Analysis of Conformational Preferences in Caffeine

Abstract

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.

The Role of Hydrogen Bonding in the Raman Spectral Signals of Caffeine in Aqueous Solution

“…Geometrical and energetic aspects of isolated and hydrated forms of caffeine have been the subject of investigation in earlier studies [38,40,[60][61][62]. Structural analysis of caffeine has revealed small barriers associated with the rotation of the methyl groups [47] which are reported to be affected by non-covalent interaction with their neighboring functional groups and by different degrees of hyperconjugation [39,63]. Despite its limited solubility in water that is certainly overcome at moderate temperatures, caffeine solutions can be seen as a series of non-covalent interactions, mainly HBs.…”

“…After extracting 200 uncorrelated snapshots from the trajectory and cutting them into a solute-centered sphere with a radius of 17 Å (Figure 1), QM/FQ calculations were carried out at the B3LYP/6-311++G(d, p)/FQ level in the Gaussian16 package [90] exploiting the FQ parametrization proposed by Rick et al [91]. The same QM level of theory has been employed in other computational works concerning caffeine and xanthines [38][39][40]47,61,63,70,77]. In spectral calculations, the caffeine molecule is the only part of the system treated at the QM level.…”