Salt additives as activity boosters: a simple strategy to access heterometallic cooperativity in lactide polymerisation †

Inorganic salt additives can activate carbonyl groups towards organic addition reactions. Here, we translate this concept to ring-opening polymerisation for the first time, generating hetero-metallic ProPhenol catalysts in situ , which show similar activity enhancements to pre-formed heterometallic complexes. Extremely high activities are observed, with K/Mg and K/Ca combinations converting 4 85 eq. lactide in 5 s at room temperature.

Heterometallic cooperativity can boost catalyst performance, yet heterometallic catalyst development lags behind homometallic analogues due to the synthetic challenge of preparing heterometallic complexes. 1A simple and attractive route to heterometallic cooperativity involves the in situ addition of inorganic salts (e.g.LiCl) to homometallic reagents.This method has been exploited in nucleophilic addition, deprotonative metallation and metal-halogen exchange. 2][5] Lewis acidic salt additives can activate carbonyl compounds towards addition reactions via carbonyl coordination. 6,7For example, lanthanide salts (LnCl 3 Á2LiCl, Ln = La, Ce or Nd) have facilitated 1,2-addition of Grignard reagents (Fig. 1). 8This concept is relevant to the ring-opening polymerisation (ROP) of carbonyl-containing rac-lactide (rac-LA), as Lewis acidic monomer activation via coordination to a metal is a key mechanistic step and promotes nucleophilic attack from a M-OR group (Fig. 1). 9rac-LA ROP is an efficient route to produce biodegradable and biocompatible poly(lactic acid) (PLA), 9,10 with packaging, 11 electronic and biomedical applications. 12While the use of simple inorganic salts has not been explicitly explored in ROP, recent studies hinted that salts may act as activity boosters.Use of a silver salt with a non-coordinating anion (BArF = tetrakis[3,5-bis(trifluoromethyl)phenyl]borate) ''switched on'' the reactivity of a Ti(salen) complex; 13 a 1: 1 Ti(salen): AgBArF mixture converted 76 eq.rac-LA in 1 h while the homometallic counterparts were inactive after 4 h (R.T., DCM).Our preliminary studies suggested that in situ addition of potassium benzoxide (KOBn) to a bis-Zn Trost ProPhenol complex gave significant activity enhancements in rac-LA ROP. 14 Among isolated heterometallic ROP catalysts, the highest activities have generally been observed when a hard metal (M 1 , e.g.Group 1/Ln) is paired with a softer, more carbophilic metal (M 2 , e.g.Mg/Zn), 14,15 with large and Lewis acidic M 1 proposed to provide additional monomer coordination sites and thus accelerate ROP.These heterometallic catalytic features could potentially also be accessed by combining inorganic salts with homometallic ROP catalysts.This would give access to a wide range of heterocombinations that can be more rapidly tested than isolated heterometallic catalysts.Herein, this concept is investigated in rac-LA ROP for the first time, comparing the activities using in situ salt additives to isolated heterometallic catalysts.The catalyst solution-state structures are investigated by NMR spectroscopy, highlighting the dynamic equilibria and complex nature of catalytic species in solution.
Fig. 1 The inorganic salt effect in addition chemistry and potential effect in LA ROP.
