Application of pH-responsive methylpropargyl leucine polymer in enantioselective crystallization

    Application of pH-responsive methylpropargyl leucine polymer in enantioselective crystallization Jie Zhang, Ningyu Chen, Yuheng Cui, Liqun Zhang, Dongmei Yue PII: DOI: Reference:

S1381-5148(16)30025-6 doi: 10.1016/j.reactfunctpolym.2016.02.006 REACT 3634

To appear in: Received date: Revised date: Accepted date:

10 November 2015 9 February 2016 10 February 2016

Please cite this article as: Jie Zhang, Ningyu Chen, Yuheng Cui, Liqun Zhang, Dongmei Yue, Application of pH-responsive methylpropargyl leucine polymer in enantioselective crystallization, (2016), doi: 10.1016/j.reactfunctpolym.2016.02.006

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ACCEPTED MANUSCRIPT Application of pH-Responsive Methylpropargyl Leucine Polymer in Enantioselective Crystallization

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Jie Zhanga, Ningyu Chena, Yuheng Cuia, Liqun Zhanga b, Dongmei Yuea b

a

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State Key Laboratory of Organic-Inorganic Composites, Beijing University of

Chemical Technology, Beijing 100029, People’s Republic of China b

Key Laboratory of Beijing City on Preparation and Processing of Novel

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Polymer Materials, Beijing 100029, People’s Republic of China

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Corresponding author: Dongmei Yue

Fax: +86-010- 64436201

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Tel.: +86-010-64436201

ABSTRACT

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E-mail: [email protected]

In this study, novel 1-methylpropargyl alcohol derivatives containing leucine

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side groups on their side chains were successfully synthesized and polymerized using (nbd)Rh+[η6-C6H5B−(C6H5)3] as catalyst. Circular dichroism (CD) and ultraviolet–visible (UV–Vis) spectra revealed that the polymers took predominantly one-handed helical structures that were stable under heat. Deprotection of the t-butyloxycarboryl (Boc) groups in the homopolymers under acidic conditions produced polymers with primary amine moieties on the side chains. The polymers were soluble in aqueous medium, and turbidity test revealed that they were pH-responsive. Amino acid-based polymers were further used in the enantionselective crystallization of alanine enantiomers and L-alanine was preferably induced to crystallize with the L-leucine-based polymer. Keywords:

helical

polymer,

polyacetylene,

leucine,

pH-responsive,

ACCEPTED MANUSCRIPT enantionselective crystallization 1. Introduction The helical structure is the most important structural motif in natural

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macromolecules, which can endow polymers with intricate biological activities1

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and sophisticated functions.2,3,4 Since the discovery of helical polypropylene

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with an isotactic structure,5 various types of helical polymers have been synthesized.6,7,8 Synthetic polymers attract more attention, because they can not only imitate natural polymers in many ways, but also assume various forms

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and structures, such as homopolymers,9 random copolymers,10 graft copolymers,11 and block copolymers.12 Among those synthetic helical

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polymers, polyacetylenes together with other conjugated polymers such as polyisocyanides13 and polysilanes14 have attracted more research interest,

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predominantly because of their unique functions based on their helical

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conformations as well as conjugated structures. Earlier studies demonstrated that polyacetylenes have good liquid crystalline properties,15,16 electrical

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conductivity,17 biological compatibility,18 and stimulus responsiveness.19,20 In addition, the introduction of specially designed functional groups into the polyacetylene backbones always endows the polymers with a wide variety of

such

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specific functions.21 So far, there have been many kinds of polyacetylenes as

polyphenylacetylene,22

poly

(N-propargylsulfamides)23

and

poly(N-propargylamides).24 In 2007, Sanda and Masuda’s group found that chiral 1-methylpropargyl alcohol is a simple and powerful helical source for substituted polyacetylenes,25 and they synthesized poly(1-methylpropargyl alcohol) derivatives containing carbazole and ferrocene groups.26,27 In the past few decades, there has been significant interest in polymers with amino acid groups on either the main chains or side chains.28,29 Amino acids are central components of proteins,3 and the primary structures of proteins are formed by covalent linkage of amino acids. Synthetic polymers with amino acids and peptide residues are of utmost importance, because the introduction of amino acid groups to polymers not only induces an ordered regular structure

ACCEPTED MANUSCRIPT and improves the polymers’ solubility in water through inter- or intramolecular noncovalent bonding such as hydrogen bonding, hydrophobic stacking, and electrostatic interactions, but also induces other properties such as optical

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activity9 and stimulus responsiveness30 to the polymers. In 2013, De’s group found that the homopolymer of Boc-L/D-leucine methacryloyloxyethyl ester

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and its copolymer with 2-(2-methoxyethoxy)-ethyl methacrylate exhibit dual pH and temperature response. The homopolymer also shows a chiral recognition ability toward racemic 1,1’-bi-2-naphthol.

