First-principles prediction of the pK(a)s of anti-inflammatory oxicams

The gas- and aqueous-phase acidities of a series of oxicams have been computed by combining M05-2X/6-311+G(3df,2p) gas-phase free energies with solvation free energies from the CPCM-UAKS, COSMO-RS, and SMD solvent models. To facilitate accurate gas-phase calculations, a benchmarking study was further carried out to assess the performance of various density functional theory methods against the high-level composite method G3MP2(+). Oxicams are typically diprotic acids, and several tautomers are possible in each protonation state. The direct thermodynamic cycle and the proton exchange scheme have been employed to compute the microscopic pK(a)s on both solution- and gas-phase equilibrium conformers, and these were combined to yield the macroscopic pK(a) values. Using the direct cycle of pK(a) calculation, the CPCM-UAKS model delivered reasonably accurate results with MAD ~ 1, whereas the SMD and COSMO-RS models' performance was less satisfactory with MAD ~ 3. Comparison with experiment also indicates that direct cycle calculations based on solution conformers generally deliver better accuracy. The proton exchange cycle affords further improvement for all solvent models through systematic error cancellation and therefore provides better reliability for the pK(a) prediction of compounds of these types. The latter approach has been applied to predict the pK(a)s of several recently synthesized oxicam derivatives.     

Quantum chemical calculations based on ONIOM and the DFT methods in the inclusion complex: doxycycline/2-O-Me-β-cyclodextrin

A computational study of inclusion complexes of 2-methyl-βCD with Doxycycline tautomeric (enol and keto form) has been performed with several combinations of ONIOM hybrid calculations. The reliability of the ONIOM2 calculations at the integrated level, ONIOM2 (M05-2X/6-31G(d): M05-2X/3-21G*), ONIOM2 (M05-2X/6-31G(d):HF/3-21G*), ONIOM2 (B3LYP/6-31G(d):HF/3-21G*), ONIOM2 (B3LYP/6-31G(d):B3LYP/3-21G*) and ONIOM2 (B3PW91/6-31G(d):B3PW91/3-21G*) was examined. Their complexation, binding, deformation and stabilization energies, and geometrical data were compared with those of the target geometry structure optimized at the M05-2X/6-31G(d) level of theory. Mixed combinations ONIOM2 (M05-2X 6-31G(d):HF 3-21G*) and ONIOM2 (B3LYP 6-31G(d):HF 3-21G*) reproduces nearly the target geometry structure and provides realistic energetic results at a relatively low computational cost.     

Theoretical prediction of pKa values of seleninic, selenenic, sulfinic, and carboxylic acids by quantum-chemical methods

Aqueous acid dissociation constants of substituted areneseleninic, areneselenenic, arenesulfinic, and benzoic acids are calculated by ab initio (MP2) and DFT (B3LYP) methods in combination with bulk solvation models (IEFPCM, CRSrad) from appropriate thermodynamic cycles. Mean absolute deviations (MAD) between experimental and calculated pK(a) values are quite large for basis sets without diffuse functions; however, trends are reasonably well described. Best agreement with experiment as described by MAD as well as correlation coefficient and slope of the correlation equation pK(a) = a*ΔG(calc)/RT ln(10) + b is obtained with the CPCM solvation model using the defaults optimized within COSMO-RS (CRSrad; MAD = 1.54, R(2) = 0.94, a = 0.83). Sulfenic (selenenic) acid tautomers are significantly more stable than the corresponding sulfoxide (selenoxide) forms.     

Dependence of pKa on solute cavity for diprotic and triprotic acids

A systematic study of ΔG(aq)/pK(a) for monoprotic, diprotic, and triprotic acids has been carried out based on DFT/aug-cc-pVTZ combined with CPCM and SMD solvation modeling. All DFT/cavity set combinations considered showed similar accuracy for ΔG(aq)(1)/pK(a1) (70% within ±2.5 kcal mol(-1) of experiment) while only the M05-2X/Pauling cavity combination gave reasonable results for ΔG(aq)(2)/pK(a2) when both pK(a) values are separated by more than three units (70% within ±5.0 kcal mol(-1) of experiment). The choice of experimental data is critical to the interpretation of the calculated accuracy especially for several inorganic acids. For the calculation of ΔG(aq)(3)/pK(a3), the larger experimental uncertainty and an unrealistic orbital population of diffuse function for trianions in the gas phase hinders an evaluation of the predictive performance. We find the M05-2X functional with the Pauling cavity set is the best choice for ΔG(aq)(2)/pK(a2) prediction in aqueous media while all DFT/cavity sets considered were competitive for ΔG(aq)(1)/pK(a1).     

