Insights on the mechanism of proton transfer reactions in amino acids

In the present work, the joint use of the potential energy, the reaction electronic flux profiles and NBO analysis along the intrinsic reaction coordinate within the framework of the reaction force analysis allows us to gain insights into the mechanism of the proton transfer process in amino acids. The reaction was studied in alanine and phenylalanine in the presence of a continuum and with addition of one water molecule acting as a bridge, the results were compared to those of tryptophan. The bridging water molecule stabilizes the zwitterionic form and increases the reaction barriers by a factor of two. This result is interpreted in terms of the energy required to bring the amino acid and the water molecule closer to each other and to promote the proton transfer through the reordering of the electron density. Furthermore, the bridging water molecule induces a concerted asynchronous double proton transfer, where the transfer of the carboxyl hydrogen atom is followed by the second proton transfer to the ammonium group. In addition, a second not intervening water molecule was added, which changes the proton acceptor and donor properties of the reactive water molecule modulating the reaction mechanism. The aforementioned methods allow us to identify the order of the transferred protons and the asynchronicity, thereby, evolving as promising tools to not only characterize but also manipulate reaction mechanisms.     

Theoretical Study of the Intramolecular Proton Transfer in the Tautomers of Cytosine Assisted by Water

Ab initio MP2 and DFT studies on the tautomers of cytosine and the related hydrated tautomers have been carried out. The ground‐state structures of four tautomers of cytosine and related transition states were fully optimized. The vibrational frequency analysis was performed on all the optimized structures. Detailed intrinsic reaction coordinate (IRC) calculations were carried out to guarantee the optimized transition‐state structures being connected to the related tautomers. We obtained the relative stability order for the tautomers of cytosine and the related hydrated tautomers. In the isolated and hydrated condition, the bond types of C(2) O(7) and C(4) N(8) greatly affect the stability of the cytosine tautomers. Moreover, we have explored the influence of the water molecules on the intramolecular proton transfer between the keto and enol forms of the cytosine tautomers. The first water molecule obviously decreases the isomerization activation energy for the monohydrated cytosine tautomers. It is shown that the isomerization energy barrier changes only a little when the second and third water molecules are added in the reaction loop. The solvent effects have an obvious influence on the proton‐transfer barrier of the isolated cytosine. However, the solvent effects seem to be insignificant for the isomerization energy barriers of the monohydrated, dihydrated and trihydrated cytosine. The water molecule in these complexes can be looked on as the explicit water. Therefore, the explicit water model may be more credible to explore the intramolecular proton transfer, in comparison with the PCM which is the implicit water model.     

Solvent effects on glycine II. Water-assisted tautomerization

The water-assisted tautomerization of glycine has been investigated at the B3LYP/6-31+G** level using supermolecules containing up to six water molecules as well as considering a 1:1 glycine-water complex embedded in a continuum. The conformations of the tautomers in this mechanism do not display an intramolecular H bond, instead the functional groups are bridged by a water molecule. The replacement of the intramolecular H bond by the bridging water reduces the polarity of the N-H bond in the zwitterion and increases that of the O-H bond in the neutral, stabilizing the zwitterion. Both the charge transfer effects and electrostatic interactions stabilize the nonintramolecularly H-bonded zwitterion conformer over the intramolecularly hydrogen bonded one. The nonintramolecularly H-bonded neutral is favored only by charge transfer effects. Although there is no strong evidence whether the intramolecularly hydrogen bonded or non hydrogen bonded structures are favored in the bulk solution represented as a dielectric continuum, it is likely that the latter species are more stable. The free energy of activation of the water-assisted mechanism is higher than the intramolecular proton transfer channel. However, when the presumably higher conformational energy of the zwitterion reacting in the intramolecular mechanism is taken into account, both mechanisms are observed to compete. The various conformers of the neutral glycine may form via multiple proton transfer reactions through several water molecules instead of a conformational rearrangement.     

DFT explorations of tautomerism of 2-mercaptoimidazole in aqueous solution

A systematic investigation of the proton transfer in the tautomerization of 2-mercaptoimidazole was undertaken. Calculations in aqueous solution were performed using the combined supramolecular/continuum and the direct continuum models, respectively. Complexes containing one and two water molecules around the hydrophilic site of 2-mercaptoimidazole were used for the combined supramolecular/continuum calculation. DFT results predict that the barrier height for non-water-assisted intramolecular proton transfer is very high (175.8 kJ/mol). Hydrogen bonding between 2-mercaptoimidazole and the water molecule(s) will dramatically lower the barrier by the concerted multiple proton transfer mechanism. The proton transfer process through a eight-member ring formed by 2-mercaptoimidazole and two water molecules is found to be more efficient one and the calculated barrier height is reduced to ca. 72 kJ/mol.     

