Mechanistic Aspects of the Polymerization of Lactide Using a Highly

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Mechanistic Aspects of the Polymerization of Lactide Using a Highly Efficient Aluminum(III) Catalytic System Carine Robert,† Thibault E. Schmid,† Vincent Richard,† Pierre Haquette,† Sumesh K. Raman,† Marie-Noelle Rager,† Régis M. Gauvin,‡ Yohann Morin,‡ Xavier Trivelli,§ Vincent Guérineau,∥ Iker del Rosal,⊥,# Laurent Maron,*,⊥,# and Christophe M. Thomas*,† †

Chimie ParisTech, PSL Research University, CNRS, Institut de Recherche de Chimie Paris, 75005 Paris, France Univ. Lille, CNRS, Centrale Lille, ENSCL, Univ. Artois, UMR 8181 − UCCS − Unité de Catalyse et Chimie du Solide, F-59000 Lille, France § Univ. Lille, CNRS, UMR 8576 − UGSF − Unité de Glycobiologie Structurale et Fonctionnelle, F-59000 Lille, France ∥ Institut de Chimie des Substances Naturelles, CNRS UPR2301, Université Paris-Sud, Université Paris-Saclay, Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France ⊥ Université de Toulouse; INSA, UPS; LPCNO (IRSAMC), 135 avenue de Rangueil, F-31077 Toulouse, France # CNRS; UMR 5215 (IRSAMC), F-31077 Toulouse, France ‡

S Supporting Information *

ABSTRACT: We report here a unique example of an in situ generated aluminum initiator stabilized by a C2-symmetric salen ligand which shows a hitherto unknown high activity for the ROP of rac-lactide at room temperature. Using a simple and robust catalyst system, which is prepared from a salen complex and an onium salt, this convenient route employs readily available reagents that afford polylactide in good yields with narrow polydispersity indices, without the need for time-consuming and expensive processes that are typically required for catalyst preparation and purification. In line with the experimental evidence, DFT studies reveal that initiation and propagation proceed via an external alkoxide attack on the coordinated monomer.

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fine-tuned and potentially employed on an industrial scale. These species had a significant impact in polymerization methodologies, in particular in CO2/epoxide and cyclic anhydride/ epoxide copolymerizations.8 For ROP of LA, most studies using salen systems have been carried out with aluminum-based complexes. Although this strategy permits the generation of well-controlled polymers, one fundamental drawback of these species is their low catalytic activities and productivities requiring high temperatures.9 Efforts to obviate these limitations have focused on the development of metal-based catalysts in combination with an onium salt as a cocatalyst, to achieve higher catalytic activity. Indeed, as early as 1985,10 Inoue described the catalytic behavior of an aluminum porphyrin system in combination with quaternary ammonium or phosphonium salts for the homopolymerization of epoxide and for the alternating copolymerization of epoxide and cyclic anhydride to provide the corresponding polymers. From this study, several research groups anticipated that salen metal complexes combined with onium cocatalysts would be of

INTRODUCTION Aliphatic polyesters are a class of technologically important biodegradable and/or biocompatible polymers.1 Among them, polylactide (PLA) has unique mechanical and physical properties that make it useful in a wide range of commodity applications and also in life science.2 In this context, there is increasing interest in methods that allow for the preparation of PLAs in a reproducible and controlled fashion. The established synthesis of PLA relies upon the ring-opening polymerization (ROP) of the corresponding lactide (LA) with well-defined metal complexes.2,3 In particular, a large number of investigations have been directed toward synthesizing efficient alkoxide initiators and studying their reactivities.2 Although noteworthy successes were realized for the polymerization of lactide, use of commercially available (or easily accessible), air stable catalysts that exhibit high activities under mild reaction conditions, is rare.4,5 In this regard, salen catalysts have given rise during the last decades to a number of versatile catalytic systems.6,7 Their unique diversity makes them useful for a variety of applications. Their ease of synthesis and handling are important advantages toward the development of a catalyst system that can be © 2017 American Chemical Society

