Brønsted Acid Catalyzed Morita–Baylis–Hillman Reaction: A New Mechanistic View for Thioureas Revealed by ESI‐MS(/MS) Monitoring and DFT Calculations

A Morita–Baylis–Hillman (MBH) reaction catalyzed by thiourea was monitored by ESI‐MS(/MS) and key intermediates were intercepted and characterized. These intermediates suggest that thiourea acts as an organocatalyst in all steps of the MBH reaction cycle, including the rate‐limiting proton‐transfer step. DFT calculations, performed for a model MBH reaction between formaldehyde and acrolein with trimethylamine as base and in the presence or the absence of thiourea, suggest that thiourea accelerates MBH reactions by decreasing the transition‐state (TS) energies through bidentate hydrogen bonding throughout the whole catalytic cycle. In the rate‐limiting proton‐transfer step, the thiourea acts not as a proton shuttle, but as a Brønsted acid stabilizing the basic oxygen center that is formed in the TS.     

A density functional theory study on diazotization and nitration of 3,5‐diamino‐1,2,4‐triazole

The reaction mechanism, thermodynamic and kinetic properties for diazotization and nitration of 3,5‐diamino‐1,2,4‐triazole were studied by a density functional theory. The geometries of the reactants, transition states, and intermediates were optimized at the B3LYP/6‐31G (d, p) level. Vibrational analysis was carried out to confirm the transition state structures, and the intrinsic reaction coordinate (IRC) method was used to explore the minimum energy path. The single‐point energies of all stagnation points were further calculated at the B3LYP (MP2)/6‐311+G (2d, p) level. The statistical thermodynamic method and Eyring transition state theory with Wigner correction were used to study the thermodynamic and kinetic characters of all reactions within 0–25°C. Two reaction channels are computed, including the diazotization and nitration of 3‐NH₂ or 5‐NH₂, and there are six steps in each channel. The reaction rate in each step is increased with temperature. The last step in each channel is the slowest step. The first, second, and fifth steps are exothermic reactions, and are favored at lower temperature in the thermodynamics. © 2010 Wiley Periodicals, Inc. Int J Quantum Chem, 2011     

Quantum chemical investigation on the reaction mechanism of tertiary phosphines with unsaturated carboxylic acids: An insight into kinetic data

The structures of intermediates and transition states in the reaction of tertiary phosphines with unsaturated carboxylic acids have been calculated at the B3LYP level of theory using the 6‐31+G(d,p) basis set. Analysis of the results shows that [1,3]‐intramolecular migration of carboxylic proton to carbanionic center of generated zwitterionic intermediate is strongly kinetically unfavorable, and external proton‐donor source is essential to complete quaternization. A molecular cluster of the intermediate with one molecule of water has been modeled for intermolecular reaction pathway, but even in this case, the proton transfer remains to be the rate‐determining step that is in a good agreement with previous kinetic investigations on this reaction. The data obtained for this reaction have much in common with recent studies on the mechanisms of the Morita–Baylis–Hillman reaction and phosphine‐catalyzed [3+2] cycloaddition, which revealed paramount importance of proton‐transfer steps. © 2013 Wiley Periodicals, Inc.     

Density functional theory calculation of cyclic carboxylic phosphorus mixed anhydrides as possible intermediates in biochemical reactions: Implications for the Pro‐Tide approach

