Singlet Nitrene Research Articles

Synthesis of Sulfilimines via Visible-Light-Mediated Triplet Energy Transfer to Sulfonyl Azides.

Sulfilimines and their derivatives have garnered considerable interest in both synthetic and medicinal chemistry. Photochemical nitrene transfer to sulfides is known as a conventional synthetic approach to sulfilimines. However, the existing methods have a limited substrate scope stemming from the incompatibility of singlet nitrene intermediates with nucleophilic functional groups. Herein, we report the synthesis of N-sulfonyl sulfilimines via visible-light-mediated energy transfer to sulfonyl azides, uncovering the previously overlooked reactivity of triplet nitrenes with sulfides. This reaction features broad functional group tolerance, water compatibility, and amenability to the late-stage functionalization of drugs. Thus, this work represents an important example of energy transfer chemistry that overcomes challenges in traditional synthetic methods.

Efficient and Robust Dynamic Crosslinking for Compatibilizing Immiscible Mixed Plastics through In Situ Generated Singlet Nitrenes.

Creating a sustainable economy for plastics demands the exploration of new strategies for efficient management of mixed plastic waste. The inherent incompatibility of different plastics poses a major challenge in plastic mechanical recycling, resulting in phase-separated materials with inferior mechanical properties. Here, this study presents a robust and efficient dynamic crosslinking chemistry that effectively compatibilizes mixed plastics. Composed of aromatic sulfonyl azides, the dynamic crosslinker shows high thermal stability and generates singlet nitrene species in situ during solvent-free melt-extrusion, effectively promoting C─H insertion across diverse plastics. This new method demonstrates successful compatibilization of binary polymer blends and model mixed plastics, enhancing mechanical performance and improving phase morphology. It holds promise for managing mixed plastic waste, supporting a more sustainable lifecycle for plastics.

A Photochemical Strategy for the Synthesis of Caprolactams via Dearomative Ring Expansion of Nitroarenes

AbstractThis paper outlines a novel strategy for the preparation of seven-membered-ring lactams from simple nitroarenes. The approach is based on a photochemical dearomative ring expansion starting with the conversion of the nitro group into a singlet nitrene. This process is mediated by blue light, occurs at room temperature and overall enables the insertion of the nitro N-atom into the benzenoid framework. This step transforms the aromatic starting material into a seven-membered ring azepine that, following hydrogenation and hydrolysis, is converted into the desired caprolactams in just three steps.

Aziridination via Nitrogen-Atom Transfer to Olefins from Photoexcited Azoxy-Triazenes.

Herein, we report that readily accessible azoxy-triazenes can serve as nitrogen atom sources under visible light excitation for the phthalimido-protected aziridination of alkenes. This approach eliminates the need for external oxidants, precious transition metals, and photocatalysts, marking a departure from conventional methods. The versatility of this transformation extends to the selective aziridination of both activated and unactivated multisubstituted alkenes of varying electronic profiles. Notably, this process avoids the formation of competing C-H insertion products. The described protocol is operationally simple, scalable, and adaptable to photoflow conditions. Mechanistic studies support the idea that the photofragmentation of azoxy-triazenes results in the generation of a free singlet nitrene. Furthermore, a mild photoredox-catalyzed N-N cleavage of the protecting group to furnish the free aziridines is reported. Our findings contribute to the advancement of sustainable and practical methodologies for the synthesis of nitrogen-containing compounds, showcasing the potential for broader applications in synthetic chemistry.

Synthesis of polysubstituted azepanes by dearomative ring expansion of nitroarenes.

