Mass spectrometry in organic and bio-organic catalysis: Using thermochemical properties to lend insight into mechanism.

In this review, we discuss gas phase experimentation centered on the measurement of acidity and proton affinity of substrates that are useful for understanding catalytic mechanisms. The review is divided into two parts. The first covers examples of organocatalysis, while the second focuses on biological catalysis. The utility of gas phase acidity and basicity values for lending insight into mechanisms of catalysis is highlighted.

A Computational Analysis of the Proton Affinity and the Hydration of TEMPO and Its Piperidine Analogs.

The study investigated the impact of protonation and hydration on the geometry of nitroxide radicals using B3LYP and M06-2X methods. Results indicated that TEMPO exhibited the highest proton affinity in comparison to TEMPOL and TEMPONE. Two pathways contribute to hydrated protonated molecules. TEMPO shows lower first enthalpies of hydration (ΔH1-M), indicating stronger H-bonding interactions, while TEMPONE shows higher values, indicating weaker interactions with H2O. Solvent effects affect charge distribution by decreasing their atomic charge. Spin density (SD) is primarily concentrated in the NO segment, with minimal water molecule contamination. Protonation increases SD on N-atom, while hydration causes a more pronounced redistribution for water molecules. The stability of the dipolar structure (>N⋅+-O-) is evident in SD redistributions. The frontier molecular orbital (FMO) analysis of TEMPONE reveals a minimum EHOMO-LUMO gap (EH-L), enhancing the piperidine ring's reactivity. TEMPO is the most nucleophilic species, while TEMPONE exhibits strong electrophilicity. Transitioning from NO radicals to protonated forms increases the EH-L gap, indicating protonation stabilizes FMOs. Increased water molecules make the molecule less reactive, while increasing hydration decreases this energy gap, making the molecule more reactive. A smaller EH-L gap indicates the compound becomes softer and more prone to electron density and reactivity changes.

An Investigation of the Structures of [(Glycine)(1-Methyluracil)]M+ Complexes (M = H, Li, Na, K) in the Gas Phase by IRMPD Spectroscopy and Theoretical Methods.

The presence of ions in the complexation of molecules can profoundly affect the structure, resulting in changes to functionality and stability. These non-covalent interactions drive many biological processes both necessary and inimical and require extensive research to understand and predict their effects. Protonated and alkali metalated complexes of glycine (Gly) and 1-methyluracil (1-mUra) were studied using infrared multiphoton dissociation (IRMPD) spectroscopy and density functional theory (DFT) calculations. The experimental and simulated vibrational spectra were compared to help elucidate the structure of each complex. The lowest energy structure for [(Gly)(1-mUra)]H+ consists of amine protonated Gly bound to O4 of canonical 1-mUra through a single ionic hydrogen bond with another, intraglycine ionic hydrogen bond between the protonated amine group and the carbonyl oxygen. For [(Gly)(1-mUra)]Li+, [(Gly)(1-mUra)]Na+ and [(Gly)(1-mUra)]K+, the experimental spectra are most consistent with the metal cations binding in a trigonal planar geometry with 1-mUra bound to the metal cation via the O4 carbonyl. In [(Gly)(1-mUra)]Li+ and [(Gly)(1-mUra)]Na+, the metal cation is bound to canonical Gly via the carbonyl oxygen and amine nitrogen, but in [(Gly)(1-mUra)]K+, Gly is bound through both oxygens and contains an intraglycine hydrogen bond from the hydroxyl to the amine nitrogen.

Tuning proton affinity on Co-N-C atomic interface to disentangle activity-selectivity trade-off in acidic oxygen reduction to H2O2.

