Sulfondiimines are an emerging sulfur(VI) functional group with increasing use in synthesis and medicinal chemistry, yet their photochemical behavior has remained largely unexplored. In this work, the photochemistry of a series of six N‐substituted, N′‐tosyl diphenyl sulfondiimines was analyzed. Upon direct UV irradiation, five derivatives underwent efficient photodenitrenation in a consistent, stepwise order: extrusion of the N‐substituent nitrene followed by release of the N‐tosyl nitrene from the corresponding sulfilimine. This sequential nitrene release is a rare behavior that has not been observed previously. Quantum yield measurements reveal strong substituent dependence, with aryl substituents exhibiting substantially higher photochemical efficiency (0.22–0.31) than alkyl substituents (~0.1), whereas the NH‐substituted compound remained photoinert under our conditions. Product profiles and trapping experiments support the S–N cleavage in sulfondiimines to release the nitrene through a singlet manifold. Photosensitization experiments revealed the triplet manifold is dissociative as well, albeit with a greater number of side reactions. Quantum chemical calculations further supported this mechanism by relating the release order to relative S–N bond strengths and identifying a dissociative excited state along the S–N coordinate.

Computational analysis was conducted to determine the bond dissociation enthalpies (BDEs) of S-O bonds in eight molecules, which were subsequently compared to their experimentally derived BDEs. Computational BDEs were determined utilizing various combinations of density functional theory (DFT) functionals with an assortment of basis sets. Specifically, DFT methods including M06-2X, mPW1LYP, omega B97X-D3, PBE0, and B3P86 were paired with basis sets def2-TZVP/J, def2-TZVP, aug-cc-pV(T + d)Z, 6-311 + G(2df,2p), and def2-QZVP. The comparison between computational and experimental BDEs was evaluated through graphical representation, yielding slope, coefficient of determination (R2), and root mean square error (RMSE) metrics. Additionally, comparative analyses were expanded to include complete basis set methods (CBS-QB3 and CBS-4M), which exhibited comparatively lower accuracy in predicting experimentally determined S-O BDEs than the DFT methods. Among all methods tested, the B3P86/aug-cc-pV(T + d)Z and B3P86/def2-QZVP methods are recommended for computational prediction of BDEs for sulfoxides.

Photodeoxygenation of aryl sulfoxides, such as dibenzothiophene S-oxide (DBTO), produces atomic oxygen [O(P-3)] in solution. The mechanism of alkene oxidation with O(P-3) remains uncertain. To address this, the current study utilized kinetic isotope effects (KIEs) and computational approaches to study the reaction of O(P-3) with styrene and its isotopologues. Notably, the 2 degrees CH/D KIE at the internal and terminal carbons of the reactive pi-bond was similar to 1.00 and similar to 0.87, respectively. These findings indicate a terminal addition of O(P-3) to the pi-bond, supporting a stepwise oxidation pathway. Both epoxide and aldehyde products go through the same rate-determining transition state and then diverge based on the intermediate conformation. The O-C-C-C dihedral angle (phi) on the triplet surface dictates the product distribution, where phi = 50 degrees or 310 degrees leads to epoxide formation and phi = 180 degrees leads to aldehyde formation. Computational modeling suggests that the epoxide is formed through rapid ring closure upon intersystem crossing from the triplet to the singlet ground state. Similarly, the aldehyde is generated via a 1,2-H shift immediately following intersystem crossing. This study integrates experimental and computational methods to understand the O(P-3)-mediated oxidation of alkenes, providing supporting evidence for a stepwise addition mechanism.

