Intersystem Crossing Enables 4‑Thiothymidine to Act as a Photosensitizer in Photodynamic Therapy: An Ab Initio QM/MM Study

Motivated by its potential use as a photosensitizer in photodynamic therapy, we report the first ab initio quantum mechanics/molecular mechanics (QM/MM) study of 4-thiothymidine in aqueous solution. The core chromophore 4-thiothymine was described using the multiconfigurational CASSCF and CASPT2 QM methods, while the ribose and the solvent water molecules were treated at the MM level (CHARMM and TIP3P, respectively). The minima of the five lowest electronic states (S₀, S₁, S₂, T₁, and T₂) and six minimum-energy intersections were fully optimized at the QM­(CASSCF)/MM level, and their energies were further refined by single-point QM­(CASPT2)/MM and CASPT2 calculations. The relevant spin–orbit couplings were also computed. We find that (1) there are three efficient photophysical pathways that account for the experimentally observed ultrafast formation of the lowest triplet state with a quantum yield of nearly unity, (2) the striking qualitative differences in the photophysical behavior of 4-thiothymine and thymine originate from the different electronic structure of their S₁ states, and (3) environmental effects play an important role. The present QM/MM calculations provide mechanistic insight that may guide the design of improved photosensitizers for photodynamic therapy

Adiabatic and Nonadiabatic Bond Cleavages in Norrish Type I Reaction

One of the fundamental photoreactions for ketones is Norrish type I reaction, which has been extensively studied both experimentally and theoretically. Its α bond-cleavage mechanisms are usually explained in an adiabatic picture based on the involved excited-state potential energy surfaces, but scarcely investigated in terms of a nonadiabatic picture. In this work, the S1 α bond-cleavage reactions of CH3OC(O)Cl have been investigated by using the CASSCF and MRCI-SD calculations, and the ab initio based time-dependent quantum wavepacket simulation. The numerical results indicate that the photoinduced dissociation dynamics of CH3OC(O)Cl could exhibit strong nonadiabatic bond-fission characteristics for the S1 α C–Cl bond cleavage, while the dynamics of the S1 α C–O bond cleavage is mainly of adiabatic characteristics. This nonadiabatic mechanism for Norrish type I reaction of CH3OC(O)Cl is uncovered for the first time. The quantum wavepacket dynamics, based on the reduced-dimensional coupled potential energy surfaces, to some extent illustrates the significance of the nonadiabatic effect in the transition-state region on the dynamics of Norrish type I reaction

Intramolecular Hydrogen Bonding Plays a Crucial Role in the Photophysics and Photochemistry of the GFP Chromophore

In commonly studied GFP chromophore analogues such as 4-(4-hydroxybenzylidene)-1,2-dimethyl-1H-imidazol-5­(4H)-one (PHBDI), the dominant photoinduced processes are cis–trans isomerization and subsequent S₁ → S₀ decay via a conical intersection characterized by a highly twisted double bond. The recently synthesized 2-hydroxy-substituted isomer (OHBDI) shows an entirely different photochemical behavior experimentally, since it mainly undergoes ultrafast intramolecular excited-state proton transfer, followed by S₁ → S₀ decay and ground-state reverse hydrogen transfer. We have chosen 4-(2-hydroxybenzylidene)-1H-imidazol-5­(4H)-one (OHBI) to model the gas-phase photodynamics of such 2-hydroxy-substituted chromophores. We first use various electronic structure methods (DFT, TDDFT, CC2, DFT/MRCI, OM2/MRCI) to explore the S₀ and S₁ potential energy surfaces of OHBI and to locate the relevant minima, transition state, and minimum-energy conical intersection. These static calculations suggest the following decay mechanism: upon photoexcitation to the S₁ state, an ultrafast adiabatic charge-transfer induced excited-state intramolecular proton transfer (ESIPT) occurs that leads to the S₁ minimum-energy structure. Nearby, there is a S₁/S₀ minimum-energy conical intersection that allows for an efficient nonadiabatic S₁ → S₀ internal conversion, which is followed by a fast ground-state reverse hydrogen transfer (GSHT). This mechanism is verified by semiempirical OM2/MRCI surface-hopping dynamics simulations, in which the successive ESIPT-GSTH processes are observed, but without cis–trans isomerization (which is a minor path experimentally with less than 5% yield). These gas-phase simulations of OHBI give an estimated first-order decay time of 476 fs for the S₁ state, which is larger but of the same order as the experimental values measured for OHBDI in solution: 270 fs in CH₃CN and 230 fs in CH₂Cl₂. The differences between the photoinduced processes of the 2- and 4-hydroxy-substituted chromophores are attributed to the presence or absence of intramolecular hydrogen bonding between the two rings

