Benchmark approach to search of cost-effective and accurate density functional for homolytic cleavage of C─Mg bond of Grignard reagent

Grignard reactions are of importance in organic chemistry for the synthesis β-keto esters and diethyl malonate, alcohols, aldehydes or ketones, monocarboxylic acids, and other organometallic compounds. Generally, the heterolytic dissociation of C─Mg bond in Grignard reagent is the key step in these reactions. Recently, homolytic cleavage of the C─Mg bond in Grignard reagents has been reported in the preparation of stable radicals. These reactive species react with other compounds, which result in the formation of hydrocarbons and their derivatives. Therefore, the study of homolytic cleavage of C─Mg bonds is quite vital to better understand the kinetics and thermodynamics of these reactions. In the current study, a benchmark approach is adopted to find a cost-effective and accurate density functional (DF) for bond dissociation energies measurement of the C─Mg bond of Grignard reagents. Twenty-nine DFs from 13 density functional theory (DFT) classes with three types of basis sets (Pople' 6-31G(d) and 6-311G(d), Dunning's aug-cc-pVDZ, and Karlsruhe' def2-SVP basis sets) are implemented for the measurement of dissociation energies of the C─Mg bond. Theoretical dissociation energy values are compared with experimental reported values of the C─Mg bond of selected Grignard reagents. TPSSTPSS of the meta-GGA class with 6-31G (d) basis set gave accurate results, and its Pearson's correlation is 0.95. SD, root mean square deviation, and mean unsigned error of this method are 2.36 kcal mol⁻¹, 2.33 kcal mol⁻¹, and −0.46 kcal mol⁻¹, respectively. TPSSTPSS of the meta-GGA class is a one-electron, self-interaction, error-free Tao-Perdew-Staroverov-Scuseria functional that performed better with the 6-31G(d) basis set.     

Highly reusable support‐free copper(II) complex of para‐hydroxy‐substituted salen: Novel,efficient and versatile catalyst for C─N bond forming reactions

An air‐stable, highly active and versatile method for C─N bond forming reactions is reported. Under mild conditions using a highly reusable support‐free Cu(II)–salen complex, structurally diverse N ‐aryl‐substituted compounds were obtained via direct C─N bond forming reaction of HN‐heterocycles with aryl iodides or three‐component C─N bond forming reaction of 2‐bromobenzaldehyde, aniline derivatives and sodium azide in good to excellent yields. C─N bond forming reaction for benzimidazole derivatives was also performed in the presence of the catalyst under ambient conditions. A series of hybrid benzimidazoles bearing morpholine, tetrazole and quinoxaline backbones were produced using this method. All reactions were performed in short times under air. The Cu(II) catalyst could be reused up to eight times in the direct cross‐coupling reaction of 9H –carbazole with iodobenzene without any decrease in its catalytic activity.     

Cytosine catalysis of nitrosative guanine deamination and interstrand cross-link formation

Effects are discussed of the anisotropic DNA environment on nitrosative guanine deamination based on results of an ab initio study of the aggregate 3 formed by guaninediazonium ion 1 and cytosine 2. Within 3, the protonation of 2 by 1 is fast and exothermic and forms 6, an aggregate between betaine 4 (2-diazonium-9H-purin-6-olate) and cytosinium ion 5. Electronic structure analysis of 4 shows that this betaine is not mesoionic; only the negative charge is delocalized in the pi-system while the positive charge resides in the sigma-system. Potential energy surface exploration shows that both dediazoniation and ring-opening of betaine 4 in aggregate 6 are fast and exothermic and lead irreversibly to E-11, the aggregate between (E)-5-cyanoimino-4-oxomethylene-4,5-dihydroimidazole E-10 and 5. The computed pair binding energies for 3, 6, and E-11 greatly exceed the GC pair binding energy. While 1 can be a highly reactive intermediate in reactions of the "free nucleobase" (or its nucleoside and nucleotide), the cyanoimine 10 emerges as the key intermediate in nitrosative guanine deamination in ds-DNA and ds-oligonucleotides. In essence, the complementary nucleobase cytosine provides base catalysis and switches the sequence of deprotonation and dediazoniation. It is argued that this environment-induced switch causes entirely different reaction paths to products as compared to the respective "free nucleobase" chemistry, and the complete consistency is demonstrated of this mechanistic model with all known experimental results. Products might form directly from 10 by addition and ring closure, or their formation might involve water catalysis via 5-cyanoamino-4-imidazolecarboxylic acid 12 and/or 5-carbodiimidyl-4-imidazolecarboxylic acid 13. The pyrimidine ring-opened intermediates 10, 12, and 13 can account for the formations of xanthosine, the pH dependency and the environment dependency of oxanosine formation, the formation of the classical cross-link dG(N(2)())-to-dG(C2), including the known sequence specificity of its formation, and the formation of the structure-isomeric cross-link dG(N1)-to-dG(C2).     