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This study deals with the synthesis and polymerization of 1-methylpropargyl alcohol derivatives containing leucine side groups on their side chains.

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Polymers with leucine side chains are of paramount importance because of their hydrophobicity and reported role in the formation of α-helical structures.19,30

polymers

have

been

synthesized

by

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Leucine-based

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conventional free-radical polymerization and living polymerization. In this study, coordination polymerization was achieved using (nbd)Rh+[η6-C6H5B−(C6H5)3]

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as catalyst. The free amine in the resulting polymer endowed the polymer with pH responsiveness, and such pH-responsive polymer may find a potential value in the fields of self-healing materials31 and environment-responsive

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gels.32 Similarly to some other helical polymers,33,34 the leucine-based polymer can be used as a chiral inducer of enantionselective crystallization, using alanine as the racemic compounds. 2. Experimental Section 2.1 Materials 3-Butyn-2-ol

(Alfa

Aesar),

Boc-L-leucine

4-dimethylaminopyridine

(TCI),

Boc-D-leucine

(DMAP,

1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride

(TCI),

Aladdin), (EDC·HCl,

Aladdin) and alanine (Alfa Aesar) were used as-received. Solvents were distilled by the standard methods, and (nbd)Rh+[η6-C6H5B−(C6H5)3] was prepared as reported in ref. [35]. 2.2 PhysicoChemical Characterization

ACCEPTED MANUSCRIPT Molecular weight (Mn) and molecular weight distribution (PDI, Mw/Mn) were determined by gel permeation chromatography (GPC) on a Waters 515-2410 system (using tetrahydrofuran (THF) as eluent; calibrated by polystyrene

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standards). 1H nuclear magnetic resonance (NMR) spectra were recorded on a Bruker AV400 spectrometer. Fourier transform infrared (FTIR) spectra were

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recorded on KBr pellets using a Bruker TENSOR 27 FTIR spectrometer (Bruker, Germany). Circular dichroism (CD) and UV–Vis spectra were recorded on a Jasco J-810 spectropolarimeter. Elemental analysis was

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conducted on a Thermo Flash EA1112 elemental analyzer (Thermo Fischer Scientific, Italy). Positive-mode electrospray ionization-mass spectrometry

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(ESI–MS) was performed on a Kevo G20-TOF-MS system (Waters Corporation). Specific rotations ([а]D) were determined on a Jasco P-1020

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digital polarimeter with a sodium lamp as light source. Scanning electron

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microscope (SEM) images were obtained with an S-470 scanning electron microscope. Size analysis was carried out using a dynamic light scattering

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instrument (DLS) (Malvern Instruments Ltd, Nano-ZS90). X-ray diffraction (XRD) analyses were performed using a Shimadzu XRD-6000 diffractometer. 2.3 Synthesis

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2.3.1 Monomer Synthesis 1-Methylpropargyl Boc-leucine esters were prepared through an esterification process. Let us take L-leucine-based ester (monomer 1) for example. Boc-L-leucine (1.632 g, 7.056 mmol) was added to CH2Cl2 (30 ml) in an ice water bath under stirring for 10 min. Then EDC·HCl (1.624 g, 8.471 mmol) and DMAP (0.086 g, 0.705 mmol) were added one by one to the solution, and the resulting mixture was stirred at 0°C under dry N2. After 15 min of stirring, 3-butyn-2-ol (0.83 ml, 10.586 mmol) was added dropwise for 10 min, and the resulting solution was stirred at room temperature for 24 h. The reaction mixture was washed with 1 N HCl, saturated aqueous NaHCO3 solution, and water sequentially. Afterward, the organic layer was dried over anhydrous MgSO4, filtered, and concentrated to obtain the target monomer. For further

ACCEPTED MANUSCRIPT purification, the monomer was recrystallized from hexane thrice. The monomer was obtained as a white powder with 30% yield. D-leucine-based ester (monomer 2) was synthesized similarly to monomer 1.