Received: February 24, 2017 Published: April 11, 2017 6217

DOI: 10.1021/jacs.7b01749 J. Am. Chem. Soc. 2017, 139, 6217−6225

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Journal of the American Chemical Society interest in order to achieve effective polymerization reactions.11 These combinations were essentially investigated with chromium-,12 cobalt-13 and aluminum-based systems for epoxide/ CO2 copolymerization reactions. However, most initiating systems are extremely slow in the ROP of LA and effective rac-LA polymerization under mild reaction conditions remains a challenge. Taking into account recent developments in our prior research on salen catalysts, namely (1) the tandem synthesis of alternating polyesters14 and (2) the ROP of α-amino acid-N-carboxyanhydride monomers (NCA),15 we set out to capitalize on these catalytic schemes to synthesize polylactide with in situ generated salen intermediates. Herein we introduce a practical route to aluminum alkoxide complexes by way of a straightforward activation reaction using commercial derivatives. This process provides direct access to active polymerization catalysts. The presented catalytic results reveal the viability of the approach, and mechanistic and theoretical studies allow us to elucidate the origin of the unprecedented activity.

Figure 2. Kinetic profiles of rac-lactide conversion using different preactivation times. Reaction conditions: Al-1/[PPN]Cl mixture preactivated in THF for 16 h (⧫), in PO for 3 h (■) and in PO for 16 h (▲), followed by the addition of 50 equiv of rac-lactide in a glovebox.

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system in PO (16 h) gave a higher reaction rate than with 3 h activation time. As a control experiment, we also carried out the reaction with a 48 h preactivation time and observed a comparable result (Figure S3). Notably, the average molecular masses were monitored by injecting crude samples periodically, and showed a similar profile to the conversion of lactide and a polydispersity index of around 1.15 for conversions up to 80%. Interestingly, the values for Mn,exp approximately corresponded to Mn,theo/2, suggesting the formation of two polymeric chains per metal center. With these results in hand, we were interested in evaluating the catalytic productivity of our system using the same methodology, and studied the conversion of larger amount of raclactide in PO with a 16 h preactivation time. Different parameters were varied in order to optimize the reactivity of the catalytic system. In all cases, high polymerization activity was observed at room temperature (Table 1). The molar ratio of catalyst to cocatalyst was first investigated in the presence of 100 equiv of rac-lactide (Table 1, Entries 1−4). A Al-1/[PPN] Cl ratio of 2:1 exhibited relatively slow kinetics with a lactide conversion of only 27% for a reaction time of 8 h (Table 1, Entry 1). By contrast, ratios of 1:1 and 1:2 afforded PLA in 67% and 77% respectively, with narrow distributions and Mn values close to Mn,theo/2 (Table 1, Entries 2 and 3). This behavior was confirmed as a higher ratio of the iminium salt (1:5) allowed full conversion to be reached. However, a low number-average molecular mass and a broad distribution were observed for the resulting polymer (Table 1, Entry 4). In agreement with previous observations,13 these results indicate that the six coordinate aluminate species of the form trans-(salen)AlCl2− derived from (salen)AlCl and onium salt should be the first complex generated.8,14 The next step in the process involves binding and subsequent ring-opening of PO. Therefore, the role of the Lewis base cocatalyst is to labilize the metal-nucleophile bond of either the initiator or growing polymer chain toward heterolytic bond cleavage. Also, when the polymerization reaction was conducted during only 2 h, a conversion of 83% and an average mass of 4.4 kg mol−1 were obtained (Table 1, Entry 5), indicating that side-reactions are likely to occur if the reaction is left to react after full conversion (Table 1, Entry 4). Indeed, detrimental side-reactions, such as intramolecular and intermolecular transesterifications, can lead to a broadening of the molecular weight distribution and have been described as a function of the monomer conversion.2d In addition, MALDI-TOF mass

RESULTS AND DISCUSSION The high NCA polymerization activities observed with Al-1 led us to investigate this salen aluminum complex for the ROP of rac-LA. In addition, the use of discrete (salen)Al(III) alkoxides has been explored for the ring-opening of lactide at high temperatures.9 As we recently reported the catalytic activity of in situ generated alkoxide complexes for the one-pot synthesis of polypeptides, we chose to use the same reaction conditions in this study.15 The aluminum complex Al-1 was preactivated in the presence of 2 equiv of [PPN]Cl ([PPN]+ = bis(triphenylphosphoranylidene)iminium) in THF for 16 h and the polymerization step was conducted with 100 equiv lactide in propylene oxide (PO) (Figure 1). Satisfyingly, the resulting

