, 61, 5358
9) Meyer , W.L.; Vaughn, W.R. J. Org. Chem. 1957, 22, 98;
Chem. Abstr. 51, 11316g
10) Cava, M.P.; Van Meter, J. P. J. Org. Chem. 1969, 34, 538;
Chem. Abstr. 70, 106288k
11) Oren, J.; Schleifer, L.; Shmueli, U.; Fuchs, B.
Tetrahedron Lett. 1984, 25, 981; Chem. Abstr. 101,
37932k
12) Newman, M.S.; Dhawan, B.; Khanna, V.K. J. Org. Chem.
1986, 51, 1631; Chem. Abstr. 104, 206875p
Rohm and Haas : the Sodium Borohydride Digest
13) Jpn. Kokai 72 14,183 1972; Chem. Abstr. 77,
140123g
14) Ger.Offen 2,166327 1973; Chem. Abstr. 84,
180271e
15) Walser, A. et. al. J. Org. Chem. 1978, 43, 936;
Chem. Abstr. 88, 12122s
16) U.S. 3,895,032 1975; Chem. Abstr. 83, 193094d
17) Coutts, R.T.; Wibberley, D.G.; J. Chem. Soc. 1963,
4610; Chem. Abstr. 59, 12799e
18) Coutts, R.T. J. Chem. Soc. C 1969, 713; Chem.
Abstr. 70, 96351j
19) Coutts, R.T. et. al. Can. J. Chem. 1965, 43, 3221;
Chem. Abstr. 64, 5083b
20) Coutts, R.T. et. al. Can. J. Chem. 1966, 44, 1733;
Chem. Abstr. 65, 8810d
21) Coutts, R.T. et. al. Can. J. Chem. 1967, 45, 975;
Chem. Abstr. 67, 11467s
22) U.S. 4,229,455 1980; Chem. Abstr. 94, 156906b
23) Jpn. Kokai Tokkyo Koho 83 41,864 1983; Chem.
Abstr. 101, 91321y
24) Ninomyia, I.; Hashimoto, C.; Kiguchi, T.; Naito, T.
J. Chem. Soc., Perkin Trans. 1 1985, 941; Chem.
Abstr. 103, 160747x
25) Jpn. Kokai Tokkyo Koho 84, 53, 485 1984; Chem.
Abstr. 101, 91321y
*For Online Consulting Only
press <CTRL>-F for Searching
121
26) Jpn. Kokai Tokkyo Koho 85 56,978 1985; Chem. Abstr.
103, 160753w
27) Naito, T.; Kojima, N.; Miyata, O.; Ninomiya, I. J. Chem.
Soc., Chem. Commun. 1985, 1611; Chem. Abstr. 104,
225079y
28) Zhao, D.; Zhong, J. et. al. Yaoxue Xuebao 1982, 17, 28;
Chem. Abstr. 96, 199248x
29) Ger. Offen. 3,426,906 1986; Chem. Abstr. 105, 97473d
30) Stork, G.; Sher, P.M. J. Am. Chem. Soc. 1986, 108, 303
31) Hanessian, S.; Leger, R. J. Am. Chem. Soc. 1992, 114,
3115
32) Taber, D.F.; Wang, Y.; Stachel, S.J. Tetrahedron Lett.
1993, 34, 6209
33) Manescalchi, F.; Nardi, A.R.; Savoia, D. Tetrahedron
Lett. 1994, 35, 2775
34) McClure, C.K.; Mishra, P.K.; Grote, C.W. J. Org. Chem.
1997, 62, 2437
35) Heathcock, C.H.; Brown, R.C.D.; Norman, T.C. J. Org.
Chem. 1998, 63, 5013
36) Aelterman, W.; De Kiompe, N.; Declercg, J. Org. Chem.
1998, 63, 6
37) Wang, X.; De Silva, S.O.; Reed, J.N.; Billadeau, R.;
Griffen, E.J.; Chan, A.; Snieckus, V. Org. Synth. 1993, 72,
163
38) Dinsmore, C.J.; Ingman, J.M. J. Org. Chem. 1998, 63,
4131
Rohm and Haas : the Sodium Borohydride Digest
DEHALOGENANTIONS
Alembic: 9, 52, 55, 61
Under normal reaction conditions, alkyl and
aryl halides are inert to NaBH4. Under solvolytic
conditions, however, secondary and tertiary alkyl
halides which are capable of forming stable carbonium
ions are reducible to the corresponding hydrocarbon (13).
Good to excellent yields are reported in
dehalogenantion of bezhydril chloride to diphenyl
methane, t-cumyl chloride to cumene and triphenyl
methyl chloride to triphenylmethane. (See also section
on carbonium ion reductions.)
In addition, several authors have reported
dehalogenantion of gem-dihalo compounds with sodium
borohydride (4,5).
New developments in the catalyzed NaBH4
reduction of halo compounds have broaden the
applicability of this reaction.(6-8) Photo-catalyzed
reduction of halogenated aromatic hydrocarbons has
been reported (9-11). Inorganic catalysts such as
palladium chloride or nickel chloride (in situ nickel
boride) have proven effective for site specific
deuteration of aryl halides (12,13), for dechlorination of
various pesticides and PCB’s (14-17) and for analytical
determination of organic solids bound halides (18,19).
*For Online Consulting Only
press <CTRL>-F for Searching
122
Dicyclopentadienyltitanium dichloride has also been used to
catalyze NaBH4 dehalogenantions (20). The combination of
triakly tin halides with NaBH4, in which the dehaolganting
agent is R3SnH has been used to advantage (21-23). Other
main group alkyl reagents can catalytically dehalogenate
aromatic and aliphatic halides with sodium borohydride. (24)
Tetrabutylamonnium borohydride can reduce
aromatic and aliphatic halogenated compounds in THF in high
yields. (25). PCB’s can be reduced in diglyme at elevated
temperatures with NaBH4 or NaBH4 and LiCl (26). LiBH4 can
dehalogenate both aromatic and aliphatic halides
chemoselectively. (27)
Alkyl halides are reduced with borohydride exchange
resins spiked with Ni(OAc)2 at room temperature.(28) Zinc
cyanoborohydride can dehalogenate both aromatic and
aliphatic halides at the reflux temperature of methanol. (29)
γ-Lindene and α-chlorotolulene can be completely
dehalogenated with NaBH2(OCH2CH2OCH3)2 at elevated
temperatures. (30) The addition of transition metal chlorides
to the above stated reagent such as PdCl2 and NiCl2 have
dehalogenated chlorophenols and chlorobenzenes. (31) Other
alkoxy borohydrides have declorinated PCB’s at the reflux
temperature of THF (32)
Recent applications include the preparation of tritium
labeled retinoic acid (33) CNS-active 2,3-dihydroergolines
(34) and triabicycloheptane substituted prostaglandin
Rohm and Haas : the Sodium Borohydride Digest
analogues (35), which are cardiovascular agents useful
in treating thrombotic disease.
Allylic chlorides have been dechlorinated with
sodium borohydride to form bucky ball type structures.
(36)
References:
1) Brown, H.C.; Bell, H.M.; J. Org. Chem. 1962, 27,
1928; Chem. Abstr. 57, 12353g
2) Bell, H.M.; Brown, H.C. J. Am. Chem. Soc. 1966,
88, 1473; Chem. Abstr. 64, 15695c
3) St. Clair, T.L.; Diss Abstr. Int. B 1972, 33, 200;
Chem. Abstr. 78, 57424f
4) Groves, J.T.; MA. K.W. J. Am. Chem. Soc.; 1974,
96, 6527; Chem. Abstr. 81, 151239h
5) Levitin, I.Y.; Dvoletski, M.; Volpin, M.E. Kinet.
Katal. 1972, 13, 690; Chem. Abstr. 77, 100449m
6) Schwartz, J.; Liu, Y.; J. Org. Chem. 1994, 59, 940
7) Schwartz, J.; Liu, Y. Tetrahedron 1995, 51, 4471
8) Cavallaro, C.L.; Liu, Y.; Schwartz, J.; Smith, P.
New J. Chem. 1996, 20, 253
9) Barltrop, J.A.; Bradbury, D. J. Am. Chem. Soc.
1973, 95, 5086; Chem. Abstr. 79, 85589c
10) Tsuijmoto, K.; Tasaka, S.; Ohashi, M. J. Chem.
Soc., Chem. Commun. 1975, 758; Chem. Abstr. 83,
192246t
*For Online Consulting Only
press <CTRL>-F for Searching
123
11) Abeywickrema, A.N.; Beckewith, A.L. J. Tetrahedron
Lett. 1986, 27, 109; Chem. Abstr. 105, 171926x
12) Bosin, T.R.; Raymond, M.G.; Buckpitt, A.R.; Tetrahedron
Lett. 1973, 4699; Chem. Abstr. 80, 120462a
13) Stiles, M. J. Org. Chem. 1994, 59, 5381
14) Dennis, W.H.; Cooper, W. J. Bull. Environ. Contam.
Toxicol. 1975, 14, 738; Chem. Abstr. 84, 100851f
15) Dennis, W.H.; Cooper, W. J. Bull. Environ. Contam.
Tpoxicaol. 1976, 16, 425; Chem. Abstr. 86, 66792s
16) U.S. Pat. Appl. 794,928 1986; Chem. Abstr. 104,229975k
17) Kozloski, R.J. J. Chromatr. 1985, 318, 211; Chem. Abstr.
102, 124849c
18) Lassova, L.; Lee, H.K.; Hor, T.S.A. J. Org. Chem. 1998,
63, 3538
18) Egil, R.A. Helv. Chim. Acta 1968, 51, 2090; Chem. Abstr.
70, 28501h
19) Egli, R.A. Z. Anal. Chem. 1969, 247, 39; Chem. Abstr. 71,
131377s
20) Meunier, B. J. Organomet. Chem. 1980, 204, 345; Chem.
Abstr. 94, 191816u
21) Parnes, H.; Pease, J. J. Porg. Chem. 1979, 44, 151; Chem.
Abstr. 90, 55156u
22) Corey, E.J.; Marfat, A.; Hoover, D. J. Tetrahedron Lett.
1981, 22, 1587; Chem. Abstr. 95, 114733h
Rohm and Haas : the Sodium Borohydride Digest
23) Gurjar, M.K.; Yadav, J.S.; Rama Rao, A.V. Indian
J. Chem. Sect. B 1983, 22b, 1139; Chem. Abstr.
101, 91377w
24) Nakamura, T.; Yorimitsu, H.; Shinokubo, H.;
Oshima, K. Synlett 1999, 1415
25) Narasimhan, S.; Swamalakshmi, S.; Balakumar, R.;
Velmathi, S. Synth. Commun. 1999, 29, 685
26) Yang, C.; Pittman, C.U. Tetrahedron Lett. 1997,
38, 6561
27) Cho, B.T.; Yoon, N.M. J. Korean Chem. Soc. 1983,
27, 46
28) Yoon, N.M.; Lee, H.J.; Ahn, J.H.; Choi, J. J. Org.
Chem. 1994, 59, 4687
29) Kim, S.; Kim, Y.J.; Ahn, K.H. Tetrahedron Lett.
1983, 24, 3369
30) Tabaei, S.M.H.; Pittman, C.U. Haz. Waste Haz.
Mater. 1993, 10, 431
31) Tabaei, S.M.H.; Pittman, C.U. Tetrahedron Lett.
1993, 34, 3263
32) Tabaei, S.M.H.; Pittman, C.U.; Mead, K.T. J. Org.
Chem. 1992, 57, 6669
33) Ger Offen. 3,142,975 1983; Chem. Abstr. 99,
71034u
34) Ger Offen. 3,411,981 1985; Chem. Abstr. 105,
43137d
33) U.S. 4,588,742 1986; Chem. Abstr. 105, 78746d
*For Online Consulting Only
press <CTRL>-F for Searching
34) Zhang, H.R.; Wang, K.K. J. Org. Chem. 1999, 64, 7996
124
press <CTRL>-F for Searching
Rohm and Haas : the Sodium Borohydride Digest
33), prostaglandin derivatives (19, 20,34,35), porphyrins
(36,37) and avermectins (38).
DEMERCURATIONS
The oxymercuration of olefinic bonds,
followed by reductive demercuartion with sodium
borohydride, is an extremely efficient method for the
stereoselective, high yield Markownikov hydration of
olefins: (1)
OH
Hg(OAc)2
R
CH2
R
THF/H2O
OH
HgOAc NaBH4
NaOH
H
H
R
H
This procedure originally developed by H.C. Brown et.
al. (2) has been the subject of two review articles (3,4).
The mechanism (5-8) and stereochemical
implication (9-12) of this reaction have been
investigated extensively. From extensions of this basic
reaction, new synthetic methods have been developed to
provide alkylation (13-16) and cyclization (17-20)
reactions,
peroxymercuration
(21,22),
aminomercuration (23-25) and azidomercuration (26).
Phase transfer catalysis (27-28) and micelle mediation
(29-30) have been applied to oxymercuration
demercuration reactions.
Demercuration with NaBH4 has found practical
applications in the synthesis of juvenile hormones (31*For Online Consulting Only
125
References:
1) Russell, G.A.; Jiang, W.; Hu, S.S.; Khanna. R.K. J. Org.
Chem. 1986, 51, 5499
2) Brown, H.C.; Geoghegan, P. J. Am. Chem. Soc. 1967, 89,
1522; Chem. Abstr. 67, 99540u
3) Lorock, C. Angew. Chem. Int. Ed. Engl. 1978, 17, 27
4) Seyferth, D. Organomet. Chem. Rev., Sec. B, Ann. Rev.
1971, 8, 425; Chem. Abstr. 76, 59682w
5) Quirk, R.P.; Lea, R.E. J. Am. Chem. Soc. 1976, 98, 5973;
Chem. Abstr. 85, 191940u
6) Pasto, D.J.; Gontarz, J. A. J. Am. Chem. Soc. 1971, 93,
6902; Chem. Abstr. 76, 33692z
7) Pasto, D.J.; Gontarz, J. A. J. Am. Chem. Soc. 1969, 91,
719; Chem. Abstr. 70, 67337d
8) Giese, B.; Kretzschmar, G. Chem. Ber. 1984, 117, 3175;
Chem. Abstr. 102, 61581m
9) Jasseerand, D. et. al. Tetrahedron 1976, 32, 1535; Chem.
Abstr. 86, 43091y
10) Kitching, W.; Atkins, A.R.; Wickham, G.; Albert, V. J.
Org. Chem. 1981, 46, 563; Chem. Abstr. 94, 83505h
11) Harding, K.E.; Marman, T.H. J. Org. Chem. 1984, 49,
2838; Chem. Abstr. 101, 72865n
Rohm and Haas : the Sodium Borohydride Digest
12) Gouzoules, F.H.; Whitney, R.A. J. Org. Chem.
1986, 51, 2024
13) Giese, B.; Meister, J. Chem. Ber. 1977, 110, 2588;
Chem. Abstr. 87, 133845x
14) Henning, R.; Uraback, H. Tetrahedron Lett. 1983,
24, 5343; Chem. Abstr. 100, 139572q
15) Barluenga, J.; Campos, P.J.; Lopez-Padro, J.;
Asensio, G. Synthesis 1985, 1985, 1125; Chem.
Abstr. 105, 171935z
16) Bellec, N.; Guillemin, J.C. Tetrahedron Lett. 1995,
36, 6883
17) Harding, K.E.; Burks, S.R. J. Org. Chem. 1981, 46,
3920; Chem. Abstr. 95,115183r
18) Carruthers, W.; Williams, M.J.; Cox, M.T. J. Chem.
Soc., Chem. Commun. 1984, 1235; Chem. Abstr.
102, 131883n
19) Jpn. Kokai Tokkyo Koho 84 10,577 1984; Chem.
Abstr. 101, 90657a
20) Jpn. Kokai9 Tokkyo Koho 85, 243,079 1985;
Chem. Abstr. 104, 207038e
21) Bloodworth, A.J.; Courtneidge, J.L. J. Chem. Soc.,
Perkin Trans. 1 1982, 1807; Chem. Abstr. 97,
198305x
22) Corey, E.J.; Schmidt, G.; Shimoji, K. Tetrahedron
Lett. 1983, 24, 3169; Chem. Abstr. 100, 34340j
*For Online Consulting Only
press <CTRL>-F for Searching
126
23) Barluenga, J.; Perez-Prieto, J. Bayon, A.M.; Asensio, G.
Tetrahedron 1984, 40, 1199; Chem. Abstr. 101, 171056f
24) Davtyan, S.Z.; Badanyan, S.O. Arm. Khim. Zh. 1983, 36,
508; Chem. Abstr. 100, 67447c
25) Roubaud,V.; Le Moigne, F.E.; Mercier, A.; Mordo, P.
Synth. Commun. 1996, 26, 1507
26) Grunewald, G.L.; Bartlett, W.J. et. al. J. Med. Chem.
1986, 29, 1972; Chem. Abstr. 105, 225990j
27) Rolla, F. J. Org. Chem. 1981, 46, 3909; Chem. Abstr. 95,
114927z
28) Barluenga, J.; Lopez-Prado, J.; Campos, P.J.; Asensio G.
Tetrahedron 1983, 39, 2863; Chem. Abstr. 100, 68122e
29) Link, C.M.; Jansen, D.K.; Sukenik, C.N. J. Am. Chem.
Soc. 1980, 102, 7798; Chem. Abstr. 94, 30237r
30) Sutter, J.K.; Sukenik, C.N. J. Org. Chem. 1984, 49, 1295;
Chem. Abstr. 100, 138928y
31) U.S. 3,923,868 1975; Chem. Abstr. 84, 58672w
32) Camps, F.; Coll, J.; Seba, M.E. An. Quim. 1979, 75, 401;
Chem. Abstr. 91, 210947u
33) Tolstikov, G.A.; Rozenstsvet, O.A. Izv, Akad. Nauk SSSR,
Ser. Khim. 1984, 816; Chem. Abstr. 101, 170676w
34) Corey, E.J.; Kewck, G.E.; Szekely, I J. Am. Chem. Soc.
1977, 99, 2006; Chem. Abstr. 86, 189264d
35) Suzuki, M.; Yanagisawa,A.; Noyori, R. Tetrahedron Lett.
1983, 24, 1187; Chem. Abstr. 99, 70430h
Rohm and Haas : the Sodium Borohydride Digest
36) Smith, K.M.; Langry, K.C. J. Org. Chem. 1983, 48,
500; Chem. Abstr. 98, 89036k
37) Smith, K.M.; Langry, K.C.; Minnetian, O.M. J.
Org. Chem. 1984, 49, 4602; Chem. Abstr. 101,
230212d
38) U.S. 4,423,209 1983; Chem. Abstr. 100, 175208j
*For Online Consulting Only
press <CTRL>-F for Searching
127
128
press <CTRL>-F for Searching
Rohm and Haas : the Sodium Borohydride Digest
DOUBLE BONDS
Olefinic bonds are reducible by sodium
borohydride only when activated. Any functional group
which sufficiently polarizes the double bond can
activate this group for borohydride reduction. Several
classes of activated double bonds have been reported
including: α−β unsaturated nitriles (1-4), aldehydes,
ketones (5), nitro (6,8), esters (9-11) and lactones
(12,13): carbon-carbon double bonds alpha to an aryl
ring (14,15); unsaturated amines (e.g. enamines 16-21).
Several examples where activated double bonds have
been reduced are shown below:
R"
R"
N
N
NaBH4
N
N
(17)
R
R
N
N
R'
R'
O
O
O
O
O
O
O
NaBH4
O
O
O
(20)
NMe
NaBH4
HN
NMe
(16)
AcO
AcO
O2N
H
H
O2N C
H
C
NaBH4
HN
O
O
CO2R
*For Online Consulting Only
(22)
CO2R
O
R
O
NaBH4
NaBH4
R
O
O
OH
OH
hυ
(23)
H
129
press <CTRL>-F for Searching
Rohm and Haas : the Sodium Borohydride Digest
OH
R
H
HO
OH
This type of reaction is used to convert a
dihydropyridine to the tetrahydro from in the
manufacture of the substituted benzazocines (24) which
are used as analgesic agents.
Several authors have recently reported the use
of sodium borohydride for reduction of photo excited
aromatic compounds (25,26):
*For Online Consulting Only
OH
Catalyzed NaBH4 reduction of acetylenes to olefins
has also been reported (27-29).
Metal salt such as BiCl3, Cu2+, NiCl2 and CoCl2 have
been used to modify the reactivity of sodium borohydride so
that it can easily reduce olefins to alkanes. (30-35).
The use of low molecular weight alcohols and acetic
acids with sodium borohydride to promote the reduction of
alkenes to alkanes has been demonstrated. (36-38)
Zinc borohydride has been shown to reduce primary
nitroalkenes to nitroalkanes while converting disubstituted
nitroalkenes to oximes. (39,40)
Borohydride exchange resins in MeOH at RT have
reduced α−β unsaturated nitroalkenes to nitroalkanes in high
yields. (41). CuSO4 and borohydride exchange resins in
MeOH at RT reduces α−β unsaturated esters, amides, and
cyanides to their corresponding alkane.(42) Nickel chloride
Rohm and Haas : the Sodium Borohydride Digest
and borohydride exchange resins can reduce electron
deficient alkenes to alkanes in high yields.(43) Zinc
borohydride supported on aluminophosphates have
hydrogenated both aromatic alkenes and alkynes. (44)
Selective reduction of terminal over substituted
alkenes has been accomplished using calcium
borohydride and MeOH in THF at reflux temperatures.
(45)
The use of borane generated in situ using
sodium borohydride and I2 at 0o C has been shown to
reduce α−β keto alkenes to alkanes. (46)
References:
1) Pepin, Y.; Nazemi, H.; Payette, D. Can. J. Chem.
1978, 56, 41; Chem. Abstr. 89, 41994h
2) Toda, F.; Kanno, M. Bull. Chem. Soc. Jpn. 1976,
49, 2643; Chem. Abstr. 86, 55130y
3) Jung, M.E.; Lam, P.; Mansuri, M.M.; Speltz, L.M.
J. Org. Chem. 1985, 50, 1087; Chem. Abstr. 102,
148972p
4) Vartanyan, R.S.; Shaginyan, R.S. et. al. Arm. Khim.
Zh. 1985, 38, 304; Chem. Abstr. 105, 78803v
5) Formasier, R.; Lucchini, V.; Scrimin, P.; Tonellato,
U. J. Org. Chem. 1986, 51, 1769; Chem.Abstr. 104,
206747y
*For Online Consulting Only
press <CTRL>-F for Searching
130
6) Backman, G.B.; Maleski, R.J. J. Org. Chem. 1972, 37,
2810; Chem. Abstr. 104, 206747y
7) Varma, R.S.; Kabalka, G.W. Synth. Commun. 1985, 15,
151; Chem. Abstr. 103, 53338t
8) Bhattacharjya, A.; Mukhopasdhyay, R.; Pakrashi,S.C.
Synthesis 1985, 886; Chem. Abstr. 015, 42400x
9) Setoi, H.; Takeno, H.; Hashimoto, M. J. Org. Chem. 1985,
50, 3948; Chem. Abstr. 103, 1607842s
10) Wiunterfeldt, E.; Freund, R. Liebigs Ann. Chem. 1986,
1262; Chem. Abstr. 105, 60796k
11) Eur. Pat. Appl. 156,261 1985; Chem. Abstr. 104, 148757p
12) Chhowdhury, P.K.; Barua, N.C. et. al. J. Org. Chem.
