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17 de Thi Hoc Ki 1 Mon Hoa Hoc Lop 10
17 de Thi Hoc Ki 1 Mon Hoa Hoc Lop 10
CLICK CHEMISTRY
APPROACHES, APPLICATIONS
AND CHALLENGES
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CHEMISTRY RESEARCH
AND APPLICATIONS
CLICK CHEMISTRY
APPROACHES, APPLICATIONS AND
CHALLENGES
YU CHEN
AND
ZONG-RUI TONG
EDITORS
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Chapter 1
THE INTRODUCTION OF
CLICK CHEMISTRY REACTION
Yu Chen*
School of Materials Science and Engineering,
Beijing Institute of Technology, Beijing, China
ABSTRACT
Click chemistry, which is also called as linkage chemistry, dynamic,
combinatorial chemistry or quick linking combinatorial chemistry,
describes the reaction that joins molecular fragments as simple, efficient
and versatile as clicking a mouse. The two units with specific click
structures can be linked by click reaction, no matter what is attached to
the structure and only the specific click structures can be joined. It
emphasizes the development of new combinatorial chemistries on the
basis of the synthesis of efficient and highly selective carbon-heteroatom
bond (C-X-C) and effectively prepares molecules with high diversity by
these simple reactions. It significantly simplified and promoted the
development of synthesis chemistry. Click chemistry has become one of
the most useful and attractive synthetic strategy in many fields. In the
current chapter, the definition of the click chemistry was explained, the
characteristics and types of the click chemistry was introduces, some
specific reaction types were focused. Application of click chemistry in
different fields and its development were briefly introduced. It is helpful
*
Corresponding Author Email: cylsy@163.com.
2 Yu Chen
9) Click chemical reaction is also characterized with high yield and low-
cost.
1) Cycloaddition reaction
The thiol-ene click reaction was first discovered by Posner in 1905 [48].
Later in 1938, Kharasch et al. [49] proposed photochemical reaction
mechanism of the thioltor absorbs photons to produce free radicals that seize a
hydrogen from the thiol compounds nearby to convert thiol into thiyl radicals.
The thiol radicals attack the e-ene as shown in Figure 5. The reaction is subject
to three stages: photoinitiation, free radical addition, and free radical
termination. During the first stage of photoinitiation, the initialectron-rich
double bonds to undergo the free radical addition reaction. The free radicals
complete the thiol-ene photochemical reaction with the participation of thiols.
The unreacted thiol radicals combine with each other to terminate the reaction.
In the early 1990s, Jacobine [50] systematically reviewed the different
types of thiol-ene reaction and their reaction mechanisms, and pointed out the
great potential of the thiol-ene click chemistry reaction in the fields of UV-
curable adhesives and coatings. At the early 21st century, Hoyle et al. [51]
summarized the research status of thiol-ene photochemical reaction in the past
ten years and concluded that the photocrosslinking of thiol-ene had a
promising application prospect in the preparation of polymers with tunable
mechanical properties and physicochemical properties. In recent years, Holye
and Bowman [52-53] pointed out that the free radicals produced by the
photocleavage of the photoinitiator functioned as the catalyst to catalyze the
highly selective reaction between the specific regions with functional group.
The thiol-ene photocrosslinking reaction combines the advantages of
photoinitiation and click chemistry. The thiol-ene/yne click chemistry,
especially the combination of thiol-ene/yne click chemistry and controllable
polymerization, provides a new strategy for the synthesis of organic functional
materials.
10 Yu Chen
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12 Yu Chen
[45] Chan, JW; Shin, J; Hoyle, CE; Bowman, CN; Lowe AB. Synthesis,
thiol-yne “click” photo-polymerization, and physical properties of
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[46] Fairbanks, BD; Scott, TF; Kloxin, CJ; Anseth, KS; Bowman, CN.
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[48] Posner T. Information on unsaturated compounds II The addition of
mercaptan to unsaturated hydrocarbon. Berichte der deutschen
chemischen Gesellschaft, 1905, 38: 646-657.
[49] Kharasch, MS; May, EM; Mayo, FR. The peroxide effect in the addition
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promise for the future. Journal of Polymer Science Part A: Polymer
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[52] Hoyle, CE; Bowman, CN. Thiol–ene click chemistry. Angewandte
Chemie International Edition, 2010, 49(9), 1540-1573.
[53] Hoyle, CE; Lowe, AB; Bowman, CN. Thiol-click chemistry: a
multifaceted toolbox for small molecule and polymer synthesis.
Chemical Society Reviews, 2010, 39(4), 1355-1387.
[54] El-Sagheer, AH; Brown, T. Click chemistry with DNA. Chemical
Society Reviews, 2010, 39(4), 1388-1405.
[55] Kumar, R; El-Sagheer, A; Tumpane, J; Lincoln, P; Wilhelmsson, LM;
Brown, T. Template-directed oligonucleotide strand ligation, covalent
intramolecular DNA circularization and catenation using click
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The Introduction of Click Chemistry Reaction 17
[56] Zhou, QH; Zheng, JK; Shen, ZH; Fan, XH; Chen, XF; Zhou, QF.
Synthesis and hierarchical self-assembly of rod rod block copolymers
via click chemistry between mesogen-jacketed liquid crystalline
polymers and helical polypeptides. Macromolecules, 2010, 43(13),
5637-5646.
[57] Goldmann, AS; Walther, A; Nebhani, L; Joso, R; Ernst, D; Loos, K;
Barner-Kowollik, C; Barner, L; Muller, AHE. Surface modification of
poly(divinylbenzene) microspheres via thiol-ene chemistry and alkyne-
azide click reactions. Macromolecules, 2009, 42(11), 3707-3714.
[58] Wu, XM; Wang, LL; Wang, Y; Gu, JS; Yu, HY. Surface modification of
polypropylene macroporous membrane by marrying RAFT
polymerization with click chemistry. Journal of Membrane Science,
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[59] Wong, CH; Zimmerman, SC. Orthogonality in organic, polymer, and
supramolecular chemistry: from Merrifield to click chemistry. Chemical
Communications, 2013, 49(17), 1679-1695.
[60] Binder, WH; Sachsenhofer, R; Straif, CJ; Zirbs, R. Surface-modified
nanoparticles via thermal and Cu(I)-mediated “click” chemistry:
Generation of luminescent CdSe nanoparticles with polar ligands
guiding supramolecular recognition. Journal of Materials Chemistry,
2007, 17(20), 2125-2132.
[61] Whittaker, MR; Urbani, CN; Monteiro, MJ. Synthesis of 3-miktoarm
stars and 1st generation mikto dendritic copolymers by “living” radical
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[62] Gopin, A; Ebner, S; Attali, B; Shabat, D. Enzymatic activation of
second-generation dendritic prodrugs: Conjugation of self-immolative
dendrimers with poly(ethylene glycol) via click chemistry. Bioconjugate
Chemistry, 2006, 17(6), 1432-1440.
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polymerization and click chemistry: A versatile method for the
preparation of end-functional polymers. Macromolecular Rapid
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Synthesis and characterization of end-functional polymers on silica
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399.
18 Yu Chen
[65] Ghosh, KK; Ha, HH; Kang, NY; Chandran, Y; Chang, YT. Solid phase
combinatorial synthesis of a xanthone library using click chemistry and
its application to an embryonic stem cell probe. Chemical
Communications, 2011, 47(26), 7488-7490.
[66] Ismail, HM; Barton, VE; Panchana, M; Charoensutthivarakul, S;
Biagini, GA; Ward, SA; O’Neill, PM. A click chemistry-based
proteomic approach reveals that 1,2,4-trioxolane and artemisinin
antimalarials share a common protein alkylation profile. Angewandte
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distillation-precipitation polymerization and click chemistry: fabrication
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of glycoproteins. Journal of Materials Chemistry B, 2014, 2(21), 3254-
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Research Reviews, 2008, 28(2), 278-308.
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biomolecular probing and intracellular imaging by AIE fluorogen on a
TLC plate through a thiol-ene click mechanism. Chemistry- A European
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[74] Chu, CH; Liu, RH. Application of click chemistry on preparation of
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The Introduction of Click Chemistry Reaction 19
Chapter 2
NITRILE N-OXIDE-BASED
CLICK REACTIONS ACCOMPANYING
C-C BOND FORMATION
ABSTRACT
This article provides a review on the recent progress concerning
nitrile N-oxide-based click reactions, which allow to fabricate the multi-
component organic architectures. Chapter 1 deals with a brief summary
of the preparation method of nitrile N-oxide. Eight types of precursors are
reported to be available for the preparation of nitrile N-oxide, whose
characteristics are discussed on the basis of the historical survey. Chapter
2 focuses on the reactions of nitrile N-oxide, in which we first describe
the feasibility and problems of the 1,3-dipolar cycloaddition reaction of
nitrile N-oxide related to the click reaction. The problem comes mainly
from the instability or high reactivity in its use. Subsequently, we discuss
Corresponding author: Y. Koyama: Tel: +81-766-56-7500 (ext. 782), E-mail: ykoyama@pu-
toyama.ac.jp
†
Corresponding author: T. Takata: Tel: +81-3-5734-2898, Fax: +81-3-5734-2888, E-mail:
ttakata@ polymer.titech.ac.jp.
22 Yasuhito Koyama and Toshikazu Takata
INTRODUCTION
Development of new sophisticated systems is always required in the broad
areas of scientific and technological fields. The term “system” refers to an
assembly of several units that exhibit some specific interactions. For instance,
a personal computer can be referred to an information system, comprising a
rational combination of hardware, software, and the internet. The situation is
the case for chemistry and related areas such as chemical biology, polymer
chemistry, and supramolecular chemistry. Even in organic chemistry, an
assembly of modified molecules can produce various functional systems
including molecular probes and sensors containing sites for molecular
recognition and emission, high performance polymers with versatile functions,
and supramolecular systems that link a function to the response of stimuli.
Regarding the organic synthesis of such systems, we must carefully bind
functionalized units in consideration of each molecular skeleton. The first
problem an organic chemist faces is to decide what bond-forming reactions are
most suitable for connecting different units. We should select an efficient
reaction based on ideal conditions, such as high reactivity, chemo-selectivity,
free of byproduct and catalyst, and easy purification, that take into account the
Nitrile N-Oxide-Based Click Reactions Accompanying C-C Bond … 23
chemical reactivity and stability of each unit and the intended functions of the
product.
Click reactions are categorized as one of the covalent bond-forming
reactions useful for synthesizing organic systems [1]. If the click reaction is
applied to the connection of a few units, new architectures can be easily
obtained without optimizing the reaction conditions. The most frequently used
click reaction is a copper-catalyzed alkyne-azide 1,3-dipolar cycloaddition
reaction, i.e., Huisgen reaction [2]. In contrast to it, the authors have
extensively studied the synthesis of stable nitrile N-oxide agents and their use
for the 1,3-dipolar cycloaddition as the click reaction.
Nitrile N-oxide is recognized as a highly reactive species since the 1930s
[3]. The dipole comprises sp hybridized orbitals similar to that of the azide
functionality. To date, the structure [4] and physical property [5] of nitrile N-
oxide have been considerably investigated. The reaction of nitrile N-oxide
often appears in multi-step synthesis of bioactive natural products, which is
used for introducing -ketol or 1,3-diketone framework to the molecular
skeleton [6]. According to Sustman’s classification of 1,3-dipoles based on its
reactivity [7], nitrile N-oxide is categorized as having an ambiphilic dipole
(type II) with a high reactivity with both electron-rich and -deficient
unsaturated bonds. However, it is hardly utilized as a tool for chemical
ligation, probably due to the complexity of handling nitrile N-oxide. The high
reactivity of nitrile N-oxide is accompanied by chemical instability, leading to
spontaneous self-decomposition reactions. Despite its disadvantageous
instability, we are still interested in its use for click reaction. Because the
reaction has several advantages compared with those of the Huisgen reaction,
such as (i) the 1,3-dipolar cycloaddition of nitrile N-oxide with dipolarophile
does not require catalyst, (ii) the reaction can avoid the use of azide which is
usually explosive, (iii) the reaction is applicable to various unsaturated bonds
as reaction points, and (iv) the reaction with alkene and alkyne proceeds with
C-C bond-formation. Considering these merits, we have developed chemically
stable nitrile N-oxide-based click agents as a new ligation tool.
This review comprises of the following four chapters: in Chapter 1, we
describe the preparation methods of nitrile N-oxide. In Chapter 2, we describe
the 1,3-dipolar cycloaddition reactions and the self-decomposition reactions of
nitrile N-oxide, where the intramolecular cycloaddition of nitrile N-oxide to a
benzene ring is also introduced. In Chapter 3, we discusses the precise
structure of nitrile N-oxide in solution as determined by 13C NMR and UV
spectroscopic studies of 13C-labelled nitrile N-oxides, in addition to the
crystalline structure. In Chapter 4, we introduce the development and
24 Yasuhito Koyama and Toshikazu Takata
1. PREPARATION METHODS
OF NITRILE N-OXIDE
Despite its high reactivity as described above, nitrile N-oxide has hardly
been utilized as a chemical ligation tool, possibly due to its instability. Nitrile
N-oxide is not ordinarily isolable and spontaneously self-decomposes (Scheme
4). Although the dimerization to furoxan has long been considered the primary
reason for self-decomposition (Scheme 4, I) [8a, 11, 23], degradation via
polymerization (II) [24] and thermal and photochemical isomerization to
isocyanate (III) have also been reported [25].
The self-decompositions (I) and (II) can be suppressed by two methods.
One method is the use of nitrile N-oxide precursor in the presence of an excess
dipolarophile as the reactant. Because the slow generation of nitrile N-oxide
leads to lower concentration of nitrile N-oxide than that of the dipolarophile,
the cycloaddition reaction of nitrile N-oxide with the dipolarophile is
preferential over the self-reactions between the generated nitrile N-oxides. The
second method is the introduction of bulky substituents around nitrile N-oxide
moiety, resulting in the isolation of kinetically-stabilized nitrile N-oxides
(Scheme 4, IV) [26]. When nitrile N-oxide has a quaternary carbon center or
an ortho-disubstituted aromatic ring at the neighboring position of the CNO
moiety, the compounds often become isolable. The substituents suppress the
self-reactions of nitrile N-oxides increase by increasing bulkiness. Some
aromatic nitrile N-oxides with high crystallinity can be isolated as a crystal
even if there is no bulky substituent for kinetic stabilization [27]. However, the
suppression method of self-decomposition III has not been reported. Our
Nitrile N-Oxide-Based Click Reactions Accompanying C-C Bond … 27
Figure 1. Homoditopic nitrile N-oxide (A), orthogonal agent (B), and one-pot
introduction of nitrile N-oxide moiety to compound R (C).
28 Yasuhito Koyama and Toshikazu Takata
attributed to the steric repulsion between the methoxy group at the peri
position and the C = N bond on the isoxazoline ring.
As shown in Table 1, the reaction of meta-substituted substrate (2b)
proceeded most smoothly to give the cyclization product 3b (entry 2), whereas
only a trace amount of 3c was obtained from ortho-substituted one 2c. These
results suggest that the steric hindrance of o-methyl group toward the nitrile N-
oxide group (2c) may destabilize the transition state of the [3 +
2]cycloaddition reaction, being much different from that of the meta-positions
(2b).
Reprinted with permission from ref [31]. Copyright 2012 American Chemical Society.
30 Yasuhito Koyama and Toshikazu Takata
the 13C NMR spectrum. The nitrile N-oxide carbon signals were remarkably
upfield-shifted compared with those expected from unsaturated carbons such
as carbonyl and nitrile carbons, clearly indicating the strong shielding effect of
the nitrile N-oxide group.
The reason for the triplet splitting of the signal is caused by the scalar
coupling to the adjacent 14N nucleus (I = 1), and the coupling constants (1JCN)
are 53.5 Hz for 7 and 43.2 Hz for 8. The magnitudes are significantly larger
than those of typical nitrogen-containing compounds [35].
We performed VT-13C NMR measurements of 7 and 8 to evaluate the
temperature dependence on the electronic and/or structural characteristics of
them. Figure 3 shows the VT-13C NMR spectrum of 7. The labeled signal was
split to a triplet signal in the temperature region higher than room temperature,
whereas the signal fused to a singlet at low temperature. The signal pattern
change was reversible, indicating the reversible electronic and/or structural
change of the nitrile N-oxide moiety in the NMR time scale. The similar
reversible pattern change was also observed in the VT-13C NMR spectra of 8.
Figure 2. 13C NMR spectra (100 MHz, 293 K, CDCl3) of (a) 5, (b) 6 (in DMSO-d6), (c)
7, and (d) 8. Reprinted with permission from ref [34]. Copyright 2015 Elsevier.
Nitrile N-Oxide-Based Click Reactions Accompanying C-C Bond … 33
Figure 3. VT-13C NMR spectra of 7 (100 MHz, CDCl3) at (a) 313 K, (b) 293 K, (c) 273
K, (d) 253 K, (e) 243 K, (f) 233 K, and (g) 223 K. Reprinted with permission from ref
[34]. Copyright 2015 Elsevier.
Figure 4 displays the plots of 1JCN, the chemical shift of nitrile N-oxide
carbon, 1JCC, and the chemical shift of Ca, as a function of temperature. Both
plots of 1JCN and 13C NMR chemical shift in (A) monotonously changed with
inflections at 260 and 300 K, respectively, implying the electronic and/or
structural change of 7 at the temperature around the inflections. The plots of
1J
CC and the chemical shift of Ca in (B) clearly contrast those in (A), which had
no inflection point. These results indicate that the chemical environment
around the C-N bond of the nitrile N-oxide moiety could be parted on the
inflection temperature, whereas that of the C-C bond between the nitrile N-
oxide moiety and the aromatic ring was hardly influenced by temperature. The
temperature dependencies of the coupling constants and chemical shifts of 8
were almost similar to those of 7.
34 Yasuhito Koyama and Toshikazu Takata
Figure 4. (A) Effects of temperature on 1JCN of 7 (circle) and 13C chemical shift of
nitrile N-oxide (square) and (B) effects of temperature on 1JCC between nitrile N-oxide
and Ca of 7 (square) and 13C chemical shift of Ca (circle).
Figure 5. VT-UV-vis spectra of 7 (THF, 100 M). Reprinted with permission from ref
[34]. Copyright 2015 Elsevier.
Scheme 11. Catalyst-free connection between PAN and PEG mediated by the
orthogonal agent 14.
A bulky initiator for anionic polymerization was first prepared from sec-
BuLi and 1,1-diphenylethene in THF at -78C. The living anionic
polymerization started by the addition of a vinyl monomer to the initiator.
