"clickable" thiacalix[4]arene derivatives bearing polymerizable 1,3-butadiyne fragments: Synthesis and incorporation into polydiacetylene vesicles

Article abstract of DOI:10.1039/c6ra07555j

p-tert-Butylthiacalix[4]arene derivatives in 1,3-alternate stereoisomeric form bearing polymerisable 1,3-butadiyne fragments on the one side and amino/carboxylic groups on another were synthesized using stepwise functionalisation. Calixarene 7 embedded in polydiacetylene nanoparticles showed a selective colorimetric response toward lanthanide ions.

Full text of DOI:10.1039/c6ra07555j

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“Clickable” thiacalix[4]arene derivatives bearing polymerizable
1,3-butadiyne fragments: synthesis and incorporation into
polydiacetylene vesicles.
Received 00th January 20xx,
Accepted 00th January 20xx
Vladimir Burilov †,a, Alsu Valiyakhmetovaa, Diana Mironovaa, Roman Safiullinc, Marsil Kadirovb,c
,
DOI: 10.1039/x0xx00000x
Kamil Ivshina, Olga Kataevaa,b, Svetlana Solovievaa,b and Igor Antipina,b
.
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cycloaddition (CuAAC)18-20
.
p-tert-butylthiacalix[4]arene derivatives in 1,3
– alternate
stereoisomeric form bearing polymerisable 1,3-butadiyne
fragments on the one side and amino/carboxylic groups in
So, the combination of unique receptor properties of calixarene
derivatives with PDA as a signaling unit is very challenging in
another were synthesized usind stepwise functionalisation. creation of colorimetric sensors. Thus, charged calixarene
receptors, non-covalently embedded within vesicles comprising
phospholipids and the PDA were successfully used for the color
fingerprinting of proteins21. Nevertheless direct covalent bounding
of calixarene with PDA signaling unit is at high interest but
represented only in covalent incorporation of calixarenes with PDA
Calixarene 7 embedded in polydiacetylene nanoparticles showed
seletive colorimetric response toward lanthanide ions.
Recently, polymeric materials that undergo spectra
changes in response to the external mechanical stimuli have matrix via ester-linkage22, which is not hydrolytically stable in
gained much attention1,2
polydiacetylene (PDA), has
materials. PDA can be prepared from various kinds of self-
.
A
conjugated polymer,
acidic/base conditions or in the presence of carboxylic ester
It is noteworthy that thiacalix[4]arenes scaffold
adopting 1,3-alternate stereoisomeric form is in a great importance
a
special place among such hydrolases23
.
assembled diacetylene monomers by simple photo since selective stepwise functionalization of macrocycle lower rim
polymerization3 and can be used for colorimetric detection of
allows to create two molecular domains with quite different
ions4, chemicals5, biomolecules6,7, bacteria8,9 and pH10 or
properties located on the opposite sides from macrocycle plane
temperature changes11. The key mechanism of PDA
(Scheme 1). One of them provides polymerisable 1,3-butadiynic
colorimetric response lies in distortion of π-conjugated
backbone by external stimuli and appears in rapid color (blue-
to-red) and fluorescence changes (none-to-red)12. Functional
groups on the surface of PDA nanoparticles or bilayer plays the
key role in colorimetric detection of target substrate.
fragments; on other the target receptor fragments can be easily
introduced and varied using click chemistry approach.
(Thia)calix[4]arene derivatives are well-known objects of
supramolecular chemistry with unique properties: variety of
stereoisomeric configurations, easy functionalization of both
upper and lower rim and preorganization effect13,14. Their
ability to form host-guest complexes and to bind both organic
molecules and metal ions is successfully used in extraction;
recognition of different substrates and as components of
molecular devices15-17. Azide- or terminal alkyne functionalities
can essentially extend the synthetic potential of calixarene
platform by using of the copper-catalyzed azide-alkyne
Scheme 1.
Herein we report a new synthetic strategy for the wide series of
thiacalix[4]arene – based bifunctional receptors in 1,3-alternate
stereoisomeric form bearing polymerizable 1,3-butadiyne
fragments on the one side and azidopropyl fragments for the
CuAAC reaction on another and the study of colorimetric response
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Structures of compounds 1-3 were characterized by NMR,
MALDI-TOF, IR and elemental analysis (see SI). For compound 1
single crystals suitable for X-ray diffraction studies were obtained.
