Grignard reaction - Carbonyl reactivity
Abstract
The Grignard reaction is a versatile method to form a new carbon-carbon bonds. It involves a nucleophilic organomagnesium halide reagent, known as Grignard reagent and of a general formula R-MgX where R is an organic group and X is a halogen (either Br or Cl). This reagent reacts with an electrophilic carbonyl compound via a nucleophilic addition, yielding a new carbon-carbon bond, after acidic aqueous workup.
Keywords
Aldehyde, Ketone, Ester, Carbon dioxide, Gilman, Organomagnesium, Organocuprate, Alcohol.
Category
Aldehyde/Ketone, Alkane
Mechanism
General statement: In the general case involving a simple carbonyl group, whether it be an aldehyde or a ketone, the Grignard reaction starts with the nucleophilic addition of the organomagnesium halide onto the electrophilic carbonyl carbon. A tetrahedral intermediate is then obtained, stabilized by coordination to the magnesium center. An acidic aqueous workup is performed in order to protonate the alkoxide and give the desired primary (in the case of formaldehyde), secondary (in the case of aldehyde) or tertiary (in the case of ketone) alcohol.
Ester case: Whether it be with an ester, the addition of the organomagnesium halide leads to an addition-elimination reaction where the alkoxide act as leaving group, departing as RO-MgX. The ketone is released as an intermediate in situ. This latter is immediately exposed to a second equivalent of Grignard reagent, which adds again to offer, after acidic workup, a tertiary alcohol.
Carbon dioxide: In the presence of carbon dioxide, the Grignard reagent adds onto the electrophilic carbonyl carbon of CO2, giving a carboxylic acid after acidic workup .
Organocuprate: in the presence of copper(I) halide and an organolithium compound, a diorganocuprate is formed (also known as Gilman reagent). This latter in the presence of an 1,4-Michael acceptor reacts differently from a classic Grignard reagent. Whereas a Grignard reagent typically performs a 1,2-addition directly onto the carbonyl carbon, the Gilman reagent undergoes 1,4-conjugate addition, with the nucleophile being delivered to the β-carbon (position 4) rather than to the carbonyl carbon (position 2). This selectivity is rationalized by the HSAB principle (Hard and Soft Acids and Bases): the β-carbon of a Michael acceptor is a soft electrophilic site, and copper, being a soft metal, confers soft nucleophilic character to the organocuprate. After acidic workup, the saturated ketone or aldehyde product is formed.
