Organophotoredox/palladium dual catalytic decarboxylative Csp3–Csp3 coupling of carboxylic acids and π-electrophiles

A dual catalytic decarboxylative allylation and benzylation method for the construction of new C(sp³)–C(sp³) bonds between readily available carboxylic acids and functionally diverse carbonate electrophiles has been developed. The new process is mild, operationally simple, and has greatly improved upon the efficiency and generality of previous methodology. In addition, new insights into the reaction mechanism have been realized and provide further understanding of the harnessed reactivity.

A dual catalytic decarboxylative allylation and benzylation method for the construction of new C(sp³)–C(sp³) bonds between readily available carboxylic acids and functionally diverse carbonate electrophiles has been developed.     

Photocatalytic decarboxylative amidosulfonation enables direct transformation of carboxylic acids to sulfonamides

Sulfonamides feature prominently in organic synthesis, materials science and medicinal chemistry, where they play important roles as bioisosteric replacements of carboxylic acids and other carbonyls. Yet, a general synthetic platform for the direct conversion of carboxylic acids to a range of functionalized sulfonamides has remained elusive. Herein, we present a visible light-induced, dual catalytic platform that for the first time allows for a one-step access to sulfonamides and sulfonyl azides directly from carboxylic acids. The broad scope of the direct decarboxylative amidosulfonation (DDAS) platform is enabled by the efficient direct conversion of carboxylic acids to sulfinic acids that is catalyzed by acridine photocatalysts and interfaced with copper-catalyzed sulfur–nitrogen bond-forming cross-couplings with both electrophilic and nucleophilic reagents.

Sulfonamides are now accessible directly from carboxylic acids by a one-step, tricomponent decarboxylative amidosulfonation that provides the missing link between the two key functionalities.     

Brønsted acid catalysis of photosensitized cycloadditions

Catalysis is central to contemporary synthetic chemistry. There has been a recent recognition that the rates of photochemical reactions can be profoundly impacted by the use of Lewis acid catalysts and co-catalysts. Herein, we show that Brønsted acids can also modulate the reactivity of excited-state organic reactions. Brønsted acids dramatically increase the rate of Ru(bpy)₃²⁺-sensitized [2 + 2] photocycloadditions between C-cinnamoyl imidazoles and a range of electron-rich alkene reaction partners. A combination of experimental and computational studies supports a mechanism in which the Brønsted acid co-catalyst accelerates triplet energy transfer from the excited-state [Ru*(bpy)₃]²⁺ chromophore to the Brønsted acid activated C-cinnamoyl imidazole. Computational evidence further suggests the importance of driving force as well as geometrical reorganization, in which the protonation of the imidazole decreases the reorganization penalty during the energy transfer event.

Brønsted acids can catalyze triplet energy transfer reactions, and DFT computations suggest the unexpected importance of reorganization energy for catalysis.     

Photoactive electron donor–acceptor complex platform for Ni-mediated C(sp3)–C(sp2) bond formation

A dual photochemical/nickel-mediated decarboxylative strategy for the assembly of C(sp³)–C(sp²) linkages is disclosed. Under light irradiation at 390 nm, commercially available and inexpensive Hantzsch ester (HE) functions as a potent organic photoreductant to deliver catalytically active Ni(0) species through single-electron transfer (SET) manifolds. As part of its dual role, the Hantzsch ester effects a decarboxylative-based radical generation through electron donor–acceptor (EDA) complex activation. This homogeneous, net-reductive platform bypasses the need for exogenous photocatalysts, stoichiometric metal reductants, and additives. Under this cross-electrophile paradigm, the coupling of diverse C(sp³)-centered radical architectures (including primary, secondary, stabilized benzylic, α-oxy, and α-amino systems) with (hetero)aryl bromides has been accomplished. The protocol proceeds under mild reaction conditions in the presence of sensitive functional groups and pharmaceutically relevant cores.