According to the X-ray data O-substituted aromatic rings of the
macrocycle are parallel to each other (Fig. 1). We found that it is
general observation for distal disubstituted thiacalix[4]arene
derivatives27,28. Moreover, this is completely different from the
behavior of disubstituted classical calix[4]arene (C[4]A)
toward d-metal ions by receptors embedded in 10,12-
pentacosadiynoic acid (PCDA) vesicles.
Mitsunobu reaction is the most convenient method for the
stepwise functionalization of thiacalix[4]arene lower rim by two
different electrophilic reagents and leads to non-symmetrical tetra-
substituted products in 1,3-alternate stereoisomeric form24,25
containing different functional groups on the opposite sides of the
macrocycle (Scheme 2).
derivatives29
, in which both O-R fragments are fixed by
intramolecular hydrogen bonding resulting in the rigid cup-shaped
structure.
Figure 1. Structure of 1 according to the X-ray data (hydrogen
atoms are omitted for clarity) and intramolecular hydrogen bonding
in C[4]A and TC[4]A derivatives.
The reason of such behavior in disubstituted TC[4]A derivatives
is 15% larger ring size of thiacalix[4]arene30, that’s why only one
phenolic hydroxyl group can take part in hydrogen bonding (Fig. 1).
Scheme 2. Two pathways for synthesis of bifunctional
thiacalixarene 3.
Stereoisomeric form of 3 was assigned as 1,3-altenate by the
presence of high symmetric structure confirmed by 1H NMR spectra
and 2D NOESY NMR due to the existence of cross-peaks between
The stereoselective synthesis of polymerisable diazido precursor
3 was accomplished in a convergent fashion. The synthesis utilizes
the 5-phenyl-2,4-pentadiyn-1-ol and 3-azido-1-propanol as building
blocks. Building blocks were synthesized by Cadiot–Chodkiewicz
coupling reaction of propargyl alcohol with phenyl acetylene in the
presence of Cu(I) chloride26 and nucleophilic substitution of 3-
bromo-1-propanol with sodium azide, correspondingly.
Obviously, there are two pathways (A or B on the Scheme 2) to
the target precursor, that differ in the sequence of reactions. On
the first step the substituents bearing terminal azide or 1,3-
butadiynoic fragments were introduced on the macrocycle.
Reactions of parent thiacalix[4]arene with 5-phenyl-2,4-pentadiyn-
1-ol and 3-azido-1-propanol lead to the formation of expected distal
disubstituted derivatives 1 and 2 in good yields. It is important to
note that no Staudinger by-products (reaction of azides with
triphenyl phosphine) were detected. So, azido-containing fragments
can be directly attached to calixarene platform in Mitsunobu
reaction conditions. Earlier azide-groups were only introduced on
the thiacalix[4]arene platform by nucleophilic substitution of
corresponding halogen derivatives25
.
Figure 2. 2D NOESY NMR spectra of 3, CDCl3.
signals of methylene protons of azidopropyl fragments (δ = 4.04;
3.07; 1,63 ppm) and neighboring aromatic protons (δ = 7.35 ppm)
as well as cross-peaks between signals of methylene protons of 5-
phenylpenta-2,4-diyn fragments (δ = 4.65 ppm) and neighboring
aromatic protons (δ = 7.56 ppm) (Fig. 2).
In this way thiacalixarene 3 was obtained by Mitsunobu reaction
of 1 or 2 with 3-azido-1-propanol and 5-phenyl-2,4-pentadiyn-1-ol,
respectively, and there was no significant difference in the yields.
So, the sequence of the reactions has no effect on the total yield of
the final product.
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Reaction of calixarene 3 with several alkynes was performed potential of polymerized vesicles is in full accordance with the
both in Cu(I)- catalyzed (for compounds 4, 5) and uncatalyzed (for 7) nature of calixarene dopants. In the case of anionic calixarene 7 ξ-
conditions (Scheme 3). Reaction of 3 with acetylenedicarboxylic potential of negatively charged PDA vesicles is increased up to -62
acid gave tetraacid 7, reaction with N-propargyl phthalimide mV. , whereas the presence of cationic calixarene 6 leads to its
following by hydrazinolysis gave diamine 6 with good yields. No decreasing (-37 mV).
products of calixarene 3 self-cyclization were found. Low reactivity
of disubstituted 1,3-butadiyne derivatives in the cycloaddition
reaction with azides 31 is a reason of such result.
Table 1. DLS and ξ-potential data for PCDA-calixarene vesicle
solution before and after UV polymerizationa.
