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Pyrazine‑2‑amidoxime (PAOX) is a prototypical sp2-hybridized amidoxime. Although, we described first time in details PAOX structure in solid state, the profile of PAOX behavior in aqueous solution still needs to be improved. While, acid-base properties of PAOX have been tried to define just once, the presented description was not complete and based only on the results of potentiometry during complexometric studies. The selection of method gives rise problems to observation the protonation or deprotonation processes of compound studied. Due to above, the presented studies show first time the complete description of PAOX acid-base properties by obtaining its pKa, solubility, partition (P) and distribution (D) coefficients using various methods. Among them, experiments: potentiometry; UV spectrophotometry by using Hammett's function and pH-metric titrations; cyclic voltammetry (CV) with glassy carbon electrode (GCE) and with GCE electropolymerized by poly‑ l ‑glycine (PGGCE); 1H NMR and theoretical calculations (DFT). Generally, combined four types of experimental and theoretical methods were used to estimate PAOX macro acidic-dissociation constants values. Moreover, log P and log D were determined spectrophotometrically and calculated also by DFT methods. No previous reports were found in the presented form regarding the complete drug-like properties, including negative together with positive values of pKa. Additionally, we proved by our electrochemical results that the quantitative analysis of PAOX do not need the special conditions of the electrode used in research. Hence, the comparison of our results to those described in the literature about analysis made for others, amidoxime derivatives.

For favored and rare prototropic tautomers of isocytosine (iC), geometric consequences of ionization, one-electron loss (iC − e → iC+ ) and one-electron gain (iC + e → iC− ), have been studied. Effects of protonation and deprotonation on geometry of neutral isocytosine (iC + H+ → iCH+ and iC − H+ → iC−H−) as well as of its charged radicals (iC− + H+ → iCH and (iC+ − H+ → iC−H ) have also been examined for selected isomers. Bond length alternation for the ground states of individual isomers, investigated in two extreme environments at the B3LYP/6-311+G(d,p) and PCM(water)//B3LYP/6-311+G(d,p) levels, have been quantitatively described using the geometry-based HOMED (harmonic oscillator model of electron delocalization) index. Generally, one-electron loss, one-electron gain, and proton-transfer reactions change electron delocalization in isocytosine isomers, and consequently the HOMED values. However, the HOMED indices calculated for structures optimized at the DFT level vary analogously to those optimized with PCM. When compared to other pyrimidine bases, cytosine (C) and uracil (U), exhibiting analogous tautomeric equilibria, rotational and/or geometric isomerism of exo groups ( NH2/ NH and/or OH/ O), linear trends can be distinguished between the HOMED values of negatively ionized isomers (iC− , C− , and U− ). For positively ionized isomers (iC+ , C+ , and U+ ), relations between the HOMED indices seem to be more complex. This indicates some similarities in mechanisms of one-electron gain and some differences in mechanisms of one-electron loss for isomers of pyrimidine bases. Hence, the HOMED descriptor can be considered as some kind of ‘marker index’ for ionization mechanism in analogous series of tautomeric π-electron systems.

Quantum chemical calculations were carried out for deprotonated (P−) and protonated purine (PH+) and for adducts with one alkali metal cation (P−M+ and PM+, where M+ is Li+ or Na+) in the gas phase {B3LYP/6-311+G(d,p)}, a model of perfectly apolar environment, and for selected structures in aqueous solution {PCM(water)//B3LYP/6-311+G(d,p)}, a reference polar medium for biological studies. All potential isomers of purine derivatives were considered, the favored structures indicated, and the preferred sites for protonation/deprotonation and cationization reactions determined. Proton and metal cation basicities of purine in the gas phase were discussed and compared with those of imidazole and pyrimidine. Bond-length alternations in the P, PH+, P−M+, and PM+ forms were quantitatively measured using the harmonic oscillator model of electron delocalization (HOMED) indices and compared with those for P. Variations of the HOMED values when proceeding from the purine structural building blocks, pyrimidine and imidazole, to the bicyclic purine system were also examined. Generally, the isolated NH isomers exhibit a strongly delocalized π-system (HOMED > 0.8). Deprotonation slightly increases the HOMED values, whereas protonation and cationization change the HOMED indices in different way. For bidentate M+-adducts, the HOMED values are larger than 0.9 like for the largely delocalized P−. The HOMED values correlate well in a comprehensive relationship with the relative Gibbs energies (ΔG) calculated for individual isomers whatever the purine form is, neutral, protonated, or cationized. When PCM-DFT model was utilized for P−, PH+, PM+, and P−M+ (M+ = Li+) both electron delocalization and relative stability are different from those for the molecules in vacuo. The solvation effects cause a slight increase in HOMEDs, whereas the ΔEs decrease, but in different ways. Hence, contribution of particular isomers in the isomeric mixtures of PH+, PM+, and P−M+ also varies.

Compounds containing biguanide moiety, such as buformin, phenformin, and metformin are well recognized for their antihyperglycaemic action. Imeglimin is a dihydro-1,3,5-triazine that can be conside...

Quantum-chemical calculations have been performed for twenty-one favored and rare isomers of neutral isocytosine in two extreme media, in the gas phase {B3LYP/6-311+G(d,p)} and in aqueous solution {PCM(water)//B3LYP/6-311+G(d,p)}. In aqueous solution, the most aromatic hydroxy-amino form, favored in the gas phase, becomes a rare form, and less delocalized amino-oxo forms predominate. Monoprotonation of the favored isomers leads also to two different forms, the N1-protonated hydroxy-amino cation in the gas phase, and the N1-protonated amino-oxo cation in aqueous solution. Electron delocalization for the solvated isocytosine isomers is parallel to that observed for the isolated molecules. However, aromaticity is not the main factor that influences isomeric stabilities. Geometric and energetic results for neutral isocytosine isomers, compared to those for other pyrimidine bases (uracil and cytosine), show interesting similarities in electron delocalization and important differences in energetic stabilities. Some parallelism in energetic parameters exists for amine-imine and enamine-imine conversions, and separately for amide-iminol and keto-enol ones.