This works demonstrates the implementation of an electron donor–acceptor (EDA) complex platform toward Ni-catalyzed C(sp³)–C(sp²) bond formation, circumventing the need for exogenous photocatalysts, additives, and stoichiometric metal reductants.     

Sequential C–O decarboxylative vinylation/C–H arylation of cyclic oxalates via a nickel-catalyzed multicomponent radical cascade

A selective, sequential C–O decarboxylative vinylation/C–H arylation of cyclic alcohol derivatives enabled by visible-light photoredox/nickel dual catalysis is described. This protocol utilizes a multicomponent radical cascade process, i.e. decarboxylative vinylation/1,5-HAT/aryl cross-coupling, to achieve efficient, site-selective dual-functionalization of saturated cyclic hydrocarbons in one single operation. This synergistic protocol provides straightforward access to sp³-enriched scaffolds and an alternative retrosynthetic disconnection to diversely functionalized saturated ring systems from the simple starting materials.

A selective, sequential C–O decarboxylative vinylation/C–H arylation of cyclic alcohol derivatives enabled by visible-light photoredox/nickel dual catalysis has been described.     

Near-infrared absorbing Ru(ii) complexes act as immunoprotective photodynamic therapy (PDT) agents against aggressive melanoma

Mounting evidence over the past 20 years suggests that photodynamic therapy (PDT), an anticancer modality known mostly as a local treatment, has the capacity to invoke a systemic antitumor immune response, leading to protection against tumor recurrence. For aggressive cancers such as melanoma, where chemotherapy and radiotherapy are ineffective, immunomodulating PDT as an adjuvant to surgery is of interest. Towards the development of specialized photosensitizers (PSs) for treating pigmented melanomas, nine new near-infrared (NIR) absorbing PSs based on a Ru(ii) tris-heteroleptic scaffold [Ru(NNN)(NN)(L)]Cl_n, were explored. Compounds 2, 6, and 9 exhibited high potency toward melanoma cells, with visible EC₅₀ values as low as 0.292–0.602 μM and PIs as high as 156–360. Single-micromolar phototoxicity was obtained with NIR-light (733 nm) with PIs up to 71. The common feature of these lead NIR PSs was an accessible low-energy triplet intraligand (³IL) excited state for high singlet oxygen (¹O₂) quantum yields (69–93%), which was only possible when the photosensitizing ³IL states were lower in energy than the lowest triplet metal-to-ligand charge transfer (³MLCT) excited states that typically govern Ru(ii) polypyridyl photophysics. PDT treatment with 2 elicited a pro-inflammatory response alongside immunogenic cell death in mouse B16F10 melanoma cells and proved safe for in vivo administration (maximum tolerated dose = 50 mg kg⁻¹). Female and male mice vaccinated with B16F10 cells that were PDT-treated with 2 and challenged with live B16F10 cells exhibited 80 and 55% protection from tumor growth, respectively, leading to significantly improved survival and excellent hazard ratios of ≤0.2.

Ru(ii) photosensitizers (PSs) destroy aggressive melanoma cells, triggering an immune response that leads to protection against tumor challenge and mouse survival.     

Tuning phenoxyl-substituted diketopyrrolopyrroles from quinoidal to biradical ground states through (hetero-)aromatic linkers

Strongly fluorescent halochromic 2,6-di-tert-butyl-phenol-functionalised phenyl-, thienyl- and furyl-substituted diketopyrrolopyrrole (DPP) dyes were deprotonated and oxidised to give either phenylene-linked DPP1˙˙ biradical (y₀ = 0.75) with a singlet open shell ground state and a thermally populated triplet state (ΔE_ST = 19 meV; 1.8 kJ mol⁻¹; 0.43 kcal mol⁻¹) or thienylene/furylene-linked DPP2q and DPP3q compounds with closed shell quinoidal ground states. Accordingly, we identified the aromaticity of the conjugated (hetero-)aromatic bridge to be key for modulating the electronic character of these biradicaloid compounds and achieved a spin crossover from closed shell quinones DPP2q and DPP3q to open shell biradical DPP1˙˙ as confirmed by optical and magnetic spectroscopic studies (UV/vis/NIR, NMR, EPR) as well as computational investigations (spin-flip TD-DFT calculations in combination with CASSCF(4,4) and harmonic oscillator model of aromaticity (HOMA) analysis). Spectroelectrochemical studies and comproportionation experiments further prove the reversible formation of mixed-valent radical anions for the DPP2q and DPP3q quinoidal compounds with absorption bands edging into the NIR spectral region.

