stereochemistry paper.pdf

REvIEWS Stereochemical enhancement of polymer properties Joshua C. Worch1, Hannah Prydderch1, Sètuhn...

REvIEWS Stereochemical enhancement of polymer properties Joshua C. Worch1, Hannah Prydderch1, Sètuhn Jimaja1, Panagiotis Bexis1, Matthew L. Becker2 and Andrew P. Dove1* Abstract | The importance of stereochemistry to the function of molecules is generally well understood. However, to date, control over stereochemistry and its potential to influence properties of the resulting polymers are, as yet, not fully realized. This Review focuses on the state of the art with respect to how stereochemistry in polymers has been used to influence and control their physical and mechanical properties, as well as begin to control their function. A brief overview of the synthetic methodology by which to access these materials is included, with the main focus directed towards the effect of stereochemistry on mechanical properties, biodegradation and conductivity. In addition, advances in applications of stereodefined polymers for enantioseparation and as supports for catalysts in asymmetric transformations are discussed. Finally, we consider the opportunities that the rich stereochemistry of sustainably sourced monomers might offer in this field. Where possible, we have drawn parallels between design principles in order to identify opportunities and limitations that these approaches may present in their effects on materials properties, performance and function. Nature has evolved the ability to create large and com- The distinct influence of the stereochemistry in plex molecules in which the precise control over both biopoly­mers on their structure and, hence, perfor- the sequence and spatial arrangement of the atoms is mance makes it reasonable to expect such aspects of critical to their performance. The 3D topological con­trol synthetic materials to be equally important. Yet, this over the arrangement of bonds is as important to the area has received relatively little study, which is part­ function and behaviour of molecules as any other fac- ially a con­sequence of the challenges of creating large tor, and is critical to the structure–function relationships macro­molecules with well-defined sequence and stereo­ that occur within biological systems. While the effects chemistry at each repeat unit. Clearly, creating mate­ of stereochemistry on functionality are probably best rials with controlled stereochemistry in particular has known for small-molecule drugs such as thalidomide the potential to result in novel materials with complex (one enantiomer is effective against morning sickness, behaviour and function. While much of our knowledge the other is teratogenic) or naproxen (one enantiomer in this area results from the significant advances over is used to treat arthritis pain, the other causes liver poi- the past 70 years with polyolefins, this aspect of polymer soning and has no analgesic effect), it is also clearly rep- design has significant room to grow given the rich stereo­ resented in biopolymers in which stereochemistry has chemistry of many sustainable or renewably sourced pronounced effects on structure and, hence, function. monomer feedstocks and the increasing drive towards For example, DNA, which is at the heart of all biological their use. This Review examines the work to date in which systems, requires the chirality of the deoxyribose sugar control over stereochemistry in the polymer has led to in its backbone to ensure that the double-​helical struc- a notable change in thermal or mechanical properties, ture can form by supramolecular interaction between the or has enabled the functional behaviour of the material 1 School of Chemistry, complementary nucleobase residues that are attached to to be manipulated. It will further consider areas and The University of Birmingham, them. Furthermore, the simple, stereochemical differ- define opportunities in which stereochemistry could be Edgbaston, Birmingham, UK. ence between natural rubber and gutta-​percha (the cis used to enhance both the properties and function of the 2 Department of Chemistry, Duke University, Durham, and trans isomers of high molecular weight poly­ polymers and materials that result. NC, USA. isoprene, respectively) results in remarkable differences There are several ways that stereochemistry can *e-​mail: [email protected] in their mechanical properties, with gutta-​percha being be incorporated into polymers in order to influence https://doi.org/10.1038/ a harder, more brittle and less elastic material than the properties of materials that are formed from them s41570-019-0117-z its isomer. (Box 1). Although definitions of stereochemistry in Nature Reviews | Chemistry Reviews Box 1 | Polymer stereochemistry tacticity describes the relation between adjacent stereocentres using the Bovey formalization, where i = iso (same) and s = syndio (different). the relation between two stereocentres is referred to as a diad, between three stereocentres a triad, four a tetrad and so on. the distance that tacticity in polymers can be detected varies depending on the polymer structure. Diad Triad Tetrad Pentad i s s i s i i s s i s s s i i i i s s s s i s i s Isotactic Syndiotactic Heterotactic Atactic a polymer stereocomplex is a stereoselective interaction between two complementary stereoregular polymers that interlock and form a new composite, demonstrating altered physical properties in comparison to the parent polymer. typically, these are polymers with different stereoregular structures, such as isotactic and syndiotactic poly(methyl methacrylate) or poly(l-​lactide) and poly(d-​lactide). polymers can vary in some instances, for the purposes materials and provide access to other stereocontrolled of this Review, we have followed literature precedent1,2 to architectures. Presently, state-​of-the-​art methods for define the different ways in which stereochemistry forms stereo­controlled vinyl poly­merizations generally fea- part of polymers as follows: main-​chain stereochemistry ture single-site transition-metal catalysts7. The stereo­ refers to polymers that contain stereochemistry within chemistry in the resulting polymers is dictated by the backbone of the polymer; and side-​chain stereo- well-defined metal catalysts that enable enantiomorphic chemistry refers to polymers in which the stereochem- site control (chirality of the catalyst face) or chain-​end istry is not directly connected to the backbone (these control (chirality of the end group). There are many types of polymer are largely excluded from this Review reviews outlining the general synthetic mechanisms for on account of the minimal influence that the majority such stereospecific α-​olefin polymerizations8–13. Here, we of these groups have on the behaviour of the resulting will instead focus on how stereochemistry affects the bulk material). Finally, even in cases where there is not clear material properties. In order to illustrate the importance chirality or stereochemistry in the polymer structure, of stereochemistry on polymer properties, exemplary atropisomerism can be directed to create right-​handed classes of vinyl polymers (PP, PS and PMMA) will be and left-​handed polymer helices (that is, creating poly- examined. One of the most prominent factors affecting mer stereochemistry). While we have not discussed this thermomechanical properties is the crystallinity of the topic at length (on account of other articles that ade- sample (Fig. 1). Crystallinity can, in turn, be thought of quately cover that area), some discussion of this poten- as an indication of order at the molecular level and this tially important area has been included and is focused is heavily dependent upon the relative orientation of the on the use of monomers with additional chiral groups. side-​chain substituents (tacticity) along the polymer chain. Thus, this concept will be extremely critical to Main-​chain stereochemistry the following discussion. Main-​chain stereochemistry includes both cis–trans PP is perhaps the most well studied of the vinyl (geometric) isomerism (for example, in polyisoprene), in polymers and its properties are largely dependent on which the planar rigidity of the double bond or ring unit tacticity. The thermal properties — such as glass tran- leads to stereoisomerism, and optical stereoisomers, in sition temperature (Tg) and melt temperature (Tm) — of which a chiral centre sits on the polymer backbone (for atactic