Cation⋯π interaction and microhydration effects in complexes formed by pyrrolidinium cation and aromatic species in amino acid side chains

Abstract

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 n → π* interaction: a rapidly emerging non-covalent interaction

“…27 The dispersion interaction also becomes significant in the case of the cation-p interaction when the bulkiness of the cation increases. 19,20 In Section 2.2.3, the competition between the lpÁ Á Áp interaction and hydrogen bonding in the complexes of 7-azaindole and several 2,6-substituted fluoropyridines studied by Das and co-workers has been discussed. 34 They found that the binding energies of the 7-azaindoleÁ Á Á2,6-substituted fluoropyridines calculated at the B3LYP level of theory are very much less than those obtained at the dispersion-corrected DFT and MP2 levels.…”

“…[1][2][3][4][5] Intermolecular interactions involving p-systems, which are also very popular and well studied, are p-stacking, p-hydrogen bonding and cation-p interactions. [9][10][11][12][13][14][15][16][17][18][19][20][21] However, quite recently, two more non-covalent interactions involving p-electrons, namely anion-p and np* interactions, have been recognized by the scientific community. Neither of these interactions were appreciated earlier in spite of their widespread presence in biology and materials, because the attractive interaction between an electron rich species and the p-electron cloud is counterintuitive in nature.…”

It Is Important to Compute Intramolecular Hydrogen Bonding in Drug Design?

“…Useful information can be obtained from experimental gas-phase hydration/solvation studies augmented with theoretical calculations [108][109][110][111][112][113][114][115][116] or specific theoretical calculations for hydrated amino acid side chains, nucleotid base and sugar models [117][118][119][120][121].…”

Systematic testing of Gaussian and complete basis set methods with dispersion corrections for environmentally relevant clusters

“…For instance, the binding energy with CBS-QB3 for (CH 3 OH) 3 is −15.42 kcal mol −1 and −25.52 kcal mol −1 for (CH 3 OH) 4 , for which experiment predict values of −12.52 and −23.01 kcal mol −1 , respectively. The corresponding CBS-QB3 errors, per hydrogen bond, are surprisingly large, 0.97 kcal mol −1 in the case of (CH 3 OH) 3 and 0.63 kcal mol −1 for (CH 3 OH) 4 . Evidently, there are still shortcomings in the CBS-QB3 method when treating larger systems with multiple H-bonding interactions.…”

“…A major challenge when modeling large molecular systems, are the weak attractive interactions, in particular, the non-covalent interactions that hold together molecular clusters and their solvation shells [1][2][3][4]. The gold standard for non-covalent interactions (hydrogen bonding, electrostatic and dispersion interactions) are structures and energies at the coupled-cluster CCSD(T)/CBS level of theory [5,6].…”