Confinement-controlled selective CO2 insertion into a dicopper dihydride core: A multiscale mechanistic study

CO2 is an abundant C1 feedstock for fuel and chemical synthesis. We have previously demonstrated experimentally a stepwise insertion of CO2 into a [Cu2H2] core via a solid-gas in crystallo reaction, forming formate species that are unstable and inaccessible under solution-phase conditions. This work elucidates how structural confinement within the crystal lattice enables such selective reactivity. In particular, co-crystallized tetrahydrofuran molecules induce site asymmetry around the [Cu2H2] unit, modulating both the local electronic environment and CO2 diffusion pathways. Using a multiscale computational approach that combines classical molecular mechanics, hybrid quantum mechanics/molecular mechanics molecular dynamics, and enhanced-sampling free energy calculations, we demonstrate how site asymmetry affects CO2 binding affinities and reaction pathways. These results provide detailed mechanistic insight into CO2 insertion and hydride transfer, highlighting key differences between crystal- and solution-phase pathways and offering a general framework for understanding how lattice confinement shapes chemical reactivity.