Hydrolyzable polyureas bearing hindered urea bonds

Article abstract of DOI:10.1021/ja5093437

Hydrolyzable polymers are widely used materials that have found numerous applications in biomedical, agricultural, plastic, and packaging industrials. They usually contain ester and other hydrolyzable bonds, such as anhydride, acetal, ketal, or imine, in their backbone structures. Here, we report the first design of hydrolyzable polyureas bearing dynamic hindered urea bonds (HUBs) that can reversibly dissociate to bulky amines and isocyanates, the latter of which can be further hydrolyzed by water, driving the equilibrium to facilitate the degradation of polyureas. Polyureas bearing 1-tert-butyl-1-ethylurea bonds that show high dynamicity (high bond dissociation rate), in the form of either linear polymers or cross-linked gels, can be completely degraded by water under mild conditions. Given the simplicity and low cost for the production of polyureas by simply mixing multifunctional bulky amines and isocyanates, the versatility of the structures, and the tunability of the degradation profiles of HUB-bearing polyureas, these materials are potentially of very broad applications.

Full text of DOI:10.1021/ja5093437

Communication
pubs.acs.org/JACS
Hydrolyzable Polyureas Bearing Hindered Urea Bonds
Hanze Ying and Jianjun Cheng*
Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States
S Supporting Information
*
reaction of widely available, di- or multifunctional isocyanates
and amines that do not require the use of catalysts and extreme
reaction conditions and do not produce any byproducts. Urea is
one of the most stable chemical bonds against further reactions
including hydrolysis due to the conjugation stabilization effects
of its dual amide structure. However, urea bonds can be
destabilized by incorporating bulky substituents to one of its
nitrogen atoms, by means of disturbing the orbital coplanarity
of the amide bonds that diminishes the conjugation effect
ABSTRACT: Hydrolyzable polymers are widely used
materials that have found numerous applications in
biomedical, agricultural, plastic, and packaging industrials.
They usually contain ester and other hydrolyzable bonds,
such as anhydride, acetal, ketal, or imine, in their backbone
structures. Here, we report the first design of hydrolyzable
polyureas bearing dynamic hindered urea bonds (HUBs)
that can reversibly dissociate to bulky amines and
isocyanates, the latter of which can be further hydrolyzed
by water, driving the equilibrium to facilitate the
degradation of polyureas. Polyureas bearing 1-tert-butyl-
18
(Scheme 1). Urea bonds bearing a bulky substituent, or
a
Scheme 1. Illustration of Hydrolysis Mechanism of HUBs
1-ethylurea bonds that show high dynamicity (high bond
dissociation rate), in the form of either linear polymers or
cross-linked gels, can be completely degraded by water
under mild conditions. Given the simplicity and low cost
for the production of polyureas by simply mixing
multifunctional bulky amines and isocyanates, the
versatility of the structures, and the tunability of the
degradation profiles of HUB-bearing polyureas, these
materials are potentially of very broad applications.
a
Urea bond is destabilized by bulky substituents induced bond
rotation and loss of conjugation effect.
olymers with transient stability in aqueous solution, also
P
known as hydrolyzable polymers, have been applied in
many biomedical applications, such as in the design of drug
HUBs, can reversibly dissociate into isocyanate and amines and
show interesting dynamic property. The fast reversible
reactions between HUBs and isocyanates/amines have been
1
2
delivery systems, scaffolds for tissue regeneration, surgical
3
4
sutures, and transient medical devices and implants. These
applications usually require short functioning time and
complete degradation and clearance of materials after their
use. Hydrolyzable polymers have also been applied in the
design of controlled release systems in agriculture and food
industries and used as degradable, environmentally friendly
19
the basis in our recent design of self-healing polyureas.
Because isocyanates can be subject to hydrolysis in aqueous
solution to form amines and carbon dioxide, an irreversible
process that shifts the equilibrium to favor the HUB
dissociation reaction and eventually lead to irreversible and
complete degradation of HUBs (Scheme 1), we reason that
HUBs can be used to design easily available hydrolyzable
polymers potentially for the numerous applications above-
mentioned. Herein, we report the development of HUB-based
polyureas that can be hydrolyzed with hydrolytic degradation
kinetics tunable by the steric hindrance of the HUB structures.
