Synthesis, X-ray crystal studies and metal picrates extraction properties of lipophilic benzocrown ethers

Article abstract of DOI:10.1071/CH10112

The preparation of 16 macrocycles based on 2-(2-hydroxyethoxy) phenol with both aliphatic and aromatic linkers has been achieved. Macrocycles varying in ring sizes (2328 atoms), number of aromatic groups (24), and donor atoms (610 including oxygen and nit

Full text of DOI:10.1071/CH10112

Full Paper
CSIRO PUBLISHING
Aust. J. Chem. 2010, 63, 1348–1357
www.publish.csiro.au/journals/ajc
Synthesis, X-ray Crystal Studies and Metal Picrates Extraction
Properties of Lipophilic Benzocrown Ethers
Ewa Kowalska,A Jaywant Phopase,A and Nicholas GathergoodA,B
ADepartment of Chemical Sciences and National Institute of Cellular Biotechnology,
Dublin City University, Glasnevin 9, Ireland.
BCorresponding author. Email: nick.gathergood@dcu.ie
The preparation of 16 macrocycles based on 2-(2-hydroxyethoxy) phenol with both aliphatic and aromatic linkers has been
achieved. Macrocycles varying in ring sizes (23–28 atoms), number of aromatic groups (2–4), and donor atoms (6–10
including oxygen and nitrogen) were synthesized. Binding affinities were also assessed by extraction studies against a
series of metal picrates. X-ray crystal structures were solved for four macrocycles.
Manuscript received: 6 March 2010.
Manuscript accepted: 27 May 2010.
O
Introduction
O
O
Macrocyclic ligand complexes play a significant role in many
fundamental biological systems, such as photosynthesis and
the transport of oxygen in mammalian and other respiratory
systems.[1]
O
O
N
N
CH3
H3C
O
O
Nature has created many elegant chiral hosts, including cyclic
peptides (e.g. valinomycin), and nonactin, containing ester and
ether binding sites.[2] Compounds that can bind and transport
ions are referred to as ionophores.The antibacterial properties of
ionophores arise from their perturbation of ion gradients across
the cell.[3] The presence of heteroatoms that act as ligands is
key for the complexation of inorganic cations. Complexation
of alkali metal cations and their non-covalent interactions with
host molecules have engaged considerable interest owing to their
importance in chemical[4] and biological systems.[5] In recent
years, large metal complexes (e.g. La,[6] Cu,[7] Co,[8] Zn[9]) with
chiral ligands have also been recognized as efficient catalysts in
asymmetric synthesis.
O
O
O
O
O
O
O
O
O
Fig. 1. Dibenzo-24-crown-8. Top: chiral targets. Bottom: achiral model,
current study.
We are interested in designing and synthesizing new hosts
(Fig. 1) with varied conformational, electronic and chemical
properties for ionophoric antibiotics, metal catalysis and sen-
sor applications. Herein, we describe our progress towards a
series of benzocrown ethers, with a lipophilic exterior and
hydrophilic central cavities of different sizes possessing oxy-
gen and nitrogen atoms that can serve as ligands for metal
cations and small organic molecules. A modular, short and con-
vergent synthesis was a priority, with the scope to prepare a
diverse library. The compounds reported herein are the basis
for the development of a stereoselective synthesis of macrocy-
cles incorporating the morphine alkaloid scaffold (highlighed in
blue, Fig. 1). Metal binding affinity, metal templation effects and
X-ray crystallographic data were obtained to assist the devel-
opment of future medicinal chemistry, macrocycle synthesis
(e.g. templation effects), asymmetric catalysis and analytical
chemistry applications.
Results and Discussion
Synthesisofphenoxy-linkedopenstructures2–6and 8havebeen
reported previously.[10–13] Macrocyclic precursors 2–8 were
synthesized following the known literature procedure.[12] Com-
mercially available 2-(2-hydroxyethoxy)phenol 1 was reacted
with the corresponding dihalides in DMF at 120◦C in the pres-
ence of 3 equiv. of K2CO3 as base to give the desired product
(Scheme 1). These reactions occurred in moderate to high yields
varying from 54% for 2 to 92% yield for 8. Diol macrocycle
precursor 7 containing an ortho-substituted aromatic linker was
synthesized in 76% yield.
Alkyl dibromides were also used for the alkylation of diol
1. In all cases, yields were lower compared with the dichlo-
rides, except for diol 2, which is prepared from an aliphatic
dihalo linker without ethereal backbone (see Table 1). Diol 4
was synthesized using 1,2-bis-(2-iodoethoxy)ethane; however,
© CSIRO 2010 Open Access
10.1071/CH10112
0004-9425/10/091348

Benzocrown Ethers: Synthesis and Binding Studies
1349
R
employing hydroxides with a small cationic radius, e.g. LiOH,
and relatively large cationic radius, such as Ba(OH)2, gave poor
results, with the formation of the product not observed. This is
most likely due to the fact that the cations with a smaller radius
than potassium cannot fit effectively to template the macrocycle
for efficient ring closure.[14] Fig. 2 depicts the behavior of the
macrocyclic precursor 3, in the presence of a potassium cation
templating agent. This shape is the consequence of interactions
between the metal cation and oxygen donor atoms. In the absence
of a templating agent, 3 adopts a linear conformation and in that
shape, oligomeric products are more likely to be formed.
Synthesis yield of the desired product was higher in the exper-
iments carried out in 1,4-dioxan (entries 2, 3 versus 6, 7). The
presence of the iodide salt improved reaction yields further by
nucleophilic displacement of Cl with KI (Finkelstein reaction)
via an alkyl iodide intermediate.[15] Presence of 10 mol% of KI
inthering-closurereactiontosynthesize11improvedconversion
by 15% (entries 3 versus 11). From the series of experiments with
varied amount of bases, it was observed that the optimal num-
ber of equivalents of base required to effect ring closure was 12
(entries 11–17), with the preferred base being potassium hydrox-
ide. No macrocycle was formed in experiments carried out using
less than 6 equiv. of base. These experiments demonstrated that
in general, if THF is replaced by 1,4-dioxan, conversion of start-
ing materials tends to increase (entries 10, 11). Synthesis of 11
occurs most efficiently using at least 10 equiv. of KOH and 0.1
equiv. of KI in refluxing 1,4-dioxan (entries 11, 15). The optimal
molar ratio of base to substrate was 12 for the highest conver-
sion, in the presence of KI. In addition, the effect of sodium and
potassium hydrides on the macrocyclization was investigated.
Reactions were stirred at 0◦C in THF for 6 h, then at room tem-
peratureovernight;however, onlylowconversionswererecorded
(entries 18, 19).
O
O
O
O
OH
R
K2CO3, DMF, Δ
ϩ
X
X
O
X ϭ Cl or Br
OH
1
OH
OH
Linker
Diol macrocycle
precursor
Cl
Cl
Cl
2
3
O
Cl
O
O
4
Cl
Cl
5
6
Cl
Cl
Cl
Cl
7
8
Cl
Cl
Cl
Cl
N
Scheme 1. Preparation of diol macrocycle precursors 2–8.
Table 1. Isolated yields for diol macrocycle precursors 2–8
2
3
4
5
6
7
8
Isolated yields [%]
Dialkyl or diaryl chloride
Dialkyl or diaryl bromide
54
63
86
68
81
–
88
77
91
71
78
76
92
54
A study to establish the optimum concentration of the diol
macrocycle precursor for the macrocyclization reaction was also
investigated, to determine whether it is the template effect of K+
orhighdilutionthatbenefitsthereactionmost. Experimentswere
carried out on a 1 mmol scale of 3 in 1,4-dioxan together with
12 equiv. of potassium hydroxide and 0.2 equiv. of potassium
iodide.
For the concentration range 4–25 mM, conversions between
60 and 75% were observed, with a maximum at 8 mM.At 50 mM,
the conversion decreased to 40% and only trace product formed
at 125 mM. This suggests the importance of the template effect,
which appears to play a key role in the macrocyclization step.
Previous experiments (Table 2) also show that the use of bases
with lithium or sodium counter cations proceeded with lower
reaction conversions compared with reactions carried out in the
presence of potassium bases.
