Ring Opening Copolymerization of Boron-Containing Anhydride with Epoxides as a Controlled Platform to Functional Polyesters

Boron-functionalized polymers are used in opto-electronics, biology, and medicine. Methods to produce boron-functionalized and degradable polyesters remain exceedingly rare but relevant where (bio)dissipation is required, for example, in self-assembled nanostructures, dynamic polymer networks, and bio-imaging. Here, a boronic ester-phthalic anhydride and various epoxides (cyclohexene oxide, vinyl-cyclohexene oxide, propene oxide, allyl glycidyl ether) undergo controlled ring-opening copolymerization (ROCOP), catalyzed by organometallic complexes [Zn(II)Mg(II) or Al(III)K(I)] or a phosphazene organobase. The polymerizations are well controlled allowing for the modulation of the polyester structures (e.g., by epoxide selection, AB, or ABA blocks), molar masses (9.4 < Mn < 40 kg/mol), and uptake of boron functionalities (esters, acids, “ates”, boroxines, and fluorescent groups) in the polymer. The boronic ester-functionalized polymers are amorphous, with high glass transition temperatures (81 < Tg < 224 °C) and good thermal stability (285 < Td < 322 °C). The boronic ester-polyesters are deprotected to yield boronic acid- and borate-polyesters; the ionic polymers are water soluble and degradable under alkaline conditions. Using a hydrophilic macro-initiator in alternating epoxide/anhydride ROCOP, and lactone ring opening polymerization, produces amphiphilic AB and ABC copolyesters. Alternatively, the boron-functionalities are subjected to Pd(II)-catalyzed cross-couplings to install fluorescent groups (BODIPY). The utility of this new monomer as a platform to construct specialized polyesters materials is exemplified here in the synthesis of fluorescent spherical nanoparticles that self-assemble in water (Dh = 40 nm). The selective copolymerization, variable structural composition, and adjustable boron loading represent a versatile technology for future explorations of degradable, well-defined, and functional polymers.


Synthesis of dimethyl phthalate pinacolboronate ester, (BPin-DMP)
An oven-dried 250 mL round bottom Schlenk flask was loaded with a large magnetic stir bar and finely ground potassium acetate (5.42 g, 55.2 mmol), capped and gently heated, under high vacuum, to remove any traces of moisture. After cooling to room temperature, dimethyl 4-bromophthalate (5.00 g, 18.4 mmol), bis(pinacolato)diboron (5.61 g, 22.1 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex, (0.45 g, 0.55 mmol) were loaded, and the flask then placed under an inert atmosphere of N2. Then, dry dioxane (80 mL) was added by cannula, the rubber septum was replaced with a Teflon-lined screw cap and the flask sealed under N2. The reaction mixture was degassed, via three freeze/pump/thaw cycles, and then heated to 85 °C, with vigorous stirring for 20 hours, during which time a dark purple precipitate formed.
Analysis of a reaction aliquot by 1 H NMR spectroscopy indicated full conversion to the pinacolborate product.

Kinetics of BPin-PA/epoxide ROCOP and PA/epoxide ROCOP using [ZnMg].
Inside a glovebox, a 7 mL glass vial, with a Teflon-lined screw cap, was loaded with a magnetic stirrer and [ZnMg] (10 mg, 0.01 mmol, 1 equiv.). Then, 1,4-BDM (6 mg, 0.04 mmol, 4 equiv.) and BPin-PA or PA (1.00 mmol, 100 equiv.) were added along with epoxide (1.3 mL of CHO or vCHO). The vial was sealed and transferred to an oil bath, which was preheated to 80 °C. At appropriate time intervals, the polymerization was stopped by submersion into an acetone/dry ice bath and the reaction vial was taken into the glovebox, where an aliquot was taken for analysis by NMR spectroscopy to determine BPin-PA or PA conversion. Specifically, the amount of unreacted BPin-PA at a given time t was determined by integration of the peaks for BPin-PA (centered at 8.30 ppm for one aromatic signal) and BPin polyester (centered at 7.40 ppm for one aromatic signal) according to the percent of unreacted BPin-PA = (A8.30/A7.40) × 100, where A8.30 is the total integral for the peak centered at 8.30 ppm and A7.40 is the total integral for the peak centered at 7.40 ppm. Conversely, the percent of unreacted PA at a given time t was determined by integration of the peaks for PA (centered at 8.02 ppm for one aromatic signal) and PA polyester (centered at 7.67 ppm for one aromatic signal) according to the percent of unreacted PA = (A8.02/A7.67) × 100, where A8.02 is the total integral for the peak centered at 8.02 ppm and A7.67 is the total integral for the peak centered at 7.67 ppm. The apparent rate constants (kapp) were extracted from linear fit plots of [BPin-PA]t or [PA]t vs time t.
The aliquots were also analysed by gel permeation chromatography to determine Mn and Ð values.                Figure S30 displaying the isotope distribution pattern, and (b) the calculated isotope distrubtions for the molecular formula C250H307B11O68Na, which is consistent with the 11 th -mer repeat unit of the pinacol ester-protected polymer P(Pin/vCHO) (featuring BDM/proton end-groups and sodium salt).

