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Emulsion Polymerization of 2‑Methylene-1,3-Dioxepane and Vinyl

Acetate: Process Analysis and Characterization
Matthew C. D. Carter,* Andrew Hejl, Miroslav Janco, Jim DeFelippis, Peilin Yang, Michelle Gallagher,
and Yifei Liang
Cite This: Macromolecules 2023, 56, 5718−5729 Read Online

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ABSTRACT: The development of polymerization methods that install

weak links or degradable bonds in the backbone of otherwise all-carbon
chains could accelerate the design and commercialization of new classes
of recyclable, upcyclable, or biodegradable polymers. Cyclic ketene
acetals including widely studied 2-methylene-1,3-dioxepane (MDO) can
be used as comonomers in conventional free-radical polymerizations to
insert labile ester bonds into addition polymer backbones. However, the
key obstacle in deploying MDO in water-borne, industrially relevant
processes is hydrolysis of the monomer itself. Optimized conditions
including relatively low temperatures, mildly alkaline pH, and consistent
radical flux lead to high in-process conversions, a rapid rate of polymerization, and a low degree of MDO hydrolysis. Although MDO
hydrolysis competes strongly with copolymerization, degradation can be minimized during aqueous emulsion polymerization with
vinyl acetate to give robust incorporations of ∼90% MDO. The methods and quantitative analysis tools reported here provide
principles for the copolymerization of MDO in aqueous media and will drive innovations in the circular polymer economy.

■ INTRODUCTION
Polymers obtained by free-radical polymerization and designed
to contain cleavable linkages within the backbone could lead to
the development of degradable materials on a large scale and
directly address issues of plastic waste. Using this approach,
commodity polymers containing otherwise all “carbon−
carbon” backbones can be broken down into smaller fragments
for recycling, composted industrially, or degraded in the
environment at end-of-life.1−4 It remains a fundamental
challenge in the field to develop new, affordable monomers
that copolymerize with conventional starting materials and
install labile groups within a growing polymer chain. In this
context, cyclic ketene acetals (CKAs) have been explored with
increasing enthusiasm over the last several years. 2,5,6
Heteroatomic cyclic structures containing an exocyclic double
bond, CKAs can undergo radical ring-opening copolymeriza-
tion with conventional vinyl and ethylenically unsaturated
monomers to yield ester bonds within a polymer backbone.
Although this approach was pioneered by Bailey in the
1980s,7−12 surging interest in the design of sustainable
polymers has driven a renaissance in the exploration and
development of CKA chemistry.2,5
The most well-studied CKA is 2-methylene-1,3-dioxepane
(MDO) and recent work by many researchers has led to the
development of MDO-based and ester bond-containing
degradable polymers for functional coatings and interfa-
ces,13−18 nanoparticles,19,20 drug delivery,21,22 and a variety
of other applications where degradability is desired.23−32 MDO
is synthesized from commodity starting materials in good
yields and has been produced industrially in the past.33−35
However, MDO and other related CKA derivatives suffer from
a variety of problems including unfavorable reactivity ratios
with other monomers,36−39 the potential to polymerize in the
unwanted ring-closed form, and hydrolytic instability in
aqueous media.2,5 Degradation in the presence of water has
long been recognized as a key practical issue in working with
MDO,11,12 and past polymerizations have therefore been
performed in anhydrous organic solvents. MDO-containing
polymers can then be dispersed or dissolved in water, owing to
the stability of the ring-opened unit under various
conditions.19,20,22,23,25,30 Other work has sought to side-step
MDO stability issues by designing related classes of
heteroatom-containing monomers that can undergo productive
radical ring-opening reactions in aqueous media with conven-
tional monomers, including both CKA derivatives with
increased hydrophobicity40 and thionolactones for polymer-
ization-induced self-assembly (PISA) by controlled polymer-
ization methods.41−43
Received: March 29, 2023
Revised: June 30, 2023
Published: July 26, 2023

© 2023 American Chemical Society https://doi.org/10.1021/acs.macromol.3c00571

5718 Macromolecules 2023, 56, 5718−5729
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Scheme 1. General Scheme Showing the Copolymerization Reaction of VA and MDO, as well as the Undesirable Hydrolysis
Byproducts of Both VA and MDO Monomers
We recently reported that MDO can undergo radical ring-
opening copolymerization with the commodity monomer vinyl
acetate (VA) in aqueous media.44 Our approach was based on
the emulsion polymerization of VA and MDO at relatively low
temperatures and at slightly alkaline pH. We reported that
poly(VA-co-MDO) (VM) copolymers can be obtained using a
conventional latex polymerization process running at 40 °C
and pH 8.0 in-process, with MDO feed fractions from 5 to 15
mol % with incorporations of ∼90% (i.e., less than ∼10%
MDO hydrolyzed). At acidic pH, MDO hydrolysis began to
dominate and incorporation dropped below 50% between pH
6.0 and 5.0. We hypothesized that hydrolysis was minimized in
our reaction conditions by not only controlling temperature
and pH but also running a semibatch process at high
instantaneous conversion of VA in order to rapidly or
instantaneously copolymerize MDO, thereby minimizing the
time MDO is in contact with water. Moreover, in an emulsion
system, unreacted MDO in process may diffuse into and reside
inside a growing hydrophobic latex particle, further reducing
unwanted hydrolysis.
To the best of our knowledge, our initial report described
the first successful copolymerization of MDO by emulsion
polymerization, and many researchers are actively exploring
related approaches to degradable latex particles.40−43,45 A
recent report attempted to replicate our findings and found
lower MDO incorporation, leading to scrutiny of our original
results and data interpretation.45 Here, we report additional in-
process and final characterization of the copolymerization of
VA and MDO, as well as a series of studies reproducing both
our initial results and those of other researchers. Our results
confirm that under the right conditions, the copolymerization
of VA and MDO is robust and that high in-process conversion
of VA and judicious control over pH is necessary to suppress
MDO hydrolysis. In-process analysis of VA conversion,
temperature, and pH, together with complementary 1H and
13
C NMR spectroscopy and gas chromatography (GC) studies
show that MDO incorporation reproducibly reaches ∼90%
under optimized emulsion polymerization conditions. The
aqueous copolymerization of MDO and other CKA derivatives
with conventional monomers will continue to drive the
development of new sustainable polymers and soft materials.
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Article
■ RESULTS AND DISCUSSION
Our recently reported approach to VM copolymers containing
degradable backbone linkages exploits optimized semibatch
emulsion polymerization conditions at low temperatures and
mildly alkaline pH, using a redox initiator system (composed
of ammonium persulfate, tert-butyl hydroperoxide, Bruggolite
FF6M reducing agent, and Fe2+/EDTA tetrasodium salt).44
We established that gradual addition of a monomer mixture of
VA and MDO, at a run temperature of ∼40 °C and an in-
process pH of 8.0, favored the radical ring-opening
copolymerization of MDO at up to ∼15% mol of the
comonomer to give a final latex with ∼30% solid content.
We observed MDO incorporations of ∼90% by 1H NMR
spectroscopy, and we did not observe polymerization in the
unwanted ring-closed form (1,2-vinyl addition). As noted in
our original report, the favorable reactivity ratios for VA and
MDO (rVA = 1.71, rMDO = 0.95) as compared to other
conventional monomers26 were, in part, a motivating factor for
investigating this system. At this time, we hypothesized that
high instantaneous conversion of VA in the reactor was
necessary to promote the copolymerization of the minor
component MDO; in this way, VA polymerization would
“sweep” MDO into the growing polymer chains and composi-
tional drift could be minimized during the polymerization
process. Scheme 1 shows the copolymerization of VA and
MDO, together with the various hydrolysis byproducts that
may occur.
Our work on VM emulsion copolymerization has generated
significant interest in the community, and more recent work by
Kordes et al. suggested that our initial report suffered, in part,
from mischaracterization of the data that led to overestimation
of MDO incorporation.45 Our quantification of MDO
incorporation relied on 1H NMR spectroscopy data. Polymer
samples showed the presence of a peak near ∼4.0 ppm that we
assigned to the ester protons of ring-opened MDO;46−48
however, this peak was interfered with by the presence of 4-
hydroxybutyl acetate (4-HBA), a hydrolyzed byproduct of
MDO, as shown in Scheme 1. We therefore proposed that
diffusion-edited 1H NMR could be used to eliminate the
signals arising from the small molecule 4-HBA and correctly
interpret the spectra. Based on these data, we concluded that
near-quantitative incorporation of MDO (>90%) could be
achieved at pH 8.0, whereas 76% was incorporated at pH 6.0,
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Figure 1. 1H NMR spectra for VM-2, VM-3, and VM-4, with select peak assignments made directly on the figure. The integrations of the VV and
VM diad peaks are also given. The sharp peak adjacent to B′ at ∼3.6 ppm is due to the surfactant used in the polymerization (ethylene oxide units).
See Figure S1 for the corresponding diffusion-edited spectra.

