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Grignard’s reagent: preparation, applications, examples

The reagent owes its name to its creator, the French chemist Victor Grignard in 1900, winning the Nobel Prize in 1912 for his work. It is prepared by reacting an organohalogen with magnesium, preferably under a nitrogen atmosphere .

General scheme of the Grignard reaction for Br

In this reaction, diethyl ether or tetrahydrofuran (THF) is usually used as solvent. Meanwhile, water should be avoided as it reacts strongly with Grignard’s reagent. This reagent is a strong base and a nucleophile, that is, when it reacts, it gives up a pair of electrons.

They also react with the halogenated compounds of certain metals to form their alkyl derivatives.

Grignard reagent preparation

Grignard’s reagent and its reactions with various carbonyl compounds. Source: Calvero via Wikipedia.

Reagents

Grignard reagents are prepared by adding small pieces of magnesium to the organohalogens (RX). Magnesium must be previously activated, since it is usually presented in the form of ribbons coated with magnesium oxide, which makes it incapable of being used in the Grignard reaction.

Solvents and equation

The preparation is carried out in a flask containing diethyl ether or tetrahydrofuran as solvent, with the organohalogen (RX) and magnesium. The flask is equipped with a reflux condenser, in order to reduce the loss of solvent through evaporation.

The components of the mixture are heated in a water bath for 20 or 30 minutes, the following reaction occurring:

RX + Mg → RMgX

The solvents used must be aprotic, that is, without acidic hydrogens. Water and alcohols should be avoided as they protonate the Grignard reagent, causing its destruction:

RMgX + H 2 O → RH + Mg (OH) X

This occurs because the carbon in the Grignard reagent is very nucleophilic, leading to the formation of a hydrocarbon. It is also recommended that the reaction be carried out in a nitrogen atmosphere, to avoid the action of oxygen.

The Grignard reagent is sensitive to humidity and oxygen, so tests of its good condition are carried out, using indicators of it, such as menthol, phenanthroline or 2,2′-biperidine.

Applications

The main synthetic application of Grignard’s reagent is its reaction with compounds that have carbonyl groups for the production of alcohols. The formation of carbon-carbon bonds is rapid and exothermic when the Grignard reagent reacts with an aldehyde or a ketone.

Reaction of Grignard’s reagent with formaldehyde

Formaldehyde reacts with Grignard’s reagent to form a primary alcohol. This reaction occurs in two stages.

In the first stage, the formaldehyde reacts with the Grignard reagent in the presence of the solvent diethyl ether, forming a complex of the formaldehyde and the Grignard reagent.

In a second stage, the hydrolysis of the previous complex occurs by the action of dilute sulfuric acid (H 3 O + ), producing a primary alcohol that presents an additional carbon to the number of carbons presented by the Grignard reagent.

To simplify the representation of the global process, the two stages are synthesized in one to make it appear as if the process of formation of the primary alcohol occurred in a single stage:

Reaction between formaldehyde and a Grignard reagent. Source: Gabriel Bolívar via ChemSketch.

Reaction of Grignard’s reagent with an aldehyde

The aldehydes when reacting with the Grignard reagent give rise to a secondary alcohol. The equation is similar to the one above, with the difference that the formula for the resulting alcohol is R 2 CHOH.

Reaction of Grignard’s reagent with a ketone

The Grignard reagent when reacting with a ketone produces a tertiary alcohol:

Reaction of Grignard’s reagent with a ketone. Source: Gabriel Bolívar via ChemSketch.

Note how this reagent is used to obtain alcohols with higher carbon numbers.

Reaction of Grignard’s reagent with an ester

In this synthesis reaction, the methyl ester and the ethyl ester are most often used. Two moles of Grignard’s reagent are required per mole of ester. The first mole of the Grignard reagent reacts with the ester, forming a ketone and the methoxymagnesium halide (CH 2 OMgX):

RMgX + R’-C (O) -OCH 3     → R’-C (O) -R + CH 2 OMgX

Meanwhile, the second mole of Grignard’s reagent reacts with the ketone to produce a tertiary alcohol. This reaction was already represented in the previous image.

Reaction of Grignard’s reagent with an epoxide

In this reaction a primary alcohol is formed:

Reaction between Grignard’s reagent and an epoxide. Source: Gabriel Bolívar via ChemSketch.

Reaction of Grignard’s reagent with carbon dioxide

When the Grignard reagent reacts with carbon dioxide, carboxylic acids are produced.

Some of the applications mentioned here were shown in the first image.

Examples

Example 1

Reaction of ethylmagnesium bromide with formaldehyde. Source: Gabriel Bolívar via ChemSketch.

Note that the ethyl segment joins the CH 2 group of formaldehyde to form 1-propanol, a primary alcohol.

Example 2

Reaction of butylmagnesium chloride with ethanal. Source: Gabriel Bolívar via ChemSketch.

In this reaction a secondary alcohol is produced: 2-hexanol.

Example 3

Reaction of methylmagnesium chloride with propanone (ketone). Source: Gabriel Bolívar via ChemSketch.

In this example, propanone, being a ketone, is transformed into the tertiary alcohol 3-butanol by reacting with methylmagnesium chloride.

Example 4

Reaction of pentylmagnesium bromide with ethylene oxide (epoxide). Source: Gabriel Bolívar via ChemSketch.

In this example the ethylene oxide reacts with the pentylmagnesium chloride to form the alcohol 1-heptanol.

Other examples of Grignard reagent reactions

Arylmagnesium bromide and diethyl ether react with a vinyl halide, RCH = CHX or R 2 C = CHX, to synthesize styrene. This compound is used to make rubbers, plastics, insulating materials, pipes, food containers, auto parts, etc.

Grinard’s reagent is used in the production of Tamoxifen, a drug used in the treatment of breast cancer.

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