Synthesis, X-ray crystallographic, and dynamic 1H NMR studies of crown-tetrathia[3.3.3.3]metacyclophanes - Conformational control by cooperative intramolecular C-H?π interaction both in solid state and in solution

Article abstract of DOI:10.1016/j.tet.2005.07.071

Crown-tetrathia[3.3.3.3]metacyclophanes 3a-c were synthesized via intermolcular coupling reaction in 22-30% yields. X-ray crystal analysis of 3b revealed that it adopted a perpendicular conformation (3b-B or 3b-C) in which two aromatic rings were inclined to be perpendicular to the opposite aromatic rings, driving two internal methyl groups into the π-cloud of the corresponding benzene rings. Furthermore, this perpendicular structural feature led to benzylic protons of thia-bridges being in close proximity to the adjacent aromatic rings. As a result, the induced upfield shifts for the two internal methyl protons and four benzylic protons were clearly observed in dynamic ¹H NMR spectra at low temperature, indicating that the intramolecular C-H?π interaction became increasingly important at low temperature. The energy barrier for inter-conversion between 3b-B and 3b-C was estimated to be 12.1 kcal mol^-1 by using a coalescence method. The total stabilization enthalpy of the C-H?π interactions was quantitatively calculated to be 7.9±0.8 kcal mol^-1 by the dynamic NMR spectroscopy. In contrast, 3a showed two non-interconvertible conformers at room temperature, which tended to interconvert at elevated temperature, however, many conformers co-existed at low temperature.

Full text of DOI:10.1016/j.tet.2005.07.071

Tetrahedron 61 (2005) 9248–9256
1
Synthesis, X-ray crystallographic, and dynamic H NMR studies
of crown-tetrathia[3.3.3.3]metacyclophanes—conformational
control by cooperative intramolecular C–H/p interaction both
in solid state and in solution
Jian-Wei Xu,a,b Wei-Ling Wanga and Yee-Hing Laia,
*
aDepartment of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore
bInstitute of Materials Research and Engineering, 3 Research Link, Singapore 117602, Singapore
Received 11 May 2005; revised 6 July 2005; accepted 21 July 2005
Available online 11 August 2005
Abstract—Crown-tetrathia[3.3.3.3]metacyclophanes 3a–c were synthesized via intermolcular coupling reaction in 22–30% yields. X-ray
crystal analysis of 3b revealed that it adopted a perpendicular conformation (3b-B or 3b-C) in which two aromatic rings were inclined to be
perpendicular to the opposite aromatic rings, driving two internal methyl groups into the p-cloud of the corresponding benzene rings.
Furthermore, this perpendicular structural feature led to benzylic protons of thia-bridges being in close proximity to the adjacent aromatic
rings. As a result, the induced upfield shifts for the two internal methyl protons and four benzylic protons were clearly observed in dynamic
1H NMR spectra at low temperature, indicating that the intramolecular C–H/p interaction became increasingly important at low
temperature. The energy barrier for inter-conversion between 3b-B and 3b-C was estimated to be 12.1 kcal molK1 by using a coalescence
method. The total stabilization enthalpy of the C–H/p interactions was quantitatively calculated to be 7.9G0.8 kcal molK1 by the dynamic
NMR spectroscopy. In contrast, 3a showed two non-interconvertible conformers at room temperature, which tended to interconvert at
elevated temperature, however, many conformers co-existed at low temperature.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
interaction on molecular folding by using a ‘slow rotation’
strategy.16–17 Oki utilized the same strategy to take 1,9-
¯
The understanding of non-covalent weak interactions such
as hydrogen-bonding, C–H/O/N, C–H/p, and N/O–H/
p interactions, etc., is not only important in fundamental
science, but also has implications for the development of
various applications in crystal engineering and molecular
design of materials.1–7 Among these weak interactions, the
C–H/p interaction, first explored by Nishio,8–10 is
considered as one of weak hydrogen bonds, in which the
C–H and p-system acts as a soft acid and a soft base,
respectively. The C–H/p interaction is of particular
importance in influencing molecular recognition,11–14
conformational preference,15–24 biological processes, and
the structure of biomacromolecules.25–29 For example,
Tsuzuki reported on the preferential conformation of
crownophanes, which is determined by the co-effect of the
C–H/p and C–H/O interactions.15 Wilcox designed a
sophisticated system to investigate the effect of the C–H/p
disubstituted triptycenes as a model for the C–H/p
interaction.18–20 Additionally, many theoretical calcu-
lations30–35 demonstrated that the C–H/p interaction is
an attractive force in nature, and plays a role in stabilizing
crystal packing.
