Fluoride Exchange Research Articles

Progress in Radical Fluorosulfonyl Reagents

AbstractSulfur(VI) fluoride exchange (SuFEx) chemistry that relies on the unique reactivity–stability balance of high valent organosulfur has emerged as a promising topic for the next-generation click reaction. Sulfonyl fluorides are the most widely used connective hubs of the SuFEx click reaction with widespread applications in the fields of chemical biology, drug discovery, and materials science. Compared with current methods, direct fluorosulfonylation with fluorosulfonyl radicals has emerged as a concise and efficient approach for the production of sulfonyl fluorides. The highly active SO2F radical was an unstable and inaccessible precursor until it was observed in the decomposition of fluorosulfonyl azide, which inspired efforts towards the production of fluorosulfonyl radical precursors for direct radical fluorosulfonylation processes. This review presents and discusses current breakthroughs in the generation of fluorosulfonyl radicals from various radical precursors, as well as their application in the synthesis of diverse functionalized sulfonyl fluorides.1 Introduction2 FSO2Cl as a Radical Precursor3 Benzimidazolium Fluorosulfonates as Radical Precursors4 Alk-1-ynylsulfonyl Fluorides as Radical Precursors5 (Diarylmethylene)sulfamoyl Fluorides as Radical Precursors6 Vinyl Fluorosulfates as Radical Precursors7 Conclusion and Outlook

Lewis Acid-Catalyzed Sulfur Fluoride Exchange.

A new method uses metal Lewis acids as catalysts to convert sulfonyl fluorides, fluorosulfates, and sulfamoyl fluorides with silyl amines into S-N bond-containing compounds via sulfur fluoride exchange. The reaction successfully employs Ca(NTf2)2 as a catalyst to form sulfonamides, sulfamates, and sulfamides using in situ-generated or commercially available silyl amines in 35-99% yields. Other metal Lewis acids are also demonstrated to be catalysts in SuFEx, forming sulfonamides and sulfamates in yields comparable to those of Ca(NTf2)2.

Sulfur (VI) Fluoride Exchange (SuFEx) via Glass–Assisted Organocatalysis

Sulfur (VI) Fluoride Exchange (SuFEx) via Glass–Assisted Organocatalysis

A Practical Guide to SuFEx Chemistry: An Overview of S(VI)-SuFEx Linkers and Their Reactivity

AbstractSulfur(VI)–fluoride exchange (SuFEx) is a second generation, metal-free click chemistry concept introduced by Sharpless in 2014. Since the introduction of the concept, a large variety of synthetic methodologies to S(VI)-SuFEx hubs, and their derivatization with oxygen-, nitrogen-, and carbon-based nucleophiles have been developed. Herein, we provide a concise and practical overview for their preparation, SuFExability, inclusive of which substituents are tolerated. The stereoselective synthesis of aza-derivatives is also discussed.1 Introduction2 Synthesis of SuFEx Hubs2.1 Sulfonyl Fluorides2.2 Fluorosulfates2.3 Sulfamoyl Fluorides2.4 Sulfonimidoyl Fluorides2.5 Sulfuramidimidoyl Fluorides and Sulfurofluoridoimidates2.6 Sulfondiimidoyl Fluorides3 Reactivity of SuFEx Hubs3.1 Reactivity of Sulfonyl Fluorides3.2 Reactivity of Fluorosulfates3.3 Reactivity of Sulfamoyl Fluorides3.4 Reactivity of Sulfonimidoyl Fluorides3.5 Reactivity of Sulfurofluoridoimidates3.6 Reactivity of Sulfondiimidoyl Fluorides4 Stereochemical Considerations in SuFEx Chemistry5 Conclusion and Outlook

N-Fluorosulfurylamidines Enable Modular Synthesis of 1,5-Disubstituted Tetrazoles.

