Degradation in Order: Simple and Versatile One-Pot Combination of Two Macromolecular Concepts to Encode Diverse and Spatially Regulated Degradability Functions

Article abstract of DOI:10.1002/anie.202103143

The clever one-pot combination of two macromolecular concepts, ring-opening polymerization (ROP) and step-growth polymerization (SGP), is demonstrated to be a simple, yet powerful tool to design a library of sequence-controlled polymers with diverse and spatially regulated degradability functions. ROP and SGP occur sequentially at room temperature when the organocatalytic conditions are switched from basic to acidic, and each allows the encoding of specific degradable bonds. ROP controls the sequence length and position of the degradability functions, while SGP between the complementary vinyl ether and hydroxyl chain-ends enables the formation of acetal bonds and high-molar-mass copolymers. The result is the rational combination of cleavable bonds prone to either bulk or surface erosion within the same macromolecule. The strategy is versatile and offers higher chemical diversity and level of control over the primary structure than current aliphatic polyesters or polycarbonates, while being simple, effective, and atom-economical and having potential for scalability.

Full text of DOI:10.1002/anie.202103143

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Accepted Article
Title: Degradation in order: simple and versatile one-pot combination
of two macromolecular concepts to encode diverse and spatially
regulated degradability functions
Authors: Tiziana Fuoco
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RESEARCH ARTICLE
Degradation in order: simple and versatile one-pot combination
of two macromolecular concepts to encode diverse and spatially
regulated degradability functions
Tiziana Fuoco*[a]
[
a]
Dr, T., Fuoco
Department of Fibre and Polymer Technology, School of Engineering Sciences in Chemistry, Biotechnology and Health
KTH Royal Institute of Technology
Teknikringen, 56-58, SE 100-44 Stockholm, Sweden
E-mail: tiziana@kth.se
Supporting information for this article is given via a link at the end of the document
Abstract: The clever one-pot combination of two macromolecular
concepts, ring-opening polymerization (ROP) and step-growth
polymerization (SGP), is demonstrated to be a simple yet, powerful
tool to design a library of sequence-controlled polymers with diverse
and spatially regulated degradability functions. ROP and SGP
sequentially occur at room temperature by switching the organo-
catalytic conditions from basic to acidic, each allowing the encoding
of specific degradable bonds. The ROP controls the sequence length
and position of the degradability functions, while the SGP between the
complementary vinyl ether and hydroxyl chain-end, enables the
formation of acetal bonds and high molar mass copolymers. The
result is the rational combination of cleavable bonds prone to either
bulk or surface erosion along the same macromolecule. The strategy
is versatile and offers higher chemical diversity and level of control
over the primary structure than current aliphatic polyesters or
polycarbonates while being simple, effective, atom-economical and
having potential for scalability.
mechanical integrity which are however, accompanied by a
negligible mass loss. The erosion rate further decreases when
hardly degradable crystalline domains accumulate after the
amorphous phase of the material has degraded.[
5]
Several publications report the ring-opening copolymerization[6]
of various monomers aiming to change the composition and the
macromolecular structure of polyesters and speed up or slow
down the bulk degradation process.[ Although the synthesis of
statistical copolyesters may seem sufficient to adjust the bulk
properties of the resulting material for many applications, the
elegant work of Meyer and colleagues demonstrated that, beyond
7]
[
8]
composition, a precise design of the primary structure has a
tremendous impact on the macroscopic degradability outcome
and could overcome the pitfalls of the heterogeneous bulk
degradation.[9] Sequence-controlled poly(lactic acid-co-glycolic
acid) showed indeed a linear degradation kinetics, different from
the exponential decrease of the molar mass featured by the
random counterpart. Nevertheless, the synthetic methodology
was based on a tedious iterative process[10] impeding access to
high molar mass and large-scale production and did not meet
green chemistry principles, such as atom-economy and
elimination of protection (and deprotection) strategies.
