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Stereo- reversed E2 unlocks Z- selective C–H functionalization

14 October 2025

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Introduction

The stereoselective functionalization of C–H bonds represents a central challenge in modern organic synthesis. Despite decades of innovation in C–H activation chemistry, methods for Z- selective functionalization of alkenes have eluded synthetic practitioners. terminal alkenes present the biggest challenge for Z- selectivity as they require selective cleavage of the more hindered of two otherwise virtually identical C–H bonds (Fig. 1A).

Fig. 1A C–H Functionalization approach to Z- olefin synthesis from terminal alkenes.

Recently, Researchers from the University of Wisconsin–Madison, led by Professor Zachary K. Wickens, have published an article titled "Stereo-reversed E2 unlocks Z-selective C–H functionalization" in Science [1].

The study describes the transformation of alkenes into transient 1,2- bis- sulfonium intermediates found to undergo Z- selective elimination, overturning a textbook E2 stereoselectivity rule through stabilizing interactions. Researchers identify paired electrolysis as an enabling strategy to both selectively generate the requisite bis- sulfonium intermediate and drive its rapid elimination in situ. the resultant Z- alkenyl sulfonium linchpins provide access to a wide array of Z- alkene targets from inexpensive feedstocks through robust cross- coupling reactions.

This Work

Discovery of a Z- selective E2 and translation to Z- selective thianthrenation

The most fundamental breakthrough of this study lies in the discovery of a Z-selective elimination reaction that defies the classical E2 rule and its subsequent development into a practical synthetic method. While investigating the reactivity of thianthrene (TT) with alkenes under electrochemical conditions, researchers serendipitously observed an unambiguous correlation: the bis-sulfonium adduct (bis-adduct) generated in the reaction was positively correlated with the Z-selectivity of the final product (Fig. 2A). This finding stands in direct contrast to the E-selectivity predicted by textbook models.

Fig. 2A Unexpected discovery: bis- and mono- adducts undergo stereodivergent eliminations.

Under conventional reaction conditions, the bis-sulfonium adduct required for Z-selectivity is only a minor byproduct, while the mono-sulfonium adduct (mono-adduct) predominates as the major product, ultimately leading to the undesired E-alkene (Fig. 2B).

Fig. 2B Major challenges in achieving a bis- selective thianthrenation protocol.

The research team innovatively employed an undivided cell paired electrolysis (Fig. 2C). The cathode played a crucial dual role: firstly, it maintained a high concentration of thianthrene (TT) via reduction, thereby suppressing undesirable side-reaction pathways; secondly, it generated precisely the requisite amount of base in situ. This base was sufficient to promote rapid elimination of the bis-sulfonium adduct while avoiding inhibition of the reaction system.

Fig. 2 (C) Design strategy for Z- selectivity: undivided cell paired electrolysis. (D) Validation of strategy: reactor- dependent thianthrenation selectivity.

Scope and synthetic utility of Z-alkenyl thianthrenium salts

The authors subsequently investigated a diverse range of terminal alkenes bearing various functional groups (Fig. 3A), demonstrating the method's excellent functional group compatibility. The resulting Z-alkenyl thianthrenium salts exhibited high crystallinity, allowing for the isolation of nearly stereopure products via simple recrystallization. This effectively addresses the long-standing challenge of separating Z/E isomers in traditional alkene synthesis.

Nitrogen-containing functional groups: primary amines, secondary amines, amides, and sulfonamides were all compatible. Amines were protonated under the acidic reaction conditions, thereby avoiding oxidation.

Oxygen-containing functional groups: alcohols and carboxylic acids were compatible, with alcohols being protected in situ by trifluoroacetic anhydride using a labile trifluoroacetyl group.

Some electron-rich groups, such as sulfides and enolizable ketones, were incompatible. However, ketone-containing Z-alkene products remained accessible since alkenes bearing Weinreb amides (19) underwent efficient Z-selective thianthrenation.

