Synthesis and evaluation of new ditopic cyclophane receptors for benzoic acid

Article abstract of DOI:10.1002/poc.981

As potential receptors for a benzoic acid guest, new ditopic cyclophane host molecules, each with a π electron-rich portion and a pyridine ring-containing portion, are synthesized. Complexation of benzoic acid guest by the potential molecular receptors is probed by infrared spectroscopy, proton magnetic resonance titration experiments and solid-state structure determination. Copyright

Full text of DOI:10.1002/poc.981

JOURNAL OF PHYSICAL ORGANIC CHEMISTRY
J. Phys. Org. Chem. 2005; 18: 1107–1115
Published online 8 August 2005 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/poc.981
Synthesis and evaluation of new ditopic cyclophane
receptors for benzoic acid
Christopher M. Stetson,1 Shiro Nishikawa,1 David W. Purkiss,1 N. Kent Dalley2 and Richard A. Bartsch1*
1Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas 79409-1061, USA
2Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602-5700, USA
Received 16 May 2005; accepted 17 June 2005
ABSTRACT: As potential receptors for a benzoic acid guest, new ditopic cyclophane host molecules, each with a ꢀ
electron-rich portion and a pyridine ring-containing portion, are synthesized. Complexation of benzoic acid guest by
the potential molecular receptors is probed by infrared spectroscopy, proton magnetic resonance titration experiments
and solid-state structure determination. Copyright # 2005 John Wiley & Sons, Ltd.
Supplementary electronic material for this paper is available in Wiley Interscience at http://www.interscience.
wiley.com/jpages/0894-3230/suppmat/
KEYWORDS: molecular recognition; supramolecular chemistry; cyclophanes receptors
INTRODUCTION
n ¼ 1, the strongest binding of n-propylammonium pi-
crate was observed.
During the past four decades, a wide variety of macro-
cyclic receptor molecules, which exhibit selectivity in
binding of ionic1 and molecular2–4 species, has been
synthesized. Molecular receptors with at least one aro-
matic ring bridged by at least one aliphatic n-membered
bridge (n 5 0) are designated as cyclophanes.
We now report the synthesis of new, ditopic cyclo-
phanes 4 and 5 for which it was envisaged that a benzoic
acid guest would be encapsulated and oriented with the
phenyl ring of the guest towards the ꢀ electron-
rich hydrophobic portion of the receptor and the
carboxylic acid group would be hydrogen bonded to the
2,6-diaminopyridine portion. The structures of cyclo-
phanes 4 and 5 differ in that the additional methyl groups
in the latter should provide enhanced hydrophobicity.
We have been using the relatively unexplored bisphe-
nol 15 (Fig. 1) as a ꢀ electron-rich hydrophobic unit for
the construction of new types of cyclophanes.6–10 By
connecting the oxygen atoms of two molecules of 1 with
multi-methylene spacers, the rigidity of the two ꢁ,ꢁ0-
di(4-oxyphenyl)-1,4-diisopropylbenzene units provides
open structures in which the dimensions of the central
cavity can be varied systematically by changing the
number of carbon atoms in the spacers. We have reported
solid-state structures of molecular receptors 2 and their
complexes with aromatic guest species.7–9 Thus cyclo-
phanes 2 with n ¼ 3 and 5 form complexes in which p-
xylene7 and anthracene,8 respectively, are located within
the central cavities of the hosts. We have also prepared
ditopic receptors 3 and assessed their binding of alky-
RESULTS AND DISCUSSION
Synthesis of ditopic cyclophanes 4 and 5
For cyclophanes 4 and 5, the hydrophobic units were
formed by reaction of phenol and 2,6-dimethylphenol,
respectively, with commercially available ꢁ,ꢁ,ꢁ’,ꢁ’-tet-
ramethyl-1,4-benzenedimethanol and gaseous HCl. Re-
sultant bisphenols 1 and 6 were alkylated with ethyl 4-
bromobutanoate and K2CO3 in acetone to form diesters 7
and 8 in 85% and 88% yields, respectively (Fig. 2). Basic
hydrolysis followed by acidification gave dicarboxylic
acids 9 and 10 in 70% and 93% yields, respectively. The
diacids were converted quantitatively into corresponding
di(acid chlorides) 11 and 12 by reaction with thionyl
chloride and a catalytic amount of DMF in benzene.
Under high dilution conditions, equimolar THF solutions
of the di(acid chloride) and 2,6-diaminopyridine were
1
lammonium picrates in solution by H NMR spectro-
scopy and solvent extraction.6 For cyclophane 3 with
*Correspondence to: R. A. Bartsch, Department of Chemistry and
Biochemistry, Texas Tech University, Lubbock, Texas 79409-1061,
USA.
E-mail: richard.bartsch@ttu.edu
Contract/grant sponsor: The Welch Foundation; Contract/grant num-
ber: D-0775.
Copyright # 2005 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2005; 18: 1107–1115

1108
C. M. STETSON ET AL.
Me
Complexation of benzoic acid by ditopic
cyclophanes 4 and 5 and their precursor
macrocyclic diamides 13 and 14
Me
Me
Me
Me
OH
OH
Me
Me
O(CH2)nO
Me
Me
To determine if proton transfer took place when benzoic
acid was complexed by the ditopic cyclophanes, the
infrared absorptions of benzoic acid in carbon tetrachlor-
ide in the absence and presence of one equivalent of
cyclophane 4 were measured. For benzoic acid alone, the
carbonyl absorption was at 1690 cmꢀ1. For an equimolar
solution of benzoic acid and cyclophane 4, the carbonyl
absorption shifted only slightly to 1696 cmꢀ1, revealing
that proton transfer from the guest to the host was not
taking place.