Preparation of macrocycles 12–26 from a variety of dialkyl
chlorides using the optimized conditions (Table 2, entry 15) was
carried out on a 1 mmol scale, employing 12 mmol of metal
hydroxide under dilute conditions (8 mM) in 1,4-dioxan at reflux
temperature (Scheme 4).
This synthetic approach gave good yields (38–59%), allowing
the preparation of macrocycles with varied ring sizes (23–28
atoms), number of aromatic rings (2–4), and number of donor
atoms (6–10 including oxygen and nitrogen).
a significant drop in yield (54% yield, from 81%) for 1,2-bis-(2-
chloroethoxy)ethane was observed.
The preparation of benzocrown ethers was based on the
approach that the macrocyclization process can be promoted
either by suppressing the intermolecular reaction (resulting in
polymerization) or facilitating the intramolecular cyclization.
We chose to combine these approaches by suppressing compet-
ing reactions, via the use of moderate to high dilution conditions,
while promoting cyclization via the template effect. First, syn-
thesis of macrocycles 9 and 10 containing both ethereal and
ester groups was performed by an acylation reaction on the cor-
responding linear precursors 5 and 6 respectively. In both cases,
the reactions were carried out on a 1 mmol scale in reflux-
ing dichloromethane in the presence of 8 equiv. of K2CO3
(Scheme 2). Macrocycles 9 and 10 were isolated by column
chromatography in 44 and 48% yield respectively.
Before the synthesis of the target macrocycles 11–26, opti-
mization of the macrocyclization reaction conditions was per-
formed. Preparation of macrocycle 11 from diol 3 was chosen
as a model reaction for the optimization of reaction conditions
(Scheme 3).The ring-closure reaction was carried out on diol 3 to
determine the most favourable reaction conditions, considering
various factors such as equivalents of base, additives (NaI, KI),
choice of solvent and concentration. Bases (e.g. NaH, NaOH,
KH, KOH, CsOH and Ba(OH)2) in different solvents (e.g. THF,
1,4-dioxan) were screened (Table 2).
In all the cases, the ring-closure reaction gave higher
yields of the respective macrocycles with the shortest spacer
meta-xylene (12, 16, 20, 23) compared with longer spacers (20
versus 21).Thesymmetry exhibited by these benzocrown macro-
Among the metal hydroxides, potassium hydroxide proved to
be more effective in promoting alkylation of the primary alcohol,
with subsequent macrocyclization (entries 1–5). Experiments
1
cycles can be seen from both H and 13C NMR spectroscopy.

1350
E. Kowalska, J. Phopase, and N. Gathergood
Cl
Cl
O
O
N
O
O
O
O
O
O
O
O
O
K2CO3, DCM, reflux
O
HO
OH
N
O
O
5
9, 44% yield
Cl
Cl
N
O
O
O
O
O
O
O
O
O
O
O
O
O
K2CO3, DCM, reflux
N
OH OH
O
6
10, 48% yield
Scheme 2. Macrocyclization of macrocyclic precursors 5 and 6 with 2,6-pyridine dicarbonyl dichloride.
O
Kϩ
O
O
O
O
O
O
O
O
O
O
O
O
O
O
Cl
Cl
O
O
1 mmol
OϪ
HO
Base, solvent, heat
Kϩ as a templating agent
OH
OH
1 mmol
3
Fig. 2. Macrocyclic precursor 3 in the presence of the template.
11
Scheme 3. Preparation of 11.
The complexation behaviour of macrocycles 9–14, 18–19
and 22–26 towards alkali, alkaline and transition metal cations
was assessed by metal picrate extraction from aqueous solution
into chloroform. The percentage extraction values for metal
cations were calculated according to a procedure described by
Pedersen.[16] The extraction data show significant binding of
several macrocyclic structures towards sodium picrate (Table 3).
Among the 13 macrocyclic systems, the highest Na+ extraction
values were observed for 22 (72.0%), 23 (71.0%), 10 (64.3%),
18 (57.4%) and 9 (54.6%) (Fig. 3). The common feature link-
ing these compounds is the presence of four aromatic rings in
their structures arranged to form a rigid cavity surrounded by
six donor oxygen atoms. According to the data in the table and
from analysis of cavity sizes in the crystallographic literature,
we would expect metal picrates with cation diameters larger than
sodium to be bound more effectively.[16b] The most efficient
cation extractions were observed with macrocycles containing
four aromatic rings (e.g. 22, 23, 24) instead of three, in which
the xylene linker is replaced by an ethereal chain (e.g. 12, 13,
14). This suggests that the presence of four aromatic rings in the
macrocycle prevents binding to the larger cation. Macrocycle
11 exhibits relatively low extraction values for Na+, 21.1%, and
even lower for K+, 6.8%, whereas for macrocycle 14, the cavity
selectivity towards Na+ over K+ increased and extraction values
were 41.7 and 4.0% respectively. Macrocycles containing a pyri-
dine ring 9, 10 and 24 gave high extraction values for Na+ (64.3,
54.6 and 52.6 respectively) and proved to have significant bind-
ing affinity for La3+ (9.0, 10.1 and 7.2%) and to bind relatively
weakly to K+. Macrocycle 22 showed an excellent 72% extrac-
tion value for Na+ and 4.8% for K+. The results show that the
highest extraction values of Na+ are consistent with tetrabenzo
23- and 24-crown-6 polyether rings. Significant extractability of
Table 2. Optimization of reaction conditions for preparation of macro-
cycle 11 (reaction time = 46 h, 1 mmol scale) as shown on Scheme 3
Entry Base
Base
Additives
SolventE Conversion [%]B
equiv. (10 mol%)
1
2
3
4
5
6
7
8
LiOH
NaOH
KOH
CsOH
Ba(OH)2
NaOH
KOH
NaOH
NaOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
NaH
12
10
10
12
12
10
10
10
10
10
10
4
–
–
–
–
–
–
–
NaI
NaI
KI
KI
KI
KI
KI
KI
KI
KI
–
1,4-DA
1,4-DA
1,4-DA
1,4-DA
1,4-DA
THF
THF
THF
1,4-DA
THF
1,4-DA
1,4-DA
1,4-DA
1,4-DA
1,4-DA
1,4-DA
1,4-DA
THFD
THFD
0
35
50
40
0
28
44
30
38
50
65 (48)C
0
35
55
70 (54)C
60 (40)C
60 (43)C
25
9
10
11
12
13
14
15
16
17
18
19
6
8
12
16
20
10
10
KH
–
30
A1,4-Dioxan; Bdetermined by 1H NMR; Cisolated yield; D6 h 0◦C and 18 h
room temperature; Ereflux.
Whereas structures 2–6 and 8 proved to be excellent precursors
to undergo ring-closure reaction, compound 7 did not give any
macrocycle. Every attempt to introduce different linkers into the
structure of 7 failed.

Benzocrown Ethers: Synthesis and Binding Studies
1351
R
order of Na+ > K+ > Cs+ and was also the only macrocycle to
exhibit binding over 3% towards caesium picrate (16%). Com-
pared with 23 (lower part contains ortho-substituted aromatic
linkers), the cavities of hosts 19 and 26 are relatively large (upper
and lower part contains para or meta-substituted aromatic link-
ers), and their binding parameters correspond to the scaffold of
24-crown-8. Macrocycle 23 exhibits good extraction for potas-
sium and caesium compared with compound 12, in which the
upper part of the macrocycle contains an ethereal chain with
extra oxygen instead of an aromatic ring. It appears that the pres-
ence of one or more extra aromatic rings may not only change or
rearrange the conformation of the binding pocket but also pro-
vide an additional source of π-electrons. Therefore, it is likely
that complex formation is stabilized by the cation–π interaction
when the metal cation is surrounded by the four benzene rings.[9]
Percentage extractabilities for all tested ligands towards alkaline
earth metals Mg2+, Ca2+, Sr2+ and Ba2+ were low, <2.1%.