After the polymerization, 1,1-diphenylnitroethene or trans--nitrostyrene as a
terminator was added to the polymerization mixture to lead to the
functionalization of the propagation end by the terminator. After the
confirmation of the consumption of the terminator by TLC, conc. H2SO4 (10
eq.) was added in one portion to the reaction mixture. The resulting mixture
was warmed up to 0°C and stirred for 30 min to complete the dehydration
reaction. Typical work-up and purification by reprecipitation afforded the
corresponding polymer nitrile N-oxide in an excellent yield. This method is
applicable to various vinyl polymers except for polystyrene homopolymer.
Polymer nitrile N-oxide prepared from styrene was not stable and
Nitrile N-Oxide-Based Click Reactions Accompanying C-C Bond … 41
Scheme 13. Grafting reactions of polymer nitrile N-oxide onto unsaturated bond-
containing polymers.
42 Yasuhito Koyama and Toshikazu Takata
CONCLUSION
This review article deals with the development and application of nitrile
N-oxide-type click agents. Kinetically stabilized nitrile N-oxides displayed
sufficiently high reactivity to various unsaturated bond-containing molecules,
macromolecules, and materials involving surfaces under catalyst- and solvent-
free conditions. Because the internal olefins and nitrile groups in the polymer
chain are available as the click reaction points for nitrile N-oxides, the polymer
modifications by the click chemistry using nitrile N-oxides mentioned above
might develop a new polymer chemistry exploiting common polymers as a
scaffold for molecular integration. Although the reactions of nitrile N-oxides
have been utilized in the creation of limited organic systems [46] at present
time, the use of nitrile N-oxide agent will be widely spread by recognizing
their advantageous merits such as C-C bond forming catalyst-free reaction
besides the their stability and safely in comparison with azides. Some of these
nitrile N-oxide-type click agents will be commercially available soon. We
hope that the present review article contributes to the creation of versatile
sophisticated and useful organic systems in the near future.
ACKNOWLEDGMENTS
The authors thank all co-workers and collaborators for their great
contributions to the studies covered in this review. Moreover, the authors are
grateful to the financial support from JSPS KAKENHI (Grant Numbers:
22750101, 21106508, 24685023, and 25102510), the Mizuho Foundation for
the Promotion of Science, and the Eno Foundation for the Promotion of
Science.
44 Yasuhito Koyama and Toshikazu Takata
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46 Yasuhito Koyama and Toshikazu Takata
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50 Yasuhito Koyama and Toshikazu Takata
Chapter 3
BI-1,2,3-TRIAZOLES: SYNTHESIS
AND PERSPECTIVES
ABSTRACT
Bi-1,2,3-triazoles are interesting molecules derived from copper-
catalyzed alkyne-azide cycloaddition (CuAAC) under oxidative
conditions. Other methods to synthesize bi-1,2,3-triazoles involve
condensation reactions or palladium catalyzed couplings. On the other
hand, bi-1,2,3-triazoles have attracted to many research groups due to
their promising properties as ligands for catalysis as well as the design of
compounds with photochemical properties.
1. INTRODUCTION
4,4’-(1,2,3-triazolyl)-1,2,3-triazoles, namely, bi-1,2,3-triazoles (1, Scheme
1), are interesting molecules derived in most cases from copper-catalyzed
alkyne-azide cycloaddition (CuAAC) under oxidative conditions. Since their
*
Corresponding Author Email: ecuevasy@uaemex.mx
52 Ivette Santana-Martinez and Erick Cuevas-Yañez
2. SYNTHESIS OF BI-1,2,3-TRIAZOLES
2.1. Condensations and Non-Catalyzed Cycloadditions
Before the arrival of the Click Chemistry approach, the synthesis of bi-
1,2,3-triazoles was limited to some condensation/cycloaddition reactions.
Initial reports by Dornow and Rombusch showed that bisacetylenes, such as
molecule 8, in the presence of phenyl azide gave bi-1,2,3-triazole 9 under
thermal conditions (Scheme 2) [6]. A similar behavior was observed by
Tikhonova et al. using benzyl azide with uncoupled and conjugated
diacetylenes [7].
However, the role played by the counterion or ligand is not clear. For
instance, when a CuI/Et3N mixture was used to synthesize bi-1,2,3-triazoles 49
and 54. The compound 49 was obtained as the only reaction product in 40%
yield from diazidoferrocene 47 and tetrahydro-[5]-helicenequinone 48
(Scheme 16), contrary to the use of CuSO4/sodium ascorbate which generates
exclusively 1,2,3-triazole [26]. In this case, a cyclic copper triazolide is
proposed in order to rationalize the formation of a chiral compound and the
stability required to favor the bi-1,2,3-triazole formation.
A similar behavior was observed when bisazide 50 was treated with the
corresponding alkynes in the presence of catalytic amounts of CuI/DIPEA to
yield bistriazoles 52 and cyclic bi-1,2,3-triazoles 51 as major products
Bi-1,2,3-Triazoles 61
(Scheme 17) [27]. Moreover, the best bi-1,2,3-triazole yields were detected
using bulkier alkynes which can be an additional factor for oxidative CuAAC
dimerization.
On the other hand, compound 54 was obtained in 23% yield as a mixture
together with the corresponding triazole 55 (Scheme 18) [28]. Therefore, a
definitive conclusion is not possible to determine from these results.
Other catalytic systems designed for the synthesis of bi-1,2,3-triazoles
involve the use of copper (I) complexes. N-heterocyclic Carbene copper (I)
complex 58 catalyzed the last step of a multicomponent synthesis of triazoles
in water at room temperature through the generation of a micellar medium
which promotes the in situ formation of organic azides followed by oxidative
CuAAC to produce compounds 59 and 60 (Scheme 19) [29].
In addition, the effect of phenylboronic acid/CuSO4 catalyst on the
CuAAC reaction was studied by López-Ruiz et al. which found that when
benzyl azide 21 and 4-Ethynylbenzonitrile 61 were combined at room
temperature, a mixture of triazole 62 and bi-1,2,3-triazole 69 was obtained
(Scheme 20) [30]. The oxidative CuAAC process was possible due to the
phenylboronic acid’s reducing power at room temperature, which produces
copper (I) species for the synthesis of the bi-1,2,3-triazole product.
According to Zhu and coworkers, copper (II) acetate catalyzes the
formation of bi-1,2,3-triazoles from organic azides and terminal alkynes using
K2CO3 and tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA) as
additives under an oxygen atmosphere (Scheme 21) [31].
Scheme 23. Synthesis of metal complexes 68 and 71 from bi-1,2,3-triazoles 66 and 69.
3. REACTIONS OF BI-1,2,3-TRIAZOLES
In spite of bi-1,2,3-triazole chemistry having been recently developed, the
applications found for this class of compounds are quite promising. Two
particular properties should be taken into account to understand the chemistry
of bi-1,2,3-triazoles, the presence of a series of consecutive lone pair electrons
around nitrogen atoms, and the high aromaticity/low reactivity from the
heterocyclic moiety. These properties contribute to the role of bi-1,2,3-
triazoles as nucleophiles or ligands.
The nucleophilic properties of bi-1,2,3-triazoles were observed and used
almost simultaneously by the groups of Bertrand [33] and Aizpurua [34, 35]
on bi-1,2,3-triazoles 66 and 69 which were methylated to give bitriazolium
salts 67 and 70 respectively (Scheme 23). These bitriazolium salts were
departure materials to synthesize metal complexes 68 and 71 through the
formation of abnormal N-heterocyclic carbene ligands which were bound to
metal centers as both monodentate or bidentate ligands.
The tendency of carbenes derived from bitriazolium salts to react as
bidentate ligands is displayed in bitriazolium salt 72 that was functionalized
and coordinated to ruthenium and iridium salts to generate complexes 73 and
74 (Scheme 24). These compounds were used as catalysts in the conversion of
nitrobenzene to various products through a hydrogenation transfer process
[36], as well as catalytic oxygenations [37].
64 Ivette Santana-Martinez and Erick Cuevas-Yañez
Scheme 24. Synthesis of metal complexes 73 and 74 from bi-1,2,3-triazolium salt 72.
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In: Click Chemistry ISBN: 978-1-53611-903-9
Editors: Y. Chen and Z. R. Tong ©2017 Nova Science Publishers, Inc.
Chapter 4
ABSTRACT
In recent years, natural polymers, such as chitosan, cellulose, starch,
alginate, collagen, gelatine, chondroitin sulphate, hyaluronic acid,
heparin, and so on, have been attracted more and more attentions in
different fields for their versatile properties, such as biocompatibility,
biodegradability, nontoxicity, econony and environmental friendly. The
above natural polymers are also easy to be modified by chemical grafting
of new functional groups to promote their properties.
Nowadays, click chemistry has become a powerful tool for materials
modification by material chemists for their number of advantages such as
readily available starting material, high reaction rate, high reliability, mild
reaction conditions, high oxygen and moisture stability, good
stereoselectivity, high yield, simple workup and easy purification. Click
chemistry not only has broad applications in synthetic organic chemistry,
but also has been employed in immobilizing small molecules, linear
polymers, dendrimers and biological macromolecules into the skeleton of
natural polymers. Modification of natural polymers by click chemistry
will help to overcome their shortages such as complicated reaction
*
Corresponding Author Email: cylsy@163.com.
70 Yu-Tong Zhang, Zhu-Yun Li and Yu Chen
conditions, low selectivity, various side reactions and low yields, and
remarkably improve their immobilizing efficiency.
In the current chapter, we want to introduce the progress in
modification of the natural polymers through the click reactions, and the
application of the above composite in different fields.
INTRODUCTION
Proposed by Sharpless and coworkers in 2001, click chemistry is the most
excellent chemical reactions to connect a diversity of structures. There are
about 4 kinds of “click” chemistry: ① The Cu (I) catalyzed azide-alkyne 1, 3 -
dipolar cycloaddition, including Diels-Alder reactions [1]. Among these
reactions, Cu (I) catalyzed Huisgen 1, 3-dipolar cycloaddition of azide and
terminal alkyne functionalities to form 1, 2, 3-triazoles, which called “cream
of the crop” in the field of “click chemistry.” But it is difficult in the
modification of polysaccharides introducing the azide or alkyne functionalities
necessary for the subsequent CuAAc reaction. ②Nucleophilic ring opening
reaction, especially the tension of heterocyclic electrophilic reagents open
loop. ③Non-alcoholic aldehyde carbonyl reactions. ④Addition reactions of
carbon-carbon bonds, especially the oxidation of epoxidation reaction.
The substance of “click chemistry” is to choosing the raw material which
is easy to get, achieving the linking of C-X-C by reliable, efficient and
selective chemistry reactions. It is a low cost, efficient way to synthesizing lots
of new compounds. The core of “click” chemistry is to using a series of
reliable and modular reactions to produce heteroatom-containing
compounds [2].
These days, ‘click’ chemistry explores some new approach in organic and
polymer synthesis, involving a number of functional groups, reactions. It has a
lot of good features, such as wide range of applications, mild reaction
conditions, high selectivity and high purity. For these outstanding
characteristics, “click” chemistry reactions have been widely applied in many
research areas.
This chapter mainly introduces the way for application of different nature
polymers including application of natural polymers derivatives, natural
polymers hydrogels, natural polymers nanomaterials and the linked
fluorophore in the natural polymers via “click” chemistry.
Click Chemistry of Natural Polymers 71
generated by removal of the acetyl group, was 1.6891 × 10−4 mol/g. The
prepared 6-OH substituted macrocyclic compound derivatives of chitosan with
high loading capacity have superb application prospect in the field of chemical
biosensor, slow release drug carrier, chromatographic support, and so on.
(ASCs) within the gel matrix in vitro. Cell culture showed that this metal-free
hydrogel could support survival and multiplication of ASCs. A preliminary in
vivo study demonstrated the effectiveness of the hydrogel as an injectable
scaffold for adipose tissue engineering. These characteristics provide a
potential opportunity to utilize the metal-free click chemistry to prepare the
biocompatible hydrogels for soft tissue engineering applications.
Figure 11. Chemical structures of CS–OB (a), HA–AA (b) and formed hydrogel (c).
The hydrogel is crosslinked via a metal-free click chemistry.
In this research, furan groups were combined with chitosan chain via
reaction of 6-azido-6-deoxy chitosan and furfuryl propargyl ether. Via this
method, 6-azido-6-deoxy chitosan was synthesized by bromination and the
subsequent nucleophilic substitution with sodium azide on the C6 hydroxyl
groups of a previously amino-protected N-phthaloyl chitosan. Next,6-azido-6-
deoxy chitosan was reacted with furfuryl propargyl ether by the Cu(I)-
catalyzed Huisgen 1,3-dipolar cycloaddition reaction, resulting in an o-
84 Yu-Tong Zhang, Zhu-Yun Li and Yu Chen
cells without damaging them. They created the click alginate hydrogels by the
reaction of AIg-N and AIg-T. Figure 15 shows the reaction. The click alginate
hydrogel can be altered after gelation to display cell adhesion peptides for 2D
cell culture utilizing thiol-ene chemistry. In addition, click alginate hydrogels
combine the numerous benefits of alginate hydrogels with powerful
bioorthogonal click chemistry for utilizing in tissue engineering applications
such as stable encapsulation, delivery of cells and bioactive molecules.
Figure 16. Synthesis of radiolabeled glycol chitosan nanoparticles with 64Cu via click
reaction.
Figure 17. General procedure for the introduction of azide functionalities onto
cellulose substrates using (3-azidopropyl)triethoxysilane and subsequent click reaction
with propargylated Rhodamine B. Conditions: a)NaOH, water; b)L-ascorbic acid,
CuSO4·5H2O, water.
Click Chemistry of Natural Polymers 95
Figure 18. Click reaction between yne-functional oxo-vanadium Schiff and thiol-
functionalized nanocrystalline starch.
96 Yu-Tong Zhang, Zhu-Yun Li and Yu Chen
There are chemically modified cellulose nanofibrils (CNF) with furan and
maleimide groups, and selectively labeled the modified CNF with fluorescent
probes [41] which are 7-mercapto-4-methylcoumarin and fluorescein diacetate
5-maleimide through two specific click chemistry reactions: Diels−Alder
cycloaddition and the thiol-Michael reaction. Figure 19 shows that
Diels−Alder cycloaddition’s reaction scheme. Feature by solid-state 13C NMR
and infrared spectroscopy was utilized to follow the surface modification and
estimate the substitution degrees. Navarro’s team found that the two
luminescent dyes could be selectively labeled onto CNF, yielding a multicolor
CNF that was marked by UV/visible and fluorescence spectroscopies. It was
demonstrated that the multicolor CNF could be imaged that using a confocal
laser scanning microscope. It was found through the study of fourier transform
infrared spectroscopy and solid-state that the first step in the surface
modification of CNF interest for biological application such as multimodality
molecular imaging.
Figure 19. Grafting Furan Groups for Diels-Alder Cycloaddition onto Cellulose
Nanofibrils.
Click Chemistry of Natural Polymers 97
Biocompatible the silk fibroin is, being widely studied as well as applied
as biomaterial for diverse applications. And full-bodied protein polymer that
can be made optically trans-parent mechanically [48]. Its chemical alteration is
off absorbing a way for tuning the properties and broaden its adhibition
aspects. Herein, PEG grafting on the surface of regenerated silk fibroin films is
incurred by direct linking via a click reaction between the azido activated silk
surface and an alkyne terminated PEG. Thus the surface properties have been
improved through the so obtained PEGylated films, compares to the
unmodified films.
Figure 21. Reaction scheme for PEG grafting onto silk fibroin films.
100 Yu-Tong Zhang, Zhu-Yun Li and Yu Chen
Primarily the silk from Bombyx mori silk fibres are composed of two
types of protein: the antigenic gum-like protein surrounding the fibres called
sericin, and fibroin, the core fibres. Silk fibroin belongs to a group of high
molecular weight organic polymers characterized by repetitive hydrophobic
and hydrophilic peptide sequences [50].
Synthesized the Azide silk fibroin (azido SF) and alkyne terminal
polyethylene glycol) (PEG) 2000 (acetylene-terminal PEG 2000) are, Azido
SF would have reaction with acetylene-terminal PEG 2000 results in
producing films through a copper-mediated 7,3-cycloaddition ('click'
chemistry) generating a triazole linkage along with the networking forming
reaction. Novel silk-based films with various weight ratios were prepared and
investigated through click chemistry.
With diazonium coupling chemistry, an aromatic azide functional moiety
was successfully introduced into SF. Similarly, an alkyne functional group was
successfully introduced into PEG 2000 via esterification.
6. PROSPECT
Click chemistry has been noticed by more and more scientists since the
click chemistry is put forward, for its several advantages that simple materials,
mild reaction conditions, high yield, good selectivity and easy separation and
purification and so on [51]. Click chemistry have been entered into the
practical application from the original research in drug and polymer
development. However, the development and application of click chemistry
are still in the initial stage. Next target of click chemistry is that scientists are
Click Chemistry of Natural Polymers 101
able to find more reaction which is efficient, reliable, rapid and high selectivity
and expending its application from the original drug exploitation to the
synthesis of polymer, nanotechnology, supra-momolecular science, surface
modification and other fields. In terms of nature polymers, they will be easier
to be modified by chemical grafting of new functional groups to promote their
properties via click chemistry. This kind of method will be the main
technology in all kinds of fields about nature polymers in the future.
REFERENCES
[1] Solimana S M A, Colombeaua L, Nouvela C, et al. Amphiphilic
photosensitive dextran-g-poly (o-nitrobenzyl acrylate)glycopolymers.
Carbohydrate Polymers 136 (2016) 598-608.
[2] Liu Z, Wei Z, Zhu X, et al. Dextran- based hydrogel formed by thiol-
Michael addition reaction for 3D cell encapsulation. Colloids and
Surfaces B: Biointerfaces 128 (2015) 140-148.
[3] Chen Y, Wang F, Yun D, et al. Preparation of a C6 Quaternary
Ammonium Chitosan Derivative Through a Chitosan Schiff Base with
Click Chemistry [J]. 2013.
[4] Peng P, Cao X, Peng F, et al. Binding cellulose and chitosan via click
chemistry: Synthesis, characterization, and formation of some hollow
tubes [J]. Journal of Polymer Science Part A: Polymer Chemistry, 2012,
50(24): 5201-10.
[5] Jirawutthiwongchai J, Krause A, Draeger G, et al. Chitosan-
Oxanorbornadiene: A Convenient Chitosan Derivative for Click
Chemistry without Metal Catalyst Problem [J]. ACS Macro Letters,
2013, 2(3): 177-80.
[6] Chen Y, Ye Y, Jing Y, et al. The Synthesis of the Locating Substitution
Derivatives of Chitosan by Click Reaction at the 6-Position of Chitin [J].
International Journal of Polymer Science, 2015, 2015:1-9.
