Facile Organocatalyzed Synthesis of Poly(ε-lysine) - ACS Publications

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Facile Organocatalyzed Synthesis of Poly(ε-lysine) under Mild Conditions Jinlong Chen, Maosheng Li, Wenjing He, Youhua Tao,* and Xianhong Wang Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Renmin Street 5625, Beijing 130022, China S Supporting Information *

ABSTRACT: Functional poly(amino acid)s such as poly(ε-lysine) have many potential high-value applications. However, the effective chemosynthetic strategy for these materials remains a big challenge in polymer chemistry; the key issue is how to design and protect amino groups for the effective ring-opening polymerization (ROP). Our lab succeeded in chemosynthesis of poly(εlysine) via delicate design of a 2,5-dimethylpyrrole protecting group and metal-catalyzed ROP processes, but harsh reaction conditions (e.g., ca. 260 °C) were required. Herein, we developed a superbase t-BuP4-catalyzed ROP of ε-lactam derivatives, affording high molecular weight poly(ε-lysine) bearing pendant protected amino groups with high monomer conversion (up to 95%). The organocatalytic polymerization could proceed at low reaction temperature (e.g., 60 °C) compatible with readily removable protecting groups, providing a sustainable and new methodology toward facile preparation of poly(ε-lysine).

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preparation of ε-PL, relying on ε-lactam derivatives (Scheme 1).34 The cyclization reaction of biorenewable lysine followed by protection led to a ε-lactam monomer bearing a protected amino group. Sodium-catalyzed ROP of this monomer in bulk at 260 °C, followed by the cleavage of the protecting group, ultimately afforded chemosynthetic ε-PL. In spite of this significant progress, the synthesis of ε-PL still suffers from the high polymerization temperature (>200 °C) because of its low polymerizability and high melting point of ε-lactam derivatives. These temperature requirements significantly compromise the protecting group scope. At high temperatures readily removable amino protecting groups could not guarantee high stability. Although the 2,5-dimethylpyrrole protecting group that shows remarkable stability toward high temperatures has been successfully exploited for ε-PL synthesis, the complete removal of the 2,5-dimethylpyrrole suffers from the prolonged reaction time (72 h) and poor yield (30%). These challenges prompt us to improve upon the harsh reaction conditions and develop a new polymerization method of ε-lactam derivatives compatible with readily removable protecting groups. To establish a new method, the following two challenges need to be addressed: (1) the polymerization must proceed in solution as bulk polymerization requires high temperatures, due to the high melting point of ε-lactam monomers, and (2) the catalysts must feature

INTRODUCTION Poly(amino acid)s (PAAs, also known as polypeptides) are attractive biomaterials for their intriguing properties such as stimuli-responsiveness, secondary structures, and hierarchical self-assembly.1−5 These polymers are traditionally synthesized through the ROP of α-amino acid N-carboxyanhydrides (NCAs).6−17 Among various PAAs, functional PAAs such as poly(ε-lysine) (lysine monomers connected between αcarboxyl and ε-amino groups, ε-PL) and poly(γ-glutamic acid) (glutamic acid monomers connected between α-amino and γ-carboxylic acid groups, γ-PGA) are of particular interest due to their unique structure, nontoxicity for humans, and rich side-chain functionality.18−23 Functional PAAs thus provide various applications in food, cosmetic, biomedical, agricultural, and other industries.24−30 However, because of the synthetic difficulties encountered with large cyclic monomers (ninemember ε-NCA of lysine and seven-member γ-NCA of glutamic acid), the chemosyntheses of ε-PL and γ-PGA are typically difficult.31,32 In the past, ε-PL and γ-PGA are mainly produced by microorganisms through fermentation.33 However, the biosynthetic method can only produce ε-PL with lower molecular weight (Mn < 4000 g/mol). In addition, the composition and properties of the functional PAAs from biosynthesis are hard to regulate. The chemosynthesis route can be applied to prepare macromolecules with diverse structures. Most recently, we first demonstrated a novel chemical approach for the © XXXX American Chemical Society

Received: November 6, 2017

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DOI: 10.1021/acs.macromol.7b02331 Macromolecules XXXX, XXX, XXX−XXX

