Experimental Basicities of Phosphazene, Guanidinophosphazene, and Proton Sponge Superbases in the Gas Phase and Solution.

Experimental gas-phase superbasicity scale spanning 20 orders of magnitude and ranging from bicyclic guanidine 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene to triguanidinophosphazenes and P3 phosphazenes is presented together with solution basicity data in acetonitrile and tetrahydrofuran. The most basic compound in the scale-triguanidinophosphazene Et-N═P[N═C(NMe2)2]3-has the highest experimental gas-phase basicity of an organic base ever reported: 273.9 kcal mol(-1). The scale includes besides the higher homologues of classical superbasic phosphazenes and several guanidino-substituted phosphazenes also a number of recently introduced bisphosphazene and bis-guanidino proton sponges. This advancement was made possible by a newly designed Fourier transform ion cyclotron resonance (ICR) mass spectrometry setup with the unique ability to generate and control in the ICR cell sufficient vapor pressures of two delicate compounds having low volatility, which enables determining their basicity difference. The obtained experimental gas-phase and solution basicity data are analyzed in terms of structural and solvent effects and compared with data from theoretical calculations.

Solution and gas-phase acidities of all-trans (all-E) retinoic acid: an experimental and computational study.

Retinoic acid is of fundamental biological importance. Its acidity was determined in the gas phase and in acetonitrile solution by means of mass spectrometry and UV/Vis spectrophotometry, respectively. The intrinsic acidity is slightly higher than that of benzoic acid. In solution, the situation is opposite. The experimental systems were described theoretically applying quantum chemical methods (wave function theory and density functional theory). This allowed the determination of the molecular structure of the acid and its conjugate base, both in vacuo and in solution, and for computational estimates of its acidity in both phases.

Superacidity of closo-dodecaborate-based Brønsted acids: a DFT study.

The structures and intrinsic gas-phase acidities (GA) of some dodecaborane acids, the derivatives of YB12H11H (Y = PF3, NH3, NF3, NMe3), B12H12H2, and B12H12H(-) (HA, H2A, and HA(-), respectively) have been computationally explored with DFT B3LYP method at the 6-311+G** level of theory as new possible directions of creating superstrong Brønsted acids. Depending on the nature and number of the substituents different protonation geometries were investigated. In general, the GA values of the neutral systems varied according to the substituents in the following order: CF3 < F < Cl and in case of anionic acids: CF3 < Cl < F. The dodecatrifluoromethyl derivative of H2A, B12(CF3)12H1H2, emerges as the strongest among the considered acids and is expected to be in the gas phase at least as strong as the undecatrifluoromethyl carborane, CB11(CF3)11H1H. The GA values of the respective monoanionic forms of the considered acids all, but the (CF3)11 derivative, remained higher than the widely used threshold of superacidity. The HA derivatives' (Y = PF3, NF3) GA's were approximately in the same range as the H2A acids'. In the case Y = NH3 or NMe3 the GA values were significantly higher. Also, the pKa values of B12H12H2, CB11H12H, and their perfluorinated derivatives in 1,2-dichloroethane (DCE) were estimated with SMD and cluster-continuum model calculations. The obtained estimates of pKa values of the perfluorinated derivatives are by around 30 units lower than that of trifluoromethylsulfonylimide, making these acids the strongest ever predicted in solution. The derivatives of B12H12H2 are as a rule not significantly weaker acids than the respective derivatives of CB11H12H. This is important for expanding practical applicability of this type of acids and their anions, as they are synthetically much more accessible than the corresponding CB11H12(-) derivatives.

Basicity Limits of Neutral Organic Superbases.

The potential limits of superbasicity achievable with different families of neutral bases by expanding the molecular framework are explored using DFT computations. A number of different core structures of non-ionic organosuperbases are considered (such as phosphazenes, guanidinophosphazenes, guanidino phosphorus ylides). A simple model for describing the dependence of basicity on the extent of the molecular framework is proposed, validated, and used for quantitatively predicting the ultimate basicities of different compound families and the rates of substituent effect saturation. Some of the considered bases (guanidino phosphorus carbenes) are expected to reach gas-phase basicity around 370 kcal mol(-1), thus being the most basic neutral bases ever reported. Also, the classical substituted alkylphosphazenes were predicted to reach pK(a) values of around 50 in acetonitrile, which is significantly higher than previously expected.

