Asymmetric Photochemical [2 + 2]-Cycloaddition of Acyclic Vinylpyridines through Ternary Complex Formation and an Uncontrolled Sensitization Mechanism.

Stereochemical control of photochemical reactions that occur via triplet energy transfer remains a challenge. Suppressing off-catalyst stereorandom reactivity is difficult for highly reactive open-shell intermediates. Strategies for suppressing racemate-producing, off-catalyst pathways have long focused on formation of ground state, substrate-catalyst chiral complexes that are primed for triplet energy transfer via a photocatalyst in contrast to their off-catalyst counterparts. Herein, we describe a strategy where both a chiral catalyst-associated vinylpyridine and a nonassociated, free vinylpyridine substrate can be sensitized by an Ir(III) photocatalyst, yet high levels of diastereo- and enantioselectivity in a [2 + 2] photocycloaddition are achieved through a preferred, highly organized transition state. This mechanistic paradigm is distinct from, yet complementary to current approaches for achieving high levels of stereocontrol in photochemical transformations.

Visible Light-Mediated, Highly Diastereoselective Epimerization of Lactams from the Most Accessible to the More Stable Stereoisomer.

Most known methods to access δ-lactams with stereogenic centers at the α- and ß-positions are highly selective for the contra-thermodynamic syn diastereomer, typically via hydrogenation of the corresponding pyridinones or quinolinones. We describe here the development of a photoredox-mediated hydrogen atom transfer (HAT) approach for the epimerization of δ-lactams to access the more stable anti diastereomers from the contra-thermodynamic syn isomers. The reaction displays broad functional group compatibility, including acid, ester, 1°, 2° and 3° amide, carbamate, and pyridyl groups, and was effective for a range of differently substituted monocyclic and bicyclic lactams. Experimentally observed diastereoselectivities are consistent with the calculated relative stabilities of lactam diastereomers. Convergence to the same diastereomer ratio from the syn- and anti- diastereomers establishes that reversible epimerization provides an equilibrium mixture of diastereomers. Additionally, deuterium labeling and luminescence quenching studies shed further light on the mechanism of the reaction.

Proton-coupled energy transfer in molecular triads.

We experimentally discovered and theoretically analyzed a photochemical mechanism, which we term proton-coupled energy transfer (PCEnT). A series of anthracene-phenol-pyridine triads formed a local excited anthracene state after light excitation at a wavelength of ~400 nanometers (nm), which led to fluorescence around 550 nm from the phenol-pyridine unit. Direct excitation of phenol-pyridine would have required ~330-nm light, but the coupled proton transfer within the phenol-pyridine unit lowered its excited-state energy so that it could accept excitation energy from anthracene. Singlet-singlet energy transfer thus occurred despite the lack of spectral overlap between the anthracene fluorescence and the phenol-pyridine absorption. Moreover, theoretical calculations indicated negligible charge transfer between the anthracene and phenol-pyridine units. We construe PCEnT as an elementary reaction of possible relevance to biological systems and future photonic devices.

Effects of the serotonin 5-HT1B receptor agonist CP 94253 on the locomotor activity and body temperature of preweanling and adult male and female rats.

Serotonin 5-HT1A receptor agonists increase locomotor activity of both preweanling and adult rodents. The part played by the 5-HT1B receptor in locomotion is less certain, with preliminary evidence suggesting that the actions of 5-HT1B receptor agonists are not uniform across ontogeny. To more fully examine the role of 5-HT1B receptors, locomotor activity and axillary temperatures of preweanling and adult male and female rats was assessed. In the first experiment, adult (PD 70) and preweanling (PD 10 and PD 15) male and female rats were injected with the 5-HT1B agonist CP 94253 (2.5-10 mg/kg) immediately before locomotor activity testing and 60 min before axillary temperatures were recorded. In the second experiment, specificity of drug action was determined in PD 10 rats by administering saline, WAY 100635 (a 5-HT1A antagonist), or GR 127935 (a 5-HT1B antagonist) 30 min before CP 94253 (10 mg/kg) treatment. CP 94253 significantly increased the locomotor activity of preweanling rats on PD 10, an effect that was fully attenuated by GR 127935. Conversely, CP 94253 significantly decreased the locomotor activity of male and female adult rats, while CP 94253 did not affect the locomotor activity of PD 15 rats. Regardless of age, CP 94253 (2.5-10 mg/kg) significantly reduced the axillary temperatures of preweanling and adult rats. When considered together, these results show that 5-HT1B receptor stimulation activates motor circuits in PD 10 rats; whereas, 5-HT1B receptor agonism reduces the overall locomotor activity of adult rats, perhaps by blunting exploratory tendencies.

Reciprocal cross-sensitization between cocaine and RU 24969 in male and female preweanling rats.

