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Amino-Acid-Based Chiral Nanoparticles for Enantioselective Crystallization Laura C. Preiss, Liora Werber, Viktor Fischer, Sadaf Hanif, Katharina Landfester, Yitzhak Mastai,* and Rafael Muñoz-Espí* Chirality is one of the key factors in molecular recognition, which is extremely important in many chemical, biological, and medical applications.[1] Discovering efficient methods to produce and separate enantiomerically pure chiral compounds is critical for further development of pharmaceuticals, because enantiomers of drugs may have different pharmacologic and toxicological effects.[2] In recent years, chirality has also been envisaged for new applications in nanotechnology.[3] This is the case, for example, of chiral self-assembled structures for the formation of chiral nanometric surfaces[4] or mesoporous materials imprinted with different chiral functionalities.[5] Chiral polymers are an important class of chiral materials that have been used for many years in stationary phases[6] and molecular imprinting.[5a] They have also been used as additives for the resolution of enantiomers by crystallization.[7] Inspite of the great developments in asymmetric synthesis, chiral resolution by so-called preferential crystallization continues to be one of the main methods to obtain pure entantiomers because of its simplicity, wide range of applications, and cost efficiency.[8] In previous work, Mastai and co-workers reported the preparation of micrometric chiral polymeric particles and their use for chiral resolution by crystallization.[9] Although the application of polymer particles in the nanometric scale would increase significantly the specific surface area and open up new possibilities, their synthesis remains very challenging. In recent years, Deng’s research group has been active in the preparation of chiral polymeric and inorganic–polymeric hybrid nanoparticles based on optically active helical polymers.[10] Via reversible addition–fragmentation chain transfer (RAFT) miniemulsion polymerization, Zhu and co-workers obtained chiral nanoparticles that were used to test the ability of the enantioselective recognition of racemates in ethanol solutions.[11] Further research in the area of chiral polymeric nanomaterials has been conducted by O’Reilly's group, which has developed new methods for the synthesis of chiral micelles and nanoparticles for applications

L. C. Preiss, Dr. V. Fischer, S. Hanif, Prof. K. Landfester, Dr. R. Muñoz-Espí Max Planck Institute for Polymer Research Ackermannweg 10, 55128 Mainz, Germany E-mail: [email protected] L. Werber, Prof. Y. Mastai Department of Chemistry and Institute of Nanotechnology Bar-Ilan University Ramat-Gan 52900, Israel E-mail: [email protected]

DOI: 10.1002/adma.201405531

Adv. Mater. 2015, DOI: 10.1002/adma.201405531

in organocatalysts.[12] Similarly, Hansen et al.[13] have also designed new chiral beads for asymmetric organocatalysis. In this work, we present a general and very simple chemical route based on miniemulsion polymerization for the synthesis of polymeric chiral nanoparticles of amino acids derivatives. The chiral discriminatory ability of the prepared nanoparticles was demonstrated with the enantioselective crystallization of racemic mixtures of amino acids. Finally, we used isothermal titration calorimetry (ITC) to measure the adsorption energy of enantiomers onto the surface of chiral polymeric nanoparticles and prove their enantiospecificity. The optically active amino acid monomers were prepared by an Einhorn modification of a Schotten–Baumann reaction following a reported pathway.[14] As representative monomers, we prepared acrylate derivatives of the D and L form of glutamic acid (represented in the following as LGlu and DGlu), threonine (LThr and DThr), and phenylalanine (LPhe and DPhe) (Scheme S1, Supporting Information). The synthesized monomers were dissolved in toluene and polymerized in miniemulsion (see chemical structures of the prepared polymers in Scheme S2, Supporting Information). The size of the obtained chiral polymer particles ranged from 150 to 260 nm, as determined by dynamic light scattering (DLS). The number average molar mass of the polymers (Mn), determined by gas permeation chromatography (GPC), was in the order of 30 000 g·mol−1 (Table 1). Scanning electron microscopy (SEM) images of the prepared samples, presented in Figure 1, show fairly well distributed particles of sizes consistent with those obtained by DLS. The optical properties of the poly(acryl amino acid) nanoparticles were studied by circular dichroism (CD) spectroscopy (Figure S1, Supporting Information). The enantiomeric pairs of chiral nanoparticles exhibited positive and negative CD ellipticities at wavelength below 250 nm and reached a maximum intensity at wavelength of around 225 nm. As expected, the enantiomers of the prepared chiral nanoparticles show dichroic absorption of equal magnitude but with opposite sign. All particles present also a characteristic maximum at ≈200 nm. To demonstrate the stereoselectivity of the synthesized nanoparticles, we focus on one application, namely the enantioselective crystallization. Although in recent decades there has been a remarkable advance in the separation of enantiomers by many techniques, large-scale separation technology is still based on classical crystallization methods. We propose to use the chiral polymeric nanoparticles to develop a new approach for the resolution of chiral compounds by enantioselective crystallization on the surface of chiral polymeric nanoparticles. Our basic hypothesis is that the chiral polymeric nanoparticles will act as