1983, 48, 732; Chem. Abstr. 98, 143670c
13) El-Feraly, F.; Benigni, D.A.; McPhail, A.T. J. Chem. Soc.,
Perkin Trans 1 1983, 355; Chem. Abstr. 98, 215814c
14) Dauzonne, D.; Royer, R. Synthesis 1984, 1054; Chem.
Abstr. 103, 5956w
15) Kametani, T.; Yukawa, H.; Suzuki, Y.; Honda, T. J.
Chem. Soc., Perkin Trams. 1 1985, 2151; Chem. Abstr.
104,186682t
16) Kudo, T.; Nose, A.; Yakugaku Zasshiu 1974, 94, 1475;
Chem. Abstr. 82, 125255m
17) Swiss 593,965 1977; Chem. Abstr. 88, 105181e
18) Bata, I.; Heja, G.; Kiss, P.; Korbonits, D. J. Chem. Soc.,
Perkin Trans 1 1986, 9; Chem. Abstr. 105, 225559a
19) Eur. Pat. Appl. 80,847 1983; Chem. Abstr. 99, 1094979p
Rohm and Haas : the Sodium Borohydride Digest
20) U.S. 3,641,005 1972; Chem. Abstr. 76, 141213c
21) Toyooka, N.; Yoshida, Y.; Yotsui, Y.; Momose, T.
J. Org. Chem. 1999, 64, 4914
22) Chandrasekaran, S.; Kluge, A.F.; Edwards, J.A. J.
Org. Chem. 1977, 42, 3972; Chem. Abstr. 88,
6819n
23) Chan, W.R.; Gibbs, J.A.; Taylor, D.R. J. Chem.
Soc., Perkin Trans. 1 1973, 1047; Chem. Abstr. 79,
18886j
24) U.S. 3,250,678 1966; Chem. Abstr. 65, 7157g
25) Bradbury, D.; Barltrop, J. J. Chem. Soc. Chem.
Commun. 1975, 842; Chem. Abstr. 84, 42863y
26) Nishiki, M.; Miyataka, H. et. al. Tetrahedron Lett.
1982, 23, 193; Chem. Abstr. 96, 217296t
27) Suzuki, N.; Tsukanaka, T. et. al. J. Chem. Soc.,
Chem. Commun. 1983, 515; Chem. Abstr. 99,
157759w
28) Kijuma, M.; Nambu, Y.; Endo, T. Chem. Lett.
1985, 1851; Chem. Abstr. 105, 114651e
29) Jpn. Kokai Tokkyo Koho 84 33,300 1984; Chem.
Abstr. 101, 111269t
30) Narasimhan, S.; Prasad, K.G.; Madhavan, S.
Tetrahedron Lett. 1995, 36, 1141
31) Cowan, J.A. Tetrahedron Lett. 1986, 27, 1205
*For Online Consulting Only
press <CTRL>-F for Searching
131
32) Roush, W.R.; Kageyama, M.; Riva, R.; Brown, B.B.;
Warmus, J.S. Moriarty, K.J. J. Org. Chem. 1991, 56, 1192
33) Ihara, M; Tokunaga, Y.; Fukumoto, K. J. Org. Chem.
1990, 55, 4497
34) Dondoni, A.; Perrone, D.; Semola, M.T. J. Org. Chem.
1995, 60, 7929
35) Morimoto, Y.; Iwahashi, M. Synlett 1995, 1221
36) Varma, R.S.; Kabalka, G.W. Synth. Commun. 1985, 15,
151
37) Hanessian, S.; Roy P.J.; Petrini, M.; Hodges, P.J.; Di
Fabio, R.; Carganico, G. J. Org. Chem. 1990, 55, 5766
38) Rao, C.S.; Chakrasali, R.T.; Ila, H.; Junjappa, H.
Tetrahedron 1990, 46, 2195
39) Ranu, B.C.; Chakraborty, R. Tetrahedron 1992, 48, 5317
40) Ranu, B.C.; Chakraborty, R. Tetrahedron Lett. 1991, 32,
3579
41) Goudgaon, N.M.; Wadgaonkar, P.P.; Kabalka, G.W.
Synth. Commun. 1989, 19, 805
42) Sim, T.B.; Yoon, N.M. Synlett 1995, 726
43) Sim, T.B.; Choi, J.; Joung, M.J.; Yoon, N.M. J. Org.
Chem. 1997, 62, 2357
44) Campelo, J.M.; Chakraborty, R.; Marinas, J.M. Synth.
Commun. 1996, 26, 1639
45) Narasimhan, S.; Prasad, K.G.; Madhavan, S. Tetrahedron
Lett. 1995, 36, 1141
Rohm and Haas : the Sodium Borohydride Digest
46) Das, B.; Kashinatham, A.; Madhusudhan, P.
Tetrahedron Lett. 1998, 39, 677
*For Online Consulting Only
press <CTRL>-F for Searching
132
Rohm and Haas : the Sodium Borohydride Digest
EPOXIDES
Alembic 48, 50, 55
Sodium borohydride is generally unreactive
toward any epoxide groups and ahs been effectively to
remove impurities in materials such as ethylene oxides
(1), propylene oxide (2), and glycidylmethacrylate (3).
However, some authors have reported the use
of sodium borohydride for selective opening of strained
or activated epoxides (4-8). In some instances it is not
clear whether the borohydride ion BH4- or an in situ
generated derivative e.g. B(OR)3H- was actually
responsible for the ring opening reaction.
In sodium borohydride reduction of vicinal
epoxy alcohols, only the trans epoxy alcohol and not the
corresponding cis compound was reduced (9). This
selective reactivity should be extremely useful in the
synthesis of pharmaceutical compounds.
The use of supported borohydride reagents has
gained popularity in reducing many functional groups
including epoxides. The use of zinc borohydride on
zeolites, aluminophosphates and silica gel has been
demonstrated to ring open epoxides. (10-12)
Sodium borohydride in low molecular weight
alcohols have been shown to reduce epoxy esters to
*For Online Consulting Only
press <CTRL>-F for Searching
133
diols (13) and cyclic epoxides in diglyme to mono alcohols.
(14)
Reduction of epoxides with cyanoborohydride and
BF3•Et2O in refluxing THF has been used to synthesis natural
product compounds (15,16).
Lithium borohydride with titanium tetraisopropoxide
has reduced epoxides to alcohols. (17).
Solid state reactions of lithium borohydride in hexane
and epoxides have formed the corresponding alcohols in high
yield (18).
The reaction of NaBH4 and PhSeSePh has been used
to ring open epoxide esters at RT (19).
Cyclodextrin has been used to directionlize the ring
opening of styrene oxides with sodium borohydride. (20)
References:
1) U.S. 3,213,113 1965; Chem. Abstr. 64, 3482g
2) Ger. 1,144,704 1963; Chem. Abstr. 59, 6367d
3) Jpn 70 17,661 1970; Chem. Abstr. 73, 87776m
4) Stevens, C.L. et. al. J. Org. Chem. 1972, 37, 3130; Chem.
Abstr. 77, 151756p
5) Yoneta, T.; Matuno, T.; Nanahoshi, H.; Fukatsu, S. Chem.
Pharm. Bull. 1981, 29, 3469; Chem. Abstr. 96, 143219w
6) Soai, K.; Ookawa, A.; Oyamada, H.; Takase, M.
Heterocycles 1982, 19, 1371; Chem. Abstr. 97, 144694e
Rohm and Haas : the Sodium Borohydride Digest
7) Steliou, K.; Poupart, M.A. J. Am. Chem. Soc. 1983,
105, 7130; Chem. Abstr. 99, 212319e
8) Falck, J.R.; Manna, S. et. al. Tetrahedron. Lett.
1983, 24, 5715; Chem. Abstr. 100, 138804e
9) Weissenbergf, M.; Krinsky, P.; Glotter, E. J.
Chem. Soc., Perkin Trans 1 1978, 565; Chem.
Abstr. 89, 147129v
10) Sreekumar, R.; Padmakumar, R.; Rugmini, P.
Tetrahedron Lett. 1998, 39, 5151
11) Campelo, J.M.; Chakraborty, R.; Marinas, J.M.
Synth. Commun. 1996, 26, 415
12) Ranu, B.C.; Das, A.R. J. Chem. Soc., Chem.
Commun. 1990, 1334
13) Lanier, M.; Pastor, R. Tetrahedron Lett. 1995, 36,
2491
14) Huwe, C.M.; Blechert, S. Tetrahedron Lett. 1995,
36, 1621
15) Tone, H.; Nishi, T.; Oikawa, Y.; Hikota, M.;
Yonemitsu, O. Tetrahedron Lett. 1987, 28, 4569
16) Taber, D.F.; Houze, J.B. J. Org. Chem. 1994, 59,
4004
17) Dai, L.X.; Lou, B.L.; Zhang, Y.Z.; Guo, G.Z.
Tetrahedron Lett. 1986, 27, 4343
18) Sugita, K.; Onaka, M.; Izumi, Y. Tetrahedron Lett.
1990, 31, 7467
*For Online Consulting Only
press <CTRL>-F for Searching
134
19) Miyashita, M, Hoshino, M.; Suzuki, T.; Yoshikoshi, A.
Chem. Lett. 1988, 507
20) Ravichandran, R.; Divakar, S. J. Mol. Catal. A 1999,
137, 31
Rohm and Haas : the Sodium Borohydride Digest
ORGANO CALCOGEN COMPOUNDS
Alembic: 58
A number of workers have reported the
reduction of organic disulfides to thiols (1-5) and of
diselenides to the corresponding selenol (6) or
organoselenides anions (7-9). This reduction has been
developed into a method of disulfides analysis (10)
since sulfides and mercaptans do not interfere (11), and
has been used to measure naturally occurring urinary
disulfides in cystinuric patients (12). NaBH4 has been
used to distinguished organic polysulfides from
disulfides (13); in addition to thiol formation, hydrogen
sulfides is produced from polysulfides, but not from
disulfides. Di and polysulfide reductions have been
applied to the study of trypsinogens (14), the
modification of sporidesmin-type antibiotics which
contain the epithiodioxopiperazine system (I) common
to a number of fungal metabolites (15), the preparation
of rubber crosslinking agents (16),
O
N
S
O
*For Online Consulting Only
(1)
S
NR
135
press <CTRL>-F for Searching
And to the resolution of racemic cyclic disulfides (17).
The combination of sodium borohydride and NiCl2 or
CoCl2 has been demonstrated to desulfurize thiols, thioethers,
sulfons and sulfonates in high yield. (18,19)
Sodium borohydride has been demonstrated to have
the ability to reduce sulfonyl chlorides to disulfides or
completely remove the group with the addition of pyridine.
(20-22)
Borohydride exchange resins has been used to form
symmetrical and unsymmetrical thioether from thiols or
disulfides with organic halides in high yields. (23-25)
While xanthates in general are not reduced (26),
phenyl xanthates can be reduced to thiophenols (27).
RO
S
NaBH4
R'
HS
R'
O
A number of recent publications show the general
applicability of NaBH4 to the reduction of cationic sulfur
heterocycles (28) such as benzoxathiolium (II) (29) to the
corresponding thiole,
H
S
+
X
NaBH4
S
X= O
X=S
X
R1
R
R
R3
NO2
NO2
NaBH4
S
S
Se
Se
Ph
NaBH4
2 Ph
SeNa
such as nuciferine (V), and apomorphine dimethyl ether,
(IV).
*For Online Consulting Only
R4
V R1=R2= OCH3; R3,R4=H ÆR1=OCH3;R2=OH;R3=R4=H
VI R1=R2= H; R3,R4= OCH3 ÆR1;R2=H;R3=OH, R4=OCH3
Reduction of o-nitrophenylslenocyanate provides the
arylselenium anion which was used in a synthetic sequence
resulting in (a)-deoxyvernolepin (33).
S
Aryl selenium anions produced by NaBH4
reduction are proving to be synthetically useful
reagents. Sodium benzylselenolate, (IV) has been used
for regioselective
o-demethylation of aporphine
alkaloids (32)
Ph
NMe
R2
Benzodithiolium (III) (30) and thiopyrilium to the
thiopyran (31).
S
+
136
press <CTRL>-F for Searching
Rohm and Haas : the Sodium Borohydride Digest
NO2
NaBH4
SeCN
NO2
Se-
High purity symmetrical diselenides has been
synthesized in excellent yield form both aliphatic and aromatic
aldehydes (34) by NaBH4 reduction of a mixture of aldehyde,
sodium hydrogen selenide and an amine catalyst such as
piperidine or morpholine.
press <CTRL>-F for Searching
Rohm and Haas : the Sodium Borohydride Digest
NaBH4
O
2
R
+
2 NaHSe
H
Amine
R
Se
Se
R
Use of 0.25 molar equivalent of borohydride results in
maximum diselenide yield with little selenol
contamination. The NaHSe is conveniently prepared by
NaBH4 reduction of elemental selenium in absolute
ethanol (35).
NaBH4, and more recently NaBH3CN, are
being applied with increasing frequency to the
desulfonation of p-toluene- and methanesulfonates.
This reaction is often used to convert alcohols
to the corresponding hydrocarbon (36-41).
The
selective reduction of a mesylate in the presence of a
tosylate has been reported in studies elucidating the
chirality in tetrahydroquinoxalines (42).
OTs
N
OTs
H
N
CH2OMs NaBH4
H
CH3
N
N
H
H
Selenoether compounds synthesized by
reducing Se metal or Alkyl dibromoselenide and
*For Online Consulting Only
137
halocarbons with borohydride exchange resins or sodium
borohydride. (43-45)
It has been demonstrated that aryl nitriles can be
reduced with NaBH4 in the presence of Se metal to form
seleno amides in high yield (46)
Both seleno ethers and diselenides can be reduced to
selenols in high yielded with sodium borohydride. (47- 49)
Telluerium ether compounds can be synthesized in
high yield from the reduction of ArTeCl3 with sodium
borohydride and a organic halide in THF at 0o C. (50) Di
tellurides has been reduced to telluriol in high yielded using
sodium borohydride. (51,52)
References:
1) Bosman, W.P.; Van der Linen, H.G.M. J. Chem. Soc.,
Chem. Commun. 1977, 714; Chem. Abstr. 88, 145344s
2) Belg. 866,910 1978; Chem. Abstr. 90, 137816y
3) Ookawa, A.; Yokoyama, S.; Soai, K. Synth. Commun.
1986, 819; Chem. Abstr. 105, 208549e
4) Fr. Demande 2,566,400 1985; Chem. Abstr. 105, 152688e
5) Jpn. Kokai Tokkyo Koho 85, 2222, 485 1985; Chem.
Abstr. 105, 78751b
6) Rinaldi, A.; Dernini, S. Dessy, M.R.; DeMarco, C. Anal.
Biochem. 1975, 69, 289; Chem. Abstr. 84, 432242g
Rohm and Haas : the Sodium Borohydride Digest
7) Entwistle, I.D.; Johnstone, R.A.W.; Varley, J.H. J.
Chem. Soc., Chem. Commun. 1976, 61; Chem.
Abstr. 84, 121363p
8) Liotta, D.; Sunay, U.,; Santiesteban, H.;
Markiewicz, W. J. Org. Chem. 1981, 46, 2605;
Chem. Bastr. 95, 41572t
9) Kuroda, C.; Theramongkol, P.; Engebrecht, J.R.;
White, J.D. J. Org. Chem. 1986, 51, 957; Chem.
Abstr. 104, 186207s
10) Stahl, C.R.; Siggia, S. Anal. Chem. 1957, 29, 154;
Chem. Abstr. 51, 17611a
11) Sjoeberg, B.; Herdevall, S. Acta Chem. Scand.
1958, 12, 1347; Chem. Abstr. 54, 2281I
12) Bir, K.; Crawhall, J.C.; Mauldin, D. Clin, Chem.
Acta 1970, 30, 183; Chem. Abstr. 73, 32989t
13) Klayman, D.L.; Griffin, T.S.; Woods, T.S. Int. J.
Sulfur Chem. 1973, 8, 53; Chem. Abstr. 81, 32989t
14) Sondack, D.L.; Light, A. J. Biol. Chem. 1971, 246,
1630; Chem. Abstr. 74, 107621t
15) Ottenheijm, H.C.; Herscheid, J.D.M.; Kerkhoff,
G.P.C.; Spande, T.F. J. Org. Chem. 1976, 41, 3433;
Chem. Abstr. 85, 160025v
16) PCT Int. Appl 84 04,921 1984; Chem. Abstr. 102,
185115g
*For Online Consulting Only
press <CTRL>-F for Searching
138
17) Ottenheijm, H.C.J.; Herscheid, J.D.M.; Nivard, R.J.F. J.
Org. Chem. 1977, 42, 925; Chem. Abstr. 86, 140001b
18) Back, T.G.; Baron, D.L.; Yang, K. J. Org. Chem. 1993,
58, 2407
19) Alcaide, B.; Casarrubios, L.; Dominguesz, G.; Sierra,
M.A. J. Org. Chem. 1994, 59, 7934
20) Suzuki, H.; Nakamura, T.; Yoshikawa, M. J. Chem.
Research (S) 1994, 70
21) Volonterio, A.; Vergani, B.; Crucianelli, M.; Znadfa, M.;
Bravo, P. J. Org. Chem. 1998, 63, 7236
22) Zhang, M.H.; Zheng, M.; Cheng, T.; Wang, S.X. Organic
Prep. Proc. Int. 1996, 28, 467
23) Yoon, N.M.; Choi, J.; Ahn, J.H. J. Org. Chem. 1994, 59,
3490
24) Choi, J.; Yoon, N.M. Synth. Commun. 1995, 25, 2655
25) Nah. J. H.; Choi, J.; Yoon, N.M. Bull. Korean Chem. Soc.
1996, 17,
26) Lightner, D.A.; Djerassi, C. Tetrahedron 1965, 21, 583;
Chem. Abstr. 62, 13206c
27) Overberger, C.G.; Lebovits, A. J. Am. Chem. Soc. 1956,
78, 4792; Chem. Abstr. 51, 1896a
28) Boyd, P.D.W.; Hope, J.; Martin, R.L. J. Chem. Soc.,
Dalton Trans. 1986, 8877; Chem. Abstr. 105, 90017z
29) Degani, I.; Fochi, R. Synthesis 1976, 757; Chem. Abstr.
86, 139900n
Rohm and Haas : the Sodium Borohydride Digest
30) Nakayama, J.; Fugiwaw, K.; Hishoni, M. Bull.
Chem. Soc. Jpn. 1976, 49, 3567; Chem. Abstr. 86,
155545f
31) Iddon, B.; Suschitzky, H.; Taylor, D.S.;
Chippendale, K.E. J. Chem. Soc., Perkin Trans 1
1974, 2500; Chem. Abstr. 82, 111966g
32) Ahmad, R.; Saa, J.M.; Cava, M.P. J. Org. Chem.
1977, 42, 1228; Chem. Abstr. 86, 155837c
33) Grieco, P.A.; Noguez, J.A.; Masaki, Y. J. Org.
Chem. 1977, 42, 1228; Chem. Abstr. 86, 72908a
34) Lewicki, J.W.; Guenther, W.H.H.; Chu, J.Y.C. J.
Org. Chem. 1978, 43, 2672; Chem. Abstr. 89,
59740g
35) Klayman, D.L.; Griffin, T.S. J. Am. Chem. Soc.
1973, 95, 197; Chem. Abstr. 78, 110774y
36) Marshall, J.A.; Wuts, P.G.M. J. Am. Chem. Soc.
1978, 100, 1627; Chem. Abstr. 88, 170333v
37) Agosta, W.C.; Wolff, S. J. Am. Chem. Soc. 1977,
99, 3355; Chem. Abstr. 87, 67743j
38) Grethe, G.; Mitt, T.; Williams, T.H.; Uskokovic,
M.R. J. Org. Chem. 1983, 48, 5309; Chem. Abstr.
100 7015a
39) Barrette, E.P.; Goodman, L. J. Org. Chem. 1984,
49, 176; Chem. Abstr. 100, 34748y
*For Online Consulting Only
press <CTRL>-F for Searching
139
40) Hamada, T.; Nishida, A.; Yonemitsu, O. J. Am. Chem.
Soc. 1986, 108, 140; Chem. Abstr. 104, 51101g
41) Eur. Pat. Appl. 165,595 1985; Chem. Abstr. 104, 168761p
42) Fisher, G.H.; Schultz, H.P. J. Org. Chem. 1974, 39, 635;
Chem. Abstr. 80, 95885f
43) Takanohashi, Y.; Funakoshi, H.; Akabori, S. Synthesis
Commun. 1994, 24, 2733
44) Weber, J.V.; Faller, P.; Kirsch, G.; Schneider, M.
Synthesis 1984, 1044
45) Yamada, K.; Fujita, T.; Yamada, R. Synlett 1998, 971
46) Zhao, X.R.; Ruan, M.D.; Fan, W.Q.; Zhou, X.J. Synth.
Commun. 1994, 24, 1761
47) Back, T.G.; Birss, V.I.; Edwards, M.; Krishna, M.V. J.
Org. Chem. 1988, 53, 3815
48) Engman, L.; Laws, M.J.; Malmstrom, J.,; Schiesser, C.H.;
Zugaro, L.M. J. Org. Chem. 1999, 64, 6764
49) Flores, F.G.C.; Mendoza, P.G.; Mateo, F.H.; Garcia, J.I.;
Gonzales, F.S. J. Org. Chem. 1997, 62, 3944
50) Chieffi, A.; Menezes, P.H.; Comasseto, J.V.
Organometallic 1997, 16, 809
51) Kanda, T.; Engman, L.; Cotgreave, I.A. Powls, G. J. Org.
Chem. 1999, 64, 8161
52) Dabdoub, M.J.; Dabdoub, V.A.; Comasseto, J.V.
Tetrahedron Lett. 1992, 33, 2261
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
OZONIDES
2)
Ozonides are reduced by NaBH4 to the
corresponding alcohol. The reduction of the ozonides of
indene (1), 3-acetyl-digitoxigenin (2), cytochlasin E (3),
and a number of other compounds (4-6) have been
reported. Sousa and Bluhm (7) have used this reduction
to cleave olefins to alcohols in good yields, with out the
necessity of isolating the ozonide. When the ozonides
of branched olefins are reduced with NaBH4, a mixture
of alcohols is obtained which correctly, and without by
products, locates the double bond position (8).
Ozonide reduction with NaBH4 has been used
on making anti-inflammatory derivatives of 6-oxo-1-anaphthoic acid (9) and hydroxyl-terminated low
molecular weight polymers for subsequent condensation
with anhydrides to form polyesters (10).
The reduction of ozonides can be accomplished
with sodium borohydride to form compounds such as
sugars(11), Triquinane type skeleton (12) and Zaragoic
Acid (13). Ozononolyis of lactams and subsequent
reduction with SBH forms allylic ethers. (14)
3)
4)
5)
6)
7)
8)
9)
10)
11)
12)
13)
References:
1) Warnell, J.L.; Shriner, R.L. J. Am. Chem. Soc.