Here we report the modular synthesis of 1,5-disubstituted tetrazoles using two highly chemoselective reactions, ligations of N-fluorosulfurylamidines with amines and diazotransfer reactions between FSO2N3 and N-monosubstituted amidines, respectively. Enabled by sulfur(VI) fluoride exchange (SuFEx) click chemistry, we have successfully synthesized a series of N-fluorosulfurylamidines and identified them as stable and scalable organic synthons. We then discover that N-fluorosulfurylamidines react selectively toward a series of aliphatic amines, resulting in the formation of N-monosubstituted amidines that can react further with FSO2N3 to deliver 1,5-disubstituted tetrazoles. Our work provides a new platform for generating a library of 1,5-disubstituted tetrazoles with diverse structures, which is unprecedented.

Application of Sulfonyl Fluorides in Organic Transformation

ulfonyl fluorides, due to their balanced potential reactivity and stability as well as their compatibility with biological systems, have become important synthetic intermediates and building blocks in the fields of organic synthesis, drug discovery, and materials science. Especially after the report of sulfur(VI) fluoride exchange (SuFEx) chemistry by Sharpless and others, research on sulfonyl fluoride compounds and related compounds has increased significantly.This review summarizes the applications of sulfonyl fluorides in organic synthesis over the past decade, different types of organic reactions including C–X bond formation (including C–C, C–N, C–F bond formation etc.), S–C bond formation, S–N bond formation, S–O bond formation, multicomponent “one-pot” synthesis, and cyclization were discussed.

Evaluation of engineered binderless alumina – titania beads for fluoride removal from impaired water resources

Groundwater is often contaminated with various species, with fluoride concentrations being of particular concern. Numerous studies have used adsorbents for fluoride uptake, but most are tested only as powders and not commercially acceptable engineered shapes. Therefore, it was necessary to evaluate the performance of the newly developed Al2O3/TiO2 sorbents in their beaded form to assess their efficacy in comparison to activated alumina granules. Binderless sorbent beads were self-bound with the alumina and titania phases present. The fluoride exchange kinetics of Al2O3/TiO2 beads were comparable to the powdered form. Moreover, the Al2O3/TiO2 beads had higher fluoride loading than commercially available alumina (0.17 meq/g compared to 0.13 meq/g). The Al2O3/TiO2 beads also removed: barium, calcium, lithium, magnesium, manganese, potassium, silica, and strontium from groundwater. In fixed bed column tests, the beads-maintained fluoride within acceptable limits for 42 bed volumes, which substantially outperformed activated alumina (2.5 bed volumes). This study demonstrated that Al2O3/TiO2 beads outperformed commercially available activated alumina materials. Notably, transforming the materials into beaded forms significantly improved their suitability for fluoride removal in industrially relevant fixed-bed column environments. Future studies should focus on enhancing material binding properties to increase crush strength and attrition resistance. A deeper knowledge of regeneration strategies may also facilitate cost reduction.

Leveraging Covalency to Stabilize Ternary Complex Formation For Cell-Cell "Induced Proximity".