In oxygen reduction reaction to H2O2via two-electron pathway (2e- ORR), adsorption strength of oxygen-containing intermediates determines both catalytic activity and selectivity. However, it also causes activity-selectivity trade-off. Herein, we propose a novel strategy through modulating the interaction between protons and *OOH intermediates to break the activity-selectivity trade-off for highly active and selective 2e- ORR. Taking the typical cobalt-nitrogen-carbon single-atom catalyst as an example, boron heteroatoms doped into second coordination sphere of CoN4 (Co1-NBC) increase proton affinity on catalyst surface, facilitating proton attack on the former oxygen of *OOH and thereby promoting H2O2 formation. As a result, Co1-NBC simultaneously achieves prominent 2e- ORR activity and selectivity in acid with onset potential of 0.724 V vs. RHE and H2O2 selectivity of 94%, surpassing most reported catalysts. Furthermore, Co1-NBC exhibits a record-high H2O2 productivity of 202.7 mg cm-2 h-1 and a remarkable stability of 60 h at 200 mA cm-2 in flow cell. This work provides new insights into resolving activity-selectivity trade-off in electrocatalysis.

Benchmark ab initio proton affinity and gas-phase basicity of α-alanine based on coupled-cluster theory and statistical mechanics.

We determine the proton affinity (PA) and gas-phase basicity (GB) of amino acid α-alanine at a chemically accurate level by performing explicitly-correlated CCSD(T)-F12b/aug-cc-pVDZ geometry optimizations and normal mode vibrational frequency calculations as well as CCSD(T)-F12b/aug-cc-pVTZ energy computations at the possible neutral and protonated geometries. Temperature effects at 298.15 K considering translational, rotational, and vibrational enthalpy and entropy corrections are obtained via standard statistical mechanics utilizing the molecular geometries and the harmonic vibrational energy levels. Both the amino nitrogen (N) and the carbonyl oxygen (O) atoms are proven to be potential protonation sites and a systematic conformational search reveals 3 N- and 9 O-protonated conformers in the 0.00-7.88 and 25.43-30.43 kcal/mol energy ranges at 0 K, respectively. The final computed PA and GB values at (0)298.15 K in case of N-protonation are (214.47)216.80 and 207.07 kcal/mol, respectively, whereas the corresponding values for O-protonation are (189.04)190.63 and 182.31 kcal/mol. The results of the benchmark high-level coupled-cluster computations are utilized to assess the accuracy of several lower-level cost-effective methods such as MP2 and density functional theory with various functionals (SOGGA11-X, M06-2X, PBE0, B3LYP, M06, TPSS).

Reactivity of a N-Coordinated Germylene-Borane Complex: From Ge→B to Ge→Ga Coordination.

Reactivity studies of the GeII →B complex L(Cl)Ge⋅BH3 (1; L=2-Et2 NCH2 -4,6-tBu2 -C6 H2 ) were performed to determine the effect on the GeII →B donation. N-coordinated compounds L(OtBu)Ge⋅BH3 (2) and [LGe⋅BH3 ]2 (3) were prepared. The possible tuning of the GeII →B interaction was proved experimentally, yielding compounds 1-PPh2 -8-(LGe)-C10 H6 (4) and L(Cl)Ge⋅GaCl3 (5) without a GeII →B interaction. In 5, an unprecedented GeII →Ga coordination was revealed. The experimental results were complemented by a theoretical study focusing on the bonding in 1-5. The different strength of the GeII →E (E=B, Ga) donation was evaluated by using energy decomposition analysis. The basicity of different L(X)Ge groups through proton affinity is also assessed.

Synthesis and Investigation of Novel CHCA-Derived Matrices for Matrix-Assisted Laser Desorption/Ionization Mass Spectrometric Analysis of Lipids.

