Uncharged water-soluble amide derivatives of pillar[5]arene: synthesis and supramolecular self-assembly with tetrazole-containing polymers

Article abstract of DOI:10.1007/s11172-020-2728-4

New uncharged water-soluble pillar[5]arene derivatives bearing 2-hydroxyethylamide and 2-hydroxypropylamide moieties have been for the fi rst time synthesized via aminolysis. A detailed analysis performed for the spectral data (UV, IR; and 1H, 13C, NOESY, and HSQC NMR) allowed us to determine the spatial structure of the synthesized macrocycles. Aggregation properties of the obtained compounds with water-soluble tetrazole-containing polymers, viz. poly-5-vinyltetrazole (PVT) and polyvinyl(tetrazolyl)ethyl ether (PVTE), were evaluated. Pillar[5]-arene containing 2-hydroxyethylamide moieties formed monodisperse nanoscale aggregates with an average hydrodynamic diameter of 117 nm in the presence of PVTE in aqueous solution. The morphology of resulting particles was determined by scanning electron microscopy.

Full text of DOI:10.1007/s11172-020-2728-4

Russian Chemical Bulletin, International Edition, Vol. 69, No. 1, pp. 97—104, January, 2020
97
Uncharged water-soluble amide derivatives of pillar[5]arene:
synthesis and supramolecular self-assembly
with tetrazole-containing polymers*
D. N. Shurpik,a A. A. Nazarova,a L. I. Makhmutova,a V. N. Kizhnyaev,b and I. I. Stoikova
aKazan Federal University, A. M. Butlerov Institute of Chemistry,
18 ul. Kremlevskaya, 420008 Kazan, Russian Federation.
Fax: +7 (843) 233 7416. E-mail: Ivan.Stoikov@mail.ru
bIrkutsk State University,
1 ul. K. Marksa, 664003 Irkutsk, Russian Federation
New uncharged water-soluble pillar[5]arene derivatives bearing 2-hydroxyethylamide and
2-hydroxypropylamide moieties have been for the first time synthesized via aminolysis.
A detailed analysis performed for the spectral data (UV, IR; and 1H, 13C, NOESY, and HSQC
NMR) allowed us to determine the spatial structure of the synthesized macrocycles. Aggregation
properties of the obtained compounds with water-soluble tetrazole-containing polymers, viz.
poly-5-vinyltetrazole (PVT) and polyvinyl(tetrazolyl)ethyl ether (PVTE), were evaluated. Pillar[5]-
arene containing 2-hydroxyethylamide moieties formed monodisperse nanoscale aggregates
with an average hydrodynamic diameter of 117 nm in the presence of PVTE in aqueous solution.
The morphology of resulting particles was determined by scanning electron microscopy.
Key words: water-soluble synthetic receptors, pillar[5]arene, self-organization, supramo-
lecular chemistry, macrocycles, self-assembly.
Recent advances in the pharmaceutical chemistry
are associated with the development of new drugs bear-
ing a tetrazole ring as the structural moiety.1,2 Tetrazoles
have not been found in the nature. With minor excep-
tions, these compounds do not exhibit any significant
biological activity, but at the same time, they are resis-
tant to a biodegradation.3 This particular property allows
tetrazoles to be used as convenient pH-dependent
functional moieties for the design of new drugs and for
the development of drug delivery systems based on
them.1—4
Carbon nanotubes, liposomes, polymers, den-
drimers, macrocyclic capsule molecules, and magnetic
nanoparticles are currently being intensively investigated
as the drug delivery systems.5—8 Polymer nanoparticles
are of particular interest due to their stability, bio- and
functional compatibility.6 At this end, polymer com-
positions based on polyvinyltetrazoles (PVT) are con-
sidered as promising carriers for the development of
targeted drug delivery systems.9 PVT-based polymers
exhibit a pronounced antiinflammatory activity, pro-
mote blood coagulation, and accelerate wound healing.9
However, it should be noted that the PVT-based poly-
mer compositions do not form stable nanoscale aggre-
gates in aqueous solutions.10 To obtain the nanosized
particles with the given shape and size,10 the polymer
compositions containing polyfunctional macrocyclic
compounds11,12 are employed. These macrocyclic com-
pounds possess a number of attractive characteristics
such as preorganized spatial structure, the macrocyclic
cavity capable of containing the guest molecule, and
functional groups that regulate receptor properties of
the macrocyclic system.13,14 To date, the most promis-
ing macrocyclic compounds are pillar[n]arenes, repre-
sentatives of the new class of para-cyclophanes.15 In
contrast to relative classes of macrocycles (calix[n]-
arenes, cyclodextrins, and cucurbit[n]urils), pillar[n]-
arenes are synthetically available and can be easily
functionalized thus providing the opportunity to work
under the conditions that are not suitable for other
macrocycles (pH, aqueous and buffer systems).16—18
In the present work, we describe the first example
of application of uncharged water-soluble pillar[5]arene
derivatives bearing 2-amidoethanol and 3-amidopro-
panol moieties for the preparation of nanosized associates
with poly-5-vinyltetrazole (PVT) and polyvinyl(tetrazol-
5-yl)ethyl ether (PVTE) via supramolecular self-as-
sembly.
* Based on the materials of the V International Scientific
Conference "Advances in Synthesis and Complexing" (April
22—26, 2019, Moscow, Russia).
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 0097—0104, January, 2020.
1066-5285/20/6901-097 © 2020 Springer Science+Business Media, Inc.

