Scalable Synthesis of Multivalent Macromonomers for ROMP

Abstract

The polymerization of functional monomers provides direct access to functional polymers without need for postpolymerization modification; however, monomer synthesis can become a bottleneck of this approach. New methods that enable rapid installation of functionality into monomers for living polymerization are valuable. Here, we report the three-step convergent synthesis (two-step longest linear sequence) of a divalent exo-norbornene imide capable of efficient coupling with various nucleophiles and azides to produce diversely functionalized branched macromonomers optimized for ring-opening metathesis polymerization (ROMP). In addition, we describe an efficient iterative procedure for the synthesis of tri-and tetra-valent branched macromonomers. We demonstrate the use of these branched macromonomers for the synthesis of Janus bottlebrush block copolymers as well as for the generation of bottlebrush polymers with up to three conjugated small molecules per repeat unit. This work significantly expands the scalability and diversity of nanostructured macromolecules accessible via ROMP.

Graphical Abstract

Recent years have witnessed major advances in the fields of macromolecular design and synthesis thanks to the interplay between catalysis, organic synthesis, and polymer chemistry.¹ Bottlebrush polymers have garnered particularly extensive interest due to the development of novel methods for their synthesis and to their advantageous properties.² Ring-opening metathesis polymerization (ROMP) of norbornene-based macromonomers (MMs) is a powerful strategy for the synthesis of complex functional bottlebrush polymers with diverse functions and applications.^1b,c,3 Multiple functionalities can be installed into such polymers via copolymerization of different MMs, the combination of MMs with small molecule monomers, or by the use of branched MMs that carry several functional species within a single MM; the latter allows for the syntheses of highly uniform multivalent branched bottlebrush polymers (BBPs).⁴ For example, we have established a first-generation branched norbornene MM precursor (G1, Scheme 1A) that contains two orthogonal functional sites: an alkyne for copper-catalyzed alkyne azide cycloaddition (CuAAC) and a carboxylic acid for carbodiimide coupling, which enables the synthesis of bivalent MMs with two functional domains (e.g., polymers, drug molecules, imaging agents, and ligands).⁵ A six-carbon spacer between the tertiary amide branch point was found to be critical for the ROMP of MMs with bulky groups (e.g., polymers and/or drug molecules) to high conversion. This strategy has provided BBPs and related polymers with applications that span multiple disciplines (e.g., self-assembly, drug delivery, and molecular imaging).^4c,d,6

Scheme 1.

(A) Previous Synthesis of G1;⁸ (B) This work: Synthesis of G2

Though G1 works exceptionally well for ROMP of complex MMs, it suffers three key drawbacks: (1) its synthesis involves a four-step linear sequence that requires multiple chromatographic purifications, which severely limits its scalability, (2) it is a viscous oil that is difficult to handle in neat form, and (3) it can only be conjugated to two functional species. In an effort to translate our BBPs to practical applications that require large quantities of material, an improved route to a G1 equivalent was required. In addition, a facile method to expand the valency of our branched MMs would provide an approach to increasing the loading of functional species, for example, drugs and imaging agents, within BBPs.

Herein, we describe a three-step convergent synthesis (two-step longest linear sequence) that provides a novel norbornene alkyne-branch-COOtBu derivative (G2, Scheme 1B) in 92% yield on the 100 g scale (compared to 43% for the 0.1 g scale synthesis of G1).⁵ G2 differs from G1 by the placement of a single carbonyl group as well as the presence of a tert-butyl ester. The latter makes G2 a readily handled powder rather than a viscous oil. We show that branched MMs prepared from G2 are excellent substrates for BBP synthesis via ROMP. We also introduce an iterative synthesis of G2 derivatives with two and three alkynes, which provides access to novel tri- and tetravalent MMs and BBPs. This work establishes an efficient synthetic route to multivalent norbornene derivatives that significantly advance the scale and diversity of functional polymers that are accessible by ROMP.

The synthesis of G2 (Scheme 1B, see Supporting Information (SI) for detailed procedures) commenced with the preparation of alkyne 1⁷ and carboxylic acid 2⁸ both in 96% yield following literature procedures. Notably, 1 and 2 were isolated as pure compounds following rotary evaporation and liquid–liquid extraction, respectively; no chromatography was needed. Standard carbodiimide-mediated amidation followed by recrystallization or silica gel chromatography gave the desired compound G2 as an easy-to-handle white solid (96% yield from recrystallization, Scheme 1B, inset). Altogether, the route shown in Scheme 1B provided G2 in 92% yield over three steps (compared to 43% typical overall yield and four chromatographic purifications for G1).

