The Grignard Reaction

Definition:

"The Grignard reaction is an organometallic chemical reaction in which alkyl- or aryl- magnesium halides (Grignard reagents) add to a carbonyl group in an aldehyde or ketone. This reaction is an important tool for the formation of carbon-carbon bonds. The reaction of an organic halide with magnesium is not a Grignard reaction, but provides a Grignard reagent."

https://en.wikipedia.org/wiki/Grignard_reaction

Who discovered it?

During the early 1900s, a French chemist by the name of François Auguste Victor Grignard was conducting research into this reaction and its reagents at the University of Nancy in France. He went on to become the recipient of the Nobel Prize in Chemistry in 1912.

What is organometallic chemistry?

Organometallic chemistry is, as the name suggests, the study of compounds containing carbon-metal bonds with largely covalent character. Naturally this incorporates a combination of aspects from both inorganic and organic chemistry.

Forming Grignard reagents

The simple answer is through the reaction between an alkyl/aryl halide with magnesium (solid) which takes place in an etherial solvent to produce ligands. A ligand is a functional group that binds to a central metal atom to form a coordination complex - typically through the donation of the ligand's electron pairs. In this case, the halide ion is the ligand. The reaction initially begins as a single electron transfer (or one-electron reduction) until the Grignard formation reaction, where a second electron transfer occurs, turning free radicals into carbanions.

R−X + Mg → R−X^•− + Mg^•+

R−X^•− → R^• + X⁻

R^• + Mg^•+ → RMg⁺

RMg⁺ + X^- → RMgX

Grignard reagents do not react readily with alkyl halides through an S_N2 mechanism due to a problem in the initiation stage. However, they do readily undergo transmetalation reactions: RMgX + ArX → ArR + MgX₂ 

Most Grignard reagents (e.g. methylmagnesium bromide/chloride, phenylmagnesium bromide etc.) are commercially available as tetrahydrofuran (THF) or diethyl ether solutions. 

Grignard reaction mechanism

Grignard reaction mechanism

The Grignard reagent behaves as a nucleophile, attracted to the electrophilic carbon atom that exists between the polar bond of a carbonyl group. The addition of the Grignard reagent to the carbonyl usually happens through an intermediate of a six-membered ring state.

Industrial application

In the process described above, the Grignard reagents formed are used in the production of organometallic compounds and primary materials/intermediates for agrochemicals and pharmaceuticals.

Organometallic compounds:

1. Organotin compounds - Grignard reagents and tin tetrachloride. Its two main uses are: to stabilise vinyl chloride resins and to catalyse the hardening of urethane/silicon resin.
2. Organosilicon compounds - Grignard reagents and appropriate raw silicon compounds produces different types of symmetric/asymmetric di-, tri- and tetra- organosilicon compounds. They are used as intermediates in pharmaceutical synthesis and as protective groups in organic synthesis.
3. Organophosphorus compounds - an example being the phosphine compound (Grignard reagents + halide phosphates) which are used for vitamin synthesis, the additives for various synthetic resins and other industrial applications.

Combatting Parkinson's

The synthesis of biperiden (an antiparkinsonian agent) involves the nucleophilic addition of acetylnorbornene with a suitable Grignard reagent - plus water to form the final product.