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Shurpik et al.
Results and Discussion
3-aminopropanol in methanol afforded desired amides 7
and 8 in the yields of 92 and 95%, respectively.
Pillar[5]arenes bearing various hydrophilic groups
Structures of all the obtained products were confirmed
by a set of physicochemical methods: 1D and 2D NMR
spectroscopy, IR spectroscopy, and their compositions
were confirmed by elemental analysis and mass spectrom-
etry. Thus, the 1H NMR spectrum of macrocycle 4 (Fig. 1)
contains a signal from the protons of amide group as a
broadened singlet at  7.71. Signals from H(1) and H(3)
aromatic protons of the macrocycle were observed as a
singlet ( 6.81), which is typical of decasubstituted de-
rivatives of the pillar[5]arene.18,19 Proton signals from the
OC(4)H2C(O) groups were observed as an AB spin system
(carboxyl, ammonium, amide, and amino groups) are the
most studied homologues of pillar[n]arenes. These com-
pounds are highly soluble in water and exhibit a high
complexing ability.15
We have previously developed19 the procedure for
introducing amide groups into a pillar[5]arene framework.
Diamines containing the both primary and tertiary amino
groups were used as the amidating agents. In the present
work, we have selected commercially available 2-amino-
ethanol and 3-aminopropanol as the amidating agents.
Starting macrocycles 1 and 2 were synthesized according
to the known procedure.20 Subsequent aminolysis of de-
caester 2 with 2-aminoethanol or 3-aminopropanol in
methanol afforded macrocycles 3 and 4 in the yields of 89
and 86%, respectively (Scheme 1).
2
( 4.39 and 4.40) with JH,H = 12.9 Hz. Protons of the
hydroxy groups resonate as a multiplet in the range of
 4.10—4.15. A singlet at  3.76 corresponds to signals
from the H(2) protons of methylene bridges. The H(5),
H(6), and H(7) protons of propylidene moieties resonate
as multiplets in the range  1.35—3.39. The chemical shifts,
ratio of integral intensities, and multiplicity of the proton
Model compounds 7 and 8 were prepared in order to
evaluate an effect of the macrocyclic platform of pillar[5]-
arene on its aggregation properties with poly-5-vinyltetr-
azole and polyvinyl(tetrazol-5-yl)ethyl ether. For this
purpose, diester 6 was obtained by alkylation of p-hydro-
quinone 5 according to the procedure reported previ-
ously,21 aminolysis of which with 2-aminoethanol and
1
signals in the H NMR spectrum of pillar[5]arene 4 are
in a good agreement with the proposed structure.
It has been previously observed22 that an introduction of
the bulky substituents into the structure of pillar[5]arene
inhibits the oxygen-through-the-annulus rotation of its aro-
Схема 1
n = 1 (3, 7), 2 (4, 8)
Reagents and conditions: i. BrCH2COOH, K2CO3, KI, MeCN; ii. H2N(CH2)n+1OH, MeOH.

