The acylation of neutral phosphoramidates

Abstract

Kinetic studies of the acylation of neutral secondary phosphoramidates by acid halides and anhydrides are reported. The reactions produce both N-acylphosphoramidates and carboxamides by cleavage of the P–N bond. The extent of carboxamide formation varies with the stregth of the acid co-product and with steric and electronic factors associated with both the acylating agent and the nitrogen substituent of the phosphoramidate. Except for pivaloyl chloride, the presence of a base diminishes the amount of carboxamide formed. With either acid halides or anhydrides tertiary phosphoramidates produce carboxamides directly. The formation of both N-acylphosphormidate and carboxamide follow the equation: rate =k₂[phosphoramidate][acid halide or anhydride]. Second-order rate constants, k₂, for the formation of N-acylphosphoramidates vary with the structure of the acylating agent: AcBr is 18 times more reactive than AcCl; in solvent pyridine the Hammett ρ-value for substituted benzoyl chlorides is 1.8; in solvent CCl₄ Taft ρ* and δ values for substituted acid chlorides are 0.7 and 0.76 respectively. These data are best interpreted in terms of a bimolecular substitution reaction involving nucleophilic attack by the phosphoramidate nitrogen atom at the carbonyl carbon of the acylating agent to form an N-acylphosphoramidate cation (5). Breakdown of this cation can give either the N-acylphosphoramidate via deprotonation, or the carboxamide via P–N bond cleavage. Carboxamide formation is favoured for reactions where P–N bond cleavage either relieves steric strain or the carboxamide is a good nucleofuge.

Catalysis of the reaction between phosphoramidates and acetic anhydride by electrophiles such as AcX and HX is shown to involve acylation by AcX followed by a rapid re-formation of AcX from Ac₂O and HX.