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Article Cite This: Macromolecules 2018, 51, 8248−8257

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Functional Polyamides: A Sustainable Access via Lysine Cyclization and Organocatalytic Ring-Opening Polymerization Wenjing He,†,‡ Youhua Tao,*,†,‡ and Xianhong Wang†,‡ †

Key Laboratory of Polymer Ecomaterials and, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Renmin Street 5625, Changchun 130022, P. R. China ‡ University of Science and Technology of China, Hefei 230026, P. R. China

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S Supporting Information *

ABSTRACT: Functional polyamides are very important polymers that have a variety of valuable applications. However, the effective synthesis of these polymers is still a long-going challenge. Herein, the efficient cyclization of lysine derivative was presented as a universal approach to synthesize ε-lactam monomers bearing pendant benzyl-protected hydroxyl, allyloxy, and oligo-ethylene glycol groups. Superbase tBuP4-catalyzed polymerization could proceed under very mild conditions (e.g., 25 °C) compatible with a wide range of functional pendants, affording high molecular weight (up to 47.7 kg/mol) functional polyamides with high monomer conversion (up to 99%). Of importance, the allyloxy groups were stable toward the initiating and propagating species under mild polymerization conditions. Such an allyloxy-functionalized ε-lactam and organocatalytic polymerization to well-defined allylated polyamide has not been reported in the literature and allows further incorporation of an unprecedented range of functional groups onto polyamides through the thiol−ene click reaction. The resulting functional polyamides demonstrated variable glass transition temperatures, had minimal cytotoxicity to HeLa cells, and exhibited the ability to form nanostructures in aqueous solution, suggesting their great potential for biomedical applications.

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INTRODUCTION Synthetic polyamides (PAs, also known as nylons) that mimic structural motifs of naturally occurring proteins show tremendous potential as biomedical material for their therapeutic potential, biodegradability, low toxicity, and tunable mechanical properties.1−10 As one important member of polyamide family, poly(ε-caprolactam) (PCL) is a high performance semicrystalline thermoplastic with large industrial applications.11−13 It has typically been produced by ringopening polymerization (ROP) of ε-caprolactam.14−18 Decisive advantages of poly(ε-caprolactam) for uses in biological and medical applications in comparison with e.g. poly(lactic acid) and poly(ε-caprolactone) are their remarkable combination of excellent mechanical strength, flexibility, toughness, and structural similarity to peptides (amide bonds).19 In addition to the classic poly(ε-caprolactam), Rieger and Winnacker have recently reported the synthesis of renewable poly(ε-caprolactam) starting from the bio-based terpenoid.20−23 Despite their great potential, the biomedical applications of poly(ε-caprolactam) suffer from one critical issue. It is desirable to have poly(ε-caprolactam) encoding a wide variety of functional pendants to expand its versatility and tune properties such as crystallinity, hydrophilicity, and biodegradability or to further conjugate biomacromolecules and fluorescence probes pendant to the backbone.24,25 The very limited pendant diversity of poly(ε-caprolactam) hampered the © 2018 American Chemical Society

investigation of its potential biological and medical applications: most reported examples were simple carboxyl or hydroxyl groups appended to the backbone, as shown in Scheme 1.25−29 This limitation in functionality was related to constraints on ε-lactam derivatives synthesis and harsh polymerization conditions. First, the most convenient strategy Scheme 1. Functional ε-Caprolactam Monomers Reported in the Literature

Received: August 18, 2018 Revised: September 24, 2018 Published: October 10, 2018 8248

DOI: 10.1021/acs.macromol.8b01790 Macromolecules 2018, 51, 8248−8257

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Scheme 2. Lysine Derivative Cyclization and Organocatalytic Ring-Opening Polymerization for the Synthesis of Functional Polyamides

