FIVE
METHODS OF
PREPARING
ALCOHOLS
1
5 METHODS OF PREPARING ALCOHOLS
1. Hydroxide ions (OH-) replace halogens in unhindered alkyl
halides (Me° and 1°) via an SN2 reaction.
The product is an alcohol.
..
..
:O
H
H +
..
..
Br :
C
H
H
H
..
..O
C
H
..
Br :
..
H
..
..O
HH
H
C
H
H
..
+ : Br :
..
transition state
CH3
CH3
CH3CHCH2I + NaOH (aq)
isobutyl iodide
CH2CH2Cl
+
NaOH (aq)
1-chloro-2-phenylethane
CH3CHCH2OH + NaI
isobutyl alcohol
CH2CH2OH
+
NaCl
2-phenylethanol
2
5 METHODS OF PREPARING ALCOHOLS
But when a hindered alkyl halide (2° or 3°) is treated with a strong
base such as NaOH, dehydrohalogenation occurs producing an
alkene – an E2 reaction.
The Nu:- removes an H+ from a b-carbon &
the halogen leaves forming an alkene.
H
-
Nu:
+
b
C

C
C
C
+
-
X
+
Nu
H
X
KOH in ethanol
Br
-HBr
bromocyclohexane
+ KBr + H2O
cyclohexene
KOH
Br
no reaction
bromobenzene
Aryl and vinyl halides do not react via SN1, SN2, E1or E2 reactions.
3
5 METHODS OF PREPARING ALCOHOLS
2. Alkenes are hydrated by heating with dilute aq. H2SO4 (catalyst).
H
H
H+HSO4-
H
CH3
H
..
O
..
H
+
H
H
+
CH3
H
O
..
HSO4-
CH3
H
H
 The E+ (H+) adds to the less
substituted sp2 C Nu:- in the p-bond
forming the more stable C+
intermediate. The C+ may rearrange.
 Water, a weak
Nu:-,
adds to the
C +.
H
H
..
O
..
CH3
 The oxonium ion is deprotonated (loses H+) by H2O or HSO4-,
regenerating the catalyst and forming the Markovnikov alcohol
(1-methylcyclohexanol in this example).
4
5 METHODS OF PREPARING ALCOHOLS
 Recall that oxymercuration, demercuration also produces the
Markovnikov alcohol, but without C+ rearrangement.
CH3
CH
CH2
1 Hg(CH3COO-)2, THF, H2O
2 NaBH4
CH3
CH
CH3
OH
1-methyl-1-vinylcyclopentane
1-(1-methylcyclopentyl)ethanol
 The Hg ion adds first and forms a bridge to the C+, stabilizing it
and preventing rearrangement.
5
5 METHODS OF PREPARING ALCOHOLS
 Recall that hydroboration, oxidation produces the antiMarkovnikov alcohol without C+ rearrangement.
1 BH3, THF
2 NaOH, H2O2, pH8
CH3
1-methylcyclohexene
OH
CH3
2-methylcyclohexanol
6
5 METHODS OF PREPARING ALCOHOLS
Carbonyl compounds are reduced to alcohols.
DIGRESSION: Order of reactivity of carbonyls.
:O:
R
C
..
O
..
acid chloride
: O:
C
R
R
C
: O:
R
C
R
..
OH
..
R
C N:
R
R
C
C
: O:
R
C
:O:
nitrile
carboxylate
C
:O:
carboxylic acid
amide
..
Cl
.. :
R
C
: O:
C
most
: O:
ketone
ester
: O:
R
acid anhydride
aldehyde
: O:
carbonyl
group
reactive
H
..
O
..
..
R
H
N
H
.. _
O
..:
least
reactive
7
5 METHODS OF PREPARING ALCOHOLS
Sodium borohydride (NaBH4),lithium aluminum hydride (LiAlH4)
and Grignards (RMgX) reduce many carbonyls to alcohols.
acid chloride
acid anhydride
aldehyde
ketone
ester
carboxylic acid
amide
nitrile
carboxylate
Reduced to
alcohols by
NaBH4
NaBH4 is a
good Nu:and is safe
to use in
water.
Reduced to
alcohols by
Grignards
(RMgX)
Grignards
(RMgX) are
very strong
bases and
are
destroyed by
water and
other weak
acids.
LIAlH4 is a
powerful Nu:and is
explosive
water.
LiAlH4
reduces all
carbonyls.
