Stereo-electronic contributions in yttrium-mediated stereoselective ring-opening polymerization of functional racemic β-lactones: ROP of 4-alkoxymethylene-β-propiolactones with bulky exocyclic chains

Abstract

Stereoselective ring-opening polymerization (ROP) of cyclic esters is the privileged strategy to access stereoregular polyesters that are widely applied in various domains, such as in particular the biomedical and packaging fields. The production of synthetic stereo-enriched polyhydroxyalkanoates (PHAs) derived from racemic β-lactones by ROP is still a challenge. In this context, linear, high molar mass, narrowly dispersed PHAs, namely PBPL^CH₂OiPr, PBPL^CH₂OtBu and PBPL^CH₂OTBDMS (M_n,SEC up to 94 300 g mol⁻¹; Đ_M = 1.06–1.18; TBDMS = SitBuMe₂), with syndiotactic enrichment (P_r = 0.76–0.87) were successfully synthesized by stereoselective ROP of the corresponding functional racemic β-propiolactones, rac-BPL^CH₂OiPr, rac-BPL^CH₂OtBu and rac-BPL^CH₂OTBDMS, respectively, which are promoted by diverse achiral diamino-bis(phenolate) yttrium complexes featuring various R′/R′′ substituents (Y{ONNO^R′,R′′}, 2a–d). The influence of the steric hindrance of the BPL^FG side-functionality, with FG = CH₂OiPr, CH₂OtBu, and CH₂OTBDMS, on the ROP kinetics, stereoselectivity and thermal properties of the resulting PHAs, as a function of 2a–d catalysts, was compared to that of the previously reported similar but less hindered BPL^FG monomers, with FG = CH₂OMe, CH₂OAllyl, CH₂OBn, and CH₂OPh. Overall, this study evidenced that, for the newly prepared rac-BPL^CH₂OiPr, rac-BPL^CH₂OtBu and rac-BPL^CH₂OTBDMS monomers, due to steric constraints induced by the monomer alkoxy/silyloxy side-functionality, all ROPs afforded syndio-enriched polyesters, regardless of the catalyst used. Conversely, only combinations of a BPL^FG monomer containing two sets of methylene hydrogens within the side-functionality, i.e. with FG = CH₂OCH₂X with X = H, CH = CH₂ and C₆H₅ as in BPL^CH₂OMe, BPL^CH₂OAllyl, and BPL^CH₂OBn, with a yttrium catalyst bearing ortho/para-chloro substituents (2a), gave isotactic functional PHAs. With the latter three monomers, a catalyst with highly sterically crowded substituents on the ligand platform (2a,b) was necessary to recover syndio-enriched PBPL^{CH₂OMe,OAll,OBn}.

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Introduction

Stereoselective ring-opening polymerization (ROP) of chiral racemic lactones is a field of topical interest as it allows accessing polymers with variable microstructures (i.e., tacticities), and hence polymer materials with differentiated and controlled properties.¹ One of the most ubiquitous examples in this area is probably the ROP of racemic lactide (rac-LA) which has opened large avenues, in particular toward the formation of isotactic PLA stereocomplexes with significantly enhanced thermal characteristics.^1a–e The formation of isotactic polyesters from the ROP of racemic lactones is clearly much less common than that of their syndiotactic (heterotactic) counterparts; indeed, the latter syndio/hetero tacticities are often the result of a chain-end stereocontrol^1a,b where the minimization of steric tilting in the transition state induces the regular, alternated enchainment of consecutive monomer units with the opposite configuration. On the other hand, the formation of isotactic polyesters from racemic cyclic esters usually requires the use of chiral catalysts, most often metal-based ones,² to proceed via a so-called enantiomorphic site control; isoselective ROP of racemic lactones with achiral catalysts is even less frequent and largely focused on rac-LA.^1,3 A recent, remarkable addition is the stereoselective ROP of eight-membered racemic cyclic diolides mediated by discrete rare earth-based catalysts developed by the group of Chen, which affords a variety of perfectly isotactic (P_m up to 0.99)‡ polyhydroxyalkanoates (PHAs).⁴ In our longstanding research on the stereoselective ROP of racemic β-lactones⁵ with achiral alkoxyamino- or diamino-bisphenolate-yttrium catalysts ({Y{ON(X)O^R′,R′′}),⁶ we have reported that only the use of catalysts bearing halogeno ortho/para-substituents (R′,R′′ = Cl, F or Br) on the phenolate ligand platform allowed the highly isoselective ROP of the specific racemic 4-alkoxymethylene-β-propiolactones (rac-BPL^CH₂OR, Scheme 1);⁷ actually, this was proved to be effective (i.e., isoselective) only for R = 4-methoxy (OMe), -allyloxy (OAll) or benzyloxy (OBn) derivatives, that is, the monomers having two methylene groups apart from the oxygen in the side-functionality (i.e., with a CH₂(referred to as “inner”)-O–CH₂(referred to as “outer”)X group).⁸ As supported by DFT computations, such isoselectivity apparently relies on attractive non-covalent interactions (NCIs)⁹ between the halogen ortho-substituents on the yttrium ligand with the “inner” and/or “outer” methylene hydrogens within the side-functional group of the last inserted monomer unit within the growing polymer chain (Scheme 1).⁷ As a matter of fact, the ROP of rac-BPL^CH₂OR monomers without such an “outer” methylene group, e.g. with R = OPh, or with two “inner” methylene groups, i.e. rac-BPL^{CH₂CH₂OCH₂Ph}, with an isoselective Y{ONNO^Cl,Cl} catalytic system, all recovered syndio-enriched polymers (P_r = 0.75–0.77).^10;§ The contribution of the “outer” methylene group in the pendant arm of BPL^CH₂OCH₂X is thus still an open question.

