Quino[7,8-h]quinoline,a New Type of “Proton Sponge”

So far, “proton sponges” have been defined as bis(dialkylamino)arenes whose dialkylamino groups are in close spatial proximity.^[1] The unusual basicity of these compounds is ascribed to the destabilizing overlap of the lone electron pairs on the nitrogen atoms, to the formation of especially strong hydrogen bonds in the monoprotonated diamines, and to the hydrophobic shielding of these hydrogen bonds. In order to differentiate and assess the relative importance of these factors, we were interested in quino[7,8-h]quinoline 1 , whose nitrogen atoms exhibit a mutual orientation similar to that in 1,8-bis(dimethylamino)naphthalene 2 (“proton sponge”). In contrast to 2 , however, 1 lacks the hydrophobic shielding of the hydrogen bonds of its monoprotonated derivative. This shielding is considered to be responsible for the low rates of proton transfer, which make the “proton sponges” reported so far unsuitable as auxiliary bases in chemical reactions.     

Proton Sponges and Hydrogen Transfer Phenomena

Recent advances in the studies of hydrogen transfer (protonation, hydrogen bonding, hydride transfer and CH acidity) in proton sponges, its influence on the structure, stereodynamics and reactivity of these superbasic compounds and the use of the above phenomena for modelling enzyme catalysis have been discussed.     

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. On the contrary, for proton sponges having in ortho-positions the electron-donating groups with lesser steric demands, both the buttressing and the polar effects act in the same direction. This is the reason for the exceptionally high basicity of 2,7-dimethoxy- (2) and tetrakis(dimethylamino)- (3a) naphthalenes. It has been found that bis(trimethylsilyl)-bis(dimethylamino)naphthalene 7d has an in-out configuration of the NMe2 groups in the solid that is the first example of its kind in the series of naphthalene proton sponges. The origin of a yellow coloring of 2,7-disubstituted proton sponges is also discussed.     

Rational design and first-principles studies toward the remote substituent effects on a novel tetracyclic proton sponge

According to reliable density functional theory (DFT) calculations, 11,12-dimethyl-11,12-diazatetracyclo[6.2.1.1(3,6).0(2,7)]dodecane derivatives have been predicted as superorganic bases in the gas phase, acetonitrile, and the aqueous phase. The basicities of these tetracyclic proton sponges were modulated through remote substituent effects. Barriers for proton transfer between the N atoms of the diamine cations are also reported.     

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. 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.     

Infrared study of hydrogen bonds involving N-heterocyclic bases and phenols

The hydrogen bond complexes between phenols and N-heteroaromatic bases 2,4,6-tri(2-pyridyl)-1,3,5-triazine, 2,2′,2′-terpyridine, quinoxaline, pyrido[2,3-b]pyrazine, pyzazino [2,3f]quinoxaline and 5-nitrozphenanthroline are investigated by infrared spectroscopy in 1,2-dichloroethane. The stability constants of the complexes involving N-heteroaromatic bases characterized by tow vicinal nitrogen atoms having lone pairs pointing to each other are higher than predicted from their basicity. Possible differences between protonation and hydrogen bond formation are discussed. Nheteroaromatic bases such as tri(2-pyridyl)-1,3,5-triazine or phenanthrolines cannot be considered as proton sponges but their behaviour is intermediate between that of the classical heteroaromatic bases and the proton sponges.     

Evaluation of the use of liquid dishwashing compounds to control bacteria in kitchen sponges

