Ab initio study of catalyzed and uncatalyzed amide bond formation as a model for peptide bond formation: Ammonia-Glycine reactions

As a model reaction for peptide and bond formation, the S_N2 reactions between glycine and ammonia have been studied with and without amine catalysis: using ab initio molecular-orbital methods. For each of the catalyzed and uncatalyzed reactions, two reaction mechanisms have been examined: a two-step and a concerted mechanism. The stationary points of each reaction, including intermediate and transition states, have been identified and free energies calculated for all geometry-optimized reaction species to determine the thermodynamics and kinetics of the reaction. The calculations demonstrate that a second ammonia molecule catalyzes amide bond formation, and that the two-step mechanism is more favorable than the concerted one for the catalyzed reaction, while for the uncatalyzed reaction both mechanisms are competitive.     

Is the peptide bond formation activated by Cu(2+) interactions? Insights from density functional calculations

The catalytic role that Cu(2+) cations play in the peptide bond formation has been addressed by means of density functional calculations. First, the Cu(2+)-(glycine)2 --> Cu(2+)-(glycylglycine) + H2O reaction was investigated since mass spectrometry low collision activated dissociation (CAD) spectra of Cu(2+)-(glycine)2 led to the elimination of a water molecule, which suggested that an intracomplex peptide bond formation might have occurred. Results show that this intracomplex condensation is associated to a very high free energy barrier (97 kcal mol(-1)) and reaction free energy (66 kcal mol(-1)) because of the loss of metal coordination during the reaction. Second, on the basis of the salt-induced peptide formation theory, the condensation reaction between two glycines was studied in aqueous solution using discrete water molecules and the conductor polarized continuum model (CPCM) continuous method. It is found that the synergy between the interaction of glycines with Cu(2+) and the presence of water molecules acting as proton-transfer helpers significantly lower the activation barrier (from 55 kcal/mol for the uncatalyzed system to 20 kcal/mol for the Cu(2+) solvated system) which largely favors the formation of the peptide bond.     

Catalyzed Peptide Bond Formation in the Gas Phase. Role of Bivalent Cations and Water in Formation of 2-Aminoacetamide from Ammonia and Glycine and in Dimerization of Glycine

The formation of 2-aminoacetamide from ammonia and glycine and N-glycylglycine from two glycine molecules with and without Mg²⁺, Cu²⁺, and Zn²⁺ cations as catalysts have been studied as model reactions for peptide bond formation using the B3LYP functional with 6–311+G(d,p) and 6–31G(d) basis sets. The B3LYP method was also used to characterize the nine gas–phase complexes of neutral glycine, its amide (2-aminoacetamide), and N-glycylglycine with Lewis acids Mg²⁺, Cu²⁺, and Zn²⁺, respectively. Further, the gas-phase hydration of metal-coordinated complexes of glycine, 2-aminoacetamide, and N-glycylglycine was also investigated. Finally, the effect of water on the structure and reactivity of the metal coordinated complexes was determined. Enthalpies and Gibbs energies for the stationary points of each reaction have been calculated to determine the thermodynamics of the reactions investigated. A substantial decrease in reaction enthalpies and Gibbs energies was found for glycine–ammonia and glycine–glycine reactions coordinated by Mg²⁺, Cu²⁺, and Zn²⁺ ions compared to those of the uncoordinated 2-aminoacetamide bond formation. The formation of a dipeptide is a more exothermic process than the creation of simple 2-aminoacetamide from glycine. The energetic effect of the transition metal ions Cu²⁺ and Zn²⁺ is of similar strength and more pronounced than that of the Mg²⁺ cation. The basicity order of the amides investigated shows the order: NH₂CH₂CO₂H < NH₂CH₂CONH₂ < NH₂CH₂CONHCH₂CO₂H. Interaction enthalpies and Gibbs energies of metal ion–amide complexes increase as Mg²⁺2+2+. In both reactant (glycine) and reaction products (2-aminoacetamide, N-glycylglycine) dihydration caused considerable reduction (about 200–500 kJ-mol^–1) of the strength of the bifurcated metal–amide bonds. Solvent effects also reduce the reaction enthalpy and Gibbs energy of reactions under study.     

