SuFEx and Sulfonyl Fluorides: From S(VI)–F Click Ligation Reactions to Covalent Tools in Chemical Biology

I. Conceptual Starting Point: First Distinguish SuFEx from Sulfonyl Fluorides

SuFEx (sulfur(VI) fluoride exchange) is a class of ligation reactions, rather than a specific molecule. Its core feature is the use of exchange reactions at sulfur(VI)–fluoride bonds to form new S–O, S–N, and related linkages under suitable conditions. In 2014, Dong, Krasnova, Finn, and Sharpless systematically proposed and clarified SuFEx as an important member of click chemistry, and this work is commonly regarded as the key starting point for the modern resurgence of SuFEx research.[1]

Sulfonyl fluoride (R–SO₂F) is a specific functional group. It can serve both as a substrate in SuFEx reactions and as a covalent reactive group in chemical biology, where, after a molecule first completes reversible recognition, controlled covalent fixation occurs within a protein binding site. In other words, SuFEx focuses on “how to construct linkages around the S(VI)–F bond,” whereas sulfonyl fluoride focuses on “which specific motif is most commonly used for this type of ligation, or further developed into a covalent chemical biology tool.” Understanding this difference in hierarchy first helps clarify the later discussion of reaction design, protein reactivity, and application boundaries.[1,2]

1.1 Conceptual Distinction Across Three Levels

Level	Representative Object	How It Should Be Understood
Reaction methodology	SuFEx	A class of click ligation reactions centered on S(VI)–F bond exchange
Specific functional group	Sulfonyl fluoride (R–SO₂F)	One of the most common and most extensively studied S(VI)–F motifs
Related family members	Aryl fluorosulfates, sulfamoyl fluorides, iminosulfur oxydifluorides, etc.	These belong to the same broader family, but their stability, the conditions under which they are most suitable for reaction, and their application scenarios are not the same.

1.2 Why This Topic Merits Attention

One major reason SuFEx continues to attract attention is that it provides a highly reliable class of S(VI)–F ligation reactions. Unlike CuAAC, which mainly generates triazole linkages, the core of SuFEx is the construction of stable sulfur-centered linkages around sulfur(VI) fluoride bonds. As the applications of related motifs such as sulfonyl fluorides and aryl fluorosulfates in chemical biology have continued to expand, this route has further extended into controlled covalent interactions that depend on molecular recognition and the protein microenvironment.[1]

Subsequent studies have shown that some S(VI)–F motifs are not simply strongly electrophilic tags that “react rapidly and indiscriminately with any nucleophile they encounter.” Representative motifs such as sulfonyl fluorides and aryl fluorosulfates often follow a “binding first, bond formation second” process: reversible recognition occurs first, and then spatial proximity together with the protein microenvironment helps complete the covalent reaction. In their 2015 review, Narayanan and Jones described sulfonyl fluorides as a “privileged warhead” that combines aqueous stability with protein reactivity; meanwhile, the 2018 review and original studies on aryl fluorosulfates further emphasized that their reactivity is highly dependent on pocket environment. For this reason, this line of research has expanded from synthetic methodology into target discovery, covalent probes, and chemical proteomics.[2,3,5]

II. Property Differences and Division of Roles Among Different S(VI)–F Motifs

Belonging to the same S(VI)–F family does not mean these species function as the same chemical tool. A more practically useful way to evaluate them in research is not merely to note that they all contain a sulfur(VI)–fluoride bond, but to compare how they differ in hydrolytic stability, intrinsic reactivity, modes of bond formation in protein environments, and the research tasks for which they are best suited.[2,3,6,8]

A systematic 2023 profiling study of a group of sulfur(VI) fluorides provided direct evidence for this view. The study showed that different S(VI)–F reactive groups differ markedly in hydrolytic stability, amino acid side-chain reactivity, protein modification efficiency, and chemical proteomics performance. They therefore should not be understood simply as different points along a single scale of “stronger” versus “weaker” reactivity.[8]

