Transition State For Proton Transfer Research Articles

Mechanism of the Oxidative Ring-Closure Reaction during Gliotoxin Biosynthesis by Cytochrome P450 GliF.

During gliotoxin biosynthesis in fungi, the cytochrome P450 GliF enzyme catalyzes an unusual C-N ring-closure step while also an aromatic ring is hydroxylated in the same reaction cycle, which may have relevance to drug synthesis reactions in biotechnology. However, as the details of the reaction mechanism are still controversial, no applications have been developed yet. To resolve the mechanism of gliotoxin biosynthesis and gain insight into the steps leading to ring-closure, we ran a combination of molecular dynamics and density functional theory calculations on the structure and reactivity of P450 GliF and tested a range of possible reaction mechanisms, pathways and models. The calculations show that, rather than hydrogen atom transfer from the substrate to Compound I, an initial proton transfer transition state is followed by a fast electron transfer en route to the radical intermediate, and hence a non-synchronous hydrogen atom abstraction takes place. The radical intermediate then reacts by OH rebound to the aromatic ring to form a biradical in the substrate that, through ring-closure between the radical centers, gives gliotoxin products. Interestingly, the structure and energetics of the reaction mechanisms appear little affected by the addition of polar groups to the model and hence we predict that the reaction can be catalyzed by other P450 isozymes that also bind the same substrate. Alternative pathways, such as a pathway starting with an electrophilic attack on the arene to form an epoxide, are high in energy and are ruled out.

Acetate Assistance in Regioselective Hydroamination of Allenamides: A Combined Experimental and Density Functional Theory Study.

A key factor in the development of selective nucleophilic addition to allenamides is controlling the reactivity of electrophilic intermediates, which is generally achieved using an electrophilic activator via conjugated iminium intermediates. In this combined experimental and computational study, we show that a general and highly chemoselective hydroamination of allenamides can be accomplished using a combination of 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) and NaOAc. Experimental mechanistic studies revealed that HFIP mediates proton transfer to activate the allenamide, while the acetate additive significantly contributes to N-selective interception. This strategy enables a general hydroamination of allenamides without the use of metals. We demonstrated that various functionalized 1,3-diamines could be readily synthesized and diversified into value-added structural motifs. Detailed mechanistic investigations using the density functional theory revealed the role of NaOAc in the formation of reactive electrophilic intermediates, which ultimately governed the selective formation of 1,3-diamine products. Critically, calculations of the potential energy surface around the proton-transfer transition state revealed that two different reactive electrophilic intermediates were formed when NaOAc was added.

A molecular-level mechanistic framework for interfacial proton-coupled electron transfer kinetics.

Electrochemical proton-coupled electron transfer (PCET) reactions can proceed via an outer-sphere electron transfer to solution (OS-PCET) or through an inner-sphere mechanism by interfacial polarization of surface-bound active sites (I-PCET). Although OS-PCET has been extensively studied with molecular insight, the inherent heterogeneity of surfaces impedes molecular-level understanding of I-PCET. Herein we employ graphite-conjugated carboxylic acids (GC-COOH) as molecularly well-defined hosts of I-PCET to isolate the intrinsic kinetics of I-PCET. We measure I-PCET rates across the entire pH range, uncovering a V-shaped pH-dependence that lacks the pH-independent regions characteristic of OS-PCET. Accordingly, we develop a mechanistic model for I-PCET that invokes concerted PCET involving hydronium/water or water/hydroxide donor/acceptor pairs, capturing the entire dataset with only four adjustable parameters. We find that I-PCET is fourfold faster with hydronium/water than water/hydroxide, while both reactions display similarly high charge transfer coefficients, indicating late proton transfer transition states. These studies highlight the key mechanistic distinctions between I-PCET and OS-PCET, providing a framework for understanding and modelling more complex multistep I-PCET reactions critical to energy conversion and catalysis.

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.

Computational Evidence of the Incipient Oxocarbenium Ion as a "Hidden Intermediate" During the Cyclization of Hydroxyenol Ether into Spiroketal Under Mild Acidic Condition.