PP (aPP) and isotactic PP (iPP) vary considera- example, in polypropylene (PP) or polylactide (PLA)). bly, with the different isomers also displaying divergent Of course, it remains possible to have more than one mechanical properties. While aPP is soft, rubbery and type of stereochemistry present in one polymer chain. amorphous in nature, iPP is a hard thermoplastic with a distinct melt transition (Tm ≈ 160 °C) as a direct con- Optical stereoisomerism sequence of ordered chain packing between the poly- Vinyl polymers. The importance of stereochemistry in mer chains (Fig. 2). Perhaps most importantly, neither polymeric structures has been recognized ever since the stereo­pure iPP or aPP homopolymers are commonly first report discussing structural differences of poly(vinyl used as a result of their undesirable mechanical pro­ ethers)3. Initial developments in polymer stereochemistry perties. Instead, a formulation of PP having some degree focused on the ubiquitous class of plastics known as vinyl of stereoregularity and stereoirregularity produces a polymers, with some of the most notable achievements material with superior mechanical properties. Natta was being the synthesis of isotactic (Box 1) forms of PP4, poly­ the first to produce and characterize PP that contained styrene (PS)5 and poly(methyl methacrylate) (PMMA)6. both isotactic (crystalline) and atactic (amorphous) Soon after, researchers started to seek improved syn- segments, resulting in a material possessing high ten- thetic methods to modulate the stereochemistry in such sile strength and elasticity, and, today, these materials www.nature.com/natrevchem  Reviews Stereocomplexation Crystalline Heterostereocomplex Semi-crystalline Stereocomplexed enantiomeric polymer Isotactic Largely amorphous Homopolymer (all cis or trans) Syndiotactic Alternating (trans-a-cis) Heterotactic Amorphous Mixture cis–trans Atactic Cis–trans Optical isomerism isomerism Fig. 1 | schematic representation of the relationship between polymer stereochemistry and crystallinity. The circle at the centre represents the highest level of crystallinity or order. When considering a specific polymer, the degree of crystallinity may be described according to the stereochemical environment of the polymer. For example, an isotactic polymer will likely possess a more ordered morphology relative to its atactic variant. are known as thermoplastic elastomers (TPEs)14 (Fig. 2a). iPS to academic investigations29,30. The thermal sta- Subsequent efforts have focused on rational tuning of bility of sPS (and iPS) are greater compared with the the relative ratio or placement of stereoblocks (isotactic atactic variant, indicating that stereochemistry can also versus atactic regions) in order to improve mechanical influence thermal degradation profiles31. Furthermore, pro­perties15–20. It is worth mentioning that syndiotactic while sPS retains the attractive characteristics of aPS, PP (sPP) (first synthesized by Natta21 in 1962) has sig- such as mouldability, excellent electrical properties and nificant crystallinity but is not as mechanically robust resilience to hydrolytic degradation, it is more viable as the isotactic analogue, as a consequence of its unique in manufacturing operations (for example, injection morphology that is characterized by disorder and large moulding or extrusion) because of its rapid crystalliza- fractures within the crystal lattice22–24. Nevertheless, the tion32. Finally, sPS is a more robust material because the tailoring of important properties, such as melt visco­ entanglement molecular weight (Me) is approximately half elasticity, is possible by synthesizing structures with of the value for iPS owing to higher rotational energy amorphous regions interspersed between sPP domains25. barriers of the phenyl groups33. Another interesting type An important lesson from studying PP reveals that crys- of PS is the stereoblock copolymer sPS-​b-aPS architec- tallinity is a significant component in determining the ture that exhibits thermal properties that are dependent properties of a material, but it alone cannot be used upon sPS content; that is, the Tm and crystallization rates to fully predict properties such as toughness, strength increase as a function of sPS content34,35. Substituted and/or elasticity. Hence, other factors need to be consid- analo­gues of PS, such as poly(α-​methylstyrene), also dis- ered when seeking to design materials with enhanced play improved properties for syndiotactic-​rich samples, thermomechanical properties. such as higher decomposition and glass transition tem- PS is one of the oldest yet most important industrial peratures36. The syndiotactic form of PS is, then, the most plastics. Before Natta’s discovery of isotactic PS (iPS) in interesting in terms of material properties. This stands 1960 (ref.5), it was known only in an amorphous, atac- in contrast to sPP, which is less robust than its isotactic tic (aPS) form. There is little difference in most thermal counterpart, even though both have similar degrees of properties (for example, Tg and heat capacity (ΔCp)) crystallinity. The examination of PS tacticity demon- between the aPS and iPS polymers, but iPS is capa- strates an important concept in polymer stereochem- ble of crystallizing upon annealing (60% crystallinity, istry: generalizations about polymer stereochemistry Tm ≈ 250 °C). This imbues the material with improved must be made with extreme caution, since subtle per- mechanical properties relative to its disordered, glassy turbations can yield divergent properties. Furthermore, analogue, especially at temperatures greater than their by tuning polymer stereochemistry, the mechanical respective Tgs (~100 °C). However, iPS has found little properties of a polymer can be greatly enhanced to pro- commercial use, as the crystallization process is too duce a useful material. Specifically, while aPS has very slow for industrial processing techniques26. Conversely, poor mechanical properties, sPS is a tough thermoplastic syndiotactic PS (sPS) was serendipitously produced in with mechanical properties comparable to some nylons. 1986 and found to be markedly different from both the Even though all carbon-​based vinyl polymers have Entanglement molecular atactic and the isotactic versions27. The equilibrium melt garnered significant attention over the past decades, weight temperature of sPS is approximately 50 °C greater than polar vinyl polymers (for example, acrylics) have also (Me). The molecular weight above which the material that of iPS28. sPS also has the added advantage that it become ubiquitous owing to advances in catalyst devel- displays the characteristic can crystallize at an appreciable rate, approximately an opment37. The stereochemistry of PMMA in syndiotactic properties of a plastic. order of magnitude faster than iPS, largely relegating (sPMMA) and isotactic (iPMMA) forms was discovered Nature Reviews | Chemistry Reviews a Tacticity Atactic Isotactic x x TPE material Isotactic Isotactic x y z c Stereocomplex O O O O O b Main chain x x Mixture O Atactic of isomers Atactic H H H H O N N O O N N O x y z O O O O Stereocomplexed degradable TPE x y z Cis Syndiotactic Syndiotactic Fig. 2 | Polymer stereochemistry has been crucial to the development of thermoplastic elastomers. a | Tacticity was modulated in isotactic and atactic stereoblock polypropylene to furnish a phase-​separated material featuring hard and soft segments. b | Cis–trans isomerism of alkenes in the polybutadiene block was controlled to enhance the thermomechanical properties of polystyrene-​b-polybutadiene-​b-polystyrene rubber, a well-​known thermoplastic elastomer (TPE). c | Stereocomplexed poly(l-​lactide)/poly(d-​lactide) can provide a ‘hard block’ in polyurethane-b-polylactide-​b-polyurethane TPEs. contemporaneously with Natta’s findings on polyolefins6. can be mostly attributed to the poor tolerance of state-​ In contrast to the stereochemical trends observed for of-the-​art, stereoselective, synthetic methods that cannot most non-​polar vinyl polymers, the stereochemistry be applied in the polymerization of functionally diverse of PMMA has a very noticeable effect on thermal tran- monomers as a result of either steric constraints and/or sitions between syndiotactic and isotactic analogues functional group tolerance. A recent report that features (ΔTg > 70 °C)38–40. Even though iPMMA softens at a an innovative stereocontrolled synthesis to produce iso- much