A significant area of study and upgrading for increasing sensitivity and general performances of matrix-assisted laser-desorption ionization (MALDI) mass spectrometry (MS) is related to matrix design. Several efforts have been made to address the challenge of low-mass-region interference-free for metabolomics analysis and specifically for lipidomics. To this aim, rationally designed matrices as 4-chloro-α-cyanocinnamic acid (ClCCA) were introduced and reported to provide enhanced analytical performances. We have taken this rational design one step further by developing and optimizing new MALDI matrices with a range of modifications on the CHCA core, involving different functionalities and substituents. Of particular interest was the understanding of the electron-withdrawing (e.g., nitro-) or donating (e.g., methoxy-) effects along with the extent of conjugation on the ionization efficiency. In the present work, ten matrices were designed on a reasonable basis, synthesized, and characterized by NMR and UV spectroscopies and laser desorption ionization. With the assistance of these putative MALDI matrices, samples containing phospholipids (PL), and neutral di-/tri-acylglycerols (DAG, TAG) were investigated using milk, fish, blood, and human plasma extracts. In comparison with CHCA and ClCCA, four of them, viz. [(2E,4E)-2-cyano-5-(4-methoxyphenyl)penta-2,4-dienoic acid] (1), [(2E,4E)-2-cyano-5-(4-nitrophenyl)penta-2,4-dienoic acid] (2), [(E)-2-cyano-3-(6-methoxynaphthalen-2-yl)acrylic acid] (6) and [(E)-2-cyano-3-(naphthalen-2-yl)acrylic acid] (7) displayed good to even excellent performances as MALDI matrices in terms of ionization capability, interference-free spectra, S/N ratio, and reproducibility. Especially compound 7 (cyano naphthyl acrylic acid, CNAA) was the election matrix for PL analysis and matrix 2 (cyano nitrophenyl dienoic acid, CNDA) for neutral lipids such as DAG and TAG in positive ion mode.

Benchmark calculations of proton affinity and gas-phase basicity using multilevel (G4 and G3B3), B3LYP and MP2 computational methods of para-substituted benzaldehyde compounds.

This study presents the benchmark calculations of proton affinities (PAs) and gas-phase basicities (GBs) of 8-para substituted benzaldehyde compounds using the multilevel model chemistries (G3B3 and G4), density-functional quantum model (B3LYP) and ab initio model (MP2). The results show that the computed properties are strongly correlated with the available experimental data. The PAs and the GBs of other eight para-substituted benzaldehyde compounds, for which the experimental data does not currently exist, have been calculated using G3B3 and B3LYP methods. The correlations between the experimental PAs and GBs with the computed properties such as PA, GB, chemical properties (bond lengths, electron density and δ1 H NMR chemical shift) of the investigated benzaldehydes have been studied and statistically analyzed. The influence of the substituted groups has been discussed in terms of inductive effect and electron donating and electron withdrawing effect. The results obtained show that the chemical properties of the benzaldehyde compounds are controlled by the strong coupling between the CHO group and the nature of the para-substituent groups through the benzene ring as a conducting linkage.

Proton-Coupled Electron Transfer (PCET) with 1,4-Bisguanidino-Benzene Derivatives: Comparative Study and Use in Acid-Initiated C-H Activation.

Proton-coupled electron transfer (PCET) is of key importance in modern synthetic chemistry. Redox-active guanidines were established by our group as valuable alternatives to toxic high-potential benzoquinones in a variety of different PCET reactions. In this work, the PCET reactivity of a series of 1,4-bisguanidino-benzenes varying in their redox potentials and proton affinities is evaluated. The relevant redox and protonation states are fully characterized, and the compounds sorted with respect to their PCET reactivity by comparative PCET experiments supplemented by quantum-chemical calculations. Depending on the studied reactions, the driving force is either electron transfer or proton transfer; thereby the influence of both processes on the overall reactivity could be assessed. Then, two of the PCET reagents are applied in representative oxidative aryl-aryl coupling reactions, namely the intramolecular coupling of 3,3''-4,4''-tetramethoxy-o-terphenyl to give the corresponding triphenylene, the intermolecular coupling of N-ethylcarbazole to give N,N'-diethyl-3,3'-bicarbazole, and in the oxidative lactonization of 2-[(4-methoxyphenyl)methyl]-benzoic acid. Under mild conditions, the reactions proceed fast and efficient. Only small amounts of acid are needed, in clear contrast to the corresponding coupling reactions with traditional high-potential benzoquinones such as DDQ or chloranil requiring a large excess of a strong acid.

Antiradical Properties of trans-2-(4-substituted-styryl)-thiophene.

