Conformational behavior of dithia[n.3.3](1,3,5)cyclophanes and dithia[n.3.3](1,2,6)cyclophanes

Article abstract of DOI:10.1016/j.tet.2005.01.027

The conformational behavior of a series of crown-fused dithia[n.3.3](1,2,6) cyclophanes (126-CPs) and dithia[n.3.3](1,3,5)cyclophanes (135-CPs) was investigated by variable-temperature ¹H and ¹³C NMR spectroscopy, X-ray crystallography and density functional theory (DFT) calculations. Single crystal X-ray structure analysis showed that two thia-bridges in 126-CPs adopted a pseudochair-pseudochair (cc) conformation and the cyclophane decks underwent a ring-tilting motion in the case of [10.3.3](1,2,6)cyclophane (1a). In contrast, the thia-bridges in 135-CPs took both cc and pseudoboat-pseudochair (bc) conformations, and the ring-tilting process was also found in [10.3.3](1,3,5)cyclophane (2a). Variable temperature ¹H NMR study revealed that there was no wobbling-motion for two thia-bridges in 126-CPs while thia-bridges in 135-CPs experienced a wobbling-process with a conformational barrier of 9.21 and 8.80 kcal mol ^-1, respectively, for 2a and [13.3.3](1,3,5)cyclophane (2b). DFT calculations for the two cyclophanes series revealed that 126-CPs preferred a cc conformation which was consistent with the experimental observation; similarly, 135-CPs took a preferential cc conformation, agreeing with 2a having a predominant cc conformer (cc:bc ratio=70:30), but not 2b having a predominant bc conformer (cc:bc ratio=15:85) in the solid state.

Full text of DOI:10.1016/j.tet.2005.01.027

Tetrahedron 61 (2005) 2431–2440
Conformational behavior of dithia[n.3.3](1,3,5)cyclophanes
and dithia[n.3.3](1,2,6)cyclophanes
Jian-Wei Xu,a Ting-Ting Lina and Yee-Hing Laib,
*
aInstitute of Materials Research and Engineering, 3 Research Link, Singapore 117602
bDepartment of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543
Received 7 September 2004; revised 6 December 2004; accepted 7 January 2005
Available online 28 January 2005
Abstract—The conformational behavior of a series of crown-fused dithia[n.3.3](1,2,6)cyclophanes (126-CPs) and dithia[n.3.3](1,3,5)-
cyclophanes (135-CPs) was investigated by variable-temperature 1H and 13C NMR spectroscopy, X-ray crystallography and density
functional theory (DFT) calculations. Single crystal X-ray structure analysis showed that two thia-bridges in 126-CPs adopted a
pseudochair–pseudochair (cc) conformation and the cyclophane decks underwent a ring-tilting motion in the case of [10.3.3](1,2,6)cyclo-
phane (1a). In contrast, the thia-bridges in 135-CPs took both cc and pseudoboat–pseudochair (bc) conformations, and the ring-tilting
process was also found in [10.3.3](1,3,5)cyclophane (2a). Variable temperature 1H NMR study revealed that there was no wobbling-motion
for two thia-bridges in 126-CPs while thia-bridges in 135-CPs experienced a wobbling-process with a conformational barrier of 9.21 and
8.80 kcal molK1, respectively, for 2a and [13.3.3](1,3,5)cyclophane (2b). DFT calculations for the two cyclophanes series revealed that
126-CPs preferred a cc conformation which was consistent with the experimental observation; similarly, 135-CPs took a preferential cc
conformation, agreeing with 2a having a predominant cc conformer (cc:bc ratioZ70:30), but not 2b having a predominant bc conformer
(cc:bc ratioZ15:85) in the solid state.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
pseudoboat–pseudoboat (bb) conformation as a result of the
formation of an intramolecular hydrogen-bonding network.
Likewise, 9-amino-18-nitro-2,11-dithia[3.3]MCP takes a
pseudoboat–pseudochair (bc) conformation due to the
presence of an intramolecular S/H–N hydrogen bonding.
Other factors such as the dipole moment of a molecule
sometimes may have an effect on the predominant
conformation.11
Conformational analysis plays an important role in
cyclophane chemistry.1 The understanding of preferred
conformations in cyclophane (CP) is of importance in the
design of various supramolecular systems. Small-sized CP
molecules, such as, 2,11-dithia[3.3]metacyclophane
(MCP)2–6 frequently act as a model to explore the mobility
of such CPs due to the presence of a variety of
conformational processes including ring-flipping, ring-
tilting, bridge-wobbling and syn-anti isomerization. It is
well understood that the conformational characteristics
of [3.3]MCP are dependent particularly upon the ‘internal’
(9, 18-position) substitution, the attribute of the ‘internal’
atom and the nature of the bridge heteroatoms (Chart 1).7–10
The ‘internal’ substituents in [3.3]MCP are able to direct its
conformation preference when non-covalent interaction
such as hydrogen bonding between substituents and bridges
is present.8 For example, 9-amino-2,11-dithia[3.3]MCP,
being different from its precursor syn-9-nitro-2,11-
dithia[3.3]MCP, is anti. However, 9-18-diamino-2,11-
dithia[3.3]MCP shows syn and its thia-bridges adopt a
Keywords: Conformation; (1,3,5)Cyclophane; (1,2,6)Cyclophane.