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Scheme 1. Previously Reported Sodium-Catalyzed ROP of ε-Lactam Derivative for the Synthesis of Poly(ε-lysine), and t-BuP4Catalyzed ROP, Compatible with Readily Removable Protecting Groups

extensive screening of the relatively nonpolar solvents led us to identify anisole (ANI) as a superb solvent for the desired polymerization, furnishing the targeted polymer not only in good monomer conversion of 60% but also with higher molecular weight (Mn = 12.1 kg mol−1, entry 4). The polymerization catalyzed by t-BuP4 also gave satisfactory Mn in other nonpolar solvents, including isopropylbenzene (IPB) and tert-butylbenzene (TBB) (entries 5 and 6). It should be noted that polymerization at temperatures e.g. ca. 100−140 °C is industrial favorable, in view of energy-saving production process.66 Thus, we have demonstrated that superbase t-BuP4mediated ROP of ε-lactam derivatives provides a sustainable and new approach toward more facile preparation of poly(εlysine). With the promising preliminary results in hand, we next examined the polymerization using different reaction conditions, co-initiators, and bases. First, the impact of the reaction time, ranging from 1 to 6 h, was investigated (entries 4, 7, and 8). An increase of the time led to higher conversion, and the best results were obtained at 6 h. Second, increasing the monomer concentration [M1] from 1.0 to 10.0 M while keeping other conditions the same, the conversion enhanced significantly from 39% to 67% (entries 4 and 9−12) with only a little change in molecular weight (Mn = 10.1−12.5 kg mol−1). Third, decreasing the monomer-to-t-BuP4 ratio ([M1]/[B]) from 100/1 to 50/1 to 25/1 resulted in the increase of monomer conversion (entries 4, 13, and 14). Especially, when the [M1]/[B] was 25/1, monomer conversion up to 95% was achieved. Correspondingly, as is similarly noted in the sodiumcatalyzed system, the Mn of the polymer was decreased from 15.1 to 9.8 kg mol−1 by decreasing the [M1]/[B].34 On the other hand, increasing the amount of I1 from 0.5 to 1.0 to 2 equiv relative to t-BuP4, the conversion enhanced significantly from 24% (entry 15) to 95% (entry 14) to 96% (entry 16) with a decrease in polymer Mn from 11.1 to 7.2 kg mol−1. Fourth, as the addition of co-initiator considerably enhanced the activity of the ROP of M1 catalyzed by t-BuP4, we subsequently examined the ROP behavior as a function of the steric bulk and electronic properties of co-initiators. In a monomer/base/coinitiator ratio of 25:1:1, the ROPs with sterically bulkier coinitiators I2 and I3 showed a lower activity (84% conversion with I2 and 64% conversion with I3, entries 17 and 18) than the ROP with I1 (95% conversion); this can be attributed to their steric bulk, which might suppress the nucleophilic attack

potent deprotonating capability and good solubility in organic solvents. Given the stronger organic bases can be served as excellent deprotonating agents and are well suited to a range of solvents,35−54 we anticipated that organic bases could possibly realize effective ROP of ε-lactam derivatives to ε-PL under mild conditions. Similar to the sodium-catalyzed process, the organic base deprotonates ε-lactam and generates the reactive ε-lactamate anion, with subsequent ring-opening leading to polymer formation. Widely used organic bases such as 1,5,7triazabicyclo[4.4.0]dec-5-ene (TBD) 42 and the 1,8diazabicycloundec-7-ene/thiourea (DBU/TU) catalyst systems43,44 were initially tested for the polymerization of 2,5dimethylpyrrole protected ε-lactam (M1) but failed to catalyze the polymerization in dimethylacetamide (DMAC) at 140 °C within 24 h. Compared to TBD or DBU, phosphazene t-BuP4 [1-tert-butyl-4,4,4-tris(dimethylamino)-2,2-bis[tris(dimethylamino)phosphoranylidenamino]-2λ5,4λ5-catenadi(phosphazene)] is one of the strongest known organic bases (pKa ∼ 32 in DMSO) due to its corresponding soft and bulky cation.55−65 This led us to hypothesize that the superbase tBuP4 may promote effective ROP of ε-lactam to ε-PL under mild conditions via formation of highly active “activated monomers” through deprotonation of ε-lactam employing tBuP4, followed by the ROP events. Herein, we report on the unprecedented superbase t-BuP4 catalytic approach to ε-PL from ε-lactam derivatives under mild conditions compatible with readily removable protecting groups, thus providing a highly sustainable method for these important functional poly(amino acid)s (Scheme 1).