N-phenyl dibenzothiophene sulfoximine has been demonstrated to produce phenyl nitrene and dibenzothiophene S-oxide upon irradiation with UV-A light, and dibenzothiophene S-oxide upon further irradiation releases triplet atomic oxygen. Thus, N-phenyl dibenzothiophene sulfoximine exhibits a rare dual-release capability in its photochemistry. In this work, N-substituted dibenzothiophene sulfoximine derivatives are irradiated with UV-A light to compare their photochemistry and quantum yield of dibenzothiophene S-oxide production with that of N-phenyl dibenzothiophene sulfoximine. Both N-aryl and N-alkyl derivatives of dibenzothiophene sulfoximine are examined to observe their effects on the quantum yield of the photolysis reaction. Adding electron withdrawing N-aryl substituents is shown to increase the quantum yield of dibenzothiophene S-oxide production, while adding electron donating N-aryl substituents is shown to decrease the quantum yield. The quantum yield was slightly lowered or not increased by most N-alkyl substituents. Furthermore, the quantum yield was not augmented by branching and steric hindrance effects associated with the N-alkyl substituents. These results suggest that electronic modulation of the sulfoximine bonds affects the observed photolysis reaction.

Lipid oxidation by reactive oxygen species (ROS) provide several different oxidation products that have been implicated in inflammatory responses. Ground state atomic oxygen [O(3 P)] is produced by the photodeoxygenation of certain heterocyclic oxides and has a reactivity that is unique from other ROS. Due to the reactive nature of O(3 P), the site of O(3 P)-generation is expected to influence the products in heterogenous solutions or environments. In this work, the oxidation of low-density lipoprotein (LDL) by lipids with covalently bound O(3 P)-photoprecursors was compared to more hydrophilic O(3 P)-photoprecursors. Lipid oxidation products were quantified after Bligh-Dyer extraction and pentafluorobenzyl bromide (PFB) derivatization by GC-MS. Unlike the more hydrophilic O(3 P)-photoprecursors, the oxidation of LDL during the irradiation of lipid-(O3 P)-photoprecursor conjugates showed little quenching by the addition of the O(3 P)-scavenging sodium allyl sulfonate. This indicated that lipophilic O(3 P)-photoprecursors are expected to generate lipid oxidation products where other more hydrophilic O(3 P)-photoprecursors could be quenched by other reactive groups present in solution or the environment.

Sulfoximines are popular scaffolds in drug discovery due to their hydrogen bonding properties and chemical stability. In recent years, the role of reactive intermediates such as nitrenes has been studied in the synthesis and degradation of sulfoximines. In this work, the photochemistry of N ‐phenyl dibenzothiophene sulfoximine [5‐(phenylimino)‐5 H ‐5λ 4 ‐dibenzo[ b,d ]thiophene S ‐oxide] was analyzed. The structure resembles a combination of N ‐phenyl iminodibenzothiophene and dibenzothiophene S ‐oxide, which generate nitrene and O( 3 P) upon UV‐A irradiation, respectively. The photochemistry of N ‐phenyl dibenzothiophene sulfoximine was explored by monitoring the formation of azobenzene, a photoproduct of triplet nitrene, using direct irradiation and sensitized experiments. The reactivity profile was further studied through direct irradiation experiments in the presence of diethylamine (DEA) as a nucleophile. The studies demonstrated that N ‐phenyl dibenzothiophene sulfoximine underwent S–N photocleavage to release singlet phenyl nitrene which formed a mixture of azepines in the presence of DEA and generated moderate amounts of azobenzene in the absence of DEA to indicate formation of triplet phenyl nitrene.

Photodeoxygenation of dibenzothiophene S-oxide and its derivatives have been used to generate atomic oxygen [O(3P)] to examine its effect on proteins, nucleic acids, and lipids. The unique reactivity and selectivity of O(3P) have shown distinct oxidation products and outcomes in biomolecules and cell-based studies. To understand the scope of its global impact on the cell, we treated MDA-MB-231 cells with 2,8-diacetoxymethyldibenzothiophene S-oxide and UV-A light to produce O(3P) without targeting a specific cell organelle. Cellular responses to O(3P)-release were analyzed using cell viability and cell cycle phase determination assays. Cell death was observed when cells were treated with higher concentrations of sulfoxides and UV-A light. However, significant differences in cell cycle phases due to UV-A irradiation of the sulfoxide were not observed. We further performed RNA-Seq analysis to study the underlying biological processes at play, and while UV-irradiation itself influenced gene expression, there were 9 upregulated and 8 downregulated genes that could be attributed to photodeoxygenation.

