Polyether-bridged cyclophanes incorporating bisphenol A units as neutral receptors for quats: Synthesis, molecular structure and binding properties

Article abstract of DOI:10.1002/poc.380

Two novel neutral polyoxyethylene bridged cyclophanes (2a and 2b) incorporating bisphenol A units were synthesized and characterized by means of x-ray crystal structure determination. The binding properties of 2a and 2b toward tetramethylammonium, N-methylpyridinium, and acetylcholine cations were evaluated by means of ¹H NMR spectroscopy. Consistent with indications provided by the molecular structure, the cavity in the basket-like cyclophanes is large enough to accommodate the given guest cations conveniently. Circumstantial evidence was obtained that 1,1,2,2-tetrachloroethane is too large to enter the cavity of the smaller cyclophane 2a, but can be included in the cavity of the larger cyclophane 2b.

Full text of DOI:10.1002/poc.380

JOURNAL OF PHYSICAL ORGANIC CHEMISTRY
J. Phys. Org. Chem. 2001; 14: 425–431
DOI:10.1002/poc.380
Polyether-bridged cyclophanes incorporating bisphenol A
units as neutral receptors for quats: synthesis, molecular
structure and binding properties
Antonella Dalla Cort,1* Maija Nissinen,2 Daniele Mancinetti,1 Elena Nicoletti,1 Luigi Mandolini1 and
Kari Rissanen2
1Dipartimento di Chimica e Centro CNR sui Meccanismi di Reazione, UniversitaÁ La Sapienza, Box 34, Roma 62, 00185 Rome, Italy
2Department of Chemistry, University of JyvaÈskylaÈ, P.O. Box 35, 40351 JyvaÈskylaÈ , Finland
Received 24 December 2000; Revised 22 February 2001; Accepted 5 March 2001
ABSTRACT: Two novel neutral polyoxyethylene bridged cyclophanes (2a and 2b) incorporating bisphenol A units
epoc
were synthesized and characterized by means of x-ray crystal structure determination. The binding properties of 2a
and 2b toward tetramethylammonium, N-methylpyridinium, and acetylcholine cations were evaluated by means of 1H
NMR spectroscopy. Consistent with indications provided by the molecular structure, the cavity in the basket-like
cyclophanes is large enough to accommodate the given guest cations conveniently. Circumstantial evidence was
obtained that 1,1,2,2-tetrachloroethane is too large to enter the cavity of the smaller cyclophane 2a, but can be
included in the cavity of the larger cyclophane 2b. Copyright  2001 John Wiley & Sons, Ltd.
Additional material for this paper is available from the epoc website at http://www.wiley.com/epoc
KEYWORDS: cyclophanes; molecular recognition; cation–p interactions; supramolecular chemistry; x-ray crystal
structures
INTRODUCTION
chloroform solution with low affinity, which was ascribed
to the high conformational mobility of these receptors. It
was felt that reduction of the conformational mobility of
the cyclophane structure by means of polyoxyethylene
bridges would hopefully result in a higher level of
preorganization of the toroidal cavity defined by the
cyclophane structure itself and, consequently, in a
substantial improvement of the binding properties towards
quats. We therefore synthesised the polyether bridged
cyclophanes 2a and 2b, determined their x-ray crystal
structures and compared their binding properties with
those of 1 towards tetramethylammonium (TMA), N-
methylpyridinium (NMP) and acetylcholine (ACh) salts.
The importance of non-covalent interactions between
aromatic compounds and positively charged species
(cation–p interactions) in the molecular recognition of
quats and other cations in both biological and artificial
systems is well recognized.1 Because of the strong
desolvation penalty suffered by the reaction partners
upon complexation, efficient binding of quats in solution,
in the absence of other stabilizing interactions, can only
be achieved through multiple interactions with a number
of strategically positioned aromatic units. Much work has
been devoted in recent years to the design and synthesis
of neutral receptors for quats, such as cyclophanes
belonging to various structural types,2–5 cryptophanes,6
calixarenes,7 homooxacalixarenes8 and cyclic peptides
incorporating arene units.9
We have recently reported4a that simple cyclophanes
incorporating bisphenol A units such as 1 bind to quats in
*Correspondence to: A. Dalla Cort, Dipartimento di Chimica e Centro
CNR sui Meccanismi di Reazione, Universita` La Sapienza, Box 34,
Roma 62, 00185 Rome, Italy.
