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PhD-Dissertation Chapter5.typ
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== Materials and methods<materials-and-methods>=== Chemical sourcing<chemical-sourcing>Materials were purchased from Sigma-Aldrich unless otherwise mentioned.(APMA, 98%), Jeffamine ED-600, poly(ethylene glycol) (PEG) methyl ethermethacrylate (950 g/mol, PEGMA950), 2-Hydroxyethyl methacrylate (HEMA,98%), (CPA), (99%), pyridine (anhydrous, 99%), dichloromethane (DCM,anhydrous, 99%), dioxane (99%), CuBr#sub[2] (99%),1,5,7-triazabicyclo\[4.4.0\]dec-5-ene (TBD, 98%), (EBPA, 97%), (, 99%),1,1,3,3-tetramethylguanidine (TMG, 99%), and azobisisobutyronitrile(AIBN, 99%), were used as received. Glycidyl methacrylate (GMA, 99%),butyl methacrylate (BMA, 99%), 2-ethyhexyl methacrylate (EHMA, 98%),2-methoxyethyl methacrylate (MEMA, 99%), and 2-(methacryloyloxy)ethylmethacrylate (AAEM, 95%) were passed through a column of basic aluminato remove inhibitors. CuBr (99.9%) was purified by stirring in glacialacetic acid. Tris(2-pyridylmethyl)amine (TPMA, 98%), tris2-(dimethylamino)ethyl amine (Me#sub[6]TREN, 98%), cyclopentylmethylether (CPME, 99%), and 2-cyano-2-propyl dodecyl trithiocarbonate (CPDT,97%) was purchased from TCI (Tokyo, Japan) and used as received.Methanol (99%), toluene (99%), dimethylformamide (DMF, 99%), isopropanol(99%), calcium chloride (99%) diethyl ether (anhydrous, 99%),tetrahydrofuran (THF, 99%), HCl (concentrated), reduced iron powder,copper turnings, basic alumina, and neutral alumina were purchased fromThermo Fisher (Waltham, MA) and used as received.
=== Synthesis of polyinitiator and vitrimers containing GMA<synthesis-of-polyinitiator-and-vitrimers-containing-gma>Details of the synthesis of poly(BIEM), linear vitrimers, andbottlebrush vitrimers, and their formulation can be found in Chapter3.2.
=== Representative PEG shielded and control polymer synthesis<representative-peg-shielded-and-control-polymer-synthesis>Poly(GMA_-co-_PEGMA950), poly(AAEM_-co-_PEGMA950), and of all molar ratiosand degree of polymerization (DP) were synthesized by reversibleaddition-fragmentation chain transfer (RAFT) polymerization. Each reactionwas fed 0.01 moles of monomer total. For example, 0.71 g (0.005 mol)GMA, 0.72 g (0.005 mol) MEMA, 0.0559 g CPA (0.2 mmol), 6.6 mg AIBN (0.04mmol) (\[50\]:\[1\]:\[0.2\] \[M\]:\[CTA\]:\[I\], where \[M\]:\[CTA\]defines the DP), 4 mL of 1,4-dioxane, and a stir bar were added to a 20mL scintillation vial. Polymers containing APMA were synthesized in 1:1dioxane:water. The vial was sealed with a rubber septum and the solutionwas purged with N#sub[2] (g) for $tilde.op$20-30 min in an ice bath toprevent solvent and monomer evaporation (PEGMA solutions were bubbled incool water to prevent PEG crystallization). Subsequently, the vial wasplaced in a thermostated aluminum reaction block at 60 °C on top of amagnetic stir/hot plate. The reaction was left to stir overnight,yielding a viscous liquid. The solution was removed from heat andexposed to air to terminate the polymerization. The solution wasprecipitated into cold (-20 °C) ether, the solid washed twice more withcold ether, and dried at 0.01 mbar overnight. Polymers containing APMAwere poured into a small amount of cold ether, shaken, then isopropanolwas added to precipitate the polymer.