C calix,
mM
C
Z-
PDI
Z-
PDIb
ξ, mVb
Calix
PCDA
, mM
average,
nm
averageb,
nm
-
6
7
-
0.2
0.2
0.2
217±1
1719±9 0.988
215±3 0.491
0.522
155±11 0.482
1032±8 0.577
-50±1
-37±4
-62±4
0.02
0.02
129±2
0.420
a Measurements were done at 10 mM Tris buffer, рН = 7.4.
b After polymerization.
According to the TEM data the shape of polymerized PDA
vesicles has both spherical and tapered forms with size 150-200 nm,
PDA doped with calixarene 6 has 200 nm single tapered particles
and shapeless aggregates, and PDA doped with calixarene 7 has
spherical shape particles with 100 nm in diameter. Non-spherical
shape can be the main reason of high polydispersity indexes in DLS
measurements.
Scheme 3. Synthesis of triazoles 4-7, reaction conditions: CuI,
NEt3, Toluene, RT (for 4, 5); acetone, reflux (7) and NH2-NH2*H2O,
EtOH, reflux (6).
Figure3. TEM images of polymerized PDA vesicles (a), PDA-6 (b) and PDA-7 (c) vesicles, C(PCDA) = 0.2 mM, C (Calix)= 0.02 mM.
Calixarenes 6 and 7 were used in copolymerization with 10,12- Since PDA nanomaterial’s with different functional groups on
pentacosadiynoic acid (PCDA), which is the most often used PDA the surface were successfully used in detection of such ions as lead,
source capable for vesicle formation32. Despite low topochemical
matching of diynoic fragments of calixarene and PCDA it is quite
expected that calixarenes can form functional domains on the
vesicle surface after polymerization. PCDA-calixarene vesicles were
formed by well-known film hydration method. According to DLS
data (Table 1) PCDA itself forms 200-nm sized vesicles, addition of
anionic calixarene 7 at pH 7.4 doesn’t significantly affect to the size
of vesicles, but addition of calixarene 6, which is mostly in cationic
form at pH 7.4, causes high aggregation of PCDA. Polymerization of
PCDA-calixarene vesicles was performed under irradiation of 254
nm light in quarts 10 mm cuvettes was controlled by UV-visible
spectroscopy. The maximum absorbance peak at 674 nm, which
Figure 4. Photograph of a portion of a 96-well plate containing: (a)
1 mM of different metal ions chloride salts (except Dy3+, Ba2+,
Pd2+, Gd3+, Tb3+ and Hg2+ were nitrates) and PDA-7 vesicles (blank
B-0); (b) PDA-7 (blank B-1) or (c) PDA vesicles (blank B-2) with
Dy3+, Gd3+, Tb3+ nitrates; (C(PCDA) = 0.2 mM, C (Calix)= 0.02mM
(a) or 0.04mM (b) in 10 mM Tris Buffer, pH = 7.4.
corresponds to the “blue” form of PDA vesicles, appeared after 15
minutes of irradiation, and then polymer began to convert in “red”
form. Thus 15 minutes is the optimal time for complete
polymerization of PDA vesicles. The size of vesicles after
polymerization decreases in all cases at about 30 % (Table 1). Zeta-
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silver, zinc, cadmium, manganese, silver, mercury33-35, the study of
Acknowledgments
the effect of calixarene doping on the colorimetric response of PDA
vesicles in the presence of different metal ions was done. According
to the obtained data (Fig. 4, a) PDA-7 vesicles with 10% mol content
of calixarene has a colorimetric response to lanthanide ions (Gd3+,
Tb3+ and Dy3+ were tested). Importantly that addition of other metal
ions (except iron (II) and (III) ions that’s colored due to the partial
hydrolysis at pH 7.4) has no color effect on PDA-7 vesicles solution.
Therefore selectivity upon lanthanide ions can be successfully used
for lanthanide determination in the presence of other metal ions.
The increase of calixarene content in PDA vesicles up to 20 mol %
(Fig.4, b) lead to significant increase of the colorimetric response
toward lanthanide ions. Minimum detection limit is 0.01 mM (see
pic. 2 in SI).
TEM images were carried out in the laboratory of
“Transmission electron microscopy” of Kazan National
Research Technological University. We thank the Russian
Scientific Foundation for the financial support of this work
(grant № 14-13-01151).
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Thiacalix[4]arene-functionalized polydiacetylene (PDA) vesicles showed selective colorimetric response toward several lanthanide ions. This
approach can be a good basis for lanthanide express analysis.