Synthesis of polymers with positioned protected selenols

Among the several specialized synthetic routes, which enable sequence-regulation in synthetic polymers, the styrene and maleimide copolymerization via timed monomer additions was selected in this study.¹⁰⁸ This simple kinetically-control polymerization method allows placement of reactive groups at desired positions, which can be virtually anywhere along the growing polymer chains.¹⁷⁵ Recently, it was reported that Nitroxide Mediated Polymerization (NMP) of electron-rich functional styrene derivatives, such as methylstyrene, 4-acetoxystyrene and 4-tert-butoxystyrene, with a non-stoichiometric amount of maleimides allowed likewise the synthesis of copolymers with well-controlled molecular weight distribution and local insertions of maleimides.²⁰⁸ In the present work, the commercially available 4-tert-butoxystyrene monomer (StyOtBu), bearing a protected functionality on the para position of the aromatic ring was selected as electron-rich monomer. The protected alcohol

30 fragment located on this electron-rich monomer offers the opportunity for subsequent polymer backbone post functionalization.²⁰⁸

As acceptor monomer, a N-substituted maleimide bearing a protected selenol moiety was designed in the aim to introduce reactive selenol groups at desired positions within a polymer chain. To avoid interference of selenol in the polymerization process, this functionality was protected with a p-methoxybenzyl fragment (Mob) which is a common protecting group for selenol side group in peptide chemistry.²⁰⁹ N-(2-p-methoxy-benzylselenoethyl) maleimide (MISeMob) was successfully synthesized over four steps (Scheme 9). A common synthetic route for the preparation of maleimide derivatives is the treatment of maleic anhydride with substituted primary amines, leading to maleamic acid, followed by a dehydration step. Thus, the first two steps of this synthesis consisted in the preparation of a compound bearing both a primary amine and the protected selenol fragment.

First, elemental selenium was reduced with hydrazine monohydrate and sodium hydroxide to generate sodium diselenide (Na2Se2), followed by reaction with p-methoxybenzyl chloride.²¹⁰ To introduce the required primary amine, the resulting bis-(p-methoxybenzyl) diselenide was reduced with sodium borohydride (NaBH4) and the released selenolates reacted with 2-bromoethylamine.²¹¹ Then, nucleophilic attack of the primary amine on maleic anhydride lead to the formation of maleamic acid in extremely mild conditions. Dehydration of maleamic acid occurred at high temperature with an excess of sodium acetate in acetic anhydride to induce N-substituted maleimide cyclization.²¹² The purification of the desired maleimide was performed by column chromatography and led to a yellow solid with 32% yield over the last three steps.

Scheme 9. Synthetic route for the preparation of N-(2-p-methoxy-benzylselenoethyl) maleimide (MISeMob).

Sequence-controlled polymerization of 4-tert-butoxystyrene with the N-functionalized maleimide (MISeMob) was then investigated according to a protocol previously described in litterature.²⁰⁸ The commercially available Blocbuilder MA (BB) was used to initiate the

31 polymerization. This initiator is composed of a SG1 nitroxide fragment (N-tert-butyl-N -(1-diethylphosphono-2,2-dimethylpropyl)-N-oxyl, Figure 7), that allows controlled radical polymerization of a broad range of monomers compared to the commonly established TEMPO nitroxide (2,2,6,6-tetramethylpiperidinyl-1-oxy) and its derivatives.²¹³ The sequence-controlled polymerization started with the homopolymerization of StyOtBu at 120°C in anisole with the ratio [StyOtBu: BB] = [100: 1]. The polymerization kinetic was monitored by ¹H NMR spectroscopy. Injections of MISeMob maleimides were performed at different time during the homopolymerization of StyOtBu (Figure 7). One equivalent of MISeMob was added to the polymerization at approximatively 10% of 4-tert-butoxystyrene conversion, and a second addition of 1 equivalent of maleimide was performed at approximately 45%. The copolymerization was stopped in the range of 53% of 4-tert-butoxystyrene monomer conversion. The copolymerization kinetic demonstrated the full and fast incorporation of the functional maleimide units on both sides of the formed polystyrene chains (Figure 8A). For both additions, the conversion of maleimides reached 100% (1 unit of maleimide was added in average in each growing chain), while StyOtBu conversion gained 7% only (7 styrene units were added in average in each growing chain).

