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Chiral polymeric nanoparticles for aldol reaction
Reactive and Functional Polymers 96 (2015) 1–4
Contents lists available at ScienceDirect
Reactive and Functional Polymers journal homepage: www.elsevier.com/locate/react
Chiral polymeric nanoparticles for aldol reaction Shira R. Adler, Yitzhak Mastai ⁎ Department of Chemistry and the Institute of Nanotechnology, Bar-Ilan University, Ramat-Gan 52900, Israel
a r t i c l e
i n f o
Article history: Received 21 February 2015 Received in revised form 15 August 2015 Accepted 29 August 2015 Available online 6 September 2015 Keywords: Polymeric nanoparticles Organocatalysts Proline Miniemulsion polymerization Enantioselective synthesis
a b s t r a c t In this paper, we report on the preparation and use of chiral polymeric nanoparticles, based on proline, as nanocatalysts for the asymmetric aldol reaction. The chiral polymeric nanoparticles were synthesized using a novel technique based on miniemulsion polymerization of chiral N-oleoyl-D/L-proline monomers. This method led to the formation of chiral polymeric nanoparticles with average size of 160 nm. Moreover, the polymeric chiral nanoparticles prepared by miniemulsion polymerization are of high surface area, and the entire particle, not just the surface, is chiral. The efficiency of the polymeric chiral nanoparticles for asymmetric aldol reaction in organic solvents and water is demonstrated. Although the chiral selectivity of the polymeric nanoparticles is low compared to free amino acid still they have the advantage of the low catalyst loading that is required and the opportunity to recycle the polymeric nanoparticle catalysts. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Chirality is one of the key factors in molecular recognition, which is extremely important in many chemical, biological, and medical applications [1]. Chirality is an important tool in the field of pharmaceuticals since different enantiomers or diastereomers often have different biological activities. Discovering efficient methods to produce, control and separate enantiomerically pure chiral compounds is critical for any further development of pharmaceuticals, agrochemicals and food additives. Asymmetric synthesis [2], namely the use of small amounts of chiral catalysts to promote reactions that lead to the formation of enantiomerically pure or enriched products, is an important tool in the field of chirality. Generally, in asymmetric synthesis, three different kinds of chiral catalysts are employed: chiral metal–ligand complexes, chiral organocatalysts and biocatalysts. In recent years, organocatalysts have been envisaged to play an important role in asymmetric synthesis. In this respect, one well-known example is the use of proline as an organocatalyst for aldol addition reactions [3]. Proline is an abundant chiral molecule that is inexpensive and available in both enantiomeric forms. The most common application of proline is as catalyst for asymmetric aldol reactions but proline has been also successfully used for many other organic transformations [4–8]. Polymeric micro-size particles [9,10] with chiral surface functionalization were used as organocatalysts for example T. Hansen et al. [11] described the synthesis of acrylic polymer beads containing proline and prolineamides and their application as
⁎ Corresponding author. E-mail address: [email protected] (Y. Mastai).
http://dx.doi.org/10.1016/j.reactfunctpolym.2015.08.011 1381-5148/© 2015 Elsevier B.V. All rights reserved.
catalysts in organocatalytic reactions. Recently, the use of nanoparticles functionalized with proline as organocatalysts has evolved rapidly. The group of R. O'Reilly pioneered the use of chiral nanoparticles for organocatalysts, for example the group has synthesized hydrophobic gel nanoparticles containing proline residues as a new nanoorganocatalyst [12–16]. Another example is the work of Panahi et al. [17] who prepared magnetic nanoparticles with L-proline moieties for application as novel magnetic recyclable organocatalysts for applications in organic synthesis [17]. Also proline-coated gold nanoparticles were prepared and used as a highly efficient nanocatalyst for aldol reactions in water [14,18]. In recent years, we and others have shown that chiral polymeric microspheres or nanoparticles could be used for chiral resolution based on enantioselective crystallization [19–22]. For example, we reported a new synthetic method for the preparation of porous and hollow chiral polymeric microspheres based on poly-(N-vinyl-L-phenylalanine). The chiral-discrimination ability of these chiral microspheres was studied for DL-valine crystallization and demonstrated an enantiomeric excess (ee) of ca. 25% for L-valine in the chiral microspheres. In another paper, we demonstrated the feasibility of templating nanopolymeric particles by chiral block copolymers based on an amino acid and poly(ethylene oxide) block. The obtained chiral nanoparticles were proven to be effective for chiral discrimination by crystallization with a high value of enantiomeric excess. In this paper, we describe the synthesis of chiral polymeric nanoparticles, based on proline, and their utilization as a nanosized organocatalyst for the aldol reaction. Typically, chiral polymeric particles are prepared by chiral surface functionalization. Chiral particles, formed by surface functionalization, exhibit good chiral properties; however it is obvious that chiral nanoparticles with high chiral surface areas are advantageous for asymmetric synthesis.
