Proton Sponge Zwitterions with Positively and Negatively Charged Hydrogen Bonds: Extremely Polar Organic Compounds and Interplay of [NHN] and [NHN] Properties.

Six previously unknown zwitterions with positively and negatively charged [NHN] hydrogen bonds were synthesized by acylation of 4,5-bis(dimethylamino)-1-tosylamino-8-aminonaphthalene with subsequent alkaline treatment of the resulting 8-acylamino derivatives. Using NMR and XRD measurements in conjunction with quantum chemical DFT/PBE1PBE/6-311++G(d,p) calculations, it was shown that the negatively charged [NHN] bond in such compounds commonly differs from the [NHN] bond by significantly lower linearity, higher asymmetry, and moderate to strong paramagnetic shift of the chelated NH proton signal. Among other remarkable findings, the most important are (1) unusually high polarity (μ = 21-26 D) of the obtained zwitterions, (2) sharp difference in structures of the solid 1,8-bis(tosylated) zwitterion (BTZ) grown from MeCN or DMF, and (3) registration for one of the stereoisomers of BTZ with the record short [NHN] hydrogen bridge (N···N = 2.

Substitution reactions in the acenaphthene analog of quino[7,8-]quinoline and an unusual synthesis of the corresponding acenaphthylenes by -elimination.

The possibility of functionalization of dipyrido[3,2-:2',3'-]acenaphthene containing a quino[7,8-]quinoline fragment and being a highly basic diazine analog of 1,8-bis(dimethylamino)naphthalene ("proton sponge") has been studied for the first time. In addition to the pronounced tendency of the title compound to form associates with an intramolecular hydrogen bond of the NHN type (new examples with the participation of pyridine rings, including self-associates are shown) and its inertness to amination reactions of the pyridine rings, the naphthalene core at positions 5(8) and the CHCH bridge (dehydrogenation) undergo chemical modifications under mild conditions, giving the corresponding acenaphthylenes. The latter can also be obtained in an unusual way by -elimination from 5,8-dibromodipyridoacenaphthene by reaction with neutral or anionic bases.

Synthesis, structure, and properties of switchable cross-conjugated 1,4-diaryl-1,3-butadiynes based on 1,8-bis(dimethylamino)naphthalene.

A set of novel 1,4-diaryl-1,3-butadiynes terminated by two 7-(arylethynyl)-1,8-bis(dimethylamino)naphthalene fragments was prepared via the Glaser-Hay oxidative dimerization of 2-ethynyl-7-(arylethynyl)-1,8-bis(dimethylamino)naphthalenes. The oligomers synthesized in this way are cross-conjugated systems, in which two conjugation pathways are possible: π-conjugation of 1,8-bis(dimethylamino)naphthalene (DMAN) fragments through a butadiyne linker and a donor-acceptor aryl-C≡C-DMAN conjugation path. The conjugation path can be "switched" simply by protonation of DMAN fragments.

Synthesis, conformational stability and molecular structure of 4-aryl- and 4,5-diaryl-1,8-bis(dimethylamino)naphthalenes.

4-Bromo- and 4,5-dibromo-1,8-bis(dimethylamino)naphthalenes were arylated with arylboronic acids under Suzuki reaction conditions to provide 4-aryl- and 4,5-diaryl-1,8-bis(dimethylamino)naphthalenes, respectively. The interaction of 4,5-dibromo-1,8-bis(dimethylamino)naphthalene with pyridin-3-ylboronic acid was accompanied by heterocyclization leading unexpectedly to the formation of ,,,-tetramethylacenaphtho[1,2-]pyridine-3,4-diamine. Dynamic H NMR experiments showed fast interconversion between and conformers of 4,5-diaryl-1,8-bis(dimethylamino)naphthalenes in CDCl solution at room temperature.

Organometallic Synthesis of 2,3,6,7-Tetrasubstituted 1,8-Bis(dimethylamino)naphthalenes for Investigation of the Double Buttressing Effect in Proton Sponges.

