Synthesis of new chiral calix[4]arene thiourea derivatives for enantiomeric recognition of carboxylate anions

Article abstract of DOI:10.1007/s10847-015-0579-7

The study of enantiomeric recognition of amino acid and carboxylic acid compounds is of significance since these compounds are basic building blocks of biological molecules. Enantiomeric recognition and separation of these compounds are among the main top

Full text of DOI:10.1007/s10847-015-0579-7

J Incl Phenom Macrocycl Chem (2016) 84:35–41
DOI 10.1007/s10847-015-0579-7
ORIGINAL ARTICLE
Synthesis of new chiral calix[4]arene thiourea derivatives
for enantiomeric recognition of carboxylate anions
Selahattin Bozkurt1,2 Mustafa Burak Turkmen1 Cengiz Soykan3
•
•
Received: 18 September 2015 / Accepted: 3 November 2015 / Published online: 11 November 2015
Ó Springer Science+Business Media Dordrecht 2015
Abstract The study of enantiomeric recognition of amino
acid and carboxylic acid compounds is of significance
since these compounds are basic building blocks of bio-
logical molecules. Enantiomeric recognition and separation
of these compounds are among the main topics of
supramolecular chemistry since they are basic building
blocks of biological molecules and a number of them are
known to possess potent biological activities. In this study
the synthesis of novel chiral calix[4]arene thiourea
derivatives has been reported. The enantioselectivity of
chiral receptors was investigated by using UV–Vis spec-
troscopy. All the chiral calix[4]arene derivatives exhibited
certain chiral recognition towards the enantiomers of a-
hydroxy isovaleric acid (HIVA), mandelic acid (MA),
2-chloromandelic acid (2-ClMA) and N-Boc-alanine (N-
BocAl). The receptors with hydrogen bonding sites and
aromatic groups showed considerable higher stereoselec-
tivities. As a chiral receptor, calix[4]arene 2-hydroxy-1,2
diphenyl ether thiourea derivative has enantiomeric dis-
criminating ability for 2-chloromandelic acid (up to KR/
KS = 2.80) at 25 °C. The enantiomeric recognition abili-
ties for guests are also discussed from a thermodynamic
point of view.
Keywords Chiral calix[4]arene Á Enantiomeric
recognition Á Carboxylate anions Á Thiourea Á Hydrogen
bonding
Introduction
Calixarenes are cyclic oligomer based on a hydroxyl
alkylation product of phenols and aldehydes. Calixarenes
of varying cavity size can form variety of host–guest type
of inclusion complexes similar to cyclodextrins. However,
calixarene host molecules have unique compositions that
include benzene groups, which provide p–p interaction and
hydroxyl groups for hydrogen bonding [1]. Therefore,
calixarenes can be used as molecular recognition, [2–4] ion
sensitive sensors, [5, 6] in HPLC stationary phases, [7]
selective membranes, [8] enantiomeric recognition, [9–11]
and asymmetric synthesis [12].
One of the great problems faced by the pharmaceutical
industry involves the quantitation of undesirable enan-
tiomers in drug raw material. Quite often only one enan-
tiomer of a chiral compound is actually a bioactive
therapeutic. It is therefore essential that final product be
properly analyzed for enantiomeric purity [13]. Chirality is
a prominent feature of most biological systems. As a
consequence, metabolic and regulatory processes mediated
by biological systems are sensitive to stereochemistry.
Enantiomerically pure compounds such as amino acids,
carboxylic acids are particularly important synthons for the
preparation of pharmaceuticals because they are incorpo-
rated in a number of bioactive molecules. Therefore, a
better understanding of the interactions operating in chiral
recognition is helpful in developing new methods of
asymmetric synthesis, chromatographic resolution of
enantiomers, [14] new pharmaceutical agents [15, 16] and
& Selahattin Bozkurt
sbozkurt420@yahoo.com; selahattin.bozkurt@usak.edu.tr
1
Scientific Analysis Technological Application and Research
Center, Usak University, 64200 Usak, Turkey
2
Vocational School of Health Services, Usak University,
64200 Usak, Turkey
3
Department of Materials Science and Nanotechnology
Engineering, Usak University, 64200 Usak, Turkey
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J Incl Phenom Macrocycl Chem (2016) 84:35–41
separation materials [17]. Chiral receptors that are based on
the calixarene platform may have potential applications in
the preparation, separation, and analysis of enantiomers. In
this regard, investigations conducted on the synthesis and
chiral recognition properties of chiral calix[4]arene
derivatives have attracted considerable attention.