Introduction
For a long time, aliphatic polyesters have had a leading position
among the degradable polymers for biomedical applications.[
Currently, their ability to degrade is valued outside the biomedical
field as an opportunity to minimize the environmental pollution.[
Indeed, degradability, the possibility for chemical recycling and
utilization of renewable feedstock for the synthesis, make
polyesters outstand also among sustainable polymers.[3]
Despite being considered degradable, the degradation process
of e.g. poly(lactide), PLA, and poly(-caprolactone), PCL, is a
controversial matter. The complete degradation of PLA hardly
occurs in the environment or in fresh and seawater.[4] While under
hydrolytic and/or physiological conditions the physical properties
are at the level of the demanded application for weeks to months,
the erosion and complete biodegradation take from years to
decades to occur. Therefore, a quite short service lifetime is
followed by a long temporal gap during which, the polymer matrix
remains in the service environment without being able to perform
any function, lacking mechanical integrity. This process is
described as heterogeneous bulk degradation and is typical of
polyesters. The slower hydrolysis of the ester bonds than the rate
of water uptake and their relative hydrophilicity result in hydrolytic
chain scissions throughout the polymer bulk. The outcome is an
exponential decrease of molar mass and an early loss of
Despite the complexity of the factors governing degradation and
erosion of polyesters,[1a] the degradation kinetics are determined
1]
by mechanisms that occur at molecular scale. The available
options for material optimization are, for both of the above-
described strategies, limited by the fact that degradation arises
2]
[5]
exclusively from the hydrolytic cleavage of ester bonds.
Although the degradation time and profile are altered, none of the
two approaches allows for changing or selecting the mechanism
and the conditions in which degradation is triggered. Being able
to trigger different degradation pathways by selective and
orthogonal stimuli, would instead enhance the spatio-temporal
regulation of the material properties depending on the
[11]
surrounding environment. Thus, to advance the applications’
scope while enabling new abilities for degradable polymers,
innovative synthetic routes should be identified to devise hybrid
polyesters with controlled primary structure that begets
programmable functions and performance, without sacrificing
scalability and benignity.
Hence, the aim was to establish a simple, effective, versatile
and atom-economical synthetic strategy to advance in sequence
control of degradable polymers while precisely positioning diverse
degradability functions. A very simple polymer chemistry was
conceived to enable the design of a library of degradable
1
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RESEARCH ARTICLE
polymers with higher, but properly devised, structural complexity
and degradability functions’ diversity than currently available
aliphatic polyesters. The strategy rationally combines two
traditional macromolecular concepts in one-pot, ring-opening
polymerization (ROP) and step-growth polymerization (SGP),
which occur neatly and sequentially by a simple catalyst switch.
ROP and SGP each allow the encoding of specific and spatially
regulated degradability functions able to undergo different
degradation pathways, Figure 1.
polymerization, it is atom-economical, proceeds at rt and uses
commercially available reagents and monomers. The approach is
also more facile and straightforward than recently reported
synthetic procedures to prepare polyesters with acid-sensitive
ortho-ester groups along the chains.[17]
Results and Discussion
The focus was on expanding the degradability functions from
esters to reactive groups that enable surface erosion, such as
The general scheme of the synthetic strategy is reported in
Figure 1a. Ethylene glycol vinyl ether was identified as the
simplest initiator that could meet the scope of the reaction which
[
12]
acetal bonds. Surface erosion ensures better control of long-
term properties but it has not been hitherto achieved for
was
optimized
using
CL
as
monomer.
1,5,7-
[
5, 13]
polyesters.
