Studies of Reaction Mechanism Intermediates by ESI-MS

Rong Qian, Jing Zhou, Shengun Yao, Haoyang Wang and Yinlong Cuo 

Applications of atmospheric pressure ionization mass spectrometry (API-MS) to the study of reaction intermediates and mechanisms are reviewed. API-MS, especially ESI-MS, has provided many opportunities to intercept and characterize the key intermediates from the reaction mixtures. Combined with tandem mass spectro-metric (MS/MS) methods, this technique has been extensively used for structural characterization of organic compounds and mechanism deduction of some organic reactions. Furthermore, API-MS affords a straightforward approach to trapping and identifying short-lived intermediates. 

Although this study did not provide quantitative or detailed structural information about the intermediates, it was able to analyze the reaction mixture and observe mass spectra that correspond to the two key intermediates in the proposed mechanism for the Suzuki reaction. These results demonstrate that ESI-MS can be a valuable mechanistic tool when used in conjunction with other techniques. 

Recently, we have used electron spray ionization Fourier transform ion cyclotron mass spectrometry (ESI-FTICRMS) to intercept and characterize several organome-tallic species in Pd-catalyzed reactions of 2,3-allenoate with two organoboronic adds 

Another major reaction we studied by ESI-FTICRMS was the Pd(0)-catalyzed three-component tandem double addition cydization reaction [3]. This reaction provides an effident route to polysubstituted ds-pyrrolidine derivatives with matched relay and excellent regio- and stereoselectivity. In principle, there are two types of 

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Ricci and coworkers [64] studied oxazoline moiety fused with a cyclopenta[P]thio-phene as ligands on the copper-catalyzed enantioselective addition of Et2Zn to chalcone. The structure of the active Cu species was determined by ESI-MS. Evans and coworkers [65] studied C2-symmetric copper(II) complexes as chiral Lewis acids. The catalyst-substrate species were probed using electrospray ionization mass spectrometry. Comelles and coworkers studied Cu(II)-catalyzed Michael additions of P-dicarbonyl compounds to 2-butenone in neutral media [66]. ESI-MS studies suggested that copper enolates of the a-dicarbonyl formed in situ are the active nucleophilic species. Schwarz and coworkers investigated by ESI-MS iron enolates formed in solutions of iron(III) salts and [3-ketoesters [67]. Studying the mechanism of palladium complex-catalyzed enantioselective Mannich-type reactions, Fujii and coworkers characterized a novel binuclear palladium enolate complex as intermediate by ESI-MS [68]. 

Probing the mechanisms of nonmetal-catalyzed reactions by ESI-MS/MS have also been carried out by chemists. Eberlin and coworkers have described the use of ESI-MS for the interception and characterization of the organocatalytic intermediates in the DABCO-catalyzed Baylis-Hillman reaction (Scheme 4.5) [19]. Through the ESI-MS study, most proposed intermediates were successfully intercepted and characterized as protonated species, which provided strong evidence for the currently accepted catalytic cycle. In addition, the Baylis-Hillman reaction catalyzed by Lewis adds [20] and dissolved in ionic liquids [21] has also been investigated by Eberlin and coworkers. 

All these cases suggest the necessity to perform a rigorous analysis to probe unambiguously that the species detected by ESI are the ones prevailing in solution, and more importantly to confirm that they are indeed reactive intermediates on the reaction path. An outstanding methodology is to isolate in the gas phase the species assumed to participate in the reaction mechanism and perform ion/molecule reactions with the substrate of the reaction solution. This methodology is a very powerful way to reject side-products and to assure the reliability of the analysis. Another important method is to study well-known reactions and compare the data obtained by ESI-MS with other spectroscopic techniques. 

In 2008, Kim and Chang reported on the catalytic aziridination of styrenes and other olefins by 2-pyridylsulfonamide and PhROAc), using copper complexes [86]. These reactions do not require preformed (arylsulfonylimino)iodobenzenes PhlNS02Ar. During investigations of the mechanism, a copper PhINS02Ar complex was detected by ESI-MS as a major species (Scheme 21). A chelated nitrenoid complex derived from an unusual hypervalent iodine intermediate (Scheme 22) was proposed, based on Hammett plot analysis, kinetics and computational studies. 

In summary, through the use of rapid chemical quench techniques, multiple studies demonstrated the formation of a single tetrahedral intermediate in the reaction pathway of EPSP synthase (Scheme 4, pathway a) which is formed by an attack of the 5-OH group of shikimate-3-phosphate on C-2 of PEP. A complete kinetic and thermodynamic description of this enzyme reaction pathway could be demonstrated, including the isolation and structural elucidation of a tetrahedral enzyme intermediate as originally proposed by Sprinson. This work established the catalytic mechanism and definitively showed that no covalent enzyme—PEP adduct is formed on the reaction pathway. Subsequent work using rapid mixing pulsed-flow ESI—MS studies and solution phase NMR " provides additional support for the catalytic pathway in Scheme 4, pathway a. 

A study of the catalytic a-acetoxylation reaction of acetophenone by electrospray ionization tandem mass spectrometry (ESI-MS/MS) has confirmed the mechanism shown in Scheme 4.2. In particular, the trivalent iodine species was detected when iodobenzene and mCPBA in acetic acid were mixed, which indicated the facile oxidation of a catalytic amount of Phi to the iodine(III) species by mCPBA. Most importantly, the protonated alkyliodonium intermediate 3 (R = Ph, = H) was observed at m/z 383 from the reaction solution and this ion gave the protonated a-acetoxylation product 1 at m/z 179 in MS/MS by an intramolecular reductive elimination of Phi [17]. 

TeCl4 has been found to display reactivity toward alkynes similar to that of p-methoxyphenyltellurium trichloride, whereas it reacts with aromatic and 3-hydro-xyalkynes by different mechanisms as shown by the characteristic stereochemistries of the products. The complete anti-stereospedfidty of the additions of TeCU to all propargyl alcohols studied is consistent with a cyclic chelated telluronium ion intermediate 87 in this reaction (Figure 3.8). Using ESI-MS and ESI-MS(/MS),... 

However, reaction mechanism studies based on ESI-MS and MS" require appropriate control experiments to clarify the origins and identities of detected species unambiguously as real transient intermediates of a reaction path under consideration. It is of special importance that these control experiments be carefully chosen and properly conducted to reliably exclude the formation of artefact ions by ESI, which can dramatically mislead the interpretations. 

In 2012, Ramos and collaborators also studied this mechanistic pathway by means of ESI-MS, NMR, and theoretical calculations in their approach [9]. In this work, the mechanism of the Biginelli reaction was explored by studying the influence of Lewis acid catalysts in the presence of ionic liquids. Once again, the researchers noticed the exclusive formation of iminium intermediate m/z 149 (Figure 4), indicating that xmder Lewis Acid catalysis and in ionic liquids, the preferred mechanistic pathway was the iminium mechanism [9]. 

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