SPRING 2008 CH221 ORGANIC CHEMISTRY 1
NOTES FOR CHAPTER 12
OXIDATION AND REDUCTION
12.1 Introduction
It was shown in Chapter 4 that to tell whether an organic compound has been
oxidized or reduced during a chemical reaction, it is necessary to compare the
relative number of C-H and C-Z bonds (Z = a more electronegative element
than C) in the starting material and product.

Oxidation results in an increase in the number of C-Z (usually C-O)
bonds or a decrease in the number of C-H bonds.

Reduction results in a decrease in the number of C-Z (usually C-O)
bonds or an increase in the number of C-H bonds.
A general scheme for the oxidation and reduction of organic compounds is
shown below, where replacing C-H bonds by C-O bonds is oxidation (symbol
[O]), whereas the reverse is true for reduction (symbol [H]).
Sometimes two carbon atoms are involved in a single oxidation or reduction
reaction: in these cases, the net change of C-H or C-Z bonds at both atoms must
be considered. Thus, alkynes are reduced to alkenes, which in turn, are reduced
to alkanes, as shown below.
12.2 Reducing Agents
Oxidation and reduction are always complementary, so that to reduce an organic
compound, a substance that is itself oxidized must be used: it is called a
reducing agent. Reducing agents provide the equivalent of two hydrogen atoms.
There are three types of reductions considered in this chapter and these differ in
how the elements of H2 are added to the organic compound being reduced.
1. Addition of molecular hydrogen. Reduction of this type is carried with a
transition metal catalyst and is known as catalytic hydrogenation.
2. Addition of two protons and two electrons. Reduction of this kind is
carried out by alkali metals (Li, Na or K) (these supply electrons) in liquid
ammonia (which supplies the protons). They are sometimes called
dissolving metal reductions.
3. Addition of a hydride (H-) and a proton. Simple hydrides (e.g. KH) can
be used, but more useful are the complex metal hydrides sodium
borohydride (NaBH4) and lithium aluminum hydride (LiAlH4). These
reagents deliver H- to the substrate and the proton comes from a protic
solvent (H2O or an alcohol).
12.3 Reduction of Alkenes
Alkenes are reduced by molecular hydrogen, in the presence of a solid catalyst.
The process is known as (heterogeneous) catalytic hydrogenation. There is a
homogeneous version (not mentioned in this chapter). The catalyst is usually a
transition metal (often Pd, Pt or Ni) adsorbed onto a finely divided inert solid,
such as charcoal. The catalyst 10% Pd on carbon is very widely used, but Pt is
also common and oxides (e.g. PtO2) or even mixtures can be used.
Catalytic Hydrogenation
C
C
+
H
H
weak  bond
tranisition metal,
metal oxide
or mixed catalyst
C
C
H
H
Alkane
Alkene
The expensive catalyst can be recovered after the experiment and reused.
Addition of H2 is often syn. This and other aspects of catalytic hydrogenation
are demonstrated by the examples below.
CH3
CH3
H2
CH3
PtO2
CH3
Illustrating stereoselectivity:
often (but not always) syn
addition
H
CH3
H
Cis mainly
CH3
H2
(1 equiv.)
Illustrating group selectivity:
only the less hindered C=C
is reduced
PtO2
CH3
CH3
CH(CH3)2
CH2
CH3
CH3
H2
CH3
CH3H
CH3
Illustrating stereochemistry:
hydrogenation occurs on less
hindered side (with syn addition)
Pd/C
H
-pinene
Hydrogenation and Alkene Stability
Like other alkene additions, hydrogenation reactions are exothermic because
the bonds in the product are stronger than those in the starting materials. The
heat of hydrogenation can be measured and used to determine the relative
stabilities of alkenes. For example the heat of hydrogenation of cis-2-butene is
less than that of trans-2-butene, indicating the greater stability of the latter:
cis 2-Butene
CH3
CH3
C
H
C
H
trans 2-Butene
H2
H2
CH3CH2CH2CH3
H
C
Pd-C
Pd-C
Ho = _ 28.6 kcal/mol
CH3
H
C
CH3
Ho = _ 27.6 kcal/mol
More stable starting material,
less heat released
The Mechanism of catalytic Hydrogenation
It is generally accepted that adsorbed atoms and molecules react on the surface
of the catalyst, having been activated by it.
The hydrogen atoms are transferred sequentially to the alkene to produce the
alkane, which is then desorbed, because there is no longer a metal- bond
attraction. The above mechanism is able to explain several features of catalytic
hydrogenation shown in the examples earlier:

Syn addition (though this is not 100% reliable).

