Strong Bases and beyond: The Prominent Contribution of Neutral Push-Pull Organic Molecules towards Superbases in the Gas Phase.

In this review, the principles of gas-phase proton basicity measurements and theoretical calculations are recalled as a reminder of how the basicity PA/GB scale, based on Brønsted-Lowry theory, was constructed in the gas-phase (PA-proton affinity and/or GB-gas-phase basicity in the enthalpy and Gibbs energy scale, respectively). The origins of exceptionally strong gas-phase basicity of some organic nitrogen bases containing N-sp3 (amines), N-sp2 (imines, amidines, guanidines, polyguanides, phosphazenes), and N-sp (nitriles) are rationalized. In particular, the role of push-pull nitrogen bases in the development of the gas-phase basicity in the superbasicity region is emphasized. Some reasons for the difficulties in measurements for poly-functional nitrogen bases are highlighted. Various structural phenomena being in relation with gas-phase acid-base equilibria that should be considered in quantum-chemical calculations of PA/GB parameters are discussed. The preparation methods for strong organic push-pull bases containing a N-sp2 site of protonation are briefly reviewed. Finally, recent trends in research on neutral organic superbases, leaning toward catalytic and other remarkable applications, are underlined.

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.

Metal Triflates as Catalysts in Organic Synthesis: Determination of Their Lewis Acidity by Mass Spectrometry.

Metal triflates have shown a large variety of possibilities as catalysts in organic reactions. Some selected examples of their catalytic activity, in particular in C-O and C-C bond formation are presented. A better understanding of the mode of interaction between these Lewis acids and organic functional groups as ligands should allow for an easier choice of a tailored metal cation for a given reaction. Electrospray ionization mass spectrometry enables the characterization and the quantification of the donor/acceptor interactions involved in the catalytic processes. Both gas-phase and solution-phase interactions between various metal triflates and organic functionalities were studied. Based on an original probabilistic model, ligand displacement experiments lead us to establish quantitative affinity scales of ligands toward the metal centers. The main structural effects governing the ranking are identified and discussed.

Evolution of Chemical Research in Nice, Côte d'Azur: From Early Laboratories to the 'Institut de Chimie de Nice'.

The 'Institut de Chimie de Nice' (ICN), founded in 2012, celebrates its 10th anniversary in 2022. Today, the ICN is part of the University Côte d'Azur (UCA), one out of nine excellence universities in France. ICN is also affiliated to the CNRS. We use the institute's anniversary to reflect on the origins and the successful evolution of research in chemical sciences in Nice, France. We outline research topics and their development towards modern chemistry in Nice that are characterized by innovation and territorial anchoring. At present, four research axes, namely aroma and perfume chemistry, medicinal chemistry, radiochemistry, and material chemistry structure the institute. ICN has created five start-up companies and includes a technological platform. The ICN is central part of the university and contributes to the advancement in chemical sciences as evidenced by both fundamental research and active contributions to local partnerships.

Enthalpies of Adduct Formation between Boron Trifluoride and Selected Organic Bases in Solution: Toward an Accurate Theoretical Entry to Lewis Basicity.

The Lewis basicity of selected organic bases, modeled by the enthalpies of adduct formation between gaseous BF3 and bases in dichloromethane (DCM) solution, is critically examined. Although experimental enthalpies for a large number of molecules have been reported in the literature, it may be desirable to estimate missing or uncertain data for important Lewis bases. We decided to use high-level ab initio procedures, combined with a polarized continuum solvation model, in which the solvated species were the clusters formed by specific hydrogen bonding of DCM with the Lewis base and the Lewis base/BF3 adduct. This mode of interaction with DCM corresponds to a specific solvation model (SSM). The results essentially showed that the enthalpy of BF3 adduct formation in DCM solution was clearly influenced by specific interactions, with DCM acting as hydrogen-bonding donor (HBD) molecule in two ways: base/DCM and adduct/DCM, confirming that specific solvation is an important contribution to experimentally determined Lewis basicity scales. This analysis allowed us to conclude that there are reasons to suspect some gas-phase values to be in error by more than the stated experimental uncertainty. Some experimental values in DCM solution that were uncertain for identified reasons could be complemented by the computed values.

