Manganese Catalyzed Oximation of Hydrocarbons to Oximes

Manganese Catalyzed Oximation of Hydrocarbons to Oximes | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Physical Sciences - Article Manganese Catalyzed Oximation of Hydrocarbons to Oximes Jianliang Xiao, Menghui Song, Hong Li, Li Xie, Xiaoxin Zhang, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5773373/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 09 Jan, 2026 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version 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 a new approach that enables the direct 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 new avenues for oxime synthesis and is anticipated to have broad applications in the production of fine and commodity chemicals, bioactive molecules, and new materials. Physical sciences/Chemistry/Catalysis/Homogeneous catalysis Physical sciences/Chemistry/Organic chemistry/Synthetic chemistry methodology Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Full Text 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 paints 5 . 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 tons 6 . 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 processes 1 , 2 , 5 , 11 . Because carbonyls, such as ketones, can be synthesized from the more easily available, more economic, saturated hydrocarbons, direct oximation of the latter would make the synthesis of oximes more economic and greener. The major industrial process of 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 is 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 multistep 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 NH 3 and H 2 O 2 5,12 . More recently, synthesis of cyclohexanone oxime has been made possible via ammoximation with H 2 O 2 in-situ generated from H 2 and O 2 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-4). 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, directly generating oximes from primary petrochemicals instead of their derivatives (Fig. 1b) 14 – 18 . Furthermore, C-H bonds are ubiquitous in organic molecules. Selective oximation of such bonds would open a new, 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(sp 3 )–H bond that renders the reaction kinetically and thermodynamically difficult (e.g. BDE of H-CH(CH 3 ) 2 : 99 kacl/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 HNO 3 5,19 . Both processes rely on highly corrosive nitrosating reagents and are energy inefficient. Radical nitrosation of cycloalkanes with t BuONO via UV irradiation has also been reported, which gives a mixture of nitrosocycloalkanes and cycloalkanone oxime 20 . 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 direct oxidative oximation of a broad range of hydrocarbons with H 2 O 2 and (NH 2 OH) 2 •H 2 SO 4 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 biocompatible 21 , 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 direct oximation of hydrocarbons 16 , 21 – 23 . We have shown previously that manganese complexes bearing tetradentate amino ligands catalyze efficient benzylic oxidation of alkyl arenes to aryl ketones with H 2 O 2 , and if the alkyl chain bears a primary amino moiety, cyclic imines are generated via in-situ attack of the amine at the ketone 24 . 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 NH 2 OH and product oximes are known to coordinate to metals 2 and could thus easily deactivate a metal catalyst. In addition, oximes are difficult to be protonated at the nitrogen atom 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 H 2 O 2 and (NH 2 OH) 2 •H 2 SO 4 , 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 H 2 O 2 /substrate (SI, 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 6.5 ). 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-5). The formation of the oxime 1a was found to proceed via the intermediacy of cyclododecanone 1-one resulting from the oxidation of 1 with H 2 O 2 . Monitoring the reaction with NMR showed that 1-one was formed progressively, but neither protonated nor neutral oxime was detected. In fact, 1-one was isolated in 85% yield when basification was omitted (SI, Section 6.4 ). The formation of 1a occurs only after basification of the solution and the oximation of 1-one appears to be much faster than the formation of 1-one (SI, Section 6.3 ; Table S-14). This is not surprising, as the hydroxyamine is protonated (pKa 5.9) and not expected to attack the ketone 26 . Figure 2b shows the time course of the formation of 1a . Little multiple oxidation was 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 species 27 . However, the hydroxylammonium sulfate also plays a key role, as a mixture of polyketone products was generated in its absence with 1-one isolated in only 38% yield (Fig. 2c). Further studies revealed that it also exerts a significant effect on the chemo and site-selectivity in the oxidation of more complex molecules (see examples in SI, Sections 6.6–7.7 ). While the mechanism of the hydroxylammonium effect remains to be elucidated, clearly the ion suppresses the oxidation ability of the catalyst, as indicated by the disappearance rate of 1 ( c.f. Figure 2 b and 2c) as well as the further oxidation of 1-one . Our preliminary investigations show that the introduction of the salt affects the formation of high valent manganese-oxygen species from rac - C1 (SI, Section 6.8 ). 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 over oxidation 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-3, S-4 ) . 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 difference 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. S5) 28 – 31 . Larger scale oximation was also demonstrated, as seen with cyclododecane (Fig. 3a, also see SI, Sections 10 ). The ability to oximate these unfunctionalized alkanes is remarkable. Traditional methods in accessing such oximes, when starting from cheap hydrocarbon substrates, are usually multi-step reactions under harsh conditions (Figs. S-3, S-4). Functionalized cyclic alkanes were next examined (Fig. 3b). Good yields were generally obtained across the ring systems. For the 5 membered ring substrates, oxidation took place highly selectively at the remote methylene site. Regio-isomers were seen in substituted 6 and 7 membered ring compounds (for their separation, see SI, section 12 ). For the 7 membered, the δ C-H bond appears to be more prone to undergo oxidation, as would be expected based on the deceasing deactivating effect of the electron-withdrawing substituent 27 , 28 , 32 . For the 6 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 site 28 . 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 other 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 moiety 27 , 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 alcohols 27 . 