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In this case, the monomer was obtained as a white powder with 35% yield. 2.3.2 Polymerization

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The polymerization reaction was carried out with (nbd)Rh+[η6-C6H5B−(C6H5)3] as catalyst under nitrogen protection. Let us take L-leucine-based polymer (Poly(1)) for example. Monomer 1 (0.2 g, 0.71 mmol) was added to 1 ml of THF,

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and the mixture was stirred in dry N2 at room temperature for 10 min. Then (nbd)Rh+[η6-C6H5B−(C6H5)3] (0.0073 g, 0.0142 mmol) dissolved in 1.0 ml of

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THF was injected to the solution. The resulting mixture was kept at 40°C for 12 h. After polymerization, the resulting mixture was poured into a large amount of

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heptane to precipitate the formed polymer, which was then separated by

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filtration with a membrane filter and dried under reduced pressure. The polymer was obtained as a yellow powder with 80% yield.

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D-leucine-based polymer (Poly(2)) was synthesized similarly to Poly(1) with a yield of 85%.

2.3.3 Deprotection of Boc-Protected Polymer

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Deprotection of Boc-protected polymers was conducted in trifluoroacetic acid (TFA)/CH2Cl2 solution to obtain amino acid-based polymers with primary amino functional groups. Typically, 1.0 ml of TFA was added to a solution of the polymer (0.1 g) in 1.5 ml of CH2Cl2 in a 25-mL round-bottom flask. Then, the solution was stirred in an ice water bath for 1.5 h. After the deprotection reaction, the mixture was diluted with some CH2Cl2 and concentrated by a rotary evaporator several times to remove the residual TFA. Afterward, the product was precipitated with a large amount of hexane, separated by filtration with a membrane filter, and dried under vacuum at 45°C for 4 h. The polymer was obtained as a pale-yellow powder with 90% yield. 2.4 Enantioselective Crystallization Approximately 5 mg of the amino acid-based polymer was added to a

ACCEPTED MANUSCRIPT supersaturated alanine aqueous solution (0.2 g/ml, 35°C) and stirred for 1 h. Then, the resulting mixture was cooled to 0°C. After 4 days, the crystals were extracted, separated by filtration with a membrane filter, and subjected to

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characterization. 3. Results and Discussion

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3.1 Monomer Synthesis

1-Methylpropargyl Boc-leucine ester monomers were synthesized through the esterification of Boc-L/D-leucine with 3-butyn-2-ol using DMAP as catalyst and

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EDC·HCl as condensation agent. The structures of the monomers were confirmed by 1H NMR, FTIR spectra, mass spectrometry, and elemental

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analysis.

Monomer 1: 1H NMR (CDCl3, δ, ppm) (Fig. 1): δ = 0.976 (6H, CH3), 1.472 (9H,

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CH3), 1.551 (3H, CH3), 1.629 (1H, CH ), 1.756 (2H, CH2), 2.467 (1H, HC≡C),

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4.321 (H, CH). FTIR (cm−1) (Fig. S1): 1702 (C=O), 2118, 3312 (C≡C), 3228 (N–H). ESI–MS: observed for [1a + Na+] = 306.17 m/z; calculated for [1a + Na+]

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= 306.38 m/z. [а]D = -67° (determined in CHCl3 at room temperature, c = 0.1 g/dL)

Monomer 2: 1H NMR (CDCl3, δ, ppm) (Fig. S2): δ = 0.974 (6H, CH3), 1.469 (9H,

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CH3), 1.549 (3H, CH3), 1.626 (1H, CH ), 1.753 (2H, CH2), 2.468 (1H, HC≡C), 4.318 (H, CH), 4.882 (1H, CH). ESI–MS: observed for [1a + Na+] = 306.21 m/z; calculated for [1a + Na+] = 306.38 m/z. [а]D = +99° (determined in CHCl3 at room temperature, c = 0.1 g/dL) 3.2 Polymerization and Secondary Structure of Formed Polymer A large number of transition metal catalysts are available for the polymerization of substituted acetylenes. Of them, Rh catalysts tolerate a wide range of functional groups, and the cis- and transoid isomers can be selectively obtained.

The

polymerization

was

thus

conducted

with

(nbd)Rh+[η6-C6H5B−(C6H5)3] as catalyst in THF at 40°C for 12 h. Polymers with moderate Mn (2 × 104–3 × 104) and PDI (1.40–1.80) with high yields (80–85%) were obtained. Let us take Poly(1) for example. The 1H NMR spectrum (Fig. 1)

ACCEPTED MANUSCRIPT shows a signal corresponding to the olefinic proton (δ = 6.5) of the main chain and no signal attributed to ethynyl protons (δ = 2.5) could be observed. The FTIR spectra (Fig. S3) of the polymers also confirm the formation of

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substituted polyacetylenes. The formed polymers were soluble in a wide variety of organic solvents such as CHCl3, THF, toluene, methanol (MeOH)

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and dimethylformamide (DMF), but insoluble in nonpolar solvents such as hexane and heptane.

