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The influence of structure and lipophilicity of hydantoin derivatives on anticonvulsant activity
(1999)
Quinoxalines XV : convenient synthesis and structural study of pyrazolo[1,5-alpha]quinoxalines
(2009)
A series of aryloxymethylquinoxaline oximes, hitherto unknown and synthesized from the corresponding aldehydes, afforded in only one step pyrazolo[1,5-;]quinoxalines in the presence of acetic anhydride at high temperatures. A formal [3,5]-sigmatropic rearrangement was proposed as the mechanistic rationale for this unprecedented transformation. Saponification with potassium hydroxide furnished the free phenol derivatives which were studied by NMR spectroscopy and accompanying theoretical DFT calculations, establishing intramolecular hydrogen bonding and the spatial magnetic properties. Additionally, mass spectrometric fragmentation was investigated by B/E-linked scans and collision-induced dissociation experiments. The fragmentation pattern devoted a new gas phase rearrangement process, which proved to be unique and characteristic for pyrazolo[1,5-;]quinoxalines.
Trithiaazapentalene derivatives were prepared by the reaction of 2-alkylidene-4-oxothiazolidines with Lawesson's reagent. They are classified as two structurally different trithiaazapentalene compounds that have different contributions of monocyclic 1,2-dithiole and 1,2,4-dithiazole structures and degrees of aromaticity of the bicyclic trithiaazapentalene system. The electron-donating ability of substituents at the C(5) position of the trithiaazapentalene system is recognized as the main cause for changes in pi-Celectron distribution. This is the first complete study of substituent effects on the structure of trithiapentalenes. (C) 2013 Elsevier Ltd. All rights reserved.
1-Oxo-1,3-dithiolane (4) and its cis- and trans-2-methyl (5,6), -4-methyl (7,8) and -5-methyl (9,10) derivatives were prepared by oxidizing the corresponding 1,3-dithiolanes (1-3) with NaIO(4) in water. The oxides were purified and their isomers separated using thin layer chromatography. The structural characterization was carried out with (1)H and (13)C NMR spectroscopy and molecular modelling. The sulfoxides 4-6 and 8-10 attain two S(1) type envelopes (sometimes slightly distorted) the S=O(ax) envelope greatly dominating. Cis-4-methyl-1-oxo-1,3-dithiolane is a special case exhibiting both two closely related S=O(ax) (30 and 27%) as well as S=O(eq) (21 and 22%) forms [S(1) and C(4) envelopes, respectively]. The relative energies of these conformations, the values of (1)H-(1)H coupling constants and (1)H and (13)C chemical shifts were estimated by computational methods and they support well the conclusions based on the experimental data.
The nature of the major steric substituent constant scales for alkyl substituents, i.e. Omega(S), E-R and E-S' scales, was studied with the aid of the NBO and the natural steric (STERIC) analyses. Cyclohexyl esters R-3-CCOOC6H11 (R = alkyl or H) were used as the model compounds. Special emphasis was laid on the potential contribution of the polar component in these steric substituent parameters. In the light of our model the Omega(S) scale seems to be dominantly a steric substituent constant scale as is seen on the strengths of the good correlation between the Omega(S) constants of the CR3 group and the total steric exchange energy values E-TSEE for the model compounds. However, the Omega(S) values also seem to include a minor electronic component due to the varying electrostatic effect via the C alpha atom. On the other hand, E-R and E-S' parameters largely hinge on the size dependent polar effect of the CR3 alkyl group. By way of our model this repulsive interaction can be quantified by descriptor Delta q(OCO), the natural charge difference q(C)(C=O) - Sigma qO for the O-C(=O) functional group. Delta q(OCO) depends on the E-TSEE values, on qC alpha and on the polarization coefficients of the oxygen hybrid in the NBO of the pi(C=O) bond. The size sensitivity of the kinetic E-S' constants can be connected to variation of the Burgi-Dunitz angle in the transition state for the standard reaction used. A comparison is made for the q(C)(C=O) or Delta q(OCO) values computed on the one hand with the NBO formalism and on the other hand with the Hirshfeld formalism. A practical novel substituent constant q(C)(C=O) for the size of the alkyl groups is introduced.
