Counter-current chromatographic estimation of hydrophobicity of Z-(cis) and E-(trans) enalapril and kinetics of cis/trans isomerization

The kinetics of Z-(cis)/E-(trans) isomerization of enalapril was investigated by reversed phase high-performance liquid chromatography (RP-HPLC) using a monolith ODS column under a series of different temperature and pH conditions. At a neutral pH 7, the rate (k(obs)) of Z-(cis)/E-(trans) isomerization of enalapril at 4 degrees C (9.4 x 10(-3)min(-1)) is much lower than at 23 degrees C (1.8 x 10(-1)min(-1)), while the fractional concentration of Z-(cis) isomer is always higher than that of E-(trans) isomer in the pH range 2-7. The fractional concentration of the E-(trans) isomer becomes a maximum (about 40%) in the pH range 3-6, where enalapril exists as a zwitterion. The hydrophobicity (logP(O/W)) of both isomers was estimated by high-speed counter-current chromatography (HSCCC). Normal phase HSCCC separation using a tert-butyl methyl ether-acetonitrile-20mM potassium phosphate buffer (pH 5) two-phase solvent system (2:2:3, v/v/v) at 4 degrees C was effective in partially separating the isomers, and the partition coefficient (K) of each isomer was directly calculated from the retention volume (V(R)). The logP(O/W) values of Z-(cis) and E-(trans) isomers were -0.46 and -0.65, respectively.     

Syntheses, characterization, and catalytic ability in alkane oxygenation of chloro(dimethyl sulfoxide)ruthenium(II) complexes with tris(2-pyridylmethyl)amine and its derivatives

New ruthenium(II) complexes having a tetradentate ligand such as tris(2-pyridylmethyl)amine (TPA), tris[2-(5-methoxycarbonyl)pyridylmethyl]amine [5-(MeOCO)3-TPA], tris(2-quinolylmethyl)amine (TQA), or bis(2-pyridylmethyl)glycinate (BPG) have been prepared. The reaction of the ligand with [RuCl2(Me2SO)4] resulted in a mixture of trans and cis isomers of the chloro(dimethyl sulfoxide-kappaS)ruthenium(II) complexes containing a TPA or a BPG, whereas a trans(Cl,N(amino)) isomer was selectively obtained for 5-(MeOCO)3-TPA and TQA. The trans and cis isomers of the [RuCl(TPA)(Me2SO)]+ complex were easily separated by fractional recrystallization. The molecular structures of trans- and cis(Cl,N(amino))-[RuCl(TPA)(Me2SO)]+ complexes and the trans(Cl,N(amino))-[RuCl{5-(MeOCO)3-TPA}(Me2SO)]+ complex have been determined by X-ray structural analyses. The reaction of TPA with [RuCl2(PhCN)4] gave a single isomer of the chloro(benzonitrile)ruthenium(II) complex, whereas the bis(benzonitrile)ruthenium(II) complex was obtained with BPG. The cis(Cl,N(amino))-[RuCl(TPA)(Me2SO)]+ complex is thermodynamically much less stable than the trans isomer and isomerizes in dimethyl sulfoxide at 65-100 degrees C. Oxygenation of alkanes catalyzed by these ruthenium(II) complexes has been examined. The chloro(dimethyl sulfoxide-kappaS)ruthenium(II) complexes with TPA and its derivatives using m-chloroperbenzoic acid as a cooxidant showed high catalytic ability. Adamantane was efficiently and selectively oxidized to give 1-adamantanol up to 88%. The chloro(dimethyl sulfoxide-kappaS)ruthenium(II) complex with 5-(MeOCO)3-TPA was found to be the most active catalyst among the complexes examined.     