The effect of hydrogen bonding on the excited-state proton transfer in 2-(2'-hydroxyphenyl)benzothiazole: a TDDFT molecular dynamics study

The dynamics of the excited-state proton transfer (ESPT) in a cluster of 2-(2'-hydroxyphenyl)benzothiazole (HBT) and hydrogen-bonded water molecules was investigated by means of quantum chemical simulations. Two different enol ground-state structures of HBT interacting with the water cluster were chosen as initial structures for the excited-state dynamics: (i) an intramolecular hydrogen-bonded structure of HBT and (ii) a cluster where the intramolecular hydrogen bond in HBT is broken by intermolecular interactions with water molecules. On-the-fly dynamics simulations using time-dependent density functional theory show that after photoexcitation to the S(1) state the ESPT pathway leading to the keto form strongly depends on the initial ground state structure of the HBT-water cluster. In the intramolecular hydrogen-bonded structures direct excited-state proton transfer is observed within 18 fs, which is a factor two faster than proton transfer in HBT computed for the gas phase. Intermolecular bonded HBT complexes show a complex pattern of excited-state proton transfer involving several distinct mechanisms. In the main process the tautomerization proceeds via a triple proton transfer through the water network with an average proton transfer time of approximately 120 fs. Due to the lack of the stabilizing hydrogen bond, intermolecular hydrogen-bonded structures have a significant degree of interring twisting already in the ground state. During the excited state dynamics, the twist tends to quickly increase indicating that internal conversion to the electronic ground state should take place at the sub-picosecond scale.     

A quantum generalization of intrinsic reaction coordinate using path integral centroid coordinates

We propose a generalization of the intrinsic reaction coordinate (IRC) for quantum many-body systems described in terms of the mass-weighted ring polymer centroids in the imaginary-time path integral theory. This novel kind of reaction coordinate, which may be called the "centroid IRC," corresponds to the minimum free energy path connecting reactant and product states with a least amount of reversible work applied to the center of masses of the quantum nuclei, i.e., the centroids. We provide a numerical procedure to obtain the centroid IRC based on first principles by combining ab initio path integral simulation with the string method. This approach is applied to NH(3) molecule and N(2)H(5) (-) ion as well as their deuterated isotopomers to study the importance of nuclear quantum effects in the intramolecular and intermolecular proton transfer reactions. We find that, in the intramolecular proton transfer (inversion) of NH(3), the free energy barrier for the centroid variables decreases with an amount of about 20% compared to the classical one at the room temperature. In the intermolecular proton transfer of N(2)H(5) (-), the centroid IRC is largely deviated from the "classical" IRC, and the free energy barrier is reduced by the quantum effects even more drastically.     

Proton transfer reaction in 4-hydroxy-3-formyl benzoic acid in protic solvents at room temperature and 77K and some theoretical aspects

Proton transfer processes of 4-hydroxy-3-formyl benzoic acid (HFBA) have been studied in a number of different protic solvents by means of absorption, emission and nanosecond transient spectroscopy at room temperature and 77K. Intermolecular interaction occurs in polar protic solvents only in presence of a base in the ground state whereas in the excited state, intermolecular complex formation and proton transfer occurs even in pure protic solvents. The dianion is detected in water, methanol, ethanol and TFE in presence of base. HFBA shows phosphorescence in pure ethanol at 77K. The occurrence of phosphorescence is due to rupture of the intramolecular bond and rotation of the formyl group. We have calculated quantum yields of fluorescence and also estimated decay rates from nanosecond measurements. The energetics of the ground and excited state proton transfer in HFBA have been investigated at the AM1 level of approximation. The ground singlet is predicted to have a large activation barrier on the proton transfer path, while the barrier height is much lower on the corresponding excited singlet surface.     

