Activation Free Energy Barrier Research Articles

Surface Diffusion of Underpotential‐Deposited Lead Adatoms on Gold Nanoelectrodes

AbstractA simple and readily applicable voltammetric approach is described to characterize and measure the site‐hopping surface diffusion of underpotential‐deposited (UPD) metal adatoms at nanoelectrodes. UPD refers to the deposition of atoms on foreign metal supports at potentials lower than those predicted by Nernst law for a bulk deposition. Despite its importance in several fields of catalysis, advanced nanofabrication or even atomic nanoengineering by atomic layer epitaxy, diffusion of UPD adatoms is difficult to observe at micro‐ and macroelectrodes. In fact, at electrodes of usual dimensions, UPD adatoms surface diffusion is masked by other electrochemical phenomena of greater relative amplitudes. Conversely, at nanowires electrodes sealed in glass, only an extremely small fraction of the surface of the wires is exposed to the electrolyte solution and is rapidly loaded. This allows the spillage of UPD adatoms onto the much larger area of the nanowire rod which is immune to Faradaic reactions due to its isolation from the electrochemical solution by the glass casing. Therefore, surprisingly for a UPD process, voltammetric peaks currents and integral desorption charges primarily reflect these diffusional surface processes so that the integral charges vary linearly with the inverse of the square root of the scan rate. This is easily observable and measurable with usual bench‐level electrochemical instrumentation. In this work, by using nanoelectrodes with diameters between 90 and 260 nm, we were able to establish the major involvement of this site‐hopping surface diffusion of UPD Pb adatoms on polycrystalline gold (Au) and characterize it quantitatively. The equivalent surface diffusion coefficient of UPD Pb adatoms was determined to be ∼4.4×10−11 cm2 s−1 at room temperature, corresponding to a Gibbs free energy activation barrier of ca. 18.72 kJ mol−1 (i. e., 0.19 eV per Pb adatom) for the reaction of inter‐sites exchange of Pb adatoms on a polycrystalline Au surface.

A DFT mechanistic study of two possible hydrolytic evolution pathways of thiamethoxam; implications in food and environmental safety

A detail density functional theoretical mechanistic study of two possible hydrolytic evolution pathways for the degradation of the popular neonicotinoid based pesticide: thaimethoxam, is conducted. Hydrolysis of this compound under conditions of high humidity and neutral pH is highly feasible, occurring via two successive asynchronous cyclic transition states of moderate free energies: 178.15 and 11.57 kJ; energy barriers allowing rapid hydrolysis under warm humid conditions. Alternately, the photo-induced hydrolytic transformation, initiated by excitation of ground state thimethoxam (So→S1:236.6 nm), leads to an overall exergonic degradation process, involving two free-radical followed by two successive non-radical steps; the latter processes occurring via activation free energy barriers of 147.01 and 81.13 kJ, respectively. Though both enthalpy driven pathways occur rapidly, indicating low environmental residence time for this pesticide, the highly stable final product is of unknown toxicity.

Chromatographic separation of the interconverting enantiomers of imidazo- and triazole-fused benzodiazepines

The toolbox of medicinal chemists includes the 1,4-benzodiazepine scaffold as a “privileged scaffold” in drug discovery. Several biologically active small molecules containing a 1,4-benzodiazepine scaffold have been approved by the FDA for the treatment of various diseases, with most of them being used for their psychotropic effects. The therapeutic potential of 1,4-benzodiazepines has stimulated the interest of synthetic chemists in developing new synthetic strategies to a range of substituted analogues for biological evaluation. A structural variation of the classical benzodiazepine skeleton is observed e.g. in alprazolam, midazolam, and related benzodiazepines, which contain a 1,2,4-triazole or an imidazole ring fused to the benzodiazepine core. Irrespective of the presence of the fused heterocyclic ring, the seven-membered diazepine ring is far from planar, and its shape resembles a twist chair. Then, the unsymmetrical substitution pattern around the seven membered cycle renders these molecules chiral, as they lack any reflection-type symmetry element. However, chirality of this molecules is labile at room temperature, becausea simple ring flipping process converts one enantiomer into the other, and 1,4-benzodiazepines exist as a mixture of rapidly interconverting conformational enantiomers in solution at or near room temperature. Physical separation of the interconverting enantiomers of diazepam and of other related 1,4-benzodiazepin-2-ones can be accomplished by low temperature HPLC on chiral stationary phases (CSPs). If the HPLC column is cooled down to temperatures where the interconversion rate is sufficiently low, compared to the chromatographic separation rate, distinct separated peaks can be observed, provided the CSP is sufficiently enantioselctive. The apparent rate constants for the on-column enantiomerization and the corresponding free energy activation barriers were obtained by simulation of exchange-deformed HPLC profiles using a computer program based on the stochastic model. Here we report on the dynamic HPLC investigations carried out on a set of fused imidazo and triazolo-benzodiazepines (alprazolam, midazolam, triazolam and estazolam) The experimental dynamic chromatograms and the corresponding interconversion barriers reported in this paper show that the third fused heterocyclic ring increase the energy barrier by 2 kcal/mol.