A large number of experimental and computational gas-phase basicity data for monocyclic and polycyclic aromatic azines, including values taken from the recent literature, were examined to explore how internal (structural) effects influence gas-phase basicity (GB) and/or proton affinity (PA) of aza nitrogen. Substituent electron withdrawing effects on the pyridine ring may induce a decrease in PA as large as 200 kJ mol −1 . Polarizability of alkyl and aryl groups increases experimental PA by up to 100 kJ mol −1 , as in the case of 1- and 2-aza[6]helicene. The many computational studies involving azines, often performed in search of “superbasicity”, were reviewed. Calculations at the DFT level, carried out on chelating azine systems bearing strong electron donor substituents, yielded PAs much higher than the current upper limit of the experimental scale. The structural variety of aromatic azines, from hexaazabenzene to the phosphazeno derivative of azacalix[3](2,6)pyridine, generates aza-nitrogen PAs ranging from ca. 650 up to 1300 kJ mol −1 .

The guanylated bioamine agmatine, H 2 N ( CH 2 ) 4 N C ( NH 2 ) 2 ⇌ H 2 N ( CH 2 ) 4 NH C ( NH 2 ) NH , formed by decarboxylation of the proteinogenic amino acid arginine, plays an important role in the physiological processes of living organisms. Its structure is marked by the flexibility of the four-carbon chain connecting the two potentially basic amino and guanidino sites. Owing to these noteworthy properties and the questionable literature data on its protonated forms, its structure and intrinsic basicity were carefully scrutinized at the B3LYP/6–311+G(d,p) level. Three types of isomerism (prototropy and geometrical isomerism of the guanidino group, and rotational isomerism of the chain) were considered in this structural investigation. Various tautomers, as well as E/Z-isomers of the free guanidino group, various coiled and open conformations of the alkyl chain, and potential protonation sites (alkylamino and guanidine imino) were analyzed. Due to n-π conjugation in the guanidino group, its amino nitrogen (erroneously taken in the literature as the site of monoprotonation) is the least probable candidate as a protonation site. The H2N(CH2)4 N C(NH2)2 tautomer slightly predominates in the tautomeric mixture. One of its coiled conformations, facilitating the formation of an internal hydrogen-bond, possesses the lowest enthalpy, whereas one of its open conformations has the lowest Gibbs energy. The guanidine imino-nitrogen is without any doubt the favored site of protonation in the gas phase and in solution. Monoprotonated agmatine prefers the coiled conformations, all stabilized by intramolecular H-bonding, in a scorpion-shaped arrangement. The DFT-estimated PA of agmatine is higher than the experimental PAs reported for other bidentate bioamines (cadaverine, putrescine, and histamine) and close to that of the superbasic bicyclic guanidine MTBD. A guanylation of one amino group of diamines (NH2 in putrescine or NMe2 in tetramethyldiamines) increases their PA by ca. 60 kJ mol−1.

The results of the first structural studies (with the use of both experimental and theoretical methods) on pyrazine-2-amidoxime (PAOX) were shown and discussed. FT-IR spectra were recorded in different concentrations of the PAOX in apolar solvent to check the possibility of the inter- or intramolecular hydrogen-bond formation. All possible tautomers–rotamers of PAOX were then theoretically considered at the DFT(B3LYP)/6-311+G** level in vacuo. For selected isomers, calculations were also performed at higher levels of theory {B3LYP/6-311+G(3df,2p) and G3B3}. Based on the results of DFT calculations, the most stable isomers were found, and their total free energies and infrared spectra were calculated. The energy variation plots for the N8C7N9O10 and N1C2C7N9 dihedral angles were also computed to find two energy barriers, one for E/Z isomerization around the C7N9 double bond and the other one for rotation of the pyrazinyl ring around the C2C7 single bond. The results show that the stability of the PAOX isomers strongly depend on their configuration and orientation of the substituents. The possibilities of inter- and intramolecular hydrogen bonds were also experimentally and theoretically checked. Finally, a potential of mean force was determined in CHCl3 for a dimer of PAOX with hexamethylphosphoramide. Both, experimental and theoretical results are in agreement. Copyright © 2016 John Wiley & Sons, Ltd.

Effects of positive and negative ionization, deprotonation and protonation, cationization with the simplest metal cation (Li+), and hydrogen-bond formation with the simplest acid (HF) on bond lengths alternation have been studied for the psychoactive stimulant caffeine by quantum-chemical methods. For investigations, the recently extended geometry-based HOMED (harmonic oscillator model of electron delocalization) descriptor has been applied to n-π and π-π conjugated monocyclic and bicyclic fragments of caffeine. This structural index quantitatively describes variations of electron delocalization when proceeding from neutral to ionized, deprotonated, protonated, cationized, and H-bonded forms. Ionization directly affects the number of electrons delocalized in caffeine and cause the greatest HOMED variations. Deprotonation and protonation of caffeine moderately change the bond lengths alternation. Noncovalent interactions, in particular cationization, only slightly influence caffeine-aromaticity. Investigations on protonation, cationization, and H-bonding of caffeine show additionally that the favored basicity site is not always the same in this polyfunctional alkaloid.