8
5 METHODS OF PREPARING ALCOHOLS
Prep. of NaBH4 & LiAlH4 are shown. These reactions are reversible.
empty 2pz
orbital
very good
nucleophile
H
H
Na
H
+
borane
lithium
hydride
H
H
H
sodium borohydride
NaBH4
empty 2pz
orbital
very good
nucleophile
H
H
good
electrophile
H
sodium
hydride
Li
B
H
+
H
H
Li+
Al
H
Al
Na+
B
H
H
H
good
aluminum electrophile
hydride
lithium aluminum hydride
LiAlH4
9
5 METHODS OF PREPARING ALCOHOLS
 NaBH4 and LiAlH4 dissociate in the presence of carbonyl
compounds producing hydride (H:-) ion, an excellent Nu:-.
 Grignards (RMgX) dissociate in the presence of carbonyl
compounds producing an alkide (R:-) ion, an excellent Nu:3. Reduction of aldehydes with NaBH4 or LiAlH4 producing
1° alcohols.
Mechanism:
Nu:
-
: O:
R
C H
aldehyde
E
+
Nu:
-
1. H:
2.
..
: O:
R
C
..
H
H
H
alkoxide
..
O+
:O
H
H
E
+
R
C
H
H
+
H
..
O
..
H
alcohol
10
H
5 METHODS OF PREPARING ALCOHOLS
3. Reduction of ketones with NaBH4 or LiAlH4 producing
2° alcohols.
Mechanism:
2.
..
: O:
: O:
R
C
ketone
R
1. H:
R
C
..
O+
H
R
H
..
H
:O
H
R
C
H
R
+
H
..
O
..
H
alkoxide
2° alcohol
 Although both NaBH4 and LiAlH4 are effective, NaBH4 is
normally used as it is safer. LiAlH4 is reserved for less reactive
carbonyl compounds such as esters and carboxylic acids.
11
H
5 METHODS OF PREPARING ALCOHOLS
Draw and name the products of the following hydride reduction
reactions.
OH
O
1 NaBH4
+
H
O
CH2
3
C
2
H
cyclohexylmethanol
cyclohexylmethanal
O
2-cyclopenten-1-one
1 NaBH4
+
2 H3O
OH
H
2-cyclopenten-1-ol
Hydrides do not react with alkenes. Both are nucleophiles.
12
5 METHODS OF PREPARING ALCOHOLS
4. Reduction of esters (and carboxylic acids) with LiAlH4
producing 1° alcohols. NaBH4 is not strong enough.
LiAlH4 must be used for these carbonyls.
Mechanism:
alkoxide
..
:O:
R
E
C
+
..
O
..
-
:O:
Nu:
R
ester
-
1. H:
R
C
..
O
..
: O:
R
R
H
: O:
: O:
C H
aldehyde
1. H:
R
C
..
H
alkoxide
..
O+
H
H
H
C
aldehyde
2.
..
R
..
: OR..
:O
H
H
R
C
H
H
+
H
..
O
..
H
alcohol
13
H
5 METHODS OF PREPARING ALCOHOLS
 Note that aldehydes and ketones have no leaving groups. The
alkoxide intermediate will not lose a H:- or R:- so NaBH4 only
adds once. Esters, however, lose an alkoxide (OR-).
 OR- (pKb = -2) , like OH- (pKb = -1.74), is a poor leaving group
but LiAlH4 is powerful enough to displace it from the carbonyl.
Two moles of LiAlH4 are required for reduction of esters.
Draw and name the product of hydride reduction of the ester,
methyl benzoate.
O
C
O
CH3
2 equiv.
1 LiAlH4
+
2 H3O
OH
CH2
+
CH3OH
methyl benzoate
benzyl alcohol
14
5 METHODS OF PREPARING ALCOHOLS
Carboxylic acids react with 3 moles LiAlH4 producing 1° alcohols.
MECHANISM:
: O:
C
R
..
O
..
: O:
pKb = -21
H
-
1. H:
R
..
O
..:
C
: O:
AlH3
C
R
..
pKa = 5
: O:
2.
..
: O:
: O:
C H
aldehyde
-
1. H:
R
C
..
H
H
H
alkoxide
:O
H
H
R
C
AlH3
H
..
O+
..
O
..
C
R
AlH3
H:-
carboxylate
carboxylic acid
R
..
O
..
H
H
+
H
..
O
..
H
alcohol
15
H
5 METHODS OF PREPARING ALCOHOLS
LiAlH4 is reactive enough to reduce even carboxylates, the weakest
electrophile of the carbonyl compounds.