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Therefore, in this paper we have developed a new synthetic route for the preparation of polymeric chiral nanoparticles, where the entire particle, and not just the surface, is chiral. In this paper, we use miniemulsion polymerization [23,24] as the method of preparation of the chiral polymeric nanoparticles. It is known that the miniemulsion polymerization technique can be used for the preparation of polymeric nanoparticles in the size range of 30 to 500 nm. It is has also been shown that organic reactions such as esterifications, saponification, crystallization processes and polymerization, as well as polyaddition and polycondensation, can be carried out in the miniemulsion, which permits the formulation of a variety of polymers, copolymers, or hybrid particles that have not been synthesized previously by other processes.
2. Experimental 2.1. Preparation of N-oleoyl-D/L-proline monomer The preparation of N-oleoyl-D/L-proline was carried out using the oleic N-hydroxysuccinimide ester [25]. Oleic acid (4.23 g, 15 mmol) was dissolved in 1,4-dioxane (10 mL) and placed in 250 mL roundbottom flask, followed by addition of N-hydroxysuccinimide (1.73 g, 15 mmol). The mixture was stirred, and di-t-butyl dicarbonate (4.91 g, 22.5 mmol, 1.5 eq) dissolved in dioxane (20 mL) was added, followed by addition of triethyl-amine (1.31 g, 15 mmol, 1 eq). Another 20 mL of the solvent 1,4-dioxane was added (total 50 mL). After 5 min of stirring 4-(dimethylamino)-pyridine (DMAP; 0.92 g, 7.5 mmol, 0.5 eq) was added when bubbling of carbon dioxide appeared. The mixture was stirred at room temperature for 3.5 h (1H NMR indicated 90% active ester; 7% oleic acid and 3% SuOBOC) before the next step. In the next step, D/L-proline (2.88 g, 25 mmol, 1.6 eq) was dissolved in water (50 mL) followed by addition of sodium bicarbonate (3.19 g, 38 mmol, 2.25 eq). This solution was added to the active-ester reaction solution and the turbid mixture was stirred overnight (20 h) at 40 °C. The dioxane was evaporated, and the unclear solution was acidified to pH 2 by adding HCl (32% ~4 mL), which led to separation of an oil. The aqueous solution was washed twice with 20 mL ethyl acetate and evaporation of the organic layer that gave 5 g of the crude product as yellow oil (77% pure; by 1H NMR). Purification: the yellow oily crude was dissolved in 20 mL hexane and the solution was washed with mixture of ethanol water 4:1 (20 + 5 mL). After being washed with 2 × 5 mL of hexane, the ethanolic solution was evaporated to give 4.65 g (5.17 g—10% solvents) of N-oleoyl-D-proline as a yellowish oil (N 95% pure; by 1H NMR). 1H NMR, 13C NMR (see Fig. S2) and MS m/z of N-oleoyl-D-proline: N-oleoyl-D-proline; (19/03/14): C23H41NO3 379. Major isomer: 1H NMR (CDCl3, 300 MHz) δ 5.35 (m, 2H), 4.61 (dd, J = 8, 3 Hz, 1H), 3.57 (m, 1H), 3.46 (m, 1H), 2.52 (m, 1H), 2.02 (m, 3H), 2.02 (q, J = 7 Hz, 4H), 2.36 (t, J = 7 Hz, 2H), 1.65 (pt, J = 7 Hz, 2H), 1.32 (s, 8H), 1.27 (s, 12H), 0.88 (t, J = 7 Hz, 3H). (For L isomer; CDCl3, 400 MHz) δ 175.77 (C), 171.96 (C), 130.05 (CH), 129.72 (CH), 60.07 (CH2), 47.96 (CH2), 34.47 (CH2), 31.92 (CH2), 29.9 (± 0.4) (8CH2), 27.24 (CH2), 27.19 (2CH2), 24.79 (CH2), 24.53 (CH2), 14.11 (CH3). MS m/z (ES+) 782 ([2MH+Na+], 21), 760 (2[MH+], 61), 402 (MNa+, 19), 380 (MH+, 100).