Among transition metal binding abilities investigated, 25
and 26 exhibited low extractability of up to 3.2% and up to
4.3% respectively, whereas higher extraction values (>5%) were
observed in macrocycles 9, 10, 13, 18, 19, 24, 25 and 26 towards
lanthanum picrate (Table 3 and Fig. 4). Compounds 9 and 18
displayed highest extraction values of 10.1 and 10.6%, whereas
10 and 19 showed >9% extractability towards La3+. The pres-
ence of aromatic rings (e.g. meta- or para-substituted benzene
or pyridine) increased the extractability of La3+ compared with
extraction values for macrocycles containing extra oxygen like
11 (1.3%) or 14 (4.7%). As expected, macrocycles with large
cavity size showed higher binding affinity towards La3+ com-
pared with the macrocycles with a small cavity size (9 versus
10, 18 versus 19). Ligands 12 and 13 are poor hosts for all the
alkali and transition metal picrates tested. The presence of three
rigid ortho-substituted aromatic rings in the macrocyclic struc-
ture of 12 might direct the two attached arms in a semiconvergent
arrangement, which may influence the binding.
Apart from interactions between the cation and donor oxy-
gen atoms, the complexation process may also be favoured by
cation–π interactions with π-electrons from the aromatic rings.
None of the tested ligands exhibited a high affinity for potassium
and caesium, whose hydroxides played a significant role in the
ring-closure step. The optimal metal for the preorganization of
the acyclic precursor to facilitate ring closure does not necessary
have optimal fit with the macrocyclic product. Careful selection
of templates to assist synthesis versus binding metal studies is
always an important compromise. The extraction studies do not
take into account the stoichiometry of the complexes, and the
ratio of complexing agent:metal picrate is assumed to be 1:1
for the purpose of the calculations. However, it is well known
that the ratio can be more complex and formation of 1:2 or 2:3
complexes could also take place.[17,18]
R
RЈ
O
O
O
O
O
O
O
O
Cl
Cl
O
O
KOH, KI
1,4-dioxan, Δ
OH
OH
RЈ
Diol macrocycle
precursor
Linker
Macrocycle
Isolated
yield [%]
52
3
12
Cl
Cl
3
4
4
13
14
15
45
38
58
Cl
Cl
N
Cl
Cl
Cl
Cl
59
4
16
Cl
Cl
38
38
43
4
5
5
17
18
19
Cl
Cl
N
Cl
Cl
Cl
Cl
5
20
48
Cl
Cl
O
O
5
44
47
5
6
6
21
22
23
Cl
Cl
Cl
Cl
Cl
Cl
43
38
49
6
8
8
24
25
26
Cl
Cl
N
N
Cl
Cl
Cl
Cl
Scheme 4. General scheme for synthesis of benzocrown ethers from their
precursors.
Conclusions
We report a concise, two-step general methodology for the
preparation of 16 new lipophilic benzocrown ether-based macro-
cycles with varying cavity sizes. Reaction conditions for the
ring-closure step have been optimized in order to improve
yields. Thirteen macrocycles have been tested for cation bind-
ing. Alkali metal picrate extraction studies from water into
chloroform confirmed the binding properties of the differ-
ent hosts with metal picrates. Although an ability to extract
multiple metal picrates was more common, some of these prod-
ucts (22 > 23 > 10 > 18 > 9) exhibit significant binding towards
Na+ has also been observed for macrocycles containing four aro-
matic rings including the pyridine ring and ester groups. 10 and 9
extract Na+ with 64.3 and 54.6% extraction values respectively.
Macrocycles 22 and 23 coordinate Na+ with almost identical
extractability (71–72%), whereas extractability towards sodium
picrate with 9, 18 and 24 was between 52.6 and 57.4%.
Allmacrocyclesscreenedexhibitlowtomoderateextractabil-
ity towards potassium and caesium picrates. Compound 23 gave
the highest extraction levels (23.1%) for potassium, with an

1352
E. Kowalska, J. Phopase, and N. Gathergood
Table 3. Percentage extractability of alkali metal picrates from water into chloroform, at 20◦C
Liquid–liquid extraction of alkali metal picrate by benzocrown macrocycles. Extraction conditions: aqueous phase: 6 mL of water, metal picrate = 7 × 10−5 M;
organic phase: 6 mL of dichloromethane, ionophore = 1.75 × 10−5 M. The two-phase mixture was shaken for 1 h at 20◦C. The extractability was determined
spectrophotometrically from a decrease in the absorbance of the picrate in the aqueous phase
9
10
11
12
13
14
18
19
22
23
24
25
26
Li+
1.0
54.6
3.1
0.3
0.8
1.2
1.2
2.0
0.5
2.2
0.6
0.7
10.1
0.1
64.3
2.3
0.7
0.8
2.1
1.3
1.2
1.0
2.1
0.0
0.6
9.0
1.3
21.1
6.8
0.4
0.6
1.3
1.0
2.1
1.4
1.0
0.9
0.5
1.3
1.7
2.8
1.3
0.6
0.9
1.0
0.0
0.7
0.2
2.1
0.0
0.5
2.3
0.2
4.6
0.1
0.0
0.2
0.3
0.2
0.1
0.1
1.9
0.3
0.2
5.5
0.0
41.7
4.0
0.3
0.0
0.0
1.2
1.0
0.1
1.9
0.0
0.3
4.7
1.9
57.4
13.8
3.0
1.2
1.5
1.6
0.9
1.7
0.6
0.7
29.7
3.8
1.2
0.9
1.2
1.0
2.1
1.1
2.0
0.9
1.5
9.7
1.2
72.0
4.8
0.1
0.0
0.0
0.0
0.0
0.3
0.9
0.0
0.5
4.3
0.8
71.0
23.1
16.1
1.1
0.9
0.5
0.7
0.5
1.9
0.9
0.0
2.6
0.2
52.6
1.7
1.2
1.4
1.3
1.1
0.7
1.2
2.0
1.4
0.7
7.2
0.2
32.5
5.8
1.0
1.2
0.3
1.0
0.7
1.1
3.2
1.7
0.7
6.7
0.5
10.1
4.7
0.0
0.1
1.4
1.0
0.9
0.5
4.3
0.9
0.8
7.4
Na+
K+
Cs+
Mg2+
Ca2+
Sr2+
Ba2+
Co2+
Cu2+
Zn2+
Pb2+
La3+
1.9
1.0
10.6
O
O
O
O
O
O
O
O
9
O
O
10
22
O
O
O
O
O
O
O
O
N
N
O
O
O
64.3%
72.0%
O
54.6%
O
O
O
O
O
O
O
O
O
O
18
O
O
23
O
O
24
O
O
O
O
N
71.0%
52.6%
57.4%
Fig. 3. Macrocycles with strongest extractability [%] for sodium.
sodium and lanthanum picrate (9 and 18). The preference exhib-
ited by several macrocycles to bind with sodium suggests that the
binding affinities of the novel crown ether analogues for cations
are not only based on ionic size. Further investigations would be
required in order to determine whether these macrocycles (9 and
18) with their higher affinity for La3+ might have applications
as possible cocatalysts in asymmetric synthesis.
The work presented is a preface to the preparation of chi-
ral macrocycles based on the morphine alkaloid scaffold and is
ongoing. A study of the antimicrobial activity of the compounds
reported herein will be published in due course.
the residual solvent signal. Coupling constants values (J) are
in Hertz [Hz]. Chemical shift assignments for 1H and 13C
spectra were assisted with correlation spectroscopy (COSY),
distortionless enhancement of polarisation transfer (DEPT) and
heteronuclear multiple quantum coherence (HMQC) experi-
ments. The splitting patterns for NMR spectra are designated as
follows: s (singlet), d (doublet), t (triplet), q (quartet), p (quintet),
dd (doublet of doublets), ddd (doublet of doublet of doublets), dt
(doublet of triplet) and m (multiplet). Crystal data were collected
using a Bruker SMART APEX CCD area detector diffractome-
ter. A full sphere of reciprocal space was scanned by phi-omega
scans. Pseudo-empirical absorption correction based on redun-
dant reflections was performed by the program SADABS (X-1).
The structures were solved by direct methods using SHELXS-97
(X-2) and refined by full matrix least-squares on F2 for all data
using SHELXL-97 (X-2). Hydrogen atoms were added at calcu-
lated positions and refined using a riding model. Their isotropic
temperature factors were fixed to 1.2 times (1.5 times for methyl
groups) the equivalent isotropic displacement parameters of the
Experimental
Methods and Materials
NMR spectra were obtained on a Bruker AC 400 NMR spectro-
meter operating at 400 MHz for 1H NMR and 100 MHz for
1
13C NMR. The H and 13C NMR shifts are expressed in ppm
relative to tetramethylsilane and were internally referenced to

Benzocrown Ethers: Synthesis and Binding Studies
1353
O
O
O
O
O
O
O
O
O
O
O
O
9
O
O
O
O
24
10
O
O
O
O
N
N
N
O
O
7.2%
9.0%
10.1%
O
O
O
O
N
O
O
O
O
O
18
O
O
O
19
26
O
O
O
O
O
O
N
7.4%
9.7%
10.6%
Fig. 4. Macrocycles with significant extractability [%] for La3+
.
carbon atom the H atom is attached to. Anisotropic thermal
displacement parameters were used for all non-hydrogen atoms.
