Mechanisms of formation of hemiacetals: intrinsic reactivity analysis

The reaction mechanism of the hemiacetal formation from formaldehyde and methanol has been studied theoretically at the B3LYP/6-311++G(d,p) level. In addition to the study of the reaction between the isolated reactants, three different kinds of catalysis have been explored. The first one examines the use of assistants, especially bridging water molecules, in the proton transfer process. The second one attempts to increase the local electrophilicity of the carbon atom in formaldehyde with the presence of a Br?nsted acid (H(+) or H(3)O(+)). The last one considers the combined effect of both catalytic strategies. The reaction force, the electronic chemical potential, and the reaction electronic flux have been characterized for the reaction path in each case. In general, it has been found that structural rearrangements represent an important energetic penalty during the activation process. The barriers for the reactions catalyzed by Br?nsted acids show a high percentage of electronic reorganization contribution. The catalytic effects for the reactions assisted by water molecules are due to a reduction of the strain in the transition state structures. The reaction that includes both acid catalysis and proton assistance transfer shows the lowest energy barrier (25.0 kJ mol(-1)).     

Acid/base catalysis by pure water: the aldol reaction

[reaction: see text] The mechanism of aldol reactions in pure water has been studied with density functional calculations (B3LYP/6-311++G(3d,3p)//B3LYP/6-31G(d)). The reaction is a three-step process that involves: (1) water autoionization generates catalytic hydroxide and hydronium ions, (2) hydroxide and hydronium ions rapidly convert donor aldehyde or ketone into enol, and (3) C-C bond formation and proton transfer occur to give the aldol product. This study provides a general basis for understanding acid/base catalysis by pure water.     

Chiral Brønsted acid catalysis for enantioselective Hosomi-Sakurai reaction of imines with allyltrimethylsilane

The chiral Br?nsted acid (1b or 1c) has been shown to initiate the Hosomi-Sakurai reaction of imines with excellent enantioselectivities. The combined Br?nsted acid system has been developed to offer a new class of chiral Br?nsted acid catalysis. The present system proceeds through regeneration of the chiral Br?nsted acid by proton transfer from additional Br?nsted acid to silylated chiral Br?nsted acid, a newly elucidated mechanism for the role of the additional Br?nsted acid.     

Dehydrogenative Silylation of Alkenes for the Synthesis of Substituted Allylsilanes by Photoredox,Hydrogen‐Atom Transfer,and Cobalt Catalysis

A synergistic catalytic method combining photoredox catalysis, hydrogen‐atom transfer, and proton‐reduction catalysis for the dehydrogenative silylation of alkenes was developed. With this approach, a highly concise route to substituted allylsilanes has been achieved under very mild reaction conditions without using oxidants. This transformation features good to excellent yields, operational simplicity, and high atom economy. Based on control experiments, a possible reaction mechanism is proposed.     

Dehydrogenative Silylation of Alkenes for the Synthesis of Substituted Allylsilanes by Photoredox,Hydrogen‐Atom Transfer,and Cobalt Catalysis

A synergistic catalytic method combining photoredox catalysis, hydrogen‐atom transfer, and proton‐reduction catalysis for the dehydrogenative silylation of alkenes was developed. With this approach, a highly concise route to substituted allylsilanes has been achieved under very mild reaction conditions without using oxidants. This transformation features good to excellent yields, operational simplicity, and high atom economy. Based on control experiments, a possible reaction mechanism is proposed.     

An Unexpected α‐Oxidation of Cyclic Ketones with 1,4‐Benzoquinone by Enol Catalysis

The first direct and asymmetric α‐aryloxylation of cyclic ketones via enol catalysis has been achieved using quinones as the reaction partners. Catalytic amounts of a phosphoric acid promote the exclusive formation of α,α‐disubstituted ketones from the corresponding α‐substituted ketones in good yields and enantioselectivities (up to 96.5:3.5 er). Preliminary mechanistic experiments suggest that this reaction proceeds via a proton‐coupled electron transfer (PCET) followed by radical recombination.     

