Synthesis and structural analysis of isomeric pyridinophanes and thiacyclophanes

Article abstract of DOI:10.1016/j.tetlet.2004.12.033

A one-pot synthesis of structurally isomeric tetrathiacyclophanes through four-centre coupling reactions of suitable bromides and thiols is reported. The structures of the isomers were confirmed by spectroscopy and XRD analysis. Single crystal X-ray analy

Full text of DOI:10.1016/j.tetlet.2004.12.033

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 995–999
Synthesis and structural analysis of isomeric pyridinophanes and
thiacyclophanes
Perumal Rajakumar,a,* Manickam Dhanasekaran,a Sivashanmugam Selvanayagam,b
Venkatachalam Rajakannan,b Devadasan Velmuruganb and Krishnan Ravikumarc
aDepartment of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600 025, India
bDepartment of Crystallography and Biophysics, University of Madras, Guindy Campus, Chennai 600 025, India
cLaboratory of X-ray Crystallography, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 4 October 2004; revised 29 November 2004; accepted 8 December 2004
Abstract—A one-pot synthesis of structurally isomeric tetrathiacyclophanes through four-centre coupling reactions of suitable bro-
mides and thiols is reported. The structures of the isomers were confirmed by spectroscopy and XRD analysis. Single crystal X-ray
analysis reveals interestingly shaped molecular structures with large cavities.
Ó 2004 Published by Elsevier Ltd.
Cyclophanes are macrocyclic compounds with bridged
aromatic units, which have been investigated since the
1950s because of the unique interactions of the p-elec-
tron systems of the benzene rings and for their potential
applications as molecular hosts.1 The synthesis and
design of cyclophanes and cage compounds with novel
shapes and geometries continues to be of interest.2 Var-
ious cyclophane architectures have been used in mole-
cular recognition, catalysis, liquid crystals and mimicry
of natural enzymes.3 Thiacyclophanes are an important
class in the cyclophane family as they can undergo inter-
esting functional group transformations4 and aromatic
ring-tilting and bridge flipping processes.5 Hart and
co-workers reported the synthesis of rigid cavity, non-
collapsible pyridinophanes6 and a one-pot synthesis of
a cyclophane with two conformers from a coupling reac-
tion of a tetrathiol and a tetrabromide.7 Recently,
Takemura et al. reported the synthesis of isomeric pyr-
idinophanes and the effect of topology (spatial arrange-
ment) of the isomeric pyridinophanes in complexation
behaviour.8 We wish to report herein the synthesis and
structural analysis of structurally isomeric pyridino-
phanes 1 and 2 and the cyclophanes 3 and 4 from a
one-pot reaction involving a four centre, two-fold cou-
pling of a suitable tetrathiol and a dibromide or a
four-centre, four-fold coupling of a suitable tetrathiol
and a tetrachloride (Fig. 1).
The synthetic pathway leading to the structurally iso-
meric pyridinophanes 1 and 2 is outlined in Scheme 1.
The reaction of o-xylenyl dibromide with 2.1 equiv of
ethyl 5-hydroxyisophthalate gave the tetra-ester 5a,
which was reduced using LAH in THF to afford the tet-
ra-alcohol 6a. Treatment of the tetra-alcohol 6a with
SOCl2 and pyridine in CH2Cl2 led to the tetrachloride
7a in excellent yield. The latter was smoothly converted
into the corresponding tetrathiol 8a.9 The reaction of one
equivalent of the tetrathiol 8a with 2.1 equiv of 2,6-
bis(bromomethyl)pyridine (9) in the presence of KOH
in benzene/ethanol (1:9) led to a mixture of the pyridino-
phanes 1 and 2. A careful column chromatographic sepa-
ration of the mixture on silica gel (ethyl acetate and
hexane 1:9) afforded the isomeric pyridinophanes 110
and 211 in 8% and 42% yields, respectively (Scheme 1).
The 1H NMR spectrum (Fig. 4) of pyridinophane 1
showed the S-methylene groups as two singlets at d
3.81 and 3.94 and the O-methylene protons as a singlet
at d 4.99. The pyridine protons appeared as a doublet at
d 6.85 for four protons and as a triplet at d 7.15 for two
protons. In the isophthalic moiety, the four protons
ortho to oxygen appeared as a singlet at d 6.54 and the
two protons para to oxygen appeared as a singlet at d
6.85. The o-xylenyl protons appeared as two doublet
Keywords: Isomeric cyclophanes; Pyridinophanes; One-pot; Four-
centre; Self-assembly.
*
Corresponding author. Tel.: +91 44 22351269213; fax: +91 44
22352494; e-mail: perumalrajakumar@hotmail.com
0040-4039/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.12.033

