Modeling Biologically Important NH···π Interactions Using -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, MeNH, 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.

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 HBF 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 NMe 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 3HBF-6HBF vary between 7.

10-Dimethylamino Derivatives of Benzo[h]quinoline and Benzo[h]quinazolines: Fluorescent Proton Sponge Analogues with Opposed peri-NMe2/-N═ Groups. How to Distinguish between Proton Sponges and Pseudo-Proton Sponges.

For the first time, 10-dimethylamino derivatives of benzo[h]quinoline 6 and benzo[h]quinazoline 7a-e as mixed analogues of archetypal 1,8-bis(dimethylamino)naphthalene ("proton sponge") 1 and quino[7,8-h]quinoline 2a have been examined. Similar to 1 and 2, compounds 6 and 7 display rather high basicity, forming chelated monocations. At the same time, unexpected specifics of the protonated NMe2/-N═ systems consist of a strong shift of the NH proton to the 10-NMe2 group, contrary to the "aniline-pyridine" basicity rule.

4,5-Bis(dimethylamino)quinolines: proton sponge versus azine behavior.

Two first representatives, 5 and 6, of the still unknown 4,5-bis(dimethylamino)quinoline have been synthesized and studied. While the former, being protonated either at the peri-NMe(2) groups or at the ring nitrogen, has been shown to display properties of both a proton sponge and azine, its counterpart 6 behaves exclusively as azine giving only a quinolinium salt.

H-bond-assisted intramolecular nucleophilic displacement of the 1-NMe2 group in 1,8-bis(dimethylamino)naphthalenes as a route to multinuclear heterocyclic compounds and strained naphthalene derivatives.

It has been shown that azomethines, hydrazones, and oximes derived from 2(7)-carbonyl derivatives of 1,8-bis(dimethylamino)naphthalene can undergo acid-catalyzed heterocyclization leading to a nucleophilic displacement of the 1-NMe(2) group. The process is believed to be directly connected with the proton sponge nature of the substrates, in which 1-NMe(2), being a poor leaving group, is preliminary activated via the formation of a chelated protonated form. A number of difficult to access derivatives of benzo[g]indazole, benzo[g]quinazoline, naphtho[2,1-d]isoxazole, and 8-dimethylamino-1-naphthol have been prepared in moderate to high yields.

Naphthalene proton sponges as hydride donors: diverse appearances of the tert-amino-effect.

It has been shown that the 1-NMe(2) group in the 2-substituted 1,8-bis(dimethylamino)naphthalenes (proton sponges) can intramolecularly donate a hydride ion to an appropriate electron-accepting ortho-substituent such as diarylcarbenium ion, β,β'-dicyanovinyl or methyleneiminium group. This produces the 1-N(+)(Me)=CH(2) functionality and triggers a number of further transformations (tert-amino effect) including peri-cyclization, ortho-cyclization or hydrolytic demethylation. In each particular case, the course of the reaction is determined by the nature of the ortho-substituent and the most potent nucleophile presenting in the reaction mixture.