The general the synthesis of a Grignard reagent involves the reaction of an alkyl halide (RX, where X = Cl, Br, I) with magnesium metal in a suitable ether solvent, Equation 1.

(1)

While diethyl ether (Et₂O) and tetrahydrofuran (THF) are commonly used as solvents, other polar non-protic solvents are suitable, including: triethylamine (NEt₃), dimethylsulphide (Me₂S), dimethylselenide (Me₂Se), and dimethyltelluride (Me₂Te).

In general the alkyl halide is added to an excess of magnesium suspended in the solvent. In most cases it is necessary to activate the magnesium, by the addition of iodine (I₂), 1,2-dibromoethane, or sonication. If the halide is very inert reaction can be promoted by the co-condensation of magnesium and THF under vacuum.

There is often an induction period after the initial addition of alkyl halide. However, since the reaction, Equation 1, is highly exothermic care should be taken to ensure that the reaction does not run-away. For this reason it is normal to initially add a small quantity of the alkyl halide to ensure the reaction initiates. Once reaction is initiated, the addition of alkyl halide is maintained at a suitable rate to ensure the reaction is maintained until all the alkyl halide is consumed. The excess reaction magnesium is removed from the reaction mixture by filtration.

It is not always necessary to use a liquid or solid halide dissolved in the solvent. Bubbling methyl chloride (MeCl) through an Et₂O suspension of magnesium yields MeMgCl. The advantage of a gaseous alkyl halide is that the reaction is very clean as all the magnesium is consumed and the excess alkyl halide is bubbled away.

The purity of the magnesium is very important. For his original experiments Grignard used magnesium of a purity of 99.2%. However, it is now more typical to use 99.8% pure magnesium. It is important that the magnesium not be too pure since it is thought that the transition metal impurities catalyze the reaction.

The relative order of reactivity of the alkyl halide follows the trend:

(2)

In fact alkyl fluorides are sufficiently inert that highly coordinating polar solvents such as THF or dimethylformamide (DMF) must be used.

If the reaction is allowed to get too hot then several possible side reactions can occur. In THF reaction with the solvent occurs:

(3)

Alternatively, a transition metal catalyzed radical coupling between the Grignard and unreacted alkyl halide is observed irrespective of the identity of the solvent, Equation 4.

(4)

The mechanism for Grignard formation is thought to be radical in nature; however, a study of the surface of the magnesium during the reaction has shown the presence of corrosion pits. It is generally agreed that initiation occurs at surface dislocations, but the major reaction occurs at a polished surface.

The kinetics of the reaction is 1^st order with respect to the alkyl halide concentration, but it has also been claimed to be 1^st order with respect to the solvent concentration. It has therefore been concluded that the rate-determining step involves the metal solvent interface.

The reaction of magnesium with aryl bromides has been studied and is proposed to occur by two reactions. The first involves electron transfer between the aryl halide and the metal, while the second involves aryl radical formation.

(5)

A number of alternative synthetic routes are used with polyhalogenated hydrocarbons, Equation 6 and Equation 7, and where the alkyl radical is unstable, Equation 8.

(6)

(7)

(8)

The solid state structure of Grignard reagents is controlled by the presence and identity of the solvent used in the synthesis. In this regard the size and the basicity of the solvent is important. For example, the structure of EtMgBr crystallized from diethyl ether exists as a 4-ccordinate monomer (Figure 2a), while the use of the sterically less demanding THF results in a 5-coordinate monomeric structure (Figure 2b). In contrast, the use of triethylamine yields a dimeric bromide bridged structure (Figure 2c), and the use of a chelate bidentate amine gives a structure (Figure 2d) similar to that observed with diethyl ether (Figure 2a).

Figure 2: Molecular structure of EtMgBr in (a) diethyl ether, (b) THF, (c) triethyl amine, and (d) tetramethyletheylenediamine (TMED).

In solution, Grignards are fluxional such that no single defined structure is present. The series of exchange reactions are known as an extended Schlenk equilibrium (Figure 3).

Figure 3: Schematic representation of the extended Schlenk equilibrium observed for Grignard compounds in solution.

