Boosting the Reactivity of Bis-Lactones to Enable Step-Growth Polymerization at Room Temperature

The development of new sustainable polymeric materials endowed with improved performances but minimal environmental impact is a major concern, with polyesters as primary targets. Lactones are key monomers thanks to ring-opening polymerization, but their use in step-growth polymerization has remained scarce and challenging. Herein, we report a powerful bis(γ-lactone) (γSL) that was efficiently prepared on a gram scale from malonic acid by Pd-catalyzed cycloisomerization. The γ-exomethylene moieties and the spiro structure greatly enhance its reactivity toward ring-opening and enable step-growth polymerization under mild conditions. Using diols, dithiols, or diamines as comonomers, a variety of regioregular (AB)n copolymers with diverse linkages and functional groups (from oxo-ester to β-thioether lactone and β-hydroxy-lactame) have been readily prepared. Reaction modeling and monitoring revealed the occurrence of an original trans-lactonization process following the first ring-opening of γSL. This peculiar reactivity opens the way to regioregular (ABAC)n terpolymers, as illustrated by the successive step-growth polymerization of γSL with a diol and a diamine.


Materials
All reactions and manipulations were carried out under argon atmosphere using standard Schlenk techniques unless otherwise stated.Dry, oxygen-free solvents were employed.
All organic reagents were obtained from commercial sources and used as received or prepared from known literature procedures.The complex [(SCS) iPr Pd]2 and lactone 1a were synthesized using the method previously reported. 1Catalyst loadings are given relative to the effective Pd content.

Characterization methods
Nuclear magnetic resonance (NMR) spectroscopy. 1H and 13 C spectra were obtained on a Bruker Avance 300, 400 or 500 MHz.Chemical shifts are given in ppm relative to residual solvent as an internal standard.Unless otherwise stated, NMR spectra were recorded at 293 K.
Gel permeation chromatography (GPC).Gel permeation chromatography (GPC) was performed on a Waters equipment provided with refractive index (RI) and ultraviolet (UV) detectors.For this, 100 µL of 0.1 (wt/vol) sample solution in THF or DMF with LiBr (depending on the polymer structure) was injected and the analysis was performed at a flow-rate of 0.5 mL min −1 .HR5E and HR2 Waters linear Styragel columns (7.8 mm × 300 mm, pore size 103 -104 Å) packed with cross-linked polystyrene (PS) and protected with a pre-column were used.Molar mass averages and distributions were calculated against poly(methyl methacrylate) (PMMA) standards.
High Resolution Mass Spectrometry (HRMS): Mass spectra were recorded on a Waters GCT premier apparatus and Waters Xevo G2 QTOF apparatus.
Differential scanning calorimetry (DSC).DSC analyses were performed with DSC 25 TA instruments under Nitrogen atmosphere at a heating and cooling rate of 10 ⁰C.min -1 .
Measurements were performed, depending on the sample, in a range of temperature from -80 ⁰C to 150 ⁰C.
Thermogravimetric analyses (TGA).TGAs were performed with a TGA/Q500 TA instrument under Nitrogen atmosphere in a platinum crucible at a heating rate of 10 ⁰C.min-1 from 25 ⁰C to 800 ⁰C.
All the spectroscopic data were in accordance with the literature. 4 Scheme S2. Preparation of lactone spiro-bislactone γSL Preparation of 4. To a suspension of NaH (472 mg, 11.8 mmol, 1 equiv.) in THF (30 mL), Dimethyl propargylmalonate (1.79 mL, 11.8 mmol) was added dropwise at 0 °C.After stirring for 30 min while warming to rt, the suspension was cooled to 0 °C and Propargyl bromide (2.62 mL, 80% in toluene, 2 equiv.)was added at this temperature.The reaction mixture was stirred while being allowed to warm up to r.t.overnight.Then, solvent ere evaporated and the residue was dissolved in ethyl acetate (20 mL), washed with water (15 mL), brine (15 mL) and dried over Na2SO4.After filtration, the solvents were removed in vacuo.The obtained solid was suspended in pentane, filtered and washed three times with pentane to afford pure product 4 (1.36g, 55%) as a white solid.S6 g, 5.0 equiv.) was prepared with a minimal amount of water and added to the methanol solution.The reaction was allowed to stir overnight at room temperature.Then, the reaction was concentrated in vacuo to dryness.The residue was dissolved in HCl 3M and the aqueous phase was washed DCM (3 × 30 mL).The aqueous phase was, then, evaporated until dryness.The residue was extracted with MeOH from the KCl salt, then, concentrated and extracted a second time with DCM.DCM was finally evaporated to yield the di-acid 5 as a pure white solid (900 mg, 76%) and was used without further purification.
1 H NMR (300 MHz, Deuterium Oxide) δ 7.18 (s, 4H), 5.23 (s, 2H).All the spectroscopic data were in accordance with the literature. 6 Preparation of γSL. 5 (900 mg, 5 mmol) was dissolved in a biphasic medium CHCl3/H2O (10mL/10mL).[(SCS) iPr Pd]2 complex 1 was added and the reaction mixture was heavily stirred overnight.Then, the orange organic phase was separated and the aqueous phase was extracted with DCM (2 × 10 mL).The combined organic phase were concentrated in vacuo to yield an orange solid.This residue was dissolved in a minimum of DCM and then pentane was added to render a white precipitate.The solid was filtered and washed with pentane to afford the spiro dilactone γSL as a pure white solid (850 mg, 94%).

