Synthesis, characterisation and metal ion binding properties of crown ethers incorporating 4,5-dioxyxanthones

Article abstract of DOI:10.1039/a806487c

An efficient preparation of 4,5-dihydroxyxanthone, 5, is described, and its incorporation into crown ethers with 18-, 21- and 24-membered macrocyclic arrays, 3 (n = 3, 4 and 5), and a model compound, 4,5-diethoxyxanthone, 10. Metal ion complexation of the

Full text of DOI:10.1039/a806487c

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Synthesis, characterisation and metal ion binding properties of
crown ethers incorporating 4,5-dioxyxanthones
Brian G. Cox,a Tracey V. Hurwood,b L. Prodi,c M. Montalti,c F. Bollettac and C. Ian F. Watt*b
a Zeneca FCMO, North of England Works, PO Box A38, Huddersfield, Huddersfield,
UK HD2 1FF
b Chemistry Department, University of Manchester, Manchester, UK M13 9PL
c Universita degli studi di Bologna, Dipartimento di Chimica ‘G. Ciamician’, Via Selmo 2,
I 40126, Bologna, Italy
Received (in Cambridge) 17th August 1998, Accepted 25th November 1998
An efficient preparation of 4,5-dihydroxyxanthone, 5, is described, and its incorporation into crown ethers with 18-,
21- and 24-membered macrocyclic arrays, 3 (n = 3, 4 and 5), and a model compound, 4,5-diethoxyxanthone, 10.
Metal ion complexation of the crowns causes a strong quenching of the highly fluorescent 4,5-diethoxyxanthone
chromophore. Binding constants for complex formation with sodium, potassium, and caesium ions in methanolic
solution have been measured by spectrofluorimetric and conductimetric methods and range from <102 for 3 (n = 5)
binding sodium ion to 4.1 × 103 for 3 (n = 4) binding potassium ion. The behaviour of the 4,5-dioxyxanthones in
aqueous sulfuric acid mixtures has been examined by UV spectroscopy and treatment of the data by the excess
acidity method yields Ϫ2.6 < pKa < Ϫ2.3 for the conjugate acids with 0.33 < m* < 0.40. The behaviour of the
crowns containing 4,5-dioxyxanthones is compared with that of analogues containing 1,8-dioxyxanthones.
Introduction
O
n
n = 3, 4, or 5
The structure of xanthone (xanthen-9-one) (Fig. 1) and its
photophysical properties suggest that its incorporation into
crown ethers or related structures would yield ionophores with
a number of desirable features. X-Ray crystallography1 and
electron diffraction2 reveal a planar structure, and its dipole
moment (3.11 D)3 is consistent with a contributing dipolar
form. Appropriate annulation of a polyethylene oxide chain
could yield macrocycles with either xanthone oxygen in a pos-
ition to participate in binding to guest species. Xanthone itself
shows a double phosphorescence4 which might be modified in
the crowns and responsive to ion binding in ways dependent on
the mode of incorporation of the xanthone.
O
O
1: Y = CO, X = O
2: Y = CHOH, X = O
Y
X
3: Y = O, X = CO
4: Y = O, X = CHOH
O
O
O
O
O
O
O
O
Mn+
Mn+
O
-
O
O
O
1 (n = 3)
We have already described the preparation,5 structures,6 and
some properties of macrocycles with 18-, 21- and 24-membered
rings based on 1,8-dioxyxanthone, 1 (n = 3, 4, 5). These have
also been converted to the corresponding xanthydrols, 2, and
equilibria between these alcohols and their derived carbo-
cations have been measured. The 1,8-dioxyxanthone-based
crowns were not strongly fluorescent themselves, but showed
strong fluorescence enhancement and appearance of a long
lived delayed fluorescence upon binding to alkaline earth
cations, especially Ba2ϩ, which make them suitable for con-
struction of multi-sensory devices.7 In this series, the ketonic
oxygen of the xanthone residue lies within the macrocycle, and
has near ideal placement and polarity for involvement in
metal ion complexation (Fig. 2), and its close association with
a bound metal ion is clearly a factor in the desirable photo-
physical behaviour of these crowns.
O
+
O
O
O
O
O
O
O
O
O
M+
M+
O
O
O
+
3 (n = 3)
O
-
O
O
Fig.
2
Structures of crown ethers incorporating 1,8- and 4,5-
dioxyxanthones and interactions in binding to metal ions.
Attachment of polyethylene oxide chains to the xanthone
nucleus via its 4- and 5-positions would yield macrocycles
incorporating the more electropositive ethereal xanthone
oxygens in the crown macrocycle. This oxygen may be less
basic than the carbonyl oxygen (and oxygens in simpler
phenolic ethers) but the macrocycle thus formed would have
the benefit of an uninterrupted set of –C–C–O– sequences. The
-
O
O
1
8
2
3
7
6
O
O
+
4
5
Fig. 1 Structure and contributing canonical forms of xanthone.
J. Chem. Soc., Perkin Trans. 2, 1999, 289–296
289

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consequences of such an arrangement on the binding
properties and photophysical behaviour of such macrocycles
in the presence and absence of metal ions is the topic of
this paper, and we here describe the preparation and charac-
terisation of 18-, 21- and 24-membered crowns incorporating
the 4,5-dioxyxanthone residue, 3 (n = 3, 4 and 5).
with three adjacent hydrogens and the other with two adjacent
hydrogens. We speculated that this was a trihydroxyxanthone,
probably 9, arising from an air oxidation of one ring of
the 2,2Ј,3,3Ј-tetrahydroxybenzophenone prior to cyclization.