From the perspective of specific types:

a) Sulfonyl fluorides remain the most common and most deeply studied class of specific motifs. Their importance lies in the fact that they often achieve a useful balance between aqueous stability compatible with biological experiments and reactivity that can be selectively activated by the protein microenvironment. For this reason, they have long been regarded as one of the representative covalent warheads in chemical biology.[2]

b) Aryl fluorosulfates, by contrast, often more clearly exemplify the principle that “the binding-site environment determines the covalent outcome.” The 2018 review pointed out that the behavior of these motifs toward Tyr, Lys, Ser, His, and other residues shows clear context-dependent characteristics, relying more heavily on the cooperative effects of reversible binding, spatial proximity, and the pocket microenvironment. They therefore should not be simply viewed as universally highly reactive electrophilic tags.[3]

c) SOF₄-derived iminosulfur oxydifluorides reflect yet another type of value. They are better suited to serving as multifunctional connection centers for subsequent SuFEx transformations under mild conditions, and they have already been used in the bioconjugation of DNA and proteins. Their significance therefore lies more in acting as connective hubs for multidimensional ligation and bioconjugation, rather than being directly interpreted within the standard usage logic of sulfonyl fluoride warheads.[6]

Thus, these species share the same S(VI)–F chemical theme, but each has a different emphasis in terms of the stability–reactivity balance, dependence on the protein environment, and application scenario. For exactly this reason, in specific experimental design, one cannot assume they are interchangeable simply because they all belong to the S(VI)–F family.[2,3,6,8]

III. Why Sulfonyl Fluorides Have Become One of the Most Important Motifs

The importance of sulfonyl fluorides lies in the fact that they often achieve a balance among operability, stability, and selectively activatable reactivity. A 2015 review pointed out that, compared with related electrophilic motifs that are more reactive but also more prone to loss of control, sulfonyl fluorides are better suited for use in chemical biology settings; one of their key advantages is that they combine appropriate aqueous stability with protein reactivity.[2]

This balance between stability and reactivity gives sulfonyl fluorides two major kinds of application value at the same time. First, they are well suited as commonly used motifs in ligation reactions, enabling molecular coupling and rapid derivatization while maintaining good practical operability. Second, they are also well suited as covalent reactive groups: after a molecule first enters the target pocket through noncovalent recognition and adopts a suitable spatial arrangement, the sulfonyl fluoride can form a more selective covalent fixation under the promotion of the protein microenvironment. A 2025 review further summarized this direction as sulfonyl exchange chemical biology and emphasized its continuing value in expanding the space of druggable targets.[2,10]

However, it must be emphasized that sulfonyl fluorides should not be simplistically understood as “strong electrophilic tags” that react rapidly and indiscriminately with protein nucleophilic sites in all systems. A more accurate understanding should include the following three points:

1. First, the advantage of sulfonyl fluorides is not that they are simply more reactive, but that they achieve a more suitable balance between aqueous stability and protein reactivity. It was precisely from this perspective that the 2015 review summarized them as a representative covalent warhead in chemical biology.[2]

2. Second, the classic studies on aryl fluorosulfates showed that bond formation by certain S(VI)–F motifs is highly dependent on reversible binding, spatial proximity, and the protein pocket microenvironment. This indicates that S(VI)–F reactions are not always crude, environment-independent processes driven only by high intrinsic reactivity.[3]

3. Finally, the same degree of caution should also be applied when evaluating sulfonyl fluorides themselves. Their actual bond-forming outcome depends not only on the name of the warhead, but also on the combined effects of hydrolytic stability, intrinsic reactivity, the molecular scaffold, and the environment of the protein binding site; the 2023 profiling study provided further support for this point.[2,3,8]

IV. Four Core Research Uses of SuFEx and Sulfonyl Fluorides

SuFEx and sulfonyl fluorides are important because together they form a continuous application chain across four levels: ligation chemistry, covalent molecule design, chemical proteomics, and bioconjugation.[1,6,7,9,10]