SARS-CoV-2 clade dynamics and their associations with hospitalisations during the first two years of the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic was characterised by rapid waves of disease, carried by the emergence of new and more infectious SARS-CoV-2 virus variants. How the pandemic unfolded in various locations during its first two years has yet to be sufficiently covered. To this end, here we are looking at the circulating SARS-CoV-2 variants, their diversity, and hospitalisation rates in Estonia in the period from March 2000 to March 2022. METHODS: We sequenced a total of 27,550 SARS-CoV-2 samples in Estonia between March 2020 and March 2022. High-quality sequences were genotyped and assigned to Nextstrain clades and Pango lineages. We used regression analysis to determine the dynamics of lineage diversity and the probability of clade-specific hospitalisation stratified by age and sex. RESULTS: We successfully sequenced a total of 25,375 SARS-CoV-2 genomes (or 92%), identifying 19 Nextstrain clades and 199 Pango lineages. In 2020 the most prevalent clades were 20B and 20A. The various subsequent waves of infection were driven by 20I (Alpha), 21J (Delta) and Omicron clades 21K and 21L. Lineage diversity via the Shannon index was at its highest during the Delta wave. About 3% of sequenced SARS-CoV-2 samples came from hospitalised individuals. Hospitalisation increased markedly with age in the over-forties, and was negligible in the under-forties. Vaccination decreased the odds of hospitalisation in over-forties. The effect of vaccination on hospitalisation rates was strongly dependent upon age but was clade-independent. People who were infected with Omicron clades had a lower hospitalisation likelihood in age groups of forty and over than was the case with pre-Omicron clades regardless of vaccination status. CONCLUSIONS: COVID-19 disease waves in Estonia were driven by the Alpha, Delta, and Omicron clades. Omicron clades were associated with a substantially lower hospitalisation probability than pre-Omicron clades. The protective effect of vaccination in reducing hospitalisation likelihood was independent of the involved clade.

Relativistic effects on acidities and basicities of Brønsted acids and bases containing gold.

It is usually believed that relativistic effects as described by the Dirac-Schrödinger equation (relative to the classical or time-independent Schrödinger equation) are of little importance in chemistry. A closer look, however, reveals that some important and widely known properties (e.g., gold is yellow, mercury is liquid at room temperature) stem from relativistic effects. So far the influence of relativistic effects on the acid-base properties has been mostly ignored. Here we show that at least for compounds of gold such omission is completely erroneous and would lead to too high basicity and too low acidity values with errors in the range of 25-55 kcal mol(-1) (or 20 to 44 powers of ten in pK(a) units) in the gas-phase. These findings have important implications for the design of new superstrong acids and bases, and for the understanding of gold-catalysed reactions.

A new class of organosuperbases, N-alkyl- and N-aryl-1,3-dialkyl-4,5-dimethylimidazol-2-ylidene amines: synthesis, structure, pK(BH+) measurements, and properties.

A series of stable organosuperbases, N-alkyl- and N-aryl-1,3-dialkyl-4,5-dimethylimidazol-2-ylidene amines, were efficiently synthesized from N,N'-dialkylthioureas and 3-hydroxy-2-butanone and their basicities were measured in acetonitrile. The derivatives with tert-alkyl groups on the imino nitrogen were found to be more basic than the tBuP(1) (pyrr) phosphazene base in acetonitrile. The origin of the high basicity of these compounds is discussed. In acetonitrile and in the gas phase, the basicity of the alkylimino derivatives depends on the size of the substituent at the imino group, which influences the degree of aromatization of the imidazole ring, as measured by (13)C NMR chemical shifts or by the calculated ΔNICS(1) aromaticity parameters, as well as on solvation effects. If a wider range of imino-substituents, including electron-acceptor substituents, is treated in the analysis then the influence of aromatization is less predominant and the gas-phase basicity becomes more dependent on the field-inductive effect, polarizability, and resonance effects of the substituent.

Calculations of pKa of superacids in 1,2-dichloroethane.

Acidity calculations for some CH and NH superacids in 1,2-dichloroethane (DCE) were carried out using SMD and COSMO-RS continuum solvation models. After comparing the results of calculations with respective experimental pK(a) values it was found that the performance of SMD/M05-2X/6-31G* method is characterized by the mean unsigned error (MUE) of 0.5 pK(a) units and the slope of regression line of 0.915. The similar SMD/B3LYP/6-31G* approach was slightly less successful. The strong correlation over entire data set is confirmed by R(2) values of 0.990 and 0.984 for M05-2X and B3LYP functionals, respectively. The COSMO-RS method, while providing the value of the linear regression line slope similar to the corresponding values from SMD approach, characterized by rather loose correlation (R(2) = 0.823, MUE = 1.7 pK(a) units) between calculated and experimental pK(a) values in DCE solution.

