Photoinduced Cycloaddition Research Articles

Photoclick and Release for Spatiotemporally Localized Theranostics of Single Cells via In Situ Generation of 1,3-Diaryl-1H-benzo[f]indazole-4,9-dione.

Bioorthogonal click-release chemistry is a cutting-edge tool for exploring and manipulating biomolecule functions in native biological systems. However, it is challenging to achieve the precise regulation or therapy of individual cells via click-release strategies driven by proximity and thermodynamics. Herein, we propose a novel photoclick-release approach based on a photo-induced cycloaddition between 4,4'-bis(N-arylsydnone) or C-bithienyl-diarylsydnone and 2-arylamino-naphthoquinone via irradiation with 405 or 485 nm light. It constructs 1,3-diaryl-1H-benzo[f]indazole-4,9-dione (BIZON) as a pharmacophore while releases an arylamine for fluorescence turn-on probing. Both photoclick reagents were tailored by connecting to the triphenyl phosphonium delivery motif for enrichment in the mitochondria of live cells. This enables an intracellular photoclick and release under the control of 405 or 485 nm light. We then discovered that the in situ photo-generated BIZON is capable of photosensitizing upon 485 or 520 nm light to produce singlet oxygen inside the mitochondria under aerobic conditions. Therefore, we realized wash-free fluorescence tracking and subsequent anti-cancer efficacy at single-cell resolution using global illumination, which provides a foundation for wavelength-gated single-cell theranostics.

Dearomative Construction of 2D/3D Frameworks from Quinolines via Nucleophilic Addition/Borate-Mediated Photocycloaddition.

Dearomative construction of multiply-fused 2D/3D frameworks, composed of aromatic two-dimensional (2D) rings and saturated three-dimensional (3D) rings, from readily available quinolines has greatly contributed to drug discovery. However, dearomative cycloadditions of quinolines in the presence of photocatalysts usually afford 5,6,7,8-tetrahydroquinoline (THQ)-based polycycles, and dearomative access to 1,2,3,4-THQ-based structures remains limited. Herein, we present a chemo-, regio-, diastereo-, and enantioselective dearomative transformation of quinolines into 1,2,3,4-THQ-based 6-6-4-membered rings without any catalyst, through a combination of nucleophilic addition and borate-mediated [2+2] photocycloaddition. Detailed mechanistic studies revealed that the photoexcited borate complex, generated from quinoline, organolithium, and HB(pin), accelerates the cycloaddition and suppresses the rearomatization that usually occurs in conventional photocycloaddition. Based on our mechanistic analysis, we also developed further photoinduced cycloadditions affording other types of 2D/3D frameworks from isoquinoline and phenanthrene.

Dearomative Construction of 2D/3D Frameworks from Quinolines via Nucleophilic Addition/Borate‐Mediated Photocycloaddition

AbstractDearomative construction of multiply‐fused 2D/3D frameworks, composed of aromatic two‐dimensional (2D) rings and saturated three‐dimensional (3D) rings, from readily available quinolines has greatly contributed to drug discovery. However, dearomative cycloadditions of quinolines in the presence of photocatalysts usually afford 5,6,7,8‐tetrahydroquinoline (THQ)‐based polycycles, and dearomative access to 1,2,3,4‐THQ‐based structures remains limited. Herein, we present a chemo‐, regio‐, diastereo‐, and enantioselective dearomative transformation of quinolines into 1,2,3,4‐THQ‐based 6–6–4‐membered rings without any catalyst, through a combination of nucleophilic addition and borate‐mediated [2+2] photocycloaddition. Detailed mechanistic studies revealed that the photoexcited borate complex, generated from quinoline, organolithium, and HB(pin), accelerates the cycloaddition and suppresses the rearomatization that usually occurs in conventional photocycloaddition. Based on our mechanistic analysis, we also developed further photoinduced cycloadditions affording other types of 2D/3D frameworks from isoquinoline and phenanthrene.

