Oxidation and Reduction

Oxidation and Reduction Occur Together: We cannot oxidize

a chemical species using a chemical reaction without
simultaneously reducing another chemical species.

Organic oxidation requires a simultaneous reduction reaction

usually of inorganic reagents

Reduction of an organic compound generally involves

concomitant oxidation of inorganic reagents.

Redox Reactions Involve Electron Transfer:

Redox reactions involve the overall transfer of electrons from one
species to another species. The chemical species being oxidized loses
electrons to the chemical species being reduced.

Inorganic Redox Reactions. The ionic inorganic redox reaction

involving Fe and Cu ions
( Figure 17.001) illustrates this electron transfer.

The two balanced ionic half-reactions

Organic Redox Reactions. Electron transfer is usually difficult to

see in the organic reactant(s) and product(s) in an organic redox
reaction.
1
For example the conversion of a 2 alcohol to a ketone (Figure
17.003) is oxidation, but it is not obvious that electron transfer has
occurred by looking at the alcohol and ketone structures.

This electron transfer is generally visible, however, in the inorganic

reagents and products of redox reactions. In the case of oxidation of an
alcohol to a ketone, an oxidizing agent can be a chromium compound with
Cr in its +6 oxidation state (Cr(VI)). During the reaction, Cr is
reduced to Cr(III) in a +3 oxidation state showing that it gains electrons
from the alcohol as it is oxidized to the ketone.

When we use an oxidizing agent of chromium compound

Change in Oxidation state: Cr(VI) Cr(III) showing that it gains
electrons from the alcohol as it is oxidized to the ketone.

Oxidation Levels of Organic Compounds :

We can demonstrate the oxidation or reduction of an organic
compound by calculating oxidation numbers for the C atoms that
are oxidized or reduced.

Definitions of Organic Oxidation and Reduction. You can see by

looking at the compounds in Table 17.01, that oxidation of a C atom in an
organic compound involves one or more of the following changes:
(1) an increase in the multiple bond order of the C
(2) addition of O to a C
(3) replacement of an H on a C by O
We combine these criteria in the statement that "oxidation of organic
molecules involves a gain in oxygen and/or loss of hydrogen". Look at
each oxidation reaction in the following sections to see that one or more of
these criteria are met.
2
Redox Reactions to be discussed:
i) Oxidation of Alcohols and Aldehydes),
ii) Oxidation of Carbon-Carbon Multiple Bonds,
iii) Oxidation of Alkyl Groups (17.4), and
iv) Formation ofPhenols and Quinones

Oxidation of Alcohols and Aldehydes

Oxidation Using Cr(VI) Reagents

Chromate and Dichromate Reagents.

We prepare these Cr(VI) reagents by adding sodium or potassium

dichromate (Na2Cr2O7 or K2Cr2O7), or chromium trioxide (CrO3), to
aqueous solutions of sulfuric or acetic acid.

Several Cr(VI) species are present in these solutions

in equuilibria with each other.

Some Typical Chromate and Dichromate Species

3
 Table 17.02. Cr(VI) Species Present in Solutions of
K2Cr2O7, Na2Cr2O7, or CrO3 in Sulfuric or Acetic Acid.

Unwanted Oxidation of Aldehydes.

We can prevent this by i) using modified Cr(VI) reagents, ii)

distilling the intermediate aldehyde from the reaction mixture as it
forms before it is oxidized further.

Oxidation of Cyclic Ketones

When ketones react with Cr(VI) reagents at high temperatures,

the result is a complicated mixture of products.

An exception is oxidation of cyclic ketones that give good yields of

dicarboxylic acids

Jones Oxidation. Because acyclic ketones are relatively stable to Cr(VI) oxidations,
acetone is frequently used as the solvent for Cr(VI) oxidations of alcohols. In these
reactions,
a CrO3/H2SO4/H2O mixture is slowly added to an acetone solution of the alcohol, or the
alcohol is mixed with an acetone solution of CrO3/H2SO4/H2O. Both the
CrO3/H2SO4/H2O
mixture and that mixture in acetone are called the Jones reagent while the resultant
oxidation
reaction is called a Jones oxidation.

Advantages of using acetone as solvent: Besides being stable to

oxidation, acetone dissolves many higher molecular mass
alcohols that have relatively low solubility in water, and it is easy
to remove from the reaction mixture because of its low boiling
point (56C).
4
Modified Cr(VI) Reagents. Organic chemists have developed modified Cr(VI)
reagents
that are weaker oxidizing agents than the Jones reagent and permit the formation of
aldehydes
without their subsequent oxidation to carboxylic acids. Three of these are complexes of
pyridine with Cr(VI) species (Figure 17.009).

Modified Cr(VI) Reagents are weaker oxidizing agents than the Jones reagent and
permit the formation of aldehydes without their subsequent oxidation to carboxylic
acids

Oxidation of Allylic Alcohols.

