Isocyanate-functionalized starch as biorenewable backbone for the preparation and application of poly(ethylene imine) grafted starch

Article abstract of DOI:10.1007/s00706-016-1913-5

Reactive supports provide versatile platforms for surface decoration, affording various functional materials widely used in chemical and biological research. Considering the biodegradability, biocompatibility, and economy, starch is a suitable support med

Full text of DOI:10.1007/s00706-016-1913-5

Monatsh Chem
DOI 10.1007/s00706-016-1913-5
ORIGINAL PAPER
Isocyanate-functionalized starch as biorenewable backbone
for the preparation and application of poly(ethylene imine)
grafted starch
Lixia Fu1 Yanqing Peng1
•
Received: 3 November 2016 / Accepted: 30 December 2016
Ó Springer-Verlag Wien 2017
Keywords Reactive support Á Starch Á Isocyanate Á
Abstract Reactive supports provide versatile platforms for
surface decoration, affording various functional materials
widely used in chemical and biological research. Consid-
ering the biodegradability, biocompatibility, and economy,
starch is a suitable support media with high functionality
for further chemical modifications. In this proof-of-concept
study, isocyanate-functionalized starch was prepared using
symmetric diisocyanates as bridging block. Its potential as
a reactive platform support was evaluated from the aspects
of reactivity and storage stability. Polyamine could be
grafted onto this reactive support via urea linkage. The
applicability of PEI grafted starch as organic base catalyst
was then tested in Knoevenagel condensation as a model
reaction. Moreover, the feasibility of PEI grafted starch as
a scavenger was also demonstrated in the capture of acid
fluorescent dye and excess electrophilic reagent.
Catalyst Á Scavenger
Introduction
Platform supports are reactive but stable (during storage)
materials for subsequent modification, providing struc-
turally diverse and versatile functional materials which
could be used in chemical and biological studies. Natural
polysaccharides are the most abundant renewable and
degradable polymers produced in the biosphere, with
advantages, such as cheapness, accessibility, non-toxicity,
carbon neutral, and the great number of hydroxy groups
on the surface capable of chemical modification [1]. From
the viewpoints of sustainability and biocompatibility,
natural starch is an appropriate candidate of platform
support.
Graphical abstract
A range of surface modification methods of the
polysaccharide have been developed during the past dec-
ades [2]. In general, the chemical modification of
polysaccharides was carried out through two routes as
schematically represented in Scheme 1a. One might be
described as the direct route (Scheme 1a, route 1), namely,
the functional molecule was grafted on the polysaccharide
support by the reaction between active group G1 and sur-
face hydroxy groups. Another method followed an indirect
way Scheme 1a, route 2). First, the surface hydroxy groups
were chemically modified to afford a ‘‘reactive support’’.
The functional molecule was then linked to the polysac-
charide through the reaction of active group G2 with G1.
Each method has its advantages. However, in the case of
high-throughput generation of functionalized polysaccha-
rides in a parallel fashion, the reactive support strategy
(Scheme 1a, route 2) is much efficient and time-saving.
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-016-1913-5) contains supplementary
material, which is available to authorized users.
& Yanqing Peng
yqpeng@ecust.edu.cn
1
Shanghai Key Laboratory of Chemical Biology, School of
Pharmacy, East China University of Science and Technology,
Shanghai 200237, China
123