Email: antonella.dallacort@uniromal.it
Contract/grant sponsor: MURST.
Copyright  2001 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2001; 14: 425–431

426
A. DALLA CORT ET AL.
Scheme 1. Synthesis of cyclophanes 2a and 2b. 0i) K2CO3, CH3CN; 0ii) LiAlH4, THF; 0iii) PBr3, dioxane; 0iv) KOH, DMSO, high
dilution
Suitable crystals for x-ray diffraction studies of 2a
were obtained by slow diffusion of CH2Cl2 into hexane,
and of 2b from a 1:1 mixture of methanol and chloro-
form. The crystal data are presented in Table 1. In the
solid state both cyclophanes adopt a similar, basket-like
conformation with the crown ether chains forming the
handle and the aromatic moieties the bottom of the basket
(Fig. 1). Both cyclophanes crystallize out with a solvent
molecule included into the basket-like cavity (CH2Cl2 in
2a and CHCl3 in 2b). Solvent inclusion is facilitated by
weak hydrogen bonding of the solvent molecules to the
ether oxygens. In 2a the dichloromethane interacts
RESULTS
Syntheses and crystal structures
Cyclophanes 2a and 2b were obtained in low yields by
reacting 2 mol equiv. of bisphenol A with the correspond-
ing tetra(bromomethyl) compounds 7a and 7b under high
dilution conditions. The observed low yields are not
surprising, because of the occurrence of two intermol-
ecular and two intramolecular covalent bond formations
in a single reaction step. Intermediates 7a and 7b were
prepared by alkylation of the diethyl ester of 5-
hydroxyisophthalic acid with tri- and tetraethylene glycol
ditosylate, respectively, followed by standard group
transformations, as shown in Scheme 1.
weakly with O47, O53 and O56 [C100 047 =
ÁÁÁ
3.596(3), C100 O53 = 3.322(3) and C100 O56 =
3.482(4) A] and in 2b the chloroform is weakly hydrogen
ÁÁÁ
ÁÁÁ
˚
Table 1. Crystallographic data for cyclophanes 2a and 2b
2a
2b
Empirical formula
C H O CH Cl 0.5 C H
C H O CHCl
8Á
2Á
9Á
52 54
934.96
2
6
14
54 58
970.37
3
M (g molÀ1
T (K)
)
173.0 (2)
Triclinic
P-1 (No. 2)
173.0 (2)
Monoclinic
P21/c (No. 14)
Crystal system
Space group
Crystal size (mm)
0.20 Â 0.40 Â 0.60
0.05 Â 0.10 Â 0.15
Dcalc (mg m3)
1.226
1.292
˚
a (A)
11.9628(4)
15.7064(5)
15.9992(3)
105.442(2)
108.658(2)
105.464(1)
2533.4(1)
2
17.3565(6)
12.2683(5)
24.8724(9)
90
˚
b (A)
˚
c (A)
a (°)
b (°)
g (°)
109.669(2)
90
3
˚
V (A )
4987.2(3)
4
Z
m(mmÀ1
)
0.182
0.240
Reflections collected
Unique reflections
Rint
13501
11626
8814
11626
0.019
0.000
À3
˚
Drmax, Drmin (e A
)
0.578, À0.239
0.049, 0.113
1.046
0.500, À0.347
0.076, 0.1362
0.987
R1, wR2 [I >2ꢀI]
S
Copyright  2001 John Wiley & Sons, Ltd.
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BRIDGED CYCLOPHANES AS RECEPTORS FOR QUATS
427
Figure 1. Molecular structures of 2a and 2b showing thermal ellipsoids at the 50% probability level. The weak hydrogen bonds
of the included dichloromethane and chloroform 0only the most populated orientations are shown), respectively, are shown with
dotted lines
bonded to O50 and O53 [C100 O50 = 3.273(6) and
is not able to assemble itself into the space between the
handle and the bottom. Instead, the chain is in close
contact with the aromatic ring C34—C39 of the adjacent
molecule, giving an arrangement in which the cavities are
exactly facing and not slightly shifted as is found in the
tennis ball-like structure (Fig. 2, left). The n-hexane
molecules fill the interstices of the crystal lattice.