Figure 1. Ring-opening polymerization of rac-lactide promoted by salen complexes Al-1 and Al-2.

catalytic system immediately proceeded to convert lactide into polylactide in short reaction times, and showed monomodal narrow distributions ([lactide] = 1 M, reaction time 5 h, Mn = 4.0 kg mol−1, Mw/Mn = 1.16). In addition, no poly(propylene oxide) formation could be detected by NMR spectroscopy. Therefore, we decided to focus on the reactivity of the aluminum species Al-1: as monomodal molecular-weight distributions were observed, we assumed that the catalytic system gave rise to only one active species. The effect of the activation time was then studied by following the kinetics of lactide conversion. As shown on Figure 2, activations of the catalytic system were carried out either in bulk PO or in a THF solution containing excess PO. Generally, neat conditions were optimal and an overnight formation of the 6218


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Journal of the American Chemical Society Table 1. Ring-Opening Polymerization of rac-Lactide Catalyzed by Al-1/[PPN]Cla entry 1 2 3 4 5 6 7 8 9 10 11 12f

[LA]/[Al-1] ([LA]) 100 100 100 100 100 100 100 100 200 200 400 400

(1 M) (1 M) (1 M) (1 M) (1 M) (0.5 M) (1 M) (2 M) (2 M) (2 M) (2 M) (2 M)

[Al-1]/[PPNCl] 2/1 1/1 1/2 1/5 1/5 1/2 1/2 1/2 1/2 1/2 1/2 1/2

t (h)

conv. (%)b

8 5 5 5 2 4 4 4 10 12 24 8

27 67 77 100 83 41 66 78 92 98 90 55

Mn,expc (kg mol−1) ND 3.7 4.8 3.1 4.4 2.7 4.2 5.7 6.2 8.1 7.6 3.7

e

Mw/Mnc

Mn,theod (kg mol−1)

ND 1.11 1.16 2.19 1.20 1.12 1.14 1.13 1.23 1.36 1.21 1.14

3.9 9.6 11.1 14.4 11.9 5.9 9.5 11.2 26.5 28.2 51.9 31.7

a

All reactions were carried out at room temperature with [Al-1]/[PPN]Cl after a 16 h preactivation in neat PO followed by the addition of rac-LA and stirring for the indicated time. bConversion was determined by 1H NMR spectroscopy by calculating the integral ratio between the methine regions of rac-LA and PLA. cMn,exp and Mw/Mn of polymer determined by SEC-RI calibrated with polystyrene standards at 35 °C and using the Mark−Houwink correcting factor 0.58. dMn,theo = [LA]/[I] × % conv. (LA) × M(LA) eNot determined. fT = 50 °C.

aluminum-based system remains the moderate stereocontrol achieved in the ROP of racemic lactide (Pm value up to 0.65, Figure S56),16 while other Al(III) alkoxides, such as those supported by salen ligands, lead to highly isotactic PLAs.17 The reactivity of L-lactide was therefore investigated and compared to the one previously observed with its racemic counterpart, and a full conversion of 100 equiv was reached in 3 h while 5 h were not sufficient to achieve complete polymerization of 100 equiv of rac-lactide in the same conditions (Table 1, Entry 3). These results indicate that the catalytic system exhibits a (slight) preference for the polymerization of L-lactide over D-lactide. However, we also observed that the isotacticity of the resulting PLLA decreases with conversions, suggesting that epimerization takes place during the catalytic process (Figure S56). This finding is consistent with previous observations that the high basicity of ionic alkoxide species can result in epimerization of chiral centers in the PLA backbone.2f The occurrence of such types of side reactions might also explain the fairly modest enantiodiscrimination observed for the polymerization of rac-lactide. Mechanistic Studies. The preactivation pathway depicted in Figure 3 explains the observed reactivity for the catalytic