The C–H and p-system in many organic molecules are in
close proximity in crystalline state, however, it is sometime
difficult to observe the C–H/p interaction in solution. This
is because the mobility of a molecular structure usually
results in conformationally averaged signals, for example,
in the NMR spectra. Recently, as a parallel work of [n.3.3]
(1,2,6)cyclophanes,36–37 we are focusing on the study of the
synthesis, conformation, and complexation properties of
[n.3.3](1,3,5)cycophanes.38–39 Apart from the formation of
cyclophanes as expected in the cyclization reaction, we
isolated a dimeric product of a tetrathia[3.3.3.3]metacyclo-
phane. X-ray single crystal analysis indicated that the
intramolecular C–H/p interaction existed in solid state.
Further dynamic NMR analysis revealed that cooperative
intramolecular C–H/p (alkyl–aryl) interaction dominated
Keywords: Synthesis; Cyclophane; C–H/p Interaction; Conformation.
*
Corresponding author. Tel.: C65 6874 2914; fax: C65 6779 1691;
e-mail: chmlaiyh@nus.edu.sg
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.07.071

J.-W. Xu et al. / Tetrahedron 61 (2005) 9248–9256
9249
the conformation preference in solution, and its confor-
mation at low temperature was similar to that in solid state.
In the present paper, we report on their synthesis, X-ray
structural characterization, and conformational behaviors of
tetrathia[3.3.3.3]metacyclophanes.
of 2a–c were determined using electrospray ionization (ESI)
mass spectrometry. The isolated compound derived from 2a
showed molecular ions at 1027.5 ([MCNa]C, 100).
Similarly the compound derived from 2b showed molecular
ions at 1115.5 ([MCNa]C, 30) and 1131.6 ([MCK]C, 100)
and that from 2c at 1182.7 (MC, 24), 1205.8 ([MCNa]C,
14), and 1221.8 ([MCK]C, 5). The above observation
clearly confirmed that the corresponding compounds
isolated were of dimeric nature. In the relatively simple
1H NMR spectrum of 3b, it appeared as three singlets at d
2.47, 2.31, and 1.98 (integration ratio 1:1:1) corresponding
to the three different pairs of methyl groups. This was
further confirmed by a 13C NMR DEPT experiment, which
proved that there were three different types of methyl carbon
signals at d 14.86, 12.85, and 12.23, respectively, and two
types of bridge carbon signals at d 31.96 and 30.14. The
above NMR data were collectively consistent with the
structure of 3b because the higher symmetry in 4, 5, or 6
should result in only two types of methyl protons or carbon
signals. Although the 1H NMR and 13C NMR spectra of 3c
were very similar to those of 3b, in particular the three types
of protons and carbon NMR signals for the methyl groups,
the spectra of 3a were relatively more complicated.
Compound 3a showed six methyl protons signals in an
integration ratio of 0.7:1:1:0.7:1:0.7 in CD2Cl2. This
suggests the presence of two separate conformers that are
non-interconverting in solution at room temperature.
Additional evidence came from the 12 aromatic and four
benzylic carbon signals observed in the 13C NMR spectrum
of the mixture (Fig. 1).
2. Results and discussion
2.1. Synthesis of crown-tetrathia[3.3.3.3]
metacyclophanes
The synthetic route leading to 3 is shown in Scheme 1. First,
treatment of 2,4,6-trimethylphenol with a series of
oligoethylene glycol dibromides in THF/NaOH solution
afforded compounds 1a–c. Bromomethylation of com-
pounds 1a–c in 47% hydrobromic acid/acetic acid and
1,3,5-trioxane using N,N,N-trimethyltetradecyl ammonium
bromide as a phase transfer catalyst40 was carried out to give
tetrabromides 2a–c in intermediate yields. As the reaction
temperature was increased, the tribromide and tetrabromide
gradually formed and their presence could be readily
monitored by thin layer chromatography (TLC). Chroma-
tography of the product mixture from the respective
bromomethylation reactions gave 2a, 2b, and 2c as white
solids. In the 1H NMR spectra of 2a, 2b, and 2c, no aromatic
proton signals were observed indicating that the aromatic
positions in 1a, 1b, and 1c were fully bromomethylated.
