A General Platform for Visible Light Sulfonylation Reactions Enabled by Catalytic Triarylamine EDA Complexes.

Catalytic electron donor-acceptor (EDA) complexes have recently emerged as a powerful and sustainable alternative to iridium- and ruthenium-based photoredox synthetic methods. Yet, these complexes remain underexplored and reliant on the use of meticulously designed acceptors that require previous installation. Herein, we report a novel EDA complex employing tris(4-methoxyphenyl) amine as a catalytic donor for the sulfonylation of alkenes using inexpensive and readily available sulfonyl chlorides. Applying this operationally simple, visible-light-mediated general platform, we report both the redox-neutral and net-reductive functionalization of more than 60 substrates, encompassing vinylic or allylic sulfonylation, hydrosulfonylation, and sulfamoylation of activated and unactivated alkenes and alkynes.

Triarylamines as catalytic donors in light-mediated electron donor-acceptor complexes.

Recently, photochemistry of Electron Donor-Acceptor (EDA) complexes employing catalytic amounts of electron donors have become of interest as a new methodology in the catalysis field, allowing for decoupling of the electron transfer (ET) from the bond-forming event. However, examples of practical EDA systems in the catalytic regime remain scarce, and their mechanism is not yet well-understood. Herein, we report the discovery of an EDA complex between triarylamines and α-perfluorosulfonylpropiophenone reagents, catalyzing C-H perfluoroalkylation of arenes and heteroarenes under visible light irradiation in pH- and redox-neutral conditions. We elucidate the mechanism of this reaction using a detailed photophysical characterization of the EDA complex, the resulting triarylamine radical cation, and its turnover event.

EDA mediated S-N bond coupling of nitroarenes and sodium sulfinate salts.

Despite their long-known photochemical properties and their industrial value, the use of nitroarenes as a productive photochemical handle in organic synthesis has remained relatively unexplored. More specifically, the photochemical formation of nitrogen-sulfur bonds from nitroarenes remains to be demonstrated. Herein, we report the design and application of a sulfinate-nitroarene electron donor-acceptor (EDA) complex and its subsequent use in the first light mediated catalyst-free synthesis of N-hydroxy-sulfonamides. The presence of the EDA was assessed spectroscopically and studied via DFT and TD-DFT calculations. A total of 32 examples including both electron withdrawing and electron donating groups were synthesized under our oxygen- and water-tolerant conditions.

Synthesis of α-(perfluoroalkylsulfonyl)propiophenones: a new set of reagents for the light-mediated perfluoroalkylation of aromatics.

In response to the demand for late-stage perfluoroalkylation in synthetic chemistry, we report the synthesis of a series of bench-stable α-(perfluoroalkylsulfonyl)propiophenones. Their application as photocleavable reagents was tested with electron-rich aromatics under metal-free, redox- and pH-neutral conditions to enable late-stage perfluorooctylation, perfluorohexylation, and perfluorobutylation.

Modern methods for the synthesis of perfluoroalkylated aromatics.

Perfluoroalkyl-containing substances (PFAS), have become omnipresent materials in the modern world for both commercial and research applications. Compounds such as perfluoroalkylated arenes and heteroarenes have found uses in surfactants, lubricants, and flame retardants as a result of their astonishing chemical stability. Consequently, the synthesis of such compounds encompasses a large body of scientific articles and patents developed in the previous century. Most recent reviews on this subject have thus focused on summarizing this traditional literature, and have thereby spurred the development of a new wave of reaction manifolds employing modern synthesis principles. This new generation of methodologies focuses on the greener synthesis of perfluoroalkylated aromatic scaffolds, through the use of more efficient organometallic reactions, as well as by photochemical and electrochemical strategies. Herein, we will summarize this cohort of reactions while highlighting current challenges and future desirable outcomes for their environmentally friendly synthesis.

Green chemistry meets medicinal chemistry: a perspective on modern metal-free late-stage functionalization reactions.

The progress of drug discovery and development is paced by milestones reached in organic synthesis. In the last decade, the advent of late-stage functionalization (LSF) reactions has represented a valuable breakthrough. Recent literature has defined these reactions as the chemoselective modification of complex molecules by means of C-H functionalization or the manipulation of endogenous functional groups. Traditionally, these diversifications have been accomplished by organometallic means. However, the presence of metals carries disadvantages related to their cost, environmental hazard and health risks. Fundamentally, green chemistry directives can help minimize such hazards through the development of metal-free LSF methodologies. In this review, we expand the current discussion on metal-free LSF reactions by providing an overview of C(sp2)-H, and C(sp3)-H functionalizations, as well as the utilization of heteroatom-containing functional groups as chemical handles. Selected topics such as metal-free cross-dehydrogenative coupling (CDC) reactions, organocatalysis, electrochemistry and photochemistry are also discussed. By writing the first review on metal-free LSF methodologies, we aim to highlight current advances in the field with examples that reveal specific challenges and solutions, as well as future research opportunities.

Light-enabled metal-free pinacol coupling by hydrazine.

Efficient carbon-carbon bond formation is of great importance in modern organic synthetic chemistry. The pinacol coupling discovered over a century ago is still one of the most efficient coupling reactions to build the C-C bond in one step. However, traditional pinacol coupling often requires over-stoichiometric amounts of active metals as reductants, causing long-lasting metal waste issues and sustainability concerns. A great scientific challenge is to design a metal-free approach to the pinacol coupling reaction. Herein, we describe a light-driven pinacol coupling protocol without use of any metals, but with N2H4, used as a clean non-metallic hydrogen-atom-transfer (HAT) reductant. In this transformation, only traceless non-toxic N2 and H2 gases were produced as by-products with a relatively broad aromatic ketone scope and good functional group tolerance. A combined experimental and computational investigation of the mechanism suggests that this novel pinacol coupling reaction proceeds via a HAT process between photo-excited ketone and N2H4, instead of the common single-electron-transfer (SET) process for metal reductants.

The OECD Principles for (Q)SAR Models in the Context of Knowledge Discovery in Databases (KDD).

The steps followed in the knowledge discovery in databases (KDD) process are well documented and are widely used in different areas where exploration of data is used for decision making. In turn, while different workflows for developing quantitative structure-activity relationship (QSAR) models have been proposed, including combinatorial use of QSAR, there is now agreement on common requirements for building trustable predictive models. In this work, we analyze and confront the steps involved in KDD and QSAR and present how they comply with the OECD principles for the validation, for regulatory purposes, of QSAR models.