Acidity of anilines: calculations vs experiment

The gas-phase acidities of ca. 60 monosubstituted anilines (with acidity span of almost 50 kcal mol(-1)) have been calculated using density functional theory (DFT) at the B3LYP/6-311+G** level. At this relatively simple level of theory the calculated (ΔG(calc)) and available experimental (ΔG(exp)) acidities are in reasonable quantitative correlation according to the following equation: ΔG(obs) = a + bΔG(calc), where a=20.79, b=0.942, n=27, R(2)=0.990, and s=0.78 kcal·mol(-1). The slope is not far from its ideal value. Substituent effects on the acidities were dissected separately into those operating in the neutral acid molecule and in its conjugated anion using the isodesmic homodesmotic reactions. All in all, both forms, neutral and anionic, are contributing in combination to make up the gross acidity of anilines. However, the contributions of the anions into the gross substituent effects are much larger than the substituent effects in the neutral anilines. Some of the systems were used in testing a relatively new theoretical model, COSMO-RS (conductor-like screening model for real solvents), using it for the prediction of pK(a) values in DMSO. The method proved to be rather accurate for showing pK(a) trends (R(2)=0.980 in DMSO). However, the predicted absolute pK(a) values were all somewhat lower (rmsd=2.49 kcal·mol(-1)) than the respective experimental values.     

Si~2Cl~6分子的内旋转能垒和振动基频的理论研究

用从头算方法HF/6-31G^*^*和密度函方法B3LYP/6-31G^*^*,对Si~2Cl~6分子的平衡几何构型进行优化,优化的结果与实验结果吻合得较好.并用上述两种不同的方法计算Si~2Cl~6分子的内旋转能垒,结果分别为8.786和6.694kJ/mol,其中DFT方法的计算结果与实验结果4.18kJ/mol吻合得较好.对Si~2Cl~6分子的振动基频进行计算.用HF/6-31G^*^*SQM力场所计算的频率理论值与实验值的平均误差为7.3cm^-^1,用B3LYP/6-31G^*^*未标度的力场所计算的频率理论值与实验值的平均误差为6.0cm^-^1.该密度泛函方法(B3LYP/~6-31G^*^*)的理论计算值比用HF/6-31G^*^*标度后的SQM力场计算的频率与实验值(除Si--Si键扭转振动基频之外的11条振动基频)吻合得更好.并给出了Si--Si键扭转振动基频的预测值。     

Hydride affinity scale of various substituted arylcarbeniums in acetonitrile

Combined with the integral equation formalism polarized continuum model (IEFPCM), the hydride affinities of 96 various acylcarbenium ions in the gas phase and CH(3)CN were estimated by using the B3LYP/6-31+G(d)//B3LYP/6-31+G(d), B3LYP/6-311++G(2df,2p)//B3LYP/6-31+G(d), and BLYP/6-311++G(2df,2p)//B3LYP/6-31+G(d) methods for the first time. The results show that the combination of the BLYP/6-311++G(2df,2p)//B3LYP/6-31+G(d) method and IEFPCM could successfully predict the hydride affinities of arylcarbeniums in MeCN with a precision of about 3 kcal/mol. On the basis of the calculated results from the BLYP method, it can be found that the hydride affinity scale of the 96 arylcarbeniums in MeCN ranges from -130.76 kcal/mol for NO(2)-PhCH(+)-CN to -63.02 kcal/mol for p-(Me)(2)N-PhCH(+)-N(Me)(2), suggesting most of the arylcarbeniums are good hydride acceptors. Examination of the effect of the number of phenyl rings attached to the carbeniums on the hydride affinities shows that the increase of the hydride affinities takes place linearly with increasing number of benzene rings in the arylcarbeniums. Analyzing the effect of the substituents on the hydride affinities of arylcarbeniums indicates that electron-donating groups decrease the hydride affinities and electron-withdrawing groups show the opposite effect. The hydride affinities of arylcarbeniums are linearly dependent on the sum of the Hammett substituent parameters σ(p)(+). Inspection of the correlation of the solution-phase hydride affinities with gas-phase hydride affinities and aqueous-phase pK(R)(+) values reveals a remarkably good correspondence of ΔG(H(-)A)(R(+)) with both the gas-phase relative hydride affinities only if the α substituents X have no large electron-donating or -withdrawing properties and the pK(R)(+) values even though the media are dramatically different. The solution-phase hydride affinities also have a linear relationship with the electrophilicity parameter E, and this dependence can certainly serve as one of the most effective ways to estimate the new E values from ΔG(H(-)A)(R(+)) or vice versa. Combining the hydride affinities and the reduction potentials of the arylcarbeniums, we obtained the bond homolytic dissociation Gibbs free energy changes of the C-H bonds in the corresponding hydride adducts in acetonitrile, ΔG(HD)(RH), and found that the effects of the substituent on ΔG(HD)(RH) are very small. Simple thermodynamic analytic platforms for the three C-H cleavage modes were constructed. It is evident that the present work would be helpful in understanding the nature of the stabilities of the carbeniums and mechanisms of the hydride transfers between carbeniums and other hydride donors.     