2.2. Minemulsion preparation of proline nanoparticles For the preparation of the miniemulsion system for the polymerization of proline nanoparticles, we used cyclohexane and water as the two emulsion phases. The organic phase and the water were mixed in (O/W) 1:4 ratios. In a typical experiment, 50 mg of sodium dodecyl sulfate (S.D.S.) was mixed with 4 mL of d.d. water, at room temperature. 200 mg of the N-oleoyl-D/L-proline monomer, 10 mg of hexadecane, and 15 mg of azobisisobutyronitrile (AIBN) were added to 1 mL of cyclohexane, and the solution was mixed. The water and cyclohexane were mixed together for 5 min. Afterwards, the solution was sonicated for 5 min in icy water (using 5 second pulses on with 5 off seconds). The emulsion solution was immediately transferred to a glass vial at 75 °C and polymerized overnight. We prepared a cross-linked miniemulsion as well (2% cross-linked) using the N-oleoyl-D-proline. The same conditions as the other emulsion were applied and we added 2% divinylbenzene (in respect to N-oleoyl-D-proline) to the organic phase. 3. Asymmetric aldol reaction For the asymmetric aldol reaction we used the reaction condition as reported in the literature [14,18]. In short, 4 nitro-benzaldehyde (2.4 mg, 16 mmol), cyclohexanone (6.65 mL, 64 mmol), and water (1 mL of d.d water containing 0.76 mmol of the catalyst and 10 mmol of sodium hydroxide) were mixed together at room temperature. The reaction mixture was stirred for 48 h and worked out as reported. 4. Experimental techniques Particle size and size distribution were determined by dynamic light scattering (DLS) with a PCCS (Nanophox particle analyzer, Sympatec GmbH, Germany). Electron microscopy: transmission electron microscope (TEM) images were taken with a 2100 JEOL microscope working at a voltage of 100 V and scanning electron microscope (SEM) images were taken with an FEI model Inspect S, and the samples for SEM were prepared by sampling a small amount (ca. 500 μL) of the chiral polymeric nanoparticles on silicon wafer. Specific light rotation was measured with a Jasco digital polarimeter (Model P-1010 l = 586 nm a ± 0.05° accuracy) using a cylindrical quartz cell (5 mL) at room temperature. 5. Results and conclusions In this work, we used N-oleoyl-D/L-proline (see Fig. S1) as the chiral monomer for the synthesis of the polymeric chiral nanoparticles. The synthetic pathway for the preparation of the chiral monomer of Noleoyl-D/L-proline is shown in Fig. 1 [25]. The oleic acid was activated to give the active ester that reacts in the next step with D-proline under basic conditions at 40 °C. The resulting mixture was stirred overnight, and further purification and evaporation led to the separation of the final product as yellow oil. As can be seen in the supporting information, the final product has 2 isomers (see Fig. S1).
Fig. 1. Synthetic pathway for the preparation of the chiral monomer of N-oleoyl-D/L-proline.
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Fig. 2. SEM microscopy image of the polymeric nanoparticles. (a) Low magnification scale bar 1 μm and (b) high magnification scale bar = 200 nm.
In the next step, we polymerized the monomers via a miniemulsion system, as described in the Experimental section. The chiral N-oleoyl-D/L-proline nanoparticles were then characterized. In Fig. S3, the dynamic light scattering (DLS) of the polymeric nanoparticle is shown. As can be seen, the average polymeric particle size is 180 nm with a relatively broad size distribution of 15%. The transmission electron microscopy image of the polymeric nanoparticle (Fig. S4) shows spherical particles with a typical size of 100 nm. In Fig. 2, we show low and high magnification SEM images of the polymeric nanoparticles which are ca. 150 nm in size and with a relative broad size distribution. These results are in agreement with the DLS, however, the average particles sizes from the TEM images do not coincide with the particle sizes measured from SEM and DLS. This observation is well known since the DLS was related to the hydrodynamic radius of the polymeric particles while TEM images measured the radius of the dry nanoparticles. TEM results. To summarize this part, we have demonstrated that miniemulsion polymerization can be used to prepare chiral nanoparticles of N-oleoyl-D/L-proline with sizes of ca. 150 nm and with broad size distribution. In the next stage of our study, we aimed to use our chiral nanoparticles as a chiral catalyst for aldol reactions. First, as a model system for an aldol reaction, we chose the reaction between 4-nitro-benzaldehyde and cyclohexanone (Fig. S5). This reaction was conducted in DMSO as reported previously [26], for 24 h at room temperature. We first performed the aldol reaction and used the free amino acid of D-proline (10% molar vs the benzaldehyde) as the chiral catalyst to examine the stereoselectivity of the reaction and to have a reference value. The reaction solution was put into a polarimeter and measurements of the specific optical rotation were taken over time using a time-resolved method. These measurements enabled us to calculate the enantiomeric excess (e.e.) of the reaction, as shown in Fig. 3. As can be seen, pure Dproline shows high e.e. values up to a value of 70%. The above results regarding the e.e. for pure proline as the chiral catalyst are in agreement with other reported values in the literature [26]. In the next step, we performed the aldol reaction with 10% (v/v) with the polymeric chiral nanoparticles in the reaction solution. It should