The synthesis of functionalized nitrogen heterocycles is integral to discovering, manufacturing and evolving high-value materials. The availability of effective strategies for heterocycle synthesis often biases the frequency of specific ring systems over others in the core structures of bioactive leads. For example, while the six- and five-membered piperidine and pyrrolidine are widespread in medicinal chemistry libraries, the seven-membered azepane is essentially absent and this leaves open a substantial area of three-dimensional chemical space. Here we report a strategy to prepare complex azepanes from simple nitroarenes by photochemical dearomative ring expansion centred on the conversion of the nitro group into a singlet nitrene. This process is mediated by blue light, occurs at room temperature and transforms the six-membered benzenoid framework into a seven-membered ring system. A following hydrogenolysis provides the azepanes in just two steps. We have demonstrated the utility of the strategy with the synthesis of several azepane analogues of piperidine drugs.

A Photochemical Strategy for ortho-Aminophenol Synthesis via Dearomative-Rearomative Coupling Between Aryl Azides and Alcohols.

ortho-Aminophenols are aromatic derivatives featuring vicinal N- and O-based functionalities commonly found in the structures of many high-value materials. These molecules are generally prepared using multistep strategies that follow the rules of electrophilic aromatic substitution (SE Ar) chemistry. Despite their high fidelity, such approaches cannot target substrates featuring a "contra-SE Ar" arrangement of N- and O-groups. Here we report an alternative strategy for the preparation of such ortho-aminophenols using aryl azides as the precursors. The process utilizes low-energy photoexcitation to trigger the decomposition of aryl azides into singlet nitrenes that undergo a dearomative-rearomative sequence. This allows the incorporation of alcoholic nucleophiles into a seven-membered ring azepine intermediate via temporary disruption of aromaticity, followed by electrophile-induced re-aromatization. The net retrosynthetic logic is that the alcohol displaces the azide, which, in turn, moves to its ortho position and furthermore is converted into an amide. The synthetic value and complementarity of this strategy has been demonstrated by the coupling of aryl azides with complex, drug-like alcohols and phenols as well as amines, thiols and thiophenols, which provides a general platform for the fast and selective heterofunctionalization of aromatics.

Eine photochemische Strategie für die Synthese von ortho‐Aminophenolen durch dearomative‐rearomative Kupplung zwischen Arylaziden und Alkoholen

AbstractOrtho‐Aminophenole sind aromatische Derivate mit vicinalen N‐ und O‐basierten Funktionalitäten, welche häufig in den Strukturen vieler hochwertiger Materialien zu finden sind. Diese Moleküle werden in der Regel durch mehrstufige Synthesen hergestellt, bei denen die Regeln der elektrophilen aromatischen Substitution (SEAr) gefolgt werden. Trotz ihrer hohen Zuverlässigkeit können solche Ansätze nicht auf Substrate abzielen, welche eine “Kontra‐SEAr”‐Anordnung von N‐ und O‐Gruppen aufweisen. Hier berichten wir über eine alternative Strategie für die Herstellung solcher ortho‐Aminophenole unter Verwendung von Arylaziden als Vorstufen. Dieser Prozess verwendet energiearme Photoanregung um die Zersetzung von Arylaziden zu Singulett Nitrenen auzulösen, welche dann eine dearomative‐rearomative Sequenz durchlaufen. Dadurch wird der Einbau von alkoholischen Nukleophilen in ein siebengliedrigen Azepin‐Ring Intermediat durch vorübergehende Unterbrechung der Aromatizität ermöglicht, gefolgt von einer elektrophil‐induzierten Rearomatisierung. Der synthetische Wert und die Komplementarität dieser Strategie wurden durch die Kopplung von Arylaziden mit komplexen, wirkstoffartigen Alkoholen und Phenolen sowie mit Aminen, Thiolen und Thiophenolen nachgewiesen, was eine allgemeine Plattform für die schnelle und selektive Heterofunktionalisierung von Aromaten bietet.

Synthesis and Reactivity of a Cobalt-Supported Singlet Nitrene.