The cleavage of acetal bonds is faster than water
Triazabicyclo[4.4.0]dec-5-ene (TBD) was selected as the basic
organocatalyst to promote the ROP of CL at rt[18] and in THF to
penetration in the polymer bulk and readily occurs under
hydrolytic or acidic conditions forming lower molar mass, neutral
compounds, prone to diffuse out of the polymeric surface and
therefore, fostering surface erosion.[ All these aspects differ from
the bulk degradation of polyesters, and if both types of bonds are
combined in the same chain, new degradability outcomes can be
achieved, relevant to both biomedical[14] and widespread
yield vinyl ether oligoCL with controlled length and
complementary chain-ends. Vinyl ethers are in fact stable under
basic conditions and a basic catalyst was necessary to prevent
5]
[19]
side reactions of the initiator to form cyclic acetals (Scheme S1)
or premature SGP,
[20]
while allowing the synthesis of the
envisioned vinyl ether oligoCL at rt. Changing the reaction
conditions from basic to acidic by addition of an excess (3 equiv.
to TBD) of the Brønsted acid diphenyl phosphate (DPP) to the
polymerization mixture, easily resulted in switching from ROP to
[
15]
applications. For instance, PLA chains including acetal bonds
degraded in both distilled and seawater.[15a] These ester acetal
copolymers were prepared by ROP of cyclic esters bearing an
acetal moiety,[15a, 16] which needed to be ad hoc synthesized and
their copolymerization with other monomers does not allow the
controlled positioning of the acetal groups along the chains.
Instead, the strategy developed here, combining ROP and SGP
in a single synthetic procedure, allows the concomitant formation
and controlled positioning of the acetal bonds during the
SGP.
The vinyl ether oligoCLs were therefore, the
heterotelechelic macromonomers undergoing acid-catalyzed
SGP between the complementary chain-ends. The mechanism is
a Markovnikov direct addition of the OH to the CH CHO
2
producing acetal bonds.
Figure 1. Scope and versatility of the developed approach. (a) Reaction scheme of the polymerization approach combining two macromolecular concepts, i.e., ring-
opening polymerization (ROP) followed by step growth polymerization (SGP) with CL as model monomer; (b) monomers’ scope; (c) degradability functions
incorporated along the macromolecules and (d) designed microstructures.
2
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RESEARCH ARTICLE
Table 1. Ring-opening polymerization using ethylene glycol vinyl ether as initiator and sequential step-growth polymerization.[a]
Entry[a]
I step, ROP
II step, SGP
Number of
acetal
bonds
-
1
n,SEC [g mol-1]
[d,f]
Ratio
CL:initiator
Monomer
conversion [%][
Oligomer
length
M
(Ð)
n,SEC [g mol ]
M
(Ð)
time [h]
time [h]
b]
[c]
[d,e]
[g]
1
2
3
4
5
6
7
8
9
1:1
0.5
>99
>99
>99
>99
91
1.8
1.7
5.9
10
300 (1.6)
24
48
96
96
96
96
96
96
96
24
2300 (2.4)
8
1:1
4 min
4
300 (1.4)
10900 (1.9)
44700 (1.7)
78400 (1.6)
66700 (1.9)
60500 (1.8)
46000 (1.7)
20550 (1.7)
37500 (1.6)
15550 (1.5)j
36
5:1
1600 (1.5)
3200 (1.4)
5600 (1.4)
7450 (1.2)
10200 (1.4)
1700 (1.9)
2050 (1.9)
1800 (2.1)
2200 (1.8)
2700 (1.5)
1400 (2.0)
28
10:1
4
25
20:1
4.5
18
11
30:1
4.5
80
23
8
40:1
4.5
86
33
4.5
7.3
18
10:1 (LA)[h,i]
10:1 (TMC)
10:1 (DX)[h,i]
a 10:1 (LA)[h,i]
b 10:1 (CL)][h]
5:5:1 (CL/LA)[i]
2 h
99
8.2
9.2
8.3
11
2 h
99
10
11
12
2.5 h
3.5 h
3.5 h
24 h
85
2.5
99
48
48
11300 (1.8)
15300 (1.7)
~ 4.5
11
99
11
99
10.5
[
=
a] Reaction conditions: CL = 20 mmol; THF = 5 mL; TBD = 0.11 mmol (0.5 mol% to monomer); ethylene glycol vinyl ether varying from 20 mmol to 0.5 mmol; DPP
1
0.32 mmol. [b] Conversion of monomer in vinyl ether oligomer determined from H NMR spectra of the crude oligomerization mixtures. [c] Number of monomeric
1
units constituting the vinyl ether oligomer, determined from H NMR spectra of the crude oligomerization mixtures. [d] Number-average molar mass and dispersity
-
1
determined by SEC (CHCl
correction factors were utilized. [f] SEC analysis performed on the purified sample. [g] Number of acetal bonds as estimated by comparison of the M
ester acetal copolymer and the former vinyl ether oligoester. [h] Reaction performed in CH Cl . [i] TBD = 1 mol% to monomer. [j] The detected molar mass is
probably an underestimation of the real molar mass of the sample: the value likely reflects only the low molar mass, soluble faction of the polymer, indeed, poly(p-
3
, 0.5 ml min ) vs polystyrene standards. [e] SEC analysis performed on the crude polymerization mixture of the first step, the ROP. No
n
values of the
2
2
dioxanone) has very poor solubility in CHCl
.
