Synthesis and self-assembly of dendritic–linear block copolymers containing poly(mandelic acid) with discrete molecular weights and stereochemical structures

In this work, we present the synthesis of uniform PMAs, where the number of repeat units and their stereochemical arrangement are precisely defined. Utilizing an iterative convergent approach with orthogonally protected dimandelic acid building blocks, we achieved high molecular weight PMAs with the desired number of repeat units, extending up to 144 mandelic acids. Additionally, stereochemically defined poly(l-mandelic acid)s with up to 32 repeat units were successfully synthesized. These uniform PMAs were subsequently coupled with uniform branched poly(ethylene glycol) blocks to create uniform dendritic–linear block copolymers. The self-assembly of these block copolymers in solution was systematically investigated. In solution self-assembly, the synthesized block copolymers showed multiple phases from cylinder to inverse cubic as the molecular weight of PMA increased. In the case of solvent diffusion-evaporation-mediated self-assembly, the block copolymers underwent a phase transition as the rate of water addition decreased.


Introduction
2][3] Traditionally, PMA synthesis via bulk ringopening polymerization of mandelide lacked control over its molecular weight and distribution.High-temperature ROP led to stereocenter epimerization and racemization. 4,5][7][8][9][10] Thermal analyses of linear and cyclic PMAs have indicated high glass transition temperatures (T g = 109 °C) and crystallinity (T m = 180 °C) without compromising degradability. 11These results strongly support PMA as a biodegradable alternative to traditional plastics.[10] In this study, we present the synthesis of PMAs with precisely dened molecular weight and stereochemical structures.This was achieved through an iterative exponential growth process utilizing orthogonally protected dimandelic acid as a building block.Our approach yielded uniform PMAs with up to 144 mandelic repeat units, preventing stereocenter epimerization.We also conducted thermal property and crystallization analyses of isotactic L-PMA.As an application example of PMAs as PS alternatives, we incorporated uniform PMAs with varying molecular weight poly(ethylene glycol) (PEG) segments into the PMA backbone and explored solution self-assembly (Fig. 1).

Synthesis of discrete poly(mandelic acid)s
We synthesized poly(mandelic acid)s with uniform molecular weights (uPMAs) through the iterative convergent pathway, employing dimandelic acid with t-butylsilyl and allyl protecting groups as a building block (MA2 in Scheme 1).The allyl ester group was selected as a protecting group owing to susceptibility of mandelic acid to decomposition via hydrogenolysis.Subsequently, the allyl protecting group was removed through an allyl exchange reaction with piperidine in the presence of Pd(PPh 3 ) 4 .Following orthogonal deprotection of MA2, the carbodiimidemediated coupling of HO-MA2-allyl and TBDMS-MA2-COOH produced the tetramer of MA aer purication (MA4 in Scheme 1).This iterative convergence and purication process led to the generation of oligomeric and polymeric MAs with discrete molecular weights (Scheme 1, upper).High molecular-weight uPMAs were puried using preparative size-exclusion chromatography (prep-SEC), capitalizing on the molecular weight differences between deprotected precursors and coupled products (Fig. S1 and S2 †).Additionally, we synthesized uPMA with the desired molecular weight through cross-convergence between two precursors of different molecular weights (Scheme 1, below).All uPMAs underwent comprehensive characterization through 1 H and 13 C NMR, gel permeation chromatography (GPC), and matrix-assisted laser desorption ionization time-of-ight (MALDI-TOF) mass spectrometry, conrming their monodispersity in molecular weight (Fig. S5, S6, S12, S14-S23 † and 2).Molecular weight values of all uPMAs analyzed by MALDI-TOF and GPC are summarized in Table 1.2][3][4][5] We determined the T g s of PMAs through differential scanning calorimetry (DSC).The measured T g s increased proportionally with the number of repeating units.T g s of MAn (n > 48) reached a plateau at 360 K (Fig. 3A).A Flory-Fox plot of the T g of MA8-MA128 against the 1/M values (Fig. 3B) corroborated that the T g of an innitely long MAn (T g,N = 370.10K) aligns with the literature values for amorphous PMAs. 5