Table 1. Summary of Additional Characterization and Analysis on Latexes VM-2 through VM-4
in-process MDO, %incorp., 1H NMR, diffusion- MDO %incorp., 1H MDO, %incorp.,
latexa fraction MDO (wt%) f MDO (mol%) pHb editedc NMRd GCe
VM-2 5.0 3.6 8.0 112 ± 8 105 ± 7 89 ± 13
VM-3 5.0 3.6 5.0 29 ± 2 37 ± 3 55 ± 11
VM-4 5.0 3.6 10.0 90 ± 6 127 ± 9f 91 ± 15
a
Naming of the latexes follows the convention from reference 44. bIn-process pH ± 0.2 units, as described in the main text. cDetermined by
integration of the VA CH backbone (1H) and MDO (2H) ester signals by diffusion-edited 1H NMR spectroscopy (see Figure S1). dDetermined
by integration of the CH backbone proton in VV and VM diad units; error was determined assuming ±5% in all integration values (see Figure 1).
e
Determined by GC analysis of 4-HBA; error values were determined using the standard deviation of duplicate measurements and standard error
propagation rules. fArtificially high due to the presence of PVOH-containing polymers; see the main text for full details.

and only 29% incorporation was observed at pH 5.0 under
otherwise identical conditions.44 Using the same methodology,
we demonstrated that increases in the polymerization temper-
ature resulted in increased MDO hydrolysis: from ∼90%
incorporation at 40 °C to 55% at 60 °C and down further to
38% at 80 °C.49
Kordes et al., writing in Macromolecules, argued that our
interpretation of VM copolymer 1H NMR spectroscopy
diffusion-edited data was incorrect because 4-HBA is not the
only possible interferant at ∼4.0 ppm in the spectral data.45
The authors were concerned that both (i) poly(vinyl-acetate-
co-vinyl alcohol) [P(VA-co-VOH)] copolymers arising from
adventitious hydrolysis during polymerization and (ii) cross-
5720
linked PVA chains display signals in the same region as the
ester protons of the incorporated MDO. Therefore, it was
suggested that a more accurate measure of MDO incorporation
and hydrolysis could be obtained by integrating the non-
diffusion-edited 1H NMR spectra and exploiting the relation-
ship between VV and VM diads. Note that for either method,
the small fraction of the comonomer 2-acrylamido-2-methyl-1-
propanesulfonate (0.5 mol %) in all samples was ignored.
Figure 1 shows the results of data re-analysis by this method
for three illustrative VM samples from our original report.44
For consistency, we have maintained the same numbering
convention, and select properties of the latex samples together
with the amount of MDO in the feed and the in-process pH
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Table 2. Summary of Composition and Various Properties of VM Latexes

fraction in-
MDO (wt f MDO process MDO, %incorp., 1H MDO %incorp., MDO % particle size, Tg, °C %conv. %hydrolysis,
a
latex %) (mol%) pHb NMR, diffusion-editedc 1
H NMRd incorp., GCe DLS (nm) (DSC) VAe VA (HPLC)f
VM-5 15.0 11.8 8.0 98 ± 7 87 ± 6 n/d 92 20.3 99.7 0.7
VM-5′ 15.0 11.8 8.0 99 ± 7 88 ± 6 93 ± 2 106 16.3 99.3 1.0
VM-5- 15.0 11.8 8.0 68 ± 5 64 ± 5 77 ± 1 132 19.4 99.7 2.1
M1
VM-5- 15.0 11.8 8.0 73 ± 5 71 ± 5 82 ± 3 129 16.8 99.7 2.0
M2
a
VM-5′ (repeat of VM-5); VM-5-M1 and VM-5-M2, based on reference 44 (see the main text for full details). bIn-process pH ± 0.2 units.
c
Determined by integration of the VA CH backbone (1H) and MDO (2H) ester signals by diffusion-edited 1H NMR spectroscopy; (see Figures S1
and S7). dDetermined by integration of the CH backbone proton in VV and VM diad units (see Figure 2). Error was determined assuming ±5% in
all integration values and standard error propagation rules. eDetermined by GC; “n/d” − not determined. fDetermined by HPLC for acetic acid.

Figure 2. 1H NMR spectra for VM-5′, VM-5-M1, and VM-5-M2, with select peak assignments made directly on the figure. The integrations of the
VV and VM diad peaks are also given. The sharp peak at ∼3.6 ppm is due to the surfactant used in the polymerization. See Figure S6 for 2D NMR
spectra of VM-5′ and Figures S3 and S7 for the corresponding diffusion-edited spectra of VM-5′, VM-5-M1, and VM-5-M2.