Amide derivatives of pillar[5]arene
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 1, January, 2020
99
matic units. However, the rotation speed increases upon
increasing the temperature of system.22 It should be noted
that in macrocycle 4, spin-spin coupling constants for the
AB spin systems of OC(4)H2C(O) groups are ~13 Hz, and
the H(5) protons of methylene moieties of the amide group
(see Fig. 1) form two four-spin non-first-order systems that
were not analyzed. The proton nonequivalence is most likely
caused by an inhibition of the rotation of aryl moieties by
long substituents at the aryl moieties, by planar chirality of
pillar[5]arene 4, and also by formation of cyclic hydrogen
bonds between the amide moieties. Thus, the assignment of
signals from each proton and carbon atom of the 3-amido-
propanol moiety of macrocycle 4 was carried out by the
the aryl moieties.23 In the case of macrocycle 3, a different
1H NMR pattern was observed. For compound 3, signals of
the methylene protons at the amide group ( 3.35) and the
protons of the OCH2C(O) groups ( 4.37) are observed as
the broadened multiplets, which indicates the absence of the
cyclic amide hydrogen bond and rotation of the aromatic
moieties in pillar[5]arene 3.
To confirm the hypothesis about the presence of the
cyclic hydrogen bond inhibiting the rotation of the aro-
matic moieties in macrocycle 4, IR spectra of compounds
3, 4, 7, and 8 were investigated. Table 1 shows character-
istic bands of the stretching vibrations of pillar[5]arenes
3, 4 and model compounds 7, 8. In the IR spectra, the
stretching vibrations bands of amide moieties of macro-
cycles 3 and 4 are different. Thus, intense (С=О) (amide
I) at 1681.6 cm–1 and less intense (NH) (amide II) at
1654.2 cm–1 bands indicate the presence of free amide
groups in the structure of macrocycle 3. For macrocycle
4, intense (С=О) (amide I) at 1643.3 cm–1 and less in-
tense (NH) (amide II) at 1640.5 cm–1 bands are observed,
which corresponds to the associated amide group. In model
compounds 7 and 8, the both characteristic bands of
1
analysis of cross-peaks in the 2D H—13C HSQC NMR
spectrum (see Fig. 1). One can see from the spectrum that
signals from the two non-equivalent H(5) protons correspond
to the signal from the C(5) carbon atom at the amide group,
while signals from the equivalent H(6) and H(7) protons
correspond to the signals from the C(6) and C(7) carbon
atoms, which is in a good agreement with the integral inten-
sity of signals in the 1H NMR spectrum. This fact indicates
an absence of the dynamic processes caused by rotation of
H(4)
H(7)
H(1), H(3)
H(6)
H(5)
H(2)
H(8)
NH

0
10
20
C(5)/H(5)
C(2)
C(6)
30
C(5)
C(6)/H(6)
40
50
C(7)
C(4)
60
C(7)/H(7)
70
80
90
100
110
120
C(1),
C(3)
7.50 7.00 6.50 6.00 5.50 5.00 4.50 4.00 3.50 3.00 2.50 2.00 1.50

1
Fig. 1. H—13C HSQC spectrum of compound 4 (DMSO-d6, 25 C, Bruker Avance-400). The numbering of atoms in compound 4
does not correspond to the IUPAC nomenclature and was used for the interpretation of NMR spectra.

