Manganese catalyzed oximation of hydrocarbons to oximes

Domain: chemistry
Published: 2026-01-09
Editorial outcome: major_revision

Abstract
Oximes are used in many scientific and industrial domains, ranging from organic synthesis through biotechnology to materials science. Traditionally, their synthesis necessitates the use of hydrocarbons with specific functional groups, such as carbonyls, which are often more challenging and expensive to obtain compared to their non-functionalized counterparts. Here we introduce an approach that enables the synthesis of oximes from hydrocarbons via the oxidative oximation of methylene C-H bonds—the most prevalent molecular unit in the world of molecules. Under the catalysis of a manganese complex with hydrogen peroxide as the oxidant and hydroxylamine sulfate as the amine source, we demonstrate that a diverse array of molecules—from simple chemicals like propane and cyclohexane to complex compounds such as the antimalarial drug artemisinin—can be oximated at methylene C-H bonds with synthetically significant yields under mild conditions. The catalyst displays a good level of functionality tolerance and often predictable site selectivity in complex molecule settings. Our approach opens an avenue for oxime synthesis and is anticipated to have broad applications in the production of fine and commodity chemicals, bioactive molecules, and new materials.

Introduction
Oximes play important roles in diverse fields of science and technology. For example, they are used as building blocks in organic synthesis, active components of drugs, food sweeteners, herbicides, linkers for the conjugation of biomolecules and biomaterials, and “chameleons” in plant metabolism (Fig. 1a; also see Figs. S-1 and S-2)1–4. The largest industrial application of oximes is in the manufacturing of nylon-6, nylon-12, and anti-skinning agents in paints5. In 2024, the global production capacity for nylon-6 is expected to exceed 8.8 million metric tons, while that for nylon-12 has reached hundred thousand tons6.

Oximes can be synthesized by a variety of methods. These methods usually rely on the conversion of a pre-installed functionality, such as carbonyl and amino moieties (Fig. 1b)1,2,7–10. The vast majority of oximes are synthesized by oximation of carbonyl compounds with hydroxylamine, and this is particularly the case in large scale industrial processes1,2,5,11. Because carbonyls, such as ketones, can be synthesized from the more easily available, more economic, saturated hydrocarbons, oximation of the latter would make the synthesis of oximes more economic and greener. The major industrial process of the synthesis of nylon-6 is illustrative (Fig. 1b)5. The process starts with aerobic oxidation of cyclohexane, yielding a mixture of cyclohexanone and cyclohexanol, referred to as KA oil, with a selectivity of 80–85%. To avoid overoxidation, the conversion is kept low, at 10–12%; thus large recycles of unreacted cyclohexane are necessary. The cyclohexanone is separated and the remaining cyclohexanol is dehydrogenated to cyclohexanone. Reaction of the cyclohexanone with hydroxylamine sulfate affords cyclohexanone oxime, which is then subjected to Beckmann rearrangement to form the nylon-6 precursor, caprolactam. Nylon-12 has been synthesized similarly. Clearly, this multi-step process is inefficient and highly energy-intensive. In recent years, great progress has been made in improving the process—globally ca. 50% of the cyclohexanone oxime is now being synthesized by a new process involving ammoximation of cyclohexanone with NH3 and H2O2 5,12. More recently, synthesis of cyclohexanone oxime has been made possible via ammoximation with H2O2 in-situ generated from H2 and O2 13. However, in all these processes, cyclohexanone, instead of cyclohexane, is the hydrocarbon feedstock. An example of fine chemicals is seen in the synthesis of 2-pentanone oxime, an anti-skinning agent used in the coating industry (Fig. 1b). The process comprises again a series of reactions, starting with expensive 1,3-pentadiene (Fig. S-5).

Generating oximes from primary petrochemicals instead of their derivatives, oximation of the methylene C-H bonds in hydrocarbons via oxidation presents an ideal approach for the construction of oximes (Fig. 1b)14–18. Furthermore, C-H bonds are ubiquitous in organic molecules. Selective oximation of such bonds would open a short-cut pathway for oxime synthesis, allowing oximes of diverse properties to be more easily accessible. This is challenging, however, because of (1) the strong C(sp3)–H bond that renders the reaction kinetically and thermodynamically difficult (e.g. BDE of H-CH(CH3)2: 99 kcal/mol), (2) the presence of multiple methylene C-H bonds of similar BDEs that can lead to low site selectivity, (3) possible catalyst poisoning by the amine substrate and oxime product, and (4) functionalities in complex substrates that may not tolerate the oxidation conditions employed. Not surprisingly, there have been only a few reported reaction systems capable of converting inactive C–H bonds into oximes, but these either require harsh conditions or face poor selectivity issues. For instance, cyclohexanone oxime has been synthesized industrially by photonitrosation of cyclohexane with a mixture of NOCl and HCl under UV irradiation and by nitration of cyclohexane with HNO3 5,19. Both processes rely on highly corrosive nitrosating reagents and are energy inefficient. Radical nitrosation of cycloalkanes with tBuONO via UV irradiation has also been reported, which gives a mixture of nitrosocycloalkanes and cycloalkanone oxime20. For fine chemical and pharmaceutical synthesis, such C-H oximation methods would be of only limited use, as they would not be expected to offer good chemo and site-selectivity and tolerate diverse functional groups. Thus, there remains a large space to improve the efficacy of direct C-H oximation of hydrocarbons for oxime synthesis.

Herein, we report a manganese catalyst-centered protocol that enables the oxidative oximation of a broad range of hydrocarbons with H2O2 and (NH2OH)2•H2SO4 under mild conditions, affording various acyclic and cyclic ketone oximes including the lactam precursors for nylons 5, 6 and 12 (Fig. 1c). Adding to the advantage of a one-pot reaction, manganese is one of the most abundant base metals, of low toxicity and biocompatible21,22. Manganese as well as iron-based catalysts have been intensively studied in selective oxidation reactions in recent years; however, none is known to catalyze the oximation of hydrocarbons16,21–23.

Results
Reaction development
We have shown previously that manganese complexes bearing tetradentate amino ligands catalyze efficient benzylic oxidation of alkyl arenes to aryl ketones with H2O2, and if the alkyl chain bears a primary amino moiety, cyclic imines are generated via in-situ attack of the amine at the ketone24. Replacing the intramolecular amine moiety with an exogeneous hydroxylamine, we might be able to obtain an oxime under the manganese catalysis. However, both the substrate NH2OH and product oximes are known to coordinate to metals2 and could thus easily deactivate a metal catalyst. In addition, oximes are difficult to be protonated at the nitrogen atom (pKa < 1)25; thus, if coordination of an oxime is to be suppressed, a strong acid would be necessary. With these considerations in mind, we chose at the outset the common industrial feedstock hydroxylammonium sulfate as the oxime source (Fig. 2). We started by examining the oxidative oximation of cyclododecane 1 with H2O2 and (NH2OH)2•H2SO4, the oxime product of which is the precursor to nylon-12. On screening a wide range of reaction variables, we found that the manganese complex rac-C1, i.e. C1 containing a racemic pyridine-bipiperidine ligand (PYBP), catalyzes the efficient oxidative oximation of cyclododecane under the conditions shown (Fig. 2a). The yield of the oxime product 1a was found to be influenced by a variety of parameters, including catalyst, solvent, amount of acidic additive and the ratio of H2O2/substrate (Table S-2). Thus, the PYBP ligands with electron-donating, bulky substituents tend to give a higher oxime yield, with the one bearing a 5,5′-triisopropylsilyl group being most effective (rac-C1) (Fig. 2a). Of note is that the meso-C2 and meso-C3 complexes showed little activity while meso-C1 compares well with rac-C1. Acidic conditions and the use of the protonated hydroxylamine are essential; no reaction took place under neutral conditions or when free hydroxylamine was used (Table S-2, and SI, Section 6.7). Under the conditions established, the cyclododecanone oxime 1a was obtained in an isolated yield of 91%. Compared with the related ketonization reactions, the yield of 1a is higher (Fig. S-6; also see SI, Section 6.6).

