Controlling dispersity in aqueous atom transfer radical polymerization: rapid and quantitative synthesis of one-pot block copolymers

The dispersity (Đ) of a polymer is a key parameter in material design, and variations in Đ can have a strong influence on fundamental polymer properties. Despite its importance, current polymerization strategies to control Đ operate exclusively in organic media and are limited by slow polymerization rates, moderate conversions, significant loss of initiator efficiency and lack of dispersity control in block copolymers. Here, we demonstrate a rapid and quantitative method to tailor Đ of both homo and block copolymers in aqueous atom transfer radical polymerization. By using excess ligand to regulate the dissociation of bromide ions from the copper deactivator complexes, a wide range of monomodal molecular weight distributions (1.08 < Đ < 1.60) can be obtained within 10 min while achieving very high monomer conversions (∼99%). Despite the high conversions and the broad molecular weight distributions, very high end-group fidelity is maintained as exemplified by the ability to synthesize in situ diblock copolymers with absolute control over the dispersity of either block (e.g. low Đ → high Đ, high Đ → high Đ, high Đ → low Đ). The potential of our approach is further highlighted by the synthesis of complex pentablock and decablock copolymers without any need for purification between the iterative block formation steps. Other benefits of our methodology include the possibility to control Đ without affecting the Mn, the interesting mechanistic concept that sheds light onto aqueous polymerizations and the capability to operate in the presence of air.

Size-exclusion chromatography (SEC). SEC was measured on a Shimadzu equipment comprising a CBM-20A system controller, LC-20AD pump, SIL-20A automatic injector, 10.0 bead-size guard column (50 x 7.5 mm) followed by three KF-805L columns (300 x 8 mm, bead size: 10 , pore size maximum: 5000 Å), SPD-20A ultraviolet detector, and an RID-20A differential refractive index detector. The column temperature was maintained at 40 using a ℃ CTO-20A oven. The flow rate was set to 1 ml/min and with N, N-dimethylacetamide (DMAc, Acros, HPLC grade, with 0.03 w/v LiBr) as the eluent. Molecular weights were determined relative poly(methyl methacrylate) standards with molecular weights ranging from 5,000 to 1.5 x 10 6 g/mol (Agilent Technologies). All SEC samples were dissolved in DMAc and passed through 0.45 filters prior to analysis.

Polymerization of PNIPAM.
To a vial fitted with a magnetic stir bar and a rubber septum, H 2 O (3 mL) and varying amounts of Me 6 TREN (depending on the target dispersity) were charged and the mixture was bubbled with nitrogen for 10 min. CuBr (12.7 mg, 0.0884 mmol) was then carefully added under continuous nitrogen bubbling. The nitrogen bubbling was left to proceed for another 10 min and then the blue suspension with purple red color copper (0) powder was allowed to stir at ambient temperature. At the same time, to another vial fitted with a rubber septum, H 2 O (3 mL), 2, 3-dihydroxypropyl 2-bromo-2-methylpropanoate (8.9 mg, 0.0368 mmol) and NIPAM (0.5 g, 4.42 mmol) were charged and the mixture was bubbled with nitrogen for 15 min. Subsequently, the degassed monomer/initiator aqueous solution was transferred via a degassed syringe to the vial with Cu (0)/CuBr 2 /Me 6 TREN catalyst. The solution was allowed to polymerize at 0 °C for 6-10 min.
To a vial fitted with a magnetic stir bar and a rubber septum, H 2 O (3 mL) and Me 6 TREN (70.9 L, 0.2651 mmol) were charged and the mixture was bubbled with nitrogen for 10 min. CuBr (12.7 mg, 0.0884 mmol) was then carefully added under continuous nitrogen bubbling. The nitrogen bubbling was left to proceed for another 10 min and then the blue suspension with purple red color copper (0) powder was allowed to stir at ambient temperature. At the same time, to another vial fitted with a rubber septum, H 2 O (3 mL), 2, 3-dihydroxypropyl 2-bromo-2-methylpropanoate (8.9 mg, 0.0368 mmol) and NIPAM (0.5 g, 4.42 mmol) were charged and the mixture was bubbled with nitrogen for 15 min. Subsequently, the degassed monomer/initiator aqueous solution was transferred via a degassed syringe to the vial with Cu (0)/CuBr 2 /Me 6 TREN catalyst to initiate polymerization. The solution was allowed to polymerize at 0 °C for 6 min. Subsequently, an aliquot of degassed NIPAM (1 g, 8.83 mmol) in H 2 O (6 mL) was injected via a degassed syringe and the polymerization was left to proceed for 15 min.
