Over the class of the following 24 hebdomads the aim of this undertaking is to ( 1 ) : Synthesize a well defined polymer utilizing a CRP ( Controlled extremist polymerization ) procedure. ( 2 ) Unite it with some of the new techniques that have late been highlighted, which will be described subsequently, in order to sequence specify the ordination of the monomers. ( 3 ) Characterise that we have produced a sequenced defined polymer ( 4 ) Finally, scale up the reaction utilizing high throughput methods
Puting the scene
Before reading the recent literature in this country of chemical science, it would be utile to put the scene by saying what is meant by a polymer which is “ sequence defined ” .
When bring forthing a gay polymer where a individual repetition unit ( known as a monomer ) is present, sequencing within the concatenation is non necessary ( Polymer 1 in Figure 1 ) . When two monomers are present ( i.e. A and B ) there are a assortment of sequence structures the copolymer can follow. The diagram below high spots these:
Copolymers consist of two monomers joined together to do a polymer. How these monomers are structured is the cardinal involvement we have. Polymer 2 in Figure 1 shows a block copolymer. These are synthesised in “ blocks ” and a assortment of different techniques, such as life anionic polymerization and ATRP ( Atom reassign extremist polymerization ) are used to do these polymers in high yields2.
Polymer 3 in Figure 1 demonstrates the sequencing in an alternating copolymer. In this illustration two monomers, A and B are present giving rise to a reiterating A-B-A-B-A… ..etc construction with equal sums of A and B. We will be utilizing the term “ sequence defined ” to province that we want control over the reiterating sequence of the monomer units in a polymer concatenation, in an jumping sequence as demonstrated in Polymer 3 in Figure 1.
A assortment of different methods of bring forthing sequenced defined polymers have been demonstrated in both solid and liquid stages. We start by presenting the construct of solid stage synthesis.
Solid support polymer sequencing
A peptide concatenation in nature is basically a sequenced defined polymer that when synthesised has to run into a grade of truth that is to the point of perfection3. Synthesizing the incorrect peptide concatenation could take an falsely coded Deoxyribonucleic acid construction and therefore lead to a mutation4. Such systems hence use biological enzymes, metal accelerators and a whole scope of biological conditions which are hard to accomplish in a research lab. The most important and still the original innovator to synthesizing reiterating peptide ironss is Robert Merrifield ‘s solid stage synthesis5.
This manner of bring forthing peptide ironss involves the 1 by one fond regard of protected monomers to a polystyrene support. Addition of the first protected amino acid forms a covalent bond between the carboxyl end point and the polystyrene support. Deprotection of the amino end point so allows the 2nd amino acid carboxyl end point to organizing a new covalent bond, and therefore the synthesis of the concatenation continues. Using a polystyrene support incorporating a chlorobenzyl group helps with the synthesis of the first C end point and allows the support to be easy removed from the reaction.
Once the procedure is complete intervention of the peptide with anhydrous hydrofluoric acid ( HF ) cleaves the polymer from the support and removes the Boc protecting groups, giving the peptide. Due to nature of utilizing HF, this is where this synthesis has its chief drawback. However, subsequently altering the Boc protecting groups to Fmoc protecting groups allowed piperidine to take the protecting groups, and TFA ( Trifluoroacetic acid ) to take the peptide from the support which led to an machine-controlled procedure being achived6, 7.
Although originally intended for production of biological peptides many not biological polymers have been synthesised utilizing the same solid support methods8-11. A more comprehensive reappraisal of these is besides highlighted here3, 12, 13. However, our concern of sequenced defined polymers lies in developing a liquid stage reaction.
Liquid stage polymer sequencing
Liquid stage synthesis is the alternate method of sequencing polymer ironss. Basically there are two ways in which polymers can be produced in liquid stage synthesis. Either by a measure growing or a concatenation growing polymerisation14. In a measure growing polymerisation the reaction involves an A2 + B2 type mechanism whereby the monomers A and B have the same functional group at either terminal of the molecule. Chemical reaction of A with B leads to a new polymer, but allows the polymer to go on turning since a responding functional group still remains at either monomer.
These polymers produce a big polydispersity typically about 2, ( polydispersity ( P.D ) , a step of the distribution of molecular weights ) due to polymers responding at different rates and bring forthing varied polymer concatenation lengths. This does non mean adequate control over the reaction, and for that ground concatenation growing polymers have a important advantage over measure growing polymers.