In situ Light‐Writable Orientation Control in Liquid Crystal Elastomer Film Enabled by Chalcones

AbstractLiquid crystal elastomers (LCEs) are stimulus‐responsive materials with intrinsic anisotropy. However, it is still challenging to in situ program the mesogen alignment to realize three‐dimensional (3D) deformations with high‐resolution patterned structures. This work presents a feasible strategy to program the anisotropy of LCEs by using chalcone mesogens that can undergo a photoinduced cycloaddition reaction under linear polarized light. It is shown that by controlling the polarization director and the irradiation region, patterned alignment distribution in a freestanding LCE film can be created, which leads to complex and reversible 3D shape‐morphing behaviors. The work demonstrates an in situ light‐writing method to achieve sophisticated topography changes in LCEs, which has potential applications in encryption, sensors, and beyond.

In situ Light-Writable Orientation Control in Liquid Crystal Elastomer Film Enabled by Chalcones.

Liquid crystal elastomers (LCEs) are stimulus-responsive materials with intrinsic anisotropy. However, it is still challenging to in situ program the mesogen alignment to realize three-dimensional (3D) deformations with high-resolution patterned structures. This work presents a feasible strategy to program the anisotropy of LCEs by using chalcone mesogens that can undergo a photoinduced cycloaddition reaction under linear polarized light. It is shown that by controlling the polarization director and the irradiation region, patterned alignment distribution in a freestanding LCE film can be created, which leads to complex and reversible 3D shape-morphing behaviors. The work demonstrates an in situ light-writing method to achieve sophisticated topography changes in LCEs, which has potential applications in encryption, sensors, and beyond.

Facile access to thieno[2,3-b]thiophenes and poly-substituted thiophenes through divergent annulation of ketene 1,3-dithietanes

A Lewis acid-catalyzed tandem nucleophilic addition/C–S cleavage/intramolecular annulation of ketene 1,3-dithietanes with aldehydes and photo-induced cycloaddition of ketene 1,3-dithietanes with alkynes were developed in this work.

Intramolecular Coumarin-Dimer Containing Polyurethanes: Optical Tuning via Single- and Two-Photon Absorption Processes

The synthesis of an isomer-pure intramolecular coumarin dimer (ICD) in virtually unlimited amounts using a photo flow reactor is described. Based on this compound, polyurethanes with different ratios of hexamethylene diisocyanate and polytetrahydrofuran were synthesized and characterized. The reversibility of the photoinduced cycloaddition and cycloreversion reactions, one of the critical features, was compared for polymers prepared from closed ICDs and open ICDs. It was found that closed ICDs lead to a pre-orientation of the photoactive groups in the polymers, which results in a reduced loss in photoswitchable absorption. By varying the ICD content of the polymers, refractive indices ranging from 1.47 to 1.59 were achieved. With illumination, refractive index changes of Δn ≥ 0.02, as well as fluorescence changes, were achieved. Photoreactions induced by both single-photon absorption (SPA) and two-photon absorption (TPA) were studied. For the TPA-induced reaction, an autocatalytically sensitized mechanism was found. These novel polymers based on an intramolecular dimeric coumarin compound have great potential as optical materials with light-switchable properties, in particular, by TPA processes.

Superfast Tetrazole-BCN Cycloaddition Reaction for Bioorthogonal Protein Labeling on Live Cells.

Here we report the design of a superfast bioorthogonal ligation reactant pair comprising a sterically shielded, sulfonated tetrazole and bicyclo[6.1.0]non-4-yn-9-ylmethanol (BCN). The design involves placing a pair of water-soluble N-sulfonylpyrrole substituents at the C-phenyl ring of diphenyltetrazoles to favor the photoinduced cycloaddition reaction over the competing nucleophilic additions. First-principles computations provide vital insights into the origin of the tetrazole-BCN cycloaddition's superior kinetics compared to the tetrazole-spirohexene cycloaddition. The tetrazole-BCN cycloaddition also enabled rapid bioorthogonal labeling of glucagon receptors on live cells in as little as 15 s.

Action Plots in Action: In-Depth Insights into Photochemical Reactivity.