differential UV spectrometry in acetonitrile. The UV–Vis
spectra were measured at 20, 25, 30 and 35 °C with a ther-
mostated cell compartment by Perkin Elmer Lambda 35
spectrometer. The same concentrations of guest solution
were added to the sample cell and reference cell (light
path = 1 cm). The association constants were determined
at 247 nm. The concentration of the hosts is 1.33 9 10-4
mol dm-3 with the increasing concentration between 0.0 and
15.0 9 10-3 mol dm-3 of the added guest. All anions used
in this report were in the form of tetrabutylammonium salt.
Neutral receptors typically contain an N–H fragment
(such as amides) which acts as an H-bond donor. Espe-
cially, thiourea contains two rigidly positioned N–H frag-
ments suitable for the interaction with Y-shaped anions,
like carboxylates [17]. Many literatures [18–20] describe
the thiourea containing receptors form stable complexes
with various anions [21, 22]. Therefore; in the present
study, we report the synthesis of novel calix[4]arene
derivatives bearing a chiral thiourea moiety at the lower
rim and their recognition abilities for carboxylic acid by a
UV–Vis titration method in acetonitrile.
Tetrabutylammonium salts
The tetrabutylammonium salts were prepared by adding 1
equiv tetrabutylammonium hydroxide in methanol to a
solution of corresponding carboxylic acid (1 equiv) in
methanol [21]. The mixture was stirred at room tempera-
ture for 2 h and evaporated to dryness under reduced
pressure. The resulting syrup was dried at high vacuum for
24 h, stored in the desiccators.
Experimental
General
Syntheses
Melting points were measured on an Electro thermal 9100
apparatus and uncorrected. Elemental analyses for C, H
and N were carried out using a LECO-932 CHNS -O
Elemental Analyzer. 1H and 13C NMR spectra were
recorded at room temperature on a Varian 400 MHz
spectrometer in CDCl3. Infrared (IR) spectra were recorded
neat on a Perkin Elmer Spectrum Two FTIR-ATR spec-
trometer. Ultraviolet–Visible (UV–Vis) spectra were
measured with a Perkin Elmer Lambda 35 spectrometer.
Optical rotations were measured on an Atago AP-100
digital polarimeter.
General procedure for the synthesis of compounds 5 and 6
2.5 equiv. of amino alcohol derivatives ((1S,2R)-(-)-1-
Amino-2-indanol or (1S,2R)-(?)-2-Amino-1,2-dipheny-
lethanol) were added to a solution of 5,11,17,23-tetra-tert-
butyl-25,27-di(isothiocyanoopropoxy)-26,28-hydroxy calix
[4]arene (4) (87.5 mg, 0.10 mmol, 1.0 equiv.) in dry THF
(20 mL). The resulting mixture was stirred at room tem-
perature. After the completion of the reaction (TLC) the
solvent was removed under vacuum. The crude product
was purified by flash chromatography on silica gel (EtOAc/
n-hexane; from 1:5 to 1:1).
Analytical TLC was performed using Merck prepared
plates (silica gel 60 F254 on aluminum). Flash chro-
matography separations were performed on a Merck Silica
Gel 60 (230–400 Mesh). All reactions, unless otherwise
noted, were conducted under a nitrogen atmosphere. All
starting materials and reagents used were of standard
analytical grade from Fluka, Merck and Aldrich and used
without further purification. Toluene was distilled from
CaH2 and stored over sodium wire. Other commercial
grade solvents were distilled, and then stored over molec-
ular sieves. The drying agent employed was anhydrous
MgSO4. Analytical grade amino acid and carboxylic acids
were purchased from Aldrich and employed without further
purification as guest molecules.
