Deprotonation Pathway Research Articles

Three-body deprotonation fragmentation dynamics of C6H63+ induced by electron-impact ionization.

The three-body fragmentation dynamics of benzene trications C6H63+ induced by 200eV electron-impact produced by a photoemission cathode is investigated. All three fragment ions are detected in coincidence, and their momentum vectors are determined by employing a COLTRIMS reaction microscope. The detailed kinematical information of three deprotonation fragmentation channels of H+ + C3H2+ + C3H3+, H+ + C2H3+ + C4H2+, and H+ + C2H2+ + C4H3+ are obtained. By analyzing the momentum and energy correlation spectra among all the three fragment ions, we find that all the three channels are primarily generated by sequential fragmentation processes. Each channel has two deprotonation pathways, corresponding to proton emission in the first or second step of sequential fragmentation, respectively. These results provide insight into the mechanisms and dynamics of deprotonation and ring-breaking reactions in the three-body fragmentation processes of aromatic ring molecules.

Observing one-divalent-metal-ion-dependent and histidine-promoted His-Me family I-PpoI nuclease catalysis in crystallo.

Metal-ion-dependent nucleases play crucial roles in cellular defense and biotechnological applications. Time-resolved crystallography has resolved catalytic details of metal-ion-dependent DNA hydrolysis and synthesis, uncovering the essential roles of multiple metal ions during catalysis. The histidine-metal (His-Me) superfamily nucleases are renowned for binding one divalent metal ion and requiring a conserved histidine to promote catalysis. Many His-Me family nucleases, including homing endonucleases and Cas9 nuclease, have been adapted for biotechnological and biomedical applications. However, it remains unclear how the single metal ion in His-Me nucleases, together with the histidine, promotes water deprotonation, nucleophilic attack, and phosphodiester bond breakage. By observing DNA hydrolysis in crystallo with His-Me I-PpoI nuclease as a model system, we proved that only one divalent metal ion is required during its catalysis. Moreover, we uncovered several possible deprotonation pathways for the nucleophilic water. Interestingly, binding of the single metal ion and water deprotonation are concerted during catalysis. Our results reveal catalytic details of His-Me nucleases, which is distinct from multi-metal-ion-dependent DNA polymerases and nucleases.

Observing one-divalent-metal-ion-dependent and histidine-promoted His-Me family I-PpoI nuclease catalysis in crystallo

Metal-ion-dependent nucleases play crucial roles in cellular defense and biotechnological applications. Time-resolved crystallography has resolved catalytic details of metal-ion-dependent DNA hydrolysis and synthesis, uncovering the essential roles of multiple metal ions during catalysis. The histidine-metal (His-Me) superfamily nucleases are renowned for binding one divalent metal ion and requiring a conserved histidine to promote catalysis. Many His-Me family nucleases, including homing endonucleases and Cas9 nuclease, have been adapted for biotechnological and biomedical applications. However, it remains unclear how the single metal ion in His-Me nucleases, together with the histidine, promotes water deprotonation, nucleophilic attack, and phosphodiester bond breakage. By observing DNA hydrolysis in crystallo with His-Me I-PpoI nuclease as a model system, we proved that only one divalent metal ion is required during its catalysis. Moreover, we uncovered several possible deprotonation pathways for the nucleophilic water. Interestingly, binding of the single metal ion and water deprotonation are concerted during catalysis. Our results reveal catalytic details of His-Me nucleases, which is distinct from multi-metal-ion-dependent DNA polymerases and nucleases.

Variations in proton transfer pathways and energetics on pristine and defect-rich quartz surfaces in water: Insights into the bimodal acidities of quartz

HypothesisUnderstanding the mechanisms of proton transfer on quartz surfaces in water is critical for a range of processes in geochemical, environmental, and materials sciences. The wide range of surface acidities (>9 pKa units) found on the ubiquitous mineral quartz is caused by the structural variations of surface silanol groups. Molecular scale simulations provide essential tools for elucidating the origin of site-specific surface acidities. SimulationsWe used density-functional tight-binding-based molecular dynamics combined with rare-event metadynamics simulations to probe the mechanisms of deprotonation reactions from ten representative surface silanol groups found on both pristine and defect-rich quartz (101) surfaces with Si vacancies. FindingsThe results show that deprotonation is a highly dynamic process where both the surface hydroxyls and bridging oxygen atoms serve as the proton acceptors, in addition to water. Deprotonation of embedded silanols through intrasurface proton transfer exhibited lower pKa values with less H-bond participation and higher energy barriers, suggesting a new mechanism to explain the bimodal acidity observed on quartz surface. Defect sites, recently shown to comprise a significant portion of the quartz (101) surface, diversify the coordination and local H-bonding environments of the surface silanols, changing both the deprotonation pathways and energetics, leading to a wider range of pKa values (2.4 to 11.5) than that observed on pristine quartz surface (10.4 and 12.1).

