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Chem Res Toxicol. 2004 Mar;17(3):378-82.

2,6-diarylaminotetrahydropyrans from reactions of glutaraldehyde with anilines: models for biomolecule cross-linking.

Author information

1
School of Natural Sciences--Chemistry, Bedson Building, University of Newcastle upon Tyne, Newcastle upon Tyne NE1 7RU, United Kingdom. alistair@email.unc.edu

Abstract

Glutaraldehyde reacts with weakly nucleophilic anilines, e.g., 3-fluoro-4-nitroaniline, which are models for amino groups in DNA, to give meso-2,6-disubstituted tetrahydropyrans, e.g., meso-2,6-di-(3-fluoro-4-nitroanilino)tetrahydropyran, that were characterized spectroscopically and by X-ray crystal structure analysis. This contrasts with the outcome of reactions with more strongly nucleophilic amines, which give rise to N-substituted 1,4-dihydropyridines. The mechanism of formation of the tetrahydropyrans is proposed to involve initial attack of the amine on one of the aldehyde groups of glutaraldehyde to give a carbinolamine intermediate. The ensuing cyclization to a tetrahydropyran, rather than dehydration to an imine leading to a dihydropyridine, is explained as a result of a competition between the lone pair of the amino function of the carbinolamine and the two lone pairs of the hydroxyl group. The formation of the tetrahydropyran is more likely with an amino function of low nucleophilicity, whereas dehydration to an imine leading to a dihydropyridine is favored with an amino function of higher nucleophilicity. The formation of tetrahydropyrans may be relevant to the toxicology of glutaraldehyde by providing a mechanistic basis for DNA adduction or DNA-protein cross-linking.

PMID:
15025508
DOI:
10.1021/tx034177t
[Indexed for MEDLINE]

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