The synthesis of spiroketals has gained attention because of their importance in chemical and biological reactions. Yet, the mechanistic investigation of mild acid-catalyzed spiroketalization remains elusive and less explored in the literature and speculated that such transformations may proceed through the oxocarbenium ion intermediate; however, the existence of such species in mild acid-catalyzed spiroketalization is not documented. The computational study has been performed at M06-2X/6-31+G(d) level to examine the kinetically controlled product formation for such reactions and the intrinsic reaction coordinates of 1 d suggest that the reaction proceeds via a "one-step, two-stage" mechanism with the formation of transient oxocarbenium as a "hidden intermediate" in the reaction. This study reveals that stereoelectronic interactions devoid the formation of stable oxocarbenium ion intermediate after the proton transfer transition state in the mild acid catalyzed spiroketalization process.

Two-lattice-vibration theory for proton transfer in cubic perovskites: Barium zirconate versus potassium tantalate

Proton transfer (PT) in proton-conducting oxides is an intrinsically quantum phenomenon, due to the very strong quantization of the OH stretching vibration (ℏω~ 0.4 eV). Up to high temperatures, the proton is frozen in the ground state associated with the OH stretching motion, and thus does not undergo the thermal agitation for this vibration. Therefore, these are the thermal fluctuations of the (heavier) lattice atoms which make PT possible, at least above ~ half the Debye temperature of the lattice. These fluctuations may occasionally and randomly produce specific lattice configurations in which the quantum protonic ground levels in the two wells are equalized (coincidence), making PT possible, however with a certain probability. An analytical expression of this transfer probability may be obtained as the solution of a curve-crossing quantum-mechanical problem, and thus described by the Landau-Zener (LZ) formula. Two lattice vibrations play a fundamental role in intra-octahedral PT: (i) a reorganization of the lattice, that sends the protonated system from its initial self-trapped configuration up to the coincidence manifold, and (ii) a reduction of the (donor) oxygen - (acceptor) oxygen distance Q, which facilitates PT by leading the system to coincidence configurations with smaller proton barrier, and thus larger LZ probability. In cubic perovskites, the set of the coincidence configurations plays the role of the transition state for PT. The implementation of this theory of proton transfer [G. Geneste, Solid State Ionics 323, 172 (2018)] is here strongly improved on several points: description of the coincidence configurations, proton zero-point energies and proton potential at coincidence. It is then re-applied to barium zirconate (BZO), and also to potassium tantalate (KTO), with parameters derived from density-functional theory (DFT) calculations. The theory confirms the adiabatic PT regime in BZO, common to most proton conductors, with a negligible contribution of non-adiabatic tunneling transfers to the transfer rate. In KTO, by contrast, the relative contribution of non-adiabatic tunneling transfers is larger than in BZO, especially below ~ 250–300 K. The present work helps to characterize intrinsic features common to most proton conductors, at least from the point of view of proton mobility within the lattice. The activations energies for proton transfer at high temperature are predicted at 0.11 eV (BZO) and 0.25 eV (KTO).

How accurate are approximate quantum chemical methods at modelling solute-solvent interactions in solvated clusters?

In this paper, the performance of a wide range of DFT methods is assessed for the calculation of interaction energies of thermal clusters of a solute in water. Three different charge states (neutral, proton transfer transition state and zwitterion) of glycine were solvated by 1 to 40 water molecules as sampled from molecular dynamics simulations. While some ab initio composite methods that employ insufficiently large basis sets incurred significant errors even for a cluster containing only 5 water molecules relative to the W1X-2 benchmark, the DLPNO-CCSD(T)/CBS and DSD-PBEP86 (triple zeta basis set) levels of theory predicted very accurate interaction energies. These levels of theory were used to benchmark the performance of 16 density functionals from different rungs of Jacob's Ladder. Of the Rung 4 functionals examined, the ωB97M-V and ωB97X-V functionals stood out for predicting absolute interaction energies in 40-water clusters with mean absolute deviations (MAD) ∼4 kJ mol-1. The B3LYP-D3(BJ) functional performed exceptionally well with a MAD ∼1.7 kJ mol-1 and is the overall best performing method. Calculations of relative interaction energies allow for cancellation of systematic errors, including basis set truncation and superposition errors, and the ωB97M-V and B3LYP-D3(BJ) double zeta basis set calculations yielded relative interaction energies that are within ∼3 kJ mol-1 of the benchmark. The ONIOM approximation provides another strategy for accelerating the calculation of accurate absolute interaction energies provided that the calculations have converged with respect to the size of the "high-level-layer".