[7] Agag T, Vietmeier K, Chernykh A, et al. Side-chain type benzoxazine-
functional cellulose via click chemistry [J]. Journal of Applied Polymer
Science, 2012, 125(2): 1346-51.
[8] Lee D E, Na J H, Lee S, et al. Facile method to radiolabel glycol
chitosan nanoparticles with (64)Cu via copper-free click chemistry for
MicroPET imaging [J]. Molecular pharmaceutics, 2013, 10(6): 2190-8.
102 Yu-Tong Zhang, Zhu-Yun Li and Yu Chen
Chapter 5
ABSTRACT
Hydrogels are polymer cross-linked networks with ability to retain
large amount water yet remain insoluble. With this special property, quite
a lot of studies have been done on biomedical and tissue-engineering
applications of hydrogel. In recent years, hydrogel synthesized through
“Click-Chemistry” method has developed in large range. Because the
“Click-Chemistry” reactions could happen in relatively mild environment
(temperature and PH similar to organism's internal environment) with
highly selectivity and controllable gelation-time. Meanwhile, “Click-
Chemistry” also allows further functionalization of hydrogels which
greatly enlarges the applications of hydrogels. In this chapter, we will
cover some of the popular synthesis methods of hydrogels through
“Click-Chemistry” in recent years. The properties of different hydrogels
*
Corresponding Author email: cylsy@163.com
108 Mi-Heng Dong and Yu Chen
solution. Then, the mixture was sonicated with a probe-tip sonicator (26 W)
for 30 min. The mixture was centrifuged (13 000 rpm) for 90 min, and then
decants were collected. The 30 mg mL−1 of a-PVA, 6 mM of bis-azide and 10
mM CuSO4·5H2O in aqueous solution were prepared with 0.1 M KCl as the
supporting electrolyte. Next, the hydrogel was deposited on the ITO-coated
glass electrode by chronoamperometry and the reduction potential of Cu (II)
was applied. In this approach, the apparent electrochemically active surface
area in the pre-gelation solution with CNTs was 2.27 times larger than that
without CNTs, leading to a faster deposition of hydrogels with increased Cu
(I) catalysts concentration. At pH=8, the release rate of model drug
tetracycline is faster than pH=5, indicating that this might be a new method for
in situ electro-stimulated drug delivery system [4].
Figure 1. The synthesis of CNT enhanced hydrogel (a) and the drug release
model (b) [4].
However, due to the use of toxic Cu (I) as catalyst, the application of this
method in biomedical is limited. Azide-Alkyne reaction of same strategy that
doesn’t require catalyst was found in recent years. In 2014, Truong et al.
reported click reaction between PEG-alkyne and CS azide. The hydrogel
formed within 5–60 min at 37°C. It was prepared in 10 mL vials previously
silanized with Sigmacote® to prevent gels adhering to the glassware. In a
typical procedure for a hydrogel with [azide]; [alkyne] of 1; 1, 25 μL of PEG-
alkyne solution (80 wt%) was added to 200 μL of a 2.25 wt% solution of CS-
110 Mi-Heng Dong and Yu Chen
azide and then mixed for 5 s using a vortex mixer before transferring into a
water bath at 37°C. The gelation time was determined by vial tilt method. The
human mesenchymal stem cells (MSCs) was encapsulated in vitro and cell
viability was assessed after 24 hours. MSCs demonstrated high viability
(>95%). MCSs seeded to formed hydrogel and cultured for 7days also showed
adhesion to hydrogel with no cytotoxic response. The hydrogels were also
shown to display a rupture compressive stress of 81 ± 11, 160 ± 15 and 192 ±
20 kPa. During this process density of hydrogel are also found to be enhanced
with higher polymer concentration of precursor [5].
SPAAC. The hydrogel was firstly synthesized through AAm, BAAm, PAm by
photoinitiated free radical polymerization. To imitate the functionalization of
hydrogel through Cu (I) catalyzed click reaction, 2-azidomethyl pyrene (Py-
N3) was used. The fluorescence spectra showed successful functional reaction
[6].
The azide groups could not only be applied to enable further functionality
as mentioned in the previous example, it could also be utilized as a part of the
reaction cycle to realize auto-adjust temperature control of hydrogels. He et al.
synthesized a self-regulated hydrogel to realize the automatic temperature
control through the several exothermic catalytic reactions containing a click
reaction. The thermal-response of poly (N-isopropylacrylamide) is enabled by
4 reactions including the click reaction between ‘click’ reaction between
octylazide and phenylacetylene catalyzed by Cu (PPh3)2NO3 as illustrated in
the Figure 5. The shape change of this temperature responsive hydrogel is also
shown in Figure 6. Although the hydrogel synthesis is not directly related to
the click reaction in this example, we can still get a broad idea of the potential
application of hydrogels with click reactions.
Figure 10. The precursors of hydrogel (a) and the polymerization of hydrogel [17].
peptides showed less than 2% lysis as compared to the control (1% Triton X-
100). It could be generalized that this new hydrogel has a high antibacterial
property with low hazard to red blood cells [18].
3. STRAIN-PROMOTED AZIDE-ALKYNE
CYCLOADDITION (SPAAC)
SPAAC is a method that could enable cyclooctyne molecules with azides
to react quickly without copper catalyst as a result of ring strain and electron-
withdrawing fluorine substituents [1].
As mentioned in the previous chapters, the thiol-ene reaction has been
used to control the stiffness of hydrogel. To further enable more diversified
118 Mi-Heng Dong and Yu Chen
Figure 14. The reaction between Chitosan-PEG and DBCO-Sulfo-NHS Ester with the
fluorescein [23].
120 Mi-Heng Dong and Yu Chen
Figure 22. The successful myoglobin (green) and ubiquitin (red) fluorescence images
in multilayer structures [24].
124 Mi-Heng Dong and Yu Chen
Figure 24. Structures and Naming of Macromers and the Orthogonally Cross-Linked
ClickGel Networks [29].
Synthesis and Functionalization of Hydrogel … 125
4. DIELS-ALDER REACTION
4.1. Common Diels-Alder Reaction
HA is not the only materials that could be utilized to enhance the property
of hydrogel. Cellulose nanocrystals (CNCs) are nanoentities obtained from the
partial hydrolysis of a variety of cellulosic materials with length of 100–
500nm and width of 5-30nm [36, 37]. Utilizing Maleimide-grafted cellulose
nanocrystals (CNC-Mal) as cross-linkers in Diels-Alder Click reaction,
García-Astrain et al. synthesized new hydrogel of which G’ and G” stays in
high level during Dynamic modulus tests in all frequencies. This fact proved
the enhancement provided by nanocrystals as cross-linkers [38].
Figure 28. The Diels-Alder click reaction between GF and CNC-Mal [38].
Figure 30. The precursors A, B, C, the click reaction D, and the encapsulation
of cells [16].
CONCLUSION
Hydrogels have broad application in medical treatment and industry.
Through various types click chemistry, it is expected to get versatile new
hydrogel products with versatile properties. In this chapter, we have covered 6
main hydrogel synthesis methodology (CuAAC, thiol-ene, SPAAC, Diels
Alder, thiol-yne, Thiol-Michael reaction), especially two uncommon Diels-
Alder reactions (Hetero-Diels-Alder reaction and inverse electron demand
Diels-Alder reaction). The mechanical properties, chemical properties and
their influences on application has been introduced. The corresponding
relationship with click chemistry is also stated to provide readers a broad view
on how to combine new materials, use various click chemistry process for one
hydrogel to improve the property of hydrogels via click chemistry.
Functionalization of hydrogels such as electro-control and thermos-response
via click reactions are also described. Moreover, this chapter also shed lights
on potential new applications of hydrogels. Hydrogel could have further
application with the progress of researches.
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[5] Truong VX, Ablett MP, Gilbert HTJ, Bowen J, Richardson SM,
Hoyland JA, et al. In situ-forming robust chitosan-poly (ethylene glycol)
hydrogels prepared by copper-free azide-alkyne click reaction for tissue
engineering. Biomater Sci. 2014;2 (2):167-75.
[6] Yilmaz G, Kahveci MU, Yagci Y. A One Pot, One Step Method for the
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Kowollik C, et al. Limitations of radical thiol-ene reactions for polymer–
polymer conjugation. Journal of Polymer Science Part A: Polymer
Chemistry. 2010;48 (8):1699-713.
[9] Lin C-C, Raza A, Shih H. PEG hydrogels formed by thiol-ene photo-
click chemistry and their effect on the formation and recovery of insulin-
secreting cell spheroids. Biomaterials. 2011;32 (36):9685-95.
[10] Shih H, Fraser AK, Lin C-C. Interfacial Thiol-ene Photoclick Reactions
for Forming Multilayer Hydrogels. ACS Appl Mater Interfaces. 2013;5
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[11] Rossow T, Heyman JA, Ehrlicher AJ, Langhoff A, Weitz DA, Haag R,
et al. Controlled Synthesis of Cell-Laden Microgels by Radical-Free
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[12] Miroshnikova YA, Jorgens DM, Spirio L, Auer M, Sarang-Sieminski
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[13] Leight JL, Wozniak Ma Fau - Chen S, Chen S Fau - Lynch ML, Lynch
Ml Fau - Chen CS, Chen CS. Matrix rigidity regulates a switch between
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[14] Levental KR, Yu H, Kass L, Lakins JN, Egeblad M, Erler JT, et al.
Matrix Crosslinking Forces Tumor Progression by Enhancing Integrin
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[15] Ki CS, Shih H, Lin C-C. Effect of 3D Matrix Compositions on the
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[17] McKinnon DD, Kloxin AM, Anseth KS. Synthetic hydrogel platform for
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JAW, Liskamp RMJ. Convenient Preparation of Bactericidal Hydrogels
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Thiol–ene Click Chemistry. ACS Macro Letters. 2014;3 (5):477-80.
[19] DeForest CA, Anseth KS. Cytocompatible click-based hydrogels with
dynamically tunable properties through orthogonal photoconjugation and
photocleavage reactions. Nat Chem. 2011;3 (12):925-31.
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Synthesis and Functionalization of Hydrogel … 137
Chapter 6
ABSTRACT
Since the “click” reaction has been reported, it has become a useful
and powerful tool for chemistry. Using the “click” reaction, elastomer or
rubber can be conveniently prepared and modified. Different researchers
have reported a lot of new materials and surface modification methods. In
this review, a series of works were introduced. The main progresses of
the research on various “click” reactions applied to elastomer and rubber
were pointed out.
*
Corresponding Author Email: cylsy@163.com.
140 Ya-Lun Wang and Yu Chen
INTRODUCTION
Elastomer is a kind of polymer that has a crosslinked network and shows
rapid and large reversible strain in response to stress.1 So it shows a high
elasticity and resilience than ordinary liner polymer. The crosslinked network
within an elastomer can be formed through chemistry or physical methods,
such as linked through sulfur bridge, a typical chemistry method, or and
through hydrogen bond, a physical method.
Different methods can obviously change the properties of final product.
For example, if we combine a polymer through building hydrogen bond, we
can change the situation to connect or disconnect this bond. In this way,
crosslinked network may be reconstructable and the material may be reusable
or self healing after broken. Or crosslink degree will affect to the glass
transform temperature (Tg) and modulus of an elastomer, i.e., a higher
crosslink degree usually means a higher Tg and modulus. Thus, controlling the
crosslink process is an effect way to gain an ideal material with great
properties.
In the other hand, single material, in many cases, usually need to be
conjuncted with other materials for better properties. So it is necessary to
combine variety materials together, such as form a silicone rubber coating on
natural rubber (NR) to anti-ozone. Thus, we need to think that, how to
combine two or more material stably.
“Click” chemistry gave us a new enlightenment to reach these purposes.
Since the term, “click” reaction was proposed in 2001, more and more
new processes and materials have been developed. These reactions have
various advantages such as rapid reaction rate, high yields, minimal oxygen or
water sensitive and developed tremendously over the past decade. 2 Therefore,
“click” reactions are used between monomers or crosslink reagents to obtain
various elastomers, to introduce different functional groups to change
properties of products, or just for increasing reaction rate or reducing reaction
temperature. In the other words, the using of “click” reaction enriched our
method to improve both of these performance and efficiency of the materials.
widely used for the preparation, modification and recycling of the elastomers
and rubbers. Besides, more reactions were used to aim to various purposes and
applications.
Figure 2. PFPE-dialkyne ether and triazide formed the gel, finally got a three-
dimensional body structure.
micro tube to form droplets and “fly in” the co-flowing silicone oil. That will
form small droplets. Then let the droplets exposed under ultraviolet irradiation
about 2s to crosslink to form an elastomer network (Figure 5). The network
shows a fully reversible contraction upon heating. This work showed us a new
method for preparing particles.
composite film via UV-light initiated thiol-ene reaction. The crosslink process
will give the product a well and stable mechanical properties. By changing the
content ratio of mCNCs from 0 wt% to 80 wt%, they studied the effect of
weight fractions on the composite structure with TEM, mechanical and
thermal properties. They found that the increasing of the mCNCs weight
fraction will cause an uncommon abrupt transition from soft PBD-dominated
to reinforced mCNCs-dominated structure. All of the composite shows
stability to air humidity. The work found a way to improve the mechanical
properties by using biomimetic compositions.14
TMPMA. It showed that the mass fraction of 2 wt%, and 3 wt% TMPMA
form individual fibers.17 But they found that the hydrophilicity of fiber mat
was decreased. So they modified the electrospun fiber mats via photo
initialized thiol-ene reaction and this stage will be explained in next part.
According to the results of above studies, we can find that kinds of “click”
reactions offer us a powerful tool to prepare more high performance
elastomers and rubbers. The above reactions have become a powerful tool for
formation of the elastomers and rubbers.
150 Ya-Lun Wang and Yu Chen
rough, etc. Exploiting the carbon double bond inside NR via “click” reaction,
certain groups can be introduced efficiently to modify the surface of NR.
The carbon double bond in the natural rubber causes it has a low oxidation
resistance. This property limits the application of NR. Shown in Figure 8,
Zheng et al. reported a polymethylvinylsiloxane (PMVS) coating layer
combined on natural rubber and given the elastomers a well ozone-resistance.
Using PMVS, trimethylolpropane tris(3-mercaptopropionate) (TMPMP) as a
crosslink reagent, 2-methyl-4-(methylthio)-2-morpholinopropiophenone as
photoinitiator, they prepared the coating layer via UV initiated thiol-ene
reaction. TMPMP crosslinked the PMVS to form the coating layer and offered
covalent crosslinking between natural rubber layer and PMVS layer. The
PMVS layer showed a great anti-ozone properties that, only microcracks can
be observed on the surface of coated elastomer, while pure natural rubber has
wider cracks at the same ozone concentration.19
used of indole will cause the reaction temperature rise to 120℃ or higher. An
indole functionalized substrate was prepared via thiol-ene reaction between
reactive self-assembled monolayers (SAMs) and thiol functionalized indole
derivative. Then the film was contacted with a PDMS stamp and was soaked
with ATRP-TAD solution in acetonitrile to get the micropatterns. After the
printing step, the substrates were immersed into 2,4-hexadien-1-ol solution in
DMF or α-phellandrene, to erase the micropattern by transclick reaction. This
step ATRP-TAD would detach to regain indole groups on the surface. At that
time, it can be printed again.22
The works showed above described high versatility for the preparation of
reversible chemical structure. The introduction of functional groups was more
easy to occur with kinds of “click” reactions.
CONCLUSION
In summary, various “click” reactions can rapidly combine two parts
together with high selectivity. Therefore, it will be more simple to develop
kinds of elastomer. Thus, introduction of functional group will be more
convenient, and then obtained elastomer will get ideal physical and chemical
properties, even unimaginable new features. For preparing processes, “click”
reaction is a powerful tool to create a stable crosslinked network, to give
obtained elastomer a suitable modulus or Tg. Or by using a pair of groups
likes diene and dienophile, a reversible network will be obtained. That mains,
the elastomer is an environment friendly renewable elastomer. For
modification processes, a special group or structure which is hard to combine
with a matrix will be easily linked with “click” reaction and change properties
of elastomer. Or for this process, by using “click” reaction, reaction time or
energy cost can be reduced obversely. So, we can focus on the design of
polymer, crosslink reagent and modified components but not the reaction that
how to combine them together. Compared with traditional chemical synthesis
methods, this process has great advantage, such as diversified, controllable,
efficient, low-consumption and low-pollution. Nowaday, elastomer industry
focus on not only just economic benefits of producing a elastomer, but also
impact on the environment and energy saving. And “click” reaction will
promote the rapid development of rubber and elastomer industry.
154 Ya-Lun Wang and Yu Chen
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[12] Alzahrani, A. A.; Nair, D. P.; Smits, D. J.; Saed, M.; Yakacki, C. M.;
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[13] Fleischmann, E.-K.; Forst, F. R.; Koeder, K.; Kapernaum, N.; Zentel, R.,
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156 Ya-Lun Wang and Yu Chen
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In: Click Chemistry ISBN: 978-1-53611-903-9
Editors: Y. Chen and Z. R. Tong ©2017 Nova Science Publishers, Inc.
Chapter 7
ABSTRACT
Herein, we review methods to prepare and/or functionalize monoliths
through a plethora of click chemistries in view of developing materials
meant for flow-through applications. The latter range from separation
science (electrochromatography, chromatography, preceoncentration) and
catalysis technology (microreactor). The emphasis is on copper-catalyzed
azide-alkyne Huisgen dipolar cycloaddition, thiol-ene and thiol-yne
coupling, thiol-(meth)acrylate and thiol-epoxy reactions and Diels-Alder
1. INTRODUCTION
Control at the molecular-leveled of the chemical nature of pores surface is
of utmost importance for predicting the overall behavior of porous materials
with potential flow-through uses [1]. This is notably true for monoliths which
are defined as single continuous pieces of highly cross-linked and porous
materials. Monoliths of organic, inorganic and hybrid nature, have
continuously gained interest over the last quarter of century as stationary
phases for capillary chromatographic and electrochromatographic applications,
as solid sorbents for extraction and preconcentration purposes [2, 3].
Monoliths exhibit unmatched intrinsic properties as they offer, for instance,
highly efficient mass transfer kinetics in contrast to their particulate
counterparts. Monoliths can be prepared via different synthetic strategies as
the traditional free radical polymerization and vinyl-like monomers and the
inorganic polymerization, i.e., sol-gel process, of silane precursors [4, 5]. With
the aim to combine both properties of organic and inorganic materials, hybrid
monoliths have also met great success.