The isomerization equilibrium between cis and trans chloride ruthenium olefin metathesis catalysts from quantum mechanics calculations

The cis-trans chloride isomerization of a ruthenium olefin metathesis catalyst is studied using quantum mechanics (B3LYP DFT), including the Poisson-Boltzmann (PBF) continuum approximation. The predicted geometries agree with experiment. The energies in methylene chloride, lead to DeltaG = -0.70 kcal/mol and a cis:trans ratio of 76:24, quite close to the experimental value of DeltaG = -0.78 kcal/mol or c:t 78:22. In contrast, we predict that in benzene c:t = 4:96 in agreement with the experimental observation of only the trans isomer. Our calculated relative activation energies explain the observed difference in initiation rates and suggest that each isomer should be isolable in high ratio by simply changing solvent.     

Stereochemistry of the [4 + 2] cycloadditions of trans,trans- and cis,trans-2,4-hexadiene to C(60)

The [4 + 2] cycloaddition of trans,trans-2,4-hexadiene with C(60) proceeds via a concerted mechanism with retention of stereochemistry in the cycloadduct 1a. However, when cis,trans-2,4-hexadiene reacts with C(60), isomerization of the cis,trans to the thermodynamically more stable trans,trans isomer occurs. Subsequently, the cis,trans diene isomerized to the trans,trans isomer and cycloadds to C(60), to form adduct 1a. When the reaction is carried out at higher temperatures, the formation of cycloadduct 1b is also obtained. This result is consistent with a concerted cycloaddition of cis,trans-2,4-hexadiene with C(60), which is more reactive at elevated temperatures and leads to the formation of the Diels-Alder adduct 1b.     

Direct measurement indicates a slow cis/trans isomerization at the secondary amide peptide bond of glycylglycine.

Spectral differences between the cis and the trans isomer of a secondary amide peptide bond were used to follow the time course of the cis/trans isomerization of Gly-Gly, Gly-Ala, Ala-Gly, and Ala-Ala dipeptides in the UV/vis region at 220 nm. Isomerization rates and Eyring activation energies were calculated from pH- and LiCl-mediated solvent jump experiments. Rate constants were found to be in a narrow range of 0.29 to 0.64 s(-)(1) for the zwitterionic dipeptides at 25 degrees C. The isomerization rate is about 2-fold higher for the monoionic forms of Gly-Gly. The zwitterionic Gly-Gly has an activation enthalpy DeltaH() of 71.6 +/- 4.9 kJ mol(-)(1) that is in the range of the rotational barriers of aromatic side chain dipeptides that have been measured by (1)H NMR magnetization transfer experiments. Late stages of protein backbone rearrangements often involve crossing the energy barrier for rotational isomerization of imidic peptide bonds. Our findings are consistent with the idea that a wide range of secondary amide peptide bonds are also able to induce slow rate-limiting steps in protein restructuring.     

Time-resolved IR spectroscopy of N-methylthioacetamide: trans-->cis isomerization upon n-pi and pi-pi excitation and cis-->trans photoreaction

Time-resolved infrared spectroscopy was used to study the photoisomerization of N-Methylthioacetamide (NMTAA) in D2O in both the cis-->trans and the trans-->cis direction upon selective excitation of the n-pi (S1) and pi-pi (S2) electronic transitions. While isomerization and the return to the ground state takes place on two distinct time scales (cis isomerization is 30-40%, independent of the electronic state excited, while the cis-->trans isomerization proceeds with a 60-70% quantum efficiency. These results support a mechanism by which isomerization takes place via one common intermediate state independent of electronic excitation energy and initial conformation.     

cis,cis- and trans,trans-ceratospongamide, new bioactive cyclic heptapeptides from the Indonesian red alga Ceratodictyon spongiosum and symbiotic sponge Sigmadocia symbiotica