1957, 79, 3165; Chem. Abstr. 51, 15509f
*For Online Consulting Only
14)
140
Boutagy, J.S.; Thomas, R.E. Aust. J. Chem. 1971, 24,
2723; Chem. Abstr. 76, 141179w
Aldridge, D.C.; Greatbanks, D.D; Turner, W.B.N. J.
Chem. Soc., Chem. Commun. 1973, 551; Chem. Abstr. 79,
126471d
Sundaraaraman, P.; Barth, G.; Djerassi, C. J. Org. Chem.
1980, 45, 5231; Chem. Abstr. 94, 83490z
Arffin, A.A.B. J. Rubber Res. Inst. Malays. 1981, 29, 96;
Chem. Abstr. 96, 2011035w
Takatsuko, S.; Ikekawa, N. Tetrahedron Lett. 1983, 24,
773; Chem. Abstr. 99, 54059p
Sousa, J.A.; Bluhm, A.L. J. Org. Chem. 1960, 25, 108;
Chem. Abstr. 54, 15286f
Hoffman, J.; Smidova, J.; Landa, S. Collect. Czech.
Chem. Commun. 1970, 35, 2174; Chem. Abstr. 73,
65937n
U.S. 3,644,500 1972; Chem. Abstr. 76, 140060p
Japan. 73 11,235 1973; Chem. Abstr. 80, 121713v
Lautens, M.; de Frutos, O.; Stammers, T.A. Tetrahedron
Lett. 1999, 40, 8317
Kocovsky, P.; Dunn, V.; Gogoll, A.; Langer, V. J. Org.
Chem. 1999, 64, 101
Maezaki, N.; Gijsen, H.J.M.; Suna, L.Q.; Paquette, L.A.
J. Org. Chem. 1996, 61, 6685
Alcaide, B.; Casarrubios, L.; Dominguesz, G.; Sierra,
M.A. J. Org. Chem. 1995, 60, 6012
press <CTRL>-F for Searching
Rohm and Haas : the Sodium Borohydride Digest
PEROXIDES AND HYDROPEROXIDES
Jensen (1) has reported the NaBH4 reduction of
some organic peroxides to be extremely rapid at room
temperature. Organic peracids and peroxides formed in
most ethers are also reduced. Hydrogen peroxide can
react violently with sodium borohydride. Reactions
with concentrated solutions have resulted in explosions.
The literature describes the NaBH4 reduction
of cholesterol hydroperoxide to the alcohol (2),
naturally occuring terpene hydroperoxide such as
neoconcinndiol hydroperoxide (3) and peroxyferolide
(4), and numerous other (5-8).
Rapid selective
hydroperoxide reduction in the presence of keto and
iodo functionalities has been reported for the 1phenylhexanone derivative formed by hydrolysis of a
benziodolium cation (9).
Bu
OOH
O
I
Bu
OH
O
NaBH4
Ph
I
Ph
Peroxides formed in photosensitized oxidations
of homosemibullvalene (10), stilbene derivatives (11),
cyclobutane dioxetanes (12), The natural sesquiterpene
*For Online Consulting Only
141
valencene (13) and dienes of norbornane (14) have been
reduced to the corresponding alcohol.
Allylic hydroperoxides formed by autoxidation of
methyl oleate are reduced to the corresponding allylic alcohols
(15), Permitting accurate quantitative determination of their
composition; previous methods were subject to significant
errors.
Hydroperoxides reduction has been reported in one
synthetic route to the prostaglandines PGE1 and PGF1a (16).
The reduction of a hydroperoxide group in an
intermediate towards the synthesis of dihydroxyvitamin D3 has
been accomplished with sodium borohydride. (17)
Sodium borohydride in MeOH have reduced
peroxides to diols. (18)
References:
1) Jensen, E.H. “ A Study on Sodium Borohydride”, Nyt.
Nordisk Forlag Arnold Busck, Copenagen 1954 (out of
print); Chem. Abstr. 49, 13010a
2) Kulig, M.J.; Smith, L.L. J. Org. Chem. 1974, 39, 3398;
Chem. Abstr. 82, 53949r
3) Howard, B.M.; Fennical, W.; Finer, J.; Hirotsu, K.;
Clardy, J. J Am. Chem. Soc. 1977, 99, 6440; Chem. Abstr.
87, 184722n
Rohm and Haas : the Sodium Borohydride Digest
4) Doskotch, R.W.; El-Feraly, F.S.; Fairchild, E.H.;
Haung, C.T. J. Org. Chem. 1977, 42, 3614; Chem.
Abstr. 87, 180643q
5) Johnson, W.S.; Dumas, D.J.; Berner, D. J. Am.
Chem. Soc. 1982, 104, 3510; Chem. Abstr. 97,
24076h
6) Adam, W.; Hannemann, K.; Wilson, R.M. J. Am.
Chem. Soc. 1984, 106, 7646; Chem. Abstr. 102,
5437g
7) Bull, A.; Nigro, N.D. et al. Cancer Res. 1984, 44,
4924; Chem. Abstr. 102, 19325f
8) Van Kuijk, F.J.G.M.; Thomas, D.W.; Stephens,
R.J.; Dratz, E.A.; J. Free Radicals Biol. Med. 1985,
1, 215; Chem. Abstr. 104, 48268m
9) Beringer, F.M.; Ganis, P.; Avitabile, G.; Jaffe, H. J.
Org. Chem. 1972, 37, 879; Chem. Abstr. 76,
126504e
10) Sakai, M.; Harris, D.L.; Winstein, S. J. Org. Chem.
1972, 37, 2631; Chem. Abstr. 77, 100898g
11) Saito, I.; Matsuura, T. Chem. Lett. 1972, 1169;
Chem. Abstr. 78, 83937v
12) Rigaudy, J.; Capdevielle, P.; Maumy, M.
Tetrahedron Lett. 1972, 4997; Chem. Abstr. 78,
123619b
*For Online Consulting Only
press <CTRL>-F for Searching
142
13) Schaffer, G.W.; Eschinasi, E.H.; Purzycki, K.L.; Doerr,
A.B. J. Org. Chem. 1975, 40, 2181; Chem. Abstr. 83,
97599b
14) Jefford, C.W.; Rimbault, C.G. J. Org. Chem. 1978, 43,
1908; Chem. Abstr. 88, 189637u
15) Garwood, R.F.; Khambay, B.P.S.; Weedon, B.C.L.;
Frankel, E.N. J. Chem. Soc., Chem. Commun. 1977, 364;
Chem. Abstr. 87, 183915r
16) U.S. 3,953,499 1976; Chem. Abstr. 86, 16342z
17) Linker, T.; Frohlich, L. J. Am. Chem. Soc. 1995, 117,
2694
18) Carless, H.A.J.; Oak, O.Z. Tetrahedron Lett. 1989, 30,
1719
Rohm and Haas : the Sodium Borohydride Digest
III. INORGANIC APPLICATIONS
A. Inorganic Reductions
Alembic: 6
Sodium borohydride is a tremendously
versatile reducing agent and ligand for inorganic
reactions, as shown by the wealth of literature which as
appeared in the last 50 years. Some excellent reviews
have appeared in the literature and are recommended (16). In addition Rohm and Haas over the past 30 years
has complied and regularly updates a full bibliographic
database pertaining to the reduction of metals. We are
prepared to answer all questions relating to the
application of borohydrides and amine boranes for the
reduction of metals.
METAL CATION REDUCTIONS
Alembic: 6
A substantial number of metal cations are
reduced by borohydride in protic or aprotic solvent.
Reduction can be classified according to the product
obtained. The products may be a lower valence
compound, the free element, a volatile hydride or a
*For Online Consulting Only
press <CTRL>-F for Searching
143
metal “boride’. These reductions are summarized in Periodic
Table form in Figure 11.
In addition to a references cited in this table, the following
publications are significant:
- “Catalytically Active Borohydride-Reduced Nickel and
Cobalt Systems” (7),
- “Reactions
of
Sodium
Tetrahydroborate
and
Cyanotrihydroborate with Divalent Cobalt, Nickel,
Copper, Palladium and Platinum in the Presence of
Triphenyl Phosphines” (8)
- Hydride Complexes of iron (II) and ruthenium (II)” (9)
- The Mechanism of the reduction of the Inorganic
compounds with alkali Metal Borohydride” (10),
- “Sodium tetrahydroborate as a new reagent in the
Systematic Course of Qualitative Analysis I. Reduction of
Sodium Tetrahydroborate with metal cations” (11).
Reduction of toxic or valuable heavy metals in process waste
streams is an important industrial application for sodium
borohydride.(12-14). Quantitative reduction and recovery of
mercury (15- 18), lead (19), silver (20, 21), gold (22, 23),
copper (13,14), and platinum group metals (24-26) can be
accomplished.
The use of NaBH4 in the development process for
color reversal photographic film is well documented (27-29)
Rohm and Haas : the Sodium Borohydride Digest
Cation reductions with NaBH4 are being used
commercially in the area of electroless plating,
particularly of nickel, on both metallic and non-metallic
substrates.
Practical aspects of this application have been published
(30, 31), and extended plating bath life and ease of
regeneration have been cited as advantages. These
coatings contain up to 5% boron and, when annealed,
consist of a dispersion of Ni3B in a nickel matrix (32)
which provides a wear resistant finish of superior
hardness. Cobalt (33, 34), gold (35,36), copper (37, 38)
and iridium (39) have also been plated by NaBH4
reduction. The copper deposits, on plating glass, are
used in solar control windows having reflective bronze
finish. Russian publications report NaBH4 reduction of
electroless plating of silver (40), iron (41), palladium
(42), platinum (43), and ruthenium (44). NaBH4 is also
reported to be effect in pretreating or sensitizing noncatalytic substrates for subsequent electroless plating
(45, 46, 47). A recent patent has been issued for a
process for electroless plating of polymer or resins with
Ag, Co, Ru, Ce, Fe, Mn, Ni, Rh, and/or V. (48)
Several metal compounds such as cobalt
chloride (49) chromium oxide, Cr2O3 (50 44),
molybdenum and tungsten oxides (51 45) and
molybdenum chloride (52 46), have been reduced by
*For Online Consulting Only
press <CTRL>-F for Searching
144
heating these compounds together with sodium borohydride in
the absence of any solvent to produce metal powders. NaBH4
reduction has also been applied to the manufacturing of
amorphous metal alloy (53), extremely fine metal powders of
copper (54 55), silver (56), ruthenium (57), gold (58, 59), Pt
(60), Fe (61) and nickel or cobalt (62), and magnetic metal
powders for tape recording
media (63, 64, 65, 66). Other recent applications include
boiler scale removal (67), the preparation of methanol
reforming catalysts (68), The preparation of a cobalt catalyst
for the hydrogenantion of glucose to sorbetol (69) and of
catalytic converters for automobile exhausts gases (70).
Reacting metal salts and sodium borohydride at elevated
temperatures have formed mixed metal alloys. (71- 80)
The kinetics of the reaction of the ammonium ion
with the borohydride anion in liquid ammonia to produce
ammonia-borane, NH3BH3, has been reported (81).
The borohydride reduction of nanogram quantities of
arsenic (82-87), antimony (82-84, 87), bismuth (82, 83), tin
(82-87), germanium (84) mercury (86), tellurium (86),
selenium (82, 83), indium and thallium (88) and lead (86, 89)
to produce volatile hydrides for detection by atomic
absorption, gas chromatography and emission spectroscopy
has been widely reported and is extensively used by analysts.
Elemental powered selenium and sodium borohydride
react rapidly in water or ethanol to give either NaHSe or
Rohm and Haas : the Sodium Borohydride Digest
Na2Se2 (90). The reduction of Sb2O3 with sodium
borohydride in ethylene glycol produces a finely
divided antimony powder useful as a catalyst for
polyester manufacture (91). The mechanism of the
reduction of arsenic (III) chloride and oxide and the
preparation of arsine by the borohydride reduction of
these compounds has been reported (92).
METAL ANION REDUCTIONS
Alembic: 6
An Important industrial use of sodium
borohydride is the reduction of the bisulfite anion to
produce dithionite (hydrosulfite) anion (93, 94):
*For Online Consulting Only
press <CTRL>-F for Searching
145
BH4- + 8 HSO3- + H+ Æ 4 S2O42- + H3BO3 + 5 H2O
Hydrosulfite (S2O4)2- generated by NaBH4 reduction of
tetravalent sulfur species is widely applied industrially in
bleaching mechanical pulps (95, 96). Other anions which have
been studied systematically, mainly in the USSR, include
Rhenium dioxide and perrhenate to Re (V), (III), or (II)
(97,98); Osmium tetraoxide to Os (VII), (VI), and (IV) (99);
Pertechneate to Tc.
Figure 11 : Studies of Na BH4 Reductive Strength
Rohm and Haas : the Sodium Borohydride Digest
*For Online Consulting Only
press <CTRL>-F for Searching
146
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
(0) (100); Vanadate to V (III) and (IV) (101,102);
Molybdate to Mo (V) and “molybdenum blue” (103,
104); Tungstate to W (IV) and tungsten blue (105,
106); Permanganate to MnO2 and Mn (II) (107);
hexacyanoferrate to Fe (II) (108, 109); and iodine (in
DMF) to NaI = B2H6, BH2I, BH2I2 and B2H5I (110,
111).
The utilization of sodium borohydride as an
efficient energy storage media has been demonstrated.
The 8 electron electrochemical oxidation of sodium
borohydride in aqueous alkaline solution produced
specific energies of greater then 180 Wh/kg (based on
total fuel wt.) and power densities greater then
20mW/cm2 at room temp and greater then 60mW/cm2
at 70 degree C. (112)
5) Ephritikhine, M. Chem. Rev. 1997, 97, 2193
6) Klabunde, K.J.; Stark, J.V.; Koper, O.; Mohs, C.; Khalell,
A.; Glavee, G.; Zhang, D.; Sorensen, C.M.; Hadjipanaylis,
G.C. Nanophase Materials, 1994, 1
7) Wade, R.C.; Holah, D.G.; Hughes, A.N.; Hui, D.C. Catal.
Rev. Sci. Eng. 1976, 14, 2111; Chem. Abstr. 86, 22275w
8) Holah, D.G.; Hughes, A.N.; Hui, B.C.; Wright, K. Can. J.
Chem. 1974, 52, 2990; Chem. Abstr. 81, 144867h
9) Peet, W.P.; Gerlak, D.H. Inorg. Synth. 1974, 15, 38;
Chem. Abstr. 81, 130285e
10) Hanzlik, J. Chem. Listy 1973, 67, 1239; Chem. Abstr. 80,
66215g
11) Khain, V.S.; Chazov, M.M.; Krivokorytova, L.A. Tr.
Tyumen. Ind. Inst. 1972, 241; Chem. Abstr. 82, 132525c
12) Jula, T.F. Process Eng. 1975 123; Chem. Abstr. 83,
151770r
13) Cook, M.M.; Lander, J.A. Pollut. Eng. 1981, 13, 36;
Chem. Abstr. 967, 168042w
14) Ulman, J.A. Spec. Chem. 1985, 5, 27; Chem. Abstr. 103,
128490x
15) U.S. 3,736,253 1973; Chem. Abstr. 79, 45540y
16) U.S. 3,764,528 1973; Chem. Abstr. 80, 30452t
17) U.S. 3857,704 1974; Corresponding to Brit. 1,368,966
1974; Chem. Abstr. 82, 89846u
18) Ger. Offen. 3,335,127 1985; Chem. Abstr. 102, 207132q
References:
1) James, D.B. Wallbridge, M.G.H. Prog. Inorg.
Chem. 1970, 11, 99; Chem. Abstr. 73, 41276v
2) Marks, T.J.; Kolb, J.R. Chem. Rev. 1977, 77, 263;
Chem. Abstr. 86, 140116t
3) Kadlec, V.; Kadlecova, H; Masek, J. Chem. Listy
1976, 70, 673; Chem. Abstr. 85, 136308u
4) Jula, T.F. “Inorganic Reductions with sodium
borohydride” Ventron Corp. 1974
*For Online Consulting Only
147
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
19) Ger. Offen. 2,408,995 1974; Chem. Abstr. 82,
160007d
20) U.S. 4,279,644 1981; Chem. Abstr. 95, 223522j
21) Jpn. Kokai Tokkyo koho 86 34,125 1986; Chem.
Abstr. 104, 228180k
22) Jpn. Kokai, Tokkyo Koho 85, 159, 134 1985;
Chem. Abstr. 104, 8756n
23) McPartland, J. S.; Bautista, R. G. Met. Sep.
Technol. Beyond 2000: Proc. Symp., 1999, 105
24) U.S. 4,319,923 1982; Chem. Abstr. 96, 203153g
25) Jpn. Kokai Tokkyo Koho 85, 251, 233 1985;
Chem. Abstr. 104, 190311p
26) U.S. 5,304,233 1994
27) U.S. 2,984, 567 1961; Chem. Abstr. 55, 21936a
28) U.S. 3,554, 748 1971; corresponds to Fr. 1,548,
122 1968; Chem. Abstr. 71, 86594x
29) U.S. 4,259,114 1981; Chem. Abstr. 95, 52631n
30) Lang, K. Electroplating Metal Finishing 1966,
19, 86; Chem. Abstr. 65, 10252h
31) Neiderpruem, H.; Klein, H.G. Metal Finishing J.
1971, 17, 18; Chem. Abstr. 75, 37956r
32) Matusuoka, M. Hayashi, T. Denki Kagaku 1978,
46, 163; Chem. Abstr. 89, 93640j
33) Valsiuniene, J.; Prokopoikas, A. Liet. TSR Mokslu Akad.
Darb., Ser. B 1972, 1, 19; Chem. Abstr. 77, 78564w
34) U.S. 3,096,182 1963; Chem. Abstr. 59, 8443h
35) Okinaka, Y. J. Electrochem. Soc. 1973, 120, 739; Chem.
Abstr. 79, 26529k
36) U.S. 3,697,296 1972; Chem. Abstr. 78, 19607k
37) U.S. 3,671,291 1972; Chem. Abstr. 77, 78794w
38) U.S. 4,082,898 1978; Chem. Abstr. 89, 63663b
39) Jpn. Kokai Tokkyo Koho JP 11131249 A2 19990518
1999; Chem. Abstr. 130, 341516
40) Valsiuiene, J. Prokopchik, A.Y.; Kaskelis, A. Liet. Tsr
Mokslu Akad. Darb. Ser B 1975, 6, 3; Chem. Abstr,
111619h
41) Valsiuniene, J.; Zielys, H.; Prkopchik, A.Y. Liet. Tsr
Mokslu Akad. Darb. Ser B 1976, 1, 27; Chem. Abstr. 85,
164326s
42) Valsiuniene, J.; Prokopchik, A.Y.; Kaskelis, A. Liet. Tsr
Mokslu Akad. Darb. Ser B 1976, 4, 25; Chem. Abstr. 86,
125406u
43) Valsiuniene, J.; Vinkevicius, J.; Prokopchik, A.Y. Liet.
Tsr Mokslu Akad. Darb. Ser B 1976, 5, 25; Chem. Abstr.
87, 27130a
*For Online Consulting Only
148
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
44) Valsiuniene, J. Norgailaite, A. Issled. Obl.
Elektroosazhdeniya
Met.
Resp.
Konf.
Elektrokhim. Lit. SSR, 14th 1976, 215; Chem.
Abstr. 87, 27136g
45) U.S. 3,962,494 1976; Chem. Abstr. 85, 165396b
46) U.S. 3,993,801 1976; Chem. Abstr. 86, 94685c
47) U.S. 4,323,594 1982; Chem. Abstr. 97, 7563x
48) Eur. Pat. Appl. EP 913498 A1 19990506, 1999;
Chem. Abstr. 130, 300137
49) Sterlyadkena, Z.K.; Alekseeva, L.S.; Maltseva,
N.N. Zh. Neorg. Khim. 1973, 18, 260; Chem.
Abstr. 78, 91990x
50) Alekseeva, L.S. et. al. Zh. Neorg. Khim. 1975, 20,
2339; Chem. Abstr. 83, 201393t
51) Alekseeva, L.S. et. al. Zh. Neorg. Khim 1976, 21,
277; Chem. Abstr. 84, 115375c
52) Alekseeva, L.S. et. al. Zh. Neorg. Khim 1977, 22,
1695; Che. Abstr. 87, 61817q
53) U.S. 4,585,617 1986; Che. Abstr. 105, 47448d
54) Jpn. Kokai Tokkyo Koho 85, 86, 203 1985, Che.
Abstr. 103, 900911v
55) Qiu, S.; Dong, J.; Chen, G. J. Colloid Interface
Sci., 1999, 216, 230
56) Shirtcliffe, N.; Nickel, U.; Schneider, S. J. Colloid
Interface Sci. 1999, 211, 122; Chem. Abstr. 130, 242696
57) Jpn. Kokai. Tokkyo Koho, 1999; JP 11031417 A2
19990202; Chem. Abstr. 130, 155069
58) Chen, S.; Kimura, K. Langmuir, 1999, 15,1075-1082 ;
Chem. Abstr. 130, 213995
59) Bronstein, L. M.; Platonova, O.A.; Yakunin, A. N.;
Yanovskaya, I.M.; Valetsky, P. M.; Dembo, A. T.;
Obolonkova, E. S.; Makhaeva, El. E.; Mironov, A. V.;
Khokhlov, A.R. Colloids Surf., A 1999, 147, 221-231 ;
Chem. Abstr. 130, 253037
60) Dykman, L. A.; Lyakhov, A.A.; Bogatyrev, V. A.;
Shchyogolev, S. Yu. Colloid J. 1998, 60, 700-704 ;
Chem. Abstr. 130, 144556
61) Wang, C. Y.; Chen, Z. Y.; Cheng, B.; Zhu, Y. R.; Liu, H.
J. Mater. Sci. Eng., B, 1999, B60, 223
62) Jpn Kokai Tokkyo Koho 84, 160, 539 1984; Chem. Abstr.
102, 29286h
62) U.S. 4,394,160 1983; Chem. Abstr. 99, 98069w
63) Jpn. Kokai Tokkyo Koho 86 48,503 1986; Chem. Abstr.
105, 47074d
64) Duxin, N.; Pileni, M. P.; Wernsdorfer, W.; Barbara, B.;
Benoit, A.; Mailly, D. Langmuir
*For Online Consulting Only
149
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
65) Rittenberg, Durrell K.; Sugiura, Ken-ichi; Sakata,
Yoshiteru; Guzei, Ilia A.; Rheingold, Arnold L.;
Miller, Joel S. Chem.--Eur. J. 1999, 1874
66) U.S. 4,610728 1986; Chem. Abstr. 105, 230807j
67) Jpn. Kokai Tokkyo Koho 86 50,639 1986; Chem.
Abstr 105, 45828d
68) Li, H.; Li, H.; Wang, W; Deng, J.-F Chem. Lett.
1999, 629
70) Jpn. Kokai Tokkyo Koho 84, 160,539 1984; Che.
Abstr. 102, 31299
71) Stolk, J.; Manthiram, A Mater. Sci. Eng., B, 1999,
B60, 112-117
72) Pan, H.; Chen, Y.; Chen, C.; Wang, Q. Jinshu
Xuebao, 1999, 35, 300 Chem. Abstr. 130,
314363
73) Chen, M.; Nikles, D. E. J. Appl. Phys. 1999, 85
Pt. 2B, 5504; Chem. Abstr. . 131, 21468.
