O-carboxyanhydrides Research Articles

Efficient Access to Sequence-Controlled Poly(α-hydroxy acids) with Ax(BC)yDz-Type and Ax(BC)yAz-Type Triblock Structures via Self-Switchable Ring-Opening Polymerization of Monomer Mixtures.

Synthesizing block-sequence-controlled poly(α-hydroxy acids) of three or four α-hydroxy acids remains challenging in one step. In this study, a strategy was employed using three monomers of O-carboxyanhydrides (OCAs) consisting of one α-hydroxy acid (A), asymmetric cyclic diester (B and C, two different α-hydroxy acids of B and C), and symmetric cyclic diester (one α-hydroxy acid of D) with remarkably different activities toward a stereoselective, regioselective, and chemoselective initiator of a zirconium complex. Then, via a self-switchable approach, these monomers can be copolymerized in a well-controlled block sequence of Ax(BC)yDz and Ax(BC)yAz without an external stimulus. Moreover, upon addition of more monomer mixtures during the copolymerization process, more complicated sequence-controlled poly(α-hydroxy acids) can be achieved with up to 15 blocks.

Facile Tandem Copolymerization of O-Carboxyanhydrides and Epoxides to Synthesize Functionalized Poly(ester-b-carbonates).

The synthesis of well-defined degradable block copolymers from mixtures of monomers is one of the foremost challenges in the sustainable plastics industry. For example, the currently available one-pot strategies for preparing poly(ester-co-carbonates)─which combine two commonly used degradable polymers─are energy- and material-intensive, requiring high-pressure CO2 gas and elevated temperatures. Here, we report an atom-economical, scalable method for block copolymerization of O-carboxyanhydrides (OCAs) and epoxides to prepare functionalized poly(ester-b-carbonates) with high molecular weights (MWs) (>200 kDa) and narrow MW distributions (D̵ < 1.1) by using a single Lewis acidic zinc complex at room temperature in the absence of pressurized CO2. Kinetic studies showed that the first stage of the process, ring-opening polymerization of the OCAs, exhibited zero-order kinetics, suggesting that the polymerization rate was independent of monomer concentration and thus allowing for a sharp switch in mechanism without the tapering effect. The obtained degradable poly(ester-b-carbonates) showed better toughness than their corresponding homopolymers and outperformed some commodity polyolefins.

Monomer Controlled Switchable Copolymerization: A Feasible Route for the Functionalization of Poly(lactide)

AbstractSwitchable polymerization is an attractive strategy to enable the sequential selectivity of multi‐block polyesters. Besides, these well‐defined multi‐block polyesters could enable further modification for wider applications. Herein, based on the reversible insertion of CO2 by Salen‐MnIII, a new monomer controlled self‐switchable polymerization route was developed. Chemoselective ring opening copolymerization of O‐carboxyanhydrides (OCAs) and lactide (LA) was explored without cocatalyst. The sequential conversion of OCAs and LA into the polymer chain could form multi‐block polyesters. Based on this strategy, a series of multi‐block polyesters with different pendant groups were synthesized. Furthermore, by modifying the propargyl‐containing copolymers with quaternary ammonium groups, we have realized antibacterial functionalization of PLA. These results imply the potential application of this strategy for the fabrication of functional polymers for biomedical applications.

Monomer Controlled Switchable Copolymerization: A Feasible Route for the Functionalization of Poly(lactide).

Switchable polymerization is an attractive strategy to enable the sequential selectivity of multi-block polyesters. Besides, these well-defined multi-block polyesters could enable further modification for wider applications. Herein, based on the reversible insertion of CO2 by Salen-MnIII , a new monomer controlled self-switchable polymerization route was developed. Chemoselective ring opening copolymerization of O-carboxyanhydrides (OCAs) and lactide (LA) was explored without cocatalyst. The sequential conversion of OCAs and LA into the polymer chain could form multi-block polyesters. Based on this strategy, a series of multi-block polyesters with different pendant groups were synthesized. Furthermore, by modifying the propargyl-containing copolymers with quaternary ammonium groups, we have realized antibacterial functionalization of PLA. These results imply the potential application of this strategy for the fabrication of functional polymers for biomedical applications.

