Ryan J.
Pounder
,
David J.
Fox
,
Ian A.
Barker
,
Michael J.
Bennison
and
Andrew P.
Dove
*
Department of Chemistry, University of Warwick, Coventry, UK. E-mail: a.p.dove@warwick.ac.uk; Tel: +44(0)24 7652 4107
First published on 19th July 2011
The synthesis and ring-opening polymerization (ROP) of an O-carboxyanhydride (OCA) monomer derived from L-malic acid (L-malOCA) is reported. Application of 4-dimethylaminopyridine as catalyst led to the observation of a number of undesirable side products. Investigation of different para-substituted pyridines as catalysts identified 4-methoxypyridine to have the ideal balance of activity and selectivity to enable the controlled ROP of L-malOCA. Deprotection of the benzyl ester side groups of the resultant polymers was achieved by hydrogenolysis and the resulting hydrophilic poly(α-malic acid) was observed to fully degrade within 7 days in aqueous solution.
Poly(ester)s are commonly accessed by either polycondensation methods or by the ring-opening polymerization (ROP).5–8 Of these, the latter is generally preferred on account of the high levels of control that are possible over the molecular parameters of the resultant polymers including attainment of polymers with predictable molar mass, low molar mass distributions, high end-group fidelity and even control over polymer tacticity.7–11 Despite these favorable characteristics, poly(ester) synthesis by ROP is largely limited to monomers that do not contain high levels of functional groups. This largely results from the prevalence of transesterification side reactions that occur in the presence of even simple groups such as alcohols, amines and esters hence resulting in a loss of control over the molecular parameters.
A wide range of monomers have been synthesized and studied to incorporate functional groups along poly(ester) backbones.3,4,6,11–15 The derivation of monomers around a β-propriolactone structure has provided a particularly wide range of functional group incorporation.3,4,12,14,15 Notably, malic acid has been utilized to excellent effect to produce derivatives of poly(β-malic acid) with excellent effect.3,4,12,14–29 While several studies have investigated the ROP of 6-membered cyclic esters derived from a range of sources,6,13,15,30 relatively few have focused on the application of malic acid, either derived from aspartic acid or obtained directly.14 Kimura et al. reported the synthesis of 3-(S)-[(benzyloxycarbonyl)methyl]-1,4-dioxane-2,5-dione (BMD) with ROP mediated by stannous(II) octanoate (Sn(Oct)2) resulting in relatively poorly defined poly(ester)s (e.g. [M]/[I] = 100; Mn = 10 500 g mol−1; PDI = 2.0).31–33 Concurrently with Bourissou and coworkers who used a related monomer derived from glutamic acid,34 we have demonstrated that the application of highly specific catalysis has enabled the controlled ROP of this monomer.35 In common with many other hindered cyclic diester monomers, synthesis of poly(α-malic acid) derivatives by the controlled ROP of the symmetrical 3,6-(S)-[di(benzyloxycarbonyl)methyl]-1,4-dioxane-2,5-dione (malide) however remains challenging.35,36 Recent developments have detailed the synthesis and ROP of 1,3-dioxolane-2,5-diones or O-carboxyanhydrides (OCAs) that provide activated equivalents of cyclic diesters that are driven entropically by release of CO2 rather than enthalpically by ring-strain.37,38 Following their initial report that the ROP of 5-(S)-methyl-1,3-dioxolane-2,4-dione (L-lacOCA) using a mild 4-dimethylaminopyridine (DMAP) catalyst resulted in the isolation of a polymer equivalent to poly(L-lactide),37 Bourissou, Martin-Vaca and coworkers demonstrated that the ROP of the OCA derived from O-benzyl-L-glutamic acid (L-gluOCA) resulted in the synthesis of well controlled functional poly(ester)s.39 Most notably, the derivatized monomer was polymerized more rapidly than L-lacOCA, eliminating the retardation of ROP commonly observed with bulky substituents on 6-membered cyclic diesters and hence making this an extremely attractive route for the future synthesis of side-chain-functional poly(ester)s. A computational mechanistic investigation revealed the key role of multiple hydrogen bonding in the ROP with a general base activation of the initiating/propagating alcohol and monomer being more energetically favorable than the nucleophilic activation of the monomers.40,41 Herein we report the application of commercially available L-malic acid in the synthesis of functional poly(ester)s via an OCA monomer to provide a potentially versatile route to a range of stereopure side-chain functional poly(ester)s.