74) Mitov, M.; Popov, A.; Dragieva, I. Colloids
Surf., A 1999, 149; Chem. Abstr. 1999, 243226
75) Seita, M.; Kusaka, M.; Nawafune, H.; Mizumoto,
S Plat. Surf. Finish. 1999, 86, 62; Chem. Abstr.
130, 314985
76) Mitov, M.; Popov, A.; Dragieva, I J. Appl. Electrochem.
1999, 29, 59; Chem. Abstr. 130, 288352
77) Cassagneau, Thierry; Fendler, Janos H J. Phys. Chem. B
1999, 103, 1789; Chem. Abstr. 130, 257713
78) Forster, G. D.; Fernandez Barquin, L.; Pankhurst, Q. A.;
Parkin, I. P. J. Non-Cryst. Solids 1999, 244, 44; Chem.
Abstr. 130, 284883
79) Osvath, P.; Sargeson, A.M.; McAuley, A.; Mendelez,
R.E.; Subramanian, S.; Zaworotko, M. J.; Broge, L.
Inorg. Chem. ACS ASAP
80) Rakovich, E. V.; Sviridov, V. V Vestsi Nats. Akad. Navuk
Belarusi, Ser. Khim. Navuk 1998, 9; Chem. Abstr.
130:314694
81) Broiggs, T.S. Jolly, W.L. Inorg. Chem. 1975, 14, 2267;
Chem. Abstr. 83, 137450e
82) Schmidt, F.J.; Royer, J.L.; Muir, S.M. Anal. Lett. 1975, 8,
123; Chem. Abstr. 83, 212178c
83) Schmidt, F.J.; Royer, J. Anal. Lett. 1973, 6, 17; Chem.
Abstr. 78, 92121b
84) Kadeg, R.D.; Christian, G.D. Anal. Chim. Acta 1977, 88,
117; Chem. Abstr. 86, 182495w
85) Braman, R.S. et. al. Anal. Chem. 1977, 49, 621; Chem.
Abstr. 87, 34003q
*For Online Consulting Only
150
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
86) Dujmovic, M. GIT Fachz. Lab. 1977, 21, 761;
Chem. Abstr. 87, 21619f
87) Frolov, I.A; kulakov, S.I.; Yakush, G.M. Zh.
Prikl. Khim. 1977, 50, 2561; Che. Abstr. 88,
42199u
88) Yan, D.; Yan, Z.; Cheng, G.; Li, A. Talanta 1984,
31, 133; Chem. Abstr. 100, 150274q
89) Vijan, P.N.; Wood, G.R. Analyst 1976, 101, 966;
Chem. Abstr. 86, 182500u
90) Klayman, D.; Griffin, T.S. J. Am. Chem. Soc.
1973, 95,197; Chem. Abstr. 78, 110774y
91) Japan. Koaki 74 15,137 1974; Chem. Abstr. 82,
17737m
92) Kulakov, S.I. et. al. Zh. Neorg. Khim. 1974, 19,
3239; Chem. Abstr. 82, 67604m
93) Panson, G.S.; Weil, C.E. J. Inorg. Nucl. Chem.
1960, 15, 184; Chem. Abstr. 55, 5216b
94) Luner, P. LaPlaine, R. Wade, R. Pulp Paper Mag.
Canada 1964, 65, T-101
95) Gerrie, J.W. Pulp Paper Mag. Canada 1974, T251; Chem. Abstr. 81, 17676b
96) U.S. 5,129987 1992; U.S. 5,094833 1992; U.S. 5188807,
1993; U.S. 5,391261 1995; 5,336479 1994; 5,429716,
1995)
97) Khain, V.S.; Antsygina, N.N. Zh. Neorg. Khim. 1977, 22,
2987; Chem. Abstr. 88, 31322c
98) Pacer, R.A. J. Inor. Nucl. Chem. 1973, 35, 1375; Chem.
Abstr. 78, 131585c
99) Khain, V.S. Fomina, E.V.; Volkov, A.A. Zh. Neorg.
Khim. 1977, 22, 2987; Chem. Abstr. 88, 31322c
100) Pacer, R.A. J. Inorg. Nucl. Chem. 1976, 38, 817;
Chem. Abstr. 84, 188858x
101) Andreev, F.I.; Khain, V.S. Zh. Neorg. Khim. 1976, 21,
1228; Chem. Abstr. 85, 56030g
102) Khain, V.S.; Andreeev, F.I.; Kinet. Katal. 1977, 18,
267; Chem. Abstr. 86, 128068w
103) Khain, V.S.; Andreeev, F.I. Neorg. Khim. 1978, 23,
977; Chem. Abstr. 89, 52634s
104) Andreev, F.I.; Khain, V.S. Zh. Obshch. Khim. 1975, 45,
2099; Chem. Abtsr. 86, 128068w
105) Khain, V.S.; Andreev, F.I. Zh. Obshch. Khim. 1977, 47,
715; Chem. Abstr. 87, 15322b
106) Khain, V.S.; Andreev, F.I. Zh. Neorg. Khim. 1977, 22,
534; Chem. Abstr. 86, 132741c
*For Online Consulting Only
151
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
107)
116) Waller, Sr. M.C. “Inorganic Chemistry of borohydride”
Metal hydride inc.
117) Warburton, C.D.; Przbylowicz, E.P. Phot. SSCci. Eng.
1966, 10, 86; Chem. Abstr. 64, 15226e
118) Shah, A.R.; Padma, D.K.; Murthy, A.R.V. Indian J.
Chem. 1971, 9, 885; Chem. Abstr. 75, 136669f
119) Castellani-Bisi, C. Ann. Chim. 1959, 49, 2057; Chem.
Abstr. 54, 17137b
120) Chaikin, S.W. Anal. Chem. 1953, 25, 831; Chem. Abstr.
47, 7371g
121) Andreev, F.I.; Tsivelev, R.P.; Khain, V.S. Zh. Neorg.
Khim. 1978, 23, 2847; Chem. Abstr. 89, 225385s
122) Sterlyadkina, Z.K.; Alekseeva, L.S.; Mikheeva, V.I. Zh.
Neorg. Khim. 1969, 14, 2677; Chem. Abstr. 72, 38350p
123) Alekseeva, L.S. Zh. Neorg. Khim. 1975, 20, 2339;
Chem. Abstr. 83, 201393t
124) Freund, T.; Neunkle, N. J. Am. Chem. Soc. 1961, 83,
3378; Chem. Abstr. 56, 1125d
125) Freund, T. J. Inorg. Nucl. Chem. 1959, 9, 246; Chem.
Abstr. 53, 16665h
126) Mochalov, K.N.; Khain, V.S. Zh. Fiz. Khim. 1965, 39,
1960; Chem. Abstr. 63, 15846b
108)
109)
110)
111)
112)
113)
114)
115)
Khain, V.S.; Maretynova, V.F.; Zh. Neorg.
Khim. 1978, 23, 680; Chem. Abstr. 88, 181734c
Khain, V.S.; Fomina, E.V.; Volkov, A.A. Zh.
Obshch. Khim. 1977, 47, 1929; Chem. Abstr.
87, 189975g
Giniyatullin, N.G.; Kargin, Y.M. Izv. Vyssh.
Uchebn. Zaved., Khim. Tekhnol. 1976, 19,
1668; Chem. Abstr. 86, 64862t
Khain, V.S.; Val’kova, V.P.; Kotelevets, E.S.
Zh. Neorg. Khim. 1977, 22, 338; Chem. Abstr.
86, 132740b
Khain, V.S.; Val’kova, V.P. Zh. Obshch. Khim
1977, 47, 961; Chem. Abstr. 87, 29619r
Amendola, S. C.; Onnerud, P.; Kelly, M. T.;
Petillo, P. J.; Binder, M. Proc. - Electrochem.
Soc., 1999, 98 , 47
Gardiner, J.A. Collat, J.W. J. Am. Chem. Soc.
1965, 87, 1692; Chem. Abstr. 62, 13899b
Gardiner, J.A. Collat, J.W Inorg. Chem. 1965,
4, 1208; Chem. Abstr. 63, 6610e
Jolly, W.L.; J. Am. Chem. Soc. 1961, 83, 335;
Chem. Abstr. 55, 12126c
*For Online Consulting Only
152
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
127) Freitag, W.O.; Sharp, T.A.; Baltz, A.;
Suchodolski, V. J. Applied Phys. 1979, 50,
7801; Chem. Abstr. 92, 87038q
128) Schlesinger, H.I. et al. J. Am. Chem. Soc. 1953,
75, 199; Chem. Abstr. 47, 3741h
129) McBride, D.G.; Vlasak, G.P. J. Electrochem.
Soc. 1971, 118, 2055; Chem. Abstr. 76, 62788r
130) Pratt, J.M.; Swinden, G. J. Chem. Soc., Chem.
Commun. 1969, 1321; Chem. Abstr. 72, 47951
131) Paul, R.; Buisson, P.; Joseph, N. Ind. And Eng.
Chem. 1952, 44, 1006; Chem. Abstr. 46, 9960e
132) Thonnart, P. Lenfart, P.; Legas, C.C. R. Acad.
Sci. Paris 1964, 258, 5207
133) Hofer, L.J.E.; Shultz, J.F.; Panson, R.D.;
Anderson, R.B. Inorg. Chem. 1964, 3, 1783;
Chem. Abstr. 62, 4886b
134) Brown, C.A. J. Org. Chem. 1970, 35, 1900;
Chem. Abstr. 73, 29374t
135) Waller, M.C.; Miniatas, B.O.; Hohnstedt, L.F.
Anal. Chem. 1965, 37, 1163; Chem. Abstr.
10641c
136) Mochalov, K.N.; Bashkirova, T.I. Zavod. Lab.
1969, 35, 795; Chem. Abstr. 72, 74415x
137) Prokopoikas, A.; Sakalauskiene, J. Liet. Tsr Mokslu
Akad. Darb., Ser B. 1971, 117; Chem. Abstr. 76,
63968m
138) Rozovskis, G. Issled. Obl. Osazhdeniya Metal., Mater.
Respub. Konf. Electrokhim., Litov SSR, 11th 1971, 133;
Chem. Abstr. 77, 23789t
139) Piper, T.S.; Wilson, K.M. J. Inorg. Nucl. Chem. 1957,
4, 22; Chem. Abstr. 51, 7924e
140) Maklen, E.D. J. Chem. Soc. 1959, 1989; Chem. Abstr.
53, 14805g
141) Jolly, W.L. et. al. J. Inorg. Nucl. Chem. 1960, 14, 190
142) Gunn, S.R.; Jollly, WL.; Green, L.G. J. Phys. Chem.
1960, 64, 1334; Chem. Abstr. 55, 8026f
143) Mochalov, K.N. et. al. Dokl. Akad. Nauk. SSSR 1966,
64, 1334; Chem. Abstr. 64, 17009f
144) Mochalov, K.N.; Polovnyak,V.K.; Groisberg, A. T. Izv.
Vyssh. Ucheb. Zaved., Khim,. Khim. Tekhnol. 1973, 16,
1115; Chem. Abstr. 79, 111314f
145) Alekseeva, L.S. et. al. Zh. Neorg.Khim. 1976, 21, 277;
Chem. Abstr. 84, 115375c
146) Brown, H.C.; Brown, C.A. J. Am. Chem. Soc. 1962, 84,
1493; Chem. Abstr. 57, 111b
*For Online Consulting Only
153
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
147) Mochalov, K.N.; Ostryakova, T.A.; Tremasov,
N.V. Tr. Kazan. Khim. Teknol. Inst. 1969, 40,
186; Chem. Abstr. 75, 44502t
148) Khain, V.S.; Volkov, A.A. Zh. Prikl. Khim.
1983, 56, 663; Chem. Abstr. 98, 226838q
149) Borgonostesev, A.S.; Timofeeva, G.P. Tr.
Kazan. Inzh. Stroit. Inst. 1967, 142; Chem.
Abstr. 74, 37951q
150) Svata, M..; Jindra, J. Colllect. Czech. Chem.
Commun. 1970, 35, 692; Chem. Abstr. 72,
95972s
151) U.S.S.R. 269, 670 1970; Chem. Abstr. 73,
58794k
152) Schaeffer, G.W.; Emilius, M. J. Am. Chem.
Soc. 1954, 76, 1203; Chem. Abstr. 48, 6303h
153) Evans, D.H. Anal. Chem. 1964, 36, 2435;
Chem. Abstr. 62, 3399f
154) Zorin, A.D.; Frolov, I.A.; Morozova, T.V. Sh.
Obshch. Chim. 1972, 42, 900; Chem. Abstr. 77,
83043e
155) Khain, V.S.; Kotelevets, E.S. Zh. Neorg. Khim.
1982, 27, 1199; Chem. Abstr. 97, 32674s
156) Lyttle, D.A.; Jensen, E.H.; Struck, W.A. Anal. Chem.
1952, 24, 1843; Chem. Abstr. 47, 1005h
157) Mochalov, K.N.; Gilmanashin, G.G.; Giniyatullinm,
N.G.; Polovnyak, V.K. Tr. Kazan. Khim. Tekhnol. Inst.
1969, 40, 143; Chem. Abstyr. 75, 14489b
158) Khain, V.S.; Zhomova, M.I.; Andreev, F.I. Zh. Neorg.
Khim. 1985, 30, 360; Chem. Abstr. 102, 142133u
159) Khain, V.S. Zh. Prikl. Khim. 1980, 53, 2745; Chem.
Abstr. 94, 149364v
160) Volkov, A.A.; Khain, V.S. Zh. Anal. Khim. 1982, 37,
876; Chem. Abstr. 97, 103483s
161) Marshall, E.D.; Widing, R.A. U.S.A.E.C. Report
AECD-2914 1950
162) Romain, P.; Merland, R. Laubie, H. Bull. Soc. Pharm.
Bordeaux 1954, 92, 131; Chem. Abstr. 50, 722e
*For Online Consulting Only
154
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
B. Organometallic
organophosphorus ligands has been reported for iron (2-4),
ruthenium (2) and cobalt (5).
Examples of NaBH4 reduction to lower valent metal
complexes are the octaethylporphyrin complexes of Rh (I) (6)
and Fe (II) (7,8) made from the corresponding M(III) complex
chlorides, and the bis-dehyrocorrin complex of Co(I) made
from the corresponding dicyanocobalt (III) complex (9).
The most familiar type of demetallation or cleavage
of organometallics by NaBH4, is demercuration, which is
covered in a separate section. The analogous reduction of
organothallium compounds has also been reported (10,11).
Other cleavages include those of serinato copper (II)
complexes (12), a tetracarbonylallyliron cation (13), dimeric
cienyl rhodium complexes (14), and cephem-π-allyl palladium
dichloride (15). Complex formation and reduction in the last
instance is utilized to isomerize 2-cephenms to 3-cephems.
Published examples involve cleavage of magnesium and lead
macrocycles (16), a palladium pyrazinoindole complex (17),
silver and copper porphyrins (18), and heterocyclic amino acid
complexes of copper and nickel (19).
The conversion of organometallic halides to the
corresponding hydride or hydride halide, by reduction with
NaBH4 is widely used and has been applied to complexes of
The rapid growth of organometallic
chemistry in recent years has given rise to numerous
applications of sodium borohydride’s reducing
capabilities. From a survey of literature citations
using NaBH4 in this specialized field, it quickly
becomes apparent that, in general, five major types of
reactions are involved: initial formation of
organometallic compounds and complexes, reduction
to lower valent metal compounds, demetallation or
cleavage or organometallics to the metal and organic
species, conversion of organometallic halides to the
corresponding hydride or hydride halide, and
reduction of organometallic cations to neutral species.
The formation of organometallics via NaBH4
reduction is typified by the formation of cobalt (II)
thiol complex catalysts where the thiol ligands are
derived from amino acids such as serine, cysteine and
cysteamine (1); these catalysts are effective in the
reduction of acetylene. The use of NaBH4 in the
synthesis
of
hydridometal
complexes
with
*For Online Consulting Only
155
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
chromium (20), iron (21), cobalt (22), nickel (23,24),
molybdenum (25), tungsten (25), tin (26,27),
ruthenium (28), rhodium (29,30) palladium (23),
osmium (31,32), platinum (29,33,34), and iridium
(35). The generation of organometallic hydrides has
also been used on the analytical determination of
organometallic species in various matrices, e.g. Ge
(36), Sn (37) and Pb (38).
Organometallic cations are often reduced by
NaBH4 to give neutral organometallic compounds, as
in the cases of Mo (39), Mn (40), Re (41), Ru (42), Co
(43), and Fe (44).
The preparation of several hydrogenantion
catalysts bound to polymers has been reported,
including palladium (45), rhodium (45,46), iridium
(47), and others (48).
NaBH4 reduction of metal carbonyls,
followed by acidification, has been used as a general
synthetic method for transition metal hydrido carbonyl
clusters (49).
Other used include a commercial nickel
phosphine catalyst for ethylene oligomerization to
linear alpha-olefins (50-53), the reduction of optically
pure deuterated amino acid complexes of Co (III) to provide
optically pure amino acids without loss of deuterium (54), an
active homogeneous molybdenum carbonyl catalyst for the
water gas shift reaction (55), and the generation of spent
hydroformylation catalysts (56).
*For Online Consulting Only
References:
1) Sugiura, Y.; Kikuchi, T.; Tanaka, H. J. Chem. Soc., Chem.
Commun. 1977, 795
2) Gerlach, D.H.; Peet, W.G.; Muetterties, E.L. J. Am. Chem.
Soc. 1972, 94, 4545; Chem. Abstr. 77, 62114p
3) Dapporto, P.; Fallani, G.; Midollini, S.; Sacconi, L. J. Am.
Chem. Soc. 1973, 95, 2021; Chem. Abstr. 78, 13154k
4) Giannoccaro, P.; Sacco, A. Inorg. Synth. 1977, 17, 69;
Chem. Abstr. 88, 12113d
5) Carriedo, C.; Gomez-Sal, P. et. al. J. Organomet. Chem.
1986, 301, 79; Chem. Abstr. 104, 179029g
6) Ogoshi, H.; Sntsune, J.; Tyoshida, Z. J. Am. Chem. Soc.
1977, 99, 3869; Chem. Abstr. 887, 135837v
7) Dolphin, D.; Sams, J.R.; Tsin, T.B.; Wong, K.L. J. Am.
Chem. Soc. 1976, 98, 6970
8) Jpn. Kokai Tokkyo Koho 78, 112, 900 1978; Chem.
Abstr. 90, 121679v
156
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
9) Murakami, Y.; Aoyama, Y.; Nakanishi, S.; Chem.
Lett. 1977, 991;Chem. Abstr. 87, 126495e
10) Bach, R.D.; Holubka, J.W. J. Am. Chem. Soc.
1974, 96, 7814; Chem. Abstr. 82, 16203x
11) Uemura, S.; Miyoshi, M.: Tara, H.; Okano, M.;
Ichikawa, K. J. Chem. Soc., Chem. Commun.
1976, 218; Chem. Abstr. 85, 46802w
12) O’Conner, M.J.; Smith, J.F.; Teo, S. Aust. J.
Chem. 1976, 29, 375; Chem. Abstr. 84, 180114f
13) Pearson, A.J. Aust. J. Chem. 1976, 29, 1841;
Chem. Abstr. 86, 16771p
14) Eaton, P.E.; Patterson, D.R. J. Am. Chem. Soc.
1978, 100, 2573; Chem. Abstr. 89, 43537k
15) Jpn. Kokai 77 105,192 1977; Chem. Abstr. 88,
105372t
16) Mandal, S.K.; Nag, K.J. J. Org. Chem. 1986, 51,
3900; Chem. Abstr. 105, 1724435y
17) Hegedus, L.S.; Mulhern, T.A.; Asada, H. J. Am.
Chem. Soc. 1986, 108, 6224; Chem. Abstr. 105,
172406q
18) Cowen, J.A/; Sanders, J.K.M. Tetrahedron Lett.
1986, 27, 1202; Chem. Abstr. 105, 90145q
19) Teo, S.B.; Tech, S.G. Inorg. Chem. Acta 1985, 107, 35;
Chem. Abstr. 103, 63855y
20) Koola, J.D.; Brintzinger, H.H. J. Chem. Soc., Chem.
Commun. 1976, 388; Chem. Abstr. 85, 124088j
21) Nesmeyanov, A.N.; Chapovskii, Y.A.; Ustynyuk, Y.A.
Izv. Akad. Nauk SSSR, Ser. Khim. 1966, 1871; Chem.
Abstr. 66, 64860a
22) Chao, T.; Epsenson. J.H. J. Am. Chem. Soc. 1987, 100,
129; Chem. Abstr. 88, 111148r
23) Saito, T.; Munakata, H.; Imoto, H. Inorg. Synth. 1977, 17,
83; Chem. Abstr. 88, 121313e
24) Takagi, K. Chem. Lett. 1986, 265; Chem. Abstr. 105,
208796h
25) Meakin, P.; Guggenberg, L.J.; Peet. W.G.; Muetterties,
E.L.; Jesson, J.P. J. Am. Chem.Soc. 1973, 95, 1467; Chem.
Abstr. 78, 101033c
26) Corey, E.J.; Suggs, J.W. J. Org. Chem. 1975, 40, 2554;
Chem. Abstr. 83, 130658v
27) Birnbaum, E.R.; Javora, P.H. J. Organomet. Chem. 1967,
9, 379; Chem. Abstr. 68, 22026u
28) Young, R.; Wilkinson, G. Inorg. Synth. 1977, 17, 75;
Chem. Abstr. 88, 105484f
*For Online Consulting Only
157
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
29) Empsail, H.D.; Hyde, E.M.; Pawson, D.; Shaw,
B.L. J. Chem. Soc., Dalton Trans 1977, 1292;
Chem. Abstr. 87, 168176g
30) Eur. Pat. Appl. 55, 487 1982; Chem. Abstr. 98,
4675v
31) Bell, B.; Chatt, J.; Lkeigh, G.J. J. Chem. Soc.,
Dalton Trans. 1973, 997; Chem. Abstr. 78,
154371u
32) Werner, H.; Zenkert, K. J. Chem. Soc., Chem.
Commun. 1985, 1607; Chem. Abstr. 105, 97654p
33) Moulton, C.J.; Shaw, B.L. J. Chem. Soc., Chem.
Commun. 1976, 365; Chem. Abstr. 85, 136363h
34) Meyer, W.R.: Venanzi, L.M. Angew, Chem. 1984,
96, 505; Chem. Abstr. 101, 64917r
35) Greene, T.R.; Roper, W.R. J. Organomet. Chem.
1986, 299, 245; Chem. Abstr. 105, 226938k
36) Hambrick, G.A.; Froelich, P.N.; Andreae, M.O.;
Lewis, B.L. Anal. Chem. 1984, 56, 421; Chem.
Abstr. 100, 90972d
37) Hattori, Y.; Kobayashi, A. et. al. J. Chromatogr.