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www.MaterialsViews.com Table 1. Size and molecular weight of the prepared polymer nanoparticles. Monomer

Monomer abbreviation

Particle size [nm]a)

Molecular weight [g·mol−1]b) Mn

Mw

N-acryl-di-tert-butyl-L-glutamic acid

LGlu

220 ± 60

27 400

56 300

N-acryl-di-tert-butyl-D-glutamic acid

DGlu

220 ± 30

28 200

83 100

N-acryl-tert-butyl ester L-phenylalanine

LPhe

230 ± 40

28 300

181 500

N-acryl-tert-butyl ester D-phenylalanine

DPhe

200 ± 70

27 100

63 600

N-acryl-O-tert-butyl methyl ester-L-threonine

LThr

260 ± 60

31 000

75 300

N-acryl-O-tert-butyl methyl ester-D-threonine

DThr

150 ± 20

31 900

92 600

a)Determined

by DLS; b)determined by GPC.

pseudoracemates (sometimes called racemic solid solution).[16] A conglomerate is an equimolar physical mixture of the individual homochiral crystals of the two opposite enantiomers. A racemic compound consists of crystals in which the two enantiomeric molecules of opposite chirality are paired up in the unit cell of the crystal lattice. Finally, a pseudoracemate consists of the two enantiomeric molecules of opposite chirality arranged randomly in the same crystal lattice. Only between 5% and 10% of all chiral compounds crystallize as conglomerates. The separation of a conglomerate system is easier than the separation of a racemic system, because of their different composition. In this work, we studied the crystallization of a representative conglomerate system: rac-asparagine. To find the optimum crystallization conditions for the experiments, the crystallization of asparagine (in the L-, D-, and rac-forms) from a supersaturated solution at controlled cooling rates was studied by turbidimetry (Figure S2 and Table S1, Supporting Information). The induction time (i.e., the time in which nucleation occurs) is different for the different forms, being the values of the racemic form (rac-asparagine: ≈50 min) intermediate between the ones corresponding to the two enantiomers (L-asparagine: ≈60 min, D-asparagine: ≈39 min). When the crystallization of the racemic mixture takes place in the presence of poly(LGlu) and poly(DGlu) nanoparticles, the time before the onset edge of crystallization (i.e., the edge at which crystallization occurs very rapidly and the intensity of the transmitted light drops off) is slightly lower (4–7 min less) than for pure rac-asparagine. However, it is remarkable that the induction time tends to zero and even before the onset edge the transmitted light decreases progressively (i.e., crystal growth takes place), which is related with the presence of the nanoparticle seeds. When comparing the calculated precipitation rates (rmax, Table S2, Supporting Information) in the presence of the particles, Figure 1. SEM images of a) poly(LGlu), b) poly(DGlu), c) poly(LThr), d) poly(DThr), e) poly(LPhe), the values are higher than for pure rac-Asn (but lower than for pure L-Asn and D-Asn). and f) poly(DPhe) nanoparticles.