Scheme 3. Synthesis of Functional ε-Lactam Monomersa

Reagents and conditions: (i) NaNO2, AcOH/H2O, 0−25 °C, K2CO3, MeOH; (ii) SOCl2, MeOH, 0 °C; (iii) H2, Pb/C, MeOH, rt; (iv) NaOH, MeOH, rt; (v) NaH, anhydrous THF, 0 °C−rt; (vi) t-BuOK, anhydrous DMF, 0 °C−rt. Using NaH, OEGCL was obtained in 140 °C) due to the low polymerizability of ε-lactams.32−34 These temperature requirements greatly compromised the functional group scope. At high temperatures reactive functional groups, including alkenes, could not guarantee high stability. Therefore, an

efficient and modular synthetic strategy to a wide variety of functional ε-lactams, and further implementation of their polymerization under mild conditions, might be preferable and open new horizons in the production of functional polyamides. Particularly, a general preparation scheme based on renewable sources would be beneficial.35−38 Lysine, one of the most sufficient amino acids, represents significant building blocks in the development of novel renewable materials.39−41 As part of our interests in functional ε-lactam monomers from renewable resources, we hypothesized that the delicate cyclization of lysine would lead to a structure which closely resembles ε-lactam, and this could be 8249


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Figure 1. 1H NMR spectra of (A) BnOCL, (B) AylOCL, and (C) OEGCL in CDCl3 at 25 °C.

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applied in rational design of functional ε-lactams which might lead to interesting findings. In addition, Hedrick et al. pioneered the development of organocatalytic ROP to overcome the limitations of metal or enzyme catalysts.42 Indeed, considering the biomedical applications, it would be desirable that functional poly(ε-caprolactam) could be produced by organocatalytic (metal free) ROP. However, very few organocatalytic procedures to obtain functional poly(ε-caprolactam) have previously been reported.43 We have recently demonstrated the cyclization reaction of biorenewable lysine for the synthesis of a ε-lactam monomer with a protected amino group.40,43,44 ROP of the obtained monomer, followed by deprotection, resulted in the polyamides with pendant amines [poly(ε-lysine)]. To further realize the structural diversity and tune the performance of polyamides, we herein conducted similar cyclization of lysine derivative to synthesize a set of ε-lactam monomers bearing pendant benzyl-protected hydroxyl, allyloxy, and oligo-ethylene glycol groups by further evolving the method we reported previously (Scheme 2). Organocatalytic polymerization of the ε-lactam monomers was performed using phosphazene base tBuP4 as a catalyst in THF at 25 °C and furnished a series of functional polyamides with molecular weight higher than 47 kg/mol. Particularly, the resultant allylated polyamides further enabled facile incorporation of a wide range of functional pendants onto polyamides.

RESULTS AND DISCUSSION Monomer Synthesis. One aspect of this work was to synthesize the functional ε-lactam monomers using sustainable lysine as a feedstock. Our group has reported the cyclization reaction of lysine and catalytic ROP processes to prepare poly(ε-lysine), wherein α-amino-ε-caprolactam was achieved as a intermediate (Scheme 2A).43,44 However, the special amino protecting groups (e.g., 2,5-dimethylpyrrole) have limited the utility of this intermediate. Here, we focused on a hydroxyl-functionalized intermediate, α-hydroxyl-ε-caprolactam (Scheme 2B). We also used inexpensive lysine as starting materials since its α-amino groups can be readily converted to hydroxyl groups.45,46 Hydroxyl lysine methyl ester was prepared from the Nε-carboxybenzyl (Cbz) protected lysine, as shown in Scheme 3. This derivative was then directly converted to α-hydroxyl-ε-caprolactam, in the presence of sodium hydroxide, with no complications arising from the hydroxyl functionality. Benzyl-protected hydroxyl-substituted ε-lactam (BnOCL) was then prepared by nucleophilic substitution reaction of α-hydroxy-ε-caprolactam with benzyl bromide, followed by column chromatography purification and recrystallization (Scheme 3). After recrystallization, BnOCL turned to a white solid with isolated yield of ∼50%. 1H NMR, 13 C NMR, and ESI-MS confirmed the monomer structure (Figure 1A, Figures S5 and S8). Figure 1A exhibits the 1H NMR spectrum of BnOCL monomer, which displays characteristic resonances of benzyloxy group and caprolactam moiety. The characteristic signals of methylene of a benzyloxy 8250


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Macromolecules Table 1. Results of Ring-Opening Polymerization of Functional ε-Lactam Monomersa entry

monomer

catalyst (C)

[M]:[C]:[I]

[M] (mol/L)

