Pharmaceutical Organic Chemistry-III (BP401T) Dr. Panchabhai Vivek B.
Unit –V:- Reaction of Synthetic Importance
Syllabus:- Metal hydride reduction (NaBH4 and LiAlH4), Clemmensen reduction, Birch reduction, Wolff Kishner reduction, Oppenauer-
oxidation and Dakin reaction, Beckmanns rearrangement and Schmidt rearrangement. Claisen-Schmidt condensation
Reduction Reaction:-
Metal hydride reduction (NaBH4 and LiAlH4), Clemmensen reduction,
Birch reduction, Wolff Kishner reduction.
1. Metal hydride reduction (NaBH4 and LiAlH4):-
Common reducing agents are : *lithium aluminium hydride (LiAlH4) *Sodium
borohydride (NaBH4)
LiAlH4 are the stronger reducing agent.
Can be used to reduce carboxylic acids, aldehydes and ketones.
NaBH4 only strong enough to reduce aldehydes and ketones.
NaBH4 is much easier to use than LiAlH4 and usually preferred for the reduction of
aldehydes and ketones.
Reduction Reaction with Lithium aluminum hydride (LiAlH4)-
Preparation
It was first prepared by treating lithium hydride (LiH) with aluminum chloride (AlCl3).
In industrial scale, it is prepared from sodium aluminum hydride which is prepared by
reaction of sodium, aluminum and hydrogen at high temperature and pressure (Scheme 2).
Reduction of Aldehydes and Ketones with Lithium aluminum hydride (LiAlH4) or Sodium
Borohydride (NaBH4) -
Aldehydes are converted to primary alcohols, and ketones to secondary alcohols, by
treatment with either NaBH4 (sodium borohydride) or LiAlH4 (lithium aluminum hydride).
Pharmaceutical Organic Chemistry-III (BP401T) Dr. Panchabhai Vivek B.
The generic scheme below depicts these two reactions, where “M” is either boron or
aluminum. There are essentially only two steps: nucleophilic attack of a hydride ion on the
electrophilic carbonyl carbon; and protonation of the resulting alkoxide by water or some other
acid. This latter step may occur in the same medium as the first step, or the proton source may be
added later.
Both BH4− and AlH4− deliver hydride as a nucleophile to the carbonyl carbon. We
have to be very clear about this: hydride ions are negatively charged and behave as bases or
nucleophiles, unlike protons which are positively charged and are Lewis acidic. Do not confuse
hydrogen atoms, hydride ions or protons with one another!
Reduction of carboxylic acids with Lithium aluminum hydride (LiAlH4)-
Carboxylic acids can be converted to 1o alcohols using Lithium aluminum hydride
(LiAlH4). Note that NaBH4 is not strong enough to convert carboxylic acids or esters to alcohols.
An aldehyde is produced as an intermediate during this reaction, but it cannot be isolated because
it is more reactive than the original carboxylic acid.
Possible Mechanism
Step Reaction
1) Deprotonation
2) Nucleopilic attack by the
hydride anion
3) Leaving group removal
Pharmaceutical Organic Chemistry-III (BP401T) Dr. Panchabhai Vivek B.
4) Nucleopilic attack by the
hydride anion
5) The alkoxide is
protonated
Reduction Reaction with Sodium Borohydride (NaBH4)-
Reduction of Aldehydes and Ketones with sodium borohydride [NaBH 4]-
In the enzyme catalyzed reduction of glucose, a proton along with 2 electrons adds to the
carbonyl carbon and a proton adds to the carbonyl oxygen. A proton with 2 electrons, or H -, is called
a hydride.
RCHO + H- + H+ RCH2OH
NADPH is one source of H- in biological systems. We use smaller (and much cheaper) hydride
sources for reduction reactions in the laboratory.
One of the most common hydride reagents is sodium borohydride [NaBH 4].
In the first reaction above H- is transferred from the nucleophilic borohydride reagent to the
electrophilic carbonyl carbon. This forms an alkoxide salt and BH3. The second step is the protonation
of the basic alkoxide with a acid to form the alcohol.
Pharmaceutical Organic Chemistry-III (BP401T) Dr. Panchabhai Vivek B.
The reaction between a ketone and sodium borohydride is analogous.
Reduction of Carboxylic Acids with sodium borohydride [NaBH 4]-
The carbonyl carbon of a carboxylic acid is even more electrophilic than the carbonyl carbon in
an aldehyde or ketone. However, there is also an acid proton from the carboxylic acid that can react with
hydride reagents. For this reason, sodium borohydride does not reduce a carboxylic acid.
