9-Fluoro-18-hydroxy-[3.3]metacyclophane: Synthesis and estimation of a C-F...H-O hydrogen bond

Article abstract of DOI:10.1002/ejoc.200300698

A cyclophane composed of fluorobenzene and phenol units was synthesized in order to observe the C-F...H-O hydrogen bond. In the crystal structure, 20% of the molecule clearly shows the intramolecular hydrogen bond and the other 80% is free from hydrogen bonding. On the other hand, a distinct low-field shift of the phenolic OH proton was observed in the ¹H NMR spectrum compared to that of the F-free analog. Furthermore, O-H...F through-space coupling was observed. From the results of the crystallographic analysis, IR, and NMR spectra, the C-F...H-O hydrogen bond energy of this system was estimated to be 0.84-3.7 kJ·mol^-1. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200300698

FULL PAPER
9-Fluoro-18-hydroxy-[3.3]metacyclophane: Synthesis and Estimation of a
C؊F···H؊O Hydrogen Bond
Hiroyuki Takemura,*[a] Masayuki Kotoku,[b] Mikio Yasutake,[c][‡] and Teruo Shinmyozu[c]
Keywords: Hydrogen bonds / Fluorine / Cyclophanes / X-ray diffraction
A cyclophane composed of fluorobenzene and phenol units
was synthesized in order to observe the C−F···H−O hydrogen
bond. In the crystal structure, 20% of the molecule clearly
shows the intramolecular hydrogen bond and the other 80%
is free from hydrogen bonding. On the other hand, a distinct
low-field shift of the phenolic OH proton was observed in
the 1H NMR spectrum compared to that of the F-free analog.
Furthermore, O−H···F through-space coupling was observed.
From the results of the crystallographic analysis, IR, and
NMR spectra, the C−F···H−O hydrogen bond energy of this
system was estimated to be 0.84−3.7 kJ·mol−1
.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
range). Therefore, they concluded that the interaction is
weak. On the other hand, Caminati et al. observed the free
jet millimeter wave spectra of the CH2F2···H2O system, and
The CϪF···HϪX (X ϭ O, N) hydrogen bonds are a new
type of hydrogen bond, which was first proposed by
Glusker et al. in 1983.[1] Following their work, research
studies and discussions have been continued by many re-
searchers who are still making efforts to confirm the hydro-
gen bonds using a variety of methods. This tendency indi-
cates that CF···HϪX hydrogen bonds are not widely dis-
tributed even in modern chemistry. Various methods are
employed for the search, i.e., statistical methods utilizing a
crystallographic database,[2,3] crystallographic analyses,
˚
concluded that the optimized distance r(F···H) ϭ 2.20 A
and the angles Є(F···HϪO) and Є(CϪF···H) are 135 and
93°, respectively.[14]
Our studies of the CϪF···Mϩ interaction revealed that
the CϪF unit attracts all kinds of cations by
a
cationϪdipole interaction as the main driving force.[15]
Therefore, we can deduce that CϪF can be a proton ac-
ceptor because the interaction also operates in the polarized
X
δϪϪHδϩ (X ϭ O, N) system.
spectroscopic
methods,[4Ϫ9]
and
theoretical
Based on this speculation, we employed the cyclophane
calculations.[10Ϫ12] Howard et al. adopted fluoromethane
and fluoroethene as CϪF donors and concluded that the
average F···H distance of the C(sp3)ϪF···HϪO,
skeleton for investigating the CϪF···HϪO hydrogen bond.
Phenol and fluorobenzene units in cyclophane 1 are fixed
and close to each other (Figure 1). Its spectral features can
be compared to those of the structurally analogous cyclo-
2
˚
C(sp )ϪF···HϪO hydrogen bond is 1.9 A using ab initio
calculations.[13] They also found that examples of
CϪF···HϪO and CϪF···HϪN hydrogen bonds are rare in
the Cambridge Structural Database System (CSDS) and
showed that the F···HϪX angles are dispersed (the statisti-
cally found CϪF···HϪO angles are not within the certainty
˚
phanes 2 and 3. The CϪF···HϪO distance (ca. 1.9 A) and
CϪF···H and F···HϪO angles (ca. 99.5 and 156°) of 1 were
estimated using simple molecular-model considerations.