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.

On the Lewis Basicity of Phosphoramides: A Critical Examination of Their Donor Number through Comparison of Enthalpies of Adduct Formation with SbCl5 and BF3.

The Lewis basicity of a series of phosphoryl compounds was examined using DFT and ab initio methods, including solvation effects. The enthalpies of adduct formation with two archetypal Lewis acids, antimony pentachloride and boron trifluoride, used to define the donor number DN and the BF3 affinity (BF3 A) respectively, were examined. The BF3 adducts allow the use of the high-accuracy G4 approach, whereas for SbCl5 adducts, three different DFT formalisms, including empirical dispersion corrections, were used because the G4 formalism is not available for third-row elements. For a comparison with experimental data, solvation effects were taken into account by using the polarizable continuum model. The experimental BF3 affinities were well reproduced by G4 calculations when including PCM solvation. Conversely, comparisons of our calculated values and experimental results reported in the literature show that SbCl5 enthalpies for phosphoramides are in error. In particular the DN for HMPA should be revised.

Quality Control of a Functionalized Polymer Catalyst by Energy Dispersive X-ray Spectrometry (EDX or EDS).

Energy dispersive X-ray spectrometry (EDX or EDS) is a technique often implemented on scanning electron microscopes and a regularly used method for qualitative characterization of solid catalysts. This Technical Note reports a method for the determination of the metal content in a sulfonated polyether ether ketone in the form of an indium(III) salt. The possibility of quantitative determination of the sulfur/indium ratio by EDX was assessed by calibration with two indium salts (sulfide and sulfate) readily available in good purity. The accuracy of the uncorrected instrument response was better than 1% under our conditions. A protocol for investigating the metal content of the solid catalyst is proposed, also providing information about the homogeneity of the metal distribution. Because of the simplicity of the sample preparation, the small quantity of material needed, and the rapidity of the EDX measurements, the method appears to be promising for quantitative characterization of solid catalysts.

On the Significance of Lone Pair/Lone Pair and Lone Pair/Bond Pair Repulsions in the Cation Affinity and Lewis Acid/Lewis Base Interactions.

Interaction of H2O, H2S, H2Se, NH3, PH3, and AsH3 with cations H+, CH3 +, Cu+, Al+, Li+, Na+, and K+ was studied from the energetic and structural viewpoint using B3LYP/6-311++G(d,p) method. The charge transfer from the Lewis bases to the cations reduces lone pair/lone pair (LP/LP) repulsion in H2O, H2S, and H2Se and LP/bond pair (LP/BP) repulsion in NH3, PH3, and AsH3. In parallel, changes in the H-M-H angles (M = O, S, Se, N, P, and As) are observed. The change in the H-M-H angle during the interactions was proportional to the amount of charge transferred from the bases to the cations and electron density (ρ) at the molecule/cation bond critical point. Also, the opposite trend for proton affinities of these two families, that is, NH3 > PH3 > AsH3 and H2O < H2S < H2Se, was interpreted on the basis of LP/BP repulsion in their neutral and protonated forms. Interaction of the Lewis bases with neutral Lewis acids including BeH2, BeF2, and BH3 was studied energetically and structurally. The calculated energies for interactions of H2O and NH3 with BeH2, BeF2, and BH3 are larger than the corresponding values for H2S, H2Se, PH3, and AsH3. This difference was interpreted on the basis of the lower stability of H2O and NH3 because of large LP/LP and LP/BP repulsion in H2O and LP/BP repulsion in NH3.

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.

Directionality of Cation/Molecule Bonding in Lewis Bases Containing the Carbonyl Group.

