Nitriles with High Gas-Phase Basicity-Part II Transmission of the Push-Pull Effect through Methylenecyclopropene and Cyclopropenimine Scaffolds Intercalated between Different Electron Donor(s) and the Cyano N-Protonation Site.

This work extends our earlier quantum chemical studies on the gas-phase basicity of very strong N-bases to two series of nitriles containing the methylenecyclopropene and cyclopropenimine scaffolds with dissymmetrical substitution by one or two electron-donating substituents such as Me, NR2, N=C (NR2)2, and N=P (NR2)3, the last three being strong donors. For a proper prediction of their gas-phase base properties, all potential isomeric phenomena and reasonable potential protonation sites are considered to avoid possible inconsistencies when evaluating the energetic parameters and associated protonation or deprotonation equilibria B + H+ = BH+. More than 250 new isomeric structures for neutral and protonated forms are analyzed. The stable structures are selected and the favored ones identified. The microscopic (kinetic) gas-phase basicity parameters (PA and GB) corresponding to N sites (cyano and imino in the cyclopropenimine or in the substituents) in each isomer are calculated. The macroscopic (thermodynamic) PAs and GBs, referring to the isomeric mixtures of favored isomers, are also estimated. The total (pushing) substituent effects are analyzed for monosubstituted and disubstituted derivatives containing two identical or two different substituents. Electron delocalization is examined in the two π-π conjugated transmitters, the methylenecyclopropene and cyclopropenimine scaffolds. The aromatic character of the three-membered ring is also discussed.

Purine tautomeric preferences and bond-length alternation in relation with protonation-deprotonation and alkali metal cationization.

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. HOMED variations for the favored neutral, deprotonated, protonated, and lithiated forms of purine in the gas phase and aqueous solution.

Effects of Positive and Negative Ionization on Prototropy in Pyrimidine Bases: An Unusual Case of Isocytosine.

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 of neutral and ionized forms. Ionization energies depend on localization of labile protons. Tautomeric equilibria for neutral and ionized isocytosine, favored sites of protonation and deprotonation, and favored structures of protonated and deprotonated forms strongly depend on environment. Acidity of iC+• is close to that of the iC conjugate acid, and basicity of iC-• is close to that of the iC conjugate base. This increase of acid-base properties of charged radicals explains the proton-transfer in ionized pairs of nucleobases. When compared to other pyrimidine bases such as uracil (U) and cytosine (C), which exhibit analogous tautomeric equilibria between nine prototropic tautomers as isocytosine, the tautomeric preferences for iC, iC+•, iC-•, U, U+•, U-•, C, C+•, and C-• are completely different. The differences suggest that acid-base properties of functional groups, their stabilities, and ionization energies play a principal role in proton-transfers for pyrimidine bases and influence compositions of tautomeric mixtures.

Exceptionally High Proton and Lithium Cation Gas-Phase Basicity of the Anti-Diabetic Drug Metformin.

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 structure of the neutral system. The calculated proton affinity and gas-phase basicity of the two molecules reach the domain of superbasicity. By contrast, the lithium cation prefers to bind the less stable, not fully conjugated, tautomer (NR2)C(═NH)-NH-C(═NH)NH2 of biguanides, in which the two C═NH groups are separated by NH. This less stable form of biguanides binds Li+ as a bidentate ligand, in agreement with what was reported in the literature for other metal cations in the solid phase. The quantitative assessment of resonance in biguanide, in metformin and in their protonated forms, using the HOMED and HOMA indices, reveals an increase in electron delocalization upon protonation. On the contrary, the most stable lithium cation adducts are less conjugated than the stable neutral biguanides, because the metal cation is better coordinated by the not-fully conjugated bidentate tautomer.

Enhanced Basicity of Push-Pull Nitrogen Bases in the Gas Phase.

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 containing push-pull side chains, nucleobases, and their nucleosides and nucleotides, is also analyzed. Progress and perspectives of experimental determinations of GBs and PAs of highly basic compounds, termed as "superbases", are presented and benchmarked on the basis of theoretical calculations on existing or hypothetical molecules.

Effects of ionization on stability of 1-methylcytosine - DFT and PCM studies.

