Dramatic Effect of Solvent Hydrogen Bond Basicity on the Regiochemistry of S_NAr Reactions of Electron-Deficient Polyfluoroarenes

Abstract

It was found that solvent hydrogen bond basicity (SHBB) significantly affects the regiochemistry of the S(N)Ar reaction between secondary amines and activated polyfluoroarenes. A plausible mechanism involving a six-membered transition state is invoked for the formation of an ortho-substituted isomer, which is likely organized by a hydrogen bond. Evidence for this hypothesis is presented, and a regioselective amination reaction of activated polyfluoroarenes has been developed.

Evidences for the Key Role of Hydrogen Bonds in Nucleophilic Aromatic Substitution Reactions

“…[20] Recent kinetic or solvent studies support the hydrogen-bond (HB) hypothesis, without rigorously demonstrating it. [21][22][23][24][25] The computational study presented here allows us to rationalize all these experimental results.…”

“…As the gas phase is very similar to apolar solvents, this explains the reported data from the literature. [11,24] The addition of methylamine to 2,4-dichloronitrobenzene always proceeds in a single step. The TS energies are 11.3 and 15.1 kcal mol À1 , respectively, for the ortho and the para substitution in methanol, and 13.0 and 22.6 kcal mol À1 in the gas phase.…”

Predicting Regioselectivity in Nucleophilic Aromatic Substitution

“…44 They could not predict the experimentally observed rate increase in going from protic to dipolar aprotic solvents by using DFT/ PCM calculations, but QM/MM Monte Carlo simulations gave useful results. 44 In another paper, Wang and co-workers reported that the regiochemistry of the S N Ar reaction between secondary amines and different electron-deficient difluoroarenes was highly affected by the hydrogen bond basicity of the Reaction of (3 in Figure 1) Reaction of (8 in Figure 1) with dimethylamine j 45 Including these types of effects in regioisomeric predictions is obviously beyond the capabilities of PCM.…”

The kinetics and mechanisms of organic reactions in liquid ammonia

“…In support of this, entropy of activation for the ortho-isomer is less negative than that for the para-isomer ( 228 it would not explain why this favourable interaction cannot occur with 2-NAB. The generation of negative charge on the nitro group oxygens in the σ-adduct formed from 4-NFB requires solvation and restriction of solvent molecules giving rise to a slightly more negative entropy of activation.…”