Hydrophobic `lock and key' recognition of N-4-nitrobenzoylamino acid by strychnine

Abstract

During racemic resolution of N-4-nitrobenzoyl-DL-amino acids (alanine, serine and aspartic acid) by a fractional crystallization of strychninium salts, crystals of both diastereomeric salts were grown, and the crystal structures of strychninium N-4-nitrobenzoyl-L-alaninate methanol disolvate (1a), strychninium N-4-nitrobenzoyl-D-alaninate dihydrate (1b), strychninium N-4-nitrobenzoyl-D-serinate dihydrate (2a), strychninium N-4-nitrobenzoyl-L-serinate methanol solvate hydrate (2b), strychninium hydrogen N-4-nitrobenzoyl-L-aspartate 3.75 hydrate (3a) and strychninium hydrogen N-4-nitrobenzoyl-D-aspartate 2.25 hydrate (3b) were determined. The strychninium cations form corrugated layers, which are separated by hydrogen-bonded anions and solvent molecules. Common features of the corrugated layers are deep hydrophobic grooves at their surfaces, which are occupied by the 4-nitrobenzoyl groups of suitable anions. The hydrophobic ;lock and key' recognition of 4-nitrobenzoyl groups of amino acid derivatives in deep grooves of the strychnine self-assembly causes the resulting surface to have more hydrophilic properties, which are more appropriate for interactions in the hydrophilic environments from which strychninium salts were crystallized. In the crystal structure of (2a) and (3a), such hydrophobic ;lock and key' recognition is responsible for the lack of N-H+...O- hydrogen bonds that are usually formed between the protonated tertiary amine N atom of the strychninium cation and the deprotonated carboxyl group of the resolved acid. In the crystal structure of (2a) and (3a), the protonated amine N atom is a donor of hydrogen bonds, while the hydroxyl group of the serine derivative and water molecules are their acceptors. In light of the hydrophobic recognition, chiral discrimination depends on the nature of the hydrogen-bond networks, which involve anions, solvent molecules and the protonated amine N atom of strychninium cations.

Resolution of 2‐chloromandelic acid with (R)‐(+)‐N‐benzyl‐1‐phenylethylamine: chiral discrimination mechanism

“…This kind of packing mode was not very common in less soluble slats but was reported in a few papers. 14,19 Stacking of aromatic groups, CH/p interactions, and p/p interaction. CH/p interaction was conventionally believed to be very weak compared with hydrogen bond.…”

“…The crystal structure of the less soluble diastereomeric salt ( R )‐2‐ClMA·( R )‐BPA was obtained by single crystal X‐ray diffraction. The chiral discrimination mechanism was investigated by examining the weak intermolecular interactions in crystals, such as hydrogen bond, CH/π, and van der Waals interactions, and supramolecular packing mode, which is a promising approach employed by many researchers to explore the chiral recognition in diastereomeric salt resolution …”

“…The chiral discrimination mechanism was investigated by examining the weak intermolecular interactions in crystals, such as hydrogen bond, CH/p, and van der Waals interactions, and supramolecular packing mode, which is a promising approach employed by many researchers to explore the chiral recognition in diastereomeric salt resolution. [10][11][12][13][14][15] EXPERIMENTAL Materials (RS)-2-chloromandelic acid with 98% absolute purity, (R)-2-chloromandelic acid with 99% e.e. optical purity, (R)-(+)-N-benzyl-1-phenylethylamine, and (S)-(+)-N-benzyl-1-phenylethylamine with 99% e.e.…”

Chiral discrimination in diastereomeric salts of chlorine‐substituted mandelic acid and phenylethylamine

“…Much research has been conducted to investigate the stability difference between a pair of diastereomeric salts on the basis of crystal structures 4–14. The rationale has hinged on an expectation of getting valuable insight into chiral discrimination as well as for predicting and designing a suitable resolving agent for a given racemate.…”

“…The difference in stability between less and more soluble diastereomeric salts is largely dependent on the existence and/or magnitude of these three interactions. Among these interactions, the hydrogen‐bonding interaction is believed to account for much of the chiral discrimination 5, 9, 13. The hydrogen‐bonding patterns in structures of two distereomeric salt crystals are usually far from identical, whereas the hydrogen bonding patterns in less soluble salts with high resolution efficiency have similar characteristics 5, 8…”