ROP of L-malOCA was initially attempted with neo-pentanol initator and DMAP as a catalyst at 25 °C in CH2Cl2 solution, comparable to the conditions successfully applied to the ROP of L-lacOCA and L-gluOCA. Initial studies focussed on a DMAP:initator ratio of 1:1 with a monomer-to-initiator ratio of 20 ([M]/[I] = 20) with progress of the polymerization being monitored by the observation of the reduction of the methine resonance at δ = 5.09 ppm of the monomer and the appearance of the corresponding broadened multiplets at δ = 5.61–5.51 ppm in poly(β-benzyl α-(L)-malate), P(L-BMA), using 1H NMR spectroscopy. Upon completion of the allotted time, polymerizations were quenched via a 1.0 M HCl(aq) wash to remove DMAP before being precipitated into ice cold petroleum ether (b.p. 40–60 °C). Under these conditions, the ROP of L-malOCA achieved >90% monomer conversion in less than one minute with SEC analysis of the resultant P(L-BMA)20 indicating that the polymerization was well controlled, displaying a number-average molar mass (Mn) of 3 700 g mol−1 with a PDI of 1.19 (theoretical Mn = 4 208 g mol−1). Further investigation of the ‘living’ characteristics of the polymerization resulted in the observation of a linear correlation between Mn and initial monomer to initiator ratio and a second-feed experiment in which the chain extension of a P(L-BMA)20 macroinitiator (Mn = 3 700 g mol−1; PDI = 1.19) with 20 equiv. L-malOCA resulted in the isolation of a P(L-BMA)40 that exhibited a doubling in molar mass (Mn = 7 390 g mol−1) while maintaining a low PDI of 1.20. Furthermore, leaving the resultant P(L-BMA)40 for 2 h (24 times longer than required to reach >90% monomer conversion) in the presence of DMAP resulted in negligible changes in both the molar mass (Mn = 7 050 g mol−1) and molar mass distribution (PDI = 1.19) suggesting that transesterification side reactions were minimal despite full monomer consumption.
End group analysis by 1H NMR spectroscopy of a P(L-BMA) ([M]/[I] = 20; Mn = 4 210 g mol−1; PDI = 1.22) confirmed a DP = 23 polymer based on the integration of the tert-butylneo-pentyl ester resonances at δ = 0.87 ppm against those of the main chain methine protons at δ = 5.55 ppm (Fig. 1a) and further analysis by matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS) revealed a single distribution centered around m/z = 4234.3 which corresponds to a sodium charged DP20 polymer chain with a neo-pentyl ester end group; a regular spacing equal to the molar mass of the repeat unit of benzyl α-(L)-malate (m/z = 206) demonstrates that no significant transesterification of the polymer chains occurs (Fig. 1b).
Fig. 1 (a) 1H NMR spectrum (400 MHz; CDCl3) and (b) MALDI-TOF MS of a P(L-BMA)20 (Mn = 4 210 g mol−1, PDI = 1.22) prepared by ROP of L-malOCA ([L-malOCA]0 = 0.32 M) catalyzed with 5 mol% DMAP using neo-pentanol as the initiator and the presence of impurities (*). |
Despite the evidence suggesting that the DMAP-catalyzed ROP of L-malOCA proceeds in a highly controlled manner, polymer impurities were clearly visible in both the 1H NMR and MALDI-TOF MS spectra of the polymer obtained (Fig. 1). By integration of the impurities at δ = 2.90 ppm against that of the equivalent desired polymer resonances at δ = 3.18 ppm in the 1H NMR spectrum the impurities were estimated to be up to 5% of the isolated product. The 13C NMR spectrum of the polymer also reveals several resonances in the carbonyl region (see ESI) which indicate the presence of polymer impurities resulting from side reactions. Initial attempts to remove these side products through sequential precipitation into ice cold acidified methanol was successful in the removal of the major impurities observed in the 1H NMR spectrum however analysis viaMALDI-TOF MS indicated that the larger main side product distribution remained. Furthermore, precipitation resulted in a significant detrimental effect on the yield, decreasing to 19%.