T (°C)

t (h)

convb (%)

Mnc (kg/mol)

Đ (Mw/Mn)c

1 2 3 4 5 6 7 8 9 10 11 12 13 14

BnOCL BnOCL BnOCL BnOCL BnOCL BnOCL BnOCL BnOCL BnOCL BnOCL BnOCL BnOCL AylOCL OEGCL

t-BuP4 t-BuP4 t-BuP4 t-BuP4 t-BuP4 t-BuP4 t-BuP4 t-BuP4 t-BuP4 t-BuP4 t-BuP2 t-BuP2 t-BuP4 t-BuP4

25:1:1 25:1:1 25:1:1 25:1:0.5 25:1:2 10:1:1 50:1:1 50:1:1 100:1:1 150:1:1 25:1:1 100:1:1 25:1:1 25:1:1

3 3 3 3 3 3 3 5 5 5 3 5 5 3

25 25 25 25 25 25 25 60 60 60 25 60 25 25

6 1 3 6 6 6 6 6 12 12 6 12 6 6

98 65 88 91 99 99 65 86 66 42 57 18 53 98

8.8 7.1 7.3 15.0 7.1 6.1 20.5 29.8 37.0 47.7 4.9 5.6 9.0 6.8

1.42 1.48 1.42 1.29 1.26 1.32 1.34 1.36 1.17 1.31 1.38 1.41 1.40 1.32

Polymerization: monomer and co-initiator (I) were mixed first, followed by catalyst. bThe conversion could be measured from the peak intensity ratio of the Cα−H resonance at 3.8 ppm of polymer to the corresponding monomer at 4.1 ppm. cMeasured by SEC at 50 °C in DMF (0.01 M LiBr), polystyrene as standard.

a

Figure 2. 1H NMR spectra of (A) poly(BnOCL), (B) poly(AylOCL), and (C) poly(OEGCL) in CDCl3 at room temperature. Polymers were prepared by [M]:[C]:[I] = 25/1/1 at 25 °C.

Overall, the lysine cyclization strategy toward functional εlactam monomers was performed under mild reaction conditions and thus avoided interference to the functional groups. ROP of Functional ε-Lactam Monomers. Among all organic catalysts, commercially available phosphazene bases are known as one category of the most efficient organocatalysts for ROP of cyclic esters,47−49 cyclosiloxanes,50 and epoxides.51−56

group at 4.4−4.8 ppm along with diagnostic resonance are attributable to the methylene protons next to amide bond at 3.1, 3.5, and 4.1 ppm, confirming successful synthesis of target molecule. The allyloxy and oligo-ethylene glycol (OEG)functionalized ε-lactams were synthesized upon substitution with their corresponding bromides (Scheme 3). The structures of AylOCL and OEGCL were identified by 1H NMR, 13C NMR, and ESI-MS (Figures 1B and 1C, Figures S6−S8). 8251