Relationship between the C═O-X+ (X = H, Li, Na, K, Al, Cu) angle and covalent characteristic of the X+-M (M = CH2O, CH3CHO, acetone, imidazol-2-one (C2H2N2O), cytosine, γ-butyrolactone) was investigated, theoretically. The calculated electron densities ρ at the bond critical points revealed that the covalency of the M-X+ interaction depended on the nature of the cation and varied as H+ > Cu+ > Al+ > Li+ > Na+ > K+. The alkali cations tended to participate in electrostatic interactions and aligned with the direction of the molecule dipole or local dipole of C═O group to form linear C═O-X geometries. Because of overlapping with lone-pair electrons of the sp2 carbonyl oxygen, the H+ and Cu+ formed a bent C═O-X angle. Al+ displayed an intermediate behavior; the C═O-Al angle was 180° in [CH2O/Al]+ (mainly electrostatic), but when the angle was bent (146°) under the effect of local dipole of an adjacent imine group in cytosine, the covalency of the CO-Al+ interaction increased. The C═O-X angles in M/X+ adduct ions were scanned in different O-X bond lengths. It was found that the most favorable C═O-X angle depended on the O-X bond length. This dependency was attributed to variation of covalent and electrostatic contributions with O-X distance. In addition, the structures of [CH2S/X]+ and [CH2Se/X]+ were studied, and only bent C═S-X and C═Se-X angles were obtained for all cations, although the dipole vectors of CH2S and CH2Se coincide with the C═S and C═Se bonds. The bending of the C═S-X and C═Se-X angles was attributed to the covalent characteristic of S-X and Se-X interactions due to high polarizability of S and Se atoms.

Bond Strength and Reactivity Scales for Lewis Superacid Adducts: A Comparative Study with In(OTf)3 and Al(OTf)3.

Metal triflates, often called Lewis superacids, are potent catalysts for organic synthesis. However, the reactivity of a given Lewis superacid toward a given base is difficult to anticipate. A systematic screening of catalysts is often necessary when developing synthetic methodologies. Presented herein is the development of quantitative reactivity and bond strength scales by using mass spectrometry (MS). By applying a collision-induced dissociation (CID) technique to the adducts formed between Lewis superacids Al(OTf)3 or In(OTf)3 with a series of amides bases, including monodentate and bidentate ligands, different dissociation pathways were observed. Quantitative relative energy scales were established by performing energy-resolved mass spectrometry (ERMS) analysis on the adducts. ERMS of the adducts affords a bond strength scale when the fragmentation leads to the loss of a ligand, and reactivity scales when the dissociation leads to the C-F bond activation of one triflate anion or the deprotonation of the ligand. Al(OTf)3 was found to bind stronger to amides than In(OTf)3 and to provide the most reactive adducts.

Quantitative Ligand Affinity Scales for Metal Triflate Salts: Application to Isomer Differentiation.

Owing to the importance of metal triflates in catalysis, the affinity of the cationic center for a selection of organic ligands was explored for InIII and ZnII triflates. The organic Lewis bases include a variety of carbonyls (amides, unsaturated ketones, a lactone) and cyclic 1,2-diols. The relative affinity of the ligands for the cationic center in triflates was quantitatively determined on the basis of relative ion concentrations determined by electrospray-ionization mass spectrometry. The affinity scales were discussed with reference to gas-phase proton basicity and Lewis basicity scales. Structural isomers and stereoisomers display significant affinity differences in several cases. In the case of isomer mixtures, a model describing the relative peak intensities in the mass spectra was developed. On this basis, an isomer titration method was set up. Remarkably, this MS-based method overcame the blindness of mass spectrometry to isomers without the need for isotope labeling or MS/MS experiments. This model may prove to have applications in analytical chemistry and catalysis.

Effect of the Number of Methyl Groups on the Cation Affinity of Oxygen, Nitrogen, and Phosphorus Sites of Lewis Bases.