When the tetrabromides 2a–c were separately treated with
2 equiv of Na2S$9H2O in 95% ethanol/benzene under high
dilution conditions, a mixture of the intramolecularly
coupled product38 and the corresponding tetrathia[3.3.3.3]-
metacyclophanes 3a–c were obtained.
Taking the cyclization of 2b as an example, the isolated
product could in principle be any of 3b, 4, 5, and 6. The
mass spectra of the compounds isolated from the cyclization
Scheme 1. The synthetic route for compounds 3a–c. Reagents and
conditions: (a) Br(CH2CH2O)nCH2CH2Br, NaOH, THF; (b) 1,3,5-trioxane,
HBr/HOAc, C14H29N(CH3)3Br; (c) Na2S, Cs2CO3, C2H5OH/benzene.
Figure 1. Part of 13C NMR spectrum of compound 3a in CDCl3 at room
temperature.

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Figure 2. (a) ORTEP drawing of 3b and (b) space-filling drawing of 3b illustrating intramolecular close contacts.
2.2. X-ray crystallographic study of 3b
H41B and H59B) are also in close proximity to the adjacent
phenyl periphery (models b and c in Fig. 3). The distances
between these benzylic protons concerned and Csp2 of
Single crystals of 3b were grown by evaporative crystal-
lization from a mixture of chloroform and acetonitrile
solution, however, suitable crystals were not obtained for 3a
and 3c. A drawing of the crystal structure of 3b is shown in
Figure 2. The four benzene rings (designated as A, B, C, and
D in Fig. 2) in 3b did not lie on the same plane as expected
and each of them formed different dihedral angles (54.28
(ring B–ring A), 64.08 (ring C–ring D), 75.88 (ring B–ring
C), and 71.78 (ring A–ring D)) with one another. The two
oxa-crown macrorings were inclined to be approximately
perpendicular to each other by bending the central
thia-crown unit. Therefore, the whole molecule looked
like an L-shape with two approximately perpendicular
planes. In the crystal of 3b, two internal methyl groups (C40
and C58) were pointing toward the opposite aromatic rings B
˚
aromatic rings varied from 2.666 to 3.049 A, being much
shorter or approximately equal to that of van der Waals
9
contact of H and Csp2 (2.9–3.1 A) (Table 1). This type of
˚
C–H/p interaction is essentially comparable to the
reported model,33,41 in which the methylene group adopted
a synclinal conformation, thus, leading to the methylene
protons approaching the adjacent aromatic p-system.
It has been reported that the intramolecular edge–face
aromatic interaction contributes to the stabilization of
˚
and A, respectively. The short distances (3.048 A for C40-
˚
ring A and 3.430 A for C58-ring B) between two internal
methyl carbon atoms (C40 and C58) and the geometrical
centre of aryl rings (ring B and ring A) imply that they are
subject to a C–H/p interaction (model a) as presented in
Figure 3. Interestingly, four benzylic protons (H31B, H41A
/
Figure 3. The intramolecular C–H/p interaction modes in 3b.

J.-W. Xu et al. / Tetrahedron 61 (2005) 9248–9256
9251
˚
Table 1. Non-bonded interatomic contacts (A) and carbon/centroid
distances in 3b
˚
Distance (A)
˚
Distance (A)
Intramolecular
contacts
Intramolecular
contacts
H59B–C5
H59B–C4
H31B–C24
H31B–C25
H41A–C55
H41A–C54
H41B–C54
H41B–C53
C59–C4
2.743
2.764
2.666
2.713
2.867
2.795
2.887
3.049
3.545
C59–C5
C41–C53
C41–C54
C41–C55
C31–C24
C31–C25
C40–centroid
C58–centroid
3.250
3.545
2.982
3.459
3.174
3.451
3.048a
3.430b
a The distances between C40 and geometric centre of ring A (C1–C2–C3–
C4–C5–C6).
b The distance between C58 and geometric centre of ring B (C20–C21–C22
C23–C24–C25).
–
Figure 4. The variable-temperature 1H NMR spectra of 3b in CD2Cl2.
