Non-covalent immobilization of asymmetric organocatalysts

Abstract

The immobilization of organocatalysts is one of the most explored approaches to overcome the limitations associated with organocatalytic systems such as high catalyst loading, difficult product separation and catalyst recycling. When compared with the commonly used covalent immobilization methods, which usually involve tedious synthetic manipulations, the non-covalent attachment of organocatalysts to supports offers facile and modular construction of immobilized chiral catalysts with maintained or even improved activity and stereoselectivity. This review summarizes the successful application of non-covalent interactions, such as acid–base interaction, ion–pair interaction, hydrophobic interaction and so on, in assembling recoverable and reusable organocatalysts.

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Long Zhang

Long Zhang graduated from Nankai University in 2005 with a major of chemistry. He spent five years studying for a Ph.D in a joint project between Nankai University and the Institute of Chemistry, Chinese Academy of Sciences (ICCAS) under the supervision of Prof. Jin-Pei Cheng and Prof. Sanzhong Luo. Afterwards, he joined Prof. Luo's group as a research assistant in July, 2010. His work focuses on de novo design and synthesis of functionalized chiral ionic liquids and their applications as asymmetric organocatalysts.

Sanzhong Luo

Sanzhong Luo graduated from Zhengzhou University in 1999, and then spent his graduate studies at Nankai University, the Chinese Academy of Sciences and the Ohio State University and received his PhD under the supervision of Prof. Jin-Pei Cheng in 2005. He has been at the Institute of Chemistry, Chinese Academy of Sciences (ICCAS) since 2005. He was a visiting scholar at Stanford University in 2009. He won the National Science Fund for Distinguished Young Scholars in 2010. His research is to develop novel, viable and reliable asymmetric catalysts and asymmetric synthesis of natural products.

Jin-Pei Cheng

Jin-Pei Cheng received his PhD from Northwestern University under the supervision of Prof. F. G. Bordwell in 1987. He then spent one year as a postdoctoral fellow at Duke University. Since 1989, he has been a full professor at Nankai University. In 2001, he was elected as a fellow of the Chinese Academy of Sciences. He is an adjunct professor at ICCAS since 2002. His research interests include physical organic chemistry, chemistry of organic hydrides and NO donors, and asymmetric catalysis.

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Introduction

The past decade has witnessed a renaissance of organocatalysis in the field of asymmetric catalysis.¹ Compared with the well-established asymmetric transition metal catalysts and natural enzymes, organocatalysts are readily available, much easier to handle and free of metal contaminations which are problematic in pharmaceutical processes. Consequently, organocatalytic reactions are frequently deemed to be environmentally-benign and sustainable processes. Notwithstanding these attractive features, organocatalysts have been seldom applied in industry,² a fact that can be largely ascribed to their insufficient efficiency and the difficulties in catalyst separation and recycling.³ One viable approach to address these challenges would be the heterogenization of organocatalysts. Indeed, catalyst immobilization has been widely explored with asymmetric transition metal catalysts and enzymes aiming to improve their applicability and practicability. Similarly, the immobilization strategy has also been frequently attempted for organocatalysis even before its renaissance in 2000s.⁴ Typically, the immobilization of organocatalysts has been achieved via covalent attachment onto solid supports such as polystyrene, poly(ethylene glycol) (PEG), dendrimers and inorganic solids.⁵ However, most of these supported organocatalysts demonstrated reduced activity and selectivity comparing with their small molecular parent catalysts, consequently higher catalyst loading (both w/w% and mol%) is required to attain reasonable yields. In addition, multiple synthetic manipulations are necessary to achieve the covalent immobilization and significant structural perturbations to the parent catalyst skeletons are generally not avoidable in such circumstances.

