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Amide pyramidalization in carbamazepine: a flexibility problem in crystal structure prediction?

Amide pyramidalization in carbamazepine: a flexibility problem in crystal structure prediction?
Amide pyramidalization in carbamazepine: a flexibility problem in crystal structure prediction?
Carbamazepine is known to exist in various polymorphic forms. Here we report on crystal structure prediction calculations for carbamazepine in an attempt to examine the predictability and relative stability of the various polymorphs. Hypothetical crystal structures generated in 10 of the most common space groups were compared to the observed polymorphs. Particular attention has been given to the influence of amide pyramidalization on the relative energies of the predicted structures. While the actual generation of possible crystal structures was found to be independent of the degree of deformation of the amide group, their final ranking in energy was greatly affected by pyramidalization of the amide nitrogen. This effect was examined in detail through systematic variation of the NH2 geometry for each of the low-energy crystal structures; different amide geometries were favored in the various low-energy crystal structures. The results demonstrate that energetically feasible deformation of the amide group may occur in order to optimize hydrogen-bond interactions, and we conclude that neglect of amide pyramidalization introduces significant errors in crystal structure prediction for carbamazepine and similar molecules.
1528-7483
1858-1866
Cruz Cabeza, Aurora J.
132b18f8-54d3-4eaa-b783-9c629b6fcff7
Day, Graeme M.
e3be79ba-ad12-4461-b735-74d5c4355636
Motherwell, W.D. Samuel
1eaf126c-8f3a-45b7-8a98-4a0493ee838e
Jones, William
3173abf0-1cfa-45f0-996e-2586b385c21e
Cruz Cabeza, Aurora J.
132b18f8-54d3-4eaa-b783-9c629b6fcff7
Day, Graeme M.
e3be79ba-ad12-4461-b735-74d5c4355636
Motherwell, W.D. Samuel
1eaf126c-8f3a-45b7-8a98-4a0493ee838e
Jones, William
3173abf0-1cfa-45f0-996e-2586b385c21e

Cruz Cabeza, Aurora J., Day, Graeme M., Motherwell, W.D. Samuel and Jones, William (2006) Amide pyramidalization in carbamazepine: a flexibility problem in crystal structure prediction? Crystal Growth & Design, 6 (8), 1858-1866. (doi:10.1021/cg0601756).

Record type: Article

Abstract

Carbamazepine is known to exist in various polymorphic forms. Here we report on crystal structure prediction calculations for carbamazepine in an attempt to examine the predictability and relative stability of the various polymorphs. Hypothetical crystal structures generated in 10 of the most common space groups were compared to the observed polymorphs. Particular attention has been given to the influence of amide pyramidalization on the relative energies of the predicted structures. While the actual generation of possible crystal structures was found to be independent of the degree of deformation of the amide group, their final ranking in energy was greatly affected by pyramidalization of the amide nitrogen. This effect was examined in detail through systematic variation of the NH2 geometry for each of the low-energy crystal structures; different amide geometries were favored in the various low-energy crystal structures. The results demonstrate that energetically feasible deformation of the amide group may occur in order to optimize hydrogen-bond interactions, and we conclude that neglect of amide pyramidalization introduces significant errors in crystal structure prediction for carbamazepine and similar molecules.

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e-pub ahead of print date: 27 June 2006
Organisations: Organic Chemistry: Synthesis, Catalysis and Flow, Chemistry, Computational Systems Chemistry

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Local EPrints ID: 343452
URI: http://eprints.soton.ac.uk/id/eprint/343452
ISSN: 1528-7483
PURE UUID: dec71d0d-b5ce-4851-852e-74ec1397a3b1
ORCID for Graeme M. Day: ORCID iD orcid.org/0000-0001-8396-2771

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Date deposited: 05 Feb 2013 13:41
Last modified: 17 Dec 2019 01:38

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Contributors

Author: Aurora J. Cruz Cabeza
Author: Graeme M. Day ORCID iD
Author: W.D. Samuel Motherwell
Author: William Jones

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