Bimolecular Proton Transfer Research Articles

Switching of Protonation Sites in Hydrated Nicotine via a Grotthuss Mechanism.

The switching of the protonation sites in hydrated nicotine, probed by experimental infrared (IR) spectroscopy and theoretical ab initio calculations, is facilitated via a Grotthuss instead of a bimolecular proton transfer (vehicle) mechanism at the experimental temperature (T = 130 K) as unambiguously confirmed by experiments with deuterated water. In contrast, the bimolecular vehicle mechanism is preferred at higher temperatures (T = 300 K) as determined by theory. The Grotthuss mechanism for the concerted proton transfer results in the production of nicotine's bioactive and addictive pyrrolidine-protonated (Pyrro-H+) protomer with just 5 water molecules. Theoretical analysis suggests that the concerted proton transfer occurs via hydrogen-bonded bridges consisting of a 3 water molecule "core" that connects the pyridine protonated (Pyri-H+) with the pyrrolidine-protonated (Pyrro-H+) protomers. Additional water molecules attached as acceptors to the hydrogen-bonded "core" bridge result in lowering the reaction barrier of the concerted proton transfer down to less than 6 kcal/mol, which is consistent with the experimental observations.

A theoretical study on the mechanisms of the reactions between 1,3-dialkynes and ammonia derivatives for the formation of five-membered N-heterocycles.

The reactions between 1,3-dialkynes and ammonia derivatives (such as hydrazine and hydroxylamine) for the formation of five-membered N-heterocycles (i.e. 3,5-disubstituted pyrazole and 3,5-disubstituted isoxazole) have been investigated using the density functional theory (DFT) method. The calculated results indicate that the favorable mechanism of this kind of reaction generally contains four processes: (1) the Cope-type hydroamination reaction between the reactants coupled with the hydrazine/hydroxylamine-assisted proton transfer process or the trimolecular hydroamination reaction via a six-membered transition state, (2) the bimolecular proton transfer process for the formation of an allenyl oxime intermediate, (3) the cyclization process, and (4) another bimolecular or hydrazine/hydroxylamine-assisted proton transfer process to afford the final products (3,5-disubstituted pyrazole and 3,5-disubstituted isoxazole). The computational results demonstrate that the novel bimolecular proton transfer process occurs in a stepwise manner and the first step of the novel bimolecular proton transfer process is calculated to be the rate-determining step in both the reactions, and their energy barriers are 28.45 kcal mol(-1) associated with the formation of 3,5-disubstituted pyrazole and 31.07 kcal mol(-1) associated with the formation of 3,5-disubstituted isoxazole. In particular, the novel bimolecular proton transfer process has reasonably explained in detail on how and why this kind of reaction occurs, and this would provide valuable clues for the rational design of Brønsted acid/base catalysts to promote the synthesis of the five-membered N-heterocyclic compounds.

A DFT study on the reaction mechanisms of isocyanide-based multicomponent synthesis of polysubstituted cyclopentenes

In this study, the reaction mechanisms of isocyanide-based three-component synthesis of polysubstituted cyclopentenes have been firstly investigated using density functional theory (DFT). Three possible reaction channels (including channels 1, 2, and 3) have been suggested and investigated in detail. For channels 1 and 2, the reaction is initiated by the nucleophilic attack of 2-morpholinoethyl isocyanide (R1) on 2-benzylidenemalononitrile (R2). While for channel 3, the reaction is initiated by the nucleophilic attack of reactant R1 on the reactant (E)-(2-nitrovinyl)benzene (R3). Our calculated results indicate that reaction channel 2 is the most energetically favorable channel. The computational results reveal that channel 2 contains three reaction steps. Firstly, it is the nucleophilic attack on R2 by R1. The second step is the formation of five-membered ring through a [3+2] cycloaddition process. The last step is a bimolecular proton transfer process. The 16.21kcal/mol energy barrier for channel 2 demonstrates that the reaction can occur easily at the room temperature, which is in good agreement with the experiment. Moreover, the substituent effects have been considered by constructing four different model systems based on the experiments. The detailed reaction mechanisms should be helpful for people to understand the reaction at molecular level, and the suggested novel bimolecular proton transfer process provides some valuable insights on rational design of the suitable Brønsted acid/base catalysts for this type of reaction.