lower temperature than sPMMA, the former is able tactic poly(vinyl ethers) with robust thermomechanical to crystallize, while the latter is amorphous and behaves properties is particularly encouraging47. Still, relating similarly to atactic PMMA (aPMMA). Stark differences stereochemistry to material properties has yet to be between dynamic, mechanical properties also exist with fully explored and continued improvement of synthetic relaxation processes occurring at lower temperatures in protocols are vital in this regard. isotactic polymers41,42. It has been suggested that these Vinyl polymers are arguably the most significant class peculiar features of the isotactic version are due to the of materials, with over three hundred formulations that adoption of a helical conformation, something that is are available commercially, featuring a range of tailored not observed for sPMMA or aPMMA42. Apart from thermomechanical properties48. Unsurprisingly, numer- thermal and mechanical properties, other bulk material ous critical concepts in polymer stereochemistry were properties also affected by stereochemistry. For example, refined by studying these materials. Although there gas permeation properties43 and chemical degradation are still opportunities to innovate, the most important rates44,45 are very sensitive to stereochemistry. The most advancements will likely come from applying these les- obvious benefit for acrylic and other vinyl polymers sons to emerging polymer classes. Specifically, the fate is the vast array of potential derivatives owing to their of waste vinyl polymer plastics is of high importance ease of functionalization and consistent polymerization worldwide and biodegradable materials from renew- chemistry. A recent example of a vinyl polymer with car- able sources are likely to become the dominant com- bazole side-​chain units (a non-​conjugated electro­active modity polymers. In order to improve the properties polymer) displayed a positive correlation between con- of renewable polymers to enable them to compete with ductivity and isotacticity46. Nevertheless, many stereo­ vinyl plastics, stereochemistry must be rationally lev- controlled vinyl polymers are simply unknown. This eraged. A recent example involving the stereoselective www.nature.com/natrevchem  Reviews Ring-opening polymerization of a biosourced, polar vinyl monomer, ROP techniques also enables more facile control over the polymerization α-​m ethylene-γ-​butyrolactone (MBL), furnished a order of insertion of monomers into the polymer chain (ROP). A type of chain growth renewable polymer with thermal properties superior to based on their respective stereochemistry65,66. polymerization in which the petroleum-​based plastics such as PMMA49. Poly(α-​hydroxy acid)s are a particularly attractive end of the growing polymer class of polymer because of the presence of asymmetric chain reacts with a cyclic monomer, resulting in ring Degradable polymers. Degradable polymers, natural carbon atoms in the backbone. Lactic acid (2-hydroxy- opening. polymers and modern synthetic polymers derived from propanoic acid) is the simplest α-​hydroxy acid with a sustainably sourced monomers form the basis for a chiral carbon atom and it exists as two optical isomers. Step-​growth new generation of sustainable, eco-​efficient plastics50–53. Lactide, the cyclic diester of lactic acid, therefore pos- polycondensation Multifunctional monomers Presently, industrially produced synthetic polymers sesses two stereocentres and three distinct diastereo­ combine to form dimers, are sourced from petroleum, which is currently heav- isomers: (S,S)-lactide or l-​l actide; (R,R)-lactide or trimers and oligomers before ily depleted by our increasing energy demands54 and d-​lactide; and the optically inactive meso-​lactide, which these ultimately combine to a large contributor to environmental waste concerns contains one of each stereocentre. All isomers are com- produce polymers. and greenhouse gases55,56. Thus, the use of renewable, mercially available as enantioenriched samples or as a Chain-​growth biomass-​sourced and biodegradable materials is consid- racemic mixture (rac-​lactide) of l-​lactide and d-​lactide. polymerization ered to be an interesting route by which to replace petro- In turn, a variety of microstructures (for example, atac- Polymer chains are formed and chemical counterparts and is a long-​standing academic tic, isotactic, heterotactic and syndiotactic) can be con- grow by the addition of and industrial challenge in which several polymers, structed from this basic set of monomers, with each one monomers one at a time to the end of a chain. which typically have rich stereochemistry (Fig. 3), have possessing unique physicochemical and thermome- been developed. To be ultimately successful, the manu­ chanical properties, as well as different degradation pro- facturing processes of these polymers must become files65,67–69. Notably, in contrast to many vinyl polymers, more cost-​effective, their specific-​target performance the lactide monomer possesses inherent stereochemistry must match or even exceed the current standards and and the synthetic challenge in producing stereoregular their end-​of-use options must be diverse50. Leveraging PLAs is different, although there are many similarities in stereochemistry will certainly be a crucial factor in the catalyst design and mechanistic considerations. development of these technologies. The physical properties of PLA make it a useful alter- The most widely known, sustainably sourced poly­ native to more common petroleum-​derived polymeric mer is PLA57–59. It is renowned for its renewability, materials (especially PS, as a consequence of their similar biocompatibility60 and biodegradability61. It has gar- thermomechanical properties), as well as being suitable nered a significant amount of interest in both aca- for more specialized applications in the pharmaceutical, demic and industrial research for everything from biomedical and microelectronics fields70. While most packaging to biomedical applications62,63. PLA is most ROP protocols result in predominantly atactic PLA, an commonly produced through the fermentation of amorphous polymer of low-​value, heterotactic PLA is starch to lactic acid, followed by the synthesis of the commonly reported. As a result of the lactide mono- cyclic ester monomer lactide and its subsequent ring-​ mer possessing two stereocentres, it is common to form opening polymerization (ROP). While PLA can also be heterotactic PLA (hPLA) from the ROP of rac-​lactide, prepared by step-​growth polycondensation of lactic acid, in which the stereocentres doubly alternate (that is, the chain-​growth polymerization yields a greater degree –SSRRSSRR–). These polymers are generally amor- of control of the molar mass, molar mass distribution phous with a Tg of ~30 °C, thus further narrowing the (dispersity, ÐM), stoichiometric control of composition, range of potential applications68. While the stereoselec- as well as higher end-​group fidelity compared with the tive ROP of meso-​lactide can also lead to hPLA, it can polycondensation reactions64. Finally, the application of be more usefully polymerized to syndiotactic PLA — a Substituting polyolefins with sustainable polymers Commodity polyolefins Sustainable polymers with known stereocomplexes O O O n n O n n n O O Polypropylene Polylactide Polymenthide Polyhydroxyalkanoates Polystyrene O O O O n n O O n n O Polyisoprene Poly(propylene succinate) Poly(limonene carbonate) Fig. 3 | Degradable polymers with defined stereochemistry as replacements for vinyl polymers. Sustainable (degradable and/or biosourced) polymers are being developed to compete with commodity plastics and stereochemistry (optical isomerism or tacticity), as well as stereocomplexation, will be crucial to achieving comparable thermal and mechanical properties. Nature Reviews | Chemistry Reviews semi-​crystalline material with a Tm of ~150 °C, which is Tm ≈ 180 °C and high stiffness); however, it embrittles significantly lower than that of PLAs with higher side-​ more rapidly as a consequence of its thermal proper- chain stereoregularity65. Few studies have focused on ties. Since biosourced PHB is always isotactic (iPHB), the synthesis of this polymer and its full utility perhaps access to PHB with alternative microstructures must remains to be uncovered. Stereocontrolled ROP of the be synthetically achieved, usually via ROP of racemic