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 effect 27 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 oxidation 27 , 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 SI, Table S-10). Similar effect has been noted before 27 – 29 . A theoretical study of n -dodecane bearing a terminal electron-withdrawing group (-NH 3 + ) shows that the positive charge on the methylene hydrogen atoms stops varying after the fifth carbon 36 . Comparing the yields of and selectivities to 30a and 46a indicates that the protonated oxime is more deactivating and hence more directing than a methyl ester. 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 stem from possible steric repulsion between the ligand and the approaching substrate during oxidation 28 . 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. Prompted by the utility of allylic oxidation in natural product synthesis 37 , 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 (SI, Table S-5). 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-7 ), 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. Oxmiation of benzylic substrates was also demonstrated (Fig. 4b). rac - C2 was again shown to be more productive than rac - C1 (SI, Table S-8). 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 and methyl groups did not cause competitive aromatic oxidation 40 , 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 analogues 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 challenging 42 , 43 . 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 directly and thus should be of value in the synthesis of nonnatural amino acid derivatives 3 , 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 ( E and Z mixture) 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 antimalaria drug artemisinin provides a further example. To date, late stage oxyfunctionalization of artemisinin has been limited to enzymatic 46 , 47 and iron catalysis 48 , 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 direct 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 H 2 O 2 and economic (NH 2 OH) 2 •H 2 SO 4 , 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 nonactivated 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. Declarations Acknowledgments: We gratefully acknowledge the financial support of the State Key Laboratory of Petroleum Molecular & Process Engineering, the Fundamental Research Funds for the National Natural Science Foundation of China (21971156), the Shaanxi Provincial Natural Science Foundation (2020JM267), the Fundamental Research Funds for the Central Universities (GK202307002), the start-up funds from Shaanxi Normal University, and the 111 project (B14041). We also thank Professor Zhaotie Liu and group for assistance in propane oxidation, Professor Heyong He and group for discussions, and Yan Zhang for assistance in managing peroxides. Author contributions : C.Q.L. and J.L.X. conceived and designed the project and wrote the manuscript. M.H.S. and H.L. conducted the experiments and analyzed the data. All authors contributed to the experiments and/or manuscript preparation. Competing interests : All authors declare no other competing financial interests. Data availability: All data are available in the main text or the supplementary materials. Crystallographic data are available from the Cambridge Crystallographic Data Centre (CCDC) with the following codes: rac -C1 (CCDC 2372363); meso -C1 (CCDC 2372362); rac -C2 (CCDC 2372364); E -22a-δ-oxime (CCDC 2372355); E - 65a (CCDC 2372353); 2 E , 4 E -119a (CCDC 2372356); E -120a (CCDC 2372360); Z -120b (CCDC 2372361) References Kölmel DK, Kool ET (2017) Oximes and hydrazones in bioconjugation: mechanism and catalysis. Chem Rev 117:10358–10376 Bolotin DS, Bokach NA, Demakova MY, Kukushkin V (2017) Y. Metal-involving synthesis and reactions of oximes. 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J Am Chem Soc 128:4598–4611 Guillemard L, Kaplaneris N, Ackermann L, Johansson MJ (2021) Late-stage C–H functionalization offers new opportunities in drug discovery. Nat Rev Chem 5:522–545 Zhan JX et al (2002) Microbial metabolism of artemisinin by mucor polymorphosporus and aspergillus niger. J Nat Prod 65:1693–1695 Zhang K et al (2012) Controlled oxidation of remote sp 3 C – H bonds in artemisinin via P450 catalysts with fine-tuned regio- and stereoselectivity. J Am Chem Soc 134:18695–18704 Chen MS, White MC (2007) A predictably selective aliphatic C–H oxidation reaction for complex molecule synthesis. Science 318, 783 – 787 Gormisky PE, White MC (2013) Catalyst-controlled aliphatic C – H oxidations with a predictive model for site-selectivity. J Am Chem Soc 135:14052–14055 Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryInformation.pdf Manganese Catalyzed Oximation of Hydrocarbons to Oximes Cite Share Download PDF Status: Published Journal Publication published 09 Jan, 2026 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5773373","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Physical Sciences - Article","associatedPublications":[],"authors":[{"id":406300603,"identity":"fcdccf64-54cd-4cd6-b78f-886a94a9a00d","order_by":0,"name":"Jianliang Xiao","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAt0lEQVRIiWNgGAWjYBACxgbGBgaGCgseKD+BWC1nJEjQAtHXJgFjEqGFeUZy44eP8yRkDA4wP/zA2JZGhAU9B5slZ26T4DE4wGYswdiWQ4SW9sYGaV6gFskGBjOgCyuI0NLM2Pybdw5IC/s3IrW0N7ZJ8zZI8PAz8IBsIcZhPQfbLGccA2ph5imWSDhHhPcNZ6Q/vvGhxsaejb1944cPZclEaGmAsZgZiIxIeWIUjYJRMApGwQgHAEOQMBANHlbvAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0003-2010-247X","institution":"University of Liverpool","correspondingAuthor":true,"prefix":"","firstName":"Jianliang","middleName":"","lastName":"Xiao","suffix":""},{"id":406300604,"identity":"2bd1006c-b9c8-4249-a209-1c9d576f5bc4","order_by":1,"name":"Menghui Song","email":"","orcid":"","institution":"Shaanxi Normal University","correspondingAuthor":false,"prefix":"","firstName":"Menghui","middleName":"","lastName":"Song","suffix":""},{"id":406300605,"identity":"f4b2e0b0-8281-4181-8e37-6fe0d23beef3","order_by":2,"name":"Hong Li","email":"","orcid":"","institution":"Shaanxi Normal University","correspondingAuthor":false,"prefix":"","firstName":"Hong","middleName":"","lastName":"Li","suffix":""},{"id":406300606,"identity":"65248d03-97f1-4c5a-8d07-3e86b845fe1a","order_by":3,"name":"Li Xie","email":"","orcid":"","institution":"Sinopec Research Institute of Petroleum Processing","correspondingAuthor":false,"prefix":"","firstName":"Li","middleName":"","lastName":"Xie","suffix":""},{"id":406300607,"identity":"9310af7a-33fd-41f3-85ee-3a28c9ee52fd","order_by":4,"name":"Xiaoxin Zhang","email":"","orcid":"","institution":"Sinopec Research Institute of Petroleum Processing","correspondingAuthor":false,"prefix":"","firstName":"Xiaoxin","middleName":"","lastName":"Zhang","suffix":""},{"id":406300608,"identity":"1bef1843-4a25-498c-860c-62755a1f0ec2","order_by":5,"name":"Xiaotian