Functional Polycarbonate of a d-Glucal-Derived Bicyclic Carbonate via

Letter pubs.acs.org/macroletters

Functional Polycarbonate of a D‑Glucal-Derived Bicyclic Carbonate via Organocatalytic Ring-Opening Polymerization Alexander T. Lonnecker, Young H. Lim, and Karen L. Wooley* Departments of Chemistry, Chemical Engineering, and Materials Science and Engineering, and Laboratory for Synthetic−Biologic Interactions, Texas A&M University, College Station, Texas 77842, United States S Supporting Information *

ABSTRACT: Herein, we demonstrate the synthesis of a bicyclic carbonate monomer of a D-glucal derivative, which originated from the natural product D-glucose, in an efficient three-step procedure and its ring-opening polymerization (ROP), initiated by 4methylbenzyl alcohol, via organocatalysis. The ROP behavior was studied as a function of time, catalyst type, and catalyst concentration by using size exclusion chromatography (SEC) and nuclear magnetic resonance (NMR) spectroscopy. Using a cocatalyst system of 1,8-diazabicyclo[5.4.0]undec-7-ene and 1(3,5-bis(trifluoromethyl)phenyl)-3-cyclohexyl-2-thiourea (5 mol %) afforded poly(D-glucal-carbonate) (PGCC) with almost complete monomer conversion (ca. 99%) within 1 min, as analyzed by 1H NMR spectroscopy, and a monomodal SEC trace with dispersity of 1.13. The resulting PGCCs exhibited amorphous characteristics with a relatively high glass transition temperature at ca. 69 °C and onset decomposition temperature at ca. 190 °C, as analyzed by differential scanning calorimetry and thermogravimetric analysis, respectively. This new type of potentially degradable polymer system represents a reactive functional polymer architecture.

A

Recently, our group reported synthetic methodologies wherein a natural product, D-glucose, was converted into poly(D-glucose carbonate)s (PGCs) with four different backbone regioconnectivities20 or with alkyne side-chain functionalities useful for postpolymerization modification,21 with the intention to reduce reliance on petroleum feedstocks and further increase biocompatibility. It is noteworthy that these PGCs have the potential to degrade into their bioresorbable starting material, D -glucose, and CO 2 .22 Beyond their degradable and biocompatible properties, carbohydrates display specific interactions with proteins making them desirable for targeted drug and gene delivery.23 Expanding these efforts, we designed a functional bicyclic carbonate monomer, starting from a D-glucose-based feedstock, i.e., tri-O-acetyl-D-glucal, which has been widely used as a chiral starting material in organic chemistry toward glycoconjugates24 and noncarbohydrate natural products.25 Using this D-glucal as a starting material not only leads to a streamlined synthetic strategy but also enables the further incorporation of a wide range of chemically reactive functionalities, making it a versatile platform for the synthesis of adaptable APCs. Herein, we report the synthesis of a D-glucal-based bicyclic carbonate monomer by an efficient three-step procedure and its controlled ROP as a function of time, catalyst type, and catalyst concentration.

n increasing demand for degradable biomaterials has led to utilization of aliphatic polyesters (APEs) in the field of biomedical and pharmaceutical sciences.1 However, the ester backbone linkage of the APEs often results in undesired hydrolytic degradation, acidic microenvironments created by degradation products, and incompatibility with pH-sensitive materials, which limit their use as biomaterials.2 In comparison, retarded hydrolytic degradation rates of aliphatic polycarbonates (APCs), allowing for long-term durability and an absence of acidic byproducts during in vivo degradation, make APCs an excellent candidate for biomedical applications.3,4 To expand their applications in biomedical and pharmaceutical applications, it is imperative to develop new synthetic approaches for versatile and functional APCs. APCs can be synthesized via ring-opening polymerization (ROP) in a controlled manner, for which anionic,5,6 cationic,7,8 enzymatic,9 metal-catalyzed,10 and organo-catalyzed11,12 methods are known. For instance, poly(trimethylene carbonate) (PTMC), used in commercial applications as degradable sutures13 and orthopedic fixation devices,14 is a structurally simple form of APC synthesized by ROP of the six-membered cyclic carbonate monomer, TMC. However, PTMC often does not fulfill some requirements, due to their high hydrophobicity and/or lack of reactive centers for attachment of bioactive molecules such as drugs, peptides, and/or proteins.15 Toward this end, significant efforts have been made to synthesize functional APCs containing various functional pendant groups, e.g., halogen,16 alkene,17 alkyne,18 and saccharide.19 © XXXX American Chemical Society

Received: May 17, 2017 Accepted: June 22, 2017

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triphosgene in the presence of pyridine in dichloromethane (DCM) at room temperature, yielding the bicyclic carbonate monomer, 3, in modest yields (ca. 40%). Compared to the instability of compound 2, the resulting cyclic carbonate, 3, proved stable indefinitely, over one year, when stored in a glovebox (argon gas-filled, 30 °C). Characterization of each synthesized compound was conducted by NMR (1H, 13C, COSY, and HSQC) spectroscopy, infrared (IR) spectroscopy, and electrospray ionization mass spectrometry (Figure 1, Figure 2, and Figures S1−S18).