Evidence for the formation of a mo-h intermediate in the catalytic cycle of formate dehydrogenase

DFT/BP86/TZVP and DFT/B3LYP/TZVP have been used to investigate systematically the reaction pathways associated with the H-transfer step, which is the rate-determining step of the reaction HCOO(-) ? CO(2) + H(+) + 2e(-), as catalyzed by metalloenzyme formate dehydrogenase (FDH). Actually, the energetics associated with the transfer from formate to all H (proton or hydride) acceptors that are present within the FDH active site have been sampled. This study points to a viable intimate mechanism in which the metal center mediates H transfer from formate to the final acceptor, i.e. a selenocysteine residue. The Mo-based reaction pathway, consisting of a β-H elimination to metal with concerted decarboxylation, turned out to be favored over previously proposed routes in which proton transfer occurs directly from HCOO(-) to selenocysteine. The proposed reaction pathway is reminiscent of the key step of metal-based catalysis of the water-gas shift reaction.     

Origin of tight binding of a near-perfect transition-state analogue by cytidine deaminase: implications for enzyme catalysis

Cytidine deaminase (CDA) is a zinc metalloenzyme that catalyzes the hydrolytic deamination of cytidine to uridine. Zebularine (ZEB) binds to CDA, and the binding process leads to a near-perfect transition-state analogue (TSA) inhibitor at the active site with an estimated K(i) value of 1.2 x 10(-)(12) M. The interaction of CDA with the TSA inhibitor has become a paradigm for studying the tight TSA binding by enzymes. The formation of the TSA is catalyzed by CDA by a mechanism that is similar to the formation of the tetrahedral intermediate during the CDA-catalyzed reaction (i.e., through the nucleophilic attack of a Zn-hydroxide group on C(4)). It is believed that the TSA formed at the active site is zebularine 3,4-hydrate. In this paper, it is shown from QM/MM molecular dynamics and free energy simulations that zebularine 3,4-hydrate may in fact be unstable in the enzyme and that a proton transfer from the Zn-hydroxide group to Glu-104 during the nucleophilic attack could be responsible for the very high affinity. The nucleophilic attack by the Zn-hydroxide on C(4) is found to be concerted with two proton transfers. Such concerted process allows the TSA, an alkoxide-like inhibitor, to be stabilized through a mechanism that is similar to the transition-state stabilization in the general acid-base catalysis. It is suggested that the proton transfer from the Zn-hydroxide to Glu-104, which is required to generate the general acid for protonating the leaving ammonia, may play an important role in lowering the activation barrier during the catalysis.     

Excited state dynamics and catalytic mechanism of the light-driven enzyme protochlorophyllide oxidoreductase

The reduction of protochlorophyllide (Pchlide) to chlorophyllide, catalysed by the enzyme protochlorophyllide oxidoreductase (POR), is the penultimate step in the chlorophyll biosynthetic pathway and is a key light-driven reaction that triggers a profound transformation in plant development. As POR is light-activated it can provide new information on the way in which light energy can be harnessed to power enzyme reactions. Consequently, POR presents a unique opportunity to study catalysis at low temperatures and on ultrafast timescales, which are not usually accessible for the majority of enzymes. Recent advances in our understanding of the catalytic mechanism of POR illustrate why it is an important model for studying enzyme catalysis and reaction dynamics. The reaction involves the addition of one hydride and one proton, and catalysis is initiated by the absorption of light by the Pchlide substrate. As the reaction involves the Pchlide excited state, a variety of ultrafast spectroscopic measurements have shown that significant parts of the reaction occur on the picosecond timescale. A number of excited state Pchlide species, including an intramolecular charge transfer complex and a hydrogen bonded intermediate, are proposed to be required for the subsequent hydride and proton transfers, which occur on the microsecond timescale. Herein, we review spectroscopic investigations, with a particular focus on time-resolved transient absorption and fluorescence experiments that have been used to study the excited state dynamics and catalytic mechanism of POR.     

