Heteroselective Polymerization of rac-Lactide in the Presence of Dialkylgallium Alkoxides: The Effect of Lewis Base on Polymerization Stereoselectivity

Abstract

Well-defined dialkylgallium alkoxides derived from (S)-methyl lactate, (S,S)-[Me2Ga(μ-OCH(Me)CO2Me)]2 (1), and 2-methoxyethanol, [Me2Ga(μ-OCH2CH2OMe)]2 (2), have been used as model complexes for the ring-opening polymerization of lactide. (S,S)-[Me2Ga(μ-OCH(Me)CO2Me)]2 (1) can polymerize rac-lactide in solution in a living manner to give atactic polylactide (PLA). The addition of Lewis base to 1 gives heterotactically enriched polylactide at 40 °C, in CH2Cl2 with 6 equiv of THF (P r = 0.60, P r = probability of heterotactic enchainment) and in THF (P r = 0.68) or in CH2Cl2 with 6 equiv of γ-picoline (P r = 0.78), which reveals that heteroselectivity is strongly related to coordination efficiency of a Lewis base to gallium. The polymerization with 1 at 40 °C is living, as evidenced by the narrow polydispersities that remain essentially constant during the polymerizations. A temperature increase to 70 °C leads to transesterification reactions and to a decrease in heteroselectivity. Despite the latter, heterotacticly enriched PLA can be obtained in the melt at 130 °C. [Me2Ga(μ-OCH2CH2OMe)]2 (2) with achiral alkoxide ligands revealed essentially the same activity and stereoselectivity as 1, indicating a chain-end control mechanism. The application of gallium complexes for the controlled and stereoselective polymerization of rac-lactide and the effect of Lewis base on the stereoselectivity were discussed.

Probing the Effect of Six-Membered N-Heterocyclic Carbene—6-Mes—on the Synthesis, Structure and Reactivity of Me2MOR(NHC) (M = Ga, In) Complexes

“…As we were unable to isolate any stable alkoxide Me2InOR(6-Mes) complex, we focused on the activity of 1 in the ROP of rac-LA. Due to the reactivity of 1 towards CH2Cl2, which led to the almost quantitative and instant formation of [Me2Ga(μ-OCH2CH2OMe)]2 [9,35], no activity of 1 in the ROP of rac-LA in CH2Cl2, at −20 °C was observed. On the other hand, the polymerization of rac-LA with 1 (25:1) in toluene led to essentially full conversion after 12 hours (−20 °C) or 10 minutes (room temperature).…”

Dialkylgallium alkoxides – a tool for facile and stereoselective synthesis of PLA–drug conjugates

“…We have shown that dialkylgallium catalysts [R 2 Ga(m-OR)] 2 , which constitute a rare example of gallium catalysts for the polymerisation of lactide or other cyclic esters, 9 can catalyse the polymerisation of rac-LA to PLA in a controlled and stereoselective manner, 10 leading to a non-cytotoxic PLA. 6 Dialkylgallium alkoxides exhibit unique features with regard to the stereoselective polymerisation of rac-lactide (rac-LA).…”

“…In this case the addition of a Lewis base (LB), such as pyridines or THF, to non-selective [R 2 Ga(m-OR)] 2 complexes resulted in the formation of heteroselective [R 2 Ga(m-OR)] 2 /LB catalytic systems offering tuneable heteroselectivity in the range of 0.5 o P r r 0.85 (P r = probability of racemo linkages in PLA). 10,11 On the other hand, the addition of N-heterocyclic carbenes or organosuperbases to [R 2 GaOR] 2 led to isoselective species, resulting in a facile stereoselectivity switch, 12 …”

“…Noteworthily, a weak Ga-N bond to the fifth coordinate site of gallium was observed for 1-3, while the Ga-N bond distances increased in the order 1 (2.333(4) Å) o 2 (2.359(1) Å) o 3 (2.548(1) Å) with growing steric hindrances on the R and R 0 substituents. As the structures of 1-3 were similar, both in the solid state and solution (see the ESI †), to [Me 2 Ga(m-OCH(Me)CO 2 Me)] 2 which mimics active centres in the ROP of lactide, 10,11 we expected that PLA-drug conjugates could be synthesized due to insertion of lactide into the Ga-O alkoxide group of 1-3, moreover, in a stereoselective fashion. In this case, the weak Ga-N chelate bond, as well as Ga-OQC resulting from the interaction of the growing PLA chain with gallium, 10 should not affect the insertion of lactide into the Ga-O alkoxide bond of 1-3 or any other [Me 2 Ga(b-blocker)] 2 , which is advantageous in comparison with e.g.…”

“…As the structures of 1-3 were similar, both in the solid state and solution (see the ESI †), to [Me 2 Ga(m-OCH(Me)CO 2 Me)] 2 which mimics active centres in the ROP of lactide, 10,11 we expected that PLA-drug conjugates could be synthesized due to insertion of lactide into the Ga-O alkoxide group of 1-3, moreover, in a stereoselective fashion. In this case, the weak Ga-N chelate bond, as well as Ga-OQC resulting from the interaction of the growing PLA chain with gallium, 10 should not affect the insertion of lactide into the Ga-O alkoxide bond of 1-3 or any other [Me 2 Ga(b-blocker)] 2 , which is advantageous in comparison with e.g. analogous aluminium complexes, which form considerably stronger chelate bonds with both Lewis base functionalities of alkoxide ligands or growing PLA chains.…”