Scheme 1 Previously reported stereoselective ROP of 4-alkoxymethylene-β-propiolactones by Y{ON(X)O^R′,R′′} catalytic systems, with stereoselectivity outcomes depending on the stereo-electronic characteristics of the catalyst. The bottom-right structure depicts the transition state with attractive non-covalent Cl⋯H interactions allegedly driving the isoselectivity.⁷

To gain a better insight into the factors that govern the isoselectivity observed in the ROP of some rac-BPL^CH₂OR monomers mediated by the Y{ONNO^Cl,Cl} catalytic system and to probe further the possible decisive influence of “outer” methylene hydrogens (–CH₂OCH₂X), we have herein explored the yttrium-mediated ROP of three β-propiolactones which do not feature an “outer” methylene group within the alkoxide moiety and which display an alkoxy tertiary or quaternary carbon/silicon, namely rac-BPL^CH₂OiPr, rac-BPL^CH₂OtBu, and rac-BPL^CH₂OTBDMS (TBDMS = SitBuMe₂; Scheme 2),¹¹ respectively, in comparison with the related rac-BPL^CH₂OPh which is depleted of the outer methylene (-OCH₂X) moiety.¹⁰ These three rac-BPL^{CH₂OiPr/OtBu/OTBDMS} monomers, two of which are new and all of which are readily prepared by carbonylation of the parent glycidyl ethers (see the ESI†),^11,12 have been chosen so as to replace the “outer” methylene hydrogens (as in R = OCH₂H, OCH₂CH = CH₂ and OCH₂Ph) with one or two methyl groups (as in R = OiPr and OtBu). This should allow one to assess whether the “outer” alkoxide methylene may contribute to the iso-stereocontrol of the ROP of such functional BPL^CH₂ORs. In addition, rac-BPL^CH₂OTBDMS was selected to probe, besides the impact of a missing “outer” methylene in the side function of the monomer, the impact of the steric bulkiness on the alkoxy functionality (OiPr and OtBu vs. OSiMe₂tBu). Further comparison with the β-propiolactone featuring a somewhat bulky aryloxy moiety, namely BPL^CH₂OPh, which was shown to give a syndiotactic polyester,¹⁰ could then be made. In addition, PHAs derived from rac-BPL^CH₂OTBDMS are of further interest as they could subsequently provide access to hydrophilic polyesters upon deprotection of –OTBDMS into pendant hydroxyl groups also available for post-polymerization modification, as for instance to chemically bound a biological moiety for theranostic outcomes. Four catalysts {Y{ONNO^R′,R′′}, 2a–d, having different R′,R′′ ortho/para-substituents installed on the bisphenolate platform and which have previously revealed quite distinctive and effective stereocontrol abilities in the ROP of racemic functional β-lactones due to their different stereo-electronic characteristics,^6,7 have been selected for the present study.

Scheme 2 4-Alkoxymethylene-β-propiolactones with bulky alkoxy side-functionalities depleted of an “outer” methylene group, investigated in the present study.

Experimental section

See the ESI† for additional details.

Synthesis and characterization of BPL^CH₂OR monomers

BPL^CH₂OR monomers were synthesized by carbonylation of the corresponding racemic or enantiopure glycidyl ethers (rac-/(S)-Glyc^CH₂OR) using a previously reported procedure.^11,12 All rac-BPL^CH₂OR and (S)-BPL^CH₂OR monomers were characterized (refer to the ESI) and stored under argon at −27 °C.

Typical BPL^CH₂OR polymerization procedure

In a typical experiment,¹³ in a glovebox, a Schlenk flask was charged with [Y(N(SiHMe₂)₂)₃](THF)₂ (8.8 mg, 14 μmol) and {ONNO^tBu2} (1d, 7.4 mg, 14 μmol), and toluene (0.25 mL) was next added. To this solution, iPrOH (107 μL of a 1% (v/v) solution in toluene, 1 equiv. vs. Y) was added under stirring at room temperature (ca. 20 °C). After 5 min of stirring, a solution of rac-BPL^CH₂OR (0.84 mmol, 60 equiv.) in toluene (0.5 mL) was added rapidly and the mixture was stirred at 20 °C for 1 h. The reaction was quenched by the addition of acetic acid (ca. 0.5 mL of a 1.6 mol L⁻¹ solution in toluene). The resulting mixture was concentrated to dryness under vacuum and the conversion was determined by ¹H NMR analysis of the residue in CDCl₃. The crude polymer was then dissolved in CH₂Cl₂ (ca. 1 mL), precipitated in cold pentane (ca. 5 mL), filtered and dried. PBPL^CH₂OiPr, PBPL^CH₂OtBu and PBPL^CH₂OTBDMS were recovered as a colorless oil, yellowish oil, and colorless solid, respectively. All recovered polymers were then analyzed by NMR spectroscopy, mass spectrometry, SEC, and DSC analyses.