Less hindered C=C reacts more readily than hindered C=C.

Addition occurs on less hindered side of alkene.
Hydrogenation Data and Degrees of Unsaturation
In Chapter 10, it was shown that the number of degrees of unsaturation gives
the total number of rings and bonds in a molecule. Hence hydrogenation can
enable the determination of the number of bonds and rings by comparison of the
number of degrees of unsaturation before and after hydrogenation. This is
illustrated by Sample Problem 12.1.
Hydrogenation of Other Double Bonds
Other unsaturated systems can be reduced using catalytic hydrogenation.
Sometimes these compete successfully with C=C bond reduction (e.g. –COCl
and NO2). Others, such as aldehydes, carboxylic acids, esters and ketones react
more slowly than alkene functions, so that C=C can often be reduced in the
presence of, say, a ketone function, with the latter being unaffected. Benzene
rings are hydrogenated only with difficulty, requiring the use of a Raney nickel
catalyst.
12.4 Application: Hydrogenation of Oils
Partial hydrogenation of the unsaturated long chain fatty acid chains of the
triacylglyceride molecules in vegetable oils is used to prepare many processed
foods, such as cake, cookies, margarine, and peanut butter.
The fewer double bonds in the triacylglycerols result in a higher melting point
(m.p.) of the lipid, thus giving a material of semi solid consistency (a low melting
point solid). The greater the extent of hydrogenation, the higher the m.p. of the
resulting material. Hence it is possible to produce hard and soft fats by this
process, which is commercially known as hardening. Hydrogenation increases
the shelf life of the lipid by lowering the number of allylic carbon atoms. These
carbon atoms are most susceptible to oxidation that causes off-flavors (rancidity).
12.5 Reduction of Alkynes
An alkyne can be reduced either to the alkene with one equivalent of the
elements of H2 or to the alkane by using two equivalents of the elements of H 2. In
the case of partial reduction to the alkene, the elements of H2 may be added in a
syn or anti fashion, depending on the catalyst.
syn Addition gives cis alkene
H2 (1 equiv)
catalyst
R
R
C
C
H
R
C
C
H
one further
equiv of H2
R
R
H2 (1 equiv)
catalyst
H
C
H
C
R
H
H
C
C
H
H
R
Alkane
R
anti Addition gives trans alkene
Reduction of an Alkyne to an Alkane
Reaction of an alkyne with two equivalents of molecular hydrogen, in the
presence of a catalyst (as for alkene hydrogenation) results in the formation of
the corresponding alkane. When normal catalysts (e.g. 10% Pd-C) are used, syn
addition occurs to give the alkene, which is then further reduced to the alkane.
The alkene is not isolated and indeed, normal hydrogenation catalysts are too
reactive to allow hydrogenation to stop at the alkene: if an alkene product is
required, special techniques are needed, as described next.
Reduction of an Alkyne to a cis Alkene
Alkynes can be hydrogenated to cis alkenes by the use of a partially poisoned
(deactivated) catalyst, known as a Lindlar catalyst:
H2
R
C
C
R
R
R
C
Pd on CaCO3 with added
lead acetate and quinoline
(Lindlar catalyst)
C
H
H
cis Alkene
This reaction is more or less specific for alkyne triple bonds and the product
alkene is unreactive toward further hydrogenation under these conditions. An
example is given in Problem 12.10.
C=O and C=C
unaffected
O
O
CH2
CH3
C
C
CH2CH3
H2
CH2
H
Lindlar catalyst
C
syn addition
of one equivalent
of H2
C
CH2CH3
H
CH3
cis-Jasmone (aroma component
of jasmine flower)
Reduction of an Alkyne to a trans Alkene
Complementary to the above technique, it is possible to partially reduce an
alkyne to the trans alkene. This time hydrogenation is not used, instead a
dissolving metal reduction delivers the elements of H2 in an anti fashion.
The mechanism of dissolving metal reduction (sometimes known as Birch
reduction) for Na in NH3 is shown below. It involves sequential electron
transfers (from Na to organic species) and proton transfers (from NH3 to
organic species) and includes the formation of a radical anion, a radical and a
carbanion.
_
e (from Na)
R1
C
C
R2
.
C
R1
_
..
C
R2
a radical anion
_
..
C
.
C
R1
.
C
R1
H
R2
R2
NH2
.
C
R1
_
-NH2
R2
C
H
a radical
_
e (from Na)
R2
_
..
C
C
H
C
H
R1
an anion (in preferred
trans configuration)
H
_
..
C
NH2
R2
C
H
R1
H
R2
C
_
-NH2
C
R1
H
trans alkene
In the 3rd step, the carbanion is formed preferentially in a trans configuration, thus
giving trans stereoselectivity to the whole process. The trans carbanion is
sterically less hindered than the cis isomer.
H
R
C
R
H
C
.._
More stable vinyl anion
C
R
_
..
C
R
Unfavorable steric
interactions destabilize
this vinyl anion (which
would give cis alkene)
trans Alkene
12.6 Reduction of Polar C-X  Bonds
Compounds containing polar C-X  bonds that react with strong nucleophiles can
be reduced with metal hydride reagents, especially lithium aluminum hydride.
Two common functional groups that have both these characteristics are alkyl
halides and epoxides.
Reduction of these C-X  bonds is another example of nucleophilic substitution
and because H- is a strong nucleophile, the reaction follows an SN2 mechanism.
_
H3Al
R
H
+
CH2
R
SN2
X
_
H
CH2
+
X
+
AlH3
LiAlH4 donates H- to electrophilic C
Two examples are given below, illustrating the easier reduction of 1o alkyl halides
and the orientation of hydride transfer from AlH4- to the epoxide.
12.7 Oxidizing Agents
Oxidizing agents are broadly of two types:

Reagents that contain an oxygen-oxygen bond.

Reagents that contain metal-oxygen bonds.
Oxidizing agents with O-O bonds include O2, O3 (ozone), H2O2 (hydrogen
peroxide), (CH3)3COOH (tert-butyl hydroperoxide) and RCO3H (peroxyacids). Of
these, peroxy acids are the most widely used: examples are shown below.
O
O
C
R
O
OH
CH3
O
O
C
C
O
C
O
O
OH
OH
_
CO2
Peroxyacetic acid
Peroxyacid
Cl
meta-chloroperoxybenzoic
acid
mCPBA
OH
Mg2+
2
Magnesium monoperoxyphthalate
MMPP
The two most common oxidizing agents that contain metal-oxygen bonds are
based on Mn(VII) and Cr(VI). Potassium permanganate (KMnO 4) is the most
usual Mn(VII) reagent, used in acidic, neutral or alkaline conditions, depending
on the substrate to be oxidized and the desired degree of oxidation. Cr(VI)
reagents include chromium (VI) oxide, and acidified sodium or potassium
dichromate (H+/Cr2O72- or H2SO4/K2Cr2O7)). These are all strong oxidizing agents
with little selectivity. Much more selective is pyridinium chlorochromate
(PCC), which can be used in chlorinated organic solvents (e.g. CH2Cl2), without
strong acid.
6+ oxidation
state
6+ oxidation
state
O
O
_
Cr
O
+
N
O
Chromium (VI) oxide
CrO3
O
Cr
Cl
O
H
Pyridinium chlorochromate
PCC
The types of oxidation of alkenes, alkynes and alcohols that can be performed
using one or other of the above oxidizing agents is shown below and is the main
topic for the rest of Chapter 12.
12.8 Epoxidation

