Integrating hydroformylations into a methanol economy

Integrating hydroformylations into a methanol economy | 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 Integrating hydroformylations into a methanol economy Troels Skrydstrup, Andreas Bonde, Joakim Jakobsen, Alexander Ahlers, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4182149/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 In almost all man-made chemical products, the carbon skeletons originate from unsustainable fossil resources 1 . As the green transition gains traction, introducing CO 2 as a feedstock for organic synthesis will be one of the keys to a carbon-neutral chemical industry 2-4 . However, redesigning large scale processes for alternative feedstocks is challenging. Methanol sourced from CO 2 is presently becoming available, linked to the emergence of a methanol economy utilising it as circular fuel 5,6 . This presents an ideal entry point to rethink the highly interconnected chemical production chains. Here, we report that interlocking a ruthenium-catalysed methanol-to-syngas reforming with a low-pressure rhodium-catalysed hydroformylation in a two-reactor setup affords oxo-products in high yields and selectivity. This study elucidates the kinetics and selectivity of gas formation and their key role in matching both catalytic cycles. Finally, the utilisation of fuel-grade green methanol as a syngas source is demonstrated. If combined with methanol-to-olefin processes and green methanol production, oxo-products could thus be generated using solely CO 2 as the carbon feedstock through a methanol platform. The here developed dual catalysis can be considered a blueprint for remodelling industrial processes. Physical sciences/Chemistry/Catalysis/Homogeneous catalysis Physical sciences/Chemistry/Chemical synthesis/Synthetic chemistry methodology Physical sciences/Chemistry/Green chemistry/Sustainability Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Products of the chemical industry, such as plastics, textiles, fertilisers, pharmaceuticals, and others, are ubiquitous and greatly impact the quality of human life. While the demand for these products increases every year, so does the consumption of fossil feedstocks that sit at the start of the vast majority of all chemical value chains. With the current trends in decarbonising transportation and energy production, the chemical industry is set to be the principal consumer of fossil fuels 1 . It has become clear that to avert catastrophic impacts of human consumption on the planet, a significant shift of this industrial sector away from unsustainable feedstocks to a circular carbon economy and renewable energy is a pressing necessity 2-4 . These goals have also been formulated in the Paris Agreement 7 , the fulfilment of which will be crucial in order to offset climate change. Using CO 2 to construct the multitude of carbon skeletons in diverse sets of molecules is a challenging imperative. For example, life cycle assessment studies on synthetic polymers revealed that besides efficient recycling, both biomass and captured CO 2 have to be implemented as feedstocks, in order to achieve a sustainable economy for plastics within the planetary boundaries 2 . For introducing renewable carbon into chemical production chains, redesigning the complexly interconnected plethora of processes from scratch, and utilising CO 2 in various chemical processes, is problematic 8 . Instead, rerouting access points to established productions from fossil resources to sustainable platforms would be preferable. Green methanol, available from biomass or captured CO 2 , is materialising as a sustainable energy carrier. George Olah first proposed methanol as carbon neutral fuel system (Fig 1A), as it is easier to handle in storage and transportation than gaseous hydrogen 5 . Currently, considerable investments are driving the strong expansion of green methanol production across EU countries. Estimations predict an annual production of 135 Mt bio-methanol from biomass, and 250 Mt e -methanol from captured CO 2 by 2050 6 . The advent of the first cargo ship running purely on green methanol in 2023, both bio-methanol and e -methanol 9 , signals the acceleration of the energy transitions. This development is further supported by the growing implementation of power-to-X concepts using excess CO 2 -neutral energy to produce green hydrogen and methanol 10 . For carbon-neutral chemical synthesis, the increasing availability of green methanol becomes an ideal entry point to rethink value chains for the generation of sustainable chemicals. As methanol is already integrated into several large-scale chemical processes 11-14 , extending its utilisation to access other commodity chemicals is tangible 15 . For example, the implementation of methanol-to-olefin (MTO) processes on an industrial scale for accessing important alkenes, demonstrates the worth of this principle on a commercial level 12 . Reforming methanol into CO and H 2 (syngas) is challenging 16 , but could be another central transformation for utilising it as a C1 building block 17-19 . Recently, Leitner et al. reported the first homogenous catalysed system for this valuable reaction 20 (Fig. 1B). Hydroformylations are highly relevant for accessing a variety of products from bulk to fine chemicals, including plasticisers, vitamins, fragrances, and flavours, as well as many organic building blocks. It is a central transformation as it introduces molecular complexity into simple hydrocarbon feedstocks 21-24 . Currently, olefins with syngas (H 2 /CO mixture) are reacted with molecular rhodium or cobalt catalysts to oxo-products with an annual production of >12 million metric tons 21-23 As of now, the carbon skeleton of industrial oxo-products derives entirely from virgin grade fossil resources (Fig. 1C). To minimise them, Huber et al. recently reported the hydroformylation of pyrolysis oils 25 . This elegant approach could serve to upcycle low-value polyolefin waste to valuable aldehydes. We recognised that the conversion of methanol to syngas could be interlocked with hydroformylations of terminal olefins via a sequential dual catalysis. Here in, we identify the success criteria for matching the kinetics and selectivity of both catalytic cycles, allowing access to various aldehydes in up to excellent selectivity and yields. The protocol for hydroformylations relies on a two-reactor setup, separating the catalytic reactions within a closed system. Syngas is released by a ruthenium-catalysed acceptorless dehydrogenation 20 of stoichiometric amounts of methanol with respect to the alkene, while a rhodium-based catalyst consumes syngas yielding aldehydes from alkenes in the adjacent reactor. While not mimicking the conditions of industrial processes, this work represents a blueprint study on how redesigning such processes can be approached and achieved. Furthermore, by combining this concept with MTO processes using bio- or e-methanol for the synthesis of olefins, or bioethanol to ethylene processes, which also have also been implemented at scale 26 , oxo-products could be generated solely from CO 2 as chemical feedstock. Preliminary investigations for developing the dual catalysis focused on exploring the efficiency and selectivity of the low-pressure hydroformylation regarding the H 2 /CO ratio. Experiments were conducted using estragole ( 1a ) as a benchmark substrate (Fig. 1D). As allylbenzenes present challenging linear-to-branched selectivity for oxo product formation and the isomerisation to the corresponding β-methyl styrene is preferred, we considered it a suitable model olefin for selectivity-focused studies. Rh(acac)(CO) 2 and 6-diphenylphosphanyl-1 H -pyridine-2-one (6-DPPon) were chosen as catalytic system suitable for low-pressure hydroformylations 27,28 . In order to precisely control the ratio of gases, stochiometric gas releases for each