Intramolecular noncovalent C-bonding driven conformational preference in spiroisatin-based N-acyl hydrazones

Abstract

Noncovalent carbon bonding (C-bonding), a recently explored σ-hole interaction, has primarily been characterized through X-ray structural and computational studies. Evidence of C-bonds in solution is scarce, especially in highly polar solvents like DMSO where solvation effects typically overshadow weak non-covalent interactions. In this work, we present three novel spiroisatin-based N-acyl hydrazones (1–3) in which C-bonds play a critical role in stabilizing the cis conformation in solution. Despite the steric preference for the NH–amide bond to adopt the trans geometry (H–N–CO ≈ 180°), ¹H and ¹³C NMR spectra of compounds 1 and 2 in DMSO-d₆ reveal a rotameric mixture with a higher percentage of the cis conformation (82% and 76%, respectively), attributed to the stability provided by intramolecular C-bonding. Compound 3 also predominantly adopts the cis conformation in DMSO but to a lesser extent (60%) than compounds 1 and 2, due to competing intramolecular hydrogen bonding. Single-crystal X-ray analysis of compounds 1 and 2 confirmed the cis conformation, consistent with the solution-state preference. In contrast, compound 3 crystallized in the trans form, likely due to intramolecular hydrogen bonding and solid-state packing effects, which reinforce the steric preference for the trans geometry. Density functional theory (DFT) calculations corroborated the experimental data, predicting greater stability for the cis conformations in compounds 1, 2, and 3 in solution. The ability of intramolecular C-bonding to stabilize the cis conformation, even in highly polar solvents like DMSO, highlights the broader significance of this interaction in supramolecular chemistry and related fields.