Transition states of amine-catalyzed aldol reactions involving enamine intermediates: theoretical studies of mechanism, reactivity, and stereoselectivity

The mechanisms, transition states, relative rates, and stereochemistries of amine-catalyzed aldol reactions involving enamine intermediates have been explored with density functional theory (B3LYP/6-31G*) and CPCM solvation models. Primary enamine-mediated aldol reactions involve half-chair transition states with hydrogen bonding leading to proton transfer. This leads to charge stabilization and low activation energies as compared to secondary enamine-mediated aldol reactions. Oxetane intermediates can be formed when C-C bond formation occurs without H-transfer in the transition state. The stereoselectivities of reactions of ketone enamines with aldehydes, including the facial stereoselectivity involving chiral aldehydes, were modeled and compared with experimental results. Transition states for the intramolecular aldol reactions leading to the formation of hydrindanone-beta-ketol and decalone-beta-ketol aldol products showed a preference for the formation of the cis-fused rings, in agreement with experimental results.     

Activation of methane by the iron dimer cation. A theoretical study

A detailed investigation of the reaction mechanisms underlying the observed reactivity of the iron dimer cation with respect to methane has been performed by density functional hybrid (B3LYP) and nonhybrid (BPW91) calculations. Minima and transition states have been fully optimized and characterized along the potential energy surfaces leading to three different exit channels for both the ground and the first excited states of the dimer. A comparison with our previous work covering the reactivity of the Fe(+) monomer was made to underline similarities and differences of the reaction mechanisms. Results show that geometric arrangements corresponding to bridged positions of the ligands with respect to iron atoms are always favored and stabilize intermediates, transition states and products, facilitating their formation. Binding energies of reaction products have been computed and compared with experimental measurements, and ELF analysis of the bond has been performed to rationalize trends as a function of the structure.     

Theoretical examination of Mg(2+)-mediated hydrolysis of a phosphodiester linkage as proposed for the hammerhead ribozyme

The hammerhead ribozyme is an RNA molecule capable of self-cleavage at a unique site within its sequence. Hydrolysis of this phosphodiester linkage has been proposed to occur via an in-line attack geometry for nucleophilic displacement by the 2'-hydroxyl on the adjoining phosphorus to generate a 2',3'-cyclic phosphate ester with elimination of the 5'-hydroxyl group, requiring a divalent metal ion under physiological conditions. The proposed S(N)2(P) reaction mechanism was investigated using density functional theory calculations incorporating the hybrid functional B3LYP to study this metal ion-dependent reaction with a tetraaquo magnesium (II)-bound hydroxide ion. For the Mg(2+)-catalyzed reaction, the gas-phase geometry optimized calculations predict two transition states with a kinetically insignificant, yet clearly defined, pentacoordinate intermediate. The first transition state located for the reaction is characterized by internal nucleophilic attack coupled to proton transfer. The second transition state, the rate-determining step, involves breaking of the exocyclic P-O bond where a metal-ligated water molecule assists in the departure of the leaving group. These calculations demonstrate that the reaction mechanism incorporating a single metal ion, serving as a Lewis acid, functions as a general base and can afford the necessary stabilization to the leaving group by orienting a water molecule for catalysis.     

Theoretical insights into the mechanism of acetylcholinesterase-catalyzed acylation of acetylcholine

Acylation of acetylcholine (ACh) catalyzed by acetylcholinesterase (AChE) has been studied using high-level theoretical calculations on a model system that mimics the reaction center of the enzyme, and compared with uncatalyzed acylation reaction. The geometries of all the intermediates and transition states, activation energies, and solvent effects have been calculated. The calculations predict simultaneous formation of two short-strong hydrogen bonds (SSHB) in the rate-determining transition state structures [the first SSHB involves the hydrogen atom of Ser-200 (H(s)) and another involves the hydrogen atom of His-440 (H(h))]. In the intermediate states, the H-bond corresponding to H(h) involves SSHB, whereas the one corresponding to H(s) does not.     