Reinvestigation of tandem dimerization and 1,3-alkyl shift in 3-benzylbenzothiazolylidene carbene: Experimental and theoretical results

The reaction of 3-benzylbenzothiazolium bromide with triethylamine generates initially two products as revealed by the TLC. However, on purification, only one compound is obtained, which is the same compound as reported by Baldwin and co-worker. A theoretical investigation at the B3LYP/6–31+G(d) level could identify two possible routes involving successive dimerization and 1,3-benzyl shift of the N-heterocyclic carbene, namely 3-benzylbenzothiazolylidene leading to two isomeric products. The second step is found to be the rate-determining step. The activation free energy barriers of both steps for the isomer actually obtained are comparatively lower than for the other product. Furthermore, the two isomers are found to be atropisomers separated by a small activation free energy barrier which is insufficient to keep the identities of the two isomers intact, with the result that the less stable atropisomer changes into the more stable one. Thus it has been possible to rationalize the experimental results by the theoretical investigation.

The mechanism of conversion of substituted glycals to chiral acenes via Diels-Alder reaction: a computational study.

Synthesis of linearly fused aromatic systems using a glycal-based diene with an aryne is a long-standing topic of interest in glycal chemistry. We have examined the mechanistic pathways for the transformation of substituted glycals to chiral fused aromatic cores via Diels-Alder (DA) reaction using the SMDACN-M06-2X/6-31G(d) level of theory. The DA reactions of E (1a) and Z (1a') forms of C-2 alkenyl glycal and an aryl glycal (1b) as a diene were examined with a benzyne intermediate generated as a dienophile. The computational results reveal that 1a and 1b can only be transformed into the fused aromatic cores by the base-catalyzed reaction because a [1,5] sigmatropic hydrogen shift is not feasible. The activation free energy barrier for the base-catalyzed proton abstraction process is 4.2 kcal mol-1 and there is almost no barrier for stereoisomeric 1a DA-complexes. The activation free energy barrier values for stereoisomeric 1b DA-complexes for the base-catalyzed proton abstraction process are 10.8 and 12.4 kcal mol-1. The appropriate orientation of glycal-ring-oxygen and hydrogen at the 5th position of Z (1a') forms of C-2 alkenyl glycal facilitates the [1,5] sigmatropic hydrogen shift; however, the base-catalyzed reaction is energetically more favored than the former case. The rate-determining step for 1a and 1a' is the ring-opening step (18.2 and 19.5 kcal mol-1 for the S-stereoisomer), whereas the DA adduct formation step is the rate-determining step for 1b (16.1 kcal mol-1 for the S-stereoisomer). The structural analysis reveals the formation of the preferred S-stereoisomer over the R-stereoisomer with the respective dienes.