are given in Table 1. In all cases, we assumed an error of ±5%
in the integration values; standard error propagation rules were
applied to generate final associated errors (see the Supporting
Information for sample calculations).
Analysis of the 1H NMR spectra of VM-2, VM-3, and VM-4
by the method of Kordes et al. revealed qualitatively similar
results to those obtained by the original diffusion-edited
technique. Table 1 shows that the percent incorporation of
MDO for sample VM-2 (under the optimized conditions and
therefore high incorporation) was near-quantitative and agreed
5721
within error with our previous result. Close inspection of the
1
H NMR spectrum of VM-2 in Figure 1 reveals small, sharp
signals indicating very low levels of 4-HBA as expected; these
peaks are much more pronounced in VM-3, a polymer
obtained from polymerization at pH 5.0�conditions known to
give poor MDO incorporation. Analysis of this spectrum
suggested only 37 ± 3% incorporation, a value higher than 29
± 2% according to our earlier results. Under highly alkaline
conditions, VM-4 gave 127 ± 9% incorporation by this
analysis; however, this result can be rationalized by taking into
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account that 7.0 wt % of acetate groups were hydrolyzed
during polymerization at pH 10.0.44 Hydrolysis of VA reduces
the number of VV diads and therefore decreases the
integration value of the corresponding peak and increases the
observed ratio of VM to VV (note that hydrolysis may also
reduce the VM peak area, but a study of hydrolysis selectivity is
beyond the scope of this paper). Ultimately, this technique is
unsuitable for the analysis of partially hydrolyzed VM
copolymers (e.g., VM-4), but highly alkaline VM-4 polymer-
ization conditions are not of interest.
The hydrolysis of VA and PVA side chains during
polymerization was discussed briefly in our original report.44
At that time, we observed <1.0 wt % hydrolyzed VA under
optimized polymerization conditions at pH 8.0, and therefore,
very low amounts of PVOH-containing polymers are present in
VM latexes. The likelihood of PVOH-containing polymers
interfering with the determination of MDO incorporation by
1
H NMR diffusion-edited spectroscopy is therefore negligible.
Nevertheless, we return to this point in the discussion below
and provide additional characterization of the absence of
PVOH-containing species.
To confirm the 1H NMR spectroscopy results shown in
Table 1, we quantified MDO hydrolysis byproducts in
polymers VM-2, VM-3, and VM-4 by GC−MS. Analysis of
the latexes revealed the presence of 4-HBA and 1,4-
diacetoxybutane (in highly alkaline VM-4, acetamide was
also observed, presumably arising from the reaction of acetic
acid and ammonium hydroxide under the separation
conditions). In all samples, the integration of 1,4-diacetox-
ybutane was <10% of the total byproduct peak area, and we
therefore focused our attention on the major component 4-
HBA (1,4-diacetoxybutane was <5% in VM-2 and VM-3 but
increased at high pH for VM-4; see Figure S2). The presence
of low levels of the hydrolysis byproducts of MDO implies that
MDO was incorporated into the polymer. As summarized in
Table 1, the data show that 89 ± 13% of MDO was
incorporated in VM-2, in good agreement with analysis by
both 1H NMR techniques. VM-3 and VM-4 showed both low
and high levels of MDO incorporation at 55 ± 11 and 91 ±
15%, respectively, as anticipated by the 1H NMR spectra. We
do not yet understand why the GC technique suggests higher
MDO incorporation in VM-3 as compared to 1H NMR
analysis, albeit with relatively high associated error. The high
overall error in the GC results appears to arise from large
standard deviations between duplicates and may indicate the
need to run additional samples or reflect the difficult nature of
analyzing the hydrolysis byproducts, which may undergo
hydrolysis or condensation reactions during analysis. We
return to a discussion of the GC−MS method below and
implement several refinements that increase robustness for the
analysis of new latex samples synthesized here.
To shed light on the optimized polymerization mechanism
at pH 8.0, we carried out a series of experiments designed to
(i) reproduce our past results, (ii) characterize in-process
reaction conditions, (iii) further address criticism that 1H
NMR spectroscopy may be an ineffective technique due to
interference from PVOH-containing polymers and/or cross-
linked PVA chains, and (iv) repeat and explain the results
described in Kordes et al. in which the authors achieved low
MDO incorporation using a modified version of our optimized
process.45 The samples shown in Figure 1 and Table 1
contained relatively low levels of MDO; thus, we repeated the
synthesis of an earlier VM polymer with 15 wt % MDO in the
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feed44 to increase the observable VM peak area by 1H NMR
spectroscopy. Table 2 shows a summary of the data for VM-5,
reported earlier, and VM-5′, a repeat process carried out here.
We used the same experimental setup and procedure as before
to obtain VM-5′ (see the Supporting Information for
additional details) and obtained similar results. Figure 2 and
Table 2 show that MDO polymerization in the ring-opened
form was 87 ± 6 and 88 ± 6% for VM-5 and VM-5′,
respectively. In diffusion-edited spectra, 98 ± 7% of MDO was
incorporated in VM-5 as compared to 99 ± 7% incorporation
for VM-5′, suggesting that the diffusion-edited technique may
slightly overestimate incorporation (within error, however, the
values from both techniques tend to agree). Overlaying the 1H
NMR spectra for VM-5′ (before and after diffusion-edit)
confirmed our earlier observation that the small molecule
byproducts of MDO hydrolysis were eliminated without
reducing the intensity of the polymer peaks of interest (see
Figure S3).44 We also analyzed VM-5′ after dialysis to remove
4-HBA and other small molecules; the percent incorporation
by 1H NMR (no diffusion filter applied) matched the value
observed earlier (see Figure S4; note that we selected dialysis
over other isolation methods including precipitation or
centrifugation to avoid potentially fractionating the molecular
weight distribution). Table 2 also shows that the particle size,
Tg, and percent hydrolysis of VA were consistent between VM-
5 and the repeat sample VM-5′. Additional particle size data
and the level of acetaldehyde observed in various samples are
given in Supporting Information Figure S5 and Table S1. GC−
MS analysis found 93 ± 1% MDO incorporation in the final
latex when the byproducts were analyzed using the same
method as above (and incorporating several refinements; see
the Supporting Information). Finally, 2D heteronuclear
correlation NMR spectroscopy was carried out on VM-5′ to
further characterize the polymer microstructure and highlight
the connectivity between VA and MDO units in the backbone
(see Figure S6).
The absence of significant levels of acetic acid in VM-5 and
VM-5′ strongly suggests that very little PVOH-containing
polymer is present in these samples (see Scheme 1 and Table
2). However, Kordes et al. hypothesized that MDO
quantification by 1H NMR diffusion-edited spectroscopy
suffers from peak interference by PVOH-containing species.
To further illustrate the absence of interference in both
diffusion and non-diffusion-edited spectra, we prepared a series
of partially hydrolyzed PVA copolymers. P(VA-co-VOH)
copolymers were prepared by acidic methanolysis of a
commercial PVA,50 and the degrees of hydrolysis were
determined using widely accepted literature methods based
on 1H NMR51 (full details are available in Figure S8 and the
Supporting Information). Figure 3 shows quantitative 13C
NMR spectra for three P(VA-co-VOH) polymers with
compositions of 88/12, 74/26, and 51/49 (PVA/PVOH,
mol%, determined by 1H NMR spectroscopy) together with
VM-5′. Key diagnostic peaks including the backbone carbon
atoms of VOH-VA diads at 42.1 ppm and VOH-VOH diads at
45.4 pm appear in the spectra of the P(VA-co-VOH)
copolymers and increase in intensity with the degree of
hydrolysis (the large peak at ∼40.0 ppm is the VA−VA diad
and obscured by non-deuterated DMSO).50,52 There are no
signals in the VM-5′ spectra which match these diagnostic
peaks, strongly suggesting the absence of detectable VA
hydrolysis. For completeness, we also analyzed 1H NMR
spectra of all three P(VA-co-VOH) copolymers: there are no
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Figure 3. Quantitative 13C NMR spectra for VM-5′ and three P(VA-co-VOH) copolymers. Data were obtained in CDCl3 (VM-5′) and in DMSO-
d6 [P(VA-co-VOH)]. The composition of the P(VA-co-VOH) copolymers is given in mol% on the figure together with structures representing key
peaks of interest. Residual methanol is observed at ∼49 ppm in the spectra of P(VA-co-VOH) 88/12 and 74/26. See Figure S9 for additional 13C
NMR spectra and analysis.