Living Polymerization of Chiral O-Carboxyanhydride of Mandelic Acid and Precise Stereoblock Copolymer Syntheses Using Highly Active OOO-Tridentate Bis(phenolate) Zinc Complexes

The synthesis of highly stereoregular poly(mandelic acid) (PMA) via controllable polymerization is a considerable challenge because of the easy racemization of monomers during polymerization; consequently, precise stereoblock copolymers of PMA have not been reported so far. In this work, highly stereoregular PMA was synthesized through a living ring-opening polymerization of O-carboxyanhydrides (OCAs) of mandelic acid using highly active OOO-tridentate bis(phenolate)/zinc catalysts. In this polymerization system, the side reaction of racemization was suppressed very well via decreasing the basicity of ligands in zinc complexes. The molecular weight increases linearly as the ratio of monomer to initiator increases and can be high up to 32.5 kg/mol with narrow molecular weight distributions. Meanwhile, for the living polymerization feature, stereodiblock and stereotriblock copolymers with controllable molecular weights were obtained upon sequential one-pot monomer addition within 45 min. Thermal and X-ray diffraction characterizations indicated that these stereoblock copolymers crystallized in a stereocomplex phase with a distinct melting temperature (Tm) up to 178 °C, and the solubility behaviors of stereoblock PMAs and enantiomeric homopolymers of PMAs are remarkably different.

Unimolecular Anion‐Binding Catalysts for Selective Ring‐Opening Polymerization of O‐carboxyanhydrides

AbstractAnion‐binding can regulate anion transport in chloride channels through dynamic non‐covalent interactions, which gives insights into the designing of new organocatalytic transformations but is surprisingly unexplored in polymerization catalysis. Herein, we describe an effective unimolecular anion‐binding organocatalysis where 4‐(dimethylamino)pyridine is anchored to a thiourea for ring‐opening polymerization of O‐carboxyanhydrides (OCAs) to furnish highly isotactic poly(phenyllactic acid) (Ph‐PLA) with molecular weight (MW) up to 150.0 kDa, which well addresses the formidable challenge of synthesizing high MW stereoregular polyesters. Calculations and experimental studies indicate a dynamic cooperative anion‐binding mechanism, where the dynamic anion‐binding interaction of thiourea moiety to propagating species facilitates efficient chain propagation and the synergetic decarboxylation retains high selectivity for OCA ring‐opening over side reactions (such as cyclization, epimerization, and transesterification).

Unimolecular Anion‐Binding Catalysts for Selective Ring‐Opening Polymerization of O‐carboxyanhydrides

AbstractAnion‐binding can regulate anion transport in chloride channels through dynamic non‐covalent interactions, which gives insights into the designing of new organocatalytic transformations but is surprisingly unexplored in polymerization catalysis. Herein, we describe an effective unimolecular anion‐binding organocatalysis where 4‐(dimethylamino)pyridine is anchored to a thiourea for ring‐opening polymerization of O‐carboxyanhydrides (OCAs) to furnish highly isotactic poly(phenyllactic acid) (Ph‐PLA) with molecular weight (MW) up to 150.0 kDa, which well addresses the formidable challenge of synthesizing high MW stereoregular polyesters. Calculations and experimental studies indicate a dynamic cooperative anion‐binding mechanism, where the dynamic anion‐binding interaction of thiourea moiety to propagating species facilitates efficient chain propagation and the synergetic decarboxylation retains high selectivity for OCA ring‐opening over side reactions (such as cyclization, epimerization, and transesterification).

Synthesis of Sustainable Polyesters via Organocatalytic Ring-Opening Polymerization of O-carboxyanhydrides: Advances and Perspectives.

Sustainable polyesters can be furnished via ring-opening polymerization (ROP) of O-carboxyanhydrides (OCAs). Various catalysts, especially metal-based catalysts, are devised to achieve controlled ROP of OCAs. In the following mini review, the recent progress on the organocatalytic ROP of OCAs, including the usage of thiourea-based bifunctional single-molecule organocatalysts for eliminating epimerization in OCAs polymerization is summarized. Moreover, the future development of the organocatalytic ROP of OCAs for the synthesis of sustainable polyesters will be discussed.

Ring-Opening Alternating Copolymerization of O-Carboxyanhydrides of Lactic Acid and Malic Acid Using Hafnium Alkoxide Initiators with Different Stereo Selectivities and Activities.