O(CH2 )n O
Me
Me
Me
O
Me
2
1
R
H
Me
Me
Me
O(CH2)4N
Me
Me
O(CH2 )4 N
O
O
R
R
N
O(CH2)4N
O(CH2 )4 N
O
Me
Me
H
R
3
R
H
Me
4
5
Association constants for interactions of benzoic acid
with ditopic cyclophanes 4 and 5 and their precursor
macrocyclic diamides 13 and 14 in CDCl3 were measured
by NMR titration. Binding was determined from the
relationship of the benzoic acid (guest) concentration
relative to the change in signal (in Hz) of affected
nuclei in the host molecule, whose concentration was
held constant. Data were analyzed using the HOSTEST
II program developed by Professor Craig S. Wilcox to
calculate binding constants of binary complexes by spec-
troscopic methods.11,12 For this program, concentrations
Figure 1. Structures of di-ꢁ,ꢁ,ꢁ’,ꢁ’-tetramethyl-1,4-
benzenedimethanol (1) and cyclophanes derived therefrom
added simultaneously to a vigorously stirred mixture of
K2CO3 in toluene to form macrocyclic diamides 13 and
14 in 35% and 29% yields, respectively. Reduction of the
diamides with BH3–THF gave 90% yields of ditopic
cyclophanes 4 and 5.
R
R
R
Me
Me
Me
Me
Me
Me
Me
O(CH2)3CO2H
O(CH2)3CO2H
Me
Me
OH
OH
Me
Me
O(CH2 )3 CO2 Et
O(CH2 )3 CO2 Et
a
b
R
R
R
R
R
R
Me
R
R
R
R
H
R
H
R
H
9
1
6
7
8
10 Me
Me
Me
c
R
R
Me
O
Me
Me
Me
Me
O(CH2)3CN
H
Me
Me
O(CH2)3C(O)Cl
O(CH2)3C(O)Cl
d
e
R
R
R
R
4, 5
N
O(CH2)3CNH
O
Me
R
R
R
H
R
H
13
11
14 Me
12 Me
Figure 2. Synthetic scheme for the preparation of ditopic cyclophanes 4 and 5. Reagents/solvent: (a) ethyl 4-bromobutanoate,
K2CO3/acetone; (b) NaOH/aq. EtOH, or H3Oþ; (c) SOCl2, cat. DMF/benzene; (d) 2,6-diaminopyridine, K2CO3/toluene; (e) BH3–
THF/THF
Copyright # 2005 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2005; 18: 1107–1115

NEW DITOPIC CYCLOPHANE RECEPTORS FOR BENZOIC ACID
1109
Table 1. Concentrations of host and guest, observed NMR signal changes, association constants and Weber p values for
complexation of benzoic acid guest by ditopic cyclophane hosts 4 and 5 and precursor macrocyclic diamide hosts 15 and 16 in
CDCl3 at 23 ꢁC
[Host]
(mM)
[Guest]
(mM)
Proton
Signal
change (Hz)
Association
constant (M
Weber
p value
ꢀ1
Host
in hosta
)
4
0.30
0.20
2.4
0.10–0.70
0.10–0.80
7.4–95.4
0.0–6.9
Hd
Hh
Hx
Hd
Hh
Hx
Hc
He
Hx
Hc
He
Hx
ꢀ12.2
þ17.5
þ16.4
ꢀ12.9
þ7.1
þ2.2
ꢀ5.5
þ3.9
þ4.5
ꢀ2.4
þ9.0
þ5.7
5800
5400
6400
4900
5200
5100
700
0.48–0.74
0.44–0.72
0.42–0.75
0.42–0.75
0.34–0.67
0.42–0.76
0.60–0.75
0.60–0.75
0.67–0.83
0.53–0.74
0.43–0.63
0.50–0.71
5
13
14
700
1200
700
400
3.5
600
a See Fig. 3.
of the components in solution are entered together with
the corresponding spectroscopic shifts. The program
output includes a binding constant and a statistical
measure of the value of the data, the Weber ‘p’ value.
The Weber ‘p’ value should be within the range of 0.2–
0.8. Values outside this range indicate that the concentra-
tions of host and/or guest chosen for the experiment are
inappropriate.
chemical shift changes were observed upon addition of
benzoic acid are shown in Fig. 3. As can be seen,
association constants for the interaction of benzoic acid
guest by macrocyclic diamide hosts 13 and 14 are nearly
an order of magnitude lower than those for the ditopic
cyclophane hosts 4 and 5. This can be attributed to greater
basicity in the polar portions of hosts 4 and 5 compared
with 13 and 14. Also, it appears that the association
constants become lower when two additional methyl
groups are incorporated into the host (i.e. 4 vs. 5 and 13
Results from the NMR titration experiments are pre-
sented in Table 1. The protons of the host for which
CH3
CH3
CH
3
NH
N
H3C
O
O
NH
N
H3C
O
CH3
CH3
Hy
Hy
He Hg
He Hg
Ha
H3C
Ha
Hx
Hx
N
Hi
H3C
Hb
O
N
Hi
Hf
Hb CH2
Hc
Hh
O
CH2
Hc Hd
Hf
Hh
O
Hd
C Hd
Hd
5
4
CH3
CH3
CH3
NH
H3C
O
O
NH
H3C
O
CH3
CH3
N
Hy
N
Hx
He Hg
He
Hg
Ha
H3C
Hb
Ha
H3C
Hx
Hx
N
Hi
O
N
Hi
O
CH2
Hc
Hf
O
CH2
Hc Hd
Hf
Hb
Hd
C
Hd
14
13
Hd
O
Hl
C
OH
Hm
Hn
Figure 3. Protons in cyclophane hosts 4, 5, 13 and 14 affected by addition of benzoic acid in NMR titration experiments
Copyright # 2005 John Wiley & Sons, Ltd. J. Phys. Org. Chem. 2005; 18: 1107–1115

1110
C. M. STETSON ET AL.
tion. These efforts were successful only for macrocyclic
diamide 13 and a complex of cyclophane triamine host 4
with benzoic acid. The asymmetric unit of 13 consisted of
two very similar molecules.