The method could be readily scaled to the decagram scale using inexpensive graphite and stainless-steel electrodes, demonstrating its potential for practical application (Fig. 3B). When substrates contained both a terminal alkene and an acrylate, the reaction occurred selectively on the terminal alkene. This selectivity profile complements transition metal-catalyzed alkenyl C–H activation reactions, which typically employ acrylate derivatives as substrates. The method was not applicable to 1,1-disubstituted alkenes or internal alkenes.

Fig. 3. Z- selective C–H thianthrenation.

The resulting Z-alkenyl thianthrenium salts serve as versatile linchpin intermediates that can be diversified through a series of mainstream cross-coupling reactions with excellent retention of the Z-configuration.

Coupling with various carbon nucleophiles was successfully achieved, including reactions with alkynes (Sonogashira, forming C(sp) bonds), aryl/alkyl boronic acids (Suzuki, forming C(sp²) bonds), and alkyl zinc reagents (Negishi, forming C(sp³) bonds) (Fig. 4A).

To highlight the synthetic utility, the authors selected several notable natural products—such as the silkmoth sex pheromone Bombykol, the spongy moth sex pheromone (±)-cis-Disparlure, and the pear fragrance component ethyl decadienoate—as target molecules. Starting from inexpensive, simple terminal alkenes, they efficiently synthesized these molecules in just two steps (Z-selective thianthrenation followed by a single cross-coupling step), demonstrating the power and simplicity of this strategy (Fig. 4B).

Fig. 4. Synthetic applications.

Origins of Z-selectivity

Through density functional theory (DFT) calculations, the authors discovered that although the reactant conformation leading to the Z-alkene (gauche-Z) is slightly higher in energy (+0.7 kcal/mol), the anti-elimination transition state forming the Z-alkene (TS-anti-Z) is substantially lower in energy than its E-forming counterpart (TS-anti-E) (energy barrier difference ΔΔG‡ = 3.2 kcal/mol). This explains the predominance of the Z-product (fig. S17).

Extensive geometric reorganization is required to proceed from gauche-E to TS-anti-E (the dihedral angle S–C–C–S between the two thianthrenium groups contracts by 15.5°). This restructuring process disrupts many key stabilizing noncovalent interactions (such as C–H···S hydrogen bonding), leading to a higher energy barrier.

In contrast, the geometric change required from gauche-Z to TS-anti-Z is minimal (the S–C–C–S dihedral angle expands by only 1.0°). Consequently, the stabilizing interactions present in gauche-Z (particularly C–H···S hydrogen bonding and π-π stacking) are largely preserved in the transition state, making this pathway energetically more favorable (Fig. 5A).

Further analysis revealed that the lowest-energy pathway for forming the E-alkene is actually a syn-elimination (TS-syn-E). This pathway sacrifices the ideal anti-periplanar geometry to retain key hydrogen bonding interactions. Its calculated energy barrier shows excellent agreement with the experimentally observed selectivity (Fig. 5B).

To validate the critical role of hydrogen bonding, the researchers synthesized a structural analog of thianthrene (bis-O), where the neutral sulfur atoms were replaced with oxygen atoms. Theoretical predictions indicated that this subtle change would disrupt the critical C–H···S hydrogen bonding, leading to a significant reduction in Z-selectivity. Experimental results confirmed that the Z/E selectivity of the elimination products from bis-O indeed dropped substantially (to 1.6:1), providing strong support for the theoretical model (Fig. 5C).

Fig. 5 Origins of Z- selectivity.

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Key Reagent

Thianthrene serves as a versatile model in organic chemistry, primarily undergoing stepwise oxidation to its sulfoxide and sulfone derivatives and participating in electrophilic substitution at the 2- and 7-positions, which makes it valuable for studying reaction mechanisms and redox processes.

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References

[1]Verardi P J, Ryutov E A, Mukherjee P, et al. Stereo-reversed E2 unlocks Z-selective C–H functionalization[J]. Science, 2025, 389(6766): 1239-1245.

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