selective chiral nuclei and lead to enantioselective crystallization of one enantiomer onto the polymeric nanoparticles. The assumption is supported by previous research on the enantioselective crystallization of L-glutamic acid on chiral self-assembled multilayers surfaces.[15] We studied the enantioselective crystallization of amino acids because they are the basis of all life processes and crystallization is one of the key steps in their preparation. Chiral compounds crystallize from solution in three forms of racemic solids: conglomerates, racemic compounds, and

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The enantioselective evolution of the crystallization process in the presence of the chiral nanoparticles was monitored by polarimetry. The chiral particles acted as nucleation centers in the supersaturated solution of the rac-amino acid, leading to preferential crystallization of one enantiomer. Figure 2 pre-

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60 °C and the e.e. during the Figure 2. Evolution of the optical rotation α 365nm crystallization from a supersaturated solution of rac-asparagine in the presence of a) poly(LGlu) and poly(DGlu), b) poly(LThr) and poly(DThr), and c) poly(LPhe) and poly(DPhe) nanoparticles. The blue curves show the blank crystallization in the absence of any particle.

sents the evolution of the measured optical rotation and the corresponding enantiomeric excess (e.e.) as a function of time in the absence and presence of glutamic, threonine, and phenylalanine particles. When rac-asparagine is crystallized in the absence of any particle, a minor spontaneous preferential crystallization of the L-enantiomer of about 2% is observed (blue curves). In the presence of chiral particles, we assume that L-asparagine adsorbs preferentially on the L-particles and acts as nucleating seeds for L-asparagine crystals. The increase in the optical rotation after ≈75 min indicates the start of the growth process. At the highest point in the curve, D-asparagine also starts to crystallize and the optical rotation decreases to reach again zero when the crystallization is complete. In the presence of D-particles, a mirror image of the curve is obtained, with negative sign for the optical rotation, which implies a preferential crystallization of D-Asn. The results were very similar for the particles prepared with the different monomers and the e.e. ranged from 15% to 23% (Table S2, Supporting Information). For a practical separation of the enantiomers, a separation at the maximum of the curves should be carried out and a circular process would be needed to enrich the desired enantiomers in different cycles. As a control experiment to see the effect of unspecific particle surfaces, we carried out similar crystallization experiments of rac-asparagine in the presence of poly(methyl methacrylate) nanoparticles prepared by miniemulsion polymerization (size of about 200 nm). As expected, these particles showed no enantioselectivity in the crystallization process (Figure S3, Supporting Information). Analogous crystallization experiments with rac-glutamic acid on the different chiral particles showed no chiral discrimination (Figure S4, Supporting Information). It is known that rac-glutamic acid can crystallize in two forms depending on temperature: an anhydrous conglomerate form and the monohydrate racemic compound.[17] The racemic compound is formed in our experiments, which explains why the preferential crystallization is not successful. It is important to indicate that the enantioselective crystallization does not seem to be related to a specific molecular recognition (glutamic acid groups do not necessarily resolve glutamic acid groups), but rather to a “chiral recognition”: L-particles promote the crystallization of the L-form and D ones promote the D-form. To study the influence of the protection of the carboxylic groups (see protecting groups in Scheme S1, Supporting Information), we also prepared cross-linked particles that can be subsequently deprotected. The sizes of the cross-linked particles were similar to the non-cross-linked ones (Figure S5, Supporting Information). Although the redispersability is more complicated after deprotection, the general behavior in the crystallization experiments was analogous to the protected particles, with successful enantioselective crystallization from the conglomerate rac-asparagine. (Figure S7, Supporting Information). Since the main applications for chiral nanoparticles involve enantioselective molecular interactions, we selected enantio-differentiating adsorption as a relevant analysis tool. The experiments should also provide an insight in the understanding of the mechanism related with enantioselective crystallization processes. For this purpose, we applied ITC, a technique that compares the adsorption enthalpy of enantiomers. Mastai and