Cyclic acyl phosphoramidates (CAPAs) are important components in several fundamental biological reactions such as protein synthesis and phosphorylation. These structures are particularly interesting in the nucleotide pro‐drug approach, Pro‐Tide, since they are putative intermediates in one of the hydrolysis steps required for activation. The central role played by the amino acid carboxylate function suggests first the formation of a cyclic mixed phosphorus anhydride, rapidly followed by water attack. To investigate such speculations, we performed quantum mechanical calculations using the B3LYP/6‐311+G** level of theory for the plausible mechanisms of action considered. In the five‐membered ring case, transition state theory demonstrated how the overall, gas‐phase, mechanism of action could be split into two in‐line addition–elimination (A–E) steps separated by a penta‐coordinate phosphorane intermediate. The difference between five‐membered and six‐membered ring first A–E was also explored, revealing a single step, unimolecular reaction for the six‐membered ring A–E profile. Implicit solvent contribution further confirmed the importance of CAPAs as reactive intermediates in such kind of reactions. Lastly, the second A–E pathway was analyzed to understand the complete pathway of the reaction. This analysis is the first attempt to clarify the putative mechanism of action involved in the activation of Pro‐Tides and casts light also on the possible mechanism of action involved in primordial protein syntheses, strengthening the hypothesis of a common cyclic mixed phosphorus anhydride species as a common intermediate. © 2012 Wiley Periodicals, Inc.     

5,10-CH+-THF向邻苯二胺转移一碳单元反应的理论研究

叶酸辅酶在酶催化的一碳单元转移过程中具有重要的作用,已有大量的实验及实验模拟对其生物学功能进行了研究分析.本文用PM3半经验方法对5,10-CH⁺-THF向邻苯二胺转移一碳单元的反应进行了理论研究.结果表明,5,10-CH⁺-THF中的咪唑啉环有两种开环方式,从而使得该反应可以通过两种途径实现,每一种途径都经历了6个反应步骤,其中包括限制速度的两次质子转移步骤.优化计算了每个步骤所有可能的中间体和过渡态的结构和能量,并通过比较分析得到了各反应阶段的最优中间体和过渡态结构.     

2，3－二甲基－1－对氯苯磺酰基咪唑啉盐与邻氨基苯酚反应的量子化学研究

用量子化学方法对叶酸辅酶模型化合物2，3－二甲基－1－对氯苯磺酰基咪唑 啉盐与邻氨基苯酚的反应进行了理论研究。结果表明，咪唑啉环有两种开环方式， 反应可以通过两种途径实现，得到较稳定的中间体或者实现一碳单元的完全转移。 通过优化计算所有步骤的中间体和过渡态的结构可知，各个中间体和过渡态具有不 同的构型、构象，有些过程的构象变化是进行下一步反应所必需的，在所有过程中 质子转移步骤过渡态的能量最高，是反应的限速步骤。     

3,4,4-三甲基-1-乙酰基咪唑啉盐向邻苯二胺转移一 碳单元反应的理论研究

用PM3-MO半经验方法对叶酸辅酶模型化合物3,4,4-三甲基-1-乙酰基咪唑啉盐向邻苯二胺转移一碳单元的反应进行了理论研究。结果表明,咪唑环有两种开环方式,该反应可能通过两种途径实现,每一种途径都经历了六个反应步骤,包括两次质子转移步骤,其中第二次质子转移是限速步骤。优化计算了所有步骤的中间体和过渡态的结构,各个中间体和过渡态具有不同的构型,构象和能量。     

A DFT Study on the Reaction Mechanism Involved in the Synthesis of Sodium Azide via Hydrazine Hydrate Method

Sodium azide is a widely used inorganic compound. Besides the commonly used method of "Wislicenus process" which uses ammonia, nitrous and sodium as materials, the hydrazine hydrate route is also employed for the preparation of sodium azide particularly in laboratory. However, because many species are involved in the reaction system, the reaction details for the hydrazine hydrate route are still unclear. A comprehensive understanding of the reaction mechanism may provide meaningful help for optimizing the production process. In this work, the reaction mechanism for the synthesis of sodium azide by hydrazine hydrate route has been studied using density function theory(DFT) method. On the basis of our calculations, the reaction details, including the energetics of ten elementary steps, the structures of intermediates and transition states as well as the influence of inorganic acids and alcohols, were illuminated at the atomistic level. Both the two steps, the generation of key intermediate(NH_2-NH-NO) and the trans-cistransformation of NH_2-NH-NO, are suggested to be the possible rate-limiting step, corresponding to the energy barriers of 20.3 and 22.7 kcal/mol, respectively. In the early reaction steps to generate NH_2-NH-NO, the main role of sulphuric acid is to donate proton, which can be replaced by nitric acid or hydrochloric acid. From the energy point of view, isopropanol has similar reactivity as methanol and ethanol.     

Metabolic‐intermediate complex formation with cytochrome P450: Theoretical studies in elucidating the reaction pathway for the generation of reactive nitroso intermediate

Mechanism‐based inhibition (MBI) of cytochrome P450 (CYP) can lead to drug–drug interactions and often to toxicity. Some aliphatic and aromatic amines can undergo biotransformation reactions to form reactive metabolites such as nitrosoalkanes, leading to MBI of CYPs. It has been proposed that the nitrosoalkanes coordinate with the heme iron, forming metabolic‐intermediate complex (MIC), resulting in the quasi‐irreversible inhibition of CYPs. Limited mechanistic details regarding the formation of reactive nitroso intermediate and its coordination with heme‐iron have been reported. A quantum chemical analysis was performed to elucidate potential reaction pathways for the generation of nitroso intermediate and the formation of MIC. Elucidation of the energy profile along the reaction path, identification of three‐dimensional structures of reactive intermediates and transition states, as well as charge and spin density analyses, were performed using the density functional B3LYP method. The study was performed using Cpd I [iron (IV‐oxo] heme porphine with SH^? as the axial ligand) to represent the catalytic domain of CYP, simulating the biotransformation process. Three pathways: (i) N‐oxidation followed by proton shuttle, (ii) N‐oxidation followed by 1,2‐H shift, and (iii) H‐abstraction followed by rebound mechanism, were studied. It was observed that the proton shuttle pathway was more favorable over the whole reaction leading to reactive nitroso intermediate. This study revealed that the MIC formation from a primary amine is a favorable exothermic process, involving eight different steps and preferably takes place on the doublet spin surface of Cpd I . The rate‐determining step was identified to be the first N‐oxidation of primary amine. © 2012 Wiley Periodicals, Inc.     

Ethanol reforming on Co(0001) surfaces: a density functional theory study

A computational study using density functional theory is carried out to investigate the reaction mechanism of ethanol steam reforming on Co(0001) surfaces. The adsorption properties of the reactant, possible intermediates, and products are carefully examined. The reaction pathway and related transition states are also analyzed. According to our calculations, the reforming mechanism primarily consisting of dehydrogenation steps of ethanol, ethoxy, methanol, methoxy, and formic acid, is feasible on Co(0001) surfaces. It is also found that the reaction of formaldehyde yielding formic acid and hydrogen may not be an elementary reaction. The dehydrogenation of ethoxy possesses the highest barrier and is accordingly identified as the rate-determining step.     

Quantum chemistry studies of adenosine 2503 methylation by S‐adenosylmethionine‐dependent enzymes

Ribosome methylation is important for life processes and is mainly catalyzed by radical S‐Adenosylmethionine (SAM) enzymes. Two SAM molecules serve as the cofactor by providing the 5 ′‐deoxyadenosyl radical for substrate activation and the methyl. Recently, Booker and coworkers (Science 2011, 332, 604) proposed an alternative mechanism for a pair of radical SAM enzymes, RlmN and Cfr, which respectively methylate the C2 and C8 of adenosine 2503. Their deuterium labeling experiments reveal that methyl group does not transfer directly from SAM to adenosine, instead it passes to Cys³⁵⁵ first, then onto adenosine. In this article, this new reaction mechanism is studied using density functional theory with B3LYP hybrid functional. The reaction system is simulated using small model compounds in the gas phase, and the protein environment is approximated using polarizable continuum model. The structures of the transition states and the intermediates are identified, and their free energies are calculated. The activation barriers indicate that the proposed reaction mechanism is plausible. The formation of a disulfide bond is found to be the rate‐limiting step. © 2012 Wiley Periodicals, Inc.     

Mechanistic Investigation of Chiral Phosphoric Acid Catalyzed Asymmetric Baeyer–Villiger Reaction of 3‐Substituted Cyclobutanones with H2O2 as the Oxidant

The mechanism of the chiral phosphoric acid catalyzed Baeyer–Villiger (B–V) reaction of cyclobutanones with hydrogen peroxide was investigated by using a combination of experimental and theoretical methods. Of the two pathways that have been proposed for the present reaction, the pathway involving a peroxyphosphate intermediate is not viable. The reaction progress kinetic analysis indicates that the reaction is partially inhibited by the γ‐lactone product. Initial rate measurements suggest that the reaction follows Michaelis–Menten‐type kinetics consistent with a bifunctional mechanism in which the catalyst is actively involved in both carbonyl addition and the subsequent rearrangement steps through hydrogen‐bonding interactions with the reactants or the intermediate. High‐level quantum chemical calculations strongly support a two‐step concerted mechanism in which the phosphoric acid activates the reactants or the intermediate in a synergistic manner through partial proton transfer. The catalyst simultaneously acts as a general acid, by increasing the electrophilicity of the carbonyl carbon, increases the nucleophilicity of hydrogen peroxide as a Lewis base in the addition step, and facilitates the dissociation of the OH group from the Criegee intermediate in the rearrangement step. The overall reaction is highly exothermic, and the rearrangement of the Criegee intermediate is the rate‐determining step. The observed reactivity of this catalytic B–V reaction also results, in part, from the ring strain in cyclobutanones. The sense of chiral induction is rationalized by the analysis of the relative energies of the competing diastereomeric transition states, in which the steric repulsion between the 3‐substituent of the cyclobutanone and the 3‐ and 3′‐substituents of the catalyst, as well as the entropy and solvent effects, are found to be critically important.     

Insight into the Reaction Mechanism of α‐Amino Phosphonate Synthesis Using Succinic Acid as a Catalyst: Computational Kinetic Approach

The reaction mechanism in the synthesis of particular α‐amino phosphonates from 4‐methyl benzaldehyde, aniline, and trimethyl phosphite in the presence of succinic acid is theoretically investigated. The profile of the potential energy surface is constructed at both HF /6‐31 + G(d,p) and B3LYP /6‐31 + G(d,p) levels of theory for evaluating all the steps involved in the reaction mechanism. In order to investigate the effect of the structure on reactivity, some para ‐substituted benzaldehydes are subjected to kinetic examination. The overall reaction in the presence of electron‐withdrawing groups is thermodynamically much more favorable than in the presence of the electron‐donating groups; similarly, the reaction is kinetically more favorable and much easier in the presence of electron‐withdrawing groups. Moreover, step 2 (imine formation) is recognized as the rate‐determining step at both levels of theory. Also, step 1 is diffusion‐controlled with both electron‐withdrawing and electron‐donating groups, while the other steps are chemically controlled in the reaction mechanism.     

A DFT study on the formation of a phosphohistidine intermediate in prostatic acid phosphatase

Histidine phosphatases are a class of enzymes that are characterized by the presence of a conserved RHGXRXP motif. This motif contains a catalytic histidine that is being phosphorylated in the course of a dephosphorylation reaction catalyzed by these enzymes. Prostatic acid phosphatase (PAP) is one such enzyme. The dephosphorylation of phosphotyrosine by PAP is a two-step process. The first step involves the transfer of a phosphate group from the substrate to the histidine (His12). The present study reports on the details of the first step of this reaction, which was investigated using a series of quantum chemistry calculations. A number of quantum models were constructed containing various residues that were thought to play a role in the mechanism. In all these models, the transition state displayed an associative character. The transition state is stabilized by three active site arginines (Arg11, Arg15, and Arg79), two of which belong to the aforementioned conserved motif. The work also demonstrated that His12 could act as a nucleophile. The enzyme is further characterized by a His257-Asp258 motif. The role of Asp258 has been elusive. In this work, we propose that Asp258 acts as a proton donor which becomes protonated when the substrate enters the binding pocket. Evidence is also obtained that the transfer of a proton from Asp258 to the leaving group is possibly mediated by a water molecule in the active site. The work also underlines the importance of His257 in lowering the energy barrier for the nucleophilic attack.     