Predicting wavelength-dependent photochemical reactivity is challenging. Herein, we revive the well-established tool of measuring action spectra and adapt the technique to map wavelength-resolved covalent bond formation and cleavage in what we term "photochemical action plots". Underpinned by tunable lasers, which allow excitation of molecules with near-perfect wavelength precision, the photoinduced reactivity of several reaction classes have been mapped in detail. These include photoinduced cycloadditions and bond formation based on photochemically generated o-quinodimethanes and 1,3-dipoles such as nitrile imines as well as radical photoinitiator cleavage. Organized by reaction class, these data demonstrate that UV/vis spectra fail to act as a predictor for photochemical reactivity at a given wavelength in most of the examined reactions, with the photochemical reactivity being strongly red shifted in comparison to the absorption spectrum. We provide an encompassing perspective of the power of photochemical action plots for bond-forming reactions and their emerging applications in the design of wavelength-selective photoresists and photoresponsive soft-matter materials.

(Invited) Photoluminescence Study of Carbon Nanomaterial Interactions with the Immune System

Carbon nanomaterials such as graphene and carbon nanotubes have attracted tremendous attention for various applications in science and technology. However, increasing use of carbon nanomaterials also necessitates careful scrutiny of their impact on human health. Understanding their interactions with different components of the innate immune system is of particular importance.Myeloperoxidase (MPO), a key enzyme released by neutrophils during inflammation, has been shown to catalyze the biodegradation of carbon nanomaterials. We investigated the changes in photoluminescence (PL) properties of graphene oxide (GO) and single-walled carbon nanotubes (SWCNT) during MPO degradation. Increased fluorescence emission was observed with the progression of enzymatic oxidation of GO as a result of the formation of graphene quantum dots (GQDs). In contrast, the fluorescence of surfactant-coated SWCNT was either quenched or remained almost unchanged (depending on the surfactant used) during 5-day degradation. The two different PL systems were combined as SWCNT/GO nanoscrolls into ratiometric fluorescence sensors to monitor MPO activity.Lipid metabolites play an important role in the immune response. We demonstrated a photo-induced cycloaddition reaction between oxygenated lipid metabolites containing enone functional group and SWCNTs. By creating covalent and tunable sp3 defects in the sp2 carbon lattice of SWCNTs, this photochemical reaction results in the gradual appearance of the bright red-shifted near-IR photoluminescence in SWCNTs.

2π + 2π] Photocycloaddition of Enones to Single-Walled Carbon Nanotubes Creates Fluorescent Quantum Defects.

Single-walled carbon nanotubes (SWCNTs) have been widely applied in biomedical fields such as drug delivery, biosensing, bioimaging, and tissue engineering. Understanding their reactivity with biomolecules is important for these applications. We describe here a photoinduced cycloaddition reaction between enones and SWCNTs. By creating covalent and tunable sp3 defects in the sp2 carbon lattice of SWCNTs through [2π + 2π] photocycloaddition, a bright red-shifted photoluminescence was gradually generated. The photocycloaddition functionalization was demonstrated with various organic molecules bearing an enone functional group, including biologically important oxygenated lipid metabolites. The mechanism of this reaction was studied empirically and using computational methods. Density functional theory calculations were employed to elucidate the identity of the reaction product and understand the origin of different substrate reactivities. The results of this study can enable engineering of the optical and electronic properties of semiconducting SWCNTs and provide understanding into their interactions with the lipid biocorona.

Phase-transfer catalysis and the ion pair concept

AbstractThis review outlines the recent advances in the field of asymmetric phase-transfer catalysis and the ion-pair concept including alkylation of amino acids and peptides, oxyindoles and other substrates, conjugate additions, fluorinations, photo-induced phase-transfer catalysis, Nitro-Mannich reactions, heterocyclizations and cycloadditions for the preparation of heterocycles, derivatization of isoxazoles, umpolung conjugate addition of imines and other three asymmetric reactions.

Fluorescent bioorthogonal labeling of class B GPCRs in live cells.

