Modeling Biologically Important NH···π Interactions Using peri-Disubstituted Naphthalenes

For the first time, systematic studies of 8-aryl and 8-pyrrolyl derivatives of 1-aminonaphthalene as simple, synthetically available, and nicely preorganized models were conducted for a better understanding the properties of NH···π interactions involved in the stabilization of the secondary and tertiary protein structures as well as the recognition of guest molecules by biological receptors. It was shown that the NH···π binding is especially effective when the NH-donor is a positively charged group, for example, Me2NH+, and the π-donor is an electron-rich aromatic substituent, in particular, the 1-pyrrolyl or the 4-hydroxyphenyl group. Using protonated tetrafluoroborate salts, a strong counterion effect was demonstrated by means of theoretical calculations. Through several mechanisms, including short CH···F contacts, bifurcation, and long-range dispersion, the counterion promotes considerable structural changes and weakens the NH···π interactions from 12–15 kcal mol–1 in “naked” cations to 5–9 kcal mol–1 in the salts. To this end, 8-(2,5-dimethylpyrrol-1-yl)-N,N-dimethylnaphthalene-1-ammonium tetrafluoroborate, with the record linearity and shortness (2.07 Å) of the NH···π-centroid bond, was recognized as the most appropriate model with the strongest NH···π interaction ever described.