Monday, August 8

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GRIGNARD REAGENTS


Grignard reagents are organometallic compounds having Mg-C bond. Magnesium can
form two covalent bonds with carbon. Of the various organomagnesium compounds
possible, organomagnesium halides and to a lesser extent dialkyl magnesium compounds
are widely used for synthesis. Although the Grignard reagents are usually formulated as
RMgX, but in reality they are a mixture of a variety of species. The ratio of the species in
solution varies with the organic group, the halogen, the solvent, the concentration and the
temperature. It is believed that in case of organomagnesium chlorides (RMgCl) in diethyl
ether, the predominant species over a wide range of concentrations is a solvated, halogenbridged
dimer 1. The degree of association varies as the halide is changed to Br or I.




However, in case of THF, due to the highly coordinating nature of the solvent, there is a
lesser degree of association. Therefore, monomeric species dominate in THF, however,
there are significant concentrations of R2Mg, MgX2 and RMgX in equilibirium.

 

 Addition of Grignard Reagents to Carbonyl Groups

The addition of Grignard reagents to carbonyl group is one of the most important
methods for carbon-carbon bond formation. Though the overall reaction is quite simple
but it is highly susceptible to a number of side reactions. The reactivity of Grignard
reagents towards different carbonyl group containing compounds also varies thus giving
rise to different end products depending on reactants




The mechanism of this reaction is usually depicted to consist of the following steps-

  •  Complexation of the organomagnesium species with the substrate


  • The next step involves nucleophilic attack of organic moiety of Grignard reagent
on the electron deficient carbon of carbonyl group via a molecular complex

  • The intermediate formed in the above step is hydrolyzed to give a tertiary alcohol.
 However, if the carbonyl group is attached with a leaving group (i.e., if R1= OR)
then the tetrahedral adduct can break down to regenerate a C=O group that
undergoes a fast second addition step


However, a number of methods have been devised to stop the reaction at the aldehyde or
ketone stage. Such protocols involve the formation of a masked carbonyl compound,
which releases the desired compound on hydrolysis


In case of reaction of Grignard reaction with carbon dioxide, the reaction stops at the
carboxylate (RCO2-) stage as it is resistant to further nucleophilic attack

Grignard reactions are prone to undergo side reactions. The reaction of a sterically
hindered ketone with a Grignard reagent having a β-H shows a tendency towards
reduction of the carbonyl group












 

 The Stereochemistry of Grignard Reaction

The stereochemical outcome of Grignard reaction can be predicted on the basis of Cram’s
rule. To apply Cram’s rule we designate the groups on the carbon adjacent to the
carbonyl group as small (S), medium (M) and large (L). The preferred conformation of 2-
phenyl-propanaldehyde has carbonyl group staggered between methyl group (M) and hydrogen atom (S). Now according to Cram’s rule, the nucleophilic attack by phenylmagnesium bromide will take place from the least hindered position between methyl group and hydrogen atom.



In the case of the Grignard addition to chiral substrates that possess a heteroatom in the
α- or β- position, a modification in the application of the Cram’s rule is required. In the
reaction of (S)- 2-methoxy-1-phenylpropanone with methyl magnesium bromide, a cyclic
structure where the methoxy group is synperiplanar to carbonyl group is formed. This
results in the restriction in the freedom of the diasteroselective transition state and thus
the attack takes place from the least hindered side having the methyl and the methoxy
groups


Other Uses of Grignard Reagents

Grignard reagents are not only useful reagents for organic transformation but they are
also useful in the synthesis of other useful organometallic reagents such as organosilicon
and organophosphorus reagents. For example, the reaction of Grignard reagents with
SiCl4 and PCl3 gives triphenylphosphine and tetramethylsilane, respectively.














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A chemist, a teacher and a passionate blogger. Currently pursuing his PhD from School of Chemistry, University of Hyderabad is creative head of this blog and lives with a motto of teaching what he knows and exploring what he don't.

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