1984, 315; 341; Chem. Abstr. 102, 100497k
38) D’Uliva, A.; Fouco, R.; Papoff, P. Talanta 1986,
33, 401; Chem. Abstr. 105, 90513h
39) Brunner, H.; Watchter, J. J. Organomet. Chem. 1980, 201,
453; Chem. Abstr. 94, 102685k
40) Brookhart, M.; Lukacs, A. J. Am. Chem. Soc. 1984, 106,
4161; Chem. Abstr. 101, 91137t
41) Sullivan, B.P.; Meyer, T.J. J. Chem. Soc., Chem.
Commun. 1984, 1244; Chem. Abstr. 102, 55034u
42) Davies, D.L.; Knox, S.A.R. et. al. J. Chem. Soc., Dalton
Trans. 1984, 2293; Chem. Abstr. 102, 113688y
43) Jacobsen, E.N.; Bergman, R.G. J. Am. Chem. Soc. 1985,
107, 2023; Chem. Abstr. 102, 149512a
44) Catheline, D.; Lapinte, C.; Astruc, D.C. R. Acad. Sci., Ser
2 1985, 301, 479; Chem. Abstr. 104, 186591n
45) Latov, V.K.; Belikov, V.M.; Belyaeva, T.A.;
Vinogradova, A.I.; Soinov, S.I. Izv. Akad. Nauk SSR, Ser.
Khim. 1977, 2481; Chem. Abstr. 88, 104852n
46) Holy, N.L. Tetrahedron Lett. 1977, 3703; Chem. Abstr.
88, 104735b
47) U.S. 4,062,803 1977 Corresponds to Ger. Offen.
2,600,634 1976; Chem. Abstr. 85, 198875k
48) U.S. 4,313,018 1982; Chem. Abstr. 96, 141870c
49) Kaesz. H.D. Chem. Brit. 1973, 9, 344; Chem. Abstr. 79,
86879j
50) U.S. 3,676, 523 1972; Chem. Abstr. 77, 100710q
*For Online Consulting Only
158
Rohm and Haas : the Sodium Borohydride Digest
51)
52)
53)
54)
U.S. 3,686, 351 1972; Chem. Abstr. 77, 151422e
U.S. 3,737, 475 1973; Chem. Abstr. 79, 31448n
U.S. 3,825,615 1974; Chem. Abstr. 81, 119895h
Keyes, W.E.; Legg, J.I. J. Am. Chem. Soc. 1976,
98, 4970; Chem. Abstr. 85, 108969s
55) King, R.B.; Frazier, C.C.; Hanes, R.M.; King,
A.D. J. Am. Chem. Soc. 1978, 100 2925; Chem.
Abstr. 88, 198376k
56) Jpn. Kokai Tokkyo Koho 84, 115,752 1984;
Chem. Abstr. 101, 213057q
*For Online Consulting Only
press <CTRL>-F for Searching
159
160
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
C. NaBH4 Derivatives
via rapid and reversible protonation of the β-carbon generating
a readily reducible imminium salt:
NaBH3CN
Alembic 1, 3, 7, 8, 15, 18, 23, 44, 46
Sodium cyanoborohydride, which is soluble
in a wide variety of solvents and is hydrolytically
stable to a pH of approximately 3, has extremely
interesting properties (1-4). Under neutral conditions
in water and methanol, the reduction of aldehydes and
ketones is insignificant; however, at pH 3-4, rapid
reduction to the alcohol occurs (5,6). The imine
group, >C=N-, is reduced by cyanoborohydride much
more rapidly than carbonyls, providing a convenient
and efficient route to the reductive amination of
aldehydes and ketones (5,7-10).
RR’C=O + R”NH2 + NaBH3CNÆ RR’CHNHR”
The reaction is general for ammonia, primary and
secondary amines, all aldehydes and unhindered
ketones. Smooth reductions of acid chlorides and
enamines are also possible with NaBH3CN, the latter
*For Online Consulting Only
N
H
H+
BH3CN-
N+
H
H
N
H
H
H
The versatility of this reagent is further demonstrated
in a number of selective reductions of a variety of organic
functional groups, for example, in the selective reduction of
aldehydes and ketones to hydrocarbons via their tosy
hydrazones (11-14), selective reduction of alkyl bromides,
iodides and tosylates to hydrocarbon (15,16), reductive
alkylation of amines and hydrazines (17,18) and of amides
(19). NaBH3CN has also been applied in some interesting
synthetic reactions, e.g. synthesis of N-labeled alkaloids (20),
and amino acids (5), reduction of pyridines exclusively to the
1,4 dihydro derivatives (21), and synthesis of epoxy-Nnitrocarbamates (22).
An excellent review article on the utility and
applications of cyanoborohydride has been published (23).
Rohm and Haas : the Sodium Borohydride Digest
Polymer bound borohydride reducing reagents
(borohydride exchange resins)
Alembic 13, 52
100
BER in MeOH
80
60
Polymeric-bound borohydride (24,25), PNR3+BH4-, (borohydride exchange resins) offer several
advantages over sodium borohydride. The primary
advantage are the convenience of use of these
materials and the minimal introduction of ionic
species or organic by products into the treated bulk
media. The reactivity of these borohydride exchange
resins depends on the skeletal structure/pore size of
the resins, the nature of the solvents, the nature of the
reducing reagent and the type of co reagent used.(26)
Fig. 12 Stability of Borohydride Exchange Resins in
Alcohols
*For Online Consulting Only
161
press <CTRL>-F for Searching
NaBH4 in MeoH
40
BER in 95%Et OH
20
0
0
50
100
NaBH4 in
95%Et OH
Ti m e M i nu t e s
Borohydride exchange resins have been shown to be
an effective reducing agents for the reduction of many
functional groups such as aldehyde and ketones (27-34), azides
(35,36), reductive amination (37-39), synthesis of thioethers
(40-43), thiols (44) and disulfides (45,46), hydroboration of
alkenes (47,49) and alkynes (50,51), dehalogenantion (52-55),
carboxylic acids (56-57), nitro (58), anhydrides (59),
hydrazones (60), cyanides (61), oximes (62), deoxygenantion
of amine N-oxides (63-65) and the coupling of alkenes and
halides (66-69). Chiral reductions of ketones have been
achieved using chiral polymers as support. (70-71)
The combination of sodium borohydride and ion
exchange resins stabilize the borohydride towards solvolysis
with protic solvents such as methanol and ethanol. The graphs
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
which follows demonstrate the stability that can be
achieved by combing ion exchange resins with sodium
borohydride.
Other applications in which borohydride
exchange resins have been used for are; purification of
solvents, generation of volatile hydrides and reduction
of metal ions. The anion exchange resins are
generally of the styrene/divinylbenzene gel and
macroreticular types such as Amberlitetm 400,
although the triethylmethyl ammonium cellulose
anion exchange has been reported (72-73)
Anion
exchange
resin
supported
cyanoborohydride
(styrene/divinylbenzene
macroreticular type) has been utilized in a variety of
reductions previously developed for the sodium salt
(23). While the reductions are slower with resin,
selectivity is retained.
alkenes, alkynes, imines, nitro, esters, and reductive amination
of aldehydes and ketones in high yields and under mild
reaction conditions in polar solvents such as tetrahydrofuran..
(74-83) This technique has been extended to other solid
supports such as alumina (84-86), zeolites (87) and alumino
phosphates (88,89).
Other Solid Supports for Borohydrides
It has been demonstrated that silica gel
impregnated with NaBH4 or Zn(BH4)2 can selectively
reduce ketones and aldehydes in nonpolars such as
hexane, and other functional groups such as epoxides,
*For Online Consulting Only
Alembic: 4
NaBH2S3 (Lalancette’s Reagent)
When sodium borohydride and sulfur are allowed to
react at room temperature in THF (90) there is a rapid
evolution of hydrogen, and sulfurated sodium borohydride
NaBH2S3 is formed: 8 NaBH4 + 3 S8 Æ 8 NaBH2S3 + 8 H2.
This reagent reduces aldehydes to the alcohols at low
temperatures (91,92) and form sulfides and thiols at about 60o
C (93). The reagent has also been used to prepared thioacetals
in quantitative yields (94).
The reduction of ketones (95,96), oximes (97-99),
epoxides (100) and episulfides (101) has also been reported.
NaBH2S3 is intermediate in reducing potential between LiAlH4
and NaBH4 and reductions of functional groups containing
nitrogen are particularly facile (97-105). Aromatic nitro
162
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
compounds are reduced to amines selectively;
halogen, ether olefin nitriles, ester, acid groups are
inert to the sulfurated borohydride. Primary aliphatic
nitro groups are converted to the nitrile and secondary
to a mixture of ketones and the corresponding oxime,
amides and nitroso compounds are reduced to amines,
as are aromatic nitriles when the reducing agent is
present in excess. When excess nitrile is present, the
corresponding thioamide is formed.
A number of trialkoxy derivatives have been reported,
including R= Me, Et, CH(CH3)2, CHEtMe (110-112) and
CH2CH2OCH3
(2-methoxyethoxy)
(113).
Trialkoxyhydridoborates reduce aldehydes, ketones, acid
chlorides, and acid anhydrides. At low temperatures acid
chlorides are reduced to aldehydes. Ester and nitriles are
slowly reduced at elevated temperatures. The bulky secbutoxy derivatives, NaBH(OCHEtMe)3, have been used in the
stereoselective reduction of steroidal ketones (114).
Reductive amination of aldehydes and ketones with
amines have been demonstrated in high yields using alkoxy
borohydrides.
Many examples of nitrogen – carbon double bonds
have been reduced to amines in high yields using this reagent.
Bis and tris aryl methanol can be reduced to alkanes
using trialkoxy borohydrides.
NaBH(OR)3, Sodium Hydridotrialkoxyborates
Alembic: 14, 25, 31, 33
Over the years many papers relating to the
reduction of many functional groups such as indoles,
imines, enamines, oximes, amides, nitriles, alcohols to
hydrocarbon, ketones to hydrocarbon, acetals, ketals,
ethers, aldehydes, ketones, and alkenes or reductive
amination of ketones and aldehydes have been
published. Summaries of these works have been
published in a few informative reviews. (106-109)
Examples of these reactions are shown below.
*For Online Consulting Only
NaBH4 Polyamine polymers
By chelating the sodium ion with polyamine, PMDT
(N,N,N’,N’,N’-pentamethyldiethylenetriamine),
CH3N[CH2CH2NCH3)2]2, NaBH4 becomes solubulized in
hydrocarbon solvents (115). Many reductions can be carried
out in non-polar solvents.(116)
163
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
The multi amine containing organic
molecules, DABCO (117,118) and polyvinyl pyridine
(119,120), polypyrazine (121, 122) can complex to
sodium and zinc borohydride to form very efficient
reducing reagents.
group. A major use of potassium borohydride is in the
synthesis of lithium borohydride. Potassium borohydride is
synthesized by the reaction of sodium borohydride with
potassium hydroxide in water. The potassium borohydride
drops out of solution and is isolated as a white solid in high
yield and purity. (126-127)
Lithium Borohydride (LiBH4)
Alembic 52
Lithium borohydride (LBH) is a stronger
reducing agent then either potassium or sodium
borohydrides. LBH will reduce aldehydes, ketones,
acid chlorides, esters, epoxides, lactones and nitriles.
It can be formed in situ by reacting either sodium or
potassium borohydride with lithium chloride in an
ether solvent or liquid ammonia. (123-125)
Potassium Borohydride (KBH4)
Alembic 53
Potassium borohydride (KBH) has the same
solubility and reductive power as sodium borohydride.
KBH will reduce aldehydes, ketones, acid chlorides
and epoxides, and lactones that contain α-withdrawing
*For Online Consulting Only
Calcium Borohydride (Ca(BH4)2)
Calcium borohydride (CaBH) has similar solubility
and reductive power as lithium borohydride. CaBH will reduce
aldehydes, ketones, acid chlorides, esters and epoxide.
Calcium borohydrides is used to synthesize lactones from
hemiesters and to stereoselectively reduce ketones by forming
a sterically hindering metal complex. CaBH is synthesized by
combining CaCl2 and sodium borohydride in either THF or
methanol. Solid Ca(BH4)2•6THF is isolated when THF is
used as the reaction solvent. (128, 129)
Zinc Borohydride (Zn(BH4)2
Alembic 48, 58
Zinc borohydride is a strong reducing agent that will
reduce aldehydes, ketones, acid chlorides, esters, epoxide,
azides, α,β ethylenic ketones to allylic alcohols, and
164
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
carboxylic acids. Zinc borohydride can selectively
reduce aldehydes in the presence of ketones and
aliphatic ketones in the presence of aromatic ketones.
Reviews on the use of this reagent have been
published. (130,131) This reagent has been combined
with solid supports such as silica gel and ion exchange
resins to make a more robust reducing reagent.(132137) Polypyrazine and DABCO have been combined
with zinc borohydride to form a polymeric solid
reducing reagent. Zinc borohydride can exist as a
dimeric compound when synthesized from LBH and
ZnCl2 in diethyl ether. A more complex solution of
zinc borohydrides are formed when prepared from
SBH and ZnCl2 in THF or DME. In most cases this
reagent is formed in situ and used as a freshly made
before each use. (138-144)
Esters and Acids
The system using NaBH4 and AlCl3 in dyglme,
reported by brown and co-workers (145,146) gives good yields
in the reduction of saturated acids and esters to alcohol at
Room temperature. Unsaturated esters, diesters and diacids
are also reduced, but the reaction is complicated by formation
of difficulty hydrolyzed boron complexes.
LiCl and NaBH4 in THF (147-149) also reduce esters
readily to alcohols; LiBH4 is formed and consumed in situ.
NaBH4 and CaCl2 in ethanol also effectively reduce esters
(150-15).
Enhanced reduction efficiency of NaBH4 has been
reported in the presence of TiCl4 (153). Not only are esters
reduced, but also many other functional groups causing
problems with NaBH4 and AlCl3 are smoothly reduced using a
4 to 1 molar ratio of NaBH4 to TiCl4 in diglyme. This system
reduces diesters and anhydrides to diols.
Mixed Hydrides
Several systems have been devised, adding to
the number of functional groups that can be reduced
effectively with NaBH4. In these, the reducing power
of NaBH4 is enhanced to differing degrees.
*For Online Consulting Only
Acetals and ketals
NaBH4 in combination with either AlCl3 or BF3 in
diglyme reduces acetals and ketals to their corresponding ether
(154).
165
Rohm and Haas : the Sodium Borohydride Digest
Hydroboration
Alembic 60
Diborane, prepared from NaBH4 and I2, BF3,
Me3SlCl, TiCl4 or H2SO4 reacts rapidly and
quantitatively in ether solvents with organic
unsaturation to form organoboranes (155,156),
>B-H + CH2=CHR Æ B-CH2CH2R
which can serve as reactive intermediates in organic
synthesis. This methodology is also capable of
reducing the following functional groups: nitrile
(157,158), epoxides (159,160), carboxylic acids (161171), amides (172-176), esters (177), oximes (178),
nitro (179,180), olefinic bonds (181, 182) as well as
reductive amination of ketones and aldehydes (183186). Stereoconfiguration is retained and, in contrast
with Grignard reagents, the reagent is compatible with
most functional groups.
The intermediates organoboranes undergo a
wide variety of reactions, as shown in Table VI,
including isomerization (187,188), displacement (189,
*For Online Consulting Only
press <CTRL>-F for Searching
190), cyclization (188, 191), protonolysis to hydrocarbons
(192), oxidation to alcohols (193), ketones (194 ), and
carboxylic acids (195) (depending on the reagents used),
amination (196, 197), metallation (198), coupling (199, 200)
and 1, 2, 3 and 4 carbon homoolgations, alkylation and
arylation (201) and conjugated addition (202).
Carbonlyation of organoboranes at low pressures
provides a route to primary, secondary and tertiary alcohols
(203-205), aldehyde (206) and ketones, methanol derivatives
and polycyclics (207).
166
press <CTRL>-F for Searching
Rohm and Haas : the Sodium Borohydride Digest
Table VI Organoborane Reactions
Reaction
Amination
Coupling
Cyclization
Reactants
C-B
2 (C-B)
C-C H-B
Means
H2NOSO3H
Alk. AgNO3
heat
Prodcdut
C-NH2
C-C
C-B
Displacment
Homologation
1C
2C
R-C-C-B
R’CH=CH2
RCH=CH2
C-B
3C
CO
α-haloester
(+ KOtBu)
CH2=CHCHO
4C
CH2=CHC(O)CH3
C-C-B
CCH2CO2R
CCH2CH2CHO
CCH2CH2C(O)CH3
C-C-C-B
Isomerization
Metalation
Oxidation
To alcohols
To Ketones
To Acids
Protonation
C-C-C
B
C-B
heat
Alk. M salt
Alk. H2O2
H2CrO4
1. H2CrO4
2. RCOOOH
RCOOH + heat
*For Online Consulting Only
C-M
C-OH
C=O
C-CO2H
C-H
Other Derivatives
The reducing power of sodium borohydride can
further be enhanced in the presence of a reagent such as
carboxylic acid, thiol compounds or anilide. Such systems are
becoming more important and have greatly extended the scope
of this reagent. The active species in these systems have not
been isolated and the reducing agent are prepared and used insitu. Table VII summarizes the results.
167
Table VII Alkoxyborohydrides
Reagent (mole
ratio)
NaBH4/
CH3CO2H
(1:3.25)
Proposed
intermediate
STAB
NaBH4./
CH3CO2H
(1:1)
NaBH4/
CH3CO2H
(excess)
SMAB
NaBH4/
CH3CO2H
(6.5:1)
NaBH4/
RCO2H
(excess)
NaBH4./
CF3CO2H
(excess)
STAB
STRB
STFAB
*For Online Consulting Only
168
press <CTRL>-F for Searching
Rohm and Haas : the Sodium Borohydride Digest
Reduction
ref
Reduction of
aldehydes
Reductive
alkylation of
quinoline and
isoquinoline
Reduction of
amides and
amines
N-alkylation of
aromatic amines
and indoles
Reductive
deoxygenantion of
carbonyl tosyl
hydrazones
Reduction of
nitrimines to
nitramines
Reductive
alkylation of
oximes
Reduction of
carbonols and
ketones to alkanes
208 209
210
211 212
213
214
216
215
NaBH4
/CF3CO2H (1:1)
NaBH4/phthalic
acid (1:1)
NaBH4/thiol
SMFAB
NaH2B
(phthalato)
NaBH4/anilide
(1:1)
NaH3B
anilido)
NaBH4/ NaOH)
NaH3BOH
STAB= NaBH(O2CCH3)3
SMAB= NaBH3(O2CCH3)
STRB= NaBH(O2CR)3
STFAB=NaBH(O2CCF3)3
SMFAB=NaBH3(O2CCF3)
Reduction of
nitriles to amines
Reduction of
nitriles to amines
Reduction of nitro
compounds,
esters, amides and
imide
Reduction of
esters, aldehydes
and ketones, acid
chlorides
Reduction of
esters, nitriles and
nitro compounds
217
218
219
220
221
222223224
225226
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
References:
1) Wade, R.C.; Sullivan, E.A.; Berschied, Jr, J.R.;
Purccell, K.F. Inorg. Chem. 1970, 9, 2146; Chem.
73, 83350
2) Kreevoy, M.M.; Hutchins, J.E.C. J. Am. Chem.
Soc. 1969, 91, 4329; Chem. Abstr. 71, 54148p
3) Berschied, Jr. J.R.; Purcell, K.F. Inorg. Chem.
1970, 9, 624; Chem. Abstr. 72, 96136j
4) Levine, L.A.; Kreevoy, M.M. J. Am. Chem. Soc.
1972, 94, 3346; Chem. Abstr. 77, 10408t
5) Borch, R.F.; Bernstein, M.D.; Durst, H.D. J. Am.
Chem. Soc. 1971, 93, 2897; Chem. Abstr. 75,
49525n
6) Pfeil, J.L.; Kukolja, S.; Paquette, L.A. J. Org.
Chem. 1981, 46, 827; Chem. Abstr. 94, 139711s
7) Rosen, G.M.; J. Med. Chem. 1974, 17, 358;
Chem. Abstr. 81, 33187
8) Inokoshi, J.; Nakagawa, A.; Tanaka, H. Omura, S.
J. Antibiot 1983, 36, 1713; Chem. Abstr. 100,
97722e
9) Mathis, C.A.; Shulgin, A.T.; Sargent, T. J.
Labelled Cmpd. Radiopharm. 1986, 23, 115;
Chem. Abstr. 105, 225903
10) U.S.4,593,118 1986; Chem. Abstr. 105, 97020d
11) Hutchins, R.O.; Marynoff, B.E.; Milewski, C.A. J. Am.
Chem. Soc. 1971, 93, 1793; Chem. Abstr. 77, 113763j
12) Hutchins,R.O.; Karcher, M.; Rau, J. Org. Chem. 1975,
40, 923; Chem. Abstr. 85, 122714m
13) Mahajan, J.R.; de Araujo, H.C. Synthesis 1981, 49; Chem.
Abstr. 94, 204868d
14) Avasthi, K.; Salomon, R.G. J. Org. Chem. 1986, 51, 2556;
Chem. Abstr. 105, 23981w
15) Hutchins, R.O.; Kandasamy, D.; Marynoff, C.A.;
Masiamani, D.; Marynoff, B.E. J. Org. Chem. 1977, 42,
82; Chem. Abstr. 86, 54918z
16) Mazzocchi, P.; Ammon, H.L. et. al. J. Org. Chem. 1981,
46, 4530; Chem. Abstr. 95, 187016m
17) Borch, R.F.; Hassid, A.I. J. Org. Chem. 1972, 37, 1673;
Chem. Abstr. 77, 19272b
18) Gidley, M.J.; Sanders, J.K.M. Biochem. J. 1982, 203, 331;
Chem. Abstr. 97, 35620g
19) Basha, A.; Orlando, J.; Winreb, S.M. Synth. Commun.
1977, 7, 549; Chem. Abstr. 88, 136117t
20) Leete, E.; Isaacson, H.V.; Durst, H.D. J. Label.
Compounds 1971, 7, 313; Chem. Abstr. 76, 14762f
*For Online Consulting Only
169
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
21) Eiser, U.; Kuthan, J. Chem. Rev. 1972, 72, 1;
Chem. Abstr. 76, 723221x
22) Pdwa, A.; Cimiluca, P.; Eastman, D. J. Org.
Chem. 1972, 37, 805; Chem. Abstr. 76, 126164u
23) Hutchins, R.O.; Natale, N.R. Org. Prep. Proced.
Int. 1979, 11, 201; Chem. Abstr. 92, 40740x
24) U.S. 4,107,099 1978; Chem. Abstr. 90, 55971f
25) Gibson, H.W.; Baily, F.C. J. Chem. Soc., Chem.
Commun. 1977, 815; Chem. Abstr. 88, 152171m
26) Sande, A.R.; Jagadale, M.J. Tetrahedron Lett.
1984, 3501
27) Yoon, N.M.; Gyong, Y.S. Bull Korean Chem.
Soc. 1987, 8, 162
28) Yoon, N.M.; Park, K.B. Gyoung, Y.S.
Tetrahedron Lett. 1983, 5367
29) Bangar, B.P.; Kshinsagar, S.N. Wadgaonkar, P.P.
