In-Flow Heterogeneous Triplet-Triplet Annihilation Upconversion.

Photon upconversion based on triplet-triplet annihilation (TTA-UC) is an attractive wavelength conversion with increasing use in organic synthesis in the homogeneous phase; however, this technology has not performed with canonical solid catalysts yet. Herein, a BOPHY dye covalently anchored on silica is successfully used as a sensitizer in a TTA system that efficiently catalyzes Mizoroki-Heck coupling reactions. This procedure has enabled the implementation of in-flow reaction conditions for the synthesis of a variety of aromatic compounds, and mechanistic proof has been obtained by means of transient absorption spectroscopy.

Unlocking Photocatalytic Activity of Acridinium Salts by Anion-Binding Co-Catalysis.

The in situ generation of active photoredox organic catalysts upon anion-binding co-catalysis by making use of the ionic nature of common photosensitizers is reported. Hence, the merge of anion-binding and photocatalysis permitted the modulation of the photocatalytic activity of simple acridinium halide salts, building an effective anion-binding - photoredox ion pair complex able to promote a variety of visible light driven transformations, such as anti-Markovnikov addition to olefins, Diels-Alder and the desilylative C-C bond forming reactions. Anion-binding studies, together with steady-state and time-resolved spectroscopy analysis, supported the postulated ion pair formation between the thiourea hydrogen-bond donor organocatalyst and the acridinium salt, which proved essential for unlocking the photocatalytic activity of the photosensitizer.

A new green-to-blue upconversion system with efficient photoredox catalytic properties.

The design and development of new triplet-triplet annihilation upconversion (TTA-UC) systems combining triplet sensitizers with acceptor compounds have attracted considerable interest. In this vein, sensitizers made from purely organic dyes rather than transition-metal complexes appear to be more convenient from an environmental point of view. BODIPYs are a very well-known class of dyes with applications in a widespread range of scientific areas. Owing to the versatility of BODIPYs, we present herein a new asymmetric BODIPY with excellent photophysical properties to be used as an appropriate sensitizer in a bimolecular TTA-UC system. Detailed spectroscopic measurements demonstrated the ability of this new design to sensitize TTA-UC by combination with a suitable acceptor such as 2,5,8,11-tetra-tert-butylperylene (TBPe), allowing a successful conversion of green to blue light. The singlet-excited TBPe so obtained is capable of activating aryl chlorides reductively which initiated the functionalization of N-methylpyrrole (Meerwein-type arylation) and formation of both substituted triarylethylenes (Mizoroki-Heck reaction) and heteroarene phosphonates (photo-Arbuzov reaction). Product yields reveal that our TTA-UC system behaved as a highly efficient photocatalytic entity.

Dual-mode colorimetric/fluorescent chemosensor for Cu2+/Zn2+ and fingerprint imaging based on rhodamine ethylenediamine bis(triazolyl silsesquioxane).

A novel dual functional and visual rhodamine ethylenediamine bis(triazolyl silsesquioxane) (RBS) chemosensor was successfully synthesized using "click" chemistry. The results have unambiguously demonstrated that RBS can act in fluorescent and colorimetric sensing of Cu2+ and Zn2+ by their respective coordination with triazole structures and, more importantly, it has also been found that triazole-amide of RBS could turn on chelation-enhanced fluorescence (CHEF) of Cu2+. Remarkably, the addition of Cu2+ triggered an enhanced fluorescent emission by 63.3-fold (ϕF = 0.41), while Zn2+ enhanced it 48.3-fold (ϕF = 0.29) relative to the original RBS (ϕF = 0.006) in acetonitrile (MeCN) solvent. The fluorescent limit of detection for Cu2+ and Zn2+ is similar and fall within 3.0 nM, while under colorimetric sensing the responses were 2.14 × 10-8 and 4.0 × 10-8 mol L-1, respectively. Moreover, the effective sensing profile of RBS and extended applications of RBS-Cu2+ and RBS-Zn2+ for fingerprinting detection and imaging were observed with adequate sensitivity, stability and legibility under the dual visual responses.

Effective Formation of New C(sp2 )-S Bonds via Photoactivation of Alkylamine-based Electron Donor-Acceptor Complexes.