Recent advances in the field of translational chemical biology use diverse "proximity-inducing" synthetic modalities to elicit new modes of "event driven" pharmacology. These include mechanisms of targeted protein degradation and immune clearance of pathogenic cells. Heterobifunctional "chimeric" compounds like Proteolysis TArgeting Chimeras (PROTACs) and Antibody Recruiting Molecules (ARMs) leverage these mechanisms, respectively. Both systems function through the formation of reversible "ternary" or higher-order biomolecular complexes. Critical to function are key parameters, such as bifunctional molecule affinity for endogenous proteins, target residence time, and turnover. To probe the mechanism and enhance function, covalent chemical approaches have been developed to kinetically stabilize ternary complexes. These include electrophilic PROTACs and Covalent Immune Recruiters (CIRs), the latter designed to uniquely enforce cell-cell induced proximity. Inducing cell-cell proximity is associated with key challenges arising from a combination of steric and/or mechanical based destabilizing forces on the ternary complex. These factors can attenuate the formation of ternary complexes driven by high affinity bifunctional/proximity inducing molecules. This Account describes initial efforts in our lab to address these challenges using the CIR strategy in antibody recruitment or receptor engineered T cell model systems of cell-cell induced proximity. ARMs form ternary complexes with serum antibodies and surface protein antigens on tumor cells that subsequently engage immune cells via Fc receptors. Binding and clustering of Fc receptors trigger immune cell killing of the tumor cell. We applied the CIR strategy to convert ARMs to covalent chimeras, which "irreversibly" recruit serum antibodies to tumor cells. These covalent chimeras leverage electrophile preorganization and kinetic effective molarity to achieve fast and selective covalent engagement of the target ternary complex protein, e.g., serum antibody. Importantly, covalent engagement can proceed via diverse binding site amino acids beyond cysteine. Covalent chimeras demonstrated striking functional enhancements compared to noncovalent ARM analogs in functional immune assays. We revealed this enhancement was in fact due to the increased kinetic stability and not concentration, of ternary complexes. This finding was recapitulated using analogous CIR modalities that integrate peptidic or carbohydrate binding ligands with Sulfur(VI) Fluoride Exchange (SuFEx) electrophiles to induce cell-cell proximity. Mechanistic studies in a distinct model system that uses T cells engineered with receptors that recognize covalent chimeras or ARMs, revealed covalent receptor engagement uniquely enforces downstream activation signaling. Finally, this Account discusses potential challenges and future directions for adapting and optimizing covalent chimeric/bifunctional molecules for diverse applications in cell-cell induced proximity.

Arginine Accelerates Sulfur Fluoride Exchange and Phosphorus Fluoride Exchange Reactions between Proteins.

Sulfur fluoride exchange (SuFEx) and phosphorus fluoride exchange (PFEx) click chemistries are advancing research across multiple disciplines. By genetically incorporating latent bioreactive unnatural amino acids (Uaas), these chemistries have been integrated into proteins, enabling precise covalent linkages with biological macromolecules and paving the way for new applications. However, their suboptimal reaction rates in proteins limit effectiveness, and traditional catalytic methods for small molecules are often incompatible with biological systems or in vivo applications. We demonstrated that introducing an arginine adjacent to the latent bioreactive Uaa significantly boosts SuFEx and PFEx reaction rates between proteins. This method is effective across various Uaas, target residues, and protein environments. Notably, it also enables efficient SuFEx reactions in acidic conditions, common in certain cellular compartments and tumor microenvironments, which typically hinder SuFEx reactions. Furthermore, we developed the first covalent cell engager that substantially enhances natural killer cell activation through improved covalent interaction facilitated by arginine. These findings provide mechanistic insights and offer a biocompatible strategy to harness these robust chemistries for advancing biological research and developing new biotherapeutics.

Arginine Accelerates Sulfur Fluoride Exchange and Phosphorus Fluoride Exchange Reactions between Proteins

AbstractSulfur fluoride exchange (SuFEx) and phosphorus fluoride exchange (PFEx) click chemistries are advancing research across multiple disciplines. By genetically incorporating latent bioreactive unnatural amino acids (Uaas), these chemistries have been integrated into proteins, enabling precise covalent linkages with biological macromolecules and paving the way for new applications. However, their suboptimal reaction rates in proteins limit effectiveness, and traditional catalytic methods for small molecules are often incompatible with biological systems or in vivo applications. We demonstrated that introducing an arginine adjacent to the latent bioreactive Uaa significantly boosts SuFEx and PFEx reaction rates between proteins. This method is effective across various Uaas, target residues, and protein environments. Notably, it also enables efficient SuFEx reactions in acidic conditions, common in certain cellular compartments and tumor microenvironments, which typically hinder SuFEx reactions. Furthermore, we developed the first covalent cell engager that substantially enhances natural killer cell activation through improved covalent interaction facilitated by arginine. These findings provide mechanistic insights and offer a biocompatible strategy to harness these robust chemistries for advancing biological research and developing new biotherapeutics.

