Combining RAFT precipitation polymerization and surface-initiated RAFT polymerization: an efficient approach to prepare hairy particles—supported proline

Abstract

In this paper, a simple and efficient approach for obtaining hairy particles supported proline system is described. The catalysts were synthesized by the modification of polymer microspheres via surface-initiated RAFT polymerization. Microspheres containing either carboxyl or ester groups were synthesized by RAFT precipitation copolymerization, and the functional groups influenced the yield and asymmetric selectivity of chiral product in different DMF–H₂O solvents during a representative aldol reaction. Compared with hairy particles 2 with ester groups, hairy particles 1 with carboxyl groups exhibited better catalytic activity and asymmetric selectivity, providing more suitable microenvironments for the aldol reaction. Importantly, the hairy particles 1, as catalyst, can be easily recovered and recycled, and show no significant loss of activity and selectivity after 6 cycles. The application of RAFT precipitation polymerization together with the facile surface-grafting approach provides a general and promising way for chiral catalyst load.

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1. Introduction

The asymmetric aldol reaction, one of the most important carbon–carbon bond forming reactions in synthetic organic chemistry, has been intensively studied. Since list reported the direct aldol reaction catalyzed by L-proline under mild reaction conditions,¹ L-proline and its derivatives have been widely used in asymmetric organic reactions.^2–4 Important efforts have been made to improve the catalytic performance and the recovery of proline.⁵ Numerous strategies have been used to immobilize proline such as polystyrene (beads),^6–9 merrifield resin,¹⁰ ionic liquids,^11,12 dendrimers,¹³ and inorganic particles or crosslinked insoluble polymers.^14,15 In general, soluble polymer-supported catalysts have the advantages of homogeneous catalysts (high catalytic activity and high stereoselectivity) but the recovery of the catalyst requires precipitation, which may not be quantitative and simple. Ionic liquid as support for proline is effective for the reaction but ionic liquids are still expensive and the recovery of products by extraction is tedious. Inorganic particles, or crosslinked insoluble polymers supported catalysts can be easily separated (e.g., by centrifugation or filtering), but the catalytic activities are lower than those of the non-supported and linear soluble polymer-supported catalysts.¹⁵ The preparation of efficient and recoverable supports of the organocatalyst for direct asymmetric aldol reaction still remains challenging.^16–20

Hairy particles are a kind of core shell particles whose shell is composed of linear polymer chains having high affinity for the dispersion medium. Hairy particles have attracted increasing attention in the past decade because of a number of potential applications in bioscience, engineering, electronic and optical devices.^21–24 However, only a few examples of catalysts immobilized on hairy particles have been reported. Christopher et al. synthesized a class of Fe₃O₄ nanoparticles-supported Co(III)-salen by ATRP, and their results proved that their catalyst can efficiently catalyze the ring-opening of epoxides and can be recovered and reused.²⁵ In addition, they prepared polymer-oxide hybrid materials based on nonporous silica-supported sulfonic acid, and those polymer brushes supported sulfonic acid catalysts were used for the hydrolysis of ethyl lactate.²⁶ Zhao et al. reported the synthesis of a hairy particle-supported DAAP catalyst; the hairy particles were found to efficiently catalyze the acylation of secondary alcohols and Baylis–Hillman reaction, and were recyclable.²⁷ The above mentioned results prove that unlike covalently immobilized small molecules, which are completely fixed on the substrate, polymer brushes on the surface of hairy particles are a dynamic system possessing a certain degree of mobility. Therefore, whether organic catalysts are incorporated into the grafted polymer chains, hairy particles supported organocatalysts can combine the advantages of both homogeneous and heterogeneous catalysts, and provide a new and practical way for supporting catalysts. To the best of our knowledge, the synthesis of organocatalysts supported on hairy particles for asymmetric reaction has not been reported.