(a) 298 K; (b) 253 K; (c) 243 K; (d) 233 K and (e) 223 K; *, residual water
signal in CD2Cl2.
conformation of flexible molecules.42 Similarly, intra-
molecular alkyl–aromatic interaction can perform the
same role. This is because the methyl group possesses a
three-fold axial symmetry and has more surface contact than
aromatic edge–face interaction, which only has one
interaction site. In fact the study of conformation population
in the molecular folding reported by Wilcox has adduced the
evidence that the intramolecular alkyl–aryl interaction has
the same significance as the edge–face aromatic interaction
in directing the conformation.16–17 In general, intra-
molecular closeness between the C–H and p system results
from the structural rigidity of a molecule, an attractive force
between the C–H and p system or a consequence of crystal
packing, which arises from the overall balance of
interactions in a crystal structure. In the present case, the
crowded structure of the C–H and the p system in 3b does
not come from intrinsic structural rigidity because 3b can
take non-congested conformations (see infra). The distances
of Csp2–Csp3 observed in 3b was shorter than that of van der
Waals contact for Csp2–Csp3 by 4–19%. It seems persuasive
that interactions (models a, b, and c in Fig. 3) are
attributable to the stabilization of crystal packing. Taken
together, these intramolecular cooperative C–H/p inter-
actions would significantly exert a synergistic effect to force
3b to take a perpendicular conformation in solid state.
dynamic equilibrium of all conformers. As the temperature
decreased there were changes in their chemical shifts and
they reappeared as four broad signals at d 2.7, 2.4, 2.3, and
1.3, respectively. The signals began to sharpen at lower
temperatures and at 223 K, 12 relatively sharp singlets with
similar integration areas were observed for the methyl
protons. It is particularly noteworthy that two substantially
shifted signals emerged at d 1.36 and 1.19. Meanwhile, three
sets of signals at d 3.17, 2.84, and 2.14 with an integration
ratio of 2:1:1, which is very likely to correspond to benzylic
protons namely H41A/H41B, H59B, and H31B (see Fig. 2a),
respectively, were observed at the same temperature.
Considering the possible conformations with high sym-
metry, five different conformational structures of 3b (Fig. 5)
could correspond to that observed in the low temperature
limit. These are 3b-A (parallel), 3b-B (perpendicular) or its
mirror 3b-C, 3b-D (planar), and 3b-E (stacked). The
parallel conformer 3b-A and planar conformer 3b-D do
not have any of its internal methyl groups lying within the
shielding zone of another benzene ring and thus, should not
have any significantly shielded methyl protons. Whereas a
conformer like stacked 3b-E is ruled out because it has all
four internal methyl protons locating in the shielding zone
of the opposite pair of aromatic rings. If the frozen
conformation of 3b were similar to that in the solid state
as represented by perpendicular 3b-B or 3b-C, then there
would be two shielded methyl proton signals that were
consistent with what was observed. It was also observed that
the three sets of benzylic signals were upfielded shift by ca.
0.47, 0.81, and 1.50 ppm43 relative to that at room
temperature. This concurs with the fact that the magnitude
of upfield shifts observed correlates to the intra-atomic
2.3. Dynamic NMR spectroscopic study
Compound 3b. As mentioned above, the close contacts
between the C–H groups and p system in the solid state may
stem from the attractive C–H/p interaction instead of
crystal packing. However, in solution, if the C–H/p
interaction observed functions effectively, 3b is likely to
prefer to a similar conformation to that in solid state when
the effect of entropic factors on the conformation preference
is reduced to an insignificant level at low temperature. For a
flexible molecule, the conformation preference in solution
is, however, pertinent to not only the enthalpic but also
entropic factors due to the internal mobility42 even though
these C–H/p interactions are energetically attractive.
Thus, in comparison with the conformation in solid state,
separation in solid state (H31B–Csp2!H59B–Csp2
!
41A(H41B)–Csp2), suggesting that the conformation in
H
solution at low temperature agrees perfectly with that in
solid state. Moreover, the 13C NMR spectrum at 178 K
might provide useful conformational information (Fig. 6).
