The nature and strength of weak C–H⋯F–C and C–F⋯F–C interactions and their role in organofluorine molecular crystals were studied using periodic DFT coupled with CSD data mining and experimental sublimation enthalpies.

The QM/MM simulations followed by electron density feature analysis are carried out to deepen the understanding of the reaction mechanism of cephalosporin hydrolysis in the active site of the L1 metallo-β-lactamase. The differences in reactivity of ten similar cephalosporin compounds are explained by using an extended set of bonding descriptors. The limiting step of the reaction is characterized by the proton transfer to the nitrogen atom of the cephalosporin thiazine ring accompanied with formation of the C₄ C₃ double bond in its N–C₄–C₃ fragment. The temporary N⋯H–O_w hydrogen bond, which is formed in the transition state of the limiting step of the reaction was recognized as a key atomic interaction governing the reactivity of various cephalosporins. Non-local real-space bonding descriptors show that different extent of localization of electron lone pair at N atom in the transition state affect the reactivity of compounds: smaller electron localization is typical for the less reactive species. In particular, the Fermi hole analysis shows how exchange electron correlation in the N⋯H–O_w fragment control electron lone pair localization. Delocalization tensor, linear response kernel and source function indicate that features of electron delocalization in the N–C₄–C₃ fragment of cephalosporins in the transition state complexes determine the differences in C₄–C₃ bond for substrates with high and low rate constants. The C₄–C₃ bond of the N–C₄–C₃ fragment at the transition state is similar to that of the preceding intermediate for the less reactive species and resembles the features of the enzyme–product complex for more reactive compounds. The power and limitations of the descriptors applied for solving the problem are discussed and the generality of approach is stressed.