Unexpected Direct Hydride Transfer Mechanism for the Hydrogenation of Ethyl Acetate to Ethanol Catalyzed by SNS Pincer Ruthenium Complexes

The hydrogenation of ethyl acetate to ethanol catalyzed by SNS pincer ruthenium complexes was computationally investigated by using DFT. Different from a previously proposed mechanism with fac‐[(SNS)Ru(PPh₃)(H)₂] ( 5′ ) as the catalyst, an unexpected direct hydride transfer mechanism with a mer‐SNS ruthenium complex as the catalyst, and two cascade catalytic cycles for hydrogenations of ethyl acetate to aldehyde and aldehyde to ethanol, is proposed base on our calculations. The new mechanism features ethanol‐assisted proton transfer for H₂ cleavage, direct hydride transfer from ruthenium to the carbonyl carbon, and C?OEt bond cleavage. Calculation results indicate that the rate‐determining step in the whole catalytic reaction is the transfer of a hydride from ruthenium to the carbonyl carbon of ethyl acetate, with a total free energy barrier of only 26.9 kcal mol^?1, which is consistent with experimental observations and significantly lower than the relative free energy of an intermediate in a previously postulated mechanism with 5′ as the catalyst.     

A Mechanistic Study of the Spontaneous Hydrolysis of Glycylserine as the Simplest Model for Protein Self‐Cleavage

A common feature of several classes of intrinsically reactive proteins with diverse biological functions is that they undergo self‐catalyzed reactions initiated by an N→O or N→S acyl shift of a peptide bond adjacent to a serine, threonine, or cysteine residue. In this study, we examine the N→O acyl shift initiated peptide‐bond hydrolysis at the serine residue on a model compound, glycylserine (GlySer), by means of DFT and ab initio methods. In the most favorable rate‐determining transition state, the serine ?COO^? group acts as a general base to accept a proton from the attacking ?OH function, which results in oxyoxazolidine ring closure. The calculated activation energy (29.4 kcal mol^?1) is in excellent agreement with the experimental value, 29.4 kcal mol^?1, determined by ¹H NMR measurements. A reaction mechanism for the entire process of GlySer dipeptide hydrolysis is also proposed. In the case of proteins, we found that when no other groups that may act as a general base are available, the N→O acyl shift mechanism might instead involve a water‐assisted proton transfer from the attacking serine ?OH group to the amide oxygen. However, the calculated energy barrier for this process is relatively high (33.6 kcal mol^?1), thus indicating that in absence of catalytic factors the peptide bond adjacent to serine is no longer a weak point in the protein backbone. An analogous rearrangement involving the amide N‐protonated form, rather than the principle zwitterion form of GlySer, was also considered as a model for the previously proposed mechanism of sea‐urchin sperm protein, enterokinase, and agrin (SEA) domain autoproteolysis. The calculated activation energy (14.3 kcal mol^?1) is significantly lower than the experimental value reported for SEA (≈21 kcal mol^?1), but is still in better agreement as compared to earlier theoretical attempts.     

Proton transfer at the carboxylic sites of amino acids: A single water molecule catalyzed process

Ab initio calculations at MP2 level of theory were used to study the proton transfer at the carboxylic sites of amino acids, in the isolated, mono‐ and di‐hydrated forms. In the case of water dimer, two interaction modes with glycine neutral structures (see Fig. 3 ) were explored, corresponding to the concerted and stepwise reaction pathways. Their transition states can be described as (H₂O? H? OH₂)⁺ [Fig. 4 (a)] and (H₂O‐‐‐H? OH₂)⁺ [Fig. 4 (b)], respectively. The energy analysis indicated that the concerted pathway is preferred. In the isolated, mono‐ and di‐hydrated glycine complexes, the activation barriers of the proton transfer at the carboxylic sites were calculated to be 34.49, 16.59, and 13.36 kcal mol^?1, respectively. It was thus shown that the proton transfer is significantly assisted and catalyzed by water monomer so that it can take place at room temperature. Instead, the further addition of water molecules plays solvent effects rather than catalytic effects to this proton transfer process. The above results obtained with discrete water molecules were supported by the solvent continuum calculated data. It was also observed that the heavy dependence of the solvent continuum models on dipole moments may produce misleading results. © 2008 Wiley Periodicals, Inc. Int J Quantum Chem, 2009     

Density functional theory studies on the external OH−‐induced barrierless proton dissociation mechanism for the forced hydrolysis reaction of Al3+(aq)

