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Study of the cis to trans isomerization of 1-phenyl-2,3-disubstituted tetrahydro-beta-carbolines at C(1). Evidence for the carbocation-mediated mechanism.

ABSTRACT: The present study was undertaken to shed light on the mechanism of the epimerization of cis-1,2,3-trisubstituted tetrahydro-beta-carbolines into the trans isomers via a potential carbocationic intermediate at C(1). In order to study the pathway involved in C(1)-N(2) bond cleavage, the electronic character of the carbon atom at C-1 was altered by substitution of electron-rich and electron-poor phenyl rings at this position. This provided direct evidence of the effects of charge at the proposed site of the carbocationic intermediate. In this regard, a diverse set of 1-(phenyl substituted)-2-benzyl-3-ethoxycarbonyl-1,2,3,4-tetrahydro-beta-carbolines has been synthesized via the Pictet-Spengler reaction by condensation of l-tryptophan derivatives with electron-poor and electron-rich aromatic aldehydes. The epimers involved in the isomerization mechanism were investigated by dynamic (1)H and (13)C NMR spectroscopic and X-ray crystallographic analyses. The kinetic studies, which involved conversion of cis diastereomers into their trans counterparts, were carried out in dilute TFA/CH(2)Cl(2). The 1-(4-methoxyphenyl) cis diastereomer epimerized at a much faster rate into the corresponding trans diastereomer than the related 1-(4-nitrophenyl) cis diastereomer epimerized. These observations provide support for the carbocationic intermediate in the C(1)-N(2) scission process. The understanding of this epimerization process is of importance when Pictet-Spengler reactions are carried out under acidic conditions during the synthesis of indole alkaloids.

SUBMITTER: Kumpaty HJ

PROVIDER: S-EPMC2758420 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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Study of the cis to trans isomerization of 1-phenyl-2,3-disubstituted tetrahydro-beta-carbolines at C(1). Evidence for the carbocation-mediated mechanism.

Kumpaty Hephzibah J HJ Van Linn Michael L ML Kabir M Shahjahan MS Försterling F Holger FH Deschamps Jeffrey R JR Cook James M JM

The Journal of organic chemistry 20090401 7

The present study was undertaken to shed light on the mechanism of the epimerization of cis-1,2,3-trisubstituted tetrahydro-beta-carbolines into the trans isomers via a potential carbocationic intermediate at C(1). In order to study the pathway involved in C(1)-N(2) bond cleavage, the electronic character of the carbon atom at C-1 was altered by substitution of electron-rich and electron-poor phenyl rings at this position. This provided direct evidence of the effects of charge at the proposed si ...[more]

PMID: 19275130

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Project description:Synthesis and X-ray diffraction structures of cis and trans isomers of ruthenium and osmium metal complexes of general formulas (nBu4N)[cis-MCl4(NO)(Hind)], where M = Ru (1) and Os (3), and (nBu4N)[trans-MCl4(NO)(Hind)], where M = Ru (2) and Os (4) and Hind = 1H-indazole are reported. Interconversion between cis and trans isomers at high temperatures (80-130 °C) has been observed and studied by NMR spectroscopy. Kinetic data indicate that isomerizations correspond to reversible first order reactions. The rates of isomerization reactions even at 110 °C are very low with rate constants of 10(-5) s(-1) and 10(-6) s(-1) for ruthenium and osmium complexes, respectively, and the estimated rate constants of isomerization at room temperature are of ca. 10(-10) s(-1). The activation parameters, which have been obtained from fitting the reaction rates at different temperatures to the Eyring equation for ruthenium [?H(cis-trans)‡ = 122.8 ± 1.3; ?H(trans-cis)‡ = 138.8 ± 1.0 kJ/mol; ?S(cis-trans)‡ = -18.7 ± 3.6; ?S(trans-cis)‡ = 31.8 ± 2.7 J/(mol·K)] and osmium [?H(cis-trans)‡ = 200.7 ± 0.7; ?H(trans-cis)‡ = 168.2 ± 0.6 kJ/mol; ?S(cis-trans)‡ = 142.7 ± 8.9; ?S(trans-cis)‡ = 85.9 ± 3.9 J/(mol·K)] reflect the inertness of these systems. The entropy of activation for the osmium complexes is highly positive and suggests the dissociative mechanism of isomerization. In the case of ruthenium, the activation entropy for the cis to trans isomerization is negative [-18.6 J/(mol·K)], while being positive [31.0 J/(mol·K)] for the trans to cis conversion. The thermodynamic parameters for cis to trans isomerization of [RuCl4(NO)(Hind)]-, viz. ?H° = 13.5 ± 1.5 kJ/mol and ?S° = -5.2 ± 3.4 J/(mol·K) indicate the low difference between the energies of cis and trans isomers. The theoretical calculation has been carried out on isomerization of ruthenium complexes with DFT methods. The dissociative, associative, and intramolecular twist isomerization mechanisms have been considered. The value for the activation energy found for the dissociative mechanism is in good agreement with experimental activation enthalpy. Electrochemical investigation provides further evidence for higher reactivity of ruthenium complexes compared to that of osmium counterparts and shows that intramolecular electron transfer reactions do not affect the isomerization process. A dissociative mechanism of cis?trans isomerization has been proposed for both ruthenium and osmium complexes.

Dataset Information

Study of the cis to trans isomerization of 1-phenyl-2,3-disubstituted tetrahydro-beta-carbolines at C(1). Evidence for the carbocation-mediated mechanism.

Publications

Study of the cis to trans isomerization of 1-phenyl-2,3-disubstituted tetrahydro-beta-carbolines at C(1). Evidence for the carbocation-mediated mechanism.

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