optically pure monomers (l-​lactide or d-​lactide) leads β-​butyrolactone88,89. Alternatively, the physical blending to isotactic, semi-​crystalline PLA polymers (iPLA), in of iPHB with synthetic amorphous atactic PHB (aPHB) which all the stereocentres are aligned and has a Tm of has been investigated as a method to alter polymer prop- ~180 °C and a Tg near 50 °C. These isotactic polymers are erties. In such blends, there is considerable melting-​point referred to as poly(l-​lactide) and poly(d-​lactide), PLLA depression relative to biosourced iPHB90,91. Perhaps not and PDLA, respectively71. The thermal and mechanical surprisingly, the elasticity can be significantly improved properties are dependent on the molar mass and the per- (~tenfold) but this comes at the expense of toughness, centage content of the minor enantiomeric unit in the and the degradation kinetics are accelerated in blended final polymer chain (via epimerization of the enantiopure samples92. Metal-​catalysed ROP has also been used to monomer during ROP or from the incorporation of the access syndiotactic PHB (sPHB) from racemic mono- meso-​lactide units into the stereoregular PLLA/PDLA mer mixtures66,93–98, as well as by vary­ing the feed ratios chain) and led to a deterioration of the properties of the of optically active β-​butyrolactones99. Highly syndio- final material65,72,73. The mechanical properties of these tactic samples have a similar Tg to iPHB but the Tm is polymers follow a similar trend to the thermal behaviour much lower (ΔTm > 100 °C) and sPHB displays elasto- and are clearly dependent on the stereochemical makeup meric properties94,99. Although there is a large number of the polymer’s backbone. Semi-​crystalline, isotactic of structurally similar polyhydroxyalkanoates, only PLLA (iPLLA) has an approximate tensile modulus of a limited number of examples have been synthesized 4 GPa, tensile strength of ~70 MPa, flexural modulus directly. The role of stereochemistry and its effect on of 5 GPa, flexural strength of 100 MPa and an elongation bulk properties has been overlooked, since most of the at break of about 5%. Therefore, it is generally preferred monomers are easily obtained from biosources (plants) over the amorphous polymer (tensile modulus 1.2 GPa, as single enantiomers. It is possible to synthetically tensile strength 59 MPa and flexural strength 88 MPa) produce other polyhydroxyalkanoates in a stereo­ for applications that require stiffer materials57,74. controlled fashion with controlled alternating microstruc- Despite the accessibility of PLA microstructures, the tures100–102 that may yet yield promising new functional most interesting materials are stereocomplexed (Box 1) materials. Furthermore, there is interest in producing architectures, which will be thoroughly discussed in copolymers by combining PHB with other polyhydroxy- the stereocomplexation section. Even so, the semi-​ alkanoates103–110 or PLLA104,111–116 in order to modulate crystalline nature of iPLA has made it an ideal candidate material properties; however, the stereochemistry of for crystallization-​driven self-​assembly, and many well-​ PHB has been controlled in only a few cases109–111,115,116. defined architectures have been produced using PLLA Taking stereochemistry into consideration in such sys- block copolymers75–80. PLA is currently the gold standard tems should afford many interesting opportunities for in the field of biorenewable polyesters, but other promis- biomedical applications117. As an example, the degrada- ing, chiral biodegradable polymers are of interest. It is the tion of polyhydroxyalkanoate microparticles has been unique properties of PLA — biocompatibility, defined shown to be dependent on the overall stereochemis- degradation under physiological conditions and forma- try, with more controlled release kinetics observed for tion of non-​toxic degradation products — that make it stereoregular structures109. so attractive. Expanding the use and capturing market Poly(propylene glycol) (PPG), poly(propylene car- share from polyolefins and other vinyl polymers will bonate) (PPC) and poly(cyclohexylene carbonate) require improvements to brittleness, thermal properties (PCHC) are other common, biorenewable polymer and stability. classes that have exploitable stereochemistry118,119. While Analogous to poly(α-​hydroxy acid)s, polyhydroxy- stereochemistry is the focus here, it must be noted that alkanoates are polyesters with chiral carbon atoms regiochemistry is important for PPG or PPC, and this that are obtained from the fermentation processes of a too can modulate material properties. Transition-​ variety of bacterial strains. Aside from the advantages metal-catalysed stereoselective epoxide polymeri- associated with biorenewability and biodegradability, zation and copolymerization is well developed and the final constitution of the polymer (that is, a specific has led to many useful architectures120–123. Stereopure functional group at the stereocentre) can be modulated PPG is a crystalline, yet rubbery, polyester that has by changing the chemical feedstock available to the bac- been synthesized with many different catalysts124–131. teria, thus providing a very versatile platform for tar- Surprisingly, the Tg and Tm seem to be independent of geted material properties81–83. Poly(β-​hydroxybutyrate) stereochemistry126,130–132, since both isotactic131,133,134 and (PHB) is the simplest and most studied analogue and atactic132 isomers are crystalline. Moreover, the stereo- provides an excellent representative material for its class. chemistry of the PPG unit in triblock architectures of Biosynthesized PHB is highly crystalline and optically PPG-​b-poly(ethylene glycol) (PEG)-b-​PPG copolymers active due to its isotacticity84–86. Recently, perfectly iso­ has little effect on material properties135. In order to tactic PHB was synthesized for the first time from a racemic enhance the thermal properties of poly(propylene oxide) monomer mixture87. In some respects, the thermo­ (PPO), it can be copolymerized with CO2 to yield PPC. mechanical properties are similar to iPP (for example, Stereopure (atactic, isotactic and syndiotactic-​enriched) www.nature.com/natrevchem  Reviews PPC is a ductile thermoplastic that has been studied for correlate bulk material properties to stereochemical some time136–141. However, thermal and mechanical data effects or trends are highlighted. There are a few exam- on the stereopure materials is noticeably lacking, except ples of conjugated polymers with main-​chain chiral- for one study that examined the effects of regioregular- ity, but the area is comparatively nascent and only one ity in PPC and derivatives136. To date, one of the most report (binaphthyl-​containing polyfluorenes) features interesting epoxide-​b ased polymers is enantiopure stereochemistry–property relationships167. Moreover, poly(propylene succinate)142. By mixing the two enantio- conjugated chiral small molecules or oligomeric spe- pure, isotactic polymers that display slow crystallization cies often exhibit supramolecular self-​assembly to form kinetics, a stereocomplex was formed with a dramatic higher-​order macromolecular structures, but these cases improvement in the crystallization rate and Tm. Isotactic are beyond the scope of this Review, since they are not PCHC (iPCHC) is a brittle thermoplastic that has been considered polymeric in nature168,169. Finally, optically prepared from a variety of catalytic protocols143–153. As a active conducting polymers often possess distinct heli- result of its stereoregularity, iPCHC is highly crystalline city and this characteristic is a major point of focus in (although there is no clear trend between % crystallinity many studies, but it will not be examined in this section. and % enantiomeric excess (e.e.) of the polymer), with When considering morphology, an optically active a Tm greater than atactic PCHC (though there is much poly(azomethine) was shown to self-​assemble into a variation in the reported melting temperatures)143–146. highly ordered fibrous structure, while the racemic The only systematic study relating Tm to % e.e. showed counterpart did not display any solid-​state ordering170. a positive correlation (Tm = 234–267 °C) between the Similarly, more high-​order phases were observed in properties for samples ranging from 78% to 99% e.e.143. a polyacetylene with a chiral side chain than in a non-​ On the other hand, syndiotactic-​enriched