Concerted Proton Transfer Research Articles

Effects of C5-substituent group on the hydrogen peroxide-mediated tautomerisation of protonated cytosine: a theoretical perspective

ABSTRACTThe direct tautomerism (path A) and H2O2 as a catalyst (path B) have been studied in conversion of Cyt2t+ into CytN3+ isomer. The protonated 5-carboxycytosine (5-caCyt) is represented and has been further explored in the presence of H2O2 (path C). In going from a four-membered-ring transition state in the case of the direct tautomerism to the six-membered ring for H2O2, the H2O2 significantly contributes to decreasing the free energy barrier of tautomerisation. Although the carboxylic substituent of 5-carboxycytosine has certain affected on the electron distribution of the pyrimidine ring, the six-membered-ring transition state has not changed. This result illustrates that the C5-carboxylation has no significant effect on the H2O2-mediated isomerisation of Cyt2t+ to CytN3+ isomer. Meanwhile, these paths A–C have been further explored in the presence of two water molecules. Use of implicit solvent models (PCM) does not significantly alter the energetics of water-mediated paths A–C compared to those in gas phase. Furthermore, the rate constant with Wigner tunnelling correction of path A is obviously smaller than those of paths B and C. Finally, the lifetime τ99.9% of paths B and C is 10−5 s, which is implemented by the mechanism of the concerted synchronous double proton transfer.

Photophysical properties and excited state proton transfer in 1,8-Dihydroxydibenzo[a,h]phenazine: A theoretical study

The photophysical properties as well as proton transfer process from normal form (Enol) to tautomer form (Keto) in 1,8-Dihydroxydibenzo[a,h]phenazine [DHBP] have been theoretically investigated by TDDFT method. The potential energy profiles of the reaction paths for concerted proton transfer and stepwise proton transfer via single-proton transferred intermediate (INT) are examined, and the results show that proton transfer occurs in locally excited state following the stepwise mechanism at the lowest excitation energy in the gas phase. The concerted reaction path is found to be unstable with respect to anti-symmetric mode statically. The steady state emission band detected in Piechowska et al. experiment was assigned to INT, while emissions from Enol and Keto are less likely to be observed. The low intensity of the fluorescence at INT can be explained by the inter-system crossing between the lowest singlet state S1 with the triplet states T1 and T2 instead of the internal conversion from S1 to S0 introduced by torsion at INT structure at current computational level. This study provides new insight into the quenching mechanism in π-extended rigid molecule DHBP.

Theory after experiment on sensing mechanism of a newly developed sensor molecule: Converging or diverging?

Fluoride ion sensing mechanism of 3,3′-bis(indolyl)-4-chlorophenylmethane has been analyzed with density functional and time-dependent density functional theories. Extensive theoretical calculations on molecular geometry & energy, charge distribution, orbital energies & electronic distribution, minima on potential energy surface confirmed strong hydrogen bonded sensor-anion complex with incomplete proton transfer in S0. In S1, strong hydrogen bonding extended towards complete ESDPT. The distinct and single minima on the PES of the sensor-anion complex for both ground and first singlet excited states confirmed the concerted proton transfer mechanism. Present study well reproduced the experimental spectroscopic data and provided ESDPT as probable fluoride sensing mechanism.

Mechanistic insights into the γ-elimination reaction of l-methionine catalyzed by methionine γ-lyase (MGL)

The γ-elimination mechanism of l-methionine catalyzed by methionine γ-lyase was studied by employing the combined quantum mechanics and molecular (QM/MM) calculations. Based on the two crystal structures of methionine γ-lyase from Clostridium sporogenes and Citrobacter freundii, a computational model that contains the enzyme and the external aldimine intermediate was constructed. According to the results of our calculations, the whole catalytic reaction can be divided into two parts. Part I describes the formation of external aldimine intermediate from the internal aldimine intermediate, in which the key protonation step within the tetrahedral intermediate (IM2) should require the assistance of one water molecule, and the dissociation of Lys210 from the internal aldimine intermediate corresponds to an overall energy barrier of 13.5 kcal/mol. In Part II, the external aldimine intermediate converts to the aminocrotonate intermediate, which contains complex asynchronous and concerted proton transfer processes, including those of Cα-proton and Cβ-proton of the substrate as well as the C4′-proton of PLP, in which the pocket residues Tyr113 and Lys210 play key roles. The abstraction of Cβ-proton and the transfer of C4′-proton correspond to very similar barrier heights (16.5 and 16.2 kcal/mol) on the potential energy surface, implying that both steps are possibly rate-limiting. Besides, the calculated overall energy barrier is close to the free energy barrier estimated from the experiment (16.3 kcal/mol). These results may provide useful information for further understanding the catalysis of pyridoxal 5′-phosphate (PLP)-dependent lyase.

