Synthesis of new optically active acridino-18-crown-6 ligands and studies of their potentiometric selectivity toward the enantiomers of protonated 1-phenylethylamine and metal ions

Article abstract of DOI:10.1016/j.tetasy.2009.11.011

Starting from commercially available and relatively inexpensive chemicals, new enantiopure diisobutyl- and dioctyl-substituted acridino-18-crown-6 ether-type ligands [(R,R)-3] and [(R,R)-4], respectively were prepared. The two lipophilic isobutyl [(R,R)-3

Full text of DOI:10.1016/j.tetasy.2009.11.011

Tetrahedron: Asymmetry 20 (2009) 2795–2801
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Tetrahedron: Asymmetry
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Synthesis of new optically active acridino-18-crown-6 ligands and studies
of their potentiometric selectivity toward the enantiomers of protonated
1-phenylethylamine and metal ions
b
c
d
d,e
Júlia Kertész a, Péter Huszthy a,b, , Attila Kormos , Ferenc Bertha , Viola Horváth , George Horvai
*
a Research Group for Alkaloid Chemistry of the Hungarian Academy of Sciences, H-1521 Budapest, PO Box 91, Hungary
b Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, H-1521 Budapest, PO Box 91, Hungary
c Egis Pharmaceuticals PLC, H-1475 Budapest, PO Box 100, Hungary
d Research Group for Technical Analytical Chemistry of the Hungarian Academy of Sciences, H-1521 Budapest, PO Box 91, Hungary
e Department of Inorganic and Analytical Chemistry, Budapest University of Technology and Economics, H-1521 Budapest, PO Box 91, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Starting from commercially available and relatively inexpensive chemicals, new enantiopure diisobutyl-
and dioctyl-substituted acridino-18-crown-6 ether-type ligands [(R,R)-3] and [(R,R)-4], respectively were
prepared. The two lipophilic isobutyl [(R,R)-3] and octyl [(R,R)-4] groups on the stereogenic centers of
these macrocycles made it possible to use them as potentiometric sensor molecules when incorporated
into plasticized PVC membrane electrodes. Ligand (R,R)-3 showed appreciable enantioselectivity toward
the enantiomers of 1-phenylethylammonium chloride while macrocycle (R,R)-4 exhibited a high selectiv-
ity toward the silver ion.
Received 8 October 2009
Accepted 13 November 2009
Available online 6 January 2010
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
Herein, we report on the development of sensor molecules for
the enantiomers of protonated primary amines and heavy metal
Enantiomeric recognition is a generally occurring phenomenon
in Nature. Examples of its action include the observation that only
ions such as the silver ion.
Primary amines are of great biological importance. They are
formed in living systems during the degradation of amino acids,
or serve as neurotransmitters. It is known that the enantiomers
of biogen primary amino compounds have different biological
activities; thus their enantioseparation and determination of their
enantiomeric composition are essential, especially in the pharma-
ceutical, plant-protection, and food industries.
D
-sugars and L-amino acids take part in the metabolic processes.
Enantiomers can have different biological and physiological activ-
ities; frequently only one enantiomer of a drug is effective while
the other might even be toxic. Therefore, the synthesis of new chi-
ral host molecules and their use as enantioselective sensor or
selector molecules is of great importance.
The role of chiral host molecules is not exclusively confined to
enantioselective differentiation. Naturally occurring ionophores
acting in different biosynthetic pathways are also chiral and mostly
involved in chiral discrimination between enantiomeric forms of
chiral molecules for example, amino acids, sugars, etc. However,
among them there are examples such as valinomycin, which selec-
tively binds an achiral guest, the potassium ion, thereby regulating
its transport through the cell membrane. Moreover, it has been
proven that stereochemical arrangements can play a crucial role
in the formation of host–achiral guest complexes.1 This principle
was exploited to create Ag+-specific podand-type ionophores by
the proper combination of ligand geometry and stereospecific
substitution.2
Silver and its compounds are used in electrical contacts and
conductors, in mirrors, in the catalysis of chemical reactions, in
photographic films, and as disinfectants. The traditional Ag2S-
based solid state electrode has a very high primary ion selectivity
and can be used to determine Ag+ in many applications; however
Hg2+ causes serious interference.3 This governs the activity of
developing ionophore-based Ag+-selective electrodes.
