
==== Front
Beilstein J Org Chem
Beilstein J Org Chem
Beilstein Journal of Organic Chemistry
1860-5397
Beilstein-Institut Trakehner Str. 7-9, 60487 Frankfurt am Main, Germany

10.3762/bjoc.20.183
Review
Chemistry
Organic Chemistry
Factors influencing the performance of organocatalysts immobilised on solid supports: A review
Fehér Zsuzsanna https://orcid.org/0000-0001-8203-4711
1
Richter Dóra 1
Dargó Gyula https://orcid.org/0000-0003-4997-5151
1
Kupai József https://orcid.org/0000-0002-4212-4517
kupai.jozsef@vbk.bme.hu
1
Burke Anthony Guest Editor
1 Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, Műegyetem rkp. 3., H-1111 Budapest, Hungary https://ror.org/02w42ss30 https://www.isni.org/isni/0000000121800451
2024
26 8 2024
20 21292142
10.3762/bjoc.20.18330 3 2024
1 8 2024
Copyright © 2024, Fehér et al.
2024
Fehér et al.
https://creativecommons.org/licenses/by/4.0/ This is an open access article licensed under the terms of the Beilstein-Institut Open Access License Agreement (https://www.beilstein-journals.org/bjoc/terms/terms), which is identical to the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0). The reuse of material under this license requires that the author(s), source and license are credited. Third-party material in this article could be subject to other licenses (typically indicated in the credit line), and in this case, users are required to obtain permission from the license holder to reuse the material.
Organocatalysis has become a powerful tool in synthetic chemistry, providing a cost-effective alternative to traditional catalytic methods. The immobilisation of organocatalysts offers the potential to increase catalyst reusability and efficiency in organic reactions. This article reviews the key parameters that influence the effectiveness of immobilised organocatalysts, including the type of support, immobilisation techniques and the resulting interactions. In addition, the influence of these factors on catalytic activity, selectivity and recyclability is discussed, providing an insight into optimising the performance of immobilised organocatalysts for practical applications in organic chemistry.

asymmetric synthesis
catalyst recycling
heterogenisation
organocatalysis
solid support
National Research, Development and Innovation Office http://dx.doi.org/10.13039/501100018818 FK138037 National Research, Development, and Innovation Office RRF-2.3.1-21-2022-00015 Richter Gedeon Excellence PhD Scholarship Richter Gedeon Talentum Foundation, Gedeon Richter Plc. Jozsef Varga Foundation Excellence Postdoctoral Scholarship This research was funded by the National Research, Development, and Innovation Office (grant number FK138037), the Jozsef Varga Foundation (J. K.), and the Richter Gedeon Excellence PhD Scholarship of the Richter Gedeon Talentum Foundation, Gedeon Richter Plc. (Z. F., D. R., G. D.). Project no. RRF-2.3.1-21-2022-00015 has been implemented with the support provided by the European Union.All costs related to the publication of this open access article were entirely funded by the Beilstein-Institut.

This article is part of the thematic issue "5th International Symposium on Synthesis and Catalysis (ISySyCat 2023)".
==== Body
pmcIntroduction

Organocatalysts are small molecules that do not contain a metal atom in the reaction centre and are able to increase the speed of reactions. They have proven their place among the efficient and robust catalysts on numerous occasions since the two seminal works [1–2] published in 2000. Since then, organocatalysis has been combined with many other areas of research, such as photocatalysis, electrochemistry and mechanochemistry [3–5], while List and MacMillan were awarded the Nobel Prize in 2021 for the development of asymmetric organocatalysis [6]. To date, industrial companies have used a number of asymmetric organocatalytic processes to synthesise pharmaceuticals and fine chemicals on large scales [7].

Catalyst recycling is key from both an economic and an environmental perspective. An efficient catalytic process is characterised by the fact that the catalyst can be easily and, if possible, completely separated from the reaction mixture. Catalysts can be classified into homogeneous and heterogeneous catalysts. In homogeneous catalysis, the reaction components and the catalyst are in the same phase. Active catalytic sites are readily accessible to the reactants and therefore generally result in higher catalytic activity and selectivity [8]. As a result, homogeneous catalysis is generally preferred to heterogeneous catalysis, especially in the fine chemical and pharmaceutical industries [9]. The limitation of homogeneous catalysts, however, is their complex, time-consuming and energy-intensive recovery and subsequent recycling. Therefore, synthetic modification of catalysts is a commonly used method to aid their recovery.

Obstacles to the recycling of homogeneous catalysts can be addressed by heterogenisation of homogeneous catalysts [10], either following their application as homogeneous catalysts or before their application (heterogeneous catalysis). In heterogeneous catalysis, catalysts and reactants are present in different phases. Heterogeneous catalysts are easy to handle and can be easily separated from the reaction mixture by filtration, centrifugation or magnetic force, thus allowing catalysts to be recycled multiple times. Most highly stable and recyclable catalysts are attached to solid supports [11].

Solid supports are generally insoluble materials preferably with a large surface area to maximise the number of active sites for catalyst attachment. The advantages of such supports have been demonstrated by numerous reports on immobilised catalysts [12–14]. The type of support and the immobilisation technique have a major influence on the properties and thus performance of the resulting heterogeneous catalyst.

However, immobilisation and structural modification introduce additional steps in the synthesis of the catalyst. Moreover, the catalytic activity and selectivity of immobilised catalysts are often lower than those of the corresponding native catalysts. In addition, inactivation due to degradation may also occur. For long-term use, consistently high yields (and selectivity) are required over repeated runs, as these are indicative of the robust nature of the catalyst system.

A real challenge is to develop a supported organocatalyst whose catalytic efficiency can be reproduced over a sufficient number of reaction cycles. Despite the difficulty of the challenge, the design of heterogeneous, recyclable organocatalytic systems is of high interest [8]. The continued development of efficient catalytic recovery methods, such as the application of immobilised organocatalysts [14–15] and heterogeneous organocatalysis [16–18], could be a potential driver for the introduction of, for example, enantioselective organocatalysis in the pharmaceutical industry [19]. Knowledge of the factors that influence catalyst performance is crucial to the development of high performance immobilised organocatalysts.