The property of a dynamic covalent bond can be expressed
5
plastics and packaging materials. Besides polyesters, a class of
6
widely used, conventional hydrolyzable materials, a large7
variety of other hydrolyzable polymers bearing anhydride,
8
9
10
11
11,12
13
orthoester, acetal, ketal, aminal, hemiaminal,
phosphoester, and phosphazene bonds have also been
reported. Syntheses of these polymers usually involve
imine,
1
4
15
2
d
16
condensation or ring-opening polymerization,2 and these
d
by its K , the binding constant showing the thermodynamic
syntheses typically involve removal of byproducts and use of
eq
2d
6b
stability of the dynamic bond, and its k , the dissociation rate
high reaction temperature and/or metal catalysts, which
complicates materials preparation. In this study, we report the
design of polyureas bearing hindered urea bonds (HUBs) as
potentially one of the least expensive degradable polymers that
can be easily synthesized by mixing multifunctional bulky
amines and isocyanates, expanding the family of hydrolyzable
polymers.
−1
of the dynamic bond. According to the hydrolytic degradation
mechanism of a HUB shown in Figure 1a, the rate of hydrolysis
equals to the rate of the formation of product D, which can be
expressed by eq 1 considering addition of B and water is the
rate-determining step:
Polyureas are commonly used as fiber, coating, and adhesive
materials. They can be readily synthesized via addition
Received: September 10, 2014
1
7
©
XXXX American Chemical Society
A
dx.doi.org/10.1021/ja5093437 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
hydrolysis. This is consistent with the notion that more
dynamic HUBs (more bulky N-substituents) give faster
hydrolytic degradation. To confirm this, we analyzed the
19a
dynamic parameters
and the hydrolysis kinetics of five
different HUB-containing model compounds (1−5, Figure 1b)
with their dynamicity and hydrolytic degradation parameters
summarized in Figure 1c (see all the measurement details in
Figures S1−S20). All five compounds were synthesized by
mixing the corresponding isocyanates and amines at 1:1 molar
ratio. Compounds 1−3 have similar bulkiness, which are all
based on 1,1-tert-butylethylurea (TBEU, R3 = tert-butyl)
structure. They show nearly identical k . Compounds 4 and
−1
5
have less bulky 1-iso-propyl-1-ethylurea (IPEU, R = iso-
3
propyl) structure, which show lower dynamicity than 1−3
(
higher K and lower k ). For these two IPEU-based
eq
−1
compounds, 4 shows higher dynamicity than 5 with lower
Keq and higher k−1 due to its more bulky isocyanate structure
(
more bulky R and R ).
1 2
We went on to analyze the hydrolytic degradation profiles of
1
1
6
−5 by H NMR. The compound was dissolved in a mixture of
d -DMSO and D O (v(d -DMSO)/v(D O) = 5:1). The
2
6
2
percentage of the hydrolyzed products was analyzed after the
mixture was incubated for 24 h at 37 °C (Figure 1d; the
hydrolytic degradation of 3 was shown as an example). All three
TBEU-based compounds (1−3) showed over 50% of hydro-
lytic degradation of their urea bonds, with 2 showing the fastest
degradation (85%) due to its lowest K . Compound 4, bearing
eq
less bulky (less dynamic) IPEU structure, showed slower
hydrolytic degradation (∼10%) compared to 1−3. No
detectable hydrolysis was observed for compound 5 because
of its least substituent bulkiness (lowest dynamicity, Figure 1c).
These results are consistent with the conclusion drawn from eq
3
.
