Chromatographic identification of (E)- and (Z)-isomers of unsaturated organic compounds using their physicochemical characteristics

The values of physicochemical properties determine completely the sequence of chromatographic elution of (Z)- and (E)-isomers of 1,2-disubstituted unsaturated compounds and can therefore be used as reference data for their GC-identification. The isomer with the minimum boiling point, relative density, and refractive index has the least retention parameters. By the ratio of the values of these properties the (Z)- and (E)-isomers form two groups: (Z) > (E) and (Z) < (E). This feature is due to the larger polarity of the (Z)-isomers of asymmetrically substituted compounds containing polar substituents at the double bond C=C. The discovered regularities may be extended to the cis- and trans-isomers of 1,2-disubstituted cycloalkanes and even to the position isomers of substituted arenes.     

Palladium-catalyzed isomerization of (Z)-1-functionalized-4-acetoxy-2-butenes: Solvent and substituent effects

The Pd(PPh₃)₄-catalyzed isomerization of (Z)-1,4-diacetoxy-2-butene, (Z)-1-(t-butyldimethylsilyloxy)-4-acetoxy-2-butene and (Z)-1-(t-butyldiphenylsilyloxy)-4-acetoxy-2-butene affords the corresponding (E)-isomers and 1,2-difunctionalized-3-butenes. In THF, the formation of the (E)-isomers is mainly due to reaction from an η¹-allylpalladium intermediate while an η³-allylpalladium is the main key intermediate in DMF. The time to reach equilibrium between the products and their respective concentrations depend on the nature of the substituents and the solvent.     

Triphenylphosphine as an effective catalyst for ketoximes addition to acylacetylenes: regio- and stereospecific synthesis of (E)-(O)-2-(acyl)vinylketoximes

Triphenylphosphine catalyzes the regio- and stereospecific addition of ketoximes to acylacetylenes, whereas classical conditions using acetylene (KOH/DMSO, 70 °C) are unsuitable for this purpose. The reaction proceeds under mild conditions (CH₂Cl₂, rt, 7 h) to afford (E)-(O)-2-(acyl)vinylketoximes (92-98% stereoselectivity) in a yield of up to 85%. The (E)-adducts obtained are energetically less favorable than the corresponding (Z)-isomers and are gradually enriched with (Z)-isomers, thus indicating the kinetic control of (E)-stereoselectivity of the reaction.     

4,4-Diorganyl-1,1,3,6-tetrachloro-1,4-tellura(IV)silafulvenes - New class of tellurium-silicon containing heterocycles

The reaction of TeCl₄ with diorganyl diethynyl silanes RR¹Si(CCH)₂ in CHCl₃ at room temperature leads to regio- and stereoselective formation of a new class of unsaturated five-membered heterocycles, 4,4-diorganyl-1,1,3,6-tetrachloro-1,4-tellura(IV)silafulvenes, in high yields. In the case of dialkyl substituents at the silicon atom the reaction proceeds with 100% stereoselectively to afford only E-isomers, while for cyclic diethynyl silanes the spiro-heterocycles formed have Z- and E-configurations, E-isomers being the predominant ones. Structures of the heterocycles have been proved by the multinuclear (¹H, ¹³C, ²⁹Si, ¹²⁵Te) NMR spectroscopy, 2D NOESY NMR spectroscopy and mass-spectrometry. Z-Isomers are characterized by a long-range spin-spin interaction of protons through five bonds with ⁵J_HH 0.2-0.5 Hz lacking in E-isomers. In the mass spectra the heterocycles manifest themselves as the fragment ions [M−Cl₂]⁺.     