The more active K-based complexes 3 and 5 displayed reduced polymerisation control vs. Na-based 4 (Ð = 1.83, 1.51 and B1.24, respectively, Table 1).MALDI-ToF analysis indicated that 3 and 5 (+1 eq.BnOH) produced transesterified (D(m/z) = 72 g mol À1 ) a-benzoxy, o-hydroxy (major) and a-hydroxy, o-hydroxy capped or cyclic (minor) PLA (Fig. S18 and S22, ESI †).While the same endgroups were observed with 4/BnOH, the improved polymerisation control suggested less transesterification occurs with this system.Indeed, with 4 the major series observed was non-transesterified PLA (D(m/z) = 144 g mol À1 ) but the non-quantitative nature of  MALDI-ToF should be noted (Fig. S19-S21, ESI †).Importantly, despite the presence of 1-2 eq.HMDSH with complexes 3-5 (Scheme 1), no HMDS-capped PLA was detected by MALDI-ToF analysis.We previously reported that no rac-LA ROP occurs with BnOH and HMDSH in the absence of a metal complex. 16nOH was essential for the high activity of 3-5, as low rac-LA conversions were observed without it (entries 1, 3 and 6, Table 1).Combined with the relative stability of the Na/Kphenoxide unit towards BnOH, 14 this initially suggested that 3-5 operate via an activated-monomer mechanism with BnOH. 17However, studying the reaction of 3-5 with 1 eq.BnOH in THF-d 8 by 1 H and DOSY NMR revealed that the in situ generated alcoholysis products (and thus the mechanism) are more complicated, as multi-component product mixtures are formed (see ESI †).While complex, some components of these mixtures could be identified, with the % product composition quantified based on the relative L resonances.The known products generated from 3/BnOH comprised of 2 (50%) and previously reported [LMg 2 OBn] (8, 16%), whereas 4/BnOH gave 1 (13%) and previously reported [LCa 2 OBn] (9, 13%), and 5/BnOH gave 2 (29%) and 9 (trace). 14,16In situ formation of unligated [Mg(OBn) 2 ] 2 and [Ca(OBn) 2 ] 2 salts from 3 and 5 with 1 eq.BnOH, respectively, was also proposed based on 1 H NMR and DOSY analysis, although the formation of heterometallic benzoxide salts cannot unequivocally be ruled out.No M(OBn) 2 species formed with 4/BnOH and instead, a greater proportion of asymmetric ligated products was generated.The complexity of the reaction mixtures formed here reflect the ''black box'' of multiple solution-state species observed with (TMP)MgClÁLiCl in THF-d 8 , which were characterised using DOSY NMR several years after the initial report of this ground-breaking Turbo-Grignard. 18While many ROP catalysts involve alcohol co-initiators, most studies do not disclose the nature of the alcoholysis product(s).Our results highlight the importance of such investigations, as other systems are also likely to undergo in situ rearrangements in the presence of an alcohol to generate ligated and/or non-ligated homometallic species.In some cases, the presumed active catalyst species may actually not be present at all in a complex mixture of components.
Combining 1 or 2 with 1 eq.Mg(OBn) 2 or Ca(OBn) 2 gave similar solution-state products to those observed via alcoholysis of 3-5 with BnOH, as evidenced by NMR analysis (refer to ESI †).For instance, 2:Mg(OBn) 2 gave the same three species as observed with 3/BnOH (2, 8 and an asymmetric product), albeit in a different ratio (33 : 27 : 40 vs. 50 : 16 : 34 with 3/BnOH; Fig. S26 and S41, ESI †).These results suggest that dynamic solution equilibria may generate similar catalytic species when isolated heterometallic ProPhenol complexes are reacted with BnOH (Route A) and when homometallic ProPhenol complexes are combined with M(OBn) 2 salts (Route B), explaining why similar activity enhancements were observed in LA ROP via both routes.This approach shows that heterometallic activity enhancements can be harnessed without isolating heterometallic complexes, and this concept may be applicable to other ROP systems.
In summary, our studies show that salt additives can boost the activity of homometallic ROP initiators, giving similar activity enhancements to isolated heterometallic complexes.With some heterocombinations (e.g.K/Mg, Na/Ca), the same species were formed via both routes, highlighting the importance of probing the solution-state catalyst structure after alcoholysis (which is often not disclosed for heterometallic ROP catalysts).The salt additive approach is attractive as it allows rapid screening of different heterocombinations and avoids heterometallic complex syntheses enabling access to synthetically challenging heterometallic precursors.With both approaches, K/Mg and K/Ca combinations convert 485 eq.rac-LA in just 5 s at R.T., exhibiting the highest heterometallic LA ROP activities to date.The boosted activity is primarily attributed to enhanced LA activation, likely by the large and Lewis acidic K + centre, as K/Mg and K/Ca systems outperform the Na/Ca analogue.These activity enhancements are somewhat analogous to organic addition reactions, where salt additives are assumed to activate Lewis acidic carbonyl groups.To the best of our knowledge, these results are the first example of employing simple salt additives in ROP.There is significant scope to explore other unstudied heterocombinations and activities with salt additives in ROP, as well as ring-opening copolymerisation and other polymerisations.