Thermal Safety and Structure-Related Reactivity Investigation of Five-Membered Cyclic Sulfamidates

Abstract

Five-membered cyclic sulfamidates are very valuable electrophiles in organic synthesis and readily used on a multikilogram scale. However, their thermal degradation is underreported and might lead to unforeseen and undesirable safety events. In addition, ring or nitrogen substitution can have a tremendous influence on cyclic sulfamidate reactivity toward bases and therefore impact the overall safety assessment of a process. An understanding of such behavior is therefore of high importance in the industry while designing a synthetic route, as a change of, e.g., a protecting group can increase the thermal safety of a step on scale. We report herein the thermal degradation investigation as well as the structure-related reactivity exploration of cyclic sulfamidates, including their use in combination with strong bases. The design of a predictive model to rapidly assess the thermal hazard based on collected data and selected molecular descriptors is also presented.

Development, Validation, and Application of a Custom-Made Mini-Reaction Calorimeter for Thermal Safety Screening

“…All chemicals used in this work were purchased from common suppliers and used without further purification. The compounds for the reactivity tests were synthesized in-house …”

“…The main objective of the study was to perform reaction screening and compare the reactivity of various compounds. 4 During the course of the project, many molecules had to be synthesized in-house; therefore, a significant advantage of the developed mini-reaction calorimeter resided in the small quantities of products (approximately 120 mg per test) required to perform all measurements. All experiments were performed following the same procedure and in triplicate, ensuring comparability and accuracy.…”

“…The compounds for the reactivity tests were synthesized inhouse. 4 ■ ASSOCIATED CONTENT * sı Supporting Information…”

“…In particular, we were interested in assessing how a library of molecules would react with bases of different strengths. 4 As only very limited quantities of material were available for testing and because of the extreme exotherms observed in some cases, it was necessary to develop an instrument that used sub-milliliter volumes for the reactivity screening.…”

“…The prototype we present was developed to address the need in our research laboratory to perform quick and accurate reaction enthalpy screening with very small reaction volumes. In particular, we were interested in assessing how a library of molecules would react with bases of different strengths . As only very limited quantities of material were available for testing and because of the extreme exotherms observed in some cases, it was necessary to develop an instrument that used sub-milliliter volumes for the reactivity screening.…”