Intramolecular proton-transfers (prototropic conversions) have been studied for the guanine building block isocytosine (iC), and effects of positive ionization, called one-electron oxidation (iC – e → iC+•), and negative ionization, called one-electron reduction (iC + e → iC–•), on tautomeric conversions when proceeding from neutral to ionized isocytosine have been discussed. Although radical cations and radical anions are very short-lived species, the ionization effects could be investigated by quantum-chemical methods. Such kind of studies gives some information about the labile protons and the most basic positions in the neutral and radical forms of the tautomeric system. For investigations, the complete isomeric mixture of isocytosine has been considered and calculations performed in two extreme environments, apolar {DFT(B3LYP)/6-311+G(d,p)} and polar {PCM(water)//DFT(B3LYP)/6-311+G(d,p)}. For selected isomers, the G4 theory has also been applied. There are no good relations for energetic parameters o...

Pyrazine-2-amidoxime (PAOX) is a structural analogue of a popular drug, i.e. pyrazine-2-carboxamide (PZA). The crystalline PAOX was obtained by diffusion as a method of crystallization. Various types of intermolecular interactions between the H-bond donors (CH, NH, and OH) and H-bond acceptors (hydroxyl O, imino N, aza N) were found between PAOX molecules in X-ray diffraction studies. It was observed in the crystal structure that PAOX forms not only dimers but also stable helical-like polymers, stabilized by intermolecular interactions between two neighbouring molecules. Their geometric, energetic and spectroscopic properties were also characterised by DFT methods. Thermal decomposition of PAOX was examined with the use of a TG-IR analysis (20–1000 °C), and the results were further resolved. Electrochemical behaviour of the compound studied in acetonitrile in the absence or presence of methanol was described in detail, and mechanisms of the anodic oxidation and cathodic reduction were proposed. The complexometric properties of PAOX were examined against selected d-block metal ions in acetonitrile, as well as in aqueous solution. Biological assay of PAOX was performed to determine the antimicrobial activity and potential pharmaceutical applications. The minimum inhibitory (MIC) and minimal bactericidal (or fungicidal) concentrations (MBC/MFC) for PAOX were determined against six microorganisms.

The complete tautomeric mixture consisting of nine prototropic tautomers has been studied in the gas phase at the DFT(B3LYP)/6-311+G(d,p) level for neutral, oxidized, and reduced cytosine. Rotational isomerism of the exo –OH group and geometrical isomerism of the exo =NH group have also been considered. Tautomeric conversions possible for cytosine have been compared with those for its structural models, 4-amino- and 2-hydroxypyrimidine. Effects of intramolecular interactions between neighboring groups for cytosine are analogous to those observed for model compounds. Although they are not very strong, they are sufficient to influence tautomeric equilibria and relative stabilities of individual tautomers. One-electron oxidation and one-electron reduction change tautomeric preferences. Tautomers that are rare forms for neutral cytosine become favored ones for oxidized and reduced cytosine. Aromaticity is not the main factor that dictates the tautomeric preferences. Stability of functional groups seems to be more important than full electron delocalization.

DFT calculations have been performed for a series of push-pull nitriles [(R2N)n(X═Y)iC≡N, where i = 0, 1, or 2, n = 1, 2, or 3, R2N = H2N, Me2N, or C4H8N, X = CH, N, or P, Y = CH or N]. The possible protonation N-sites (N-cyano, N-imino, and N-amino) have been examined and their proton affinities (PA) estimated. For all compounds in the series, even for those containing the guanidino, phosphazeno, and diphosphazeno pushing groups, the N-cyano atom is the favored site of protonation. The n-π conjugation strongly decreases the PA value of the pushing amino group in favor of the pulling cyano one. Nitriles with the phosphazeno groups [(R2N)3P═N-P(R2N)2═N and (R2N)3P═N] exhibit the strongest basicity in the series. Some of them (with PA1000 kJ mol(-1)) are stronger bases than DMAN, the so-called "proton sponge". Nitriles bearing the guanidino group [(R2N)2C═N] are less basic than those with the phosphazeno group [(R2N)3P═N] but more basic than those with the formamidino group (R2N-CH═N) containing the same substituent R. The N-imino atoms, present in the transmitter group (X═N, X = CH, N, or P), display PA values lower than those of the N-cyano site by more than 30 kJ mol(-1). When proceeding from the unsubstituted derivatives (R = H) to the methylated ones (R = Me), the Me groups at the N-amino atom increase the PA value of the N-cyano site for Me2N-X═Y-C≡N (X, Y = CH or N) by ca. 30-60 kJ mol(-1). For the guanidino and phosphazeno derivatives containing two and three amino groups, respectively, this effect is not additive. The four Me groups for (Me2N)2C═N-C≡N and the six Me groups for (Me2N)3P═N-C≡N increase the PA(N-cyano) values by only 30-50 kJ mol(-1). The C≡N bond lengths of the neutral forms are well correlated with the PA(N-cyano) values.

Effects of the pushing groups (electron donors) for nitriles increase as follows: H2N < H2N–NN < H2N–CHCH < H2N–CHN < (H2N)2CCH < (H2N)2CN < (H2N)3PN. The G2(MP2)-calculated PA(N-cyano) for (H2N)2CN–CN and (H2N)3PN–CN are larger than that of HCN by 186 and 250 kJ mol−1, respectively. The hypothesis of protonation in the gas phase at the N-imino and N-amino atoms, corresponding respectively to PAs weaker by 30 and 70 kJ mol−1 than that of the N-cyano site, can be rejected.

Heterocycles containing one or more amidine moieties {–NH–C(R) N–} such as adenine and its building blocks, imidazole, 4-aminopyrimidine, and purine, are excellent examples of tautomeric systems for which changes of position(s) of labile proton(s) cause parallel changes of geometric and energetic parameters for prototropic tautomers. One-electron oxidation has a slight effect on this relationship. The amino-imine conversions within the amidine group(s) are favored. Well delocalized (aromatic) tautomers, containing labile proton(s) at heteroatom(s), are major, minor, or rare forms. Non-aromatic tautomers with a labile proton at the C atom can be considered as very rare isomers. Dramatic changes take place for reduced heterocycles. Electron delocalization is not the main factor that dictates tautomeric preferences. The HOMED/ΔE relationship seems to be more complex. The enamino-imine conversions predominate and some very rare forms have the lowest energies. This clearly shows the importance of very rare tautomers, often neglected in proton-transfer, electron-transfer, and ion–radical reactions.

