Perspective pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Tackling Challenges in Industrially Relevant Homogeneous Catalysis: The Catalysis Research Laboratory (CaRLa), an Industrial−Academic Partnership Thomas Schaub,*,†,‡ A. Stephen K. Hashmi,*,‡,§ and Rocco A. Paciello*,† †
BASF SE, Synthesis and Homogeneous Catalysis, Carl-Bosch-Strasse 38, 67056 Ludwigshafen, Germany Catalysis Research Laboratory, Im Neuenheimer Feld 584, 69120 Heidelberg, Germany § Organisch-Chemisches Institut, Heidelberg University, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany Downloaded via UPPSALA UNIV on October 23, 2018 at 13:10:36 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
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ABSTRACT: Industrial−academic collaborations are broadly used for the development of new industrial processes. To achieve a strong and deep collaboration in the field of homogeneous catalysis, BASF and the Heidelberg University have been running the Catalysis Research Laboratory together in Heidelberg since 2006. This Perspective highlights the concept of this laboratory and our experiences over the past few years in this joint laboratory. How this collaboration works is explained in more detail using three selected projects: sodium acrylate based on CO2, the selective decomposition of cyclohexyl hydroperoxide to cyclohexanone, and the asymmetric amination of ketones with NH3/H2
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INTRODUCTION Industrial−academic partnerships enable the development of new industrial processes and products. The interaction of industrial experience and skills from academic basic research has proven to be quite fruitful. BASF has a significant track record when searching in new directions over the last 150 years of successful innovations resulting from collaborations with academia. Some highlights are • The industrial synthetic production of Indigo in 1897 by Adolf von Bayer (University Munich, Nobel Prize in Chemistry 1905), Karl Heumann (ETH Zürich), and Heinrich Caro (BASF)1 • The Ammonia-Syntheses in 1913 by Fritz Haber (KWI Berlin, Nobel Prize in Chemistry 1918), Carl Bosch (BASF, Nobel Prize in Chemistry 1931), and Alwin Mittasch (BASF)2 • Polystyrene in 1930 by Hermann Staudinger (University Freiburg, Nobel Prize in Chemistry 1953) and Carl Wolff (BASF)3 • Synthesis of Vitamin A in 1963 by Georg Wittig (Heidelberg University, Nobel Prize in Chemistry 1979) and Horst Pommer (BASF)4 • Strobilurine fungizides in 1996 by Timm Anke (TU Kaiserslautern), Wolfgang Steglich (University Bonn), and Hubert Sauter (BASF)5 © XXXX American Chemical Society
Rooted in this great tradition, a joint laboratory between the Heidelberg University and BASF SE, the Catalysis Research Laboratory (CaRLa), was established in 2006 to tackle challenges in homogeneous catalysis for organic synthesis. The goal is to develop new industrial processes from scratch or to improve existing ones by utilizing the different and synergistic perspectives of industry and academia. This Perspective will give our insights into this 10-year-old successful collaboration, focusing on the motivation, setting, project organization, criteria for new projects, and lessons learned. We will illustrate how this whole concept works using three selected projects.