CO 29 and H 2 30 were conducted in a three-reactor system. While an overshot of hydrogen resulted in alkene hydrogenation and, to a minor degree, favoured olefin isomerisation, the hydroformylation was found to be most efficient at a 2:1 H 2 to CO ratio. At increasing CO concentrations, decreasing aldehyde yields were obtained, possibly due to inhibition of the catalyst by CO. Based on this, methanol should be an ideal syngas source for the tested catalytic system. However, the dependency on gas mixture also highlights the importance of matching the kinetics and selectivity of gas release to the hydroformylation, as hydrogen and carbon monoxide must be liberated close to simultaneously in the correct ratio. The experimental investigations were initiated by attempting to match the Ru-MACHO catalysed methanol dehydrogenation with the Rh(acac)(CO) 2 /6-DPPon hydroformylation system on estragole 1a (Fig. 2A). In the original report, Ru-MACHO in neat methanol was heated to 150 °C in an autoclave in order to form H 2 /CO at the stoichiometric limit of 2:1 ratio 20 . However, the hydroformylation proceeds in THF at room temperature 27,28 . As the two methods require vastly different reaction temperatures, a two-reactor setup with a reflux condenser integrated into the syngas-releasing reactor was designed (see supplementary material). Performing the syngas formation in neat methanol (10 equivalents with respect to olefin 1a ), as reported by Leitner et al . 20 , the dual catalysis resulted in only 28% yield of the aldehyde after 16 h. Meanwhile, 32% of estragole isomerised to the internal olefin, while 39% was hydrogenated. The distribution of products indicates that the hydrogen release is considerably favoured over the CO release, resulting in a gas mixture unsuitable for efficient hydroformylation. The methanol to syngas reforming formally proceeds through two consecutive dehydrogenations 20,31 . The first one liberates hydrogen and formaldehyde, which then reacts with methanol, releasing hydrogen under the formation of methyl formate. This intermediary formate then serves as CO. We recognised that in an apolar reaction medium, the consecutive steps could potentially proceed at higher rates as releasing the polar intermediates from the catalyst into the solution should be less favoured. To evaluate this hypothesis, methanol was dissolved in toluene (1.0 mL). Using 10 equivalents of methanol (6.2 M) resulted in a slight decrease in side-product formation with further decreasing methanol amounts improving the selectivity. Gratifyingly, applying 1.5 equivalents of methanol (1.4 M) significantly increased the yield of the combined aldehydes ( 2a ) to almost quantitative and with a linear-to-branched ratio ( l : b ) of 9:1. Decreasing the methanol amount further to 1.1 equivalents was found to be slightly less efficient, potentially due to overall a low partial pressure of gaseous reagents. Therefore, the studies were continued using 1.5 equivalents of methanol. Reducing the reaction temperature to 130 °C proved to be less effective, but nonetheless yielded the linear aldehyde in good yield and high selectivity. As both methyl formate and paraformaldehyde have been reported to act as intermediates in the catalytic syngas release 20,31 , we were interested in testing them as syngas surrogates instead of methanol. Indeed, both compounds liberated suitable syngas mixtures in the dual catalysis set-up, although unreacted starting material 1a was detected in both cases. Lastly, alternative MACHO-derived metal complexes were considered. However, none of the tested candidates led to an overall more efficient system than Ru-MACHO. With both the rate of the gas release and the composition of the gas mixture being crucial for interlocking the two catalytic cycles, we were interested in elucidating the kinetics of the dehydrogenation process. In order to observe the kinetic profiles, the pressure inside the reactor was monitored using a Keller pressure manometer (Fig. 2B–D). The investigation was initiated on methanol by running the reaction with and without the consecutive hydroformylation step that would consume the gaseous reagents (Fig. 2B). In the absence of the gas-consuming reaction (Fig. 2B, dark blue), a steep increase in pressure reaching approximately 4.8 bars within 2 h demonstrates efficient gas release, whereafter the pressure stabilises. If run with the hydroformylation in the adjacent reactor (Fig. 2B, light blue), the pressure tops at a lower maximum of 4.5 bars before declining again. This reveals that the hydroformylation is initiated before full gas release is achieved and stresses the need for close to simultaneous CO and H 2 release from the beginning. After 6 h the pressure stagnates at 3.8 bar, signalling full consumption of the olefin. Lastly, MeOH- d 4 was tested in the acceptorless dehydrogenation (Fig. 2B, violet). The gas formation was found to be significantly slower but viable with the pressure reaching its maximum after 4 h. This discrepancy can be explained by the kinetic isotope effect observed with deuterated methanol. Next, the proposed intermediates of syngas formation 20,31 were tested to compare the efficiency of the gas release. Using paraformaldehyde instead of methanol (Fig. 2C, light blue) resulted in a significantly slower increase in pressure. However, using a 1:1 mixture of methanol and paraformaldehyde revealed a kinetic profile which superimposes well with pure methanol (Fig. 2C, dark blue). Methyl formate alone (Fig. 2D, light blue) was found to react considerably slower than methanol and paraformaldehyde. Here again, combining methanol together with methyl formate resulted in a profile well matched to methanol only (Fig. 2D, dark blue). Potentially, this hints at methanol supporting the deconstruction of the following intermediates into hydrogen and carbon monoxide. In turn, using paraformaldehyde or methyl formate as syngas surrogate would be detrimental. Lastly, for methanol, paraformaldehyde, and methyl formate, the gas composition was measured for each during the pressure build up using gas chromatography. For methanol, a close to the ideal 2:1 mixture of H 2 and CO was consistently observed after 1 h and 2 h. For both paraformaldehyde and methyl formate, the gas mixture was found to be less consistent over time and contained a lower ratio of hydrogen vs CO than that of methanol. Considering that these two syngas surrogates resulted in incomplete consumption of estragole in the dual catalysis set-up (Fig. 2A), these results align with the conclusion of the preliminary studies on the hydroformylation using different H 2 to CO ratios (Fig. 1D), indicating that a 2:1 ratio H 2 to CO is ideal. Furthermore, this study stresses that both the gas mixture and the release rate must match with the hydroformylation, with toluene as reaction medium aiding a consistent ratio between hydrogen and CO being released from methanol. With the optimised reaction conditions at hand, we turned our attention to exploring the substrate scope of the hydroformylation reaction. Several terminal olefins (Fig. 3, 1 – 32 ) of various molecular complexity were subjected to the catalytic conditions, all of which yielded the corresponding aldehydes in good to quantitative yields and with good to excellent selectivity towards the linear ( l ) regioisomer with styrenes being an anticipated exception. Allylbenzene derivates with various functional groups ( 1 – 16 ) were used to probe functional group tolerance and sterical effects. Alkyl-substituted, as well as unsubstituted allylbenzenes, undergo hydroformylation with a comparable efficiency to 1 ( 2 – 4 ). Several functional groups that can be utilised for orthogonal C–C or C–X bond formations, such as (pseudo)halides and pinacol boronic esters 32-34 , are well tolerated ( 5 – 7 ). Furthermore, substrates with free and protected alcohol groups ( 8 – 10 ), anilines ( 12 and 13 ), as well as esters ( 11 ), nitro groups, nitriles ( 14 and 15 ), and thioethers ( 16 ) afford excellent yields of the hydroformylated products. For all allylbenzene substrates the l : b selectivity is good and commonly at a ratio of 10:1, however, for electron-deficient systems, the selectivity is reduced ( 5 , 7 , 11 , 14 and 15 ). For the homoallylated analogue of the benchmark olefin ( 17 ) and a paracetamol-derived homoallyl ( 18 ), the selectivity for n -aldehydes was found to be significantly better than for the allylic counterparts. Styrenes are also viable starting materials in this transformation, providing corresponding aldehydes in excellent yields with the branched isomer as the major product ( 19 and 20 ) 28,35 . The two regioisomers of 20 can be separated, making it possible to utilise the branched aldehyde for the synthesis of Naproxen 35 . In chemical industries, a central role of hydroformylations is introducing molecular functionality into acyclic alkyl olefin platforms acquired from naphtha feedstock 36 . Among certain others, oxo products made from C 8 -olefins are of high economic importance. Using the here-developed dual catalysis approach, n -octene was converted to n -nonanal ( 21 ) in close to quantitative yield with excellent selectivity using methanol. More complex aliphatic compounds also undergo hydroformylation smoothly and selectively, affording the desired n -aldehydes in excellent yields ( 22 – 24 ). To demonstrate the value of this protocol for research and development laboratories, the hydroformylation of various natural product derivatives ( 25 – 27 ) and drug precursors ( 28 – 32 ) containing a diverse range of functionalities commonly displayed in drug-like compounds was conducted. The natural product quinine, containing an N -heterocycle, underwent the reaction seamlessly with excellent selectivity ( 25 ). A protected sugar and an allylated estradiol steroid derivative presented themselves as suitable substrates and afforded the corresponding aldehyde ( 26 ) and lactol ( 27 ), respectively. Finally, five drug precursors ( 28 – 32 ) were prepared in excellent yields but with various selectivity using the methanol-based hydroformylation. It should be noted that the linear regioisomers of 28 – 32 can in a single transformation be converted into the respective drug molecules ( 28 to buspirone, 29 to diphenidol, 30 to mebeverine, 31 to vilanterol, and 32 to crispine A), thus this protocol may be of interest for late-stage isotopic labelling 35 . In line with evaluating the potential application of this protocol in pharmaceutical R&D laboratories, we conducted stable isotope labelling of compound 1a by simply substituting the methanol source for commercial methanol- 13 C or methanol- d 4 (Fig. 4A). As expected, utilising methanol- 13 C in the syngas-releasing reactor with the optimised conditions (Fig. 2A) did not affect either the yield or regioselectivity of the hydroformylation reaction, and aldehyde 33 was isolated with excellent incorporation of carbon-13 of 98% at the carbonyl position. We reasoned that quantitative incorporation is not achieved as both precatalysts contain unlabelled carbonyl ligands, totalling a theoretical 2.3 mol% unlabelled carbon monoxide available in the reaction. Next, we investigated the use of methanol- d 4 as an enriched isotope source. Once again, the hydroformylation reaction proceeded well though with a slightly lowered yield of 92% of the product, but with excellent regioselectivity towards the linear aldehyde 34 and with a deuterium incorporation of 1.99. As isotopically labelled methanol is widely available and introduction of stable isotopes into new pharmaceutically active entities is of high importance for drug metabolism studies, this protocol could represent an interesting contribution to drug development programs. Finally, to investigate the potential for accessing renewable carbon-based oxo-products, we turned to testing samples of industrial grade e -methanol for syngas release. Vulcanol™ is the first commercial e-methanol produced from Carbon Recycling International (CRI) in Iceland from the hydrogenation of flue gas with e -hydrogen 37 . To our delight, utilising 1.5 equiv of fuel-grade Vulcanol™ in the hydroformylation of olefin 1a directly from a bottle obtained from CRI without any form for purification except degassing with argon afforded 2a in an excellent yield of 97% and with a satisfactory l : b -selectivity of 13:1, using the optimised conditions (Fig. 2A). With the potential for large-scale applications in mind, we were interested in exploring the scalability of the here-developed method. Once again, our benchmark reaction using estragole ( 1a ) was now performed on a gram-scale (3.71 g, 25.0 mmol) in a two-reactor system with a volume of 430 mL in total (Fig. 4B), representing an upscaling of 25 times. With Vulcanol™ as the syngas source, 2a was isolated in a gratifying 84% yield with a l : b -selectivity of 14:1. This preliminary upscaling attempt applying e -methanol highlights the robustness of the interlocking catalysis. In summary, we report the successful union of two valuable catalytic cycles, the acceptorless dehydrogenation of methanol to syngas and hydroformylations of olefins. We demonstrate the importance of the rate and selectivity of the syngas release, and how matching it with a low-pressure rhodium-catalysed hydroformylation results in an efficient methodology for accessing oxo products. Furthermore, it is possible to replace coal- or natural gas-derived syngas with fuel-grade e -methanol accessed from CO 2 capture and hydrogenation on gram scale. While these conditions do not mimic those applied in industrial settings producing bulk chemicals, we consider this dual catalysis a proof-of-concept for the possibility of synthesising oxo-products entirely from CO 2 as renewable carbon feedstock and integrating this important transformation into a methanol economy. It is our expectation that redesigning the chemical value chains to extend from renewable platforms such as methanol may be an important part of establishing a sustainable chemical industry. Declarations Acknowledgements: We thank Jens Christian Kondrup for aiding in the development of the refluxing two-reactor system. We Also thank Carbon Recycling International—particularly Ómar Sigurbjörnsson—for providing us with e -methanol, Vulcanol™. We are grateful to Johannes Eberhard Reiner and Lisa Klimper for their support with gas chromatography for syngas composition studies. Funding: We are highly appreciative of the financial support from the Danish National Research Foundation (grant no. DNRF118), the Novo Nordisk Foundation CO 2 Research Center that was funded by the Novo Nordisk Foundation (grant no. NNF21SA0072700), NordForsk (grant no. 85378), and Aarhus University. Support from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No 859910 is also gratefully acknowledged. This publication reflects the views only of the authors, and the Commission cannot be held responsible for any use which may be made of the information contained therein. Author contributions: A.B., J.B.J., and T.S. conceived the concept. A.B. designed the experiments and conducted the experimental investigations with J.B.J., W.H., and A.A. A.B. performed visualisations and wrote the manuscript with J.B.J., A.A., and T.S., who also directed the research. Funding acquisition was conducted by T.S., M.B., and R.J. Competing interests: T.S. is co-owner of SyTracks A/S, which commercialises CO tubes. Data and materials availability: All data are available in the manuscript or the supplementary materials. 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Thomas, A. A., Zahrt, A. F., Delaney, C. P. & Denmark, S. E. Elucidating the Role of the Boronic Esters in the Suzuki–Miyaura Reaction: Structural, Kinetic, and Computational Investigations. J. Am. Chem. Soc. 140 , 4401-4416 (2018). Pedersen, S. K., Gudmundsson, H. G., Nielsen, D. U., Donslund, B. S., Hammershøj, H. C. D., Daasbjerg, K. & Skrydstrup, T. Main element chemistry enables gas-cylinder-free hydroformylations. Nat. Catal. 