Introduction to sequenced defined polymers

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Over the course of the next 24 weeks the objective of this project is to (1): Synthesise a well defined polymer using a CRP (Controlled radical polymerisation) process. (2) Combine it with some of the new techniques that have recently been highlighted, which will be described later, in order to sequence define the ordering of the monomers. (3) Characterise that we have produced a sequenced defined polymer (4) Finally, scale up the reaction using high throughput methods

Setting the scene

Before reading the recent literature in this area of chemistry, it would be useful to set the scene by stating what is meant by a polymer which is "sequence defined".

When producing a homo polymer where a single repeating unit (known as a monomer) is present, sequencing within the chain is not necessary (Polymer 1 in Figure 1). When two monomers are present (i.e. A and B) there are a variety of sequence structures the copolymer can adopt. The diagram below highlights these:

Copolymers consist of two monomers joined together to make a polymer. How these monomers are structured is the key interest we have. Polymer 2 in Figure 1 shows a block copolymer. These are synthesised in "blocks" and a variety of different techniques, such as living anionic polymerisation and ATRP (Atom transfer radical polymerisation) are used to make these polymers in high yields2. Polymer 3 in Figure 1 demonstrates the sequencing in an alternating copolymer. In this example two monomers, A and B are present giving rise to a repeating A-B-A-B-A.....etc structure with equal amounts of A and B. We will be using the term "sequence defined" to state that we want control over the repeating sequence of the monomer units in a polymer chain, in an alternating sequence as demonstrated in Polymer 3 in Figure 1.

A variety of different methods of producing sequenced defined polymers have been demonstrated in both solid and liquid phases. We start by introducing the concept of solid phase synthesis.

Solid support polymer sequencing

A peptide chain in nature is essentially a sequenced defined polymer that when synthesised has to meet a degree of accuracy that is to the point of perfection3. Synthesising the wrong peptide chain could lead an incorrectly coded DNA structure and hence lead to a mutation4. Such systems therefore use biological enzymes, metal catalysts and a whole range of biological conditions which are difficult to achieve in a laboratory. The most significant and still the original pioneer to synthesising repeating peptide chains is Robert Merrifield's solid phase synthesis5. This way of producing peptide chains involves the one by one attachment of protected monomers to a polystyrene support. Addition of the first protected amino acid forms a covalent bond between the carboxyl terminus and the polystyrene support. Deprotection of the amino terminus then allows the second amino acid carboxyl terminus to forming a new covalent bond, and hence the synthesis of the chain continues. Using a polystyrene support containing a chlorobenzyl group helps with the synthesis of the first C terminus and allows the support to be easily removed from the reaction.

Once the process is complete treatment of the peptide with anhydrous hydrofluoric acid (HF) cleaves the polymer from the support and removes the Boc protecting groups, yielding the peptide. Due to nature of using HF, this is where this synthesis has its main drawback. However, later changing the Boc protecting groups to Fmoc protecting groups allowed piperidine to remove the protecting groups, and TFA (Trifluoroacetic acid) to remove the peptide from the support which led to an automated process being achived6, 7.

Although originally intended for production of biological peptides many non biological polymers have been synthesised using the same solid support methods8-11. A more comprehensive review of these is also highlighted here3, 12, 13. However, our concern of sequenced defined polymers lies in developing a liquid phase reaction.

Liquid phase polymer sequencing

Liquid phase synthesis is the alternative method of sequencing polymer chains. Essentially there are two ways in which polymers can be produced in liquid phase synthesis. Either by a step growth or a chain growth polymerisation14. In a step growth polymerisation the reaction involves an A2 + B2 type mechanism whereby the monomers A and B have the same functional group at either end of the molecule. Reaction of A with B leads to a new polymer, but allows the polymer to continue growing since a reacting functional group still remains at either monomer.

These polymers produce a large polydispersity typically around 2, (polydispersity (P.D), a measure of the distribution of molecular weights) due to polymers reacting at different rates and producing varied polymer chain lengths. This does not signify enough control over the reaction, and for that reason chain growth polymers have a significant advantage over step growth polymers.