The formation of the oxime 1a was found to proceed via the intermediacy of cyclododecanone 1-one resulting from the oxidation of 1 with H2O2. Monitoring the reaction with NMR showed that 1-one was formed progressively. Subsequent basification of the reaction mixture then afforded 1a, which was necessary as hydroxylamine is protonated (pKa 5.9) and thus might not be able to attack the ketone26. Indeed, 1-one was isolated in 85% yield when the basification was omitted (SI, Section 6.6). However, further study into the oxidation of cyclododecane, cyclohexane, and derivatives with GC and NMR indicates that oxime was formed from the ketone almost immediately after its formation from the hydrocarbon without basification, and the resulting oxime could be in equilibrium with its solid form, sulfate salt, which releases the free oxime upon basification (SI, Sections 6.2–6.3). The oximation of 1-one appears to be much faster than the formation of 1-one (SI, Section 6.5; Table S-16). Figure 2b shows the time course of the formation of 1a from 1.

Little multiple oxidations were noted in the reaction. This is presumably due to the ketone moiety introduced imparting a deactivating effect on the remaining methylene C-H bonds toward oxidation by electrophilic Mn(V)=O species27. However, the oximation also plays an important role, as a mixture of polyketone products was generated in the absence of hydroxylammonium, with 1-one isolated in only 38% yield (Fig. 2c). Like carbonyl, the oxime group is deactivating, as shown by the oxidation of 1a vs 1-one, the former being markedly resistant toward further oxidation (SI, Section 6.4). In addition, comparing the disappearance rate of 1 (c.f. Fig. 2b, c) suggests that the hydroxylammonium ion may suppress the oxidation ability of the catalyst, rendering overoxidation less likely. Further studies showed that the hydroxylammonium ion also exerts a significant effect on the chemo and site-selectivity in the oxidation of more complex molecules (for examples, see SI, Sections 6.9–6.10). While the detailed mechanism of the hydroxylammonium effect remains to be elucidated, our preliminary investigations suggest that the introduction of the hydroxylammonium cation affects the formation of high valent manganese-oxygen species from rac-C1 and it could be involved in the step of C-H bond oxidation (SI, Sections 6.11–6.13; for a suggested mechanism, see Section 6.14).

Oximation of unactivated C(sp3)-H bonds
Under the optimized conditions, a range of nonfunctionalized cyclic and acyclic alkanes have been converted to the corresponding ketone oximes (1.0 mmol scale, Fig. 3a). Cyclic oximes ranging from cyclopentanone to cyclododecanone oximes were obtained in high yields with little overoxidation observed. However, the larger sized cyclopentadecanone oxime was obtained in a lower 74% yield, where a small amount of multi-oxidation products was observed. The bicyclic norbornane 7 was oximated at a methylene site with no oxidation at the tertiary C-H position observed. For the more challenging acyclic alkanes, a larger amount of HOAc was required to achieve a satisfied yield (Tables S-4 and S-5). Under such conditions, acyclic alkanes ranging from propane to pentane were oximated exclusively at the methylene C-H bond next to the terminal methyl group, as would be expected from the steric accessibility and bond strength effect. For longer alkanes, e.g., 11a and 12a, regio-isomers (all mono-oxime products) were formed because of diminishing steric and electronic differences between the methylene units. However, oximation of the terminal methylene units remained dominating (see SI for more examples), and the regioselectivity of rac-C1 in oxidizing 11 and 12 is generally higher than that of other catalysts in related ketonization reactions (Fig. S6)28–31. Larger scale oximation and lower catalyst loading were also demonstrated, as seen with cyclododecane (Fig. 3a; also see Table S-4 and Section 10). The ability to oximate these unfunctionalized alkanes is remarkable. Traditional methods of accessing such oximes, when starting from cheap hydrocarbon substrates, are usually multi-step reactions under harsh conditions (Figs. S-3–S-5).

Functionalized cyclic alkanes were next examined (Fig. 3b). Good yields were generally obtained across the ring systems. For the five-membered ring substrates, oxidation took place highly selectively at the remote methylene site. Regio-isomers were seen in substituted six and seven-membered ring compounds (for their separation, see SI, Section 12). For the seven-membered, the δ C-H bond appears to be more prone to undergo oxidation, as would be expected based on the decreasing deactivating effect of the electron-withdrawing substituent27,28,32. For the six-membered, the γ position is slightly favored when a statistic correction is applied. This may be ascribed to the alleviation of the substituent-imposed 1,3-diaxial strain upon HAT at this site28. An exception is seen in the acetate substituted 16a, where the γ site is less favored. This may be due to a higher axial population of the acetate group (ΔG eq/ax = 0.8 kcal/mol at 193 K)33 than others substituents, which disfavors γ oxidation because of increased steric clash with the catalyst. In both cases, the yields of the phthalimide derivatives are significantly lower (19a, 22a), reflecting the strong deactivating role of the phthalimide moiety27,34,35. The norbornane 24 only afforded the δ oxime 24a as a result of the steric and electronic effect of the substituent. The yields of and selectivities to these oxime products are comparable to those reported for the related ketones; they are, however, lower than those observed when the oxidation was carried out in perfluorinated alcohols27. Note that all the oximes exist in E and Z forms except for those having plane symmetry (ignoring the hydroxy unit).

Acyclic alkanes bearing various functionalities were also oximated (Fig. 3b). Particularly notable is the oximation of pyridine, amine, and oxime-bearing alkanes (35a, 36a, 38a-40a, 43a, 46a), the tolerance of which is likely due to the protonation of the heteroatoms that prevents their coordination to and hence the deactivation of the metal center. The protonation-elicited polarity reversal effect27 may have also contributed to the higher site selectivity. Surprisingly somehow, with only one methylene unit separating the reacting C-H bond and the deactivating ester, methyl butyrate also underwent the reaction, affording a cyclized isoxazoline 26a’, albeit in a low yield. A comparison of the yields of oximes reveals the directing effect on site selectivity of electron-withdrawing substituents, which deactivate the proximal C-H bonds toward oxidation27,28,32. Thus, when the most remote methylene unit is less than 3-4 carbons away from the substituent, oxidation occurred selectively at that site. However, when the methylene is further away, oxidation of the proximal methylene units took place, resulting in regio-isomeric mono-oxidation products (e.g., 27a vs 30a, 41a vs 47a. Also see Table S-12). Similar effects have been noted before27–29. A theoretical study of n-dodecane bearing a terminal electron-withdrawing group (-NH3+) shows that the positive charge on the methylene hydrogen atoms stops varying after the fifth carbon36. Comparing the yields of and selectivities to 30a and 46a indicates that the oxime is more deactivating and hence more directing than a methyl ester (also see SI, Section 6.4). The site selectivity and product yield are also affected sterically. Thus, making the substrate bulkier, regardless in the chain or by the functionality, increased the selectivity to the remote methylene, albeit at the expense of the oxime yield (c.f. 27a vs 28a, 30a vs 31a and 32a). This likely stems from possible steric repulsion between the ligand and the approaching substrate during oxidation28. Although the yields of some of these functionalized oximes tend to be low, the reaction may still offer advantages in the context of complex molecule or nature product synthesis.