An ORTEP drawing for one of the two molecules of
13ꢂacetone is shown in Fig. 4. (An ORTEP drawing
for the second molecule is shown in Fig. ES1 in the
electronic supplement.) For both molecules, there is
an associated molecule of acetone solvent located above
the plane of the molecule. The carbonyl oxygen of
the acetone is hydrogen bonded to the N—H of one
amide group. The hydrogen bond data are given in
Table 2. This host molecule is seen to be in an open
conformation with a well-formed cavity.
An ORTEP drawing for the 1:1 complex of benzoic
acid with ditopic cyclophane host 4 is presented in Fig. 5.
Instead of the expected inclusion complex with the guest
located within the central cavity of the host, the molecule
of 4 is folded with the pyridine ring nitrogen and the
hydrogens on the two amine groups pointed outward
towards an external benzoic acid molecule. The benzoic
acid guest is disordered in two sites to allow the carboxyl
oxygen to hydrogen bond (Table 2) with one or the other
amine hydrogens. It was not possible to locate the acid
hydrogen atom of the carboxylic acid group of either
partial benzoic acid. However, it appears that the car-
boxyl oxygens are hydrogen bonded to the two amine
groups of the host (see Fig. 5). The hydrogen bond data
are given in Table 2. This folding of the cyclophane host
to hydrogen bond with an external benzoic acid guest is
consistent with the unexpected shifts of meta pyridyl ring
hydrogens, Hx, upon addition of benzoic acid to cyclo-
phanes 4, 5, 13 and 14 in the NMR titration experiments
(vide infra).
Figure 4. An ORTEP drawing with numbering system for
one structure of cyclophane diamide 13 with a solvating
molecule of acetone. Thermal ellipsoids are drawn at the
30% probability level. Hydrogen atoms of 13 (except for
H38) and the solvating acetone molecule are omitted for
clarity
vs. 14). This could arise from unfavorable steric interac-
tions between the guest and the hydrophobic portions of
host 13 compared with 4 and host 14 compared with 5.
Although the observed shifts in NMR signals for some of
the protons on the terminal phenylene groups and in the
polymethylene chains connecting the hydrophobic and
polar portions of the cyclophane are consistent with
complexation of the benzoic acid guest within the cav-
ities of the host molecules, the NMR signal shifts
observed for Hx, the meta protons on the pyridine ring,
are not.
Nuclear Overhauser effect studies of ditopic
cyclophane 4 and macrocyclic diamides 13 and 14
in solution
For further investigation of the cyclophane host struc-
tures, nuclear Overhauser effect (NOE) studies were
performed for macrocycles 4, 13 and 14 and for 4 in
the presence of equimolar benzoic acid in CDCl3
solution.
Solid-state structure determinations
In an effort to obtain additional information about the
structures of the new cyclophane host molecules and their
complexes with benzoic acid guest, attempts were made
to grow crystals suitable for x-ray structure determina-
Absorptions for the different protons in the 300 MHz
NMR spectrum of macrocyclic diamide 13 (see Fig. 3 for
Table 2. Hydrogen bonding in the two molecules 13ꢂacetone and in 4ꢂbenzoic acid
D—Hꢃ ꢃ ꢃO ( ꢁ)
˚
D—H (A)
˚
˚
Molecule
D
H
A
Hꢃ ꢃ ꢃA (A)
Dꢃ ꢃ ꢃA (A)
13ꢂAcetone
N38
N88
N3
H38
H88
H3
O43
O93
O510
O51
1.18
0.86
1.18
1.17
2.11
2.39
1.89
1.71
3.17
3.18
2.99
2.79
148
154
153
151
4ꢂBenzoic
acid
N38
H38
Copyright # 2005 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2005; 18: 1107–1115

NEW DITOPIC CYCLOPHANE RECEPTORS FOR BENZOIC ACID
1111
Figure 5. An ORTEP drawing with numbering system for the 1:1 complex of cyclophane 4 and benzoic acid. Thermal ellipsoids
are drawn at the 30% probability level. Hydrogen atoms of 4 and benzoic acid are omitted for clarity
proton designations) are identified as ꢂ: 1.63 (s) Hb; 2.20
(p) Hf; 2.58 (t) Hg; 3.93 (t) He; 6.69 (d) Hd; 7.98 (s) Ha;
7.12 (d) Hc; 7.61 (br s) Hi; 7.63 (t) Hy; 7.89 (d) Hx. Upon
irradiation of the signal for Hd, only the signals for
adjacent protons Hc and He exhibited the NOE. When
the signal for Hx was irradiated, the NOE was observed
only for the adjacent pyridyl ring proton Hy. In both
instances, only nuclei near the irradiated nuclei gave
signal enhancements. This is in agreement with an open
conformation of the type found in the solid-state structure
(Fig. 4).
For macrocyclic diamide 14 (see Fig. 3 for proton
designations), the proton absorptions in the 300 MHz
NMR spectrum are identified as ꢂ: 1.63 (s) Hb; 2.07 (s)
Hd; 2.20 (p) Hf; 2.68 (t) Hg; 3.76 (t) He; 6.59 (s) Hc; 7.17
(s) Ha; 7.63 (t) Hy; 7.72 (br s) Hi, 7.94 (d) Hx. Irradiation
of the singlet for Hd gave signal enhancements for
neighboring protons Hc and He. There was also a small,
but clearly discernable, enhancement for the amide pro-
ton Hi, suggesting some folding of the molecule. When
the signal for Hx was irradiated, the NOE was noted only
for the adjacent pyridyl ring proton Hy.
Absorptions for the different protons (see Fig. 3 for the
proton designations) in the macrocyclic triamine 4 are
identified as ꢂ: 1.58 (s) Hb; 1.69 (p) Hg; 1.73 (p) Hf; 3.14
(q) Hh; 3.92 (t) He; 4.24 (br t) Hi; 5.55 (d) Hy; 6.66 (d) Hd;
6.97 (s) Ha; 7.02 (t) Hx; 7.02 (d) Hc. Irradiation of the
signal for Hd gave the NOE only of signals for adjacent
protons Hc and He. When the signal for He was irradiated,
signal enhancements were observed only for neighboring
protons Hf and/or Hg (these protons are indiscernible in
the difference spectra) and Hd. Irradiation of the signal
for Hx produced the NOE for adjacent pyridyl ring proton
Hy and amine proton Hi, with possible enhancements for
more distant Hh and He. When the signal for Hh was
irradiated, the expected NOE of the signals for adjacent
protons Hf and/or Hg was observed. In addition, there was
an unanticipated NOE of the signal for Hx. This is only
possible if the pyridine ring in 4 is flipped so that the
pyridyl nitrogen points away from the macrocylic cavity.