PCHC has chiral counterpart171. Varying the processing conditions been qualitatively described as ‘amorphous’ but no ther- of polythiophenes bearing chiral thioether side chains mal data were reported154. Terpolymers with constituent led to materials with morphological characteristics units of CO2, propylene oxide and cyclohexylene oxide that correlated with the shape, size and sign of the cir- have been thoroughly characterized according to overall cular dichroism (CD) signal172. Polyanilines, in which polymer composition, but stereochemical effects were a chiral conformation has been induced by the pres- not described147,149. Although PPG homopolymers are ence of a chiral counterion (d-​camphorsulfonic acid or relatively uninteresting materials on their own, more l-camphorsulfonic acid), have been used to create highly promising copolymeric and terpolymeric materials with ordered conducting microfibres or nanofibres173–176, nano- variable composition and stereodependent properties, sheets177 and ‘hexagonal superlattices’ that mimic β-​sheet in some cases, are known. The diversity of such com- protein structures178. Moreover, chiral poly(arylacetylene) plex architectures should galvanize further investigation was manipulated into a variety of chiral nanostructures of stereochemistry in more sophisticated degradable via metal complexation179 and aromatic ester polymers polycarbonates and polyesters. were shown to form chiral nanoparticles180. The formation of such higher-​order structures is certainly influenced Optically active conducting polymers with chiral side by the chiral nature of the polymers. In another example, chains. Polyacetylene was the first reported conducting the electrochemical properties (oxidation and reduction polymer featuring a chiral side chain155; however, the potentials) of a chiral polypyrrole varied according to the introduction of large side chains to polyacetylene tends stereochemical configuration of the side chain181. to disrupt the conjugative pathway along the polymer Benzotriazole–thiophene copolymers with chiral side backbone, making these materials unsuitable for applica- chains have been thoroughly investigated and compared tions involving organic semiconductors. Thus, attention to racemic analogues182. Although optical solid-​state eventually turned to other conjugated backbones, such properties were similar between the achiral and chiral as polythiophenes, polypyrroles and polyanilines, since polymers (aside from a chiral response in CD analysis), these polymers are easily functionalized and often retain experiments that clearly investigate side-​chain chirality in conductivity even when bulky substituents are present156. this manner are the refreshing exception to the rule. Although conducting polymers are most recognizable In a similar manner, another study examined benzo­ in organic optoelectronics, they also have great potential in thiadiazole copolymers by comparing the optically pure sensing applications (for example, bioelectronics)157,158 polymers with the racemic analogues183. In this case, as a result of their dynamic properties (for example, X-ray scattering analysis revealed that the optically active electro­chromism, solvatochromism or thermochro- polymers had more ordered morphologies due to tighter mism and switchable redox chemistry) that can some- chain packing, and this was corroborated by a red shift times be amplified with chirality159,160. A good example in the solid-​state absorbance profile. That such simple of this enhancement is described for an organic thin-​film stereochemical differences lead to changes in polymer transistor endowed with chiral side groups that showed properties in some cases and not others will hopefully improved responsiveness in sensing applications161. stimulate researchers to undertake further investigations. Furthermore, the conductivity and charge transport of conducting polymers in devices is intimately coupled to Helical polymers. Helices are fascinating chiral objects morphology162–166 and chirality may be able to provide that are ubiquitous in nature, with the most illustrative advantages in the form of increased solid-​state ordering. examples being the double-​stranded helix of DNA as the Since the field of conducting polymers bearing chiral side carrier of genetic information184 and the α-​helices in pro- groups is so expansive, only examples that specifically teins185. Historically, the first synthetic helical polymer Nature Reviews | Chemistry Reviews was characterized during Natta’s investigations on poly- amount of chiral units among achiral units to allow an olefins when the chains of iPP were found to adopt a optimal transfer of chirality, while the majority rules helical conformation in the solid state4,186. This polymer discard the obligation of using enantiopure monomers was, however, incapable of maintaining its conforma- to attain high enantiomeric excess. Together, they open tion in solution, a recurrent challenge for the creation the road to the facile synthesis of high-​purity chiral of helical polymers. Nevertheless, the current interest in polymers from inexpensive components. helical polymers has recently increased, with focus on Perhaps the most obvious application for helical applications in catalysis, chiral recognition and the study polymers is chiral recognition for enantiodiscrimina- of biological systems187,188. Chirality and optical activity tion187,194 (Fig. 4). In this area, they have been success- can be inherent to helical polymers stemming from fully developed for enantioselective adsorption195,196 and atropisomerism (stereoisomerism as a result of sterically enantio­selective permeation (membranes)197. For exam- restricted rotation) and they can be classified as having ple, a hydrogel developed by imprinting chiral sites with backbone stereochemistry while not having any chiral helical polymers displayed prominent enantioselective moieties in the backbone189–191. Significant attention has adsorption behaviour198. Moreover, chiral recognition also been devoted to the assembly of helical polymers can be exploited in the case of static helical polymers into unique supramolecular structures, but that is also such as polyisocyanide196,199 and poly(triphenylmethyl beyond the scope of this Review187 (Box 2). methacrylate)200–202, which have also found utility as Polymer helices can be divided into two major groups, chiral stationary phases for high-​performance liquid depending on the respective helix inversion energy. Most chromatography columns. The dynamic and helical enantiopure polymers (such as aliphatic polyisocyanides, memory properties of polyacetylene have been leveraged polyacetylenes, polysilanes and polyguanidines) have a for the same application but with the added advantage low inversion energy and display rapid helix inversion of a switchable chirality to potentially alter the elution in solution. Meanwhile, static helical polymers (such as order of the enantiomers203,204. Another interesting pro­ PMMAs/poly(methyl acrylamide)s and polyisocyanides perty of helical polymers is the amplification of optical bearing bulky aryl groups or poly(quinoxaline-2,3-diyl)s) activity from monomer to polymer, due to the syner- have a high helix inversion energy and are conforma- gistic effect with the helical backbone, as observed in tionally stable structures, typically due to side-​chain metal-​complexed helical polymers, in which an induced interactions (steric bulk). The copolymers of both types enantioselectivity was observed205,206. When applying of helical polymers are remarkable because of the two this principle to dynamic helical polymers, it is possi- major rules that govern their helicity: the ‘sergeants ble to produce an asymmetric catalyst with switchable and soldiers’192 and the ‘majority rules’193. The ser- enantioselectivity207 (Fig. 4). The enantioselectivity of geants and soldiers rule permits the use of a very small organocatalysts can be improved208–211 or even entirely Box 2 | Common types of helical polymers Static helical polymer Dynamic helical polymer Foldamer Low inversion barrier Non-helical Helical High inversion barrier Inversion or Chiral agent * R*1 R* R R n n N N Si n O O n R2 n O Ph Ph Ph n static helical polymer with high inversion barrier Bulky pendant groups prevent inversion of the helix, yielding optically active polymers. Dynamic helical polymer with low inversion barrier Pendant groups are not sufficiently