996
P. Rajakumar et al. / Tetrahedron Letters 46 (2005) 995–999
O
O
O
O
Ha
S
O
N
O
O
O
Ha
S
Hd
O
S
S
S
Hb
O
S
S
S
S
S
SS
Hb
N
S
S
S
S
Hc
O
O
N
N
Hc
Hd
2
1
He
Hf
4
3
Figure 1. The structures of the isomeric cyclophanes.
OH
O
O
i
+
Br
a = ortho
Br
EtO C
2
CO Et
2
E
E
E
E
5(a, b) E = CO Et
2
b = meta
ii
6(a, b) E = CH OH
2
vi
2
4
1
+
iii
from 8a
7(a, b) E = CH Cl
2
iv, v
8(a, b) E = CH SH
2
vii
from 8b
3
+
Scheme 1. Reagents and conditions: (i) K2CO3, DMF, N2, rt, 80%; (ii) LAH, THF, 60 °C, 78%; (iii) SOCl2, py, CH2Cl2, 90%; (iv) H2NCSNH2,
THF; (v) H2N(CH2)2NH2, dioxane, H2O, 65%; (vi) 2.1 equiv 2,6-bis(bromomethyl)pyridine (9), KOH, EtOH/benzene, 12h, (vii) 1 equiv 7a, KOH,
EtOH/benzene, 12h.
of doublets between d 7.38–7.47. The 13C NMR of 1
showed the S-methylene and O-methylene carbons at d
38.5 and 67.9 in addition to the aromatic carbons. The
1H NMR spectrum (Fig. 5) of pyridinophane 2 is differ-
ent from that of 1. The two protons of the S-methylene
groups are not equivalent and are more shielded than
the corresponding protons in pyridinophane 1. The S-
methylene protons exhibited geminal coupling and
appeared as two AB0qs at 3.52and 3.94 with J = 13.5
and 14.2Hz, respectively. This is due to the anisotropy
introduced by the molecular geometry. The O-methyl-
ene protons are slightly deshielded and appeared as a
singlet at d 5.06. Similarly, deshielding and shielding
effects were observed for the protons derived from the
isophthalic acid and pyridine moieties (Table 1). The
13C NMR of 2 showed the S -methylene and O-methyl-
ene carbons at d 35.0, 36.6 and 69.5, in addition to other
aromatic carbons. The ORTEP diagram of the bicyclic
Figure 2. ORTEP diagram of bicyclic pyridinophane 2.
pyridinophane 2 is shown in Figure 2.

P. Rajakumar et al. / Tetrahedron Letters 46 (2005) 995–999
997
Figure 3. (a) ORTEP diagram of cyclophane 4: A view of crystal packing in the cyclophane 4: (b) vertical arrangement (c) linear arrangement by
C–Hꢀ ꢀ ꢀS intermolecular hydrogen bond.
Figure 4. 1H NMR spectra of pyridinophanes 1 and 2.
The synthesis and NMR spectral features of pyridino-
phanes 1 and 2 prompted our attention to the synthesis
of the structurally isomeric cyclophanes 3 and 4 via a
fourfold coupling reaction. The desired tetrathiol 8b
was synthesized by bis-alkylation of m-xylenyl dibro-
mide with 2.1 equiv of ethyl 5-hydroxyisophthalate,
followed by conventional functional group trans-
formations as depicted in Scheme 1. Reaction of
tetrathiol 8b with tetrachloride 7a in the presence of
KOH in benzene/ethanol (1:9) afforded a mixture of
cyclophanes 312 and 4.13 The two isomeric cyclophanes
3 and 4 were separated by column chromatography on
silica gel (ethyl acetate and hexane 1:9) in 7% and 38%
yields (Scheme 1).
1
The H NMR spectrum (Fig. 4) of cyclophane 3 dis-
played S-methylene and O-methylene protons as singlets
at d 3.75, 3.78 and at 4.75, 4.84, respectively. The

