Protonation Sites Research Articles

Preferences of interaction sites for proton-induced photophysical signalling with a derivatized rhodamine probe

Chemosensors for selective and sensitive detection of analytes were developed following various structural, functional and operational design methodologies. The interaction between probe and analyte has been vital in chemosensor-based detection technologies. A pertinent question in such a system is to be convincingly addressed, that if the probes incorporating spatially-positioned multiple interaction sites offer preferences towards analyte binding for a favourable and optimal interaction. The derivatized Rhodamine based probe 1 exhibiting proton-induced dual mode signalling here contained several protonation sites. The absorption and fluorescence signal enhancement on protonation of the probe attributed to its proton-mediated spiro-ring opening. Out of several plausible conformations of protonated probe [1.H+], their DFT calculations revealed the proton binding preferentially to the N-donor atom on spiro-ring of 1 instead at other probable sites of protonation such as other hetero- donor atoms on the xanthene core or the carbonyl O- atom on the spiro-ring as the energetically favourable conformation. It was verified with the protonated probe complex's X-ray diffracted single crystal structure.

Vibrational and electronic spectra of protonated vanillin: exploring protonation sites and isomerisation.

Photofragmentation spectra of protonated vanillin produced under electrospray ionisation (ESI) conditions have been recorded in the 3000-3700 cm-1 (vibrational) and 225-460 nm (electronic) ranges, using room temperature IRMPD (infrared multiphoton dissociation) and cryogenic UVPD (ultraviolet photodissociation) spectroscopies, respectively. The cold (∼50 K) electronic UVPD spectrum exhibits very well resolved vibrational structure for the S1 ← S0 and S3 ← S0 transitions, suggesting long excited state dynamics, similar to its simplest analogue, protonated benzaldehyde. The experimental data were combined with theoretical calculations to determine the protonation site and configurational isomer observed in the experiments.

Identification of Amide Oxygen as First Protonation Site in Gaseous Short Peptides: Theoretical Evidence from a First-Principles Study

Identification of Amide Oxygen as First Protonation Site in Gaseous Short Peptides: Theoretical Evidence from a First-Principles Study

Advances and challenges in designing active site environments in zeolites for Brønsted acid catalysis.

Zeolites contain proton active sites in diverse void environments that stabilize the reactive intermediates and transition states formed in converting hydrocarbons and oxygenates to chemicals and energy carriers. The catalytic diversity that exists among active sites in voids of varying sizes and shapes, even within a given zeolite topology, has motivated research efforts to position and quantify active sites within distinct voids (synthesis-structure) and to link active site environment to catalytic behavior (structure-reactivity). This Feature Article describes advances and challenges in controlling the position of framework Al centers and associated protons within distinct voids during zeolite synthesis or post-synthetic modification, in identifying and quantifying distinct active site environments using characterization techniques, and in determining the influence of active site environments on catalysis. During zeolite synthesis, organic structure directing agents (SDAs) influence Al substitution at distinct lattice positions via intermolecular interactions (e.g., electrostatics, hydrogen bonding) that depend on the size, structure, and charge distribution of organic SDAs and their mobility when confined within zeolitic voids. Complementary post-synthetic strategies to alter intrapore active site distributions include the selective removal of protons by differently-sized titrants or unreactive organic residues and the selective exchange of framework heteroatoms of different reactivities, but remain limited to certain zeolite frameworks. The ability to identify and quantify active sites within distinct intrapore environments depends on the resolution with which a given characterization technique can distinguish Al T-site positions or proton environments in a given zeolite framework. For proton sites in external unconfined environments, various (post-)synthetic strategies exist to control their amounts, with quantitative methods to distinguish them from internal sites that largely depend on using stoichiometric or catalytic probes that only interact with external sites. Protons in different environments influence reactivity by preferentially stabilizing larger transition states over smaller precursor states and influence selectivity by preferentially stabilizing or destabilizing competing transition states of varying sizes that share a common precursor state. We highlight opportunities to address challenges encountered in the design of active site environments in zeolites by closely integrating precise (post-)synthetic methods, validated characterization techniques, well-defined kinetic probes, and properly calibrated theoretical models. Further advances in understanding the molecular details that underlie synthesis-structure-reactivity relationships for active site environments in zeolite catalysis can accelerate the predictive design of tailored zeolites for desired catalytic transformations.