=== Copolymer solution preparation<copolymer-solution-preparation>Polymer solutions were initially prepared to be 50 wt% polymer. Forexample, 0.3 g of polymer was dissolved in 0.3 g of solvent, andcrosslinker was added such that the nucleophilic functional group wasequimolar with the total epoxide concentration. To control for theconcentration of crosslinking points in solution, polymers weresubsequently formulated to be 1 M of epoxide in solution. Each samplewas vortexed for 5 sec to ensure complete mixing before proceeding withrheometry or sonication.
For all experiments crosslinked with amines, reactions were conducted ina solvent system of 1:1 BuOH:DMF. Alcohols are known to catalyze thereaction between amines and epoxides through the formation of atrimolecular complex.@ehlers2007 Thiol-crosslinked reactions wereconducted in MeCN with 10 µL of 2 M LiOH as a catalyst, necessary todeprotonate the thiols in order to perform a nucleophilic attack on theepoxide ring.@gadwal2015 Poly(APMA_-co-_MEMA) was first treated withpyridine to deprotonate the pendent amines.
=== Parallel plate rheology<parallel-plate-rheology>Gelation times and storage moduli ($G'$), and tanδ of polymersolutions/gels were determined on a Kinexus Pro parallel plate rheometer(Netzsch, Selb, Bayern, Germany). Measurements were run on a 20 mm platewith a 1 mm gap at 1 % strain and 1 -- 100 rad s#super[-1] frequency sweep. Eachfrequency sweep lasted approximately 5 min, and the entire measurementlasted approximately 15 hr. The gel point was defined using theWinter-Chambon criterion, for which the time of gelation is defined asthe point at which tanδ becomes frequency independent at smallfrequencies.@winter1986@chambon1985@chambon1987 For samples with veryhigh modulus, the elastic modulus was determined using compressiverheology by taking the slope of the stress strain curve of cured gelswith a 4 mm diameter. Rheological experiments were analyzed using IRISRheo-Hub (IRIS Development, Amherst, MA).@poh2022 For samples treatedwith 30 % strain, single frequency measurements were conducted at 1 Hzand 30 % strain for 10 minutes in between each frequency sweep.
=== Time-temperature superposition measurements<time-temperature-superposition-measurements>Time-temperature superposition was conducted by performing frequencysweeps at 30 °C intervals with a DMA 850 (TA Instruments) equipped witha tension clamp. Frequency sweeps were performed at 0.01 % strain with apreload of 0.01 N .
== Limitations<limitations>Thermosetting materials have come far from the crosslinked latex rubbersfirst developed by ancient Mesoamericans, and have transformed the worldalong the way. Polymer chemists have and continue to produce ever moresophisticated ways to prepare narrowly disperse polymers with diversefunctionality enabling the synthesis of more and more exotic polymerarchitecture. Taking advantage of multiple methods of controlled/livingpolymerization enabled the bottom up molecular design of novelmechanosensitive comb polymers, highly crosslinked molecularbottlebrushes, and living hydrogels. While these materials do fill unmetneeds for thermosetting resins and soft biocompatible materials, theystill suffer from several drawbacks. Here I will detail the limitationsof my approaches and how they might be overcome.
=== PEG-shielded polymers require high strain and/or strain rates to induce crosslinking<peg-shielded-polymers-require-high-strain-andor-strain-rates-to-induce-crosslinking>Ultrasound is a convenient method for applying strong shear forces athigh shear rates to polymers in solution on a laboratory scale. However,it is not necessarily a scaleable technique or easily accessible outsideof laboratory environments. More relevant techniques involve parallelplate shear by forcefully spreading liquid on a solid substrate orextrusion of liquids through a narrow opening. To simulate these methodsof straining polymer solutions, solutions pGMA_-co-_PEGMA950 and ethylenediamine were subjected to 30 % shear at 1 Hz on a parallel platerheometer and extruded through a 27 Ga needled. Neither method showedany increase in the rate of gelation. Shear thinning was observed in thepolymer solution, evidenced by a decrease in $G'$ after strain was applied(@fig:pegstrain). At a minimum, 20 kHz ultrasound at 10 %amplitude (50 W) was required to induce gelation of PEG shieldedpolymers. To enable more diverse applications, thermosetting polymersthat are more sensitive to mechanical force should be developed.