Polymerization of high-to-high dispersity PNIPAM-block-PHEAM diblock copolymer. To a vial fitted with a magnetic stir bar and a rubber septum, H 2 O (3 mL) and Me 6 TREN (70.9 L, 0.2651 mmol) were charged and the mixture was bubbled with nitrogen for 10 min. CuBr (12.7 mg, 0.0884 mmol) was then carefully added under continuous nitrogen bubbling. The nitrogen bubbling was left to proceed for another 10 min and then the blue suspension with purple red color copper (0) powder was allowed to stir at ambient temperature. At the same time, to another vial fitted with a rubber septum, H 2 O (3 mL), 2, 3-dihydroxypropyl 2-bromo-2-methylpropanoate (8.9 mg, 0.0368 mmol) and NIPAM (0.5 g, 4.42 mmol) were charged and the mixture was bubbled with nitrogen for 15 min. Subsequently, the degassed monomer/initiator aqueous solution was transferred via a degassed syringe to the vial with Cu (0)/CuBr 2 /Me 6 TREN catalyst to initiate polymerization. The solution was allowed to polymerize at 0 °C for 6 min. Subsequently, an aliquot of degassed HEAM (1.02 g, 8.83 mmol) in H 2 O (2.25 mL) was injected via a degassed syringe and the polymerization was left to proceed for 15 min.
Polymerization of high-to-low dispersity PNIPAM diblock copolymer. To a vial fitted with a magnetic stir bar and a rubber septum, H 2 O (3 mL) and Me 6 TREN (70.9 L, 0.2651 mmol) were charged and the mixture was bubbled with nitrogen for 10 min. CuBr (12.7 mg, 0.0884 mmol) was then carefully added under continuous nitrogen bubbling. The nitrogen bubbling was left to proceed for another 10 min and then the blue suspension with purple red color copper (0) powder was allowed to stir at ambient temperature. At the same time, to another vial fitted with a rubber septum, H 2 O (3 mL), 2, 3-dihydroxypropyl 2-bromo-2-methylpropanoate (8.9 mg, 0.0368 mmol) and NIPAM (0.5 g, 4.42 mmol) were charged and the mixture was bubbled with nitrogen for 15 min. Subsequently, the degassed monomer/initiator aqueous solution was transferred via a degassed syringe to the vial with Cu (0)/CuBr 2 /Me 6 TREN catalyst to initiate polymerization. The solution was allowed to polymerize at 0 °C for 6 min. Subsequently, an aliquot of degassed NIPAM (1 g, 8.83 mmol) and NaBr (0.455 g, 4.42 mmol) in H 2 O (9 mL) was injected via a degassed syringe and the polymerization was left to proceed for 15 min.
Polymerization of low-to-high dispersity PNIPAM diblock copolymer. To a vial fitted with a magnetic stir bar and a rubber septum, H 2 O (3 mL) and Me 6 TREN (15.7 L, 0.0589 mmol) were charged and the mixture was bubbled with nitrogen for 10 min. CuBr (12.7 mg, 0.0884 mmol) was then carefully added under continuous nitrogen bubbling. The nitrogen bubbling was left to proceed for another 10 min and then the blue suspension with purple red color copper (0) powder was allowed to stir at ambient temperature. At the same time, to another vial fitted with a rubber septum, H 2 O (3 mL), 2, 3-dihydroxypropyl 2-bromo-2-methylpropanoate (8.9 mg, 0.0434 mmol) and NIPAM (0.5 g, 0.0368 mmol) were charged and the mixture was bubbled with nitrogen for 15 min. Subsequently, the degassed monomer/initiator aqueous solution was transferred via a degassed syringe to the vial with Cu (0)/CuBr 2 /Me 6 TREN catalyst to initiate polymerization. The solution was allowed to polymerize at 0 °C for 6 min. Subsequently, an aliquot of degassed NIPAM (1 g, 8.83 mmol) and Me 6 Tren (31.5 L, 0.0118 mmol) in H 2 O (6 mL) was injected via a degassed syringe and the polymerization was left to proceed for 15 min.
