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Bifunctional squaramides with benzyl-like fragments: analysis of CH⋯π interactions by a multivariate linear regression model and quantum chemical topology

We analyzed 15 bifunctional squaramides with benzyl-like fragments in a Michael addition. These substituents are susceptible to form CH⋯π interactions and have distinct properties: electronic features, a stereogenic center, as well as additional cyclic groups which offer a more rigid moiety with a f...

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Bibliographic Details
Published in:Organic chemistry frontiers an international journal of organic chemistry 2021-06, Vol.8 (13), p.3217-3227
Main Authors: Díaz-Salazar, Howard, Jiménez, Eddy I, Vallejo Narváez, Wilmer E, Rocha-Rinza, Tomás, Hernández-Rodríguez, Marcos
Format: Article
Language:English
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Summary:We analyzed 15 bifunctional squaramides with benzyl-like fragments in a Michael addition. These substituents are susceptible to form CH⋯π interactions and have distinct properties: electronic features, a stereogenic center, as well as additional cyclic groups which offer a more rigid moiety with a fixed orientation of the aryl group. We found that non-cyclic substituents, the benzyl group, had better selectivity than the chiral phenylethyl analog, and the electronic properties of the phenyl ring were not a decisive factor. The cyclic substituents also have different results. The non-chiral tricyclic groups were less selective because the orientation of the phenyl group has an undesirable arrangement to form the considered weak interactions. In contrast, the chiral 1-tetrahydronaphthyl group seemed to have the aryl ring in an optimal disposition. These trends were correlated using a multivariate linear regression model that considers the strength of CH⋯π contacts and the energy to adopt the “active” conformation to form these contacts. This model suggests that the most selective catalyst that incorporates commercially available 1-aminotetraline amine could be explained by the phenyl group already being in the optimal position which is its lowest energy conformation, and the phenyl ring has a double inductive effect from the vicinal alkyl groups. This catalyst was further explored and offered high selectivities across different nucleophiles and electrophiles. Finally, a quantum chemical topology analysis of the weak interactions revealed that the transition state that leads to the major enantiomer has an additional hydrogen bond with the nucleophile and a stronger association with the electrophile.
ISSN:2052-4110
2052-4110
DOI:10.1039/d0qo01610a