Chemoselective umpolung of thiols to episulfoniums for cysteine bioconjugation.

Cysteine conjugation is an important tool in protein research and relies on fast, mild and chemoselective reactions. Cysteinyl thiols can either be modified with prefunctionalized electrophiles, or converted into electrophiles themselves for functionalization with selected nucleophiles in an independent step. Here we report a bioconjugation strategy that uses a vinyl thianthrenium salt to transform cysteine into a highly reactive electrophilic episulfonium intermediate in situ, to enable conjugation with a diverse set of bioorthogonal nucleophiles in a single step. The reactivity profile can connect several nucleophiles to biomolecules through a short and stable ethylene linker, ideal for introduction of infrared labels, post-translational modifications or NMR probes. In the absence of reactive exogenous nucleophiles, nucleophilic amino acids can react with the episulfonium intermediate for native peptide stapling and protein-protein ligation. Ready synthetic access to isotopologues of vinyl thianthrenium salts enables applications in quantitative proteomics. Such diverse applications demonstrate the utility of vinyl-thianthrenium-based bioconjugation as a fast, selective and broadly applicable tool for chemical biology.

Reductive Cross-Coupling of a Vinyl Thianthrenium Salt and Secondary Alkyl Iodides.

We report the first reductive vinylation of alkyl iodides. The reaction uses a vinyl thianthrenium salt, a palladium catalyst, and an alkyl zinc intermediate formed in situ to trap the Ln PdII (vinyl) complex formed after oxidative addition before it undergoes undesired homocoupling to form butadiene.

Halogen-atom and group transfer reactivity enabled by hydrogen tunneling.

The generation of carbon radicals by halogen-atom and group transfer reactions is generally achieved using tin and silicon reagents that maximize the interplay of enthalpic (thermodynamic) and polar (kinetic) effects. In this work, we demonstrate a distinct reactivity mode enabled by quantum mechanical tunneling that uses the cyclohexadiene derivative γ-terpinene as the abstractor under mild photochemical conditions. This protocol activates alkyl and aryl halides as well as several alcohol and thiol derivatives. Experimental and computational studies unveiled a noncanonical pathway whereby a cyclohexadienyl radical undergoes concerted aromatization and halogen-atom or group abstraction through the reactivity of an effective H atom. This activation mechanism is seemingly thermodynamically and kinetically unfavorable but is rendered feasible through quantum tunneling.

Applications of Halogen-Atom Transfer (XAT) for the Generation of Carbon Radicals in Synthetic Photochemistry and Photocatalysis.

The halogen-atom transfer (XAT) is one of the most important and applied processes for the generation of carbon radicals in synthetic chemistry. In this review, we summarize and highlight the most important aspects associated with XAT and the impact it has had on photochemistry and photocatalysis. The organization of the material starts with the analysis of the most important mechanistic aspects and then follows a subdivision based on the nature of the reagents used in the halogen abstraction. This review aims to provide a general overview of the fundamental concepts and main agents involved in XAT processes with the objective of offering a tool to understand and facilitate the development of new synthetic radical strategies.

High Site Selectivity in Electrophilic Aromatic Substitutions: Mechanism of C-H Thianthrenation.

The introduction of thianthrene as a linchpin has proven to be a versatile strategy for the C-H functionalization of aromatic compounds, featuring a broad scope and fast diversification. The synthesis of aryl thianthrenium salts has displayed an unusually high para regioselectivity, notably superior to those observed in halogenation or borylation reactions for various substrates. We report an experimental and computational study on the mechanism of aromatic C-H thianthrenation reactions, with an emphasis on the elucidation of the reactive species and the nature of the exquisite site selectivity. Mechanisms involving a direct attack of arene to the isolated O-trifluoracetylthianthrene S-oxide (TT+-TFA) or to the thianthrene dication (TT2+) via electron transfer under acidic conditions are identified. A reversible interconversion of the different Wheland-type intermediates before a subsequent, irreversible deprotonation is proposed to be responsible for the exceptional para selectivity of the reaction.

Merging Halogen-Atom Transfer (XAT) and Cobalt Catalysis to Override E2-Selectivity in the Elimination of Alkyl Halides: A Mild Route toward contra-Thermodynamic Olefins.