A novel visible light promoted formation of CAryl- S bonds through electron donor-acceptor (EDA) complexes of alkylamines with 5- and 6-membered (hetero)arene halides is presented. This represents the first EDA-based thiolation method not relying on π-π or a thiolate-anion-π interactions and provides a facile access to heteroarene radicals, which can be suitably trapped by disulfide derivatives to form the corresponding versatile arylsulfides. Mechanistic investigations on the aspects of the whole process were conducted by spectroscopic measurements, demonstrating the hypothesized EDA complex formation. Moreover, the strength of this method has been proven by a gram-scale synthesis of thiolated products and the late-stage derivatization of an anticoagulant drug.

Accessible Low-Cost Laser Pointers for the Reduction of Aryl Halides via Triplet-Triplet Annihilation Upconversion in Aerated Gels.

The search for economic alternatives in the use of expensive scientific equipment represents a way of providing many laboratories access to scientific developments that, otherwise, might be hampered by economic constraints. This inspired the purpose of this work, which was to demonstrate for the first time that we can carry out the photoreduction of aryl halides via green-to-blue upconversion in an aerated gel medium, using a simple economic set-up based on easily accessible and low-cost laser pointers. The optimized set-up consists of three laser pointers connected to a switching-mode power supply. One laser should be aligned to Z-axis and separated 5 cm from the sample, while the light incidence of the other two lasers should be adjusted to 45° and separated ca. 3 cm from the sample. The results of this study were found to be reproducible in random experiments and demonstrated that the photoreduction of several aryl halides can be carry out within 24 h of irradiation with comparable yields and mass balances, to those obtained with other very expensive pulsed laser sources. An economic estimation of the expenses concludes that we can easily reduce by >98% the total cost of this type of research by using the described set-up. Our work offers many groups with limited resources a feasible alternative to work in this area without the necessity of extremely expensive devices.

Photon Upconversion Systems Based on Triplet-Triplet Annihilation as Photosensitizers for Chemical Transformations.

Photon upconversion (UC) based on triplet-triplet annihilation (TTA) is considered one of the most attractive methodologies for switching wavelengths from lower to higher energy. This two-photon process, which requires the involvement of a bimolecular system, has been widely used in numerous fields such as bioimaging, solar cells, displays, drug delivery, and so on. In the last years, we have witnessed the harnessing of this concept by the organic community who have developed new strategies for synthetic purposes. Interestingly, the generation of high-energetic species by this phenomenon has provided the opportunity not only to photoredox activate compounds with high-energy demanding bonds, expanding the reactivity window that lies outside the energy window of the initial irradiation wavelength, but also to sensitized conventional photocatalysts through energy transfer processes even employing infrared irradiation. Herein, an overview of the principal examples found in literature is described where TTA-UC systems are found to be suitable photosensitizers for several chemical transformations.

Photoredox catalysis powered by triplet fusion upconversion: arylation of heteroarenes.

In this work, the feasibility of triplet fusion upconversion (TFU, also named triplet-triplet annihilation upconversion) technology for the functionalization (arylation) of furans and thiophenes has been successfully proven. Activation of aryl halides by TFU leads to generation of aryl radical intermediates; trapping of the latter by the corresponding heteroarenes, which act as nucleophiles, affords the final coupling products. Advantages of this photoredox catalytic method include the use of very mild conditions (visible light, standard conditions), employment of commercially available reactants and low-loading metal-free photocatalysts, absence of any sacrificial agent (additive) in the medium and short irradiation times. The involvement of the high energetic delayed fluorescence in the reaction mechanism has been evidenced by quenching studies, whereas the two-photon nature of this photoredox arylation of furans and thiophenes has been manifested by the dependence on the energy source power. Finally, the scaling-up conditions have been gratifyingly afforded by a continuous-flow device.

Controlled Synthesis of Up-Conversion NaYF4:Yb,Tm Nanoparticles for Drug Release under Near IR-Light Therapy.

Up-Conversion materials have received great attention in drug delivery applications in recent years. A specifically emerging field includes the development of strategies focusing on photon processes that promote the development of novel platforms for the efficient transport and the controlled release of drug molecules in the harsh microenvironment. Here, modified reaction time, thermal treatment, and pH conditions were controlled in the synthesis of NaYF4:Yb,Tm up-converted (UC) material to improve its photoluminescence properties. The best blue-emission performance was achieved for the UC3 sample prepared through 24 h-synthesis without thermal treatment at a pH of 5, which promotes the presence of the ß-phase and smaller particle size. NaYF4:Yb,Tm has resulted in a highly efficient blue emitter material for light-driven drug release under near-IR wavelength. Thus, NaYF4:Yb,Tm up-converted material promotes the N-O bond cleavage of the oxime ester of Ciprofloxacin (prodrug) as a highly efficient photosensitized drug delivery process. HPLC chromatography and transient absorption spectroscopy measurements were performed to evaluate the drug release conversion rate. UC3 has resulted in a very stable and easily recovered material that can be used in several reaction cycles. This straightforward methodology can be extended to other drugs containing photoactive chromophores and is present as an alternative for drug release systems.