With their multiple catalytic moieties residing in rather small skeletons, small structural modifications of organocatalysts may lead to serious deterioration of their catalytic behaviours. It becomes even more challenging when connecting those privileged organocatalysts onto large solid supports. Therefore, an ideal catalyst immobilization strategy should provide (1) minimal synthetic modification and structural perturbations to the parent catalysts, and (2) a facile catalyst linkage that allows for combinatorial screening of (3) a synergistic support to achieve optimal activity and selectivity. To this end, non-covalent immobilization strategies recently appeared as attractive solutions with their powers being well-demonstrated in asymmetric transition metal catalysis.⁶ There has also been increasing examples of supported organocatalysts via non-covalent strategies starting to show their potentials in this field. This perspective summarizes the major progresses regarding the development of non-covalently supported asymmetric organocatalysts since 2005, with a focus on the immobilization methods, their advantages, applications and limitations. The classification of this review is based on different modes of immobilization, such as acid–base, ion–pair, hydrophobic as well as self-assembled gel-type organocatalysts. The classic biphasic immobilization of organocatalysts is also incorporated in this review owing to their non-covalent features.

1 Acid–base immobilization

Acid–base assembly of chiral amines has been proven to be one of the most efficient bifunctional amine catalysts.⁷ The acids used in these examples were essential units that dramatically impacted the catalytic activity and stereoselectivity. Taking advantage of the acid–base principle, Luo and Cheng developed a non-covalent immobilization strategy for chiral amines by utilizing solid acids.⁸ Similar solid acid–base strategy has previously been successfully applied in attaching transition-metal catalysts onto solid supports with good activity and reusability.⁹ The acid–base immobilization of chiral amine organocatalysts is distinct from these previous reports as a result of the dual functions of the solid-acids: first, they act as an anchor for the chiral diamines and second they act as a critical modulator for the catalytic activity and stereoselectivity.

In Luo's study, the main solid acids they used were polyoxometalates (POMs) and polystyrene sulfonic acids. POMs belong to a large family of metal-oxide clusters, best-known for their strong acidity and redox properties. The POM-supported organocatalyst could be realized by simply mixing the two components in certain ratio and a plethora of readily available chiral diamines could be immobilized on POMs without any additional modifications (Scheme 1). The non-covalent feature of acid–base interactions allows for screening different POMs, chiral amines and their combinations for optimal catalysts. Several thus identified optimal catalysts are listed in Scheme 1. These hybrid solids have biphasic properties and are soluble in polar organic solvents such as acetone, DMP, DMF and DMSO, but insoluble in less polar solvents like hexane, toluene and diethyl ether. Another interesting feature is that they are well dispersed in water. Optical microscopy shows uniform micelle-like aggregates with 0.4 μm mean diameter (Scheme 1, bottom), rendering these hybrid solids potential asymmetric surfactant-type catalysts in aqueous media.

Scheme 1 POM immobilized chiral amines and their suspension in water. (Left: optical microscopy of 1a; right: SEM picture of 3.)

The POM supported secondary–tertiary diamine catalyst 1a was found to catalyze the direct aldol reaction of ketones effectively^7a,b (Scheme 2, eqn (1)). The catalyst loading could be reduced to less than 0.33 mol% (1 mol% chiral amine loading), such a low loading is extremely rare in enamine-based organocatalysts, particularly for reusable ones. The reaction could be conducted in both neat and wet conditions. Under neat condition, the catalyst could be recycled by precipitation with the addition of diethyl ether. When aqueous condition was used, the aqueous phase containing the catalyst after product extraction could be used directly in the next run. In both cases, the catalysts could be reused for six runs with similar enantioselectivity but slightly reduced activity. POM hybrid catalyst 1b with H₄SiW₁₂O₄₀ as the solid support could also catalyze the asymmetric Michael addition of ketones to nitrostyrenes under aqueous condtions^7b (Scheme 2, eqn (2)).

Scheme 2 POM supported organocatalyst catalyzed reactions.

The POM supported primary–tertiary diamine catalyst 2 showed very good catalytic activities in the direct aldol reactions of α-hydroxyketones with 20 mol% loading^7c (Scheme 2, eqn (3)). Up to 97% yield, 99% ee and 30 : 1 syn diastereoselectivity could be obtained. The catalyst could be reused up to four times with slightly decreased activity and selectivity in the third and fourth run.