Consequences of ionization were studied by quantum-chemical methods (DFT and PCM) for 1-methylcytosine (MC)-a model of the nucleobase cytosine (C) connected with sugar in DNA. For calculations, three prototropic tautomers (one amino and two imino forms) and two imino zwitterions were considered, including conformational or configurational isomerism of exo heterogroups. Ionization and interactions between neighboring groups affect intramolecular proton-transfers, geometric and thermodynamic parameters, and electron delocalization for individual isomers. We discovered that an imino isomer is present in the isomeric mixture in the highest amount for positively ionized MC. Its contribution in neutral and negatively ionized MC is considerably smaller. Acid-base parameters for selected radical ions were estimated in the gas phase and compared to those of neutral MC. Gas-phase acidity of radical cations is close to that of the conjugate acid of MC, and gas-phase basicity of radical anions is close to that of the conjugate base of MC. Various routes of amino-imino conversion between neutral and ionized isomers were considered. Energetic-barrier for intramolecular proton-transfer in MC is close to that in the parent system-formamidine.

Can Nitriles Be Stronger Bases Than Proton Sponges in the Gas Phase? A Computational Analysis.

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 PA > 1000 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.

Geometric consequences of electron delocalization for adenine tautomers in aqueous solution.

Geometric consequences of electron delocalization were studied for all possible adenine tautomers in aqueous solution by means of ab initio methods {PCM(water)//DFT(B3LYP)/6-311+G(d,p)} and compared to those in the gas phase {DFT(B3LYP)/6-311+G(d,p)}. To measure the consequences of any type of resonance conjugation (π-π, n-π, and σ-π), the geometry-based harmonic oscillator model of electron delocalization (HOMED) index, recently extended to the isolated (DFT) and hydrated (PCM//DFT) molecules, was applied to the molecular fragments (imidazole, pyrimidine, 4-aminopyrimidine, and purine) and also to the whole tautomeric system. For individual tautomers, the resonance conjugations and consequently the bond lengths strongly depend on the position of the labile protons. The HOMED indices are larger for tautomers (or their fragments) possessing the labile proton(s) at the N rather than C atom. Solvent interactions with adenine tautomers slightly increase the resonance conjugations. Consequently, they slightly shorten the single bonds and lengthen the double bonds. When going from the gas phase to water solution, the HOMED indices increase (by less than 0.15 units). There is a good relation between the HOMED indices estimated in water solution and those in the gas phase for the neutral and ionized forms of adenine. Subtle effects, being a consequence of intramolecular interactions between the neighboring groups, are so strongly reduced by solvent that the relation between the HOMED indices and the relative energies for the neutral adenine tautomers seems to be better in water solution than in the gas phase.

Variations of the tautomeric preferences and π-electron delocalization for the neutral and redox forms of purine when proceeding from the gas phase (DFT) to water (PCM).

Quantum-chemical calculations were performed for all possible nine neutral tautomers of purine and their oxidized and reduced forms in water {PCM//DFT(B3LYP)/6-311+G(d,p)} and compared to those in the gas phase {DFT(B3LYP)/6-311+G(d,p)}. PCM hydration influences geometries, π-electron delocalization, and relative energies of purine tautomers in different ways. Generally, the harmonic oscillator model of electron delocalization (HOMED) indices increase when proceeding from the gas phase to aequeous solution for the neutral and redox forms of purine. Their changes for the neutral and oxidized tautomers are almost parallel to the relative energies showing that aromaticity plays an important role in the tautomeric preferences. Tautomeric stabilities and tautomeric preferences vary when proceeding from the gas phase to water indicating additionally that intra- and intermolecular interactions affect tautomeric equilibria. The tautomeric mixture of neutral purine in the gas phase consists mainly of the N9H tautomer, whereas two tautomers (N9H and N7H) dominate in water. For oxidized purine, N9H is favored in the gas phase, whereas N1H in water. A gain of one electron dramatically changes the relative stabilities of the CH and NH tautomers that C6H and C8H dominate in the tautomeric mixture in the gas phase, whereas N3H in water. These variations show exceptional sensitivity of the tautomeric purine system on environment in the electron-transfer reactions.

