Dynamics of Oxygen-Independent Photocleavage of Blebbistatin as a One-Photon Blue or Two-Photon Near-Infrared Light-Gated Hydroxyl Radical Photocage

Development of versatile, chemically tunable photocages for photoactivated chemotherapy (PACT) represents an excellent opportunity to address the technical drawbacks of conventional photodynamic therapy (PDT) whose oxygen-dependent nature renders it inadequate in certain therapy contexts such as hypoxic tumors. As an alternative to PDT, oxygen free mechanisms to generate cytotoxic reactive oxygen species (ROS) by visible light cleavable photocages are in demand. Here, we report the detailed mechanisms by which the small molecule blebbistatin acts as a one-photon blue light-gated or two-photon near-infrared light-gated photocage to directly release a hydroxyl radical (•OH) in the absence of oxygen. By using femtosecond transient absorption spectroscopy and chemoselective ROS fluorescent probes, we analyze the dynamics and fate of blebbistatin during photolysis under blue light. Water-dependent photochemistry reveals a critical process of water-assisted protonation and excited state intramolecular proton transfer (ESIPT) that drives the formation of short-lived intermediates, which surprisingly culminates in the release of •OH but not superoxide or singlet oxygen from blebbistatin. CASPT2//CASSCF calculations confirm that hydrogen bonding between water and blebbistatin underpins this process. We further determine that blue light enables blebbistatin to induce mitochondria-dependent apoptosis, an attribute conducive to PACT development. Our work demonstrates blebbistatin as a controllable photocage for •OH generation and provides insight into the potential development of novel PACT agents

Two Photon Dissociation Dynamics of NO₂ and NO₂ + H₂O

To explore the dynamics of OH formation from two photon absorbed NO2 with H2O, a high-level multiconfigurational perturbation theory was used to map the potential energy profiles of NO2 dissociation to O (1D) + NO (X̃2Π), and subsequent hydrogen abstraction producing 2OH (X̃2Π) + NO (X̃2Π) in the highly excited SPP (Ẽ2A′, 2ππ*) state. The ground state NO2 is promoted to populate in the SNP1 (Ã2A″, 2nπ*) intermediate state by one photon absorption at ∼440 nm, one thousandth of which is further excited to SPP (Ẽ2A′, 2ππ*) state and undergoes a medium-sized barrier (∼11.0 kcal/mol) to give rise to OH radicals. In comparison with the hydrogen abstraction reaction in highly vibrationally excited NO2 ground state, two photon absorption facilitates NO2 dissociation to O (1D) and O (1D) + H2O → 2OH (X̃2Π) but results in low quantum yield of NO2** since there is a weak absorption upon the second beam light at ∼440 nm. It can be concluded that the reaction of two photon absorbed NO2 with H2O makes negligible contributions to the formation of OH radicals. In contrast, single photon absorption at <554 nm is a possible process on the basis of the present and previous computations

Ground-State Intermolecular Proton Transfer of N₂O₄ and H₂O: An Important Source of Atmospheric Hydroxyl Radical?

To evaluate the significance of the generation of atmospheric hydroxyl radical from reaction of N₂O₄ with H₂O, CASPT2//CASSCF as well as CASPT2//CASSCF/Amber QM/MM approaches were employed to map the minimum-energy profiles of sequential reactions, NO₂ dimerization and ground-state intermolecular proton transfer of <i>trans</i>-ONONO₂ as well as the photolysis of HONO. A highly efficient ground-state intermolecular proton transfer of <i>trans</i>-ONONO₂ is found to dominate the generation of hydroxyl radical under atmospheric conditions. Although proton transfer occurs with high efficiency, the precursor reaction of dimerization producing <i>trans</i>-ONONO₂ has to overcome a 17.1 kcal/mol barrier and cannot compete with the barrierless channel of symmetric O₂N–NO₂ formation from isolated NO₂ monomers. Our computations reveal that the photolysis of HONO without a barrier definitely makes significant contributions to the concentration of the atmospheric hydroxyl radical, but its importance is influenced by the lack of <i>trans</i>-ONONO₂ isomer in the atmospheric environment

Nonadiabatic Curve-Crossing Model for the Visible-Light Photoredox Catalytic Generation of Radical Intermediate via a Concerted Mechanism