In this work, hairy particles supported proline were designed and synthesized by the grafting of chiral polymer brushes onto the preformed polymer microspheres via surface-initiated RAFT polymerization (Scheme 1). In comparison with the previously reported preparation methods (i.e., inorganic particles supported catalyst system), our approach is more simple and efficient. On one hand, polymer microspheres with surface-immobilized dithioester groups were synthesized by the addition of the RAFT agent during the process of conventional precipitation polymerization, which requires only one step.^28,29 On the other hand, functional microspheres with various functional groups (such as hydroxyl, carboxylic and epoxy groups) can be prepared by the RAFT precipitation co-polymerization of functional monomers (such as methyl methacrylate, hydroxylethyl methacrylate, 4-vinylpyridine) with a crosslinker.³⁰ The functional groups can adjust hydrophilic–hydrophobic balance of polymer microspheres to offer suitable microenvironments for catalytic asymmetric reactions. In view of the versatility of RAFT polymerization, a large number of chiral polymer brushes with predetermined molecular weights, compositions and monomer sequences can be easily prepared. The presence of chiral polymer brushes on the obtained hairy particles was confirmed by Fourier transform infrared spectrum (FTIR), scanning electron microscope (SEM), field emission scanning electron microscopy (FESEM) and elemental analysis. Quantitative information including the molecular weight and polydispersity of the grafted polymer brushes and catalyst loading were characterized in detail. Furthermore, the obtained catalysts were used in representative aldol reaction between cyclohexanone and 4-nitrobenzaldehyde. The catalytic activity, asymmetric selectivity and recyclability were further investigated.

Scheme 1 Synthesis of hairy particles supported proline by the modification of polymer microspheres via surface-initiated RAFT polymerization.

2. Experimental

2.1 Materials

Methyl methacrylate (MMA, sinopharm chemical, China, AR), Methacrylic acid (MAA, Aladin, 98%), ethylene glycol dimethacrylate (EGDMA, Alfa Aesar, 98%), and N,N-dimethylformamide (DMF, Jiangtian Chemicals, China) were purified by distillation under vacuum. L-Hydroxyproline was purchased from Biodee. Azobisisobutyronitrile (AIBN, Chemical Plant of Nankai University, AR) was recrystallized from ethanol. Cumyl dithiobenzoate (CDB)³¹ and O-methyl acroloyl-L-hyp hydrochloride³² were prepared following the literature procedure, and all the other chemicals were used as received.

2.2 Measurements

¹H NMR spectra were recorded on a Bruker AV-400 NMR spectrometer. FT-IR spectra were recorded on a Nicolet NEXUS Fourier transform infrared spectrometer using KBr pellets. Elemental analysis was performed on a Thermo FLASH 1112 elementar. MS analysis was performed on Bruker mirOTOF II Focus mass spectrometer. The morphologies and sizes of the samples were characterized using scanning electron microscopy (SEM, JSM-6390LV) and field-emitting scanning electron microscope (FESEM, JEOL-JSM-6700F). Molecular weights of the polymers were measured with GPC using PS as a standard, DMF as a mobile phase and RI detector was used. Two shodex LF-404 columns were conditioned at 35 °C and at a flow rate of 0.3 mL min⁻¹. HPLC analysis was carried out on Agilent TM 1100 HPLC equipment using DAICEL Chiralpack AD-H chromatographic column, with mobile phase hexane/i-propanol = 90/10 and a flow rate of 1.0 mL min⁻¹.

2.3 Preparation of the hairy particles supported catalyst

2.3.1 Preparation of poly(MAA-co-EGDMA) microspheres by RAFT. MAA (0.12 g, 1.50 mmol), CDB (18.2 mg, 0.66 mmol), EGDMA (1.41 mL, 7.50 mmol), and a mixture of methanol and water (4/1, v/v, 120 mL) were added successively into a one-neck round bottom flask (250 mL). After stirring for 30 min at room temperature, AIBN (54.1 mg, 0.33 mmol) were added. The reaction mixture was purged with nitrogen for 30 min and sealed. The flask was then attached to the rotor-arm of an evaporator, submerged in a 60 °C oil bath and rotated slowly (ca. 20 rpm) for 24 h. The resulting polymer particles were collected by filtration and purified with methanol. After drying at 40 °C under vacuum for 48 h, a light pink solid was obtained with a yield of 69%. Elem. anal.: C, 58.74; H, 7.03; S, 2.48% (the CTA loading was 0.39 mmol g⁻¹).

2.3.2 Preparation of poly(MMA-co-EGDMA) microspheres by RAFT. Poly(MMA-co-EGDMA) microspheres (light pink solid) was prepared and purified under identical conditions except the change of comonomer from MAA to MMA (yield:73%). Elem. anal.: C, 58.71; H, 7.16; S, 3.08% (the CTA loading was 0.48 mmol g⁻¹).

