Click Step-Growth Polymerization and E/ Z Stereochemistry Using Nucleophilic Thiol-yne/-ene Reactions: Applying Old Concepts for Practical Sustainable (Bio)Materials

Abstract

Polymer sustainability is synonymous with "bioderived polymers" and the zeitgeist of "using renewable feedstocks". However, this sentiment does not adequately encompass the requirements of sustainability in polymers. In addition to recycling considerations and mechanical performance, following green chemistry principles also needs to be maximized to improve the sustainability of polymer synthesis. The synthetic cost (i.e., maximizing atom economy, reducing chemical hazards, and lowering energy requirements) of producing polymers should be viewed as equally important to the monomer source (biomass vs petrol platform chemicals). Therefore, combining the use of renewable feedstocks with efficient syntheses and green chemistry principles is imperative to delivering truly sustainable polymers. The high efficiency, atom economy, and single reaction trajectories that define click chemistry reactions position them as ideal chemical approaches to synthesize polymers in a sustainable manner while simultaneously expanding the structural scope of accessible polymers from sustainably sourced chemicals.Click step-growth polymerization using the thiol-yne Michael addition, a reaction first reported over a century ago, has emerged as an extremely mild and atom-efficient pathway to yield high-performance polymers with controllable E/Z stereochemistry along the polymer backbone. Building on studies of aromatic thiol-yne polymers, around 10 years ago our group began investigating the thiol-yne reaction for the stereocontrolled synthesis of alkene-containing aliphatic polyesters. Our early studies established a convenient path to high-molecular-weight (>100 kDa) E-rich or Z-rich step-growth polymers by judiciously changing the catalyst and/or reaction solvent. This method has since been adapted to synthesize fast-degrading polyesters, high-performance polyamides, and resilient hydrogel biomaterials. Across several systems, we have observed dramatic differences in material properties among polymers with different alkene stereochemistry.We have also explored the analogous thiol-ene Michael reaction to create high-performance poly(ester-urethanes) with precise E/Z stereochemistry. In contrast to the stereoselective thiol-yne polymerization, here the use of monomers with predefined E/Z (geometric) isomerism (arising from either alkenes or the planar rigidity of ring units) affords polymers with total control over stereochemistry. This advancement has enabled the synthesis of tough, degradable materials that are derived from sustainable monomer feedstocks. Employing isomers of sugar-derived isohexides, bicyclic rigid-rings possessing geometric isomerism, led to degradable polymers with fundamentally opposing mechanical behavior (i.e., plastic vs elastic) simply by adjusting the stereochemistry of the isohexide.In this Account, we feature our investigation of thiol-yne/-ene click step-growth polymers and efforts to establish structure-property relationships toward degradable materials with practical mechanical performance in the context of sustainable polymers and/or biomaterials. We have paid attention to installing and controlling geometric isomerism by using these click reactions, an overarching objective of our work in this research area. The exquisite control of geometric isomerism that is possible within polymer backbones, as enabled by convenient click chemistry reactions, showcases a powerful approach to creating multipurpose degradable polymers.

Figure 1

Nucleophilic and radical mechanisms for thiol addition to alkenes and alkynes (left) and nucleophilic thiol–yne/–ene polymerization to afford step-growth polymers with well-defined stereochemistry (right).

Scheme 1. Proposed Mechanism for the Base-Catalyzed Thiol–yne Addition to Activated Acetylenes

Figure 2

(a) Synthesis of thiol–yne materials from dialkyne and dithiol precursors. (b) Exemplar stress vs strain data for polymers with high Z- and high E-alkene content. Polymer data: high Z (80% Z), M_w = 148 kDa and Đ_M = 5.6; high E (32% Z), M_w = 125 kDa and Đ_M = 3.68. Adapted with permission from ref (1). Copyright 2016 The Authors. Published by Wiley under the Creative Commons Attribution 4.0 International (CC BY 4.0) License.