L. Fu, Y. Peng
Scheme 1
A
B
Many of methodologies have been presented for the
chemical derivatization of polysaccharides. Dialdehyde
starch or cellulose (Scheme 1b, 1) was produced by con-
trolled periodate oxidative cleavage of the C2–C3 bond of
anhydro-glucopyranoside ring, forming a pair of aldehyde
groups by which other functional molecules could be
attached [3]. The primary hydroxy groups on the polysac-
charide chains could be chlorinated by thionyl chloride and
pyridine. The chloromethylated cellulose (Scheme 1b, 2)
further modified with amines could be applied for
adsorption [4]. Carboxymethyl polysaccharides (Sche-
me 1b, 3), especially carboxymethyl cellulose, were
obtained economically by reaction with chloroacetic acid
and derivatized in virtue of the reactivity of carboxyl group
[5]. Epoxy-functional polysaccharides (Scheme 1b, 4) are a
serial of platform supports with good performance. They
were typically prepared by the reaction between
epichlorohydrin and alkali pre-treated polysaccharides [6].
Nucleophilic reagents (e.g., amines) could be grafted to the
supports based on the ring opening of epoxide moiety [7].
Functionalized triethoxysilanes are often used for the
derivatization of surface hydroxy groups on inorganic
supports. Nowadays, this method has also been proved to
be efficient in the chemical modifications of expanded
starch (Scheme 1b, 5) [8].
Isocyanate group is chemically reactive to various
nucleophiles, such as hydroxyl, amino, and thiol com-
pounds. Functional isocyanates have been employed for the
chemical modification of polysaccharides through the
direct modification method (Scheme 1a, route 1) [9].
Symmetric diisocyanate can be anchored on the surface of
polysaccharides by forming carbamate linkage, with
another isocyanate group remained as a reaction site for
further decoration (Scheme 2b, 6). Therefore, this type of
materials might be employed as reactive platform supports
in the preparation of structurally diverse functional poly-
mers. Diisocyanate-modified polysaccharides have been
reported elsewhere for the preparation of polysaccharide-
based materials [10–12].
The present work focused on the applicability of iso-
cyanate-functionalized polysaccharide as versatile platform
support for further derivatization. The satisfactory reac-
tivity of this platform support is relied on the high
reactivity of isocyanate groups. Unfortunately, isocyanate
123

Isocyanate-functionalized starch as biorenewable backbone for the preparation and…
Scheme 2
A
B
group is routinely sensitive to moisture. In this manuscript,
we confirmed that the isocyanate-functionalized polysac-
charide is stable enough during storage. This fact means
that it is suitable to be used as platform support for further
applications. As a proof-of-concept task, poly(ethylene
imine) was then grafted onto isocyanate-functionalized
starch to demonstrate the practicability of our reactive
support. The practicability of as-prepared functional
material was also demonstrated in heterogeneous catalysis
and scavenging processes.
isocyanate group with nucleophiles, such as amines. In this
respect, isocyanate-functional polysaccharides (Sche-
me 1b, 6) are superior to frequently used epoxy-functional
ones (Scheme 1b, 4). Due to the complexity of the
heterogeneous reaction between a solid support and func-
tional molecule (or macromolecule), the difference in
reaction rates might be comprehended by homogeneous
mimic reactions. Namely, model compound like propylene
oxide is used to represent the substructure of epoxy-func-
tional support, while phenyl isocyanate represents
isocyanate-functional support. The epoxide moiety is a
strained but apparently stable three membered ring system.
Ring opening of propylene oxide with aliphatic primary
amine often needs the presence of catalysts (e.g., [15]
catalyst BiCl3, room temperature, 24 h) or elevated tem-
perature (e.g., [16] catalyst-free, 65 °C, 24 h). In
comparison with propylene oxide, phenyl isocyanate reacts
with aliphatic primary amine in a much faster way (e.g.,
[17] catalyst-free, room temperature, 1 h). In a practical
example of starch modification, ethylene diamine grafted
starch was prepared by the reaction of epoxy-functional
starch and ethylene diamine in basic solution under 60 °C
for 12 h [18]. Thus, in our investigation, a short reaction
time and mild condition (room temperature, 3 h) were
chosen for grafting procedure.
Results and discussion
Poly(ethylene imine) (PEI) is a branched, water-soluble
polymer used for a wide variety of applications, including
food, cosmetic, paper manufacture, and pharmaceutical
research. In the fields of biomedical research, for example,
PEI-DNA is a good candidate for gene delivery vector
in vitro and in vivo transfection with an excellent safety
profile [13]. PEI is routinely synthesized via cationic ring
opening polymerization of ethylene imine. It is generally
recognized that PEI is a complicated polymer without
uniform repeat units [14]. Its structure contains linear
regions and branched regions with primary amino functions
as terminal units and secondary amino functions as linear
units. The dendritic units consist of tertiary amines (Sche-
me 2a). In the present work, PEI was chosen as a functional
motif for grafting. Food grade maize starch was used as
feedstock without pre-treatment. As illustrated in Sche-
me 2b, the starch granules were first activated by treating
with p-phenylene diisocyanate to obtain a reactive support
(denoted as ICS), followed by grafting of poly(ethylene
imine) to afford PEI grafted starch (denoted as S-g-PEI).
One of the potential advantages using isocyanate-func-
tionalized support relies on the excellent reactivity of
Initially, isocyanate-functionalized starch (ICS) was
prepared by coupling starch with p-phenylene diisocyanate
(1 equiv. per glucose unit) in anhydrous acetonitrile for
12 h at room temperature. Chemical transformations were
confirmed by Fourier transform infrared spectroscopy as
shown in Fig. 1.
The spectrum of unmodified starch exhibited adsorption
bands at 1150 (anti-symmetric stretching of the C–O–C
bridge), 1081, and 1019 cm-1 (skeletal vibration involving
the C–O stretching) are characteristic of saccharide struc-
ture (Fig. 1a). The appearance of the characteristic
123