CuCl2催化（2-甲基辛烷-2，3-二烯-4-基）磷酸乙酯氯代环化反应机理理论研究

采用密度泛函理论（DFT）中的B3LYP方法对CuCl2催化的（2-甲基辛烷-2,3-二烯-4-基）磷酸乙酯氯代环化反应机理进行了理论研究．在6-31＋G（d）基组水平上对反应机理中所有反应物、过渡态、中间体和产物进行了优化,通过能量和振动频率分析以及IRC计算证实了中间体和过渡态的合理性．在相同基组水平上应用自然键轨道（NBO）理论和分子中的原子（AIM）理论分析了复合物的成键特征和轨道间相互作用．反应物R和催化剂CuCl2可通过IA和IB两条可行反应通道生成中间体IM9,控制步骤活化能分别是129．61和142．10kJ／m01．中间体IM9到产物P也有两条反应路径PA和PB,控制步骤活化能分别是179．55和9．83kJ／m01．整个反应机理中IA—PB和IB—PB反应通道可能同时发生,反应控制步骤活化能最低反应通道为IA→PB．     

Understanding the mechanism of the intramolecular stetter reaction. A DFT study

The mechanism of the N-heterocyclic carbene (NHC)-catalyzed intramolecular Stetter reaction of salicylaldehyde 1 to yield chromanone 3 has been theoretically studied at the B3LYP/6-31G** level. This NHC-catalyzed reaction takes place through six elementary steps, which involve: (i) formation of the Breslow intermediate IN2; (ii) an intramolecular Michael-Type addition in IN2 to form the new C-C s bond; and (iii) extrusion of the NHC catalyst from the Michael adduct to yield chromanone 3. Analysis of the relative free energies in toluene indicates that while formation of Breslow intermediate IN2 involves the rate-determining step of the catalytic process, the intramolecular Michael-type addition is the stereoselectivity determining step responsible for the configuration of the stereogenic carbon a to the carbonyl of chromanone 3. An ELF analysis at TSs and intermediates involved in the Michael-type addition allows for the characterization of the electronic changes along the C-C bond-formation.     

Ligand-tuned regioselectivity of a cobalt-catalyzed Diels-Alder reaction. A theoretical study

Quantum chemical calculations at the BP86/def2-SVP levels of theory have been carried out for the reaction pathways of the [Co(L)] (+)-catalyzed Diels-Alder reaction of isoprene with phenylacetylene, with L = dppe, iminA, iminB. The calculations suggest that the reactions take place in a stepwise fashion, starting with the formation of the complex [Co(L)(isoprene)(phenylacetylene)] (+) as precursor for the consecutive C-C bond formation. The actual Diels-Alder ring-closing reaction proceeds as an intramolecular addition of the ligands isoprene and phenylacetylene, yielding a metallacyclic intermediate after generation of the first carbon-carbon bond, which determines the regioselectivity of the reaction. There are four different conformations of the starting complexes [Co(L)(isoprene)(phenylacetylene)] (+) which initiate four different pathways yielding the 1,3-cyclohexadiene product. The energetically most stable conformations do not lead to the reaction pathways that have the lowest activation energies. All conformations and the associated pathways must be considered in order to obtain the kinetically most favorable reaction course. The calculated values for the regioselectivities of the [Co(L)] (+)-catalyzed Diels-Alder reaction agree exceptionally well with the experimental values. The calculations concur with the experimental finding that the para product is kinetically favored for L = dppe while the formation of the meta product is kinetically favored when L = iminA or iminB. The different regioselectivies for L = dppe and L = iminA or iminB come from (a) the steric interactions of the bidentate ligands with the isoprene and phenylacetylene moieties in [Co(L)(isoprene)(phenylacetylene)] (+), which determine the distance between the carbon atoms forming the C-C bond, and (b) the relative energies of the different starting complexes. The first C-C bond formed in the rate-determing step of the [Co(dppe)] (+)-catalyzed reaction yielding the para product is the C4-C1' bond, and for the meta product it is the C1-C1' bond. The opposite order is found for the [Co(iminA)] (+)- and [Co(iminB)] (+)-catalyzed reactions, where the C1-C2' bond formation is the initial step toward the para product, while the C4-C2' bond is first formed in the reaction yielding the meta product. The calculations suggest that a less polar solvent should reduce the preference for formation of the meta product in the [Co(iminA)] (+)- and [Co(iminB)] (+)-catalyzed reactions but would enhance the formation of the para product in the [Co(dppe)] (+)-catalyzed reaction. Experimental tests using toluene as solvent instead of dichloromethane confirm the theoretical predictions.     