R-Pyridine | pKa | Time (min) | Monomer Conversion (%) | M n c (g mol−1) | M w/Mnc | DP b |
---|---|---|---|---|---|---|
a [L-malOCA]0 = 0.32 M; [ROH] = 0.016 M; 5 mol% amine catalyst, 25 °C. b Determined by 1H NMR Spectroscopy. c Determined by SEC analysis. d Polymer impurity observed by MALDI-TOF MS analysis. e Polymer impurity observed by 1H NMR Spectroscopy. f Polymer impurity observed by MALDI-TOF MS analysis at low catalyst concentration only. | ||||||
4-dimethyl-amino-d,e | 9.7 | 5 | >95 | 3730 | 1.19 | 23 |
4-morpholino-d,e | 8.8 | 60 | 94 | 3870 | 1.14 | 19 |
4-methoxy-d | 6.6 | 90 | 95 | 3860 | 1.10 | 22 |
4-methyl-f | 6.0 | 160 | 95 | 2950 | 1.12 | 17 |
H-f | 5.3 | 435 | 93 | 2100 | 1.13 | 16 |
ROP of L-malOCA ([M]/[I] = 20), initiated by neo-pentanol with 1 equivalent of substituted pyridine per alcohol was studied. Application of less basic pyridines led to a sequential decrease in polymerization activity. While SEC analysis of P(L-BMA)20 synthesized using 4-morpholinopyridine indicated that the polymerization was well controlled (Mn = 3 870 g mol−1; PDI = 1.14). Both 1H NMR spectroscopy and MALDI-TOF MS analysis indicated that side products were still present. Application of 4-methoxypyridine again resulted in a well controlled polymerization (Mn = 3 860 g mol−1; PDI = 1.10) however notably, 1H NMR spectroscopic analysis of the polymer did not reveal any side-product formation (Fig. 2a) and 13C NMR revealed only a minor amount of racemization of the monomer occurred during polymerization in comparison to the DMAP-catalyzed reaction. MALDI-TOF MS analysis indicated a main distribution centered around m/z = 4234.5 corresponding to a DP of 20 however, an impurity remained visible by MALDI-TOF MS analysis (Fig. 2b) but was able to be removed using column chromatography (Fig. 2c).
Fig. 2 (a) 1H NMR spectrum (400 MHz; CDCl3), (b) crude MALDI-TOF MS and (c) MALDI-TOF MS after column chromatography of a P(L-BMA) ([M]/[I] = 20) (Mn = 3 860 g mol−1, PDI = 1.10) prepared by ROP of L-malOCA ([L-malOCA]0 = 0.32 M) catalyzed with 5 mol% 4-methoxypyridine using neo-pentanol as the initiator. |
Further decreasing the basicity of the pyridine catalyst led to no impurities being observed by 1H or 13C NMR spectroscopy or MALDI-TOF MS. Notably, the molecular weights and corresponding degrees of polymerization of the resultant polymers obtained using 4-methyl pyridine or pyridine as catalyst were markedly lower than that predicted by the monomer:initiator ratio (Table 1). Variation of the molar equivalence of pyridine catalyst resulted in the observation of molar masses closer to those predicted although concurrent increased levels of impurities were observed by MALDI-TOF MS (Fig. 3).
Fig. 3 MALDI-TOF MS analysis of P(L-BMA)s ([M]/[I] = 50) prepared by ROP of L-malOCA ([L-malOCA]0 = 0.32 M) catalyzed with pyridine at; 2.5:1 to neo-pentanol (A), 20:1 to neo-pentanol (B) and 50:1 to neo-pentanol (C). |
Interestingly, inspection of the 1H NMR spectra measured during the polymerization of L-malOCA, catalyzed by pyridine, revealed notable differences in the chemical shift of the neo-pentyl group of the initiating/propagating species during the initial stages of the ROP of L-malOCA (See ESI). With high pyridine concentrations, the neo-pentyl group is observed as a singlet at δ = 0.86 ppm throughout the polymerization however, at lower pyridine concentrations this resonance is observed to change during the polymerization such that in the latter stages of the polymerization a singlet at δ = 0.86 ppm is observed while in the initial stages, multiple, resonances between δ = 0.94–0.84 ppm are observed. These observations indicate that at high pyridine concentrations, initiation is efficient whereas low pyridine concentrations lead to inefficient initiation and thus may lead to undesirable side reactions that consume monomer without yielding isolable polymer products.