* Corresponding author. Tel.: C65 6874 2914; fax: C65 6779 1691;
e-mail: chmlaiyh@nus.edu.sg
Chart 1.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.01.027

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J.-W. Xu et al. / Tetrahedron 61 (2005) 2431–2440
On the other hand, examples of the synthesis and
conformational analysis of multibridged cyclophanes were
studied 30 years ago. Boekelheide first reported the
synthesis of 2,11,20-trithia[33](1,3,5)CP12 in which one
thia-bridge underwent a wobbling-process in the solid
state.13 Shinmyozu studied the synthesis and conforma-
tional behavior of [33](1,3,5)CP, in which one bridge
experienced a wobbling-process with an activation energy
2. Results and discussion
2.1. Synthesis of 126-CPs and 135-CPs
First, 1a and 1b were synthesized as shown in Scheme 1.
Compound 2,6-diformylphenol 3, which was prepared by
tetrabromination of 2,6-dimethylphenol acetate followed by
hydrolysis in NaOAc/HOAc,21 was used as a starting
material. Compound 5a was obtained in a 48% yield when
the reaction temperature was maintained at 60–70 8C and
the mixture stirred for 24 h. A near quantitative yield of
tetrol 5b was obtained by reducing 5a with NaBH4 in
refluxing THF. Treatment of 5b with phosphorus tribromide
in dry CH2Cl2 readily gave tetrabromide 5c in 80% yield.
Finally 1a was obtained by intramolecular cyclization of 5c
with Na2S under high dilution conditions. The method
of preparation of 1b was the same as that of other analogs
1c–d.18,19
barrier of 12.4 kcal molK1 14
.
Fluorine-substituted
[33](1,3,5)CP whose p–p absorption bands correlate to
the number of fluorine atoms were also investigated.15
Bodwell reported the synthesis of [n.3.3](1,3,5)CPs as
tethered [2.2]MCPs precursors with various lengths of
alkyl tether.16,17 Recently, our interest has focused on
the synthesis and complexation properties of crown-
fused dithia[n.3.3](1,2,6)CPs (126-CPs) and dithia[n.3.3]-
(1,3,5)CPs (135-CPs) (Chart 1).18–20 Their binding proper-
ties towards alkali metal ions largely relate to the ring-tilting
motion of two aromatic rings. Herein we wish to further
report the syntheses, X-ray crystal structure and the
conformational analysis of crown-fused 126-CPs and
The synthesis of 2a–c was attempted (Scheme 2). First,
compound 9 was prepared from bromomethylation of 2,4,6-
trimethylanisole in 47% HBr/HOAc in the presence of
a phase transfer catalyst N,N,N-trimethyltetradecyl
ammonium bromide.22 Compound 9 was converted to 10
by reacting with thiourea followed by hydrolysis in
refluxing 10% KOH aqueous solution. The compound
1
135-CPs in solution by variable-temperature H and 13C
NMR spectroscopy. The energy-minimized structures based
on the DFT calculations are presented and compared
with those from the X-ray crystallography and variable-
temperature NMR spectroscopy.
Scheme 1. The synthetic route for 1a–b. Reagents and conditions: (i) K2CO3, DMF, 60–70 8C; (ii) NaBH4, THF, reflux; (iii) PBr3, CH2Cl2, 0 8C; (iv) Na2S,
ethanol/benzene, high dilution conditions, rt; (v) Br(CH2CH2O)2CH2CH2Br, K2CO3, acetone, reflux.

J.-W. Xu et al. / Tetrahedron 61 (2005) 2431–2440
2433
Scheme 2. The synthetic route for 2a–c. Reagents and conditions: (i) 1,3,5-trioxane, HOAc, aq HBr (48%), 95 8C; (ii) (NH2)2CS, aq KOH, reflux, 9 M H2SO4;
(iii) KOH, benzene, ethanol, high dilution conditions, rt; (iv) BBr3, CH2Cl2.
syn-13, together with its isomer anti-11 was prepared from
the cross-coupling reaction of dibromide 9 and dithiol 10
under high dilution conditions. The two isomers could be
readily separated by column chromatography. Demethyl-
ation of anti-11 was carried out using BBr3 in CH2Cl2 to
afford anti-12. A similar reaction attempted using the
isomer syn-13 however was unsuccessful. The significant
steric hindrance of the ortho-methyl and opposite aryl
groups might have discouraged the reaction. An alternative
synthesis of 2a–c was achieved starting from 2,4,6-
trimethylphenol 15 which reacted with polyethylene glycol
dibromide, followed by tetrabromomethylation and intra-
molecular cyclization with sodium sulfide to afforded
2a–c.20
2.2. Crystal structures of 126-CPs and 135-CPs
The X-ray single crystal structures of 1a–d and 2a–b were
determined. All the single crystal structures of 1a–d clearly
showed a pseudochair–pseudochair (cc) conformation
for both thia-bridges. Their normal C–S bond lengths and
C–S–C bond angles were similar and close to expected
values.23–26 It was noteworthy that 1a showed that there
were two different non-interconverting structures 1a-(I) and
1a-(II) in the crystalline state. The ORTEP drawings of
1a-(I) and 1b are illustrated in Figure 1. However, 1a(I) and
1a(II) did not exhibit significant differences between their
bond lengths, bond angles and thia-bridge conformations.
Figure 2 clearly manifests the ring-tilting process in 1a.
Analysis of other single crystal structures of 1c–d showed
the same cc conformation for thia-bridges and no disorder of
thia-bridges was observed.18,19 This appears to indicate that
the wobbling process of thia-bridges is restricted by the
‘internal’ substitution for 126-CPs series.
Similar to 1a, two independent conformers (2a-(I) and
2a-(II)) of 2a were also found in the crystalline state and
one of the two thia-bridges in a conformer (2a-(II)) was
triply disordered.20 Both thia-bridges in 2a-(II) adopted
the pseudochair conformation with C–S bond lengths and
C–S–C bond angles very close to those observed in 1a.