Monomer sequence controllable syntheses of copolymers, including copolyesters, remain a challenge in polymer science. Although alternating sequence-controlled copolymerization of O-carboxyanhydrides (OCAs) can be achieved via using syndioselective initiators, the alternating copolymerization of lactic acid-derived O-carboxyanhydride (LacOCA) with other monomers still suffers from a lack of highly syndioselective initiators. In this work, a highly syndioselective system for the ring-opening polymerization (ROP) of LacOCA was achieved using a bulky amine tris(phenolate) hafnium alkoxide initiator with a high Pr value of 0.91. However, the stereoselectivities of amine tris(phenolate) hafnium alkoxide initiators for the ROP of malic acid O-carboxyanhydride (MalOCA) change to be modestly or lowly isoselective. Interestingly, despite the different stereoselectivities of this system for the two different monomers, the high syndioselectivity of the initiator for the ROP of LacOCA and the low activity of MalOCA in the ROP allow comparatively high rates of cross-propagation; consequently, the ring-opening alternating copolymerization (ROAP) of LacOCA and MalOCA was achieved successfully.

Amorphous random copolymers of lacOCA and manOCA for the design of biodegradable polyesters with tuneable properties

Biodegradable polymers derived from renewable resources can be interesting materials for a plethora of applications and have therefore gained increased interest over the last decades. We herein report for the first time the synthesis of random copolymers based on lactic and mandelic acid via ring-opening-polymerisation of their corresponding O-carboxyanhydrides (OCA). Copolymers with tailored glass transition temperature and degradation time were obtained by adjusting the co-monomer feed during copolymerisation. Molecular weight analyses of the obtained copolymers indicated lower molecular weights in comparison to the target values. Our hypothesis that keto-enol tautomerisation of the OCA-monomers was the cause for this anomaly was substantiated by a mechanistic study of the OCA-polymerization reaction using lacOCA and manOCA as case study.

In vivo cancer targeting via glycopolyester nanoparticle mediated metabolic cell labeling followed by click reaction

We developed glycopolyesters (GPs) via azido-sugar initiated ring-opening polymerization of O-carboxyanhydrides (OCAs) and achieved efficient in vivo cancer targeting via GP-nanoparticle (GP-NP) mediated metabolic cell labeling followed by Click reaction. GP-NP shows controlled release of azido-sugars and can efficiently label LS174T colon cancer cells with azido groups in tumor-bearing mice. The exogenously introduced azido groups render excellent in vivo cancer targeting and retention of dibenzocyclooctyne-Cy5 (DBCO-Cy5) with an increasing tumor retention enhancement over time (68% at 6 h, 105% at 24 h, and 191% at 48 h) compared to control mice without azido labeling. The tumor accumulation of DBCO-doxorubicin is also significantly enhanced in GP-NP pretreated mice, resulting in improved in vivo anticancer efficacy. This study, for the first time, proposes the use of azido-sugar initiated polymerization of OCAs to form sugar delivery vehicles with high stability and controlled release, and demonstrates the increasing tumor targeting effect of DBCO-cargo over time by azido-modified tumor cells.

Eugenol-grafted aliphatic polyesters: Towards inherently antimicrobial PLA-based materials exploiting OCAs chemistry

PLA-based materials with eugenol moieties covalently bonded to the macromolecular chains were synthesized for potential application in bioactive food packaging. The synthetic strategy relies on the exploitation of O-Carboxyanhydrides (OCAs) as versatile and easily modifiable monomers. More precisely, eugenol-bearing L-malic acid-derived OCA (L-MalOCA) was synthesized and used as monomer, in homo- and co-polymerization reactions. In the latter case, two different ratios of functionalized L-MalOCA were employed, with respect to the standard L-lactic acid-derived OCA (L-LacOCA) monomer. Homopolymer and copolymers were fully characterized and their thermal properties were investigated, highlighting the effect on the final polymer of varying the concentration of the L-MalOCA-derived monomer. A moderate antimicrobial activity was detected for the eugenol-rich L-MalOCA-derived homopolymerization product, making it promising for developments in the field of bioactive and biodegradable PLA-based materials.

Highly isoselective ring-opening polymerization of rac-O-carboxyanhydrides using a zinc alkoxide initiator.