3 , 843-850 (2020). Breit, B. & Seiche, W. Recent Advances on Chemo-, Regio- and Stereoselective Hydroformylation. Synthesis 2001 , 0001-0036 (2001). Marlin, D. S., Sarron, E. & Sigurbjörnsson, Ó. Process Advantages of Direct CO 2 to Methanol Synthesis. Front. Chem. 6 (2018). Additional Declarations Yes there is potential Competing Interest. Troels Skrydstrup is co-owner of SyTracks A/S, which commercialises CO tubes. 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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-4182149","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Physical Sciences - Article","associatedPublications":[],"authors":[{"id":308160193,"identity":"3aad14c3-d447-4a1d-97c2-7389a87f03ae","order_by":0,"name":"Troels Skrydstrup","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAApElEQVRIiWNgGAWjYFAC5gPMMKZkAzEaeBjYEkjWwmNAohZ7/jMfPxdUbGPgn5HAeHMGUbZI5G6WnnHmNoPEjQRmyw3EaeHdxszbdpuB4UYCm+QDorTwn3nGzPvvNoM88VoYctiYeRtuMxiAtBDnsBtpxtI8x27zGJ552GxJlPfZ+w8//MxTc1tO7njywZs9xGhBOJCBsYEUDaNgFIyCUTAK8AEAjeQuKJljxtYAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0001-8090-5050","institution":"Aarhus University","correspondingAuthor":true,"prefix":"","firstName":"Troels","middleName":"","lastName":"Skrydstrup","suffix":""},{"id":308160194,"identity":"259c6db5-0250-4cc2-8f55-b33339b12bac","order_by":1,"name":"Andreas Bonde","email":"","orcid":"https://orcid.org/0000-0002-3546-6703","institution":"Aarhus University","correspondingAuthor":false,"prefix":"","firstName":"Andreas","middleName":"","lastName":"Bonde","suffix":""},{"id":308160195,"identity":"a3ad4389-2537-4095-a719-3422e36b7ed7","order_by":2,"name":"Joakim Jakobsen","email":"","orcid":"https://orcid.org/0000-0003-4369-3858","institution":"Aarhus University","correspondingAuthor":false,"prefix":"","firstName":"Joakim","middleName":"","lastName":"Jakobsen","suffix":""},{"id":308160196,"identity":"7cef896d-da91-4456-b9a2-2f7d9187957c","order_by":3,"name":"Alexander Ahlers","email":"","orcid":"","institution":"Aarhus University","correspondingAuthor":false,"prefix":"","firstName":"Alexander","middleName":"","lastName":"Ahlers","suffix":""},{"id":308160197,"identity":"d144e289-23cd-490a-b87d-08f2b70bbc41","order_by":4,"name":"Weiheng Huang","email":"","orcid":"","institution":"Leibniz-Institut für Katalyse","correspondingAuthor":false,"prefix":"","firstName":"Weiheng","middleName":"","lastName":"Huang","suffix":""},{"id":308160198,"identity":"0d1be2b7-dc2d-485d-9b56-aebeb115f1a7","order_by":5,"name":"Ralf Jackstell","email":"","orcid":"https://orcid.org/0000-0002-1948-0417","institution":"LIKAT","correspondingAuthor":false,"prefix":"","firstName":"Ralf","middleName":"","lastName":"Jackstell","suffix":""},{"id":308160199,"identity":"24e6775f-d323-415d-9291-8852731aaae9","order_by":6,"name":"Matthias Beller","email":"","orcid":"https://orcid.org/0000-0001-5709-0965","institution":"Leibniz Institute for Catalysis","correspondingAuthor":false,"prefix":"","firstName":"Matthias","middleName":"","lastName":"Beller","suffix":""}],"badges":[],"createdAt":"2024-03-28 12:10:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4182149/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4182149/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":57821273,"identity":"594d4a0e-3d24-4808-91bb-e5576c463d2f","added_by":"auto","created_at":"2024-06-06 05:53:56","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":539620,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eConcept for accessing oxo-products based on renewable carbon \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003evia\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e dual catalysis.\u003c/strong\u003e \u003cstrong\u003ea\u003c/strong\u003e, Illustration of a circular methanol economy using MeOH as energy carrier and chemical building block. \u003cstrong\u003eb\u003c/strong\u003e, Homogenously Ru-catalysed acceptorless dehydrogenation of methanol to H\u003csub\u003e2\u003c/sub\u003e and CO reported by Leitner \u003cem\u003eet al.\u003c/em\u003e\u003csup\u003e20\u003c/sup\u003e\u003cem\u003e.\u003c/em\u003e \u003cstrong\u003ec\u003c/strong\u003e, Illustration of current non-renewable and here proposed renewable value chains yielding CO\u003csub\u003e2\u003c/sub\u003e-derived oxo-products. \u003cstrong\u003ed\u003c/strong\u003e, Efficiency and selectivity of low-pressure hydroformylation depending on H\u003csub\u003e2\u003c/sub\u003e/CO ratio. Reactions were performed in a three-reactor system.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4182149/v1/13a8346078eb464516560079.png"},{"id":57821272,"identity":"2f5abecf-1420-4518-a532-8ff29e383964","added_by":"auto","created_at":"2024-06-06 05:53:56","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":764891,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eOptimisation of dual catalysis approach and kinetics of syngas formation. a\u003c/strong\u003e, Variations of conditions for matching methanol dehydrogenation to hydroformylation. \u003cstrong\u003eb\u003c/strong\u003e, Pressure profile for syngas released from methanol. \u003cstrong\u003ec\u003c/strong\u003e, Pressure profile for syngas released from paraformaldehyde. \u003cstrong\u003ed\u003c/strong\u003e, Pressure profile for syngas released from methyl formate. \u003cstrong\u003ee\u003c/strong\u003e, \u0026nbsp;Composition of released gas as determined by GC.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4182149/v1/ff03e6cb40ccae72d5729814.png"},{"id":57821884,"identity":"ed11eb84-8029-4c4f-a771-bb7df5208de3","added_by":"auto","created_at":"2024-06-06 06:01:56","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":748090,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSubstrate scope of diverse oxo products accessed through dual catalysis.\u003c/strong\u003e All reactions were performed in a 25 mL modified two-reactor system. General hydroformylation reaction conditions: olefin (1.00 mmol, 1.0 equiv), Rh(acac)(CO)\u003csub\u003e2\u003c/sub\u003e (0.67 mol%), 6-DPPon (3.3 mol%), THF (2.0 mL), room temperature, 16 h. General syngas release conditions: methanol (1.5 equiv), Ru-MACHO-BH (1.0 mol%), toluene (1.0 mL), 150 °C, 16 h. Presented yields are combined isolated yields of the linear and branched aldehydes as an average of two runs. The linear-to-branched ratio is given as \u003cem\u003el\u003c/em\u003e:\u003cem\u003eb\u003c/em\u003e. \u003csup\u003e[a]\u003c/sup\u003e48 h reaction time. \u003csup\u003e[b]\u003c/sup\u003eIsolated as the corresponding lactol. \u003csup\u003e[c]\u003c/sup\u003eYields determined by \u003csup\u003e1\u003c/sup\u003eH NMR spectroscopy using mesitylene as internal standard.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4182149/v1/76d55d337ec49d74aa1018dd.png"},{"id":57822208,"identity":"13a915e8-e381-45c0-927d-dc032813f439","added_by":"auto","created_at":"2024-06-06 06:09:56","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":946765,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eUtilisation of stable isotope labelled and e-methanol in dual catalysis.\u003c/strong\u003e \u003cstrong\u003ea\u003c/strong\u003e, \u003csup\u003e2\u003c/sup\u003eH and \u003csup\u003e13\u003c/sup\u003eC labelling of aldehydes. (\u003cstrong\u003eB\u003c/strong\u003e) Utilisation of \u003cem\u003ee\u003c/em\u003e-methanol (Vulcanol™) for accessing oxo-products on gram scale.