2.3.3 Synthesis of chiral monomer (Boc-protected O-acrylic hydroxyproline). O-Methyl acroloyl-L-hyp hydrochloride (2.01 g, 8.50 mmol) and 50 mL CH₂Cl₂ were added in a round flask, and then 2.2 mL triethylamine was added to adjust the pH of the solution to about 9. Then, di-tert-butyl pyrocarbonate (4.61 g, 21.10 mmol) was added in batch and stirred for 2 h under reflux. After the reaction, an appropriate amount of KHSO₄ aqueous solution was added to adjust the pH of the solution to 2–3, and extracted with dichloromethane. The organic phase was washed with 50 mL × 3 saturated NaCl solution, dried with MgSO₄, filtered and concentrated to give the crude product of yellow oil. The oil was further purified by silica flash column chloromatography using an eluent of 4 : 1 petroleum ether–EtOAc, and a yellow oil product was obtained with 78% isolated yield. ¹H NMR (CDCl₃/TMS): δ 1.44–1.48 (d, 9H, –(CH₃)₃), 1.94 (s, 3H, –CH₃), 2.24–2.54 (m, 2H, –CH₂), 3.58–3.80 (m, 2H, –CH₂CHCOOH), 4.35–4.52 (t, 1H, –CHCOOH), 5.35 (m, 1H, –COOCH), 5.62 (s, 1H, CH₂ = C), 6.11 (s, 1H, CH₂ = C), MS (m/z): [M + H]⁺ calculated for C₁₄H₂₂NO₆: 300.32, found: 300.24.

2.3.4 Grafting chiral polymer brushes onto polymer microspheres. The microspheres with grafted polymer brushes were prepared via surface-initiated RAFT polymerization according to the following procedure: poly(MMA-co-EGDMA) or poly(MAA-co-EGDMA) microspheres (CTA loading 0.26 mmol), Boc-protected O-acrylic hydroxyproline (3.27 g, 10.89 mmol), CDB (30.4 mg, 0.11 mmol), AIBN (3.3 mg, 0.02 mmol), and DMF (5 mL) were successively added to a two-neck round-bottom flask (25 mL). After being degassed with five freeze–pump–thaw cycles, the flask was sealed and immersed in a thermostat oil bath at 75 °C and stirred for 24 h. After centrifugation, the resulting solid products were thoroughly washed with DMF and methanol, and then dried at 30 °C under vacuum to give a pale powder. The supernatant solutions were precipitated in ether, filtered and dried at 30 °C under vacuum for 48 h, which gives the free N-Boc protected polymer.

2.3.5 Deprotection of polymer brushes. The abovementioned hairy particles (1.00 g) were dispersed in dry CH₂Cl₂ (5 mL), and the solution of TFA (5 mL) and CH₂Cl₂ (5 mL) was added dropwise for 0.5 h over an ice bath. Then, the mixture was stirred for 0.5 h at ambient temperature. After centrifugation, the solid products were thoroughly washed with water and methanol, and then dried at 40 °C under vacuum to obtain final particles (1) with carboxyl groups and (2) ester groups.

The free polymer was also deprotected according to the abovementioned method. After the reaction, the free polymer solution was concentrated and purified by precipitation in diethyl ether, filtered and dried at 30 °C under vacuum for 48 h, providing the homogeneous polymer supported proline.

Elem. anal. of the hairy particles (1): C, 59.71; H, 7.17; N, 0.51; S, 1.79% (the proline loading was 0.36 mmol g⁻¹).

Elem. anal. of the hairy particles (2): C, 59.69; H, 7.16; N, 0.47; S, 1.77% (the proline loading was 0.34 mmol g⁻¹).

2.4 General procedure for the asymmetric aldol reaction

4-Nitrobenzaldehyde (38 mg, 0.25 mmol) and cyclohexanone (104 μL, 1.0 mmol) were dissolved in solvent (1 mL), then the catalyst was added and the mixture was stirred at 0 °C for 48 h. The reaction mixture was isolated by centrifugation, and the hairy particles were washed with dichloromethane, and dried in vacuum to be reused. The aqueous layer was extracted into ethyl acetate, and the organic layers were combined and dried over MgSO₄. The solvent was removed under vacuum, and the crude residue was purified by flash column chromatography on silica gel (petroleum ether–EtOAc = 4 : 1, v/v) and yielded the pure aldol product. The diastereomeric ratio (dr) was determined by ¹H NMR spectroscopy, and the enantiomeric excess (ee) was determined by chiral HPLC.

