Grignard Reaction Mechanism

What is Grignard Reaction?

The Grignard reaction refers to the addition of the Grignard reagents to an aldehyde or ketone, that would then yield secondary or tertiary alcohol. However, the addition of Grignard reagent to formaldehyde leads to the formation of primary alcohol. In a Grignard reaction, the chemical process involved two main intermediate processes:

  • Grignard Reagent Formation: In this step, Grignard reagents are synthesized from several compounds like aldehydes, ketones, esters, carbon dioxide, useful in many industrial applications.

  • Grignard Addition of a Carbonyl to form Alcohol: In this step, there's a nucleophilic reaction that takes place to create ethanol. 

Recognized after the Nobel Laureate and French scientist Francois Auguste Victor Grignard, this process is widely used to synthesize organometallic reagents.

Grignard Reagent Mechanism

The haloalkanes, in the presence of the sp3 or sp2 hybridized carbon atoms in the aryl and vinyl halides, are introduced to magnesium metal and generate organomagnesium halides known as a Grignard reagent. 

Grignard reagents typically have a formula of RMgx, where x is a halogen, and R represents an alkyl or aryl group (expressed as a benzene ring). An example of a Grignard reagent would be CH₃CH₂MgBr.

Being a strong nucleophile, these compounds can easily form carbon-carbon bonds in 1°, 2°, and 3° alkyl halides that then differ in respective reactivities, as the aryl halides are slower in reactions to that of the amido magnesium halides. As Grignard reagents are prepared primarily in diethyl ether; therefore, the cyclic ether in this reaction generally comes at higher boiling points and is more rigorous than others. 

  • At first, an alkyl or aryl halide needs to react with magnesium, to undergo a transformation of electrophilic alkyl halide into nucleophilic carbanion molecules. 

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Here the diethyl ether (ether solvent) CH₃CH₂O - CH₂CH₃, has a crucial role in the Grignard reagent synthesis.

  • This then gets added to the Grignard reagent via a nucleophilic addition into a carbonyl and further generates alcohol. 

The chemical reaction involved in the process of Grignard reagent formation are: 

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Since the reactivity of halogens gets decreased in the series of  I > Br > Cl > > F, therefore the reactivity of organofluorides isn't used at all to synthesize Grignard reagents. The Carbon and Magnesium bonding in Grignard reagents makes them extremely polar and accordingly can efficiently react to the carbonyl atoms of an aldehyde, ketones, and esters. 

Reaction of Ester with Grignard Reagent

The Grignard reagent on reaction with orthoformates may lead to the formation of the aldehyde acetals formed from the displacement of the alkoxy group. In these types of reactions, the heterocyclic Grignard reagents from alkyl, aryl, vinyl, and other functional groups react with diethyl ether at room temperatures to yield orthoesters. The respective Grignard reaction with ester would look as follows:

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Upon treating Grignard reagents with dichloromethane, they form several sensitive acetals that may further yield allyl reagents that form unsaturated acetals at low temperatures like -80°C. 

You can also use alkynes and orthoesters to be catalyzed by several zinc salts, and can also come as an alternative to yield aldehyde acetals than synthesizing it from orthoformate via Grignard reaction. By using Zinc salts, the reaction would require ketone acetals to complete efficiently.  The reaction would look as follows: 

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Preparation of Alcohol From Grignard Reagent

The Grignard reagent with alcohol and water reacts rapidly to undergo protonation and yield several compounds; however, when it reacts with aldehydes and ketones, it forms alcohol. The steps include:

Step I:

The Grignard facilitates the carbon-carbon bonding and results in an alkoxide (the conjugatory base of the alcohol).

Step II:

Upon the addition of the acid towards the end of the reaction, may lead the protonation of the negatively charged oxygen atom, thus forming alcohol in the process.

The overall chemical reaction looks like:

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Taking heavily from the above reaction, Grignard reaction with ketone can lead to the formation of alcohols and look like:

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Grignard Reaction with Alcohol Mechanism

Grignard reagent would react with alcohol to form magnesium alkoxide and alkane of the respective alkyl halide, a key element in the Grignard synthesis. The reaction of alcohol with Grignard reagent would be an acid-base reaction, thus will lead to no significant yields since it would lead to protonate the Grignard reagent, thus making it fall outside of the nucleophile-electrophile reaction.

Here's how it works,

  • The alcohol R-OH (R represents an alkyl group), would react with that of the Grignard reagent (R'MgX)

Since the alkyl group would have a nucleophile R', but there isn't an electrophile present in the alcohol, that is acidic enough to protonate the organomagnesium halide, because of its H⁺ proton.

The Grignard reaction with alcohol would be expressed as:

R - OH + R’MgX ⟶ R - O( - )(MgX)⁺ + R - H

FAQ (Frequently Asked Questions)

Q1. Upon the Contact of Grignard Reagent with Water, What Reaction Occurs?

A. The Grignard reagents can react with water to yield alkanes that can disrupt other reactions. The reaction would appear as:

CH3CH2MgBr + H2O ⟶ CH3CH3 + Mg(OH)Br

Therefore, all the different reactions that include Grignard reagent need to be done in an arid environment. Often termed as water being bad for Grignard reactions in general, moisture may disrupt many crucial results if not taken proper care. The other yielded compound, Mg (OH) Br (also known as the basic bromide) can be considered as an intermediate stage between magnesium bromide and magnesium hydroxide. 

Q2. What are the Limitations of the Grignard Reaction?

A. Since the Grignard reagents depend on the acidic nature of the functional groups, if the same is present in the halogen compounds, the Grignard reagent gets destroyed in the chemical process involving water, alcohol, or carboxylic acid groups. In the case of a carbonyl compound with a hydroxyl group, similar reactions occur that would lead to the instantaneous destruction of Grignard reagent because of the undergoing protonation.

The chemical reaction taking place in the destruction of Grignard reagent can be expressed as:

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