M. Centnerszwer's seminal 1899 report investigated the stereochemical relationship between optical antipodes of different substances using melting-point behavior. One intriguing melting-point phase diagram produced from this early investigation combined (+)-2-chlorosuccinic acid [(+)- 1 ] and (−)-2-bromosuccinic acid [(−)- 2 ]. While Centnerszwer's data clearly indicates the formation of a quasiracemic phase – i.e. , materials constructed from pairs of isosteric molecules of opposite handedness – at the 1 : 1 component ratio, this material is energetically less favorable than the chiral counterparts. The consequence of this crystal instability is significant as evident by the absence of literature sited crystal structures for the quasiracemic phase (+)- 1 /(−)- 2 and racemates (±)- 1 and (±)- 2 . This study circumvented this challenge by generating multi-molecular assemblies using additional crystallizing agents capable of complementing the hydrogen-bond abilities of succinic acids 1 and 2 . Both imidazole (Im) and 4,4′-bipyridyl- N , N ′-dioxide (BPDO) served as tailor-made additives that effectively modified the crystal packing landscape of quasiracemate of (+)- 1 /(−)- 2 . Combining imidazole with the quasiracemate, racemate, and enantiopure forms of 1 and 2 resulted in crystal structures characterized as molecular salts with layered motifs formed from highly directional N + –H⋯carboxylate and carboxyl⋯carboxylate interactions. In contrast to the enantiopure [(+)- 1 ·Im and (−)- 2 ·Im] and racemic [(±)- 1 ·Im and (±)- 2 ·Im] systems, neighboring molecular layers observed in quasiracemate (+)- 1 /(−)- 2 ·Im are organized by approximate inversion symmetry. Assessment of the crystal packing efficiency for this series of molecular salts via crystal densities and packing coefficients ( C k ) indicates imidazole greatly alters the crystal landscape of the system in favor of racemic and quasiracemic crystal packing. A similar desymmetrized crystal environment was also realized for the ternary cocrystalline system of (+)- 1 /(−)- 2 ·BPDO where the components organize via N + –O − ⋯carboxyl contacts. This study underscores the importance of molecular shape to molecular recognition processes and the stabilizing effect of tailor-made additives for creating new crystalline phases of previously inaccessible crystalline materials.
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Amino acid hydrogen oxalate quasiracemates – hydrocarbon side chains
Amino acid quasiracemates – generated from the assembly of pairs of chemically distinct amino acids of opposite handedness – continue to provide important opportunities to understand how self-assembly can be promoted despite using components with drastically different sizes and molecular shapes. Previous studies by Görbitz et al. and others cataloged 32 crystal structures of amino acid quasiracemates, with each showing the building blocks aligned with near inversion symmetry similar to their racemic counterparts. This investigation examined the impact of using a secondary coformer molecule, hydrogen oxalate, on the cocrystalline landscape of amino acid quasiracemates with hydrocarbon side chains. Eight racemic (4) and quasiracemic (4) hydrogen oxalate structures were generated. Crystal structures of these systems show the hydrogen oxalate moieties assembled into C(5) molecular columns by the construction of robust O–H⋯O − hydrogen bonds with the amino acid enantiomers and quasienantiomers linked to these column motifs using a complex blend of N + –H⋯O − , O–H⋯O − , and N + –H⋯OC contacts. The racemates and quasiracemates form similar packing motifs; however, due to the chemically non-identical nature of the quasiracemic components, the outcome is that the amino acids organize with near inversion symmetry. Both the conformational similarity ( χ RMS ) and degree of inversion symmetry ( C i ) of related pairs of quasienantiomeric components have been systematically assessed using readily available structural tools. This study shows how coformer molecules such as hydrogen oxalate can provide new and critical insight into the molecular recognition process of quasiracemic materials.
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- NSF-PAR ID:
- 10338134
- Date Published:
- Journal Name:
- CrystEngComm
- Volume:
- 23
- Issue:
- 46
- ISSN:
- 1466-8033
- Page Range / eLocation ID:
- 8053 to 8060
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Abstract Proline residues within proteins lack a traditional hydrogen bond donor. However, the hydrogens of the proline ring are all sterically accessible, with polarized C−H bonds at Hα and Hδ that exhibit greater partial positive character and can be utilized as alternative sites for molecular recognition. C−H/O interactions, between proline C−H bonds and oxygen lone pairs, have been previously identified as modes of recognition within protein structures and for higher‐order assembly of protein structures. In order to better understand intermolecular recognition of proline residues, a series of proline derivatives was synthesized, including 4
R ‐hydroxyproline nitrobenzoate methyl ester, acylated on the proline nitrogen with bromoacetyl and glycolyl groups, and Boc‐4S ‐(4‐iodophenyl)hydroxyproline methyl amide. All three derivatives exhibited multiple close intermolecular C−H/O interactions in the crystallographic state, with H⋅⋅⋅O distances as close as 2.3 Å. These observed distances are well below the 2.72 Å sum of the van der Waals radii of H and O, and suggest that these interactions are particularly favorable. In order to generalize these results, we further analyzed the role of C−H/O interactions in all previously crystallized derivatives of these amino acids, and found that all 26 structures exhibited close intermolecular C−H/O interactions. Finally, we analyzed all proline residues in the Cambridge Structural Database of small‐molecule crystal structures. We found that the majority of these structures exhibited intermolecular C−H/O interactions at proline C−H bonds, suggesting that C−H/O interactions are an inherent and important mode for recognition of and higher‐order assembly at proline residues. Due to steric accessibility and multiple polarized C−H bonds, proline residues are uniquely positioned as sites for binding and recognition via C−H/O interactions.
- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1039/D1CE01213D