A theoretical study of the uncatalyzed and BF3-assisted Baeyer-Villiger reactions

The mechanisms for the uncatalyzed and boron trifluoride (BF3) assisted Baeyer-Villiger reactions between acetone and hydrogen peroxide have been investigated using high level ab initio [MP2 and CCSD(T)] and density functional theory (B3LYP) methods. Both steps in the uncatalyzed reaction are found to have very high transition state energies. It is clear that detectable amounts of the Crieege intermediate or the products cannot be formed without the aid of a catalyst. The main function of BF3 in both the addition step and the rearrangement (migration) step is to facilitate proton transfer. In the addition step the complexation of hydrogen peroxide with BF3 leads to an increased acidity of the attacking OH group, while in the rearrangement step BF3 takes active part in the proton-transfer process. This latter step is found to be rate determining with an activation free energy of 17.7 kcal/mol in organic solution. The products of the reaction are BF2OH, hydrogen fluoride, and methyl acetate. Thus, BF3 is not directly regenerated from the reaction.     

Computational study of the aminolysis of esters. The reaction of methylformate with ammonia

The aminolysis of esters is a basic organic reaction considered as a model for the interaction of carbonyl group with nucleophiles. In the present computational study the different possible mechanistic pathways of the reaction are reinvestigated by applying higher level electronic structure theory, examining the general base catalysis by the nucleophile, and a more comprehensive study the solvent effect. Both the ab initio QCISD/6-31(d,p) method and density functional theory at the B3LYP/6-31G(d) level were employed to calculate the reaction pathways for the simplest model aminolysis reaction between methylformate and ammonia. Solvent effects were assessed by the PCM method. The results show that in the case of noncatalyzed aminolysis the addition/elimination stepwise mechanism involving two transition states and the concerted mechanism have very similar activation energies. However, in the case of catalyzed aminolysis by a second ammonia molecule the stepwise mechanism has a distinctly lower activation energy. All transition states in the catalyzed aminolysis are 10-17 kcal/mol lower than those for the uncatalyzed process.     

C-N bond formation followed by N-Cl bond breaking. One more and unexpected case of the formation of a hydroxamic group via heterolytic bond cleavage

An unexpected and previously unknown reaction sequence in the interactions of the acyl halides with nitrosobenzenes, which involves carbon-nitrogen bond formation followed by heterolytic nitrogen-chlorine bond cleavage giving the corresponding unsubstituted N-phenylalkylhydroxamic acids (or N-phenylarylhydroxamic acids) and chlorine as the products has been observed. The kinetic and other evidence obtained suggest that the carbon-nitrogen bond formation is the consequence of a nucleophilic interaction of an N-phenylchlorohydroxylamine intermediate, formed in the first reaction step, with the acyl halide in the second step of the complex sequence, which leads to an N-acyl-N-chlorophenylhydroxylamine cation intermediate. The key reaction step involves the interaction of an N-acyl-N-chlorophenylhydroxylamine cation intermediate with chloride ion, which leads to the N-Cl heterolytic bond cleavage and the final formation of the hydroxamic group and a molecule of chlorine.     

o-Quinone methide as alkylating agent of nitrogen, oxygen, and sulfur nucleophiles. The role of H-bonding and solvent effects on the reactivity through a DFT computational study