Melting point determinations were carried out using a Stuart
SMP3 melting point apparatus. Infrared spectra were recorded
on a Perkin Elmer Fourier-transform (FT)-IR system spectrum
GX spectrometer and are reported in wavenumbers [cm−1].
High-resolution mass spectrometry (HRMS) was carried out on
a liquid chromatography time-of-flight mass spectrometer. All
chemicals were purchased from commercial suppliers, and used
without further purification.THF was distilled from sodium with
benzophenone as indicator under nitrogen. Dichloromethane
was distilled from CaH2, DMF and 1,4-dioxan were purchased
anhydrous from Sigma–Aldrich.
General Synthetic Procedure for Benzocrown Ethers 9, 10
Diol macrocyclic precursor (1.0 mmol) was dissolved in dry
dichloromethane (150 mL) under a nitrogen atmosphere, potas-
sium carbonate (1.66 g, 12.0 mmol) was added, followed by the
acyl dichloride (1.0 mmol) in one portion and the mixture was
refluxed over night. The reaction mixture was then quenched
with distilled water (70 mL), the organic phase separated, dried
over MgSO4, filtered, and organic solvent removed via rotary
evaporation. Purification of the product was carried out by
column chromatography on silica gel.
14,20-Dioxo-3,10,13,21,24,31-hexaoxa-38-
azapentacyclo[31.2.2.115,19.04,9.025,30]octatriaconta-
1(35),4(9),5,7,15,17,19(38),25(30),26,28,33,36-
dodecaen-8-yl 9
General Synthetic Procedure for Phenoxy-Linked
The general procedure was used with 5 (0.41 g, 1.0 mmol) and
2,6-pyridinedicarbonylchloride(0.21, 1.0 mmol). Product 9was
isolated by column chromatography (silica; EtOAc elution) as a
white solid (0.24 g, 0.44 mmol, 44% yield), mp 185–187◦C. Rf
0.64 (EtOAc). νmax (KBr)/cm−1 2932, 1759, 1591, 1503, 1460,
1388, 1293, 1254, 1126, 1019. δH (400 MHz, [D6]DMSO) 8.18
(2H, d, J 7.6, ArH), 7.71 (1H, t, J 7.6, ArH), 7.16–6.92 (12H, m,
ArH), 4.99(4H, s, –OCH2Ar), 4.79(4H, t, J4.4, –OCH2CH2O–),
4.47 (4H, t, J 4.4, –OCH2CH2O–). δC (100 MHz, [D6]DMSO)
163.78, 148.31, 147.90, 147.83, 139.21, 136.40, 128.19, 126.89,
121.60, 121.34, 115.20, 113.89, 69.70, 66.17, 63.58. HRMS
(EI, 70 eV) found [M + H]+ 542.1810; C31H28NO+8 requires
542.1809.
Open Structures 2–8
A mixture of 2-(2-hydroxyethoxy)phenol 1 (10.0 mmol), alkyl
dihalide (5.0 mmol) and potassium carbonate (15.0 mmol) in
dry DMF (5.0 mL) was stirred for 7 h at 120◦C. The reaction
mixture was then cooled to room temperature, distilled water
(30 mL) added and the precipitate filtered.The solid was washed
with copious amounts of water. Crude product was recrystallized
from chloroform/hexane or when necessary separated by flash
chromatography.[15]
1,2-Bis[2-(2-hydroxyethoxy)phenoxy]-o-xylene 7
Thegeneralprocedurewasusedwith2-(2-hydroxyethoxy)phenol
1 (10.0 mmol), and α,αꢀ-dibromo-o-xylene (1.32 g, 5.0 mmol).
Recrystallization from chloroform/hexane (5:1) gave the title
compound as a white powder (1.56 g, 3.8 mmol, 76% yield),
and 78% yield (1.60 g, 3.9 mmol) when α,αꢀ-dichloro-o-xylene
was used as a starting material. Mp 66–68◦C. νmax (KBr)/cm−1
3267, 2901, 1590, 1505, 1395, 1323, 1256, 1126, 1040, 1000.
δH (400 MHz, CDCl3) 7.37 (2H, dd, J 5.6 and 3.6, ArH), 7.23
(2H, dd, J 5.6 and 3.6, ArH), 6.88–6.77 (8H, m, ArH), 5.26 (4H,
s, –OCH2Ar), 3.96 (4H, t, J 4.2, –OCH2CH2OH), 3.75 (4H, t,
J 4.2, –OCH2CH2OH). δC (100 MHz, CDCl3) 148.27, 146.96,
134.32, 128.27, 127.33, 121.27, 120.34, 114.89, 112.83, 69.70,
69.22, 60.09. HRMS (EI, 70 eV) found [M + H]+ 411.1805;
C24H27O+6 requires 411.1802.
14,20-Dioxo-3,10,13,21,24,31-hexaoxa-38-
azapentacyclo[31.3.1.115,19.04,9.025,30]octatriaconta-
1(36),4(9),5,7,15,17,19(38),25(30),26,28,33(37),
34-dodecaen-8-yl 10
The general procedure was used with 6 (0.41 g, 1.0 mmol) and
2,6-pyridine dicarbonyl chloride (0.21 g, 1.0 mmol). Product 10
was isolated by column chromatography on silica gel using
EtOAc as a white solid (0.26 g, 0.48 mmol, 48% yield), mp
164–166◦C. Rf 0.66 (EtOAc). νmax (KBr)/cm−1 2942, 1743,
1588, 1506, 1450, 1378, 1291, 1256, 1125, 1081. δH (400 MHz,
CDCl3) 7.92 (2H, d, J 7.6, ArH), 7.66 (1H, t, J 7.6, ArH), 7.44
(1H, s, ArH), 7.12–7.10 (3H, m, ArH), 6.94–6.84 (8H, m, ArH),

1354
E. Kowalska, J. Phopase, and N. Gathergood
4.92 (4H, s, –OCH2Ar), 4.69 (4H, t, J 4.4, –OCH2CH2O–), 4.37
(4H, t, J 4.4, –OCH2CH2O–). δC (100 MHz, CDCl3) 163.17,
148.45, 148.42, 146.89, 136.71, 136.43, 128.08, 127.07, 126.67,
125.40, 121.48, 121.39, 116.32, 115.07, 71.21, 66.70, 63.39.
HRMS (EI, 70 eV) found [M + H]+ 542.1791; C31H28NO+8
requires 542.1809.
was isolated by column chromatography on silica gel using
EtOAc/CHCl3 (3:1) as a white solid (0.21 g, 0.45 mmol, 45%
yield), mp 150–152◦C. Rf 0.25 (EtOAc/CHCl3, 3:1). νmax
(KBr)/cm−1 2933, 1599, 1509, 1460, 1258, 1131, 1058. δH
(400 MHz, CDCl3) 7.67 (1H, t, J 7.6, ArH), 7.35 (2H, d, J
7.6, ArH), 6.85–6.81 (8H, m, ArH), 4.82 (4H, s, CH2Ar),
4.14 (4H, t, J 4.4, –OCH2CH2O–), 4.03 (4H, t, J 4.8,
–OCH2CH2O–), 3.93 (4H, t, J 4.4, –OCH2CH2O–), 3.83 (4H,
t, J 4.8, –OCH2CH2O–). δC (100 MHz, CDCl3) 158.08, 149.17,
149.04, 137.41, 121.60, 121.37, 119.89, 114.87, 113.80, 74.58,
70.29, 69.63, 69.42, 69.31. HRMS (EI, 70 eV) found [M + H]+
482.2169; C27H32NO+7 requires 482.2173.
