3.1.2 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 (Scheme 7).

Scheme 7

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 methylmagnesium bromide, a cyclic structure where the methoxy group is syn periplanar 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 (Scheme 8).

Scheme 8

3.1.1.2 Reactions with Alkyl/Alkenyl/Aryl Halides

In presence of transition metal-catalysis, Grignard reagents proceed reaction with alkyl, alkenyl and aryl halides to give C-C cross-coupled products. The details of those studies are covered latter in transition-metal-catalyzed reactions. For examples, Scheme 9 presents some examples on cobalt and nickel-catalyzed cross-coupling reactions of Grignard reagents with alkyl, vinyl and aryl halides. For details of the mechanism, please see lecture 35.

Scheme 9

3.1.1.3 Reactions with Inorganic Halides

Grignard reagents are not only useful reagents for organic transformation but they are also useful in the synthesis of other organometallic reagents such as organosilicon and organophosphorus reagents. For example, Grignard reagents react with SiCl₄ and PCl₃ to give triphenylphosphine and tetramethylsilane, respectively (Scheme 9).