Richard
Todd
a,
Gabriel
Rubio
ab,
Daniel J.
Hall
a,
Sarah
Tempelaar
a and
Andrew P.
Dove
*a
aDepartment of Chemistry, University of Warwick, Coventry, CV4 7AL, UK. E-mail: a.p.dove@warwick.ac.uk; Tel: +44 (0)24 7652 4107
bUniversity of Barcelona, Martí i Franquès Street, 1 08028, Barcelona, Spain
First published on 12th December 2012
The synthesis and application of a dibenzyl-functionalized bispidine, in combination with 1-(3,5-bis(trifluoromethyl)phenyl)-3-cyclohexylthiourea (TU) co-catalyst, has been demonstrated to be an excellent catalyst for the controlled ring-opening polymerisation (ROP) of lactide and cyclic carbonate monomers. Notably, the polymerisation proceeds with negligible transesterification or epimerisation, with the polymerisation of stereopure L-lactide affording highly crystalline poly(lactide) with a Tm of 156 °C. ROP of racemic lactide results in the observation of a modest degree of stereocontrol such that the probability of isotactic enchainment, Pm = 0.74. Comparison of a range of alternative hydrogen bond donor co-catalysts revealed that TU displayed the highest polymerisation rates in combination with the dibenzyl-functionalized bispidine.
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Fig. 1 Ring opening-polymerisation catalysts. |
In addition to its uses in ROP, (−)-sparteine has a number of other uses such as a chiral ligand in asymmetric deprotonations, substitutions and metalations.23–26 Despite this widespread use and utility, (−)-sparteine has become increasingly difficult to acquire through commercial sources. Several potential routes to obtain (−)-sparteine exist including isolation from the abundant Scotch Broom (Cytisus scoparius),27 or total synthesis via a multistep route that has varying overall yields.28,29 Furthermore, the derivation of synthetic replacements may enable more highly active and stereoselective analogues to be realised.
These challenges to obtaining (−)-sparteine have led to the investigation of synthetically simple analogues. Aided by computational modelling, Hedrick and co-workers recently identified several commercially available tertiary amines that displayed similar nitrogen–nitrogen spacing (∼3 Å) and lone pair orientations to (−)-sparteine.30 Of the tertiary amines selected, tris[2-dimethylamino)ethyl]amine (Me6TREN) and 1,4,7-trimethyl-1,4,7-triazacyclononane (TACN), in combination with TU, proved the most effective co-catalysts in the ROP of lactide. While TACN displayed comparable polymerization kinetics to (−)-sparteine, transesterification was noted to occur rapidly upon complete conversion of the monomer. Application of Me6TREN led to better polymerisation control albeit at a slightly longer polymerisation time.
We hypothesised that a closer structural analogue to (−)-sparteine would lead to more comparable behaviour in ROP, and hence targeted the preparation of analogous bispidines. Herein we report the improved synthesis of a dibenzyl-functional bispidine, chosen for its identical backbone and similar basicity (pKa = 21.25) to (−)-sparteine in addition to its apparent ease of synthesis,17 and explore its activity in the ROP of lactide, comparing directly to that of (−)-sparteine and Me6TREN. Extension of the application of this species with a range of co-catalysts and other monomer feedstocks is also demonstrated.
