Pillar[5]arene-catalyzed anti-Markovnikov halogenations through cationic intermediates stabilization in confined spaces

Domain: neuroscience
Published: 2026-04-01
Editorial outcome: major_revision

Abstract
The confinement of reactants within catalytic cavities is important for achieving efficient and selective chemical transformations. Macrocyclic organic covalent hosts, which mimic enzymatic environments, offer well-defined, tunable cavities capable of substrate accommodation. These robust and synthetically accessible hosts can be engineered into catalysts by functionalizing their rims, where substrate selectivity emerges from size- or shape-complementary binding. This positioning brings reactive sites into proximity with catalytic functional groups at the rims of covalent hosts, accelerating reactions. Cationic intermediates are pivotal in many chemical transformations, and stabilizing these reactive species within confined microenvironments could unlock unconventional selectivity for synthesizing high-value compounds. Despite this potential, leveraging the cavities of covalent hosts to stabilize and confine cationic intermediates for regioselective reactions remains underexplored. Here we report that the π-basic cavity of pillar[n]arenes can effectively stabilize bromiranium intermediates generated during olefin halogenation, confining them in a controlled microenvironment. This strategy overrides the intrinsic Markovnikov preference, enabling highly selective anti-Markovnikov halogenation. Furthermore, we extend this catalytic system to achieve size-selective anti-Markovnikov halogenation of olefins. This approach opens new pathways for selective transformations through the confinement of a cationic intermediate.

Introduction
The confinement of reactants within a catalyst pocket is one of the key factors for achieving efficient and selective catalytic transformations.1-2 Synthetic host molecules (sometimes regarded as artificial enzymes) such as macrocyclic organic covalent hosts and self-assembled molecular cage nanoreactors offer well-defined cavities that are suitable for substrate accommodation in catalysis due to their restricted dimensions.3-13 They have garnered significant interest as platforms for catalysis by acting as a noncovalent protective group or an anchoring template to offer various selective reactions. Among these, macrocyclic organic covalent hosts, which can also be considered as organocatalysts,14-15 such as cyclodextrins (CD),16 crown ethers,17 cucurbiturils (CB),18 calixarenes,19 and pillarenes (PA)20 have gained continuous attention. These covalent hosts are not only easy to synthesize and highly robust but also feature tunable cavities with persistent gates, enabling substrate accommodation without the need for specialized reaction conditions.

For catalytic applications, covalent host systems are typically functionalized with catalytic sites at their rims. Substrate selectivity is determined by the complementary fit between the host cavity and the size or shape of the guest substrate molecule. Reaction acceleration of the designated pathway can be achieved by positioning the substrate’s reactive sites in close proximity to the rim-anchored catalytic groups (Fig. 1a). To ensure satisfactory reaction performance, a super-stoichiometric amount of covalent hosts is usually required to suppress product inhibition. Several reactions using this strategy have been documented in the literature.21-23 A few studies have demonstrated that accommodating appropriately orientated and sized substrates within covalent host cavities can improve the reaction selectivity. A landmark work was carried out by Breslow and coworker in which an excess amount of CD was used to encapsulate phenol so that the CD rim’s oxygen could be brought into close proximity to the para-position of phenol, enhancing the selectivity of para-chlorination (Fig. 1b).24-25 Ogoshi and coworkers conducted a representative competition experiment where a PA-derived phase-transfer catalyst preferentially accommodated the less bulky linear olefin over the branched olefin, allowing the linear olefin to be positioned near the phosphonium permanganate at the rim of PA for a more efficient oxidation (Fig. 1c).26 Nau and coworkers documented the encapsulation of bicyclic azoalkanes by excessive CB and Ag(I) to enhance the selectivity in photodeazetation.27 The CB rim’s carbonyl was proposed to bring the Ag(I) near the azo group, improving the selectivity of 1,5-hexadiene (HD) over bicyclo[2.2.0]hexane (BCH) (Fig. 1d). Some relevant works by Rebek and co-workers used cavitands as stoichiometric reaction nano-vessels to accommodate aliphatic substrates in folded conformation, facilitating macrocyclization over oligomerization in water.28-29