L. Fu, Y. Peng
Fig. 1 FT-IR spectra of (a) unmodified starch, (b) ICS, and (c) S-g-
PEI
absorption band at 2280 cm-1 is attributed to the iso-
cyanate groups stretching vibration, while the absorption
peaks at 1639 and 1561 cm-1 are related to C=O stretching
vibration and N–H bending vibration, respectively
(Fig. 1b). These evidences proved that the starch has been
modified by diisocyanate through a carbamate linkage. The
characteristic peak of isocyanate disappeared after the ICS
was treated with PEI (Mw & 600, Aldrich) in acetonitrile
for 3 h at room temperature (compare b and c), indicating
the completed conversion of isocyanate groups during
grafting. It also showed a broad overlapped absorption
band at 3419–3300 cm-1 corresponding to N–H and O–H
(in starch matrix) group stretches.
Fig. 2 SEM images of (a) unmodified starch and (b) S-g-PEI
The chemical modification of the starch was also con-
firmed by the amine loadings. On the other hand, the amino
concentration of the sample must be assessed, because it is
a crucial datum for the application of S-g-PEI in catalysis
and isolation processes. The loading of amino groups on
S-g-PEI was determined as 7.5 mmol/g by acid–base
titration analysis. The amine content was further estimated
by elemental analysis. From the result of nitrogen content,
we calculated an amine group loading of 8.3 mmol/g. The
difference between two measured values might be partly
attributed to the existence of nitrogen in the linkages.
The surface morphology of unmodified starch and PEI
grafted starch was observed through SEM images, as
shown in Fig. 2. It shows that the starch granules present
regular surface morphology with a mean size of around
2–4 lm (Fig. 2a). Only slightly differences could be
observed in two samples; namely, the loading of PEI had
no significant effect on the surface morphology, indicating
that the structure of starch support had not been destroyed
during the surface grafting.
for evaluation. In other words, it is necessary to consider
the balance between surface reactivity and stability.
Therefore, the storage stability of ICS over a period of 8
months was investigated by FT-IR spectra. Freshly pre-
pared sample (Fig. 3a) was stored in a glass reagent bottle
commonly used in laboratory without specific moisture-
proof measures. The sample was characterized by FT-IR
spectra after 2 weeks (Fig. 3b) and 8 months (Fig. 3c),
respectively. The characteristic absorption band of iso-
cyanate group was also observed obviously even after 8
months of storage at room temperature. Results obtained
from these tests demonstrate that the isocyanate-function-
alized starch is a promising platform support from the
aspect of stability.
With the desired S-g-PEI in hand, we next turn our
attention to the practical application of this material in
catalysis. The Knoevenagel condensation is an important
and widely employed method for C–C bond formation in
organic synthesis with numerous applications in the syn-
thesis of fine chemicals, involving a nucleophilic addition
between carbonyl compounds and an active methylene
compound [19]. A large number of catalysts, especially
Despite of its satisfactory efficiency in derivatization,
isocyanate group is sensitive to moisture. As a platform
support, the stability during storage is an important index
123