In this method paper, we describe the protocols for selective labeling of GCGR, a member of the class B GPCR family regulating glucose homeostasis, in live cells. A two-step procedure is presented in which a strained alkene chemical reporter is inserted into any desired location within the GPCR in the first step, followed by a robust bioorthogonal ligation reaction with a fluorophore-conjugated tetrazine or tetrazole reagent in the second step. The amber codon suppression strategy was adopted for site-specific incorporation of the strained alkene reporter, either spirohexene or trans-cyclooctene, in HEK293T cells. Subsequently, the inverse electron-demand Diels-Alder reaction with an AF647-conjugated 3,6-di (2-pyridyl)-S-tetrazine (DpTz) was performed with the alkene-encoded GCGR on live-cell surface. Alternatively, a photo-induced cycloaddition with a Cy5-conjugated, sterically shielded tetrazole was carried out, giving rise to faster fluorescent labeling along with excellent selectivity. Owing to their robust reaction kinetics and excellent chemoselectivity, the bioorthogonal labeling protocols described here could be readily adapted to labeling any accessible protein targets, e.g., membrane proteins, in live cells.

Bimodal role of fluorine atoms in fluorographene chemistry opens a simple way toward double functionalization of graphene

Photo-triggered and double functionalization of graphene without use of aggressive photo-generated radicals is a challenging task in two-dimensional chemistry. This was here-in achieved by unravelling the bimodal role of fluorine atoms in fluorographene chemistry: (i) they rendered graphene's double bonds susceptible to reaction with a photo-activated diene and (ii) allowed nucleophilic substitution on F-bonded carbons. Theoretical calculations indicated that the presence of F atoms in the vicinity of sp2 carbon domains significantly increased bond polarization, turning the otherwise unfeasible on pristine graphene photo-cycloaddition into a very efficient functionalization strategy. Following this strategy, we prepared new graphene derivatives densely and homogeneously covered by functional groups. Furthermore, photo-induced cycloaddition following amine nucleophilic substitution on fluorographene enabled preparation of a bis-functionalized graphene derivative. The reported procedure paves the way toward unexplored graphene derivatives not attainable through known graphene chemistries, which can be utilized in many applications such as dual read-out sensors, drug delivery systems, catalysis, and energy storage.

Theoretical studies on photo-induced cycloaddition and (6-4) reactions of the thymidine:4-thiothymidine dimer in a DNA duplex.

Thio-substituted nucleobases have received long-standing interest from experimental and theoretical scientists due to their potential applications in photodynamic therapy and crosslinking studies. Though the thymidine:4-thiothymidine dimer is an important structure in the DNA duplex, the molecular-level photoreaction mechanisms are still obscure. Herein, high-level QM/MM methods were adopted to investigate the photoinduced cycloaddition and (6-4) reactions of the thymidine:4-thiothymidine dimer in the DNA duplex, namely, d(ACCT(4ST)CGC:TGGAAGCG). Based on the calculated results, we identified five efficient nonadiabatic decay pathways to populate the T1 state from the initially occupied S2 state of Tp4ST via two crucial intersection structures, i.e., S2/S1 and S2/T2/S1/T1. Such photophysical processes are mainly localized on the 4-thiothymidine chromophore. After hopping to the T1 state, the light-induced [2+2] cycloaddition reaction could take place via a stepwise and nonadiabatic reaction pathway, which starts from Tp4ST via T1cc or T1cs intermediates in the T1 state and ends up with S5-thietane in the S0 state. By contrast, the concerted and thermal cycloaddition pathway in the ground state has a remarkable energy barrier, which is mechanistically less important. The subsequent generation of S5-(6-4) from S5-thietane is a concerted process in the S0 state with the simultaneous fission of the C4-S8 bond and the formation of the S8-H9 bond. In the end, we believe our present work will provide important mechanistic insights into photo-isomerization of thio-substituted nucleobases in DNA duplexes.

Photoinduced cycloaddition of biomass derivatives to obtain high-performance spiro-fuel

A self-sensitized [2 + 2] cycloaddition process is developed to convert biomass-derived β-pinene and isophorone to high-performance spiro-fuel, which possesses high density and excellent cryogenic properties.