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RESULTS AND DISCUSSION

Ring-Opening Polymerization of M1 by t-BuP4. Initially, we evaluated the ROP of M1 using t-BuP4 alone (2.0 mol %) in DMAC at 140 °C. Indeed, the ROP proceeded to some extent, achieving 10% conversion after 6 h and affording Poly(1) with Mn = 5.2 kg mol−1 and molecular weight distribution Đ (Mw/Mn) = 1.73 (entry 1). When using 1 equiv of co-initiator (I1), relative to t-BuP4, we were pleased to observe that the conversion was enhanced substantially to 21% (entry 2). In an attempt to further improve the conversion and Mn, several solvents were screened. The employment of solvent like diethylene glycol dimethyl ether (DME) gave improved conversion but mediocre Mn of 7.3 kg mol−1 (entry 3). Further B

DOI: 10.1021/acs.macromol.7b02331 Macromolecules XXXX, XXX, XXX−XXX

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Macromolecules Table 1. Results of Ring-Opening Polymerization of ε-Lactam Derivative M1 by t-BuP4a entry

base (B)

co-initiator [I]

M/B/I ratio

T (°C)

solvent

[M1] (mol/L)

t (h)

conv (%)b

Mn (kg mol−1)c

Đ (Mw/Mn)c

DPd

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27

t-BuP4 t-BuP4 t-BuP4 t-BuP4 t-BuP4 t-BuP4 t-BuP4 t-BuP4 t-BuP4 t-BuP4 t-BuP4 t-BuP4 t-BuP4 t-BuP4 t-BuP4 t-BuP4 t-BuP4 t-BuP4 t-BuP4 t-BuP4 t-BuP4 t-BuP4 t-BuP4 t-BuP4 t-BuP2 NaH KH

I1 I1 I1 I1 I1 I1 I1 I1 I1 I1 I1 I1 I1 I1 I1 I2 I3 I4 I5 I1 I1 I1 I1 I1 I1 I1

50/1/0 50/1/1 50/1/1 50/1/1 50/1/1 50/1/1 50/1/1 50/1/1 50/1/1 50/1/1 50/1/1 50/1/1 100/1/1 25/1/1 25/1/0.5 25/1/2 25/1/1 25/1/1 25/1/1 25/1/1 25/1/1 25/1/1 10/1/1 5/1/1 25/1/1 25/1/1 25/1/1

140 140 140 140 140 140 140 140 140 140 140 140 140 140 140 140 140 140 140 140 120 100 80 60 140 140 140

DMAC DMAC DME ANI IPB TBB ANI ANI ANI ANI ANI ANI ANI ANI ANI ANI ANI ANI ANI ANI ANI ANI ANI ANI ANI ANI ANI

5 5 5 5 5 5 5 5 1 3 8 10 5 5 5 5 5 5 5 5 5 4.5e 2.5e 1.5e 5 5 5

6 6 6 6 6 6 1 3 6 6 6 6 6 6 6 6 6 6 6 6 6 12 54 96 6 24 24

10 21 33 60 44 43 20 42 39 52 65 67 12 95 24 96 84 64 97 98 35 14 28 26 41 0 0

5.2 6.9 7.3 12.1 10.2 10.8 8.5 13.5 11.3 10.1 11.9 12.5 15.1 9.8 11.1 7.2 9.2 8.6 9.4 8.2 6.4 7.7 4.5 1.7 8.5

1.73 1.63 2.16 2.21 2.40 2.34 2.41 1.61 2.22 3.31 2.67 2.67 1.74 2.67 2.00 1.47 2.43 2.10 2.77 2.19 1.59 1.46 1.44 1.30 2.85