Formation of this by-product was almost completely sup-
pressed when the reaction was run in buffered medium with
hydroquinone added as an oxygen scavenger. Isolated yields of
the 4,5-dihydroxyxanthone 5 were then greater than 90%, as
a dark solid remaining after sublimation of all of the more
volatile impurities. Further purification and characterisation
was possible by conversion to its known diacetate.8
Preparation and structures
Synthesis is by attachment of an appropriate polyethylene
oxide chain to 4,5-dihydroxyxanthone, 5 (Scheme 1). This is
The alkylation of 4,5-dihydroxyxanthone with excess ethyl
iodide in DMF with potassium carbonate provided a single
detectable product, crystallising from ethanol as colourless
needles, with a UV spectrum (methanol) showing maxima at
248 and 354 nm, and its IR spectrum showing a typical
MeO
Li
OMe
xanthone carbonyl stretching band at 1648 cmϪ1 1H NMR
.
+
spectroscopy confirmed the presence of ethoxy groups, and two
doublets and a triplet (at 7.24, 7.30 and 7.91 ppm respectively)
in the aromatic region, were consistent with the bis-O-alkyl-
ation in the anticipated 4,5-diethoxyxanthone 10. The 13C
NMR spectrum showed the expected nine signals.
OMe
MeO
OHC
OMe
H
OH
MeO
OMe
OMe
8
EtO
OEt
CrO3–H+–acetone
O
EtI
K2CO3–DMF
O
HO
OH
10
O
O
HO
OH
OMe
MeO
HBr
HO
HO
O
OH
MeO
O
OMe
6
7
Br
Br
O
n
5
water, 220 °C
OH
3 (n = 3, 4, and 5)
K2CO3–DMF
Scheme 2 Alkylations of 4,5-dihydroxyxanthone.
HO
O
O
O
For preparations of the 18-, 21- and 24-membered rings,
reactions with appropriate polyethylene dibromides in
DMF were carried out following the pattern used earlier in
cyclizations with 1,8-dioxyxanthone.4 For preparation of 18-
and 21-membered rings, the base was potassium carbonate. For
the 24-membered ring, acceptable yields were only obtained
with use of higher dilution, lower reaction temperature, and
replacement of potassium carbonate by caesium carbonate.
In all cases crystallised yields of macrocycle were over 40%. The
aromatic regions of the 13C and 1H NMR spectra of these com-
pounds were superimposable on that of 4,5-diethoxyxanthone,
as were their UV spectra.
Attempts to produce crystals of 3 (n = 3, 4 or 5) or of 10
suitable for crystallography have not yet proved successful, but
molecular mechanics calculations using the MM3 forcefield11
(shown to reproduce well experimentally determined structural
features in the 1,8-dioxyxanthone series6) have been carried
out on all three crowns and the model 4,5-diethoxyxanthone.
Minimum energy conformations and associated steric energies
are shown in Fig. 3.
In 4,5-diethoxyxanthone 10, the xanthone tricycle is planar,
and the pendant ethyl groups are anti-coplanar to the central
ring of the xanthone. There are, however, four low energy con-
formations (within 4.18 kJ molϪ1 of global minimum) having
different torsions about the exocyclic C–O bonds.
In the minimum energy conformation of 3 (n = 3), the
xanthone is non-planar, with the central rings adopting a
flattened boat conformation with an angle of 167Њ between the
planes of the two benzenes of the xanthone. The sequences of
torsion angles around bonds in the –O–C–C– repeating units in
+
OH
O
OH
9
5
Scheme 1 Preparation of 4,5-dihydroxyxanthone.
a known compound, first prepared by Finnegan and Merkel,8
by heating 2,2Ј,3,3Ј-tetrahydroxybenzophenone 6 in water at
220–230 ЊC. This cyclization seemed promising, but a photo-
Fries rearrangement employed by Finnegan and Merkel in their
preparation of precursor 6 was low yielding and did not seem
amenable to scale-up to give the amounts of 4,5-dihydroxy-
xanthone demanded by this work. We avoided this step by
exploiting the directed lithiation of 1,2-dimethoxybenzene.9
Coupling of the resulting organolithium with veratraldehyde
yields 2,2Ј3,3Ј-tetramethoxybenzhydrol, 8; Jones oxidation then
provides 2,2Ј3,3Ј-tetramethoxybenzophenone, 7, in high yield,
and demethylation by hydrobromic acid yields the required
cyclization precursor, 6, efficiently (Scheme 1).
First attempts to reproduce the hot water cyclizations10 of
Finnegan and Merkel did not cleanly yield the desired 4,5-
dihydroxyxanthone, which is a profoundly intractable high
melting (mp > 350 ЊC) solid. In small scale test reactions it was
always the major product, but was accompanied by significant
amounts of a second phenolic compound, separable as yellow
crystals by sublimation from 4,5-dihydroxyxanthone. Mass
spectrometry of the sublimate gave a molecular formula,
C13H8O5, its IR spectrum showed a band at 1649 cmϪ1, and its
1H NMR spectrum indicated the presence of one aromatic ring
290
J. Chem. Soc., Perkin Trans. 2, 1999, 289–296

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Fig. 3 Minimum energy conformations of 4,5-dioxyxanthones and steric energies from molecular mechanics calculations.
Absorption spectra, luminescence spectra and
excited-state lifetimes
The absorption spectra in methanol solution of the 4,5-
dioxyxanthone crowns, 3 (n = 3, 4 and 5) and model compound
10 are very similar (λmax = 355 nm and εmax = 5700 MϪ1 cmϪ1).
All, however, differ markedly from the analogous 1,8-
dioxyxanthone derivatives and Fig. 4 compares the UV spectra
of corresponding compounds of each series.