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-4182149/v1/6a6a072e094ec8045c0abc77.png"},{"id":57822228,"identity":"132f20cc-a011-40d5-a06b-b2abbfd31b64","added_by":"auto","created_at":"2024-06-06 06:10:02","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3681593,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4182149/v1/81c0c581-742e-477b-8b7c-fe52c1181f76.pdf"},{"id":57821271,"identity":"0293d8b8-b1cc-496a-acc8-fdf70d382b5c","added_by":"auto","created_at":"2024-06-06 05:53:56","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":2107545,"visible":true,"origin":"","legend":"SI (Skrydstrup)","description":"","filename":"SISkrydstrup.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4182149/v1/ae82f2cb9e9c8d72ca2030c7.pdf"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential Competing Interest.\nTroels Skrydstrup is co-owner of SyTracks A/S, which commercialises CO tubes.","formattedTitle":"Integrating hydroformylations into a methanol economy","fulltext":[{"header":"Introduction","content":"\u003cp\u003eProducts of the chemical industry, such as plastics, textiles, fertilisers, pharmaceuticals, and others, are ubiquitous and greatly impact the quality of human life. While the demand for these products increases every year, so does the consumption of fossil feedstocks that sit at the start of the vast majority of all chemical value chains. With the current trends in decarbonising transportation and energy production, the chemical industry is set to be the principal consumer of fossil fuels\u003csup\u003e1\u003c/sup\u003e. It has become clear that to avert catastrophic impacts of human consumption on the planet, a significant shift of this industrial sector away from unsustainable feedstocks to a circular carbon economy and renewable energy is a pressing necessity\u003csup\u003e2-4\u003c/sup\u003e. These goals have also been formulated in the Paris Agreement\u003csup\u003e7\u003c/sup\u003e, the fulfilment of which will be crucial in order to offset climate change. Using CO\u003csub\u003e2\u003c/sub\u003e to construct the multitude of carbon skeletons in diverse sets of molecules is a challenging imperative. For example, life cycle assessment studies on synthetic polymers revealed that besides efficient recycling, both biomass and captured CO\u003csub\u003e2\u003c/sub\u003e have to be implemented as feedstocks, in order to achieve a sustainable economy for plastics within the planetary boundaries\u003csup\u003e2\u003c/sup\u003e. For introducing renewable carbon into chemical production chains, redesigning the complexly interconnected plethora of processes from scratch, and utilising CO\u003csub\u003e2\u003c/sub\u003e in various chemical processes, is problematic\u003csup\u003e8\u003c/sup\u003e. Instead, rerouting access points to established productions from fossil resources to sustainable platforms would be preferable.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Green methanol, available from biomass or captured CO\u003csub\u003e2\u003c/sub\u003e, is materialising as a sustainable energy carrier. George Olah first proposed methanol as carbon neutral fuel system (Fig 1A), as it is easier to handle in storage and transportation than gaseous hydrogen\u003csup\u003e5\u003c/sup\u003e. Currently, considerable investments are driving the strong expansion of green methanol production across EU countries. Estimations predict an annual production of 135 Mt bio-methanol from biomass, and 250 Mt \u003cem\u003ee\u003c/em\u003e-methanol from captured CO\u003csub\u003e2\u003c/sub\u003e by 2050\u003csup\u003e6\u003c/sup\u003e. The advent of the first cargo ship running purely on green methanol in 2023, both bio-methanol and \u003cem\u003ee\u003c/em\u003e-methanol\u003csup\u003e9\u003c/sup\u003e, signals the acceleration of the energy transitions. This development is further supported by the growing implementation of power-to-X concepts using excess CO\u003csub\u003e2\u003c/sub\u003e-neutral energy to produce green hydrogen and methanol\u003csup\u003e10\u003c/sup\u003e.\u0026nbsp;For carbon-neutral chemical synthesis, the increasing availability of green methanol becomes an ideal entry point to rethink value chains for the generation of sustainable chemicals. As methanol is already integrated into several large-scale chemical processes\u003csup\u003e11-14\u003c/sup\u003e, extending its utilisation to access other commodity chemicals is tangible\u003csup\u003e15\u003c/sup\u003e. For example, the implementation of methanol-to-olefin (MTO) processes on an industrial scale for accessing important alkenes, demonstrates the worth of this principle on a commercial level\u003csup\u003e12\u003c/sup\u003e. Reforming methanol into CO and H\u003csub\u003e2\u003c/sub\u003e (syngas) is challenging\u003csup\u003e16\u003c/sup\u003e, but could be another central transformation for utilising it as a C1 building block\u003csup\u003e17-19\u003c/sup\u003e. Recently, Leitner \u003cem\u003eet al.\u003c/em\u003e reported the first homogenous catalysed system for this valuable reaction\u003csup\u003e20\u003c/sup\u003e (Fig. 1B).\u003c/p\u003e\n\u003cp\u003eHydroformylations are highly relevant for accessing a variety of products from bulk to fine chemicals, including plasticisers, vitamins, fragrances, and flavours, as well as many organic building blocks. It is a central transformation as it introduces molecular complexity into simple hydrocarbon feedstocks\u003csup\u003e21-24\u003c/sup\u003e. Currently, olefins with syngas (H\u003csub\u003e2\u003c/sub\u003e/CO mixture) are reacted with molecular rhodium or cobalt catalysts to oxo-products with an annual production of \u0026gt;12 million metric tons\u003csup\u003e21-23\u003c/sup\u003e As of now, the carbon skeleton of industrial oxo-products derives entirely from virgin grade fossil resources (Fig. 1C). To minimise them, Huber \u003cem\u003eet al.\u003c/em\u003e recently reported the hydroformylation of pyrolysis oils\u003csup\u003e25\u003c/sup\u003e. This elegant approach could serve to upcycle low-value polyolefin waste to valuable aldehydes.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;We recognised that the conversion of methanol to syngas could be interlocked with hydroformylations of terminal olefins \u003cem\u003evia\u003c/em\u003e a sequential dual catalysis. Here in, we identify the success criteria for matching the kinetics and selectivity of both catalytic cycles, allowing access to various aldehydes in up to excellent selectivity and yields. The protocol for hydroformylations relies on a two-reactor setup, separating the catalytic reactions within a closed system. Syngas is released by a ruthenium-catalysed acceptorless dehydrogenation\u003csup\u003e20\u003c/sup\u003e of stoichiometric amounts of methanol with respect to the alkene, while a rhodium-based catalyst consumes syngas yielding aldehydes from alkenes in the adjacent reactor. While not mimicking the conditions of industrial processes, this work represents a blueprint study on how redesigning such processes can be approached and achieved. Furthermore, by combining this concept with MTO processes using bio- or e-methanol for the synthesis of olefins, or bioethanol to ethylene processes, which also have also been implemented at scale\u003csup\u003e26\u003c/sup\u003e, oxo-products could be generated solely from CO\u003csub\u003e2\u003c/sub\u003e as chemical feedstock. \u0026nbsp;Preliminary investigations for developing the dual catalysis focused on exploring the efficiency and selectivity of the low-pressure hydroformylation regarding the H\u003csub\u003e2\u003c/sub\u003e/CO ratio. Experiments were conducted using estragole (\u003cstrong\u003e1a\u003c/strong\u003e)\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eas a benchmark substrate (Fig. 1D). As allylbenzenes present challenging linear-to-branched selectivity for oxo product formation and the isomerisation to the corresponding \u0026beta;-methyl styrene is preferred, we considered it a suitable model olefin for selectivity-focused studies. Rh(acac)(CO)\u003csub\u003e2\u003c/sub\u003e and 6-diphenylphosphanyl-1\u003cem\u003eH\u003c/em\u003e-pyridine-2-one (6-DPPon) were chosen as catalytic system suitable for low-pressure hydroformylations\u003csup\u003e27,28\u003c/sup\u003e. In order to precisely control the ratio of gases, stochiometric gas releases for each CO\u003csup\u003e29\u003c/sup\u003e and H\u003csub\u003e2\u003c/sub\u003e\u003csup\u003e30\u003c/sup\u003e were conducted in a three-reactor system. While an overshot of hydrogen resulted in alkene hydrogenation and, to a minor degree, favoured olefin isomerisation, the hydroformylation was found to be most efficient at a 2:1 H\u003csub\u003e2\u003c/sub\u003e to CO ratio. At increasing CO concentrations, decreasing aldehyde yields were obtained, possibly due to inhibition of the catalyst by CO. Based on this, methanol should be an ideal syngas source for the tested catalytic system. However, the dependency on gas mixture also highlights the importance of matching the kinetics and selectivity of gas release to the hydroformylation, as hydrogen and carbon monoxide must be liberated close to simultaneously in the correct ratio.