bulky to inhibit inversion of the helix, but optically active polymers can still be induced by chiral bias. Foldamer Foldamers are polymers with a strong tendency to form helical conformations in certain solvents or through interaction with chiral guests. the latter can yield an optically active polymer. www.nature.com/natrevchem  Reviews Optically active helical polymers His Enantiospecific Ser Glu binding Glu Tyr Phe Leu Val Ser Asp n Glu Asp n Asp Glu Synthetic N Val Leu Val Ser mimics Cyt Cyt Ala Phe His Ser Tyr Polypeptides Proteins and helical pockets Chiral recognition Fig. 4 | synthetic helical polymers with biomimetic behaviour. Proteins are complex 3D structures formed from stereopure polypeptides. The precision of the polypeptide backbone is crucial for the formation of higher-​order structures (such as secondary, tertiary and quarternary). For example, hydrogen bonding can induce the formation of helices, leading to defined binding pockets for enzymatic biological reactions. Synthetic polymers that assemble into helical structures have been used to mimic enzymatic behaviour via chiral recognition and/or enantioselective catalysis. induced212,213 by the helical polymer scaffold. Using tree, respectively222, but synthetic variants can be synthe- poly­mer helicity to effect enantioselectivity bears resem- sized by the direct polymerization of isoprene. As with blance to the ways in which proteins containing α-​helices other non-​polar vinyl monomers, the polymerization of catalyse asymmetric transformations and, thus, realises a isoprene can proceed via radical, anionic and cationic step towards the creation of a synthetic enzyme. mechanisms; however, coordination–insertion poly­ As a further example of the utility of stereopure chiral merization using metal catalysts (particularly organo­ materials, a polyisocyanide with peptide side chains was metallic lanthanides) has emerged as the preferred developed as a biomimetic polymer gel displaying stress-​ method, since the microstructure can be controlled to stiffening responses comparable to biological tissue214 mimic natural rubber, gutta-​percha or compositions in (Fig. 4). As a consequence of the ubiquity of helicity in nat- between7,222–224. For example, recently developed proto- urally occurring polymers, it is likely that synthetic var- cols using lanthanide catalysts have yielded cis–trans iants will have a sizeable impact in the biomedical field, stereoblock architectures225,226. Less commonly, isoprene particularly in regenerative medicine. In addition to bio- can be polymerized via a 1,2 insertion mechanism to medical applications, polyisocyanates215 and polysilanes216 produce 1,2-polyisoprene featuring a pendant vinyl have been investigated in optical data-​storage devices group227. However, further discussion of this is beyond owing to their dynamic nature. It is theorized that the the scope of this section (main-​chain stereochemistry) chiral information from the helicity (P and M) could be and the side-​chain stereochemistry for exemplary vinyl used as an analogue to the number-​based binary (0 and 1) polymers has been previously covered. In the remainder used in current computing technology. Not only could of this section, stereochemistry will be correlated to bulk this diversify the data-​storage or data-​processing indus- properties of the materials. tries but it could also improve the renewability of future The cis and trans isomers of polyisoprene possess technological hardware. Finally, there has been renewed divergent properties that are dependent on main-​chain interest in higher-​order helical structures such as ‘helix-​ stereochemistry. Examining the thermal properties, both in-helix’ superstructures217 or the triple-​helical structure isomers have similar Tg; however, trans-​polyisoprene has of stereocomplexed PMMA189,190,218,219, which is a rare a much higher Tm than the cis variant (Tm trans = 89 °C example of a multistranded synthetic helix. Moreover, and Tm cis = 34 °C)223. It should be noted that the diblock such structures have been implicated in ‘molecular sort- architectures incorporating trans-1,4-polyisoprene seg- ing’ based on the molecular weight of constituent polymer ments display melt transitions according to differential strands220,221. From a topological viewpoint, multistranded scanning calorimetry (DSC) analysis228,229 but similar systems closely mimic natural helical assemblies such as polymers with cis segments are generally described as RNA, DNA and certain proteins, making them crucial to amorphous. These observations are corroborated when future nanomaterials development. comparing the mechanical properties between the iso- meric polymers. Cis-​polyisoprene is amorphous, soft, Cis–trans stereoisomerism flexible and elastic, whereas trans-​polyisoprene is com- Polydienes. In a manner similar to side-​chain stereo- paratively crystalline (existing in two dynamic, ordered chemistry, the primary concepts of main-​chain poly- phases, α or β)230 and tough231. This observation has been mer stereochemistry developed as a result of studies on attributed to the better chain packing of the natural rub- polyolefins. Early discoveries focused on characterizing ber unimers, though seemingly counterintuitive, com- biosourced natural rubber (cis-​polyisoprene) and gutta-​ pared with that of gutta-​percha. The cis configuration percha (trans-​polyisoprene) (Fig. 5). The two polymers of natural rubber imparts flexibility, because it leads to are harvested from the rubber tree and gutta-​percha random coiling at room temperature; when stretched, Nature Reviews | Chemistry Reviews H3C 1,4-Polybutadiene is the unsubstituted analogue to polyisoprene and the absence of the methyl group yields a softer polymer and lower Tg, affording a mate- H3C n rial with a wider operating temperature range than CH3 CH3 n Cl Cl n polyisoprene. Polybutadiene (from 1,3-butadiene) Gutta-percha Rubber Chloroprene was first synthesized in a stereocontrolled manner c0 = 4.72 A c0 = 8.10 A c0 = 4.79 A using Zeigler–Natta-​type catalysts (transition metal and lanthanide complexes), which, despite relatively little development, remain useful today236,238. Anionic polymerizations were also found to be effective (and remain so) for stereoselective polymerization, in which the cis:trans ratio can be tuned by the choice of solvent and/or organometallic initiator239. Different ratios of 90° b0 = 10.24 A the three isomers (cis, trans and vinyl) of polybutadiene 90° b0 = 11.78 A L R L R have a dramatic effect on both polymer properties and R L material performance, and can be controlled by catalyst choice. As with 1,2-polyisoprene, vinyl polybutadiene will not be covered in this Review. Polybutadiene with low trans content is easily processable, and although b0 = 8.89 A 90° high trans content confers great abrasion resistance, it Fig. 5 | structures of rubber, gutta-​percha and chloroprene. The crystal structures of is much harder to process at tolerable temperatures240. natural isomers (cis and trans) of polyisoprene and trans-​polychloroprene. Although the One of the most important applications of polybutadiene crystal structures of trans-​polyisoprene and trans-​polychloroprene display similarities as is its incorporation into block copolymer architectures a consequence of the trans orientation of the double bond, the mechanical properties of to afford high-​performance TPEs (Fig. 2b). The modu- trans-​polychloroprene are more similar to cis-​polyisoprene. Crystal structures adapted lation of stereochemistry for polystyrene–polybutadi- with permission from ref.231, The Royal Society. ene (SB)-based polymers is well described for both the polybutadiene segment (cis or trans) and the styrenic section (tacticity), but full characterization that seeks the chains are partially aligned, which improves tough- to relate material properties to microstructure and ness. When the stretching force is released, the polymer stereo­chemistry is often absent241. There are a number chains return to a coiled configuration and the sample of reports on stereocontrolled SB-​based polymers that returns to its original length, displaying a high degree of describe thermal properties, but these studies are aimed elasticity232. This strain-​induced crystallization process at altering polymer properties according to block length, of natural rubber is a self-​reinforcing effect: crystalliza- as opposed to changing the stereochemistry of