Kinetic studies of model reactions with n-butanol
All model reactions were carried out at 25 °C in DMF-d7 and monitored by 1 H NMR spectroscopy.In a representative experiment, in a glovebox, 0.6 mmol of lactone and 0.6 mmol of n-butanol were added to a reaction tube.The reactants were solubilized in 0.5 ml of anhydrous DMF and 0.1 ml of a DBU (or the corresponding catalyst) solution in DMF (C = 0.6 M) was added to the reaction medium (0.03 mmol, 0.05 eq).and spectra were recorded at different reaction times.
The second-order kinetics were calculated as the following: ), which was confirmed by the linear relationship between t and 1/(1 − p), being t the time and p the fraction of the ring-opened adduct.Rate constants, k, were calculated for each kinetic model.

Synthesis and characterization of the polyesters
All reactions were carried out inside an N2-filled glove box.45 mg (0.25 mmol, 1 eq.) of γSL and the corresponding diol were added to a glass vial.Next, 30 or 60 μL of a DBU solution (76 mg/mL, DMF or CHCl3, 5 % or 10 % DBU) were added, and DMF or CHCl3 was added until a final volume of 0.75 mL (0.4 M) or 0.12 mL (2.2 M).After stirring for 24 h at 25 °C, an aliquot was taken out for conversion calculation and then precipitated in H2O (from DMF) or hexanes (from CHCl3).The polymers were precipitated two times, isolated by centrifugation and dried under a vacuum.

Model reactions with dilactone monomer (γSL) and monofunctional alcohols
The model reaction was carried out at 25 °C in DMF-d7 and monitored by 1 H NMR spectroscopy.In a glovebox, 0.6 mmol of γSL and 1.2 mmol of the monoalcohol (i.e.nbutanol) were added in a reaction tube.The reactants were solubilized in 0.5 ml of anhydrous DMF and 0.1 ml of a DBU solution in DMF (C = 0.6 M) was added to the reaction medium (0.03 mmol, 5 %) and spectra were recorded at different reaction times.The reaction was monitored by 1 H NMR and after 2 h, full conversion was observed.
Then, the reaction mixture was concentrated and purified via flash chromatography (Pentane: Ethyl acetate: 80/20) to afford 96 mg of a colorless oil (96% Yield).The reaction was monitored by 1 H NMR and after 3 h, full conversion was observed.
Then, the reaction mixture was concentrated and purified via flash chromatography (Pentane: Ethyl acetate: 80/20) to afford 93 mg of a colorless oil (96% Yield).
Then, the reaction mixture was concentrated and purified via flash chromatography (Pentane: Ethyl acetate: 80/20) to afford 143 mg of a colorless oil (99% Yield).