N-Heterocyclic Carbenes–Cu

The electronic structures of N-heterocyclic carbenes (NHC) imidazolinylidene, thiazolinylidene, imidazolylidene, thiazolylidene, and 1,2,4-triazolylidene and their complexes with cuprous halides (CuX, X = Cl, Br, I) were investigated theoretically at the B3LYP/def2-SVP level. In contrast to other NHCs, imidazolylidene and 1,2,4-triazolylidene do not dimerize owing to the negligible coefficient of the vacant p-orbital at the carbene centre in their respective LUMOs. This is further supported by their greater thermodynamic and kinetic stabilities revealed by greater activation free energies and smaller standard free energies for their dimerization. Second-order perturbation interactions in the natural bond orbital (NBO) analysis of the NHCs indicate that six π electrons are delocalized in imidazolylidene, thiazolylidene, and 1,2,4-triazolylidene, conferring aromatic character and thereby enhancing their thermodynamic stability. NBO analysis reveals the existence of effective back bonding from a d orbital of Cu to the NHC, increasing the Wiberg bond index of the C–Cu bond to ~1.5. Owing to the large electronic chemical potential (μ) and high nucleophilicity indices, NHCs are able to transfer their electron density effectively to the cuprous halides having low μ values and high electrophilicity indices to yield stable NHC–CuI complexes. Large values of the Fukui function f(r) at the carbene centre of the NHCs and Cu atom of the NHC–CuI complexes indicate their softness. Imidazolylidene was found to be the softest, rationalizing wide use of this class of NHCs as ligands. The coordination of the NHCs to cuprous halides is either barrierless or has a very low activation free energy barrier. In the A3 reaction wherein NHC–Cu(I) complexes are used as catalyst, the reaction of NHC–CuI with phenylacetylene changes the latter into acetylide accompanied by raising the energy level of its HOMO considerably compared with the level of the uncomplexed alkyne, making its reaction with benzaldehyde barrierless.

Mechanistic Insights into the Conversion of Biorenewable Levoglucosanol to Dideoxysugars

A molecular understanding of the conversion of biorenewable threo- and erythro-levoglucosanol (LGOL) to 3,4-dideoxysugars in aqueous medium is provided based on first-principles simulations. The synthetic importance of this transformation is that these intermediates can be quantitatively hydrogenated to (S,S)/(S,R) hexane-1,2,5,6-tetrol (tetrol), whose stereochemistry depends on which dideoxy sugar intermediates are formed during LGOL conversion. The thermodynamic and kinetic feasibility of the acetal (R₂C(OR)₂) hydrolysis in LGOL is investigated via computing the free energy profile. In aqueous medium, the rate-determining step of LGOL hydrolysis is the protonation of the anhydro-bridge oxygen atom of LGOL concurrent with ring opening, yielding the cyclic forms of 3,4-dideoxymannose (DDM) and 3,4-dideoxyglucose (DDG) from threo- and erythro-LGOL, respectively. The measured activation energies of LGOL hydrolysis are 20.5 and 23.6 kcal/mol for DDM and DDG formation, respectively. These values are in agreement with the computed protonation free energies of 17.1 and 18.2 kcal/mol, respectively. Based on the simulations, a Bronsted base-catalyzed isomerization from DDG or DDM to 3,4-dideoxy fructose (DDF) is preferred with lower apparent activation free energy barriers compared to the acid-catalyzed isomerization. In summary, this study provides mechanistic information about the conversion of the biomass-derived anhydro-sugar LGOL to 3,4-dideoxy sugars, which are precursors to renewable high-value chemicals.

Generation and trapping of non-aromatic cycloimines via diazotization/dediazotization of N-amino cyclic amines: theoretical and experimental results

A theoretical investigation of the model diazotization/dediazotization of N-aminopiperidine and N-aminomorpholine at the DFT (B3LYP/6-31+G(d)) level indicated that the corresponding cycloimines can be generated transiently, which can be trapped with dimethyl acetylenedicarboxylate (DMAD) to form a 1,4-dipole followed by cycloaddition of the latter with a second molecule of DMAD to give the corresponding pyrido-annelated products. All steps have low activation free energy barriers and are thermodynamically favoured. Based on the theoretical results, we carried out successfully diazotization of N-amino cyclic amines, namely N-aminopiperidine, 4-aminomorpholine and 1-amino-4-methylpiperazine with tert.-butyl nitrite followed by dediazotization to generate transiently the corresponding cycloimines, which could be trapped with dimethyl acetylenedicarboxylate. to afford new annelated pyridine derivatives, namely tetramethyl 9H-5,6,7,8-tetrahydroquinolizine-1,2,3,4-tetracarboxylate, tetramethyl 5,6,8,9-tetrahydropyrido[2,1-c][1,4]oxazine-1,2,3,4-tetracarboxylate and tetramethyl 9H-5,6,7,8-tetrahydro-7-methylpyrido[1,2-a]pyrazine-1,2,3,4-tetracarboxylate which were duly characterized.