Review

Characteristics of the solid support

Considering the support type, organic polymer-supported, silica-supported [20–25], glass beads [26] and magnetic nanoparticle-supported [27–32] organocatalysts are pivotal in the field of immobilised organocatalysts. Polymer-supported organocatalysts are commonly immobilised on polystyrene (PS) [28,33–38], as well as on other materials such as nylon 6,6 [15], chitosan [39–40], and polymethylhydrosiloxane (PMHS) [41]. The role of the polymers as supports for catalysts is not merely passive. These supports significantly influence the reaction environment and catalytic efficiency [42]. Attachment methods, spacer lengths, and polymer nature profoundly impact the catalyst's performance and recyclability. Various immobilization strategies, including covalent bonding and encapsulation, cater to different polymer types. Soluble polymers enhance diffusion, while insoluble ones ensure stability and high loading capacities [42]. Silica is also widely applied due to its ease of functionalisation and thermal stability [43]. The controllability of surface, geometry, and pore size makes silica-based materials sustainable and functionalisable supports for organocatalytic reactions [44].

The particle morphology of mesoporous silica can be tuned to various shapes, including spheres, tubes, and rods of various dimensions [45], by using a co-condensation method performed under low surfactant concentration conditions [46–50], changing the concentration, molecular size, and hydrophilicity/hydrophobicity of the organoalkoxysilane precursors [51]. Various morphologies of mesoporous silica, including fibre, platelet, rod, and film, can be generated by altering the reaction conditions during synthesis [52–57] or by using potassium chloride or ammonium fluoride salts as additives [58–60]. In a comprehensive study [61], the catalytic properties of three types (rope, rod and fibre) of mesoporous silica Santa Barbara Amorphous (SBA-15) and small pore-sized Mobil Composition of Matter (MCM-41) were applied and compared as supports of an organocatalyst. These silicas were modified by incorporating an organosulfonic acid group (propylenesulfonic acid) through a post-synthesis grafting method. Their catalytic performance was studied and compared in the esterification of methanol or glycerol with oleic acid (1). It was observed that substrate conversion and product yield also depended on the particle morphology. Rope-type propylsulfonic SBA-15 mesoporous silica gel showed the highest catalytic activity in both studied esterification reactions (Scheme 1).

Scheme 1 Esterification of oleic acid (1) with propylsulfonic acid (Pr-SO3H)-functionalised mesoporous silica catalyst 4.

By adjusting the pore size of the support, the catalyst selectivity can be influenced. To counteract the decrease in selectivity caused by catalyst immobilisation, the concept of “confinement” was introduced [62], which involves forcing the catalytic moieties into confined spaces. The confinement of the heterogeneous version of cinchona amine and thiourea catalysts was reported, leading to improved enantioselectivity values in the Michael addition of nitromethane (5) to chalcone (6) through modification of the pore size of mesoporous silica 8 or 9 (Scheme 2) [63]. Thus, for cinchona thiourea, enantioselectivity not only increased with reduced pore size but even reached the level of the homogeneous catalyst when the support pore size was reduced to 6.3 nm. This resulted in obtaining the (R)-configured product 7 with 63% yield and 93% ee, as opposed to a 55% yield and 39% ee for a pore size of 11.3 nm [64].

Scheme 2 Using confinement of organocatalytic units for improving the enantioselectivity of silica-supported organocatalysts in the Michael addition of nitromethane (5) to chalcone (6).

Catalyst supports must meet certain criteria, including being chemically inert, and the supported catalyst should exhibit high stability across various reaction conditions while also being easily recyclable [8,64]. When the solid support is not inert, it can lead to a decrease in selectivity.

Connon and co-workers have attached a cinchona thiourea organocatalyst to magnetic nanoparticles 13 for the Michael addition of dimethyl malonate (10) to trans-β-nitrostyrene (11) (Scheme 3) [31].

Scheme 3 Michael addition catalysed by cinchona thiourea immobilised on magnetic nanoparticles (13).

To explore the potential impact of nanoparticles on catalyst efficiency, experiments were conducted. It was discovered that the nanoparticles themselves catalysed the formation of the racemic product in the absence of the thiourea catalyst. This finding elucidates the relatively poor enantioselectivity observed in reactions catalysed by the magnetic nanoparticle-supported organocatalyst. To validate this hypothesis, the Michael addition was repeated in the presence of both unsupported thiourea 14 and the nanoparticles. The resulting product was isolated with only 84% ee, indicating that the nanoparticles compete with the thiourea catalyst 14 for the substrate under these conditions (Scheme 4).

Scheme 4 Michael addition catalysed by cinchona thiourea in the presence of magnetic nanoparticles.

Thiel and co-workers examined N-benzylthiazolium salts 17 anchored covalently to mesoporous materials in a benzoin condensation reaction (Scheme 5) [65]. Initially good yields were observed, even after a short reaction time, but a drop in yield was seen after reusing the catalysts for a second run. This decrease was attributed to the use of a protic solvent, MeOH, in combination with basic Et3N, which could degrade the surface of the support and result in the leaching of the active sites or the restructuring of the mesoporous material. This could have been avoided by performing reactions in a less protic and less polar solvent.

Scheme 5 Benzoin condensation catalysed by N-benzylthiazolium salt attached to mesoporous material.

Attaching catalysts to solid supports also offers the potential for enhancing catalyst stability. Boyer and co-workers reported the use of silica nanoparticle-supported eosin Y 21 as a photocatalyst in reversible addition fragmentation chain transfer (RAFT) photo-polymerisation reactions (Scheme 6) [24]. Previous endeavours utilising the homogeneous catalyst led to catalyst degradation or failure to remove the catalyst properly which resulted in the degradation of the polymer itself [66]. By employing the supported photocatalyst, reduced contamination was demonstrated in the final product and the catalyst could be recycled over five polymerisation cycles at ultralow catalyst loadings (6 ppm), thereby confirming the stability of the catalyst.

Scheme 6 Photoinduced RAFT polymerisation of n-butyl acrylate (19) catalysed by silica nanoparticle-supported eosin Y 21, which could be recycled over five reaction cycles.

Immobilisation methods

Catalysts are generally immobilised via various interactions between the support and the active catalytic species. These methods can be classified into four categories: covalent bonding, non-covalent interactions (physisorption), ionic bonding, and encapsulation. The catalysts are connected to the support via strong chemical bonds in covalent bonding. In non-covalent interactions, the catalysts are adsorbed onto the support surface through weaker intermolecular forces, such as van der Waals forces and hydrogen bonding. Ionic catalysts form ionic bonds or those that can be ionised under immobilisation conditions. Encapsulation involves physically trapping the catalyst within the pores or cavities of the support [8,67].