Cationic intermediates are involved in many reactions and the stabilization of these intermediates is crucial for satisfactory reaction performance. Although very challenging, there is a strong aspiration to confine the cationic intermediates within the microenvironment in order to attain unconventional selectivity for the synthesis of valuable products that are nontrivial to obtain.1-3 In a study by Scarso and coworkers, it was found that PA could accelerate the mono-allylation of primary amines with allyl bromide in CDCl3. Based on NMR studies, the ratio of secondary/tertiary amine product was improved in the presence of PA (Fig. 1e). It was proposed that the cavity of PA might accelerate the SN2 reaction by stabilizing the developing charge on the nitrogen atom through electrostatic interactions with its aromatic units.30

Electrophilic reactions of unactivated olefins, such as halogenation, represent a fundamental class of transformations.31 A classic example involves the formation of three-membered haliranium cationic intermediates (e.g., bromiranium A from a Br+ source), followed by nucleophilic attack at the more substituted carbon, adhering to Markovnikov’s rule as well-accepted textbook knowledge (Fig. 1f, bottom left).32 However, achieving anti-Markovnikov selectivity, which would unlock access to a distinct class of valuable compounds, has remained a challenge. Although several elegant strategies enable anti-Markovnikov hydrofunctionalization through alternative mechanisms (e.g., radical or metal-catalyzed pathways),33-39 direct intermolecular catalytic anti-Markovnikov electrophilic halogenation of unactivated alkenes remains an unsolved problem in synthetic chemistry. Overcoming this limitation could provide an alternative route to functionalized products that are non-trivial to access.

Here we report a study of PA-catalyzed anti-Markovnikov bromination of unactivated olefins (Fig. 1f, bottom right). Inspired by the concept of stabilizing bromiranium by Lewis bases (e.g. species A),40-42 we hypothesize that the π-basic cavity of PA would stabilize the cationic bromiranium intermediate in a confined microenvironment and selectively shield the more substituted carbon (typically favored in Markovnikov addition). Thus, the less substituted (and less active) carbon could be more accessible to the nucleophiles. This microenvironmental control could override the intrinsic Markovnikov preference, offering a strategy for accessing elusive anti-Markovnikov halogenated products. By exploiting the catalytic application of the confined π-basicity of PA, we aim to establish a paradigm shift in electrophilic functionalization, moving beyond typical rim-based covalent host catalysis toward cavity-controlled reaction engineering.

Results
Our study was initiated using olefin 1a and BzOH (2a) as the reaction partners and 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) as the halogen source in methylcyclohexane (Fig. 2a). No reaction was observed in the absence of a catalyst. Several common base (e.g. triphenylphosphine sulfide) and acid (e.g. MsOH, copper salt) catalysts were investigated, yielding a product mixture with a preference for Markovnikov selectivity, consistent with typical literature findings. The use of dimethylpillar[5]arene PA1 as a catalyst at room temperature afforded a moderate yield with a preference for the Markovnikov product 3aa’. However, lowering the reaction temperature to –10 °C reversed the selectivity, favoring the anti-Markovnikov product with a 60:40 r.r. (3aa:3aa’) and a 30% yield. These outcomes imply that pillar[5]arene could catalyze the bromination but lacks sufficient steric hindrance to effectively block nucleophilic attack at the more substituted carbon of the bromiranium species. Pillar[5]arenes PA2-PA4 having different substituents were examined and moderate-to-good anti-Markovnikov selectivity was observed. To our delight, catalyst PA5 bearing n-hexyl groups at the rim gave good yield of 3aa (82%) and excellent anti-Markovnikov selectivity (r.r. > 20:1). Solvent polarity influenced the reaction outcome. While a more polar solvent afforded a higher yield, it resulted in poorer r.r., which could be attributed to an enhanced background reaction occurring outside the host (see Supplementary Information, Fig. S5). Pillar[6]arene PA6 with a larger cavity could not favor the formation of the anti-Markovnikov product 3aa, indicating that the relatively large size pillar[6]arene might not be effective in encapsulating the bromiranium species. We also studied some common covalent hosts such as -cyclodextrin CD, hexylcalix[4]arene CA and cucurbit[6]uril CB, but they were found to be ineffective in providing anti-Markovnikov selectivity (Fig. 2a).

