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

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)_<i>n</i>(XY)_<i>i</i>CN, where <i>i</i> = 0, 1, or 2, <i>n</i> = 1, 2, or 3, R₂N = H₂N, Me₂N, or C₄H₈N, X = CH, N, or P, Y = CH or N]. The possible protonation <i>N</i>-sites (<i>N</i>-cyano, <i>N</i>-imino, and <i>N</i>-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 <i>N</i>-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 <i>N</i>-imino atoms, present in the transmitter group (XN, X = CH, N, or P), display PA values lower than those of the <i>N</i>-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 <i>N</i>-amino atom increase the PA value of the <i>N</i>-cyano site for Me₂NXYCN (X, Y = CH or N) by <i>ca</i>. 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(<i>N</i>-cyano) values by only 30–50 kJ mol^–1. The CN bond lengths of the neutral forms are well correlated with the PA­(<i>N</i>-cyano) values

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: <i>N,N</i>-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

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