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

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.

S‐Trifluoromethylation of Thiols by Hypervalent Iodine Reagents: A Joint Experimental and Computational Study

“…This functional group displays ahigh degree of chemoselectivity,a sd emonstrated, for example, by an octapeptide derived from Sandostatin, [18,19] or by co-enzymeA. [21][22][23][24][25][26][27][28][29][30] We previously investigatedt he electronica nd structural properties leadingt o the distinct reactivity of reagent 1 as well as polar mechanistic details in combination with N-a nd S-nucleophiles. [21][22][23][24][25][26][27][28][29][30] We previously investigatedt he electronica nd structural properties leadingt o the distinct reactivity of reagent 1 as well as polar mechanistic details in combination with N-a nd S-nucleophiles.…”

“…[20] Although the chemistry of iodanes is well established,o nly recent computational studies revealed the mechanistic versatility of l 3 -iodanes, reminiscent of that of transition metals. [24,25,30] Thus, the activation of reagent 1 by protonation is essential. [24,25,30] Thus, the activation of reagent 1 by protonation is essential.…”

“…[24,25,30] Thus, the activation of reagent 1 by protonation is essential. [30] In addition, these reactionsa re very sensitivet os olvent effects. [30] In addition, these reactionsa re very sensitivet os olvent effects.…”

“…[22] N-Trifluoromethylation of the solventa cetonitrile( MeCN) by protonated reagent 1,a st he key step in aR itter-type reaction, [14] likely proceeds by polar reductivee limination (RE), whereas Snucleophiles follow concomitantly RE and nucleophilic substitution( S N )p athways. [22,30] Radicalt rifluoromethylations with l 3 -iodaner eagentsw ere reported involving ab readtho f initiators. [22,30] Radicalt rifluoromethylations with l 3 -iodaner eagentsw ere reported involving ab readtho f initiators.…”

“…Amongt hese, coppera nd photocatalysis by rhodium or iridium catalysts feature mostp rominently. [30] Moreover,aradicalp athway appearst ob er ealistic also for alkynylationsoft hiols with l 3 -iodanes. [34][35][36][37] In the course of an ab initio metadynamics study on the trifluoromethylation of at hiol it waso bserved that ar adicalm echanism possibly plays an important role.…”