Synthesis, structural revision, and biological activities of 4′-chloroaurone, a metabolite of marine brown alga Spatoglossum variabile

4′-Chloroaurone (1a), the only aurone reported from a marine source, Spatoglossum variabile was synthesized from 2-hydroxyacetophenone along with six structural analogs. The products obtained were Z-isomers and these were converted into E-isomers by photoisomerization. The E and Z isomers of aurones showed distinct proton and carbon chemical shifts. However, the spectroscopic data of either Z-4′-chloroaurone (1a) or its E-isomer (2a) did not match with those reported for the natural product and thus requires revision of the structure assigned. The proton NMR spectroscopic data reported for the natural product matches with those reported for a known isocoumarin (5). The synthesized E and Z aurones were evaluated for their antioxidant and antibacterial activities. The aurone, Z-2-[(3,4-dihydroxyphenyl)methylene]benzo[b]furan-3-one exhibited significant antioxidant activity. Interestingly, Z-aurones are active against Gram-positive and Gram-negative bacteria, whereas the corresponding E-aurones were inactive.     

Convenient synthesis of t-butyl Z-3-substituted glycidates under conditions of phase-transfer catalysis

Reactions of mixtures of t-butyl E- and Z-3-substituted glycidates 1a-h with 50% aq. sodium hydroxide and a catalyst, benzyltriethylammonium chloride, TEBAC in dichloromethane (phase-transfer catalysis, PTC) led to preferential hydrolysis of the E-isomers to afford pure (90-98%) t-butyl Z-3-substituted glycidates 1a-i in good yields; PTC cleavage of glycidates additionally substituted at C-2, 1g or C-3, 1h,i suggests that an aryl group in the Z isomers hampers attack of HO⁻ on the carbonyl carbon atom. As described in the literature, the diastereoselective PTC synthesis of Z-3-substituted glycidates and glycidonitriles consists of fast hydrolysis of E isomers present in mixtures with Z ones.     

Oxidation of acyclic monoterpenes by P450 BM-3 monooxygenase: influence of the substrate E/Z-isomerism on enzyme chemo- and regioselectivity

Oxidized terpenes and terpenoids are highly valuable compounds for organic chemistry. Cytochrome P450 monooxygenase P450 BM-3 from Bacillus megaterium is able to catalyze oxidation of terpenes with high efficiency. Mutations at the amino acid positions 47, 51, and 87 resulted in significantly enhanced activity and regioselectivity of the enzyme during oxidation of geranylacetone and related compounds. The activity of the mutant R47L/Y51F/F87V was in the order of ketone>alcohol>aldehyde>acid. An effect of the substrate cis/trans-isomerism on the enzyme chemo- and regioselectivity was studied. P450 monooxygenase demonstrated similar NADPH turnovers with cis/trans isomers, nerylacetone/geranylacetone (1.9×10³/2.1×10³ min⁻¹) and nerol/geraniol (5.7×10²/5.9×10² min⁻¹), however, resulted in different number of products and product distribution. The Z-isomers, nerylacetone and nerol, were oxidized resulting in several products (five and three, respectively), including allylic alcohols. In contrast, E-isomers were epoxidized exclusively. Geranylacetone was converted with high activity (2080 min⁻¹) and enantioselectivity (97% ee) to 9,10-epoxygeranylacetone, while geraniol was enantioselectively epoxidized to the 6,7-epoxide (250 min⁻¹, 90% ee) with 90% regioselectivity.     

Dimethylaluminium 4,4-dimethylpent-2-en-2-olate: (Z)- and (E)-isomers and their association

The (Z)- and (E)-isomers of dimethylaluminium 4,4-dimethylpent-2-en-2-olate, Me₂AlOC(Me)=CH-t-Bu, have been obtained. The (Z)-isomer is dimeric; the (E)-isomer can be isolated either as a dimer or as a trimer.The enolates are O-acetylated by acetic anhydride to the corresponding enol acetates (no C-acetylation is observed). They form 1/1 complexes with trimethylamine oxide, pyridine, hexamethylphosphoramide and triphenylphosphine oxide.     