Formation and hydrolysis of gas-phase [UO2 (R)]+ : R═CH3 , CH2 CH3 , CH═CH2 , and C6 H5.

The goals of the present study were (a) to create positively charged organo-uranyl complexes with general formula [UO2 (R)]+ (eg, R═CH3 and CH2 CH3 ) by decarboxylation of [UO2 (O2 C─R)]+ precursors and (b) to identify the pathways by which the complexes, if formed, dissociate by collisional activation or otherwise react when exposed to gas-phase H2 O. Collision-induced dissociation (CID) of both [UO2 (O2 C─CH3 )]+ and [UO2 (O2 C─CH2 CH3 )]+ causes H+ transfer and elimination of a ketene to leave [UO2 (OH)]+ . However, CID of the alkoxides [UO2 (OCH2 CH3 )]+ and [UO2 (OCH2 CH2 CH3 )]+ produced [UO2 (CH3 )]+ and [UO2 (CH2 CH3 )]+ , respectively. Isolation of [UO2 (CH3 )]+ and [UO2 (CH2 CH3 )]+ for reaction with H2 O caused formation of [UO2 (H2 O)]+ by elimination of ·CH3 and ·CH2 CH3 : Hydrolysis was not observed. CID of the acrylate and benzoate versions of the complexes, [UO2 (O2 C─CH═CH2 )]+ and [UO2 (O2 C─C6 H5 )]+ , caused decarboxylation to leave [UO2 (CH═CH2 )]+ and [UO2 (C6 H5 )]+ , respectively. These organometallic species do react with H2 O to produce [UO2 (OH)]+ , and loss of the respective radicals to leave [UO2 (H2 O)]+ was not detected. Density functional theory calculations suggest that formation of [UO2 (OH)]+ , rather than the hydrated UV O2 + , cation is energetically favored regardless of the precursor ion. However, for the [UO2 (CH3 )]+ and [UO2 (CH2 CH3 )]+ precursors, the transition state energy for proton transfer to generate [UO2 (OH)]+ and the associated neutral alkanes is higher than the path involving direct elimination of the organic neutral to form [UO2 (H2 O)]+ . The situation is reversed for the [UO2 (CH═CH2 )]+ and [UO2 (C6 H5 )]+ precursors: The transition state for proton transfer is lower than the energy required for creation of [UO2 (H2 O)]+ by elimination of CH═CH2 or C6 H5 radical.

DFT and MP2 Calculations on Tautomers and Water-Assisted Proton Transfer on 1,2,5-Oxadiazol-4,3-diamine

In this work a detailed quantum-chemical comparison of the relative stability of six tautomers of 1,2,5-oxadiazol-4,3-diamine studied in the gas phase and solution. Theoretical calculations are carried out by the density functional theory (DFT/B3LYP) and MP2 methods using the standard 311++G(d,p) basis set. The results indicate that A is the most stable form in the gas phase and also is the predominant tautomer in solution at the DFT and MP2 methods. The transition states of proton transfer reaction are calculated. The variation of dipole moments and charges on atoms are studied in various solvent. Specific solvent effects with addition of one water molecule near the electrophilic centers of tautomer investigated. Also the transition state of proton transfer assisted by a water molecule was investigated.

Cp*CoIII-Catalyzed C-H Alkenylation/Annulation Reactions of Indoles with Alkynes: A DFT Study.