Searching low-energy conformers of neutral and protonated di-, tri-, and tetra-glycine using first-principles accuracy assisted by the use of neural network potentials.

In the last ten years, combinations of state-of-the-art gas-phase spectroscopies and quantum chemistry calculations have suggested several intuitive trends in the structure of small polypeptides that may not hold true. For example, the preference for the cis form of the peptide bond and multiple protonated sites was proposed by comparing experimental spectra with low-energy minima obtained from limited structural sampling using various density functional theory methods. For understanding the structures of polypeptides, extensive sampling of their configurational space with high-accuracy computational methods is required. In this work, we demonstrated the use of deep-learning neural network potential (DL-NNP) to assist in exploring the structure and energy landscape of di-, tri-, and tetra-glycine with the accuracy of high-level quantum chemistry methods, and low-energy conformers of small polypeptides can be efficiently located. We hope that the structures of these polypeptides we found and our preliminary analysis will stimulate further experimental investigations.

Factors governing the protonation of Keggin-type polyoxometalates: influence of the core structure in clusters.

Atomic substitution is a promising approach for controlling structures and properties for developing clusters with desired responses. Although many possible coordination candidates could be deduced for substitution, not all can be prepared. Therefore, predicting the correlation between structures and physical properties is important prior to synthesis. In this study, regarding Keggin-type polyoxometalates (POMs) as a model cluster, the dominant factors affecting the protonation were investigated by atomic substitutions and geometry changes. The valence of Keggin-type POMs and the constituent elements of the cluster shell structure affect the charge and potential distribution, which change the protonation sites. Furthermore, the valence of Keggin-type POMs and the bond length between the core and shell structure determine the protonation energy. These factors also affect the HOMO-LUMO gap, which governs photochemical and redox reactions. These governing factors derived from actual parameters of the α-isomer of Keggin-type POMs enabled us to deduce the protonation energy of the β-isomer, which is more difficult to prepare and isolate than the α-isomer.

In English

Molecular models for tin dioxide nanoparticles containing 1-7 metal atoms and coordinated or constitutive water have been constructed. Dependent on the composition of the models, the coordination number of the tin atom varied from 4 to 6, and that of oxygen was 2 or 3. The considered models contained both terminal (Sn–OH) and bridging (Sn–OH–Sn) hydroxyl groups, and also bridging (Sn–O–Sn) groups. Their equilibrium spatial and electronic structures were calculated using the second-order Møller-Plesset perturbation theory method with the SBKJC valence-only basis set. To assess the gas-phase acidity of the dioxide surface, the deprotonation energy of the studied models was determined. The adsorption energy of water molecules and hydroxide ions on aprotic (incompletely coordinated) tin atoms, which act as Lewis acid centers, was calculated. In order to estimate the pKa value of the surface of tin dioxide, the Gibbs free energy was calculated for the process of formation of ion pairs due to the proton transfer from hydroxyl groups to adsorbed water molecules. Based on the analysis of the energy effects of the coordination of water molecules and of hydroxide ion, the removal of a proton and its transfer on the hydrated surface of tin dioxide, quantitative estimates have been made of the acid-base characteristics of the active sites of the SnO2 surface. The dependence of the acidity of hydroxyl groups and coordinated water molecules on the coordination number of the oxygen atom and the neighboring tin atom, as well as on the dimensions of the cluster model, was revealed. It is shown that the acidity of protonic and aprotic sites naturally decreases with an increase in the coordination number of the tin atom. The method of calculating the value of pKa used in the work for the smallest model of the SnO2×2H2O composition allows one to reproduce the experimental data for stannic acids.