Chemical investigation of the marine red alga (Rhodophyta) Ceratodictyon spongiosum containing the symbiotic sponge Sigmadocia symbiotica collected from Biaro Island, Indonesia, yielded two isomers of a new and bioactive thiazole-containing cyclic heptapeptide, cis,cis-ceratospongamide (1) and trans, trans-ceratospongamide (2). Isolation of these peptides was assisted by bioassay-guided fractionation using a brine shrimp toxicity assay (Artemia salina). The structures of the ceratospongamides, which each consist of two L-phenylalanine residues, one (L-isoleucine)-L-methyloxazoline residue, one L-proline residue, and one (L-proline)thiazole residue, were established through extensive NMR spectroscopy, including (1)H-(13)C HMQC-TOCSY, and (1)H-(15)N HMBC experiments, as well as chemical degradation and chiral analysis. cis,cis- and trans,trans-ceratospongamide are stable conformational isomers of the two proline amide bonds. Molecular modeling of these two ceratospongamide isomers showed the trans, trans isomer to be quite planar, whereas the cis,cis isomer has a more puckered overall conformation. trans,trans-Ceratospongamide exhibits potent inhibition of sPLA(2) expression in a cell-based model for antiinflammation (ED(50) 32 nM), whereas the cis,cis isomer is inactive. trans,trans-Ceratospongamide was also shown to inhibit the expression of a human-sPLA(2) promoter-based reporter by 90%.     

Tetrathiafulvalenenaphthalenophanes: planar chirality and cis/trans photoisomerization

A cyclophane incorporating one 1,5-dioxynaphthalene ring system and one tetrathiafulvalene (TTF) unit bridged by [SCH(2)CH(2)O] linkages has been synthesized. In this cyclophane, the TTF unit can adopt either cis or trans configurations. In addition, the 1, 5-dioxynaphthalene ring system imposes one element of planar chirality on this cyclophane. A second element of planar chirality is introduced by the trans form of the TTF unit. Thus, the cyclophane exists in diastereoisomeric forms as three pairs of enantiomers. The enantiomeric pairs associated with the cis form of the TTF unit, as well as one of those associated with the trans form, have been isolated by crystallization, and their structures assigned in the solid state by single-crystal X-ray analyses. In solution, cis/trans isomerization occurs when either the cis or the trans form of the cyclophane is exposed to light. The photoisomerization reaction can be followed by (1)H NMR and UV-vis spectroscopies, as well as by HPLC. The photoisomerization quantum yield has been measured at two different excitation wavelengths (406 and 313 nm). In both cases, the trans --> cis process (Phi = 0.20 at 406 nm) is much more efficient than the reverse cis --> trans process (Phi = 0.030 at 406 nm). Since the absorption spectra of the trans and cis isomers are different and the quantum yield of the trans --> cis photoisomerization reaction depends on the excitation wavelength, the mole fraction of the two diastereoisomers present at the photostationary state depends on the wavelength of the exciting light. No isomerization occurs when the solutions, regardless of the mole fraction of the two diastereoisomers, are stored in the dark.     

Dichlorobis(2-phenylazopyridine)ruthenium(II) complexes: characterisation, spectroscopic and structural properties of four isomers

The didentate ligand 2-phenylazopyridine (azpy) can--in theory--give rise to five different isomeric complexes of the type [Ru(azpy)2Cl2], of which three have been known since 1980. The molecular structures of the cis-dichlorobis(2-phenylazopyridine) ruthenium(II) complexes alpha-[Ru(azpy)2Cl2] and beta-[Ru(azpy)2Cl2](in which the coordinating pyridine nitrogen atoms are in mutually trans and cis positions, respectively, whilst the azo nitrogen atoms are in mutually cis positions) were unambiguously determined in the early 1980s. The third isomer, gamma-[Ru(azpy)2Cl2], has for two decades, erroneously, been assumed to be the all-trans isomer. In a recent communication we have proven that for this gamma isomer the chloride ions are indeed in a trans geometry, but the pyridine nitrogen and azo nitrogen atoms of the two azpy ligands are in mutually cis geometries. In this paper the isolation of a fourth isomer is presented, the hitherto unknown delta-[Ru(azpy)2Cl2]. The isomeric structure of delta-[Ru(azpy)2Cl2] has been determined by 1H-NMR spectroscopy and single-crystal X-ray diffraction analysis, and is the all-trans isomer. The bis(azpy)-ruthenium(II) isomers are of interest because of the pronounced cytotoxicity they exhibit against tumour cell lines and could be very useful in the search for structure-activity relationships of antitumour-active ruthenium complexes, as among the isomers there is a significant difference in activity. It is of paramount importance to have a good understanding of the structural and spectroscopic properties of these complexes, which in this paper are compared and discussed, with a particular emphasis on 1D and 2D 1H NMR spectroscopies.     