peaks near ∼4.0 ppm in the spectra of the 88/12 copolymer,
which displays the lowest level of hydrolysis and could have
interfered with diffusion-edited 1H NMR analysis reported
earlier; peaks near 4.0 ppm do appear at higher degrees of
P(VA-co-VOH) hydrolysis (see Figure S8), but our samples do
not display levels of VA hydrolysis >1 wt %. Based on these
data, we remain confident that hydrolysis of VM copolymers is
limited under our polymerization conditions and interpretation
of 1H NMR spectra is not hampered by the presence of
PVOH-containing chains.
Kordes et al. also raised the possibility that diffusion-edited
1
H NMR analysis in the ∼4.0 ppm region may suffer from
interference by cross-linked PVA chains. Our reaction
conditions were designed to minimize the possibility of
cross-linking by running at relatively low temperature and
low radical flux and by chasing the residual monomer at the
end of feeds under mild conditions, all of which minimize the
possibility of hydrogen atom abstraction events from the
polymer backbone that would result in backbone−backbone
coupling and cross-linking. Nevertheless, PVA is well-known to
undergo chain-transfer reactions during polymerization, which
could lead to possible cross-linking reactions. Chain-transfer to
the monomer is expected to lead to side-chain branches,
whereas chain-transfer to the polymer will lead to branching
(abstraction of a side-chain methyl hydrogen) or cross-linking
(abstraction of the backbone alpha-hydrogen and interchain
radical−radical combination).53,54 The degree of cross-linking
5723
in PVA-containing copolymers can be assessed, in part, by the
presence or absence of a peak at ∼84 ppm in the 13C NMR
spectra, which has been assigned to backbone carbon atoms of
cross-linked polymer chains.55 This peak is not present in the
spectra of VM-5′; it is also absent in the spectrum of a PVA-
only polymer made by the same process (see Figure S9).44
Finally, we carried out a solubility experiment with VM-5′ at a
concentration of 2 mg/mL in tetrahydrofuran (THF) and
obtained a gravimetric solubility of 87 ± 2%. We note that
THF may not be an ideal solvent, but the high solubility
observed further confirmed the largely un-cross-linked nature
of the latex and that, if cross-links are present, they were
undetectable by NMR spectroscopy.
To further explore the factors that control the incorporation
of MDO in VM emulsion polymerization, we analyzed the in-
process data for VM-5 and duplicate reaction VM-5′. Figure 4
shows (A) VA conversion data, (B) and (C) MDO hydrolysis
byproduct levels, (D) percent conversion of MDO as
determined via the byproduct levels, (E) in-process pH, and
(F) temperature throughout the 60 min long feed. The figure
also shows the properties of a sample obtained post monomer
chase (labeled “C” on the figure) and the final sample (labeled
“F”). Inspection of the data reveals good agreement between
the two VM-5-type runs: VA conversion rapidly reached ∼80%
within ∼10 min of starting the feeds and maintained >90%
conversion throughout the remainder of the process. MDO
hydrolysis appeared low throughout the feeds in VM-5′ when
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Figure 4. In-process polymerization reaction data showing (A) percent conversion of VA, (B) level of 4-HBA and (C) 1,4-diacetoxybutane
observed by GC−MS, (D) percent conversion of MDO (determined from the levels of hydrolysis byproducts observed), (E) measured in-process
pH in the reactor, and (F) reactor temperature for VM-5 (solid), VM-5′ (dotted), VM-5-M1 (dashed), and VM-5-M2 (dash-dot). The “C” and the
“F” on the x axis indicate the sample acquired after the “chase” and the “final” sample, respectively. In (E,F), no pH adjustment was made, and the
temperature was not recorded after the chase. In (B−D), data for VM-5 are not shown. Error bars were calculated using the standard deviation of
replicate measurements and standard error propagation rules, see the Supporting Information for more details. In (E), for VM-5-M2, the pH was
measured every 5 min as shown on the plot and then immediately adjusted up to pH ∼ 8.0 as required; these data are shown in full in Figure S10.