#figure(image("Images/C5F1.png", width: 100.0%), placement: bottom, caption: [ PEG shielded polymers are not activated by parallel plate shear. $G'$ evolution over time of pGMA_-co-_PEGMA950 at 1 % and 30 % strain. ])<fig:pegstrain>
=== Steric shielding by PEG is not generalizable to all crosslinking chemistries<steric-shielding-by-peg-is-not-generalizable-to-all-crosslinking-chemistries>Although the PEG shielding groups are easily accessible and installedalongside reactive monomers on polymer backbones, they are not suitablefor shielding all kinds of reactive monomers. Different applicationsdemand different crosslinking chemistry. For example, ethylene diaminecan be replaced with Jeffamines for decorative applications that requirehigh clarity and transparency. Jeffamines are a class of amineterminated poloxamers developed specifically for preparing crosslinkedepoxies, and their structure can be tuned to modulate the properties ofthe final crosslinked material. However, their large polymeric structureprevents them from diffusing to reactive sites flanked by large PEGshielding groups and forming crosslinks (@fig:jeffamineshield).
#figure(image("Images/C5F2.png", width: 100.0%), placement: auto, caption: [ PEG shielding completely prevents gelation with Jeffamine. $G'$ evolution over time of pGMA_-co-_PEGMA950 in the presence of Jeffamine ED-900. ])<fig:jeffamineshield>
Other applications require quicker crosslinking kinetics@zoller2016 orreversible crosslinks.@denissen2015 For such applications, acetoacetoxyfunctional polymers offer an attractive option, forming vinylogousurethane bonds in the presence of primary amines. However, the(acetoacetoxy)ethyl ester is quite large, and most likely significantlyalters chain conformations, lessening the steric effects of pendent PEG.Additionally, the tendency of the acetoacetoxy pendent groups to selfassemble through hydrogen-bonding@schlaad2004 likely preemptively bringsreactive monomers into contact, increasing the apparent rate ofcrosslinking. As such, PEG shielding groups are insufficient to protectacetoacetoxy reactive groups (@fig:aaemshield). To overcome this,more aggressive shielding methods are required.
#figure(image("Images/C5F3.png", width: 100.0%), placement: auto, caption: [ pAAEM_-co-_PEGMA950 rapidly gels in the presence of primary amines. $G'$ evolution over time of pAAEM_-co-_PEGMA950 in in the presence of pAPMA_-co-_MEMA. ])<fig:aaemshield>
=== Grafting-from produces unstable brushes<grafting-from-produces-unstable-brushes>One of the most important properties of thermosetting coatings andadhesives is shelf stability. The formulated resin should remain inertuntil the user desires the material to crosslink. To simplifyapplication, one pot formulations are ideal. To produce highly shieldedacetoacetoxy polymers, I turned to core-shell bottlebrush polymerscomposed of an inner core of crosslinkable AAEM and an outer shell ofrubbery EHMA. These polymers were prepared by the \"grafting from\"method as it enables longer side chain lengths. Initially it wasbelieved that ATRP of AAEM would be impossible due to the 1,3-dicarbonylinterfering with the copper complex. However, some reports have shownthe controlled polymerization of AAEM through traditional ATRP mediatedby CuBr.@mandal2018
To minimize the amount of copper halide required, poly(AAEM) wassynthesized by SARA ATRP with Cu(0) as the reducing agent. This produceda polymer with a bimodal molecular weight distribution with the peak atshorter retention time being roughly double the molecular weight of thepeak at longer retention time (@fig:saraaaem a). It is assumedthat this is due to radical-radical coupling facilitated by chelation ofcoper bringing growing chains into close proximity. #super[1]H NMRclearly showed the presence of the acetoacetoxy group as well as themethacrylate backbone (@fig:saraaaem b). Replacing Cu(0) withFe(0) as the reducing agent produced no polymer. This is to my knowledgethe first SARA ATRP reported of AAEM.