Isocyanate-functionalized starch as biorenewable backbone for the preparation and…
1 mol of amine group) was added to an ethanol solution of
rhodamine B (2 mM) and then stirred at room temperature
for predetermined time. After centrifugation, the residual
dye was determined by UV–Vis spectroscopy by measur-
ing the absorbance at
absorbance.
a wavelength of maximum
It can be seen from the absorption spectra that the
intensity of peaks at 544 nm associated with RB decreased
remarkably within 8 h, demonstrating a good adsorption
capacity of S-g-PEI for the adsorption of RB dye (Fig. 4a).
Over 90% of RB was removed as calculated through these
curves and the adsorption capacity (Qeq) value of S-g-PEI
for RB reached up to 324 mg/g after adsorption equilib-
rium. The capture ability was also shown by photographs
recorded before and after the adsorption processes
(Fig. 4b). A significant color change from bright rose red to
nearly colorless could be observed easily by the naked eye.
Under ultraviolet light (excitation at 365 nm), the initial
rhodamine B solution showed a brilliant yellow fluores-
cence, which changed to very weak fluorescence emission
after adsorption. For comparison, methylene blue was
treated with S-g-PEI under the same conditions for RB. In
contrast, S-g-PEI showed unsatisfactory adsorption capac-
ity for MB. After 8 h, no distinguishable change in color
could be observed by the naked eye, which might be due to
the weak interaction between S-g-PEI and non-acidic MB.
The exploration and utilization of combinatorial chem-
istry as a drug discovery technology evolved rapidly in the
past decade. Combining the purification advantages of
solid-phase synthesis with the flexibility of solution-phase
synthesis, polymer-supported scavengers have been proved
as an attractive and practical tool for the clean and efficient
construction of various chemical libraries with potential
application in the pharmaceutical or agrochemical research
[22, 23]. However, most of scavengers are based on syn-
thetic resins from fossil feedstock. The group of Steel and
Chesney has reported the use of tris(2–aminoethyl)amine
derivatized cellulose (nitrogen content: 2.2 mmol/g) as a
biodegradable scavenger resin for solution-phase combi-
natorial synthesis [24].
Fig. 3 Storage stability tests of isocyanate-functionalized starch. FT-
IR spectra of freshly prepared sample (a) and samples stored after 2
weeks (b) and 8 months (c)
various organic bases, are used for this reaction. Supported
amine, such as a tertiary amine-functionalized polyacry-
lonitrile fiber, has been reported as efficient heterogeneous
catalyst in this transformation [20]. Therefore, the Kno-
evenagel reaction was chosen as a model to test the activity
of S-g-PEI as a solid base catalyst.
In a standard reaction, aromatic aldehyde and ethyl
cyanoacetate (1.2 equiv.) reacted in refluxed ethanol cat-
alyzed by 10%mol of S-g-PEI. A variety of aromatic
aldehydes with both electron-donating and -withdrawing
substituents were employed to examine the scope of this
reaction. In general, the reaction proceeded smoothly and
yielded the corresponding products in excellent yields after
purification by column chromatography (Table 1). The
possibility of catalyst recycling was also checked. The
catalyst used in one cycle of reaction was recovered by
filtration, washed thoroughly with ethanol, and dried under
vacuum before used in next cycle of reaction. It was found
that the catalyst did not show virtually any erosion of
activity up to the sixth cycle, in which a yield as high as
92% was still observed.
The feasibility of S-g-PEI as a scavenger was investi-
gated in the next stage. As a solid base, theoretically
speaking, S-g-PEI can capture acidic compounds from the
external environment via acid–base interaction (ion pair
formation). On the other hand, as an amine-functionalized
solid, S-g-PEI can sequestrate electrophiles by covalent
bonding in purification processes.
The efficiency of S-g-PEI as nucleophilic scavenger
(amino loading: 7.5 mmol/g) was checked by a represen-
tative reaction of aniline with phenyl isothiocyanate, in
which the excess isothiocyanate was selectively removed
in the presence of thiourea product (Fig. 5a). In the first
step, aniline is treated with excess phenyl isothiocyanate
(1.2 equiv.) in anhydrous DMF. Removal of excess
isothiocyanate by quenching the reaction with S-g-PEI
affords N,N0-diphenylthiourea in excellent purity as deter-
Amine-functionalized polysaccharides have been
applied as bio-adsorbents for acid dyes [21]. Hence, the
dye adsorption performance of S-g-PEI was examined
using an acid dye rhodamine B (RB) and a non-acid dye
methylene blue (MB) in batch dye adsorption experiments,
which permits convenient evaluation of parameters that
influence the adsorption process, such as contact time and
adsorbent dose. Excess amount of S-g-PEI (0.1 mol of RB/
1
mined by H NMR and HPLC.
In typical scavenging procedures, large excess amount
of scavenger resins are often needed to clean up the reac-
tion products. Therefore, the necessary molar ratio of S-g-
123