Fig. 4 Plot of [M]/[I] versus Mn and PDI for ROP of L-malOCA ([L-malOCA]0 = 0.32 M) using 5 mol% 4-methoxypyridine and neo-pentanol as the initiator at a ratio of 1:1. |
Furthermore, as a consequence of the decreased rate of polymerization compared to DMAP-catalyzed ROP, it was also possible to observe a linear relationship between Mn and monomer conversion (Fig. 5). The ‘living’ characteristics of this polymerization were again confirmed through a second-feed experiment in which to a P(L-BMA)20 macroinitiator initiated from neo-pentanol ([M]/[I] = 20) (Mn = 3 860 g mol−1; PDI = 1.10), the further ROP of L-malOCA ([M]/[I] = 20) enabled a chain extended P(L-BMA)40 to be isolated that exhibited a double molar mass (Mn = 7 760 g mol−1) while maintaining a low PDI of 1.12. Leaving the resultant P(L-BMA)40 for 8 h (5 times longer than required to reach >90% monomer conversion) in the presence of 4-methoxypyridine resulted in negligible changes in both the molar mass (Mn = 8 030 g mol−1) and molar mass distribution (PDI = 1.11) again suggesting that transesterification side reactions were minimal despite full monomer consumption.
Fig. 5 Plot of monomer conversion versus Mn and PDI for ROP of L-malOCA ([L-malOCA]0 = 0.32 M) using 5 mol% 4-methoxypyridine and neo-pentanol as the initiator at a ratio of 1:1. |
We postulated that this impurity occurred as a consequence of a misinsertion of the propagating chain end into the disfavored 2-position of the OCA ring resulting in a carbonate linkage and a carboxylic acid ω-chain end group, capable of supporting a second sodium charge but incapable of further propagation (Scheme 1). To confirm the presence of the second sodium atom, the cationization agent used for the MALDI-TOF MS analysis was changed from sodium trifluoroacetate (NaTFA) to lithium chloride (LiCl). The resultant spectrum (See ESI) showed a major peak that was shifted from m/z = 4918.1 to m/z = 4886.5 respectively corresponding to a difference of m/z = 32, equal to the difference in mass between two sodium atoms and two lithium atoms thus confirming the proposed structure for this side product.
Scheme 1 Products of ring-opening of L-malOCA at (a) 5-position of the OCA ring and (b) 2-position of the OCA ring. |
DFT calculations were performed in order to calculate the energy difference in the ring opening transition states for opening at the two different carbonyl groups.42 Two transition structures for the model DMAP-catalyzed ring opening of lactic acid OCA at the ester like carbonyl group (Fig. 6, pathway i) with methanol first reported by Cossio, Bourissou and coworkers were recalculated using the same basis set with insignificant differences from those reported.41 We then found two related transition structures for the ring opening at the carbonate-like carbonyl group (Fig. 7, pathway ii). At the B3LYP/6-31G(d) level (after ZPE correction) the relative energies for the two ester-forming (pathway i) transition structures were +2.8 kJ mol−1 (TS1) and 0 kJ mol−1 (TS2), and for the two carbonate-forming (pathway ii) transition structures +6.5 kJ mol−1 (TS3) and +16.4 kJ mol−1 (TS4). A combination of these four pathways can be used to estimate a relative reaction rate of roughly 17 to 1 in favor of ester-formation (pathway i) opening at a temperature of 300 K. Comparable calculations using 4-methoxypyridine suggest that this catalyst results in reduced selectivity compared to the DMP-catalyzed reaction (9 to 1 in favor of ester formation at 300 K - see ESI for more details). These results are consistent with the proposal that, while less frequent, opening of OCAs catalyzed by substituted pyridines at the carbonate-like carbonyl (pathway ii) is indeed energetically feasible.
