CHM 401

Organic Synthesis
By
Dr Isah, S.
Caleb University

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 Reduction Reactions
Introduction
Most of the reduction techniques, despite their differences in
mechanism and reagents, accomplish the same or similar functional
group changes. There are, of course, differences in functional group
reactivity as well as chemoselectivity and stereochemistry for the
various reagents. This course is organized by type of reduction, with a
discussion of applicable functional group transformations. The
monograph on reduction by Hudlicky categorized reductions as
reduction with complex hydrides, catalytic hydrogenation,
electroreduction, reduction with metals, and reductions with
non-metals. This includes an extensive survey of specific organic
functional group reductions. The order of topics in this section of
reduction attempts to correlate a type of reduction with its relative
utility in organic synthesis. We will begin with hydride reductions since
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are probably the most widely used, followed by catalytic 28
 Hydride Reductions

The two most common hydride reducing agents are lithium

aluminum hydride (LiAlH4) and sodium borohydride (NaBH4 .
Lithium aluminum hydride was prepared by reaction of lithium
hydride (LiH) with aluminum chloride (AlCl3). Sodium borohydride
was first prepared by reaction of sodium hydride (NaH) with
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trimethylborate, B(OMe) .
 Hydride Reactions

Reduction of carbonyl compounds

Lithium aluminum hydride rapidly reduces most carbonyl
compounds, including aldehydes and ketones, carboxylic acids, acid
anhydrides, acid chlorides, esters, lactones, amides, carbamates,
imides, and lactams

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 Hydride Reduction

Complex 1 has also been proposed as an intermediate.

Alkoxide 2 contains three additional active hydrides, so a
second equivalent of carbonyl can react to give bis(alkoxide)
3. Similarly, a third equivalent gives 4 and a fourth gives 5.
The final alcohol product from the reduction of R2C=O is
generated by treatment of 5 (or any other alkoxyaluminate
product) with aqueous acid or with aqueous base via
protonation of the alkoxide base.
The rate of reduction of aldehydes is faster than that of
ketones, because there is less steric hindrance for delivery of
hydride to the carbonyl carbon.
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 Hydride Reduction

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 Hydride Reduction

Reduction of α,β-unsaturated carbonyl derivatives poses a potential

problem. Reduction of benzalacetone (10) can lead to either the
allylic alcohol (11) via normal 1,2-addition of hydride to the carbonyl,
or to the saturated alcohol (12) via 1,4-reduction (delivery of hydride
to the alkenyl carbon).

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 Hydride Reduction

Reduction of Carboxylic Acid

Reduction of carboxylic acids with one equivalent of LiAlH4 consumes

three of the four,25 and the reduction product is an alcohol. The acidic
hydrogen of the COOH unit reacts first. Subsequent reduction of the
carbonyl unit leads to the alkoxyaluminate, which is hydrolyzed to the
alcohol.

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 Hydride Reduction
Ester Reduction

Reduction of the tert-butyl ester group 20 gave alcohol 21 in 91% yield

after hydrolysis (the silyl enol ether moiety was hydrolyzed to the ketone
simultaneously)

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 Hydride Reduction
The reduction of cyclic esters (lactones) leads to diols, as
in the reduction of δ-valerolactone to give an 85% yield of
1,5-pentanediol.

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 Hydride Reduction
lithium aluminum hydride Reduction of non-carbonyl heteroatom
Functional Groups

As shown by Gaylord, lithium aluminum hydride reduces heteroatom-

containing functional groups. This section will explore the reduction of
several functional groups that are commonly seen in synthesis.

1.Epoxide Reduction to alcohol

95% yield

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Lithium aluminum hydride Reduction of non-
carbonyl heteroatom Functional Groups

Nitrile

Reduction of the cyano group with LiAlH4 usually gives a

primary amine.

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Lithium aluminum hydride Reduction of non-
carbonyl heteroatom Functional Groups

Ozonides
Ozonolysis of alkenes initially generates an ozonide that can be reduced
by a variety of reagents. Dimethyl sulfide or zinc in acetic acid are the
most common reagents for the reduction of an ozonide to an aldehyde or
ketone. Reduction of the ozonide with the more powerful LiAlH4, however,
gives direct the alcohol directly.