Reshaping the tumor microenvironment by degrading glycoimmune checkpoints Siglec-7 and -9.

Cancer treatment has been rapidly transformed by the development of immune checkpoint inhibitors targeting CTLA-4 and PD-1/PD-L1. However, many patients fail to respond, especially those with an immunosuppressive tumor microenvironment (TME), suggesting the existence of additional immune checkpoints that act through orthogonal mechanisms. Sialic acid-binding immunoglobulin-like lectin (Siglec)-7 and -9 are newly designated glycoimmune checkpoints that are abundantly expressed by tumor-infiltrating myeloid cells. We discovered that T cells express only basal levels of Siglec transcripts; instead, they acquire Siglec-7 and -9 from interacting myeloid cells in the TME via trogocytosis, which impairs their activation and effector function. Mechanistically, Siglec-7 and -9 suppress T cell activity by dephosphorylating T cell receptor (TCR)-related signaling cascades. Using sulfur fluoride exchange (SuFEx) click chemistry, we developed a ligand that binds to Siglec-7 and -9 with high-affinity and exclusive specificity. Using this ligand, we constructed a Siglec-7/9 degrader that targets membrane Siglec-7 and -9 to the lysosome for degradation. Administration of this degrader induced efficient Siglec degradation in both T cells and myeloid cells in the TME. We found that Siglec-7/9 degradation has a negligible effect on macrophage phagocytosis, but significantly enhances T cell anti-tumor immunity. The degrader, particularly when combined with anti-CTLA-4, enhanced macrophage antigen presentation, reshaped the TME, and resulted in long-lasting T cell memory and excellent tumor control in multiple murine tumor models. These findings underscore the need to consider exogenous checkpoints acquired by T cells in the TME when selecting specific checkpoint blockade therapy to enhance T cell immunity.

Innovative Peptide Bioconjugation Chemistry with Radionuclides: Beyond Classical Click Chemistry.

Background: The incorporation of radionuclides into peptides and larger biomolecules requires efficient and sometimes biorthogonal reaction conditions, to which click chemistry provides a convenient approach. Methods: Traditionally, click-based radiolabeling techniques have focused on classical click chemistry, such as copper(I)-catalyzed alkyne-azide [3+2] cycloaddition (CuAAC), strain-promoted azide-alkyne [3+2] cycloaddition (SPAAC), traceless Staudinger ligation, and inverse electron demand Diels-Alder (IEDDA). Results: However, newly emerging click-based radiolabeling techniques, including tyrosine-click, sulfo-click, sulfur(VI) fluoride exchange (SuFEx), thiol-ene click, azo coupling, hydrazone formations, oxime formations, and RIKEN click offer valuable alternatives to classical click chemistry. Conclusions: This review will discuss the applications of these techniques in peptide radiochemistry.

Cone Angles Quantify and Predict the Affinity and Reactivity of Anion Complexes between Trifluoroborates and Rigid Macrocycles.

Steric manipulation is a known concept in molecular recognition but there is currently no linear free energy relationship correlating sterics to the stability of receptor-anion complexes nor to the reactivity of the bound anion. By analogy to Tolman cone angles in cation coordination chemistry, we explore how to define and correlate cone angles of organo-trifluoroborates (R-BF3 -) to the affinities observed for cyanostar-anion binding. We extend the analogy to a rare investigation of the anion's reactivity and how it changes upon binding. The substituent on the anion is used to define the cone angle, θ. A series of 10 anions were studied including versions with ethynyl, ethylene, and ethyl substituents to tune steric bulk across the sp, sp2 and sp3 hybridized α-carbons bearing 0, 1 and 2 hydrogen atoms. A linear relationship between affinity and cone angle is observed for anions bearing substituents larger than the -BF3 - headgroup. This correlation predicted affinities of two new anions to within ±5 %. We explored how complexation affects the reactivity of fluoride exchange. The yield of fluoride transfer from R-BF3 - to Lewis acid triphenylborane is correlated with cone angle. We predict that other rigid macrocycles, like commercially available bambusuril, could follow these trends.

