Henderson Alistair P, Bleasdale Christine, Clegg William, Golding Bernard T
School of Natural Sciences--Chemistry, Bedson Building, University of Newcastle upon Tyne, Newcastle upon Tyne NE1 7RU, United Kingdom.
Chem Res Toxicol. 2004 Mar;17(3):378-82. doi: 10.1021/tx034177t.
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.
戊二醛与弱亲核性的苯胺（例如3-氟-4-硝基苯胺，它是DNA中氨基的模型）反应，生成内消旋-2,6-二取代四氢吡喃（例如内消旋-2,6-二-(3-氟-4-硝基苯胺基)四氢吡喃），通过光谱和X射线晶体结构分析对其进行了表征。这与与更强亲核性胺反应的结果形成对比，更强亲核性胺反应会生成N-取代的1,4-二氢吡啶。四氢吡喃的形成机制被认为涉及胺对戊二醛的一个醛基的初始进攻，生成一个甲醇胺中间体。随后环化生成四氢吡喃，而不是脱水生成亚胺进而生成二氢吡啶，这是由于甲醇胺氨基官能团的孤对电子与羟基的两个孤对电子之间的竞争。低亲核性的氨基官能团更易形成四氢吡喃，而高亲核性的氨基官能团更倾向于脱水生成亚胺进而生成二氢吡啶。四氢吡喃的形成可能通过为DNA加合或DNA-蛋白质交联提供机制基础，与戊二醛的毒理学相关。