DNA‐Templated [2+2] Photocycloaddition: A Straightforward Entry into the Aplysinopsin Family of Natural Products

AbstractBiosynthetic considerations inspired us to harness the templating properties offered by DNA to promote a [2+2] photoinduced cycloaddition. The method was developed based on the dimerization of (E)‐aplysinopsin, which was previously shown to be unproductive in solution. In sharp contrast, exposure of this tryptophan‐derived olefin to light in the presence of salmon testes DNA (st‐DNA) reproducibly afforded the corresponding homo‐dimerized spiro‐fused cyclobutane in excellent yields. DNA provides unique templating interactions enabling a singular mimic of the solid‐state aggregation necessary for the [2+2] photocycloaddition to occur. This method was ultimately used to promote the prerequisite dimerizations leading to both dictazole B and tubastrindole B, thus constituting the first example of a DNA‐mediated transformation to be applied to the total synthesis of a natural product.

DNA-Templated [2+2] Photocycloaddition: A Straightforward Entry into the Aplysinopsin Family of Natural Products.

Biosynthetic considerations inspired us to harness the templating properties offered by DNA to promote a [2+2] photoinduced cycloaddition. The method was developed based on the dimerization of (E)-aplysinopsin, which was previously shown to be unproductive in solution. In sharp contrast, exposure of this tryptophan-derived olefin to light in the presence of salmon testes DNA (st-DNA) reproducibly afforded the corresponding homo-dimerized spiro-fused cyclobutane in excellent yields. DNA provides unique templating interactions enabling a singular mimic of the solid-state aggregation necessary for the [2+2] photocycloaddition to occur. This method was ultimately used to promote the prerequisite dimerizations leading to both dictazole B and tubastrindole B, thus constituting the first example of a DNA-mediated transformation to be applied to the total synthesis of a natural product.

Regulated basal and bolus insulin release from glucose-responsive core-shell microspheres based on concanavalin A-sugar affinity

Individual insulin therapy considering the heterogeneity of insulin resistance between patients may bring more benefits than conventional therapy. Therefore, in glucose-responsive insulin delivery systems, more attention should be paid on further regulation of insulin release to meet individual requirements. Our study shows the feasibility of using a photo-crosslinkable shell layer to regulate basal and bolus insulin release from glucose-responsive Con A-polysaccharides network. Core-shell microspheres were fabricated through a two-step high-speed shear-emulsification method. The morphology was observed by SEM and TEM, and the core-shell structure was confirmed by the differences in chemical composition between core-shell and single-layer microspheres obtained from XPS and IR analysis. In vitro insulin release test revealed that the core-shell microspheres with or without light-irradiation could maintain corresponding bolus and basal insulin release in response to different glucose concentration but enable much lower burst release compared with single-layer microspheres without shell. Meanwhile, insulin release rate and amount could be further decreased upon light-irradiation owing to the photo-induced cycloaddition of cinnamate pendant groups of the shell material. The released insulin was proved to remain active according to fluorescence and circular dichroism analysis. The HDF cell viability assessment suggested that the core-shell microspheres possessed no in vitro cytotoxicity.

Design of Redox/Radical Sensing Molecules via Nitrile Imine-Mediated Tetrazole-ene Cycloaddition (NITEC).

The current study introduces a novel synthetic avenue for the preparation of profluorescent nitroxides via nitrile imine-mediated tetrazole-ene cycloaddition (NITEC). The photoinduced cycloaddition was performed under metal-free, mild conditions allowing the preparation of a library of the nitroxide functionalized pyrazolines and corresponding methoxyamines. High reaction rates and full conversion were observed, with the presence of the nitroxide having no significant impact on the cycloaddition performance. The formed products were investigated with respect to their photophysical properties in order to quantify their "switch on/off" behavior. The fluorescence quenching performance is strongly dependent on the distance between the chromophore and the free radical spin as demonstrated theoretically and experimentally. Highest levels of fluorescence quenching were achieved for pyrazolines with the nitroxide directly fused to the chromophore. Importantly, the pyrazoline profluorescent nitroxides were shown to efficiently act as sensors for redox/radical processes.