Cr(VI) Oxidation Mechanisms.

5
This summary shows there are intermediate Cr(V) and Cr(IV) species,
and intermediate organic free radicals on the paths from alcohol to
ketone or aldehyde.

MnO2: This Mn(IV) reagent selectively oxidizes allylic and benzylic alcohols to ketones
Or aldehydes and the Mn(IV) is reduced to Mn(II).

Sodium Hypochlorite (NaOCl). This simple inorganic reagent is frequently used in

commercial applications of oxidation such as conversion of 2alcohols to ketones

6
OH groups that are not allylic or benzylic are not oxidized, and the aldehyde
products do not further oxidize to carboxylic acids.

Organic Oxidizing Agents

Peroxycarboxylic acids such as peroxytrifluoroacetic acid (trifluoroperacetic
acid)

Synthesis of Peroxycarboxylic Acids. Peroxycarboxylic acids (or

peracids) can be prepared from reactions of carboxylic acids with
hydrogen peroxide (H2O2) as we show for trifluoroperacetic acid.

Baeyer-Villiger rearrangement

Ketones to Esters

Mechanism of Baeyer-Villiger rearrangement

7
A key step is migration of the R' group with its bonding
electron pair from C to O (fourth step).
The relative rate (relative ease) of migration of this R'
group is
R' = H > 3 > 2, aryl > 1 > CH3.

8
A key step is migration of the R' group with its bonding
electron pair from C to O (fourth
step).

The relative rate (relative ease) of migration of this R' group

is R' = H> 3 > 2, aryl > 1 > CH3.

9
This migration selectivity has synthetic utility. For example, we can convert compounds
of
the structure R-C(=O)-CH3 exclusively into the alcohols R-OH by the sequence of
reactions.

In contrast the facile migration ability of H transforms aldehydes R-C(=O)-H into the
corresponding carboxylic acids R-C(=O)-OH.

Synthesis of lactones from cycloalkanones.

Aldehydes to Carboxylic Acids and Alcohols.

Cannizzaro reaction,

The mechanism of Cannizzaro reaction

10
The key step is the transfer of an H with its bonding electron pair (a hydride transfer)
from
the intermediate anion to another molecule of aldehyde.

Alcohols to Ketones or Aldehydes.

The mechanism of this Oppenauer oxidation
A simple ketone such as acetone ((CH3)2C=O) can serve as an oxidizing
agent for the oxidation of a 1 or 2 alcohol to an aldehyde or ketone

11
Both the alkoxide species (R2CHO-) and acetone are bonded to Al in an aluminum
trialkoxide molecule (Figure 17.027) formed by reaction of R2CHOH with a molecule
such as Al(O-C(CH3)3).

Dimethylsulfoxide. A more recent organic oxidizing agent is

dimethylsulfoxide (DMSO) ((CH3)2S=O) that can oxidize primary alcohols
and halogenated compounds to aldehydes or
Ketones.

The mechanism of this Swern oxidation is complex.

12
Oxidation of Carbon-Carbon Multiple Bonds
There are a variety of oxidation reactions in which C=C bonds add oxygen or
are cleaved to oxygenated products

Addition of Oxygen to C=C Bonds

When oxygen adds to C=C bonds, the products are epoxides or 1,2-diols

Epoxide Formation Using Peroxyacids. oxidation of C=C bonds using

peroxycarboxylic acids such as m-chloroperbenzoic acid, perbenzoic acid, or peracetic
acid,
The reaction mechanism is a single step (concerted) transfer of an oxygen atom to the
C=C.

Formation of syn-1,2-Diols Using OsO4 or MnO4-. Osmium tetroxide (OsO4), or

potassium permanganate (KMnO4) in aqueous base, react with alkenes to yield 1,2-
diols

13
These reactions give stereospecific syn addition of the two OH groups

Osmium tetratoxide gives excellent yields of 1,2-diols, but it is toxic (it causes
blindness) and
expensive. Potassium permanganate is inexpensive and safer to use, but it gives much
lower
yields of diols.

Formation of anti-1,2-Diols.

Oxidative Cleavage of Carbon-Carbon Multiple Bonds (17.3B)

Oxidizing reagents that cleave C=C or CC bonds as they add oxygen to the C atoms
include
ozone (O3), CrO3, and KMnO4 (in neutral or acidic solution)

14
Cleavage Using Ozone (O3). The mechanism of the reaction between ozone (O3)
and an
alkene involves direct addition of O3 to give an unstable intermediate that decomposes
to an
ozonide intermediate

We do not isolate the ozonide (it usually is an explosive compound), but react it with
zinc
metal in acetic acid to give the product carbonyl compounds

Aldehyde products do not oxidize to carboxylic acids under these reaction conditions.