spectrometry spectra of the polymers revealed the presence of both even-membered and odd-membered oligomers, consistent with some intermolecular transesterification occurring in parallel to polymerization (vide inf ra).2e The amount of [PPN]Cl therefore appeared to be crucial to generate a potent catalytic system: a high quantity of [PPN]Cl favored substantial chain transfer reactions while a small amount of iminium salt resulted in slower systems. We decided to select a Al-1/[PPN]Cl ratio of 1:2, as it offers the best compromise between polymerization control and reaction rate. We then investigated the influence of the concentration of the monomer, and higher conversions were observed for the most concentrated experiments (Table 1, Entries 6−8). The reaction of 200 equiv of rac-lactide, at a concentration of 2 M, was examined, and a conversion of 92% was obtained in 10 h, with a narrow polydispersity of 1.23 (Table 1, Entry 9). Additionally, an extra 2 h allowed the reaction to reach full conversion but a broadening of the molecular weight distribution was observed (Table 1, Entry 10). The reaction of 400 equiv of rac-lactide was attempted, and even though high conversions could be reached and the controlled character of the polymerization reaction could be retained with polydispersity values of around 1.20, the average masses of the resulting polymers deviated even further from what was observed in the conversion of 200 equiv of lactide (Table 1, Entry 11). Raising the temperature to 50 °C resulted in a significant increase in the rate of polymerization and allowed to obtain a narrower polydispersity, but Mn values were also lower than expected (Table 1, Entry 12). For [LA]/[Al-1] < 100, the controlled formation of two polymeric chains per unit of catalyst seemed to occur, as the produced polymers reveal narrow molecular-weight distributions and experimental Mn close to Mn,theo/2. However, for higher ratios, experimental Mn values do not correspond well with calculated Mn values and this mismatch possibly arises from the high nucleophilicity of the alkoxides formed, therefore enabling chain-scission processes. This tendency was enhanced at higher temperatures and indicated that chain transfer/ cleavage phenomena were likely to happen as conversion increased. In marked contrast with what was observed for other salenbased initiators,2 homopolymerization of rac-lactide with the in situ generated system Al-1/[PPN]Cl proceeds rapidly at room temperature. However, a rather surprising feature of this

Figure 3. Activation mechanism using (salen)AlCl. For the aluminate species, the cationic PPN+ moiety has been omitted for clarity.

system. This activation mechanism comprises the formation of the mono(alkoxide) species, similarly to what was reported in the PO/CO2 copolymerization or in the ROP of NCAs.15,18,19 In addition, polymers obtained from the ROP of lactide showed that the aluminum-based system Al-1/[PPN]Cl was likely to 6219


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resonances consistent with the formation of secondary (R) monoalkoxide previously discussed but also a new set of signals. For instance, the resonance for the methine (CHMeO) carbon is only shifted ca. 0.2 ppm upfield (δ = 67.1 ppm) with respect to that in the neutral aluminum-based monoalkoxide, indicating that this group remains coordinated in solution onto the metal center, which is thus 6-coordinated. Indeed the ionic character in a [PPN] alkoxide species, as opposed to the one in an aluminate alkoxide derivative, is more pronounced and therefore the resulting methine carbon would be more deshielded and would give a (much) higher chemical shift.23 The NMR spectra of the other Al-1/[PPN]Cl/PO combinations in chloroform-d showed many resonances and proved arduous to analyze due to their complexity caused by severe overlapping (Figures S51−S55). This reflects the coexistence of several primary and secondary alkoxide species (and possibly aggregated ones) in solution and the exact nature of the initiating catalytic species is clearly difficult to determine. This is in accordance with previous observations that demonstrated that the ring-opening of PO occurs by competitive pathways and that only bulky epoxides favor ring-opening at the methylene carbon of the epoxide, owing to the steric hindrance at the methine carbon.8d,19 In agreement with our experimental results, we also observed by density functional theory (DFT) computations that both primary and secondary alkoxides can be obtained from the ring-opening of PO by Cl−, thus confirming that the nucleophilic attack can occur on the less and the more substituted carbon atoms of PO (Figure S62). Therefore, as primary alkoxides are more nucleophilic than secondary derivatives, we assumed that the initiating step would preferentially occur via the attack of the less hindered (−OCH2CHMeCl) alkoxide group. Currently, we cannot rule out the possibility of an initiation mechanism involving a secondary alkoxide unit, although theoretical calculations are consistent with a mechanism initiated by a primary alkoxide (vide inf ra). When salen-complex/[PPN]Cl catalyst systems are used, several types of mechanisms may be envisaged for the lactide ring-opening by a nucleophile (Figure 4).24 First, single-site