3
and, as the molar mass increases, the polymer precipitates.
Polyacetals can in fact be prepared by SGP of diols with di-vinyl
ethers,[21],[22] or of hydroalkyl vinyl ethers[20] in the presence of a
strong acidic catalyst such as p-toluenesulfonic acid (PTSA) in
relatively short times, 1-6 h, and with high molar mass. The
weaker acidity of DPP (pKa ~ 3.73.9)[23] than PTSA and the rt
may justify the longer reaction time, 24-96 h, necessary to achieve
high molar masses (Table 1). Although the ROP of CL also occurs
in presence of DPP as catalyst,[18b] in the current polymerization
system, the preferred polymerization pathway in acidic conditions
is the reaction between the vinyl ether bond and the –OH chain
ends, leading to SGP of the macromonomers and hence, the
formation of the acetal bonds. In fact, by quenching the ROP step
at ca. 85 mol% of CL conversion, it was observed by NMR
analysis that the double bonds of the vinyl ether end groups were
consumed and fully disappeared and, the signals typical of the
acetal groups appeared. On the contrary, the ratio of the CL
monomer and CL units along the polymer chains remained almost
constant during the course of the SGP, 2.5 mol% consumption of
CL over 72 h (Figure S1).
principle, its degradation profile. The versatility of the synthetic
approach in designing different primary structures was proven by
preparing an array of copolymers with increasing ester sequence
length by varying the ratio of CL to ethylene glycol vinyl ether from
1
1:1 to 40:1 (Figure 1d; Table 1, entry 1-7). The H NMR spectra
of the vinyl ether oligoCL of different lengths and of the relative
ester acetal copolymers are presented, along with the SEC data,
in Figure 2. A thorough peak assignment[24] is provided in Figure
S2.
The vinyl ether oligomers featured high end-group fidelity as
indicated by the agreement between the integrals of the signals
2
of the vinyl (CHO; 6.5 ppm) and the methylene (CH OH; 3.6
ppm) protons. Their intensities decreased by increasing the
amount of CL respect to the initiator (Figure 2a). MALDI-ToF MS
analysis displayed a single population of species initiated from
ethylene glycol vinyl ether, confirming the structure and end-
group fidelity of the vinyl ether oligoCL (Figure S3).
n
The M values obtained by SEC analysis revealed a perfectly
linear increase of the molar mass of the vinyl ether oligoCL with
1
The ratio of monomer to initiator, which was intentionally
decided at the set-up polymerization step, regulated the length of
the ester sequence produced by ROP and the position of the
acetal bonds formed during SGP respectively, begetting
sequence-control over the primary structure. If the primary
structure of a copolymer is thoroughly controlled, it is possible to
precisely dictate the bulk properties of the final material, and in
increasing the ratio of monomer to initiator (Figure 3a). H NMR
analysis indicated that the 10:1 sample exhibited the best
agreement between the oligoCL length and the ratio of the
monomer to initiator. Lower ratio resulted, instead, in a higher
number of units incorporated than the feed ratio, independently
on the reaction time, indicating a faster rate of propagation than
initiation in the presence of TBD.