Results and discussion

ROP of rac-BPL^CH₂OiPr

The ROP of rac-BPL^CH₂OiPr was explored under the same general operating conditions as those used for the above-mentioned reference ROPs mediated by similar Y{ONNO^R′,R′′} catalytic systems, that is, in toluene solution at room temperature, using in situ combinations of 2a–d/iPrOH (1 : 1) (Table 1).¹⁰ The reactivity trend observed for the different yttrium catalytic systems followed the one established with other similar β-lactones:^6b,7 the Cl substituted catalyst 2d was the least active, with only partial conversion of 30 monomer equiv. even after prolonged reaction time (TOF_2d = ca. 0.2 h⁻¹, entry 1); the Me-substituted catalyst 2c achieved nearly complete consumption of ca. 60 and 100 monomer units within 12 and 24 h, respectively (TOF_2c = ca. 5 h⁻¹, entry 2); a much higher reactivity was observed with the catalytic systems bearing bulky substituted ligands (cumyl, tBu, 2a–b), and almost quantitative conversion of 30–250 equiv. of rac-BPL^CH₂OiPr was typically achieved within 5–20 min (TOF_2a–b > 750 h⁻¹, entries 4–10).

Table 1 ROP of rac-BPL^CH₂OiPr mediated by the 2a–d/iPrOH catalytic systems^a

Entry	Cat.	[BPL^CH2OiPr]0/[2]0/[iPrOH]0	Time^b (min)	BPL^CH2OiPr Conv.^c (%)	M n,theo ^d (g mol^−1)	M n,NMR ^e (g mol^−1)	M n,SEC ^f (g mol^−1)	Đ M ^f	P r ^g
a Reactions performed with [BPL^CH2OiPr]0 = 1.0 M in toluene at room temperature. b Reaction times were not necessarily optimized. c Conversion of BPL^CH2OiPr as determined by ^1H NMR analysis of the crude reaction mixture. d Molar mass calculated according to Mn,theo = ([BPL^CH2OiPr]0/[2]0 × conv.BPL(CH2OiPr) × MBPL(CH2OiPr)) + MiPrOH with MBPL(CH2OiPr) = 144 g mol^−1 and MiPrOH = 60 g mol^−1. e Molar mass determined by ^1H NMR analysis of the isolated polymer, from the resonances of the terminal OiPr group. f Number-average molar mass (uncorrected values) and dispersity (Mw/Mn) determined by SEC analysis in THF at 30 °C vs. polystyrene standards. g P r is the probability of racemic linkages between BPL^CH2OiPr units as determined by ^13C{^1H} NMR analysis of the isolated PBPL^CH2OiPrs. h ROP of enantiopure (S)-BPL^CH2OiPr.
1	2d	30 : 1 : 1	24 × 60	19	850	1100	1400	1.15	0.70
2	2c	60 : 1 : 1	12 × 60	96	8350	7550	9500	1.09	0.71
3	2c	100 : 1 : 1	24 × 60	90	13 000	15 000	15 900	1.18	0.72
4	2b	30 : 1 : 1	5	100	4400	3700	5400	1.09	0.84
5	2b	60 : 1 : 1	5	100	8700	9400	10 700	1.11	0.84
6	2b	100 : 1 : 1	15	100	14 450	14 400	15 300	1.13	0.85
7	2b	250 : 1 : 1	20	100	36 050	36 500	38 300	1.08	0.85
8	2b	500 : 1 : 1	210	100	72 100	68 700	48 900	1.06	0.86
9	2a	60 : 1 : 1	5	100	8700	9000	10 050	1.10	0.82
10	2a	100 : 1 : 1	15	100	14 450	17 000	18 600	1.13	0.82
11^h	2b	30 : 1 : 1	60	94	4100	4600	5600	1.10	<0.05

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The ROP of rac-BPL^CH₂OiPr with the 2a–d/iPrOH systems proceeded with quite good control in terms of macromolecular parameters. All the polymers showed a linear topology with α-isopropoxycarbonyl and ω-hydroxy chain-end groups, as unambiguously established by ¹H and J-MOD NMR spectroscopy and MALDI-ToF mass spectrometry analyses (see the ESI; Fig. S1–S6†). Also, alongside narrow dispersities (Đ_M = 1.06–1.18), the calculated (M_n,theo) and experimental (M_n,NMR, M_n,SEC) molar mass values were in quite good agreement. A linear relationship between the experimental molar mass values and the rac-BPL^CH₂OiPr monomer loading/conversion up to 250 equiv. was observed with the 2b/iPrOH (1 : 1) catalytic system (Fig. 1). Altogether, these results confirm the limited extent or the absence of irreversible transfer/side-reactions (typical inter- and intra-molecular undesirable transesterification reactions, i.e. reshuffling and backbiting reactions, respectively) and suggest essentially active polymerization features.

