Quantifying Homo‐ and Heteromolecular Hydrogen Bonds as a Guide for Adduct Formation

An investigation into the predictability of molecular adduct formation is presented by using the approach of hydrogen bond propensity. Along with the predictions, crystallisation reactions ( 1a – 1j ) were carried out between the anti‐malarial drug pyrimethamine ( 1 ) and the acids oxalic ( a ), malonic ( b ), acetylenedicarboxylic ( c ), adipic ( d ), pimelic ( e ), suberic ( f ), azelaic acids ( g ), as well as hexachlorobenzene ( h ), 1,4‐diiodobenzene ( i ), and 1,4‐diiodotetrafluorobenzene ( j ); seven ( 1a to 1g ) of these successfully formed salts. Five of these seven salts were found to be either hydrated or solvated. Hydrogen bond propensity calculations predict that hydrogen bonds between 1 and acids a – g are more likely to form rather than the H bonds involved in self‐association, providing a rationale for the observation of the seven new salts. In contrast, propensity of hydrogen bonds between 1 and h – j is much smaller as compared to other bonds predicted for self‐association/solvate formation, in agreement with the observed unsuccessful reactions.