A series of substrates was then investigated (Fig. 2b). The catalytic anti-Markovnikov bromination proceeded efficiently to give the desired products 3 in good-to-excellent yields and regioselectivity. Besides, various substituted benzoic acid were compatible with the catalytic protocol. In particular, olefins with trimethylsiloxyl group furnished products 3aa–3ae in excellent regioselectivity (r.r. >20:1). Other olefinic substrates with alkyl (1b), ether (1c-1f), ester (1g-1i), halogen (1j-1k), and ketone (1l) substituents were studied and good yield and regioselectivity of the corresponding anti-Markovnikov products 3b-3l were generally obtained, showcasing the high functional group compatibility of this catalytic protocol. We have also studied substates 1m and 1n with bulky substituents and longer hydrocarbon chains, and they are compatible with the catalytic protocol to give 3m (70%, r.r. > 20:1) and 3n (76%, r.r. = 12:1).

The power of this catalytic system is further demonstrated in the anti-Markovnikov halogenation of olefinic amide 1o. Typically, such substrates undergo facile intramolecular halocyclization43-45 to form six-membered rings46 because this pathway is highly favored entropically. In our control experiment, halocyclization of 1o proceeded exclusively with triphenylphosphine as the Lewis base catalyst, giving the six-membered ring Markovnikov selective lactam 4 (80%) even in the presence of BzOH as the external nucleophile (Fig. 2c). Outcompeting this inherent preference with an intermolecular reaction is exceptionally challenging. Nonetheless, with catalyst PA5, a 1:1 mixture of 1o and BzOH undergoes completely selective intermolecular anti-Markovnikov halogenation to furnish 3o (78%, r.r. = 11:1) with no detectable cyclized product 4, attributed to the unfavorable cyclization inside the host. To the best of our knowledge, this represents the first example where a stoichiometric nucleophile outcompetes such a favorable intramolecular cyclization.

The resultant products can readily be converted to valuable commodity chemicals (Fig. 2d). For instance, the anti-Markovnikov products 3ba and 3o could easily be converted into allyl benzoates 5 and 6, which are valuable building blocks.47-48 Furthermore, aliphatic azides 7–9, valuable building blocks of detergents for membrane protein studies,49-50 were prepared from compound 3 in a single step using sodium azide. These methods establish straightforward and efficient alternatives to the typically tedious synthetic routes required for these important molecules.

Competition experiments were conducted to evaluate the site-selectivity. Substrates bearing two olefinic moieties on the same molecule were then examined in the intramolecular competition (Fig. 3a). Electrophilic halogenation of bulky olefins is favored by the inductive effect but disfavored by the steric effect. Thus, achieving regio and site-selective bromination of bis-olefinic substrates such as 10a is challenging because multiple isomers could be formed. Indeed, when using triphenylphosphine sulfide as the catalyst, only 23% of 11a was detected and a mixture of bromination side products (~30%) together with 41% of unreacted substrate 10a was observed (Supplementary Information, Fig. S1). In sharp contrast, site-selective anti-Markovnikov bromination product 11a (63%) was obtained as the sole product when using catalyst PA5. Similarly, 11b (68%) was obtained smoothly when using 10b as the substrate. These results could be explained by the fact that the linear portion of the molecule could fit into the cavity of PA5 more readily to perform the anti-Markovnikov halogenation.

It was also found that the catalytic protocol was able to distinguish linear and branched olefinic substrates in the anti-Markovnikov halogenation (Fig. 3b). For instance, a 1:1 mixture of 1a and 12a was subjected to the study and four products (anti-Markovnikov and Markovnikov products from both 1a and 12a) could be obtained in principle. However, 3aa that was synthesized from the anti-Markovnikov halogenation of the linear olefin 1a was obtained as the major product in good yield (79%). In contrast, when using the typical catalysts such as triphenylphosphine sulfide, a product mixture favoring Markovnikov products was obtained (Supplementary Information, Fig. S2). Competition experiments were also performed using other linear (1b or 1d) and branched (12b) olefins, and products 3ba and 3da with good anti-Markovnikov selectivity were furnished.

