Designed Synthesis of Polyphosphazene Block Copolymers for Self

Chapter 10

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Designed Synthesis of Polyphosphazene Block Copolymers for Self-Assembly Gabino A. Carriedo, Raquel de la Campa, and Alejandro Presa Soto* Departamento de Química Orgánica e Inorgánica (IUQOEM), Facultad de Química, Universidad de Oviedo, Julián Clavería 8, 33006 Oviedo, Spain *E-mail: [email protected].

This Chapter outlines recent advances on the designed synthesis of polyphosphazene two-block copolymers having a predetermined property specifically located in the phosphazene block. These materials represent a class of versatile polymers able to generate a great variety of different well-defined nanomorphologies by self-assembly in solution and in thin films. Particular focus is placed in the synthesis of linear block copolymers composed by two polyphosphazene chains (PP-b-PP), or hybrid polymers combining one PP chain and polystyrene segment (PP-b-PS). We also survey the effects of crystalline, rigid or chiral PP core-forming blocks on the self-assembly of these macromolecules to show the morphological diversity and structural complexity of the nanostructures generated in thin films or in selective solvents to one of the blocks.

© 2018 American Chemical Society

Introduction: Polyphosphazene Block Copolymers in Self-Assembly Polyphosphazenes (1, 2) (PP) are macromolecules consisting of [N=P(R1,R2)]n repeating units with a pentavalent phosphorus bearing two substituents R (equal or different), and a trivalent nitrogen. The alternating –P=N-P=N- displays no electron delocalization. Because of their unique properties, such as biodegradability (3–7), high fire resistance (8, 9) and elasticity (10–12), that can be easily modified by choosing the appropriate R substituents, they are among the most fascinating class of inorganic (non-carbon based main-chains) polymers and have already found a variety of potential and real applications (1, 2, 13, 14), specially in biomedicine (e.g. bio-stable or bio-erodible materials, drug delivery systems, biomaterials and nanofabrication) (15, 16). Polyphosphazene two block copolymers are an special class of polyphosphazenes that consist of two linear phosphazene chains of different chemical composition linked by a chemical bond [(R1,R2)P=N]n-b-[(R3,R4)P=N]m ([PP-b-PP]). There are also hybrid inorganic-organic polymers having a phosphazene chain joined to a polymeric segment of a different nature, [PP-b-(Polym)]; Polym = non-phosphazenic polymer, such as, for example, a polyolefin. As most block copolymers (BCPs), block copolyphosphazenes have the ability of self-assembly in a variety of different nanostructured architectures. However, and despite the great interest aroused in the last 15 years by the self-assembly of BCPs both in thin films (17–21) or in solvents selective for one of the segments (22–30), block copolyphosphazenes have been scarcely employed in self-assembly studies. Thus, before 2012, the literature registered a sole example of the self-assembly of PP-b-PP, in which Allcock and coworkers reported the formation of spherical micelles by the self-assembly of the amphiphilic block copolymer, [N=P(O(CH2CH2O)2CH3)2]n-b-[N=PPh(O(CH2CH2O)2CH3)]m (15 in Scheme 3), in aqueous media (31). This process was not studied in detail, and no experimental evidence on the nature of the spherical aggregates (i.e. if those aggregates are star-like micelles or hollow vesicles) was given (31). The self-assembly of linear hybrid BCPs having a PP block and other segment of different chemical nature has been also insufficiently explored, and most of the works have been made with PP-b-PS (PS = polystyrene) and PP-b-PEO [PEO = poly(ethylene oxide)]. Thus, H. R. Allcock et al. studied the micellar formation of different PP-b-PS having aqueous soluble PP blocks like [N=P(O(CH2CH2O)2CH3)2]n (MEET, 52 in Figure 6) (32), [N=P(OC6H4-CO2Na)2]n (KPCPP, 53 in Figure 6) (33), or PP blocks having [adamantly/β-Cyclodextrin] complexes linked to phosphorus atoms (54 in Figure 6) (34). In all those examples, the self-assembly produced spherical vesicles in which, presumably, the PS is located at the capsule wall, being the PP water-soluble block at the inner and outer coronas. The same authors also reported the self-aggregation in aqueous media of PP-b-PEO (PP = [N=P(NHCH2CO2Et)2]n (35); or [N=P(OCH2CF3)2]n (36)), and PP-b-poly[(dimethylamino)ethyl methacrylate] with PP = [N=P(OCH2CF3)2]n) (37) generating spherical aggregates (vesicle, star-like micelle, compound micelle, etc.) that were not structurally characterized. More detailed self-assembly studies were recently reported with PP-b-PFS, where PP = [N=P(OCH2CF3)2]n and 212