the tion increases with increasing elongation and contributes respective block and/or blocks229,242–248. Furthermore, a to a high ultimate tensile strength222,233,234. Owing to its cis description of mechanical properties is missing for these stereochemistry, natural rubber is more reactive and the systems. Nevertheless, there is one significant example physical and mechanical properties can be altered more to discuss featuring a triblock copolymer of polystyrene-​ easily than gutta-​percha using numerous chemical mod- b-polybutadiene-​b-polystyrene with precise microstruc- ifications223,232. Vulcanization of natural rubber increases ture and stereochemistry (sPS and cis-​polybutadiene). the tensile strength so that it becomes competitive with This material possessed a very well-​defined phase-​ gutta-​percha, but the elongation at break still remains separated morphology and superior thermal properties far superior223,235. Although biosourced polyisoprene is to the atactic analogue, but the polybutadiene stereo- still industrially important, synthetic production using chemistry remained unchanged and mechanical data pure monomers provides better control of cis:trans ratios are omitted245. Simultaneous tuning of both geomtric and it has been shown that the addition of impurities and optical stereochemistry of block copolymer archi- or additives (compounding with reinforcing fillers, for tectures should provide a plethora of interesting mate- example, carbon black and silica) can be controlled in rials. However, there needs to be an effort to explicitly order to tailor mechanical properties236. Another indus- connect stereochemistry to bulk properties in order to trially important substituted polydiene is polychloro- design future materials more coherently. prene (neoprene). Despite the structural similarity to polyisoprene, neoprene is produced exclusively with a Step-​growth polymers containing unsaturated ethers, trans-​rich form (approximately 85% trans-​chloroprene, thioethers and azaethers. Following their introduction 10% cis-​chloroprene and 5% vinyl chloroprene), with a by Kolb, Finn and Sharpless249, click-​chemistry methods similar main-​chain structure to β-​gutta-percha. Even have emerged as a powerful tool for both polymer syn- with a high degree of crystallinity, it has similar mechan- thesis and modification250–254. Within polymer chemistry, ical properties to natural rubber at room temperature, the thiol–ene/thiol–yne addition reactions, in which as a consequence of a unique chain packing–repulsion thiols are added across unsaturated carbon–carbon interplay between the CH2 and Cl moieties231 (Fig. 5). bonds, have proven to be particularly useful. Three pos- There has been one report of cis-​polychloroprene but it sible mechanistic pathways exist for the thiol–yne click was synthesized via post-​polymerization modification reaction: radical mediated (photo or thermally initi- and was not thoroughly characterized237. ated), transition metal catalysed and Michael addition www.nature.com/natrevchem  Reviews (nucleophilic addition), but only the latter two mecha- polymers and/or different overall material compositions, nisms readily result in an unsaturated, monofunction- precluded direct material comparisons. alized product251. Transition-​metal-based catalysts (for example, Ru, Ir, Ni, Pd, Pt, Au and Zr) have been shown Other polymers with double bonds in the backbone. to produce stereoregular vinyl sulfides via a migratory Polynorbornenes are a very important commod- insertion mechanism that has been successfully trans- ity polymer class. They are most commonly synthe- lated to polymer chemistry255,256. The nucleophilic addi- sized from ring-​opening metathesis polymerization tion pathway requires a base (for example, tertiary amine (ROMP) of norbornenes and the stereochemistry of or phosphine)257,258 and allows isolation of the unsatu- the resultant C=C bond in the backbone can be tuned rated product in good yields259,260. The stereochemistry accordingly270–272. It is possible to synthesize stereopure of the resultant alkene can be tuned by the appropri- polynorbornene270–272 with judicious choice of catalyst ate choice of catalyst, solvent polarity, substrate choice, and careful manipulation of the reaction conditions. sequential monomer addition and post-​polymerization For example, the use of Grubbs-​type, ruthenium-​based UV irradiation256,258,261. As such, the nucleophilic addi- catalysts, particularly with bulkier monomers, results tion approach remains the preferred synthetic method in predominantly cis-​polynorbornene273. Employing for creating stereochemically defined polymers through Schrock-​type molybdenum or tungsten catalysts can the thiol–yne reaction. also yield stereocontrolled materials274,275. Additionally, The control afforded over the double-​bond stereo­ tacticity must be considered in polynorbornenes chemistry in thiol–yne addition step-​g rowth poly- because endo–exo isomerism leads to four possible mers has led to an interesting new class of elastomers stereo­isomeric structures, all of which can be obtained that exhibit substantial, stereochemically dependent in stereopure form275. However, most reports (apart properties. Here, high-​c is-content materials were from a theoretical structure–property investigation)276 confirmed to be crystalline according to wide-​angle have focused exclusively on developing stereocontrolled X-ray scattering (WAXS) and DSC analysis (80% cis, synthetic methods with minimal investigation of stereo­ Tm = 80 °C). Conversely, polymers with significant chemical influence on material properties. Thus, there trans content (>30%) were amorphous and had a are significant opportunities to characterize the physical lower Tg (ΔTg = 20 °C). Most dramatically, high-​cis properties of stereopure polynorbornenes. materials (80% cis) were very tough yet remained The extension of ROMP methodologies to create ductile (ultimate tensile strength = 54.3 ± 6.5 MPa polyacetylene provides an interesting method by which and elongation at break = 1,495 ± 66%), while high-​ to create materials with high cis-​double bond contents, trans materials (68% trans) were much softer (ulti- yet this methodology has not been fully explored for mate tensile strength = 2.8 ± 0.4 MPa and elongation this purpose. Instead, polyacetylene is most commonly at break = 2,970 ± 137%). The dramatic differences in accessed by coordination–insertion polymerization mechanical properties between isomers was ration- methods. It is the simplest, yet arguably the most fun- alized to be caused by altered chain packing that was damental, polymer in the field of conducting polymers dependent on the relative stereochemistry of the alk- and, by examining its properties, another critical stereo­ ene moiety259. Importantly, these trends in the effect of chemistry lesson can be demonstrated277. The geome- cis–trans stereochemistry on mechanical properties are try of polyacetylene can be either cis or trans and can opposite to the effects observed for unsaturated polyole- be controlled through modification of the reaction fins (natural rubber and gutta-​percha). These differences conditions278. Apart from the observation that cis-​ are non-​intuitive and reconciling such observations is polyacetylene279 is rubbery and somewhat elastomeric279 important to the advancement of the field. Switchable while trans-​polyacetylene is much more brittle and crys- cis–trans photoisomerization has been used as a post-​ talline, the trans isomer has conductivity that is several polymerization technique to alter the stereochemical orders of magnitude greater, as a result of increased configuration of sulfur-​rich acetylenic polymers. It electron delocalization along the backbone enabled was found that the optical application potential of the by improved orbital overlap278,280. Thus, optoelectronic 100% trans (Z)-double-​bond-containing polymer was properties are also highly sensitive to stereochemistry. greater (approximately three times) when compared to Stilbene (1,2-diphenylethylene) is another simple moi- the analogous polymers with low cis:trans ratios, demon- ety that appears to be suitable for incorporation into strating a dependence of optoelectronic properties on conjugated polymers, since it possesses a photoisomer- stereochemistry256. Several other studies have used the izable C=C bond between the phenyl rings. However, stereocontrolled thiol–yne polymerization