Development of intramolecular chalcogen bonding activated SuFEx click chemistryIn order to improve the reactivity of alkyl sulfonyl fluoride towards nucleophilic attack through intramolecular non-bonding 1,5-S···F interactions53, we designed the alkyl sulfonyl fluorides bearing γ-S (S-SuFEx hubs). These S-SuFEx hubs were synthesized via the robust thiol-ene reaction between readily available thiols and ESF. To evaluate the reactivity of S-SuFEx hubs, alkyl sulfonyl fluoride 1a was used as the model compound, and its analog 2a/2b without γ-S was used as the control compound. Significantly, the SuFEx reaction of 1a with phenol 4a performed well in a near quantitative yield to give the desired product 5a using 0.5 equiv. of BTMG (2-tert-butyl-1,1,3,3-tetramethylguanidine) as the base (Fig. 2a, Eq. 1). Under identical reaction conditions, 2a/2b reacted with phenol very slowly, delivering sulfonate 6a/6b in only 23%/16% yield (Fig. 2a, Eq. 2). These results exhibited that the intramolecular ChB interaction has dramatically improved the efficiency of the SuFEx reaction. Changing the thiol precursor from 1a to 1b/1c leads to a similar high reactivity. Nor Me3Si- group or (EtO)3Si- group has an impact on the reactivity of S-SuFEx reaction, and (EtO)3Si- group was well retained under the reaction conditions (Fig. 2a, Eq. 3 and 4). To further prove the effect of ChB on this reaction, 1a and 1b were oxidized to the corresponding sulfones (3a and 3b), which hindered the formation of ChB. As expected, the SuFEx reaction between 3a and 3b with phenol gave sulfonates 7 in extremely low yield (Fig. 2a, Eq. 5 and 6).Fig. 2: The development of ChB-activated SuFEx chemistry.a SuFEx reaction efficiencies of different alkyl sulfonyl fluorides. Reaction conditions: alkyl sulfonyl fluoride (0.3 mmol), phenol (0.3 mmol), and BTMG (0.15 mmol) were stirred in MeCN-d3 (1 mL) for 2 h at room temperature. b Variation in phenol concentration over time in its reaction with 1b, 2b, or SO2F2. Reaction conditions: alkyl sulfonyl fluoride 1b or 2b (0.3 mmol), phenol (0.3 mmol), and BTMG (0.15 mmol) were stirred in MeCN-d3 (1 mL) for 2 h at room temperature. SO2F2 was introduced by needle from a balloon filled with the gas.Subsequently, we explored the activation of alkyl sulfonyl fluorides through intermolecular ChB interaction. Dibutyl sulfide (1.0 equiv.) was introduced into the SuFEx reaction to act as the intermolecular ChB donor. However, despite this addition, there was no observed enhancement in the reaction efficiency between 2b/3b and phenol (Fig. 2a, Eq. 7 and 8). This outcome unequivocally highlights that the efficiency of SuFEx reactions can only be augmented through intramolecular ChB interaction. To compare the reactivity of SO2F2, 1b, and 2b in SuFEx reactions, we monitored the variation in phenol concentration over time for these three reactions (Fig. 2b, Supplementary Table 2). The results indicated that 1b exhibited significantly higher reactivity compared to 2b and even surpassed SO2F2, widely acknowledged as one of the most efficient SuFEx hubs with excellent reactivity towards phenols3. These findings substantiate the effectiveness of ChB activation in S-SuFEx chemistry as well.Design of S-SuFEx click hub for organic-inorganic linkingAfter establishing the S-SuFEx chemistry, we devised S-SuFEx hub 1c to enable efficient covalent organic-inorganic linkages. The chemical structure of S-SuFEx hub 1c comprises three functional moieties: a sulfonyl fluoride group, a ChB donor, and an anchoring group (Fig. 3). The sulfonyl fluoride group reacts with a variety of O, N-nucleophiles, forming a covalent bond that links the organic compound to the hub. Concurrently, the ChB donor enhances the reactivity of the sulfonyl fluoride through intramolecular non-bonding 1,5-S···F interactions, initiating the S-SuFEx reaction. The trialkoxy silane group can effectively anchor the organic moiety linked to the hub onto the inorganic surface by the formation of stable Si–O–X covalent bonds, as its capability to react with hydroxyl groups on the surface of inorganic materials has been extensively validated54. The synthesis of 1c has been achieved via a straightforward thiol-ene reaction between a prevalent silicon coupling agent, 3-mercaptopropyltriethoxysilane, and ESF.Fig. 3Design of the S-SuFEx hub 1c for efficient covalent organic-inorganic linking.We continued to explore the reactivity of 1c towards different O, N-nucleophiles. Given the high reactivity of trialkoxy silane group towards water, its analog 1b with a trimethyl silane group was employed as the model compound for the study to avoid the hydrolysis of the trialkoxy silane group during the aqueous workup process.The S-SuFEx chemistry with phenolsWe initiated our exploration by examining the reaction between S-SuFEx hub 1b with phenols. Upon optimizing the reaction conditions (see Supplementary Section 2.1.5), it was determined that the addition of 0.5 equiv. of BTMG represented the most favorable condition for triggering the reaction. No supplementary silicon additives or elevated temperatures, typically employed in accelerated SuFEx click chemistry, were deemed necessary. The required amount of BTMG could be further reduced by employing a sacrificial base, such as triethylamine (see Supplementary Section 2.1.8). The substrate scope investigation revealed the successful reactivity of the S-SuFEx hub with a wide range of phenols (Fig. 4). Phenols, whether containing electron-donating or electron-withdrawing groups on the aromatic ring, demonstrated comparable reactivity and were smoothly converted into sulfonates 8. Various functional groups, including fluoride (8d), chloride (8e), hydroxy (8j), amide (8k, 8q), aldehyde (8 l), carboxylate (8 m, 8w), ester (8o), ketone (8 v), and alkenyl (8w), at the p, o, m-positions, were well-tolerated in the reaction. Significantly, this reaction also highlights the exceptional chemoselectivity of phenols compared to anilines (8k, 8t) and alcohols (8j). Regarding bisphenols (8z, 8aa, 8ag, 8ah), the precise control of monosulfonate or bissulfonate formation is achievable by adjusting the amount of sulfonyl fluoride added. Moreover, in order to highlight the potential applicability of this synthetic protocol, fluorescein (8af) and a selection of bioactive phenols, such as acetaminophen (8n), triclosan (8ab), vitamin E (8ac), and estrone (8ae) were subjected to the S-SuFEx reaction with 1b, resulting in the production of the desired products with excellent yields ranging from 81% to 99%. Additionally, the reaction between 1b and 4a using DCM/H2O (v/v, 4/1) as the solvent produced an 85% yield of 8a. Even when employing a PBS buffer solution (pH = 7.4) as the solvent for the reaction between 1b and 4a, a moderate yield of 48% was still achieved (see Supplementary Section 2.1.9).Fig. 4: Substrate scope for the S-SuFEx chemistry with phenols.Reaction conditions: alkyl sulfonyl fluoride 1b (0.3 mmol), phenol 4 (0.3 mmol), and BTMG (0.15 mmol) were stirred in MeCN (1 mL) for 2 h at room temperature. aReaction run for 0.5 h. bWith BTMG (0.3 mmol). cPhenol (0.15 mmol). dIn DMF.The S-SuFEx chemistry with aliphatic alcoholsThe SuFEx reactions involving alkyl sulfonyl fluorides and alkyl alcohols present a more significant challenge than those with phenols, which have been notably elusive within the reported SuFEx chemistry. However, this investigation explored the compatibility of S-SuFEx chemistry with alcohols. Remarkably, the S-SuFEx reactions of 1b with various alcohols exhibited excellent reactivity (Fig. 5). Primary alcohols (10a–10d) and more sterically hindered secondary alcohols (10e) all gave excellent yields ranging from 72% to 97%. Notably, primary alcohols exhibited relatively higher reactivity compared to the more hindered secondary and tertiary alcohols (see Supplementary Section 7.8). Cyclic enols (10 f, 10i) also reacted smoothly under the reaction conditions. The excellent chemoselectivity of S-SuFEx chemistry was once again exemplified by its remarkable tolerance of various functional groups (10c, 10e, 10 f) and the distinct selectivity of alcohols over primary amines (10b). In the case of amino alcohol 9b, only the target product 10b derived from the reaction between the hydroxyl group and sulfonyl fluoride was detected, with the remaining mass balance accounted for by the unreacted starting material.Fig. 5: Substrate scope for the S-SuFEx chemistry with aliphatic alcohols.Reaction conditions: alkyl sulfonyl fluoride 1b (0.3 mmol), aliphatic alcohol 9 (0.3 mmol) and BTMG (0.15 mmol) were stirred in MeCN (1 mL) for 6 h at room temperature. aReaction run for 0.5 h.The S-SuFEx chemistry with aminesN-nucleophiles constitute a wide spectrum of bioactive compounds. Harmonious with N-nucleophiles, click chemistry will offer substantial potential for the progression of functionalized materials and novel drugs. In contrast to the enduring challenges posed by conventional SuFEx chemistry when dealing with N-nucleophiles, particularly primary amines, our investigation revealed the remarkable efficacy of the innovative S-SuFEx chemistry in facilitating smooth reactions with primary, secondary, and cyclic amines, anilines, as well as diverse N-heteroaromatic compounds (Fig. 6). Generally, aliphatic amines showed higher reactivity compared to anilines, with secondary amines proving to be the most reactive N-nucleophiles in S-SuFEx chemistry. High yields were achieved with both linear (12a-12c) and cyclic (12d–12i) secondary amines. In the case of amino alcohol (12 f), S-SuFEx chemistry exhibited higher selectivity toward cyclic secondary amines compared to secondary alcohols, resulting in a moderate yield of 64%. Although primary amines displayed slightly lower reactivity than secondary amines, the S-SuFEx reactions with primary amines, including sterically hindered primary amines (12k) and benzyl amines (12l–12q), also gave high yields by extending the reaction time to 12 h. Anilines, while less nucleophilic than aliphatic amines, also proved effective in S-SuFEx chemistry when the reaction time was further extended to 24 h\. Anilines with electron-donating MeO- groups (12w) yielded a perfect 94%, while anilines with electron-withdrawing groups (12x, 12 y) resulted in slightly lower yields. Additionally, N-heteroaromatic compounds, such as pyrrole (12aa), indoles (12ab), imidazoles (12ad) and benzimidazole (12ae), also exhibited high compatibility with S-SuFEx chemistry. To further underscore the potential applications of S-SuFEx chemistry in constructing bioactive functionalized materials, we extended our testing to a series of drugs and pesticides, including amlodipine (12 v), melatonin (12ac), and carbendazim (12ae). Remarkably, all of them yielded perfect sulfonylation products, with sensitive functional groups like ester and amide remaining entirely unaffected. These results demonstrate the potential of S-SuFEx chemistry for broad synthetic applications.Fig. 6: Substrate scope for the S-SuFEx chemistry with amines.Reaction conditions: alkyl sulfonyl fluoride 1b (0.3 mmol), amine 11 (0.3 mmol), and BTMG (0.3 mmol) were stirred in MeCN (1 mL) for 12 h at room temperature. aReaction run for 2 h. bReaction run for 24 h. cWith BTMG (0.15 mmol); Reaction run for 2 h.Organic-inorganic linking via S-SuFEx click chemistryUpon establishing the pronounced reactivity of the S-SuFEx click hub with various O, N-nucleophiles, we proceeded to apply click hub 1c for the creation of functionalized SAMs on the surface of inorganic materials via organic-inorganic linking. Glass slides were selected as the exemplar inorganic substrates. To prepare functionalized SAM, we initiated the process by coupling 1c with the selected organic compounds using S-SuFEx chemistry. Notably, 1c displayed a slightly higher reactivity than its analog 1b, reacting smoothly with phenols, alcohols, and amines in the presence of 0.2 equiv. BTMG. The reactions between 1c and the 15 tested substrates gave 76–99% yields (Fig. 7a). In a typical approach for the preparation of SAM, the reaction mixture of 1c and organic compounds can be directly employed to react with the glass surface without the need for purification. Covalent linkage between the glass and selected organic compounds is achieved by simply immersing the glass slides in the hydrolysate of the reaction mixture for 24 h (Fig. 7b). The hydrolyzed trialkoxy silane group effectively anchors the organic moiety onto the glass surface, forming SAMs. In this study, we examined the linkage of four representative organic compounds to the glass surface, namely, triclosan (TC), fluorescein (FR), 1H,1H,2H,2H-perfluoro-1-decanol (PD), and nonylphenol (NP).Fig. 7: Organic-inorganic linking via S-SuFEx click chemistry using 1c.a SuFEx reactivity of the S-SuFEx hub 1c. Reaction conditions: alkyl sulfonyl fluoride 1c (0.3 mmol), 13 (0.3 mmol), and BTMG (0.06 mmol) were stirred in MeCN (1 mL) for 2 h at room temperature. b Preparation of functionalized SAM using 1c on the surface of inorganic material.The glass slides linked with TC, FR, PD and NP displayed no significant changes in appearance, remaining colorless and transparent. However, the contact angles of water on their surfaces were markedly changed (Fig. 8 and Supplementary Fig. 8). Atomic force microscopy (AFM) analysis revealed that both the pristine slide and the TC linked slides exhibited a rough surface with irregularities and protuberances. The subsequent AFM-IR spectra provided further confirmation of the covalently linked TC molecules on the glass surfaces (Fig. 8b, c). TC is a widely recognized antimicrobial agent. Covalently linking TC to the glass surface was expected to render it antibacterial. Indeed, the antibacterial tests confirmed that the SAM exhibited excellent antibacterial efficacy against Staphylococcus aureus, with a remarkable reduction in the counts of S. aureus, resulting in an antibacterial efficacy (R) of 4.59 (Fig. 9a and Supplementary Fig. 9). Furthermore, linking FR to the glass surface using the S-SuFEx hub 1c resulted in a glass surface with fluorescence, as confirmed by fluorescence microscope images (Fig. 9b and Fig. Supplementary Fig. 10). This provides an effective method for preparing inorganic materials with fluorescence labeling. Functionalizing the glass surface with PD and NP rendered it hydrophobic. The highest hydrophobicity of 98.5 degree was achieved with PD functionalized glass surfaces (Fig. 9c). As expected, NP-functionalized glass surfaces also exhibited excellent antibacterial properties against S. aureus (Supplementary Fig. 9). Using FR-functionalized glass as the model, we tested the stability of this organic-inorganic linking system. The results indicated that the system exhibited excellent stability, with robust tolerance to acid (pH = 2) (Supplementary Fig. 11), high temperature (Supplementary Fig. 12) or flushing with organic solvents (Supplementary Fig. 13). However, the functionalized glass slides showed poor base tolerance, which was primarily caused by the dissolution of Si–O–Si network structure in a strong alkaline environment55. Furthermore, we specifically attempted to immobilize the peptide oxytocin on the glass surface using 1c (Supplementary Fig. 14). The successful outcomes of the peptide immobilization process suggested that this clickable platform may have significant application value in biological detection. In summary, the covalent linkage of various functional organic molecules and inorganic materials has been successfully established, showcasing the general versatility and simplicity of the organic-inorganic linking strategy using 1c. This approach generates a versatile platform for achieving any desired organic-inorganic linking.Fig. 8: AFM-IR images and contact angle measurements of untreated and treated glass slides.a AFM image of the untreated glass slide. b AFM-IR image obtained at 1475 cm−1 of the triclosan-functionalized glass surface. c AFM-IR spectra obtained at untreated glass surface (CK), and triclosan-functionalized SAM on glass surface (TC).Fig. 9: Assessment of glass surfaces with functionalized SAM.a Antibacterial effect against S. aureus of the glass surface with triclosan-functionalized SAM. b Fluorescence imaging of the glass surface with fluorescein-functionalized SAM. The experiment was independently repeated three times with similar results. c Hydrophobicity of glass surface functionalized with 1H,1H,2H,2H-perfluoro-1-decanol.Mechanistic investigationsA series of experiments were conducted to elucidate the mechanism of S-SuFEx click chemistry, using the SuFEx reaction between 1b and phenol 4a as the model reaction. Initial investigations focused on the base’s role in this process, as illustrated in Fig. 10. The absence of BTMG resulted in no observable reaction between 1b and 4a, underscoring the indispensable role of BTMG (Fig. 10a). With BTMG present, two potential reaction mechanisms were considered. The first hypothesis suggests that the base deprotonates the α-position of 1b to form intermediate 15, which then reacts with nucleophile 4a to yield the final product 8a through a deprotonation-elimination-addition mechanism, involving sulfene 16 as the reactive intermediate (Fig. 10d). Alternatively, BTMG might first interact with 4a to produce deprotonated phenol 17, which could then undergo an SN2 reaction with 1b to form the final product (Fig. 10e). To determine the prevailing mechanism, further experiments were conducted. Introduction of 0.5 equiv. of BTMG to 1b in MeCN-d3 revealed partial deprotonation at the α-position to give 15 through 1H NMR analysis (Fig. 10b and Supplementary Fig. 16), yet without evidence of S-F bond dissociation according to the 19F NMR (Fig. 10c), indicating the absence of sulfene 16 formation. Further adding 1.0 equiv. of phenol 4a to the deprotonated alkyl sulfonyl fluoride 15 and stirring for 2 hours led to no detectable product 8a, suggesting the reaction between alkyl sulfonyl fluorides and BTMG was a non-productive side pathway. Conversely, introducing BTMG to a MeCN-d3 solution of 4a induced a significant upfield shift in the aromatic region of the 1H NMR spectrum (Supplementary Fig. 17), indicative of the formation of 175. Addition of 1b to the solution of 17 resulted in a quantitative yield of the product 8a (Fig. 10b), strongly supporting the SN2 pathway between 1b and 17 as the primary reaction route. Considering the high yields achieved with most substrates, it is hypothesized that the side reaction between 1b and BTMG progresses much more slowly than the favorable SN2 reaction.Fig. 10: Mechanistic investigations.a 1H NMR spectra for the reaction between 1b and 4a with or without BTMG (500 MHz, MeCN-d3). b 1H NMR spectra for the control reaction (500 MHz, MeCN-d3). c 19F NMR spectra for the reaction between BTMG and 1b (500 MHz, MeCN-d3). d Proposed mechanism disproved by experiments. e Proposed mechanism. f Electrostatic potential map of 1b. Red = electron excess and blue = electron deficiency. g The S···F distance of 1b is 3.11 Å, falling into the range of chalcogen bonding distance. The E(2) is the second order perturbation stabilization energy. h Role of phenoxide guanidinium complex in the S-SuFEx process. i Further expansion of the S-SuFEx chemistry.Despite the generally slow SN2 reactions observed with most alkyl sulfonyl fluorides, we propose that the presence of an intramolecular ChB could significantly increase the electrophilicity of 1b, thereby enhancing its reactivity towards nucleophiles. To validate our hypothesis, we undertook computational studies. The initial step involved determining the conformation of 1b using DFT computations at the M062X/6-311 G(d,p) level. Our findings indicated that the gauche conformation of 1b is only marginally less stable than its anti counterpart, with a free energy barrier of approximately 1.0 kcal/mol between them (Supplementary Fig. 18). This barrier is sufficiently low to allow for easy interconversion between these conformations at room temperature. Further analysis was focused on the electrostatic potential map of the gauche conformation (Fig. 10f), revealing distinct electrostatic interactions between the negatively charged fluorine and the positively charged sulfur atoms. We further computationally measured the distance and strength of the ChB between S and F in 1b using NBO analysis. The measured distance was 3.11 Å, which is less than the sum of their van der Waals radii (∑rvdW (S···F) = 3.27 Å)56. The strength of this interaction was measured to be 5.37 kcal/mol (Fig. 10g). These computational insights strongly advocate for the existence of an intramolecular ChB between sulfur and fluorine in the gauche conformation. The ChB will make the fluorine a better leaving group and thus accelerating the S-SuFEx chemistry.Furthermore, inspired by the discovery of BTMG as an exceptional SuFEx catalyst by Moses et al.5, we hypothesized that the phenoxide guanidinium complex 17 might also facilitate sulfonyl fluoride group activation via hydrogen bonding with fluorine. Empirical validation involved direct interaction of 1b with sodium phenoxide 4a’, achieving an impressive 87% yield of 8a (Fig. 10h, Eq. 9), albeit slightly lower than the 99% yield obtained with 4a and BTMG (Fig. 10h, Eq. 3). Conversely, the reaction of 3b with sodium phenoxide yielded a mere 31% of 8a (Fig. 10h, Eq. 10), underscoring the intramolecular ChB as the predominant factor in alkyl sulfonyl fluoride activation, with the phenoxide guanidinium complex playing a supportive role in this activation process.Given the established activation of alkyl sulfonyl fluorides through non-bonding 1,5-S···F interactions, we explored the possibility of achieving a similar activation effect via 1,6-S···F interactions. Accordingly, we synthesized compound 18, using 1-propanethiol, and 2-propene-1-sulfonyl fluoride as precursors and 2,2’-azobis(2-methylpropionitrile) as the reagent. The reaction between 18 and 4a, in the presence of 0.5 equiv. of BTMG, gave an exceptional 99% yield of 19 within 0.5 h (Fig. 7i, Eq. 11), demonstrating the feasibility of ChB activation by 1,6-S···F interactions. The Markovnikov addition product 20 and 4a also exhibited high reactivity towards nucleophile 4a, achieving a 99% yield using 0.5 equiv. of BTMG within 0.5 h (Fig. 10i, Eq. 12). Furthermore, the reactivity of phenyl fluorosulfonate could also be moderately enhanced by a 2-thio group via a 1,6-S···F interaction (see Supplementary Section 3.7). These outcomes collectively underscore the broader applicability of the intramolecular ChB-activated S-SuFEx reaction, demonstrating its potential for diverse synthetic applications.