Chain growth polymerisation reactions occur by a series of radical initiation, propagation and termination steps, and allow a greater degree of control over molecular weight than step growth polymerisation reactions14. These reactions are often referred to as a controlled radical process (CRP). Living polymerisation is a type of chain growth polymerisation. The difference in the rate of reaction between the initiation, propagation and termination steps in these reactions is large so that few termination steps occur. Hence, providing no termination steps occur in a reaction, the reaction remains "living". The rates of these steps can be illustrated by the following equation in Figure 3, whereby the rate of initiation is rapid, propagation occurs after initiation until the unreacted monomer is used up, and termination is very slow - and in the case of living anionic polymerisation, doesn't occur14. This allows control over molecular weight, distribution and also allows a way to produce block co polymers14.

ki ≥ kp >>kt

A recent new living polymerisation reaction that will be used is Atom Transfer Radical Polymerisation (ATRP)15. Similar to living polymerisation2, it allows the formation of a controlled molecular weight C-C backbone, but without the need for rigorous removal of moisture. ATRP is a radical process16, which relies on using a transition metal catalyst, typically Cu, containing two oxidation states (CuI and CuII) that need to be accessible. Fe17, 18 and Ni19, 20 catalysts have also been proven to work successfully. The catalyst combined with a suitable ligand causes an equilibrium between the growing propagating radical polymer chain and the dormant species, allowing the rate of termination to be very slow16. This is a much simpler way to producing narrow molecular weight polymers (P.D ~ 1.3) than traditional methods2, and allows the customisation of one end of the polymer using the initiator, whilst leaving a reactive halide on the opposite end for further reactions15. The mechanism of a typical ATRP reaction is shown below.

A whole range of popular monomers such as styrenes, acrylates and methacrylates19, 22, 23 can be used to produce controlled molecular weight polymers. The first example of this kind of reaction was the polymerisation of styrene at 130°C, using 1-phenylethylchloride as the initiator, CuCl as the transition metal species and 2,2-bipyridine as the ligand15.

Controlling the sequencing in these systems is challenging. The propagation steps use reactive radical intermediates which react in a statistical manner1, and are therefore hard to control in a one pot synthesis like ATRP.

"The way in which a comonomer can pair to copolymerise and react spontaneously depends on the polarity of the double bond"14, 21. "Electron acceptor monomers with low electron density double bonds will favour reacting with an electron donating substituent than with their own radical"21. This can be illustrated by the Q-e classification, where Q states the monomer reactivity and e states its polarisation.

Pairing of two monomers is favoured when their e values are of high order and opposite signs14, 21. The first reported paper using this was by Hirroka et al. who used a Lewis acid to increase the e value of the polar accepting monomer24. The mechanism of the Lewis acid coupling process is still not fully understood, however three separate mechanisms highlighted below have been proposed25.

Such systems have recently become very popular. Lutz and Matyjaszewski21 demonstrated the ability to use styrene combined with methyl methacrylate as the accepting monomer and a Lewis Acid (diethylaluminium chloride) for a variety of controlled radical polymerisation systems (CRP) such as ATRP. Their findings with ATRP as the CRP proved unsuccessful due to the ligands used in ATRP having side reactions with the Lewis acid. However success with the CRP RAFT (Reversible addition-fragmentation chain transfer) polymerisation was proven, showing an average polydispersity of 1.5 indicating the reaction was still controlled21. Polymers with a molecular weight greater than 40,000g mol-1 could not be achieved. Hawker et al. demonstrated a similar system, but using a 9:1 ratio of styrene to maleic anhydride25. This time molecular weights up to 100,000g/mol were achieved with a polydispersity of 1.3. Neither ATRP nor RAFT CRP techniques worked for this reaction so the use of a ?-hydrido alkoxyamine and a nitroxide was used instead by a process known as nitroxide medicated polymerisation (Figure 8).

Due to the large excess of styrene after 1.5 hours no detectable amounts of maleic anhydride could be observed. Observation by 1H NMR suggested that the copolymerisation of styrene and maleic anhydride had taken place, and that the only reaction remaining was the polymerisation of pure styrene. This showed that a defined short copolymer chain could be produced, connected to a long polystyrene chain25.