Fig. 1 Illustration of the variation of M_n,NMR ■, M_n,SEC ○, and M_n,theo (the solid line) molar mass values of PBPL^CH₂OiPr synthesized from the ROP of rac-BPL^CH₂OiPr mediated by the 2b/iPrOH (1 : 1) catalytic system as a function of the BPL^CH₂OiPr monomer loading/conversion (Table 1, entries 4–8).

A close examination of the carbonyl (δ r = ca. 169.65, δ m = ca. 169.55 ppm), methine (δ r = ca. 68.12, δ m = ca. 68.03 ppm) and methylene (δ r = ca. 35.94, δ m = ca. 36.05 ppm) main-chain carbons’ signals in the ¹³C NMR spectra allowed establishing the polymers’ tacticity (Fig. 2). For the sake of comparison, a pure isotactic PBPL^CH₂OiPr system was prepared from the ROP of enantiopure (S)-BPL^CH₂OiPr (Table 1, entry 11). Regardless of the catalyst used in the 2a–d series, the ROP of rac-BPL^CH₂OiPr gave syndio-enriched polymers. It is noteworthy that the 2c system (Me substituents) exhibited approximately the same syndiotacticity (P_r = 0.71–0.72) as the one obtained from 2d (Cl substituents, P_r = 0.69–0.70). This suggests the absence of any electronic effect from 2d but, instead, the preponderance of a pure, yet limited steric control, in tuning the tacticity of PBPL^CH₂OiPr. Along the same line, catalytic systems 2a–b that bear bulkier cumyl and tert-butyl substituents resulted in better syndio-enrichments (P_r = 0.82–0.85), which are close to those obtained for PBPL^CH₂OMe, PBPL^CH₂OAll and PBPL^CH₂OBn (P_r = 0.78–0.90).⁷

Fig. 2 Zoomed regions of the ¹³C{¹H} NMR spectra (125 MHz, CDCl₃, 23 °C) of PBPL^CH₂OiPr prepared by ROP of rac-BPL^CH₂OiPr, except for the top spectrum of enantiopure (S)-BPL^CH₂OiPr (Table 1, entry 11), mediated by the 2a, 2b, 2c, or 2d/iPrOH (1 : 1) catalytic systems (Table 1, entries 9, 7, 3 and 1, respectively).

ROP of rac-BPL^CH₂OtBu

The stereoselective ROP of rac-BPL^CH₂OtBu was similarly examined (Table 2). The activity trend of catalysts 2a–d (ca. 75 monomer equiv.) was very comparable to the aforementioned ROP of rac-BPL^CH₂OiPr: TOF_2d = ca. 0.7 h⁻¹ (entry 1) vs. TOF_2c = ca. 10 h⁻¹ (entry 4) vs. TOF_2a–b > 900 h⁻¹ (entries 6 and 11). Also, the corresponding characteristic data of PBPL^CH₂OtBu (NMR spectra, M_n and dispersity values, and linear molar mass increase correspondingly to larger monomer loadings) revealed well-defined α-isopropoxycarbonyl, ω-hydroxy telechelic PHAs with chain-end fidelity and an overall quite good control of the polymerization (see the ESI, Fig. S7–S11†).

Table 2 ROP of rac-BPL^CH₂OtBu mediated by the 2a–d/iPrOH catalytic systems^a

Entry	Cat.	[BPL^CH2OtBu]0/[2]0/[iPrOH]0	Time ^b (min)	BPL^CH2OtBu Conv. ^c (%)	M n,theo (g mol^−1)	M n,NMR ^e (g mol^−1)	M n,SEC ^f (g mol^−1)	Đ M ^f	P r ^g
a Reactions performed with [BPL^CH2OtBu]0 = 1.0 M in toluene at room temperature. b Reaction times were not necessarily optimized. c Conversion of BPL^CH2OtBu as determined by ^1H NMR analysis of the crude reaction mixture. d Molar mass calculated according to Mn,theo = ([BPL^CH2OtBu]0/[2]0 × conv.BPL(CH2OtBu) × MBPL(CH2OtBu)) + MiPrOH with MBPL(CH2OtBu) = 158 g mol^−1and MiPrOH = 60 g mol^−1. e Molar mass determined by ^1H NMR analysis of the isolated polymer, from the resonances of the terminal OiPr group. f Number-average molar mass (uncorrected values) and dispersity (Mw/Mn) determined by SEC analysis in THF at 30 °C vs. polystyrene standards. g P r is the probability of racemic linkages between BPL^CH2OtBu units as determined by ^13C{^1H} NMR analysis of the isolated PBPL^CH2OtBus. h ROP of enantiopure (S)-BPL^CH2OtBu.
1	2d	25 : 1 : 1	24 × 60	67	2600	2500	2400	1.12	0.70
2	2d	75 : 1 : 1	27 × 60	28	3300	3400	3000	1.06	0.71
3	2c	25 : 1 : 1	60	100	3600	3100	3200	1.09	0.74
4	2c	75 : 1 : 1	7 h	90	10 700	10 900	13 600	1.16	0.75
5	2b	30 : 1 : 1	30	100	4300	3900	4300	1.12	0.83
6	2b	73 : 1 : 1	5	100	11 600	11 300	14 800	1.10	0.84
7	2b	120 : 1 : 1	10	100	18 800	18 800	24 000	1.14	0.83
8	2b	250 : 1 : 1	15	99	39 100	40 000	49 900	1.15	0.84
9	2b	500 : 1 : 1	15	99	78 300	80 000	94 300	1.18	0.84
10	2a	30 : 1 : 1	30	100	4300	4300	4000	1.12	0.78
11	2a	75 : 1 : 1	5	100	11 900	10 900	15 200	1.14	0.78
12^h	2b	70 : 1 : 1	30	100	11 100	10 300	14 300	1.09	<0.05

