Continuing with our interest in the guanidinium group and the different interactions than can establish, we have carried out a theoretical study of the complexes formed by this cation and the aromatic amino acids (phenylalanine, histidine, tryptophan and tyrosine) using DFT methods and PCM-water solvation. Both hydrogen bonds and cation-π interactions have been found upon complexation. These interactions have been characterized by means of the analysis of the molecular electron density using the Atoms-in-Molecules approach as well as the orbital interactions using the Natural Bond Orbital methodology. Finally, the effect that the cation-π and hydrogen bond interactions exert on the aromaticity of the corresponding amino acids has been evaluated by calculating the theoretical NICS values, finding that the aromatic character was not heavily modified upon complexation.

A computational study has been performed for studying the characteristics of the interaction of phenol with ammonium and methylammonium cations. The effect of the presence of water molecules has also been considered by microhydrating the clusters with up to three water molecules. Clusters of phenol with ammonium and methylammonium cations present similar characteristics, though ammonium complexes have been found to be more stable than the methylammonium ones. The first water molecule included in the complexes interacts with a N-H group of ammoniun cations and simultaneously with the hydroxyl oxygen atom of phenol (or the aromatic ring). This first water molecule is more tightly bound in the complex, so the stability gain as more water molecules are included drops significantly by 2-3 kcal mol(-1) with respect to the first one. As more water molecules are included, the differences between favorable coordination sites (the cation, the hydroxyl group or a previous water molecule) decrease. As a consequence, several of the most stable complexes located including three water molecules already exhibit hydrogen bonds between the hydroxyl group and one water molecule. The results indicate that a cyclic pattern formed by a series of hydrogen bonds: π···H-N-H···O-H···O-ϕ, is characteristic of the most stable minima, being kept as more water molecules are included in the system. Therefore, this pattern can be expected to be crucial in ammonium cations···phenol interaction if exposed to the solvent to any degree.

A computational study has been carried out in complexes formed by pyrrolidinium cation and aromatic units present in amino acid side chains. The interaction is stronger with indole (-21.9 kcal mol(-1) at the CCSD(T) complete basis set level) than with phenol (-17.4 kcal mol(-1)) or benzene (-16.1 kcal mol(-1)). Most stable structures show a N-H···π contact between pyrrolidinium cation and the phenyl ring of the three aromatic species, except in phenol complexes where the most stable minimum shows a N-HO hydrogen bond. In phenol and indole complexes, secondary contacts are established between the C-H groups of the carbon skeleton of pyrrolidinium and the aromatic rings or hydroxyl oxygen, being the main reason for the enhanced stability with respect to benzene, where these contacts are not possible. The interaction is mainly controlled by electrostatics, but contributions from induction and dispersion are also significant, especially the latter in indole complexes. These three attractive contributions increase their intensity when going from benzene to phenol and indole. Microhydration effects have been estimated by including up to three water molecules in the complexes. In monohydrated pyrrolidiniumbenzene complex the most stable structure shows the water molecule coordinated to the cation without interacting with the ring. In phenol and indole, otherwise, the water molecule interacts with both the cation and the aromatic species, forming a cyclic hydrogen bond pattern π(phenyl)···H-N-H···O-H···X (X = π, O). This pattern is also present among the most stable structures found for complexes with two and three water molecules, though a variety of almost isoenergetic minima showing different hydrogen bond patterns have been found. Water molecules remove the stability differences between phenol and indole complexes, which already with two water molecules show similar stabilities, though around 5 kcal mol(-1) larger than benzene ones.

The interaction of the guanidinium cation with phenylalanine, tyrosine and tryptophan has been studied using a variety of computational methods. Benchmark values for the interaction have been estimated using the CCSD(T) method extrapolated to the complete basis set limit, indicating that the complexation energy amounts to -123.0, -124.4 and -134.2 kJ mol(-1) for Phe, Tyr and Trp, respectively. Most stable minima correspond to neutral folded amino acids, with the cation interacting simultaneously with the carboxyl oxygen, the amino nitrogen and the aromatic ring. However, complexes with the amino acids as zwitterions are as stable as neutral ones. The final relative stability of the different structures results from a complex balance among different contributions to the complexation energy. Extended neutral structures are favored by larger electrostatic and smaller repulsion contributions, as well as by smaller deformation costs for bringing the amino acid to its final geometry into the complex. Zwitterions show large electrostatic and induction contributions that cancel out the huge deformation cost needed to transfer the proton to the amino group. The presence of the cation···π contact in folded minima introduces larger contributions from induction and dispersion (also as a consequence of the bulky guanidinium cation) that are able to overcome other effects, making folded minima the most stable together with zwitterionic ones.

Complexes formed by the imidazolium cation and the aromatic amino acids, phenylalanine, tyrosine, tryptophan, and histidine have been studied by using computational methods. Complexation energies estimated at the MP2.X level amount to -123.3, -124.6, -131.5 and -145.5 kJ mol(-1) for Phe, Tyr, Trp and His, respectively. The results obtained for Phe, Tyr and Trp complexes are similar, with the most stable minima corresponding to structures with the imidazolium cation stacked over the rings. The cation forms hydrogen bonds with the amino acid while establishing cationπ contacts with the aromatic rings. Extended structures with the amino acids in zwitterionic form are almost equally stable, though. The interaction is controlled by electrostatics and induction, though the preference for the stacked minima is due to larger contributions from induction and dispersion despite the energy cost of folding the amino acid. His complexes exhibit a totally different behaviour, and no structures displaying cationπ interactions are found among the most stable minima. Most favourable complexes of His show the cation hydrogen bonded to the amino acid in extended zwitterionic form. Overall, Phe, Tyr and Trp complexes can show parallel structures in competition with similarly stable zwitterionic ones, while His only shows zwitterionic minima, with a stability even larger than any of the other aromatic amino acids, though lacking participation of the π cloud in the interaction.