A carboxylic acid can react with an alcohol, in the presence of a small amount of an acid, to form
a carboxylic acid ester. Then the ester can be reduced.
The reaction of the methyl ester with sodium borohydride is below.
Pharmaceutical Organic Chemistry-III (BP401T) Dr. Panchabhai Vivek B.
The addition of the hydride to the carbonyl carbon is followed by a second step that eliminates
the CH3O- group and reforms the C-O double bond. Overall, this is a substitution of CH 3O- for H- at the
carbonyl carbon but it proceeds through an intermediate in which the "carbonyl carbon" is bonded to 4
groups and has tetrahedral geometry.
2. Clemmensen Reduction:-
The Clemmensen Reduction allows the deoxygenation of aldehydes or ketones, to produce the
corresponding hydrocarbon.
The substrate must be stable to strong acid. The Clemmensen Reduction is complementary to
the Wolff-Kishner Reduction, which is run under strongly basic conditions. Acid-labile molecules
should be reduced by the Wolff-Kishner protocol.
Mechanism of the Clemmensen Reduction:-
The reduction takes place at the surface of the zinc catalyst. In this reaction, alcohols are not
postulated as intermediates, because subjection of the corresponding alcohols to these same reaction
conditions does not lead to alkanes. The following proposal employs the intermediacy of zinc
carbenoids to rationalize the mechanism of the Clemmensen Reduction:
Pharmaceutical Organic Chemistry-III (BP401T) Dr. Panchabhai Vivek B.
3. Wolff-Kishner Reduction
The reduction of aldehydes and ketones to alkanes. Condensation of the carbonyl compound with
hydrazine forms the hydrazone, and treatment with base induces the reduction of the carbon coupled
with oxidation of the hydrazine to gaseous nitrogen, to yield the corresponding alkane.
The Clemmensen Reduction can effect a similar conversion under strongly acidic conditions, and
is useful if the starting material is base-labile.
Mechanism of the Wolff-Kishner Reduction
4. Birch Reduction:-
The Birch reduction is an organic reaction where aromatic rings undergo a 1,4-reduction to
provide unconjugated cyclohexadienes. The reduction is conducted by sodium or lithium metal in liquid
ammonia and in the presence of an alcohol.
The Birch Reduction offers access to substituted 1,4-cyclohexadienes.
Mechanism of Birch Reduction
The question of why the 1,3-diene is not formed, even though it would be more stable through
conjugation, can be rationalized with a simple mnemonic. When viewed in valence bond terms,
electron-electron repulsions in the radical anion will preferentially have the nonbonding electrons
separated as much as possible, in a 1,4-relationship.
Pharmaceutical Organic Chemistry-III (BP401T) Dr. Panchabhai Vivek B.
This question can also be answered by considering the mesomeric structures of the dienyl
carbanion:
The numbers, which stand for the number of bonds, can be averaged and compared with the 1,3-
and the 1,4-diene. The structure on the left is the average of all mesomers depicted above followed by
1,3 and 1,4-diene:
The difference between the dienyl carbanion and 1,3-diene in absolute numbers is 2, and
between the dienyl carbanion and 1,4-diene is 4/3. The comparison with the least change in electron
distribution will be preferred.
Reactions of arenes with +I- and +M-substituents lead to the products with the most highly
substituted double bonds:
The effect of electron-withdrawing substituents on the Birch Reduction varies. For example, the
reaction of benzoic acid leads to 2,5-cyclohexadienecarboxylic acid, which can be rationalized on the
basis of the carboxylic acid stabilizing an adjacent anion:
Alkene double bonds are only reduced if they are conjugated with the arene, and occasionally
isolated terminal alkenes will be reduced.
Pharmaceutical Organic Chemistry-III (BP401T) Dr. Panchabhai Vivek B.
Oxidation Reaction:-
1. Oppenauer-oxidation:-
Oppenauer oxidation is a gentle method for selectively oxidizing secondary alcohols to
ketones. The alcohol is oxidized with aluminium isopropoxide in excess acetone.
acetone This shifts the
equilibrium toward the product
roduct side.
OR
The aluminium-catalyzed
catalyzed hydride shift from the α
α-carbon
carbon of an alcohol component to the
carbonyl carbon of a second component, which proceeds over a six six-membered
membered transition state, is
named Meerwein-Ponndorf-Verley--Reduction (MPV) or Oppenauer Oxidation (OPP) depending on the
isolated product. If aldehydes or ketones are the desired products, the reaction is viewed as the
Oppenauer Oxidation.
