Complementary Base Lowers the Barrier in SuFEx Click Chemistry for Primary Amine Nucleophiles

Abstract

The sulfur­(VI) fluoride exchange (SuFEx) reaction is an emerging scheme for connecting molecular building blocks. Due to its broad functional group tolerance and rather stable resulting linkage, it is seeing rapid adoption in various fields of chemistry. Still, to date the reaction mechanism is poorly understood, which hampers further development. Here, we show that the mechanism of the SuFEx reaction for the prototypical example of methanesulfonyl fluoride reacting with methylamine can be understood as an SN2-type reaction. By analyzing the reaction path with the help of density functional theory in vacuo and under consideration of solvent and co-reactant influence, we identify the often used complementary base as a crucial ingredient to lower the reaction barrier significantly by increasing the nucleophilicity of the primary amine. With the help of energy decomposition analysis at the transition state structures, we quantify the underlying stereoelectronic effects and propose new avenues for experimental exploration of the potential of SuFEx chemistry.

The Emerging Applications of Sulfur(VI) Fluorides in Catalysis

“…This hydrogen bonding-like interaction significantly increased the nucleophilicity of the amine and lowered the barrier for the SuFEx reaction. 23 Collectively, these studies suggest that the role of DBU and other nucleophilic bases may be highly dependent on the system (e.g., silyl protected alcohol vs free alcohols).…”

SuFEx-Enabled, Chemoselective Synthesis of Triflates, Triflamides and Triflimidates

“…While this mechanism coincides with the findings of Luy and Tonner, the AIMtD simulations result in a Helmoltz free energy of activation (ΔF ‡ ) of 29 ± 4 kcal mol -1 , which exceeds a barrier that can readily be crossed at ambient conditions. [42] As the nonactivated triflylation of 55 yielded 49% of product at room temperature after 18 hours (Figure 1B, entry 1), the obtained high activation barrier raises questions on the validity of this mechanism. When adding a base such as DMAP (A, II) or Et3N (A, III) to the simulation box, a significantly reduced ΔF ‡ is observed (13 ± 1 kcal mol -1 and 22.1 ± 0.05 kcal mol -1 , respectively, Figure 1A).…”

“…As a result, we hope to shed light on the observed chemoselectivity, by comparing our simulations for secondary amines with the better-studied mechanism of phenol SuFEx reactions. [40,42] To achieve this goal, we use ab initio Scheme 5. Synthesis of triflamides by reaction of CF3SO2F with amines and azoles.…”

Alkyne-Functionalized Cyclooctyne on Si(001): Reactivity Studies and Surface Bonding from an Energy Decomposition Analysis Perspective

“…In a second step, the bifunctional molecule can then react with further organic molecules, introducing the desired functionality. As a mechanism for the attachment of a second organic layer, click reactions [19][20][21] are a notable approach [22][23][24][25]. From a computational point of view, the presence of two reactive groups in bifunctional molecules leads to complex reactivity patterns.…”