Nucleophilic substitution reactions promoted by oligoethylene glycols: a mechanistic study of ion‐pair S_N2 processes facilitated by Lewis base

Abstract

We present a mechanistic study for nucleophilic substitution (SN2) reactions facilitated by multifunctional n‐oligoethylene glycols (n‐oligoEGs) using alkali metal salts MX (M+ = Cs+, K+, X– = F–, Br–, I–, CN–) as nucleophilic agents. Density functional theory method is employed to elucidate the underlying mechanism of the SN2 reaction. We found that the nucleophiles react as ion pairs, whose metal cation is ‘coordinated’ by the oxygen atoms in oligoEGs acting as Lewis base to reduce the unfavorable electrostatic effects of M+ on X–. The two terminal hydroxyl (−OH) function as ‘anchors’ to collect the nucleophile and the substrate in an ideal configuration for the reaction. Calculated barriers of the reactions are in excellent agreement with all experimentally observed trends of SN2 yields obtained by using various metal cations, nucleophiles and oligoEGs. The reaction barriers are calculated to decrease from triEG to pentaEG, in agreement with the experimentally observed order of efficiency (triEG < tetraEG < pentaEG). The observed relative efficiency of the metal cations Cs+ versus K+ is also nicely demonstrated (larger [better] barrier [efficiency] for Cs+ than for K+). We also examine the effects of the nucleophiles (F–, Br–, I–, CN–), finding that the magnitudes of reaction barriers are F– > CN– > Br– > I–, elucidating the observation that the yield was lowest for F–. It is suggested that the role of oxygen atoms in the promoters is equivalent to that of –OH group in bulky alcohols (tert‐butyl or amyl‐alcohol) for SN2 fluorination reactions previously studied in our lab. Copyright © 2012 John Wiley & Sons, Ltd.

Tri–tert‐Butanolamine as an Organic Promoter in Nucleophilic Fluorination

“…Reaction of linear aliphatic substrates containing iodo as leaving group in the presence of (tri‐ t BuOH)A, gave 80 % yield of the desired fluoroproduct along with 16 % corresponding alkene by‐product (entry 5). In contrast to this result, the same reaction with 1‐iodoundecane in the presence of [2.2.2]cryptand furnished the by‐product as major and fluoro product as minor (31 % yield, entry 6) . These results suggest that the elimination of by‐product is favored over nucleophilic fluorination in cryptand catalyzed reaction due to the generation of “naked” fluorine in much higher concentration in the reaction.…”

A Computational Study of 2-(chloromethyl)oxirane Ring Opening by Bromide and Acetate Anions Considering Electrophilic Activation with Cations of Alkali Metals

“…ECH, nucleophiles and their ionic pairs (bromide anion; acetate anion; lithium, sodium, and potassium bromides and acetates) were chosen as modelling objects for Scheme 1. The choice is due to computational simplicity of this model [26,27] and its versatility for prediction of the experimental kinetic data. Thus, similar quantum chemical simulations were used in our previous works to predict the possibility of interaction, reactivity and mechanism in the reactions of anhydrous curing of epoxy resin ED-20 [23,28] and ECH ring opening by benzoic acid.…”

“…Structures of the transition state are obtained by only one imaginary harmonic frequency, and also by carrying out the intrinsic reaction coordinate (IRC) analysis along the reaction pathway. [15,25,27,33] Energy gradient threshold = 10 -4 a.u., scale factor = 0.96 in all computations. [34,35] The harmonic frequencies were used to calculate activation energies Ea, enthalpies ΔH ‡ , entropies ΔS ‡ , and free energies ΔG ‡ at 298.15 K and 1 atm, using the standard formulas of statistic thermodynamics.…”

“…This may be expected, because the electrostatic influence of compact lithium cation is more significant than that of large potassium cation, which means stronger reduction of the nucleophilicity of anion by the smaller cations. [27] The reaction in the presence of free ions is highly exothermic, which gives it an advantage over the endothermic reaction with the ionic pairs.…”

“…Bromide anion represent the particle from the origin catalyst (tetraalkylammonium halide) and acetate anion is from the real catalyst, whose formation is expected during the reaction with acetic acid. Recent studies [27] showed that SN2 reactions can proceed extremely well when halides react with alkali metal cation as counterion.…”