IEF-PCM Solvation Model Research Articles

Keto-enol tautomerism, spectral (infrared, Raman and NMR) studies and Normal coordinate analysis of 4-Methyl-2-hydroxyquinoline using quantum mechanical calculations

The Raman (3500−100 cm−1) and mid-infrared (4000−400 cm−1) spectra of 4-Methyl-2-hydroxyquinoline (MHQ) have been recorded. Owing to the keto-enol tautomerism and rotation of methyl group around C4–C13 single bond, six structures (S1–S6) were hypothetically proposed. Full geometry optimization and frequency calculations were performed for keto (quinolone) and enol (hydroxyquinoline) structures using the DFT methods including B3LYP, ωB97XD and mPW1PW91 with basis sets up to 6–311+G(2d,p). In addition, 1H/13C NMR chemical shifts (δ, ppm) were estimated utilizing GIAO approach and IEF-PCM solvation model. The computational outcomes favor keto tautomer, 4-Methylquinolin-2-one (MQO) while the methyl group is staggered to C4–C5 bond (S5). However, other structures were excluded owing to high energy differences besides having an imaginary wavenumber for the transition state structures S2, S4 and S6. These results agree with the observed/calculated vibrational spectral data along with 1H/13C NMR chemical shifts. Aided by the calculated wavenumbers and normal coordinate analysis, complete assignments for the observed infrared/Raman bands to their corresponding vibration modes were quantitatively reported herein for keto- MQO. Employing B3LYP/6–311+(2d,p) structural parameters, the thermo kinetic parameter F-number (5.3936707 cm−1) is estimated along with V3 barrier (1067±48/1219±62 cm−1, 3.05±0.14/3.48±0.18 kcal/mol) using the calculated/observed methyl torsion at 217/233 cm−1.

Synthesis, spectral and quantum mechanical studies and molecular docking studies of Schiff base (E)2-hydroxy-5-(((4-(N-pyrimidin-2-yl)sulfamoyl)phenyl)imino)methyl benzoic acid from 5-formyl salicylic acid and sulfadiazine

A new Schiff base (E)2-hydroxy-5-(((4-(N-pyrimidin-2-yl)sulfamoyl)phenyl)imino)methyl benzoic acid (5FSADA) compound was synthesized by condensation of 5-formyl salicylic acid and sulfadiazine, and the product formed was characterized using FTIR and UV–Visible spectroscopy. The geometry was optimized using DFT. The FTIR were computed from DFT and is compared with experimental spectra, followed by detailed vibrational assignment, which shows that the experimental and simulated data is in close agreement. The UV–Vis spectrum calculated using TD-DFT, IEFPCM solvation model with DMSO as solvent. Wave function based properties like localized orbital locator, electron localization function and non-covalent interactions has been studied extensively. The physical properties (ADMET) of the compound 5FSADA indicated that the compound has excellent drug likeness and PASS studies showed that it has anti-infective properties, which is confirmed by a docking score of −9.0 ​kcal/mol.

Evaluation of electronic and biological interactions between N-[4-(Ethylsulfamoyl)phenyl]acetamide and some polar liquids (IEFPCM solvation model) with Fukui function and molecular docking analysis

The structural parameter, electron behaviour, wave function, and biological properties of N-[4-(Ethylsulfamoyl)phenyl]acetamide are investigated using the Gaussian 16 W DFT tool. In the solvent phase, optimised geometrical properties, wave functional properties such as electron localization functions, and inter molecular interaction (NCI) analysis, reduced density gradient are investigated in a polar aprotic liquid. From HOMO-LUMO orbital’s band gap energy are determined in water and DMSO. From MEP analysis in polar (protic) and polar (aprotic) liquids the evidence about reactivity of the compound is analysed. By using, NBO method intra molecular interactions are studied and the charge transfer energies are explained. Vibrational spectroscopic assignment for title compound is determined by quantum computation. Furthermore, the properties of the drug mechanism ADMET and mol inspiration values are predicted. Finally, a molecular docking study is carried out to investigate the fungal and cancer activities of the headline compound.

