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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)NH2of 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.

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 iCconjugate acid, and basicity of iC–•is close to that of the iCconjugate 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.

Tautomeric and basicity center preferences for isolated neutral and monoprotonated histamine were studied by means of ab initio calculations (HF, MP2 and DFT). The polarizable continuum model (PCM) was applied to the study of the variations of the tautomeric and basicity center preferences in histamine on going from the gas phase to aqueous solution. Twelve solvents of different polarities (from n-heptane to water) were chosen and calculations were performed for geometries optimized at the HF/6–31G* level. In low-polarity solvents and in the gas phase the protonation site is identical. A change of the preferred site of protonation takes place in solvents containing heteroatoms (except tetrachloromethane). Under the same conditions, a variation of the tautomeric preference in the monocation occurs. The ring N²-protonated form (ImH⁺)—favored in gas phase—is also preferred in non-polar solvents (n-heptane, benzene, tetrachloromethane). The ImH⁺ form becomes less important in more polar solvents. In such a case, the chain N³-protonated form (AmH⁺-T1) predominates. For the neutral histamine, solvation has a relatively small influence on the relative energies (variations are less than 1 kcal mol⁻¹), and does not change the tautomeric preference (HA-T2). Calculated basicity parameters were compared with those obtained experimentally in the gas phase and in aqueous solution. In the gas phase, the experimental (‘macroscopic’) basicity parameter (PA) is close to the ‘microscopic’ PA calculated for the gauche conformation. In aqueous solution, the microscopic pKa order is similar to that of the Eprot calculated for the trans conformation. In the solid state, both forms of histamine (neutral and monoprotonated) prefer the trans conformation. Some exceptions occur for complexes with metals. Copyright © 2003 John Wiley & Sons, Ltd.

Tautomeric and basicity center preferences for isolated neutral and monoprotonated histamine were studied by means of ab initiocalculations (HF, MP2 and DFT). The polarizable continuum model (PCM) was applied to the study of the variations of the tautomeric and basicity center preferences in histamine on going from the gas phase to aqueous solution. Twelve solvents of different polarities (from n‐heptane to water) were chosen and calculations were performed for geometries optimized at the HF/6–31G* level. In low‐polarity solvents and in the gas phase the protonation site is identical. A change of the preferred site of protonation takes place in solvents containing heteroatoms (except tetrachloromethane). Under the same conditions, a variation of the tautomeric preference in the monocation occurs. The ring N2‐protonated form (ImH+)—favored in gas phase—is also preferred in non‐polar solvents (n‐heptane, benzene, tetrachloromethane). The ImH+form becomes less important in more polar solvents. In such a case, the chain N3‐protonated form (AmH+‐T1) predominates. For the neutral histamine, solvation has a relatively small influence on the relative energies (variations are less than 1 kcal mol−1), and does not change the tautomeric preference (HA‐T2). Calculated basicity parameters were compared with those obtained experimentally in the gas phase and in aqueous solution. In the gas phase, the experimental (‘macroscopic’) basicity parameter (PA) is close to the ‘microscopic’ PAcalculated for the gaucheconformation. In aqueous solution, the microscopic pKaorder is similar to that of the Eprotcalculated for the transconformation. In the solid state, both forms of histamine (neutral and monoprotonated) prefer the transconformation. Some exceptions occur for complexes with metals. Copyright © 2003 John Wiley & Sons, Ltd.

Consequences of proton-transfer reactions in guanidine in the solid state, solution and gas phase are discussed. Y-delocalization, resonance and symmetry strongly influence the basicity of guanidine in the gas phase. These effects are, however, insufficient to explain the basicity of guanidine which in aqueous solution is stronger than that of trisubstituted alkylamines and proton sponge (DMAN). The intrinsic (gas-phase) basicity of guanidine is close to that of triethylamine. The large difference between the basicities of amines and guanidine in solution is attributed to the important role played by effects such as polarizability and internal and external solvation. Copyright © 2003 John Wiley & Sons, Ltd.

Consequences of proton‐transfer reactions in guanidine in the solid state, solution and gas phase are discussed. Y‐delocalization, resonance and symmetry strongly influence the basicity of guanidine in the gas phase. These effects are, however, insufficient to explain the basicity of guanidine which in aqueous solution is stronger than that of trisubstituted alkylamines and proton sponge (DMAN). The intrinsic (gas‐phase) basicity of guanidine is close to that of triethylamine. The large difference between the basicities of amines and guanidine in solution is attributed to the important role played by effects such as polarizability and internal and external solvation. Copyright © 2003 John Wiley & Sons, Ltd.

Quantum‐chemical calculations (ab initioand semiempirical) were performed for neutral and monoprotonated model compounds of general formula HiXNH (where X is C, N, S or P and i= 1, 2 or 3) and thermodynamic parameters for the protonation reaction were calculated. All derivatives belong to the family of nitrogen bases. The basicity of H2SNH is larger than that of H2CNH and lower than that of H3PNH, indicating that derivatives with the SN group can form a ‘bridge’ between guanidines and phosphazenes in the gas‐phase superbasicity scale. The basicity of HNNH is lower than that of H2CNH. Topological analysis of electron density distributions in +H3SNH, H2SNH2+and two neutral isomers of H2SNH showed significant differences in the properties of critical points on N‐ and S‐protonations. All parameters such as ρ, laplacian atomic volumes and dipoles and also bond properties are affected on protonation. Copyright © 2002 John Wiley & Sons, Ltd.