The Cp*CoIII-catalyzed C-H functionalization reaction of indoles with alkynes was examined using M06-level DFT calculations. The C≡C bond in the alkyne was inserted into the Co-C bond of an intermediate alkenyl-Co complex given by the acetate-assisted C-H bond activation step. Then the reaction pathway bifurcated into alkenylation and annulation pathways. In the case where AcOH, which was eliminated by ligand exchange for the alkyne, recoordinated to the Co atom, alkenylation proceeded via proton transfer. On the other hand, the annulation pathway to give pyrroloindolone became significant in the case where the ring-closure C-C bond formation was followed by the attachment of AcOH. At a high temperature (393 K), the difference in the Gibbs free energy between the transition state for proton transfer in the alkenylation pathway and that for the ring-closure C-C bond formation in the annulation pathway was relatively small, so both reactions could proceed. In addition, we also found another pathway to provide the directing-group migration on the way to annulation. This finding well elucidates the recent experimental report that tetrasubstituted alkenes were obtained as the major product under different conditions.

Special Pairs Are Decisive in the Autoionization and Recombination of Water.

Although water's chemical properties are no less important than its exceptional physical properties, its acid-base behavior is relatively poorly understood. In fact, the Grotthus trajectories for ion recombination predicted by density functional theory do not comport well with the almost 100-fold slower diffusive trajectories observed in time-resolved spectroscopy. And, in the reverse reaction, the barrier to autoionization is not well characterized. Here we develop a self-consistent picture of both processes based on the occurrence and role of ultrashort hydrogen bonds. The predicted populations of these special pairs in bulk water are consistent with the high frequency electrodynamics of water and its pressure dependence. The rate-limiting role of the special pairs manifests in autoionization as a two-stage barrier, first to form a contact ion pair and then to separate it by one water molecule. From this configuration, similar frequencies are observed for further separation vs recombination. The requirement of ultrashort hydrogen bonds for proton transfer in autoionization is consistent with the rise in Kw with increasing pressure and points to a role for density fluctuations in autoionization events. In neutralization, the manifestation of the role of special pairs is the prolonged diffusional process observed in time-resolved spectroscopy experiments. The requirement of special pairs as transition states for proton transfer is less obvious for neutralization in isolated water chains than in the bulk liquid only because an unbroken sequence of ultrashort H-bonds is more easily formed in a 1D H-bonded chain than in a 3D H-bonded network.

Application of DFT and MP2 calculations on structural and water-assisted proton transfer in 3-amino-4-nitrofurazan

Density functional theory (DFT) and MP2 calculations have been employed to study of 3-amino-4-nitrofurazan molecule using the standard 6-311++G(d,p) basis set. The chemical properties of the 3-amino-4-nitrofurazan have been extensively studied. The geometries of molecules in the gas phase were optimized and compared with the crystallography of this substance. The results suggest that A form is the most stable form in the gas phase and it is the predominant tautomer in solution according to the DFT and MP2 calculations, respectively. In addition, variation of dipole moments in the gas phase, the specific solvent effects with addition of one molecule of water near the electrophilic centers of tautomers, the transition state of proton transfer assisted by a water molecule, the NBO charges of atoms and the potential energy surface were investigated. The calculated highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) are presented.

Enhanced proton-transfer activity in imidazole@MIL-53(Al) systems revealed by molecular-dynamics simulations

Proton-transfer reactions in imidazole molecules confined in the metal-organic framework MIL-53(Al) were studied by means of Born-Oppenheimer molecular-dynamics simulations employing the density-functional tight-binding method. The statistical analysis of the trajectories revealed an essential impact of the framework on the orientation of the molecules in its channels and, thus, on the hydrogen-bond network. The one-dimensional hydrogen-bond network is one reason for faster reorientation dynamics compared to liquid imidazole. A lifetime in the order of 100 fs could be attributed to the proton-transfer transition state, a Zundel-like ion, and the combined imidazole@MIL-53(Al) system exhibited shorter times between hopping events compared to the liquid phase. This goes along with experimental findings of enhanced proton conductivity in this system.