Synthesis, single crystal (XRD), Hirshfeld surface analysis, computational study (DFT) and molecular docking studies of (E)-4-((2-hydroxy-3,5-diiodobenzylidene)amino)-N-(pyrimidine)-2-yl) benzenesulfonamide

The Schiff base (E)-4-((2-hydroxy-3,5-diiodobenzylidene)amino)-N-(pyrimidine)-2-yl) benzene sulfonamide (DIDA) compound was synthesis with condensation of 3,5-diiodosalicylaldehyde and sulfadiazine. The compound characterized with FTIR, X-ray crystallography and electronic spectra. The titled compound associated with experimental and theoretical method, DFT used for the theoretical method. The IR was calculated from DFT mode with B3LYP/GENSEP basic set. The electronic spectra computed from TD-DFT method with CAM-B3LYP functional, with IEFPCM solvation model and DMSO used as the solvent. Wave function based properties like localized orbital locator, electron localization function and non-covalent interactions have been studied extensively. The ADMET properties of the compound DIDA indicated that the compound has excellent drug likeness properties and PASS studies showed that it has anti-infective properties, which is confirmed by a docking score of -7.4 kcal/mol.

Intermolecular interaction study of l-Threonine in polar aprotic Solvent: Experimental and theoretical study

The present paper accounts for the interacting nature of CO, CH and OH vibrational modes of l-Threonine in polar aprotic solvent Dimethyl Formamide(DMF) using Raman spectroscopic and infrared(IR) techniques. The intermolecular interaction between l-Threonine and DMF are analyzed using Density Functional Theory (DFT), IEFPCM and M062X methods, each with a basis set 6–311++G (d, p)to predict the favourable interacting sites of the two molecules and to validate the experimental data with the theoretical calculations. The variation in peak frequencies has been explained for neat l-Threonine and their interactions at different concentrations (0.1 M, 0.3 M, 0.5 M, 0.7 M and 0.9 M). The wavenumbers of all the stretching modes (CO, CH and OH) shows a redshift. The intensity and the topology parameters of the intermolecular hydrogen bond at the bond critical points have been analyzed using the AIM theory of DFT and M062X methods. The intermolecular hydrogen bonding for the mentioned complexes and the study of the surface charge that encompasses the molecular cavity has also been carried out using the IEF-PCM solvation model under the same basis set. Electronic properties such as MEP surface study, frontier orbital analysis, and their corresponding energy gap have also been analyzed using DFT calculation. The frequencies derived from the computational and experimental data are found in good correlation to each other.

Stability Series for the Complexation of Six Key Siderophore Functional Groups with Uranyl Using Density Functional Theory.

Determining stability constants of uranyl complexes with the principal functional groups in siderophores and identifying stability series is of great importance to predict which siderophore classes preferentially bind to UVI and, hence, impact uranium speciation in the environment. It also helps to develop resins for scavenging UVI from aqueous solutions. Here, we apply a recently developed computational approach to calculate log β values for a set of geochemically relevant uranium organometallic complexes using Density Functional Theory (DFT). We determined the stability series for catecholate, hydroxamate, α-hydroxycarboxylate, α-aminocarboxylate, hydroxy-phenyloxazolonate, and α-hydroxyimidazole with the uranyl cation. In this work, the stability constants (logβ110) of α-hydroxyimidazolate and hydroxy-phenyloxazolonate are calculated for the first time. Our approach employed the B3LYP density functional approximation, aug-cc-pVDZ basis set for ligand atoms, MDF60 ECP for UVI, and the IEFPCM solvation model. DFT calculated log β110 were corrected using a previously established fitting equation. We find that the siderophore functional groups stability decreases in the order: α-hydroxycarboxylate bound via the α-hydroxy and carboxylate groups (logβ110 = 17.08), α-hydroxyimidazolate (logβ110 = 16.55), catecholate (logβ110 = 16.43), hydroxamate (logβ110 = 9.00), hydroxy-phenyloxazolonate (logβ110 = 8.43), α-hydroxycarboxylate bound via the carboxylate group (logβ110 = 7.51) and α-aminocarboxylate (logβ110 = 4.73). We confirm that the stability for the binding mode of the functional groups decrease in the order: bidentate, monodentate via ligand O atoms, and monodentate via ligand N atoms. The stability series strongly suggests that α-hydroxyimidazolate is an important functional group that needs to be included when assessing uranyl mobility and removal from aqueous solutions.