Electrogeneration of (Z)-α-aroyloxy-β-aroylthiostilbenes and (Z)-4,5-diaryl-2-arylimino-1,3-oxathioles by cathodic reduction of monothiobenzils in the presence of electrophilic reagents. Computational B3LYP and RI-MP2 study on the relative stability of oxathiole compounds

Electrochemical reductions of monothiobenzils in the presence of either aroyl or carbonimidoyl dichlorides were carried out, yielding products with sulfur retention. Electrolyses in the presence of aroyl chlorides led to previously unknown (Z)-α-aroyloxy-β-aroylthiostilbenes in high to quantitative yields, whereas reactions in the presence of arylcarbonimidoyl dichlorides provided novel 4,5-diaryl-2-arylimino-1,3-oxathioles in fair to high yields. The molecular structures of (Z)-α-benzoyloxy-β-benzoylthio-4,4′-dimethylstilbene and (Z)-2-(2,4-dichlorophenylimino)-4,5-diphenyl-1,3-oxathiole were determined by X-ray crystallography. Also, ab initio HF, density functional B3LYP, and Møller-Plesset RI-MP2 procedures were applied to oxathiole compounds revealing that (Z)-isomers are more stable than (E)-isomers and that both isomers are separated by a relatively low activation barrier.     

Mass-spectral Study of 9-[α(β,γ)-Picolylidene]-1(4)-azafluorenes

A mass-spectral study was carried out on the behavior of the Z- and E-isomers of 9-picolylideneazafluorenes. A possible mechanism for the elimination of a hydrogen atom from the M⁺ ion of the Z- and E-isomers of 1(4)-azafluorene derivatives was examined. Mass spectrometry permitted a distinction between compounds isomeric relative to the position of the nitrogen atom in the azafluorene fragments and also the Z- and E-isomers of picolylidene derivatives of 1- and 4-azafluorenes possessing - and -pyridyl substituents.     

Synthesis and Stereoisomerization of 2-(1-Alkoxyimino-2,2,2-trifluoroethyl)-5-trimethylsilylfurans

2-(1-Alkoxyimino-2,2,2-trifluoroethyl)-5-trimethylsilylfurans were synthesized by the condensation of 2-(trifluoroacetyl)-5-trimethylsilylfuran with alkoxyamines. According to ¹H and ¹⁹F NMR spectroscopic data, the alkoxyimino group in the E-isomers descreens the H-3 and H-4 protons of the furan ring more strongly than in the Z-isomers, shifting their signals downfield. The fluorine atoms of the α-trifluoromethyl group in the Z-isomer are characterized by a downfield shift in relation to the E-isomer. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 834–838, June, 2005.     

Practical synthesis and mechanistic study of polysubstituted tetrahydropyrimidines with use of domino multicomponent reactions

The practical synthesis of polysubstituted tetrahydropyrimidines 4 from but-2-ynedioates 1, amines 2, and formaldehyde 3 through a domino process of one-pot multicomponent reactions (MCRs) and the detailed mechanistic studies are described. The MCRs were performed under extremely mild reaction conditions and offered the desired products in excellent yields. The detailed studies on the mechanism of the MCRs proved that: (1) the proton-promoted domino sequence is composed of hydroamination, aza-ene-type reaction, nucleophilic addition, and dehydration-cyclization; (2) solvents could control the hydroamination stereoselectivity of 1 and 2: Z-isomers in proton solvents with Z/E up to 95:5 and E-isomers in non-proton solvents with E/Z up to 98:2, and Z-isomers are more stable than E-isomers; (3) Z- and E-enamine intermediates led to the same desired products via aza-ene-type reaction model. Calculations verified the aza-ene-type process in the MCRs.     

Synthesis, structural and conformational studies of Z- and E-isomers of fluorinated C-6 isobutenyl N-methyl thymine derivatives

A new series of conformationally restricted pyrimidine derivatives bearing C-6 isobutenyl side-chain (2-9) has been prepared. The novel fluoroalkenyl pyrimidine nucleoside mimetic 3 as model compound for development of tracer molecule in positron emission tomography (PET) was synthesized by fluorination reaction of methoxytritylated pyrimidine derivative using diethylaminosulfur trifluoride (DAST). Conversion of one hydroxyl group to methoxytritylated, fluorinated, mesylated and acetylated pyrimidine derivatives (2, 3, 5-7 and 9) afforded a mixture of Z- and E-isomers in which Z-isomers were predominant. Conformational study of 1, and its fluorinated structural congeners 3 and 4 by the use of NOE experiments revealed predominant conformation of compounds where vinyl H-1′ proton is spatially close to N-1 methyl and H-3′b methylene protons and on the other hand H-3′a methylene protons are close to C-5 methyl protons. The stereostructure of 1,3-dihydroxyisobutenyl N-methyl thymine 1 was unambiguously confirmed by X-ray crystal structure analysis.     