The effect of number of CH3 groups (n) on the cation (H+, Li+, Na+, Al+, CH3+) affinity, polarizability, and dipole moment of 14 simple molecules was investigated. Linear correlations were observed between the polarizabilities and the number of methyl groups. The variations of the cation affinities and dipole moments with the number of methyl groups (n) were not linear, and a quadratic function was proposed for obtaining a good fit of the experimental data. Also, because the proton affinities (PA), lithium cation affinities (LCA), sodium cation affinities (SCA), aluminum cation affinity (AlCA), and methyl cation affinity (MCA) varied quadratically with polarizabilities (α), a formula of the form [cation affinities] = a + bα + cα2 was proposed. After correction of the PAs, LCAs, SCAs, AlCA, and MCA for the dipole/charge interaction (Eµ), linear relationships were observed between the corrected cation affinities and n or α. The contribution of Eµ to PA and MCA was small (less than 20%), and its contribution to LCA and SCA was large (>50%). The electrostatic contribution to AlCA was considerable (20-50%); however, it was smaller than the electrostatic contribution to LCA and SCA.

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.

Aluminum monocation basicity and affinity scales.

The experimental aspects of the determination of thermochemical data for the attachment of the aluminum monocation Al(+) to neutral atoms and molecules are reviewed. Literature aluminum cation affinities (enthalpy scale) and basicities (Gibbs energy scale) are tabulated and discussed. Ab initio quantum chemical calculations at the G4 level on 43 adducts provide a consistent picture of the energetics of the adducts and their structures. The Al(+)-ligand bonding is analyzed in terms of natural bond orbital and atom-in molecule analyses. A brief comparison of the Al(+) basicity scales and other gas- phase cation basicities is presented.

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.

Dinuclear copper intermediates in copper(I)-catalyzed azide-alkyne cycloaddition directly observed by electrospray ionization mass spectrometry.

The mechanism of the CuAAC reaction has been investigated by electrospray ionization mass spectrometry (ESI-MS) using a combination of the neutral reactant approach and the ion-tagging strategy. Under these conditions, for the first time, putative dinuclear copper intermediates were fished out and characterized by ESI(+)-MS/MS. New insight into the CuAAC reaction mechanisms is provided and a catalytic cycle is proposed.

Gas-phase lithium cation basicity: revisiting the high basicity range by experiment and theory.

According to high level calculations, the upper part of the previously published FT-ICR lithium cation basicity (LiCB at 373 K) scale appeared to be biased by a systematic downward shift. The purpose of this work was to determine the source of this systematic difference. New experimental LiCB values at 373 K have been measured for 31 ligands by proton-transfer equilibrium techniques, ranging from tetrahydrofuran (137.2 kJ mol(-1)) to 1,2-dimethoxyethane (202.7 kJ mol(-1)). The relative basicities (ΔLiCB) were included in a single self-consistent ladder anchored to the absolute LiCB value of pyridine (146.7 kJ mol(-1)). This new LiCB scale exhibits a good agreement with theoretical values obtained at G2(MP2) level. By means of kinetic modeling, it was also shown that equilibrium measurements can be performed in spite of the formation of Li(+) bound dimers. The key feature for achieving accurate equilibrium measurements is the ion trapping time. The potential causes of discrepancies between the new data and previous experimental measurements were analyzed. It was concluded that the disagreement essentially finds its origin in the estimation of temperature and the calibration of Cook's kinetic method.

Catalytic effect of cesium cation adduct formation on the decarboxylation of carboxylate ions in the gas phase.

The effect of Cs(+) ligation on the decarboxylation of malonic acids (unsubstituted and methyl-, dimethyl-, ethyl-, and phenyl-substituted) in their carboxylate form was studied in the gas phase using tandem mass spectrometry. The study is based on the comparison of the decarboxylation of the bare monoanion (hydrogen malonates) and of the cesium adduct of the cesium salt (Cs(+) [cesium hydrogen malonates]) under collisional activation. Energy-resolved dissociation curves of the negative and positive ions exhibit major differences. Decarboxylation of the cationic adducts of substituted malonic acid salts occurs at significantly lower collisional activation than for the corresponding bare hydrogen malonate anions. The conclusions from these experiments are supported by DFT calculations. The calculated activation parameters (enthalpy and Gibbs energy) confirm that the cesium cation coordination assists the decarboxylation of the carboxylate form.