Acidity of anilines: calculations vs experiment.

The gas-phase acidities of ca. 60 monosubstituted anilines (with acidity span of almost 50 kcal mol(-1)) have been calculated using density functional theory (DFT) at the B3LYP/6-311+G** level. At this relatively simple level of theory the calculated (ΔG(calc)) and available experimental (ΔG(exp)) acidities are in reasonable quantitative correlation according to the following equation: ΔG(obs) = a + bΔG(calc), where a=20.79, b=0.942, n=27, R(2)=0.990, and s=0.78 kcal·mol(-1). The slope is not far from its ideal value. Substituent effects on the acidities were dissected separately into those operating in the neutral acid molecule and in its conjugated anion using the isodesmic homodesmotic reactions. All in all, both forms, neutral and anionic, are contributing in combination to make up the gross acidity of anilines. However, the contributions of the anions into the gross substituent effects are much larger than the substituent effects in the neutral anilines. Some of the systems were used in testing a relatively new theoretical model, COSMO-RS (conductor-like screening model for real solvents), using it for the prediction of pK(a) values in DMSO. The method proved to be rather accurate for showing pK(a) trends (R(2)=0.980 in DMSO). However, the predicted absolute pK(a) values were all somewhat lower (rmsd=2.49 kcal·mol(-1)) than the respective experimental values.

Polytrifluoromethylation versus polyfluorination of the isomers of Kekulé benzene and phenol: a theoretical study.

The study of the polyfluorination and polytrifluoromethylation effects on electronic structure and intrinsic acidities has been performed using DFT B3LYP and NBO calculations for the valence isomers of benzene and phenol, i.e., the structures of prismane, benzvalene, Kekulé, and Dewar systems. Also the isodesmic reaction analysis approach to estimate the effects of the substituents on the acidity of the compounds has been used. Although in some systems the additivity of fluorine substituents was more than 100%, the acidifying effects of the fluorine substituents were comparable to that of the CF(3) in only one case. Isodesmic reaction analysis of substituent effects shows that steric effects of poly-CF(3) substitution in the alicyclic cage compounds are significantly smaller. The relative thermodynamic stabilities of the valence isomers of Kekulé benzene were significantly lower than that of the aromatic cycle. The introduction of fluorine substituents often destabilized the compounds even further. Out of the fluorinated hydroxy derivatives of prismane, Dewar benzene, and benzvalene, not all are predicted to be stable enough to be able to undergo a reversible protonation-deprotonation process. In the case of several hydroxy derivatives deprotonation is accompanied by the rupture of a C(α)-C(ß) bond and in some cases by the rearrangement to the corresponding phenolate anion. The isomerization of benzene derivatives resulted in more cases where the acidities increased compared with the respective phenol derivatives. The only hydroxy compound with significantly higher acidity than the respective phenol was pentafluorinated 2-OH-Dewar benzene, which was expected to rival the gas-phase acidity of perfluoro-1-adamantanol, currently the most acidic experimentally measured perfluorinated alcohol.

Boratabenzene Anions C5B(CN)6(-) and C5B(CF3)6(-) and the superacidic properties of their conjugate acids.

Designing superacids: A computational study of protonated boratabenzenes and the gas-phase acidity of their conjugate acids is presented. Conjugate acids of boratabenzenes substituted with CN or CF(3) groups (see figure) are highly acidic species; the protonated hexacyanoboratabenzene and hexakis(trifluoromethyl)boratabenzene have computational gas-phase acidities of 250.5 and 276.8 kcal mol(-1), respectively.

Gas-phase Brønsted superacidity of some derivatives of monocarba-closo-borates: a computational study.

The structures and gas-phase acidities (GA) of several CB(11)H(12)H-based carborane acid derivatives (HA) have been calculated with DFT B3LYP method using 6-311+G**, 6-311++G** basis sets. In order to verify the obtained GA values, several systems were also studied at G3(MP2) level of theory. Inserted substituents (CF(3), F, Cl, Br, I, CN, CH(3), etc.) followed the "belts" of the monocarborane cage starting from the boron antipodal to the carbon. In general, the predicted intrinsic gas-phase acidities of the systems varied according to the substituents in the following order of decreasing strength: CF(3) > F > Cl > Br > I > CN > CH(3). Nevertheless, some inconsistencies occurred. F and CN derivatives with lower degree of substitution had weaker intrinsic acidities than the respective Cl derivatives, but the situation was reversed in the case of a larger number of substituents. To obtain better understanding how the substituents influence the basicity of the carborane anion, three hypothetical reaction series were investigated, in which the protonation center was fixed on the boron atom (B(12)), antipodal to the carbon (C(1)), and a single substituent replaced the hydrogens at the vertexes of the three remaining positions (C(1), B(2), and B(7)). The intrinsic gas-phase acidities in these series of neutral carborane-based acids CB(11)X(1)H(11)H are found to clearly depend on the field-inductive and resonance effects of the substituent X. Some influence of the polarizability of X on the reaction center (B(12)) could be detected only in the alpha position (B(7)).

