PhD-Dissertation / Chapter5.typ

*#align(center)[#smallcaps[@conclusions-limitations-and-future-directions[Chapter]]]*
= #smallcaps[Conclusions, limitations, and future directions]
<conclusions-limitations-and-future-directions>
== Conclusions
<conclusions>
This dissertation has presented novel methods to design mechanosensitive
graft polymers, highly crosslinked bottlebrush polymers, and living
hydrogels. Utilizing shielding PEG chains to provide a steric barrier to
an otherwise efficient crosslinking reaction between amines or thiols
and epoxides, I was able to produce mechanosensitive polymers that
undergo a sol-gel transition in response to ultrasound. This approach to
creating strain sensitive materials provides a facile route to creating
strain responsive materials using commercially available monomers and
simple techniques. I demonstrated, for the first time, a sol-gel
transition accelerated under force using shielded reactive polymers. I
synthesized novel thermosetting bottlebrush polymers containing both
reactive glycidyl groups and rubbery butyl methacrylate. By adjusting
polymer architecture I was able to suppress intermolecular crosslinks
and increase the toughness of highly crosslinked bottlebrush polymers.
In doing so I demonstrated a method for creating very high molecular
weight thermosetting polymers with high toughness and modulus.
Additionally, I demonstrated bis(xan)-mediated PI polymerizations to be
tolerant to oxygen and produce telechelic polymers. Xanthate-capped
hydrophilic polymers were shown to crosslink in the presence of a
tri-functional crosslinker in $tilde.op$1.5 min. This approach provides
a facile route to quick hydrogel fabrication using light in the visible
spectrum, at physiological temperature, in air and water, and without
radical initiators and their decomposition products. In all cases,
careful design of initiator structure and polymer architecture enabled
the production of novel materials. I foresee that this work will enable
the development of new high performance coatings, adhesives, and
biocompatible materials.

== 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 ether
methacrylate (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)ethyl
methacrylate (AAEM, 95%) were passed through a column of basic alumina
to remove inhibitors. CuBr (99.9%) was purified by stirring in glacial
acetic acid. Tris(2-pyridylmethyl)amine (TPMA, 98%), tris
2-(dimethylamino)ethyl amine (Me#sub[6]TREN, 98%), cyclopentylmethyl
ether (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 from
Thermo 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, and
bottlebrush vitrimers, and their formulation can be found in Chapter
3.2.

=== 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 ratios
and degree of polymerization (DP) were synthesized by reversible
addition-fragmentation chain transfer (RAFT) polymerization. Each reaction
was 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 (0.04
mmol) (\[50\]:\[1\]:\[0.2\] \[M\]:\[CTA\]:\[I\], where \[M\]:\[CTA\]
defines the DP), 4 mL of 1,4-dioxane, and a stir bar were added to a 20
mL scintillation vial. Polymers containing APMA were synthesized in 1:1
dioxane:water. The vial was sealed with a rubber septum and the solution
was purged with N#sub[2] (g) for $tilde.op$20-30 min in an ice bath to
prevent solvent and monomer evaporation (PEGMA solutions were bubbled in
cool water to prevent PEG crystallization). Subsequently, the vial was
placed in a thermostated aluminum reaction block at 60 °C on top of a
magnetic stir/hot plate. The reaction was left to stir overnight,
yielding a viscous liquid. The solution was removed from heat and
exposed to air to terminate the polymerization. The solution was
precipitated into cold (-20 °C) ether, the solid washed twice more with
cold ether, and dried at 0.01 mbar overnight. Polymers containing APMA
were poured into a small amount of cold ether, shaken, then isopropanol
was added to precipitate the polymer.

=== Copolymer solution preparation
<copolymer-solution-preparation>
Polymer solutions were initially prepared to be 50 wt% polymer. For
example, 0.3 g of polymer was dissolved in 0.3 g of solvent, and
crosslinker was added such that the nucleophilic functional group was
equimolar with the total epoxide concentration. To control for the
concentration of crosslinking points in solution, polymers were
subsequently formulated to be 1 M of epoxide in solution. Each sample
was vortexed for 5 sec to ensure complete mixing before proceeding with
rheometry or sonication.