Investigating the proton transferring route in a heteroaromatic compound part I: a trial to develop di- and trifunctional benzimidazole model compounds inducing the molecular packing structure with a hydrogen bond network

Di- and trifunctional benzimidazole molecules, 1 and 2, have been synthesized as the model compounds to identify their molecular packing structure and hydrogen bond network, which is possibly involved in the proton transfer system belonging to its heteroaromatic functional groups. By carrying out the simple reaction between acid chloride and diamine, the desired benzimidazole model compounds are obtained with high yield above 60%. The comparison studies between the model compounds and benzimidazole reveal that the model compounds show well-packing structure with intermolecular hydrogen bonds similar to those observed in benzimidazole. The presence of solvent with 2 leads to the unique intermolecular hydrogen bonds between one molecule of 2 and six molecules of solvent (i.e., 2-propanol) resulting in the solvent-assisted intramolecular hydrogen bond network among benzimidazole functional groups. The comparative studies of the effect of temperature on the packing structure and hydrogen bond in the model compounds indicate that the development of the benzimidazole unit from monofunctional to difunctional and finally trifunctional enhances the intermolecular interaction between the molecules and results in the stronger molecular packing structure of the compounds. A study on proton conductivity by preparing the sulfonated poly(ether ether ketone) (SPEEK) membranes with benzimidazole, 1, and 2 for 15 phr equivalent to benzimidazole group clarifies (i) incorporation of benzimidazole compounds improves the proton conductivity of SPEEK in dry condition and (ii) the increase in proton conductivity is relevant to the number of benzimidazole group on molecule.     

Water- and acid-mediated excited-state intramolecular proton transfer and decarboxylation reactions of ketoprofen in water-rich and acidic aqueous solutions

We present an investigation of the decarboxylation reaction of ketoprofen (KP) induced by triplet excited-state intramolecular proton transfer in water-rich and acidic solutions. Nanosecond time-resolved resonance Raman spectroscopy results show that the decarboxylation reaction is facile in aqueous solutions with high water ratios (water/acetonitrile ≥50%) or acidic solutions with moderate and strong acid concentration. These experimental results are consistent with results from density functional theory calculations in which 1) the activation energy barriers for the triplet-state intramolecular proton transfer and associated decarboxylation process become lower when more water molecules (from one up to four molecules) are involved in the reaction system and 2) perchloric acid, sulfuric acid, and hydrochloric acid can shuttle a proton from the carboxyl to carbonyl group through an initial intramolecular proton transfer of the triplet excited state, which facilitates the cleavage of the C-C bond, thus leading to the decarboxylation reaction of triplet state KP. During the decarboxylation process, the water molecules and acid molecules may act as bridges to mediate intramolecular proton transfer for the triplet state KP when KP is irradiated by ultraviolet light in water-rich or acidic aqueous solutions and subsequently it generates a triplet-protonated carbanion biradical species. The faster generation of triplet-protonated carbanion biradical in acidic solutions than in water-rich solutions with a high water ratio is also supported by the lower activation energy barrier calculated for the acid-mediated reactions versus those of water-molecule-assisted reactions.     

Ab initio molecular dynamics study of glycine intramolecular proton transfer in water

We use ab initio molecular-dynamics simulations to quantify structural and thermodynamic properties of a model proton transfer reaction that converts a neutral glycine molecule, stable in the gas phase, to the zwitterion that predominates in aqueous solution. We compute the potential of mean force associated with the direct intramolecular proton transfer event in glycine. Structural analyses show that the average hydration number (N(w)) of glycine is not constant along the reaction coordinate, but rather progresses from N(w) = 5 in the neutral molecule to N(w) = 8 for the zwitterion. We report the free-energy difference between the neutral and charged glycine molecules, and the free-energy barrier to proton transfer. Finally, we identify the approximations inherent in our method and estimate the corresponding corrections to our reported thermodynamic predictions.     

Characterization of intramolecular hydrogen bonds by atomic charges and charge fluxes

The electronic charge redistribution and the infrared intensities of the two types of intramolecular hydrogen bonds, O-H···O and O-H···π, of o-hydroxy- and o-ethynylphenol, respectively, together with a set of related intermolecular hydrogen bond complexes are described in terms of atomic charges and charge fluxes derived from atomic polar tensors calculated at the B3LYP/cc-pVTZ level of theory. The polarizable continuum model shows that both the atomic charges and charge fluxes are strongly dependent on solvent. It is shown that their values for the OH bond in an intramolecular hydrogen bond are not much different from those for the "free" OH bond, but the changes are toward the values found for an intermolecular hydrogen bond. The intermolecular hydrogen bond is characterized not only by the decreased atomic charge but also by the enlarged charge flux term of the same sign producing thus an enormous increase in IR intensity. The overall behavior of the charges and fluxes of the hydrogen atom in OH and ≡CH bonds agree well with the observed spectroscopic characteristics of inter- and intramolecular hydrogen bonding. The main reason for the differences between the two types of the hydrogen bond lies in the molecular structure because favorable linear proton donor-acceptor arrangement is not possible to achieve within a small molecule. The calculated intensities (in vacuo and in polarizable continuum) are only in qualitative agreement with the measured data.     