Cleavage Using CrO3 or KMnO4.

The aldehyde products do oxidize further when they arise in reactions of alkenes with
the powerful oxidizing agents CrO3, or KMnO4 in neutral or acidic solution.

We obtain the highest yields of carbonyl compound products using KMnO4 dissolved in
benzene containing a Crown ether. It permits KMnO4 to dissolve in benzene by
solvating
15
the K+ ion

KMnO4 in basic solution yields 1,2-diols without cleavage of the original C=C bond.
These 1,2-diols are likely intermediates when we react CrO3, or KMnO4, with alkenes in
neutral or acidic solution.
However, under these reaction conditions they further oxidize to ketones and/or
aldehydes, and aldehydes further oxidize to carboxylic acids.

Cleavage of 1,2-Diols Using HIO4 or Pb(OAc)4. We can also oxidatively cleave C=C
bonds using the sequence of two reactions

The aldehyde products do oxidize further when they arise in reactions of alkenes with
the powerful oxidizing agents CrO3, or KMnO4 in neutral or acidic solution. These
reagents cleave the C=C bond, and oxidize each of the C=C carbons to the highest
oxidation state consistent with their substitution patterns
This sequence of two separate reactions gives high yields of relatively pure products in
each step. Once again, aldehydes are stable to further oxidation under these reaction
conditions.

16
Oxidation Using Singlet Oxygen.
Molecular oxygen (O2) in air is an oxidizing agent and one of its
oxidation reactions ("autoxidation") is oxidation of alkyl groups.
Atmospheric O2 exists in i) a "triplet" electronic state (3O2) (with an
unpaired electron on each O atom and acts as a free radical .O-O.).
ii) can also exist in a "singlet" electronic state (1O2) that has no
unpaired electrons.
We show three types of reactions of singlet oxygen with molecules
containing C=C bonds:-

Preparation of Singlet Oxygen

We can form singlet O2 chemically by reaction between H2O2 and
NaOCl. It also forms by irradiation of O2 with light in the presence
of organic molecules called photosensitizers.
Oxidation of Alkyl Groups

Several different reagents oxidize alkyl groups (R) bonded to double

bonds (allylic R groups), or to aromatic rings (benzylic R groups).
The products can be alcohols, ketones or aldehydes, and carboxylic
acids.
Several different reagents oxidize alkyl groups (R) bonded to double
bonds (allylic R groups), or to aromatic rings (benzylic R groups).
The products can be alcohols, ketones or aldehydes, and carboxylic
acids.

17
Metal Oxide Oxidations :
Oxidizing agents include potassium permanganate (KMnO4), chromium trioxide
(CrO3),chromyl chloride (Cl2CrO2), and selenium dioxide (SeO2).

KMnO4 and CrO3. The strong oxidizing agents KMnO4 or CrO3 oxidize alkyl groups on
aromatic rings to carboxylic acid groups (directly attached to the ring) if there is at
least one H
on the C attached to the ring.
These reagents are so powerful that we limit their use to simple aromatic systems with
no
other oxidizable functional groups.

Cl2CrO2. In contrast, the milder oxidizing agent chromyl chloride (Cl 2CrO2)
oxidizes methyl groups on aromatic rings to aldehyde groups without
further oxidation to carboxylic acids.

SeO2 Oxidations. Even more selectively, selenium dioxide (SeO2) oxidizes allylic R
groups to alcohols, and benzylic R groups to alcohols or carbonyl compounds.

18
This reagent is particularly useful because it does not oxidize other functional groups
that
may be oxidized by KMnO4 or CrO3. For example, the double bonds in the allylic
systems
above are easily oxidized by either KMnO4 or CrO3 as we previously described, but are
stable to SeO2. SeO2 also selectively oxidizes CH2 groups attached () to carbonyl
groups

O2 Oxidations (Autoxidation) (17.4B)

Atmospheric oxygen (O2) sometimes reacts with organic compounds to
give peroxides.
This autoxidation reaction is generally an unwanted occurrence
organic chemists try to avoid by keeping reaction mixtures or stored
samples of organic compounds free of oxygen.
Autooxidation is catalyzed by light so organic compounds are usually
packaged in bottles that are opaque or made of dark brown glass.