Interestingly, the length of olefins also influenced the reactivity in this protocol. For the competition experiments on a 1:1 mixture of linear olefins 1a (longer) and 1p-1r (shorter), the longer substrate 1a preferentially reacted to give the anti-Markovnikov product 3aa, and bromination of the shorter substrates was not observed. Substrates bearing different sizes of silyl groups remote from the olefins could also be differentiated using this catalytic protocol. For example, when using triisopropylsilyl (TIPS) substrate 1s in the competition experiment against 1a bearing a relatively smaller TMS group, 3aa was obtained as the sole product, and no bromination originating from 1s was detected, attributed to the bulky TIPS group that disfavors the substrate accommodation (Supplementary Information, Figs. S15-S16). However, substrate 1m bearing TIPS but with a longer hydrocarbon chain could yield 3m smoothly (Fig. 2b).

The catalytic protocol was also able to differentiate the size of nucleophilic partners. For example, a 1:1 mixture of benzoic acids 2a and 2h was subjected to the reaction with olefin 1a, and benzoylated product 3aa was obtained in 80% yield (Fig. 3c). In addition, no adduct corresponding to the bulkier benzoic acid was detected. In theory, the bulkier carboxylic acid, which is also a more electron-rich nucleophile, could be more reactive in the halogenation reaction. Indeed, in the benchmarking reaction using triphenylphosphine sulfide as the catalyst, a significant amount of products associated with 2h (Marknovnikov and anti-Markovnikov) were detected (Supplementary Information, Fig. S3). Competition experiments using other bulkier carboxylic acids 2i-2k against benzoic acid (2a) were studied and excellent size-selectivity of the nucleophilic partner was observed, giving 3aa as the sole product.

Arene 13, which is a key component of PA5, was used as a catalyst for the bromination but no reaction was observed, suggesting that the pillar[5]arene cavity is necessary for the catalytic effect (Fig. 4a). NMR experiments were conducted to study the reaction mechanism. When mixing PA5 and the olefinic substrate 1c, Ha in 1c shifted upfield, attributed to the encapsulation of 1c in the shielded environment (Fig. 4b, species B). Job’s plot was performed on the mixture PA5 and 1c and the results indicated that the binding stoichiometry between PA5 and 1c is 1:1 (Supplementary Information, Fig. S8). However, the binding constant (6.12 M-1 ± 0.24) between substrate 1 and PA5 was found to be small (Supplementary Information, Fig. S9), suggesting that substrate binding in PA5 might not be the critical factor to promote the bromination.

Further studies were performed to probe the encapsulated bromiranium species, which is believed to be the key intermediate of the reaction. In order to generate a sufficient amount of unstable bromiranium species, we used bromotosylate 14 in acidic media to generate bromiranium species 15 in situ.51 Thus, 2D ROESY NMR experiment on a mixture of 14/TFA/PA5 was carried out and Hc (in 15) and Hd (in PA5) have considerable 1H-1H long-range interaction (Supplementary Information, Fig. S11). In situ IR experiment was also conducted to gain more information (Fig. 4c). Upon mixing 14 and TFA, a new signal at 1370 cm-1 that could correspond to the bromiranium species 15 emerged. The addition of PA5 to the bromiranium species led to a blue shift of the absorption (Supplementary Information, Fig. S12). While multiple factors could contribute to the blue shift, we believe that one of the key factors could be the bond contraction caused by the nuclear repulsions of the bromiranium species within the confined cavity of PA5.