Sensor molecules can be built into potentiometric membrane
electrodes, optodes, amperometric biosensors, and immunosen-
sors.4–7 Chiral crown ethers are among the most effective enantio-
selective sensor molecules for primary amine-containing
compounds.8 Since the 1980’s several crown ethers have been used
as enantioselective sensor molecules in potentiometric membrane
electrodes.9–13
Crown ethers are also effective host molecules in Ag+-selective
potentiometric sensors and optodes.14–16
In connection with our present work it should be mentioned
* Corresponding author. Tel.: +36 1 463 1071; fax: +36 1 463 3297.
E-mail address: huszthy@mail.bme.hu (P. Huszthy).
that crown ethers containing
a pyridine unit have shown
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.11.011

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J. Kertész et al. / Tetrahedron: Asymmetry 20 (2009) 2795–2801
outstanding complexation properties toward heavy metal ions and
protonated primary amines because of the nitrogen atom and the
aromatic ring.8,17–19 Studies on the complexes of the optically
active pyridino-crown ethers and the enantiomers of chiral proton-
ated primary aralkyl amines proved that the enantioselectivity is
based on three independent interactions: tripodal hydrogen bond-
brane ion-selective electrodes (ISEs). This method is very
attractive, because it is fast, requires simple instrumentation and
very low amounts (typically 1 mg) of the substance.
2. Results and discussion
2.1. Synthesis
ing,
p–p stacking, and steric repulsion. To enhance the p–p inter-
action, we prepared macrocycles containing a more extended
aromatic p ,
-system, for example, phenanthrolino-20, phenazino-21
The synthesis of new enantiopure diisobutyl-substituted-acridi-
no-18-crown-6 ligand (R,R)-3 was carried out in two ways as out-
lined in Scheme 1. In the first case, acridinediol 521 was reacted
with enantiopure diisobutyl-substituted tetraethyleneglycol
ditosylate (S,S)-626 in the presence of a weak base K2CO3 under
similar conditions as described for the synthesis of macrocycle
(R,R)-2.21 Under these conditions, the reactions proceed by an
SN2 mechanism with total inversion of configuration in accordance
with similar reactions.21,22,26–28 In the second case the reported27
acridono-crown ether (R,R)-7 was reduced to acridino-crown ether
(R,R)-3 in a good yield using sodium metal in propyl alcohol by a
modification of the method described29 for the reduction of several
acridones to acridines.
The new enantiopure dioctyl-substituted macrocycle (R,R)-4
was prepared as shown in Scheme 2. The reported enantiopure tet-
raethylene glycol (R,R)-830 was treated with tosyl chloride in a
dichloromethane–water mixture using a strong base KOH to obtain
tetraethylene glycol ditosylate (R,R)-9 in good yield. Dihydroxyac-
ridone 1031 was then reacted with ditosylate (R,R)-9 in the pres-
ence of a weak base K2CO3 according to the procedure described
for the synthesis of the parent achiral acridono-crown ether31 to
render ligand (R,R)-11 in a low yield. Acridono-crown ether (R,R)-
11 was then reduced with sodium metal in propyl alcohol to give
acridino-crown ether (R,R)-4 in an excellent yield.
Improved procedures were used for the preparation of the re-
ported acridine-4,5-diol 521 and 4,5-dimethoxyacridine 1432
(Scheme 3). Reducing dihydroxyacridone 10 with sodium metal
in propyl alcohol was a more efficient method than heating 4-
amino-5-methoxyacridine in phosphoric acid at 180 °C as re-
ported.21 Strong electron-releasing groups (deprotonated pheno-
lic hydroxyls in this case) greatly increase the tendency of
acridanes to be oxidized to acridines;33 accordingly acridane-
4,5-diol could not be detected in the reaction mixture. Dimeth-
oxyacridone 12 was reduced with sodium metal to give dimeth-
oxyacridane 13 with a better yield than using amalgamated
sodium as described in the literature.32 Acridane 13 was then
oxidized with molecular oxygen in acetic acid to give dimethoxy-
acridine 14 instead of using NaNO2 in a mixture of concentrated
sulfuric acid, acetic acid, and water as reported.32 Dimethoxyac-
ridine 14 was also prepared starting from dimethoxyacridone
12 without isolating the acridano-derivative 13. Dimethoxyacri-
dine 14 could also be converted to acridinediol 5 using 48%
aqueous HBr, but only in low yield.
and acridino-21crown ethers. The relatively rigid structure of these
host molecules also contributes to their improved selectivity, and
as they are fluoro- and chromogenic, their complexation can be
studied using sensitive photophysical methods.