A test procedure for evaluating the effect of adding commercial liquid hand dishwashing detergents to kitchen sponges to control microbial growth is described. Claims for this type of application are being made on dishwashing detergents throughout the world. In this evaluation, commercially available kitchen sponges were stripped of antimicrobial compounds. Sponges were then inoculated with a pool of 7 microorganisms which consisted of gram positives, gram negatives, and yeast. Inoculated sponges were treated with the detergent as recommended by the manufacturer and allowed to incubate for 16 h at ambient temperature. Surviving microorganisms were then quantitated using either the spiral or pour plate method. Tests were run using both clean sponges and sponges soiled with 0.5% nonfat dry milk (NFDM). Untreated sponges showed stasis or slightly increased bacterial populations after the incubation period in the absence of NFDM. Significant increases of up to 3 log cfu/mL were observed for untreated sponges when soiled with NFDM. Statistically significant reductions were observed for clean sponges (99.8-99.9998%) and sponges soiled with NFDM (87.6-99.9%) when detergents making "antibacterial sponge" claims were added to the inoculated sponges. Statistically significant differences between detergents making "antibacterial sponge" claims were also observed.     

Beryllium‐Based Anion Sponges: Close Relatives of Proton Sponges

Through the use of high‐level ab initio and density functional calculations it is shown that 1,8‐diBeX‐naphthalene (X=H, F, Cl, CN, CF₃, C(CF₃)₃) derivatives behave as anion sponges, very much as 1,8‐bis(dimethylamino)naphthalene derivatives behave as proton sponges. The electron‐deficient nature of the BeX substituents, which favors strong charge transfer from the anion towards the former, results in anion affinities that are among the largest ones reported for single neutral molecules.     

“Proton Sponges” and the Geometry of Hydrogen Bonds: Aromatic Nitrogen Bases with Exceptional Basicities

Certain aromatic diamines (the “proton sponges”) are found to have exceptionally high basicity constants: this is due to spatial interaction of the basic centers, which are in close proximity. The two factors which are most important in causing this effect are, on the one hand, the extreme steric strain in these systems and the destabilizing effect of the overlap of the nitrogen lone pairs of the neutral diamines and, on the other, the strong N?H?N hydrogen bonds which are formed on monoprotonation and which lead to a considerable relaxation of the steric strain. By the systematic variation of the structures of such aromatic diamines we have been able to study these effects as a function of steric factors, in particular of the geometry and the bond length of the N?H?N hydrogen bonds, by means of X-ray structural analysis. The hydrophobic shielding of the basic centers and the N?H?N hydrogen bonds, which was characteristic of the “proton sponge” compounds studied previously, is indeed responsible for the extremely low rate of protonation and deprotonation of these compounds; however, it apparently has no influence on their high thermodynamic basicity. The recent synthesis and basicity determination of a new type of “proton sponge” with no hydrophobic shielding whatever show that not only very strong but also kinetically active bases are accessible using the “proton sponge” concept. Their unusual properties, which are discussed here as the result of steric interactions between two basic centers, provide examples of the fact that cooperative steric interactions of reactive structural elements can lead to properties which cannot be derived from an isolated consideration of the various functional groups. Such “proximity effects” are certainly of general importance in chemistry and biochemistry; the study of their structure-function relationships is worthy of closer consideration.     

Hybrid organic-inorganic catalytic mesoporous materials with proton sponges as building blocks

Non-ordered organic-inorganic mesoporous hybrid materials with basic sites have been synthesized following a fluoride-catalysed sol-gel process at neutral pH and low temperatures that avoids the use of structural directing agents (SDAs). Proton sponges have been used as the organic builder of the hybrids, while the inorganic part corresponds to silica tetrahedra. The proton sponges are diamines that exhibit very high basicity and, after functionalization, have been introduced as part of the walls of the mesoporous silica by one-pot synthesis. Several hybrids with different organic loadings have been synthesized and characterized by gas adsorption, thermogravimetric and elemental analysis, solid state MAS-NMR and FTIR spectroscopy. These hybrids show high activity as base catalysts and can be recycled.     

Intra-annular cyclophane diamines as proton sponges: a computational study

Gas-phase proton affinities of cyclophanes containing intra-annular amino groups were calculated using density functional theory (DFT) at the B3LYP/6-31+G^∗∗//B3LYP/6-31G^∗ level. They are higher in magnitude as those for proton sponges such as 1,8-bisaminonaphthalene, however, they are slightly weaker bases than 1,8-bis(dimethylamino)naphthalene. The high basicity of the cyclophane diamines is attributed mainly to their structural flexibility, which allows them to maximize the hydrogen bond strength in the cations by achieving N-H?N linearity, while strain relief upon protonation is less important. Another contributing factor is the stabilizing interaction of the added proton with adjacent phenyl π systems of the cyclophanes. Barriers for proton transfer between the nitrogen atoms of the diamine cations are also reported.     

