Enhanced catalytic activity of copper complexes in microgels for aerobic oxidation of benzyl alcohols

Dominic Schäfer a, Fabian Fink a, Denise Kleinschmidt bc, Kristina Keisers a, Fabian Thomas a, Alexander Hoffmann a, Andrij Pich *bcd and Sonja Herres-Pawlis *a
aChair of Bioinorganic Chemistry, Institute for Inorganic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany. E-mail: sonja.herres-pawlis@ac.rwth-aachen.de
bInstitute of Technical and Macromolecular Chemistry, RWTH Aachen University, Worringerweg 2, 52074 Aachen, Germany. E-mail: pich@dwi.rwth-aachen.de
cLeibniz-Institute for Interactive Materials (DWI), Forckenbeckstraße 50, 52074 Aachen, Germany
dAachen Maastricht Institute for Biobased Materials (AMIBM), Maastricht University, Brightlands Chemelot Campus, Urmonderbaan 22, 6167 RD Geleen, The Netherlands

Received 6th April 2020 , Accepted 23rd April 2020

First published on 24th April 2020

Catalytically active copper bis(pyrazolyl)methane complexes have been anchored into pVCL-GMA microgels on specified positions within the microgel network. Functionalized microgels act as nanoreactors providing a tailored environment and stabilization for the copper complexes thus increasing the product yield. The oxidation of benzyl alcohols to their respective aldehydes was chosen as a test reaction to show the enhancement of catalytic activity due to the immobilization of the copper complex compared to the copper salt and the molecular copper complex.

One of the most common reactions in industry and organic chemistry is the oxidation of alcohols to their respective carbonyl compounds.1 Oxidation reactions have been used in numerous processes in all areas of chemical industries, e.g. agrochemicals, pharmaceuticals and large-scale commodities.2,3 Especially the synthesis of bulk chemicals predominantly uses molecular oxygen as an oxidant which is due to its low costs, harmlessness and availability. For high reaction rates and selectivity, metal catalysts are needed in those oxidation reactions.4

Therefore, the Cu mediated alcohol oxidation has been of interest in research for a long time. In nature, copper acts as catalytic center of numerous enzymes (e.g. galactose oxidase) catalyzing former mentioned reactions.5 The first Cu-catalyzed aerobic oxidation of primary alcohols was reported by Semmelhack in 1984. Cu and TEMPO (2,2,6,6-tetramethyl-1-piperidine-N-oxyl) were used in DMF as solvent for the catalysis of activated primary alcohols.6 Sheldon and co-workers showed a mild method (room temperature) for the oxidation of primary alcohols using TEMPO and a Cu(II) complex with 2,2′-bipyridine (bpy) as a ligand. High conversions were obtained by using air instead of pure oxygen for the reaction.7,8

The immobilization of catalysts on solid or polymeric supports is an often-used method in all industrial fields due to its advantage of controllable properties of the catalyst and an easy separation from the reaction mixture. Many polymerization routes are established in the synthesis of functional polymers and provide a high degree of control over the composition and architecture of the polymer supports.9–12 This can be used to design polymer supports with defined catalytic behaviour.13,14 Microgels as polymeric systems offer this high degree of control over their properties and architecture but also have unique properties, like stimuli responsiveness, size variation by controlled swelling–deswelling, softness, and surface charge and therefore have attracted great interest in recent time as carriers for catalysts.15–20 The swelling of microgels in different solvents leads to highly accessible porous polymer networks which can easily take up substrates and offer the catalyst a specified reaction environment.21–23 When in a de-swollen state the microgels are easy to separate from the respective reaction mixture and can be re-used after being washed and redispersed.15,36

Herein, we report for the first time the successful immobilization of a well-defined copper complex into a microgel. Precisely, we anchor a bis(pyrazolyl)methane copper complex into a temperature-responsive poly(N-vinylcaprolactam-co-glycidyl methacrylate) (pVCL-GMA) microgel. We chose bis(pyrazolyl)methane copper complexes since they have already proven to be highly useful for biomimetic hydroxylation reactions,24–27 aminations28 and Sonogashira coupling.29

After screening different types of microgel families, we found pVCL most useful due to its excellent chemical resistance towards acids and bases, metal ions and other additives, its responsiveness to temperature and bio-compatibility.21,30,31

In our approach, the epoxy-groups incorporated as side groups into the microgel network are used to attach covalently amine-substituted bis(pyrazolyl)methane (BPM) ligands able to form copper complexes in situ after addition of CuCl (Fig. 1). This modular approach allows flexible variation of the amount and localization of copper complexes within the microgel network. Finally, the functionalized microgel is used for the aerobic oxidation of different benzyl alcohol derivatives.

image file: d0cc02433c-f1.tif
Fig. 1 Functionalization of pVCL-GMA microgels with amine ligand and subsequent loading with copper.