Nevertheless, in conformer 2a-(I), one thia bridge was
Figure 1. ORTEP drawings of (a) 1a-(I) and (b) 1b.

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J.-W. Xu et al. / Tetrahedron 61 (2005) 2431–2440
Figure 2. A diagram illustrating the tilting motion in the two conformers of 1a-(I) and 1a-(II). Two independent structures are indicated by solid line and
dashed line, respectively.
Table 1. A comparison of the dihedral angles of two aryl rings and the centroid–centroid distances of aromatic rings in 1a–d, 2a–b and compound 16
˚
Centroid–centroid distance of two aryl rings (A)
CP
Dihedral angle of two aryl rings (8)
1a-(I)
1a-(II)
1b
1c
1d
16.2
15.5
14.2
13.4
12.8
3.50
3.49
3.49
3.45
3.43
2a-(I)
2a-(II)
2b
16.1
13.6
12.9
3.59
3.55
3.56
16
!1
3.19
‘normal’ but the sulfur atom in the second was triply
disordered with an occupancy ratio of 0.4:0.3:0.3. The
observation indicates a possible inter-conversion among bc
and cc conformations in the solid state. Similarly, one of
thia-bridges in 2b was disordered, resulting in a 2b-bc
conformation as a major component (85%). The coexistence
of bc and cc conformers has also been found previously12,13
except that the cc conformation was the predominant isomer
(80%). In comparison to the conformers in 2a with a ratio of
70:30 (cc:bc, inclusive of 2a(I) and 2a(II)), 2b with a ratio
of 15:85 (cc:bc) has significantly more preference for the bc
conformer. In addition to the probable effect of crystal
packing, we believe this is in part as a result of the great
difference in their ground state energies, that is, an increase
in ground state energy going from bc to cc.
phenolic oxygen atom in the crown ether moiety and thus
the strong preference for only the cc conformer. In contrast,
in 2a–b a pair of similar steric interactions would be
experienced in both the cc and bc conformations, thus the
There is a possible explanation why a wobbling-process in
one of the thia-bridges was only observed for 2a and 2b but
not in the series of 126-CPs. In 1a, for example, the bc
conformation would experience a significant steric repul-
sion between the pseudo-boat sulfur atom and the central
Figure 3. The tilting process of 126-CPs and 135-CPs.
Figure 4. The possible conformation of 1c in solution.

J.-W. Xu et al. / Tetrahedron 61 (2005) 2431–2440
2435
disorder in one of the thia-bridges even in the solid state was
observed. On the basis of a buttressing effect, the cc
conformation would be relatively less stable, and thus 135-
CPs have a preference to the propelling bc conformation
similar to that observed13 of which one of the sulfur bridges
experiences rapid wobbling.
rings are nearly parallel, the two benzene rings in each of 2a
and 2b were tilted at an angle in the range of 12.9–16.18 in
the reverse manner to 126-CPs (Fig. 3). There was also a
decreasing trend in dihedral angle going from 2a to 2b. The
decrease in tilting dihedral angle following an increase in
chain length of the crown ether link could be explained by
an increasing demand for a larger cavity size of the crown
ether. A smaller dihedral angle going from 1a to 1b is
however not understood. If the steric demand of the methyl
groups in 1b is taken into consideration, the dihedral angle
in 1b would be expected to be larger. In this series of 126-
CPs, an identical transannular distance accompanied by a
varying dihedral angle of two aryl rings indirectly supports a
breathing mechanism (in solution)19 of the crown ether unit
The benzene rings in all 126-CPs and 135-CPs in the solid
state were not parallel to each other. The centroid arene–
arene stacking (interplanar) distances and dihedral angles
(tilting angle) for aromatic rings are summarized in Table 1.
The interplanar distances were slightly larger than the
˚
normal arene–arene stacking distance of 3.4 A. Unlike
2,11,20-trithia[33](1,3,5)CP12 (16) in which two benzene
Figure 5. The variable temperature 1H NMR spectra of (I) 2a: (a) 300, (b) 253, (c) 203, (d) 193, (e) 188, (f) 185, (g) 183 and (h) 178 K; and (II) 2b: (a) 300 K,
(b) 273 K, (c) 213 K, (d) 193 K, (e) 188 K, (f) 185 K, (g) 183 K and (h) 178 K in CD2Cl2.

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J.-W. Xu et al. / Tetrahedron 61 (2005) 2431–2440
as described. The change in dihedral angle would result in a
change in the conformation and cavity size of the crown
ether and thus its complexation ability.
freezing out of the wobbling processes of the thia-bridges,
leading to a conformation in which the two initially (room
temperature) identical methyl groups are now magnetically
non-equivalent. The dynamic NMR study of 2b revealed a
similar phenomenon (Fig. 5(II)). An analysis of the general
conformational behavior will be discussed using 2b as an
example.
2.3. Dynamic NMR spectroscopy study
Although 1a–d take the cc conformations as observed in the
solid state, it is not possible to rule out the wobbling
processes cc5bc5cb5bb as well as their diastereotopic
conformers of thia-bridges in solution as illustrated in
Figure 4 using 1c as an example. Therefore we examined the
dynamic NMR (500 MHz) spectra of 1a–d over the
temperature range from 298 to 178 K, however we did not
observe the freezing of this wobbling process of the thia-
bridges indicating either a relatively low energy conversion
barrier or less opportunity to adopt bc, cb, or bb due to the
electronic repulsion between sulfur and phenolic oxygen.
Thus, it would be more interesting to find out whether the
bridge wobbling processes of the thia-bridges in 135-CPs
series could be observed. The aryl rings in 135-CPs are
hexa-substituted and thus the relatively higher steric
demand might allow observation of the freezing of the
bridge wobbling processes at a reasonable temperature
within the experimental limitations.