Unlike catalyst 1 and 2, a multidentate chiral amine was employed in catalyst 3.^7d It was found that self-assembled catalyst 3 could efficiently catalyze the Diels–Alder reactions of α-substituted acroleins under aqueous condition (Scheme 2, eqn (4)). The Diels–Alder products were obtained with up to 96% yield, 95 : 5 exo/endo ratio and 83% ee. In addition, the catalyst could be easily recycled and reused six times with slightly reduced activity and selectivity.

In 2008, Luo and Cheng reported the PS-sulfonic acid supported diamine catalysts via acid–base strategy^7e (Scheme 3). A series of PS-sulfonic acid with different acid loading was synthesized and used in the immobilization. Surprisingly, the one with medium loading gave the best catalytic results in the direct aldol reaction. In their study, the PS-sulfonic acid supported primary–tertiary diamine catalyst 4a and 4b showed great capability in direct aldol reactions, while the PS-sulfonic acid supported secondary–tertiary diamine catalyst 5 was preferred in Michael addition reactions of nitrostyrenes. The catalyst can be recovered via filtration and reused up to 6 rounds. Notably, the deactivated catalyst can be reactivated via an acid-washing/amine-recharge protocol.

Scheme 3 Polystyrene supported organocatalysts via acid–base interaction.

Recently, Li and co-workers reported a SO₃H-hollow nanosphere immobilized primary–tertiary diamine catalyst and evaluated its catalytic capability in direct aldol reactions¹⁰ (Scheme 4, left). Although good yields and selectivities could be obtained, the recyclability was rather poor for obvious loss of activity was observed in the third and fourth runs. Itsuno and co-workers also reported a series of sulfonic acid functionalized polymer immobilized MacMillan catalysts for the Diels–Alder reactions of cinnamaldeyhde¹¹ (Scheme 4, right). However, both the catalytic activity and selectivity was inferior to the non-immobilized catalyst.

Scheme 4 Other solid sulfonic acids supported organocatalysts.

2 Ion–pair immobilization

Ion–pair strategy probably represents one of the most early explored non-covalent immobilization methods due to the ubiquitous nature of ion pairs in many catalytic processes.¹² In a broad sense, acid–base immobilization would belong to the ion–pair category as described here. Therefore, we will limit this section to those immobilized catalysts prepared via typical ion–exchange processes. In this regard, the section is further classified according to the different ionic support such as ionic polymer, clays and ionic liquids.

2.1 Ion–pair immobilization on polymers. Chiral quaternary ammonium salts have been widely studied as phase transfer catalysts (PTC). Their intrinsic ionic structures make the ion–pair interaction an easily conceivable immobilization strategy. However, the early immobilization studies for this series of catalysts invariably utilized covalent strategies.¹³ In 2008, Itsuno and co-workers reported a novel type of supported chiral quaternary ammonium PTCs comprising an ionic bond between the ammonium moieties and the polymer-achored sulfonate anions based on their early studies.^14,15 Two methods were introduced in their immobilization (Scheme 5): one is the direct polymerization of the chiral quaternary ammonium sulfonate monomer (Scheme 5, method A), and the other is the post ion–exchange of chiral quaternary ammonium salts with sulfonate salts functionalized polymers (Scheme 5, method B). The supported catalysts obtained from the two methods 10Ab and 10Bb exhibited similar performance in the asymmetric PTC alkylation reactions (Scheme 5). Most interestingly, the supported catalyst 10b showed significantly improved enantioselectivity compared with the unsupported catalysts 8 and 9, albeit with a little sacrifice of the activity. Nevertheless, comparable yields could only be obtained by extending the reaction time. In spite of the known ion–pair dissociation–association steps in PTC catalysis, the ion–pair supported catalysts such as 10Bb are quite stable and can be quantitatively recovered. The recovered polymerized catalyst was successfully used for two additional runs without any loss of activity and enantioselectivity.

Scheme 5 Methods for non-covalent immobilization of quaternary ammonium salts.