MoP(001)表面苯胺C―N键断裂机理

油品脱氮可以减少燃烧过程中氮氧化物的排放,并且减弱催化剂的中毒现象,过渡金属磷化物因具有高催化活性和优异的稳定性而成为最具应用前景的新型加氢脱氮(HDN)催化剂。本工作基于周期性平板模型,通过密度泛函理论(DFT)计算研究了苯胺在磷化钼(MoP)(001)表面的吸附以及C―N断键机理。结果表明在MoP(001)表面,苯胺吸附以平躺吸附构型为主,有较大的吸附能,C―C键和C―N键均被吸附活化;苯胺C―N键的直接断裂路径主要起始于与共吸附H_2发生反应,产物为苯和氨,吸附的环己胺的C―N键断裂主要路径是环己胺与共吸附的H发生反应脱去氨基,生成产物为环己烯和氨。     

Substituent Effects on Site Selectivity (C=C vs C=N) in Heterocumulene-Heterodiene [4 + 2] Cycloadditions: Density Functional and Semiempirical AM1 Molecular Orbital Calculations

The effect of substituents on the site selectivity (C=C vs C=N) in the [4 + 2] cycloaddition between heterocumulenes (ketene imines) 2a-g with heterodienes (acroleines 9a-n and 4-acylfuran-2,3-diones 1a-d) is treated by semiempirical AM1 molecular orbital and density functional calculations using Becke's three-parameter hybrid method (B3LYP/6-31G). For some reactions calculations were also done at the B3LYP/6-31+G level of theory. For reaction of the oxa 1,3-dienes with ketene imines unsubstituted at the terminal carbon invariably addition across the C=C heterocumulene double bond has a lower activation energy than addition across the C=N double bond. Substitution of methyl or especially phenyl groups at the ketene imine C-terminus leads to a reversal of the respective activation energies. Incorporation of the oxa 1,3-diene system into the heterocyclic dione 1 substantially enhances the reactivity ( approximately 10 kcal mol(-1) lower activation energies) as compared to similarly substituted acroleins. At the DFT level of theory all reactions are found to proceed via a concerted asynchronous mechanism.     

Quantum mechanics study and Monte Carlo simulation on the hydrolytic deamination of 5-methylcytosine glycol

The efficient formation of 5-methylcytosine glycol (mCg) and its facile deamination to thymine glycol (Tg) may account for the prevalent C → T transition mutation found at methylated CpG site (mCpG) in human p53 gene, a hallmark for many types of human tumors. In this work, the hydrolytic deamination of mCg was investigated at the MP2 and B3LYP levels of theory using the 6-311G(d,p) basis set. In the gas phase, three pathways were explored, paths A-C, and it indicates that the direct deamination of mCg with H(2)O by either pathway is unlikely because of the high activation free energies involved in the rate-determining steps, the formation of the tetrahedral intermediate for paths A and B as well as the formation of the Tg tautomer for path C. In aqueous solution, the role of the water molecules in the deamination of mCg with H(2)O was analyzed in two separate parts: the direct participation of one water molecule in the reaction pathway, called the water-assisted mechanism; and the complementary participation of the aqueous solvation. The water-assisted mechanism was carried out for mCg and the cluster of two water molecules by quantum mechanical calculations in the gas phase. This indicates that the presence of the auxiliary water molecule significantly contributes to decreasing all the activation free energies. The bulk solution effect on the water-assisted mechanism was included by free energy perturbation implemented on Monte Carlo simulations, which is found to be substantial and decisive in the deamination mechanism of mCg. In this case, the water-assisted path A is the most plausible mechanism reported for the deamination of mCg, where the calculated activation free energy (22.6 kcal mol(-1) at B3LYP level of theory) agrees well with the experimentally determined activation free energy (24.8 kcal mol(-1)). The main striking results of the present DFT computational study which is in agreement with previous experimental data is the higher rate of deamination displayed by mCg residues with respect to 5-methylcytosine (mC) bases, which supports that the deamination of mCg contributes significantly to the C → T transition mutation at mCpG dinucleotide site.     

