# Unanticipated Reactivity toward Nucleophilic Attack in the Synthesis of Saccharyl-1,3,4-Thiadiazolyl Conjugates: Structure and Mechanistic Insights

## TL;DR

This paper reports an unexpected chemical reaction during the synthesis of a copper chelator, revealing new insights into its structure and reactivity.

## Contribution

The study identifies a novel compound formed via unexpected nucleophilic attack and provides mechanistic insights through quantum calculations and crystallography.

## Key findings

- A novel compound, BMTT, was unexpectedly formed from the reactivity of 5-methyl-1,3,4-thiadiazole-2-thiol.
- Quantum chemical calculations suggest nucleophilic attack by nitrogen at position 3 of the thiadiazole ring.
- X-ray crystallography confirmed the structures of MTSB and BMTT hybrids.

## Abstract

Along with the synthetic process optimization of 3-[(5-methyl-1,3,4-thiadiazole-2-yl)­sulfanyl]-1,2-benzothiazole
1,1-dioxide (MTSB), a selective copper chelator with potential interest
in cancer chemotherapy, the unprecedented isolation of a novel compound,
3-(1,1-dioxidobenzo­[d]­isothiazol-3-yl)-5-methyl-1,3,4-thiadiazole-2­(3H)-thione (BMTT), evidenced an unexpected reactivity of
the starting 5-methyl-1,3,4-thiadiazole-2-thiol. To shed light into
the reaction mechanisms, quantum chemical calculations were conducted
at the M06-2X/def2-TZVPP/PCM­(THF)//M06-2X/6-31++G­(d,p)
level of theory. The results conjecture the formation of BMTT from
nucleophilic attack of the nitrogen at position 3 of the thiadiazole
ring, involved in an S-to-N delocalized thiadiazole-2-thiolate structure,
which is thermodynamically more favorable in the presence of Na+. Experimental assays refute a plausible concerted 1,3-sigmatropic
S- to N-rearrangement of MTSB that would lead to BMTT. Hence, contradicting
the nucleophilicity indices of sulfur (from thiol) and nitrogen atoms
of 5-methyl-1,3,4-thiadiazole-2-thiol, it is believed that an exotic
nucleophilic attack by the nitrogen at 3-position of this reagent
to the sp2 carbon in position 3 of pseudo-saccharyl chloride
should take place. Besides, the crystal structures of the MTSB and
BMTT hybrids were investigated in detail by X-ray crystallography.