The stereoselective ring-opening polymerization (ROP) of O-carboxyanhydrides (OCAs) remains a major challenge due to the easy epimerization of monomers. In this work, using a zinc alkoxide initiator, highly efficient ROP of enantiopure 5-methyl-1,3-dioxolane-2,4-dione (LacOCA), 5-benzyl-1,3-dioxolane-2,4-dione (PheOCA), and 5-(4-(benzyloxy)benzyl)-1,3-dioxolane-2,4-dione (Try(Bn)OCA) was achieved without obvious epimerization. Moreover, highly isoselective ROP of rac-LacOCA, rac-PheOCA, and rac-Try(Bn)OCA was successful with the highest isoselectivity of Pm = 0.97 at -70 °C.

Living Ring-Opening Polymerization of O-Carboxyanhydrides: The Search for Catalysts.

Biodegradable poly(α-hydroxy acids) can be synthesized by means of ring-opening polymerization (ROP) of O-carboxyanhydrides (OCAs). Numerous catalysts have been developed to control the living polymerization of OCAs. Here we review the rationale for the use of OCA, the desirable features for and important attributes of catalysts for the ROP of OCAs, and specific examples that have been developed.

Synergetic Organocatalysis for Eliminating Epimerization in Ring-Opening Polymerizations Enables Synthesis of Stereoregular Isotactic Polyester.

Ring-opening polymerization of O-carboxyanhydrides (OCAs) can furnish polyesters with a diversity of functional groups that are traditionally hard to harvest by polymerization of lactones. Typical ring-opening catalysts are subject to unavoidable racemization of most OCA monomers, which hampers the synthesis of highly isotactic crystalline polymers. Here, we describe an effective bifunctional single-molecule organocatalysis for selective ring-opening polymerization of OCAs without epimerization. The close vicinity of both activating groups in the same molecule engenders an amplified synergetic effect and thus allows for the use of mild bases, thereby leading to minimal epimerization for polymerization. Ring-opening polymerization of manOCA monomer (OCA from mandelic acid) mediated by the bifunctional single-molecule organocatalyst yields highly isotactic poly(mandelic acid) (PMA) with controlled molecular weights (up to 19.8 kg mol-1). Mixing of the two enantiomers of PMA generates the first example of a crystalline stereocomplex in this area, which displayed distinct Tm values around 150 °C. Remarkably, the bifunctional catalysts are moisture-stable, recyclable, and easy to use, allowing sustainable and scalable synthesis of a stereoregular functional polyester.

Recent Advances in Ring-Opening Polymerization of O-Carboxyanhydrides

Poly(α-hydroxy acids) are important biodegradable polymers with wide applications. Recently O-carboxyanhydrides (OCAs) have emerged as promising monomer equivalents of lactides to synthesize poly(α-hydroxy acids). We will highlight recent advances in controlled ring-opening polymerization of OCAs catalyzed by organocatalysts, enzymes, or organometallic complexes.1 Introduction2 Organocatalysts for O-Carboxyanhydride Polymerization2.1 Synthesis of O-Carboxyanhydride Monomers2.2 Ring-Opening Polymerization of O-Carboxyanhydrides Catalyzed by 4-Dimethylaminopyridine2.3 Epimerization in the Ring-Opening Polymerization of O-Carboxyanhydrides Catalyzed by the Pyridine Base2.4 N-Heterocyclic Carbenes for Ring-Opening Polymerization of O-Carboxyanhydrides3 Enzymes for O-Carboxyanhydride Polymerization4 Organometallic Catalysts for O-Carboxyanhydride Polymerization4.1 Early Efforts4.2 Ring-Opening Polymerization Catalyzed by Zn Complexes4.3 Photoredox Ring-Opening Polymerization Catalyzed by Zn/Ni Complexes5 Conclusion and Perspective

Alternating Sequence Controlled Copolymer Synthesis of α-Hydroxy Acids via Syndioselective Ring-Opening Polymerization of O-Carboxyanhydrides Using Zirconium/Hafnium Alkoxide Initiators.