Accurate prediction of basicity in aqueous solution with COSMO-RS

The COSMO-RS method, a combination of the quantum chemical dielectric continuum solvation model COSMO with a statistical thermodynamics treatment for realistic solvation simulations, has been used for the prediction of base pK(a) constants. For a variety of 43 organic bases the directly calculated values of the free energies of dissociation in water showed a very good correlation with experimental base pK(a) values (r2 = 0.98), corresponding to a standard deviation of 0.56 pK(a) units. Thus, we have an a priori prediction method for base pK(a) with the regression constant and the slope as only adjusted parameters. In accord with recent findings for pK(a) acidity predictions, the slope of pK(a) vs. DeltaG(diss) was significantly smaller than the theoretically expected value of 1/RTln(10). The predictivity of the presented method is general and not restricted to certain compound classes, but systematic corrections of 1 and 2 pKa units for secondary and tertiary aliphatic amines are required, respectively. The pK(a) prediction method was validated on a set of 58 complex multifunctional drug-like compounds, yielding an RMS accuracy of 0.66 pK(a) units.     

Inclusion complexes of ortho-anisidine and β-cyclodextrin: A quantum mechanical calculation

The structural aspects for the complexation of ortho-anisidine (O-AN)/β-cyclodextrin were explored by using PM6, density function theory B3LYP/6-31G*, M05-2X/6-31G*, B3PW91/6-31G*, MPW1PW91/6-31G*, HF/6-31G* methods and several combinations of ONIOM2 hybrid calculations. Calculations were performed upon the inclusion complexation of β-cyclodextrin (β-CD) with neutral (O-AN1) and cationic (O-AN2) species of ortho-anisidine. The obtained results with PM6 method clearly indicate that the formed complexes are energetically favored, the complex of O-AN2/β-CD in B orientation is significantly more favorable than the others energetically. The structures show the presence of several intermolecular hydrogen bond interactions that were studied on the basis of natural bonding orbital (NBO) analysis, employed to quantify the donor–acceptor interactions between ortho-anisidine and β-CD.     

Tert-butyl N-(2-bromocyclohex-2-enyl)-N-(2-furylmethyl)carbamate的结构和振动光谱

The molecular structure, conformafional stability, and vibrational frequencies of ten-butyl N-（2- bromocyclohex-2-enyl）-N-（2-furylmethyl）carbamate （TBBFC） were investigated by utilizing the Hartree-Fock （HF） and density functional theory （DFT） ab initio calculations with 6-31G ^＊ and 6-31G^＊ ＊ basis sets. The optimized bond length and angle values obtained by HF method showed the best agreement with the experimental values. Comparison of the observed and calculated fundamental vibrational frequencies indicated that B3LYP was superior to the scaled HF approach for molecular problems. Optimal uniform scaling factors calculated for the title compound are 0.899/0.904, 0.958/0.961, and 0.988/0.989 for HF, B3LYP, and BLYP （6-31G ^＊/6-31G ^＊ ＊）, respectively.     

Novel H-bonded base dimers as repeat units for information-bearing self-associative duplexes: a B3LYP/6-31G* search

Density functional theory at the B3LYP/6-31G* level with counterpoise correction has been employed to study six sets of nitrogenous bases for the capacity of each to form H-bonded dimers restricted to a chosen pairing configuration. These results are augmented by MP2/6-311++G(d,p) single point calculations on the B3LYP/6-31G* optimized geometries. Each set has two bases, including substituted azoles, imidazoles, pyrimidines, and fused ring systems. This study aims to determine the suitability of each set to furnish H-bonded base pairs which may serve as repeat units for self-associative H-bonded macromolecular duplexes with the capacity to store and replicate information at the molecular level. Out of the various possibilities tested here, a set of two substituted pyrimidines best satisfies the prescribed criteria and may be put forward as a good candidate to yield isomorphic repeat units for designing such synthetic information-bearing macromolecular duplexes. The optimized configurations of these chosen base pairs as calculated at the B3LYP/6-31G* level compare well with those calculated at the B3LYP/6-31++G(d,p) and MP2/6-31G(d,p) levels, and indicate that isomorphism of the two base pairs is independent of method used. Assuming a one-to-one correspondence for encoding information in the macromolecule, such a set of two bases can allow the macromolecule to encode up to 8 types of encrypted species.     