the byproducts were analyzed by GC−MS using the same
method as above (and incorporating several refinements; see
the Supporting Information). Temperature and pH were also
controlled at 40 ± 2 °C and 8.0 ± 0.2 units, respectively, as
reported previously (with the exception of one unintended
drop to pH ∼ 7.2 in VM-5 at early times due to operator
error). We were pleased to observe the high, near-
instantaneous conversion of VA throughout the majority of
the process together with low levels of 4-HBA and 1,4-
diacetoxybutane and therefore relatively high MDO con-
version. The data suggest that high VA conversion enhances
the incorporation of MDO. We also note that early in the
reaction, the reactor contents were transparent, with the
exception of large oil droplets presumed to contain VA and
MDO. However, after 5−10 min, the reactor contents
transitioned to a white, semitransparent mixture indicating
the formation of polymer particles, as confirmed by dynamic
light scattering (data not shown). The reaction then became
opaque and proceeded with tight control over in-process pH
and temperature.
The work of Kordes et al. questioned the robustness of our
optimized VM polymerization. These researchers reported two
attempts to reproduce our original process but failed to
incorporate more than ∼12% of the total MDO feed as
determined by the 1H NMR spectroscopy technique described
above.45 To further qualify process reproducibility and
potentially uncover differences between reports, we carried
out repeat polymerizations under conditions that matched, as
closely as possible, those used by Kordes et al. Although these
researchers have taken care in reproducing our work, we
observed three potentially critical deviations from our
optimized process: (i) in our work, EDTA tetrasodium salt
(chelant for Fe2+) was charged to the reactor prior to starting
the polymerization feeds and not cofed to the reactor over
time, (ii) we carefully maintained the pH of the reaction media
at pH = 8.0 ± 0.2 and yet in reference 45, drops to pH ∼ 5.5
were observed during the feeds, and finally (iii) Kordes et al.
reported undesirable temperature fluctuations of +5 °C from
5724
the reaction setpoint. An additional minor change may lie in
the initiation step: to build up initiator radicals in the reactor,
promote rapid initiation, and drive to high conversion, the
initiator cofeeds began 1 min prior to the start of monomer
addition in our process. These cofeeds started simultaneously
in the comparative study. We explore each of these possibilities
in the text that follows.
To evaluate the conditions of Kordes et al., we synthesized
VM-5-M1 and VM-5-M2. In this notation, the “M” indicates
that these two polymers were synthesized according to the
method in reference 45, and both contained the same 15 wt %
MDO in the feed as VM-5 and VM-5′. Polymer VM-5-M1 was
synthesized by incorporating change (i) listed above: EDTA
tetrasodium salt was placed in the initiator cofeed solution, as
opposed to in the reactor upfront. EDTA is a key component
of the initiator system and is required to maintain the solubility
of Fe2+, which serves as the reducing agent for the initiators
(oxidizing agents). The oxidized Fe3+ form is then reduced by
FF6 back to Fe2+, completing one redox cycle.56 Shifting the
EDTA salt to the cofeed had a significant negative effect on VA
conversion: Figure 4A shows that conversion reached only
∼60% in the first ∼10 min, as opposed to ∼80% as observed
for VM-5 and VM-5′. Critically, conversion then decreased and
reached a minimum of only ∼25% at 25% of feeds; by the
same point, VM-5 and VM-5′ had achieved near-quantitative
instantaneous conversion of VA. As predicted, Figure 4B−D
shows a significant increase in MDO hydrolysis and a
correspondingly lower percent conversion that corelates with
the behavior of VA over the same time. VA conversion
recovered slowly in VM-5-M1 and did not reach levels
comparable to those observed in the optimized process until
50% of feeds; MDO conversion also recovered but remained
lower throughout the remainder of feeds as compared to VM-
5′. At the same time, however, Figure 4E,F shows that pH and
temperature control were as desired in VM-5-M1, suggesting
that additional modifications may have been made to the
optimized procedure and were not reported in reference 45.
Overall, Table 2 shows that we observed 68 ± 5 and 64 ± 5%
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MDO incorporation by the 1H NMR spectroscopy techniques
described earlier and a Tg of 19.4 °C. At the same time, GC−
MS analysis showed 77 ± 1% incorporation.
Next, we synthesized VM-5-M2 by holding the EDTA salt in
the cofeed and allowing the pH to drift during feeds. We also
began the initiator and monomer feeds at the same time.
Kordes et al. imply that, in their hands, the pH dropped from
8.0 to 5.5 within 5 min during this process, but then it was
adjusted back to pH 8.0. We have never observed or allowed
the pH to decrease so substantially from the setpoint in the
optimized process, because we previously established that
polymerization at pH = 5.0 resulted in poor MDO
incorporation of ∼29%.44 To mimic the process and
observations of Kordes et al., we adjusted the initial reactor
contents to pH = 8.0 (as usual) and then only readjusted to
pH = 8.0 in 5 min intervals. Figure 4E shows that the system
dropped to pH ∼ 7 within the first 5 min of polymerization, at
which point it was brought back to ∼8.0 and allowed to drift
down again. This process was repeated throughout the feeds
(note that the figure does not show the induced recovery of the
pH after each 5 min interval; for these data, see Figure S10).
While we observed precipitous decreases to pH < 7 in the first
∼40% of feeds, the polymerization ran closer to pH ∼ 7.5
during the last 50% of feeds. We did not, however, observe a
decrease to pH = 5.5 at any point during the reaction, as
reported by Kordes et al., suggesting that these authors may
not have continuously monitored and adjusted the in-process
pH of the reactor contents as we did, further raising the
possibility that additional unreported process changes are a
factor in reference 45. Table 2 summarizes that 1H NMR
spectroscopy analysis found 71−73% MDO incorporation
under these conditions and we observed a Tg of 16.8 °C (see
Figure S3 for additional 1H NMR spectral overlays of the two
techniques for both samples). GC−MS analysis found 82 ± 3%
incorporation in the final sample.
The modifications that Kordes et al. applied to our
optimized process clearly had a negative effect on MDO
incorporation. Nevertheless, we observed ∼64 and ∼71%
incorporation in VM-5-M1 and VM-5-M2, respectively, which
far surpassed the ∼12% reported. As stated above, we speculate
that one key difference between the reported procedures lies in
the pH and temperature fluctuations observed by Kordes et al.
Figure 4E,F shows that our VM-5-type samples do not suffer
from in-process drops in pH or a temporary loss of
temperature control; both factors are known to promote
MDO hydrolysis. Importantly, the optimized conditions lead
to higher instantaneous conversion of VA, particularly in the
first half of feeds, and this result is tied to minimized MDO
hydrolysis. The in-process MDO byproduct levels shown in
Figure 4B,C for both VM-5-M1 and VM-5-M2 tend to peak
when VA conversion reaches a minimum, whereas high
instantaneous VA conversion in VM-5′ promotes MDO
copolymerization. Note that any unpolymerized MDO is
hydrolyzed during analysis and the byproduct levels observed
are expected to be higher than those in the reactor itself (i.e.,
there is unreacted MDO present in the reactor but not
observed by GC−MS). In this way, the byproduct levels do
not measure the true in-process hydrolysis of MDO but they
do reflect the propensity for MDO to copolymerize. More
closely following the mass balance through the deployment of
additional in-process analytical tools, including those described
by Kordes et al., would be an interesting area for future
research.
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For all samples, the same amount of VA/MDO was fed to
the reactor at a given time, wherein MDO will partition
between the aqueous phase and surfactant-stabilized VA/
MDO droplets present at early times (i.e., prior to the
formation of latex particles). MDO may be moderately
protected from hydrolysis in the monomer droplets, but it is
susceptible to hydrolysis in the aqueous phase. Therefore, we
speculate that rapid initiation coupled to latex particle
formation is critical: when nucleation is fast, MDO fed to
the reactor is more likely to be consumed by polymerization
than reside in the water phase. Moreover, latex particles
provide a high surface area and hydrophobic environment into
which unreacted MDO is expected to diffuse and remain at
least partially protected. This proposal is supported by
experimental observations: the appearance of a white, colloidal
mixture in the reactor was delayed under the VM-5-M1 and
VM-5-M2 conditions to approximately 20 min (or ∼25% of
feeds), whereas nucleation was observed within 5−10 min in
VM-5′. The data in Figure 4 show reduced VA monomer
conversion and accelerated MDO hydrolysis at early times in
VM-5-M1 and VM-5-M2 relative to VM-5′, which corelates
with the delayed onset of particle formation.
Two additional differences are also observed in Table 2. The
particle size for VM-5-type polymers was ∼100 nm, while
those of VM-5-M1 and VM-5-M2 were ∼130 nm (the solid
contents of the latexes were 30.2, 31.1, and 29.2%,
respectively). In emulsion polymerization, a smaller particle
size under otherwise identical conditions indicates the
presence of more particles. In this case, the ratio of the
particle size diameters implies that our optimized process
resulted in ∼2.2× the number of particles as compared to the
Kordes et al. modifications. Smith−Ewart theory states that the
rate of polymerization during the bulk of the process is given
by eq 1 as follows:
n × Np
R p = k p[M ]p
NA (1)
where kp is the propagation rate constant, [M]p is the
concentration of the monomer in particles, n is the average
number of radicals per particle, Np is the number of particles,
and NA is Avogadro’s number.57 We assume that kp will be
similar between samples with the same comonomer
composition, and because the same number of initiator
radicals is expected (ignoring the effect of minor disturbances
in the temperature and pH on radical flux, as observed in VM-
5-M2), we approximate the average number of radicals per
particle as equal (this value is taken to be 0.5, on average, in
Smith−Ewart theory) and calculate that the rate of polymer-
ization, Rp, for the VM-5 process is ∼2× the rate for VM-5-M1
and VM-5-M2. This conclusion is supported by the data in
Figure 4A showing that VA conversion was low for the first
∼50% of feeds and is likely related to an inadvertent decrease