Adsorption is a non-covalent reversible technique for attaching organocatalysts to supports. It offers a facile and modular construction of immobilised chiral catalysts with maintained or even improved activity and stereoselectivity [68–70]. The main advantages of catalyst immobilisation by adsorption are that minimal modifications of the parent catalysts are required, few reagents are needed, and it is a relatively cheap and easily implemented method [69,71]. Therefore, adsorption is a popular method for immobilising catalysts. However, this method has a major drawback as the catalyst can easily leach into the solution as it reaches equilibrium between the absorbed species on the surface and the solubilised species. To improve the stability of the supported catalyst, it is important to modify the catalyst and support to enable hydrogen bonding.

This method can also bring the catalyst closer to the support, impacting electronic properties and ligand conformation. With large catalyst molecules, the pores of an ordered mesoporous material being similar in size to the catalyst can create significant diffusion barriers as the catalyst attempts to enter the pores. As a result, the pore channels that are distant from the pore openings are unlikely to be accessible to the catalyst [72].

Ionic bonding is a straightforward and economical immobilisation method. This form of non-covalent immobilisation can be reversed by altering the temperature and ionic strength [71]. Furthermore, the electrostatic interaction between the homogeneous catalyst and the support is robust enough to reduce leaching significantly [67,73]. However, a potential drawback of this technique is that the presence of a charged support can lead to complications, such as distortion of the catalyst structure and changes in the reaction kinetics.

The non-covalent immobilisation of chiral organocatalysts can also be carried out within deep eutectic solvents (DESs). Very recently, a cinchonidine-squaramide organocatalyst was immobilised in three types of natural DESs, namely betaine/sorbitol/water, betaine/xylitol/water, and betaine/mannitol/water [74]. In these systems, the recyclability of the organocatalyst was investigated and several reaction cycles were performed using the same DESs and organocatalyst. For example, in the Michael addition of methyl 2-oxocyclopentane-1-carboxylate and trans-β-nitrostyrene, the recyclability of the organocatalyst in the betaine/sorbitol/water DES system was demonstrated up to 10 cycles without any significant decrease in yield (up to 99%) or stereoselectivity (up to 96% ee).

Encapsulation is an irreversible method and the only catalyst immobilisation process that does not require any interaction between the catalyst and the support. Because of this, it is the sole technique which attempts to mimic the homogeneously catalysed reaction process [75]. It typically results in enhanced properties, e.g., augmented morphological stability, tailored physicochemical permeability, and reduced catalyst leakage [76].

When constructing a support around a catalyst, the catalyst must remain stable under the synthesis conditions of the support. If the catalyst can be easily synthesised in a few steps, assembling it within the pores is preferable. However, if the catalyst is difficult to synthesise but remains stable, forming the support around it is advisable [67]. Another limitation of the encapsulation method is that the size of the pore openings in the support must be smaller than the kinetic size of the immobilised catalyst [77].

Covalent tethering is a method of bonding that creates stable catalysts and minimises catalyst leaching. However, this technique has some limitations. Some covalent immobilisation methods involve complex synthetic manipulations, making them unsuitable for large-scale preparations. Furthermore, catalysts bound to carriers may experience restrictions in mobility, limiting their ability to undergo conformational changes necessary for catalysis, especially in the case of enzymes [72,78]. Overall, covalent tethering techniques are the preferred approach to designing stable heterogeneous organocatalysts, provided that the covalent modification does not involve complex synthetic steps.

Recent advancements in materials synthesis and nanotechnology have expanded the repertoire of techniques available for designing catalysts with controlled structures to promote complex reactions selectively. A recent review of Francuisco Zaera [79] discusses key research directions in the transition from homogeneous to heterogeneous catalysis. Special nanostructures, the so-called metal-organic frameworks (MOF), covalent organic frameworks (COF), porous organic frameworks (POF), and hyperbranched systems are formed with a special case of tethering. The ability to predesign both primary and high-order structures serves as a great advantage in these catalytic systems, making them easily fine tuneable. Catalytically active sites can be formed by direct condensation or post-synthetic modifications. In the case of catalyst immobilisation post-synthetic modifications play a more important role.

MOFs are a type of porous crystalline polymers where organic ligands are coordinated to metal clusters [80–90]. The framework can be post-synthetically modified by functional organic sites, often specifically chiral functionalities, giving easily recyclable asymmetric catalysts. The asymmetric sites can be different types, commonly they are binaphthyl-, biphenyl- [91–93] and proline-based [94–95].

COFs are a type of crystalline porous material, consisting of covalently linked organic ligands [96–97]. Since the framework only has organic building blocks, both condensation [98] and post-synthetic modification [99] methods can be used to immobilise organocatalysts. Asymmetric organocatalysis is commonly achieved by pyrrolidone ligands, with great results in a variety of reactions, such as Michael [100] and aldol [101] reactions.

POFs [102] are hydrocarbon systems that contain pores, of which COFs are a subgroup. POFs are widely applied in the fields of gas adsorption and storage, the separation of gases, catalysis, energy storage, photocatalysis, etc., and have many different types, such as hyper-cross-linked polymers (HCPs), polymers of intrinsic microporosity (PIMs), covalent organic frameworks (COFs), extrinsic porous molecules, and porous organic cages [103] etc. Since in terms of organocatalyst immobilisation COFs are the most important, further discussion of POFs is not included in this review.

Hyperbranched systems [104–106] and dendrimers [107–109] have also emerged as alternative soluble supports for catalyst immobilisation. In these systems the catalyst moieties can be built in at the core, at the periphery, or at intermediate positions, affecting the catalytic performances differently [110]. An advantage of dendrimer-supported organocatalysts are their enzyme-like properties [111–112]. Selective binding and cooperative catalysis can give the catalyst high selectivity and activity.