General Synthetic Procedure for Benzocrown Ethers 11–26
The diol macrocyclic precursor (1.0 mmol) was dissolved in dry
1,4-dioxan (80 mL) under a nitrogen atmosphere, then potas-
sium hydroxide (0.67 g, 12.0 mmol) was added and the mixture
was heated at 60◦C for 30 min. Alkyl dichloride (1.0 mmol) and
potassium iodide (0.03 g, 0.2 mmol) were added in one por-
tion and reaction mixture heated at reflux for 36 h. Solvent was
removed by rotary evaporation, and distilled water (70 mL) was
added to the residue.The aqueous phase was extracted with chlo-
roform (6 × 30 mL). The organic phase was dried over MgSO4
and solvent removed via rotary evaporation. Purification of the
product was carried out by column chromatography on silica gel.
3,6,13,16,19,22,29,32-Octaoxatetracyclo[32.2.2.07,12
23,28]octatriaconta-1(36),7,9,11,23(28),24,26,34,37-
nonaen-10-yl 14
.
0
The genꢀeral procedure was used with 4 (0.42 g, 1.0 mmol)
and α,α -dichloro-p-xylene (0.17 g, 1.0 mmol). Product 14
was isolated by column chromatography on silica gel using
EtOAc/CHCl3 (1:1) as a white solid (0.19 g, 0.38 mmol, 38%
yield), mp 104–106◦C. Rf 0.63 (EtOAc/CHCl3, 1:1). νmax
(KBr)/cm−1 2928, 1595, 1507, 1454, 1334, 1259, 1125, 1048. δH
(400 MHz, CDCl3) 7.33 (4H, s, ArH), 6.88–6.77 (8H, m, ArH),
4.62 (4H, s, CH2Ar), 4.12 (4H, t, J 4.4, –OCH2CH2O–), 4.07
(4H, t, J 4.8, –OCH2CH2O–), 3.79 (4H, t, J 4.4, –OCH2CH2O–),
3.74 (4H, t, J 4.8, –OCH2CH2O–), 3.56 (4H, s, –OCH2CH2O–).
δC (100 MHz, CDCl3) 148.98, 137.71, 127.93, 121.49, 121.46,
114.31, 114.07, 73.15, 70.88, 69.79, 69.18, 69.06, 68.41. HRMS
(EI, 70 eV) found [M + H]+ 525.2486; C30H37O+8 requires
525.2483.
3,6,13,16,19,26,29-Heptaoxatetracyclo[29.3.1.07,12
20,25]pentatriaconta-1(35),7(12),8,10,20(25),
21,23,31,33-nonaene 11
.
0
The genꢀeral procedure was used with 3 (0.38 g, 1.0 mmol)
and α,α -dichloro-m-xylene (0.17 g, 1.0 mmol). Product 11
was isolated by column chromatography on silica gel using
EtOAc/CHCl3 (1:1) as a white solid (0.19 g, 0.40 mmol, 40%
yield), mp 90–92◦C. νmax (KBr)/cm−1 2930, 1594, 1505, 1449,
1357, 1256, 1123, 1041. Rf 0.81 (EtOAc/CHCl3, 1:1). δH
(400 MHz, CDCl3) 7.35 (1H, s, ArH), 7.22–7.18 (3H, m, ArH),
6.86–6.78 (8H, m, ArH), 4.61 (4H, s, –OCH2Ar), 4.11 (4H, t,
J 4.6, –OCH2CH2O–), 4.08 (4H, t, J 4.8, –OCH2CH2O–), 3.82
(4H, t, J 4.6, –OCH2CH2O–), 3.80 (4H, t, J 4.8, –OCH2CH2O–).
δC (100 MHz, CDCl3) 149.40, 149.02, 138.45, 128.41, 127.43,
127.11, 121.89, 121.60, 115.87, 114.42, 73.46, 70.29, 69.72,
69.30, 68.78. HRMS (EI, 70 eV) found [M + H]+ 481.2215;
C28H33O+7 requires 481.2221.
3,6,13,16,19,22,29,32-Octaoxatetracyclo[32.3.1.07,12
23,28]octatriaconta-1(37),7(12),8,10,23(28),
24,26,34(38), 35-nonaen-8-yl 15
.
0
The genꢀeral procedure was used with 4 (0.42 g, 1.0 mmol)
and α,α -dichloro-m-xylene (0.17 g, 1.0 mmol). Product 15
was isolated by column chromatography on silica gel using
CHCl3/EtOAc (3:1) as a white solid (0.31 g, 0.58 mmol, 58%
yield), mp 109–111◦C. Rf 0.51 (CHCl3/EtOAc, 3:1). νmax
(KBr)/cm−1 2928, 2872, 1594, 1511, 1447, 1348, 1259, 1126,
1047. δH (400 MHz, CDCl3) 7.28 (1H, s, ArH), 7.24–7.22 (3H,
m,ArH), 6.82–6.78(8H, m,ArH), 4.60(4H, s, CH2Ar), 4.11(4H,
t, J 4.4, –OCH2CH2O–), 4.05 (4H, t, J 4.8, –OCH2CH2O–), 3.79
(4H, t, J 4.4, –OCH2CH2O–), 3.71 (4H, t, J 4.8, –OCH2CH2O–),
3.53 (4H, s, –OCH2CH2O–). δC (100 MHz, CDCl3) 149.08,
148.99, 138.46, 128.56, 127.32, 127.22, 121.64, 121.51, 114.50,
73.45, 70.89, 69.80, 69.43, 69.22, 68.80. HRMS (EI, 70 eV)
Na adduct found [M + Na]+ 547.2320; C30H36O8Na+ requires
547.2308.
2,5,14,17,24,27,30-Heptaoxatetracyclo
[29.4.0.07,12.018,23]pentatriaconta-1(31),7,9,
11,18(23),19,21,32,34-nonaen-8-yl 12
The general procedure was used with 3 (0.38 g, 1.0 mmol) and
α,αꢀ-dichloro-o-xylene (0.17 g, 1.0 mmol). Product 12 was iso-
lated by column chromatography on silica gel using CHCl3 as
a white solid (0.25 g, 0.50 mmol, 50% yield), mp 109–111◦C.
Rf 0.30 (CHCl3). νmax (KBr)/cm−1 2931, 1593, 1509, 1452,
1260, 1130, 1030. δH (400 MHz, CDCl3) 7.33 (2H, dd, J 5.6
and 3.2, ArH), 7.22 (2H, dd, J 5.6 and 3.2, ArH), 6.88–6.79
(8H, m, ArH), 4.71 (4H, s, CH2Ar), 4.13–4.08 (4H, m, –
OCH2CH2O–), 3.95 (4H, t, J 4.4, –OCH2CH2O–), 3.77 (4H,
t, J 4.6, –OCH2CH2O–). δC (100 MHz, CDCl3) 149.40, 148.68,
136.71, 129.02, 127.78, 121.81, 121.32, 115.30, 113.59, 71.29,
70.21, 69.58, 68.90, 68.69. HRMS (EI, 70 eV) found [M + H]+
481.2240; C28H33O+7 requires 481.2221. HRMS (EI, 70 eV)
Na adduct found [M + Na]+ 503.2052; C28H32O7Na+ requires
503.2040.
2,5,14,17,24,27,30,33-Octaoxatetracyclo[32.4.0.07,12
18,23]octatriaconta-1(34),7(12),8,10,18(23),
19,21,35,37-nonaen-19-yl 16
.
0
The genꢀeral procedure was used with 4 (0.42 g, 1.0 mmol)
and α,α -dichloro-o-xylene (0.17 g, 1.0 mmol). Product 16
was isolated by column chromatography on silica gel using
CHCl3/EtOAc (3:1) as a white solid (0.32 g, 0.59 mmol,
59% yield), mp 91–93◦C. Rf 0.5 (CHCl3/EtOAc, 3:1). νmax
(KBr)/cm−1 2922, 1594, 1511, 1454, 1261, 1127, 1055. δH
(400 MHz, CDCl3) 7.35 (2H, dd, J 5.6 and 3.2, ArH), 7.20
3,6,13,16,19,26,29-Heptaoxa-35-azatetracyclo
[29.3.1.07,12.020,25]pentatriaconta-1(34),7(12),8,10,
20(25),21,23,31(35),32-nonaen-8-yl 13
The general procedure was used with 3 (0.38 g, 1.0 mmol) and
2,6-bis(chloromethyl)pyridine (0.17 g, 1.0 mmol). Product 13

Benzocrown Ethers: Synthesis and Binding Studies
1355
(2H, dd, J 5.6 and 3.2, ArH), 6.81–6.76 (8H, m, ArH), 4.69
(4H, s, CH2Ar), 4.08–4.03 (8H, m, –OCH2CH2O–), 3.78–
3.75 (8H, m, –OCH2CH2O–), 3.62 (4H, s, –OCH2CH2O–).
