Ever since the realization that the most complex functions in Nature are achieved by macromolecules that gain their properties from the sequence of their building blocks, such as DNA and proteins, efforts to achieve the synthesis of sequence-controlled polymers have been made by chemists to replicate such properties.1-5 Mainly using biologically relevant building blocks (such as nucleotides),6 a large body of work is dedicated to the synthesis of biomolecule-mimicking polymers and the respective materials properties (such as DNA origami).7 These elegant approaches to sequence control, such as DNA templating,8-15 suffer from scale and cost issues. This is a considerable drawback when contemplating the use of such methods for the exploration of materials with properties derived from their sequence. Another straightforward and high yielding fashion to obtain sequence-controlled polymers is the use of pre-formed templates that dictate the order of the building blocks.16-21
Stemming from the introduction of reversible-reactivation radical polymerization techniques, these efforts have escalated in the past few decades with the synthesis of complex copolymers such as block, graft, alternating and gradient polymers.22 Achieving truly sequence-controlled polymers is however still intangible as polymerizations only allow the statistical control of the synthesized macromolecule, thus resulting in compositional drift even within the same polymerization mixture. It has been recently shown that in order to accurately control the monomer sequence of a macromolecule synthesized via RAFT polymerization, careful consideration of
the kinetic parameters (i.e., initiation rate, chain transfer rate, propagation rate, etc.)
is necessary,23 as deviation from complete and single monomer insertion results in the previously mentioned compositional drift. One proposed method to overcome this limitation is the extensive purification of small oligomers, as shown by Junkers
et al. who performed single (on average) monomer insertions onto a RAFT chain
transfer agent followed by “recycling size exclusion chromatography (SEC)”, thus allowing the isolation of a monodisperse oligomer. Nevertheless, this approach is scrupulous and low yielding.24 Truly monodisperse sequence-controlled polymers have been produced via step-growth techniques with extensive purification steps,
such as solid-phase peptide synthesis.25 Such monodisperse precision polymers are the result of the addition of one – and only one – repeat unit on the growing chain end and usually involve an iterative addition-activation process.26-41
One-pot methods for the synthesis of sequence-ordered polymers whereby the sequence is defined by cascade orthogonal reactions have been reported, although the most prominent limitation of this method is the demanding synthesis of the starting materials.42-44 Hillmyer et al. reported the synthesis of a truly sequence-ordered
subsequent polymerization afforded a polymer with the functionalities at regular intervals.45,46
Sawamotoet al.have also reported the tandem catalysis of the radical polymerization
of methacrylates and the transesterification of the monomers. In the presence of a metal alkoxide and an alcohol, the ruthenium-catalyzed radical polymerization of primary methacrylates proceeded concurrently with the transesterification of the repeat units, depending on the reaction temperature, the alkoxide species, and the relative concentrations of the reagents. The resulting copolymers exhibited a somewhat regulated sequence attributed to the synchronization of the two processes, thus forming gradient block copolymers.47
Recently, the concept of multi-block copolymers has been extensively studied whereby the production of high molecular weight macromolecules with complex composition relies on the sequential oligomerization of different monomers. This has been achieved by controlled polymerizations such as ring-opening polymerization (ROP),48reversible addition-fragmentation chain transfer (RAFT) polymerization49-52 and transition metal-catalyzed radical polymerizations (such as atom transfer radical polymerization, ATRP).53-61
Another interesting approach towards controlling the sequence of conventional polymers involves polymerization via temporal reactions. This approach allows the
“on/off” switching of a dynamic system, such as polymerizations, and thus permitting greater control and precision.62-65 Typically directed by a stimulus (such as irradiation), the propagating species of the polymerization reaction is reversibly rendered inactive only to be re-activated by a second stimulus. Such a system in ROMP was introduced by Sijbesma et al. whereby a latent ruthenium catalyst was
de-activation process was reported to be slow rendering the system inefficient for sequence-controlled polymerizations.66
An approach of interest involves processes whereby the sequence of the polymer is kinetically regulated and therefore minimal interference is required. These approaches commonly involve chain growth polymerizations and careful selection of the monomers and/or initiators that dictate the preferential cross-polymerization of the building blocks. Although limited by the specificity of the reagents, a few such examples have emerged in living anionic polymerizations,67-69 while an early demonstration of such a method involved oligomerization of styrenic monomers and vinyl ethers via living cationic polymerization.70 In a similar fashion, Russell et al.