Hydrogen-bonding interactions of (CF3)3CH and (CF3)3C- in the gas phase. An experimental (FT-ICR) and computational study.

Hydrogen-bonding interactions involving 2-(trifluoromethyl)-1,1,1,3,3,3-hexafluoropropane (1H) and 1(-) have been quantitatively studied by means of Fourier transform ion cyclotron resonance spectrometry. The existence of the species (1HCl)(-) and (1H1)(-) was demonstrated, and their thermodynamic stabilities were determined experimentally and computationally. In addition, some of their structural features were analyzed.

Revision of the gas-phase acidity scale below 300 kcal mol(-1).

The gas-phase acidity (GA) scale from (CF(3)CO)(2)NH to (C(2)F(5)SO(2))(2)NH--about a 24 kcal mol(-1) range of gas-phase acidities--was reexamined using the Fourier transform ion cyclotron resonance equilibrium measurement approach. Some additions and modifications to the standard methodology of GA measurements were introduced (estimation of partial pressures from mass spectra of the compounds, instead of the pressure gauge readings and use of long reaction times) to achieve higher reliability. Gas-phase acidities of 18 compounds were determined for the first time. The results reveal a contraction of the previously published values in this part of the scale. In particular, the GA values of (CF(3)SO(2))(2)NH and (C(2)F(5)SO(2))(2)NH (important components of lithium ion battery electrolytes and ionic liquids) were revised toward stronger acidities from 291.8 kcal mol(-1) to 286.5 kcal mol(-1) and from 289.4 kcal mol(-1) to 283.7 kcal mol(-1) (i.e., by 5.3 and 5.7 kcal mol(-1)), respectively. Experimental and computational evidence is presented in support of the current results.

Pentakis(trifluoromethyl)phenyl, a sterically crowded and electron-withdrawing group: synthesis and acidity of pentakis(trifluoromethyl)benzene, -toluene, -phenol, and -aniline.

A general route to functionalized pentakis(trifluoromethyl)phenyl (C6(CF3)5) derivatives, promising building blocks for designing novel stable carbenes, radical species, superacids, weakly coordinating anions and other practically and theoretically useful species, is presented. This pertrifluoromethylation route proceeds via conveniently pregenerated (trifluoromethyl)copper (CF3Cu) species in DMF, stabilized by addition of 1,3-dimethyl-2-imidazolidinone (DMI). These species react with hexaiodobenzene at ambient temperature to give the potassium pentakis(trifluoromethyl)phenoxide along with hexakis(trifluoromethyl)benzene and pentakis(trifluoromethyl)benzene in a combined yield of 80%. A possible reaction pathway explaining the formation of pentakis(trifluoromethyl)phenoxide is proposed. Pentakis(trifluoromethyl)phenol gives rise to easily functionalized pentakis(trifluoromethyl)chlorobenzene and pentakis(trifluoromethyl)aniline. Pertrifluoromethylation of pentaiodochlorobenzene and pentaiodotoluene allows straightforward access to pentakis(trifluoromethyl)chlorobenzene and pentakis(trifluoromethyl)toluene, respectively. XRD structures of several C6(CF3)5 derivatives were determined and compared with the calculated structures. Due to the steric crowding the aromatic rings in all C6(CF3)5 derivatives are significantly distorted. The gas-phase acidities (Delta Gacid) and pKa values in different solvents (acetonitrile (AN), DMSO, water) for the title compounds and a number of related compounds have been measured. The origin of the acidifying effect of the C6(CF3)5 group has been explored using the isodesmic reactions approach.

Brønsted basicities of diamines in the gas phase, acetonitrile, and tetrahydrofuran.

