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Gas-phase nazarov cyclization of protonated 2-methoxy and 2-hydroxychalcone: an example of intramolecular proton-transport catalysis.

ABSTRACT: Upon CA, ESI generated [M + H](+) ions of chalcone (benzalacetophenone) and 3-phenyl-indanone both undergo losses of H(2)O, CO, and the elements of benzene. CA of the [M + H](+) ions of 2-methoxy and 2-hydroxychalcone, however, prompts instead a dominant loss of ketene. In addition, CA of the [M + H](+) ions of 2-methoxy-beta-methylchalcone produces an analogous loss of methylketene instead. Furthermore, the [M + D](+) ion of 2-methoxychalcone upon CA eliminates only unlabeled ketene, and the resultant product, the [M + D - ketene](+) ion, yields only the benzyl-d(1) cation upon CA. We propose that the 2-methoxy and 2-hydroxy (ortho) substituents facilitate a Nazarov cyclization to the corresponding protonated 3-aryl-indanones by mediating a critical proton transfer. The resultant protonated indanones then undergo a second proton transport catalysis facilitated by the same ortho substituents producing intermediates that eliminate ketene to yield 2-methoxy- or 2-hydroxyphenyl-phenyl-methylcarbocations, respectively. The basicity of the ortho substituent is important; for example, replacement of the ortho function with a chloro substituent does not provide an efficient catalyst for the proton transports. The Nazarov cyclization must compete with an alternate cyclization, driven by the protonated carbonyl group of the chalcone that results in losses of H(2)O and CO. The assisted proton transfer mediated by the ortho substituent shifts the competition in favor of the Nazarov cyclization. The proposed mechanisms for cyclization and fragmentation are supported by high-mass resolving power data, tandem mass spectra, deuterium labeling, and molecular orbital calculations.

SUBMITTER: George M

PROVIDER: S-EPMC2694139 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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Publications

Gas-phase nazarov cyclization of protonated 2-methoxy and 2-hydroxychalcone: an example of intramolecular proton-transport catalysis.

George Mathai M Sebastian Valarkottu S VS Reddy Putluri Nagi PN Srinivas Ragampeta R Giblin Daryl D Gross Michael L ML

Journal of the American Society for Mass Spectrometry 20081231 5

Upon CA, ESI generated [M + H](+) ions of chalcone (benzalacetophenone) and 3-phenyl-indanone both undergo losses of H(2)O, CO, and the elements of benzene. CA of the [M + H](+) ions of 2-methoxy and 2-hydroxychalcone, however, prompts instead a dominant loss of ketene. In addition, CA of the [M + H](+) ions of 2-methoxy-beta-methylchalcone produces an analogous loss of methylketene instead. Furthermore, the [M + D](+) ion of 2-methoxychalcone upon CA eliminates only unlabeled ketene, and the re ...[more]

PMID: 19230703

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Project description:We have performed a series of first-principles electronic structure calculations to examine the reaction pathways and the corresponding free energy barriers for the ester hydrolysis of protonated cocaine in its chair and boat conformations. The calculated free energy barriers for the benzoyl ester hydrolysis of protonated chair cocaine are close to the corresponding barriers calculated for the benzoyl ester hydrolysis of neutral cocaine. However, the free energy barrier calculated for the methyl ester hydrolysis of protonated cocaine in its chair conformation is significantly lower than for the methyl ester hydrolysis of neutral cocaine and for the dominant pathway of the benzoyl ester hydrolysis of protonated cocaine. The significant decrease of the free energy barrier, approximately 4 kcal/mol, is attributed to the intramolecular acid catalysis of the methyl ester hydrolysis of protonated cocaine, because the transition state structure is stabilized by the strong hydrogen bond between the carbonyl oxygen of the methyl ester moiety and the protonated tropane N. The relative magnitudes of the free energy barriers calculated for different pathways of the ester hydrolysis of protonated chair cocaine are consistent with the experimental kinetic data for cocaine hydrolysis under physiologic conditions. Similar intramolecular acid catalysis also occurs for the benzoyl ester hydrolysis of (protonated) boat cocaine in the physiologic condition, although the contribution of the intramolecular hydrogen bonding to transition state stabilization is negligible. Nonetheless, the predictability of the intramolecular hydrogen bonding could be useful in generating antibody-based catalysts that recruit cocaine to the boat conformation and an analog that elicited antibodies to approximate the protonated tropane N and the benzoyl O more closely than the natural boat conformer might increase the contribution from hydrogen bonding. Such a stable analog of the transition state for intramolecular catalysis of cocaine benzoyl-ester hydrolysis was synthesized and used to successfully elicit a number of anticocaine catalytic antibodies.

Dataset Information

Gas-phase nazarov cyclization of protonated 2-methoxy and 2-hydroxychalcone: an example of intramolecular proton-transport catalysis.

Publications

Gas-phase nazarov cyclization of protonated 2-methoxy and 2-hydroxychalcone: an example of intramolecular proton-transport catalysis.

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