Remarkably strong polarization of amidine fragment in the crystals of 1-imino-1H-isoindol-3-amine

Results of the X-ray diffraction studies of 1-imino-1H-isoindol-3-amine and its derivatives reveal unusual distribution of bond lengths within the NH₂–C=N amidine fragment in the considered crystals. In the crystal phase, single C–N bond is shorter or at most has the same length as double C=N bond, while in isolated molecules both these bonds have expected lengths, according to the calculations by MP2/6-311G(d,p) and MP2/cc-pvtz methods. It is demonstrated that so unusually strong polarization of the amidine fragment is induced by polar environment in solid state. This effect stabilizes the amino-imino tautomer of 1-imino-1H-isoindol-3-amine, which becomes more stable than the diimino tautomer possessing the lowest energy in the gas phase.     

Electron Attachment to Hydrated Oligonucleotide Dimers: Guanylyl‐3′,5′‐Cytidine and Cytidylyl‐3′,5′‐Guanosine

The dinucleoside phosphate deoxycytidylyl‐3′,5′‐deoxyguanosine (dCpdG) and deoxyguanylyl‐3′,5′‐deoxycytidine (dGpdC) systems are among the largest to be studied by reliable theoretical methods. Exploring electron attachment to these subunits of DNA single strands provides significant progress toward definitive predictions of the electron affinities of DNA single strands. The adiabatic electron affinities of the oligonucleotides are found to be sequence dependent. Deoxycytidine (dC) on the 5′ end, dCpdG, has larger adiabatic electron affinity (AEA, 0.90 eV) than dC on the 3′ end of the oligomer (dGpdC, 0.66 eV). The geometric features, molecular orbital analyses, and charge distribution studies for the radical anions of the cytidine‐containing oligonucleotides demonstrate that the excess electron in these anionic systems is dominantly located on the cytosine nucleobase moiety. The π‐stacking interaction between nucleobases G and C seems unlikely to improve the electron‐capturing ability of the oligonucleotide dimers. The influence of the neighboring base on the electron‐capturing ability of cytosine should be attributed to the intensified proton accepting–donating interaction between the bases. The present investigation demonstrates that the vertical detachment energies (VDEs) of the radical anions of the oligonucleotides dGpdC and dCpdG are significantly larger than those of the corresponding nucleotides. Consequently, reactions with low activation barriers, such as those for O? C σ bond and N‐glycosidic bond breakage, might be expected for the radical anions of the guanosine–cytosine mixed oligonucleotides.     

CH3N3与C60(NCH3)2作用生成三氮杂富勒烯衍生物的反应机理

利用AM1半经验算法和密度泛函理论, 研究了CH3N3进攻C60(NCH3)2生成三氮杂富勒烯衍生物C60(NCH3)3的反应机理及区域选择性. 计算结果表明, CH3N3加成在C60(NCH3)2的两个不同位置的5/6单键上的反应均遵循分步机理. 反应途径上都存在3个过渡态和3个中间体. 从整个反应活化能、表观活化能以及速控步活化能来看, 生成稳定产物的反应并不占优势.     

Theoretical study on the hydrolysis mechanism of N,N-dimethyl-N'-(2-oxo-1, 2-dihydro-pyrimidinyl)formamidine: water-assisted mechanism and cluster-continuum model

The hydrolysis reaction of N,N-dimethyl-N'-(2-oxo-1, 2-dihydro-pyrimidinyl)formamidine (DMPFA), a model compound of the antivirus drug amidine-3TC (3TC = 2', 3'-dideoxy-3'-thiacytidine), is investigated by the hybrid density functional theory B3LYP/6-31+G (d,p) method. The hydrolysis reaction of the title compound is predicted to undergo via two pathways, each of which is a stepwise process. Path A is the addition of H2O to the C=N double bond in the amidine group to form a tetrahedral structure in its first step, and then the transfer of the H atom of hydroxyl leads to the corresponding products via four possible channels. Path B simultaneously involves the nucleophilic attack of H2O to the C atom of the C=N bond and the proton transfer to the N atom of amino group leading to the cleavage of the C-N single bond in the amidine group. The results indicate that path A is more favorable than path B in the gas phase. Moreover, to simulate the title reaction in aqueous solution, water-assisted mechanism and the cluster-continuum model, based on the SCRF/CPCM model, are taken into account in our work. The results indicate that it is rational for two water molecules served as a bridge to assist in the first step of path A and that cytosine rather than the cytosine-substituted formamide should be released from the tetrahedral intermediate via s six-membered cycle transition state (channel 2). Our calculations exhibit that the process toward the tetrahedral intermediate is the rate-determining step both in the gas phase and in aqueous solution.     

