Recent Advances in Externally Controlled Ring-opening Polymerisations

Switchable catalysis is a powerful tool in the polymer chemist’s toolbox as it allows on demand access to a variety of polymer architectures. Switchable catalysts operate by the generation of a species which is chemically distinct in behaviour and structure to the precursor. This difference in catalytic activity has been exploited to allow spatiotemporal control over polymerisations in the synthesis of (co)polymers. Although switchable methodologies have been applied to other polymerisation mechanisms for quite some time, for ring opening polymerisation (ROP) reactions it is a relatively young area of research. Despite its infancy, the field is accelerating rapidly. Here, we review recent developments for selected external stimuli for ROP, including redox chemistry, light, allosteric and mechanical control. Furthermore, a brief review on switch catalysis involving exogeneous gases will also be provided, although this area differs from traditional switchable catalysis techniques. An outlook on the future of switchable catalysis is also provided. a Pt(II) both a a ligand, a state and closed state. semi-open form was inactive towards ROP of L-LA, quantitative conversion. (II) complexes which undergo reversible trans-cis isomerisation upon light/thermal treatment. 8


Introduction
Switchable catalysis involves the use of an external stimulus to switch between multiple states of a single species allowing enhanced control of a system. [1][2][3] Precisely controlled polymer synthesis to generate materials with highly regular structures remains a formidable challenge for polymer chemists. The preparation of well-defined polymers is dependent on a high degree of control since even slight changes to microstructural features i.e., tacticity, chain sequence and topology, can have a profound influence on the properties of these materials. 4,5 Switchable catalysis is a viable solution to some of the challenges faced in this area and for this reason it has been expanding rapidly over the past two decades. There have been reports of several methods that allow spatial and temporal regulation to be achieved including light, 6-9 electrical current, 10,11 redox control, [12][13][14][15] and mechanical control. 16 Switchable catalysis offers the possibility of achieving control over activity and regio-, chemo-, or -stereoselectivities by the incorporation of stimulus responsive units into the catalyst structure. An ideal switchable system includes at least two reversible forms of the molecule which respond to an external stimulus, fast response times, thermal stability, and fatigue resistance. Traditionally, these catalysts have been designed to include a distinct active and inactive species which allows the reaction to be toggled between an "on" or "off" state. Externally controlled polymerisation methodologies could facilitate one-pot reactions featuring several substrates for the synthesis of copolymers. More recent developments in the area include tandem catalysis where multiple mechanistic pathways can occur i.e., photocontrolled ROP and radical polymerisations. 17