Density Functional Theory (DFT) calculations were also performed to gain insights into the plausible mechanism. To address dispersion interactions between the reactants, all geometry optimizations were carried out with the long-range-corrected ωB97XD functional,52-54 and the 6-31G(d,p) basis set.55 Single-point solvation energy correction (in methylcyclohexane) was conducted using Truhlar’s STMD model.56 Energies were further refined at the ωB97XD/6-311+G(d,p) level of theory. The relative Gibbs energies (ΔG) in kcal/mol are provided with respect to the infinitely separated reactants. Extensive conformational searches for the most stable geometry of pillar[5]arene were first conducted to locate the starting catalyst structure.

The energy profile of the reaction using pillar[5]arene PA1 was first calculated (Fig. 5a and Supplementary Information, Figs. S20-S26). It was found that reaction components included 1a, DBDMH, BzOH, and PA1 assembled to give PTSPA1 with a free energy increased by 5.9 kcal/mol. The free energy profile indicates that the transfer of the bromonium ion (Br+) from DBDMH to the encapsulated olefin (1a) proceeds via transition state TS1PA1 with an activation barrier (∆G‡) of 9.3 kcal/mol. This process leads to the formation of a transient bromiranium intermediate IM1PA1, followed by a structural reorganization to give intermediate IM2PA1 with energy reduced by 6.5 kcal/mol (with respect to IM1PA1). Finally, IM2PA1 undergoes nucleophilic ring-opening of the bromiranium species by the benzoate to give the highly stable anti-Markovnikov addition product PPA1 via TS2PA1 (∆G‡ = 8.4 kcal/mol). The pathway to the Markovnikov product via TS3PA1 was also evaluated, and the energy was found to be 1.0 kcal/mol higher than that of the anti-Markovnikov pathway via TS2PA1. This could be attributed to the increased steric repulsion when the benzoate approaches the more shielded (and the more substituted) carbon for the inherent Markovnikov selectivity.

In sharp contrast, in the absence of pillarene, the formation of bromiranium species IM1 (∆G = 31.6 kcal/mol) by a bromonium transfer from DBDMH to the olefin 1a in PTS (∆G = 9.6 kcal/mol) was found to be highly unfavorable (Fig. 5b and Supplementary Information Fig. S27). Thus, the pillarene-catalyzed anti-Markovnikov halogenation is favorable as indicated by the smaller barrier compared to the non-encapsulated bromiranium species and the exergonic nature.

Next, we analyzed the bromiranium cationic species in the optimal catalyst PA5. Interaction of DBDMH and BzOH with olefin 1a in the cavity of PA5 is promoted to give PTSPA5 (∆G = 1.9 kcal/mol), followed by the formation of bromiranium species IM1PA5 (∆G = 6.0 kcal/mol) (Fig. 5b and Supplementary Information Fig. S17). The close resemblance of the structure and energy of PTSPA5 and IM1PA5 (from PA5) and that of species PTSPA1 and IM1PA1 (from the less bulky PA1) provided us with strong confidence that the smaller system used to study the reaction mechanism is adequate. Similar to the situation in IM1PA1, the less substituted carbon of the bromiranium moiety in IM1PA5 is more exposed to the rim of PA5, and therefore, more accessible by the benzoate nucleophile to give the experimentally observed anti-Markovnikov product. It was realized that the bromiranium species is considerably more stabilized in PA5 than PA1, indicated by the more significant reduction in free energy between IM1/IM1PA5 (∆G = -25.6 kcal/mol) as compared with that between IM1/IM1PA1 (∆G = -18.5 kcal/mol). This finding is also consistent with the experimental results in which PA5 exhibited a better catalytic efficiency than PA1 (Fig. 2a).

IBSI,57 NBO58 and AIM analysis59-60 revealed that the bromiranium cationic species engages favorably inside the cavity of PA5 via multiple non-covalent interactions (Fig. 5c and Supplementary Information Fig. S18-S19). Specifically, a significant C=C(π)→Br-C(σ*) interaction between the phenyl group of PA5 and the bromiranium cation was observed. In addition, a number of C-H hydrogen bond interactions [C=C(π)→H-C(σ*) and O(LP)→H-C(σ*)] between PA5’s phenyl ether groups and the bromiranium’s C-Hs were found to be crucial in the stabilization. An energy decomposition analysis (sobEDA and sobEDAw)61 was also performed to provide more insight into the interaction between PA5 and the reactants (Supplementary Information, Table S1), and it suggests that while electrostatic interaction primarily drives the formation of the bromiranium ion in PA5, dispersion forces also make a substantial contribution to the stabilization of this host-guest complex.