The forced hydrolysis reaction of aqueous aluminum ion (Al³⁺) is of critical importance in Al chemistry, but its microscopic mechanism has long been neglected. Herein, density functional calculations reveal an external OH⁻‐induced barrierless proton dissociation mechanism for the forced hydrolysis of Al³⁺(aq). Dynamic reaction pathway modeling results show that the barrierless deprotonations induced by the second‐ or third‐shell external OH⁻ proceed via the concerted proton transfer through H‐bond wires connected to the coordinated waters, and the inducing ability of the external OH⁻ decreases with increasing hydration layers between Al(H₂O)₆³⁺ and the external OH⁻. The OH⁻‐induced forced hydrolysis mechanism of Al³⁺(aq) is quite different from its self‐hydrolysis mechanism without OH⁻. The inducing ability is a unique characteristic of OH⁻, rather than other anions such as F⁻ or Cl⁻.     

Unraveling the Mechanism and Regioselectivity of the B12‐Dependent Reductive Dehalogenase PceA

PceA is a cobalamin‐dependent reductive dehalogenase that catalyzes the dechlorination of perchloroethylene to trichloroethylene and then to cis‐dichloroethylene as the sole final product. The reaction mechanism and the regioselectivity of this enzyme are investigated by using density functional calculations. Four different substrates, namely, perchloroethylene, trichloroethylene, cis‐dichloroethylene, and chlorotheylene, have been considered and were found to follow the same reaction mechanism pattern. The reaction starts with the reduction of Co^II to Co^I through a proton‐coupled electron transfer process, with the proton delivered to a Tyr246 anion. This is followed by concerted C?Cl bond heterolytic cleavage and proton transfer from Tyr246 to the substrate carbon atom, generating a Co^III?Cl intermediate. Subsequently, a one‐electron transfer leads to the formation of the Co^II?Cl product, from which the chloride and the dehalogenated product can be released from the active site. The substrate reactivity follows the trend perchloroethylene>trichloroethylene?cis‐dichloroethylene?chlorotheylene. The barriers for the latter two substrates are significantly higher compared with those for perchloroethylene and trichloroethylene, implying that PceA does not catalyze their degradation. In addition, the formation of cis‐dichloroethylene has a lower barrier by 3.8 kcal mol^?1 than the formation of trans‐dichloroethylene and 1,1‐dichloroethylene, reproducing the regioselectivity. These results agree quite well with the experimental findings, which show cis‐dichloroethylene as the sole product in the PceA‐catalyzed dechlorination of perchloethylene and trichloroethylene.     

Theoretical Study on the Cyclization Mechanism of Dipeptides

Cyclization is an important chemical reaction for the dipeptides containing N‐alkyl groups. The cyclization mechanism has been examined by theoretical calculations. Our calculation results indicate that the most favorable mechanism is the piperidine‐catalyzed stepwise mechanism, in which piperidine acts as a proton shuttle. The attack of the N‐terminal amino nitrogen at the C‐terminal carbonyl carbon along with the proton transfer is the rate‐limiting step. The effect of the alkyl substituent on the amide N on the cyclization reaction was then examined. Finally, the influence of the solvation effect, electronic effect and steric effect on the cyclization was investigated. It is found that all of these effects contribute to the cyclization.     

Boron Arylations of Subporphyrins with Aryl Zinc Reagents

Boron arylations of B‐(methoxo)triphenylsubporphyrin have been developed with a combined use of ArZnI?LiCl and trimethylsilyl chloride. Aryl zinc reagents bearing bromo, cyano, amide, and ester groups can be employed for the B‐arylation reaction to provide the corresponding B‐arylated subporphyrins in moderate yields. Postmodifications of B‐arylated subporphyrins have been demonstrated without loss of the B?C bond. These modifications include conversion of the cyano group into a benzoyl group with PhMgBr, hydrolysis of the ester group to give B‐(4‐carboxyphenyl)subporphyrin, and Pd‐catalyzed Suzuki–Miyaura coupling of the 4‐bromophenyl group to give a 1,4‐phenylene‐bridged subporphyrin–Zn^II porphyrin hybrid that displays intramolecular excitation energy transfer from the subporphyrin to the porphyrin. The newly synthesized B‐arylated subporphyrins have been fully characterized by NMR, UV/Vis absorption and fluorescence spectroscopies, mass spectrometry, electrochemical measurements, and X‐ray diffraction analysis.     