Interactions between the support and other components

The interaction between the solid support and the organocatalyst [113], reactants [114], product [115] or solvent [116] can significantly impact catalytic activity. These interactions often manifest in various forms of adsorption: physisorption, involving forces like van der Waals interactions and hydrogen bonding, or chemisorption, which may involve ionic or covalent bonding. These adsorptive interactions can alter the electronic properties and conformation of the supported organocatalyst, thereby influencing its catalytic activity compared to its homogeneous counterpart. For instance, Fotaras et al. showed that the incorporation of a tripeptide-like prolinamide-thiourea organocatalyst onto commercially available resins (JandaJel, polystyrene-divinylbenzene, and ChemMatrix) results in diminished catalytic activity, both in terms of yield and enantiomeric excess values, compared to the homogeneous analogue [117]. On the contrary, Dumesic and co-workers showed that the activity of a difunctional organocatalyst in lactose hydrolysis was improved 5.2-fold by immobilisation on different solid supports that mimic the active site channels of enzymes [113].

In a solid-supported system, the solvent can exert a different influence on the catalytic activity compared to a homogeneous catalyst. Solvent molecules present on the support surface might partially obstruct the active sites of the catalyst. Therefore, selecting the appropriate solvent may require adjustments to optimise the performance of the solid-supported organocatalyst [116]. Moreover, before the immobilisation of catalysts, it is necessary to consider whether the solid support itself can catalyse the desired or side reactions. This could be advantageous in some cases, i.e., when the solid support cooperatively helps the reaction [118], but in asymmetric synthesis, background activity of the solid support can lead to lower stereoselectivity, as previously shown in Scheme 4.

Solutions for limitations of solid-supported organocatalysts

The properties and applicability of an immobilised catalyst depend not only on the immobilisation method and the physicochemical characteristics, porosity, and dimensions of the support, but can also be influenced by several other factors. In a homogeneous system, rapid diffusion, and creation of catalyst–reactant interactions are possible because the organocatalyst is dissolved in the reaction mixture. However, in a solid-supported organocatalyst, the reactants need to diffuse to the active sites on the solid support. Diffusion limitations can decrease the effective concentration of reactants at the catalytic sites, resulting in lower reaction rates compared to the homogeneous catalyst. Thus, optimising reactor design, including appropriate mixing and flow characteristics, can help to minimise these limitations. Higher reactant concentrations may also be necessary to overcome diffusion limitations and maintain suitable concentrations at the active sites [119].

Fülöp and co-workers proved the diffusion dependence by employing the Koros–Nowak criterion test [120] in the conjugate addition of propanal (22) and trans-β-nitrostyrene (11) catalysed by a simple solid-supported peptidic catalyst 24 using a continuous flow reactor. To overcome the diffusion limitations, elevated pressure was applied. Increasing the pressure from atmospheric to 60 bar resulted in a 12% increase in yields, however, further increase in pressure proved to be non-beneficial. Moreover, increasing the temperature provided higher yields at optimised pressure (60 bar) but also led to lowered enantioselectivity (Scheme 7) [121].

Scheme 7 Pressure and temperature dependence of the 1,4-addition of propanal to trans-β-nitrostyrene under continuous flow conditions.

Zhang and co-workers prepared a novel polymer with an ordered mesoporous system, resulting in a high surface area and uniform pore size. As a result, a high degree of dispersion of the piperazine active sites was achieved, leading to a catalyst exhibiting comparable activity and selectivity to that of a homogenous organocatalyst. Moreover, the hydrophobic surface of the catalyst enhanced the mass transport of organic reactants in water [122]. Based on similar mesoporous catalysts [123–124], it can be concluded that with a properly designed pore size resulting in a high density of active catalytic sites, diffusion control could be diminished.

Furthermore, the solid support may impose restrictions on access to the active sites of the organocatalyst. If the active sites are too close to the support backbone or situated within the porous structure of the support, they are less accessible for larger reactant molecules, thereby affecting the catalytic activity and selectivity. Proper design of the linker between the catalytic sites and the support surface, along with careful selection of the solid support, can help to optimise the accessibility of the active sites and mitigate this limitation [65,125].

Consequently, the properties of the supported organocatalyst also depend on the density of catalytic sites on the support surface, as well as the nature and length of the linker [8]. Additionally, the linker itself could serve as a competitive active site. In the case of enantioselective catalysis, the linker could promote the formation of racemic products, leading to lower stereoselectivity. Moreover, in catalyst co-polymerisation, the organocatalyst might be enclosed within the inner part of the polymer bead, rendering it inaccessible for reactants, or the repeating unit of the polymer could act as a competitive active site.

On the other hand, in some cases, the support surface can even impede unwanted side reactions. Pericàs and co-workers immobilised a thiourea organocatalyst on PS (28) and applied it in the enantioselective α-amination of 1,3-dicarbonyl compounds [36]. Unlike homogeneous thioureas, catalyst 28 is not irreversibly deactivated by azodicarboxylate reagents. In the attempt to recycle catalyst 28 for the reaction between ethyl 2-oxocyclopentanecarboxylate (25) and di-tert-butyl azodicarboxylate (26) (Scheme 8), a decline in catalytic activity was initially noticed. While this could be attributed to the nucleophilic deactivation of thioureas by azodicarboxylates in a homogeneous phase, as noted by Takemoto [126], it was suggested that this interaction would be significantly impeded by the polymer backbone. Alternatively, it was proposed that this degradation could be due to protonation of the basic tertiary amine unit. It was found that washing the resin with triethylamine between reaction cycles was sufficient to regenerate the catalyst. Consequently, high yields (85–94%) and enantiomeric excess values (90–92%) were consistently achieved over 9 reaction cycles.

Scheme 8 α-Amination of ethyl 2-oxocyclopentanecarboxylate catalysed by PS-THU which could be recycled over 9 reaction cycles.

In a previous work conducted in our research group, we investigated the influence of various linkers of cinchona squaramide organocatalysts immobilised on a poly(glycidyl methacrylate) (PGMA) solid support [127]. The support consisted of well-defined monodispersed PGMA microspheres, which were prepared through thorough parameter optimisation. Three amine-functionalised cinchona derivatives 29–31 were immobilised on this polymer support by utilising its reactive epoxy groups (Scheme 9).

Scheme 9 Preparation of supported catalysts C29–C31 from cinchona squaramides 29–31 modified with a primary amino group.