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CONCEPT Cooperation with academic groups and BASF on different topics in the field of homogeneous catalysis was frequently done before the Catalysis Research Laboratory was founded. In such “classic” collaborations, the projects were carried out with an appropriate academic group providing the right skills for the task. In most cases, the research was performed in the laboratories of the academic partner and funded by BASF for the period of the Special Issue: Excellence in Industrial Organic Synthesis 2019 Received: September 12, 2018 Published: October 1, 2018 A
DOI: 10.1021/acs.joc.8b02362 J. Org. Chem. XXXX, XXX, XXX−XXX
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The Journal of Organic Chemistry
working on. The team is supported by a lab technician, who takes care of running the lab, and a Ph.D. student supervised by the quantum chemistry group at BASF, who performs all the computational chemistry necessary in the projects hand in hand with the postdocs doing the experiments. The Ph.D. student is also supervised by a professor of the university and can use the IT infrastructure of both BASF and the university for the calculations. To get further input, other groups from the university and researchers from the central research of BASF are involved in the different projects. The inclusion of the BASF researchers within the projects (project meetings are held every 6−8 weeks) helps significantly when transferring the projects, if successful, for further process development in the company. This goal was achieved in the last four years for seven different projects, showing the feasibility of this concept. The topics for the projects are usually defined by industrial needs for new approaches in homogeneous catalysis, which are of significant academic interest and where examples from academia are rare. Another important aspect of this collaboration is that the academic researchers learn about the specific industrial problems, details impossible to obtain without such a collaboration. The projects must also fulfill some other requirements to be appropriate for research at CaRLa. As it is an academic−industrial partnership, the projects should be long term (>1 year) to provide the scientist sufficient material for publication. In addition, we also try to patent all relevant results for a possible industrial application prior to publication. These are usually shared patent applications with inventors from both parties. So far, we have published 70 peer-reviewed papers in established journals as well as filed 25 patent applications based on the results from CaRLa (see the up to date publication list on our homepage at www.carla-hd.de). The projects require a deep mechanistic understanding for a rational development of new catalytic systems. In most of the projects, we also use quantum-chemical calculations and modeling to evaluate catalytic mechanisms to rationalize our experimental work. CaRLa does not carry out short-term projects, custom synthesis, or pure screening projects. The CaRLa was the first of BASF’s satellite laboratories based on equal partnerships at leading universities worldwide. Many other collaborative laboratories followed. For Heidelberg University, CaRLa, with its industry-on-campus concept, complemented in an ideal way the portfolio of different institutionalized longterm collaborations with industry enabling transfer. For example, other transfer activities in other departments include the Institute for Scientific Computing (IWR, with the Department of Mathematics and Informatics since 1987), the Nikon Imaging Center (NIC, with the Department of Biology since 2005), the Heidelberg Collaboratory for Image Processing (HCI, with the Department of Mathematics and Informatics since 2008), the InnovationLab GmbH (iL another collaboration involving BASF SE, in the field of materials science, with the Department of Chemistry and the Department of Physics and Astronomy since 2008), or the M2OLIE Research Campus (with the Department of Medicine at Mannheim since 2012).
project. Exchange in the project with the industrial partner usually occurred a couple of times, and the collaboration partner was usually different from project to project. Despite achieving good results with this approach over the years, a new way of partnership between academia and industry was initiated with the concept for the CaRLa (Figure 1). Due to
Figure 1. Timeline of the CaRLa.
long and successful relations with the Heidelberg University, both parties decided in 2006 to start up a new, dedicated laboratory, funded by both parties and the Federal Government of Baden-Württemberg, to work together on industrially relevant challenges in homogeneous catalysis. A laboratory fitting the requirements for state-of-the art basic research in homogeneous catalysis on industrial relevant topics was installed from scratch in new rooms in the “Technology Park” in Heidelberg (Figure 2). The laboratory is close to the
Figure 2. Organization of the CaRLa in Heidelberg.
