Kinetic Analysis of the Redox-Neutral Catalytic Mitsunobu Reaction: Dehydration, Kinetic Barriers, and Hopping...

Denton's redox-neutral catalytic Mitsunobu reaction is remarkable in that it translates a reaction traditionally driven by the consumption of sacrificial chemical reagents to an additive-free catalytic manifold. Rational attempts to improve the system have been met with only marginal improvements, and a lack of consensus concerning the rate-determining step continues to limit effective reaction development. Here, we analyze the reaction mechanism focusing on a critical, largely overlooked element: the removal of water using a Dean-Stark apparatus. Experimental analysis of the water removal process, coupled with extensive kinetic simulations, demonstrates that the overall rate of the reaction is intimately tied to the rate of water removal. This process can be viewed as a transition between potential energy surfaces and, consequently, subsequent steps of the reaction can progress spontaneously in the absence of water, allowing an explanation of how Le Chatelier's principle, a thermodynamic effect, can have a profound kinetic influence over the rate of the reaction. We identify three bottlenecks in the reaction that inform catalyst design. Additionally, we (a) clarify the ongoing discussion regarding the rate-determining step, (b) provide clear advice concerning future reaction design taking into account the role of water and, (c) discuss the redox-neutral catalytic Mitsunobu reaction in the context of formally endergonic esterification reactions, noting parallels with ratchet mechanisms. Finally, we highlight general principles of catalyst/reaction design that emerge from our analysis and implement our findings to demonstrate a 50% rate acceleration resulting from improved water removal, a substantially greater reaction enhancement than previously obtained from computationally guided catalyst structural changes.