Kinetics and mechanism of p-isopropenylphenol synthesis via hydrothermal cleavage of bisphenol A

Although bishydroxyarylalkanes are known to be reactive in high-temperature (T > 200 degrees C) liquid water (HTW), no mechanistic insight has been given to explain the reactivity of methylene bridge-containing diaryls under hydrothermal conditions. We examined the kinetics and mechanism of p-isopropenylphenol (IPP) synthesis via bisphenol A (BPA) cleavage in HTW. The cleavage reaction is first order in BPA. Cleavage of BPA in HTW occurs by specific acid catalysis, by specific base catalysis, and by general water catalysis. Under neutral conditions, the dominant mechanism is general base catalysis with water serving as the proton acceptor. We generated a detailed chemical kinetics model for the decomposition reaction based on a base-catalyzed mechanism in the literature. This three-parameter model fit the experimental data for BPA disappearance and formation of IPP and phenol and accurately predicted the yield of the IPP hydrolysis product acetone. Using acid- and base-catalyzed mechanisms, we explain the reactivity in HTW reported for other diaryl groups linked by methylene bridges and propose criteria for assessing the reactivity of methylene bridges under hydrothermal conditions.     

Choice of solvent (MeCN vs H(2)O) decides rate-limiting step in S(N)Ar aminolysis of 1-fluoro-2,4-dinitrobenzene with secondary amines: importance of Brønsted-type analysis in acetonitrile

A kinetic study is reported for nucleophilic substitution reactions of 2,4-dinitro-1-fluorobenzene (DNFB) with a series of secondary amines in MeCN and H2O at 25.0 degrees C. The reaction in MeCN results in an upward curvature in the plot of k(obsd) vs [amine], indicating that the reaction proceeds through a rate-limiting proton transfer (RLPT) mechanism. On the contrary, the corresponding plot for the reaction in H2O is linear, implying that general base catalysis is absent. The ratios of the microscopic rate constants for the reactions in MeCN are consistent with the proposed mechanism, e.g., the facts that k2/k(-1) < 1 and k3/k2 > 10(2) suggest that formation of a Meisenheimer complex occurs before the rate-limiting step and the deprotonation by a second amine molecule becomes dominant when [amine] > 0.01 M, respectively. The Br?nsted-type plots for k1k2/k(-1) and k1k3/k(-1) are linear with betanuc values of 0.82 and 0.84, respectively, which supports the proposed mechanism. The Br?nsted-type plot for the reactions in H2O is also linear with betanuc = 0.52 which has been interpreted to indicate that the reaction proceeds through rate-limiting formation of a Meisenheimer complex. DNFB is more reactive toward secondary amines in MeCN than in H2O. The enhanced basicity of amines as well as the increased stability of the intermediate whose charges are delocalized through resonance are responsible for the enhanced reactivity in the aprotic solvent.     

CH2CHOH2+ + PN: a proton-transfer triple play

Quantum chemical calculations are used to explore the proton-transfer reactivity of O-protonated vinyl alcohol, CH2CHOH2+, with phosphorus nitride, PN. This reaction is relevant to the chemical evolution of interstellar clouds, since O-protonated vinyl alcohol has been postulated (and tentatively identified) as a product of the association reaction between interstellar H3O+ and C2H2, while PN is the most widespread and abundant phosphorus-containing molecule seen in astrophysical environments. Furthermore, the reaction exhibits an unusual mechanistic feature, namely, an extended "proton-transport catalysis" mechanism, which we characterize here as a "proton-transfer triple play". The reaction proceeds initially by proton transfer from CH2CHOH2+ to PN, then from PNH+ to CH2CHOH, and finally from CH3CHOH+ to PN, where the emphasized atom indicates the resultant site of protonation/deprotonation. Thus, the ultimate overall bimolecular proton-transfer reaction is expected to occur as CH2CHOH2+ + PN --> CH3CHO + PNH+; that is, the apparent favored product channel exhibits not only proton transfer but also keto/enol tautomerization. The triple-play mechanism can be rationalized in terms of the proton affinities of vinyl alcohol, acetaldehyde, and phosphorus nitride, which here are satisfactorily reproduced by high-level ab initio calculations. Other neutrals with a proton affinity appropriate for the possible triple-play mechanism converting CH2CHOH2+ to CH3CHO are also identified, with a view to encouraging experimental investigation of this mechanism.     