Potential of Mean Force Calculations for an SN2 Fluorination Reaction in Five Different Imidazolium Ionic Liquid Solvents Using Quantum Mechanics/Molecular Mechanics Molecular Dynamics Simulations.

The use of ionic liquids (ILs) as both catalysts and solvents in a wide range of chemical reactions has received considerable attention over the last few years due to their positive effects in enhancing reaction rates and selectivities. In this work, hybrid quantum mechanics/molecular mechanics (QM/MM) molecular dynamics simulations were carried out in conjunction with umbrella-sampling techniques to study the bimolecular nucleophilic substitution (SN2) fluorination reaction between propyl-mesylate and potassium fluoride using five ILs as solvents, specifically, 1-butyl-3-methylimidazolium mesylate ([C4mim][OMs]), 1-butyl-3-methylimidazolium tetrafluoroborate ([C4mim][BF4]), 1-butyl-3-methylimidazolium trifluoroacetate ([C4mim][CF3COO]), 1-butyl-3-methylimidazolium bromide ([C4mim][Br]), and 1-butyl-3-methylimidazolium chloride ([C4mim][Cl]) at 373.15 K. The QM region (reactive part) in all QM/MM systems was simulated using the Parametric Method 6 (PM6) semiempirical methods, and for the MM region (IL solvent), classical force fields (FF) were employed, with the FF developed within the group. The calculated activation free energy barriers (ΔG‡) for the SN2 reaction in the presence of [C4mim][OMs] and [C4mim][BF4] ILs were in agreement with the experimental values reported in the literature. On the other hand, only predicted values were obtained for the activation energies for the [C4mim][CF3COO], [C4mim][Br], and [C4mim][Cl] ILs. These activation energies indicated that the SN2 reaction would be more facile to proceed using the [C4mim][Cl] and [C4mim][OMs] ILs, in contrast with the use of [C4mim][Br] IL, which presented the highest activation energy. Energy-pair distributions, radial distribution functions, and noncovalent interactions (NCI) were also calculated to elucidate the molecular interactions between the reactive QM region and the solvents or reaction media. From these calculations, it was found that not only the reactivity can be enhanced by selecting a specific anion to increase the K-F separation but also the cation plays a relevant role, producing a synergetic effect by forming hydrogen bonds with the fluorine atom from KF and with the oxygen atoms within the mesylate leaving group. Three interactions are significant for the IL catalytic behavior, FQM-HX, KQM-anion, and OQM-HX interactions, where the FQM and KQM labels correspond to fluorine and potassium atoms from the KF salt, OQM corresponds to oxygen atoms within the mesylate leaving group (reactant), and HX refers to hydrogen atoms within the IL cation. The NCI analysis revealed that KQM-anion interactions are of weak type, indicating the importance of hydrogen bond interactions from the cation such as FQM-HX and OQM-HX for the catalytic behavior of ILs.

Accurate Diels-Alder Energies and Endo Selectivity in Ionic Liquids Using the OPLS-VSIL Force Field.

Our recently developed optimized potentials for liquid simulations-virtual site ionic liquid (OPLS-VSIL) force field has been shown to provide accurate bulk phase properties and local ion-ion interactions for a wide variety of imidazolium-based ionic liquids. The force field features a virtual site that offloads negative charge to inside the plane of the ring with careful attention given to hydrogen bonding interactions. In this study, the Diels-Alder reaction between cyclopentadiene and methyl acrylate was computationally investigated in the ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate, [BMIM][PF6], as a basis for the validation of the OPLS-VSIL to properly reproduce a reaction medium environment. Mixed ab initio quantum mechanics and molecular mechanics (QM/MM) calculations coupled to free energy perturbation and Monte Carlo sampling (FEP/MC) that utilized M06-2X/6-31G(d) and OPLS-VSIL gave activation free energy barriers of 14.9 and 16.0 kcal/mol for the endo-cis and exo-cis Diels-Alder reaction pathways, respectively (exptl. ΔH‡ of 14.6 kcal/mol). The endo selectivity trend was correctly predicted with a calculated 73% endo preference. The rate and selectivity enhancements present in the endo conformation were found to arise from preferential hydrogen bonding with the exposed C4 ring hydrogen on the BMIM cation. Weaker electronic stabilization of the exo transition state was predicted. For comparison, our earlier ±0.8 charge-scaled OPLS-2009IL force field also yielded a ΔG‡ of 14.9 kcal/mol for the favorable endo reaction pathway but did not adequately capture the highly organized solvent interactions present between the cation and Diels-Alder transition state.