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Russ. Chem. Bull., Int. Ed., Vol. 69, No. 1, January, 2020
Shurpik et al.
Table 1. Characteristic bands in the IR spectra (cm–1) of com-
pounds 3, 4, 7 and 8
A
0.6
0.4
0.2
Compo-
und
OH
C(O)NH
CAr—O—CH2
(С=О)
(NH)
3
4
7
8
3289.4
3289.5
3337.1
3360.3
1681.6
1643.3
1679.9
1673.3
1654.2
1640.5
1657.2
1661.2
1250.7
1251.1
1216.1
1232.5
3/PVTE
3
stretching vibrations of the amide moieties correspond to
the free amide groups. Therefore, the acquired experimen-
tal data indicate that in contrast to macrocycle 3, the
formation of inter- and intramolecular hydrogen bonds is
characteristic of macrocycle 4.
Investigation of the supramolecular self-assembly with
tetrazole-containing polymers. The next step of this work
was the study of self-assembly and association of the syn-
thesized macrocycles 3 and 4 in the presence of tetrazole-
containing polymers: poly-5-vinyltetrazole and
polyvinyl(tetrazol-5-yl)ethyl ether. The starting PVT and
PVTE are insoluble in water in non-ionized state,24,25
since the tetrazole moieties present in the polymer chains
are prone to the formation of multiple intra- and inter-
molecular hydrogen bonds.26 At this end, PVT and PVTE
were converted into water-soluble polyammonium salts
according to the known procedures.27,28
PVTE
250
300
350 /nm
Fig. 2. UV spectra of PVTE (10–4 mol L–1), pillar[5]arene 3
(10–5 mol L–1), and 3 (10–5 mol L–1)/PVTE (10–4 mol L–1
)
system in water.
of excess of PVT and PVTE was not observed in the UV
spectra. Apparently, the elevated baseline in the UV spectra
of pillar[5]arene 3 is due to its aggregation with PVTE.
The next step was DLS studies of the macrocycle/
polymer systems at the component ratios of 10 : 1, 5 : 1,
1 : 1, 1 : 5, 1 : 10, and 1 : 15 in the concentration range of
10–3—10–5 mol L–1. It is interesting that only in the case
of macrocycle 3 (10–4 mol L–1) in the presence of PVTE
(10–5 mol L–1) monodisperse (PDI = 0.21) stable 3/PVTE
associates with an average hydrodynamic diameter of
118 nm were formed (Table 2, Fig. 3). An increase in the
ζ potential for 3 : PVTE = 10 : 1 system (Δζ = 9.1 mV)
with time (see Table 2) has additionally confirmed the
formation of a supramolecular system that stabilizes over
time. This is apparently explained by the presence of free,
unassociated amide and hydroxy groups in macrocycle 3,
which can form multiple intermolecular macrocycle/
polymer hydrogen bonds in contrast to macrocycle 4.
According to scanning electron microscopy (SEM)
Consequently, the self-association of the obtained
compounds 3, 4, 7, and 8 and their supramolecular self-
assembly in water with the prepared salts of PVT and PVTE
were investigated. The study of self-association of com-
pounds 3, 4, 7, and 8 in water was carried out using the
dynamic light scattering (DLS). It was shown that mac-
rocycles 3 and 4 and model compounds 7 and 8 do not
form any stable self-associates in water in the studied
concentration range (10–3—10–5 mol L–1).
data, associates 3 (10–3 mol L–1)/PVTE (10–4 mol L–1
are spherical particles with an average diameter of 117 nm
)
I (%)
15
10
5
The interaction of pillar[5]arenes 3 and 4 with PVT and
1
PVTE was investigated by DLS, UV spectroscopy, H and
13C NMR spectroscopy, and 2D NMR spectroscopy. The
UV spectroscopy showed no shifts in the absorption maxima
upon the addition of excess of PVT and PVTE (they do not
absorb in the UV range) to macrocycles 3 and 4, but
in the case of macrocycle 3 (10–5 mol L–1) and PVTE
(10–4 mol L–1), there was a "rise" of the baseline (Fig. 2). In
the case of compound 4, the rise of baseline upon the addition
1•101
1•102
1•103 d/nm
Fig. 3. Size distribution for
3
(10–4 mol L–1)/PVTE
(10–4 mol L–1) associates formed in water. Particle polydisper-
sity index (PDI) is 0.21.