2-substituted thiophene compounds with electron donating and electron withdrawing p-phenyl substitution were synthesized and studied their radical scavenging properties using DPPH assay and DFT method. It is shown that p-hydroxy and p-amino phenyl substituted compound exhibit radical scavenging activity. From DFT and radical scavenging studies, a correlation between IC50 with the bond dissociation enthalpy, proton affinity, ground state dipole moment and optical band gap of compound is found. Compounds 1-3 with electron withdrawing substituent (NO2, CN, Cl) do not show any radical scavenging properties, whereas compounds 6-7 with electron donating substituent (OH, NH2) show antiradical properties. Further, the antiradical activity is reduced drastically by replacing the -OH and -NH2 with methoxy and -N-alkylating group respectively in 6 and 7. The compound with p-hydroxy phenyl substitution, exhibits stronger antiradical activity as compared to the p-amino phenyl substitution due to smaller O-H bond dissociation energy as compared to the N-H bond. From DPPH and DFT studies, it is suggested that the radical scavenging activity in 2-substituted thiophene is occurred through proton transfer mechanism. The other possible SET, SPLET mechanisms are also corroborated. Graphical Abstract Antiradical properties of trans-2-(4-substituted-styryl)-thiophene Anamika Gusain, Naresh Kumar, Jagdeep Kumar, Gunjan Pandey, Prasanta Kumar Hota.

Structural investigations, quantum mechanical studies on proton and metal affinity and biological activity predictions of selpercatinib.

Cancer of the lungs and thyroid is particularly difficult to manage and treat. Notably, selpercatinib has recently been suggested as an effective drug to combat these diseases. The entire world is currently tackling the pandemic caused by the SARS-CoV-19 virus. Numerous pharmaceuticals have been evaluated for the management of the disease caused by SARS-CoV-19 (i.e., COVID-19). In this study, selpercatinib was proposed as a potential inhibitor of different SARS-CoV-19 proteins. Several intriguing effects of the molecule were found during the conducted computational investigations. Selpercatinib could effectively act as a proton sponge and exhibited high proton affinity in solution. Moreover, it was able to form complexes with metal ions in aqueous solutions. Specifically, the compound displayed high affinity towards zinc ions, which are important for the prevention of virus multiplication inside human cells. However, due to their charge, zinc ions are not able to pass the lipid bilayer and enter the cell. Thus, it was determined that selpercatinib could act as an ionophore, effectively transporting active zinc ions into cells. Furthermore, various quantum mechanical analyses, including energy studies, evaluation of the reactivity parameters, examination of the electron localisation and delocalisation properties, as well as assessment of the nonlinear optical (NLO) properties and information entropy, were conducted herein. The performed docking studies (docking scores -9.3169, -9.1002, -8.1853 and -8.1222 kcal mol-1) demonstrated that selpercatinib strongly bound with four isolated SARS-CoV-2 proteins.

Relative glycosidic bond stabilities of naturally occurring methylguanosines: 7-methylation is intrinsically activating.

The frequency and diversity of posttranscriptional modifications add an additional layer of chemical complexity beyond canonical nucleic acid sequence. Methylations are particularly frequently occurring and often highly conserved throughout the kingdoms of life. However, the intricate functions of these modified nucleic acid constituents are often not fully understood. Systematic foundational research that reduces systems to their minimum constituents may aid in unraveling the complexities of nucleic acid biochemistry. Here, we examine the relative intrinsic N-glycosidic bond stabilities of guanosine and five naturally occurring methylguanosines (O2'-, 1-, 7-, N2,N2-di-, and N2,N2,O2'-trimethylguanosine) probed by energy-resolved collision-induced dissociation tandem mass spectrometry and complemented with quantum chemical calculations. Apparent glycosidic bond stability is generally found to increase with increasing methyl substitution (canonical < mono- < di- < trimethylated). Many biochemical transformations, including base excision repair mechanisms, involve protonation and/or noncovalent interactions to increase nucleobase leaving-group ability. The protonated gas-phase methylguanosines require less activation energy for glycosidic bond cleavage than their sodium cationized forms. However, methylation at the N7 position intrinsically weakens the glycosidic bond of 7-methylguanosine more significantly than subsequent cationization, and thus 7-methylguanosine is suggested to be under perpetually activated conditions. N7 methylation also alters the nucleoside geometric preferences relative to the other systems, including the nucleobase orientation in the neutral form, sugar puckering in the protonated form, and the preferred protonation and sodium cation binding sites. All of the methylated guanosines examined here are predicted to have proton affinities and gas-phase basicities that exceed that of canonical guanosine. Additionally, the proton affinity and gas-phase basicity trends exhibit a roughly inverse correlation with the apparent glycosidic bond stabilities.