Attention then was shifted to solutions that contained
equimolar amounts of cyclophane triamine 4 and benzoic
acid. Upon irradiation of the signal for Hd, the NOE was
observed for the signals of Hc and He with a small
enhancement of the signal for Hx. No signal enhancement
was noted for Hl, Hm, or Hn of the benzoic acid guest (see
Fig. 3 for proton designations). With irradiation of the
signal for Hx, signal enhancement for Hh was evident.
The intensity of this NOE was greater in the presence of
benzoic acid than in its absence. Also, weak signal
enhancement for Hf and/or Hg was evident. Irradiation
of the signal for He gave an NOE only of the signals for
neighboring Hd and indistinguishable Hf and/or Hg.
When the signal for Hh was irradiated there was an
intense NOE for the signal of Hx. This enhancement of
the Hx signal was much greater than when the signal for
Hh in cyclophane 4 was irradiated in the absence of
benzoic acid.
Finally, nuclei of the benzoic acid guest were probed to
see if any intermolecular NOEs could be detected. How-
ever, irradiation of signals for the aromatic ring protons
Hl, Hm and Hn gave an NOE only for signals of the other
aromatic ring protons. Thus, no intermolecular NOEs
between benzoic acid and host 4 were observed.
Results from the NOE experiments reveal some folding
of cyclophane triamine 4 into conformations in which the
Copyright # 2005 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2005; 18: 1107–1115

1112
C. M. STETSON ET AL.
pyridine ring nitrogen is oriented away from the macro-
cyclic cavity. This folding is accentuated by the presence
of an equimolar amount of benzoic acid guest. These
findings suggest that the host–guest geometrical relation-
ship for cyclophane 4 and benzoic acid in solution
resembles that found in the solid-state structure for the
complex (Fig. 5).
Bisphenol 6. The procedure was identical to that given for
the preparation of bisphenol 1, except for the replacement
of phenol with 2,6-dimethylphenol. Crude bisphenol 6
was recrystallized from EtOH to give very large prisms
(76.00 g, 73%), m.p. 156–157 ꢁC. ꢃmax (deposit on a
NaCl plate from CH2Cl2 solution) (cmꢀ1): 3478 (OH)
and 1183 (C—O). ꢂH (200 MHz, CDCl3): 1.62 (s, 12H),
2.19 (s, 12H), 4.46 (s, 2H), 6.83 (s, 4H), 7.11 (s, 4H). ꢂC
(50 MHz, CDCl3): 16.09, 30.85, 41.58, 122.19, 126.08,
126.93, 142.35, 147.80, 149.86. MS (EI, 70 eV)[m/e,
(%)]: 41.10 (38.55) 186.00 (31.38), 387.35 (100),
M þ 402.35 (29.56), Mþ1 (8.10), Mþ2 (1.50). Found:
C, 83.79; H, 8.50. Calc. for C28H34O2: C, 83.54; H, 8.51.
EXPERIMENTAL
General methods and materials
Unless specified otherwise, reagent-grade reactants and
solvents were used as received from chemical suppliers.
Acetone was distilled from and stored over anhydrous
K2CO3. Tetrahydrofuran was distilled from benzophe-
none-sodium ketyl and used immediately. Dimethyl
Diester 7. To acetone (250 ml) in a 500-ml flask was
added bisphenol 1 (22.00 g, 63 mmol), anhydrous K2CO3
(34.00 g, 252 mmol) and ethyl 4-bromobutanoate
(37.00 g, 189 mmol). The mixture was refluxed for 24 h
and evaporated in vacuo. To the residue, CH2Cl2 was
added and the mixture was filtered. The filtrate was
evaporated in vacuo to provide a pale yellow oil. After
addition of warm EtOH (20 ml) and allowing the solution
to stand for 2 days at room temp, 31.00 g (85%) of diester
7 was obtained as large needles, m.p. 64–65 ꢁC. ꢃmax
˚
formamide was distilled from BaO and stored over 4 A
molecular sieves. Reagent-grade benzene and toluene
were stored over sodium ribbon.
Infrared (IR) spectra were obtained with a Perkin-
Elmer 1600 FTIR spectrophotometer and are reported
in wavenumbers. The 1H and 13C nuclear magnetic
resonance (NMR) spectra were obtained with a Bruker
IBM AF-200 (200 MHz) or AF-300 (300 MHz) spectro-
meter. Chemical shifts (in ppm) are reported downfield
from TMS. Mass spectra (MS) were recorded with a
Hewlett-Packard GC/MS 5995 spectrometer. Combus-
tion analysis was performed by the Desert Analytics
Laboratory of Tucson, Arizona.
(deposit on NaCl plate from CDCl3 solution) (cmꢀ1):
—
1734 (C O) and 1249 (C—O). ꢂ (200 MHz, CDCl ):
—
3
H
1.23 (t, J ¼ 7.1 Hz, 6H), 1.61 (s, 12H), 2.07 (d of t, J ¼ 7.9
and 6.3 Hz, 4H), 2.48 (t, J ¼ 7.2 Hz, 4H), 3.95 (t,
J ¼ 6.0 Hz, 4H), 4.12 (q, J ¼ 7.0 Hz, 4H), 6.75 (d,
J ¼ 6.7 Hz, 4H), 7.07 (s, 4H), 7.12 (d, J ¼ 6.7 Hz, 4H).