L. Fu, Y. Peng
Table 1 Knoevenagel reaction catalyzed by S-g-PEI
Entry
K1
R
H
Time/h
Yield/%
3 (Run 1)
95
93
95
95
94
92
92
98
91
98
96
3 (Run 2)
3 (Run 3)
3 (Run 4)
3 (Run 5)
3 (Run 6)
K2
K3
K4
K5
K6
4-Me
4
3
3
3
2
2-MeO
2-Cl
4-NO2
3,4-MeO
twofold excess of S-g-PEI (based on amine group) showed
satisfactory performance in scavenging process (curve c).
No isothiocyanate could be detected by HPLC after 8 h.
Unmodified starch was employed as a blank sample
because of the isothiocyanate might also be captured by the
surface hydroxy groups on the starch matrix via the for-
mation of thiocarbamate linkage (curve a). The HPLC
analysis revealed that only very small amount of isothio-
cyanate could be scavenged by starch, implying that the
isothiocyanate was captured actually by the grafted
polyamine.
A
B
Conclusion
In conclusion, the potential of isocyanate-functionalized
polysaccharides as reactive platform supports has been
demonstrated in this proof-of-concept study. Starch teth-
ered with isocyanate groups was obtained by treating starch
granules with symmetric diisocyanates. High reactivity in
derivatization as well as satisfactory stability during stor-
age made this material a promising reactive platform
support for the future applications in chemical and bio-
logical research. The practicability of polyamine functional
starch from PEI grafting was also demonstrated in
heterogeneous catalysis and scavenging processes. S-g-PEI
showed good activity in Knoevenagel condensation as a
solid base. This catalyst can be conveniently recovered
from the reaction mixture and reused several times without
Fig. 4 a UV–Vis spectroscopic study of the time-dependant removal
of RB (2 mM) with S-g-PEI. b Photographs of RB solution before
(left) and after (right) adsorption with S-g-PEI under visible light and
UV (365 nm)
PEI (calculated on the basis of amine groups) to excess
isothiocyanate was determined by HPLC tracing. As can be
seen from the sequestration profile (Fig. 5b), equimolar of
S-g-PEI (1 mol of isothiocyanate/1 mol of amine group)
was insufficient to remove excess reagent (curve b), while
123