Catalytic Mechanisms for Cofactor-Free Oxidase-Catalyzed Reactions: Reaction Pathways of Uricase-Catalyzed Oxidation and Hydration of Uric Acid.

First-principles quantum mechanical/molecular mechanical (QM/MM)-free energy calculations have been performed to uncover how uricase catalyzes metabolic reactions of uric acid (UA), demonstrating that the entire reaction process of UA in uricase consists of two stages-oxidation followed by hydration. The oxidation consists of four steps: (1) chemical transformation from 8-hydroxyxythine to an anionic radical via a proton transfer along with an electron transfer, which is different from the previously proposed electron-transfer mechanism that involves a dianion intermediate (UA2-) during the catalytic reaction process; (2) proton transfer to the O2- anion (radical); (3) diradical recombination to form a peroxo intermediate; (4) dissociation of H2O2 to generate the dehydrourate. Hydration, for the most favorable pathway, is initiated by the nucleophilic attack of a water molecule on dehydrourate, along with a concerted proton transfer through residue Thr69 in the catalytic site. According to the calculated free energy profile, the hydration is the rate-determining step, and the corresponding free energy barrier of 16.2 kcal/mol is consistent with that derived from experimental kinetic data, suggesting that the computational insights into the catalytic mechanisms are reasonable. The mechanistic insights not only provide a mechanistic base for future rational design of uricase mutants with improved catalytic activity against uric acid as an improved enzyme therapy, but also are valuable for understanding a variety of other cofactor-free oxidase-catalyzed reactions involving an oxygen molecule.

Concerted transfer of multiple protons in acid-water clusters: [(HCl)(H2O)]2 and [(HF)(H2O)]4.

Molecular dynamics simulations using directly ab initio potentials are carried out for the ionically bonded clusters [(Cl-)(H3O+)]2 and [(F-)(H3O+)]4 to explore their transitions to the hydrogen-bonded [(HCl)(H2O)]2 and [(HF)(H2O)]4 structures during the first picosecond of simulation. Both the ionic and the H-bonded structures that are formed are highly symmetric. It is found that proton transfers are concerted in all trajectories for [(Cl-)(H3O+)]2. For [(F-)(H3O+)]4, the fully concerted mechanism is dominant but partially concerted transfers of two or three protons at the same time also occur. The concerted mechanism also holds for the reverse process of ionization of neutral acid molecules. It is suggested that the high symmetry of the ionic and the H-bonded structures plays a role in the preference for concerted transfers. Possible implications of the results for proton transfers in other systems are discussed.

The mechanism for the formation of OH radicals in condensed-phase water under ultraviolet irradiation.

Irradiation on liquid water and ice by ultraviolet light in the range of 150-200 nm can create volatile OH radicals which react with other organic and inorganic molecules actively. However, the mechanism for OH radical formation in the condensed-phase water in this energy range is still unclear. To uncover this mechanism we studied the excited-state behaviors of ice using first-principles calculations based on many-body Green's function theory. First, we showed that the long-wavelength optical absorption at the Urbach tail (190-300 nm) can be attributed to inherent hydroxide ions or transient structures formed in the autoionization process. Second, we revealed that creation of the OH radicals can be attributed to two mechanisms. Irradiation by the light at the Urbach tail excites an electron out of the hydroxide ion, leaving a neutral OH radical behind. By the light around 150 nm, OH radicals can be produced barrierlessly via direct water photolysis through concerted proton and electron transfer. Our results provide valuable insights into the excited-state dynamics of condensed-phase water, helping us understand in depth the photocatalytic reactions, radiation biology and chemistry.

