Design and synthesis of ninhydrin-based cyclophanes as potential neutral receptors for quaternary ammonium cations

Article abstract of DOI:10.1016/j.tetlet.2004.08.078

Four ninhydrin-based cyclophanes 4a, 4b, 6a, and 6b were designed and synthesized. Two rectangular type cyclophanes (4a and 4b) and two square type cyclophanes (6a and 6b) were prepared in 8-43% yields.

Full text of DOI:10.1016/j.tetlet.2004.08.078

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7435–7440
Design and synthesis of ninhydrin-based cyclophanes as
potential neutral receptors for quaternary ammonium cations
Jeong Eun Na,a Shim Sung Leeb and Jae Nyoung Kima,*
aDepartment of Chemistry and Institute of Basic Sciences, Chonnam National University, Kwangju 500-757, South Korea
bDepartment of Chemistry and Research Institute of Natural Sciences, Gyeongsang National University, Jinju 660-701, South Korea
Received 27 May 2004; revised 5 July 2004; accepted 13 August 2004
Abstract—Four ninhydrin-based cyclophanes 4a, 4b, 6a, and 6b were designed and synthesized. Two rectangular type cyclophanes
(4a and 4b) and two square type cyclophanes (6a and 6b) were prepared in 8–43% yields.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Due to the well-known coordinative ability of oxygen
atoms of ether, polyether chains are the fundamental
constituents of many classes of cyclic and acyclic recep-
tors that are well established ligands for metal and
ammonium cations.1 However, the contribution of the
polyether chains for the binding of quaternary ammo-
nium cations is not an important factor.2 A more impor-
tant contribution for the binding of quaternary
ammonium cations is believed to arise from the attrac-
tion between the positive charge of the guest and the
electron rich faces of the aromatic rings (cation-p
interaction).3
Although the complexation of quaternary ammonium
cations by negatively charged cyclophanes in aqueous
phase has been extensively studied,4 the binding of qua-
ternary ammonium cations by neutral cyclophane hosts
in non-aqueous solution is less common.5,6 Thus, the
design and synthesis of neutral hosts for the binding of
quaternary ammonium cations in organic media is a
CH3
CH3
CH3
H3C
H3C
O(CH2)5O
O
O
R
R
R
R
CH3
CH3
O(CH2)5O
CH3
D
O
O
O
O
O
H3C
H3C
A: R,R = (CH2)5
B: R = CH3
C: R = H
O
E
Figure 1.
Keywords: Cyclophanes; Ninhydrin; Receptors; Quaternary ammonium cations.
*
Corresponding author. Tel.: +82 62 530 3381; fax: +82 62 530 3389; e-mail: kimjn@chonnam.ac.kr
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.078

7436
J. E. Na et al. / Tetrahedron Letters 45 (2004) 7435–7440
OH
O
O
Cl
Cl
1:2a = 1:5
O
O
K2CO3 (3 equiv)
CH3CN, 50-60 oC, 24 h
O
OH
1
Cl
O
Cl
1:2a = 1:1
2a
3a (48%)
K2CO3 (4 equiv)
CH3CN (dilute condition)
reflux, 54 h
1 (1 equiv)
K2CO3 (4 equiv)
CH3CN (dilute condition)
reflux, 6 days
29%
12%
O
O
O
O
O
O
O
O
4a
Scheme 1.
1
1:2b = 1:5
O
Br
Br
K2CO3 (3 equiv)
O
+
CH3CN, 40-50 oC, 16 h
Br
Br
O
2b
O
1:2b = 1:1
K2CO3 (3 equiv)
CH3CN (dilute condition)
reflux, 2 days
5%
3b (45%)
1 (1 equiv)
K2CO3 (4 equiv)
CH3CN (dilute condition)
reflux, 90 h
43%
O
O
O
O
O
O
O
O
4b
Scheme 2.
very important target. Most of the reported neutral cyclo-
phanes have been synthesized from bisphenol deriva-
tives.6,7 Recently, Cort and Mandolini have reported
the synthesis and binding properties of novel cyclophane
A–C (Fig. 1).6a The most efficient cyclophane A for
the quaternary ammonium cations was prepared from

