Controlled-Radical Polymerization of α-Lipoic Acid: A General Route to Degradable Vinyl Copolymers

Here, we present the synthesis and characterization of statistical and block copolymers containing α-lipoic acid (LA) using reversible addition–fragmentation chain-transfer (RAFT) polymerization. LA, a readily available nutritional supplement, undergoes efficient radical ring-opening copolymerization with vinyl monomers in a controlled manner with predictable molecular weights and low molar-mass dispersities. Because lipoic acid diads present in the resulting copolymers include disulfide bonds, these materials efficiently and rapidly degrade when exposed to mild reducing agents such as tris(2-carboxyethyl)phosphine (Mn = 56 → 3.6 kg mol–1). This scalable and versatile polymerization method affords a facile way to synthesize degradable polymers with controlled architectures, molecular weights, and molar-mass dispersities from α-lipoic acid, a commercially available and renewable monomer.


H nuclear magnetic resonance spectroscopy
Solution state 1 H nuclear magnetic resonance (NMR) spectra were recorded on a Varian VNMRS 600 MHz spectrometer.Chemical shifts (δ) are reported in ppm relative to residual protio solvent in CDCl3 (7.26 ppm).

Size-exclusion chromatography instrumentation
Size-exclusion chromatography (SEC) was performed on a Waters instrument using a differential refractive index detector and two Tosoh columns (TSKgel SuperHZM-N, 3 μm polymer, 150 × 4.6 mm) with THF at 35 °C or chloroform containing 0.25% TEA at 35 °C for the mobile phase.Molar masses and molar mass dispersities (Đ) were determined against narrow PS standards (Agilent).

Dynamic Light Scattering (DLS)
The DLS experiment was performed with disposable 4 mL plastic cuvettes for the DLS instrument with 1 mL of aqueous solution.The light scattering signals were measured by using a Marvin Instrument Ltd. nanoZS Zetasizer.

Photoluminescence
Solution-state photoluminescent data were obtained using a Jobin-Yvon HORIBA FluoroMax-4 (xenon source, 1.0 nm excitation, and emission slit widths, 1 nm step size, λexcitation = 536 nm) equipped with a solution-state sample holder and quartz cuvette with a diameter of 1 cm.Photoluminescent data were analyzed using the FluorEssence (v3.5) software powered by Origin.Samples were prepared according to the following: A stock solution of polymer (~2.2 mg) was dissolved in 100 µL of THF.The micelles were prepared by rapidly mixing the THF solution with 3 mL of Milli-Q water.With Nile red, a 1 µg/mL solution was added to the polymer THF solution prior to micelle formation.

Thermal characterization
Thermogravimetric analysis (TGA) was performed under air on a TA Instruments Q500 at a heating rate of 10 °C min −1 with a sample size of ca. 4 mg.Differential Scanning Calorimetry (DSC) was performed using a TA Instruments DSC Q2000 at a heating/cooling rate of 10 °C/min using 3-5 mg of sample in a sealed aluminum pan.

General synthesis of degradable copolymers (nBA-co-LA) 9:1
A stock solution of AIBN was used for all RAFT polymerizations (4.2 mg mL -1 ).DTT (0.020 g, 0.05 mmol) was added to a pressure vessel with LA (0.14 g, 0.69 mmol), nBA (0.80 g, 6.24 mmol), AIBN stock solution (97 µL, 0.003 mmol), and 0.85 mL of THF.The reaction mixture was purged with Argon gas for 15 min and then placed in a 70 °C oil bath.The conversion was monitored via 1 H NMR and stopped at 50% -70% monomer conversion.The reaction vessel was quenched on ice and purified by dialysis in acetone (1 L × 2).Precipitation was not the preferred method of purification due to the partial solubility of the lipoic acid in most solvents resulting in a drastic loss of product.Low conversions were targeted to preserve high chain-end fidelity.

Degradation of nBA-co-LA with TCEP
In a 4 mL dram vial, nBA-co-LA (150 mg, 0.09 mmol) was dissolved in minimal THF.A solution of TCEP (5 equiv.to thiol) in THF/water (4:1) was added and the reaction was run for 18 h at 60 °C.DCM was added to the reaction mixture and the degraded polymer was washed with NaHCO3 (10 mL × 1) and purified via precipitation in cold methanol (15 mL × 2).Previously reported studies have shown the degraded species can be repolymerized through oxidation of the reactive thiol chain-ends. 2,3The disulfide bonds should form in a step-growth fashion to recover the high molar mass polymers.However, the high density of carboxylic acid moieties in the system yielded an incomplete oxidation of the thiols due to the competing mechanism with the pyridine.

