Analysis of Conformational Preferences in Caffeine

High level DLPNO−CCSD(T) electronic structure calculations with extended basis sets over B3LYP−D3 optimized geometries indicate that the three methyl groups in caffeine overcome steric hindrance to adopt uncommon conformations, each one placing a C−H bond on the same plane of the aromatic system, le...

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Bibliographic Details
Published in:Molecules (Basel, Switzerland) Switzerland), 2022-03, Vol.27 (6), p.1937
Main Authors: Gómez, Sara, Rojas-Valencia, Natalia, Restrepo, Albeiro
Format: Article
Language:English
Subjects:
Caffeine
Carbonyl compounds
Carbonyl groups
Carbonyls
Charge transfer
Conformation
Critical point
Electronic structure
Electrostatic properties
Electrostatics
Energy
Hydrogen
Hydrogen bonds
hyperconjugation
Imidazole
methyl rotation
Molecular Conformation
Molecular structure
NBO
Quantum Theory
Static Electricity
Steric hindrance
Xanthines
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Summary:High level DLPNO−CCSD(T) electronic structure calculations with extended basis sets over B3LYP−D3 optimized geometries indicate that the three methyl groups in caffeine overcome steric hindrance to adopt uncommon conformations, each one placing a C−H bond on the same plane of the aromatic system, leading to the C−H bonds eclipsing one carbonyl group, one heavily delocalized C−N bond constituent of the fused double ring aromatic system, and one C−H bond from the imidazole ring. Deletion of indiscriminate and selective non-Lewis orbitals unequivocally show that hyperconjugation in the form of a bidirectional −CH3 ⇆ aromatic system charge transfer is responsible for these puzzling conformations. The structural preferences in caffeine are exclusively determined by orbital interactions, ruling out electrostatics, induction, bond critical points, and density redistribution because the steric effect, the allylic effect, the Quantum Theory of Atoms in Molecules (QTAIM), and the non-covalent interactions (NCI), all predict wrong energetic orderings. Tiny rotational barriers, not exceeding 1.3 kcal/mol suggest that at room conditions, each methyl group either acts as a free rotor or adopts fluxional behavior, thus preventing accurate determination of their conformations. In this context, our results supersede current experimental ambiguity in the assignation of methyl conformation in caffeine and, more generally, in methylated xanthines and their derivatives.
ISSN:1420-3049
1420-3049
DOI:10.3390/molecules27061937