Autoxidation Mechanism. Autoxidation has a free radical chain

mechanism

While the two "propagation" steps are fast reactions, autoxidation is

usually not a rapid process
because we need to use catalysts (free radical initiators) to generate
theinitial R or RO2 that start an oxidation chain.
Atmospheric oxygen is usually notsufficiently reactive to spontaneously
generate these radicals by direct reaction with an organic compound.
19
Synthetic Utility of Autoxidation
Synthetic Utility. Autoxidation has only limited synthetic utility because so
many types of C-H bonds can be converted to C-OOH groups that it is
difficult to have selective reactions.
Industrial preparation of phenol and acetone from 2-propylbenzene
(commonly named cumene):
However, one important industrial process using autoxidation is the
conversion of
2-propylbenzene (commonly named cumene) to phenol and acetone
(Figure 17.051).
Figure 17.051

The particular C-H of cumene that is abstracted is much more reactive

than any of the other C-H's because it is both 3 and benzylic (on a C
directly attached to an aromatic ring).
The formation of the hydroperoxide (usually called cumene
hydroperoxide) is the actual autooxidation process.
The decomposition of this peroxide to phenol and acetone involves
subsequent ionic reactions that occur after oxidation.
Phenols, Hydroquinones, and Quinones

Formation of Phenols
It is difficult to directly add an OH group to a benzene ring, so we usually synthesize
phenols by transforming another functional group, already on an aromatic ring, into an
OH
group.

20
In each case, we form the intermediate substituted benzene directly or indirectly by an
electrophilic aromatic substitution reaction on benzene.
From Cumene.
Organic chemists prepare phenol commercially by autoxidation of cumene.
Cumene comes from the Friedel-Crafts alkylation of benzene

This procedure also gives substituted phenols by autoxidation of ring-substituted

cumenes.

From Aryl Halides. Another commercial preparation of phenol involves reaction of

chlorobenzene with sodium hydroxide at high temperature and pressure

While it appears that HO- might displace Cl- by nucleophilic substitution, this reaction
has an elimination-addition mechanism in which benzyne (C6H4) is an intermediate.

21
From Arylsulfonic Acids. When we "fuse" arylsulfonic acid salts (Ar-SO3-Na+) with
sodium hydroxide at high temperatures, we replace the SO3- group with an O- group.
Subsequent protonation with acid gives phenols
We synthesize arylsulfonic acids from the aromatic compound by electrophilic aromatic
sulfonation.

From Diazonium Ions. The most general method for substituting OH on an aromatic
ring is replacement of an N2+ group (a diazonium group) by an OH group
We form N2+ groups from NH2 groups by a nitrosation reaction.

22
While there is no synthetically useful direct method to place an NH2 group on an
unsubstituted aromatic ring, we can synthesize amino benzenes and other amino
arenes by
reducing a nitro group on an aromatic ring

Formation of Quinones and Hydroquinones (17.5B)

Quinones are oxidation products of phenol or p-substituted phenols

Fremy's salt ((KSO3)2N-O.) is a free radical

that oxidizes phenol by a free radical reaction
mechanism. We oxidize the p-substituted
phenols (Y = OH, NH2, X, OR, R), with Cr2O7-2
in H2SO4.
We can reduce quinones to hydroquinones
using lithium aluminum hydride (Figure 17.064)
[see above]. We describe this reaction and the reducing reagent (LiAlH4) in a later
section.

23
Swern Oxidation

The Swern Oxidation of alcohols avoids the use of toxic metals such as chromium, and can be carried out under very
mild conditions. This reaction allows the preparation of aldehydes and ketones from primary and secondary alcohols,
resp. . Aldehydes do not react further to give carboxylic acids. A drawback is the production of the malodorous side
product dimethyl sulphide.

Mechanism of the Swern Oxidation

Dimethylchlorosulphonium ion is generated in situ from DMSO and oxalyl chloride.

The reaction with an alcohol at -78C leads to an alkoxysulphonium ion:

Deprotonation of this intermediate gives a sulphur ylide, which undergoes intramolecular deprotonation via a five-
membered ring transition state and fragmentation to yield the product and DMS (odour!):

If the temperature is not kept near -78C, mixed thioacetals may result:

Recent Literature

24
New odorless method for the CoreyKim and Swern oxidations utilizing dodecyl methyl sulfide (Dod-S-Me)
S.-I. Ohsugia, K. Nishidea, K. Oonob, K. Okuyamab, M. Fudesakaa, S. Kodamaa, M. Node, Tetrahedron, 2003, 59,
8393-8398.

The fluorous Swern and Corey-Kim reaction: scope and mechanism

D. Crich, S. Neelamkavil, Tetrahedron, 2002, 58, 3865-3870.

The oxidation of primary and secondary alcohols with ion-supported methyl sulfoxide and oxalyl chloride in the
presence of triethylamine in dichloromethane efficiently gives carbonyl compunds in good yields with high purity.
Isolation of the product was achieved very easily by simple diethyl ether extraction of the reaction mixture.
Furthermore, ion-supported methyl sulfide was recovered in good yield and re-oxidized.
D. Tsuchiya, K. Moriyama, H. Togo, Synlett, 2011, 2701-2704.