Amide derivatives of pillar[5]arene
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 1, January, 2020
101
Table 2. Characteristics of light scattering for associates of mac-
rocycle 3 (10–4 mol L–1) with PVT (10–5 mol L–1) and PVTE
(10–5 mol L–1) in water immediately after preparation (I) and
24 h after preparation (II)
(Fig. 4, a and b). It should be noted that according to the
SEM data, pure macrocycle 3 (10–3 mol L–1) formed
submicron aggregates (Fig. 4, c and d), while micron-
sized dendritic aggregates were observed for PVTE
(10–4 mol L–1) (Fig. 4, e and f).
Parameter
3/PVTE
3/PVT
To estimate an effect of the macrocyclic platform of
pillar[5]arene on the formation of nanoscale associates
with PVT and PVTE, the behavior of model compounds
7 and 8 in the presence of PVT and PVTE was studied at
the compound : polymer ratios of 10 : 1, 5 : 1, 1 : 1, 1 : 5,
I
II
I
II
d/nm
PDI
ζ/mV
290 31
0.24 0.03 0.21 0.01
–8.5 0.7 –17.6 1.6
118
2
150 20
0.41 0.10 0.45 0.16
—* —*
156 31
1 : 10, and 1 : 15 in the concentration range of 10–3
—
10–5 mol L–1 by DLS. It emerged that model compounds
7 and 8 do not form any stable nanoscale associates with
PVT and PVTE in the studied concentration range.
Therefore, the acquired experimental data suggest that
Note: d is the average hydrodynamic diameter of associates, PDI
is the polydispersity index, and ζ is the electrokinetic potential.
* ζ-Potential was not measured due to the polydispersity of
system.
a
c
e
b
1 m
200 nm
d
10 m
1 m
f
1 m
10 m
Fig. 4. SEM images of pillar[5]arene 3 (10–3 mol L–1)/PVTE (10–4 mol L–1) associates (a, b), aggregates of macrocycle 3
(10–3 mol L–1) (c, d), and PVTE (10–4 mol L–1) (e, f) in water.

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Russ. Chem. Bull., Int. Ed., Vol. 69, No. 1, January, 2020
Shurpik et al.
during association an important role is played not only by
the possibility of formation of multiple hydrogen bonds,
but also by the macrocyclic platform of pillar[5]arene 3.
To verify this hypothesis, the interaction of macrocycle
ates. In the case of macrocycle 3, the 1H—1H NOESY NMR
spectrum contained cross-peaks between the protons of the
methylene groups of propylene bridge and the protons of
moieties of the (CH2) polymer chain of PVTE, cross-peaks
between the protons of the aryl moieties (ArH) of pillar[5]-
arene 3 and the protons of tetrazolylethoxyl (CH2CH2O)
moieties of PVTE (Fig. 5, a). The presence of these cross-
peaks indicates a spatial proximity of the tetrazole moieties
of PVTE polymer and aromatic moieties of pillar[5]arene
3. There were no similar cross-peaks observed in the
1H—1H NOESY NMR spectrum of 4/PVTE mixture.
1
3 with PVTE was investigated by H NMR spectroscopy.
Unfortunately, the only changes observed in the
1H NMR spectra of 3/PVTE system were broadening of
the signals from the macrocycle and polymer, which indi-
rectly indicates aggregation and formation of 3/PVTE as-
1
sociates.16 Thus, 2D H—1H NOESY and DOSY NMR
spectroscopy were used to confirm the formation of associ-
CH2CH2
a
CH2C(O)
CH2
ArH
CH2CH2
(PVTE)
CH2
(PVTE)

CH2
(PVTE)
1.0
2.0
3.0
4.0
5.0
6.0
7.0
8.0
CH2CH2
(PVTE)
CH2CH2
CH2
CH2C(O)
CH2/CH2
(PVTE)
ArH
ArH/
CH2CH2
(PVTE)
9.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0

c
b
+
NH4
+
NH4
D•1010/m2•s–1
–0.5
+
5
NH4
+
10
15
20
25
NH4
+
NH4
7.0
6.0
5.0
4.0
3.0
2.0
1.0

+
NH4
Fig. 5. 1H—1H NOESY (a) and DOSY (b) spectra (D2О, 25 C, Bruker Avance-400) for 3 (10–2 mol L–1)/PVTE (10–3 mol L–1
associates, and the proposed structure of 3/PVTE complex (c).
)

