Electrostatic Potential Differences and Halogen-Bond Selectivity

Molecular electrostatic potential based guidelines for selectivity of halogen-bond interactions were explored via systematic co-crystallizations of 9 perfluorinated halogen-bond donors and 12 ditopic acceptors presenting two binding sites with different electrostatic potentials. A total of 89 of the 108 reactions resulted in co-crystal formation (as indicated by IR spectroscopy), and 35 new crystal structures were obtained. Methanol was exclusively used as a solvent for crystal growth in order to avoid any potential solvent–solute bias throughout these experiments. The structures were organized into three different groups depending upon the specific nature of the observed halogen-bond connectivities in each case. The electrostatic potential difference between the two acceptor sites on each molecule was defined as the Δ E value. Group 1 comprised acceptor molecules with a Δ E value below 35 kJ/mol units, and in this category halogen bonding took place on both binding sites in all co-crystals (9/9). Ditopic acceptor molecules in Group 2 were characterized by a Δ E value in the 35–65 kJ/mol range, and in this group half the structures showed halogen bonding to the best acceptor (11/22) and half the structures showed halogen bonding to both binding sites (11/22). In Group 3 the Δ E value was >167 kJ/mol, and in all of the co-crystals found herein (7/7), the halogen-bond donor favored the best acceptor site. These results allow us to propose some tentative guidelines and rationales for halogen-bond preferences in competitive systems. If Δ E < 35 kJ/mol, the electrostatic potential difference is not large enough to allow the donor molecules to form halogen bonds of sufficiently different thermodynamic strength to result in any pronounced molecular recognition preference (typically both, or several acceptors are then engaged in halogen bonding). Upon the basis of data produced in this study, in combination with relevant structures from the Cambridge Structural Database, it seems reasonable to suggest that if the Δ E value between two geometrically accessible halogen-bond acceptor sites is greater than 75 kJ/mol, the thermodynamic advantage of forming halogen bonds to the best acceptor provides a strong enough driving force that the best donor consistently interacts with the best acceptor; intermolecular selectivity is the result. However, if the Δ E resides between these two proposed boundaries, the outcome is unpredictable, and other factors are then likely to be responsible for the path that a particular supramolecular reaction will follow.