To confirm that G2 was suitable for ROMP of demanding MMs, we prepared its polystyrene (PS)-branch-polylactide (PLA) derivative 3 (Figure 1A; see SI for details).^4d,5 ROMP using various ratios of 3 to Grubbs third-generation bis-pyridyl complex (Ru) provided PS-branch-PLA Janus BBPs with variable degrees of polymerization (DP): 10, 20, and 30. In each case, a very high conversion of 3 was achieved, as determined by gel permeation chromatography (GPC, Figure 1B and Table S1). Small-angle X-ray scattering (SAXS) was used to study the bulk morphology of 3 and its corresponding Janus BBPs of varied DP (Figure 1C). Samples were cast from THF solutions and annealed at 145 °C under vacuum for 6 h (see SI). Remarkably, while 3 was disordered, the three Janus BBPs prepared from it displayed a bicontinuous gyroid morphology (domain spacing, d = 13.7, 14.1, and 14.3 nm for DP 10, 20, and 30, respectively). The observation of robust assembly for Janus BBPs derived from a disordered diblock MM (i.e., 3) is consistent with our previous studies,^4d which revealed that preorganization of block copolymers on the side chains of bottlebrush polymers can drive self-assembly at χN values (where χ is the Flory–Huggins interaction parameters and N is the DP) below the threshold for assembly of the analogous linear block copolymer. Notably, in our previous work, we only observed the bicontinuous gyroid morphology for polydime-thylsiloxane-branch-poly(tert-butyl acrylate) Janus BBPs. Though PS- and PLA-based MMs have been mainstays of bottlebrush block copolymer assembly,^5,9 to our knowledge, the results presented here provide the first examples of the bicontinuous gyroid morphology for this composition.

Figure 1.

(A) Structure and graft-through ROMP of PS-branch-PLA MM 3. (B) GPC traces for 3 and Janus bottlebrush copolymers of varied DP. (C). SAXS profiles for 3 and Janus bottlebrush copolymers of varied DP.

Having shown that G2 is a suitable precursor for the synthesis of branched MMs that are applicable in the context of ROMP, we sought to expand its valency beyond two. We surmised that G2 derivatives with greater than one alkyne could be prepared by iterative coupling of 1 onto G2. In the event, G2 was exposed to trifluoroacetic acid (TFA) and the resulting carboxylic acid was coupled to 1 to generate bis-alkyne G2₂ in 79% yield (Scheme 2). Repetition of this sequence provided tris-alkyne G2₃ in 54% yield. Coupling of 3 kDa monoamine-terminated polyethylene glycol (PEG) to parent compound G2 as well as multialkynes G2₂ and G2₃ followed by conjugation of azido-triethylene glycol (TEG-N₃) afforded a set of novel branched MMs: mono-, bis-, and tris-TEG MMs (TEG₁, TEG₂, and TEG₃, respectively; Scheme 3A).

Scheme 2.

Synthesis of Bis- and Tris-Alkynes G2₂ and G2₃

Scheme 3.

(A) Synthesis of TEG_n and chex_n (n = 1, 2, or 3); (B) Schematic for Graft-through ROMP of Multivalent MMs

¹H NMR spectra for TEG_n (where n = 1, 2, or 3) MMs are provided in Figure 2A. The norbornene proton resonance is observed at ~6.25 ppm (Figure 2A, purple box), while resonances for the triazole protons and the methylene protons alpha to the triazole are observed at ~7.80 (Figure 2A, blue box) and ~4.5, respectively (Figure 2A, red box). Integration of these sets of resonances confirms that TEG₁, TEG₂, and TEG₃ possess one, two, and three triazoles, respectively. Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) further supported the proposed structures of TEG_n (Figures S32, S34, and S36). Exposure of 40 equiv of TEG_n to 1 equiv of Ru provided BBPs with ≥90% conversion of TEG_n for all n values (Figure 2B). The GPC trace for TEG₁ was very similar to that of a control polymer with identical side chains prepared from G1 (Figure S42), which supports the notion that G2 is a suitable replacement for G1. Finally, GPC traces of BBPs prepared via ROMP of TEG₃ using varied TEG₃:Ru values from 10 to 50 displayed progressively shorter retention times and high conversions (Figure 2C and Table S2); this data suggest that this MM is an excellent substrate for ROMP.

Figure 2.

(A) ¹H NMR spectra for TEG_n (n = 1, 2, or 3). Integrals of key peaks are provided. CDCl₃; ω/2π = 400 MHz. (B) GPC traces for multivalent bottlebrush polymers prepared from TEG_n with target DP = 40. (C) GPC traces for bottlebrush polymers derived from TEG₃ with various target DP values; *residual TEG_n.

In conclusion, we have demonstrated the scalable synthesis of a norbornene-based MM that contains functional groups for convenient orthogonal conjugation to small molecules and polymers. In addition, MMs containing one, two, or three alkynes were conjugated to azido-tetraethylene glycol; this approach increases the mass fraction of the conjugated species significantly (from 6.1 to 15.5% w/w for TEG). ROMP of these MMs proceeded in very high conversion in all cases. In the future, we expect to exploit the modularity and scalability of this system, as well as the enhanced loading capacity of multivalent MMs, for applications in combination drug delivery, molecular imaging, and self-assembly.