Computational Tools for Calculating log β Values of Geochemically Relevant Uranium Organometallic Complexes.

Uranium (UVI) interacts with organic ligands, subsequently controlling its aqueous chemistry. It is therefore imperative to assess the binding ability of natural organic molecules. We evidence that density functional theory (DFT) can be used as a practical protocol for predicting the stability of UVI organic ligand complexes, allowing for the development of a relative stability series for organic complexes with limited experimental data. Solvation methods and DFT settings were benchmarked to suggest a suitable off-the-shelf solution. The results indicate that the IEFPCM solvation method should be employed. A mixed solvation approach improves the accuracy of the calculated stability constant (log β); however, the calculated log β are approximately five times more favorable than experimental data. Different basis sets, functionals, and effective core potentials were tested to check that there were no major changes in molecular geometries and Δr G. The recommended method employed is the B3LYP functional, aug-cc-pVDZ basis set for ligands, MDF60 ECP and basis set for UVI, and the IEFPCM solvation model. Using the fitting approach employed in the literature with these updated DFT settings allows fitting of 1:1 UVI complexes with root-mean-square deviation of 1.38 log β units. Fitting multiple bound carboxylate ligands indicates a second, separate fitting for 1:2 and 1:3 complexes.

Raman bandshape analysis and DFT study of C[dbnd]O and C[sbnd]H stretching modes of NN-Dibutyl formamide in DMSO solvent`

The study reports the inter-molecular interactions and dynamics of CO and CH stretching modes of NN- Dibutyl Formamide (DBF) in DMSO solvent using Raman spectroscopic technique. The Raman band of CO and CH stretching modes have been deconvoluted into two distinct bands for neat as well as in DMSO solvent. Peak wavenumbers of CO stretching modes show red shift while CH stretching modes shows blue shift with the increase in solvent concentrations. The optimized geometric parameters, vibrational wavenumbers, Mulliken atomic charges and natural bond orbitals of the molecule has been computed using Density Functional Theory (DFT) method with basis set 6-31 +G (d, p). In addition, the same basis set has been carried out with counterpoise keyword accounting BSSE calculation on monomer and dimer states with DMSO solvent to present an appropriate interacting environment. IEF-PCM solvation model has also been computed using the same basis set and compares the geometrical parameters and vibrational wavenumbers of the molecules and in their complexes. In order to get a complete study of the DBF + DMSO complexes, explicit solvation model has also been calculated for Monomer DBF in two solvent molecules. Theoretical calculations of frequencies have been compared with the experimental findings and the results are found in good agreement.

Quantum Chemical Prediction of pKa Values of Cationic Ion-Exchange Groups in Polymer Electrolyte Membranes

The durability of anion-exchange membranes (AEMs) in alkaline fuel cells is largely determined by the stability of anion-exchange groups. Despite continuous research efforts, the commonly employed cations still have limited stability against hydroxide that can act as a strong base and nucleophile. This work is concerned with base-catalyzed degradation of organic cations initiated by proton abstraction to form reactive ylides or carbenes. We report on the performance of 24 methods combining density functional theory and electronic structure methods with implicit solvation calculations for predicting pKa values of organic cations in water and DMSO. The most accurate computational protocols are obtained using a combination of M06-2X/6-311++G** with the SMD solvation model for water (the mean absolute error of 0.4 pKa units) and B3LYP/aug-cc-pVTZ with the IEFPCM solvation model for DMSO (the mean absolute error of 1.4 pKa units). The aqueous pKa calculation protocol is cross-validated against the experimental...