Photophysical studies of the trans to cis isomerization of the push-pull molecule: 1-(pyridin-4-yl)-2-(N-methylpyrrol-2-yl)ethene (mepepy)

Organic molecules possessing intramolecular charge-transfer properties (D-pi-A type molecules) are of key interest particularly in the development of new optoelectronic materials as well as photoinduced magnetism. One such class of D-pi-A molecules that is of particular interest contains photoswitchable intramolecular charge-transfer states via a photoisomerizable pi-system linking the donor and acceptor groups. Here we report the photophysical and electronic properties of the trans to cis isomerization of 1-(pyridin-4-yl)-2-(N-methylpyrrol-2-yl)ethene ligand (mepepy) in aqueous solution using photoacoustic calorimetry (PAC) and theoretical methods. Density functional theory (DFT) calculations demonstrate a global energy difference between cis and trans isomers of mepepy to be 8 kcal mol(-1), while a slightly lower energy is observed between the local minima for the trans and cis isomers (7 kcal mol(-1)). Interestingly, the trans isomer appears to exhibit two ground-state minima separated by an energy barrier of approximately 9 kcal mol(-1). Results from the PAC studies indicate that the trans to cis isomerization results in a negligible volume change (0.9 +/- 0.4 mL mol(-1)) and an enthalpy change of 18 +/- 3 kcal mol(-1). The fact that the acoustic waves associated with the trans to cis transition of mepepy overlap in frequency with those of a calorimetric reference implies that the conformational transition occurs faster than the approximately 50 ns response time of the acoustic detector. Comparison of the experimental results with theoretical studies provide evidence for a mechanism in which the trans to cis isomerization of mepepy results in the loss of a hydrogen bond between a water molecule and the pyridine ring of mepepy.     

A molecular orbital study of cis and trans diaminodichloroplatinum(II)

The relativistic multiple scattering Xα method has been applied in order to calculate the eigenvalues and the charge densities of cis and trans diaminodichloroplatinum(II). The activity of the cis isomer as an antitumor agent is discussed in terms of the possible modes of coordination of certain fragments of the DNA molecule through the LUMO state of the cis Pt complex. Although possible, coordination of the trans isomer is rendered unlikely as a result of possible strain effects.     

Photochemical E (trans)-->Z (cis) isomerization in substituted 1-naphthylacrylates.

Substituted naphthylacrylates, 1-3, not showing rotamerism have been synthesized with a view to study photochemical E (trans)-->Z (cis) isomerization. Photostationary state composition of the isomers upon direct excitation, triplet sensitized isomerization, quantum yield of isomerization, and steady state and time-resolved fluorescence behavior have been studied for these naphthylacrylates. The direct excitations of the compounds yield high Z (approximately 80%) isomer composition, whereas the triplet sensitization results in less Z (approximately 20%) isomer composition. This indicates that the singlet pathway is very efficient in converting the E isomer to the Z isomer. The naphthylacrylates 1 and 2 exhibit structured fluorescence at room temperature in hexane and upon changing the solvent to CH3CN; the structure of the fluorescence is lost, indicating that the singlet excited-state develops a polar character in a polar environment. The polar nature of the singlet excited state becomes more clear in the case of 3 from its fluorescence solvatochromism. The naphthylacrylates did not exhibit excitation wavelength-dependent fluorescence at room temperature suggesting that the ground state conformers (rotamers) are not involved. Fluorescence lifetimes measured for these compounds displayed biexponential behavior, which is explained using a two-state model.     

cis/trans photoisomerization of secondary thiopeptide bonds

The reversible cis/trans photoisomerization of secondary thiopeptide bonds has been systematically studied with UV-visible absorption, capillary electrophoresis, 1H NMR spectroscopy, and circular dichroism methods. It was found that the concentration of the cis conformers could be increased from less than 1 % in the thermal equilibrated solution to up to 20 % in the photostationary state. The rotational barriers of the thiopeptide bond and the pH dependence of the isomerization rates were also studied. The quantum yields of the trans-->cis and the cis-->trans processes were determined from photokinetic analysis.     