Tandem Oxidation/Halogenation of Aryl Allylic Alcohols under Moffatt-Swern Conditions

J. Yin, C. E. Gallis, J. D. Chisholm, J. Org. Chem., 2007, 72, 7054-7057.

Mechanism:

25
Criegee Mechanism

26
Mechanism of Ozonolysis

The mechanism was suggested by Criegee (Angew. Chem. Int. Ed., 1975, 87, 745. DOI) and has been recently
revisited using 17O-NMR Spectroscopy by the Berger Group (Eur. J. Org. Chem., 1998, 1625. DOI).

First step is a 1,3-dipolar cycloaddition of ozone to the alkene leading to the primary ozonide (molozonide, 1,2,3-
trioxolane, or Criegee intermediate) which decomposes to give a carbonyl oxide and a carbonyl compound:

The carbonyl oxides are similar to ozone in being 1,3-dipolar compounds, and undergo 1,3-dipolar cycloaddition to the
carbonyl compounds with the reverse regiochemistry, leading to a mixture of three possible secondary ozonides (1,2,4-
trioxolanes):

27
These secondary ozonides are more stable than primary ozonides. Even if the peroxy bridge is shielded by steric
demanding groups leading to isolable products, they should not be isolated from an unmodified ozonolysis, because
still more explosive side products (tetroxanes) may have been formed:

As endoperoxides are investigated as antimalarial compounds, more selective methods have been developed for their
preparation (for example the Griesbaum Coozonolysis). Some reactions can be found here: V. D.B. Bonifacio, Org.
Chem. Highlights 2004, October 25. Link

28
The Criegee mechanism is valid for reactions in hydrocarbons, CH 2Cl2, or other non-interactive solvents. Alcohols react
with the carbonyl oxide to give hydroperoxy hemiacetals:

Sarett reagent:CrO3.2Py

Collins Reagent: CrO3.2Py , CH2Cl2

Ratcliffe variant for Collins reagent: CrO3.2Py complex is formed in

situ in methylene chloride solution, by adding one equivalent of CrO3
over a solution of two equivalents of pyridine in CH2Cl2.

Election of Oxidant
29
The following guidelines can help in the election of a certain
chromium-based oxidant in the laboratory:
. Jones oxidation is very easy to carry out, because of the absence
of need to keep anhydrous conditions. Furthermore, it is very cheap.
It is the oxidation of choice for robust substrates on a big scale. It is
neither suitable for very acid sensitive substrates, nor for the
preparation
of many aldehydes.
. Collins oxidation is very cheap, but has the added experimental
difficulty of having to work under anhydrous conditions. Although
sometimes it lacks the selectivity of PDC or PCC, it can produce
very good yields of aldehydes and ketones in uncomplicated
substrates.
. PDC and PCC are more expensive reagents that normally guarantee
the best results in difficult cases.
Chromium trioxide (CrO3) is a strong oxidizing agent that appears in
the form of deep-red hygroscopic crystals. Upon solution in water, it
forms chromic acid that equilibrates with polymeric anhydrides.

K2Cr2O7, Na2Cr2O7

CrO3/H2SO4/H2O.

Activated Dimethyl Sulfoxide

30
 i) Mofatt and Pfitzner (1963) first published the oxidation using
activated DMSO

ii) Mofatt et al. and Albright et al (1965) suggested the mechanism

Mechanism

It was very soon realized that other electrophiles, besides diimides,

can activate DMSO and allow the oxidation of alcohols.
Other activators: i) acetic anhydride,
ii) phosphorous pentoxide (Albright et al. and Onodera et al.,
1965)
iii) SO3 . Py (Doering and Parikh, 1967)

iv) trifluoroacetic anhydride (Swern, 1976)

v) oxalyl chloride (Swern, 1978)

, and in 1967, Doering and Parikh disclosed the use of the complex
SO3 _ Py.8 The following years witnessed the exploration of
numerous activators, belonging to almost any conceivable
electrophile kind. Thus, the Swern team carried out a very active
search for an ideal activator that led to the proposal of triXuoroacetic
anhydride9 in 1976, and culminated with the predication of oxalyl
chloride in 1978,10 as the activator of choice in what became known
as the Swern oxidation.
31
Strong activators, such as oxalyl chloride or trifluoroacetic
anhydride, produce highly reactive activated DMSO,
able to oxidize alcohols at very low temperature.
The resulting forms of highly reactive activated DMSO will also
have a tendency to decompose to the methylene sulfonium salt 12 at
relatively low temperatures.
Thus, strong activators must necessarily be used at low
temperatures for best yields.
Nomenclature of Reactions Involving Activated DMSO