Oximation of activated C(sp3)-H bonds
Prompted by the utility of allylic oxidation in natural product synthesis37,38, we next attempted the oximation of allylic substrates. For this transformation involving activated methylene C-H bonds, the sterically less demanding rac-C2 was shown to be more productive, probably partly due to the substates being more rigid and/or side reactions (Tables S-7 and S-9). As shown in Fig. 4a, a range of acrylate derivatives were oximated. Although the ester unit is deactivating, the low BDE of the allylic C-H bond makes it the primary oximation site (e.g., BDE of the allylic C-H bond in cyclohex-1-ene-carboxylic acid: 88.4 kcal/mol)39. Thus, no site selectivity issue was noted in forming 49a–51a. When there are methylene units three carbons remote from the allylic position, oxidation of these units was observed (52a–54a). However, allylic oxidation remained dominating. Epoxidation was noted as a minor reaction in some cases (SI, Table S-9), and surprisingly, on going from 64 to 64a, the olefin unit was also epoxidized, albeit in a low yield probably due to the product being less stable (<5% of 64 recovered). As with alkane oximation (Fig. 3), sterically demanding and strong electron-withdrawing substituents lower the product yield (e.g. 49a vs 55a, 50a vs 56a, and 59a vs 61a). Partial oxidation of a tertiary C-H bond to a hydroxy moiety was noted in addition to allylic oximation (62a-4’-OH). Acrylamides are also feasible (66–68). However, the oxidation of the primary amide 66 afforded an epoxide 66b as the main product (66b, 34% yield; SI, Section 12), and in the case of 67, oxidative dealkylation to give 66a was also observed. Notably, although highly strained, the cyclopropyl moiety in 68 survived. We also examined a propargylic substate 69, which was oximated in a low yield of 21%, mainly due to product instability.

Oximation of benzylic substrates was also demonstrated (Fig. 4b). rac-C2 was again shown to be more productive than rac-C1 (Table S-10). Benzylic oximes were obtained in yields generally higher than those of acyclic alkanes and acrylate derivatives, reflecting the strong activating effect of the aryl group. Notably, electron-withdrawing para-substituents, such as nitro and chloride, on the aryl rings pose little effect on the oxime yield, while the electron-donating methoxy did not cause significant competitive aromatic oxidation40,41. Also notable is the exclusive benzylic site selectivity, regardless of the presence of other methylene units (e.g. 81a, 82a, 94a). Whilst the pyridine oximes 95a and 96a were obtained in low yields, possibly due to deactivation caused by the nitrogen being protonated, the pyridine-fused analogs 97a and 98a were isolated in good yields. The high yield may stem from a lower BDE of the benzylic C-H bond in an aryl-fused alkane. The protonation-elicited deactivation is more pronounced when the nitrogen is at the ortho or para position due to the resonance effect (95a, 99a). Encouragingly, a chiral 3-amino benzyl oxime 100a was obtained in high yield, pointing to the potential of the protocol in enabling the synthesis of synthetically sought-after 1,3-difunctionalized chiral compounds. Note although benzylic oxidation reactions of functionalized alkyl arenes have been extensively studied, those featuring a pyridine group remain challenging42,43.

Synthetic applications
To probe the wider synthetic applicability of the protocol, we also carried out the oximation of a range of enantiomerically enriched substrates bearing multiple functionalities (Fig. 5). As shown in Fig. 5a, amino acid derivatives were tolerated, with the oxime yields varying with the position of the methylene unit to be oxidized. A good yield was obtained when the unit is three carbons away (c.f. 101a and 102a). The low yield of 101a is likely a result of both electronic and steric effects. On the other hand, site isomers were formed when the alkyl chain becomes longer, e.g. 103a, due to the decreased deactivating effect of the functionality. In contrast with 111, the racemic amino acid derivative 112 was oximated to 112a in a low yield. This may stem from the interplay of the C-H bond strength, steric hindrance of the substrate and the high ring strain of the product (c.f. strain energy of cyclobutanone and cyclopentanone: 28.7 vs 9.7 kcal/mol; BDE of C-H bond 97.8 in cyclobutane vs 95.6 kcal/mol in cyclopentane)44. When a substrate contains an activated methylene unit, site selectivity poses less a problem. Thus, the amino acid derivatives 115–119 were oximated at the allylic position, and 113 and 114 underwent highly efficient benzylic oximation. Note that 118a was obtained in a higher yield when using (R,R)-C2, revealing the importance of chirality match between the substrate and catalyst, which in turn indicates possible steric interactions between the ligand and substrate during the oxidation. The enantiomeric purity of 115a was measured and showed no erosion. Despite the low yields sometimes, these reactions allow multi-functionalized oximes to be accessed more directly and thus should be of value in the synthesis of non natural amino acid derivatives3,45.

The high reactivity and selectivity displayed by the catalysts provide an opportunity to effect late-stage oximation of bioactive molecules (Fig. 5b). As an example, sclareolide, a commercially available material in natural products synthesis, was oxidized to oxime 120b in 56% isolated yield (total yield of isolated E and Z isomers) alongside small amounts of 120a and 120c under the catalysis of (S,S)-C1. The structures of (E)-120a and (Z)-120b have been determined by X-ray diffraction. Compared with the ketonization of 120 effected by other catalysts, the oxidation of 120 with (S,S)-C1 shows a higher C2 regioselectivity. Another example is seen in the oxidation of the natural product methyl dehydroabietate 121, which is isolated from spruce bark and has antibacterial activity. The oximation occurred exclusively at the benzylic methylene site, affording 121a in single E form under the catalysis of (R,R)-C2. However, a small amount of the ketone intermediate 121b remained. The oximation of the antimalarial drug artemisinin provides a further example. To date, late stage oxy-functionalization of artemisinin has been limited to enzymatic46,47 and iron catalysis48,49. Subjecting artemisinin 122 to the catalysis of (R,R)-C1, the oxime 122a was isolated in 56% yield, with the oxidation occurring at the more electron rich and sterically more accessible methylene site. Note that using (S,S)-C1 as catalyst resulted in the formation of an inseparable mixture, showing again the importance of chirality match. The oxime derivatives of 120–122 have been unknown so far. Installation of an oxime functionality to such molecules may alter their bioactivity and bring about unexpected new properties.

In summary, we have demonstrated that oximes can be installed via methylene C-H oxidation. The manganese complexes C1 and C2 catalyze the oxidative oximation of methylene C-H bonds in a wide variety of simple and complex molecules with benign H2O2 and economic (NH2OH)2•H2SO4, displaying a high level of, and often predictable, chemo and site selectivity and functional group tolerance. The electron-rich, bulky C1 is more effective toward non activated C-H bonds, while the electron-rich but less bulky C2 is better for activated variants. We anticipate the catalytic system to find applications in selective oximation of hydrocarbons and in the synthesis of fine and complex organic chemicals.

Methods
Representative procedure for oximation of unactivated hydrocarbons with rac-C1
Rac-C1 (10.2 mg, 1.0 mol%), hydroxylamine sulfate (328.3 mg, 2.0 mmol, 2.0 equiv.), a hydrocarbon substrate (1.0 mmol, 1.0 equiv.), AcOH (2.8 mL for functionalized alkanes and nonfunctionalized acyclic alkane; 1.2 mL for nonfunctionalized cyclic alkanes) and tBuOH (2.0 mL) were added to a reaction tube. The mixture was cooled down to 0°C in a cryogenic bath, and then H2O2 (5.0 equiv., 5.0 mmol, 567 µL, 30% wt in H2O) in 2 mL of tBuOH was added with a syringe pump over 1 h under stirring at 0°C without nitrogen protection. After stirring for an additional 0.5 h, the reaction mixture was quenched with Na2SO3. Next, the resulting mixture was basified with Na2CO3 for 0.5 h at 0°C in a cryogenic bath. After completion of the reaction, water (5.0 mL) was added, and the solution was extracted with dichloromethane (3 × 15.0 mL). The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure to produce the crude product, which was purified by flash column chromatography to afford the desired product. For further details, please see the Supplementary Information.

