Development of radical processes triggered by the photochemical activity of transient organic intermediates

Resumen

The main scientific objective of my doctoral research was to employ and combine two powerful fields of molecule activation, photochemistry and organocatalysis, to efficiently develop new carbon-carbon bond forming transformations in an environmentally friendly way. The chemistry has largely capitalized upon the ability of electron-rich organic intermediates (phenolate anions and chiral enamines), transiently generated from photochemically inactive precursors (phenols and aldehydes), to directly reach an electronically excited state upon light absorption, while successively triggering the formation of reactive radical species from suitable alkyl iodides. Initially, I developed a metal-free photochemical strategy for the direct aromatic radical perfluoroalkylation of substituted phenols. The reaction is initiated by the photochemical activity of the phenolate anions, formed after deprotonation of substituted phenols. Upon light absorption, phenolate anions can directly reach an electronically excited-state, becoming strong reducing agents and triggering the formation of electron-deficient radicals through the reductive cleavage of the perfluoroalkyl iodide C-I bond via a single-electron transfer mechanism. Then, the electron-poor perfluoroalkyl radical is intercepted by the ground-state nucleophilic phenolate anion to afford the desired perfluoroalkylated product. The reaction protocol is operationally simple, conducted at ambient temperature with readily available substrates and reagents, and using household compact fluorescence light (CFL) bulbs as the light source. The scope of this photochemical transformation was evaluated under the optimal reaction conditions and a series of substituted phenols was transformed into the corresponding perfluoroalkylated derivatives. Preliminary mechanistic studies, which support a radical chain mechanism proceeding through a HAS (homolytic aromatic substitution) pathway, have been also performed. In a second project, I developed a new efficient enantioselective procedure for the coupling reaction between α-iodo sulfones and aldehydes under photo-organocatalytic conditions. The chemistry exploits the ability of in situ formed chiral tertiary enamines to directly reach an electronically excited state upon light absorption (irradiation wavelength = 365 nm) and then generate carbon-centered radicals by single-electron transfer reduction of the α-iodo sulfones. At the same time, the ground-state chiral enamines provide effective stereochemical control over the enantioselective radical trapping process. In the preliminary experiments carried out in batch, we obtained the desired product with good enantioselectivity but with poor chemical yields. This presented an opportunity to exploit the synthetic benefits of flow chemistry in photochemical transformations during a four-month collaboration with Professor Oliver Kappe (University of Graz, Austria), an expert in the application of flow techniques. We studied the reaction under flow conditions, building up the system and optimizing the reaction parameters (residence time, solvent, concentration). Under flow conditions, the reaction was faster with respect to the batch version (higher productivity), even though the isolated yield of the final compound was not sufficient from a methodological point of view. After that, we proceeded with a second cycle of optimization studies under batch conditions. We found that the α-iodo sulfones underwent photo-induced homolytic cleavage leading to the formation of iodine. Iodine suppresses radical chain processes, since it reacts at very fast rate with carbon-centered radicals. We found that the addition of sodium thiosulfate, a reductant able to reduce iodine but not the α-iodo sulfones, leads to a quantitative yield of the desired product in the studied transformation. Moreover, mechanistic studies have demonstrated that the chemistry proceeded through an atom-transfer radical addition (ATRA) mechanism. This is in agreement with the striking effect of iodine, which is a powerful inhibitor of iodine atom transfer chains. The synthetic potential of the photochemical transformation was evaluated, and a series of aldehydes were transformed into the corresponding enantioenriched α-alkylated adducts in good isolated yields with high enantioselectivities. The final products bear a stereogenic center decorated with a sulfone moiety, which can subsequently be converted into a methyl or a benzyl group through reductive cleavage (using either magnesium or samarium iodide) allowing for the development of a stereoselective formal methylation or benzylation of aldehydes. A large selection of the final products were successfully transformed into the corresponding α-methylated/benzylated derivatives. In conclusion, the use of photo-excited intermediates as reducing agents turned out to be an efficient way to generate reactive radicals from readily available acceptors via a single electron transfer mechanism, paving the way to the development of new interesting radical transformations. Tools used: - Standard laboratory equipment. - Tools for flow chemistry: PFE tubes, Y-mixer, HPLC type pumps, injections loops, conical and cylindrical connectors, cooling jacket, lamps. - NMR Spectroscopy (300 MHz, 400 MHz, 500 MHz). It is a research technique that exploits the magnetic properties of certain atomic nuclei. It determines the physical and chemical properties of atoms or the molecules in which they are contained. - HPLC (high-pressure liquid chromatography) or Waters ACQUITY® UPC2 using a chiral stationary phase, useful to separate the two enantiomers of the same analyte compound so to determine the enantiomeric excess. - Liquid chromatography mass spectrometry (LC-MS, or alternatively HPLC-MS). It is an analytical chemistry technique that combines the physical separation capabilities of liquid chromatography (or HPLC) with the mass analysis capabilities of mass spectrometry (MS). Its application is oriented towards the separation, general detection, and potential identification of chemicals of particular masses in the presence of other chemicals (i.e., in complex mixtures) - Gas chromatography-mass spectrometry (GC-MS). - Chiral gas chromatography (GC analysis with a chiral stationary phase). - Ultraviolet-visible Spectroscopy. - X-Ray Spectroscopy (X-Ray unit, ICIQ). Methodologies: Utilization of methodologies reported in the literature (Scientific Journals or Patent) or previously developed in our research group.