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46011-AC1
Supramolecular Synthesis of Molecular Co-crystals: A Versatile Approach to Modulating Physical Properties of Functional Molecular Solids
Christer B. Aakeroy, Kansas State University
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.
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