Theoretical study of one‐carbon unit transfer between methyl‐AICA and N1‐methyl‐N1‐acryloyl‐formamide

The mechanism of one‐carbon unit transfer between 1‐methyl‐5‐amino‐4‐carboxamide imidazole (M‐AICA) and N¹‐methyl‐N¹‐acryloyl‐formamide (the model molecule of 10‐f‐H4F) is investigated by the Hartree–Fock and DFT methods, respectively, at the 6‐31G* basis level. There are two different channels for the proton transfer, resulting in two reaction pathways with different properties. The results indicate that both channels can complete the reaction, but path a is slightly favored due to its lower active energy barrier. Furthermore, the influence of 4‐carboxamindde in M‐AICA is also discussed. This group can stabilize the reactant and intermediates, and reduce the active energy barrier through the intermolecular hydrogen bond. The intermolecular hydrogen bond results in an enlarged conjugation system and makes the transition states more stable. Our results are in agreement with experiments. © 2004 Wiley Periodicals, Inc. Int J Quantum Chem, 2005     

The mechanism of formamide hydrolysis in water from ab initio calculations and simulations

The neutral hydrolysis of formamide in water is a suitable reference to quantify the efficiency of proteolytic enzymes. However, experimental data for this reaction has only very recently been obtained and the kinetic constant determined experimentally is significantly higher than that predicted by previous theoretical estimations. In this work, we have investigated in detail the possible mechanisms of this reaction. Several solvent models have been considered that represent a considerable improvement on those used in previous studies. Density functional and ab initio calculations have been carried out on a system which explicitly includes the first solvation shell of the formamide molecule. Its interaction with the bulk has been treated with the aid of a dielectric continuum model. Molecular dynamics simulations at the combined density functional/molecular mechanics level have been carried out in parallel to better understand the structure of the reaction intermediates in aqueous solution. Overall, the most favored mechanism predicted by our study involves two reaction steps. In the first step, the carbonyl group of the formamide molecule is hydrated to form a diol intermediate. The corresponding transition structure involves two water molecules. From this intermediate, a water-assisted proton transfer occurs from one of the hydroxy groups to the amino group. This reaction step may lead either to the formation of a new reaction intermediate with a marked zwitterionic character or to dissociation of the system into ammonia and formic acid. The zwitterionic intermediate dissociates quite easily but its lifetime is not negligible and it could play a role in the hydrolysis of substituted amides or peptides. The predicted pseudo-first-order kinetic constant for the rate-limiting step (the first step) of the hydrolysis reaction at 25 degrees C (3.9x10(-10) s(-1)) is in excellent agreement with experimental data (1.1x10(-10) s(-1)).     

气态丙烯酸光致脱羧反应AM1法研究

半经验的自洽场分子轨道法(AM1)被用来研究激发单态(~1ππ~*)和三态(~3ππ~*)丙烯酸的脱羧反应. 计算结果支持Robert等人提出的光解机理. 与实验结合. 进一步推测, 丙烯酸光致脱羧反应的第一步, 是沿单态途径进行, 第二步沿三态途径进行. 单态和三态反应途径中的反应物、过渡态、中间体和产物都用能量梯度技术进行了优化. 对于过渡态和中间体, 还作了振动分析, 确证它们分别是一级鞍点和能量极小值点.     