form two chains per metal center, suggesting that the polymerization reaction can take place simultaneously on both sides of the ligand plane, via the formation of a six-coordinated aluminum salen featuring two nucleophilic groups in the two axial positions (Figure 3). Therefore, we could assume that the conditions used in this study for the activation of the salen complex promoted the formation of bis(alkoxide) species, in addition to the mono(alkoxide) derivative already suggested by our work on the ROP of NCAs.15 In agreement with previous observations with (porphyrin)AlCl complexes,18a the presence of excess [PPN]Cl can cause a displacement of the alkoxide anion by the chloride one, generating the new iminium salt [PPN]OR and ultimately leading to the formation of the corresponding bis(alkoxide) complexes. As polymerization reactions are performed with propylene oxide as a solvent, the excess of onium salt can ultimately lead to the formation of several [PPN]OR species (including oligomeric alkoxides). Also, we confirmed that no significant amount of [PPN]OR can be obtained from the ring-opening of PO by [PPN]Cl. Considering this activation scheme, the formation of the mono(alkoxide) species would occur quickly with a high conversion, while the bis(alkoxide) species are likely to only form in low quantities. In order to verify the mechanistic pathway, a series of control reactions, NMR scale experiments and DFT calculations were envisioned. First, blank reactions were conducted with Al-1, and it appeared that both [PPN]Cl and propylene oxide are required to form the active species, as no PLA (or PPO) could be observed when only one of these components was absent in the reaction mixture. On the basis of the mechanisms proposed by Inoue,20 Chisholm21 and Coates,22 we assumed that the identity of the catalytic species at the end of the activation depends on [PO]/[Al-1]. As the polymerization is performed with an excess of PO, the active species during consumption of the rac-lactide likely consist of an aluminum salen alkoxide and a [PPN]+ alkoxide, which are in equilibrium with a hexacoordinate bis(alkoxide) aluminate species. We hypothesized that these alkoxides are largely responsible for the observed reactivity owing to their high nucleophilicity. The solution structure of several (in situ generated) aluminum-based systems was investigated by 1H and 13C NMR spectroscopy (Figures S4−S55). It is worth noting that NMR scale reaction of Al-1 with excess (R)-PO in chloroform-d was indicative of the formation of a secondary alkoxide species (in combination with two primary alkoxides) with rigid C1 symmetry on the NMR time scale (Figures S11−S21). This is evidenced by the two nonsymmetry-related phenolate rings, as well as the 1H AB spin systems for the diastereotopic CHH methylene hydrogens of the alkoxo group and the two resonances for the imine groups. In these spectra, signals due to the methylene (CH2Cl) protons of the (R) monoalkoxide at δ = 3.23 and 3.16 ppm are cleanly separated from the signal due to the methine (CHMeO) proton at δ = 3.78 ppm. On the basis of prior 13C NMR assignments in chloroform-d,19 we also correlated the most intense resonances at δ = 53.5 and 67.3 ppm respectively to the methylene (CH2Cl) and methine (CHMeO) carbons of the corresponding secondary alkoxide. Upon addition of [PPN]Cl and (R)-PO to a solution of Al-1 in chloroform-d, we observed the characteristic resonances of two different secondary alkoxides and no primary alkoxide was detected (Figures S33−S38). These signals are particularly clear-cut when only 1 equiv of [PPN]Cl and 1 equiv (R)-PO are used in combination with Al-1. Room temperature 1H NMR spectra of this mixture showed a set of

Figure 4. Possible mechanisms in the ring-opening step of lactide. For the aluminate species, the cationic PPN+ moiety has been omitted for clarity.

Figure 5. Schematic representations of complexes A−E.

mechanisms can be involved in polymerization of lactide. A monometallic mechanism (type a) in which a free lactide inserts into a metal-alkoxide bond, can occur.25 Also, monometallic mechanisms (types b and c), in which a free 6220


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Figure 6. Optimized structures of complexes A−E. Hydrogen atoms are omitted for clarity. Yellow Al, blue N, red O, green Cl. Al−O bond distances are in Å.