Substituted biguanides are known for their biological effect, and a few of them are used as drugs, the most prominent example being metformin (1,1-dimethylbiguanide, IUPAC name: N,N-dimethylimidodicarbonimidic diamide). Because of the presence of hydrogen atoms at the amino groups, biguanides exhibit a multiple tautomerism. This aspect of their structures was examined in detail for unsubstituted biguanide and metformin in the gas phase. At the density functional theory (DFT) level {essentially B3LYP/6-311+G(d,p)}, the most stable structures correspond to the conjugated, push–pull, system (NR2)(NH2)C═N–C(═NH)NH2 (R = H, CH3), further stabilized by an internal hydrogen bond. The structural and energetic aspects of protonation and lithium cation adduct formation of biguanide and metformin was examined at the same level of theory. The gas-phase protonation energetics reveal that the more stable tautomer is protonated at the terminal imino C═NH site, still with an internal hydrogen bond maintaining the structu...

Quantum-chemical calculations {G2 and/or B3LYP/6-311+G(d,p)} were performed in the gas phase for neutral and ionized hydroxyazines (2- and 4-hydroxy derivatives of pyridine and pyrimidine). For each derivative, all possible tautomeric conversions were considered and all possible prototropic tautomers (OH, NH, and CH) analyzed. Rotational isomerism of the OH group was also taken into account. An interesting change of the relative stabilities takes place when proceeding from the neutral to ionized forms. Positive ionization favors the NH tautomers, and negative ionization the CH ones, except 2-hydroxypyrimidine for which the NH tautomer predominates for both ionized forms. A good relation exists between prototropy and electron delocalization solely for the neutral NH and CH tautomers. The OH forms are separated from the subfamily of the NH and CH tautomers due to significant differences between the stabilities of the tautomeric oxo and hydroxy groups. Intramolecular interactions affect both the geometric and energetic parameters, but the relative stabilities in higher degree. When compared to series of aminoazines, the total geometric effects of the exo OH/ O and NH2/ NH groups are similar for neutral azines.

Quantum-chemical calculations were performed for neutral 2-aminopyrimidine (2APM) and for its ionized forms (2APM − e → 2APM+ and 2APM + e → 2APM− ) in the gas phase {DFT(B3LYP)/6-311+G(d,p)} and in water solution {PCM(water)//DFT(B3LYP)/6-311+G(d,p)}. For calculations, the complete tautomeric mixture containing the amino and imino forms was considered. Geometric isomerism of the exo NH group for the imino forms was also taken into account. There is a good correlation between prototropy and electron delocalization for the neutral isomers of 2APM. The aromatic amine NH2 tautomer is favored for neutral and ionized 2APM in the gas phase and in water solution. Positive and negative ionization increase the stability of the imine NH isomers containing the labile proton at the endo N-aza atom that their contribution cannot be neglected in the positively and negatively ionized tautomeric mixture. Ionization influences also electron delocalization. For the major and minor forms of 2APM, the exo N atom may lose preferentially one of the non-bonding electrons, and the pyrimidine ring may gain one excess electron. The adiabatic ionization potential and the adiabatic electron affinity change when going from the gas phase to water solution by ca. 2 eV.

Electron delocalization, which plays a principal role for the tautomeric adenine system, was studied for all possible major, minor, and rare tautomers of neutral, oxidized, and reduced adenine. The recently extended geometry-based HOMED (harmonic oscillator model of electron delocalization) index, which measures any type of resonance conjugation (π–π, n–π, and σ–π), was applied to the geometries of adenine isomers optimized at the DFT(B3LYP)/6-311+G(d,p) level. For neutral adenine, variations of the HOMED indices estimated for the whole tautomeric systems (eleven bonds) are almost parallel to those of the relative Gibbs energies (Δ G ), which measure the thermodynamic stabilities of individual isomers. Some subtle effects, being a consequence of intramolecular interactions of neighboring groups and variability of electron delocalization for the imidazole and pyrimidine fragments, perturb this relation. One-electron oxidation has slight effect on the general HOMED/Δ G relation. The favored canonical NH NH tautomer is well delocalized for both neutral and oxidized adenine. One-electron reduction dramatically changes electron delocalization and thermodynamic stability of individual tautomers that two subfamilies can be distinguished on the HOMED vs Δ G plot, one for the NH NH tautomers and the other one for the NH CH isomers. The reduced canonical NH NH tautomer (although well delocalized) is not the favored one. The non-aromatic NH CH tautomer predominates in the tautomeric mixture, indicating that aromaticity is not the main factor that dictates the tautomeric preference for reduced adenine.

Nitrogen bases containing one or more pushing amino-group(s) directly linked to a pulling cyano, imino, or phosphoimino group, as well as those in which the pushing and pulling moieties are separated by a conjugated spacer (C═X)n, where X is CH or N, display an exceptionally strong basicity. The n-π conjugation between the pushing and pulling groups in such systems lowers the basicity of the pushing amino-group(s) and increases the basicity of the pulling cyano, imino, or phosphoimino group. In the gas phase, most of the so-called push–pull nitrogen bases exhibit a very high basicity. This paper presents an analysis of the exceptional gas-phase basicity, mostly in terms of experimental data, in relation with structure and conjugation of various subfamilies of push–pull nitrogen bases: nitriles, azoles, azines, amidines, guanidines, vinamidines, biguanides, and phosphazenes. The strong basicity of biomolecules containing a push–pull nitrogen substructure, such as bioamines, amino acids, and peptides contai...

