Hindered urea bond: A bilaterally responsive chemistry to hydrogen peroxide

Article abstract of DOI:10.1002/ejoc.201801307

As a type of safe, clean, and bio-relevant oxidant, hydrogen peroxide has been widely used as a trigger in the design of stimuli-responsive materials. Hindered urea bond (HUB) is a type of dynamic covalent bond which can reversibly dissociate into isocyanate and amine. Quenching of isocyanate or amine will shift the equilibrium and facilitate the degradation of HUB bond. Herein, we report that one of the HUB moiety – 1,1-tert-butylethylurea (TBEU) can react with hydrogen peroxide (H₂O₂) resulting in two opposing outcomes. Perhydrolysis of isocyanate and oxidation of amine lead to the bond fracture, while formation of urethane product with an oxygen inserted into the original TBEU structure was also observed giving a stabilized form of linkage. More precise kinetic control of the two distinct pathways are expected to make hydrogen peroxide a trigger to either degrade or fix the HUB based polymeric materials.

Full text of DOI:10.1002/ejoc.201801307

DOI: 10.1002/ejoc.201801307
Communication
Hindered Urea Bond | Very Important Paper |
Hindered Urea Bond: A Bilaterally Responsive Chemistry to
Hydrogen Peroxide
Hanze Ying,[a] Yingfeng Yang,[a] Kaimin Cai,[a] and Jianjun Cheng*[a,b]
Abstract: As a type of safe, clean, and bio-relevant oxidant, (H2O2) resulting in two opposing outcomes. Perhydrolysis of iso-
hydrogen peroxide has been widely used as a trigger in the cyanate and oxidation of amine lead to the bond fracture, while
design of stimuli-responsive materials. Hindered urea bond formation of urethane product with an oxygen inserted into
(HUB) is a type of dynamic covalent bond which can reversibly the original TBEU structure was also observed giving a stabi-
dissociate into isocyanate and amine. Quenching of isocyanate lized form of linkage. More precise kinetic control of the two
or amine will shift the equilibrium and facilitate the degradation distinct pathways are expected to make hydrogen peroxide a
of HUB bond. Herein, we report that one of the HUB moiety – trigger to either degrade or fix the HUB based polymeric mate-
1,1-tert-butylethylurea (TBEU) can react with hydrogen peroxide rials.
Introduction
and fast exchange kinetics in ambient condition. Therefore,
TBEU can be facilely incorporated into high molecular weight
polymers (pTBEU) with swift chain exchange at low tempera-
ture. Due to the dynamic properties of TBEU, the polymeric
state of pTBEU is responsive to a variety of chemical signals that
can interact with its dissociative intermediates, such as amine,
alcohol, water, etc. They were demonstrated to shift the chemi-
cal equilibrium and reduce the size of polymers. However, none
of these triggers can stabilize (shut off the dynamicity of) the
DCB without breaking the linkage. Such a type of reaction has
been achieved for other DCBs such as hydrogenation of dy-
namic imine[28,29] or alkene bonds.[30] This reaction is very use-
ful in the case that the bond dynamic exchange is required
during the synthesis, but needs to be turned-off for the stabi-
lized form of final products, such as in the synthesis of macro-
cycles.[28–30] Herein, we report H2O2 as the chemical trigger that
can react with HUB in two distinct pathways leading to both
bond fracture and fixation (Scheme 1).
Stimuli-responsive materials[1] have been widely used in the de-
sign of drug-delivery,[2–3] tissue engineering,[4] sensors,[5] and
tunable catalysis.[6] A variety of external stimuli can be used for
the triggered degradation, such as pH,[7] light,[8] temperature,[9]
redox reagents,[10] enzyme,[11] etc. Hydrogen peroxide (H2O2) is
gaining popularity in the designs of stimuli-responsive materi-
als in recent years as a safe, clean, and massively-produced
oxidant.[12] It is also a type of reactive oxygen species (ROS)
existing in living creatures related to diseases such as cancer
or inflammation.[13–14] Many drug carriers incorporate chemical
bonds that are responsive to H2O2 to selectively release the
drug.[15–16] A lot of chemistries have been developed that can
selectively respond to H2O2, such as boron esters,[17–18] thio-
ketal,[10] thioether,[19] oxalate,[20] benzil,[21] etc. Most of these
chemistries show bond fracture (reduction of molecular size)
when being treated by H2O2. However, other types of effects
have rarely been reported.
Hindered urea bond (HUB) is a type of dynamic covalent
bond (DCB),[22–24] which can reversibly dissociate into isocyan-
ate and amine.[25–27] Among them, 1,1-tert-butylethylurea
(TBEU) is one of HUBs that has both large equilibrium constant
[a] Department of Materials Science and Engineering, Department of
Bioengineering, Department of Chemistry, Beckman Institute for Advanced
Science and Technology, Micro and Nanotechnology Laboratory, Institute
of Genomic Biology, Materials Research Laboratory, University of Illinois at
Urbana-Champaign,
Scheme 1. H2O2 induced degradation or fixation of TBEU bond.