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The stereochemistry of PBPL^CH₂OtBu prepared by ROP of rac-BPL^CH₂OtBu mediated by the 2a–d/iPrOH systems closely resembles that of PBPL^CH₂OiPr. All the isolated PBPL^CH₂OtBu samples revealed a syndio-enrichment regardless of the catalyst used (2a–d) (Fig. 3) (δ r(C=O) = ca. 169.77, δ m(C=O) = ca. 169.70 ppm; δ r(CH) = ca. 62.18, δ m(CH) = ca. 62.11 ppm; δ r(CH₂) = ca. 35.97, δ m(CH₂) = ca. 36.06 ppm). While 2d (Cl substituents) afforded almost the same enrichment of PBPL^CH₂OtBu as that of PBPL^CH₂OiPr (P_r = ca. 0.70), catalyst 2c (Me substituents) contributed to a slightly higher syndiotacticity (P_r = 0.75 vs. 0.71), while catalyst 2a (cumyl substituents) exhibited a slightly inferior syndio-regularity (P_r = 0.78 vs. 0.82). Finally, catalyst 2b (tBu substituents) produced the highest enrichment of PBPL^CH₂OtBu (P_r = 0.84), again reminiscent of that of PBPL^CH₂OiPr (P_r = 0.85). Hence, the general reactivity trend of the 2a–d catalysts to yield syndio-enriched PBPL^CH₂OtBu is the same as the one observed for PBPL^CH₂OiPr, but with minor differences in the PHA enrichment in the case of catalysts 2a,c.

Fig. 3 Zoomed regions of the ¹³C{¹H} NMR spectra (125 MHz, CDCl₃, 23 °C) of PBPL^CH₂OtBu prepared by ROP of rac-BPL^CH₂OtBu, except for the top spectrum of enantiopure (S)-BPL^CH₂OtBu (Table 2, entry 12), mediated by the 2a, 2b, 2c, or 2d/iPrOH (1 : 1) catalytic systems (Table 2, entries 2, 4, 6 and 11, respectively).

ROP of rac-BPL^CH₂OTBDMS

Representative results of the investigation of the ROP of rac-BPL^CH₂OTBDMS mediated by the 2a–d/iPrOH catalytic systems are summarized in Table 3. With both 2c–d systems (Me, Cl substituents), incomplete low monomer conversions were obtained for rac-BPL^CH₂OTBDMS loadings of 30–60 equiv. after 2–3 days (entries 1–3), exhibiting very low TOF_2c–d of ca. 0.1–0.2 h⁻¹. The 2a–b systems (tBu and cumyl substituents) led to complete or almost complete conversions of 30–500 equiv. of rac-BPL^CH₂OTBDMS after 1–8 h (entries 4–9), with higher TOF_2a–b > 100 h⁻¹. Hence, the 2a–d/iPrOH catalytic systems featured a regular trend toward the ROP of rac-BPL^CH₂OTBDMS, yet with an overall lower activity as compared to the ROP of rac-BPL^CH₂OiPr and rac-BPL^CH₂OtBu.