Two internal methyl carbons subjected to the C–H/p
interaction downfielded shift by 0.45 and 1.57 ppm with
respect to the chemical shifts at room temperature, while,
another pair of internal methyl carbon without being
1
3b was examined by H NMR spectroscopy at 500 MHz
over the temperature range of 298–223 K. (Fig. 4). At
ambient temperature, the signals observed in 1H NMR
spectrum come from the averaged signals due to the

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J.-W. Xu et al. / Tetrahedron 61 (2005) 9248–9256
Figure 5. Possible conformation of 3b in solution.
subjected to the C–H/p interaction experienced an
upfielded shift of more than 1.57 ppm.
entropy (DS8) in terms of the following equations:42,45
Observed internal methyl chemical shift Z P1d1 C3ð1KP1Þd2
On the other hand, the inter-conversion between 3b-B53b-
C would be established as the temperature was raised. The
well-separated pair of significantly shielded methyl signals at
highfieldservedasthebestprobe inthisconformationalstudy.
Using the Eyring equation,44 the energy barrier (DGcs) of
inter-conversion between 3b-B53c-C was estimated to be
about 12.1 kcal molK1 (TcZ253 K, DnZ86 Hz).
À
Á
Conformation with CH ꢀ p interaction P1
K
À
Á
#Conformation without CH ꢀ p interaction 1KP1
ꢀ
ꢁ
1KP1
TDS8KDH8
K Z
Z exp
As shown in Figure 4, all conformers convert rapidly on the
NMR time scale at temperatures higher than 253 K. The
chemical shifts of internal methyl protons are temperature
dependent and are considered as weighted average signals,
therefore, it is possible to estimate the enthalpy (DH8) and
P1
RT
Where P1 is defined as the fractional population of
conformers subject to C–H/p interaction and 1KP1 is
the fractional population of conformers without C–H/p
interaction. d1 and d2 represent the chemical shifts of
internal methyl probe with or without C–H/p interaction,
respectively. The calculated stabilization enthalpy and
entropy are 7.9G0.8 kcal molK1 and 23G3 cal molK1
respectively. The DH8 is much larger than the contribution
from a single C–H/p interaction (1.45 kcal molK1 31
and
,
)
it is high enough to repel 3b to take a complete
perpendicular conformation as observed at low temperature
at which the entropic effect was suppressed to a suitable low
level. Therefore, we can conclude that in view of the
enthalpy, the C–H/p interaction, which was amplified due
to the cooperativity effect,9–10,46 was responsible for the
preferential conformation at low temperature.
Compound 3a. NMR analysis indicated two non inter-
converting conformers of 3a in solution at room tempera-
ture. It would thus, be interesting to determine whether they
undergo inter-conversion at high temperature. The tempera-
1
Figure 6. Part of the 13C NMR spectrum of 3b at 178 K. Top: 298 K and
bottom: 178 K.
ture-dependent H NMR spectra of 3a were measured in
deuterated-nitrobenzene from room temperature to 393 K. As

J.-W. Xu et al. / Tetrahedron 61 (2005) 9248–9256
9253
assignment or structural feature could be deduced, but the
broad peaks around d 1.40 in the NMR spectra at low
temperature gave us an indication that the C–H/p
interaction exists. The observation in general also indicated
that the molecule 3a could adopt many possible confor-
mations at the low temperature limit but at room
temperature two major conformers were present with a
relatively high conformational barrier to inter-conversion.
3. Conclusions
In summary, crown-tetrathia[3.3.3.3]metacyclophanes were
synthesized via cesium carbonate-assisted high dilution
method with intermediate yields. X-ray crystallographic
analysis of 3b demonstrated that one pair of internal methyl
groups was in close proximity to the opposite aromatic rings
and, meanwhile, four benzylic protons approached the
periphery of adjacent aromatic rings. The variable tempera-
ture NMR spectroscopic experiments showed that the
chemical shifts of one pair of methyl groups and four
benzylic protons were upfielded shift at low temperature.
The change in chemical shifts intimated that the confor-
mation in solution at low temperature was congruent to that
observed in solid state. The correspondence in conformation
between solid state and solution as well as the determination
of total stabilization enthalpy of the C–H/p interaction
revealed that the intramolecular cooperative C–H/p
interaction dominated the preferential conformation both
in solid state and in solution.
Figure 7. The variable-temperature 1H NMR spectra of 3a in deuterated
nitrobenzene. (a) 300 K; (b) 315 K; (c) 352 K; (d) 368 K; (e) 373 K; (f) 383
and 393 K; *, residual water signal in deuterated nitrobenzene.
the temperature was raised to 393 K, the 12-methyl proton
signals broadened and were partially overlapped to appear
as four broad signals suggesting a possible inter-conversion
between the two conformers or others (Fig. 7).