Determination of pKa values and deprotonation order of methotrexate using a combined experimental-theoretical study and binding constants of the methotrexate-Laponite complex at different pH values

The pKa values of the cancer drug methotrexate (MTX) were calculated, using experimental UV–Vis spectroscopic data and with the aid of the Stability Quotients from Absorbance Data (SQUAD) in addition to its deprotonation pathway from theoretical calculations using Gaussian 09 package (M062X functional and 6–311++g** basis set), since there is a discrepancy in the order of deprotonation. Also, the binding constants (K) of the complex formed between MTX and the nano clay called Laponite (Lap) were calculated at two pH values. From the log β values obtained with SQUAD, three pKa values for MTX were calculated: 2.68 ± 0.07, 4.11 ± 0.05 and 5.48 ± 0.01 associating the first pKa value to the carboxyl group attached to the alpha carbon and the second pKa value to the carboxyl group of the gamma carbon. The interaction between the chemical species of this drug (MTXH3+ and MTX2−) and Lap was studied with UV–Vis spectrophotometry and SQUAD at pH values 2.0, and 7.5, resulting in a single equilibrium for the formation of the MTX-Lap complex with log K 4.36 ± 0.01 (1:1) and 1.99 ± 0.04 M−1 (1:1) respectively. Lastly, the free and encapsulated MTX percentage was calculated from the chemical-species distribution diagram of the MTX-Lap system at pH 1.4, which agrees with those determined experimentally.

Taming secondary benzylic cations in catalytic asymmetric SN1 reactions.

Benzylic stereogenic centers are ubiquitous in natural products and pharmaceuticals. A potentially general, though challenging, approach toward their selective creation would be asymmetric unimolecular nucleophilic substitution (SN1) reactions that proceed through highly reactive benzylic cations. We now report a broadly applicable solution to this problem by identifying chiral counteranions that pair with secondary benzylic cations to engage in catalytic asymmetric C-C, C-O, and C-N bond-forming reactions with excellent enantioselectivity. The critical cationic intermediate can be accessed from different precursors via Lewis- or Brønsted acid catalysis. Key to our strategy is the use of only weakly basic, confined counteranions that are posited to prolong the lifetime of the carbocation, thereby avoiding nonproductive deprotonation pathways to the corresponding styrene.

Dehydrogenative Cross-Coupling of α,β-Unsaturated Compounds with Unactivated Olefins via Co(III) Catalysis.

An oxidative cross-coupling of α,β-unsaturated compounds with unactivated alkenes via cobalt-catalyzed vinylic C-H activation has been developed. The present catalytic reaction was examined with various differently functionalized unsaturated compounds and unactivated olefins. In these reactions, highly valuable amide functionalized butadienes and indenones were prepared in good to excellent yields. A possible reaction mechanism is proposed involving directed olefinic C-H activation through a base-assisted deprotonation pathway.

Reconstructed Ir‒O‒Mo species with strong Brønsted acidity for acidic water oxidation

Surface reconstruction generates real active species in electrochemical conditions; rational regulating reconstruction in a targeted manner is the key for constructing highly active catalyst. Herein, we use the high-valence Mo modulated orthorhombic Pr3Ir1−xMoxO7 as model to activate lattice oxygen and cations, achieving directional and accelerated surface reconstruction to produce self-terminated Ir‒Obri‒Mo (Obri represents the bridge oxygen) active species that is highly active for acidic water oxidation. The doped Mo not only contributes to accelerated surface reconstruction due to optimized Ir‒O covalency and more prone dissolution of Pr, but also affords the improved durability resulted from Mo-buffered charge compensation, thereby preventing fierce Ir dissolution and excessive lattice oxygen loss. As such, Ir‒Obri‒Mo species could be directionally generated, in which the strong Brønsted acidity of Obri induced by remaining Mo assists with the facilitated deprotonation of oxo intermediates, following bridging-oxygen-assisted deprotonation pathway. Consequently, the optimal catalyst exhibits the best activity with an overpotential of 259 mV to reach 10 mA cmgeo−2, 50 mV lower than undoped counterpart, and shows improved stability for over 200 h. This work provides a strategy of directional surface reconstruction to constructing strong Brønsted acid sites in IrOx species, demonstrating the perspective of targeted electrocatalyst fabrication under in situ realistic reaction conditions.