5,11,17,23-tetra-tert-butyl-25,27-bis([(1S,2R)-2-
hydroxyindan-1-yl] thioureido propxy)-26,28-
hydroxycalix[4]arene (5)
The crude product was purified by flash chromatography on
silica gel to afford 5 as a white solid. Yield 72 %; white
crystal; Mp 148–151 °C; a2D5 = -18.56 (c 1.24, CHCl3).
1
IR (ATR): 1562 cm-1; H NMR (400 MHz,) d 7.85 (s,
2H), 7.60 (s, 2H), 7.28–7.16 (m, 4H), 7.13–6.97 (m, 4H),
6.94 (t, J = 1.9 Hz, 4H), 6.80 (t, J = 2.3 Hz, 4H), 5.79 (s,
2H), 4.68 (q, J = 5.9 Hz, 2H), 4.01 (d, J = 12.0 Hz, 3H),
3.97–3.85 (m, 3H), 3.69 (d, J = 13.2 Hz, 2H), 3.39 (s, 2H),
3.23 (d, J = 13.2 Hz, 2H), 3.13 (d, J = 13.2 Hz, 2H), 2.96
(dd, J = 16.2, 6.4 Hz, 2H), 2.48 (dd, J = 16.2, 5.3 Hz,
2H), 2.28 (q, J = 6.3 Hz, 4H), 1.75 (s, 3H), 1.26 (s, 18H),
0.98 (s, 18H); 13C NMR (100 MHz, CDCl3): d (ppm):
UV spectral measurement
The recognition abilities of chiral calix[4]arenes with
thiourea derivatives were determined on the basis of the
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J Incl Phenom Macrocycl Chem (2016) 84:35–41
37
UV spectral titrations
181.7, 151.4, 149.8, 149.5, 148.5, 139.5, 138.2, 132.2,
127.9, 127.7, 127.4, 126.1, 126.0, 125.3, 124.6, 74.7, 73.7,
61.9, 41.9, 40.3, 34.1, 33.9, 32.1, 31.4, 27.9; Anal. Calcd
for C70H88N4O6S2 (1145.60): C, 73.39 %; H, 7.74 %; N,
4.89 %; S, 5.60 %. Found: C, 73.41 %; H, 7.72 %; N,
4.91 %; S, 5.58 %.
Molecular recognition, and in particular chiral recognition,
is a fundamental characteristic in the biochemical systems.
The study of synthetic model systems could contribute to
the understanding of these processes and, at the same time,
offer new perspectives for the development of pharma-
ceuticals, enantioselective sensors, catalysts, and other
molecular devices [21]. To evaluate the binding abilities of
calix[4]arene receptors 5–6 towards different carboxylic
acids and N-protected amino acid (Fig. 1), we carried out
UV–Vis experiments.
5,11,17,23-tetra-tert-butyl-25,27-bis([(1S,2R)-2-hydroxy-
1,2-diphenylethyl] thioureido propxy)-26,28-
hydroxycalix[4]arene (6)
The crude product was purified by flash chromatography on
silica gel to afford 6 as a white solid. Yield 78 %; white
crystal; Mp 174–177 °C; a2D5 = -11.49 (c 0.86, CHCl3).
The binding constants (K) of inclusion complexes of
above-mentioned chiral calix[4]arene receptors with car-
boxylate were determined on the basis of the differential
UV spectrometry in acetonitrile. Acetonitrile was chose as
the solvent considering the solubility of anions. The
titration experiments showed that the absorption maxi-
mum of all hosts gradually decreased with the addition of
various concentrations of carboxylic acid derivatives
(Fig. 2).
