Nucleophilic heteroaromatic substitution: Kinetics of the reactions of nitropyridines with aliphatic amines in dipolar aprotic solvents

Abstract

Rate data are reported for the reactions of 2-chloro-5-nitropyridine 2a, 2-chloro-3-nitropyridine 2b, and the corresponding 2-phenoxy derivatives 2c with n-butylamine, pyrrolidine and piperidine and 2d with n-butylamine and pyrrolidine in dimethyl sulfoxide (DMSO) as solvent. The same reactions in acetonitrile had been reported earlier (Crampton et al., Eur J Org Chem 2007, 1378-1383. Values in these solvents are compared with those of 2,4-dinitrochlorobenzene 3a, 2,6-dinitrochlorobenzene 3b, and the corresponding nitroactivated diphenyl ethers 3c and 3d. Reactions with n-butylamine in both solvents gave values of k obs , which increase linearly with amine concentration indicating that nucleophilic attack is rate limiting. The only exception is the reactions in acetonitrile with 2c where base catalysis was observed. Values of k 1 , the rate constant for the nucleophilic attack, decrease in the order pyrrolidine > piperidine > n-butylamine. In acetonitrile, kinetic data show that kratios are more than unity while the inverse is the case in DMSO. With the phenoxy derivatives, substitution was the only process observed. Base catalysis detected in the reactions of the 1-phenoxy derivatives is attributed to rate-limiting deprotonation of the initially formed zwitterionic intermediate. Our results shed more light on fundamental aspects of activation, hydrogen bonding, and steric effects associated with an aza or a nitro group in the molecules investigated as it affects the nucleophilic aromatic substitution (S N Ar) reaction pathways.

Reaction mechanisms : Part (iii) Polar reactions

“…Rate constants have been reported of the reaction of 1-chloro-nitropyridines 128 and 1-phenoxy-nitropyridines 129 with n-butylamine, pyrrolidine and piperidine in DMSO as solvent. 71 Base catalysis detected in the phenoxy derivatives was attributed to rate limiting proton-transfer from the zwitterionic intermediates 130 to base. The results obtained were used to shed light on the fundamental aspects of activation, hydrogen bonding and steric effects associated with an aza or nitro group in the molecules as it affects the S N Ar reaction pathways.…”

Substituent Effects on the Activation Parameter Changes for the Aminolysis in the Bimolecular Nucleophilic Reactions in Solution

“…Normally, general base catalysis occurs in nonpolar aprotic solvents [54,55]. However, in dipolar aprotic solvents the general base catalysis is not observed [56][57][58]. Obviously, the formation of complex (rate constant k 1 ) and its decomposition (rate constants k 2 or k 3 [=NH] ) are presumed to be rate -determined [14][15][16][17][54][55][56][57][58][59][60][61].…”

“…However, in dipolar aprotic solvents the general base catalysis is not observed [56][57][58]. Obviously, the formation of complex (rate constant k 1 ) and its decomposition (rate constants k 2 or k 3 [=NH] ) are presumed to be rate -determined [14][15][16][17][54][55][56][57][58][59][60][61]. If in a stepwise reaction an addition of amine to the substrate (rate constant k 1 in Scheme 1) or a decomposition of intermediate (rate constant k 2 ) is the single rate -determining step (RDS), it can be supposed that the effect of the substituents R in the leaving group of compounds 3 -14, the nonleaving group of compounds 20 -23, 25, 27, 30 -33 and nucleophiles 36 -38 on the changes of the reaction constants X (X = H, S, G) can be similar in according to eqns (3) and (4) for all BNRs proceeding also by concerted mechanism (cf.…”