Triple Isotope Effects Support Concerted Hydride and Proton Transfer and Promoting Vibrations in Human Heart Lactate Dehydrogenase.

Transition path sampling simulations have proposed that human heart lactate dehydrogenase (LDH) employs protein promoting vibrations (PPVs) on the femtosecond (fs) to picosecond (ps) time scale to promote crossing of the chemical barrier. This chemical barrier involves both hydride and proton transfers to pyruvate to form l-lactate, using reduced nicotinamide adenine dinucleotide (NADH) as the cofactor. Here we report experimental evidence from three types of isotope effect experiments that support coupling of the promoting vibrations to barrier crossing and the coincidence of hydride and proton transfer. We prepared the native (light) LDH and a heavy LDH labeled with 13C, 15N, and nonexchangeable 2H (D) to perturb the predicted PPVs. Heavy LDH has slowed chemistry in single turnover experiments, supporting a contribution of PPVs to transition state formation. Both the [4-2H]NADH (NADD) kinetic isotope effect and the D2O solvent isotope effect were increased in dual-label experiments combining both NADD and D2O, a pattern maintained with both light and heavy LDHs. These isotope effects support concerted hydride and proton transfer for both light and heavy LDHs. Although the transition state barrier-crossing probability is reduced in heavy LDH, the concerted mechanism of the hydride-proton transfer reaction is not altered. This study takes advantage of triple isotope effects to resolve the chemical mechanism of LDH and establish the coupling of fs-ps protein dynamics to barrier crossing.

The interplay of proton accepting and hydride donor abilities in the mechanism of step-wise boron hydrides alcoholysis

The reaction mechanism for the step-wise alcoholysis of BH4−, THF·BH3, Me2NH·BH3 and BH3 by ROH [ROH=CH3OH, CF3CH2OH (TFE) and (CF3)2CHOH (HFIP)] was studied computationally. The calculations were performed in gas phase at the DFT/M06/6-311++G(d,p) theory level taking into account non-specific solvent effects by SMD approach. The dihydrogen bonded complexes BH⋯HOR are the intermediates of this cascade borohydride alcoholysis, which set the proper orientation of the reactants molecules and direct their further activation. The consecutive introduction of RO groups instead of hydride ligands in [(RO)nBH(4−n)]− (n=0–3) decreases the dihydrogen bond strength due to the stabilization of borohydride HOMO orbital and the decrease of molecular electrostatic potential. Nevertheless the BH bond polarization and thermodynamic hydricity (hydride donor ability) increase with substitution, leading to the decrease of the reaction barrier. The HH bond formation can be considered as a result of concerted proton and hydride transfer in transition state. For BH4− alcoholysis the highest activation barrier was computed for the first reaction step: BH4−+HOR→H2+[(RO)BH3]− and the reaction is self-accelerating. The proton accepting and hydride donor abilities of neutral 4-coordinate borohydrides X·BH3 (X=THF, NHMe2) are lower than those of BH4−. Accordingly the activation barriers change in the order BH4−<THF·BH3<Me2NH·BH3 and at any reaction stage they remain higher than the barrier for the reaction of [(RO)BH3]− with the same alcohol. Together with low activation barrier for BX bond dissociation (X=O, N) this suggests the ligand exchange and the switch to the kinetically more favorable [(RO)BH3]− alcoholysis.

Chirality recognition in concerted proton transfer process for prismatic water clusters

Proton transfer and chiral conversion via hydrogen bonds (HBs) are important processes in applications such as chiral recognition, enzymatic catalysis, and drug preparation. Herein, we investigate the chiral conversion and interlayer recognition, via concerted intralayer proton transfer (CIPT) processes, of small prismatic water clusters, in the form of bilayer n−membered water rings (BnWRs, n = 4, 5, 6). Density functional theory (DFT) calculations show that despite the small energy variations between the initial and final states of the clusters of less than 0.3 kcal·mol−1, the vibrational circular dichroism (VCD) spectrum provides clear chiral recognition peaks in the range of 3,000 to 3,500 cm−1. The vibrational modes in this region correspond to stretching of intralayer HBs, which produces strong signals in the infrared (IR) and Raman spectra. The electronic circular dichroism (ECD) spectrum also reveals obvious chiroptical characteristics. The molecular orbitals involved in the interlayer interaction are dominated by O 2p atomic orbitals; the energy of these orbitals increased by up to 0.1 eV as a result of the CIPT processes, indicating corresponding recognition between monolayer water clusters. In addition, isotopic substitution by deuterium in the BnWRs results in characteristic peaks in the VCD spectra that can be used as fingerprints in the identification of the chiral structures. Our findings provide new insights into the mechanism of chiral recognition in small prismatic water clusters at the atomic level as well as incentives for future experimental studies.