1
IR (ATR): 1548 cm-1; H NMR (400 MHz,) d 8.12 (s,
2H), 7.38–6.78 (m, 29H), 5.88 (s, 2H), 5.36–5.01 (m, 2H),
4.02 (ddd, J = 61.7, 13.2, 8.9 Hz, 14H), 3.36 (dd,
J = 13.1, 7.9 Hz, 4H), 2.04 (s, 2H), 1.67 (s, 2H), 1.30 (s,
18H), 1.04 (s, 18H); 13C NMR (100 MHz, CDCl3): d
(ppm): 180.2, 150.7, 149.5, 149.4, 148.3, 143.4, 142.1,
132.4, 130.4, 129.5, 128.9, 127.9, 127.6, 127.4, 127.3,
126.0, 125.9, 76.9, 74.8, 64.9, 42.1, 34.3, 33.6, 32.1, 31.8,
27.6; Anal. Calcd for C80H96N4O6S2 (1273.77): C,
75.43 %; H, 7.60 %; N, 4.40 %; S, 5.03 %. Found: C,
75.45 %; H, 7.56 %; N, 4.38 %; S, 5.04 %.
With the assumption of a 1:1 stoichiometry, the com-
plexation of carboxylic acid derivatives (G) with chiral
calix[4]arene (H) is expressed by Eq. (1):
K
H þ G ꢀ HÁG
ð1Þ
Under the conditions employed, the concentration of
calix[4]arene derivatives (1.33 9 10-4 mol dm-3) is much
smaller than that of guest molecules, i.e. [H]0 ꢀ [G]0.
Therefore, the stability constant of the supramolecular
system formed can be calculated according to the modified
Hildebrand–Benesi equation [26], Eq. (2), where [G]0
denotes the total concentration of guest, [H]0 refers to the
total concentration of calix[4]arene derivative, De is the
difference between the molar extinction coefficient for the
free and complexed calix[4]arene derivative, DA denotes
the changes in the absorption of the modified calix[4]arene
on adding guest molecules.
Result and discussion
Design and synthesis of the new hosts
Calix[4]arene based chiral thiourea receptors 5 and 6 were
synthesized from known precursors 2, [23] 3, [24] and 4,
[25] respectively. Condensation of 2.5 equiv. (1S,2R)-(?)-
2-Amino-1,2-diphenylethanol or (1S,2R)-(-)-1-Amino-2-
indanol with 1.0 equiv. of p-tert-butylcalix[4]arene dipro-
poxy isothiocyanate 4 in dichloromethane gave thiourea 5
and 6 in 72 and 78 % yields, respectively (Scheme 1) The
structures of all the compounds 5 and 6 were confirmed
from their spectroscopic and analytical data. The IR spectra
of 5 and 6 showed characteristic C=S stretching bands at
1562 and 1548 cm-1, respectively. The conformational
characteristics of calix[4]arenes were conveniently esti-
mated by way of the splitting pattern of the ArCH2Ar
1=DA ¼ 1=KDe½HŠ ½GŠ0þ1=De½HŠ
ð2Þ
0
0
For all guest molecules examined, plots of calculated 1/
DA values as a function of 1/[G]0 values give good straight
lines, supporting the 1:1 complex formation. Typical plots
are shown for the complexation of compound 6 with R-2-
chloromandelic acid in Fig. 3.
methylene protons in the H and 13C NMR spectroscopy.
1
The free-energy change (DG) for inclusion complexes
formed by chiral calix[4]arene thiourea derivatives and
guest molecules is calculated from the equilibrium constant
K by Eq. (3) and is related to (Fig. 4)
1H and 13C NMR data showed that newly synthesized p-
tert-butylcalix[4]arene derivatives 5 and 6 are in a cone
conformation. The cone conformation of all compounds
were reflected in the characteristic AB system for the
methylene groups bridging the aromatic rings in the 1H and
13C NMR spectra. In addition, ArCH2Ar methylene groups
showed four doublets instead of two doublets.
DG ¼ ÀRT lnK
ð3Þ
the enthalpic and entropic changes (DH and DS) through
the Gibbs–Helmholtz Eq. (4). Combining Eqs. (3) and (4),
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Scheme 1 (i) K2CO3, N-(bromopropyl)phtalaimide, acetone, reflux; (ii) hydrazine hydrate, ethanol, reflux; (iii) BaCO3, Cl2CS, DCM, rt; (iv)
(1S,2R)-(?)-2-Amino-1,2-diphenylethanol or (1S,2R)-(-)-1-Amino-2-indanol, DCM
Fig. 1 Chemical structures of
chiral N-protected amino acid
and carboxylic acids
we obtain Eq. (5) which describes the temperature depen-
dence of K. Thus, plots of the ln K values, as a function of
the inverse of temperature gave good linear relationships
for working temperature range.
with an aromatic group attached to the nitrogen of the thiourea
units could have p–p interaction with that of 2-ClMA and MA
as an additional binding force. As a result, stronger binding
was realized in all cases.