A DFT study on the mechanisms of three-component reaction between imidazoles, isocyanates and cyanophenylacetylene

In this paper, two possible competitive reaction channels, including the C(2)-vinylation of 1-substituted imidazoles with cyanophenylacetylene (channel 1) and the three-component reaction to form N-(Z)-alkenylimidazole-2-carbomide with the presence of isocyanates (channel 2), have been investigated in detail using density functional theory (DFT). There are three reaction processes in channel 1: the formation of zwitterion, proton transfer, and ring rearrangement. The channel 2 share the same processes in the former two steps (i.e. formation of zwitterion and the proton transfer), then the intermediate carbene reacts with another reactant isocyanate, and the last step is also a ring rearrangement process. Our calculated results indicate that channel 2 is more energy favorable than channel 1, so the product of the channel 2 is the main product, which is in good agreement with the experimental results. Moreover, our calculated results show that the solvent effects have little influence on the selectivity in this reaction. The detailed reaction mechanisms should be helpful for people to understand the three-component reaction at molecular level, and the suggested novel bimolecular proton transfer process provides some valuable insights on rational design of the efficient Brønsted acid/base catalysts for this type of reaction.

Intermolecular Cope‐Type Hydroamination of Alkenes and Alkynes

Keep it simple! Intermolecular hydroamination can be achieved simply upon heating alkynes and alkenes with aqueous hydroxylamine. Alkynes react to afford oximes in good to excellent yields, and the formation of Markovnikov products is favored. A mechanism involving Cope-type hydroamination followed by bimolecular proton transfer is suggested and supported by DFT studies.

Aqueous bimolecular proton transfer in acid–base neutralization

We report on a comparative femtosecond infrared study of the bimolecular proton transfer reaction dynamics of the photoacid pyranine (8-hydroxy-1,3,6-trisulfonate-pyrene, abbreviated as HPTS) with the family of carboxylate bases −OOCCH (3− x) Cl x ( x = 0–3) in aqueous solution. We use a generalized reaction model consisting of n proton transfer reaction pathways between photoacid and base, each pathway characterized by the number n of water molecules functioning as solvent switch facilitating an efficient transfer. The dynamics of the different proton transfer pathways have been followed by inspection of appropriate vibrational modes marking the progress of the reaction, and allow the direct observation of the transient relay mechanism of proton through one bridging water molecule in a loose photoacid–base configuration of the type HPTS −⋯H 3O +⋯ −OOCCH (3− x) Cl x ( x = 0–3). By applying a global fit procedure on the n-coupled reaction pathways, with full reversibility and detailed balance, we find for the reaction series that the encounter complex formed after mutual diffusion between photoacid and base, and subsequent desolvation, follows in general the loose complex pathway with one water molecule bridging acid and base. Only for the weakest base studied, trichloroacetate, larger solvent switches with n ⩾ 2 water molecules are important in the transfer dynamics. Whereas transfer in the tight complex with no water spacer ( n = 0) occurs within time resolution of 150 fs, the transfer in the loose ( n = 1) complex proceeds in a sequential fashion where the first transfer occurs within time resolution, irrespective of base strength, whereas the second transfer from the water to the base is activated and conforms to a correlation between free energy and reaction rate.

Ultrafast Chemistry: Using Time‐Resolved Vibrational Spectroscopy for Interrogation of Structural Dynamics

AbstractFor Abstract see ChemInform Abstract in Full Text.

ULTRAFAST CHEMISTRY: Using Time-Resolved Vibrational Spectroscopy for Interrogation of Structural Dynamics

Time-resolved infrared (IR) and Raman spectroscopy elucidates molecular structure evolution during ultrafast chemical reactions. Following vibrational marker modes in real time provides direct insight into the structural dynamics, as is evidenced in studies on intramolecular hydrogen transfer, bimolecular proton transfer, electron transfer, hydrogen bonding during solvation dynamics, bond fission in organometallic compounds and heme proteins, cis-trans isomerization in retinal proteins, and transformations in photochromic switch pairs. Femtosecond IR spectroscopy monitors the site-specific interactions in hydrogen bonds. Conversion between excited electronic states can be followed for intramolecular electron transfer by inspection of the fingerprint IR- or Raman-active vibrations in conjunction with quantum chemical calculations. Excess internal vibrational energy, generated either by optical excitation or by internal conversion from the electronic excited state to the ground state, is observable through transient frequency shifts of IR-active vibrations and through nonequilibrium populations as deduced by Raman resonances.

