Dynamic Ureas with Fast and pH-Independent Hydrolytic Kinetics

Article abstract of DOI:10.1002/chem.201801138

Low cost, high performance hydrolysable polymers are of great importance in biomedical applications and materials industries. While many applications require materials to have a degradation profile insensitive to external pH to achieve consistent release profiles under varying conditions, hydrolysable chemistry techniques developed so far have pH-dependent hydrolytic kinetics. This work reports the design and synthesis of a new type of hydrolysable polymer that has identical hydrolysis kinetics from pH 3 to 11. The unprecedented pH independent hydrolytic kinetics of the aryl ureas were shown to be related to the dynamic bond dissociation controlled hydrolysis mechanism; the resulting hindered poly(aryl urea) can be degraded with a hydrolysis half-life of 10 min in solution. More importantly, these fast degradable hindered aromatic polyureas can be easily prepared by addition polymerization from commercially available monomers and are resistant to hydrolysis in solid form for months under ambient storage conditions. The combined features of good stability in solid state and fast hydrolysis at various pH values is unprecedented in polyurea material, and will have implications for materials design and applications, such as sacrificial coatings and biomaterials.

Full text of DOI:10.1002/chem.201801138

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Title: Dynamic Ureas with Fast and pH-independent Hydrolytic Kinetics
Authors: Kaimin Cai, Hanze Ying, and Jianjun Cheng
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10.1002/chem.201801138
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COMMUNICATION
Dynamic Ureas with Fast and pH-independent Hydrolytic Kinetics
Kaimin Cai, Hanze Ying, and Jianjun Cheng*
Abstract: Low cost, high performance hydrolysable polymers are of
great importance in biomedical applications and materials industries.
While many applications require materials to have a degradation
profile insensitive to external pH to achieve consistent release
profiles under varying conditions, hydrolysable chemistry developed
so far have pH-dependent hydrolytic kinetics. Here, we report the
design and synthesis of a new type of hydrolysable polymer that has
identical hydrolysis kinetics from pH 3 to 11. The unprecedented pH
independent hydrolytic kinetics of the aryl ureas were shown to be
related to the dynamic bond dissociation controlled hydrolysis
mechanism; the resulting hindered poly(aryl urea) can be degraded
with hydrolysis half-life of 10 minutes in solution. More importantly,
these fast degradable hindered aromatic polyureas can be easily
prepared by addition polymerization from commercially available
monomers and resistant to hydrolysis in solid form for months under
ambient storage conditions. The combined features of good stability
in solid state and fast hydrolysis at various pH is unprecedented in
polyurea material, which will have remarkable implications in
materials design and applications such as sacrificial coatings and
biomaterials.
demonstrated to degrade to half the molecular weight within ten
minutes at room temperature in solution while ambient storage
of the solid powder showed negligible hydrolysis over two
months. The transient feature of the HAU and its facile
preparation will have remarkable implications in materials design
and applications such as sacrificial coatings and biomaterials.
Our previous studies have shown that by incorporating a
secondary hindered substituent onto the nitrogen atom, the
resulting hindered urea bond (HUB) was shown to be dynamic
and can reversibly dissociate into secondary amine and
isocyanate.[12] The isocyanate can be hydrolyzed to a primary
amine, which leads to the breakdown of HUB by water.[13]
Although isocyanates hydrolysis is highly pH dependent,[14] we
hypothesized that by incorporating
a pH-insensitive urea
dissociation as the rate-limiting step, the hydrolysis of this type
of “pro-isocyanate” bond can be pH independent (Scheme 1). To
further achieve a faster hydrolytic kinetics, we designed to
replace the previous aliphatic isocyanate with aryl isocyanate.
Aryl amines, as the degradation product of aromatic hindered
ureas, have much lower nucleophilicity than aliphatic amines
and generate undesired non-dynamic urea side product[13] that is
not well soluble in common solvents.
Hydrolysble materials have been widely used in a variety of
fields including biomedical applications[1] and environmental
science.[2] Engineered materials that release encapsulated cargo
consistently independent of surrounding environment, especially
pH, have found tremendous significance in industries of
encapsulation and drug delivery.[3] Orally delivered drugs, for
example, often have varied in vivo bioavailability and thus
uncontrolled therapeutic efficacy due to the variation of drug
release kinetics in response to the change of gastrointestinal pH.