A DFT investigation into the structure and energetics for nonadiabatic proton transfer in the benzophenone/N,N-dimethylaniline contact radical ion pair

For the past 60 years, the standard model for the interpretation of the mechanism for proton transfer has been based upon transition-state theory, which posits that the transition state is found in the proton transfer coordinate involving the breaking and making of bonds. However, the observed dynamics of proton transfer within the triplet contact radical ion pair, derived from a variety of substituted benzophenones complexed with N,N-dimethylaniline, cannot be accounted for within the standard model for proton transfer. Instead, the kinetic behavior is in accord with nonadiabatic proton transfer theory that has the transition state in the solvent coordinate. Evidence for the importance of the solvent coordinate comes from the existence of an inverted region; as the driving force for reaction increases, the rate of proton transfer decreases. This kinetic behavior is not found in the standard model. The present paper employs density function theory to examine the question as to whether the inverted region can be attributed to the transition state being in the solvent coordinate or whether the inverted region is an artifact produced by changes in the structure of the triplet contact radical ion pair with the placement of substituents upon the p,p′ positions of benzophenone. It is concluded that the inverted region is not an artifact of substituent effects upon structure. These results support the conclusion that the transition state for proton transfer resides in the solvent coordinate and challenges the validity of the standard model for interpreting the mechanism of proton transfer. Copyright © 2014 John Wiley & Sons, Ltd.

Theoretical studies on tautomerism of 1H-pyrazole-5-thiol

The chemical properties of the 1H-pyrazole-5-thiol have been extensively studied. In the present study, the relative stability of all tautomers in the gas phase and solution (PCM model) are evaluated at DFT and MP2 levels using the 6-311G++(d, p) basis set. The results suggest that 1H-pyrazole-3-thiol (B2 form) and 1H-pyrazole-5-thiol (A form) are the most stable forms in the gas phase and 1,2-dihydropyrazole-3-thione (C form) and 1H-pyrazole-3-thiol (B2 form) are the predominant tautomers in solution at the DFT and MP2 methods, respectively. In addition, variation of dipole moments in the gas phase and solution, the specific solvent effects with addition of one molecule of water near the electrophilic centers of tautomers, the transition state of proton transfer assisted by a water molecule and the NBO charges of atoms were investigated. In addition, it was found that aggregation with water molecule does not change the order of stability of isomers, but proton-transfer reaction assisted by a water molecule needs less energy than the intramolecular process. .

How is the anionic tetrahedral intermediate involved in the isomerization of aspartyl peptides to iso-aspartyl ones? A DFT study on the tetra-peptide

An isomerization reaction of a tetra-peptide, Ac-Gly-Asp-Gly-Gly-NHMe → Ac-Gly-isoAsp-Gly-Gly-NHMe, was investigated by DFT calculations. Thirteen water molecules were added to the peptide for simulating proton transfers during the isomerization. As a starting analysis, the number (m) of water molecules participating in ready proton transfers was examined by the use of a small model system, H(3)C-NH-C(=O)-CH(2)-CH(2)-COOH and (H(2)O)(m). The m = 2 stepwise path was found to be of the smallest activation free energy. On the basis of this result, the first isomerization path of the tetra-peptide was obtained with four elementary processes. The m = 2 proton-transfer pattern is involved in them. A different proton transfer gives the second isomerization path with six elementary processes. The second path (with ionization) is more likely than the first one (without ionization). Formation of the five membered rings of the aminosuccinimidyl-residue and anionic tetrahedral intermediates enhances the encapsulation of H(3)O(+) through the wound tetra-peptide ring. The role of the hydrogen bonds on the encapsulation was discussed in terms of the optimized geometries of proton-transfer transition states and intermediates.

Studies on tautomerism in the triazoline dione

The chemical properties of the triazoline dione have been extensively studied. The relative stability of three tautomers in the gas phase and solution (using PCM model) are evaluated using HF and DFT methods and compared with MP2 level using different basis sets. The results of the calculations indicate that 4H-1,2,4-triazole-3,5-dione (K form) is more stable in the gas phase than in solution. In addition, the transition states of proton transfer reaction is calculated. The vibrational frequencies and corresponding normal mode assignments of 4H-1,2,4-triazole-3,5-dione and 5-hydroxy-3H-1,2,4-triazol-3-one (E1 form) are also theoretically examined. In addition, the variation of dipole moments and charges on atoms with change of solvent is studied. Specific solvent effects with addition of one molecule of water near the electrophilic centers of three tautomers and the transition state of proton transfer assisted by a water molecule was investigated. Aggregation with water molecules does not change the order of stability of isomers, but proton transfer reaction assisted by a water molecule needs less energy than the intramolecular process.