J. E. Na et al. / Tetrahedron Letters 45 (2004) 7435–7440
7437
Figure 2. ORTEP drawing of cyclophane 4b.
O
O
1 (5 equiv)
O
O
OH
OH
K2CO3 (2 equiv)
CH3CN, 70 oC, 55 h
O
O
O
O
3a
4a (13%)
+
O
O
O
O
5a (36%)
O
O
3a (1 equiv)
O
O
O
O
K2CO3 (4 equiv)
O
O
O
O
CH3CN (dilute condition)
reflux, 9 days
O
O
O
O
6a (8%)
Scheme 3.
1,3-bis(bromomethyl)benzene and 1,10-bis(hydroxyphenyl)-
cyclohexane in 10% yield. Bisphenol-based other cyclo-
phanes like as D and E have been synthesized.6b,c
dolini already described in their paper that the cycloph-
anes showed a substantial degree of conformational
looseness.6a Among the cyclophanes, the pentamethyl-
ene analog A is the least mobile than other analogs.
Thus, we intended to synthesize the analogs of A–C with
more rigid linker. 2,20-Bis(4-hydroxyphenyl)-1,3-indane-
dione (1) can act as the rigid linker.8 Moreover the
We think the moderate yields of products and less-effec-
tive binding properties of the cyclophanes A–E might
arise from the flexibility of the linkage. Cort and Man-

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J. E. Na et al. / Tetrahedron Letters 45 (2004) 7435–7440
oxygen atoms at the ninhydrin moiety could serve as
another strong complexation site.
similar yield (45%) after 16h at 40–50ꢁC. The reaction
of 3b and 1 (K2CO3, CH3CN, reflux, 90h) afforded the
final product 4b in 43% yield in dilute condition
(0.3mmol of 3b in 100mL of CH3CN). The cyclophane
4b can also be prepared directly in 5% yield from the
reaction of 1 and 2b in a dilute condition (Scheme 2).9
The starting material 1 was synthesized form ninhydrin
and phenol in the presence of H2SO4 in acetic acid in
76% yield.8 We prepared two cyclophanes 4a and 4b
starting from 1 and 4,40-bis(chloromethyl)-1,10-biphenyl
(2a) and a,a0-dibromo-p-xylene (2b) as shown in
Schemes 1 and 2. We used stepwise method5a initially
for the preparation of 4a and 4b. As expected, the cyclo-
phanes 4a and 4b were obtained in good yields presum-
ably due to the less mobile conformation of the
intermediates 3a and 3b, and the partner 1. We could
obtain the same compounds 4a and 4b directly although
in lower yields from the reaction of 1 and 2a or 2b.5a
1
The structures of 4a and 4b were confirmed by H, 13C
NMR, MALDI-TOF mass, and eventually by X-ray
structure analysis for 4b.10 The ORTEP drawing of 4b
is shown in Figure 2. As shown, two molecules of
CH2Cl2 were positioned inside and two outside of the
cyclophane. The inside CH2Cl2 guest was positioned in
a manner that the slightly acidic hydrogen atoms of
CH2Cl2 directing the benzene ring of phenol moiety pre-
sumably by the weak cation-p interaction.3,6d,e Maybe
this is the reason why the growing of crystal of 4b was
successful in a mixed solvent of Et2O and CH2Cl2.6d,e
The synthesis of rectangular type cyclophanes 4a and 4b
is straightforward (Schemes 1 and 2). The reaction of 1
and 2a (1:5 ratio) in the presence of K2CO3 in CH3CN
gave the intermediate 3a in 48% yield after 24h at 50–
60ꢁC. The reaction of 3a and 1 (K2CO3, CH3CN, reflux,
6days) afforded the final product 4a in 29% yield in
dilute condition (0.3mmol of 3a in 100mL of CH3CN).
The cyclophane 4a can also be prepared directly in 12%
yield from the reaction of 1 and 2a in a dilute condition.
Similarly, the reaction of 1 and 2b (1:5 ratio) in the pres-
ence of K2CO3 in CH3CN gave the intermediate 3b in a
As a next trial we started the preparation of square type
cyclophanes such as 6a and 6b. The synthesis of these
compounds is depicted in Schemes 3 and 4, respectively.
The reaction of 3a and 1 (1:5 ratio) in CH3CN (70ꢁC,
55h) gave 4a (13%) and desired intermediate 5a in mod-
erate yield (36%). The reaction of 5a and 3a under dilute
conditions afforded 6a in 8% isolated yield. Similarly,
the reaction of 3b and 1 (1:5 ratio) in CH3CN (70ꢁC,
O
O
1 (5 equiv)
K2CO3 (2 equiv)
CH3CN, 70 oC, 27 h
3b
O
O
OH
OH
+
4b (7%)
O
O
O
O
5b (32%)
O
O
O
O
O
O
O
O
3b (1 equiv)
K2CO3 (4 equiv)
O
O
O
O
CH3CN (dilute condition)
reflux, 9 days
O
O
O
O
O
O
6b (15%)
Scheme 4.