ÁÁÁ
˚
C100 O53 = 3.407(6) A]. Both cyclophanes pack into
ÁÁÁ
dimeric pairs held together via weak intermolecular C—
H
ÁÁÁ
O hydrogen bonds. In 2b the crown ether chain
forms a loop, which is self-complementary to the space
between the handle and the bottom of the adjacent basket,
giving tennis ball-like dimers (Fig. 2, right). Closest
contacts are observed from methylene carbon C2 to O56
˚
and O59 (3.23 and 3.34 A, respectively). Carbon C2 is
located between the electron-withdrawing ether oxygen
and aromatic unit, thus giving it a slightly electropositive
character and therefore facilitating weak hydrogen
bonding with ether oxygens. In addition to these weak
interactions between the hosts, the steric efficiency of the
packing contributes significantly to dimer formation. The
dimers pack into continuous chains with additional close
Binding studies
Owing to the magnetic anisotropy of the cyclophane
aromatic units, 1H NMR spectroscopy is an ideal tool for
the detection and measurement of the inclusion of guest
species in the cyclophane cavity.10 Binding studies were
carried out by addition of increasing amounts of a very
dilute stock solution of quaternary salt to a weighed
amount of cyclophane contained in an NMR tube.
Maximum host concentrations allowed by solubility
C—H O contacts between the neighbouring cyclo-
ÁÁÁ
˚
phanes (O10 C55* = 3.33, O1 C2** = 3.35 A), sta-
ÁÁÁ
ÁÁÁ
bilizing the packing. The shorter crown ether chain of 2a
Figure 2. The dimeric packing of 2a and 2b. The dimerization of 2b is tennis ball-like whereas with 2a the cavities are exactly
facing. Hydrogen atoms and n-hexane molecules are excluded for clarity
Copyright  2001 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2001; 14: 425–431

428
A. DALLA CORT ET AL.
form complexes of definite stability with TMA, NMP and
ACh cations, clearly showing that the polyoxyethylene
bridges have a profound influence on the preorganization
of the cyclophane receptors and, consequently, on their
binding abilities toward quats.
The longer polyoxymethylene bridge in 2b compared
with 2a renders the size of the cavity in the former
slightly larger than in the latter, as can be appreciated by
visual inspection of the van der Waals surfaces of the
crystal structure (Fig. 4), and also shown by the fact that
˚
the distance between the bridging benzene rings is 9.52 A
˚
in 2b and 8.59 A in 2a. The above difference does not
appear to have a significant influence on the stability of
complexes formed by the two cyclophane hosts in
chloroform solution (Table 2). The large negative values
of the complexation-induced shifts indicate that inclusion
of the guests into the host cavity is extensive in all cases.
Interestingly, the shift induced in the TMA protons upon
complexation with 2a is larger than that with 2b, which
indicates that the cavity of 2a is large enough to
accommodate the TMA cation conveniently. A similar
situation holds for the inclusion of NMP. Here the
observed shift patterns suggest that all part structures of
the guest are similarly exposed to the shielding zones of
the arene units, which is consistent with the idea of a
loose host–guest complex,6 in which the guest retains
substantial rotational freedom. The shift patterns ob-
served for the ACh complexes, which are comparable to
those observed in analogous complexes with crypto-
phanes,6 homooxacalixarenes12 and calix[5]arenes,11
suggest that the trimethylammonium head is more deeply
buried into the host cavity, whereas the acetoxy tail
points towards the exterior. Presumably, the much larger
shifts suffered by the NCH3 and CH3CO signals of ACh
upon complexation with 2b indicate deeper penetration
of ACh into the cavity of the larger cyclophane 2b.
