{"paper_id":"40cbf78b-e383-45fd-b1ce-4c1bca8a1d11","body_text":"Amide Synthesis via Molecular Shuffling of Carboxylic Acids | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Amide Synthesis via Molecular Shuffling of Carboxylic Acids Tieqiao Chen, Chenglong Li, Qihang Tan, Qiang Wu, Yun Fu, Yongmei Wang, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7819613/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract The amide bond represents the most fundamental functional group in chemistry and biology. Amides are key building blocks of peptides, pharmaceuticals, polymers, advanced materials and biologically active compounds. The synthesis of amides has been ranked as the most common reaction performed by synthetic chemists in the last century. While the most common approach by far involves the condensation of carboxylic acids and amines, this approach has been historically limited by the positional connectivity of the key carboxylic acid group. Herein, we report a new approach to amide synthesis that relies on molecular shuffling of carboxylic acid functional group. It is found that amino benzoic acids engage in oxidative addition to a Pd(0) complex, and CO generated by decarbonylation undergoes transfer insertion into the C–Pd bond formed by alkene insertion before the last reductive elimination, achieving carbonyl shuttle amidation. The carbonyl shuttle amide synthesis is precisely controlled by ligand selection, where the reaction pathway can be fully switched to a divergent amine synthesis by decarbonylative amination. This approach is characterized by a particularly wide substrate scope and excellent functional group tolerance, including bioactive molecules and late-stage functionalization. The method is scalable, which highlights the practical utility of this new method for the synthesis of amides. Moreover, this strategy is applicable to the synthesis of linear amides. The study opens new avenues for the synthesis of amides by carbonyl reshuffling and advances an accelerated utilization of amides as critical building blocks in chemical science. Physical sciences/Chemistry/Chemical synthesis/Synthetic chemistry methodology Physical sciences/Chemistry/Organic chemistry/Synthetic chemistry methodology Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Full Text The amide bond represents the most fundamental structural motif in chemistry and biology 1 . For decades, amides have been the most ubiquitous functional group in pharmaceuticals 2,3 , polymers 4,5 , materials science 6,7 and other fields of science 8–10 . The synthesis of amides has been studied for over a century with a key discovery of activated carboxylic acid derivatives by Sheehan in 1955 11 , which enabled the synthesis of penicillin antibiotics (Figure 1A) 12,13 . The most common synthetic route to amides involves condensation of such activated carboxylic acids with amines, while the importance of this pathway is highlighted by thousands of examples in the synthesis of pivotal amide bonds in all facets of chemical science 14,15 . Furthermore, this method has been widely exploited in intramolecular amidations, where macrocyclic amide linkages are key targets in drug discovery 16–18 , molecular receptors 19–21 and conformational recognition 22,23 . After the studies by Sheehan, a significant collection of activating reagents has been established, including carbodiimides, uronium salts, triazines and phosphonium salts 24–27 , while more recent studies have focused on amidations using boron-based reagents 28–31 and N -heterocyclic carbenes 32 . However, this classic approach is limited by the positional connectivity of the key carboxylic acid group. Herein, we report a new approach to the synthesis of amides that relies on molecular shuffling of the carboxylic acid functional group (Figure 1B). In this paradigm, amino benzoic acids engage in oxidative addition to a Pd(0) complex, and CO generated by decarbonylation undergoes transfer insertion into the C–Pd bond formed by alkene insertion before the last reductive elimination, achieving carbonyl shuttle amidation. The carbonyl shuttle amide synthesis is precisely controlled by ligand selection, where the reaction pathway can be fully switched to a divergent amine synthesis by decarbonylative amination. Moreover, this strategy is applicable to the synthesis of linear amides. The study opens new avenues for the synthesis of amides by carbonyl reshuffling and advances an accelerated utilization of amide functional groups as critical building blocks in chemical science. Recent years have witnessed the development of shuttle catalysis of carboxylic acid derivatives for organic synthesis (Figure 1C) 33–39 . This approach capitalizes on the ubiquitous nature of carboxylic acids, where due to the ready accessibility and key importance, developing highly efficient transformations of carboxylic acids facilitates the synthesis of target compounds and enables late modification strategies of common molecules bearing carboxylic acid functional groups. In this context, significant advances have been made in transition-metal-catalyzed activation of carboxylic acids during the past decade (Figure 1D) 40–50 . Thus, carboxylic acids can serve as an acyl source to produce the target carboxylic derivatives 43,44 or ketones 45,46 or alternatively carboxylic acids can be engaged in decarboxylative couplings mediated by transition metals in the presence of oxidants 47,48 . Another pathway involves decarbonylative coupling of carboxylic acids, which has emerged as a powerful method for constructing chemical bonds 49,50 . In the process, carboxylic acids are in situ activated to form an active ester or acid derivative, and then act as powerful electrophiles to participate in diverse cross-couplings through decarbonylation under redox-neutral conditions. A wide range of chemical bonds has been efficiently accessed by this strategy. Considering the importance of amide bonds in chemical synthesis and our expertise in this area, we proposed a novel approach to the construction of amides by merging the fields of shuttle catalysis and redox-neutral decarbonylative transformations. By carefully optimizing a bidentate phosphine/Pd system, CO generated via decarbonylation can efficiently re-insert into the C–Pd bond formed by alkene insertion prior to reductive elimination, thus enabling carbonyl shuttle amidation. This amide synthesis is fully catalyst controlled, where electron-rich, monodentate phosphines, such as cataCXium A, result in decarbonylative amination, resulting in a divergent pathway to afford valuable amines. This general approach well overcomes the competing decarbonative side reactions during the reaction and represents the first successful carbonyl shuttle catalysis to form amide bonds. This approach is characterized by a particularly wide substrate scope and excellent functional group tolerance, including bioactive molecules and late-stage functionalization. The method is scalable, which highlights the practical utility of this new method for the synthesis of amides. Extensive mechanistic studies provide key insights into this novel process. Overall, this novel pathway reforms the toolbox of amide bond synthesis by re-routing the classical carboxylic acid/amine condensation to carboxylic acid re-shuffling. Considering the significance of amides in pharmaceuticals, functional materials and polymers, this approach opens new vistas for broad applications in chemical science. We initiated our investigation by examining the model reaction of 2-(phenylamino)benzoic acid 1a with norbornene 1b and the selected optimization results are summarized in Table 1. We found that in the presence of Pd(PPh 3 ) 4 (5 mol%) and bidentate phosphine ligand dppb (10 mol%), a mixture of 1a (0.2 mmol), 1b (4 equiv) and Piv 2 O (2 equiv) was heated in dioxane at 110 °C to produce the carboxylic acid reshuffled amide product in 87% yield with excellent selectivity (Table 1, Entry 1). The structure was initially assigned by 13 C NMR comparison, with the carbonyl group appearing at ca. 170 ppm, characteristic to amides. Next, the structure was unambiguously confirmed by x-ray crystallographic analysis (Figure 2). As shown, the ORTEP drawing reveals that the product resulted from the CO shuttle of the carboxylic acid to the distal position of the amine. The reaction represents the first example of the amide bond formation by CO shuttle catalysis of carboxylic acids. Several other optimization results are worth noting. First, we deduced that