δC (100 MHz, CDCl3) 147.94, 147.91, 135.58, 127.89, 126.70,
120.38, 120.31, 113.16, 113.07, 70.02, 69.90, 68.66, 68.09,
67.92, 67.80. HRMS (EI, 70 eV) Na adduct found [M + Na]+
547.2315; C30H36O8Na+ requires 547.2308.
3,10,13,22,25,32-Hexaoxapentacyclo[32.2.2.04,9
15,20.026,31]octatriaconta-1(36),4(9),5,7,15(20),
16,18,26(31),27,29,34,37-dodecaen-16-yl 20
.
0
The general procedure was used with 5 (0.41 g, 1.0 mmol) and
α,αꢀ-dichloro-o-xylene (0.17 g, 1.0 mmol). Product 20 was iso-
lated by column chromatography on silica gel using CH2Cl2 as
a white solid (0.26 g, 0.48 mmol, 48% yield), mp 175–177◦C.
Rf 0.44 (CH2Cl2). νmax (KBr)/cm−1 2933, 1591, 1509, 1452,
1259, 1125, 1028. δH (400 MHz, CDCl3) 7.41 (4H, s, ArH),
7.36 (2H, dd, J 5.6 and 3.2, ArH), 7.21 (2H, dd, J 5.6 and 3.2,
ArH), 6.96–6.82 (8H, m, ArH), 5.00 (4H, s, CH2Ar), 4.67 (4H,
s, CH2Ar), 4.12 (4H, t, J 4.4, –OCH2CH2O–), 3.77 (4H, t, J 4.4,
–OCH2CH2O–). δC (100 MHz, CDCl3) 149.49, 149.05, 136.85,
136.44, 128.95, 127.79, 127.43, 121.83, 121.59, 115.19, 114.52,
71.21, 70.99, 69.32, 69.05. HRMS (EI, 70 eV) Na adduct found
[M + Na]+ 535.2079; C32H32O6Na+ requires 535.2091.
3,6,13,16,19,22,29,32-Octaoxa-38-azatetracyclo
[32.3.1.07,12.023,28]octatriaconta-1(37),7(12),8,10,
23(28),24,26,34(38),35-nonaen-8-yl 17
The general procedure was used with 4 (0.42 g, 1.0 mmol) and
2,6-bis(chloromethyl)pyridine (0.17 g, 1.0 mmol). Product 17
was isolated by column chromatography on silica gel using
EtOAc/CHCl3 (3:1) as a white solid (0.20 g, 0.38 mmol, 38%
yield), mp 144–146◦C. Rf 0.19 (EtOAc/CHCl3, 3:1). νmax
(KBr)/cm−1 2932, 2866, 1594, 1508, 1452, 1258, 1125, 1055.
δH (400 MHz, CDCl3) 7.89 (1H, t, J 7.2,ArH), 7.54 (2H, d, J 7.2,
ArH), 6.88–6.80 (8H, m, ArH), 4.78 (4H, s, CH2Ar), 4.15 (4H,
t, J 4.2, –OCH2CH2O–), 4.07 (4H, t, J 4.8, –OCH2CH2O–),
3.90 (4H, t, J 4.2, –OCH2CH2O–), 3.76 (4H, t, J 4.8,
–OCH2CH2O–), 3.56 (4H, s, –OCH2CH2O–). δC (100 MHz,
CDCl3) 157.68, 148.78, 137.21, 121.40, 120.23, 113.83, 113.45,
73.61, 70.80, 69.92, 69.34, 68.71. HRMS (EI, 70 eV) found
[M + H]+ 526.2432; C29H36NO+8 requires 526.2435.
3,10,13,16,19,22,25,32-Octaoxatetracyclo
[32.2.2.04,9.026,31]octatriaconta-1(36),4,6,8,
26(31),27,29,34,37-nonaen-6-yl 21
The general procedure was used with 5 (0.41 g, 1.0 mmol) and
1,2-bis-(2-chloroethoxy)ethane (0.19 g, 0.10 mL, 1.0 mmol).
Product 21 was isolated by column chromatography on sil-
ica gel using EtOAc/Et2O (1:1) as a white solid (0.027 g,
0.05 mmol, 5% yield), mp 84–86◦C. Rf 0.28 (EtOAc/Et2O,
1/1). νmax (KBr)/cm−1 2931, 1593, 1506, 1452, 1336, 1255,
1125, 1046. δH (400 MHz, CDCl3) 7.42 (4H, s, ArH), 6.92–
6.81 (8H, m, ArH), 5.05 (4H, s, CH2Ar), 4.12 (4H, t, J 4.4,
–OCH2CH2OAr), 3.84 (4H, t, J 4.4, –OCH2CH2OAr), 3.69 (4H,
t, J 4.6, –OCH2CH2O–), 3.54 (4H, t, J 4.6, –OCH2CH2O–),
3.52 (4H, s, –OCH2CH2O–). δC (100 MHz, CDCl3) 149.38,
148.61, 136.99, 127.71, 121.87, 121.32, 115.48, 113.82, 71.21,
71.06, 70.79, 70.72, 69.74, 69.09. HRMS (EI, 70 eV) found
[M + H]+ 525.2477; C30H37O+8 requires 525.2483. HRMS (EI,
70 eV) Na+ adduct found [M + Na]+ 547.2284; C30H36O8Na+
requires 547.2302.
3,10,13,20,23,30-Hexaoxapentacyclo[30.2.2.215,18
4,9.024,29]octatriaconta-1(34),4(9),5,7,15,17,
24(29),25,27,32,35,37-dodecaene 18
.
0
The general procedure was used with 5 (0.41 g, 1.0 mmol) and
α,αꢀ-dichloro-p-xylene (0.17 g, 1.0 mmol). Product 18 was iso-
lated by column chromatography on silica gel using CHCl3 as
a white solid (0.19 g, 0.38 mmol, 38% yield), mp 135–137◦C.
Rf 0.32 (CHCl3). νmax (KBr)/cm−1 1591, 1506, 1451, 1257,
1216, 1124, 1097, 1049, 1015. δH (400 MHz, CDCl3) 7.41 (4H,
s, ArH), 7.15 (4H, s, ArH), 6.97–6.82 (8H, m, ArH), 5.03 (4H, s,
CH2Ar), 4.59 (4H, s, CH2Ar), 4.15 (4H, t, J 4.2, –OCH2CH2O–),
3.79 (4H, t, J 4.2, –OCH2CH2O–). δC (100 MHz, CDCl3)
149.29, 148.56, 137.50, 136.78, 127.70, 127.62, 121.70,
121.08, 114.79, 113.12, 73.00, 71.02, 68.83, 68.08. HRMS
(EI, 70 eV) found [M + H]+ 513.2265; C32H33O+6 requires
513.2272.
3,6,13,21,28,31-Hexaoxapentacyclo[31.2.2.115,19
7,12.022,27]octatriaconta-1(35),7(12),8,10,15,17,
19(38),22(27),23,25,33,36-dodecaene 22
.
0
The general procedure was used with 6 (0.41 g, 1.0 mmol) and
α,αꢀ-dichloro-p-xylene (0.17 g, 1.0 mmol). Product 22 was iso-
lated by column chromatography on silica gel using CHCl3 as
a white solid (0.22 g, 0.44 mmol, 44% yield), mp 155–157◦C.
Rf 0.21 (CHCl3). νmax (KBr)/cm−1 2922, 1592, 1505, 1455,
1374, 1254, 1122, 1008. δH (400 MHz, CDCl3) 7.37 (4H, s,
ArH), 7.25–7.11 (4H, m, ArH), 6.86–6.82 (8H, m, ArH), 4.99
(4H, s, CH2Ar), 4.60 (4H, s, CH2Ar), 4.14 (4H, t, J 4.2,
–OCH2CH2O–), 3.83 (4H, t, J 4.2, –OCH2CH2O–). δC
(100 MHz, CDCl3) 149.37, 148.71, 138.45, 136.78, 128.71,
127.69, 126.88, 126.82, 121.81, 121.28, 115.02, 113.69, 73.70,
71.01, 69.38, 68.89. HRMS (EI, 70 eV) found [M + H]+
513.2285; C32H33O+6 requires 513.2272.