For all experiments crosslinked with amines, reactions were conducted in
a solvent system of 1:1 BuOH:DMF. Alcohols are known to catalyze the
reaction between amines and epoxides through the formation of a
trimolecular complex.@ehlers2007 Thiol-crosslinked reactions were
conducted in MeCN with 10 µL of 2 M LiOH as a catalyst, necessary to
deprotonate the thiols in order to perform a nucleophilic attack on the
epoxide ring.@gadwal2015 Poly(APMA_-co-_MEMA) was first treated with
pyridine to deprotonate the pendent amines.

=== Parallel plate rheology
<parallel-plate-rheology>
Gelation times and storage moduli ($G'$), and tanδ of polymer
solutions/gels were determined on a Kinexus Pro parallel plate rheometer
(Netzsch, Selb, Bayern, Germany). Measurements were run on a 20 mm plate
with a 1 mm gap at 1 % strain and 1 -- 100 rad s#super[-1] frequency sweep. Each
frequency sweep lasted approximately 5 min, and the entire measurement
lasted approximately 15 hr. The gel point was defined using the
Winter-Chambon criterion, for which the time of gelation is defined as
the point at which tanδ becomes frequency independent at small
frequencies.@winter1986@chambon1985@chambon1987 For samples with very
high modulus, the elastic modulus was determined using compressive
rheology by taking the slope of the stress strain curve of cured gels
with a 4 mm diameter. Rheological experiments were analyzed using IRIS
Rheo-Hub (IRIS Development, Amherst, MA).@poh2022 For samples treated
with 30 % strain, single frequency measurements were conducted at 1 Hz
and 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 frequency
sweeps at 30 °C intervals with a DMA 850 (TA Instruments) equipped with
a tension clamp. Frequency sweeps were performed at 0.01 % strain with a
preload of 0.01 N .

== Limitations
<limitations>
Thermosetting materials have come far from the crosslinked latex rubbers
first developed by ancient Mesoamericans, and have transformed the world
along the way. Polymer chemists have and continue to produce ever more
sophisticated ways to prepare narrowly disperse polymers with diverse
functionality enabling the synthesis of more and more exotic polymer
architecture. Taking advantage of multiple methods of controlled/living
polymerization enabled the bottom up molecular design of novel
mechanosensitive comb polymers, highly crosslinked molecular
bottlebrushes, and living hydrogels. While these materials do fill unmet
needs for thermosetting resins and soft biocompatible materials, they
still suffer from several drawbacks. Here I will detail the limitations
of 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 at
high shear rates to polymers in solution on a laboratory scale. However,
it is not necessarily a scaleable technique or easily accessible outside
of laboratory environments. More relevant techniques involve parallel
plate shear by forcefully spreading liquid on a solid substrate or
extrusion of liquids through a narrow opening. To simulate these methods
of straining polymer solutions, solutions pGMA_-co-_PEGMA950 and ethylene
diamine were subjected to 30 % shear at 1 Hz on a parallel plate
rheometer and extruded through a 27 Ga needled. Neither method showed
any increase in the rate of gelation. Shear thinning was observed in the
polymer 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 shielded
polymers. To enable more diverse applications, thermosetting polymers
that 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 installed
alongside reactive monomers on polymer backbones, they are not suitable
for shielding all kinds of reactive monomers. Different applications
demand different crosslinking chemistry. For example, ethylene diamine
can be replaced with Jeffamines for decorative applications that require
high clarity and transparency. Jeffamines are a class of amine
terminated poloxamers developed specifically for preparing crosslinked
epoxies, and their structure can be tuned to modulate the properties of
the final crosslinked material. However, their large polymeric structure
prevents them from diffusing to reactive sites flanked by large PEG
shielding 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 or
reversible crosslinks.@denissen2015 For such applications, acetoacetoxy
functional polymers offer an attractive option, forming vinylogous
urethane bonds in the presence of primary amines. However, the
(acetoacetoxy)ethyl ester is quite large, and most likely significantly
alters chain conformations, lessening the steric effects of pendent PEG.
Additionally, the tendency of the acetoacetoxy pendent groups to self
assemble through hydrogen-bonding@schlaad2004 likely preemptively brings
reactive monomers into contact, increasing the apparent rate of
crosslinking. As such, PEG shielding groups are insufficient to protect
acetoacetoxy 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 and
adhesives is shelf stability. The formulated resin should remain inert
until the user desires the material to crosslink. To simplify
application, one pot formulations are ideal. To produce highly shielded
acetoacetoxy polymers, I turned to core-shell bottlebrush polymers
composed of an inner core of crosslinkable AAEM and an outer shell of
rubbery EHMA. These polymers were prepared by the \"grafting from\"
method as it enables longer side chain lengths. Initially it was
believed that ATRP of AAEM would be impossible due to the 1,3-dicarbonyl
interfering with the copper complex. However, some reports have shown
the controlled polymerization of AAEM through traditional ATRP mediated
by CuBr.@mandal2018