Consequences of one-electron oxidation and one-electron reduction were studied for imidazole (I) in the gas phase and in water (apolar and polar environment, respectively) using quantum-chemical methods {DFT(B3LYP)/6-311+G ** , G2, G2(MP2), G3B3, and PCM//B3LYP/6-311+G(d,p)}. For calculations, all possible prototropic tautomers (NH and CH) were considered for the neutral and redox forms of I. Independently on environment (gas phase or water), an interesting change of the composition of the tautomeric mixture takes place when going from the neutral to reduced form of imidazole. One-electron reduction (I + e → I − ) increases stability of the CH tautomers (non-aromatic forms). On the other hand, one-electron oxidation (I − e → I + ) has no important effect on the tautomeric preferences. The NH tautomers predominate for both neutral (I) and oxidized imidazole (I + ). For the favored forms in the gas phase, the oxidation Gibbs energy is close to 200 kcal mol −1 , and the reduction Gibbs energy is more than ten times lower. In water, these energies are lower by more than 50 kcal mol −1 . Independently on the state of oxidation, π-electrons are more delocalized for the NH than CH tautomers.

Quantum-chemical calculations {DFT(B3LYP)/6-311+G(d,p)} were performed for all possible tautomers (aromatic and nonaromatic) of neutral 2- and 4-aminopyridines and their oxidized and reduced forms. One-electron oxidation has no important effect on the tautomeric preference for 2-aminopyridine. The amine tautomer is favored. However, oxidation increases the stability of the imine NH tautomer, and its contribution in the tautomeric mixture cannot be neglected. In the case of 4-aminopyridine, one-electron oxidation increases the stability of both the amine and imine NH tautomers. Consequently, they possess very close energies. As major tautomers, they dictate the composition of the tautomeric mixture. The CH tautomers may be considered as very rare forms for both neutral and oxidized aminopyridines. A reverse situation takes place for the reduced forms of aminopyridines. One-electron reduction favors the C3 atom for the labile proton for both aminopyridines. This may partially explain the origin of the CH tautomers for the anionic states of nucleobases containing the exo NH(2) group.

The HF, MP2, and DFT structures of neutral (N 6 ) and monoprotonated (N 6 H + ) hexazine, nitrogen analogues of benzene, were discussed. For neutral N 6 , the extended geometry-based HOMED (harmonic oscillator model of electron delocalization) index, being a measure of π-electron delocalization, is close to that of benzene. Protonation of one N atom in planar N 6 has no important effect on the HOMED value. Contrary to benzene, planar N 6 H + does not lose its aromatic character. π-Electrons of the ring are not engaged in the formation of the NH bond. The proton affinity (PA) of N 6 seems to be considerably lower than that of benzene (by ca. 16 kcal mol −1 at the G2 level), indicating great N N lone pairs repulsion and electron-withdrawing effects of the N-aza groups (ca. 12 kcal mol −1 for each N atom).

Quantum-chemical calculations were performed for all possible isomers of neutral aniline and its redox forms, and intramolecular proton-transfer (prototropy) accompanied by π-electron delocalization was analyzed. One-electron oxidation (PhNH(2) - e → [PhNH(2)](+•)) has no important effect on tautomeric preferences. The enamine tautomer is preferred for oxidized aniline similarly as for the neutral molecule. Dramatical changes take place when proceeding from neutral to reduced aniline. One-electron reduction (PhNH(2) + e → [PhNH(2)](-•)) favors the imine tautomer. Independently on the state of oxidation, π- and n-electrons are more delocalized for the enamine than imine tautomers. The change of the tautomeric preferences for reduced aniline may partially explain the origin of the CH tautomers for reduced nucleobases (cytosine, adenine, and guanine).

Amide–iminol tautomerism was studied for oxamic acid (OA) in the gas phase using various quantum-chemical methods (HF, MP2, DFT, and G2). All possible twenty tautomers–rotamers, four amide and sixteen iminol forms, were considered for the neutral molecule. At each level of theory, the amidization process (amide ← iminol) is favored for OA similarly as for the parent compound (formamide). Three amide and fourteen iminol rotamers of OA are found to be thermodynamically stable, among which the intramolecularly H-bonded amide structure has the lowest Gibbs free energy (G) in the gas phase. Low relative energies for the two other amide structures indicate that all of them may be present in the tautomeric mixture of OA. The G value of the most stable iminol structure is larger than those of the three amide isomers by ca. 10 kcal mol−1. This suggests that the amide form(s) of OA may be responsible for binding with large biomolecules (proteins, enzymes, receptors) and particularly for bioseparation of lactate dehydrogenase (LDH).

Change of the tautomeric preference was observed at the DFT(B3LYP)/6-311+G(d,p) level when proceeding from neutral to reduced phenol. One-electron reduction (PhOH + e → [PhOH] − ) favors the keto tautomer (2,4-cyclohexadienone). On the other hand, one electron oxidation (PhOH − e → [PhOH] + ) has no important effect on the tautomeric preference. The enol tautomer is preferred for oxidized phenol, similarly as for the neutral molecule. Independently on the state of oxidation, π-electrons are more delocalized for the enol tautomer than for the keto ones. Aromaticity dictates the tautomeric preference solely for the neutral and oxidized forms.