3,10,13,21,24,31-Hexaoxapentacyclo[31.2.2.115,19
4,9.025,30]octatriaconta-1(35),4(9),5,7,15,17,
19(38),25(30),26,28,33,36-dodecaen-34-yl 19
.
0
The general procedure was used with 5 (0.41 g, 1.0 mmol) and
α,αꢀ-dichloro-m-xylene (0.17 g, 1.0 mmol). Product 19 was iso-
lated by column chromatography on silica gel using CHCl3 as
a white solid (0.22 g, 0.43 mmol, 43% yield), mp 159–161◦C.
Rf 0.26 (CHCl3). νmax (KBr)/cm−1 2924, 1591, 1505, 1455,
1374, 1254, 1121, 1121, 1008. δH (400 MHz, CDCl3) 7.37 (4H,
s, ArH), 7.24–7.12 (4H, m, ArH), 6.93–6.84 (8H, m, ArH)
4.99 (4H, s, CH2Ar), 4.61 (4H, s, CH2Ar), 4.15 (4H, t, J 4.4,
–OCH2CH2O–), 3.84 (4H, t, J 4.4, –OCH2CH2O–). δC
(100 MHz, CDCl3) 149.38, 148.72, 138.47, 136.78, 128.60,
127.59, 126.90, 126.82, 121.80, 121.29, 115.03, 113.70, 73.71,
71.02, 69.42, 68.89. HRMS (EI, 70 eV) found [M + H]+
513.2291; C32H33O+6 requires 513.2272.
3,10,13,22,25,32-Hexaoxapentacyclo[32.3.1.04,9
15,20.026,31]octatriaconta-1(37),4(9),5,7,15(20),16,18,
26(31),27,29,34(38),35-dodecaen-8-yl 23
.
0
The general procedure was used with 6 (0.41 g, 1.0 mmol) and
α,αꢀ-dichloro-o-xylene (0.17 g, 1.0 mmol). Product 23 was iso-
lated by column chromatography on silica gel using CHCl3 as
a white solid (0.16 g, 0.29 mmol, 29% yield), mp 84–86◦C. Rf

1356
E. Kowalska, J. Phopase, and N. Gathergood
0.34 (CHCl3). νmax (KBr)/cm−1 2930, 1592, 1506, 1452, 1378,
1255, 1124, 1097, 1021. δH (400 MHz, CDCl3) 7.67 (1H, s,
ArH), 7.27–7.23 (3H, m, ArH), 7.21 (2H, dd, J 5.6 and 3.2,
ArH), 7.15 (2H, dd, J 5.6 and 3.2,ArH), 6.93–6.77 (8H, m,ArH),
5.02 (4H, s, CH2Ar), 4.65 (4H, s, CH2Ar), 4.08 (4H, t, J 4.4,
–OCH2CH2O–), 3.72 (4H, t, J 4.4, –OCH2CH2O–). δC
(100 MHz, CDCl3) 149.78, 149.01, 138.04, 136.78, 129.21,
128.29, 127.67, 127.21, 127.09, 122.20, 121.37, 116.61, 114.33,
72.19, 71.42, 69.01, 68.72. HRMS (EI, 70 eV) Na adduct found
[M + Na]+ 535.2092; C32H32O6Na+ requires 535.2091.
114.89, 113.52, 73.70, 72.51, 69.37, 68.+66. HRMS (EI, 70 eV)
found [M + H]+ 514.2245; C30H31N2O6 requires 514.2230.
Accessory Publication
X-ray crystal studies and metal picrates extraction properties
of lipophilic benzocrown ethers are available from the journal’s
website.
Acknowledgements
The authors wish to thank Dublin City University (E.K.) and Irish Research
Council for Science, Engineering & Technology (J.P.) for funding and Helge
Muller-BunzatUniversityCollegeDublin, Ireland, forX-raycrystallography
studies. Authors E.K. and J.P. contributed equally.
3,10,13,21,24,31-Hexaoxa-38-azapentacyclo
[31.3.1.115,19.04,9.025,30]octatriaconta-1(36),4(9),5,7,15,
17,19(38),25(30),26,28,33(37),34-dodecaen-8-yl 24
The general procedure was used with 6 (0.41 g, 1.0 mmol) and
2,6-bis(chloromethyl)pyridine (0.17 g, 1.0 mmol). Product 24
was isolated by column chromatography on silica gel using
EtOAc/CHCl3 (3:1) as a white solid (0.22 g, 0.43 mmol, 43%
yield), mp 178–180◦C. Rf 0.39 (EtOAc/CHCl3, 3:1). νmax
(KBr)/cm−1 2937, 1597, 1508, 1459, 1377, 1258, 1127, 1059,
1008. δH (400 MHz, CDCl3) 7.67 (1H, t, J 7.6, ArH), 7.54–7.46
(6H, m,ArH), 7.02–6.83(8H, m,ArH), 4.96(4H, s, CH2Ar), 4.63
(4H, s, CH2Ar), 4.12 (4H, t, J 4.6, –OCH2CH2O–), 3.81 (4H,
t, J 4.6, –OCH2CH2O–). δC (100 MHz, CDCl3) 158.38, 148.78,
148.69, 137.60, 137.14, 130.03, 129.45, 127.14, 121.22, 120.89,
119.45, 112.91, 111.90, 74.32, 70.98, 70.43, 69.83. HRMS
(EI, 70 eV) found [M + H]+ 514.2224; C31H32NO+6 requires
514.2224.
References
[1] (a) H. R. Diril, X. Chang, S. K. Zhang, J. A. Larsen, C. G. Polenza,
H. J. Pierpont, S. Schugar, S. Isted, D. N. Hendrickson, J. Am. Chem.
Soc. 1987, 109, 6207. doi:10.1021/JA00254A063
(b) T. J. Wydrzynski, K. Satoh, J. A. Frejman, Advances in Photo-
synthesis and Respiration 2005, 22, 235.
[2] (a) S. Omura, Macrolide Antibiotics: Chemistry, Biology, and
Practice, 2nd edn 2002 (http://www.elsevier.com/wps/find/
bookdescription.cws_home/679343/description#description).
(b) Y. Inai, M. Yabuki, T. Kanno, J. Akiyama, T. Yasuda, K. Utsumi,
Cell Struct. Funct. 1997, 22, 555. doi:10.1247/CSF.22.555
[3] (a) F. G. Riddell, Chirality 2002, 14, 121. doi:10.1002/CHIR.10052
(b) M. M. Faul, B. E. Huff, Chem. Rev. 2000, 100, 2407. doi:10.1021/
CR940210S
[4] J. A. A. de Boer, J. W. H. M. Uiterwijk, J. Geevers, S. Harkema, D. N.
Reinhoudt, J. Org. Chem. 1983, 48, 4821. doi:10.1021/JO00173A008
[5] (a) G. W. Gokel, S. L. DeWall, E. S. Meadows, Eur. J. Org. Chem.
2000, 2967. doi:10.1002/1099-0690(200009)2000:17<2967::AID-
EJOC2967>3.0.CO;2-O
3,10,13,21,24,31-Hexaoxa-37-azapentacyclo
[31.3.1.115,19.04,9.025,30]octatriaconta-1(37),4(9),5,7,
15(38),16,18,25(30),26,28,33,35-dodecaen-16-yl 25
(b) G. W. Gokel, L. J. Barbour, R. Ferdani, J. Hu, Acc. Chem. Res.
