Dividing a complex reaction involving a hypervalent iodine reagent into three limiting mechanisms by ab initio molecular dynamics

Journal of Computational Chemistry
Oliver SalaJürg Hutter

Abstract

The electrophilic N-trifluoromethylation of MeCN with a hypervalent iodine reagent to form a nitrilium ion, that is rapidly trapped by an azole nucleophile, is thought to occur via reductive elimination (RE). A recent study showed that, depending on the solvent representation, the S(N)2 is favoured to a different extent over the RE. However, there is a discriminative solvent effect present, which calls for a statistical mechanics approach to fully account for the entropic contributions. In this study, we perform metadynamic simulations for two trifluoromethylation reactions (with N- and S-nucleophiles), showing that the RE mechanism is always favoured in MeCN solution. These computations also indicate that a radical mechanism (single electron transfer) may play an important role. The computational protocol based on accelerated molecular dynamics for the exploration of the free energy surface is transferable and will be applied to similar reactions to investigate other electrophiles on the reagent. Based on the activation parameters determined, this approach also gives insight into the mechanistic details of the trifluoromethylation and shows that these commonly known mechanisms mark the limits within which the reaction proceeds.

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Citations

Feb 15, 2017·Chemistry : a European Journal·Jiří VáclavíkAntonio Togni
Dec 10, 2015·Physical Chemistry Chemical Physics : PCCP·Halua Pinto de MagalhãesPatrick Bultinck
Feb 20, 2016·Chemical Communications : Chem Comm·D KatayevA Togni
Apr 30, 2019·Chemical Communications : Chem Comm·Heming JiangHenry F Schaefer
Sep 6, 2019·Acta Crystallographica. Section C, Structural Chemistry·Ruimin WangUlli Englert
Nov 27, 2020·Chemistry : a European Journal·Jorna KalimAntonio Togni
Jun 10, 2015·Organic Letters·Fan TengCarsten Bolm
Oct 11, 2017·The Journal of Organic Chemistry·Halua Pinto de MagalhãesHans Peter Lüthi
Mar 26, 2020·Journal of Chemical Theory and Computation·Mauro SchillingSandra Luber

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