Research Task	Best Prioritized Option	Core Problem Solved
Rapid construction of structurally diverse molecules	SuFEx ligation reactions	Forms S–O / S–N and related linkages with relatively high reliability, suitable for rapid derivatization and library construction
Upgrading a reversible ligand into a covalent probe or covalent inhibitor	Sulfonyl fluorides	Introduces site-specific covalent fixation while retaining the recognition scaffold
Performing live-cell target engagement studies and chemical proteomics	Sulfonyl fluorides or related probes bearing clickable handles	Facilitates enrichment, site identification, competition experiments, and family-selectivity analysis
Carrying out DNA/protein conjugation or multidirectional molecular assembly	SOF₄-related systems	Exploits the advantages of multifunctional connection centers to achieve multidimensional ligation and post-modification

Among these four use categories, the first two more strongly represent the applications of “sulfonyl fluorides” as specific warheads/building blocks, whereas the latter two more clearly reflect the expansion of the SuFEx family toward connective hubs such as SOF₄ and iminosulfur oxydifluorides.

Among these four uses, the most representative shift is that this route has extended traditional covalent design strategies, which were largely centered on Cys, toward the exploration of Tyr, Lys, and other non-cysteine residues. It should be emphasized that this does not mean all systems can universally and efficiently target these residues; rather, S(VI)–F chemistry provides rationally designable and experimentally testable opportunities for these sites, and in doing so has promoted the development of beyond-cysteine covalent chemistry.[2,3,8,10]

V. The Developmental Value of SuFEx and Sulfonyl Fluorides Through Representative Cases

a) In 2017, the XO44 study reported by Zhao and co-workers showed that a lysine-targeting sulfonyl fluoride probe could covalently label as many as 133 endogenous kinases in live cells and could be used to analyze the intracellular kinase binding profile of dasatinib. The significance of this work lies not simply in “labeling a relatively large number of proteins,” but in demonstrating that sulfonyl fluoride probes can be brought into live-cell chemical proteomics studies directed at the kinase family.[4]

b) In 2018, the “Inverse Drug Discovery” strategy proposed by Mortenson and co-workers further showed that aryl fluorosulfates are not highly reactive groups that react indiscriminately whenever they encounter a nucleophilic site, but rather resemble latent covalent motifs that require participation of the protein binding site for activation. Using this strategy, the researchers identified and validated 11 human protein targets, some of which had previously lacked available small-molecule probes.[5]

c) In 2020, Kitamura and co-workers introduced intermediates bearing iminosulfur oxydifluoride sites, which could undergo further SuFEx derivatization, into a high-throughput medicinal chemistry workflow. Starting from a SpeB inhibitor with an initial Ki of 8 μM, they rapidly generated 460 analogs and improved the activity to 18 nM. This case shows that SuFEx is not only suitable for molecular ligation, but is also well suited to rapid hit-to-lead optimization workflows combined with direct-to-biology strategies.[7]

d) In 2019, Liu and co-workers demonstrated the feasibility of using SOF₄-derived iminosulfur oxydifluoride multifunctional connection centers for DNA and protein bioconjugation under mild buffer conditions; in 2023, Chen and co-workers used a set of paired enantiomeric clickable chiral sulfonyl fluoride probes to systematically map 634 ligandable Tyr/Lys sites in intact cells. The former shows that SuFEx is not limited to small-molecule ligation, while the latter shows that this route has advanced from proof-of-concept studies on individual targets to the stage of systematic site-resource construction.[6,9]

VI. The Most Important Points to Watch When Selecting and Using Them

In experimental design involving SuFEx and sulfonyl fluorides, the most important judgment is not “whether this group is popular,” but whether the actual research goal is ligation or site-directed covalent action. If the goal is to rapidly construct and screen a set of structurally diverse molecules, SuFEx is better considered as a ligation method; if the goal is to upgrade an existing reversible ligand into a covalent probe or inhibitor with a defined site of action, sulfonyl fluorides or related S(VI)–F covalent reactive groups deserve priority evaluation.[1,2,7,10]