Epoxidation involves the addition of a single oxygen atom to an
alkene to form an epoxide.
O
O
C
+
m-ClC6H4
O
OH
C
O
+
m-ClC6H4
mCPBA
The mechanism is a concerted addition of O to the alkene  bond, rather like the
first step in halogenation that forms the bridged halonium ion intermediate.
..
O:
R
R
C
The peroxide
(O-O) bond
is broken
=
..
O:
C
:O
..
H
..
O
..
C
C
..
O:
R
C
H
:O
..
O
C
H
:O
..
..
O
..
C
C
C
OH
Stereochemistry of Epoxidation
The concerted mechanism above requires syn addition of O to the double bond
thus leading to retention of configuration (a cis alkene gives a cis epoxide).
The addition can occur from either above or below the plane of the double bond,
giving the reaction a stereospecific character, as illustrated for the epoxidation
of cis- and trans-2-butenes, below.
Attack from below
Attack from above
CH3
CH3
O
mCPBA
C C
H
H
cis-2-Butene
CH3
H
C * C*
+
CH3
H
CH3
H
*
C
C*
CH3
H
O
Achiral meso compound
CH3
H
C
C
H
mCPBA
CH3
Attack from below
Attack from above
O
CH3
H
C*
C*
H
CH3
+
CH3
H
*
C
*
C
H
CH3
O
trans-2-Butene
Enantiomers
The Synthesis of Disparlure
Disparlure, the sex pheromone of the female gypsy moth is synthesized by a
sequence of steps, the last of which is an epoxidation reaction. The synthesized
compound (as a cheap racemate) is mixed with a sticky substance and used as a
lure or trap for male moths. The males can detect single molecules of disparlure
and flock to the source of the pheromone, where they become stuck in the sticky
substance and eventually die. This is an example of a pheromone trap – a way to
kill insect pests without the need for an environmentally unfriendly insecticide.
The gypsy moth has been responsible for the deaths of many broadleaf trees: it
has a voracious appetite for the leaves. The retrosynthetic analysis and actual
synthesis of disparlure are shown next.
12.9 Dihydroxylation (or Perhydroxylation)

Dihydroxylation is the addition of two hydroxy groups (the elements
of H2O2) to a double bond to form a 1,2-diol (glycol).
This is illustrated for cyclohexene below, where it can be seen that choice of
reagent is important in deciding the major diasteroisomerism of the product (i.e.
whether it is cis or trans).
1. RCO3H
2. H+(aq) or OH-(aq)
OH
anti Addition
OH
OH
syn Addition
Either KMnO4/OH-(aq)
or
1. OsO4
2. NaHSO3(aq)
OH
The epoxidation of cyclohexane followed by hydrolysis route leads to trans-1,2cylclohanediol. This can be explained by the necessity of a backside attack by
H2O on the protonated (activated) epoxide, so that the two C-O bonds are
formed on opposite sides of the ring.
OH
Attack from below
at C2
OH
..
: OH2
RCO3H
: O:
Cyclohexene
H+
2
1
+
:O
-H+
Racemic transcyclohexane-1,2-diol
H
..
: OH2
-H+
Attack from below
at C1
OH
OH
In practice, racemic trans-1,2-cyclohexanediol is formed, illustrating the principle
that an achiral substrate plus achiral reagent give either an achiral or a racemic
product.
In contrast, alkaline KMnO4 or OsO4 followed by aqueous NaHSO3 convert
cyclohexene to cis-1,2-cyclohexanediol.
O
O
O
O
O
Os
+
O
..
Os
O
NaHSO3/H2O
O
OH
OH
Note the syn addition
cis-Cyclohexane-1,2-diol
_
O
O
pH > 7
O
Mn
+
O
O
O
..
Mn
O
_
H2O
O
Potassium permanganate is cheap and relatively nontoxic, but is not soluble in
organic solvents (although it can be used with phase transfer catalysts). Osmium
tetroxide is more expensive and highly toxic, but is soluble in organic solvents
and is more selective than KMnO4. N-methyl morpholine N-oxide, with a catalytic
amount (a few %) of OsO4 can be used in place of OsO4 itself.
_
CH3
+
N
O
N-Methylmorpholine N-oxide
The N-methylmorpholine N-oxide first oxidizes Os(VI) to Os(VIII), which then
adds O to the alkene double bond and is reduced back to Os(VI). This cycle
continues throughout the reaction.
12.10 Oxidative Cleavage of Alkenes
This involves complete rupture (breaking both  and  bonds) of the double
bond to form two carbonyl groups – aldehydes or ketones, depending on
the extent of substitution at each alkene C atom.
OH
OH
The most common way of doing this is by ozonolysis: oxidative cleavage with
ozone, followed by treatment with either Zn and water or dimethyl sulfide.
The mechanism of ozonolysis involves addition of O 3 to C=C as the first step.
The initial addition product then undergoes rearrangement to an ozononide which
is then reductively cleaved by Zn/H2O (older method) or (CH3)2S to afford
carbonyl compounds.
Sample Problem 12.3 shows two examples: the second part illustrates the
usefulness
of
ozonolysis
in
preparing
,-dicarbonyl
cycloalkenes. Otherwise the technique is synthetically limited.
compounds from
Ozonolysis was once a good method for the determination the locations of
double bonds in unknown molecules: an example is shown below for the terpene
limonene and also in Sample Problem 12.4.
12.11 Oxidative Cleavage of Alkynes
Alkynes undergo ozonolysis to give carboxylic acids and CO 2, depending on
whether the alkyne C atoms are internal or terminal.
12.12 Oxidation of Alcohols
Alcohols can be oxidized to a variety of carbonyl compounds, depending
on the type of alcohol (1o, 2o or 3o) and the reagent. Oxidation occurs by
replacement of C-H bonds on the carbon bearing the OH group with C-O bonds.
Cr(VI) reagents are the usual oxidizing agents:

