The Underlying Kinetic-Thermodynamic Relationship in Asynchronous Reactions

While kinetic-thermodynamic relationships help understand patterns in reactivity and energy responses, strongly asynchronous reactions often present a weak or erratic kinetic-thermodynamic response, often observed as outliers and noise. This undermines its applicability and significance, the interpolative framework no longer being preserved. The standard practice of directly fitting asynchronous reactions conflates reaction phases, which can lead to negative and/or arbitrarily large local gradients, which are to be understood as artefacts rather than evidence of exotic chemical phenomena. We have found that by decoupling the reaction stages, we obtain the meaningful kinetic-thermodynamic response of concerted asynchronous reactions in a way directly comparable to concerted synchronous reactions. The method restores causality in the kinetic-thermodynamic relationship: it recovers the underlying responses and can be used to probe whether a reaction is elementary and synchronous. We rationalise the origin of these spurious, apparent local gradients in terms of the relative energy trends between the main and secondary stages of the reaction. Through computational calculations of representative examples, including 1,2-hydride shifts, a (3+2) ynolate-nitrone cycloaddition and a gold(I) 6-endo-dig cyclisation, we recover well-behaved, physically interpretable kinetic-thermodynamic relationships by isolating phases through constraining key internal coordinates, separating the energy response of interest from the confounding variable secondary processes. This work shows that even highly asynchronous reactions can be analysed, as well as the key practical differences with concerted synchronous reactions, restoring the interpretative power of thermodynamic dependences for such systems. This can serve as a further practical tool to diagnose the synchronicity of a given presumed reaction step experimentally and to extract the relative energetics of the constituent stages.