Poly(1) and Poly(2) showed [а]D values of +719° and −667°, respectively. The

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amplification effect in the [а]D of polymers compared with their corresponding monomers was attributed to their helical structures. 30 The secondary

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structures of Poly(1) and Poly(2) were also examined by CD and UV–Vis spectroscopy. According to the previous studies, helical monosubstituted

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polyacetylenes exhibited prominent UV–Vis signals between 300 and 400

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nm.25 For one-handed helical polyacetylenes, large CD absorption peaks were also observed at the same position. Figure 2 depicts the CD and UV–Vis

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spectra of polymers measured in CHCl3. The prominent CD and UV–Vis signals around 350 nm reveal that the polymers have predominantly one-handed helical structures. Poly(1) and Poly(2) exhibit mirrored CD signals

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(Fig. 2) and opposite optical rotations to each other. Those results demonstrate that Poly(1) and Poly(2) have opposite helical structures and their helix sense is determined by the chiral groups in leucine side groups. We further examined the solvent stability of the helical structures formed by those polymers. Let us take Poly(1) for example, which shows intense CD and UV–Vis signals in the absorption region in solvents with different polarities and hydrogen-bonding abilities (Fig. 3). The fact that the helical structure of Poly(1) is hardly affected by the solvent shows that the helical structure is probably formed by steric effect rather than hydrogen bonding. The hydrophobic interactions derived from the leucine moieties may also facilitate the helical conformation of polymers.30 In order to confirm this conclusion, we examined the effect of MeOH content on the stability of the helical structure. As shown in

ACCEPTED MANUSCRIPT Figure 4, the CD and UV–Vis signals change only slightly with the increase of MeOH content. Thus, we can conclude that solvent polarity and hydrogen bonding ability have a weak effect on the stability of the helical structure.

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Further, we studied the thermal stability of the helical conformations. As depicted in Figure 5, the intensities of the peaks in the CD and UV–Vis spectra

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measured in DMF are almost independent of temperature from 0°C to 80°C, indicating that the helical structure was thermally stable. The ester groups in Poly(1) probably do not interact sharply with the solvent; thus, there are almost

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no intermolecular forces that can be affected by the solvent temperature. Furthermore, the shielding effect from the bulky side groups and the

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hydrophobic interactions of the leucine moieties can effectively maintain the helical conformation.

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3.3 Deprotection of Boc-Protected Polymer

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Deprotection of Boc-protected polymers was conducted in TFA/CH2Cl2 solution to obtain Poly(1)’ and Poly(2)’. The disappearance of the Boc signal (δ

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= 1.30) in the 1H NMR spectra (Figs. 6 and S7) indicates the removal of the Boc groups. After Boc deprotection, polymers with primary amine functional groups were obtained. Figure 7 depicts the pH dependence of the CD and spectra of Poly(1)’ measured in deionized water. The obvious

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UV–Vis

decrease of the CD and UV–Vis signals with decreasing pH indicates the change of helical structure, probably because the amino groups of poly(1)’ interact significantly with the hydrogen protons in water. 3.4 pH Responsiveness pH-Responsive polymers contain ionizable pendants that can accept and donate protons; thus, they are responsive to pH changes. We hypothesized that the primary amine functional groups in Poly(1)’ impart the pH responsiveness to the polymer. A turbidity test using the UV–Vis spectrum was carried out to verify this hypothesis. The polymer (0.1 wt%) was dissolved in deionized water, and the pH was adjusted by adding 0.05 N HCl or 0.05 N NaOH. As shown in Figure 7, the CD and UV–Vis signals weaken with

ACCEPTED MANUSCRIPT decreasing pH below 5.80. Furthermore, no signal appears in the spectra at pH > 6.01. The primary amine groups on the side chains are probably protonated and become hydrophilic under acidic conditions.27 Figure 8(a)

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depicts the effect of pH on the UV–Vis signals of the polymer at 600 nm. A phase transition occurs between pH 5.80 and 6.01. Size analysis (see Fig. 8(b))

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also confirmed the conclusion. The phase transition is reversible and can be attributed to the protonation and deprotonation of the primary amine groups. 3.5 Enantioselective Crystallization

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As a chiral material, the leucine-based polymer has several potential applications. In this part, we used the leucine-based polymer as the chiral

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inducer of enantionselective crystallization, using alanine as racemic compounds (Scheme. 2).

