DFT-GIAO Calculations Research Articles

New pecS-n (n = 1, 2) basis sets for quantum chemical calculations of the NMR chemical shifts of H, C, N, and O nuclei.

This paper demonstrates the performance of our previously suggested property-energy consistent method on the example of the generation of effective basis sets, pecS-1 and pecS-2, suited for the calculation of hydrogen, carbon, nitrogen, and oxygen chemical shifts. The new basis sets were successfully approbated in the GIAO-DFT calculations of the chemical shifts of 35 molecules using six different functionals. The pecS-1 basis set demonstrated very good accuracy, which makes this small basis set an effective means for the large-scale computations. At the same time, the pecS-2 basis set also gave very accurate results, thus putting it on a par with the other commensurate basis sets suited for the chemical shifts calculations.

Spirostanol Sapogenins and Saponins from Convallaria majalis L. Structural Characterization by 2D NMR, Theoretical GIAO DFT Calculations and Molecular Modeling.

Two new spirostanol sapogenins (5β-spirost-25(27)-en-1β,2β,3β,5β-tetrol 3 and its 25,27-dihydro derivative, (25S)-spirostan-1β,2β,3β,5β-tetrol 4) and four new saponins were isolated from the roots and rhizomes of Convallaria majalis L. together with known sapogenins (isolated from Liliaceae): 5β-spirost-25(27)-en-1β,3β-diol 1, (25S)-spirostan-1β,3β-diol 2, 5β-spirost-25(27)-en-1β,3β,4β,5β-tetrol 5, (25S)-spirostan-1β,3β,4β,5β-tetrol 6, 5β-spirost-25(27)-en-1β,2β,3β,4β,5β-pentol 7 and (25S)-spirostan-1β,2β,3β,4β,5β-pentol 8. New steroidal saponins were found to be pentahydroxy 5-O-glycosides; 5β-spirost-25(27)-en-1β,2β,3β,4β,5β-pentol 5-O-β-galactopyranoside 9, 5β-spirost-25(27)-en-1β,2β,3β,4β,5β-pentol 5-O-β-arabinonoside 11, 5β-(25S)-spirostan-1β,2β,3β,4β,5β-pentol 5-O-galactoside 10 and 5β-(25S)-spirostan-1β,2β,3β,4β,5β-pentol 5-O-arabinoside 12 were isolated for the first time. The structures of those compounds were determined by NMR spectroscopy, including 2D COSY, HMBC, HSQC, NOESY, ROESY experiments, theoretical calculations of shielding constants by GIAO DFT, and mass spectrometry (FAB/LSI HR MS). An attempt was made to test biological activity, particularly as potential chemotherapeutic agents, using in silico methods. A set of 12 compounds was docked to the PDB structures of HER2 receptor and tubulin. The results indicated that diols have a higher affinity to the analyzed targets than tetrols and pentols. Two compounds (25S)-spirosten-1β,3β-diol 1 and 5β-spirost-25(27)-en-1β,2β,3β,4β,5β-pentol 5-O-galactoside 9 were selected for further evaluation of biological activity.

A novel quinoxalinedione-bicapped tri-ruthenium carbonyl cluster [Ru3(μ-H)2(CO)6(μ3-HDCQX)2]: synthesis, characterization, anticancer activity and theoretical investigation of Ru–Ru and Ru–Ligand bonding interactions