Chain growing polymerization reactions occur by a series of extremist induction, extension and expiration stairss, and let a greater grade of control over molecular weight than measure growing polymerization reactions14. These reactions are frequently referred to as a controlled extremist procedure ( CRP ) . Populating polymerization is a type of concatenation growing polymerization. The difference in the rate of reaction between the induction, extension and expiration stairss in these reactions is big so that few expiration stairss occur. Hence, supplying no expiration steps occur in a reaction, the reaction remains “ populating ” . The rates of these stairss can be illustrated by the undermentioned equation in Figure 3, whereby the rate of induction is rapid, extension occurs after induction until the unreacted monomer is used up, and expiration is really slow – and in the instance of life anionic polymerization, does n’t occur14. This allows control over molecular weight, distribution and besides allows a manner to bring forth block carbon monoxide polymers14.
qi & A ; Ge ; kp & gt ; & gt ; kt
A recent new populating polymerization reaction that will be used is Atom Transfer Radical Polymerisation ( ATRP ) 15. Similar to populating polymerisation2, it allows the formation of a controlled molecular weight C-C anchor, but without the demand for strict remotion of wet. ATRP is a extremist process16, which relies on utilizing a passage metal accelerator, typically Cu, incorporating two oxidization provinces ( CuI and CuII ) that need to be accessible. Fe17, 18 and Ni19, 20 accelerators have besides been proven to work successfully.
The accelerator combined with a suited ligand causes an equilibrium between the turning propagating extremist polymer concatenation and the hibernating species, leting the rate of expiration to be really slow16. This is a much simpler manner to bring forthing narrow molecular weight polymers ( P.D ~ 1.3 ) than traditional methods2, and allows the customisation of one terminal of the polymer utilizing the instigator, whilst go forthing a reactive halide on the opposite terminal for farther reactions15. The mechanism of a typical ATRP reaction is shown below.
A whole scope of popular monomers such as cinnamenes, propenoates and methacrylates19, 22, 23 can be used to bring forth controlled molecular weight polymers. The first illustration of this sort of reaction was the polymerization of cinnamene at 130 & A ; deg ; C, utilizing 1-phenylethylchloride as the instigator, CuCl as the passage metal species and 2,2-bipyridine as the ligand15.
Controling the sequencing in these systems is disputing. The extension stairss use reactive group intermediates which react in a statistical manner1, and are hence difficult to command in a one pot synthesis like ATRP.
“ The manner in which a comonomer can partner off to copolymerize and respond spontaneously depends on the mutual opposition of the dual bond ” 14, 21. “ Electron acceptor monomers with low negatron denseness dual bonds will favor responding with an negatron donating substituent than with their ain extremist ” 21. This can be illustrated by the Q-e categorization, where Q states the monomer responsiveness and e provinces its polarization.
Pairing of two monomers is favoured when their vitamin E values are of high order and opposite signs14, 21. The first reported paper utilizing 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 matching procedure is still non to the full understood, nevertheless three separate mechanisms highlighted below have been proposed25.
Such systems have late become really popular. Lutz and Matyjaszewski21 demonstrated the ability to utilize cinnamene combined with methyl methacrylate as the accepting monomer and a Lewis Acid ( diethylaluminium chloride ) for a assortment of controlled extremist polymerization systems ( CRP ) such as ATRP. Their findings with ATRP as the CRP proved unsuccessful due to the ligands used in ATRP holding side reactions with the Lewis acid. However success with the CRP RAFT ( Reversible addition-fragmentation concatenation transportation ) polymerization was proven, demoing an mean polydispersity of 1.5 bespeaking the reaction was still controlled21.
Polymers with a molecular weight greater than 40,000g mol-1 could non be achieved. Hawker et Al. demonstrated a similar system, but utilizing a 9:1 ratio of cinnamene to maleic anhydride25. This clip 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 usage of a? -hydrido alkoxyamine and a nitroxide was used alternatively by a procedure known as nitroxide medicated polymerization ( Figure 8 ) .
Due to the big surplus of cinnamene after 1.5 hours no noticeable sums of maleic anhydride could be observed. Observation by 1H NMR suggested that the copolymerisation of cinnamene and maleic anhydride had taken topographic point, and that the lone reaction staying was the polymerization of pure cinnamene. This showed that a defined short copolymer concatenation could be produced, connected to a long polystyrene chain25.