In the analysis of a conformational process using dynamic
NMR spectroscopy the free energy of activation ðDGsc Þ,
which represents the conformational barrier, could be
estimated by the coalescence temperature method. Employ-
ing a pair of non-coupled signals as the probe for
conformational analysis, the value of DGsc could be derived
from the Eyring equation:27
kc Z 0:707pDn
DGsc Z 2:303RTcð10:319 Clog Tc Klog kcÞ
Where Dn is the frequency difference at the low temperature
limit, Tc is the coalescence temperature and DGsc is the
transition state free energy at coalescence temperature.
The temperature-dependent 1H NMR (500 MHz) spectra of
2a were recorded in CD2Cl2 in the temperature range of
178–300 K (Fig. 5(I)). In general the NMR signals
broadened significantly as the temperature was lowered
from 300 to 178 K. Although the oxyethylene protons in the
crown unit were clearly resolved at 300 K, broadening of
these signals upon cooling led to weak and overlapped
signals. This phenomenon is however consistent with a
slowing down of the conformational processes in the
macroring. The diastereotopic bridge methylene protons
(–CH2SCH2–) also appeared clearly as an AB quartet at d
4.23 and 3.79 at room temperature. These signals broadened
and finally coalesced at about 180 K. They were expected to
reappear as two separate AB quartets at the low temperature
limit, but in our study, the limitation of the temperature was
near 175 K at which these signals were not fully resolved.
Actually, a broad incipient triplet was observed in both
spectra of 2a and 2b at 178 K.
Although the crown ether link in 2b is relatively longer than
that in 2a their conformational barriers for the thia-bridge
wobbling processes seem to be very similar (Table 2). These
barriers are in fact relatively lower than that observed for a
similar wobbling process in [3.3]-MCP (10.8 kcal molK1).5
In contrast, similar bridge wobbling processes of aza-
bridges in N,N,N-tritosyl-2,11,20-triaza[33](1,3,5)CP
(13.6 kcal molK1 28 and [33](1,3,5)CP (12.4 kcal molK1 14
)
)
however, involved a higher energy barrier.
The methyl protons in 2a appeared as two singlets at d 2.46
and 2.24 in an integration ratio of 1:2 at room temperature.
Thus, the latter could be readily assigned to the two methyl
groups adjacent to the crown ether unit. The two methyl
groups were certainly also adjacent to the two thia-bridges
and thus could be used as proton probes for the
conformational analysis of the bridge wobbling processes
by dynamic 1H NMR spectroscopy. As the temperature was
lowered, the signals corresponding to this pair of methyl
groups (at d 2.24 at 300 K) broadened and coalesced at
186 K. This signal became gradually resolved again as the
temperature was further lowered and reappeared as two
singlets at d 2.26 and 2.22 at 178 K. This in fact indicates the
Figure 6. Possible conformations of 2b in solution.
Table 2. The coalescence temperature and activation energy of 2a–b
DGsc (kcal molK1
)
Tc (K)
Dn (Hz)
kc (Hz)
2a
2b
186
186
30
34
60
76
9.21
8.80

J.-W. Xu et al. / Tetrahedron 61 (2005) 2431–2440
2437
Possible conformational processes of the three bridges in 2b
are illustrated in Figure 6. The large crown ether unit is
expected to undergo the extreme ‘left to right’ swing
resulting in the two series of conformers 2b-bb–2b-cc
and 2b-bb0–2b-cc0 (2b-bb is equivalent to 2b-bb0, 2b-bc to
2b-cb0, 2b-cb to 2b-bc0 and 2b-cc to 2b-cc0). The crown
ether link is relatively longer and more flexible and thus
would involve a much lower energy barrier. On the other
hand, it could be assumed that the resolution of the proton
signals of methyl groups at aromatic C2/C20 and C6/C60 is
dependent only on the restricted conformational changes of
the thia-bridges. There should be no resolution of these
methyl proton 0signals if the frozen conformation is either
2b-bb52b-bb or 2b-cc52b-cc0 due to their symmetry.
Thus, it could be concluded that the experimentally
observed frozen conformer of 2b in the dynamic NMR
study 0 was 2b-bc52b-cb0 and 2b-cb52b-bc0 (2b-cb5
2b-bc is not identical to 2b-bc52b-cb0 and the two pairs
are not inter-converting). In fact a crystallographic structure
of 2b also indicates the same conformational preference in
the solid state. The two resolved methyl proton signals for
2b at the low temperature limit 0appeared at d 2.29 and 2.24,
respectively. In 2b-bc52b-cb or 2b-cb52b-bc0, one of
the sulfur atoms is in close 0proximity to the methyl groups
attached to aromatic C2/C2 and C6/C60 for 2b-bc, 2b-cb0,
2b-cb and 2b-bc0, (the methyl groups at C6/C60 and C2/
C20). The anisotropic effect of this sulfur atom might induce
a small downfield shift of the methyl signal concerned, thus
resulting in its r0esolution from the signal of the methyl
groups at C2/C2 and C6/C60 for 2b-bc/2b-cb0 or 2b-c0b/
2b-bc0, respectively, in 2b-bc52b-cb0 or 2b-cb52b-bc .