low reaction temperature could facilitate CO capture, thus favoring the formation of the amide. Indeed, when the reaction was conducted at a higher reaction temperature (130 °C or 140 °C), the yield of amide decreased (Table 1, Entries 2 and 3). However, further lowering the reaction temperature to 90 °C led to a decrease of the yield (Table 1, Entry 4). The result would be ascribed to a more difficult decarbonylation under these conditions. Finally, a very high yield of 1c was obtained by extending the reaction time to 24 h at 110 °C with full selectivity (Table 1, Entry 5). Second, there is a very significant ligand effect on the reaction, with the carboxylic acid reshuffling being completely controlled by the ancillary ligand. As such, we found that when electron-rich monodenate phosphine ligands such as cataCXium A (20 mol%) are used, the reaction after slightly tuning the reaction conditions is completely switched to a divergent decarbonylative amination to produce the corresponding decarbonylative cyclization product in 96% yield with full selectivity (Table 1, Entry 6). The phosphine ligand is essential to this reaction (Table 1, Entry 9). Other selected phosphine ligands, such as PCy 3 , PPh 3 , Xantphos, dppe, dppb, dpph, dppf and dppm, are less selective (Table 1, Entries 10–17). In terms of solvents, the reaction progressed slowly in NMP, PhOMe, toluene and cyclohexane (Table 1, Entries 18–21). The anhydride activator is essential (Table 1, Entry 22), as expected for the decarbonylative pathway. Finally, it should be noted that full selectivity for the formation of amide reshuffling product is observed using the bidenate dppb ligand. In general, we also noticed that increasing olefin and activator concentration results in higher yields and selectivity (vide infra, mechanistic studies). With the optimized reaction conditions in hand, the substrate scope of this novel amide synthesis was investigated. As outlined in Table 2, this approach is broadly general and permits for a synthesis of a wide range of amides by carbonyl reshuffling. Particularly worth noting is high functional group tolerance. Various valuable functional groups such as alkyl, methoxyl, fluoro, chloro, silyl, boric, thiomethoxyl, trifluoromethyl, nitro, vinyl, phenyl, carbonyl, ester and heterocyclic groups are well tolerated under the present reaction conditions. High yields were achieved using both electron-rich and electron-deficient amines. For instance, derivatives bearing alkyl, methoxy, halo (F and Cl), carbonyl, CF 3 and NO 2 all showed high reactivity under the reaction conditions (Table 2, 2c – 14c ). Boric, thiomethyl, silyl, and vinyl groups were well compatible (Table 2, 15c – 18c ). It is worth noting that the products could be easily further utilized as functional handles through transformation of these functional groups. π-Extended and heterocyclic N -Ar 1 also well-compatible in this reaction (Table 3, 19c – 24c ). It is known that alkyl groups increase the basicity of amines and have a negative effect on catalyst deactivation and side-reactions. To our delight, substrates with various N -alkyl groups also produced the desired products in good yields (Table 3, 25c – 27c ). Moreover, various N -Ar 2 including those with various sensitive functional groups could all efficiently promote this novel amide synthesis (Table 3, 28c – 41c ). In addition, functionalized norbornenes were also suitable to this reaction and gave the CO shuttle amide transform in high yields (Table 3, 42c – 44c ). Furthermore, as demonstrated in Table 3, the approach to the divergent decarbonylative amine synthesis is also general and proceeds with full chemoselectivity. Thus, the decarbonylative amination is also characterized by a very broad substrate scope. Amino benzoic acids with alkyl and methoxy groups at the N -Ar 1 produced the corresponding products in high yields (Table 3, 2d – 7d ). High steric hindrance was well-tolerated (Table 3, 9d and 18d ). It is worth noting is that halo (F and Cl) groups remained intact (Table 3, 8d , 9d , 10d ). Boric, silyl and coordinating thiomethoxyl were also compatible under the decarbonylative conditions (Table 3, 11d – 13d ). High yields were also obtained from substrates bearing electron-deficient N -aryl groups bearing carbonyl, trifluoromethyl and even nitro groups (Table 3, 14d – 16d ). π-Extended and heterocyclic N -aryl groups were also amenable to this reaction, furnishing the products in excellent yields (Table 3, 17d – 23d ). Furthermore, acid derivatives bearing N -alkyl groups were also compatible, furnishing the desired indolines in high yields (Table 3, 24d – 26d ). The N -Ar 2 substitution was also investigated, and substrates bearing both electron-rich and electron-deficient N -Ar 2 reacted readily to produce the corresponding amines in high yields. Electron-donating alkyl and methoxy groups also afforded high yields (Table 3, 27d – 29d ). Biologically-relevant fluorine and trifiluoromethyl groups were well-tolerated (Table 3, 30d – 32d ). The vinyl group was compatible (Table 3, 33d ). High yields were also obtained from substrates containing π-extended and heterocyclic groups (Table 3, 34d – 39d ). Finally, norbornenes bearing various functional groups, such as ether, ester and phenyl group were also amenable, furnishing the expected products in high yields (Table 3, 40d – 42d ). Crucially, this novel approach to amide synthesis by carboxylic acid reshuffling is readily applicable to transformation of pharmaceuticals and bioactive carboxylic acids (Table 4). For example, mefenamic acid is used as an antipyretic, analgesic, and nonsteroidal anti-inflammatory drug in clinlic. This compound participated readily in the carboxylic acid reshuffling to afford the amide product in high yield (Table 4, 45c ). Clofenamic acid, flufenamic acid and meclofenamic acid are also nonsteroidal anti-inflammatory drugs used to treat inflammation and as analgesics. These drugs are also well-suitable substrates for carboxylic acid reshuffling (Table 4, 46c – 48c ). The substrates bearing bioactive fragment eugenol and isoeugenol also showed high reactivity in the current catalytic system to furnish amides (Table 4, 49c , 50c ). Conversely, the divergent nature of this catalytic CO shuttle amidation renders facile access to the corresponding amines in high yields. For example, this decarbonylative amination readily produced target products of flufenamic acid, isoeugenol and eugenol (Table 4, 43d – 45d ) in high yields. The results outlined above in the direct functionalization of biologically active drugs that inherently feature carboxylic acid moieties demonstrate a considerable potential of the present bond reshuffling methodology in medicinal chemistry and drug discovery campaigns. While our initial focus was on the reaction discovery of the carboxylic acid reshuffling for amide synthesis in the intramolecular context, we were pleased to find that this methodology is also applicable to linear amides (Figure 3 and Table 5). This establishes CO shuttle catalysis concept for the synthesis of acyclic amides by CO migration from common carboxylic acids. In practical terms, it is critical to point out that this carboxylic acid reshuffling is readily scalable (Figure 4A). For example, the mixture of 1a (5 mmol) and 1b was heated under standard reaction conditions to afford the corresponding amide on a gram scale in 80% isolated yield. Similarly high yield was also achieved in decarbonylative amination on a gram scale. As demonstrated in the substrate scope studies, this novel process for amide synthesis is distinguished by functional group tolerance to many valuable functional groups, facilitating further derivatization to afford target amide products that are not easily obtained by other methods. Furthermore, the amide itself provides a highly valuable handle for streamlined synthesis as a versatile synthetic intermediate (Figure 4B). Taking 1c as an example, the amide bond can be easily reduced with LiAlH 4 to produce the corresponding six-membered cyclic amine g in 77% yield. Likewise, the amide bond can efficiently react with organometallic reagents, such as MeLi, to generate cyclic amine h . Furthermore, Ti(OPr i ) 4 -mediated Kulikovich cyclopropanation with EtMgBr delivers the spiro amine i . Finally, treatment with DIBAL-H and dehydration furnishes the active imine salt j in high yield. These reactions further highlight the synthetic value of the present carboxylic acid reshuffling amide bond synthesis. Furthermore, quinoline