organic chemistry department of Heidelberg University. Resources from the University as well as from central research at BASF in Ludwigshafen are frequently used within the projects. This allows a tight collaboration using the strengths of both partners for ambitious homogeneous catalysis research and fosters the transfer of fundamental academic research to industrial applications. The laboratory is managed by two scientific heads to bring researchers from both sides close together and to get as much intellectual input as possible from the academic and the industrial partners: one professor from the Heidelberg University and one experienced scientist from BASF. The two scientific heads decide together about the projects, recruiting, and general topics about the lab. The daily lab management is done by the BASF scientist located at CaRLa. A steering committee, consisting equally of representatives from the university and BASF management, meets twice a year to evaluate the project portfolio and output as well as to plan how the laboratory will continue. Currently, at least eight postdocs are working together on different projects. They are cofinanced by both partners and supervised by both scientific heads, independent of which project they are
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PROJECTS AT CARLA Three projects have been selected to show how this concept is addressing different industrial needs and what can be achieved. They give an insight into how industrial challenges in homogeneous catalysis can be addressed by using academic basic research in a joint laboratory. Sodium Acrylate from Ethylene and CO2. The synthesis of sodium acrylate based on the carboxylation of ethylene is an B
DOI: 10.1021/acs.joc.8b02362 J. Org. Chem. XXXX, XXX, XXX−XXX
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The Journal of Organic Chemistry Scheme 1. Synthesis of Sodium Acrylate Based on Propylene as well as on Ethylene and CO2
At this stage, the main learning was that bidentate donor ligands in combination with nickel are suitable for all elementary steps in catalysis. The sodium base must provide a basicity in the range of alcoholates or phenolates to allow the deprotonation of the metallalactones but not react irreversibly with CO2 under the reaction conditions to stable and less basic carbonates. To find an appropriate combination of ligand/metal/base and solvent for a catalysis in this design space, hte was also included in the project. This subsidiary of BASF is focused on high-throughput screening and provided a significant extension of the autoclave capacities for the screening as well as know-how in the design of experiments. After testing of combinations from 84 ligands (mainly bidentate phosphines), ten bases and seven solvents, catalysis was achieved in 2014 with nickel12 as well as with palladium.13 After this proof of concept for a real one-pot catalysis, the project was moved to the next stage to address the needs for a potential continuous process. The project setting was changed, as we were now moving more from basic to applied research, but still enough open points remained which required the skills of an academic−industrial lab. This work was then performed at CaRLa together with the process development group at BASF. Some major drawbacks of the catalyst system with the fluorophenolate bases had to be surmounted in order to design a continuous process: • The reaction solvents should be nonmiscible with water to facilitate separation of the product from the catalyst after the reaction. • The zinc additive has to be removed. • A base is necessary which is easily recyclable but which does not undergo side reactions such as the Kolbe−Schmitt reaction, which can occur on the 2-fluorophenolates. • The turnover number has to be increased. The approach using phenolates was further optimized by investigating combinations of 10 phenolate bases with substituents in both ortho positions, 11 organic solvents providing a mixing gap with water, as well as 18 bidentate bisphosphine ligands.14 We found that no Zn as additive is necessary for the catalysis in the case of palladium with the right catalyst−precursor using anisole as solvent and lipophilic and diortho-substituted phenolate bases. Two liquid phases were formed by adding water after the reaction. The sodium acrylate went into the aqueous phase, while the substituted phenolate shown in Scheme 2 as well as the Pd−dcpe catalyst went to the anisole phase. Less than 1 ppm were found in the aqueous phase. Besides the higher activity, this was another reason to switch to palladium, as in the case of nickel >2 ppm metal went to the aqueous phase and would remain in the product. This is a no-go for products for human purpose. By adding NaOH to the organic phase, the phenolate base can be regenerated via distillative removal of water and recycled to the reaction together with the catalyst. From a process concept point of view, this system was still not an ideal solution: The bases used have a high molecular mass, reducing the space time yield of the reaction, catalyst activity remained low, and the harsh conditions of the phenolate-base regeneration in the presence of the catalysts are not beneficial for a long catalyst lifetime. After detailed thermal and spectroscopic investigation of the carbonates of simple alkoxide bases like
