Chelation‐Controlled Radical Chain Reactions Studied by Electrospray Ionization Mass Spectrometry

Abstract

Electrospray ionization mass spectrometry (ESI-MS) is a novel tool for the investigation of chemical reactions in solution and for the direct detection and identification of reactive intermediates. The tributyltin hydride mediated addition of tert-butyl iodide to dimethyl 2-cyclohexyl-4-methyleneglutarate (2) in the presence of Lewis acids was investigated by ESI-MS using a microreactor coupled on-line to an ESI mass spectrometer. For the first time we have been able to show that transient radicals in radical chain reactions can be detected unambiguously under steady-state conditions in the reaction solution and can be characterized by ESI-MS/MS and accurate mass determination. The detection of different heterodimer radical complexes by ESI-MS/MS has provided new insights into the mechanism of Lewis acid controlled radical chain reactions. Dimeric chelate complexes of glutarates, such as 2 and 3, and Lewis acids, like Sc(OTf)3, MgBr2OEt2 and LiClO4, were observed as well as higher aggregates with additional equivalents of Lewis acid. Evidence for a dynamic equilibrium of the complexes in solution was found by NMR spectroscopy. The ESI-MS investigation of the chelation of glutarate 2 with various Lewis acids has led to the conclusion that the tendency for Lewis acids to form dimeric chelate complexes and higher aggregates has an important effect on the stereoselective outcome of the radical reactions.

Radical Cations in Electrospray Mass Spectrometry: Formation of Open‐Shell Species, Examination of the Fragmentation Behaviour in ESI‐MSn and Reaction Mechanism Studies by Detection of Transient Radical Cations

“…[98] Expanding the classical focus of charged species analysis by MS, even reactions that progress through uncharged radical intermediates were examined successfully by ESI-MS. For that purpose, nitroxide spin traps such as 5,5-dimethyl-1-pyrrolidine N-oxide (DMPO) are utilized to transform transient radicals into stable spin-trapped adducts amenable to ESI-MS analysis and structure elucidation by ESI-MS/ MS. [99][100][101][102][103][104] Additionally, neutral radical intermediates can be detected by complexation with charged species: Lewisacid controlled radical chain reactions, for example. [41,42] In another interesting example of reaction mechanism examinations, not only are the unique properties of ESI for soft ion transfer from the solution into the gas phase included in the analytical strategy, but the special experimental setup of ESI is consciously incorporated as well. Here, peroxide is added to solutions of selected reagents and these mixtures experience the effects of the high voltage applied to the needle tip of the ESI capillary and are transferred further on into charged droplets in the ES ion source.…”

“…[41,42,106] Examination of this reaction was carried out with an experimental setup comprising a microreactor coupled to an ESI-MS instrument. A solution of tert-butyl iodide (9), dimethyl 2-cyclohexyl-4-methyleneglutarate (10) and Sc(OTf) 3 in diethyl ether saturated with air and a solution of tributyltin hydride containing triethylborane under argon were mixed and immediately introduced into the ESI source.…”

“…[37][38][39][40][41][42] For these studies a microreactor was coupled directly to a mass spectrometer fitted either with an ES or with an atmospheric pressure chemical ion source. [37][38][39][40][41][42] To investigate the electron-transfer-initiated reaction in solution, which proceeds via radical cations as reactive intermediates, catalytic amounts of tris(p-bromophenyl)aminium hexachloroantimonate (6) were used as radical mediator to initiate the stereoselective [2 + 2] cycloaddition of trans-anethole (7) to give 1,2-bis(4-methoxyphenyl)-3,4-dimethylcyclobutane (8; see Scheme 4). [38,40] Kinetic studies regarding the stereo-and regioselective dimerization process for this conversion suggested a radical chain reaction mechanism.…”

Studies of Reaction Mechanism Intermediates by ESI‐MS

“…The highly stereo-and regioselective dimerization of trans-anethole to give the head-to-head trans, -anti, trans-cyclobutane initiated by aminium salt proceeds by a radical cation chain mechanism (Scheme 4.4) and this method was further used to study the transient radical cations intermediates in electron transfer-initiated D-A reactions [12][13][14]. The highly stereo-and regioselective dimerization of trans-anethole to give the head-to-head trans, -anti, trans-cyclobutane initiated by aminium salt proceeds by a radical cation chain mechanism (Scheme 4.4) and this method was further used to study the transient radical cations intermediates in electron transfer-initiated D-A reactions [12][13][14].…”

On‐line Monitoring Reactions by Electrospray Ionization Mass Spectrometry

“…F€ urmeier and coworkers studied tin hydride-mediated radical additions to dialkyl 2-alkyl-4-methyleneglutarates in the presence of Lewis acids (Scheme 5.5) [28,43]. However, it is well known that radical reactions can be mediated by Lewis acids if the substrate acts as a Lewis base by chelating the metal atom of a Lewis acid in solution.…”