Amide derivatives of pillar[5]arene
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 1, January, 2020
103
Bruker Avance 400 spectrometer with an STE pulse sequence of
the bipolar pulse gradient (stebpgp1s). The 16 scans and 16000
data points were recorded. The maximum gradient force obtained
along the z axis was 5.35 G mm–1. The duration of magnetic field
pulse gradients () was optimized for the each diffusion time (Δ)
in order to obtain a 2% residual signal with the maximum gradient
strength. The values of  and Δ were 1.800 s and 100 ms, respec-
tively. The pulse gradients were increased from 2 to 95% of the
maximum gradient strength in a linear ramp.29 IR spectra were
recorded on a Spectrum 400 (Perkin Elmer) Fourier spectrom-
eter equipped with an ATR imaging accessory in the wavenumber
range of 400—4000 cm–1: resolution of 1 cm–1, acquisition of
64 scans, and recording time of 16 s. Particle sizes in the solution
were determined by dynamic light scattering (DLS) using a
Zetasizer Nano ZS (Malvern) nanoparticle size analyzer equipped
with a He—Ne laser (4 mW) operating at the wavelength of
633 nm, scattered light detection angle of 173, and with an au-
tomatic determination of the measurement position inside the cell.
To prepare solutions of macrocycles 3, 4 and ammonium salts of
the PVT and PVTE polymers, deionized water with the specific
resistance of 18.0 M cm at 25 C obtained in the Millipore-Q
purification system was used. Solutions of individual macrocycles
(3 and 4) and polymers (PVT and PVTE) were mixed during the
experiment at the macrocycle : polymer ratios of 10 : 1, 5 : 1, 1 : 1,
The formation of 3/PVTE associates was additionally
confirmed by the 2D DOSY spectroscopy (Fig. 5, b).
Diffusion coefficients were determined at 298 K for pillar[5]-
arene 3 (10–2 mol L–1), PVTE (10–3 mol L–1), and 3
(10–2 mol L–1)/PVTE (10–3 mol L–1) associates. In the
DOSY spectrum of 3/PVTE associates, there is only the
one type of the signals lying along a straight line with one
diffusion coefficient (D = 2.11•10−10 m2 s−1), which is
much smaller than the self-diffusion coefficient of macro-
cycle 3 (D = 5.53•10−10 m2 s−1) under the same conditions.
An analysis of the data acquired using the 2D NMR spec-
troscopy allowed us to conclude that association of macro-
cycle 3 with PVTE results in host-guest complexes, in which
the tetrazole moieties are incapsulated within the cavity of
pillar[5]arene 3 (Fig. 5, c) and several chains are associated
into one. The formation of additional intermolecular mac-
rocycle—polymer hydrogen bonds leads to a compaction
of the polymer into nanoscale associates.
In conclusion, the present work is the first report on the
synthesis of uncharged water-soluble derivatives of pillar[5]-
arenes 3 and 4 bearing 2-amidoethanol and 3-amidopro-
panol fragments. The structures of the obtained products
were fully confirmed by a set of physicochemical methods.
The DLS method revealed that pillar[5]arenes 3 and 4 do
not form stable self-associates in an aqueous solution. The
1 : 5, 1 : 10, and 1 : 15 in the concentration range of 10–3
—
10–5 mol L–1. The solutions were kept for 1 h, and the size of the
resulting particles was then measured. The measurements were
repeated after 3 and 5 h under the similar conditions in order to
assess the kinetic stability of systems. Electronic absorption spec-
tra were recorded on a Shimadzu UV-3600 spectrometer, the
