Molecular Recognition and Shape Studies of 3- and 4-Substituted Diarylamide Quasiracemates

Abstract

Families of quasiracemic materials constructed from 3- and 4-substituted chiral diarylamide molecular frameworks were prepared, where the imposed functional group differences systematically varied from H to CF3–9 unique components for each isomeric framework. Cocrystallization from the melt via hot stage thermomicroscopy using all possible racemic and quasiracemic combinations probed the structural boundaries of quasiracemate formation. The crystal structures and lattice energies (differential scanning calorimetry and lattice energy calculations) for many of these systems showed that quasienantiomeric components organize with near inversion symmetry and lattice energetics closely resembling those found in the racemic counterparts. This study also compared the shape space of pairs of quasienantiomers using an in silico alignment-based method to approximate the differences in molecular shape and provide a diagnostic tool for quasiracemate prediction. Comparing these results to our recent report on related 2-substituted diarylamide quasiracemates shows that functional group position can have a marked effect on quasiracemic behavior and provide critical insight to a more complete shape space, essential for defining molecular recognition processes.

Benzoyl Valine Quasiracemates: Pairing CF3 Quasienantiomers with H to t-Butyl

“…Similar to recent reports from our group describing the quasiracemic behavior of 2, 3 and 4-substituted diarylamide 18,19 (2), 4-substituted naphthylamide 20 (3) and 4substituted benzoyl leucine/phenylalanine 21 (4) systems, the framework based on 1 consists of chiral components (valine) and easily derivatized benzoyl components in the 4-position that, together, promote the construction of homologous sets of quasienantiomeric building blocks. Progress from using molecular architectures based on 2 and 3 to benzoyl valine 1 offers a fundamental change in the quasiracemate design approach, where increased crystal lattice stabilization is achieved by creating more extensive hydrogen-bond networks via an added carboxyl group.…”

“…Since processing the crystallographic data requires removing the atoms responsible for the molecular difference, alternative methods are needed that allow for the variation in quasiracemic components. Our recent efforts in this area showed the value of using an in-silico method based on a 3D grid approach . The development of this diagnostic tool for comparing the shape space of pairs of quasienantiomers is ongoing and will be the focus of a future report.…”

Dual space divergence in small molecule quasiracemates: benzoyl leucine and phenylalanine assemblies

“…The challenge arises in the design stage, where the inherent flexibility of the term quasiracemate -equimolar ratios of chemically unique compounds of opposite handedness -intentionally lacks details of the chemical frameworks, functional groups and structural difference limitations needed for successful quasiracemate formation. Literature reports suggest that the structural variation between small molecule quasienantiomers occurs at only one site with a relatively minor imposed structural difference -e.g., Cl/Br [21][22][23][24][25] and CH 3 /Cl 21,23,26 represent common pairings. Though this strategy continues to show success with quasiracemate assembly, it also presents questions relating to a broader understanding of the term quasiracemate and the degree of structural tolerance permitted during quasiracemate assembly.…”

“…Literature reports suggest that the structural variation between small molecule quasienantiomers occurs at only one site with a relatively minor imposed structural difference – e.g. , Cl/Br 21–25 and CH 3 /Cl 21,23,26 represent common pairings. Though this strategy continues to show success with quasiracemate assembly, it also presents questions relating to a broader understanding of the term quasiracemate and the degree of structural tolerance permitted during quasiracemate assembly.…”

“…1), the leucine and phenylalanine systems include additional functionalization using the CH 3 /Cl (%DV = 4.0) and H/ CF 3 (%DV = 138.7) substituent pairs. While CH 3 /Cl 21,23,26 are familiar group selections with only modest size and shape space differences, the H/CF 3 combination is absent in small molecule quasiracemates, likely owing to their considerable topological differences. The design element using two sites of chemical difference provides an opportunity to examine sizable families of ten cocrystalline materials that differ iteratively in their shape space and pendant functional groups X and X 0 , where X/X 0 represents the CH 3 /Cl and H/CF 3 pairings.…”