Table 3 ROP of rac-BPL^CH₂OTBDMS mediated by the 2a–d/iPrOH catalytic systems^a

Entry	Cat.	[BPL^CH2OTBDMS]0/[2]0/[iPrOH]0	Time^b (h)	BPL^CH2OTBDMS Conv. ^c (%)	M n,theo (g mol^−1)	M n,NMR (g mol^−1)	M n,SEC ^f (g mol^−1)	Đ M ^f	P rM ^g
a Reactions performed with [BPL^CH2OTBDMS]0 = 1.0 M in toluene at room temperature. b Reaction times were not necessarily optimized. c Conversion of BPL^CH2OTBDMS as determined by ^1H NMR analysis of the crude reaction mixture. d Molar mass calculated according to Mn,theo = ([BPL^CH2OTBDMS]0/[2]0 × conv.BPL(CH2OTBDMS) × MBPL(CH2OTBDMS)) + MiPrOH with MBPL(CH2OTBDMS) = 216 g mol^−1 and MiPrOH = 60 g mol^−1. e Molar mass determined by ^1H NMR analysis of the isolated polymer, from the resonances of the terminal OiPr group. f Number-average molar mass (uncorrected values) and dispersity (Mw/Mn) determined by SEC analysis in THF at 30 °C vs. polystyrene standards. g P r is the probability of racemic linkages between BPL^CH2OTBDMS units as determined by ^13C{^1H} NMR analysis of the isolated PBPL^CH2OTBDMSs. h ROP of enantiopure (S)-BPL^CH2OTBDMS. i Not determined.
1	2d	30 : 1 : 1	48	16	1800	2500	1000	1.07	0.76
2	2c	30 : 1 : 1	8	30	2000	1600	2500	1.14	n.d.^i
3	2c	60 : 1 : 1	72	25	3300	3750	3000	1.12	0.77
4	2b	60 : 1 : 1	4	96	12 500	13 500	9000	1.13	0.83
5	2b	120 : 1 : 1	8	95	24 700	23 400	19 200	1.12	0.84
6	2b	250 : 1 : 1	5	100	47 100	37 600	24 300	1.07	0.81
7	2b	500 : 1 : 1	5	100	94 300	86 900	30 000	1.06	0.81
8	2a	30 : 1 : 1	1	98	6400	7600	8000	1.11	0.87
9	2a	60 : 1 : 1	4	99	12 900	12 350	10 000	1.10	0.87
10^h	2a	50 : 1 : 1	4	99	10 300	9100	8400	1.15	<0.05

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The M_n and dispersity data summarized in Table 3, the linear variation of the M_n,NMR and M_n,SEC molar mass values of PBPL^CH₂OTBDMS as a function of the monomer loading/conversion and the NMR spectra (see the ESI Fig. S12–S16†), all testify a similar well-controlled polymerization of rac-BPL^CH₂OTBDMS to the 2a–d/iPrOH catalytic systems, as that observed for rac-BPL^CH₂OiPr and rac-BPL^CH₂OtBu, affording well-defined α-isopropoxycarbonyl, ω-hydroxy end-capped PHAs. Also, similar to PBPL^CH₂OiPr and PBPL^CH₂OtBu discussed above, all the PBPL^CH₂OTBDMS systems revealed to be syndio-enriched (P_r = 0.76–0.87; Fig. 4) (δ r(C=O) = ca. 169.61, δ m(C=O) = ca. 169.52 ppm; δ r(CH) = ca. 71.16, δ m(CH) = ca. 71.08 ppm; δ r(CH₂O) = ca. 63.50, δ m(CH₂O) = ca. 63.35 ppm). Obviously, the stereochemistry of the ROP of rac-BPL^CH₂OTBDMS is controlled by steric components only, where the ascending catalyst selectivity trend is as follows: 2d (Cl substituents); P_r = 0.76 < 2c (Me substituents); P_r = 0.77 < 2b (tBu substituents); P_r = 0.84 < 2a (cumyl substituents); P_r = 0.87.

Fig. 4 Zoomed regions of the ¹³C{¹H} NMR spectra (125 MHz, CDCl₃, 23 °C) of PBPL^CH₂OTBDMS prepared by ROP of rac-BPL^CH₂OTBDMS, except for the top spectrum of enantiopure (S)-BPL^CH₂OTBDMS (Table 3, entry 10), mediated by the 2a, 2b, 2c, or 2d/iPrOH (1 : 1) catalytic systems (Table 3, entries 9, 5, 3 and 1, respectively); *stands for residual monomer resonances.

Kinetics of the ROP of rac-BPL^{CH₂OiPr/OtBu/OTBDMS}

Monitoring of NMR-scale polymerizations of rac-BPL^{CH₂OiPr/OtBu/OTBDMS} performed with 2a–d/iPrOH confirmed the kinetic trends assessed from the batch experiments (Tables 1–3). Linear semi-logarithmic plots established that all reactions were first-order in the monomer, with apparent rate constants k_app > 55 min⁻¹ for BPL^{CH₂OiPr/OtBu}/2a–b (complete conversion was observed after only 5 min under these conditions; see Table 1, entry 9 and Table 2, entry 11); k_app = 1.143 ± 0.072 min⁻¹ for BPL^CH₂OTBDMS/2a; 0.797 ± 0.031 min⁻¹ for BPL^CH₂OTBDMS/2b; 0.323 ± 0.033 min⁻¹ for BPL^CH₂OtBu/2c; 0.265 ± 0.032 min⁻¹ for BPL^CH₂OiPr/2c; 0.046 ± 0.041 min⁻¹ for BPL^CH₂OtBu/2d; 0.0088 ± 0.0021 min⁻¹ for BPL^CH₂OiPr/2d; 0.0037 ± 0.0033 min⁻¹ for BPL^CH₂OTBDMS/2c (Fig. 5). Overall, the major trend for the ability of the monomers to ring-open polymerize was thus BPL^CH₂OtBu ≥ BPL^CH₂OiPr ≫ BPL^CH₂OTBDMS, while the catalysts’ activity thus generally followed the order 2a–b ≫ 2c ≫ 2d, as previously observed for the ROP of various BPL^FGs β-lactones (FG = CH₂OAll, CH₂OBn, CH₂OMe, CH₂OPh, CH₂CH₂OBn, and CH₂SPh) promoted by these catalytic systems (vide supra).^7,10