Weilian","email":"","orcid":"","institution":"Shaanxi Normal University","correspondingAuthor":false,"prefix":"","firstName":"Xiaotian","middleName":"","lastName":"Weilian","suffix":""},{"id":406300609,"identity":"4ef14ae3-5e0a-4197-9b2e-30703414aa37","order_by":6,"name":"Rucao Wang","email":"","orcid":"","institution":"Shaanxi Normal University","correspondingAuthor":false,"prefix":"","firstName":"Rucao","middleName":"","lastName":"Wang","suffix":""},{"id":406300610,"identity":"5d2fbd7b-b893-40a5-a572-4b9505f87a79","order_by":7,"name":"Alexander Steiner","email":"","orcid":"","institution":"University of Liverpool","correspondingAuthor":false,"prefix":"","firstName":"Alexander","middleName":"","lastName":"Steiner","suffix":""},{"id":406300611,"identity":"c7e7a743-6964-4781-8d18-5aaa8564e62a","order_by":8,"name":"Huaming Sun","email":"","orcid":"","institution":"Shaanxi Normal University","correspondingAuthor":false,"prefix":"","firstName":"Huaming","middleName":"","lastName":"Sun","suffix":""},{"id":406300612,"identity":"953602af-6a80-4d9d-a367-05bf13823622","order_by":9,"name":"Chao Wang","email":"","orcid":"https://orcid.org/0000-0003-4812-6000","institution":"Shaanxi Normal University","correspondingAuthor":false,"prefix":"","firstName":"Chao","middleName":"","lastName":"Wang","suffix":""},{"id":406300613,"identity":"232da272-0e3d-4146-a49e-3b5123051d34","order_by":10,"name":"Chaoqun Li","email":"","orcid":"","institution":"University of South Florida","correspondingAuthor":false,"prefix":"","firstName":"Chaoqun","middleName":"","lastName":"Li","suffix":""}],"badges":[],"createdAt":"2025-01-06 11:30:24","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5773373/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5773373/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41467-025-66576-0","type":"published","date":"2026-01-09T05:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":77204234,"identity":"196e0f07-2587-46ba-803f-f01c7fbf42c1","added_by":"auto","created_at":"2025-02-26 08:05:07","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":351721,"visible":true,"origin":"","legend":"\u003cp\u003eExamples of industrial oxime products and their synthesis with established and new methods. \u003cstrong\u003ea\u003c/strong\u003e. Examples of oximes found in fine and commodity chemicals and drug molecules. \u003cstrong\u003eb\u003c/strong\u003e. Common methods for oxime synthesis (FG can be a functional or nonfunctional group) and industrial routes for cyclohexanone and 2-pentanone oximes. The green line highlights a desired approach. \u003cstrong\u003ec\u003c/strong\u003e. The new route reported in this paper.\u003c/p\u003e","description":"","filename":"image1.png","url":"https://assets-eu.researchsquare.com/files/rs-5773373/v1/8db77ed54750777c3026a4f8.png"},{"id":77204236,"identity":"16024f26-e843-4a09-8591-50706c2f2caa","added_by":"auto","created_at":"2025-02-26 08:05:07","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":518378,"visible":true,"origin":"","legend":"\u003cp\u003eOximation of cyclododecane \u003cstrong\u003e1\u003c/strong\u003e via oxidation with H\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e under manganese catalysis. (a) Effect of catalysts on the oximation. Reaction conditions: \u003cstrong\u003e1\u003c/strong\u003e (0.5 mmol), catalyst (1 mol%), (NH\u003csub\u003e2\u003c/sub\u003eOH)\u003csub\u003e2\u003c/sub\u003e•H\u003csub\u003e2\u003c/sub\u003eSO\u003csub\u003e4 \u003c/sub\u003e(1.0 mmol) and AcOH (0.6 mL) dissolved in \u003csup\u003e\u003cem\u003et\u003c/em\u003e\u003c/sup\u003eBuOH (1.0 mL), and then H\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e (2.5 mmol) in 1.0 mL of \u003csup\u003e\u003cem\u003et\u003c/em\u003e\u003c/sup\u003eBuOH introduced with a syringe pump over 1 h under stirring at 0 \u003csup\u003eo\u003c/sup\u003eC. After an additional 0.5 h, the solution was quenched with Na\u003csub\u003e2\u003c/sub\u003eSO\u003csub\u003e3\u0026nbsp;\u003c/sub\u003eand then basified with Na\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e for 0.5 h at 0\u0026nbsp;\u003csup\u003eo\u003c/sup\u003eC. (b) Time course of the formation of oxime \u003cstrong\u003e1a\u003c/strong\u003e under conditions given. (c) Time course of the formation of ketone \u003cstrong\u003e1-one\u003c/strong\u003e under conditions given. The yield of polyketone products is calculated from the yield of \u003cstrong\u003e1-one\u003c/strong\u003e and remaining \u003cstrong\u003e1\u003c/strong\u003e.\u0026nbsp;\u0026nbsp;\u003c/p\u003e","description":"","filename":"image2.png","url":"https://assets-eu.researchsquare.com/files/rs-5773373/v1/2dbb1ca48d984e99a5c396bb.png"},{"id":77205574,"identity":"0ef6d630-6d35-43e4-9dd5-d15ae82616d2","added_by":"auto","created_at":"2025-02-26 08:13:08","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":492833,"visible":true,"origin":"","legend":"\u003cp\u003eOximation of unactivated hydrocarbons with \u003cem\u003erac\u003c/em\u003e-\u003cstrong\u003eC1\u003c/strong\u003e. General reaction conditions: substrate (1.0 mmol), \u003cem\u003erac\u003c/em\u003e-\u003cstrong\u003eC1\u003c/strong\u003e (1 mol%), (NH\u003csub\u003e2\u003c/sub\u003eOH)\u003csub\u003e2\u003c/sub\u003e•H\u003csub\u003e2\u003c/sub\u003eSO\u003csub\u003e4 \u003c/sub\u003e(2.0 mmol) and AcOH (2.8 mL) dissolved in \u003csup\u003e\u003cem\u003et\u003c/em\u003e\u003c/sup\u003eBuOH (2.0 mL), and then H\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e (5.0 mmol) in 2 mL of \u003csup\u003e\u003cem\u003et\u003c/em\u003e\u003c/sup\u003eBuOH introduced with a syringe pump over 1 h under stirring at 0 \u003csup\u003eo\u003c/sup\u003eC. After stirring for an additional 0.5 h, the solution was quenched with Na\u003csub\u003e2\u003c/sub\u003eSO\u003csub\u003e3\u0026nbsp;\u003c/sub\u003eand then basified with Na\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e for 0.5 h at 0\u0026nbsp;\u003csup\u003eo\u003c/sup\u003eC. Isolated yield reported (GC yield in parentheses).\u003csup\u003e\u003cem\u003e a\u003c/em\u003e\u003c/sup\u003e\u003csup\u003e \u003c/sup\u003eAcOH (1.2 mL). \u003csup\u003e\u003cem\u003eb\u003c/em\u003e\u003c/sup\u003e 10 mmol scale affording 1.64 g of \u003cstrong\u003e1a\u003c/strong\u003e, 83% isolated yield. \u003csup\u003e\u003cem\u003ec\u003c/em\u003e\u003c/sup\u003e Yields based on hydroxyamine sulfate; hydrocarbon in excess.