The synthesis, characterization, and reactivity of a series of cobalt terminal imido complexes supported by an N-anchored tripodal tris(carbene) chelate is described, including a Co-supported singlet nitrene. Reaction of the CoI precursor [(TIMMNmes)CoI](PF6) (TIMMNmes = tris-[2-(3-mesityl-imidazolin-2-ylidene)-methyl]amine) with p-methoxyphenyl azide yields a CoIII imide [(TIMMNmes)CoIII(NAnisole)](PF6) (1). Treatment of 1 with 1 equiv of [FeCp2](PF6) at -35 °C affords a formal CoIV imido complex [(TIMMNmes)Co(NAnisole)](PF6)2 (2), which features a bent Co-N(imido)-C(Anisole) linkage. Subsequent one-electron oxidation of 2 with 1 equiv of AgPF6 provides access to the tricationic cobalt imido complex [(TIMMNmes)Co(NAnisole)](PF6)3 (3). All complexes were fully characterized, including single-crystal X-ray diffraction (SC-XRD) analyses, infrared (IR) vibrational, ultraviolet/visible (UV/vis) electronic absorption, multinuclear NMR, X-band electron paramagnetic resonance (EPR), electron nuclear double resonance (ENDOR), and high-energy-resolution fluorescence-detected X-ray absorption spectroscopy (HERFD XAS). Quantum chemical calculations provide additional insight into the electronic structures of all compounds. The dicationic CoIV imido complex 2 exhibits a doublet ground state with considerable imidyl character as a result of covalent Co-NAnisole bonding. At room temperature, 2 readily converts to a CoII amine complex involving intramolecular C-H bond amination. Electronically, tricationic complex 3 can be understood as a singlet nitrene bound to CoIII with significant CoIV imidyl radical character. Verifying the pronounced electrophilicity, nucleophiles such as H2O and tBuNH2 add to 3─analogous to the parent free nitrene─in the para position of the aromatic substituent, thus, clearly corroborating singlet nitrene-type reactivity.

Photochemical Nitrene Transfer Reactions of Iminoiodinanes with Sulfides

AbstractPhotochemical, metal‐free nitrene transfer reactions for C−H amination, aziridination, or sulfilimination are highly desirable. Yet, photochemical sulfilimination reactions of nitrenes with sulfides are underdeveloped as singlet nitrene species would be required for a productive reaction. Herein, we describe the blue‐light‐mediated sulfilimination reaction using iminoiodinanes. We developed a protocol for a highly efficient stoichiometric reaction, which allows for the synthesis of sulfilimines in only 10 minutes reaction time. We further applied our reaction procedure towards allyl sulfides for the synthesis of sulfenamides in a sulfilimination/rearrangement cascade reaction. Moreover, we performed computational calculations and uncovered the participation of a singlet nitrene intermediate, which rapidly reacts with methyl phenyl sulfide to give the desired product.

Di‐ and Trifluorinated 2‐Azidobenzimidazole Derivatives: Synthesis, Photooxygenation, and 19F NMR Prediction

AbstractThe photoreactivity of a series of hitherto unknown, multiply fluorinated 2‐azidobenzimidazole derivatives was investigated. The synthesis of the starting material includes regioselective p‐defluorination of nitrobenzene derivatives employing Ogoshi's conditions. If the 6‐position was unsubstituted, irradiation in the presence of N‐protected amino acids at 300 nm (Rayonet) led to the formation of arylesters by oxygenation of the 6‐position in good to excellent yields and perfect regioselectivity. We did not observe any displacement of fluoride. If the 6‐position itself was fluorinated, alternative positions of the benzene portion were attacked. Mechanistically, the reaction proceeds through ring opening of the singlet nitrene to the cyanodiimine or via the iminobenzimidazolium ion. The availability of a set of fluorinated photo‐adducts prompted the quantum chemical calculation of their 19F NMR chemical shifts. Even with the most suitable method investigated (ωB97XD/TApr‐cc‐pVDZ), deviations of up to 5 ppm from the experimental values were observed, underlining the importance of experimental measurements.

