Sebastián Barata-Vallejo

Recent Advances in Trifluoromethylation Reactions with Electrophilic Trifluoromethylating Reagents

Electrophilic trifluoromethylation reactions have been the latest approach to achieve the fluoroalkylation of compounds with newly-discovered reagents, such as the Tognis (1-trifluoromethyl-1,2-benziodoxol-3-(1 H)-one), Umemotos (S-(trifluoromethyl)dibenzothiophenium tetrafluoroborate), Yagupolskiis (S-(trifluoromethyldiarylsulfonium salts), Shreeves (S-(trifluoromethyl)dibenzothiophenium triflate), and Shibatas (trifluoromethylsulfoximine salts) reagents. All these reagents produce an electrophilic trifluoromethylating (CF3 (+) ) species that undergoes reaction with nucleophiles. In addition, these latter reactive species (i.e. CF3 (+) ) can undergo electron-transfer (ET) processes affording CF3 (⋅) radicals that expand the scope to substrates other than conventional nucleophiles that can undergo reaction. In this Review, we shall discuss the trifluoromethylation reactions of diverse families of organic substrates of biological interest as a means to comparing the reagents scope and best reaction conditions. Some, though not all, of these reactions require the assistance of metal or organometallic catalysts. Some require additives and catalysts to promote the fluoroalkylation reaction, but invariably all are initiated and carried out by electrophilic trifluoromethylating species.

Radiation chemical studies of methionine in aqueous solution: understanding the role of molecular oxygen.

The oxidation of methionine is an important reaction in the biological milieu. Despite a few decades of intense studies, several fundamental aspects remain to be defined. We have investigated in detail the gamma-radiolysis of free methionine in the absence and presence of molecular oxygen followed by product characterization and quantification. The primary site of attack by HO(*) radicals and H(*) atoms is the sulfur atom of methionine. We have disclosed that HO(*) radicals do not oxidize methionine to the corresponding sulfoxide in either the presence or the absence of oxygen; the oxidizing species is H(2)O(2) derived either from the radiolysis of water or from the disproportionation of the byproduct O(2)(*-). 3-Methylthiopropionaldehyde is the major product of HO(*) radical attack in the presence of molecular oxygen. Together with the direct oxidation at sulfur as the major product, the potential of H(*) atoms is also proven to be highly specific for sulfur atom attack under anoxic and aerobic conditions. The major products derived from the H(*) atoms attack are found to be alpha-aminobutyric acid or homoserine, in the absence or presence of oxygen, respectively. All together, these results help clarify the fate of methionine related to a biological environment and offer a molecular basis for envisaging other possible pathways of in vivo degradation as well as other markers.

Difluoromethylation Reactions of Organic Compounds

The relevance of the -CF2 H moiety has attracted considerable attention from organic synthetic and medicinal chemistry communities, because this group can act as a more lipophilic isostere of the carbinol, thiol, hydroxamic acid, or amide groups. Being weakly acidic, the CF2 H moiety can establish hydrogen-bonding interactions to improve the binding selectivity of biologically active compounds. Therefore, the hydroxyl, amino, and thio substituents of lead structures are routinely replaced by a CF2 H motif in drug discovery, with great benefits in the pharmacological activity of drugs and drug candidates and agrochemicals. Consequently, the late-stage introduction of CF2 H is a sought-after strategy in designing bioactive compounds. Secondly, but nonetheless relevant and meaningful, is the study of synthetic pathways to introduce a CF2 -Y moiety (Y≠H, F) into organic substrates because compounds that contain a CF2 -Y functionality have also found vast applications in medicinal chemistry and in other areas, such as that of fungicides, insecticides, etc., and thus, this functionality deserves special attention. Although emphasis is made on difluoromethylation strategies to functionalize different families of organic compounds, three main methodological protocols will be presented in this review article for the late-stage introduction of a CF2 H or CF2 Y moieties into organic substrates: i) a metal-photoredox catalysis; ii) through transition metal-catalyzed thermal protocols; and iii) from transition-metal-free strategies.

Perfluoroalkylation reactions of (hetero)arenes

Perfluoroalkylation reactions of arenes have not been the subject of intense study as has been the case for the trifluoromethylation reactions of aromatics. However, the new synthetic methods proposed for achieving homolytic aromatic substitution reactions with perfluoroalkyl moieties have begun to claim a relevant role in functionalization reactions, as revealed by the interesting properties of arenes with large perfluoroalkyl chains. Methods for achieving Ar–Rf bonding reactions can be classified into thermal and photochemical, which can in turn make use of transition metals or be non-metal catalyzed. Reactions are mainly radical in nature. Radical methods for introducing Rf moieties into arenes have resulted as being the most popular and versatile options available to synthetic chemists.