#figure(image("Images/C5F4.png", width: 100.0%), placement: bottom, caption: [ Characterization of pAAEM produced by SARA ATRP. (a) GPC chromatogram of pAAEM. (b) #super[1]H NMR of pAAEM. Spectra recorded at 500 MHz in CDCl#sub[3]. THF used as eluent. ])<fig:saraaaem>
Still, bottlebrush polymers with AAEM and ethylhexyl methacrylatecopolymer sidechains were prepared by the same technique. However, allcopolymers prepared were extremely unstable, often forming insolublegels instantaneously upon precipitation. Only a single sample, pBIEM-_g_-(AAEM-_b_-EHMA), couldbe analyzed by NMR and GPC. GPC of showed a small shoulder at shorterretention times, indicating some amount of radical-radical coupling@fig:aaembrush a). #super[1]H NMR clearly showed the successfulsequential polymerization of AAEM and EHMA from the BIEM backbone(@fig:aaembrush b).
#figure(image("Images/C5F5.png", width: 100.0%), placement: auto, caption: [ Characterization of pBIEM_-g-_(AAEM_-b-_EHMA) prepared by SARA ATRP. (a) GPC chromatogram of pBIEM_-g-_(AAEM_-b-_EHMA). (b) #super[1]H NMR of pBIEM_-g-_(AAEM_-b-_EHMA). Spectra recorded at 500 MHz in CDCl#sub[3]. THF used as eluent. ])<fig:aaembrush>
Bottlebrush polymers prepared by ATRP \"grafting from\" are known toform C--C crosslinks at sidechain ends in the solid phase, even in thepresence of ppm amounts of copper.@nese2011 Removal of copper from AAEMbottlebrushes was very difficult, presumably as a result of chelationbetween brush hairs, with copper being clearly visible even afterpassing through alumina. To make it easier to produce shelf stablebottlebrushes, AAEM was replaced with GMA, and EHMA was replaced withBMA. These bottlebrush polymers were able to be isolated as white solidsafter passing over alumina to remove the copper salts, but still wereonly stable for a few days at -20 °C. A different approach to synthesiswould be required to produce highly shielded, reactive bottlebrushpolymers with a long shelf life.
=== GMA is not suitable for transesterification based vitrimers<gma-is-not-suitable-for-transesterification-based-vitrimers>Crosslinked bottlebrushes with GMA (co)polymer sidechains tend to havesubstantially lower elastic moduli compared to their linearcounterparts. Controlling for total number of crosslinks possible, thissuggests that not all crosslinking sites are being utilized. Ihypothesized that the onset of vitrification during the cure processprevented the full conversion of epoxides by restricting chain mobility.In an attempt to overcome this and improve the elastic modulus of thebottlebrush polymers, I formulated vitrimers by incorporating atransesterification catalyst, TBD. Described in 2011 by Montarnal etal., vitrimers (sometimes referred to as covalent adaptable networks)are crosslinked thermosets with dynamic bonds that flow like glassesabove a certain temperature.@montarnal2011
#figure(image("Images/C5F6.png", width: 100.0%), placement: auto, caption: [ pGMA_-b-_BMA performs well as a reprocessible adhesive. (a) Fragments of crosslinked pGMA_-b-_BMA are melt pressed into a homogeneous solid. (b) An image of a rheometer stage showing that the epoxy adhesive securing sandpaper to the bottom plate has failed, while pGMA_-b-_BMA is still adhering the bottom sandpaper and top plate. ])<fig:gmavitrimer>
TBD is well understood to enable network topology rearrangement aboveits characteristic topology freezing temperature through bond exchangereactions at β-hydroxyl-esters. As a practical test, crosslinkedpGMA_-b-_BMA was broken into pieces and pressed in a mold at 120 °C,reforming into a disk within minutes (@fig:gmavitrimer a).Remarkably, it even outperformed a commercial epoxy glue during parallelplate rheology at 155 °C (@fig:gmavitrimer b). To attempt tomeasure the activation energy of vitrimer flow, I employedtime-temperature superposition measurements using DMA.@meng2022 However,we were unable to cleanly superimpose the elastic modulus data (@fig:tts a) and no such vitrimer flow was recorded by DMA, even attemperatures exceeding 180 °C (@fig:tts b). It remains unclearwhat exactly caused this behavior. Additionally, pGMA, pGMA_-co-_BMA,pBIEM_-g-_GMA, pBIEM_-g-_(GMA_-b-_BMA), pBIEM_-g-_(BMA_-b-_GMA), andpBIEM_-g-_(GMA_-co-_BMA) all failed to superimpose cleanly and showed noability to be reformed by melt pressing. Different dynamic crosslinkingchemistry is required to drive polymeric vitrimers to full conversion.