On the Use of Popular Basis Sets: Impact of the Intramolecular Basis Set Superposition Error.

The magnitude of intramolecular basis set superposition error (BSSE) is revealed via computing systematic trends in molecular properties. This type of error is largely neglected in the study of the chemical properties of small molecules and it has historically been analyzed just in the study of large molecules and processes dominated by non-covalent interactions (typically dimerization or molecular complexation and recognition events). In this work we try to provide proof of the broader prevalence of this error, which permeates all types of electronic structure calculations, particularly when employing insufficiently large basis sets.

Large Proton-Affinity Enhancements Triggered by Noncovalent Interactions.

High affinity: The proton affinity (PA) of the OH group of YHx OH compounds is always increased by noncovalent interaction (NCI) with a Lewis base (LB; see figure). This PA enhancement depends on the type of NCI. Weak NCIs can give rise to PA enhancements equal to or even larger than strong NCIs. The binding energies of protonated species play a major role in the case of sigma-hole interactions.

An Assessment of Computational Methods for Calculating Accurate Structures and Energies of Bio-Relevant Polysulfur/Selenium-Containing Compounds.

The heavier chalcogens sulfur and selenium are important in organic and inorganic chemistry, and the role of such chalcogens in biological systems has recently gained more attention. Sulfur and, to a lesser extent selenium, are involved in diverse reactions from redox signaling to antioxidant activity and are considered essential nutrients. We investigated the ability of the DFT functionals (B3LYP, B3PW91, ωB97XD, M06-2X, and M08-HX) relative to electron correlation methods MP2 and QCISD to produce reliable and accurate structures as well as thermochemical data for sulfur/selenium-containing systems. Bond lengths, proton affinities (PA), gas phase basicities (GPB), chalcogen⁻chalcogen bond dissociation enthalpies (BDE), and the hydrogen affinities (HA) of thiyl/selenyl radicals were evaluated for a range of small polysulfur/selenium compounds and cysteine per/polysulfide. The S⁻S bond length was found to be the most sensitive to basis set choice, while the geometry of selenium-containing compounds was less sensitive to basis set. In mixed chalcogens species of sulfur and selenium, the location of the sulfur atom affects the S⁻Se bond length as it can hold more negative charge. PA, GPB, BDE, and HA of selenium systems were all lower, indicating more acidity and more stability of radicals. Extending the sulfur chain in cysteine results in a decrease of BDE and HA, but these plateau at a certain point (199 kJ mol-1 and 295 kJ mol-1), and PA and GPB are also decreased relative to the thiol, indicating that the polysulfur species exist as thiolates in a biological system. In general, it was found that ωB97XD/6-311G(2d,p) gave the most reasonable structures and thermochemistry relative to benchmark calculations. However, nuances in performance are observed and discussed.

Revealing Germylene Compounds to Attain Superbasicity with Sigma Donor Substituents: A Density Functional Theory Study.

Compounds of GeII are shown for the first time to function as superbases. Two B(N=PiPr3 )2 groups attached to a germanium(II) center show a gas-phase proton affinity of 296.2 kcal mol-1 , which is close to the range of a hyperbase as revealed by B3LYP-D3/6-31G(2d,p) level of theory. These DFT calculations showed better agreement of geometrical parameters for the reported stable germylene compound 1 than previously reported calculations. A systematic study with different substitutions of GeII revealed that such a system can achieve basicity close to a hyperbase. The stabilities of these superbases were examined with dimerization energy and singlet-triplet state energy difference (ΔES-T ). Furthermore, the calculated gas-phase proton affinity values also show good correlation with the most negative valued point (Vmin ) in electron-rich regions from the molecular electrostatic potential. The high PA values of compounds were also supported by ionization potential, electron affinity, absolute electronegativity, and absolute hardness calculations. The energetics for the reaction with BH3 and AlMe3 further suggest that the lone pair of GeII can act as a Lewis base and display higher donor-acceptor bond strengths.

Relationship between proton affinities and structures of proton-bound dimers.