be noted that in this case we used cross-linked (2%) polymeric nanoparticles. In principal, in organic solvents such as DMSO, the free polymer of chiral N-oleoyl-D/L-proline has some solubility and tends to release the N-oleoyl-D/L-proline polymer from the polymeric nanoparticles into the reaction solution. Therefore in DMSO cross-linking is required, however in aqueous solutions the solubility of the chiral Noleoyl-D/L-proline polymer is very low and no cross-linking is needed. The e.e. results with the polymeric nanoparticles in DMSO are shown in Fig. 3 and display lower e.e.; with maximum e.e. value obtained is 20%. Catalytic asymmetric reactions that can be performed in water are important, since water is a good solvent with respect to environmental concerns and cost. However, the use of water as a reaction solvent is not always useful for asymmetric catalytic reactions because water can inhibit or alter the enantioselectivity. However, it has been shown that
direct asymmetric aldol reactions can be performed in water [27] and also using polymeric nanoparticles in water. We therefore performed the aldol reaction in water using the free amino acid of L- and Dproline and polymeric chiral nanoparticles. However, here we did not use cross-linked nanoparticles. In Fig. 4, the results of these measurements are shown. For free L-proline (5% molar), the reaction reaches a maximum of 40% e.e., a value that is lower than that reported in the literature. With the chiral polymeric nanoparticles of L-proline, we carried out the aldol reaction using different volumes of polymeric nanoparticles. In these experiments, we used 2 mg/mL, 10 mg/mL and 20 mg/mL of polymeric nanoparticles, keeping all the other reaction conditions the same as for pure L-proline. Generally, we can see that there is not a large difference in the reaction e.e. between the different volumes of the polymeric nanoparticles. For example, in the case of 20 mg/mL, we observed fast reaction kinetics at the early stages of the reaction and these shift to moderate kinetics reaching 15% e.e. at the end of the reaction. In other experiments, for example for 2 mg/mL and 10 mg/mL of the chiral polymeric nanoparticles show similar behavior and reach a final e.e. of ca. 15–20%. In our work, as opposed to the previous literature, the amine group of the proline amino acid is free and available for catalysis. As one can understand from previous literature, the aldol catalysis mechanism is basically a general acid-based mechanism. Therefore we decided to conduct another control experiment using Fmoc-L-proline in which the amine moiety is not free for asymmetric aldol reaction, as in the case of our chiral polymeric nanoparticles. A series of similar experiments of the aldol reaction with Fmoc-L-proline as catalyst was carried out and the results showed similar results in terms of the e.e. as for the chiral polymeric nanoparticles.
Fig. 3. Enantiomeric excess as a function of time measured using specific optical rotation: (A) pure D-proline, (B) 10% polymeric chiral nanoparticles of D-proline.
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that the proposed approach of using chiral polymeric nanoparticles as chiral auxiliaries in synthesis will provide further insight into chiral synthesis, and will help in understanding chiral recognition. Acknowledgments Shira R. Adler acknowledges the Bar-Ilan President's Ph.D. Scholarship Foundation. This research was supported by the Israel Science Foundation (ISF) (grant no. 775/11). Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.reactfunctpolym.2015.08.011. References
Fig. 4. Enantiomeric excess as a function of time for aldol reaction in water: (A) pure L -proline,
(B) 2 mg/mL, (C) 10 mg/mL, and (D) 20 mg/mL polymeric nanoparticles of
L -proline.
Recovery and recycling of the chiral polymeric nanoparticles were investigated. After the aldol reaction has ended, we isolated the polymeric nanoparticles by centrifugation. The polymeric nanoparticles were washed first with ethanol and then with water and recovered polymeric nanoparticles were reused in a new aldol reaction. Using this procedure, the polymeric nanoparticles were successfully recycled and reused for four cycles. A reduction of about 12% in the e.e. conversion was observed for the third and 20 for the fourth cycles. In conclusion, this paper presents the preparation and application of chiral polymeric nanoparticles as new nanocatalysts for the asymmetric aldol reaction. The chiral polymeric nanoparticles were synthesized using a novel technique, based on the miniemulsion polymerization of N-oleoyl-D/L-proline monomers. The efficiency of the chiral polymeric nanoparticles compared to free amino acid of proline in the catalytic aldol reaction was demonstrated. Although the chiral selectivity of the polymeric nanoparticles is low compared to free amino acid, they have the advantage of the low catalyst loading that is required and the opportunity to recycle the polymeric nanoparticle catalysts. While the e.e. values for the polymeric nanoparticles are not very high, the basic idea of using chiral polymeric nanoparticles for enantioselective synthesis is demonstrated. Future studies with optimized polymer architectures and chiral functionalities will potentially result in significant improvements in the e.e. of the polymeric nanoparticles as catalysts. The possibility of creating chiral polymeric nanoparticles with a variety of sizes, architectures, and chemical functionalities provides opportunities for developing new chiral organocatalysts. Moreover, we believe