Microwave dielectric relaxation spectroscopy study of propylene glycol/ethanol binary mixtures: Temperature dependence

Complex dielectric permittivity measurements of propylene glycol (PG) in ethanol at various mole fractions were measured by using open-ended coaxial probe technique at different temperatures in the frequency range 0.02<ν/GHz<20. The dipole moment (μ), excess dipole moment (Δμ),excess permittivity (εE), excess inverse relaxation time(1/τ)E, Bruggeman parameter (fB), excess Helmholtz energy (ΔFE) are determined using experimental data. From the minimum energy based geometry optimization, dipole moments of individual monomers of propylene glycol and ethanol and their binary system have been evaluated theoretically at gaseous state as well as alcoholic medium by using PCM and IEFPCM solvation models from the Hatree-Fock (HF) and Density Functional Theory (DFT-B3LYP) methods with 6-311G* and 6-311G** basis sets. The obtained results have been interpreted in terms of the short and long range ordering of the dipoles, Kirkwood correlation factor (geff), thermodynamic parameters, mean molecular polarizability (αM) and interaction in the mixture through hydrogen bonding.

The Role of Negative Hyperconjugation in Decomposition of Bicarbonate and Organic Carbonate Anions

Intrinsic electronic effects of the bicarbonate anion and its organic derivatives have been examined computationally. Decomposition pathways of methyl hydrogen carbonate and a series of methyl aryl/alkyl carbonate diesters, via the bicarbonate anion and aryl/alkyl carbonate anions, respectively, to final products CO2 and the hydroxide anion or aryloxide/alkoxide anions, have been calculated at the MP2(full)/6-311+G(2d,p) level of theory in the gas phase as well as with the IEFPCM solvation model. The optimized geometries of the bicarbonate anion and its derivatives have revealed that the O2C−OH/Ar/R bond is noticeably elongated. In addition, NBO analysis has indicated that the transfer of electron density from the carboxylate moiety into the antibonding σ* orbital of the O2C−OH/Ar/R bond occurs, weakening the bond noticeably. In aromatic carbonates, the anionic charge is further delocalized to the aromatic ring, additionally reducing the negative charge in the carboxylate moiety and weakening the O2C−OAr bond. These indicators show that the negative (inverse) hyperconjugation is operative in these anions, determining their thermodynamic and kinetic stability toward both the recombination with a cation and further decomposition.

Conformation of six fentanyls revisited

Conformation of fentanyl and its five derivatives was studied at the B3LYP/6-31G∗∗ level. Two stereoisomers for α-methyl-β-hydroxy fentanyl and four for the ohmefentanyl were taken into account. Conformation in the gas phase and water, simulated using the IEF-PCM and SMD implicit models of solvents, was independently optimized using 27 starting structures resulted from rotations about the most important three torsion angles. The role of the Grimme’s D3 correction for the dispersion forces was additionally considered for each medium. The correction appeared to influence more the gas phase than water dissolved structures. Moreover, the correction influences more the conformations of N-phenylpropionamide group than those of the modified phenylethyl substituent. In water solution simulated by the IEF-PCM and SMD solvation models, the conformers connected to the phenylethyl moiety, are substantially different only for the two derivatives, for which indications coming from different computational variants are the most vague. However, for the conformers connected to the N-phenylpropionamide group, the IEF-PCM model favors the t conformation for three derivatives while SMD prefers sum of the g+ and g− conformations for the other three derivatives. For the ohmefentanyl stereoisomers, irrespectively, the solvation or presence of the D3 correction, all the methods concordingly predict the N-phenylpropionamide group conformation twisted by either −120° or to 120°.

Solvation enthalpies and Gibbs energies of the proton and electron: Influence of solvation models

A comprehensive examination of the solvation enthalpies and Gibbs energies of the proton and electron in twenty solvents of different polarities was carried. Eleven quantum mechanical methods were applied in conjunction with the 6-311++G(d,p) basis set and C-PCM solvation model. It was found that different methods produce consistent values for the solvation enthalpy and Gibbs energy of the proton in all solvents, while the corresponding values for the electron are mutually notably different. The fact that the Minnesota functionals often produced inconsistent solvation enthalpy and Gibbs energy values of the electron indicates their unreliable performance without the corresponding SMD solvation model, whereas other studied methods only slightly depend on solvation models. A comparison of the results of the present investigation to those obtained by employing SMD reveals that C-PCM produces slightly more negative (less positive) solvation enthalpies and Gibbs energies of the electron, and less negative values for the proton. These results are also in accord with the literature data where the IEF-PCM solvation model was used.