Gas-phase acidity and C–H bond energy of diacetylene

Threshold energies for the proton transfer reaction C 4H −+C 2H 2 → C 4H 2+C 2H − and for competitive collision-induced dissociation of the proton-bound complex of diacetylide and acetaldehyde, [HC 4··H··CH 2CHO] −, are measured using guided ion beam tandem mass spectrometry. From the bimolecular proton transfer threshold, the gas-phase acidity of diacetylene is Δ acid H 0(C 4H 2)≥1500±8 kJ/mol as a lower limit. The competitive dissociation is modeled using RRKM theory, yielding Δ acid H 0(C 4H 2)=1508±12 kJ/mol. Using the literature electron affinity of C 4H, the derived bond dissociation energy of diacetylene is D 0(HC 4–H)=539±12 kJ/mol.

Intermolecular proton transfer in catalysis by carbonic anhydrase V

The dehydration of bicarbonate catalyzed by carbonic anhydrase is accompanied by the transfer of a proton from solution to the zinc-bound hydroxide. We have investigated the properties of proton transfer from donors in solution, mostly derivatives of imidazole and pyridine, to a truncated mutant of carbonic anhydrase V with replacements that render the active site cavity less sterically constrained, Tyr 64 →> Ala and Phe 65 →> Ala. Catalysis was measured by determining the rate of exchange of 18O between the CO2-HCO3- system and water, and rate constants for proton transfer were estimated as the rate-limiting step in the release of H218O from the enzyme to solution. Each proton donor enhanced catalytic activity in a saturable manner. The resulting rate constants for proton transfer when compared with the values of pKa of the donor and acceptor gave a Brønsted plot of high curvature. These data could also be described by Marcus theory which showed an intrinsic barrier for intermolecular proton transfer near 0.8 kcal/mol and a work term or thermodynamic contribution to the free energy of reaction near 10 kcal/mol. This low intrinsic kinetic barrier for proton transfer is very similar to nonenzymic bimolecular proton transfer between nitrogen and oxygen acids and bases in solution. However, the significant thermodynamic contribution suggests appreciable involvement of solvent and active-site organization prior to proton transfer. These Marcus parameters are very similar to those describing intramolecular proton transfer from His 64 in carbonic anhydrase, suggesting similarities in the intra- and intermolecular proton transfer processes.Key words: carbonic anhydrase, proton transfer, Marcus theory, carbon dioxide.

A Mechanistic Study of the Influence of Proton Transfer Processes on the Behavior of Thiol/Disulfide Redox Couples

The mechanism of the oxidation of 2-mercapto-5-methyl-1,3,4-thiadiazole (McMT) to its disulfide dimer and its subsequent reduction has been examined with a combined approach employing experimental data and digital simulation. In order to elucidate the influence of proton transfers on these redox processes, special attention has been paid to the influence of various bases, including triethylamine, pyridine, 3-chloropyridine, lutidine and 2,6-di-tert-butylpyridine, and proton donors, including methanesulfonic acid and trifluoromethanesulfonic acid, on both the oxidation and reduction reactions. On the basis of detailed comparisons of the experimental data with simulations of several mechanistic models, it is found that proton transfer pathways have a pronounced influence on both the oxidative and reductive pathways. In particular, McMT oxidation is facilitated by a rapid bimolecular proton transfer from McMT to weak bases such as Py that produces McMT-, the thiolate form, which is then oxidized. There is no such facilitation in the presence of the sterically hindered base 2,6-di-tert-butylpyridine, suggesting that the facilitation occurs through the formation of a discrete hydrogen-bonded complex. The overall kinetic scheme by which these redox processes proceed both in the presence and absence of proton transfer agents is discussed, especially with regard to the potential use of a related dithiolate compound as a cathode material in Li secondary batteries.

Intermolecular proton transfer in catalysis by carbonic anhydrase V

The dehydration of bicarbonate catalyzed by carbonic anhydrase is accompanied by the transfer of a proton from solution to the zinc-bound hydroxide. We have investigated the properties of proton transfer from donors in solution, mostly derivatives of imidazole and pyridine, to a truncated mutant of carbonic anhydrase V with replacements that render the active site cavity less sterically constrained, Tyr 64 →> Ala and Phe 65 →> Ala. Catalysis was measured by determining the rate of exchange of 18O between the CO2-HCO3- system and water, and rate constants for proton transfer were estimated as the rate-limiting step in the release of H218O from the enzyme to solution. Each proton donor enhanced catalytic activity in a saturable manner. The resulting rate constants for proton transfer when compared with the values of pKa of the donor and acceptor gave a Brønsted plot of high curvature. These data could also be described by Marcus theory which showed an intrinsic barrier for intermolecular proton transfer near 0.8 kcal/mol and a work term or thermodynamic contribution to the free energy of reaction near 10 kcal/mol. This low intrinsic kinetic barrier for proton transfer is very similar to nonenzymic bimolecular proton transfer between nitrogen and oxygen acids and bases in solution. However, the significant thermodynamic contribution suggests appreciable involvement of solvent and active-site organization prior to proton transfer. These Marcus parameters are very similar to those describing intramolecular proton transfer from His 64 in carbonic anhydrase, suggesting similarities in the intra- and intermolecular proton transfer processes.Key words: carbonic anhydrase, proton transfer, Marcus theory, carbon dioxide.