Computational Studies on Reactions of Some Organic Azides with C−H Bonds

AbstractThe computational methods, B3LYP and MP2 with the basis set 6‐311++G(d,p) have been used to decipher the energetics and mechanisms of different nitrene reactions, namely organic azide decomposition, singlet and triplet nitrene addition to different kinds of C−H bonds, azide insertion into C−H bonds and substitution reaction of azides to alkanes. The addition of singlet nitrene to the C−H bond is exothermic, with one‐step addition accompanied by a considerable barrier, where the sequence of facility H>Ac>Me indicates the electrophilic nature of the nitrene reactant. In the case of triplet nitrene, the initial step involves smaller barriers and is endothermic due to the formation of radicals as intermediate products, and the final step involves the coupling of radicals and is hence exothermic. The direct azide addition has higher barrier then the stepwise addition reaction. The Hammond postulate can be used to differentiate the transition state geometries for different reaction steps as “early” or “late”.

On the Reactivity Enhancement of Graphene by Metallic Substrates towards Aryl Nitrene Cycloadditions.

Pristine graphene is fairly inert chemically, and as such, most application-driven studies use graphene oxide, or reduced graphene oxide. Using substrates to modulate the reactivity of graphene represents a unique strategy in the covalent functionalization of this otherwise fairly inert material. It was found that the reactivity of pristine graphene towards perfluorophenyl azide (PFPA) can be enhanced by a metal substrate on which graphene is supported. Results on the extent of functionalization, defect density, and reaction kinetics all show that graphene supported on Ni (G/Ni) has the highest reactivity toward PFPA, followed by G/Cu and then G/silicon wafer. DFT calculations suggest that the metal substrate stabilizes the physisorbed nitrene through enhanced electron transfer to the singlet nitrene from the graphene surface assisted by the electron rich metal substrate. The G/Ni substantially stabilizes the singlet nitrene relative to G/Cu and the free-standing graphene. The product structure is also predicted to be substrate dependent. These findings open up opportunities to enhance the reactivity of pristine graphene simply through the selection of the substrate. This also represents a new and powerful approach to increasing the reactivity of singlet nitrenes through direct electronic communication with graphene.

Insights into the Thermal and Photochemical Reaction Mechanisms of Azidoacetonitrile. Spectroscopic and MS-CASPT2 Calculations.

This work studies the photochemical and thermal decompositions of azidoacetonitrile (N3 CH2 CN) from both the experimental and theoretical points of view. The data of the photochemical experiments are taken from the literature, while the thermal decomposition have been carried out by us. In addition, we have performed ab initio calculations of the multiconfigurational type [complete active space self-consistent field (CASSCF) and the multistate multireference perturbation theory (MS-CASPT2)]. It is found that the first step of both type of decompositions is N2 elimination and formation of closed shell singlet nitrene. Afterwards, the nitrene tends to rapidly rearrange into formimidoyl cyanide (HNCHCN). As both reactions progress, the imine isomerizes into formimidoyl isocyanide (HNCHNC). The photoisomerization of the imine takes places thorough a conical intersection, while the same reaction on the ground electronic state occurs via a conventional transition state. The last step of the global reaction is decomposition of the imines into HCN and CNH. In photochemical conditions, the conjunction of the imines and its dissociation products (HCN and CNH) yields adenine.

Insights into the Photodecomposition of Azidomethyl Methyl Sulfide: A S2/S1 Conical Intersection on Nitrene Potential Energy Surfaces Leading to the Formation of S-Methyl-N-sulfenylmethanimine.

UV photodecomposition of azidomethyl methyl sulfide (AMMS) yields a transient S-methylthiaziridine which rapidly evolves to S-methyl-N-sulfenylmethanimine at 10 K. This species was detected by infrared matrix isolation spectroscopy. The mechanism of the photoreaction of AMMS has been investigated by a combined approach, using low-temperature matrix isolation FTIR spectroscopy in conjunction with two theoretical methods, namely, complete active space self-consistent field and multiconfigurational second-order perturbation. The key step of the reaction is governed by a S2/S1 conical intersection localized in the neighborhood of the singlet nitrene minimum which is formed in the first reaction step of the photolysis, that is, N2 elimination from AMMS. Full assignment of the observed infrared spectra of AMMS has been carried out based on comparison with density functional theory and second-order perturbation Møller-Plesset methods.