The hydrolysis of conventional degradable polymers including
esters,[4] anhydrides,[5] orthoesters,[6] carbonate,[7] acetal,[8]
phosphoesters,[9] are generally logarithmically pH dependent. So
far, only complex formulations can achieve pH independent
cargo release[10] due to the lack of simple chemistries that can
degrade consistently irrespective of pH change over a wide
range.[11] Here, we report a pH-independent, hydrolysable
materials based on hindered aromatic ureas (HAU). Degradation
profiles of the HAU were shown to be correlated with urea bond
dissociation irrespective of the solution pH. Polymeric HAU was
Scheme 1. Fast and pH-independent hydrolysis of hindered aromatic ureas
(HAU). The hydrolytic kinetics is limited by the urea bond dissociation rate k-1,
which is independent of solution pH.
We first designed a set of aryl ureas with distinguished
electronic effect on the conjugated phenyl ring (Table 1) and
1
studied the corresponding Keq by H NMR through exchanging
of the urea with a set of bulky amines in d-chloroform (Figure
S1-S12). Similar to our previous findings,[12] the equilibrium
constant of the aryl urea bond increases as the bulkiness of the
substitution on amine decreases (Table S1). All of the three t-
butyl-ethylureas (tBEU) showed high Keq (> 2×104) and the Keq
increases as the phenyl ring becomes more electron deficient
(Table 1). The dissociation constant k-1 was measured by
exchange study of the ureas with N-methyl-t-butyl amine or t-
butyl amine (Figure S13-S18) and calculated through linear
[*]
Dr. K. Cai, Dr. H. Ying, Prof. Dr. J. Cheng
Department of Materials Science and Engineering
Prof. Dr. J. Cheng
[푐
]
푡퐵퐸푈
regression of ln(
− A) -t.[12] Remarkably, the amine
]
0
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
1304 W. Green Street,
[푐
tBEU
exchange of the tBEU could reach equilibrium within one hour at
room temperature in d-chloroform (Figure S13-S15). The k-1 of
tBEU with aryl substitution is two orders of magnitudes larger
than the reported aliphatic urea (Table 1) and among the fastest
dynamic chemistries reported so far.[15] In addition, the
calculated k1 is larger than 105 M-1·h-1 indicating that the urea
formation can complete within seconds upon mixing. The
substituent on the arene can remotely affect the HUB through
Urbana, IL, 61801, USA
E-mail: jianjunc@illinois.edu;
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/chem.201801138
Chemistry - A European Journal
COMMUNICATION
electronic effect, thus offering an extra tunability on the Keq and
k-1 of the bond, which is unprecedented in hindered urea
chemistry. The large value of Keq also makes it possible to
prepare high molecular weight polymeric aromatic hindered urea
materials.
instead of the isocyanate hydrolysis. Kinetic analysis of the
hydrolytic kinetics (Supporting Information page S5) confirmed
that the overall urea degradation rate is determined by the urea
dissociation and can be expressed as
푑[푨]
(
)
[ ]
= 푘−1 푨
푟 ℎ푦푑푟표푙푦푠ꢀ푠 = −
푑푡
Table 1. Equilibrium constants and dissociation rates of different N-t-butyl-N-
ethyl ureas (tBEU) in d-chloroform at room temperature. k1 is calculated as
Keq×k-1. The constant of aliphatic HUB (4) was adapted from reference[12] for
comparison.
The above equation indicates that the hydrolysis is a first order
reaction and the apparent hydrolysis rate kobs equals to the HAU
bond dissociation constant k-1, which well matched the
experimental results.
Polymeric HAU (pHAU) were then prepared to characterize
the hydrolytic feature of HAU in polymeric materials. Considering
the wide availability of aryl isocyanates and bulky amines, a
gigantic library of pHAU structures can be potentially generated
by combination of the two components. As a proof of concept,
we chose to adopt a simple alternating polymer structure by
addition polymerization of methylene diphenyl diisocyanate (MDI)
and N,N'-di-t-butyl-ethylenediamine at 1:1 molar ratio (Figure 2a).
The polymer was then analyzed by gel permeation
chromatography (GPC). Based on the calibration of polystyrene
standards, the Mw of the MDI-tBEU polymer was calculated to be
4.5 kDa. In the presence of 5 % water (v/v) in THF at room
We next studied the hydrolytic product of the aryl tBEU in
water containing solvent. The degradation of the aryl tBEU in d6-
DMSO were analyzed by 1H NMR. All of the three ureas showed
fast degradation kinetics with hydrolysis half-life less than 1.5
o
hours at 37 C in 5 % water (v/v) containing d6-DMSO (Figure
o
temperature (23 C), the polymer degraded into less than 50 %
S19), which is 10 times faster than aliphatic HUB under the
same condition.[13] Furthermore, the lowered reactivity of the aryl
amines greatly suppresses the formation of stable urea (Figure
S20-S22) as the arylamine and secondary amine were the
exclusive degradation products observed when the conjugated
arene structure is electron deficient (Figure S22).
of the original Mw within 10 minutes (Figure 2b and 2c) while the
less bulky N,N-diethyl urea showed negligible Mw change under
the same condition (Figure S24). On the other hand, MDI-tBEU
polymer was extremely stable under ambient storage condition.