2, 5-二间氮杂氧茚氢醌激发态质子转移反应机理的研究

用AM1+INDO/SDCI方法对2, 5-二间氮杂氧茚氢醌分子内激发态质子转移反应进行了理论研究, 求得了基态和激发态反应的位能面、势垒、过渡态, 并对有关化合物的光谱进行了理论指认, 所有理论计算结果均与实验结果符合较好。在此基础上对反应机理进行了探讨, 认为有利的是单质子转移反应不是双质子转移反应。     

Stereochemistry of eudesmane cation formation during catalysis by aristolochene synthase from Penicillium roqueforti

The aristolochene synthase catalysed cyclisation of farnesyl diphosphate (1) has been postulated to proceed through (S)-germacrene A (3). However, the active site acid that reprotonates this neutral intermediate has so far proved difficult to identify and, based on high level ab initio molecular orbital and density functional theory calculations, a proton transfer mechanism has recently been proposed, in which proton transfer from C12 of germacryl cation to the C6,C7-double bond of germacryl cation (2) proceeds either directly or via a tightly bound water molecule. In this work, the stereochemistry of the elimination and protonation reactions was investigated by the analysis of the reaction products from incubation of 1 and of [12,12,12,13,13,13-(2)H(6)]-farnesyl diphosphate (15) with aristolochene synthase from Penicillium roqueforti (PR-AS) in H(2)O and D(2)O. The results reveal proton loss from C12 during the reaction and incorporation of another proton from the solvent. Incubation of with PR-AS in D(2)O led to the production of (6R)-[6-(2)H] aristolochene, indicating that protonation occurs from the face of the 10-membered germacrene ring opposite the isopropylidene group. Hence these results firmly exclude proton transfer from C12 to C6 of germacryl cation. We propose here Lys 206 as the general acid/base during PR-AS catalysis. This residue is part of a conserved network of hydrogen bonds, along which protons could be delivered from the solvent to the active site.     

A computational study of the intramolecular deprotonation of a carbon acid in aqueous solution

Proton transfer reactions are the rate-limiting steps in many biological and synthetic chemical processes, often requiring complex cofactors or catalysts to overcome the generally unfavourable thermodynamic process of carbanion intermediate formation. It has been suggested that quantum tunnelling processes enhance the kinetics of some of these reactions, which when coupled to protein motions may be an important consideration for enzyme catalysis. To obtain a better fundamental and quantitative understanding of these proton transfer mechanisms, a computational analysis of the intramolecular proton transfer from a carbon acid in the small molecule, 4-nitropentanoic acid, in aqueous solution is presented. Potential-energy surfaces from gas-phase, implicit and QM/MM (quantum mechanical/molecular mechanical) explicit solvation quantum chemistry models are compared, and the potential of mean force, for the full reaction coordinate, using umbrella-sampling molecular dynamics is analysed. Semi-classical multidimensional tunnelling corrections are also used to estimate the quantum tunnelling contributions and to understand the origin of the primary deuterium kinetic isotope effects (KIEs). The computational results are found to be in excellent agreement with the KIEs and the energetics obtained experimentally.     