4. Experimental
4.1. General
1
In contrast, the temperature-dependent H NMR spectra of
3a in CD2Cl2 were also determined down to the lower limit
of 178 K (Fig. 8). At 300 K, the six methyl proton signals
were resolved at d 2.41, 2.31, 2.25, 2.13, 2.07, and 1.92, the
last three being broad singlets. When the temperature was
lowered, the three broad signals coalesced at about 273 K,
and the other three began to broaden at about 253 K. At and
below 233 K many new signals began to appear in the
‘aromatic methyl proton’ range. The spectra at the low
temperature range were rather complicated and no peak
All melting points were determined with a Sybron/
Thermolyne MP-12615 melting point apparatus and were
uncorrected. The H NMR spectra were determined using
1
CDCl3 (unless otherwise stated) as solvent at room
temperature on a Bruker ACF (300 MHz) or on a Bruker
AMX (500 MHz) Fourier transform nuclear magnetic
resonance spectrometer. All chemical shifts are reported
in ppm downfield from tetramethylsilane as an internal
standard. All 13C NMR were determined in CDCl3 at room
temperature on a Bruker ACF (300 MHz) spectrometer.
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. Relative intensities are
given in parenthesis. Microanalysis was performed by the
Microanalytical Laboratory of the Department of
Chemistry, National University of Singapore.
4.2. Preparation of compounds 1
General procedure. Sodium hydroxide (1.76 g, 44 mmol)
was added to a solution of 2,4,6-trimethylphenol (6.0 g,
44 mmol) in THF (100 mL) to form the corresponding
phenoxide ion. Oligoethylene glycol dibromide (22 mmol)
was then added, and the mixture was stirred and refluxed
overnight. After the reaction was complete, the THF in
Figure 8. The variable-temperature 1H NMR spectra of 3a in CD2Cl2.
(a) 298 K; (b) 283 K; (c) 273 K; (d) 253 K; (e) 233 K; (f) 193 K and
(g) 178 K; *, residual water signal in CD2Cl2.

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J.-W. Xu et al. / Tetrahedron 61 (2005) 9248–9256
mixture was removed under the reduced pressure, and then
the residue was then poured into water and the product was
extracted with dichloromethane. The organic layer was
washed, dried, and evaporated. The crude product mixture
was chromatographed on silica gel using ethyl acetate/
hexane as eluent to give the desired product.
4.3.2. 1,11-Bis(2,4,6-trimethyl-3,5-dibromomethyl-
phenoxyl)-3,6,9-trioxaundecane (2b). Yield: 68%; white
solid: mp 131–134 8C; IR (KBr) 3004, 2925, 2870, 1456,
1417, 1379, 1346, 1308, 1263, 1208, 1138, 1105, 1051,
1017, 927, 871, 836, 792, 761, 704, 680, 628, 593, 570, 551,
467 cmK1. 1H NMR d 2.36 (12H, s, CH3), 2.40 (6H, s, CH3),
3.75 (8H, s, oxyethylene), 3.85 (8H, m, oxyethylene), 4.55
(8H, s, CH2Br); MS (EI) m/z 642 (MCK279Br, 1). Anal.
Calcd for C30H42Br4O5: C, 44.91; H, 5.28. Found: C, 45.30;
H, 5.24.
4.2.1. 1,8-Bis(2,4,6-trimethylphenoxyl)-3,6-dioxaoctane
(1a). Yield: 64%; white solid: mp 98.5–100 8C; IR (KBr)
3005, 2923, 2895, 2874, 2857, 1486, 1453, 1365, 1322,
1307, 1275, 1236, 1215, 1135, 1041, 955, 904, 858, 783,
595 cmK1. 1H NMR d 2.22 (6H, s, CH3), 2.25 (12H, s, CH3),
3.79 (4H, s, oxyethylene), 3.82–3.87 (4H, m, oxyethylene),
3.91–3.95 (4H, m, oxyethylene), 6.81 (4H, s, aromatic); MS
(EI) m/z 386 (MC, 69). Anal. Calcd for C24H34O4: C, 74.58;
H, 8.87. Found: C, 74.28; H, 9.10.