OR
Non-enolizable
enolizable ketones with a relatively low reduction potential, such as benzophenone, can
serve as the carbonyl component used as the hydride acceptor in this oxidation .
Mechanism of oppenauer oxidation
oxidation:-
In the first step of the mechanism
mechanism, the alcohol (1) coordinates to the aluminium to form a
complex (3), which then, in the seco
second step, gets deprotonated by an alkoxide ion (4) to generate an
alkoxide intermediate (5). In the
he third step, both the oxidant acetone (7) and the substrate alcohol are
bound to the aluminium. The acetone is coordinated to the aluminium which activates it for fo
the hydride transfer from the alkoxide. The aluminium
aluminium-catalyzed
catalyzed hydride shift from the α-carbon
α of the
alcohol to the carbonyl carbon of acetone proceeds over a six
six-membered transition state (8). The desired
ketone (9) is formed after the hydride transfer.
Pharmaceutical Organic Chemistry-III (BP401T) Dr. Panchabhai Vivek B.
[Link] reaction:-
The Dakin oxidation iss an organic redox reaction in which an ortho or para-
hydroxylated phenyl aldehyde (2-hydroxybenzaldehyde
hydroxybenzaldehyde or 4-hydroxybenzaldehyde
hydroxybenzaldehyde) or ketone reacts
with hydrogen peroxide in base to form a benzenediol and a carboxylate.. Overall, the carbonyl group is
oxidized, and the hydrogen
gen peroxide is reduced.
Mechanism of dakin oxidation:-
The Dakin oxidation starts with nucleophilic addition of a hydroperoxide anion to
the carbonyl carbon, forming a tetrahedral intermediate (2). The intermediate collapses, causing [1,2]-
[1,2]
aryl migration, hydroxide elimination
elimination, and formation of a phenyl ester (3). ). The phenyl ester is
subsequently hydrolyzed:: nucleophilic ad
addition
dition of hydroxide from solution to the ester carbonyl carbon
forms a second tetrahedral intermediate ((4), which collapses, eliminating a phenoxide and forming
a carboxylic acid (5).
). Finally, the phenoxide extracts the acidic hydrogen from thet carboxylic acid,
yielding the collected products (6).
Pharmaceutical Organic Chemistry-III (BP401T) Dr. Panchabhai Vivek B.
Rearrangement Reaction:-
1. Beckmann Rearrangement.
An acid-induced rearrangement of oximes to give amides.
This reaction is related to the Hofmann and Schmidt Reactions and the Curtius Rearrangement,
in that an electropositive nitrogen is formed that initiates an alkyl migration.
Mechanism of Beckmann Rearrangement
Oximes generally have a high barrier to inversion, and accordingly this reaction is envisioned to
proceed by protonation of the oxime hydroxyl, followed by migration of the alkyl substituent "trans" to
nitrogen. The N-O bond is simultaneously cleaved with the expulsion of water, so that formation of a
free nitrene is avoided.
2. Schmidt Reaction:-
The acid-catalysed reaction of hydrogen azide with electrophiles, such as carbonyl compounds,
tertiary alcohols or alkenes. After a rearrangement and extrusion of N 2, amines, nitriles, amides or
imines are produced.
a. b.
c. d.
Pharmaceutical Organic Chemistry-III (BP401T) Dr. Panchabhai Vivek B.
e.
Mechanism of Schmidt Reaction
Reaction of carboxylic acids gives acyl azides, which rearrange to isocyanates, and these may be
hydrolyzed to carbamic acid or solvolysed to carbamates. Decarboxylation leads to amines.
The reaction with a ketone gives an azidohydrin intermediate, which rearranges to form an amide:
Alkenes are able to undergo addition of HN3 as with any HX reagent, and the resulting alkyl
azide can rearrange to form an imine:
Pharmaceutical Organic Chemistry-III (BP401T) Dr. Panchabhai Vivek B.
Condensation Reaction:-
1. Claisen-Schmidt condensation::-
The reaction between an aldehyde/ ketone and an aromatic carbonyl compound lacking an
alpha-hydrogen (cross aldol condensation
condensation) is called the Claisen-Schmidt
Schmidt condensation.
condensation .
Mechanism of Claisen-Schmidt
Schmidt condensation
condensation:-