The amine ligand was prepared in a three-step synthesis starting from 2,2-dimethoxyethanamine following a literature procedure.32 The temperature responsive microgels based on pVCL were synthesized by free-radical precipitation polymerization in water.33 In order to immobilize the amine ligand, functional groups in the microgels are needed and therefore 10 wt% glycidyl methacrylate (GMA) was used as co-monomer. The randomly distributed epoxide groups were used to easily incorporate the ligand into the microgel (Fig. 1). They were reacted with the amine-functionalized bis(pyrazolyl)methane ligands in water over night and subsequent dialysis removed the excess of ligand. After lyophilization of the functionalized microgels, DLS measurements were executed to analyze the hydrodynamic radius of the microgels in DMSO (Fig. S3–S5, ESI). The measurements showed that pVCL-GMA microgels have a hydrodynamic radius of Rh = 341.9 ± 8.9 nm in comparison to the functionalized microgels (pVCL-GMA-BPM) which have a hydrodynamic radius of Rh = 303.6 ± 7.5 nm. The DLS measurements performed in aqueous solution indicate a similar trend, namely that pVCL-GMA and functionalized pVCL-GMA-BPM show a hydrodynamic radius of Rh = 446.5 ± 4.0 nm and Rh = 366.0 ± 7.2 nm, respectively. The slight reduction of the hydrodynamic radii after modification is due to the partial deswelling of the microgel network induced by the hydrophobic character of bis(pyrazolyl)methane ligands.33 In addition, the primary amine reacts with the epoxide group to the secondary amine which itself can react with another epoxide to the tertiary amine.34,35 This process results in a higher cross-linking within the microgels and therefore smaller radii. After redispersion of the dried microgels in the respective solvent the copper complexes were formed in situ by adding CuCl to the mixture. The amount of introduced copper is related to a hypothetical complete functionalization of all epoxide groups with one amine ligand molecule (10 wt%). The addition of copper results in stable microgels that do not coagulate or precipitate due to metal salt and preserve their size and structure (in the following referred to as Cu@pVCL-GMA-BPM). The morphology of Cu@pVCL-GMA-BPM was analyzed via SEM and showed sphere-like microgels (Fig. 2). The hydrodynamic radius of the copper-loaded microgels in DMSO is Rh = 320.8 ± 12.6 nm and was examined after single dialysis step. By now, no fitting analytic method was found to investigate the structure of the BPM copper complex inside the interior of the microgel. Though, single crystals of the corresponding copper(II) chloride complex with the amine ligand suitable for X-ray analysis were obtained providing a first insight into the inner coordinative structure of the loaded microgels (see ESI).

image file: d0cc02433c-f2.tif
Fig. 2 SEM image of pVCL-GMA based microgels functionalized with a bis(pyrazolyl)methane copper complex (see also ESI).

Inductively coupled plasma mass spectrometry (ICP-MS) measurements were performed (Table S3, ESI). After single dialysis of the copper-loaded functionalized microgels the determined copper concentration was 12% of the theoretically expected value further reduced to 5% after twofold dialysis. The reduction of copper concentration in microgels after dialysis indicates the formation of tertiary amines during the synthesis, which was also indicated by the change of size after the functionalization of the microgels, and thus less copper complexes are anchored inside the microgel. Even so, no further leakage of copper due to further dialysis was observed. The ICP-MS measurements are supported by the results obtained by EPR analysis (see ESI).

The activity of Cu@pVCL-GMA-BPM microgels in the aerobic oxidation of primary alcohols to the corresponding aldehydes was systematically investigated as test reaction. The conversions were monitored by gas chromatography. The amount of microgel, used in the reaction, was equivalent to 5 mol% catalyst in relation to the substrate. It was considered that all GMA groups (10 wt%) were functionalized with ligand and therefore the maximum amount of catalyst could be estimated. The dried pVCL-GMA-BPM microgels were redispersed in the solvent and copper(I) chloride was added to form the copper complex in situ. Subsequently the substrate was added, and the addition of TEMPO marked the start of the reaction. To compare the performance of the microgel catalyst, reference reactions with only CuCl and the CuCl BPM complex were carried out.

