Decoding the Nested, Multicycle Mechanism of Ni-Catalyzed Redox-Neutral Cross-Coupling through Temperature Scanning Reaction Calorimetry

Catalytic reactions involving multiple cycles are common in many key organic transformations. We report a detailed mechanistic analysis of one such network of "nested" cycles, the Ni-catalyzed cross-coupling of alkyl sulfonyl hydrazides with (hetero)aryl halides, employing a battery of techniques, including Temperature Scanning Reaction (TSR) calorimetry coupled with Reaction Progress Kinetic Analysis (RPKA), quantitative NMR time-course analysis, kinetic modeling, linear free energy analysis, and density functional theory (DFT) quantum chemical calculations. TSR/RPKA studies yield the simultaneous determination of the thermodynamic enthalpy of the reaction, the kinetic rate law, and the activation parameters (Δ<i>H</i>^‡, Δ<i>S</i>^‡, Δ<i>G</i>^‡), for the rate-determining step. Expanding the analysis to the coupling of an array of electron-poor and electron-rich sulfonyl hydrazides (each readily accessible on the decagram scale) with a range of (hetero)aryl halide coupling partners introduces the concept of "kinetics matching," and demonstrates that optimal yields may be obtained when the reactivities of the separate cycles are tuned to work in unison. These requirements for reaction networks involving nested catalytic cycles are showcased by several real-world examples. Our work highlights the predictive power of this kinetics-focused mechanistic approach, which may be extended to other nested catalytic networks to select appropriate catalyst and substrate combinations for optimal outcomes.