Recent advances in selected external stimuli 2.1 Redox control
Redox controlled ROP systems have attracted considerable attention since the first report by Gibson and Long in 2006, 18 whereby a redox switchable titanium salen bis(isopropoxide) complex (1 ox/red ) was used to alter the rate of ROP of rac-lactide (Scheme 1). Redox switchable catalysts can be designed so that the redox responsive unit is incorporated into the ligand backbone, which is distant to the catalytically active metal centre, or alternatively a change in oxidation state can occur on the active metal centre itself. Reports of redox switchable polymerisation catalysts have also increasingly been complemented with theoretical studies to unravel complex mechanistic and structural aspects, therefore some of the recent advances in computational studies will also be reviewed. Scheme 1: Switchable ROP of rac-lactide by a titanium salen bis(isopropoxide) complex with the reduced form 1 red and the oxidised form 1 ox . 18 Redox "non-innocent" ligands have garnered popularity over the past decade since altering the electronic properties of the ligand can be used to control the reactivity of the metal centre i.e., change in electron density and Lewis acidity. 19,20 In the context of ROP, ferrocene has undoubtedly been the most vastly utilised redox moiety, as is highlighted in a comprehensive review by Diaconescu and coworkers. 21 Diaconescu et al. reported the first redox-switchable copolymerisation for L-lactide (L-LA) and ε-caprolactone (CL) with a titanium (IV) catalyst in 2014. 22 A series of group IV catalysts were synthesised and characterised (Scheme 2). The reduced forms (2a-c red ) exhibited higher activity towards L-LA, whereas the oxidised forms (2a-c ox ) were more active towards CL. For example, 2a red polymerised 90% L-LA in 2 h, whilst the oxidised form, 2a ox afforded < 5% conversion in the same period. A reverse activity trend was observed for CL with < 5% conversion in 24 h, compared to 98% for the reduced form. The switching behaviour of the zirconium complexes could not be extended to the formation of block copolymers because the polymerisation of CL did not occur when L-LA was initially polymerised. This was presumably due to the strong coordination of the LA monomer to the metal centre. However, the less electrophilic titanium-based complex allowed formation of a diblock copolymer of L-LA and CL, although the activity was low.
A copolymerisation study followed in 2016 where the polymerisation of several cyclic esters and epoxides was investigated using (salfan)Zr(O t Bu) 2 (2a red ) (salfan = 1,1' -di(2-tert-butyl-6-N-methylmethylenephenoxy)ferrocene) to form diblock and triblock copolymers. 12 In 2017, a mechanistic study of the zirconium (2a-c red/ox ) complex was reported using density functional theory (DFT) to probe the cyclohexene oxide (CHO) polymerisation mechanism and also the influence of one monomer over another in copolymerisations. 23 In 2019, Diaconescu and coworkers. reported the redox activity of a zirconium complex bearing a fully conjugated ligand, (salfen)Zr(OiPr) 2 (salfen = N,N'-bis(2,4di-tertbutylphenoxy)-1,1'-ferrocenediimine) (3 red/ox ) (Scheme 3). 24  -di(2,4-di-tert-butyl-6-thiophenoxy)ferrocene). 30 The polymerisation of several cyclic monomers including L-LA, CL, -valerolactone (VL) and trimethylene carbonate (TMC) were investigated using both the reduced and oxidised species. For L-LA, the reduced form (4 red ) afforded 88% conversion after 24 h at 70 ℃, whilst the oxidised form (4 ox ) displayed < 5% conversion at 100 ℃ in 24 h. For CL, VL and TMC, both the reduced and oxidised forms were capable of polymerisation and the differences in activity were less pronounced compared to that of L-LA. DFT studies also revealed that chelation of the monomer plays a key role in polymerisation. Moreover, L-LA is more easily controlled than other monomers because the propagation is usually much slower than initiation.
Following the findings of a computational study, 31  The ability to switch between multiple catalytically active states i.e., more than one or two oxidation states of the same catalyst, is highly advantageous since it could facilitate the polymerisation of several monomers in a one pot system. Stepwise oxidation to form three redox active species has been previously reported for olefin polymerisations, 35 however this approach has only been reported very recently for ROP reactions. 36 Diaconescu and coworkers have described a redox-switchable ferrocene containing dimeric yttrium complex, which displayed three oxidation states, the first of its kind in ROP reactions (Scheme 5). 36   Scheme 5: A redox switchable dimeric yttrium complex displaying three oxidation states upon stepwise oxidation leading to a mono-oxidised (6 ox1 ) and a doubly oxidised species (6 ox2 ). 36 Most of the reports of redox switchable catalysts have involved redox control of the ligand, as is demonstrated with ferrocene derivatives. Reports of systems where redox control of the metal centre are not as widespread, even though these types of catalysts would permit a wider range of ligands to be used.
Diaconescu and co-workers described the first redox switchable ROP catalyst system where the change in oxidation state occurred on the metal rather than on the ligand. 39 A cerium complex bearing tetradentate salen-type ligands could be switched between Ce(III) and Ce(IV) to control the rate of L-LA polymerisation. The neutral species polymerised 29% of L-LA within 15 min at ambient temperature after which the addition of an oxidising agent ceased activity. Okuda and co-workers have also reported a cerium-based system with [OSSO]-type ligands where switching between Ce(III) and Ce(IV) was used to control the ROP of meso-LA. 40 Iron based redox systems form the basis of many biological pathways and chemists designing synthetic systems have sought inspiration from nature. 41,42 Iron-based ROP catalysts are a highly attractive option due to their low cost, earth abundance, relatively low toxicity, and most importantly their wide range of redox potentials, which can be easily tuned with the appropriate choice of ligand. 43 The Byers group has long been interested in redox switchable ROP iron catalysts. 14,15,44,45 In 2013, they reported the first such catalyst for LA polymerisation. 14 The oxidised species iron (III) bis(imino)pyridine bisalkoxide complex was completely inactive towards the ROP of LA and could therefore be used to effectively activate and deactivate the polymerisation, whilst retaining molecular weight control through redox switching events.
In 2016, the same group extended the use of iron bis(imino)pyridine bisalkoxide complexes to other monomers to form block copolymers. 44 Generally, oxidised systems are more active towards CHO polymerisation compared to the reduced states. 12,23,30,46 A cationic iron (III) complex (7 ox ) displayed activity towards epoxides, whereas the neutral iron (II) complexes (7 red ) were inactive. (Scheme 6) An opposite reactivity trend was observed for LA polymerisation. The redox switchable behaviour in ROP of CHO showed that activity ceased upon addition of CoCp 2 and resumed upon addition of an oxidising agent (Figure 1). This change in chemoselectivity induced by the oxidation state of the catalyst could be used to form block copolymers of CHO and LA.  The Byers' group also described the synthesis of poly(lactic acid) (PLA) cross-linked polymers in 2016, using redox switchable iron bis(imino)pyridine alkoxide complexes (Figure 2). 45 Cross-linking PLA usually requires impractical methods involving high energy light or electron-beam irradiation. 47 ROP of LA occurred with the iron (II) complex, with oxidation to the iron (III) complex triggering CHO polymerisation, resulting in chemical cross-linking of the polymer. study of iron alkoxide catalysts bearing bis(imino)pyridine ligands for ROP of lactones. 48 The influence of the alkoxide initiator, spin state and oxidation state on polymerisation activity was investigated. The initiation step of ROP was computed to investigate the influence of spin state which showed that high spin complexes were found to be more Lewis acidic than low spin complexes, and therefore had a greater propensity to initiate the polymerisation. Furthermore, the overall reactivity of a particular system is influenced largely by coordination of the monomer. In 2020, Long and coworkers investigated the effects of metal centre and number of redox active units on catalytic performance and switchability. 50 The catalytic activity of previously reported symmetrical titanium catalysts bearing two redox moieties (1 red/ox ), 18  was generated in-situ and no increase in conversion was detected. It is also suggested that the metal centre has a drastic effect on catalytic activity, stability and switchability. The differentiation in catalytic activity of zirconium complex 8b was around double that of the Ti analogue 8a. (12/13 red/ox ). It was proposed that a hafnium analogue (12 red/ox ) may be a more superior redox switchable catalyst than the zirconium analogue (10 red/ox ). Also, switching the donors in the supporting ligand from S to Se (13 red/ox ) presented a larger energy barrier difference between the reduced and oxidised states which could translate to greater differentiation in catalytic activity between the two forms.  Furthermore, CHO is more sensitive towards the Lewis acidity of the metal centre compared to LA, due to its greater nucleophilicity.
These theoretical studies provide valuable insight into redox switching mechanisms, as well as structural factors affecting catalytic activity and redox switchability i.e., metal centre, auxiliary ligand, oxidation states and spin states, which should be taken into consideration when designing new redox switchable systems for ROP.