Even more pronounced differences are found in the
fluorescence spectra of the two different families of dioxy-
xanthone derivatives. In contrast to the 1,8-dioxyxanthone
derivatives whose fluorescence intensity is very weak, all
the 4,5-dioxyxanthone derivatives are strongly fluorescent
even at room temperature (λmax = 437 nm, φem = 0.3). For
1,8-dioxyxanthone derivatives and related crowns, the low
fluorescence quantum yield was explained7 in terms of ground
state conformations (found in the X-ray crystal structures)
Fig. 4 UV spectra for methanol solutions of 4,5-diethoxyxanthone
(trace a) and 1,8-diethoxyxanthone (trace b).
the polyethylene oxide parts of the macrocyclic array deviate
from the ideal anti–anti–gauche sequence found in linear
polyethylene glycols,12 presumably reflecting the restrictions
imposed by the xanthone structure on four contiguous bonds
in each macrocycle. Seven additional low energy conformations
are found and, notably, the next most stable conformation
(0.7 kJ molϪ1 above the global minimum) has a planar xanthone
array and should be extensively populated at 25 ЊC. This
pattern is repeated in the structures of 3 (n = 4) and 3 (n = 5)
where the global minima have non-planar xanthones with
interplane angles in the xanthone of 168Њ and 172Њ respectively,
but in both cases there is a closely lying second structure with a
planar xanthone array.
containing a non-planar xanthone chromophore whose
first excited state was a non-emitting n–π* state. Binding of
the crowns incorporating 1,8-dioxyxanthones, 1 (n = 3, 4
and 5), to alkali earth cations yielded highly fluorescent
complexes, and it was suggested that metal ion incorporation
stabilised conformations containing planar xanthones whose
lowest excited state is probably a π–π* state. As discussed
earlier, molecular modelling shows that the most stable
conformation of 4,5-diethoxyxanthone 10 incorporates a
planar xanthone array, and that the crowns also can accom-
modate such arrays, so that the close similarity of the
absorption and fluorescence spectra of 10 and 3 (n = 3, 4
and 5) reflects the close similarity in their xanthone chromo-
phore structures. In the case of 10 and 3 (n = 3, 4 and 5),
in deaerated solution, no delayed luminescence was observed
(as was the case for the complexed 1,8-dioxyxanthone crown
ethers) indicating that in the 4,5-dioxyxanthones the energy
gap between the fluorescent lowest singlet state and the lower
lying triplet state is higher, and cannot be overcome even at
room temperature.
The xanthone arrays in all the 4,5-dioxyxanthone derivatives
are more nearly planar than in the corresponding 1,8-
dioxyxanthones, and differ from them in having energetically
accessible conformations with planar xanthones. This pre-
sumably reflects the absence in the former of the >C᎐O group
᎐
which would parallel C–O bond dipoles at adjacent 1- and
8-positions in the planar conformations of the latter.
J. Chem. Soc., Perkin Trans. 2, 1999, 289–296
291

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RO
H
O
OR
RO
OR
+
O
?
+ H+
O
O
10 or 3 (n = 3, 4, and 5)
?
+ H+
RO
OR
O
Fig. 5 Fluorescence quenching in response to addition of potassium
bromide to a methanolic solution of 3 (n = 3).
+
O
H
Table 1 Stability constants and luminescence properties of complexes
formed between 4,5-dioxyxanthone based crown ethers and sodium,
potassium and caesium ions in methanol at 25 ЊC
Fig. 6 Possible protonation sites in 4,5-dioxyxanthones.
The decrease in fluorescence intensity of the crown ethers
upon complexation can be attributed to a change in the
structure of the xanthone chromophore induced by the
presence of a positive charge near the ethereal oxygen atom
of the central xanthone ring. Co-ordination of the metal ion at
this oxygen would destabilise the planar conformation in which
through-conjugation from oxygen lone pairs to the xanthone
carbonyl places positive charge on that atom, and enhances
folding of the xanthone with production of a non-emitting
n–π* first excited state. The effect of metal ion binding on the
chromophore is thus exactly the opposite to that observed in
the 1,8-dioxyxanthone based crowns.
The 4,5-dioxyxanthones 3 (n = 3, 4 and 5) may be regarded
as modified dibenzo-annulated crown ethers, and we briefly
compare their binding constants with those of the familiar
dibenzo-18-crown-6, dibenzo-21-crown-7 and dibenzo-24-
crown-8.14 The 4,5-dioxyxanthones are less effective ligands
for sodium (ionic radius = 0.95 Å) by a factor of at least 10.
With larger potassium and caesium ions (ionic radii = 1.33 and
1.69 Å) binding constants for the same ring sizes are again
less for the 4,5-dioxyxanthones but by less than a power of ten.
This reduction is surprisingly small in view of the unfavourable
polarity of the ethereal xanthone oxygen, and the rigidity
associated with restriction of no less than seven adjacent atoms
of the macrocycle by their incorporation into the xanthone
tricycle.
4,5-Dioxyxanthone
Ion
Kass/MϪ1
Irel
t/ns
10
Naϩ
Naϩ
Naϩ
Naϩ
100
46 ( 1)
30 ( 1)
12.0
5.0
3.0
3 (n = 3)
3 (n = 4)
3 (n = 5)
0.8 ( 0.3) × 103
0.3 ( 0.1) × 103
<0.2 × 103
10
Kϩ
Kϩ
Kϩ
Kϩ
100
12.0
5.0
4.5
4.0
3 (n = 3)
3 (n = 4)
3 (n = 5)
2.0 ( 0.1) × 103
4.1 ( 0.1) × 103
1.6 ( 0.3) × 103
30 ( 1)
39 ( 1)
36 ( 1)
10
Csϩ
Csϩ
Csϩ
Csϩ
100
12.0
3.0
2.0
3.0
3 (n = 3)
3 (n = 4)
3 (n = 5)
1.4 ( 0.3) × 103
2.6 ( 0.2) × 103
3.4 ( 0.2) × 103
32 ( 1)
25 ( 2)
38 ( 2)
Binding to metal ions
1
The effects of added metal ions on the H NMR spectra of
methanolic solutions of 3 (n = 3) were briefly examined. This
crown incorporates an 18-crown-6 and might be expected to
bind Kϩ and Ba2ϩ. Even with large excesses of potassium or
barium bromide, however, changes in chemical shifts and line
shapes were difficult to detect and measure. Effects of added
ions on the UV spectra of methanolic solutions were also small,
and neither of these spectroscopic methods was well adapted to
quantitative measuring of the binding constants for these
crowns.
