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. 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.
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.
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.
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
+
BF
4
–
–6H
+
BF
4
–
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
+
BF
4
–
–6H
+
BF
4
–
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
+
BF
4
–
, 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.
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.
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