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P. Rajakumar et al. / Tetrahedron Letters 46 (2005) 995–999
Figure 5. 1H NMR spectra of cyclophanes 3 and 4.
Table 1. Comparison of the 1H NMR spectra of the isomeric pyridinophanes 1 and 2
Entry
–S–CH2
–O–CH2
Isophthalic-H
Pyridine-H
Ha
Hb
Hc
Hd
1
2
3.81(s)
3.52(ABq)
3.94(s)
3.94(ABq)
4.99(s)
5.06(s)
6.54(s)
6.69(s)
7.26(s)
6.61(s)
6.85(d)
7.21(d)
7.15(t)
7.65(t)
Table 2. Comparison of the 1H NMR spectra of isomeric pyridinophanes 3 and 4
Entry
–S–CH2
–O–CH2
Isophthalic-H
m-Xylene-H
Hf
Ha and Hc
Hb and Hd
He
3
4
3.75(s)
3.27(s)
3.78(s)
3.36(s)
4.75(s)
4.99(s)
4.84(s)
5.03(s)
6.48(s)
6.49(s)
6.76(s)
6.77(s)
7.02(d)
7.13(t)
6.35(s)
6.40(s)
6.42(s)
6.63(s)
7.16(d)
7.31(t)
protons derived from the isophthalic moieties appeared
as singlets at d 6.48, 6.49, 6.76 and 6.77. A two proton
doublet and a one proton triplet were observed for the
m-xylene moiety at d 7.02and 7.13, respectively. In the
13C NMR of 3, the S-methylene and O-methylene
carbons appeared at d 38.5, 38.6, 67.9 and 69.9. In the
1H NMR spectrum of cyclophane 4 (Fig. 5), the S-meth-
ylene protons were shielded and appeared as singlets at
assembling view of tetrathiacyclophane 4 is shown in
Figure 3.
In conclusion, we have developed an efficient route to
synthesize structurally isomeric cyclophanes by one-
pot coupling reactions of appropriate chlorides and thi-
ols. The largest cyclophane system that we prepared also
proved to have the most interesting crystal structure,
self-assembling through C–H ꢀ ꢀ ꢀ S hydrogen bonds.
The synthesis and structural analysis of other isomeric
cyclophanes and self-assembling properties of such
cyclophanes are under way.
1
d 3.27 and 3.36, in contrast to the H NMR spectrum
of bicyclic pyridinophane 2. The anisotropy introduced
by the molecular geometry in 4 is lost due to the enlarge-
ment of the cavity size and the S-methylene protons
become indistinguishable. The O-methylene protons of
4 are deshielded and appeared as singlets at d 4.99
and 5.03. However, all the protons of the isophthalic
moiety in 4 are shielded compared to those of 3 and ap-
peared as singlets at d 6.35, 6.40, 6.42and 6.63. Similar
shielding and deshielding effects were observed for the
m-xylene protons (Table 2). Due to the poor solubility
of cyclophane 4 in organic solvents, the 13C NMR
could not be recorded. The ORTEP diagram and self-
Crystallographic data for the structures (pyridinophane
2 and cyclophane 4) in this paper have been deposited
with the Cambridge Crystallographic Data Centre as
supplemental publications CCDC 258295 and 258296.
Copies of the data can be obtained, free of charge, on
application to CCDC, 12Union Road, Cambridge
CB2 1EZ, UK (fax: +44 0 1223 336033 or e-mail:
deposit@ccdc.cam.ac.uk).

