Ortho substitution effects on the acidic and alkaline hydrolyses of formanilides

The objectives of this project were to determine the reaction schemes of formanilide and substituted formanilides in acidic and alkaline solutions, to quantiate the kinetics of hydrolysis, to propose reaction mechanisms, and to assess the role of ortho words substitution in formanilide hydrolysis kinetics.

A set of thirty substituted formanilides were synthesized and characterized. Hydrolysis of the formanilides was carried out under first order conditions in hydrochloric acid (0.01-8 M, 40°C) and in hydroxide solutions (0.01-3 M, 25°C and 40°C). Hydrolysis kinetics were evaluated in terms of temperature (20°C- 60°C), solvent composition (0-50 % dimethyl sulfoxide, dioxane, ethanol and acetone) and ionic strength (0.1-1) effects. The degradation products were separated and identified using RP-HPLC, and the alkaline and acidic reaction schemes were proposed.

For acidic hydrolysis of formanilides, the observed rate constants were proportional to the hydronium concentrations. Modified Hammett plots constructed using the second order rate constants for specific acid catalysis were linear. The ortho effect was analyzed using the Fujita-Nishioka method. In alkaline solutions the observed rate constants showed mixed first and second order dependences with respect to hydroxide concentration. A complex degradation scheme was used to estimate individual rate constants and to construct Hammett plots. Ortho effects were examined for the first order hydroxide concentration dependent pathway.

Arrhenius plots for substituted formanilides were linear in both acidic and alkaline media. Ionic strength did not show any effect on the acidic and alkaline hydrolysis rates. In both acidic and alkaline media the rate of hydrolysis decreased with increase in organic solvent content.

Formanilide hydrolyzes in acidic solutions by specific acid catalysis and the kinetic study results were consistent with A_AC2 mechanism. Ortho substitution led to reduction in rates. The orthoeffect could be split in steric inhibition of resonance, retardation due to steric bulk and through space interactions. In alkaline solutions a complicated kinetic scheme was used to describe the multiple pathways of degradation. The results from the kinetic studies could be explained using a modified B_AC2 mechanism. The hydrolysis of meta and parasubstituted formanilides in alkaline conditions did not show substituent effects however ortho substitution led to an decrease in rate constants proportional to the steric bulk of the substituent.