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Macromolecules Especially, the phosphazene base t-BuP4, [1-tert-butyl-4,4,4t r i s ( d i m e t h y l a m i n o ) - 2 , 2 -b i s [ t r i s ( d i m e t h y l a m i n o ) phosphoranylidenamino]-2γ 5 ,4γ 5 -catenadi(phosphazene)], which is one of the strongest organic bases with low nucleophilicity,57 has been shown to be effective for the ROP of ε-lactams producing polyamides.34,43 However, harsh polymerization conditions (>140 °C) were required because of low polymerizability of ε-lactams. This temperature requirement greatly compromised the functional group scope. At high temperatures reactive functional groups, including alkenes, could not guarantee high stability. It is desired that the polymerization is performed under mild conditions. Here, tBuP4 was initially tested in the ROP of BnOCL at 25 °C with N-benzoyl-α-benzyloxy-ε-caprolactam (N-BzCL) as co-initiator ([BnOCL]/[t-BuP4]/[N-BzCL] = 25/1/1) in THF. Pleasingly, the ROP proceeded smoothly, achieving 98% conversion at 6 h, providing poly(BnOCL) with Mn of 8.8 kg mol−1 and Đ (Mw/Mn) of 1.42 (Table 1, entry 1). This result was in contrast to the case observed for t-BuP4-catalyzed synthesis of polyamides with pendent amines,43 in which polymerization with 95% conversion must be proceeded under relatively higher temperature (>140 °C), probably owing to the less steric hindrance of pendant groups in BnOCL. Encouraged by the promising initial result, we investigated the ROP of functional ε-lactams by t-BuP4 in more detail. First, the effect of the polymerization time was studied (Table 1, entries 1−3). The raise of time resulted in higher conversion, and the optimal polymerization time was 6 h. Second, enhancing the co-initiator-to-catalyst ratio ([I]/[C]), the conversion increased from 91% to 99% (Table 1, entries 1, 4, and 5) with a reduce in Mn from 15.0 to 7.1 kg mol−1. On the other hand, reducing the monomer-to-catalyst ratio ([M]/ [C]) from 50/1 to 25/1 to 10/1 led to the improvement of conversion (Table 1, entries 1, 6, and 7). Particularly, when [M]/[C] was 10/1, conversion as high as 99% was obtained. Correspondingly, as was similarly demonstrated in the other tBuP4-mediated system, the Mn decreased from 20.5 to 6.1 kg mol−1 by reducing the [M]/[C]. Third, the impact of temperature on the polymerization was investigated. The monomer conversion increased with temperature increasing from 25 to 60 °C (Table 1, entries 7−10). At 60 °C, we were pleased to observe poly(BnOCL) with a Mn = 47.7 kg/mol, and a Đ value = 1.31 was achieved. Fourthly, the basicity of the catalysts had a significant effect on the polymerization. Under equal conditions, t-BuP2 (pKa = 21.5 in DMSO) with weaker basicity decreased the conversion by ∼50% (Table 1, entries 1 and 11, entries 9 and 12) in comparison with that by t-BuP4 (pKa = 30.2 in DMSO). A similar trend in phosphazenecatalyzed γ-butyrolactone ROP was also observed by Chen et al.58 The structure of poly(BnOCL) was confirmed by 1H NMR, 13C NMR, 1H−1H COSY NMR, and MALDI-TOF-MS (Figures 2A and 3, Figures S9 and S12). The ROP was confirmed by the observation of the reduction of the Cα−H resonance at 4.1 ppm of the monomer and the appearance of the corresponding broadened multiplets at 3.8 ppm of the polymer using 1H NMR spectroscopy. In addition, besides the major peaks attributed to the repeating units of the monomer, minor signals originating from co-initiator were also seen. The benzoyl groups of the co-initiator at the α-end were observed at 7.8 ppm. The MALDI-TOF MS spectrum displayed a series of peaks separated by a 219.3 Da interval, corresponding exactly to molar mass of the repeat unit (Figure 3). The intercept of the plot, 122.1, accounting for the total mass of

Figure 3. Analysis of poly(BnOCL) by MALDI-TOF-MS spectra. SEC curves and Mn of poly(BnOCL) and Mn vs repeated unit number plots are inserted. The polymer was prepared by [M]:[C]:[I] = 25/1/ 1 at 25 °C.

chain ends plus the mass of Na+ [Mend = 99.1 (PhCO/OH) + 23.0 (Na+) g/mol], demonstrated the polymer possessing one benzoyl unit at the initiating terminal and a −COOH unit at the capping terminal. In addition, the MALDI-TOF MS result also illuminated that there were no side reactions during the ROP process and was in contrast to the case observed for tBuP4-mediated synthesis of polyamides with pendent amines,43 in which the MALDI-TOF MS spectrum consisted of two series of peaks. It should be noted that the acylated lactam chain ends of polyamides could be converted to carboxy groups almost quantitatively by quenching in benzoic acid solution. Overall, via the superbase-catalyzed polymerization of functional ε-lactam monomers, we have provided a sustainable and mild method toward more facile production of functional polyamides. A remarkable characteristic of our strategy is to offer manifold opportunities to implement ROP of a wide range of functional ε-lactams under very mild conditions. We first conducted the t-BuP4-mediated ROP of AylOCL under similar conditions (Table 1, entry 13). This resulted in polyamide with terminal alkenes on its side chains, enabling further functionalization via various transformations. The obtained poly(AylOCL) demonstrated Mn of 9.0 kg/mol and Đ of 1.4, as determined by SEC. All the 1H NMR, 13C NMR, and 1 H−1H COSY NMR spectra suggested that the allyloxy groups were stable toward the initiating and propagating species under mild polymerization conditions (Figure 2B, Figures S10 and S13). Such an allyloxy-functionalized ε-lactam and organocatalytic polymerization to well-defined allylated polyamide has not been reported in the literature and facilitates its further functionalization by various transformations. We also applied the OEG-functionalized ε-lactam for organocatalytic polymerization, applying the optimized polymerization conditions. This resulted in polyamide (Mn = 6.8 kg/mol, Đ = 1.32, Table 1, entry 14) with hydrophilic side chains, facilitating its future application. The 1H NMR, 13C NMR, and 1H−1H COSY 8252