13C NMR spectrum of 2b was measured at 178 K and the
assignment of selected carbon signals is listed in Table 3 It
was worthy to note that while only an averaged singlet at d
12.31 was observed at room temperature for the methyl
carbons attached to C2, 20, 6 and 60, however, four singlets
with a 1:1 ratio appeared in the spectrum taken at 178 K at d
11.97, 11.86, 11.16 and 11.02, respectively. Simulta-
neously, the singlet at 30.83 corresponding to the bridge
carbon emerged as four singlets. Moreover, three aromatic
carbon signals were separated to two sets of singlets in a 1:1
ratio (Fig. 7). It implie0s that two conformers (2b-bc or 2b-
cb0 and 2b-cb or 2b-bc ) exist at this temperature. It is clear
that there are two pairs of relatively well-resolved
(Ddz0.8 ppm) methyl signals. This is also consistent with
the argument that the anisotropic effect of sulfur results in
the deshielding of the carbons in close proximity.
Table 3. The selected chemical shifts of 2ba at 298 and at 178 K
Chemical shift
298 K
178 K
C(1)
C(3,5)
C(4)
C(2,6)
C(10,11)
C(9)
152.55
132.09
130.24
127.44
30.83
155.98, 149.95
131.01, 130.45
129.09, 128.43
126.35
29.75, 29.56, 29.49, 29.35
17.26, 17.05
11.97, 11.86, 11.16, 11.02
2.4. Computational study of conformers
17.80
12.31
A series of DFT calculations (BLYP/DNP) were performed
to determine the relative energy for the different conformers
of 126-CPs and 135-CPs together with syn-9,18-dimeth-
oxy[3.3]MCP (17) for comparison, and the results are
summarized in Table 4. For both series, all cc conformers
had the global minimum energy. The bc, cb and bb
conformers of 126-CPs series had a higher energy by
4.30–11.91 kcal molK1 than their corresponding cc con-
formers. The electronic repulsion and steric hindrance
between sulfur and phenolic oxygen accounts for the high-
energy difference among conformers in 126-CPs series. The
global energy minimum conformers of 126-CPs exactly
responded to the structures in solution and in the solid state.
In contrast, the differences (0.89–3.69 kcal molK1) between
cc and other conformers in 135-CPs series were much less
than those in 126-CPs series. The relative population of
these conformers (Table 5) was thus estimated based on the
data of Table 4. It was shown that the total population of bb,
bc and cb conformers was found to be negligible for
126-CPs. In contrast, there were more than totally 37 and
36% of bc and cb conformers, for example, for 2a and 2b,
respectively. The calculated ratio of cc:(bc/cb) (63:37) for
2a is approximately close to the experimental value (70:30)
in the solid state, however, the order of conformers ratio of
cc:(bc/cb) (63:36) for 2b was reversed when compared to
C(7,8)
a The numbering of carbon atoms is shown in Figure 6.
Figure 7. 13C NMR spectra of 2b (a) at 298 K and (b) at 178 K in CD2Cl2.
Table 4. The relative energy (kcal molK1) of conformers of 1a–d, 2a–c and compound 17 (BLYP/DNP)
CP
1a
1b
1c
1d
2a
2b
2c
17
bb
bc
cb
cc
11.24
7.37
5.69
0
11.91
5.22
5.10
0
9.23
5.19
4.93
0
8.50
4.30
4.36
0
2.90
0.89
1.60
0
2.51
1.09
1.24
0
3.69
1.60
2.02
0
10.28
5.65
0

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J.-W. Xu et al. / Tetrahedron 61 (2005) 2431–2440
Table 5. The population of conformers of 1a–d and 2a–c at 298 Ka
CP
1a
1b
1c
1d
2a
2b
2c
bb
bc
cb
cc
0
0
0
100
0
0
0
100
0
0
0
100
0
0
0
100
0
28
9
1
0
11
6
20
16
63
63
83
a The population was calculated based on the data of Table 4.
the experimental values (15:85). The discrepancy in
calculated and experimental population may be a conse-
quence of the effect of crystal packing as mentioned above.
complete set available in the code. The gradient-corrected
BLYP functional,31,32 a finite basis-set cutoff of 4.0 A and a
˚
‘fine’quality(convergencetolerances:energy1.0!10K5 Ha;
˚
maximum force 0.002 Ha/A; maximum displacement
0.005 A. SCF tolerance: 1.0!10K6) were used. During
˚
modeling, the crown moiety in cyclophane was maintained
to tilt to one side and two thia-bridges took cc, bc or bb
conformation during the calculation.
3. Conclusions
We have demonstrated that the preferential conformations
of 126-CPs were cc as a result of the electronic repulsion
between sulfur and internal phenolic oxygen, while 135-
CPs had a tendency to take cc and bc conformations.
Dynamic NMR analyses in solution were in agreement with
the analyses of conformation by X-ray crystallography. The
conformational barriers for the wobbling-process estimated
4.2.1. 1,8-Bis(2,6-diformylphenoxyl)-3,6-dioxaoctane
(5a).
A mixture of 2,6-diformylphenol (300 mg,
2.0 mmol), triethylene glycol dibromide (276 mg,
1.0 mmol) and anhydrous K2CO3 (500 mg) was stirred in
dry DMF (10 mL) at 60–70 8C under nitrogen for 24 h. The
reaction mixture was poured into ice water (50 mL) and
stirred for 30 min. The resulting precipitate was collected by
filtration and washed with water. The crude product was
purified by chromatography on silica gel using ethyl acetate
and hexane (2:3) as eluent to give 5a (210 mg, 51%) as a
light yellow solid: mp 120–121.5 8C; 1H NMR 3.64
(oxyethylene, s, 4H), 3.83 (oxyethylene, m, 4H), 4.33
(oxyethylene, m, 4H), 7.34 (aromatic, t, 2H, JZ7.6 Hz),
8.59 (aromatic, d, 4H, JZ7.6 Hz), 10.44 (–CHO, s, 4H); IR
(KBr) 1676 cmK1 (–CHO); MS (ESI) (m/z) 437.2 (MC
NaC, 93); Anal. Calcd for C22H22O8: C, 63.76; H, 5.35.
