Electronic Properties of Common Psychostimulants in Aqueous Environments

We employed advanced quantum chemical methods to investigate the electronic properties of five widely consumed psychostimulants: nicotine, cotinine, caffeine, theophylline, and theobromine. Molecular geometries were optimized in an aqueous environment using density functional theory (DFT) with the B3LYP exchange-correlation functional and an extensive basis set. The calculated structures showed excellent agreement with experimentally determined solid-state structures deposited in the Cambridge Crystallographic Data Centre (CCDC). Full vibrational analyses enabled the determination of thermodynamic properties, including Gibbs energies. For the neutral ground states, we calculated dipole and quadrupole moments, dipole polarizabilities, zero-point vibrational energies, and entropic contributions. Adiabatic ionization energies and electron affinities were obtained from optimized cationic and anionic geometries and used to derive molecular electronegativities, chemical hardnesses, and electrophilicity indices. Reaction Gibbs energies for ionization and reduction were converted into absolute oxidation and reduction potentials. To improve accuracy, we additionally employed the highly correlated DLPNO-CCSD(T) method for ionization energies and electron affinities in water. Finally, the electronic and global properties of biologically relevant protonated forms nicotinium, cotinium, caffeinium, theophyllinium, and theobrominium were investigated, providing a description of these compounds in aqueous solution. This approach enabled comparison of their structural, thermodynamic, electronic, and redox properties across the investigated molecular series. In addition to the implicit Conductor-like Polarizable Continuum Model (CPCM), an explicit solvation approach involving several water molecules was also tested for the nicotine-water aggregate.