The validity of the Taft equation: log(k(R)/k(CH3)) = rho*sigma* + delta E-S was studied with the aid of NBO computational results concerning cyclohexyl esters RCOOC6H11 [R = Methyl, Ethyl, n-Propyl, Isopropyl, n-Butyl, Isobutyl, sec-Butyl, tert-Butyl, Neopentyl, CH(CH2CH3)(2), CH(CH3)C(CH3)(3), C(CH3)(2)CH2CH3, C(CH3)(2)C(CH3)(3), CH(CH3)(Np), CH(iPr)(tBu), C(Me)(Et)(iPr), C(Et)(2)(tBu) or C(Et)(iPr)(tBu)]. It was proved that the sigma*(alkyl) value is a composite substitutent constant including the polar and steric contributions. A novel computational sigma(q)* substituent constant scale is presented based on the NBO atomic charges of the alpha-carbon and the computational total steric exchange energies E(ster) of the cyclohexyl esters specified above. The method used offers a useful way to calculate sigma*(alkyl) values for alkyl groups for which experimental Taft's polar sigma* parameters are not available.
The proportion of the axial conformer increases in the ax reversible arrow eq equilibrium of cyclohexyl acetates (RCOOC(6)H(11), R reversible arrow Me, Et, iPr, tBu, CH(2)Cl, CHCl(2), CO(3). CH(2)Br, CHBr(2), CBr(3)) with the increasing size of the acyloxy substitution. The nature of this unexpected steric substituent effect, which is opposite to general stereochemical concepts, was studied by means of ab kiln MO method, accompanied by NBO and isodesmic calculations. NBO parameters seem to be good descriptors for quantitative prediction of the experimental Delta G degrees value of the title conformational equilibrium. The origin and propagation of the substituent effect of the polar substitutions (CH(2)Cl, CHCl(2), CCl(3), CH(2)Br, CHBr(2), CBr(3)) differ, however, from those of the pure alkyl (Me, Et, iPr, tBu) substitutions. The Delta G degrees value of the polar derivatives depends on the qC8 charges, on the occupation of the sigma(center dot)(C1-07) orbital and on the hyperconjugative pi(center dot)(c=O) -> sigma(center dot)(C10-X) and sigma(center dot)(C10-X) -> pi(center dot)(c=O) interactions. The substituent sensitivity of these NBC parameters for the two conformers differ to the effect that the ax reversible arrow eq equilibrium is shifted to the left side with increasing electron withdrawing character of the acyloxy group. The Delta G degrees values of the alkyl derivatives are interpreted in terms of the calculated dipole moments. The destabilization in the non-polar medium (the experimental Delta G degrees values used were measured in CD(2)Cl(2)) due to the enhanced dipolar character is more prominent in the case of the equatorial alkyl conformers. As the consequence, the ax reversible arrow eq equilibrium is shifted to the left despite the increasing size of the R group when going from Me to tBu substitution.