Dissociation Mode of the O-H Bond in Betanidin, pKa-Clusterization Prediction, and Molecular Interactions via Shape Theory and DFT Methods.

Betanidin (Bd) is a nitrogenous metabolite with significant bioactive potential influenced by pH. Its free radical scavenging activity and deprotonation pathway are crucial to studying its physicochemical properties. Motivated by the published discrepancies about the best deprotonation routes in Bd, this work explores all possible pathways for proton extractions on that molecule, by using the direct approach method based on pKa. The complete space of exploration is supported by a linear relation with constant slope, where the pKa is written in terms of the associated deprotonated molecule energy. The deprotonation rounds 1, …, 6 define groups of parallel linear models with constant slope. The intercepts of the models just depend on the protonated energy for each round, and then the pKa can be trivially ordered and explained by the energy. We use the direct approximation method to obtain the value of pKa. We predict all possible outcomes based on a linear model of the energy and some related verified assumptions. We also include a new measure of similarity or dissimilarity between the protonated and deprotonated molecules, via a geometric-chemical descriptor called the Riemann-Mulliken distance (RMD). The RMD considers the cartesian coordinates of the atoms, the atomic mass, and the Mulliken charges. After exploring the complete set of permutations, we show that the successive deprotonation process does not inherit the local energy minimum and that the commutativity of the paths does not hold either. The resulting clusterization of pKa can be explained by the local acid and basic groups of the BD, and the successive deprotonation can be predicted by using the chemical explained linear models, which can avoid unnecessary optimizations. Another part of the research uses our own algorithm based on shape theory to determine the protein's active site automatically, and molecular dynamics confirmed the results of the molecular docking of Bd in protonated and anionic form with the enzyme aldose reductase (AR). Also, we calculate the descriptors associated with the SET and SPLET mechanisms.

Experimental-theoretical study to determine the pKa values of the ocular hypotensive Dorzolamide from UV–Vis spectroscopy

The pKa values of the ocular hypotensive dorzolamide (Dor) were calculated by experimental UV–Vis spectrophotometric data and with the aid of the Stability Quotients from Absorbance Data (SQUAD) software, resulting in an additional pKa value for this drug. From the global formation constants (log β) calculated with SQUAD, three pKa values were determined: 4.14 ± 0.06, 6.13 ± 0.04, and 8.36 ± 0.01 associating only pKa1 to the secondary amino group. With theoretical calculations, the geometries of all the Dor chemical species involved in acid-base equilibria were optimized using an experimental reproduction criterion (UV–Vis spectra) resulting in four of five possible Dor species: DorH4+, DorH3, DorH2− and DorH2−. The Dor3− species was theoretically shown not to exist or if it is formed, to tend towards the formation of the DorH2−. Finally, a deprotonation pathway is proposed for this drug.

Electronically controlled regioselective hydroarylation of gem-difluoroallenes

All-carbon quaternary centers are ubiquitous structural motifs in natural products, bioactive molecules, and pharmaceuticals. The formation of these crowded carbon centers is well known to be challenging, and methods to access them remain in high demand. Transition-metal-based strategies have emerged as a powerful approach to quaternary carbons, primarily relying on cross-coupling reactions and olefin arylation processes. Herein is presented a straightforward method to create benzylic all-carbon quaternary centers employing gem -difluoroallenes. Features of this method include room temperature C–H functionalization, excellent regioselectivity in the insertion of gem -difluoroallenes, and generation of gem -difluoroalkene products, which have widespread applications in synthesis and pharmaceutical sciences. Mechanistic studies support a turnover limiting rhodium-catalyzed C–H cleavage that likely proceeds via a concerted metalation deprotonation pathway. Regioselective insertion of the gem -difluoroallene is controlled by electronic effects. • Efficient and facile construction of all-carbon quaternary benzylic centers • Preparation of versatile gem -difluoroalkenes via hydroarylation is shown • Regioselective insertion of 1,1-difluoroallene is controlled by electronic effects • Gram-scale synthesis and diverse synthetic transformations are observed Efficient construction of all-carbon quaternary centers is vital owing to their ubiquity in natural products, bioactive molecules, and drugs. Here, Wang et al. develop an example of hydroarylation of gem -difluoroallenes to prepare versatile gem -difluoroalkenes with an all-carbon quaternary center.