\u003c/p\u003e\n\u003cp\u003eThe experimental investigations were initiated by attempting to match the Ru-MACHO catalysed methanol dehydrogenation with the Rh(acac)(CO)\u003csub\u003e2\u003c/sub\u003e/6-DPPon hydroformylation system on estragole \u003cstrong\u003e1a\u003c/strong\u003e (Fig. 2A). In the original report, Ru-MACHO in neat methanol was heated to 150 \u0026deg;C in an autoclave in order to form H\u003csub\u003e2\u003c/sub\u003e/CO at the stoichiometric limit of 2:1 ratio\u003csup\u003e20\u003c/sup\u003e. However, the hydroformylation proceeds in THF at room temperature\u003csup\u003e27,28\u003c/sup\u003e. As the two methods require vastly different reaction temperatures, a two-reactor setup with a reflux condenser integrated into the syngas-releasing reactor was designed (see supplementary material).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePerforming the syngas formation in neat methanol (10 equivalents with respect to olefin \u003cstrong\u003e1a\u003c/strong\u003e), as reported by Leitner \u003cem\u003eet al\u003c/em\u003e.\u003csup\u003e20\u003c/sup\u003e, the dual catalysis resulted in only 28% yield of the aldehyde after 16 h. Meanwhile, 32% of estragole isomerised to the internal olefin, while 39% was hydrogenated. The distribution of products indicates that the hydrogen release is considerably favoured over the CO release, resulting in a gas mixture unsuitable for efficient hydroformylation. The methanol to syngas reforming formally proceeds through two consecutive dehydrogenations\u003csup\u003e20,31\u003c/sup\u003e. The first one liberates hydrogen and formaldehyde, which then reacts with methanol, releasing hydrogen under the formation of methyl formate. This intermediary formate then serves as CO. We recognised that in an apolar reaction medium, the consecutive steps could potentially proceed at higher rates as releasing the polar intermediates from the catalyst into the solution should be less favoured. To evaluate this hypothesis, methanol was dissolved in toluene (1.0 mL). Using 10 equivalents of methanol (6.2 M) resulted in a slight decrease in side-product formation with further decreasing methanol amounts improving the selectivity. Gratifyingly, applying 1.5 equivalents of methanol (1.4 M) significantly increased the yield of the combined aldehydes (\u003cstrong\u003e2a\u003c/strong\u003e) to almost quantitative and with a linear-to-branched ratio (\u003cem\u003el\u003c/em\u003e:\u003cem\u003eb\u003c/em\u003e) of 9:1. Decreasing the methanol amount further to 1.1 equivalents was found to be slightly less efficient, potentially due to overall a low partial pressure of gaseous reagents. Therefore, the studies were continued using 1.5 equivalents of methanol. Reducing the reaction temperature to 130 \u0026deg;C proved to be less effective, but nonetheless yielded the linear aldehyde in good yield and high selectivity.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAs both methyl formate and paraformaldehyde have been reported to act as intermediates in the catalytic syngas release\u003csup\u003e20,31\u003c/sup\u003e, we were interested in testing them as syngas surrogates instead of methanol. Indeed, both compounds liberated suitable syngas mixtures in the dual catalysis set-up, although unreacted starting material \u003cstrong\u003e1a\u003c/strong\u003e was detected in both cases. Lastly, alternative MACHO-derived metal complexes were considered. However, none of the tested candidates led to an overall more efficient system than Ru-MACHO.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWith both the rate of the gas release and the composition of the gas mixture being crucial for interlocking the two catalytic cycles, we were interested in elucidating the kinetics of the dehydrogenation process. In order to observe the kinetic profiles, the pressure inside the reactor was monitored using a Keller pressure manometer (Fig. 2B\u0026ndash;D). The investigation was initiated on methanol by running the reaction with and without the consecutive hydroformylation step that would consume the gaseous reagents (Fig. 2B). In the absence of the gas-consuming reaction (Fig. 2B, dark blue), a steep increase in pressure reaching approximately 4.8 bars within 2 h demonstrates efficient gas release, whereafter the pressure stabilises. If run with the hydroformylation in the adjacent reactor (Fig. 2B, light blue), the pressure tops at a lower maximum of 4.5 bars before declining again. This reveals that the hydroformylation is initiated before full gas release is achieved and stresses the need for close to simultaneous CO and H\u003csub\u003e2\u003c/sub\u003e release from the beginning. \u0026nbsp;After 6 h the pressure stagnates at 3.8 bar, signalling full consumption of the olefin. Lastly, MeOH-\u003cem\u003ed\u003c/em\u003e\u003csub\u003e4\u003c/sub\u003e was tested in the acceptorless dehydrogenation (Fig. 2B, violet). The gas formation was found to be significantly slower but viable with the pressure reaching its maximum after 4 h. This discrepancy can be explained by the kinetic isotope effect observed with deuterated methanol. Next, the proposed intermediates of syngas formation\u003csup\u003e20,31\u003c/sup\u003e were tested to compare the efficiency of the gas release. Using paraformaldehyde instead of methanol (Fig. 2C, light blue) resulted in a significantly slower increase in pressure. However, using a 1:1 mixture of methanol and paraformaldehyde revealed a kinetic profile which superimposes well with pure methanol (Fig. 2C, dark blue). Methyl formate alone (Fig. 2D, light blue) was found to react considerably slower than methanol and paraformaldehyde. Here again, combining methanol together with methyl formate resulted in a profile well matched to methanol only (Fig. 2D, dark blue).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePotentially, this hints at methanol supporting the deconstruction of the following intermediates into hydrogen and carbon monoxide. In turn, using paraformaldehyde or methyl formate as syngas surrogate would be detrimental. Lastly, for methanol, paraformaldehyde, and methyl formate, the gas composition was measured for each during the pressure build up using gas chromatography. For methanol, a close to the ideal 2:1 mixture of H\u003csub\u003e2\u003c/sub\u003e and CO was consistently observed after 1 h and 2 h. For both paraformaldehyde and methyl formate, the gas mixture was found to be less consistent over time and contained a lower ratio of hydrogen vs CO than that of methanol. Considering that these two syngas surrogates resulted in incomplete consumption of estragole in the dual catalysis set-up (Fig. 2A), these results align with the conclusion of the preliminary studies on the hydroformylation using different H\u003csub\u003e2\u003c/sub\u003e to CO ratios (Fig. 1D), indicating that a 2:1 ratio H\u003csub\u003e2\u003c/sub\u003e to CO is ideal. Furthermore, this study stresses that both the gas mixture and the release rate must match with the hydroformylation, with toluene as reaction medium aiding a consistent ratio between hydrogen and CO being released from methanol.