Polymerization of PNIPAM in the presence of NaOH. A 0.1 M NaOH stock solution was first prepared. To a vial fitted with a magnetic stir bar and a rubber septum, H 2 O (3 mL), Me 6 TREN (15.7 L, 0.0136 mmol), and various amounts of 0.1 M NaOH stock solution were charged and the mixture was bubbled with nitrogen for 10 min. CuBr (12.7 mg, 0.0884 mmol) was then carefully added under continuous nitrogen bubbling. The nitrogen bubbling was left to proceed for another 15 min and then the blue suspension with purple red color copper (0) powder was allowed to stir at ambient temperature. At the same time, to another vial fitted with a rubber septum, H 2 O (3 mL), 2, 3-dihydroxypropyl 2-bromo-2-methylpropanoate (8.9 mg, 0.0434 mmol) and NIPAM (0.5 g, 0.0368 mmol) were charged and the mixture was bubbled with nitrogen for 15 min.
Polymerization of in-situ high-dispersity PNIPAM decablock copolymer. To a vial fitted with a magnetic stir bar and a rubber septum, H 2 O (3 mL) and Me 6 TREN (70.9 L, 0.2651 mmol) were charged and the mixture was bubbled with nitrogen for 10 min. CuBr (12.7 mg, 0.0884 mmol) was then carefully added under continuous nitrogen bubbling. The nitrogen bubbling was left to proceed for another 10 min and then the blue suspension with purple red color copper (0) powder was allowed to stir at ambient temperature. At the same time, to another vial fitted with a rubber septum, H 2 O (3 mL), 2, 3-dihydroxypropyl 2-bromo-2-methylpropanoate (8.9 mg, 0.0368 mmol) and NIPAM (0.5 g, 4.42 mmol) were charged and the mixture was bubbled with nitrogen for 15 min. Subsequently, the degassed monomer/initiator aqueous solution was transferred via a degassed syringe to the vial with Cu (0)/CuBr 2 /Me 6 TREN catalyst to initiate polymerization. The solution was allowed to polymerize at 0 °C for 10 min. During polymerization, 9 aliquots of NIPAM (0.125 g, 1.10 mmol) solution in water (0.75 mL) were bubbled with nitrogen and injected subsequently to each other into the reaction after quantitative conversion of the previous block.

Polymerization of in-situ high-dispersity PNIPAM-block-PHEAM-block-PNIPAM-block-PHEAM-block-PNAM pentablock copolymer.
To a vial fitted with a magnetic stir bar and a rubber septum, H 2 O (1.5 mL) and Me 6 TREN (35.4 L, 0.1326 mmol) were charged and the mixture was bubbled with nitrogen for 10 min. CuBr (6.35 mg, 0.0442 mmol) was then carefully added under continuous nitrogen bubbling. The nitrogen bubbling was left to proceed for another 10 min and then the blue suspension with purple red color copper (0) powder was allowed to stir at ambient temperature. At the same time, to another vial fitted with a rubber septum, H 2 O (1.5 mL), 2, 3-dihydroxypropyl 2-bromo-2-methylpropanoate (4.4 mg, 0.0184 mmol) and NIPAM (0.25 g, 2.21 mmol) were charged and the mixture was bubbled with nitrogen for 15 min. Subsequently, the degassed monomer/initiator aqueous solution was transferred via a degassed syringe to the vial with Cu (0)/CuBr 2 /Me 6 TREN catalyst to initiate polymerization. The solution was allowed to polymerize at 0 °C for 10 min. During polymerization, 1 aliquot of NIPAM (0.5 g, 4.42 mmol) solution in water (4.5 mL), 2 aliquots of HEAM (0.509 g, 4.42 mmol) solution in water (5 mL), and 1 aliquot of NAM (0.624 g, 4.42 mmol) in water (6 mL) were bubbled with nitrogen and injected subsequently to each other into the reaction after quantitative conversion of the previous block.

Polymerization of in-situ high-dispersity block-PHEAM-block-PNIPAM-block-PHEAMblock-PNAM pentablock copolymer in the presence of air.
To a vial fitted with a magnetic stir bar and a rubber septum, H 2 O (3 mL) and Me 6 TREN (92.1 L, 0.345 mmol) were charged. CuBr (16.5 mg, 0.115 mmol) was then added and stirred until a blue suspension with purple red color copper (0) powder formed. At the same time, to another vial fitted with a rubber septum, H 2 O (4.5 mL), 2, 3-dihydroxypropyl 2-bromo-2-methylpropanoate (1.15 mg, 0.0479 mmol) and NIPAM (0.65 g, 5.74 mmol) were charged and the mixture was transferred via a non-degassed syringe to the vial with Cu (0)/CuBr 2 /Me 6 TREN catalyst to initiate polymerization. The solution was allowed to polymerize at 0 °C for 10 min. During polymerization, 1 aliquot of NIPAM (0.163 g, 1.44 mmol) solution in water (1 mL), 2 aliquots of HEAM (0.165 g, 1.44 mmol) solution in water (1 mL), and 1 aliquot of NAM (0.203 g, 1.44 mmol) in water (6 mL) were prepared and injected subsequently to each other into the reaction after quantitative conversion of the previous block.