1304 W. Green Street, Urbana, IL, 61801, USA
E-mail: jianjunc@illinois.edu
cheng.matse.illinois.edu
Results and Discussion
[b] Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices,
Institute of Functional Nano & Soft Materials (FUNSOM), Soochow
University,
The reaction between TBEU bond and H2O2 was first observed
in a degradation study of linear pTBEU. Dynamic polymers
pTBEUs were synthesized by polyaddition reaction of diiso-
cyanate and diamine with 1:1 equivalence. Here, ꢀ-branched
Suzhou 215123, Jiangsu, China
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201801307.
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instead of linear isocyanates were used to synthesize pTBEU,
Next, we used dynamic urea model compound 3 to explore
which increased solubility of the resulting polymers in organic the degradation process of TBEU bond by H2O2 in molecular
solvent. Compounds m-xylylene diisocyanate (1) and N,N′-di- details. Urea 3 was synthesized by mixing isocyanate 4 and
tert-butylethylenediamine (2) were mixed with 1:1 equivalence amine 5 in 1:1 equivalence. Due to the dynamic property of
in dimethylformamide (DMF, 25 % weight ratio) giving TBEU bond, 3 can dissociate, giving back the starting com-
poly(1/2) (Figure 1a). Polymer with molecular weight of around pounds 4 and 5 reversibly (Scheme 2). We postulated that the
9.0 kDa was obtained as shown in gel permeation chromatogra- degradation of TBEU is caused by reaction of its dissociative
phy (GPC) characterization. We then did the polymer degrada- intermediates with H2O2, so we first studied the reaction of
tion study directly in DMF solution without purification. The H2O2 with 4 and 5, separately. With [D3]acetonitrile as the sol-
polymer solution was added 0.05 mol/mol urea bond of H2O2 vent, isocyanate 4 was treated with H2O2 or water and moni-
1
(as a form of 30 % aqueous solution) and incubated at 37 °C. tored by H NMR spectroscopy. Hydrolysis product urea 6 was
The molecular weight reduction of polymer was monitored by observed for both reactions. However, the reaction in H2O2 is
GPC. Gradual right shift of GPC peaks was observed over time much faster. In the NMR spectra, we also observed an interme-
(Figure 1b). After 24 h, the molecular weight of poly(1/2) de- diate during the hydrolysis process in H2O2, which was not
creased from 9.0 kDa to 2.5 kDa (Figure 1c). To confirm that the found in the solution with only the addition of water (Figure
degradation is not only from water in H2O2 solution, same S4). The intermediate was assumed to be formed by H2O2 at-
weight of water was added to the polymer solution, and the tacking isocyanate, which was supported by ESI mass spectrum
molecular weight change was also monitored as a control (Figure S5). Here H2O2 is a better nucleophile than water, which
study. Although water can also degrade the HUB by quenching accelerates the hydrolysis kinetics of isocyanate group (also
the isocyanate dissociative intermediate, the degradation is named as perhydrolysis).[31] Later, the reaction of H2O2 with an-
much slower than H2O2. Little change of molecular weight for other dissociative intermediate amine 5 was examined. We ob-
poly(1/2) was observed after 24 h (from 9.0 kDa to 8.2 kDa, served that the amine 5 could be oxidized to hydroxylamine 7
Figure S1) at the same temperature. The degradation study was and further to amine oxide zwitterion 8 with the existence of
also performed on another pTEBU synthesized from 1,3-bis(iso- H2O2 after 24 h at 37 °C in [D3]acetonitrile (Figure S6–S7).[32]
cyanatomethyl)cyclohexane (S1) and 2, and the similar results
were obtained (Figure S2). Also to demonstrate that the H2O2
interacts with TBEU bond rather than the other parts of poly-
meric chains, we synthesized a control polymer poly(S1/S2) by
mixing S1 with N,N′-di-isopropylethylenediamine (S2) in 1:1
molar ratio. In the new polymer, the urea bond is substituted
with less hindered group (less dynamic, k-1 = 0.0015 h–1 com-
pared with 0.21 h–1 for TBEU[25]). No matter the polymer was
treated with H2O2 or water under the same condition, no reduc-
tion of molecular weight was shown, demonstrating that the
reaction only happens at the urea bond with high bulkiness,
and the rest part of the polymer backbone is stable to H2O2
(Figure S3).
Scheme 2. Proposed reaction process after treating TBEU with H2O2. Bond
fracture products 5~8 and bond fixation product 9 were all observed at the
same time.