Complete tautomeric equilibria and π-electron delocalization were studied at the B3LYP/6-311+G** level for neutral purine (P) and its charged radicals (P+• and P−•). All possible nine tautomers (four NH and five CH forms) and all possible 36 tautomeric equilibria (six NiH NkH, twenty NH CH, and ten CiH CkH conversions) were considered. The greatest variations of the tautomeric equilibrium constants (as pKT) were observed for the NH CH conversions when proceeding from neutral to reduced purine (P + e P−•). These variations completely change the tautomeric preferences. One-electron oxidation (P − e P+•) has considerably smaller effect on the pKT values and does not change the tautomeric preferences. π-Electron delocalization depends on the position of the moving proton and on the type of the electron transfer. For individual tautomers, some linear relations between the relative stabilities and the HOMA (harmonic oscillator model of aromaticity) indices occur for neutral and oxidized purine. For reduced purine, a scatter plot is found. Copyright © 2010 John Wiley & Sons, Ltd.

Although series of N(1), N(1)-dimethyl-N(2)-arylformamidines and of 1,1,3,3-tetraalkyl-2-arylguanidines are structurally analogous and similar electron-ionization mass spectral fragmentation may be expected, they display important differences in the favored routes of fragmentation and consequently in substituent effects on ion abundances. In the case of formamidines, the cyclization-elimination process (initiated by nucleophilic attack of the N-amino atom on the 2-position of the phenyl ring) and formation of the cyclic benzimidazolium [M-H](+) ions dominates, whereas the loss of the NR(2) group is more favored for guanidines. In order to gain information on the most probable structures of the principal fragments, quantum-chemical calculations were performed on a selected set. A good linear relation between log{I[M-H](+)I [M](+*)} and sigma(R)(+) constants of substituent at para position in the phenyl ring occurs solely for formamidines (r = 0.989). In the case of guanidines, this relation is not significant (r = 0.659). A good linear relation is found between log{I[M-NMe(2)](+)/I [M](+*)} and sigma(p)(+) constants (r = 0.993).

To understand the formation and degradation processes of uric acid (UA) in living organisms we considered all possible tautomers–rotamers of UA by semiempirical (AM1) method, and next we used the ab initio (HF, MP2, and G2) and DFT methods to the most stable five isomers of UA selected at the AM1 level. Our calculations show evidently that at least two CH–NH forms should be considered in the tautomeric mixture of UA to understand the formation of the intermediate 5-hydroxyisourate (HIU) upon the UA oxidation by uricase. Intramolecular interactions and π-electron delocalization for UA are very similar to those occurring for its building blocks {purine (P), uracil (U), and 2-imidazolone (I)}. Tautomeric equilibrium constants for NH → OH, NH → CH, and OH → CH conversions in UA are close to those for U and I. Tautomeric equilibrium constants for NH → NH conversions in UA are close to those for P. Favored tautomers for UA, U and I are strongly stabilized by intramolecular interactions between the amide groups, whereas that for P is stabilized by π-electron delocalization and N9H⋯N3 intramolecular interaction. Aromaticity seems to be very important factor that influences the tautomeric preference for the systems which do not possess the exo functional groups.

Complete tautomeric equilibria were investigated for uracil at the DFT(B3LYP)/6-311+G(d,p) level to establish the stability order of all possible 18 tautomers-rotamers in the gas phase and to characterize their internal effects, polarity and aromatic character. Although the di-NH form strongly predominates (100%) in the mixture, the NH–OH, di-OH and CH–NH forms can be also considered. The favored tautomer is moderately stabilized by intramolecular interactions (attractions of the NH and C=O groups); it is also moderately polar and moderately delocalized. Stability of the functional groups (both amide functions) seems to be more important than intramolecular interactions, polarity and aromaticity. This is probably the main factor that dictates the tautomeric preferences in the uracil molecule.

Two types of bimolecular adducts were studied for the substrate and inhibitor of lactate dehydrogenase (LDH), one type of adducts between ionic species, α-keto-carboxylates (pyruvate and oxamate) and the guanidinium cation, and the other type of adducts between neutral species, α-ketocarboxylic (pyruvic and oxamic) acids and guanidine. Calculations were performed in the gas phase and aqueous solution using the MP2 and PCM methods and the 6-31++G** basis set. Application of the DFT(B3LYP) and PCM methods led to similar results. A change of the adducts' preference was observed when proceeding from the gas phase to aqueous solution. This change is in good agreement with the acidity–basicity scales in both phases. Formation constant (KHB) for adduct between neutral species is greater for pyruvic than for oxamic acid in the gas phase, whereas a reverse situation takes place in aqueous solution, where the KHB value for adduct between ionic species is smaller for pyruvate than for oxamate. The water molecules favor interactions of more polar oxamate with the guanidinium cation. Stronger interaction with this cation, a model of the arginine fragment of the LDH pocket, suggests that oxamate (inhibitor of LDH) has stronger binding properties in aqueous solution than pyruvate (substrate of LDH). Copyright © 2008 John Wiley & Sons, Ltd.

To study the N-aza effects on tautomeric equilibria, intramolecular interactions and π-electron delocalization in six-membered hydroxy derivatives, quantum-chemical calculations were performed for isolated phenol ( 1 ), its aza derivatives ( 2 – 20 ), and uracil ( U ). All possible tautomers–rotamers were considered for each derivative, and all possible tautomeric interconversions were analysed. An introduction of the N-aza group at 2-, 4- and/or 6-position in the phenol ring dramatically affects tautomeric equilibria. Although effects of the N-aza group(s) are not very high ( −1 ), they are sufficient to change the tautomeric preferences and the relative stabilities of individual tautomers. These changes partially explain, why the di-NH form (instead of more aromatic di-OH form) predominates for molecular uracil, and why the rare NH–CH form of uracil has exceptional stability. Profitable and unprofitable intramolecular interactions seem to be similar for azaphenols and uracil. The HOMED (harmonic oscillator model of electron delocalization) index, based on the original idea of the HOMA (harmonic oscillator model of aromaticity) index, describes well π-electron delocalization for phenol, azaphenols and uracil. Generally, the HOMED index diminishes when the number of the N-aza groups increases in the ring. It also decreases when going from OH through NH to CH tautomers.

