Conformational Analysis of Diastereomeric a-Amino Nitriles

Rumiko SAKURAIa †, Akira UCHIDAb, Tetsutaro HATTORIa* and Masanori YAMAURAc

aGraduate School of Environmental Studies, Tohoku University
6-6-11 Aramaki-Aoba, Aoba-ku, Sendai 980-8579, Japan
bFaculty of Science, Toho University
2-2-1 Miyama, Funabashi 274-8510, Japan
cFaculty of Pharmacy, Iwaki Meisei University
5-5-1 Iino, Chuodai, Iwaki 970-8551, Japan

(Received: July 1, 2008; Accepted for publication: September 16, 2008; Advance publication: November 4, 2008)

Conformational analysis of diastereomeric a-amino nitriles [1S,2R,(S)]- and [1S,2R,(R)]-N-cyanophenylmethyl-1-aminoindan-2-ol [(S)-1 and (R)-1] has been carried out at the DFT B3LYP/6-31G* level. It was found that these compounds consist of tens of conformers: There are three stable conformations S1-S3 for (S)-1 within a narrow energy window (0.4 kcal/mol) with the population being 43% (S1), 24% (S2), and 22% (S3), respectively (Table 1). On the other hand, the global minimum conformation of (R)-1 (R1) is more than 1.51 kcal/mol more stable than the other conformations and occupies 76% of the population (Table 2). The difference in the total energy between the two diastereomers is small (DE = -0.09 kcal/mol), which is in reasonable agreement with the fact that the two diastereomers equilibrate with a ratio of 50:50 in DMSO. On the contrary, it has been shown that (S)-1 is more stable than (R)-1 in the crystal form. The crystal-state conformation of (S)-1 (S0) determined by an X-ray crystallographic analysis agrees well with S3 (Figure 1, Table 3). In the crystals, one molecule binds to four neighboring molecules with hydrogen bonds (Figure 2b). In addition, the crystal density of (S)-1 is higher than that of (R)-1. These observations suggest that the S3 molecules are packed tightly together to form, with assistance of the intermolecular hydrogen bonds, a stable crystal. On the other hand, the crystal-state conformation of (R)-1 (R0) is different from R1 with regard to the conformation of the phenyl moiety, as well as the mode of an intramolecular hydrogen bond (Figure 1, Table 3). Taking account of the low crystal density of (R)-1, it seems that R1 is not likely to crystallize in its conformation. Therefore, the R1 molecules are assumed to change the conformation and the hydrogen-bond mode upon crystallization to narrowly form a not so stable crystal.

Keywords: Conformation analysis, Crystal structure, Packing force, Hydrogen bond


Present affiliation: Faculty of Pharmacy, Iwaki Meisei University
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