Peer review rounds
[{"round": 1, "reviewer_comments": {"reviewer_1": "J. Xiao and C. Li, along with their colleagues, have developed a method for the methylene oximation of hydrocarbons using hydrogen peroxide, hydroxylammonium sulfate, and manganese catalysts. This approach enables the synthesis of oximes with good to excellent selectivity and yield across a broad substrate scope. Notably, this catalytic system addresses a long- standing challenge in the field: the direct synthesis of oximes from more abundant and economical hydrocarbons. This advance represents a significant milestone in the field of C-H oxidation catalysis and holds broad interest for researchers in inorganic chemistry, organic chemistry, catalysis, and industry. The manuscript is well-written and clearly presents the research and results. The reviewer recommends the publication of this manuscript in Nature Communications as an article with minor revisions.\n1) From an industrial standpoint, the cost-effectiveness of reagents is a critical consideration. Ammonium sulfate is significantly cheaper than hydroxylammonium sulfate, and its use could potentially lower the overall cost of the process. And ammonium sulfate can also be oxidated to hydroxylammonium sulfate under certain oxidation conditions. If ammonium sulfate is used instead of hydroxylammonium sulfate as an amine source, what will be observed in the oxidation of cyclododecane under the reaction conditions?\n2) In Figure 2 and Table S-2 (page 24) of the supplementary information, the weakly coordinating anions (OTf-, OAc-, SO42- ) influence the reactivity and selectivity of the manganese catalyst by affecting its electronic properties and coordination environment. In contrast, non-coordinating anions, such as BF4- and SbF6-, which do not interact with the catalyst, could alter its behavior by minimizing anion-catalyst interactions. These changes might result in variations in activity, selectivity, or stability. To investigate this further, additional experiments with manganese catalysts utilizing non-coordinating anions (e.g., [Mn(BF4)₂] or [Mn(SbF₆)₂]) could be conducted. The results from these experiments would be compared with the existing data to elucidate the role of anion coordination in the catalytic cycle. Such insights would enhance our understanding of the reaction's mechanistic aspects and could be incorporated into the revised manuscript.\n3) In Figure 2. hydroxylammonium sulfate has a significant effect on the selectivity of oximation of cyclododecane. The role of hydroxylammonium sulfate on affecting could be elucidated. Hydroxylammonium sulfate may influence the regioselectivity for functionalized alkanes by interacting with the functional groups on the substrate or by modulating the reactivity of the manganese catalyst.\nTo clarify this, the authors could perform additional experiments with functionalized alkanes (e.g., substrates 17 and 30), comparing the regioselectivity of the oximation reaction in the presence and absence of hydroxylammonium sulfate. This would help clarify whether hydroxylammonium sulfate plays a direct role in directing the reaction to specific sites on the substrate. The results could be added in the manuscript or SI.\n4) In the SI (Page 13), the numbers next to R groups on the pyridine derivatives should be superscript for consistency and clarity.", "reviewer_2": "The manuscript presents a one-pot synthesis of oximes from hydrocarbons through manganese-catalyzed oxidation, leading to the formation of ketones, followed by condensation with hydroxylamine. Though similar catalysts have been reported for the oxidation of hydrocarbons, this work shows improved catalytic efficiency for certain substrates (see Figure S-5) by fine- tuning the catalyst structure and optimizing reaction conditions, such as solvent choice and the ratio of H2O2 to substrate. The authors also established through control experiments that hydroxylamine sulfate is essential for the selectivity of ketones during the first oxidation step of this reaction. This method can accommodate a range of hydrocarbons, including both activated and inactivated ones, as well as some complex structures. Given the significance of oximes and the direct functionalization of hydrocarbons, I believe this work merits acceptance in the journal, provided that the following questions are addressed:\n1. The statement \"the direct synthesis of oximes from hydrocarbons via the oxidative oximation of methylene C-H bonds\" is misleading. Initially, I interpreted it as implying that the oximes were formed directly, without the intermediate formation of ketones.\n2. The catalyst loadings used are between 1-2 mol%. Is it possible to reduce this, considering the significant improvement in reactivity? One potential application of this reaction is for large-scale production of oximes, and 1 mol% of a metal complex with a sophisticated ligand may not be practical for such applications.\n3. Are these catalysts stable throughout the reaction? Additionally, do the silyl group or the Csp3–H bonds in the catalysts participate in the reaction?\n4. The role of hydroxylamine sulfate should be clarified, as it is a key difference compared to previous reports on this type of reaction. Could the anion (OTf) surrounding the manganese atom be substituted with (SO4)²⁻ or (HSO4)⁻?\n5. The E/Z ratios should be included in the main text figures, as they are important and show significantly different reactivities for various configurations. Some ratios in the supporting information are imprecise according to the NMR spectra; for example, the calculation for compound 61a shows 0.91:0.13, which simplifies to 7:1 rather than the reported 9:1. Additionally, how is the E/Z configuration of the oxime assigned? Is the E configuration always the dominant isomer? There may be other factors that affect this ratio, such as hydrogen bonding.\n6. Some HRMS data are incorrect: 62a-5'-OH, 115a.\n7. Some expressions are incorrect, such as p-ClPh, Php-Br in Fig 3. Ph represents C6H5. 99 kacl on page 2 should be 99 kcal.", "reviewer_3": "The present work by Xiao and co-workers demonstrates the catalytic oxidation of alkanes to carbonyl compounds, followed by oxime formation under controlled conditions using well-defined Mn-PYBP catalytic systems. The catalysts demonstrate a broad substrate scope and high functional group tolerance. The authors claimed that their method offers a superior approach to oxime synthesis and reported an 81% yield for the oxime of cyclohexane. However, they do not address the issue of cyclohexanone formation as a side product. This is analogous to the conventional process, where cyclohexanone must be separated before oximation. If their method still results in a mixture of cyclohexanone and its oxime, then the fundamental inefficiency of requiring separation steps remains unaddressed. A direct comparison of selectivity, separation requirements, and overall process efficiency would be necessary to justify the superiority of their approach. It seems that the primary role of the catalyst is to oxidize the alkanes to the corresponding carbonyl, while basification facilitates the release of free hydroxylamine, which subsequently forms the oxime. The authors have already shown that analogous manganese complexes bearing tetradentate amino ligands can catalyze the benzylic oxidation of alkyl arenes to aryl ketones with H2O2 (Angew. Chem. Int. Ed. 2022, 61, e202205983). The role of the catalyst in this oximation step is not clear. SI, section 6.3, it is clear that the catalyst is not needed during the oximation step, or if there is any role, it is not mentioned. In fact, the role of the catalyst or the ligand is not clearly mentioned anywhere in the manuscript. While the study presents a potentially valuable oximation method, the lack of mechanistic depth, insufficient control experiments, and novelty make it unsuitable for publication in \"Nature Communication\" at this stage. The authors should address the following points before submitting this work elsewhere.\n1. The influence of hydroxylammonium sulfate on oxidation should be further explored. Specifically, the effect of protonation on hydroxylamine reactivity and oxime coordination to the metal catalyst needs further elaboration.\n2. The role of acidic additives in influencing the reaction should be discussed. Why is a higher amount of acid required for challenging acyclic alkanes?\n3. The authors stated that \"Bypassing the intermediacy of ketones, oximation of the methylene C-H bonds in hydrocarbons via oxidation presents an ideal approach for the construction of oximes,\" However, their reaction proceeds via the intermediate carbonyl formation. The statement should be checked.\n4. The authors stated that \"the PYBP ligands with electron-donating, bulky substituents tend to give a higher oxime yield, with the one bearing a 5,5’-triisopropylsilyl group being most effective.