Finally, the structural and thermal properties of the resulting polymers were characterized extensively by various analytical techniques. Our approach involved three consecutive synthetic steps, starting from tri-O-acetyl-D-glucal and conducting a Ferrier rearrangement to give 1, followed by deprotection and finally installation of a cyclic carbonate upon 2, to yield a vinylfunctionalized bicyclic carbonate monomer, 3 (Scheme 1). Scheme 1. Synthesis of D-Glucal-Based Bicyclic Carbonate Monomer, 3

During the Ferrier rearrangement, the cyclic enol ether with the allylic acetyl leaving group of tri-O-acetyl-D-glucal readily underwent nucleophilic displacement with propan-2-ol in the presence of Lewis acids, i.e., boron trifluoride diethyl etherate (BF3·EtO2), to afford 1 (Scheme 2).26 Initially, methanol was

Figure 1. 1H NMR spectra of the polymer 4 (a) and the monomer 3 (b).

Scheme 2. Proposed Ferrier Rearrangement

utilized as a model nucleophile to afford the 2,3-unsaturated glycosyl product. However, separation of the resulting compound from the residual starting material proved challenging, due to the similar solubilities and retention factor values during silica gel column chromatography. In addition, in subsequent chemical steps, the 1H nuclear magnetic resonance (NMR) signal of the introduced methoxy group (i.e., 3.45 and 3.47 ppm, α and β, respectively) overlapped with that of the benzylic methyl protons of the polymerization initiator, 4methylbenzyl alcohol, making the end group analysis difficult. To avoid these complications in purification and analysis, propan-2-ol was chosen as an alternative nucleophile, resulting in compound 1 in high yield (ca. 95%), favoring the α product in a 4.5:1 ratio, based on 1H NMR peak integrals (Figure S1). Bisdeacetylation of compound 1 under Zemplén conditions afforded the pseudoglucal, 2, in quantitative yield. Although purified as a white solid, it underwent decomposition into a brown oil within a week under ambient conditions and was stable only when stored under dry conditions at −20 °C for 1− 2 months. Thus, compound 2 was used as unpurified for the next step. Several ring-closing reaction conditions, not involving phosgene derivatives, were considered in our initial study, but it was imperative to use triphosgene due to the inefficient ringclosing reaction, as observed with similar glucose-based bicyclic carbonates22,27 and, especially, the anticipated increase in ring strain caused by the presence of a double bond in the bicyclic ring. The ring-closing reaction was performed successfully using

Figure 2. 13C NMR spectra of compound 4(a) and compound 3(b).

ROP of 3 was conducted via an initiator/chain-end activation mechanism, and its polymerization behavior was investigated as a function of time, catalyst type, and catalyst concentration (Scheme 3). Table 1 summarizes the examination of three different organocatalyst systems, i.e., 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), and a two-component catalyst of 1-(3,5-bis(trifluoromethyl)-phenyl)-3-cyclohexyl-2-thiourea (TU) and DBU. The number-average molecular weight (Mn) was obtained by size exclusion chromatography (SEC) and also 749