More late a method utilizing ATRP to show similar sequencing in ironss has been discovered by Lutz26, 27. The construct once more relies on the usage of the Q-e categorization system ( Table 1 ) where a difference in copolymerisation of select monomers has been used. In this illustration N-substituted maleimides have been reacted at timed intervals with cinnamene ( Figure 9 ) . Using ATRP means that all the polymer ironss are turning at the same rate ( CRP procedure ) , and utilizing two monomers which co-polymerise together instead than homo-polymerise allows the sequencing to be defined27.
Four different N substituted maleimides in 1 mole ratios, combined with 100 tantamount molar ratios of cinnamene led to subdivisions of the polymer being sequenced. The consequences showed that after 10 proceedingss of the reaction, 99 % of the maleimides had reacted whereas merely 10 % of the cinnamene had, exemplifying a clear penchant for copolymerisation.
A narrow polydispersity of 1.2 was obtained excessively, bespeaking that the concluding copolymers had a controlled molecular weight. The concluding samples characterised both by 1H NMR and MALDI at timed intervals throughout the reaction showed similar consequences to those obtained by Hawker25. Data obtained from the early parts of the reaction showed the presence of maleimides, and subsequently informations showed merely styrene nowadays.
Unfortunately neither the 1H NMR nor the MALDI spectrums showed informations that the polymer ironss exhibit individual maleimide cinnamene reiterating units, they merely showed that the sequence distribution was narrow. Therefore for the minute, although the consequences indicated there was a possibility of defined sequencing, it could non be proven on a molecular graduated table. For that affair a procedure such as Robert Merrifield ‘s solid stage synthesis method is still needed5. Here we introduce the subject of click reactions.
Click Chemistry applicable to polymers
Click chemical science as termed by K. Barry Sharpless in 2001 is a comparatively new chemical construct which is used to depict a reaction which meets a set standard of conditions28. Very loosely these conditions are:
The reaction gives really high outputs
If byproducts are generated they can be removed easy, i.e. by filtration
It can be purified easy
It must be able to be performed in simple conditions, and ideally insensitive to H2O and O
A whole scope of reactions fall into these classs and an first-class reappraisal high spots many different reactions considered to be click reactions28, 29. Although click chemical science was originally intended as a tool for organic synthesis for the intents of this debut we will concentrate on two reactions that have late become really popular in the development of sequenced defined polymers. These are viz. the Huisgen 1,3 cycloaddition and the hydrothiolation reaction, besides known as the “ thiol-ene ” click reaction.
Huisgen 1,3 cycloaddition reaction
The Huisgen 1,3 cycloaddition reaction is a comparatively old reaction which has since been rediscovered by K. Barry Sharpless, and is now normally known as the azide/alkyne chink reaction28. It involves the 1,3 cycloaddition between a C-C or C-N ternary bond and an alky/azide to bring forth a 1,2,3 triazole. Importantly, the reaction fulfils all of the basic needs to be a click reaction, uniting high outputs with insensitiveness to environing environments. The reaction altered by Sharpless and his squad from the original30, now frequently incorporates a metal accelerator which are normally CuI salts, and provides the reaction its “ chink ” characteristics.
There are many illustrations of this reaction showing its utility into polymer chemical science, runing from the early work foremost by Frechet and Hawker for the readying of dendrimers32-35 and functionalised additive polymers33, 36. Star shaped polymers37-39, transplant polymers40 and non to advert the legion illustrations of chink reactions which have been used aboard ATRP reactions41.
Following from the usage of integrating click reactions into ATRP, one really recent illustration by Pfeifer and Lutz has highlighted the potencies of utilizing click reactions to bring forth sequence ordered polymer segments42.
A polystyrene support was foremost prepared utilizing ATRP and formed the footing from which the sequencing could take topographic point. In each of the three different illustrations of support used ( see Figure 11 ) two different chink reactions, AB and CD were used. These reactions were viz. the 1,3 cycloaddition azide/alkyne click reaction and the amidification of carboxylic acids with primary amides. Continuing in a selective mode caused an ABCD multifunctional mixture, whereby A reacted with D and B reacted with C. This hence led to the sequence defined polymer highlighted below42.
