Direct S(N)2 or S(N)2X Manifold-Mechanistic Study of Ion-Pair-Catalyzed Carbon(sp(3))-Carbon(sp(3)) Bond Formation

Density functional theory (DFT) is used in this work to predict the mechanism for constructing congested quaternary-quaternary carbon(sp(3))-carbon(sp(3)) bonds in a pentanidium-catalyzed substitution reaction. Computational mechanistic studies were carried out to investigate the proposed S(N)2X manifold, which consists of two primary elementary steps: halogen atom transfer (XAT) and subsequent S(N)2. For the first calculated model on original experimental substrates, XAT reaction barriers were more kinetically competitive than an S(N)2 pathway and connect to thermodynamically stable intermediates. Extensive computational screening modeling was then done on various substrate combinations designed to study the steric influence and to understand the mechanistic rationale, and calculations reveal that sterically congested substrates prefer the S(N)2X manifold over S(N)2. Different halides as leaving groups were also screened, and it was found that the reactivity increases in the order of I > Br > Cl > F, in agreement with the strength of C-X bonds. However, DFT modeling suggests that chlorides can be a viable substrate for the S(N)2X process, which should be further explored experimentally. ONIOM calculations on the full catalyst model predicted the correct stereochemical outcome, and further catalyst screening with cationic Me4N+ and K+ predicted that pentanidium is still the choice for S(N)2X C-C bond formation.