Determination of monomer conversion. Monomer conversions were determined by NMR spectroscopy. For PNIPAM, integrals of the vinyl protons ( ~ 5.6-6.1 ppm) from the monomer were compared to the integral of the -NCH-protons ( ~ 3.7-4.0 ppm) from both the monomer and polymer. To calculate monomer conversion for individual PNIPAM blocks in quasi-block copolymers, the same calculation principle applies but -NCH-signals corresponding to previous blocks were subtracted prior to comparison with the vinyl integrals. For the pentablock copolymer, the same principles apply, only with different ppm shifts characteristic of the different monomers.
-NCH 2 -protons for PHEAM ( ~ 3.4-3.7 ppm) and PNAM ( ~ 3.6-3.8 ppm) were compared with their respective vinyl protons ( ~ 5.6-6.3 ppm for PHEAM blocks, ~ 5.6-6.7 ppm for PNAM blocks) to determine monomer conversion.         a the discrepancy between the theoretical and SEC-derived M n is due to a combination of the different hydrodynamic volume of PNIPAM in the GPC eluent (N, N-dimethylacetamide) compared to the poly(methyl methacrylate) standards, and some apparent loss of bromide functionality from the GlyBiB initiator in water. To probe the effect of the end groups (bromineless GlyBiB on one end, bromine on the other) on the SEC M n, PNIPAM was synthesized via RAFT polymerization using azobisisobutyronitrile as the initiator and analyzed by SEC (Table S11, Figure S24). The SEC M n of RAFT-PNIPAM was 34% higher than the theoretical value, a trend also found in the literature. Then, to test whether some dissociation of GlyBiB occurs in water, photo-ATRP of methyl acrylate (as poly(methyl acrylate) gives much more accurate values in SEC) was performed with GlyBiB in DMSO. Relatively good agreement (~14% difference) between theoretical and SEC M n was found (Table S12, Figure S25), suggesting that the dissociation is much higher in water than organic solvent. Therefore, the discrepancy between the theoretical and SEC-M n is a result of both the different hydrodynamic behavior compared with the PMMA polymer standard and loss of some bromide group from the initiator in water.      . The points on the plot correspond to 1.6 eq, 2.4 eq, 4.8 eq, and 7.2 eq Me 6 Tren and are converted to mM concentrations.
Rearranging the K d equation, we get = (S1) [ -] Meanwhile, we have the base equilibrium Combining Eq S1 and S2, we get [ -] ( -
It is worth noting that the discrepancy between the theoretical and experimental Đ 12 can be attributed to a combination of factors such as dead chains from the first block, possible chain length-dependence of the deactivation rate, and the inaccuracies in measuring dispersity. Similarly, the presence of dead chains and inaccuracies of measurements lead to a higher calculated Đ 2.        Table S9. Summary for the synthesis of PNIPAM-block-PHEAM-block-PNIPAM-block-PHEAMblock-PNAM pentablock copolymer. Table S10. Summary for the synthesis of in-situ PNIPAM-block-PHEAM-block-PNIPAM-block-PHEAM-block-PNAM pentablock copolymer without prior degassing and in the presence of ~6.5 ml headspace (8.5 ml of initial polymerization solution in 15 ml vial). Figure S23. SEC traces of in-situ PNIPAM-block-PHEAM-block-PNIPAM-block-PHEAM-block-PNAM pentablock copolymer without prior degassing and in the presence of ~6.5 ml headspace (8.5 ml of initial polymerization solution in 15 ml vial). Table S11. RAFT polymerization of PNIPAM (DP = 120) using 2-cyano-2-propyl dodecyltrithiocarbonate Figure S24. SEC trace of RAFT-PNIPAM. Experimental conditions outlined in Table S10. Table S12. Photo-ATRP of methyl acrylate in DMSO using GlyBiB as the initiator Figure S25. SEC trace of poly(methyl acrylate) synthesized via photo-ATRP in DMSO using GlyBiB as the initiator. Experimental conditions outlined in Table S11.