Fig. 6 (a) The two pathways (i and ii) for DMAP-catalyzed ring opening of lacOCA with nucleophilic attack of methanol at either of the two carbonyl groups; (b) calculated structures for ester-forming transition states; (c) calculated structures for carbonate-forming transition states. Key: Grey = Carbon; Red = Oxygen; Blue = Nitrogen; White = Hydrogen. |
Fig. 7 Deconvoluted ESI MS of a PMA ([M]/[I] = 20) (Mn = 1 100 g mol−1; PDI = 1.10) prepared through the hydrogenation of P(L-BMA)20 prepared by ROP of L-malOCA ([L-malOCA]0 = 0.32 M) catalyzed with 5 mol% pyridine using neo-pentanol as the initiator. Right-hand side: expanded region between m/z = 2380 and 2480. |
Polymer | M n c (g mol−1) | M w/Mnc | DP b |
---|---|---|---|
a [L-malOCA]0 = 0.32 M; 5 mol% MeOPy catalyst, 25 °C. b Degree of Polymerization, determined by 1H NMR Spectroscopy. c Determined by SEC analysis. | |||
MeO-PEO112-OH | 8 200 | 1.04 | — |
MeO-PEO227-OH | 16 270 | 1.03 | — |
PEO112-b-P(L-BMA)20 | 11 540 | 1.18 | 21 |
PEO227-b-P(L-BMA)20 | 19 440 | 1.03 | 23 |
PLLA20-OH | 2 640 | 1.11 | — |
PLLA50-OH | 7 680 | 1.06 | — |
PLLA20-b-P(L-BMA)20 | 5 890 | 1.12 | 22 |
Scheme 2 Deprotection of poly(benzyl α-(L)-malate), P(L-BMA), using hydrogenolysis to yield PMA. |
Electrospray MS analysis, obtained at high resolution provided additional confirmation of deprotection through observation of PMA20 as a doubly charged species with the major peak at m/z = 1203.5 that upon deconvolution (Fig. 7) resulted in a major peak at m/z = 2408.3 equal to the desired PMA20 along with additional peaks correlating to PMA20 species with a sodium charge (m/z = 2430.2) and with an additional sodium counterion resulting from exchange with a proton of one of the acid side-chain groups (m/z = 2452.1). A species displaying a lower molar mass was also present at m/z = 2390.2 matching ring closure of the PMA20 end group resulting in the loss of H2O. Additional analysis of both P(L-BMA)20 and PMA20 by SEC using a 0.1 M citric acid in THF solution as the eluent exhibited distributions with (Mn = 4 980 g mol−1; PDI = 1.06) and (Mn = 1 100 g mol−1; PDI = 1.10) respectively (compared to poly(styrene) standards). We postulated that the significant difference in molar mass that was observed between P(L-BMA)20 and PMA20viaSEC analysis is a result of interactions between the PMA20 and the eluent solvent system resulting in tightly coiled polymers thus leading to low observed molar mass values.
Hydrolytic degradations were performed in H2O at room temperature on a PMA ([M]/[I] = 15) at a concentration of 0.48 mmol L−1. The degradations were monitored via acid–base titration using a 0.45 mmol L−1 aqueous NaOH solution with four drops of a phenolphthalein pH indicator in methanol solution. Degradation was complete after 10 days determined when two equivalents of the NaOH solution was required to neutralize the reaction. Examination of 1H NMR spectra during the degradation in D2O demonstrates a gradual reduction of resonances attributed to PMA15 at δ = 5.67 and 3.17–2.96 ppm with a corresponding increase of new resonances at δ = 4.53 and 2.93–2.76 ppm respectively resulting from the degradation products. Electrospray (ESI) MS (Fig. 8) provided a useful method to monitor the loss of molar mass during the PMA degradation. Significant reduction in molar mass was observed early in the degradation after 30 h that subsequently continued at a slower rate realising near complete degradation to L-malic acid (m/z = 133.0) after 7 days with the final oligomers requiring an additional 3 days to fully degrade.
Fig. 8 ESI MS analysis of the degradation of PMA ([M]/[I] = 15) ([PMA15]0 = 0.36 mmol L−1) in H2O at room temperature. |
The versatility of the polymerization system was shown through the successful initiation from alcohols including PEO and PLLA as macroinitiators in the preparation of block copolymers. Removal of the benzyl protecting groups was successful without any polymer backbone scission to yield hydrophilic poly(ester)s and degradation studies of the resultant PMA15 in H2O was demonstrated to occur fully within 10 days as determined by titration, 1H NMR and mass spectrometry.
Footnotes |
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c1py00254f |
‡ Retention of the stereochemistry was confirmed through measurement of their specific rotation viapolarimetry observing [α]33D values of −21.9° (in CHCl3, c = 5.96 g L−1); other methods to confirm this were not possible as a consequence of the reactivity of the monomer or lack of heavy atoms in the monomer. ROP using pyridine result in the observation of only 2 carbonyl resonances (using DMAP results in several such resonances) which indicates that the monomer is indeed stereopure. |
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