UV–Vis spectroscopic studies indicate that chiral
selector 5 and 6 show strong binding and good recognition
ability for the enantiomers of 2-ClMA and MA.
DG ¼ DHÀTDS
lnK ¼ ÀDH=R T þ DS=R
ð4Þ
ð5Þ
Table 1 also shows the enantiomeric discrimination of
a pair of guest molecules, characterized by the value of
KD/KL, which are 1.11–2.80 or DDG0 of -0.26 to
-2.55 kJ mol-1 for chiral calix[4]arene receptors 5 and 6.
It was found that chiral host 6 gave stronger binding and
better recognition ability for carboxylic acids containing an
aromatic group than for those possessing an aliphatic
group. This is presumably due to multiple hydrogen
bonding and p–p stacking interaction between the receptor
The association constants (K), the free-energy change
(DDG0) calculated from the slope and the intercept, and the
thermodynamic parameters are summarized in Table 1,
along with the enantioselectivity KL/KD for the complex-
ation of D/L N-protected amino acid and R/S carboxylic
acids by these hosts 5 and 6.
From the data shown in Table 1, all hosts have greater
K values toward the enantiomers of 2-ClMA and MA than
HIVA. This may be due to the fact that the chiral calix[4]arene
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J Incl Phenom Macrocycl Chem (2016) 84:35–41
39
Fig. 2 UV–Vis spectra of 6
(1.33 9 10-4 mol dm-3) in the
presence of R-2-chloromandelic
acid (0.0–15.0 9 10-3 mol
dm-3) in acetonitrile solution
and the plot of ln K versus 1/T
for the host–guest complexation
Fig. 3 The plot of ln K versus 1/T for the host–guest complexation of
6 and R-2-chloromandelic acid
Fig. 4 Typical Benesi–Hildebrand plot of 1/DA versus 1/[G]0
and the aromatic side chain of carboxylic acid. Also, it is
important that thiourea contains two rigidly positioned N–
H fragments suitable for the interaction with carboxylates.
Mandelic acid and 2-chloromandelic acid have aromatic
group, which can bind a guest by hydrogen bonding and p–
p stacking interactions. Other guests are capable of com-
plexing aromatic hosts by hydrogen bonding interactions
only. The steric hindrance between the benzene ring and
aromatic moieties around the stereogenic centers of the
host may also play an important role in chiral recognition.
Therefore, the R or D-isomers of carboxylic acid form
more favourable complexes with the chiral selectors than
the S or L-isomers.
The complexation of chiral calix[4]arene thiourea
derivatives with carboxylic acids possibly occurs through
interaction of the hydrogen atom in the thiourea loop and
the oxygen atoms in the carboxylates. Noncovalent inter-
actions between the guests and hydrogen bonding sites
defined by phenolic oxygen contribute to the stabilization
of these complexes as well as p–p interactions
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Table 1 Binding constants (K), enantioselectivities (KL/KD) and thermodynamic parameters for the complexation of L/D-N-protected amino
acid and R/S carboxylic acid with the chiral receptors 5–6 in acetonitrile at 25 °C
Entry Host Guest
K (M-1
)
KL/KD –DG (kJ mol-1
)
–DDGa DH (kJ mol-1
)
DDHb DS (J mol-1
)
DDSc
1
5
5
5
5
5
5
5
5
6
6
6
6
6
6
6
6
R-2-ClMA
S-2-ClMA
R-HIVA
392.1 0.6
256.3 0.5
77.1 0.4
69.4 0.3
95.9 0.4
78.9 0.2