Computational study on mechanisms of the anticancer drug: Cisplatin and novel polynuclear platinum(II) interaction with sulfur-donor biomolecules and DNA purine bases

In this paper, we explore the monofunctional substitution reactions between cisplatin and novel polynuclear platinum(II) (BBR3005 and BBR3464) hydrolyzed complexes and sulfur-donor biomolecules (glutathione, methionine and cysteine) and purine bases (guanine and adenine) in DNA with two different DFT-B3LYP/M06 functional methods and IEF-PCM solvation model. The computed activation energy barrier of chloroaqua-Pt (BBR3464) and diaqua-Pt (BBR3464) complexes binding to guanine (G), adenine (A), and glutathione (GSH) in the aqueous solution with B3LYP functional method is 17.9/17.9kcal/mol, 19.9/19.8kcal/mol, and 13.2/14.6kcal/mol, respectively. What is more, the computed activation energy barrier for substitution reaction of diaqua-cisplatin with DNA by B3LYP functional method is 20.1kcal/mol (11.2kcal/mol for M06 functional method) for guanine (G) (experimental value=18.3kcal/mol) and 22.3kcal/mol (15.5kcal/mol for M06 functional method) for adenine (A), which shows that the B3LYP functional method may be more suitable for platinum–DNA system calculation compared with M06 functional method. Our calculation demonstrates that GSH is more favorable intracellular targets than Met, Cys and DNA purine bases for BBR3464, which is also consistent with the results that platinum(II) has high affinity for binding to S-donors biomolecules especially glutathione compared with N-donors biomolecules such as DNA purine bases.The calculated activation energies barrier of interaction of polynuclear platinum(II) with purine bases are lower than those of cisplatin no matter we use B3LYP or M06 functional method, which confirms that anticancer activity of polynuclear platinum(II) is higher than cisplatin as suggested by experiment.

Experimental and computational study of CO2 storage and sequestration with aqueous 2-amino-2-hydroxymethyl-1,3-propanediol (TRIS) solutions.

Experimental solubility data of CO2 in (5 and 10) mass% TRIS aqueous solutions were measured at (318.15 and 333.15) K and up to 10 MPa. The solubility data were well correlated with the modified Kent-Eisenberg model. The reaction mechanism, reaction energies, and equilibrium constants for the formation of bicarbonate and carbamate from CO2, H2O, and TRIS were studied using the quantum-chemical approach COSMO-RS (conductor-like screening model for real solvents) at the BP/TZVP level. The bicarbonate and carbamate formations were confirmed by using Fourier transform infrared (FTIR) spectroscopy. The results demonstrate that the formation of the bicarbonate anion is the main product formed by the direct reaction of CO2 with water and TRIS, and reveal that the carbamate anion was formed by a proton transfer from TRIS-CO2 zwitterion to TRIS. Density functional theory (DFT) calculations with transition-state optimization and intrinsic reaction coordinate (IRC) in water using IEF-PCM solvation model at the B3LYP/6-311++G(d,p) levels of theory were employed to support the reaction pathway for the bicarbonate and carbamate formations. The conversion of the absorption product to stable carbonate (CaCO3) was also investigated experimentally by adding various Ca(2+) sources, CaCl2·2H2O aqueous solution, and artificial seawater.

Theoretical study on the mechanism of reaction of novel iminoether-containing Pt(II) anticancer drugs with biological targets

The reaction mechanisms of the novel potential anticancer agents trans-[PtCl2{(E)HNC(OCH3)CH3}2](trans-EE), trans-[PtCl2(NH3){(E)HNC(OCH3)CH3}](trans-E) and trans-[PtCl2(NH3){(Z)HNC(OCH3)CH3}](trans-Z) binding to DNA purine bases and amino acid residues (AAR) are explored by utilizing DFT-B3LYP functional theory and IEF-PCM solvation models. Our calculations suggest that all reaction processes can generate very similar trigonal-bipyramidal transition state configurations. Hydrogen bonds are widespread in all species and play a key role in stabilizing these species. Complete or partial proton transfer has been found in the reactant complexes. All reactants were selected the relative stable conformations. Two kinds of reaction paths with HH (head-to-head) and HT (head-to-tail) were found in bifunctional substitution. Comparison of the activation energies of these iminoether-containing Pt(II) indicates that the anticancer activity of trans conformations are higher than cis isomers, and the trans-EE showing the highest activity. The activation energies were simulated in aqueous solution (ε=78.39) and protein environment (ε=4.24). Our data suggest that environment donates little effect on the activation energy which can be ignored in terms of overall reactions on some extent. Those potential drugs have a similar mechanism to cisplatin.