Simulating Crystal Structure, Acidity, Proton Distribution, and IR Spectra of Acid Zeolite HSAPO-34: A High Accuracy Study.

It is a challenge to characterize the acid properties of microporous materials in either experiments or theory. This study presents the crystal structure, acid site, acid strength, proton siting, and IR spectra of HSAPO-34 from the SCAN + rVV10 method. The results indicate: the crystal structures of various acid sites of HSAPO-34 deviate from the space group of R3¯; the acid strength inferred from the DPE value likely decreases with the proton binding sites at O(2), O(4), O(1),and O(3), contrary to the stability order in view of the internal energy; the calculated ensemble-averaged DPE is about 1525 kJ/mol at 673.15 K; and the proton siting and the proton distribution are distinctly influenced by the temperature: at low temperatures, the proton is predominantly located at O(3), while it prefers O(2) at high temperatures, and the proton at O(4) assumedly has the least distribution at 273.15-773.15 K. In line with the neutron diffraction experiment, a correction factor of 0.979 is needed to correct for the calculated hydroxyl stretching vibration (ν(O-H)) of HSAPO-34. It seems that the SCAN meta-GGA method, compensating for some drawbacks of the GGA method, could provide satisfying results regarding the acid properties of HSAPO-34.

Determining protonation site in fentanyl protomers using ion mobility-aligned MS/MS fragmentation

Drug overdoses in the United States totalled over 100,000 in 2022, with an estimated 68 % of those being attributed to illicitly manufactured fentanyls (IMFs). Their ease and low cost of synthesis have prompted a proliferation of new fentanyl analogues in the illicit drug market, and further created demand for analytical tools capable of identifying these new substances. Ion mobility-mass spectrometry (IM-MS) has emerged as a strong candidate to lead this effort, but the presence of multiple mobility peaks for a single fentanyl compound has created ambiguity in analysis. Herein, we use a combination of IM and tandem mass spectrometry (MS/MS) and determine that the multiple mobility peaks correspond to protonation site isomers, or ‘protomers’, where protonation can occur at either the N-piperidine ring and N-amide. Unique fragmentation spectra and energy-resolved CID revealed characteristic dissociation pathways for each protomer. Furthermore, this approach was applied to another analogue, despropionyl ortho-methylfentanyl, and was subsequently able to annotate its protomers as well. This approach holds tremendous promise for identification of future novel opioids including fentanyl analogues.

Protomer of Imipramine Captured in Cucurbit[7]uril.

Small molecules possessing multiple proton-accessible sites are important not only to many biological systems but also to host-guest chemistry; their protonation states are causal to boosting or hindering specific host-guest interactions. However, determining the protonation site is not trivial. Herein, we conduct electrospray ionization ion mobility spectrometry-mass spectrometry to imipramine, a known molecule with two protonation sites, based on the introduction of cucurbit[7]uril as a host molecule. For protonated imipramine, the proposed strategy allows clear distinction of the two protomers as host-guest complex ions and can be leveraged to capture the energetically less preferable protomer of the protonated imipramine.

Acidity constants and protonation sites of cyclic dinucleotides determined by capillary electrophoresis, quantum chemical calculations, and NMR spectroscopy.