observed the different reactivities of styrene and maleic anhydride under nitroxide- mediated polymerization (NMP) conditions, thus allowing the synthesis of block copolymers in a one-pot reaction.71The favorable cross-propagation between the two monomers, which constitute an electron donor-acceptor pair, has been extensively exploited by Lutz et al. for the synthesis of “precision polymers”4 – that is
macromolecules whose structure is more sharply defined than typical (co)polymers (Figure 2.1). By taking advantage of the high reactivity of N-substituted maleimides
towards styrenic monomers during their radical polymerization,72 a series of functionalities have been incorporated into a polystyrene backbone in a sequential manner.73 This strategy has been employed for the synthesis of polymers with a variety of pendent functionalities74-81 as well as to achieve more complex structures (i.e.graft, branch, dendritic polymers).82, 78, 83-85
Figure 2.1.Microstrucures of the polymers and semilogarithmic plots from the copolymerization of maleimide-type monomers and styrene depending on the styrene
conversion.86
Indeed, more recently Lutzet al.have shown the possibility of further controlling the
sequence of the polymer by automated synthetic protocols.87 These kinetic approaches are bridging the gap between selective and precise introduction of reactive functionalities and scalable and readily accessible polymeric materials. However, one fundamental drawback of the use of the styrenic/maleimide pair is the statistical,88, 89 rather than precise monomeric, incorporation of the functional (maleimide) monomer at low conversion regimes of the auxiliary (styrenic) monomer. A solution has been shown to be time-controlled consecutive feeds of the two monomers, however it adds a further layer of complexity to the synthetic approach (Figure 2.1).86
Ring-opening metathesis polymerization (ROMP) is a living polymerization method,90, 91the simplicity and versatility of which has allowed its use in industrial processes.92-94 Undeniably, the ability to synthesize nearly monodisperse polymers and complex architectures relies on the range of powerful catalysts available. These
thermodynamically driven selective bond formation between the explored monomers, such as in the case of dienes and diacrylates.95-103, 12, 104-107 These examples demonstrate the tremendous potential of ROMP in its use towards the synthesis of sequence-defined polymers; however they often suffer from broad molecular weight distributions. It should also be noted that these unique monomer pairs have not been studied in systems where one functional monomer is added in precise locations on the polymer backbone of the auxiliary, in a fashion similar to the styrene-N-substituted maleimide monomer pair.
It has been shown that whileexonorbornenes rapidly undergo ROMP in the presence
of ruthenium-based catalysts, endo norbornenes exhibit far slower polymerization
kinetics attributed primarily to steric interactions between the growing polymer chain and the incoming monomer.108, 109 The two prevailing models (Figure 2.2) suggest that the substituents of endo monomers sterically interact either with the
metallacyclobutane upon metathesis, or with the growing polymer chain upon coordination with the ruthenium atom, thus resulting in the decreased reactivity of
endo norbornenes in ROMP. This has hitherto been perceived as a drawback to
using an endo/exo monomer mixture as the overall polymerization rate decreases
relative to a pure exomonomer feed.110 Nonetheless, based on the kinetic regulation
approach for the synthesis of sequence-controlled polymers, endo norbornenes are
expected to slowly form the polymer backbone and addition of exo norbornene
batches should therefore result in their rapid insertion onto the growing polymer chain.
Figure 2.2.Schematic representation of (A) the steric interaction between the metallacyclobutane and theendonorbornene substituent and (B) the growing polymer chain and theendonorbornene substituent (adapted from the literature108).
Perhaps obvious, the prerequisites in this approach are that endo norbornenes
undergo living polymerization, addition of the exo monomer does not alter the
overall endo reaction rate, and that the difference in the relative reactivity is
significant to allow a short sequence of incorporated exo monomers at a specific
position along the chain. In terms of exploring the material properties of precision polymers, a significant advantage of this system is the homogeneous copolymer backbone, due to the fact that the genericendoandexomonomers are stereoisomers.