Acylation between N-(tert-butoxycarbonyl)-L-phenylalanine and Malononitrile: Mechanism of Chemical Change

Dr. Mudassar Altaf, Associate Professor, Department of Higher Education, Government of the Punjab, Pakistan

Contents:

Definition
Overall reaction
Mechanism of chemical change
A brief account of the chemicals

Definition:

The addition of an acyl group (RCO-) to methylene (-CH₂-) of an active methylene compound is called acylation.

Overall Reaction:

A general view of acylation reaction is shown as under.

N-(tert-butoxycarbonyl)-L-phenylalanine [N-(t-Boc)-L-Pa] is acyl group bearing compound that can undergo into acylation with malononitrile – an active methylene compound. Consequently, a carbon, carbon double bond is formed between two compounds. A detailed mechanism is given here.

Mechanism of Chemical Change:

N-(t-Boc)-L-Pa first of all reacts with 1,1’-Carbonyldiimidazole to form an intermediate molecule. The reaction takes place in methylene bichloride (or dichloromethane CH₂Cl₂) solvent. Imidazole replaces hydroxyl group of N-(t-Boc)-L-Pa by making a single covalent bond between N of imidazole and carbon of carbonyl of Pa, and an intermediate compound is produced. Further, 1H-imidazole-1-carboxylic acid is also formed.

In the presence of base, malononitrile loses its acidic hydrogen (H⁺) and carbanion is formed that plays its role as active methylene compound.

The intermediate of N-(t-Boc)-L-Pa reacts with carbanion of malononitrile and acylation takes place. The carbon-carbon sigma bond is formed by substituting imidazole as zwitter ion which ultimately forms imidazolinium salt with chloride.

Hydrogen of dicyanomethylene group (red) shifts to oxide ion of the carbonyl and makes hydroxyl group, thus, unsaturation occurs between carbon-carbon bond in the final product, shown below.

A Brief Account of the Chemicals:

The name Malononitrile is derived from malonic acid [CH₂(COOH)₂] that occurs in fruits, wheat and vegetables. Melon is a Greek word, meaning apple. Malononitrile is a white crystalline powder, having m.pt. 32°C. It is widely used in pharmaceutical industry. The other names of malononitrile are propanedinitrile, dicyanomethane, malonodinitrile.

N-(tert-butoxycarbonyl)-L-phenylalanine consisted of phenylalanine and tertiary butoxycarbonyl. Phenylalanine is an amino acid to which tert-butoxycarbonyl is bonded with its nitrogen of amine group by means of carbonyl group as shown in the figure. L stands for levorotatory. N-(t-Boc)-L-Pa is a white solid having melting point 86°C.