Alkyl Substituent Effect in the Deprotonation of Unsymmetrical Ketones

The effect of various degrees of alkyl substitution on the relative rates of deprotonation from the two distinct sites in several unsymmetrical ketones in the gas phase is examined. The infrared multiple photon activation of an appropriately deuterium-labeled alkoxide ion generates the ion−molecule complex for the half-reaction of the bimolecular proton transfer process between an alkyl anion and an unsymmetrical ketone with one deprotonation site selectively deuterated. The resulting products are enolate ions generated by the removal of either a deuteron or a proton and, thus, are distinguishable by mass. The measurement of the enolate ion product ratios, along with an independent measurement of the kinetic isotope effect, allowed the kinetic effect of the alkyl environment on the relative proton transfer rates to be determined. The primary and secondary isotope effects are also estimated from the enolate ion product ratios. By examining the magnitude of the kinetic alkyl effect, the primary isotope effe...

18] Proton transfer in carbonic anhydrase measured by equilibrium isotope exchange

Kinetic and structural studies demonstrate the pathways of inter- and intramolecular proton transfer in the hydration of CO2 catalyzed by carbonic anhydrase. A histidine residue at position 64 is the most efficient of the carbonic anhydrases, carbonic anhydrase II, and acts as a transfer group shuttling protons between the buffer in solution and the zinc-bound water at the active site. This conclusion is confirmed by mutations to replace His-64 that results in the inactivation of catalysis. Mutations to introduce His-64 in the less efficient carbonic anhydrase III results in activation, with the mutant showing proton transfer properties, similar to the efficient form of the enzyme. In a series of site-specific mutants of isozyme III, the rate constants for proton transfer obeys a Brønsted correlation and show sharp curvature characteristic of facile proton transfers. Application of Marcus rate theory shows that this proton transfer has the small intrinsic energy barrier (near 1.5 kcal/mol) characteristic of rapid bimolecular proton transfer between nitrogen and oxygen acids and bases in solution. The observed overall energy barrier (near 10 kcal/mol) for proton transfer in the catalysis indicates the involvement of accompanying energy-requiring processes, such as solvent reorganization or conformational change. Some of this barrier is likely to involve the formation of hydrogen-bonded water in the active-site cavity through the intramolecular proton transfer that occurs.

Mechanism of CH 2 + Transfer from Distonic Ions X ‐ CH 2 + (X = CH 2 O, CH 2 CH 2 ) to π‐ and n‐Electron Bases in the Gas Phase. A Fourier Transform Ion Cyclotron Resonance (FTICR) Study Supplemented by ab initio MO Calculations

The reactions of acetonitrile, propyne, acetylene, trimethyl-silylacetylene, and tetramethylsilane, with distonic ions CH2XCH2+ [X = CH2 (2), O (3)] are studied in the gas phase using Fourier Transform Ion Cyclotron Resonance (FTICR) mass spectrometry. In line with previous studies, CH2+ is transferred to the electron Ione-pair of the nitrogen atom of CH3CN to generate CH3CN–CH2+ (4); upon collisional excitation, this ion undergoes competitive losses of H* and CH*. While both neutrals originate from the “methylene” unit of 4′, detailed studies employing labeled substrates and using various types of collision experiments reveal an intriguing dissociation pattern in that the dissociations are preceded by two intramolecular hydrogen migrations giving rise to CH3C(H) = NCH* + (6) and CH3C = N(H)CH*+ (7). While 6 serves as intermediate en route to loss of H* from the “CH” moiety, 7 is the actual precursor to generate, by loss of CH*, protonated acetonitrile, CH3CNH+ (12) (Scheme 5). In addition, 12 is formed by bimolecular proton transfer. In this reaction, translationally excited CX3CN – CY2+ * (X, Y = H, D) transfers X +- to neutral CX3CN to generate CX3CNX+ (Scheme 4). The bimolecular proton transfer as well as the intramolecular isomerizations of 4 to 6 and 7 are subject to very large kinetic isotope effects. In the transfer of CH2+ to CH3C = CH two products are formed [i.e. H3C - C ≡ C - CH3+ (16) and CH2  C = CHCH3+ (l7) presumably via intermediate 18 (Scheme 6)]; the latter is formed by addition of CH2+ to the less hindered carbon atom of HC ≡ CCH3 reflecting the higher stability of the so-formed intermediate compared with addition to C-2, Reactions of 2 and 3 with HC ≡ CH do not result in the formation of a detectable CH2+-transfer product. When using CH2CH2CH2+ (2) the reaction is prohibited by the endothermicity to generate the initial complex (structurally related to 18). On the other hand, when CH2OCH2+ (3) is employed, the intermediate of CH2+ transfer is formed with sufficient energy to split off a hydrogen atom. Preliminary experiments with silicon-containing molecules, like Si(CH3)4 or HC ≡ CSi(CH3)3, demonstrate that the favored processes of these neutrals with 2 and 3 are due to charge transfer (in the form of an electron or an anion like CH-3 or C2H-) from the silicon-containing molecule to the distonic ions. The experimental results obtained for the CH3CN/CH2+ system are supported by ab initio MO calculations (3-21G/3-21G + ZPVE).