Figure S13.
Representative SEC trace with normalized differential refractive index (dRI) detection for poly(butyl acrylate-co-methyl lipoate) (nBA-co-MLp) as synthesized (top) and after degradation with TCEP (middle), and repolymerized with I2/pyridine (bottom).By using methyl lipoate for the repolymerization study, the oxidation reaction was able to go to quantitative completion.

Methylation of nBA-co-LA
In a 4 mL dram vial, nBA-co-LA (100 mg, 0.001mmol) was dissolved in 2 mL of THF.To the stirring solution, methanol (0.2 mL, 4.9 mmol) was added followed by a dropwise addition of TMS-diazomethane (~5 drops, 0.2 M in ether) or until a light-yellow color remained in the stirring solution.The reaction mixture was left overnight to stir at room temperature and quenched with AcOH (6 drops) or until a colorless solution remained.The polymer was precipitated into cold methanol (50 mL × 5).

Figure S1. 1 H
Figure S1. 1 H NMR analysis of nBA-co-LA with characteristic resonances highlighted.

Figure S6 .
Figure S6.SEC trace with normalized differential refractive index (dRI) detection for nBA-co-LA with 10% feed of LA.

Figure S7 .
Figure S7.SEC trace with normalized differential refractive index (dRI) detection for nBA-co-LA with 30% feed of LA.

Figure S9 .
Figure S9.Uncontrolled vs. controlled reactivity ratios of nBA for the nBA-LA copolymerization.

Figure S10 .
Figure S10.SEC trace with normalized differential refractive index (dRI) detection for nBA-co-LA copolymerization.Each trace depicts a time point taken during the copolymerization reaction.

Figure S11 .
Figure S11.Representative SEC trace with normalized differential refractive index (dRI) detection for nBA-co-LA before (solid line) and after degradation (dashed line) with TCEP.

Figure S12 .
Figure S12.Representative SEC trace with normalized differential refractive index (dRI) detection for nBA-co-LA as synthesized (top), after degradation with TCEP (middle), and repolymerized with I2/pyridine (bottom).Previously reported studies have shown the degraded species can be repolymerized through oxidation of the reactive thiol chain-ends.2,3The disulfide bonds should form in a step-growth fashion to recover the high molar mass polymers.However, the high density of carboxylic acid moieties in the system yielded an incomplete oxidation of the thiols due to the competing mechanism with the pyridine.

Figure S14 .
Figure S14.Representative SEC trace with normalized differential refractive index (dRI) detection for nBA-co-LA before (solid line) and after degradation (dashed line) with NaBH4.

Figure S15 .
Figure S15.Representative SEC trace with normalized differential refractive index (dRI) detection for nBA-co-LA before (solid line) and after degradation (dashed line) with AgNO3.

Figure S16. 1 H
Figure S16. 1 H NMR analysis of nBA-co-LA with characteristic resonances highlighted.

Figure S18 .
Figure S18.DSC thermograms of acrylate copolymers.The second heat, with a ramp rate of 10 °C min −1 , is plotted for clarity and plotted with exotherm up.

Figure S19 .
Figure S19.Representative TGA thermographs of nBA-co-LA copolymers in air with a ramp rate of 10 °C/ min .

Figure S20 .
Figure S20.Copolymerization with lipoic acid and methyl methacrylate results in poly(methyl methacrylate) homopolymer due to incompatible reactivity with lipoic acid. 1 H NMR analysis of characteristic resonances highlighted.

Figure S21 .
Figure S21.SEC trace with normalized differential refractive index (dRI) detection for reaction depicted in Figure S20.

Figure S22 .
Figure S22.Copolymerization with lipoic acid and styrene results in polystyrene homopolymer due to incompatible reactivity with lipoic acid. 1 H NMR analysis of characteristic resonances highlighted.

Figure S23 .Figure S24. 1 H
Figure S23.SEC trace with normalized differential refractive index (dRI) detection for reaction depicted in Figure S22.

Figure S25. 1 H
Figure S25. 1 H NMR analysis of DA oligomer after fractional precipitation with characteristic resonances highlighted.

Table S1 .
1olecular characterization of nBA-co-LA.THF SEC analysis with PS standards in kg mol -1 .bDeterminedusing end-group analysis via1H NMR and reported in kg mol -1 .Compositions are based on reactions quenched at 70% conversion. a