Electrochemical control
Redox switchable systems have traditionally involved the addition of oxidising and reducing agents which present several drawbacks including environmental problems and difficulties in upscaling. The application of electrochemistry helps to alleviate some of the challenges presented in using stoichiometric amounts of redox agents. 54  Similarly, in 2020 Tong and co-workers reported a stereoselective Co/Zn catalytic system for electrochemical ROP of O-carboxyanhydrides to prepare high molecular weight polymers (> 140 kDa). 10 Remarkably, they also demonstrated an electrochemically stereoselective polymerisation of racemic O-carboxyanhydrides by modulation of the ligands on the metal centre making these catalysts either isoselective or syndioselective in the formation of block copolymers. brushes appended on to solid state surfaces using a redox controlled process (Figure 5). 55 Research interest into polymer brushes has flourished over the last two decades due to their mechanical and chemical robustness and ease of functionalisation, 56

Mechanochemical control
Although mechanochemical control offers many advantages in the way of green chemistry, for polymerisation processes it is a rather unconventional stimulus. The application of mechanical force in the production of polymers is generally viewed as a destructive approach as excessive force on polymeric materials can cause degradation and impedes access to high molecular weight materials. To our knowledge, only one report for mechanochemically controlled ROP

Allosteric control
Allosteric regulation is evident in many biological functions including protein activity modulation. 63,64 The term allosteric translates to 'other-space' in Greek and is fittingly used for this mechanism because effectors operate by binding to a site other than the active site which can induce conformational changes capable of directly modulating activity. 63 Allosteric control has been applied to switchable ROP by Mirkin and coworkers in 2010 with a cleverly designed triple-layer catalyst consisting of Rh(I)Cl side arms with Clplaying the role of the effector (Scheme 9). 65 In the presence of Cl -, the active metal centre of the complex