In this regard, many research efforts have been devoted to implement easy
elaboration methods with a special focus over the last 15 years on using click
chemistry. The copper I-catalyzed Huisgen and Diels-Alder implementations
are cycloaddition reactions involving 6π (4+2) electrons ended up with the
formation of 5- and 6-membered cycles, respectively. In contrast, the addition
Surface Engineering of Porous Monoliths via Click Chemistry 159
Figure 2. General scheme of the most commonly implemented reactions of the ‘‘click’’
type so far developed for the synthesis and functionalization of monoliths.
these click reactions have been discovered a long time ago but so far neglected
by scientists that only found them a limited synthetic interest.
techniques such as NMR, FT-IR, XPS and Raman spectroscopy for instance.
Indeed, clickable functions generally possess particular chemical functions,
e.g., azides, alkynes, alkenes, thiols, etc. that have very specific signature as
examined using such physico-chemical techniques.
All these above-mentioned click reactions have been extensively
implemented during the last 15 years in macromolecular engineering and for
the conception of smart advanced materials and nanomaterials [58] and
especially for the design and synthesis of chromatographic supports based on
inorganic, hybrid or polymeric monoliths.
First discovered by Rolf Huisgen [59] in 1963 and considered in the early
2000’s as the cream of the crop of the click reactions, CuAAC reaction has
since been fallen into disuse when compared to other click reactions. Its
reaction mechanism has not been elucidated for a long time. Recent studies
notably bring to light two distinct possible routes to this mechanism, thanks to
the isolation of CuAAC reaction intermediates [60, 61]. In a general manner, it
involves the regioselective copper(I)-catalyzed cycloaddition between an azide
and a terminal alkyne, as shown on Figure 2a. More precisely, two
concomitant pathways can lead to the formation of the triazole ring (Figure 4).
While the first one, slow, involves mononuclear catalytic species, the second
one, underpinned by the isolation of bis(copper) key intermediates, relies on a
fast and thus kinetically favoured synthetic route.
However, this reaction is more and more abandoned because of the
potential toxicity of the required copper catalyst, even though it is generally
removed from the products in a nearly quantitative fashion. Nevertheless, a
strain promoted version of the CuAAC reaction [62] has been since developed
especially by Bertozzi and collaborators [63] that implemented the strain-
promoted azide-alkyne cycloaddition (SPAAC) reaction that is a copper-free
version of the CuAAC, involving in this case cyclooctyne-based compounds.
The main advantage in that particular version relies in the absence of the
copper catalyst that notably allows for using such click reaction for
biofunctionalization and modification of biomolecules in living systems
notably. Nevertheless, it has been extensively implemented for the
functionalization of monoliths with selectors of interest for applications in
166 S. Ibrahima Kebe, H. Kammoun, M. Guerrouache et al.
The alkyne-based version of the thiol-ene reaction, i.e., the thiol-yne click
reaction, operates in the same conditions but allows in that particular case for
the grafting of two thiol-containing compounds per alkyne moiety (Figure 2c)
[70, 71]. In surface chemistry area, this is actually an important parameter to
take into consideration when one wants to obtain a denser surface
functionalization with the thiol-containing compound, provided that steric
hindrance is limited. It is worth mentioning that in such an attempt of denser
surface functionalization, the supports should bear alkyne functions.
168 S. Ibrahima Kebe, H. Kammoun, M. Guerrouache et al.
catalyst to the less substituted carbon of the activated C-C double bond via a
1,4-Michael type addition. The zwiterrionic intermediate then abstracts a
hydrogen from a thiol molecule in the medium. Finally the as-formed thiolate
substitutes the catalyst, thus generating the corresponding thioether (Figure 7).
In order for this reaction to proceed, the alkene-containing substrate requires
an electron-withdrawing group (generally an ester, a ketone or an aldehyde)
directly conjugated to the C-C double bond to proceed.
and can then achieve the nucleophilic addition, as shown on Figure. The last
step of the reaction involves hydrogen abstraction from another thiol molecule
in the medium to afford the final -mercaptoalcohol.
Figure 10. Scanning electron microscopy images showing the morphology of hybrid
monolith prepared by through photodriven thiol-ene click chemistry using different
tetra-vinyl monomers and muli-thiols. Reproduced from ref 84 by permission of Royal
Society of Chemistry.
The same group applied thiol-yne click chemistry type in the area of
monolithic materials [85].
Dual-process for the preparation of organic-inorganic monolith, involving
simultaneous polycondensation and thiol-mediated radical addition, has also
been exploited by the group of Huanghao Yang from the Fuzhou University
[86]. Glutathione, a molecular combination of three proteins building blocks,
namely cysteine, glycine and glutamine, was used in mixture with 2,2-
azobisisobutyronitrile (AIBN), hydrolyzed tetramethyloxysilane (TMOS) and
γ-methacryloxypropyltrimethoxysilane (γ-MAPS) to provide multifunctional
monoliths (Figure 11). A two-step thermal treatment involving, initial heating
at 40°C for 12 h and additional treatment at 70°C for another 12 h was applied
174 S. Ibrahima Kebe, H. Kammoun, M. Guerrouache et al.
Figure 11. Schematic illustration of the synthetic path developed to synthesize hybrid
monolith zwitterionic surface functionality through thiol-ene click chemistry.
Reproduced from ref 86 by permission of elsevier.
Although vinyl-POSS derivatives have gained great interest over the last
years for the preparation of organic polymer-based materials they suffer from
low reactivity of the tightly tethered vinyl group in free radical polymerization.
Radical-mediated step-growth process in the presence of thiol and initiator has
been exploited to the chemical cross-linking of POSS precursors in an efficient
and controlled way [87].
Thiol-methacrylate Michael addition click reaction between multi-
methacrylate polyhedral oligomeric silsesquioxane and multi-thiols was
reported as a facile strategy for the direct preparation of hybrid monolithic
capillary columns [88]. Methacrylate-polyhedral oligomeric silsesquioxane
(POSS-MA) (cage mixture, n = 8, 10, 12, POSS-MA) was allowed to
react with different multi-thiol crosslinkers – 1,6-hexanedithiol (HDT),
trimethylolpropane tris(3-mercaptopropionate) (TPTM) and pentaerythritol
tetrakis(3-mercaptopropionate) (PTM) – in a two component (n-propanol and
PEG 200) porogenic system. The Michael addition was efficiently catalyzed
Surface Engineering of Porous Monoliths via Click Chemistry 175
found in the range 0.19 – 60.51 x 10-14 m2 for the POSS-epoxy–PTM hybrid
monoliths depending on the composition of the binary porogenic mixture
(EtOH/PEG 10,000) and catalyst (KOH) content. The same research team
extended successfully the thiol-epoxy approach to other multi-epoxy monomer
– tetraphenylolethane glycidyl ether – and multi-thiol monomer –
trimethylolpropane tris(3-mercaptopropionate) and pentaerythritol tetrakis(3-
mercaptopropionate) – using ternary porogenic system – DMSO/PEG200/H2O
– as ascertained by systematic characterizations of the obtained monoliths by
complementary methods including SEM, FT-IR spectroscopy, pore size
measurement, thermal gravimetric analysis and nitrogen adsorption/desorption
measurement [91].
In another implementation, methacrylate-silica monolithic columns of
hybrid nature and bearing sulfonic acid surface groups were newly synthesized
within capillary columns through a one pot approach [92]. To establish
the method, organic monomer (3-sulfopropyl methacrylate potassium) and
initiator (2,2’-azobis (2-methyl propionamidine) dihydrochloride) were
simply added to the hydrolysis solution of TMOS and mercaptopropyl-
trimethoxysilane (MPTS) so that polycondensation and thiol-ene click reaction
occurred simultaneously between the precondensed siloxanes and organic
monomers. The reaction was conducted in presence of urea, PEG and acetic
acid at low temperature (35 –55°C) for 12h. Monolithic materials with both
homogeneous structure and good permeability, and referred to as ideal
monoliths by the authors, were obtained only using an intermediate
temperature of 45°C. The morphology was found to be highly dependent on
the amount of added porogen. Low and high PEG amounts led to monoliths
with poor permeability and weak attachment onto the silica wall, respectively.
A multi-step and elegant preparation approach was implemented by
Cuicui Liu with the aim to design two-dimensional monoliths within capillary
columns for biomolecules analysis [93, 94]. The 1st dimension acted as pre-
concentration segment. The corresponding monolithic structure was in situ
prepared in a single step via Michael addition reaction and radical
polymerization. Such mechanism combination involved thiol graphene (500
m2/g), 4-vinylphenylboronic acid (VPBA), ethylene dimethacrylate (EDMA),
1-vinyl-3-octylimidazolium chloride (ViOcIm+Cl−) and was initiated at 70°C
in presence of 2, 2-azobis(isobutyronitrile) (AIBN). Extensive ultra-sonication
was required to dissolve the graphene derivative in a N,N-dimethylformamide
and 1,4-butanediol solvent mixture.
Surface Engineering of Porous Monoliths via Click Chemistry 177
Figure 12. Schematic illustration of the synthetic path developed to synthesize POSS-
based hybrid monolith through thiol-ene click chemistry. Reproduced from ref 89 by
permission of Royal Society of Chemistry.
178 S. Ibrahima Kebe, H. Kammoun, M. Guerrouache et al.
Figure 13. Schematic illustration of the synthetic path developed to synthesize POSS-
based hybrid monolith through thiol-epoxy click chemistry. Reproduced from ref 90 by
permission of Elesevier.
subsequently react with a selector/ligand bearing an azide unit and vice versa.
This allows a variety of combination taking advantage of the numerous and
commercially available functional thiols, alkenes, alkynes, azides, epoxy,
methacrylates… Extended this introductive section to silica-based monoliths,
alkynyl- or azido-hybrid monoliths can be prepared through condensation of
the hydrolyzed silane precursors tetramethoxysilane and (3-iodopropyl)-
trimethoxysilane in the presence of neutralized functional amine,
propargylamine or 11-azido-3,6,9-trioxaundecan-1-amine, respectively [98].
Using ethylene dimethacrylate (EDMA), as a crosslinker, and glycidyl
methacrylate, as monomer, P(GMA-EDMA) monoliths carrying epoxy surface
groups have proved very useful to serve as generic platforms for the
preparation of monolithic materials with a variety of functionality
(hydrophobic, hydrophilic, anion/cation exchange, chiral, affinity) [5]
including, more recently, clickable groups.
P(GMA-EDMA) can be prepared by free radical polymerization using
heavy alcohol (cyclohexanol/dodecanol mixtures) as porogen. Svec et al.
reported on the synthesis of thiol monoliths by one-[99, 100] and two-step
[101, 102] surface modification of GMA-based monoliths. Surface thiols were
obtained by direct aminolysis of epoxy groups with 2-aminoethanethiol while
the grafting of 2,2′-dithiobis(ethylamine) required additional treatment under
reducing conditions to provide disruption of the S-S bonds. Considering the
surface modification of generic P(GMA-co-EDMA) with cystamine, the same
group of authors showed that repeating the grafting twice (1.0 mol/L
cystamine dihydrochloride in 2.0 mol/L aqueous sodium hydroxide at RT for 1
h and subsequent heating at 50°C for 1 h) enables increasing the sulfur content
from 2.6% to 3.7%. Such monolith with enriched sulfur, i.e., thiol, content can
serve as versatile clickable platform for efficient grafting of methacrylate
monomers.
Lämmerhofer proposed the bonding of thiolated polymers instead of their
molecular counterparts to design tentacle-like surface-structured monoliths
with the aim to enhance both surface coverage of functional groups and
sample loading abilities [103]. The proof of principle was proposed for
polythiol-grafted monoliths following a three-step derivatization protocol.
Poly(GMA-co-EDMA) was subjected to (i) amination – ammonia – (ii)
vinylation – allyl glycidyl ether – and (iii) coating – poly-3-mercaptopropyl
methylsiloxane (PMPMS*) – in combination with crosslinking by thermally-
driven radical addition click reaction. Such an approach allowed more than a
2-fold increase in thiol coverage as compared to a control monolith obtained
through direct functionalization by nucleophilic substitution with PMPMS.
180 S. Ibrahima Kebe, H. Kammoun, M. Guerrouache et al.
its general feasibility in pores [108]. The use of bridging phenylazide moieties
offer a variety of unique possibilities for the grafting of nearly any desired
chemical functionality via click chemistry. Surface functionalization was
achieved through click grafting of an alkyne-modified fluorescein onto azide-
containing aerogel-like monoliths. Fluorescence imaging in combination to
spatially resolved IR spectroscopy measurements highlighted undoubtedly the
possibility to generate chemical gradient through this elegant approach.
Although the authors did not report applications they claimed that materials
exhibiting property gradients – chemical, optical and structural – may be
potential candidates for uses requiring directionality as it is the case for
chromatography.
Beside the more conventional methacrylate- and styrenic-based monoliths,
polycarbonate monoliths were also considered as functional platforms with
click reactivity [109]. Bisphenol A (BPA), 4,4′-(1-methylethylidene)bis(2-
allylphenol) (MBP) and 4-nitrophenyl chloroformate (NPC) were initially
dissolved in acetonitrile and the polymerization was further conducted under
argon at 70°C during 20 h after addition of 4-dimethylaminopyridine (DMAP)
and triethylamine. Polycarbonate with allyl side units was thus obtained and
further processed in a monolithic structure through a phase separation
approach. Cyclohexane was used as precipitation solvent providing 3-D
porous network with specific surface area of 145 m2/g as determined by
adsorption/desorption measurements.
Thiol-sensitive monoliths were also prepared in their hybrid variant
through sol-gel process [110, 80]. Inorganic polymerization of
tetramethoxysilane (TMOS) and γ-methyl methacrylate trimethoxysilane (γ-
MAPS) in presence of PEG (6000, 10000 and 20000 g/mol) urea and acetic
acid provided hybrid skeleton with the required flow-through properties and
carrying clickable C=C units [110].
Other implementation of the “generic monolith” concept with easy surface
functionalization features and thus allowing fast preparation of supports with
versatile surface properties was proposed by some of us nearly 10 years ago
[24]. Organic polymer monoliths were prepared in UV-transparent fused-silica
capillaries by photo-triggered free radical copolymerization of N-
acryloxysuccinimide as reactive monomer, ethylene dimethacrylate as
crosslinker, azobisisobutyronitrile as initiator and toluene as porogen.
Chemical and porous structures of such N-hydroxysuccinimide (NHS)
decorated monoliths can be simply tuned through judicious choice of synthesis
conditions. Addition of a limited amount of polar solvent (DMF or DMSO) to
toluene allows controlling the pore size in the range 0.4 – 2.2 µm, whereas
182 S. Ibrahima Kebe, H. Kammoun, M. Guerrouache et al.
Figure 14. Schematic illustration of the strategy developed by our group to design
functional monoliths via the post-functionalization of generic monolithic skeleton with
N-hydroxysuccinimide surface functionality.
Surface Engineering of Porous Monoliths via Click Chemistry 183
Figure 15. Schematic illustration of the strategy developed by our group to prepare
clickable monoliths based on glycerol carbonate methacrylate. Surface
functionalization of the monolith through thiol-ene click chemistry is also presented.
Reproduced from ref 116 by permission of Royal Society of Chemistry.
Surface Engineering of Porous Monoliths via Click Chemistry 185
Figure 17. Schematic illustration of the synthetic path developed by our group to
functionalize the surface of ene-monolith through thiol-ene click chemistry.
Reproduced from ref 11 by permission of Elsevier.
Indeed, monoliths involving a click step in their preparation process have been
designed to fulfill specifications for the different chromatography modes.
Reversed phase capillary (electro)chromatography requires the use of
stationary phases with apolar surface features in combination with aqueous-
based mobile phase containing usually methanol or acetonitrile as organic
modifiers. As such monolith with aliphatic-graft have been prepared as
analogous to the famous C4, C8, C18 particulate stationary phases [102]. The
said monoliths with dodecyl or octadecyl grafts provided efficient solutions for
the separation of low (alkylbenzenes) and large (protein) molar mass analytes.
Chromatographic properties of POSS-containing monoliths have been
thoroughly investigated under reversed phase separation mode [88, 89]. POSS-
epoxy–pentaerythritoltetrakis(3-mercaptopropionate) (PTM) and POSS-
epoxy–trimethylolpropanetris (3-mercaptopropionate) (TPTM) provided the
baseline separation of five alkylbenzenes according to their hydrophobicity,
from low to high (Figure 20) [90]. Using ACN/H2O mixture (50/50, v/v) as
mobile phase, the former provided lower retention time and lower plate height
(of about 6 µm). Both columns were further applied for the separation of five
polycyclic aromatic hydrocarbons (PAHs), six phenols, six anilines, five
benzoic acids, five pesticides, three dipeptides and four intact proteins. These
results demonstrated the potentiality of this type of monoliths for the analysis
of both small molecules and (bio)macromolecules.
Additionally, POSS-epoxy–PTM monolith was implemented for cLC–
MS/MS analysis of BSA digest. Fifty three unique peptides were positively
identified with protein sequence coverage of 58.65%, while C18-particle-
packed column, used for comparison purpose, provided lower analytical
performances where 51 unique peptides were positively identified with protein
sequence coverage of 56.01%.
Monolithic matrices, easily prepared through thiol ene, with carbon rich
skeleton exhibit hydrophic surface properties as suggested by contact angle
measurements indicating values well above 90°C [82]. This behavior can be
used for the LC separation of apolar solutes such as alkylbenzenes. For such
homologous series, selectivity values were extracted from the plots of log k =
f(n) with n being the number of carbon atom in the aliphatic side chain and
were found to increase from 1.27 to 1.43 when the ACN content was changed
from 80 to 65%. The separation properties were further investigated towards
five basic compunds, four pesticides and EPA610, consisting of sixteen
priority PAHs pollutants with potential health hazards (Figure 21). The authors
claimed for very high columns efficiency with values up to 1130,000
192 S. Ibrahima Kebe, H. Kammoun, M. Guerrouache et al.
Figure 21. Separation of (A) basic compounds, (B) pesticides (C) EPA610 obtained
under reversed phase chromatographic mode using organic monoliths prepared by
photothiol-ene click chemistry. Reproduced from ref 82 by permission of Elsevier.
Surface Engineering of Porous Monoliths via Click Chemistry 193
Figure 22. Separation of (A) nucleosides, (B) and (C) nucleotides obtained under
hydrophilic interaction chromatographic mode using organic-silica hybrid monoliths
prepared by thiol-ene click chemistry. Reproduced from ref 83 by permission of
Elsevier.
Figure 23. Separation of phenol obtained under (a) hydrophilic interaction and (b)
reversed phase electrochromatographic modes using (a) oligoethylene-clicked and (b)
C6-grafted monoliths having the same generic skeleton. Reproduced from ref 11 by
permission of Elsevier.
complex chemical nature and topology that may generates false results. As
such bioanalysis requires combining advanced technology relevant to
microfluidics, surface science, analytical chemistry…
One area of great interest relies on the utilization of monolithic supports,
especially the one made of polymers, as building elements of bioanalytical
setups [134].