and indoline heterocycles have featured many prominent applications in drug discovery and materials science. To gain mechanistic insights into this reaction, extensive studies were conducted. First, we synthesized the mixed anhydride la and found that it could be converted into 1c in 91% yield and into 1d in 94% yield, indicating that the mixed anhydride is the active intermediate (Figure 4C, left). As mentioned, the N–H moiety can be acylated by anhydride to produce f as detected by GC-MS. To verify whether N -Piv product could participate in the reaction, we synthesized this potential intermediate and subjected it to the reaction conditions. However, when f was reacted under the respective conditions, only a trace amount of 1d was generated, while 1c was not detected (Figure 4C, right). These results suggest that f is an unproductive byproduct of this process. In the CO shuttle amidation, CO was re-utilized with very high efficiency. Thus, we carried out a reaction in glass tubes with different volumes (Figure 4D, left). The yields in 10 mL, 25 mL, and 100 mL reactor did not change significantly and were 94%, 93% and 82%, respectively. We also conducted the reaction with different loading of CO adsorbent and found that the yields also varied from 89–91% (Figure 4D, right). These results indicate that CO does not permeate outside the reaction system and coordinates with palladium during the reaction, thus enabling the successful utilization of carboxylic acid reshuffling. To gain insight into the selectivity of this process, intermolecular competition experiments were conducted (Figure 4E and 4F). When 8a and 1a were allowed to react with NBE under carboxylic acid reshuffling conditions, 7c and 1c were produced in 14% and 25% yields, respectively (Eq 1). When 20a competed with 1a , 13c was obtained in 19% yield, while 1c was generated in 20% yield (Eq 2). The competition between 8a and 20a produced 7c and 13c in 15% and 22% yields (Eq 3). Similar results were obtained for decarbonylative amination (Eqs 7–9). These results indicate that although the electronic effect of N -Ar 1 is not significant, substrates with electron-deficient N -aryl 1 are inherently favored. Meanwhile, allowing 34a to compete with 1a under carboxylic acid reshuffling conditions produced 30c and 1c in 14% and 30% yields, respectively (Eq 4). When 38a competed with 1a , 34c was obtained in 35% yield, while 1c was produced in 11% yield (Eq 5). The competition of 34a with 38a also generated 30c and 34c in 4% and 20% yields (Eq 6). Similar results were obtained for decarbonylative amination (Eqs 10–12). These results indicate that electron-deficient benzoic acids are inherently favored. The Hammett analysis was next subsequently conducted 51 . A positive slope ( ρ = 0.259) was observed for the CO shuttle amidation of benzoic acids having para -substituted N -Ar with NBE 1b (Figure 5a). A larger value ( ρ = 1.909) was obtained for the same reaction of benzoic acids bearing para -substituted benzene ring with 1b (Figure 5b). In the decarbonylative amination, similar slope values were observed (Figure 5c and 5d). The data indicates that electron-deficient substrates are inherently more favorable. Compared with N -Ar, the electronic effect at the benzene ring of benzoic acids is comparatively larger and thus contributes more significantly to the rate-determining step. The Hammett plot results are consistent with intermolecular competition experiments. Next, the kinetic analysis was performed for the CO shuttle amidation and showed that the rate was first-order dependent on benzoic acids, palladium and olefins, indicating that norbornenes had a significant effect on the rate (Figure 5e–5g). The activation energy was calculated as 26.43 kcal/mol based on the temperature effect (Figure 5h) 52 . However, in the case of decarbonylative amination, the outcome was different. The rate was first-order dependent on benzoic acids and palladium catalyst, but close to zero-order dependent on norbornenes (Figure 5i–5k). These results suggest that norbornenes do not have a major effect on the rate during the reaction and that the process is a mono-palladium catalytic process. The activation energy also increased (30.35 kcal/mol), which is consistent with the comparatively higher temperature employed in this reaction (Figure 5l). On the basis of control experiments, competition studies, Hammett analysis and kinetic studies, a plausible mechanism is proposed as shown in Figure 6. Benzoic acids are first activated to give the active mixed anhydrides, which undergo oxidative addition of Pd(0) into the C(O)-acyl bond to produce the acyl palladium species II . The resulting intermediate undergoes decarbonylation, alkene insertion, intramolecular ligand exchange and reductive elimination via direct decarbonylative pathway. However, when the ligand is switched from cataCxium A to bidenate dppp, a transient decarbonylation of species Ⅱ takes place to afford the CO-ligated aryl palladium Ⅲ . This intermediate undergoes alkene insertion, intramolecular ligand exchange, and key CO re-insertion to generate amides after reductive elimination. This cycle represents a novel approach to amide synthesis, where the carboxylic acid is positionally reshuffled to form N–C(O) bonds in analogy to the venerable acid/amine condensation. In conclusion, amide bonds have been at the heart of organic synthesis for more than a century. The classical and most widely utilized method for amide synthesis involves condensation of activated carboxylic acids with amines, and this approach has been exploited in every facet of chemical science on daily basis. Herein, we developed a novel paradigm for the synthesis of amides that capitalizes on molecular reshuffling of the carboxylic acid functional group. In this blueprint, amino benzoic acids engage in oxidative addition to a low valent metal, and CO generated by decarbonylation undergoes transfer insertion into alkenes before the last reductive elimination. This carbonyl shuttle amide synthesis is precisely controlled by ligand selection, where the reaction pathway can be fully switched to a divergent amine synthesis by decarbonylative amination. This novel transform is capable of forming amides by the repositioned classical carboxylic acid/amine condensation and should greatly advance vistas on the synthesis of valuable amide bonds by carbonyl reshuffling. Declarations Data availability The data supporting the findings of the study are available in the paper and its supplementary information. All data are available from the corresponding authors upon request. Acknowledgments T.C. thanks the National Nature and Science Foundation of China (Grant Nos. 22261015, 21871070) and the Key R&D project of Hainan province (No. ZDYF2020168, XTCX2022STA01) for financial support. M.S. thanks Rutgers University and the NSF (CAREER CHE-1650766) for financial support. Author contributions Conceptualization: M. S. and T. C.; Methodology: C. L., Q. W., Y. F. and Y. W.; Investigation: C. L.; Visualization: C. L. and Q. W.; Funding acquisition: T. C.; Project administration: M. S. and T. C.; Supervision: M. S. and T. C.; Writing – original draft: M. S. and T. C.; Writing – review & editing: C. L., Q, T., B. S., T. H., L. L., M. S. and T. C.pt. Competing interests Authors declare that they have no competing interests. Correspondence and requests for materials should be addressed to Michal Szostak and Tieqiao Chen. References Greenberg, A., Breneman, C. M. & Liebman, J. F. 