Key Question	More Accurate Judgment
Are we discussing a method, or a functional group?	SuFEx is a ligation reaction; sulfonyl fluoride is a specific motif
Is stronger reactivity always better?	No. What truly matters is stability, selectivity, controllability, and compatibility with the system
Can bond formation be predicted solely from the warhead name?	No. Binding, orientation, nearby residues, and microenvironment are equally important
Can different S(VI)–F motifs be used interchangeably?	No. They differ substantially in both stability and use
If only an activity change is observed, does that prove the correct site has been targeted?	No. More reliable evidence should include site identification, competition experiments, mutational validation, and, where necessary, structural data

The common logic behind these points is that what SuFEx and sulfonyl fluorides truly seek is not faster indiscriminate reactivity, but more reliable, more interpretable, and more verifiable ligation or covalent action in complex chemical and biological environments. This is also why high-quality work in recent years has tended to discuss activity, site, competition relationships, and structural evidence together, rather than merely reporting that “a reaction occurred” or “labeling was observed.”[4,5,8,9,10]

VII. Future Outlook: Directions Worth Sustained Attention

What is truly worth watching in this field is not whether it will replace other click reactions or existing covalent drug strategies, but whether it can continue to expand its own application boundaries. Three aspects are especially worth attention at present:

1. To further expand the developable space of non-cysteine residues, enabling Tyr, Lys, and other sites to be used more systematically in covalent probe and drug design.

2. To more robustly extend S(VI)–F-related chemistry to broader classes of molecules, including peptides, proteins, oligonucleotides, RNA, and carbohydrates.

3. To establish more systematic resource maps of Tyr, Lys, and other reactive sites in combination with chemical proteomics.

The 2025 review followed exactly this main line in summarizing the stage-by-stage progress of sulfonyl exchange chemical biology in drug discovery and fundamental research.[6,9,10]

At the same time, the 2023 systematic profiling of S(VI)–F reactive motifs also suggested that, for this field to mature further, it will require more predictable reactivity control, clearer structure–reactivity relationships, and more complete systems for evaluating intracellular selectivity. In other words, the application value of SuFEx and sulfonyl fluorides has already been well demonstrated, but the best design rules for them are still continuing to evolve.[8,10]