Oxidations involving ::-

i) DCC or any other carbodiimide as activator. Mofatt
oxidations or PfitznerMofatt oxidations.
ii) oxalyl chloride (Swern oxidation)
iii) trifluoroacetic anhydride (OmuraSharmaSwern oxidation)
iv) SO3 . Py (ParikhDoering oxidation)
v) acetic anhydride (AlbrightGoldman oxidations)
vi) phosphorous pentoxide (AlbrightOnodera oxidations)
When less common activators are used, the corresponding oxidation
can be named as Mofatt oxidation mediated by the corresponding
activator. e.g., an oxidation induced by triphosgene (Triphosgene-
mediated Mofatt oxidation)

vii) An oxidation in which activated DMSO is not generated by

activation of DMSO, but by oxidation of dimethyl sulphide by
either chlorine or N-chlorosuccinimide CoreyKim
oxidations)

Oxidation of dimethyl sulfide with chlorine:

Oxidation of dimethyl sulfide with N-chlorosuccinimide:

32
The CoreyKim procedure is the oxidation method of choice for the
transformation of -hydroxycarbonyl compounds into 1,3-dicarbonyl
compounds.
Treatment of -hydroxycarbonyl compounds under CoreyKim
conditions leads to an intermediate 1,3-dicarbonyl compound 33 that
reacts in situ with activated DMSO, resulting in the generation of a
stable sulphur ylide 34.
This sulfur compound can be transformed into the desired 1,3-
dicarbonyl compound by reduction with zinc in acetic acid.

Hypervalent Iodine Compounds

Iodine compounds in a high valence state behave as strong
oxidants.
Nevertheless, its use in organic synthesis has been very limited due
to its i) general lack of stability and ii) poor solubility in most
organic solvents.
In 1983 a landmark publication of Dess and Martin showed
that the hypervalent iodine compound (35)nowadays known as
Dess-Martin periodinaneis able to transform alcohols into
aldehydes and ketones in an extraordinary effective manner.
Contrary to other hypervalent iodine compounds, Dess-Martin
periodinane (35) is a stable compound with a high solubility in most
organic solvents.

33
With Dess-Martin periodinane(DMP), the alcohols are oxidized to the
corresponding aldehydes and ketones, DMP is transformed into the
organic iodinane (38) and acetic acid.

Side reactions caused by the acidic nature of acetic acid can be

prevented by the addition of a base, such as pyridine or sodium
bicarbonate.
The periodinane (38) can be removed either by:
. Hydrolysis with 1.3 M NaOH, resulting in o-iodosobenzoic acid (39)
that can be separated by washing with an aqueous sodium
bicarbonate solution.
. Treatment with sodium thiosulfate, resulting in reduction to 2-
iodobenzoic acid that can be removed by washing with an aqueous
sodium bicarbonate solution.

34
The o-iodosobenzoic or o-iodobenzoic acids, recovered from the
work-up of oxidations with Dess-Martin periodinane, can be recycled
back to this oxidant by oxidation to IBX, followed by transformation
of IBX into Dess-Martin periodinane.

It is possible to perform an oxidation with Dess-Martin periodinane

under almost neutral conditions by adding pyridine to the reaction
flask in order to neutralize the acetic acid, which is generated during
the oxidation and performing the work-up by treatment with sodium
thiosulfate in the presence of a sodium bicarbonate buffer.

WARNING:DESS-MARTIN PERIODINANE IS AN EXPLOSIVE

COMPOUND.
An explosion has been reported during an operation with
Dess-Martin periodinane.

Although pure Dess-Martin periodinane seems to be refractory to

explosion and the explosive properties of this compound have been
attributed to the presence of impurities.
Dess-Martin periodinane produces an exotherm during
decomposition due to heat; therefore, care must be taken during its
handling.

when tert-butyl alcohol is used for the acceleration of Dess-Martin periodinane oxidation

Initially, the use of Dess-Martin periodinane in the oxidation of

alcohols was plagued with reproducibility problems and puzzling
reports claiming that better yields were obtained using old batches
of impure material or performing the oxidation with no exclusion of
moisture, something very odd considering that Dess-Martin
periodinane is moisture sensitive.

35
This confusing state of affairs was clarified in 1994 by Meyer and
Schreiber, in a very elegant paper, in which they proved that reaction
of Dess-Martin periodinane with water results in the formation of the
acetoxyiodinane oxide (44), that is able to oxidize alcohols much
quicker and efficiently than Dess-Martin periodinane.

o -Iodoxybenzoic Acid (IBX)

36
The o-iodoxybenzoic acidcommonly known as IBXwas prepared
for the first time more than a century ago by Hartman and Meyer
(1893) by oxidation of o-iodobenzoic acid with KBrO3.

A preparation of IBX needing less toxic reagents than the classic

ones, was described by Santagostino et al. involving the oxidation of
o-iodobenzoic acid with oxoneR.

The difficult oxidations that could be done with IBX:

. Transformation of 1,2-diols into a-dicarbonyl compounds with no
oxidative breakage of a C-C bond.
. Oxidation of 1,4-diols to lactols with no over-oxidation to lactones.
. Oxidation of alcohols with a nitrogen-containing functionality at the
4 position, resulting in aminals with no over-oxidation to lactams.
. Oxidation of alcohols with no interference from amines in the same
molecule, including the very oxidation-prone primary amines.