Repeating the procedure 4 times increased the polymer concatenation length and thereby increased the molecular weight. Pfeifer and Lutz used a combination of GPC, 1H NMR and FT-IR to find the polymer sections. Shown in Figure 12 is their GPC and IR consequences, exemplifying the disappearing of the azide functionality ( ? = 2105cm-1 ) after the click reaction in the IR, and the addition in molecular weight of the polystyrene support upon the fond regard of oligomers in the GPC.
This is the first known illustration utilizing the incorporation of azide/alkyne chink reactions42 which provides a similar agencies to synthesising sequenced defined polymers as first demonstrated by Merrifield5, but with one important difference ; no protecting groups involved. We are hence interested in taking this construct farther.
Sadly, although enormously utile the azide/alkyne click reaction does hold one or two drawbacks. Sodium Azide is toxic ; the reaction is limited by the demand for a metal accelerator, a dissolver is required for the reaction, and it is unable to be controlled by photochemical methods. The alternate to such reactions is the thiol-ene chink reaction.
The thiol-ene chink reaction
The thiol ene reaction is once more another old reaction that has been re invented following the development of the chink concept43. This reaction is perchance less widely used as the old, but provides the all the relevant chink characteristics combined with less toxic starting stuffs and the ability of UV visible radiation which is able to trip the extremist species44. Highlighted below is the thiol-ene extremist reaction.
The huge bulk of these reactions in polymer chemical science have been developed by Hawker and his squad for the synthesis of dendrimers45.
In this illustration, utilizing the thiol east northeast click reaction caused an array of C-S bonds to make a dendritic anchor. The reaction was controlled through the presence of photochemical intitation, and without the demand for a solvent45. Since printing this article similar characteristics following the hardiness of the reaction have been besides been demonstrated by Rissing and Son for the synthesis of mulitifunctional branched organosilanes46, 47.
Recently Hawker has demonstrated these click reactions utilizing controlled polymerization techniques to prove the efficency of the reactions by both photochemical and thermic methods of production48. The thiol-ene photocoupling method was found to bring forth higher outputs, was less sensitive to environing environments and much quicker than the thermic method. The orthoganilty between the thiol-ene reactions and the azide/alkyne click reaction utilizing a “ asymmetric telechelic ” polymer ( shown below ) was besides demonstrated demoing the demand for no protecting groups.
So far the thiol-ene chink reactions have non yet been incorporated into a sequenced defined polymer system affecting an AB monomer and Cadmium monomer, as antecedently demonstrated utilizing the azide/alkyne reaction42. The thiol-ene reaction provides many advantages over the good known azide/alkyne reaction, from solvent-free conditions, to non necessitating a metal accelerator, and to holding a reaction clip to 100 % completion in 15 proceedingss under photochemical conditions48. Based on these set of fortunes, this provides an gap for a new reaction into the subject of sequenced defined polymers.
ATRP and thiol chemical science has been demonstrated before through the usage of a disulphide S-S bond initiator49, 50. The disulphide S-S bond is efficaciously a weak bond in a polymer concatenation, and can under the right conditions be cleaved. Here butyl methacrylate was combined with the intiator, reacted utilizing ATRP, and the S-S bond cleaved to bring forth two individual good 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 utilize to synthesize our thiol ended polymer, shown below in Figure 16.
After bring forthing the well defined polymer which we plan to characterize by 1H NMR and GPC, we will so reiterate a series of jumping thiol-ene ( monomer AB ) and primary amide/carboxylic acid chink reactions ( monomer Cadmium ) to sequence specify the polymer. The addition in molecular weight will be monitored by GPC and the add-on of functionalised groups such as amide bonds, will be characterised by an FT-IR spectrum. We are interested at this phase in reiterating the rhythm twice to bring forth four sequenced defined monomers. If success is achieved the procedure will be repeated utilizing high throughput methods. The diagram in Figure 17 illustrates the construct.
In decision to this debut it has been shown that sequence defined polymers are presently a really of import subject in polymer chemical science. A whole scope of reactions have been highlighted, but many still fail to fit Robert Merrifield ‘s original solid stage support method. The end of developing a successful new method of sequenced defined polymers is rebelliously deriving closer, with constructs such as click reactions and CRP processes, more control over polymer molecular weights, functional groups and now monomer sequencing can be gained. The discovery of developing a one pot synthesis to bring forth sequenced defined polymers in high outputs could now merely be a few stairss off.
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