Unusual Photochemistry in Aromatic Dithioimides: Quantitative Thione Reduction Promoted by Ether Solvents.

We report a mechanistic investigation of an aromatic dithioimide (2SS) displaying puzzling yet efficient photochemistry in ether solvents. Perplexingly, 2SS dissolved in ether solvents in a sealed and degassed vial was photochemically converted to the corresponding diimide (2OO), as determined by 1H NMR following product extraction. With no external sources of oxygen in the sample, could the oxygen in 2OO be from the ether itself? To study this unprecedented proposition, we attempt to uncover the ether's involvement in this reaction. As seen by laser-flash photolysis, 2SS appears to first react with the solvent from its singlet excited state. Following the reaction by NMR under rigorously oxygen- and water-free conditions led to the identification of a photoreductive pathway that quantitatively transformed one thione into a methylene to yield 2SH2. Subsequent oxidation of 2SH2 or irradiation of 2SS under air proved that molecular oxygen was indeed necessary to observe an oxidative pathway leading to 2OO, ruling out the initially proposed involvement of an ether oxygen. An explanation of 2SS desulfurization was further revealed through the study of solvent by-products by GC-MS analysis. Supported by DFT calculations, a mechanism is proposed to involve a chain reaction initiated by photochemically generated ether radical.

Insight into the nature of carbon-metal bonding for N-heterocyclic carbenes in gold/silver complexes and nanoparticles using DFT-correlated Raman spectroscopy: strong evidence for π-backbonding.

N-Heterocyclic carbenes (NHCs) have emerged as promising ligands for stabilizing metallic complexes, nanoclusters, nanoparticles (NPs) and surfaces. The carbon-metal bond between NHCs and metal atoms plays a crucial role in determining the resulting material's stability, reactivity, function, and electronic properties. Using Raman spectroscopy coupled with density functional theory calculations, we investigate the nature of carbon-metal bonding in NHC-silver and NHC-gold complexes as well as their corresponding NPs. While low wavenumbers are inaccessible to standard infrared spectroscopy, Raman detection reveals previously unreported NHC-Au/Ag bond-stretching vibrations between 154-196 cm-1. The computationally efficient r2SCAN-3c method allows an excellent correlation between experimental and predicted Raman spectra which helps calibrate an accurate description of NHC-metal bonding. While π-backbonding should stabilize the NHC-metal bond, conflicting reports for the presence and absence of π-backbonding are seen in the literature. This debate led us to further investigate experimental and theoretical results to ultimately confirm and quantify the presence of π-backbonding in these systems. Experimentally, an observed decrease in the NHC's CN stretching due to the population of the π* orbital is a good indication for the presence of π-backbonding. Using energy decomposition analysis - natural orbitals for chemical valence (EDA-NOCV), our calculations concur and quantify π-backbonding in these NHC-bound complexes and NPs. Surprisingly, we observe that NPs are less stabilized by π-backbonding compared to their respective complexes-a result that partially explains the weaker NHC-NP bond. The protocol described herein will help optimize metal-carbon bonding in NHC-stabilized metal complexes, nanoparticles and surfaces.

Towards routine organic structure determination using Raman microscopy.

Raman microscopy can reveal a compound-specific vibrational "fingerprint" from micrograms of material with no sample preparation. We expect this increasingly available instrumentation to routinely assist synthetic chemists in structure determination; however, interpreting the information-dense spectra can be challenging for unreported compounds. Appropriate theoretical calculations using the highly efficient r2SCAN-3c method can accurately predict peak positions but are less precise in matching peak heights. To limit incorrect biases while comparing experimental and theoretical spectra, we introduce a user-friendly software that gives a match score to assist with structure determination. The capabilities and limitations of this approach are demonstrated for several proof-of-concept examples including the characterization of intermediates in the total synthesis of deoxyaspidodispermine.

Targeted proximity-labelling of protein tyrosines via flavin-dependent photoredox catalysis with mechanistic evidence for a radical-radical recombination pathway.

Flavin-based photocatalysts such as riboflavin tetraacetate (RFT) serve as a robust platform for light-mediated protein labelling via phenoxy radical-mediated tyrosine-biotin phenol coupling on live cells. To gain insight into this coupling reaction, we conducted detailed mechanistic analysis for RFT-photomediated activation of phenols for tyrosine labelling. Contrary to previously proposed mechanisms, we find that the initial covalent binding step between the tag and tyrosine is not radical addition, but rather radical-radical recombination. The proposed mechanism may also explain the mecha-nism of other reported tyrosine-tagging approaches. Competitive kinetics experiments show that phenoxyl radicals are generated with several reactive intermediates in the proposed mechanism-primarily with the excited riboflavin-photocatalyst or singlet oxygen-and these multiple pathways for phenoxyl radical generation from phenols increase the likelihood of radical-radical recombination.