PFS = poly(ferrocenyl(dimethyl)silane) (46a-d in Scheme 8) (38, 39). In thin films, these materials gave different morphologies as a function of the volume fraction of the PFS block (φPFS). Thus, cylinders (φPFS = 0.40, 46c) or spheres (φPFS = 0.21, 46d) of PFS blocks were observed in the in the matrix formed by [N=P(OCH2CF3)2]n chains (Figure 1) (38). On the other hand, pointed-oval shaped micelles of uniform shape and size were obtained from the self-assembly of PFS54-b-[N=P(OCH2CF3)2]290 (46d in Scheme 8) in propan-2-ol (selective solvent for the [N=P(OCH2CF3)2]n blocks) (39).

Figure 1. Bright field TEM micrographs of drop-cast thin films PFS-b-PP block copolymers 6c and 6d showing cylinders (left image) and spheres (right image). Adapted with permission from ref (38). Copyright 2009, American Chemical Society. Considering their achievable chemical compositions, it is clear that block copolyphosphazenes allow the location of an extensive variety of specific properties (e.g., degree of flexibility, solubility in different solvents, hydrophilicity, etc.) into the PP segments. Therefore, they should be especially useful to investigate the effects of those properties on the nanostructures resulting by their self-organization. However, for those studies, the synthesis of block copolymers with well-defined chemical composition and with narrow polydispersity indexes (PDI < 1.2) is strictly necessary, as well as the fine control of the molecular weights. Unquestionably, it has been the lack of efficient synthetic routes to polyphosphazene block copolymers fulfilling those requirements, the main factor hampering the use of those copolymers in self-assembly. In 2012, our group undertook the systematic study of linear two block copolymers focusing on: (i) the development of new synthetic methodologies leading to well-defined PP-b-PP and PP-b-polystyrene (PP-b-PS) BCP´s; and (ii) the study of the self-assembly of these materials incorporating crystalline, rigid or chiral PP core-forming blocks. In this chapter we will review the synthesis of well defined (in terms of chemical composition, structure, distribution of molecular weights and low polydispersity indexes) phosphazene block copolymers, rationally designed to investigate their self-assembly as conducted by different properties, such as crystallinity, rigidity and chirality.

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Synthesis of Linear Polyphosphazene-b-polyphosphazene Block Copolymers (PP-b-PP) A great variety of polyphosphazenes (more than 700 examples) have been prepared starting from the very important precursor poly(dichloro)phosphazene) [N=PCl2]n (1) by means of the very versatile and efficient macromolecular nucleophilic substitution reaction, that can be carried out sequentially (1, 2, 40) (See Chart 1). The possibilities of this macromolecular substitution for the preparation of homo and random copolymers with very different chemical compositions has been reviewed elsewhere (1, 2, 16).

Chart 1. The precursor Poly(dichloro)phosphazene [N=PCl2]n (1) and the general synthesis to polyphosphazenes, homopolymers and random copolymers, by nucleophilic macromolecular substitution. This route, however, leads to homo and random copolymers which have very high molecular weights and PDIs (PDI ≥ 2). The synthesis of linear two blocks polyphosphazenes with narrow PDI was not possible until 1995 when the living cationic chain–growth condensation polymerization of the phosphoranimine Cl3P=N-SiMe3 (2) promoted by PCl5 at ambient temperature was discovered (Scheme 1) (41), permitting the preparation of living poly(dichloro)phosphazene with controlled molecular weights (It should be noted that living and controlled polymerization are not necessary the same concepts (30).

