# Dihalogens Binding and Activation by Imidazoline‐2‐Chalcogenone Model Derivatives: Insight from a Computational Approach

## TL;DR

This paper uses computational methods to study how imidazoline-based compounds interact with dihalogens, shedding light on drug mechanisms for treating hyperthyroidism.

## Contribution

The study reveals unique reactivity patterns and stability differences in chalcogenone-dihalogen interactions, particularly for sulfur and iodine combinations.

## Key findings

- Three reaction products are identified: a CT adduct, a T-shaped intermediate, and a T-shaped hypercoordinate species.
- For sulfur and iodine combinations, the CT adduct is more stable than the TY species.
- Activation strain analysis explains the stability exception observed in sulfur-iodine interactions.

## Abstract

Chalcogenone donors represent a fundamental chemical class of compounds in the treatment of hyperthyroidism; particularly, imidazoline‐based systems are associated with the strongest affinity for I2. Therefore, the reactivity of these types of donors with dihalogens may be insightful to understand the mechanism of action of popular drugs, such as methimazole (1‐methyl‐4‐imidazoline‐2‐thione, MMI). In this work, the reactivity of 1,3‐dimethyl‐4‐imidazoline‐2‐chalcogenone (S, Se, Te) with dihalogens X2 (X = Cl, Br, I) is evaluated for any combination through a systematic computational study. Three different products are found: a linear charge transfer (CT) “spoke” adduct, a “T‐shaped” intermediate (TI), and a “T‐shaped” hypercoordinate species (TY). The halogen and chalcogen effects are discussed separately as for the solvation effects. Furthermore, only the TY species formed from the reaction between 1,3‐dimethyl‐4‐imidazoline‐2‐thione and I2 resulted to be disfavored with respect to the corresponding CT adduct; therefore, this peculiarity is rationalized in the framework of activation strain analysis. Lastly, a possible alternative mechanism involving the formation of a cationic intermediate species is considered.

1,3‐dimethyl‐4‐imidazoline‐2‐chalcogenones react with dihalogens, initially forming a charge‐transfer (CT) adduct, which may evolve to the most stable T‐shaped hypercoordinate (TY) species. However, in silico results show that the CT adduct is more stable than the corresponding TY species for the sulfur and iodine combination. This exception is rationalized within the framework of activation strain analysis.