Stronger effects were observed on the fluorescence spectra,
where the intensity of the band showed a strong quenching
upon addition of sodium, potassium or caesium bromide,
accompanied by a reduction in the fluorescence lifetime. The
dependence of fluorescence intensity on the amount of metal
ion added to a methanol solution of the crown (as exemplified
in Fig. 5) followed an isotherm anticipated for 1:1 binding13
of metal ion and crown, and we associate the quenching with
complex formation [eqn. (1)].
Acid–base behaviour
Dilute acid solutions of the 4,5-dioxyxanthone crowns, 3 (n = 3,
4 and 5), and model compound, 10, are colourless, showing
characteristic UV absorptions with λmax at 250 (log ε = 4.42),
292 (shoulder, 3.45) and 362 (3.50) nm, resembling the spectra
in methanol solution shown earlier. Solutions in strong acid
(aq. 90% H2SO4) are yellow, and the spectra develop new
absorptions at λmax = 272 (4.55), 330 (3.99), 366 (shoulder, 3.56)
and 440 (3.42) nm. Under these conditions also, the fluorescence
band of the 4,5-dioxyxanthone crowns, 3 (n = 3, 4 and 5),
and of the model compound, 10 are no longer present, while
a lower energy band (λmax = 552 nm) appears. Dilution and
extraction of the acid solutions recovers the xanthones, and
we associate the colour changes with formation in solution of
their conjugate acids.
Protonation of xanthone itself, believed to be on the carb-
onyl oxygen, yields intensely fluorescent ions.15 The behaviour
of the 4,5-dioxyxanthone derivatives thus appears atypical,
raising the possibility that their protonation involves the
ethereal rather than the carbonyl oxygen of the xanthone
(Fig. 6). Certainly the pendant oxygens positioned meta relative
Kass
Crown ϩ Mnϩ
[Crown:M]nϩ
(1)
Values of association constants extracted from the curves
are also presented in Table 1 and were in excellent agreement
with measurements using conductivity changes observed on the
addition of the crowns to methanolic metal ion solutions for
both bromides and perchlorates of these ions.
The fluorescence spectra of the crowns were not affected by
addition of the alkali earth metal ions; neither were changes
observed in the conductivity experiments, showing that the
constants for binding between 3 (n = 3, 4 and 5) and the alkali
earth metal ions are below 200 MϪ1
.
292
J. Chem. Soc., Perkin Trans. 2, 1999, 289–296

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Table 2 pKa and m* values for the 4,5-dioxyxanthones, 3 (n = 3, 4 and
5) and model compound, 10, using the excess acidity function
evaporated from deuteriated chloroform or as KBr discs.
Ultraviolet absorption spectra were recorded on a Hewlett
Diode-array Spectrophotometer (Manchester) or a Perkin-
Elmer λ16 (Bologna). The fluorescence lifetimes (uncertainty
5%) were obtained with an Edinburgh single-photon counting
apparatus, in which the flash lamp was filled with D2. In order
to allow comparison of emission intensities, corrections for
instrumental response, inner filter effects, and phototube
sensitivity were performed.23 A correction for differences in the
refraction index was introduced when necessary. Mass spectra
were recorded on a Kratos MS25 or a Fisons VG Trio 2000.
Modes of ionisation are indicated as follows: electron impact
(EI), positive chemical ionisation (ϩCI/NH3) and fast atom
bombardment (FAB). Melting points were recorded on a Kofler
heated stage microscope and are uncorrected. All temperatures
are quoted in degrees Celsius (ЊC). Thin layer chromatography
(TLC) was carried out on Polygram Sil G/UV254 0.25 mm
silica gel plates with solvent systems as indicated. Analytical
HPLC was carried out using: Waters 510 HPLC pump, Waters
‘Z’ module with 4 µ ODS Nova-Pak 100 × 8 mm column,
Perkin-Elmer LC480 Diode Array System with detection at
255 nm, premixed degassed solvent system 75:25 MeOH–
H2O, flow rate 2 ml minϪ1, injections as stated. Elemental
analyses were carried out at the micro-analytical laboratories at
the University of Manchester under the direction of Mr M.
Hart.
4,5-Dioxyxanthone
m*
pKa
10
0.40
0.35
0.33
0.40
Ϫ2.6 ( 0.2)
Ϫ2.5 ( 0.2)
Ϫ2.3 ( 0.2)
Ϫ2.5 ( 0.2)
3 (n = 3)
3 (n = 4)
3 (n = 5)
to the carbonyl group are expected to reduce its basicity [σm
(MeO) = ϩ0.10],16 by induction, while possibly providing add-
itional internal solvation to stabilise a proton co-ordinated at
the ethereal oxygen.