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of 25 and Đ of 1.20. Under these conditions, undesired transesterification was minimized, leading to ROP in a controlled fashion. Use of a single Lewis base system, DBU, suffered from slower rates and higher Đ values in the absence of the Lewis acid, TU, which could be explained by the introduction of a competitive initiation and alternate zwitterionic reaction mechanism.30,31 The detailed analyses for the kinetic study of ROP by SEC and 1H NMR spectroscopy are described in the Supporting Information (Figures S19−25). The rapid monomer conversion during ROP with the employed three different types of catalytic systems in relatively low monomer concentrations, in general, may be explained by the increased ring strain in the presence of the endocyclic double bond within the bicyclic ring system. The ring strain of the six-membered carbonate ring was evident from a large shift in the carbonyl absorption band in the IR spectrum, occurring at 1751 cm−1 (neat), from that of trimethylene carbonate32 and various substituted six-membered cyclic carbonates, 32,33 typically occurring at ca. 1730 cm−1 (neat). The structure of the resulting polycarbonate, 4, was confirmed by IR and NMR (1H and 13C) spectroscopies (Figure 1, Figure 2, and Figures S16−18). As illustrated in Figure 1, a significant NMR resonance peak shift between compounds 3 and 4 occurred for the pyranoside methine proton: i.e., from 4.65 to 5.12 ppm, the methylene protons α to the carbonate linkage C6, i.e., from two distinct doublet− doublet peaks at 4.56 and 4.30 ppm to a multiplet at 4.33 ppm, and the alkenyl proton on C3, i.e., from 6.11 to 5.82 ppm. These resonance peak shifts could arise from an electronic effect of the adjacent carbonyl group and the geometric conformational changes on the glycosidic ring upon opening of the six-membered bicyclic carbonate. Proton NMR resonances led to facile calculations of conversions and molecular weights. The upfield shift of the alkenyl proton at the C3 position, i.e., from 6.11 ppm of 3 to 5.82 ppm of 4, created two nonoverlapping peaks, allowing for the straightforward calculation of conversion. The values of Mn estimated by 1H NMR end-group analysis, based on the integral ratio of the methine isopropyl proton in the repeat unit, at 3.96 ppm, to that of the benzylic methyl protons of the initiator at the αchain end, at 2.34 ppm, were in agreement with the SECestimated values and the theoretical values of 10 833 g/mol (DP50) and 5477 g/mol (DP25). The 13C NMR spectra showed the characteristic downfield shift, from 148 to 155 ppm, of the carbonyl carbon resonance upon ring opening (Figure 2). A closer look at the carbonyl

Scheme 3. ROP of D-Glucal-Based Bicyclic Carbonate Monomer, 3, Initiated by 4-Methylbenzyl Alcohol, Using Three Different Types of Organocatalyst

calculated by comparing the 1H NMR peak integral ratio of the benzylic methyl protons (2.34 ppm) of the initiator and the methine protons (3.96 ppm) of the isopropyl group of the repeat units (Figure 1, Figures S19−S25). When compared with the polymerization rate of previously reported D-glucosebased cyclic carbonate monomer (i.e., ca. 99% within 10 min at 0.5 M monomer concentration, by 2 mol % TBD),22,27 a much faster conversion of 3, i.e., ca. 99% within 2 min, was observed in more dilute conditions, 0.3 M (Table 1, polymer 4). Lowering the catalyst loading concentration to 1 mol % slowed the reaction (Table 1, polymer 5), allowing for a full conversion within 6 min, again significantly faster than the previously reported ROP of D-glucose-derived22,27 and mannose-derived28 six-membered cyclic carbonate monomers.11 The SEC traces showed bimodal molecular weight distributions with high molecular weight shoulders (Figures S19 and S20) with relatively high dispersity (Đ) ranging from 1.21 to 1.31. This result of broadened Đ could be ascribed to the undesired transcarbonation of the polymer chains by TBD during ROP.29 The uniform growth of D-glucal-based polymer, i.e., Đ < 1.20, without adverse transesterification reaction, was observed using a less reactive cocatalyst system, DBU/TU. By lowering its concentration to 2 mol %, a complete conversion of 3 was reached within 5 min. The obtained polymer, 9, maintained a comparable number-averaged degree of polymerization (DPn)

Table 1. ROP of D-Glucal-Based Monomer, 3, Initiated by 4-Methylbenzyl Alcohol, via Organocatalysis polymer

catalyst

catalyst mol %

[M]0/[I]0a

[M]b

time (min)

conv. (%)c

Mn,NMR (g/mol)d

Mn,SEC (g/mol)e

Mw,SEC (g/mol)f

Đf

4 5 6 7 8 9 10

TBD TBD DBU DBU/TU DBU DBU/TU DBU

2 1 5 5 2 2 1

50 50 25 25 25 25 25

0.3 0.3 0.3 0.3 0.3 0.3 0.3

2 6 10 1 10 5 10

>99 >99 98 99 86 >99 57

11800 10800 4000 4400 1800 5500 1000

9800 9400 3800 3400 1600 5000 610

12500 11400 4300 3700 2100 6000 840

1.31 1.21 1.13 1.13 1.31 1.20 1.38

a Polymerization of 3 was carried out with TBD, DBU, or DBU/TU in the presence of 4-methylbenzyl alcohol in DCM in the glovebox, at 30 °C under argon atmosphere. bMonomer/initiator feed ratio. cConcentration of 3 in mol/L. dMonomer conversion to polymer, calculated by 1H NMR analysis. eNumber-average molecular weight, calculated by 1H NMR spectra. fNumber-average molecular weight and dispersity, obtained by SEC as a THF eluent using polystyrene standards.