Fig. 5 Semi-logarithmic first-order plots for the ROP of rac-BPL^FGs (FG = CH₂OiPr, CH₂OtBu, and CH₂OTBDMS) mediated by 2a–d/iPrOH (20 °C, toluene; [BPL^FG]₀/{[2a–c]₀/[iPrOH]₀} = 60–75 : 1 : 1 and [BPL^FG]₀/{[2d]₀/[iPrOH]₀} = 25–30 : 1 : 1): 2a (Table 1, entry 9; Table 2, entry 11; Table 3, entry 9); 2b (Table 1, entry 6; Table 2, entry 6; Table 3, entry 4); 2c (Table 1, entry 2; Table 2, entry 4; Table 3, entry 3) and 2d (Table 1, entry 1; Table 2, entry 1); plots from 2a–b all overlap due to similar higher activity of these catalysts regardless of the monomer functionality, and are represented as ▲. The slow kinetics of the ROP of rac-BPL^OTBDMS with 2d (Table 3, entry 1) is not shown.

The thermal characteristics of PBPL^CH₂ORs synthesized by ROP of rac-BPL^CH₂OR (R = iPr, tBu, and TBDMS) were enhanced by the 2a–d catalytic systems.

The thermal signature of the new functional PHAs synthesized in this work was briefly investigated by differential scanning calorimetry (DSC, Fig. S17–S20†). The glass transition temperature (T_g) values of syndio-enriched PBPL^{CH₂OiPr/CH₂OtBu/CH₂OTBDMS} slightly changed from one to another PHA, and ranged from −18 to +9 °C (Table 4). When compared to the corresponding values gathered for PBPL^{CH₂OMe/CH₂OAllyl/CH₂OBn} (T_g ranging from −38 to 0 °C, Table 4), these values appear to grossly increase with the steric hindrance imparted by the alkoxy/silyloxy side-functionality which decreases the motion of the macromolecules. Also, among the different syndio-enriched polymers herein prepared, only PBPL^CH₂OTBDMS featured a semi-crystalline behavior with T_m values of 118–119 °C (Fig. S19 and S20†).

Table 4 Overall sketch of the stereoselective ROP of rac-BPL^{CH₂OMe/CH₂OAll/CH₂OBn/CH₂OiPr/CH₂OtBu/CH₂OTBDMS} as a function of catalytic systems {Y{ON(X)O^R′,R′′} 2a–d, with P_r, T_g and T_m values of the resulting PBPL^{CH₂OMe/CH₂OAll/CH₂OBn/CH₂OiPr/CH₂OtBu/CH₂OTBDMS}

rac-BPL^FGs
Cat 2 (R′ = R′′)	rac-BPL^CH2OMe [7]	rac-BPL^CH2OAll [7]	rac-BPL^CH2OBn [7]	rac-BPL^CH2OiPr (this work)	rac-BPL^CH2OtBu (this work)	rac-BPL^CH2OTBDMS (this work)
a Table 1, entry 8. b Table 2, entry 5. c Table 3, entry 6; similar values (Tg = 8 °C, Tm = 118 °C) were recorded for the sample in Table 3, entry 7. d Not determined.
Crowded (cumyl, tBu) ( 2a–b )	Syndiotactic	Syndiotactic	Syndiotactic	Syndiotactic	Syndiotactic	Syndiotactic
	P r = 0.78–0.81	P r = 0.81–0.84	P r = 0.85–0.90	P r = 0.82–0.86	P r = 0.78–0.84	P r = 0.81–0.87
	T g = −12 °C	T g = −38 °C	T g = 0 °C	T g = −18 °C^a	T g = −6 °C^b	T g = 9 °C^c
	T m = 116 °C	T m = 85 °C	no Tm obsv.	no Tm obsv. a	no Tm obsv. b	T m = 119 °C c
Aliphatic non-crowded (Me; 2c)	Atactic	Atactic	Atactic	Syndiotactic	Syndiotactic	Syndiotactic
	P r = 0.49	P r = 0.49	P r = 0.50	P r = 0.71–0.72	P r = 0.74–0.75	P r = 0.77
	T g = −18 °C	T g = −40 °C	T g = −6 °C	T g, Tm = n.d.^d	T g, Tm = n.d.^d	T g, Tm = n.d.^d
Halogenated non-crowded (Cl, 2d)	Isotactic	Isotactic	Isotactic	Syndiotactic	Syndiotactic	Syndiotactic
	P r = 0.10	P r = 0.09	P r = 0.10	P r = 0.70	P r = 0.70–0.71	P r = 0.76
	T g = −18 °C	T g = −39 °C	T g = 0 °C	T g, Tm = n.d.^d	T g, Tm = n.d.^d	T g, Tm = n.d.^d