Proton dissociation and transfer in hydrated phosphoric acid clusters

The dynamics and mechanisms of proton dissociation and transfer in hydrated phosphoric acid (H₃PO₄) clusters under excess proton conditions were studied based on the concept of presolvation using the H₃PO₄–H₃O⁺–nH₂O complexes (n = 1–3) as the model systems and ab initio calculations and Born–Oppenheimer molecular dynamics (BOMD) simulations at the RIMP2/TZVP level as model calculations. The static results showed that the smallest, most stable intermediate complex for proton dissociation (n = 1) is formed in a low local‐dielectric constant environment (e.g., ε = 1), whereas proton transfer from the first to the second hydration shell is driven by fluctuations in the number of water molecules in a high local‐dielectric constant environment (e.g., ε = 78) through the Zundel complex in a linear H‐bond chain (n = 3). The two‐dimensional potential energy surfaces (2D‐PES) of the intermediate complex (n = 1) suggested three characteristic vibrational and ¹H NMR frequencies associated with a proton moving on the oscillatory shuttling and structural diffusion paths, which can be used to monitor the dynamics of proton dissociation in the H‐bond clusters. The BOMD simulations over the temperature range of 298–430 K validated the proposed proton dissociation and transfer mechanisms by showing that good agreement between the theoretical and experimental data can be achieved with the proposed rate‐determining processes. The theoretical results suggest the roles played by the polar solvent and iterate that insights into the dynamics and mechanisms of proton transfer in the protonated H‐bond clusters can be obtained from intermediate complexes provided that an appropriate presolvation model is selected and that all of the important rate‐determining processes are included in the model calculations. © 2015 Wiley Periodicals, Inc.     

Computational studies on electron and proton transfer in phenol‐imidazole‐base triads

The electron and proton transfer in phenol‐imidazole‐base systems (base = NH₂^? or OH^?) were investigated by density‐functional theory calculations. In particular, the role of bridge imidazole on the electron and proton transfer was discussed in comparison with the phenol‐base systems (base = imidazole, H₂O, NH₃, OH^?, and NH₂^?). In the gas phase phenol‐imidazole‐base system, the hydrogen bonding between the phenol and the imidazole is classified as short strong hydrogen bonding, whereas that between the imidazole and the base is a conventional hydrogen bonding. The n value in spⁿ hybridization of the oxygen and carbon atoms of the phenolic CO sigma bond was found to be closely related to the CO bond length. From the potential energy surfaces without and with zero point energy correction, it can be concluded that the separated electron and proton transfer mechanism is suitable for the gas‐phase phenol‐imidazole‐base triads, in which the low‐barrier hydrogen bond is found and the delocalized phenolic proton can move freely in the single‐well potential. For the gas‐phase oxidized systems and all of the triads in water solvent, the homogeneous proton‐coupled electron transfer mechanism prevails. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010     

A QM/MM study on the reaction pathway leading to 2‐Aceto‐2‐hydroxybutyrate in the catalytic cycle of AHAS

The reaction between the intermediate 2‐hydroxyethyl‐thiamin diphosphate (HEThDP^?) and 2‐ketobutyrate, in the third step of the catalytic cycle of acetodydroxy acid synthase, is addressed from a theoretical point of view by means of hybrid quantum/molecular mechanical calculations. The QM region includes one molecule of 2‐ketobutyrate, the HEThDP^? intermediate, and the residues Arg 380 y Glu 139; whereas the MM region includes the rest of the protein. The study includes potential energy surface scans to identify and characterize critical points on it, transition state search and activation barrier calculations. The results show that the reaction occurs via a two‐step mechanism corresponding to the carboligation and proton transfer in the first stage; and the product release in the second step. © 2014 Wiley Periodicals, Inc.     

Solid‐State NMR Study of the Tautomerism of Acetylacetone Included in a Host Matrix

The tautomerism of the enol form of acetylacetone (=pentane‐2,4‐dione; 1 ) inside a host cavity has been studied by means of solid‐state ¹³C‐NMR spectroscopy (SSNMR) using the variable‐temperature CPMAS technique. It appears that the enol form, 4‐hydroxypent‐3‐en‐2‐one ( 1a ), exists in an equilibrium with an identical tautomer ( 1c ) trough O H ⋅⋅⋅O proton transfer. The experimental results (energy barrier and chemical shifts) were rationalized by means of MP2 and GIAO calculations.     