By variation of spacer aromaticity, a spin crossover from thienylene/furylene-linked quinones DPP2q/DPP3q to phenylene-bridged biradical DPP1˙˙ (y₀ = 0.75) with a singlet open shell ground state (ΔE_ST = 19 meV) was achieved.     

Is there a photochemical Hammond postulate?

The Hammond postulate is a useful tool for approximating the energy and the structure of transition states. It was designed for use in ground state reactions, and has been applied successfully on many occasions. On the other hand, its usefulness for photochemical reactions is more questionable, as different energy surfaces are involved. So far, no systematic studies on the validity of the Hammond postulate for photochemical reactions are available. The present work aims at filling this gap by providing a simple, unbiased series of test reactions based on the stereospecificity of isotopically labelled substrates.

In this work, a series of photochemical reactions were performed on isotopically labelled substrates to explore the validity of Hammond''s postulate for the excited state.     

Triazole-based osmium(ii) complexes displaying red/near-IR luminescence: antimicrobial activity and super-resolution imaging

Cellular uptake, luminescence imaging and antimicrobial activity against clinically relevant methicillin-resistant S. aureus (MRSA) bacteria are reported. The osmium(ii) complexes [Os(N^N)₃]²⁺ (N^N = 1-benzyl-4-(pyrid-2-yl)-1,2,3-triazole (1²⁺); 1-benzyl-4-(pyrimidin-2-yl)-1,2,3-triazole (2²⁺); 1-benzyl-4-(pyrazin-2-yl)-1,2,3-triazole (3²⁺)) were prepared and isolated as the chloride salts of their meridional and facial isomers. The complexes display prominent spin-forbidden ground state to triplet metal-to-ligand charge transfer (³MLCT) state absorption bands enabling excitation as low as 600 nm for fac/mer-3²⁺ and observation of emission in aqueous solution in the deep-red/near-IR regions of the spectrum. Cellular uptake studies within MRSA cells show antimicrobial activity for 1²⁺ and 2²⁺ with greater toxicity for the meridional isomers in each case and mer-1²⁺ showing the greatest potency (32 μg mL⁻¹ in defined minimal media). Super-resolution imaging experiments demonstrate binding of mer- and fac-1²⁺ to bacterial DNA with high Pearson''s colocalisation coefficients (up to 0.95 using DAPI). Phototoxicity studies showed the complexes exhibited a higher antimicrobial activity upon irradiation with light.

Cellular uptake, luminescence imaging and antimicrobial activity of facial and meridional isomers of Os(ii) triazole-based complexes against methicillin-resistant S. aureus, MRSA.     

Efficient alkene hydrosilation with bis(8-quinolyl)phosphine (NPN) nickel catalysts. The dominant role of silyl-over hydrido-nickel catalytic intermediates

A cationic nickel complex of the bis(8-quinolyl)(3,5-di-tert-butylphenoxy)phosphine (NPN) ligand, [(NPN)NiCl]⁺, is a precursor to efficient catalysts for the hydrosilation of alkenes with a variety of hydrosilanes under mild conditions and low catalyst loadings. DFT studies reveal the presence of two coupled catalytic cycles based on [(NPN)NiH]⁺ and [(NPN)NiSiR₃]⁺ active species, with the latter being more efficient for producing the product. The preferred silyl-based catalysis is not due to a more facile insertion of alkene into the Ni–Si (vs. Ni–H) bond, but by consistent and efficient conversions of the hydride to the silyl complex.

