Experimental and Theoretical Studies of Boronic Acids as a Co-Crystal Former

Sammanfattning: Multi-component molecular crystal materials have become a surging research subject due to their potential for applications in various fields such as pharmaceutics, energetic materials, electronics, etc. Their properties are governed by the arrangement of the constituent molecules and the various non-covalent interactions between them in their solid-state structure. Variation of the constituents based on their interactions can be used to design new materials with tailor made properties in so-called cocrystals, which is a strand of crystal engineering. There is always a demand for new functional groups that can form strong intermolecular interactions such as hydrogen bonds with target molecules in co-crystals, and thus form useful materials. The purpose of this thesis is to explore boronic acids (BA) as a potential co-crystal former in crystal engineering. The inspiration behind the choice of BA was that it can act as a hydrogen bond donor or hydrogen bond acceptor depending upon the complementarity with target molecules and their functional groups. Though BA shows flexibility in adopting different forms, they are not well explored in crystal engineering, especially the number of theoretical studies on BA are very limited.The main objective of this thesis is to gain fundamental understanding of the intermolecular interactions formed by BA such as 4-hydroxyphenylboronic acid (4HPBA) and 4-cyanophenylboronic acid (4CyBA), with traditional hydrogen bond forming potential constituents, of which we have studied 4,4’-bipyridine (bpy), 1,2-bis(4-pyridyl)ethene (bpyee), phenazine (Phen), 1,10-phenanthroline (110Phen), 4,7-phenanthroline (47Phen), and melamine (mel). We have then extended our study by using a bio-active entity, theophylline, as a co-crystal former with various BAs including 4HPBA, 4CyBA, 4-chlorophenylboronic acid (4ClBA), 4-bromophenylboronic acid (4BrBA) and 1,4-phynelendiboronic acid (4BDBA) to improve its stability against humidity. Theophylline is an active pharmaceutical ingredient (API) known for its application in the treatment of acute asthma and in tumor therapy. The solid state structures were determined experimentally using single crystal X-ray diffraction (SXRD). In addition, powder X-ray diffraction (PXRD) and thermogravimetric analysis (TGA) was further used to perform more detailed analyses. These studies were extended by theoretical simulations of intermolecular interaction energies and lattice energies using density functional theory (DFT). The interaction energies were simulated with gas phase simulations using PBE and B3LYP functional using Grimme’s dispersion correction (DFT-D3). While periodic DFT was used to simulate lattice energy and to analyze the interaction energies in detail to establish viable design strategies for new co-crystal materials.Our crystal structure analysis shows that BA prefers to form hydrogen bonds with complementary functional groups rather than interacting with another BA, which can be utilized in design of new multicomponent complexes. This study has also shown that BA competes with phenols, which are well studied in crystal engineering, in forming hydrogen bonds with other co-crystal formers. The interaction energies and electron localization function (ELF) analyses are used to find the strength of the various hydrogen bonds present in the crystal lattice. The lattice energy simulations using periodic DFT has shown the stability of complexes over their single component counterparts. This thesis demonstrates the ability of BA as a potential co-crystal former in the crystal engineering field. It also illustrates that experimental studies along with computational modelling gives good understanding of the structural aspects of a complex which can further be implemented to design new materials.Keywords: crystal engineering, boronic acids, X-ray diffraction, DFT, lattice energies,