New insights into the mechanism of the Schiff base hydrolysis catalyzed by type I dehydroquinate dehydratase from S. enterica: a theoretical study

The reaction pathway of Schiff base hydrolysis catalyzed by type I dehydroquinate dehydratase (DHQD) from S. enterica has been studied by performing molecular dynamics (MD) simulations and density functional theory (DFT) calculations and the corresponding potential energy profile has also been identified. On the basis of the results, the catalytic hydrolysis process for the wild-type enzyme consists of three major reaction steps, including nucleophilic attack on the carbon atom involved in the carbon-nitrogen double bond of the Schiff base intermediate by a water molecule, deprotonation of the His143 residue, and dissociation between the product and the Lys170 residue of the enzyme. The remarkable difference between this and the previously proposed reaction mechanism is that the second step here, absent in the previously proposed reaction mechanism, plays an important role in facilitating the reaction through a key proton transfer by the His143 residue, resulting in a lower energy barrier. Comparison with our recently reported results on the Schiff base formation and dehydration processes clearly shows that the Schiff base hydrolysis is rate-determining in the overall reaction catalyzed by type I DHQD, consistent with the experimental prediction, and the calculated energy barrier of ～16.0 kcal mol(-1) is in good agreement with the experimentally derived activation free energy of ～14.3 kcal mol(-1). When the imidazole group of His143 residue is missing, the Schiff base hydrolysis is initiated by a hydroxide ion in the solution, rather than a water molecule, and both the reaction mechanism and the kinetics of Schiff base hydrolysis have been remarkably changed, clearly elucidating the catalytic role of the His143 residue in the reaction. The new mechanistic insights obtained here will be valuable for the rational design of high-activity inhibitors of type I DHQD as non-toxic antimicrobials, anti-fungals, and herbicides.     

A Theoretical Investigation on N7(H)→N9(H)Tautomerization of Isolated and Monohydrated 2,6-Dithiopurine Combined with IPCM Solvent Model

The tautomerization reaction mechanism has been reported between N7(H) and N9(H) of isolated and monohydrated 2,6‐dithiopurine using B3LYP/6‐311+G(d,p). The isodensity polarized continuum model (IPCM) in the self‐consistent reaction field (SCRF) method is employed to account for the solvent effect of water on the tautomerization reaction activation energies. The results show that the two pathways P(1) (via the carbene intermediate I1) and P(2) (via the sp³‐hybrid intermediate I2) are found in intramolecular proton transfer, and each pathway is composed by two primary steps. The calculated activation energy barriers of the rate‐determining steps in isolated 2,6‐dithiopurine N7(H)→N9(H) tautomerism are 308.2 and 220.0 kJ·mol^?1 in the two pathways, respectively. Interestingly, in one‐water molecule catalyst, it dramatically lowers the N7(H)→N9(H) energy barriers by the concerted double proton transfer mechanism in P(1), favoring the formation of 2,6‐dithiopurine N9(H). However, the single proton transfer mechanism assisted with out‐of‐plane water in the first step of P(2) increases the activation energy barrier from 220.0 to 232.3 kJ·mol^?1, while the second step is the out‐of‐plane concerted double proton transfer mechanism, indicating that they will be less preferable for proton transfer. Additionally, the results also show that all the pathways are put into the aqueous solution, and the activation energy barriers have no significant changes. Therefore, the long‐range electrostatic effect of bulk solvent has no significant impact on proton transfer reactions and the interaction with explicit water molecules will significantly influence proton transfer reactions.     

Investigation of the Impact of Water on the Enantioselectivity Displayed by CALB in the Kinetic Resolution of δ‐Functionalized Alkan‐2‐ol Derivatives

It is shown that the low enantioselectivity of Candida antarctica lipase B (CALB)‐catalyzed transesterification of a δ‐functionalized alkan‐2‐ol to its acetate does not correlate at all with the high enantioselectivity of the CALB‐catalyzed hydrolysis of the corresponding acetate in water. This lack of correlation is unusual and for unfunctionalized alkan‐2‐ol derivatives there is a very good correlation between the enantioselectivity of transesterification of the alcohol and hydrolysis of the corresponding acetate (E>200 in both cases). The results confirm previous predictions from molecular modeling. The water effect was mimicked by CALB variant Ala281Ser, which showed an enhanced enantioselectivity in transesterification of δ‐functionalized alkan‐2‐ols compared to wild‐type CALB.     