Targeted sulfur(VI) fluoride exchange-mediated covalent modification of a tyrosine residue in the catalytic pocket of tyrosyl-DNA phosphodiesterase 1

Developing effective inhibitors of the DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 (TDP1) has been challenging because of the enzyme shallow catalytic pocket and non-specific substrate binding interactions. Recently, we discovered a quinolone-binding hot spot in TDP1’s active site proximal to the evolutionary conserved Y204 and F259 residues that position DNA. Sulfur (VI) fluoride exchange (SuFEx) is a biocompatible click chemistry reaction that enables acylation of protein residues, including tyrosine. Selective protein modifications can provide insights into the biological roles of proteins and inform ligand design. As we report herein, we used SuFEx chemistries to prepare covalent TDP1-bound binders showing site-specific covalent bonds with Y204. Our work presents the first application of SuFEx chemistries to TDP1 ligands. It validates the ability to covalently modify specific TDP1 residues by designed targeting and adds to the chemical biology resource toolbox for studying TDP1.

Sulfur Fluoride Exchange Enabled Polysufate Adsorbents: Flexible Group Embedded in Polymer Backbone Regulation Strategy for Organic Solvent Removal from Water.

Removal of organic solvents (such as chloroform, toluene, etc.) in trace amounts using adsorbents from water is a challenge due to their low removal efficiencies and poor selectivities. Herein, four polysulfates (P1-P4) with different flexible group embedded backbones were synthesized via a sulfur fluoride exchange (SuFEx) reaction, and their swelling behaviors in organic solvents were investigated. P1 with a flexible ethyl group on its backbone can selectively swell in aprotic organic solvents with medium and high polarities about 30-fold its original weight, which is much higher than that of P4 with rigid benzene on its backbone. Moreover, molecular dynamic (MD) simulation results showed that the swelling mechanism could be put down to the electrostatic and van der Waals forces between the polysulfates and organic solvents. Surprisingly, the polysulfates can be used to remove chloroform and toluene from water with removal efficiencies of up to 99.26 and 99.42%, respectively. Furthermore, the polysulfates also exhibited high selectivities and anti-interference performances toward chloroform in the presence of other pollutants and different acid/base environments. Our work provides a strategy to construct adsorbents with high efficiencies for removal of low concentrations of organic solvents from water.

Engineering SuFEx-derived macrocyclic polysulfates for superior dynamic iodine capture at high temperatures

Efficient dynamic capture of radioiodine vapor from reprocessing of spent nuclear fuel under industrial conditions (∼423.15 K) is critically required due to its detrimental environmental and health impacts. However, conventional adsorbents often suffer from reduced binding affinity and structural degradation at elevated temperatures. To address these challenges, we have engineered a series of advanced polysulfate networks using sulfur (VI) fluoride exchange (SuFEx) click chemistry. These innovative networks integrate supramolecular macrocycle calix[4]pyrrole (C[4]P) and nitrogen-rich co-monomers as building blocks, and utilize polar sulfate bonds as important linkers, which provide availability of adsorptive sites and enhance the structural stability, thereby affording unexpected iodine capture performance at high temperatures. Among these SuFEx-derived materials, C[4]P-Azo exhibits exceptional iodine affinity through cooperative interactions involving multiple binding motifs, achieving an impressive iodine uptake capacity of 0.45 g g−1 at 423.15 K under dynamic adsorption conditions, setting a new benchmark in this field. Comprehensive characterizations and DFT calculations elucidate that advanced linker sulfate bonds enabling the marriage of C[4]P and N-rich monomers, play pivotal roles in facilitating iodine adsorption and maintaining structural integrity. These findings may pave the way for designing robust macrocyclic polysulfate-based adsorbents for dynamic radioiodine capture under industrial conditions.