To minimize the amount of copper halide required, poly(AAEM) was
synthesized by SARA ATRP with Cu(0) as the reducing agent. This produced
a polymer with a bimodal molecular weight distribution with the peak at
shorter retention time being roughly double the molecular weight of the
peak at longer retention time (@fig:saraaaem a). It is assumed
that this is due to radical-radical coupling facilitated by chelation of
coper bringing growing chains into close proximity. #super[1]H NMR
clearly showed the presence of the acetoacetoxy group as well as the
methacrylate backbone (@fig:saraaaem b). Replacing Cu(0) with
Fe(0) as the reducing agent produced no polymer. This is to my knowledge
the 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 methacrylate
copolymer sidechains were prepared by the same technique. However, all
copolymers prepared were extremely unstable, often forming insoluble
gels instantaneously upon precipitation. Only a single sample, pBIEM-_g_-(AAEM-_b_-EHMA), could
be analyzed by NMR and GPC. GPC of showed a small shoulder at shorter
retention times, indicating some amount of radical-radical coupling
@fig:aaembrush a). #super[1]H NMR clearly showed the successful
sequential 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 to
form C--C crosslinks at sidechain ends in the solid phase, even in the
presence of ppm amounts of copper.@nese2011 Removal of copper from AAEM
bottlebrushes was very difficult, presumably as a result of chelation
between brush hairs, with copper being clearly visible even after
passing through alumina. To make it easier to produce shelf stable
bottlebrushes, AAEM was replaced with GMA, and EHMA was replaced with
BMA. These bottlebrush polymers were able to be isolated as white solids
after passing over alumina to remove the copper salts, but still were
only stable for a few days at -20 °C. A different approach to synthesis
would be required to produce highly shielded, reactive bottlebrush
polymers 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 have
substantially lower elastic moduli compared to their linear
counterparts. Controlling for total number of crosslinks possible, this
suggests that not all crosslinking sites are being utilized. I
hypothesized that the onset of vitrification during the cure process
prevented the full conversion of epoxides by restricting chain mobility.
In an attempt to overcome this and improve the elastic modulus of the
bottlebrush polymers, I formulated vitrimers by incorporating a
transesterification catalyst, TBD. Described in 2011 by Montarnal et
al., vitrimers (sometimes referred to as covalent adaptable networks)
are crosslinked thermosets with dynamic bonds that flow like glasses
above 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 above
its characteristic topology freezing temperature through bond exchange
reactions at β-hydroxyl-esters. As a practical test, crosslinked
pGMA_-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 parallel
plate rheology at 155 °C (@fig:gmavitrimer b). To attempt to
measure the activation energy of vitrimer flow, I employed
time-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 at
temperatures exceeding 180 °C (@fig:tts b). It remains unclear
what exactly caused this behavior. Additionally, pGMA, pGMA_-co-_BMA,
pBIEM_-g-_GMA, pBIEM_-g-_(GMA_-b-_BMA), pBIEM_-g-_(BMA_-b-_GMA), and
pBIEM_-g-_(GMA_-co-_BMA) all failed to superimpose cleanly and showed no
ability to be reformed by melt pressing. Different dynamic crosslinking
chemistry 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 to
creep, temperature, and solvent, as well as their light weight. These
same properties however make reprocessing and recycling impossible.
Covalently crosslinked thermosets traditionally do not dissolve in
solvent or melt at high temperature, unlike thermoplastics, meaning
their shape is set at the onset of gelation. Additionally, the onset of
gelation imposes vitrification on thermosetting resins whose $T_(c u r e)
< T_g$, hampering further conversion of reactive sites. This is
particularly problematic for bottlebrush polymers, whose large size
produces already sluggish motion, making it very difficult to achieve
full conversion and maximum modulus. I propose to introduce dynamic
crosslinks to bottlebrush polymers in order to maximize the elastic
modulus of bottlebrush thermosets by facilitating bond exchange through
melt 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. Imine
crosslinked polymers can be prepared by reacting aldehyde functional
polymers in the presence of primary amines. Copolymer vitrimers based on
2-(methacryloyloxy)ethyl vanillin, and aldehyde functional monomer, and
plasticizing monomers have been demonstrated to undergo dynamic bond
exchange.@stouten2023 Additionally, imine exchange requires no
additional catalyst and occurs at lower temperatures. To prepare
bottlebrush vitrimers in particular the use of styrenic monomers is
preferred, both for their superior hydrolytic stability compared to
(meth)acrylic monomers as well as for access to atom transfer nitroxide
radical coupling reactions (ATNRC) for facile transformations of chain
end 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 give
VBA in high yield, one by hydrolysis of p-(chloromethyl)styrene followed
by oxidation to VBA (@fig:4vba a),@foyer2015 another by Wittig
olefination of 4-(diethoxymethyl)benzaldehyde followed by deprotection
(@fig:4vba b).@sun2007 RAFT polymerization of VBA has been
reported,@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 bottlebrush
polymers with long side chains, it also produces ill-defined polymers.
Residual initiating sites on side chain ends can also cause irreversible
crosslinking in the solid phase, limiting their shelf life.
Additionally, control over the final brush architecture is limited to
only being able to adjust the sequence of the side chains, meaning the
ends of the brush always presented exposed reactive groups to the
environment, resulting in rapid crosslinking. Though it was not
quantified, the initiation efficiency and monomer conversion for the
bottlebrush side chains was likely quite low.@neugebauer2015 It's
possible this could be avoided by an ATRP approach favoring deactivation
of the propagating radicals.@xie2018 I propose to use the \"grafting
through\" technique, by which olefin terminated macromonomers are
polymerized into bottlebrushes, to create a new class of
mechanosensitive \"nanocapsule\" bottlebrush thermosets that are able to
crosslink in response to weak shear forces.