These values are close to those estimated by Howard et al.
and Caminati et al. Therefore, cyclophane is thought to be
an appropriate system for the observation of the
CϪF···HϪO hydrogen bond. In this report, synthesis of the
[a]
Department of Chemistry, Faculty of Science, Kyushu
University,
Ropponmatsu 4-2-1, Chuo-ku, Fukuoka 810-8560, Japan
Fax: (internat.) ϩ 81-92-726-4755
E-mail: takemura@chem.rc.kyushu-u.ac.jp
[b]
Department of Chemistry, Faculty of Science, Kyushu
University,
Hakozaki 6-10-1, Higashi-ku, Fukuoka 812-8581, Japan
[c]
Institute for Materials Chemistry and Engineering, Kyushu
University,
Hakozaki 6-10-1, Higashi-ku, Fukuoka 812-8581, Japan
[‡]
Present address: Department of Applied Chemistry, Faculty of
Engineering, Saitama University,
255 Shimo-ohkubo, Sakuraku, Saitama 338-8570, Japan
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Figure 1. Structures of cyclophanes 1Ϫ3
Eur. J. Org. Chem. 2004, 2019Ϫ2024
DOI: 10.1002/ejoc.200300698
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2019

H. Takemura, M. Kotoku, M. Yasutake, T. Shinmyozu
FULL PAPER
Scheme 1. Synthetic strategies of the cyclophane 1: 1) Bu4NI, CH2Cl2/aq. NaOH; 2) concd. HCl; 3) Zn/HCl (g), diethyl ether; 4) 10%
Pd/C, HCOONH4, MeOH; 5) NaH, DMF; 6) concd. HCl; 7) NH2NH2·H2O, KOH, diethylene glycol: * each yield was calculated based
1
on the integration of signals in H NMR spectrum
cyclophane, structural analysis and spectral features are dis- One of them has an OϪH proton almost parallel to the
cussed as one approach for investigating the CϪF···HϪO benzene ring, which was observed in 80% probability.
hydrogen bond.
An OϪH of another molecule is twisted and the
proton is near the F atom. In Figure 2, these protons
are shown in one molecule. The dihedral angles
Results and Discussion
are ЄC(17)ϪC(18)ϪO(1)ϪH(19)
ϭ
1.7° and
Є
Synthesis
C(17)ϪC(18)ϪO(1)ϪH(20) ϭ 51.3°. The F···H(20) distance
The [3.3]metacyclophane skeleton was constracted by the
TosMIC method (Scheme 1).[16] However, an unexpected
ether product 8 was obtained by the initially chosen stra-
tegies employing a cyclization reaction between the acetyl-
protected dibromide 4b and TosMIC derivative 5 in DMF
with NaH as the base at room temperature. This disadvan-
tage was overcome by altering the protecting group from
an acetyl to a benzyl group. The phase-transfer reaction
between 4a and 5 followed by treatment of the reaction mix-
ture with aq. HCl afforded the diketone 6 in 50.1% yield.
The WolffϪKischner reduction of the cyclophane diketone
6 gave 7 and an ether product 9, but the separation of each
product from the mixture was difficult. Therefore, com-
pound 6 was reduced by the modified Clemmensen re-
duction procedure,[17] which gave 7 in 70.9% yield. Depro-
tection and dechlorination were simultaneously achieved by
treating compound 7 with 10% Pd/C in the presence of am-
monium formate. Cyclophane 1 was thus obtained in good
yield from 7 (96.9%). The analogous reference compounds
2 and 3 were synthesized using the literature method re-
ported by Osada et al.[18]
˚
is 2.11 A, which is much shorter than the sum of the van
˚
˚
der Waals radii (2.67 A) of the H atom (1.20 A) and F atom
[19]
˚
(1.47 A).