Theoretical study on the bifunctional substitution reactions between gold(III) dithiocarbamate derivative Au(DMDT)Cl2 (DMDT = N,N-dimethyldithiocarbamate) and target molecules

The complex Au(DMDT)Cl2 (DMDT=N,N-dimethyldithiocarbamate) is one of the most potential anticancer drugs with the strong cytotoxicity. However, the mechanisms of its monofunctional adducts as the active species for the formation of bifunctional adducts have not been established, thus substitution reactions between hydrated [Au(DMDT)(H2O)Cys(S, N)]2+, [Au(DMDT)(H2O)Cys(N, O)]2+, and [Au(DMDT)(H2O)G]2+ and target molecules were studied by our laboratory at the DFT level using B3LYP hybrid functional and IEF-PCM solvation model. Firstly, the reactant complex (RC) via similar trigonal bipyramidal transition state (TS) structure generates product complex (PC), and with the structural analysis towards RC, PC and TS, we know the hydrogen bond (H-bond) playing an indispensable role in the stabilization of these complexes for the bifunctional substitutions. In addition, it is worth noting that there is competition of intrinsic kinetic among different active sites of cysteine. In the bifunctional substitution reactions, the result appears to be that the N7 of guanine is the strongest site and superior to active sites (S, N) of cysteine. The soft metal center Au prefers S site of cysteine over N site interactions with hydrated [Au(DMDT)(H2O)Cys]2+ complexes and the O site of cysteine is the weakest for all reactions in the aqueous solution. Besides, the [Au(DMDT)GG]2+ head-to-head path has the lowest free energy of activation at 3.7kcal/mol and its head-to-tail path at 6.2kcal/mol, while the [Au(DMDT)GA]2+ head-to-head path has the lowest barrier of 13.3kcal/mol, and then the following head-to-tail path at 18.9kcal/mol. There was something else: the calculations show the TS for amino group acts as the attacking group to be more stable than that for sulphydryl, when the monofunctional adduct [Au(DMDT)G(H2O)]2+ acts as the reactant. A favorable reaction pathway of bifunctional substitution process is proposed by our theoretical computation.

A DFT-based model for calculating solvolytic reactivity. The nucleofugality of aliphatic carboxylates in terms of Nf parameters.

The most comprehensive nucleofugality scale, based on the correlation and solvolytic rate constants of benzhydrylium derivatives, has recently been proposed by Mayr and co-workers (Acc. Chem. Res., 2010, 43, 1537-1549). In this work, the possibility of employing quantum chemical calculations in further determination of nucleofugality (Nf) parameters of leaving groups is explored. Whereas the heterolytic transition state of benzhydryl carboxylate cannot be optimized by quantum chemical calculations, the possibility of an alternative model reaction is examined in order to obtain nucleofugality parameters of various aliphatic carboxylates, which can properly be included in the current nucleofugality scale. For that purpose, ground and transition state structures have been optimized for the proposed model reaction, which includes anchimerically assisted heterolytic dissociation of cis-2,3-dihydroxycyclopropyl trans-carboxylates. The validity of the model reaction as well as of applied DFT methods in the presence of the IEFPCM solvation model is verified by correlating calculated free energies of activation of the model reaction with literature experimental data for solvolysis of reference dianisylmethyl carboxylates. For this purpose the ability of several functionals (including popular B3LYP) is examined, among which the M06-2X gives the best results. The very good correlation indicates acceptable accurate relative reactivities of aliphatic carboxylates, and enables the estimation of rate constants for solvolysis of other dianisylmethyl carboxylates in aqueous ethanol mixtures, from which the corresponding Nf parameters are determined using mentioned Mayr's equation. In addition, DFT calculations confirm the previous experimental observation that the abilities of aliphatic carboxylate leaving groups in solution are governed by the inductive effect of substituents attached to the carboxyl group.

