Change in Rate-Determining Step in an E1cB Mechanism during Aminolysis of Sulfamate Esters in Acetonitrile

Abstract

The kinetics of the reactions of the nitrogen-sulfur(VI) esters 4-nitrophenyl N-methylsulfamate (NPMS) with a series of pyridines and a series of alicyclic amines and of 4-nitrophenyl N-benzylsulfamate (NPBS) with pyridines, alicyclic amines, and a series of quinuclidines have been investigated in acetonitrile (ACN) in the presence of excess amine at various temperatures. Pseudo-first-order rate constants (k(obsd)) have been obtained by monitoring the release of 4-nitrophenol/4-nitrophenoxide. From the slope of a plot of k(obsd) vs [amine], second-order rate constants (k'(2)) have been obtained for the pyridinolysis of NPMS, and a Brønsted plot of log k'(2) vs pK(a) of pyridine gave a straight line with beta = 0.45. However, aminolysis with alicyclic amines of NPMS gave a biphasic Brønsted plot (beta(1) = 0.6, beta(2) approximately equal to 0). Pyridinolysis and aminolysis with alicyclic amines and quinuclidines of NPBS also gave similar biphasic Brønsted plots. This biphasic behavior has been explained in terms of a mechanistic change within the E1cB mechanism from an (E1cB)(irrev) (less basic amines) to an (E1cB)(rev) (more basic amines), and the change occurs at approximately the pK(a)'s (in ACN) of NPMS (17.94) and NPBS (17.68). The straight line Brønsted plot for NPMS with pyridines occurs because the later bases are not strong enough to substantially remove the substrate proton and initiate the mechanistic change observed in the reaction of NPMS with the strong alicyclic amines and quinuclidines. An entropy study supports the change from a bimolecular to a unimolecular mechanism. This is the first clear demonstration of this E1cB mechanistic changeover involving a nitrogen acid substrate.

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

“…For almost 10 years we have been studying the aminolysis and hydrolysis of various sulfamate esters of type 10 (Scheme 2). 10,[12][13][14] As the work progressed we have become more and more aware of the importance of certain of these materials in medicinal chemistry as outlined in the introduction above. We began to look on these sulfamate esters as models for the biologically active compounds and to regard the aminolysis reaction as a model for the enzymatic inhibition that occurs when compounds such as 6-9 are used.…”

“…10a and b were prepared in earlier work in this laboratory. 10 For preparation of 10c the method of Wong et al 11 was used. All reagents were used as obtained from Aldrich unless otherwise specified.…”

“…The pK a 's of 10a, b and c were previously determined in this laboratory in ACN and found to be 17.9 and 17.7 and 17.8 respectively. 10…”

On the Basicity of Organic Bases in Different Media

“…Piperidine 110-89-4 11.22 [58] 10.85 [61] 19.35 [37] [e] 14.3 [37] 220.0 N-Me-piperidine 626-67-5 10.08 [58] 8.4 ± 1.2 [d] 18.24 [37] [e] 12.9 [37] 224.7 Piperazine 110-85-0 9.72 [64] 10.50 [77] 18.69 [37] [e] 14.2 [37] 218.6 N,N′-Me 2 -Piperazine 106-58-1 8.54 [67] 7.7 ± 1.2 [d] 17.38 [37] [e] 12.4 [37] 228.8 [g] Pyrrolidine 123-75-1 11.27 [58] 11.06 [61] 19.62 [33] [e] 13.5 [63] 218.8 Quinuclidine 100-76-5 11.0 [75] 9.8 [75] 19.7 [78] 13.1 ± 1.8 [d] 227.7 DABCO 280-57-9 8.82 [75] 9.06 [61] 18.29 [34] 11.7 ± 1.8 [d] 223.4 Bispidine 280-74-0 21.56 [37] [e] 14.8 ± 1.8 [d] 232.7 [g] Aromatic heterocycles…”

A Sequential Dual Cleavage of the Arylsulfamate Linker to Provide Both Sulfamate and Phenol Derivatives

“…The type of cleavage we call «nucleophilic» here is not strictly speaking nucleophilic, but this type of reaction was studied in detail by Spillane et al [27][28][29][30]. The mechanism is a two-step base-catalysed E1cb-type mechanism that probably involves a bimolecular complex between a base and the sulfamate NH as intermediate, which is then attacked by a nucleophile to release the phenol.…”