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

Density Functional Theory Studies of Negishi Alkyl–Alkyl Cross-Coupling Reactions Catalyzed by a Methylterpyridyl-Ni(I) Complex

Density functional theory calculations were done to examine the potential energy surfaces of Ni(I)-catalyzed Negishi alkyl–alkyl cross-coupling reactions by using propyl iodide and isopropyl iodide as model alkyl electrophiles and CH3ZnI as a model alkyl nucleophile. A four-step catalytic cycle involving iodine transfer, radical addition, reductive elimination, and transmetalation steps were characterized structurally and energetically. The reaction mechanism for this catalytic cycle appears feasible based on the calculated free energy profiles for the reactions. The iodine transfer step is the rate-determining step for the Ni(tpy)-CH3 (tpy = 2,2′6′,2″-terpyridine) reactions with alkyl iodides. For secondary alkyl electrophiles, the oxidative addition intermediate, Ni(III), prefers to undergo decomposition over reductive elimination, whereas for the primary alkyl electrophiles, Ni(III) prefers to undergo reductive elimination over decomposition based on comparison of the relative reaction rates for these two types of steps. In addition, thermodynamic data were employed to help explain why the yield of the coupled product is very low from the Ni(II)-alkyl halide reactions with organozinc reagents

Density Functional Theory Investigation of the Reactions of Isodihalomethanes (CH₂X−X Where X = Cl, Br, or I) with Ethylene: Substituent Effects on the Carbenoid Behavior of the CH₂X−X Species

We investigated the chemical reactions of isodihalomethane (CH2X−X) and CH2X radical species (where X = Cl, Br, or I) with ethylene and the isomerization reactions of CH2X−X using density functional theory calculations. The CH2X−X species readily reacts with ethylene to give the cyclopropane product and an X2 product via a one-step reaction with barrier heights of ∼2.9 kcal/mol for CH2I−I, 6.8 kcal/mol for CH2Br−Br, and 8.9 kcal/mol for CH2Cl−Cl. The CH2X reactions with ethylene proceed via a two-step reaction mechanism to give a cyclopropane product and X atom product with much larger barriers to reaction. This suggests that photocyclopropanation reactions using ultraviolet excitation of dihalomethanes most likely occurs via the isodihalomethane species and not the CH2X species. The isomerization reactions of CH2X−X had barrier heights of ∼14.4 kcal/mol for CH2I−I, 11.8 kcal/mol for CH2Br−Br, and 9.1 kcal/mol for CH2Cl−Cl. We compare our results for the CH2X−X carbenoids to results from previous calculations of the Simmons−Smith-type carbenoids (XCH2ZnX) and Li-type carbenoids (LiCH2X) and discuss their differences and similarities as methylene transfer agents

To Photoredox or Not in Neutral Aqueous Solutions for Selected Benzophenone and Anthraquinone Derivatives

The experimental and theoretical results in neutral aqueous solutions reported here indicate that a proton-coupled electron transfer (PCET) from an alcohol C–H bond to the para-carbonyl is the initial and crucial process for the photoredox reaction of 2-(1-hydroxyethyl)-anthraquinone (HEAQ) to occur while the counterpart 3-(hydroxymethyl)-benzophenone (3-BPOH) compound displays a different PCET from an alcohol O–H bond to the carbonyl as the first step, followed by an intersystem crossing process that does not lead to the analogous photoredox, which is caused by a subtle charge-radical coupled effect between HEAQ and 3-BPOH. This can account for experimental results in the literature that HEAQ can undergo efficient photoredox but 3-BPOH does not under neutral aqueous conditions. These results have implications for the pH-dependent photochemical behavior of aromatic carbonyl compounds in aqueous media

Samarium(III) Carbenoid as a Competing Reactive Species in Samarium-Promoted Cyclopropanation Reactions

The trivalent samarium carbenoid I2SmCH2I-promoted cyclopropanation reactions with ethylene have been investigated and are predicted to be highly reactive, similarly to the divalent samarium carbenoid ISmCH2I. The methylene transfer and carbometalation pathways were explored and compared with and without coordination of THF solvent molecules to the carbenoid. The methylene transfer was found to be favored, with the barrier to reaction going from 12.9 to 9.2 kcal/mol compared to barriers of 15.4−17.5 kcal/mol for the carbometalation pathway upon the addition of one THF molecule

Methylene Transfer or Carbometalation? A Theoretical Study to Determine the Mechanism of Lithium Carbenoid-Promoted Cyclopropanation Reactions in Aggregation and Solvation States

Density functional theory calculations for the lithium carbenoid-promoted cyclopropanations in aggregation and solvation states are presented in order to investigate the controversy of the mechanistic dichotomy, that is, the methylene-transfer mechanism and the carbometalation mechanism. The methylene-transfer mechanism represents the reaction reality, whereas the carbometalation pathway does not appear to compete significantly with the methylene-transfer pathway and should be ruled out as a major factor. A simple model calculation for monomeric lithium carbenoid-promoted cyclopropanations with ethylene in the gas phase is not sufficient to reflect the reaction conditions accurately or to determine the reaction mechanism since its result is inconsistent with the experimental facts. The aggregated lithium carbenoids are the most probable reactive species in the reaction system. The calculated reaction barriers of the methylene-transfer pathways are 10.1 and 8.0 kcal/mol for the dimeric (LiCH2F)2 and tetrameric (LiCH2F)4 species, respectively, compared with the reaction barrier of 16.0 kcal/mol for the monomeric LiCH2F species. In contrast, the reaction barriers of the carbometalation pathways are 26.8 kcal/mol for the dimeric (LiCH2F)2 and 33.9 kcal/mol for the tetrameric (LiCH2F)4 species, compared with the reaction barrier of 12.5 kcal/mol for the monomeric LiCH2F species. The effects of solvation were investigated by explicit coordination of the solvent molecules to the lithium centers. This solvation effect is found to enhance the methylene-transfer pathway, while it is found to impede the carbometalation pathway instead. The combined effects of the aggregation and solvation lead to barriers to reaction in the range of 7.2−9.0 kcal/mol for lithium carbenoid-promoted cyclopropanation reactions along the methylene-transfer pathway. Our computational results are in good agreement with the experimental observations

