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.

Nucleophilic Substitution of Hydrogen Atom in Initially Inactivated Pyrrole Ring.

It has been found that 1-dialkylamino-8-(pyrrolyl-1)naphthalenes 1 and 6, upon treatment with an equimolar amount of HBF4 under ambient conditions, produce 1-dialkylammonium salts which are transformed into 7,7-dialkyl-7 H-pyrrolo[1,2- a]perimidine-7-ium tetrafluoroborates 5 and 7, respectively. The reaction proceeds in a highly selective manner and represents the first case of nucleophilic substitution of hydrogen in the initially inactivated pyrrole ring. The scope and limitations of the transformation, apparently operating due to the joint action of the "proximity effect" and proton catalysis, are outlined.

Neutral Pyrrole Nitrogen Atom as a π- and Mixed n,π-Donor in Hydrogen Bonding.

9-Dimethylaminobenzo[ g]indoles 3-6 and 1-dimethylamino-8-(pyrrolyl-1)naphthalene 7 were examined as possible models for establishing the ability of the pyrrole nitrogen atom to participate in [NHN]+ hydrogen bonding as a proton acceptor. Indoles 3-5 (to a lesser extent 6) form rather stable tetrafluoroborates, with the proton mostly located on the NMe2 group but simultaneously engaged in the formation of a charged intramolecular [NHN]+ hydrogen bond (IHB) with the pyrrole N atom. The theoretically estimated energies of IHB in salts 3H+BF4--6H+BF4- vary between 7.0-10.7 and 6.2-7.0 kcal mol-1 in vapor and MeCN, respectively. The pyrrole N atom undergoes a perceptible pyramidalization but still remains involved in the 6π-electron aromatic system, suggesting that the hydrogen bonding in salts 3H+BF4--6H+BF4- represents a previously unknown mixed NH···N(n,π) interaction. Despite the favorable orientation of the N-H bond and the pyrrole ring in salt 7H+BF4-, no signs of NH···N(n) bonding in it were noticed, and the existing interaction was classified as pure NH···N(π). The results obtained may be useful in studies of secondary protein structures, especially those α-helix sections which contain tryptophan residues.