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Hioki, Y. et al. Overcoming the limitations of Kolbe coupling with waveform-controlled electrosynthesis. Science 380 , 81–87 (2023). Lu, H. et al. Selective decarbonylation via transition-metal-catalyzed carbon-carbon bond cleavage. Chem. Rev. 121 , 365–411 (2021). Boehm, P. et al. Palladium-catalyzed decarbonylative iodination of aryl carboxylic acids enabled by ligand-assisted halide exchange. Angew. Chem. Int. Ed. 60 , 17211–17217 (2021). Hansch, C., Leo, A. & Taft, R. W. A survey of Hammett substituent constants and resonance and field parameters. Chem. Rev. 91 , 165–195 (1991). Nakamura, K. & Takayanagi, T. A modified Arrhenius equation. Chem. Phys. Lett. 160 , 295–298 (1989). Tables Tables 1 to 5 are available in the Supplementary Files section. Additional Declarations There is NO Competing Interest. Supplementary Files 230417a.cif Extended Data 1 220514d.cif Extended Data 2 Supportinginformation.pdf Supplementary Information Tables.docx Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {\"props\":{\"pageProps\":{\"initialData\":{\"identity\":\"rs-7819613\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":false,\"archivedVersions\":[],\"articleType\":\"Article\",\"associatedPublications\":[],\"authors\":[{\"id\":533842813,\"identity\":\"61798fae-1d15-4eeb-9ac6-7b2364cd0238\",\"order_by\":0,\"name\":\"Tieqiao Chen\",\"email\":\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7klEQVRIiWNgGAWjYDACCRBhwMDAxsDA+BgilECElgMQLczGJGiBMNmkidLCP7v52OMPBTayfeyHj1UX7jjMwM+eY8DwcwceS+4cSzc4YJBm3MaTlnZ75pnDDJI9bwwYe8/g1mIgkWMmccDgcGIbQ47Zbd62wwwGN3IMmBnb8GnJ/wbU8j+xjf+NWTFIiz1hLTlsQC0HEtuA1jGDbZEgoEXiRpqZxBmDZOM2iWfJ0rxt6TwSZ54VHOzFo4V/RvIziYo/drLz+5MPfuZts5bjb0/e+OAnHi0wwNgAZfCAiAOENSBpGQWjYBSMglGAAQAkmkzhkDh3vAAAAABJRU5ErkJggg==\",\"orcid\":\"https://orcid.org/0000-0002-9787-9538\",\"institution\":\"Hainan University\",\"correspondingAuthor\":true,\"prefix\":\"\",\"firstName\":\"Tieqiao\",\"middleName\":\"\",\"lastName\":\"Chen\",\"suffix\":\"\"},{\"id\":533842814,\"identity\":\"d7b17919-f969-4a85-8af2-fa5a43551be5\",\"order_by\":1,\"name\":\"Chenglong Li\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Hainan 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University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Tianzeng\",\"middleName\":\"\",\"lastName\":\"Huang\",\"suffix\":\"\"},{\"id\":533842821,\"identity\":\"9fdf83ef-5cb7-4676-94dc-f5f4e7e1101e\",\"order_by\":8,\"name\":\"Long Liu\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Hainan University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Long\",\"middleName\":\"\",\"lastName\":\"Liu\",\"suffix\":\"\"},{\"id\":533842822,\"identity\":\"26c4aa4f-b777-484e-a697-f4cefec5097a\",\"order_by\":9,\"name\":\"Michal Szostak\",\"email\":\"\",\"orcid\":\"https://orcid.org/0000-0002-9650-9690\",\"institution\":\"Rutgers University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Michal\",\"middleName\":\"\",\"lastName\":\"Szostak\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2025-10-09 16:21:20\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-7819613/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-7819613/v1\",\"draftVersion\":[],\"editorialEvents\":[],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":94248115,\"identity\":\"82c2afaa-94cb-4b63-a10d-1fe6179f2fa1\",\"added_by\":\"auto\",\"created_at\":\"2025-10-24 05:56:37\",\"extension\":\"png\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":164463,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eAmide Synthesis and Transition-Metal Catalyzed Transformation of Carboxylic Acids\\u003c/strong\\u003e.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"1.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7819613/v1/59359a066a834ae3f63f5480.png\"},{\"id\":94248928,\"identity\":\"740e0bed-a294-4b1e-8c7f-a4625b86a998\",\"added_by\":\"auto\",\"created_at\":\"2025-10-24 06:12:37\",\"extension\":\"png\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":118354,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eORTEP Drawing of Compound 1c. \\u003c/strong\\u003eThermal ellipsoids: 50% probability. Selected bond lengths (Å) and angles (deg): C1–C2 = 1.507 (16), C1–N1 = 1.370 (14), C1–O1 = 1.232 (13), C5–N1 = 1.474 (15), C15–N1 = 1.433 (14), C2–C1–O1 = 119.6 (12), C5–N1–C15 = 119.4 (10), C1–N1–C15 = 119.2 (11), C5–N1–C1 = 121.3 (10).\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"2.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7819613/v1/58c41345d5186a36f840201e.png\"},{\"id\":94248305,\"identity\":\"170c1541-d438-4086-b037-9133c0c67654\",\"added_by\":\"auto\",\"created_at\":\"2025-10-24 06:04:37\",\"extension\":\"png\",\"order_by\":3,\"title\":\"Figure 3\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":166608,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eORTEP Drawing of Compound 1e. \\u003c/strong\\u003eThermal ellipsoids: 50% probability. Selected bond lengths (Å) and angles (deg): C1–C2 = 1.499 (3), C1–N1 = 1.343 (3), C1–O1 = 1.213 (2), C19–N1 = 1.450 (3), C21–N1 = 1.447 (3), C2–C1–O1 = 121.5 (2), C19–N1–C21 = 116.1 (2), C1–N1–C19 = 118.84 (19), C21–N1–C1 = 124.7 (2).\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"3.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7819613/v1/117b49b66a0dcebe57dced20.png\"},{\"id\":94248122,\"identity\":\"8f511790-7693-4894-96e6-bbfa5a3bf2c0\",\"added_by\":\"auto\",\"created_at\":\"2025-10-24 05:56:37\",\"extension\":\"png\",\"order_by\":4,\"title\":\"Figure 4\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":218085,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eSynthetic Applications and Mechanistic Studies.\\u003c/strong\\u003e\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"4.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7819613/v1/aae759bb3e9500f33e780acd.png\"},{\"id\":94248307,\"identity\":\"9e5b6b8f-b377-4da1-a170-491a8370b8f8\",\"added_by\":\"auto\",\"created_at\":\"2025-10-24 06:04:37\",\"extension\":\"png\",\"order_by\":5,\"title\":\"Figure 5\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":230673,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eHammett effects and kinetic analysis.\\u003c/strong\\u003e Hammett plots of \\u003cem\\u003eCO\\u003c/em\\u003e shuttle amidation: (a) Benzoic acids having \\u003cem\\u003epara\\u003c/em\\u003e-substituted \\u003cem\\u003eN\\u003c/em\\u003e-Ar with \\u003cem\\u003eNBE\\u003c/em\\u003e \\u003cstrong\\u003e1b\\u003c/strong\\u003e; (b) Benzoic acids bearing \\u003cem\\u003epara\\u003c/em\\u003e-substituted benzene ring with \\u003cem\\u003eNBE\\u003c/em\\u003e \\u003cstrong\\u003e1b\\u003c/strong\\u003e; hammett plots of decarbonylative amination: (c) Benzoic acids having \\u003cem\\u003epara\\u003c/em\\u003e-substituted \\u003cem\\u003eN\\u003c/em\\u003e-Ar with \\u003cem\\u003eNBE\\u003c/em\\u003e \\u003cstrong\\u003e1b\\u003c/strong\\u003e; (d) Benzoic acids bearing \\u003cem\\u003epara\\u003c/em\\u003e-substituted benzene ring with \\u003cem\\u003eNBE\\u003c/em\\u003e \\u003cstrong\\u003e1b\\u003c/strong\\u003e; kinetic analysis of \\u003cem\\u003eCO\\u003c/em\\u003e shuttle amidation: (e) 2-(Phenylamino)benzoic acid vs initial rate, (f) \\u003cem\\u003eNBE\\u003c/em\\u003e vs initial rate, (g) [Pd] vs initial rate, (h) arrhenius plot: plot of ln \\u003cem\\u003ek\\u003c/em\\u003e vs 1/T; kinetic analysis of decarbonylative amination: (i) 2-(phenylamino)benzoic acid vs initial rate, (j) \\u003cem\\u003eNBE\\u003c/em\\u003e vs initial rate, (k) [Pd] vs initial rate, (l) arrhenius plot: plot of ln \\u003cem\\u003ek\\u003c/em\\u003evs 1/T.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"5.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7819613/v1/7e1978c4019d3ceefc4a758b.png\"},{\"id\":94248120,\"identity\":\"c8e905b0-5fdc-424f-9717-88f8ea80ff00\",\"added_by\":\"auto\",\"created_at\":\"2025-10-24 05:56:37\",\"extension\":\"png\",\"order_by\":6,\"title\":\"Figure 6\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":115173,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eProposed Catalytic Cycle\\u003c/strong\\u003e\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"6.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7819613/v1/c4a6cafee11ca2d7ffc1b025.png\"},{\"id\":97142325,\"identity\":\"368e9fb9-92ca-428f-b183-4f7a2fa87a38\",\"added_by\":\"auto\",\"created_at\":\"2025-12-01 10:07:31\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":1481950,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7819613/v1/109ef98f-19ff-44ca-a0fa-238377383803.pdf\"},{\"id\":94248114,\"identity\":\"69fc7732-5962-44d7-adaf-03fdd54fd663\",\"added_by\":\"auto\",\"created_at\":\"2025-10-24 05:56:37\",\"extension\":\"cif\",\"order_by\":1,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":16367,\"visible\":true,\"origin\":\"\",\"legend\":\"Extended Data 1\",\"description\":\"\",\"filename\":\"230417a.cif\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7819613/v1/438a9f65456b218d039f9724.cif\"},{\"id\":94248118,\"identity\":\"cf0f29f7-798c-46f1-8942-5fc709cc9fef\",\"added_by\":\"auto\",\"created_at\":\"2025-10-24 05:56:37\",\"extension\":\"cif\",\"order_by\":2,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":14041,\"visible\":true,\"origin\":\"\",\"legend\":\"Extended Data 2\",\"description\":\"\",\"filename\":\"220514d.cif\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7819613/v1/8404780e194eee028586bba7.cif\"},{\"id\":94248124,\"identity\":\"1c2651a0-ac3f-4e32-aa2f-3b5c918f7f0a\",\"added_by\":\"auto\",\"created_at\":\"2025-10-24 05:56:38\",\"extension\":\"pdf\",\"order_by\":3,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":23417170,\"visible\":true,\"origin\":\"\",\"legend\":\"Supplementary Information\",\"description\":\"\",\"filename\":\"Supportinginformation.