ꢂC (50 MHz, CDCl3): 14.20, 24.65, 30.81, 30.85, 41.79,
60.38, 66.52, 113.70, 126.16, 127.72, 142.96, 147.79,
156.57, 173.27. MS (EI, 70 eV)[m/e, (%)]: 42.95 (12.33),
87.00 (33.57), 115.10 (100), M þ 574.45 (6.03), Mþ1
(2.19), Mþ2 (0.43). Found: C, 75.40; H, 8.03. Calc. for
C36H46O6: C, 75.23; H, 8.07.
Synthesis of compounds
Bisphenol 15. A 500-ml, three-neck flask was charged with
ꢁ,ꢁ,ꢁ’, ꢁ’-tetramethyl-1,4-benzenedimethanol (50.00 g,
0.26 mol) and phenol (240.00 g, 2.60 mol) and the mixture
was heated to 80 ꢁC. Upon melting of the reactants,
mechanical stirring was initiated and HCl gas was
introduced under the surface of the liquid through a glass
tube. The reaction mixture was saturated with gaseous
HCl for 30 min, after which the addition of HCl
was terminated. Stirring was continued for 3 h and the
mixture was poured into water (500 ml). Repeated
washing of the crude oil with water gave a light brown
solid. Recrystallization from EtOH produced 1 (54.20 g,
65%) as a white powder, m.p. 188–189 ꢁC. ꢃmax (deposit on
a NaCl plate from CH2Cl2 solution) (cmꢀ1): 3241 (OH)
and 1244 (C—O). ꢂH (200 MHz, CDCl3): 1.55 (s, 12H),
6.68 (d, J ¼ 6.5 Hz, 4H), 7.00 (d, unresolved, 4H), 7.02 (s,
4H), 7.10 (s, 2H). ꢂC (50 MHz, CDCl3): 30.77, 41.62,
114.57, 126.00, 127.67, 142.08, 147.76, 154.03. MS (EI,
70 eV )[m/e, (%)]: 17.90 (100), 18.20 (99.19), 331.30
(62.94), 135.15, (29.01), M þ 346.30 (16.74), Mþ1
(4.18), Mþ2 (0.69).
Diester 8. The procedure was the same as that employed
in the synthesis of diester 7 except for the use of bi-
sphenol 6 (20.00 g, 50 mmol) instead of bisphenol 1.
Large transparent needles of diester 8 (27.20 g, 88%)
with m.p. 74–75 ꢁC were crystallized after addition of
warm EtOH (20 ml) to the crude oil product. ꢃmax
(deposit on a NaCl plate from CDCl3 solution) (cmꢀ1):
—
1731 (C O) and 1224 (C—O). ꢂ (200 MHz, CDCl ):
—
H
3
1.26 (t, J ¼ 7.1 Hz, 6H), 1.61 (s, 12H), 2.08 (d of t,
unresolved, 4H), 2.19 (s, 12H), 2.58 (t, J ¼ 6.2 Hz, 4H),
3.76 (t, J ¼ 6.0 Hz, 4H), 4.15 (q, J ¼ 7.1 Hz, 4H), 6.83 (s,
4H), 7.10 (s, 4H). ꢂC (40 MHz, CDCl3): 14.24, 16.46,
25.70, 30.85, 30.92, 41.84, 60.37, 70.56, 126.15, 127.19,
129.76, 145.79, 147.71, 153.43, 173.40. MS (EI,
70 eV)[m/e, (%)]: 87.00 (35.55), 115.10 (100),
M þ 630.70 (1.49), M þ 1 (0.73). Found: C, 76.33; H,
8.79. Calc. for C40H54O6: C, 76.16; H, 8.63.
Diacid 9. To a solution of diester 7 (32.00 g, 56 mmol) in
EtOH (200 ml) was added a solution of KOH (15.00 g,
Copyright # 2005 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2005; 18: 1107–1115

NEW DITOPIC CYCLOPHANE RECEPTORS FOR BENZOIC ACID
1113
268 mmol) in H2O (150 ml). The suspension was refluxed
for 1 h, cooled to 0 ꢁC and acidified with 15% aqueous
HCl. After stirring the mixture gently overnight to
promote aggregation, the crude product was filtered.
The solid was dissolved in toluene and dried with a
Dean-Stark trap. The dried toluene solution was placed
in a freezer overnight to afford 9 (22.00 g, 70%) as a
white powder, m.p. 218–219 ꢁC. ꢃmax (deposit on a NaCl
ing di(acid chloride) 12 (2.10 g) as a yellow solid with
m.p. 101–102 ꢁC. This solid was used directly in the next
step. ꢃmax (deposit on a NaCl plate from CDCl3 solution)
(cmꢀ1): 1798 (C O). ꢂ (200 MHz, CDCl3): 1.62 (s,
—
—
H
12H), 2.16 (t of t, unresolved, 4H), 2.19 (s, 12H) 3.21 (t,
J ¼ 7.2 Hz, 4H), 3.77 (t, J ¼ 5.9 Hz, 4H), 6.84 (s, 4H),
7.09 (s, 4H). ꢂC (50 MHz, CDCl3): 16.47, 25.91, 30.83,
41.86, 43.86, 69.27, 126.17, 127.31, 129.64, 146.11,
147.66, 153.10, 173.73.
plate from THF solution) (cmꢀ1): 3300–2500 (COOH)
—
and 1692 (C O). ꢂ (200 MHz, DMSO-d6): 1.55 (s,
—
H
12H), 1.88 (t of t, J ¼ 7.2, 7.2, 6.6, 6.6 Hz, 4H), 2.35 (t,
J ¼ 7.2 Hz, 4H), 3.91 (t, J ¼ 6.4 Hz, 4H), 6.79 (d,
J ¼ 8.6 Hz, 4H), 7.07 (s, 4H), 7.11 (d, J ¼ 8.6 Hz, 4H),
12.16 (br s, 2H). ꢂC (50 MHz, DMSO-d6): 24.30, 30.15,
30.55, 41.36, 66.42, 113.84, 125.97, 127.46, 142.26,
147.51, 156.29, 174.15. MS (EI, 70 eV)[m/e, (%)]:
40.95 (30.3), 331.20 (100), 417.30 (30.1), M þ 518.40
(2.97), M þ 1 (1.02). Found: C, 74.35; H, 7.38. Calc. for
C32H38O6: C, 74.11; H, 7.38.