A cationic nickel complex of the bis(8-quinolyl)(3,5-di-tert-butylphenoxy)phosphine (NPN) ligand, [(NPN)NiCl]⁺, is a precursor to efficient catalysts for the hydrosilation of alkenes with hydrosilanes under mild conditions and low catalyst loadings.     

The central role of the metal ion for photoactivity: Zn– vs. Ni–Mabiq

Photoredox catalysts are integral components of artificial photosystems, and have recently emerged as powerful tools for catalysing numerous organic reactions. However, the development of inexpensive and efficient earth-abundant photoredox catalysts remains a challenge. We here present the photochemical and photophysical properties of a Ni–Mabiq catalyst ([Ni^II(Mabiq)]OTf (1); Mabiq = 2-4:6-8-bis(3,3,4,4-tetramethyldihydropyrrolo)-10-15-(2,2-biquinazolino)-[15]-1,3,5,8,10,14-hexaene1,3,7,9,11,14-N₆)—and of a Zn-containing analogue ([Zn^II(Mabiq)OTf] (2))—using steady state and time resolved optical spectroscopy, time-dependent density functional theory (TDDFT) calculations, and reactivity studies. The Ni and Zn complexes exhibit similar absorption spectra, but markedly different photochemical properties. These differences arise because the excited states of 2 are ligand-localized, whereas metal-centered states account for the photoactivity of 1. The distinct properties of the Ni and Zn complexes are manifest in their behavior in the photo-driven aza-Henry reaction and oxidative coupling of methoxybenzylamine.

The development of earth-abundant photoredox catalysts remains a challenge. Studies of Ni- and Zn-Mabiq complexes demonstrate how the coordinating metal ion influences the photochemistry, photodynamics and reactivity of photocatalysts.     

Orthogonally aligned cyclic BODIPY arrays with long-lived triplet excited states as efficient heavy-atom-free photosensitizers

In photosensitizers, long triplet excited state lifetimes are key to their efficient electron transfer or energy transfer processes. Herein, we report a novel class of cyclic trimeric BODIPY arrays which were efficiently generated from easily accessible meso-mesityldipyrrinone and arylboronic acids in one pot. Arylboronic acid, for the first time, was used to provide a boron source for BODIPY derivatives. Due to the well-defined and orthogonally aligned BODIPY cores as verified by X-ray crystallography, these BODIPY arrays show strong exciton coupling effects and efficient intersystem crossings, and are novel heavy-atom-free photosensitizers with a long-lived triplet excited state (lifetime up to 257.5 μs) and good reactive oxygen species generation efficiency (up to 0.72) contributed by both ¹O₂ and O₂⁻˙ under light irradiation.

Cyclic BODIPY trimers showed strong exciton coupling in singlet excited states and long-lived triplet excited states, and generated both singlet oxygen and superoxide radicals under light irradiation, giving good reactive oxygen quantum yields and promising PDT results in vitro.     

Long-lived triplet charge-separated state in naphthalenediimide based donor–acceptor systems

1,4,5,8-Naphthalenediimides (NDIs) are widely used motifs to design multichromophoric architectures due to their ease of functionalisation, their high oxidative power and the stability of their radical anion. The NDI building block can be incorporated in supramolecular systems by either core or imide functionalization. We report on the charge-transfer dynamics of a series of electron donor–acceptor dyads consisting of a NDI chromophore with one or two donors linked at the axial, imide position. Photo-population of the core-centred π–π* state is followed by ultrafast electron transfer from the electron donor to the NDI. Due to a solvent dependent singlet–triplet equilibrium inherent to the NDI core, both singlet and triplet charge-separated states are populated. We demonstrate that long-lived charge separation in the triplet state can be achieved by controlling the mutual orientation of the donor–acceptor sub-units. By extending this study to a supramolecular NDI-based cage, we also show that the triplet charge-separation yield can be increased by tuning the environment.

Ultrafast electron transfer from singlet and triplet excited states in equilibrium results in the population of both singlet and triplet charge-separated states.     