3. Results and discussion

3.1 Preparation of the hairy particles supported catalyst

3.1.1 Preparation of poly(MAA-co-EGDMA) microspheres by RAFT. Polymer microspheres with surface-immobilized dithioester groups were prepared via RAFT precipitation polymerization (RAFTPP) following the ref. 28. The incorporation of functional monomers (e.g. MAA) into the polymerization system can lead to copolymer microspheres with extra surface-immobilized functional groups;³³ functional groups can improve the stability of hairy particles in polar solvent. The polymerization was performed with CDB as the chain transfer agent and AIBN as the initiator at 60 °C for 24 h with the reactant composition of MAA/EGDMA/AIBN/CDB being 4/20/0.88/1.76 (molar ratio). After being thoroughly purified by solvent washing, light pink polymer microspheres were obtained and showed high hydrophilicity. The obtained particles were characterized with SEM (Fig. 1a), and the result verified the formation of microspheres with number-average diameters (D_n) of 2.46 μm. The FT-IR spectra of the polymer microspheres revealed the presence of a characteristic peak corresponding to C=S stretching vibration (around 1048 cm⁻¹) (Fig. 2c), confirming the existence of dithioester group. The strong band at 3565 cm⁻¹ was assigned to the OH of carboxyl group. The elemental analysis of the microspheres was carried out to determine their chemical composition and crosslinking density. If we assume that the obtained particles contain x moles of the bonded MAA unit (molecular formula: C₄H₆O₂) and y moles of the bonded EGDMA unit (molecular formula: C₁₀H₁₄O₄), the following equations can be obtained for the weight fractions of carbon (C_C) and hydrogen (C_H):

C_C = (4x + 10y)M_C/(xM_MAA + yM_EGDMA)

C_H = (6x + 14y)M_H/(xM_MAA + yM_EGDMA)

where M_C is the atomic weight of carbon, M_H is the atomic weight of hydrogen, M_MAA is the molecular weight of MAA, and M_EGDMA is the molecular weight of EGDMA. The molar fractions of the bonded EGDMA unit in the particles (i.e., y/(x + y), which can also be utilized to express the crosslinking density of the particles) can thus be obtained by introducing C_C and C_H values (determined by the elemental analysis). According to the elemental analysis, the crosslinking density of about 80% was obtained for the microspheres.

Fig. 1 SEM images of no grafted poly(MAA-co-EGDMA) microspheres (a), hairy particles (1) (b), no grafted poly(MMA-co-EGDMA) microspheres (c) and hairy particles (2) (d).

Fig. 2 Fourier transform infrared (FT-IR) spectra of no grafted poly(MAA-co-EGDMA) microspheres (a), and the corresponding grafted ones before deprotection (b), no grafted poly(MMA-co-EGDMA) microspheres (c), and the corresponding grafted ones before deprotection (d).

3.1.2 Preparation of poly(MMA-co-EGDMA) microspheres by RAFT. To investigate the effect of functional group in asymmetric reactions, we prepared poly(MMA-co-EGDMA) microspheres as reference. The synthesized method was identical to that of poly(MAA-co-EGDMA) microspheres. From SEM images (Fig. 1c), it is apparent that spherical microspheres were formed. The average diameter was 2.07 μm, which was smaller than poly(MAA-co-EGDMA) microspheres. The polymer microspheres showed hydrophobicity. From FTIR (Fig. 2a), the characteristic peak corresponding to C=S stretching vibration (around 1048 cm⁻¹) was also observed. According to the elemental analysis, a crosslinking density of about 75% was obtained for the microspheres.