Found: C, 63.89; H, 5.55.
1
by variable-temperature H NMR, were 9.21 and 8.80 kcal
molK1, respectively, for 2a and 2b, less than that of
[33](1,3,5)CP. The 13C NMR spectra at low temperature
suggested two conformers with a 1:1 ratio coexisted,
corresponding to the results in the solid state. The DFT
calculations provided the evidence on the conformational
analysis of 126-CPs and 135-CPs.
4. Experimental
4.1. General
4.2.2. 1,8-Bis(2,6-dihydroxyphenoxyl)-3,6-dioxaoctane
(5b). A mixture of compound 5a (150 mg, 3.62 mmol)
and sodium borohydride (100 mg) in THF (10 mL) was
heated at reflux for 1 h. The mixture was cooled and the
THF was removed under reduced pressure. The residue was
extracted with CHCl3 and the organic layer was washed,
dried and evaporated to afford tetrol 5b (145 mg, 95%) as a
colorless oil: 1H NMR d 3.42 (–OH, br. s, 4H), 3.69
(oxyethylene, s, 4H), 3.73–3.76 (oxyethylene, m, 4H), 4.03–
4.06 (oxyethylene, m, 4H), 4.58 (–CH2OH, s, 8H), 6.98
(aromatic, t, 2H, JZ7.6 Hz), 7.18 (aromatic, d, 4H, JZ
7.6 Hz); MS (EI) (m/z) 368.1 (MCK3H2O, 12); IR (KBr)
3364 cmK1 (–OH); Anal. Calcd for C22H30O8: C, 62.55; H,
7.16. Found: C, 62.30; H, 7.30.
The NMR spectra were determined on a Bruker ACF
(300 MHz) FT-NMR spectrometer, operating at 300.13 and
1
75.47 MHz for H and 13C, respectively in CDCl3 at room
temperature. The temperature-dependent NMR experiments
were performed on a Bruker AMX (500 MHz) NMR
spectrometer in CD2Cl2. All chemical shifts are reported
in ppm downfield from tetramethylsilane as an internal
standard. Infrared spectra were recorded on a Perkin–Elmer
1310 infrared spectrometer. Mass spectra were determined
on a VG Micromass 7035 mass spectrometer at 70 eV with
electron impact or on a Finnegan TSQ mass spectrometer
with electrospraying ionization (ESI). Relative intensities
are given in parenthesis. Microanalysis was performed by
the Microanalytical Laboratory of the Department of
Chemistry, National University of Singapore.
4.2.3. 1,8-Bis(2,6-dibromomethylphenoxyl)-3,6-dioxa-
octane (5c). PBr3 (1.0 g, 3.7 mmol) was added to a solution
of 5b (0.20 g, 0.47 mmol) in dry 1,4-dioxane (10 mL) at
0 8C. The mixture was further stirred for 5 h at 0 8C, and
then the mixture was poured into ice water/dichloro-
methane. The organic layer was separated and the water
layer was extracted three times with dichloromethane. All
organic layers were combined and washed with 10%
NaHCO3, water, and then evaporated. The residue was
chromatographed on silica gel using ethyl acetate/hexane
(9:1) as eluent to yield the product 5c (0.24 g, 75%) as a
white solid: mp 115–116 8C (lit.: 116–117 8C33); 1H NMR d
4.2. Calculation method
The structures of 135-CPs and 126-CPs series were
optimized using the density functional theory electronic
structure program-DMol3 available as part of Materials
Studio (Accelrys Inc).29,30 In this code electronic wave
function is expanded in a localized atom-centered basis set
with each basis function defined numerically on a dense
radial grid. All-electron calculations were performed with
a double numeric polarized (DNP) basis set (which is
analogous to the Gaussian 6-31(d,p) basis set), the most

J.-W. Xu et al. / Tetrahedron 61 (2005) 2431–2440
2439
3.87 (oxyethylene, s, 4H), 3.95–3.98 (oxyethylene, m, 4H),
4.30–4.33 (oxyethylene, m, 4H), 4.64 (–CH2Br, s, 8H), 7.11
(aromatic, t, 2H, JZ7.6 Hz), 7.41 (aromatic, H, d, 4H, JZ
7.6 Hz).
nonahydrate (480 mg, 2.0 mmol) to yield 1b (140 mg,
31%) as colorless crystals: mp 223–225 8C; 1H NMR d 2.11
(methyl, s, 6H), 3.29 (–CH2SCH2–, d, 4H, JZ14.5 Hz),
3.63–3.66 (oxyethylene, m, 4H), 3.90–3.92 (oxyethylene,
m, 4H), 3.96 (oxyethylene, s, 4H), 4.51 (–CH2SCH2–, d, 4H,
JZ14.5 Hz), 6.80 (aromatic, s, 4H); 13C NMR d 153.34,
133.01, 130.52, 129.74, 73.26, 69.95, 69.39, 30.29, 20.57;
MS (EI) (m/z) 446 (MC, 23); Anal Calcd for C24H30O4S2:
C, 64.54; H, 6.77. Found: C, 64.70; H, 6.50.