P. Rajakumar et al. / Tetrahedron Letters 46 (2005) 995–999
999
9. Kannan, A.; Rajakumar, P.; Kabaleeswaran, V.; Rajan, S.
S. J. Org. Chem. 1996, 61, 5090.
Acknowledgements
10. Yield 8%; dec >300 °C; 1H NMR (400 MHz, CDCl3) d
3.81 (s, 8H), 3.94 (s, 8H), 4.99 (s, 4H), 6.54 (s, 4H), 6.85 (d,
4H, J = 7.6 Hz), 7.15 (t, 2H, J = 7.6 Hz), 7.26 (s, 2H),
7.38–7.47 (m, 4H); 13C NMR (100.4 MHz, CDCl3) d
38.58, 67.92, 111.44, 113.70, 125.63, 128.26, 128.90,
135.23, 139.09, 151.03, 158.82; m/z (FAB-MS) 680 (M+).
Anal. Calcd for C38H36N2O2S4: C, 67.02; H, 5.33; N, 4.11.
Found. C, 67.21; H, 5.40; N, 4.20.
The Authors thank DST, UGC-Special Assistance Pro-
gram to the Department of Organic Chemistry and
CSIR (SRF to M.D.) for financial assistance.
References and notes
1
11. Yield 42%; dec >300 °C; H NMR (400 MHz, CDCl3) d
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3.52(AB q, 8H, J = 13.5 Hz), 3.94 (ABq, 8H, J = 14.2Hz),
5.06 (s, 4H), 6.61 (s, 2H), 6.69 (s, 4H), 7.21 (d, 4H,
J = 7.7 Hz), 7.41–7.46 (m, 4H), 7.65 (t, 2H, J = 7.6 Hz);
13C NMR (100.4 MHz, CDCl3) d 35.09, 36.61, 69.50,
111.45, 113.89, 121.16, 121.76, 128.98, 130.69, 135.98,
139.78, 151.82, 159.02; m/z (FAB-MS) 680 (M+). Anal.
Calcd for C38H36N2O2S4: C, 67.02; H, 5.33; N, 4.11.
Found. C, 67.25; H, 5.50; N, 4.18.
12. Yield 7%; dec >300 °C; 1H NMR (400 MHz, CDCl3) d
3.75 (s, 8H), 3.78 (s, 8H), 4.75 (s, 4H), 4.84 (s, 4H), 6.48 (s,
4H), 6.49 (s, 4H), 6.76 (s, 2H), 6.77 (s, 2H), 7.02 (d, 2H,
J = 7.8 Hz), 7.08–7.25 (m, 4H), 7.13 (t, 1H, J = 7.8 Hz),
7.52(s, 1H); 13C NMR (100.4 MHz, CDCl3) d 38.57,
38.65, 67.98, 69.98, 114.13, 114.28, 124.73, 124.83, 125.45,
125.87, 127.51, 127.59, 128.06, 134.39, 137.39, 138.68,
158.50, 158.83; m/z (FAB-MS) 812(M +). Anal. Calcd for
C48H44O4S4: C, 70.90; H, 5.45. Found. C, 71.04; H, 5.38.
1
13. Yield 38%; dec >300 °C; H NMR (400 MHz, CDCl3) d
3.27 (s, 8H), 3.36 (s, 8H), 4.99 (s, 4H), 5.03 (s, 4H), 6.35 (s,
2H), 6.40 (s, 2H), 6.42 (s, 4H), 6.63 (s, 4H), 7.14 (s, 1H),
7.16 (d, 2H, J = 7.8 Hz), 7.31 (t, 1H, J = 7.8 Hz), 7.08–7.25
(m, 6H); m/z (FAB-MS) 812(M +). Anal. Calcd for
C48H44O4S4: C, 70.90; H, 5.45. Found. C, 71.12; H, 5.55.