3.1.3 Preparation of microspheres with surface-grafted chiral polymer brushes. Surface-initiated RAFT polymerization was then performed by the polymer microsphere using surface-immobilized dithioester groups as the immobilized RAFT agent, AIBN as the initiator, and DMF as the solvent. A certain amount of CDB was also added to the reaction system as the sacrificial chain transfer agent to increase the control over polymerization.²⁸ Polymerization was performed at 75 °C with stirring for 24 h, and the resulting microspheres were thoroughly washed with DMF to remove the physically adsorbed chiral polymer. Weight increases of 12.5 wt% and 13.8 wt% were observed for microspheres. It is important to stress here that the increased weight of the modified particles mainly resulted from the surface-grafted polymer brushes because the rather high crosslinking density (around 80%) of the particles would prevent them from swelling in the reaction media and only allow the occurrence of surface polymerization, as reported by Tirelli and coworkers.³⁴ FT-IR was also employed to characterize the grafted polymer microspheres (Fig. 2b and d). In addition to the peaks corresponding to the ungrafted one, some characteristic peaks, such as the amide I band (1490 cm⁻¹, C=O stretching), amide II band (1394 cm⁻¹, C–N stretching), were also observed, further confirming the successful grafting of chiral polymer brushes. The average surface grafting density can be calculated according to the following method: by assuming the homogeneous grafting of polymer brushes on the microspheres and an average density ρ = 1 g cm⁻³ for the particle cores, the average surface grafting densities of polymer brushes (β) can be estimated by the following equation:
where ΔW refers to the increased weight percentage for the modified microspheres due to surface-grafted polymer brushes (ΔW = 12.5% and 13.8% for the grafted microspheres, respectively), the number-average molecular weight of the grafted chiral polymer brushes (M_n = 58 300 and 55 300, respectively), N_A the Avogadro constant, S the average surface area of the particle core [S = 4π(D_n/2)²] is utilized here and V the average volume of the particle core [V = (4/3) × π(D_n/2)³)]. An average surface grafting density of about 0.59 and 0.70 chains per nm² can be derived for the grafted polymer microspheres.²⁸

The free N-Boc protected polymer was further characterized with ¹H-NMR (Fig. 3b), it can be seen that the vinyl proton signals (at 5.62, 6.11 ppm) of methacryloyl group from the monomer have completely disappeared from the spectrum, further confirming that the unreacted monomer has been completely removed from the purified polymer. In addition, the chemical shifts and peak integrations of all the protons in the polymer are consistent with its expected structure.

Fig. 3 ¹H-NMR spectra of monomer Boc-protected O-acrylic hydroxyproline in CDCl₃ (a), the free polymer before deprotection in DMSO-d₆ (b), and the free polymer after deprotection in DMSO-d₆ (c).

It is generally accepted that the component, molecular weight and polydispersity of the free polymer generated in the surface-initiated RAFT polymerization system (due to the addition of sacrificial chain transfer agent) are essentially identical to those of the grafted polymer brushes, such that free polymer properties can be utilized to represent those of the grafted polymer brushes.³⁵ Therefore, the obtained free polymers were characterized with GPC, from which the number-average molecular weights (M_n) of the grafted polymer brushes on the particles were evaluated to be 58 300 and 55 300 and their PDI were 1.35 and 1.10. The low polydispersity of the polymer brushes suggested that the surface-initiated RAFT polymerization occurred in a well controlled manner.

3.1.4 Preparation of the hairy particles (1) and (2). The Boc protecting groups for the amine can be readily deprotected under acidic conditions.²⁶ Thus, the chiral polymer on the polymer microspheres was deprotected in dry CH₂Cl₂ in the presence of trifluoroacetic acid (TFA) to afford the final hairy particles. Successful deprotection was confirmed by comparing the ¹H NMR signals of the free polymer given in Fig. 3b and c. The tBu signals (at 1.11–1.55 ppm) disappeared following deprotection, confirming that the deprotection of hairy particles was successful. The morphology and particle size of the hairy particles supported proline were characterized with SEM (Fig. 1b and d), and the result clearly showed that the particles were still separate microspheres. The number-average diameters (D_n) of the hairy particles were determined to be 2.74 and 2.81 μm, and increases of 80 and 74 nm in D_n values were obtained for the grafted polymer microspheres, from which layer thicknesses of 40 and 37 nm (i.e., ΔD_n/2) could be derived for the grafted polymer brushes (in the dry state). The FESEM image (top right corner of Fig. 1b and d) confirmed the existence of polymer brushes on the surface of cores. The N contents of hairy particles from elemental analysis were 0.51 wt% and 0.47 wt%, corresponding to 0.36 mmol and 0.34 mmol catalyst per g particles, respectively.