A new tri-ruthenium dihydrido cluster, [Ru3(μ-H)2(CO)6(HDCQX)2] (1), in which two HDCQX (H2DCQX = 6,7-dichloroquinoxaline-2,3-dione) ligands cap both faces of the tri-ruthenium triangle similarly through oxygen atoms, has been synthesized and characterized by mass, IR, NMR (1H and 13C) and electronic spectroscopy. DFT calculations, in both gas and solution (CPCM/DMSO) phases, were performed to analyze the electronic structure of the cluster and interpret its vibrational and NMR spectra. The presence of non-equivalent bridging hydrides was assigned by 1H NMR as two singlet resonances at δ −16.85 and −17.67 ppm and confirmed by theoretical DFT-GIAO calculations at δ −12.92 and −14.48 ppm. Time-dependent density functional theory (TD-DFT) calculations, performed to characterize the frontier orbitals and interpret the electronic spectrum, indicated that the lowest-energy transition of 1 originates from a highly delocalized HOMO with Ru–Ru (σ), Ru–CO (π) and Ru–CO (σ*) contributions and ends in the LUMO with Ru1–Ru2–Ru3 (σ*) and QX/QX′ (π*) anti-bonding character. The natural transition orbital (NTO) corresponding to this transition revealed a decrease of the electron density on the Ru1Ru2(CO)4 fragment and an increase of the electron density on the Ru1–Ru2–Ru3 unit and the HDCQX ligands. The Ru–Ru and Ru–ligand bonding was studied by the quantum theory of atoms in molecules (QTAIM) and electron localization function (ELF) methods. Both confirmed the presence of unique bonding between the Ru1 and Ru2 atoms and not between Ru3 and the other Ru atoms. While the QTAIM assigned the Ru1–Ru2 bonding as a transit between pure closed-shell and pure shared-shell interactions, the ELF analysis suggested that this bond is dominated by a fluctuation of electron density. The covariance analysis indicated that the core basin populations C(Ru1) and C(Ru2) account for 76% of the V(Ru1, Ru2) variance. Natural bond orbital (NBO) analysis of the Ru3(µ-H)2O4(CO)6 unit indicated a 2c–2e bonding type for the Ru–O, Ru–C and Ru–Ru bonds with orbital occupations of 1.88–1.95, 1.95–1.96, and 1.57 e, respectively, and a 3c–2e bonding for the Ru–H–Ru bonds with an orbital occupation of ca. 1.7 e. NBO second-order perturbative energy analysis was performed to estimate the strength of the Ru–CO π-back-donation and to establish a correlation between the stabilization energy (E(2)) and the spectroscopic data. Although the calculated stabilization energy (E(2)total) follows the expected trend of decreasing the CO stretching frequency (νCO) and increasing the 13CO chemical shift with the extent of the Ru–CO π-back-donation, the latter parameter was more consistent in estimating the strength of such interactions. The in vitro anticancer activities of the title compound and cisplatin were determined against three common types of human cancer cell lines, HCT-116 (colon), HELA (cervix) and MCF-7 (breast). The IC50 values of 3.18 ± 0.40, 4.21 ± 0.29 and 5.39 ± 0.52 μM, respectively, represent 4- and 2-times improvement in potency relative to cisplatin (12.06 ± 1.28, 10.34 ± 2.08 and 6.29 ± 1.68 μM, respectively) against the HCT-116 and HeLa cancer cell lines.

Assignment of the relative stereochemistry of two novel vicinal dibromo compounds using NMR and DFT-GIAO calculations

Bromination reactions are among the most important reactions in organic synthesis and can be carried out using bromine or many other bromine donor compounds. Among them, one of the best known is the addition of bromine to the C–C double bond to provide vicinal dibromides. Although the classical mechanism indicates the formation of bromonium ion as intermediate of the reaction delivering products in a stereospecific way, some substrates may lead to the mechanism via carbocation or may still have competition between the two types of mechanism. In this work, the addition of bromine to (2E,4E)-N-butylhexa-2,4-dienamide (1) produced erythro and threo diastereoisomers that were identified by comparing the experimental and calculated NMR chemical shifts. The theoretical values were obtained employing DFT-GIAO method and the comparisons were made using MAE values, CP3, and DP4 probabilities. For a better understanding of the bromination of 1, rate-limiting step and reaction energies were calculated for both mechanisms via bromonium and via carbocation.

Colletofurans A-E, 1-Octyl-1,3-dihydroisobenzofuran Derivatives from Colletotrichum boninense AM-12-2.

3-(3-Hydroxy-2-(hydroxymethyl)phenyl)propanoic acid, 2-hydroxymethyl-3-hydroxy-(E)-cinnamic acid, and colletofurans A-E were isolated from Colletotrichum boninense AM-12-2. Colletofurans A-E are the first natural compounds featuring a 1-octyl-1,3-dihydroisobenzofuran core. Their structures were initially established by 1D/2D-NMR and HRESITOFMS. Mosher's ester method was used to determine the absolute configurations of secondary alcohols in colletofurans A-C. The structures of colletofurans A and B-E were further confirmed by DFT GIAO calculations and the X-ray crystalline sponge method, respectively.

