Synthesis of Grignard reagent

General Aim

Synthesis of Grignard reagent

Method

Grignard reagents can be prepared by the reaction of magnesium and alkyl halides (halogenoalkane) or aryl halides in an ether solvent (diethyl ether). The flask is fitted with a reflux condenser, and the mixture is warmed over a water bath for 15-30 minutes. This reaction must be carried out in the ether for two reasons as ether stabilizes the Grignard compound. Moreover, ethers are not protic solvents, which would destroy the Grignard compound. Tetrahydrofuran is another popular choice of solvent for the synthesis of Grignard reagents. Everything must be perfectly dry because Grignard reagents react with water.

Theoretical Background

The Grignard reaction (pronounced Grin-yard) involves an R-Mg-X, a carbon chain bound to a magnesium halide, typically used to form alcohols by attacking carbonyls such as in aldehydes or ketones. The Grignard reaction mechanism explains the addition of alkyl/vinyl/aryl magnesium halides to any carbonyl group in an aldehyde/ketone. The reaction is considered an important tool to form carbon-carbon bonds. These alkyl, vinyl or aryl magnesium halides are referred to as Grignard reagents. Grignard reagents are strong nucleophiles and can form carbon-carbon bonds. Being nucleophiles, meaning that they (specifically the carbon bound to Mg) will readily donate a pair of electrons to an appropriate electrophile. The Grignard is so useful in synthesis due to its high nucleophilicity. In addition, the carbanion in the Grignard is very unstable and very reactive.

A typical Grignard reagent might be CH₃CH₂MgBr. Magnesium (Mg) is a Group II metal with very low electronegativity. This is intensified by the electronegative halide, which gives it even more positive character. Compared to magnesium, carbon has a much higher electronegativity, so that when bound to Mg, it behaves almost like a carbanion. Carbanions are very reactive due to the unstable negative charge on carbon. It is important to note that the reagent can be made with alkyl chlorides, bromides, and iodides but not with fluorides. The synthesis of the Grignard reagent occurs on the surface of the magnesium metal. Therefore, breaking up the magnesium into smaller chunks can increase the effective surface area and accelerate the speed of the reaction. The formation of magnesium oxide on the surface of the magnesium metal can also hinder the reaction as it is quite unreactive with alkyl halides. The breaking up of the magnesium metal also exposes fresh, unoxidized magnesium to the reaction. The complete dryness of the solvent and apparatus will also help the reaction as water is quite harmful to Grignard reagents. Therefore, the reaction of magnesium with alkyl or aryl halides gives the Grignard reagent as a product, which is quite useful in the synthesis of alcohols, aldehydes or ketones. The Grignard reaction can also facilitate the formation of carbon-carbon bonds.

Figure 1. Synthesis of Grignard reagents

It can be noted that the reactions between metallic magnesium and organic halides are NOT Grignard reactions. However, they yield Grignard reagents.

Principle Of Work

The process of preparing Grignard reagents is described in the points provided below. 

• These reagents are prepared via the treatment of magnesium with organic halides such as alkyl or aryl halides.
• This is done with the help of solvents comprising ethers (which are described by the formula R-O-R’) because the ligands provided by these solvents help in the stabilization of the organomagnesium compound.
• Water and air are very harmful to this synthesis and can quickly destroy the Grignard reagent which is being formed via protonolysis or via oxidation of the reagent. Therefore, the process must be carried out in air-free conditions.

The synthesized Grignard reagent is highly nucleophilic as discussed earlier. This reagent attacks the electrophilic carbon in the polar bond of the carbonyl group. The mechanism of this Grignard reaction proceeds through a six-membered ring transition state, as shown below:

Figure 2: Grignard reaction mechanism

The R group can be any carbon chain including simple alkyl groups (no pi bonds) to more complex pi systems such as aryl or vinyl groups.

The Mg-X is NOT reactive, but it makes the R group nucleophilic and very reactive. Carbonyl groups are capable of resonance with partially negative oxygen and partially positive carbon. This is the electrophile in the reaction. In other words, the partially negative ‘carbanion-like’ carbon atom will use the C-Mg electrons to attack the partially positive carbon of the carbonyl. The resulting alkoxide is negative and will require an acid workup to neutralize the final product.

Figure 3: Nucleophilic reaction in the Grignard reaction 

The final step requires a proton added to the negative oxygen. This is called ‘quenching’ or doing an ‘acid workup’. This step could be achieved by H⁺, H₂O, or H₃O⁺, or even just an ‘acid workup’ for this step. Great caution should be taken in the order of the quenching. If you add the acid workup before the Grignard attacks, the carbanion will attack the easier to reach and more acidic proton, rather than the less reactive carbonyl carbon. This will destroy the Grignard and result in no reaction.

Figure 4: Acid workup in the Grignard reaction