On the other hand, the F···H(19) distance is
˚
2.90 A and thus, H(19) apparently has no interaction with
the F atom. The observed angles, ЄC(9)ϪF···H(20) ϭ
105.5° and OϪH(20)···F ϭ 131.6°, and the F···H(20) dis-
tance are fairly near the values reported by Howard et al.
and Caminati et al. The former found the potential mini-
2
˚
mum of the C(sp )ϪF···HϪO hydrogen bond at 1.9 A and
the latter observed the angles and distances of
Є
˚
CϪF···HϪO ϭ 93°, ЄOϪH···F ϭ 135° and r ϭ 2.20 A in
the CH2F2ϪH2O system. Furthermore, the OϪH(20) dis-
˚
˚
tance is 0.99 A, while OϪH(19) is 0.82 A. The two facts,
formerly described as the short F···H(20) distance and the
elongated OϪH(20) bond, apparently indicate the existence
of a hydrogen bond between H(20) and the F atom. How-
ever, the proportion of the hydrogen-bonded H atom is only
20%, and it is thus a weak interaction. According to the
Boltzmann distribution law, the energy difference between
O(19)ϪH and O(20)ϪH is only 1.6 kJ molϪ1, which can
roughly be considered as the stabilization energy of the
CϪF···HO hydrogen bond of this system at 123 K.
Crystallographic Analysis
Crystallographic analysis of 1 at low temperature (123 K) Spectroscopic Investigations
revealed that two kinds of molecules exist in the crystal.
2020
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2004, 2019Ϫ2024

9-Fluoro-18-hydroxy-[3.3]metacyclophane
FULL PAPER
is equivalent to the CϪF···HϪO hydrogen bond energy of
0.84Ϫ1.1 kJ·molϪ1
.
NMR Spectra
Because the IR spectra in solution did not give any infor-
mation, the 1H and 19F NMR spectra were evaluated. These
results are summarized in Table 2. The chemical shifts of
the phenolic OH protons of 1 and 2 in CDCl3 at the con-
centrations of 1.0 ϫ 10Ϫ1, 1.0 ϫ 10Ϫ2 and 1.0 ϫ 10Ϫ3
mol·dmϪ3 were the same within the experimental errors
[δOH(1) ϭ 4.87 ppm; δOH(2) ϭ 4.61 ppm]. On the other
hand, the OH proton of 1 in [D14]methylcyclohexane
showed concentration-dependent chemical shifts, i.e., the
OH proton signal appeared at δ ϭ 4.75 ppm (1.0 ϫ 10Ϫ1
Figure 2. Molecular structure of the cyclophane 1
mol·dmϪ3), 4.62 ppm (1.0
ϫ
10Ϫ2 mol·dmϪ3), and
4.60 ppm (1.0 ϫ 10Ϫ3 mol·dmϪ3). In the case of cyclophane
2, such chemical shifts were not observed at a concentration
of 1.0 ϫ 10Ϫ1 to 1.0 ϫ 10Ϫ3 mol·dmϪ3; it appears at δ ϭ
4.20 ppm as a singlet. Although an interaction with CDCl3
is apparent, the OH signal of 1 appears at a lower field than
that of 2, and this is the same in the noninteracting solvent,
[D14]methylcyclohexane. Therefore, the CϪF···HϪO hydro-
IR Spectra
In the IR spectra (Table 1), the νOH bands of 1 and 2
appeared as a sharp band around 3620 cmϪ1 in methyl-
cyclohexane and CCl4 at the concentration of 1.0 ϫ 10Ϫ1
mol dmϪ3. However, in diluted solution (10Ϫ2, 10Ϫ3 and
10Ϫ4 mol dmϪ3), no substantial changes were observed.
1
gen bond is obvious in the H NMR spectra. Moreover,
specific phenomena were seen in the spectrum of 1, viz., the
OH signal appeared as a doublet (JH,F ϭ 6.0 Hz) which
shows the through-space coupling with the fluorine atom.
By irradiation of the F atom, the coupling disappeared and
the doublet became a singlet. Furthermore, in a donating
solvent such as [D6]DMSO, the signal appeared as a singlet.
This is further evidence of an O-H···F interaction.
The δF values of cyclophanes 1 and 3 were compared in
their 19F NMR spectra (Table 2). The differences were
small, but in both CDCl3 and [D14]methylcyclohexane,
chemical shifts of the F signal of cyclophane 1 are higher
than those of 3 (1.0Ϫ1.6 ppm). This high-field shift of the
F signal reminds us of similar phenomena in the metal com-
plexes of fluorinated cage compounds.[22] The CϪF···Mϩ
attractive interaction has now been unambiguously estab-
lished by this group and Plenio et al.,[23,24] and the high-
field shift of the F signal usually occurs during the
CϪF···Mϩ interaction. Therefore, in the CϪF···HδϩϪOδϪ
system, the same phenomena should also be observed.
