OrganoLithium Reagents

Organolithium reagents are one of the most useful nucleophillic reagents in organic
synthesis. They are also highly basic in nature. However, due to their thermal instability
and extremely high reactivity they require elaborate precautions during use. Many
organolithiums are commercially available as dilute solution in hydrocarbon solvents. In
such solvents they are polymeric species with n = 4 to 6. In ethers, however, they are
mostly tetrameric in nature. In the presence of strong donating molecules such as HMPA
and DMPU, the degree of association decreases and they exist as monomeric species.
This leads to an enhancement in their reactivity. Tetrameric structures are based on
distorted cubic structures where the lithium atoms occupy alternate corners of the cube
and the alkyl groups occupy a face of the cube.

Preparation

Organolithium reagents are usually prepared by the reaction of organic halides with
lithium (Scheme 1). The order of reactivity of the organic halides decreases in the
following order RI > RBr > RCl.

Another route to organolithium compounds is the use of metal halogen exchange
reactions. In these reactions the equilibirium lies to the right if the organic group is able
to accommodate the electron density than the organic species on the left.

The replacement of a hydrogen by a lithium (known as lithiation) can also be used to

generate organolithium species. This reaction is essentially an acid base reaction.
However in case, where there is activation by a coordinating group, the reaction occurs
with considerable ease. This type of activation is particularly helpful in introducing an
ortho substituent to a preexisting coordinating group.

The ortho-directing groups are usually arranged in the following order in order of their

reactivity: SO2NR2 > SO2Ar > CONR2 > oxazolinyl > CONHR > CSNHR, CH2NR2 >
OR > NHAr > SR > CR2O-. .

 Reaction with Carbonyl Compounds

Organolithium reacts with carbonyl compounds as that of the Grignard reagents. In

comparison to Grignard reagents, organolithium reagents are less susceptible to steric
factors and react with hindered ketones to give the corresponding tertiary alcohols.

 Reactions with Epoxides

Epoxides react with organolithium reagents to give primary alcohols (as in the case of

Grignard reagents). Use of unsaturated organolithium reagent gives unsaturated alcohols

Reactions with Carbon Dioxide

A major difference between the reactivity of Grignard reagents and organolithium
reagent is observed in their reactivity towards CO2. The reaction of Grignard reagents
with CO2 stops at the carboxylate stage, while in case of organolithium reagents, the
carboxylate ion formed reacts with another equiv of organolithium to generate a ketone.

 

 Reactions with Alkyl Cyanide

As in the case of Grignard reagents, the reactions of organolithium reagents with alkyl
cyanides give imine salts, which undergo hydrolysis in the presence of water to give
ketones

 Electrophilic Displacement

Reaction of an organic halide with an organometallic compound is known as metalhalogen

exchange reaction is example for electrophilic displacement. This reaction is
useful for the synthesis of vinyl- and phenyl lithium

 Nucleophilic Displacement

Reactions of alkyl anxd aryl halides can be reacted with alkyl and aryl lithium reagents to

give hydrocarbons. The reaction of alkyl halides with alkyl lithium takes place by SN2
mechanism. While aryl halides react with aryl lithum via addition-elimination process

 Mechanism

  Reaction with α,β-Unsaturated Carbonyl Compounds

In the case of Grignard reagents, α,β-unsaturated carbonyl compounds undergo reaction

either at 1,2- or 1,4-addition depending on the structure of the carbonyl compound. The
main reason is steric hinderance. While the organolithium reagents undergo reaction
exclusively to give 1,2-addition products

 Exclusive formation of 1,4-addition product, however, can be achieved using lithium
dialkylcuprates

 Deprotonation

The basic nature of organolithiums can also be put to good use in achieving umpolang at
the carbonyl centre of an aldehyde. In this protocol a C=O function is first protected by 1,
3-dithiane and then the proton is removed by an organolithium

 The stereochemical outcome of the nucleophillic addition of organolithiums is similar to
that of Grignard reaction. It can be predicted on the basis of Cram’s rule

 Ortholithiation

It is useful because the starting material does not need to have a halogen atom. For
example, in the case of benzyldimethylamine, the nitrogen atom directs attack of the
butyllithium

:Summary of the Reactions of Organolithium Reagents:

 

 Refrences:
J. Clayden, N. Greeves, S. Warren, P. Wothers, Organic Chemistry, Oxford University
Press, 2001.

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