These structurally diverse precatalysts were prepared by modifying the cinchona skeleton at different positions to investigate how the amino group-containing linker affects them. The immobilised organocatalysts' catalytic activities and enantioselectivity values were evaluated in the Michael addition of pentane-2,4-dione (32) and trans-β-nitrostyrene (11). The catalysts could be reused over five reaction cycles through centrifugation, without significant loss of activity (Scheme 10).

Scheme 10 Application of PGMA-supported organocatalysts C29–C31 in the asymmetric Michael addition of pentane-2,4-dione (32) and trans-β-nitrostyrene (11).

The catalysts showed no significant differences in terms of yields. However, catalysts C30 and C31 achieved higher enantiomeric excess values (up to 79% ee and 59% ee, respectively) compared to catalyst C29 (up to 31% ee). Among the immobilised catalysts, C30 produced the best results. Catalyst C29, which showed lower selectivity, features a 1,2,3-triazole-4-yl unit as the substituent at the tertiary amine-containing quinuclidine motif, whereas C30 and C31 have an ethyl group attached to the ring in this position. Additionally, catalyst C31 has a longer-chain linker, but its squaramide NH groups are more acidic due to binding with an electron-withdrawing group. This acidity can result in stronger hydrogen bonds between the substrate and the catalyst C30, which contains a bis(trifluoromethyl)phenyl-modified squaramide moiety. This stronger interaction potentially enhances the catalyst–substrate interaction, allowing for more precise stereocontrol of the reaction [128–132]. Therefore, the difference in enantioselectivity values may be attributed to these electronic effects. Ultimately, the most favourable outcomes were achieved with catalyst C30 at 0 °C, with yields reaching up to 84% and enantiomeric excess reaching 96%.

As highlighted in this review, different factors can aid in the design and optimisation of solid-supported organocatalysts, ensuring their catalytic activity is comparable or even superior to their homogeneous counterparts. A notable example of a highly recyclable solid-supported organocatalyst was demonstrated by List and co-workers, who showcased the robustness of a cinchona alkaloid-based sulfonamide organotextile catalyst 36 (immobilised on nylon 6,6) through hundreds of recycling experiments (Scheme 11) [15]. The organotextile catalyst 36 exhibited a very similar enantioselectivity (93% ee) to the homogeneous catalyst (94% ee) in the alcoholytic desymmetrisation of a cyclic anhydride 34 albeit requiring a slightly longer reaction time. Compared to polymer films, textile fibres offer a significantly higher surface area, potentially contributing to the maintenance of high enantioselectivity (>90% ee) for over 250 cycles.

Scheme 11 Alcoholytic desymmetrisation of a cyclic anhydride 34 catalysed by polyamide-supported cinchona sulfonamide 36.

Conclusion

Solid-supported organocatalysts can provide an environmentally friendly and economical solution even for industrial processes. To maximise their adoption by industry, efficient catalysts that can be easily recycled need to be developed. Immobilisation on solid supports such as polymers, silica, glass beads and magnetic nanoparticles has proven effective, although each method presents unique challenges regarding catalytic activity, selectivity and stability. A number of factors need to be taken into account during the development process. The surface area, morphology and pore size of the solid support have a strong influence on the catalytic properties. Innovative approaches such as confinement effects and advanced material designs such as MOFs, COFs and hyperbranched systems offer promising solutions to enhance catalyst efficiency and selectivity. It is also crucial that the supports meet certain requirements: they must be chemically inert, stable and easily recyclable. Examples can also be found where the stability of the catalyst is increased through the attachment to the support.

Of the immobilisation methods, covalent tethering is preferred because of the resulting stable immobilisation. However, simple catalyst grafting with few steps is important and favourable for industrial applications. Interactions between the support, the catalytically active site and other components must also be taken into account in catalyst development. Additionally, the selection of the appropriate solvent is critical.

To mitigate diffusion limitation, it is important to ensure appropriate mixing and flow characteristics and adequate concentration of reactants and catalytic units. Flow chemistry can be easily combined with solid-supported organocatalysis, while even elevated pressure can be applied to reduce diffusion limitations. The size, rigidity and character of the linker also play an important role in catalyst design.

Despite these advances, the development of highly efficient and recyclable organocatalysts remains a challenge. Trade-offs between immobilisation methods and the catalytic performance require further research. Future directions include improving immobilisation strategies, exploring new support materials and optimising reaction conditions to alleviate diffusion limitations and improve the availability of active sites.

In summary, the evolving development of solid-supported organocatalysts has significant potential for industrial applications, particularly in the pharmaceutical and fine chemical industry. The design of recyclable, robust and high-performance organocatalyst systems will continue to encourage innovation in this area, contributing to more sustainable and efficient catalytic processes.