thickness of transmission layer was 1 cm. The purity of compounds
was monitored by 1H NMR spectroscopy. The purity of compounds
was additionally controlled by TLC on Silica 200 m, UV 254
plates (Sorbtech); and spots of the substances were visualized
under UV light ( = 254 nm). Scanning electron microscopy
(SEM) was performed using a Carl Zeiss Auriga Cross Beam
microscope on a silicon support. The samples were diluted with
water to the final concentration of 1•10–4 g mL–1, poured onto
the silicon support, and dried in a vacuum desiccator for 1 h.
Elemental analysis of the crystalline samples was carried out on a
Perkin Elmer 2400 Series II analyzer. Melting points were deter-
mined on a Boetius heating stage. MALDI-TOF spectra were
recorded on an Ultraflex III mass spectrometer; p-nitroaniline was
used as the matrix.
1
DLS, UV spectroscopy, H and 13C NMR spectroscopy,
and 2D NMR spectroscopy data confirmed the association
of macrocycle 3 with polyvinyl(tetrazol-5-yl)ethyl ether
(PVTE). The association of macrocycle 3 with PVTE at the
molar ratio of 10 : 1 results in the formation of 3
(10–4 mol L–1)/PVTE (10–5 mol L–1) monodisperse nano-
sized particles, whose polydispersity index is 0.21. According
to the SEM data, 3/PVTE associates possess a spherical
shape and an average hydrodynamic diameter of 117 nm.
It was shown using 2D NOESY and DOSY NMR spectros-
copy that pillar[5]arene 3 host-guest complexes with tetr-
azole moieties of PVTE were formed. Supramolecular
self-assembly of nanoscale PVT and PVTE associates with
uncharged water-soluble derivatives of pillar[5]arene bear-
ing 2-amidoethanol and 3-amidopropanol moieties provides
additional opportunities to employ high molecular weight
derivatives of tetrazoles and their supramolecular associates
of the given morphology in the personalized medicine and
high-tech health care for the design of new targeted thera-
peutic agents.
Compounds 1, 2, and 6 were synthesized according to the
known procedures.20,21 Poly-5-vinyltetrazole and
polyvinyl(tetrazol-5-yl)ethyl ether were obtained according to
the known procedures.24,25
Synthesis of macrocycles 3 and 4 (general procedure).
Compound 2 (0.3 g, 0.2 mmol) in methanol (30 mL) and 2-ami-
noethanol (or 3-aminopropanol) (6.1 mmol) were placed in a
round-bottomed flask equipped with a magnetic stirrer and a
reflux condenser. The mixture was refluxed for 72 h, and the
solvent was evaporated under a reduced pressure. The residue
was dissolved in dichloromethane (20 mL) and washed with
distilled water (2×30 mL). The organic layer was separated, dried
over anhydrous Na2SO4, and the solvent was evaporated under
a reduced pressure. The products were isolated by recrystalliza-
tion from propan-2-ol as light yellow powders.
Experimental
1H and 13C NMR spectra were recorded on a Bruker Avance
400 spectrometer (operating frequencies of 400.0 and 100.0 MHz,
respectively). Chemical shifts in the 13C NMR spectra are re-
ported relative to the Me4Si standard, and chemical shifts in the
1H NMR spectra are given relative to the residual proton signals
of deuterated solvent: HDO ( 4.79) and DMSO-d5 ( 2.50). The
concentration of analyzed solutions was 3—5 wt.%. Diffusion
ordered spectroscopy (DOSY) was performed in D2O using a
4,8,14,18,23,26,28,31,32,35-Deca[(N-2-hydroxyethyl)car-
bamoylmethoxy]pillar[5]arene (3). The yield was 0.29 g (89%),
m.p. 115 C. IR, ν/cm–1: 3289 (ОН), 3088 (N—H), 1682 (С=О),