Scheme 1. Living cationic polymerization of Cl3P=N-SiMe3 (2) promoted by PCl5. 214

According to the accepted mechanism of this reaction, the phosphoranimine Cl3P=N-SiMe3 (2) reacts with two equivalents of PCl5 forming the reactive cationic initiator [Cl3P=N=PCl3][PCl6] ([3]PCl6 in Scheme 2) (41–43). Subsequent condensation reactions between initiator [3]PCl6 and Cl3P=N-SiMe3 (2) with elimination of Cl-SiMe3 yield the poly(dichloro)phosphazene, Cl2P=N-[Cl2P=N](n+1)-PCl3+ [PCl6]- (1[PCl6]), having available and reactive –PCl3+ end-groups (see Propagation Step in Scheme 2).

Scheme 2. Proposed mechanism for the living cationic polymerization of Cl3P=N-SiMe3 (2) in the presence of catalytic amount of PCl5. The living nature of the poly(dichloro)phosphazene (1[PCl6]), provided access to a number of polyphosphazene block copolymers (PP-b-PP). Thus, when a phosphoranimine bearing alkyl or aryl groups on phosphorus is added to (1[PCl6]), it undergoes polymerization from the reactive –PCl3+ end-group forming a block copolymer with a PP chain and a [N=PCl2]n block (sequential living polymerization). The macromolecular substitution of the chlorine atoms in the latter with an appropriate nucleophile [NaOCH2CF3 or NaO(CH2CH2O)2CH3] allows the preparation of a variety of block copolymers (see Scheme 3) (31, 44, 45). Besides Cl3P=N-SiMe3 (2), several other phosphoranimines of the type (X)(R1)(R2)P=N-SiMe3, having alkyl, aryl, alkoxy and halogen substituents on the phosphorus, also undergo living cationic polymerization (see Scheme 4) (46–48), leading to phosphazene homopolymers (25-32) with narrow molecular weight distributions. The reaction, however is not general and not all phosphoranimines give well-defined materials. Moreover, as in the case of the living poly(dichloro)phosphazene (1[PCl6]), the living nature of the resulting homopolymers (25-32), should allow a sequential monomer polymerization with a second phosphoranimine giving PP-b-PP block copolymers. (Scheme 5). 215

Scheme 3. Synthesis of linear polyphosphazene two-block copolymers 14-21 by sequential living polymerization of phosphoranimines followed by a macromolecular substitution.

Scheme 4. Synthesis of polyphosphazene homopolymers 25-32 by living cationic polymerization of phosphoranimines of general formula (X)(R1)(R2)P=N-SiMe3.

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Scheme 5. General synthesis of PP-b-PP block copolymers by sequential monomer addition polymerization of two different phosphoranimines of general formula (X)(R1)(R2)P=N-SiMe3. In spite of its great potential, this general methodology is strongly hampered by several problems. Firstly, with most of the known organo-phosphoranimines (XR2P=N-SiMe3; X = F, Cl or Br; R = alkyl, aryl or alkoxy) the polymerizations are incomplete even after long reaction times (typically from 4 to 7 days), giving low molecular weight (Mn) oligomers and uncontrolled amounts of non-reacted monomers. Furthermore, to date, the optimal reaction conditions (time, temperature, solvent, etc.) have not been well established (41–48). Not surprisingly, therefore, the sequential polymerization of two different phosphoranimines is scarcely practical being limited to the examples in Scheme 4 in which a second phosphoranimine polymerizes only from living blocks of 1[PCl6] giving block copolymers. However, and although Allcock and coworkers suggested that the polymerization of Cl(Me)(Ph)P=N-SiMe3 (33) can be carried out in the presence of living chains of polyphosphazene 27 ([N=P(Me)(Et)]n-P+(Me)(Et)Cl, see Scheme 6), yielding the block copolyphosphazene [N=P(Me)(Et)]n-b-[N=P(Me)(Et)]m (34) (45), this approach to the synthesis of [N=PR1R2]n-b-[N=PR3R4]m BCPs cannot be generalized.