Photolysis of 5-Azido-3-Phenylisoxazole at Cryogenic Temperature: Formation and Direct Detection of a Nitrosoalkene.

To enhance the versatility of organic azides in organic synthesis, a better understanding of their photochemistry is required. Herein, the photoreactivity of azidoisoxazole 1 was characterized in cryogenic matrices with IR and UV-Vis absorption spectroscopy. The irradiation (λ = 254 nm) of azidoisoxazole 1 in an argon matrix at 13 K and in glassy 2-methyltetrahydrofuran (mTHF) at 77 K yielded nitrosoalkene 3. Density functional theory (DFT) and complete active space self-consistent field (CASSCF) calculations were used to aid the characterization of nitrosoalkene 3 and to support the proposed mechanism for its formation. It is likely that nitrosoalkene 3 is formed from the singlet excited state of azidoisoxazole 1 via a concerted mechanism or from cleavage of an intermediate singlet nitrene that does not undergo efficient intersystem crossing to its triplet configuration.

A theoretical study of electronic effects in alkyne‐linked reactive intermediates: (nitrenoethynyl)methylenes, (nitrenoethynyl)silylenes, and (nitrenoethynyl)germylenes

Acetylene‐linked reactive intermediates of (nitrenoethynyl)‐X‐methylenes, (nitrenoethynyl)‐X‐silylenes, and (nitrenoethynyl)‐X‐germylenes are almost experimentally unreachable (X–M–C≡C–N; X=H (1), CN (2), OH (3), NH2 (4), NO2 (5), and CHO (6); M=C, Si, and Ge). The effects of the electron‐donating and electron withdrawing groups were compared and contrasted at seven levels of theory. All singlet species as ground states with one local open‐shell singlet carbene subunit (π1π1) and another local open‐shell singlet nitrene subunit (π1π1) were found to be more stable than their corresponding triplets including one local open‐shell singlet carbene (δ1π1) (or one local closed‐shell singlet carbene [δ2π0]) and another local triplet nitrene subunit (π1π1) with 45.94–77.996 kcal/mol singlet–triplet energy gap (ΔEs‐t). Their relative silylenes and germylenes made reduction of ΔEs‐t, so the triplet ground states were found for species 3 Si, 4 Si, 5 Si, 2 Ge, 3 Ge, 4 Ge, and 5 Ge. All the singlet silylenes/germylenes formed by one local closed‐shell singlet silylenes/germylenes (δ2π0) and one local closed‐shell singlet nitrene subunit (π2π0). Also, one local closed‐shell singlet silylene/germylene subunit (δ2π0) and one local triplet nitrene subunit (π1π1) were observed for triplet silylenes/germylenes. The singlet and triplet species 3 Si, 4 Si, 3 Ge, and 4 Ge, due to their electrophilic (Si4/Ge4) and nucleophilic (X5) centers, could be identified as intermediates in chemical reactions.

Trimethylsilylnitrene and Its Surprising Rearrangement to N-(Dimethylsilyl)methanimine via Silaziridine and Silaazomethine Ylide.

Photolysis of trimethylsilyl azide at 254 nm in Ar matrix at 15 K generates the triplet ground state trimethylsilylnitrene 2 aT, observed by ESR spectroscopy (|D/hc|=1.540 cm-1 ; |E/hc|=0.0002 cm-1 ). Calculations at the CASPT2(14,13) level reveal the open-shell singlet nitrene 2 aS(1 A") is a discrete intermediate lying ≈38 kcal mol-1 above the triplet. The normally expected rearrangement of the nitrene 2 aS to dimethylsilanimine 3 a has a high calculated barrier (33 kcal mol-1 ), which explains why this product has never been observed. Instead, the singlet nitrene 2 aS inserts into a methyl C-H bond to yield silaziridine 12 via an activation barrier of only 6 kcal mol-1 . Ring opening of 12 generates a 1-silaazomethine ylide 13, in which a facile 1,2-H shift yields N-(dimethylsilyl)methanimine 5, all with barriers well below the energy of the singlet nitrene.

