Grignard reagent


Grignard reagents or Grignard compounds are chemical compounds with the general formula, where X is a halide, R is an organic group, S is an ether, and n is usually 2. Usually, the ether groups are omitted from the formula. Thus, two typical examples are methylmagnesium chloride and phenylmagnesium bromide. They are a subclass of the organomagnesium compounds.
Grignard compounds are popular reagents in organic synthesis for creating new carbon–carbon bonds.
The carbon-magnesium bond in Grignard reagent is a polar covalent bond. The carbon atom has negative excess charge and acts as a nucleophile.
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 complexes 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 with magnesium metal. Ethers are required to stabilize the organomagnesium compound. Water and air, which rapidly destroy the reagent by protonolysis or oxidation, are excluded. Although the reagents still need to be dry, ultrasound can allow Grignard reagents to form in wet solvents by activating the magnesium such that it consumes the water.
As is common for reactions involving solids and solution, the formation of Grignard reagents is often subject to an induction period. During this stage, the passivating oxide on the magnesium is removed. After this induction period, the reactions can be highly exothermic. This exothermicity must be considered when a reaction is scaled-up from laboratory to production plant.
Most organohalides will work, but carbon-fluorine bonds are generally unreactive, except with specially activated magnesium.

Magnesium

Typically the reaction to form Grignard reagents involves the use of magnesium ribbon. All magnesium is coated with a passivating layer of magnesium oxide, which inhibits reactions with the organic halide. Many methods have been developed to weaken this passivating layer, thereby exposing highly reactive magnesium to the organic halide. Mechanical methods include crushing of the Mg pieces in situ, rapid stirring, and sonication. Iodine, methyl iodide, and 1,2-dibromoethane are common activating agents. The use of 1,2-dibromoethane is advantageous as its action can be monitored by the observation of bubbles of ethylene. Furthermore, the side-products are innocuous:
The amount of Mg consumed by these activating agents is usually insignificant. When treated with small amounts of mercuric chloride, magnesium pieces become coated with an amalgam, enhancing its reactivity.
Addition of preformed Grignard reagent is often used as the initiator and oxidiser
Specially activated magnesium, such as Rieke magnesium, circumvents this problem. The oxide layer can also be broken up using ultrasound, using a stirring rod to scratch the oxidized layer off, or by adding a few drops of iodine or 1,2-Diiodoethane. Another option is to use sublimed magnesium or magnesium anthracene.
"Rieke magnesium" is prepared by a reduction of an anhydrous magnesium chloride with a potassium:

Mechanism

In terms of mechanism, the reaction proceeds through single electron transfer:

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. This method offers the advantage that the Mg transfer tolerates many functional groups. An illustrative reaction involves isopropylmagnesium chloride and aryl bromide or iodides:

From alkylzinc compounds (reductive transmetalation)

A further method to synthesize Grignard reagents involves reaction of Mg with an organozinc compound. This method has been used to make adamantane-based Grignard reagents, which are, due to C-C coupling side reactions, difficult to make by the conventional method from the alkyl halide and Mg. The reductive transmetalation achieves:

Organomagnesium fluorides

Grignard reagents with chloride, bromide, and iodide are routine reagents. The corresponding fluorides RMgF were not synthesized until 1970. In 1920 Swarts reported the reduction of amyl fluoride to the corresponding hydrocarbon with activated magnesium, while no intermediates were separated. Alkylmagnesium fluoride was first prepared by Ashly and co-workers in 1970, using metal magnesium and catalytic iodine in refluxing tetrahydrofuran or 1,2-dimethoxyethane from the corresponding alkyl fluoride.

Testing Grignard reagents

Because Grignard reagents are so sensitive to moisture and oxygen, many methods have been developed to test the quality of a batch. Typical tests involve titrations with weighable, anhydrous protic reagents, e.g. menthol in the presence of a color-indicator. The interaction of the Grignard reagent with phenanthroline or 2,2'-biquinoline causes a color change.

Reactions of Grignard reagents

As nucleophiles

Grignard reagents react with a variety of carbonyl derivatives.
Such reactions usually involve an aqueous acidic workup, though this step is rarely shown in reaction schemes.
The most common application of Grignard reagents is the alkylation of aldehydes and ketones, i.e. the Grignard reaction:
Note that the acetal functional group does not react.
Grignard reagents also react with many "carbonyl-like" electrophiles:
Compounds with labile protons are unsuitable electrophiles, because Grignard reagents are strong bases, and protonative quenching occurs much faster than addition.
Grignard reagents are nucleophiles in nucleophilic aliphatic substitutions for instance with alkyl halides in a key step in industrial Naproxen production:
In the Bruylants reaction, a nitrile can be replaced by the Grignard nucleophile, rather than the Grignard attacking the nitrile to form an imino structure.

Reactions as a base

Grignard reagents are basic and react with alcohols, phenols, etc. to give alkoxides. 1,3-Diketones and related substrates are also acidic enough that the Grignard reagent RMgX functions merely as a base, liberating the alkane RH to give a magnesium enolate.

Alkylation of metals and metalloids

Like organolithium compounds, Grignard reagents usefully form carbon–heteroatom bonds with many metal-based electrophiles.
For example, they undergo transmetallation with cadmium chloride to give dialkylcadmium:

Schlenk equilibrium

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

Precursors to magnesiates

Grignard reagents react with organolithium compounds to give ate complexes :

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 Trisiron, after workup with NaOH to hydrolyze the ester, shown as follows. Without the Fe3, the Grignard reagent would attack the ester group over the aryl halide.
For the coupling of aryl halides with aryl Grignard reagents, nickel chloride in tetrahydrofuran is also a good catalyst. Additionally, an effective catalyst for the couplings of alkyl halides is the Gilman catalyst lithium tetrachlorocuprate, prepared by mixing lithium chloride and copper chloride in THF. The Kumada-Corriu coupling gives access to styrenes.

Oxidation

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

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.

Allyl Grignard reagents

Allyl Grignard reagents exhibit high reactivity and special selectivity compared to alkyl ones.

Industrial use

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

Specialized literature

Category:Organometallic chemistry
Category:Carbon-carbon bond forming reactions
Category:Carbon-heteroatom bond forming reactions
Category:Reagents for organic chemistry
Category:Magnesium
Category:Chemical tests
Category:Organomagnesium compounds