2-巯基吡啶质子迁移过程的理论研究

采用密度泛函理论,在B3LYP/6-311G**基组水平上,计算并考察了2-巯基吡啶分子硫醇式结构和硫酮式结构进行结构互变质子迁移过程中的4种可能途径:(a)分子内质子迁移,(b)水助质子迁移,(c)同种二聚体双质子迁移和(d)异种二聚体间双质子迁移.计算结果表明,途经c所需要的活化能最小(9.73 kJ.mol-1,逆反应则为55.28 kJ.mol-1),而过程a所需要的活化能最大(106.02 kJ.mol-1),途径b和d的活化能居中间(分别为32.05和15.91 kJ.mol-1).研究还表明,氢键在降低反应活化能方面起着重要的作用.     

4(3H)-嘧啶酮及其类似物互变异构的理论研究

采用密度泛函理论,在B3LYP/6-311G**基组水平上,计算并考察了4(3H)-嘧啶酮及其类似物(5-氟-4(3H)-嘧啶酮、4-巯基嘧啶和5-氟-4-巯基嘧啶)醇式结构和酮式结构进行结构互变质子迁移过程中的2种可能途径:(a)分子内质子迁移;(b)水助质子迁移.计算结果表明,途经b所需要的活化能较小.研究还表明,氢键在降低反应活化能方面起着重要的作用.     

A comparative ab initio study of intramolecular proton transfer in model alpha-hydroxyalkoxides

A comparative ab initio study was performed on the intramolecular proton-transfer reaction that occurs in alpha-hydroxyethanoxy, alpha-hydroxyphenoxide, and alpha-hydroxyethenoxy anions. The intramolecular proton transfer occurs in a five-member atom arrangement, between two oxygen atoms separated by a carbon-carbon bond. The chosen systems serve as models for alpha-hydroxyalkoxide molecules where the carbon-carbon bond varies from a single bond (the glycolate anion or alpha-hydroxyethanoxide anion) to a part of an aromatic ring (the alpha-hydroxyphenoxide anion), and finally to a double bond (the alpha-hydroxyethenoxide anion). Particular attention was given to the evolution along the intrinsic reaction coordinate of such properties as energies, relevant structural parameters, Mulliken charges, dipole moments, and 1H-NMR chemical shifts to reveal the similarities and differences for the proton transfer in the model systems.     

Theoretical insights into excited-state process for the novel 2,3-bis[(4-diethylamino-2-hydroxybenzylidene)amino]but-2-enedinitrile system

In this present work, we clarify the excited-state intramolecular proton transfer (ESIPT) mechanism for 2,3-bis[(4-diethylamino-2-hydroxybenzylidene)amino]but-2-enedinitrile (BDABE) system. We present the fact that excited-state single proton transfer can occur along with one hydrogen bond, even though BDABE form consists of two intramolecular hydrogen bonds. Based on the density functional theory and time-dependent density functional theory methods, we theoretically investigate and elaborate the excited-state intramolecular dual hydrogen-bonding interactions. By simulating the electrostatic potential surface, we verify the formation of dual intramolecular hydrogen bonds for BDABE molecule in the S₀ state. Furthermore, comparing the primary bond lengths and bond angles as well as the infrared vibrational spectra, we find that the double hydrogen bonds should be strengthened in the S₁ state. When it comes to photoexcitation process, we discover the charge redistribution around hydrogen bonding moieties. The increased electronic density around proton acceptor plays the important roles in strengthening hydrogen bonds and in facilitating ESIPT reaction. In view of the possible ESIPT reaction paths (i.e., stepwise and synchronization double proton transfer) for BDABE molecule, we explored the S₀-state and S₁-state potential energy curves. This work explains experimental results and further clarifies the excited-state behaviors for BDABE system.     

2-羟基吡啶质子转移过程的理论研究

采用量子化学中的密度泛函理论,在B3LYP/6-31G(d)基组水平上,计算并考察了2-羟基吡啶分子醇式结构和酮式结构进行结构互变的质子转移过程中的4种可能途径:(a)分子内质子转移,(b)水助催化质子转移,(c)同种二聚体双质子转移和(d)异种二聚体间双质子转移.计算结果表明,途经c所需要的活化能最小(2.6 kJ•mol－1,逆反应则为27.1 kJ•mol－1),而过程a所需要的活化能最大(137.2 kJ•mol－1),途径b和d的活化能居中间(分别为38.7和17.3 kJ•mol－1).研究还表明,氢键在降低反应活化能方面起着重要的作用.     

