The Grignard reaction is an organometallic chemical reaction involving alkyl- or aryl- magnesium halides which are called Grignard reagents. The Grignard reaction is important in the formation of carbon-carbon bonds. Such reactions are irreversible due to the high pKa value of the alkyl component (pka = ~60). Grignard reagents react with electrophilic chemical compounds. It should be noted that such reactions are not ionic; the Grignard reagent exists as an organometallic cluster (in ether). Victor Grignard (University Of Lyons, France) was awarded the 1912 Nobel Prize in Chemistry for the discovery of such reagents. The following reagents can be used in the Grignard reaction (products shown are after workup when necessary):

• Ketones yield tertiary alcohols
• Esters yield ketone and then tertiary alcohols
• Acid chlorides yield tertiary alcohols
• Aldehydes yield secondary alcohols
• Nitriles yield ketones
• Halides yield extended alkanes and arenes
• Secondary amides yield ketones.
• Tertiary amides yield ketones.
• Cyanides yield ketones
• Hydrogen donors containing OH or NH functional groups lead to neutralization.

Grignard reagent formation

Grignard reagents are formed by reacting the appropriate alkyl or aryl halide with magnesium metal. This reaction is conducted in ether to avoid a neutralization reaction between the Grignard reagent and the proton donor: water. An iodine crystal is often added to expose the magnesium's metallic surface via the removal of its passivating oxide film. The reaction with magnesium confers a negative charge on the terminal carbon atom, which is otherwise difficult to achieve. Bromides are most often used, as they react the fastest and are readily available. Iodides and chlorides are also used, but fluorides are generally unreactive towards magnesium. The Grignard reaction is exothermic, but because of an oxide layer present on the magnesium, the start of the reaction is sometimes delayed. To start the reaction it is often necessary to squash the magnesium, heavily stir the mixture with glass shards, or to add a small amounts of iodine, methyl iodide, or 1,2-dibromomoethane (which forms ethene bubbles and can also be mixed with the halide to monitor the reaction). All these methods weaken the oxide layer and expose the magnesium to the halide. Many Grignard reagents such as phenylmagnesium bromide are available commercially in tetrahydrofuran or diethyl ether solutions.

Grignard reagents form complex equilibria known as the Schlenk equilibrium.

Nucleophilic addition reactions

In reactions involving Grignard reagents, it is important to ensure that no water is present, which would otherwise cause the reagent to rapidly decompose. Thus, most Grignard reactions occur in solvents such as anhydrous diethyl ether or tetrahydrofuran, because the oxygen of these solvents stabilizes the magnesium reagent. The reagent may also react with oxygen present in the atmosphere, inserting an oxygen atom between the carbon base and the magnesium halide group. Thus, many of these reactions are carried out in nitrogen or argon atmospheres.

An example is a key step in the industrial production of Tamoxifen :

Grignard reagents react with formaldehyde to form primary alcohols, with other aldehydes to form secondary alcohols, and with ketones to form tertiary alcohols. Quenching a Grignard with dry ice yields the carboxylic acid . The Bouveault aldehyde synthesis is a one-pot chemical reaction that converts a primary alkyl halide to an aldehyde one carbon longer. In the Fujimoto-Belleau reaction Grignard reagents react with α,β-unsaturated enol-lactones.

Coupling reactions

A Grignard reagent can also be involved in a coupling reaction. For example nonylmagnesium bromide reacts with an aryl chloride to a nonyl benzoic acid. An iron catalyst is used and not an expensive palladium catalyst such as used in Heck reactions. Acac stands for acetylacetonate. For the coupling of aryl halides with aryl grignards nickel chloride in THF is a very good catalyst. A very effective catalyst for couplings of alkyl halides is dilithium tetrachlorocuprate (Li₂CuCl₄), prepared from mixing lithium chloride (LiCl) and copper(II) chloride (CuCl) in THF.

Oxidation

The oxidation of a Grignard reagent with oxygen takes place through a radical intermediate to a magnesium hydroperoxide. Hydrolysis of this complex yields hydroperoxides and reduction with an additional equivalent of Grignard reagent gives an alcohol.

The synthetic utility of Grignard oxidations can be increased by a reaction of Grignards with oxygen in presence of an alkene to an ethylene extended alcohol . This modification requires aryl or vinyl Grignards. Adding just the Grignard and the alkene does not result in a reaction demonstrating that the presence of oxygen is essential. Only drawback is the requirement of at least two equivalents of Grignard although this can partly be circumvented by the use of a dual Grignard system with a cheap reducing Grignard such as n-butylmagnesium bromide.

Nucleophilic substitution

Grignard reagents are nucleophiles in nucleophilic aliphatic substitutions for instance with alkyl halides in a key step in industrial Naproxen production:

See also

• The Barbier reaction is an alternative to a Grignard reaction and organolithium reagents are an alternative to Grignard reagents.
• The Gilman reaction is also an alternative and is naturally controlled.
• In the Sakurai reaction allylic silanes replace the Grignard reagent.
• In the Bodroux-Chichibabin aldehyde synthesis the Grignard reagent reacts with triethyl orthoformate

References

1. Grignard Reagents: New Developments H. G. Richey (Editor) ISBN 0-471-99908-3
2. Butyric acid, α-methyl- Henry Gilman and R. H. Kirby Organic Syntheses, Coll. Vol. 1, p.361 (1941); Vol. 5, p.75 (1925).online article.
3. 4-Nonylbenzoic Acid A. Fürstner, A. Leitner, G. Seidel. Org. Synth. 2004, 81, 33-42. online article from Organic Syntheses
4. Air-Assisted Addition of Grignard Reagents to Olefins. A Simple Protocol for a Three-Component Coupling Process Yielding Alcohols Youhei Nobe, Kyohei Arayama, and Hirokazu Urabe J. Am. Chem. Soc.; 2005; 127(51) pp 18006 - 18007 Abstract

External links

Reagents for organic chemistry | Magnesium | Organometallic compounds

Grignard-Reaktion | Reattivi di Grignard | תרכובת גריניאר | Grignardreactie | グリニャール試薬 | Reação de Grignard | 格林尼亚试剂