Model reactions with 1 or γSL and monofunctional thiols and amines
General prodedure for the reactions with benzyl mercaptan in CDCl3.In a glovebox, 1 or γSL (1 equiv.)and Benzyl mercaptan (1 or 2 equiv.)were added in a schlenk tube.
The reactants were solubilized anhydrous CDCl3 ([C] = 0.2 M) and a DBU solution (2.5 or 5 %mol) in CDCl3 (C = 0.063 M) was added to the reaction medium and the reaction was stirred at 25 °C.
Then, the reaction mixture was concentrated and purified via flash chromatography (Pentane: Ethyl acetate: 80/20) to afford 115 mg of a colorless oil (97% Yield).
General prodedure for the reactions with Benzylamine in CDCl3.In a glovebox, 1 or γSL (1 equiv.)and Benzylamine (1 or 2 equiv.)were added in a schlenk tube.The reactants were solubilized anhydrous CDCl3 ([C] = 0.2 M) and the reaction was stirred at 25 °C.
Model lactone 1 with benzylamine does not require the presence of DBU, although the reaction is rather slow at rt (full conversion is observed after 24h in 0.2 M CDCl3).Clean formation of the corresponding β-oxo-amide was observed (supported by disappearance on the 1 H NMR spectrum of the signal corresponding to the C=C moiety at 4.38 and 4.82 ppm and the appearance of a new s signal at 2.17 ppm attributed to the methyl ketone group).The addition of DBU (2.5%) at this stage of the reaction, or passing the reaction media through a silica pad, led to the rapid formation of the β-hydroxy-lactame as a mixture of diastereomers, resulting from the intramolecular nucleophilic addition of the secondary amide moiety of the β-oxo-amide to the ketone group (disappearance on the 1 H NMR spectrum of the signal corresponding to the methyl ketone group and apparition of a new s signal at 1.57/1.53ppm attributed to the methyl groups).
40 mg (0.22 mmol, 1 eq.) of γSL and the corresponding dithiol were added to a glass vial.Next, 50 μL of a DBU solution (36.6 mg/mL, DMF) was added, and DMF was added until a final volume of 0.11 mL (2.0 M, 5% DBU) of DMF.After stirring for 24 h at 25 °C, an aliquot was taken out for conversion calculation and then precipitated in H2O.The polymers were precipitated two times, isolated by centrifugation and dried under a vacuum.2).

Figure
Figure S9.a) Scheme of the ring-opening of 1 M γSL with 2 equivalents of different monotopic alcohols using 5 % DBU at 25 ºC in DMF-d7.b) Representative example of 1 H-NMR spectra of the reaction recorded at t = 3 min, and corresponding assignation of the key signals for each reaction product.c) Time-conversion curves for the reaction of γSL with each alcohol (Fracton of final adduct 7).Magnification from 50-100 % of conversion to final product in the first 2.5 h of reaction time (• 2-methoxyethanol; ▲ 3,5-dimethoxybenzyl alcohol; ■ n-butanol).
Scheme S10.Reaction of lactone 1 with benzyl amine and DBU
Scheme S11.Reaction of lactone γSL with 2 equivalents of benzyl amine and DBU

Figure S15 .
Figure S15.Stacked 13 C NMR spectra of P(N2a-c) in CDCl3, purified by precipitation.Different stereoisomers are indicated as a,b,c and # corresponds to the kinetic product, thioester structure.
40 mg (0.22 mmol, 1 eq.) of γSL and the corresponding diamine were added to a glass vial.Next, 50 μL of a DBU solution (36.6 mg/mL, DMF) were added, and DMF was added until a final volume of 0.11 mL (2.0 M, 5% DBU) of DMF.After stirring for 24 h at 25 °C, an aliquot was taken out for conversion calculation and then precipitated in H2O.The polymers were precipitated two times, isolated by centrifugation and dried under a vacuum.

Figure
Figure S20. 1 H NMR spectrum of the reaction crude of the reaction of γSL with 0.5 equiv. of 1,4-benzenedimethanol.

Table S1 .
Screening of the reaction conditions for polyester synthesis with diols.