Here, again, the hydrogen bond is confirmed by comparison
of the 19F NMR spectra of cyclophanes 1 and 3.
Table 1. IR spectra (νOH in cmϪ1) of 1 and 2: (A) crystal (transmit-
tance IR), (B) KBr pellet, (C) in methylcyclohexane (1.0 ϫ 10Ϫ4
mol dmϪ3), and (D) in CCl4 (1.0 ϫ 10Ϫ4 mol dmϪ3
)
1
2
(A)
(B)
(C)
(D)
3610, 3560
3610, 3560
3620
3541, 3471
3542, 3473
3618
3621
3621
As seen in the crystallographic analysis, 20% of the OH
proton binds to the F atom of 1. Therefore, the IR spectra
of the crystalline state are essential to detect the hydrogen
bond. In the crystal lattice, the OH group is independent
and no intermolecular interaction was observed (see Sup-
porting Information; footnote on the first page of this arti-
cle). Therefore, the band in the transmittance spectra of 1
should show the bands of the hydrogen-bond-free OϪH
and the CϪF···HϪO band. The transmittance IR spectra
of the crystals of 1 and 2 were almost identical to those
measured in KBr pellets. Both cyclophanes 1 and 2 have
The temperature-dependent shift of the OH proton is an-
two νOH bands. In the case of 1, a relatively broad band other interesting feature in the study of the hydrogen bond.
appears at 3560 cmϪ1 accompanied by a sharp band at 3610 Variable-temperature 1H NMR spectra of 1 and 2 were
cmϪ1. Similarly, compound 2 has a relatively broad band at measured in nonpolar and polar solvents, [D14]methylcy-
3471 cmϪ1 and a sharp band at 3541 cmϪ1. Unfortunately, clohexane and [D6]DMSO. As shown in Figure 3, the OH
crystallographic analysis of compound 2 failed, so the mo- proton spectra of 1 and 2 are strongly temperature-depen-
lecular arrangement and information about the hydrogen- dent, especially below 240 K. In the case of 2, two kinds of
bond pattern in the crystal are unknown.[20] Further dis- OH proton signals appeared below 243 K. At this tempera-
cussion seems to be difficult because assignment of those ture, conformational changes of the trimethylene bridge
Ǟ
ǟ
νOH bands cannot be achieved. However, we can speculate (boat chair) are involved.[25] Therefore, the two OH pro-
that the CϪF···HϪO hydrogen bond may have anti-hydro- tons correspond to those of the conformational isomers. In
gen-bond character because both bands of 1 are blue- the case of cyclophane 1, conformational changes also oc-
shifted (70Ϫ90 cmϪ1) compared to those of 2.[21] The ∆νOH cur below 243 K. However, only one kind of OH proton
Eur. J. Org. Chem. 2004, 2019Ϫ2024
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2021

H. Takemura, M. Kotoku, M. Yasutake, T. Shinmyozu
FULL PAPER
Table 2. NMR shifts of OH and F signals (1.0 ϫ 10Ϫ2 mol·dmϪ3) of the cyclophanes at 25 °C (A) in [D14]methylcyclohexane, and (B)
in CDCl3
1H, δ(OH)
19F, δ(19F)
(B)
(A)
(B)
(A)
1
2
3
4.60 [d, J(HϪF) ϭ 6.6 Hz]
4.21 (s)
Ϫ
4.86 [d, J(HϪF) ϭ 6.0 Hz]
4.58 (br. s)
Ϫ
Ϫ120.3 (br. s)
Ϫ
Ϫ118.7 (s)
Ϫ119.9 (br. s)
Ϫ
Ϫ118.9 [d, J(HϪF) ϭ 3.5 Hz]
was observed. In the polar solvent ([D6]DMSO), the OH Conclusion
signal of 1 is shifted to a high-field region compared to that
A [3.3]metacyclophane, which is composed of a phenol
unit and a fluorobenzene unit, was synthesized. It is a sim-
ple model for the investigation of the CϪF···HϪO hydrogen
bond. The cyclophane skeleton is suitable for realizing the
ideal F···HϪO distance and angles, and to obtain the en-
tropy. Actually, evidence for the CϪF···HϪO hydrogen
bond is observed from the results of the crystallographic
analysis. Two kinds of OH hydrogen atoms are observed
and one of them is pointing towards the fluorine atom. The
H···F distance is shorter than the sum of the van der Waals
radii of the H and F atoms, and the OϪH bond is longer
than that of another proton which is separated from the F
of 2 (∆δ ϭ Ϫ0.25 ppm at 298 K). This phenomenon reflects
that the hydrogen bond between 1 and DMSO is inhibited
by the intramolecular hydrogen bond.