\" Why does a bulky ligand produce a more profound effect?\n5. It seems that \"rec-C1\" exhibits higher compatibility with certain substrates, such as cycloalkanes, while \"rac-C2\" is more effective for others. Can the authors provide insights into the factors driving this reactivity difference? Specifically, does the ligand environment play a role in influencing substrate selectivity, and if so, how?\n6. The manuscript does not provide a catalytic cycle or strong experimental evidence for key intermediates. Radical trapping experiments (e.g., TEMPO, BHT) should be conducted to confirm whether the reaction follows a radical or non-radical pathway. Kinetic isotope effect (KIE) studies should be performed to understand the rate-determining step. The role of the catalyst and the ligands should be mentioned.\n7. SI, Section 6.8, How do the UV-vis measurements support the formation of (rac-L1)Mn(III) and/or (rac-L1)Mn(III)(μ-O)₂Mn(IV) species (65–68) upon mixing rac-1 with H₂O₂, and what role does hydroxylamine sulfate play in accelerating this oxidation process. Can they provide more substantial evidence, such as EPR, to support this claim?\n8. What is the oxidation state of the metal in the native complexes. Additional spectroscopic data (such as EPR/XPS) is required to confirm the oxidation state.\n9. Why electron-withdrawing substituents deactivate the proximal C-H bond toward oxidation.\n10. In SI, Section 6.1, the authors use both \"rac-C1\" and [Mn], possibly to designate the same catalytic system. It isn't very clear, given that they used other Mn-catalysts. For example, in Table S6, \"rac-C2\" is the chosen system, yet the corresponding scheme uses \"[Mn]\". It is difficult to follow which system is being used for a particular work. I would suggest considering replacing [Mn] with \"rac-C1\", \"rac-C2\"…..\n11. In SI, Section 6.2, eq. 1, \"NNR\" should be replaced with NMR."}, "author_response": "We thank all the reviewers for their valuable comments and have revised the manuscript and Supplementary Information (SI) accordingly. In particular, following the comments, more than 100 new experiments have been carried out, which provide more insightful information for the manganese catalyzed oxidative oximation of hydrocarbons to oximes. A major revision arises from the finding that the oximation takes place while the ketone intermediate is being formed instead of post basification as posited in the previous submission (Scheme 1), and the resulting oxime is deactivated towards further C-H oxidation, contributing to enhanced chemoselectivity. Our point- to-point response to the reviewers’ comments and explanation concerning Scheme 1 are given below.\nScheme 1. Reaction pathways for the manganese-catalyzed oxidative oximation of hydrocarbons to oximes, proposed based on new experiments conducted during the revision.\nReviewer 1:\na) “From an industrial standpoint, the cost-effectiveness of reagents is a critical consideration. Ammonium sulfate is significantly cheaper than hydroxylammonium sulfate, and its use could potentially lower the overall cost of the process. And ammonium sulfate can also be oxidated to hydroxylammonium sulfate under certain oxidation conditions. If ammonium sulfate is used instead of hydroxylammonium sulfate as an amine source, what will be observed in the oxidation of cyclododecane under the reaction conditions?\"\nResponse:\nWe thank the reviewer for this out and for the valuable suggestion. Based on the suggestion, we conducted control experiments using ammonium sulfate instead of hydroxylammonium sulfate as the amine source for the oximation of substrate 1 under standard reaction conditions. However, only the ketone products (1-one and 1-one’) were observed, with no formation of the oxime product (1a) (see SI, Table S-3, entry 5, page 25). This result indicates that ammonium sulfate cannot be oxidized in situ to hydroxylammonium sulfate under our current reaction conditions, highlighting the essential role of hydroxylamine as the direct oxime precursor in the current transformation.\nb) “In Figure 2 and Table S-2 (page 24) of the supplementary information, the weakly coordinating anions (OTf-, OAc-, SO 2-) influence the reactivity and selectivity of the manganese catalyst by affecting its electronic properties and coordination environment. In contrast, non-coordinating anions, such as BF4- and SbF6-, which do not interact with the catalyst, could alter its behavior by minimizing anion-catalyst interactions. These changes might result in variations in activity, selectivity, or stability. To investigate this further, additional experiments with manganese catalysts utilizing non-coordinating anions (e.g., [Mn(BF4)₂] or [Mn(SbF₆)₂]) could be conducted. The results from these experiments would be compared with the existing data to elucidate the role of anion coordination in the catalytic cycle. Such insights would enhance our understanding of the reaction's mechanistic aspects and could be incorporated into the revised manuscript.”\nResponse:\nWe thank the reviewer for the valuable suggestion. Based on the suggestion, we synthesized two additional manganese complexes to investigate the counter anion effect: rac-17 with a coordinating Cl- anion and rac-18 with a non-coordinating SbF - anion (see SI, section 4.3, pages 20-22). These catalysts were then evaluated alongside rac- 1 (with weakly coordinating OTf⁻ anion) for the oximation of substrate 1 at both 1 mol% and 0.2 mol% catalyst loadings. Notably, rac-18 (SbF₆⁻) demonstrated comparable activity to rac-1 (OTf⁻), while both showed higher catalytic efficiency than rac-17 (Cl⁻) (see SI, Table S-2, entries 32-36, page 24). The observed activity trend (rac- 18 ≈ rac-1 > rac-17) demonstrates that non or weakly coordinating anions are necessary in this oximation reaction, most likely for the activation of H O at the metal center. Further studies show that not only chloride ion but other potentially coordinating anions, such as phosphate, also inhibit the oxidation reaction (See SI, Table S-3, page 25).\nc) “In Figure 2. hydroxylammonium sulfate has a significant effect on the selectivity of oximation of cyclododecane. The role of hydroxylammonium sulfate on affecting could be elucidated. Hydroxylammonium sulfate may influence the regioselectivity for functionalized alkanes by interacting with the functional groups on the substrate or by modulating the reactivity of the manganese catalyst. To clarify this, the authors could perform additional experiments with functionalized alkanes (e.g., substrates 17 and 30), comparing the regioselectivity of the oximation reaction in the presence and absence of hydroxylammonium sulfate. This would help clarify whether hydroxylammonium sulfate plays a direct role in directing the reaction to specific sites on the substrate. The results could be added in the manuscript or SI.”\nResponse:\nWe thank the reviewer for the valuable suggestion. Hydroxylammonium sulfate not only significantly influences the chemoselectivity of cyclododecane oxidation (Figure 2) but also markedly affects that of allylic substrates (see SI, Section 6.9, pages 55-57) and substrate 120 (see SI, Section 6.10, page 58). Additionally, it alters the kinetic isotope effect in the reaction of cyclohexane vs cyclohexane-d₁₂ (see SI, Section 6.12, pages 59-66).\nHydroxylammonium sulfate may play a dual role in the oximation reaction:\nI) Interaction with the manganese catalyst to modulate the reaction pathway. Although the mechanistic details of this effect remain unclear, our UV-vis measurements (see SI, Section 6.13, pages 66-72) show that the oxidation of rac-1 with H O to higher oxidation states is accelerated by hydroxylammonium cation, but inhibited by free NH OH (for effect on catalysis, see SI, Section 6.7, page 52) and excess Cl-, PO 3- and to a smaller degree SO 2- (for effect on catalysis, see SI, Section 5, Table S-3, page 25). The results indicate possible coordination of the hydroxylammonium ion to manganese during oxidation (see SI, Section 6.14, pages 72-73, for a proposed mechanism, and also see response to Reviewer 3).\nII) Acting as an amine source to react with ketones, forming oximes and oxime salts that influence reaction selectivity. New experiments were conducted, which revealed that once formed, the oxime becomes much less reactive towards further oxidation compared with the corresponding ketone substrate (see SI, Section 6.4, pages 49-50). The oxime moiety is thus deactivating, contributing to a higher chemoselectivity in oxidative oximation than in ketonization.\nFollowing the reviewer recommendation, we also conducted additional experiments to investigate the regioselectivity of the manganese-catalyzed C–H oxidation of substrates 17 and 30 under conditions without hydroxylammonium sulfate. Comparing the results obtained with vs without hydroxylammonium sulfate reveals that the oxime products (17a and 30a) exhibited slightly higher regioselectivities than the corresponding ketone products (17-one and 30-one). These results, which have been included in the updated SI (see SI, Section 6.8, pages 52-55), demonstrate that hydroxylammonium sulfate also plays a role in affecting the regioselectivity in this manganese-catalyzed C–H oxidation system.