VIII. Product Navigation for SuFEx and Sulfonyl Fluorides: Quickly Locate Tables 1–4 by Research Task

Research Task / Experimental Need	Product Types to Focus On	Recommended Table to Read First	Navigation Notes
Want to first establish a SuFEx entry point by converting phenols, amines, and related substrates into precursors that can undergo further reaction	Fluorosulfonylation installation reagents, aryl fluorosulfate precursors	Table 1	Table 1 is most suitable as a starting point for introductory selection. If your goal is first to convert substrates into fluorosulfates or related S(VI)–F precursors and then proceed to subsequent ligation or derivatization, Table 1 is the most direct place to start.
Want to carry out SuFEx methodology development by first using several representative substrates to understand conditions, substrate compatibility, and electronic effects	Basic aryl sulfonyl fluorides, activated aryl sulfonyl fluorides, heteroaryl sulfonyl fluorides	Table 2	Table 2 brings together a set of core sulfonyl fluorides most suitable for condition screening and substrate comparison. It is well suited for reaction scouting, catalyst optimization, substituent-effect comparison, and representative substrates in methodology papers.
Want to compare how different scaffolds affect sulfonyl fluoride reactivity or application performance	Aryl, heteroaryl, fused-ring, alkenyl, and small-ring aliphatic sulfonyl fluorides	Table 2	If your focus is on what changes are introduced by scaffold differences, Table 2 is the most representative because it simultaneously covers several common structural classes, including aromatic, heterocyclic, fused-ring, alkenyl, and aliphatic examples.
Want to perform medicinal chemistry or probe design by introducing a sulfonyl fluoride warhead that can undergo subsequent reaction within a molecule	Structurally clear, general-purpose sulfonyl fluoride building blocks suitable for use as warheads	Table 2	When the goal is to embed a sulfonyl fluoride as a functional site within a molecular scaffold, rather than simply to demonstrate a reaction, the basic and activated building blocks in Table 2 are better starting points as warheads.
Want to use more advanced “further-assemblable” building blocks for later coupling, deprotection, tag installation, or linker extension	Bifunctional and multifunctional aryl sulfonyl fluoride building blocks	Table 3	Table 3 is suitable for research that has moved beyond a single sulfonyl fluoride substrate. The products here are more appropriate for probe platforms, two-site assembly, subsequent coupling, and modular structural expansion.
Want to design chemical probes, clickable probes, or chemical biology tool molecules	Advanced building blocks bearing bromine, formyl, TMS-alkyne, and other sites for continued derivatization	Table 3	If your goal is not simply to run a reaction, but to further attach fluorophores, affinity tags, or bioorthogonal handles, Table 3 is usually more practical than Table 2.
Want to study sulfamoyl fluorides as a class of nitrogen-containing S(VI)–F structures, or create nitrogen-containing linking units distinct from conventional sulfonyl fluorides	Sulfamoyl fluoride building blocks	Table 3	The products of this type in Table 3 are better suited for introducing nitrogen-containing S(VI)–F units, comparing reactivity, and expanding structure, and they serve well as an entry point from ordinary sulfonyl fluorides to more advanced systems.
Need rapid inhibition of serine proteases for protein extraction, enzyme activity protection, or related experiments	AEBSF, PMSF, and their ready-to-use solutions	Table 4	Table 4 focuses less on synthetic building blocks and more on products ready for direct biochemical use. If the experimental priority is sample protection, enzyme inhibition, or routine biochemical operations, Table 4 is the most practical place to begin.
Want to understand “sulfonyl fluoride” as a chemical biology warhead rather than merely as a synthetic substrate	Classic reference molecules such as AEBSF/PMSF + advanced probe building blocks	First read Table 4, then combine it with Table 3	Table 4 helps clarify the classic uses of sulfonyl fluorides in protein and enzyme systems; Table 3 is more suitable for moving further toward probe design, tag installation, and structural optimization. Reading them together best matches the logic of chemical biology-oriented selection.
Simply want to build a rapid overall understanding of the product landscape in this topic, but are unsure where to begin	Platform reagents + general-purpose building blocks	First read Table 1, then Table 2	For readers encountering SuFEx and sulfonyl fluorides for the first time, the most reliable sequence is to first read Table 1 to understand how the precursors are introduced, and then read Table 2 to understand the common substrates. This is the easiest way to build an overall framework.

Table 1 | SuFEx Precursor-Installation Reagents and Fluorosulfate Precursors

Category	CAS No.	Aladdin Catalog No.	Name	Specification or Purity	Product Features and Applications
SuFEx fluorosulfurylation installation reagent	2172794-56-6	A588152	(4-Acetamidophenyl)(fluorosulfonyl)sulfamoyl fluoride	≥98%	An AISF-type stable solid fluorosulfurylation reagent that can convert phenols or amines into fluorosulfates or sulfamoyl fluorides. It is suitable for SuFEx precursor installation, methodology development, and subsequent modular ligation.
SuFEx fluorosulfurylation installation reagent	2179072-33-2	F351007	1-(Fluorosulfonyl)-2,3-dimethyl-1H-imidazol-3-ium trifluoromethanesulfonate	≥95%	This is SuFEx-IT, a representative fluorosulfurylation reagent commonly used for the efficient conversion of phenols, amines, and related substrates into fluorosulfates or sulfonyl fluoride-related precursors. It is a highly important precursor-introduction reagent in SuFEx systems.
Aryl fluorosulfate substrate	141694-39-5	N486692	2-Naphthalenyl ester fluorosulfuric acid	——	This molecule is essentially an aryl fluorosulfate, an important substrate class in SuFEx alongside sulfonyl fluorides. It can serve as a fluorosulfate-type ligation unit and can also be used in coupling/derivatization reactions and studies of aryl fluorosulfate reactivity.