Cyclophane diamide 13. A solution of di(acid chloride)
11 (1.10 g, 1.90 mmol) in THF (40 ml) was drawn into an
oven-dried, 50-ml glass syringe. A solution of 2,6-dia-
minopyridine (0.21 g, 1.90 mmol) in THF (40 ml) was
drawn into a second oven-dried, 50-ml glass syringe.
With two Sage Instruments syringe pumps, the two
solutions were added simultaneously over an 8-h period
at room temperature to a vigorously stirred suspension of
anhydrous K2CO3 (1.30 g, 9.5 mmol) in toluene (300 ml)
in a flame-dried, 1-l Morton flask. The mixture was
stirred for an additional 48 h after the addition was
completed. The mixture was filtered and evaporated in
vacuo. The resultant light brown oil was dissolved in
CH2Cl2 and the solution was passed through a short
column of flash silica gel (2.4 ꢄ 10 cm) with EtOAc–
hexane (1:3) as eluent. The eluent was evaporated in
vacuo and the resultant pale yellow oil was chromato-
graphed on a flash silica gel column (2.4 ꢄ 40 cm) with
EtOAc–hexane (1:19) as eluent to provide a cream-
colored solid. Recrystallization by slow evaporation of
its CHCl3–hexane (9:1) solution gave cyclophane dia-
mide 13 (0.40 g, 35%) as a white solid, m.p. 244–246 ꢁC.
ꢃmax (deposit on a NaCl plate from CDCl3 solution)
Diacid 10. The procedure described for the synthesis of
diacid 9 was utilized with the exception that diester 8
(27.00 g, 43 mmol) was a reactant. Recrystallization of
the crude product from toluene gave diacid 10 (26.00 g,
93%) as a white powder, m.p. 243–246 ꢁC. ꢃmax (deposit
on a NaCl plate from THF solution) (cmꢀ1): 3424–2519
—
(COOH) and 1716 (C O). ꢂ (200 MHz, DMSO-d6):
H
—
1.61 (s, 12H), 2.05 (p, unresolved, 4H), 2.19 (s, 12H),
2.51 (t, J ¼ 7.3 Hz, 4H), 3.78 (t, J ¼ 6.3 Hz, 4H), 6.89 (s,
4H), 7.12 (s, 4H). ꢂC (50 MHz, DMSO-d6):16.23, 25.36,
30.18, 30.44, 41.35, 70.46, 125.95, 126.77, 129.37,
145.19, 147.30, 153.19, 174.20. MS (EI, 70 eV)[m/e,
(%)]: 163.15 (21.0), 387.25 (100), 388.35 (32.6),
M þ 574.45 (7.3). Found: C, 75.03; H, 7.77. Calc. for
C36H46O6: C, 75.23; H, 8.07.
(cmꢀ1): 3436, 3272 (N—H) and 1684 (C O). ꢂ
—
—
H
(200 MHz, CDCl3): 1.61 (s, 12H), 2.19 (t of t, unresolved,
4H), 2.59 (t, J ¼ 5.8 Hz, 4H), 3.93 (t, J ¼ 6.0 Hz, 4H),
6.69 (d, J ¼ 6.8 Hz, 4H), 6.69 (s, 4H) 7.12 (d, J ¼ 6.8,
4H), 7.63, br s, 2H), 7.69 (t, J ¼ 8.0 Hz, 1H), 7.90 (d,
J ¼ 8.0 Hz, 2H). ꢂC (50 MHz, CDCl3): 24.43, 30.53,
33.51, 41.62, 65.50, 109.41, 113.57, 125.89, 127.70,
140.86, 142.42, 148.11, 149.26, 156.43, 170.77. MS
(EI, 70 eV)[m/e, (%)]: 18.00 (70.33), 178.10 (49.59),
246.15 (100), Mþ591.40 (2.73). Found: C, 74.82; H,
6.84; N, 6.83. Calc. for C37H41N3O4: C, 75.10; H, 6.98;
N, 7.10.
Di(acid chloride) 11. To a solution of diacid 9 (1.00 g,
1.8 mmol) in benzene (10 ml) was added thionyl chloride
(0.47 g, 4.0 mmol) and two drops of DMF. The solution
was refluxed for 3 h and evaporated in vacuo. To the
residue, benzene was added and the mixture was filtered
through an oven-dried, sintered glass funnel. The filtrate
was evaporated in vacuo leaving a pale yellow solid
(1.00 g) with m.p. 91–92 ꢁC, which was utilized without
purification in the next step. ꢃmax (deposit on a NaCl plate
from CDCl3 solution) (cmꢀ1): 1797 (C O). ꢂ
—
—
H
(200 MHz, CDCl3): 1.63 (s, 12H), 2.16 (t of t, J ¼ 7.0,
5.9, 5.8, 7.0 Hz, 4H), 3.13 (t, J ¼ 5.8 Hz, 4H), 3.77 (t,
J ¼ 5.8 Hz, 4H), 7.07 (s, 4H), 7.13 (d, J ¼ 8.8 Hz, 4H). ꢂC
(50 MHz, CDCl3): 24.92, 30.84, 41.85, 43.81, 65.46,
113.70, 126.18, 127.82, 143.38, 147.79, 156.25, 173.68.