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co-workers recently used ITC to study the molecular chiral interactions in solutions[18] at crystals surfaces,[19] and in zeolites.[20] This method was selected because of its exceptionally high sensitivity (0.1 µW), which allows the direct measurement of heat changes and the analysis and interpretation of binding[21] and chiral molecular interactions. In a set of ITC experiments, we measured the adsorption enthalpy of L- and D-valine solutions injected into the chiral polymeric nanoparticles of poly(LPhe). Valine was chosen as the chiral probe molecule because of its low heat of dilution in water. The adsorption enthalpy was determined at 30 °C. Intensities and areas of the ITC peaks of L-valine injected into chiral polymeric nanoparticles of poly(LPhe) are larger than the peaks of D-valine. The average ΔHbinding can be calculated for those peaks, so that the difference in the binding enthalpies between L-valine and the polymeric nanoparticles is approximately 1.65 times stronger than the chiral interactions of D-valine. Thus, we can differentiate by ITC measurements between the enantiomers interactions at the chiral polymeric nanoparticles. The results from ITC measurements reveal that valine enantiomers with the same chirality as polymeric nanoparticles show higher binding energy. In other words, L-valine interacted more favorably than D-valine with L-nanoparticles. These results are in-line with the general approach of stereochemical interactions and chiral recognition at the chiral surfaces. In summary, we have shown the preparation of chiral nanoparticles and their application in enantioselective crystallization. After the synthesis of the amino acid derivative monomers, the corresponding chiral polymer nanoparticles were prepared by miniemulsion polymerization. When the conglomerate system rac-asparagine is crystallized in the presence of theses D- or L-particles, a preferential enantioselective crystallization is observed, with an enantiomeric excess of up to 23%. This observation demonstrates that the synthesized nanoparticles are suited for the development of new chiral resolution processes and can also contribute to a better understanding of the chiral recognition on polymer surfaces.

Experimental Section Materials: L-Glutamic acid di-tert-butyl ester hydrochloride (Merck), acid di-tert-butyl ester hydrochloride (Orpegen Peptide Chemicals), O-tert-butyl-L-threonine methyl ester hydrochloride (Merck), O-tert-butyl-D-threonine methyl ester hydrochloride (Iris Biotech), L-phenylalanine-tert butyl ester hydrochloride (Sigma, p.a. ≥ 99%), D-phenylalanine-tert butyl ester hydrochloride (Orpegen Peptide Chemicals), acryloyl chloride (Sigma-Aldrich, p.a. ≥ 97%), ethyl acetate (Sigma-Aldrich, p.a. ≥ 99.5%), sodium chloride (Sigma-Aldrich), toluene (Sigma-Aldrich, p.a. ≥ 99.7%), Azobisisobutyronitrile (AIBN, Fluka, p.a. ≥ 98%), triethylamine (Fluka, p.a. ≥ 99.5%), sodium hydrogen sulfate (Acros Organics), sodium hydrogen carbonate (Fisher Scientific), dichlormethane (Fisher Scientific, HPLC grade), trifluoro acetic acid (Sigma-Aldrich, p.a. ≥ 99%), diethyl ether (Sigma-Aldrich ≥99.8%), racasparagine (Sigma-Aldrich ≥99%), L-asparagine (Acros Organics ≥99%), D-asparagine (Sigma-Aldrich ≥99%) and rac-glutamic acid (SigmaAldrich ≥99%) were used as received. Ultrapure MilliQ water was used through all the experiments. Monomer Synthesis: The protected amino acid hydrochloride (5.0 g) and triethylamine (2.5 equivalents) were dissolved in dichloromethane (50 mL) and the mixture was cooled to 0 °C. Subsequently, acryloyl chloride (1.5 equivalents) was added dropwise to the mixture. The color D-glutamic