3-卤代吡唑质子转移过程的理论研究

采用密度泛函B3LYP/6-311G**方法,对3-卤(-F、-Cl、-Br)代吡唑几何构型进行了全自由度优化,获得了它们的几何结构和电子结构。计算结果显示,N1-H型的稳定性大于N2-H型。计算并考察了3-卤代吡唑进行结构互变的质子转移过程的四种可能途径:(a)分子内质子转移;(b)水助质子转移;(c)同种二聚体双质子转移;(d)异种二聚体双质子转移。计算结果表明(以3-氟代吡唑为例),途径d所需要的活化能最小(54.89 kJ/mol),而途径a所需要的活化能最大(198.83kJ/mol),途径b和c的活化能居中间分别为(104.05 kJ/mol和69.05 kJ/mol)。研究还表明氢键在降低活化能方面起着重要的作用,卤素(-F、-Cl、-Br)对活化能的影响不大。     

Charge Transfer in 1,8-Naphthalimide: A Combined Theoretical and Experimental Approach

Photophysics of 1,8-naphthalimide (NAPMD) in different solvents has been delineated in this paper. Theoretically calculated bond distance of N–H and C=O groups rule out any intramolecular proton transfer in the excited state. Concomitant increase in negative charge on O atom compared to N atom and dipole moment hints at possible intramolecular charge transfer. Progressive redshift with polarity of solvents in emission and absorption spectra also confirms the theoretical prediction. Weakening of N–H bond helps hydrogen abstraction and anion formation in water with decay time of 2.54 ns through intermolecular proton transfer. This was corroborated from the ground state photoexcitation of laboratory synthesized anion of NAPMD. Amide hydrolysis in higher pH and excess proton availability at low pH are responsible for anion emission quenching. A possible electron transfer diminishes phosphorescence at 77 K with changing pH.     

Proton transfer mediated by the vibronic coupling in oxygen core ionized states of glyoxalmonoxime studied by infrared-X-ray pump-probe spectroscopy

The theory of IR-X-ray pump-probe spectroscopy beyond the Born-Oppenheimer approximation is developed and applied to the study of the dynamics of intramolecular proton transfer in glyoxalmonoxime leading to the formation of the tautomer 2-nitrosoethenol. Due to the IR pump pulses the molecule gains sufficient energy to promote a proton to a weakly bound well. A femtosecond X-ray pulse snapshots the wave packet route and, hence, the dynamics of the proton transfer. The glyoxalmonoxime molecule contains two chemically nonequivalent oxygen atoms that possess distinct roles in the hydrogen bond, a hydrogen donor and an acceptor. Core ionizations of these form two intersecting core-ionized states, the vibronic coupling between which along the OH stretching mode partially delocalizes the core hole, resulting in a hopping of the core hole from one site to another. This, in turn, affects the dynamics of the proton transfer in the core-ionized state. The quantum dynamical simulations of X-ray photoelectron spectra of glyoxalmonoxime driven by strong IR pulses demonstrate the general applicability of the technique for studies of intramolecular proton transfer in systems with vibronic coupling.     

Neutral hydrolyses of carbon disulfide: An ab initio study of water catalysis

The water-catalyzed hydrolysis reaction of carbon disulfide (CS(2)) has been investigated at the levels of HF and MP2 with the basis set of 6-311++G(d,p) using the combined supramolecular/continuum models, in which up to six water molecules are involved in the hydrolysis and the effect of water bulk solvent is taken into account according to the polarizable continuum model (PCM). The activation Gibbs free energies in water solution, DeltaG(sol) (not equal) (298 K), for the rate-determining steps of one up to six water hydrolyses are 247.9, 184.2, 152.3, 141.8, 134.4, and 118.9 kJ/mol, respectively. The most favorable hydrolysis path of CS(2) involves a sort of eight-membered ring transition structure formed by six water molecules, among which three water molecules are not involved in the proton transfer, two near to the nonreactive sulfur atom, and one below the parent carbon disulfide. This suggests that the hydrolysis of CS(2) can be mediated with the water molecule(s) and be significantly facilitated by the cooperative effects of the water molecule(s) in the nonreactive region. The catalytic effects of water molecule(s) due to the alleviation of ring strain in the proton transfer process may result from the synergistic effects of rehybridization and charge reorganization from the prereaction complex to the rate-determining transition state structure induced by water molecule(s). PCM solvation models could significantly lower the rate-determining activation Gibbs free energies by 20-38 kJ/mol when two up to six explicit water molecules involved in the neutral hydrolysis of CS(2).