\u003c/p\u003e\n\u003cp\u003eWith the optimised reaction conditions at hand, we turned our attention to exploring the substrate scope of the hydroformylation reaction. Several terminal olefins (Fig. 3, \u003cstrong\u003e1\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e32\u003c/strong\u003e) of various molecular complexity were subjected to the catalytic conditions, all of which yielded the corresponding aldehydes in good to quantitative yields and with good to excellent selectivity towards the linear (\u003cem\u003el\u003c/em\u003e) regioisomer with styrenes being an anticipated exception. Allylbenzene derivates with various functional groups (\u003cstrong\u003e1\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e16\u003c/strong\u003e) were used to probe functional group tolerance and sterical effects. Alkyl-substituted, as well as unsubstituted allylbenzenes, undergo hydroformylation with a comparable efficiency to \u003cstrong\u003e1\u003c/strong\u003e (\u003cstrong\u003e2\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e4\u003c/strong\u003e). Several functional groups that can be utilised for orthogonal C\u0026ndash;C or C\u0026ndash;X bond formations, such as (pseudo)halides and pinacol boronic esters\u003csup\u003e32-34\u003c/sup\u003e, are well tolerated (\u003cstrong\u003e5\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e7\u003c/strong\u003e). Furthermore, substrates with free and protected alcohol groups (\u003cstrong\u003e8\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e10\u003c/strong\u003e), anilines (\u003cstrong\u003e12\u003c/strong\u003e and \u003cstrong\u003e13\u003c/strong\u003e), as well as esters (\u003cstrong\u003e11\u003c/strong\u003e), nitro groups, nitriles (\u003cstrong\u003e14\u003c/strong\u003e and \u003cstrong\u003e15\u003c/strong\u003e), and thioethers (\u003cstrong\u003e16\u003c/strong\u003e) afford excellent yields of the hydroformylated products.\u003c/p\u003e\n\u003cp\u003eFor all allylbenzene substrates the \u003cem\u003el\u003c/em\u003e:\u003cem\u003eb\u003c/em\u003e selectivity is good and commonly at a ratio of 10:1, however, for electron-deficient systems, the selectivity is reduced (\u003cstrong\u003e5\u003c/strong\u003e,\u003cstrong\u003e\u0026nbsp;7\u003c/strong\u003e,\u003cstrong\u003e\u0026nbsp;11\u003c/strong\u003e,\u003cstrong\u003e\u0026nbsp;14\u003c/strong\u003e and \u003cstrong\u003e15\u003c/strong\u003e). For the homoallylated analogue of the benchmark olefin (\u003cstrong\u003e17\u003c/strong\u003e) and a paracetamol-derived homoallyl (\u003cstrong\u003e18\u003c/strong\u003e), the selectivity for \u003cem\u003en\u003c/em\u003e-aldehydes was found to be significantly better than for the allylic counterparts. Styrenes are also viable starting materials in this transformation, providing corresponding aldehydes in excellent yields with the branched isomer as the major product (\u003cstrong\u003e19\u003c/strong\u003e and \u003cstrong\u003e20\u003c/strong\u003e)\u003csup\u003e28,35\u003c/sup\u003e. The two regioisomers of \u003cstrong\u003e20\u003c/strong\u003e can be separated, making it possible to utilise the branched aldehyde for the synthesis of Naproxen\u003csup\u003e35\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eIn chemical industries, a central role of hydroformylations is introducing molecular functionality into acyclic alkyl olefin platforms acquired from naphtha feedstock\u003csup\u003e36\u003c/sup\u003e. Among certain others, oxo products made from C\u003csub\u003e8\u003c/sub\u003e-olefins are of high economic importance. Using the here-developed dual catalysis approach, \u003cem\u003en\u003c/em\u003e-octene was converted to \u003cem\u003en\u003c/em\u003e-nonanal (\u003cstrong\u003e21\u003c/strong\u003e) in close to quantitative yield with excellent selectivity using methanol. More complex aliphatic compounds also undergo hydroformylation smoothly and selectively, affording the desired \u003cem\u003en\u003c/em\u003e-aldehydes in excellent yields (\u003cstrong\u003e22\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e24\u003c/strong\u003e). To demonstrate the value of this protocol for research and development laboratories, the hydroformylation of various natural product derivatives (\u003cstrong\u003e25\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e27\u003c/strong\u003e) and drug precursors (\u003cstrong\u003e28\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e32\u003c/strong\u003e) containing a diverse range of functionalities commonly displayed in drug-like compounds was conducted. The natural product quinine, containing an \u003cem\u003eN\u003c/em\u003e-heterocycle, underwent the reaction seamlessly with excellent selectivity (\u003cstrong\u003e25\u003c/strong\u003e). A protected sugar and an allylated estradiol steroid derivative presented themselves as suitable substrates and afforded the corresponding aldehyde (\u003cstrong\u003e26\u003c/strong\u003e) and lactol (\u003cstrong\u003e27\u003c/strong\u003e), respectively.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFinally, five drug precursors (\u003cstrong\u003e28\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e32\u003c/strong\u003e) were prepared in excellent yields but with various selectivity using the methanol-based hydroformylation. It should be noted that the linear regioisomers of \u003cstrong\u003e28\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e32\u003c/strong\u003e can in a single transformation be converted into the respective drug molecules (\u003cstrong\u003e28\u003c/strong\u003e to buspirone, \u003cstrong\u003e29\u003c/strong\u003e to diphenidol, \u003cstrong\u003e30\u003c/strong\u003e to mebeverine, \u003cstrong\u003e31\u003c/strong\u003e to vilanterol, and \u003cstrong\u003e32\u003c/strong\u003e to crispine A), thus this protocol may be of interest for late-stage isotopic labelling\u003csup\u003e35\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eIn line with evaluating the potential application of this protocol in pharmaceutical R\u0026amp;D laboratories, we conducted stable isotope labelling of compound \u003cstrong\u003e1a\u003c/strong\u003e by simply substituting the methanol source for commercial methanol-\u003cem\u003e\u003csup\u003e13\u003c/sup\u003eC\u003c/em\u003e or methanol-\u003cem\u003ed\u003csub\u003e4\u003c/sub\u003e\u003c/em\u003e (Fig. 4A). As expected, utilising methanol-\u003cem\u003e\u003csup\u003e13\u003c/sup\u003eC\u003c/em\u003e in the syngas-releasing reactor with the optimised conditions (Fig. 2A) did not affect either the yield or regioselectivity of the hydroformylation reaction, and aldehyde \u003cstrong\u003e33\u003c/strong\u003e was isolated with excellent incorporation of carbon-13 of 98% at the carbonyl position. We reasoned that quantitative incorporation is not achieved as both precatalysts contain unlabelled carbonyl ligands, totalling a theoretical 2.3 mol% unlabelled carbon monoxide available in the reaction. Next, we investigated the use of methanol-\u003cem\u003ed\u003csub\u003e4\u003c/sub\u003e\u003c/em\u003e as an enriched isotope source. Once again, the hydroformylation reaction proceeded well though with a slightly lowered yield of 92% of the product, but with excellent regioselectivity towards the linear aldehyde \u003cstrong\u003e34\u003c/strong\u003e and with a deuterium incorporation of 1.99. As isotopically labelled methanol is widely available and introduction of stable isotopes into new pharmaceutically active entities is of high importance for drug metabolism studies, this protocol could represent an interesting contribution to drug development programs.