Azimine IV. Kinetik und Mechanismus der thermischen Stereoisomerisierung von 2,3-Diaryl-1-phthalimido-aziminen

Azimines IV. Kinetics and Mechanism of the Thermal Stereoisomerization of 2,3-Diaryl-1-phthalimido-azimines¹) Mixtures of (1E, 2Z)- and (1Z, 2E)-2-phenyl-1-phthalimido-3-p-tolyl-azimine ( 3a and 3b , resp.) and (1E, 2Z)- and (1Z, 2E)-3-phenyl-1-phthalimido-2-p-tolylazimine ( 4a and 4b , resp.) were obtained by the addition of oxidatively generated phthalimido-nitrene (6) to (E)- and (Z)-4-methyl-azobenzene ( 7a and 7b , resp.). Whereas complete separation of the 4 isomers 3a, 3b, 4a and 4b was not possible, partial separation by chromatography and crystallization led to 5 differently composed mixtures of azimine isomers. The spectroscopic properties of these mixtures (UV., ¹H-NMR.) were used to determine the ratios of isomers in the mixtures, and served as a tool for the assignment of constitution and configuration to those isomers which were dominant in each of these mixtures, respectively. Investigation of the isomerization of the azimines 3a, 3b, 4a and 4b within the 5 mixtures at various concentrations by ¹H-NMR.-spectroscopy at room temperature revealed that only stereoisomers are interconverted ( 3a ? 3b; 4a ? 4b) and that the (1E, 2Z) ? (1Z, 2E) stereoisomerization is a unimolecular reaction. These observations exclude an isomerization mechanism via an intermediate 1-phthalimido-triaziridine (2) or via dimerization of 1-phthalimido-azimines (1) , respectively. The 3-p-tolyl substituted stereoisomers 3a and 3b isomerized slightly slower than the 3-phenyl substituted ones 4a and 4b , an effect which is consistent with the assumption that the rate determining step of the interconversion of (1E, 2Z)- and (1Z, 2E)-1-phthalimido-azimines (1a ? 1b) is the stereoisomerization of the stereogenic center at N(2), N(3), either by inversion of N(3) or by rotation around the N(2), N(3) bond. The total isomerization process is assumed to occur via the thermodynamically less stable (1Z, 2Z)- and (1E, 2E)-isomers 1c and 1d , respectively, as intermediates in undetectably low concentrations which stay in rapidly established equilibria with the observed, thermodynamically more stable (1E, 2Z)- and (1Z, 2E)-isomers 1a and 1b , respectively. At higher temperatures, the azimines 3 and 4 are transformed into N-phenyl-N,N′-phthaloyl-N′-p-tolyl-hydrazine (8) with loss of nitrogen.     

Inorganic base-mediated stereoselective hydroamination of arylalkynes with imidazole: An efficient access to N-vinylimidazoles

A metal-free inorganic base-mediated highly stereoselective hydroamination of arylalkynes with imidazoles has been developed, and the corresponding N-vinylimidazoles were obtained in good yields and with moderate to excellent stereoselectivities (up to 99:1). For the electron rich alkynes, the reaction system of CsOH·H₂O/NMP/140?°C led to the predominant formation of E-addition products, while the reaction system of KOH/NMP/90?°C afforded the Z-isomers as the major product. The electron deficient alkynes furnished predominantly the E-addition products in both reaction systems. This study essentially provides a general and an efficient protocol for the synthesis of E-isomer of the N-vinylimidazoles.     