Photochemical control
The use of light as an external trigger to control a reaction presents many advantages over other stimuli and provides many of the necessary characteristics of an ideal system, such as its noninvasive nature, easy handling, and the ability to exert high levels of control by simple manipulation of wavelength or intensity of the light source. The benefits of light have been manifested across both heterogeneous and homogeneous catalysis for a wide array of chemical In 2013, Biewlaski and coworkers reported a photoswitchable organocatalyst for the ROP of cyclic esters (Scheme 10). 71 Prior to this, reports of photocontrolled polymerisation processes were limited mostly to other processes, such as atom-transfer radical polymerisations. 72 and TMC, however the generated acid was incapable of polymerising LA. 78 In 2018, the same group reported a photocaged tetramethyl guanidine capable of polymerising L-LA (Scheme 12). 79 Irradiation of 2-(nitrophenyl)propoxycarbonyl-1,1,3,3tetramethylguanidine (NPPOC-TMG) (18) with 320-400 nm light released TMG (19), an organocatalyst only previously reported for ROP of N-butyl N-carboxyanhydride. 80 NPPOC-TMG was inactive towards L-LA, however switching to UV light for 15 minutes released the active TMG species, which converted 90% of the monomer in 3 h. The photoinduced ROP of -VL was also attempted with the photocaged catalyst, although the addition of a thiourea cocatalyst was necessary for monomer activation. 81 After a period of 76 h, 34% monomer conversion was observed which was considerably slower than using the free TMG base devoid of the photolabile protecting NPPOC group (93% conversion in 23 h). Photoacids are molecules which generate a strong acid upon irradiation with light of an appropriate wavelength and have been used to achieve spatiotemporal control across several disciplines. 82 Xu and Boyer have reported a visible-light mediated process for the proton-catalysed ROP of cyclic esters using a photoacid. 17  In 2020, You and coworkers developed a series of composite photoacid generators for the living/controlled cationic ROP (CROP) of lactones under visible light. 86 The system consisted of a common photocatalyst and an onium salt. Irradiation with light generated radicals from the excited photocatalyst/onium salt which could abstract a proton (H + ) from the monomer or solvent. H + could catalyse the living cationic ring opening polymerisation of lactones.
Moreover, the generation of radical species allowed a simultaneous CROP/reversible-additionfragmentation chain transfer reaction. It is important to note that light was not used to switch between two states once the polymerisation started and light simply acted as a trigger for generating a more active species (H + ) which allowed polymerisation to commence.
Similarly, in 2021 Liao and coworkers reported a visible light regulated ROP using an aromatic alcohol as the photocatalyst (Scheme 14). 87 The irradiation of aromatic alcohols is known to generate a high-acidity excited state which is more catalytically active. 82 The same group had previously explored this area and reported that naphthols were inefficient for this purpose due to weak absorption of visible light in the absence of photosensitisers. 88    containing an azobenzene linkage which could acts as a molecular tweezer in the light regulated ROP of L-LA (Figure 8). 100 The same group had previously reported the use of crown ethers to accelerate the ROP of L-LA through the in-situ generation of free ions. 101 The use of azobenzene as a bridge could allow a controllable system where more active species are generated "on-demand". Light was used to transform the K +-OAc ion pair-like into free ion catalysts through E/Z isomerisation. The ROP of L-LA which proceeded under UV light resulted in increased polymerisation rates (k fast /k slow ~ 10).

Gas control
Recently gas-controlled systems have gained attention for switchable polymerisation catalysis because they appeal to greener chemistry approaches and can be used to synthesise sequencecontrolled block polymers from a mixture of monomers. A key advantage of these systems is the easy removal of exogeneous gases which enables switching between multiple polymerisation pathways. Removal of these exogeneous gases often requires a simple purge of the system, without any further complex purification required. The Williams group have long been interested in switch catalysis; 102,103 however, it is important to note that the type of switch catalysis explored here differs from the examples mentioned elsewhere in this review. Here, the term 'switch' catalysis refers to switching between multiple catalytic cycles, as opposed to switching between an active and dormant state through the application of an external stimulus.
In 2014, Williams and co-workers reported a switchable system based on a dizinc catalyst capable of forming block copolymers from ROCOP of CO 2 /CHO and ROP of ε-CL ( Figure   9). 104 In the presence of CO 2 , poly(cyclohexene carbonate) was formed, and after removal of CO 2 a metal alkoxide-species was generated which catalysed ROP to afford polycaprolactone. This reactivity was explained by the zinc chain end groups controlling selectivity. ROCOP or ROP was catalysed by the zinc alkoxide chain end group, whereas the zinc carboxylate/carbonate chain end group only catalysed ROCOP.  Significant effort has been expended into the area of switchable catalysis since some of the earliest works and the literature presented here clearly indicates that there is great potential in this area. Whilst it is difficult to make direct comparisons between external stimuli, areas such as redox control and photocontrol have forged ahead of others and provide the greatest potential for highly controllable system, however there is still much work needed to fulfil the requirement of systems capable of controlling one-pot polymerisations with several monomers.

Prospects
The infancy of the field means that most reports are based on simply designed experiments merely involving "on/off" or "fast/slow" species, although there is evidence to suggest that research groups in this area are setting themselves more complex objectives e.g., orthogonal polymerisation methods combining multiple mechanisms. The stringent criteria required for switchable catalysts to be highly effective i.e., high conversions, fatigue resistance and a sizeable differentiation in catalytic activity between distinct states, means that the rational design of new catalysts should also consider mechanistic and structural aspects. Gas controlled systems have rapidly advanced over the last decade with highly selective catalysts capable of forming multiblock polymers from mixtures of monomers, and we expect that this area will