Disregarding some 9-substituted derivatives,22 up to now only
two acridino-18-crown-6 ligands have been synthesized, the achi-
ral macrocycle 1 and the enantiomerically pure ligand (R,R)-221
(Fig. 1). Complexes of crown ether (R,R)-2 with the enantiomers
of protonated primary amines have been studied by fluorescence23
and circular dichroism24,25 spectroscopy, and showed greater
enantioselectivity23 than its pyridino-18-crown-6 ether analog. A
chiral stationary phase containing a derivative of crown ether
(R,R)-2 was prepared by attaching the ligand to silica gel through
a spacer at the 9-position of the acridine ring and it was applied
successfully for the enantioseparation of racemic protonated pri-
mary aralkyl amines.22 It should also be noted here that the com-
plexation properties of acridino-18-crown-6 ethers with metal
ions have not yet been reported.
Herein, we report the synthesis of two new enantiopure acridi-
no-18-crown-6 ethers (see Fig. 2): (R,R)-3, with isobutyl groups at
the stereogenic centers exhibiting reasonable selectivity toward
the enantiomers of protonated 1-phenylethylamine, and (R,R)-4
containing octyl groups one carbon–carbon bond further away
from the acridine unit showing selectivity for Ag+ ions. It is remark-
able to note that the latter ionophore exhibits high selectivity over
Hg2+ ion (higher than Ag+ ionophores offered commercially) while
the selectivities over alkali, alkaline earth, and transition metal
ions are also good.
The selectivity of the new crown ethers is assessed by potenti-
ometry incorporating the ionophores into plasticized PVC mem-
N
N
O
O
O
O
H3C
O
O
O
O
CH3
O
O
1
(R,R)-2
Figure 1. Schematics of reported acridino-crown ethers.
2.2. Potentiometric characterization of a PVC membrane
containing ionophore (R,R)-3
Ionophore (R,R)-3 was incorporated into a plasticized PVC-
based ion-selective membrane and calibrated in different concen-
trations of phenylethylammonium chloride (PEAH+Clꢀ). The cali-
bration curve is shown in Figure 3.
The electrode, as expected, gives a near-Nernstian response to
PEAH+ ions with a slope of 52.9 mV/decade. The calibration curve
is linear between 10ꢀ1 and 10ꢀ4 M concentrations, with a detection
limit below 10ꢀ5 M.
N
N
iBu
O
O
O
O
iBu
O
O
O
O
octyl
octyl
O
O
(R,R)-3
(R,R)-4
The enantioselectivity of ligand (R,R)-3 for the enantiomers of
PEAH+Clꢀ was assessed with potentiometry, by alternatingly
Figure 2. New enantiopure acridino-crown ethers.

J. Kertész et al. / Tetrahedron: Asymmetry 20 (2009) 2795–2801
2797
O
N
OH
OH
O
N
H
5
iBu
O
O
O
O
iBu
K2CO3
Na
(R,R)-3
+
DMF
(21%)
PrOH
(93%)
TsO
iBu
O
O
OTs
iBu
O
(R,R)-7
(S,S)-6
Scheme 1. Synthesis of diisobutyl-substituted crown ether (R,R)-3.
octyl
O
octyl
octyl
O
octyl
O
TsCl
HO
O
O
OH
CH2Cl2
TsO
O
OTs
50% aq. KOH
(84%)
(R,R)-8
(R,R)-9
O
O
N
H
(R,R)-9
Na
O
O
O
(R,R)-4
N
H
PrOH
(96%)
K2CO3 / DMF
(10%)
OH
OH
octyl
O
octyl
O
10
(R,R)-11
Scheme 2. Synthesis of dioctyl-substituted crown ether (R,R)-4.
