biostudies-literatureGomez SUniversity of Antioquia1937https://www.ebi.ac.uk/biostudies/studies/S-EPMC8949453biostudies-literatureUnknown27(6)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 interactionsMolecules (Basel, Switzerland)Analysis of Conformational Preferences in Caffeine.PMC8949453Estrategia para la sostenibilidad. Internal project 2019-25332Rojas-Valencia NGomez SRestrepo AfalseAnalysis 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, 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 interactions2022-01-01T00:00:00Z2022 Mar2025-04-22T01:41:13.072Z2025-04-05T20:06:41.628ZS-EPMC89494533533530110.3390/molecules27061937