Cyclic dinucleotides (CDNs) are important second messengers in bacteria and eukaryotes. Detailed characterization of their physicochemical properties is a prerequisite for understanding their biological functions. Herein, we examine acid-base and electromigration properties of selected CDNs employing capillary electrophoresis (CE), density functional theory (DFT), and nuclear magnetic resonance (NMR) spectroscopy to provide benchmark pKa values, as well as to unambiguously determine the protonation sites. Acidity constants (pKa) of the NH+ moieties of adenine and guanine bases and actual and limiting ionic mobilities of CDNs were determined by nonlinear regression analysis of the pH dependence of their effective electrophoretic mobilities measured by CE in aqueous background electrolytes in a wide pH range (0.98-11.48), at constant temperature (25°C), and constant ionic strength (25mM). The thermodynamic pKa values were found to be in the range 3.31-4.56 for adenine and 2.28-3.61 for guanine bases, whereas the pKa of enol group of guanine base was in the range 10.21-10.40. Except for systematic shifts of ∼2pKa, the pKa values calculated by the DFT-D3//COSMO-RS composite protocol that included large-scale conformational sampling and "cross-morphing" were in a relatively good agreement with the pKas determined by CE and predict N1 atom of adenine and N7 atom of guanine as the protonation sites. The protonation of the N1 atom of adenine and N7 atom of guanine in acidic background electrolytes (BGEs) and the dissociation of the enol group of guanine in alkaline BGEs was confirmed also by NMR spectroscopy.

Identification of the Photoreactive Species of Protonated N-Nitrosopiperidine in Acid Medium: A CASPT2 and DFT Study.

In this work, we have studied the initial reaction step after photoexcitation of protonated N-nitrosopiperidine both in the gas and condensed phases. To achieve this end, we have applied the CASPT2 and MP2 wave function methods and the density functional theory approach. It is found that the site of protonation of N-nitrosopiperidine in acid medium depends on the solvent: protonation occurs at the oxygen atom in protic solvents, while in aprotic solvents, the proton is bonded at the N-atom of the amine moiety. Furthermore, protonation at such an N-atom is the unique protonated species that absorbs in the visible range and directly dissociates into aminium radical cation and nitric oxide.

Revised Centrality Measures Tell a Robust Story of Ion Conduction in Solids.

The three most commonly used centrality measures in network theory have been adapted to consider ion conduction time rather than the number of steps. Flow-IN centrality highlights sites with the largest flow of ions from the nearest neighbor sites. Return-flow centrality highlights sites with a fast rate of first returns for the conducting ion. Flow-through centrality highlights which sites support significant flow of conducting ions and appears more robust to removal of the most central vertices. Exploring these centrality measures with the sample system of proton conduction in yttrium doped barium zirconate shows flow-through centrality to provide a robust picture with high contrast between sites involved in the most probable long-range periodic conduction paths and kinetic Monte Carlo trajectories versus sites rarely visited. The flow-through centrality, including all paths further highlights that when the most central proton site is filled, the remaining highest flow-through centrality sites are nearby, corroborating earlier studies suggesting proton pair motion. Finally, while both return-flow and flow-through centrality measure images deteriorate with noise, image restoration is possible when a detailed balance is used to calculate the smaller rate constant in a forward/backward pair.

Highly Efficient Intramolecular Proton Transfer in p-Aminobenzoic Acid by a Single Ammonia Molecule as a Vehicle.

Proton transfer is classified into two mechanisms: the Grotthuss (proton-relay) and vehicle mechanisms. It has been well studied on gas-phase proton transfer by a proton relay involving multiple molecules. However, a vehicle mechanism in which a single molecule transports a proton has rarely been reported. Here, we have obtained clear evidence that the proton transfers efficiently between the two protonation sites in protonated p-aminobenzoic acid (PABA·H+) by a single ammonia molecule as a vehicle. The gaseous PABA·H+ ions were reacted with NH3 or ND3 under single-collision conditions in a cold ion trap, and the proton-transferred ions were identified by cryogenic ion mobility-mass spectrometry. A reaction intermediate PABA·H+·NH3 was also detected for the first time. The reaction pathway search calculations and ab initio molecular dynamics simulations supported the present experimental finding that intramolecular proton transfer occurs very efficiently by the vehicle mechanism.

