Hydrogen and halogen bonding in co-crystallization: from fundamentals to applications




Perera, Manomi Dharshika

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Kansas State University


The impact of the molecular electrostatic potential values (MEPs) in halogen and hydrogen bond interactions were explored using two acceptors with multiple acceptor sites with twelve hydrogen-bond donors, five halogen bond donors and four mixed halogen and hydrogen bond donors. The results suggested if the difference between the two acceptor sites is above 38 kJ/mol both hydrogen and halogen bond donors prefer the acceptor site with the highest MEP value and this selectivity was lost if the difference is below 26 kJ/mol. To examine the potential of halogen-bond donors in organocatalysis, a halogen-bond donor molecule was synthesized and the catalytic activity was measured using a benchmark Ritter type solvolysis reaction. Results suggested the catalytic activity of the halogen-bond donor molecule with > 90 % conversion of the product with the use of a stoichiometric amount of the catalyst for 96 hrs. Successful use of the control molecules confirm that the catalytic activity is an outcome of having halogen-bond donors in the molecule. The benefit of using a structural mimic in landscaping the structural outcomes of poorly soluble molecules was explored using an anticancer drug erlotinib. A structural mimic was synthesized by maintaining all binding sites that are important to design a structural landscape and the structural outcomes were analyzed using five FDA approved dicarboxylic acids. The results suggested that the structural outcomes of the mimic can be related to the actual drug erlotinib. Solubility and thermal behavior analysis of the co-crystals also suggested that with the systematic changes of the co-crystallization agent, it is possible to make predictable changes to the physical properties. To observe the effect of co-crystallization technology in reducing the chemical reactivity and sensitivity of an energetic compound dinitrobenzotriazole, a series of co-crystallization experiments was carried out using fourteen nitrogen and oxygen based acceptors. Four co-crystals were obtained and the acceptors were identified as supramolecular protecting groups which led to successful diminish of chemical instability and decreased impact sensitivity. Hygroscopicity and chemical reactivity of tetranitrobisimidazole, a potential RDX replacement, was successfully decreased by protecting the acidic N-H protons in the molecule by introducing suitable co-formers. Introduction of the N-oxide based acceptors into the system enhanced the stability while retaining most of the desirable energetic properties.



Hydrogen bonding, Halogen bonding, Co-crystallization

Graduation Month



Doctor of Philosophy


Department of Chemistry

Major Professor

Christer B. Aakeröy