Proton transfer pathways in an aspartate-water cluster sampled by a network of discrete states

Proton transfer reactions are complex transitions due to the size and flexibility of the hydrogen-bonded networks along which the protons may “hop”. The combination of molecular dynamics based sampling of water positions and orientations with direct sampling of proton positions is an efficient way to capture the interplay of these degrees of freedom in a transition network. The energetically most favourable pathway in the proton transfer network computed for an aspartate-water cluster shows the pre-orientation of water molecules and aspartate side chains to be a pre-requisite for the subsequent concerted proton transfer to the product state.

Ketyl Radical Formation via Proton-Coupled Electron Transfer in an Aqueous Solution versus Hydrogen Atom Transfer in Isopropanol after Photoexcitation of Aromatic Carbonyl Compounds.

The excited nπ* and ππ* triplets of two benzophenone (BP) and two anthraquinone (AQ) derivatives have been observed in acetonitrile, isopropanol, and mixed aqueous solutions using time-resolved resonance Raman spectroscopic and nanosecond transient absorption experiments. These experimental results, combined with results from density functional theory calculations, reveal the effects of solvent and substituents on the properties, relative energies, and chemical reactivities of the nπ* and ππ* triplets. The triplet nπ* configuration was found to act as the reactive species for a subsequent hydrogen atom transfer reaction to produce a ketyl radical intermediate in the isopropanol solvent, while the triplet ππ* undergoes a proton-coupled electron transfer (PCET) in aqueous solutions to produce a ketyl radical intermediate. This PCET reaction, which occurs via a concerted proton transfer (to the excited carbonyl group) and electron transfer (to the excited phenyl ring), can account for the experimental observation by several different research groups over the past 40 years of the formation of ketyl radicals after photolysis of a number of BP and AQ derivatives in aqueous solutions, although water is considered to be a relatively "inert" hydrogen-donor solvent.

Direct Evidence of a Tryptophan Analogue Radical Formed in a Concerted Electron-Proton Transfer Reaction in Water.

Proton-coupled electron transfer (PCET) is a fundamental reaction step of many chemical and biological processes. Well-defined biomimetic systems are promising tools for investigating the PCET mechanisms relevant to natural proteins. Of particular interest is the possibility to distinguish between stepwise and concerted transfer of the electron and proton, and how PCET is controlled by a proton acceptor such as water. Thus, many tyrosine and phenolic derivatives have been shown to undergo either stepwise or concerted PCET, where the latter process is defined by simultaneous tunneling of the electron and proton from the same transition state. For tryptophan instead, it is theoretically predicted that a concerted pathway can never compete with the stepwise electron-first mechanism (ETPT) when neat water is the primary proton acceptor. The argument is based on the radical pK(a) (∼4.5) that is much higher than that for water (pK(a)(H3O(+)) = 0), which thermodynamically disfavors a concerted proton transfer to H2O. This is in contrast to the very acidic radical cation of tyrosine (pK(a) ∼ -2). However, in this study we show, by direct time-resolved absorption spectroscopy on two [Ru(bpy)3](2+)-tryptophan (bpy = 2,2'-bipyridine) analogue complexes, that also tryptophan oxidation with water as a proton acceptor can occur via a concerted pathway, provided that the oxidant has weak enough driving force. This rivals the theoretical predictions and suggests that our current understanding of PCET reactions in water is incomplete.

Controlling reactivity by remote protonation of a basic side group in a bifunctional photoacid.