Kinetics of gas-phase hydrolysis of ethyl acetate catalyzed by immobilized lipase

Reactions catalyzed by supported enzymes present important advantages when compared with those in aqueous media or organic solvents: separation of enzymes from substrate is easily accomplished, enzyme stability may be improved, and control of the reaction products is more accurate. We present the experimental results of the kinetic study of ethyl acetate hydrolysis in gaseous phase catalyzed by a commercial immobilized lipase (Lipozyme IM; Novo Nordisk). The hydrolysis reaction was studied as a function of ethyl ester and water partial pressure at a constant temperature of 318 K. The amount of biocatalyst used was varied between 100 and 300 mg, and the reaction was studied in a flow-through glass microreactor. Under the conditions used, water was an important parameter in the gas-phase reaction. Activation energy was 24.8 kJ/mol and the overall order of reaction was one. Finally a Bi-Bi reaction mechanism is proposed.     

Simulation of slow reaction with quantum character: Neutral hydrolysis of carboxylic ester

By computer simulation, using both quantum and classical dynamics, we determined the rate constant and the kinetic isotope effect of the rate-determining step in the neutral hydrolysis of p-methoxyphenyl dichloroacetate in aqueous solution. This step involves a proton transfer concerted with the formation of a C O bond. A method of biased sampling was used; the Gibbs free energy of the biased configuration from which proton transfer is likely to occur was determined by a combination of semiempirical quantum calculations and thermodynamic integration. The proton dynamics was modeled with the quantum-dynamical density matrix evolution method that includes nonadiabatic pathways. The proton dynamics is driven by a fluctuating proton potential that was derived from a classical molecular dynamics simulation of the system including solvent. The calculated rate constant of 3×10⁻² s⁻¹ agrees within the error of the calculation with the experimentally observed value of 2.78×10⁻³. The calculated pseudo-first-order kinetic isotope effect of 3.9 is in good agreement with the experimentally observed value of 3.2. The results show the feasibility of computational approaches to slow reactions in complex environments, where proton transfer with an essential quantum-dynamical nature is the rate-limiting step. ©1999 John Wiley & Sons, Inc. J Comput Chem 20: 886–895, 1999     

DFT studies of cobalt hydride intermediate on cobaloxime‐catalyzed H2 evolution pathways

Chemical, electrochemical, and photochemical methods all had been utilized to explore proton reduction catalysis by cobaloxime complexes. It was postulated in these studies that the initial step toward making H₂ was protonation of Co^I to form a Co^III hydride intermediate. However, in the following steps, different results from electrochemical studies had led to both monometallic and bimetallic pathways. In this article, theoretical computation method (BP86/6‐31G*) was firstly performed on possible cobalt hydride intermediates involved in the reactive pathway of cobaloxime‐catalyzed H₂ evolution. The monometallic pathway B was excluded, both monometallic pathway A and bimetallic pathway were the possible process. However, the Gibbs free energy change for generation of H₂ following monometallic pathway A was much more negative than that following bimetallic pathway. The calculation on monometallic pathway A indicated that the main driving force of the reaction (i) came from the step of the reduction of 11 . The proton transfer steps were also studied in detail. The protonation of cobalt hydride intermediates could directly happen on the dimethylglyoximate part. All the results refer to gas‐phase calculations, not considering the solution. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2011     

Dynamic Kinetic Resolution of Homoallylic Alcohols: Application to the Synthesis of Enantiomerically Pure 5,6‐Dihydropyran‐2‐ones and δ‐Lactones

Dynamic kinetic resolution of various homoallylic alcohols with the use of Candida antarctica lipase B and ruthenium catalyst 2 afforded homoallylic acetates in high yields and with high enantioselectivity. These enantiopure acetates were further transformed into homoallylic acrylates after hydrolysis of the ester function and subsequent DMAP‐catalyzed esterification with acryloyl chloride. After ring‐closing metathesis 5,6‐dihydropyran‐2‐ones were obtained in good yields. Selective hydrogenation of the carbon? carbon double bond afforded the corresponding δ‐lactones without loss of chiral information.     

底物,水量对脂肪酶不对称拆分萘普生的影响

选择了一种便于底物－产物分离的微水－有机两相体系,将对Ｓ－（＋＿萘普生酯有高度对映体选择性的ＣＣＬ脂肪酶固定于硅藻土上。合成了了一种能提高酶催化反应速度的激活的酯－萘普生氯乙酯。