We report here a mechanistically distinct tactic to carry E2-type eliminations on alkyl halides. This strategy exploits the interplay of α-aminoalkyl radical-mediated halogen-atom transfer (XAT) with desaturative cobalt catalysis. The methodology is high-yielding, tolerates many functionalities, and was used to access industrially relevant materials. In contrast to thermal E2 eliminations where unsymmetrical substrates give regioisomeric mixtures, this approach enables, by fine-tuning of the electronic and steric properties of the cobalt catalyst, to obtain high olefin positional selectivity. This unprecedented mechanistic feature has allowed access to contra-thermodynamic olefins, elusive by E2 eliminations.

Vinyl Thianthrenium Tetrafluoroborate: A Practical and Versatile Vinylating Reagent Made from Ethylene.

The use of vinyl electrophiles in synthesis has been hampered by the lack of access to a suitable reagent that is practical and of appropriate reactivity. In this work we introduce a vinyl thianthrenium salt as an effective vinylating reagent. The bench-stable, crystalline reagent can be readily prepared from ethylene gas at atmospheric pressure in one step and is broadly useful in the annulation chemistry of (hetero)cycles, N-vinylation of heterocyclic compounds, and palladium-catalyzed cross-coupling reactions. The structural features of the thianthrene core enable a distinct synthesis and reactivity profile, unprecedented for other vinyl sulfonium derivatives.

Radical hydroxymethylation of alkyl iodides using formaldehyde as a C1 synthon.

Radical hydroxymethylation using formaldehyde as a C1 synthon is challenging due to the reversible and endothermic nature of the addition process. Here we report a strategy that couples alkyl iodide building blocks with formaldehyde through the use of photocatalysis and a phosphine additive. Halogen-atom transfer (XAT) from α-aminoalkyl radicals is leveraged to convert the iodide into the corresponding open-shell species, while its following addition to formaldehyde is rendered irreversible by trapping the transient O-radical with PPh3. This event delivers a phosphoranyl radical that re-generates the alkyl radical and provides the hydroxymethylated product.

A photochemical dehydrogenative strategy for aniline synthesis.

Chemical reactions that reliably join two molecular fragments together (cross-couplings) are essential to the discovery and manufacture of pharmaceuticals and agrochemicals1,2. The introduction of amines onto functionalized aromatics at specific and pre-determined positions (ortho versus meta versus para) is currently achievable only in transition-metal-catalysed processes and requires halogen- or boron-containing substrates3-6. The introduction of these groups around the aromatic unit is dictated by the intrinsic reactivity profile of the method (electrophilic halogenation or C-H borylation) so selective targeting of all positions is often not possible. Here we report a non-canonical cross-coupling approach for the construction of anilines, exploiting saturated cyclohexanones as aryl electrophile surrogates. Condensation between amines and carbonyls, a process that frequently occurs in nature and is often used by (bio-)organic chemists7, enables a predetermined and site-selective carbon-nitrogen (C-N) bond formation, while a photoredox- and cobalt-based catalytic system progressively desaturates the cyclohexene ring en route to the aniline. Given that functionalized cyclohexanones are readily accessible with complete regiocontrol using the well established carbonyl reactivity, this approach bypasses some of the frequent selectivity issues of aromatic chemistry. We demonstrate the utility of this C-N coupling protocol by preparing commercial medicines and by the late-stage amination-aromatization of natural products, steroids and terpene feedstocks.

Aminoalkyl radicals as halogen-atom transfer agents for activation of alkyl and aryl halides.

Organic halides are important building blocks in synthesis, but their use in (photo)redox chemistry is limited by their low reduction potentials. Halogen-atom transfer remains the most reliable approach to exploit these substrates in radical processes despite its requirement for hazardous reagents and initiators such as tributyltin hydride. In this study, we demonstrate that α-aminoalkyl radicals, easily accessible from simple amines, promote the homolytic activation of carbon-halogen bonds with a reactivity profile mirroring that of classical tin radicals. This strategy conveniently engages alkyl and aryl halides in a wide range of redox transformations to construct sp3-sp3, sp3-sp2, and sp2-sp2 carbon-carbon bonds under mild conditions with high chemoselectivity.

A case of chain propagation: α-aminoalkyl radicals as initiators for aryl radical chemistry.

The generation of aryl radicals from the corresponding halides by redox chemistry is generally considered a difficult task due to their highly negative reduction potentials. Here we demonstrate that α-aminoalkyl radicals can be used as both initiators and chain-carriers for the radical coupling of aryl halides with pyrrole derivatives, a transformation often employed to evaluate new highly reducing photocatalysts. This mode of reactivity obviates for the use of strong reducing species and was also competent in the formation of sp2 C-P bonds. Mechanistic studies have delineated some of the key features operating that trigger aryl radical generation and also propagate the chain process.