Draw and name the product of the following hydride reductions.
O
C
OH
3 equiv.
1 LiAlH4
+
2 H3O
dodecanoic acid
O
Cl
C
O- Na+
sodium 4-chlorobenzoate
CH2OH
1-dodecanol
1 LiAlH4
+
2 H3O
Cl
CH2OH
(4-chlorophenyl)methanol
16
5 METHODS OF PREPARING ALCOHOLS
5. Reduction of carbonyls with Grignards (RMgX) producing
alcohols.
 Grignards (RMgX) dissociate in the presence of carbonyl
compounds producing an alkide (R:-) ion, an excellent Nu:O- +MgX
O
C
1. RMgX in ether
C R
2.
H3O+
OH
C R
+
HOMgX
 Grignards are prepared by mixing finely divided Mg and an alkyl
halide in ether solvent. Mg is inserted between the alkyl group
and the halogen.
R-X + Mg  R-MgX
where R = 1º, 2, or 3 alkyl, aryl, or vinylic
where X = Cl, Br, or I
17
5 METHODS OF PREPARING ALCOHOLS
 Grignards react with formaldehyde, CH2=O, to give
1 alcohols. They react with higher aldehydes to give 2
alcohols and esters to give 3 alcohols.
H
MgBr
+
O
1. Mix
C
+
2. H3O
H
H
cyclohexyl
magnesium
bromide
MgBr
+
formaldehyde
CH3
O
CH3CHCH2 C H
C
OH
H
cyclohexylmethanol
(a 1º alcohol with a longer C chain)
1. Mix in ether
+
2. H3O
CH3
OH
CH3CHCH2 C
H
phenyl
magnesium
bromide
3-methylbutanal
3-methyl-1-phenyl-1-butanol
(a 2º alcohol)
18
5 METHODS OF PREPARING ALCOHOLS
 Grignards react with ketones and esters to give 3 alcohols.
O
CH3CH2MgBr
1. Mix in ether
+
OH
CH2CH3
+
2. H3O
ethyl
magnesium
bromide
cyclohexanone
O
CH3CH2CH2CH2 C
1-ethylcyclohexanol
( a 3º alcohol)
1. 2 CH3MgBr
OCH2CH3
ethyl pentanoate
2.
+
2 H3O
OH
CH3CH2CH2CH2 C
+
CH3
2 MgBrOH
+ CH3CH2OH
CH3
2-methyl-2-hexanol
( a 3º alcohol)
19
5 METHODS OF PREPARING ALCOHOLS
 Unlike LiAlH4, Grignards do not reduce carboxylic acids to
alcohols.
 Grignards (strong bases) neutralize carboxylic acids to
carboxylates, but, unlike LiAlH4, Grignards are not strong
enough nucleophiles to react with carboxylates (weak
electrophiles) .
O
CH3CH2 C
O
CH3
O
propanoic acid
H
MgBr
CH3CH2 C
methane
O- +MgBr +
CH4
magnesium bromide acetate
20
5 METHODS OF PREPARING ALCOHOLS
 Grignards are destroyed (protonated) by even very weakly
acidic functional groups.
 All the groups listed below have a H acidic enough to protonate
the highly basic Grignard reagents.
pKa
ArCOOH
RCOOH
ArSH
RSH
ArOH
R-OH
amide
-CC-H
ArNH2
RNH2
4
5
7
10
10
16
17
25
~30
35
Assuming alkyl amines (pKa =35) to be the weakest acid that
would protonate a Grignard, calculate the approximate pKb of a
Grignard.
pKeq = pKa + pKb – 14
0 = 35 + pKb -14
pKb = 14 – 35 = -21
21
5 METHODS OF PREPARING ALCOHOLS
Draw products formed when methyl magnesium bromide (CH3MgBr)
reacts with the following.
O
excess
1 CH3MgBr
+
2 H3O
OH
CH3
1-methylcyclopentanol
O
C
benzophenone
excess
1 CH3MgBr
+
2 H3O
OH
C
CH3
1,1-diphenylethanol
22
5 METHODS OF PREPARING ALCOHOLS
The following product was formed using Grignards.
Draw all possible sets of reagents.
O
H3C
OH
H3C
C
C
CH2
CH3
+
MgBr
O
CH2
CH3
C
2-phenyl-2-butanol
CH2
CH3
+
CH3
MgBr
O
C
CH3
+
CH3CH2
MgBr
23
Do the practice
problems in your
purchased notes!
24