Prediction of acidity in acetonitrile solution with COSMO-RS

The COSMO-RS method, a combination of the quantum chemical dielectric continuum solvation model COSMO with a statistical thermodynamics treatment for realistic solvation simulations, has been used for the prediction of pK(a) values in acetonitrile. For a variety of 93 organic acids, the directly calculated values of the free energies of dissociation in acetonitrile showed a very good correlation with the pK(a) values (r(2) = 0.97) in acetonitrile, corresponding to a standard deviation of 1.38 pK(a) units. Thus, we have a prediction method for acetonitrile pK(a) with the intercept and the slope as the only adjusted parameters. Furthermore, the pK(a) values of CH acids yielding large anions with delocalized charge can be predicted with a rmse of 1.12 pK(a) units using the theoretical values of slope and intercept resulting in truly ab initio pK(a) prediction. In contrast to our previous findings on aqueous acidity predictions the slope of the experimental pK(a) versus theoretical DeltaG(diss) was found to match the theoretical value 1/RT ln (10) very well. The predictivity of the presented method is general and is not restricted to certain compound classes. However, a systematic correction of -7.5 kcal mol(-1) is required for compounds that do not allow electron-delocalization in the dissociated anion. The prediction model was tested on a diverse test set of 129 complex multifunctional compounds from various sources, reaching a root mean square deviation of 2.10 pK(a) units.     

吡啶-BH~3相互作用复合物的理论研究

对吡啶-BH~3复合物分别用MP2/6-31+G^*和B3LYP/6-31+G^*进行理论计算以预测该复合物的构型及解离能，得到四种构型，在MP2优化构型基础上作CCSD/6-31+G^*单点能量计算以验证MP2与B3LYP结果的可靠性，然后用B3LYP作振动频率分析，计算了各构型的垂直电离势，最后用更大基组作单点能量计算和自然键轨道(NBO)分析。结果表明，N-B直接相连的构型最稳定，其解离能为141.50kJ/mol,MP2和B3LYP对N-H接近的构型结果相关较大，另外两种构型稳定性介于二者之间，解离能分别为15.18kJ/mol,14.06kJ/mol(MP2/6-31+G^*)。     

2,3,7,8-四氯苯并二英分子结构与热力学性质的理论研究

用密度泛函理论(DFT)和从头算(ab initio)方法,在B3LYP/6-31G、 B3LYP/6-31G*、 B3LYP/6-311G*和MP2/6-31G*水平上全优化计算了2,3,7,8-四氯苯并二英(2,3,7,8-TCDD)的几何构型、电子结构和振动频率,并用校正后的频率计算了298～1500 K的标准热力学函数,同时用半经验的PM3 SCF-MO进行了同样的计算,计算结果与实验值及文献值较好地吻合.     

Structure and conformational stability of CH2CHCH2X (X=F, Cl and Br) molecules—post Hartree–Fock and density functional theory methods

The molecular structure and conformational stability of CH₂CHCH₂X (X=F, Cl and Br) molecules were studied using ab initio and density functional theory (DFT) methods. The molecular geometries of 3-fluoropropene were optimized employing BLYP and B3LYP levels of theory of DFT method implementing 6-311+G(d,p) basis set. The MP2/6-31G^*, BLYP and B3LYP levels of theory of ab initio and DFT methods were used to optimize the 3-chloropropene and 3-bromopropene molecules. The structural and physical parameters of the molecules are discussed with the available experimental values. The rotational potential energy surface of the above molecules were obtained at MP2/6-31G^* and B3LYP/6-311+G(d,p) levels of theory. The Fourier decomposition of the rotational potentials were analyzed. The HF/6-31G^* and MP2/6-31G^* levels of theory have predicted the cis conformer as the minimum energy structure for 3-fluoropropene, which is in agreement with the experimental values, whereas the BLYP/6-311+G(d,p) and B3LYP/6-311+G(d,p) levels of theory reverses the order of conformation. The ΔE values calculated for 3-chloropropene at MP2/6-31G^*, BLYP/6-311+G(d,p) and B3LYP/6-311+G(d,p) levels of theory show that the gauche form is more stable than the cis form, which is in agreement with the experimental value. The same levels of theory have also predicted that the gauche form is stable than cis for 3-bromopropene molecule. The maximum hardness principle has been able to predict the stable conformer of 3-fluoropropene at HF/6-31G^* level of theory, but the same level of theory reverses the conformational stability of 3-chloropropene and 3-bromopropene molecules and MP2/6-31G^* level of theory predicted the stable conformer correctly.     