Highly Functionalized SuFEx-able Hub Bearing All-Carbon Quaternary Center via Rapid Brønsted Superbase Catalysis.

A rapid Brønsted superbase catalysis for highly functionalized sulfur(VI)-fluoride exchange (SuFEx) hubs bearing all-carbon quaternary centers was developed. Remarkable functional group tolerance toward esters and nitriles was achieved by Michael addition of cyanoacetate derivatives to ethenesulfonyl fluoride with low catalyst loadings (∼0.5 mol %) within a short reaction time (0.5-30 min). Gram-scalability, water tolerance, and compatibility in polymeric catalysis showcase its unique practicability. SuFEx click conjugations were demonstrated using various amines, including DNA-tethered biomolecules.

A Unified Synthesis of Diazenes from Primary Amines Using a SuFEx/Electrochemistry Strategy.

The electrochemical synthesis of 1,2-disubsituted diazenes via anodic oxidation of bench stable symmetrical and unsymmetrical sulfamides is reported. This work capitalizes on the streamlined preparation of diverse N,N'-disubstituted sulfamides using Sulfur(VI) Fluoride Exchange (SuFEx) click chemistry that were subsequently subjected to electrochemical oxidation to afford the desired diazenes. The electrochemical nature of the reaction conditions obviated the need for chlorinating reagents, which considerably improved the sustainability of the overall process. Noteworthy, in addition to the synthesis of alkyl diazenes, these milder conditions were shown to be competent for the formation of azobenzenes, albeit in lower yields. Mechanistic experiments were conducted to delineate the reaction pathway and to rationalize the formation of side products observed during the electro-oxidation of N,N'-diarylsulfamides.

Cone Angles Quantify and Predict the Affinity and Reactivity of Anion Complexes between Trifluoroborates and Rigid Macrocycles

AbstractSteric manipulation is a known concept in molecular recognition but there is currently no linear free energy relationship correlating sterics to the stability of receptor‐anion complexes nor to the reactivity of the bound anion. By analogy to Tolman cone angles in cation coordination chemistry, we explore how to define and correlate cone angles of organo‐trifluoroborates (R−BF3−) to the affinities observed for cyanostar‐anion binding. We extend the analogy to a rare investigation of the anion's reactivity and how it changes upon binding. The substituent on the anion is used to define the cone angle, θ. A series of 10 anions were studied including versions with ethynyl, ethylene, and ethyl substituents to tune steric bulk across the sp, sp2 and sp3 hybridized α‐carbons bearing 0, 1 and 2 hydrogen atoms. A linear relationship between affinity and cone angle is observed for anions bearing substituents larger than the −BF3− headgroup. This correlation predicted affinities of two new anions to within ±5 %. We explored how complexation affects the reactivity of fluoride exchange. The yield of fluoride transfer from R−BF3− to Lewis acid triphenylborane is correlated with cone angle. We predict that other rigid macrocycles, like commercially available bambusuril, could follow these trends.

Fe-Catalyzed Fluorosulfonylation of Alkenes via Sulfur Dioxide Insertion: Synthesis of Lactam-Functionalized Alkyl Sulfonyl Fluorides.

A novel Fe-catalyzed fluorosulfonylation of alkenes with Na2S2O4 and N-fluorobenzenesulfonimide (NFSI) for assembling various lactam-functionalized alkyl sulfonyl fluorides is disclosed. In this reaction, Na2S2O4 acts as both an SO2 source and a reductant. Furthermore, the resulting products can be efficiently transformed into valuable chemicals, including sulfonyl esters and sulfonamides, via the sulfur(VI) fluoride exchange (SuFEx) click reaction. Preliminary mechanistic studies suggest that the transformation proceeds through intramolecular radical cyclization, SO2 insertion, sulfite anion formation, and fluorination.