Isocyanate-functionalized starch as biorenewable backbone for the preparation and…
spectrometer (ionization potential 70 eV). The morphology
of the samples was observed using JEOL JSM-6360 LV
scanning electron microscope. HPLC analysis was per-
formed on a Hewlett-Packard 1100 instrument.
Synthesis of isocyanate-functionalized starch (ICS)
In a typical procedure, 16.01 g of p-phenylene diisocyanate
(100 mmol) was dissolved in mixed solvent of 20 cm3
anhydrous acetonitrile and 50 cm3 anhydrous DMF in a
250 cm3 round-bottomed flask equipped with a drying tube.
Then, 16.20 g of maize starch (100 mmol according to
glucose unit; pre-dried in an oven) was added in one portion.
The resulting suspension was stirred at room temperature for
12 h. Afterwards, ICS was collected by filtration, washed
successively with anhydrous DMF (20 cm3 9 3) and
anhydrous ethyl acetate (20 cm3 9 3) to remove unreacted
isocyanate, and dried under vacuum at 40 °C for 2 h. 26.80 g
of ICS was obtained as a white powder.
Synthesis of poly(ethylene imine) grafted starch
(S-g-PEI)
ICS (14.00 g) was suspended in a solution of 14.00 g PEI
(MW 600) in 50 cm3 anhydrous acetonitrile. The mixture
was stirred at room temperature for 3 h. On completion, the
grafted starch was filtered and washed with acetonitrile
(10 cm3 9 4). After being dried at 60 °C under vacuum,
19.92 g of S-g-PEI was obtained as free-flowing white
powders. Excess PEI could be recovered from the filtrate
by simple evaporation.
Fig. 5 a Removal of excess reagent (phenyl isothiocyanate) with
S-g-PEI in a model reaction. b Sequestration profile using unmodified
starch and different amounts of S-g-PEI
obvious loss in efficiency. As an amine-functionalized
solid base, S-g-PEI could be employed for the capture of
acidic dye or electrophilic reagent by acid–base interaction
or covalent bonding, respectively.
Determination of amino content
HCl solution (40 cm3, 0.05 M) was added to 0.1 g of the S-
g-PEI and conditioned for 15 h on a vibromatic shaker. The
residual concentration of HCl was estimated through
titration against 0.05 M NaOH solution using phenolph-
thalein as indicator. The amino-group concentration (in
mmol/g of S-g-PEI) was calculated by the following
equation:
Experimental
All chemicals were purchased from commercial suppliers
(Aldrich or Shanghai Aladdin Reagent Co. Ltd.) and used
without further purification. Maize starch used in this work
was a food grade product purchased from RONGS Co. Ltd.
(Shanghai, China). The PEI was purchased from Aldrich
with an average molecular weight of 600 g/mol. Melting
points were recorded on a Bu¨chi B-540 apparatus. FT-IR
spectra were taken on a Thermo Nicolet 6700 FT–IR
spectrophotometer using KBr pellets. UV–Vis absorption
spectroscopy measurements were conducted on a Perkin
Elmer UV/Vis Spectrometer Lambda 25. 1H and 13C NMR
spectra were measured on a Bruker AC 400 instrument in
CDCl3 using TMS as an internal standard. Mass spectra
were recorded on a Shimadzu QP 1100 EX mass
ðM1 À M2Þ Â 40
Loading of amino group ¼
;
0:1
where M1 and M2 are the initial and final concentration of
HCl, respectively.
General procedure for S-g-PEI catalyzed
Knoevenagel reaction
S-g-PEI (67 mg, 10% mol) was added to a stirred solution
of aromatic aldehyde (5 mmol) and 0.68 g ethyl cyanoac-
etate (6 mmol) in 5 cm3 anhydrous ethanol. The mixture
123

L. Fu, Y. Peng
People’s Republic of China (2011BAE06B02) is gratefully
acknowledged.
was stirred under reflux for an appropriate time, as shown
in Table 1. After completion of the reaction (monitored by
TLC), the mixture was cooled to room temperature and
filtered. The catalyst was then washed with anhydrous
ethanol (5 cm3 9 3). The solvent was removed under
reduced pressure and the residue was purified by column
chromatography on silica gel with a mixture of EtOAc:PE
(v/v = 1:10) to afford pure product.
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Acknowledgements Financial support from National Key Technol-
ogy R&D Program, Ministry of Science and Technology of the
123