1
atom. In the H NMR spectrum, the OH proton signal of
1 appears at a lower field than that of the fluorine-free ana-
log 2. Furthermore, through-space coupling between the F
atom and OH proton is observed. Although the IR spectra
did not give a clear result, it is speculated that the
CϪF···HϪO hydrogen bond has an anti-hydrogen-bond
character. The CϪF···HϪO hydrogen bond energy in this
system was estimated to be 0.84Ϫ3.7 kJ·molϪ1 according to
the results of the crystallographic analysis and the IR and
NMR spectra. Although the CϪF···HϪO hydrogen bond
is very rare in the crystallographic database, it is possible
to observe it by this simple molecular design. A forcibly
approached OH and CF unit with the appropriate distance
and angle clarified this weak interaction.
Figure 3. Plots of δOH in [D6]DMSO and [D14]methylcyclohexane
at various temperatures
Experimental Section
The difference of chemical shift of the OH proton, ∆δ,
between 1 and 2 is almost constant (∆δ ഠ 0.5 ppm in
[D14]methylcyclohexane) between 273 and 363 K, and the
∆δ value indicates the C-F···HϪO binding energy. Schaefer
represented the relationship between hydrogen-bond energy
and chemical shift of ortho-substituted phenols.[26] The em-
pirical equation ∆δOH ϭ Ϫ0.4 ϩ E (E is the hydrogen-bond
energy in kcal·molϪ1) can be applied to our cyclophane sys-
tem. According to the equation, the C-F···HϪO hydrogen
General Procedure: Melting points (uncorrected): Yanaco MP-
500D apparatus in Ar sealed tubes. NMR: Bruker DPX-400
(400.1 MHz for 1H, 100.6 MHz for 13C, and 376.5 MHz for 19F
with TMS and CFCl3 as internal references, respectively) and
JEOL GSX 270 (270 MHz for H and 67.9 MHz for 13C). IR: JA-
1
SCO IR-700 [methylcyclohexane in NaCl cells (0.1 and 0.5 mm) at
25°C]. FAB and EI MS: JEOL JMS-SX/SX102A. Elemental analy-
sis: the Service Centre of the Elementary Analysis of Organic Com-
pounds affiliated with the Faculty of Science, Kyushu University.
bond of 1 is estimated to be 0.89 kcal·molϪ1 (3.7 kJ molϪ1
in [D14]methylcyclohexaneand 0.65
kcal·molϪ1
(2.7 kJ·molϪ1) in [D6]DMSO at 298 K.
)
Crystallographic Data of 1: C18H19OF, Mr ϭ 270.35 g·mo1Ϫ1
platelet crystal (grown from n-hexane), size 0.40 ϫ 0.20 ϫ 0.05 mm,
,
From the results of the crystallographic analysis, IR spec-
tra and NMR spectra, we estimated the C-F···HϪO hydro-
gen bond energy of 1 to be 0.84Ϫ1.6 kJ·molϪ1 in the solid
state and 2.7Ϫ3.7 kJ·molϪ1 in solution.