\u003c/p\u003e","description":"","filename":"image3.png","url":"https://assets-eu.researchsquare.com/files/rs-5773373/v1/9b67942e6d7d85dc12096b7a.png"},{"id":77205572,"identity":"8b1c2c6f-8cfa-481d-ab23-ee0b03733044","added_by":"auto","created_at":"2025-02-26 08:13:07","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":498863,"visible":true,"origin":"","legend":"\u003cp\u003eOximation of activated hydrocarbons with \u003cem\u003erac\u003c/em\u003e-\u003cstrong\u003eC2\u003c/strong\u003e. \u003cstrong\u003ea\u003c/strong\u003e) Conditions: substrate (1.0 mmol), \u003cem\u003erac\u003c/em\u003e-\u003cstrong\u003eC2\u003c/strong\u003e (1 mol%), (NH\u003csub\u003e2\u003c/sub\u003eOH)\u003csub\u003e2\u003c/sub\u003e•H\u003csub\u003e2\u003c/sub\u003eSO\u003csub\u003e4 \u003c/sub\u003e(2.0 mmol) and AcOH (2.0 mL) dissolved in \u003csup\u003e\u003cem\u003et\u003c/em\u003e\u003c/sup\u003eBuOH (2.0 mL), and then H\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e (5.0 mmol) in 2 mL of \u003csup\u003e\u003cem\u003et\u003c/em\u003e\u003c/sup\u003eBuOH introduced with a syringe pump over 1 h under stirring at 0 \u003csup\u003eo\u003c/sup\u003eC;\u003cstrong\u003e b\u003c/strong\u003e) conditions: substrate (0.5 mmol), \u003cem\u003erac\u003c/em\u003e-\u003cstrong\u003eC2\u003c/strong\u003e (2 mol%), (NH\u003csub\u003e2\u003c/sub\u003eOH)\u003csub\u003e2\u003c/sub\u003e•H\u003csub\u003e2\u003c/sub\u003eSO\u003csub\u003e4 \u003c/sub\u003e(1.5 mmol) and AcOH (0.6 mL) dissolved in \u003csup\u003e\u003cem\u003et\u003c/em\u003e\u003c/sup\u003eBuOH (1.0 mL), and then H\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e (2.5 mmol) in 0.5 mL of \u003csup\u003e\u003cem\u003et\u003c/em\u003e\u003c/sup\u003eBuOH introduced similarly to \u003cstrong\u003ea\u003c/strong\u003e. In both cases, after stirring for an additional 0.5 h, the solution was quenched with Na\u003csub\u003e2\u003c/sub\u003eSO\u003csub\u003e3\u0026nbsp;\u003c/sub\u003eand then basified with Na\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e for 0.5 h at 0\u0026nbsp;\u003csup\u003eo\u003c/sup\u003eC (\u003cstrong\u003ea\u003c/strong\u003e) or 50\u0026nbsp;\u003csup\u003eo\u003c/sup\u003eC (\u003cstrong\u003eb\u003c/strong\u003e). Isolated yields reported.\u003c/p\u003e","description":"","filename":"image4.png","url":"https://assets-eu.researchsquare.com/files/rs-5773373/v1/4183979eb200349a5803128f.png"},{"id":77204239,"identity":"980eede0-d5ca-4c24-a7dc-94b82cf49015","added_by":"auto","created_at":"2025-02-26 08:05:08","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":585838,"visible":true,"origin":"","legend":"\u003cp\u003eOximation of amino acid derivatives and drug/natural products. General conditions: for substrates \u003cstrong\u003e101\u003c/strong\u003e-\u003cstrong\u003e112\u003c/strong\u003e, Fig. 3 conditions used; for \u003cstrong\u003e113-114\u003c/strong\u003e, Fig. 4b conditions used; for \u003cstrong\u003e115\u003c/strong\u003e-\u003cstrong\u003e119\u003c/strong\u003e, Fig. 4a conditions used. Isolated yield reported. \u003csup\u003e\u003cem\u003ea\u003c/em\u003e\u003c/sup\u003e Substrate was recycled twice.\u003c/p\u003e","description":"","filename":"image5.png","url":"https://assets-eu.researchsquare.com/files/rs-5773373/v1/da3c8d3fbf3288354b935ad8.png"},{"id":99935280,"identity":"766e62b2-5109-4c31-8e98-626b3bf24154","added_by":"auto","created_at":"2026-01-10 08:09:53","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3264848,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5773373/v1/1cd3ae1b-4ea5-4c3a-aa26-58f01ae777d1.pdf"},{"id":77204240,"identity":"f96efeae-4bca-4dfe-84fa-93ba6bba1575","added_by":"auto","created_at":"2025-02-26 08:05:08","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":19869020,"visible":true,"origin":"","legend":"Manganese Catalyzed Oximation of Hydrocarbons to Oximes","description":"","filename":"SupplementaryInformation.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5773373/v1/c4a9ff7ae8bda812ffa0def9.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Manganese Catalyzed Oximation of Hydrocarbons to Oximes","fulltext":[{"header":"Full Text","content":"\u003cp\u003eOximes 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 \u0026ldquo;chameleons\u0026rdquo; in plant metabolism (Fig.\u0026nbsp;1a; also see Figs. S-1 and S-2)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. The largest industrial application of oximes is in the manufacturing of nylon-6, nylon-12, and anti-skinning agents in paints\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. In 2024, the global production capacity for nylon-6 is expected to exceed 8.8\u0026nbsp;million metric tons while that for nylon-12 has reached hundred thousand tons\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eOximes 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.\u0026nbsp;1b)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. The vast majority of oximes are synthesized by oximation of carbonyl compounds with hydroxylamine, and this is particularly the case in large scale industrial processes\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Because carbonyls, such as ketones, can be synthesized from the more easily available, more economic, saturated hydrocarbons, direct oximation of the latter would make the synthesis of oximes more economic and greener. The major industrial process of synthesis of nylon-6 is illustrative (Fig.\u0026nbsp;1b)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. 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\u0026ndash;85%. To avoid overoxidation, the conversion is kept low, at 10\u0026ndash;12%; thus large recycles of unreacted cyclohexane is 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 multistep process is inefficient and highly energy intensive. In recent years, great progress has been made in improving the process \u0026ndash; globally \u003cem\u003eca\u003c/em\u003e. 50% of the cyclohexanone oxime is now being synthesized by a new process involving ammoximation of cyclohexanone with NH\u003csub\u003e3\u003c/sub\u003e and H\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e\u003csup\u003e5,12\u003c/sup\u003e. More recently, synthesis of cyclohexanone oxime has been made possible via ammoximation with H\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e in-situ generated from H\u003csub\u003e2\u003c/sub\u003e and O\u003csub\u003e2\u003c/sub\u003e\u003csup\u003e13\u003c/sup\u003e. 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.\u0026nbsp;1b). The process comprises again a series of reactions, starting with expensive 1,3-pentadiene (Fig. S-4).\u003c/p\u003e\n\u003cp\u003eBypassing the intermediacy of ketones, oximation of the methylene C-H bonds in hydrocarbons via oxidation presents an ideal approach for the construction of oximes, directly generating oximes from primary petrochemicals instead of their derivatives (Fig.