Figure 7. Calculated lowest energy reaction pathway for the first insertion of LA. Values under bracket correspond to the energy levels calculated for the secondary alkoxide. Black pathway: nucleophilic attack of one carbonyl carbon of LA. Red pathway: nucleophilic attack of the opposite carbonyl carbon.

Figure 9. Schematic representations of intermediates 3, 5, 7, 9, 10 and 11.

(a) and (d), nucleophilic species in the lactide ring-opening step should be a six coordinate aluminate complex (e.g., (salen)Al(OR)2− or (salen)Al(OR)(Cl)− since neutral aluminum alkoxide derivatives are inactive at room temperature (vide supra). To find further evidence of this reaction mechanism, we performed MALDI-TOF mass spectrometry analysis on several PLA samples obtained from the aluminum-based catalytic system, and consistently showed a distribution of peaks corresponding to polymer chains terminated by a chloroalkoxide moiety, resulting from the PO opening (Figure S1). Moreover, each group of peaks showed by the MALDI-TOF analyses were always separated by a mass unit of 72, which indicates that transesterification phenomenon are occurring during the polymerization process.28 These experiments therefore confirmed that the initiating groups proposed in the preactivation mechanism in Figure 3 are found in the final polymers chains.

Figure 8. Optimized structure of aluminum-based intermediate 1. Hydrogen atoms are omitted for clarity. Yellow Al, blue N, red O, green Cl.

nucleophile attacks a lactide bound to the metal center, can be operative. Second, as postulated for the asymmetric ringopening of epoxides,26,27 a bimetallic mechanism (type d) can lead to dual activation of nucleophile and electrophile by two different metal centers: in this pathway, one metal complex activates the monomer for nucleophilic attack by an alkoxide that is delivered from the other metal center. Finally, in mechanisms 6221


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Figure 10. Optimized structures of aluminum-based intermediates 3, 5, 7, 9, 10 and 11. Hydrogen atoms are omitted for clarity. Yellow Al, blue N, red O, green Cl.

To gain further insight into the reaction mechanism, possible reaction pathways were computed using DFT methods. The first and second insertions of lactide were investigated as well as primary and secondary alkoxides with different stereochemistries (Figure S58−S61). Insertion of both lactide enantiomers was considered and it was found that L-LA and D-LA react in the same way with equivalent energies. Only the lowest energy pathways are presented hereafter. The additional calculations are represented in Supporting Information. We performed DFT calculations using the five coordinate aluminum complex (salen)Al(alkoxide) A, and the six coordinate aluminate species (salen)Al(alkoxide)(Cl)− B, (salen)Al(alkoxide)2− C, D and E (Figures 5 and 6). As control experiments, the putative initiations mediated by the secondary alkoxide ligand in C and E were investigated and were found to be less efficient than the one induced by a primary alkoxide group in D (Figure 7, values under bracket indicate the energy levels calculated for the secondary alkoxide in C). We observed that the lowest energy pathway was the one assuming the formation of the bis(alkoxide) complex D. The initiation step can be classically decomposed into three microsteps, namely the nucleophilic attack, the ringopening and a coordination/decoordination step (Figure 7). Interestingly, the coordination of LA to the Al metal center (complex 1, Figure 8) induces the decoordination of the alkoxide ligand, which can therefore act as an external nucleophile as proposed in Figure 4. From the LA-adduct, the nucleophilic addition to LA proceeds via two equivalent pathways depending on which carbonyl carbon is the site of the first alkoxide attack (Figure 7). In Figure 7, the black pathway represents the nucleophilic attack of one carbonyl carbon of LA and the red pathway

Figure 11. Calculated lowest energy reaction pathway for the second insertion of LA.

