Solid-Phase Synthesis of Well-Defined Multiblock Copolymers by Atom Transfer Radical Polymerization

Solid-phase polymer synthesis, historically rooted in peptide synthesis, has evolved into a powerful method for achieving sequence-controlled macromolecules. This study explores solid-phase polymer synthesis by covalently immobilizing growing polymer chains onto a poly(ethylene glycol) (PEG)-based resin, known as ChemMatrix (CM) resin. In contrast to traditional hydrophobic supports, CM resin’s amphiphilic properties enable swelling in both polar and nonpolar solvents, simplifying filtration, washing, and drying processes. Combining atom transfer radical polymerization (ATRP) with solid-phase techniques allowed for the grafting of well-defined block copolymers in high yields. This approach is attractive for sequence-controlled polymer synthesis, successfully synthesizing di-, tri-, tetra-, and penta-block copolymers with excellent control over the molecular weight and dispersity. The study also delves into the limitations of achieving high molecular weights due to confinement within resin pores. Moreover, the versatility of the method is demonstrated through its applicability to various monomers in organic and aqueous media. This straightforward approach offers a rapid route to developing tailored block copolymers with unique structures and functionalities.


Instrumentation Nuclear Magnetic Resonance (NMR)
1 H NMR spectra were recorded on Bruker Avance III 500 MHz spectrometers with D2O, CDCl3 or DMSO-d 6 used as the solvent.

Size Exclusion Chromatography (SEC)
SEC measurements of poly(methyl acrylate), poly(ethyl acrylate), poly(methoxyethyl acrylate) and multi-block copolymers were conducted using PSS columns (SDV 10 2 , 10 3 , 10 5 A ) with THF as an eluent at 35 °C and the flow rate of 1 mL/min.Linear poly(methyl methacrylate) standards were used for calibration.SEC measurements of p(OEOMA300) were performed using PSS columns (GRAM 10 2 , 10 3 , 10 5 A ) with DMF containing 0.05 M LiBr as an eluent at 50 °C and a 1 mL/min flow rate.
Linear poly(methyl methacrylate) standards were used for calibration.

Synthesis of ATRP-initiator functionalized ChemMatrix resin (CM-BIB)
ChemMatrix resin bearing benzylic hydroxyl groups (0.40-0.65 mmol/g, 1 g) was taken in a 100 mL round bottom flask with a magnetic stirrer.DCM (50 mL) and triethyl amine (0.8 mmol, 112 μL) were taken into the flask and placed in an ice bath.In the reaction flask, αbromoisobutyryl bromide (BIB-Br, 0.8 mmol, 100 μL) in DCM (10 mL) was slowly added.The reaction mixture was kept stirring overnight at room temperature and filtered off.The filtered solid was washed with water, methanol, and diethyl ether and dried under vacuum to give pure CM-BiB (Figure 1).Fourier Transform Infrared Spectroscopy (FTIR) analysis of native CM (CM-OH) and ATRP initiator functionalized CM (CM-BiB) revealed diminishing -OH peak (broad peak at 3300 cm -1 ) and a sharp peak for ester functional group (OC = O at 1700 cm -1 ) that confirm the functionalization.Additionally, other peaks remained unchanged showing that the reaction conditions did not degrade the resins (Figure S1).Prior to polymerization, stock solutions of HOBiB (15.8 mg in 1.0 mL DMSO), CuBr2 (33.5 mg in 20.0 mL DMSO), TPMA (13.1 mg in 1.0 mL DMSO) and SP (110 mg in 2 mL HPLC water)

Polymerization results of multiblock copolymer synthesis
were prepared.
In a 5 mL volumetric flask, 450 mg of OEOMA300 was weighed.CuBr2 stock (200 µL), TPMA stock (100 µL), HO-EBiB stock (100 µL), SP stock (1 mL), DMSO (100 µL) and 10X PBS solution (500 µL) were then added.Finally, water was added to the mark on the volumetric flask, and the reaction mixture was stirred on a vortex (Figure S1D).The final concentrations were OEOMA300 (300 mM), HOBiB (1.5 mM), SP (100 mM), CuBr2 (0.3 mM), TPMA (0.9 mM), DMSO (10% v/v).In an 8 mL SPE cartridge fitted with a 0.2 microns filter, 20 mg of CM-BIB was transferred, followed by 4.4 mL of the ATRP cocktail along with a magnetic stirrer.The polymerization mixture was stirred at 500 rpm for 30 min for CM-BIB to swell and homogenize before irradiating the cartridge under violet LEDs (λ = 404 nm, 10 mW/cm 2 ) at a stirring rate of 500 rpm fully open to air.Samples were taken and analyzed by 1 H NMR and SEC techniques.