It has been reported that IBX behaves as an explosive similar to

trinitrotoluene.
Apparently, the tendency to explosion on impact or on heating
depends very much on IBX purity, being pure samples of reagent
much safer.
37
While a wet sample of IBX can explode above 130oC, a pure sample
explodes above 200oC.
SIBX :Very recently, it was discovered that IBX mixed with benzoic
and iso-phthalic acids lacks any explosive property. The
corresponding formulation containing 49% of IBX, 22% of benzoic
acid and 29% of isophthalic acidhas been patented as SIBX and it
has been claimed that it is a safe alternative to IBX with the same
oxidizing efficiency.

Ruthenium tetroxide (RuO4) would have a behaviour resembling

osmium tetroxide (OsO4).
It is a much stronger oxidant than OsO4. Invariance with OsO4, RuO4
reacts very violently with common organic solvents, such as
benzene, ether or pyridine.
RuO4 must be used in organic solvents refractory to ignition, such as
carbon tetrachloride in which it is quite soluble.
RuO4, although not as expensive and toxic as OsO4, is quite costly
and normally used in catalytic amounts with sodiummetaperiodate
as a secondary oxidant.
Because of its very strong oxidizing properties, RuO4 is used in
organic synthesis to perform oxidations for which very few
alternative oxidants are available, such as i) transformation of ethers
into esters,ii) degradative oxidation of aromatic appendages into
carboxylic acids or iii) even introduction of oxygen atoms on
unfunctionalized saturated hydrocarbons.

Perruthenate and Ruthenate Ions

As expected, ruthenium compounds possessing a lower oxidation
state than RuO4 (8+), behave as milder oxidants.
Thus, both the perruthenateRuO4- (7+)and the ruthenateRuO2-
(6+)ions are milder oxidants than RuO4, being able to oxidize
38
alcohols and alkenes but reacting very slowly, if at all, with ethers
and benzene rings.
The perruthenate ion is unstable in aqueous solution because it
produces the oxidation of water.
The ruthenate ion suffers dismutation in water, resulting in the
generation of perruthenate and ruthenium dioxide.
This dismutation can be avoided under very basic conditions with a
pH above 12.
(TPAP)

TEMPO and Related Stable Nitroxide Radicals

(Anelli Oxidation)
2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)

39
m-Chloroperbenzoic acid oxidizes TEMPO (55) to an oxoammonium
salt 56. This oxoammonium salt can react with the alcohol
producing an intermediate 57, which can deliver a carbonyl
compound by a Cope-like elimination.

The resulting hydroxylamine 58 can further react with the

oxoammonium salt 56, resulting in the formation of two equivalents
of TEMPO that, therefore, is able to re-enter into a catalytic cycle.
Mukaiyama Oxidation
In 1968, Mukaiyama et al.70 discovered that magnesium alkoxides
generated by reaction of Grignard reagents with aldehydeswhen
treated in situ with 1,1-(azodicarbonyl)dipiperidine (ADD)(69), suffer
oxidation to the
corresponding ketones.

40
Fetizons Reagent: Silver Carbonate on Celite*
2,3-Dichloro-5,6-dicyano-p-quinone (DDQ)

Mechanism of DDQ reaction:

41
Selective Oxidations of Secondary Alcohols via Protection of
Primary Alcohols
It is possible to perform the regioselective protection of primary
alcohols in the presence of secondary ones with almost any
protecting group, thanks to the substantially less crowded
environment of primary alcohols.
Examples of this strategy include the use of silyl and trityl
ethers.
The employment of trityl trifluoroborate is particularly interesting.
This reagent is able to introduce trityl groups on both primary and
secondary alcohols and to selectively oxidize secondary trityl ethers
to ketones in the presence of primary trityl ethers.

Modified Swern oxidation at -30 oC:

42
 Very low temp avoided. i) Et3N(4 eq),
-30 oC/30 min
Cl OH ii) evaporate
THF, + solvent
N N O S
R1 H
-30 oC/30 min R1 R2 iii) quench
+ S O + with water R1
O S
Cl N Cl
N N R2
O + Me2S
-30 oC/30 min R2
Cl
Cyanuric Chloride
Cl N Cl

2) -Chlorination of ketone and concomitant oxidation of OH group:

43
MnO2: ((CH3)2S=O)
((CH3)2C=O)

44
We can think of phenols, hydroquinones, and quinones
(Figure 17.052), as successive oxidation products of
benzene.
Cumene hydroperoxide to phenol mechanism

45
methylthiomethyl ether

Using solvents of low polarity also minimizes the formation of methylthiomethyl

ethers. That is why, oxidations with activated DMSO are normally carried out in
CH2Cl2, a solvent of low polarity possessing good solubilizing power.