Synth. Commun. 1995, 25, 941
30) Ahindra, N.; Ashio, S. Synth. Commun. 1987,
1007
31) Caycho, J.R.; Tellado, F.G.; Armas, P.D.; Tllado,
J.J.M. Tetrahedron Lett. 1997, 38, 277
32) Tamami, B.; Gourdarzian, N. J. Chem. Soc. ,
Chem. Commun. 1994, 1079
33) Gyoung, Y.S.; Yoon, N.M.; Joen, D.H. Bull. Korean
Chem. Soc. 1987, 8, 162
34) Yoon, N.M.; Choi, J. Shon, Y.S. Synth. Commun. 1993,
23, 3047
35) Kalbalka, G.W.; Wadgaonkar, P.P.; Chatla, N. Syn.
Commun. 1990, 20, 293
36) Yoon, N.M.; Kim, E.G.; Son, H.S.; Choi, J. Synth.
Commun. 1990, 23, 1595
37) Lee, S.Y.; Cho, B.T.; Yoon, N.M. Bull. Korean Chem.
Soc. 1998, 19, 1268
38) Nah, J.H.; Kim, S.Y.; Yoon, N.M. Bull. Korean Chem.
Soc. 1998, 19, 269
39) Yoon, N.M.; Choi, J.; Ahn, J.H. J. Org. Chem. 1994, 59,
3490
40) Nah, J.H.; Choi, J.; Yoon, N.M. Bull. Korean Chem. Soc.
1996, 17, 73
41) Choi, J.; Lee, D.W.; Yoon, N.M. Bull. Korean Chem. Soc.
1995, 16, 189
42) Lee, D.W.; Choi, J. Yoon, N.M. Synth. Commun. 1996,
2189
43) Choi, J.; Yoon, N.M. Synth. Commun. 1995, 2655
44) Choi, J; Yoon,N.M. JJ. J. Org. Chem. 1995, 60, 3266
45) Choi, J.; Yoon, N.M. Synlett 1995, 1073
*For Online Consulting Only
170
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
46) Chen, J.W.; Qin, C.Q. Chinese Chem. Letter.
1991, 2, 125
47) Choi, J.; Yoon, N.M. Synthesis, 1996, 596
48) Yoon, N.M.; Sim, T.B. Bull. Korean Chem. Soc.
1993, 14, 749
49) Choi, J. Yoon, N.M. Tetrahedron Lett. 1996, 37,
1057
50) Yoon, N.M.; Park, K.B.; Lee, H.J.; Choi, J.
Tetrahedron Lett. 1996, 37, 8527
51) Yoon, M.N.; Lee, H.J. Ahn, J.H.; Choi, J. J. Org.
Chem. 1994, 59, 4687
52) Yoon, M.N.; Choi, J.; Lee, H.J. Bull. Korean
Chem. Soc. 1993, 14, 543
53) Krishnamurthy, S.; Brown, H.C. J. Org. Chem.
1982, 47, 276
54) Krishnamurthy, S.; Brown, H.C. J. Org. Chem.
1983, 48, 3085
55) Anand, R.C.; Vimal Tetrahedron Lett. 1998, 39,
917
56) Joshi, D.D.; Sagar, A.D.; Hilage, N.P.; Salunkhe,
M.M. Indian J. Chem. 1993, 32b, 1201
57) Yoon, N.M.; Choi, J. Synlett 1993, 135
58) Bandgr, B.P.; Modhave, R.K.; Wadgaonkar, P.P.; Sande,
A.R. J. Chem. Soc. Perkin Trans 1 1996, 1993
59) Kim, S.Y.; Yoon, N.M. Bull. Korean Chem. Soc. 1998,
19, 891
60) Yoon, N.M.; Choi, J. Synlett 1993, 135
61) Bandagar, B.P.; Nikat, S.M. Synth. Commun. 1995, 25,
863
62) Yoon, N.M.; Pure and Appl. Chem. 1996, 68, 843
63) Bangar, B.P.; Kshinsagar, S.N. Wadgaonkar, P.P. Synth.
Commun. 1995, 25, 863
64) Sim, T.B.; Ahn, J.H. Yoon, N.M. Synthesis, 1996, 324
65) Sim, T.B.; Choi, N.M. Tetrahedron Lett. 1996, 37, 3137
66) Cekovic, Z.; Saicic, R. Tetrahedron Lett. 1986, 27, 5893
67) Ahn, J.H.; Lee, D.W.; Joung, M.J.; Lee, K.H.; Yoon,
N.M. Synlett. 1996, 1224
68) Joung, M.J.; Ahn, J.H.; Lee, D.W.; Yoon, N.M. J. Org.
Chem. 1998, 63, 2755
69) Adjidjonou, K.; Caze, C. Eur. Poly. J. 1994, 30, 395
70) Adjidjonou, K.; Caze, C. Eur. Poly. J. 1995, 31, 749
71) Cook, M.M.; Wagner, S.E. Mikulki, R.A.; Demko, D.P.;
Clements, J.G. ACS Symp. Ser. #187, 1980, 195; Chem.
Abstr. 94, 65044c
*For Online Consulting Only
171
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
72) Perrier, D.M.; Denerito, R.R. Appl. Polym. Symp.
No 29, 1976, 213; Chem. Abstr. 85, 65052t
72) U.S. 4,032,292 1977; Chem. Abstr. 87, 54485b
73) Ranu, B.C.; Das, A.R. J. Chem. Soc. Perkin
Trans. 1 1992, 1881
74) Ranu, B.C.; Das, A.R. J. Chem. Soc. Chem.
Commun. 1990, 1334
75) Ranu, B.C.; Chakraborty, R.; Saha, M.
Tetrahedron Lett. 1993, 34, 4659
76) Ranu, B.C.; Sarkar, A.; Saha, M.; Charkraborty,
R. Tetrahedron 1994, 50, 6579
77) Ranu, B.C.; Das, A.R. J. Org. Chem. 1991, 56,
4796
78) Ranu, B.C.; Majee, A. Sarkar, A. J. Org. Chem.
1998, 63, 370
79) Yakabe, S.; Hirano, M.; Morimoto, T. Synth.
Commun. 1999, 29, 295
80) Ranu, B.C.; Sarkar, A.; Majee, A. J. Org. Chem.
1997, 62, 1841
81) Ranu, B.C.; Basu, M.K. Tetrahedron Lett. 1991,
32, 3243
82) Ranu, B.C.; Charkraborty, R. Tetrahedron, 1992,
48, 5317
83) Yakabe, S.; Hirano, M.; Morimoto, T. Can J. Chem..
1998, 76, 1916
84) Yakabe, S.; Hirno, M.; Clark, J.H.; Morimoto, T. J. Chem.
Research (S) 1998, 322
85) Varma, R.S.; Saini, R.K. Tetrahedron Lett. 1997, 38, 4337
86) Sreekumar, R.; Padmakumar, R.; Rugmini, P.
Tetrahedron Lett. 1998, 5151
87) Campelo, J.M.; Chakraborty, R.; Marinas, J.M. Synth.
Commun. 1996, 26, 415
88) Campelo, J.M.; Chakraborty, R.; Marinas, J.M. Synth.
Commun. 1996, 26, 1639
90) Lalancette, J.M.; Freche, A.; Monteux, R. Can. J. Chem.
1968, 46, 2754; Chem. Abstr. 69, 83101g
91) Lalancette, J.M.; Freche,A; Brindle, J.R.; Laiberte, M.
Synthesis 1972, 526; Chem. Abstr. 78, 4403s
92) Lalancette, J.M.; Freche, A. Can. J. Chem. 47, 739; Chem.
Abstr. 70, 77506x
93) Brindle, J.R. Liard, J.L. Can. J. Chem. 1975, 53, 1480;
Chem. Abstr. 83, 163753a
94) Lalancette, J.M.; Lachance, A. Can. J. Chem. 1969, 47,
859; Chem. Abstr. 70, 77245m
95) Lalancette, J.M.; Freche, A. Can. J. Chem. 1970, 48,
2366; Chem. Abstr. 73, 76616h
*For Online Consulting Only
172
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
96) Ramanujam, V.M.S.; Ffieff, N.M. J. Chem. Soc.,
Perkin 2 1976, 1811; Chem. Abstr.. b86,
154933u
97) Lalancette, J.M.; Brindle, J.R. Can. J. Chem.
1970, 48, 2366; Chem. Abstr. 72, 110402b
98) Jpn. Kokai Tokkyo Koho 81, 122,386 1981;
Chem. Abstr. 96, 122832a
99) Yamaguchgi, I. Kenkyu Kio-Tokyo Kasei
Daigaku 1984, 24, 155; Chem. Abstr. 103,
104662d
100) Lalancette, J.M.; Freche, A. Can. J. Chem. 1971,
49, 4047; Chem. Abstr. 76, 85121g
101) Lalancette, J.M. Freche, A Tetrahedron Lett.
1973, 47, 1404; Chem. Abstr. 79, 52911y
102) Lalancette, J.M. Freche, A Tetrahedron Lett.
1971, 49, 1990; Chem. Abstr. 75, 151488q
103) Brindle, J.R.; Liard, J.L.; Berube, N.
Tetrahedron Lett 1976, 54, 871; Chem. Abstr.
85, 123471s
104) Miller, R.B.; Frincke, J.M. J. Org. Chem. 1980,
45, 5312; Chem. Abstr. 94, 47103s
105) Jpn. Kokai Tokkyo Koho 85, 152,497 1985;
Chem. Abstr. 104, 69119d
106) Gribble, G.W.; Nutatitis, C.F. Org. Prep Proc. Int. 1985,
17, 317
107) Gribble, G.W. Reduction in Organic Synthesis, ACS
Symposium Series, 1996, 641, 167
108) Gribble, G.W. Chemtech 1996, 12, 26
109) Gribble, G.W. Chemical Society Reviews 1998, 27, 395
110) Brown, H.C. Mead, E.J. J. Am. Chem. Soc. 1953, 75,
6263; Chem. Abstr. 5705e
111) Brown, H.C. Mead, E.J.; Shoaf, C.F. J. Am. Chem. Soc.
1953, 75, 6263; Chem. Abstr. 51, 3435g
112) Brown, H.C.; Cha, J.S.; Nazer, B. Inorg.Chem. 1984, 23,
2929; Chem. Abstr. 100, 121881a
113) Kriz, O.; Stucklik, J.; Socochor, P.; Stronf, O. Collect.
Czech. Chem. Commun. 1977, 42, 421; Chem. Abstr. 86,
188544h
114) U.S. 3,853,927 1974; Chem. Abstr. 82, 86499x
115) Ger. Offen. 2,137, 273 1972; Chem. Abstr. 77, 22412c
116) Private communication. W.R. Moser, Badger Company,
Inc., Waltham, Mass.
117) Firouzabadi, H.; Adibi, M.; Zeynizadeh, B. Synth.
Commun. 1998, 28, 1257
118) Tamami, B.; Goudarzian, N. J. Chem. Soc., Chem.
Commun. 1994, 1079
*For Online Consulting Only
173
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
119) Tamami, B.; Lakouraj, M.M. Synth. Commun.
1995, 25, 3089
120) Kuznetsov, N.T.; Moltseva, N.N.; Kedrova,
N.S.; Saidov, B.I.; Chumaevskii, N.A. Koord.
Khim. 1992, 18, 456
121) H.C.; Choi, Y.M.; Narasimhan, S. Inorg. Chem.
1982, 21,3657
122) JP 04224585 1992
123) EP 0072897 1983
124) U.S. 2,741,539 1956
125) U.S. 2,741,540 1956
126) Brown, E.; Robin, J.P.; Dhal, R. Tetrahedron
1982, 38, 2569
127) Brown, E.; Robin, J.P.; Dhal, R. Tetrahedron
1989, 45, 141
128) Narasimhan, S.; Balakumar, R. Aldrichimica
Acta, 1998, 31, 19
129) Ranu, B.C. Synlett 1993, 885
130) Ranu, B.C.; Majee, A.; Sarkar, A. J. Org. Chem.
1998, 63, 370
131) Ranu, B.C.; Sarkar, A.; Saha, M.; Chakraborty,
R. Tetrahedron 1994, 6579
132) Sreekumar, R.; Padmakumar, R.; Rugmini, P.
Tetrahedron Lett. 1998, 5151
133) Campelo, J.M.; Chakroborty, R.; Marinas, J.M. Synth.
Commun. 1996, 26, 1639
134) Campelo, J.M.; Chakroborty, R.; Marinas, J.M. Synth.
Commun. 1996, 26, 412
135) Tamami, B.; Goudarzian, N.; Kiasat, A.R. Eur. Polym.
J. 1997, 33, 977
136) Brown, H.C.; Krishnamurthy, S. Tetrahedron 1979, 25,
567
137) Kim, S.; Hong, C.Y.; Yang, C. Angew. Chem. Int. Ed.
Engl. 1983, 22, 562
138) Oishi, T.; Nakata, T. Acc. Chem. Res. 1984, 17, 338
139) Ranu, B.C. Synlett 1993, 885
140) Walker, E.R.H. Chem. Soc. Rev. 1976, 35, 449
141) Salunkhe, A.K.; Brown, H.C. Tetrahedron Lett. 1995, 36,
7989
142) Crabbe, P.; Garcia, G.A.; Rius, C. J. Chem. Soc., Perkin
Trans. 1 1973, 810
143) Brown, H.C.; Subba Rao, B.C. J. Am. Chem. Soc. 1955,
77, 3164; Chem. Abstr. 50, 3995c
144) Brown, H.C.; Subba Rao, B.C. J. Am. Chem. Soc. 1956,
78, 2582; Chem. Abstr. 51, 1077c
*For Online Consulting Only
174
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
145) Paul, R.; Joseph, N. Bull. Soc. Chim. France
1952, 550; Chem. Abstr. 47, 3265I
146) Heeres, J.; Backx, L.J.J.; Van Cutsem, J. J. Med.
Chem. 1977, 20, 1516; Chem. Abstr. 87,
167942s
147) U.S. 4,512,991 1985; Chem. Abstr. 103, 71338x
148) Banerji, J.; Das, B. Heterocycels 1985, 23, 661;
Chem. Abstr. 102, 220614t
149) Takata, T.; Kuo, M. et. al. Chem. Lett. 1985,
939; Chem. Abstr. 104, 5808v
150) Jpn Kokai Tokkyo Koho 875, 178, 845 1985;
Chem. Abstr. 104, 8816s
151) Subba Roa, B.C.; Current Sci. 1961, 30, 218;
Chem. Abstr. 56, 3326c
152) Subba Rao, B.C.; Janaki, N.; Pathak, K.D.
Indian J. Chem. 1965, 3, 123; Chem. Abstr. 63,
5548g
153) Brown, H.C. “ Hydroboration:” W.A.
Benjamin, Inc. New York, N.Y. 1962
154) Brown, H.C. “ Organic Synthesis via Boranes”,
John Wiley and sons, New York, N.Y. 1975
155) Urabe, H.; Aoyama, Y.; Sato, F. J. Org. Chem.
1992, 57, 5056
156) Giannis, A.; Snadhoff, K. Angew. Chem. Int. Ed. Engl.
1989, 28, 218
157) Tone, H.; Nishi, T.; Oikawa, Y.; Hikota, M.; Yonemitsu,
O. Tetraherdron Lett. 1987, 28, 4569
158) Taber, D.F.; Houze, J.B. J. Org. Chem. 1994, 59, 4004
159) Prasa, A.S.B.; Kanth, J.V.B.; Periasamy, M.
Tetrahedron, 1992, 48, 4623
160) J. V. B. Kanth and M. Periasamy, J.Org. Chem. 1991, 56,
5964
161) J. W. Simek et al., J. Chem. Ed. 1997, 74, 107
162) A. I. Meyers, K. Drauz et al., J. Org. Chem. 1993, 58,
3568
163) Giannis, A.; Sandoff, K. Angew. Chem. Int. Ed. Engl..
1989, 28, 218
164) Dharanipragada, R.; Alarcon, A.; Hruby, V. J. Org. Prep.
Prac. Int. 1991, 23, 396
165) Boesten, W.H.; Schepers, C.H.M.; Roberts, M.J.A. EPO
322982 A2 1989
166) Wann, S.R.; Thorsen, P.T.; Kreevoy, M.M. J. Org.
Chem. 1981, 46, 2579
167) Abiko, A.; Masamiune, S. Tetrahedron Lett. 1992, 33,
5517
*For Online Consulting Only
175
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
168) Kabno, S.; Tanaka, Y.; Sugino, E.; Hibino, S.
Synthesis 1980, 695
169) Ravikumar, K.S.; Shandrasekaran, S. J. Org.
Chem. 1996, 61, 826
170) Prasa, A.S.B.; Kanth, J.V.b.; Periasamy, M.
Tetrahedron, 1992, 48, 4623
171) Akabori, S.; Takanohashi, Y. J. Chem. Soc..;
Perkin Trans 1, 1991, 479
172) Sengupta, S.; Sahu, D.P.; Chatterjee, S.K. Indian
J. Chem. 1994, 33b, 285
173) Wann, S.R.; Thorsen, P.T.; Kreevoy, M.M. J.
Org. Chem. 1981, 46, 2579
174) Kabno, S.; Tanaka, Y.; Sugino, E.; Hibino, S.
Synthesis 1980, 695
175) Prasa, A.S.B.; Kanth, J.V.b.; Periasamy, M.
Tetrahedron, 1992, 48, 4623
176) Barby, D.; Champagne, P. Synth. Commun.
1995, 25, 3503
177) Kano, S.; Tanaka, Y.; Sugino, E.; Hibino, S.
Synthesis 1980, 695
178) Giannis, A. Sandhoff, K. Angew. Chem. Int. Ed.
Engl. 1989, 28, 218
179) Das, B.; Kashinatham, A.; Madhusudhan, P. Tetrahedron
Lett. 1998, 39, 677
180) A. Snow, M. Zhao and P.J. Reider et al. (Merck),
Tetrahedron Letters. 1997, 38, 2641
181) Barney, C.L.; Huber, E.W.; McCarthy, J.R. Tetrahedron
Lett. 1990, 31, 5547
182) Verardo, G.; Giumanini, A.G.; Strazzolini, P.; Poiana, M.
Synthesis 1993, 121
183) Verardo, G.; Giumanini, A.G.; Strazzolini, P. Synth.
Commun. 1994, 24, 609
184) Vyskocil, S.; Smrcina, M.; Hanus, V.; Polasek, H.;
Kocovsky, P. J. Org. Chem. 1998, 63, 7738
185) Brown, H.C. Subba Rao, B.C. J. Am. Chem. Soc. 1959,
81, 6434; Chem. Abstr. 54, 8604f
186) Brown, H.C.; Zweifel, G. J. Am. Chem. Soc. 1966, 88,
1433; Chem. Abstr. 64, 15909a
187) Brown, H. C.; Subba, Rao, B.C. J. Org. Chem. 1957, 22,
1136; Chem. Abstr. 52, 7136c
188) Koester, R. Ann. Chem. 1958, 618, 31; Chem. Abstr. 53,
10014g
189) Koester, R. Angew. Chem. Int. Ed. Engl. 1964, 3, 174
190) Brown, H.C.; Murray, K.J. J. Am. Chem. Soc. 1959, 81,
4108; Chem. Abstr. 54, 5435f
*For Online Consulting Only
176
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
191) Zweifel, G; Brown, H.C.; “Organic Reactions”
1963, 13, 22 J. Wiley and Sons; Chem. Abstr.
60, 7881a
192) Brown, H.C.; Garg, C.P. J. Am. Chem. Soc.
1961, 83, 2951; Chem. Abstr. 56, 9983e
193) Brown, H.C.; Kabalka, G.W.; Rathke, M.W. J.
Am. Chem. Soc. 1967, 89, 4530; Chem. Abstr.
67, 99594q
194) Brown, H.C et. al. J. Am. Chem. Soc. 1964, 86,
35654; Chem. Abstr. 61, 11886c
195) Rathke, M.W. et. al. J. Am. Chem. Soc. 1966, 88,
2870; Chem. Abstr. 65, 7072e
196) Honeycutt, Jr. J.B. Riddle, J.M. J. Am. Chem.
Soc. 1960, 82, 3051; Chem. Abstr. 55, 5330b
197) Brown, H.C.; Snyder, C.H. J. Am. Chem. Soc.
1961, 83, 1001; Chem. Abstr. 55, 14283e
198) Brown, H.C.; Verbrugge, C.; Synder, C.H. J.
Am. Chem. Soc. 1961, 83, 1001; Chem. Abstr.
55, 16392b
199) Brown, H.C.; Rogic, M.M. Organomet. Chem.
Syn. 1972, 1, 305; Chem. Abstr. 77, 75239h
200) Brown, H.C.; Midland, M.M. Angew. Chem. Int. Ed.
Engl. 1972, 11, 692; Chem. Abstr. 77, 75239h
201) Brown, H.C.; Rathke, M.W. J. Am. Chem. Soc. 1967, 89,
2737; Chem. Abstr. 67, 99562c
202) Brown, H.C.; Rathke, M.W. J. Am. Chem. Soc. 1967, 89,
2738; Chem. Abstr. 67, 99566g
203) Brown, H.C.; Rathke, M.W. J. Am. Chem. Soc. 1967, 89,
2740; Chem. Abstr. 67, 54196v
204) Brown, H.C.; Colman, R.A.; Rathke, M.W. J. Am. Chem.
Soc. 1968, 90, 499; Chem. Abstr. 68, 104335h
205) Brown, H.C.; Negishi, E. J. Am. Chem. Soc. 1967, 89,
5478; Chem. Abstr. 68, 21596t
206) Gribble, G.W.; Ferguson, D.C. J. Chem. Soc., Chem.
Commun. 1975, 535; Chem. Abstr. 83, 131278h
207) Gribble, G.W.; Heald, P.W. Synthesis 1975, 650; Chem.
Abstr. 84, 43791k
208) Umino, N.; Iwakuma, T. Itoh, N. Tetrahedron Lett. 1976,
763; Chem. Abstr. 85, 20719z
209) Gribble, G.W. et. al. J. Am. Chem. Soc. 1974, 96, 7812;
Chem. Abstr. 82, 16650r
210) Marchini, P. et. al. J. Org. Chem. 1975, 40, 3453; Chem.
Abstr. 83, 20861s
*For Online Consulting Only
177
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
211) Hutchiuns, R.O.; Natale, N.R. J. Org. Chem.
1978, 43, 2299; Chem. Abstr. 89, 5969v
212) Gribble, G.W.; Leiby, R. W.; Sheehan, M.N.
Synthesis 1977, 856; Chem. Abstr. 88, 89018z
213) Haire, M.J. J. Org. Chem. 1977, 42, 3446;
Chem. Abstr. 87, 183524n
214) Gribble, G.W.; Leese, R.M.; Evans, B.E.
Synthesis 1977, 172; Chem. Abstr. 86, 170986u
215) Umino, N.; Iwakuma, T.; Itoh, N. Tetrahedron
Lett. 1976, 2875; Chem. Abstr. 86, 16375n
216) Ger. Offen. 2,701,888; Chem. Abstr. 87,
1284194s
217) Maki, Y. et. al. Chem. Lett. 1975, 1093; Chem.
Abstr. 83, 192711r
218) Maki, Y. et. al Tetrahedron Lett. 1975, 3295;
Chem. Abstr. 83,192758m
219) Maki, Y. et. al Chem. Ind. 1976, 332; Chem.