The reactivity of the alkylating agent o-quinone methide (o-QM) toward NH(3), H(2)O, and H(2)S, prototypes of nitrogen-, oxygen-, and sulfur-centered nucleophiles, has been studied by quantum chemical methods in the frame of DF theory (B3LYP) in reactions modeling its reactivity in water with biological nucleophiles. The computational analysis explores the reaction of NH(3), H(2)O, and H(2)S with o-QM, both free and H-bonded to a discrete water molecule, with the aim to rationalize the specific and general effect of the solvent on o-QM reactivity. Optimizations of stationary points were done at the B3LYP level using several basis sets [6-31G(d), 6-311+G(d,p), adding d and f functions to the S atom, 6-311+G(d,p),S(2df), and AUG-cc-pVTZ]. The activation energies calculated for the addition reactions were found to be reduced by the assistance of a water molecule, which makes easier the proton-transfer process in these alkylation reactions by at least 12.9, 10.5, and 6.0 kcal mol(-1) [at the B3LYP/AUG-cc-pVTZ//B3LYP/6-311+G(d,p) level], for ammonia, water, and hydrogen sulfide, respectively. A proper comparison of an uncatalyzed with a water-catalyzed reaction mechanism has been made on the basis of activation Gibbs free energies. In gas-phase alkylation of ammonia and water by o-QM, reactions assisted by an additional water molecule H-bonded to o-QM (water-catalyzed mechanism) are favored over their uncatalyzed counterparts by 5.6 and 4.0 kcal mol(-1) [at the B3LYP/6-311+G(d,p) level], respectively. In contrast, the hydrogen sulfide alkylation reaction in the gas phase shows a slight preference for a direct alkylation without water assistance, even though the free energy difference (DeltaDeltaG(#)) between the two reaction mechanisms is very small (by 1.0 kcal mol(-1) at the B3LYP/6-311+G(d,p),S(2df) level of theory). The bulk solvent effect, evaluated by the C-PCM model, significantly modifies the relative importance of the uncatalyzed and water-assisted alkylation mechanism by o-QM in comparison to the case in the gas phase. Unexpectedly, the uncatalyzed mechanism becomes highly favored over the catalyzed one in the alkylation reaction of ammonia (by 7.0 kcal mol(-1)) and hydrogen sulfide (by 4.0 kcal mol(-1)). In contrast, activation induced by water complexation still plays an important role in the o-QM hydration reaction in water as solvent.     

Ring cleavage of aziridines by difluoroamine: mechanistic insights from ab initio and DFT study

cis-2,3-Dimethylaziridine reacts with difluoroamine to give the corresponding alkene and nitrogen with retention of configuration. We have carried out a DFT study of this reaction to clarify the reaction mechanism by considering a multistep reaction pathway with possible intermediacy of several three- and four-membered cyclic intermediates and transition states (TSs). The energetics of this reaction shows that the reaction takes place in four steps including a three-membered azamine intermediate. Both the energetics and the stereochemical outcome of this reaction rule out the formation of a four-membered diazetine intermediate during the reaction. Although the first N-N bond formation step is rate determining, the final step, asynchronous concerted cleavage of the azamine intermediate, explains the stereochemistry of this reaction. The asynchronous nature of the final step makes the reaction Woodward-Hoffmann allowed, as reported by Yamabe and Minato (J. Phys. Chem. A 2001, 105, 7281). Computations at HF and MP2 levels confirm the same trends in energetics. Single point energy computations at B3LYP, MP2, and QCISD levels with the 6-311++G(d,p) and cc-pVTZ basis sets show that the larger basis sets predict higher free energies of activation and less negative free energies of reaction. Intrinsic reaction coordinate (IRC) analyses reveal the asynchronous nature of the first and the last steps of the reaction. The deamination of trans-2,3-dimethylaziridine was shown to follow a course of reaction similar to that of the cis isomer.     