Besides the side–chain immobilized organocatalysts mentioned above, Itsuno and co-workers also developed a main–chain functionalized polymer via ion–pair interactions ¹⁶ (Scheme 6), i.e., self-assembly of a bis-quaternary ammonium salts 11 and disulfonate salts 12 to form a polymeric ions, reminiscent of self-supported catalysts developed by Ding et al.¹⁷ Mixing aqueous solution of 12 with powdered 11 led to the formation of polymeric ionic 13, for which NMR spectra and inherent viscosity ([η] 0.1–0.2) serve as direct proofs of a polymeric structure. The catalytic ability of this polymer was also tested in the benzylation of N-diphenylmethylene gylcine tert-butyl ester, showing again increased enantioselectivity but loss of activity. Catalyst 13 can be easily recycled and reused with no loss of activity and enantioselectivity in the second and third runs. It remains unclear how the polymeric ion–pair participates in the phase transfer process.

Scheme 6 Main–chain functionalized polymers.

2.2 Ion–pair immobilization on clays. The montmorillonite (mont), which comprises negatively charged layers and interlayer with alternating Na⁺ species, has been explored as macroanionic catalyst support, particularly for those large cationic species due to its solvent-tunable interlayer. In 2008, Kaneda and co-workers prepared the montmorillonite immobilized Macmillan catalyst via cation–exchange strategy¹⁸ (Scheme 7). The immobilized catalyst 14 showed comparable activity and selectivity with the homogeneous one, and meanwhile could be recycled and reused for four times without any loss of activity and selectivity. Following the same strategy, Nakamura and co-workers entrapped N-(2-thiophenesulfonyl)prolinamide into the montmorillonites, providing good recyclability in direct aldol reactions¹⁹ (Scheme 7, 15). Meanwhile, Pucheault, Vaultier and co-workers reported Mont-supported proline catalyst in the direct aldol reactions²⁰ (Scheme 7, 16). Interestingly, the co-immobilization of a trimethylbutyl ammonium salt was shown to significantly increase both the reaction activity and enantioselectivity. The function was proposed to enlarge the basal spacing between the mont layers, which is beneficial for the proline catalysis.

Scheme 7 Montmorillonite immobilized organocatalysts.

Chiral anionic organocatalysts have also been shown to promote the transformations such as Michael addition reaction and cyanosilylation reaction.²¹ One conceivable way to immobilize this type of catalysts would be ion–exchange with cationic supports. Layered double hydroxide (LDH) appears as such a type of inorganic solid support. LDH consists of stacks of positively charged metal hydroxide layers and interlayer anions. Both inorganic and organic anions could be entrapped into the interlayer. In 2002, Choudary and co-workers reported the synthesis of LDH entrapped proline via anion–exchange method²² (Scheme 8, left). LDH-supported proline 17 was found to promote several transformations including aldol reaction and Michael addition reaction with good activity but low enantioselectivity. Nakayama reported a calcination–reconstruction method for the immobilization of amino acids including L-proline onto LDH,²³ but no catalytic performance was presented. Using this method, He and co-workers synthesized the LDH supported proline 18²⁴ (Scheme 8, right) and examined its catalytic ability in asymmetric direct aldol reactions. Surprisingly, the direct aldol reaction of acetone and benzaldehyde proceeded extremely well in the presence of catalyst 18 with up to 94% enantioselectivity, standing in sharp contrast with that of catalyst 17. The reason for the different performances of 17 and 18 is not very clear, but may be ascribed to the intrinsic structure discrepancy caused by different preparation methods. Later, Pitchumani and co-workers prepared a similar catalyst like He's and examined its catalytic ability in the asymmetric Michael addition, showing low to moderate enantioselectivity.²⁵

Scheme 8 LDH immobilized proline catalyzed aldol reactions.