Cyclophane diamide 14. Using the procedure described
for the preparation of cyclophane diamide 13, solutions
of di(acid chloride) 12 (5.00 g, 8.2 mmol) in THF (50 ml)
and 2.6-diaminopyridine (0.89 g, 8.2 mmol) in THF
(50 ml) were added simultaneously over a 12-h period
at room temperature to a vigorously stirred suspension of
K2CO3 (11.3 g, 82 mmol) in 2.5 l of toluene. Following
the addition, the suspension was stirred for another 18 h
and then filtered. The filtrate was evaporated in vacuo to
give a brown oil that was dissolved in CH2Cl2 and passed
through a short column of flash silica gel (4.3 ꢄ 8.0 cm)
Di(acid chloride) 12. To a solution of diacid 10 (2.00 g,
3.5 mmol) in benzene (15 ml) were added thionyl chlor-
ide (0.86 g, 7.2 mmol) and two drops of DMF. The
remaining procedure and work-up were the same as
employed in the synthesis of di(acid chloride) 11 provid-
Copyright # 2005 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2005; 18: 1107–1115

1114
C. M. STETSON ET AL.
with EtOAc-hexane (3:17) as eluent. After evaporation of
the eluent in vacuo, the resultant yellow oil was chroma-
tographed on flash silica gel (2.4 ꢄ 40 cm) with EtOAc-
hexane (1:19) as eluent to give a white powder (1.53 g,
29%), m.p. 272–273 ꢁC. ꢃmax (deposit on a NaCl plate
layer was dried over anhydrous NaHCO3 and evaporated in
vacuo to provide a tan, light-sensitive oil, which was
dissolved in a minimum amount of CH2Cl2. The solution
was loaded onto an alumina column (2.4 ꢄ 15 cm). The
column was eluted with EtOAc–hexanes (1:49) under
pressure until the more mobile components were evident
upon TLC analysis of the eluent. When the desired product
was predicted by TLC to be the next off the column, the
eluent was changed to EtOAc–hexanes (3:2). The product
appeared as the brightest of several fluorescing purple spots
on TLC (silica gel) when visualized with an UV lamp.
(When in solution, this compound was very sensitive to UV
light.) The desired fractions were evaporated in vacuo to
yield diamine 5 (430 mg, 90%) as a white solid, m.p. 182–
183 ꢁC. ꢃmax (deposit on a NaCl plate from CDCl3 solu-
tion) (cmꢀ1): 3394 (N—H). ꢂH (200 MHz, CDCl3): 1.53 (s,
12H), 1.64 (t of t, unresolved, 4H), 1.70 (t of t, unresolved,
4H), 2.04 (s, 12H), 3.12 (d of t, J ¼ 6.0, 6.0, 4H), 3.67 (t,
J¼ 6.6 Hz, 4H), 4.06 (t, J ¼ 6.0 Hz, 2H), 5.55 (d,
J¼ 7.9 Hz, 2H), 6.58 (s, 4H), 7.00 (s, 4H), 7.06 (d,
J¼ 7.9 Hz, 1H). ꢂC (50 MHz, CDCl3): 16.81, 26.06,
27.89, 30.24, 41.75, 41.90, 72.18, 94.68, 126.27, 127.11,
129.53, 138.73, 146.21, 147.73, 153.79, 158.29. MS (EI,
70 eV) [m/e, (%)]: 176.20 (25.82), 218.25 (100), 302.35
(14.39), M þ 619.55 (38.76), M þ 1 620.54 (17.11),
621.55 (4.23) 622.45 (0.56). Found: C, 79.28; H, 8.63; N,
6.60. Calc. for C41H52N3O2: C, 79.44; H, 8.62; N, 6.78.
from CDCl3 solution) (cmꢀ1): 3429, 3300 (N—H) and
—
1682 (C O). ꢂ (200 MHz, CDCl ): 1.63 (s, 12H), 2.06
—
H
3
(s, 12H), 2.18 (p, unresolved, 4H), 2.65 (d of t, J ¼ 2.6,
5.8 Hz, 4H), 3.73 (t, J ¼ 5.9 Hz, 4H), 6.58 (s, 4H), 7.16 (s,
4H), 7.65 (t, J ¼ 8.1 Hz, 1H), 7.68, br s, 2H), 7.93 (d,
J ¼ 8.0 Hz, 2H). ꢂC (50 MHz, CDCl3): 16.40, 25.52,
30.33, 33.64, 41.83, 69.07, 109.19, 126.53, 127.15,
129.57, 140.83, 147.14, 147.34, 149.32, 152.97, 170.98.
MS (EI, 70 eV)[m/e, (%)]: 178.10 (25.07), 219.15
(26.46), 246.15 (100), M þ 647.55 (0.60), M þ 1 (0.28).
Found: C, 76.02; H, 7.60; N, 6.59. Calc. for C41H49N4O3:
C, 76.01; H, 7.62; N, 6.49.
Cyclophane triamine 4. To a solution of diamide 13
(100 mg, 0.17 mmol) in THF (10 ml) at 0 ꢁC was added
1.0 M BH3–THF in THF (0.51 ml, 0.51 mmol). The solu-
tion was refluxed for 4 h and allowed to cool to room
temperature. A few drops of 10% aqueous HCl were
added and the THF was removed in vacuo. To the residue,
EtOAc (50 ml) was added. The suspension was washed
with 10% aqueous NaHCO3 (3 ꢄ 25 ml), distilled water
(2 ꢄ 25 ml) and brine (25 ml). The organic layer was
dried over anhydrous NaHCO3 and evaporated in vacuo
to produce a white solid that was dissolved in a minimal
amount of THF. Chromatography of this solution on an
alumina column (2.4 ꢄ 17 cm) with EtOAc–hexanes (1:1)
as eluent gave cyclophane triamine 4 (86 mg, 90%) as a
white solid, m.p. 226–227 ꢁC. ꢃmax (CDCl3 solution)
(cmꢀ1): 3426 (N—H) and 1249 (C—O). ꢂH (200 MHz,
CDCl3): 1.63 (s, 12H), 1.79 (t of t, unresolved, 4H), 1.82
(t of t, unresolved, 4H), 3.21 (d of t, J ¼ 5.9, 6.7, 4H), 3.99
(t, J ¼ 5.9 Hz, 4H), 4.20 (t, J ¼ 5.9 Hz, 2H), 5.64 (d,
J ¼ 7.9 Hz, 2H), 6.73 (d, J ¼ 8.8 Hz, 4H), 7.04 (s, 4H),
7.09 (d, J ¼ 8.8 Hz, 4H), 7.09 (t, unresolved), 1H) ꢂC
(50 MHz, CDCl3): 26.02, 26.53, 30.45, 41.70, 41.88,
67.28, 94.55, 113.88, 126.06, 127.72, 139.12, 142.82,
148.08, 156.65, 157.98. MS (EI, 70 eV) [m/e, (%)]:
134.15 (82.28), 135.15 (75.06), 176.20 (100),
M þ 563.40 (50.67), M þ 1 (19.63), M þ 2 (4.45). Found:
C, 78.66; H, 8.16; N, 4.80. Calc. for C37H45N2O3: C,
78.55; H, 8.02; N, 4.95.