Spectra were examined in a series of sulfuric acid mixtures
of varying strength, and extents of protonation were followed
by measuring the absorption at 272 nm for solutions of crown
or model compound. Plots of log I against acid strength as
17
measured by Ho were linear, but had slopes between 0.4
and 0.6, showing that these ketones were not behaving as
Hammett bases.18 The data were therefore treated using the
excess acidity (X) method19 to obtain acidity constants, Ka, for
the conjugate acids (BHϩ) referred to dilute aqueous solution
[eqn. (2)]. The appropriate relationship, eqn. (3), uses both m*
Ka
BHϩ
B ϩ Hϩ
(2)
(3)
ϩ
log I Ϫ log cH = m*X ϩ pKa
2,2Ј,3,3Ј-Tetramethoxydiphenylmethanol, 8
1,2-Dimethoxybenzene (49.24 g; 0.357 mol) was dissolved
in dry THF (500 ml) in a two litre round-bottomed flask
fitted with a septum cap under nitrogen and with stirring.8
The reaction vessel was cooled to Ϫ78 ЊC and n-butyllithium
solution (199 ml of 1.61 M solution in hexane; 0.32 mol) was
added by syringe. The reaction was then stirred at room
temperature for 3 hours, before cooling to Ϫ78 ЊC and adding
dropwise a solution of 2,3-dimethoxybenzaldehyde (53.12 g,
0.32 mol) in THF (150 ml). The reaction was stirred at room
temperature overnight until it appeared clear orange in colour,
then hydrolysed by addition of water (200 ml). The organic
phase was separated and the aqueous phase extracted with
ether (3 × 50 ml). The combined organic phases were dried
(Na2SO4) and evaporation under reduced pressure then gave
a viscous orange liquid, (84.06 g, 86%) (Found: C, 67.7; H,
6.2%. C17H20O5 requires C, 67.5; H, 6.0%); λmax (CH2Cl2)/nm
(log ε), 274 (3.72), 316 (3.01); νmax (CDCl3)/cmϪ1 3448, 2937,
2834, 1266, 1082, 1006, 944, 791, 751; δH (200 MHz; CDCl3)
3.07 (1H, d, J 6), 3.70 (6H, s), 3.85 (6H, s), 6.35 (1H, d, J 6),
6.8–7.1 (6H, m); m/z (EI) 304 (Mϩ, 45), 273 (26), 165 (100), 151
(73%); (ϩCI/NH3) 304 (29), 287 (100), 165 (11%).
and pKa as parameters to be determined, and the values
obtained are presented in Table 2.
In practical terms these compounds require ca. 65% sulfuric
acid for half protonation. They have Ϫ2.6 < pKa < Ϫ2.3, and
0.33 < m* < 0.40, and show no trend that we can discern
between ring size and basicity. They are considerably more
basic than xanthone itself (pKa reported as Ϫ4.812), and are
less basic than the corresponding compounds of the
1,8-dioxyxanthone series, 1 (n = 3, 4 and 5) where Ϫ2.37 <
pKa < Ϫ1.78 and m* values are close to 1. The difference in
values of m* between the series indicates significantly different
demands for solvation around the protonation site, and may
be consistent with a change in the protonation site. How-
ever, even with a series of substituted benzophenones20 where
carbonyl protonation is expected to occur constantly on
carbonyl oxygen, wide variations in values of m* have been
found, and a conclusion has not yet been reached.
Conclusions
The search for new chemosensors presents one of the more
challenging of current chemical problems. Luminescent sensors
have particular advantages in their sensitivity and ease of
measurement.21 The 4,5-dioxyxanthone base crowns described
here and the isomeric 1,8-dioxyxanthones described earlier7
have both shown desirable behaviour. Although the binding of
the 4,5-dioxyxanthones to potassium ions was disappointingly
small, the absence of binding to the alkali earth ions of the
same ionic size is a useful selectivity. Indeed, there is a com-
plementarity between the binding and luminescence responses
of the 1,8-dioxyxanthone series and the 4,5-dioxyxanthones
which may be exploitable in the construction of multi-sensory
devices to yield concentrations of these ions in complex
mixtures.22
2,2Ј,3,3Ј-Tetramethoxybenzophenone, 7
Crude 2,2Ј,3,3Ј-tetramethoxydiphenylmethanol (70 g) was dis-
solved in dry acetone (700 ml). The reaction was cooled to
5 ЊC and Jones reagent (0.27 g CrO3 per ml aq. H2SO4)24 was
added dropwise until a persistent orange colour was seen (~60
ml). Excess oxidant was destroyed by addition of propan-2-ol,
the reaction mixture was filtered, and the chromium residues
washed with ether. The combined organics were then stirred
with saturated aqueous sodium bicarbonate solution, before
separation, drying over Na2SO4, and evaporation. The crude
product was recrystallized twice from absolute ethanol to
produce the 2,2Ј,3,3Ј-tetramethoxybenzophenone in fine white
needle shaped crystals (40.0 g, 41%, based on 2,3-dimethoxy-
benzaldehyde in first stage); mp 98 ЊC (Found: C, 67.2; H, 6.0%.
C17H18O5 requires C, 67.5; H, 5.96%); λmax (CH2Cl2)/nm (log ε),
258 (4.33), 306 (3.86); νmax (CDCl3)/cmϪ1 1665, 1473, 1266,
1002, 783, 755; δH (200 MHz; CDCl3) 3.60 (6H, s), 3.90 (6H, s),
7.0–7.1 (6H, m); m/z (EI) 302 (Mϩ, 25), 165 (78), 151 (100%);
(ϩCI/NH3) 320 (3), 304 (35), 303 (100), 287 (20%).