Enantioselective synthesis of highly oxygenated acyclic quaternary center-containing building blocks via palladium-catalyzed decarboxylative allylic alkylation of cyclic siloxyketones

The development of a palladium-catalyzed enantioselective decarboxylative allylic alkylation of cyclic siloxyketones to produce enantioenriched silicon-tethered heterocycles is reported. The reaction proceeds smoothly to provide products bearing a quaternary stereocenter in excellent yields (up to 91% yield) with high levels of enantioselectivity (up to 94% ee). We further utilized the unique reactivity of the siloxy functionality to access chiral, highly oxygenated acyclic quaternary building blocks. In addition, we subsequently demonstrated the utility of these compounds through the synthesis of a lactone bearing vicinal quaternary-trisubstituted stereocenters.

The development of a palladium-catalyzed enantioselective decarboxylative allylic alkylation of cyclic siloxyketones to produce enantioenriched silicon-tethered heterocycles is reported.     

Tuning the Triplet Excited State of Bis(dipyrrin) Zinc(II) Complexes: Symmetry Breaking Charge Transfer Architecture with Exceptionally Long Lived Triplet State for Upconversion

Zinc(II) bis(dipyrrin) complexes, which feature intense visible absorption and efficient symmetry breaking charge transfer (SBCT) are outstanding candidates for photovoltaics but their short lived triplet states limit applications in several areas. Herein we demonstrate that triplet excited state dynamics of bis(dipyrrin) complexes can be efficiently tuned by attaching electron donating aryl moieties at the 5,5′-position of the complexes. For the first time, a long lived triplet excited state (τ_T=296 μs) along with efficient ISC ability (Φ_Δ=71 %) was observed for zinc(II) bis(dipyrrin) complexes, formed via SBCT. The results revealed that molecular geometry and energy gap between the charge transfer (CT) state and triplet energy levels strongly control the triplet excited state properties of the complexes. An efficient triplet–triplet annihilation upconversion system was devised for the first time using a SBCT architecture as triplet photosensitizer, reaching a high upconversion quantum yield of 6.2 %. Our findings provide a blueprint for the development of triplet photosensitizers based on earth abundant metal complexes with long lived triplet state for revolutionary photochemical applications.     

Solvent-controlled E/Z isomerization vs. [2 + 2] photocycloaddition mediated by supramolecular polymerization

Control over the photochemical outcome of photochromic molecules in solution represents a major challenge, as photoexcitation often leads to multiple competing photochemical and/or supramolecular pathways resulting in complex product mixtures. Herein, we demonstrate precise and efficient control over the photochemical behaviour of cyanostilbenes in solution using a straightforward solvent-controlled approach based on supramolecular polymerization. To this end, we designed a π-extended cyanostilbene bolaamphiphile that exhibits tuneable solvent-dependent photochemical behaviour. Photoirradiation of the system in a monomeric state (in organic solvents) exclusively leads to a highly reversible and efficient E/Z photoisomerization, whereas a nearly quantitative [2 + 2] photocycloaddition into a single cyclobutane (anti head-to-tail) occurs in aqueous solutions. These results can be rationalized by a highly regular and preorganized antiparallel J-type arrangement of the cyanostilbene units that is driven by aqueous supramolecular polymerization. The presented concept demonstrates a novel approach towards solvent-selective and environmentally friendly photochemical transformations, which is expected to broaden the scope of supramolecular polymerization.

Controlled supramolecular polymerization is used to switch the photoresponsive behaviour of cyanostilbenes from a reversible E/Z photoisomerization in organic solvents to a highly efficient and selective [2 + 2] photocycloaddition in aqueous media.     

Mangana(iii/iv)electro-catalyzed C(sp3)–H azidation

Manganaelectro-catalyzed azidation of otherwise inert C(sp³)–H bonds was accomplished using most user-friendly sodium azide as the nitrogen-source. The operationally simple, resource-economic C–H azidation strategy was characterized by mild reaction conditions, no directing group, traceless electrons as the sole redox-reagent, Earth-abundant manganese as the catalyst, high functional-group compatibility and high chemoselectivity, setting the stage for late-stage azidation of bioactive compounds. Detailed mechanistic studies by experiment, spectrophotometry and cyclic voltammetry provided strong support for metal-catalyzed aliphatic radical formation, along with subsequent azidyl radical transfer within a manganese(iii/iv) manifold.