The lithiation of 2,7-disubstituted derivatives of 1,8-bis(dimethylamino)naphthalene (DMAN, proton sponge) bearing potentially -directing OMe, NMe, and SMe groups was studied. It has been shown that OMe groups facilitate selective dual β-lithiation of the naphthalene moiety while the 2(7)-NMe groups allow only monolithiation presumably due to the decreased acidity of the ring C-H bonds and conformational immobilization after coordination to the lithium atom. In contrast, the SMe groups provided no ring lithiation and underwent deprotonation of their methyl fragment.

Combination of "Buttressing" and "Clothespin" Effects for Reaching the Shortest NHN Hydrogen Bond in Proton Sponge Cations.

A series of previously unknown 2,4,5-tri- and 2,4,5,7-tetrasubstituted 1,8-bis(dimethylamino)naphthalenes and their salts with HBF containing bulky spherically shaped substituents (Me, Br, and SiMe) in the naphthalene ring has been synthesized. Using XRD analysis of 11 samples, the influence of the so-called "buttressing" and "clothespin" effects on their molecular structure and the NHN hydrogen bond geometry in the solid cations were investigated. The combined action of both effects has been shown to significantly increase the compression of the hydrogen bond.

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.

Proton-induced fluorescence in modified quino[7,8-h]quinolines: dual sensing for protons and π-donors.

The synthesis, as well as spectral, structural and photoluminescence properties of dipyrido[3,2-e:2',3'-h]acenaphthene 5 and quinazolino[7,8-h]quinazolines 6 as representatives of the bidentate -N[double bond, length as m-dash]/-N[double bond, length as m-dash] superbases, are reported. These nitrogen bases being more rigid (5) or π-extended (6) analogs of optically-mute quino[7,8-h]quinoline are both active in terms of fluorescence with quantum yields up to φ = 0.71-0.

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.

Ring lithiation of 1,8-bis(dimethylamino)naphthalene: another side of the 'proton sponge coin'.

It has been found that 1,8-bis(dimethylamino)naphthalene (DMAN), unlike N,N-dimethylaniline, undergoes ring metallation in the n-BuLi-TMEDA-Et2O system with a low selectivity and in poor total yields. The situation is significantly improved in the t-BuLi-TMEDA-n-hexane system when 3- and 4-lithium derivatives become the only reaction products obtained in good yields. The formation of 3-Li-DMAN is especially desired since no method of direct meta-functionalization of DMAN is known to date.

The first proton sponge-based amino acids: synthesis, acid-base properties and some reactivity.

The first hybrid base constructed from 1,8-bis(dimethylamino)naphthalene (proton sponge or DMAN) and glycine, N-methyl-N-(8-dimethylamino-1-naphthyl)aminoacetic acid, was synthesised in high yield and its hydrobromide was structurally characterised and used to determine the acid-base properties via potentiometric titration. It was found that the basic strength of the DMAN-glycine base (pKa = 11.57, H2O) is on the level of amidine amino acids like arginine and creatine and its structure, zwitterionic vs.

Multiple transformations of 2-alkynyl-1,8-bis(dimethylamino)naphthalenes into benzo[g]indoles. Pd/Cu-dependent switching of the electrophilic and nucleophilic sites in acetylenic bond and a puzzle of porcelain catalysis.

By means of Sonogashira reaction, a series of 2-alkynyl- and 2,7-dialkynyl derivatives of 1,8-bis(dimethylamino)naphthalene ("proton sponge") have been obtained from the corresponding iodides. It was disclosed that changing the reaction conditions and isolation protocol or conducting the model experiments with the authentic acetylenes results in several types of palladium- and copper-assisted heterocyclizations with the participation of the C≡C bond and 1-NMe2 group. These include: (i) a cyclization into isomeric 1H-benzo[g]indoles with [1,3] migration of the N-methyl group into the newly formed pyrrole ring; (ii) a similar cyclization with a loss of the methyl group; (iii) a tandem process of cyclization into benzo[g]indoles and their subsequent 3,3'-dimerization; and (iv) a copper-catalyzed oxidative transformation into 3-aroylbenzo[g]indoles.

Out-basicity of 1,8-bis(dimethylamino)naphthalene: the experimental and theoretical challenge.