The gas-phase lithium cation basicities (LCBs) were obtained for histamine (HA) and its agonist 2-(β-aminoethyl)-pyridine (AEP) from collision-induced dissociation of lithium adducts using Fourier-transform ion cyclotron resonance mass spectrometry (FT-ICR-MS). For measurements, MeO(CH 2 ) 2 OMe, Et 3 P O and (Me 2 N) 3 P O (HMPA) were used as the reference compounds. The experimental LCB of AEP was located between those of Et 3 P O and (Me 2 N) 3 P O. The experimental LCB of HA was found to be higher than those of AEP and HMPA by more than 2 kcal mol −1 clearly indicating that the LCB of HA is higher than any LCB for a neutral base yet measured (crown-ethers excepted). The experimental LCBs of the parent bases (pyridine and imidazole) are lower by more than 10 kcal mol −1 . In parallel, DFT calculations {B3LYP/6-31G*//B3LYP/6-31G* and B3LYP/6-311+G**//B3LYP/6-31G*} were performed for HA, AEP and their lithium adducts. Among the 22 reasonable conformations of the HA-Li + adduct, only one appears to be significantly more stable than the others. This is also the case for one structure among seven conformations of the AEP-Li + adduct. These two stable structures have the ‘scorpion’ conformation, in which the Li + cation is almost equally chelated by two basic nitrogen atoms, the ring N-aza and the chain N-amino. Other HA-Li + and AEP-Li + conformations have noticeably higher energies than the ‘scorpion’ structures. The difference between the DFT calculated LCBs of HA and AEP (about 4 kcal mol −1 ) is in agreement with that experimentally obtained (>2 kcal mol −1 ). The high experimental and theoretical values of LCB for HA and AEP militate in favor of a strong chelation of Li + by both ligands in the gas-phase. This chelation effect was also evidenced previously for the proton gas-phase basicity.

Keto-enol tautomeric interconversions and variations of the pi-electron distribution were studied for 11 isolated monohydroxyarenes at the DFT(B3LYP)/6-311++G(2df,2p) level. For two monohydroxyarenes (phenol and 9-anthrol), the PCM model of solvation (water) was also applied to the DFT geometries. The geometry-based HOMA index was applied to estimate pi-electron delocalization in the keto and enol tautomeric forms. Thermodynamic parameters of tautomeric interconversions (DeltaET, DeltaGT, TDeltaST, pKT) were calculated to estimate relative stabilities of individual tautomers and their percentage contents in the tautomeric mixtures. In almost all cases, the aromatic enol forms are strongly favored. An exception is 9-anthrol, which prefers its keto form. The resonance stabilization of this form comes from the central ring. Generally, aromaticity is the main factor that influences tautomeric equilibria in monohydroxyarenes. Hydration effect is considerably smaller and it does not change the tautomeric preference.

FT-IR spectra were recorded for α-keto pyruvic acid in three solvents (CCl 4 , CH 2 Cl 2 , and benzene) at room temperature. In parallel, quantum–chemical calculations were performed for all stable tautomers–rotamers: three stable keto and six stable enol structures using the DFT(B3LYP) method and various basis sets 6–31++G** and/or 6–311++G(3df, 3pd). Comparison of the experimental FT-IR and the computed DFT-IR spectra indicates that pyruvic acid may exist as a mixture of at least four isomers, three keto ( Tce , Tte and Cte ) and one enol (E1), among which the intramolecularly H-bonded keto Tce structure highly predominates. Intensity of the ν (OH) band assigned to the enol form (E1) varies when proceeding from CCl 4 to other solvents. It increases in CH 2 Cl 2 (weak H-bond donor solvent) and decreases in benzene (weak H-bond acceptor solvent) in comparison to the ν (OH) band assigned to the most stable keto form ( Tce ). Independently on solvent properties, in each case the keto Tce structure is favoured.

The DFT calculations using B3PW91 hybrid functional and 6-311++G** basis set were performed for the two most stable isomers of cytisine ( 1a and 1b ). The conformation 1a differs from 1b by the orientation ( equatorial and axial , respectively) of the hydrogen atom at the piperidine nitrogen atom. In terms of the Gibbs free energy, the conformation 1a is less stable than 1b by 0.25 kcal mol −1 , only. The isomers are separated by 3.6 kcal mol −1 —an activation energy barrier, which is higher in energy than the vibrational modes inverting one isomer into another. Presence of such a barrier explains the existence of the two isomers ( equatorial and axial ) observed previously in apolar solvents.

Tautomeric interconversions (keto–enol and nitroso–oxime combined according to the 1,5-proton shift into nitrosoenol–ketoxime) and related variations of π-electron delocalization were studied for o-nitrosophenol at the B3LYP/6–311 + G(2df,2p) level. The geometry- and magnetism-based indices (HOMA and NICS) were applied to estimate π-electron delocalization. The relative electronic (ΔE) and Gibbs free energies (ΔG) between the tautomers–rotamers were calculated to estimate tautomeric equilibrium and percentage content of the tautomeric mixture. Aromaticity of the phenyl ring and intramolecular H-bonding were found to be the main factors stabilizing tautomeric forms (two isomeric nitrosoenols and one ketoxime) via increasing π-electron delocalization in the chelating (quasi) ring and lowering push–pull interaction between ortho substituents. Copyright © 2005 John Wiley & Sons, Ltd.