After we learned that both dissociative intermediates of
TBEU can react with H2O2, we then performed the experiments
adding H2O2 to solution of urea compound 3 (Figure S8). As
expected, we observed the production of 5, 6 and 8 by treating
3 with H2O2. However, the formation of another product 9 was
also detected, indicating an opposing result of this reaction that
we did not expect initially. Compound 9 was identified as a
urethane compound with an oxygen atom inserted between
carbonyl and hindered nitrogen atom of the original urea 3,
which can possibly be formed from addition reaction between
isocyanate 4 and hydroxylamine 7. The reaction between iso-
cyanate and hydroxylamine was demonstrated to be very fast
(confirmed by model reaction between 4 and commercial avail-
able diethylhydroxylamine 10, see Figure S11), which strongly
drives the competition reaction towards the urethane side once
the isocyanate 4 and hydroxylamine 7 is available from dissoci-
ation of 3 and oxidation of 5. As control experiments, urea 3
was treated with same amount of water. No degradation was
observed at 37 °C after 24 h, proving that the triggered-
Figure 1. Degradation of pTBEU by hydrogen peroxide (H2O2). (a) synthesis
of poly(1/2); (b) GPC curves showing degradation by H2O2 over time at 37 °C.
(c) Change of molecular weight of poly(1/2) after treating with H2O2 over
time.
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response effect was from hydrogen peroxide (Figure S9). Fur- been demonstrated in our previous work.[25–26] Although we
thermore, we examined the reaction of less hindered urea 3′ have not achieved the complete elimination for one of the
under the same H2O2 reaction condition (Figure S10). No reac- process, the experiment clearly showed that the kinetics of two
tion was identified either, demonstrating that the reversibility pathways can be tuned through change of reaction conditions.
of the bond is necessary for the reaction to happen.
Based on the results above, we identified two distinct out-
comes of the reaction between TBEU and H2O2. The TBEU bond
Conclusions
dissociates into two intermediates – isocyanate and amine,
In summary, we demonstrated that H2O2 can be used as the
both of which are quenched by H2O2 (product 5, 6, 8) and
trigger to change the bonding state of TBEU. Perhydrolysis of
cannot reform the TBEU bond (bond fracture). However, one of
isocyanate and oxidation of amine quench the dissociative in-
the oxidation products of amine – hydroxylamine can bind with
termediates, shift the chemical equilibrium and degrade the
isocyanate and reform the bond (product 9) with dynamic
TBEU bond. Besides the bond fracture process, an opposing
property turned-off (bond fixation). These two pathways lead
result of the reaction was also identified. The binding of
to completely different outcomes of pTBEU materials after the
hydroxylamine and isocyanate gives a urethane product with
H2O2 triggered reaction. While the first pathway results in the
an oxygen inserted into the TBEU bond, which retains the link-
reduction of chain length of polymers and weakening of mate-
age and turns off the dynamic property. An example was shown
rials, the second one maintains the degree of polymerization
that the kinetics ratio between the two pathways can be tuned
and eliminates the reversible property to strengthen the materi-
to be more favored towards the fixation process through addi-
als.
tion of hindered amine. Our work demonstrates the feasibility
It will be significant if we can have a better control of the
to use oxidation methods to either degrade or stabilize the
competition between these two pathways. Figure 2 shows one
TBEU selectively, which is expected to be further improved by
of the example that can tune the kinetics between two path-
discovering more finely-engineered oxidants or reaction condi-
ways. Two solutions of 3 in [D3]acetonitrile were prepared, and
tions that can completely suppress either one of the process.[33]
one of them was added additional amine molecule 5 that was
used to synthesize 3 (Figure S12–13). After treating both solu-
tions with H2O2 for 24 h at 37 °C, all compound 3 were con-
sumed. However, the ratios of bond fracture product 6 and
bond fixation product 9 are quite different. For the solution
without the addition of 5, two pathways are almost equivalent
Acknowledgments
This work is supported by United States National Science Foun-
dation (NSF CHE 17-09820) and American Chemical Society Pe-
troleum Research Fund (58671-ND7).
([6]/[9] = 53:47). In contrast, for the solution with the addition
of 5, the bond fixation pathway dominates ([6]/[9] = 17:83). The
reason for the change of ratio is that the addition of amine
molecule can suppress the urea hydrolysis process, which has
Keywords: Dynamic covalent bond · Hindered urea ·
Hydrogen peroxide · Degradation · Stabilization
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Received: August 22, 2018
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Hindered Urea Bond
H. Ying, Y. Yang, K. Cai,
J. Cheng* .............................................. 1–5
Hindered Urea Bond: A Bilaterally
Responsive Chemistry to Hydrogen
Peroxide
The hindered urea bond, a type of dy- lead to the bond fracture; while forma-
namic covalent bond which can re- tion of a urethane product with an
versibly dissociate into isocyanate and oxygen inserted into the original urea
amine, responds to hydrogen peroxide structure gives a stabilized form of
in two opposing ways: Perhydrolysis of linkage.
isocyanate and oxidation of amine
DOI: 10.1002/ejoc.201801307
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