Rational tailoring of architectures and microenvironment on MOFs/natural clay hybrid materials for efficiently boosted performance of hybrid proton exchange membranes

AbstractMetal–organic frameworks (MOFs) is now becoming the most fascinating conductive materials due to designable structure and pores at molecular level, and available crystal structure for the study of conduction mechanism. Nevertheless, comparing to the design of molecular structures of MOFs, the hybrid of MOFs with special micro/nano‐structured materials is considered to be a more effective approach for improved properties. In this study, the PAT@UiO‐66‐SO3H hybrid material was constructed with high conductive UiO‐66‐SO3H, a famous kind of MOFs, and polydopamine‐coated natural clay attapulgite (PAT), then the prepared hybrid material was blended with chitosan (CS) to prepare proton exchange membranes (PEMs). Owing to the special architectures and microenvironment, combining with the advantages of composition with UiO‐66‐SO3H and attapulgite, the prepared composite membranes showed considerable improved performances, including tensile strength, thermal and structural stability, fuel resistance ability, conduction and single cell performances. The CS/PAT@UiO‐66‐SO3H‐5 composite membrane exhibited the highly enhanced tensile strength of 67 MPa and improved thermal stability with Tg value of 235°C, as well as the lowest methanol crossover value of 1.2 × 10−6 cm2 s−1. Besides, the highest proton conductivity of 38.8 mS cm−1 at 80°C and power density of 37.9 mWcm−2 was achieved with CS/PAT@UiO‐66‐SO3H‐3 composite membrane, these performances were higher than pristine CS of 22.7 mS cm−1 and 32.2 mW cm−2 respectively. Our investigation reveals great application potential of MOFs based hybrid materials in fabricating of high performance composite PEMs.Highlights PAT@UiO‐66‐SO3H hybrid materials were constructed from MOFs and natural clay. The hybrid materials possessed special architectures and microenvironment. The PAT@UiO‐66‐SO3H introduced consecutive channels and proton sites. The hybrid membranes achieved excellent performances.

Quantum Computer Simulation of Protein Protonation.

In attempts to simulate the protonation of proteins, a major challenge is that the number of protonation states grows rapidly as a function (2N) of the number of protonation sites (N). Expression on the free energy of the protonation state as an N-site Ising model ─ using an empirical Generalized-Born model ─ allows a quantum computer to efficiently determine the important states at a given pH value and subsequently reconstruct the pH titration process at all sites. Compared with the exact results painstakingly obtained with classical computers, the results obtained using quantum computers show good agreement for staphylococcal nuclease and excellent agreement for α-lactalbumin. This work illustrates the effectiveness of quantum computers in sampling important physical states, which may be useful in attacking challenging biomolecular problems.

Protonation Isomer Specific Ion-Molecule Radical Reactions.

Through a combination of ion-mobility filtering and laser-equipped quadrupole ion-trap mass spectrometry, the gas-phase reaction kinetics of two protonation isomers of the distonic-radical quinazoline cation are independently measured with ethylene. For these radical addition reactions, protonation site variations drive significant changes in nearby radical reactivity, and this is primarily due to through-space electrostatic effects. Furthermore, quantum chemical methods specifically designed for calculating long-range interactions, such as double-hybrid density functional theory, are required to rationalize the experimentally measured difference in reactivity.

Phosphoric acid-catalyzed synthesis of fused pyridocoumarins and their acidochromic applications

Pyridocoumarins are well known to exhibit various potent applications in optoelectronics, fluorescent probes, and sensors due to their unique photophysical properties. A concise and effective approach has been demonstrated to synthesize pyridocoumarins via a relatively inexpensive phosphoric acid-catalyzed Povarov reaction and their photophysical properties has also been investigated. The structures of all the synthesized compounds were well characterized by using 1H NMR, 13C NMR, IR, HRMS, and single crystal X-ray structure analysis. Detailed spectroscopic studies revealed that all the synthesized pyridocoumarins displayed acidochromic properties in solutions, which could be utilized as acid-base vapor sensors, and anti-counterfeiting agents. The detection limit was also calculated for all the synthesized acid sensors, which were found to be in the range of 41–103.8 ppm (parts per million). DFT and TDDFT studies were also performed to understand the protonation sites and the electronic transitions involved in these compounds. HOMO–LUMO energy gap of the synthesized pyridocoumarins ranges from 3.50 to 3.90 eV.