Figure 7. NMP sequence-controlled copolymerization of StyOtBu with MISeMob initiated by Blocbuilder MA in anisole with the ratio [BB: StyOtBu: MISeMob : anisole] = [1: 100: 2: 35% vol.] at 120°C.

The resulting copolymer was isolated to afford a linear sequence-controlled prepolymer with positioned MISeMob functionalities (poly(StyOtBu-co-MISeMob)) and was characterized by SEC chromatography in tetrahydrofuran (THF) and ¹H NMR. The SEC analysis evidenced the formation of macromolecules with controlled molecular weights and narrow molecular weight distributions (SEC in THF, Mn, app = 10700, Ð = 1.10), indicating that the insertion of MISeMob did not interfere in the CRP process (Figure 8B). The NMR spectrum confirmed the incorporation of maleimide units in the growing polymer chains.

32 Signals corresponding to the methoxybenzyl group of the functional maleimides could be observed at 7.17, 6.80 and 3.70 ppm (Figure 9). The integral intensities indicated that approximatively 2 maleimides were introduced in average in the polymer chains of DPn ≈ 50.

Figure 8. A) Semilogarithmic plot of monomer conversion vs. time of the sequence-controlled copolymerization. B) SEC trace of the isolated poly(StyOtBu-co-MISeMob).

N-substituted maleimides bearing selenol fragments were successfully incorporated at desired positions along the polymer chain. In fact, the maleimides were introduced in narrow regions and thus the obtained copolymers were not strictly sequence defined. However, both incorporation windows were narrowed down to 7 StyOtBu units in average and thus the obtained copolymers still exhibit a relatively precise chain-to-chain sequence distribution. It should be emphasized that the sequence-controlled polymerization and functionality positioning are limited in precision by the statistical radical growth process. It is reasonable to assume that a minor fraction of poly(StyOtBu-co-MISeMob) chains could contain one or three maleimide units per chain.

Figure 9. ¹H NMR spectrum in CD2Cl2 of the isolated copolymer poly(StyOtBu-co-MISeMob) prepared by NMP sequence-controlled copolymerization.

33 3.1.2. Polymer backbone deprotection

The subsequent step consisted in the deprotection of the tert-butyl groups located on the backbone phenolic units. The tert-butyl moiety is a common acidic-labile protecting group, widely used in peptide chemistry.²¹⁴ First deprotection attempts were conducted in trifluoracetic acid (TFA) in the presence of water and triethylsilane as scavenger. However, evident re-alkylations of released tert-butyl fragment on phenolic units were observed and could not be constantly avoided even in the presence of scavengers. Thus, removal was successfully achieved by hydrolysis with aqueous hydrochloric acid (HCl) in dioxane at high temperature (Scheme 10).²⁰⁸ The deprotection reaction fully occurred and yielded in the formation of a linear poly(4-hydroxystyrene) with positioned protected selenol segments (l-poly(StyOH-co-MISeMob)). The polymer modification reaction was verified by ¹H NMR.

Disappearance of the signals assigned to the tert-butyl resonances at 1.0 - 1.5 ppm confirmed a quantitative deprotection of phenol units while the characteristic peaks corresponding to the Mob-protected selenol group (SeMob) remained unchanged (Figure 10). Moreover, the SEC chromatography in dimethylacetamide (DMAc) confirmed a clean polymer modification reaction, showing the formation of macromolecules with controlled molecular weight and narrow molecular weight distribution (Mn, app = 14700, and Ð = 1.11).

Scheme 10. Tert-butyl groups deprotection reaction achieved by HCl catalysed hydrolysis, resulting in the deprotected linear precursor l-poly(StyOH-co-MISeMob).

It should be pointed out that a shift of the polymer peak to higher elution volume in the SEC chromatogram was expected after removal of the tert-butyl fragments. However, a shift to lower elution volume was noticed, indicating a higher hydrodynamic volume. This observation reflected a potential swelling of the polymer chain due to polymer-solvent interaction via hydrogen-bond interaction in dimethylacetamide.

34 Figure 10. ¹H NMR spectrum in CD3OD of the isolated copolymer l-poly(StyOH-co-MISeMob) after tert-butyl deprotection achieved by HCl catalysed hydrolysis.

3.1.3. Synthesis of cyclic polymers by forming intramolecular diselenide bridge