J. E. Na et al. / Tetrahedron Letters 45 (2004) 7435–7440
7439
J. S.; Pawlak, K.; Bruening, R. L.; Tarbet, B. J. Chem.
Rev. 1992, 92, 1261; (k) Murakami, Y.; Kikuchi, J.-i.;
Hisaeda, Y.; Hayashida, O. Chem. Rev. 1996, 96, 721; (l)
Diederich, F.; Griebel, D. J. Am. Chem. Soc. 1984, 106,
8037.
27h) gave 4b (7%) and desired intermediate 5b in 32%
yield. The reaction of 5b and 3b under dilute conditions
afforded 6b in 15% isolated yield. The structures of 6a
1
and 6b were also confirmed by H, 13C NMR, MAL-
DI-TOF mass.11 Unfortunately, our attempts to grow
single crystals of 6a and 6b failed at this stage presum-
ably due to their conformational flexibility.
5. For the synthesis and binding properties of water-insol-
uble cyclophanes, see: (a) Saigo, K.; Lin, R.-J.; Kubo, M.;
Youda, A.; Hasegawa, M. J. Am. Chem. Soc. 1986, 108,
1996; (b) Masci, B. Tetrahedron 1995, 51, 5459; (c)
Casnati, A.; Jacopozzi, P.; Pochini, A.; Ugozzoli, F.;
Cacciapaglia, R.; Mandolini, L.; Ungaro, R. Tetrahedron
1995, 51, 591; (d) Colquhoun, H. M.; Williams, D. J.; Zhu,
Z. J. Am. Chem. Soc. 2002, 124, 13346.
We expected that the cyclophanes 4a, 4b, 6a, and 6b
could recognize the quaternary ammonium cations by
the cation-p interaction6a,7a,d as well as some non-polar
compounds such as biphenyl or naphthalene with the
aid of p–p interaction.4l,6b,c However, unfortunately,
we could not find any suitable guest until now. We
carried out NMR binding studies with some guest
molecules including N-methylpyridinium iodide, benzyl-
trimethylammonium bromide, p-cresol, biphenyl, naph-
thalene, anthracene, azobenzene. But, the expected
upfield shifts of guest molecules in NMR spectra were
negligible in all the cases, which suggested insufficient
inclusion into the host molecule.12 Further studies on
the binding properties of the cyclophanes and growing
of the crystals are under progress.
6. For the synthesis and binding properties of cyclophanes
derived from bisphenols, see: (a) Cattani, A.; Cort, A. D.;
Mandolini, L. J. Org. Chem. 1995, 60, 8313; (b) Nissinen,
M.; Cort, A. D.; Amabile, S.; Mandolini, L.; Rissanen, K.
J. Inclusion Phenom. Mol. Recognit. Chem. 2001, 39, 229;
(c) Bartsch, R. A.; Kus, P.; Dalley, N. K.; Kou, X.
Tetrahedron Lett. 2002, 43, 5017; (d) Dalley, N. K.; Kou,
X.; Bartsch, R. A.; Czech, B. P.; Kus, P. J. Inclusion
Phenom. Mol. Recognit. Chem. 1997, 29, 323; (e) Ratila-
inen, J.; Airola, K.; Nieger, M.; Bohme, M.; Huuskonen,
J.; Rissanen, K. Chem. Eur. J. 1997, 3, 749; (f) Apel, S.;
Nitsche, S.; Beketov, K.; Seichter, W.; Seidel, J.;
Weber, E. J. Chem. Soc., Perkin Trans. 2 2001, 1212.
7. For the synthesis and binding properties of other types of
cyclophane, see: (a) Sarri, P.; Venturi, F.; Cuda, F.;
Roelens, S. J. Org. Chem. 2004, 69, 3654; (b) Lukyanenko,
N. G.; Kirichenko, T. I.; Lyapunov, A. Y.; Bogaschenko,
T. Y.; Pastushok, V. N.; Simonov, Y. A.; Fonari, M. S.;
Botoshansky, M. M. Tetrahedron Lett. 2003, 44, 7373; (c)
Kim, B. H.; Jeong, E. J.; Jung, W. H. J. Am. Chem. Soc.
1995, 117, 6390; (d) Bartoli, S.; Nicola, G. D.; Roelens, S.
J. Org. Chem. 2003, 68, 8149.
Acknowledgements
This work was supported by a Korea Research Founda-
tion Grant (KRF-2002-015-CP0215). We would like to
express our thanks to Dr. Sangku Lee (KRIBB, Taejon)
and Prof. CheHun Jung (Department of Chemistry,
CNU) for their helpful taking of MALDI-TOF mass
spectra.
8. Song, H. N.; Lee, H. J.; Kim, H. R.; Ryu, E. K.; Kim,
J. N. Synth. Commun. 1999, 29, 3303.
9. The synthesis of 4a and 4b follows the typical experimen-
tal procedures. The macrocyclization was conducted in
dilute condition (0.3mmol/100mL). After the reaction,
removal of CH3CN, usual aqueous workup with
CH2Cl2 followed by column chromatographic purification
process (CH2Cl2/hexanes, 1:17) we obtained the desired
products. Spectroscopic data of 4a and 4b are as
follows.
References and notes
1. Comprehensive Supramolecular Chemistry; Atwood, J. L.,
Davies, J. E. D., MacNicol, D. D., Vogtle, F., Eds.;
Pergamon: Oxford, 1996; Vol. 1.
2. Rudiger, V.; Schneider, H.-J.; SolovÕev, V. P.; Kaza-
chenko, V. P.; Raevsky, O. A. Eur. J. Org. Chem. 1999,
1847.
1
Compound 4a: 29%; H NMR (300MHz, CDCl3): d 5.11
3. For cation-p interactions, see: (a) Ma, J. C.; Dougherty,
D. A. Chem. Rev. 1997, 97, 1303; (b) Arnecke, R.;
Bohmer, V.; Cacciapaglia, R.; Cort, A. D.; Mandolini, L.
Tetrahedron 1997, 53, 4901; (c) Roelens, S.; Torriti, R. J.
Am. Chem. Soc. 1998, 120, 12443; (d) Dvornikovs, V.;
Smithrud, D. B. J. Org. Chem. 2002, 67, 2160.
(s, 8H), 6.80 (d, J = 9.0Hz, 8H), 7.11 (d, J = 9.0Hz, 8H),
7.38 (d, J = 8.1Hz, 8H), 7.52 (d, J = 8.1Hz, 8H), 7.87–7.90
(m, 4H), 8.06–8.08 (m, 4H); 13C NMR (75MHz, CDCl3):
d 65.83, 69.66, 109.73, 114.92, 115.32, 124.04, 127.30,
127.47, 127.96, 129.78, 129.96, 130.82, 136.11, 136.19,
140.27, 141.45, 157.84, 200.05; MALDI-TOF calcd for
C70H48O8+Na 1039.3247, found 1039.3324.
4. For the synthesis and binding properties of water-soluble
cyclophanes, see: (a) Inoue, M. B.; Velazquez, E. F.;
Inoue, M.; Fernando, Q. J. Chem. Soc., Perkin Trans. 2
1997, 2113; (b) Jorgensen, W. L.; Nguyen, T. B.; Sanford,
E. M.; Chao, I.; Houk, K. N.; Diederich, F. J. Am. Chem.
Soc. 1992, 114, 4003; (c) Garel, L.; Lozach, B.; Dutasta,
J.-P.; Collet, A. J. Am. Chem. Soc. 1993, 115, 11652; (d)
Kearney, P. C.; Mizoue, L. S.; Kumpf, R. A.; Forman, J.
E.; McCurdy, A.; Dougherty, D. A. J. Am. Chem. Soc.
1993, 115, 9907; (e) Cowart, M. D.; Sucholeiki, I.;
Bukownik, R. R.; Wilcox, C. S. J. Am. Chem. Soc. 1988,
110, 6204; (f) Mordasini Denti, T. Z.; van Gunsteren, W.
F.; Diederich, F. J. Am. Chem. Soc. 1996, 118, 6044; (g)
Miller, S. P.; Whitlock, H. W., Jr. J. Am. Chem. Soc. 1984,
106, 1492; (h) An, H.; Bradshaw, J. S.; Izatt, R. M. Chem.
Rev. 1992, 92, 543; (i) Izatt, R. M.; Pawlak, K.; Bradshaw,
J. S. Chem. Rev. 1995, 95, 2529; (j) Izatt, R. M.; Bradshaw,
1
Compound 4b: 43%; H NMR (300MHz, CDCl3): d 5.08
(s, 8H), 6.78 (d, J = 9.0Hz, 8H), 7.10 (d, J = 9.0Hz, 8H),
7.28 (s, 8H), 7.87–7.90 (m, 4H), 8.05–8.08 (m, 4H); 13C
NMR (75MHz, CDCl3): d 65.85, 69.56, 115.29, 124.03,
127.04, 129.79, 130.84, 136.08, 136.69, 141.47, 157.81,
200.03; MALDI-TOF calcd for C58H40O8+Na 887.2621,
found 887.2651.
10. Single crystals of 4b were obtained by crystallization of
pure 4b from the mixed solvent (ether and CH2Cl2)
according to the literature.6e Crystal data for 4b: empirical
formula C31H24Cl4O4, Fw = 602.30, crystal dimensions
0.30 · 0.20 · 0.20mm3, monoclinic, space group P 2(1)/n,
˚
˚
˚
a = 6.7567(4)(A), b = 11.0494(7)(A), c = 37.858(3)(A), a =
3
˚
90ꢁ, b = 90.660(2)ꢁ, c = 90ꢁ, V = 2826.2(3)(A) , Z = 4,
Dcalcd = 1.416mg/m3,
F000 = 1240,
MoKa
(k =
˚
0.71073(A)), R1 = 0.0899, wR2 = 0.2332 (I > 2r(I)).

7440
J. E. Na et al. / Tetrahedron Letters 45 (2004) 7435–7440
11. Spectroscopic data of square compounds is as follows.
Compound 6a: 8%; 1H NMR (300MHz, CDCl3): d 5.07 (s,
16H), 6.90 (d, J = 9.0Hz, 16H), 7.18 (d, J = 9.0Hz, 16H),
7.44 (d, J = 8.1Hz, 16H), 7.57 (d, J = 8.1Hz, 16H), 7.85–
7.91 (m, 8H), 8.03–8.08 (m, 8H); 13C NMR (75MHz,
CDCl3): d 66.24, 69.70, 114.99, 124.07, 127.33, 127.84,
129.93, 130.58, 136.00, 136.10, 140.48, 141.54, 158.21,
J = 9.0Hz, 16H), 7.16 (d, J = 9.0Hz, 16H), 7.37 (s, 16H),
7.85–7.89 (m, 8H), 8.04–8.08 (m, 8H); 13C NMR (75MHz,
CDCl3): d 66.23, 69.63, 114.95, 124.06, 127.57, 129.92,
130.56, 136.09, 136.65, 141.53, 158.15, 200.16; MALDI-
TOF calcd for
1751.5177.
C116H80O16+Na 1751.5344, found
12. As an example, the upfield shifts data (in parts per million)
of N-methylpyridinuim iodide with cyclophane 4b are as
follows (CDCl3, host:guest = 2.5:1): 0.018 (N-CH3), 0.032
(H-4), 0.084 (H-2).
200.18; MALDI-TOF calcd for
C140H96O16+Na
2055.6596, found 2055.6754. Compound 6b: 15%; 1H
NMR (300MHz, CDCl3): d 5.02 (s, 16H), 6.87 (d,