We next examined if polymers bearing HUBs (pHUBs)
could also be degraded by water. Linear pHUBs were
synthesized by mixing diisocyanates and diamines at 1:1
molar ratio in DMF. Although the bulky substituents in HUBs
destabilize the urea bond, the HUBs still have sufficiently large
5
binding constants (Keq ∼ 10 , see Figure 1c) to form high
Figure 1. Dynamicity and hydrolytic degradation of HUB-containing
model compounds. (a) Parameters related to the hydrolytic
degradation of HUBs. (b) Structures of five HUB-containing model
molecular weight polymers. Poly(6/9), poly(7/9), poly(8/10),
and poly(6/10), four different pHUBs with descending
dynamicity, were prepared by mixing the corresponding
diisocyanate (1,3-bis(isocyanatomethyl)cyclohexane (6), 1,3-
bis(isocyanatomethyl)benzene (7) or 1,3-bis(1-isocyanato-1-
methylethyl)benzene (8)), and diamine (N,N′-di-tert-butyle-
thylenediamine (9) or N,N′-di-iso-propylethylenediamine
compounds. (c) Binding constants (K ), dissociation rates (k ), and
eq
−1
water degradation kinetics of five HUB-containing model compounds
shown in (b). (d) Representative NMR spectra showing the
degradation of 3. The percentage of hydrolysis was determined by
the integral ratio of peaks corresponding to starting compounds and
hydrolysis products as shown in the inset.
(
1
10)). The HUB structure of poly(6/9), poly(7/9), poly(8/
0), and poly(6/10) resembles the corresponding model
d[D]
dt
compounds 2−5 (Figure 2a). The M ’s of these four polymers
r(hydrolysis) =
= k [B][H O]
n
2
2
(1)
were 22, 22, 44, and 120 kDa, as characterized by gel
permeation chromatography (GPC), and showed correlation
Since the isocyanate B is a dissociative intermediate with very
low concentration, a steady-state approximation expressed as eq
with their K ’s. To study the hydrolytic degradation of these
eq
pHUBs, 5% of water was added to the DMF solutions of each
polymer. These solutions were vigorously stirred and incubated
at 37 °C, and the molecular weights were monitored by GPC at
selected time. MW decrease was observed for TBEU-based
poly(6/9) and poly(7/9) (Figure 2b). For IPEU-based
polymers, poly(8/10) showed limited degradation, while
2
is thus deduced:
k [B][H O] + k [B][C] = k [A]
(2)
2
2
1
−1
As Keq = k /k , eq 3 can thus be deduced from eq 1 and 2:
1
−1
k [A][H O]
2
2
r(hydrolysis) =
poly(6/10) barely showed any change of its M after 24 h
n
k
2
K [C] + k [H O]
(Figures 2c and S25−S28). After incubation for 48 h, the
percentages of MW reduction for poly(6/9), poly(7/9), and
poly(8/10) were 88%, 81%, and 43%, respectively. The MW of
poly(8/10) did not further decrease for elongated incubation
eq
2
(3)
−1
According to eq 3, the hydrolysis kinetics is related to both
Keq and k , with smaller K and larger k−1 giving faster
−1
eq
B
dx.doi.org/10.1021/ja5093437 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Figure 2. Water degradation of pHUBs. (a) Synthesis of four different
types of pHUBs by simply mixing diisocyanates and diamines. (b)
GPC curves showing water degradation of poly(6/9) and poly(7/9) in
H O/DMF = 5:95 after 24 h incubation at 37 °C. (c) Plot showing
2
molecular weight reduction of four polymers drawn in (a) in H O/
Figure 3. Water degradation of pHUBs. (a) Triisocyanate and diamine
cross-linked into organogel in DMF with the preaddition of water. (b)
Synthesis of urea-based cross-linked hydrophilic polymer G1 and G2
by UV polymerization. (c) Organogel synthesized from (a) collapsed
into solution after 24 h incubation at 37 °C. (d) Weight change of G1
2
DMF = 5:95 for various incubation time at 37 °C.