Initially, the aerobic oxidation was tested with different reaction conditions in water (see ESI for reaction conditions) because the unique properties of pVCL microgels, like thermo-responsiveness, are only available in the former mentioned solvent. Furthermore, water as a “green” solvent is preferable compared to other organic solvents. Our results indicate that the copper salt had higher conversions than both copper complex and Cu@pVCL-GMA-BPM (see ESI). The reason for this effect is the reduction of the colloidal stability of microgels under reaction conditions. Cu@pVCL-GMA-BPM microgels are stable in water after in situ formation of the copper complexes, but they coagulate and precipitate after around two hours after addition of the substrate and TEMPO. Because of the precipitation the transport of substrates to the catalytic centers in the microgel is highly limited and higher conversions are not possible.

To tackle the problem of microgel precipitation, the reaction conditions were optimized and DMSO was chosen as solvent. Furthermore, the substrate scope was increased (Table 1). In DMSO the Cu@pVCL-GMA-BPM catalyst has the highest conversion for all substrates except for 4-nitrobenzaldehyde (Table 1, entry 2). The highest conversion (99.7%) is reached with benzyl alcohol whereby the substrate is fully consumed (Table 1, entry 1). Conversions over 90% are also reached for several other substrates (Table 1, entries 4 and 6). In the case of the CuCl BPM complex and the copper salt the catalytic activity follows no tendency. CuCl has the highest conversion at 63.8% for 4-hydroxybenzaldehyde which is still lower than the 67.5% of the microgel catalyst (Table 1, entry 5). Otherwise the conversion of CuCl are ranged at around 40–60%. The copper complex is most active for p-tolualdehyde (Table 1, entry 6) with 92.0% conversion. It is shown that the immobilization of the copper complex into a microgel enhances its catalytic activity due to the protective environment for the catalyst. We relate the reported enhanced reactivity of the microgel-anchored copper complexes to a smaller extent of copper ion aggregation after every catalytic cycle. Moreover, the unpolar environment in the microgel facilitates the reduction back to copper(I). Both effects may lead to a higher catalytic activity of every single copper ion leading to a lower needed loading with copper ions. Most substrates were transformed with over 80% conversion. Furthermore, it must be noticed that the concentration of catalytically active centers within the microgel is probably smaller than presumed which is shown by ICP-MS analysis. Hence, the presented microgel catalyst is even more active in comparison to the copper complex and copper salt which have a concentration of 5 mol% (see Tables S8–S10, ESI).

Table 1 Oxidation of primary alcohols to the corresponding aldehydes. All catalytic runs were performed twice using 5 mol% catalyst. Average conversions determined via twofold gas chromatography measurements are displayed

image file: d0cc02433c-u1.tif

Entry Substrate Conversion to aldehyde [%]
1 image file: d0cc02433c-u2.tif 42.6 66.9 99.7
2 image file: d0cc02433c-u3.tif 40.6 73.9 52.8
3 image file: d0cc02433c-u4.tif 55.8 58.9 83.0
4 image file: d0cc02433c-u5.tif 45.5 48.7 92.1
5 image file: d0cc02433c-u6.tif 63.8 31.7 67.5
6 image file: d0cc02433c-u7.tif 40.6 92.0 97.3
7 image file: d0cc02433c-u8.tif 51.5 45.4 77.5

In conclusion, we showed the successful functionalization of pVCL-GMA microgels with an amine ligand which subsequently forms and stabilizes bio-inspired copper(I) complexes within the microgels. These copper complex containing microgels enhance the catalytic activity of the chosen complex in the aerobic oxidation of benzyl alcohols in DMSO. Due to the very small amount of active centers as evidenced by ICP-MS, the catalytic activity of the Cu@pVCL-GMA-BPM microgels is even higher in comparison to CuCl and the CuCl BPM complex. Therefore, the unique properties of microgels and tailor-made environments inside the microgel framework offer new possibilities for the immobilization of metal complexes and their improvement to higher yields and conversions. Further work will concentrate on the optimization of the microgel functionalization with the amine ligand, investigations about the exact localization of copper complexes within the microgel, the recycling of the catalyst and on using the catalytically active microgels on a broader range of reactions.

The authors thank Sonderforschungsbereich SFB 985 (project A1 and C6) “Functional Microgels and Microgel Systems” of DFG Deutsche Forschungsgemeinschaft, Volkswagen Foundation and Center for Chemical Polymer Technology CPT, which was supported by the EU and the federal state of North Rhine-Westphalia (grant EFRE 30 00 883 02). We also thank Julia Nießen for carrying out the ICP-MS measurements.

Conflicts of interest

There are no conflicts to declare.

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Electronic supplementary information (ESI) available. CCDC 1988615. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d0cc02433c
These authors contributed equally to this work.

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