#figure([#box(image("Images/C5F7a.png", width: 100.0%)) #box(image("Images/C5F7b.png", width: 100.0%))
], placement: auto, caption: [ Time-temperature superposition of pGMA_-b-_BMA. (a) Time-temperature superposition of the elastic modulus of pGMA_-b-_BMA. (b) Time-temperature superposition of the loss factor of pGMA_-b-_BMA. ])<fig:tts>
== Future directions<future-directions>
=== Improving elastic modulus of thermoset bottlebrushes<improving-elastic-modulus-of-thermoset-bottlebrushes>High-performance thermosetting resins are prized for their resistance tocreep, temperature, and solvent, as well as their light weight. Thesesame properties however make reprocessing and recycling impossible.Covalently crosslinked thermosets traditionally do not dissolve insolvent or melt at high temperature, unlike thermoplastics, meaningtheir shape is set at the onset of gelation. Additionally, the onset ofgelation imposes vitrification on thermosetting resins whose $T_(c u r e)< T_g$, hampering further conversion of reactive sites. This isparticularly problematic for bottlebrush polymers, whose large sizeproduces already sluggish motion, making it very difficult to achievefull conversion and maximum modulus. I propose to introduce dynamiccrosslinks to bottlebrush polymers in order to maximize the elasticmodulus of bottlebrush thermosets by facilitating bond exchange throughmelt processing.
#figure(image("Images/C5F8.png", width: 100.0%), placement: auto, caption: [ Proposed route to reactive bottlebrush polymers with labile side chains. ])<fig:bbpscheme>
Though there are many available chemistries used to prepare vitrimers,imine exchange is most commonly used for polymeric vitrimers. Iminecrosslinked polymers can be prepared by reacting aldehyde functionalpolymers in the presence of primary amines. Copolymer vitrimers based on2-(methacryloyloxy)ethyl vanillin, and aldehyde functional monomer, andplasticizing monomers have been demonstrated to undergo dynamic bondexchange.@stouten2023 Additionally, imine exchange requires noadditional catalyst and occurs at lower temperatures. To preparebottlebrush vitrimers in particular the use of styrenic monomers ispreferred, both for their superior hydrolytic stability compared to(meth)acrylic monomers as well as for access to atom transfer nitroxideradical coupling reactions (ATNRC) for facile transformations of chainend halogens (@fig:bbpscheme).@teo2019 4-vinylbenzaldehyde (VBA)is an easily accessible monomer, though not commercially available.There are many reported routes to VBA, but I will relay two that giveVBA in high yield, one by hydrolysis of p-(chloromethyl)styrene followedby oxidation to VBA (@fig:4vba a),@foyer2015 another by Wittigolefination of 4-(diethoxymethyl)benzaldehyde followed by deprotection(@fig:4vba b).@sun2007 RAFT polymerization of VBA has beenreported,@sun2007 but not ATRP.