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Contents lists available at ScienceDirect
Reactive and Functional Polymers journal homepage: www.elsevier.com/locate/react
Chiral polymeric nanoparticles for aldol reaction Shira R. Adler, Yitzhak Mastai ⁎ Department of Chemistry and the Institute of Nanotechnology, Bar-Ilan University, Ramat-Gan 52900, Israel
a r t i c l e
i n f o
Article history: Received 21 February 2015 Received in revised form 15 August 2015 Accepted 29 August 2015 Available online 6 September 2015 Keywords: Polymeric nanoparticles Organocatalysts Proline Miniemulsion polymerization Enantioselective synthesis
a b s t r a c t In this paper, we report on the preparation and use of chiral polymeric nanoparticles, based on proline, as nanocatalysts for the asymmetric aldol reaction. The chiral polymeric nanoparticles were synthesized using a novel technique based on miniemulsion polymerization of chiral N-oleoyl-D/L-proline monomers. This method led to the formation of chiral polymeric nanoparticles with average size of 160 nm. Moreover, the polymeric chiral nanoparticles prepared by miniemulsion polymerization are of high surface area, and the entire particle, not just the surface, is chiral. The efficiency of the polymeric chiral nanoparticles for asymmetric aldol reaction in organic solvents and water is demonstrated. Although the chiral selectivity of the polymeric nanoparticles is low compared to free amino acid still they have the advantage of the low catalyst loading that is required and the opportunity to recycle the polymeric nanoparticle catalysts. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Chirality is one of the key factors in molecular recognition, which is extremely important in many chemical, biological, and medical applications [1]. Chirality is an important tool in the field of pharmaceuticals since different enantiomers or diastereomers often have different biological activities. Discovering efficient methods to produce, control and separate enantiomerically pure chiral compounds is critical for any further development of pharmaceuticals, agrochemicals and food additives. Asymmetric synthesis [2], namely the use of small amounts of chiral catalysts to promote reactions that lead to the formation of enantiomerically pure or enriched products, is an important tool in the field of chirality. Generally, in asymmetric synthesis, three different kinds of chiral catalysts are employed: chiral metal–ligand complexes, chiral organocatalysts and biocatalysts. In recent years, organocatalysts have been envisaged to play an important role in asymmetric synthesis. In this respect, one well-known example is the use of proline as an organocatalyst for aldol addition reactions [3]. Proline is an abundant chiral molecule that is inexpensive and available in both enantiomeric forms. The most common application of proline is as catalyst for asymmetric aldol reactions but proline has been also successfully used for many other organic transformations [4–8]. Polymeric micro-size particles [9,10] with chiral surface functionalization were used as organocatalysts for example T. Hansen et al. [11] described the synthesis of acrylic polymer beads containing proline and prolineamides and their application as
⁎ Corresponding author. E-mail address: [email protected] (Y. Mastai).
http://dx.doi.org/10.1016/j.reactfunctpolym.2015.08.011 1381-5148/© 2015 Elsevier B.V. All rights reserved.
catalysts in organocatalytic reactions. Recently, the use of nanoparticles functionalized with proline as organocatalysts has evolved rapidly. The group of R. O'Reilly pioneered the use of chiral nanoparticles for organocatalysts, for example the group has synthesized hydrophobic gel nanoparticles containing proline residues as a new nanoorganocatalyst [12–16]. Another example is the work of Panahi et al. [17] who prepared magnetic nanoparticles with L-proline moieties for application as novel magnetic recyclable organocatalysts for applications in organic synthesis [17]. Also proline-coated gold nanoparticles were prepared and used as a highly efficient nanocatalyst for aldol reactions in water [14,18]. In recent years, we and others have shown that chiral polymeric microspheres or nanoparticles could be used for chiral resolution based on enantioselective crystallization [19–22]. For example, we reported a new synthetic method for the preparation of porous and hollow chiral polymeric microspheres based on poly-(N-vinyl-L-phenylalanine). The chiral-discrimination ability of these chiral microspheres was studied for DL-valine crystallization and demonstrated an enantiomeric excess (ee) of ca. 25% for L-valine in the chiral microspheres. In another paper, we demonstrated the feasibility of templating nanopolymeric particles by chiral block copolymers based on an amino acid and poly(ethylene oxide) block. The obtained chiral nanoparticles were proven to be effective for chiral discrimination by crystallization with a high value of enantiomeric excess. In this paper, we describe the synthesis of chiral polymeric nanoparticles, based on proline, and their utilization as a nanosized organocatalyst for the aldol reaction. Typically, chiral polymeric particles are prepared by chiral surface functionalization. Chiral particles, formed by surface functionalization, exhibit good chiral properties; however it is obvious that chiral nanoparticles with high chiral surface areas are advantageous for asymmetric synthesis.