in initiator efficiency caused by moving the EDTA salt out of
the reactor. The faster rate of polymerization agrees well with
our earlier hypothesis that reducing MDO contact time with
water is critical to promoting incorporation. In addition, the
greater number of particles in our optimized process results in
a larger polymer surface area, and potentially favors diffusion of
unpolymerized MDO to the protective hydrophobic environ-
ment of the growing latex particles. Finally, Table 2 shows that
we observed VA hydrolysis levels ∼2× higher in VM-5-M1 and
VM-5-M2 than in VM-5 and VM-5′ (overall hydrolysis was
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still relatively low, however). Presumably, VA hydrolysis was
more favored in the modified processes at early stages, when
conversion was low.
We carried out a final series of experiments to evaluate the
backbone degradability of the samples by GPC, following
previously reported methods.44 Figure 5 shows the results of
Figure 5. GPC chromatograms of VM-5′ (solid), VM-5-M1 (dotted),
and VM-5-M2 (dashed), before (black) and after (gray) degradation.
Samples were analyzed using N,N-dimethylacetamide (containing 50
mM LiBr) as the eluent. Mn and Mw for each sample before
degradation and given in kDa were as follows: VM-5′ 62/394, VM-5-
M1 104/475, and VM-5-M2 78/576. After degradation: VM-5′ 2.2/
3.0, VM-5-M1 2.5/3.7, and VM-5-M2 2.5/3.7.
subjecting latex samples to base-accelerated degradation at 150
°C for 24 h. The molecular weight at the peak maxima, Mp, of
the native samples were as follows: VM-5′: 131 kDa; VM-5-
M1: 182 kDa; and VM-5-M2: 316 kDa. After degradation, the
observed Mp values were as follows: VM-5′: 2.3 kDa; VM-5-
M1: 2.8 kDa; and VM-5-M2: 2.4 kDa. Calculations using Mp
for VM-5′ and 90% incorporation of MDO into randomly
distributed backbone ester units suggest that the degraded
oligomer molecular weight should be approximately 500 Da, a
value lower than the Mp observed. These results closely match
analyses carried out and reported earlier.44
We propose that the observed degraded molecular weights
are higher than the theoretical values due to the following
factors: (i) MDO is not fully randomly inserted within the
backbone, as evidenced by the presence of MM diads in the 1H
NMR spectra at ∼2.3 ppm (see Figure 2),47 and (ii) MDO
back-biting leading to short, side-chain branches is well known
and observed at ∼0.9 ppm in the same 1H NMR spectra (see
also Figure S6).46,47 Each of these factors effectively reduces
the number of cleavable units and may help to explain the
disparity between the final degraded molecular weight relative
to the theoretical. Finally, although we did not observe cross-
linked polymer chains by 13C NMR as discussed above, low
levels of cross-linking that are below the spectroscopic
detection limit could also directly lead to higher-than-expected
degraded molecular weights. These proposals are in-line with
recent results from Galanopoulo et al. who examined the
degradation of poly(methyl methacrylate) (PMMA) particles
containing ring-opened and degradable 5,6-benzo-2-methyl-
ene-1,3-dioxepane (BMDO) units; these authors also reported
a discrepancy between the theoretical and actual degraded
molecular weight observed by GPC and offered similar
plausible explanations.40 The instrumental setup may be an
additional factor: separation efficiency in the low molecular
weight range may be relatively poor and the GPC molecular
weights are not absolute but relative to PMMA standards (in
our case). We note here that in our original report we provided
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evidence that the actual molecular weight of VM latex
degradation products is significantly lower by MALDI than
by GPC44�indeed suggesting that GPC may overestimate the
oligomer molecular weight.
Additional insights can be gained from past publications that
describe the backbone degradation of VM copolymers made in
solvent.46,47 However, these reports lack sufficient data to draw
quantitative conclusions about the incorporation of MDO via
degradation (perhaps due to the difference in solubility
between the native copolymer and the degradation products,
and the lack of a GPC instrument with common solvent).
However, a study by Zhu and co-workers48 describes the
synthesis and degradation of a copolymer obtained by cobalt-
mediated radical polymerization and containing 21 mol %
MDO. GPC analysis gave a shift from Mn = 31.4 kDa to Mn =
1.6 kDa in N,N-dimethylformamide with similar dispersity
against poly(styrene) standards (the sample was degraded in a
sulfuric acid/acetic acid mixture, presumably to avoid VA side-
chain deacetylation). A copolymer with the given Mn and
number of MDO units would be expected to degrade to
oligomers of ∼550 Da. The authors’ observation of oligomers
with ∼3× higher molecular weight than theoretical agrees with
our results and the discussion surrounding Figure 5.
For comparative purposes, we also synthesized a solvent-
borne poly(VA-co-MDO) copolymer in a batch process, with a
target composition that matched those of the VM latex samples
(i.e., FMDO = 15.0 wt % or f MDO = 11.8 mol %). 1H NMR
spectroscopy analysis gave 8−10 mol % MDO in poly(VA-co-
MDO), depending on the method used (see the Supporting
Information). Prior to degradation, the polymer displayed a
multimodal molecular weight distribution with Mn = 20 kDa
and Mw = 57 kDa when analyzed by GPC. Degradation gave a
unimodal Mn = 2.5 kDa and Mw = 3.7 kDa, as compared to a
theoretical value of 1.3 kDa (based on Mn, see Figure S11).
These results agree with those reported by Zhu et al., further
supporting the possibility that GPC analysis may not
accurately quantify the exact oligomer molecular weight and
providing potential directions for future research.
Visual inspection and comparison of the 1H NMR
spectroscopy data of a latex synthesized by Kordes et al.
(reference 45, Figure S23) with our current results (e.g., Figure
2) clearly show that higher levels of MDO incorporation can
be obtained. Based on the data reported here, we conclude that
the differences in MDO incorporation reported by Kordes et
al. can be attributed to seemingly minor process modifications
that cause significant changes. Cofeeding EDTA salt (as
opposed to loading it in the reactor upfront with iron sulfate)
reduces the initiator efficiency and radical flux, thereby creating
stalled conditions at the start of the reaction. Failing to control
pH and temperature during the process are also particularly
deleterious. Although we previously reported the negative
effects of acidic pH and high temperature on MDO
incorporation, the results by Kordes et al. suggest a lack of
tight control on these process parameters. Variations on the
optimized process also affect the particle number and rate of
polymerization; the unintended outcome is higher MDO
hydrolysis. However, as shown here, repeating the process of
Kordes et al. to the best of our ability based on the published
details led to higher MDO incorporation than reported by
these researchers, suggesting that the process is relatively
robust. Because no in-process data were reported, it is
challenging to pinpoint the exact sources of the error that
led to poor incorporation as described above. Finally, we also
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note here that differences in reactor geometry (round-bottom
flask vs jacketed reactor), heating/cooling capabilities of the
reactor setup (isothermal vs nonisothermal), the purity of
MDO or other reagents, and other reaction parameters could
lead to differences in the results in ways that we do not yet
understand. Overall, the additional process and character-
ization data reported here will continue to accelerate the
development of new, backbone-degradable polymers fabricated
by water-borne and industrially relevant methods.
■ CONCLUSIONS
The emulsion polymerization of VM latex at pH 8.0 and 40 °C
yields relatively high MDO incorporation of ∼90% in the ring-
opened form. Characterization by two 1H NMR spectroscopy
methods and GC is internally consistent and can be used to
quantify incorporation and polymer compositions, but further
refinement and the development of other analytical tools to
study VM polymers may complement these techniques. Based
on in-process reaction data, we conclude that high monomer
conversion, together with tight control over in-process pH and
temperature are critical. Deviations from the temperature and
pH setpoints in the optimized process cause unwanted
hydrolysis of MDO. In addition, the process breaks down
when EDTA salt is not added to the reactor upfront: radical
flux decreases as evidenced by a precipitous drop in monomer
conversion at early times. An additional outcome that appears
to negatively affect MDO incorporation is a change in particle
size and number, together with a decrease in the rate of
polymerization. With proper control over key process variables,
VM latex polymerization appears robust. The process
parameters and in-process data reported here provide guide-
lines for the development of environmentally friendly aqueous
polymerization processes and the design of degradable free-
radical polymers.
■ ASSOCIATED CONTENT
* Supporting Information
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.macromol.3c00571.
Description of the polymerization reactor setup and
additional GC−MS and NMR spectroscopy data (PDF)
■ AUTHOR INFORMATION
Corresponding Author
Matthew C. D. Carter − Dow Construction Chemicals, The
Dow Chemical Company, Collegeville, Pennsylvania 19426,
United States; orcid.org/0000-0003-1678-2636;
Email: mccarter1@dow.com
Authors
Andrew Hejl − Dow Construction Chemicals, The Dow
Chemical Company, Collegeville, Pennsylvania 19426,
United States
Miroslav Janco − Analytical Sciences, The Dow Chemical
Company, Collegeville, Pennsylvania 19426, United States
Jim DeFelippis − Analytical Sciences, The Dow Chemical
Company, Collegeville, Pennsylvania 19426, United States
Peilin Yang − Analytical Sciences, The Dow Chemical
Company, Lake Jackson, Texas 77566, United States
Michelle Gallagher − Analytical Sciences, The Dow Chemical
Company, Collegeville, Pennsylvania 19426, United States
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Yifei Liang − Analytical Sciences, The Dow Chemical
Company, Collegeville, Pennsylvania 19426, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.macromol.3c00571
Notes
The authors declare no competing financial interest.
■ ACKNOWLEDGMENTS
We thank Ligeng Yin for helpful discussions on MDO
chemistry, as well as Prof. A. van Herk and Prof. Y. Guillaneuf
for ongoing interest in our work.
■ REFERENCES
(1) Delplace, V.; Nicolas, J. Degradable vinyl polymers for
biomedical applications. Nat. Chem. 2015, 7, 771−784.
(2) Tardy, A.; Nicolas, J.; Gigmes, D.; Lefay, C.; Guillaneuf, Y.