6-Hydroxy-2-naphthoic acid and its sulfonate derivatives belong to a family of bifunctional photoacids where the -OH group acts as a proton donor and the -COO(-) group acts as a proton acceptor. Upon electronic excitation, the -OH group becomes more acidic and the -COO(-) group turns more basic. Change in the ionization state of one functional group causes a change (switch) in the reactivity of the other functional group. Using picosecond time-resolved and steady state spectroscopy, we find clear evidence for an ultrafast reactivity switch caused by a diffusional proton transfer through the water solvent between the two functional groups with no evidence of a concerted proton transfer.

H-Bond Isomerization in Crystalline Cellulose IIII: Proton Hopping versus Hydroxyl Flip-Flop.

Based on density-functional theory calculations, we discuss three forms of cellulose IIII that are characterized by different intersheet H-bonding patterns. Two alternative mechanisms can facilitate the interconversion between these H-bonding patterns: the rotation of hydroxy groups ("flip-flop") or a concerted proton transfer from one hydroxy group to the other ("proton hopping"). Both mechanisms have energy barriers of very similar height. Electronic structure theory methods allow us to study effects that involve the breaking/forming bonds, like the hopping of protons. In many of the force field formulations, in particular, the ones that are typically used to study cellulose, such effects are not considered. However, such insight at the atomistic and electronic scale can be the key to finding energy-efficient means for cellulose deconstruction.

Stepwise vs concerted excited state tautomerization of 2-hydroxypyridine: Ammonia dimer wire mediated hydrogen/proton transfer.

The stepwise and concerted excited state intermolecular proton transfer (PT) and hydrogen transfer (HT) reactions in 2-hydroxypyridine-(NH3)2 complex in the gas phase under Cs symmetry constraint and without any symmetry constraints were performed using quantum chemical calculations. It shows that upon excitation, the hydrogen bonded in 2HP-(NH3)2 cluster facilitates the releasing of both hydrogen and proton transfer reactions along ammonia wire leading to the formation of the 2-pyridone tautomer. For the stepwise mechanism, it has been found that the proton and the hydrogen may transfer consecutively. These processes are distinguished from each other through charge translocation analysis and the coupling between the motion of the proton and the electron density distribution along ammonia wire. For the complex under Cs symmetry, the excited state HT occurs on the A″((1)πσ*) and A'((1)nσ*) states over two accessible energy barriers along reaction coordinates, and excited state PT proceeds mainly through the A'((1)ππ*) and A″((1)nπ*) potential energy surfaces. For the unconstrained complex, potential energy profiles show two (1)ππ*-(1)πσ* conical intersections along enol → keto reaction path indicating that proton and H atom are localized, respectively, on the first and second ammonia of the wire. Moreover, the concerted excited state PT is competitive to take place with the stepwise process, because it proceeds over low barriers of 0.14 eV and 0.11 eV with respect to the Franck-Condon excitation of enol tautomer, respectively, under Cs symmetry and without any symmetry constraints. These barriers can be probably overcome through tunneling effect.

Unraveling the Crucial Role of Metal-Free Catalysis in Borazine and Polyborazylene Formation in Transition-Metal-Catalyzed Ammonia–Borane Dehydrogenation

Though the recent scientific literature is rife with experimental and theoretical studies on transition-metal (TM)-catalyzed dehydrogenation of ammonia–borane (NH3·BH3) due to its relevance in chemical hydrogen storage, the mechanistic knowledge is mostly restricted to the formation of aminoborane (NH2BH2) after 1 equiv of H2 removal from NH3·BH3. Unfortunately, the chemistry behind the formation of borazine and polyborazylene, which happens only after more than 1 equiv of H2 is released from ammonia–borane in these TM-catalyzed homogeneous reactions, largely remains unknown. In this work we use density functional theory to unravel the curious function of “free NH2BH2”. Initially, free NH2BH2 molecules form oligomers such as cyclotriborazane and B-(cyclodiborazanyl)aminoborohydride. We show that, through a web of concerted proton and hydride transfer based dehydrogenations of oligomeric intermediates, cycloaddition reactions, and hydroboration steps facilitated by NH2BH2, the development of the polyborazylene framework occurs. The rate-determining free energy barrier for the formation of a polyborazylene template is predicted to be 25.7 kcal/mol at the M05-2X(SMD)/6-31++G(d,p)//M05-2X/6-31++G(d,p) level of theory. The dehydrogenation of BN oligomeric intermediates by NH2BH2 yields NH3·BH3, suggesting for certain catalytic systems that the role of the TM catalyst is limited to the dehydrogenation of NH3·BH3 to maintain optimal amounts of free NH2BH2 in the reaction medium to enable polyborazylene formation. TM catalysts that fail to produce borazine and polyborazylene falter because they rapidly consume NH2BH2 in TM-catalyzed polyaminoborane formation, thus preventing the chain of events triggered by NH2BH2.