\nd) “In the SI (Page 13), the numbers next to R groups on the pyridine derivatives should be superscript for consistency and clarity”\nResponse:\nWe thank the reviewer for pointing this out and have corrected the structure of compounds L3-11 in Section 4.2 B.\nReviewer 2:\nA) “The statement \"the direct synthesis of oximes from hydrocarbons via the oxidative oximation of methylene C- H bonds\" is misleading. Initially, I interpreted it as implying that the oximes were formed directly, without the intermediate formation of ketones.”\nResponse:\nWe thank the reviewer for pointing this out and have revised the main text accordingly.\nB) “The catalyst loadings used are between 1-2 mol%. Is it possible to reduce this, considering the significant improvement in reactivity? One potential application of this reaction is for large-scale production of oximes, and 1 mol% of a metal complex with a sophisticated ligand may not be practical for such applications.”\nResponse:\nWe thank the reviewer for pointing this out and the valuable suggestion. Based on the suggestion, we further examined the oximation of substrate 1 by reducing the catalyst loading to 0.2 mol% and 0.1 mol% (see SI, Table S- 4, pages 25-26). Key findings are:\nI) With 0.2 mol% catalyst loading (2 mmol reaction scale, with 4.8 mL of AcOH), we achieved 90% NMR yield and 84% isolated yield of oxime 1a;\nII) At 0.1 mol% catalyst loading (2 mmol reaction scale, with 6.0 mL of AcOH), a 72% NMR yield of 1a was obtained.\nThese results demonstrate that the catalyst loading can be successfully reduced to 0.1-0.2 mol%, and suggest that further optimization may enable even lower catalyst loadings.\nC) “Are these catalysts stable throughout the reaction? Additionally, do the silyl group or the Csp3–H bonds in the catalysts participate in the reaction?”\nResponse:\nWe thank the reviewer for raising this important point and for the insightful question. Both our experimental observations and literature reports (ACS Catal. 2023, 13, 6403-6414) suggest that the manganese catalysts can undergo deactivation. This might happen through catalyst dimerization, ligand dissociation, and/or oxidation of either the silyl groups or Csp³–H bonds in the ligand framework. However, under our experimental conditions, we did not detect any identifiable degradation products of the catalyst. Being bulky, the silyl group may affect how a substrate, particularly the bulky and/or conformationally flexional one, approaches the Mn=O unit where C-H oxidation occurs, resulting in effects on selectivity (ACS Catal. 2020, 10, 8611−8631).\nD) “The role of hydroxylamine sulfate should be clarified, as it is a key difference compared to previous reports on this type of reaction. Could the anion (OTf) surrounding the manganese atom be substituted with (SO4)²⁻ or (HSO4)⁻?”\nResponse:\nWe thank the reviewer for pointing this out and the suggestion. Based on our control experiments, hydroxylammonium sulfate not only significantly influences the chemoselectivity of cyclododecane oxidation (Figure 2) but also markedly affects that of allylic methylene oxidation (see SI, Section 6.9, pages 55-57) and substrate 120 (see SI, Section 6.10, page 58). Additionally, it alters the kinetic isotope effect in the reaction of cyclohexane vs cyclohexane-d₁₂ (see SI, Section 6.12, page 59-66).\nHydroxylammonium sulfate may play a dual role in the oximation reaction:\nI) Interaction with the manganese catalyst to modulate the reaction pathway. Although the mechanistic details of this effect remain unclear, our UV-vis measurements (see SI, Section 6.13, pages 66-72) show that the oxidation of rac-1 with H O to higher oxidation states is accelerated by hydroxylammonium cation, but inhibited by free NH OH (for effect on catalysis, see SI, Section 6.7, page 52) and excess Cl-, PO 3- and to a smaller degree SO 2- (for effect on catalysis, see SI, Section 5, Table S-3, page 25). The results indicate possible coordination of the hydroxylammonium ion to manganese during oxidation (see SI, Section 6.14, pages 72-73, for a proposed mechanism, and also see response to Reviewer 3).\nII) Acting as an amine source to react with ketones, forming oximes and oxime salts that influence reaction selectivity. New experiments were conducted, which revealed that the oxime is quickly formed in the oxidation without basification (for details, see our response to Reviewer 3, question A), and once formed, it becomes much less reactive towards further oxidation compared with the corresponding ketone substrate (see SI, Section 6.4, pages 49-50). The oxime moiety is thus deactivating, contributing to a higher chemoselectivity in oxidative oximation than in ketonization.\nBased on reviewer questions, we synthesized three manganese catalysts with different anion coordination strengths [rac-17 (with strong coordinating Cl- anion), rac-1 (with weak coordinating OTf- anion), and rac-18 (with non- coordinating SbF - anion)] for the oximation of substrate 1. Notably, rac-1 (OTf⁻) and rac-18 (SbF₆⁻) showed comparable catalytic activity, while rac-17 (Cl⁻) exhibited lower efficiency (see SI, Table S-2, entries 32-36, page 24). These results suggest that under the reaction conditions, the original OTf⁻ anions surrounding the manganese center are most likely replaced by species such as H O , HOAc and/or hydroxylammonium ion. Note that like Cl- and PO 3-, the anions SO₄²⁻ and HSO₄⁻ inhibit the oxidation when present in excess, presumably via weak coordination (see SI, Table S-3, page 25). That this effect is less pronounced in a standard reaction is largely due to the low solubility of the sulfate salts in the reaction system.\nFurther studies into oxime formation under the reaction conditions are described below in the response to Reviewer 3.\nE) “The E/Z ratios should be included in the main text figures, as they are important and show significantly different reactivities for various configurations. Some ratios in the supporting information are imprecise according to the NMR spectra; for example, the calculation for compound 61a shows 0.91:0.13, which simplifies to 7:1 rather than the reported 9:1. Additionally, how is the E/Z configuration of the oxime assigned? Is the E configuration always the dominant isomer? There may be other factors that affect this ratio, such as hydrogen bonding.”\nResponse:\nWe thank the reviewer for pointing these out and the question. Due to space constraints in the main text including figures and our primary focus being on regioselectivity, we omitted the E/Z ratios in the main text. However, detailed information on both regioselectivity and E/Z ratios for all products can be found in Section 12 of the SI (pages 102- 186). The E/Z ratio indicated has been corrected. Regarding the E/Z configuration assignment, we have included a detailed explanation of the assignment method in the SI (see Section 3, page 8; and Section 12, pages 102-186). For most of the oxime products, E configuration is presumed to be the dominant isomer although caution has been raised (SI, page 8). As the reviewer pointed out, hydrogen bonding may influence the E/Z isomeric ratio of the oxime products. For example, product 100a, where the oxime hydroxyl group forms hydrogen bonds with the β-amine, is obtained as a single isomer. In contrast, product 113a, which exhibits no or weaker hydrogen bonding between the oxime hydroxyl group and the γ-amine, exists as a mixture of E and Z isomers (E/Z = 11:1). This difference likely stems from the influence of hydrogen bonding.\nF) “Some HRMS data are incorrect: 62a-5'-OH, 115a.”\nResponse:\nWe thank the reviewer for pointing this out and have corrected the HRMS data for 62a-5'-OH and 115a.\nG) “Some expressions are incorrect, such as p-ClPh, Php-Br in Fig 3. Ph represents C H . 99 kacl on page 2 should be 99 kcal.”\nResponse:\nWe thank the reviewer for pointing this out and have revised the main text.\nReviewer 3:\nA) “The authors claimed that their method offers a superior approach to oxime synthesis and reported an 81% yield for the oxime of cyclohexane. However, they do not address the issue of cyclohexanone formation as a side product. This is analogous to the conventional process, where cyclohexanone must be separated before oximation. If their method still results in a mixture of cyclohexanone and its oxime, then the fundamental inefficiency of requiring separation steps remains unaddressed.”