Neuronal adaptations involving dopaminergic, glutamatergic, and serotonergic neurotransmitter systems are responsible for behavioral sensitization. Because of common underlying mechanisms, cross-sensitization between compounds of different drug classes can be observed. The purpose of the present study was to determine whether a one- or four-day pretreatment regimen of RU 24969 (a 5-HT1A/1B receptor agonist) would reciprocally cross-sensitize with cocaine or methamphetamine in male and female preweanling rats. Rats were pretreated with RU 24969 (0 or 5 mg/kg) for 4 days (PD 17-20) and then challenged with cocaine (10 or 20 mg/kg) or methamphetamine (1 or 2 mg/kg) on PD 22. Reciprocal cross-sensitization was also assessed (i.e., rats were pretreated with psychostimulants and tested with RU 24969). In a follow-up experiment, the ability of RU 24969 and cocaine to reciprocally cross-sensitize was assessed using a one-day pretreatment regimen. Reciprocal cross-sensitization between cocaine and RU 24969 was evident in preweanling rats, whereas methamphetamine and RU 24969 did not cross-sensitize. When a one-trial pretreatment regimen was used, cross-sensitization was only detected when rats were pretreated with RU 24969 and tested with cocaine, but not the reverse. In sum, the present results show that the nonselective 5-HT1A/1B receptor agonist RU 24969 cross-sensitizes with cocaine, but not methamphetamine, in preweanling rats. This dichotomy may be a function of cocaine having a greater affinity for the serotonin transporter than methamphetamine.

Solvent and Temperature Effects on Photoinduced Proton-Coupled Electron Transfer in the Marcus Inverted Region.

Concerted proton-coupled electron transfer (PCET) in the Marcus inverted region was recently demonstrated (Science 2019, 364, 471-475). Understanding the requirements for such reactivity is fundamentally important and holds promise as a design principle for solar energy conversion systems. Herein, we investigate the solvent polarity and temperature dependence of photoinduced proton-coupled charge separation (CS) and charge recombination (CR) in anthracene-phenol-pyridine triads: 1 (10-(4-hydroxy-3-(4-methylpyridin-2-yl)benzyl)anthracene-9-carbonitrile) and 2 (10-(4-hydroxy-3-(4-methoxypyridin-2-yl)benzyl)anthracene-9-carbonitrile). Both the CS and CR rate constants increased with increasing polarity in acetonitrile:n-butyronitrile mixtures. The kinetics were semi-quantitatively analyzed where changes in dielectric and refractive index, and thus consequently changes in driving force (-ΔG°) and reorganization energy (λ), were accounted for. The results were further validated by fitting the temperature dependence, from 180 to 298 K, in n-butyronitrile. The analyses support previous computational work where transitions to proton vibrational excited states dominate the CR reaction with a distinct activation free energy (ΔG*CR ∼ 140 meV). However, the solvent continuum model fails to accurately describe the changes in ΔG° and λ with temperature via changes in dielectric constant and refractive index. Satisfactory modeling was obtained using the results of a molecular solvent model [J. Phys. Chem. B 1999, 103, 9130-9140], which predicts that λ decreases with temperature, opposite to that of the continuum model. To further assess the solvent polarity control in the inverted region, the reactions were studied in toluene. Nonpolar solvents decrease both ΔG°CR and λ, slowing CR into the nanosecond time regime for 2 in toluene at 298 K. This demonstrates how PCET in the inverted region may be controlled to potentially use proton-coupled CS states for efficient solar fuel production and photoredox catalysis.

Divergent Hammett Plots of the Ground- and Excited-State Proton Transfer Reactions of 7-Substituted-2-Naphthol Compounds.

The rational design of photoacids requires accessible predictive models of the electronic effect of functional groups on chemical templates of interest. Here, the effect of substituents on the photoacidity and excited-state proton transfer (PT) pathways of prototype 2-naphthol (2OH) at the symmetric C7 position was investigated through photochemical and computational studies of 7-amino-2-naphthol (7N2OH) and 7-methoxy-2-naphthol (7OMe2OH). Time-resolved emission experiments of 7N2OH revealed that the presence of an electron-withdrawing versus electron-donating group (EWG vs EDG, NH3+ vs NH2) led to a drastic decline in photoacidity: p Ka* = 1.1 ± 0.2 vs 9.6 ± 0.2. Time-dependent density functional theory calculations with explicit water molecules confirmed that the excited neutral state (x = NH2) is greatly stabilized by water, with equation-of-motion coupled cluster singles and doubles calculations supporting potential mixing between the La and Lb states. Similar suppression of photoacidity, however, was not observed for 7OMe2OH with EDG OCH3, p Ka* = 2.7 ± 0.1. Hammett plots of the ground- and excited-state PT reactions of substituted 7-x-2OH compounds (x = CN, NH3+, H, CH3, OCH3, OH, and NH2) vs Hammett parameters σp showed breaks in the linearity between the EDG and EWG regions: ρ ∼ 0 vs 1.14 and ρ* ∼ 0 vs 3.86. The divergent acidic behavior most likely arises from different mixing mechanisms of the lowest Lb state with the La and possible Bb states upon substitution of naphthalene in water.

Nuclear membrane disassembly and rupture.

The nuclear envelope consists of two membranes traversed by nuclear pore complexes. The outer membrane is continuous with the endoplasmic reticulum. At mitosis nuclear pore complexes are dismantled and membranes disperse. The mechanism of dispersal is controversial: one view is that membranes feed into the endoplasmic reticulum, another is that they vesiculate. Using Xenopus egg extracts, nuclei have been assembled and then induced to breakdown by addition of metaphase extract. Field emission scanning electron microscopy was used to study disassembly. Strikingly, endoplasmic reticulum-like membrane tubules form from the nuclear surface after the addition of metaphase extracts, but vesicles were also observed. Microtubule inhibitors slowed but did not prevent membrane removal, whereas Brefeldin A, which inhibits vesicle formation, stops membrane disassembly, suggesting that vesiculation is necessary. Structures that looked like coated buds were observed and buds were labelled for beta-COP. We show that nuclear pore complexes are dismantled and the pore closed prior to membrane rupturing, suggesting that rupturing is an active process rather than a result of enlargement of nuclear pores.