25 34 35 59 50 52 41 66 55 49 58 61 73 48 54 35 45 42 46 40 31 37 22 8 41

Polymerization conditions: [M1] = 5 M; monomer and base were mixed first, followed by co-initiator. bMonomer conversion measured by 1H NMR. cMn and Đ were determined by SEC at 80 °C in DMF relative to polystyrene standards. dDP is the number-average degree of polymerization. e The maximum concentration achievable in ANI at this temperature. a

Figure 1. (A) MALDI-TOF-MS spectra of Poly(1). (B) 1H NMR spectrum (CDCl3, 25 °C) of Poly(1). The polymer was prepared by t-BuP4/I4 = 1/1 at 140 °C.

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Macromolecules Scheme 2. Proposed Mechanism for the ROP of ε-Lactam Derivative by t-BuP4 in the Presence of Co-Initiator

of a ε-lactamate anion. In addition, electron-deficient coinitiators I4 and I5 could facilitate ROP with good conversion (entries 19 and 20). Finally, we were very interested in knowing the effect of temperature for the ROP of M1. The monomer conversion decreased with decreasing temperature in the range of 140−80 °C (entries 14 and 21−23). Surprisingly, the polymerization proceeded even at 60 °C, albeit with lower monomer conversion and Mn (entry 24). The basicity of the phosphazenes has a strong impact on the polymerization reaction. Under the same conditions for the base/co-initiator system, the weaker base t-BuP2 decreased the conversion by about 50% (entry 25) compared with that by tBuP4. These results indicated that the polymerization activity reduces with decreasing the basicity of the superbase, which correlates well with the degree of monomer activation as disclosed by 1H NMR measurement (Figure S14). Moreover, we also studied the performance of some inorganic bases including NaH and KH. Overall, these bases showed no or extremely low propensity to polymerize M1 at 140 °C in ANI, even for longer reaction times of 24 h (entries 26 and 27). Mechanism Considerations. To obtain an insight into the mechanism of the ROP, we characterized the chain-end groups of Poly(1) produced by t-BuP4/I4 (1:1 ratio) with MALDITOF mass spectrum and 1H NMR. As shown in Figure 1A, the MALDI-TOF mass spectrum of Poly(1) consisted of two series of peaks, which presumably corresponded to the structure a with 4-(trifluoromethyl) benzoyl/acylated lactam chain ends and the structure b with H/acylated lactam chain ends. The corresponding 1H NMR spectrum of Poly(1) is depicted in Figure 1B, showing, besides the major signals at δ 4.8, 3.2, 2.5, and 1.3 ppm for the main chain protons, minor signals attributed to the 4-(trifluoromethyl)benzoyl end groups are clearly visible. Overall, these results are consistent with the mechanism indicated in Scheme 2 involving deprotonation of ε-lactam by tBuP4 to generate the reactive ε-lactamate anion, which then reacts with either co-initiator (pathway a) or monomeric εlactam (pathway b). Acylated co-initiator (I4) is activated