to synthesize it has not found widespread application in this area281. new structures; however, the effect of stereochemistry The cis-​stilbene moiety has a notoriously short lifetime, on the properties of the polymers has, to date, not been and the material displays overall photochemical insta- investigated261–264. Similarly, other nucleophilic addition bility (for example, photocrosslinking reactions and reactions (such as phenol–yne263 or amino–yne)265–269 production of oxidized side products)282. Moreover, have yielded stereocontrolled unsaturated polymers, but photooxidation issues can be exacerbated for extended structure–property relationships were also not investi- conjugated systems. Poly(azomethine)s is an alternative gated, most likely as a result of initial difficulties in con- system that contains –HC=N− moieties (isoelectronic trolling the cis:trans ratio of the prepared polymers in to HC=CH groups present in the archetypal conjugated these reactions. In many cases, certain limitations, such polymers) and theoretically possesses cis–trans isomer- as widely variable molecular weights between isomeric ism. Importantly, these species avoid the photooxidative Nature Reviews | Chemistry Reviews and chemical instability that hamper stilbenes, since the of stereospecific monomers. Additionally, the rigidity imine bond is thermodynamically stabilized through imparted by the fused-​ring system and non-​toxic nature conjugation283–287. A relatively recent aza-​Wittig protocol of the isohexides can be incorporated into mechanically was used to produce crystalline trans-​poly(azomethine)s robust, biocompatible polymers301. Isosorbide (endo/exo capable of supramolecular self-​assembly288. However, the –OH groups) and isomannide (endo/endo –OH groups) stereochemistry of the imine bond is rarely mentioned are both sourced from depolymerized polysaccharides51 and only structures featuring the more stable trans and commercially available. However, isoidide (exo/exo isomer have been noted288,289. Thus, stereochemistry –OH groups) can only be synthesized on a small scale has not yet been fully explored and there are signi­ from isosorbide302 or isomannide56,57,303–305. In most ficant opportunities in this area if synthetic methods cases, the hydroxyl group is transformed to a more are developed to access polymers with high cis content. reactive functional group (such as an amine, carboxylic Furthermore, as a consequence of the robust nature of acid or isocyanate) that is amenable for step-​growth the conjugated imine functionality, it might be harnessed polymerization301. Amino-​functionalized isohexides as a phototunable π bond. afforded a series of polyamides in which the Tg (when observed before decomposition) was dependent on Ring-​based polymers. The introduction of aliphatic stereochemistry (Tg of isosorbide < isomannide < iso­ rings into polymer backbones can impart rigidity (that idide) and the isoidide polymers had the greatest degree is, improved thermal properties) and provide access to of crystallinity306. Similar thermal trends were found materials with fixed stereochemistry along the poly- in isohexide-​containing polyacetals307, polyesters308,309 mer backbone. The most common ring systems in such and isohexide-​based polyureas/polyurethanes310, with polymers are derived from 1,4-cyclohexylene, which observable differences in physical appearance noted is of particular interest because it can be sustainably on some occasions311. Polyurethanes incorporating sourced and is often incorporated into robust plastics290. lactone units (analogous to isohexides) displayed sim- 1,4-Cyclohexanedimethanol (CHDM) was copolymer- ilar stereochemistry trends. The endo/endo version ized with 2,5-furandicarboxylate to yield materials with (d-​mannaro dilactone) displayed superior thermal various cis and trans contents. The trans content (25–98%) properties to the endo/exo (d-​glucaro dilactone) poly- of CHDM was positively correlated to the degree of mer312. Polytriazoles, synthesized from isohexide-​azides crystallinity, Tg, Tm (maximum Tm of 252 °C for 98% and isohexide-​alkynes, have also been investigated. trans content) and improved material toughness291. Materials featuring isomannide displayed the best ther- Similar trends have been found in polyamides contain- mal properties and the Tg was markedly lowered by ing 1,4‐cyclohexanedicarboxylic acid or 1,4-diamino- the introduction of isosorbide or isoidide units313,314. cyclohexane, in which higher trans content correlated Isohexides have also been paired with other renewable with improved thermal properties292. Investigations on monomers, such as hydroxymethylfurfural in copoly- the stereochemistry of other 1,4-cyclohexylene-​based mer compositions. Surprisingly, the isosorbide deriva- aliphatic polyesters also found increased crystallinity tives possessed superior thermomechanical properties and better thermal properties for high trans formu- to the isomannide counterpart for similar molecular lations293–297. However, a triblock copolymer system weights. However, rheological data suggested that the incorporating cis-1,4-cyclohexylene showed increased entanglement molecular weight (Me) for the isosorbide elongation at break and concomitantly increased tensile structure was lower, which could explain the apparent modulus and strength, even though the crystallinity was discrepancy315. Observations on the copolymer systems reduced compared with the trans analogue298. However, highlights the difficulties associated with determining it should be noted that this polymer possessed properties structure–property relationships for polymers with sto- analogous to TPEs, that is, hard–soft domains, which chastic monomer sequences (that is, random sequences must be considered. Nevertheless, this result encourages of endo–exo, endo–endo and exo–exo diads or copolymer caution in generalizing stereochemistry-​based struc- compositions), since generic structure–property trends ture–property relationships. The significant literature can break down. Thus, there remains considerable examining 1,4-cyclohexylene-​based polymers demon- work to synthesize and fully characterize such complex strate stereochemical tuning of material properties and copolymers. Despite the emergence of some stereochem- it is encouraging to see thorough structure–property ical trends, the use of polycondensation reactions with relationships being developed in these systems. A–A/B–B-​type isosorbide-​based monomers can result Polymers derived from sugar-​based monomers are in regiochemical differences between materials. These currently being intensely investigated because they methods typically yield amorphous polymers (isoman- are relatively inexpensive, they exhibit stereochemical nide and isoidide yield more crystalline, regioregular diversity and the renewability of carbohydrates is an architectures), which is to be expected as a result of the added advantage over petrochemical counterparts299. reduced order of the system316,317. Again, this highlights Carbohydrate monomers featuring the fused-​r ing that regiochemistry of the polymer structure cannot be 1,4:3,6-dianhydrohexitols (or isohexides) have garnered ignored if present, since it can distort structure–property much attention. Isohexides are particularly interest- relationships. ing since they possess structural diversity according The incorporation of sugar-​based building blocks to the relative stereochemistry of the hydroxyl groups provides a facile platform to robust, stereodefined mate- in the fused rings300. The hydroxyl group lends itself to rials, since the stereopure monomers are easily sourced facile functionalization, providing access to a wide range and derivatized. As such, a large number of recent www.nature.com/natrevchem  Reviews studies report on sugar-​derived polymers using isohex- either pure component. If such a complex is composed ides or isohexide derivatives with defined stereochemis- of isomeric polymers that differ in terms of tacticity or try301,307,310,311,313,315,317–321. However, most have either failed chirality, then it can be referred to as a stereocomplex to assess mechanical properties and/or overlooked the that generally features enhanced molecular order. As influence of stereochemistry in this regard. Additionally, such, stereocomplexation has emerged as a powerful in some cases, only certain derivatives (most commonly tool to improve the thermal and/or mechanical pro­