Mechanistic Insight into Phenol Dearomatization by Hypervalent Iodine: Direct Detection of a Phenoxenium Cation.

Phenol dearomatization is one of several oxidation reactions enabled by hypervalent iodine reagents. However, the presence of a proposed free phenoxenium intermediate in phenol dearomatization is a matter of debate in the literature. Here, we report the unambiguous detection of a free phenoxenium intermediate in the reaction of an electron-rich phenol, 2,4,6-trimethoxyphenol, and (diacetoxyiodo)benzene using UV-vis and resonance Raman spectroscopies. In contrast, we predominantly detect single electron oxidation products of less electron-rich phenols or alkoxy-substituted aromatics in their reaction with (diacetoxyiodo)benzene using UV-vis and electron paramagnetic resonance (EPR) spectroscopies. We conclude that the often-postulated free phenoxenium intermediate, while possible with highly stabilizing substituents, is unlikely to be a general mechanistic pathway in the reaction of typical phenols with hypervalent iodine reagents. The polar solvent 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) or the use of more strongly oxidizing hypervalent iodine reagents, such as [bis(trifluoroacetoxy)iodo]benzene (PIFA) or [hydroxy(tosyloxy)iodo]benzene (HTIB), can help reduce the formation of radical byproducts and favors the formation of phenoxenium intermediates.

Long-term Stability of Epitheliotropic Factors in Frozen Serum Eye Drops.

The objective of this experimental study was to investigate the stability of functional proteins in human serum eye drops, which are used for the treatment of ocular surface disorders, after prolonged storage of 6 months at -20°C. After obtaining whole blood from 3 volunteers and preparing 100% (S100), 50% (S50), and 20% (S20) serum eye drops, fibronectin was quantified before and after storage for 6 months at -20°C using appropriate enzyme-linked immunoassay kits. The pH and microbial contamination of preparations were also evaluated longitudinally. The fibronectin concentration showed no significant reduction in undiluted (S100) or diluted (S50 and S20) serum after 6 months of frozen storage at -20°C. None of the preparations showed any microbial contamination and no significant changes in pH were noted during storage. Frozen serum eye drops appear stable after prolonged storage at -20°C. Fibronectin in serum is temperature and time resistant after prolonged storage at -20°C. While the impact of individual serum proteins on ocular surface health remains unclear, our results suggest that freezing up to 6 months provides adequate preservation of epitheliotropic factors and a minimal risk of microbial contamination.

Characterization of Triphenylamine and Ferrocenyl Donor-π-donor Vinyl BODIPY Derivatives as Photoacoustic Contrast Agents.

The photophysical and electrochemical properties for a series of BODIPY dyes with incremental 3- and 3,5-vinyl conjugation, as well as incremental electron-donating groups (anisole < triphenylamine < ferrocenyl), are presented. Insight into the influence of each vinyl-conjugated electron-donating group on both vis-NIR absorption and fluorescence emission properties is provided. These trends are further corroborated by density functional theory computational analysis. Two of this series containing the 3,5-bis(vinyltriphenylamine) and 3,5-bis(vinylferrocenyl) substituents exhibit significant absorption cross sections in the biological transparency window justifying further investigation of their photoacoustic emission properties via both optical photoacoustic z-scan and photoacoustic tomography experiments. Both the 3,5-bis(vinyltriphenylamine) and 3,5-bis(vinylferrocenyl) substituted BODIPY dyes exhibit quantitative photoacoustic quantum yields. Relative to the commercially available methylene blue and indocyanine green molecular photoacoustic contrast agents, the 3,5-bis(vinyltriphenylamine)-derived BODIPY exhibits the greatest photoacoustic emission and contrast upon excited-state absorption at 685 nm excitation at a low power laser fluence (<20 mJ cm-2 ).

Exploring Curious Covalent Bonding: Raman Identification and Thermodynamics of Perpendicular and Parallel Pancake Bonding (Pimers) of Ethyl Viologen Radical Cation Dimers.