Abstr. 85, 62767u
220) Kikugawa, Y. Chem. Lett. 1975, 1029; Chem.
Abstr. 83, 192759n
221) Kikugawa, Y. Chem. Pharm. Bull. 1976, 24,
1059; Chem. Abstr. 85, 108365s
222) Kikugawa, Y.; Yokayama, Y. Chem. Pharm. Bull. 1976,
24, 1939; Chem. Abstr. 86, 43522q
223) Reed, J.W.; Ho, H.H.; Jolly, W.L. J. Am. Chem. Soc.
1974, 96, 1248; Chem. Abstr. 80, 103345x
224) Reed, J.W.; Jolly, W.L. J. Org. Chem. 1977, 42, 3963;
Chem. Abstr. 88, 6495d
*For Online Consulting Only
178
press <CTRL>-F for Searching
Rohm and Haas : the Sodium Borohydride Digest
IV.
ANALYTICAL
BOROHYDRIDES
PROCEDURES
FOR
Disclaimer:
These methods were developed for internal use by Rohm and
Haas and are provided as an aid to our customers and other
interested parties. While we believe the information
contained herein to be reliable, we assume no liability for its
use. It is suggested that the user validate these procedures
for his/her own specific needs and samples.
Assay Methods
Sodium
borohydride
may
be
determined
gasometically, the hydrogen evolution method (1-5),
or volumetrically (6-9).
Jensen (8) lists four volumetric methods of
assay: acid and base titration (1), the iodate method
(7), a hypochlorite method (6), and a potentiometric
titration with permanganate. Sodium borohydride has
also been determined volumetrically by an iodine
method (2,10), a Chloramine T method (11) and the
argentimetric method of Brown and Boyd (12).
Other methods that have been reported to be
successful include an indirect spectrophotometric
*For Online Consulting Only
method based on the reduction of acetone to isopropyl alcohol
(13), a gas chromatographic method based on the reduction of
isobutyaldehyde to isobutyl alcohol (2), and a polarographic
method (14, 15)
Of the above methods, the gasometric or hydrogen
evolution method is reported to be the most accurate (13,16,
17).
In the volumetric methods, especially those involving
oxidation-reductions in acid media, there are two competing
reactions: the oxidation-reduction reaction, involving sodium
borohydride and the oxidizing species; and the hydrolysis
reaction. Harzdoff (9) reports that, in some cases, upon
acidification of the alkaline iodate-sodium borohydride
solution, gas evolution was observed. For quantitative results
using iodometric methods, the borohydride must react with
iodine or an iodine complex at a much faster rate than the rate
of hydrolysis. The mechanism is reported to be most
complicated (18). Lichtenstein (13) reports that results from
his indirect spectrophotometric method agree with the
hydrogen evolution method. He also reports that the iodate
results vary with the concentration of the iodate used. In a
Rohm and Haas study (16), the results from the hydrogen
evolution technique agreed well with those obtained by the gas
179
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
chromatographic method. The iodate results were 1 to
2 % lower.
The method most commonly used at Rohm
and Haas for assays are the hydrogen evolution and
iodate methods. The hydrogen evolution method is
used for finished goods where high accuracy and
precision is required. The iodate method is used for inprocess control, in kinetic studies and by customers
who do not want to use the hydrogen evolution
method since it requires more specialized equipment
than is usually available in the laboratory.
solutions used in the assay method. This method will detect as
low as 20 ppm of NaBH4.
Other methods used successfully for trace
borohydride determinations include the NAD+ method (20,21),
the crystal violet method (22, 23), the phosphomolybdic acid
method (24) and the NBC+ method (25,26)
In the NAD+ method, NaBH4 reduces nicotinamide
adenine dinucleotide to a UV absorbing species, and the
NADH is detected spectrophotometrically at 340 nm. In the
crystal violet method, a solution of crystal violet in DMF is
employed to titrate an organic solution containing borohydride
to a purple end point.
In the colorimetric method, phosphomolybdic acid is
reduced with sodium borohydride to a blue color. The color
can be measured at 665 nm.
Table VIII lists the advantages and disadvantages of the
various methods used at Rohm and Haas Company.
Trace Methods for Borohydride
The hydrogen evolution and iodate methods
are both useful for the determination of small amounts
of sodium borohydride (2). In the hydrogen evolution
method, the 2000-mL reservoir used in the assay
method is replaced with a 100-mL gas burette. A
confining solution designed to dissolve only small
amounts of gas (19) is used in place of water. This
method will easily detect 100 ppm NaBH4. In the
iodate method, 0.025 N iodate and 0.01 N thiosulfate
solutions are used in place of the more concentrated
*For Online Consulting Only
180
Rohm and Haas : the Sodium Borohydride Digest
Table VIII Analytical Methods for NaBH4
Test
Method
Advantages Disadvantages
Assay
Hydrogen A highly
Requires
evolution accurate
specialized
absolute
glassware and
method
close
based on
temperature
gas laws.
control
Assay
Iodate
Rapid
Results are
method
about 1 to 2%
Glassware
low due to a
readily
slight
available
hydrolysis
side reaction
in the
acidification
step.
Trace 30- Hydrogen Simple,
Requires
300 ppm
Evolution Fast
specialized
glassware.
Trace 20- Iodate
Rapid
Other
200 ppm
method
oxidants and
Glassware
reductants
*For Online Consulting Only
181
press <CTRL>-F for Searching
Trace 1200 ppm
NAD+
Trace 12000 ppm
Crystal
Violet
readily
available
Rapid,
simple
method
applicable
over a wide
pH range
Rapid,
simple
method
interfere.
Reagent is
expensive and
unstable.
Must be done
in aqueous
solution.
Not
applicable to
caustic
solutions or
where strong
nucleophiles
are present.
Has been
applied to
aqueous and
non-aqueous
systems.
Rohm and Haas : the Sodium Borohydride Digest
NaBH4 Assay-Hydrogen Evolution Method
A. Apparatus
See Figure 13.
B. Reagents
1) Distilled Water
2) Hydrochloric Acid (6 N)- Mix equal amounts
of concentrated HCl and distilled water.
C. Procedure
1) Weigh a 3 to 4 g sample of a stabilized water
solution of sodium borohydride, or a 0.5 g
sample of the dry product to the nearest
0.0001g, into flask F, which is fitted with a
rubber stopper.
2) Rinse down column C with a stream of
distilled water to remove any acid from a
previous run. Dry the inner glass tubing (8
mm O.D. tubing shown in the diagram just
below the inner seal of column C) with a
paper towel.
3) Fill the 2000-mL bulb G with distilled water
through the 20 mL bulb H and then adjust the
height of the H-shaped tube until the water
level is the same at A and B.
*For Online Consulting Only
press <CTRL>-F for Searching
4) Remove the rubber stopper and immediately attach
flask F to the apparatus and secure it with a strong
rubber band.
5) Being sure that column C and tubing below the inner
seal are dry, vent flask F to the atmosphere by
opening and closing the 2 mm stopcock. The water
level at A and B should not change. NOTE: If the
water level at B drops, add more water through the
bulb H. If water overflows at E discard the water.
6) Place a tared 2-liter beaker under E and lower the Hshaped tube until B is at a level with D. No water
should overflow at E if the system is airtight and
properly adjusted
7) Slowly add through C and the 2 mm stopcock: 10 mL
of water, 10 mL of HCl (1:1) and 10m mL of
concentrated HCl. Cool flask F momentarily in a
water bath whenever the reaction is too vigorous. Do
not allow any air into the system through C. Rock the
apparatus back and forth to insure completeness of
reaction.
8) When gas evolution has ceased, cool flask F to room
temperature in a water bath. This will pull water from
B back into G. Take enough water from the 2-liter
182
Rohm and Haas : the Sodium Borohydride Digest
beaker and adjust the height of the H-shaped
tube so that the water level in B is the same
as the water level in the 2000-mL bulb G.
9) Record the temperature of the water in the 2liter beaker. Record the barometer pressure.
Record the weight of the water and the 2-liter
beaker. The net weight of the water is the
weight of water displaced by the hydrogen
evolved.
% NaBH4 =
W2-W1
-V
D
B-P
15.17
273 + t
W(1000)
W2 = Weight of beaker and contents in grams
W1 = Weight of empty beaker in grams
D = Density of water at temperature t in grams/mL.
V = Volume of water and acid added to flask in mL.
t = Temperature of the water in the 2-liter beaker in
o
C. This should represent the temperature of the
system.
B = Barometric pressure in millimeters of Hg.
*For Online Consulting Only
press <CTRL>-F for Searching
P = Barometric pressure correction in millimeters of Hg due to
the vapor pressure of water at temperature t. A 3 millimeter
correction is added to the vapor pressure of water to correct for
the difference in expansion of the mercury and the brass scale
of the barometer (see Table IX).
W = Sample weight in grams
Table IX Hydrogen evolution procedure for the determination
of NaBH4.
Water
Barometric
Density of
Temperature
Pressure
Water
(oC)
Correction (-)
(g/mL)
15.0
15.8
0.9991
15.5
16.2
16.0
16.6
0.9990
16.5
17.1
17.0
17.5
0.9988
17.5
18.0
18.0
18.5
0.9986
18.5
19.0
19.0
19.5
0.9984
19.5
20.0
20.0
20.5
0.9982
183
20.5
21.0
21.5
22.0
22.5
23.0
23.5
24.0
24.5
25.0
25.5
26.0
26.5
27.0
27.5
28.0
28.5
29.0
29.5
30.0
30.5
31.0
21.0
21.6
22.2
22.8
23.4
24.1
24.7
25.4
26.0
26.7
27.5
28.2
29.0
29.7
30.5
31.3
32.2
33.0
33.9
34.8
35.7
36.7
*For Online Consulting Only
184
press <CTRL>-F for Searching
Rohm and Haas : the Sodium Borohydride Digest
0.9980
0.9978
0.9976
0.9973
31.5
32.0
32.5
33.0
33.5
34.0
34.5
35.0
37.7
38.7
39.7
40.0
41.8
42.9
44.0
45.2
0.9971
0.9968
0.9965
0.9963
0.9960
0.9957
0.9954
Figure 13
0.9951
0.9947
0.9944
0.9941
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
NaBH4 Assay- Iodate Method
Warning: Chloroform is a cancer suspect
agent
A. Generation of iodine in situ:
IO3- + 5 I- + 6 H+ Æ 3 I2 + 3 H2O
3.
Reaction with sodium borohydride:
BH4- + 4 I2 + 10 H2OÆ B(OH)3 + 8 I- + 7
H30+
4.
Titration of excess iodine with thiosulfate:
I2 + 2 S2O3-2 Æ S4O6-2 + 2 I-
5.
B. Reagents
6.
1.
2.
6N H2SO4, Cautiously add 100 mL of
concentrated H2SO4 to 500 mL of distilled
water while stirring. Mix and cool.
Starch Indicator Solution. Mix 4 grams of
soluble starch and 10 milligrams of HgI2 with
*For Online Consulting Only
40 mL of distilled water. Add the starch paste, with
stirring, to 1000 mL of boiling distilled water. Allow
to cool and settle. Use the supernatant liquid.
Alternately, 1 mL of chloroform may be used in place
of the HgI2.
Potassium Iodide. Free Flowing. The highest purity
reagent should be used. It should be checked before
using, for iodate as follows: dissolve 1g in 25 mL of
water; add 2 mL of starch solution and 1 mL of 6 N
H2SO4. There should be no immediate appearance of
a blue color. If there is the bottle should be rejected.
Sodium Hydroxide (1N). Dissolve 40 grams of high
purity NaOH pellets in 500 mL of distilled water.
Cool. Dilute to one liter.
Potassium Iodate (0.25N). Dissolve 8.9173 grams of
primary standard KIO3 in freshly boiled and cooled
water. Dilute to one liter.
Sodium Thiosulfate (0.1N) Dissolve 25 grams of
Na2S2O3• 5H2O in one liter of freshly boiled and
cooled water. Add 0.1 gram of Na2CO3 to the
solution and allow the solution to stand for a day
before standardizing.
Standardize as follows:
Transfer 15 to 18 mL of the standard iodate solution
185
Rohm and Haas : the Sodium Borohydride Digest
to a 250-mL glass stoppered iodine flask.
Add 50 mL of distilled water and 2 grams of
KI. When the KI has dissolved, add 10 mL
of 6 N H2SO4. Titrate with the Na2S2O3
solution to a faint yellow. Add starch
indicator solution and continue the titration to
the disappearance of the blue color.
Calculate the normality for the Na2S2O3
solution as follows. Record to four places
behind the decimal.
N=
Volume of KIO3, mL x N
Volume of Na2S2O3, mL
Alternately, this solution may be standardized against
a potassium iodate “standardette” available from
Chemical Services Laboratories, P.O. Box 281, Largo,
Florida 33540
*For Online Consulting Only
press <CTRL>-F for Searching
186
187
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
1. Procedure for Dry NaBH4
• Weigh a 0.5-gram sample, to the nearest 0.0001g
into a stoppered vial and quantitatively transfer to a
250-mL volumetric flask with 1 N NaOH.
• Dilute to the mark with 1 N NaOH and mix well.
• Pipette a 10.0 mL aliquot into a clean iodine flask
and immediately add 35.0 mL of 0.25 N KIO3
solution.
• Transfer the iodine flask to a top loading balance
and add 2g of KI crystals. Swirl to dissolve KI.
• Add 10 mL of 6N H2SO4, stopper, swirl to mix and
allow to stand in a cool, dark place for 2 to 3
minutes.
• Wash down the stopper and the sides of the flasks
with distilled water. Titrate with 0.1 N Na2S2O3,
using starch indicator, to a colorless end point.
2. Procedure for aqueous NaBH4
• Weigh a 0.2 to 0.3 gram sample to the nearest 0.0001g into a
clean dry stoppered iodine flask containing 10 mL of 1N
NaOH
• Add 0.25 N KIO3 solution according to the following table:
% NaBH4 = (XN1-YN2) x 11.83
W
X = Volume of KIO3, mL
N1 = Normality KIO3
Y = Volume of Na2S2O3, mL
N2 = Normality Na2S2O3
W = Sample weight in grams
*For Online Consulting Only
Sample size, Grams
0.15
0.20
0.25
0.30
Volume of iodate to
be added (mL)
30
35
40
45
• Transfer the iodine flask to a top loading balance and add 2
grams of KI crystals. Swirl to dissolve the KI.
• Add 10 mL of 6N H2SO4, stopper, swirl to mix, and allow to
stand in a cool, dark place for 2-3 minutes.
• Wash down the stopper and the sides of the flask with
distilled water. Titrate with 0.1N Na2S2O3, using starch
indicator, to a colorless end point.
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
% NaBH4 = (XN1-YN2) x 0.4731
W
2.
Legend of symbols : see dry NaBH4
3.
Trace NaBH4 Assay-Hydrogen Evolution
Apparatus
4.
See Figure 14
1.
2.
Reagents and Solutions
Confining solution: Dissolve 200 g of
Na2SO4 in a solution composed of 800 mL of
water and 40 mL of concentrated H2SO4
Concentrated H2SO4
Procedure:
1. In order to expel all the air from measuring
burette (B)- the leveling bulb is raised while
stopcock is open. A small amount of
confining liquid is expelled to insure absence
of air, and stopcock S is then closed. The
*For Online Consulting Only
5.
6.
7.
8.
level in measuring burette should remain constant
when leveling bulb is lowered.
Weigh a 100 g sample to the nearest 0.0001 g into a
250-mL evolution flask F.
Attach the evolution flask F to apparatus with
stopcock E open. Close stopcock E and open S to
evolution flask.
Add 20 mL of concentrated H2SO4 through dropping
column D while magnetic stirrer is stirring solution.
NOTE: Strength of acid depends on material to be
decomposed and hydride to be determined.
Keep solution in evolution flask at the same
temperature as confining liquid.
Read the volume of evolved hydrogen by raising and
lowering leveling bulb until its level is the same as
the level inside the burette (V2).
Record temperature (t) of confining liquid and
barometric pressure (B).
Run blank on NaBH4 free sample. Record volume
displaced, (V1).
188
Rohm and Haas : the Sodium Borohydride Digest
Calculation
% NaBH4 = (V2-V1) x (B-3-P)* x 15.17
1000 x (273+t) x W
ppm NaBH4 = % NaBH4 x 104
V2 = The volume of gas evolved when sample is reacted, mL
V1 = The volume of gas evolved when blank is used, mL
B = Recorded barometric pressure in mm of Hg.
P = The vapor pressure in mm of the confining solution at the
temperature t. See Figure 15.
t = Recorded room temperature in oC
W = Sample weight in grams.
*3 mm are subtracted from the observed barometric pressure
to correct for the difference in expansion of the mercury and
the brass scale at different temperatures. Exact corrections
can be found in any chemical handbook.
*For Online Consulting Only
press <CTRL>-F for Searching
Figure 14
189
Rohm and Haas : the Sodium Borohydride Digest
Figure 15
*For Online Consulting Only
press <CTRL>-F for Searching
190
Rohm and Haas : the Sodium Borohydride Digest
Trace NaBH4 Assay- Iodate Method
Generation of iodine in situ:
IO3- + 5 I- + 6 H+ Æ 3 I2 + 3 H2O
Reaction with sodium borohydride:
BH4- + 4 I2 + 10 H2OÆ B(OH)3 + 8 I- + 7 H30+
Titration of excess iodine with thiosulfate:
I2 + 2 S2O3-2 Æ S4O6-2 + 2 IA. Reagents and Solutions
1.
2.
3.
0.025 M Potassium Iodate 0.8917g/L
0.01N Sodium Thiosulfate –2.5g/L
(NaS2O3•5 H20)
Starch solution 4g of soluble starch per
liter of boiling distilled water. Use HgI2
or chloroform as a preservative.
*For Online Consulting Only
press <CTRL>-F for Searching
4.
5.
6N H2SO4- 100 mL of concentrated H2SO4 in
500mL of H2O.
1N NaOH –40g/L
B. Procedures:
1. Weigh a 100-gram sample to the nearest 0.0001 g
and transfer it to a 500 mL iodine flask with 1N
NaOH
2. Add 50-75 mL of H2O (two layers developorganic and an aqueous layer if the sample is
organic).
3. Add equivalent amount of 0.025 N KIO3 (1 mL
0.025 N= 0.00012 g NaBH4) plus 10 mL in
excess.
4. Add 2 g of potassium iodide and 10 mL of 6N
H2SO4 for every 10 mL of 1N NaOH present.
5. Titrate to yellow end point with 0.01 N Na2S2O3,
shaking vigorously while titrating.
6. Add 5 mL of starch and continue titration to clear
end point.
7. Calculation:
191
Rohm and Haas : the Sodium Borohydride Digest
g NaBH4 =[(V1 x N1) – (V2 x N2)] x 0.004731
g sample
Weight of the sample
V1 = Volume of KIO3, mL
N1= Concentration of KIO3 solution
V2= Volume of Na2S2O3, mL
N2= Concentration of Na2S2O3 solution
ppm NaBH4 = (g NaBH4/ g sample) x 106
*For Online Consulting Only
press <CTRL>-F for Searching
192
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
NaBH4 Trace Assay -NBC
(Nicotinamide Benzyl Chloride)
A. Reagents and Solutions
1. KOH (0.5M)- Prepared by dissolving 3.27
grams of 85 % KOH in water and diluting to
one liter.
2. HNO3 (4N, 25 %)
3. Tris(hydroxymethyl)aminomethane
(THAM®)-99.9 min
4. Trisbuffer (0.5M)-Prepared by dissolving
6.06 grams of THAM in water and diluting to
one liter. The pH is adjusted to 8.5 with 4N
HNO3 using a pH meter.
5. Nicotinamide benzyl chloride (NBC)- see
section B for synthesis.
6. NBC solution (0.5M) – prepared by
dissolving 0.62 grams of NBC in 50 mL of
water.
7. NaBH4- high purity (99%). Rohm and Haas
Product
8. NaBH4 stock solution (200 µg/mL)- prepared
by weighing 20 mg of NaBH4 to the nearest
*For Online Consulting Only
9.
0.0001g into a 100-mL volumetric flask and diluting
to the mark with 0.5 M KOH. This solution should
be made freshly daily.
NaBH4 working solution (20 µg/mL)-Prepared by
pipeting 10 mL of the NaBH4 stock solution into a
100 mL volumetric flask and diluting to the mark
with 0.5M KOH. This solution should be prepared
freshly daily.
B. Synthesis of Nicotinamide Benzyl Chloride (26)
1. Charge a 250-mL round bottom flask, fitted with a
drying tube and reflux condenser, with 12.2 g of
nicotinamide
and
100
mL
of
methanol
(spectrophotometric grade).
2. Dissolve 12.6 g of benzyl chloride in 20 mL of
methanol and add to the flask in step 1.
3. Heat the solution under reflux conditions for eighteen
hours.
4. Cool the reaction flask to ambient temperature and
collect the crystalline salt, which precipitates, on a
filter paper.
193
Rohm and Haas : the Sodium Borohydride Digest
5.
Wash the crystals with three 1.5 mL portions
of cold (0 oC) methanol and dry to constant
weight in a vacuum oven (0.5 mm Hg and 25
o
C)
C. Calibration
1. Immediately before use, prepare a reagent
mixture of 50 mL of 0.05M NBC and 850
mL of 0.05 THAM buffer. Dispense 85 mL
of this mixture into each of six 100-mL
volumetric flask.
2. Add 8 mL of 0.05M KOH to each flask.
3. Add 0.0, 1.0, 2.0, 3.0, 4.0 and 5.0 mL of the
NaBH4 working solution (20, 40, 60, 80, 100
µg NaBH4) to each flask, dilute to volume
with 0.05 M KOH and mix well.
4. Zero the spectrophotometer at 360 nm using
the blank (no NaBH4) solution in the 1.0 cm
reference and sample cells.
5. After 10 minutes measure the absorbance of
each of the standards at 360 nm.
6. Prepare a calibration curve by plotting
absorbance versus amount of NaBH4.
*For Online Consulting Only
press <CTRL>-F for Searching
D. Procedure
1. Dispense 85 mL of the THAM/NBC mixture (see C
1) into each of two 100 mL volumetric flasks.
2. Add 8 mL of 0.05 M KOH to each flask.
3. Add up to 5 mL of the sample containing NaBH4 to a
100-mL volumetric flask. Add 5 mL of sample
matrix containing no NaBH4 (blank sample) to a
second 100-mL flask.
4. Dilute the contents of the flasks to 100 mL with 0.05
M KOH.
5. Measure the absorbance of each solution at 360 nm
after 10 minutes.
E. Calculations
NaBH4 concentration (ppm) = (S-B)( C )(D)
W
S = absorbance of NaBH4 – treated sample
B = absorbance of blank
C= slope of calibration curve, µg NaBH4/ absorbance unit
D = dilution factor, if any
W = Weight of sample in g
194
Rohm and Haas : the Sodium Borohydride Digest
NaBH4 Trace Assay – Crystal Violet Method
A. Reagents and solutions
1. Crystal Violet (CV+)- Aldrich 22,928-8, 95
% or equivalent
2. N,N dimethylformamide (DMF)- must be
specto -grade.