4.2.4. 18,27-Dithia-1,4,7,10-tetraoxa-[10.3.3](1,2,6)cyclo-
phane (1a). A solution of 95% sodium sulfide nonahydrate
(480 mg, 2.0 mmol) in 95% ethanol (300 mL) and a solution
of 5c (674 mg, 1.0 mmol) in benzene (300 mL) in separate
rotaflow dropping funnels were added dropwise simul-
taneously at the same rate to nitrogen purged 95% ethanol
(1 L). After the addition, the mixture was stirred for another
15 h and the bulk of the solvent was removed under reduced
pressure. Water and dichloromethane were added to the
residue, and the mixture was stirred until all solids
dissolved. The organic layer was separated, dried, and
evaporated. The residue was chromatographed on silica gel
using ethyl acetate/dichloromethane (1:40) as eluent to yield
1a (140 mg, 33%) as colorless crystals: mp 213–215 8C; 1H
NMR (CDCl3) d 3.34 (–CH2SCH2–, d, 4H, JZ14.5 Hz),
3.66–3.69 (oxyethylene, m, 4H), 3.92–3.95 (oxyethylene,
m, 8H), 4.55 (–CH2SCH2–, d, 4H, JZ14.5 Hz), 6.64
(aromatic, t, 2H, JZ7.6 Hz), 6.97 (aromatic, d, 4H, JZ
7.6 Hz); 13C NMR d 155.28, 131.09, 129.19, 123.99, 73.15,
69.85, 69.24, 30.35; MS (EI) (m/z) 418 (MC, 77); Anal.
Calcd for C22H26O4S2: C, 63.13; H, 6.26; Found: C, 63.30;
H, 6.30.
4.2.8. 2,4,6-Trimethyl-3,5-bis(bromomethyl)anisole (9).
2,4,6-Trimethylanisole (10 g, 66.6 mmol) was added to a
mixture of 47% aq HBr (40 mL) and glacial acetic acid
(180 mL), followed by 1,3,5-trioxane (18.0 g, 0.20 mol) and
tetradecyltrimethyl ammonium bromide (0.50 g). The
mixture was heated up and the temperature kept at 95 8C
for 5 h (thin layer chromatography (TLC) was performed to
monitor the completeness of the reaction). After cooling to
room temperature, the white precipitate was filtered, washed
with plenty of water and then dissolved in dichloromethane.
The organic layer was washed with 5% bicarbonate, water
and dried. The organic solvent was removed under the
reduced pressure and residue was chromatographed on silica
gel using ethyl acetate and hexane (10:90) as eluent to afford
the pure 9 (8.3 g, 31%) as a white solid: mp 137–138.5 8C;
1H NMR d 2.36 (methyl, s, 6H), 2.42 (methyl, s, 3H), 3.67
(methoxy, s, 3H), 4.57 (–CH2Br, s, 4H); MS (EI) (m/z) 338
(MCC4, 70), 336 (MCC2, 83), 334 (MC, 72), 176 (MC
K279Br); Anal. Calcd for C12H16Br2O: C, 42.89; H, 4.80.
Found: C, 43.10; H, 4.65.
4.2.5. 1,8-Bis(4-methyl-2,6-dihydroxymethylphenoxyl)-
3,6-dioxaoctane (7a). Triethylene glycol dibromide
(4.92 g, 17.8 mmol) was added under nitrogen to a
suspension of anhydrous K2CO3 (10 g, 72.4 mmol) and
2,6-dihydroxymethylphenol (6.0 g, 35.7 mmol) in acetone
(70 mL). The mixture was maintained at gentle reflux for 5
days and the acetone was then removed under reduced
pressure. The residue was poured into a mixture of water
and dichloromethane. The organic layer was washed, dried,
and then evaporated. The residue was chromatographed on
silica gel using ethyl acetate/dichloromethane (15:85, then
40:60) as eluent to yield 7a (5.35 g, 67%) as a colorless oil
which crystallized on long standing when kept at 0 8C: mp
93–96 8C; 1H NMR d 2.28 (methyl, s, 6H), 3.78 (oxyethyl-
ene, s, 4H), 3.82–3.86 (oxyethylene, m, 4H), 4.12–4.15
(oxyethylene, m, 4H), 4.64 (–CH2OH, s, 8H), 7.07
(aromatic, s, 4H); IR (KBr) 3387 cmK1 (–OH); MS (EI)
(m/z) 414 (MCK2H2O, 7), 396 (MCK3H2O, 48). Anal.
Calcd for C24H34O8: C, 63.98; H, 7.61, 28.41. Found: C,
63.75; H, 7.77.
4.2.9. 2,4,6-Trimethyl-3,5-bis(mercaptomethyl)anisole
(10). Compound 9 (3.63 g, 10.9 mmol) was added to a
stirred solution of thiourea (1.65 g, 23.6 mmol) in absolute
ethanol (40 mL). After addition, the mixture was continued
to reflux for another 2 h, and then the mixture was cooled to
room temperature, filtered and dried under vacuum to give
2,4,6-trimethyl-3,5-bis(isothioureamethyl)anisole dibro-
mide crude salt (5.0 g). The salt was used in the next step
without further purification. A solution of 5.0 g of salt in
20% KOH (50 mL) was boiled under reflux for 5 h. After
the mixture was cooled to room temperature, 9 M aqueous
H2SO4 was added to neutralize the alkaline solution until pH
to 7. The neutralized mixture was extracted with dichloro-
methane. The organic layer was washed with water, dried
and concentrated. The residue was chromatographed on
silica gel using ethyl acetate and hexane as eluent (1:9) to
give 10 (2.17 g, 83%) as a pale yellowish solid: mp 109–
110 8C; 1H NMR d 1.59 (–SH, t, 2H, JZ6.4 Hz), 2.34
(methyl, s, 6H), 2.40 (methyl, s, 3H) 3.66 (methoxy, s, 3H),
3.77 (–CH2SH, d, 4H, JZ6.4 Hz); MS (EI) (m/z) 242 (MC,
87); Anal. Calcd for C12H18OS2: C, 59.46; H, 7.48. Found:
C, 59.70; H, 7.30.