Table 2 | Common Sulfonyl Fluoride Building Blocks and Reaction Substrates

Category	CAS No.	Aladdin Catalog No.	Name	Specification or Purity	Product Features and Applications
Basic aryl sulfonyl fluoride building block	368-43-4	B474308	Benzenesulfonyl fluoride	≥99%	One of the most fundamental representative aryl sulfonyl fluorides. It can serve as a foundational reference substrate for SuFEx and sulfonyl fluoride methodology, nucleophilic substitution reactions, warhead comparison, and building-block development.
Basic aryl sulfonyl fluoride building block	455-16-3	I170441	p-Toluenesulfonyl fluoride	≥98%	A common and stable basic aryl sulfonyl fluoride building block, suitable as a standard substrate in SuFEx/sulfonyl fluoride methodology development and often used for comparison with more activated or more complex substrates.
Activated aryl sulfonyl fluoride building block	33719-37-8	C1013904	4-Cyanobenzene-1-sulfonyl fluoride	_	The para-cyano group provides additional electron-withdrawing effect and further derivatization potential, making this a relatively reactive aryl sulfonyl fluoride building block suitable for electronic-effect comparison and medicinal chemistry modification.
Activated aryl sulfonyl fluoride building block	349-96-2	N467252	4-Nitrobenzenesulfonyl fluoride	≥95%	A typical strongly electron-withdrawing activated aryl sulfonyl fluoride, commonly used for reactivity comparison, SuFEx condition screening, and the construction of aryl warheads that are more readily recognized or transformed.
Heteroaryl sulfonyl fluoride building block	382-99-0	T467266	2-Thiophenesulfonyl fluoride	≥95%	A heteroaryl sulfonyl fluoride building block that combines a thiophene heterocycle with a sulfonyl fluoride warhead. It can be used for heterocycle-directed SuFEx derivatization, medicinal chemistry lead modification, and chemical biology probe design.
Heteroaryl sulfonyl fluoride building block	878376-35-3	P160051	Pyridine-2-sulfonyl Fluoride	≥98%	A heteroaryl sulfonyl fluoride containing pyridine nitrogen, combining heterocyclic recognition characteristics with a sulfonyl fluoride ligation site. It is commonly used in heteroaryl building-block expansion, medicinal chemistry molecule modification, and chemical biology ligand design.
Fused-ring aryl sulfonyl fluoride building block	325-12-2	N467239	2-Naphthalenesulfonyl fluoride	≥95%	A fused-ring aryl sulfonyl fluoride building block with a more hydrophobic aromatic surface than basic phenyl systems. It is suitable for aryl sulfonyl fluoride reactivity comparison, molecular scaffold expansion, and the introduction of hydrophobic fragments into ligands/probes.
Alkenyl sulfonyl fluoride building block	405-18-5	P467275	2-Phenylethenesulfonyl fluoride	≥95%	A representative alkenyl sulfonyl fluoride substrate that combines an alkenyl site for further transformation with a sulfonyl fluoride ligation site. It is suitable for SuFEx methodology, alkenyl sulfonyl fluoride reactivity studies, and covalent fragment expansion.
Small-ring aliphatic sulfonyl fluoride building block	822-49-1	C467424	Cyclopropanesulfonyl fluoride	≥95%	A small-ring aliphatic sulfonyl fluoride that reflects the characteristics of sp3-rich sulfonyl fluoride building blocks. It is suitable for introducing small-ring fragments in medicinal chemistry, reactivity comparison, and non-aryl warhead design.