Propagation of inductive and resonance effects of phenyl substituents within 1-(substituted phenyl)-6,7- dimethoxy-3,4-dihydro- and -1,2,3,4-tetrahydroisoquinolines were studied with the aid of C-13 and N-15 NMR chemical shifts and ab initio calculations. The substituent-induced changes in the chemical shift (SCS) were correlated with a dual substituent parameter equation. The contributions of conjugative (rho(R)) and nonconjugative effects (rho(F)) were analyzed, and mapping of the substituent-induced changes is given over the entire isoquinoline moiety for both series. The experimental results can be rationalized with the aid of the resonance polarization concept. This means the consideration of the substituent-sensitive balance of different resonance structures, i.e., electron delocalization, and the effect of the aromatic ring substituents on their relative contributions. With tetrahydroisoquinolines, the delocalization of the nitrogen lone pair (stereoelectronic effect) particularly contributes. Correlation analysis of the Mulliken atomic charges for the dihydroisoquinoline derivatives was also performed. The results support the concept of the substituent-sensitive polarization of the isoquinoline moiety even if the polarization pattern achieved via the NMR approach is not quite the same as that predicted by the computational charges. Previously the concepts of localized pi- polarization and extended polarization have been used to explain polar substituent effects within aromatic side-chain derivatives. We consider that the resonance polarization model effectively contributes to the understanding of the polar substituent effects
The conformations of N-benzylideneani lines p-X-C6H4-CH=N-C6H4 p-Y (X, Y = NO2, CN, CF3, F, Cl, Br, H, Me, OMe, NMe2) have been studied by B3LYP density functional (DFT) hybrid method in combination with the 6-31G* or 6-311G* split valence basis set. The twist of the plane of the aniline ring with respect to the other part of the molecule (tau(2)) is systematically controlled by substituents X and Y, the effect of Y being larger. The value of the dihedral angle tau(2), correlates nicely with equation tau(2) = rho(F)(Y)(x)sigma(F)(Y)+rho(+R)(Y)(x)sigma(+)(R)(Y) + k(x) or tau(2) = rho(F)(X)(y)sigma(F)(X)+rho(-)(R)(X)(y)sigma(+)(R)(X) + k(y), respectively, when aniline or benzylidene substituent is varied. ED substituents X diminish the sensitivity of tau(2) to the aniline substituent Y[rho(F)(Y)(x) and rho(+)(R)(Y)(x)] while ED substituents Y increase the sensitivity Of T2 to the benzylidene substituent X[rho(F)(X)(y) and rho(+)(R)(X)(y)]. There seems to be two competitive conjugative interactions for the aniline ring n electrons: one with the nitrogen lone pair and one with the C=N unit. Substituents X and Y adjust the extent of these interactions and therefore the conformation of the molecule. A good correlation is observed between the dihedral angle tau(2) and the experimental C-13 NMR chemical shift of the C=N carbon of N-benzylideneanilines in CDCl3 (C) 2007 Elsevier B.V. All rights reserved.
Equilibria between the Z (tau(1) = 0 degrees) and E (tau(1) = 180 degrees) conformers of p-substituted phenyl acetates 4 and trifluoroacetates 5 (X = OMe, Me, H, Cl, CN, NO2) were studied by ab initio calculations at the HF/6-31G* and MP2/6-31G* levels of theory. The preference for the Z conformer, Delta E(HF), was calculated to be 5.36 kcal mol(-1) and 7.50 kcal mot(-1) for phenyl acetate and phenyl trifluoroacetate (i.e., with X = H), respectively. The increasing electron-withdrawing ability of the phenyl substituent X increases the preference of the Z conformer. An excellent correlation with a negative slope was observed for both series between Delta E of the E-Z equilibrium and the Hammett sigma constant. By using an appropriate isodesmic reaction, it was shown that electron-withdrawing substituents decrease the stability of both conformers, but the effect is higher with the E conformer. Electron-withdrawing phenyl substituents decrease the delocalization of the lone pair of the ether oxygen to the C=O antibonding orbital (n(O) -> pi*(C=O)) in both the E and Z forms and in both series studied; this effect is higher in the E conformer than in the Z conformer. The n(O) -> pi*(C=O) electron donation has a minimum value with