N,N-二(对氟苄基)-N'-(2',3'-二脱氧-3'-硫代胞苷)甲脒水解反应的理论研究

采用密度泛函理论方法B3LYP/6-31++G(d,p)//B3LYP/6-31G(d,p)和导体极化连续模型B3LYP/CPCM/6-31++G(d,p)方法对苯环对位上有F取代的N,N-二(对氟苄基)-N′-(2′,3′-二脱氧-3′-硫代胞苷)甲脒(FBFA-3TC)水解反应机理和溶剂效应进行了研究. 考虑两条可能反应途径: 水分子首先进攻C=N双键的途径(Path A)和先进攻C-N单键的途径(Path B). 计算结果表明, 气相和水中两条途径的第一步都是速率控制步骤, Path A 比Path B 更有利. 对优势途径Path A的第二步反应的进一步研究发现, 中间体的羟基H原子转移到双键N比单键N更容易, 从而形成2′,3′-二脱氧-3′-硫代胞苷(3TC)的最终水解产物.     

Mechanism of the S-->N isomerization and aquation of the thiocyanato pentaammine cobalt(III) ion

All of the stationary points on the potential energy surface of the S-->N isomerization and aquation of the Co(NH3)5SCN2+ ion have been investigated with ab initio quantum chemical methods. Also the corresponding anations of the Co(NH3)5OH2(3+) ion by the N and S ends of SCN- and the substitution of thiocyanate via the D mechanism have been studied. All calculations have been performed by taking into account hydration. The most favorable reaction of Co(NH3)5SCN2+ is the isomerization. It is concerted, follows the I or Id mechanism, depending on the applied criteria, and proceeds via a T-shaped transition state. The aquations of Co(NH3)5SCN2+ and Co-(NH3)5NCS2+ and the corresponding inverse reactions, the anations, all proceed via the Id mechanism. The activation energies, calculated for the isomerization and aquation, agree with experiment, and so does the difference of the activation energies for the anations by the two donors of SCN-. This energy difference reflects the disparate nucleophilicities of the N and S ends of SCN- and shows that bond making in the transition state is significant for the Id mechanism. Isomerization and aquation are two parallel reactions which proceed via two disparate transition states. The computed activation energy for the SCN- substitution via the D mechanism is the highest, and therefore, this pathway is unlikely to operate for the isomerization and aquation of Co(NH3)5SCN2+. The S-->N isomerization and the SCN- substitution via the D mechanism were furthermore computed for the free ions in the gas phase: the isomerization would require a higher activation energy and follow the Ia mechanism. The activation energy for the SCN- substitution via the D mechanism would be very high, because of the large electrostatic work which is required for the removal of an anion from a (formally) 3+ charged cation.     

Computational Study on the Hetero-Diels-Alder Reactions between Phosphonodithioformate and Butadienes

The mechanism, catalytic effect and substituent effect of the hetero-Diels-Alder reactions between phosphonodithioformate and butadienes have been investigated theoretically using density functional theory at the B3LYP/6-31G（d） level. The results show that all of these reactions proceed in a concerted but asynchronous way. In some reactions the formation of C-S bond is prior to that of C-C and opposite result is found in other reactions. The BF3 catalyst and trimethylsilyloxy group may lower the activation barriers by changing the energies of FMOs for reactant molecules. With the BF3-catalyzed reactions, the complete regioselectivity observed experimentally has well been reproduced by theoretical calculation and these results originate probably from blue-shifting C-H...F hydrogen bond interaction in some transition states.     

Metal catalyzed C(sp(3))-H bond amination of 2-alkyl azaarenes with diethyl azodicarboxylate

Metal-catalyzed direct C(sp(3))-H bond amination of 2-alkyl azaarenes with N[double bond, length as m-dash]N double bonds has been developed, which expands the scope of C(sp(3))-H bond activation reactions and provides a new access to medicinally important azaarene derivatives.     