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Scheme 1 Benzyl bispidine synthesis. (a) Paraformaldehyde, KOH, 95 °C; (b) LiAlH4, THF; (c) 6a: I2, Pred, 120 °C; 6b: PBr3, 100 °C; (d) benzylamine, toluene, reflux. |
The ROP of L-lactide, LA, using 10 mol% TU and 5 mol% 2, was studied in CDCl3 ([LA]0 = 0.7 M) at ambient temperature using 1-phenylethanol as the initiator at a monomer-to-initiator ratio of 50 ([M]0/[I]0 = 50). Monitoring the polymerisation by 1H NMR spectroscopy revealed that it had reached 87% monomer conversion after only 81 min. Analysis of the resultant polymer by gel-permeation chromatography (GPC) revealed a number average molecular weight (Mn) of 13.4 kg mol−1 with a narrow dispersity (ĐM = 1.08). Under the same conditions, polymerisation of L-LA with (−)-sparteine and Me6TREN in place of 2 reached 93% and 92% monomer conversion after 66 and 450 min respectively with similar molecular parameters for the resulting PLA observed by GPC analysis (Table 1). To more precisely compare catalyst reactivities, kinetic studies of LA ROP for each catalyst system were investigated in triplicate (Fig. 2). First order kinetic plots of ln([M]0/[M]t) against time reveal a linear correlation, with apparent rate constants (Kapp) calculated as 1.35 h−1, 2.53 h−1 and 0.38 h−1 for 2, (−)-sparteine and Me6TREN in combination with TU respectively. Under these conditions, while the bispidine catalyses lactide ROP at a lower rate than (−)-sparteine, the polymerisation occurs almost four times faster then when Me6TREN is applied.
Catalysta | Conversionb (%) | Time (min) | M n (g mol−1) | Đ M | K app (h−1) |
---|---|---|---|---|---|
a Conditions: 1 ml of CDCl3 at room temperature; [L-LA] = 0.7 M; 1-phenylethanol as initiator; 5 mol% tertiary amine; 10 mol% of TU; [M]0/[I]0 = 50. b Determined by 1H NMR spectroscopy. c Determined by GPC analysis in CHCl3. | |||||
(−)-Sparteine | 93 | 66 | 14![]() |
1.08 | 2.53 |
2 | 87 | 81 | 13![]() |
1.08 | 1.35 |
Me6TREN | 92 | 450 | 12![]() |
1.09 | 0.38 |
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Fig. 2 Semi-log kinetic plot for the ROP of L-LA using TU in combination with a tertiary amine cocatalyst. (Red = (−)-sparteine; blue = 2; green = Me6TREN). |
The controlled nature of the benzyl bispidine-catalysed polymerisation was further verified by the linear correlation between Mn values obtained by GPC and the monomer conversion determined by 1H NMR spectroscopy (Fig. 3a) and the [M]/[I] ratio (Fig. 3b). The resultant PLAs all displayed narrow dispersities (1.18–1.03, Table 2) which indicates that minimal transesterification is occurring. Further analysis of the resultant polymers by matrix-assisted laser desorption ionisation time of flight mass spectrometry (MALDI-ToF MS) revealed only single distributions with spacings of 144 m/z between neighbouring peaks (Fig. 4). The absence of a second distribution with spacings of 72 m/z is consistent with the absence of transesterification side reactions.
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Fig. 3 (a) Number-average molecular weight (Mn) against % monomer conversion and (b) number-average molecular weight (Mn) and dispersity (ĐM) against initial monomer-to-initiator ratio ([M]0/[I]0) for the ROP of L-LA using TU and 2. |
[M]/[I] | Conversionb (%) | Time (min) | M n (g mol−1) | Đ M |
---|---|---|---|---|
a Conditions: CDCl3; room temperature; [L-LA] = 0.7 M; 1-phenylethanol as initiator; 5 mol% of 2; 10 mol% of TU. b Determined by 1H NMR spectroscopy. c Determined by GPC analysis in CHCl3. | ||||
10 | 90 | 21 | 3280 | 1.18 |
20 | 94 | 43 | 6050 | 1.09 |
50 | 92 | 75 | 13![]() |
1.08 |
100 | 89 | 137 | 26![]() |
1.06 |
250 | 90 | 366 | 61![]() |
1.03 |
Thermal analysis of PLLAs with a degree of polymerisation (DP) of 100 synthesised using TU with both 2 and (−)-sparteine observed a melting temperature, Tm, of 156 and 158 °C respectively. These match the previously reported melting points for isotactic PLLA prepared using (−)-sparteine.34,35 In combination with the observation of a singlet resonance in both the homonuclear decoupled 1H NMR and 13C NMR spectra of PLLA synthesised in this manner, these observations confirm the absence of stereo errors, and hence an absence of epimerisation, with identical levels resulting from both (−)-sparteine and 2 catalysed polymerisations.36–39