A comprehensive basicity study of alpha,omega-alkanediamines and related bases has been carried out. Basicities in acetonitrile (AN, pK(a) values), tetrahydrofuran (THF, pK(alpha) values), and gas phase (GP, GB values), were measured for 16, 14, and 9 diamine bases and for several related monoamines. In addition the gas-phase basicities and equilibrium geometries were computed for 19 diamino bases and several related monoamines at the DFT B3LYP 6-311+G** level. The effects of the different factors (intrinsic basicity of the amino groups, formation of intramolecular hydrogen bonds, and molecular strain) determining the diamine basicities were estimated by using the method of isodesmic reactions. The results are discussed in terms of molecular structure and solvation effects. The GP basicity is determined by the molecular size and polarizability, the extent of alkylation, and the energy effect of intramolecular hydrogen bond formation in the protonated base. The basicity trends in the solvents differ very much from those in GP: 1) The solvents severely compress the basicity range of the bases studied (3.5 times for the 1,3-propanediamine family in AN, and 7 times in THF), and 2) while stepwise alkylation of the basicity center leads to a steady basicity increase in the gas phase, the picture is complex in the solvents. Significant differences are also evident between THF and AN. The high hydrogen bond acceptor strength of THF leads to this solvent favoring the bases with "naked" protonation centers. In particular, the basicity order of N-methylated 1,3-propanediamines is practically inverse to that in the gas phase. The picture in AN is intermediate between that of GP and THF.

Experimental gas-phase basicity scale of superbasic phosphazenes.

Seventeen superbasic phosphazenes and two Verkade's bases were used to supplement and extend the experimental gas-phase basicity scale in the superbasic region. For 19 strong bases the gas-phase basicity values (GB) were determined for the first time. Among them are such well-known bases as BEMP (1071.2 kJ/mol), Verkade's Me-substituted base (1083.8 kJ/mol), Et-N=P(NMe2)2-N=P(NMe2)3 (Et-P2 phosphazene, 1106.9 kJ/mol), and t-Bu-N=P(NMe2)3 (t-Bu-P1 phosphazene, 1058.0 kJ/mol). For the first time experimental GB values were determined for P2 phosphazenes. Together with our previous results self-consistent experimental gas-phase basicity scale between 1020 and 1107 kJ/mol is now established. This way an important region of the gas-phase basicity scale, which was earlier dominated by metal hydroxide bases, is now covered also with organic bases making it more accessible for further studies. The GB values for several superbases were calculated using density functional theory at the B3LYP/6-311+G** level. For the phosphazene family the standard deviation of the correlation between the experimental and theoretical values was 6.5 kJ/mol.

Guanidinophosphazenes: design, synthesis, and basicity in THF and in the gas phase.

A principle for creating a new generation of nonionic superbases is presented. It is based on attachment of tetraalkylguanidino, 1,3-dimethylimidazolidine-2-imino, or bis(tetraalkylguanidino)carbimino groups to the phosphorus atom of the iminophosphorane group using tetramethylguanidine or easily available 1,3-dimethylimidazolidine-2-imine. Seven new nonionic superbasic phosphazene bases, tetramethylguanidino-substituted at the P atom, have been synthesized. Their base strengths are established in tetrahydrofuran (THF) solution by means of spectrophotometric titration and compared with those of eight reference superbases designed specially for this study, P2- and P4-iminophosphoranes. The gas-phase basicities of several guanidino- and N',N',N'',N''-tetramethylguanidino (tmg)-substituted phosphazenes and their cyclic analogues are calculated, and the crystal structures of (tmg)3P=N-t-Bu and (tmg)3P=N-t-Bu x HBF4 are determined. The enormous basicity-increasing effect of this principle is experimentally verified for the tetramethylguanidino groups in the THF medium: the basicity increase when moving from (dma)3P=N-t-Bu (pKalpha = 18.9) to (tmg)3P=N-t-Bu (pKalpha = 29.1) is 10 orders of magnitude. A significantly larger basicity increase (up to 20 powers of 10) is expected (based on the high-level density functional theory calculations) to accompany the similar gas-phase transfer between the (dma)3P=NH and (tmg)3P=NH bases. Far stronger basicities still are expected when, in the latter two compounds, all three dimethylamino (or tetramethylguanidino) fragments are replaced by methylated triguanide fragments, (tmg)2C=N-. The gas-phase basicity (around 300-310 kcal/mol) of the resulting base, [(tmg)2C=N-]3P=NH, having only one phosphorus atom, is predicted to exceed the basicity of (dma)3P=NH by more than 40 powers of 10 and to surpass also the basicity of the widely used commercial [(dma)3P=N]3P=N-t-Bu (t-BuP4) superbase.