The merger of manganese-catalyzed C–H functionalization with electrosynthesis enabled C(sp³)–H azidation devoid of chemical oxidants or photochemical irradiation. Detailed mechanistic studies are supportive of a manganese(iii/iv) electrocatalysis.     

Facile synthesis of axially chiral styrene-type carboxylic acids via palladium-catalyzed asymmetric C–H activation

A novel method by a one-step introduction of axial chirality and sterically hindered group has been developed for facile synthesis of axially chiral styrene-type carboxylic acids. With the palladium-catalyzed C–H arylation and olefination of readily available cinnamic acid established, this transformation demonstrated excellent yield, excellent stereocontrol (up to 99% yield and 99% ee), and broad substrate scope under mild conditions. The axially chiral styrene-type carboxylic acids produced have been successfully applied to Cp*Co^III-catalyzed asymmetric C–H activation reactions, indicating their potential as chiral ligands or catalysts in asymmetric synthesis.

Palladium-catalyzed asymmetric C–H functionalization to yield axially chiral styrene-type carboxylic acids is described, in which axial chirality and sterically hindered group were incorporated in one-step.     

Functional group divergence and the structural basis of acridine photocatalysis revealed by direct decarboxysulfonylation

The reactivity of the sulfonyl group varies dramatically from nucleophilic sulfinates through chemically robust sulfones to electrophilic sulfonyl halides—a feature that has been used extensively in medicinal chemistry, synthesis, and materials science, especially as bioisosteric replacements and structural analogs of carboxylic acids and other carbonyls. Despite the great synthetic potential of the carboxylic to sulfonyl functional group interconversions, a method that can convert carboxylic acids directly to sulfones, sulfinates and sulfonyl halides has remained out of reach. We report herein the development of a photocatalytic system that for the first time enables direct decarboxylative conversion of carboxylic acids to sulfones and sulfinates, as well as sulfonyl chlorides and fluorides in one step and in a multicomponent fashion. A mechanistic study prompted by the development of the new method revealed the key structural features of the acridine photocatalysts that facilitate the decarboxylative transformations and provided an informative and predictive multivariate linear regression model that quantitatively relates the structural features with the photocatalytic activity.

Carboxylic acids can now serve as a single point of entry to several sulfonyl functional groups by a one-step organophotocatalytic sulfonylation, revealing structural effects that enable the photocatalysis.     

The non-adiabatic nanoreactor: towards the automated discovery of photochemistry

The ab initio nanoreactor has previously been introduced to automate reaction discovery for ground state chemistry. In this work, we present the nonadiabatic nanoreactor, an analogous framework for excited state reaction discovery. We automate the study of nonadiabatic decay mechanisms of molecules by probing the intersection seam between adiabatic electronic states with hyper-real metadynamics, sampling the branching plane for relevant conical intersections, and performing seam-constrained path searches. We illustrate the effectiveness of the nonadiabatic nanoreactor by applying it to benzene, a molecule with rich photochemistry and a wide array of photochemical products. Our study confirms the existence of several types of S₀/S₁ and S₁/S₂ conical intersections which mediate access to a variety of ground state stationary points. We elucidate the connections between conical intersection energy/topography and the resulting photoproduct distribution, which changes smoothly along seam space segments. The exploration is performed with minimal user input, and the protocol requires no previous knowledge of the photochemical behavior of a target molecule. We demonstrate that the nonadiabatic nanoreactor is a valuable tool for the automated exploration of photochemical reactions and their mechanisms.

The nonadiabatic nanoreactor is a tool for automated photochemical reaction discovery that extensively explores intersection seams and links conical intersections to photoproduct distributions.