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S.R. Adler, Y. Mastai / Reactive and Functional Polymers 96 (2015) 1–4
Therefore, in this paper we have developed a new synthetic route for the preparation of polymeric chiral nanoparticles, where the entire particle, and not just the surface, is chiral. In this paper, we use miniemulsion polymerization [23,24] as the method of preparation of the chiral polymeric nanoparticles. It is known that the miniemulsion polymerization technique can be used for the preparation of polymeric nanoparticles in the size range of 30 to 500 nm. It is has also been shown that organic reactions such as esterifications, saponification, crystallization processes and polymerization, as well as polyaddition and polycondensation, can be carried out in the miniemulsion, which permits the formulation of a variety of polymers, copolymers, or hybrid particles that have not been synthesized previously by other processes.
2. Experimental 2.1. Preparation of N-oleoyl-D/L-proline monomer The preparation of N-oleoyl-D/L-proline was carried out using the oleic N-hydroxysuccinimide ester [25]. Oleic acid (4.23 g, 15 mmol) was dissolved in 1,4-dioxane (10 mL) and placed in 250 mL roundbottom flask, followed by addition of N-hydroxysuccinimide (1.73 g, 15 mmol). The mixture was stirred, and di-t-butyl dicarbonate (4.91 g, 22.5 mmol, 1.5 eq) dissolved in dioxane (20 mL) was added, followed by addition of triethyl-amine (1.31 g, 15 mmol, 1 eq). Another 20 mL of the solvent 1,4-dioxane was added (total 50 mL). After 5 min of stirring 4-(dimethylamino)-pyridine (DMAP; 0.92 g, 7.5 mmol, 0.5 eq) was added when bubbling of carbon dioxide appeared. The mixture was stirred at room temperature for 3.5 h (1H NMR indicated 90% active ester; 7% oleic acid and 3% SuOBOC) before the next step. In the next step, D/L-proline (2.88 g, 25 mmol, 1.6 eq) was dissolved in water (50 mL) followed by addition of sodium bicarbonate (3.19 g, 38 mmol, 2.25 eq). This solution was added to the active-ester reaction solution and the turbid mixture was stirred overnight (20 h) at 40 °C. The dioxane was evaporated, and the unclear solution was acidified to pH 2 by adding HCl (32% ~4 mL), which led to separation of an oil. The aqueous solution was washed twice with 20 mL ethyl acetate and evaporation of the organic layer that gave 5 g of the crude product as yellow oil (77% pure; by 1H NMR). Purification: the yellow oily crude was dissolved in 20 mL hexane and the solution was washed with mixture of ethanol water 4:1 (20 + 5 mL). After being washed with 2 × 5 mL of hexane, the ethanolic solution was evaporated to give 4.65 g (5.17 g—10% solvents) of N-oleoyl-D-proline as a yellowish oil (N 95% pure; by 1H NMR). 1H NMR, 13C NMR (see Fig. S2) and MS m/z of N-oleoyl-D-proline: N-oleoyl-D-proline; (19/03/14): C23H41NO3 379. Major isomer: 1H NMR (CDCl3, 300 MHz) δ 5.35 (m, 2H), 4.61 (dd, J = 8, 3 Hz, 1H), 3.57 (m, 1H), 3.46 (m, 1H), 2.52 (m, 1H), 2.02 (m, 3H), 2.02 (q, J = 7 Hz, 4H), 2.36 (t, J = 7 Hz, 2H), 1.65 (pt, J = 7 Hz, 2H), 1.32 (s, 8H), 1.27 (s, 12H), 0.88 (t, J = 7 Hz, 3H). (For L isomer; CDCl3, 400 MHz) δ 175.77 (C), 171.96 (C), 130.05 (CH), 129.72 (CH), 60.07 (CH2), 47.96 (CH2), 34.47 (CH2), 31.92 (CH2), 29.9 (± 0.4) (8CH2), 27.24 (CH2), 27.19 (2CH2), 24.79 (CH2), 24.53 (CH2), 14.11 (CH3). MS m/z (ES+) 782 ([2MH+Na+], 21), 760 (2[MH+], 61), 402 (MNa+, 19), 380 (MH+, 100).