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ACS Macro Letters carbon resonance region revealed three sets of signals. The proposed mechanism for the dual activation of ROP, catalyzed by DBU-TU or TBD, involves an activated alcohol attacking the cyclic carbonate in a nucleophilic acyl-substitution reaction, whereby the OH nucleophile first adds to the CO of the carbonate to give a hydrogen-bonded tetrahedral intermediate that subsequently collapses to a hydroxyalkylcarbonate.34 In this case, acyl oxygen bond cleavage at the different sides of the carbonyl carbon leads to two possible hydroxyalkylcarbonates. As a result, successive addition of D-glucal-based cyclic carbonate monomers at one of the two types of chain terminal alcohols can lead to three regiochemistries: head-to-head (HH), head-to-tail (HT), and tail-to-tail (TT) (Figure 2). Similar trends were also observed in the ROP of glucose-based carbonates, which was further supported through 13C NMR spectroscopy and electrospray ionization tandem mass spectrometry analyses, which may have been influenced by the methoxy protecting groups.22 It has been demonstrated that excessively bulky substituents, e.g., 2,2-diphenyl, can have an effect on ring opening of six-membered cyclic carbonates.35 Interestingly, removal of large side groups and inserting a double bond into the ring had an effect on the polymer regioregularity. Resonances from all three types of linkages were present in the 13C NMR spectrum of 4, where the intensity of the HT signal, at 154.9 ppm, was significantly greater than the HH and TT signals, at 154.6 and 155.5 ppm, respectively. If the acyl−oxygen bond cleavage occurred randomly at either side of the carbonyl, then the probability ratio of HH:HT:TT should be 1:2:1. However, the actual integration ratio of the three signals in Figure 2 was 1.0:4.3:0.9, indicating that the acyl−oxygen bond cleavage occurred preferentially on one side of the carbonate carbonyl. The thermal properties of 4 were evaluated by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) (Figure 3). A single endothermic peak appeared in the heating cycles of the DSC thermogram in Figure 3(a), representing a glass transition temperature (Tg) at 69 °C. This relatively high Tg for an APC could be attributed to the chain rigidity of the 2,3-dideoxy enopyranoside structure in the repeat unit. However, the Tg value was lower than other reported homopolymers derived from sugar-based six-membered cyclic carbonates.22,27,36 No information to indicate a crystallization temperature was observed, though heating scans did not exceed 150 °C in temperature due to concerns of thermal degradation. Thermal degradation occurred at relatively low temperatures, ca. 200−310 °C, for initial to >70% mass loss (Figure 3(b)). The addition of the carbon− carbon double bond to the glycosidic ring appeared to make the polymer more thermally sensitive, when compared to previously reported D-glucose-based polycarbonates.22 In summary, we demonstrated the synthesis of a D-glucalbased bicyclic carbonate monomer following an efficient threestep synthetic procedure and investigated its ROP behavior using three different types of organocatalytic systems, DBU, TBD, and TU/DBU, to afford well-defined polycarbonates. The presence of the strained bicyclic carbonate structure of the monomer led to a rapid polymerization rate in dilute conditions with low catalyst loading. This synthetic methodology expanded the use of D-glucose derivatives for the preparation of polycarbonates. Moreover, this synthetic design would allow for not only facile introduction of a variety of functional cyclic carbonate monomers but also postpolymerization modifications, such as thiol−ene “click” reactions using the double bond

Figure 3. (a) Differential scanning calorimetry analysis of 4. The Tg value determined from the heating cycle is confirmed by the cooling cycle. (b) Thermogravimetric analysis of 4.

present in the polymer backbone. Furthermore, thermal analyses revealed that this D-glucal-based polycarbonate exhibited an amorphous character and comparably higher Tg than common aliphatic polycarbonates, making it attractive for a broad range of potential applications. In particular, such materials may impact numerous fields ranging from hydrolytically or thermally degradable materials to tissue engineering and nanotherapeutic delivery vehicles.

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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/acsmacrolett.7b00362.

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Detailed experimental procedures and characterizations (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Karen L. Wooley: 0000-0003-4086-384X Notes

The authors declare no competing financial interest. 751

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ACKNOWLEDGMENTS We gratefully acknowledge financial support from the National Science Foundation (CHE-1610311) and the Welch Foundation (A-0001).

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