Table 3 | Advanced Sulfonyl Fluoride Building Blocks for Further Derivatization

Category	CAS No.	Aladdin Catalog No.	Name	Specification or Purity	Product Features and Applications
Bifunctional aryl sulfonyl fluoride building block	7612-88-6	B469651	4-(Bromomethyl)benzenesulfonyl fluoride	≥97%	Contains both a benzylic bromide and a sulfonyl fluoride as operable sites, making it suitable for linker installation, subsequent SN2 derivatization, and two-site assembly of SuFEx probes/ligands. It is a highly practical bifunctional building block.
Multifunctional probe-type sulfonyl fluoride building block	2088829-15-4	B463419	3-Bromo-5-((trimethylsilyl)ethynyl)benzenesulfonyl fluoride	≥95%	A multifunctional aryl sulfonyl fluoride building block containing both an aryl bromide and a TMS-protected alkyne site, enabling further coupling, deprotection, and probe assembly. It is suitable for subsequent expansion of SuFEx chemical probes and chemical biology warhead platform molecules.
Multifunctional probe-type sulfonyl fluoride building block	2088829-13-2	F463417	3-Formyl-5-((trimethylsilyl)ethynyl)benzenesulfonyl fluoride	≥95%	A trifunctional sulfonyl fluoride building block combining a formyl group, a TMS-alkyne, and a sulfonyl fluoride. It can be used for chemical probe synthesis, tag installation, and directed derivatization, making it an advanced building block with a stronger chemical biology orientation.
Sulfamoyl fluoride building block	354-44-9	N588847	N,N-Dimethylsulfamoyl fluoride	≥95%	A representative sulfamoyl fluoride building block suitable for introducing nitrogen-containing S(VI)–F ligation units, studying sulfamoyl fluoride reactivity, and synthesizing SuFEx-related nitrogen-containing derivatives.

Table 4 | Biochemical Tool-Type and Chemical Biology Reference Molecules

Category	CAS No.	Aladdin Catalog No.	Name	Specification or Purity	Product Features and Applications
Biochemical tool-type sulfonyl fluoride (AEBSF)	30827-99-7	A109762	4-(2-Aminoethyl)benzenesulfonyl fluoride hydrochloride	≥98%	AEBSF in solid raw-material form, suitable for preparing working solutions according to experimental needs. In SuFEx/sulfonyl fluoride applications, it functions more as a chemical biology and enzyme inhibition tool molecule than as a synthetic installation reagent.
Biochemical tool-type sulfonyl fluoride (AEBSF)	30827-99-7	A423184	4-(2-Aminoethyl)benzenesulfonyl fluoride hydrochloride	10mM in DMSO	AEBSF is a classic broad-spectrum irreversible serine protease inhibitor and also a highly representative aryl sulfonyl fluoride warhead in chemical biology. It can be used for protein sample protection, enzymatic inhibition experiments, and as a reference for the biological reactivity of sulfonyl fluorides.
Biochemical tool-type sulfonyl fluoride (AEBSF)	30827-99-7	A301905	AEBSF Solution	50mg/ml in H2O	A ready-to-use aqueous AEBSF solution suitable for direct addition to lysis buffers, protein samples, or enzyme reaction systems. Its main uses are serine protease inhibition and biological sample protection.
Biochemical tool-type sulfonyl fluoride (PMSF)	329-98-6	P105539	Phenylmethanesulfonyl fluoride	Moligand™, ≥98%(GC)	PMSF in powder form is a classic irreversible serine protease inhibitor and also a representative tool molecule for understanding the covalent modification of protein active sites by sulfonyl fluorides.
Biochemical tool-type sulfonyl fluoride (PMSF)	329-98-6	P301906	PMSF Solution	100mM in ethanol	PMSF is one of the most classic sulfonyl fluoride-type irreversible serine protease inhibitors. This specification is suitable for direct use in protein extraction, enzyme activity protection, and rapid addition in biochemical experiments.
Biochemical tool-type sulfonyl fluoride (PMSF)	329-98-6	P408676	PMSF	10mM in DMSO	A ready-to-use PMSF working solution suitable for experiments requiring low-volume addition or compatibility with DMSO-based systems. Within this topic, it mainly serves as a commonly used sulfonyl fluoride reference molecule in chemical biology.