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soluble in CHCl3 but was insoluble in water. However, poly(HOCL) showed opposite solubility in those solvents; it was slightly soluble in MeOH and water but insoluble in CHCl3. To confirm the integrity of the polyamide backbone upon hydrogenolysis, poly(HOCL) was retreated under the same deprotection conditions for another 24 h to allow for SEC measurements. The SEC plots of poly(HOCL) after retreatment showed similar peak shape and elution time with that of poly(HOCL), which suggested the minimal impact of hydrogenolysis on the polyamide backbone (Figure 4B). Thermal Properties of the Polymers. The obtained functional polyamides were investigated by thermal gravimetric analysis (TGA), and the data are collected in Table S1. In contrast to conventional polyamides, these functional polyamides exhibited lower decomposition temperature, probably owing to the pyrolysis of pendant functional groups.25,68 Figure 5 shows the DSC curves of various functional polyamides. Poly(BnOCL) had a Tg of 22.2 °C. After the deprotection of benzyl groups, poly(HOCL) exhibited higher Tg value of 53.4 °C. By contrast, poly(OEGCL) displayed Tg value of −12.7 °C because of its flexible OEG side chains. Glucose-modified P4 showed a Tg value of 42 °C, much higher than that of the unmodified poly(AylOCL) (5.5 °C), due to the bulky rigid glucose pendants. The Tgs of all these functional polyamides spanned an extended temperature range of roughly 66 °C, indicating the significant impact of pendant groups on the segment mobility of polyamides. In contrast to crystalline poly(ε-caprolactam), which has a melting peak around 220 °C,25 most of the functional polyamides do not show melting transition (Figure 5). This might be due to the introduction of side groups. In contrast, we were pleased to observe that poly(OEGCL) was semicrystalline polymer, and DSC curves showed obvious endothermic peaks at 70 °C (Figure 5 and Figure S24), probably because the hydrogen-bonding interactions between OEG pendants promoted the backbone packing.60

NMR spectra agreed with expected structure of poly(OEGCL) (Figures 2C, Figures S11 and S14). In brief, the organocatalytic ROP of 7-membered lactam building blocks is indeed a very powerful novel strategy for the synthesis of functional polyamides based on sustainable lysine. Thiol−Ene Postmodification. Thiol−ene chemistry has emerged as a general and very powerful tool for the functionalization of polymers.59−67 As shown in Scheme 4 Scheme 4. Thiol−Ene Addition of Poly(AylOCL)

and Table 2, we successfully conducted the thiol−ene reaction of an unprecedented range of functional thiols onto poly(AylOCL) through radical addition mechanisms by applying 2,2-dimethoxy-2-phenylacetophenone (DMPA) as a photoinitiator and a thiol/olefin ratio of 5:1, yielding functional polyamides P1−P6. In all cases, the thiol−ene addition onto poly(AylOCL) achieved >99% conversion over 4 h, with alkenyl peaks totally disappearing after reaction, as demonstrated by 1H NMR (Figures S17−S22). As expected, the SEC analysis showed an increase in molecular weight of P1−P6 as compared with that of poly(AylOCL) (Table 2). Deprotection of Benzyl Groups. The benzyl groups of the poly(BnOCL) were removed via Pd/C-mediated hydrogenolysis, resulting in polyamides bearing hydroxyl functionalities [poly(HOCL)]. 1H NMR results displayed the disappearance of all of the aromatic peaks at 7.3 ppm (Figure 4A), suggesting the complete deprotection. Further identification was achieved from the change in solubility of the deprotected polymer. Before deprotection, poly(BnOCL) was Table 2. Postmodification of Allylated Polyamidea

a

Conditions: 4 h, rt, hv, 365 nm, 36 W; [RSH]:[double bond] = 5:1; P1, P2, P3, P4, and P6 were performed in THF; P5 was performed in CH2Cl2. bDetermined by 1H NMR analysis. cDetermined by SEC at 50 °C in DMF (0.01 M LiBr), PS as standards. 8253