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Conclusions

Table 4 summarizes the stereoselectivity outcome of the ROP of rac-BPL^{CH₂OMe/CH₂OAll/CH₂OBn/CH₂OiPr/CH₂OtBu/CH₂OTBDMS} as a function of yttrium catalytic systems, differentiating the latter ones according to the presence of highly sterically crowded substituents (i.e., tBu, cumyl; 2a–b), simple aliphatic non-crowded substituents (Me, 2c) and halogeno non-crowded substituents (Cl, 2d). Highly syndio-enriched PBPL^{CH₂OiPr/OtBu/OTBDMS} were obtained from 2a–b, alike PBPL^{CH₂OMe/OAll/OBn} (P_r = 0.78–0.87 vs. 0.78–0.90; respectively). However, substitution of one or two hydrogen atoms in the alkoxide “outer” methylene group of rac-BPL^{CH₂OMe/OAll/OBn} by one or two methyl groups – as in rac-BPL^CH₂OiPr and rac-BPL^CH₂OtBu – or with rac-BPL^CH₂OTBDMS resulted in: (i) changing the stereoregularity of the polymer from atactic to syndio-enriched polymers with catalyst 2c (P_r = 0.49/0.50 vs. 0.71–0.77, respectively), and (ii) switching from isotactic to syndio-enriched polymers with catalyst 2d (P_r = 0.09–0.10 vs. 0.76–0.71, respectively). Obviously, these observations evidence that the stereocontrol in the ROP of racemic 4-alkoxymethylene-β-propiolactones is driven, systematically by steric considerations, but in a few specific cases by electronic ones as well. For rac-BPL^CH₂OiPr, rac-BPL^CH₂OtBu and rac-BPL^CH₂OTBDMS, apparently due to the large steric constraints induced by the alkoxy(silyloxy) side-functionality, all reactions lead to the formation of syndio-enriched polymers, regardless of the catalyst – a crowded one or a non-crowded one – used. This is what is expected from a ‘regular’ chain-end stereocontrol mechanism, in which minimization of steric repulsions in the transition state favors the enchainment of monomer units alternately with opposite absolute configurations (and hence the formation of syndiotactic/heterotactic polymers).¹ Only the specific combination of a BPL^FG monomer containing two methylene hydrogens apart from the central oxygen on the methylene alkoxy side-functionality (i.e., FG = CH₂OMe, CH₂OAllyl, and CH₂OBn) with a catalyst bearing chloro-substituents (2a) produced isotactic PHAs; this is assumed to arise from attractive interactions between the ligand chloro substituents and the hydrogen atoms on the alkoxy (methoxy, allyloxy, and benzyloxy) side chain of the ring-opened monomer/growing polymer chain.⁷ On the other hand, a catalyst with highly sterically crowding substituents on the ligand platform is necessary to recover syndio-enriched PHAs from the latter BPL^{CH₂OMe,CH₂OAll,CH₂OBn} monomers, which show no major steric bulkiness on the side chain alkoxymethylene moiety. Thus, at this stage of our investigations, in a ROP mediated by a typically isoselective yttrium catalyst, bulkiness of the –OR methylene-alkoxy/silyloxy moiety of BPL^CH₂OR monomers is not sufficient to impart isoselectivity, while the presence of two methylene groups adjacent to the oxygen within these BPL^{CH₂OMe,CH₂OAllyl,CH₂OBn} still appears mandatory to access desirable synthetic isotactic PHAs that mimic their natural analogues. Ongoing work by our group aims at examining further the contribution of the two methylene groups, apart from the oxygen in the side-functionality, in the stereoselective ROP of functional β-lactones towards the synthesis of isotactic functional PHAs.

Author contributions

CRediT: Rama M. Shakaroun: investigation (lead) and writing – original draft (supporting); Ali Dhaini: investigation (supporting) and writing – review & editing (supporting); Romain Ligny: investigation (supporting); Ali Alaaeddine: supervision (supporting); Sophie Guillaume: conceptualization (lead), supervision (lead), writing – original draft (supporting), and writing – review & editing (lead); Jean-François Carpentier: conceptualization (lead), supervision (lead), writing – original draft (lead), and writing – review & editing (lead).

Conflicts of interest

There are no conflicts of interest to declare.

Acknowledgements

This research was financially supported in part by the University of Rennes (Ph.D. grants to R. S., A. D. and R. L.), the Lebanese University (Ph.D. grants to R. S. and A. D.) and the Région Bretagne (Ph.D. ARED grant to R. L.). We are grateful to CRMPO and UAR ScanMAT, especially to Philippe Jéhan, Elsa Caytan, and Marielle Blot for MS, NMR and chiral HPLC chromatography analyses, respectively.

References

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Footnotes

† Electronic supplementary information (ESI) available: General conditions, synthesis and characterization of BPL^CH₂OR monomers, NMR and mass spectra, and DSC traces. See DOI: https://doi.org/10.1039/d2py01573k

‡ P_m is the probability of meso linkages, that is, the enchainment of two monomer units with the same configuration. P_m = 1 − P_r, where P_r is the probability of racemo linkage, that is, the enchainment of two monomer units with the opposite configuration.

§ Note that, similarly, the ROP of the parent sulfur BPL^CH₂^SPh recovered the corresponding syndiotactic PHA; see ref. 10.

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