Beyond the Isolated Halogen-Bond Dimer: Cooperative and Anticooperative Motifs in C6F4I2···HMTA.

Abstract

Halogen bonding (XB) is often analyzed in terms of isolated dimers, yet under realistic solution conditions, it coexists with a dense, rapidly fluctuating network of weaker contacts whose net effect on bond strength is difficult to quantify. Here, we combine gas-phase quantum-chemical calculations with explicit-solvent ab initio molecular dynamics (AIMD) in chloroform to dissect how specific noncovalent interactions modulate the I···N halogen bond in ortho-, meta-, and para-C6F4I2···HMTA complexes. Gas-phase DFT, Quantum Theory of Atoms in Molecules (QTAIM), Natural Bond Orbital (NBO), and SAPT0 analyses show that the intrinsic I···N bond in the three isomers is relatively strong and nearly degenerate, with equilibrium distances around 2.83 Å and very similar electronic descriptors. In contrast, AIMD in CHCl3 reveals that the solution-phase geometry reflects a dynamic balance between frequent, short-lived C-H···N contacts to HMTA, which act anticooperatively and lengthen the halogen bond by ≈0.02-0.05 Å, and less populated but more cooperative donor-side C-H···I and C-H···F contacts to the C6F4I2 fragment, which shorten it by up to ≈0.05 Å. A contact-resolved and microstate-based analysis shows that each isomer samples a small number of recurrent solvation motifs with characteristic patterns of C-H···N/C-H···I/C-H···F coordination, and that the relative populations of these motifs control the average I···N distance in solution. Targeted cluster calculations containing only one additional interaction at a time demonstrate that extra C-I···N halogen bonds are intrinsically anticooperative toward the primary I···N bond, whereas C-H···F hydrogen bonding, π···π stacking, and especially C-H···I contacts provide genuine cooperative reinforcement, in line with the trends observed in AIMD. Together, these results establish a quantitative solution-phase hierarchy of cooperative and anticooperative motifs around σ-hole donors and rationalize why gas-phase dimers systematically overestimate halogen-bond robustness relative to chloroform solution, where anticooperative C-H···N hydrogen bonding is ubiquitous. More broadly, the combination of explicit-solvent AIMD with contact-resolved and microstate-based analysis provides a transferable framework for dissecting environmental cooperativity in halogen-bonded and other σ-hole-driven assemblies in liquid phases.