Chapter 1
Defining the Field of Sequence-Controlled Polymers

Jean-François Lutz

Université de Strasbourg, CNRS, Institut Charles Sadron UPR22, 23 rue du Loess, 67034 Strasbourg Cedex 2, France

1.1 Introduction

This book is fully devoted to an exploding area in fundamental and applied polymer science, namely the synthesis, characterization, and utilization of sequence-controlled polymers (SCPs) [1]. This topic is at the same time very old and very new: old because monomer sequence regulation is a central concept in biology and has therefore been thoroughly studied in biochemistry and biophysics for several decades. Thus, efficient methods are available for the synthesis and characterization of sequence-defined biopolymers such as deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and proteins [2]. In comparison, however, the development of man-made polymers with controlled monomer sequences is a much more recent area of research. As pointed out in early essays and reviews [3-5], very little research efforts have been devoted to that topic until about 10 years ago. However, the subject has recently gained significant academic attention, in particular during the last 5 years. This recent emerging trend is actually what is described in the present book, and all the authors of the following chapters have been actively participating in the development of that new discipline. Yet, it should be clearly stated that the field of SCPs was not started 5 years ago. Studies on monomer sequences began with the development of the first synthetic copolymers and can therefore be tracked back to the early days of polymer science [6, 7]. However, as described in a recent historical summary [8], the subject has been stuck for more than 50 years and was mostly limited to the synthesis of classical copolymers such as statistical, alternating, periodic, and block copolymers. More complex degrees of sequence regulation were regarded by the polymer science community as difficult to achieve or as the preserve of biochemists. This state of mind is exactly what has changed during the last few years, which have witnessed the emergence of a large number of original ideas and concepts for making SCPs [1]. As a consequence, the description of monomer sequences in man-made polymers has started to get outdated in classical textbooks. In particular, many copolymers that have been reported in recent years are difficult to describe using current polymer nomenclature and terminology [9]. In this context, the objective of the present volume is to define, rationalize, and categorize that burgeoning new field of research.

As a key to decode the present volume, the reader should always keep in mind that the field of SCPs is actually a hybrid discipline located at the interface between biology and polymer science, as depicted in Figure 1.1. Biological polymers, such as nucleic acids and proteins, are indeed archetypal examples of macromolecules with perfectly controlled monomer sequences. Thus, one important trend in the field consists in using biological principles to synthesize SCPs. Protein engineering [10] and DNA-templated polymerizations [11] are good examples of strategies following this school of thought (see Chapters 3 and 4 of this volume for details). However, a second important trend in the field of SCPs aims to synthesize non-natural macromolecules that are as structurally defined as biopolymers [4]. In such approaches, man-made chemistry concepts are used to synthesize the polymers. These tools can be classical polymerization approaches such as chain-growth and step-growth polymerizations but also tools that are imported from other areas of chemistry such a solid-phase synthesis and molecular machines [12, 13]. Solid-phase iterative chemistry was first introduced for the chemical synthesis of biopolymers such as proteins [14, 15] and nucleic acids [16, 17]. However, it was later demonstrated that such approaches can also be used for preparing a wide variety of synthetic sequence-defined polymers (see Chapters 5-7 for details), which includes peptide-polymer bio-hybrid structures [18], peptidomimetics such as peptoids [19], as well as fully unnatural macromolecules such as information-containing polymers [20, 21]. Yet, such multistep growth approaches remain overall experimentally demanding as well as time consuming, and consequently more straightforward sequence-controlled polymerization strategies have been also investigated in the past years. For instance, living or pseudo-living chain-growth polymerizations such as carbanionic polymerization, cationic polymerization, and controlled radical polymerization have been extensively studied for monomer sequence regulation (see Chapters 8-11 for details). Original step-growth polymerization concepts have also been recently examined for the preparation of periodic SCPs (see Chapter 12 for details). Furthermore, efficient chemical transformations known as "click" reactions, which have become quite popular in synthetic polymer chemistry during the last decade [22, 23], have also been shown to be useful tools for the preparation and modification of sequence-controlled macromolecules (see Chapter 13).

Figure 1.1 The field of sequence-controlled polymers is at the crossroads between biology (red) and polymer science (blue). One trend in the field consists in importing sequence-defined biopolymers in materials science and nanotechnology applications, whereas the opposite one consists in rendering synthetic macromolecules as structurally defined as natural ones. In that regard, sequence-controlled polymers constitute a new category of macromolecules that fills the gap between evolution-optimized biopolymers and conventional plastics.

This recent progress in the synthesis of SCPs has also raised a large number of new questions and challenges in the broad field of polymer science. Indeed, the emerging domain of SCPs is not restricted to polymer synthesis but also opens up new directions in polymer physics, analytical chemistry, engineering, materials science, and nanotechnology. For instance, the characterization of SCPs requires the development of new analytical approaches [24]. Besides standard polymer analytics such a nuclear magnetic resonance spectroscopy and size-exclusion chromatography, SCPs call for more specific sequencing methods that permit the full characterization of monomer sequences (see Chapter 16). As highlighted in Figure 1.1, engineering aspects will also probably play an increasing role in the field of SCPs in the near future. Indeed, although SCPs are not foreseen to be used as large-scale commodity polymers, the development of automated protocols and combinatorial approaches seem mandatory for facilitating their synthesis and processing. Last but not least, SCPs have already opened up many new opportunities for the design of applied polymer materials. The range of applications of SCPs is particularly broad and includes areas that are as diverse as data storage, catalysis, anti-counterfeiting technologies, information technologies, microelectronics, automotive industry, nanomedicine, and biotechnology (see Chapter 15).

The field of SCPs is therefore an exciting multidisciplinary domain with its own terminology, topics, challenges, and frontiers. In order to guide the readers through this new scientific universe, this chapter provides a succinct general overview about SCPs. In particular, the following sections introduce, in a few words, the main aspects and topics that will be developed in more detail throughout the whole book. At first, some general terms and definitions are briefly presented. Afterward, the different mechanisms, either biological or man-made, that permit the synthesis of SCPs are presented and categorized. Biological sequence-regulated polymerizations that occur in living organisms are briefly described, but the reader is guided to specialized biology textbooks for more detailed information [2]. Man-made approaches are presented more comprehensively and ranked in subcategories. Finally, some general considerations about the sequencing and properties of SCPs are presented at the end of this chapter. Overall, this introductory chapter should serve as a useful starting point for understanding what SCPs are.

1.2 Glossary

As mentioned in the introduction, the field of SCPs is still relatively new and therefore definitions and terminologies are still malleable. However, it is noteworthy that traditional polymer vocabulary is not sufficient for describing the different kinds of SCPs that have been reported in recent years [9]. For instance, only standard copolymers such as block, alternating, random, statistical, and periodic copolymers are described in official IUPAC polymer terminology [25]. This language comes mostly from chain-growth copolymerizations (i.e., reactivity ratios driven copolymerizations) and is limited for describing other situations. Thus, some broader definitions are proposed below. These definitions are not yet official (unless noted) and may still evolve.

Sequence-controlled polymer. A sequence-controlled polymer is a macromolecule in which monomer sequences are controlled to some degree. This control can be absolute but is not necessary. For example, an alternating copolymer prepared by radical chain-growth polymerization is a sequence-controlled polymer, although it is also a nonuniform polymer in which chains have different lengths and slightly different compositions.

Sequence-defined polymer. Syn. sequence-specific polymer, sequence-ordered...