Synthesis of isotactic and syndiotactic mandelic acid
Ring-opening polymerization of mandelide is prone to racemization of ⍺-hydrogen, resulting in stereoirregular PMAs. 12,13To overcome this issue, Buchard and coworkers reported that the ROP of cyclic O-carboxyanhydride (L-manOCA) could produce stereoregular PMAs. 6However, achieving absolute control of the stereochemistry of PMA at the monomer level through conventional ROPs remains challenging.Therefore, we synthesized isotactic and syndiotactic uPMA, with chains containing up to 32 L-mandelic acid (L-MA32).
Employing iterative convergent pathways using isotactic and syndiotactic MA2 as building blocks, we successfully synthesized discrete oligo(mandelic acid)s with dened   and B).L-MA32 showed T g of 87.9 °C at rst heating/freezing cycle, 15 which is higher than that of amorphous MA32 (76.0 °C, Fig. 3A).Conversely, 3mPEG15-b-LMA32 showed a T m of 95.4 °C at rst heating cycle.5][16][17] 3mPEG15-b-LMA32 was dissolved in acetonitrile (1 mg mL −1 ) and heated at 90 °C, followed by a slow cooling and equilibrium at 25 °C without perturbation for 24 h.The resulting solution was   diluted by acetonitrile and analyzed through TEM.9][20] TEM images showed a crystalline structure with the diameter of L n = 34.8nm, L w = 37.5 nm, and L w /L n = 1.08 with various lengths (Fig. 4C and S36 †).

Synthesis of block copolymers and self-assembly
8][29][30] Based on the  Im3m to Pn3m was observed, and the number of pores on the surface of particles reduced (Fig. 6F and I).In the range of 112 to 128 repeating units with acetone and 20% dioxane condition, Im3m phases were observed with particle and chunk formations in TEM and SEM images (Fig. S37 and S38 †).
To reduce the rate of water addition to the polymer solution, 29 we conducted solvent diffusion-evaporation-mediated self-assembly (SDESA) for 3mPEG15-b-MA96, 3mPEG15-b-MA112, and 3mPEG15-b-MA128, using dioxane as the organic solvent.The organic solvent containing the block copolymer (0.5 mg mL −1 ) was placed in a small aluminum basket and located in a vial saturated with water.Aer 24 h, the organic solution became cloudy.Phase transitions were monitored aer dialysis in pure water for 24 h.Comparatively, SDESA of 3mPEG15-b-MA96 exhibited a phase transition from at bilayers to a sponge phase, while 3mPEG15-b-MA112 maintained Im3m symmetry (Fig. 7A and B).In contrast, 3mPEG15-b-MA128 underwent a transition from Im3m to Pn3m phases with angular shapes (Fig. 7C).Calculated from diameter measurements, the polydispersity index (PDI) of each block copolymer in SDESA displayed narrow values (PDI < 1.10, Fig. 7G-I and Table S8 †).

Conclusion
In summary, we successfully synthesized discrete poly(mandelic acid) with up to 144 repeating units and stereospecic discrete oligo(mandelic acid), including 32 repeating units of discrete poly(L-mandelic acid), using an iterative convergent method.Our research demonstrates that the iterative convergent method offers a means to synthesize poly(mandelic acid) with minimal polydispersity and precise control over stereochemistry, leading to the synthesis of isotactic and syndiotactic oligo(mandelic acid)s.Additionally, we synthesized dendriticlinear discrete 3mPEG-b-uPMA block copolymers.Our ndings reveal that an increase in the hydrophobic block chain length, achieved by increasing uPMA repeating units, results in selfassemblies with higher-curvature structures and smaller molecular weights compared to using PS.These results indicate that the morphologies of block copolymers can be nely controlled by adjusting block ratios with an exact number of repeating units, utilizing discrete polymers.

Table 1
Molecular weight analysis of uniform linear PMAs + ) Found ([M + Na] + ) M n a (kDa) M w a (kDa) PDI aa GPC was calibrated with a linear PS standard kit.

Table 2
Molecular weight analysis of 3mPEG15-b-uPMAs a GPC was calibrated with a linear PS standard kit.