Relative energies were calculated at different semi-empirical (CNDO, INDO, MINDO/3, MNDO, AM1, and PM3) and ab initio levels (RHF/STO-3G//STO-3G, RHF/STO-4G//STO-4G, RHF/3-21G//3-21G, RHF/6-31G//6-31G, RHF/6-31G*//6-31G, RHF/6-31G*//6-31G*, RHF/6-31 ++ G**//6-31G*, RHF/6-311 ++ G**/6-31G*, RHF/6-31G**//6-31G**, RHF/31 ++ G**//6-31 ++ G**, MP2/6-31G*//6-31G* and MP2/6-31G**//6-31G**) for so-called ‘essential’ (trans) and ‘scorpio’ (gauche) conformations of the neutral and monoprotonated histamine tautomers. For the monocationic forms, the polarizable continuous model was applied to geometries optimized at the RHF/6-31G* level. The comparison shows that, generally, both types of calculation (semi-empirical and ab initio) predict the same tautomeric preference for the conformations of histamine and its monoprotonated cation when not interacting with the environment, i.e. for conditions corresponding to the gas phase. For the monocation, the ring N-aza protonated form (ImH⁺) is favoured in the gas phase for both conformations (trans and gauche); this is contrary to water solution, where the chain N-amino (AmH⁺-T1) predominates. This difference results mainly from the high polarizability of the imidazole ring in the gas phase which is strongly reduced in solution. Some ‘discrepancies’ are only observed for neutral histamine, for which the relative energy is close to zero. Good agreement of results predicted by various methods can result from the fact that in histamine the proton is transferred between atoms of the same element (nitrogen). Copyright © 2001 John Wiley & Sons, Ltd.

Relative energies were calculated at different semi‐empirical (CNDO, INDO, MINDO/3, MNDO, AM1, and PM3) and ab initiolevels (RHF/STO‐3G//STO‐3G, RHF/STO‐4G//STO‐4G, RHF/3‐21G//3‐21G, RHF/6‐31G//6‐31G, RHF/6‐31G*//6‐31G, RHF/6‐31G*//6‐31G*, RHF/6‐31 ++ G**//6‐31G*, RHF/6‐311 ++ G**/6‐31G*, RHF/6‐31G**//6‐31G**, RHF/31 ++ G**//6‐31 ++ G**, MP2/6‐31G*//6‐31G* and MP2/6‐31G**//6‐31G**) for so‐called ‘essential’ (trans) and ‘scorpio’ (gauche) conformations of the neutral and monoprotonated histamine tautomers. For the monocationic forms, the polarizable continuous model was applied to geometries optimized at the RHF/6‐31G* level. The comparison shows that, generally, both types of calculation (semi‐empirical and ab initio) predict the same tautomeric preference for the conformations of histamine and its monoprotonated cation when not interacting with the environment, i.e. for conditions corresponding to the gas phase. For the monocation, the ring N‐aza protonated form (ImH+) is favoured in the gas phase for both conformations (transand gauche); this is contrary to water solution, where the chain N‐amino (AmH+‐T1) predominates. This difference results mainly from the high polarizability of the imidazole ring in the gas phase which is strongly reduced in solution. Some ‘discrepancies’ are only observed for neutral histamine, for which the relative energy is close to zero. Good agreement of results predicted by various methods can result from the fact that in histamine the proton is transferred between atoms of the same element (nitrogen). Copyright © 2001 John Wiley & Sons, Ltd.

An Erratum for this article has been published in Journal of Mass Spectrometry 36(9) 2001, 1074 The beginning of the twentieth century saw the development of new theories of acidity and basicity, which are currently well accepted. The thermochemistry of proton transfer in the absence of solvent attracted much interest during this period, because of the fundamental importance of the process. Nevertheless, before the 1950s, few data were available, either from lattice energy evaluations or from calculations using the emerging molecular orbital theory. Advances in mass spectrometry during the last 40 years allowed studies of numerous systems with better accuracy. Thousands of accurate gas‐phase acidities or basicities are now available, for simple atomic and molecular systems and for large biomolecules. The intrinsic effect of structure on the Brønsted basic or acidic properties of molecules and the influence of solvents have been unravelled. In this tutorial, the basics of the thermodynamic principles involved are given, and the mass spectrometric techniques are briefly reviewed. Advances in the design and measurements of gas‐phase superacids and superbases are described. Recent studies concerning biomolecules are also evoked. Copyright © 2001 John Wiley & Sons, Ltd.

The basicity of the hydrogen bonds of formamidines 1–19was measured by means of the formation constant KHBof their complexes with p-fluorophenol and the frequency shift Δν(OH) of methanol hydrogen-bonded to 1–19. The study of the ν(C=N) band shows that hydrogen bonding takes place with the imino nitrogen atom. On the hydrogen-bonding basicity scale, the formamidines appear to be more basic than the corresponding amides and pyridines, and as basic as the imidazoles. The field effect of electron-withdrawing substituents and the steric effect of bulky alkyl groups on the imino nitrogen atom markedly decrease the hydrogen-bonding basicity.

Comparison of the thermodynamic (logKHBwith 4-fluorophenol in CCI4, pKain azeotropic ethanol and GBin the gas phase) with spectroscopic basicities (ΔvOHof methanol in CCI4) for N1, N1-dimethylformamidines shows good correlation only between the pKaand ΔVOHvalues; no general simple linear model can be applied to the logKHB/ΔvOHand GB/ΔVOHrelations.