Based on the abovementioned studies, pillarene could serve two key functions in the anti-Markovnikov halogenation: (1) catalyzing bromination by fitting the substrate with an appropriate size and stabilizing the bromiranium cationic intermediate within its π-basic cavity, and (2) encapsulating the intermediate to enforce anti-Markovnikov selectivity through spatial confinement.

In summary, we have developed a supramolecular strategy utilizing the π-basic cavity of pillarenes to stabilize bromiranium intermediates, enabling selective shielding of the more substituted carbon and redirecting nucleophilic attack toward the less substituted position. This catalytic approach successfully achieves anti-Markovnikov bromination, demonstrating how microenvironmental control can override intrinsic reactivity biases to access challenging products. While covalent macrocyclic hosts have been used as nanoreactors to accelerate reactions, their use in stabilizing cationic intermediates for selective transformations remains in its infancy. We anticipate that this research will inspire further research into the design of tailored host systems for selective reaction control, opening new avenues in synthetic chemistry.

Methods
General procedure for anti-Markovnikov intermolecular bromoesterification

To a stirred solution of carboxylic acid 2 (0.1 mmol, 1 equiv), catalyst PA5 (0.01 mmol, 10 mol%) in methylcyclohexane (0.35 mL) was added olefinic substrate 1 (0.1 mmol, 1 equiv). The solution was stirred at 0 oC and DBDMH (0.1 mmol, 1 equiv) was added. The resultant mixture was stirred for 60 h at the same temperature and quenched with a saturated aqueous Na2SO3 solution. The organic phase was separated, and the aqueous phase was extracted with CH2Cl2 (2 mL × 3). The combined organic phase was washed with brine (3 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified over silica gel column chromatography (EtOAc:hexanes, 1:100 to 1:20) to afford the desired anti-Markovnikov halogenation product 3.