The ring-opening polymerization (ROP) of O-carboxyanhydrides (OCAs) can give diverse poly(α-hydroxy acid)s (PAHAs) with different functional groups because of easy modification of the side group of OCAs, which can extend applications of PAHAs widely. The stereoselective polymerization of O-carboxyanhydrides and further sequence controlled alternating copolymerization of OCAs were still big challenges until now for lack of suitable catalysts/initiators. In this work, a highly syndioselective ROP of OCAs system as the first stereoselective example in this area is reported using zirconium/hafnium alkoxides as initiators with the highest Pr value up to 0.95. Furthermore, these initiators were successfully applied in the precisely alternating sequence controlled copolymerization of PheOCA and Tyr(Bn)OCA, and alternating copolymerization of LacOCA and PheOCA was also achieved.

Controlled Ring-Opening Polymerization of O-Carboxyanhydrides Using a β-Diiminate Zinc Catalyst.

Recently O-carboxyanhydrides (OCAs) have emerged as a class of viable monomers which can undergo ring-opening polymerization (ROP) to prepare poly(α-hydroxyalkanoic acid) with functional groups that are typically difficult to achieve by ROP of lactones. Organocatalysts for the ROP of OCAs, such as dimethylaminopyridine (DMAP), may induce undesired epimerization of the α-carbon atom in polyesters resulting in the loss of isotacticity. Herein, we report the use of (BDI-IE)Zn(OCH(CH3 )COOCH3 ) ((BDI)Zn-1, (BDI-IE)=2-((2,6-diethylphenyl)amino)-4-((2,6-diisopropylphenyl)imino)-2-pentene), for the controlled ROP of various OCAs without epimerization. Both homopolymers and block copolymers with controlled molecular weights, narrow molecular weight distributions, and isotactic backbones can be readily synthesized. (BDI)Zn-1 also enables controlled copolymerization of OCAs and lactide, facilitating the synthesis of block copolymers potentially useful for various biomedical applications. Preliminary mechanistic studies suggest that the monomer/dimer equilibrium of the zinc catalyst influences the ROP of OCAs, with the monomeric (BDI)Zn-1 possessing superior catalytic activity for the initiation of ROP in comparison to the dimeric (BDI)Zn complex.

Controlled Ring‐Opening Polymerization of O‐Carboxyanhydrides Using a β‐Diiminate Zinc Catalyst

AbstractRecently O‐carboxyanhydrides (OCAs) have emerged as a class of viable monomers which can undergo ring‐opening polymerization (ROP) to prepare poly(α‐hydroxyalkanoic acid) with functional groups that are typically difficult to achieve by ROP of lactones. Organocatalysts for the ROP of OCAs, such as dimethylaminopyridine (DMAP), may induce undesired epimerization of the α‐carbon atom in polyesters resulting in the loss of isotacticity. Herein, we report the use of (BDI‐IE)Zn(OCH(CH3)COOCH3) ((BDI)Zn‐1, (BDI‐IE)=2‐((2,6‐diethylphenyl)amino)‐4‐((2,6‐diisopropylphenyl)imino)‐2‐pentene), for the controlled ROP of various OCAs without epimerization. Both homopolymers and block copolymers with controlled molecular weights, narrow molecular weight distributions, and isotactic backbones can be readily synthesized. (BDI)Zn‐1 also enables controlled copolymerization of OCAs and lactide, facilitating the synthesis of block copolymers potentially useful for various biomedical applications. Preliminary mechanistic studies suggest that the monomer/dimer equilibrium of the zinc catalyst influences the ROP of OCAs, with the monomeric (BDI)Zn‐1 possessing superior catalytic activity for the initiation of ROP in comparison to the dimeric (BDI)Zn complex.

O-Carboxyanhydrides: Useful Tools for the Preparation of Well-Defined Functionalized Polyesters.

Over the last ten years, O-carboxyanhydrides (OCA) have attracted increasing attention as ring-opening polymerization (ROP) monomers. They are readily available from α-hydroxyacids and are significantly more reactive than 1,4-dioxane-2,5-diones. Thus, softer catalysts and milder reaction conditions can be used, allowing for a better control of the polymerization. Most attractive are the functionalized OCA that enable the introduction of functional groups along the polyester backbone and thereby vary and finely tune their physicochemical properties. In this viewpoint, the achievements made over the last years are critically overviewed. Particular attention is paid to the different catalytic approaches that have been reported for the ROP of these heterocycles and to the comparison with lactide ROP. In addition, the most representative examples of functionalized polyesters and polymer conjugates prepared from OCA are discussed.