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of the reaction mixture changed from colorless to orange. The mixture was allowed to warm to 25 °C and stirred for 12 h. The solvents were removed by rotation evaporation. The product was dissolved in ethyl acetate (100 mL) and the solid crystals of triethylammonium chloride were removed by filtration. The organic phase was washed three times with 1 M solutions of NaHSO4, NaHCO3, solution, and NaCl. The organic phase was dried over MgSO4 and the solvent was removed in vacuum by rotation evaporation. The product was purified by column chromatography (ethyl acetate/hexane 1:1). N-Acryl-di-tert-butyl-L-glutamic acid (LGlu) and N-Acryl-di-tert-butyl-Dglutamic acid (DGlu): 1H-NMR (300 MHz, CDCl3,TMS) δ: 6.40–6.17 (m, 2H), 6.06 (dd, J = 17.0, 10.2 Hz, 1H), 5.60 (dd, J = 10.2, 1.5 Hz, 1H), 4.51 (td, J = 7.9, 4.5 Hz, 1H), 2.42 – 2.01 (m, 3H), 1.94 – 1.77 (m, 1H), 1.39 (d, J = 12.2 Hz, 18H); 13C-NMR (300 MHz, CDCl3, TMS) δ: 171.73 (d, J = 87.2 Hz), 165.17, 130.55, 126.84, 82.41, 80.73, 52.28, 31.56, 28.01 (d, J = 5.5 Hz), 27.67. N-Acryl-tert-butyl ester L-phenylalanine (LPhe) and N-Acryl-tert-butyl ester D-phenylalanine (DPhe): 1H-NMR (300 MHz, CDCl3, TMS) δ: 7.29 – 6.99 (m, 6H), 6.21 (dd, J = 17.0, 1.5 Hz, 1H), 6.15 – 6.09 (m, 1H), 6.06 – 5.96 (m, 1H), 5.58 (dd, J = 10.2, 1.5 Hz, 1H), 4.77 (dt, J = 7.7, 5.9 Hz, 1H), 3.06 (d, J = 5.9 Hz, 2H), 1.34 (s, 9H);13C NMR (300 MHz, CDCl3, TMS) δ: 170.62, 164.77, 136.09, 130.55, 129.55, 128.34, 126.92 (d, J = 6.2 Hz), 82.54, 53.52, 38.00, 27.96. N-Acryl-O-tert-butyl methyl ester-L-threonine (LThr) and N-Acryl-Otert-butyl methyl ester-D-threonine (DThr): 1H-NMR (300 MHz, CDCl3, TMS) δ: 6.32–6.27 (m, 0H), 6.26 – 6.20 (m, 1H), 6.18 – 6.11 (m, 1H), 5.63 (dd, J = 9.8, 2.1 Hz, 1H), 4.56 (dd, J = 9.4, 1.8 Hz, 1H), 4.19 (qd, J = 6.3, 1.9 Hz, 1H), 3.65 (s, 3H), 1.12 (d, J = 6.2 Hz, 3H), 1.06 (s, 9H); 13CNMR (300 MHz, CDCl3, TMS) δ: 171.20, 165.74, 130.50, 127.03, 77.47, 74.15, 67.52, 52.17, 28.29, 20.94. Preparation of Chiral Polymer Nanoparticles: The continuous phase was prepared by dissolving SDS (12 mg) in water (4 mL). For the disperse phase, the monomer (500 mg), AIBN (10 mg), and hexadecane (10 mg) were dissolved in toluene (1 g). For the preparation of cross-linked nanoparticles, in addition, 1,4-butanediol diacrylate (5 mol% with respect to the monomer) was added to the dispersed phase. Both phases were mixed and stirred for 30 min and then emulsified by ultrasonication (1/4” tip; 3 min, 10 s pulse and 2 s pause, 70% amplitude), while cooling in an ice–water bath. The resulting miniemulsions were stirred at 60 °C for 16 h, cooled down to room temperature and filtered. For the crystallization experiments, the toluene and the excess of surfactant (SDS) had to be removed. To eliminate toluene, 10 mL of water was added to the dispersion, which was subsequently stirred for 3 h in an open vial. For SDS removal, the particles were dialyzed against deionized water. Deprotection of the Nanoparticles: A mixture of dichloromethane and trifluoro acetic acid (1:1) was added to the cross-linked particles for the deprotection of the particles and stirred at room temperature overnight. Subsequently, the deprotected particles were precipitate with ice cold diethyl ether and dried at room temperature under vacuum. Characterization Techniques: Scanning electron microscopy was performed with a LEO Gemini 1530 Zeiss microscope operated at 0.6 kV. Particle sizes were obtained from ≈0.1 wt% diluted dispersions on a Nicomp 380 Submicron particle sizer. Circular dichroism (CD) of ≈0.1 wt% diluted dispersions was measured with a Chirascan-CD Spectrometer (Applied Photophysics). Standard gel permeation chromatography (GPC) was performed with THF as the mobile phase (flow rate 1 mL min−1) on a SDV column set from PSS (Mainz, Germany, SDV 1000, SDV 105, SDV 106) at 30 °C. Turbidity Measurements: Experimental details in Supporting Information. Enantioselective Crystallization Experiments: Supersaturated solutions were prepared by dissolving the racemic amino acid (either 4 g of racasparagine or 1.5 g rac-glutamic acid) in water (40 mL, 100 g·L−1), stirring at 60 °C until complete dissolution (≈10 min). Afterwards, a certain volume of the suspension of chiral nanoparticles (corresponding to 16 mg of particles, taking into account the solid content of the suspension) was added, and the mixtures was stirred for 15 min. The solution was then cooled down according to the following cooling rates:

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e.e.(%) =

α × 100 α max

(1)

where α is the measured specific rotation and αmax is the maximum specific rotation. The maximum specific rotation was measured for solutions (100 g·L−1, as in the crystallization experiments) of the pure enantiomer (either L or D amino acid) of asparagine in water (the αmax value at 365 nm for asparagine is ± 1.019. Isothermal Titration Calorimetry (ITC): ITC measurements were performed with a VP-ITC calorimeter of MicroCal (Northampton, MA). The volume of the reservoir cell was 1.442 mL, thermostated at 30 °C. Before measurements, solutions were degassed under vacuum for 5 min to eliminate air bubbles. The sample cell was loaded with 1.442 mL of a 0.2 wt.% suspension of the chiral polymeric nanoparticles in water, and the 300 µL syringe was filled with 200 mM D- or L-valine solution. A titration run consisted of consecutive injections of 5 µL and a duration of 8.5 s each, with an interval of 300 s between them. The cell was constantly stirred with a stirring rate of 300 rpm. To eliminate the nonspecific heat effects and the heat of the dilution of the chiral solutions, we carried out controlled experiments in which L and D valine stock solutions (5 µL) were injected into double distilled water at 30 ºC.

Supporting Information Supporting Information is available from the Wiley Online Library or from the author.

Acknowledgements The authors thank S. Seywald for GPC measurements and Dr. D. Weller (Prof. M. Schmidt’s group, Institute of Physical Chemistry, University of Mainz) for the assistance with the CD measurements. Received: December 3, 2014 Revised: February 26, 2015 Published online:

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60 °C → 45 °C in 15 min; 45 °C → 35 °C in 10 min; 35 °C → 30 °C in 10 min; 30 °C → 25 °C in 10 min; and 25 °C → 22 °C in 30 min. To monitor the crystallization, aliquots of 2 mL were taken from the solution at different times. The aliquots were filtered with a 0.2 µm Nylon syringe filter (Chromacol) and the optical rotations of the filtrated solutions were measured in a polarimeter (Rudolph Research Analytical Autopol IV) at 60 °C at a wavelength of 365 nm. The high temperature was necessary to prevent crystal formation inside the polarimeter tube during the measurement. The enantiomeric excess was calculated according to