While the \"grafting through\" technique is not able to prepare
bottlebrushes with side chain lengths matching that of \"grafting
from,\" it possesses several advantages of its own. Linear macromonomers
are able to be easily characterized prior to polymerization into
bottlebrush polymers, meaning the length of bottlebrush hairs can be
precisely tuned. Different bottlebrush morphologies (comb, rodlike side
chain, stretched backbone, stretched sidechain) can be precisely
prepared. Bottlebrush block copolymers can be easily prepared by
sequential addition of macromonomers. Additionally, bottlebrush polymers
prepared this way possess a side chain on every monomer (if only
macromonomers 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 bottlebrush
polymers is known to induce significant tension along the polymer
backbone, on the order of nanonewtons,@panyukov2009 the same or higher
than the force required to break C--C
bonds.@grandbois1999@willis-fox2018 These prestrained brushes may be
easier to mechanochemically cleave, exposing the reactive core (@fig:nanocapsule). Indeed, it has been shown that the limiting contour
length for bottlebrush polymers is dramatically shorter than linear
polymers, and bottlebrush polymers approach this limit under sonication
much more quickly.@li2016 Other methods of inducing strain, such as
parallel plate shear or extrusion, may be able to \"activate\" molecular
brushes with a reactive core more easily, particularly those in the
stretched backbone regime or those adsorbed to surfaces, which can
experience up to 100 nN of tension along the backbone. Scission at the
hair-backbone junction will also generate unshielded reactive linear
polymers.@peterson2019@peterson2021@noh2021 Further, the propensity for
hairs to be released into solution can be tuned by weakening the
alkoxyamine C--O bond with highly sterically hindered nitroxides
(proposed structure #strong[1]),@pauly2025@jing2014 or by preparing
bottlebrush 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 be
prepared as well. Amine functional styrenes protected with
trimethylsilane groups have been prepared by living anionic
polymerization.@hirao2002 Carbanion chain ends of polymers prepared by
living anionic polymerization can be easily converted to terminal
chlorines for use in ATNRC (@fig:polymerchlor).@satoh2019 It's
possible that protected amine functional styrenes could be directly
polymerized by ATRP, though aryl amines (R = NH#sub[2]) will likely
polymerize slowly if at all by increasing the dissociation energy of the
chain end carbon-halogen bond and slowing propagation.@yoshioka2019
Choosing a strongly hydrogen bonding solvent may be able to overcome
this by reducing the electron donating ability of the amine through
intermolecular interactions. There are some reports of polymerization of
unprotected 4-(vinylaniline) by ATRP.@rebelo2019 In any case, the amines
should remain protected until use as they will both deactivate the ROMP
catalyst preventing bottlebrush synthesis@sutthasupa2010 and the
unprotected 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 process
has been much studied since the process was first introduced.@keddie2012
RAFT agents typically take the form of #strong[2] (@fig:waterxanth). The Z group (in this case O-ethyl) is generally
responsible for modifying the rate of addition of propagating radicals
and the rate of fragmentation of intermediate radicals in the main RAFT
equilibrium. R is generally meant to act as an excellent homolytic
leaving group capable of initiating polymerization. I use a symmetrical
xanthogen disulfide, meaning modifications to the R group
can 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 less
activated monomers. Xanthates have dramatically lower reactivity towards
radical addition, qualitatively understood by the resonance contribution
of the oxygen lone pair to the C=S double bond, meaning more activated
monomers ((meth)acryloyl monomers) which produce less reactive radical
species do contributing to lower transfer constants of the xanthate and
poorer control. However, the C=S double bond can be made more reactive
by lessening the contribution of the oxygen lone pair by installing
electron withdrawing groups attached to the oxygen, lessening the
contribution of the oxygen lone pair on the C=S double bond. Xanthates
possessing the Z groups of #strong[3]@li2018a and
#strong[4]@destarac2002 have shown superior control over polymerization
of acrylic monomers, importantly with no change in polymerization
kinetics, and should be explored as xanthogen disulfide photoiniferters.