Radical Ring-Opening Polymerization: Scope, Limitations, and
Application to (Bio)Degradable Materials. Chem. Rev. 2017, 117,
1319−1406.
(3) Schneiderman, D. K.; Hillmyer, M. A. 50th Anniversary
Perspective: There Is a Great Future in Sustainable Polymers.
Macromolecules 2017, 50, 3733−3749.
(4) Becker, G.; Wurm, F. R. Functional biodegradable polymers via
ring-opening polymerization of monomers without protective groups.
Chem. Soc. Rev. 2018, 47, 7739−7782.
(5) Agarwal, S. Chemistry, chances and limitations of the radical
ring-opening polymerization of cyclic ketene acetals for the synthesis
of degradable polyesters. Polym. Chem. 2010, 1, 953−964.
(6) Deng, Y.; Mehner, F.; Gaitzsch, J. Current Standing on Radical
Ring-Opening Polymerizations of Cyclic Ketene Acetals as Homo-
polymers and Copolymers with one another. Macromol. Rapid
Commun. 2023, No. e2200941.
(7) Bailey, W. J.; Ni, Z.; Wu, S. R. Free radical ring-opening
polymerization of 4,7-dimethyl-2-methylene-1,3-dioxepane and 5,6-
benzo-2-methylene-1,3-dioxepane. Macromolecules 1982, 15, 711.
(8) Bailey, W. J.; Ni, Z.; Wu, S. R. Synthesis of poly-ε-caprolactone
via a free radical mechanism. Free radical ring-opening polymerization
of 2-methylene-1,3-dioxepane. J. Polym. Sci., Polym. Chem. Ed. 1982,
20, 3021.
(9) Bailey, W. J.; Wu, S. R.; Ni, Z. Free radical ring-opening
polymerization of 4-n-hexyl- and 4-n-decyl-2-methylene-1,3-dioxo-
lanes. J. Macromol. Sci., Chem. 1982, 18, 973.
(10) Bailey, W. J.; Endo, T.; Gapud, B.; Lin, Y. N.; Ni, Z.; Pan, C. Y.;
Shaffer, S. E.; Wu, S. R.; Yamazaki, N.; Yonezawa, K. Synthesis of
functionally-terminated oligomers by free radical ring-opening
polymerization. J. Macromol. Sci., Chem. 1984, 21, 979.
(11) Bailey, W. J. Free Radical Ring-Opening Polymerization. Polym.
J. 1985, 17, 85−95.
(12) Bailey, W. J.; Chou, J. L.; Feng, P.-Z.; Issari, B.; Kuruganti, V.;
Zhou, L. L. Recent advances in free-radical ring-opening polymer-
ization. J. Macromol. Sci., Chem. 1988, 25, 781.
(13) Undin, J.; Finne-Wistrand, A.; Albertsson, A.-C. Adjustable
Degradation Properties and Biocompatibility of Amorphous and
Functional Poly(ester-acrylate)-Based Materials. Biomacromolecules
2014, 15, 2800−2807.
(14) Hedir, G.; Stubbs, C.; Aston, P.; Dove, A. P.; Gibson, M. I.
Synthesis of Degradable Poly(vinyl alcohol) by Radical Ring-Opening
Copolymerization and Ice Recrystallization Inhibition Activity. ACS
Macro Lett. 2017, 6, 1404−1408.
(15) Tardy, A.; Honore, J.-C.; Tran, J.; Siri, D.; Delplace, V.; Bataille,
I.; Letourneur, D.; Perrier, J.; Nicoletti, C.; Maresca, M.; Lefay, C.;
Gigmes, D.; Nicolas, J.; Guillaneuf, Y. Radical Copolymerization of
Vinyl Ethers and Cyclic Ketene Acetals as a Versatile Platform to
Design Functional Polyesters. Angew. Chem., Int. Ed. 2017, 56,
16515−16520.
https://doi.org/10.1021/acs.macromol.3c00571
Macromolecules 2023, 56, 5718−5729
Macromolecules pubs.acs.org/Macromolecules
(16) Xie, Q.; Xie, Q.; Pan, J.; Ma, C.; Zhang, G. Biodegradable
polymer with hydrolysis-induced zwitterions for antibiofouling. ACS
Appl. Mater. Interfaces 2018, 10, 11213−11220.
(17) Ai, X.; Pan, J.; Xie, Q.; Ma, C.; Zhang, G. UV-curable
hyperbranched poly(ester-co-vinyl) by radical ring-opening copoly-
merization for antifouling coatings. Polym. Chem. 2021, 12, 4524−
4531.
(18) Kamiya, T.; Komatsu, S.; Kikuchi, A. Protein Removal from
Hydrogels through Repetitive Surface Degradation. ACS Appl. Bio
Mater. 2021, 4, 8498−8502.
(19) Asoh, T.-A.; Nakajima, T.; Matsuyama, T.; Kikuchi, A. Surface-
Functionalized Biodegradable Nanoparticles Consisting of Amphi-
philic Graft Polymers Prepared by Radical Copolymerization of 2-
Methylene-1,3-Dioxepane and Macromonomers. Langmuir 2015, 31,
6879−6885.
(20) Jackson, A. W.; Chennamaneni, L. R.; Thoniyot, P. Main-chain
degradable, pH-responsive and covalently cross-linked nanoparticles
via a one-step RAFT-based radical ring-opening terpolymerization.
Eur. Polym. J. 2020, 122, No. 109391.
(21) Hedir, G. G.; Arno, M. C.; Langlais, M.; Husband, J. T.;
O’Reilly, R. K.; Dove, A. P. Poly(oligo(ethylene glycol) vinyl
acetate)s: A Versatile Class of Thermoresponsive and Biocompatible
Polymers. Angew. Chem., Int. Ed. 2017, 56, 9178−9182.
(22) Zhu, C.; Denis, S.; Nicolas, J. A Simple Route to Aqueous
Suspensions of Degradable Copolymer Nanoparticles Based on
Radical Ring-Opening Polymerization-Induced Self-Assembly (rRO-
PISA). Chem. Mater. 2022, 34, 1875−1888.
(23) Hedir, G. G.; Bell, C. A.; Ieong, N. S.; Chapman, E.; Collins, I.
R.; O’Reilly, R. K.; Dove, A. P. Functional Degradable Polymers by
Xanthate-Mediated Polymerization. Macromolecules 2014, 47, 2847−
2852.
(24) Hedir, G. G.; Bell, C. A.; O’Reilly, R. K.; Dove, A. P. Functional
Degradable Polymers by Radical Ring-Opening Copolymerization of
MDO and Vinyl Bromobutanoate: Synthesis Degradability and Post-
Polymerization Modification. Biomacromolecules 2015, 16, 2049−
2058.
(25) Carter, M. C. D.; Jennings, J.; Appadoo, V.; Lynn, D. M.
Synthesis and Characterization of Backbone Degradable Azlactone-
Functionalized Polymers. Macromolecules 2016, 49, 5514−5526.
(26) Lena, J.-B.; Van Herk, A. M. Toward Biodegradable Chain-
Growth Polymers and Polymer Particles: Re-Evaluation of Reactivity
Ratios in Copolymerization of Vinyl Monomers with Cyclic Ketene
Acetal Using Nonlinear Regression with Proper Error Analysis. Ind.
Eng. Chem. Res. 2019, 58, 20923−20931.
(27) Tardy, A.; Gil, N.; Plummer, C. M.; Siri, D.; Gigmes, D.; Lefay,
C.; Guillaneuf, Y. Polyesters by a Radical Pathway: Rationalization of
the Cyclic Ketene Acetal Efficiency. Angew. Chem., Int. Ed. 2020, 59,
14517−14526.
(28) Liausvia, F.; Rusli, W.; van Herk, A. Prediction of the Oligomer
Distribution after Degradation of (Co)Polymers with Inserted Break
Points. Macromol. Theory Simul. 2021, 30, No. 2100038.
(29) Zeng, T.-Y.; Xia, L.; Zhang, Z.; Hong, C.-Y.; You, Y.-Z.
Dithiocarbamate-mediated controlled copolymerization of ethylene
with cyclic ketene acetals towards polyethylene-based degradable
copolymers. Polym. Chem. 2021, 12, 165−171.
(30) Bossion, A.; Zhu, C.; Guerassimoff, L.; Mougin, J.; Nicolas, J.
Vinyl copolymers with faster hydrolytic degradation than aliphatic
polyesters and tunable upper critical solution temperatures. Nat.
Commun. 2022, 13, 2873.
(31) Jackson, A. W.; Mothe, S. R.; Ang, P.; Chennamaneni, L. R.;
Herk, A. M. V.; Thoniyot, P. Backbone degradable poly(acrylic acid)
analogue via radical ring-opening copolymerization and enhanced
biodegradability. Chemosphere 2022, 293, No. 133487.
(32) Fuchs, A.; Mecking, S. Controlled Cobalt-Mediated Free-
Radical Co- and Terpolymerization of Carbon Monoxide. J. Am.
Chem. Soc. 2022, 144, 15879−15884.
(33) Filachione, E. M. A New Synthesis of Acetals of
Chloroacetaldehyde and Bromoacetaldehyde. J. Am. Chem. Soc.
1939, 61, 1705−1706.
5728
Article
(34) Mathur, S. C.; Vanderbilt, J. J. Purification of Cyclic Ketene
Acetal. US 5,164,516, 1992.
(35) Fleischmann, G.; Eck, H.; Pflaum, S. Process for Preparing
Ketene Acetals. US 5,455,361, 1995.
(36) Lena, J.-B.; Jackson, A. W.; Chennamaneni, L. R.; Wong, C. T.;
Lim, F.; Andriani, Y.; Thoniyot, P.; Van Herk, A. M. Degradable
Poly(alkyl acrylates) with Uniform Insertion of Ester Bonds,
Comparing Batch and Semibatch Copolymerizations. Macromolecules
2020, 53, 3994−4011.
(37) Tardy, A.; Gil, N.; Plummer, C. M.; Zhu, C.; Harrisson, S.; Siri,
D.; Nicolas, J.; Gigmes, D.; Guillaneuf, Y.; Lefay, C. DFT-calculation-
assisted prediction of the copolymerization between cyclic ketene
acetals and traditional vinyl monomers. Polym. Chem. 2020, 11,
7159−7169.
(38) Wenzel, F.; Hamzehlou, S.; Pardo, L.; Aguirre, M.; Leiza, J. R.
Kinetics of Radical Ring Opening Polymerization of the Cyclic Ketene
Acetal 2-Methylene-1,3-dioxepane with Vinyl Monomers. Ind. Eng.
Chem. Res. 2021, 60, 10479−10488.
(39) Lena, J.-B.; Ramalingam, B.; Rusli, W.; Rao Chennamaneni, L.;
Thoniyot, P.; Van Herk, A. M. Insertion of ester bonds in three
terpolymerization systems. Eur. Polym. J. 2022, 181, No. 111627.
(40) Galanopoulo, P.; Sinniger, L.; Gil, N.; Gigmes, D.; Lefay, C.;
Guillaneuf, Y.; Lages, M.; Nicolas, J.; D’Agosto, F.; Lansalot, M.
Degradable vinyl polymer particles by radical aqueous emulsion
copolymerization of methyl methacrylate and 5,6-benzo-2-methylene-
1,3-dioxepane. Polym. Chem. 2023, 14, 1224−1231.
(41) Lages, M.; Gil, N.; Galanopoulo, P.; Mougin, J.; Lefay, C.;
Guillaneuf, Y.; Lansalot, M.; D’Agosto, F.; Nicolas, J. Degradable
Vinyl Copolymer Nanoparticles/Latexes by Aqueous Nitroxide-
Mediated Polymerization-Induced Self-Assembly. Macromolecules
2022, 55, 9790−9801.
(42) Galanopoulo, P.; Gil, N.; Gigmes, D.; Lefay, C.; Guillaneuf, Y.;
Lages, M.; Nicolas, J.; Lansalot, M.; D’Agosto, F. One-Step Synthesis
of Degradable Vinylic Polymer-Based Latexes via Aqueous Radical
Emulsion Polymerization. Angew. Chem., Int. Ed. 2022, 61,
No. e202117498.
(43) Galanopoulo, P.; Gil, N.; Gigmes, D.; Lefay, C.; Guillaneuf, Y.;
Lages, M.; Nicolas, J.; D’Agosto, F.; Lansalot, M. RAFT-Mediated
Emulsion Polymerization-Induced Self-Assembly for the Synthesis of
Core-Degradable Waterborne Particles. Angew. Chem., Int. Ed. 2023,
62, No. e202302093.
(44) Carter, M. C. D.; Hejl, A.; Woodfin, S.; Einsla, B.; Janco, M.;
DeFelippis, J.; Cooper, R. J.; Even, R. C. Backbone-Degradable Vinyl
Acetate Latex: Coatings for Single-Use Paper Products. ACS Macro
Lett. 2021, 10, 591−597.
(45) Kordes, B. R.; Ascherl, L.; Ruedinger, C.; Melchin, T.; Agarwal,
S. Competition between Hydrolysis and Radical Ring-Opening
Polymerization of MDO in Water. Who Makes the Race? Macro-
molecules 2023, 56, 1033−1044.
(46) Agarwal, S.; Kumar, R.; Kissel, T.; Reul, R. Synthesis of
degradable materials based on caprolactone and vinyl acetate units
using radical chemistry. Polym. J. 2009, 41, 650−660.
(47) Undin, J.; Illanes, T.; Finne-Wistrand, A.; Albertsson, A.-C.
Random introduction of degradable linkages into functional vinyl
polymers by radical ring-opening polymerization, tailored for soft
tissue engineering. Polym. Chem. 2012, 3, 1260−1266.
(48) Ding, D.; Pan, X.; Zhang, Z.; Li, N.; Zhu, J.; Zhu, X. A
degradable copolymer of 2-methylene-1,3-dioxepane and vinyl acetate
by photo-induced cobalt-mediated radical polymerization. Polym.
Chem. 2016, 7, 5258−5264.
(49) Carter, M. C. D.; DeFelippis, J.; Even, R. C.; Hejl, A. Aqueous
Dispersion of Copolymer Particles of Vinyl Acetate and a Cyclic
Ketene Acetal Monomer. US 11,111,328, 2021.
(50) Moritani, T.; Fujiwara, Y. 13C- and 1H-NMR Investigations of
Sequence Distribution in Vinyl Alcohol-Vinyl Acetate Copolymers.
Macromolecules 1977, 10, 532−535.
(51) Budhlall, B. M.; Landfester, K.; Sudol, E. D.; Dimonie, V. L.;
Klein, A.; El-Aasser, M. S. Characterization of Partially Hydrolyzed
Poly(vinyl alcohol). Effect of Poly(vinyl alcohol) Molecular
https://doi.org/10.1021/acs.macromol.3c00571
Macromolecules 2023, 56, 5718−5729
Macromolecules pubs.acs.org/Macromolecules Article