Experimental
Proton NMR spectra were recorded on a Varian Gemini-200
(200 MHz) spectrometer or a Varian Unity-500 (500 MHz)
spectrometer, and carbon-13 NMR spectra were recorded on a
Brüker AC-300 (75 MHz). Infrared spectra were recorded on
an ATI Mattson Genesis Series FTIR and were run as films
J. Chem. Soc., Perkin Trans. 2, 1999, 289–296
293

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2,2Ј,3,3Ј-Tetrahydroxybenzophenone, 6
cooling, the solution was filtered, diluted with water (50 ml) and
extracted with chloroform. Drying (Na2SO4) and evaporation
yielded a brown crude product which was taken up in THF
and passed through a short column of silica. Evaporation and
recrystallisation from ethanol yielded fine beige needles, (0.15 g,
45%); mp 204–206 ЊC (Found: C, 71.88; H, 5.63%. C17H16O4
requires C, 71.83; H, 5.63%); λmax (CH3CN)/nm (log ε),
240 (shoulder, 4.34), 248 (4.46), 286 (shoulder, 3.49), 354
(3.62); νmax (CDCl3)/cmϪ1 2973, 2903, 1658, 1598, 1496, 1445,
1405, 1356, 1330, 1285, 1227, 1112, 1072, 1017, 912, 743;
δH (200 MHz; CD3CN) 1.60 (6H, t, J 6.3), 4.27 (4H, q, J 8), 7.28
(4H, m), 7.91 (2H, d, J 8); δC (75 MHz; CDCl3) 14.81, 65.42,
117.29, 117.66, 122.61, 123.57, 146.82, 148.38, 177.31; m/z (EI)
285 (26), 284 (Mϩ, 97), 270 (5), 256 (17), 255 (10), 229 (15),
228 (100), 227 (15), 190 (10), 171 (23), 115 (24%); (ϩCI/
NH3) 302 (2), 287 (5), 286 (35), 285 (100), 271 (9).
To 2,2Ј,3,3Ј-tetramethoxybenzophenone, 7 (1.0 g, 3.3 mmol)
(in a 50 ml round-bottomed flask) was added glacial acetic acid
(15 ml), with stirring, followed by 60% HBr (10 ml) and the
mixture was heated under reflux for 6 hours. The reaction was
then cooled and a red precipitate which had formed was filtered
off. Water (35 ml) was then added and the mixture extracted
with chloroform until the extracts were almost colourless. The
combined organic extracts were dried (Na2SO4), and the solvent
evaporated to leave a greenish viscous liquid which formed
bright yellow crystals on addition of water (20 ml) and cooling.
(0.757 g, 93%); mp 120–121 ЊC (lit.7 121–122 ЊC) (Found: C
62.9; H, 3.94%. C13H10O5 requires C, 63.4; H, 4.06%); λmax (abs.
EtOH)/nm (log ε), 232 (3.88), 280 (3.97), 354 (3.44); νmax
(CDCl3)/cmϪ1 3550–3100, 1625, 1580, 1451, 1248, 1226, 852,
748; δH (200 MHz; CDCl3) 5.80 (2H, s), 6.88 (2H, t, J 9), 7.22
(4H, m), 10.70 (2H, s); m/z (EI) 246 (Mϩ, 9), 137 (51), 136
(36%); (ϩCI/NH3) 264 (6), 247 (51), 134 (100), 117 (40%).
1,11-Dibromo-3,6,9-trioxaundecane, 1,14-dibromo-3,6,9,12-
tetraoxatetradecane and 1,17-dibromo-3,6,9,12,15-pentaoxa-
heptadecane
4,5-Dihydroxyxanthone, 5
These dibromides were prepared from the corresponding
polyethyleneglycols using previously described methods.4
A buffer of ionic strength 0.01 was prepared from acetic acid
(2.4 g, 2.28 ml, 0.04 mol), and sodium acetate (0.82 g, 0.01 mol),
placed in a 100 ml volumetric flask and diluted with water up
to the mark. 2,2Ј,3,3Ј-Tetrahydroxybenzophenone, 6 (1.0 g,
4.07 mmol), hydroquinone (1.0 g, 9.08 mmol), and the buffer
(8 ml) were added to a stainless steel bomb and blanketed with
nitrogen. The bomb was sealed and heated for 17 h at 220 ЊC.
After cooling, the bomb was opened, the contents emptied into
a round-bottomed flask and water evaporated under reduced
pressure. The reaction mixture was then sublimed (170 ЊC, 15
mmHg, for 30 minutes) to remove hydroquinone, leaving a dark
gritty product (0.87 g, 94%); mp >320 ЊC (lit.8 >350 ЊC); νmax
(KBr)/cmϪ1 3341, 2922, 1645, 1603, 1499, 1466, 1292, 1153,
1075, 1025, 738; δH (500 MHz; DMSO-d6) 7.38 (2H, t, J 8),
7.44 (2H, d, J 8), 7.70 (2H, d, J 8); m/z (EI) 229 (14), 228 (100),
200 (10), 171 (7%); (ϩCI/NH3) 245 (14), 230 (11), 229 (100%).
Crude 4,5-dihydroxyxanthone, 5 (344 mg) was dissolved in
methanol (250 ml) in a conical flask. Activated charcoal (25 mg)
was added and the mixture refluxed for 5 minutes. The solution
was filtered hot through celite, and the methanol was removed
in vacuo yielding a light green product (304 mg, 88%).
1,11-(4,5-Dioxyxanthone)-3,6,9-trioxaundecane,† 3 (n ؍ 3).