Origin of the SN2 benzylic effect

The S N2 identity exchange reactions of the fluoride ion with benzyl fluoride and 10 para-substituted derivatives (RC6H 4CH 2F, R = CH3, OH, OCH 3, NH2, F, Cl, CCH, CN, COF, and NO2) have been investigated by both rigorous ab initio methods and carefully calibrated density functional theory. Groundbreaking focal-point computations were executed for the C6H5CH 2F + F (-) and C 6H 5CH2Cl + Cl (-) SN2 reactions at the highest possible levels of electronic structure theory, employing complete basis set (CBS) extrapolations of aug-cc-pV XZ (X = 2-5) Hartree-Fock and MP2 energies, and including higher-order electron correlation via CCSD/aug-cc-pVQZ and CCSD(T)/aug-cc-pVTZ coupled cluster wave functions. Strong linear dependences are found between the computed electrostatic potential at the reaction-center carbon atom and the effective SN2 activation energies within the series of para-substituted benzyl fluorides. An activation strain energy decomposition indicates that the SN2 reactivity of these benzylic compounds is governed by the intrinsic electrostatic interaction between the reacting fragments. The delocalization of nucleophilic charge into the aromatic ring in the SN2 transition states is quite limited and should not be considered the origin of benzylic acceleration of SN2 reactions. Our rigorous focal-point computations validate the benzylic effect by establishing SN2 barriers for (F (-), Cl (-)) identity exchange in (C6H5CH2F, C6H 5CH2Cl) that are lower than those of (CH3F, CH3Cl) by (3.8, 1.6) kcal mol (-1), in order.     

Theoretical Study on the Hetero-Diels-Alder Reactions between 3-Pyridinedithioesters and 1-Phenylsulfanylbutadiene

The mechanism, catalytic effect and solvent effect of the hetero-Diels-Alder reac- tions between 3-pyridinedithioesters and 1-phenylsulfanylbutadiene have been studied theoretically using density functional theory (DFT) at the B3LYP/6-31G(d) level. The results show that all of these reactions proceed in a concerted but asynchronous way. In some reactions the formation of C-S bond is prior to that of C-C bond and the opposite results are found in other reactions. The BF3 catalyst may lower the activation barriers by changing the energies of LUMO for 3-pyridine- dithioester. THF solvent has trivial influence on the potential energy surface of these reactions. With the BF3-catalyzed reactions, regioselectivity and stereoselectivity observed experimentally were predicted correctly by calculations and these results originate probably from C-H···F interaction in two transition states.     

The impact of protonation and deprotonation of 3-methyl-2'-deoxyadenosine on N-glycosidic bond cleavage

The enzyme-substrate contacts that are believed to be involved in depurination by proton transfer have been modelled by protonation and deprotonation of 3-methyl-2'-deoxyadenosine (3-MDA) using quantum mechanical calculations in the gas-phase and solution media. The change in the charge distribution on the sugar ring and nucleobase that is introduced by the protonation and deprotonation strongly affects the N-glycosidic bond length. The unimolecular cleavage and hydrolysis of the N-glycosidic bond, involving D(N)*A(N) and A(N)D(N) pathways, have been considered at several levels of theory. The trend in the energy barriers is A(N)D(N) > cleavage > D(N)*A(N). All probable proton transfer reactions resulting from enzyme-substrate contacts do not facilitate the N-glycosidic bond cleavage of 3-MDA. The deprotonation of 3-MDA that may result from the interaction between H6 and enzyme do not facilitate bond cleavage. The protonation at N7 induces more positive charge on the sugar ring and further facilitates the depurination relative to the protonation at N1. The changes in the charges calculated on the ribose and nucleobase are in good relationship with the C1'-C2', C1'-O4', and N-glycosidic bond lengths along the cleavage. The change in energy barrier ΔE of glycosidic bond cleavage from the gas-phase to solution media strongly depends on the charge of the species.     