Figure 3

(a) Synthesis of thiol–yne copolymers from dialkyne and dithiol precursors. (b) Exemplar stress vs strain curves for the thiol–yne polymer with 80% Z-alkene content composed of propane-1,3-dipropiloate (C_3EA) and 1,6-hexanedithiol (C_6T). (c) Exemplar stress vs strain curves for thiol–yne polymer with 78% Z-alkene content composed of C_3EA and 90% C_6T/10% DTT. Data for three samples are shown to illustrate the reproducibility. (d) Surface energy data for C_3EA–C_6T and C_3EA–(90% C_6T/10% DTT). Polymer data: C_3EA–C_6T (80% Z) M_w = 148 kDa and Đ_M = 5.6; (78% Z) M_w = 110 kDa and Đ_M = 3.77. This figure was produced using data taken from ref (1).

Figure 4

¹⁹F NMR spectrum of the C_3EA–C_6T thiol–yne step-growth polymer following end-capping with 2,2,2-trifluoroethanethiol (376 MHz, CDCl₃ + 0.01% v/v CF₃COOH). Adapted with permission from ref (1). Copyright 2016 The Authors. Published by Wiley under the Creative Commons Attribution 4.0 International (CC BY 4.0) License.

Figure 5

(a) Synthesis of succinate-containing thiol–yne materials from dialkyne and dithiol precursors. (b) Demonstration of independent control over degradability (weight loss vs time for samples under accelerated hydrolysis conditions) and mechanical properties (stress vs strain curves) for polymers with different succinate monomer content and/or alkene stereochemistry. Polymer data: 79% Z (9% succinate), M_w = 111 kDa and Đ_M = 3.74; 59% Z (9% succinate), M_w = 117 kDa and Đ_M = 3.42; 59% Z (9% succinate), M_w = 124 kDa and Đ_M = 2.36. Adapted with permission from ref (52). Copyright 2021 The Authors. Published by Springer Nature under the Creative Commons Attribution 4.0 International (CC BY 4.0) License.

Figure 6

(a) Structure of polyamide C_3AA–C_6T. (b) Images to show the physical appearance and moldability of C_3AA–C_6T (nylon 6 included for comparison). (c) DSC thermograms of the first heating cycle for C_3AA–C_6T, nylon 6, and nylon 6,6 to demonstrate the amorphous nature of C_3AA–C_6T. (d) Bar chart to show how Young’s modulus and the change for C_3AA–C_6T at different E/Z ratios. Error bars represent 1 s.d. Polymer data for C_3AA–C_6T: 82% Z, M_w = 105 kDa and Đ_M = 3.35; 73% Z, M_w = 131 kDa and Đ_M = 3.39; 46% Z, M_w = 112 kDa and Đ_M = 3.84; 35% Z, M_w = 113 kDa and Đ_M = 4.7. Adapted with permission from ref (2). Copyright 2021 The Authors. Published by Springer Nature under the Creative Commons Attribution 4.0 International (CC BY 4.0) License.

Figure 7

(a) Nucleophilic thiol–yne addition schematic. (b) Schematic of the PEG hydrogel precursors with notation. (Gels were formed from mixtures of alkyne and thiol precursors as indicated.) (c) Stress vs strain data for the compression analysis of hydrogels. Adapted with permission from ref (58). Copyright 2017 American Chemical Society.

Figure 8

(a) Schematic of an interpenetrating hydrogel prepared by introducing a secondary loose network based on electrostatically cross-linked natural polymers (i.e., alginate/calcium) and nucleophilic thiol–yne addition. (b) Representative tensile stress vs strain curve for PEG/natural polymer hydrogels. (c) Photographs of the self-healed PEG/alginate hydrogel against a PEG-only control. (d) Photograph of a re-healed PEG/alginate hydrogel undergoing tensile testing showing that the fracture site is not at the healed site. Adapted with permission from ref (64). Copyright 2018 The Authors. Published by Royal Society of Chemistry under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0).