\u0026nbsp;1b)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. Furthermore, C-H bonds are ubiquitous in organic molecules. Selective oximation of such bonds would open a new, 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(sp\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e)\u0026ndash;H bond that renders the reaction kinetically and thermodynamically difficult (e.g. BDE of H-CH(CH\u003csub\u003e3\u003c/sub\u003e)\u003csub\u003e2\u003c/sub\u003e: 99 kacl/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\u0026ndash;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 HNO\u003csub\u003e3\u003c/sub\u003e\u003csup\u003e5,19\u003c/sup\u003e. Both processes rely on highly corrosive nitrosating reagents and are energy inefficient. Radical nitrosation of cycloalkanes with \u003csup\u003e\u003cem\u003et\u003c/em\u003e\u003c/sup\u003eBuONO via UV irradiation has also been reported, which gives a mixture of nitrosocycloalkanes and cycloalkanone oxime\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. 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.\u003c/p\u003e\n\u003cp\u003eHerein, we report a manganese catalyst-centered protocol that enables the direct oxidative oximation of a broad range of hydrocarbons with H\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e and (NH\u003csub\u003e2\u003c/sub\u003eOH)\u003csub\u003e2\u003c/sub\u003e\u0026bull;H\u003csub\u003e2\u003c/sub\u003eSO\u003csub\u003e4\u003c/sub\u003e under mild conditions, affording various acyclic and cyclic ketone oximes including the lactam precursors for nylons 5, 6 and 12 (Fig.\u0026nbsp;1c). Adding to the advantage of a one-pot reaction, manganese is one of the most abundant base metals, of low toxicity and biocompatible\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. 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 direct oximation of hydrocarbons\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eWe have shown previously that manganese complexes bearing tetradentate amino ligands catalyze efficient benzylic oxidation of alkyl arenes to aryl ketones with H\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e, and if the alkyl chain bears a primary amino moiety, cyclic imines are generated via in-situ attack of the amine at the ketone\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. 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 NH\u003csub\u003e2\u003c/sub\u003eOH and product oximes are known to coordinate to metals\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e and could thus easily deactivate a metal catalyst. In addition, oximes are difficult to be protonated at the nitrogen atom\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e; 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.\u0026nbsp;2). We started by examining the oxidative oximation of cyclododecane \u003cstrong\u003e1\u003c/strong\u003e with H\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e and (NH\u003csub\u003e2\u003c/sub\u003eOH)\u003csub\u003e2\u003c/sub\u003e\u0026bull;H\u003csub\u003e2\u003c/sub\u003eSO\u003csub\u003e4\u003c/sub\u003e, 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 \u003cem\u003erac\u003c/em\u003e-\u003cstrong\u003eC1\u003c/strong\u003e, i.e. \u003cstrong\u003eC1\u003c/strong\u003e containing a racemic pyridine-bipiperidine ligand (PYBP), catalyzes the efficient oxidative oximation of cyclododecane under the conditions shown (Fig.\u0026nbsp;2a). The yield of the oxime product \u003cstrong\u003e1a\u003c/strong\u003e was found to be influenced by a variety of parameters, including catalyst, solvent, amount of acidic additive and the ratio of H\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e/substrate (SI, 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\u0026rsquo;-triisopropylsilyl group being most effective (\u003cem\u003erac\u003c/em\u003e-\u003cstrong\u003eC1\u003c/strong\u003e) (Fig.\u0026nbsp;2a). Of note is that the \u003cem\u003emeso\u003c/em\u003e-\u003cstrong\u003eC2\u003c/strong\u003e and \u003cem\u003emeso\u003c/em\u003e-\u003cstrong\u003eC3\u003c/strong\u003e complexes showed little activity while \u003cem\u003emeso\u003c/em\u003e-\u003cstrong\u003eC1\u003c/strong\u003e compares well with \u003cem\u003erac\u003c/em\u003e-\u003cstrong\u003eC1\u003c/strong\u003e. 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 \u003cstrong\u003e6.5\u003c/strong\u003e). Under the conditions established, the cyclododecanone oxime \u003cstrong\u003e1a\u003c/strong\u003e was obtained in an isolated yield of 91%. Compared with the related ketonization reactions, the yield of \u003cstrong\u003e1a\u003c/strong\u003e is higher (Fig. S-5).\u003c/p\u003e\n\u003cp\u003eThe formation of the oxime \u003cstrong\u003e1a\u003c/strong\u003e was found to proceed via the intermediacy of cyclododecanone \u003cstrong\u003e1-one\u003c/strong\u003e resulting from the oxidation of \u003cstrong\u003e1\u003c/strong\u003e with H\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e. Monitoring the reaction with NMR showed that \u003cstrong\u003e1-one\u003c/strong\u003e was formed progressively, but neither protonated nor neutral oxime was detected. In fact, \u003cstrong\u003e1-one\u003c/strong\u003e was isolated in 85% yield when basification was omitted (SI, Section \u003cstrong\u003e6.4\u003c/strong\u003e). The formation of \u003cstrong\u003e1a\u003c/strong\u003e occurs only after basification of the solution and the oximation of \u003cstrong\u003e1-one\u003c/strong\u003e appears to be much faster than the formation of \u003cstrong\u003e1-one\u003c/strong\u003e (SI, Section \u003cstrong\u003e6.3\u003c/strong\u003e; Table S-14). This is not surprising, as the hydroxyamine is protonated (pKa 5.9) and not expected to attack the ketone\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. Figure\u0026nbsp;2b shows the time course of the formation of \u003cstrong\u003e1a\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eLittle multiple oxidation was 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)\u0026thinsp;=\u0026thinsp;O species\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. However, the hydroxylammonium sulfate also plays a key role, as a mixture of polyketone products was generated in its absence with \u003cstrong\u003e1-one\u003c/strong\u003e isolated in only 38% yield (Fig.\u0026nbsp;2c). Further studies revealed that it also exerts a significant effect on the chemo and site-selectivity in the oxidation of more complex molecules (see examples in SI, Sections \u003cstrong\u003e6.6\u0026ndash;7.7\u003c/strong\u003e). While the mechanism of the hydroxylammonium effect remains to be elucidated, clearly the ion suppresses the oxidation ability of the catalyst, as indicated by the disappearance rate of \u003cstrong\u003e1\u003c/strong\u003e (\u003cem\u003ec.f. Figure\u0026nbsp;2\u003c/em\u003eb and 2c) as well as the further oxidation of \u003cstrong\u003e1-one\u003c/strong\u003e. Our preliminary investigations show that the introduction of the salt affects the formation of high valent manganese-oxygen species from \u003cem\u003erac\u003c/em\u003e-\u003cstrong\u003eC1\u003c/strong\u003e (SI, Section \u003cstrong\u003e6.8\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eUnder the optimized conditions, a range of nonfunctionalized cyclic and acyclic alkanes have been converted to the corresponding ketone oximes (1.0 mmol scale, Fig.