B(C6F5)3/Chiral Phosphoric Acid Catalyzed Ketimine–Ene Reaction of 2‐Aryl‐3H‐indol‐3‐ones and α‐Methylstyrenes

AbstractThe enantioselective ketimine–ene reaction is one of the most challenging stereocontrolled reaction types in organic synthesis. In this work, catalytic enantioselective ketimine–ene reactions of 2‐aryl‐3H‐indol‐3‐ones with α‐methylstyrenes were achieved by utilizing a B(C6F5)3/chiral phosphoric acid (CPA) catalyst. These ketimine–ene reactions proceed well with low catalyst loading (B(C6F5)3/CPA=2 mol %/2 mol %) under mild conditions, providing rapid and facile access to a series of functionalized 2‐allyl‐indolin‐3‐ones with very good reactivity (up to 99 % yield) and excellent enantioselectivity (up to 99 % ee). Theoretical calculations reveal that enhancement of the acidity of the chiral phosphoric acid by B(C6F5)3 significantly reduces the activation free energy barrier. Furthermore, collective favorable hydrogen‐bonding interactions, especially the enhanced N−H⋅⋅⋅O hydrogen‐bonding interaction, differentiates the free energy of the transition states of CPA and B(C6F5)3/CPA, thereby inducing the improvement of stereoselectivity.

B(C6 F5 )3 /Chiral Phosphoric Acid Catalyzed Ketimine-Ene Reaction of 2-Aryl-3H-indol-3-ones and α-Methylstyrenes.

The enantioselective ketimine-ene reaction is one of the most challenging stereocontrolled reaction types in organic synthesis. In this work, catalytic enantioselective ketimine-ene reactions of 2-aryl-3H-indol-3-ones with α-methylstyrenes were achieved by utilizing a B(C6 F5 )3 /chiral phosphoric acid (CPA) catalyst. These ketimine-ene reactions proceed well with low catalyst loading (B(C6 F5 )3 /CPA=2 mol %/2 mol %) under mild conditions, providing rapid and facile access to a series of functionalized 2-allyl-indolin-3-ones with very good reactivity (up to 99 % yield) and excellent enantioselectivity (up to 99 % ee). Theoretical calculations reveal that enhancement of the acidity of the chiral phosphoric acid by B(C6 F5 )3 significantly reduces the activation free energy barrier. Furthermore, collective favorable hydrogen-bonding interactions, especially the enhanced N-H⋅⋅⋅O hydrogen-bonding interaction, differentiates the free energy of the transition states of CPA and B(C6 F5 )3 /CPA, thereby inducing the improvement of stereoselectivity.

Predicting Ionic Diffusion in Glass from Its Relaxation Behavior.

In low-viscosity liquids, diffusion is inversely related to viscosity via the Stokes-Einstein relation. However, the Stokes-Einstein relation breaks down near the glass transition as the supercooled liquid transitions into the non-ergodic glassy state. The nonequilibrium viscosity of glass is governed by the liquid-state viscous properties, namely, the glass transition temperature and the fragility. Here, a model is derived to predict the ionic diffusivity of a glass from its nonequilibrium viscosity, accounting for the compositional dependence of the glass. The free energy activation barrier for diffusion is related to the activation enthalpy for viscous flow using the Mauro-Allan-Potuzak model of nonequilibrium viscosity [Mauro, J. C.; Allan, D. C.; Potuzak, M. Nonequilibrium Viscosity of Glass. Phys. Rev. B 2009, 80, 094204]. These insights allow for accurate prediction of activation barriers for diffusion of alkali ions. The model is supported by experimental results and nudged-elastic band calculations applied to sodium silicate and borate glasses.