Considering the activation pathway presented in Figure 4, we were interested in the activity of the isopropoxide-containing complex Al-2 in the described conditions. The latter species was then tested in the benchmark conversion of 100 equiv rac-lactide (Figure 1). The alkoxide functionalized complex Al-2 exhibited a similar reactivity than its chloride counterpart Al-1. Moreover, MALDI-TOF analysis displayed a two overlapping distributions of peaks, one corresponding to chloroalkoxide-terminated chains, similarly to what was observed with the Al-1/[PPN]Cl system, as well as isopropoxide-terminated polymers (Figure S2). The incorporation of the isopropoxide moiety as an end-group indicates that it also acts as an initiating group, and is therefore consistent with the proposed preactivation mechanism which would give rise to the resulting bis(alkoxide) species. 6222


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Figure 12. Optimized TS structures TS(1−2), TS(2−3), TS(1−3), TS(3−4), TS(4−5) and TS(3−5). Hydrogen atoms are omitted for clarity. Yellow Al, blue N, red O, green Cl.

corresponds to the nucleophilic attack of the opposite carbonyl carbon. In both cases, the final product 3 (Figures 9 and 10) displays a LA ring with the nucleophilic alkoxide attached to the carbonyl carbon. This step is both kinetically and thermodynamically favorable. Unlike other complexes,29 the subsequent ring-opening is predicted to occur in two steps where the first one is a low energy isomerization of complex 3 allowing the coordination of the intracyclic oxygen adjacent to the attacked carbonyl carbon (Figures 10 and 12). It should be noted that the direct ring-opening process from 3 was computed and found to occur at much higher energy (30.9 kcal/mol vs 16.7 kcal/mol). This step is both kinetically and thermodynamically favorable. Thereafter, the next insertion starting from complexes 3 or 5 was investigated (Figure 11). The possible decoordination of the nucleophile was studied and found to be thermodynamically unfavorable, indicating that LA coordination is required (formation of complexes 7 and 9, Figures 11 and 12). Starting from 3, the nucleophilic attack can occur kinetically but is strongly thermodynamically disfavored (12.8 kcal/mol) so that this pathway can be ruled out. Therefore, the polymerization can only take place from complex 5. The nucleophilic attack from 5 is kinetically favorable (23.4 kcal/mol) and the ring-opening step from complex 10 (Figure 10) is thermodynamically driving the reaction to form complex 11 (Figure 11). The barrier for the ring-opening is relatively high (25.2 kcal/mol) but has to be compared with the barrier of 30.9 kcal/mol found for the direct ring-opening in the initiation step. Therefore, a similar two-step process for the ring-opening

may also occur in the second insertion step but could not have been considered computationally.

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CONCLUSION In this study, we have disclosed the catalytic activity of an aluminum-salen complex in the ROP of lactide to produce polylactide. The system based on complex Al-1 is of particular interest as it is the very first example of an aluminum-based catalyst active for the ROP of lactide at room temperature. We have shown, with the help of mechanistic studies and the support of DFT calculations that the origin of the unprecedented activity of the aluminum system in lactide ROP is very likely to be caused by the formation of highly active alkoxide species. A detailed DFT study unveiled the mechanisms of initiation and propagation of lactide polymerization. DFT-level calculations are in excellent agreement with experimental results. Moreover, the origin of the experimentally observed activity has been tracked back to the formation of an external nucleophilic alkoxide. Clearly, more experimental and theoretical work is required to get deeper insight into these subtle effects and eventually take profit of these for the design of even more efficient catalyst systems. Efforts directed at the isolation of model compounds similar to those computed are ongoing in our laboratories.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.7b01749. Supporting methods, figures, and tables (PDF) 6223


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AUTHOR INFORMATION

Corresponding Authors

*[email protected] *[email protected] ORCID

Régis M. Gauvin: 0000-0002-4788-4363 Laurent Maron: 0000-0003-2653-8557 Christophe M. Thomas: 0000-0001-8014-4255 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS ENSCP, ANR (grant ANR-10-PDOC-010-01), Fondation Pierre-Gilles de Gennes, and CNRS are thanked for financial support of this work. This work was performed using HPC resources from CALMIP-EOS (grant p0833). We would like to thank Purac for a generous loan of rac-lactide. C.M.T. is grateful to the Institut Universitaire de France (IUF). Financial support from the TGIR-RMN-THC Fr3050 CNRS for conducting the research is gratefully acknowledged.

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DEDICATION Dedicated to Professor Geoffrey W. Coates on the occasion of his 50th birthday.

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Mechanistic Aspects of the Polymerization of Lactide Using a Highly

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