Organocatalytic (5+1) benzannulation of Morita–Baylis–Hillman carbonates: synthesis of multisubstituted 4-benzylidene pyrazolones

DABCO-catalyzed (5+1) cycloaddition of MBH carbonate undergoes an α-double deprotonation pathway to de novo assemble the benzene ring.

Effect of Transition Metals on Chemodivergent Cross-Coupling of Acrylamides with Vinyl Acetate via C-H Activation.

A novel chemodivergent cross-coupling of acrylamides and vinyl acetates has been realized via metal-catalyzed vinylic C-H activation. The selective olefinic C-H vinylation and alkenylation reaction was examined with a variety of differently functionalized acrylamides. The reaction efficiently generates a range of highly synthetically valuable butadienes with good functional group tolerance in good to moderate yields. A possible catalytic reaction mechanism involving the chelation-assisted olefinic C-H activation via an acetate-assisted deprotonation pathway is proposed.

Photoinduced Electron vs. Concerted Proton Electron Transfer Pathways in SnIV (l-Tryptophanato)2 Porphyrin Conjugates.

Aromatic amino acids such as l‐tyrosine and l‐tryptophan are deployed in natural systems to mediate electron transfer (ET) reactions. While tyrosine oxidation is always coupled to deprotonation (proton‐coupled electron‐transfer, PCET), both ET‐only and PCET pathways can occur in the case of the tryptophan residue. In the present work, two novel conjugates 1 and 2, based on a SnIV tetraphenylporphyrin and SnIV octaethylporphyrin, respectively, as the chromophore/electron acceptor and l‐tryptophan as electron/proton donor, have been prepared and thoroughly characterized by a combination of different techniques including single crystal X‐ray analysis. The photophysical investigation of 1 and 2 in CH2Cl2 in the presence of pyrrolidine as a base shows that different quenching mechanisms are operating upon visible‐light excitation of the porphyrin component, namely photoinduced electron transfer and concerted proton electron transfer (CPET), depending on the chromophore identity and spin multiplicity of the excited state. The results are compared with those previously described for metal‐mediated analogues featuring SnIV porphyrin chromophores and l‐tyrosine as the redox active amino acid and well illustrate the peculiar role of l‐tryptophan with respect to PCET.

Rhodium(III)-Catalyzed Aerobic Oxidative C-H Olefination of Unsaturated Acrylamides with Unactivated Olefins.

A rhodium(III)-catalyzed aerobic oxidative cross-coupling of acrylamides with unactivated alkenes via vinylic C-H activation has been developed. The present cross-coupling reaction was examined with a variety of differently functionalized acrylamides and unactivated olefins. In these reactions, highly valuable amide-functionalized butadienes were prepared in good to excellent yields. This protocol was also compatible with Weinreb amides. A possible reaction mechanism involving the chelation-assisted vinylic C-H activation via a carboxylate-assisted deprotonation pathway is proposed.

Theoretical Mechanistic Studies of Rh‐Catalyzed C(sp3)—H Amination: A Comparison with Co Analogue and Metal Effects

Summary of main observation and conclusionThe mechanism of Rh‐catalyzed C(sp3)—H amination has been computationally investigated. The reaction mechanism mainly involves sequential C(sp3)—H activation, decarboxylation, nitrene migration insertion, and protonation steps. Competitive concerted metalation deprotonation (CMD) and external base assisted deprotonation (EBAD) pathways are found for the involved C(sp3)—H activation in both Rh and Co analogous systems. This is different from the previously reported C(sp2)—H activation, where the CMD is dominant. The key mechanistic difference between the two systems is found to be in the C(sp3)—H activation step. In comparison with Rh species, the lower activity of Co complex toward the C(sp3)—H activation could be ascribed to smaller atomic size of Co and thus larger steric repulsion between ancillary ligand and substrate along with the CMD pathway. In view of the EBAD pathway, however, the lower activity of Co species could be imputed to the triplet nature of Co center, which is against the electron transfer from the electron‐rich carbon atom of the deprotonating C(sp3)—H bond to the Co center. As to the subsequent decarboxylation and nitrene insertion steps, compared with the Co system, the relatively lower reactivity of Rh species is partially due to the stronger Rh—N bond, and the higher π(Rh—N) and π*(Rh—N) orbital energies of the corresponding transition state structure.