4.2.6. 1,8-Bis(4-methyl-2,6-dibromomethylphenoxyl)-
3,6-dioxaoctane (7b). The preparation of 7b follows the
similar synthetic procedure of 5b: mp 97–98 8C; 1H NMR d
2.29 (methyl, s, 6H), 3.86 (oxyethylene, s, 4H), 3.93–3.96
(oxyethylene, m, 4H), 4.26–4.28 (oxyethylene, m, 4H), 4.60
(–CH2Br, s, 8H), 7.16 (aromatic, s, 4H); MS (EI) (m/z) 698
(MC, 1), 700 (MCC2, 4), 702 (MCC4, 5.4), 704 (MCC6,
4), 706 (MCC8, 1); Anal. Calcd for C24H30Br4O4: C,
41.06; H, 4.31. Found: C, 40.90; H, 4.50.
4.2.10. 2,11-Dithia-5,7,9,14,16,18-hexamethyl-6,15-
dimethoxy[3.3](1,3)cyclophane (11/13). A solution of
dibromide 9 (3.00 g, 8.93 mmol) and dithiol 10 (2.16 g,
8.93 mmol) dissolving in benzene (500 mL) were slowly
added dropwise to 95% ethanol (1500 mL) over 8 h. The
resulting solution was stirred for another 16 h, and then the
bulky solvent was removed under the reduced pressure.
Dichloromethane was added to the residue and stirred. The
organic solvent was washed with dilute hydrochloric acid
4.2.7. 18,27-Dithia-14,22-dimethyl-1,4,7,10-tetraoxa-
[10.3.3](1.2.6)cyclophane (1b). The preparation of 1b
follows the similar synthetic procedure of 1a. Tetrabromide
7b (700 mg, 1.0 mmol) reacted with sodium sulfide

2440
J.-W. Xu et al. / Tetrahedron 61 (2005) 2431–2440
and water. The dichloromethane was removed and the
residue was chromatographed on silica gel using dichloro-
methane and hexane (1:1) to give anti-isomer (1.83 g, 49%)
and syn-isomer (0.363 g, 10%) as colorless crystals and
white solid, respectively.
References and notes
1. Mitchell, R. H. In Cyclophanes; Keehu, P. M., Rosenfeld,
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K. S.; Anker, W.; Williams, R. V.; Bushnell, G. W. Pure Appl.
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4.2.11. anti-2,11-Dithia-5,7,9,14,16,18-hexamethyl-6,15-
dimethoxy[3.3](1,3)cyclophane (11). Mp O240 8C
(decomposed); 1H NMR d 1.21 (methyl, s, 6H), 2.44
(methyl, s, 12H), 3.69 (methoxy, s, 6H), 3.67 (–CH2SCH2–,
d, 4H, JZ13.7 Hz), 3.78 (–CH2SCH2–, d, 4H, JZ13.7 Hz);
MS (ESI) no molecular ion peak was observed MS (EI)
(m/z) 416 (MC, 75); Anal. Calcd for C24H32O2S2: C, 69.19;
H, 7.74. Found: C, 69.33; H, 7.64.
4. Fukazawa, Y.; Takeda, Y.; Usui, S.; Kodama, M. J. Am. Chem.
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5. Semmelhack, M. F.; Harrison, J. J.; Young, D. C.; Gutierrez,
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dimethoxy[3.3](1,3)cyclophane (13). Mp O240 8C
(decomposed); 1H NMR d 2.07 (methyl, s, 6H), 2.34
(methyl, s, 12H), 3.61 (methoxy, s, 6H), 3.70 (–CH2SCH2–,
s, 8H); MS (EI) (m/z) no molecular ion peak was observed;
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4.2.13. anti-2,11-Dithia-5,7,9,14,16,18-hexamethyl-6,15-
dihydroxy[3.3](1,3)cyclophane (12). 1 M BBr3/CH2Cl2
(2.0 mL, 2.0 mmol) was added to the solution of anti-11
(100 mg, 0.24 mmol) in CHCl3 (5 mL) at K78 8C. The
mixture was stirred at K78 8C for 3 h, and then stirred
overnight at room temperature. The water was added to the
mixture, and then extracted with CH2Cl2. The organic layer
was washed with water, dried and filtered. CH2Cl2 was
removed and the residue was chromatographed on silica gel
using dichloromethane and acetone (3:1) as eluent to give
12 (10 mg, 11%) as a white solid: mp 250 8C (decomposed);
1H NMR d 1.21 (methyl, s, 6H), 2.38 (methyl, s, 12H), 3.67
(–CH2SCH2–, d, 4H, JZ13.8 Hz), 3.78 (–CH2SCH2–, d,
4H, JZ13.8 Hz) 4.55 (–OH, s, 2H); IR (KBr) 3545 cmK1
(–OH); MS (EI) (m/z) 388 (MC, 66); Anal. Calcd
C22H28O2S2 for: C, 68.00; H, 7.26. Found: C, 67.90; H,
7.41.
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5. Supporting materials
Crystallographic data for the structures reported in this
paper have been deposited with the Cambridge Crystallo-
graphic Data Center as supplementary publication numbers
CCDC-245673 (1a) and 245672 (1b). Copies of the data can
be obtained free of charge upon application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (fax: C44 1223
33603; e-mail: deposit@ccdc.cam.ac.uk).
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We are grateful to the National University of Singapore
(NUS) for financial support. Assoc. Prof. J. J. Vittal and Ms.
Tan Geok Kheng are acknowledged for determining the
X-ray crystallographic structures in the X-ray Diffraction
Laboratory at the Department of Chemistry, NUS.