Decolourised 4,5-dihydroxyxanthone, 5 (0.3 g, 1.3 × 10Ϫ3 mol),
and anhydrous potassium carbonate (0.6 g, 4.3 × 10Ϫ3 mol)
were dissolved in DMF (60 ml) in a 250 ml round-bottomed
flask fitted with a reflux condenser, septum cap, nitrogen
atmosphere and stirring. 1,11-Dibromo-3,6,9-trioxaundecane
(0.64 g, 2 × 10Ϫ3 mol) was added by syringe and the mixture
refluxed overnight. After cooling, the solution was filtered,
most of the DMF distilled off under reduced pressure, the resi-
due diluted with water (30 ml). Extraction with chloroform
(3 × 40 ml), drying (Na2SO4), and evaporation yielded crude
product, and recrystallization from acetonitrile gave beige
needles (0.29 g, 56%); mp 168–171 ЊC (Found: C, 65.3; H,
5.6%. C21H22O7 requires C, 65.3; H, 5.7%); λmax (CH3CN)/nm
(log ε), 240 (shoulder, 4.39), 248 (4.5), 284 (shoulder, 5.53),
354 (3.65); νmax (CDCl3)/cmϪ1 3548, 3335, 2919, 2877, 1648,
1617, 1592, 1487, 1359, 1283, 1241, 1129, 1072, 913, 746;
δH (200 MHz; CDCl3) 3.81 (4H, m), 3.86 (4H, m), 4.10 (4H,
t, J 3), 4.33 (4H, t, J 3), 7.28 (m), 7.93 (2H, d, J 8); δC (75
MHz; CDCl3) 70.27, 70.59, 71.70, 72.58, 117.37, 118.50,
123.35, 124.23, 147.31, 148.92, 177.74; m/z (EI) 386 (Mϩ, 35),
255 (20), 254 (92), 228 (28), 225 (26%); (ϩCI/NH3) 404 (100),
387 (32%).
In initial reactions run on ca. 0.1 g samples of 6 in unbuffered
medium, without added hydroquinone, sublimation at 170 ЊC,
15 mmHg, for 30 minutes yielded yellow crystals of 1,2,5-
trihydroxyxanthone, 9, νmax (KBr)/cmϪ1; δH (500 MHz; CDCl3)
7.69 (<1H, d, J 9), 7.51 (2H, d, J 9), 7.35 (1H, t, J 8), 7.08 (1H,
d, J 8); m/z (EI) 244 (5).
1,14-(4,5-Dioxyxanthone)-3,6,9,12-tetraoxatetradecane,‡
3
(n ؍ 4). Reaction of decolourised 4,5-dihydroxyxanthone, 5
(0.3 g, 1.3 × 10Ϫ3 mol), anhydrous potassium carbonate (0.6 g,
4.3 × 10Ϫ3 mol), DMF (60 ml) and 1,14-dibromo-3,6,9,12-
tetraoxatetradecane (0.72 g, 1.97 × 10Ϫ3 mol) as described
above yielded a crude product (0.3 g, 53%) which was purified
by column chromatography (basic alumina, tetrahydrofuran) to
yield an off-white solid which was washed with ether and dried
in air (0.25 g, 44%); mp 127–129 ЊC (Found: C, 61.65; H, 5.99%.
C23H26O8ؒH2O requires C, 61.61; H, 6.25%); λmax (CH3CN)/nm
(log ε), 240 (shoulder, 4.38), 248 (4.5), 288 (shoulder, 3.69), 354
(3.73); νmax (CDCl3)/cmϪ1 3336, 2923, 2857, 1655, 1598, 1495,
1445, 1354, 1329, 1285, 1226, 1133, 1114, 1076, 1023, 747; δH
(200 MHz; CD3CN) 3.58 (4H, s), 3.61–3.72 (8H, m), 3.95 (4H,
t, J 5), 4.39 (4H, t, J 5), 7.3–7.43 (4H, m), 7.81 (2H, d, J 8); δC
(75 MHz; CDCl3) 69.60, 69.78, 70.82, 71.18, 71.38, 117.36,
117.94, 122.57, 123.45, 146.61, 147.97, 176.93; m/z (EI) 430
4,5-Diacetoxyxanthone
Decolourised 4,5-dihydroxyxanthone, 5 (0.200 g, 0.88 mmol),
acetic anhydride (10 ml) and pyridine (1 ml) were refluxed for
5 h. Evaporation under vacuum yielded crystals which were
collected by filtration, rinsed with ethanol and dried under
vacuum (160 mg, 58%); mp 262–270 ЊC (lit.8 263–268 ЊC);
λmax (abs. EtOH)/nm (log ε), 246 (3.79), 268 (3.7), 338 (3.69);
νmax (CDCl3)/cmϪ1 2918, 2850, 1764, 1672, 1482, 1479, 1371,
1192, 1022, 876, 753; δH (200 MHz; CDCl3) 2.44 (6H, s), 7.40
(2H, t, J 8), 7.53 (2H, d, J 7.5), 8.22 (2H, d, J 7.5); δC (75 MHz;
CDCl3) 20.55, 123.06, 123.90, 124.31, 128.18, 139.20, 147.70,
168.0, 175.98; m/z (EI) 312 (Mϩ, 4), 270 (15), 229 (13), 228
(100), 171 (5%); (ϩCI) 330 (30), 313 (100), 285 (5), 29 (7), 228
(9%).
4,5-Diethoxyxanthone, 10
Decolourised, crude 4,5-dihydroxyxanthone,
5 (0.27 g,
† IUPAC name: 2,3,5,6,8,9,11,12-Octahydro[1,4,7,10,13,16]hexaoxa-
cyclooctadeca[2,3,4,5,6-defg]xanthen-17-one.
‡ IUPAC name: 8,9,11,12,14,15,17,18,20,21-Decahydro[1,4,7,10,13,16,
19]heptaoxacyclohenicosa[2,3,4,5,6-defg]xanthen-20-one.
1.18 × 10Ϫ3 mol), anhydrous potassium carbonate (0.54 g,
3.87 × 10Ϫ3 mol), DMF (70 ml) and iodoethane (0.34 ml,
4.77 × 10Ϫ3 mol) were refluxed under nitrogen for 2.5 h. After
294
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(Mϩ, 16), 386 (3), 342 (6), 298 (8), 255 (27), 254 (100), 253 (18),
228 (36), 226 (18), 225 (40%); (ϩCI/NH3) 448 (100), 431 (16),
430 (3), 404 (6), 360 (8), 343 (7), 330 (33), 299 (10%).
at 25 ЊC), by excitation of the solution at an isosbestic point.
