The methoxy group is generally considered as a poor leaving group for nucleophilic substitution reactions. This work verified the superior ability of the methoxy group in nucleophilic amination of arenes mediated by the sodium hydride and lithium iodide through experimental and computational approaches.
The title reactions are an important class of copper mediated nucleophilic aromatic substitution processes, which constitute a useful tool in the molecular design and synthesis of small molecules. We report the results of extensive investigation of these processes, primarily focussing on cyanodeiodination (ArI + CuCN → CuI + ArCN). Among the interesting features of these processes are: (a) an unusual rate equation involving autocatalysis by CuI product; (b) retardation by both excess nucleophile (as KCN) and excess leaving group (as KI), which compete with ArX to complex with CuNu; (c) only cuprous nucleophiles are active (ligand exchanged products from cupric salts arise from prior redox equilibria which form CuNu); (d) the halogen effect is large (kI ~ 40–100 kBr ~ 300–5000kCl) but the Hammett ρ value is zero; (e) ortho-alkyl groups do not hinder the reaction (and actually cause mild acceleration by relief of steric strain). Finally, the introduction of an ortho-COO− group accelerates the reaction by a factor of 104–105, but the general features of the accelerated reactions are also the same, again indicating a common mechanism, with entropic acceleration by ortho-carboxylate. Both kinetic and thermodynamic factors were considered in detail, the latter apparently for the first time. Applications to practical syntheses are considered, and novel mechanistic models for these interesting processes are discussed.
ABSTRACTPseudomonas aeruginosaarylsulfatase (PAS) hydrolyses sulfate and, promiscuously, phosphate monoesters. Enzyme-catalyzed sulfate transfer is crucial to a wide variety of biological processes, but detailed studies of the mechanistic contributions to its catalysis are lacking. We present an investigation based on linear free energy relationships (LFERs) and kinetic isotope effects (KIEs) of PAS and active site mutants that suggest a key role for leaving group (LG) stabilization. In LFERs wild type PAS has a much less negative Br0nsted coefficient (βleaving groupobs-Enz= −0.33) than the uncatalyzed reaction (βleavingroupobs= −1.81). This situation is diminished when cationic active site groups are exchanged for alanine. The considerable degree of bond breaking during the TS is evidenced by an18ObridgeKIE of 1.0088. LFER and KIE data for several active site mutants point to leaving group stabilization by active-site lysine K375, in cooperation with histidine H211.15N KIEs combined with an increased sensitivity to leaving group ability of the sulfatase activity in neat D2O (Δβleaving groupH-D= +0.06) suggest that the mechanism for S-Obridgebond fission shifts, with decreasing leaving group ability, from charge compensation via Lewis acid interactions towards direct proton donation.18OnonbridgeKIEs indicate that the TS for PAS-catalyzed sulfate monoester hydrolysis has a significantly more associative character compared to the uncatalyzed reaction, while PAS-catalyzed phosphate monoester hydrolysis does not show this shift. This difference in enzyme-catalyzed TSs appears to be the major factor favoring specificity toward sulfate over phosphate in this promiscuous hydrolase, since other features are either too similar (uncatalyzed TS) or inherently favor phosphate (charge).