Na
10
5
PrOH
(91%)
O
O2
Na
48% aq. HBr
(39%)
5
PrOH
(86%)
AcOH
(80%)
N
N
N
OMe H
OMe
OMe H
OMe
OMe
OMe
12
13
14
Scheme 3. Synthesis of acridine-4,5-diol 5 and 4,5-dimethoxyacridine 14.
pot
S;R
immersing the electrode into 0.1 M (R)- and (S)-phenylethylammo-
nium chloride solutions, respectively, and recording the electromo-
tive force (EMF) responses. The difference in the EMF values was
used to calculate the potentiometric selectivity. The selectivity
coefficient obtained in this way gives a good approximation of
the ratio of the stability constants of the two diastereomeric com-
plexes [(R,R)-3ꢀ(S)-PEAH+Clꢀ] and [(R,R)-3ꢀ(R)-PEAH+Clꢀ] in
water34
K
is the potentiometric selectivity coefficient, bwSL is the stabil-
ity constant of the complex formed by an enantiopure host mole-
cule with a guest molecule of (S)-configuration in water and bSwL
is the stability constant of the complex formed by an enantiopure
host molecule with a guest molecule of (R)-configuration in water.
The results are shown in Table 1. The electrode containing (R,R)-
3 shows a marked and very reproducible difference in the potential
response toward the two enantiomers. It favors the (S)-form of
PEAH+Clꢀ over the (R)-form by a factor of almost 2.
That is,
bwRL
bwSL
Potentiometric selectivity of ligand (R,R)-3 toward other ions
such as alkali and alkaline earth metal ions, transition metal ions,
H+, and ammonium ion was also determined. The selectivity coef-
ficients are shown in Table 2.
pot
S;R
K
ꢁ
;
where

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J. Kertész et al. / Tetrahedron: Asymmetry 20 (2009) 2795–2801
350
300
250
200
150
100
50
350
300
250
200
150
100
50
PEAH+
Ag+
0
0
-7
-5
-3
-1
-7
-5
-3
-1
log a
log a
Figure 3. Calibration curve of the membrane electrode containing crown ether
(R,R)-3 as ionophore with racemic 1-phenylethylammonium ion.
Figure 4. Calibration curve of the membrane electrode containing crown ether
(R,R)-4 as ionophore with silver ion and racemic 1-phenylethylammonium ion.
The plasticized PVC electrode containing ligand (R,R)-4 exhibits
a potentiometric response to both silver and phenylethylammoni-
um ions, but has a preference for silver ions.
Table 1
Selectivity of ligand (R,R)-3 for the enantiomers of PEAH+Clꢀ expressed as the EMF
difference in 0.1 M PEAH+Clꢀ solutions and the corresponding potentiometric and
enantioselectivity factors obtained by 11 measurements
The slope of the calibration curve for Ag+ is 69.7 mV/decade in
the 10ꢀ2–10ꢀ4 M concentration range, (somewhat higher than
the theoretical Nernstian response) with a detection limit of
<10ꢀ5 M. At concentrations higher than 10ꢀ2 M, the calibration line
has a negative slope, which is caused35 by the co-extraction of the
DDEMF =
(mV)
D
TVFS
ꢀ
D
EMFR
Potentiometric
Enantioselectivity
selectivity
bwSL
bwRL
pot
S;R
K
ꢀ
relatively lipophilic NO3 ion into the electrode membrane
13.40 0.45
0.558 0.011
1.79 0.035
material.
The highest slope of the calibration curve in racemic PEAH+Clꢀ
is 49.7 mV/decade between 10ꢀ3 and 10ꢀ4 M. The detection limit
is approximately 5 ꢂ 10ꢀ5 M. Above a 10ꢀ3 M concentration, we
observed a decreased slope.