Viologen radical cations can dimerize in solutions, and the resulting "pimers" were predicted to assemble into parallel and perpendicular conformers by density functional theory (DFT) calculations. Using resonance Raman, we could identify both perpendicular and parallel forms of ethyl viologen dimers. The distinction between the two forms was accomplished by studying the formation of a host-guest complex with γ-cyclodextrin. The dimer's perpendicular form was excluded due to the host cavity size, and γ-cyclodextrin addition caused a decrease in peak intensities at 1171, 1511, and 1602 cm-1 that could be assigned to the perpendicular form. DFT modeling of the vibrational spectra under preresonance conditions allowed us to assign the remaining vibrational modes for the parallel and perpendicular forms. Using variable-temperature UV-vis, the bond dissociation energy (ΔH) for this pancake-bonded dimer was measured as 13.1 ± 0.2 kcal/mol. This type of covalent pancake bonding is a challenge to properly describe using DFT methods. Previously, B97D was found to best describe the ΔG of this dimerization (Angew. Chem. 2017, 129, 9563-9567), but this method underestimates the ΔH by 6 kcal/mol. Of the 11 functionals tested, we found that B3LYP with Grimme's D3 dispersion effect can best reproduce the ΔH. Energy decomposition analysis of the bonding energy showed that solvation effects were the most important contributor-polar solvents are needed to overcome the Coulomb repulsion between the two positively charged monomers. Dispersion effects are second in importance and appear larger than the favorable orbital interaction obtained by singly occupied molecular orbital (SOMO)-SOMO orbital overlap. This study brings forth important insights into the curious cases of covalent bonding between two π-delocalized radicals.

Copper-Photocatalyzed Hydroboration of Alkynes and Alkenes.

The photocatalytic hydroboration of alkenes and alkynes is reported. The use of newly-designed copper photocatalysts with B2 Pin2 permits the formation a boryl radical, which is used for hydroboration of a large panel of alkenes and alkynes. The hydroborated products were isolated in high yields, with excellent diastereoselectivities and a high functional group tolerance under mild conditions. The hydroboration reactions were developed under continuous flow conditions to demonstrate their synthetic utility. The reaction mechanism was studied and suggested an oxidation reaction between an in situ formed borate and the Cu-photocatalyst in its excited state for the boryl radical formation.

Raman Spectra of Persistent Radical Anions from Benzophenone, Fluorenone, 2,2'-Bipyridyl, 4,4'-Di-tert-butyl-2,2'-dipyridyl, and Anthracene: Excellent Agreement between DFT and Experiment for Highly Delocalized Radical Systems.

We report detailed Raman spectra for the neutral and radical anion forms of benzophenone, fluorenone, 2,2'-bipyridyl, 4,4'-di-tert-butyl-2,2'-dipyridyl, and anthracene. Density functional theory (DFT) predictions for the Raman spectra of these molecules give additional insight into the assignment of each vibrational mode. While the use of DFT has been problematic in quantifying the thermochemistry of highly delocalized radicals, we find that DFT-predicted spectra using the popular B3LYP functional are in excellent agreement with the observed Raman spectra. In the case of the two bipyridyl compounds, the Raman spectra allowed us to conclude that the cis form of the radical anion complexed to a sodium cation was the preferred configuration. Benzophenone and fluorenone radical anions gave a significantly weakened C═O bond stretching vibrational frequency as expected from the population of an antibonding π* orbital. For benzophenone, the C═O vibration dropped from 1659 to 1403 cm-1 upon reduction. Similarly, fluorenone showed a C═O vibration observed at 1719 cm-1 for the neutral form that decreased to 1522 cm-1 for the radical anion. The structurally rigid anthracene showed relatively smaller Raman band shifts upon single-electron reduction as the π* orbital is more equally delocalized on the entire structure. In total, we correlated 65 DFT-predicted vibrational modes for the neutral molecules with an overall error of 7.1 cm-1 (root-mean-square errors (RMSEs)) and 67 DFT-predicted vibrational modes for radical anions with an overall error of 9.9 cm-1. These comparisons between theory and experiment are another example to demonstrate the power of DFT in predicting the identity and geometry of molecules using Raman spectroscopy.

Highly Photostable and Fluorescent Microporous Solids Prepared via Solid-State Entrapment of Boron Dipyrromethene Dyes in a Nascent Metal-Organic Framework.

We report a strategy to synthesize highly emissive, photostable, microporous materials by solid-state entrapment of boron dipyrromethene (BODIPY) fluorophores in a metal-organic framework. Solvent-free mechanochemistry or accelerated aging enabled quantitative capture and dispersal of the PM605 dye within the ZIF-8 framework starting from inexpensive, commercial materials. While the design of emissive BODIPY solids is normally challenged by quenching in a densely packed environment, herein reported PM605@ZIF-8 materials show excellent emissive properties and to the best of our knowledge an unprecedented ∼10-fold enhancement of BODIPY photostability. Time-resolved and steady-state fluorescence studies of PM605@ZIF-8 show that interchromophore interactions are minimal at low dye loadings, but at higher ones lead to through-pore energy transfer between chromophores and to aggregate species.