Peer review rounds
[{"round": 1, "reviewer_comments": {"reviewer_1": "This work presents a comprehensive study of the “Pillar[5]arene-Catalyzed Anti-Markovnikov Halogenations” reaction, and the mechanistic elucidation is thorough and well-supported. The authors have provided clear and well-substantiated responses to all three reviewers' comments, supplemented with appropriate additional experimental data. In its current form, the manuscript is considered suitable for publication. Nevertheless, it is suggested that the following two minor revisions could further improve the clarity and presentation of the manuscript:\n1. In line with Reviewer 3’s Comment 7 regarding the limited familiarity of 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) to a general audience, it is recommended that the chemical structure of DBDMH be included in Figure 2b where the reaction scheme is shown.\n2. Also noted is the point raised in Reviewer 3’s Comment 9 concerning the small size of the IR spectra in Figure 4. Enlarging the size of the spectra would facilitate the observation of spectral details and enhance the overall visual presentation.", "reviewer_2": "The authors report very interesting results on the regioselective opening of bromonium ions catalyzed by pillar[5]arene. High regioselectivities (>20:1) are obtained when the substrates contain a bulky terminal group (OSiR₃ or t-Bu) on one side, whereas in its absence the selectivity decreases to approximately 5:1. The control experiments convincingly demonstrate that the reaction occurs within the pillar[5]arene cavity.\nThe results appear to be well documented in the Supporting Information and are supported by DFT calculations. Overall, these findings are highly compelling and provide an elegant entry into a substance class that is otherwise difficult to access by alternative methods.\nI recommend only minor revisions.\n1) Proper citation of related pillararene work; for instance. https://pubs.acs.org/doi/10.1021/acscatal.4c04836 ; a simialr suggestion was made by former Ref. 2. Surpridingly, nothign was added. The following sentence would be appropiate:\n\"Unlike conventional strategies that rely on rim-functionalized covalent hosts to catalyze reactions, ...\"\n2) Adding details to Figures on how the yield were determined. Clearly stating if it is NMR yield (How determined? Internal standard?) or isolated yield", "reviewer_3": "The manuscript by Xu et al. is a resubmission of a previous version, reviewed for [redacted], and has undergone major revision. It reports a regioselective anti-Markovnikov bromination of alkenes catalyzed by substituted pillararene hosts. The authors have carefully addressed the reviewers’ comments and performed substantial additional work, which, in my opinion, has improved the quality and clarity of the manuscript. Overall, I am satisfied with the revised version.\nHowever, I do not fully agree with the authors’ claim that the anti-Markovnikov selectivity (regioselectivity) is determined by factors other than substrate fitting within the host. The experimental data clearly demonstrate that efficient catalysis and selectivity require appropriate substrate (intermediate) positioning. Shorter substrates show poor selectivity, while bulkier substrates do not react, and macrocycles bearing shorter rim substituents display reduced catalytic efficiency and selectivity.\nCertainly, an important advantage of the authors’ system is the high catalytic performance achieved with sub-stoichiometric amounts of the host, indicating the absence of significant product inhibition. This contrasts with many previous reports where stoichiometric host loadings are used to suppress product inhibition. In this context, the statement that excess host is required “to shift the equilibrium in favor of the guest/host complex” is misleading, as such systems typically exhibit very high host–guest binding constants.\nAfter addressing these minor clarifications, I believe the manuscript will be suitable for publication.", "reviewer_4": "In this manuscript, Huang, Yeung, and co-workers report on the unprecedented regioselectivity achieved in the anti-Markovnikov oxy-halogenation of olefins using a pillararene host.\nI have reviewed a previous iteration of this work prior to its current submission. I am pleased to observe that the authors have comprehensively and satisfactorily addressed the constructive comments raised during the previous review process, including my own. The manuscript is now significantly clearer and presents a focused narrative regarding the reactivity of alkene in the unprecedented regioselective halogenation catalyzed by pillar[5]arenes . The data analysis, methodological approach, and the interpretation of the experimental results are rigorous and solid.\nThe key findings regarding the steering of regioselectivity are of high significance to the scientific community. This work effectively highlights the potential of macrocyclic hosts in controlling reaction outcomes and will undoubtedly stimulate further investigations in the field.\nOverall, I consider the manuscript suitable for publication. I have only one minor revision regarding references and the correct contextualization of the study.\nSpecific Comments: I ask the authors to rephrase the sentence: “Here we report a proof-of-concept study demonstrating PA-catalyzed…”. It is important to give proper credit to relevant prior art in this domain. Specifically, the authors should cite ACS Catal. 2024, 14, 15850–15857. This publication is highly relevant as it demonstrated the first application of a pillar[5]arene as a supramolecular catalyst for SN2 reactions, achieved by stabilizing the reaction transition state within the cavity. Acknowledging this work will provide a more accurate historical context for the current study.", "reviewer_6": "According to the editor's requirement, I have focused my evaluation on the computational aspects of the revised manuscript. The theoretical work is performed and presented to a very high standard and significantly enhances our understanding of the role of pillar[5]arene in controlling the reaction selectivity. The revised version has fully addressed the issues raised by previous reviewers. Herein, I would like to recommend its publication."