Deprotonation of Isoxazole: A Photoelectron Imaging Study.

We report a photoelectron imaging study of gas-phase deprotonation of isoxazole in which spectroscopic data are compared to the results of electronic structure calculations for the anion products corresponding to each of three possible deprotonation sites. The observed photoelectron spectra are assigned to a mixture of the anion isomers. Deprotonation at the most acidic (C5) and the least acidic (C4) positions yields the respective C5- and C4-isoxazolide anions, while the reaction at the intermediate-acidity C3 site leads to a cleavage of the O-N bond and an opening of the ring in the anion. Following photodetachment, the ground states of neutral C5- and C4-isoxazolyl are assigned to be σ radicals (X2A'), while the ground-state neutral derived from the ring-open C3-anion is a π radical (X2A″). The relative intensities of the spectral bands exhibit sensitivity to the ion source conditions, giving evidence of competing and varying contributions of the dominant C5 and C3, as well as possible C4, deprotonation pathways.

A Structurally Robust Chiral Borate Ion: Molecular Design, Synthesis, and Asymmetric Catalysis.

Catalysis by chiral weakly-coordinating anions (WCAs) remains underdeveloped due to the lack of a molecular design strategy for exploiting their characteristics, such as the non-nucleophilic nature. Here, we report the development of a chiral borate ion comprising an O,N,N,O-tetradentate backbone, which ensures hitherto unattainable structural robustness. Upon pairing with a proton, the hydrogen borate acts as an effective catalyst for the asymmetric Prins-type cyclization of vinyl ethers, providing access to structurally and stereochemically defined dihydropyrans. The key to selectivity control is the distinct ability of the borate ion to discriminate the prochiral faces of the acyclic oxonium ion intermediate and dictate the regiochemical outcome. We anticipate that this study paves the way for exploring the untapped potential of WCA catalysis for selective chemical synthesis.

Iridium(III)-Catalyzed Intermolecular Allylic C-H Amidation of Internal Alkenes with Sulfonamides.

The Ir(III)-catalyzed direct allylic C-H amidation of substituted internal alkenes with substituted sulfonamides without having directing group is demonstrated. The present protocol provides substituted allylic amines in a highly atom- and step-economical manner. The reaction was compatible with symmetrical and unsymmetrical internal alkenes as well as substituted sulfonamides. It is interesting to note that, in the reaction of aryl-alkyl alkenes, the amidation selectively takes place at the alkyl-substituted allylic carbon. Meanwhile, the better selectivity was also observed in the unsymmetrical aryl-aryl alkenes having an electron-withdrawing substituent at one of the aryl groups. A possible reaction mechanism involving a π-allyl iridium intermediate was proposed and supported by the deuterium labeling studies. The deuterium labeling study clearly reveals that, in the reaction mechanism, the initial C-H activation step via the deprotonation pathway is reversible and the nucleophile prefers to attack at the more electrophilic carbon of the π-allyl iridium intermediate.

Reactions of Dianionic α-Diimine-Supported Dimagnesium(I) Compound [K(THF)3]2[LMg–MgL] with Nitriles

The Mg–Mg-bonded compound, [K(THF)3]2[LMg–MgL] (1, L = [(2,6-iPr2C6H3)NC(Me)]22–), exhibits good reactivity toward a series of nitriles (RC≡N). Reaction of 1 with 2.0 equiv of Me3SiCN proceeded through reductive Si–C(CN) bond cleavage to generate the cyanide ions (CN–), which serve as bridges to link the tetrameric complex [L4Mg4(μ-CN)4K4(THF)6] (2). When more (3.0 equiv) of the nitrile substrates Me3SiCN or tBuCN were reacted with 1, both Si–C(CN) [or C–C(CN)] bond cleavage and terminal coordination of the nitriles occurred, leading to the tetramers [L4Mg4(μ-CN)4(RCN)2K4(THF)4] (R = Me3Si, 3 and R = tBu, 4). More interestingly, reaction of precursor 1 with 2.0 equiv of isobutyronitrile (iPrCN) or cyclohexyl nitrile (CyCN) that has α-hydrogen atoms afforded the dinuclear complexes [{K(THF)2LMg(μ-N═C═CMe2)}2] (6) and [{K(Tol)LMg(μ-N═C═CC5H10)}2] (7) with bridging keteniminate ligands, representing a rare reductive deprotonation pathway for nitriles. All products were characterized by X-ray diffraction, NMR, and infrared spectra and density functional theory computations.