˚
monoclinic, space group P21 (no. 4), a ϭ 8.719(1) A, b ϭ 8.552(1)
A, c ϭ 9.599(1) A, V ϭ 695.3(2) A , Z ϭ 2, ρcalcd. ϭ 1.291 g·cmϪ3
,
3
˚
˚
˚
µ(Cu-Kα) ϭ 7.01 cmϪ1, F(000) ϭ 288.00, T ϭ Ϫ150 Ϯ 1 °C using
the ω-2θ scan technique to a maximum 2θ value of 136.4°. A total
2022
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Eur. J. Org. Chem. 2004, 2019Ϫ2024

9-Fluoro-18-hydroxy-[3.3]metacyclophane
FULL PAPER
of 4177 reflections were collected. The final cycle of the full-matrix
least-squares refinement was based on 1990 observed reflections [I
Ͼ 2σ(I)] and 182 variable parameters and converged with un-
9-Benzyloxy-6-chloro-18-fluoro[3.3]metacyclophane (7): Dry HCl
gas was bubbled into dry ether (80 mL) at Ϫ10 °C for 1 h, and
compound 6 (1.48 g, 3.5 mmol) was added. The resultant suspen-
weighted and weighted agreement factors of R ϭ 0.067, Rw ϭ sion was cooled to Ϫ20 °C and activated Zn powder (2.0 g) was
0.202, and GOF ϭ 1.09. The maximum and minimum peaks on added in small portions. After the addition, the temperature was
the final difference Fourier map corresponded to 0.22 and Ϫ0.25
raised to Ϫ5 °C and the mixture stirred for 2 h. The resultant mix-
Ϫ
e ·AϪ3, respectively. The ratio of two kinds of molecules in the ture was poured onto crushed ice (40 g) and the organic phase was
˚
crystal was calculated and the probability of 0.8:0.2 afforded the
optimal result. CCDC-213846 contains the supplementary crystal-
lographic data for this paper. These data can be obtained free of
charge at www.ccdc.cam.ac.uk/conts/retrieving.html [or from the
Cambridge Crystallographic Data Centre, 12 Union Road, Cam-
separated. The aqueous phase was extracted twice with ether, and
all the diethyl ether solutions were combined. They were washed
with aq. NaHCO3 and dried with MgSO4, the solvent was removed
and the resultant powder was recrystallized from n-hexane. Color-
l
less prisms (yield 980 mg, 70.9%), m.p. 102.1Ϫ102.6 °C. H NMR
bridge CB2 1EZ, UK; Fax: (internat.) ϩ 44-1223/336-033; E-mail: (CDC13): δ ϭ 7.53Ϫ7.31 (m, 5 H, ArH), 6.73 (m, 1 H, ArH), 6.63
3
deposit@ccdc.cam.ac.uk].
(dd, JH,H ϭ 7.0 Hz, 2 H, ArH), 6.52 (s, 2 H, ArH), 4.65 (s, 2 H,
CH2), 3.10Ϫ3.02 (m, 4 H, CH2), 2.52Ϫ2.33 (m, 6 H, CH2),
1.85Ϫ1.75 (m, 2 H, CH2) ppm. FAB-MS: m/z ϭ 394 [Mϩ].
C25H24ClFO (394.91): calcd. C 76.03, H 6.13; found C 75.99, H
6.10.
1-Benzyloxy-4-chloro-2,6-bis(hydroxymethyl)benzene: The com-
pound was prepared by the reaction between 4-chloro-2,6-bis(hyd-
roxymethyl)phenol and benzyl bromide with K2CO3 as a base in
acetone (86.4%). Recrystallization from toluene/methanol gave a
colorless powder; m.p. 125.2Ϫ126.9 °C. 1H NMR ([D6]DMSO):
18-Fluoro-9-hydroxy[3.3]metacyclophane (1):
A mixture of the
3
δ ϭ 7.46Ϫ7.35 (m, 5 H, ArH), 7.33 (s, 2 H, ArH), 5.27 (t, JH,H ϭ
cyclophane (197 mg, 0.50 mmol) and ammonium formate
7
3
5.5 Hz, 2 H, OH), 4.83 (s, 2 H, CH2), 4.52 (d, JH,H ϭ 6.0 Hz, 4
(221 mg, 3.5 mmol) in MeOH (60 mL) was stirred at room tem-
perature under N2; 10% Pd/C (100 mg) was added to the mixture,
which was then stirred at room temperature for 5 h. The mixture
was filtered through Celite and the solvent was removed. The re-
sultant mixture was extracted with diethyl ether and the solution
was washed with brine and dried with MgSO4. After removal of
the solvent, compound 1a was obtained as a white powder, which
was recrystallized from n-hexane. Colorless prisms (yield 131 mg,
96.9%), m.p. 84.5Ϫ84.8 °C. 1H NMR (CDC13): δ ϭ 6.63Ϫ6.53 (m,
H, CH2) ppm. FAB-MS: m/z ϭ 278.1, 280.1. C15H15ClO3 (278.73):
calcd. C 64.64, H 5.42; found C 64.72; H 5.46.