92.7 0.1
80.1 0.1
1.53
1.11
1.22
1.16
14.81 0.22
13.74 0.11
10.76 0.08
10.50 0.18
11.32 0.19
10.84 0.08
11.22 0.76
10.86 0.77
15.38 0.24
12.83 0.10
11.03 0.11
10.66 0.16
12.28 0.11
10.77 0.16
10.79 0.12
9.77 0.27
1.07
0.26
0.48
0.36
2.55
0.37
1.51
1.02
5.13 0.20
3.26 0.11
9.40 0.07
7.87 0.19
13.06 0.20
7.89 0.07
8.59 0.76
5.10 0.77
5.43 0.13
1.40 0.10
15.68 0.11
11.59 0.08
16.24 0.10
13.93 0.16
8.85 0.11
6.88 0.27
1.87
1.53
5.17
3.49
4.03
4.08
2.31
1.97
66.92 0.92
9.87
2
57.05 0.11
67.62 2.12
61.65 2.04
3
5.97
4
S-HIVA
5
(D)-MA
81.82 4.66 18.96
62.86 0.30
6
(L)-MA
7
(D)-N-Boc-Al
(L)-N-Boc-Al
R-2-ClMA
S-2-ClMA
R-HIVA
66.47 0.86 12.91
53.56 1.54
8
9
495.9 10.2 2.80
177.0 4.1
69.85 0.20 22.12
47.73 0.11
10
11
12
13
14
15
16
85.8 0.3
73.2 0.2
140.8 0.1
76.2 0.2
76.8 0.3
56.4 0.2
1.17
1.86
1.36
89.61 1.03
74.67 1.28
4.94
S-HIVA
(D)-MA
95.68 1.03 12.79
82.89 1.28
(L)-MA
(D)-N-Boc-Al
(L)-N-Boc-Al
65.92 1.21
56.56 5.65
9.36
2-ClMA 2-chloromandelic acid, MA mandelic acid, HIVA a-hydroxy isovaleric acid, N-Boc-Al N-Boc-Alanine
a
DDG = DGL - DGD
b
DDH = DHL - DHD
c
DDS = DSL - DSD
3. Bayrakci, M., Yigiter, S.: Synthesis of tetra-substituted calix[4]-
arene ionophores and their recognition studies towards toxic
arsenate anions. Tetrahedron 69, 3218–3224 (2013)
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8739–8745 (2012)
Conclusion
In conclusion, novel calix[4]arene thiourea compounds
were synthesized by the reaction of diisothiocyano
derivatives of p-tert-butylcalix[4]arene with chiral amino
alcohols. The enantioselective recognition of these recep-
tors has been studied by UV–Vis spectroscopy. Chiral
selectors 5 and 6 show strong binding and good recognition
ability for the enantiomers of 2-chloromandelic acid and
mandelic acid. The results indicate that the multiple
hydrogen bonding, steric hindrance, structural rigidity or
flexibility and p–p stacking between the aromatic groups
may be responsible for the enantiomeric recognition.
5. Chawla, H.M., Goel, P., Munjal, P.:
A new metallo-
supramolecular sensor for recognition of sulfide ions. Tetrahe-
dron Lett. 56, 682–685 (2015)
6. Marcos, P.M., Teixeira, F.A., Segurada, M.A.P., Ascenso, J.R.,
Bernardino, R.J., Brancatelli, G., Geremia, S.: Synthesis and
anion binding properties of new dihomooxacalix[4]arene diurea
and dithiourea receptors. Tetrahedron 70, 6497–6505 (2014)
7. Erdemir, S., Yilmaz, M.: Preparation and chromatographic per-
formance of calix[4]crown-5 macrocycle-bonding silica station-
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8. Adhikari, B.B., Fujii, A., Schramm, M.P.: Calixarene-madiated
liquid-membrane transport of choline conjegates. Eur. J. Org.
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Acknowledgments This work was supported by the Research
Foundation of Usak University (UBAP 2014/SB001). We also thank
Usak University Scientific Analysis Technological Application and
Research Center (UBATAM) for support of this work.
10. Bozkurt, S., Yilmaz, M., Sirit, A.: Chiral calix[4]arenes bearing
amino alcohol functionality as membrane carriers for transport of
chiral amino acid methylesters and mandelic acid. Chirality 24,
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