More recently a method using ATRP to demonstrate similar sequencing in chains has been discovered by Lutz26, 27. The concept again relies on the use of the Q-e classification system (Table 1) where a difference in copolymerisation of select monomers has been used. In this example N-substituted maleimides have been reacted at timed intervals with styrene (Figure 9). Using ATRP means that all the polymer chains are growing at the same rate (CRP process), and using two monomers which co-polymerise together rather than homo-polymerise allows the sequencing to be defined27.

Four different N substituted maleimides in 1 mole ratios, combined with 100 equivalent molar ratios of styrene led to sections of the polymer being sequenced. The results showed that after 10 minutes of the reaction, 99% of the maleimides had reacted whereas only 10% of the styrene had, illustrating a clear preference for copolymerisation. A narrow polydispersity of 1.2 was obtained too, indicating that the final copolymers had a controlled molecular weight. The final samples characterised both by 1H NMR and MALDI at timed intervals throughout the reaction showed similar results to those obtained by Hawker25. Data obtained from the early parts of the reaction showed the presence of maleimides, and later data showed only styrene present.

Unfortunately neither the 1H NMR nor the MALDI spectrums showed data that the polymer chains exhibit single maleimide styrene repeating units, they only showed that the sequence distribution was narrow. Therefore for the moment, although the results indicated there was a possibility of defined sequencing, it could not be proven on a molecular scale. For that matter a process such as Robert Merrifield's solid phase synthesis method is still needed5. Here we introduce the topic of click reactions.

Click Chemistry applicable to polymers

Click chemistry as termed by K. Barry Sharpless in 2001 is a relatively new chemical concept which is used to describe a reaction which meets a set criteria of conditions28. Very broadly these conditions are:

  • The reaction gives very high yields
  • If by-products are generated they can be removed easily, i.e. by filtration
  • It can be purified easily
  • It must be able to be performed in simple conditions, and ideally insensitive to water and oxygen

A whole range of reactions fall into these categories and an excellent review highlights many different reactions considered to be click reactions28, 29. Although click chemistry was originally intended as a tool for organic synthesis for the purposes of this introduction we will concentrate on two reactions that have recently become very popular in the development of sequenced defined polymers. These are namely the Huisgen 1,3 cycloaddition and the hydrothiolation reaction, also known as the "thiol-ene" click reaction.

Huisgen 1,3 cycloaddition reaction

The Huisgen 1,3 cycloaddition reaction is a relatively old reaction which has since been rediscovered by K. Barry Sharpless, and is now commonly known as the azide/alkyne click reaction28. It involves the 1,3 cycloaddition between a C-C or C-N triple bond and an alky/azide to produce a 1,2,3 triazole. Importantly, the reaction fulfils all of the basic needs to be a click reaction, combining high yields with insensitivity to surrounding environments. The reaction altered by Sharpless and his team from the original30, now often incorporates a metal catalyst which are usually CuI salts, and provides the reaction its "click" features.

There are many examples of this reaction demonstrating its usefulness into polymer chemistry, ranging from the early work first by Frechet and Hawker for the preparation of dendrimers32-35 and functionalised linear polymers33, 36. Star shaped polymers37-39, graft polymers40 and not to mention the numerous examples of click reactions which have been used alongside ATRP reactions41.

Following from the use of incorporating click reactions into ATRP, one very recent example by Pfeifer and Lutz has highlighted the potentials of using click reactions to produce sequence ordered polymer segments42.

A polystyrene support was first prepared using ATRP and formed the basis from which the sequencing could take place. In each of the three different examples of support used (see Figure 11) two different click reactions, AB and CD were used. These reactions were namely the 1,3 cycloaddition azide/alkyne click reaction and the amidification of carboxylic acids with primary amides. Proceeding in a selective manner caused an ABCD multifunctional mixture, whereby A reacted with D and B reacted with C. This therefore led to the sequence defined polymer highlighted below42.