I2/PhI(OAc)2-assisted oxidative CH amination protocols toward metal-free pragmatic synthesis of pyrrolo[2,3-b]indoles

We report herein an I₂/PhI(OAc)₂ catalytic system for the pragmatic construction of CN bonds through CH/NH oxidative coupling protocol. Divergent pyrrolo[2,3-b]indoles were efficiently prepared via I₂-catalyzed intramolecular C–H amination reactions from (E/Z)-2-indolylenamines under metal-free conditions. Various functional groups are tolerated under mild reaction conditions and the resulting pyrrolo[2,3-b]indoles were obtained with mostly good to excellent yields. It was interesting to observe that both the (E)- and (Z)-isomers of the starting materials were efficiently transformed into the targeted product. The I⁺-mediated catalytic cycle was proposed based on mechanistic studies for this reaction.     

Structure of (Z)-(5R)-methyl-2-(4-phenylbenzylidene)cyclohexanone as chiral component of liquid-crystalline systems

The spatial structure of (Z)-(5R)-methyl-2-(4-phenylbenzylidene)cyclohexanone prepared by photochemical isomerization of the E-isomer was studied by analyzing the magnitudes and temperature dependence of the proton spin-spin coupling constants obtained by ¹H NMR spectroscopy and the results of molecular modeling using semiempirical quantum chemical AM1 and PM3 methods and the density functional theory (DFT). Comparison of the results obtained for the Z-and E-isomers shows that in both cases the conformational equilibrium for both isomers is characterized by significant preference of the chair conformer having an equatorial methyl group, namely, − ΔH (chair a ⇌ chair e) = 1.98–2.12 and 1.36–1.54 kcal mole⁻¹ for the Z-and E-isomers, respectively. Distinctions in the non-planarity of the enone fragment and cyclohexanone ring in the Z-and E-isomers under study following from the results of mathematical modeling were confirmed by the experimental values of the geminal spin-spin coupling constants of protons of the methylene groups in α,α ′-positions with respect to the enone group. Quantum chemical calculations of the Z-isomer revealed the existence of intramolecular hydrogen bond between the carbonyl oxygen and the nearest aromatic proton in ortho-position of the benzene ring. Possible reasons for different helical twisting power of (Z)-(5R)-methyl-2-(4-phenylbenzylidene)cyclohexanone and the E-and Z-arylidene derivatives of 1R, 4R-isomenthone in the mesophase are discussed based on the results of molecular structure studies for these compounds. In the text below the unsaturated ketones under study will be called “arylidene cyclohexanone derivatives” for convenience of comparing the characteristics of methylcyclohexanone and isomenthone derivatives. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 962–972, June, 2006.     

Carbon-carbon double bond in pillar[5]arene cavity: Selective binding of cis/trans-olefin isomers

The binding behavior of pillar[5]arenes (P5As) towards a series of olefin guests ((E)-1,4-dichlorobut-2-ene (1E), (Z)-1,4-dichlorobut-2-ene (1Z), (E)-but-2-ene-1,4-diol (2E), and (Z)-but-2-ene-1,4-diol (2Z), as well as an alkyne derivative 1,4-dichlorobut-2-yne (3)) have been studied in organic solution. P5As exhibit considerable selectivities for the trans-olefin isomers (1E and 2E) over their cis-isomers (1Z and 2Z). The cis/trans-selective interactions hold the potential of utilizing P5As to separate olefin isomers.     

Cyanation of nucleophilic alkynes: easy approach to element-substituted α-cyanoenamines

The reactions of trimethylsilyl cyanide and tributyltin cyanide with ynamines proceeds as a regioselective syn-addition and provide previously unknown β-elementosubstituted α-cyanoenamines as pure E-isomers. The reaction of cyanogen bromide with ynamines as well the hydrocyanation of phosphorus substituted N,N-diethylaminoacetylenes by acetone cyanohydrin also proceeds as regioselective syn-addition, though the initially formed Z-isomers undergo an easy transformation into E-isomers. Cross-coupling reaction of β-bromo-α-cyanoenamine with arylboronic acids were shown to be an easy and convenient approach to α-dialkylaminosubstituted cynnamonitriles.