(
Figure 2c), which could be attributed to the increase of free
amine concentration that inhibits degradation (see eq 3, larger
C] gives lower degradation rate). The alteration of polymer
(
black curve) and G2 (red curve) after immersing in PBS for variant
[
time. Data represent averages of triplicate experiments. Error bars are
standard deviation (n = 3).
hydrolysis kinetics with the change of HUB bulkiness was
consistent with the results derived from the study of small
molecular model compounds 1−5.
To further demonstrate the hydrolytic degradation of TBEU-
based polymer, we prepared a cross-linked organogel by mixing
tri-isocyanate 11 with diamine 9 in DMF containing 5% water.
Because isocyanate reacts with amine much faster than with
water, 9 and 11 first reacted to form polyurea gel. The added
water slowly hydrolyzed the TBEU bond, which led to the
collapse of the gel after the gel was incubated 24 h at 37 °C
contrast, G1 showed consistent weight decrease and completely
disappeared after incubation for 4 days (Figure 3b). We should
notice that the degradation of TBEU might give a stable urea as
the product since the amine from hydrolysis of isocyanate
might react with another isocyanate molecule (as shown in the
example in Figure 1d), which will hold the network without
complete degradation. However, we observed complete
degradation of G1 in PBS, which meant that the formation of
stable urea rarely happened in this case. Several reasons might
explain the reduced probability of urea coupling: (i) much
higher water concentration in pure water environment than
organic solvent environment; (ii) protonation of amine groups
in buffered neutral pH reduces reactivity; and (iii) amine
groups are embedded by long oligo-ethylene glycol chains,
which block their reaction of the exposed isocyanate.
In conclusion, we demonstrated the potential of HUBs for
the design of water degradable polymeric materials. Kinetic
analyses of small molecule model compounds prove that more
bulky HUBs lead to faster water degradations. The same trend
applies to the polymeric materials, with TBEU as one of the
HUBs having the appropriate bulkiness for both sufficient
binding stability for polymer formation and efficient dynamicity
for water degradation. TBEU-based linear polymers degrades to
10−20% of their original size within 2 days. TBEU is also
incorporated into cross-linked hydrogel materials which render
complete water dissolution of the hydrogel within 4 days,
making pHUBs alternative building blocks of hydrolyzable
hydrogels. pHUBs provide a great new platform for the
engineering of hydrolyzable materials. First, the degradation
kinetics could be directly controlled by substituents bulkiness.
(Figure 3a,c).
To study pHUBs degradation in aqueous solution and
explore the potential of pHUBs for biomaterials applications,
we designed hydrophilic polymers bearing HUB cross-linkers.
To poly(ethylene glycol) methyl ether methacrylate monomer
(
M ∼ 500), we added HUB containing dimethacrylate 13−14
n
as cross-linkers and Irgacure 2959 as the photoinitiator. The
HUBs structures in 13−14 are TBEU and IPEU, respectively.
The mixtures were irradiated by UV light (365 nm) to prepare
the cross-linked polymers G1 and G2 (Figure 3b). We first did
dynamic exchange study of G1 and G2 by immersing them in
DMF in the presence or absence of hexylamine. In the absence
of hexylamine, both gels swelled, demonstrating they are cross-
linked polymers. In the presence of hexylamine, only G1 was
dissolved, while G2 stayed intact. This experiment demon-
strated that TBEU-containing G1 has much faster dynamic
exchange than G2, which is the requisite for efficient water
degradation. For the water degradation study, we immersed G1
and G2 into phosphate buffered saline (PBS) and monitored
the weight change at various time with the incubation at 37 °C
(
gels were pretreated with deionized water with short time to
2d
remove all the unreacted monomers). The weights of G2
remained nearly unchanged after incubation for 9 days. In
C
dx.doi.org/10.1021/ja5093437 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
While we have demonstrated the use of TBEU for water
degradable materials within days under mild conditions, less
bulky urea might be used for applications which need longer
lasting time or harsher degradation conditions (such as poly(8/
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AUTHOR INFORMATION
Corresponding Author
jianjunc@illinois.edu
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ACKNOWLEDGMENTS
■
This work is supported by United States National Science
Foundation (CHE1153122) and United States National
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