Photodynamics of Schiff Base Salicylideneaniline: Trajectory Surface-Hopping Simulations

We report a computational study on the photochemistry of the prototypical aromatic Schiff base salicylideneaniline in the gas phase using static electronic structure calculations (TDDFT, OM2/MRCI) and surface-hopping dynamics simulations (OM2/MRCI). Upon photoexcitation of the most stable cis-enol tautomer into the bright S₁ state, we find an ultrafast excited-state proton transfer that is complete within tens of femtoseconds, without any CN double bond isomerization. The internal conversion of the resulting S₁ cis-keto species is initiated by an out-of-plane motion around the C–C single bond, which guides the molecule toward a conical intersection that provides an efficient deactivation channel to the ground state. We propose that the ease of this C–C single bond rotation regulates fluorescence quenching and photocoloration in condensed-phase environments. In line with previous work, we find the S₁ cis-keto conformer to be responsible for fluorescence, especially in rigid surroundings. The S₀ cis-keto species is a transient photoproduct, while the stable S₀ trans-keto photoproduct is responsible for photochromism. The trajectory calculations yield roughly equal amounts of the S₀ cis-enol and trans-keto photoproducts. Methodologically, full-dimensional nonadiabatic dynamics simulations are found necessary to capture the preferences among competitive channels and to gain detailed mechanistic insight into Schiff base photochemistry

Photoinduced Proton Transfer and Isomerization in a Hydrogen-Bonded Aromatic Azo Compound: A CASPT2//CASSCF Study

Intramolecularly hydrogen-bonded aromatic azo compound 1-cyclopropyldiazo-2-naphthol (CPDNO) exhibits complicated excited-state behaviors, e.g., wavelength-dependent photoinduced proton transfer and photoproducts. Its photochemistry differs from that of common aromatic azo compounds in which cis–trans photoisomerization is dominant. To rationalize the intriguing photochemistry of CPDNO at the atomic level, we have in this work employed the complete active space self-consistent field (CASSCF) and its second-order perturbation (CASPT2) methods to explore the S₀, S₁, and S₂ potential-energy profiles relevant to enol–keto proton transfer and isomerization reactions. It is found that the proton transfer along the bright diabatic ¹ππ* potential-energy profile is almost barrierless, quickly forming the fluorescent ¹ππ* keto minimum. In this process, the dark ¹nπ* state is populated via a ¹ππ*/¹nπ* crossing point, but the proton transfer on this dark state is suppressed heavily as a result of a large barrier. In addition, two deactivation paths that decay the S₁ enol and keto minima to the S₀ state, respectively, were uncovered. For the former, it is exoenergetic and thereby thermodynamically favorable; for the latter, it is a little endothermic (ca. 5 kcal/mol). Both are energetically allowable concerning the available total energy. Finally, on the basis of the present results, the experimentally observed wavelength-dependent photoproducts were explained very well

Theoretical Studies on the Excited-State Decay Mechanism of Homomenthyl Salicylate in a Gas Phase and an Acetonitrile Solution