The gas-phase basicity of 2-(β-aminoethyl)-pyridine (AEP)—an agonist of the histamine H1 receptor—containing two potential basic sites (the ring N-aza and the chain N-amino) was obtained from proton-transfer equilibrium constant measurements using Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR). Comparison of the experimental gas-phase basicity found for AEP with those reported for monobasic model compounds indicates that the ring N-aza is the favoured site of protonation, as with histamine. The gas-phase basicity of AEP is lower than that of histamine by only 1.3 kcal mol−1. DFT(B3LYP)/6–31G* calculations performed for AEP, histamine and their protonated forms confirm this interpretation. The energy barriers calculated at the DFT(B3LYP)/6–31G* level for internal transfer of the proton (ITP) between the ring N-aza and the chain N-amino in AEP and histamine are extremely low, and vanish when thermal corrections are applied to obtain the enthalpies or Gibbs energies of activation for the proton transfer. This indicates that the quantum-chemical ITPs in AEP and histamine have a single-well character, similar to that proposed for the previously studied dibasic nitrogen ligand, N1,N1-dimethyl-N2-β-(2-pyridylethyl)-formamidine, where two potential nitrogen basic sites (both nitrogen atoms in sp2 hybridization) are separated by the ethylene group. Enlarging the basis set to 6-311G(2d,p) has no influence on this finding. A change of the basicity centre preference in AEP from the ring N-aza to the chain N-amino on going from the gas phase to aqueous solution was predicted using the polarizable continuum model applied to the DFT(B3LYP)/6–31G* optimized geometries of the N-aza and N-amino monoprotonated forms. This behaviour is similar to that observed for histamine. Copyright © 2005 John Wiley & Sons, Ltd.

Ab initio calculations (HF, MP2, DFT for isolated and PCM for solvated molecules) were performed for cytisine ( 1 ) and its model compounds: N-methyl-2-pyridone ( 2 ) and piperidine ( 3 ). Among three heteroatomic functions (carbonyl oxygen, pyridone and piperidine nitrogens) considered as the possible sites of protonation in 1 , surprisingly the carbonyl oxygen takes preferentially the proton in the gas phase whereas in water the piperidine nitrogen is firstly protonated. For model compounds, the piperidine nitrogen in 3 is more basic than the carbonyl oxygen in 2 in both, the gas phase and water. Keywords: Cytisine; Site of protonation; Ab initio calculations; PCM; Gas phase and Solution Introduction Proton-transfer reactions play an important role in interactions of molecules with biological systems [1]. Biologically active molecules are usually polyfunctional derivatives in which the sites of protonation or deprotonation strongly depend on acid-base properties of individual functional groups, their intra- and intermolecular interactions and environment [2,3]. Examples are alkaloids, naturally synthesized by various plants, some of which have medicinal or poisonous properties [4]. Although

FT-IR (in KBr disk) and UV (in aqueous solution) spectra were recorded for lithium, sodium, potassium and/or guanidinium pyruvates and oxamates at room temperature. In parallel, quantum-chemical calculations were performed and vibrational frequencies computed at the DFT(B3LYP)/6-31++G** level. In the experimental FT-IR spectra of solid salts, positions and intensities of the ν (αC O) and ν as(COO) bands depend on the cation and also on the anion. Oxamates are intermolecularly associated, while pyruvates are not H-bonded. The Li+, Na+ and K+ cations interact preferentially with oxygens of the COO group in pyruvates and with oxygens of the αC O and COO groups in oxamates. In the UV spectra, cations {H+, Li+, Na+, K+ and (H2N)3C+} have slight influence on the position of the n − π * band indicating the same type of interactions in hydrated salts.

Infrared and Raman spectra were recorded for solid cytisine—an agonist of nicotinic acetylcholine receptors (nAChRs), and analysed with help of the semiempirical (AM1) and ab initio {DFT(B3PW91)/6-311++G∗∗} calculations performed for monomeric and associated structures (dimer, trimer and tetramer). Among two stable conformers of cytisine (1a and 1b) identified in solution, only one (1a) is present in the solid state, where it is stabilized by intermolecular H-bonds (  C  O ⋯ HN  ). Two different environments for the associated molecules give two different spectral properties. Two component bands can be distinguished for the piperidine ν(NH) and γ(NH) as well as for the pyridine ν(CH), ν(CO) and ν(CC) contours.

The gas-phase basicity (GB) of the flexible polyfunctional N(1),N(1)-dimethyl-N(2)-beta-(2-pyridylethyl)formamidine (1) containing two potential basic sites (the ring N-aza and the chain N-imino) is obtained from proton-transfer equilibrium constant measurements, using Fourier-transform ion-cyclotron resonance mass spectrometry. Comparison of the experimental GB obtained for 1 with those reported for model amidines and azines indicates that the chain N-imino in the amidine group is the favored site of protonation. Semiempirical (AM1) and ab initio calculations (HF, MP2, and DFT), performed for 1 and its protonated forms, confirm this interpretation. These results are in contrast to those found previously for N(1),N(1)-dimethyl-N(2)-azinylformamidines (containing the amidine function directly linked to the azinyl ring), in which the ring N-aza is the most basic site in the gas phase. The separation of the two potential basic sites in 1 by the ethylene chain interrupts the resonance conjugation between the two functions and changes their relative basicities and, thus, the preferable site of protonation. It also increases the chelation effect against the proton and the gas-phase basicity of 1 in such a magnitude that consequently 1 may be classified as a superbase (GB = 241.1 kcal mol(-)(1)). A transition state corresponding to the internal transfer of the proton (ITP) between the ring N-aza and the chain N-imino in 1 is investigated at the DFT(B3LYP)/6-31G level. The energy barrier calculated for the ITP between the two basic sites is small and vanishes when zero-point vibrational terms and thermal corrections are applied to obtain the enthalpy or Gibbs energy of activation for the proton transfer. Additional calculations at the DFT(MPW1K)/6-31G level confirm this behavior. This indicates that the quantum-chemical ITP in 1 has a single-well character. The proton is located on the N-imino site, and the H-bond is formed with the N-aza site.