Structural studies of two capsaicinoids: dihydrocapsaicin and nonivamide. 13C and 15N MAS NMR supported by genetic algorithm and GIAO DFT calculations

Capsaicinoids are alkaloid type capsaicin analogs with prospective pharmacological activity. However their solid state conformations have not been studied yet. As part of the study, cross polarization (CP) magic angle spinning (MAS) solid state 13C and 15N NMR spectra of dihydrocapsaicin (DHCAP) and nonivamide (NVA) were recorded. Solid state chemical shifts differ from their solution counterparts; remarkable differences occur for carbons C2′, C6′ and C7′ linked to C1′ in DHCAP and with methylene carbons C4–C8 in NVA. The doubling of some resonances in the spectra of solid NVA indicates that there are two molecules in the crystallographic asymmetric unit. DFT GIAO calculations of shielding constants were performed for several geometric isomers, including molecules with different orientations of aliphatic chain with respect to aromatic ring. Low-energy conformers were found by genetic algorithm methodology. Comparison of experimental 13C chemical shifts with theoretical (GIAO DFT) shielding parameters was helpful in predicting the most reliable geometry in the solid state. Cross polarization time constants TCP and relaxation times in the rotating frame TH1ρ were obtained from variable-contact cross-polarization experiments. TH1ρ are longer in the order: NVA < CAP < DHCAP.

Deconvolution of fast exchange equilibrium states in NMR spectroscopy using virtual reference standards and probability theory.

A methodology for deconvolution of fast exchange equilibrium states in NMR spectroscopy (DFEQNMR) was developed based on DFT-GIAO NMR chemical shift prediction and a probability theory algorithm. Proof-of-concept studies were performed to estimate the protonation state of N-containing organic molecules involving fast proton exchange equilibrium and evaluate the solution tautomerism of a purine derivative. DFT-GIAO calculations were optimized to achieve good accuracy in 13C, 1H and 15N chemical shift prediction for protonated species. The probability theory algorithm enabled the determination of solution species ratios and yielded 95% confidence regions by comparing experimental and simulated chemical shift data sets. The calculation showed good accuracy for model partial salts with various functionalities and application in structure elucidation of complex natural product partial salts was also demonstrated. This method showed promising potential in acquisition of important insight into fast exchange equilibrium systems with only one experimental NMR chemical shift data set.

D iCE: Diastereomeric in Silico Chiral Elucidation, Expanded DP4 Probability Theory Method for Diastereomer and Structural Assignment.

NMR chemical shift prediction at the B3LYP/cc-pVDZ level of theory was used to develop a highly accurate probability theory algorithm for the determination of the stereochemistry of diastereomers as well as the regiochemistry. DFT-GIAO calculations were performed for each conformer using geometry optimization and a CPCM solvent model. Boltzmann averaged shielding constants were converted to chemical shifts for 1H and 13C, using the generalized linear scaling terms determined in four different solvents for 1H and 13C and extended to 15N in DMSO. The probability theory algorithm, D iCE, was based on the DP4 method and developed for 1H, 13C, and 15N NMR using individual and combined probability data. The chemical shift calculation errors were fitted to a Student's t-distribution for 1H and 13C and a normal distribution for 15N. The application yielded a high accuracy for structural assignment with a low computational cost.

Assignment of the relative and absolute stereochemistry of two novel epoxides using NMR and DFT-GIAO calculations

Considering the potential biological application of isobenzofuranones, especially as agrochemical defensives, two novel epoxides, (1aR,2R,2aR,5S,5aS,6S,6aS)-5-(hydroxymethyl)hexahydro-2,6-methanooxireno[2,3-f]isobenzofuran-3(1aH)-one (9), and (1aS,2S,2aR,5S,5aS,6R,6aR)-5-(hydroxymethyl)hexahydro-2,6-methanooxireno[2,3-f]isobenzofuran-3(1aH)-one (10), were synthesized from the readily available D-mannitol in six steps. The multiplicities of the hydrogens located at the bridge of the bicycle are distinct for epoxides 9 and 10 due to W coupling, and this feature was employed to confirm the assignment of these nuclei. Besides analyses of the 2D NMR spectra, the assignments of the nuclei at the epoxide ring were also inferred from information obtained by theoretical calculations. The calculated 1H and 13C NMR chemical shifts for eight candidate structures were compared with the experimental chemical shifts of 9 and 10 by measuring the mean absolute errors (MAE) and by the DP4 statistical analysis. The structures and relative configurations of 9, and 10 were determined via NMR spectroscopy assisted with theoretical calculations. As consequence of the enantioselective syntheses starting from a natural polyol, the absolute configurations of the epoxides 9 and 10 were also defined.