Photodeoxygenation of dibenzothiophene S ‐oxide (DBTO) is believed to produce ground‐state atomic oxygen [O( 3 P)] in solution. Compared with other reactive oxygen species (ROS), O( 3 P) is a unique oxidant as it is potent and selective. Derivatives of DBTO have been used as O( 3 P)‐precursors to oxidize variety of molecules, including plasmid DNA, proteins, lipids, thiols, and other small organic molecules. Unfortunately, the photodeoxygenation of DBTO requires ultraviolet irradiation, which is not an ideal wavelength range for biological systems, and has a low quantum yield of approximately 0.003. In this work, benzo[ b ]naphtho[1,2‐ d ]selenophene Se ‐oxide, benzo[ b ]naphtho[2,1‐ d ]selenophene Se ‐oxide, dinaphtho[2,3‐ b :2’,3’‐ d ]selenophene Se ‐oxide, and perylo[1,12‐ b,c,d ]selenophene Se ‐oxide were synthesized, and their ability to utilize visible light for generating O( 3 P) was interrogated. Benzo[ b ]naphtho[1,2‐ d ]selenophene Se ‐oxide produces O( 3 P) upon irradiation centered at 420 nm. Additionally, benzo[ b ]naphtho[1,2‐ d ]selenophene Se ‐oxide, benzo[ b ]naphtho[2,1‐ d ]selenophene Se ‐oxide, and dinaphtho[2,3‐ b :2’,3’‐ d ]selenophene Se ‐oxide produce O( 3 P) when irradiated with UVA light and have quantum yields of photodeoxygenation ranging from 0.009 to 0.33. This work increases the utility of photodeoxygenation by extending the range of wavelengths that can be used to generate O( 3 P) in solution.

The reactivity profile of atomic oxygen [O(3P)] in the condensed phase has shown a preference for the thiol group of cysteines. In this work, water-soluble O(3P)-precursors were synthesized by adding aromatic burdens and water-soluble sulphonic acid groups to the core structure of dibenzothiophene-S-oxide (DBTO) to study O(3P) reactivity in cell lysates and live cells. The photodeoxygenation of these compounds was investigated using common intermediates, which revealed that an increase in aromatic burdens to the DBTO core structure decreases the total oxidation yield due to competitive photodeoxygenation mechanisms. These derivatives were then tested in cell lysates and live cells to profile changes in cysteine reactivity using the isoTOP-ABPP chemoproteomics platform. The results from this analysis indicated that O(3P) significantly affects cysteine reactivity in the cell. Additionally, O(3P) was found to oxidize cysteines within peptide sequences with leucine and serine conserved at the sites surrounding the oxidized cysteine. O(3P) was also found to least likely oxidize cysteines among membrane proteins.

Dibenzothiophene 5,5-dioxide (DBTOO) derivatives have recently been shown to processes utility as fluorescent cell dyes. In an effort to extend the functionality of DBTOO-based dyes to include the visualization of cellular membranes, two lipophilic DBTOO were synthesized and their ability to incorporate into the plasma membrane of HeLa cells was examined by fluorescent microscopy. The photophysical properties of the two new DBTOO derivatives were determined and both have good fluorescent quantum yields and a visible blue emission. Due to agreeable wavelengths of excitation and emission, a standard 4 ',6-diamindino-2-phenylindole (DAPI) filter set worked well with these dyes. After co-staining, it was confirmed that both DBTOO dyes localized in the plasma membrane. The quality of the overlap was quantified using Pearson correlation coefficient, which indicated a strong overlap between the DBTOO dyes and the standard plasma membrane dye. The novel dyes also displayed relatively low toxicity to the HeLa cells with IC50 between 10 and 100 mu m. Thus, this work reports a new use of DBTOO derivatives as fluorescent microscopy stains.

A beneficial property of photogenerated reactive oxygen species (ROS) is the capability of oxidant generation within a specific location or organelle inside a cell. Dibenzothiophene S-oxide (DBTO), which is known to undergo a photodeoxygenation reaction to generate ground state atomic oxygen [O(3P)] upon irradiation, was functionalized to afford localization within the plasma membrane of cells. The photochemistry, as it relates to oxidant generation, was studied and demonstrated that the functionalized DBTO derivatives generated O(3P). Irradiation of these lipophilic O(3P)-precursors in the presence of LDL and within RAW 264.7 cells afforded several oxidized lipid products (oxLP) in the form of aldehydes. The generation of a 2-hexadecenal (2-HDEA) was markedly increased in irradiations where O(3P) was putatively produced. The substantial generation of 2-HDEA is not known to accompany the production of other ROS. These cellular irradiation experiments demonstrate the potential of inducing oxidation with O(3P) in cells.