Computational study of the deamination reaction of cytosine with H2O and OH-

The mechanism for the deamination reaction of cytosine with H(2)O and OH(-) to produce uracil was investigated using ab initio calculations. Optimized geometries of reactants, transition states, intermediates, and products were determined at RHF/6-31G(d), MP2/6-31G(d), and B3LYP/6-31G(d) levels and for anions at the B3LYP/6-31+G(d) level. Single-point energies were also determined at B3LYP/6-31+G(d), MP2/GTMP2Large, and G3MP2 levels of theory. Thermodynamic properties (DeltaE, DeltaH, and DeltaG), activation energies, enthalpies, and free energies of activation were calculated for each reaction pathway that was investigated. Intrinsic reaction coordinate analysis was performed to characterize the transition states on the potential energy surface. Two pathways for deamination with H(2)O were found, a five-step mechanism (pathway A) and a two-step mechanism (pathway B). The activation energy for the rate-determining steps, the formation of the tetrahedral intermediate for pathway A and the formation of the uracil tautomer for pathway B, are 221.3 and 260.3 kJ/mol, respectively, at the G3MP2 level of theory. The deamination reaction by either pathway is therefore unlikely because of the high barriers that are involved. Two pathways for deamination with OH(-) were also found, and both of them are five-step mechanisms. Pathways C and D produce an initial tetrahedral intermediate by adding H(2)O to deprotonated cytosine which then undergoes three conformational changes. The final intermediate dissociates to product via a 1-3 proton shift. Deamination with OH(-), through pathway C, resulted in the lowest activation energy, 148.0 kJ/mol, at the G3MP2 level of theory.     

Relationships between NMR shifts and interaction energies in biphenyls,alkanes, aza-alkanes,and oxa-alkanes with X─H…H─Y and X─H…Z (X,Y = C or N; Z = N or O) hydrogen bonding

Hydrogen–hydrogen C─H^…H─C bonding between the bay-area hydrogens in biphenyls, and more generally in congested alkanes, very strained polycyclic alkanes, and cis-2-butene, has been investigated by calculation of proton nuclear magnetic resonance (NMR) shifts and atom–atom interaction energies. Computed NMR shifts for all protons in the biphenyl derivatives correlate very well with experimental data, with zero intercept, unit slope, and a root mean square deviation of 0.06 ppm. For some congested alkanes, there is generally good agreement between computed values for a selected conformer and the experimental data, when it is available. In both cases, the shift of a given proton or pair of protons tends to increase with the corresponding interaction energy. Computed NMR shift differences for methylene protons in polycyclic alkanes, where one is involved in a very short contact (“in”) and the other is not (“out”), show a rough correlation with the corresponding C─H^…H─C exchange energies. The “in” and “in,in” isomers of selected aza- and diaza-cycloalkanes, respectively, are X─H^…H─N hydrogen bonded, whereas the “out” and “in,out” isomers display X─H^…N hydrogen bonds (X = C or N). Oxa-alkanes and the “in” isomers of aza–oxa-alkanes are X─H^…O hydrogen bonded. There is a very good general correlation, including both N─H^…H─Y (Y = C or N) and N─H^…Z (Z = N or O) interactions, for NH proton shifts against the exchange energy. For “in” CH protons, the data for the different C─H^…H─Y and C─H^…Z interactions are much more dispersed and the overall shift/exchange energy correlation is less satisfactory.     

Probing O-dealkylation and deamination aging processes in tabun-conjugated AChE: a computational study

The mechanisms of the aging process of tabun-conjugated acetylcholinesterase were explored using density functional theory calculations. The free energy surfaces were calculated for O-dealkylation (C–O bond breaking) and deamination (P–N bond breaking) pathways for the aging process of tabun-conjugated acetylcholinesterase as suggested by mass and crystallographic studies. Initially, the calculations were performed using tabun-conjugated serine (SUN) molecule. O-dealkylation mechanism proceeds via one-step S_N2 type process, whereas the deamination process proceeds via two steps addition–elimination reaction at the phosphorus center of SUN molecule. The recent proposal of another deamination mechanism using human butyrylcholinesterase (hBChE) conjugated with N-mono methyl analogue of tabun (TA4) has also been explored (Nachon et al. in Chem Biol Interact 187:44–48, 2010). The rate-determining activation barrier calculated for this deamination mechanism (26.3 kcal/mol) was comparable with O-dealkylation process (26.9 kcal/mol) with B3LYP/6-31+G* level of theory. To examine the influence of catalytic residue His447, additional calculations were performed with imidazole group of His447 residue. The incorporation of imidazole group of catalytic residue His447 showed marked decrease in the free energies of activation for all the studied aging processes of tabun-inhibited serine. The aging mechanisms have been explored with TA4-inhibited serine, and calculated results showed that the deamination with the rearrangement process is markedly preferred in this case, which supports the Nachon et al. proposal based on the crystallographic studies.