Kinetic and mechanistic studies on sulfamate esters: models of enzyme inhibitors

Abstract

Many compounds containing a sulfamate moiety, such as NH 2 SO 2 O-are now known to be medicinally important. However, very little is known about their mechanisms of reaction even under non-biological conditions. In this work the various types of elimination mechanisms that may occur have been probed by studying the kinetics of the reactions of model sulfamate substrates with amines (bases) that act as models for the enzymes involved. The principal mechanistic tool employed has been Brönsted plots and both 'normal' rectilinear and two types of biphasic plots have been found for the decomposition of the esters in acetonitrile (ACN). The mechanisms operating are seen as being of the E2 and E1cB types.

Elimination Mechanisms in the Aminolysis of Sulfamate Esters of the Type NH2SO2OC6H4X – Models of Enzyme Inhibitors

“…Compound 1a was the substrate mainly used in this study. The p K a for the ionization of 1a was found to be 17.9, in excellent agreement with a value of 17.8 previously determined in this laboratory 10. The p K a value for the second ionization gave an average value of 21.08 in ACN on the basis of three determinations by using two different analytical wavelengths.…”

“…Over much the same period of time, we have been investigating the hydrolysis and aminolysis mechanisms of various esters such as 4‐nitrophenyl methylsulfamate, 4‐nitrophenyl benzylsulfamate and a series of 4‐nitrophenyl phenylsulfamates 8,9. Latter studies have focussed more on 4‐nitrophenyl sulfamate NH 2 SO 2 OC 6 H 4 ‐NO 2 ‐4 ( 1a ), because this compound could act as a simple model for the more complex and therapeutically important esters 10. The thrust of this current work is to examine the kinetics and mechanism of reaction in acetonitrile (ACN) of compound 1a and five other phenyl sulfamate derivatives, 1b – f .…”

Acid‐catalyzed hydrolysis of 5‐substituted‐1H,3H‐2,1,3‐benzothiadiazole 2,2‐dioxides (5‐substituted benzosulfamides): kinetic behavior and mechanistic interpretations

“…The values of pK BH + of the substituted sultams = 5.96–8.3 . Sulfamate esters have pK a values of ≈ 8 in water‐organic media . Sulfamides have two electron donor nitrogen atoms.…”

“…[26] Sulfamate esters have pK a values of ≈ 8 in water-organic media. [51] Sulfamides have two electron donor nitrogen atoms. So protonation of the sulfamides might take place on nitrogen as observed for the sultams [52] and sulfinamides.…”

Reactions of Carboxylic, Phosphoric and Sulfonic Acids and their Derivatives

“…The Brønsted-type plot was biphasic, the break point at pK a ≈ 18.2 more or less corresponding to the pK a of the ester (109) (17.8). The proposed mechanism (Scheme 30) involves a sequential double deprotonation of (109) leading first, via (110), to the sulfenamine (112) and at higher basic strength to (111) and thence to a novel anionic sulfenamine (113), the products in each case being an N ,N -dialkylsulfamide (114) and p-nitrophenol. 114 Theoretical studies of the hydrolysis of N -benzyl-3-oxo-β-sultam (115) showed that the activation energies for the pathways leading to the products of C-N and S-N cleavage for the uncatalysed hydrolysis were very similar.…”