Project description:The epigenetic modification 5-methylcytosine plays a vital role in development, cell specific gene expression and disease states. The selective chemical modification of the 5-methylcytosine methyl group is challenging. Currently, no such chemistry exists. Direct functionalisation of 5-methylcytosine would improve the detection and study of this epigenetic feature. We report a xanthone-photosensitised process that introduces a 4-pyridine modification at a C(sp3 )-H bond in the methyl group of 5-methylcytosine. We propose a reaction mechanism for this type of reaction based on density functional calculations and apply transition state analysis to rationalise differences in observed reaction efficiencies between cyanopyridine derivatives. The reaction is initiated by single electron oxidation of 5-methylcytosine followed by deprotonation to generate the methyl group radical. Cross coupling of the methyl radical with 4-cyanopyridine installs a 4-pyridine label at 5-methylcytosine. We demonstrate use of the pyridination reaction to enrich 5-methylcytosine-containing ribonucleic acid.
Project description:Many important synthetic-oriented works have proposed excited organic radicals as photoactive species, yet mechanistic studies raised doubts about whether they can truly function as photocatalysts. This skepticism originates from the formation of (photo)redox-active degradation products and the picosecond decay of electronically excited radicals, which is considered too short for diffusion-based photoinduced electron transfer reactions. From this perspective, we analyze important synthetic transformations where organic radicals have been proposed as photocatalysts, comparing their theoretical maximum excited state potentials with the potentials required for the observed photocatalytic reactivity. We summarize mechanistic studies of structurally similar photocatalysts indicating different reaction pathways for some catalytic systems, addressing cases where the proposed radical photocatalysts exceed their theoretical maximum reactivity. Additionally, we perform a kinetic analysis to explain the photoinduced electron transfer observed in excited radicals on subpicosecond time scales. We further rationalize the potential anti-Kasha reactivity from higher excited states with femtosecond lifetimes, highlighting how future photocatalysis advancements could unlock new photochemical pathways.
Project description:Direct C-H functionalization of aromatic compounds is a useful synthetic strategy that has garnered much attention because of its application to pharmaceuticals, agrochemicals, and late-stage functionalization reactions on complex molecules. On the basis of previous methods disclosed by our lab, we sought to develop a predictive model for site selectivity and extend this aryl functionalization chemistry to a selected set of heteroaromatic systems commonly used in the pharmaceutical industry. Using electron density calculations, we were able to predict the site selectivity of direct C-H functionalization in a number of heterocycles and identify general trends observed across heterocycle classes.
Project description:The design and synthesis of photoactive metal-free 2D materials for selective heterogeneous photoredox catalysis continue to be challenging due to issues related to nonrecyclability, and limited photo- and chemical stability. Herein, we report the photocatalytic properties of a triazine-based porous COF, TRIPTA, which is found to be capable of facilitating both SET (single electron transfer) for photocatalytic reductive debromination of phenacyl bromide in absence of oxygen and generation of reactive oxygen species (ROS) for benzylamine photo-oxidation in the presence of oxygen, respectively, under visible light irradiation. Inspired by the latter results, we further systematically investigated different-sized benzylamine substrates in this single-component reaction and compared the results with an analogous COF (Micro-COF-2) exhibiting a larger pore size. We observed a marked improvement in the conversion of larger-sized substrates with the latter COF, thereby demonstrating angstrom-level pore size-selective photocatalytic activity of COFs.
Project description:Direct metal-free near infra-red photoredox catalysis is applied to organic oxidation, photosensitization and reduction, involving cyanines as photocatalysts. This photocatalyst is competitive with conventional reactions catalyzed under visible light. Kinetic and quenching experiments are also reported. Interestingly, these systems are compatible with water media, opening perspective for various applications.
Project description:Radical translocation processes triggered by nitrogen-centered radicals (NCRs), such as 1,5-hydrogen atom transfers (1,5-HAT), demonstrated by the well-established Hofmann-Löffler-Freytag (HLF) reaction, provide an attractive approach for the controllable and selective functionalization of remote inert C(sp3)-H bonds. Here we report an amidyl radical-triggered site-selective remote C(sp3)-H heteroarylation of amides under organic photoredox conditions. This approach provides a mild and highly regioselective reaction affording remote C(sp3)-H heteroarylated amides at room temperature under transition-metal free, weakly basic, and redox-neutral conditions. Non-prefunctionalized heteroarenes, such as purines, thiazolopyridines, benzoxazole, benzothiazoles, benzothiophene, benzofuran, thiazoles and quinoxalines, can be alkylated directly. Sequential and orthogonal C-H functionalization of different heteroarenes by taking advantage pH value or polarity of radicals has also been achieved. DFT calculations explain and can predict the site-selectivity and reactivity of this reaction. This strategy expands the scope of the Minisci reaction and serves as its alternative and potential complement.
Project description:The functionalization of an imine-based layered covalent organic framework (COF), containing phenanthroline units as ligands, has allowed the obtention of a heterobimetallated material. Photoactive Ir and Ni fragments were immobilized within the porous structure of the COF, enabling heterogeneous light-mediated Csp3-Csp2 cross-couplings. As radical precursors, potassium benzyl- and alkoxy-trifluoroborates, organic silicates, and proline derivatives were employed, which brings out the good versatility of Ir,Ni@Phen-COF. Moreover, in all the studied cases, an enhanced activity and stability have been observed in comparison with analogous homogenous systems.
Project description:Late-stage synthesis of α,β-unsaturated aryl ketones remains an unmet challenge in organic synthesis. Reported herein is a photocatalytic non-chain-radical aroyl chlorination of alkenes by a 1,3-chlorine atom shift to form β-chloroketones as masked enones that liberate the desired enones upon workup. This strategy suppresses side reactions of the enone products. The reaction tolerates a wide array of functional groups and complex molecules including derivatives of peptides, sugars, natural products, nucleosides, and marketed drugs. Notably, addition of 2,6-di-tert-butyl-4-methyl-pyridine enhances the quantum yield and efficiency of the cross-coupling reaction. Experimental and computational studies suggest a mechanism involving PCET, formation and reaction of an α-chloro-α-hydroxy benzyl radical, and 1,3-chlorine atom shift.
Project description:Bioconjugation technologies have revolutionized the practice of biology and medicine by allowing access to novel biomolecular scaffolds. New methods for residue-selective bioconjugation are highly sought to expand the toolbox for a variety of bioconjugation applications. Herein we report a site-selective methionine bioconjugation protocol that uses photoexcited lumiflavin to generate open-shell intermediates. This reduction-potential-gated strategy enables access to residues unavailable with traditional nucleophilicity-based conjugation methods. To demonstrate the versatility and robustness of this new protocol, we have modified various proteins and further utilized this functional handle to append diverse biological payloads.
Project description:Activation of aliphatic C(sp3)-H bonds in the presence of more activated benzylic C(sp3)-H bonds is often a nontrivial, if not impossible task. Herein we show that leveraging the reactivity of benzylic C(sp3)-H bonds to achieve reactivity at the homobenzylic position can be accomplished using dual organic photoredox/cobalt catalysis. Through a two-part catalytic system, alkyl arenes undergo dehydrogenation followed by an anti-Markovnikov Wacker-type oxidation to grant benzyl ketone products. This formal homobenzylic oxidation is accomplished with high atom economy without the use of directing groups, achieving valuable reactivity that traditionally would require multiple chemical transformations.