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7819613/v1/9d48a220e58b4f74a0bbe75f.pdf\"},{\"id\":94248123,\"identity\":\"7e7ce55e-a55f-43ef-a61c-00e9084bb9fb\",\"added_by\":\"auto\",\"created_at\":\"2025-10-24 05:56:37\",\"extension\":\"docx\",\"order_by\":4,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":645136,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"Tables.docx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7819613/v1/9915d126e1088d8259247209.docx\"}],\"financialInterests\":\"There is \\u003cb\\u003eNO\\u003c/b\\u003e Competing Interest.\",\"formattedTitle\":\"Amide Synthesis via Molecular Shuffling of Carboxylic Acids\",\"fulltext\":[{\"header\":\"Full Text\",\"content\":\"\\u003cp\\u003eThe amide bond represents the most fundamental structural motif in chemistry and biology\\u003csup\\u003e1\\u003c/sup\\u003e. For decades, amides have been the most ubiquitous functional group in pharmaceuticals\\u003csup\\u003e2,3\\u003c/sup\\u003e, polymers\\u003csup\\u003e4,5\\u003c/sup\\u003e, materials science\\u003csup\\u003e6,7\\u003c/sup\\u003e and other fields of science\\u003csup\\u003e8\\u0026ndash;10\\u003c/sup\\u003e. The synthesis of amides has been studied for over a century with a key discovery of activated carboxylic acid derivatives by Sheehan in 1955\\u003csup\\u003e11\\u003c/sup\\u003e, which enabled the synthesis of penicillin antibiotics (Figure\\u0026nbsp;1A)\\u003csup\\u003e12,13\\u003c/sup\\u003e. The most common synthetic route to amides involves condensation of such activated carboxylic acids with amines, while the importance of this pathway is highlighted by thousands of examples in the synthesis of pivotal amide bonds in all facets of chemical science\\u003csup\\u003e14,15\\u003c/sup\\u003e. Furthermore, this method has been widely exploited in intramolecular amidations, where macrocyclic amide linkages are key targets in drug discovery\\u003csup\\u003e16\\u0026ndash;18\\u003c/sup\\u003e, molecular receptors\\u003csup\\u003e19\\u0026ndash;21\\u003c/sup\\u003e and conformational recognition\\u003csup\\u003e22,23\\u003c/sup\\u003e. After the studies by Sheehan, a significant collection of activating reagents has been established, including carbodiimides, uronium salts, triazines and phosphonium salts\\u003csup\\u003e24\\u0026ndash;27\\u003c/sup\\u003e, while more recent studies have focused on amidations using boron-based reagents\\u003csup\\u003e28\\u0026ndash;31\\u003c/sup\\u003e and \\u003cem\\u003eN\\u003c/em\\u003e-heterocyclic carbenes\\u003csup\\u003e32\\u003c/sup\\u003e. However, this classic approach is limited by the positional connectivity of the key carboxylic acid group. Herein, we report a new approach to the synthesis of amides that relies on molecular shuffling of the carboxylic acid functional group\\u0026nbsp;(Figure 1B). In this paradigm, amino benzoic acids engage in oxidative addition to a Pd(0) complex, and CO generated by decarbonylation undergoes transfer insertion into the C\\u0026ndash;Pd bond formed by alkene insertion\\u0026nbsp;before\\u0026nbsp;the last reductive elimination, achieving carbonyl shuttle amidation. The carbonyl shuttle amide synthesis is precisely controlled by ligand selection, where the reaction pathway can be fully switched to a divergent amine synthesis by decarbonylative amination. Moreover, this strategy is applicable to the synthesis of linear amides.\\u0026nbsp;The study opens new avenues for the synthesis of amides by carbonyl reshuffling and advances an accelerated utilization of amide functional groups as critical building blocks in chemical science.\\u003c/p\\u003e\\n\\u003cp\\u003eRecent years have witnessed the development of shuttle catalysis of carboxylic acid derivatives for organic synthesis\\u0026nbsp;(Figure 1C)\\u003csup\\u003e33\\u0026ndash;39\\u003c/sup\\u003e. This approach capitalizes on the ubiquitous nature of carboxylic acids, where due to the ready accessibility and key importance, developing highly efficient transformations of carboxylic acids facilitates the synthesis of target compounds and enables late modification strategies of common molecules bearing carboxylic acid functional groups. In this context, significant advances have been made in transition-metal-catalyzed activation of carboxylic acids during the past decade\\u0026nbsp;(Figure 1D)\\u003csup\\u003e40\\u0026ndash;50\\u003c/sup\\u003e. Thus, carboxylic acids can serve as an acyl source to produce the target carboxylic derivatives\\u003csup\\u003e43,44\\u003c/sup\\u003e or ketones\\u003csup\\u003e45,46\\u003c/sup\\u003e or alternatively carboxylic acids can be engaged in decarboxylative couplings mediated by transition metals in the presence of oxidants\\u003csup\\u003e47,48\\u003c/sup\\u003e. Another pathway involves decarbonylative coupling of carboxylic acids, which has emerged as a powerful method for constructing chemical bonds\\u003csup\\u003e49,50\\u003c/sup\\u003e. In the process, carboxylic acids are in situ activated to form an active ester or acid derivative, and then act as powerful electrophiles to participate in diverse cross-couplings through decarbonylation under redox-neutral conditions. A wide range of chemical bonds has been efficiently accessed by this strategy.\\u003c/p\\u003e\\n\\u003cp\\u003eConsidering the importance of amide bonds in chemical synthesis and our expertise in this area, we proposed a novel approach to the construction of amides by merging the fields of shuttle catalysis and redox-neutral decarbonylative transformations. By carefully optimizing a bidentate phosphine/Pd system, CO generated via decarbonylation can efficiently re-insert into the C\\u0026ndash;Pd bond formed by alkene insertion prior to reductive elimination, thus enabling carbonyl shuttle amidation. This amide synthesis is fully catalyst controlled, where electron-rich, monodentate phosphines, such as cataCXium A, result in decarbonylative amination, resulting in a divergent pathway to afford valuable amines. This general approach well overcomes the competing decarbonative side reactions during the reaction and represents the first successful carbonyl shuttle catalysis to form amide bonds. This approach is characterized by a particularly wide substrate scope and excellent functional group tolerance, including bioactive molecules and late-stage functionalization. The method is scalable, which highlights the practical utility of this new method for the synthesis of amides. Extensive mechanistic studies provide key insights into this novel process. Overall, this novel pathway reforms the toolbox of amide bond synthesis by re-routing the classical carboxylic acid/amine condensation to carboxylic acid re-shuffling. Considering the significance of amides in pharmaceuticals, functional materials and polymers, this approach opens new vistas for broad applications in chemical science.\\u003c/p\\u003e\\n\\u003cp\\u003eWe initiated our investigation by examining the model reaction of 2-(phenylamino)benzoic acid \\u003cstrong\\u003e1a\\u003c/strong\\u003e with norbornene \\u003cstrong\\u003e1b\\u003c/strong\\u003e and the selected optimization results are summarized in Table 1. We found that in the presence of Pd(PPh\\u003csub\\u003e3\\u003c/sub\\u003e)\\u003csub\\u003e4\\u003c/sub\\u003e (5 mol%) and bidentate phosphine ligand dppb (10 mol%), a mixture of \\u003cstrong\\u003e1a\\u003c/strong\\u003e (0.2 mmol), \\u003cstrong\\u003e1b\\u003c/strong\\u003e (4 equiv) and Piv\\u003csub\\u003e2\\u003c/sub\\u003eO (2 equiv) was heated in dioxane at 110 \\u0026deg;C to produce the carboxylic acid reshuffled amide product in 87% yield with excellent selectivity (Table 1, Entry 1). The structure was initially assigned by \\u003csup\\u003e13\\u003c/sup\\u003eC NMR comparison, with the carbonyl group appearing at ca. 170 ppm, characteristic to amides. Next, the structure was unambiguously confirmed by x-ray crystallographic analysis (Figure\\u0026nbsp;2). As shown, the ORTEP drawing reveals that the product resulted from the CO shuttle of the carboxylic acid to the distal position of the amine. The reaction represents the first example of the amide bond formation by CO shuttle catalysis of carboxylic acids.