Data Availability

Data sharing is not applicable as no new data was generated or analyzed in this study.
==== Refs
1 List B Lerner R A Barbas C F J Am Chem Soc 2000 122 2395 2396 10.1021/ja994280y
2 Ahrendt K A Borths C J MacMillan D W C J Am Chem Soc 2000 122 4243 4244 10.1021/ja000092s
3 Nicewicz D A MacMillan D W C Science 2008 322 77 80 10.1126/science.1161976 18772399
4 Chauhan P Chimni S S Beilstein J Org Chem 2012 8 2132 2141 10.3762/bjoc.8.240 23243475
5 Némethová V Krištofíková D Mečiarová M Šebesta R Chem Rec 2023 23 e202200283 10.1002/tcr.202200283 36703542
6 The Nobel Prize organisation; Press Release The Nobel Prize in Chemistry 2021 27 3 2024 Available from: https://www.nobelprize.org/prizes/chemistry/2021/press-release/
7 Bulger P G Industrial Applications of Organocatalysis Comprehensive Chirality 2012 9 Amsterdam, Netherlands Elsevier 228 252 10.1016/b978-0-08-095167-6.00911-3
8 Piermatti O Abu-Reziq R Vaccaro L Benaglia M Puglisi A Strategies to Immobilized Catalysts Catalyst Immobilization: Methods and Applications 2019 Weinheim, Germany Wiley-VCH 1 22 10.1002/9783527817290.ch1
9 Hübner S de Vries J G Farina V Adv Synth Catal 2016 358 1 3 25 10.1002/adsc.201500846
10 Collis A E C Horváth I T Catal Sci Technol 2011 1 912 919 10.1039/c1cy00174d
11 Molnár Á Papp A Coord Chem Rev 2017 349 1 65 10.1016/j.ccr.2017.08.011
12 Munnik P de Jongh P E de Jong K P Chem Rev 2015 115 14 6687 6718 10.1021/cr500486u 26088402
13 Fulgheri T Della Penna F Baschieri A Carlone A Curr Opin Green Sustainable Chem 2020 25 100387 10.1016/j.cogsc.2020.100387
14 Rodríguez‐Escrich C Pericàs M A Chem Rec 2019 19 9 1872 1890 10.1002/tcr.201800097 30230219
15 Lee J-W Mayer-Gall T Opwis K Song C E Gutmann J S List B Science 2013 341 6151 1225 1229 10.1126/science.1242196 24031014
16 Wang X Blechert S Antonietti M ACS Catal 2012 2 1596 1606 10.1021/cs300240x
17 Liu X Tang B Long J Zhang W Liu X Mirza Z Sci Bull 2018 63 502 524 10.1016/j.scib.2018.03.009
18 Ötvös S B Pericàs M A Kappe C O Chem Sci 2019 10 11141 11146 10.1039/c9sc04752b 32206263
19 Han B He X-H Liu Y-Q He G Peng C Li J-L Chem Soc Rev 2021 50 3 1522 1586 10.1039/d0cs00196a 33496291
20 Huh S Chen H-T Wiench J W Pruski M Lin V S-Y Angew Chem, Int Ed 2005 44 12 1826 1830 10.1002/anie.200462424
21 Yu P He J Guo C Chem Commun 2008 2355 2357 10.1039/b800640g
22 Brunelli N A Jones C W J Catal 2013 308 60 72 10.1016/j.jcat.2013.05.022
23 Leyva‐Pérez A García‐García P Corma A Angew Chem, Int Ed 2014 53 33 8687 8690 10.1002/anie.201403049
24 Shanmugam S Xu S Adnan N N M Boyer C Macromolecules 2018 51 779 790 10.1021/acs.macromol.7b02215
25 Erigoni A Hernández-Soto M C Rey F Segarra C Díaz U Catal Today 2020 345 227 236 10.1016/j.cattod.2019.09.041
26 Amorim A C Fonseca D P Carreiro E P Hermann G J Federsel H-J Burke A J Synlett 2022 33 1756 1762 10.1055/a-1916-4858
27 Keller M Perrier A Linhardt R Travers L Wittmann S Caminade A-M Majoral J-P Reiser O Ouali A Adv Synth Catal 2013 355 9 1748 1754 10.1002/adsc.201300120
28 Riente P Yadav J Pericàs M A Org Lett 2012 14 3668 3671 10.1021/ol301515d 22758605
29 Wang B G Ma B C Wang Q Wang W Adv Synth Catal 2010 352 2923 2928 10.1002/adsc.201000508
30 Riente P Mendoza C Pericás M A J Mater Chem 2011 21 7350 7355 10.1039/c1jm10535c
31 Gleeson O Davies G-L Peschiulli A Tekoriute R Gun'ko Y K Connon S J Org Biomol Chem 2011 9 22 7929 7940 10.1039/c1ob06110k 21989817
32 Kong Y Tan R Zhao L Yin D Green Chem 2013 15 2422 2433 10.1039/c3gc40772a
33 Rueping M Sugiono E Steck A Theissmann T Adv Synth Catal 2010 352 281 287 10.1002/adsc.200900746
34 Kasaplar P Riente P Hartmann C Pericàs M A Adv Synth Catal 2012 354 2905 2910 10.1002/adsc.201200526
35 Whiteoak C J Henseler A H Ayats C Kleij A W Pericàs M A Green Chem 2014 16 1552 1559 10.1039/c3gc41919c
36 Kasaplar P Ozkal E Rodríguez-Escrich C Pericàs M A Green Chem 2015 17 3122 3129 10.1039/c5gc00496a
37 Cañellas S Ayats C Henseler A H Pericàs M A ACS Catal 2017 7 2 1383 1391 10.1021/acscatal.6b03286
38 Rodríguez‐Rodríguez M Maestro A Andrés J M Pedrosa R Adv Synth Catal 2020 362 13 2744 2754 10.1002/adsc.202000238
39 Andrés J M González F Maestro A Pedrosa R Valle M Eur J Org Chem 2017 3658 3665 10.1002/ejoc.201700582
40 de Gonzalo G Franconetti A Fernández R Lassaletta J M Cabrera-Escribano F Carbohydr Polym 2018 199 365 374 10.1016/j.carbpol.2018.07.009 30143140
41 Guizzetti S Benaglia M Siegel J S Chem Commun 2012 48 3188 3190 10.1039/c2cc17919a
42 Altava B Burguete M I García-Verdugo E Luis S V Chem Soc Rev 2018 47 2722 2771 10.1039/c7cs00734e 29577129
43 Ferré M Pleixats R Wong Chi Man M Cattoën X Green Chem 2016 18 881 922 10.1039/c5gc02579f