Photoredox catalysis relies on the excited-state single-electron transfer (SET) processes to drive a series of unique bond-forming reactions. In this work accurate electronic structure calculations at the CASPT2//CASSCF/PCM level of theory together with the kinetic assessment of SETs and intersystem crossing are employed to provide new insights into the SET initiation, activation, and deactivation by calculating the SET paths for a paradigm example of photoredox α-vinylation reaction mediated by iridium­(III) catalysts. The concerted photocatalysis mechanism described by the nonadiabatic curve-crossing model, in essence of Marcus electron transfer theory, is first applied for the mechanistic description of the SET events in visible-light photoredox catalysis. The C–C bond functionalization has been revealed to take place in a concerted manner along an energy-saving pathway, in which the generated α-amino radical is unlikely independent existence but strongly depends on the mutual interaction with different substrates. These mechanistic insights offer a plausible picture for the excited-state SET-mediated chemical transformations that should be applicable to further studies of photoredox catalysis in organic chemistry

<i>ON–OFF</i> Mechanism of a Fluorescent Sensor for the Detection of Zn(II), Cd(II), and Cu(II)Transition Metal Ions

An ab initio multiconfigurational (CASPT2//CASSCF) approach has been employed to map radiative and nonradiative relaxation pathways for a cyclam-methylbenzimidazole fluorescent sensor and its metal ion (Zn²⁺, Cd²⁺, and Cu²⁺) complexes to provide an universal understanding of <i>ON</i>–<i>OFF</i> fluorescent mechanisms for the selective identification of these metal ions. The photoinduced electron transfer (PET) between the receptor and the signaling unit is quantitatively attributed for the first time to a newly generated transition of S₀→S_CT(¹nπ*), which is a typical ¹nπ* excitation but exhibits a significant charge transfer character and zwitterionic radical configuration. The present study contributes the two theoretical models of the competitive coexistence of radiative/nonradiative decay channel in ¹ππ*/S_CT(¹nπ*) states for the detection of metal ions with d¹⁰ configuration (i.e., Zn²⁺, Cd²⁺, etc.) and a downhill ladder relaxation pathway through multi nona-diabatic relays for the probing of d⁹ cations (Cu²⁺, etc.). These computational results will establish a benchmark for <i>ON</i>–<i>OFF</i> mechanisms of a fluorescent sensor that coordinates various transition metal ions with different electron configuration and radius

Mechanism of the Enantioselective Intramolecular [2 + 2] Photocycloaddition Reaction of Coumarin Catalyzed by a Chiral Lewis Acid: Comparison with Enone Substrates

The asymmetric catalysis of the intramolecular enone [2 + 2] photocycloaddition reaction relies on a complicated regulation mechanism to control its reactivity and selectivity as well as quantum yield. The multiconfiguration perturbation theory associated with energy-consistent relativistic pseudopotentials offers a mechanistic comparison between representative coumarin and enone substrates. A pair of bright ππ* states govern the unselective background reaction of the free coumarin through the direct cycloaddition in the singlet hypersurface and the elimination of the reaction channel in the triplet manifold due to the existence of anti El Sayed type singlet–triplet crossing. The opening of a reaction channel in the triplet state is repeatedly verified to depend on the presence of relativistic effects, i.e., spin–orbit coupling due to heavy atoms in the chiral Lewis acid catalyst

Ultrafast Asynchronous Concerted Excited-State Intramolecular Proton Transfer and Photodecarboxylation of <i>o</i>-Acetylphenylacetic Acid Explored by Combined CASPT2 and CASSCF Studies

Photodecarboxylation was found to be an ultrafast process for o-acetylphenylacetic acid, which is triggered by excited-state intramolecular proton transfer. The reaction starts from the charge-transfer ππ* singlet state and passes through the conical intersection to the ground state. Subsequent electron transfer and proton transfer in the ground state lead to formation of the final products. This represents a completely new mechanism of photoinduced decarboxylation for various arylcarboxylic acids

Regulatory Mechanism and Kinetic Assessment of Energy Transfer Catalysis Mediated by Visible Light