Solid-state structure determination for
13-acetone and 4-benzoic acid
Crystals of macrocyclic diamide 13ꢂacetone were grown
from acetone. Slow partial evaporation of an equimolar
solution of cyclophane triamine 4 and benzoic acid in
CH2Cl2–hexane (3:2) gave the 1:1 complex.
The crystal and intensity data were obtained with a
Siemens R3m/V automated diffractometer with graphite
monochromated Mo Kꢁ radiation. The crystal data and a
summary of the experimental details are listed in Table
ES1 (see electronic supplement). The structures were
solved using the SHELXTL-PLUS13 program package
and the final refinements and display of the structures
were performed with the SHELXTL-PC program pack-
age.14 Both structures were solved using direct methods
and refined using a full matrix least-squares procedure
based on F2. Positions for hydrogen atoms bonded to
carbon atoms were calculated, whereas positions for
hydrogens bonded to nitrogen atoms were obtained
from difference maps. The two partial benzoic acid
molecules were refined as rigid bodies with bond lengths
Cyclophane diamine 5. To a solution of diamide 14 (0.50 g,
0.80 mmol) in THF (15 ml) at O ꢁC was added 1.0 M BH3–
THF (3.2 ml, 3.2 mmol). The solution was allowed to warm
to room temperature and then refluxed for 6 h. After cool-
ing the reaction solution in an ice bath, a few drops of
aqueous 1.0 M HCl were added. The solution was evapo-
rated in vacuo. The residue was made basic with aqueous
1.0 M Na2CO3 and then EtOAc (50 ml) was added. The
suspension was washed with 1.0 M Na2CO3 (2 ꢄ 20 ml),
distilled water (2 ꢄ 20 ml) and brine (20 ml). The organic
˚
of the hexagon carbons fixed at 1.39 A and bond angles
fixed at 120ꢁ. It was not possible to locate the acid
hydrogen for either site of the partial benzoic acid
molecules.
Solutions of the structures revealed that the benzoic
acid guest of the 4ꢂbenzoic acid complex was disordered
J. Phys. Org. Chem. 2005; 18: 1107–1115
Copyright # 2005 John Wiley & Sons, Ltd.

NEW DITOPIC CYCLOPHANE RECEPTORS FOR BENZOIC ACID
1115
2. Diederich F. Cyclophanes. Royal Society of Chemistry:
Cambridge, 1991.
and that the asymmetric unit of 13 contained two mole-
cules, each linked to an acetone solvent molecule. The
disorder of the benzoic acid in 4ꢂbenzoic acid was
resolved using difference maps. The occupancy factor
for the unprimed benzoic acid was 0.70 whereas that of
the primed molecule was 0.30.
¨
3. Vogtle F. Cyclophane Chemistry. Wiley: New York,
1993.
4. Gleiter R, Hopf H. Modern Cyclophane Chemstry. Wiley-VCH:
Weinheim, 2004.
5. Broderick GF, Oxenrider BC, Vitrone J. US. Patent 3,393,244, 16
July, 1969.
6. Bartsch RA, Spruce LW, Purkiss DW, Goo M-J. J. Inclus.
Phenom. Mol. Recogn. Chem. 1993; 15: 181–195 .
7. Dalley NK, Kou X, Bartsch RA, Czech BP, Kus P. J. Inclus.
Phenom. Mol. Recogn. Chem. 1997; 29: 323–334 .
8. Bartsch RA, Kus P, Dalley, NK, Kou X. Tetrahedron Lett. 2002;
43: 5017–5019 .
9. Dalley NK, Kou X, Bartsch RA, Kus P. J. Inclus. Phenom.
Macrocyclic Chem. 2003; 45: 139–148 .
10. O’Brien M, Smalley, R, Amonge, A, Raber, S, Starsota,
A, Buthelezi, T, Bartsch, RA, Wegiel, M. Microchem. J.
2005; 80: 55–63.
Tables of atomic coordinates, equivalent isotropic dis-
placement parameters, bond lengths and angles for the
two molecules of 13ꢂacetone and for 4ꢂbenzoic acid are
provided in the electronic supplement.
Crytallographic data have been deposited with the
Cambridge Crystallographic Data Center (CCDC, 12
Union Road, Cambridge, CB2 1E2, UK). The deposited
structure numbers are CCDC 271325 for 13ꢂacetone;
and CCDC 271326 for 4ꢂbenzoic acid.
11. Wilcox CS. In Frontiers in Supramolecular Organic Chemistry
and Photochemistry, Schneider H-J, Durr
Weinheim, 1991; 123–143 .
H (eds). VCH:
12. Zawaki FJ, Webb TH, Adrian JC, Wilcox CS. J. Am. Chem. Soc.
1992: 114: 10189–10197 .
REFERENCES
13. Sheldrick GM. SHELXTL-PLUS. Siemens Analytical X-ray In-
struments: Madison, WI, 1990.
14. Sheldrick GM. SHELXTL-PC, Version 5.03. Bruker Analytical X-
ray Systems: Madison, WI, 1994.
1. Bradshaw JS, Izatt RM, Bordunov AV, Zhu CY, Hathaway GW.
Comprehensive Supramolecular Chemistry, vol. 1, Gokel GW
(ed.). Pergamon Press: New York, 1996; 35–96 .
Copyright # 2005 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2005; 18: 1107–1115