Grignard Reaction

Grignard's reaction:

The Grignard Reaction is the addition of an organomagnesium halide (Grignard reagent) to a ketone or aldehyde, to form a tertiary or secondary alcohol, respectively. The reaction with formaldehyde leads to a primary alcohol.

A Grignard reagent is an organomagnesium compound which can be described by the chemical formula ‘R-Mg-X’ where R refers to an alkyl or aryl group and X refers to a halogen.

Grignard Reagents:

Grignard reagents (RMgX) are commonly used for organic synthesis. However, these highly reactive compounds are supplied inflammable solvents, which cause extra complexity in their transport. Herein we note that Grignard reagents with linear alkyl chains can be trapped and stabilized by the macrocyclic host pillar arene while retaining their reactivity.

Reactions that form carbon-carbon bonds are among the most beneficial to synthetic organic chemist. In 1912, Victor Grignard was awarded the Nobel Prize in Chemistry for his discovery of a new sequence of reactions resulting in the creation of a carbon-carbon bond. Grignard synthesis involves the preparation of an organomagnesium reagent through the reaction of an alkyl bromide with magnesium metal.

The Grignard reaction is an organic reaction used to produce a variety of products through the reaction of an organomagnesium compound, also known as an electrophilic “Grignard reagent,” followed by an acidic reaction. The Grignard reagent is formed by the reaction of an alkyl or aryl halide with magnesium metal via a radical mechanism.

Preparation of Grignard Reagents

The process of preparing Grignard reagents is described in the points provided below. It can be noted that many of these reagents can also be purchased commercially.

1. These reagents are prepared via the treatment of magnesium with organic halides such as alkyl or aryl halides.
2. This is done with the help of solvents comprising ethers (which are described by the formula R-O-R’) because the ligands provided by these solvents help in the stabilization of the organomagnesium compound.
3. Water and air are very harmful to this synthesis and can quickly destroy the Grignard reagent which is being formed via protonolysis or via oxidation of the reagent. Therefore, the process must be carried out in air-free conditions.
4. Alternatively, the magnesium can be activated to make it consume water when wet solvents are used with the help of ultrasound.
5. After the slow induction period of the reaction, the process can be quite exothermic. This is a very important factor to consider while industrially producing the Grignard reagent.
6. The organic halides used in these reactions include aryl or alkyl chlorides, bromides, and iodides. Aryl fluorides and alkyl fluorides are not very reactive and are hence not commonly used. However, with the help of Rieke metals, the magnesium can be activated to make the fluoride more reactive.

An illustration detailing the preparation of these reagents is provided below.

The quality testing of the synthesized Grignard reagents is done via titrations involving protic reagents that do not contain water (since these reagents are highly sensitive to oxygen and water) and a colour indicator. One suitable compound for these titrations is methanol.

Grignard Reagents are also used in the following important reactions: 

The addition of an excess of a Grignard reagent to an ester or lactone gives a tertiary alcohol in which two alkyl groups are the same, and the addition of a Grignard reagent to a nitrile produces an unsymmetrical ketone via a metalloimine intermediate. (Some more reactions are depicted below)

Mechanism of the Grignard Reaction:

While the reaction is generally thought to proceed through a nucleophilic addition mechanism, sterically hindered substrates may react according to an SET (single electron transfer) mechanism:

With sterically hindered ketones the following side products are received:

The Grignard reagent can act as base, with deprotonation yielding an enolate intermediate. After work up, the starting ketone is recovered.

A reduction can also take place, in which a hydride is delivered from the β-carbon of the Grignard reagent to the carbonyl carbon via a cyclic six-membered transition state.

Additional reactions of Grignard Reagents:

With carboxylic acid chlorides:

Esters are less reactive than the intermediate ketones, therefore the reaction is only suitable for synthesis of tertiary alcohols using an excess of Grignard Reagent:

With nitriles:

With CO2 (by adding dry ice to the reaction mixture):

With oxiranes: