Catalytic Electrophilic Arene C–H Chlorination by Rethinking of the Century-old Willgerodt Reagent

Catalytic Electrophilic Arene C–H Chlorination by Rethinking of the Century-old Willgerodt Reagent | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Catalytic Electrophilic Arene C–H Chlorination by Rethinking of the Century-old Willgerodt Reagent Youwei Xie, Qi-Qi Hu, Yao Xiang, Zhaobo Ying, Yu Zhou, Hui Zhou This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8374240/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract A highly anticipated yet elusive variant of the Willgerodt reagent, III , has been successfully synthesized and characterized unambiguously by both nuclear magnetic resonance (NMR) and single-crystal X-ray crystallography. Compared to previous I–Cl type λ 3 -iodanes, this compound has an unusually short I–Cl bond length due to the trans-influence of the endocyclic sulfonate moiety, and this feature endows III with significantly enhanced reactivity in arene electrophilic C–H chlorination reactions. A catalytic C–H chlorination of deactivated arenes via in situ formation of III is achieved with catalytical amount of readily available 2-iodobenzenesulfonic acid as the precursor of III . The relative mildness of this protocol has been showcased by the late-stage chlorinations of various highly functionalized drugs and natural products. Mechanistic studies as well as density functional theory (DFT) calculations are carried out to shed light on the origin of the enhanced reactivity in electrophilic arene C–H chlorination. Physical sciences/Chemistry/Catalysis/Homogeneous catalysis Physical sciences/Chemistry/Chemical synthesis/Synthetic chemistry methodology Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Introduction Chlorinated (hetero)arenes are frequently encountered structural motifs in various natural products, 1 and these chemicals have widespread applications in materials, 2 agrochemicals, 3 pharmaceuticals, 4 etc. Additionally, they are versatile synthetic intermediates 5 and can serve as useful electrophiles in cross-coupling reactions. 6 In industry, as introduced in canonical organic chemistry textbooks, chlorinated arenes are prepared by an electrophilic aromatic substitution (SEAr) process that combines gases Cl 2 and stoichiometric amounts of Lewis acids (Fig. 1 A). 7 However, the operational inconvenience associated with the handling of gaseous Cl 2 and the inherent poor selectivity and low functional group tolerance make it a second choice for experimental chemists in research laboratories. Alternatively, inorganic or organic chlorides can be applied to the chlorination of electron-rich arenes when combined with various oxidants, 8 electrochemical oxidations, 9 photoredox catalysts, 10 etc. (Fig. 1 B). Various N–Cl type reagents are commercially available, most of which are designed by tuning the other two substituents on the nitrogen atom to balance overall stability and reactivity (Fig. 1 C). 11 Many of these reagents have improved functional group tolerance and can chlorinate electronically activated arenes without the need for a catalyst. 12 Activation by a Lewis base can lead to moderate reactivity enhancement of these reagents. For example, Jiao, 13 Miura, 14 and Nishii 15 used DMSO or thioethers, respectively, as Lewis bases to activate N -chlorosuccinimide (NCS) to chlorinate relatively electron-rich arenes. On the other hand, excessive amounts of strong acids are generally required to activate these reagents for the chlorination of deactivated arenes. 16 For example, Olah used NCS with superacidic BF 3 •H 2 O as a solvent to chlorinate deactivated arenes at 100 ºC. 17 A breakthrough in this field was recently achieved by Jiao and Song, who used catalytic amount of the super Brønsted acid TfOH (5%–20%) in hexafluoroisopropanol (HFIP) to activate trichloroisocyanuric acid (TCCA) for the chlorination of deactivated arenes. 18 In sharp contrast to the wide adoption of N–Cl type reagents, hypervalent I–Cl type reagents usually are not the first resort when synthetic organic chemists need to chlorinate their substrates, although this type of reagents could trace back to at least more than a century ago, when Willgerodt introduced PhICl 2 in 1886 as a safer and easier-to-handle alternative to Cl 2 . 19 In addition to the fact that less I–Cl type reagents are commercially available, they often show inferior reactivity and poorer stability compared to the more popular N–Cl type reagents. For example, the commercially available Willgerodt reagent (PhICl 2 ) has reduced reactivity, decomposes at elevated temperatures, and is limited to highly reactive substrates. Formation of the more reactive PhI(X)Cl via a ligand exchange process from either PhICl 2 or PhI(OR) 2 is often necessary for less activated substrates (Fig. 1 D). 20 These compounds belong to a class of aryl λ 3 -iodanes ArILLꞌ (L, Lꞌ: heteroatom ligands, etc.) that adopt a T-shaped geometry in which the aryl group occupies the equatorial position and the L–I–Lꞌ triad occupies the axial position in a near linear shape. 21 The property of Lꞌ affects that of L via a well-studied phenomenon known as the “trans influence”, 22 which also determines the overall reactivity and stability of this type of compounds. 23 The enhanced reactivity of PhI(X)Cl is due to the weaker trans-influencing ligand X (longer I–X bond length) that resulted in a shorter I–Cl bond and a more electrophilic chlorine atom. 24 Unfortunately, most derivatized Willgerodt reagents in the form of PhI(X)Cl are not isolable and can only be observed in situ . 25 An exception was achieved by Dutton, who successfully isolated O 2 N–ArI(OTf)Cl by reacting 1-iodo-4-nitrobenzene with Cl 2 and TfOH. This λ 3 -iodane has an unusually short I–Cl bond (2.36 Å) and high reactivity due to the weak trans-influencing triflate ligand. 26 Another strategy to provide stability to I–Cl type λ 3 -iodanes is to introduce a cyclic structure, a strategy that is more well-known in the design of the Togni type reagents. 27 For instance, in contrast to their acyclic variants, chloroiodinanes I (by Martin) 28 and II (by Andrews and Keefer) 29 are stable and commercially available compounds (Fig. 1 E). However, these reagents are better known as synthetic intermediates to Togni type reagents rather than chlorination reagents due to the relatively long I–Cl bond, and the resulting less electrophilicity of the chlorine atom limits their applications to highly electron-rich arenes. 30 By switching the strong trans-influencing endocyclic alkoxy ligand in I to a moderate trans-influencing carboxy ligand in II , a shortening of the I–Cl bond and an increasing of the reactivity was observed. Predictably, a weak trans-influencing sulfonyloxy group ( III ) will further decrease the I–Cl bond and increase the electrophilicity of the chlorine atom. Unfortunately, III only existed in some computational studies that proposed it as an intermediate to a delicately designed variant of the Togni reagent with enhanced reactivity in electrophilic trifluoromethylation reactions. 31 To the best of our knowledge, hitherto, no synthetic route has been reported, and no reactivity profile in arene C–H chlorination reaction has been established for this promising compound. Results Synthetic attempts and characterization of λ 3 -iodane III With the aim to provide a stable and highly electrophilic λ 3 -iodane to potentially overcome the current limitations associated with I–Cl as well as N–Cl type chlorination reagents, we embarked on an endeavor to synthesize III . Unsurprisingly, by simply following the synthetic protocols of known I–Cl type λ 3 -iodane with necessary changes of the starting substrate, we failed to obtain the target compound III . In most cases, only the 2-iodobenzenesulfonic acid ( IV ) was recovered (see Figure S1 and S2 ). To gain more information about the problems associated with the synthesis of III , we carried out 1 H NMR studies of reaction progress during our synthetic attemps. For one experiment in HFIP, we found that 2-iodobenzenesulfonic acid ( IV ) could be oxidized to V (Fig. 2 A, a- 2 ). Heating V at 80 ºC or above in the presence of NaCl led to the formation of a new species X (Fig. 2 A, a- 3 ), and a mixture of V and X could be seen before full conversion of V (see Figure S7 ). However, initial efforts to isolate and characterize species X only led to isolation of I V . On the other hand, heating the solution containing X at 100 ºC overnight resulted in the formation of a mixture of IV , VI , and VII (Fig. 2 A, a- 4 ). This result is intriguing due to the fact that VI and VII are two regioisomers of the chlorination products of IV . Species X has significantly enhanced electrophilicity that could even chlorinate electron-deficient arenes such as itself upon heating. With a less deactivated arene such as chlorobenzene ( 1a ) added, a mixture of p -dichlorobenzene and o -dichlorobenzene could be obtained even at room temperature, along with the regeneration of IV (see Figure S1 0 ). We speculated the species X is the highly anticipated I–Cl type λ 3 -iodane III , and its recalcitrance from being tamed might be due to its high reactivity that led to fast hydrolysis, which was in line with the fact that our previous synthetic efforts toward III only led to the isolation of IV . After a careful anhydrous workup and crystallization, we could eventually assign species X to be III (I–Cl: 2.326 Å to 2.369 Å) unambiguously with the assistance of X-ray crystallography (CCDC 2491924). 2.326 Å represents the shortest bond length for I–Cl type λ 3 -iodane, which explains its high electrophilicity. Design and optimization of a catalytic arene C–H chlorination via in situ formation of III In order to fully utilize III as a powerful chlorinating reagent and minimize its synthetic challenges, we designed and realized a catalytic arene C–H chlorination via its in situ formation (Fig. 2 b). In this design, commercially available 2-iodobenzenesulfonic acid ( IV ) was used as the catalyst, which reacted with NaCl and Oxone in HFIP to form the highly reactive III . The electrophilicity of III could be further enhanced via hydrogen-bonding interactions with HFIP, which is the solvent required for its generation. This adduct then reacted with arenes to provide the electrophilic chlorination products and regenerate catalyst IV . Through a standard optimization process with chlorobenzene ( 1a ) as the model substrate (see the supporting information Table S2), we found that 5% of catalyst IV could was able to promote the chlorination of 1a to give 84% yield of two regioisomers, and 10% of IV could improve the yield to 94%. Control experiments showed that HFIP was crucial for the formation of this highly reactive I–Cl type λ 3 -iodane III and a mixture of DCE/HFIP (2/1) was optimal for this transformation (see the supporting information Table S5). Replacing catalyst IV with other iodine compounds that could potentially form either acyclic or cyclic I–Cl type λ 3 -iodane intermediates all gave inferior results, lending further support to the high reactivity of III that results from both cyclic structure and the weak trans-influencing endocyclic sulfonyloxy ligand (see the supporting information Table S3). Synthetic scope We then evaluated the synthetic scope of this transformation (Fig. 3 ). Generally, for most substrates tested, monochlorination products could be obtained as the major products with only negligible multichlorination products. Monohalogenated substrates could be chlorinated to give the correspoinding products as mixtures of regioisomers ( 2a – 2d ), and the selectivity for para chlorination improves with the increase of electronegativity. Electron-neutral benzene gave a mixture of mono- and double chlorination products ( 2e ). Substrates with benzylic C–H bonds were well tolerated, such as toluene and ethylbenzene, for which the arene C–H chlorination products could be obtained as mixtures of regioisomers ( 2f – 2g ). Substrate with a bulky t -Butyl group also gave the chlorination product in good yield ( 2h ). More deactivated m -difluorobenzene gave the para chlorination product in almost quantitative yield ( 2i ). Similar selectivity was also observed for m -dichlorobenzene ( 2j ) and m -dibromobenzene ( 2k ), given that less NaCl (1.0 equiv.) was used. For m -diiodobenzene, on the other hand, a mixture of two regioisomers (5:1) was obtained ( 2l ). 1,3,5-trifluorobenzene required slightly more NaCl and Oxone to give the chlorination product ( 2m ) in a good yield of 80%, while 1,3,5-trichlorobenzene ( 2n ) could be chlorinated under the standard condition. In contrast, highly electron-rich 1,3,5-trimethoxybenzene required less NaCl (1.0 equiv.) to be used for selective monochlorination ( 2o ). Delightfully, substrates with high steric hindrance, such as 1,3,5-triisopropylbenzene ( 2p ) or even 1,3,5-tri- t -butylbenzene ( 2q ), could be chlorinated under the standard condition to give the corresponding products in good yileds. 1,2,3-trichlorobenzene could be selectively chlorinated to the 1,2,3,4-tetrachlorobenzene ( 2r ) selectively. In contrast, 1,3,4,5-tetrachlorobenzene reacted sluggishly under the standard condition, this problem could be solved by adding Mg(OTf) 2 as a Lewis acid catalyst to further enhance the reactivity of III , and the corresponding product 1,2,3,4,5-pentachlorobenzene ( 2s ) could be obtained in a good yield of 88%. For highly electron-rich substates, such as phenol or phenols with electron-donating substituents, complicated mixtures of oxidation and multichlorination products were generally obtained. On the other hand, phenol with an electron-withdrawing group ( 2t ) or anisole ( 2u ) could be chlorinated successfully under the standard condition. High regioselectivity for para chlorination could be obtained when the hydroxy group was protected with a benzyl group ( 2v ) or a trifluoromethyl group ( 2w ). Other anisole derivatives with various substitution patterns could all be chlorinated to give the monochlorination products ( 2x – 2dd ) in good yields and selectivity. Unprotected anilines were not suitable substrates, however, monochlorination or dichlorination could be obtained when aniline was protected with an acyl group ( 2ee ) or a tosyl group ( 2ff ), respectively. Derivatives of benzoic acid with varying steric and electronic properties could be chlorinated under the standard condition ( 2gg – 2kk ), while the unsubstituted benzoic acid ( 2ll ), benzoate ester ( 2mm ), or halogenated benzoate esters ( 2nn – 2pp ) needed additional Lewis acid catalysis. Methyl phenylacetate has a easily enolizable benzylic position that could lead to benzylic chlorination, fortunately, arene C–H chlorination prevailed ( 2qq ). Naphthalenes substituted with various electron-withdrawing groups gave a mixture of monochlorination and dichlorination products, however, selective dichlorination products ( 2rr – 2uu ) could be obtained with 3.0 equivalents of NaCl and Oxone. Benzophenones with methoxy ( 2vv ) and methyl groups ( 2ww ) could be selectively chlorinated when 1.0 equiv. of NaCl and oxone were used. Benzophenone with chlorine substituents is highly challenging and a recent protocol relied on a two-step sequence, 32 while traditional direct C–H chlorination methods usually gave less than 10% yield. Delightfully, our method could provide direct C–H chlorination of this type of substrate in 65% isolated yiled as a 3:1 mixture of mono chlorination and dichlorination products ( 2xx ). Biphenyl derivative 1yy could be chlorinated to provide 2yy in a good yiled of 85%. Heterocyclic substrates such as 1,3-benzodioxole ( 2zz – 2aaa ), 2,3-dihydrobenzo[1,4]dioxine ( 2bbb ), and Dihydroquinolinone ( 2ccc ) are active substrates that could be chlorinated with 1–2 equivalents of NaCl and Oxone. Methoxy quinoline gave the chlorination product ( 2ddd-1 ) along with partial oxidation of the product ( 2ddd-2 ). Methoxybenzothiazole ( 2eee ) and thiophene ( 2fff ) could be chlorinated with moderate efficiency with 1 equiv. of NaCl. Finally, electron-rich styrenes often led to double bond oxidation while styrenes substituted with strong electron withdrawing groups ( 2ggg – 2hhh ) could be chlorinated with moderate efficiency. Application in late-stage C–H chlorinations Encouraged by this initial excess, we next tested the possibility of applying this protocol to the chlorination of more sophisticated substrates, such as various natural products and biologically active molecules (Fig. 4 ). Mitotane bears both a dichloromethane moiety and a diarylmethane moiety with active aliphatic C–H bonds, luckily, the arene C–H chlorination product ( 4a ) could be obtained as a mixture of monochlorination and dichlorination products (mono : di = 1 : 5). Ibuprofen methyl ester required less NaCl (1.0 equiv.) to achieve monochlorination ( 4b ). Chlorination of Clofibrate ( 4c ) was achieved in 75% isolated yield under the standard condition. The ketone moiety and the electron-rich methoxy naphthalene moiety in Nabumetone might cause several problems, however, selective C–H product 4d could be obtained in moderate yield. Fenofibrate has an benzophenone moiety with two electronically biased aryl groups, and the chlorination selectively occurred at the more electron-rich ary group ( 4e ). Selective monochlorination of Aniracetam ( 4f ) required the application of less NaCl (1.0 equiv.) at a lower temperature (80 ℃). Isoxepac has several active sites that are prone to oxidation and chlorination, fortunately, a selective chlorination product 4g was produced under the standard reaction condition. Nimesulide, Apremilast, and Triflumuron have various amide and aryl ether moieties, all of which are well tolerated, and the corresponding chlorination products ( 4h – 4j ) could be obtained in moderate to good yields. Xanthotoxin has a furan moiety and a pyranone moiety, both of which are prone to oxidative degradation, and the chlorination product 4k could still be obtained in 73% isolated yield. Similarly, the cyano group and the heterocyclic pyrimidine-2,4-dione moiety in Alogliptin did not cause any problems either, and the chlorination product 4l could be obtained in a good yield of 83%. Selective chlorination on the pyrimidine moiety in Piribedil might pose challenges to other protocols due to the presense of benzodioxole and piperazine moieties, however, the chlorination product 4m could be obtained in 61% yield. Leflunomide, Ataluren methyl ester, and Celecoxib have highly sensitive heterocylic structures such as isoxazole, 1,2,4-oxadiazole and pyrazole, delightfully, the selective chlorination products ( 4n – 4p ) could still be obtained with our protocol. Roflumilast and Berberine have a pyridine and pyridinium moiety, respectively, their selective chlorination could be achieved with moderate efficiency ( 4q – 4r ). Selective monochlorination at half of the C 2 -symmetric Bifendate gave 4s in 60% isolated yield. Finally, a phenyl glycoside derived from glucose with multiple hydroxy groups protected as acetate esters could be chlorinated to give the corresponding product 4t in high yield. Synthetic applications The synthetic potential of this protocol was justified by carrying out gram-scale syntheses of 2a and 2c , we found that results comparable to the small scale experiments were achieved and catalyst loadings could be reduced to 5 mol% for these larger-scale experiments. We also compared our method to some reported prototocols that applied either N–Cl or I–Cl type chlorination reagents. It is worth mentioning that only some electronically and/or sterically deactivated substrates ( 2n , 2q , 2ii , 2yy ) that can signify the difference between these methods are shown, while those activated substrates for which no significant defference exists between these protocols are omitted (Fig. 5 ). As predicted, product formation was not observed for these four substrates when λ 3 -iodane II (BI-Cl) was used as the chlorination reagent by following the literature report (Method 1). 30 When HFIP was used instead of DMF (Method 2), only the electronically activated but sterically hindered substrate 2q was obtained in a poor yield of 38%. These results agreed with our prediction that λ 3 -iodane III is a more reactive I–Cl type reagent, compared to I and II , for electrophilic arene C–H chlorination, which justified our efforts towards its synthesis and application in chlorination reactions. The more popular N–Cl type reagent, such as NCS, was ineffective for these substrates in the absence of additional catalysts, even in HFIP (Method 3). When NCS was activated with DMSO via a strategy developed by Jiao (Method 4), 13 again, only 43% yield was obtained for the electronically activated but sterically hindered substrate 2q , and completely no reactivity was observed for 2n , 2ii and 2yy . The state-of-the-art protocol developed by Jiao and Song 18 (Method 5) for electrophilic arene C–H chlorination of electronically deactivated arenes that applied N–Cl type reagent TCCA (0.4 equiv.) and super Brønsted acid catalysis (TfOH) in HFIP was also tested for these substrates. Similar yields were achieved for 2ii and 2yy , while our method showed significantly improved yields for 2n and 2ii . These results were sufficient to verify the predicted high ractivity of III in electrophilic arene C–H chlorination. Addtionally, the fact that III could be generated catalytically from cheap and easily available 2-iodobenzenesulfonic acid ( IV ) with NaCl as the terminal chlorine source lends further support for the synthetic potential of this protocol, which has already been justified by its broad substrate scope (Fig. 3 ) and applications in late-state C–H chlorination (Fig. 4 ). Mechanistic investigations We then carried out a series of control experiments to possibly elucidate the reaction mechanism and shed light on the origin of the high reactivity of III (Fig. 6 ). First of all, a solution of λ 3 -iodane III in DCE/HFIP (2/1) can chlorinate chlorobenzene ( 1a ) even at room temperature without any catalyst, implying the high electrophilicity of III . Additionally, our previous study showed that mixing the I -hydroxy variant V and NaCl at 80 ℃ or above could also lead to the formation of III , as a result, the combination of V and NaCl also can also chlorinate 1a in moderate yield upon heating (Fig. 6 A). A cyclic voltammetry measurement of the key components of the reaction indicated that the catalyst IV seemed to have the lowest oxidation potential (~ 2.1V vs SCE), corresponding to the oxidation of IV to I 3+ compound V (Fig. 6 B). In contrast, only a small current corresponding to the oxidation of Cl − was observed at > 3.0V vs SCE, probably due to the poor solubility of NaCl in this solvent system. This result was also in line with the observation of V upon mixing IV with Oxone. 1 H NMR spectra of III in various amounts of HFIP clearly showed a downfield shift of H b and H c as well as an upfield shift of H d , which were dependent on the volume ratio of HFIP, indicating hydrogen-bonding interactions between III and HFIP (Fig. 6 C), which might lead to further enhancement of its electrophilicity. Reaction kinetics showed the 1st order dependence of product formation rate on catalyst IV (Fig. 6 D, see supporting information SX ). The Hammett plot [log( k X / k H ) versus σ ] displayed a linear relationship with a ρ value of -2.5275 ( R 2 = 0.9922), which suggests that the reaction proceeds through a single mechanism with significant positive charge developed in the transition state, indicative of an electrophilic process with the formation of a Wheland-type intermediate (Fig. 6 E). 33 Taken together, a catalytic cycle that is in best agreement with mechanistic experiments for the title reaction was outlined in Fig. 6 F. Starting from 2-iodobenzenesulfonic acid ( IV ), oxidation of which by Oxone gives I -hydroxy λ 3 -iodane V . Heating V and NaCl in DCE/HFIP (2/1) leads to the formation of the key chlorinating reagent III , which engages in hydrogen-bonding interactions with HFIP to further increase its electrophilicity ( III + HFIPs). C–H chlorination by this adduct gives the corresponding product and regenerates catalyst IV . Heating is required for the formation of III , probably due to the low solubility of NaCl in the solvent system. It is worth mentioning that this catalytic C–H reaction is designed to address the inconvenience associated with the synthesis and isolation of highly reactive but moisture-sensitive III via its in situ formation, paradoxically, no strigent anhydrous procedure was required, and this protocol can tolerate adventitious water. To understand the origin of this feature, a small aliquot of water (20 µl) was added into a clear yellow solution of III in CDCl 3 /HFIP, and we found that it quickly decolorizes to give a white precipitate, which was determined to be a mixture of IV , V and I 5+ compound VIII in a ratio of 6 : 1 : 1.5. Apparently, IV is the catalyst, V is an active intermediate in the catalytic cycle, and VIII can decompose to IV or V 34 upon heating to reenter the catalytic cycle (see the supporting information Figure S29 ). This “self-healing” feature 35 makes this method highly efficient and practical for the application of λ 3 -iodane III in electrophilic C–H chlorination reactions. DFT Calculations To gain deeper insight into the enhanced electrophilicity of III and its role in electrophilic C–H chlorination, density functional theory (DFT) calculations were carried out. We first compared III with other N–Cl or I–Cl type chlorination reagents. Due to the “Cl + ” nature of these reagents, a lower charge density on the the chlorine atom is expected to facilitate the electrophilic chlorination step. As anticipated, the electrostatic potential map of III (Fig. 7 A) exhibits a more positive region at the chloride atom, indicating a stronger propensity for “Cl + ” transfer. Moreover, the chlorination ability of III is further enhanced in the presence of HFIP. 36 Following the methodology outlined by Wu and colleagues, 31 in which highly electron-withdrawing groups weaken the trans influence, leading to a shorter I–Cl bond and increased reactivity in electrophilic chlorination, we compared the I–Cl bond distances of various I–Cl type chlorination reagents. Remarkably, III indeed shows a shorter I–Cl bond distance ( Figure S40 ), further supporting its superior chlorinating ability. To elucidate the overall mechanism of the chlorination reaction, 1,3-difluorobenzene ( 1i ) was selected as a model substrate, and the energy profile of the chlorination process was calculated (Fig. 7 B). DFT calculations reveal that 1i undergoes electrophilic aromatic substitution (S E Ar) to afford the chlorinated product. The rate-determining step corresponds to the transfer of the chlorine cation from III to substrate 1i , with a calculated activation barrier of 24.2 kcal/mol for the involvement of one molecule of HFIP (24.8 kcal/mol for two molecules of HFIP, Figure S39 ). Subsequently, deprotonation occurs with the assistance of HFIP, leading to the formation of the final product. Notably, compound III is capable of efficiently chlorinating the highly electron-deficient arene IV even in the absence of an added substrate, highlighting its enhanced electrophilicity ( Figure S38 ). These results collectively demonstrate that III is a highly effective reagent for electrophilic arene C–H chlorination. In conclusion, we have reported in this article the successful synthesis and characterization of a highly anticipated variant of Willgerodt reagent, namely λ 3 -iodane III , which has an unusually short I–Cl bond and a resulting high electrophilicity of the chlorine atom. These features make III a highly electrophilic chlorination reagent that can chlorinate inactivated arenes without additional catalysts. In order to mitigate the influence of the moisture-sensitive nature and address the resulting synthetic inconvenience associated with III , a catalytic C–H chlorination protocol via in situ formation of III with 2-iodobenzenesulfonic acid ( IV ) as the catalyst and NaCl as the chlorine source was realized. This method has significantly enhanced substrate scope and can be applied to late-stage modifications of complex natural products and biologically relevant molecules. Based on mechanistic studies as well as DFT calculations, a catalytic cycle has been outlined with a “self-healing” mechanism, which accounts for the “moisture insensitivity” of this protocol despite the fact that III is a moisture-sensitive compound. We envisage that λ 3 -iodane III can serve as a useful intermediate to other hypervalent-iodine-based functional group transferring reagents with enhanced reactivity, and the related research is currently in progress, which will be reported in due course. Methods General procedures for the catalytic C–H chlorination via in situ generation of λ 3 -iodane III : General procedure A : To a 5 mL pressure vial equipped with a magnetic stir bar was charged with aromatic compound (0.2 mmol, 1.0 equiv.), 2-iodobenzenesulphonic acid (5.6 mg, 0.02 mmol, 0.1 equiv.), NaCl (24 mg, 0.4 mmol, 2.0 equiv.), Oxone (246 mg, 0.4 mmol, 2.0 equiv.), DCE : HFIP = 2:1 (1.0 mL). The reaction mixture was sealed and heated to the indicated temperature for the indicated period of time. After the mixture was cooled to room temperature. The solid was removed by filtration and washed with DCM, followed solvent was removed under reduced pressure, and the product was purified by flash column chromatography on silica gel to give the desired chlorination product. General procedure B To a 5 mL pressure vial equipped with a magnetic stir bar was charged with electron-deficient aromatic compound (0.2 mmol, 1.0 equiv.), 2-iodobenzenesulphonic acid (5.6 mg, 0.02 mmol, 0.1 equiv.), Mg(OTf) 2 (6.4 mg, 0.02 mmol, 0.1 equiv.), NaCl (48 mg, 0.8 mmol, 4.0 equiv.), Oxone (369 mg, 0.6 mmol, 3.0 equiv.), HFIP (1.0 mL). The reaction mixture was sealed and heated to the indicated temperature for the indicated period of time. After the mixture was cooled to room temperature. the solid was removed by filtration and washed with DCM, followed solvent was removed under reduced pressure, and the product was purified by flash column chromatography on silica gel to give the desired chlorination product. Declarations Supplementary Information is linked to the online version of the paper at www.nature.com/nature . Author Contributions Statement H. Q.-Q., and X. Y. conceived the project. H. Q.-Q., X. Y., Y. Z., and X. Y. designed and performed the experiments. Z. Y., and Z. H. carried out DFT calculations. H. Q.-Q., X. Y., Y. Z., and X. Y. analyzed the data. H. Q.-Q., Z. H., and X. Y. wrote the manuscript. Competing Interests Statement The authors declare no financial interests. Acknowledgments X. Y. acknowledges financial support provided by the National Science Foundation of China (NSFC, 22171095). Z. H. acknowledges supports from Engineering Research Center of Photoenergy Utilization for Pollution Control and Carbon Reduction, Ministry of Education (CCNU24JCPT016) and National Natural Science Foundation of China (Grant 22401102). We are grateful to the Analytic and Testing Centre of HUST for data characterization. Data availability The data that support the findings of this study are available in the article and the Supplementary Information section. Details about materials and methods, experimental procedures, characterization data, mechanistic studies, DFT calculations, and NMR spectra are available in the Supplementary Information. Cartesian coordinates of all the optimized structures are provided in Supplementary Data 1. References Zeng J, Zhan J (2019) Chlorinated natural products and related halogenases. Isr J Chem 59:387–402 Yao H, Wang J, Xu Y, Zhang S, Hou J (2020) Recent progress in chlorinated organic photovoltaic materials. Acc Chem Res 53:822–832 Kamalesh T, Kumar PS, Rangasamy G (2023) An insights of organochlorine pesticides categories, properties, eco-toxicity and new developments in bioremediation process. Environ Pollut 333:122114 Chiodi D, Ishihara Y (2023) Magic chloro: profound effects of the chlorine atom in drug discovery. 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Chem Sci 8:7009–7013 Wang Y, Bi C, Kawamata Y, Grant LN, Samp L, Richardson PF, Zhang S, Harper KC, Palkowitz MD, Vasilopoulos A, Collins MR, Oderinde MS, Tyrol CC, Chen D, LaChapelle EA, Bailey JB, Qiao JX, Baran PS (2024) Discovery of N–X anomeric amides as electrophilic halogenation reagents. Nat Chem 16:1539–1545 Rodriguez RA, Pan C-M, Yabe Y, Kawamata Y, Eastgate MD, Baran PS (2014) Palauꞌchlor: A Practical and Reactive Chlorinating Reagent. J Am Chem Soc 136:6908–6911 Song S, Li X, Wei J, Wang W, Zhang Y, Ai L, Zhu Y, Shi X, Zhang X (2020) Jiao, N. DMSO-catalysed late-stage chlorination of (hetero) arenes. Nat Catal 3:107–115 Nishii Y, Ikeda M, Hayashi Y, Kawauchi S, Miura M (2019) Triptycenyl sulfide: a practical and active catalyst for electrophilic aromatic halogenation using N-halosuccinimides. J Am Chem Soc 142:1621–1629 Kona CN, Oku R, Nakamura S, Miura M, Hirano K, Nishii Y (2024) Aromatic halogenation using carborane catalyst. Chem 10:402–413 Nimbhal A, Singh R, N-Chlorosuccinimide: (2025) A Versatile Reagent in Organic Synthesis. Curr Org Chem 29:936–950 Prakash GS, Mathew T, Hoole D, Esteves PM, Wang Q, Rasul G, Olah GA (2004) N -Halosuccinimide/BF 3 –H 2 O, Efficient Electrophilic Halogenating Systems for Aromatics. J Am Chem Soc 126:15770–15776 Wang W, Yang X, Dai R, Yan Z, Wei J, Dou X, Qiu X, Zhang H, Wang C, Liu Y, Song S (2022) Jiao, N. Catalytic electrophilic halogenation of arenes with electron-withdrawing substituents. J Am Chem Soc 144:13415–13425 Willgerodt C (1885) Ueber einige aromatische Jodidchloride. J Prakt Chem 33:154–160 Nahide PD, Ramadoss V, Juárez-Ornelas KA, Satkar Y, Ortiz‐Alvarado R, Cervera‐Villanueva JM, Alonso-Castro ÁJ, Zapata-Morales JR, Ramírez-Morales MA, Ruiz-Padilla AJ, Deveze-Álvarez MA, Solorio‐Alvarado CR (2018) In Situ Formed I III ‐Based Reagent for the Electrophilic ortho‐Chlorination of Phenols and Phenol Ethers: The Use of PIFA‐AlCl 3 System. Eur. J. Org. Chem. 485–493 (2018) Yoshimura A, Zhdankin VV (2016). Advances in synthetic applications of hypervalent iodine compounds. Chem Rev 116:3328–3435 Burdett JK, Albright TA (1979) Trans influence and mutual influence of ligands coordinated to a central atom. Inorg Chem 18:2112–2120 Ochiai M, Sueda T, Miyamoto K, Kiprof P, Zhdankin V (2006) V. trans influences on hypervalent bonding of aryl λ 3 -iodanes: Their stabilities and isodesmic reactions of benziodoxolones and benziodazolones. Angew Chem Int Ed 45:8203–8206 Sajith PK, Suresh CH (2012) Quantification of the trans influence in hypervalent iodine complexes. Inorg Chem 51:967–977 Fosu SC, Hambira CM, Chen AD, Fuchs JR, Nagib DA (2019) Site-selective C–H functionalization of (hetero) arenes via transient, non-symmetric iodanes. Chem 5:417–428 Sharp-Bucknall L, Sceney M, White KF, Dutton JL (2023) Synthesis, structural characterization, reactivity and catalytic activity of mixed halo/triflate ArI (OTf)(X) species. Dalton Trans 52:3358–3370 Yoshimura A, Saito A, Zhdankin VV (2023) Recent progress in synthetic applications of cyclic hypervalent iodine (III) reagents. Adv Synth Catal 365:2653–2675 Amey RL, Martin JC (1979) Synthesis and reaction of substituted arylalkoxyiodinanes: formation of stable bromoarylalkoxy and aryldialkoxy heterocyclic derivatives of tricoordinate organoiodine (III). J Org Chem 44:1779–1784 Andrews LJ, Keefer RM (1959) The Unusual Effects of o-Carboxyl and Carbomethoxy Substituents on the Stability of Iodobenzene Dichloride. J Am Chem Soc 81:4218–4223 Wang M, Zhang Y, Wang T, Wang C, Xue D, Xiao J (2016) Story of an age-old reagent: an electrophilic chlorination of arenes and heterocycles by 1-chloro-1, 2-benziodoxol-3-one. Org Lett 18:1976–1979 Jiang H, Sun TY, Chen Y, Zhang X, Wu YD, Xie Y, Schaefer HF (2019) Designing new Togni reagents by computation. Chem Commun 55:5667–5670 Liang T, Lyu Z, Wang Y, Zhao W, Sang R, Cheng G-J, Ye F (2025) Light-promoted aromatic denitrative chlorination. Nat Chem 17:598–605 Koleva G, Galabov B, Hadjieva B, Schaefer HF III, Schleyer PR (2015) An Experimentally Established Key Intermediate in Benzene Nitration with Mixed Acid. Angew Chem Int Ed 54:14123–14127 Koposov AY, Litvinov DN, Zhdankin VV, Ferguson MJ, McDonald R, Tykwinski RR (2006) Eur J Org Chem 4791–4795 Gatzenmeier T, Kaib PSJ, Lingnau JB, Goddard R, List B (2018) The Catalytic Asymmetric Mukaiyama-Michael Reaction of Silyl Ketene Acetals with ɑ, β-Unsaturated Methyl Esters. Angew Chem Int Ed 57:2464–2468 Charpentier J, Früh N, Togni A (2015) Electrophilic Trifluoromethylation by Use of Hypervalent Iodine Reagents. Chem Rev 115:650–682 Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryData1.docx Dataset 1. SupportingInformation.pdf Supporting Information Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8374240","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":562044701,"identity":"6ae5bdba-ce4a-4e80-bcbf-4e306791a36b","order_by":0,"name":"Youwei Xie","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAz0lEQVRIiWNgGAWjYDACZhBRcQDC4SFeyxmgFjaitYAAYxspWgyOMx+T5p13J3H+/AbGB2/bGOTNCWmRbGZLk+bd9ixxwzEGZsO5bQyGOxsIaOFn5jGTzt12OHEDGwObNG8bQ4LBAQJa2Jj5v0nnzjmcOL+Ngf03UVqAtrBJ5zYcTmw4BtROlBagX4yt/xw7bLzhWGKz5JxzEoYbCGkxOH/44c0ZNYdl5zcfPvjhTZmNPEFbgIBFAkIzNgAJCcLqgYD5A1HKRsEoGAWjYOQCAAaAPNxoeAzNAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0003-3831-4059","institution":"Huazhong University of Science and Technology","correspondingAuthor":true,"prefix":"","firstName":"Youwei","middleName":"","lastName":"Xie","suffix":""},{"id":562044702,"identity":"90da805d-f69c-4820-bd5b-abfcb9ed217b","order_by":1,"name":"Qi-Qi Hu","email":"","orcid":"","institution":"Huazhong University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Qi-Qi","middleName":"","lastName":"Hu","suffix":""},{"id":562044703,"identity":"8e8a24fc-c731-4b38-82fb-4d9bef4454fe","order_by":2,"name":"Yao Xiang","email":"","orcid":"","institution":"Huazhong University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Yao","middleName":"","lastName":"Xiang","suffix":""},{"id":562044704,"identity":"1a96ac6d-2b93-4f0b-95e9-42d12ab0320e","order_by":3,"name":"Zhaobo Ying","email":"","orcid":"","institution":"Huazhong University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Zhaobo","middleName":"","lastName":"Ying","suffix":""},{"id":562044705,"identity":"ab59949d-8d8b-4e81-b631-935872cbc336","order_by":4,"name":"Yu Zhou","email":"","orcid":"","institution":"Central China Normal University","correspondingAuthor":false,"prefix":"","firstName":"Yu","middleName":"","lastName":"Zhou","suffix":""},{"id":562044706,"identity":"2e43dc95-15b5-4574-a52f-87b657ff8b0b","order_by":5,"name":"Hui Zhou","email":"","orcid":"","institution":"Central China Normal University","correspondingAuthor":false,"prefix":"","firstName":"Hui","middleName":"","lastName":"Zhou","suffix":""}],"badges":[],"createdAt":"2025-12-16 09:31:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8374240/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8374240/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104399962,"identity":"8ddec66f-06c8-4aef-b0c8-2fe535ad6584","added_by":"auto","created_at":"2026-03-11 12:08:19","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":369007,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSelected methods for electrophilic arene C–H chlorinations. A\u003c/strong\u003e, classic chlorinations with Cl\u003csub\u003e2\u003c/sub\u003e. \u003cstrong\u003eB\u003c/strong\u003e, oxidative chlorination with halides and oxidants ([OX]: oxidations at anodes, photoredox catalysts, etc.). \u003cstrong\u003eC\u003c/strong\u003e, chlorinations with N-Cl type reagents (LA: Lewis acids; LB: Lewis bases). \u003cstrong\u003eD\u003c/strong\u003e, chlorinations by activation of the Willgerodt reagent. \u003cstrong\u003eE\u003c/strong\u003e, chlorinations with cyclic hypervalent λ\u003csup\u003e3\u003c/sup\u003e-iodane reagents.\u003c/p\u003e","description":"","filename":"image1.png","url":"https://assets-eu.researchsquare.com/files/rs-8374240/v1/0e3d04b57ccfdba8ba57d8d3.png"},{"id":103705353,"identity":"209dc467-23d1-45bd-a94c-a42ec6bdc64b","added_by":"auto","created_at":"2026-03-02 01:03:06","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":353196,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSynthesis and application of λ\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e3\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003e-iodane III. A\u003c/strong\u003e, \u003csup\u003e1\u003c/sup\u003eH NMR studies of the reaction progress during synthetic attemps of \u003cstrong\u003eIII \u003c/strong\u003eled to its identification and isolation. For clarity, all \u003csup\u003e1\u003c/sup\u003eH NMR spectra are scaled accordingly so that only the section from 7.0 ppm to 8.2 ppm are shown (see the suppoting information for the corresponding full spectra). \u003cstrong\u003eB\u003c/strong\u003e, design of a catalytic C–H chlorination of unactivated arenes via \u003cem\u003ein situ\u003c/em\u003e formation of \u003cstrong\u003eIII\u003c/strong\u003e.\u003c/p\u003e","description":"","filename":"image2.png","url":"https://assets-eu.researchsquare.com/files/rs-8374240/v1/e983feba5b2c8f5f3214f9ec.png"},{"id":103705349,"identity":"fbdc7f84-4565-4d48-9471-8bfd66316e38","added_by":"auto","created_at":"2026-03-02 01:03:06","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":698498,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCatalytic C–H chlorination of arenes and heteroarenes. \u003c/strong\u003eUnless mentioned otherwise,\u003cstrong\u003e \u003c/strong\u003ereactions were performed with \u003cstrong\u003e1\u003c/strong\u003e (1.0 equiv.), NaCl (2.0 equiv.), oxone (2.0 equiv.), 2-iodobenezenesulfonic acid (0.1 equiv.), in DCE : HFIP = 2 : 1 (0.2 M), at 100 ℃ for 24 hours, isolated yield\u003csup\u003e a\u003c/sup\u003e. Yields were determined by analyzing \u003csup\u003e1\u003c/sup\u003eH NMR using 1,1,2,2-tetrachloroethane as the internal standard\u003csup\u003e b\u003c/sup\u003e. 1.0 equiv. of NaCl was used \u003csup\u003ec\u003c/sup\u003e. 3.0 equiv. of NaCl and 3.0 equiv. of oxone were used \u003csup\u003ed\u003c/sup\u003e. HFIP (no DCE) was used as the solvent \u003csup\u003ee\u003c/sup\u003e. 4.0 equiv. of NaCl, 3.0 equiv. of oxone, and 0.1 equiv. of Mg(OTf)\u003csub\u003e2\u003c/sub\u003e were used \u003csup\u003ef\u003c/sup\u003e. (•) indicates the position for the second chlorination.\u003c/p\u003e","description":"","filename":"image3.png","url":"https://assets-eu.researchsquare.com/files/rs-8374240/v1/33e88f196d3c3a598cdca7a0.png"},{"id":103705351,"identity":"67c83867-cce3-48dc-afcb-f1287922124f","added_by":"auto","created_at":"2026-03-02 01:03:06","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":610635,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eLate-stage C–H chlorination of durgs and natural products. \u003c/strong\u003eUnless mentioned otherwise,\u003cstrong\u003e \u003c/strong\u003ereactions were performed with \u003cstrong\u003e1\u003c/strong\u003e (1.0 equiv.), NaCl (2.0 equiv.), oxone (2.0 equiv.), 2-iodobenezenesulfonic acid (0.1 equiv.), in DCE : HFIP = 2 : 1 (0.2 M), at 100 ℃ for 24 hours, isolated yield \u003csup\u003ea\u003c/sup\u003e. 3.0 equiv. of NaCl and 3.0 equiv. of oxone were used \u003csup\u003eb\u003c/sup\u003e. 1.0 equiv. of NaCl and 1.0 equiv. of oxone were used \u003csup\u003ec\u003c/sup\u003e. Reaction was performed at 80 ℃ \u003csup\u003ed\u003c/sup\u003e. 4.0 equiv. of NaCl, 3.0 equiv. of oxone and 0.1 equiv. of Mg(OTf)\u003csub\u003e2\u003c/sub\u003e were used \u003csup\u003ee\u003c/sup\u003e. (•) indicates the position for the second chlorination.\u003c/p\u003e","description":"","filename":"image4.png","url":"https://assets-eu.researchsquare.com/files/rs-8374240/v1/6b9f745c019a1e203eead34f.png"},{"id":104399949,"identity":"e03e7482-13a9-4775-85b6-6ffd25db2ec3","added_by":"auto","created_at":"2026-03-11 12:08:16","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":261254,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eEfficiency comparison. \u003c/strong\u003eMethod 1:\u003cstrong\u003e \u003c/strong\u003eBI-Cl (1.2 equiv.), DMF, 25 ℃;\u003csup\u003e30\u003c/sup\u003e Method 2: BI-Cl (1.2 equiv.), HFIP, 25 ℃; Method 3: NCS (1.2 equiv.), HFIP, 25 ℃; Method 4: NCS (1.2 equiv.), DMSO (0.2 equiv.), CHCl\u003csub\u003e3\u003c/sub\u003e, 25 ℃;\u003csup\u003e13\u003c/sup\u003e\u003cstrong\u003e \u003c/strong\u003eMethod 5: TCCA (0.4 equiv.), TfOH (5 mol%), HFIP, 60 ℃.\u003csup\u003e18\u003c/sup\u003e\u003c/p\u003e","description":"","filename":"image5.png","url":"https://assets-eu.researchsquare.com/files/rs-8374240/v1/d82dc502e58b27575d1f2a70.png"},{"id":104399942,"identity":"111f0bbf-9926-4b6a-841f-10ba310e188a","added_by":"auto","created_at":"2026-03-11 12:08:15","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":549862,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMechanistic experiments and proposed mechanism.\u003c/strong\u003e \u003cstrong\u003ea\u003c/strong\u003e, control experiments; \u003cstrong\u003eb\u003c/strong\u003e, cyclic voltammetry of key components of the reaction; \u003cstrong\u003ec\u003c/strong\u003e, \u003csup\u003e1\u003c/sup\u003eH NMR of \u003cstrong\u003eIII\u003c/strong\u003e in the presence of varying amounts of HFIP; \u003cstrong\u003ed\u003c/strong\u003e, reaction kinetics: rate of product formation with varying amounts of catalyst \u003cstrong\u003eIV\u003c/strong\u003e; \u003cstrong\u003ee\u003c/strong\u003e, Hammett plot; \u003cstrong\u003ef\u003c/strong\u003e, proposed mechanism.\u003c/p\u003e","description":"","filename":"image6.png","url":"https://assets-eu.researchsquare.com/files/rs-8374240/v1/2c1bb2fba6cba158a623968b.png"},{"id":103705355,"identity":"72e1d0a4-9b06-4433-97a5-012ecf3c6150","added_by":"auto","created_at":"2026-03-02 01:03:06","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":197729,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDFT calculations. a, \u003c/strong\u003eelectrostatic potential maps (unit: a.u.); \u003cstrong\u003eb\u003c/strong\u003e, energy profile.\u003c/p\u003e","description":"","filename":"image7.png","url":"https://assets-eu.researchsquare.com/files/rs-8374240/v1/241ea28028cd611f76ae33f1.png"},{"id":104407846,"identity":"ffa7a00b-9227-4f68-a885-49533637376d","added_by":"auto","created_at":"2026-03-11 12:40:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4006002,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8374240/v1/a62a8ba3-dec9-4743-abb9-44bc24070520.pdf"},{"id":103705354,"identity":"9a11492d-3881-466b-9c69-ca66063d71a1","added_by":"auto","created_at":"2026-03-02 01:03:06","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":152771,"visible":true,"origin":"","legend":"Dataset 1.","description":"","filename":"SupplementaryData1.docx","url":"https://assets-eu.researchsquare.com/files/rs-8374240/v1/5aaa594727c25b21f19f8c19.docx"},{"id":103705357,"identity":"b45f5159-df78-4a4f-a269-c5a952dc03d2","added_by":"auto","created_at":"2026-03-02 01:03:06","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":13476576,"visible":true,"origin":"","legend":"Supporting Information","description":"","filename":"SupportingInformation.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8374240/v1/da641ab457ca815e07ccf6df.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Catalytic Electrophilic Arene C–H Chlorination by Rethinking of the Century-old Willgerodt Reagent","fulltext":[{"header":"Introduction","content":"\u003cp\u003eChlorinated (hetero)arenes are frequently encountered structural motifs in various natural products,\u003csup\u003e1\u003c/sup\u003e and these chemicals have widespread applications in materials,\u003csup\u003e2\u003c/sup\u003e agrochemicals,\u003csup\u003e3\u003c/sup\u003e pharmaceuticals,\u003csup\u003e4\u003c/sup\u003e etc. Additionally, they are versatile synthetic intermediates\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e and can serve as useful electrophiles in cross-coupling reactions.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e In industry, as introduced in canonical organic chemistry textbooks, chlorinated arenes are prepared by an electrophilic aromatic substitution (SEAr) process that combines gases Cl\u003csub\u003e2\u003c/sub\u003e and stoichiometric amounts of Lewis acids (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA).\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e However, the operational inconvenience associated with the handling of gaseous Cl\u003csub\u003e2\u003c/sub\u003e and the inherent poor selectivity and low functional group tolerance make it a second choice for experimental chemists in research laboratories. Alternatively, inorganic or organic chlorides can be applied to the chlorination of electron-rich arenes when combined with various oxidants,\u003csup\u003e8\u003c/sup\u003e electrochemical oxidations,\u003csup\u003e9\u003c/sup\u003e photoredox catalysts,\u003csup\u003e10\u003c/sup\u003e etc. (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). Various N\u0026ndash;Cl type reagents are commercially available, most of which are designed by tuning the other two substituents on the nitrogen atom to balance overall stability and reactivity (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC).\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e Many of these reagents have improved functional group tolerance and can chlorinate electronically activated arenes without the need for a catalyst.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e Activation by a Lewis base can lead to moderate reactivity enhancement of these reagents. For example, Jiao,\u003csup\u003e13\u003c/sup\u003e Miura,\u003csup\u003e14\u003c/sup\u003e and Nishii\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e used DMSO or thioethers, respectively, as Lewis bases to activate \u003cem\u003eN\u003c/em\u003e-chlorosuccinimide (NCS) to chlorinate relatively electron-rich arenes. On the other hand, excessive amounts of strong acids are generally required to activate these reagents for the chlorination of deactivated arenes.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e For example, Olah used NCS with superacidic BF\u003csub\u003e3\u003c/sub\u003e\u0026bull;H\u003csub\u003e2\u003c/sub\u003eO as a solvent to chlorinate deactivated arenes at 100 \u0026ordm;C.\u003csup\u003e17\u003c/sup\u003e A breakthrough in this field was recently achieved by Jiao and Song, who used catalytic amount of the super Br\u0026oslash;nsted acid TfOH (5%\u0026ndash;20%) in hexafluoroisopropanol (HFIP) to activate trichloroisocyanuric acid (TCCA) for the chlorination of deactivated arenes.\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn sharp contrast to the wide adoption of N\u0026ndash;Cl type reagents, hypervalent I\u0026ndash;Cl type reagents usually are not the first resort when synthetic organic chemists need to chlorinate their substrates, although this type of reagents could trace back to at least more than a century ago, when Willgerodt introduced PhICl\u003csub\u003e2\u003c/sub\u003e in 1886 as a safer and easier-to-handle alternative to Cl\u003csub\u003e2\u003c/sub\u003e.\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e In addition to the fact that less I\u0026ndash;Cl type reagents are commercially available, they often show inferior reactivity and poorer stability compared to the more popular N\u0026ndash;Cl type reagents. For example, the commercially available Willgerodt reagent (PhICl\u003csub\u003e2\u003c/sub\u003e) has reduced reactivity, decomposes at elevated temperatures, and is limited to highly reactive substrates. Formation of the more reactive PhI(X)Cl via a ligand exchange process from either PhICl\u003csub\u003e2\u003c/sub\u003e or PhI(OR)\u003csub\u003e2\u003c/sub\u003e is often necessary for less activated substrates (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eD).\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e These compounds belong to a class of aryl λ\u003csup\u003e3\u003c/sup\u003e-iodanes ArILLꞌ (L, Lꞌ: heteroatom ligands, etc.) that adopt a T-shaped geometry in which the aryl group occupies the equatorial position and the L\u0026ndash;I\u0026ndash;Lꞌ triad occupies the axial position in a near linear shape.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e The property of Lꞌ affects that of L via a well-studied phenomenon known as the \u0026ldquo;trans influence\u0026rdquo;,\u003csup\u003e22\u003c/sup\u003e which also determines the overall reactivity and stability of this type of compounds.\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e The enhanced reactivity of PhI(X)Cl is due to the weaker trans-influencing ligand X (longer I\u0026ndash;X bond length) that resulted in a shorter I\u0026ndash;Cl bond and a more electrophilic chlorine atom.\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e Unfortunately, most derivatized Willgerodt reagents in the form of PhI(X)Cl are not isolable and can only be observed \u003cem\u003ein situ\u003c/em\u003e.\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e An exception was achieved by Dutton, who successfully isolated O\u003csub\u003e2\u003c/sub\u003eN\u0026ndash;ArI(OTf)Cl by reacting 1-iodo-4-nitrobenzene with Cl\u003csub\u003e2\u003c/sub\u003e and TfOH. This λ\u003csup\u003e3\u003c/sup\u003e-iodane has an unusually short I\u0026ndash;Cl bond (2.36 \u0026Aring;) and high reactivity due to the weak trans-influencing triflate ligand.\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e Another strategy to provide stability to I\u0026ndash;Cl type λ\u003csup\u003e3\u003c/sup\u003e-iodanes is to introduce a cyclic structure, a strategy that is more well-known in the design of the Togni type reagents.\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e For instance, in contrast to their acyclic variants, chloroiodinanes \u003cb\u003eI\u003c/b\u003e (by Martin)\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e and \u003cb\u003eII\u003c/b\u003e (by Andrews and Keefer)\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e are stable and commercially available compounds (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eE). However, these reagents are better known as synthetic intermediates to Togni type reagents rather than chlorination reagents due to the relatively long I\u0026ndash;Cl bond, and the resulting less electrophilicity of the chlorine atom limits their applications to highly electron-rich arenes.\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e By switching the strong trans-influencing endocyclic alkoxy ligand in \u003cb\u003eI\u003c/b\u003e to a moderate trans-influencing carboxy ligand in \u003cb\u003eII\u003c/b\u003e, a shortening of the I\u0026ndash;Cl bond and an increasing of the reactivity was observed. Predictably, a weak trans-influencing sulfonyloxy group (\u003cb\u003eIII\u003c/b\u003e) will further decrease the I\u0026ndash;Cl bond and increase the electrophilicity of the chlorine atom. Unfortunately, \u003cb\u003eIII\u003c/b\u003e only existed in some computational studies that proposed it as an intermediate to a delicately designed variant of the Togni reagent with enhanced reactivity in electrophilic trifluoromethylation reactions.\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e To the best of our knowledge, hitherto, no synthetic route has been reported, and no reactivity profile in arene C\u0026ndash;H chlorination reaction has been established for this promising compound.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSynthetic attempts and characterization of λ\u003csup\u003e3\u003c/sup\u003e-iodane III\u003c/h2\u003e \u003cp\u003eWith the aim to provide a stable and highly electrophilic λ\u003csup\u003e3\u003c/sup\u003e-iodane to potentially overcome the current limitations associated with I\u0026ndash;Cl as well as N\u0026ndash;Cl type chlorination reagents, we embarked on an endeavor to synthesize \u003cb\u003eIII\u003c/b\u003e. Unsurprisingly, by simply following the synthetic protocols of known I\u0026ndash;Cl type λ\u003csup\u003e3\u003c/sup\u003e-iodane with necessary changes of the starting substrate, we failed to obtain the target compound \u003cb\u003eIII\u003c/b\u003e. In most cases, only the 2-iodobenzenesulfonic acid (\u003cb\u003eIV\u003c/b\u003e) was recovered (see \u003cb\u003eFigure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e\u003c/b\u003e and \u003cb\u003eS2\u003c/b\u003e). To gain more information about the problems associated with the synthesis of \u003cb\u003eIII\u003c/b\u003e, we carried out \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003eH NMR studies of reaction progress during our synthetic attemps. For one experiment in HFIP, we found that 2-iodobenzenesulfonic acid (\u003cb\u003eIV\u003c/b\u003e) could be oxidized to \u003cb\u003eV\u003c/b\u003e (Fig.\u0026nbsp;\u0026lt;link rid=\"fig2\"\u0026gt;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u0026lt;/link\u0026gt;\u003c/span\u003eA, a-\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Heating \u003cb\u003eV\u003c/b\u003e at 80 \u0026ordm;C or above in the presence of NaCl led to the formation of a new species \u003cb\u003eX\u003c/b\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA, a-\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e), and a mixture of \u003cb\u003eV\u003c/b\u003e and \u003cb\u003eX\u003c/b\u003e could be seen before full conversion of \u003cb\u003eV\u003c/b\u003e (see \u003cb\u003eFigure S7\u003c/b\u003e). However, initial efforts to isolate and characterize species \u003cb\u003eX\u003c/b\u003e only led to isolation of I\u003cb\u003eV\u003c/b\u003e. On the other hand, heating the solution containing \u003cb\u003eX\u003c/b\u003e at 100 \u0026ordm;C overnight resulted in the formation of a mixture of \u003cb\u003eIV\u003c/b\u003e, \u003cb\u003eVI\u003c/b\u003e, and \u003cb\u003eVII\u003c/b\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA, a-\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). This result is intriguing due to the fact that \u003cb\u003eVI\u003c/b\u003e and \u003cb\u003eVII\u003c/b\u003e are two regioisomers of the chlorination products of \u003cb\u003eIV\u003c/b\u003e. Species \u003cb\u003eX\u003c/b\u003e has significantly enhanced electrophilicity that could even chlorinate electron-deficient arenes such as itself upon heating. With a less deactivated arene such as chlorobenzene (\u003cb\u003e1a\u003c/b\u003e) added, a mixture of \u003cem\u003ep\u003c/em\u003e-dichlorobenzene and \u003cem\u003eo\u003c/em\u003e-dichlorobenzene could be obtained even at room temperature, along with the regeneration of \u003cb\u003eIV\u003c/b\u003e (see \u003cb\u003eFigure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e0\u003c/b\u003e). We speculated the species \u003cb\u003eX\u003c/b\u003e is the highly anticipated I\u0026ndash;Cl type λ\u003csup\u003e3\u003c/sup\u003e-iodane \u003cb\u003eIII\u003c/b\u003e, and its recalcitrance from being tamed might be due to its high reactivity that led to fast hydrolysis, which was in line with the fact that our previous synthetic efforts toward \u003cb\u003eIII\u003c/b\u003e only led to the isolation of \u003cb\u003eIV\u003c/b\u003e. After a careful anhydrous workup and crystallization, we could eventually assign species \u003cb\u003eX\u003c/b\u003e to be \u003cb\u003eIII\u003c/b\u003e (I\u0026ndash;Cl: 2.326 \u0026Aring; to 2.369 \u0026Aring;) unambiguously with the assistance of X-ray crystallography (CCDC 2491924). 2.326 \u0026Aring; represents the shortest bond length for I\u0026ndash;Cl type λ\u003csup\u003e3\u003c/sup\u003e-iodane, which explains its high electrophilicity.\u003c/p\u003e \u003cp\u003e \u003cb\u003eDesign and optimization of a catalytic arene C\u0026ndash;H chlorination via\u003c/b\u003e \u003cb\u003ein situ\u003c/b\u003e \u003cb\u003eformation of III\u003c/b\u003e\u003c/p\u003e \u003cp\u003eIn order to fully utilize \u003cb\u003eIII\u003c/b\u003e as a powerful chlorinating reagent and minimize its synthetic challenges, we designed and realized a catalytic arene C\u0026ndash;H chlorination via its \u003cem\u003ein situ\u003c/em\u003e formation (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb). In this design, commercially available 2-iodobenzenesulfonic acid (\u003cb\u003eIV\u003c/b\u003e) was used as the catalyst, which reacted with NaCl and Oxone in HFIP to form the highly reactive \u003cb\u003eIII\u003c/b\u003e. The electrophilicity of \u003cb\u003eIII\u003c/b\u003e could be further enhanced via hydrogen-bonding interactions with HFIP, which is the solvent required for its generation. This adduct then reacted with arenes to provide the electrophilic chlorination products and regenerate catalyst \u003cb\u003eIV\u003c/b\u003e. Through a standard optimization process with chlorobenzene (\u003cb\u003e1a\u003c/b\u003e) as the model substrate (see the supporting information Table S2), we found that 5% of catalyst \u003cb\u003eIV\u003c/b\u003e could was able to promote the chlorination of \u003cb\u003e1a\u003c/b\u003e to give 84% yield of two regioisomers, and 10% of \u003cb\u003eIV\u003c/b\u003e could improve the yield to 94%. Control experiments showed that HFIP was crucial for the formation of this highly reactive I\u0026ndash;Cl type λ\u003csup\u003e3\u003c/sup\u003e-iodane \u003cb\u003eIII\u003c/b\u003e and a mixture of DCE/HFIP (2/1) was optimal for this transformation (see the supporting information Table S5). Replacing catalyst \u003cb\u003eIV\u003c/b\u003e with other iodine compounds that could potentially form either acyclic or cyclic I\u0026ndash;Cl type λ\u003csup\u003e3\u003c/sup\u003e-iodane intermediates all gave inferior results, lending further support to the high reactivity of \u003cb\u003eIII\u003c/b\u003e that results from both cyclic structure and the weak trans-influencing endocyclic sulfonyloxy ligand (see the supporting information Table S3).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSynthetic scope\u003c/h3\u003e\n\u003cp\u003eWe then evaluated the synthetic scope of this transformation (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Generally, for most substrates tested, monochlorination products could be obtained as the major products with only negligible multichlorination products. Monohalogenated substrates could be chlorinated to give the correspoinding products as mixtures of regioisomers (\u003cb\u003e2a\u003c/b\u003e\u0026ndash;\u003cb\u003e2d\u003c/b\u003e), and the selectivity for \u003cem\u003epara\u003c/em\u003e chlorination improves with the increase of electronegativity. Electron-neutral benzene gave a mixture of mono- and double chlorination products (\u003cb\u003e2e\u003c/b\u003e). Substrates with benzylic C\u0026ndash;H bonds were well tolerated, such as toluene and ethylbenzene, for which the arene C\u0026ndash;H chlorination products could be obtained as mixtures of regioisomers (\u003cb\u003e2f\u003c/b\u003e\u0026ndash;\u003cb\u003e2g\u003c/b\u003e). Substrate with a bulky \u003cem\u003et\u003c/em\u003e-Butyl group also gave the chlorination product in good yield (\u003cb\u003e2h\u003c/b\u003e). More deactivated \u003cem\u003em\u003c/em\u003e-difluorobenzene gave the \u003cem\u003epara\u003c/em\u003e chlorination product in almost quantitative yield (\u003cb\u003e2i\u003c/b\u003e). Similar selectivity was also observed for \u003cem\u003em\u003c/em\u003e-dichlorobenzene (\u003cb\u003e2j\u003c/b\u003e) and \u003cem\u003em\u003c/em\u003e-dibromobenzene (\u003cb\u003e2k\u003c/b\u003e), given that less NaCl (1.0 equiv.) was used. For \u003cem\u003em\u003c/em\u003e-diiodobenzene, on the other hand, a mixture of two regioisomers (5:1) was obtained (\u003cb\u003e2l\u003c/b\u003e). 1,3,5-trifluorobenzene required slightly more NaCl and Oxone to give the chlorination product (\u003cb\u003e2m\u003c/b\u003e) in a good yield of 80%, while 1,3,5-trichlorobenzene (\u003cb\u003e2n\u003c/b\u003e) could be chlorinated under the standard condition. In contrast, highly electron-rich 1,3,5-trimethoxybenzene required less NaCl (1.0 equiv.) to be used for selective monochlorination (\u003cb\u003e2o\u003c/b\u003e). Delightfully, substrates with high steric hindrance, such as 1,3,5-triisopropylbenzene (\u003cb\u003e2p\u003c/b\u003e) or even 1,3,5-tri-\u003cem\u003et\u003c/em\u003e-butylbenzene (\u003cb\u003e2q\u003c/b\u003e), could be chlorinated under the standard condition to give the corresponding products in good yileds. 1,2,3-trichlorobenzene could be selectively chlorinated to the 1,2,3,4-tetrachlorobenzene (\u003cb\u003e2r\u003c/b\u003e) selectively. In contrast, 1,3,4,5-tetrachlorobenzene reacted sluggishly under the standard condition, this problem could be solved by adding Mg(OTf)\u003csub\u003e2\u003c/sub\u003e as a Lewis acid catalyst to further enhance the reactivity of \u003cb\u003eIII\u003c/b\u003e, and the corresponding product 1,2,3,4,5-pentachlorobenzene (\u003cb\u003e2s\u003c/b\u003e) could be obtained in a good yield of 88%. For highly electron-rich substates, such as phenol or phenols with electron-donating substituents, complicated mixtures of oxidation and multichlorination products were generally obtained. On the other hand, phenol with an electron-withdrawing group (\u003cb\u003e2t\u003c/b\u003e) or anisole (\u003cb\u003e2u\u003c/b\u003e) could be chlorinated successfully under the standard condition. High regioselectivity for \u003cem\u003epara\u003c/em\u003e chlorination could be obtained when the hydroxy group was protected with a benzyl group (\u003cb\u003e2v\u003c/b\u003e) or a trifluoromethyl group (\u003cb\u003e2w\u003c/b\u003e). Other anisole derivatives with various substitution patterns could all be chlorinated to give the monochlorination products (\u003cb\u003e2x\u003c/b\u003e\u0026ndash;\u003cb\u003e2dd\u003c/b\u003e) in good yields and selectivity. Unprotected anilines were not suitable substrates, however, monochlorination or dichlorination could be obtained when aniline was protected with an acyl group (\u003cb\u003e2ee\u003c/b\u003e) or a tosyl group (\u003cb\u003e2ff\u003c/b\u003e), respectively. Derivatives of benzoic acid with varying steric and electronic properties could be chlorinated under the standard condition (\u003cb\u003e2gg\u003c/b\u003e\u0026ndash;\u003cb\u003e2kk\u003c/b\u003e), while the unsubstituted benzoic acid (\u003cb\u003e2ll\u003c/b\u003e), benzoate ester (\u003cb\u003e2mm\u003c/b\u003e), or halogenated benzoate esters (\u003cb\u003e2nn\u003c/b\u003e\u0026ndash;\u003cb\u003e2pp\u003c/b\u003e) needed additional Lewis acid catalysis. Methyl phenylacetate has a easily enolizable benzylic position that could lead to benzylic chlorination, fortunately, arene C\u0026ndash;H chlorination prevailed (\u003cb\u003e2qq\u003c/b\u003e). Naphthalenes substituted with various electron-withdrawing groups gave a mixture of monochlorination and dichlorination products, however, selective dichlorination products (\u003cb\u003e2rr\u003c/b\u003e\u0026ndash;\u003cb\u003e2uu\u003c/b\u003e) could be obtained with 3.0 equivalents of NaCl and Oxone. Benzophenones with methoxy (\u003cb\u003e2vv\u003c/b\u003e) and methyl groups (\u003cb\u003e2ww\u003c/b\u003e) could be selectively chlorinated when 1.0 equiv. of NaCl and oxone were used. Benzophenone with chlorine substituents is highly challenging and a recent protocol relied on a two-step sequence,\u003csup\u003e32\u003c/sup\u003e while traditional direct C\u0026ndash;H chlorination methods usually gave less than 10% yield. Delightfully, our method could provide direct C\u0026ndash;H chlorination of this type of substrate in 65% isolated yiled as a 3:1 mixture of mono chlorination and dichlorination products (\u003cb\u003e2xx\u003c/b\u003e). Biphenyl derivative \u003cb\u003e1yy\u003c/b\u003e could be chlorinated to provide \u003cb\u003e2yy\u003c/b\u003e in a good yiled of 85%. Heterocyclic substrates such as 1,3-benzodioxole (\u003cb\u003e2zz\u003c/b\u003e\u0026ndash;\u003cb\u003e2aaa\u003c/b\u003e), 2,3-dihydrobenzo[1,4]dioxine (\u003cb\u003e2bbb\u003c/b\u003e), and Dihydroquinolinone (\u003cb\u003e2ccc\u003c/b\u003e) are active substrates that could be chlorinated with 1\u0026ndash;2 equivalents of NaCl and Oxone. Methoxy quinoline gave the chlorination product (\u003cb\u003e2ddd-1\u003c/b\u003e) along with partial oxidation of the product (\u003cb\u003e2ddd-2\u003c/b\u003e). Methoxybenzothiazole (\u003cb\u003e2eee\u003c/b\u003e) and thiophene (\u003cb\u003e2fff\u003c/b\u003e) could be chlorinated with moderate efficiency with 1 equiv. of NaCl. Finally, electron-rich styrenes often led to double bond oxidation while styrenes substituted with strong electron withdrawing groups (\u003cb\u003e2ggg\u003c/b\u003e\u0026ndash;\u003cb\u003e2hhh\u003c/b\u003e) could be chlorinated with moderate efficiency.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eApplication in late-stage C–H chlorinations\u003c/h3\u003e\n\u003cp\u003eEncouraged by this initial excess, we next tested the possibility of applying this protocol to the chlorination of more sophisticated substrates, such as various natural products and biologically active molecules (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Mitotane bears both a dichloromethane moiety and a diarylmethane moiety with active aliphatic C\u0026ndash;H bonds, luckily, the arene C\u0026ndash;H chlorination product (\u003cb\u003e4a\u003c/b\u003e) could be obtained as a mixture of monochlorination and dichlorination products (mono : di\u0026thinsp;=\u0026thinsp;1 : 5). Ibuprofen methyl ester required less NaCl (1.0 equiv.) to achieve monochlorination (\u003cb\u003e4b\u003c/b\u003e). Chlorination of Clofibrate (\u003cb\u003e4c\u003c/b\u003e) was achieved in 75% isolated yield under the standard condition. The ketone moiety and the electron-rich methoxy naphthalene moiety in Nabumetone might cause several problems, however, selective C\u0026ndash;H product \u003cb\u003e4d\u003c/b\u003e could be obtained in moderate yield. Fenofibrate has an benzophenone moiety with two electronically biased aryl groups, and the chlorination selectively occurred at the more electron-rich ary group (\u003cb\u003e4e\u003c/b\u003e). Selective monochlorination of Aniracetam (\u003cb\u003e4f\u003c/b\u003e) required the application of less NaCl (1.0 equiv.) at a lower temperature (80 ℃). Isoxepac has several active sites that are prone to oxidation and chlorination, fortunately, a selective chlorination product \u003cb\u003e4g\u003c/b\u003e was produced under the standard reaction condition. Nimesulide, Apremilast, and Triflumuron have various amide and aryl ether moieties, all of which are well tolerated, and the corresponding chlorination products (\u003cb\u003e4h\u003c/b\u003e\u0026ndash;\u003cb\u003e4j\u003c/b\u003e) could be obtained in moderate to good yields. Xanthotoxin has a furan moiety and a pyranone moiety, both of which are prone to oxidative degradation, and the chlorination product \u003cb\u003e4k\u003c/b\u003e could still be obtained in 73% isolated yield. Similarly, the cyano group and the heterocyclic pyrimidine-2,4-dione moiety in Alogliptin did not cause any problems either, and the chlorination product \u003cb\u003e4l\u003c/b\u003e could be obtained in a good yield of 83%. Selective chlorination on the pyrimidine moiety in Piribedil might pose challenges to other protocols due to the presense of benzodioxole and piperazine moieties, however, the chlorination product \u003cb\u003e4m\u003c/b\u003e could be obtained in 61% yield. Leflunomide, Ataluren methyl ester, and Celecoxib have highly sensitive heterocylic structures such as isoxazole, 1,2,4-oxadiazole and pyrazole, delightfully, the selective chlorination products (\u003cb\u003e4n\u003c/b\u003e\u0026ndash;\u003cb\u003e4p\u003c/b\u003e) could still be obtained with our protocol. Roflumilast and Berberine have a pyridine and pyridinium moiety, respectively, their selective chlorination could be achieved with moderate efficiency (\u003cb\u003e4q\u003c/b\u003e\u0026ndash;\u003cb\u003e4r\u003c/b\u003e). Selective monochlorination at half of the \u003cem\u003eC\u003c/em\u003e\u003csub\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sub\u003e-symmetric Bifendate gave \u003cb\u003e4s\u003c/b\u003e in 60% isolated yield. Finally, a phenyl glycoside derived from glucose with multiple hydroxy groups protected as acetate esters could be chlorinated to give the corresponding product \u003cb\u003e4t\u003c/b\u003e in high yield.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eSynthetic applications\u003c/h3\u003e\n\u003cp\u003eThe synthetic potential of this protocol was justified by carrying out gram-scale syntheses of \u003cb\u003e2a\u003c/b\u003e and \u003cb\u003e2c\u003c/b\u003e, we found that results comparable to the small scale experiments were achieved and catalyst loadings could be reduced to 5 mol% for these larger-scale experiments. We also compared our method to some reported prototocols that applied either N\u0026ndash;Cl or I\u0026ndash;Cl type chlorination reagents. It is worth mentioning that only some electronically and/or sterically deactivated substrates (\u003cb\u003e2n\u003c/b\u003e, \u003cb\u003e2q\u003c/b\u003e, \u003cb\u003e2ii\u003c/b\u003e, \u003cb\u003e2yy\u003c/b\u003e) that can signify the difference between these methods are shown, while those activated substrates for which no significant defference exists between these protocols are omitted (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). As predicted, product formation was not observed for these four substrates when λ\u003csup\u003e3\u003c/sup\u003e-iodane \u003cb\u003eII\u003c/b\u003e (BI-Cl) was used as the chlorination reagent by following the literature report (Method 1).\u003csup\u003e30\u003c/sup\u003e When HFIP was used instead of DMF (Method 2), only the electronically activated but sterically hindered substrate \u003cb\u003e2q\u003c/b\u003e was obtained in a poor yield of 38%. These results agreed with our prediction that λ\u003csup\u003e3\u003c/sup\u003e-iodane \u003cb\u003eIII\u003c/b\u003e is a more reactive I\u0026ndash;Cl type reagent, compared to \u003cb\u003eI\u003c/b\u003e and \u003cb\u003eII\u003c/b\u003e, for electrophilic arene C\u0026ndash;H chlorination, which justified our efforts towards its synthesis and application in chlorination reactions. The more popular N\u0026ndash;Cl type reagent, such as NCS, was ineffective for these substrates in the absence of additional catalysts, even in HFIP (Method 3). When NCS was activated with DMSO via a strategy developed by Jiao (Method 4),\u003csup\u003e13\u003c/sup\u003e again, only 43% yield was obtained for the electronically activated but sterically hindered substrate \u003cb\u003e2q\u003c/b\u003e, and completely no reactivity was observed for \u003cb\u003e2n\u003c/b\u003e, \u003cb\u003e2ii\u003c/b\u003e and \u003cb\u003e2yy\u003c/b\u003e. The state-of-the-art protocol developed by Jiao and Song\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e (Method 5) for electrophilic arene C\u0026ndash;H chlorination of electronically deactivated arenes that applied N\u0026ndash;Cl type reagent TCCA (0.4 equiv.) and super Br\u0026oslash;nsted acid catalysis (TfOH) in HFIP was also tested for these substrates. Similar yields were achieved for \u003cb\u003e2ii\u003c/b\u003e and \u003cb\u003e2yy\u003c/b\u003e, while our method showed significantly improved yields for \u003cb\u003e2n\u003c/b\u003e and \u003cb\u003e2ii\u003c/b\u003e. These results were sufficient to verify the predicted high ractivity of \u003cb\u003eIII\u003c/b\u003e in electrophilic arene C\u0026ndash;H chlorination. Addtionally, the fact that \u003cb\u003eIII\u003c/b\u003e could be generated catalytically from cheap and easily available 2-iodobenzenesulfonic acid (\u003cb\u003eIV\u003c/b\u003e) with NaCl as the terminal chlorine source lends further support for the synthetic potential of this protocol, which has already been justified by its broad substrate scope (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) and applications in late-state C\u0026ndash;H chlorination (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eMechanistic investigations\u003c/h3\u003e\n\u003cp\u003eWe then carried out a series of control experiments to possibly elucidate the reaction mechanism and shed light on the origin of the high reactivity of \u003cb\u003eIII\u003c/b\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e). First of all, a solution of λ\u003csup\u003e3\u003c/sup\u003e-iodane \u003cb\u003eIII\u003c/b\u003e in DCE/HFIP (2/1) can chlorinate chlorobenzene (\u003cb\u003e1a\u003c/b\u003e) even at room temperature without any catalyst, implying the high electrophilicity of \u003cb\u003eIII\u003c/b\u003e. Additionally, our previous study showed that mixing the \u003cem\u003eI\u003c/em\u003e-hydroxy variant \u003cb\u003eV\u003c/b\u003e and NaCl at 80 ℃ or above could also lead to the formation of \u003cb\u003eIII\u003c/b\u003e, as a result, the combination of \u003cb\u003eV\u003c/b\u003e and NaCl also can also chlorinate \u003cb\u003e1a\u003c/b\u003e in moderate yield upon heating (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eA). A cyclic voltammetry measurement of the key components of the reaction indicated that the catalyst \u003cb\u003eIV\u003c/b\u003e seemed to have the lowest oxidation potential (~\u0026thinsp;2.1V \u003cem\u003evs\u003c/em\u003e SCE), corresponding to the oxidation of \u003cb\u003eIV\u003c/b\u003e to I\u003csup\u003e3+\u003c/sup\u003e compound \u003cb\u003eV\u003c/b\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eB). In contrast, only a small current corresponding to the oxidation of Cl\u003csup\u003e\u0026minus;\u003c/sup\u003e was observed at \u0026gt;\u0026thinsp;3.0V \u003cem\u003evs\u003c/em\u003e SCE, probably due to the poor solubility of NaCl in this solvent system. This result was also in line with the observation of \u003cb\u003eV\u003c/b\u003e upon mixing \u003cb\u003eIV\u003c/b\u003e with Oxone. \u003csup\u003e1\u003c/sup\u003eH NMR spectra of \u003cb\u003eIII\u003c/b\u003e in various amounts of HFIP clearly showed a downfield shift of H\u003csub\u003eb\u003c/sub\u003e and H\u003csub\u003ec\u003c/sub\u003e as well as an upfield shift of H\u003csub\u003ed\u003c/sub\u003e, which were dependent on the volume ratio of HFIP, indicating hydrogen-bonding interactions between \u003cb\u003eIII\u003c/b\u003e and HFIP (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eC), which might lead to further enhancement of its electrophilicity. Reaction kinetics showed the 1st order dependence of product formation rate on catalyst \u003cb\u003eIV\u003c/b\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eD, see supporting information \u003cb\u003eSX\u003c/b\u003e). The Hammett plot [log(\u003cem\u003ek\u003c/em\u003e\u003csub\u003e\u003cem\u003eX\u003c/em\u003e\u003c/sub\u003e/\u003cem\u003ek\u003c/em\u003e\u003csub\u003e\u003cem\u003eH\u003c/em\u003e\u003c/sub\u003e) versus \u003cem\u003eσ\u003c/em\u003e] displayed a linear relationship with a \u003cem\u003eρ\u003c/em\u003e value of -2.5275 (\u003cem\u003eR\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.9922), which suggests that the reaction proceeds through a single mechanism with significant positive charge developed in the transition state, indicative of an electrophilic process with the formation of a Wheland-type intermediate (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eE).\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eTaken together, a catalytic cycle that is in best agreement with mechanistic experiments for the title reaction was outlined in Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eF. Starting from 2-iodobenzenesulfonic acid (\u003cb\u003eIV\u003c/b\u003e), oxidation of which by Oxone gives \u003cem\u003eI\u003c/em\u003e-hydroxy λ\u003csup\u003e3\u003c/sup\u003e-iodane \u003cb\u003eV\u003c/b\u003e. Heating \u003cb\u003eV\u003c/b\u003e and NaCl in DCE/HFIP (2/1) leads to the formation of the key chlorinating reagent \u003cb\u003eIII\u003c/b\u003e, which engages in hydrogen-bonding interactions with HFIP to further increase its electrophilicity (\u003cb\u003eIII\u003c/b\u003e\u0026thinsp;+\u0026thinsp;HFIPs). C\u0026ndash;H chlorination by this adduct gives the corresponding product and regenerates catalyst \u003cb\u003eIV\u003c/b\u003e. Heating is required for the formation of \u003cb\u003eIII\u003c/b\u003e, probably due to the low solubility of NaCl in the solvent system. It is worth mentioning that this catalytic C\u0026ndash;H reaction is designed to address the inconvenience associated with the synthesis and isolation of highly reactive but moisture-sensitive \u003cb\u003eIII\u003c/b\u003e via its \u003cem\u003ein situ\u003c/em\u003e formation, paradoxically, no strigent anhydrous procedure was required, and this protocol can tolerate adventitious water. To understand the origin of this feature, a small aliquot of water (20 \u0026micro;l) was added into a clear yellow solution of \u003cb\u003eIII\u003c/b\u003e in CDCl\u003csub\u003e3\u003c/sub\u003e/HFIP, and we found that it quickly decolorizes to give a white precipitate, which was determined to be a mixture of \u003cb\u003eIV\u003c/b\u003e, \u003cb\u003eV\u003c/b\u003e and I\u003csup\u003e5+\u003c/sup\u003e compound \u003cb\u003eVIII\u003c/b\u003e in a ratio of 6 : 1 : 1.5. Apparently, \u003cb\u003eIV\u003c/b\u003e is the catalyst, \u003cb\u003eV\u003c/b\u003e is an active intermediate in the catalytic cycle, and \u003cb\u003eVIII\u003c/b\u003e can decompose to \u003cb\u003eIV\u003c/b\u003e or \u003cb\u003eV\u003c/b\u003e\u003csup\u003e34\u003c/sup\u003e upon heating to reenter the catalytic cycle (see the supporting information \u003cb\u003eFigure S29\u003c/b\u003e). This \u0026ldquo;self-healing\u0026rdquo; feature\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e makes this method highly efficient and practical for the application of λ\u003csup\u003e3\u003c/sup\u003e-iodane \u003cb\u003eIII\u003c/b\u003e in electrophilic C\u0026ndash;H chlorination reactions.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eDFT Calculations\u003c/h2\u003e \u003cp\u003eTo gain deeper insight into the enhanced electrophilicity of \u003cb\u003eIII\u003c/b\u003e and its role in electrophilic C\u0026ndash;H chlorination, density functional theory (DFT) calculations were carried out. We first compared \u003cb\u003eIII\u003c/b\u003e with other N\u0026ndash;Cl or I\u0026ndash;Cl type chlorination reagents. Due to the \u0026ldquo;Cl\u003csup\u003e+\u003c/sup\u003e\u0026rdquo; nature of these reagents, a lower charge density on the the chlorine atom is expected to facilitate the electrophilic chlorination step. As anticipated, the electrostatic potential map of \u003cb\u003eIII\u003c/b\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003eA) exhibits a more positive region at the chloride atom, indicating a stronger propensity for \u0026ldquo;Cl\u003csup\u003e+\u003c/sup\u003e\u0026rdquo; transfer. Moreover, the chlorination ability of \u003cb\u003eIII\u003c/b\u003e is further enhanced in the presence of HFIP.\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e Following the methodology outlined by Wu and colleagues,\u003csup\u003e31\u003c/sup\u003e in which highly electron-withdrawing groups weaken the trans influence, leading to a shorter I\u0026ndash;Cl bond and increased reactivity in electrophilic chlorination, we compared the I\u0026ndash;Cl bond distances of various I\u0026ndash;Cl type chlorination reagents. Remarkably, \u003cb\u003eIII\u003c/b\u003e indeed shows a shorter I\u0026ndash;Cl bond distance (\u003cb\u003eFigure S40\u003c/b\u003e), further supporting its superior chlorinating ability.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTo elucidate the overall mechanism of the chlorination reaction, 1,3-difluorobenzene (\u003cb\u003e1i\u003c/b\u003e) was selected as a model substrate, and the energy profile of the chlorination process was calculated (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003eB). DFT calculations reveal that \u003cb\u003e1i\u003c/b\u003e undergoes electrophilic aromatic substitution (S\u003csub\u003eE\u003c/sub\u003eAr) to afford the chlorinated product. The rate-determining step corresponds to the transfer of the chlorine cation from \u003cb\u003eIII\u003c/b\u003e to substrate \u003cb\u003e1i\u003c/b\u003e, with a calculated activation barrier of 24.2 kcal/mol for the involvement of one molecule of HFIP (24.8 kcal/mol for two molecules of HFIP, \u003cb\u003eFigure S39\u003c/b\u003e). Subsequently, deprotonation occurs with the assistance of HFIP, leading to the formation of the final product. Notably, compound \u003cb\u003eIII\u003c/b\u003e is capable of efficiently chlorinating the highly electron-deficient arene \u003cb\u003eIV\u003c/b\u003e even in the absence of an added substrate, highlighting its enhanced electrophilicity (\u003cb\u003eFigure S38\u003c/b\u003e). These results collectively demonstrate that \u003cb\u003eIII\u003c/b\u003e is a highly effective reagent for electrophilic arene C\u0026ndash;H chlorination.\u003c/p\u003e \u003cp\u003eIn conclusion, we have reported in this article the successful synthesis and characterization of a highly anticipated variant of Willgerodt reagent, namely λ\u003csup\u003e3\u003c/sup\u003e-iodane \u003cb\u003eIII\u003c/b\u003e, which has an unusually short I\u0026ndash;Cl bond and a resulting high electrophilicity of the chlorine atom. These features make \u003cb\u003eIII\u003c/b\u003e a highly electrophilic chlorination reagent that can chlorinate inactivated arenes without additional catalysts. In order to mitigate the influence of the moisture-sensitive nature and address the resulting synthetic inconvenience associated with \u003cb\u003eIII\u003c/b\u003e, a catalytic C\u0026ndash;H chlorination protocol via \u003cem\u003ein situ\u003c/em\u003e formation of \u003cb\u003eIII\u003c/b\u003e with 2-iodobenzenesulfonic acid (\u003cb\u003eIV\u003c/b\u003e) as the catalyst and NaCl as the chlorine source was realized. This method has significantly enhanced substrate scope and can be applied to late-stage modifications of complex natural products and biologically relevant molecules. Based on mechanistic studies as well as DFT calculations, a catalytic cycle has been outlined with a \u0026ldquo;self-healing\u0026rdquo; mechanism, which accounts for the \u0026ldquo;moisture insensitivity\u0026rdquo; of this protocol despite the fact that \u003cb\u003eIII\u003c/b\u003e is a moisture-sensitive compound. We envisage that λ\u003csup\u003e3\u003c/sup\u003e-iodane \u003cb\u003eIII\u003c/b\u003e can serve as a useful intermediate to other hypervalent-iodine-based functional group transferring reagents with enhanced reactivity, and the related research is currently in progress, which will be reported in due course.\u003c/p\u003e \u003c/div\u003e"},{"header":"Methods","content":"\u003cp\u003eGeneral procedures for the catalytic C\u0026ndash;H chlorination via \u003cem\u003ein situ\u003c/em\u003e generation of λ\u003csup\u003e3\u003c/sup\u003e-iodane \u003cb\u003eIII\u003c/b\u003e:\u003c/p\u003e \u003cp\u003e \u003cb\u003eGeneral procedure A\u003c/b\u003e: To a 5 mL pressure vial equipped with a magnetic stir bar was charged with aromatic compound (0.2 mmol, 1.0 equiv.), 2-iodobenzenesulphonic acid (5.6 mg, 0.02 mmol, 0.1 equiv.), NaCl (24 mg, 0.4 mmol, 2.0 equiv.), Oxone (246 mg, 0.4 mmol, 2.0 equiv.), DCE : HFIP\u0026thinsp;=\u0026thinsp;2:1 (1.0 mL). The reaction mixture was sealed and heated to the indicated temperature for the indicated period of time. After the mixture was cooled to room temperature. The solid was removed by filtration and washed with DCM, followed solvent was removed under reduced pressure, and the product was purified by flash column chromatography on silica gel to give the desired chlorination product.\u003c/p\u003e \u003cp\u003e \u003cb\u003eGeneral procedure B\u003c/b\u003e To a 5 mL pressure vial equipped with a magnetic stir bar was charged with electron-deficient aromatic compound (0.2 mmol, 1.0 equiv.), 2-iodobenzenesulphonic acid (5.6 mg, 0.02 mmol, 0.1 equiv.), Mg(OTf)\u003csub\u003e2\u003c/sub\u003e (6.4 mg, 0.02 mmol, 0.1 equiv.), NaCl (48 mg, 0.8 mmol, 4.0 equiv.), Oxone (369 mg, 0.6 mmol, 3.0 equiv.), HFIP (1.0 mL). The reaction mixture was sealed and heated to the indicated temperature for the indicated period of time. After the mixture was cooled to room temperature. the solid was removed by filtration and washed with DCM, followed solvent was removed under reduced pressure, and the product was purified by flash column chromatography on silica gel to give the desired chlorination product.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eSupplementary Information\u003c/h2\u003e\n\u003cp\u003eis linked to the online version of the paper at \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ewww.nature.com/nature\u003c/span\u003e\u003c/span\u003e.\u003c/p\u003e\n\u003ch2\u003eAuthor Contributions Statement\u003c/h2\u003e\n\u003cp\u003eH. Q.-Q., and X. Y. conceived the project. H. Q.-Q., X. Y., Y. Z., and X. Y. designed and performed the experiments. Z. Y., and Z. H. carried out DFT calculations. H. Q.-Q., X. Y., Y. Z., and X. Y. analyzed the data. H. Q.-Q., Z. H., and X. Y. wrote the manuscript.\u003c/p\u003e\n\u003ch2\u003eCompeting Interests Statement\u003c/h2\u003e\n\u003cp\u003eThe authors declare no financial interests.\u003c/p\u003e\n\u003ch2\u003eAcknowledgments\u003c/h2\u003e\n\u003cp\u003eX. Y. acknowledges financial support provided by the National Science Foundation of China (NSFC, 22171095). Z. H. acknowledges supports from Engineering Research Center of Photoenergy Utilization for Pollution Control and Carbon Reduction, Ministry of Education (CCNU24JCPT016) and National Natural Science Foundation of China (Grant 22401102). We are grateful to the Analytic and Testing Centre of HUST for data characterization.\u003c/p\u003e\n\u003ch3\u003eData availability\u003c/h3\u003e\n\u003cp\u003eThe data that support the findings of this study are available in the article and the Supplementary Information section. Details about materials and methods, experimental procedures, characterization data, mechanistic studies, DFT calculations, and NMR spectra are available in the Supplementary Information. Cartesian coordinates of all the optimized structures are provided in Supplementary Data 1.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eZeng J, Zhan J (2019) Chlorinated natural products and related halogenases. Isr J Chem 59:387\u0026ndash;402\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYao H, Wang J, Xu Y, Zhang S, Hou J (2020) Recent progress in chlorinated organic photovoltaic materials. Acc Chem Res 53:822\u0026ndash;832\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKamalesh T, Kumar PS, Rangasamy G (2023) An insights of organochlorine pesticides categories, properties, eco-toxicity and new developments in bioremediation process. 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Chem Rev 115:650\u0026ndash;682\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8374240/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8374240/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eA highly anticipated yet elusive variant of the Willgerodt reagent, \u003cb\u003eIII\u003c/b\u003e, has been successfully synthesized and characterized unambiguously by both nuclear magnetic resonance (NMR) and single-crystal X-ray crystallography. Compared to previous I\u0026ndash;Cl type λ\u003csup\u003e3\u003c/sup\u003e-iodanes, this compound has an unusually short I\u0026ndash;Cl bond length due to the trans-influence of the endocyclic sulfonate moiety, and this feature endows \u003cb\u003eIII\u003c/b\u003e with significantly enhanced reactivity in arene electrophilic C\u0026ndash;H chlorination reactions. A catalytic C\u0026ndash;H chlorination of deactivated arenes via \u003cem\u003ein situ\u003c/em\u003e formation of \u003cb\u003eIII\u003c/b\u003e is achieved with catalytical amount of readily available 2-iodobenzenesulfonic acid as the precursor of \u003cb\u003eIII\u003c/b\u003e. The relative mildness of this protocol has been showcased by the late-stage chlorinations of various highly functionalized drugs and natural products. Mechanistic studies as well as density functional theory (DFT) calculations are carried out to shed light on the origin of the enhanced reactivity in electrophilic arene C\u0026ndash;H chlorination.\u003c/p\u003e","manuscriptTitle":"Catalytic Electrophilic Arene C–H Chlorination by Rethinking of the Century-old Willgerodt Reagent","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-02 01:03:01","doi":"10.21203/rs.3.rs-8374240/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"8f9fffb1-3850-4941-ac78-729c60138f6e","owner":[],"postedDate":"March 2nd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":59850569,"name":"Physical sciences/Chemistry/Catalysis/Homogeneous catalysis"},{"id":59850570,"name":"Physical sciences/Chemistry/Chemical synthesis/Synthetic chemistry methodology"}],"tags":[],"updatedAt":"2026-03-02T01:03:02+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-02 01:03:01","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8374240","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8374240","identity":"rs-8374240","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}