A possibility of non-conventional two-step protonation of 1,8-bis(dimethylamino)naphthalene (proton sponge) is discussed. Unlike the generally accepted mechanism, involving relatively slow direct penetration of a proton into the cleft between the peri-NMe2 groups, it consists of the rapid addition of a proton to the out-inverted NMe2 group with the subsequent slower rotational transfer of the proton into the inter-nitrogen space to produce a stable chelated cation. The following approaches were employed during the work: (1) competitive hydrogen bond formation in a specially designed alcohol in which the OH group might chelate either the proton sponge 1-NMe2 group or another basic center (N,N-dimethylaniline) of known basicity; (2) measuring the basicity of naphtho[1,8-b,c]diazabicyclo[3.

Extreme magnetic separation of geminal protons in protonated N,N,N'-trimethyl-1,8-diaminonaphthalene. A puzzle of the fourth methyl group.

Monoprotonated N,N,N'-trimethyl-1,8-diaminonaphthalene demonstrates fast exchange of H(in) and H(out) protons, in which a counterion (BF4(-) and Br(-) were tested) participates. The process can be frozen below 185 K revealing a tremendous magnetic separation (up to Δδ = 11.6 ppm) of these otherwise equal NH protons with the enzyme-like proton transfer and a ∼7 kcal mol(-1) energetic barrier.

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.

1,8,1',8'-Tetrakis(dimethylamino)-2,2'-dinaphthylmethanols: double in/out proton sponges with low-barrier hydrogen-bond switching.

Previously unknown bis[1,8-bis(dimethylamino)naphth-2-yl]phenylmethanol (5) and bis[1,8-bis(dimethylamino)naphth-2-yl]methanol (6) have been obtained and studied by combination of X-ray, NMR, and IR techniques at variable temperature. It has been established that both proton sponge units in the solid tertiary alcohol 5 exist in nonconventional in/out form, one of which is fixed by intramolecular O-H..

2-alpha-hydroxyalkyl- and 2,7-di(alpha-hydroxyalkyl)-1,8-bis(dimethylamino)naphthalenes: stabilization of nonconventional in/out conformers of "proton sponges" via N...H-O intramolecular hydrogen bonding. A remarkable kind of tandem nitrogen inversion.

A regular set of 2-(alpha-hydroxymethyl)- and 2,7-di(alpha-hydroxymethyl)-1,8-bis(dimethylamino)naphthalenes has been prepared. Their X-ray, NMR, and IR studies have demonstrated that in tertiary mono-alcohols the orientation of free nitrogen electron pairs in crystals and solution corresponds to nonconventional in/out conformers stabilized by O-H..

[NHN]+ hydrogen bonding in protonated 1,8-bis(dimethylamino)-2,7-dimethoxynaphthalene. X-ray diffraction, infrared, and theoretical ab initio and DFT studies.

Structural (X-ray diffraction), infrared spectroscopic, and theoretical MP2 and DFT studies on the HBr and DBr adducts of 1,8-bis(dimethylamino)2,7-dimethoxynaphthalene ((CH3O)2.DMAN) were performed. This particular proton sponge has been chosen for its strong basicity and display of the buttressing effect influencing the hydrogen bond dynamics and properties.

Organometallic synthesis, molecular structure, and coloration of 2,7-disubstituted 1,8-bis(dimethylamino)naphthalenes. How significant is the influence of "buttressing effect" on their basicity?

On treatment of 2,7-dilithio- (6a) and 2,7-bis(bromomagnesio)- (6b) naphthalenes with a number of electrophiles, new "proton sponge" derivatives 7a-e,g, containing iodo, methylthio, trimethylsilyl, methyl, n-butyl, and ethoxycarbonyl groups in ortho-positions to dimethylamino groups, have been synthesized. The investigation of their molecular structure, spectral characteristics, and basicity reveals that the latter is mainly determined by two groups of factors: (1) the polar effect of ortho-substituents and (2) the so-called "buttressing effect" representing the complex combination of various sterical interactions of ortho-substituents with dimethylamino groups in corresponding bases and cations. A contradictory directionality of these interactions strongly reduces the importance of the buttressing effect in the case of compounds with bulky ortho-substituents, which is most clearly displayed in the absence of any relationship between the size of ortho-substituents and the basicity.