tau(1) = 90 degrees and a maximum value with tau(1) = 90 degrees (the Z conformer), the value with tau(1) = 180 degrees (the E conformer) being between these two values, obviously due to steric hindrance. The effects of the phenyl substituents on the reactivity of the esters studied are discussed in terms of molecular orbital interactions. ED/EW substituents adjust the availability of the pi*(C=O) antibonding orbital to interact with the lone pair orbital of the attacking nucleophile and therefore affect the reactivity: EW substituents increase and ED substituents decrease it. Excellent correlations were observed between the rate coefficients of nucleophilic acyl substitutions and pi*(C=O) occupancies of the ester series 4 and
The electronic effects of the 5- and 6-membered heterocyclic rings on the C=N-N unit of five different hydrazone derivatives of pyridine-2-, -3- and -4-carbaldehydes, pyrrole-2-carbaldehyde, furan-2- and -3-carbaldehydes and thiophene-2- and -3-carbaldehydes have been studied with the aid of 13C and 15N NMR measurements together with the natural bond orbital (NBO) analysis. As model compounds are used the corresponding substituted benzaldehyde derivatives. The polarization of the C=N unit of the hydrazone functionality of the heteroaryl derivatives occurs in an analogous manner with that of phenyl derivatives. The electron-withdrawing heteroaryl groups destabilize and the electron-donating groups stabilize the positive charge development at the CN carbon while the effect on the negative charge development is opposite. The 15N NMR chemical shift of the C=N and C=N-N nitrogens and the NBO charges at C=N-N unit can be correlated with the replacement substituent constants of the heteroaryl groups. 13C NMR shifts of the C=N carbon of N,N- dialkylhydrazones of the heteroarenecarbaldehydes can be correlated with a dual parameter equation possessing the polar substituent constant ;* of the heteroaryl group and the electronegativity of the heteroatom as variables.
The CH2Cl2/MeOH (1: 1) extract of the roots of Tephrosia villosa showed good antiplasmodial activity against the chloroquine-sensitive (D6) and chloroquine-resistant (W2) strains of Plasmodium falciparum with IC50 values of 3.1 +/- 0.4 and 1.3 +/- 0.3 mu g/mL, respectively. Chromatographic separation of the extract yielded a new rotenoid, 6 alpha-hydroxy-alpha-toxicarol, along with five known rotenoids, (rotenone, deguelin, sumatrol, 12 alpha-hydroxy-alpha-toxicarol and villosinol). Similar treatment of the extract of the stem of Tephrosia purpurea (IC50 = 4.1 +/- 0.4 and 1.9 +/- 0.2 mu g/mL against D6 and W2 strains of P. falciparum, respectively) yielded a new flavone having a unique substituent at C-7/C-8 [trivial name (+)-tephrodin], along with the known flavonoids tachrosin, obovatin methyl ether and derrone. The relative configuration and the most stable conformation in (+)-tephrodin was determined by NMR and theoretical energy calculations. The rotenoids and flavones tested showed good to moderate antiplasmodial activities (IC50 = 9 +/- 23 mu M). Whereas the cytotoxicity of rotenoids is known, the flavones (+)-tephrodin and tachrosin did not show significant cytotoxicity (IC50 > 100 mu M;) against mammalian African monkey kidney (vero) and human larynx carcinoma (HEp2) cell lines. (C) 2014 Phytochemical Society of Europe. Published by Elsevier B.V. All rights reserved.
The CH2Cl2/MeOH (1:1) extract of the aerial parts of Tephrosia subtriflora afforded a new flavanonol, named subtriflavanonol (1), along with the known flavanone spinoflavanone B, and the known flavanonols MS-II (2) and mundulinol. The structures were elucidated by the use of NMR spectroscopy and mass spectrometry. The absolute configuration of the flavanonols was determined based on quantum chemical ECD calculations. In the antiplasmodial assay, compound 2 showed the highest activity against chloroquine-sensitive Plasmodiumfalciparum reference clones (D6 and 3D7), artemisinin-sensitive isolate (F32-TEM) as well as field isolate (KSM 009) with IC50 values 1.4-4.6M without significant cytotoxicity against Vero and HEp2 cell lines (IC50>100M). The new compound (1) showed weak antiplasmodial activity, IC50 12.5-24.2M, but also showed selective anticancer activity against HEp2 cell line (CC50 16.9M). [GRAPHICS] .
