Controlled stabilization of anionic forms of the uracil derivatives: A DFT study

Area of Science:

• Computational Chemistry
• Theoretical Chemistry
• Physical Chemistry

Background:

• Uracil anions (N1, N3, O5, O6) exhibit varying stabilities influenced by their electronic structure.
• Understanding these stabilities is crucial for predicting chemical behavior in different environments.
• Solvation effects, both specific and nonspecific, play a significant role in modulating anion stability.

Purpose of the Study:

• To theoretically investigate the relative stabilities of N1/N3/O5/O6 anions of 42 substituted uracils.
• To analyze the impact of gas phase versus aqueous solution conditions on anion stability.
• To elucidate the influence of specific and nonspecific solvation, including hydrate shells, on uracil anion distribution.

Main Methods:

• Utilized the IEFPCM (SMD) - TPSS/aug-cc-pVTZ approximation for theoretical calculations.
• Simulated specific solvation using a first hydrate shell of 5 water molecules.
• Accounted for nonspecific solvation using the SMD model.

Main Results:

• In the gas phase, the N1 anion is significantly more stable than the N3 anion due to better charge delocalization.
• Hydration diminishes the stability difference (ΔG) between N1 and N3 anions, stabilizing more polar anionic states.
• Substituents at the 5 and 6 positions of the pyrimidine ring are the primary drivers of N1/N3/O5/O6 anion distribution.
• 5-substituents primarily exert influence via resonance, while 6-substituents show a more pronounced inductive effect.

Conclusions:

• The relative stability of uracil anions is highly dependent on both the presence and position of substituents on the pyrimidine ring.
• Solvation dramatically alters anion stability, favoring more polar states in aqueous solutions.
• The study clarifies the distinct mechanisms (resonant vs. inductive) by which substituents at different positions influence uracil anion stability.