General base and general acid catalyzed intramolecular aminolysis of esters. Cyclization of esters of 2-aminomethylbenzoic acid to phthalimidine

Plots of log k(0) vs pH for the cyclization of trifluoroethyl and phenyl 2-aminomethylbenzoate to phthalimidine at 30 degrees C in H(2)O are linear with slopes of 1.0 at pH >3. The values of the second-order rate constants k(OH) for apparent OH(-) catalysis in the cyclization reactions are 1.7 x 10(5) and 5.7 x 10(7) M(-)(1) s(-)(1), respectively. These rate constants are 10(5)- and 10(7)-fold greater than for alkaline hydrolysis of trifluoroethyl and phenyl benzoate. The k(OH) for cyclization of the methyl ester is 7.2 x 10(3) M(-)(1) s(-)(1). Bimolecular general base catalysis occurs in the intramolecular nucleophilic reactions of the neutral species. The value of the Bronsted coefficient beta for the trifluoroethyl ester is 0.7. The rate-limiting step in the general base catalyzed reaction involves proton transfer in concert with leaving group departure. The mechanism involving rate-determining proton transfer exemplified by the methyl ester in this series (beta = 1.0) can then be considered a limiting case of the concerted mechanism. General acid catalysis of the neutral species reaction or a kinetic equivalent also occurs when the leaving group is good (pK(a) 相似文献   

Mechanism of the Meerwein-Ponndorf-Verley-Oppenauer (MPVO) redox equilibrium on Sn- and Zr-beta zeolite catalysts

The mechanism of the Meerwein-Ponndorf-Verley (MPV) reduction of cyclohexanone with 2-butanol catalyzed by Sn-beta and Zr-beta zeolites has been theoretically investigated using density functional theory (DFT) and the cluster approach. An experimental catalytic study has shown that the active sites in the MPV reaction catalyzed by Sn-beta are the same partially hydrolyzed Sn-OH groups that were found to be active for the Baeyer-Villiger (BV) reaction. The computational study indicates that the mechanism of Sn-beta and Zr-beta catalysis is similar, and involves the following steps: adsorption of both the ketone and the alcohol on the Lewis acid center, deprotonation of the alcohol, carbon-to-carbon hydride transfer, proton transfer from the catalyst, and products exchange. As in the aluminum alkoxide catalyzed reaction, the hydride shift occurs through a six-membered transition state, and the role of the hydrolyzed and therefore more flexible M-OH bond is just to facilitate the initial deprotonation of the alcohol.     

A DFT study on the mechanism of phosphodiester cleavage mediated by monozinc complexes

Density functional theory (DFT), Tao-Perdew-Staroverov-Scuseria (TPSS), is employed to study the reaction mechanism for the zinc-mediated phosphodiester cleavage reaction. The calculations indicate a general base catalysis mechanism. The flexibility of Zn(II) ion's coordination number (5 and 6) as well as the formation of hydrogen bonds between the coordinating water and the ester are responsible for the trapping (namely, coordinating to the Zn complexes) of the phosphodiester. The hydrogen bonds, between the water, the ester, and the nitrogen-ligand, tris(6-amino-2-pyridylmethyl)amine, not only stabilize the key five-coordinated phosphorus intermediates with a trigonal pyramidal PO5 unit but also lower the energy barriers for the proton transfer within the complexes by gaining stronger solvation energies.     

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.     

The syn-oriented 2-OH provides a favorable proton transfer geometry in 1,2-diol monoester aminolysis: implications for the ribosome mechanism

A computational study of 1-formyl 1,2-ethanediol aminolysis predicts a stepwise mechanism involving syn-2-OH-assisted proton transfer. The syn-oriented 2-OH takes over the catalytic role of the external water or amine molecule previously observed in 2-deoxy ester aminolysis. It provides more favorable, that is, more linear, proton transfer geometry for the rate-limiting transition state resulting in an almost billion-fold rate acceleration of the overall reaction. These findings provide structural basis for explanation of the efficiency of the proton shuttling mechanism and imply double proton transfer catalysis by peptidyl tRNA A76 2'-OH as a possible catalytic strategy used by ribosome.