More pressingly for biomedical applications is the solubility of the
chain transfer agent. My chosen xanthate is easy to synthesize, but is
not water soluble, nor are #strong[3] or #strong[4]. Thus, I propose to
develop zwitterionic xanthogen disulfides as photoiniferters. #strong[5]
will likely provide excellent control of acryloyl functional monomers
and excellent solubility. It should be cautioned however that while
adding 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 and
hydrolysis, which will complicate cytocompatible polymerizations in
water.@thomas2004@moad2005 Tertiary alcohols should be avoided such that
Z does not become a good homolytic leaving group.@stenzel2003@coote2003

Additionally, I propose to utilize the dormant xanthogen chain ends to
introduce and pattern hydrogels post polymerization. The 3D network
structure of synthetic hydrogels nicely mimics the mechanical properties
of the native cellular environment, but not the chemical properties.
Synthetic materials, like PEG, tend to be both chemically inert and
difficult to for cells to adhere to, long noted for their antifouling
properties.@zhu2010 Hydrogels should be selectively functionalized by
stereolithography with RGD adhesion points, as well as selectively
increasing or decreasing the modulus of hydrogels. The necessary
N-acryloyl functional oligopeptides are conveniently accessible by
protease catalyzed peptide synthesis,@edson2023 and some work has been
done polymerizing N-acryloyl amino acids.@bentolila2000@li2018