Kinetics and isotope effects of the proton transfer reactions between 1-(4-nitrophenyl)-1-nitroethane to phenyltetramethylguanidine in dipolar aprotic solvents

The carbon acid 1-(4-nitrophenyl)-1-nitroethane reacts with phenyltetramethylguanidine in the aprotic solvents acetonitrile, benzonitrile, and chlorobenzene in a bimolecular proton transfer reaction. The primary isotope effects, kH/kD, for these reactions at 25 °C are 8.5 ± 0.4, 6.1 ± 0.4, and 16 in acetonitrile, benzonitrile, and chlorobenzene respectively. The magnitude of the isotope effects on the enthalpy of activation [Formula: see text] are 2.3 ± 0.2, 1.6 ± 0.7, and 4.2 ± 0.6 kcal mol−1, which indicates a contribution from proton tunnelling to the reaction rate of the normal substrate.

Neutral products from cation-molecule reactions in the gas phase

The use of neutral product analysis for examining ionic reaction pathways from electron impact is described. This approach merges techniques of mass spectrometry with those of radiation chemistry. Comparisons are made between experimental results and predictions based on density-of-states arguments using RRKM microscopic rate coefficients. The importance of examining isomer distributions is stressed with special attention given to the question of the mechanism of bimolecular proton transfer in the gas phase.

Kinetic study at 0.5 torr of the system NH 2+ + CH 3OH in the energy range 0.04–0.7 eV: Importance of termolecular formation of NH 4+ at low energy

The system NH 2 + + CH 3OH has been studied at 0.5 torr in the T eff range 350–5000 K in a drift-tube mass spectrometer apparatus (TDSM). A reaction scheme is proposed and the rate coefficients given for each step of the mechanism. One of the significant results is the observation of formation of NH 4 + as a major fraction of the total ionisation, by a termolecular reaction involving CH 3O0H as the third body, at low energy. At high temperature the only fast reaction is that of bimolecular proton transfer.

The kinetics of proton and deuteron transfer from 4-nitrophenylnitromethane and l-(4-nitrophenyl)-l-nitroethane to 2,7-dimethoxy-l,8-bis(dimethylamino)naphthalene in acetonitrile solvent

4-Nitrophenylnitromethane reacts with 2,7-dimethoxy-1,8-bis(dimethylamino)naphthalene in acetonitrile in a bimolecular proton transfer, which shows a primary deuterium isotope effect, kH/kD = 12.2 at 25 °C. The large isotope effect on the enthalpy of activation, (ΔHD≠ – ΔHH≠) = 4.6 ± 0.3 kcal mol−1 is consistent with a significant contribution of proton tunnelling to the reaction rate of the protium substrate.The analogous reaction of 1-(4-nitrophenyl)-1-nitroethane with the same base in acetonitrile gives contrasting kinetics and reaction parameters. The reaction is first order, showing no dependence on base concentration. While the isotope effect kH/kD = 9.3 at 25 °C, the enthalpy of activation difference (ΔHD≠ – ΔHH≠) is only 0.5 ± 0.1 kcal mol−1. It is concluded that the 1-(4-nitrophenyl)-1-nitroethane undergoes a slow dissociation, with a very small dissociation constant, followed by a fast association with the base to yield the carbanion ion-pair.

Proton exchange between ammonium ion, trimethyl-ammonium ion, and water. Speed of the dehydration step that precedes bimolecular proton transfer

Proton exchange between ammonium ion, trimethyl-ammonium ion, and water. Speed of the dehydration step that precedes bimolecular proton transfer