#figure(image("Images/C5F9.png", width: 100.0%), placement: auto, caption: [ Proposed routes to aldehyde functionalized styrenic monomer for improved reactive bottlebrush polymers. ])<fig:4vba>
=== Mechanosensitive nanocapsule thermosets<mechanosensitive-nanocapsule-thermosets>While the \"grafting from\" method excels at producing bottlebrushpolymers with long side chains, it also produces ill-defined polymers.Residual initiating sites on side chain ends can also cause irreversiblecrosslinking in the solid phase, limiting their shelf life.Additionally, control over the final brush architecture is limited toonly being able to adjust the sequence of the side chains, meaning theends of the brush always presented exposed reactive groups to theenvironment, resulting in rapid crosslinking. Though it was notquantified, the initiation efficiency and monomer conversion for thebottlebrush side chains was likely quite low.@neugebauer2015 It'spossible this could be avoided by an ATRP approach favoring deactivationof the propagating radicals.@xie2018 I propose to use the \"graftingthrough\" technique, by which olefin terminated macromonomers arepolymerized into bottlebrushes, to create a new class ofmechanosensitive \"nanocapsule\" bottlebrush thermosets that are able tocrosslink in response to weak shear forces.
While the \"grafting through\" technique is not able to preparebottlebrushes with side chain lengths matching that of \"graftingfrom,\" it possesses several advantages of its own. Linear macromonomersare able to be easily characterized prior to polymerization intobottlebrush polymers, meaning the length of bottlebrush hairs can beprecisely tuned. Different bottlebrush morphologies (comb, rodlike sidechain, stretched backbone, stretched sidechain) can be preciselyprepared. Bottlebrush block copolymers can be easily prepared bysequential addition of macromonomers. Additionally, bottlebrush polymersprepared this way possess a side chain on every monomer (if onlymacromonomers are polymerized).
#figure(image("Images/C5F10.png", width: 100.0%), placement: auto, caption: [ Mechanosensitive nanocapsule thermosets expose a reactive core in response to shear forces. ])<fig:nanocapsule>
Steric repulsion between side chains of densely grafted bottlebrushpolymers is known to induce significant tension along the polymerbackbone, on the order of nanonewtons,@panyukov2009 the same or higherthan the force required to break C--Cbonds.@grandbois1999@willis-fox2018 These prestrained brushes may beeasier to mechanochemically cleave, exposing the reactive core (@fig:nanocapsule). Indeed, it has been shown that the limiting contourlength for bottlebrush polymers is dramatically shorter than linearpolymers, and bottlebrush polymers approach this limit under sonicationmuch more quickly.@li2016 Other methods of inducing strain, such asparallel plate shear or extrusion, may be able to \"activate\" molecularbrushes with a reactive core more easily, particularly those in thestretched backbone regime or those adsorbed to surfaces, which canexperience up to 100 nN of tension along the backbone. Scission at thehair-backbone junction will also generate unshielded reactive linearpolymers.@peterson2019@peterson2021@noh2021 Further, the propensity forhairs to be released into solution can be tuned by weakening thealkoxyamine C--O bond with highly sterically hindered nitroxides(proposed structure #strong[1]),@pauly2025@jing2014 or by preparingbottlebrush polymers in the stretched side chain regime.
#figure(image("Images/C5F11.png", width: 100.0%), placement: auto, caption: [ Proposed polymerization and chain-end chlorination of amine functional styrenes. ])<fig:polymerchlor>
Complementary amine functionalized bottlebrush crosslinkers should beprepared as well. Amine functional styrenes protected withtrimethylsilane groups have been prepared by living anionicpolymerization.@hirao2002 Carbanion chain ends of polymers prepared byliving anionic polymerization can be easily converted to terminalchlorines for use in ATNRC (@fig:polymerchlor).@satoh2019 It'spossible that protected amine functional styrenes could be directlypolymerized by ATRP, though aryl amines (R = NH#sub[2]) will likelypolymerize slowly if at all by increasing the dissociation energy of thechain end carbon-halogen bond and slowing propagation.@yoshioka2019Choosing a strongly hydrogen bonding solvent may be able to overcomethis by reducing the electron donating ability of the amine throughintermolecular interactions. There are some reports of polymerization ofunprotected 4-(vinylaniline) by ATRP.@rebelo2019 In any case, the aminesshould remain protected until use as they will both deactivate the ROMPcatalyst preventing bottlebrush synthesis@sutthasupa2010 and theunprotected amines are unstable in air.@suzuki1989
Alternative reactive monomers include 4-vinylphenyloxirane,4-vinylphenyl glycidyl ether, 4-vinylphenol, 4-vinylthiophenol,4-(2-mercaptoethyl)styrene, and 4-vinylbenzoic acid.