2.3 Ion–pair immobilization on ionic liquids. Owing to their tunable structures and green credentials, ionic liquids have been well explored as supports for asymmetric catalysts. One of the most widely explored immobilization strategies is by covalent attachment of an organocatalytic moiety to the ionic liquid cation and the resulted functionalized chiral ionic liquids have been successfully applied as a new type of reusable asymmetric organocatalysts.²⁶ Taking advantage of its ion–pair characteristics, anionic organocatalysts can also be combined with an organic cation, leading to non-covalently supported catalysts. In 2007, Han and co-workers reported ionic liquid 19²⁷ with a proline anion (Scheme 9). Ionic liquid 19 could effectively catalyze the direct aldol reactions, but unfortunately with poor enantioselectivity. Later, Wang and co-workers synthesized anionic type ionic liquid 20 following Ohno's procedure²⁸ and systematically investigated its catalytic activity²⁹ (Scheme 9). A series of asymmetric transformations such as Michael addition, aldol reaction, aza-Diels–Alder reaction as well as Mannich reaction could be realized under the catalysis of 20 with good enantioselectivities. In addition, catalyst 20 could be recycled and reused at least for four times with similar activity and enantioselectivity.

Scheme 9 Proline anion type IL catalyzed asymmetric reactions.

The supported ionic liquids (SIL) could also be used as an cationic supports for organocatalysts. In 2007, You and co-workers reported the synthesis of a polymer supported ionic liquid 21 bearing proline anions and studied their applications in metal scavenging and heterogeneous metal catalysis³⁰ (Scheme 10, left). However, their potential application in organocatalytic process was initially ignored. Recently, Salunkhe and co-workers reported a similar supported ionic liquid 22 containing proline anion³¹ (Scheme 10, right). SIL 22 was shown to promote the Mannich type reaction of 2-naphthol with good activity but no enantioselectivity. The supported ionic liquid catalyst could be easily recycled and reused without any significant loss in chemical yield of the products.

Scheme 10 SIL supported L-proline via ion–pair interactions.

3 Immobilization via hydrophobic interaction

The marriage of supramolecular principles and systems with organocatalytic motifs has recently been shown to viable and powerful strategy to evolve new type of asymmetric supramolecular catalysts on one hand^32,33 and to enable facile catalyst recycling and reuse on the other hand. For the latter purpose, Zhang and co-workers utilized the well known cyclodextrin host and its inner hydrophobic cavity to immobilize organocatalysts via hydrophobic effect³⁴ (Scheme 11, 23). In their study, the apolar phenyl ring of 4-phenoxyproline served as the inclusion handle toward the β-cyclodextrin cavity. In the presence of 10 mol% of the immobilized catalysts, the direct aldol reaction of acetone and o-nitrobenzaldehyde was completed in 16 h with 90% yield and 83% ee. The enantioselectivity is slightly improved compared with that of the parent unsupported catalyst, suggesting the host–guest assembly is synergistic for catalysis. The assembled catalyst 23 could be recovered by filtration and employed for three subsequent runs with unchanged enantioselectivity and a slightly decreased yields, a result comparable with PEG-supported proline.³⁵ Using the same principle, Armstrong and co-workers later reported a similar catalytic system 24³⁶ (Scheme 11, 24), wherein a sulfated β-CD was employed as the host and tert-butylphenyl serves as the inclusion handle. Meanwhile, Woggon and co-workers utilized the adamantyl group as the including handle and also realized the immobilization of proline via β-CD binding³⁷ (Scheme 11, 25). The catalytic activity and selectivity are similar with catalyst 24.

Scheme 11 Cyclodextrins immobilized proline catalysts.