C-H-ax center dot center dot center dot Y-ax are a textbook prototype of steric hindrance in organic chemistry. The nature of these contacts is investigated in this work. MP2/6-31+G(d,p) calculations predicted the presence of improper hydrogen bonded C-H-ax center dot center dot center dot Y-ax of different strength in substituted cyclohexane rings. To support the theoretical predictions with experimental evidence, several synthetic 2-substituted adamantane analogues (1-24) with suitable improper H-bonded C-H-ax center dot center dot center dot Y-ax contacts of different strength were used as models of a substituted cyclohexane ring. The H-1 NMR signal separation, Delta delta(gamma-CH2), within the cyclohexane ring gamma-CH(2)s is raised when the MP2/6-31+G(d,p) calculated parameters, reflecting the strength of the H-bonded C-H-ax center dot center dot center dot Y-ax contact, are increased. In molecules with enhanced improper H-bonded contacts C-H-ax center dot center dot center dot Y-ax, like those having sterically crowded contacts (Y-ax = t-Bu) or contacts including considerable electrostatic attractions (Y-ax = O-C or O=C) the calculated DFT steric energies of the gamma-axial hydrogens are considerably reduced reflecting their electron cloud compression. The results suggest that the proton H-ax electron cloud compression, caused by the C-H-ax center dot center dot center dot Y-ax contacts, and the resulting increase in Delta delta(gamma-CH2) value can be effected not just from van der Waals spheres compression, but more generally from electrostatic attraction forces and van der Waals repulsion, both of which are improper H-bonding components.
The complete H-1 and C-13 NMR chemical shifts assignment for various 2-substituted and 2,2-disubstituted adamantane derivatives 1-38 in CDCl3 solution was realized on the basis of NMR experiments combined with chemical structure information and DFT-GIAO (B3LYP/6-31+G(d,p)-GIAO) calculations of chemical shifts in solution. Substituent-induced C-13 NMR chemical shifts (SCS) are discussed. C-H-ax center dot center dot center dot Y-ax contacts are a textbook prototype of steric hindrance in organic chemistry. The nature of these contacts will be further investigated in this work on basis of new adamantane derivatives, which are substituted at C-2 to provide models for 1,4-C-H-ax center dot center dot center dot Y-ax and 1,5-C-H-ax center dot center dot center dot Y-ax contacts. The B3LYP/6-31+G(d,p) calculations predicted the presence of NBO hyperconjugative attractive interactions between C-H-ax and Y-ax groups along C-H-ax center dot center dot center dot Y-ax contacts. The H-1 NMR signal separation, Delta delta(gamma-CH2), reflects the strength of the H-bonded C-H-ax center dot center dot center dot Y-ax contact. (C) 2015 Elsevier Ltd. All rights reserved.
Ciprofloxacin is a widely used fluoroquinolone antibiotic. In this work, a comprehensive evaluation of MP2 and DFT with different functionals and basis sets was carried out to select the most suitable level of theory for the study of the NMR properties of ciprofloxacin. Their relative predictive capabilities were evaluated comparing the theoretically predicted and experimental spectral data. Our computational results indicated that in contrast to the solid state, the molecule of ciprofloxacin does not exist as a zwitterion in gaseous state. The results of the calculations of the chemical shifts most close to the experimental were obtained with B3LYP/aug-cc-pVDZ. The F-C coupling constants were calculated systematically with different DFT methods and several basis sets. In general, the calculations of the coupling constants with the BHandH computational method including the applied in this work 6-311++G**, EPRII, and EPRIII basis sets showed a good reproducibility of the experimental values of the coupling constants.
The C-13 chemical shifts of 20 rigid bicyclic compounds have been calculated with ab initio HF and MP2 methods. The calculations showed very good reproducibility of the experimental values. The molecular orbital interactions in the rigid, nearly planar delta-syn-axial fragments in the isomeric groups of norbornane derivatives 1.x-4.x were studied in detail and were employed to explain the deshielding delta-syn-axial effect in C-13 NMR spectroscopy. (C) 2004 Elsevier B.V. All rights reserved