Temperature Methanolic ATRP
2.4.1 PEG-Br Macroinitiator Synthesis
2.4.1.1 Methods
A typical procedure for the preparation of methoxy-capped poly(ethylene glycol) initiator (PEG-Br) from a poly(ethylene glycol) mono-methyl ether (PEG-OH) with
Mn = 750 is outlined below.
PEG-OH Mn = 750 (20 g, 26.6 mmol, 1 eq.), toluene (anhydrous) (150 mL), 4-
Dimethylaminopyridine (DMAP) (0.32 g, 2.66 mmol, 0.1 eq.), and triethylamine (TEA) (4.08 mL, 2.96 g, 29.26 mmol, 1.1 eq.) were placed in a round-bottomed flask
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fitted with a magnetic stirrer bar. 2-Bromoisobutyryl bromide (3.62 ml, 2.96 g, 29.26 mmol, 1.1 eq.) was added dropwise to the solution via a syringe over around one hour. The solution was stirred overnight, after which Amberlyst resin A21 (20 g) was added to remove residual acid bromide and the mixture stirred for about one hour. The solution was then filtered over celite to remove any insoluble materials. Solvent was removed under vacuum from the resulting clear pale yellow filtrate. The white oily product was dried at 60 °C in a vacuum oven overnight and stored at ~- 2°C. The method was slightly altered for the preparation of the higher molecular weight initiators. Toluene was warmed to around 50 °C in order to dissolve the PEG-OH with molecular weights of 2000 g mol-1 and 5000 g mol-1. These products were purified by evaporation of the toluene to around a third of the original volume before precipitation into cold petroleum ether. The macroinitiator was collected on filter paper and dried under vacuum yielding white powdery products.
2.4.1.2 1H NMR Spectroscopic analysis of PEGx-Br macroinitiators.
Figure 2.3: 1H NMR (CDCl3 - ppm) analysis of a PEGx-Br macroinitiator.
Peaks were assigned as follows: 1.94 (ester CH3) (e), 3.38 (methoxy CH3) (a), 3.50-
3.80 (PEG CH2)(b), 4.32 (CH2-O-CO) (d).
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equivalent methyl groups of the tertiary bromide group. The signal at 4.33 ppm corresponds to the methylene adjacent to the ester group a ratio of the integrals of signals to the mono-methyl end-group indicated the extent of the esterification. 13C NMR (100 MHz, D2O) δ ppm 174.0, 71.5, 70.4, 70.1, 70.0, 68.8, 58.6, 30.5.
GPC (THF eluent): Initiators were diluted in THF or acetone (5 mL-1) and passed through a 200 nm syringe filter prior to injection. PEG17-Br could not be analysed by
GPC, the elution time of this initiator was not within the detection limits of the separation columns.
2.4.2 ATRP polymerisation of linear and branched linear and branched
PEG
x-b-p(HPMA) block copolymers
In a typical synthesis, PEG117-Br initiator (0.94 g, 1.03 mmol) and HPMA (7.39 g,
51.26 mmol; target DPn = 50 monomer units, and anisole (20 % w/v based on
monomer) were placed into a 100 mL round-bottomed flask. HPLC grade methanol was added (50 % w/v (initiator, monomer/solvent)) and the solution was stirred/deoxygenated using a nitrogen purge for 10 minutes. Cu(I)Cl (0.10 g,1.03 mmol) and BPY (0.19 g, 0.97 mmol) were added to the flask whilst maintaining a positive nitrogen flow. Samples of the reaction (~0.5 mL) were taken and diluted into THF for GPC analysis and d6-DMSO for 1H NMR spectroscopic analysis. End
group analysis could be performed when utilising PEG17, where integration of the
methoxy chain end (3.2 ppm) and terminal methyl group of p(HPMA) (1 – 1.22 ppm), however, this was very inaccurate and unreliable, where the peak for water (~3.19 ppm) could shift, resulting in peak overlap. For copolymers with higher molecular weight PEG (2000 and 5000 g mol-1) the methoxy chain end (3.2 ppm) could not be distinguished from the baseline, therefore end group analysis could not
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be performed, For GPC analysis, HPLC grade THF as the eluent, stabilized with 2,6- ditert-butyl-4-methylphenol, with a flow rate of 1 mL min-1. Samples for analysis of polymerisation kinetics were purified by passing over basic alumina column before removal of solvent. Dried samples were re-dissolved in THF to a concentration of 5 mg mL-1 and passed through a syringe filter (0.2 mm) prior to injection.