3
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RESEARCH ARTICLE
1
Figure 2. Array of ester acetal copolymers with increasing CL sequence length. H NMR spectra (400 MHz, CDCl
3
) of: (a) the vinyl ether oligoCL prepared by ROP
at different ethylene glycol vinyl ether to CL ratio as specified on the bottom-left of each spectrum; (b) the corresponding ester acetal copolymers obtained by SGP
after catalyst switch, exhibiting a different number of acetal bonds as specified on the top-left of each spectrum. Results obtained from SEC analysis (RI, CHCl 0.5
3
-
1
mL min , vs polystyrene standards) are also reported for each sample after ROP and SGP (Table 1, entry 1-7).
n
Figure 3. (a) Number average molar mass (M ) of the vinyl ether oligoCL and the corresponding ester acetal copolymers prepared at different CL to initiator ratio;
(b) photograph of the ester acetal copolymer samples with different number of acetal bonds and different ester sequence length; (c) number of acetal bond as a
m c
function of the catalyst to initiator ratio; (d) DSC thermograms (I heating run) and (d) melting point (T ) and degree of crystallinity (X ) of ester acetal copolymers
prepared with different CL to initiator ratio.
Shorter lengths of the oligomer chain with respect to the
theoretical value were calculated when the CL to initiator ratio was
higher than 10:1, due to the lower conversion of the monomer to
oligomer (Table 1, entry 1-7). Although the dispersity (Ð) values
in the range of 1.2-1.6 evidenced some deviation in the length of
the vinyl ether oligomers (Figure 1, Table 1), these should be
possible to be minimized in the future by exploring catalytic
systems and/or reaction conditions that allow a living character of
the ROP step and therefore, narrower dispersity.
The formation of the acetal groups by SGP was proven by the
signals appearing between 4.9-4.6 ppm and 1.4-1.3 ppm and
attributed,[ to the methine and methyl protons of the acetal
20]
4
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RESEARCH ARTICLE
moieties, respectively (Figure 2b), further confirmed by their 1J
correlation observed in the 2D COSY NMR spectrum (Figure S4).
Quantitative conversion of the macromonomers into ester acetal
copolymers was indicated by the concomitant disappearance of
the signals of the vinyl proton (CHO at 6.5 ppm. The molar
mass increased significantly after the SGP (Figure 3a), reaching
The sequence length and number of acetal bonds reflected on
a change in the appearance and physical properties of the ester
acetal copolymers (Figure 3b-e). The sample prepared at 1:1
ratio was amorphous, while samples prepared with higher
CL:initiator ratio were semicrystalline and their melting point (T
augmented by lengthening the CL segments. The degree of
crystallinity (X ) increased from 5 to 10 CL units and was
comparable for samples having longer CL segments (Figure
3d,e) being however, higher than the X of a high molar mass
m
)
the highest M
n
value for the sample prepared with a 10:1 ratio.
c
Longer polymerization time led to higher molar mass for the 1:1
sample (Table 1, entry 1-2). By keeping constant the reaction time
of the SGP to 96 h, the molar mass values decreased by
increasing the length of the vinyl ether oligoCL more than 10 CL
units (Figure 3a), probably as a result of lower probability of acetal
bonds formation due to the reduced number of chain-ends and
slower diffusion of the longer oligomers (Table 1). Nevertheless,
the positioning and number of the acetal bonds linearly decreased
from 36 to 4.5 in agreement with the ratio of monomer to initiator
c
commercial PCL sample (Table S2). Differently from other
polymers, the degree of crystallinity of PCL is lower for polymers
of high molar mass.[ Thus, the crystallinity of the ester acetal
copolymers of CL might be affected by the molar mass, the CL
sequence length and the presence of acetal groups, the last
25]
having a higher effect on T
mobility. A higher chain mobility might explain the slightly higher
for the sample prepared at 10:1 ratio. Glass transition
temperature (T ) was instead not be observed under the current
experimental conditions (Table S2).
