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

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Abstract

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-((4R)-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{(1R,E)-1-(pyridin-2-yl)-N-(1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene)ethylamine}zinc (RE-PIC-Zn) and dichloro{(1S,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 (Ecoh) 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 Ecoh values of diastereopure SE-PIC-Zn and RE-PIC-Zn were −45.8 and −44.4 kcal mol−1, respectively. The Ecoh values of the diastereomeric mixture crystal (RE-PIC-Zn·SE-PIC-Zn·2CHCl3) and its virtual counterpart lacking CHCl3 (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.

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

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Publication details

The article was received on 08 May 2019, accepted on 10 Jul 2019 and first published on 11 Jul 2019


Article type: Research Article
DOI: 10.1039/C9QI00523D
Inorg. Chem. Front., 2019, Advance Article

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

    J. Cho, J. H. Jeong, M. W. Lee and Y. K. Kang, Inorg. Chem. Front., 2019, Advance Article , DOI: 10.1039/C9QI00523D

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