Recent literature reported about the click chemistry-mediated covalent
attachment of bio-recognition elements on monolithic materials. Aptamers
which are the artificial single-stranded DNA or RNA sequences have the
ability to bind to complementary targets with high selectivity and affinity
[135]. Hence, aptamer technology offers a powerful approach for the one step
selective extraction and concentration of a target analyte from liquid matrices
as well as sample purification from solid matrices extracts. In a recent study,
affinity matrix made of organic-silica hybrid monolithic skeleton surface-
decorated with aptamer against human α-thrombin linked through thioether
bond was applied to the enrichment of trace proteins [110]. Thrombin was
extracted from human serum with recovery of 91.8%. All the results were
compared with those obtained with a monolith grafted with a DNA oligo
control.
Incorporation of nanoparticles with high surface/volume ratios within
monolithic materials greatly improved their specific surface area, especially in
the case of organic polymer monoliths (Figure 25) [93]. Such effect is
beneficial to preconcentration ability even for low abundance peptides.
Monoliths incorporating crosslinked and functionalized graphene – through
Michael addition between thiolated graphene and EDMA and 4-
vinylphenylboronic acid, respectively – exhibited large specific surface area of
about 130 m2/g and enhanced binding capacity towards glycoproteins
including horseradish peroxidase, ovalbumin, transferrin, alpha fetoprotein and
ribonudease A. The binding values were calculated as 10.16 and 10.47 mg/g
(at pH 9.0) for disease markers transferrin and alpha fetoprotein, respectively,
and were well-larger than the ones calculated for boronic acid-functionalized
monolithic materials [105, 136, 137]. Effect of the preconcentration segment
length was optimized in a further step. Indeed, short preconcentration monolith
led to poor enrichment factor while too-long preconcentration monolith
resulted in high back pressure. Reasonable compromise was obtained for 14
cm long monoliths.
198 S. Ibrahima Kebe, H. Kammoun, M. Guerrouache et al.
From the above, it is obvious that the click chemistry and monolith pair
has been to date mainly applied to separation science. However, one should
Surface Engineering of Porous Monoliths via Click Chemistry 199
Figure 26. Schematic illustration of the synthetic path developed by our group to
functionalize the surface of thiol-monolith through thiol-maleimide click chemistry.
Reproduced from ref 115 by permission of Wiley.
Figure 27. Schematic illustration of the synthetic path developed to synthesize hybrid
monolith-based enzymatic microreactors through thiol-ene click chemistry.
Reproduced from ref 138 by permission of Elsevier.
Surface Engineering of Porous Monoliths via Click Chemistry 201
Our group has reported the use of clicked monoliths for heterogeneous
catalysis applications using monolith-immobilized nano-metals as catalysts.
The proof of concept was reported in an initial paper published in 2012,
describing the versatility of thiol-yne surface click chemistry for the well-
controlled functionalization of porous polymer-based monoliths (Figure 28)
[8].
Figure 28. Schematic illustration of the synthetic path developed by our group to
functionalize the surface of ene-monolith through thiol-ene click chemistry.
Reproduced from ref 8 by permission of Royal Society of Chemistry.
Figure 29. Schematic illustration of the synthetic path developed by our group to apply
COOH-monolith obtained thiol-ene click chemistry as catalytic microreactor.
Reproduced from ref 26 by permission of Elsevier.
CONCLUSION
For about 25 years now, monolithic materials have been synthesized using
a plethora of synthetic routes enabling the fine control of both skeleton and
surface chemistry. The former affords mechanical resistance in combination
with transport properties for applications under flow conditions. The latter
ensures the functionality of the monolithic surface providing specific
interaction with analytes or reactants. Organic (methacrylate, acrylate,
carbonate) inorganic (silica, silsesquioxanes) and hybrid monolithic matrices
have all be subjects of investigation by the chemists interested in spreading
click reactions in all range of materials science. Although thiol-ene radical
addition is the prominent click method in the context of monolithic materials,
we attempted, in this contribution, to summarize the synthetic strategies,
involving a click chemistry step, developed recently for synthesizing or
functionalizing monoliths. Undoubtedly, click chemistry has allowed
developing fast, one-step, if not one-pot, preparation methods of highly
functional monoliths providing advanced solutions in analytical chemistry as
exemplified with versatile stationary phases for separation science and smart
sorbents for pretreatment of complex sample matrices preparation as well as in
micro-reactors technology.
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Chapter 8
ABSTRACT
Polymeric membranes exhibit high potentials for comprehensive
applications. However, the low surface energy and relatively high
hydrophobicity restrict their wide usage. Modulation of their bulk
and surface characteristics is especially important practically and
theoretically. The CuI-catalyzed triazo-alkynyl cycloaddition enjoys high
efficiency, less side reaction and high selectivity, and is vastly used in
polymer synthesis and preparation currently. Through this method the
polymers with low polydispersity, preset molecular weight, controlled
composition, and functionality could be introduced to membrane surface
or bulk materials. This chapter is focused on the utilization of click
chemistry for the membrane preparation and surface modification.
*
Corresponding Author Email: yhy456@ahnu.edu.cn
212 Zhu-Fang Hu, Jin Zhou and Hai-Yin Yu
INTRODUCTION
Click Chemistry
Click chemistry can be divided into two classes: those in which protons
must be shuffled about (epoxide ring opening, for example) and those in which
no -bond connections are severed (cycloaddition reactions, the most useful
and reliable being the Huisgen dipolar cycloadditions). The former tends to
benefit dramatically from an aqueous environment, while the latter reveals
little solvent dependence and are better overall in their adherence to click
chemistry ideals. Indeed, the azide acetylene triazole version of Huisgens [2 +
3] cycloaddition family of processes is about as good as a reaction can get.
Nevertheless, it is the “less ideal” epoxide and aziridine opening processes
which are the workhorses for installing, often in the penultimate step of a
block synthesis, the azide or alkyne moieties (Kolb H C, 2001a).
The following four kinds of click reactions possess the merits of click
chemistry, namely the cycloaddition reaction, nucleophilic ring-opening
reaction, aldol carbonylation reaction, carbon carbon addition reaction
214 Zhu-Fang Hu, Jin Zhou and Hai-Yin Yu
triazole, the production rate is as high as 91%, the reaction time is reduced
from the original 18 h for 8 h (Rostovtsev V V, 2002).
Over the past years, the thiol-Michael addition reaction has been tailored
to progress under mild, solventless reaction conditions using mild catalysts
to yield a highly efficient, modular click reaction. In fact, numerous thiol-
X reactions have been broadly classified as click reactions in which the
thiol reacts via pathways as diverse as radical-mediated thiol-ene reactions,
amine-catalyzed thiol-epoxy reactions, thiourethane-forming thiol-isocyanate
reactions, and thiol-halide reactions (L. A. B. Hoyle C E, Bowman C N.[J]. , , ,
2010; Hoyle, Lowe, & Bowman, 2010a).
New methods to synthesize and functionalize polymers are of constant
interest to the polymer scientist. In polymer science, a clear transition occurred
from simple plastic production to the generation of diverse functional
materials targeted for use in applications such as electronic devices,
nanomaterials, and medical treatments (Chu C, 2011; Fournier D, 2007; K. A.
K. C. m. e. Franc G, simple and greener routes to design dendrimers[J], &
MLA, 2010; K. A. K. J. Franc G, & MLA, 2010; Golas P L, 2010; L. A. B.
Hoyle C E, Bowman C N.[J]. 2010; P. Theato, and Harm-Anton Klok 2013).
Highly efficient linking reactions have played an indispensable role in polymer
science.
This chapter will provide the context of Click Chemistry Reaction used
for membrane preparation and surface modification, particularly in
functionalization, modification, orthogonally functionalizing polymers, and
its integration with Reversible Addition-Fragmentation Chain Transfer
Polymerization (RAFT). The utility of the click reaction has been
demonstrated in living radical polymerization. Among controlled free radical
polymerizations, RAFT has arguably played an important role in membrane
modification because it works with the greatest range of vinyl monomers
(Ranjan R, 2007).
Membrane Technology
important role in modern life and industry status. On the membrane surface,
the surface wettability and hydrophilicity is poor, this leads not only to low
water flux but also to serious membrane fouling. Thus, membrane materials
restrict the potential applications of these membranes in biomedical systems
and the separation of aqueous solutions. The advanced membranes should be
designed to meet specific water treatment applications by tuning their
structural and physicochemical characteristics, including hydrophilicity,
porosity, membrane charge, and thermal and mechanical stability as well as
introducing additional functionalities such as antibacterial, photocatalytic or
adsorption capabilities (Kochkodan V, 2015). Due to their exceptional
mechanical, chemical and thermal stability and conductive and antibacterial
properties carbon-based nanomaterials are among the most promising
candidates to tackle this challenge (Daer S, 2015; El-Saied H, 2003; Tian M,
2015).
Br
Esterification
OH
NaN3
S
O
S S
O
Alkyne terminated RAFT CTA
N3
O
N
S
O C12H25
N
nS S
N N O
some of the azide groups still remained on the azido-GO. Each of the process
was repeated for several times, thus MPPM was coupled with GO by the layer-
by-layer assembly to the membrane using click chemistry. Highly permeable
polypropylene membrane with remarkable protein fouling resistant and better
antibacterial was prepared via the layer-by-layer assembly of graphene oxide
(GO) nanosheets through azide-alkyne click reaction (Z. B. Zhang et al.,
2015).
The number of colonies in the bacterial culture plates gradually decrease
with the increase of layers of GO. The number of the bacterial colonies on the
5-layered GO modified MPPM decreases almost two-thirds due to that the
cutting edge can produce high membrane pressure; kill the bacteria (Figure 6).
Figure 6. Photograph showing the bacterial culture plates of E. coli for the unmodified
and modified MPPMs. (a) nascent MPPM; (b) MPPM-GO2; (c) MPPM-GO4 and (d)
MPPM-GO5, respectively.
membrane, the modified membrane can effectively reject proteins due to the
densely grafted polymer chains. A novel and distinctive strategy has been
developed for the polypropylene macroporous membrane surface modification
by marrying click chemistry with controlled radical polymerization, which can
be readily extended to other polymeric membranes. Hai-Yin Yu group report
the attachment of a RAFT polymer via the grafting-to approach. The grafted
polymer with determined structure can individually be prepared controllably
and characterized elaborately. This approach opens a new avenue to the
fabrication of polymer membrane surfaces with different functional polymers.
More research is needed to improve the reaction efficiencies: the SN2
nucleophilic exchange of bromine groups on the substrate membrane surface
with azide group; the click coupling of functional polymers with long chain
onto the membrane surfaces (X. M. Wu et al., 2012).
Xiao-Jun Huang et al. presented a novel approach to constructing
glycosylated surface for microporous membrane. Carbohydrate derivative can
be facilely bound onto the alkyne-modified membrane surface via thiol-yne
click chemistry. The glycosylated membrane surface shows an excellent
affinity adsorption to lectin on the basis of carbohydrate-protein recognition.
Click chemistry between azide and alkyne is one of the methods to
construct a “glycoside cluster effect” on the surface of microporous
polypropylene membrane (MPPM) for lectin recognition and affinity
adsorption (C. Wang, Wu, & Xu, 2010). However, the triazole moieties
derived from this azide/alkyne click reaction seems to engage in hydrogen
bonding and stacking interactions with the amino acid residues of proteins
(Manetsch et al., 2004). These unexpected interactions unavoidably cause the
nonspecific adsorption of proteins, which decrease the recognition capability
between the glycosylated membrane surface and its protein receptor.
1st step
222 Zhu-Fang Hu, Jin Zhou and Hai-Yin Yu
2nd step
3rd step
(Fairbanks, Scott, Kloxin, Anseth, & Bowman, 2009). As with the thiol-ene
reaction, the thiol-yne click chemistry proceeds rapidly under a variety of
experimental conditions and yields selectively mono- or bis- addition products
(Hoogenboom, 2010). It employs the most promising metal-free reaction and
can be catalyzed photochemically or by nucleophiles with near-quantitative
yields in a period of seconds at ambient atmosphere (Lowe, Hoyle, &
Bowman, 2010). While this robust reaction has been well-documented in the
synthesis of polymers including dendrimers (Chan, Shin, Hoyle, Bowman, &
Lowe, 2010), hyperbranched polymers (Chan, Zhou, Hoyle, & Lowe, 2009)
and polymeric networks (Konkolewicz, Gray-Weale, & Perrier, 2009), it has
been essentially overlooked in the surface modification of biomaterials
(Hensarling, Doughty, Chan, & Patton, 2009) such as membranes for
bioseparation. Herein, thiol-yne click chemistry has been firstly used to
construct a glycosylated surface on MPPM for the affinity adsorption of lectin
(C. Wang, Ren, Huang, Wu, & Xu, 2011).
Layer-by-layer (LbL) assembly is a versatile technique for fabricating
tailored thin films of diverse composition (Decher, 1997; Hon, 1991). The
majority of work has focused on the assembly of polyelectrolyte (PE) films by
either electrostatic (Hon, 1991; Losche, Schmitt, Decher, Bouwman, & Kjaer,
1998) or hydrogen bonding (Stockton & Rubner, 1997; L. Y. Wang et al.,
1997) interactions. More recent work has reported polymer multilayer
assembly facilitated by covalent bonding (Kohli & Blanchard, 2000; Serizawa,
Nanameki, Yamamoto, & Akashi, 2002). Covalently bound films offer the
advantage of higher stability due to the cross-linked polymer networks and are
not susceptible to disassembly under varying solution conditions (e.g., salt,
pH), as is typically observed for a range of electrostatically coupled and H-
bonded films (Cho & Caruso, 2003; Sukhishvili & Granick, 2000). Frank
Caruso’s group report a highly efficient and generalizable method based on
click chemistry to construct LbL polymer films.
In the work of Frank Caruso report the LbL assembly of poly (acrylic
acid) multilayer films using click chemistry. They demonstrate that this
technique provides a simple and general method for the assembly of PE films
of controlled thickness and that the click moiety provides stable cross-links
within the films. Poly (acrylic acid) with either azide (PAA-Az) or alkyne
functionality (PAA-Alk) was synthesized using living radical polymerization.
LbL assembly was performed by sequentially exposing the substrates (quartz,
silicon, or gold) to PAA-Az and PAA-Alk solutions containing copper sulfate
and sodium ascorbate for 20 min, with water rinsing after deposition of each
layer (Such, Quinn, Quinn, Tjipto, & Caruso, 2006).
224 Zhu-Fang Hu, Jin Zhou and Hai-Yin Yu
ACKNOWLEDGMENTS
This material is financially supported by National Natural Science
Foundation of China under Grant No. 21371008. This support is gratefully
acknowledged.
Click Chemistry for Membrane Preparation and Surface Modification 225
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In: Click Chemistry ISBN: 978-1-53611-903-9
Editors: Y. Chen and Z. R. Tong ©2017 Nova Science Publishers, Inc.
Chapter 9
ABSTRACT
Carbon nanostructures and Polycyclic Aromatic Hydrocarbons
(PAHs) have been widely studied over the last few decades due to their
great ability to establish supramolecular associations among them. This
gives rise to a new generation of hybrid nanomaterials with very
interesting properties. Furthermore, these species can be conjugated in
order to create electron donor-acceptor systems with potential
applications in innovative devices. Additionally, the presence of a
polyaromatic compound in the structure of a biomolecule can be used as a
marker, due to its luminescent properties, or as a scaffold for other
complex macrostructures. On the other hand, Copper catalyzed
Azide−Alkyne Cycloaddition (CuAAC), known as “Click Chemistry”, is
a simple and practical route to prepare a huge variety of new materials.
This regioselective procedure, in contrast to the uncatalyzed Huisgen 1,3-
*
Corresponding author Email: celedonio.alvarez@uva.es.
236 Celedonio M. Álvarez, Héctor Barbero and Sergio Ferrero
INTRODUCTION
Click chemistry serves as a powerful synthetic approach opening a new
area towards the assembly of original molecular entities based on 1,2,3-
triazole scaffold becoming a straightforward way to create heterocyclic
systems [1].
Since its discovery in the last century, the information about this topic is
overwhelming. In fact, a considerable number of periodic revisions attending
these chemical approaches are wealth and extensive. As a result, it is very
difficult to find specific information without getting lost in it. In order to shed
light, the reader can discover some general and interest reviews on “click
chemistry” in these references [2].
The term of click chemistry was introduced by Sharpless [3] as a general
concept for organic synthesis and became very popular. This notion is
summarized in one sentence: “all searches must be restricted to molecules that
are easy to make”.
Among the various click reactions responding to the requirements of this
concept, nowadays the most popular click reaction is based on the well-known
Huisgen 1,3-dipolar cycloaddition [4], known currently as CuAAC reaction
(copper-catalyzed azide-alkyne cycloaddition) when it is catalyzed by this
metal. It consists of the transformation of an acetylene group into a five-
membered heteroaromatic 1,2,3-triazole ring and have numerous applications
in synthetic organic chemistry [5], drug discovery [6], sugar derivatization [2g,
7], biochemistry [8], polymer chemistry [9] and materials science [10].
The main limitation of the azide-alkyne cycloaddition was associated with
the formation of two triazolinic regioisomers (1,4 and 1,5) when performed at
Copper-Mediated Click Chemistry Applications to Assemble … 237
carbon atoms considered defect sites. It has a very wide range of potential
applications in photovoltaic devices [38], transparent conductive films [39],
photosensitive transistors [40], batteries [41], supercapacitors [42], cancer
therapy [43], biosensing [44] and many more.
Fullerenes
Figure 6. Two sets of fullerene sugar balls prepared by CuAAC click chemistry
in both approaches.
Excellent examples of the first branch are the work from Schuster, Guldi
and coworkers [57], in which several connections between porphyrin and
buckminsterfullerene moieties were studied. In all cases, cycloaddition of
phenyl alkyne and a phenyl azide were obtained by using copper iodide and
sodium ascorbate in a mixture of H2O and DMSO at 80ºC with MW
244 Celedonio M. Álvarez, Héctor Barbero and Sergio Ferrero
irradiation under inert atmosphere, but the attachment to C60 was performed by
Prato reaction [58] and the link between both building blocks was not as
excellent as expected. Other approach was developed by Campidelli et al. [59]
in which they attached up to two porphyrins by CuAAC Huisgen reaction in a
dendron-like fashion so that a host-guest complexation effect was observed. In
this case, the salt [Cu(NCMe)4)]PF6 was used in near stoichiometric amounts
along with 2,6-lutidine in a mixture of degassed THF and water at room
temperature to give the expected product in moderate yields, mainly due to the
low solubility of the fullerene derivative. Other interesting approach was
applied by Jiang et al. [60] in an exceptional organic framework built by
phthalocyanine subunits. The cavities were filled by fullerenes through
copper-mediated cycloaddition to give donor-acceptor heterojunctions in the
form of [C60]y-ZnPc-COFs; y = 0.3, 0.4 and 0.5. This was achieved by stirring
all species in degassed dimethyl acetamide at 50ºC with copper (I) iodide salt
for 24h. Porphyrins were not the only photoactive groups tested in a C60
scaffold. Boron dipyrromethenes (bodipys) could be linked to this molecule in
a [5:1] hexakis-adduct by click chemistry [61] thanks to the development
previously carried out [55]. The classical method of CuSO4 and sodium
ascorbate in a biphasic mixture of DCM and water by using an azide-
functionalized fullerene was applied giving great results. It is noteworthy that
protected triple bonds did not react at all under these conditions, allowing
further synthesis to get the [5:1] model, which became an artificial light-
harvesting antenna (Figure 7).