Spectroscopic properties and solute–solvent structural analyses for ANR polypeptides in water solution: a sequential Monte Carlo/quantum mechanics (S-MC/QM) theoretical study

We present a theoretical study of the solvent influence on ANR polypeptides, with N = 1, 2, 3, 4 and 5, in the gas phase and in water solution using the sequential MC/QM methodology combined with GIAO-DFT calculations.

Conformational analysis of capsaicin using 13C, 15N MAS NMR, GIAO DFT and GA calculations

Capsaicin produced by plants from genus Capsicum exerts multiple pharmacological effects and has found applications in food and pharmaceutical industry. The alkaloid was studied by a combined approach: solid-state NMR, GA conformational search and GIAO DFT methods. The 13C CPMAS NMR spectra were recorded using variable contact time and dipolar dephasing experiments. The results of cross-polarization (CP) kinetics, such as TCP values and long T1ρH (100–200 ms), indicated that the capsaicin molecule is fairly mobile, especially at the end of the aliphatic chain. The15N MAS NMR spectrum showed one narrow signal at −255 ppm. Genetic algorithm (GA) search with multi modal optimization was used to find low-energy conformations of capsaicin. Theoretical GIAO DFT calculations were performed using different basis sets to characterize five selected conformations. 13C CPMAS NMR was used as a validation method and the experimental chemical shifts were compared with those calculated for selected stable conformers. Conformational analysis suggests that the side chain can be bent or extended. A comparison of the experimental and the calculated chemical shifts indicates that solid capsaicin does not have the same structure as those established by PWXRD.

Regioselective Diels-Alder reaction to open-cage ketolactam derivatives of C60.

Open-cage ketolactam fullerenes reacted with dienes on the rim of the orifice both regio- and stereoselectively. Unequivocal evidence for the structure of the Diels-Alder adduct was provided by 2D INADEQUATE 13C NMR studies on 13C enriched material, as well as via DFT-GIAO calculations. The theoretical calculations successfully model the regioselective and the endo stereoselective reaction, predicting molecular orbital control along with a repulsive steric interaction between the substituents on the nitrogen atom and those on the diene.

The isomeric structure of pentacoordinate chiral spirophosphoranes in solution by the combined use of NMR experiments and GIAO DFT calculations of NMR parameters.

The interplay of NMR experiments and DFT calculations of NMR parameters is a reliable method for determining the relative configurations of pentacoordinate chiral spirophosphoranes bearing two six- or five-membered rings at the phosphorus atom in solution. The major product of the Betti based derivatives corresponds to the isomers with both substituents at chiral carbons being opposite to the P-H proton. The next populated product corresponds to the isomer with different chiralities at carbons. The least populated isomer is one with both substituents being at the same side of the heterocycle as the P-H bond.

Structural determination of complex natural products by quantum mechanical calculations of (13)C NMR chemical shifts: development of a parameterized protocol for terpenes.

Nuclear magnetic resonance (NMR) spectroscopy is one of the most important tools for determining the structures of organic molecules. Despite the advances made in this technique, revisions of erroneously established structures for natural products are still commonly published in the literature. In this context, the prediction of chemical shifts through ab initio and density functional theory (DFT) calculations has become a very powerful tool for assisting with the structural determination of complex organic molecules. In this work, we present the development of a protocol for (13)C chemical shift calculations of terpenes, a class of natural products that are widely distributed among plant species and are very important due to their biological and pharmacological activities. This protocol consists of GIAO-DFT calculations of chemical shifts and the application of a parameterized scaling factor in order to ensure accurate structural determination of this class of natural products. The application of this protocol to a set of five terpenes yielded accurate calculated chemical shifts, showing that this is a very attractive tool for the calculation of complex organic structures such as terpenes.

Structural studies of malonaldehyde–glyoxal and malonaldehyde–methylglyoxal etheno adducts of adenine nucleosides based on spectroscopic methods and DFT-GIAO calculations

The substitution position in the etheno rings of M1Gx-A and M1MGx-dA was determined based on the comparison of data derived from NMR spectra with results obtained from computational calculations.