Practical and regioselective amination of arenes using alkyl amines.

The formation of carbon-nitrogen bonds for the preparation of aromatic amines is among the top five reactions carried out globally for the production of high-value materials, ranging from from bulk chemicals to pharmaceuticals and polymers. As a result of this ubiquity and diversity, methods for their preparation impact the full spectrum of chemical syntheses in academia and industry. In general, these molecules are assembled through the stepwise introduction of a reactivity handle in place of an aromatic C-H bond (that is, a nitro group, halogen or boronic acid) and a subsequent functionalization or cross-coupling. Here we show that aromatic amines can be constructed by direct reaction of arenes and alkyl amines using photocatalysis, without the need for pre-functionalization. The process enables the easy preparation of advanced building blocks, tolerates a broad range of functionalities, and multigram scale can be achieved via a batch-to-flow protocol. The merit of this strategy as a late-stage functionalization platform has been demonstrated by the modification of several drugs, agrochemicals, peptides, chiral catalysts, polymers and organometallic complexes.

Synthesis of Arylamines via Aminium Radicals.

Arylamines constitute the core structure of many therapeutic agents, agrochemicals, and organic materials. The development of methods for the efficient and selective construction of these structural motifs from simple building blocks is desirable but still challenging. We demonstrate that protonated electron-poor O-aryl hydroxylamines give aminium radicals in the presence of Ru(bpy)3 Cl2 . These highly electrophilic species undergo polarized radical addition to aromatic compounds in high yield and selectivity. We successfully applied this method to the late-stage modification of chiral catalyst templates, therapeutic agents, and natural products.

Influence of Ancillary Ligands and Isomerism on the Luminescence of Bis-cyclometalated Platinum(IV) Complexes.

The synthesis, characterization, and photophysical properties of a wide variety of bis-cyclometalated Pt(IV) complexes featuring a C2-symmetrical or unsymmetrical {Pt(ppy)2} unit (sym or unsym complexes, respectively; ppy = C-deprotonated 2-phenylpyridine) and different ancillary ligands are reported. Complexes sym-[Pt(ppy)2X2] (X = OTf(-), OAc(-)) were obtained by chloride abstraction from sym-[Pt(ppy)2Cl2] using the corresponding AgX salts, and the triflate derivative was employed to obtain homologous complexes with X = F(-), Br(-), I(-), trifluoroacetate (TFA(-)). Complexes unsym-[Pt(ppy)2(Me)X] (X = OTf(-), F(-)) were prepared by reacting unsym-[Pt(ppy)2(Me)Cl] with AgOTf or AgF, respectively, and the triflate derivative was employed as precursor for the synthesis of the homologues with X = Br(-), I(-), or TFA(-) through its reaction with the appropriate anionic ligands. The previously reported complexes unsym-[Pt(ppy)2X2] (X = Cl(-), Br(-), OAc(-), TFA(-)) are included in the photophysical study to assess the influence of the arrangement of the cyclometalated ligands. Density functional theory (DFT) and time-dependent DFT calculations on selected derivatives were performed for a better interpretation of the observed excited-state properties. Complexes sym-[Pt(ppy)2X2] (except X = I(-)) exhibit phosphorescent emissions in fluid solutions at 298 K arising from essentially (3)LC(ppy) excited states, which are very similar in shape and energy. However, their efficiencies are heavily dependent on the nature of the ancillary ligands, which affect the energy of deactivating ligand-to-ligand charge transfer (LLCT) or ligand-to-metal charge transfer (LMCT) states. The fluoride derivative sym-[Pt(ppy)2F2] shows the highest quantum yield of this series (Φ = 0.398), mainly because the relatively high metal-to-ligand charge transfer admixture in its emitting state leads to a high radiative rate constant. Complexes unsym-[Pt(ppy)2X2] emit from (3)LC(ppy) states in frozen matrices at 77 K, but their emissions are totally quenched in fluid solution at 298 K because of the presence of low-lying, dissociative LMCT excited states, which also cause photoisomerization reactions. Complexes unsym-[Pt(ppy)2(Me)X] (X = F(-), Cl(-), Br(-), TFA(-)) show strong emissions in fluid solutions at 298 K (Φ = 0.52-0.63) because deactivating LMCT states lie at high energies. However, derivative unsym-[Pt(ppy)2(Me)I] is only weakly emissive at 298 K because of the presence of low-lying LLCT [p(I) → π*(ppy)] states.

Spotlight on the ligand: luminescent cyclometalated Pt(iv) complexes containing a fluorenyl moiety.

