A theoretical study of the light-induced cross-linking reaction of 5-fluoro-4-thiouridine with thymine

In contrast to photophysics of thio-substituted nucleobases, their photoinduced cross-linking reactions with canonical nucleobases remain scarcely investigated computationally. In this work, we have adopted combined CASPT2/PCM//CASSCF and B3LYP-D3/PCM electronic structure methods to study this kind of photochemical reaction of 5-fluoro-4-thiouridine (truncated 5-fluoro-1-methyl-4-thiouracil used in calculations) and 1-methylthymine (referred to as thymine for clarity hereinafter). On the basis of CASPT2/PCM computed results, we have proposed two efficient excited-state relaxation pathways to populate the lowest T₁ state of the complex of 5-fluoro-1-methyl-4-thiouracil and thymine from its initially populated S₂(¹ππ*) state. In the first one, the S₂ system first hops to the S₁ state via an S₂/S₁ conical intersection, followed by a direct S₁ → T₁ intersystem crossing process enhanced by large S₁/T₁ spin-orbit coupling. In the second path, the resultant S₁ system first jumps to the T₂ state, from which an efficient T₂ → T₁ internal conversion occurs. The T₁ cross-linking reaction is overall divided into two phases. The first phase is a stepwise and nonadiabatic photocyclization reaction, which starts from the T₁ complex and ends up with an S₀ thietane intermediate. The second phase is a thermal reaction. The system first rearranges its four- and six-membered rings to form three new rings; then, an S₀ fluorine atom transfer occurs, followed by the formation of photoproducts. Finally, the present work paves the way for studying light-induced cross-linking reactions of thionucleobases with canonical bases in DNA and RNA.