Tunneling splittings in formic acid dimer: an adiabatic approximation to the Herring formula.

Small symmetric molecules and low-dimensional model Hamiltonians are excellent systems for benchmarking theories to compute tunneling splittings. In this work, we investigate a three dimensional model Hamiltonian coupled to a harmonic bath that describes concerted proton transfer in the formic acid dimer. The three modes include the symmetric proton stretch, the symmetric dimer rock, and the dimer stretch. These modes provide a paradigm for the symmetric and anti-symmetric coupled tunneling pathways, these being recognized in the literature as two of the more important classes of coupling. The effects of selective vibrational excitation and coupling to a bath on the tunneling splittings are presented. The splittings for highly excited states are computed using a novel method that makes an adiabatic approximation to the Herring estimate. Results, which are in excellent agreement with the exact splittings, are compared with those obtained using the Makri-Miller approach. This latter method has been shown to provide quality results for tunneling splittings including highly excited vibrational states.

Aromatic stacking interactions govern catalysis in aryl-alcohol oxidase.

Aryl-alcohol oxidase (AAO, EC 1.1.3.7) generates H2 O2 for lignin degradation at the expense of benzylic and other π system-containing primary alcohols, which are oxidized to the corresponding aldehydes. Ligand diffusion studies on Pleurotus eryngii AAO showed a T-shaped stacking interaction between the Tyr92 side chain and the alcohol substrate at the catalytically competent position for concerted hydride and proton transfers. Bi-substrate kinetics analysis revealed that reactions with 3-chloro- or 3-fluorobenzyl alcohols (halogen substituents) proceed via a ping-pong mechanism. However, mono- and dimethoxylated substituents (in 4-methoxybenzyl and 3,4-dimethoxybenzyl alcohols) altered the mechanism and a ternary complex was formed. Electron-withdrawing substituents resulted in lower quantum mechanics stacking energies between aldehyde and the tyrosine side chain, contributing to product release, in agreement with the ping-pong mechanism observed in 3-chloro- and 3-fluorobenzyl alcohol kinetics analysis. In contrast, the higher stacking energies when electron donor substituents are present result in reaction of O2 with the flavin through a ternary complex, in agreement with the kinetics of methoxylated alcohols. The contribution of Tyr92 to the AAO reaction mechanism was investigated by calculation of stacking interaction energies and site-directed mutagenesis. Replacement of Tyr92 by phenylalanine does not alter the AAO kinetic constants (on 4-methoxybenzyl alcohol), most probably because the stacking interaction is still possible. However, introduction of a tryptophan residue at this position strongly reduced the affinity for the substrate (i.e. the pre-steady state Kd and steady-state Km increase by 150-fold and 75-fold, respectively), and therefore the steady-state catalytic efficiency, suggesting that proper stacking is impossible with this bulky residue. The above results confirm the role of Tyr92 in substrate binding, thus governing the kinetic mechanism in AAO.

Ab initio molecular dynamics study of the mechanism of proton recombination with a weak base.

Despite its fundamental nature, many of the microscopic features of acid–base recombination remain poorly understood. In this work, we use ab initio molecular dynamics simulations to study the recombination of the proton with a weak base, the carbonate ion CO3(2–). Our simulations elucidate the network structure around CO3(2–) that provides a distribution of pathways over which recombination can occur. We observe that the penultimate neutralization step involves a correlated behavior of the transferred protons that is mediated by the water wires decorating the carbonate. These concerted proton transfers are coupled to collective compressions of these water wires. We show further that these processes are dynamically coupled to the reorganization of the water molecules hydrating the CO3(2–) ion. The insights from these simulations help to bridge the structural and dynamical complexity of the microscopic mechanisms with those of phenomenological models invoked by experiments in this field.