}, "author_response": "Thank you very much for spending time reviewing the manuscript \"Pillar[5]arene-Catalyzed Anti-Markovnikov Halogenations Through Cationic Intermediates Stabilization in Confined Spaces\". We thank the reviewers for their constructive comments and suggestions, which are important in improving the manuscript. The manuscript has been revised accordingly (the changes are yellow-highlighted in separate files in the attachments), and the corrections are listed below:\nReviewer 1\nComment 1\n“In line with Reviewer 3’s Comment 7 regarding the limited familiarity of 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) to a general audience, it is recommended that the chemical structure of DBDMH be included in Figure 2b where the reaction scheme is shown.”\nResponse:\nWe thank the comment by the reviewer. We agree that the structure of DBDMH should be shown in Figure 2. We have now included the structure of DBDMH in Figure 2b.\nComment 2\n“Also noted is the point raised in Reviewer 3’s Comment 9 concerning the small size of the IR spectra in Figure 4. Enlarging the size of the spectra would facilitate the observation of spectral details and enhance the overall visual presentation.”\nResponse:\nWe thank the comment by the reviewer. We have now enlarged the size of the IR spectra to show better visual presentation in Figure 4.\nReviewer 2\nComment 1\n“Proper citation of related pillararene work; for instance. https://pubs.acs.org/doi/10.1021/acscatal.4c04836 ; a simialr suggestion was made by former Ref. 2. Surpridingly, nothign was added. The following sentence would be appropiate: \"Unlike conventional strategies that rely on rim-functionalized covalent hosts to catalyze reactions, ...”\nResponse:\nWe thank the comment by the reviewer. We have now added the reference and additional description on page 3 about the study by Scarso and coworkers.\nComment 2\n“Adding details to Figures on how the yield were determined. Clearly stating if it is NMR yield (How determined? Internal standard?) or isolated yield”\nResponse:\nThe yields are isolated yields. We have now added this information to the figure captions of Figure 2 and Figure 3.\nReviewer 3\nComment 1\n“I do not fully agree with the authors’ claim that the anti-Markovnikov selectivity (regioselectivity) is determined by factors other than substrate fitting within the host. The experimental data clearly demonstrate that efficient catalysis and selectivity require appropriate substrate (intermediate) positioning. Shorter substrates show poor selectivity, while bulkier substrates do not react, and macrocycles bearing shorter rim substituents display reduced catalytic efficiency and selectivity ...”\nResponse:\nWe thank the reviewer’s comment. We agree that efficient catalysis and selectivity require appropriate positioning of the cationic intermediate within the host. A sentence “catalyzing bromination by fitting the substrate with an appropriate size and stabilizing the bromiranium cationic intermediate within its π-basic cavity” has now been added on page 11.\nComment 2\n“Certainly, an important advantage of the authors’ system is the high catalytic performance achieved with sub-stoichiometric amounts of the host, indicating the absence of significant product inhibition. This contrasts with many previous reports where stoichiometric host loadings are used to suppress product inhibition. In this context, the statement that excess host is required “to shift the equilibrium in favor of the guest/host complex” is misleading, as such systems typically exhibit very high host–guest binding constants”\nResponse:\nWe thank the reviewer for the comment. We have modified the sentence on page 3 as “a super-stoichiometric amount of covalent hosts is usually required to suppress product inhibition”.\nReviewer 4\nComment 1\n“I ask the authors to rephrase the sentence: “Here we report a proof-of-concept study demonstrating PA-catalyzed…”. It is important to give proper credit to relevant prior art in this domain. Specifically, the authors should cite ACS Catal. 2024, 14, 15850–15857. This publication is highly relevant as it demonstrated the first application of a pillar[5]arene as a supramolecular catalyst for SN2 reactions, achieved by stabilizing the reaction transition state within the cavity. Acknowledging this work will provide a more accurate historical context for the current study...”\nResponse:\nWe thank the comment by the reviewer. We have now added the reference and additional description on page 3 about the study by Scarso and coworkers.\nReviewer 6\nComment 1\n“According to the editor's requirement, I have focused my evaluation on the computational aspects of the revised manuscript. The theoretical work is performed and presented to a very high standard and significantly enhances our understanding of the role of pillar[5]arene in controlling the reaction selectivity. The revised version has fully addressed the issues raised by previous reviewers. Herein, I would like to recommend its publication...”\nResponse:\nWe appreciate the comments by the reviewer. We have further revised the manuscript according to the comments suggested by other reviewers. We believe that this revised version of the manuscript should be suitable for publication.\nThank you for your attention.\nYours sincerely,\nYing-Yeung YEUNG\nDepartment of Chemistry\nThe Chinese University of Hong Kong\nShatin, NT\nHong Kong\nPhone: (852) 39436377\nyyyeung@cuhk.edu.hk"}]

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