Highly Efficient Production of Heteroarene Phosphonates by Dichromatic Photoredox Catalysis.

A new strategy to achieve efficient aerobic phosphorylation of five-membered heteraroenes with excellent yields using dichromatic photoredox catalysis in a gel-based nanoreactor is described here. The procedure involves visible aerobic irradiation (cold white LEDs) of a mixture containing the heteroarene halide, trisubstituted phospite, N,N-diisopropylethylamine (DIPEA) as sacrificial agent, and catalytic amounts of 9,10-dicyanoanthracene (DCA) in the presence of an adequate gelator, which permits a faster process than at the homogeneous phase. The methodology, which operates by a consecutive photoinduced electron transfer (ConPET) mechanism, has been successfully applied to the straightforward and clean synthesis of a number of different heteroarene (furan, thiophene, selenophene, pyrrole, oxazole, or thioxazole) phosphonates, extending to the late-stage phosphonylation of the anticoagulant rivaroxaban. Strategically, employment of cold white light is critical since it provides both selective wavelengths for exciting first DCA (blue region) and subsequently its corresponding radical anion DCA•- (green region). The resultant strongly reducing excited agent DCA•-* is capable of even activate five-membered heteroarene halides (Br, Cl) with high reduction potentials (∼-2.7 V) to effect the C(sp2)-P bond formation. Spectroscopic and thermodynamic studies have supported the proposed reaction mechanism. Interestingly, the rate of product formation has been clearly enhanced in gel media because reactants can be presumably localized not only in the solvent pools but also through to the fibers of the viscoelastic gel network. This has been confirmed by field-emission scanning electron microscopy images where a marked densification of the network has been observed, modifying its fibrillary morphology. Finally, rheological measurements have shown the resistance of the gel network to the incorporation of the reactants and the formation of the desired products.

Aerobic Visible-Light-Driven Borylation of Heteroarenes in a Gel Nanoreactor.

Heteroarene boronate esters constitute valuable intermediates in modern organic synthesis. As building blocks, they can be further applied to the synthesis of new materials, since they can be easily transformed into any other functional group. Efforts toward novel and efficient strategies for their preparation are clearly desirable. Here, we have achieved the borylation of commercially available heteroarene halides under very mild conditions in an easy-to-use gel nanoreactor. Its use of visible light as the energy source at room temperature in photocatalyst-free and aerobic conditions makes this protocol very attractive. The gel network provides an adequate stabilizing microenvironment to support wide substrate scope, including furan, thiophene, selenophene, and pyrrole boronate esters.

Fluorescent-Labeled Octasilsesquioxane Nanohybrids as Potential Materials for Latent Fingerprinting Detection.

The recent demand for fluorescent-labeled materials (FLMs) in forensic security concepts such as latent fingerprints (LFs) that encode information for anti-counterfeiting and encryption of confidential data makes necessary the development of building new and innovative materials. Here, novel FLMs based on polyhedral oligomeric silsesquioxanes (POSS) functionalized with fluorophores via "click" reactions have been successfully synthesized and fully characterized. A comprehensive study of their photophysical properties has displayed large Stokes's shift together with good photostability in all cases, fulfilling the fundamental requisites for any legible LF detection on various surfaces. The excellent performance of the hetero-bifunctional FLM in the visualization of LF is emphasized by their legibility, selectivity, sensitivity and temporal photostability. In this study, development mechanisms have been proposed and the overall concept constitute a novel approach for vis-à-vis forensic investigations to trace an individual's identity.

Rapid Access to Borylated Thiophenes Enabled by Visible Light.

Boron-containing thiophenes are important entities in organic/medicinal chemistry as well as in material science. In this Letter, a novel, straightforward, and fast procedure for their production employing visible light as an energy source at room temperature and ambient pressure is reported. All substrates are commercially available, and the process does not require the use of any external photocatalyst.