Table 2
Potentiometric selectivity of the PVC membrane electrode containing ligand (R,R)-3
for different metal ions, NH4 and H+ in comparison to PEAH+
þ
Potentiometric ion-selectivity values with respect to Ag+ ion
pot
Mn+
pot
(log K
) were determined by the separate solution method (Ta-
log K
PEAHþ;Mnþ
Ag;M
ble 3). It can be seen that the electrode measures silver ions with
a high selectivity over many alkali, alkaline earth, and transition
Ag+
H+
ꢀ0.66
ꢀ0.82
ꢀ1.40
ꢀ2.33
ꢀ2.61
ꢀ2.88
ꢀ2.95
ꢀ3.17
ꢀ4.03
ꢀ4.44
ꢀ4.57
ꢀ4.58
ꢀ4.61
K+
þ
NH4
Na+
Fe2+
Fe3+
Table 3
Potentiometric selectivity of the PVC membrane electrode containing ligand (R,R)-4
for different metal ions, H+, and PEAH+ in comparison to Ag+ ion
Cu2+
Li+
Mn+
pot
log K
Agþ;Mnþ
Cd2+
Ca2+
Mg2+
Zn2+
H+
ꢀ1.19
ꢀ1.79
ꢀ3.29
ꢀ3.39
ꢀ3.54
ꢀ3.79
ꢀ3.99
ꢀ4.25
ꢀ4.50
ꢀ4.63
ꢀ4.96
ꢀ5.23
ꢀ5.75
ꢀ5.93
ꢀ5.95
ꢀ6.02
PEAH+
K+
Fe3+
Na+
The electrode shows high selectivity toward PEAH+ against al-
most all ions studied. The selectivity against Ag+ ion and H+ are
not as good.
þ
NH4
Cr3+
Fe2+
Cu2+
Hg2+
Li+
2.3. Potentiometric characterization of a PVC membrane
containing ionophore (R,R)-4
Cd2+
Zn2+
Co2+
Ca2+
Mg2+
Ligand (R,R)-4 was also incorporated into a plasticized PVC
membrane electrode and calibrated in the solutions of AgNO3
and racemic PEAH+Clꢀ. Calibration curves are shown in Figure 4.

J. Kertész et al. / Tetrahedron: Asymmetry 20 (2009) 2795–2801
2799
Table 4
used for TLC. Aluminum oxide (neutral, activated, Brockman I)
and Silica Gel 60 (70–230 mesh, Merck) were used for column
chromatography. Ratios of solvents for the eluents are given in vol-
umes (mL/mL). Solvents were dried and purified according to well-
established37 methods. Evaporations were carried out under re-
duced pressure unless otherwise stated.
Selectivity of ligand (R,R)-4 for the enantiomers of PEAH+Clꢀ expressed as the EMF
difference in 0.1 M PEAH+Clꢀ solutions and the corresponding potentiometric
selectivity and enantioselectivity coefficients obtained by 10 measurements
DDEMF =
(mV)
D
TVFS
ꢀ
D
EMFR
Potentiometric
selectivity
pot
Enantioselectivity
bwSL
bwRL
K
S;R
4.2. Potentiometric measurements
ꢀ1.95 0.18
1.17 0.017
0.853 0.013
To incorporate the ligands into the potentiometric sensor, the
following membrane composition was prepared: 1 mg ionophore,
33 mg PVC powder, and 66 mg dioctyl sebacate (DOS) plasticizer
were dissolved in 2 ml THF. The solution was cast into a 20 mm
diameter teflon ring. After evaporation of the solvent a 7 mm disk
cut from the membrane was incorporated into a Philips IS-561
(Glasblaserei Moller, Zurich, Switzerland) electrode body using
10ꢀ3 M racemic PEAH+Clꢀ inner filling solution. The indicator elec-
trode was used with an Ag/AgCl double-junction reference elec-
trode (Metrohm, Herisau, Switzerland) in a Radelkis OP-208/1
precision pH-meter (Radelkis Ltd, Budapest, Hungary). Potentio-
metric selectivity coefficients were determined by the separate
solution method from the EMF data measured in PEAH+Clꢀ, metal
chloride or nitrate salts. Activity coefficients were calculated using
the Debye–Hückel equation, EMF data were corrected for the diffu-
sion potentials estimated with the Henderson equation.38
metal cations. Even mercury(II) which is always a problematic
interfering ion for Ag+ ionophores, shows surprisingly little inter-
ference. Some interference is observed in the presence of H+. This
is due to the basic character of the N atom in the acridino group
which is easily protonated.
The enantioselectivity of ligand (R,R)-4 for PEAH+Clꢀ was also
assessed with potentiometry in the same way, as described for li-
gand (R,R)-3.