2.4.2.1 1H NMR Spectroscopic analysis of PEGx-Br initiated p(HPMA)
Figure 2.4: 1H NMR (CDCl3 - ppm) analysis of PEGx-Br initiated p(HPMA).
PEG17-b-p(HPMA50): 1H NMR (d6-DMSO - ppm): 0.65-1.02 (d), 1.02-1.26 (c), 1.64-
2.01 (b), 3.22-3.26 (a), 3.3-3.5 (f), 3.49-3.54 (e), 3.56-3.87 (f), 4.53-4.71 (g).
End group analysis of PEGx copolymers to determine DPn could not be accurately
performed due to overlap with water signals and (f) the small signal also deviated from the baseline when spectrum scaling was increased leading to inaccurate integration and therefore calculated DPn. In branched copolymer samples, proton
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signals in EGDMA were undetectable as the ratio of HPMA:EGDMA was extremely small and overlapped with (f) in spectra.
2.4.2.2 Kinetic Studies for ATRP linear and branched polymerisation of PEGx-b-
p(HPMA)
For kinetic studies, identical copolymerisation protocol was followed, in addition to regular sampling via removal of ~0.5 mL of the solution where a nitrogen purge was applied. A small amount of this was added to ~ 1 mL of d6-DMSO for 1H NMR
spectroscopic analysis. The remaining sample was diluted into THF (~ 5 mL) and shaken to ensure efficient termination followed by passing over a small basic alumina column and into a pre-weighed sample vial. THF was allowed to completely evaporate and the vial was then re-weighed and THF was added to achieve 5 mg mL-
1
solution for triple detection GPC analysis.
The copolymerisation of branched PEGx-b-p(HPMA) and kinetic studies of branched
p(HPMA) were performed using the same protocol that is described above. For a typical polymerisation (target DPn = 50 monomer units), HPMA (9.61 g, 66.5 mmol),
PEG17Br (1 g, 1.33 mmol) and EGDMA (0.25 g, 1.26 mmol) plus anisole as an
internal standard (20 w/v % based on HPMA feed) and methanol, 50 w/v % (initiator+monomer/methanol) were utilised. This 1: 0.95 monomer : brancher ratio was used for all of the branching polymerisations.
2.4.2.3 Chain Extension of PEG17-b-p(HPMAx) Block Copolymer
A typical procedure for the chain extension of PEG17-b-p(HPMA30) to PEG17-b- p(HPMA30)-b-p(HPMA50) is outlined here. PEG17Br initiator (1 g, 1.33 mmol),
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w/v based on monomer) were placed into a 100 mL round-bottomed flask fitted with a magnetic stirrer bar. Methanol (HPLC grade) was added (50 % w/v based on initiator and monomer) and the solution was stirred and degassed using a nitrogen purge for approximately 10 minutes. Cu(I)Cl (0.13 g, 1.33 mmol) and BPY (0.52 g, 3.32 mmol) were weighed together and promptly added to the flask whilst still maintaining a positive nitrogen flow. The nitrogen flow was removed and reaction flask sealed leaving the mixture to polymerise at ambient temperature. After ~ 80 % conversion of the initial monomer feed (previous kinetic studies determined this approximate timing and sampling of the reaction at this time gave the exact conversion), HPMA (9.57 g, 66.5 mmol; target DPn = 50 monomer units) and
methanol (50 % v/v based on HPMA monomer) was degassed in a separate flask and quickly added to the reaction via a double-ended needle whilst maintaining a positive nitrogen flow to the reaction flask. The nitrogen purge was removed and the reaction was sealed and left to polymerise under ambient conditions only subjected to termination and purification after high conversion was reached. Samples were analysed as described above.