纤维素热解形成左旋葡聚糖机理的理论研究

采用密度泛函理论UB3LYP/6-31G(d)方法,对模型化合物纤维二糖热解反应机理进行了量子化学理论计算研究。设计了三种可能的热解反应途径,对各种反应的反应物、产物、中间体和过渡态的结构进行了能量梯度全优化,计算了不同温度下热解反应的标准热力学和动力学参数。计算结果表明,糖苷键均裂而形成两个自由基中间体IM₁a和IM₁b,吸收热量为321.26kJ/mol,中间体IM₁a经过渡态TS₁a进一步形成左旋葡聚糖P₁,反应势垒为202.72kJ/mol;与分步反应相比,纤维二糖经过渡态TS₂协同反应直接形成左旋葡聚糖P₁和吡喃葡萄糖P₂的反应势垒低于分步反应的总势垒,其反应势垒为377.54kJ/mol;H⁺的加入有利于糖苷键的断裂,断裂形成的中间体IM₃很难进一步反应形成左旋葡聚糖。     

Proximity effects in monolayer films: kinetic analysis of amide bond formation at the air-water interface using (1)H NMR spectroscopy

The kinetics of amide bond formation in a monolayer film has been studied by proton NMR spectroscopy. Compression of a hexadecyl thioester of N-acetyl glycine (1) and a hexadecyl amide of glycine (2) at the air-water interface produces a single dipeptide product (4) that remains at the surface once formed. Extraction of the reaction mixture from the interface, followed by (1)H NMR spectroscopy, provides quantitative data on the rate of product formation. The kinetics of this reaction was examined as a function of surface pressure, subphase pH, and temperature. The monolayer provides an effective molarity for the reaction of approximately 500 M as compared to the bimolecular reaction of 1 and 4 in chloroform solution. The first-order rate constant for the reaction of 1 and 2 in the monolayer is less than 70-fold slower than k(cat) for condensation of the first amide bond in the enzymatic synthesis of the cyclic antibiotic gramicidin S by gramicidin S synthetase. Activation energies of the reaction were extracted from the temperature dependence of the rate constants of the reaction and are 9.9 +/- 1.0 and 2.1 +/- 0.2 kcal/mol for the chloroform solution and monolayer reactions, respectively. The pK(a) of 2 in the monolayer was estimated to be approximately 0.5 pK(a) units lower than that of related amines in solution. The lower pK(a) at the interface as compared to that in solution may be ascribed to increased electrostatic repulsion at the interface relative to solution. The rate of reaction in the monolayer was also followed by monitoring changes in surface area as a function of time. The rate constant for the reaction of 1 and 4 as determined by changes in surface area differs significantly from the rate determined by NMR. The results indicate that measurements of surface area versus time may yield erroneous rate constants for reactions in monolayers.     

Theoretical study of CH…O hydrogen bond in proton transfer reaction of glycine

Density functional theory (DFT) calculations are used to study the strength of the CH…O H‐bond in the proton transfer reaction of glycine. Comparison has been made between four proton transfer reactions (ZW1, ZW2, ZW3, SCRFZW) in glycine. The structural parameters of the zwitterionic, transition, and neutral states of glycine are strongly perturbed when the proton transfer takes place. It has been found that the interaction of water molecule at the side chain of glycine is high in the transition state, whereas it is low in the zwitterionic and neutral states. This strongest multiple hydrogen bond interaction in the transition state reduces the barrier for the proton transfer reaction. The natural bond orbital analysis have also been carried out for the ZW2 reaction path, it has been concluded that the amount of charge transfer between the neighboring atoms will decide the strength of H‐bond. © 2005 Wiley Periodicals, Inc. Int J Quantum Chem, 2006     

DFT study of the mechanism of Cu(I)-catalyzed and uncatalyzed intramolecular cyclopropanation of iodonium ylides

The mechanism of the Cu(I)-catalyzed and uncatalyzed intramolecular cyclopropanation of ketoesteric and diesteric iodonium ylides has been thoroughly explored by means of electronic structure calculation methods (DFT). All crucial reaction steps encapsulated in the entire catalyzed and uncatalyzed reaction pathways were scrutinized, while the elementary steps, the intermediates and transition states were identified through monitoring the geometric and energetic reaction profiles. It was found that CuCl efficiently catalyze the cyclopropanation of iodonium ylides only for their diesteric derivatives and their diazo analogues via stabilization of the respective carbene upon complexation with the metal center. For the ketoesteric iodonium ylides the CuCl catalyst does not affect the kinetics of the intramolecular cyclopropanation reactions which could proceed easily without the catalyst, in line with available experimental observations.