Combined Photoredox and Iron Catalysis for the Cyclotrimerization of Alkynes.

Successful combinations of visible-light photocatalysis with metal catalysis have recently enabled the development of hitherto unknown chemical reactions. Dual mechanisms from merging metal-free photocatalysts and earth-abundant metal catalysts are still in their infancy. We report a photo-organo-iron-catalyzed cyclotrimerization of alkynes by photoredox activation of a ligand-free Fe catalyst. The reaction operates under very mild conditions (visible light, 20 °C, 1 h) with 1-2 mol % loading of the three catalysts (dye, amine, FeCl2 ).

Photobinding of Triflusal to Human Serum Albumin Investigated by Fluorescence, Proteomic Analysis, and Computational Studies.

Triflusal is a platelet antiaggregant employed for the treatment and prevention of thromboembolic diseases. After administration, it is biotransformed into its active metabolite, the 2-hydroxy-4-trifluoromethylbenzoic acid (HTB). We present here an investigation on HTB photobinding to human serum albumin (HSA), the most abundant protein in plasma, using an approach that combines fluorescence, MS/MS, and peptide fingerprint analysis as well as theoretical calculations (docking and molecular dynamics simulation studies). The proteomic analysis of HTB/HSA photolysates shows that HTB addition takes place at the ε-amino groups of the Lys137, Lys199, Lys205, Lys351, Lys432, Lys525, Lys541 and Lys545 residues and involves replacement of the trifluoromethyl moiety of HTB with a new amide function. Only Lys199 is located in an internal pocket of the protein, and the remaining modified residues are placed in the external part. Docking and molecular dynamic simulation studies reveal that HTB supramolecular binding to HSA occurs in the "V-cleft" region and that the process is assisted by the presence of Glu/Asp residues in the neighborhood of the external Lys, in agreement with the experimentally observed modifications. In principle, photobinding can occur with other trifluoroaromatic compounds and may be responsible for the appearance of undesired photoallergic side effects.

Chromoselective access to Z- or E- allylated amines and heterocycles by a photocatalytic allylation reaction.

The most useful strategies for the alkylation of allylic systems are related to the Tsuji-Trost reaction or the use of different Lewis acids. Herein we report a photocatalytic approach for the allylation reaction of a variety of nucleophiles, such as heteroarenes, amines and alcohols. This method is compatible with a large variety of pyrroles and indoles, containing different substituents such as electron-withdrawing and electron-donating groups, unprotected nitrogen atoms and bromo derivatives. Moreover, this methodology enables the chromoselective synthesis of Z- or E-allylated compounds. While the use of UV-light irradiation has allowed the synthesis of the previously inaccessible Z-allylated products, E-isomers are prepared simply by changing both the light source to the visible region, and the catalytic system. Based on mechanistic and photochemical proofs, laser flash photolysis studies and DFT calculations, a rational mechanism is presented.

The Prospect of Photochemical Reactions in Confined Gel Media.

Nature is intrinsically able to control kinetics, conversion, and selectivity of biochemical processes by means of confined reaction environments such as enzyme pockets, bilayer membranes, micelles, vesicles, cells, or bioorganic frameworks. The main reason for this fact is the optimal molecular alignment and restricted motion of reactant molecules compared to those found in bulk solution. Under this inspiration, a number of synthetic photo-nanoreactors based on supramolecular self-assembled systems have been developed during the last decades, including mesoporous inorganic materials, microemulsions, micelles, vesicles, lipid bilayer foams, polyelectrolyte nanoparticles, etc. In a broader sense, nanoreactor technology constitutes nowadays a promising tool to enhance organic synthesis under sustainable reaction conditions. In general, nanoreactors change the essential properties of the molecules within them, thus affecting their chemical reactivity. Among the nanoreactor-like systems described in the literature to facilitate photochemical processes, the more recent use of viscoelastic supramolecular gels, typically made of low-molecular-weight (LMW) compounds self-assembled through noncovalent interactions, as compartmentalized reaction media is particularly appealing due to the versatility of these materials in terms of fabrication, properties, and processability. Furthermore, the high specific surface areas found in supramolecular gels, their stimuli-responsive reversibility, good diffusion properties enhancing the interactions between reactants and the three-dimensional (3D) porous network, functional tunability, and blocking effect of external oxygen are some of the most important features that can benefit photoinduced processes carried out in confined gel media. Not surprisingly, the efficiency of photochemical processes inside gel media is largely dependent on the type of reaction, characteristics of the gel network, solvent nature, reactant properties, and reaction conditions. Thus, the main focus of this Account is to provide a concise overview of the most relevant examples reported by us and others in order to illustrate the main advantages associated with the emerging use of gel-based materials as nonconventional reaction media to facilitate and control photochemical reactions. In particular, photodimerization, triplet-triplet annihilation upconversion (TTA-UC) coupled to single electron transfer (SET), photooxidation, photoreduction, and trifluoromethylation reactions will be illustrated during the discussion. These examples suggest that gel-based media can provide a versatile platform for the discovery of new reaction pathways and facilitate the way that photochemical reactions are traditionally carried out in academia and industry in terms of reaction conditions and required infrastructure. In addition, the use of physical or chemical gels as reaction systems may also accelerate high-throughput screening of photocatalysts. Overall, a judicious choice of gelators, reactants, solvent, and reaction conditions for the assembly of these gelators is crucial for controlling conversion, kinetics, and selectivity of intragel photoinduced processes.