Aliquots of salt solution (10 µl of 1 × 10Ϫ2 M) were added
and intensities recorded at the maximum of the emission band.
Readings were then fitted to the relationship Icorr = CcrφCr ϩ x
φMCr, where Ccr and x are the concentrations of the uncom-
plexed and complexed crown, and φCr and φMCr are proportion-
ality constants between the corrected emission intensity (in
arbitrary units) and the concentration of uncomplexed and
complexed crown ether respectively.
1,17-(4,5-Dioxyxanthone)-3,6,9,12,15-pentaoxahepta-
decane,§
3 (n ؍ 5). Decolourised, crude 4,5-dihydroxy-
xanthone, 5 (0.1 g, 4.386 × 10Ϫ4 mol), anhydrous caesium
carbonate (0.34 g, 1.76 × 10Ϫ3 mol), DMF (60 ml), and 1,17-
dibromo-3,6,9,12,15-pentaoxaheptadecane (0.27 g, 6.62 × 10Ϫ4
mol) were heated together under nitrogen at 120 ЊC for 72 h.
Evaporation, aqueous dilution and chloroform extraction as
before yielded a brown liquid which was applied to a basic
alumina column. Elution with tetrahydrofuran yielded an off-
white solid, which was washed with ether and dried in air (84.5
mg, 41%); mp 102–105 ЊC (Found: C, 62.96; H, 6.43%. C25H30-
O9 requires C, 63.29; H, 6.3%); λmax (CH3CN)/nm (log ε), 240
(shoulder, 4.34), 248 (4.45), 284 (shoulder, 5.52), 354 (3.59); νmax
(CDCl3)/cmϪ1 2918, 2870, 1658, 1598, 1496, 1446, 1353, 1328,
1285, 1227, 1117, 1076, 1043, 1025, 746; δH (200 MHz; CD3CN)
3.55 (8H, s), 3.60–3.75 (8H, m), 3.95 (4H, t, J 5), 4.35 (4H, t,
J 5), 7.32–7.45 (4H, m), 7.79 (2H, d, J 7.6); δC (75 MHz; CDCl3)
69.80, 69.94, 70.65, 70.92, 70.98, 71.42, 117.77, 118.15, 122.69,
123.60, 146.86, 148.21, 177.18; m/z (EI) 474 (Mϩ, 8), 255 (21),
254 (78), 253 (18), 228 (40), 226 (38%); (ϩCI/NH3) 493 (26), 492
(100), 475 (15), 374 (38), 278 (55%).
For both conductimetry and spectrofluorimetry, x satisfies
the usual binding expression where Crtot is the total concentra-
tion of crown and Mtot is the total metal ion concentration:
x2 Ϫ (Crtot ϩ Mtot ϩ 1/K)x ϩ MtotCrtot = 0. Values of the
binding constants, K, were obtained by simulation of the data
using both K and ΛMCrX as adjustable parameters using a
Newton–Raphson procedure28 to minimise the sum of squares
of the residuals.
Empirical force field calculations
The molecular modelling package was Macromodel 4.5,29
running on a Silicon Graphics 4D 240 GTX work station.
The MM3* force field of Allinger et al.11 was used for calcu-
lations with no modification of parameters. The Monte Carlo
method of conformational searching was used, and energy
minimisations used the truncated Newton conjugate gradient
(TCNG) method.
Measurement of acid–base equilibria
Aqueous sulfuric acid mixtures of known strength were
made up according to Rochester25 and stock solutions of the
xanthones (ca. 4.2 × 10Ϫ3 M in acetonitrile). Aqueous acid
solutions (3.0 ml) were pipetted into 1 cm quartz cells and a
background UV spectrum collected. The xanthone was then
added by micropipette (20 µl of stock acetonitrile solution)
to the active cell, which was stirred briefly before recording
a UV spectrum and recording absorbance at 272 nm. Each
experiment was repeated three times, and the acidity of
the protonated xanthones was determined as described in the
text.
Acknowledgements
We thank the Universitá di Bologna (Fund for Selected Topics)
for support, and Zeneca Specialties for a CASE studentship
held by T.V.H. Zeneca provided additional generous financial
support.
References
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in the cell. All solutions and the cell were thermostatted at
35 ЊC and the temperature in the conductivity cell was constant
to 0.01 ЊC during the titration. In a typical experiment, a
solution of potassium bromide in anhydrous methanol (15.0 ml
of 2.4 × 10Ϫ4 M) was placed in the cell. The crown ether 3
(n = 4) (5.350 mg) was weighed into a 5 ml volumetric flask and
made up to the mark with 5 ml of the methanolic potassium
bromide solution from the cell and the flask was sonicated to
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then the crown solution was added in 100 µl aliquots and
measurements taken after each addition. Readings were
then fitted to the relationship V = MtotΛMX ϩ x(ΛMCr Ϫ ΛMX),
where Mtot is the total metal ion concentration and x is the
concentration of the complex. Here, ΛMX and ΛMCr are pro-
portionality constants between the voltage (in mV) and the
concentration of the uncomplexed and complexed metal ion
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b) By spectrofluorimetry. Emission spectra were run for
solutions of the crown ethers in methanol (3.0 ml of 1 × 10Ϫ4 M
15 J. F. Ireland and P. A. H. Wyatt, J. Chem. Soc., Faraday Trans. 1,
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§ IUPAC name: 8,9,11,12,14,15,17,18,20,21,23,24-Dodecahydro[1,4,
7,10,13,16,19,22]octaoxacyclotetraicosa[2,3,4,5,6-defg]xanthen-23-one.
J. Chem. Soc., Perkin Trans. 2, 1999, 289–296
295

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Paper 8/06487C
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