m
and therefore on increasing chain
(
Figure 2b, Figure 3c), confirming the sequence regulation in
X
c
encoding the degradable bonds. The highest number of acetal
bonds per ester function and the prevalent formation of perfectly
alternating ester acetal sequences for the copolymers prepared
with 1:1 of CL to initiator ratio were confirmed by MALDI-ToF-MS
analysis, Figure 4.
g
Figure 4. MALDI-ToF-MS analysis of the ester acetal copolymer prepared at a 1:1 monomer to initiator ratio (Table 1, entry 2). m/z values of the peak series are
reported in Table S1.
The positioning and number of acetal bonds, controlled by
selecting the monomer to initiator ratio, reflect on the bulk
properties of the materials and their erosion profile (Figure 5).
The mass loss of films of selected ester acetal copolymers of CL
was evaluated under hydrolytic conditions over 8 days and
compared with a commercial PCL. Contrary to the PCL, each
copolymer sample showed mass loss from the early stage of
degradation and the erosion increased with the time and by
tuning the quantity of acetal to ester functionalities. Indeed, given
a certain time point, the mass loss values linearly decrease with
the monomer to initiator ratio (Figure 5). The results indicate that
surface erosion is favoured over bulk degradation and confirm
that the sequence regulation achieved during the synthesis
affords, under hydrolytic conditions, a controlled and predictable
erosion rate. This behaviour is the opposite of the bulk
degradation of aliphatic polyesters, characterized by a long
Figure 5. Mass loss (%) of selected ester acetal copolymers prepared at
different CL to initiator ratio and compared with a commercial PCL. Values are
listed in Table S3.
temporal gap between degradation and mass loss and by an
unpredictable erosion profile.[1a],[5],[7]
5
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To further expand the scope of the methodology and strengthen
its potential in designing a library of different polymers, other
monomers were evaluated (Figure 1b,c) by keeping constant the
ratio of monomer to initiator to 10:1, as it gave the best results for
the polymerization of CL (Table 1, entries 8-10).
The polymerization procedure was extended to L-lactide (LA)
evidencing the possibility of synthesizing copolymers having the
same degradability functions as for the polymerization of CL, but
with a different structure of the ester sequences. In this case, the
formation of the acetal bonds entailed the attack of a secondary
hydroxyl group on the vinyl bond, which due to steric reasons had
probably lower reactivity than the primary –OH formed by ROP of
CL. In fact, a lower molar mass was measured for the ester acetal
copolymer prepared with LA compared with CL, although the total
conversion of LA into the vinyl ether oligomers was achieved by
ROP (Table 1, entry 4,8).
attributed to the methine and methyl carbons of the acetal groups
were detected in the range of 100-99 and 20-19 ppm of the 13
NMR spectra, respectively (Figure S5).
C
Thermal analysis showed that only the copolymer prepared by
polymerization of DX was semicrystalline. While, the T values of
the three copolymers prepared by polymerization of LA, TMC and
DX, were respectively 20.6, -34.3 and -17.4 °C, lower than the T
g
g
values usually observed for the corresponding homopolymers
(Table S2, entries 8-10).[26] An analogous influence of the acetal
groups on the T
g
has also been recently observed for random
copolymers of lactide and 1,3-dioxolane.[
27]
More complex primary structures were also achieved
implementing the same strategy (Figure 1d, Figure 6).