Enhanced stabilities are seen in 1,1,2,2-tetrachloro-
ethane solution (see footnotes e and f in Table 2) for the
complexes of 2a and 2b with NMP. Enhancements of
host–guest interactions in solvents that are too bulky to
solvate the host cavity are well precedented13 (see also
Figure 3. Titration of ACh iodide with host 1 0!) and host
2a 0*) NCH3 protons. Points are experimental and curves are
calculated
were 25 mM for 2a and 2b and 15 mM for 1. In no case
were separate signals for free and bound guest observed.
In chloroform solution the signals of the quat protons
remained sharp during titration, but substantial line
broadening was observed in the experiments carried out
in 1,1,2,2-tetrachloroethane. Titration plots obtained with
hosts 2a and 2b showed in all cases a definite tendency to
saturation and were translated into equilibrium constants
(K) and limiting upfield shifts (ÀDꢁ?) as previously
reported.11 With host 1, the titration plots showed no
appreciable curvature, thus indicating that the fraction of
complexed guest was in all cases very small, i.e. K
<5 MÀ1. Typical titrations curves are shown in Fig. 3.
The results of the titration experiments are summarized in
Table 2.
DISCUSSION
The mere inclusion of solvent molecules into their cavity
(Fig. 1) clearly indicates the suitability of cyclophanes 2a
and 2b to host other small molecules of similar size.
Indeed, we found (Table 2) that both 2a and 2b, unlike 1,
Table 2. Stability constants 0K, MÀ1)a and limiting up®eld shifts 0ÀDꢁ?, ppm) for the complexes of hosts 2a and 2b with quats in
CDCl3 at 30°C
TMAb
NMPc
AChd
Host
K
ÀDꢁ?
1.48 (NCH3)
1.08 (NCH3)
K
ÀDꢁ?
K
ÀDꢁ?
2a
41 Æ 2
45 Æ 7e
42 Æ 3f
1.10 (NCH3), 1.31 (aCH),
1.63 (gCH)
1.07 (NCH3), 1.05 (aCH),
1.03 (bCH), 1.12 (gCH)
40 Æ 8
0.79 (NCH3), 0.83 (aCH2),
0.70 (bCH2), 0.21 (CH3CO)
1.38 (NCH3), 0.73 (CH3CO)
2b
25 Æ 4
35 Æ 4
a
Errors calculated as Æ2s (95% confidence limit).
Iodide salt, 1.0 Â 10À3 M.
b Picrate salt, 1.4 Â 10À4 M.
c
d Iodide salt, 2.0 Â 10À4 M.
e
In (CDCl2)2 K = 410 Æ 22, ÀDꢁ? = 0.90 (NCH3).
f In (CDCl2)2 K = 65 Æ 7, ÀDꢁ? = 0.97 (NCH3), 1.06 (aCH), 0.99 (bCH), 1.10 (gCH).
Copyright  2001 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2001; 14: 425–431

BRIDGED CYCLOPHANES AS RECEPTORS FOR QUATS
429
Figure 4. Van der Waals presentation of the empty cavities of 2a and 2b
Ref. 11 and references cited therein). These stability
enhancements are believed to arise from the lower
desolvation penalty suffered by the host upon complexa-
tion when the host itself is poorly solvated. On going
from chloroform to 1,1,2,2-tetrachloroethane, the com-
plex of NMP with 2a experiences a 10-fold increase in
stability, whereas the corresponding increase for the
analogous complex with 2b is very small. In other words,
in marked contrast to the complete lack of selectivity
observed in chloroform, in the bulkier 1,1,2,2-
tetrachloroethane host 2a binds to NMP much more
strongly than its higher homologue 2b. This remarkable
solvent effect provides a strong indication that the cavity
of the smaller cyclophane 2a undergoes a much stronger
desolvation than that suffered by 2b, which implies that
the cavity in 2b, unlike that in 2a, is large enough to
accommodate a bulky 1,1,2,2-tetrachloroethane mol-
ecule. It appears, therefore, that 1,1,2,2-tetrachloroethane
acts as a probe providing information about the cavity
size in the given cyclophanes.
(31 mmol) in 30 ml of CH3CN was then added and heated
at reflux for 16 h. The mixture was poured into water
(400 ml) and extracted with CHCl3 (3 Â 250 ml). The
organic layer was washed with 5% aqueous KOH
(6 Â 130 ml), dried (Na2SO4) and evaporated to give 5
in virtually quantitative yield.