4 Self-supported gel-type organocatalysts

Supramolecular gels are nanoscalic aggregates of small organic molecules formed via intermolecular non-covalent interactions such as solvophobic, ionic, H-bonding, van der Waals, π–π interactions.³⁸ The functional applications of gels have been a recent research focus. In this regard, the use of a supramolecular gel as asymmetric organocatalyst can be traced back to 1990, when Inoue and co-workers reported asymmetric cyanide addition catalyzed by a cyclodipeptide in the gel state.³⁹ However, subsequent studies suggested that gel-nature of the catalyst was a “significant obstacle” to elucidate the catalytic processes. The aggregation of small molecular catalyst was later considered as a problem to be avoided in many examples.⁴⁰. It is not until very recently that the work by Escuder and Miravet shed new light on supramolecular gel-type asymmetric organocatalysts.⁴¹ In fact, the heterogeneous nature of the gel was found to be an additional advantageous feature that allows easy recovery and recycling of the catalyst. Importantly, the highly ordered structures of a gel could result in enhanced catalytic efficiency associated with the aligned cooperative catalytic units or with conformational restrictions.

Miravet, Escuder and co-workers successfully developed a series of organic gel systems 26 and 27 (Scheme 12) and examined their catalytic properties in enamine-based transformations. The gels 26a–c were found to effectively promote Henry reactions as a result of the enhanced basicity caused by cooperation of neighbouring proline moieties in the gel. In sharp comparison, the non-aggregated catalysts in solution showed no catalytic activity (Scheme 13).^41d The aggregated status of organocatalyst may also impact the stereocontrol due to the aggregation-driven conformational change around the catalytic moieties. For example, in the asymmetric Michael addition catalyzed by 26, a reversal of enantioselectivity was observed with 27b when going from solution phase to the aggregated gel status (Scheme 14).

Scheme 12 L-proline derived gelators.

Scheme 13 Supramolecular gel catalyzed aldol and Henry reactions.

Scheme 14 Supramolecular gels catalyzed Michael addition reaction.

In another study, the gelator 27b was found to form an almost transparent hydrogel in water.^41g The direct aldol reaction between cyclohexanone and 4-nitrobenzaldehyde was tested in the hydrogel phase (Scheme 15), the reagents dissolved in toluene were easily loaded onto the gel and the reaction was quantitatively completed after 24 h at 5 °C with high stereoselectivity (anti : syn = 92 : 8, 88% ee). Meanwhile, the catalytic hydrogel could be reused after decantation of the toluene phase for at least three times with the same efficiency and stereoselectivity. Interestingly, gel 26a–c in acetonitrile showed good activity but only poor enantioselectivity in the same direct aldol reaction,^41c indicating dramatic solvent effect in gel catalysis. Provided with its tunable, reversible and modular features, the potential of organocatalytic gelators as self-supported catalysts remains to be further explored.

Scheme 15 Hydrogel catalyzed aldol reaction.

5 Biphasic immobilization

The environmentally benign solvents such as ionic liquids, PEGs, etc. have been widely used in organic reactions to replace volatile organic solvents.⁴² They are also widely explored in the biphasic immobilization of organocatalysts due to their polar natures. One of the most investigated organocatalyst is the ionic proline catalyst. As early as 2002, Loh and Toma independently reported the use of an ionic liquid media for proline catalyzed aldol reactions.^43,44 In both cases, they have found that the reactions in imidazolium ionic liquids such as [BMIM]PF₆ gave comparable or even higher enantioselectivities than traditional DMSO solvent.⁴⁵ Ionic liquids such as [BMIM]BF₄⁴⁶ and guanidine-derived ionic liquids⁴⁷ are also suitable solvent for the direct aldol reactions with generally better yield and enantioselectivity in guanidine type ionic liquid (Scheme 16). Other reactions such as cross-aldol reaction between aldehydes⁴⁸ and asymmetric α-aminoxylations^49,50 could also be performed in similar reaction systems (Scheme 17). The proline derivatives such as L-prolinamide (28),⁵¹ bis(prolinamide)cyclohexane (29),⁵² secondary-tertiary diamine (30)⁵³ and chiral zwitterions (31)⁵⁴ could also be immobilized in IL with good catalysts' reusability (Scheme 18). In most of the catalytic system mentioned above, the catalyst could be recycled and reused for at least 3 times. In a typical recycle procedure, the reaction mixture is extracted with organic solvents such as diethyl ether, the highly polarized ionic liquids and organocatalysts, which have low solubility in the extracting solvents, will be separated from the products. After removal of the residual organic solvents, the catalysts are directly used in the next cycle.