Combined Raman and IR spectroscopic study on the radical-based modifications of methionine

AbstractAmong damages reported to occur on proteins, radical-based changes of methionine (Met) residues are one of the most important convalent post-translational modifications. The combined application of Raman and infrared (IR) spectroscopies for the characterisation of the radical-induced modifications of Met is described here. Gamma-irradiation was used to simulate the endogenous formation of reactive species such as hydrogen atoms (•H), hydroxyl radicals (•OH) and hydrogen peroxide (H2O2). These spectroscopic techniques coupled to mass experiments are suitable tools in detecting almost all the main radical-induced degradation products of Met that depend on the nature of the reactive species. In particular, Raman spectroscopy is useful in revealing the radical-induced modifications in the sulphur-containing moiety, whereas the IR spectra allow decarboxylation and deamination processes to be detected, as well as the formation of other degradation products. Thus, some band patterns useful for building a library of spectra–structure correlation for radical-based degradation of Met were identified. In particular, the bands due to the formation of methionine sulfoxide, the main oxidation product of Met, have been identified. All together, these results combine to produce a set of spectroscopic markers of the main processes occurring as a consequence of radical stress exposure, which can be used in a spectroscopic protocol for providing a first assessment of Met modifications in more complex systems such as peptides and proteins, and monitoring their impact on protein structure. FigureThe combined use of Raman and IR spectroscopy allows to monitor the formation of the main degradation products of amino acids like methionine after radical stress exposure. In particular, Raman spectra are useful for revealing the occurrence of modifications in sulphur-containing moiety, whereas IR spectroscopy is able to detect decarboxylation and deamination processes, as well as the formation of new products

Organic Synthesis in Water Mediated By Silyl Radicals

Fil: Barata Vallejo, Sebastian. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Quimica Organica; Argentina. Consejo Nacional de Investigaciones Cientificas y Tecnicas; Argentina

Radiation chemical studies of Gly-Met-Gly in aqueous solution

Abstract Important biological consequences are related to the reaction of HO• radicals with methionine (Met). Several fundamental aspects remain to be defined when Met is an amino acid residue incorporated in the interior of peptides and proteins. The present study focuses on Gly-Met-Gly, the simplest peptide where Met is not a terminal residue. The reactions of HO• with Gly-Met-Gly and its N-acetyl derivative were studied by pulse radiolysis technique. The transient absorption spectra were resolved into contributions from specific components of radical intermediates. Moreover, a detailed product analysis is provided for the first time for Met-containing peptides in radiolytic studies to support the mechanistic proposal. By parallel radiolytical and electrochemical reactions and consequent product identification, the formation of sulfoxide attributed to the direct HO• radical attack on the sulfide functionality of the Met residue could be excluded, with the in situ generated hydrogen peroxide responsible for this oxidation. LC–MS and high resolution MS/MS were powerful analytical tools to envisage the structures of five products, thus allowing to complete the mechanistic picture of the overall Met-containing peptide reactivity.

Transition metal- and organophotocatalyst-free perfluoroalkylation reaction of amino(hetero)aromatics initiated by the complex [(TMEDA)I·I3] and visible light

Radical initiation for the perfluoroalkylation reaction of amino(hetero)aromatics has been accomplished employing the complex [(TMEDA)I·I3] and visible light. This methodology circumvents the use of metal(organo)catalysts and biologically-relevant substrates are easily substituted with RF moieties employing a mild and environmentally benign radical strategy starting from readily-available perfluoroalkyl iodides RFI.

Photoinduced Addition Reactions in Aqueous Media

The scope of this account on addition reactions in aqueous media is to demonstrate that the syntheses of useful targets or func- tionalizations can be accomplished through photoaddition reactions in benign environments. Ammination reactions of olefins and con- strained cycloalkanes, addition products derived from quinonemethides, aromatic arylation reactions of furanones and alkenes, and radi- cal addition reactions to ,!-unsaturated aldehydes performed in aqueous media constitute valuable reactions and hence interesting syn- thetic targets in organic syntheses. In studying these synthetic targets, different light sources are employed to achieve excitation. Also, photoinduced electron transfer sequences will account for the addition products. This account does exclude the photoaddition reactions performed by the aid of metals or metallic complexes, or the addition of perfluoroalkyl radicals to carbon-carbon and carbon-heteroatom multiple bonds in aqueous media.

Electron-catalyzed radical perfluoroalkylation of organic sulfides: the serendipitous use of the TMEDA/I2 complex as a radical initiator

Radical initiation for the perfluoroalkylation reaction of sulfides has been performed using the complex [(TMEDA)I·I3] and visible light. This methodology bypasses the use of metal(organo)catalysts where the complex [(TMEDA)I·I3] acts as a good electron donor/reductant radical initiating agent. Biologically relevant sulfides are easily substituted with RF moieties employing a mild and environmentally benign radical strategy starting from readily available RFI.