46011-AC1
Supramolecular Synthesis of Molecular Co-crystals: A Versatile Approach to Modulating Physical Properties of Functional Molecular Solids
Tailoring the properties of a bulk material such as a pharmaceutical compound, through non-covalent interactions, could lead to the enhancement of its physical properties without chemically modifying the individual molecules themselves.� In order to obtain a degree of control and reliability of these non-covalent interactions, we must develop a library of synthons based upon patterns of non-covalent interactions between molecules.
� We have focused on three areas during the first year of this grant; (I) Synthesis of co-crystals using carefully designed supramolecular reagents (SR's); (II) Solvent-free grinding techniques in the preparation of these crystalline materials; (III) Semi-empirically derived electrostatic potential surfaces as guidelines for hydrogen-bond driven supramolecular assembly�
� A family a N-heterocyclic amides were synthesized and an assessment of their binding selectivities was made, by evaluation of the supramolecular yield, (the frequency of occurrence of the desired connectivities).� It was found that the supramolecular yield increased with increasing basicity of the heterocyclic nitrogen atom.� However, there is a point at which the heterocycle becomes basic enough to produce salts, which often leads to unpredictable connectivity and stoichiometry.
� Once the effectiveness of the N-heterocyclic amides as supramolecular reagents was established, a series of more closely-related ditopic hydrogen-bond acceptor molecules were synthesized.� The supramolecular reagents contained imidazole and pyridine binding sites, so that the two sites differ in terms of their basicity and geometry.� An assessment of the ability of these molecules to induce selectivity when a hydrogen bond donor such as a cyanoxime or a carboxylic acid is introduced was made.� A total of nineteen crystal structures were obtained, of which one yielded a salt with unpredictable connectivity, and eighteen were co-crystals.� Ten of these were 2:1 co-crystals, which shows that the two sites are accessible for binding.� Eight were 1:1 stoichiometry, with five out of eight (63%) forming a hydrogen bond to the best acceptor.� In addition, a series of molecular electrostatic potential calculations were employed to investigate the binding preferences and probe the best donor/best acceptor hypothesis.� A ternary supermolecule was also constructed from a central, asymmetric hydrogen-bond acceptor and two different hydrogen-bond donor molecules.� It was found that the best donor, the cyanoxime, bound to the best acceptor, the imidazole nitrogen atom, while the second best donor, a carboxylic acid, bound to the second best acceptor.� The calculated molecular electrostatic potential values were used to rationalize this event.
� A series of substituted cyanophenyloxime, hydrogen bond donor molecules were synthesized and their effectiveness at forming co-crystals was examined.� It was found that simple R group substitution could have a significant effect upon the co-crystal forming ability of the hydrogen bond donors, having improved the yield from 4% and 7% in a series of co-crystallizations with closely-related oximes, to 96% with the�� cyanoximes.
� A series of di- and tritopic cyanoximes were synthesized and an assessment of their co-crystal-forming ability was made.� They were found to be equally effective at producing co-crystals as the monotopic cyanoximes, having done so in 23 out of 24 cases.� In contrast to their carboxylic acid counterparts, the polycyanoximes also exhibited excellent solubility.�
