Synthesis and structures of malonate derivative-calix[4]arene conjugates

Article abstract of DOI:10.1016/j.cclet.2015.05.017

A series of malonate derivatives-calix[4]arene conjugates were synthesized through Knoevenagel condensation reaction between formyl-tetrapropoxycalix[4]arene and malonate derivatives. The structures of the resulting malonate derivative functionalized calix[4]arenes were characterized by NMR spectroscopy, mass spectrometry and even single crystal X-ray diffraction analysis.

Full text of DOI:10.1016/j.cclet.2015.05.017

Accepted Manuscript
Title: Synthesis and structures of malonate
derivative-calix[4]arene conjugates
Author: Wen-Jing Hu Ming-Liang Ma Yahu A. Liu Jiu-Sheng
Li Biao Jiang Ke Wen
PII:
S1001-8417(15)00208-9
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.cclet.2015.05.017
CCLET 3321
To appear in:
Chinese Chemical Letters
Received date:
Revised date:
Accepted date:
31-3-2015
17-4-2015
20-4-2015
Please cite this article as: W.-J. Hu, M.-L. Ma, Y.A. Liu, J.-S. Li, B. Jiang, K.
Wen, Synthesis and structures of malonate derivative-calix[4]arene conjugates, Chinese
Chemical Letters (2015), http://dx.doi.org/10.1016/j.cclet.2015.05.017
This is a PDF file of an unedited manuscript that has been accepted for publication.
As a service to our customers we are providing this early version of the manuscript.
The manuscript will undergo copyediting, typesetting, and review of the resulting proof
before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that
apply to the journal pertain.

Graphical Abstract
Synthesis and structures of malonate derivative-calix[4]arene conjugates
Wen-Jing Hu a, Ming-Liang Ma b,*, Yahu A. Liu c, Jiu-Sheng Li a,*, Biao Jiang a,*, Ke Wen a,b,d*
a Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201210, China
b Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, East China Normal
University, Shanghai 200062, China
c Medicinal Chemistry, ChemBridge Research Laboratories Inc., San Diego, CA 92127, USA
d School of Physical Science and Technology, ShanghaiTech University, Shanghai 201210, China
A series of novel malonate derivatives-calix[4]arene conjugates were synthesized through Knoevenagel condensation reaction, and the
structures of these functionalized calix[4]arenes have been determined.
Page 1 of 5

Original article
Synthesis and structures of malonate derivative-calix[4]arene conjugates
Wen-Jing Hu a, Ming-Liang Ma b,*, Yahu A. Liu c, Jiu-Sheng Li a, Biao Jiang a, Ke Wen a,b,d ∗
a Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201210, China
b Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, East China Normal University, Shanghai 200062, China
c Medicinal Chemistry, ChemBridge Research Laboratories Inc., San Diego, CA 92127, USA
d School of Physical Science and Technology, ShanghaiTech University, Shanghai 201210, China
ARTICLE INFO
ABSTRACT
A
series of malonate derivatives-calix[4]arene conjugates were synthesized through
Article history:
Knoevenagel condensation reaction between formyl-tetrapropoxycalix[4]arene and malonate
derivatives. The structures of the resulting malonate derivative functionalized calix[4]arenes
were characterized by NMR spectroscopy, mass spectrometry and even single crystal X-ray
diffraction analysis.
Received 31 March 2015
Received in revised form 17 April 2015
Accepted 20 April 2015
Available online
Keywords:
Calix[4]arene
Malonate derivatives
Knoevenagel condensation reaction
1. Introduction
Calix[n]arenes [1] are macrocyclic compounds with interesting conformational and cavity structures, and the easy functionalization
of the rims (both upper and lower rims) of calix[n]arene skeletons makes them ideal candidates for many potential applications in
supramolecular chemistry, such as host-guest chemistry [2], molecular encapsulation [3], and as scaffolds for the construction of
multivalent ligands [4]. Calix[4]arene, the smallest member of the calix[n]arene family, can possess four different conformations and
each of the four conformational structures can be geometrically locked. Thus, the spatial arrangement of the functional groups attached
on the rims of calix[4]arenes could be controlled. The introduction of new functional groups into the calix[n]arene skeleton would
certainly diversify its structural and functional properties and broaden its applications in the area of supramolecular chemistry.
Malonate is a naturally occurring substance possessing two carboxylate functions, and was used as a competitive inhibitor of the
enzyme succinate dehydrogenase [5]. We envisioned that introduction of malonate derivatives to the calix[4]arene backbone would
afford new calix[4]arene structures with malonate derivative-based interactive sites, and these malonate derivatives might be
chemically transformed to variety of other functional groups, such as amino, amide, carboxyl and hydroxyl groups. These functional
groups would broaden the application of calix[4]arene in the areas of molecular recognition and host-guest chemistry, or even find
their practical use in biological and environmental fields [5,6]. However, research work toward these goals was almost absent in
literature report [7]. Herein, we report the synthesis and structure characterization of six calix[4]arenes with their upper rims being
functionalized by different number of malonate derivatives.
2. Experimental
Commercially available chemicals were used without further purification unless stated otherwise; compounds 1 and 2 were
1
synthesized according to literatures [8-10]. H NMR and 13C NMR spectra were recorded on a Varian Mercury 500 spectrometer in
CDCl3 with TMS as the reference. Mass spectra were recorded on a microTOF QII mass spectrometer (Bruker Daltonics, Germany).
Single crystal X-ray diffraction data were collected on a Bruker SMART APEX 2 X-ray diffractometer equipped with a normal focus
Mo-target X-ray tube (λ = 0.71073 Å) and data reduction included absorption corrections by the multi-scan method. The structures
were solved by direct methods and refined by full-matrix least-squares using SHELXS-97.
2.1. Synthesis of symmetric substituted calix[4]arenes 3a-c
———
∗Corresponding authors.
E-mail addresses: wenk@sari.ac.cn (K. Wen), mlma@brain.ecnu.edu.cn (M.-L. Ma)
Page 2 of 5

To a round bottom flask containing a methanol solution (20 mL) of tetra-formyltetrapropoxycalix[4]arene 1 (70 mg, 0.1 mmol) and
malononitrile (29 mg, 0.44 mmol) was added 0.05 mmol of piperidine and the mixture was heated to 50 °C. The formation of the
product (3a) was monitored by TLC and the reaction was completed within 8 h. The crude mixture was concentrated under reduced
pressure and the product was collected by a vacuum filtration. Alternatively, the product was purified via flash chromatography.
Compounds 3b and 3c were synthesized in the similar procedure.
1
Compound 3a: White solid (50 mg, yield: 55.7%). H NMR (500 MHz, CDCl3): δ 7.50 (s, 4H), 7.29 (s, 8H), 4.49 (d, 4H, J = 13.7
Hz), 3.97 (dd, 8H, J = 7.3, 7.6 Hz), 3.34 (d, 4H, J = 13.7 Hz), 1.94 (m, 8H), 1.04 (t, 12H, J = 7.5 Hz); 13C NMR (125 MHz, CDCl3,): δ
161.6, 158.8, 135.8, 131.7, 126.2, 113.6, 113.0, 80.6, 77.7, 30.7, 23.4, 10.2; HR-MS (ESI): m/z calcd. [M+Na+] for C56H48N8O4Na+:
919.3691; Found: 919.3674. Crystallographic data: [C56H48N8O4]; T = 173(2) K; Mr = 897.02; Monoclinic; space group P2(1)/n; a =
18.0374(6) Å; b = 14.0132(5) Å; c = 19.3730(7) Å; a = γ = 90°; β = 90°; V = 4892.5(3) Å3; Z = 4; ρcalcd = 1.218 g/cm3; crystal size =
0.34×0.27×0.20 mm; μ = 0.079 mm-1; reflections collected 56035; unique reflections 8624; data/restraints/ parameters 8624/1/613;
GOF on F2 1.018; Rint for independent data 0.0429; final R1 = 0.0584, wR2 = 0.1443; R indices (all data) R1 = 0.0824, wR2 = 0.1636;
largest diff. peak and hole: 0.705 and -0.556 e/Å-3.
Compound 3b: White solid (72 mg, yield: 62.0%). 1H NMR (500 MHz, CDCl3): δ 7.42 (s, 1H), 6.71 (s, 2H), 4.40 (d, 1H, J = 14.0
Hz), 3.85 (d, 2H, J = 8.0 Hz), 3.84 (s, 3H), 3.79 (s, 3H), 3.12 (d, 1H, J = 14.0 Hz), 1.86 (m, 2H), 0.97 (t, 3H, J = 7.5 Hz); 13C NMR
(125 MHz, CDCl3): δ 167.4, 164.5, 159.1, 142.1, 135.2, 130.2, 126.9, 123.1, 52.6, 52.4, 31.0, 23.2, 10.2; HR-MS (ESI): m/z calcd.
[M+Na+] for C64H72O20Na+: 1183.4508; Found: 1183.4482.
1
Compound 3c: White solid (70 mg, yield: 68.3%). H NMR (500 MHz, CDCl3): δ 7.90 (s, 4H), 7.36 (s, 8H), 4.47 (d, J = 13.8 Hz,
4H), 3.94 (dd, J1 = 7.3 Hz, J2 = 7.4 Hz, 8H), 3.87 (s, 12H), 3.32 (d, J = 13.6 Hz, 4H), 1.91 (m, 8H), 1.02 (t, J = 7.4 Hz, 12H); 13C NMR
(CDCl3, 125 MHz, ppm): δ 163.2, 160.8, 154.4, 135.6, 132.1, 126.5, 115.8, 100.4, 77.3, 53.0, 30.8, 23.4, 10.2; HR-MS (ESI): m/z calcd
[M+H+] for C60H61N4O12: 1029.4286; Found: 1029.4468.
2.2. Synthesis of asymmetric substituted calix[4]arene 4a-c
To a round bottom flask containing a methanol solution (20 mL) of tri-formyl-tetrapropoxycalix[4]arene 2 (810 mg, 1.2 mmol) and
malononitrile (262 mg, 3.96 mmol) was added 0.4 mmol of piperidine and the mixture was heated to 50 °C. The formation of the
product (4a) was monitored by TLC and the reaction was completed within 8 h. The crude mixture was concentrated under reduced
pressure and the product was collected by a vacuum filtration. Alternatively, the product was purified via flash chromatography.
Compounds 4b and 4c were obtained similarly.
Compound 4a: White solid, yield: 60% (591 mg). 1H NMR (500 MHz, CDCl3): δ 7.60 (s, 2H), 7.54 (d, 2H, J = 1.8 Hz), 7.47 (d, 2H,
J = 1.7 Hz), 7.24 (s, 1H), 6.90 (s, 2H), 6.35 (m, 3H), 4.46 (dd, 4H, J = 13.9, 13.8 Hz), 4.10 (m, 2H), 3.99 (m, 2H), 3.87 (t, 2H, J = 7.1
Hz), 3.74 (t, 2H, J = 7.2 Hz), 3.29 (dd, 4H, J = 14.7, 14.4 Hz), 1.89 (m, 8H), 1.06 (m, 6H), 0.96 (t, 6H, J = 7.5 Hz); 13C NMR (125
MHz, CDCl3): δ 162.9, 161.4, 159.1, 158.8, 155.7, 137.7, 136.6, 135.4, 133.0, 132.7, 131.4, 131.2, 128.2, 126.0, 125.8, 122.5, 114.0,
113.1, 112.8, 80.1, 79.7, 77.6, 77.4, 77.2, 30.9, 30.8, 23.4, 23.3, 10.5, 10.4, 10.0; HR-MS (ESI): m/z calcd. [M+Na+] for
C52H48N6O4Na+: 843.3630; Found: 843.3692.
Compound 4b: White solid, yield: 72.5% (887 mg). 1H NMR (500 MHz, CDCl3): δ 7.52 (s, 2H), 7.32 (s, 1H), 6.86 (s, 2H), 6.82 (s,
2H), 6.64 (dd, 1H, J = 8.3, 11.7 Hz), 6.50 (s, 2H), 6.37 (d, 2H, J = 7.0 Hz), 4.39 (d, 4H, J = 13.7 Hz), 3.85 (m, 8H), 3.79 (m, 18H),
3.11 (t, 4H, J = 14.5 Hz), 1.85 (m, 8H), 1.00 (m, 6H), 0.93 (t, 6H, J = 7.4 Hz); 13C NMR (125 MHz, CDCl3): δ 167.6, 167.3, 164.9,
164.7, 159.8, 142.7, 142.6, 136.5, 135.6, 134.9, 133.8, 130.8, 130.3, 130.1, 128.1, 126.7, 126.6, 122.9, 122.5, 76.9, 76.8, 52.7, 52.6,
52.5, 52.4, 31.0, 23.3, 23.2, 10.4, 10.3, 10.1; HR-MS (ESI): m/z calcd. [M+Na+] for C58H66O16Na+: 1041.4243; Found: 1041.4262.
Compound 4c: White solid, yield: 68.3% (754 mg,). 1H NMR (500 MHz, CDCl3): δ 7.94 (s, 1H), 7.89 (s, 2H), 7.37 (s, 2H), 7.34 (s,
2H), 7.28 (s, 2H), 6.59 (d, 2H, J = 7.4 Hz), 6.52 (d, 1H, J = 7.7 Hz), 4.46 (dd, 4H, J = 13.8, 13.7 Hz), 3.92 (m, 14H), 3.83 (d, 3H, J =
7.6 Hz), 3.28 (dd, 4H, J = 13.8, 13.7 Hz), 1.91 (m, 8H), 1.01 (m, 12H); 13C NMR (125 MHz, CDCl3): δ 163.6, 163.4, 161.5, 161.0,
156.1, 155.1, 154.7, 136.7, 135.7, 134.0, 132.4, 132.2, 131.7, 128.6, 126.4, 126.0, 122.7, 115.9, 99.8, 77.2, 76.9, 53.2, 53.1, 30.9, 30.8,
23.4, 23.4, 10.3, 10.2; HR-MS (ESI): m/z calcd. [M+Cl-] for C55H57N3O10Cl-: 954.3727; Found: 954.3582.
3. Results and discussion
As shown in Scheme 1, tetra-formyltetrapropoxycalix[4]arene (1) and tri-formyltetrapropoxycalix[4]arene (2) were obtained
according to literature procedures [8-10]. The malonate derivatives-calix[4]arene conjugates (3a-3c and 4a-4c) were synthesized
through Knoevenagel condensation reaction between formyl-tetrapropoxycalix[4]arenes (1 and 2) and malonate derivatives in the
presence of piperidine in methanol at 50 °C in 8h (Scheme 2). Symmetrically substituted calix[4]arenes 3a-3c were obtained in the
yields of 55.7%, 62% and 68.3%, respectively. While asymmetrically substituted calix[4]arenes 4a-4c were obtained in the yields of
60%, 72.5% and 68.3%, respectively.
Page 3 of 5

Br
Br
Br
Br
i
PrO
OPr
OPr
OPr
PrO
OPr
OPr
OPr
ii, iii
O
ii,iv
O
O
O
O
O
O
PrO
OPr
OPr
OPr
PrO
OPr
OPr
OPr
1
2
Scheme 1. Synthesis of compound 1 and 2. Conditions: (i) NBS, acetone, r.t.; (ii) n-BuLi, THF, -78 °C; (iii) excessive dry DMF, HCl; (iv) 3eq. dry DMF, HCl.
R2
R1
R1
R2
O
O
R1
R2
O
O
R2
R1
i
R2
R1
PrO
OPr
OPr
OPr
PrO
OPr
OPr
OPr
1
3a, 3b, 3c
R2
R1
R1
R2
O
O
R1
O
R2
i
R1
R2
PrO
OPr
OPr
OPr
PrO
OPr
OPr
OPr
2
3a, 4a: R1 = R2 = CN
3b, 4b: R1 = R2 = COOMe
3c, 4c: R1 =CN, R2 = COOMe
4a, 4b, 4c
Scheme 2. Synthesis of symmetric and asymmetric substituted calix[4]arene 3a-3c and 4a-4c. Conditions: (i) piperidine, methanol, 50 °C.
The 1H NMR, 13C NMR and mass spectra of 3a-3c and 4a-4c are consistent with the assigned structures. In the 1H NMR spectrum of
symmetric 3a, aromatic hydrogens display two singlets at 7.48 and 7.29 ppm, and the bridging methylene protons split into doublets at
1
4.49 and 3.34 ppm. While the H NMR spectrum of asymmetric 4a is more complex than that of the symmetric 3a, the aromatic
hydrogens of asymmetric 4a exhibit several singlets, doublets and even multiplets, and the resonance of its bridging methylene protons
1
shows two triplets, as shown in Fig. 1. Similar phenomenon in the H NMR spectra of 3b-3c, as well as 4b-4c was observed (see
Supporting information).
8
7
6
5
4
3
2
1
8
7
6
5
4
3
2
1
Fig. 1. 1H NMR of compound 3a and 4a.
The structure of 3a was unambiguously established by single crystal X-ray diffraction analysis. Single crystals of 3a have been
obtained in mixed solvent of ethyl acetate and petroleum ether. As shown in Fig. 2, calix[4]arene 3a adopts a typical, pinched cone
°
conformation with dihedral angles between the opposing phenoxy rings of 16.4 ° and 86.6 , respectively, and the centroid-to-centroid
distances between the two pairs of opposing phenyl planes are 4.876 Å and 7.555 Å, respectively. The cyano groups in each
malononitrile function are conjugated to the connected benzene ring and only slightly twisted away from the phenyl planes. The
Page 4 of 5

distances between the central carbon atoms of the two pairs of face-to face oriented malononitrile functions are 3.858 Å and 12.911 Å,
respectively. No guest molecule was found being included in the narrow void space.
Fig. 2. X-ray crystal structures of 3a: top view (i), side view (ii). Color code: N (blue), O (red), C (gray).
4. Conclusion
In summary, series of malonate derivatives functionalized calix[4]arenes were synthesized by Knoevenagel condensation of formyl-
tetrapropoxycalix[4]arene with corresponding malonate derivatives (malononitrile, methyl 2-cyanoacetate and dimethyl malonate) in
good yields. Single crystal X-ray study of malononitrile derived calix[4]arene revealed a pinched cone conformational structure. No
guest molecules were found to be included in its narrow cavity. The cyano and ester groups in these calix[4]arene structures might be
further transformed to other functional groups, such as amino, amide, carboxyl and hydroxyl groups, which could diversify the
structures and functions of the calix[4]arene analogous for potential use in molecular recognition and other related research fields.
Research works in these directions are ongoing in our laboratory.
Acknowledgment
Financial support from the National Natural Science Foundation of China (No. 21371177) is acknowledged.
References
[1] a) C.D. Gutsche, Calixarenes, An Introduction; Royal Society of Chemistry: Cambridge, U.K. 2008;
b) Z.Q. Shi, Y.Q. Feng, S.X. Meng, Novel synthesis of N-substituted-calix[4]azacrown derivatives, Chin. Chem. Lett. 21(2010) 807-809;
c) Y. Zhou, H. Li, Y.W. Yang, Controlled drug delivery systems based on calixarenes, Chin. Chem. Lett. 2015, DOI: 10.1016/j.cclet.2015.01.038;
d) H. Li, L.L. Tan, P. Jia, et al., Near-infrared light-responsive supramolecular nanovalve based on mesoporous silica-coated gold nanorods, Chem. Sci. 5
(2014) 2804-2808;
e) Y. Zhou, L.L. Tan, Q.L. Li, et al., Acetylcholine-triggered cargo release from supramolecular nanovalves based on different macrocyclic receptors, Chem.
Eur. J. 20 (2014) 2998-3004.
[2] a) Y. Sun, F. Zhang, L. Zhang, et al., Synthesis of calix[4]arene derivatives via a Pd-catalyzed Sonogashira reaction and their recognition properties towards
phenols, Chin. Chem. Lett. 25 (2014) 226-228;
b) H.H. Zhou, X.M. Shang, Z. Luo, et al., A new member of the calix[4]crown family: facile synthesis and characterization of a calix[4]crown-9 cone
conformer, Chin. Chem. Lett. 20 (2009) 143-146;
c) H.F. Wang, Y.B. Zhang, F.J. Huo, C.X. Yin, J.B. Chao, The investigation of inclusion behavior of solvent violet 9 with 4-sulfonatocalix[n]arenes and its
recognition to DNA, Chin. J. Chem. 20 (2002) 322-326.
[3] a) R. Joseph, C.P. Rao, Ion and molecular recognition by lower rim 1,3-di-conjugates of calix[4]arene as receptors, Chem. Rev. 111 (2011) 4658-4702;
b) E.V. Ukhatskaya, S.V. Kurkov, S.E. Matthews, Encapsulation of drug molecules into calix[n]arene nanobaskets, role of aminocalix[n]arenes in
biopharmaceutical field, J. Pharm. Sci. 102 (2013) 3485-3512;
c) F. Corbellini, R. Fiammengo, P. Timmerman, et al., Guest encapsulation and self-assembly of molecular capsules in polar solvents via multiple ionic
interactions, J. Am. Chem. Soc. 124 (2002) 6569-6575.
[4] a) H.Y. Guo, F.F. Yang, Z.Y. Jiao, J.R. Lin, Click synthesis and dye extraction properties of novel thiacalix[4]arene derivatives with triazolyl and hydrogen
bonding groups, Chin. Chem. Lett. 24 (2013) 450-452;
b) L. Baldini, A. Casnati, F. Sansonea, R. Ungaro, Calixarene-based multivalent ligands, Chem. Soc. Rev. 36 (2007) 254-266;
c) M.G.J. ten Cate, D.N. Reinhoudt, M. Crego-Calama, Binding of small guest molecules to multivalent receptors, J. Org. Chem. 70 (2005) 8443-8453.
[5] a) D.V. Dervartanian, C. Veeger, Studies on succinate dehydrogenase. I. spectral properties of the purified enzyme and formation of enzyme-competitive
inhibitor complexes, Biochim. Biophys. Acta. 92 (1964) 233-247;
b) G.D. Zeevalk, E. DerrYellin, W.J. Nicklas, Relative vulnerability of dopamine and GABA neurons in mesencephalic culture to inhibition of succinate
dehydrogenase by malonate and 3-nitropropionic acid and protection by NMDA receptor blockade, J. Pharmacol. Exp. Ther. 275 (1995) 1124-1130;
c) J.G. Greene, J.T. Greenamyre, Characterization of the excitotoxic potential of the reversible succinate dehydrogenase inhibitor malonate, J. Neurochem. 64
(1995) 430-436.
[6] S.Y. Li, Y.W. Xu, S.Q. Zeng, et al., Highly selective fluorescent calix[4]arene chemosensor for acidic amino acids in pure aqueous media, Tetrahedron Lett.
53 (2012) 2918-2921.
[7] a) S.T. Zhang, K. Cheng, X.H. Wang, H. Yin, Selection, synthesis and anti-inflammatory evaluation of the arylidene malonate derivatives as TLR4 signaling
inhibitors, Bioorgan. Med. Chem. 20 (2012) 6073-6079;
b) A. Kaya, H.K. Alpoguz, A. Yilmaz, Application of Cr(VI) transport through the polymer inclusion membrane with a new synthesized calix[4]arene
derivative, Ind. Eng. Chem. Res. 52 (2013) 5428-5436;
c) A. Dondoni, A. Marra, Calixarene and calixresorcarene glycosides: their synthesis and biological applications, Chem. Rev. 110 (2010) 4949-4977.
[8] C.D. Gutsche, M. Iqbal, p-tert-Butylcalix[4]arene, Org. Synth. 68 (1990) 234.
[9] C.D. Gutsche, J.A. Levine, Calixarenes. 6. Synthesis of a functionalizable calix[4]arene in a conformationally rigid cone conformation, J. Am. Chem. Soc.
104 (1982) 2652-2653.
[10] M.S. Wong, Z.H. Li, C.C. Kwok, Highly extended styrylstyrylcalix[4]arene assemblies: synthesis and optical properties, Tetrahedron Lett. 41 (2000) 5719-
5723.
Page 5 of 5