The visible-light-mediated energy transfer catalysis plays a pivotal role in the photochemical synthesis. Although many significant advances in this field have been achieved within the past decade, the knowledge of the photochemically tunable metal–ligand interaction for photocatalysts, the manipulation principle of excited-state properties, and the available electronic excitation for the free and bound substrates, which makes it possible to design some photo- and auxiliary catalysts based on the proposed mechanism, is still sparse. In the present work, we investigated the paradigm example of intermolecular [2 + 2] photocycloaddition reactions for 2′-hydroxychalcones coordinated by the chiral Lewis acids, using tris­(bipyridyl) ruthenium­(II) as a photosensitizer. The electronic structure calculations at the CASPT2//CASSCF/PCM level of theory, as well as the kinetic assessment of energy transfer process using the Fermi’s golden rule and the Dexter model, were performed to provide useful benchmarks for the elucidation of energy transfer photocatalysis. The excitation properties for the enone substrate are photochemically tunable in the presence of various metal ion based chiral Lewis acids, which rules out the background reaction of excited state intramolecular proton transfer (ESIPT). The preferable photosensitized pathway with dual catalysts can be also regulated cooperatively as a priority by the introduction of high valence d0 ions that notably decreases the triplet energy for the photocatalysis reaction but without an efficient improvement on the intersystem crossing rate of metal-chelated substrates. Our kinetic evaluation method, which has been applied to different catalysis systems, reveals various factors that determine the energy transfer efficiency, including the rigidity of substrate-chiral Lewis acid complexes, the reasonable triplet energy gap between donor and acceptor, the molecular orientation of complexes, and the electronic characters of triplet excited states

pH- and Wavelength-Dependent Photodecarboxylation of Ketoprofen

The pH- and wavelength-dependent pathways for the photodecarboxylation of ketoprofen (KP) were mapped by CASSCF/CASPT2 computations. The decarboxylation of the basic form (KP–) was found to start from a long-distance charge transfer (CT) excited state when populated by photoexcitation at 330 nm. A short-distance CT excited state populated with photoexcitation at λ 2O molecules function as a bridge to assist proton transfer in the reactions examined here

Theoretical Insight into the Photodegradation of a Disulfide Bridged Cyclic Tetrapeptide in Solution and Subsequent Fast Unfolding−Refolding Events

We report the photoinduced peptide bond (C−N) of an amide unit and S−S bond fission mechanisms of the cyclic tetrapeptide [cyclo(Boc-Cys-Pro-Aib-Cys-OMe)] in methanol solvent by using high-level CASSCF/CASPT2/Amber quantum mechanical/molecular mechanical (QM/MM) calculations. The subsequent energy transport and unfolding−refolding events are characterized by using a semiempirical QM/MM molecular dynamics (MD) simulation methodology that is developed in the present work. In the case of high-energy excitation with 1nπ* surface overcomes two barriers with ∼10.0 kcal/mol, respectively, and uses energy consumption for breaking the hydrogen bond as well as the N−C bond in the amide unit, ultimately leading to the ground state via a conical intersection of CI (SNP/S0) by structural changes of an increased N−C distance and a O−C−C angle in the amide unit (a two-dimensional model of the reaction coordinates). Following this point, relaxation to a hot molecule with its original structure in the ground state is the predominant decay channel. A large amount of heat (∼110.0 kcal/mol) is initially accumulated in the region of the targeted point of the photoexcitation, and more than 60% of the heat is rapidly dissipated into the solvent on the femtosecond time scale. The relatively slower propagation of heat along the peptide backbone reaches a phase of equilibration within 3 ps. A 300 nm photon of light initiates the relaxation along the repulsive Sσσ(1σσ*) state and this decays to the CI (Sσσ/S0) in concomitance with the separation of the disulfide bond. Once cysteinyl radicals are generated, the polar solvent of methanol molecules rapidly diffuses around the radicals, forming a solvent cage and reducing the possibility of close contact in a physical sense. The fast unfolding−refolding event is triggered by S−S bond fission and powered by dramatic thermal motion of the methanol solvent that benefits from heat dissipation. The β-turn opening (unfolding) can be achieved in about 120 ps without the inclusion of the time associated with the photochemical steps and eventually relaxes to a 310-helix structural architecture (refolding) within 200 ps