Repeating the process 4 times increased the polymer chain length and thereby increased the molecular weight. Pfeifer and Lutz used a combination of GPC, 1H NMR and FT-IR to determine the polymer segments. Shown in Figure 12 is their GPC and IR results, illustrating the disappearance of the azide functionality (?= 2105cm-1) after the click reaction in the IR, and the increase in molecular weight of the polystyrene support upon the attachment of oligomers in the GPC.

This is the first known example using the incorporation of azide/alkyne click reactions42 which provides a similar means to synthesizing sequenced defined polymers as first demonstrated by Merrifield5, but with one crucial difference; no protecting groups involved. We are therefore interested in taking this concept further.

Sadly, although tremendously useful the azide/alkyne click reaction does have one or two drawbacks. Sodium Azide is toxic; the reaction is limited by the need for a metal catalyst, a solvent is required for the reaction, and it is unable to be controlled by photochemical methods. The alternative to such reactions is the thiol-ene click reaction.

The thiol-ene click reaction

The thiol ene reaction is again another old reaction that has been re invented following the development of the click concept43. This reaction is possibly less widely used as the previous, but provides the all the relevant click features combined with less toxic starting materials and the ability of UV light which is able to activate the radical species44. Highlighted below is the thiol-ene radical reaction.

The vast majority of these reactions in polymer chemistry have been developed by Hawker and his team for the synthesis of dendrimers45.

In this example, using the thiol ene click reaction caused an array of C-S bonds to create a dendritic backbone. The reaction was controlled through the presence of photochemical intitation, and without the need for a solvent45. Since publishing this article similar features following the robustness of the reaction have been also been demonstrated by Rissing and Son for the synthesis of mulitifunctional branched organosilanes46, 47. Recently Hawker has demonstrated these click reactions using controlled polymerisation techniques to test the efficency of the reactions by both photochemical and thermal methods of production48. The thiol-ene photocoupling method was found to produce higher yields, was less sensitive to surrounding environments and much quicker than the thermal method. The orthoganilty between the thiol-ene reactions and the azide/alkyne click reaction using a "asymmetric telechelic" polymer (shown below) was also demonstrated showing the need for no protecting groups.

So far the thiol-ene click reactions have not yet been incorporated into a sequenced defined polymer system involving an AB monomer and CD monomer, as previously demonstrated using the azide/alkyne reaction42. The thiol-ene reaction provides many advantages over the well known azide/alkyne reaction, from solvent-free conditions, to not requiring a metal catalyst, and to having a reaction time to 100% completion in 15 minutes under photochemical conditions48. Based on these set of circumstances, this provides an opening for a new reaction into the topic of sequenced defined polymers.

Our work

ATRP and thiol chemistry has been demonstrated before through the use of a disulphide S-S bond initiator49, 50. The disulphide S-S bond is effectively a weak bond in a polymer chain, and can under the correct conditions be cleaved. Here butyl methacrylate was combined with the intiator, reacted using ATRP, and the S-S bond cleaved to produce two single well defined thiol ended polymers. Upon cleavage the molecular weight of the polymer was halfed, which was monitored by GPC 50. This is the reaction we will use to synthesise our thiol ended polymer, shown below in Figure 16.

After producing the well defined polymer which we plan to characterise by 1H NMR and GPC, we will then repeat a series of alternating thiol-ene (monomer AB) and primary amide/carboxylic acid click reactions (monomer CD) to sequence define the polymer. The increase in molecular weight will be monitored by GPC and the addition of functionalised groups such as amide bonds, will be characterised by an FT-IR spectrum. We are interested at this stage in repeating the cycle twice to produce four sequenced defined monomers. If success is achieved the process will be repeated using high throughput methods. The diagram in Figure 17 illustrates the concept.


In conclusion to this introduction it has been shown that sequence defined polymers are currently a very important topic in polymer chemistry. A whole range of reactions have been highlighted, but many still fail to match Robert Merrifield's original solid phase support method. The goal of developing a successful new method of sequenced defined polymers is defiantly gaining closer, with concepts such as click reactions and CRP processes, more control over polymer molecular weights, functional groups and now monomer sequencing can be gained. The breakthrough of developing a one pot synthesis to produce sequenced defined polymers in high yields could now only be a few steps away.


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