\\u003c/p\\u003e\\n\\u003cp\\u003eSeveral other optimization results are worth noting. First, we deduced that low reaction temperature could facilitate CO capture, thus favoring the formation of the amide. Indeed, when the reaction was conducted at\\u0026nbsp;a higher reaction temperature (130 \\u0026deg;C or 140 \\u0026deg;C), the yield of amide decreased (Table 1, Entries 2 and 3). However, further lowering the reaction temperature to 90 \\u0026deg;C led to a decrease of the yield (Table 1, Entry 4). The result would be ascribed to a more difficult decarbonylation under these conditions. Finally, a very high yield of \\u003cstrong\\u003e1c\\u003c/strong\\u003e was obtained by extending the reaction time to 24 h at 110 \\u0026deg;C with full selectivity (Table 1, Entry 5). Second, there is a very significant ligand effect on the reaction, with the carboxylic acid reshuffling being completely controlled by the ancillary ligand. As such, we found that when electron-rich monodenate phosphine ligands such as cataCXium A (20 mol%) are used, the reaction after slightly tuning the reaction conditions is completely switched to a divergent decarbonylative amination to produce the corresponding decarbonylative cyclization product in 96% yield with full selectivity (Table 1, Entry 6). The phosphine ligand is essential to this reaction (Table 1, Entry 9). Other selected phosphine ligands, such as PCy\\u003csub\\u003e3\\u003c/sub\\u003e, PPh\\u003csub\\u003e3\\u003c/sub\\u003e, Xantphos, dppe, dppb, dpph, dppf and dppm, are less selective (Table 1, Entries 10\\u0026ndash;17). In terms of solvents, the reaction progressed slowly in NMP, PhOMe, toluene and cyclohexane (Table 1, Entries 18\\u0026ndash;21). The anhydride activator is essential (Table 1, Entry 22), as expected for the decarbonylative pathway. Finally, it should be noted that full selectivity for the formation of amide reshuffling product is observed using the bidenate dppb ligand. In general, we also noticed that increasing olefin and activator concentration results in higher yields and selectivity (vide infra, mechanistic studies).\\u003c/p\\u003e\\n\\u003cp\\u003eWith the optimized reaction conditions in hand, the substrate scope of this novel amide synthesis was investigated. As outlined in Table 2, this approach is broadly general and permits for a synthesis of a wide range of amides by carbonyl reshuffling. Particularly worth noting is high functional group tolerance. Various valuable functional groups such as alkyl, methoxyl, fluoro, chloro, silyl, boric, thiomethoxyl, trifluoromethyl, nitro, vinyl, phenyl, carbonyl, ester and heterocyclic groups are well tolerated under the present reaction conditions. High yields were achieved using both electron-rich and electron-deficient amines. For instance, derivatives bearing alkyl, methoxy, halo (F and Cl), carbonyl, CF\\u003csub\\u003e3\\u003c/sub\\u003e and NO\\u003csub\\u003e2\\u003c/sub\\u003e all showed high reactivity under the reaction conditions (Table 2, \\u003cstrong\\u003e2c\\u003c/strong\\u003e\\u0026ndash;\\u003cstrong\\u003e14c\\u003c/strong\\u003e). Boric, thiomethyl, silyl, and vinyl groups were well compatible (Table 2, \\u003cstrong\\u003e15c\\u003c/strong\\u003e\\u0026ndash;\\u003cstrong\\u003e18c\\u003c/strong\\u003e). It is worth noting that the products could be easily further utilized as functional handles through transformation of these functional groups. \\u0026pi;-Extended and heterocyclic \\u003cem\\u003eN\\u003c/em\\u003e-Ar\\u003csup\\u003e1\\u003c/sup\\u003e also well-compatible in this reaction (Table 3, \\u003cstrong\\u003e19c\\u003c/strong\\u003e\\u0026ndash;\\u003cstrong\\u003e24c\\u003c/strong\\u003e). It is known that alkyl groups increase the basicity of amines and have a negative effect on catalyst deactivation and side-reactions. To our delight, substrates with various \\u003cem\\u003eN\\u003c/em\\u003e-alkyl groups also produced the desired products in good yields (Table 3, \\u003cstrong\\u003e25c\\u003c/strong\\u003e\\u0026ndash;\\u003cstrong\\u003e27c\\u003c/strong\\u003e). Moreover, various \\u003cem\\u003eN\\u003c/em\\u003e-Ar\\u003csup\\u003e2\\u003c/sup\\u003e including those with various sensitive functional groups could all efficiently promote this novel amide synthesis (Table 3, \\u003cstrong\\u003e28c\\u003c/strong\\u003e\\u0026ndash;\\u003cstrong\\u003e41c\\u003c/strong\\u003e). In addition, functionalized norbornenes were also suitable to this reaction and gave the CO shuttle amide transform in high yields (Table 3, \\u003cstrong\\u003e42c\\u003c/strong\\u003e\\u0026ndash;\\u003cstrong\\u003e44c\\u003c/strong\\u003e).\\u003c/p\\u003e\\n\\u003cp\\u003eFurthermore, as demonstrated in Table 3, the approach to the divergent decarbonylative amine synthesis is also general and proceeds with full chemoselectivity. Thus, the decarbonylative amination is also characterized by a very broad substrate scope. Amino benzoic acids with alkyl and methoxy groups at the \\u003cem\\u003eN\\u003c/em\\u003e-Ar\\u003csup\\u003e1\\u003c/sup\\u003e produced the corresponding products in high yields (Table 3, \\u003cstrong\\u003e2d\\u003c/strong\\u003e\\u0026ndash;\\u003cstrong\\u003e7d\\u003c/strong\\u003e). High steric hindrance was well-tolerated (Table 3, \\u003cstrong\\u003e9d\\u003c/strong\\u003e and \\u003cstrong\\u003e18d\\u003c/strong\\u003e). It is worth noting is that halo (F and Cl) groups remained intact (Table 3, \\u003cstrong\\u003e8d\\u003c/strong\\u003e, \\u003cstrong\\u003e9d\\u003c/strong\\u003e, \\u003cstrong\\u003e10d\\u003c/strong\\u003e). Boric, silyl and coordinating thiomethoxyl were also compatible under the decarbonylative conditions (Table 3, \\u003cstrong\\u003e11d\\u003c/strong\\u003e\\u0026ndash;\\u003cstrong\\u003e13d\\u003c/strong\\u003e). High yields were also obtained from substrates bearing electron-deficient\\u003cem\\u003e\\u0026nbsp;N\\u003c/em\\u003e-aryl groups bearing carbonyl, trifluoromethyl and even nitro groups (Table 3, \\u003cstrong\\u003e14d\\u003c/strong\\u003e\\u0026ndash;\\u003cstrong\\u003e16d\\u003c/strong\\u003e). \\u0026pi;-Extended and heterocyclic \\u003cem\\u003eN\\u003c/em\\u003e-aryl groups were also amenable to this reaction, furnishing the products in excellent yields (Table 3, \\u003cstrong\\u003e17d\\u003c/strong\\u003e\\u0026ndash;\\u003cstrong\\u003e23d\\u003c/strong\\u003e). Furthermore, acid derivatives bearing \\u003cem\\u003eN\\u003c/em\\u003e-alkyl groups were also compatible, furnishing the desired indolines in high yields (Table 3, \\u003cstrong\\u003e24d\\u003c/strong\\u003e\\u0026ndash;\\u003cstrong\\u003e26d\\u003c/strong\\u003e). The \\u003cem\\u003eN\\u003c/em\\u003e-Ar\\u003csup\\u003e2\\u003c/sup\\u003e substitution was also investigated, and substrates bearing both electron-rich and electron-deficient \\u003cem\\u003eN\\u003c/em\\u003e-Ar\\u003csup\\u003e2\\u003c/sup\\u003e reacted readily to produce the corresponding amines in high yields. Electron-donating alkyl and methoxy groups also afforded high yields (Table 3, \\u003cstrong\\u003e27d\\u003c/strong\\u003e\\u0026ndash;\\u003cstrong\\u003e29d\\u003c/strong\\u003e). Biologically-relevant fluorine and trifiluoromethyl groups were well-tolerated (Table 3, \\u003cstrong\\u003e30d\\u003c/strong\\u003e\\u0026ndash;\\u003cstrong\\u003e32d\\u003c/strong\\u003e). The vinyl group was compatible (Table 3, \\u003cstrong\\u003e33d\\u003c/strong\\u003e). High yields were also obtained from substrates containing \\u0026pi;-extended and heterocyclic groups (Table 3, \\u003cstrong\\u003e34d\\u003c/strong\\u003e\\u0026ndash;\\u003cstrong\\u003e39d\\u003c/strong\\u003e). Finally, norbornenes bearing various functional groups, such as ether, ester and phenyl group were also amenable, furnishing the expected products in high yields (Table 3, \\u003cstrong\\u003e40d\\u003c/strong\\u003e\\u0026ndash;\\u003cstrong\\u003e42d\\u003c/strong\\u003e).