Solid acid catalysts comprising heteropoly acids supported on SiO2, TiO2 and ZrO2: A microcalorimetric investigation of catalyst acidity and new insight into the mechanism of alcohol dehydration over HPA

Keggin-type heteropoly acids (HPAs) have strong Brønsted acidity and are widely used as acid catalysts. The aim of this work is the systematic characterisation of the acid strength of HPA catalysts comprising H3PW12O40 and H4SiW12O40 supported on SiO2, TiO2 and ZrO2 with 10–100% HPA loading and testing their activity in dehydration of alcohols to gain new mechanistic insight regarding the role of bulk-type and surface-type HPA catalysis in this reaction. The HPA catalysts were prepared by impregnation from an aqueous solution and characterised using BET, XRD, TGA, DRIFTS and ICP–OES. The acid strength of HPA catalysts was determined by NH3 adsorption microcalorimetry and found to decrease in the order HPA/SiO2 > HPA/TiO2 > HPA/ZrO2. For each type of HPA catalyst, the acid strength increased with increasing HPA loading. This can be attributed to HPA-support interaction reducing the strength of HPA proton sites at low HPA loadings. The activity of HPA catalysts was tested in the gas-phase dehydration of MeOH and i-PrOH in a fixed-bed reactor. Evidence was obtained that alcohol dehydration over HPA catalysts in a steady-state flow system occurs via the surface-type rather than bulk-type catalysis as suggested hitherto. This follows from a strong correlation between the reaction rate and the number of surface proton sites in HPA catalysts.

Gas-Phase Internal Proton-Transfer of Protonated para-Aminobenzoic Acid Catalyzed by One Methanol Molecule.

Electrospray ionization (ESI) is used to deliver analytes for mass analysis across a huge range of mass spectrometry applications. Despite its ubiquitous application and many mechanistic investigations, it remains that a fundamental understanding of ESI processes is not complete. In particular, all the factors that influence the populations of protonation isomers are elusive such that it remains a challenge to optimize experimental conditions to favor one isomer over another. The molecule para-aminobenzoic acid has emerged as an archetype for the study of protonation isomers, with both amino and carboxylic acid protonation site isomers (protomers) typically formed upon ESI, with the isomer ratio shown to be sensitive to several physical and chemical parameters. Here we report an ion-trap mass spectrometry study of the time-resolved methanol-catalyzed proton transfer between the amine and carboxylic acid moieties of para-aminobenzoic acid. The experimental and computational results presented are consistent with a bimolecular mechanism where isomerization is mediated by a single methanol rather than a multimolecular Grotthuss proton transfer process. Pseudo-first-order rate constants for protomer specific product ions are reported and confirm the depletion of the amino protomer is correlated to the growth of the carboxylic acid protomer. Under the controlled conditions of a low-pressure ion-trap mass spectrometer (2.5 mTorr, 300 K), the number of methanol molecules required to isomerize para-aminobenzoic acid is determined to be one, and the second-order rate constant for methanol-catalyzed isomerization is (1.9 ± 0.1) × 10-11 cm3 molecule-1 s-1. The para-aminobenzoic acid vehicle mechanism is explored computationally at the DSD-PBEP86-D3BJ/aug-cc-pVDZ level of theory and reveals that the transition state for proton transfer is submerged (-10 kJ mol-1) relative to the separated reactant energies. The findings from this paper show that single-solvent catalyzed intramolecular proton transfer reactions are possible and must be considered during the late stages of ESI to predict the site(s) of protonation and the ion's stability in the presence of solvent molecules.