Figure 9

(a) Synthesis of thiol–yne click-hydrogels with controllable alkene stereochemistry by adjusting the reaction parameters. (b) Stiffness of hydrogels defined as the storage modulus (G′) at 0.1% strain. (c) Cell morphology of Y201 MSCs seeded on stereocontrolled hydrogels, assessed using phalloidin and DAPI staining following 72 h of culture. Adapted with permission from ref (3). Copyright 2021 The Authors. Published by Wiley under the Creative Commons Attribution 4.0 International (CC BY 4.0) License.

Figure 10

(a) Synthesis of copolymers with stereochemically defined double bonds using the thiol–ene Michael addition of dithiols and diacrylate monomers. (i) 2.1 equiv of 2-isocyanatoethyl acrylate, 0.2 mol % of dibutyl tin(IV) dilaurate, THF, 22 °C; (ii) 1 equiv of 1,6-hexanedithiol, 2 mol % dimethylphenylphosphine (DMPP), DMF, 22 °C. (b) DSC thermograms of homopolymers for the first heating cycle (dashed lines = 10 K·min^–1 and solid lines = 1 K·min^–1). (c) Respresentative stress vs strain curves of homopolymers (n = 5). Inset data between 0 and 40% strain. (d) Dynamic mechanical thermal analysis thermograms of storage modulus vs temperature performed in the tensile configuration. Polymer data: T₁₀₀, M_w = 103 kDa and Đ_M = 3.57; S₁₀₀, M_w = 139 kDa and Đ_M = 4.51; C₁₀₀, M_w = 250 kDa and Đ_M = 7.19. Adapted with permission from ref (71). Copyright 2020 American Chemical Society.

Figure 11

Synthesis of isohexide-containing polymers from isoidide (exo/exo), isomannide (endo/endo), and isosorbide (endo/exo) by thiol–ene nucleophilic addition. Adapted with permission from ref (4). Copyright 2022 American Chemical Society.

Figure 12

(a) Structures of ISPU (urethane and isosorbide), ISNU (isosorbide only), and SAT-PU (urethane only). (b) Stress vs strain curves obtained by tensile testing of ISPU, ISNU, and SAT-PU films. Polymer data: ISPU, M_w = 110 kDa and Đ_M = 11.08; ISNU, M_w = 136 kDa and Đ_M = 6.71; SAT PU, M_w = 139 kDa and Đ_M = 4.71. Adapted with permission from ref (86). Copyright 2022 The Authors. Published by Wiley under the Creative Commons Attribution 4.0 International (CC BY 4.0) License.

Figure 13

(a) Stress vs strain curves obtained by tensile testing of IIPU (isoidide polyurethane) and IMPU (isomannide polyurethane). (Inset) Photographs of pressed films of IIPU and IMPU. (b) DSC thermograms of the first heating and cooling cycle for IIPU and IMPU (solid line = heating scan and dashed line = cooling scan). Polymer data: IIPU, M_w = 117 kDa and Đ_M = 8.12; IMPU, M_w = 95 kDa and Đ_M = 9.69. Adapted with permission from ref (4). Copyright 2022 American Chemical Society.

Figure 14

(a) Stress vs strain tensile curves of annealed IIPU, IMPU, and both a statistical copolymer (II₅₀IM₅₀) and a physical blend (bl-II₅₀IM₅₀) at 50/50 II/IM. (b) Normalized weight loss of IIPU, IMPU, co-II₅₀IM₅₀, and bl-II₅₀IM₅₀ discs in 1 M NaOH(aq) over 45 days at 25 °C. Polymer data: IIPU, M_w = 117 kDa and Đ_M = 8.12; IMPU, M_w = 95 kDa and Đ_M = 9.69; co-II₅₀IM₅₀, M_w = 79 kDa and Đ_M = 7.81; bl-II₅₀IM₅₀, M_w = 85 kDa and Đ_M = 4.82. Adapted with permission from ref (4). Copyright 2022 American Chemical Society.