Debromination of ATRP-made Wang soluble polymer supports

Highlights

• ATRP allows synthesis of well-defined soluble polymer supports.

• The terminal bromine atom of ATRP polymers can be quantitatively removed.

• Soluble polystyrene supports are optimal for sequence-controlled oligomer synthesis.

Abstract

This article describes two convenient methods for removing the ω-terminal bromine atom of well-defined soluble polymer supports prepared by atom transfer radical polymerization (ATRP). The targeted soluble supports are linear polystyrene chains that contain an acid-labile p-alkoxybenzyl ester linker (i.e. Wang linker) at their α-chain end. These polymers are synthesized by ATRP using a fluorenylmethoxycarbonyl (Fmoc)-protected amino functional ATRP initiator, namely 3-(Fmoc-amino)propyl 2-bromoisobutyrate. After polymerization and before Wang functionalization, the bromine-atom of the ATRP-made soluble supports was removed. Two different debromination approaches were considered. The first one consists in reducing the terminal alkyl bromide in the presence of a trialkyltin hydride. This method can be applied directly in the ATRP medium at the end of the polymerization or can be performed on a purified polymer sample. The latter conditions were found to be more suitable. It was also observed that the use of tributyltin hydride in the absence of additional radical initiator led to the best results. Indeed, well-defined polymer supports with controlled chain-length, molecular weight distribution and fully dehalogenated chain-ends were obtained. The second dehalogenation approach consisted in removing the terminal bromide by nucleophilic substitution with sodium azide. Afterwards, the formed terminal azide group was reacted with 1-pentyne by copper-catalyzed azide-alkyne 1, 3-dipolar Huisgen cycloaddition. This method was also found to be valid for preparing bromine-free polystyrene supports. After ω-chain-end debromination, Fmoc-deprotection was performed on the α-chain-end and the resulting amine function was reacted with 4-(hydroxymethyl)phenoxyacetic acid. Further esterification of the Wang linker is also possible.

Introduction

Soluble polymer supports are an interesting alternative to traditional crosslinked polymer resins for polymer-supported catalysis and synthesis [1], [2]. Such supports are linear, branched or dendritic macromolecules, to which are covalently attached catalysts or reagents. They can be solubilized in a liquid medium and used for homogeneous chemistry. After reaction, the polymer support is precipitated in a non-solvent, filtered and can be potentially re-used. Thus, this method elegantly combines the efficacy of solution chemistry and the handiness of solid-phase chemistry. As reviewed by Janda and coworkers [1], [2], soluble polymer supports have been widely used in supported catalysis, organic chemistry and iterative oligomer synthesis. In the latter case, they have been successfully used for peptide [3], oligosaccharide [4] and oligonucleotide [5] synthesis [1]. More recently, soluble polymer supports have been used by our group [6] and others [7], [8] to prepare non-natural sequence-defined polymers [9], [10], [11].

Soluble polymer supports can be hydrophilic or solvophilic and can be prepared by a variety of polymerization methods. However, many supports that have been described in the literature exhibit ill-defined molecular structures, i.e. broad molecular distributions and uncontrolled architectures. The current state-of-the-art in polymer synthesis allows undoubtedly preparation of better-defined polymers. For instance, controlled radical polymerization methods such as nitroxide mediated polymerization (NMP) [12], atom transfer radical polymerization (ATRP) [13], [14] and reversible addition–fragmentation chain-transfer (RAFT) [15] polymerization allow synthesis of tailor-made polymers with controlled chain-length, molecular weight distribution, topology [16], [17], [18], [19], microstructure [20], [21], [22], [23], [24] and chain-ends [25]. Janda and coworkers have reported the NMP synthesis of well-defined block and graft soluble supports [26]. Our group has also described the ATRP synthesis of polystyrene soluble supports containing acid-labile Wang [6], [27] and Rink [28] linkers. These polymers are typically prepared using functional ATRP initiators that are eventually modified after polymerization. It was shown that these supports made by ATRP are very useful for peptide synthesis [29], peptide PEGylation [30] and also for the synthesis of non-natural sequence-encoded polymers [6]. However, due to the ATRP mechanism [31], [32], these polystyrene supports possess a bromine atom at the ω-chain-end. In our previous studies [6], [29], this halogen moiety was kept on the support and was not found to promote noticeable side reactions in iterative synthesis. Yet, in some other syntheses, e.g. in iterative approaches involving radical reactions, the presence of a bromine atom might be a source of problems. Thus, the debromination of ATRP-made Wang soluble supports was studied in the present work. In particular, two different routes were studied to remove bromine atoms from the ω-chain-end of the supports. The first approach was inspired by the work of Coessens and Matyjaszewski on polymer dehalogenation using trialkyltin hydride [33]. It was shown in the 1960's by Kuivila and coworkers that organotin hydride lead to the reduction of alkyl halide via a radical mechanism [34], [35], [36]. This reaction is very useful for the debromination of ATRP polymers and was therefore tested in the present work. In the second approach, the bromine atom was removed by nucleophilic substitution with sodium azide [37], [38]. The formed reactive azide function was afterwards quenched by copper-catalyzed azide-alkyne Huisgen cycloaddition [38], [39], [40]. The validity of these two methods was studied on model Wang polystyrene supports. Size exclusion chromatography as well as ¹H and ¹³C NMR were used to characterize the polymers before and after debromination.