Vinyl ether oligo CL and vinyl ether oligoLA were prepared in two
separate reaction vessels with identical length (10:1 monomer to
n
initiator ratio) and therefore, similar M . After complete conversion
Proving the versatility of the strategy toward both structural and
degradability function diversity, copolymers having carbonate
segments and ether ester segments linked by spatially regulated
acetal bonds were successfully synthesized by polymerizing
of the monomers, the two reaction solutions were combined and
the reaction conditions switched to SGP to yield a mutiblock
copolymer, where each block consisted of either CL or LA
segment spaced by the acetal moieties (Figure 6a; Table 1, entry
n
trimethylene carbonate (TMC) and p-dioxanone (DX) respectively, 11). The increase in the absolute value of M and the monomodal
Figure 1b,c. Carbonate bonds are susceptible to enzymatic
degradation, while ether bonds undergo radical oxidation, and
both of them induce surface erosion.[ Total conversion of TMC
by ROP was achieved after 2 h and the carbonate acetal
molar mass distribution observed after the SGP step suggested
the formation of the envisaged copolymer architecture, further
confirmed by DOSY NMR where the signals of the LA and CL
segments lied at the same diffusion coefficient thus, they
belonged to the same polymeric chain (Figure 6c). In contrast, a
vinyl ether oligo(CL-ran-LA) with an average of 10.5 monomeric
units was obtained from the random oligomerization of a 50:50
mixture of CL and LA in presence of ethylene glycol vinyl ether,
which underwent SGP forming a random CL/LA copolymer with
acetal bonds discretely positioned every 10.5 ester units (Figure
6b; Table 1, entry 12). The primary structure of the synthesized
copolymers, was confirmed by analysis of the methine and
methylene regions of their C NMR spectra. Signals attributable
to consecutive LA-LA and CL-CL homosequences were solely
observed for the multiblock copolymers, while signals attributable
to LA-CL and CL-LA heterosequences were detected for the
copolymer consisting of random CL/LA segments confirming the
statistical arrangement of the ester monomeric units (Figure 6d).
5]
n
copolymer was successfully prepared with relatively high M , 37.5
-
1
kg mol , and having on average 18 acetal bonds per chain at a
distance of 9 TMC units. Slightly lower conversion, 85%, was
reached after 2.5 h for the ROP of DX, and a lower molar mass
was measured for the relative ester ether acetal copolymers
(
Table 1, entry 9,10), most likely due to poor solubility of the
polymer at increased molar mass. In other words, the low M
value obtained by SEC probably accounts only for the low molar
mass soluble faction in CHCl . Indeed, precipitation of the
n
13
3
polymer was observed during the SGP and therefore, the reaction
was terminated after 24 h. Besides the increase in molar mass
observed by SEC after the SGP step, the formation of the
envisaged copolymers was supported by NMR analysis for all the
four monomers. For instance, along with the signals of the
repeating CL, LA, TMC or DX monomeric units, the peaks
Figure 6. Reaction scheme for the synthesis of (a) multiblock and (b) random ester acetal copolymers of CL and LA. (c) DOSY NMR spectra (400 MHz, CDCl
the multiblock LA/CL copolymer with spatially regulated acetal bonds. (d) Selected region of 13C NMR spectra (101 MHz, CDCl
) of (i) ester acetal copolymer of LA;
ii) multiblock ester acetal copolymer of LA and CL (iii) random ester acetal copolymer of LA and CL and (iv) ester acetal copolymer of CL, Table 1, entry 4, 8, 11,
2.
3
) of
3
(
1
6
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The difference in the primary structures reflected on the thermal
properties of the copolymers (Figure S6). The multiblock
copolymer was semicrystalline with a T similar to the ester acetal
m
copolymer prepared by polymerization of CL, indicating the ability
of the long CL segments to crystallize. The random copolymer
g
was instead amorphous with a T much lower than the analogous
Keywords Sequence-controlled polymers; surface and bulk
degradation; ester and acetal; atom-economy; one-pot ring-
opening and step-growth polymerization.
[
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The Swedish Research Council (VR Starting Grant n. 2020-
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7
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.202103143
RESEARCH ARTICLE
Table of Contents
A dual polymerization approach creates new possibilities to access polymeric materials with sequence-controlled primary structure
and diverse degradable bonds. The methodology is overall simple and effective and involves an in situ organocatalyst switch, which
reflects on different polymerization mechanisms and respectively, in specific degradability functions encoded.
8
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