References

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[2] Narayanan A, Jones LH. Sulfonyl fluorides as privileged warheads in chemical biology. Chem Sci. 2015;6(5):2650-2659. doi:10.1039/C5SC00408J.

[3] Jones LH. Emerging Utility of Fluorosulfate Chemical Probes. ACS Med Chem Lett. 2018;9(7):584-586. doi:10.1021/acsmedchemlett.8b00276.

[4] Zhao Q, Ouyang X, Wan X, Gajiwala KS, Kath JC, Jones LH, Burlingame AL, Taunton J. Broad-Spectrum Kinase Profiling in Live Cells with Lysine-Targeted Sulfonyl Fluoride Probes. J Am Chem Soc. 2017;139(2):680-685. doi:10.1021/jacs.6b08536.

[5] Mortenson DE, Brighty GJ, Plate L, Bare G, Chen W, Li S, Wang H, Cravatt BF, Forli S, Powers ET, Sharpless KB, Wilson IA, Kelly JW. “Inverse Drug Discovery” Strategy To Identify Proteins That Are Targeted by Latent Electrophiles As Exemplified by Aryl Fluorosulfates. J Am Chem Soc. 2018;140(1):200-210. doi:10.1021/jacs.7b08366.

[6] Liu F, Wang H, Li S, Bare GAL, Chen X, Wang C, Moses JE, Wu P, Sharpless KB. Biocompatible SuFEx Click Chemistry: Thionyl Tetrafluoride (SOF₄)-Derived Connective Hubs for Bioconjugation to DNA and Proteins. Angew Chem Int Ed Engl. 2019;58(24):8029-8033. doi:10.1002/anie.201902489.

[7] Kitamura S, Zheng Q, Woehl JL, Solania A, Chen E, Dillon N, Hull MV, Kotaniguchi M, Cappiello JR, Kitamura S, Nizet V, Sharpless KB, Wolan DW. Sulfur(VI) Fluoride Exchange (SuFEx)-Enabled High-Throughput Medicinal Chemistry. J Am Chem Soc. 2020;142(25):10899-10904. doi:10.1021/jacs.9b13652.

[8] Gilbert KE, Vuorinen A, Aatkar A, et al. Profiling Sulfur(VI) Fluorides as Reactive Functionalities for Chemical Biology Tools and Expansion of the Ligandable Proteome. ACS Chem Biol. 2023. doi:10.1021/acschembio.2c00633.

[9] Chen Y, Craven GB, Kamber RA, Cuesta A, Zhersh S, Moroz YS, Bassik MC, Taunton J. Direct mapping of ligandable tyrosines and lysines in cells with chiral sulfonyl fluoride probes. Nat Chem. 2023;15(11):1616-1625. doi:10.1038/s41557-023-01281-3.

[10] Jones LH. Advances in sulfonyl exchange chemical biology: expanding druggable target space. Chem Sci. 2025;16:10119-10140. doi:10.1039/D5SC02647D.

For more related articles, please see below:

SuFEx: Sulfonyl Fluorides that Participate in the Next Click Reaction

Recent Advances in the Catalytic Transformations to Access Alkylsulfonyl Fluorides as SuFEx Click Hubs

Click Chemistry and Its Future Application Prospects

OSF/ASF Dual-Channel Toolbox: Divergent Reactions of Four-Membered Ring Sulfonyl Fluorides, Condition “Knobs,” and Selection Navigation