Figure 8. Set of sugar balls capable of inhibit a model of Ebola virus infection.
246 Celedonio M. Álvarez, Héctor Barbero and Sergio Ferrero
Figure 9. Model of the first CNO functionalized with click chemistry by Giordani
and coworkers.
Carbon Nanotubes
The pioneer work from Adronov et al. [69] disclosed the possibility of
performing click chemistry in a carbon nanotube by first appending a
propargyl aniline by known diazotization and coupling procedures in CNTs
[70] and a subsequent CuAAC cycloaddition to an azide-
functionalized polystyrene (Figure 11). An organosoluble [CuBr(PPh3)3] salt
was utilized as catalyst in DMF at temperatures from 20 to 90ºC with a large
excess of polymer. The purification was not too difficult as only an ultra-
filtration and prolonged washing of THF and aqueous ammonia were
necessary.
Figure 11. First set of polymer/CNT hybrid developed by Adronov and coworkers.
248 Celedonio M. Álvarez, Héctor Barbero and Sergio Ferrero
Other approach was further investigated by the same group [71] with
hidroxyl functionalized MWNTs. Two isocyanates bearing terminal triple
bonds were firstly attached. Then, PDMA-PNIPAM diblock copolymer
micelles of different molecular weights and polydispersity with azide groups
on the outer shell were clicked in water by using the couple CuSO4/sodium
ascorbate. Purification was similar to that discussed earlier by these authors.
The observed increase in grafting efficiency for the copolymer micelles as the
temperature increased allowed to conclude that preorganization of the reactive
polymer chains deeply influenced such efficiency. Parallel to this work, Gao’s
group reported the synthesis of amphiphilic polymer brushes on carbon
nanotubes [72] in a Gemini-grafting strategy clicking a macroinitiator that
underwent atom transfer radical polymerization (ATRP). An alkyne-
terminated carbon nanotube was used and cycloaddition occurred in degassed
DMF with CuBr and PMDETA at room temperature. Further investigations by
the same group and other groups were developed to attach nanoparticles
through a soft polymer interlayer [73], to get a sequential layer-by-layer
grafting [74], to combine Pd nanoparticles [75] and to link polymers based on
caprolactames [76] by applying previously optimized conditions.
Figure 12. MWNT/MSN nanohybrids attached with CuAAC Huisgen reaction by Qu’s
group. Carbon nanotube was depicted as SWNT for clarity.
Copper-Mediated Click Chemistry Applications to Assemble … 249
Figure 13. Carbon nanofiber functionalized with azides by Hamers’ group and
conditions for further cyclyzation with an alkyne ferrocene.
Graphene
degassed DMF, along with an excess of polymer, and the mixture was stirred
at room temperature for 48h. Similar conditions were further applied in other
studies by using the same propargyl esther or a propargyl amide [96].
The opposite approach was later performed by Peng, Huang and
collaborators by obtaining an azide-terminated amide, ready to be clicked with
a group bearing a terminal alkyne [97]. In this case, modified DNA was used
and the new composite was tested to establish interactions with gold
nanoparticles. The conditions were simple: CuSO4, an excess of sodium
ascorbate in water and stirring at room temperature for 1 day. Interestingly,
purification was easy, as only a sonication followed by PBS washing
procedures were carried out. Namazi’s group studied the possibility of
anchoring saccharides to get hydrophilic graphene nanosheets [98] for future
applications in biological recognition by developing two approaches. On the
one hand, GO was directly functionalized with azide groups on the surface,
and, on the other hand, carboxyl groups were transformed into an esther
bearing terminal azides. CuAAC click reaction was carried out in H2O/DMF
with the well-known CuSO4/sodium ascorbate system. Simultaneously,
Somwangthanaroj and coworkers applied similar conditions to those disclosed
in this paragraph to achieve a link between GO and a PEDOT:PSS ensemble
along the edge of the sheets [99]. The most interesting recent work from Al-
Jamal et al. addressed the possibility of double and orthogonal
functionalization of graphene oxide by anchoring azides and terminal triple
bonds protected by TMS in a sequential multi-step procedure [100]. Then,
click reaction occured with an alkyne-terminated building block and, after
TMS removal, a second click was performed with a different azide-terminated
moiety (Figure 17).
Regarding surface functionalization of graphene, one initial contribution
belongs to van der Wiel and coworkers [101]. In such publication, epoxide
groups on GO were attacked by sodium azide to give a graphene comprised of
OH and N3 groups. These nanosheets suffered reduction to get the amine
derivative, restoring sp2 network partially and becoming a conductor material
again. It was utilized to perform other transformations, but the previous azide-
functionalized graphene was linked to long-chain alkyne-terminated
hydrocarbons with already commented procedures. Other groups approached
in the same way [102]. Later on, the group of Strano et al. [103] added the
same alkynyl-terminated anchoring group discussed earlier [69] on the surface
of a CVD-synthesized graphene for ulterior attachment to a PEG building
block with terminal azides. Click conditions were simple: CuSO4 in
combination with sodium ascorbate were used in water with the help of
Copper-Mediated Click Chemistry Applications to Assemble … 253
THPTA as coligand and the suspension was vigorously stirred for 18h. This
methodology was later covered again [104]. In parallel with these studies, Tu
and collaborators proposed another approach by using OH groups on the
surface of GO [105]. An esther was formed by nucleophilic attack to an aryl
bromide and further functionalization to an azide derivative was carried out
and, finally, clicked to a polystyrene derivative. This approach
(functionalization of surface OH groups) was revisited later [106], and the
work published by Binder and coworkers is particularly noticeable [106b]. In
that contribution, copper (I) nanoparticles were immobilized on GO surface by
click chemistry to use the resulting nanocomposite as a renewable catalyst for
CuAAC cycloadditions (Figure 18).
Figure 16. Sketch of a pristine graphene sheet (left) and graphene oxide (right).
Figure 17. Sequential functionalization of GO using two CuAAC click reactions by Al-
Jamal’s group.
254 Celedonio M. Álvarez, Héctor Barbero and Sergio Ferrero
Pyrene
The first click reaction involving pyrene was reported by Anslyn et al.
[117]. They studied the possibility of monitoring the reaction with the system
CuSO4/ascorbate in the presence of EDTA (inhibitor by chelating copper ion)
along with different additions of other exogenous metals (effectors due to a
better coordination with EDTA releasing copper species). An observed Förster
resonance energy transfer (FRET) phenomenon occured when pyrene was
connected by triazole linkage, meaning that the reaction worked.
From that point, the chemistry of pyrene by CuAAC cycloaddition has
been widely explored and the most relevant works will be covered here.
Kim, Matthews, Vicens and collaborators developed the first calix [4]
arene with triazole-linked pyrenes for detection of Cd2+ and Zn2+ (Figure 20)
[118]. The structure of this receptor was substantially modified upon cation
coordination, affecting its emission spectra. An azidomethyl pyrene was
coupled to an alkynyl-terminated calixarene in DMF at 90ºC for 2h by using
CuI catalyst, furnishing moderate yields only. Parallel to this paper, Yang and
coworkers reported similar structures [119] and, aftwerwads, the same group
published more homologues [120].
Figure 20. First calix [4] arenes with triazole-linked pyrenes for cation detection.
Copper-Mediated Click Chemistry Applications to Assemble … 257
Other kind of tether was explored by Zhu, Cheng and collaborators [127].
In such work, a BINOL-pyrene derivative was synthesized by copper-
catalyzed azide-alkyne cycloaddition between an azidomethyl pyrene and a
dipropargyl (S)-BINOL as a sensor for Ag+ and Hg2+. Regarding click
conditions, copper (I) iodide salt was used too, along with an excess of DIPEA
for metal stabilization. All reagents were mixed in THF under N2 atmosphere
at room temperature for 12h obtaining, again, moderate yields.
Later on, Seela and coworker prepared a tripodal pyrene derivative based
upon a propargyl amine for detection of a wide variety of cations, especially
for Zn2+ [128]. This time, [Cu(NCMe)]PF6/2,6-lutidine system was employed
in acetonitrile leaving the reaction for 3 days at room temperature, having
slightly better conversions.
The best results, in terms of isolated products yields, were obtained by
Zhao and coworkers and, then, by Tárraga and Molina et al. in a TTFV
tweezer derivative and a three-armed triazole-linked compound, respectively
[129]. In the first case, CuI was also used, but in the presence of iPr2EtN, in
THF at 60ºC overnight. In the second case, [Cu(NCMe)4]PF6 was utilized
along with TBTA, sodium ascorbate and DIPEA in THF at room temperature,
getting the best yields. It is noteworthy that pyrene derivative involved in the
last examined publication is an alkynyl-terminated compound, instead of the
azidomethyl pyrene discussed in the other examples.
According to the general trends regarding functionalization of
polyaromatic structures, polymer appendage with pyrene moieties has been
explored by several chemists. Thus, Yagci and collaborators firstly reported
several polymers with pending azido groups which were linked to propargyl
pyrene [130] by using an aqueous solution of copper sulfate and sodium
ascorbate in DMSO, achieving near-quantitative conversion. Later, a
polysulfonate was functionalized with the same pyrene derivative by the that
group [131]. The most interesting contribution has been recently developed by
Qiao and coworkers [132]. An alkynyl-terminated pyrene butyrate suffered
cycloaddition with a PEG-N3 polymer by using CuBr2 and a photocatalyst
designed by them for the conversion of copper (II) into copper (I) with a light
input (Figure 22).
A different approach, hardly addressed for other polyaromatic structures,
was firstly covered by Tárraga, Molina et al. in a ferrocene-pyrene derivative
[133]. This molecule had dual-mode recognition due to electrochemical
properties from ferrocene moiety and photophysical issues from pyrene
subunit. The compound was able to bind pyrophosphate anion; it was prepared
with azidoferrocene and 1-ethynylpyrene in THF along with the couple
Copper-Mediated Click Chemistry Applications to Assemble … 259
Perylene
This molecule has been utilized in three main groups. The simplest one is
pristine perylene, in which funcionalization might be performed at peri or bay
positions. However, the most widely used are those whose peri positions are
already occupied by one imide (PMI) or by two imides (PDI). In such cases,
functionalization can be performed in imide pending group, too. All stated
possibilities are gathered in Figure 24.
The first click reaction was reported by Koshun et al.[143] for
bioconjugation between oligonucleotides and PDI. In that work, perylene
moiety had azido groups at the end of the chain supported by nitrogen atoms
and oligonucleotides had a modified phosphate bearing a terminal alkyne.
CuSO4 and sodium ascorbate, along with TBTA as stabilizing reagent, were
used in DMSO at 95ºC overnight. A separable mixture of monoadduct and
diadduct was obtained in moderate yields. PDI derivative was not quite
soluble, as high temperatures had to be used. The same group explored other
approaches with subtle modifications and yields were slightly enhanced [144].
Simultaneously, Langhals and coworker explored more deeply the chemistry
of PDI in terms of copper-mediated cycloadditions by synthesizing a set of
monoazide(or monoalkynyl)-terminated PDI derivatives, with several spacer
groups, for further click reactions [145]. In such study, all reactions were
performed with copper (I) iodide, N-ethylbis(isopropyl)amine (for stabilizing
purposes) in THF at room temperature getting a range of yields from moderate
to good. Next, Nielsen and coworkers used one alkynyl-terminated PMI
already developed by Langhal’s group to conjugate with a TTF derivative for
optical and electrochemical studies [146]. The system CuSO4/ascorbate in
DMF was used and moderate conversion was obtained. One of the greatest
advances in the study of this reaction involving perylenes came from
Finlayson and Kouwer’s groups in a publication where eight click reactions
were simultaneously carried out between an unsymmetrical PDI and a
phthalocynanine bearing eight alkynyl groups (Figure 25) [147]. Copper (I)
262 Celedonio M. Álvarez, Héctor Barbero and Sergio Ferrero
Figure 26. Amphiphilic tri and hexa adducts of PDI prepared by click chemistry.
264 Celedonio M. Álvarez, Héctor Barbero and Sergio Ferrero
Corannulene
CONCLUSION
In the last few years since CuAAC reaction was born, it has dramatically
influenced many research fields in science as inferred from the emerging
number of contributions; but development of this reaction is yet far to be
completed. Regarding the main topic of this chapter, many approaches have
been addressed in the search for an efficient way to link a diverse variety of
building blocks containing polyaromatic species. All procedures were aimed to
overcome some difficulties found in this kind of compounds, such as low
solubilities or high reactivity of the π electronic density, for instance.
The most popular protocol covered here is the use of copper sulfate along
with a reductor, but this system has had a huge number of variations in order
to obtain reasonable yields, being oftenly the selection of a solvents mixture or
the addition of a nitrogen-donor ligand for stabilizing copper catalyst.
A different proposal has consisted on the way polyaromatic structures are
functionalized. The place where the terminal azide (or alkyne) is anchored
prior to the click reaction is crucial in terms of stability, solubility or ease of
Copper-Mediated Click Chemistry Applications to Assemble … 267
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In: Click Chemistry ISBN: 978-1-53611-903-9
Editors: Y. Chen and Z. R. Tong ©2017 Nova Science Publishers, Inc.
Chapter 10
ABSTRACT
During the last ten years, click chemistry has become a powerful tool
for materials modification and application for their number of advantages
such as readily available starting material, mild reaction conditions, high
reliability, high reaction rate, high yield, good stereoselectivity, high
oxygen and moisture stability, simple workup and easy purification. A
large number of recent original publications and specialized reviews have
focused on applications of the click reaction technique in the biomedical
fields. In the current chapter, the progress on preparation via click
reaction and application of the multifunctional and intelligent materials
for chemical sensor in biomedical field, pharmaceutical science and gene
transfer carriers is summarized. The limitations and prospective
applications of the click chemistry technique in these fields are also
discussed.
*
Corresponding author Email: cylsy@163.com.
282 Yu Chen, Ying Zhang, Xiaoyu Sun et al.
INTRODUCTION
In 2001, Sharpless and co-workers coined the concept of “click chemistry”
[1] to classify a particular set of nearly perfect reactions. It is undeniably one
of the most important trends in contemporary chemistry [2]. Click chemistry
has attracted great attentions, because the click chemistry reaction can be
carried out under mild and simple reaction conditions [3, 4], it can be
proceeded well in aqueous medium and therefore may be efficiently performed
under physiological conditions [5-7], resulting in high reaction efficiency with
easy post-treatment for the obtained products [9-11]. Moreover, it holds great
chemoselectivity and can therefore be used for modifying highly functional
biomolecules such as poly-peptides, nucleic acids or polysaccharides [12, 13].
Since a large number of recent original publications and specialized
reviews have been published during the past years on applications of the click
reaction technique in the biomedical fields [14-16]. In the current chapter, the
progress on preparation via click reaction and application of the
multifunctional and intelligent materials for chemical sensor in biomedical
field, pharmaceutical science and gene transfer carriers is summarized. The
limitations and prospective applications of the click chemistry technique in
these fields are also discussed.
For most of the organic compound, because of their groups are more
easily functional, some of them even own groups that can click on the
reaction. So for the detection of this kind of material, we can use the reaction
of the click directly to the object under test, and effectively improve the
selectivity of sensors. The click reaction can also be used to achieve the
enhancement purpose to the amplified sensor signal. Therefore, this method
can significantly improve the sensitivity of the sensor [19, 20].
284 Yu Chen, Ying Zhang, Xiaoyu Sun et al.
Figure 1. A click fluorophore sensor that can distinguish Cu2+ and Hg2+ via selective
anion - induced demetallation.
Different from general organic matter detection, some biology have large
biological molecules. And some are even aggregated level. So the participate
of them in the click on the response of sensor is less reported. The report are
mostly about fixing enzymes or other active substances on the sensor by
clicking on the reaction to get detection signal which is being catalytic reaction
between enzyme and the object under test, so as to realize the detection of
object treatment test [29, 30].
Trilling [31] used click reaction to study the influence of biological
receptor of directional on the sensitivity of biosensor. For example, they
recognize FMDV viruses by VHH protein biosensor. Putting VHH protein
azide into functionalization firstly and click on the reaction with the exposed
plasma resonance chip ring sheen acetylene, by comparing VHH modified
biosensor which was many times azide functional marked or the single azide
functional marked. They found the former’s sensitivity raised 800 times than
the latter’s.
Li et al. [32] used a click reaction based on fixed glucose oxidase
biosensors for the determination of glucose. They first used azidebifunctional
molecules to get end azide carbon nanotubes (CNTs-N-3). By the way, alkynyl
modified glucose oxidase was synthesized at the same time. And then they
proceeded the click reaction under catalytic of Cu+, mixing with the help of
perfluorinated sulfonic acid soak to the surface of glassy carbon electrode, to
prepare the sensor. At the same time they studied its electrochemical
performance by cyclic voltammetry and chronoamperometry. Results showed
that the linear range of glucose was 6. 0 × 10-7 ~ 1. 4 × 10-3 mol/L, the
detection limit was 2. 0 × 10-7 mol/L.
According to the results in the relevant report, chemical sensors based on
the click chemistry have great stability and reproducibility [33, 34]. As a rapid,
simple, highly selective synthesis method, whether for quick connection fixed
sensitive content, tag material, synthesis of sensitive element, or directly or
indirectly detect click reactants, click chemistry can combine its advantages
with chemical sensor and application, greatly improve the response
performance of the sensor.
Applications of the products prepared from click chemistry in chemical
sensors is still in its initial stage, therefore, there are still some problems for
application of it in chemical sensors. Click chemistry requires specific groups,
it is preferred to the reactant functionalization. Some of the reactants to target
functionalization condition is too harsh, which limits the application range of
the click chemistry. Besides, currently the type of click reaction is less. The
reported type including azide and end group, the 1,3-azo addition reaction of
Application of Click Chemistry in Biomedical Fields 287
The completion of the work of the human genome project will enable
people to better understand the relationship between genes and diseases, so as
a new treatment gene therapy method has very broad application prospects.
