Dihalogens Binding and Activation by Imidazoline-2-Chalcogenone Model Derivatives: Insight from a Computational...

Area of Science:

• Computational chemistry
• Medicinal chemistry
• Chemical reactivity

Background:

• Chalcogenone donors, particularly imidazoline-based systems, are crucial in hyperthyroidism treatment due to their high affinity for iodine (I2).
• Understanding the reactivity of these donors with dihalogens is key to elucidating the mechanism of action for drugs like methimazole (MMI).

Purpose of the Study:

• To systematically investigate the reactivity of 1,3-dimethyl-4-imidazoline-2-chalcogenone (S, Se, Te) with various dihalogens (X2, where X = Cl, Br, I) using computational methods.
• To analyze the influence of halogen and chalcogen substituents, as well as solvation effects, on the reaction outcomes.
• To rationalize specific reaction peculiarities, such as the disfavored formation of a particular species with I2, using activation strain analysis.

Main Methods:

• Systematic computational study of the reaction pathways.
• Analysis of charge transfer (CT) adducts, T-shaped intermediates (TI), and T-shaped hypercoordinate species (TY).
• Activation strain analysis to explain reaction energetics and preferences.

Main Results:

• Three distinct product types were identified: linear CT adducts, TI, and TY species.
• Halogen and chalcogen effects on reactivity were analyzed separately, alongside solvation effects.
• A unique observation was the disfavored formation of the TY species from 1,3-dimethyl-4-imidazoline-2-thione and I2, which was rationalized through activation strain analysis.

Conclusions:

• The study provides a comprehensive computational analysis of imidazoline-based chalcogenone reactivity with dihalogens.
• The findings offer valuable insights into the reaction mechanisms relevant to hyperthyroidism drug action.
• An alternative reaction mechanism involving cationic intermediates was also considered, broadening the scope of potential pathways.