Spontaneous zwitterionic copolymerisation: An undervalued and efficacious technique for the synthesis of functional degradable oligomers and polymers

Abstract

The spontaneous zwitterionic copolymerisation (SZWIP) of compatible nucleophilic and electrophilic monomers is a relatively unknown and unexplored method for the synthesis of (predominantly alternating) degradable co- and terpolymers. A wide range of monomers allows for the synthesis of different polymer classes with various functionalities, including poly(aminoester)s, poly(ester amide)s and poly(phosphoester)s. In this review, we discuss this undervalued copolymerisation method and its potential for the facile preparation of functional polymeric systems. In this context, the polymers synthesised to date by SZWIP as well as recent insights into this polymerisation technique are highlighted. Post-polymerisation modifications and applications of polymers obtained by SZWIP are also discussed.

Introduction

The development of biocompatible and biodegradable materials has received a significant amount of attention over the last decades (a Web of Science search on “biodegradable polymer*” in September 2017 revealed almost 1800 articles and 170 reviews published since 2012). In order to be classified as biodegradable, microorganisms need to be able to completely degrade and catabolise the polymer to carbon dioxide and water under natural environmental conditions. Moreover any products generated during the degradation process should not be harmful [1]. The applications of these materials are wide ranging, from packaging materials to drug delivery systems, and each application comes with its own specific requirements for the materials used.

Over the years a broad range of biodegradable polymers has been investigated. Their primary classification is most commonly by their origin; natural, microbial or synthetic polymers [2]. Natural polymers can be divided into polysaccharides, including starch, cellulose and chitosan, and proteins, such as collagen and albumin. Microbial polymers include poly(hydroxyl alkanoate)s and poly(γ-glutamic acid). The largest class of biodegradable polymers are based on synthetic polymers. Polyesters [[3], [4], [5], [6], [7], [8], [9], [10], [11]], including poly(α-hydroxy acid)s [9,10], polylactones [4,11], polyorthoesters [12], polyphosphoesters [13] and polycarbonates [6,[14], [15], [16]], have been given significant attention in literature as a result of their straightforward synthesis and good degradability. Polyanhydrides [17], polyurethanes [18,19], polyphosphazenes [[20], [21], [22]], as well as poly(amino acid)s [[23], [24], [25]] and poly(ester amide)s [3,[26], [27], [28]] are other types of biodegradable synthetic polymers, which have frequently been studied.

Biodegradable polymers can be synthesised both by step-growth polymerisations, such as polyadditions or polycondensations [29,30], and chain growth polymerisations, such as ring-opening polymerisations (ROPs) [31]. Polyadditions and polycondensations generally need higher temperatures and longer reaction times to reach higher molecular weights and the resulting polymers typically have relatively broad molecular weight distributions as a result of the limited control over the reaction [[32], [33], [34], [35]]. Conversely, the ROP strategy allows for good control over the target molecular weight and yields narrower molecular weight distributions. However, ROP is only applicable to certain monomers limiting its use [36]. Chain-growth condensation polymerisation (CGCP) provides an interesting middle ground between the choice of monomers for polycondensation reactions and the control of chain-growth polymerisations. In CGCP reactions the polymer end groups are more reactive than the functional groups of the monomers and hence propagation of an existing polymer chain is preferred over the formation of new small molecular weight species [[32], [33], [34], [35]].

Polyesters are the best-known class of biodegradable polymers and can be synthesised by polycondensation of dicarboxylic acids with diols or transesterification of di-esters with diols, but also by ROP of cyclic esters and radical ROP of spiro-ortho-esters and cyclic ketene acetals [[3], [4], [5], [6], [7], [8], [9], [10], [11]]. Poly(amino acid)s are typically obtained by solid phase peptide synthesis or ROP of N-carboxyanhydrides [[23], [24], [25]]. The polycondensation of dicarboxylic acids with a mixture of diols and diamines yields poly(ester amide)s, as does the ROP of morpholine-2,5-diones [3,[26], [27], [28]]. Polyphosphoesters can be obtained via a variety of routes, for example from phosphodichlorides by polycondensation with bisphenols or polyadditions with epoxides, or by ROP of phospholane oxides [13]. Polyorthoesters are readily synthesised by polyadditions between diols and diketenes, as well as by transesterification of orthoesters with diols [12]. The ROP of cyclic carbonates yields polycarbonates, which can also be obtained by polycondensation of diols with phosgene, as well as radical ROP of spiro-ortho-carbonates [6,[14], [15], [16]]. Polycondensation of dicarboxylic acids yields polyanhydrides [17] and various polyaddition reactions, most commonly those between diisocyanates and diols, furnish polyurethanes [18,19]. Polyphosphazenes are typically obtained by ROP of hexachlorocyclotriphosphazene followed by substitution of the pendant chlorines to introduce other functionalities, or they can be synthesised by cationic polymerisation of trichlorophosphoranimines [[20], [21], [22]].

A lesser-known method to synthesise degradable (co-)polymers is the spontaneous zwitterionic copolymerisation (SZWIP), which takes place by the reaction of nucleophilic and electrophilic monomers through zwitterionic intermediates without the requirement of an initiator or catalyst (Fig. 1). It yields alternating copolymers that are available for further post-polymerisation modifications. The obtained materials are predominantly polyesters, poly(ester amide)s, poly(aminoester)s, poly(phosphoester)s and derivatives thereof, but also some other degradable and non-degradable co-polymers have been synthesised using SZWIP. This review discusses this polymerisation technique from initial discovery in 1971 to recent insights into polymers obtained by SZWIP, as well as post-modification and applications of these polymers. Only polymers that follow the general SZWIP mechanism as described in the next section are discussed in this review. For polymers from zwitterionic monomers [37,38] or polymers made through other zwitterionic mechanisms that require an initiator or catalyst [39,40] the reader is referred to the relevant literature.