ROP of rac-lactide was undertaken to determine if any stereoselectivity would be observed using the catalyst combination of TU and 2. Despite the absence of stereogenic centres in 2, unlike (−)-sparteine, analysis of a DP100 poly(rac-lactide) by homonuclear decoupled 1H NMR spectroscopy enabled the calculation of the probability of isotactic enchainment, Pm, to be 0.74, clearly demonstrating a preference to produce isotactic PLA from the racemic monomer mixture. This is comparable to that observed for rac-LA ROP with (−)-sparteine–TU which resulted in a Pm = 0.74 (literature value: Pm = 0.77).16
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Fig. 5 Hydrogen bond donor co-catalysts. |
The ROP of L-lactide, LA, using 5 mol% 2 with 10 mol% hydrogen bond donor co-catalyst was again studied in CDCl3 ([LA]0 = 0.7 M) at ambient temperature using 1-phenylethanol as the initiator at a monomer-to-initiator ratio of 50 ([M]0/[I]0 = 50). The limited solubility of 11 in chloroform required its application at the lower molar ratio of 5 mol% (in preference to the standard 10 mol%). To provide an accurate comparison, polymerisations using co-catalyst TU were also undertaken at 5 mol% loading. Kinetic studies for each catalyst system were investigated in triplicate by monitoring monomer conversion against time using 1H NMR spectroscopy. First order kinetic plots of ln([M]0/[M]t) against time (Fig. 6) enabled the determination of Kapp values (Table 3). The tested catalysts demonstrated a broad range of activities, with Kapp values ranging from 1.35 h−1 to 0.03 h−1. While TU at 10 mol% loading resulted in the most rapid polymerisation, the alternative co-catalysts were observed to display much lower Kapp values such that the second most active co-catalyst is m-trifluoromethylphenol, 12 with a Kapp approximately an order of magnitude lower than that observed for TU. Notably the amide catalyst 11 (5 mol% loading) remained highly active with the measured Kapp value approximately 6 times lower than that TU at the reduced 5 mol% loading. Polymerisation using co-catalyst 7 displayed extremely low reaction rate under these conditions, with <5% monomer conversion being observed after one week.
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Fig. 6 Kinetic plots resulting from variation in hydrogen bond donor. |
Co-Catalyst | [M]/[I] | Conversionc (%) | Time (min) | M n (g mol−1) | Đ M | K app (h−1) |
---|---|---|---|---|---|---|
a Conditions: 1 ml of CDCl3 at room temperature; [L-LA] = 0.7 M; 5 mol% 2; 10 mol% co-catalyst; 1-phenylethanol as initiator. b Conditions: 1 ml of CDCl3 at room temperature; [L-LA] = 0.7 M; 5 mol% 2; 5 mol% co-catalyst; 1-phenylethanol as initiator. c Determined by 1H NMR spectroscopy. d Determined by GPC analysis in CHCl3. | ||||||
TUa | 50 | 86 | 75 | 13![]() |
1.08 | 1.354 ± 0.053 |
TUb | 50 | 90 | 350 | 12![]() |
1.07 | 0.391 ± 0.027 |
8a | 50 | 86 | 1220 | 8450 | 1.06 | 0.103 ± 0.001 |
9a | 50 | 91 | 3240 | 9090 | 1.11 | 0.044 ± 0.002 |
10a | 50 | 86 | 4200 | 10![]() |
1.08 | 0.029 ± 0.001 |
11b | 50 | 92 | 2710 | 11![]() |
1.08 | 0.063 ± 0.007 |
12a | 50 | 93 | 1470 | 4010 | 1.20 | 0.138 ± 0.007 |
In each case, analysis of the molecular parameters of the resultant polymers revealed low dispersity values which suggests that the polymerisations were well controlled (Table 3). Notably however, co-catalyst 12 resulted in PLLA with lower molecular weight than predicted from the [M]0/[I]0 ratio. MALDI-ToF MS analysis of this polymer revealed two distinct distributions, both displaying the expected 144 m/z spacing for the monomer repeat unit. A molecular weight difference of ∼40 m/z was observed between the distributions. One of these distributions revealed values that correspond to sodium-charged polymer chains initiated from 1-phenylethanol as expected, however the other distribution showed values revealed values that correspond to sodium-charged polymer chains initiated from the co-catalyst 12, which possibly contributes to the increased observed rate of polymerisation. In the case of 9, in which two CF3 substituents are present on the phenol ring, co-catalyst initiation was not observed which suggests that the phenol in 9 is appropriately activated to only undertake hydrogen bonding and not serve as a source of initiation in the polymerisation.