Here, we employ the CASPT2//CASSCF and QM­(CASPT2//CASSCF)/MM approaches to explore the photochemical mechanism of homomenthyl salicylate (HMS) in vacuum and an acetonitrile solution. The results show that in both cases, the excited-state relaxation mainly involves a spectroscopically “bright” S1(1ππ*) state and the lower-lying T1 and T2 states. In the major relaxation pathway, the photoexcited S1 keto system first undergoes an essentially barrierless excited-state intramolecular proton transfer (ESIPT) to generate the S1 enol minimum, near which a favorable S1/S0 conical intersection decays the system to the S0 state followed by a reverse ground-state intramolecular proton transfer (GSIPT) to repopulate the initial S0 keto species. In the minor one, an S1/T2/T1 three-state intersection in the keto region makes the T1 state populated via direct and T2-mediated intersystem crossing (ISC) processes. In the T1 state, an ESIPT occurs, which is followed by ISC near a T1/S0 crossing point in the enol region to the S0 state and finally back to the S0 keto species. In addition, a T1/S0 crossing point near the T1 keto minimum can also help the system decay to the S0 keto species. However, small spin–orbit couplings between T1 and S0 at these T1/S0 crossing points make ISC to the S0 state very slow and make the system trapped in the T1 state for a while. The present work rationalizes not only the ultrafast excited-state decay dynamics of HMS but also its low quantum yield of phosphorescence at 77 K

Photochromic Mechanism of a Bridged Diarylethene: Combined Electronic Structure Calculations and Nonadiabatic Dynamics Simulations

Intramolecularly bridged diarylethenes exhibit improved photocyclization quantum yields because the anti-syn isomerization that originally suppresses photocyclization in classical diarylethenes is blocked. Experimentally, three possible channels have been proposed to interpret experimental observation, but many details of photochromic mechanism remain ambiguous. In this work we have employed a series of electronic structure methods (OM2/MRCI, DFT, TDDFT, RI-CC2, DFT/MRCI, and CASPT2) to comprehensively study excited state properties, photocyclization, and photoreversion dynamics of 1,2-dicyano­[2,2]­metacyclophan-1-ene. On the basis of optimized stationary points and minimum-energy conical intersections, we have refined experimentally proposed photochromic mechanism. Only an S1/S0 minimum-energy conical intersection is located; thus, we can exclude the third channel experimentally proposed. In addition, we find that both photocyclization and photoreversion processes use the same S1/S0 conical intersection to decay the S1 system to the S0 state, so we can unify the remaining two channels into one. These new insights are verified by our OM2/MRCI nonadiabatic dynamics simulations. The S1 excited-state lifetimes of photocyclization and photoreversion are estimated to be 349 and 453 fs, respectively, which are close to experimentally measured values: 240 ± 60 and 250 fs in acetonitrile solution. The present study not only interprets experimental observations and refines previously proposed mechanism but also provides new physical insights that are valuable for future experiments

Nonequilibrium H/D Isotope Effects from Trajectory-Based Nonadiabatic Dynamics

Ground-state equilibrium kinetic isotope effects can be treated well in the framework of transition state theory, whereas excited-state nonequilibrium isotope effects are theoretically less explored. In this article we show for the first time that trajectory-based nonadiabatic dynamics simulations are able to reproduce experimental values for nonequilibrium H/D isotope effects in excited-state processes. We use high-level electronic structure calculations (MS-CASPT2, DFT/MRCI, and TDDFT) and full-dimensional OM2/MRCI-based nonadiabatic dynamics simulations to study the ultrafast intramolecular excited-state proton transfer (ESIPT) and the subsequent deactivation of 7-(2-pyridyl)­indole (7PyIn) and its deuterated analogue (7PyIn-D). We evaluate a total of 1367 surface-hopping trajectories to establish the differences in the dynamical behavior of 7PyIn and 7PyIn-D. The computed H/D isotope effects for ESIPT and excited-state decay are consistent with recent experimental results from femtosecond pump–probe resonance-enhanced multiphoton ionization spectroscopy. We also analyze the influence of temperature fluctuations in the initially prepared sample on the photodynamics of 7PyIn and 7PyIn-D