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SEM images (Fig. 9(a)) show that L-alanine was preferably induced to

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crystallize with Poly(1)’ as additive to form rodlike crystals. In the cases without the addition of polymers, only disordered crystals were formed. In order to

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further study this phenomenon, we characterized those crystals with CD spectroscopy. As shown in Figure 10, the signals at 205 nm confirmed the existence of chiral alanine. The L-alanine can induce a positive signal, while

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the D-alanine can cause a negative signal. The [а]D of alanine crystals induced by Poly(1)’ was +5.5°, while the crystals obtained with Poly(2)’ had an [а]D of approximately −4.7°. Thus, we can conclude that Poly(1)’ and Poly(2)’ served as chiral inducers of racemic alanine. Let us take Poly(1)’ for example. At the beginning of crystallization, Poly(1)’ preferred to absorb L-alanine on its surface. Then, the mixture further acted as a nucleation chamber for subsequent enantioselective crystallization to separate more L-alanine. The crystals obtained through enantioselective crystallization were further subjected to XRD analyses. The resulting XRD patterns (Figs. S9 and S10) show that the chiral crystals obtained via enantioselective crystallization exhibit signals similar to those of pure L-alanine and D-alanine crystals, supporting the conclusion that Poly(1)’ and Poly(2)’ served as chiral inducers of racemic

ACCEPTED MANUSCRIPT alanine.

Conclusion

was

successfully

synthesized

and

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A novel 1-methylpropargyl alcohol derivative containing leucine side groups polymerized

using

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(nbd)Rh+[η6-C6H5B−(C6H5)3] as catalyst. Polymers with moderate molecular weights (2 × 104–3 × 104) and polydispersity indices (1.40–1.80) could be obtained with high yields (80–85%). CD and UV–Vis spectra indicated that the

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polymers took predominantly one-handed helical structures with high thermal stability. Deprotection of the Boc groups in the homopolymers under acidic

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conditions produced polymers with primary amine moieties on the side chains. The polymers were soluble in acidic water and exhibited pH-responsiveness.

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In addition, the leucine-based polymers can also be used as chiral inducers of

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enantionselective crystallization, using alanine as racemic compounds. The monomer containing amino acid groups has many potential applications. It can

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copolymerize with other monomers to produce polymers with abilities to self-assemble

and

which

can

also

be

used

as

raw material for

environment-responsive gels.

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Acknowledgment

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[33] B. Chen, J.P. Deng, X. Cui, W.T. Yang, Optically active helical substituted

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polyacetylenes as chiral seeding for inducing enantioselective crystallization of racemic N-(tert-Butoxycarbonyl)alanine, Macromolecules. 44 (2011) 7109-

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[34] W.F. Li, J.Y. Liang, W.T. Yang, J.P. Deng, Chiral functionalization of

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graphene oxide by optically active helical-substituted polyacetylene chains and its application in enantioselective crystallization, ACS Appl. Mater. Interfaces, 6

[35]

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(2014) 9790-9798. R.R.

Schrock,

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Osborn,

.pi.-Bonded

complexes

of

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tetraphenylborate ion with rhodium (I) and iridium (I), Inorg. Chem. 9 (1970) 2339-2343.

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Fig.1. 1H NMR spectra of monomer 1 and Poly(1), measured in CDCl3

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Fig.2. CD and UV–Vis spectra of Poly(1) and Poly(2), measured in CHCl3 at

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room temperature (C = 0.1 mM)

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Fig.3. CD and UV–Vis spectra of Poly(1), measured in various solvents at

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room temperature (C = 0.06 mM)

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Fig.4. CD and UV–Vis spectra of Poly(1), measured in mixtures of CHCl3 and

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MeOH at room temperature (C = 0.025 mM)

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Fig.5. Temperature dependence of CD and UV–Vis spectra of Poly(1),

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measured in DMF (C = 0.05 mM)

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Fig.6. 1H NMR spectra of Poly(1) and Poly(1)’, measured in CDCl3 and DMSO,

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Fig.7. pH Dependence of CD and UV–Vis spectra of Poly(1)’, measured in

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deionized water(C = 0.05 mM)

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Fig. 8. Effect of pH on the (a) intensities of UV–Vis signals at 600 nm and (b)

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Fig.9. SEM images of the crystals formed by alanine via enantioselective crystallization without polymers (a), with Poly(1)’ as additive (b), and with

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Poly(2)’ as additive (c)

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Fig.10. CD and UV–Vis spectra of the crystals formed by alanine via enantioselective crystallization without polymers (a), with Poly(1)’ as additive

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(b), and with Poly(2)’ as additive (c)

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Scheme. 1. Synthesis and polymerization of amino acid-based monomers,

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followed by deprotection of Boc groups

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Scheme. 2. Enantioselective crystallization

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