The mass spectrometry-induced cyclization of protonated N-[2-(benzoyloxy)phenyl]-benzamide: A gas-phase analog of a solution reaction

Srinivas

et al. 2007

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A novel gas-phase electrophilic cyclization, initiated by the protonation of a nitro group, occurs for 2-nitrophenyl phenyl ether and for the analogous sulfide and amine, leading to heterocyclic intermediates in each case. Subsequently, the cyclic intermediates dissociate via two pathways: (1) unusual step-wise eliminations of two OH radicals to afford heterocyclic cations, [phenoxazine − H] + , [phenothiazine − H] + and [phenazine + H] + , and (2) expulsion of H 2 O, to yield a heterocyclic ketone, followed by loss of CO. The proposed structures of the gas-phase product ions and reaction mechanisms are supported by chemical substitution, deuterium labeling, accurate mass measurements at high mass resolving power, product-ion mass spectra obtained by tandem mass spectrometry, mass spectra of reference compounds, and molecular orbital calculations. Using a mass spectrometer as a reaction vessel, we demonstrate that, upon protonation, a nitro group becomes an electrophile and participates in cyclization reactions in the gas-phase.

Section: Introductionmentioning

confidence: 96%

Protonated nitro group as a gas-phase electrophile: Experimental and theoretical study of the cyclization of o-nitrodiphenyl ethers, amines, and sulfides

Moolayil

Srinivas

et al. 2007

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“…Combining the results with those from DFT calculations provides a useful approach in exploring reaction mechanisms, especially for protonated or deprotonated molecules. Examples are the investigation of mechanisms of the rearrangement of protonated 2-nitophenylphenyl ethers [14, 15] and that of the Smiles rearrangement [16, 17]. …”

Section: Introductionmentioning

confidence: 99%

The Role of Methoxy Group in the Nazarov Cyclization of 1,5-bis-(2-Methoxyphenyl)-1,4-Pentadien-3-one in the Gas Phase and Condensed Phase

Cyriac

Paulose

et al. 2014

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ESI-protonated 1,5-bis-(2-methoxyphenyl)-1,4-pentadien-3-one (1) undergoes a gas-phase Nazarov cyclization and dissociates via expulsions of ketene and anisole. The dissociations of the [M+ D]+ ions are accompanied by limited HD scrambling that supports the proposed cyclization. Solution cyclization of 1 was effected to yield the cyclic ketone, 2,3-bis-(2-methoxyphenyl)-cyclopent-2-ene-1-one, (2) on a time scale that is significantly shorter than the time for cyclization of dibenzalacetone. The dissociation characteristics of the ESI-generated [M + H]+ ion of the synthetic cyclic ketone closely resemble those of 1, suggesting that gas-phase and solution cyclization products are the same. Additional mechanistic studies by density functional theory (DFT) methods of the gas-phase reaction reveals that the initial cyclization is followed by two sequential 1,2-aryl migrations that account for the observed structure of the cyclic product in the gas phase and solution. Furthermore, the DFT calculations show that the methoxy group serves as a catalyst for the proton migrations necessary for both cyclization and fragmentation after aryl migration. An isomer formed by moving the 2-methoxy to the 4-position requires relatively higher collision energy for the elimination of anisole, as is consistent with DFT calculations. Replacement of the 2-methoxy group with an OH shows that the cyclization followed by aryl migration and elimination of phenol occurs from the [M + H]+ ion at low energy similar to that for 1.

“…Proton-induced, gas-phase rearrangements may closely parallel those in solution as demonstrated by mass spectrometric studies; the acid-catalyzed Claisen rearrangement being a classic example [19]. A more recent example is the rearrangement of protonated 2-[ N -benzoyloxyphenyl] benzamide both in the gas phase and in solution [20]. Another motivation for our study relies on evidence from both experiment and theory that high-energy 1,3-H shifts take place in the gas-phase when catalyzed by a base, a process called Proton Transport Catalysis [21-24].…”

Section: Introductionmentioning

confidence: 99%

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

Sebastian

Reddy³

et al. 2009

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Upon CA, ESI generated [M ϩ H] ϩ ions of chalcone (benzalacetophenone) and 3-phenylindanone both undergo losses of H 2 O, CO, and the elements of benzene. CA of the [M ϩ H] ϩ ions of 2-methoxy and 2-hydroxychalcone, however, prompts instead a dominant loss of ketene. In addition, CA of the [M ϩ H] ϩ ions of 2-methoxy-␤-methylchalcone produces an ␤ analogous loss of methylketene instead. Furthermore, the [M ϩ D] ϩ ion of 2-methoxychalcone upon CA eliminates only unlabeled ketene, and the resultant product, the [M ϩ D Ϫ ketene] ϩ 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-arylindanones 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-hydroxyphenylphenyl-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. T he acid-catalyzed cyclization of divinyl ketones to yield cyclopentenones is known as Nazarov cyclization, a reaction that was recently reviewed [1,2]. Bronsted acids, superacids, and Lewis acids are usually needed to promote the cyclizations in solution. The mechanism involves conrotatory electrocyclic ring closure of a protonated divinyl ketone followed by deprotonation and double-bond reorganization [2]. A general and efficient method for the synthesis of biologically active 3-aryl-indanones is the Nazarov cyclization of substituted chalcones [3][4][5][6]. A variety of indanone derivatives can be synthesized by the microwave-assisted Nazarov cyclization of chalcones in trifluoroacetic acid (TFA) solution [5]. In addition, further motivation comes from the antimicrobial activity of substituted chalcones, which was evaluated recently [7].Characterization of these materials has attracted the attention of mass spectrometrists since the early 1960s , were one focus [9 -14], including an ion-structure study with an iontrap mass spectrometer [15]. Recently, the mechanisms for elimination of C 6 H 6 and CO from the atmospheric pressure chemical ionization (APCI)-generated [M ϩ H] ϩ ions of chalcones were established [16]. Three important product ions observed in the CAD mass spectrum of protonated chalcone arise from losses of H 2 O, CO, and C 6 H 6 . Studie...