Nuclear Resonance Vibrational Spectroscopy Definition of O2 Intermediates in an Extradiol Dioxygenase: Correlation to Crystallography and Reactivity.

The extradiol dioxygenases are a large subclass of mononuclear nonheme Fe enzymes that catalyze the oxidative cleavage of catechols distal to their OH groups. These enzymes are important in bioremediation, and there has been significant interest in understanding how they activate O2. The extradiol dioxygenase homoprotocatechuate 2,3-dioxygenase (HPCD) provides an opportunity to study this process, as two O2 intermediates have been trapped and crystallographically defined using the slow substrate 4-nitrocatechol (4NC): a side-on Fe-O2-4NC species and a Fe-O2-4NC peroxy bridged species. Also with 4NC, two solution intermediates have been trapped in the H200N variant, where H200 provides a second-sphere hydrogen bond in the wild-type enzyme. While the electronic structure of these solution intermediates has been defined previously as FeIII-superoxo-catecholate and FeIII-peroxy-semiquinone, their geometric structures are unknown. Nuclear resonance vibrational spectroscopy (NRVS) is an important tool for structural definition of nonheme Fe-O2 intermediates, as all normal modes with Fe displacement have intensity in the NRVS spectrum. In this study, NRVS is used to define the geometric structure of the H200N-4NC solution intermediates in HPCD as an end-on FeIII-superoxo-catecholate and an end-on FeIII-hydroperoxo-semiquinone. Parallel calculations are performed to define the electronic structures and protonation states of the crystallographically defined wild-type HPCD-4NC intermediates, where the side-on intermediate is found to be a FeIII-hydroperoxo-semiquinone. The assignment of this crystallographic intermediate is validated by correlation to the NRVS data through computational removal of H200. While the side-on hydroperoxo semiquinone intermediate is computationally found to be nonreactive in peroxide bridge formation, it is isoenergetic with a superoxo catecholate species that is competent in performing this reaction. This study provides insight into the relative reactivities of FeIII-superoxo and FeIII-hydroperoxo intermediates in nonheme Fe enzymes and into the role H200 plays in facilitating extradiol catalysis.

Metal-Free-Visible Light C-H Alkylation of Heteroaromatics via Hypervalent Iodine-Promoted Decarboxylation.

A metal-free photoredox C-H alkylation of heteroaromatics from readily available carboxylic acids using an organic photocatalyst and hypervalent iodine reagents under blue LED light is reported. The developed methodology tolerates a broad range of functional groups and can be applied to the late-stage functionalization of drugs and drug-like molecules. The reaction mechanism was investigated with control experiments and photophysical experiments as well as DFT calculations.

Photophysical and Photoacoustic Properties of Quadrupolar Borondifluoride Curcuminoid Dyes.

The synthesis and characterization of a series of donor-π-acceptor-π-donor (D-A-D) curcuminoid molecules is presented herein that incorporates π-extended aryl and electron-donating amino terminal functionalization. Computational evaluation shows these molecules possess quadrupolar character with the lowest energy transitions displaying high molar extinction coefficients with broad tunability through manipulation of terminal donating groups. Consistent with their quadrupolar nature, these molecules show varying degrees of solvatochromic behavior in both their absorption and emission spectra, which has been analyzed by Lippert-Mataga and Kamlet-Taft analysis. Photophysical and photoacoustic (PA) properties of these molecules have been investigated by the optical photoacoustic z-scan (OPAZ) method. Selected curcuminoid molecules display nonlinear behavior at a high laser fluence through excited state absorption that translates to the production of an enhanced photoacoustic emission. A relative comparison of "molar PA emission" is also presented with the crystal violet linear optical absorbing/linear PA emitting system being utilized as a standard reference material for OPAZ experiments. Furthermore, PA tomography experiments are presented to illustrate the enhanced PA contrast obtainable via an excited state absorption.

Visible-Light-Initiated Manganese Catalysis for C-H Alkylation of Heteroarenes: Applications and Mechanistic Studies.

A visible-light-driven Minisci protocol that employs an inexpensive earth-abundant metal catalyst, decacarbonyldimanganese Mn2 (CO)10 , to generate alkyl radicals from alkyl iodides has been developed. This Minisci protocol is compatible with a wide array of sensitive functional groups, including oxetanes, sugar moieties, azetidines, tert-butyl carbamates (Boc-group), cyclobutanes, and spirocycles. The robustness of this protocol is demonstrated on the late-stage functionalization of complex nitrogen-containing drugs. Photophysical and DFT studies indicate a light-initiated chain reaction mechanism propagated by . Mn(CO)5 . The rate-limiting step is the iodine abstraction from an alkyl iodide by . Mn(CO)5 .