The synthesis, electrochemistry and photophysical properties of a family of Pt(iv) complexes with cyclometalated 2-(9,9-dimethylfluoren-2-yl)pyridine (flpy) are reported. Homoleptic and heteroleptic tris-cyclometalated complexes with a meridional configuration, mer-[Pt(C^N)2(flpy)]OTf, with C^N = flpy or cyclometalated 2-phenylpyridine (ppy), were prepared by reacting the bis-cyclometalated precursors [Pt(C^N)2Cl2] with flpyH in the presence of two equivalents of AgOTf. The corresponding facial isomers were obtained by photoisomerization. The Pt(iv) complexes with flpy display intense absorptions in the near-visible region and yellow phosphorescence in fluid solutions at 298 K, with quantum yields in the range 0.06-0.28 and lifetimes of hundreds of microseconds. The emissions arise from essentially (3)LC(flpy) states in all cases, with little metal-orbital contribution. However, computational calculations and experimental data demonstrate that subtle variations in the contribution of metal orbitals to the emitting state have a profound impact on quantum yields, while nonradiative deactivation through the thermal population of deactivating LMCT states does not have a significant influence.

Aromatic C-H Activation in the Triplet Excited State of Cyclometalated Platinum(II) Complexes Using Visible Light.

The visible-light driven cyclometalation of arene substrates containing an N-donor heteroaromatic moiety as directing group by monocyclometalated Pt(II) complexes is reported. Precursors of the type [PtMe(C^N)(N^CH)], where N^CH is 2-phenylpyridine (ppyH) or related compunds with diverse electronic properties and C^N is the corresponding cyclometalated ligand, afford homoleptic cis-[Pt(C^N)2] complexes upon irradiation with blue LEDs at room temperature with evolution of methane. Heteroleptic derivatives cis-[Pt(ppy)(C'^N')] are obtained analogously from [PtMe(ppy)(N'^C'H)], where N'^C'H represents an extended set of heteroaromatic compounds. Experimental and computational studies demonstrate an unprecedented C-H oxidative addition, which is initiated by a triplet excited state of metal-to-ligand charge-transfer (MLCT) character and leads to a detectable Pt(IV) methyl hydride intermediate.

Developing strongly luminescent platinum(IV) complexes: facile synthesis of bis-cyclometalated neutral emitters.

A straightforward, one-pot procedure has been developed for the synthesis of bis-cyclometalated chloro(methyl)platinum(IV) complexes with a wide variety of heteroaromatic ligands of the 2-arylpyridine type. The new compounds exhibit phosphorescent emissions in the blue to orange colour range and represent the most efficient Pt(IV) emitters reported to date, with quantum yields up to 0.81 in fluid solutions at room temperature.

Exploring excited-state tunability in luminescent tris-cyclometalated platinum(IV) complexes: synthesis of heteroleptic derivatives and computational calculations.

The synthesis, structure, electrochemistry, and photophysical properties of a series of heteroleptic tris- cyclometalated Pt(IV) complexes are reported. The complexes mer-[Pt(C^N)2 (C'^N')]OTf, with C^N=C-deprotonated 2-(2,4-difluorophenyl)pyridine (dfppy) or 2-phenylpyridine (ppy), and C'^N'=C-deprotonated 2-(2-thienyl)pyridine (thpy) or 1-phenylisoquinoline (piq), were obtained by reacting bis- cyclometalated precursors [Pt(C^N)2 Cl2] with AgOTf (2 equiv) and an excess of the N'^C'H pro-ligand. The complex mer-[Pt(dfppy)2 (ppy)]OTf was obtained analogously and photoisomerized to its fac counterpart. The new complexes display long-lived luminescence at room temperature in the blue to orange color range. The emitting states involve electronic transitions almost exclusively localized on the ligand with the lowest π-π* energy gap and have very little metal character. DFT and time-dependent DFT (TD-DFT) calculations on mer-[Pt(ppy)2 (C'^N')](+) (C'^N'=thpy, piq) and mer/fac-[Pt(ppy)3](+) support this assignment and provide a basis for the understanding of the luminescence of tris-cyclometalated Pt(IV) complexes. Excited states of LMCT character may become thermally accessible from the emitting state in the mer isomers containing dfppy or ppy as chromophoric ligands, leading to strong nonradiative deactivation. This effect does not operate in the fac isomers or the mer complexes containing thpy or piq, for which nonradiative deactivation originates mainly from vibrational coupling to the ground state.