4.3.3. 1,14-Bis(2,4,6-trimethyl-3,5-dibromomethyl-
phenoxyl)-3,6,9,12-tetraoxatetradecane (2c). Yield:
59%; white solid: mp 114–116 8C; IR (KBr) 3005, 2949,
2874, 1455, 1420, 1377, 1348, 1309, 1263, 1208, 1141,
1118, 1108, 1072, 1052, 946, 872, 629, 553, 568, 468 cmK1
.
1H NMR d 2.36 (12H, s, CH3), 2.40 (6H, s, CH3), 3.70 (4H,
s, oxyethylene), 3.71–3.77 (8H, m, oxyethylene), 3.80–3.88
(8H, m, oxyethylene), 4.55 (8H, s, CH2Br); MS (EI) m/z 688
(MCK2Br, 0.5). Anal. Calcd for C32H46Br4O6: C, 45.41; H,
5.48. Found: C, 45.42; H, 5.61.
4.2.2. 1,11-Bis(2,4,6-trimethylphenoxyl)-3,6,9-trioxaun-
decane (1b). Yield: 83%; colorless oil; IR (neat) 3004,
2920, 2870, 2733, 1485, 1460, 1375, 1352, 1308, 1217,
1132, 1060, 1036, 955, 898, 855, 781 cmK1. 1H NMR d 2.23
(6H, s, CH3), 2.25 (12H, s, CH3), 3.69–3.77 (8H, m,
oxyethylene), 3.79–3.86 (4H, m, oxyethylene), 3.89–3.95
(4H, m, oxyethylene), 6.80 (4H, s, aromatic); MS (EI) m/z
430 (MC, 58). Anal. Calcd for C26H38O5: C, 72.53; H, 8.90.
Found: C, 72.40; H, 8.74.
4.4. Preparation of compounds 3
General procedure. A solution of 95% sodium sulfide
nonahydrate (480 mg, 2.0 mmol) in 95% ethanol (300 mL)
and a solution of tetrabromide 2 (1.0 mmol) in benzene
(300 mL) in separate rotaflow dropping funnels were added
dropwise simultaneously at the same rate to nitrogen purged
95% ethanol (1 L). After the addition the mixture was
stirred for overnight and the bulk of the solvent was
removed under reduced pressure. Water and dichloro-
methane 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 chro-
matographed on silica gel using ethyl acetate/hexane as
eluent to give 3.
4.2.3. 1,14-Bis(2,4,6-trimethylphenoxyl)-3,6,9,12-tetra-
oxatetradecane (1c). Yield: 38%; pale yellowish oil; IR
(neat) 3004, 2920, 2869, 1485, 1460, 1375, 1352, 1308,
1217, 1130, 1060, 955, 898, 855, 782 cmK1. 1H NMR d 2.23
(6H, s, CH3), 2.25 (6H, s, CH3), 2.26 (6H, s, CH3), 3.68–
3.76 (12H, m, oxyethylene), 3.80–3.84 (4H, m, oxy-
ethylene), 3.89–3.94 (4H, m, oxyethylene), 6.80 (4H, s,
aromatic); MS (EI) m/z 474 (MC, 62). Anal. Calcd for
C28H42O6: C, 70.86; H, 8.92. Found: C, 70.88; H, 8.79.
4.3. Preparation of compounds 2
4.4.1. 3,11,19,27-Tetrathia-7,15,23,31-biscrown-4-6,8,14,
16,22,24,30,32,33,34,35,36,-dodecamethyl-[3.3.3.3]meta-
cyclophane (3a). Yield: 22%; white solid: mp O300 8C; IR
(KBr) 2923, 2873, 1458, 1414, 1372, 1349, 1307, 1259,
1213, 1094, 933 cmK1. 1H NMR d 1.91 (br s, CH3), 2.10 (br
s, CH3), 2.13 (br s, CH3), 2.26 (s, CH3), 2.32 (s, CH3), 2.39
(s, total integration for the six signals 36H with the relative
intensities of the first, third, and fifth to the others being
0.7:1), 3.3–4.0 (m, 40H, CH2S and oxyethylene); 13C NMR
d 12.51, 12.61, 12.77, 12.90, 15.44, 15.71, 29.64, 30.24,
30.55, 32.24, 69.63, 70.41, 71.98, 72.14, 128.44, 128.77,
129.37, 129.55, 131.76, 131.93, 132.21, 132.67, 133.06,
133.39, 154.01, 154.26; MS (ESI) m/z 1005.5 ([MCH]C,
15), 1027.5 ([MCNa]C, 100). Anal. Calcd for C56H76O8S4:
C, 66.89; H, 7.62. Found: C, 67.21; H, 7.90.