However, the field of genetics has identified a number of genes having the
potential to treat and prevent disease, but the progress of gene therapy is very
slow. The main reason is the current lack of the appropriate gene carrier that
can deliver effectively gene drug safety to the location of the lesion and realize
nuclear expression, and gene delivery to the target cell and expression of the
corresponding protein has multiple barrier function. Therefore, the researchers
need to compress plasmid DNA into nano particles and overcome various
barriers of the carrier system, which cannot be directly used in the DNA.
Gene therapy holds a great promise for the treatment of diseases with a
genetic origin that are currently incurable. The success of gene therapy largely
depends on the availability of suitable delivery vehicles. Gene vectors include
viral vectors and non-viral vectors. Viral vectors have high gene delivery
efficiency. But the virus vector is not suitable for mass production; at the same
time, the DNA size that they can carry is limited; and the viral vectors may
cause the body’s immune response and other safety problems. So the
development of the virus vector has been restricted. More and more studies
have focused on the non-viral vectors, which including the cationic polymer
carrier, such as polyethylene imine (PEI), chitosan, poly lysine (PLL), and
methacrylic acid ethyl ester two methylamine (PDMAEMA) and its
derivatives [36]. PEI has become the most effective cationic polymer carrier
due to its strong DNA load capacity and high transfection efficiency, and it
can be a measure of cationic polymer vector of common reference [37, 38].
But the cytotoxicity of PEI is also an unavoidable problem [38]. Researchers
hope to design a new carrier that possesses high transfection efficiency and
low cytotoxicity. As the high selectivity and reaction efficiency of click
288 Yu Chen, Ying Zhang, Xiaoyu Sun et al.
study [45], the same group investigated the influence of the molecular weight
of the trehalose click polymer on polyplex stability and pDNA cellular
delivery efficiency, It was shown that a higher degree of polymerization
resulted in a higher polyplex stability, although no effect was observed in
pDNA binding affinity, cellular uptake, and DNase protection in relation to the
Mw.
Ideally, suitable polymeric transfectants should be nontoxic,
nonimmunogenic, and preferably biodegradable in a controlled manner.
Furthermore, biodegradable polymers should yield degradation products with
a molecular weight lower than 30 kDa, because these degradation products can
be excreted by the kidneys [46, 47]. To reduce the cytotoxicity of cationic
polymers, Hennink and co-workers [48] grafted a low-molecular-weight
cationic poly(2-dimetylamino) ethyl methacrylate (pDMAEMA) onto the
polymer backbone of uncharged hydrophilic polymer, poly(hydroxyethyl
methacrylate) (pHEMA), via biodegradable linkages. Both pDMAEMA and
pHEMA were synthesized by atom transfer radical polymerization (ATRP)
(Figure 3). For this goal, pDMAEMA was end-functionalized with an azide
[49], while pHEMA was randomly functionalized with acetylene moieties
[50]. The polymers were “clicked” together via the CuAAC in DMF at 50℃
with CuBr as catalyst. The molecular weight of the polymer as well as the
number of grafts could easily be varied. Upon incubation at physiological
conditions (pH 7.4, 37C), the carbonate ester bonds were readily hydrolyzed
(t1/2: 96 h). The molecular weight of the final main degradation product was
very close to that of the starting pDMAEMA, indicating that the carbonate
esters were quantitatively hydrolyzed. Furthermore, the synthesized polymers
were able to condense DNA into small particles, which were able to transfect
cells efficiently in the presence of endosome-disruptive INF/7 peptide. Finally,
the polymers had a lower toxicity compared to high molecular weight
pDMAEMA, making this an effective approach to reduce the toxicity of high-
molecular-weight cationic polymers [48].
Dervan et al. showed that macromolecules that containing various
heterocyclic residues, such as derivatives of pyrrole and imidazole, are able to
bind nucleic acids [51]. Reineke and his colleagues were inspired by them.
They used copper catalyzed azide-alkyne cycloaddition click reaction to
synthesis a series oligomeric amine modified polymers based on sugars
(trehalose/cyclodextrin) gene carriers [52-54]. Firstly, through the hydroxyl
group of sugar unit, they connected two groups of nitrogen with every
molecule, and then the molecule was polymerised with different double
acetylene based oligomers, getting the cationic polymers with different degree
290 Yu Chen, Ying Zhang, Xiaoyu Sun et al.
Note: M: main-chain (backbone) unit, DL: degradable linkage, CP: side-chain cationic
polymer.
Figure 6. Workflow of the process of hit-to-lead optimization from click chemistry and
drug candidate selection. FBDD, SAR, and QSAR studies are essential elements of this
complex paradigm. FBDD, fragment-based drug design; QSAR, quantitative SAR;
SAR, structure–activity relationship.
Rideout’s ideas and recent developments in TGS together, one could shift this
paradigm of fragment-based approaches a step foreword toward the use of
molecular fragments for direct clinical use. The approach would allow for the
in vivo - in situ synthesis of the final ligand already in close proximity to its
biological target (protein or DNA) in the host. In the context of cancer,
formation of the final drug only at close proximity of its biological targeted
can lead to amplification of selectivity between neoplastic and normal cells.
Thus, it is foreseeable that in the future, purposely prepared pharmaceutical
compositions of closely related but different fragmented prodrugs could be
designed with the help of the click chemistry precursor to synergistically
interact with specific molecular targets that have different isoforms (i.e.,
proteins) or polymorphism (i.e., genes) within patients, paving the way for
personalized prodrugs.
homologous PTPs with IC50 = 5.9 ± 0.4 μM for R1 = H against PTP1B and
IC50 = 7.1 ± 1.0 μM for R1 = Me against PTP1B.
Tang and co-workers [75] recently reported a library of benzyl 6-
triazolo(hydroxy)benzoic glucosides via the Cu(I)-catalyzed azide–alkyne 1,3-
dipolar cycloaddition. These glycoconjugates bearing alkyl chain, sugar, and
(hydroxy)-benzoic derivatives (compound 3, Figure 3) (IC50 = 8.7 ± 1.4 μM
for n = 2 and IC50 = 6.7 ± 0.5 μM for n = 3) were identified as new PTP1B
inhibitors with selectivity over T-Cell PTP (TCPTP), SH2-containing PTP-1
(SHP-1), SHP-2, and leukocyte antigen-related tyrosine phosphatase (LAR).
Zhou and co-workers [76] recently reported a potent and selective mPTPB
inhibitor (compound 4, Figure 8) with highly efficacious cellular activity, from
a combinatorial library of bidentatebenzofuran salicylic acid derivatives
assembled by click chemistry. The inhibition of mPTPB with compound (4) in
macrophages reversed the altered host immune responses induced by the
bacterial phosphatase and prevents TB growth in host cells with IC50 = 19 ±
1.5 μM against PTP1B, 1.6 ± 0.22 μM against mPTPB, and 77.3 ± 1.5 μM
against mPTPA.
product radicicol is described in which the key steps are the acylation and
ring-opening of a homophthalic anhydride to give an isocoumarin, followed by
a ring-closing metathesis to form the macrocycle. The novel triazole-
macrocyclic lactones were evaluated for Hsp90 inhibition in two Hsp90
binding assays: the fluorescence polarization (FP) assay and the TR-Fret
assay. Their growth inhibitory potency in HCT116 human colon cancer cell
line, as measured by the SRB assay, was also determined. Compound 14
(Figure 10) showed good inhibition of Hsp90 in the FP assay in the series with
IC50 = 2.7 ± 1.3 μM [85].
1, 2, 3-triazole-based molecules are useful pharmacophores for several
DNA-alkylating and cross-linking agents. A series of A/C8, C/C2, and A/C8-
C/C2-linked 1,2,3-triazole-pyrrolo[2,1-c] [1,4] benzodiazepines (PBD)
conjugates was synthesized by employing “click” chemistry. These molecules
exhibited promising DNA-binding affinity and were evaluated for their in vitro
anticancer activity in selected human cancer cell lines of breast (Zr-75-1,
MCF7), oral (KB, DWD, Gurav), ovary (A2780), colon (Colo205), lung
(A549), prostate (PC3), and cervix (SiHa) by using the sulforhodamine B
(SRB) method. Especially, compound 15 (Figure 5) showed good inhibition
(GI50 = 0.15 μM against DWD, GI50 = 0.16 μM against A2780, GI50 = 0.17
μM against PC3, and GI50 = 0.12 μM against SiHa) against various cancer
cells such as oral, ovary, colon, lung, prostate, and cervix [86].
Figure 10. Chemical structures of anticancer drugs constructed via click chemistry.
304 Yu Chen, Ying Zhang, Xiaoyu Sun et al.
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In: Click Chemistry ISBN: 978-1-53611-903-9
Editors: Y. Chen and Z. R. Tong ©2017 Nova Science Publishers, Inc.
Chapter 11
ABSTRACT
The common limitations of optical sensing are caused by the
complicated functional process, the deficiency of reporter with a robust
signal, and the poor specificity. Therefore, it is still full of challenges to
develop the rapid and simple optical sensing systems with high sensitivity
and selectivity. Click chemistry, the simple and robust connecting
approach with versatile superiorities containing easy to perform,
insensitive to oxygen and water, high specificity and high rate, becomes a
good candidate to relieve these problems of optical sensing. In this
review, we focus on several classic click reactions that used to design
*
Corresponding author: E-mail: zylin@fzu.edu.cn; Fax/Tel: 86-591-22866135.
314 Suyan Qiu, Fang Luo, Linguang Luo, Longhua Guo et al.
1. INTRODUCTION
Optical sensing has drawn great attention in biomedical [1, 2] diagnostic,
and environmental sciences [3-5] as well as industrial applications [6], because
it has significant advantages compared with conventional sensor: (i) great
sensitivity and wide dynamic range; (ii) electrical passiveness and freedom
from electromagnetic interference; (iii) easy operation and low cost; (iv) can
be carried out on site. Generally, optical sensor consists of two functional
components: an identification element to provide the selective binding with
target analytes and an optical transducer component to output the detectable
signal [7]. Several different types of optical sensings have been frequently
reported depending on the different output signals of transducer, such as
fluorescence sensors, colorimetric sensors, electrochemiluminescence sensors,
photo-luminescence sensors and surface-enhanced Raman scattering sensors.
Among these sensors, fluorescence sensors are one of the most widely
applications in diverse fields with their unique prerequisites except for the
common features of optical sensing platform [8, 9], such as low damage to
targets and easy to handle. Most of fluorescence sensors are designed
depending on the special fluorescent materials or the chemical reaction to
change the property of the fluorescence emission, such as dyes, quantum dots
(QDs) [10, 11] and nano-materials [12, 13] including nanoparticles,
nanowires, carbon nanotubes and graphene. Colorimetric sensors have drawn
high attention in biological analysis by taking into account advantages of low
cost, quick feedback, no need of any advanced instrument, and only relying on
the human eyes conveniently [14, 15]. Currently, nanoparticle-based
colorimetric sensor has attracted much concern in biological molecules
detection and metal ions recognition [16, 17].
The common difficulties of optical sensings are interferences from
multiple effects, such as complicated functional process, deficiency of reporter
with a robust signal, and poor specificity. Therefore, it is still full of challenges
to develop the rapid and simple optical sensing systems with high sensitivity
Click Chemistry: Optical Sensing in Biological Analysis 315
and selectivity. A great deal of work has been studied to improve these
characteristics, such as promoting the binding ability between targets and other
ligands, accelerating the reaction rate, increasing the yield and amplifying the
response signal by nanotechnology.
Click chemistry is termed by Sharpless as the reaction that generates
substances with high selectivity and high efficiency by joining small units
together with heteroatom links (C-X-C) [18]. It is a promising candidate for
the service in the above mentioned missions with various superiorities, such as
high yield, excellent purity and high regioselectivity, good biocompatibility,
mild conditions and high tolerance with versatile solvents [19]. Several
click chemistry reactions have been reported to date, such as copper(I)
catalyzed azide-alkyne cycloaddition (CuAAC), strain-promoted azide-alkyne
cycloaddition (SPAAC), thiol-ene reaction, oxime ligation and Diels-
Alder reaction (See Fig.1). Table 1 displays the unique advantages and
disadvantages of click chemistry among the reaction rate, yield, stability and
biocompatibility. These “click” reactions have the potential to breakthrough in
the field of labeling and functionalization with high efficiency and specificity,
whereupon becoming an ideal choice to serve as the sensing platform [20, 22].
Figure 2. (A) Sensitized Eu(III) chelate 1 generated through the CuAAC reaction in the
presence of a copper(I) glutathione complex with micromolar concentrations.
Reprinted with permission from J. Am. Chem. Soc. (ref 42). Copyright 2006 American
Chemical Society. (B) The copper(II) ions detection based on CuAAC reaction
between the alkyne (1) and the azide (2) terminated gold nanoparticles. Reprinted with
permission from Angew. Chem. Int. Ed. (ref 43). Copyright 2008 Wiley-VCH Verlag
& Co. KGaA, Weinheim, Germany.
Most of the above stated sensors are limited in the detection of copper(II)
ions and ascorbic acid, other targets are rarely involved based on the catalytic
effect. In this context, Jiang and coworkers proposed a colorimetric
Click Chemistry: Optical Sensing in Biological Analysis 319
Figure 4. A: (a) Fabrication of fluorescent pH probes 1-3; (b) Absorbance and emission
spectra of probe 3 with different pH values at 480 nm excitation wavelength. Reprinted
with permission from Bioorg. Med. Chem. Lett. (ref 59). Copyright 2012 Elsevier
B.V.. B: (a) Schematic illustration of the fluorescence turn-on sensing for fluoride
detection; (b) Fluorescence spectra and intensity with the addition of various other
anions (λex = 385 nm). Reprinted with permission from ACS Appl. Mater. Interfaces
(ref 62). Copyright 2013 American Chemical Society.
Owing to the copper toxicity to proteins and cells, the CuAAC reaction is
considered to be not appropriate for vivo detection. However, Pezacki group
found the Cu(II)-L-histidine complex (Cu(his)2) showed no significant toxicity
Click Chemistry: Optical Sensing in Biological Analysis 323
Figure 6. A: (a) Structure of PA with a cyclooctyne group. (b) Scheme of the process
of fabricating PA-decorated surfaces using the SPAAC reaction. (c) Light microscopy
image of water condensation experiment on PA-decorated glass surface (1 μM, 60
min). Reprinted with permission from J. Am. Chem. Soc. (ref 75). Copyright 2013
American Chemical Society. B: Schematic illustration of the principle for DNA (RNA)
detection based on the SPAAC reaction. Reprinted with permission from ACS Nano.
(ref 76). Copyright 2014 American Chemical Society.
could be trapped after the magnetic separation when the azido group
functionalized bacterial bound with cyclooctyne functionalized magnetic
beads. So the high specific enrichment is attributed to the high efficiency and
high selectivity of the SPAAC reaction.
Figure 7. A: Scheme of the simple fabrication for core−shell glycol AuNPs promoted
by the SPACC reaction. Reprinted with permission from ACS Appl. Mater. Interfaces
(ref 77). Copyright 2015 American Chemical Society. B: (a) Schematic depiction for
the reaction of azide terminated EpCAM with DIBO-AF594 to produce a fluorescently
labeled aptamer through the SPACC reaction (Right); (b) Dark field-fluorescent
microscopic imaging of cancer cells with EpDNA-DIBO-AF594. Left panel of each
cell line corresponds to: dark field + DAPI and on the right panel: DAPI + AF594
merged. Scale bar indicates 50 µm. Reprinted with permission from Chem. Commun.
(ref 80). Copyright 2014 Royal Society of Chemistry.
The SPAAC reaction was used to image cells as well due to its excellent
biocompatibility. In the Krishnakumar group, the SPAAC reaction was
Click Chemistry: Optical Sensing in Biological Analysis 327
thiol-labeled ODN with fluorescein reporter was added to the above solution,
which reacted with the alkene moieties to yield ODN-SiNPs conjugates via the
thiol-ene reaction. A further application of these ODN-SiNPs conjugates was
explored to detect cancer-associated miR-21 through introducing a quencher
strand (Figure 8B), suggesting that the labeling ODN-SiNPs based on the
thiol-ene reaction is carried out readily and remains highly stable in the
biological environment.
detect biological thiols including glutathione (GSH) and its dimeric form
(GSSH) based on the aggregation-induced emission (AIE) [101, 102]. The
fluorescence of these dyes can be switched on/off when the analytes alter the
aggregation behavior or change the intramolecular motions of the fluorescent
species. In the study, the GSH and GSSH can react with TPE derivatives to
form poorly soluble aggregates through the thiol-ene reaction, which turns on
the fluorescence. Thus the approach can serve as a label-free sensor for
enzymatic activity assay of glutathione reductase. Also, it is further explored
to detect the intracellular GSH in living cells, suggesting the thiol-ene reaction
shows a high specificity for vivo sensing.
2) (Figure 9A). The Förster distances (R0s) for the EGFP/rhodamine pair and
rhodamine/Dy630 pair were estimated to be 5.8 nm and 6.8 nm, respectively,
which suggesting that the distance among three-color probes were sufficient to
confer efficient FRET. Furthermore, a novel chemical conjugation through
biorthogonal oxime ligation was developed to target cancer cells in vivo by
Cheng and coworkers [109]. As shown in Figure 9Ba, an oxyamine (Oa) group
was decorated on 4T1 murine breast cancer cells through liposome delivery
and fusion firstly, and then reacted with a fluorescent rhodamine with
aldehyde groups functionalized poly(ethylene glycol)-polylactide (PEG-PLA)
nanoparticles (Ald-NPs) to form the fluorescent Ald-NPs immobilized cells,
which can be embedded into cells depending on the liposome fusion process,
inducing a intracellular fluorescence. In the study, Native 4T1 cells and o4T1
cells were treated with Cy5 labeled NPs or Ald-NPs. It was noticed from
Figure 9Bb that only a slightly higher level of NP binding or uptake were
found in native 4T1 cells treated with Ald-NPs and o4T1 cells treated with
NPs or without Ald on the surface (Figure 9Bb). The cellular binding and
internalization were significantly enhanced when the o4T1 cells were treated
with Ald-NPs, because of the specific and efficient oxime ligation between the
Oa group of cell surface and Ald group on Ald-NPs. This outcome suggests
that the cancer targeting can be greatly improved by the Oa-Ald oxime
ligation, which is important to intracellular delivery of anticancer drugs and
the efficacy against cancer cells.