[1] Y. Mastai, Chem. Soc. Rev. 2009, 38, 772. [2] J. E. Rekoske, AIChE J. 2001, 47, 2. [3] a) B. Chen, J. Deng, W. Yang, Adv. Funct. Mater. 2011, 21, 2 3 4 5 ; b) C. Song, X. Liu, D. Liu, C. Ren, W. Yang, J. Deng, Macromol. Rapid Commun. 2013, 34, 1426. [4] J. C. Love, L. A. Estroff, J. K. Kriebel, R. G. Nuzzo, G. M. Whitesides, Chem. Rev. 2005, 105, 1103. [5] a) G. Wulff, Angew. Chem. Int. Ed. 1995, 34, 1812; b) P. Paik, A. Gedanken, Y. Mastai, Acs Appl. Mater. Interfaces 2009, 1, 1834. [6] M. Kempe, Anal. Chem. 1996, 68, 1948. [7] D. Zbaida, M. Lahav, K. Drauz, G. Knaup, M. Kottenhahn, Tetrahedron 2000, 56, 6645. [8] a) H. Lorenz, A. Seidel-Morgenstern, Angew. Chem. Int. Ed. 2014, 53, 1218; b) H. Lorenz, A. Perlberg, D. Sapoundjiev, M. P. Elsner, A. Seidel-Morgenstern, Chem. Eng. Process 2006, 45, 863; c) L. Z. Gou, H. Lorenz, A. Seidel-Morgenstern, Cryst. Growth Des. 2012, 12, 5197. [9] a) D. D. Medina, J. Goldshtein, S. Margel, Y. Mastai, Adv. Funct. Mater. 2007, 17, 944; b) T. Menahem, Y. Mastai, J. Polym. Sci., Part A: Polym. Chem. 2006, 44, 3009. [10] a) B. Chen, J. P. Deng, X. Cui, W. T. Yang, Macromolecules 2011, 44, 7109; b) K. Zhou, L. Y. Tong, J. P. Deng, W. T. Yang, J. Mater. Chem. 2010, 20, 781. [11] W. Xu, Z. Cheng, L. Zhang, Z. Zhang, J. Zhu, N. Zhou, X. Zhu, J. Polym. Sci., Part A: Polym. Chem. 2010, 48, 1324. [12] B. Moore, R. O’Reilly, J. Polym. Sci., Part A: Polym. Chem. 2012, 50, 3567. [13] a) T. H. Krane Thvedt, T. E. Kristensen, E. Sundby, T. Hansen, B. H. Hoff, Tetrahedron: Asymmetry 2011, 22, 2172; b) T. E. Kristensen, K. Vestli, M. G. Jakobsen, F. K. Hansen, T. Hansen, J. Org. Chem. 2010, 75, 1620. [14] A. Bentolila, I. Vlodavsky, R. Ishai-Michaeli, O. Kovalchuk, C. Haloun, A. J. Domb, J. Medicinal Chem. 2000, 43, 2591. [15] D. H. Dressler, Y. Mastai, Chirality 2007, 19, 358. [16] J. Jacques, A. Collet, S. H. Willen, Enantiomers, Racemates and Resolutions, Wiley-VCH, New York, 1981. [17] J. Chen, A. S. Myerson, CrystEngComm 2012, 14, 8326. [18] A. Shvalb, Y. Mastai, M. Shinitzky, Chirality 2010, 22, 587. [19] A. Shval, Y. Mastai, Chem. Commun. 2011, 47, 5735. [20] C. Dryzun, Y. Mastai, A. Shvalb, D. Avnir, J. Mater. Chem. 2009, 19, 2062. [21] I. Jelesarov, H. R. Bosshard, J. Mol. Recognition 1999, 12, 3.

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Amino-acid-based chiral nanoparticles for enantioselective crystallization.

Chiral polymer nanoparticles based on amino acids are prepared by miniemulsion polymerization and are demonstrated to serve as nucleating agents for t...
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