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.

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.

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. In case of 4H(+), a rapid migration (in the NMR time scale) of the NH proton between two nitrogen atoms along the N-H···N hydrogen bond was registered at room temperature and frozen below -30 °C with the proton fixed on the NMe2 group. Two different approaches for classification of strong neutral nitrogen organic bases as proton sponges (kinetically inert compounds) or pseudo-proton sponges (kinetically active) are discussed. On this basis, benzoquinoline 6 was identified as staying closer to pseudo-proton sponges while 7a-e to proton sponges due to the presence in their molecules of bulky substituents in the pyrimidine ring. Other remarkable peculiarities of 6 and 7 are their yellow color and luminescence in the visible region distinguishing them from colorless 1 and 2a.

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, ß,ß'-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. For 2,7-disubstituted 1,8-bis(dimethylamino)naphthalenes, two types of tandem tert-amino effect with the involvement of both peri-NMe(2) groups have been registered. The conclusion was made that proton sponges are generally more active in the tert-amino reactions than the corresponding monodimethylaminoarenes. This is ascribed both to higher electron donor ability of proton sponges and markedly shortened distance between electrophilic C(α)-atom in the ortho-substituent and hydrogen atoms of the nearest NMe(2) group. Most conversions observed proceed in good to high yields and are useful for the preparation of derivatives of benzo[h]quinoline, quino[7,8:7',8']quinoline, 2,3-dihydroperimidine, N,N,N'-trimethyl-1,8-diaminonaphthalene and proton sponge itself.

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.

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.