1-Benzyloxy-2,6-bis(bromomethyl)-4-chlorobenzene (4a): The com-
pound was prepared by treatment of 1-benzyloxy-4-chloro-2,6-bi-
s(hydroxymethyl)benzene with PBr3 in diethyl ether (yield 86.8%).
The resultant powder was recrystallized from n-hexane. Colorless
1
solid, m.p. 97.3Ϫ98.5 °C. H NMR (CDC13): δ ϭ 7.53Ϫ7.39 (m,
5 H, ArH), 7.38 (s, 2 H, ArH), 5.16 (s, 2 H, CH2), 4.46 (s, 4 H,
CH2) ppm. FAB-MS: m/z ϭ 402.9, 403.9, 404.9 [M ϩ Hϩ].
C15H13Br2ClO·1/12C6H14 (411.71): calcd. C 45.22, H 3.47; found
C 45.08; H 3.30.
3
3
5 H, ArH), 6.39 (t, JH,H ϭ 7.0 Hz, 1 H, ArH), 4.87 (d, JH,H
ϭ
6.0 Hz, 1 H, CH2), 3.09Ϫ2.99 (m, 4 H, CH2), 2.65Ϫ2.54 (m, 4 H,
CH2), 2.42Ϫ2.35 (m, 2 H, CH2), 1.92Ϫ1.81(m, 2 H, CH2) ppm.
FAB-MS: m/z ϭ 270 [Mϩ]. C18H19FO (270.34): calcd. C 79.97, H
7.08; found C 79.91, H 7.08.
1-Fluoro-2,6-bis[2-isocyano-2-(4-tolylsulfonyl)ethyl]benzene (5): The
compound was synthesized by reaction between 2,6-bis(bromome-
thyl)-1-fluorobenzene and TosMIC (yield 62.8%) according to the
literature method.[16] Recrystallization from CH2Cl2/diethyl ether
1-Acetoxy-2,6-bis(bromomethyl)-4-chlorobenzene (4b): A mixture of
2,6-bis(bromomethyl)-4-chlorophenol (6.29 g, 20 mmo1), acetic an-
hydride (2.4 mL, 25 mmol), and BF3·Et2O (0.l mL, 0.8 mmol) in
dry diethyl ether (20 mL) was stirred at room temperature for 10 h.
The mixture was added to water (20 mL) and the resultant white
powder was collected by filtration and washed with water to give
the pure compound (yield 6.10 g, 85.6%). Recrystallization from
n-hexane gave colorless needles, m.p. 143.3Ϫ144.2 °C. 1H NMR
(CDC13): δ ϭ 7.39 (s, 2 H, ArH), 4.31(s, 4 H, CH2), 2.15 (s, 3
H, CH3) ppm. FAB-MS: m/z ϭ 354.9, 356.9, 358.9 [M ϩ Hϩ].
C10H9Br2ClO2 (356.44): calcd. C 33.70, H 2.55; found C 33.80,
H 2.50.
1
gave colorless fine crystals, m.p. 112 °C (dec.). H NMR (CDC13):
3
δ ϭ 7.91, 7.45 (AB q, JH,H ϭ 8.4 Hz, 8 H, ArH), 7.28Ϫ7.13 (m,
3
3 H, ArH), 4.68 (dd, JH,H ϭ 10.8 Hz, 2 H, CH), 3.73Ϫ3.04 (m, 4
H, CH2), 2.50 (s, 6 H, CH3) ppm. FAB-MS: no molecular peak
was found. C26H23FN2S2O4 (510.60): calcd. C 61.16, H 4.54, N
5.49; found C 60.88, H 4.63; N 5.52.
9-Benzyloxy-6-chloro-18-fluoro[3.3]metacyclophane-2,11-dione (6):
A mixture of CH2Cl2 (1.3 L), 40% aq. NaOH (50 mL), and nBu4NI
(1.69 g, 4.58 mmol) was heated under reflux with vigorous stirring.
To this mixture, a solution of 4a (4.05 g, 10.0 mmol) and 5 (5.62 g,
11.0 mmo1) in CH2Cl2 (250 mL) was added dropwise over a period
of 6 h. Additional heating and stirring were continued for 5 h. After
cooling, the organic phase was separated and washed with brine.