3.2 Hairy particles supported organocatalyst for the asymmetric aldol reaction

The catalytic activity of the synthesized hairy particles supported L-proline was tested using a representative aldol reaction between cyclohexanone and 4-nitrobenzaldehyde (Table 1). The reaction was first carried out at 20 mol% catalyst loading with different solvent at 0 °C. Normally, L-proline reactions are performed in polar solvents to improve the solubility of the organocatalyst, and polar aprotic solvents, such as DMF, have been frequently proven to be the optimal media to conduct these reactions.³⁶ Hence, the reaction was first carried out in DMF with the hairy particles (1) as catalyst, unfortunately the yield was very low (43%). Given the structure of the chiral polymer chains and the solubility of proline in water, it was postulated that a means toward optimizing solvent might be achieved by combining aqueous with organic solvent. Gratifyingly, when DMF and water were used as a mixed solvent, better yields, diastereo- and enantioselectivities, were observed, and the optimal solvent system was determined to be a 95/5 DMF–H₂O mixture, providing the desired aldol product with 99% yield, 98/2 dr (anti/syn) and 96% ee. When increasing the percentage of water in solvent (from 10% to 100%), the reaction yield and regioselectivity (anti/syn) decreased significantly but the ee values were still high. The aldol reaction was also carried out at 20 mol% catalyst loading with hairy particles (2) as catalyst. Interestingly, the catalyst was unsuitable for the reaction. The DMF–H₂O 95/5 mixture provided the optimal aldol product with 63% yield, 93/7 dr (anti/syn) and 95% ee. In the DMF–H₂O mixture solvent, the yield and asymmetric selectivity of hairy particles (2) were considerably poorer than hairy particles (1). These results indicated that hairy particles (1) with carboxyl groups were more effective in aldol reaction. On comparing the dispersibilities of hairy particles (1) and (2) in DMF–H₂O 95/5 mixture, hairy particles (1) was more dispersible than particles (2), the better dispersibility may also be the key factor affecting the catalytic activity. The carboxyl groups can adjust hydrophilic–hydrophobic balance of polymer microspheres in polar solvent, to offer more suitable microenvironments for catalytic asymmetric reactions. In pure water solvent, hairy particles (2) display slightly better catalytic activity. We hypothesize that the hydrophilic proline moiety and the hydrophobic surface of the particles provide a hydrophobic cavity, such a microenvironment promotes the aldol reaction with a slightly better reaction yield in water.³⁷

Table 1 Solvent effects on the aldol reaction between cyclohexanone and 4-nitrobenzaldehyde

Entry	Cat.	Solvent	% yield^a	Anti/syn^b	% ee^c (anti)
a Yield determined after chromatographic purification.b Determined by ^1H NMR spectroscopic analysis of the product.c Determined by HPLC using a chiral column.
1	Hairy particles (1)	DMF	43	82/18	89
2	Hairy particles (1)	DMF–water (95/5)	99	92/8	96
3	Hairy particles (1)	DMF–water (90/10)	89	90/10	95
4	Hairy particles (1)	DMF–water (80/20)	60	84/16	97
5	Hairy particles (1)	Water	34	89/10	96
6	Hairy particles (2)	DMF	25	85/15	87
7	Hairy particles (2)	DMF–water (95/5)	63	91/9	94
8	Hairy particles (2)	DMF–water (90/10)	42	90/10	95
9	Hairy particles (2)	DMF–water (80/20)	45	84/16	97
10	Hairy particles (2)	Water	46	85/15	88

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To further investigate the activity and selectivity of the hairy particles 1, we compared the catalytic performance of the hairy particles (1) supported system with the unsupported L-proline and the corresponding free polymer supported proline system. All the reactions were carried out using the same conditions in DMF with 5 vol% water at 0 °C for 48 h, and the results are detailed in Table 2. When lower catalyst loadings (i.e., 5 and 10 mol%) were used, yields and ee values of hairy particles 1 supported system were very close to that of the unsupported L-proline, but unsupported L-proline generated better regioselectivity (anti/syn). On increasing the catalyst loading (i.e., 20 mol%), the regioselectivity of hairy particles (1) significantly increased; the results demonstrate the similarity in both activity and selectivity between the hairy particles (1) (99% yield, 92 : 8 anti–syn, 96% ee) and unsupported L-proline (99% yield, 95 : 5 anti–syn, 95% ee).

