Nonstatistical Dynamics in the Thermal C²–C⁶/Diels–Alder Cyclization of Enyne-Allenes: Effect of Topology

Abstract

The thermal C(2)-C(6) (Schmittel) cyclization of an enyne-allene with two aryl rings at the allene terminus experimentally leads to three formal Diels-Alder (DA) cycloaddition products, two of which (involving the dimethylamino phenyl unit) are shown to form in a nonstatistical process. DFT computations on the reaction paths reveal that the two aryl rings (Ph vs PhNMe2) do not interact in a dynamic manner as their minimum energy pathways (MEPs) are separated by a large barrier. The preferential formation of the more-hindered DA product 8 (ortho to the dimethylamino group) over the less-hindered product 9 (para to the dimethylamino group), despite the higher energy TS for 8, suggests the occurrence of nonstatistical dynamics in the cyclization onto the dimethylamino phenyl unit, though. Potential energy surface (PES) computations indicate that the large amount of nonstatistical dynamics (97%) arises from facile IRC dynamics (left picture) that is compared with the non-IRC dynamics of a related system (∼76%, right picture, J. Org. Chem. 2014, 79, 2368).

The Study of Reactive Intermediates in Condensed Phases

“…Even when the branching of reaction paths does occur at a local PES minimum, classical molecular dynamics (MD) simulations have shown that one cannot rely on the validity of the statistical approximation for gas-phase reactions. 15,16,[18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] The Figure 1. Schematic depiction of a PES with a bifurcating reaction path.…”

“…Even when the branching of reaction paths does occur at a local PES minimum, classical molecular dynamics (MD) simulations have shown that one cannot rely on the validity of the statistical approximation for gas-phase reactions. ,,− The physical mechanisms that lead to IVR in an isolated molecule are not very different from those that lead to chemical transformation, and so, in hindsight, perhaps it was questionable whether one should have assumed that the time required for the former could be very much smaller than for the latter, as the statistical approximation requires.…”

Beyond static structures: Putting forth REMD as a tool to solve problems in computational organic chemistry

“…Often, a picture of this type successfully captures the key aspects of a system allowing, for example, identification of the primary mechanistic pathway [3][4][5][6][7][8][9] or rationalization of the presence of a specific intermediate. [9][10][11][12][13] Such descriptions, however, are occasionally insufficient to chemistry occurring in an experimental setting, [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] in the most extreme cases leading to disastrous failures. [34] Inside the computer, a host of factors that govern "real world" chemical reactions must necessarily be approximated or ignored altogether in a static picture.…”

Mechanistic Information from Nonstationary Points

“…Over many years, the C 2 –C 6 diradical cyclization of enyne–allenes has been investigated by numerous authors. , For the cyclization of the related enyne–carbodiimides 1 (Scheme ), we proposed in 1998 a stepwise mechanism involving a diradical intermediate based on MR-CI + Q computations (DZP basis set) and experimental kinetic data, which showed an onset temperature difference of only 21 °C between 1a and 3 (Figure ). A notable solvent dependence suggested some polar contributions in the TS of 1 , a phenomenon well-known at the boundary of diradicals and zwitterions .…”

“…After failing to find a reason for the curvature by inspection of both the TS and reactant, we decided to compare qualitatively the energy profiles of enyne–carbodiimide (concerted) and enyne–allene (stepwise) cyclizations. From a large battery of studies, , it has become evident over the years that enyne–allenes follow the stepwise pathway in their thermal cyclization. The idealized reaction coordinate (Figure ) shows a rate-determining C 2 –C 6 bond formation (first step) that is followed by the closure of the C 7 –C 8 bond (second step).…”