Assignment
Starting with Butene, demonstrate typical ozonolysis of alkene and
subsequent reduction using LiAlH4. Show all the intermediate and final
products.
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 Lithium aluminum hydride Reduction of non-
carbonyl heteroatom Functional Groups

Reduction of the azido group with LiAlH4 gives a primary

amino group (R–N3 → R–NH2).

99% yield

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 Lithium aluminum hydride
Reduction of non-carbonyl
heteroatom Functional
Nitro Compounds. Aliphatic nitro compounds can be reduced to
amines,59 so they also function as amine surrogates. Hydride reduction is
not straightforward because LiAlH4 reduction of nitrobenzene does not
give aniline but rather azo compound 56 in 84% yield.60 Catalytic
hydrogenation (see sec. 4.8.D) is the best method for the reduction of
aromatic nitro compounds to aniline derivatives. Aliphatic nitro
compounds are relatively easy to reduce with LiAlH4. The nitro group in
57 was cleanly reduced to give amine 58

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 Lithium aluminum hydride
Reduction of non-carbonyl
heteroatom Functional
Alkyl Halides. Alkyl halides are reduced by lithium aluminum hydride
to give a hydrocarbon in what is known as a hydrogenolysis reaction
(R3C–X → R3C–H; sec. 4.8.E).62 Reduction of 1-bromobutane in ether,
THF or di-n-butyl ether gave yields of n-butane in the 30-96% range

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 Sodium Borohydride Reduction
Ethanolic solutions of sodium borohydride reduce
aldehydes and ketones in the presence of epoxides,
esters, lactones, acids, nitriles or nitrogroups

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 Sodium Borohydride Reduction

Amides are not reduced directly by NaBH4, but if they are

first converted to an iminium derivative reduction to the
amine is rapid. Reaction of 109 with phosphorus oxychloride
(POCl3) gave the Vilsmeier-Haack complex138 (110), and
this was reduced to the piperidine derivative 111.

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 Catalytic Hydrogenation
Reduction of functional groups with hydrogen gas is a key reaction in
organic chemistry, dating to the first hydrogenation of ethene to ethane
by von Wilde in 1874.
Catalytic hydrogenation is used to reduce alkenes, alkynes, ketones and
aldehydes, nitriles, nitro compounds or aromatic rings. Hydrogen gas is
added to an organic molecule in the presence of a catalytic amount of a
transition metal and the reaction proceeds by adsorption of hydrogen and
the substrate on the surface of the metal. There are two major types of
catalysis: heterogeneous (catalyst insoluble in the reaction medium) and
homogeneous (catalyst soluble in the reaction medium).

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 Catalytic Hydrogenation

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 Catalytic Hydrogenation

Hydrogenation of Alkenes
The reaction with alkenes proceeds on the surface of a heterogeneous
metal catalyst, via cleavage of diatomic hydrogen and adsorption of
the hydrogen atoms. Horiuti and Polanyi proposed a mechanism in for
the reduction of ethene with hydrogen on nickel.
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 Catalytic Hydrogenation

Mechanism of Catalytic Hydrogenation

It was proposed that hydrogen gas was cleaved to hydrogen atoms

that were bound to the nickel (represented by 333). An alkene was
also bound to the surface of the metal (represented by 334),
allowing the reaction to proceed, with transfer of hydrogen to the
carbon (in 335).
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 Catalytic Hydrogenation
Homogeneous catalysts
Mechanism.
Wilkinson’s catalyst [336, (Ph3P)3RhCl] has been studied extensively.
Wilkinson’s catalyst is prepared from rhodium chloride (RhCl3) and
triphenylphosphine in ethanol (88% is a typical yield of 336).

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 Catalytic Hydrogenation

Homogeneous catalysts
Mechanism
A mechanistic picture of the reaction is shown above for the
reaction of the square planar catalyst (336) with hydrogen gas to
form a trigonal bipyramidal species, 337. Subsequent reaction
with the alkene will replace a phosphine ligand to give a species
such as 338. It is also possible that the alkene binds to the
catalyst first, followed by hydrogen. Hydrogen is transferred from
rhodium to carbon in a stepwise manner, generating a species
such as 339. Release of the alkane generates a trigonal species
(340) that reacts with additional hydrogen to regenerate 337.

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