An ab initio CBS-QB3 quantum chemical study of singlet and triplet sulfonylnitrenes insertion into acetylenes and nitriles

The reactions of methylsulfonylnitrene 1a and trifluoromethylsulfonylnitrene 1b with acetylene 2, dimethylacetylene 3, acetylenedicarboxylic acid 4, hydrogen cyanide 5, acetonitrile 6, cyanoformic acid 7 were studied theoretically at the CBS-QB3 level of theory. The main products of the reaction of triplet sulfonylnitrenes 31 with alkynes 2–4 are 1,2,3-oxathiazole 2-oxides 10 formed from triplet diradical adducts after intersystem crossing (ISC) to their singlet spin-isomers. Products 10 are also formed from singlet nitrenes 11 along with N-vinylidenesulfonamides 9 and 1-(alkylsulfonyl)-1Н-azirines 11. The latter, being antiaromatic, isomerize exothermically to 2-(alkylsulfonyl)-2Н-azirines 12. In a similar way, both singlet and triplet sulfonylnitrenes 1 react with nitriles 5–7 to give 1-(alkylsulfonyl)-1H-diazirines 16. With singlet nitrenes, nitriles 5–7 can also react with the formation of 2-(methylidyne)-1-(alkylsulfonyl)diazan-2-ium-1-ides 14, which undergo either intramolecular 1,3-cyclization to 3-(alkylsulfonyl)-3H-diazirines 17 or intramolecular 1,5-cyclization to 1,2,3,4-oxathiadiazole 2-oxides 15. Relative stability of the key products and activation barriers of their interconversion are discussed.

An N‐Heterocyclic‐Carbene–Tetracyanoethylene Zwitterion: Experimental and Theoretical Study on Its Formation and Reactivity

The direct addition of tetracyanoethylene (TCNE) to the carbene center of 1,3‐bis(2,6‐diisopropylphenyl)imidazol‐2‐ylidene (IPr) was successfully demonstrated. The IPr–TCNE adduct, that is, zwitterion 1, clearly differs from the typical [2+1]‐cycloaddition products obtained from the reaction of carbenes with olefins. The results obtained from experimental and theoretical studies suggest that adduct 1 disassembles into IPr and TCNE, which is followed by the addition of IPr to the nitrile carbon atom of TCNE and subsequent isomerization into a thermodynamically more stable singlet nitrene intermediate. This intermediate is then captured by an additional molecule of TCNE to afford another heterocycle. This study reveals a unique example of the reactivity between N‐heterocyclic carbenes and olefins.

Time-Resolved Infrared (TRIR) Studies of Oxycarbonylnitrenes.

N-Ethyloxycarbonyl-S,S-dibenzothiphene sulfilimine and N-t-butyloxycarbonyl-S,S-dibenzothiphene sulfilimine have been utilized as precursors to ethoxycarbonylnitrene and t-butyloxycarbonylnitrene. B3LYP/6-31G(d) calculations predict triplet ground states for both oxycarbonylnitrenes, albeit by small margins. Triplet ethoxycarbonylnitrene and triplet t-butyloxycarbonylnitrene have been observed following photolysis of these sulfilimine precursors by time-resolved infrared (TRIR) spectroscopy. Kinetic studies show that ethoxycarbonylnitrene reacts with solvents such as acetonitrile and cyclohexane, while t-butyloxycarbonylnitrene undergoes an intramolecular insertion reaction to produce 5,5-dimethyl oxazolidinone. Product analysis following photolysis of N-t-butyloxycarbonyl-S,S-dibenzothiphene sulfilimine confirms that the oxazolidinone is the major product with an estimated yield of 90%. The products from these two nitrenes are derived from the corresponding singlet nitrene, either directly or via thermal repopulation of the singlet from the lower-energy triplet nitrene.