Anti-inflammatory metabolites from marine sponges

Marine sponges are a rich source of biologically active secondary metabolites with novel chemical structures. Eighty four anti-inflammatory compounds have been isolated from marine sponges. This is the first comprehensive review presenting the structures and anti-inflammatory activities of marine sponge metabolites. (100 references).     

Decharging of globular proteins and protein complexes in electrospray

Electrospray ionization mass spectrometry (ESI-MS) is a valuable tool in structural biology for investigating globular proteins and their biomolecular interactions. During the electrospray ionization process, proteins become desolvated and multiply charged, which may influence their structure. Reducing the net charge obtained during the electrospray process may be relevant for studying globular proteins. In this report we demonstrate the effect of a series of inorganic and organic gas-phase bases on the number of charges that proteins and protein complexes attain. Solution additives with very strong gas-phase basicities (GB) were identified among the so-called "proton sponges". The gas-phase proton affinities (PA) of the compounds that were added to the aqueous protein solutions ranged from 700 to 1050 kJ mol(-1). Circular dichroism studies showed that in these solutions the proteins retain their globular structures. The size of the proteins investigated ranged from the 14.3 kDa lysozyme up to the 800 kDa tetradecameric chaperone complex GroEL. Decharging of the proteins in the electrospray process by up to 60 % could be achieved by adding the most basic compounds rather than the more commonly used ammonium acetate additive. This decharging process probably results from proton competition events between the multiply protonated protein ions and the basic additives just prior to the final desolvation. We hypothesize that such globular protein species, which attain relatively few charges during the ionization event, obtain a gas-phase structure that more closely resembles their solution-phase structure. Thus, these basic additives can be useful in the study of the biologically relevant properties of globular proteins by using mass spectrometry.     

N,N,N′-Trialkyl-1,8-diaminonaphthalenes: convenient method of preparation from protonated proton sponges and the first X-ray information

A simple procedure for the synthesis of N,N,N′-trialkyl-1,8-diaminonaphthalenes is described. It consists in partial demethylation (dealkylation) of commercially available proton sponge [1,8-bis(dimethylamino)naphthalene] and some of its derivatives at heating with HBr-KI-DMF system. Limitation, scope and a possible mechanistic pathway for the reaction are discussed. For isomeric 8-dimethylamino-1-methylamino- and 1-dimethylamino-8-methylamino-4-nitronaphthalenes, X-ray measurements have been conducted. The first examples of complete realkylation reactions in the naphthalene proton sponges are reported.     

peri-Naphthylenediamines

Tertiary alcohols containing the 4,5-bis(dimethylamino)-1-naphthyl group were synthesized. The carbocations that formed from α-methyl-containing alcohols in an acidic medium underwent smooth El elimination to give the corresponding unsaturated derivatives of the “proton sponge” in good yields. At the same time, the carbocation generated from 4-(α-hydroxybenzhydryl)-1,8-bis(dimethylamino)naphthalene was converted into a benzo-[a]fluorene derivative as a result of a complex reaction which has been previously unknown in the chemistry of “proton sponges.” The structure of the latter derivative was established by X-ray diffraction analysis. For Part 26, see Ref. 1; this paper simultaneously presents Part 5 of the series “Resonance-stabilized α-naphthylmethyl carbocations and derived spiro compounds;” for Part 4, see Ref. 2. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1103–1108, June, 2000.     