Assessment of density functionals for pi systems: Energy differences between cumulenes and poly-ynes; proton affinities, bond length alternation, and torsional potentials of conjugated polyenes; and proton affinities of conjugated Shiff bases

Woodcock et al. [J. Phys. Chem. A 2002, 106, 11923] pointed out that no density functional was able to obtain the correct sign of the relative energies of the allene and propyne isomers of C3H4 and that density functional theory (DFT) predicts that poly-ynes are insufficiently stabilized over cumulenes for higher homologues. In the present work, we show that the recent M05 density functional predicts the correct ordering of allene and propyne and gives a mean unsigned error (MUE) of only 1.8 kcal/mol for the relative energies of the two isomers of C3H4, C5H4, and C7H4. Two other recent functionals, M05-2X and PWB6K, also give reasonably low MUEs, 2.7 and 3.0 kcal/mol, respectively, as compared to 6.2 kcal/mol for the popular B3LYP functional. Another challenging problem for density functionals has been a tendency to overpolarize conjugated pi systems. We test this here by considering proton affinities of conjugated polyenes and conjugated Schiff bases. Again M05-2X performs quite well, with MUEs of 2.1 and 3.9 kcal/ mol, respectively, as compared to 5.8 and 5.9 kcal/mol for B3LYP. Averaged over the three problems, M05-2X has a MUE of 3.0 kcal/mol, the BMK functional of Boese et al. has an MUE of 3.2 kcal/mol, and M05 has an MUE of 5.1 kcal/mol. Twenty-two other tested functionals have MUEs of 5.2-8.1 kcal/mol averaged over the three test problems. Both M05 and M05-2X do quite well, compared to other density functionals, for torsion potentials in butadiene and styrene, and M05 does very well for bond length alternation in conjugated polyenes. Since the M05 functional has broad accuracy for main group and transition metal chemistry and M05-2X has broad accuracy for main group chemistry, we conclude that significant progress is being made in improving the performance of DFT across a wide range of problem types.     

1. 5-环辛二烯-3, 7-二炔(C~8H~4)结构和光谱性质的理论研究

采用量子化学从头算方法研究了1,5-环辛二烯-3,7-二炔(C~8H~4)的结构和光谱性质,根据等键反应分析和自然键轨道方法研究了它的稳定性、成键情况和共轭性。结果表明1,5-环辛二烯-3,7-二炔(C~8H~4)分子为平面刚性结构,可能稳定存在。分子中C≡C键与C=C键存在一定程度的共轭,可能具有芳香性。     

15N NMR chemical shifts of ring substituted benzonitriles

15N chemical shifts in an extensive series of para (15) and meta (15) as well as ortho (8) substituted benzonitriles, X-C6H4-CN, were measured in deuteriochloroform solutions, using three different methods of referencing. The standard error of the average chemical shift was less than 0.03 ppm in most cases. The results are discussed for both empirical correlations with substituent parameters and quantum chemical calculations. The 15N chemical shifts calculated at the GIAO/B3LYP/6-31 + G*//B3LYP/6-31 + G* level reproduce the experimental values well, and include nitrogen atoms in the substituent groups (range of 300 ppm with slope 0.98 and R = 0.998, n = 43). The 15N shifts in hydroxybenzonitriles are affected by interaction with the OH group. Therefore, these derivatives are excluded from the correlation analysis. The resultant 15N chemical shift correlates well with substituent constants, both in the simple Hammett or DSP relationships and the 13C substituent-induced chemical shifts of the CN carbon.     

Ab initio and DFT calculations on the initial step in thiamin catalysis

The diphosphate ester (ThDP) of thiamin (vitamin B₁) is an important cofactor of enzymes within the carbohydrate metabolism. The initial reaction step shared by all ThDP-dependent enzymes is the deprotonation of the C2–H of the thiazolium ring. The replacement of the 4′-amino group by a hydroxyl one in the pyrimidine ring leads to the oxy-ThDP analogue which is known as an antagonist in thiamin catalysis.

Ab initio and DFT calculations on the MP2/6-31G* and B3LYP/6-31G* level were performed to study the proton relay function in thiamin and oxythiamin systems. Both MP2 and B3LYP calculations show significant differences of the reaction coordinate of the ylide formation in the systems. Tautomers, protonated and deprotonated species of both systems show different trends regarding their stability. The influence of correlation effects on the results is discussed by comparison with the HF-SCF/6-31G* data. Frequency calculations on the B3LYP/6-31G* level were performed to characterize the minima and transition state structures, respectively.