Interestingly, 1H NMR spectroscopic analysis of the polymer produced using 2/8 as co-catalysts for the ROP of L-LA revealed a number of overlapping quartets in the range of 5.10–5.25 ppm, consistent with the epimerisation of the monomer during the polymerisation. Despite the previous report of the ROP of L-LA using (−)-sparteine/8 proceeding in the absence of epimerisation,22 in our hands, comparable 1H NMR spectra of the resultant polymers were also obtained for this system.
The ROP of TMC was performed using 5 mol% of 2 or (−)-sparteine with 5 mol% TU. After ca. 70 h 1H NMR spectroscopic analysis of the polymerisation mixtures revealed monomer conversions >90% (Table 4). GPC analysis of the resultant poly(TMC)s showed similar Mn values resulted from polymerisations using both catalysts with narrow dispersities observed. MALDI-ToF analysis of the poly(TMC) synthesised using 2–TU revealed a single distribution having the desired spacing of 102 m/z. No secondary distributions were observed in the MALDI-ToF spectra.
Monomer | Catalyst | [M]0/[I]0 | Conversionc (%) | Time (min) | M n (g mol−1) | Đ M |
---|---|---|---|---|---|---|
a Conditions: 0.5 ml of CDCl3 at room temperature; [TMC] = 2.0 M; 5 mol% tertiary amine; 5 mol% TU; benzyl alcohol as initiator. b Conditions: 0.5 ml of CDCl3 at room temperature; [MAC] = 0.5 M; 5 mol% tertiary amine; 10 mol% TU; benzyl alcohol as initiator. c Determined by 1H NMR spectroscopy. d Determined by GPC analysis in CHCl3. e Determined by GPC analysis in DMF. | ||||||
TMCa | (−)-Sparteine | 50 | 92 | 4280 | 9100d | 1.03d |
TMCa | 2 | 50 | 90 | 4750 | 9100d | 1.03d |
MACb | (−)-Sparteine | 20 | 90 | 400 | 6400e | 1.11e |
MACb | 2 | 20 | 90 | 410 | 6200e | 1.10e |
MACb | Me6TREN | 20 | 89 | 45 days | 6100e | 1.13e |
The polymerisations of MAC were undertaken using 5 mol% of 2 or (−)-sparteine with 10 mol% TU, as recently reported.41 Targeting a DP of 20, polymerisations catalysed by TU in combination with 2 or (−)-sparteine achieved 90% monomer conversion after 410 and 400 min respectively. Notably these results demonstrate the comparable activity of both bispidine co-catalysts for the ROP of cyclic carbonates. In both cases, GPC analysis revealed that the molecular weights and dispersities for the resulting poly(MAC) were within error and MALDI-ToF MS analysis revealed only the desired single distribution with the predicted spacing of 200 m/z that corresponds to the molecular weight of the repeat unit. Interestingly, the application of 10 mol% TU with 5 mol% Me6TREN revealed a slower polymerization such that 89% conversion was recorded after 45 days. GPC analysis of the resultant polymer revealed molecular weights and dispersities in close agreement to (−)-sparteine and 2.
Footnote |
† Electronic supplementary information (ESI) available: Experimental details, NMR spectra, polymer tacticity analysis, thermal analysis and MALDI-ToF spectra. See DOI: 10.1039/c2sc22053a |
This journal is © The Royal Society of Chemistry 2013 |