Molecular structure of the trans and cis isomers of metal-free phthalocyanine studied by gas-phase electron diffraction and high-level quantum chemical calculations: NH tautomerization and calculated vibrational frequencies

The molecular structure of the trans isomer of metal-free phthalocyanine (H2Pc) is determined using the gas electron diffraction (GED) method and high-level quantum chemical calculations. B3LYP calculations employing the basis sets 6-31G**, 6-311++G**, and cc-pVTZ give two tautomeric isomers for the inner H atoms, a trans isomer having D2h symmetry and a cis isomer having C2v symmetry. The trans isomer is calculated to be 41.6 (B3LYP/6-311++G**, zero-point corrected) and 37.3 kJ/mol (B3LYP/cc-pVTZ, not zero-point corrected) more stable than the cis isomer. However, Hartree-Fock (HF) calculations using different basis sets predict that cis is preferred and that trans does not exist as a stable form of the molecule. The equilibrium composition in the gas phase at 471 degrees C (the temperature of the GED experiment) calculated at the B3LYP/6-311++G** level is 99.8% trans and 0.2% cis. This is in very good agreement with the GED data, which indicate that the mole fraction of the cis isomer is close to zero. The transition states for two mechanisms of the NH tautomerization have been characterized. A concerted mechanism where the two H atoms move simultaneously yields a transition state of D2h symmetry and an energy barrier of 95.8 kJ/mol. A two-step mechanism where a trans isomer is converted to a cis isomer, which is converted into another trans isomer, proceeds via two transition states of C(s) symmetry and an energy barrier of 64.2 kJ/mol according to the B3LYP/6-311++G** calculation. The molecular geometry determined from GED is in very good agreement with the geometry obtained from the quantum chemical calculations. Vibrational frequencies, IR, and Raman intensities have been calculated using B3LYP/6-311++G**. These calculations indicate that the molecule is rather flexible with six vibrational frequencies in the range of 20-84 cm(-1) for the trans isomer. The cis isomer might be detected by infrared matrix spectroscopy since the N-H stretching frequencies are very different for the two isomers.     

Initiation of radical chain reactions of thiol compounds and alkenes without any added initiator: thiol-catalyzed cis/trans isomerization of methyl oleate

A kinetic study of the dodecanethiol-catalyzed cis/trans isomerization of methyl oleate (cis-2) without added initiator was performed by focusing on the initiation of the radical chain reaction. The reaction orders of the rate of isomerization were 2 and 0.5 for 1 and cis-2, respectively, and an overall kinetic isotope effect k(H)/k(D) of 2.8 was found. The initiation was shown to be a complex reaction. The electron-donor/-acceptor (EDA) complex of dodecanethiol (1) and cis-2 formed in a pre-equilibrium reacts with thiol 1 to give a stearyl and a sulfuranyl radical through molecule-assisted homolysis (MAH) of the sulfur-hydrogen bond. Fragmentation of the latter gives the thiyl radical, which catalyzes the cis/trans isomerization. A computational study of the EDA complex, MAH reaction, and the sulfuranyl radical calculated that the activation energy of the isomerization was in good agreement with the experimental result of E(A)=82?kJ M(-1). Overall, the results may explain that the thermal generation of thiyl radicals without any initiator is responsible for many well-known thermally initiated addition reactions of thiol compounds to alkenes and their respective polymerizations and for the low shelf-life stability of cis-unsaturated thiol compounds and of mixtures of alkenes and thiol compounds.     