It is observed that Grignard solutions are also slightly conducting, and magnesium is deposited at both the anode and cathode suggesting the formation of RMg⁺ and [RMgX₂]^-. The alkyl/halide exchange is thought to occur through a bridging intermediate (Figure 4).

Figure 4: Proposed structure for the alkyl/halide exchange bridging intermediate.

The most common synthesis of R₂Mg is by the reaction of a Grignard with dioxane (C₄H₈O₂), Equation 9, where the precipitation of the dihalide is the reaction driving force.

(9)

This method is useful for the synthesis of cyclic compounds, Equation 10.

(10)

An alternative synthesis that does not require dioxane involves the metal exchange reaction between magnesium metal and a dialkyl mercury compound.

(11)

Finally, in selected cases, magnesium will react with acidic hydrocarbons such as cyclopentadienyl at high temperatures (600 °C).

In the vapor phase dialkyl magnesium compounds are generally monomeric linear compounds. In solution, in the absence of coordinating solvents R₂Mg form a variety of oligomers (Figure 5a-c) in solution as determined by molecular weight measurements. In the presence of coordinating solvents 4-coordinate monomers predominate (Figure 5d).

Figure 5: Solution structure of R₂Mg (R = Me, Et) in (a – c) non-coordinating solvents, and (d) diethyl ether.

As similar trend is observed in the solid state, where polymers have been characterized in the absence of coordinating solvents (Figure 6a), while monomers or dimmers are generally observed when crystallized from a coordinating solvent (Figure 6b and c).

Figure 6: Solid state structure of R₂Mg (R = Me, Et) crystallized in (a) the absence and (b and c) the presence of a coordinating solvents.

Grignard compounds react with water to give the hydrocarbon, Equation 12, they also react with other hydroxylic compounds such as alcohols and carboxylic acids. One important use of the hydrolysis reaction is specifically deuteration, Equation 13.

(12)

(13)

The hydrogen atom on a terminal alkyne is sufficiently acidic that the reaction with Grignards occurs in an analogous manner to that of hydrolysis.

(14)

Once formed the alkynyl Grignard undergoes the same hydrolysis reaction.

(15)

Grignards react readily with carbon dioxide to form the carboxylate, which yields the associated carboxylic acid upon hydrolysis, Equation 16.

(16)

Organomagnesium compounds react with organic carbonyls (aldehydes, ketones, and esters) to yield the alcohol on hydrolysis, Equation 17. This synthetic route is useful for the formation of primary, secondary and terminal alcohols.

(17)

Unfortunately, for some carbonyls there is a competing side reaction of enolization, where the starting ketone is reformed upon hydrolysis.

(18)

When the Grignard reagent has a β-hydrogen another side reaction occurs in which the carbonyl group is reduced and an alkene is formed.

(19)

Both the enolization and reduction occur via similar 6-membered cyclic transition states (Figure 7).

Figure 7: Representation of the 6-membered transition state reaction for enolization of a ketone.

Grignards react with α,β-unsaturated ketones to give either the 1,2-addition product or the 1,4-addition product, or both.

(20)

Acyl halides react with Grignards to give ketones, Equation 21. Best results are obtained if the reaction is carried out at low temperature and in the presence of a Lewis acid catalysts (e.g., FeCl₃).

(21)

Oxirane (epoxide) rings are opened by Grignards, Equation 22, in a useful reaction that extends the carbon chain of the Grignard by two carbon atoms. This reaction is best performed with ethylene oxide since the magnesium halide formed is a Lewis acid catalyst for further reactions in the case of substituted oxiranes.

(22)

One of the most useful methods of preparing organometallic compounds is the exchange reaction of one organometallic compound with a salt of a different metal, Equation 23. This is an equilibrium process, whose equilibrium constant is defined by the reduction potential of both metals. In general the reaction will proceed so that the more electropositive metal will form the more ionic salt (usually chloride).

(23)

Grignard reagents are particularly useful in this regard, and may be used to prepare a wide range of organometallic compounds. For example:

(24)

(25)

The reaction with a Grignard is milder than the analogous reaction with lithium reagents, and leads to a lower incident of side-products.