attractive but challenging target (Scheme 1). Sodium acrylate itself is an important monomer for superabsorbents6 and currently produced on a scale of about 4 million tons per year. In the established route, propylene is oxidized in a two-stage gasphase reaction to acrylic acid,7 followed by reaction with NaOH to produce sodium acrylate. By changing the raw material base from propylene to ethylene and CO2, there is the potential for significant reduction in the raw material costs. This reaction was unknown prior to the start of the project in 2011. It was therefore necessary to start with fundamental research before thinking about any potential process. The main boundaries which had to be taken into account are as follows: • The synthesis of acrylic acid directly from ethylene and CO2 is thermodynamically not feasible, whereby the synthesis of sodium acrylate via the carboxylation of ethylene in the presence of a base is.10 • Sodium hydroxide cannot be used directly in the carboxylation, as it irreversibly forms carbonates in the presence of CO2. An appropriate base must be identified and used in the catalysis. It must be easily regenerated using NaOH for an economic process concept. • If active catalysts can be found, they should be robust and efficient to recycle. Due to the strong exploratory character, the research was carried out in different stages to develop a system which could be used for further process development. In the first stage, suitable metals, ligands, and bases had to be identified in order to show that the individual steps in a catalytic cycle were viable. In the second stage, these results were combined in a catalytic system to show the proof of principle. In the third stage, the system was further modified to meet the demands for a continuous process concept. Stoichiometric organometallic reactions on the synthesis of metallalactones from CO2 and ethylene investigated by Hoberg et al. in 19878 were the starting point of the project.9 It was clear that the metallactones formed from ethylene and CO2 could be the crucial intermediates in a potential catalysis. The β-H-elimination needed had, however, never been seen. Due to the strong exploratory character, the project was funded from 2011 to 2014 by the German Ministry of Science and Education as a collaboration between CaRLa, the technical university in Munich, the technical university in Stuttgart, and the High Throughput Experimentation (hte) Company. Basic mechanistic investigations, experimental as well as computational,10,11 showed that all productive steps essential for a catalysis are possible using nickel when using the right base and ligand. In particular, a crucial experimental observation was that addition of strong bases led to the desired rearrangement to acrylate complex. This resulted in the first synthesis of sodium acrylate based on CO2 and ethylene in a stepwise manner, where each step is stochiometric with respect to the nickel complexes used.11 The first step is CO2 rich, forming the metallalactone. For the second step, CO2 must be released before the base is added, as a carbonate would be formed with the base under the reaction conditions. This early success in the project was crucial, as it showed that a real catalysis might be possible, if the right combination of base, ligand and metal could be identified. C
DOI: 10.1021/acs.joc.8b02362 J. Org. Chem. XXXX, XXX, XXX−XXX
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The Journal of Organic Chemistry Scheme 2. Three Stages in the Collaboration Project
is involved in the main industrial route to produce cyclohexanone (Scheme 3). This is a key intermediate in the synthesis of ε-caprolactam, of which around 5 million tons are produced annually.17,18 Ideally, the dehydroperoxidation would only yield ketone and water, but possible selective catalyst are currently not used, thus requiring additional steps to convert the cyclohexanol formed to the ketone. In addition, the overall selectivity of ∼80% is low, as unwanted byproducts, e.g., from ring opening, are formed in the currently used radical decomposition and have to be separated.17 Despite some precedence in the literature for selective dehydroperoxidation using different metals like Cr, V, Co, Fe, and Mn, none of these systems has been used industrially for this step.19 Compared to the previously described project, the task here was to improve the yield and selectivity of a currently running
NaOtBu and NaOiPr we found that they are also suitable, as long as the reaction temperature in the catalysis is high enough (110−180 °C).15 Lipophilic amides as solvents like dibutylformamide or cyclohexlpyrrolidone increase the catalytic activity and gave a significant improvement (see Scheme 2). Previously unobtainable TONs of up to 500 in one run were obtained in the Pd-dcpe/NaOtBu/cyclohexylpyrrolidone system.16 This approach also allowed the design of a continuous process concept, avoiding the above-mentioned drawbacks of the phenolate system.16 At this point, the system was advanced enough that the whole project could be moved to the process development group at BASF for further development of this synthesis in continuous units. Selective Decomposition of Cyclohexylhydroperoxide to Cyclohexanone. Decomposition of cyclohexyl hydroperoxide D
DOI: 10.1021/acs.joc.8b02362 J. Org. Chem. XXXX, XXX, XXX−XXX
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The Journal of Organic Chemistry
Scheme 5. Mechanism of the Nonradical CrVI-Catalyzed Selective Conversion of Cyclohexylhydroperoxide to Cyclohexanone
Scheme 3. Production of Cyclohexanone by Oxidation of Cyclohexane