A Theoretical Study of Divalent Lanthanide (Sm and Yb) Complexes with a Triazacyclononane-Functionalized Tetramethylcyclopentadienyl Ligand

A density functional theory (DFT) study of the divalent lanthanide complexes [C5Me4SiMe2(iPr2-tacn)]LnI (Ln = Sm, Yb; tacn = 1,4-diisopropyl-1,4,7-triazacyclononane) is presented. A methodological study was done with various density functionals that employ large-core ECPs for the lanthanide atoms. The DFT results were compared with recent experimental X-ray structures for the compounds investigated here. The B3PW91 functional was found to give the best description of the complexes at an affordable level of computational effort. The geometry of the [C5Me4SiMe2(iPr2-tacn)]LnI complexes was found to be a distorted trigonal bipyramidal and the essential structural features are correctly reproduced from the DFT calculations. Further model studies show that the computations can be simplified by replacing the methyl groups (which do not interact with the lanthanide center directly) with hydrogen atoms to still provide reasonable predictions for the structure of the complex

Theoretical Study of Samarium (II) Carbenoid (ISmCH₂I) Promoted Cyclopropanation Reactions with Ethylene and the Effect of THF Solvent on the Reaction Pathways

A computational study of the cyclopropanation reactions of divalent samarium carbenoid ISmCH2I with ethylene is presented. The reaction proceeds through two competing pathways:  methylene transfer and carbometalation. The ISmCH2I species was found to have a “samarium carbene complex” character with properties similar to previously investigated lithium carbenoids (LiCH2X where X = Cl, Br, I). The ISmCH2I carbenoid was found to be noticeably different in structure with more electrophilic character and higher chemical reactivity than the closely related classical Simmons−Smith (IZnCH2I) carbenoid. The effect of THF solvent was investigated by explicit coordination of the solvent THF molecules to the Sm (II) center in the carbenoid. The ISmCH2I/(THF)n (where n = 0, 1, 2) carbenoid methylene transfer pathway barriers to reaction become systematically lower as more THF solvent is added (from 12.9 to 14.5 kcal/mol for no THF molecules to 8.8 to 10.7 kcal/mol for two THF molecules). In contrast, the reaction barriers for cyclopropanation via the carbometalation pathway remain high (>15 kcal/mol). The computational results are briefly compared to other carbenoid reactions and related species

A Density Functional Theory Study of the 5-Exo Cyclization Reactions of α-Substituted 6,6-Diphenyl-5-hexenyl Radicals

Density functional theory computations were done to study the 5-exo radical cyclization reactions of α-substituted 6,6-diphenyl-5-hexenyl radicals. The methoxy electron donor group substitution reduced the barrier to reaction by about 0.5 kcal/mol. On the other hand, the electron acceptor group substitutions (ethoxycarbonyl, carboxylic acid, carboxylate, and cyano) raised the barrier to reaction by varying amounts (0.5−2.1 kcal /mol). The entropic terms of these cyclization reactions are briefly discussed. Solvent effects on these reactions were explored by calculations that included a polarizable continuum model for the solvent. The density functional theory calculated results were found to be in good agreement with the experimental data available in the literature and help to explain some of the observed variation in these types of cyclization reactions with various substitutions. Our results also provide an explanation for why the rate constant for the carboxylate group substituted radical was found to be an order of magnitude smaller than the rate constant for those radicals with carboxylic acid and ethoxycarbonyl substitutions

A Theoretical Study of the Mechanism of the Water-Catalyzed HCl Elimination Reactions of CHXCl(OH) (X = H, Cl) and HClCO in the Gas Phase and in Aqueous Solution

A systematic ab initio investigation of the water-assisted decomposition of chloromethanol, dichloromethanol, and formyl chloride as a function of the number of water molecules (up to six) building up the solvation shell is presented. The decomposition reactions of the chlorinated methanols and formyl chloride are accelerated substantially as the reaction system involves additional explicit coordination of water molecules. Rate constants for the decomposition of chlorinated methanols and formyl chloride were found to be in reasonable agreement with previous experimental observations of aqueous phase decomposition reactions of dichloromethanol [CHCl2(OH)] and formyl chloride. For example, using the calculated activation free energies in conjunction with the stabilization free energies from the ab initio calculations, the rate constant was predicted to be 1.2−1.5 × 104 s-1 for the decomposition of formyl chloride in aqueous solution. This is in good agreement with the experimental rate constant of about 104 s-1 reported in the literature. The mechanism for the water catalysis of the decomposition reactions as well as probable implications for the decomposition of these chlorinated methanol compounds and formaldehydes in the natural environment and as intermediates in advanced oxidation processes are briefly discussed