Investigation of boronic ester transesterification using small-molecule model
In air, a 40 mL reaction vial, containing a magnetic stir bar, was loaded with dimethyl phthalate pinacolboronate ester, BPin-DMP, (160 mg, 0.5 mmol) and methylboronic acid, MBA, (5.0 or 20.0 mmol). The solids were dissolved in a solution of trifluoroacetic acid (2% or 5%) in the desired solvent, and stirred at room temperature for the appropriate time interval. At this point, aliquots were taken, diluted in acetone-d6 and analysed by 1 H NMR spectroscopy to obtain conversion data.

GPC Analysis of Boronic Acid-Polyesters.
In an Eppendorf tube, dry polymer samples were suspended in THF (1.2 mL of a 5 mg mL −1 solution).
Then, distilled H2O (10 µL) was added, and the polymer solutions were vortexed until complete dissolution.

PA/PO].
In a 50 mL round-bottom flask, a sample of mPEG-b-P(BPin-PA/PO) (270 mg, 0.5 mmol in boron units) and methylboronic acid (620 mg, 10 mmol, 20 equiv.) were loaded and dissolved in a mixture of acetone/CH2Cl2 1:1 (v:v) so that the final concentration was 0.10 M. To this solution was added trifluoroacetic acid (2%) and the resulting homogeneous and clear solution was stirred, at room temperature, for 20 h. Then, the volatiles were removed, under vacuum at 40 °C, in the rotavapor for 1 h. The resulting residue was redissolved in acetone (2 mL), and the solution evaporated, at 60 °C in the rotavapor, for 2 hours. The resulting powder was redissolved in acetone (2 mL) and precipitated thrice over a large excess of Et2O (3 × 100 mL); the polymer was then separated by centrifugation, and dried under vacuum, at 60 °C, until constant weight. Yield = 216 mg (95%).

NMR scale investigations in water
In an Eppendorf tube, dry polymer samples of B(OH)2 polyesters (~12 mg) were suspended in D2O (0.5 mL). Then, 1 equiv. of NaOD with respect to boronic acid units was added using a micropipette from a NaOD/D2O solution (40 wt%    S59

Hydrolytic Stability in Basic Aqueous Solution
In an Eppendorf tube, a dry sample of P[B(OH)2-PA/PO] (~12 mg) was suspended in D2O (0.5 mL).
Then, 1 equiv. of NaOD with respect to boronic acid units was added using a micropipette from a NaOD/D2O solution (40 wt%). The mixture was vortexed until a clear solution was obtained, and the resulting solution was analysed by NMR spectroscopy. The reaction was left standing at room temperature (25 °C) and monitored at regular intervals. In an Eppendorf tube, a dry sample of P[B(OH)2-PA/PO] (~12mg) was suspended in D2O (0.5 mL).
Then, 1 equiv. of NaOD with respect to boronic acid units was added using a micropipette from a NaOD/D2O solution (40 wt%). The mixture was vortexed until a clear solution was obtained, after which an aliquot (250 µL) was immediately quenched over THF (1.0 mL) containing benzoic acid (20 mg/mL) and neopentyl glycol (40 mg/mL). The solution was then filtered and analysed by GPC. The remaining P[B(OH)3-PA/PO] solution (250 µL) was left to stand at room temperature for 4 days, after which it was treated in a similar manner and analysed by GPC.

Monitoring of polymer degradation by NMR spectroscopy
In an Eppendorf tube, a dry sample of polyester P[B(OH)2-PA/PO] (~12 mg, 0.05 mmol of boronic acid units) was suspended in D2O (0.5 mL) containing dimethylsulfone (2 mg, 25 µmol) as an internal standard.
Then, 1 equiv. of NaOD with respect to boronic acid units was added with a micropipette from a NaOD/D2O solution (40 wt%, 3.5 µL, 0.05 mmol). The mixture was subsequently vortexed, at room temperature, until a clear solution was obtained. At this point, the polymer solution was transferred to an NMR tube and 1 H and 11 B NMR spectra were recorded at 300 K (time 0). The sample was removed from the spectrometer, a second equiv.
of NaOD was added to it, and the sealed tube was shaken vigorously, at room temperature. The NMR tube was immediately returned to the NMR spectrometer and 1 H NMR spectra were taken at regular intervals to monitor polymer degradation, at 300 K. Once the reaction was complete, a sample was diluted in distilled H2O and analysed by LC-MS.

Liquid Chromatography-Mass Spectrometry of Polymer Degradation Products
An NMR sample containing degradation products ( Figures S84-S86) in D2O was diluted in HPLC grade water, for analysis by liquid chromatography-mass spectrometry (LC-MS). Mode = negative electron-spray ionization, formic acid (HCOONa) used to facilitate ionization.