CrO3, Na2Cr2O7 and K2Cr2O7 are vigorous, nonselective reagents that
require aqueous acid.

PCC is milder and more selective, is soluble in CH2Cl2 and does not
require acid.
Oxidation of 2o Alcohols
Any of the above Cr(VI) reagents effectively oxidize 2o alcohols to ketones by the
following mechanism. The first step is formally addition of the alcohol across one
of the Cr=O bonds. This produces an alkyl chromate ester, with the Cr atom still
in oxidation state +6. The ester is then decomposed by hydrogen abstraction to
water, forming the carbonyl bond and the Cr atom being reduced to Cr(IV). By a
subsequent series of steps (not shown) Cr(IV) is further reduced to the green
Cr(III).
Step 1 Formation of chromate ester
O
R2CH
..
OH
..
Cr
+
O
(VII)
(with proton
transfer)
O
(VII)
R2CH
O
O
Cr
OH
O
Chromate ester
Step 2 Proton abstraction from the chromate ester to form the carbonyl group
O
(VII)
R2C
H
O
Cr
(IV)
OH
O
..
H2O:
R2C
O
_
CrO3H
H
+
H2O:
Oxidation of 1o Alcohols
Primary alcohols are oxidized to aldehydes or carboxylic acids depending on the
reagent: CrO3 (etc) oxidizes them all the way through to carboxylic acids, whilst
the milder PCC produces aldehydes.
The mechanism of oxidation of 1o alcohols using CrO3 or similar reagents
involves the same features of the mechanism just discussed for 2 o alcohols. The
major difference is that once the aldehyde is formed in the first part, it easily
forms a hydrate in the aqueous environment of the reaction, thereby creating
new OH bonds that can form chromate esters with excess Cr(VI), resulting in
further oxidation (parts 2 and 3).
Part 1 Oxidation of 1o alcohol to aldehyde
H
R
R
C
OH
+
Cr(VI)
C
O
+
H
H
Cr(IV)
By mechanism for
oxidation of 2o alcohols,
described previously
Aldehyde
1o Alcohol
Part 2 Addition of H2O to aldehyde to form hydrate
H
H+
R
C
O
R
H2O
+
H
C
OH
OH
Hydrate (a 1,1-diol)
Part 3 Oxidation of hydrate to carboxylic acid
..
H2O:
H
H
CrO
3
R
C
OH
R
OH
two steps
C
OH
O
O
R
Cr
O
Chromate ester
OH
C
O
+
..
_
CrO3H
+
.. +
H3O
HO
Carboxylic acid
Also similar to the mechanism described for the oxidation of 2o alcohols described previously
The oxidation of alcohols by orange Cr(VI) reagents is accompanied by a color
change to green as Cr(VI) is reduced to Cr(III). This was the basis of the first “on
the spot” alcohol testing devise, used by police on drivers suspected of having
over the legal limit of ethanol in the blood stream. The individual is required to
blow into a tube containing K2Cr2O7 and H2SO4 on an inert substance. The
exhaled gases are forced through the tube and turn the crystals green to a depth
that depends on the amount of ethanol in the breath (and hence in the blood
stream).
12.13 Green chemistry
Organic chemists have long been seeking safer, more environmentally friendly
ways of performing syntheses, including those that involve oxidation. In
particular, interest is growing on reactions in water, solventless reactions (or
those that require less solvent) and reactions that use milder, less dangerous
reagents (e.g. enzymes or microorganisms, like baker’s yeast) and produce
either safe byproducts or those that can be removed from the reaction mixture by