General procedure. Compound 1 (7 mmol) was added to a
mixture of 47% aq HBr (15 mL) and glacial acetic acid
(100 mL), followed by 1,3,5-trioxane (4.8 g, 56 mmol) and
tetradecyltrimethyl ammonium bromide (0.60 g). The
mixture was warmed up and maintained at a temperature
of 70 8C for 2 h followed by heating at 95–97 8C for 5 h
(TLC was carefully performed to monitor the completeness
of the reaction). After the reaction was complete, the
reaction mixture was cooled to room temperature. The
mixture was poured into ice-water and extracted with
CH2Cl2. CH2Cl2 was washed with 5% NaHCO3 and water,
dried, and filtered. The organic solvent was removed
under the reduced pressure and the residue was chromato-
graphed on silica gel using ethyl acetate/hexane as eluent to
afford 2.
4.4.2. 3,11,19,27-Tetrathia-7,15,23,31-biscrown-5-6,8,14,
16,22,24,30,32,33,34,35,36-dodecamethyl-[3.3.3.3]meta-
cyclophane (3b). Yield: 30%; colorless crystal: mp 146–
149 8C; IR (KBr) 2920, 2872, 1458, 1375, 1351, 1308, 1260,
1225, 1100, 936, 875, 731 cmK1. 1H NMR d 1.98 (12H, br s,
CH3), 2.31 (12H, s, CH3), 2.47 (12H, s, CH3), 3.4–4.0 (48H, br
m, CH2S and oxyethylene); 13C NMR d 12.23, 12.85, 14.86,
30.14, 31.96, 70.25, 70.48, 70.93, 72.25, 128.75, 129.96,
131.66, 133.03, 133.26, 153.94; MS (ESI) m/z 1093.5 ([MC
4.3.1.
1,8-Bis(2,4,6-trimethyl-3,5-dibromomethyl-
phenoxyl)-3,6-dioxaoctane (2a). Yield: 54%; white solid:
mp 147–149 8C; IR (KBr) 2923, 2874, 1457, 1309, 1263,
1208, 1109, 1052, 1020, 928, 873, 835, 628, 554 cmK1
.
1H NMR d 2.37 (12H, s, CH3), 2.41 (6H, s, CH3), 3.79
(4H, s, oxyethylene), 3.86 (8H, s, oxyethylene), 4.56 (8H,
s, CH2Br); MS (EI) m/z 754 (MC, 0.3). Anal. Calcd
for C28H38Br4O4: C, 44.35; H, 5.05. Found: C, 44.60; H, 4.79.

J.-W. Xu et al. / Tetrahedron 61 (2005) 9248–9256
9255
H]C, 4), 1131.6 ([MCK]C, 100). Anal. Calcd for
C60H84O10S4: C, 65.90; H, 7.74. Found: C, 65.63; H, 7.99.
´
12. Amabilino, D. B.; Ashton, P. R.; Brown, C. L.; Codova, E.;
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4.4.3. 3,11,19,27-Tetrathia-7,15,23,31-biscrown-6-6,8,14,
16,22,24,30,32,33,34,35,36,-dodecamethyl-[3.3.3.3]meta-
cyclophane (3c). Yield: 30%; white solid: mp 194–197 8C;
IR (KBr) 2916, 2868, 1458, 1420, 1373, 1351, 1309, 1260,
1
1242, 1100, 937, 877, 839 cmK1. H NMR d 2.02 (12H, s,
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CH3), 2.31 (12H, s, CH3), 2.46 (12H, s, CH3), 3.62–3.78
(56H, m, CH2S and oxyethylene); 13C NMR d 12.00, 12.69,
14.61, 30.14, 31.93, 70.26, 70.70, 70.92, 71.16, 71.45,
72.02, 128.90, 129.67, 131.80, 132.78, 133.13, 153.43; MS
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Anal. Calcd for C64H92O12S4: C, 65.05; H, 7.85. Found: C,
65.35; H, 8.00.
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5. Supporting materials
Crystallographic data (excluding structure factors) for the
structure in this paper has been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication numbers CCDC 186822 (3b). Copies of the data
can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [fax: C44 1223
336033 or e-mail: deposit@ccdc.cam.ac.uk].
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Acknowledgements
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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.
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