Quantum Mechanics/Molecular Mechanics Study on the Excited-State Relaxation Pathways of 2′-Deoxy-5-Fluorocytidine in Aqueous Solution

We have employed a high-level QM(CASPT2//CASSCF)/MM approach to investigate the excited-state properties and decay mechanism of 2′-deoxy-5-fluorocytidine (5FdCyd) in aqueous solution. The S₁(ππ*) and S₂(nπ*) states are the lowest spectroscopically bright and dark states in the Franck–Condon region with the predicted vertical excitation energies of 99.0 [4.29] and 117.3 kcal/mol [5.09 eV], respectively, at the QM(CASPT2)/MM level. Four feasible excited-state nonradiative relaxation pathways are also suggested for the initially populated S₁(ππ*) state. The photoexcited ¹ππ* state undergoes a bifurcation event that leads to fast diabatically evolution along the ¹ππ* state into its minimum ¹ππ*-MIN and transformation to the ¹nπ* state at the nearby ¹ππ*/¹nπ* conical intersection, which are followed by further deactivation to the S₀ state through the ¹ππ*/S₀ and ¹nπ*/S₀ conical intersections, respectively. The corresponding energy barriers for the ¹ππ* and ¹nπ* states' internal conversions (ICs) to the S₀ state are predicted to be 5.9 and 1.5 kcal/mol, respectively, at the QM(CASPT2)/MM level. In addition, the existence of minor intersystem crossing (ISC) routes of ¹ππ* → ¹nπ* → ³ππ₂* → ³ππ₁* and ¹ππ* → ³ππ₂* → ³ππ₁*, could transfer the system to the triplet states. Once populated to the ³ππ₁* state, it will first evolve into its minimum ³ππ₁*-MIN, from which ISC to the S₀ state occurs via the ³ππ₁*/S₀ crossing point, with the calculated spin–orbit coupling (SOC) of 4.9 cm^–1 at the QM(CASPT2)/MM level. In comparison, the involved slowly occurring ISCs can be significantly prohibited by the ultrafast and effective ICs. The present work rationalizes the ultrafast excited-state relaxation dynamics of 5FdCyd and its low quantum yields of triplet formation and fluorescence. It contributes important mechanistic insights into the in-depth understanding of the photophysics of 5FdCyd’s derivatives and analogues.