Biological sensor molecules for oxidative stress often rely on the oxidation of thiols to sulfenic acid intermediates. How this transformation induces a physiological response often relies on the fate of sulfenic acid. Sulfenic acids will react with other biologically relevant nucleophiles such as amines, thiols, and thiolates. In the presence of excess oxidants, the sulfenic acid can be further oxidized. The free energy of reaction (Delta G) and free energies of activation (Delta G double dagger) were determined for the reactions of sulfenic acid with amines, thiols, and thiolates. The methods employed included B3LYP, B3P86, HF, M06-2X, and MP2, and the effect of water solvation on the reactions was estimated using the integral equation formulation of the polarizable continuum model (IEF-PCM). A front-side approach of the sulfenic acid for amines, thiols, and thiolates was observed. In addition to front-side attack, a back-side transition state was converged for the more nucleophilic thiolates in several cases.

Photodeoxygenation of Dibenzothiophene-S-oxide (DBTO) in UV-A light produces atomic oxygen [O(3P)] and the corresponding sulfide, dibenzothiophene (DBT). Recently, DBTO has been derivatized to study the effect of UV-A light-driven photodeoxygenation in lipids, proteins, and nucleic acids. In this study, two DBTO derivatives with triphenylphosphonium groups were synthesized to promote mitochondrial accumulation. The sulfone analogs of these derivatives were also synthesized and used as fluorescent mitochondrial dyes to assess localization in mitochondria of HeLa cells. These derivatives were then used to study the effect of photodeoxygenation on MDA-MB-231 breast cancer cell line using cell viability assays, cell cycle phase determination tests, and RNA-Seq analysis. The DBTO derivatives were found to significantly decrease cell viability only after UV-A irradiation as a result of generating corresponding sulfides that were found to significantly affect gene expression and cell cycle.

Oxidation of thiols yield sulfenic acids, which are very unstable intermediates. As sulfenic acids are reactive, they form disulfides in the presence of thiols. However, sulfenic acids also oxidize to sulfinic acids (−SO2H) and sulfonic acids (−SO3H) at higher concentrations of oxidants. Hydrogen peroxide is a commonly used oxidant for the oxidation of thiols to yield sulfenic acids. However, hydrogen peroxide also oxidizes other reactive functional groups present in a molecule. In this work, the reaction intermediates arising from the oxidation of sterically hindered thiols by aryl chalcogen oxides, dibenzothiophene S-oxide (DBTO), dibenzoselenophene Se-oxide (DBSeO), and dibenzotellurophene Te-oxide (DBTeO), were investigated. Photodeoxygenation of DBTO produces triplet atomic oxygen [O(3P)], which has previously shown to preferentially react with thiols over other functional groups. Similarly, aryl selenoxides have also shown that they can thermally react selectively with thiols at room temperature to yield disulfides. Conversely, aryl telluroxides have been reported to oxidize thiols to disulfides thermally with no selectivity toward thiols. The results from this study demonstrate that sulfenic acids are an intermediate in the oxidation of thiols by DBTeO and by photodeoxygenation of DBTO. The results also showed that the oxidation of thiols by DBSeO yields sulfonic acids. Triptycene-9-thiol and 9-fluorotriptycene-10-thiol were for the thiols used in this oxidation reaction. This work expands the list of oxidants that can be used to oxidize thiols to obtain sulfenic acids.