44 Corma A Garcia H Adv Synth Catal 2006 348 1391 1412 10.1002/adsc.200606192
45 Huh S Wiench J W Yoo J-C Pruski M Lin V S-Y Chem Mater 2003 15 22 4247 4256 10.1021/cm0210041
46 Burkett S L Sims S D Mann S Chem Commun 1996 1367 1368 10.1039/cc9960001367
47 Sims S D Burkett S L Mann S MRS Online Proc Libr 1996 431 77 82 10.1557/proc-431-77
48 Macquarrie D J Chem Commun 1996 1961 1962 10.1039/cc9960001961
49 Huo Q Margolese D I Stucky G D Chem Mater 1996 8 1147 1160 10.1021/cm960137h
50 Lim M H Blanford C F Stein A J Am Chem Soc 1997 119 4090 4091 10.1021/ja9638824
51 Stein A Melde B J Schroden R C Adv Mater (Weinheim, Ger) 2000 12 1403 1419 10.1002/1521-4095(200010)12:19<1403::aid-adma1403>3.0.co;2-x
52 Yu C Fan J Tian B Zhao D Stucky G D Adv Mater (Weinheim, Ger) 2002 14 1742 1745 10.1002/1521-4095(20021203)14:23<1742::aid-adma1742>3.0.co;2-3
53 Sayari A Han B-H Yang Y J Am Chem Soc 2004 126 44 14348 14349 10.1021/ja0478734 15521742
54 Bao X Y Zhao X S J Phys Chem B 2005 109 10727 10736 10.1021/jp050449k 16852303
55 Jin Z Wang X Cui X Colloids Surf, A 2008 316 27 36 10.1016/j.colsurfa.2007.08.013
56 Johansson E M Ballem M A Córdoba J M Odén M Langmuir 2011 27 4994 4999 10.1021/la104864d 21413751
57 Björk E M Söderlind F Odén M Langmuir 2013 29 13551 13561 10.1021/la403201v 24102575
58 Schmidt-Winkel P Yang P Margolese D I Chmelka B F Stucky G D Adv Mater (Weinheim, Ger) 1999 11 303 307 10.1002/(sici)1521-4095(199903)11:4<303::aid-adma303>3.3.co;2-d
59 Zhao D Sun J Li Q Stucky G D Chem Mater 2000 12 275 279 10.1021/cm9911363
60 Björk E M Söderlind F Odén M J Colloid Interface Sci 2014 413 1 7 10.1016/j.jcis.2013.09.023 24183423
61 Jeenpadiphat S Björk E M Odén M Tungasmita D N J Mol Catal A: Chem 2015 410 253 259 10.1016/j.molcata.2015.10.002
62 Goettmann F Sanchez C J Mater Chem 2007 17 1 24 30 10.1039/b608748p
63 Zhao L Li Y Yu P Han X He J ACS Catal 2012 2 1118 1126 10.1021/cs200588c
64 Franconetti A de Gonzalo G ChemCatChem 2018 10 5554 5572 10.1002/cctc.201801459
65 Zhou Z Meng Q Seifert A Wagener A Sun Y Ernst S Thiel W R Microporous Mesoporous Mater 2009 121 145 151 10.1016/j.micromeso.2009.01.022
66 Padon K S Scranton A B J Polym Sci, Part A: Polym Chem 2001 39 5 715 723 10.1002/1099-0518(20010301)39:5<715::aid-pola1043>3.3.co;2-f
67 McMorn P Hutchings G J Chem Soc Rev 2004 33 108 122 10.1039/b200387m 14767506
68 Aprile C Giacalone F Gruttadauria M Marculescu A M Noto R Revell J D Wennemers H Green Chem 2007 9 1328 1334 10.1039/b709471j
69 Zhang L Luo S Cheng J-P Catal Sci Technol 2011 1 507 516 10.1039/c1cy00029b
70 Aguilera D A Spinozzi Di Sante L Pettignano A Riccioli R Roeske J Albergati L Corti V Fochi M Bernardi L Quignard F Eur J Org Chem 2019 3842 3849 10.1002/ejoc.201900247
71 Guisan J M Immobilization of Enzymes and Cells 2013 3rd ed. New York, NY, USA Humana Press (Methods in Molecular Biology) 10.1007/978-1-62703-550-7
72 Zhao X S Bao X Y Guo W Lee F Y Mater Today 2006 9 32 39 10.1016/s1369-7021(06)71388-8
73 Wagner H H Hausmann H Hölderich W F J Catal 2001 203 150 156 10.1006/jcat.2001.3296
74 Fonseca D P Amorim A C Carreiro E P Prates Ramalho J P Hermann G J Federsel H-J Duarte A R C Burke A J SynOpen 2023 07 374 380 10.1055/a-2117-9971
75 Sadjadi S Encapsulated Catalysts 2017 London, UK Academic Press 10.1016/c2014-0-04759-4
76 Rother C Nidetzky B Enzyme Immobilization by Microencapsulation: Methods, Materials, and Technological Applications Encyclopedia of Industrial Biotechnology: Bioprocess, Bioseparation, and Cell Technology 2014 Weinheim, Germany Wiley-VCH 1 21 10.1002/9780470054581.eib275
77 Gao C Deng X Zhang J Ma X Appl Catal, A 2023 650 119003 10.1016/j.apcata.2022.119003
78 Shen Q Yang R Hua X Ye F Zhang W Zhao W Process Biochem (Oxford, U K) 2011 46 1565 1571 10.1016/j.procbio.2011.04.010
79 Zaera F Chem Rev 2022 122 8594 8757 10.1021/acs.chemrev.1c00905 35240777
80 Hoskins B F Robson R J Am Chem Soc 1990 112 4 1546 1554 10.1021/ja00160a038
81 Lee J Farha O K Roberts J Scheidt K A Nguyen S T Hupp J T Chem Soc Rev 2009 38 1450 1459 10.1039/b807080f 19384447
82 Corma A García H Llabrés i Xamena F X Chem Rev 2010 110 8 4606 4655 10.1021/cr9003924 20359232
83 Isaeva V I Kustov L M Pet Chem 2010 50 167 180 10.1134/s0965544110030011
84 Liu J Chen L Cui H Zhang J Zhang L Su C-Y Chem Soc Rev 2014 43 16 6011 6061 10.1039/c4cs00094c 24871268
85 Zhu L Liu X-Q Jiang H-L Sun L-B Chem Rev 2017 117 12 8129 8176 10.1021/acs.chemrev.7b00091 28541694
86 Xu W Thapa K B Ju Q Fang Z Huang W Coord Chem Rev 2018 373 199 232 10.1016/j.ccr.2017.10.014
87 Dhakshinamoorthy A Li Z Garcia H Chem Soc Rev 2018 47 8134 8172 10.1039/c8cs00256h 30003212