Correlation effects on cis—trans energy differences in open-shell systems: The hoco radical as an example

Ab initio SCF and Cl calculations have shown that the most important factor in determining the relative energies of conformational isomers in free radicals is the movement of electron density into the singly occupied orbital. This is most favorable when an electron pair is situated trans to the radical site (trans correlation effect). In the HOCO radical we find that the trans isomer is more stable than the cis by 3.3 kcal/mol while SCF calculations yield virtually no energy difference between the two isomers.     

A structural and theoretical investigation of equatorial cis and trans uranyl phosphinimine and uranyl phosphine oxide complexes UO2Cl2(Cy3PNH)2 and UO2Cl2(Cy3PO)2

Phosphinimine ligands (Cy3PNH) readily react with UO2Cl2(THF)3 (THF=tetrahydrofuran) to give UO2Cl2(Cy3PNH)2, which contains strong U-N interactions and exists as cis and trans isomers in the solid and solution state. Solution NMR experiments and computational analysis both support the trans form as the major isomer in solution, although the cis isomer becomes more stabilized with an increase in the dielectric constant of the solvent. Mayer bond orders, energy decomposition analysis, and examination of the molecular orbitals and total electron densities support a more covalent bonding interaction in the U-NHPCy3 bond compared with the analogous bond of the related U-OPCy3 compounds.     

Complexation of 4‐dimethylaminoazobenzene with various kinds of cyclodextrins: Effects of cyclodextrins on the thermal cis‐to‐trans isomerization

On the basis of the change in electronic and induced circular dichroism spectra for complex formation, the complexation of 4‐dimethylaminoazobenzene (DAAB) with four kinds of cyclodextrins (α‐ and β‐cyclodextrin (CD), heptakis(2,6‐di‐O‐methyl)‐β‐cyclodextrin, and heptakis(2,3,6‐tri‐O‐methyl)‐β‐cyclodextrin) was studied in methanol–water and dimethyl sulfoxide–water mixtures. It was found that the trans and cis isomers of DAAB form two different types of complex (inclusion and lid type) with CDs, depending on the kinds of CDs and solvents. Further, we have examined the effect of CDs on the thermal cis‐to‐trans isomerization of DAAB. The accelerated or decelerated effect on the thermal isomerization was observed upon adding CDs. The effects of CDs on the thermal isomerization are discussed in connection with the complexation of the cis‐isomer of DAAB with CDs. © 2002 Wiley Periodicals, Inc. Int J Chem Kinet 34: 481–487, 2002     

Theoretical study of the mechanism of NO2 production from NO + ClO

The reaction of NO with ClO has been studied theoretically using density-functional and wave function methods (B3LYP and CCSD(T)). Although a barrier for cis and trans additions could be located at the RCCSD(T) and UCCSD(T) levels, no barrier exists at the B3LYP/6-311+G(d) level. Variational transition state theory on a CASPT2(12,12)/ANO-L//B3LYP/6-311+G(d) surface was used to calculate the rate constants for addition. The rate constant for cis addition was faster than that for trans addition (cis:trans 1:0.76 at 298 K). The rate constant data summed for cis and trans addition in the range 200-1000 K were fit to a temperature-dependent rate in the form kdi) = 3.30 x 10(-13)T(0.558) exp(305/T) cm3.molecule(-1).s(-1), which is in good agreement with experiment. When the data are fit to an Arrhenius plot in the range 200-400 K, an activation barrier of -0.35 kcal/mol is obtained. The formation of ClNO2 from ONOCl has a much higher activation enthalpy from the trans isomer compared to the cis isomer. In fact, the preferred decomposition pathway from trans-ONOCl to NO2 + Cl is predicted to go through the cis-ONOCl intermediate. The trans --> cis isomerization rate constant is kiso = 1.92 x 10(13) exp(-4730/T) s(-1) using transition state theory.