104
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 1, January, 2020
Shurpik et al.
1654 (C(O)—NH), 1251 (С—O—C). 1H NMR (DMSO-d6),
δ: 3.08—3.12 (m, 20 H, CH2); 3.33—3.37 (m, 20 H, CH2); 3.77
(s, 10 H, CH2); 4.37 (br.s, 20 H, CH2C(O)); 4.52—4.56 (m,
10 H, OH); 6.85 (s, 10 H, ArH); 7.76 (br.s, 10 H, NH). 13C NMR
(DMSO-d6), δ: 29.35, 41.51, 60.06, 68.17, 115.30, 128.46,
149.50, 168.61. MS (MALDI-TOF), m/z: 1644 [M + Na]+.
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Found (%): C, 54.86; H, 6.79; N, 7.94. C75H100N10O30
Calculated (%): C, 55.55; H, 6.22; N, 8.64.
.
4,8,14,18,23,26,28,31,32,35-Deca[(N-3-hydroxypropyl)-
carbamoylmethoxy]pillar[5]arene (4). The yield was 0.30 g (86%),
m.p. 118 C. IR, ν/cm–1: 3289 (O—H), 3088.64 (N—H), 1643
(С=О), 1640 (C(O)—NH), 1251 (С—O—C). 1H NMR
(DMSO-d6), δ: 1.32—1.36 (m, 20 H, H(6)); 3.04—3.28 (m,
20 H, H(5)); 3.30—3.39 (m, 20 H, H(7)); 3.76 (s, 10 H, H(2));
4.12—4.14 (m, 10 H, H(8)); 4.39 (АB system, 10 H, H(4),
2JH,H = 12.9 Hz); 4.40 (АB system, 10 H, H(4), 2JH,H = 12.9 Hz);
6.81 (s, 10 H, H(1), H(3)); 7.71 (br.s, 10 H, NH). 13C NMR
(DMSO-d6), δ: 28.89, 31.91, 35.94, 58.70, 67.70, 114.66, 127.91,
148.85, 168.18. MS (MALDI-TOF), m/z: 1784 [M + Na]+.
Found (%): C, 56.92; H, 6.58; N, 7.67. C85H120N10O30
Calculated (%): C, 57.94; H, 6.87; N, 7.95.
.
Synthesis of macrocycles 7 and 8 (general procedure).
Compound 6 (1g, 3.5 mmol) in methanol (20 mL) and 2-ami-
noethanol (or 3-aminopropanol) (2.1 mmol) ) were placed in a
round-bottomed flask equipped with a magnetic stirrer and a
reflux condenser. The mixture was refluxed for 72 h, and the
solvent was evaporated under a reduced pressure. The products
were isolated by recrystallization from a propan-2-ol—hexane
mixture (1 : 4) as white powders.
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1,4-Bis[(N-2-hydroxyethyl)carbamoylmethoxy]benzene (7).
The yield was 1.00 g (92%), m.p. 109 C. IR, ν/cm–1: 3337
(O—H), 1648 (С=О), 1657 (C(O)—NH), 1216 (С—О—C). 1H
NMR (DMSO-d6), δ: 3.13—3.23 (m, 4 H, CH2); 3.40—3.44 (m,
6 H, CH2); 4.39 (s, 4 H, CH2); 4.71—4.73 (m, 2 H, OH); 6.90
(s, 4 H, ArH); 7.98—7.99 (m, 2 H, NH). 13C NMR (DMSO-d6),
δ: 41.16, 59.66, 67.61, 115.70, 152.36, 167.96. MS (MALDI-
TOF), m/z: 335 [M + Na]+. Found (%): C, 52.67; H, 6.15;
N, 7.99. C14H20N2O6. Calculated (%): C, 53.84; H, 6.45; N, 8.97.
1,4-Bis[(N-(3-hydroxypropyl)carbamoylmethoxy]benzene
(8). The yield was 1.13 g (95%), m.p. 111 C. IR, ν/cm–1: 3360
(O—H), 1673 (С=О), 1661 (C(O)—NH), 1232 (С—О—C).
1H NMR (DMSO-d6), δ: 1.54—1.56 (m, 4 H, CH2); 3.17—3.19
(m, 4 H, CH2); 3.36—3.40 (m, 6 H, CH2); 4.39 (s, 4 H, CH2);
4.46—4.48 (m, 2 H, OH); 6.90 (s, 4 H, ArH); 8.04—8.06 (m,
2 H, NH). 13C NMR (DMSO-d6), δ: 32.28, 35.84, 58.62, 67.67,
115.69, 152.28, 167.75. MS (MALDI-TOF), m/z: 363 [M +
+ Na]+. Found (%): C, 55.83; H, 7.15; N, 8.02. C16H24N2O6.
Calculated (%): C, 56.46; H, 7.11; N, 8.23.
17. V. Smolko, D. Shurpik, A. Porfireva, G. Evtugyn, I. Stoikov,
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This work was financially supported by the Russian
Foundation for Basic Research (Projects Nos 18-03-00315,
18-33-01095, 18-33-00276, and 17-03-00858). The in-
vestigation of spatial structure of the compounds by NMR
spectroscopy was carried out within the framework of the
Program of the Government of the Russian Federation on
the competitive growth of the Kazan Federal University
among the leading academic centers in the world.
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References
Received July 17, 2019;
in revised form September 30, 2019;
accepted October 4, 2019
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