The 1H-NMR spectra of methylthiomethyl ethers (R-OCH2-SCH3) shows the

methyl group as a singlet at ca. 2.12.3 ppm, and the methylene group as a singlet
or as an AB quartet at ca. 4.64.8 ppm.

The activated DMSO 9 can also suffer an elimination, resulting in the highly reactive
H2C=S(+)-CH3 species that can react with the alcohol, yielding a methylthiomethyl ether 13
as a side compound. Fortunately, this elimination demands a higher temperature than the
normal temperature of oxidation, and a proper control of the temperature minimizes the
formation of the methylthiomethyl ether side compound.

Luche Reduction NaBH4, CeCl3

Sodium borohydride in combination with cerium (III) chloride (CeCl 3)
selectively reduces ,- unsaturated carbonyl compounds to the
corresponding allylic alcohols.
Typically, a stoichiometric quantity of cerium (III) chloride and sodium
borohydride is added to an ,-unsaturated carbonyl substrate in methanol at
0 C.

46
The regiochemistry of the reduction is dramatically influenced by the presence
of the lanthanide in the reaction.

Diisobutylaluminum Hydride (DIBAL): i-Bu2AlH

At low temperatures, DIBAL reduces esters to the corresponding aldehydes, and

lactones to lactols.
47
Typically, toluene is used as the reaction solvent, but other solvents have also been
employed, including dichloromethane.

Miller, A. E. G.; Biss, J. W.; L. H. J. Org. Chem. 1959, 24, 627-630.

Zakharkin, L. I.; Khorlina, I. M. Tetrahedron Lett. 1962, 3, 619-620.

Mechanism of DIBAL-Reduction:

Borane Complexes: BH3L

Borane is commonly used for the reduction of carboxylic acids in the

presence of esters, lactones, amides, halides and other functional groups.
In addition, borane rapidly reduces aldehydes, ketones, and alkenes.
Borane is commercially available as a complex with tetrahydrofuran (THF)
or dimethylsulfide in solution. In addition, though highly flammable,
gaseous diborane (B2H6) is available.
48
The borane-dimethylsulfide complex exhibits improved stability and
solubility compared to the borane-THF complex.
Competing hydroboration of carbon-carbon double bonds can limit the
usefulness of borane-THF as a reducing agent.
Lane, C. F. Chem. Rev. 1976, 76, 773-799.
Brown, H. C.; Stocky, T. P. J. Am. Chem. Soc. 1977, 99, 8218-8226.

Acidic
media!!
Not a
good
method
for H+
sensitive groups and compounds.

CrO3 (anhydrous) + pyridine (anhydrous) CrO32pyridine

49


Collins Oxidation (CrO32pyridine, CH2Cl2) (Ref.: TL 1969, 3363)

1 and 2 alcohols are oxidized to aldehydes and ketones in non-aqueous solution (CH2Cl2)
without over-oxidation
Useful for the oxidation of H+ sensitive compounds.
not particularly basic or acidic
must use a large excess of the rgt.

Pyridinium Chlorochromate (PCC, Corey-Suggs Oxidation) [ Ref: i) TL

1975 2647 ii) Synthesis 1982, 245 (review).]
CrO3 + 6M HCl + pyridine pyH+CrO3 Cl-
- Reagent can be used in close to stoichiometric amounts w/ substrate
- PCC is slighly acidic but can be buffered w/ NaOAc

50
51
Selective Oxidation of Allylic Alcohols

52
CrO3 on Celite MnO2
53
CrO3/Et2O/CH2Cl2/Celite
Oxidation of 1 allylic alcohols to -unsaturated esters

Ruthenium Tetroxide
- effective for the conversion of 1 alcohols to RCO2H and 2
alcohols to ketones.
- oxidizes multiple bonds and 1,2-diols.

54
55
56
RuO4

57
R2 = H > 3 > 2 > benzyl = phenyl > 1 >> CH3.

Reductions:-
1. Hydrogenation using metal catalyst
2. Boron Reagents
3. Aluminium Reagents
4. Tin Hydrides
5. Silanes
6. Dissolving Metal Reductions

Hydrogenations
Heterogeneous Catalytic Hydrogenation
Transition metals absorbed onto a solid support
metal: Pd, Pt, Ni, Rh
support: Carbon, alumina, silica
solvent: EtOH, EtOAc, Et2O, hexanes, etc.
- Reduction of olefins & acetylenes to saturated hydrocarbons.
58
- Sensitive to steric effects and choice of solvent
- Polar functional groups, i.e. hydroxyls, can sometimes direct the
delivery of H2.
- Cis addition of H2.

Catalyst can be "poisoned".

Directed heterogeneous hydrogenation.

59
60