\\u003c/p\\u003e\\n\\u003cp\\u003eCrucially, this novel approach to amide synthesis by carboxylic acid reshuffling is readily applicable to transformation of pharmaceuticals and bioactive carboxylic acids (Table 4). For example, mefenamic acid is used as an antipyretic, analgesic, and nonsteroidal anti-inflammatory drug in clinlic. This compound participated readily in the carboxylic acid reshuffling to afford the amide product in high yield (Table 4, \\u003cstrong\\u003e45c\\u003c/strong\\u003e). Clofenamic acid, flufenamic acid and meclofenamic acid are also nonsteroidal anti-inflammatory drugs used to treat inflammation and as analgesics. These drugs are also well-suitable substrates for carboxylic acid reshuffling (Table 4, \\u003cstrong\\u003e46c\\u003c/strong\\u003e\\u0026ndash;\\u003cstrong\\u003e48c\\u003c/strong\\u003e). The substrates bearing bioactive fragment eugenol and isoeugenol also showed high reactivity in the current catalytic system to furnish amides (Table 4, \\u003cstrong\\u003e49c\\u003c/strong\\u003e,\\u003cstrong\\u003e\\u0026nbsp;50c\\u003c/strong\\u003e). Conversely, the divergent nature of this catalytic CO shuttle amidation renders facile access to the corresponding amines in high yields. For example, this decarbonylative amination readily produced target products of flufenamic acid, isoeugenol and eugenol (Table 4, \\u003cstrong\\u003e43d\\u003c/strong\\u003e\\u0026ndash;\\u003cstrong\\u003e45d\\u003c/strong\\u003e) in high yields. The results outlined above in the direct functionalization of biologically active drugs that inherently feature carboxylic acid moieties demonstrate a considerable potential of the present bond reshuffling methodology in medicinal chemistry and drug discovery campaigns.\\u003c/p\\u003e\\n\\u003cp\\u003eWhile our initial focus was on the reaction discovery of the carboxylic acid reshuffling for amide synthesis in the intramolecular context, we were pleased to find that this methodology is also applicable to linear amides (Figure\\u0026nbsp;3\\u0026nbsp;and Table 5). This establishes CO shuttle catalysis concept for the synthesis of acyclic amides by CO migration from common carboxylic acids.\\u003c/p\\u003e\\n\\u003cp\\u003eIn practical terms, it is critical to point out that this carboxylic acid reshuffling is readily scalable (Figure 4A). For example, the mixture of \\u003cstrong\\u003e1a\\u003c/strong\\u003e (5 mmol) and \\u003cstrong\\u003e1b\\u003c/strong\\u003e was heated under standard reaction conditions to afford the corresponding amide on a gram scale in 80% isolated yield. Similarly high yield was also achieved in decarbonylative amination on a gram scale.\\u003c/p\\u003e\\n\\u003cp\\u003eAs demonstrated in the substrate scope studies, this novel process for amide synthesis is distinguished by functional group tolerance to many valuable functional groups, facilitating further derivatization to afford target amide products that are not easily obtained by other methods. Furthermore, the amide itself provides a highly valuable handle for streamlined synthesis as a versatile synthetic intermediate (Figure 4B). Taking \\u003cstrong\\u003e1c\\u003c/strong\\u003e as an example, the amide bond can be easily reduced with LiAlH\\u003csub\\u003e4\\u003c/sub\\u003e to produce the corresponding six-membered cyclic amine \\u003cstrong\\u003eg\\u003c/strong\\u003e in 77% yield. Likewise, the amide bond can efficiently react with organometallic reagents, such as MeLi, to generate cyclic amine \\u003cstrong\\u003eh\\u003c/strong\\u003e. Furthermore, Ti(OPr\\u003cem\\u003e\\u003csup\\u003ei\\u003c/sup\\u003e\\u003c/em\\u003e)\\u003csub\\u003e4\\u003c/sub\\u003e-mediated Kulikovich cyclopropanation with EtMgBr delivers the spiro amine \\u003cstrong\\u003ei\\u003c/strong\\u003e. Finally, treatment with DIBAL-H and dehydration furnishes the active imine salt \\u003cstrong\\u003ej\\u003c/strong\\u003e in high yield. These reactions further highlight the synthetic value of the present carboxylic acid reshuffling amide bond synthesis. Furthermore, quinoline and indoline heterocycles have featured many prominent applications in drug discovery and materials science.\\u003c/p\\u003e\\n\\u003cp\\u003eTo gain mechanistic insights into this reaction, extensive studies were conducted. First, we synthesized the mixed anhydride\\u0026nbsp;\\u003cstrong\\u003ela\\u003c/strong\\u003e and found that it could be converted into \\u003cstrong\\u003e1c\\u003c/strong\\u003e in 91% yield and into \\u003cstrong\\u003e1d\\u0026nbsp;\\u003c/strong\\u003ein 94% yield, indicating that the mixed anhydride is the active intermediate (Figure 4C,\\u0026nbsp;left). As mentioned, the N\\u0026ndash;H moiety can be acylated by anhydride to produce \\u003cstrong\\u003ef\\u003c/strong\\u003e as detected by GC-MS. To verify whether \\u003cem\\u003eN\\u003c/em\\u003e-Piv product could participate in the reaction, we synthesized this potential intermediate and subjected it to the reaction conditions. However, when \\u003cstrong\\u003ef\\u003c/strong\\u003e was reacted under the respective conditions, only a trace amount of \\u003cstrong\\u003e1d\\u003c/strong\\u003e was generated, while \\u003cstrong\\u003e1c\\u003c/strong\\u003e was not detected (Figure 4C,\\u0026nbsp;right). These results suggest that \\u003cstrong\\u003ef\\u003c/strong\\u003e is an unproductive byproduct of this process.\\u003c/p\\u003e\\n\\u003cp\\u003eIn the CO shuttle amidation, CO was re-utilized with very high efficiency. Thus, we carried out a reaction in glass tubes with different volumes (Figure 4D,\\u0026nbsp;left). The yields in 10 mL, 25 mL, and 100 mL reactor did not change significantly and were 94%, 93% and 82%, respectively. We also conducted the reaction with different loading of CO adsorbent and found that the yields also varied from 89\\u0026ndash;91% (Figure 4D,\\u0026nbsp;right). These results indicate that CO does not permeate outside the reaction system and coordinates with palladium during the reaction, thus enabling the successful utilization of carboxylic acid reshuffling.\\u003c/p\\u003e\\n\\u003cp\\u003eTo gain insight into the selectivity of this process, intermolecular competition experiments were conducted (Figure 4E and\\u0026nbsp;4F). When \\u003cstrong\\u003e8a\\u003c/strong\\u003e and \\u003cstrong\\u003e1a\\u003c/strong\\u003e were allowed to react with NBE under carboxylic acid reshuffling conditions, \\u003cstrong\\u003e7c\\u003c/strong\\u003e and \\u003cstrong\\u003e1c\\u003c/strong\\u003e were produced in 14% and 25% yields, respectively (Eq 1). When \\u003cstrong\\u003e20a\\u003c/strong\\u003e competed with \\u003cstrong\\u003e1a\\u003c/strong\\u003e, \\u003cstrong\\u003e13c\\u003c/strong\\u003e was obtained in 19% yield, while \\u003cstrong\\u003e1c\\u003c/strong\\u003e was generated in 20% yield (Eq 2). The competition between \\u003cstrong\\u003e8a\\u003c/strong\\u003e and \\u003cstrong\\u003e20a\\u003c/strong\\u003e produced \\u003cstrong\\u003e7c\\u003c/strong\\u003e and \\u003cstrong\\u003e13c\\u003c/strong\\u003e in 15% and 22% yields (Eq 3). Similar results were obtained for decarbonylative amination (Eqs 7\\u0026ndash;9). These results indicate that although the electronic effect of \\u003cem\\u003eN\\u003c/em\\u003e-Ar\\u003csup\\u003e1\\u003c/sup\\u003e is not significant, substrates with electron-deficient \\u003cem\\u003eN\\u003c/em\\u003e-aryl\\u003csup\\u003e1\\u003c/sup\\u003e are inherently favored. Meanwhile, allowing \\u003cstrong\\u003e34a\\u003c/strong\\u003e to compete with \\u003cstrong\\u003e1a\\u003c/strong\\u003e under carboxylic acid reshuffling conditions produced \\u003cstrong\\u003e30c\\u003c/strong\\u003e and \\u003cstrong\\u003e1c\\u003c/strong\\u003e in 14% and 30% yields, respectively (Eq 4). When \\u003cstrong\\u003e38a\\u003c/strong\\u003e competed with \\u003cstrong\\u003e1a\\u003c/strong\\u003e, \\u003cstrong\\u003e34c\\u003c/strong\\u003e was obtained in 35% yield, while \\u003cstrong\\u003e1c\\u0026nbsp;\\u003c/strong\\u003ewas produced in 11% yield (Eq 5). The competition of \\u003cstrong\\u003e34a\\u003c/strong\\u003e with \\u003cstrong\\u003e38a\\u003c/strong\\u003e also generated \\u003cstrong\\u003e30c\\u003c/strong\\u003e and \\u003cstrong\\u003e34c\\u003c/strong\\u003e in 4% and 20% yields (Eq 6). Similar results were obtained for decarbonylative amination (Eqs 10\\u0026ndash;12). These results indicate that electron-deficient benzoic acids are inherently favored.\\u003c/p\\u003e\\n\\u003cp\\u003eThe Hammett analysis was next subsequently conducted\\u003csup\\u003e51\\u003c/sup\\u003e. A positive slope (\\u003cem\\u003e\\u0026rho;\\u003c/em\\u003e = 0.259) was observed for the CO shuttle amidation of benzoic acids having \\u003cem\\u003epara\\u003c/em\\u003e-substituted \\u003cem\\u003eN\\u003c/em\\u003e-Ar with NBE \\u003cstrong\\u003e1b\\u003c/strong\\u003e (Figure\\u0026nbsp;5a). A larger value (\\u003cem\\u003e\\u0026rho;\\u003c/em\\u003e = 1.909) was obtained for the same reaction of benzoic acids bearing \\u003cem\\u003epara\\u003c/em\\u003e-substituted benzene ring with \\u003cstrong\\u003e1b\\u003c/strong\\u003e (Figure\\u0026nbsp;5b). In the decarbonylative amination, similar slope values were observed (Figure\\u0026nbsp;5c and\\u0026nbsp;5d). The data indicates that electron-deficient substrates are inherently more favorable. Compared with \\u003cem\\u003eN\\u003c/em\\u003e-Ar, the electronic effect at the benzene ring of benzoic acids is comparatively larger and thus contributes more significantly to the rate-determining step. The Hammett plot results are consistent with intermolecular competition experiments.