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Figure 4. (A) 1H NMR spectrum of poly(HOCL) in DMSO at 25 °C. (B) Overlay of GPC profiles of poly(BnOCL) (black), poly(HOCL) derived from the deprotection of the benzyl group of poly(BnOCL) in acetic acid under H2 in the presence of Pd/C catalyst (50 wt %) for 24 h (blue), and the poly(HOCL) (asterisk) derived from a further treatment of poly(BnOCL) under the same deprotection condition (solvent, catalyst, H2) for an additional 24 h (red).

Figure 6. Cell viability of poly(OEGCL) and P3 compared with PEG (5000 g/mol) as measured by MTT following treatment with polymers for 48 h. The error bars are the standard deviations of three evaluations.

polymer concentrations, revealing the poly(OEGCL) and P3 have excellent biocompatibility and can be applied as safe biomedical materials. Self Assembly of Amphiphilic Poly(OEGCL). One strategy commonly explored for hydrophobic drug delivery is the use of amphiphilic polymers that self-assemble into micelles. The resultant functional polyamide poly(OEGCL) is an amphiphilic polymer bearing hydrophilic OEG pendant groups and hydrophobic backbones. Thus, poly(OEGCL) can easily self-assemble into micelles in aqueous environments.

Figure 5. DSC profiles of various functional polyamides.

Cytotoxicity of Functional Polyamides. Poly(OEGCL) and P3 exhibited water solubility to some extent. In this context, we investigated the biocompatibility of poly(OEGCL) and P3 via the MTT assay. PEG (5000 g/mol) was used for comparison. As revealed in Figure 6, both poly(OEGCL) and P3 did not display toxicity to HeLa cells over a range of 8254


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The formation and morphology of micelles were identified by dynamic light scattering and transmission electron microscopy (Figure 7). The number-averaged hydrodynamic diameter of

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.macromol.8b01790. Experimental details and characterization data (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] (Y.T.). ORCID

Youhua Tao: 0000-0002-2138-2592 Xianhong Wang: 0000-0002-4228-705X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work is supported by the National Natural Science Foundation of China (Grants 21474101, 21805272, and 51873211) and the Jilin Science and Technology Bureau (Grants 20160414001GH and 20180201070GX). Helpful discussions with Dr. Chunsheng Xiao and Dr. Hui Yan at the same institute are gratefully acknowledged.

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Figure 7. Self-assembly of amphiphilic poly(OEGCL) into micelles. (A) Illustration on the formation of micelles. (B) TEM image of the micelle sample drop deposited from H2O onto a carbon-coated copper grid; scale bar = 100 nm. (C) Size distribution of micelle measured by DLS.

the micelles in H2O was 75.0 ± 7 nm. These results indicated amphiphilic poly(OEGCL) could be applied as potential vehicles for drug delivery.

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REFERENCES

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CONCLUSION

In summary, we have reported an efficient cyclization strategy for the synthesis of a new kind of functional ε-lactam monomers bearing pendant benzyl-protected hydroxyl, allyloxy, and oligo-ethylene glycol groups based on renewable lysine. Remarkably, the ROP of these functional ε-lactams was efficiently implemented at 25 °C using t-BuP4 as catalyst, achieving high monomer conversion and Mn up to 47.7 kg/ mol. Indeed, the very mild polymerization condition tolerant of a wide range of functional pendants did not interfere with the allyloxy groups. Moreover, the allylated polyamides also allow facile incorporation of various functional groups onto polyamides. Overall, this work not only offers an effective strategy toward new functional polyamides via the ROP of εlactam derivatives but also extends the scope of polyamide materials available for biomedical applications. 8255


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