We stored the MDI-tBEU powder in capped scintillation vial at
room temperature. No hydrolytic arylamine product was
1
detected according to H NMR analysis over 2 months. (Figure
S25).
a)
b)
c)
100
75
50
25
0
pH = 3
pH = 7
pH = 11
0 h
0.5 h
4 h
Figure 1. Hydrolysis of phenyl-tBEU in 1:1 DMSO-aqueous buffer with various
pH at room temperature analyzed by HPLC. (a) Chemical structure of Ph-
tBEU and hydrolysis product. (b) Selected plot of ln ([urea]/[urea]0)-t in buffer
solution at different pH and linear fittings. (c) Pseudo first order hydrolytic
constant (kobs) of Ph-tBEU. The dotted line marked the measured k-1 of the Ph-
tBEU through exchange with 20 equivalent t-butyl amine at neutral pH.
0
5
10
15
0
1
2
t (h)
3
4
5
Elution time (min)
Figure 2. pH independent hydrolysis of polymeric HAU at different pH. (a)
Chemical structure of degradable linear MDI-tBEU and corresponding
degradation product. (b) Representative GPC trace of MDI-tBEU before and
after water degradation in THF (5% v/v water content) at room temperature.
The spike peak at 12.5 min signals the aqueous content. (c) Relative
molecular weight change of MDI-tBEU in 5% buffer-THF solution at room
temperature.
The hydrolysis of aryl tBEU at different pH was then studied in
1:1 DMSO-aqueous buffer solution at room temperature (23 oC).
An aqueous buffer cocktail with 0.1 M Na2HPO4, (NH4)2CO3,
citric acid and HCl/NaOH was used to ensure a buffering
capacity ranging from pH 3 to 11 and eliminate the potential salt
effect on the urea degradation. As being analyzed by HPLC, the
degradation of phenyl-tBEU showed remarkably fast
degradation throughout all the pH tested (Figure 1c) and the
observed hydrolysis constant kobs was independent of pH
ranging from 3-11 (Figure 1c). Fitting of the ln([urea]/[urea]0)-t
revealed a linear relationship (R2>0.99), which indicated a first-
order reaction kinetics (Figure 1b). More importantly, the
apparent hydrolysis constant (kobs = 0.17 h-1) turned out to be
equal to the k-1 of the urea in the same solvent condition (Figure
S23), which clearly suggested that the hydrolysis rate of the
urea is exclusively determined by the dissociation of HUB
In summary, we report a class of dynamic hindered aromatic
ureas (HAU) as the first example of hydrolysable polymers with
pH-independent hydrolytic kinetics. The urea bond dissociation
of HAU is two order of magnitudes faster (k-1 >1 h-1) than the
reported aliphatic hindered ureas in organic solvent[12] and
among the fastest dynamic chemistries ever reported. The ureas
can be easily prepared within minutes by simple mixing of
commercial available aryl isocyanate with bulky secondary
amine and remain stable in powder form under ambient
condition for months while they can be quickly degraded within
tens of minutes in solution at pH 3 to 11. The combined features
of good stability in solid state and fast hydrolysis at various pH is
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10.1002/chem.201801138
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Acknowledgements
This work was supported by National Science Foundation (CHE
15-08710). K.C. acknowledges Beckman Institute Graduate
Fellowship support at the University of Illinois at Urbana-
Champaign, with funding provided by the Arnold and Mabel
Beckman Foundation.
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Conflict of interest
The authors declare no conflict of interest.
Keywords: Dynamic hindered urea
• dynamic covalent
chemistry • degradable material • pH independency
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Chemistry - A European Journal
COMMUNICATION
COMMUNICATION
Kaimin Cai, Hanze Ying and
Jianjun Cheng*
A hydrolysable material
derived from dynamic
hindered urea can hydrolyze
rapidly in a pH-independent
profile.
Dynamic Ureas with Fast
and pH-independent
Hydrolytic Kinetics
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