This work presents a structural approach for determination of proton affinities of molecules. In proton-bound dimer [X…H…M]+, M and X compete with each other to capture the proton. The correlation between proton affinities of a series of molecules, M, and X…H bond length was studied while X was a common molecule in the all proton-bound dimers. Linear relationships were observed between proton affinities of a series of alcohols, ethers, aldehydes, ketones and amines and X…H bond length, where H2O and HF were used as X. The method was employed for the measurement of proton affinities of (HF)1-10 clusters using NH3 and H2O as common molecules, [NH3…H…(HF)n]+ and [H2O…H…(HF)n]+. A linear correlation was observed for the PAs of (HF)n clusters versus N…H bond length.

Proton affinities and ion enthalpies.

Proton affinities of a number of alkyl acetates (CH3-C(=O)-OR) and of methyl alkanoates (R-C(=O)-OCH3, R=H, alkyl) have been assembled from the literature or measured using the kinetic method. It was observed that the proton affinities for the isomeric species CH3-C(=O)-OR and R-C(=O)-OCH3 are almost identical, an unexpected result as the charge in these protonated ester molecules is largely at the keto carbon atom and so this site should be more sensitive to alkyl substitution. Analysis of the data, including those from lone pair ionisation and core-electron ionisation experiments available from the literature, indicate that after protonation, extensive charge relaxation (or polarisation) takes place (as is also the case, according to the literature, after core-electron ionisation). By contrast, after lone pair ionisation, which results in radical cations, such relaxation processes are relatively less extensive. As a consequence, changes in ion enthalpies of these protonated molecules follow more closely the changes in neutral enthalpies, compared with changes in enthalpies of the corresponding radical cations, formed by electron detachment. Preliminary analyses of published energetic data indicate that the above finding for organic esters may well be another example of a more general phenomenon.

Proton solvation in protic and aprotic solvents.

Protonation pattern strongly affects the properties of molecular systems. To determine protonation equilibria, proton solvation free energy, which is a central quantity in solution chemistry, needs to be known. In this study, proton affinities (PAs), electrostatic energies of solvation, and pKA values were computed in protic and aprotic solvents. The proton solvation energy in acetonitrile (MeCN), methanol (MeOH), water, and dimethyl sulfoxide (DMSO) was determined from computed and measured pKA values for a specially selected set of organic compounds. pKA values were computed with high accuracy using a combination of quantum chemical and electrostatic approaches. Quantum chemical density functional theory computations were performed evaluating PA in the gas-phase. The electrostatic contributions of solvation were computed solving the Poisson equation. The computations yield proton solvation free energies with high accuracy, which are in MeCN, MeOH, water, and DMSO -255.1, -265.9, -266.3, and -266.4 kcal/mol, respectively, where the value for water is close to the consensus value of -265.9 kcal/mol. The pKA values of MeCN, MeOH, and DMSO in water correlates well with the corresponding proton solvation energies in these liquids, indicating that the solvated proton was attached to a single solvent molecule.

Experimental versus Calculated Proton Affinities for Aromatic Carboxylic Acid Anions and Related Phenide Ions.

Herein, we present the comparison of a large set of experimentally measured proton affinity (PA) values for 65 aromatic carboxylate anions with the values calculated by using selected popular DFT (B3LYP, PBE0, and M05-2X) and composite [G3(MP2), G4(MP2)] quantum chemistry methods. The root-mean-square error (RMSE) values for the chosen methods are RMSEPBE0 =1.7, RMSEB3LYP =4.6, RMSEM05-2X =6.6, RMSEG3MP2 =6.3, RMSEG4MP2 =4.5 kJ mol(-1) . In the second part of the study, 82 PA values for substituted phenide ions and a few heteroaromatic anions were calculated. Again, very good agreement between the calculated and experimental values has been observed: RMSEPBE0 =1.9, RMSEB3LYP =4.5, RMSEM05-2X =6.3, RMSEG3MP2 =4.9, RMSEG4MP2 =5.5 kJ mol(-1) . Our results show that, for medium-sized carboxylate anions, all tested methods give reliable results and, surprisingly, much more computationally demanding composite methods do not perform significantly better than the time-efficient DFT methods.