Deconvolution of SEC trace in Figure 5
To determine the ratio of the initiated polymer chains and non-initiated polymer chains, weight-based GPC chromatogram was converted to number-based GPC trace via dividing refractive index signal (RI) at each point by molecular weight (MW).Normalized RI/MW value plotted as black line in (Figure S3A) indicated the relative number of chains at each MW.
Number-based bimodal GPC peak was deconvoluted to five Gaussian-distributed peaks with high accuracy of R 2 value ca.99%.(Figure S3B).The area under the predominant high MW peak was approximately 85%.This high MW peak was associated with the block copolymer chain at a specific molecular weight (59 200).The summation of areas under low MW peaks and a slightly higher MW peak was approximately 15%.The ratio of the areas under the curve indicate that the initiation efficiency of the macroinitiator was ~ 90%.

Figure S5 .
Figure S5.(A) Weight-based GPC chromatogram converted to number-based GPC trace.Deconvolution of number-based bimodal GPC peak to (B) five Gaussian-distributed peaks with high accuracy of R 2 value ca.99%.
The raw data obtained from the SEC analysis has been plotted below, representing the results included in the main paper.

Figure S6 .
Figure S6.(A) Full SEC Traces of polymers with varying target degrees of polymerization in solution phase and (B) Cleaved from CM resin as shown in Figure 3 (main paper).

Figure S9 .
Figure S9.Full SEC traces of polymers in Figure6.
condition for the synthesis of PMA was as follows:[MA]/[EBiB]/[CuBr2]/[Me6TREN]/[SP] = 100/1/0.05/0.15/0.18.MA (2.5 ml, 27.5 mmol) and DMSO (2.3 mL) were taken into a scintillation vial with a magnetic stirrer.Then, the stock solutions of CuBr2 and Me6TREN in DMSO and SP in distilled water were introduced into the vial.Finally, EBiB (40.4 μL, 0.275 mmol) was added to the vial, which was placed in the photoreactor under continuous mixing.The reaction environment was exposed to UV irradiation (λ= 390 nm) in open air.After 20 minutes, the mixture was diluted with THF, passed through a short column of neutral alumina, concentrated, and precipitated in a methanol/water mixture (1/1 by volume).The solution phase was decantated, and the polymer was reprecipitated in methanol/water.The material was dissolved in DCM, and the solution phase was dried over MgSO4, filtered off, and taken under vacuum to give PMA (Mn,GPC = 9500, Đ = 1.13).Synthesis of PMA-b-PEAThe starting stoichiometric condition for the synthesis of PMA-b-PEA was as follows:[EA]/[PMA]/[CuBr2]/[Me6TREN]/[SP] = 100/1/0.05/0.15/0.18.PMA (2.12 g, 0.223 mmol) was dissolved in EA (2.38 ml, 22.3 mmol)/DMSO (2.3 mL) mixture thoroughly in a scintillation vial with a magnetic stirrer.Then, the stock solutions of CuBr2 and Me6TREN in DMSO and SP in distilled water were introduced into the vial.The vial was placed in the photoreactor under continuous mixing.The reaction environment was exposed to UV irradiation (λ = 390 nm) in open air.After 15 minutes, the mixture was diluted with THF, passed through a short column of neutral alumina, concentrated, and precipitated in a methanol/water mixture (1/1 by volume).The solution phase was decantated, and the polymer was reprecipitated in methanol/water.The material was dissolved in DCM, and the solution phase was dried over MgSO4, filtered off, and taken under vacuum to give PMA-b-PEA (Mn,GPC = 20800, Đ = 1.07).

Figure S10 .
Figure S10.SEC traces of the copolymers prepared by PICAR in DMSO.