Elucidating the role of solvents in acid catalyzed dehydration of biorenewable hydroxy-lactones

Utilizing the differential stabilization of reactant and transition state in the polar and apolar solvents to lower the activation free energy barrier for acid-catalyzed dehydration of hydroxy lactones.

Proton Acceptor near the Active Site Lowers Dramatically the O-O Bond Formation Energy Barrier in Photocatalytic Water Splitting.

The O–O bond formation process via water nucleophilic attack represents a thermodynamic and kinetic bottleneck in photocatalytic water oxidation because of the considerably high activation free energy barrier. It is therefore of fundamental significance and yet challenging to find strategies to facilitate this reaction. The microscopic details of the photocatalytic water oxidation step involving the O–O bond formation in a catalyst–dye supramolecular complex are here elucidated by density functional theory-based Car–Parrinello molecular dynamics simulations in the presence of an extra proton acceptor. Introducing a proton acceptor group (OH–) in the hydration shell near the catalytic active site accelerates the rate-limiting O–O bond formation by inducing a cooperative event proceeding via a concerted proton-coupled electron-transfer mechanism and thus significantly lowering the activation free energy barrier. The in-depth insight provides a strategy for facilitating the photocatalytic water oxidation and for improving the efficiency of dye-sensitized photoelectrochemical cells.

The theoretical study of dehydrogenation mechanism from Sr(NH2BH3)2

A first-principle study of dehydrogenation mechanism from Sr(NH2BH3)2 was performed. Three different pathways were explored for Sr(NH2BH3)2 monomer, and the most favorable dehydrogenation pathway involved the formation of the Sr-H group firstly, and then becoming the key hydride source for the consecutive H2 evolution. The intrinsic activation free energy barriers were 29.2, 30.7, 42.7, and 42.4 kcal/mol for four equivalent of H2 release at 298.15 K, which were slightly decreased by 0.3~2 kcal/mol at experimental temperature 333 and 366 K. For Sr(NH2BH3)2 dimer, the estimated intrinsic free energy barriers are 22.7, 30.4, 40.1, and 45.4 kcal/mol for four equivalent of H2 release, respectively. Although it seemed that the energy barriers for the second equivalent of H2 were still higher, considering the energy gain in the formation of dimer, − 18.1 kcal/mol, the first two equivalents of H2 release easily took place at experiment temperature. Thus, our calculations indicated that the most favorable dehydrogenation mechanism involved the strongly basic H− from Sr-H acting as a hydride source to accelerate the H2 release, and the effect of neighboring molecules in the solid phase should not be neglected. These results will shed some light on the design of the future hydrogen storage media.

Photocatalytic Water Splitting Cycle in a Dye-Catalyst Supramolecular Complex: Ab Initio Molecular Dynamics Simulations

A dye-sensitized photoelectrochemical cell (DS-PEC) is a promising device for direct conversion of solar energy into fuel. The basic idea, inspired by natural photosynthesis, is to couple the photoinduced charge separation process to catalytic water splitting. The photo-oxidized dye coupled to a water oxidation catalyst (WOC) should exert a thermodynamic driving force for the catalytic cycle, while water provides the electrons for regenerating the oxidized dye. These conditions impose specific energetic constraints on the molecular components of the photoanode in the DS-PEC. Here, we consider a supramolecular complex integrating a mononuclear Ru-based WOC with a fully organic naphthalene-diimide (NDI) dye that is able to perform fast photoinduced electron injection into the conduction band of the titanium-dioxide semiconductor anode. By means of constrained ab initio molecular dynamics simulations in explicit water solvent, it is shown that the oxidized NDI provides enough driving force for the whole photocatalytic water splitting cycle. The results provide strong evidence for the significant role of spin alignment and solvent rearrangement in facilitating the proton-coupled electron transfer processes. The predicted activation free energy barriers confirm that the O–O bond formation is the rate-limiting step. Our results expand the current understanding of the photocatalytic water oxidation mechanism and provide guidelines for the optimization of high-performance DS-PEC devices.