compared to the non-acylated lactam by its markedly more electron-deficient character. It is thus more easily opened and promotes ε-lactam ROP.67 The MALDI-TOF mass spectrum also shows a more profound occurrence of pathway a type ringopening. Unlike what was seen for the t-BuP4-mediated ROP of the “nonpolymerizable” γ-butyrolactone demonstrated by Chen and co-workers,52 the above-mentioned observation implies obvious differences in catalytic pathways in these related ROP processes. The ability of t-BuP4 to abstract H of M1 was examined by means of NMR studies of a mixture of t-BuP4 and M1 (1 equiv of each) in toluene-d8 at room temperature. Both the 1H NMR result (shift of the methyl peak from δ 2.68 to 2.56 ppm, shift of the tert butyl peak from δ 1.68 to 1.50 ppm; Figure 2A) and 31P NMR result (shift of the (Me2N)3P peak from δ 4.84 to 12.46 ppm, shift of the tBuNP peak from δ −25.34 to −23.84 ppm; Figure 2B) confirmed the formation of [t-BuP4H]+. In addition, the 1H NMR spectrum showed a downfield shift of methine (a) and methylene (e) of M1 (Figure 2A), suggesting the loss of a proton from the lactam nitrogen. However, only a slight shift of methylene (e) of M1 was observed in the 1H NMR spectrum of the mixture of t-BuP2 with M1 or TBD with M1 at room temperature (Figures S14 and S15). These results demonstrated the direct reaction of M1 with t-BuP4 formed [tBuP4H]+ paired with an anionic M1. Ring-Opening Polymerization of ε-Lactam Derivatives with Readily Removable Protecting Groups by t-BuP4. Encouraged by the results from the screening phase, a range of ε-lactam monomers with various protecting groups (M2−M4) were then investigated using t-BuP4 as catalyst under mild reaction conditions (Table 2). Under similar polymerization conditions, the t-BuP4 catalytic system was successfully amenable to a wide range of ε-lactam monomers, and good to excellent yields were achieved with monomers bearing dibenzyl (M2), di-(methoxybenzyl) (M3), and benzyl and methoxybenzyl (M4) protecting groups. All the 1H NMR and 13 C NMR spectra were consistent with the expected structures of Poly(2)−Poly(4) (Figures S11−S13). D

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Figure 2. (A) 1H NMR spectra (toluene-d8, 25 °C) of the reaction between t-BuP4 and M1 (1:1). (B) 31P NMR spectra (toluene-d8, 25 °C) of the reaction between t-BuP4 and M1 (1:1).

Table 2. t-BuP4-Catalyzed ROP of ε-Lactam Derivatives with Readily Removable Protecting Groupsa

entry

εlactam

T (°C)

t (h)

conv (%)b

Mn (kg mol−1)c

Đ (Mw/Mn)c

DPd

1 2 3

M2 M3 M4

140 140 140

6 24 6

80 65 76

9.9 5.7 7.0

2.07 2.31 1.82

32 16 21

deprotection, the peaks in the 1H NMR (Figure S16) corresponding to the methoxy benzyl groups disappeared entirely, suggesting the complete removal of the protecting groups. Moreover, 13C NMR, 1H−1H correlated, and IR spectra also demonstrated that ε-PL had been synthesized successfully via ROP (Figures S16−S18). We have thus demonstrated that t-BuP4 catalytic ROP of ε-lactam derivatives provides a more facile approach toward ε-PL.

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CONCLUSION In summary, we have described herein the facile organopolymerization of the bioderived low polymerizability ε-lactam monomers for the preparation of poly(amino acid) ε-PL. The polymerization processes were efficiently carried out at 60−140 °C to afford ε-PL bearing pendant protected amino groups with Mn values up to 13.5 kg mol−1 in good yields. Remarkably, the t-BuP4-based catalytic approach proceeds under mild conditions with excellent protecting group tolerance, critical for large-scale synthesis of ε-PL. Our ongoing efforts are to seek a better understanding of the mechanistic aspects of these

a

The polymerizations were performed in ANI with I1 as the coinitiator and t-BuP4 as the catalyst (M/B/I = 10/1/1). bMonomer conversion was measured by 1H NMR. cMn and Đ were determined by SEC at 80 °C in DMF relative to polystyrene standards. dDP is the number-average degree of polymerization.

Deprotection of Poly(3). Finally, the protecting groups of polymers such as Poly(3) can be readily hydrogenolysis under trifluoroacetic acid (TFA), affording ε-PL in 45% yield. After E

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Macromolecules catalytic processes and to develop t-BuP4-catalyzed ROP of γand δ-lactam derivatives for the production of poly(γ-glutamic acid) and poly(δ-ornithine), respectively.

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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.7b02331. Details on materials and methods, experimental procedures, characterization data, NMR spectra of all compounds (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 was supported by NSFC (Grants 21474101 and 51673192) and “The Hundred Talents Program” from the Chinese Academy of Sciences. Helpful discussions with Prof. Dongmei Cui at the same institute are gratefully acknowledged.

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REFERENCES

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Macromolecules

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DOI: 10.1021/acs.macromol.7b02331 Macromolecules XXXX, XXX, XXX−XXX