Figure 9. A: (a) Schematic illustration for the preparation of the triple FRET probe. (b)
Structural model for the calculated and experimentally determined distances of triple-
labeled protein probes. Structures of Rab1b (PDB: 3NKV) and EGFP (PDB: 2Y0G)
were used. Reprinted with permission from J. Pept. Sci. (ref 108). Copyright 2014
European Peptide Society and John Wiley & Sons, Ltd. B: (a) Scheme for cancer
targeting of aldehyde groups modified PEG-PLA nanoparticles surface depending on
the bioorthogonal oxime ligation. Cancer cells were coupled with Oxyamine (Oa)
groups by membrane fusion of liposomes bearing Oa groups (Oa-Lip). (b) Confocal
microscopic images of native 4T1 cells (4T1) and 4T1 cells with surface expressed Oa
groups (o4T1) by treating with Cy5 labeled PEG-PLA NPs (red) in the absence or
presence of Ald groups (denoted as NP and Ald-NP respectively). The nuclei were
stained with 4,6-diamidino-2-phenylindole (DAPI) (blue). Scale bar: 5 mm. Reprinted
with permission from Chem. Sci. (ref 109). Copyright 2015 Royal Society of
Chemistry.
material and simple synthetic paths for diverse molecules are provided by
click chemistry, which can be utilized to carry out the transduction of the
binding event toward analytes with adaptable affinity and specificity.
Particularly, the product can be generated quantitatively with high efficiency
and high selectivity through the clickable reaction, which offers a powerful
tool to identify targets. The sensing sensitivity can be further improved by
taking advantage of unique materials, such as nanoparticles, films and
microarrays, which enables the sensing platform to expand over a broad range
of targets in the biological analysis, even high throughput detection.
Although some restrictions of clickable reactions are discovered by taking
into account the sensing conditions. For instance, owing to the toxicity of
copper(I), the implementations of the CuAAC reaction in several living beings
readily are subject to the copper toxicity. However, the SPAAC reaction
overcomes the interference of metal toxicity, and the reaction rate and
conversion can be greatly improved by the chemical structure of cyclooctyne,
leading to a wild application in many living systems. Therefore, as described
in this review, numerous click chemistry-based optical sensing platforms have
been fashioned to illustrate the importance of biological analysis. Given the
particular advantages, click chemistry will continue to emerge as the high
efficient and robust synthetic method for the design of the optical sensors, and
continue to breakthrough for monitoring biological process in living systems.
ACKNOWLEDGMENTS
This work was financially supported NSFC for Excellent Youth Scholars
of China (21222506), NSFC (21175024, 21275031 and 21605063), Nature
Sciences Funding of Fujian Province (2014J06005), program for New Century
Excellent Talents in University (NCET-12-0619), and the innovation fund of
Jiangxi Academy of Agricultural Sciences (No. 2013CBS001).
Conflict of Interest: The authors declare that they have no conflict of interest.
334 Suyan Qiu, Fang Luo, Linguang Luo, Longhua Guo et al.
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[112] Späte, A. K.; Schart, V. F.; Häfner, J.; Niederwieser, A.; Mayer, T. U.;
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reactions. Beilstein. J. Org. Chem., 10, 2235-2242.
In: Click Chemistry ISBN: 978-1-53611-903-9
Editors: Y. Chen and Z. R. Tong ©2017 Nova Science Publishers, Inc.
Chapter 12
ABSTRACT
Solid propellants are widely used for launch vehicle and missile
applications. The polymeric fuel binder is a critical ingredient of a
composite solid propellant. It acts as the matrix for holding together the
oxidiser, metallic fuel and other additives and also imparts structural
integrity, mechanical properties to the propellant and contribute to the
combustion phenomena. In recent years, the impetus has been to improve
the energetics by the use of binders with energetic functional groups. The
introduction of ‘triazole’ groups in the polymer network via ‘Click
chemistry’ is one such approach. This imparts superior processability,
mechanical properties and ballistics to the propellant. Amongst the
different types of polymeric binders used in composite solid propellants,
*
Corresponding Author Email: reshmiskurup@gmail.com.
348 S. Reshmi, E. Arunan and C. P. Reghunadhan Nair
INTRODUCTION
Hydroxyl terminated polybutadiene (HTPB) is the most popular binder
used in solid propellants both for boosters, pyrogenigniters, gas generators and
upper stage motors [1-5].The mode of crosslinking in HTPB based systems is
through the reaction of hydroxyl groups with polyisocyanates, resulting in
polyurethanes [5]. The major limitation of this cure methodology is the low
pot life and intervention of extraneous side reactions causing microvoids in the
cured propellant matrix [6].Hence it is always desirable to have end groups
that can give crosslinked matrices wherein side reactions can be avoided [6-9].
It is also desirable if the addition product adds to the energy and ballistics of
the propellant. Several reports exist on the modification of HTPB [10-18] such
as grafting of energetic groups such as poly(glycidylazide) [14],anchoring of
iron pentacarbonyl [15], grafting of 2-(ferrocenylpropyl) dimethylsilane
(FPDS) etc. Most of these are aimed at improving the ballistic performances of
HTPB based propellants [19-20]. A comprehensive approach of achieving
Telechilic Polybutadiene Solid Propellant Binders … 349
2. EXPERIMENTAL
2.1. Materials
2.2. Instrumental
2.3.Curing
The binder PTPB was cured with GAP at an alkyne: azide equivalent ratio
of 1:0.1. The mixtures were then cast in aluminiummoulds and the curing
reaction was carried out at 60oC for a period of 5 days. For comparison,
HTPB-TDI urethanes (stoichiometric ratio of 1:1 with respect to isocyanate
and hydroxyl, NCO: OH) were also prepared and evaluated.
2.5. Synthesis
HTPB [33] and the microstructure of PTPB was found to be identical to that of
HTPB. In addition, the chemical shifts at 2.5ppm due to ─C≡C─H and the one
at 4.2 ppm due to O─CH2─ bonded to the propargyl group confirms the
anchoring of propargyl oxy groups to HTPB and this matches with reported
literature [34].
352 S. Reshmi, E. Arunan and C. P. Reghunadhan Nair
1.0 28a.001.1r.esp
0.9
k g
j f e
d O CH2 CH
HC CH2O c h
i a b n
0.8
0.7
Normalized Intensity
0.6
0.5
0.4
b,c,d
0.3
0.2
f,g
0.1 h a
,I,j
16 14 12 10 8 6 4 2 0 -2 -4
Chemical Shift (ppm)
azide molar equivalence of 1:0.1 and beyond this, phase separation occurs.
This can be attributed to the difference in the solubility parameters of the
polymers. HTPB [35] has a solubility parameter of 17.6 MPa1/2and that of
GAP [35] is 22.8 MPa1/2 which causes miscibility issues beyond a certain
concentration. The poor compatibility between GAP and HTPB due to polar
nature of azide groups and non-polar nature of HTPB backbone has been
reported by Ding et al. [29] also. The cure reaction of PTPB with GAP
resulting in the formation of triazolesfor alkyne-azide equivalence of 1:0.1
occurs in the temperature range of 110-185oC with an associated enthalpy of
50 ±2 J/g. This is followed by decomposition of the residual azide at ~186oC
(Figure.4b) as the reaction is not complete in a DSC cell. The azide groups can
also react with double bonds in polybutadiene backbone [30] which gives rises
to triazoline networks. Thus, azide-alkyne curing in PTPB with GAP results in
triazole-triazoline networks.
Figure 4.DSC Traces of Curing of PTPB with GAP a) Azide-alkyne equivalence 1:1;
b) Azide-alkyne equivalence (1:0.1).
Telechilic Polybutadiene Solid Propellant Binders … 355
The rheological behaviour of the curing reaction of PTPB and GAP (molar
stoichiometry of 1:0.1) was investigated at 80oC. The isothermal evolution of
storage modulus (G’) and loss modulus (G”) vs. reaction time for the curing
reaction for PTPB triazole is given in Figure 5.Both moduli (storage and loss)
increase as a result of the increase in crosslinking as observed in the rheogram.
The cross over point of loss modulus with storage modulus is considered as
the gel point. The gel point for PTPB triazole-triazoline system occurs after
190 minutes. A higher modulus build up may be attributed to triazole and
triazoline formation [30-35]. The gel point is higher than for HTPB-urethane
system which is 120 minutes. This indicates a higher ‘pot-life’ for the cure
reaction involving PTPB-GAP.
The peak reaction temperature is 452oC. The residue left over at 600oC is
6%. This is different from HTPB-urethane system where two-stage
decomposition is reported [39].
The mechanism of HTPB urethane has been studied by flash pyrolysis
[40] and it is reported that initially the cleavage of urethane bond occurs
liberating the curing agent which vaporises. This is followed by decomposition
of polymer back bone. The mechanism of the decomposition reaction was
investigated using pyrolysis GC-MS and TG-MS. The pyrolysis studies at
300oC gave butylated hydroxyl toluene (BHT) which is the antioxidantused in
HTPB.
Unlike in HTPB-urethane, in cured PTPB, the cleavage of triazole-
triazoline group occurs along with degradation of polymer backbone which is
supported by the pyrolysis data.Further, the pyrolysis characteristics were
studied at a higher temperature of 500oC. This revealed that at 500oC, cleavage
of the triazole group occurs (Figure 7b) liberating N2 (retention time, RT 1.74)
in addition to the degradation of polybutadiene back bone giving rise to
butadiene(RT 1.83), cyclohexadiene(RT 2.03), 4-vinyl cyclohexene (RT 4.99),
358 S. Reshmi, E. Arunan and C. P. Reghunadhan Nair
xylene (RT 5.93), methylidene(RT 10.05) and BHT (RT 14.90) as reported in
literature [39-40].
100
80
Weight (%)
60
40 HTPB-AP Propellant
PTPB-AP Propelant
20
0
0 50 100 150 200 250 300 350
o
Temperature ( C)
From the study, it can be concluded that the triazole formation has no
adverse effects on the ballistic properties of the propellant and is advantageous
with respect to the combustion products.
362 S. Reshmi, E. Arunan and C. P. Reghunadhan Nair
CONCLUSIONS
PTPB was obtained by the end functionalisation of HTPB by alkyne
functional groups through a direct method. Curing of the polymer was effected
through ‘click mechanism’ by reaction of the alkyne groups with an azide
containing polymer namely GAP to form triazole network in the presence of
cuprous iodide as cure catalyst. The curing reaction was monitored by DSC.
While, curing of PTPB with GAP occurred at higher alkyne-azide molar
equivalence, phase separation occurs due to difference in solubility parameters
of PTPB and GAP. For this system, curing occurs only at an alkyne-azide ratio
of 1:0.1. Rheological studies reveals that gel point for PTPB-GAP system
occurs after 190 minutes (at 80oC) in comparison to 120 minutes for HTPB-
TDI system, which is advantageous for processing. The mechanical properties
of the triazoles based on PTPB were evaluated and compared with HTPB-TDI
urethanes. DMA studies indicate a biphasic transition for PTPB-GAP with two
glass transitions (Tg) occurring at -40.5oC which may be due to the butadiene
backbone and the second one at 18.4oC may be due to the triazole network.
The thermal decomposition studies indicate that the thermal stability of
the neat polymers is improved by triazole-triazoline formation. The
mechanism of decomposition was elucidated by pyrolysis GC-MS. studies. It
is observed that the degradation of the polymer does not occur at lower
temperature of 250oC. At higher temperatures, the decomposition is complete
and proceeds with cleavage of triazole-triazoline groups and the polymer back
bone. The decomposition of the polymers in the presence of AP was evaluated
as oxidiser. The decomposition pattern of PTPB- propellant system is similar
to HTPB-urethane decomposition. The mechanical properties and burn rates of
the propellant based on PTPB- and are comparable to conventional HTPB-
urethane propellants. Thus, propellants based on PTPB yield more gaseous
products which are conducive for specialised applications such as gas
generator or as pyrogen igniter propellant.
ACKNOWLEDGMENT
The authors thank Director, Vikram Sarabhai Space Centre for permission
to publish this work. Support from Analytical and Spectroscopy Division,
VSSC for characterisation is acknowledged.
Telechilic Polybutadiene Solid Propellant Binders … 363
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EDITOR CONTACT INFORMATION
Dr. Yu Chen
Associate Professor
School of Material Science and Engineering
Beijing Institute of Technology
Beijing, PR China
Email: cylsy@163.com
Zong-Rui Tong
Beijing Institute of Technology
Beijing, PR China
INDEX
bitriazolium salts, 63
# bi-1,2,3-triazolyl complex formation, 64
from Condensations and Non-Catalyzed
1,3-dipolar cycloaddition, 12, 13, 14, 18, 21, Cycloadditions, 53
23, 25, 39, 45, 48, 79, 83, 97, 143, 152, from Copper-Catalyzed Alkyne-Azide
193, 212, 214, 215, 224, 236, 237, 299, Cycloaddition, 54
317, 349 from Homocoupling Reactions, 62
13C-labeled nitrile N-oxide, 31, 48
C
A
capillary, 158, 171, 174, 176
addition reaction of carbon-carbon capillary column, 158, 171, 174, 176
multibonds, 8 carbon, 8, 235, 236, 246, 255
ambiphilic dipole, 23 carbon nanostructures, 235, 236, 246, 255
application, 1, 3, 8, 9, 10, 11, 13, 18, 24, 43, carbon nanotubes, 231, 236, 238, 246, 248,
52, 65, 70, 71, 75, 82, 85, 90, 93, 95, 96, 249, 250, 251, 254, 286, 314, 339
98, 99, 100, 105, 108, 109, 112, 125, carbonyl condensation reaction, 7, 8
126, 131, 133, 135, 143, 150, 151, 152, catalytic microreactor, 202
160, 162, 172, 190, 216, 225, 226, 238, catenane, 37, 49, 133
281, 282, 283, 286, 287, 292, 305, 306, characteristics, 1, 4, 5, 13, 21, 32, 65, 70,
322, 323, 327, 329, 333, 340, 343, 344, 79, 83, 87, 160, 161, 171, 178, 185, 211,
361 212, 214, 217, 232, 293, 315, 349, 353,
356, 357, 360
B chemical, 23, 26, 30, 31, 33, 34, 36, 37, 80,
341, 351, 353
biological analysis, 314, 316, 330, 332, 333 chemical ligation, 23, 26, 36, 37, 341
biomedical engineering, 108 chemical shift, 30, 31, 33, 34, 351, 353
biomedical fields, 92, 281, 282 chemical stability, 36, 80
biomolecules, 314, 328, 329 chromatography, 18, 31, 157, 158, 181, 191,
biomolecules sensing, 314, 328, 329 193, 194, 207, 226, 293, 305, 345
370 Index
G
D
gene transfer carrier, 281, 282
dearomatization, 28, 48 grafting reaction, 41, 42, 78, 187
degradation, 22, 25, 26, 49, 84, 108, 113, graphene, 176, 197, 198, 220, 233, 236,
118, 122, 123, 125, 126, 131, 132, 136, 238, 251, 252, 253, 254, 255, 269, 274,
137, 141, 148, 289, 292, 302, 308, 357, 314, 335, 337
362
development, 1, 2, 3, 10, 11, 13, 18, 22, 23,
27, 37, 38, 39, 43, 49, 54, 71, 72, 88, 89, H
100, 116, 129, 153, 160, 216, 238, 244,
266, 282, 287, 294, 296, 297, 298, 302, homoditopic nitrile N-oxide, 22, 24, 27, 36,
304, 305, 324 37, 38, 47, 49
Diels-Alder click coupling, 170 Huisgen reaction, 8, 23, 237, 244, 248, 250,
dimerization, 22, 26, 45, 47, 61 259, 264
dipolarophile, 23, 26 Hydrogel, 87, 88, 89, 107, 108, 123, 129,
133, 135, 136
hydroxamoyl chloride, 24
Index 371
I N
P
M
pathogens, 314, 323
medical, 76, 116
pathogens detection, 314, 323
medical application, 76, 116
perylene, 236, 245, 251, 255, 261, 262, 264
membrane preparation, 211, 216
pharmaceutical science, 281, 282
membrane surface modification, 211, 217,
poly(boron enaminoketonate), 37, 49
221, 222
Poly(-aminoalcohol), 36
micro-reactor, 158, 199, 202, 203
polyaromatic, 235, 236, 258, 266
modification, 8, 10, 11, 17, 39, 40, 42, 48,
polycycloaddition, 36
49, 50, 69, 70, 75, 79, 80, 85, 93, 94, 95,
polyisoxazole, 36, 37
96, 97, 99, 100, 102, 105, 110, 139, 141,
polymer nitrile N-oxide, 40, 41, 42, 47
150, 151, 153, 154, 155, 165, 171, 178,
polyrotaxane, 37, 49
179, 199, 211, 212, 214, 216, 217, 218,
porous materials, 158
224, 225, 231, 232, 281, 305, 308, 323,
pyrene, 25, 111, 236, 249, 255, 256, 257,
340, 348, 349, 351
258, 259, 260, 261, 264, 265, 306, 307,
monolith, 158, 159, 160, 161, 162, 171, 172,
337, 339
173, 174, 177, 178, 179, 180, 181, 183,
184, 185, 186, 187, 188, 189, 190, 191,
193, 194, 195, 196, 197, 198, 199, 200, Q
201, 202, 328, 343
quadrupolar relaxation, 30
372 Index
R T
rotaxane, 37, 49, 133 thiol-ene reaction, 9, 113, 116, 117, 130,
134, 140, 143, 144, 145, 147, 149, 151,
152, 154, 166, 167, 168, 172, 173, 174,
S 193, 214, 216, 222, 314, 315, 327, 328,
329, 336, 342
self-decomposition, 23, 26, 27, 30, 31
thiol-ene/yne, 8, 9, 15, 17, 18, 80, 88, 90,
SPAAC reaction, 118, 119, 122, 128, 314,
102, 104, 113, 115, 116, 117, 127, 129,
323, 324, 325, 326, 327, 333
130, 133, 134, 139, 140, 143, 144, 145,
stable nitrile N-oxide, 23, 30, 36, 38, 49
146, 147, 149, 151, 152, 154, 155, 157,
stationary phase, 158, 160, 180, 190, 191,
159, 163, 166, 167, 168, 171, 172, 173,
193, 194, 203, 328
174, 175, 176, 177, 184, 185, 186, 187,
stimuli-responsive hydrogel, 108
192, 193, 194, 196, 198,200, 201, 202,
surface functionalization, 102, 158, 160,
203, 214, 216, 222, 228, 229, 306, 307,
167, 171, 172, 181, 184, 190, 252
314, 315, 316, 327, 328, 329, 336, 342,
surface modification, 10, 13, 17, 42, 96,
343, 344
101, 105, 136, 139, 150, 159, 179, 185,
thiol-epoxy click coupling, 170
211, 216, 217, 223, 230, 232
types, 1, 5, 9, 21, 80, 89, 100, 108, 125, 129,
133, 152, 193, 213, 294, 314, 316, 321,
347