Increasing Carbon Chain Length Using Grignard Reagents

A Grignard reagent is an organomagnesium compound with the general formula \( RMgX \), where R is an alkyl or aryl group and X is a halogen, usually bromine or iodine. The carbon directly bonded to magnesium behaves like a carbanion: it carries a partial negative charge, \( \delta^- \), because carbon is more electronegative than magnesium. This makes Grignard reagents powerful nucleophiles and, crucially for this topic, a reliable way to add carbon atoms onto an existing skeleton.

A Grignard reagent is prepared by adding a haloalkane to magnesium turnings suspended in dry ethoxyethane (diethyl ether). The magnesium inserts itself into the carbon to halogen bond:

R-X + Mg → R-MgX

For example, bromoethane reacts with magnesium to give ethylmagnesium bromide, C2H5MgBr. This single step converts an unreactive haloalkane into a highly reactive nucleophile, ready to attack an electrophilic carbon elsewhere.

The polar, \( \delta^- \) carbon of a Grignard reagent reacts instantly with even trace amounts of water, being protonated to regenerate the alkane and destroying the reagent before it can be used productively. The reagent also reacts with carbon dioxide dissolved from the air. For these reasons, the glassware, solvent and reagents must all be rigorously dried, and the reaction is often carried out under an inert atmosphere. This sensitivity is also why the deliberate reaction with carbon dioxide, described below, is such a useful synthetic step rather than an unwanted side reaction.

Once formed, a Grignard reagent is added to a carbonyl compound. The nucleophilic carbon attacks the electrophilic carbon of the carbonyl group, \( C = O \), and after the mixture is treated with dilute acid, an alcohol is produced with a longer carbon chain than either starting material had alone. This reactivity follows directly from the polarity of the carbonyl group covered in aldehydes and ketones: properties and reactions.

• Methanal, HCHO, gives a primary alcohol after workup.
• Any other aldehyde, RCHO, gives a secondary alcohol.
• A ketone, R1COR2, gives a tertiary alcohol.

The mechanism is a two-step nucleophilic addition. First, the pair of electrons in the carbon to magnesium bond attacks the \( \delta^+ \) carbonyl carbon, while the \( \pi \) electrons of the \( C = O \) bond move onto the oxygen, generating a magnesium alkoxide intermediate. Second, the alkoxide is protonated when dilute acid, such as dilute sulfuric acid, is added during workup, releasing the alcohol product.

Bubbling dry carbon dioxide through a Grignard reagent, or adding the reagent to solid carbon dioxide, gives the same type of nucleophilic addition, but the intermediate is a magnesium carboxylate rather than an alkoxide. Acidifying with dilute acid then releases a carboxylic acid with exactly one more carbon than the original haloalkane. This route is a common way to prepare a carboxylic acid that would be awkward to make by other methods; the properties of the product are covered fully in carboxylic acids, acyl chlorides and esters.

Suppose you start with bromoethane, C2H5Br, a two-carbon haloalkane, and you want to build a longer molecule.

• Convert it into the Grignard reagent: C2H5Br + Mg → C2H5MgBr, in dry ether.
• React with methanal, then add dilute acid: the product is propan-1-ol, a three-carbon primary alcohol, one carbon longer than the starting haloalkane.
• React with ethanal, CH3CHO, instead: the product is butan-2-ol, a four-carbon secondary alcohol, since the aldehyde itself contributes two carbons.
• React with propanone, CH3COCH3, instead: the product is 2-methylbutan-2-ol, a five-carbon tertiary alcohol.
• React with carbon dioxide, then acidify: the product is propanoic acid, a three-carbon carboxylic acid.

In every case, count the carbons in the Grignard's R group and the carbons in the carbonyl compound separately, then add them together to predict the length of the product chain.

Whenever a Grignard reagent adds to an aldehyde other than methanal, or to an unsymmetrical ketone, the new carbon formed in the addition step is bonded to four different groups. This produces a chiral centre, and the product forms as a racemic mixture because the nucleophile can attack either face of the flat carbonyl group with equal probability. For a full treatment of how this arises and why the two enantiomers form in equal amounts, see chirality and optical isomers.

• Forgetting that any trace of water or carbon dioxide destroys the Grignard reagent before it can react as intended.
• Mixing up which carbonyl compound gives which class of alcohol: methanal gives primary, other aldehydes give secondary, ketones give tertiary.
• Miscounting carbons: always add the carbons from the Grignard's R group to the carbons already present in the carbonyl compound or in carbon dioxide.
• Omitting the acid workup step, without which the product remains as an unreactive magnesium alkoxide or carboxylate salt.

Related lessons

• Uk A Level Chemistry