Tri0ethylene glycol) bis03,5-diethoxycarbonyl)phenyl
ether 05a). H NMR (CDCl3), ꢁ 1.41 (t, J = 7.1 Hz, 12
1
H), 3.78 (s, 4H), 3.91 (m, 4H), 4.23 (m, 4H), 4.40 (q,
J = 7.1 Hz, 8H), 7.77 (d, J = 1.4 Hz, 4H), 8.28 (t,
J = 1.3 Hz, 2H).
Tetra0ethylene glycol) bis03,5-diethoxycarbonyl)phenyl
ether 05b). 1H NMR (CDCl3), ꢁ 1.31 (t, J = 7.4 Hz, 12H),
3.66–3.74 (m, 8H), 3.86 (m, 4H), 4.19 (m, 4H), 4.36 (q,
J = 7.4 Hz, 8H), 7.74 (s, 4H), 8.24 (s, 2H).
Compounds 6a and 6b. LiAlH4 (0.76 g, 20 mmol) was
added in small portions to a solution of tetraester 5
(4.7 mmol) in dry tetrahydrofuran (250 ml) at room
temperature. The mixture was stirred at reflux for 8 h,
cooled and quenched first with portions of Na2-
EXPERIMENTAL
SO 10H O and then with H O. The inorganic precipi-
4Á
2
2
Cyclophane 1 and N-methylpyridinium iodide were
available from a previous investigation.4a Tetramethy-
lammonium picrate was obtained from the corresponding
iodide salt by anion exchange with silver picrate.
Tri(ethylene glycol) ditosylate (4a) and tetra(ethylene
glycol) ditosylate (4b) were prepared according to a
literature method.14 All other chemicals were reagent-
tate was removed by filtration and the solvent was
evaporated from the filtrate. The residue, a yellow oil,
was chromatographed [silica gel, CHCl3–MeOH (85:15)]
to give the desired pure product.
Tri0ethylene glycol) bis03,5-hydroxymethyl)phenyl ether
06a). This compound was obtained in 66% yield, m.p.
1
grade commercial samples and used as received. H and
1
13C NMR spectra were recorded on a Bruker AC 300
spectrometer and TMS was used as an internal standard.
Electrospray mass spectra were obtained on a Fisons
Instrument VG-Platform benchtop mass spectrometer.
94–95°C. H NMR (CD3)2SO, ꢁ 3.38 (s, 4H), 3.58 (m,
4H), 3.88 (m, 4H), 4.30 (d, J = 2.3 Hz, 8H), 5.08 (t,
J = 2.3 Hz, 4H), 6.63 (bs, 4H).
Tetra0ethylene glycol) bis03,5-hydroxymethyl)phenyl
ether 06b). This compound was obtained in 73% yield
as a yellow oil. 1H NMR (CD3)2SO, ꢁ 3.65 (m, 8H), 3.83
(m, 4H), 4.17 (m, 4H), 4.56 (d, J = 1.2 Hz, 8H), 5.24 (t,
J = 1.2 Hz, 4H), 6.84 (bs, 4H), 6.94 (bs, 2H).
Compounds 5a and 5b. A mixture of diethyl 5-
hydroxyisophthalate (15 g, 63 mmol) and K2CO3 (9.3 g,
67 mmol) in 100 ml of CH3CN was refluxed for 15 min
under argon. A solution of the corresponding ditosylate 4
Copyright  2001 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2001; 14: 425–431

430
A. DALLA CORT ET AL.
Compounds 7a and 7b. A solution of PBr3 (12.97 g,
57 mmol) in dioxane (20 ml) was added at room
temperature to a stirred solution of tetraol 6 in dioxane
(30 ml). When the addition was complete, stirring at
room temperature was continued for 24 h. The mixture
was poured in 20 ml of water and stirred for 1 h at 0°C. It
was then extracted with CHCl3 (2 Â 100 ml). The organic
layer was washed with aqueous NaHCO3, dried and
concentrated to give a yellow oil that was chromato-
graphed [silica gel, CHCl3–MeOH (99:1)].