=== Xanthogen disulfide optimization and hydrogel stereolithography<xanthogen-disulfide-optimization-and-hydrogel-stereolithography>The design and synthesis of chain transfer agents for the RAFT processhas been much studied since the process was first introduced.@keddie2012RAFT agents typically take the form of #strong[2] (@fig:waterxanth). The Z group (in this case O-ethyl) is generallyresponsible for modifying the rate of addition of propagating radicalsand the rate of fragmentation of intermediate radicals in the main RAFTequilibrium. R is generally meant to act as an excellent homolyticleaving group capable of initiating polymerization. I use a symmetricalxanthogen disulfide, meaning modifications to the R groupcan be ignored.
#figure(image("Images/C5F12.png", width: 100.0%), placement: auto, caption: [ Proposed xanthate structures. ])<fig:waterxanth>
Xanthogens (Z = OR$'$) are chiefly used for the polymerization of lessactivated monomers. Xanthates have dramatically lower reactivity towardsradical addition, qualitatively understood by the resonance contributionof the oxygen lone pair to the C=S double bond, meaning more activatedmonomers ((meth)acryloyl monomers) which produce less reactive radicalspecies do contributing to lower transfer constants of the xanthate andpoorer control. However, the C=S double bond can be made more reactiveby lessening the contribution of the oxygen lone pair by installingelectron withdrawing groups attached to the oxygen, lessening thecontribution of the oxygen lone pair on the C=S double bond. Xanthatespossessing the Z groups of #strong[3]@li2018a and#strong[4]@destarac2002 have shown superior control over polymerizationof acrylic monomers, importantly with no change in polymerizationkinetics, and should be explored as xanthogen disulfide photoiniferters.
More pressingly for biomedical applications is the solubility of thechain transfer agent. My chosen xanthate is easy to synthesize, but isnot water soluble, nor are #strong[3] or #strong[4]. Thus, I propose todevelop zwitterionic xanthogen disulfides as photoiniferters. #strong[5]will likely provide excellent control of acryloyl functional monomersand excellent solubility. It should be cautioned however that whileadding electron withdrawing Z (where Z is O--R' and R' is alkyl or aryl)groups to the RAFT agent will improve the control of certain monomers,it will also increase the susceptibility of it to aminolysis andhydrolysis, which will complicate cytocompatible polymerizations inwater.@thomas2004@moad2005 Tertiary alcohols should be avoided such thatZ does not become a good homolytic leaving group.@stenzel2003@coote2003
Additionally, I propose to utilize the dormant xanthogen chain ends tointroduce and pattern hydrogels post polymerization. The 3D networkstructure of synthetic hydrogels nicely mimics the mechanical propertiesof the native cellular environment, but not the chemical properties.Synthetic materials, like PEG, tend to be both chemically inert anddifficult to for cells to adhere to, long noted for their antifoulingproperties.@zhu2010 Hydrogels should be selectively functionalized bystereolithography with RGD adhesion points, as well as selectivelyincreasing or decreasing the modulus of hydrogels. The necessaryN-acryloyl functional oligopeptides are conveniently accessible byprotease catalyzed peptide synthesis,@edson2023 and some work has beendone polymerizing N-acryloyl amino acids.@bentolila2000@li2018