Architecture on Aqueous Phase Conformation. Macromolecules 2003,

36, 9477−9484.
(52) Bugada, D. C.; Rudin, A. Characterization of poly(vinyl
alcohol�acetate) by 13C n.m.r. and thermal analyses. Polymer 1984,
25, 1759−1766.
(53) Britton, D.; Heatley, F.; Lovell, P. A. Effect of Monomer Feed
Rate on Chain Transfer to Polymer in Semibatch Emulsion
Polymerization of Vinyl Acetate Studied by NMR Spectroscopy.
Macromolecules 2000, 33, 5048−5052.
(54) Britton, D.; Heatley, F.; Lovell, P. A. 13C NMR Spectroscopy
Studies of Branching and Sequence Distribution in Copolymers of
Vinyl Acetate and n-Butyl Acrylate Prepared by Semibatch Emulsion
Copolymerization. Macromolecules 2001, 34, 817−829.
(55) Britton, D.; Heatley, F.; Lovell, P. A. Chain Transfer to Polymer
in Free-Radical Bulk and Emulsion Polymerization of Vinyl Acetate
Studied by NMR Spectroscopy. Macromolecules 1998, 31, 2828−
2837.
(56) Sarac, A. S. Redox polymerization. Prog. Polym. Sci. 1999, 24,
1149−1204.
(57) Chern, C. S. Emulsion polymerization mechanisms and
kinetics. Prog. Polym. Sci. 2006, 31, 443−486.

5729 https://doi.org/10.1021/acs.macromol.3c00571
Macromolecules 2023, 56, 5718−5729