3. NaBH4- high purity (99 %) Rohm and Haas
B. Procedures:
1.Prepare a solution of CV+ in DMF using the
following guidelines:
Exempted NaBH4
Recommended concentration
Concentration, ppm of Crystal Violet Solution
0.019 g CV+ dye diluted to 1.0 L with DMF
200-2000
0.19 g CV+ dye diluted to 1.0 L with DMF
NOTE: DMF is a toxic solvent and should be
handled with gloves in the hood. Crystal violet is
a suspected cancer agent.
*For Online Consulting Only
press <CTRL>-F for Searching
2.
3.
4.
Prepare a standard solution of NaBH4 by dissolving
approximately 0.02 g 99% NaBH4 weighed to the
nearest 0.0001g in a 100-mL volumetric flask with
DMF. Use this solution to standardize the less
concentrated CV+ solution. Prepare a more dilute
NaBH4 solution by transferring a 10-mL aliquot of
the original NaBH4 standard into a 100-mL
volumetric flask and diluting to the mark with DMF.
Standardize the CV+ solution by titrating a 2.0mL
aliquot of each NaBH4 standard with the appropriate
CV+ solution to the purple endpoint.
Accurately weigh a sample, to the nearest 0.0001g
into Erlenmeyer flasks according to the guidelines
(see table X)
F= wt of SBH, g x dilution x 2 mL aliquot x 106 µg/g
100 mL
(if any)
vol of CV+
titrated, mL
5.
Add DMF to solubilize sample (if solid) or to bring
total sample and DMF volume to approximately 2-5
mL. Titrate with the appropriate CV+ solution to the
first purple endpoint which remains for 60 sec.
195
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
C. Calculations
1. Calculate the concentration of SBH in the
sample as follows:
References:
1) Davis, W.D.; Mason, L.S.; Stegeman, G. J. Am.
Chem. Soc. 1949, 71, 2775; Chem. Abstr. 43, 7805d
2) Morton Thiokol, inc. Ventron Products, Unpublished
standard methods
3) Krynitsky, J.A.; Johnson, J.E.; Carhart, H.W. Anal.
Chem. 1948, 20, 311; Chem. Abtsr. 42, 40941
4) Fatt, I.; Tashima, M. “Alkai Metal Dispersions”,
D.Van Nostrand Co. , Inc., Princeton, Newy Jersey,
1961, 98
5) Jensen, E.H. “A Study on Sodium Borohydride” Nyt
Nordisk Forlag Arnold Busck, Copenhagen 1954, 49
6) Chaikin, S.W. Anal. Chem. 1953, 25, 831; Chem.
Abstr. 47, 7371g
7) Lyttle, D.A.; Jensen, E.H.; Struck, W.A. Anal. Chem.
1953, 24, 1843
8) Jensen, E.H. “A Study on Sodium Borohydride” Nyt
Nordisk Forlag Arnold Busck, Copenhagen 1954, 49
9) Harzdorf, C.F. Anal. Chem. 1965, 210, 12; Chem.
Abstr. 63, 16f
10) Skoblionok, R.F.; Mochalov, K.N.; Berner, B.G. Zh.
Anal. Khim. 1968, 23, 1518; Chem. Abstr. 70, 16832d
ppm NaBH4 = F
Sample wt, g
Volume of CV+,
ml used for
sample titration
Where: F = Titer value of the appropriate CV+ titrant,
previously calculated in step B 3.
Table X
Expected
NaBH4
Concentration
in ppm
0-25
25-50
50-100
100-200
Suggested
Sample
Weight, g
Expected
Volume of
Titrant, mL
3
1.5
0.75
0.4
Up to 42.6
21.3-42.6
21.3-42.6
22.7-45.4
200-500
500-1000
1000-2000
1.5
0.75
0.4
17.0-42.6
21.3-42.6
22.7-45.4
*For Online Consulting Only
Recommended
CV+
Concentration
0.019g CV+/L
0.19g CV+/L
196
Rohm and Haas : the Sodium Borohydride Digest
11) Shah, A.R.; Padma, D.K.; Murthy, A.R.V.
Analyst (London) 1972, 97, 17; Chem. Abstr.
76, 94184g
12) Brown, H.C.; Boyd Jr., A.C. Anal. Chem.
1955, 27, 156; Chem. Abstr. 49, 6031e
13) Lichtenstein, I.E.; Mras, J.S.; J. Fanklin
Institute 1966, 281, 481; Chem. Abstr. 65,
6300f
14) Pecsok, R.L. J. Am. Chem. Soc. 1953, 75,
2862; Chem. Abstr. 47, 9817e
15) Gardiner, J.A.; Collat, J. J. Am. Chem. Soc.
1965, 87, 1692; Chem. Abstr. 62, 13899b
16) Morton Thiokol, inc. Ventron Products,
Unpublished Report 1967
17) Novakova, A.; Hanovsek, F.; Stuchlik, J.
Chem. Prum. 1977, 27, 293; Chem. Abstr.
88, 83074t
18) Freund, T. J. Inorg. Nucl. Chem. 1959, 9,
246; Chem. Abstr. 53, 16665h
19) Kobe, K.A.; Kenton, F.H. Ind. Eng. Chem.
Anal. Ed. 1938, 10, 76; Chem. Abstr. 32,
2459
*For Online Consulting Only
press <CTRL>-F for Searching
20) Werner, D.A.; Huang, C.C.; Aminoff, D. Anal.
Biochem. 1973, 54, 554; Chem. Abstr. 79, 61169q
21) Morton Thiokol, inc. Ventron Products, Unpublished
Report 1976
22) Bunton, C.A.; Huang, S.K.; Paik, C.H. Tetrahedron
Lett. 1976, 1445; Chem. Abstr. 85, 108063s
23) Rudie, C.N.; Demko, P.R. J. Am. Oil Chem. Soc.
1979, 56, 520; Chem. Abstr. 90, 214801u
24) Hill, W.H.; Merrill, J.M.; Larsen, R.H.; Hill, D.L.;
Heacock, J.F. Amer. Ind. Hyg. Assoc. J. 1959, 20, 5;
Chem. Abstr. 54, 13965h
25) Morton Thiokol, inc. Ventron Products, Unpublished
Report 1977
26) Beillmann, J.F.; Challot, H.J. Bull. Soc. Chim. Fr.
1968; Chem. Abstr. 69, 59060x
197
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
V. AVAILABILITY
As compared to VenPure SF granules, VenPure AF granules
do not contain an anti-caking agent, which adds to its high
purity.
Sodium borohydride is available in different forms to
satisfy a variety of process needs.
198
VenPure SF powder is a formulation of NaBH4
designed for usage in solvents, like THF, which require
a large active surface. A proprietary anti-caking agent
is used to increase the product’s flowing characteristics.
VenPure 20/20 solution is an aqueous formulation of NaBH4.
It is a pumpable liquid, that contains 20% NaOH to assure
transport-stability.
VenPure solution is an aqueous
formulation containing 40% NaOH, which makes it extremely
stable, and suitable for high temperature chemistry.
VenPure AF caplets is a NaBH4 product designed to
be dissolved in solvents like water and methanol. The
caplets are bean-shaped pellets are about 1 cm long,
which allow for a dust-free, straightforward use &
handling. It does not contain an anti-caking agent.
Sodium borohydride dry forms (powder, granules and
caplets) are shipped in polyethylene bags packed in metal
containers. They are classified by DOT regulations as
dangerous when wet. Motor freight and or boxcar can ship
unlimited quantities.
VenPure SF granules is an NaBH4 product designed
for large scale usage in solvents such as ethanol and
glymes. The particle size is comparable to table sugar
(> 0.5mm), with only small amounts of fines (typically
< 3%), which allows for a straightforward use and
handling. A proprietary anti-caking agent is used to
increase the product’s flowing characteristics.
Sodium borohydride solution is classified as a corrosive
liquid under DOT regulations. The material is packaged in 5gallon pails and 55-gallon drums containing 10% free space.
Bulk quantities are shipped via tank truck or tank car.
*For Online Consulting Only
199
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
VI. PERSONAL PROTECTIVE EQUIPMENT
Borohydride dust can contaminate personal protective
equipment and result in chemical burns -care must be taken to
keep equipment clean and serviced
Dry
Dry borohydride products are corrosive to eyes,
skin and respiratory tract. They will cause irritation or
chemical burns if left in contact with moist skin or
respiratory tract. Therefore, the use of personal
protective equipment is required upon handling. The
level of equipment required can vary depending on the
expected level of exposure. We recommend :
• Chemical goggles
• Dust mask and/or a full face shield
• Rubber gloves
• Coveralls
• Rubber boots or closed leather footwear
When the potential for exposure is significant, we
recommend wearing in addition to the above:
• Apron or chemical resistant suit
• A NIOSH-approved respirator for corrosive dusts
in place of dusk mask
*For Online Consulting Only
Solution
Sodium borohydride
solutions
contain
sodium
borohydride stabilized with sodium hydroxide. These products
are strongly alkaline and corrosive. They can be handled with
the same personal protective equipment used when handling
50 % caustic. We recommend the following personal
protective equipment when handling the solution form:
• Chemical splash goggles and a full face shield
• Impervious rubber gloves
• Coveralls
• Rubber boots with pants over boots
(Note : Sodium borohydride solutions are very corrosive to leather)
When handling larger amounts, or when the potential
for exposure is greater, a rubber apron or chemical resistant
suit can also be worn. If mist is expected, wear a NIOSH –
approved respirator for corrosive mists.
200
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
VII. FIRST AID
drinks. Do NOT induce vomiting unless directed by medical
personnel. Seek immediate medical attention.
Caplets: Give several glasses of water to drink and induce
vomiting as directed by medical personnel. Seek immediate
medical attention.
Dry
Eye contact
Immediately flush eyes with copious amounts of water
for at least 15 minutes, including under the eyelids.
Then seek immediate medical attention.
Skin Contact
Immediately flush affected area with copious amounts of
water for at least 15 minutes. For larger exposures, use
an emergency shower. Remove contaminated clothing
and shoe. Cleanse skin with soap and water, including
hair and under fingernails. Then seek immediate medical
attention.
Inhalation
Remove to fresh air. If symptoms develop, seek
immediate medical attention. If not breathing, give
artificial respiration.
Ingestion
Powder/Granules: Rinse mouth with water and give
another cupful of water to drink. Do not give carbonated
*For Online Consulting Only
Solution
Eye Contact
Immediately flush eyes with copious amounts of water for at least
15 minutes, including under the eyelids. Then seek immediate
medical attention.
Skin Contact
Immediately flush affected areas with copious amounts of water
for at least 15 minutes. For large exposure, use an emergency
shower. Remove contaminated clothing and shoes. Cleanse skin
with soap and water, including hair and under fingernails. Seek
immediate medical attention. Professionally wash clothing before
re-use.
Inhalation
If mist is inhaled, move to fresh air. Rinse mouth with water. If
symptoms develop, seek immediate medical attention. If not
breathing, give artificial respiration.
Rohm and Haas : the Sodium Borohydride Digest
Ingestion
Give several glasses of water to drink. Do not give
carbonated drinks.
Do not induce vomiting, seek
immediate medical attention.
Note to physician: Highly alkaline materials can
cause extensive and deep penetrating tissue damage.
There is danger of hemorrhage and perforation if lavage is
performed. No attempt should be made to neutralize the
base with a weak acid.
*For Online Consulting Only
press <CTRL>-F for Searching
201
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
VIII REACTIVITY
examples are polyglycols (2-5% NaBH4) and Dimethyl
formamide (over 7% NaBH4)
Dry
Dry borohydride products will react violently or
explosively in contact with concentrated oxidizers.
They will also react vigorously in contact with
concentrated acids or under acidic conditions,
generating heat and hydrogen gas.
Solutions
containing borohydride will also react to release
hydrogen in the presence of transition metal salts or
finely divided metallic precipitates.
Dry borohydride products will ignite from a free flame
due to hydrogen formation formed by decomposition
and will continue to burn as hydrogen is evolved. Dry
borohydride products also react with moisture in the
air, leading to caking. The moisture will slowly react
with the borohydride to liberate hydrogen gas.
Some organic solvents, such as acetone and methanol,
will react vigorously with borohydride.
Other
materials can generate heat and liberate hydrogen
when high concentrations of borohydride are
dissolved or slurried in these materials. Some known
*For Online Consulting Only
Solution
NaBH4 solutions will react violently or explosively in contact
with concentrated oxidizers. They will also react vigorously in
contact with strong acids or under acidic conditions,
generating heat and hydrogen gas. Solutions containing
borohydride will also react to release hydrogen in contact with
transition metal salts or finely divided metallic precipitates.
Sodium borohydride solution will also react violently with
aluminum due to the sodium hydroxide present in the solution.
In addition, material as sensitive polymerization under alkaline
conditions, such as acrylonitirle and ethylene oxide, may
polymerize upon contact with sodium borohydride solution.
This solution is also incompatible with ammonia also.
General Consideration
In all cases where borohydride products are used, some H2
generation is expected. In many cases, H2 can be safely vented
to the outside of the building. H2 should not be allowed to
collect in a closed area.
202
Rohm and Haas : the Sodium Borohydride Digest
For reaction vessels, use N2 blanking to prevent an
explosive atmosphere from forming. Under ambient
temperature and pressure, N2 will prevent such
conditions, as long as O2 concentration is below 5%.
The use of explosion proof equipment is
recommended.
*For Online Consulting Only
press <CTRL>-F for Searching
203
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
IX. FIRE FIGHTING/ FLAMMABILITY
surface. Disturbing the surface too soon can cause the hot
material to reignite.
Dry
Dry borohydride products are flammable solids and
are classified by the U.S. DOT as Division 4.3Dangerous when wet and the NFPA as a class 1 dust.
Fires involving dry sodium borohydride products
should be controlled with dry chemical extinguishers:
recommended dry chemical agents are sodium
bicarbonate based, monoammonium phosphate based
or equivalent. Do not use water, carbon dioxide or
halogen type fire extinguishers. Sand, dolomite or
lime should also be available in case the dry chemical
agent is insufficient or in windy conditions.
Firefighters and others who may be exposed to the
products of combustion should be equipped with
NIOSH-approved positive pressure self-contained
breathing apparatus (SCBS) and full protective
clothing.
Once the fire is extinguished, add additional
smothering agents such as dolomite, dry sand or lime.
Allow the material to cool before disturbing the
*For Online Consulting Only
Solution
Sodium borohydride solution is nonflammable.
Any
flammability is due to hydrogen generation upon
decomposition.
Under normal storage conditions, it is
extremely stable, decomposing less than 0.01% per year. To
prevent pressure buildup, 10% free volume is required for all
closed containers, under these conditions, containers will
normally generate less then 1 psig per year.
204
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
X. SPILL AND WASTE DISPOSAL
hazardous waste with the code D002-corrosive. Check with
local regulations and guidelines for additional requirements.
Dry
In the U.S., spills and wastes of dry sodium
borohydride products are regulated by the U.S. EPA’s
Resource Conservation and Recovery ACT (RCRA)
as a hazardous waste with the code D003-reactive and
D001-Ignitable. Check with local regulations and
guidelines for additional requirements.
When dry borohydride products are spilled, clean-up
personnel must wear appropriate personal protective
equipment. Use non-sparking tools or explosion proof
equipment to shovel or vacuum material into an
appropriate container for disposal as hazardous waste.
After removing the spill from the floor, the area
should be rinsed with water, and the rinse water
collected for disposal.
Solution
In the U.S. spills and wastes of borohydride solution
products are regulated by the U.S. EPA’s Resource
Conservation and Recovery Act (RCRA) as a
*For Online Consulting Only
In the event of an accidental spill, immediate steps should be
taken to :
1.) contain the spill,
2.) absorb the spill using an absorbent
3.) remove the spilled material for disposal.
Proper procedures and protective equipment should by
employed as outlined in the section “Personal Protective
Equipment.”
Spills of solution should be prevented from entering any sewer
or streams. Dams can be constructed by using sand, dolomite,
or other absorbent material. Solution spills can be transferred
to a container for disposal. All remaining liquids should be
absorbed using the material mentioned above and then placed
in a container for disposal.
If permitted by regulatory authorities borohydride wastes,
spills and rinse water streams can be neutralized and
hydrolyzed on site prior to discharge.
This can be
205
Rohm and Haas : the Sodium Borohydride Digest
accomplished by adding the borohydride to a large
excess of water followed by the slow addition of
dilute acid to a neutral pH. Hydrogen gas will evolve,
therefore be sure the area is well ventilated and all
sources of ignition are eliminated.
If the spill occurs indoors, adequate ventilation should
be maintained prior to proceeding with containment,
cleaning and disposal. After removing the spill, the
area should be rinsed with water and the rinse water
collected for disposal. If the spill occurs outdoors,
any contaminated soil should be removed and placed
into a container for proper disposal.
Empty drums and lines should be disposed of as
industrial waste in accordance with local regulations.
*For Online Consulting Only
press <CTRL>-F for Searching
206
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
XI. TOXICITY
Dry
Dry sodium borohydride powder and caplets have
an acute dermal LD50 on dry skin of 4000 –8000 mg
/kg and are not skin sensitizers. Toxicity is increased
in the presence of moisture and can result in severe
irritation and skin burns.
The acute oral LD50 of sodium borohydride
powder or caplets is 69-mg/kg. This product is
considered toxic under FHSA classifications.
The acute oral LD50 of potassium borohydride
powder is 160-mg/kg. This product is considered
toxic under FHSA classifications.
*For Online Consulting Only
Solution
Solution of sodium borohydride in 50 % caustic has a
dermal LD50 of 100-500 mg/Kg and is considered moderately
toxic. This is primarily attributed to caustic soda, which can
cause skin burns and irritation.
The acute oral LD50 of the SWS solution is 500-1000
mg/kg. This product is considered toxic under FHSA
classifications.
Sodium borate, the product form the reaction or
decomposition of sodium borohydride, is considered slightly
toxic orally (LD50; 2000-4000mg /kg) and nontoxic dermally
(LD50 8000 mg/kg).
207
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
XII. STORAGE AND HANDLING
Dry
Solution
Dry borohydrides products are hydroscopic
and should not be unnecessarily exposed to moisture.
Any contact with moisture will result in hydrogen
evolution. They will remain stable indefinitely in dry
air or sealed containers. Dry borohydride products
should be stored in closed containers in a dry, cool,
well ventilated area and kept separated from oxidizers,
acids and other incompatible materials.
Store only in original containers as received
or in properly marked plastic bottles, do not store in
glass due to the potential for pressure buildup and
rupture. Also do not store in aluminum containers.
This applies to the product as received or any make-up
thereof.
Empty containers can be hazardous,
following label warnings even after container is
emptied since they may retain product residues. Do
not re-use empty container without professional
cleaning for food, clothing, or product for human or
animal consumption or where skin contact can occur.
Sodium borohydride solution can be stored and
handled in the same manner as 50 % caustic. Sodium
borohydride solution may be stored in adequately ventilated
mild steel, stainless steel, polyethylene or fiberglass vessels
suitable for caustic storage. As with caustic, Aluminum
equipment must not be used with sodium borohydride
solutions.
Store only in original containers as received or in properly
marked plastic bottles. Do not store in glass due to the
potential for pressure buildup and rupture and the corrosive
nature of sodium hydroxide on glass. This applies to the
product as received or any make-of thereof.
Under normal conditions storage, the decomposition
of sodium borohydride solutions is less then 0.01% per year.
One of the decomposition products is hydrogen.
All closed containers of sodium borohydride solution should
have at least 10% free volume and should be checked
periodically. If this is followed, pressure buildup will be less
then 1 psig per year at normal storage temperatures.
*For Online Consulting Only
208
Rohm and Haas : the Sodium Borohydride Digest
Sodium borohydride solution can be stored in
stainless steel, mild steel, and approved fiberglass
vessels. Stainless (316 SS or 304 SS) is recommended
for piping, valves, pumps, etc. Sodium borohydride
solution must not be stored in vessels that react with
caustic soda, such as aluminum.
Sodium borohydride solution should be
stored at temperatures between 65o F (18o C) and 100o
F (37o C) for ease of handling. Below 65o F the
solution viscosity increases rapidly, and at
temperatures below 55o F (13o C), crystallization can
occur. If crystallization occurs, liquefy by slowly
warming to 70-90o F (21-32o C) while venting. Do
not use live steam. Heating above 100o F is not
recommended due to the increased decomposition at
these temperatures.
Transfer piping exposed to cold temperature
should be heat traced and/or insulated. Precaution
should be taken to avoid overheating the piping, as
excessive line pressure and/ or product decomposition
may result.
*For Online Consulting Only
press <CTRL>-F for Searching
209
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
XIII. SHIPPING
Dry
Solution
For transport purpose, dry borohydride products are
designated as hazardous material under U.S. DOT,
IATA/ICAO and IMO as follows:
For transport purposes sodium borohydride solutions are
designated as a hazardous material under U.S. DOT,
IATA/ICAO and IMO as follows:
Proper Shipping Name:
Sodium Borohydride
(Potassium Borohydride)
Proper Shipping Name:
For less then 1000 lb. (454 kg) of NaOH:
Sodium borohydride and Sodium Hydroxide solution
For 1000 lb. (454 kg) or more of NaOH:
RQ, Sodium borohydride and Sodium Hydroxide Solution
Hazard Class/ ID Number:
4.3/UN 1426 for NaBH4
(4.3/ UN 1870 for KBH4)
Hazard Class/ Id Number:
8/ UN3320
Packing Group:I
Packaging Group: II
Label: Dangerous when wet
Label: Corrosive
*For Online Consulting Only
210
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
Disclaimer:
To the best of our knowledge the information
contained herein is correct. All products may present
unknown health hazards and should be used with
caution. Although certain hazards are described
herein, we cannot guarantee that these are the only
hazards which exists.
Final determination of
suitability of the product is the sole responsibility of
the user. Users of the products should satisfy
themselves that thee conditions and methods of use
assure that the product is used safely.
NO
REPRESENTAIONS OR WARRANTIES, EITHER
EXPRESSED
OR
IMPLIED,
OF
MERCHANTABILITY,
FITNESS
FOR
A
PARTICULAR PURPOSE OR ANY OTHER NATURE
ARE MADE HERE UNDER WITH REPECT TO THE
NFORMATION CONTAINED HEREIN OR THE
PRODUCT TO WHICH THE INFROMATION
REFERS.
Nothing herein is intended as a
recommendation to use our products so as to infringe
any patents. We assume no liability for customer’s
violation of patents or other rights. The customer
should make his own patent investigation relative to his
proposed use.
*For Online Consulting Only
211
Rohm and Haas : the Sodium Borohydride Digest
press <CTRL>-F for Searching
Please feel free to send us your questions via venpure@rohmhaas.com, or contact one of our offices :
in America:
Rohm and Haas Company
S&PA
60 Willow Street
Phone: 1-978-557-1832
Fax: 1-978-557-1879
in Asia:
Rohm and Haas China, Inc.
23rd Floor, Hitech Plaza
No. 488 S. Wu Ning Road
Shanghai, China
Phone: +86 21 6230 6366
Fax: +86 21 6230 6377
Updated information can be found at : http://www.hydridesolutions.com/
*For Online Consulting Only
in Europe:
Rohm and Haas France S.A.
la tour de Lyon
185, rue de Bercy
F-75579 Paris
Phone: +33-1 4002 5210
Fax : +33-1 4002 5441
212