Hybrid discrete‐continuum solvation methods

AbstractHybrid discrete‐continuum approaches for solvation have been widely applied for diverse problems in chemistry suck as pKa calculation in aqueous and nonaqueous solvents, activation free energy barriers for ionic processes in solution, and surface reactions. A special version of this approach, the cluster‐continuum quasichemical model, has also been used for establishing a single‐ion solvation free energy scale in different solvents compatible with the tetraphenylarsonium tetraphenylborate assumption. The use of discrete‐continuum solvation methods can lead to meaningful improvement with respect to pure continuum solvation models for modeling diverse chemical process in solution. In the case of pKa calculations, there are cases where the root mean squared error is as large as 7 pKa units with pure continuum solvation model and becomes around 1 pKa unit with the hybrid approach. For complex reactions in solution, errors as large as 10 kcal/mol for activation free energies with the pure continuum approach can be substantially reduced with the inclusion of explicit solvent molecules. A discussion of the theory of hybrid discrete‐continuum methods is also presented and further development is expected in the coming years.This article is categorized under:Structure and Mechanism > Reaction Mechanisms and CatalysisSoftware > Quantum ChemistryMolecular and Statistical Mechanics > Free Energy Methods

Human Acetyl-CoA Carboxylase 1 Is an Isomerase: Carboxyl Transfer Is Activated by Catalytic Effect of Isomerization.

Obesity and its related diseases such as cancer and diabetes are leading life-threatening issues in the modern world. Thus, new drugs toward obesity and obesity-caused diseases are highly desired. Human acetyl-CoA carboxylase 1 (hACC1) in charge of the rate-limiting step of the human fatty acid synthesis was recognized as an attractive target for rational drug design. The fundamental reaction mechanism and nature of the transition state of hACC1 remain unclear. In this study, combined quantum mechanics and molecular mechanics (QM/MM), molecular dynamics (MD), and free-energy simulations were performed to investigate the catalytic mechanism of the hACC1-catalyzed carboxyl-transfer reaction. Our computational results show a three-step mechanism for carboxyl transferase (CT)-catalyzed reaction, including isomerization of carboxybiotin, proton-transfer from acetyl-CoA to carboxybiotin, and carboxylation of acetyl-CoA enolate. Interestingly, isomerization of carboxybiotin is the rate-limiting step of the entire reaction pathway, indicating hACC1 has the catalytic effect of isomerization and thus might be an isomerase also. The activation free-energy barrier of carboxyl-transfer catalyzed by hACC1 was calculated to be 16.4 kcal/mol, in excellent agreement with the experimental result (16.7 kcal/mol). The obtained reaction mechanism together with the nature of the transition state provides helpful knowledge not only for future investigation of other ACCs but also for rational design of hACC1 inhibitors, such as TS analogue. The catalytic effect of hACC1 isomerization is discussed.

A comparative study of the counterion effect on the perrhenate-catalyzed deoxydehydration reaction

Counterions have a significant effect on the efficiency of the deoxydehydration (DODH) reaction. Four perrhenate salts, Z+ReO4− (Z = Na+, K+, NH4+, and Bu4N+), were tested in the DODH reaction of a vicinal diol in the presence of PPh3 as the reductant. In addition, a new perrhenate salt, (2-ppyH)[ReO4] (2-ppyH+ = 2-phenylpyridinium cation), has been synthesized and characterized by X-ray crystallography and utilized as an efficient catalyst in the DODH reaction. Since so far computational studies related to the influence of the counterion in the different steps of the DODH mechanism are scarce, we have carried out a comparative investigation of the counterion effect using density functional theory (DFT) calculations. The DODH mechanism of the conversion of phenyl-1,2-ethanediol to styrene in the presence of the five perrhenate salts mentioned above, as well as bare perrhenate (ReO4−) was studied from an energetic point of view. The catalytic tests and concomitant DFT computations confirmed the general mechanistic aspect in which the counterion plays an active role in all stages of the reaction mechanism including intermediate structures, Gibbs free energy changes (ΔG°g and ΔG°sol), transition states, and activation barrier energies. The role of counterion type has been considered in three key steps of the reaction mechanism, including the proton-transfer from diol to oxo-ligand in the rhenium moiety, the nucleophilic attack of the P atom from PPh3 on the oxo-ligand, the dissociation of the OPPh3 ligand, and the olefin extrusion from the Re(V)-diolate intermediate for each perrhenate salt. The crucial roles played by the counterion in terms of structure arrangement during transition states and the activation energy barriers are finally discussed.