Scheme 6. Sequential living polymerization of phosphoranimine 33 by using active end-groups of polyphosphazene 27 as initiators. The synthesis of BCP 34 is suggested in ref. (45). However, the preparation of PP-b-PP block copolymers by sequential monomer addition of two different phosphoranimines, but using first Cl3P=NSiMe3 (2), and subsequently one the type (X)(R1)(R2)P=N-SiMe3, is potentially a very useful synthetic methodology and, therefore, further improvements are very desirable. Recently, I. Manners and co-workers demonstrated that the two –PCl3+ end-groups of the living poly(dichloro)phosphazene (1[PCl6]) have 217

different activities depending on the chain lengths of the growing polymer, leading to a bi-directional chain growth when monomer Cl3P=N-SiMe3 (2) was added over the living 1[PCl6] (49, 50). Based on these results, in 2012 our group re-investigated (theoretically and experimentally) this sequential phosphoranimine addition using model compounds (51), demonstrating that the addition of the alkyl-phosphoranimine Br(Me)2P=N-SiMe3 (35) over living chains of poly(dichloro)phosphazene, 1[PCl6], led to tri-block copolymers instead of the desired two-block copolyphosphazenes by a bi-directional chain-growth mechanism of the polyphosphazene chains (Figure 2).

Figure 2. Schematic representation of the reaction of phosphoranime 35 (circles) with living chains of poly(dichloro)phosphazene 1[PF6] leading to tri-block copolyphosphazenes by bi-directional chain growth. Computational studies (DFT) on model compounds demonstrated that the nature of the donor nucleophilic phosphoranimines and the electrophilic cationic end–groups of the living polyphosphazenes strongly affect the polymerization reaction. Thus, good electron donor phosphoranimines, such as those XR2P=N-SiMe3 bearing donor alkyl groups (R) on phosphorus and having P-N-Si angles < 180° (i.e. N atoms exhibiting imine character), react better with electron poor cationic end groups such as =N-PCl3+ (i.e., with electron withdrawing groups on the phosphorus). On the other hand, the electron deficient Cl3P=N-SiMe3 (2), having a P-N-Si angle of ca. 180°, did not show an imine-like nucleophilic character. The calculations also showed that the electron richer cationic end group =N-PMe2Cl+ LUMO is not sufficiently exposed to ensure an efficient 218

attack of nucleophiles (see Figure 3), explaining why the phosphoranimines XR2P=N-SiMe3 (R = Alkyl or Aryl; X = Cl or Br) polymerize from living chains of poly(dichloro)phosphazene (i.e. from active =PCl3+ end-groups) and not the other way around (51).

Figure 3. DFT calculations showing P-N-Si angles, HOMOs, and LUMOs of the electrophile initiators [Cl3P=N=PCl3]+ (3) and [Me3P=N=PMe2Cl]+ (36); and the monomeric phosphoranimines Cl3P=N-SiMe3 (2) and ClMe2P=N-SiMe3 (8). Reprinted and adapted with permission from ref (51). Copyright 2012, American Chemical Society. On the other hand, the undesirable bi-directional chain growth could be avoided by using mono end-capped initiators of type [Ph3P=N=PCl3][A] (A = Cl, 37[Cl]; PCl6, 37[PCl6]), with only one active -PCl3+ site to polymerize the phosphoranimine Cl3P=N-SiMe3 (2). These initiators, 37[Cl] and 37[PCl6], lead to poly(dichloro)phosphazene chains with only one active end-group (-PCl3+) able to polymerize a second phosphoranimine (Scheme 7) (51). This synthetic approach opened the access to a variety of pure (i.e. with no impurities of three block copolymers) and well-defined (i.e. controlled molecular weights and narrow polydispersity indexes) polyphosphazene two-block copolymers, PP-b-PP, having the reactive [N=PCl2]n segment, which, after a macromolecular substitution of chlorine atoms by the appropriate nucleophiles, led to phosphazene BCPs having different properties relevant in self-assembly (see Scheme 7). This approach, i.e. using end-capped initiators, was later exploited by I. Teasdale and collaborators 219

to prepare well-defined polyphosphazenes with other architectures different than that of linear di-block copolymers (52, 53). Using this methodology we prepared the synthetically very versatile block copolymer [N=PCl2]n-b-[N=PMePh]m (38) having the amorphous, flexible, and soluble in most common organic solvents [N=PMePh]m block (54–58). The corresponding macromolecular substitution of the [N=PCl2]n block with the appropriately chosen nucleophiles incorporated rigidity, chirality or crystallinity in the final copolymers (see Figure 4) (51, 59). All copolymers were synthesized with different block ratios and the GPC data confirmed the very narrow (PDI < 1.2) and Gaussian-shaped distribution of molecular weights required for self-assembly studies.

