Interrogation of fractional crystallization behavior of a newly exploited chiral resolution method for racemic 1-(pyridin-2-yl)ethylamine DFT-D3 calculations of cohesive energy

• Published in: Inorganic chemistry frontiers Vol. 6; no. 9; pp. 2325 - 2338
• Main Authors: Cho, Juhyun, Jeong, Jong Hwa, Lee, Myung Won, Kang, Youn K
• Format: Journal Article
• Published: 10.09.2019
• ISSN: 2052-1553
• DOI: 10.1039/c9qi00523d

A novel chiral resolution method for racemic 1-(pyridin-2-yl)ethylamine ( PEA ) was developed in this study. Sequential conversion of 1-(pyridin-2-yl)ethylamine to 1-(pyridin-2-yl)- N -((4 R )-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene)ethylamine ( PIC ) and to dichloro{( E )-1-(pyridin-2-yl)- N -(1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene)ethylamine}zinc ( PIC-Zn ) allowed for the spontaneous separation of dichloro{(1 R , E )-1-(pyridin-2-yl)- N -(1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene)ethylamine}zinc ( RE-PIC-Zn ) and dichloro{(1 S , E )-1-(pyridin-2-yl)- N -(1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene)ethylamine}zinc ( SE-PIC-Zn ) by fractional crystallization. The overall yields of both ( S )- and ( R )- PEA were 24.8% with estimated ee values of 98 and 99%, respectively. The preferred formation of diastereopure crystals over that of diastereomeric mixture crystals was interrogated by comparing the cohesive energies ( E coh ) of the respective crystals, as obtained via DFT calculations under periodic boundary conditions with a plane wave basis set based on the experimentally determined X-ray crystallographic structure. The E coh values of diastereopure SE-PIC-Zn and RE-PIC-Zn were −45.8 and −44.4 kcal mol −1 , respectively. The E coh values of the diastereomeric mixture crystal ( RE-PIC-Zn·SE-PIC-Zn·2CHCl 3 ) and its virtual counterpart lacking CHCl 3 ( RE-PIC-Zn·SE-PIC-Zn ) were −56.0 and −37.2 kcal mol −1 , respectively. These data provided the background underlying the spontaneous segregation of the diastereopure crystals where the energy preference for forming diastereopure crystals over their corresponding diastereomeric mixture crystals is ca . 8 kcal mol −1 . A novel chiral separation method for 1-(pyridin-2-yl)ethylamine is developed and the underlying energetics is investigated by DFT-D3.