88 Yuan S Feng L Wang K Pang J Bosch M Lollar C Sun Y Qin J Yang X Zhang P Adv Mater (Weinheim, Ger) 2018 30 1704303 10.1002/adma.201704303
89 Chen Y-Z Zhang R Jiao L Jiang H-L Coord Chem Rev 2018 362 1 23 10.1016/j.ccr.2018.02.008
90 Yang D Gates B C ACS Catal 2019 9 1779 1798 10.1021/acscatal.8b04515
91 Ma L Falkowski J M Abney C Lin W Nat Chem 2010 2 838 846 10.1038/nchem.738 20861899
92 Mo K Yang Y Cui Y J Am Chem Soc 2014 136 1746 1749 10.1021/ja411887c 24447241
93 Chen X Qiao Z Hou B Jiang H Gong W Dong J Li H-Y Cui Y Liu Y Nano Res 2021 14 2 466 472 10.1007/s12274-020-2905-7
94 Banerjee M Das S Yoon M Choi H J Hyun M H Park S M Seo G Kim K J Am Chem Soc 2009 131 22 7524 7525 10.1021/ja901440g 19438178
95 Zhang Y Guo J Shi L Zhu Y Hou K Zheng Y Tang Z Sci Adv 2017 3 e1701162 10.1126/sciadv.1701162 28835929
96 Côté A P Benin A I Ockwig N W O'Keeffe M Matzger A J Yaghi O M Science 2005 310 5751 1166 1170 10.1126/science.1120411 16293756
97 Rogge S M J Bavykina A Hajek J Garcia H Olivos-Suarez A I Sepúlveda-Escribano A Vimont A Clet G Bazin P Kapteijn F Chem Soc Rev 2017 46 11 3134 3184 10.1039/c7cs00033b 28338128
98 Zhang J Han X Wu X Liu Y Cui Y ACS Sustainable Chem Eng 2019 7 5065 5071 10.1021/acssuschemeng.8b05887
99 Xu H Chen X Gao J Lin J Addicoat M Irle S Jiang D Chem Commun 2014 50 1292 1294 10.1039/c3cc48813f
100 Xu H Gao J Jiang D Nat Chem 2015 7 905 912 10.1038/nchem.2352 26492011
101 Xu H-S Ding S-Y An W-K Wu H Wang W J Am Chem Soc 2016 138 36 11489 11492 10.1021/jacs.6b07516 27585120
102 Debruyne M Van Speybroeck V Van Der Voort P Stevens C V Green Chem 2021 23 7361 7434 10.1039/d1gc02319e
103 Das S Heasman P Ben T Qiu S Chem Rev 2017 117 1515 1563 10.1021/acs.chemrev.6b00439 28035812
104 Irfan M Seiler M Ind Eng Chem Res 2010 49 1169 1196 10.1021/ie900216r
105 Wang S Liu P Wang W-J Zhang Z Li B-G Catal Sci Technol 2015 5 7 3798 3805 10.1039/c5cy00250h
106 Nabae Y Kakimoto M-a Polymers (Basel, Switz) 2018 10 12 1344 10.3390/polym10121344
107 Kofoed J Darbre T Reymond J-L Org Biomol Chem 2006 4 17 3268 3281 10.1039/b607342e 17036115
108 Wu Y Zhang Y Yu M Zhao G Wang S Org Lett 2006 8 4417 4420 10.1021/ol061418q 16986914
109 Kehat T Portnoy M Chem Commun 2007 2823 2825 10.1039/b703016a
110 Wang D Astruc D Coord Chem Rev 2013 257 2317 2334 10.1016/j.ccr.2013.03.032
111 Kofoed J Reymond J-L Curr Opin Chem Biol 2005 9 6 656 664 10.1016/j.cbpa.2005.10.013 16260174
112 Kirkorian K Ellis A Twyman L J Chem Soc Rev 2012 41 6138 6159 10.1039/c2cs35238a 22850803
113 Chang H Stamoulis A G Huber G W Dumesic J A Green Chem 2023 25 1809 1822 10.1039/d2gc04243f 37810198
114 Kandel K Althaus S M Peeraphatdit C Kobayashi T Trewyn B G Pruski M Slowing I I J Catal 2012 291 63 68 10.1016/j.jcat.2012.04.005
115 Rodríguez‐Escrich C Pericàs M A Eur J Org Chem 2015 6 1173 1188 10.1002/ejoc.201403042
116 Di Carmine G Ragno D Massi A D’Agostino C Org Lett 2020 22 4927 4931 10.1021/acs.orglett.0c01188 32383888
117 Fotaras S Kokotos C G Kokotos G Org Biomol Chem 2012 10 5613 5619 10.1039/c2ob25693b 22717593
118 Chen T Qiu M Peng Y Yi C Xu Z Coord Chem Rev 2023 474 214863 10.1016/j.ccr.2022.214863
119 Yolsal U Horton T A R Wang M Shaver M P Prog Polym Sci 2020 111 101313 10.1016/j.progpolymsci.2020.101313
120 Koros R M Nowak E J Chem Eng Sci 1967 22 470 10.1016/0009-2509(67)80134-9
121 Ötvös S B Mándity I M Fülöp F ChemSusChem 2012 5 266 269 10.1002/cssc.201100332 22298413
122 Zhang F Yang X Jiang L Liang C Zhu R Li H Green Chem 2013 15 1665 1672 10.1039/c3gc40215k
123 Calderón F Fernández R Sánchez F Fernández-Mayoralas A Adv Synth Catal 2005 347 1395 1403 10.1002/adsc.200505058
124 Prasetyanto E A Jeong S-M Park S-E Top Catal 2010 53 3-4 192 199 10.1007/s11244-009-9417-8
125 Shylesh S Zhou Z Meng Q Wagener A Seifert A Ernst S Thiel W R J Mol Catal A: Chem 2010 332 65 69 10.1016/j.molcata.2010.08.022
126 Inokuma T Furukawa M Uno T Suzuki Y Yoshida K Yano Y Matsuzaki K Takemoto Y Chem – Eur J 2011 17 10470 10477 10.1002/chem.201101338 21812044
127 Nagy S Fehér Z Kárpáti L Bagi P Kisszékelyi P Koczka B Huszthy P Pukánszky B Kupai J Chem – Eur J 2020 26 13513 13522 10.1002/chem.202001993 32697895
128 Okino T Hoashi Y Furukawa T Xu X Takemoto Y J Am Chem Soc 2005 127 119 125 10.1021/ja044370p 15631461
129 Hamza A Schubert G Soós T Pápai I J Am Chem Soc 2006 128 13151 13160 10.1021/ja063201x 17017795
130 Kótai B Kardos G Hamza A Farkas V Pápai I Soós T Chem – Eur J 2014 20 5631 5639 10.1002/chem.201304553 24677388
131 Varga E Mika L T Csámpai A Holczbauer T Kardos G Soós T RSC Adv 2015 5 95079 95086 10.1039/c5ra19593d
132 Grayson M N J Org Chem 2017 82 8 4396 4401 10.1021/acs.joc.7b00521 28319377