Table 2 Comparison of the different catalyst system catalyzing the aldol reaction between cyclohexanone and 4-nitrobenzaldehyde at 0 °C for 48 h

Entry	Cat.	mol%	Yield^a (%)	Anti/syn^b	% ee^c (anti)
a Yield determined after chromatographic purification.b Determined by ^1H NMR spectroscopic analysis of the product.c Determined by HPLC using a chiral column.
1	No catalyst	—		No reaction
2	Poly(MAA-co-EGDMA) microspheres	—		No reaction
3	L-Proline	5	58	90/10	94
4	L-Proline	10	99	90/10	94
5	L-Proline	20	99	95/5	95
6	Hairy particles (1)	5	67	74/26	94
7	Hairy particles (1)	10	90	79/21	97
8	Hairy particles (1)	20	99	92/8	96
9	Homogeneous polymer	5	38	63/37	92
10	Homogeneous polymer	10	43	65/35	92
11	Homogeneous polymer	20	67	70/30	96

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The homogeneous polymer supported proline only generated 63/37 regioselectivity at 38% yield and 92% ee value with 5 mol% catalyst loading. Higher loading (10 mol%) catalyst slightly increased the yield (43%) and regioselectivity (65/35). When 20 mol% loading was used, the free polymer generated 70/30 regioselectivity with 67% yield and increasing ee value (96%). In contrast, the reaction catalyzed by the hairy particles supported system was more efficient than free polymers. These results show the advantage of the hairy particles supported system. To investigate the cause for their excellent catalytic performance, the reaction was carried out with poly(MAA-co-EGDMA) microspheres in DMF with 5 vol% water at 0 °C for 48 h. However, the reaction did not occur, which shows that the carboxyl groups of polymer microsphere have no acid catalysis. The high catalytic activity may be due to the inherent cooperativity built into the polymer brush materials.³⁸ In addition, surface-grafting polymer brushes supported catalysts have proven to be highly efficient for improving the dispersion.²⁷ The hairy particles (1) in DMF–H₂O (95/5) had better dispersion than the ungrafted microspheres (Fig. 4). This good dispersion is very important for catalyst to have effective catalytic activity.

Fig. 4 Images of poly(MAA-co-EGDMA) microspheres (a) and hairy particles (1) (b) in DMF–H₂O (95/5) at 0 °C for 2 h.

The recycling potential of the hairy particles (1) supported catalytic system was investigated using the same aldol reaction between 4-nitrobenzaldehyde and cyclohexanone in the 5 vol% water–DMF solvent mixture. This adjustment was done to maintain the aldol reaction at 20 mol% catalyst loading throughout different cycles. Table 3 shows the recycling efficiency of the supported system. The catalyst was successfully used in 6 cycles without losing significant activity or selectivity.

Table 3 Recycling data for the aldol reaction using the hairy particles (1) supported catalyst at 0 °C for 48 h

Cycle #	% yield	Anti/syn	% ee
1	98	92/8	96
2	99	89/11	96
3	99	90/10	95
4	98	90/10	96
5	99	91/9	95
6	99	88/12	96

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4. Conclusions

This paper proves that RAFT precipitation polymerization combined with surface-initiated RAFT polymerization is an efficient approach to obtain hairy particles supported proline system. The catalysts were used in representative aldol reaction between cyclohexanone and 4-nitrobenzaldehyde. The results proved that the hairy particles (1) with carboxyl groups were more effective than the hairy particles (2) with ester groups in the asymmetry aldol reaction. The results also proved that the reaction catalyzed by the hairy particle (1) supported system was more efficient than the homogeneous polymer supported proline. When catalyst loading increased to 20 mol%, the catalytic activity and selectivity of hairy particles supported system were very close to that of the unsupported L-proline. Importantly, the hairy particles (1) can be easily recovered and recycled without losing significant activity and selectivity after 6 cycles. The new catalyst system can combine the advantages of both homogeneous catalysts and heterogeneous catalysts, and provide a new and practical route for chiral catalyst load.

Acknowledgements

This work was supported by the National Natural Science Foundation of China (no. 21204019), the Post-doctoral Foundation of China (no. 2012M521398), the Post-doctoral Foundation of Henan Province and the International Cooperation Project of Henan Province (no. 134300510055).

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