Scheme 16 Ionic liquid as phase supports for L-proline catalyzed aldol reactions.

Scheme 17 Ionic liquid as phase supports for L-proline catalyzed cross-aldol reactions and α-aminoxylations.

Scheme 18 Other immobilized organocatalysts in ILs.

In biphasic catalysis in ionic liquids, the leaching of catalyst, contamination of products in ionic liquids, as well as the high cost of ionic liquids, are issues to be further addressed. One of the explored solutions is to use solid surface supported ionic liquid monolayer as the catalyst immobilization phase with or without additional ionic liquid.⁵⁵ In 2004, Gruttadauria and co-workers covalently attached an ionic liquid moiety to the surface of silica gel^56,57 (Scheme 19). This monolayer was then treated with more ionic liquid before being used to immobilize proline for aldol reactions. The ionic layer acted as the reaction media and enabled the easy recovery of catalysts upon filtration. Up to 8 recycles could be reached and the catalyst could be regenerated by recharging with fresh proline. In 2007, this methodology was extended to other linkers and to peptide organocatalysts.^58,59 Recently, a non-covalently supported ionic liquid on SiO₂ bed was used for MacMillan catalysts immobilization⁶⁰ with good reusability for asymmetric Diels–Alder cycloaddition (Scheme 20). Another interesting immobilization system is the (S)-proline/polyelectrolyte system,⁶¹ where the proline catalyst was immobilized on the surface of solid poly(diallyldimethylammonium) salts, however, the catalyst could only be reused for twice.

Scheme 19 Supported ionic liquids for proline immobilization and their application in aldol reactions.

Scheme 20 Supported ionic liquids for imidazolidinone immobilization.

Liquid poly(ethylene glycol)s (PEGs) could also be used as phase immobilization supports. Chandrasekhar and co-workers reported the utilization of low-weight poly(ethylene glycol) (PEG MW = 400 Da) as immobilization phase for the proline catalyzed aldol reactions.^62,63 The catalytic system proved to be as efficient as DMSO system and could be reused for more than ten times with similar enantioselectivity. Luo and Cheng also reported the PEG-200 as reaction media for the zwitterions catalyzed aldol reactions.⁵⁴ Taking advantage of the cation coordination ability of PEGs,⁶⁴ Xu and co-workers developed a host–guest complex of PEG with organocatalysts containing a positive charge unit⁶⁵ (Scheme 21), Asymmetric Michael addition reactions of unmodified ketones to nitroalkenes were tested, showing up to 97% yield and 99% enantioselectivity. A series of spectroscopy studies verified the existence of host–guest complex.⁶⁶

Scheme 21 PEGs as phase immobilization supports.

Flouro phase has also been well explored in biphasic catalysis,⁶⁷ however, further modification of the organocatalysts were usually needed, thus these will not be discussed here.

Summary and outlook

The examples covered in this perspective illustrate the powers of non-covalent strategies for evolving more practical supported organocatalysts. Intriguing features about non-covalent immobilization of organocatalyst include minimal modifications of the parent catalysts, facile catalyst linkage and combinatorial flexibility for the identifications of a optimal supported catalyst. It's even possible for de-novo design and discovery of a new organocatalyst itself by employing the non-covalent strategies.⁷ Although still early in their developments, the non-covalent immobilization is anticipated to provide a viable solution to enhance the applications of organocatalysts with “practical” credentials. Future catalysts development should be more oriented toward real problems in synthetic processes. It would be also interesting to see the explorations of other non-covalent interactions such as charge-transfer,⁶⁸ π–π stacking immobilization⁶⁹ and adsorption and entrapment in nanosized materials⁷⁰ in developing supported organocatalysts.

Acknowledgements

This work was supported by the Natural Science Foundation of China (NSFC 20632060, 20972163 and 21025208), the Ministry of Science and Technology (MoST) of China (2011CB808600) and the Chinese Acedemy of Sciences.

Notes and references

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