Quantum chemical study of the mechanism of action of vitamin K carboxylase (VKC). IV. Intermediates and transition states

We studied proposed steps for the enzymatic formation of gamma-carboxyglutamic acid by density functional theory (DFT) quantum chemistry. Our results for one potentially feasible mechanism show that a vitamin K alkoxide intermediate can abstract a proton from glutamic acid at the gamma-carbon to form a carbanion and vitamin K epoxide. The hydrated carbanion can then react with CO2 to form gamma-carboxyglutamic acid. Computations at the B3LYP/6-311G** level were used to determine the intermediates and transition states for the overall process. The activation free energy for the gas-phase path is 22 kcal/mol, with the rate-limiting step for the reaction being the attack of the carbanion on CO2. Additional solvation studies, however, indicate that the formation of the carbanion step can be competitive with the CO2 attack step in high-dielectric systems. We relate these computations to the entire vitamin K cycle in the blood coagulation cascade, which is essential for viability of vertebrates.     

Mechanistic insights on N-heterocyclic carbene-catalyzed annulations: the role of base-assisted proton transfers

The density functional theory investigation on the mechanism of NHC-catalyzed cycloannulation reaction of the homoenolate derived from butenal with pentenone is studied. The M06-2X/6-31+G** and B3LYP/6-31+G** levels of theory, including the effect of continuum solvation in dichloromethane and tetrahydrofuran, are employed. Several mechanistic scenarios are examined for each elementary step by identifying the key intermediates and the corresponding transition states interconnecting them on the respective potential energy surfaces. Both assisted and unassisted pathways for important proton transfer steps are considered, respectively, with and without the explicit inclusion of base (DBU) in the corresponding transition states. The barrier for the crucial proton transfer steps involved in the formation of the Breslow intermediate as well as in the subsequent steps is found to be significantly lowered by explicit inclusion of DBU. The energetic comparison between two key pathways, depicted as path A and path B, respectively, leading to cyclopentene and cyclopentanone derivatives, is performed. The major mechanistic bifurcation has been identified as emanating from the site of enolization of the initial zwitterionic intermediate resulting from the addition of a homoenolate equivalent to enone. If the enolization occurs nearer to the NHC moiety, the reaction is likely to proceed through path A, leading to cyclopentene. The enolization away from NHC leads to cyclopentanone product through path B. The computed results are generally in good agreement with the reported experimental results.     

Computational determination of fundamental pathway and activation barriers for acetohydroxyacid synthase‐catalyzed condensation reactions of α‐keto acids

Acetohydroxyacid synthase (AHAS) is the first common enzyme in the biosynthetic pathway leading to the production of various branched‐chain amino acids. AHAS is recognized as a promising target for new antituberculosis drugs, antibacterial drugs, and herbicides. Extensive first‐principles quantum mechanical (QM) and hybrid quantum mechanical/molecular mechanical (QM/MM) calculations have enabled us, in this study, to uncover the fundamental reaction pathway, determine the activation barriers, and obtain valuable insights concerning the specific roles of key amino acid residues for the common steps of AHAS‐catalyzed condensation reactions of α‐keto acids. The computational results reveal that the rate‐determining step of the AHAS‐catalyzed reactions is the second reaction step and that the most important amino acid residues involved in the catalysis include Glu144′, Gln207′, Gly121′, and Gly511 that form favorable hydrogen bonds with the reaction center (consisting of atoms from the substrate and cofactor) during the reaction process. In addition, Glu144′ also accepts a proton from cofactor thiamin diphosphate (ThDP) through hydrogen bonding during the catalytic reaction. The favorable interactions between the reaction center and protein environment remarkably stabilize the transition state and, thus, lower the activation barrier for the rate‐determining reaction step by ～20 kcal/mol. The activation barrier calculated for the rate‐determining step is in good agreement with the experimental activation barrier. The detailed structural and mechanistic insights should be valuable for rational design of novel, potent AHAS inhibitors that may be used as promising new anti‐tuberculosis drugs, antibacterial drugs, and/or herbicides to overcome drug resistance problem. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010