When an amide group is distorted from its planar conformation, the conjugation between the nitrogen lone pair and the π* orbital of the carbonyl is disrupted and the reactivity towards nucleophiles is enhanced. Although there are several reports on the synthesis of activated twisted amides, amide activation through mechanical twisting is much less common. Here, we report twisted amides that are stabilized through their inclusion in a self-assembled coordination cage. When secondary aromatic amides are included in a Td-symmetric cage, the cis-twisted conformation is favoured over the trans-planar one—as evidenced by single-crystal X-ray diffraction analysis—revealing that the amide can twist by up to 34°. As a consequence of this distortion, the hydrolysis of amides is significantly accelerated upon inclusion.
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The data supporting the findings of this study are available within this article and its Supplementary Information. Crystallographic data for inclusion complexes 1b•(2a)2, 1a•(2b)2, 1a•(2b•3a), 1a•(2b•4), 1a•(2c)2, 1a•2d and 1a•(2e)2 are free of charge from the Cambridge Crystallographic Data Centre (www.ccdc.cam.ac.uk) under reference nos. 1949143, 1949144, 1949145, 1949146, 1949149, 1949150 and 1949151, respectively.
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This research was supported by Grants-in-Aid for Specially Promoted Research (19H05461 to M.F.), for Young Scientists (19K15581 to H.T.) and the Noguchi Institute (to H.T.).
The authors declare no competing interests.
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Supplementary experimental details and compound characterization data.
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Takezawa, H., Shitozawa, K. & Fujita, M. Enhanced reactivity of twisted amides inside a molecular cage. Nat. Chem. 12, 574–578 (2020). https://doi.org/10.1038/s41557-020-0455-y