Sulfoxides, upon irradiation with ultraviolet (UV) light undergo α-cleavage, hydrogen abstraction, photodeoxygenation, bimolecular photoreduction, and stereo-mutation. The UV irradiation of dibenzothiophene S-oxide (DBTO) yields dibenzothiophene (DBT) as a major product along with ground-state atomic oxygen [O(3P)]. This is a common method for generating O(3P) in solution. The low quantum yield of photodeoxygenation and the requirement of UVA light are drawbacks of using this method. The sulfoxides benzo[b]naphtho-[1,2,d]thiophene S-oxide, benzo[b]naphtho [2,1,d]thiophene S-oxide, benzo[b] phenanthro[9,10-d]thiophene S-oxide, dinaphtho- [2,1-b:1’,2’-d]thiophene S-oxide, and dinaphtho[1,2-b:2’,1’-d]thiophene S-oxide have shown to deoxygenate up to three times faster than DBTO upon UVA irradiation; however, the photodeoxygenation of these sulfoxides does not appear to be limited to the production of O(3P). In this work, phenanthro[4,5-bcd]thiophene S-oxide, triphenyleno[1,12-bcd]thiophene-S-oxide, and perylo[1,12-bcd]thiophene-S-oxide were synthesized and their photodeoxygenation was studied. Phenanthro[4,5-bcd]thiophene-S-oxide, triphenyleno[1,12-bcd]thiophene-S-oxide, and perylo[1,12-bcd]thiophene-S-oxide deoxygenated upon UVA irradiation. However, the common intermediate experiments did not conclusively identify the photodeoxygenation mechanism of these sulfoxides.

Ground-state atomic oxygen [O(3P)] is an oxidant whose formation in solution was proposed but never proven. Polymer nanocapsules were used to physically separate dibenzothiophene S-oxide (DBTO), a source of O(3P), from an O(3P)-accepting molecule. Irradiation of polymer nanocapsules loaded with DBTO resulted in oxidation of the O(3P)-acceptor placed outside nanocapsules. The results rule out a direct oxygen atom transfer mechanism and are consistent with freely diffusing O(3P) as the oxidant.

Irradiation of dibenzothiophene S-oxide (DBTO) is believed to generate ground state atomic oxygen [O(3P)]. The irradiation conditions and the efficiency of the deoxygenation event are not ideal when working with biological systems. Dinaphtho[2,1-b:1′,2′-d]thiophene S-oxide (DNTO) and several other analogs were shown to allow visible light to drive deoxygenation due to red-shifted absorbance of the DBTO derivatives. Additionally, DNTO and its analogs did not substantially improved quantum yield of deoxygenation (Φdeox.). To improve both Φdeox. and absorbance, changes were made to the DBTO scaffold. The first change was an addition of an electron withdrawing group (EWG) to weaken the S O bond strength of the sulfoxide to improve Φdeox.. The second change was the addition of an aromatic substituent to enhance and red-shift the absorbance. Common intermediate experiments were performed in toluene to examine if these new DBTO analogs produced a common oxidant under both UV and visible light irradiation. The separate light sources produced different product ratios suggesting these asymmetric DBTO derivatives have wavelength-dependent mechanisms of oxidation.

Asymmetric dibenzothiophene S,S-dioxides (DBTOOs) were synthesized and their photophysical properties examined. Through examination, the molecules fluoresced at wavelengths between 371 and 492 nm with quantum yields of fluorescence nearing 0.59. Three of the sulfonic acid sodium salt analogues were chosen to be introduced to HeLa cells, resulting in illumination of the nucleus by fluorescent microscopy. These compounds function as nuclear stains while also affording the ability to predict the localization of the corresponding sulfoxide precursor to ground-state atomic oxygen.

There is a need for efficient methods for the synthesis of water-soluble dibenzothiophene (DBT) and dibenzothiophene S-oxide (DBTO) derivatives to allow for the study of atomic oxygen in biological applications. Attaining water-solubility of aromatic compounds is effectively achieved through functionalization with sulfonic acid groups. Three approaches for the synthesis were considered. An indirect approach was unsuccessful. A modular approach was found to be highly effective for one DBTO disulfonic acid derivative (>99% pure). The direct approach was the most straightforward and highest-yielding route. Additionally, a highly effective, scalable, and improved purification method was identified for disulfonic acid DBT and DBTO derivatives, allowing for the isolation of positional isomers and other modifications by using reverse-phase high-performance flash chromatography.