\u0026nbsp;3a). Cyclic oximes ranging from cyclopentanone to cyclododecanone oximes were obtained in high yields with little over oxidation 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 \u003cstrong\u003e7\u003c/strong\u003e 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-3, S-4\u003cstrong\u003e)\u003c/strong\u003e. 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. \u003cstrong\u003e11a\u003c/strong\u003e and \u003cstrong\u003e12a\u003c/strong\u003e, regio-isomers (all mono-oxime products) were formed because of diminishing steric and electronic difference between the methylene units. However, oximation of the terminal methylene units remained dominating (see SI for more examples), and the regioselectivity of \u003cstrong\u003erac\u003c/strong\u003e\u003cstrong\u003e-C1\u003c/strong\u003e in oxidizing \u003cstrong\u003e11\u003c/strong\u003e and \u003cstrong\u003e12\u003c/strong\u003e is generally higher than that of other catalysts in related ketonization reactions (Fig. S5)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. Larger scale oximation was also demonstrated, as seen with cyclododecane (Fig.\u0026nbsp;3a, also see SI, Sections \u003cstrong\u003e10\u003c/strong\u003e). The ability to oximate these unfunctionalized alkanes is remarkable. Traditional methods in accessing such oximes, when starting from cheap hydrocarbon substrates, are usually multi-step reactions under harsh conditions (Figs. S-3, S-4).\u003c/p\u003e\n\u003cp\u003eFunctionalized cyclic alkanes were next examined (Fig.\u0026nbsp;3b). Good yields were generally obtained across the ring systems. For the 5 membered ring substrates, oxidation took place highly selectively at the remote methylene site. Regio-isomers were seen in substituted 6 and 7 membered ring compounds (for their separation, see SI, section \u003cstrong\u003e12\u003c/strong\u003e). For the 7 membered, the \u0026delta; C-H bond appears to be more prone to undergo oxidation, as would be expected based on the deceasing deactivating effect of the electron-withdrawing substituent\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. For the 6 membered, the \u0026gamma; 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 site\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. An exception is seen in the acetate substituted \u003cstrong\u003e16a\u003c/strong\u003e, where the \u0026gamma; site is less favored. This may be due to a higher axial population of the acetate group (\u0026Delta;G\u003csub\u003eeq/ax\u003c/sub\u003e = 0.8 kcal/mol at 193 K)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e than other substituents, which disfavors \u0026gamma; oxidation because of increased steric clash with the catalyst. In both cases, the yields of the phthalimide derivatives are significantly lower (\u003cstrong\u003e19a\u003c/strong\u003e, \u003cstrong\u003e22a\u003c/strong\u003e), reflecting the strong deactivating role of the phthalimide moiety\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. The norbornane \u003cstrong\u003e24\u003c/strong\u003e only afforded the \u0026delta; oxime \u003cstrong\u003e24a\u003c/strong\u003e 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 alcohols\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. Note that all the oximes exist in \u003cem\u003eE\u003c/em\u003e and \u003cem\u003eZ\u003c/em\u003e forms except for those having plane symmetry (ignoring the hydroxy unit).\u003c/p\u003e\n\u003cp\u003eAcyclic alkanes bearing various functionalities were also oximated (Fig.\u0026nbsp;3b). Particularly notable is the oximation of pyridine, amine and oxime-bearing alkanes (\u003cstrong\u003e35a\u003c/strong\u003e, \u003cstrong\u003e36a\u003c/strong\u003e, \u003cstrong\u003e38a-40a\u003c/strong\u003e, \u003cstrong\u003e43a\u003c/strong\u003e, \u003cstrong\u003e46a\u003c/strong\u003e), 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 effect\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e 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 \u003cstrong\u003e26a\u0026rsquo;\u003c/strong\u003e, 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 oxidation\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. Thus, when the most remote methylene unit is less than 3\u0026ndash;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. \u003cstrong\u003e27a\u003c/strong\u003e vs \u003cstrong\u003e30a\u003c/strong\u003e, \u003cstrong\u003e41a\u003c/strong\u003e vs \u003cstrong\u003e47a\u003c/strong\u003e. Also see SI, Table S-10). Similar effect has been noted before\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. A theoretical study of \u003cem\u003en\u003c/em\u003e-dodecane bearing a terminal electron-withdrawing group (-NH\u003csub\u003e3\u003c/sub\u003e\u003csup\u003e+\u003c/sup\u003e) shows that the positive charge on the methylene hydrogen atoms stops varying after the fifth carbon\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e. Comparing the yields of and selectivities to \u003cstrong\u003e30a\u003c/strong\u003e and \u003cstrong\u003e46a\u003c/strong\u003e indicates that the protonated oxime is more deactivating and hence more directing than a methyl ester. 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 (\u003cem\u003ec.f.\u003c/em\u003e \u003cstrong\u003e27a\u003c/strong\u003e vs \u003cstrong\u003e28a\u003c/strong\u003e, \u003cstrong\u003e30a\u003c/strong\u003e vs \u003cstrong\u003e31a\u003c/strong\u003e and \u003cstrong\u003e32a\u003c/strong\u003e). This likely stem from possible steric repulsion between the ligand and the approaching substrate during oxidation\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. 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.\u003c/p\u003e\n\u003cp\u003ePrompted by the utility of allylic oxidation in natural product synthesis\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e37\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e, we next attempted the oximation of allylic substrates. For this transformation involving activated methylene C-H bonds, the sterically less demanding \u003cem\u003erac\u003c/em\u003e-\u003cstrong\u003eC2\u003c/strong\u003e was shown to be more productive, probably partly due to the substates being more rigid (SI, Table S-5). As shown in Fig.