Proton Delivery to Ferryl Heme in a Heme Peroxidase: Enzymatic Use of the Grotthuss Mechanism

We test the hypothesized pathway by which protons are passed from the substrate, ascorbate, to the ferryl oxygen in the heme enzyme ascorbate peroxidase (APX). The role of amino acid side chains and bound solvent is demonstrated. We investigated solvent kinetic isotope effects (SKIE) for the wild-type enzyme and several site-directed replacements of the key residues which form the proposed proton path. Kinetic constants for H(2)O(2)-dependent enzyme oxidation to Compound I, k(1), and subsequent reduction of Compound II, k(3), were determined in steady-state assays by variation of both H(2)O(2) and ascorbate concentrations. A high value of the SKIE for wild type APX ((D)k(3) = 4.9) as well as a clear nonlinear dependence on the deuterium composition of the solvent in proton inventory experiments suggest the simultaneous participation of several protons in the transition state for proton transfer. The full SKIE and the proton inventory data were modeled by applying Gross-Butler-Swain-Kresge theory to a proton path inferred from the known structure of APX. The model has been tested by constructing and determining the X-ray structures of the R38K and R38A variants and accounts for their observed SKIEs. This work confirms APX uses two arginine residues in the proton path. Thus, Arg38 and Arg172 have dual roles, both in the formation of the ferryl species and binding of ascorbate respectively and to facilitate proton transfer between the two.

A quantum chemical study of the mechanism for proton-coupled electron transfer leading to proton pumping in cytochrome c oxidase

The proton pumping mechanism in cytochrome c oxidase, the terminal enzyme in the respiratory chain, has been investigated using hybrid DFT with large chemical models. In previous studies, a gating mechanism was suggested based on electrostatic interpretations of kinetic experiments. The predictions from that analysis are tested here. The main result is that the suggestion of a positively charged transition state for proton transfer is confirmed, while some other suggestions for the gating are not supported. It is shown that a few critical relative energy values from the earlier studies are reproduced with quite high accuracy using the present model calculations. Examples are the forward barrier for proton transfer from the N-side of the membrane to the pump-loading site when the heme a cofactor is reduced, and the corresponding back leakage barrier when heme a is oxidised. An interesting new finding is an unexpected double-well potential for proton transfer from the N-side to the pump-loading site. In the intermediate between the two transition states found, the proton is bound to PropD on heme a. A possible purpose of this type of potential surface is suggested here. The accuracy of the present values are discussed in terms of their sensitivity to the choice of dielectric constant. Only one energy value, which is not critical for the present mechanism, varies significantly with this choice and is therefore less certain.

A Reactive Molecular Dynamics Algorithm for Proton Transport in Aqueous Systems

We present a model that incorporates the structural diffusion of a proton into a classical molecular dynamics simulation using a reactive molecular dynamics (RMD) algorithm. The transition state for proton transfer obtained from ab initio calculations is mapped onto a set of geometric and energetic triggers to describe the structural diffusion of the proton in the simulation. Numerical values of these triggers are parametrized to satisfy the experimental values of rate constant and activation energy in order to capture the molecular and macroscopic features of structural diffusion. The algorithm partitions the structural diffusion of a proton into three steps: (i) satisfaction of the triggers, (ii) instantaneous reaction, and (iii) local equilibration. The final step ensures that the ending point of the reaction provides the correct structure and heat of reaction. Hence, the reactivity is incorporated by the algorithm rather than through the development of a reactive potential. We have applied this scheme to study proton transport in bulk water and solutions of HCl. Total charge diffusion along with the structural and vehicular decomposition is studied as a function of temperature (280−320 K). The two components are found to be uncorrelated and the structural diffusion contributes 60−70% of the total charge diffusion in bulk water. The method is applied to HCl solutions (0.22−0.83 M) to study the effect of concentration on proton transport. The reduction in the total diffusivity of the charge with an increase in concentration is due to the reduction in structural diffusion.