An improved Method of 13C NMR Chemical Shift by GIAO-DFT Calculations in the Study of a Synthetic Prenylated Chalcone

An improved Method of 13C NMR Chemical Shift by GIAO-DFT Calculations in the Study of a Synthetic Prenylated Chalcone

Benchmarking quantum mechanical calculations with experimental NMR chemical shifts of 2-HADNT

In this study, both GIAO-DFT and GIAO-MP2 calculations of nuclear magnetic resonance (NMR) spectra were benchmarked with experimental chemical shifts. The experimental chemical shifts were determined experimentally for carbon-13 (C-13) of seven carbon atoms for the TNT degradation product 2-hydroxylamino-4,6-dinitrotoluene (2-HADNT). Quantum mechanics GIAO calculations were implemented using Becke-3-Lee–Yang–Parr (B3LYP) and other six hybrid DFT methods (Becke-1-Lee–Yang–Parr (B1LYP), Becke-half-and-half-Lee–Yang–Parr (BH and HLYP), Cohen–Handy-3-Lee–Yang–Parr (O3LYP), Coulomb-attenuating-B3LYP (CAM-B3LYP), modified-Perdew–Wang-91-Lee–Yang–Parr (mPW1LYP), and Xu-3-Lee–Yang–Parr (X3LYP)) which use the same correlation functional LYP. Calculation results showed that the GIAO-MP2 method gives the most accurate chemical shift values, and O3LYP method provides the best prediction of chemical shifts among the B3LYP and other five DFT methods. Three types of atomic partial charges, Mulliken (MK), electrostatic potential (ESP), and natural bond orbital (NBO), were also calculated using MP2/aug-cc-pVDZ method. A reasonable correlation was discovered between NBO partial charges and experimental chemical shifts of carbon-13 (C-13).

Solvent effects in the GIAO-DFT calculations of the 15N NMR chemical shifts of azoles and azines.

The calculation of (15)N NMR chemical shifts of 27 azoles and azines in 10 different solvents each has been carried out at the gauge including atomic orbitals density functional theory level in gas phase and applying the integral equation formalism polarizable continuum model (IEF-PCM) and supermolecule solvation models to account for solvent effects. In the calculation of (15)N NMR, chemical shifts of the nitrogen-containing heterocycles dissolved in nonpolar and polar aprotic solvents, taking into account solvent effect is sufficient within the IEF-PCM scheme, whereas for polar protic solvents with large dielectric constants, the use of supermolecule solvation model is recommended. A good agreement between calculated 460 values of (15)N NMR chemical shifts and experiment is found with the IEF-PCM scheme characterized by MAE of 7.1 ppm in the range of more than 300 ppm (about 2%). The best result is achieved with the supermolecule solvation model performing slightly better (MAE 6.5 ppm).

Induction of quinone reductase (QR) by withanolides isolated from Physalis pubescens L. (Solanaceae)

In the present study, it was demonstrated that the dichloromethane extract of Physalis pubescens L. (DEPP) had weak potential quinone reductase (QR) inducing activity, but an UPLC–ESI-MS method with glutathione (GSH) as the substrate revealed that the DEPP had electrophiles (with an α,β-unsaturated ketone moiety). These electrophiles could induce quinone reductase (QR) activity, which might be attributed to the modification of the highly reactive cysteine residues in Keap1. Herein, four withanolides, including three new compounds physapubescin B (2), physapubescin C (3), physapubescin D (4), together with one known steroidal compound physapubescin (1) were isolated. Structures of these compounds were determined by spectroscopic analysis and that of physapubescin C (3) was confirmed by a combination of molecular modeling and quantum chemical DFT-GIAO calculations. Evaluation of the QR inducing activities of all withanolides indicated potent activities of compounds 1 and 2, which had a common α,β-unsaturated ketone moiety.

A Detailed NMR- and DFT-Based Study of the Sakurai–Hosomi–Yamamoto Asymmetric Allylation Reaction

A Lewis acid complex between benzaldehyde and the silver catalyst was detected by (31)P NMR and shown to be the direct precursor to allylation within the Sakurai-Hosomi-Yamamoto reaction. Structural and thermochemical hybrid-DFT calculations indicated that benzaldehyde predominantly formed an η(1)-σ-complex with the catalyst; however, two other competing conformers involving different coordination modes were found, including an activated μ(2)-bound complex. The differences in (31)P NMR shifts upon complexation were calculated by the gauge-independent atomic orbital (GIAO-DFT) method for each conformer. The minimum energy conformer was found to correlate well with chemical shift trends observed experimentally, and an analysis of Mullikan charge populations revealed that the carbonyl carbon of the highest-energy conformer was the most electron-deficient. Furthermore, one minor and three major silicon intermediates were detected by (29)Si NMR and, with the aid of (1)H-(29)Si HSQC, were assigned by comparison with parent compounds and GIAO-DFT calculations. Finally, a tentative mechanism was proposed based on these findings.