2.2. Minemulsion preparation of proline nanoparticles For the preparation of the miniemulsion system for the polymerization of proline nanoparticles, we used cyclohexane and water as the two emulsion phases. The organic phase and the water were mixed in (O/W) 1:4 ratios. In a typical experiment, 50 mg of sodium dodecyl sulfate (S.D.S.) was mixed with 4 mL of d.d. water, at room temperature. 200 mg of the N-oleoyl-D/L-proline monomer, 10 mg of hexadecane, and 15 mg of azobisisobutyronitrile (AIBN) were added to 1 mL of cyclohexane, and the solution was mixed. The water and cyclohexane were mixed together for 5 min. Afterwards, the solution was sonicated for 5 min in icy water (using 5 second pulses on with 5 off seconds). The emulsion solution was immediately transferred to a glass vial at 75 °C and polymerized overnight. We prepared a cross-linked miniemulsion as well (2% cross-linked) using the N-oleoyl-D-proline. The same conditions as the other emulsion were applied and we added 2% divinylbenzene (in respect to N-oleoyl-D-proline) to the organic phase. 3. Asymmetric aldol reaction For the asymmetric aldol reaction we used the reaction condition as reported in the literature [14,18]. In short, 4 nitro-benzaldehyde (2.4 mg, 16 mmol), cyclohexanone (6.65 mL, 64 mmol), and water (1 mL of d.d water containing 0.76 mmol of the catalyst and 10 mmol of sodium hydroxide) were mixed together at room temperature. The reaction mixture was stirred for 48 h and worked out as reported. 4. Experimental techniques Particle size and size distribution were determined by dynamic light scattering (DLS) with a PCCS (Nanophox particle analyzer, Sympatec GmbH, Germany). Electron microscopy: transmission electron microscope (TEM) images were taken with a 2100 JEOL microscope working at a voltage of 100 V and scanning electron microscope (SEM) images were taken with an FEI model Inspect S, and the samples for SEM were prepared by sampling a small amount (ca. 500 μL) of the chiral polymeric nanoparticles on silicon wafer. Specific light rotation was measured with a Jasco digital polarimeter (Model P-1010 l = 586 nm a ± 0.05° accuracy) using a cylindrical quartz cell (5 mL) at room temperature. 5. Results and conclusions In this work, we used N-oleoyl-D/L-proline (see Fig. S1) as the chiral monomer for the synthesis of the polymeric chiral nanoparticles. The synthetic pathway for the preparation of the chiral monomer of Noleoyl-D/L-proline is shown in Fig. 1 [25]. The oleic acid was activated to give the active ester that reacts in the next step with D-proline under basic conditions at 40 °C. The resulting mixture was stirred overnight, and further purification and evaporation led to the separation of the final product as yellow oil. As can be seen in the supporting information, the final product has 2 isomers (see Fig. S1).
Fig. 1. Synthetic pathway for the preparation of the chiral monomer of N-oleoyl-D/L-proline.
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Fig. 2. SEM microscopy image of the polymeric nanoparticles. (a) Low magnification scale bar 1 μm and (b) high magnification scale bar = 200 nm.
In the next step, we polymerized the monomers via a miniemulsion system, as described in the Experimental section. The chiral N-oleoyl-D/L-proline nanoparticles were then characterized. In Fig. S3, the dynamic light scattering (DLS) of the polymeric nanoparticle is shown. As can be seen, the average polymeric particle size is 180 nm with a relatively broad size distribution of 15%. The transmission electron microscopy image of the polymeric nanoparticle (Fig. S4) shows spherical particles with a typical size of 100 nm. In Fig. 2, we show low and high magnification SEM images of the polymeric nanoparticles which are ca. 150 nm in size and with a relative broad size distribution. These results are in agreement with the DLS, however, the average particles sizes from the TEM images do not coincide with the particle sizes measured from SEM and DLS. This observation is well known since the DLS was related to the hydrodynamic radius of the polymeric particles while TEM images measured the radius of the dry nanoparticles. TEM results. To summarize this part, we have demonstrated that miniemulsion polymerization can be used to prepare chiral nanoparticles of N-oleoyl-D/L-proline with sizes of ca. 150 nm and with broad size distribution. In the next stage of our study, we aimed to use our chiral nanoparticles as a chiral catalyst for aldol reactions. First, as a model system for an aldol reaction, we chose the reaction between 4-nitro-benzaldehyde and cyclohexanone (Fig. S5). This reaction was conducted in DMSO as reported previously [26], for 24 h at room temperature. We first performed the aldol reaction and used the free amino acid of D-proline (10% molar vs the benzaldehyde) as the chiral catalyst to examine the stereoselectivity of the reaction and to have a reference value. The reaction solution was put into a polarimeter and measurements of the specific optical rotation were taken over time using a time-resolved method. These measurements enabled us to calculate the enantiomeric excess (e.e.) of the reaction, as shown in Fig. 3. As can be seen, pure Dproline shows high e.e. values up to a value of 70%. The above results regarding the e.e. for pure proline as the chiral catalyst are in agreement with other reported values in the literature [26]. In the next step, we performed the aldol reaction with 10% (v/v) with the polymeric chiral nanoparticles in the reaction solution. It should be noted that in this case we used cross-linked (2%) polymeric nanoparticles. In principal, in organic solvents such as DMSO, the free polymer of chiral N-oleoyl-D/L-proline has some solubility and tends to release the N-oleoyl-D/L-proline polymer from the polymeric nanoparticles into the reaction solution. Therefore in DMSO cross-linking is required, however in aqueous solutions the solubility of the chiral Noleoyl-D/L-proline polymer is very low and no cross-linking is needed. The e.e. results with the polymeric nanoparticles in DMSO are shown in Fig. 3 and display lower e.e.; with maximum e.e. value obtained is 20%. Catalytic asymmetric reactions that can be performed in water are important, since water is a good solvent with respect to environmental concerns and cost. However, the use of water as a reaction solvent is not always useful for asymmetric catalytic reactions because water can inhibit or alter the enantioselectivity. However, it has been shown that
direct asymmetric aldol reactions can be performed in water [27] and also using polymeric nanoparticles in water. We therefore performed the aldol reaction in water using the free amino acid of L- and Dproline and polymeric chiral nanoparticles. However, here we did not use cross-linked nanoparticles. In Fig. 4, the results of these measurements are shown. For free L-proline (5% molar), the reaction reaches a maximum of 40% e.e., a value that is lower than that reported in the literature. With the chiral polymeric nanoparticles of L-proline, we carried out the aldol reaction using different volumes of polymeric nanoparticles. In these experiments, we used 2 mg/mL, 10 mg/mL and 20 mg/mL of polymeric nanoparticles, keeping all the other reaction conditions the same as for pure L-proline. Generally, we can see that there is not a large difference in the reaction e.e. between the different volumes of the polymeric nanoparticles. For example, in the case of 20 mg/mL, we observed fast reaction kinetics at the early stages of the reaction and these shift to moderate kinetics reaching 15% e.e. at the end of the reaction. In other experiments, for example for 2 mg/mL and 10 mg/mL of the chiral polymeric nanoparticles show similar behavior and reach a final e.e. of ca. 15–20%. In our work, as opposed to the previous literature, the amine group of the proline amino acid is free and available for catalysis. As one can understand from previous literature, the aldol catalysis mechanism is basically a general acid-based mechanism. Therefore we decided to conduct another control experiment using Fmoc-L-proline in which the amine moiety is not free for asymmetric aldol reaction, as in the case of our chiral polymeric nanoparticles. A series of similar experiments of the aldol reaction with Fmoc-L-proline as catalyst was carried out and the results showed similar results in terms of the e.e. as for the chiral polymeric nanoparticles.
Fig. 3. Enantiomeric excess as a function of time measured using specific optical rotation: (A) pure D-proline, (B) 10% polymeric chiral nanoparticles of D-proline.
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that the proposed approach of using chiral polymeric nanoparticles as chiral auxiliaries in synthesis will provide further insight into chiral synthesis, and will help in understanding chiral recognition. Acknowledgments Shira R. Adler acknowledges the Bar-Ilan President's Ph.D. Scholarship Foundation. This research was supported by the Israel Science Foundation (ISF) (grant no. 775/11). Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.reactfunctpolym.2015.08.011. References
Fig. 4. Enantiomeric excess as a function of time for aldol reaction in water: (A) pure L -proline,
(B) 2 mg/mL, (C) 10 mg/mL, and (D) 20 mg/mL polymeric nanoparticles of
L -proline.
Recovery and recycling of the chiral polymeric nanoparticles were investigated. After the aldol reaction has ended, we isolated the polymeric nanoparticles by centrifugation. The polymeric nanoparticles were washed first with ethanol and then with water and recovered polymeric nanoparticles were reused in a new aldol reaction. Using this procedure, the polymeric nanoparticles were successfully recycled and reused for four cycles. A reduction of about 12% in the e.e. conversion was observed for the third and 20 for the fourth cycles. In conclusion, this paper presents the preparation and application of chiral polymeric nanoparticles as new nanocatalysts for the asymmetric aldol reaction. The chiral polymeric nanoparticles were synthesized using a novel technique, based on the miniemulsion polymerization of N-oleoyl-D/L-proline monomers. The efficiency of the chiral polymeric nanoparticles compared to free amino acid of proline in the catalytic aldol reaction was demonstrated. Although the chiral selectivity of the polymeric nanoparticles is low compared to free amino acid, they have the advantage of the low catalyst loading that is required and the opportunity to recycle the polymeric nanoparticle catalysts. While the e.e. values for the polymeric nanoparticles are not very high, the basic idea of using chiral polymeric nanoparticles for enantioselective synthesis is demonstrated. Future studies with optimized polymer architectures and chiral functionalities will potentially result in significant improvements in the e.e. of the polymeric nanoparticles as catalysts. The possibility of creating chiral polymeric nanoparticles with a variety of sizes, architectures, and chemical functionalities provides opportunities for developing new chiral organocatalysts. Moreover, we believe
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