\nResponse:\nWe thank the reviewer for the comments. There appears to be some misunderstanding, which might arise from our previous submission. Cyclohexanone is not a side product; it is the key intermediate from which oxime results. Our method differs from and advances the conventional process in the sense that oxime is produced from cyclohexane in a one-pot fashion, requiring no separation of the intermediate ketone! The method does not “results in a mixture of cyclohexanone and its oxime”; rather it affords pure oxime upon in-situ basification.\nIn our initial submission, we asserted, based on NMR analysis, that the formation of the cyclododecanone oxime 1a “occurs only after basification of the solution”. This assertation has now been proven wrong in the light of a series of new experiments. Our new investigation has shown that the oximation takes place while the ketone intermediate is being formed instead of post basification as posited in the previous submission. This has significant implications, as the resulting oxime is deactivated towards further C-H oxidation, thus contributing to enhanced chemoselectivity. Below is a summary of the results from the new experiments.\nI) A combined quantitative GC and NMR analysis showed that prior to basification, cyclododecanone reacts with hydroxylammonium sulfate, with ca 60% conversion to the oxime 1a under conditions like those employed for the oxidative oximation of cyclododecane 1 (see SI, Section 6.2, pages 37-40). Through the study, we realized that NMR cannot be reliably used to analyze the oxime salt due to decomposition resulting from sample preparation, nor can GC, due to the incompatible, high boiling point of the sample. To facilitate GC and NMR analysis, we turned attention to cyclohexane and derivatives, which are of lower boiling points and easier to analyze.\nII) By examining the oximation of cyclohexanone with hydroxylammonium sulfate without a base, we have shown that (1) oxime is almost instantly formed, (2) the oximation reaction is catalyzed by Lewis acid, such as Sc(OTf) and presumably by high valent manganese species generated from the oxidation of the catalyst with H O , and (3) the oxime salt is not detectable on GC (SI, Section 6.3, Table S-17, page 41).\nIII) By examining the hydrolysis of cyclohexanone oxime 3a, we can conclude that (1) oxime undergoes fast hydrolysis to ketone, (2) an equilibrium of the hydrolysis is established almost immediately after subjecting the oxime 3a to the reaction conditions, and (3) the hydrolysis is facilitated by both Bronsted and Lewis acid, with the later presumably generated by oxidation of the manganese to a higher oxidation state with H O (SI, Section 6.3, Tables S-18 and S-19, pages 43-46).\nIV) By following the time course of the oxidative oximation of cyclohexane with GC, we can conclude that the oxime is formed quickly in the oxidative oximation of cyclohexane and formed in a significant amount within half an hour in the oxidation (prior to basification) (SI, Section 6.3, Table S-20, pages 47-48).\nB) “A direct comparison of selectivity, separation requirements, and overall process efficiency would be necessary to justify the superiority of their approach. It seems that the primary role of the catalyst is to oxidize the alkanes to the corresponding carbonyl, while basification facilitates the release of free hydroxylamine, which subsequently forms the oxime. The authors have already shown that analogous manganese complexes bearing tetradentate amino ligands can catalyze the benzylic oxidation of alkyl arenes to aryl ketones with H2O2 (Angew. Chem. Int. Ed. 2022, 61, e202205983).”\nResponse:\nWe thank the reviewer for the comments. As mentioned above, the oxime is formed prior to basification and isolated in a one-pot fashion, involving no separation of the intermediate ketone, and notably, the oxime is much less reactive towards further oxidation compared with the corresponding ketone substrate (see SI, Section 6.4, pages 49-50). The oxime moiety is thus deactivating, contributing to a higher chemoselectivity in oxidative oximation than in ketonization. While the primary role of the catalyst is indeed to enable the oxidation of the alkanes to ketones, it also promotes the oximation of the ketone intermediate (vide supra). Our previous work (Angew. Chem. Int. Ed. 2022, 61, e202205983) is about the oxidation of benzylic C–H bonds to aryl ketones, whereas this work provides a general method to access oximes directly from abundant and cost-effective hydrocarbon feedstocks.\nC) “The role of the catalyst in this oximation step is not clear. SI, section 6.3, it is clear that the catalyst is not needed during the oximation step, or if there is any role, it is not mentioned. In fact, the role of the catalyst or the ligand is not clearly mentioned anywhere in the manuscript. While the study presents a potentially valuable oximation method, the lack of mechanistic depth, insufficient control experiments, and novelty make it unsuitable for publication in \"Nature Communication\" at this stage”\nResponse:\nWe thank the reviewer for the comments. As mentioned above, the primary role of the catalyst is to enable the oxidation of the alkanes to ketones. In addition, it also promotes the oximation of the ketone intermediate (vide supra). We have revised the main text accordingly. We acknowledge, however, that there is a lack of in-depth mechanistic investigation in the study. On the other hand, it is noted that (1) this study is primarily about a new synthetic methodology, (2) the mechanism of the oxidation of hydrocarbons to carbonyls by manganese complexes stabilized by analogous ligands under similar conditions has been widely documented (ACS Catal. 2018, 8, 4528-4538; Inorg. Chem. 2019, 58, 14842-14852; ACS Catal. 2023, 13, 6403-6414; Coord. Chem. Rev. 2019, 384, 126-139; Angew. Chem. Int. Ed. 2020, 59, 7332-7349), (3) we have conducted new experiments (vide supra), including experiments suggested by the Reviewer (vide infra), which shed light on the reaction pathway including some mechanistic aspects, (4) UV-vis measurements were taken (see SI, Section 6.13, pages 66-72), indicating that the oxidation of rac-1 with H O to higher oxidation states is accelerated by hydroxylammonium cation, but inhibited by free NH OH (for effect on catalysis, see SI, Section 6.7, page 52) and excess Cl-, PO 3- and to a smaller degree SO 2- (for effect on catalysis, see SI, Section 5, Table S-3, page 25). The results indicate possible coordination of the hydroxylammonium ion to manganese during oxidation, and (5) we have suggested a simplified mechanism for the current oxidative oximation in the SI (SI, Section 6.14, pages 72-73).\nD) “The influence of hydroxylammonium sulfate on oxidation should be further explored. Specifically, the effect of protonation on hydroxylamine reactivity and oxime coordination to the metal catalyst needs further elaboration.”\nResponse:\nWe thank the reviewer for the suggestion. Based on our control experiments, hydroxylammonium sulfate not only significantly influences the chemoselectivity of cyclododecane oxidation (Figure 2) but also markedly affects that of allylic methylene oxidation (see SI, Section 6.9, Page 55-57) and substrate 120 (see SI, Section 6.10, Page 58). Additionally, it alters the kinetic isotope effect in the reaction of cyclohexane vs cyclohexane-d₁₂ (see SI, Section 6.12, Page 59-66).\nHydroxylammonium sulfate may play a dual role in the oximation reaction:\nI) Interaction with the manganese catalyst to modulate the reaction pathway. Although the mechanistic details of this effect remain unclear, our UV-vis measurements (see SI, Section 6.13, pages 66-72) show that the oxidation of rac-1 with H O to higher oxidation states is accelerated by hydroxylammonium cation, but inhibited by free NH OH (for effect on catalysis, see SI, Section 6.7, page 52) and excess Cl-, PO 3- and to a smaller degree SO 2- (for effect on catalysis, see SI, Section 5, Table S-3, page 25). The results indicate possible coordination of the hydroxylammonium ion to manganese during oxidation (see SI, Section 6.14, pages 72-73, for a proposed mechanism, and also see response to Reviewer 3).\nII) Acting as an amine source to react with ketones, forming oximes and oxime salts that influence reaction selectivity. New experiments were conducted, which revealed that the oxime is quickly formed in the oxidation without basification (vide infra), and once formed, it becomes much less reactive towards further oxidation compared with the corresponding ketone substrate (SI, Section 6.4, pages 49-50). The oxime moiety is thus deactivating, contributing to a higher chemoselectivity in oxidative oximation than in ketonization.\nWe have previously shown that free hydroxylamine (pKa ~ 5.9), i.e. without H SO , did not afford any oxime in the oxidative oximation of cyclododecane (SI, Section 6.7, page 52), indicating the need for hydroxylamine protonation. The sulfuric acid protonates not only hydroxylamine but also the oxime product (protonated form pKa <1; Angew. Chem. Int. Ed. 2008, 47, 7523–7526) in the solvent used. As mentioned above, free hydroxylamine inhibits the oxidation of manganese catalyst with H O , presumably via coordination.