simple physical processes (such as filtration). In the realm of Cr(VI)-catalyzed
oxidation
of
alcohols,
polymer
supported CrO3 fulfills some of
the
characteristics mentioned above. Chromium oxide in acidic solution exists
partially as hydrogen chromate. This can be supported on an ion-exchange resin
such as the strongly basic macroporous Amberlyst A-26 resin (a cross-linked
polystyrene-divinylbenzene copolymer with quaternary ammonium ((CH3)3N+groups) by ion exchange.
_
HCrO4
(from CrO3(aq))
P
_
+
N(CH3)3 Cl
-Cl
Amberlyst A-26 resin
(as purchased)
P
_
+
N(CH3)3 HCrO4-
"Polymer-supported CrO3"
Stir CrO3 (aq)
with Amberlyst A-26,
filter and dry
This reagent is milder than the standard Cr(VI) reagents (see below) and the
Cr(III) residue can be filtered off with the spent polymer after the reaction. The
polymer can be regenerated.
Ph2CH
OH
HCrO4Amberlyst A-26
Ph2C
O
HCrO4Amberlyst A-26
CH3(CH2)8CH2OH
CH3(CH2)8CHO
12.14 Application: Oxidation of Ethanol
Ingested ethanol is metabolized in the liver by oxidation, first to ethanol and
finally to acetate. The enzyme performing this oxidation is liver alcohol
dehydrogenase (LAD), a protein that works with the redox coenzyme known
as nicotinamide adenine dinucleotide (NAD+ + H+ + 2e-  NADH). If more
ethanol is ingested than can be metabolized in a given time, the concentration of
the toxic acetaldehyde builds up and leads to the condition known as a hangover.
Antabuse is a drug given to alcoholics to stop them consuming alcohol. The
drug allows the metabolism of ethanol to acetaldehyde to occur, but inhibits the
oxidation of acetaldehyde to acetate, thus causing the subject to become
violently ill. Methanol (often a minor component of alcoholic beverages) is also
metabolized by liver alcohol dehydrogenase to the even more toxic formaldehyde
and formic acid. However, it is metabolized more slowly than ethanol, so that in
cases of methanol poisoning, ethanol is administered to the patient to switch the
action of LAD from methanol to ethanol. The unmetabolized methanol is then
harmlessly excreted unchanged.
12.15 Sharpless Epoxidation
It has been demonstrated in several previous chapters that an achiral starting
material reacts with an achiral reagent to give either an achiral product or a
racemic mixture of two enantiomers. In this chapter we have seen that the
synthesis of disparlure gives a racemic product, where only one of the
enantiomers is physiologically active.
A reaction that produces predominantly or exclusively one enantiomer is known
as an enantioselective reaction: if it converts an achiral starting material to
predominantly one enantiomer, it is also an asymmetric reaction. The
Sharpless epoxidation (devised by K B Sharpless in the 1980s) is an aymmetric
reaction that oxidizes allylic alcohols to epoxides. The reagent is tBuOOH, with
pure (-) or (+) diethyl tartrate and titanium (IV) isopropoxide providing the chiral
influence.
The configuration of the epoxide product can be predicted according to whether
(-)- or (+)-DET are used, as shown below.
Sample problem 12.5 serves to provide a couple of examples of Sharpless
epoxidation, along with prediction of epoxide configuration.