\\u003c/p\\u003e\\n\\u003cp\\u003eNext, the kinetic analysis was performed for the CO shuttle amidation and showed that the rate was first-order dependent on benzoic acids, palladium and olefins, indicating that norbornenes had a significant effect on the rate (Figure\\u0026nbsp;5e\\u0026ndash;5g). The activation energy was calculated as 26.43 kcal/mol based on the temperature effect (Figure\\u0026nbsp;5h)\\u003csup\\u003e52\\u003c/sup\\u003e. However, in the case of decarbonylative amination, the outcome was different. The rate was first-order dependent on benzoic acids and palladium catalyst, but close to zero-order dependent on norbornenes (Figure\\u0026nbsp;5i\\u0026ndash;5k). These results suggest that norbornenes do not have a major effect on the rate during the reaction and that the process is a mono-palladium catalytic process. The activation energy also increased (30.35 kcal/mol), which is consistent with the comparatively higher temperature employed in this reaction (Figure\\u0026nbsp;5l).\\u003c/p\\u003e\\n\\u003cp\\u003eOn the basis of control experiments, competition studies, Hammett analysis and kinetic studies, a plausible mechanism is proposed as shown in\\u0026nbsp;Figure 6. Benzoic acids are first activated to give the active mixed anhydrides, which undergo oxidative addition of Pd(0) into the C(O)-acyl bond to produce the acyl palladium species \\u003cstrong\\u003eII\\u003c/strong\\u003e. The resulting intermediate undergoes decarbonylation, alkene insertion, intramolecular ligand exchange and reductive elimination via direct decarbonylative pathway. However, when the ligand is switched from cataCxium A to bidenate dppp, a transient decarbonylation of species \\u003cstrong\\u003eⅡ\\u003c/strong\\u003e takes place to afford the CO-ligated aryl palladium \\u003cstrong\\u003eⅢ\\u003c/strong\\u003e. This intermediate undergoes alkene insertion, intramolecular ligand exchange, and key CO re-insertion to generate amides after reductive elimination. This cycle represents a novel approach to amide synthesis, where the carboxylic acid is positionally reshuffled to form N\\u0026ndash;C(O) bonds in analogy to the venerable acid/amine condensation.\\u003c/p\\u003e\\n\\u003cp\\u003eIn conclusion, amide bonds have been at the heart of organic synthesis for more than a century. The classical and most widely utilized method for amide synthesis involves condensation of activated carboxylic acids with amines, and this approach has been exploited in every facet of chemical science on daily basis. Herein, we developed a novel paradigm for the synthesis of amides that capitalizes on molecular reshuffling of the carboxylic acid functional group. In this blueprint, amino benzoic acids engage in oxidative addition to a low valent metal, and CO generated by decarbonylation undergoes transfer insertion into alkenes before the last reductive elimination. This carbonyl shuttle amide synthesis is precisely controlled by ligand selection, where the reaction pathway can be fully switched to a divergent amine synthesis by decarbonylative amination. This novel transform is capable of forming amides by the repositioned classical carboxylic acid/amine condensation and should greatly advance vistas on the synthesis of valuable amide bonds by carbonyl reshuffling.\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eData availability\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe data supporting the findings of the study are available in the paper\\u0026nbsp;and its\\u0026nbsp;supplementary\\u0026nbsp;information. All data are available from the\\u0026nbsp;corresponding authors upon request.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAcknowledgments\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eT.C. thanks the National Nature and Science Foundation of China (Grant Nos. 22261015, 21871070) and the Key R\\u0026amp;D project of Hainan province (No. ZDYF2020168, XTCX2022STA01) for financial support. M.S. thanks Rutgers University and the NSF (CAREER CHE-1650766) for financial support.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAuthor contributions\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eConceptualization: M. S. and T. C.;\\u0026nbsp;Methodology: C. L., Q. W., Y. F. and Y. W.;\\u0026nbsp;Investigation: C. L.;\\u0026nbsp;Visualization: C. L. and Q. W.;\\u0026nbsp;Funding acquisition: T. C.;\\u0026nbsp;Project administration: M. S. and T. C.;\\u0026nbsp;Supervision: M. S. and T. C.;\\u0026nbsp;Writing \\u0026ndash; original draft: M. S. and T. C.;\\u0026nbsp;Writing \\u0026ndash; review \\u0026amp; editing: C. L., Q, T., B. S., T. H., L. L., M. S. and T. C.pt.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eCompeting interests\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eAuthors declare that they have no competing interests.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eCorrespondence\\u003c/strong\\u003e and requests for materials should be addressed to Michal Szostak and Tieqiao Chen.\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\n\\u003cli\\u003eGreenberg, A., Breneman, C. M. \\u0026amp; Liebman, J. F. The Amide Linkage: Structural Significance in Chemistry, Biochemistry and Materials Science (Wiley, New York, 2000).\\u003c/li\\u003e\\n\\u003cli\\u003eBrown, D. G. \\u0026amp; Bostro¨m, J. Analysis of past and present synthetic methodologies on medicinal chemistry: Where have all the new reactions gone? \\u003cem\\u003eJ. Med. 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Amides are key building blocks of peptides, pharmaceuticals, polymers, advanced materials and biologically active compounds. The synthesis of amides has been ranked as the most common reaction performed by synthetic chemists in the last century. While the most common approach by far involves the condensation of carboxylic acids and amines, this approach has been historically limited by the positional connectivity of the key carboxylic acid group. Herein, we report a new approach to amide synthesis that relies on molecular shuffling of carboxylic acid functional group. It is found that amino benzoic acids engage in oxidative addition to a Pd(0) complex, and CO generated by decarbonylation undergoes transfer insertion into the C–Pd bond formed by alkene insertion before the last reductive elimination, achieving carbonyl shuttle amidation. The carbonyl shuttle amide synthesis is precisely controlled by ligand selection, where the reaction pathway can be fully switched to a divergent amine synthesis by decarbonylative amination. This approach is characterized by a particularly wide substrate scope and excellent functional group tolerance, including bioactive molecules and late-stage functionalization. The method is scalable, which highlights the practical utility of this new method for the synthesis of amides. Moreover, this strategy is applicable to the synthesis of linear amides. The study opens new avenues for the synthesis of amides by carbonyl reshuffling and advances an accelerated utilization of amides as critical building blocks in chemical science.\",\"manuscriptTitle\":\"Amide Synthesis via Molecular Shuffling of Carboxylic Acids\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2025-10-24 05:56:32\",\"doi\":\"10.21203/rs.3.rs-7819613/v1\",\"editorialEvents\":[],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"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\":\"0091a371-4500-4df8-8b5e-86ed8d55bce6\",\"owner\":[],\"postedDate\":\"October 24th, 2025\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"under-review\",\"subjectAreas\":[{\"id\":56755902,\"name\":\"Physical sciences/Chemistry/Chemical synthesis/Synthetic chemistry methodology\"},{\"id\":56755903,\"name\":\"Physical sciences/Chemistry/Organic chemistry/Synthetic chemistry methodology\"}],\"tags\":[],\"updatedAt\":\"2026-02-24T04:01:19+00:00\",\"versionOfRecord\":[],\"versionCreatedAt\":\"2025-10-24 05:56:32\",\"video\":\"\",\"vorDoi\":\"\",\"vorDoiUrl\":\"\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-7819613\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-7819613\",\"identity\":\"rs-7819613\",\"version\":[\"v1\"]},\"buildId\":\"8U1c8b4HqxoKbykW_rLl7\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}