\nE) “The role of acidic additives in influencing the reaction should be discussed. Why is a higher amount of acid required for challenging acyclic alkanes?”\nResponse:\nWe appreciate the reviewer’s insightful question regarding the role of carboxylic acids. Indeed, carboxylic acids are commonly employed as additives to enhance oxidation reaction rates (ACS Catal. 2020, 10, 8611-8631). The acids may function by assisting heterolytic scission of MO-OH bond to form high valent M=O species and stabilize it. In manganese-catalyzed oxidations, a higher acid loading has been shown to improve activity by stabilizing high- valent manganese intermediates, thereby facilitating the oxidation process (Adv. Synth. Catal. 2009, 351, 348-352). For more challenging acyclic alkanes, C–H bond oxidation is expected to be facilitated by high-valent metal–oxo species with sufficient reactivity and lifetime. And presumably, maintaining a higher steady-state concentration of such species can enhance catalytic efficiency. Furthermore, H O is more oxidizing under acidic conditions (Eo: 1.77 V vs SHE) than basic conditions (Eo: 0.87 V vs SHE). In addition, H O is less prone to decompose to O under acidic conditions.\nF) “The authors stated that \"Bypassing the intermediacy of ketones, oximation of the methylene C-H bonds in hydrocarbons via oxidation presents an ideal approach for the construction of oximes,\" However, their reaction proceeds via the intermediate carbonyl formation. The statement should be checked.”\nResponse:\nWe thank the reviewer for pointing this out and have revised the main text.\nG) “The authors stated that \"the PYBP ligands with electron-donating, bulky substituents tend to give a higher oxime yield, with the one bearing a 5,5’-triisopropylsilyl group being most effective.\" Why does a bulky ligand produce a more profound effect?”\nResponse:\nWe thank the reviewer for pointing this out and the question. The manganese catalyst incorporating 5,5'- triisopropylsilyl groups exhibits enhanced steric bulkiness and structural rigidity, which is expected to promote steric isolation of the metal center. This spatial protection could hinder or block catalyst degradation pathways involving, e.g. dimerization. (ACS Catal. 2020, 10, 8611−8631).\nH) “It seems that \"rac-C1\" exhibits higher compatibility with certain substrates, such as cycloalkanes, while \"rac- C2\" is more effective for others. Can the authors provide insights into the factors driving this reactivity difference? Specifically, does the ligand environment play a role in influencing substrate selectivity, and if so, how?”\nResponse:\nWe thank the reviewer for raising this important point and for the questions. As correctly noted by the reviewer, rac- C1 demonstrates higher compatibility for oxidizing non-activated C–H bonds. However, for the more active benzylic and allylic substrates, the catalyst led to overoxidation reactions, lowering chemoselectivity to desired oximes.\nI) “The manuscript does not provide a catalytic cycle or strong experimental evidence for key intermediates. Radical trapping experiments (e.g., TEMPO, BHT) should be conducted to confirm whether the reaction follows a radical or non-radical pathway. Kinetic isotope effect (KIE) studies should be performed to understand the rate-determining step. The role of the catalyst and the ligands should be mentioned.”\nResponse:\nWe thank the reviewer for the valuable suggestions. As recommended, we conducted a radical trapping experiment using TEMPO with substrate 1, and detected the TEMPO-trapped intermediate (see SI, Section 6.11, pages 58-59). This reaction thus likely involves radical species, which could diffuse to the solution before rebound occurs. Additionally, we performed both competitive and parallel experiments aimed to unearth possible kinetic isotope effect (KIE) using cyclohexane and deuterated cyclohexane-d , both in the presence and absence of hydroxylammonium sulfate. The estimated KIE values are: with hydroxylammonium sulfate: competitive KIE = 2.2, parallel KIE = 2.3; without hydroxylammonium sulfate: competitive KIE = 2.7, parallel KIE = 2.7. These moderate KIE values indicate that C-H bond cleavage may be involved in the rate limiting step of the catalysis, and the hydroxylammonium ion might participate in this step or a step prior to it. The results have been included in the updated SI (SI, Section 6.11, pages 59-66).\nRegarding the catalytic cycle and role of catalyst, please see the response above.\nJ) “SI, Section 6.8, How do the UV-vis measurements support the formation of (rac-L1)Mn(III) and/or (rac- L1)Mn(III)(μ-O)₂Mn(IV) species (65–68) upon mixing rac-1 with H₂O₂, and what role does hydroxylamine sulfate play in accelerating this oxidation process. Can they provide more substantial evidence, such as EPR, to support this claim?”\nResponse:\nWe thank the reviewer for pointing this out and the valuable suggestion. Our UV-Vis measurements show that in the presence of hydroxylammonium cation, the absorption of the manganese species in the region of >300 nm increases significantly upon addition of H O to a solution of rac-1 (See SI, Section 6.13, Figs 34-36, pages 67-68). By comparing with the literature data and conclusion [e.g. Fig 9 in Inorg. Chem. 2005, 44, 3669-3683 and Fig 7 in Inorg. Chim. Acta. 2023, 546, 121288], our results indicate that the oxidation of rac-1 with H O to higher oxidation states, e.g. (rac-L1)Mn(III) and/or (rac-L1 )Mn(III)(-O) Mn(IV)( (rac-L1 ), is accelerated by hydroxylammonium ion, but inhibited by NH OH, Cl-, SO 2- and PO 3- (See SI, Section 6.13, pages 66-72). As mentioned above, hydroxylammonium cation could coordinate to manganese, presumably via its hydroxy group, which could then affect the activation of H O and the reactivity of the resulting oxo species (see the proposed mechanism for a suggested possibility, SI, Section 6.14, pages 72-73). However, we cannot be sure which oxidation state(s) manganese is oxidized to, and unfortunately, we cannot provide EPR evidence either due to lack of expertise.\nK) “What is the oxidation state of the metal in the native complexes. Additional spectroscopic data (such as EPR/XPS) is required to confirm the oxidation state.”\nResponse:\nWe thank the reviewer for the question. The molecular structure of rac-C1 was determined by X-ray diffraction and is reported in the SI (Section 14, pages 187-194), which is fully consistent with a Mn(II). Following the reviewer’s request, we performed X-ray photoelectron spectroscopy (XPS) analysis, which again confirms the manganese to be in the +2 oxidation state (see SI, Section13, pages 187).\nL) “Why electron-withdrawing substituents deactivate the proximal C-H bond toward oxidation.”\nResponse:\nWe thank the reviewer for the question. This effect arises because EWGs reduce the electron density of the C-H bond, thereby hindering hydrogen abstraction by electrophilic metal-oxo species (Nat. Synth. 2022, 1, 682; Chem. Soc. Rev. 2022, 51, 2171.).\nM) “In SI, Section 6.1, the authors use both \"rac-C1\" and [Mn], possibly to designate the same catalytic system. It isn't very clear, given that they used other Mn-catalysts. For example, in Table S6, \"rac-C2\" is the chosen system, yet the corresponding scheme uses \"[Mn]\". It is difficult to follow which system is being used for a particular work. I would suggest considering replacing [Mn] with \"rac-C1\", \"rac-C2”…”\nResponse:\nWe thank the reviewer for pointing this out and the valuable suggestion, and we have revised the SI.\nN) “In SI, Section 6.2, eq. 1, \"NNR\" should be replaced with NMR”\nResponse:\nWe thank the reviewer for pointing this out and have revised the SI.\nWe thank all the reviewers for their supporting/constructive comments and have addressed the comment of Reviewer 2 (incorporated the comment in the SI, page 8: “Regardless, we can only confirm the isomer ratio, not the absolute E/Z configuration, for these products”).\nWe have also addressed all the editorial requests."}, {"round": 2, "reviewer_comments": {"reviewer_1": "The authors have made necessary improvements to the manuscript. I think the revised version is now acceptable for publication.", "reviewer_2": "Most of the issues raised in the previous review have been adequately addressed. However, regarding the E/Z isomerism characterization, the authors should clarify whether NOE or other spectroscopic methods were employed to unambiguously assign the configuration. If definitive structural determination is unattainable, this must be explicitly stated in the Supporting Information with a note that only the isomer ratio could be confirmed, not the absolute E/Z configuration. Providing incorrect structural assignments would mislead readers."}, "author_response": ""}]

Decision letter