Complexation of heteroaromatic N-oxides with rhodium(II) tetracarboxylates in solution: DFT and NMR investigations

Complexation of rhodium(II) tetraacetate and rhodium(II) tetrakistrifluoroacetate with a set of heteroaromatic N-oxides containing additional functional groups was investigated by means of density functional theory (DFT) calculations, and 1H, 13C and 15N nuclear magnetic resonance (NMR) spectroscopy in CDCl3 solutions. Chemical shifts for five N-oxides and their 1:1 adducts with rhodium tetraacetate were computed at the B3PW91/[6-311++G(2d,p), Stuttgart ECP)//B3LYP/[6-31G(2d), LANL2DZ] theory level applying IEF PCM (CHCl3) solvation model and taking into account various complexation modes and conformational variety. Calculated values were used for the estimation of complexation shifts Δδ (Δδ=δadduct−δligand). The largest negative complexation shift were estimated for heteroatoms bonded to Rh, from −37 to −70 ppm (N), from −100 to −160ppm (O in NO group), from −13 to −23ppm (O in OCH3 group), and from −12 to −22 ppm (Cl). For the remaining heteroatoms in adducts, the corresponding Δδ values ranged from −22 to +8.2ppm (N), from +3 to +58ppm (O) and from +6 to +51 ppm (Cl). The Δδ(1H) usually did not exceed 1ppm, whereas Δδ(13C) varied from ca. −1 to +7ppm. Some trends useful for the determination of the complexation site were extracted from calculated data sets. Theoretical findings were applied to analyse experimental NMR data.

THEORETICAL STUDY ON THE BINDING OF THE ANTICANCER DRUGS Cis/Trans-[PtCl52(NH3){HN = C(CH3)2}] AND Cis/Trans-[PtCl2{HN = C(CH3)2}2] TO PURINE BASES

The monofunctional (the first substitution reactions) and bifunctional (the second substitution reactions) binding of the title antitumor drugs to purine bases were studied computationally by using density functional theory and IEF-PCM solvation models. For the first substitutions with guanine and adenine, our calculations demonstrate that the trans monoaqua and diaqua reactant complexes (RCs) can generate trans- or cis-monoadducts via identical or very similar trigonal-bipyramidal transition-state structures, predicting that the cis-monoadducts generated by trans RCs can subsequently close by coordination to the adjacent purine bases to form 1,2-intrastrand Pt –DNA adducts and eventually distort DNA in the same way as cisplatin. Thus it is likely that the transplatin analogues have the same mechanism of anticancer activity of cisplatin. In general, the monoaqua and diaqua monofunctional substitutions prefer guanine over adenine. The calculated lowest activation free energy in aqueous solution is 15.2 kcal/mol in the monoaqua substitutions (substituted by guanine from trans- [Pt{HN = C(CH3)2}2Cl(H2O)]+ to trans/cis-monoadduct), and 11.4 kcal/mol in the diaqua substitutions (substituted by guanine from cis- [Pt{HN = C(CH3)2}2(H2O)2]2+ to cis-monoadduct). For the second substitutions, all the reactants are started from the diaqua product complexes of the first substitutions substituted by guanine. The data obtained for the complexation energy difference between guanine and adenine RCs suggest that a thermodynamic favors the formation of GG over GA adducts by ∼ 5 - 12 kcal/mol in aqueous solution. Moreover, there is a kinetic preference for the formation of GG over GA adduct for the cis-monoadduct to cis-diadduct paths, while for the trans-monoadduct to trans-diadduct paths there is no certain trend biased toward GG adduct. In addition, the second substitutions of the trans-monoadduct to trans-diadduct paths have lower activation barriers than the corresponding cis-monoadduct to cis-diadduct paths. The lowest activation energy in the bifunctional substitutions from cis-monoadduct to cis-diadduct is 20.5 kcal/mol in the Pt (acetonimine)2GG2+ head-to-head (HH) path, while it is 17.7 kcal/mol from trans-monoadduct to trans-diadduct in the Pt(NH3) (acetonimine)GA2+ head-to-tail (HT) path. For the first and second substitutions, hydrogen-bonds play an important role in stabilizing these species.