Grignard reaction
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The Grignard reaction is an organometallic chemical reaction involving alkyl- or aryl- magnesium halides which are called the Grignard reagent. The Grignard reaction is important in the formation of carbon-carbon bonds. Grignard reagents react with electrophilic chemical compounds. Victor Grignard, of the University of Lyons, won the 1912 Nobel Prize in Chemistry for his discovery of the Grignard reaction.
The following reagents can be used in the Grignard reaction:
- Ketones yield tertiary alcohols
- Aldehydes yield secondary alcohols
- Nitriles yield ketones
- Halides yield extended alkanes and arenes
- Hydrogen donors containing OH or NH functional groups lead to dehalogenation
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Grignard reagent formation
Grignard reagents are formed by reacting alkyl or aryl halides with magnesium metal, conferring 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.
Image:Grignard-Reaction Mechanism.png
An example is a key step in the industrial production of Tamoxifen Template:Ref:
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 Template:Ref. 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 Template:Ref 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.
Image:Grignard oxygen oxidation.png
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 Template:Ref. 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.
Image:Grignard oxidation example.png
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
- Template:Note Grignard Reagents: New Developments H. G. Richey (Editor) ISBN 0-471-99908-3
- Template:Note 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.
- Template:Note 4-Nonylbenzoic Acid A. Fürstner, A. Leitner, G. Seidel. Org. Synth. 2004, 81, 33-42. online article from Organic Syntheses
- Template:Note 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 Abstractde:Grignard-Reaktion
he:תרכובת גריניאר it:Reattivi di Grignard ja:グリニャール試薬 zh:格林尼亚试剂