2002, 35, 878. doi:10.1021/AR000093P
The general procedure was used with 8 (0.41 g, 1.0 mmol)
and α,αꢀ-dichloro-m-xylene (0.17 g, 1.0 mmol). Product 25 was
isolated by column chromatography on silica gel using EtOAc as
a white solid (0.19 g, 0.38 mmol, 38% yield), mp 166–168◦C. Rf
0.28 (EtOAc). νmax (KBr)/cm−1 2937, 1596, 1509, 1459, 1377,
1258, 1127, 1056. δH (400 MHz, CDCl3) δ 7.65 (t, 1H, J 7.6,
ArH), 7.58 (s, 1H, ArH), 7.53–7.44 (m, 5H, ArH), 7.02–6.83
(m, 8H, ArH), 4.94 (s, 4H, CH2Ar), 4.62 (s, 4H, CH2Ar), 4.11
(t, 4H, J 4.4, –OCH2CH2O–), 3.81 (t, 4H, J 4.4, –OCH2CH2O–).
δC (100 MHz, CDCl3) 157.57, 148.78, 148.71, 137.06, 129.98,
129.65, 129.51, 127.18, 121.30, 121.00, 119.52, 113.11, 112.13,
73.58, 71.12, 68.45, 67.89. HRMS (EI, 70 eV) found [M + H]+
514.2222; C31H32NO+6 requires 514.2224.
[6] (a) T. Mashiko, N. Kumagai, M. Shibasaki, Org. Lett. 2008, 10, 2725.
doi:10.1021/OL8008446
(b) Y. Horiuchi, V. Gnanadesikan, T. Ohshima, H. Masu, K. Katagiri,
Y. Sei, K. Yamaguchi, M. Shibasaki, Chem. Eur. J. 2005, 11, 5195.
doi:10.1002/CHEM.200500442
(c) K. Daikai, T. Hayano, R. Kino, H. Furuno, T. Kagawa, J. Inanaga,
Chirality 2003, 15, 83 (and ref. cited therein). doi:10.1002/CHIR.
10167
(d) Y. S. Kim, S. Matsunaga, J. Das, A. Sekine, T. Ohshima,
M. Shibasaki, J. Am. Chem. Soc. 2000, 122, 6506. doi:10.1021/
JA001036U
[7] (a) N. Gathergood, K. Juhl, T. B. Poulsen, K. Thordrup, K. A.
Jørgensen, Org. Biomol. Chem. 2004, 2, 1077. doi:10.1039/B316092K
(b) K. Juhl, N. Gathergood, K. A. Jørgensen, Angew. Chem. Int.
Ed. 2001, 40, 2995. doi:10.1002/1521-3773(20010817)40:16<2995::
AID-ANIE2995>3.0.CO;2-M
(c) N. Gathergood, W. Zhuang, K. A. Jørgensen, J. Am. Chem. Soc.
2000, 122, 12517. doi:10.1021/JA002593J
[8] (a)T. Katsuki, Chem. Soc. Rev. 2004, 33, 437. doi:10.1039/B304133F
(b) T.Yamada, T. Nagata, K. D. Sugi, K.Yorozu, T. Ikeno,Y. Ohtsuka,
D. Miyazaki,T. Mukaiyama, Chem. Eur. J. 2003, 9, 4485. doi:10.1002/
CHEM.200304794
3,10,13,21,24,31-Hexaoxa-37,38-diazapentacyclo
[31.3.1.115,19.04,9.025,30]octatriaconta-1(37),4(9),5,7,
15(38),16,18,25(30),26,28,33,35-dodecaen-16-yl 26
The general procedure was used with 8 (0.41 g, 1.0 mmol) and
2,6-bis(chloromethyl)pyridine (0.17 g, 1.0 mmol). Product 26
was isolated by column chromatography on silica gel using
EtOAc as a white solid (0.25 g, 0.49 mmol, 49% yield), mp
145–147◦C. Rf 0.18 (EtOAc). νmax (KBr)/cm−1 2920, 1594,
1507, 1456, 1362, 1259, 1125, 1053. δH (400 MHz, CDCl3)
7.48 (2H, d, J 7.8, ArH), 7.34 (3H, m, ArH), 7.02–6.87 (8H,
m, ArH), 6.78 (1H, t, J 7.8, ArH), 5.07 (4H, s, CH2Ar), 4.61
(4H, s, CH2Ar), 4.17 (4H, t, J 4.4, –OCH2CH2O–), 3.87 (4H,
t, J 4.4, –OCH2CH2O–). δC (100 MHz, CDCl3) 157.61, 156.47,
149.32, 148.90, 137.51, 137.20, 122.03, 121.58, 121.42, 119.40,
(c) T. Uchida, T. Katsuki, Helv. Chim. Acta 2002, 85, 3078.
doi:10.1002/1522-2675(200210)85:10<3078::AID-HLCA3078>3.0.
CO;2-1
(d) Y. Ohtsuka, K. Koyasu, T. Ikeno, T. Yamada, Org. Lett. 2001, 3,
3421. doi:10.1021/OL016676W
(e) T. Nagata, K. Yorozu, T. Yamada, T. Mukaiyama, Angew. Chem.
Int. Ed. Engl. 1995, 34, 2145. doi:10.1002/ANIE.199521451
[9] (a) J. Paradowska, M. Stodulski, J. Mlynarski,Adv. Synth. Catal. 2007,
349, 1041. doi:10.1002/ADSC.200600581

Benzocrown Ethers: Synthesis and Binding Studies
1357
(b) B. M. Trost, J. Jaratjaroonphong, V. Reutrakulb, J. Am. Chem. Soc.
2006, 128, 2778. doi:10.1021/JA057498V
(b) D. J. Maloney, S. M. Hecht, Org. Lett. 2005, 7, 4297. doi:10.1021/
OL051849T
(c) B. M. Trost, S. Hisaindee, Org. Lett. 2006, 8, 6003. doi:10.1021/
OL062485N
(d) H. D. Du, J. Long, J. Hu, X. Li, K. Ding, Org. Lett. 2002, 4, 4349.
doi:10.1021/OL027034R
[16] (a) C. J. Pedersen, Fed. Proc. Fed.Am. Soc. Expl. Biol. 1968, 27, 1305.
(b) C. J. Pedersen, Science 1988, 241, 536. doi:10.1126/SCIENCE.
241.4865.536
[17] (a) R. W. Saalfrank, S. Trummer, H. Krautscheid, V. Schünemann,
A. X. Trautwein, S. Hien, C. Stadler, J. Daub, Angew. Chem. 1996,
108, 2350. doi:10.1002/ANGE.19961081909
(b) R. W. Saalfrank, N. Löw, S. Kareth, V. Seitz, F. Hampel, D. Stalke,
M. Teichert, Angew. Chem. Int. Ed. 1998, 37, 172. doi:10.1002/(SICI)
1521-3773(19980202)37:1/2<172::AID-ANIE172>3.0.CO;2-0
[18] (a) J. Kim, M. Shamsipur, S. Z. Huang, R. H. Huang, J. L. Dye,
J. Phys. Chem. A 1999, 103, 5615. doi:10.1021/JP990685T
(b) H. J. Holdt, H. Müller, M. Pötter, A. Kelling, U. Schilde, I. Starke,
M. Heydenreich, E. Kleinpeter, Eur. J. Inorg. Chem. 2006, 2377.
doi:10.1002/EJIC.200501109
[10] A. Casnati, N. D. Ca, F. Sansone, F. Ugozzoli, R. Ungaro, Tetrahedron
2004, 60, 7869. doi:10.1016/J.TET.2004.06.058
[11] J. S. Kim, J. H. Pang, I. Y. Yu, W. K. Lee, I. H. Suh, J. K. Kim,
M. H. Cho, E. T. Kim, D. Y. Ra, J. Chem. Soc., Perkin Trans. 2 1999,
837. doi:10.1039/A808499H
[12] K. Salorinne, M. Nissinen, Tetrahedron 2008, 64, 1798. doi:10.1016/
J.TET.2007.11.103
[13] G.-P. Xue, J. S. Bradshaw, N. Su, K. E. Krakowiak, P. B. Savage,
R. M. Izatt, J. Heterocycl. Chem. 2000, 37, 1. doi:10.1002/JHET.
5570370101
[14] C. J. Pedersen, J. Am. Chem. Soc. 1967, 89, 7017. doi:10.1021/
JA01002A035
(c) S. Fery-Forgues, F. Al-Ali, J. Photochem. Photobiol. C: Photo-
chem. Rev. 2004, 5, 139. doi:10.1016/S1389-5567(04)00021-8
[15] (a) T. I. Richardson, S. D. Rychnovsky, J. Am. Chem. Soc. 1997, 119,
12360. doi:10.1021/JA971916H