Grignard reagent

Grignard reagents or Grignard compounds are

Grignard compounds are popular reagents in organic synthesis for creating new carbon–carbon bonds. For example, when reacted with another halogenated compound R'−X' in the presence of a suitable catalyst, they typically yield R−R' and the magnesium halide MgXX' as a byproduct; and the latter is insoluble in the solvents normally used. In this aspect, they are similar to organolithium reagents.

Grignard reagents are rarely isolated as solids. Instead, they are normally handled as solutions in solvents such as diethyl ether or tetrahydrofuran using air-free techniques. Grignard reagents are complex with the magnesium atom bonded to two ether ligands as well as the halide and organyl ligands.

The discovery of the Grignard reaction in 1900 was recognized with the Nobel Prize awarded to Victor Grignard in 1912.

Synthesis

From Mg metal

Traditionally Grignard reagents are prepared by treating an organic halide (normally organobromine) with magnesium metal.

"Rieke magnesium" is prepared by a reduction of an anhydrous magnesium chloride with an potassium:

MgCl₂ + 2 K → Mg + 2 KCl

Mechanism

In terms of mechanism, the reaction proceeds through

$${\displaystyle {\begin{aligned}{\ce {R-X{}+Mg}}&\longrightarrow {\ce {[R-X^{\bullet }]^{-}{}+[Mg^{\bullet }]+}}\\{\ce {[R-X^{\bullet }]-}}&\longrightarrow {\ce {R^{\bullet }{}+X-}}\\{\ce {R^{\bullet }{}+[Mg^{\bullet }]+}}&\longrightarrow {\ce {R-Mg+}}\\{\ce {R-Mg+{}+X-}}&\longrightarrow {\ce {R-MgX}}\end{aligned}}}$$

Mg transfer reaction (halogen–Mg exchange)

An alternative preparation of Grignard reagents involves transfer of Mg from a preformed Grignard reagent to an organic halide. Other organomagnesium reagents are used as well.[11] This method offers the advantage that the Mg transfer tolerates many functional groups. An illustrative reaction involves isopropylmagnesium chloride and aryl bromide or iodides:^[12]

i-PrMgCl + ArCl → i-PrCl + ArMgCl

From alkylzinc compounds (reductive transmetalation)

A further method to synthesize Grignard reagents involves reaction of Mg with an

The most common application of Grignard reagents is the alkylation of aldehydes and ketones, i.e. the Grignard reaction:^[16]

Note that the acetal functional group (a protected carbonyl) does not react.

Such reactions usually involve an aqueous acidic workup, though this step is rarely shown in reaction schemes. In cases where the Grignard reagent is adding to an aldehyde or a

Grignard reagents also react with many "carbonyl-like" compounds and other electrophiles:

Reactions as a base

Grignard reagents serve as a base for non-protic substrates (this scheme does not show workup conditions, which typically includes water). Grignard reagents are basic and react with alcohols, phenols, etc. to give alkoxides (ROMgBr). The phenoxide derivative is susceptible to formylation by paraformaldehyde to give salicylaldehyde.^[17]

Alkylation of metals and metalloids

Like

$${\displaystyle {\begin{matrix}{\ce {R4B-}}\\{\color {White}\scriptstyle {\ce {Et2O.BF3\ or\ NaBF4}}}{\Bigg \uparrow }\scriptstyle {\ce {Et2O.BF3\ or\ NaBF4}}\\{\ce {Ph2PR<-[{\ce {Ph2PCl}}]RMgX->[{\ce {Bu3SnCl}}]Bu3SnR}}\\{\color {White}\scriptstyle {\ce {B(OMe)3}}}{\Bigg \downarrow }\scriptstyle {\ce {B(OMe)3}}\\{\ce {RB(OMe)2}}\end{matrix}}}$$

Most Grignard reactions are conducted in ethereal solvents, especially diethyl ether and THF. Grignard reagents react with 1,4-dioxane to give the diorganomagnesium compounds and insoluble coordination polymer MgX₂(dioxane)₂ and (R = organic group, X = halide):

2 RMgX + dioxane ⇌ R₂Mg + MgX₂(dioxane)₂

This reaction exploits the Schlenk equilibrium, driving it toward the right.

Precursors to magnesiates

Grignard reagents react with organolithium compounds to give ate complexes (Bu = butyl):^[19]

BuMgBr + 3 BuLi → LiMgBu₃ + BuBr

Coupling with organic halides

Grignard reagents do not typically react with organic halides, in contrast with their high reactivity with other main group halides. In the presence of metal catalysts, however, Grignard reagents participate in C-C coupling reactions. For example, nonylmagnesium bromide reacts with methyl p-chlorobenzoate to give p-nonylbenzoic acid, in the presence of Tris(acetylacetonato)iron(III) (Fe(acac)₃), after workup with NaOH to hydrolyze the ester, shown as follows. Without the Fe(acac)₃, the Grignard reagent would attack the ester group over the aryl halide.^[20]

For the coupling of aryl halides with aryl Grignard reagents,

Treatment of a Grignard reagent with oxygen gives the magnesium organoperoxide. Hydrolysis of this material yields hydroperoxides or alcohol. These reactions involve radical intermediates.

$${\displaystyle {\begin{array}{lcrll}{\ce {{R-MgX}+O2->}}\ {\color {Red}{\ce {{R^{\bullet }}+[O2^{\bullet }]-}}}+{\ce {MgX+->}}&{\ce {R-O-O-MgX}}&{\color {Gray}+\ {\ce {H3O+}}}&{\ce {->{R-O-O-H}}}&{\color {Gray}+\ {\ce {{HO-MgX}+H+}}}\\&{\Bigg \downarrow }{\ce {R-MgX}}\\&{\ce {R-O-MgX}}&{\color {Gray}+\ {\ce {H3O+}}}&{\ce {->{R-O-H}}}&{\color {Gray}+\ {\ce {{HO-MgX}+H+}}}\\\end{array}}}$$

The simple oxidation of Grignard reagents to give alcohols is of little practical importance as yields are generally poor. In contrast, two-step sequence via a borane (vide supra) that is subsequently oxidized to the alcohol with hydrogen peroxide is of synthetic utility.

The synthetic utility of Grignard oxidations can be increased by a reaction of Grignard reagents with oxygen in presence of an

Elimination

In the Boord olefin synthesis, the addition of magnesium to certain β-haloethers results in an elimination reaction to the alkene. This reaction can limit the utility of Grignard reactions.

Industrial use

An example of the Grignard reaction is a key step in the (non-stereoselective) industrial production of Tamoxifen^[22] (currently used for the treatment of estrogen receptor positive breast cancer in women):^[23]

See also

• Dibutylmagnesium
• Hauser base

Gallery

• 
  Magnesium turnings are placed in a flask.
• 
  Tetrahydrofuran and a small piece of iodine are added.
• 
  A solution of alkyl bromide is added while heating.
• 
  After completion of the addition, the mixture is heated for a while.
• 
  Formation of the Grignard reagent is complete. A small amount of magnesium still remains in the flask.
• 
  The Grignard reagent thus prepared is cooled to 0°C before the addition of the carbonyl compound. The solution becomes cloudy as the Grignard reagent precipitates out.
• 
  A solution of carbonyl compound is added to the Grignard reagent.
• 
  The solution is warmed to room temperature. At this point the reaction is complete.

References