The solution was concentrated to ca. 300 mL, conc. HCl (30 mL)
Compound 8: A solution of 4b (3.56 g, 10 mmol) and 5 (5.11 g,
10 mmol) in dry DMF (500 mL) was added to a stirred mixture of
NaH (60% in mineral oil, 1.20 g, 30 mmo1) and dry DMF
(700 mL) at room temperature over a period of 10 h. Additional
was added and the mixture was stirred at room temperature for stirring was continued for 10 h and then the mixture was quenched
40 min. The organic phase was separated, washed with water and
dried with MgSO4. The solvent was removed under reduced press-
ure and a small amount of acetone was added. After several hours,
with MeOH. The solvent was removed under reduced pressure and
MeOH was added. After several hours, pale-yellow crystals precipi-
tated. The crystals were collected by filtration and dissolved in
the precipitated colorless prisms were collected (yield 2.12 g, CH2Cl2 (300 mL). Concentrated HCl (20 mL) was added to the
1
50.1%), m.p. 138.4Ϫ138.8 °C. H NMR (CDC13): δ ϭ 7.53Ϫ7.32 solution, which was stirred at room temperature for 30 min. The
3
(m, 3 H, ArH), 7.24 (s, 2 H, ArH), 7.12 (dd, JH,H ϭ 7.0 Hz, 2 H,
organic phase was separated, washed with water and dried with
3
ArH), 7.05Ϫ7.03 (m, 2 H, ArH), 6.84 (t, JH,H ϭ 7.5 Hz, 1 H, MgSO4. The solvent was removed and a small amount of acetone
ArH), 4.32 (s, 2 H, CH2), 3.80Ϫ3.15 (m, 8 H, CH2) ppm. FAB-
MS: m/z ϭ 423 [M ϩ Hϩ]. C25H20ClFO3 (422.88): calcd. C 71.01,
H 4.77; found C 71.03; H 4.78.
was added to the residue. Colorless prisms that precipitated after
several hours were collected (yield 1.10 g, 35.2%), m.p. 259.7Ϫ260.1
1
°C. H NMR (CDCl3): δ ϭ 7.17Ϫ7.13 (m, 5 H, ArH), 3.72Ϫ3.56
Eur. J. Org. Chem. 2004, 2019Ϫ2024
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2023

H. Takemura, M. Kotoku, M. Yasutake, T. Shinmyozu
FULL PAPER
(m, 8 H, CH2) ppm. FAB-MS: m/z ϭ 313 [M ϩ Hϩ]. C18H13ClO3
(312.75): calcd. C 69.13, H 4.19; found C 69.15, H 4.20.
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Compound 9: A mixture of 8 (665 mg, 2.13 mmol), 80% hydrazine
hydrate (3.4 mL, 53 mmol), diethylene glycol (30 mL), and KOH
(1.57 g, 23.8 mmol) was heated at 120 °C for 2 h, and then the
temperature was raised to 180 °C. The water generated during the
reaction was removed by a DeanϪStark condenser. Additional
heating was continued for 2 h, then the mixture was cooled, poured
into water and extracted twice with CH2Cl2. The organic phase was
washed with water and brine, then dried with MgSO4. The solvent
was removed and the residue was recrystallized from MeOH. Col-
orless needles (421 mg, 69.4%). M.p. 112.3Ϫ112.7 °C. 1H NMR
(CDC13): δ ϭ 6.97Ϫ6.89 (m, 5 H, ArH), 3.21Ϫ3.13 (m, 2 H, CH2),
2.81Ϫ2.70 (m, 2 H, CH2), 2.39Ϫ2.32 (m, 1 H, CH2), 1.76Ϫ1.55
(m, 1 H, CH2) ppm. FAB-MS: m/z ϭ 284 [Mϩ]. C18H17C1O
(284.78): calcd. C 75.92, H 6.02; found C 75.84, H 6.05.
Crystallographic analysis of p-Cl analog of 2 (6-chloro-9-
hydroxy[3.3]metacyclophane) succeeded. It showed inter-
molecular OϪH···O hydrogen bonds and even intermolecular
Cl···HϪO hydrogen bonds. Unpublished results.
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