Photogeneration of Quinone Methides as Latent Electrophiles for Lysine Targeting.

Latent electrophiles are nowadays very attractive chemical entities for drug discovery, as they are unreactive unless activated upon binding with the specific target. In this work, the utility of 4-trifluoromethyl phenols as precursors of latent electrophiles, quinone methides (QM), for lysine-targeting is demonstrated. These Michael acceptors were photogenerated for specific covalent modification of lysine residues using human serum albumin (HSA) as a model target. The reactive QM-type intermediates I or II, generated upon irradiation of 4-trifluoromethyl-1-naphthol (1)@HSA or 4-(4-trifluorometylphenyl)phenol (2)@HSA complexes, exhibited chemoselective reactivity toward lysine residues leading to amide adducts, which was confirmed by proteomic analysis. For ligand 1, the covalent modification of residues Lys106 and Lys414 (located in subdomains IA and IIIA, respectively) was observed, whereas for ligand 2, the modification of Lys195 (in subdomain IIA) took place. Docking and molecular dynamics simulation studies provided an insight into the molecular basis of the selectivity of 1 and 2 for these HSA subdomains and the covalent modification mechanism. These studies open the opportunity of performing protein silencing by generating reactive ligands under very mild conditions (irradiation) for specific covalent modification of hidden lysine residues.

Dichromatic Photocatalytic Substitutions of Aryl Halides with a Small Organic Dye.

Photocatalytic bond activations are generally limited by the photon energy and the efficiency of energy and electron transfer processes. Direct two-photon processes provide sufficient energy but the ultra-short lifetimes of the excited states prohibit chemical reactions. The commercial dye 9,10-dicyanoanthracene enabled photocatalytic aromatic substitutions of non-activated aryl halides. This reaction operates under VIS-irradiation via sequential photonic, electronic, and photonic activation of the simple organic dye. The resultant highly reducing excited photocatalyst anion readily effected C-H, C-C, C-P, C-S, and C-B bond formations. Detailed synthetic, spectroscopic, and theoretical studies support a biphotonic catalytic mechanism.

A New Pathway for Protein Haptenation by ß-Lactams.

The covalent binding of ß-lactams to proteins upon photochemical activation has been demonstrated by using an integrated approach that combines photochemical, proteomic and computational studies, selecting human serum albumin (HSA) as a target protein and ezetimibe (1) as a probe. The results have revealed a novel protein haptenation pathway for this family of drugs that is an alternative to the known nucleophilic ring opening of ß-lactams by the free amino group of lysine residues. Thus, photochemical ring splitting of the ß-lactam ring, following a formal retro-Staudinger reaction, gives a highly reactive ketene intermediate that is trapped by the neighbouring lysine residues, leading to an amide adduct. For the investigated 1/HSA system, covalent modification of residues Lys414 and Lys525, which are located in sub-domains IIIA and IIIB, respectively, occurs. The observed photobinding may constitute the key step in the sequence of events leading to photoallergy. Docking and molecular dynamics simulation studies provide an insight into the molecular basis of the selectivity of 1 for these HSA sub-domains and the covalent modification mechanism. Computational studies also reveal positive cooperative binding of sub-domain IIIB that explains the experimentally observed modification of Lys414, which is located in a barely accessible pocket (sub-domain IIIA).