Scheme 7. Synthesis of well-defined PP-b-PP by using mono end-capped poly(dichloro)phosphazene synthesized from end-capped initiators 37[Cl] or 37[PCl6], Cl3P=N-SiMe3 (2), and a second chemically different phosphoranimine (X-P(R1)(R2)N-SiMe3). The scheme also illustrates how a two sequential macromolecular substitution in the [N=PCl2]n block may yield polyphosphazene block copolymers where one of the blocks has two different substituents randomly distributed along its chain.

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Figure 4. Synthesis of PP-b-PP combining the amorphous, flexible, and ready soluble in most common organic solvent nature of the [N=PMePh]m, with the crystallinity ([N=P(OCH2CF3)2]n), rigidity ([N=P(R-O2C20H12)]n), and chirality ([N=P(R-O2C12H8)]n) of the other PP block.

The chemical versatility of the polymeric intermediate [N=PCl2]n-b[N=PMePh]m (38) also allowed the synthesis of block copolymers having functional groups randomly distributed along the chiral blocks (60, 61). Both, the nature (FG = 4-oxypyridine (39), morpholine (40) or thiomorpholine (41)) (60), and the proportion (42a-d) of the functional group (61), were conveniently modified to change the properties of the BCPs (Figure 5).

Figure 5. PP-b-PP having randomly substituted functional groups (FG) along the chirality incorporating blocks.

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Synthesis of Linear Block Copolyphosphazenes with a Non-Phosphazenic Segment (PP-b-Polym; Polym = Non-Phosphazenic Polymer) Following different methodologies polyphosphazene chains have been combined with a variety of organic segments, such as poly(dimethylsiloxane) (62, 63), poly(ethylene oxide) (35, 36, 64–66), polystyrene (32–34, 67), poly(dimethylaminoethyl methacrylate) (37), poly(propylene glycol) (68), poly(lactic acid) (69), polycaprolactone (70), poly(trimethylene carbonate) (70), and also with the organometallic block poly(ferrocenysilane) (38). The latter was obtained by promoting the polymerization of Cl3P=N-SiMe3 (2) by a macro-initiator 45, followed by a macromolecular substitution with NaOCH2CF3 (see Scheme 8).

Scheme 8. Synthesis of well-defined polyphosphazene-b-poly(ferrocenylsilane), PP-b-PFS (46a-d). Among all the polyphosphazene-b-Polym BCPs, the polyphosphazene-bpolystyrene BCPs (PP-b-PS) represent a very interesting class of hybrid BCPs combining the functionality of the PP block with the chemical stability and high solubility of the PS block. These PP-b-PS were synthesized (see Scheme 9) by a macromolecular coupling of a phosphoranimine end-functionalized polystyrene (telechelic (PS)n-P(R)2=N-SiMe3, 48 or 49) and an end-capped poly(dichloro)phosphazene (50) (34, 67). The required telechelic polystyrene 48 was synthesized by quenching the anionic polymerization of styrene with 222

Cl-PPh2 followed by a Staundinger reaction with trimethylsilyl azide (Scheme 9) (67). The polymer 49 was similarly prepared by treating the living chains of PS-Li (47) with a protected (chloroalkyl)amine followed by a deprotection step and the reaction of the resulting free –NH2 group with the phosphoranimine Br-P(OCH3CF3)2=N-SiMe3 (22, Scheme 9) (34). By using this synthetic strategy BCPs of general formula [N=PCl2]-b-PS (51) were synthesized.

Scheme 9. Synthetic routes to [N=PCl2]n-b-polystyrene (51), via macromolecular coupling of telechelic (PS)n-P(R)2=N-SiMe3, 48 and 49, with an end-capped poly(dichloro)phosphazene 50. [N=PCl2]n-b-PS (51), after the chlorine macromolecular substitution with the appropriate nucleophiles, yielded PP-b-PS BCPs having PP blocks soluble in water, such as [N=P(O(CH2CH2O)2CH3)2]n (MEET, 52) (32), [N=P(OC6H4-CO2Na)2]n (KPCPP, 53) (33), and PP blocks having [adamantly/β-Cyclodextrin] complexes (34) (54. See Figure 6). The block copolymers 52-54 were isolated in moderately good yields (