\u0026nbsp;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)\u003csup\u003e39\u003c/sup\u003e. Thus, no site selectivity issue was noted in forming \u003cstrong\u003e49a-51a\u003c/strong\u003e. When there are methylene units three carbons remote from the allylic position, oxidation of these units was observed (\u003cstrong\u003e52a-54a\u003c/strong\u003e). However, allylic oxidation remained dominating. Epoxidation was noted as a minor reaction in some cases (SI, Table \u003cstrong\u003eS-7\u003c/strong\u003e), and surprisingly, on going from \u003cstrong\u003e64\u003c/strong\u003e to \u003cstrong\u003e64a\u003c/strong\u003e, the olefin unit was also epoxidized, albeit in a low yield probably due to the product being less stable (\u0026lt;\u0026thinsp;5% of \u003cstrong\u003e64\u003c/strong\u003e recovered). As with alkane oximation (Fig.\u0026nbsp;3), sterically demanding and strong electron-withdrawing substituents lower the product yield (e.g. \u003cstrong\u003e49a\u003c/strong\u003e vs \u003cstrong\u003e55a\u003c/strong\u003e, \u003cstrong\u003e50a\u003c/strong\u003e vs \u003cstrong\u003e56a\u003c/strong\u003e, and \u003cstrong\u003e59a\u003c/strong\u003e vs \u003cstrong\u003e61a\u003c/strong\u003e). Partial oxidation of a tertiary C-H bond to a hydroxy moiety was noted in addition to allylic oximation (\u003cstrong\u003e62a-4\u0026rsquo;-OH\u003c/strong\u003e). Acrylamides are also feasible (\u003cstrong\u003e66\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e68\u003c/strong\u003e). However, the oxidation of the primary amide \u003cstrong\u003e66\u003c/strong\u003e afforded an epoxide \u003cstrong\u003e66b\u003c/strong\u003e as the main product (\u003cstrong\u003e66b\u003c/strong\u003e, 34% yield; SI, Section \u003cstrong\u003e12\u003c/strong\u003e), and in the case of \u003cstrong\u003e67\u003c/strong\u003e, oxidative dealkylation to give \u003cstrong\u003e66a\u003c/strong\u003e was also observed. Notably, although highly strained, the cyclopropyl moiety in \u003cstrong\u003e68\u003c/strong\u003e survived. We also examined a propargylic substate \u003cstrong\u003e69\u003c/strong\u003e, which was oximated in a low yield of 21%, mainly due to product instability.\u003c/p\u003e\n\u003cp\u003eOxmiation of benzylic substrates was also demonstrated (Fig.\u0026nbsp;4b). \u003cem\u003erac\u003c/em\u003e-\u003cstrong\u003eC2\u003c/strong\u003e was again shown to be more productive than \u003cem\u003erac\u003c/em\u003e-\u003cstrong\u003eC1\u003c/strong\u003e (SI, Table S-8). 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 \u003cem\u003epara\u003c/em\u003e-substituents, such as nitro and chloride, on the aryl rings pose little effect on the oxime yield, while the electron-donating methoxy and methyl groups did not cause competitive aromatic oxidation\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e40\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e. Also notable is the exclusive benzylic site selectivity, regardless of the presence of other methylene units (e.g. \u003cstrong\u003e81a\u003c/strong\u003e, \u003cstrong\u003e82a\u003c/strong\u003e, \u003cstrong\u003e94a\u003c/strong\u003e). Whilst the pyridine oximes \u003cstrong\u003e95a\u003c/strong\u003e and \u003cstrong\u003e96a\u003c/strong\u003e were obtained in low yields, possibly due to deactivation caused by the nitrogen being protonated, the pyridine-fused analogues \u003cstrong\u003e97a\u003c/strong\u003e and \u003cstrong\u003e98a\u003c/strong\u003e 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 \u003cem\u003eortho\u003c/em\u003e or \u003cem\u003epara\u003c/em\u003e position due to the resonance effect (\u003cstrong\u003e95a\u003c/strong\u003e, \u003cstrong\u003e99a\u003c/strong\u003e). Encouragingly, a chiral 3-amino benzyl oxime \u003cstrong\u003e100a\u003c/strong\u003e 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 challenging\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e42\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eTo 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.\u0026nbsp;5). As shown in Fig.\u0026nbsp;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 (\u003cem\u003ec.f\u003c/em\u003e. \u003cstrong\u003e101a\u003c/strong\u003e and \u003cstrong\u003e102a\u003c/strong\u003e). The low yield of \u003cstrong\u003e101a\u003c/strong\u003e 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. \u003cstrong\u003e103a\u003c/strong\u003e, due to the decreased deactivating effect of the functionality. In contrast with \u003cstrong\u003e111\u003c/strong\u003e, the racemic amino acid derivative \u003cstrong\u003e112\u003c/strong\u003e was oximated to \u003cstrong\u003e112a\u003c/strong\u003e 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 (\u003cem\u003ec.f.\u003c/em\u003e 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)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e. When a substrate contains an activated methylene unit, site selectivity poses less a problem. Thus, the amino acid derivatives \u003cstrong\u003e115\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e119\u003c/strong\u003e were oximated at the allylic position, and \u003cstrong\u003e113\u003c/strong\u003e and \u003cstrong\u003e114\u003c/strong\u003e underwent highly efficient benzylic oximation. Note that \u003cstrong\u003e118a\u003c/strong\u003e was obtained in a higher yield when using (\u003cem\u003eR,R\u003c/em\u003e)-\u003cstrong\u003eC2\u003c/strong\u003e, 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 \u003cstrong\u003e115a\u003c/strong\u003e was measured and showed no erosion. Despite the low yields sometimes, these reactions allow multi-functionalized oximes to be accessed directly and thus should be of value in the synthesis of nonnatural amino acid derivatives\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eThe high reactivity and selectivity displayed by the catalysts provide an opportunity to effect late-stage oximation of bioactive molecules (Fig.\u0026nbsp;5b). As an example, sclareolide, a commercially available material in natural products synthesis, was oxidized to oxime \u003cstrong\u003e120b\u003c/strong\u003e in 56% isolated yield (\u003cem\u003eE\u003c/em\u003e and \u003cem\u003eZ\u003c/em\u003e mixture) alongside small amounts of \u003cstrong\u003e120a\u003c/strong\u003e and \u003cstrong\u003e120c\u003c/strong\u003e under the catalysis of (\u003cem\u003eS,S\u003c/em\u003e)-\u003cstrong\u003eC1\u003c/strong\u003e. The structures of (\u003cem\u003eE\u003c/em\u003e)-\u003cstrong\u003e120a\u003c/strong\u003e and (\u003cem\u003eZ\u003c/em\u003e)-\u003cstrong\u003e120b\u003c/strong\u003e have been determined by X-ray diffraction. Compared with the ketonization of \u003cstrong\u003e120\u003c/strong\u003e effected by other catalysts, the oxidation of \u003cstrong\u003e120\u003c/strong\u003e with (\u003cem\u003eS,S\u003c/em\u003e)-\u003cstrong\u003eC1\u003c/strong\u003e shows a higher C2 regioselectivity. Another example is seen in the oxidation of the natural product methyl dehydroabietate \u003cstrong\u003e121\u003c/strong\u003e, which is isolated from spruce bark and has antibacterial activity. The oximation occurred exclusively at the benzylic methylene site, affording \u003cstrong\u003e121a\u003c/strong\u003e in single \u003cem\u003eE\u003c/em\u003e form under the catalysis of (\u003cem\u003eR\u003c/em\u003e,\u003cem\u003eR\u003c/em\u003e)-\u003cstrong\u003eC2\u003c/strong\u003e. However, a small amount of the ketone intermediate \u003cstrong\u003e121b\u003c/strong\u003e remained. The oximation of the antimalaria drug artemisinin provides a further example. To date, late stage oxyfunctionalization of artemisinin has been limited to enzymatic\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e46\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e and iron catalysis\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e48\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e49\u003c/span\u003e\u003c/sup\u003e. Subjecting artemisinin \u003cstrong\u003e122\u003c/strong\u003e to the catalysis of (\u003cem\u003eR\u003c/em\u003e,\u003cem\u003eR\u003c/em\u003e)-\u003cstrong\u003eC1\u003c/strong\u003e, the oxime \u003cstrong\u003e122a\u003c/strong\u003e was isolated in 56% yield, with the oxidation occurring at the more electron rich and sterically more accessible methylene site. Note that using (\u003cem\u003eS,S\u003c/em\u003e)-\u003cstrong\u003eC1\u003c/strong\u003e as catalyst resulted in the formation of an inseparable mixture, showing again the importance of chirality match. The oxime derivatives of \u003cstrong\u003e120\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e122\u003c/strong\u003e have been unknown so far. Installation of an oxime functionality to such molecules may alter their bioactivity and bring about unexpected new properties.\u003c/p\u003e\n\u003cp\u003eIn summary, we have demonstrated that oximes can be installed via direct methylene C-H oxidation. The manganese complexes \u003cstrong\u003eC1\u003c/strong\u003e and \u003cstrong\u003eC2\u003c/strong\u003e catalyze the oxidative oximation of methylene C-H bonds in a wide variety of simple and complex molecules with benign H\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e and economic (NH\u003csub\u003e2\u003c/sub\u003eOH)\u003csub\u003e2\u003c/sub\u003e\u0026bull;H\u003csub\u003e2\u003c/sub\u003eSO\u003csub\u003e4\u003c/sub\u003e, displaying a high level of, and often predictable, chemo and site selectivity and functional group tolerance. The electron-rich, bulky \u003cstrong\u003eC1\u003c/strong\u003e is more effective toward nonactivated C-H bonds while the electron-rich but less bulky \u003cstrong\u003eC2\u003c/strong\u003e 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.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAcknowledgments:\u003c/h2\u003e \u003cp\u003eWe gratefully acknowledge the financial support of the State Key Laboratory of Petroleum Molecular \u0026amp; Process Engineering, the Fundamental Research Funds for the National Natural Science Foundation of China (21971156), the Shaanxi Provincial Natural Science Foundation (2020JM267), the Fundamental Research Funds for the Central Universities (GK202307002), the start-up funds from Shaanxi Normal University, and the 111 project (B14041). We also thank Professor Zhaotie Liu and group for assistance in propane oxidation, Professor Heyong He and group for discussions, and Yan Zhang for assistance in managing peroxides.\u003c/p\u003e \u003cp\u003e \u003cb\u003eAuthor contributions\u003c/b\u003e: C.Q.L. and J.L.X. conceived and designed the project and wrote the manuscript. M.H.S. and H.L. conducted the experiments and analyzed the data. All authors contributed to the experiments and/or manuscript preparation.\u003c/p\u003e \u003cp\u003e \u003cb\u003eCompeting interests\u003c/b\u003e: All authors declare no other competing financial interests.\u003c/p\u003e\u003ch2\u003eData availability:\u003c/h2\u003e \u003cp\u003eAll data are available in the main text or the supplementary materials. Crystallographic data are available from the Cambridge Crystallographic Data Centre (CCDC) with the following codes: \u003cb\u003erac\u003c/b\u003e\u003cb\u003e-C1\u003c/b\u003e (CCDC 2372363); \u003cb\u003emeso\u003c/b\u003e\u003cb\u003e-C1\u003c/b\u003e (CCDC 2372362); \u003cb\u003erac\u003c/b\u003e\u003cb\u003e-C2\u003c/b\u003e (CCDC 2372364); \u003cb\u003eE\u003c/b\u003e\u003cb\u003e-22a-δ-oxime\u003c/b\u003e (CCDC 2372355); \u003cb\u003eE\u003c/b\u003e-\u003cb\u003e65a\u003c/b\u003e (CCDC 2372353); \u003cb\u003e2\u003c/b\u003e\u003cb\u003eE\u003c/b\u003e,\u003cb\u003e4\u003c/b\u003e\u003cb\u003eE\u003c/b\u003e\u003cb\u003e-119a\u003c/b\u003e (CCDC 2372356); \u003cb\u003eE\u003c/b\u003e\u003cb\u003e-120a\u003c/b\u003e (CCDC 2372360); \u003cb\u003eZ\u003c/b\u003e\u003cb\u003e-120b\u003c/b\u003e (CCDC 2372361)\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eK\u0026ouml;lmel DK, Kool ET (2017) Oximes and hydrazones in bioconjugation: mechanism and catalysis. 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J Am Chem Soc 135:14052\u0026ndash;14055\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-5773373/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5773373/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"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 a new approach that enables the direct 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 new avenues for oxime synthesis and is anticipated to have broad applications in the production of fine and commodity chemicals, bioactive molecules, and new materials.","manuscriptTitle":"Manganese Catalyzed Oximation of Hydrocarbons to Oximes","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-02-26 08:05:03","doi":"10.21203/rs.3.rs-5773373/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"135670ff-4c7a-4cf0-87d6-504fdd10bab9","owner":[],"postedDate":"February 26th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":43328724,"name":"Physical sciences/Chemistry/Catalysis/Homogeneous catalysis"},{"id":43328725,"name":"Physical sciences/Chemistry/Organic chemistry/Synthetic chemistry methodology"}],"tags":[],"updatedAt":"2026-01-10T08:09:43+00:00","versionOfRecord":{"articleIdentity":"rs-5773373","link":"https://doi.org/10.1038/s41467-025-66576-0","journal":{"identity":"nature-communications","isVorOnly":false,"title":"Nature Communications"},"publishedOn":"2026-01-09 05:00:00","publishedOnDateReadable":"January 9th, 2026"},"versionCreatedAt":"2025-02-26 08:05:03","video":"","vorDoi":"10.1038/s41467-025-66576-0","vorDoiUrl":"https://doi.org/10.1038/s41467-025-66576-0","workflowStages":[]},"version":"v1","identity":"rs-5773373","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5773373","identity":"rs-5773373","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}