process. We wanted to achieve this by identifying an applicable catalyst system via mechanistic investigation (Scheme 4). The need for this project was defined by the research group for oxidations within BASF. Scientists from this group were also involved as consultants, as they know the current production process quite well. Combined computational, mechanistic as well as spectroscopic investigation was required to tackle this project, a prototypical task for our joint academic-industrial research laboratory. An advantage for our extensive studies on the cyclohexyl hydroperoxide (CHHP) was that we had access to liter amounts of the crude material from the oxidation of cyclohexane in the BASF production plant in Ludwigshafen. CHHP is not available commercially, and it is difficult to obtain larger quantities from the dedicated lab synthesis.20,21 It can, however, be easily isolated out of the crude oxidation mixture. Using this as starting material, the pure hydroperoxide was accessible in gram amounts.22 In the first part of the project, we investigated the use of VV complexes bearing tridendate, dianionic nitrogen containing ligands like pyridine-2,6-dicarboxylic acids (= dipic) or easily prepared Schiff bases.20 Vanadium was chosen as it is a relatively cheap and nontoxic metal. It was known from literature that vanadium−dipic complexes react with tertiary alkyl hydroperoxides under formation of [V(O)(dipic)(OOR)] complexes, which can be used to transfer oxygen from the hydroperoxyl ligand to olefins.23 This ligand and related structures thus appeared suitable for the dehydroperoxidation. It could be shown that CHHP also coordinates in a η2-mode to the VV−dipic motif, like the tert-alkyl hydroperoxides.20 Using the vanadium−dipic complex at room temperature, 4-heptanone was obtained in up to 80% selectivity from the model compound 4-heptyl hydroperoxide. In contrast, no selectivity toward the ketone was observed when using CHP and these catalysts. Only 1:1 mixtures with the cyclohexanol were obtained. DFT
calculations indicate that the activation barrier for the selective, nonradical V-dipic-catalyzed conversion of cyclohexyl hydroperoxide to cyclohexanone is significantly higher than the one for 4-heptyl hydroperoxide to 4-hepatanone. In this case, the nonselective radical pathway for CHHP decomposition to a 1:1 alcohol−ketone mixture seems to be preferred.24 CrVI compounds are also reported in the literature as promising metal catalysts for selective dehydroperoxidation (Scheme 5).25 CrVI is not the preferred choice from an industrial point of view due to its high toxicity, especially when used as a homogeneous catalyst which can end in the wastewater streams of the process. But as homogeneous CrVI catalysts like CrO3*py (py = pyridine) were reported to show an excellent selectivity toward the ketone, this was the next choice after the failed attempts to use vanadium. From previous reports, a clear picture about the mechanism of this catalysis was still missing. It was especially of interest for us to evaluate if a pure nonradical CrVI mechanism was really going on or if maybe less harmful species such as CrIII or CrIV were involved and formed during the catalysis. After testing more than 30 CrIII and CrVI compounds, we confirmed that CrO3*py showed the highest activity and selectivities (up to 98% CyO at full conversion of CyOOH). An initiation period is required when using CrIII precursors like Cr(acac)3, and active CrVI−oxo species were formed. As with the vanadium-catalyzed dehydroperoxidation, a MO group and a high oxidation state of the metal are necessary in the case of CrVI to allow a nonradical, selective conversion of the alkyl hydroperoxide to the cyclohexanone. The mechanism of this catalysis was evaluated and confirmed by DFT calculations, NMR, UV−vis, and IR spectroscopy as well as kinetic measurements. The reaction order and the free Gibbs energy of activation determined by the kinetic measurement were in alignment with the lowest energy pathway of the catalysis obtained by DFT calculations.22
Scheme 4. Dehydroperoxidation Using a Vanadium(V)−Dipic Catalyst2
E
DOI: 10.1021/acs.joc.8b02362 J. Org. Chem. XXXX, XXX, XXX−XXX
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The Journal of Organic Chemistry The activation barrier for the CrVI-catalyzed conversion of CyOOH to CyO was significantly lower than in the vanadium case. This explains the high selectivity, as the radical decomposition is the less preferred pathway in this case. Nevertheless, the whole study clearly showed that all catalytically active species are CrVI and that after catalysis the chromium remains CrVI. To utilize the high selectivity of CrVI but avoid the issue with toxic chromium in the wastewater, we switched to CrO3 on polyvinylpyridine as a cheap and robust immobilizing agent (Table 1).19h,25d This heterogeneous catalyst showed a similar activity and selectivity to the homogeneous CrO3*py. As kinetics were also nearly identical, it seems that the chromium is in the form of single metal centers on the carrier and following the same mechanism as the homogeneous version. A hot-filtration split test confirmed that the chromium on the PVP is the active catalyst and not any leached Cr species. In solution, no chromium was detected within the detection limit of our analytical method (