Single-crystal x-ray diffraction. The crystallographic data
were collected on a Nonius Kappa CCD area-detector
diffractometer using graphite monochromatized Mo Ka
˚
radiation (ꢂ = 0.71073 A). Lattice parameters were
determined from 10 images recorded with 1° ' scans
and subsequently refined on all data. The data collections
were performed using ' and ! scans with 1° or 2° steps
(2b and 2a, respectively), an exposure time of 15 s per
frame for 2b and 30 s per frame for 2a and a crystal-to-
detector distance fixed at 35 mm. The data were
processed using DENZO-SMN v0.93.0.15 No absorption
correction was applied.
The structures were solved by direct methods using
SHELXS-9716 and refined on F2 using SHELXL-97.17
The hydrogen atoms were calculated to their idealized
positions with isotropic temperature factors (1.2 or 1.5
times the carbon temperature factor) and refined as riding
atoms. Two chlorine atoms of the included chloroform
molecule in 2b are disordered over two positions with site
occupancies of 0.455:0.545. In the structure of 2a the
chlorine atoms of the included dichloromethane and ethyl
chain C51—C52 of the cyclophane are disordered over
two positions with the occupancies of 0.427:0.573 and
0.698:0.302, respectively.
Tri0ethylene glycol) bis03,5-dibromomethyl)phenyl
ether 07a). This compound was obtained in 72% yield
as a solid, m.p. 109–110°C. 1H NMR (CDCl3), ꢁ 3.74 (s,
4H), 3.84–3.87 (m, 4H), 4.11–4.14 (m, 4H), 4.45 (s, 8H),
6.87 (m, 4H), 6.98 (m, 2H).
Tetra0ethylene glycol) bis03,5-dibromomethyl)phenyl
ether 07b). This compound was obtained in 63% yield
1
as a yellow oil. H NMR (CDCl3), ꢁ 3.67-3.72 (m, 8H),
3.80–3.83 (m, 4H), 4.07–4.10 (m, 4H), 4.38 (s, 8H), 6.84
(m, 4H), 6.96 (m, 2H).
Macrocyclization procedure. A solution of bisphenol A
(0.73 g, 3.24 mmol) and 85% KOH (0.43 g, 6.6 mmol) in
120 ml of Me2SO was kept under stirring at 62°C for
30 min. A solution of 7a or 7b (1.60 mmol) in 40 ml of
Me2SO was added dropwise over 2 h. The mixture was
stirred for an additional 7 h at 62°C, after which it was
poured in 250 ml of H2O and extracted with 450 ml of
CCl4. The organic layer was then washed with water
(5 Â 400 ml), dried and concentrated.
Crystallographic data (excluding structure factors) for
the structures reported in this paper have been deposited
with the Cambridge Crystallographic Data Centre as
supplementary publication No. CCDC-153052 and
CCDC-153053. Copies of the data can be obtained free
of charge on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK.
Acknowledgements
Cyclophane 2a. The crude product was chromato-
graphed twice on neutral alumina, first with hydroqui-
none-free tetrahydrofuran and then with tetrahydrofuran–
hexane, to afford 103 mg (0.128 mmol) of a white solid,
8% yield, m.p. 198–201°C. 1H NMR (CDCl3), ꢁ 1.55 (s,
12H), 3.69 (s, 4H), 3.80 (m, 4H), 4.01–4.03 (m, 4H), 5.07
(s, 8H), 6.66–6.71 (m, 8H), 6.80 (bs, 4H), 6.88 (m, 2H),
6.99–7.04 (m, 8H). 13C NMR (CDCl3), ꢁ 31.2, 41.5, 67.7,
70.0, 11.3, 114.9, 116.2, 127.6, 140.4, 143.0, 156.5,
This work was carried out in the frame of COST D11,
Supramolecular Chemistry. Thanks for financial support
are due to MURST, Progetto Dispositivi Supramoleco-
lari. M.N. thanks the Finnish Ministry of Education for
financial support.
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‡
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9Á
54 58
2
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Copyright  2001 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2001; 14: 425–431

BRIDGED CYCLOPHANES AS RECEPTORS FOR QUATS
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