Substituted diazatetracyclo[4.4.0.1(3,10).1(5,8)]dodecanes as stable caged proton sponges

Herein, we report a molecular framework design differing significantly from the traditional topology of proton sponges. We developed a synthetic approach to the preparation of caged secondary amines by acid-catalyzed rearrangement of fused tetracyclic heterocycles synthesized by intramolecular criss-cross cycloaddition. Alkylation of amines led to air nonsensitive diazatetracyclo[4.4.0.1(3,10).1(5,8)]dodecanes (DTDs) with rare alicyclic scaffolding in high overall yields. Their pK(BH)+ values were determined by transprotonation experiments as well as their sensitivity toward nucleophiles, acids and bases. Crystal structures of free base and monoprotonated form are discussed.     

Spin-spin coupling across intramolecular N-H(+)-N hydrogen bonds in models for proton sponges: an ab initio investigation

Ab initio calculations have been performed to obtain structures and coupling constants (1)J(N-H), (1h)J(H-N), and (2h)J(N-N) for models of proton sponges with symmetric and asymmetric N-H(+)-N intramolecular hydrogen bonds (IMHBs). For a given model, the asymmetric structure has a lower energy, a longer N-N distance, and a hydrogen bond which has a greater deviation from linearity. The computed values of (2h)J(N-N) for the models are significantly less than predicted values based on the distance dependence of (2h)J(N-N) for complexes with intermolecular N-H(+)-N hydrogen bonds. However, the reduced values of (2h)J(N-N) cannot be attributed solely to the distortion of the hydrogen bond in the models, but also reflect differences in s electron populations at the nitrogens in both the ground state and the excited states which couple to it through the Fermi-contact (FC) operator. Values of (2h)J(N-N) for IMHBs can be related quadratically to the N-N distances in the models, and demonstrate that there is no discrepancy between computed values of (2h)J(N-N) at the short N-N distances found in these systems and experimental data for proton sponges.     

Hemispiroalkaplanes: hydrocarbon cage systems with a pyramidal-tetracoordinate carbon atom and remarkable basicity

A new class of saturated hydrocarbons, in which a spiropentane-type unit is bound by a cyclic hydrocarbon, has been investigated by using ab initio molecular orbital calculations at the B3-LYP and MP2 levels. These molecules have been given the trivial name hemispiroalkaplanes. Hemialkaplanes, which are analogous molecules built-up from a neopentane-type unit and a cyclic hydrocarbon, have also been examined. The hemispiroalkaplanes are predicted to contain a pyramidal-tetracoordinate carbon atom that possesses a lone pair of electrons. Protonation at this apical carbon atom is found to be highly favourable, resulting in a remarkably high basicity for a saturated hydrocarbon. The proton affinities of the hemispiroalkaplanes are calculated to be more than 1170 kJmol(-1), even greater than that of the diamine "proton sponges". Structural parameters, heats of formation and strain energies for the novel hydrocarbons are detailed.     

Unequivocal 13C NMR assignment of cyclohexadienyl rings in bromotyrosine‐derived metabolites from marine sponges

Bromotyrosine‐derived compounds are commonly isolated from Verongida sponges and are a major class of marine natural products. Here we report on the unequivocal ¹³C NMR assignment of the brominated carbons at positions C‐2 and C‐4 of the cyclohexadiene ring, two carbons whose resonances are often incorrectly assigned. Interpretation of HMBC data acquired for a series of known bromotyrosine analogues, which included ianthesine E (1), aerothionin (2), 11‐hydroxyaerothionin (3), and 11,19‐dideoxyfistularin‐3 (4), allowed us to unequivocally assign the carbons in question, C‐2 and C‐4, through the observance of unique HMBC correlations from the C‐1 hydroxyl proton. Here we present the complete 2D NMR data sets recorded in DMSO‐d₆ for 2–4 that were used to confirm the assignment and establish the working model. Using this model, a survey of the literature revealed that many members of this structure class had been wrongly assigned. This paper serves to reassign those compounds whose ¹³C NMR assignment at positions C‐2 and C‐4 of the cyclohexadiene ring should be reversed. Copyright © 2012 John Wiley & Sons, Ltd.