Photophysics of 7-mercapto-4-methylcoumarin and derivatives: complementary fluorescence behaviour to 7-hydroxycoumarins.

The photophysical behaviour of 7-mercapto-4-methylcoumarin (C-SH) and derivatives has been studied in different solvents. In contrast to 7-hydroxy-4-methylcoumarin, C-SH shows poor emission, but high fluorescence when the thiol is alkylated. The origin and character of the lowest singlet states are discussed, specifically proposing that the thione-like C[double bond, length as m-dash]S resonance form plays a key role in excited state deactivation in C-SH.

Highly Chemoselective Iridium Photoredox and Nickel Catalysis for the Cross-Coupling of Primary Aryl Amines with Aryl Halides.

A visible-light-promoted iridium photoredox and nickel dual-catalyzed cross-coupling procedure for the formation C-N bonds has been developed. With this method, various aryl amines were chemoselectively cross-coupled with electronically and sterically diverse aryl iodides and bromides to forge the corresponding C-N bonds, which are of high interest to the pharmaceutical industries. Aryl iodides were found to be a more efficient electrophilic coupling partner. The coupling reactions were carried out at room temperature without the rigorous exclusion of molecular oxygen, thus making this newly developed Ir-photoredox/Ni dual-catalyzed procedure very mild and operationally simple.

A Drug Delivery System for Administration of Anti-TNF-α Antibody.

PURPOSE: To describe the fabrication, evaluation, and preliminary in vivo safety of a new drug delivery system (DDS) for topical anti-TNF-α antibody administration. METHODS: A DDS was fabricated using inverse template fabrication of a hydrophobic three-dimensional porous scaffold (100-300 µm in diameter porosity) loaded with 10% polyvinyl alcohol hydrogel carrying 5 mg/ml (weight/volume) of anti-TNF-α antibody. Drug-loaded DDS was sterilized with 25 kGy of gamma irradiation. Long-term in vitro antibody affinity and release was evaluated at room temperature or 37°C using enzyme-linked immunosorbent assay (ELISA) and protein fluorescence. In vivo clinical and histolopathological assessment was performed by subcutaneous implantation in BALB/c mice for 3 months. RESULTS: Gamma irradiation, repeated dry/wet cycles, and storage at room temperature for 1 year or 37°C for 1 month had no deleterious effects on antibody affinity. Anti-TNF-α release was high during the first minutes of aqueous exposure, followed by stabilization and gradual, low-dose, antibody release over the next 30 days. Histopathologic evaluation of explanted DDS showed a fibrous pseudocapsule and a myxoid acute/chronic inflammation without granuloma formation surrounding the implants. CONCLUSIONS: Sustained local delivery of anti-TNF-α antibody is feasible using the described DDS, which provides stability of the enclosed antibody for up to 1 year of storage. Preliminary results show good in vivo tolerance following subcutaneous placement for 3 months. The proposed fabrication and sterilization process opens new possibilities for the delivery of biologic agents to the anterior surface of the eye. TRANSLATIONAL RELEVANCE: The described DDS will facilitate the treatment of ocular surface diseases amenable to biologic therapy.

Photoredox Mediated Nickel Catalyzed Cross-Coupling of Thiols With Aryl and Heteroaryl Iodides via Thiyl Radicals.

Ni-catalyzed cross-couplings of aryl, benzyl, and alkyl thiols with aryl and heteroaryl iodides were accomplished in the presence of an Ir-photoredox catalyst. Highly chemoselective C-S cross-coupling was achieved versus competitive C-O and C-N cross-couplings. This C-S cross-coupling method exhibits remarkable functional group tolerance, and the reactions can be carried out in the presence of molecular oxygen. Mechanistic investigations indicated that the reaction proceeded through transient Ni(I)-species and thiyl radicals. Distinct from nickel-catalyzed cross-coupling reactions involving carbon-centered radicals, control experiments and spectroscopic studies suggest that this C-S cross-coupling reaction does not involve a Ni(0)-species.

Shining light on the dark side of imaging: excited state absorption enhancement of a bis-styryl BODIPY photoacoustic contrast agent.

A first approach toward understanding the targeted design of molecular photoacoustic contrast agents (MPACs) is presented. Optical and photoacoustic Z-scan spectroscopy was used to identify how nonlinear (excited-state) absorption contributes to enhancing the photoacoustic emission of the curcuminBF2 and bis-styryl (MeOPh)2BODIPY dyes relative to Cy3.