\u003c/p\u003e\n\u003cp\u003eFinally, to investigate the potential for accessing renewable carbon-based oxo-products, we turned to testing samples of industrial grade \u003cem\u003ee\u003c/em\u003e-methanol for syngas release. Vulcanol\u0026trade; is the first commercial e-methanol produced from Carbon Recycling International (CRI) in Iceland from the hydrogenation of flue gas with \u003cem\u003ee\u003c/em\u003e-hydrogen\u003csup\u003e37\u003c/sup\u003e. To our delight, utilising 1.5 equiv of fuel-grade Vulcanol\u0026trade; in the hydroformylation of olefin \u003cstrong\u003e1a\u003c/strong\u003e directly from a bottle obtained from CRI without any form for purification except degassing with argon afforded \u003cstrong\u003e2a\u003c/strong\u003e in an excellent yield of 97% and with a satisfactory \u003cem\u003el\u003c/em\u003e:\u003cem\u003eb\u003c/em\u003e-selectivity of 13:1, using the optimised conditions (Fig. 2A). With the potential for large-scale applications in mind, we were interested in exploring the scalability of the here-developed method. Once again, our benchmark reaction using estragole (\u003cstrong\u003e1a\u003c/strong\u003e) was now performed on a gram-scale (3.71 g, 25.0 mmol) in a two-reactor system with a volume of 430 mL in total (Fig. 4B), representing an upscaling of 25 times. With Vulcanol\u0026trade; as the syngas source, \u003cstrong\u003e2a\u003c/strong\u003e was isolated in a gratifying 84% yield with a \u003cem\u003el\u003c/em\u003e:\u003cem\u003eb\u003c/em\u003e-selectivity of 14:1. This preliminary upscaling attempt applying \u003cem\u003ee\u003c/em\u003e-methanol highlights the robustness of the interlocking catalysis.\u003c/p\u003e\n\u003cp\u003eIn summary, we report the successful union of two valuable catalytic cycles, the acceptorless dehydrogenation of methanol to syngas and hydroformylations of olefins. We demonstrate the importance of the rate and selectivity of the syngas release, and how matching it with a low-pressure rhodium-catalysed hydroformylation results in an efficient methodology for accessing oxo products. Furthermore, it is possible to replace coal- or natural gas-derived syngas with fuel-grade \u003cem\u003ee\u003c/em\u003e-methanol accessed from CO\u003csub\u003e2\u003c/sub\u003e capture and hydrogenation on gram scale. While these conditions do not mimic those applied in industrial settings producing bulk chemicals, we consider this dual catalysis a proof-of-concept for the possibility of synthesising oxo-products entirely from CO\u003csub\u003e2\u003c/sub\u003e as renewable carbon feedstock and integrating this important transformation into a methanol economy. It is our expectation that redesigning the chemical value chains to extend from renewable platforms such as methanol may be an important part of establishing a sustainable chemical industry.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003e We thank Jens Christian Kondrup for aiding in the development of the refluxing two-reactor system. We Also thank Carbon Recycling International—particularly Ómar Sigurbjörnsson—for providing us with \u003cem\u003ee\u003c/em\u003e-methanol, Vulcanol™. We are grateful to Johannes Eberhard Reiner and Lisa Klimper for their support with gas chromatography for syngas composition studies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e We are highly appreciative of the financial support from the Danish National Research Foundation (grant no. DNRF118),\u0026nbsp;the Novo Nordisk Foundation CO\u003csub\u003e2\u003c/sub\u003e Research Center that was funded by the Novo Nordisk Foundation (grant no. NNF21SA0072700), NordForsk (grant no. 85378), and Aarhus University. Support from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No 859910 is also gratefully acknowledged. This publication reflects the views only of the authors, and the Commission cannot be held responsible for any use which may be made of the information contained therein.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u003c/strong\u003e A.B., J.B.J., and T.S. conceived the concept. A.B. designed the experiments and conducted the experimental investigations with J.B.J., W.H., and A.A. A.B. performed visualisations and wrote the manuscript with J.B.J., A.A., and T.S., who also directed the research. Funding acquisition was conducted by T.S., M.B., and R.J.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e T.S. is co-owner of SyTracks A/S, which commercialises CO tubes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData and materials availability:\u003c/strong\u003e All data are available in the manuscript or the supplementary materials.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003e\u003cem\u003ePlasticEurope: Plastics - The Facts 2022, 2022.\u0026nbsp;\u003c/em\u003e\u003cem\u003ehttps://plasticseurope.org/knowledgehub/plastics-the-facts-2022/\u003c/em\u003e\u003cem\u003e\u0026nbsp;[retrieved Match 05, 2024]\u003c/em\u003e.\u003c/li\u003e\n \u003cli\u003eBachmann, M., Zibunas, C., Hartmann, J., Tulus, V., Suh, S., Guill\u0026eacute;n-Gos\u0026aacute;lbez, G. \u0026amp; Bardow, A. Towards circular plastics within planetary boundaries. \u003cem\u003eNat. 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Process Advantages of Direct CO\u003csub\u003e2\u003c/sub\u003e to Methanol Synthesis. \u003cem\u003eFront. Chem.\u003c/em\u003e \u003cstrong\u003e6\u003c/strong\u003e (2018).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4182149/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4182149/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIn almost all man-made chemical products, the carbon skeletons originate from unsustainable fossil resources\u003csup\u003e1\u003c/sup\u003e. As the green transition gains traction, introducing CO\u003csub\u003e2\u003c/sub\u003e as a feedstock for organic synthesis will be one of the keys to a carbon-neutral chemical industry\u003csup\u003e2-4\u003c/sup\u003e. However, redesigning large scale processes for alternative feedstocks is challenging. Methanol sourced from CO\u003csub\u003e2\u003c/sub\u003e is presently becoming available, linked to the emergence of a methanol economy utilising it as circular fuel\u003csup\u003e5,6\u003c/sup\u003e. This presents an ideal entry point to rethink the highly interconnected chemical production chains. Here, we report that interlocking a ruthenium-catalysed methanol-to-syngas reforming with a low-pressure rhodium-catalysed hydroformylation in a two-reactor setup affords oxo-products in high yields and selectivity. This study elucidates the kinetics and selectivity of gas formation and their key role in matching both catalytic cycles. Finally, the utilisation of fuel-grade green methanol as a syngas source is demonstrated. If combined with methanol-to-olefin processes and green methanol production, oxo-products could thus be generated using solely CO\u003csub\u003e2\u003c/sub\u003e as the carbon feedstock through a methanol platform. The here developed dual catalysis can be considered a blueprint for remodelling industrial processes.\u003c/p\u003e","manuscriptTitle":"Integrating hydroformylations into a methanol economy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-06 05:53:51","doi":"10.21203/rs.3.rs-4182149/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":"bf689040-c8e9-457f-96d3-36320be3cb6f","owner":[],"postedDate":"June 6th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":32551465,"name":"Physical sciences/Chemistry/Catalysis/Homogeneous catalysis"},{"id":32551466,"name":"Physical sciences/Chemistry/Chemical synthesis/Synthetic chemistry methodology"},{"id":32551467,"name":"Physical sciences/Chemistry/Green chemistry/Sustainability"}],"tags":[],"updatedAt":"2024-06-06T05:53:51+00:00","versionOfRecord":[],"versionCreatedAt":"2024-06-06 05:53:51","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4182149","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4182149","identity":"rs-4182149","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}