Quantum-chemical studies on the favored and rare tautomers of neutral and redox adenine.

All possible twenty-three prototropic tautomers of neutral and redox adenine (nine amine and fourteen imine forms, including geometric isomerism of the exo ═NH group) were examined in vacuo {DFT(B3LYP)/6-311+G(d,p)}. The NH → NH conversions as well as those usually omitted, NH → CH and CH → CH, were considered. An interesting change of the tautomeric preference occurs when proceeding from neutral to reduced adenine. One-electron reduction favors the nonaromatic amine C8H-N10H tautomer. This tautomeric preference is similar to that (C2H) for reduced imidazole. Water molecules (PCM model) seem to not change this trend. They influence solely the relative energies. The DFT vertical detachment energy in the gas phase is positive for each tautomer, e.g., 0.03 eV for N9H-N10H and 1.84 eV for C8H-N10H. The DFT adiabatic electron affinity for the favored process, neutral N9H-N10H → reduced C8H-N10H (ground states), is equal to 0.18 eV at 0 K (ZPE included). One-electron oxidation does not change the tautomeric preference in the gas phase. The aromatic amine N9H-N10H tautomer is favored for the oxidized molecule similarly as for the neutral one. The DFT adiabatic ionization potential for the favored process, neutral N9H-N10H → oxidized N9H-N10H (ground states), is equal to 8.12 eV at 0 K (ZPE included). Water molecules (PCM model) seem to influence solely the composition of the tautomeric mixture and the relative energies. They change the energies of the oxidation and reduction processes by ca. 2 eV.

DFT studies on one-electron oxidation and one-electron reduction for 2- and 4-aminopyridines.

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.

Consequences of one-electron oxidation and one-electron reduction for 4-aminopyrimidine--DFT studies.

The consequences of one-electron oxidation and one-electron reduction were studied for 4-aminopyrimidine (4APM), which displays prototropic tautomerism. Since experimental techniques are incapable of detecting less than 0.1% of minor tautomers, quantum-chemical calculations [DFT(B3LYP)/6-311+G(d,p)] were carried out for all possible tautomers of neutral 4AMP and its redox forms, 4APM (+ •) and 4APM (- •). Four tautomers were considered: one amine and three imine tautomers (two NH and one CH form). Geometric isomerism of the exo = NH group was also taken into account. One-electron oxidation (4APM - e → 4APM (+ •)) has no significant effect on the tautomeric preferences; it influences solely the composition of the tautomeric mixture. The amine tautomer is favored for both 4APM (+ •) and 4APM. An interesting change in the tautomeric preference occurs for 4APM (- •). One-electron reduction (4APM + e → 4APM (- •)) favors the C5 atom for the labile proton. The preference of the imine CH tautomer in the tautomeric mixture of 4APM (- •) may partially explain the origin of CH tautomers in nucleobases.

Consequence of one-electron oxidation and one-electron reduction for aniline.

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).

Change of the favored routes of EI MS fragmentation when proceeding from N1, N1-dimethyl-N2-arylformamidines to 1,1,3,3-tetraalkyl-2-arylguanidines: substituent effects.

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).

Tautomeric equilibria and pi electron delocalization for some monohydroxyarenes--quantum chemical studies.

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.

Experimental and theoretical evidence of basic site preference in polyfunctional superbasic amidinazine: N(1),N(1)-dimethyl-N(2)-beta-(2-pyridylethyl)formamidine.

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.

FT-IR spectroscopic, AM1 and PM3 computational studies of conformation of natural products: cytisine.

Infrared spectra were recorded for cytisine (1) and its model compounds: N-methyl-2-pyridone (2) and piperidine (3) in solution. Eight solvents of different polarity, polarizability and acid-base properties: CCl(4), CS(2), CHCl(3), CDCl(3) (for comparison with the NMR spectra), CH(2)Cl(2), MeOH, Et(2)O and Et(3)N were chosen. Experimental FT-IR spectra were analysed with the help of those calculated for isolated derivatives at the AM1 and PM3 levels. Influence of environment on the conformational preferences in solvated cytisine was discussed and compared with those in the solid state (X-ray measurements) and in the gas phase (quantum-mechanical calculations).