The electrode showed very little, but reproducible EMF differ-
ence for the solutions of the two enantiomers of PEAH+Clꢀ result-
ing in a low enantioselectivity (see Table 4). Unlike ligand (R,R)-
3, the ionophore (R,R)-4 has a preference for (R)-1-phenylethylam-
monium ion over the other enantiomer.
3. Conclusion
4.3. (7R,17R)-7,17-Bis(2-methylpropyl)-6,9,12,15,18-pentaoxa-
25-azatetracyclo[21.3.1.05,26.019,24]heptacosa-1(26),2,4,19,21,23
(27),24-heptaene (R,R)-3
The synthesis of new chiral crown ethers (R,R)-3 and (R,R)-4
containing an acridine unit have been achieved. New efficient pro-
cedures were used for the preparation of acridine-4,5-diol 5 and
dimethoxyacridine 14.
4.3.1. Starting from acridine-4,5-diol 5
We have demonstrated that diisobutyl-substituted ligand (R,R)-
3 and dioctyl-substituted ligand (R,R)-4 could be used as sensor
molecules built in potentiometric membrane electrodes. Ligand
(R,R)-3 showed high enantioselectivity toward 1-phenylethylam-
monium ion and most of the metal ions studied do not interfere.
Ligand (R,R)-4 exhibited poor enantioselectivity toward 1-phenyle-
thylammonium ion, but it showed high selectivity toward silver
ion even in the presence of Hg2+. These results are in accordance
with previous investigations on pyridine-crown ether analogs
which showed the effect of the alkyl groups at the stereogenic cen-
ters on enantioselectivity.36 Experiments are currently in progress
to apply the electrode-containing enantiopure ligand (R,R)-3 for
the enantiomeric discrimination toward other protonated primary
amines, amino acids and their derivatives.
A mixture of acridine-4,5-diol 5 (698 mg, 3.31 mmol), diisobu-
tyl-substituted tetraethylene glycol ditosylate (S,S)-6 (2.24 g,
3.65 mmol), finely powdered anhydrous K2CO3 (4.58 g,
33.14 mmol), and dry DMF (56 mL) were stirred vigorously under
Ar at rt for 10 min, then at 50 °C for 7 days.
The solvent was removed and the residue was taken up in a
mixture of ice-water (75 mL) and EtOAc (150 mL). The phases were
shaken well and separated. The aqueous phase was extracted with
EtOAc (3 ꢂ 75 mL). The combined organic phase was dried over
MgSO4, filtered, and the solvent was removed. The crude product
was purified by chromatography on alumina using ethanol–tolu-
ene (1:200) mixture as an eluent to give (R,R)-3 (577 mg, 36%) as
a yellow solid. After recrystallization from hexane, 339 mg (21%)
of pale yellow crystals were obtained.
Mp: 113–116 °C (hexane); Rf: 0.18 (alumina TLC, MeOH–CH2Cl2
27
578
27
546
27
436
4. Experimental
4.1. General
1:60); ½a 2D7
ꢃ
¼ ꢀ35:5; ½
a
ꢃ
¼ ꢀ37:7; ½
aꢃ
¼ ꢀ45:5; ½
aꢃ
¼ꢀ133
(c 0.52, CH2Cl2); IR (KBr) mmax 3056, 2951, 2894, 2863, 1622,
1557, 1454, 1359, 1250, 1116, 988, 941, 876, 757, 712 cmꢀ1 1H
;
NMR (500 MHz, CDCl3) d 0.92 (d, J = 6 Hz, 6H), 0.98 (d, J = 6 Hz,
6H), 1.59 (broad s, half mol of complexed H2O, 1H), 1.67–1.75
(m, 2H), 1.82–1.94 (m, 4H), 3.69–3.79 (m, 6H), 3.85–4.00 (m,
4H), 4.28–4.35 (m, 2H), 5.26–5.34 (m, 2H), 7.15 (d, J = 7 Hz, 2H),
7.41 (t, J = 6.5 Hz, 2H), 7.57 (d, J = 6 Hz, 2H), 8.66 (s, 1H); 13C
NMR (75.5 MHz, CDCl3) d 23.11, 23.32, 25.11, 39.97, 71.57, 71.79,
73.41, 78.11, 112.84, 120.62, 126.21, 128.31, 135.46, 142.19,
154.72; MS Calcd for C29H39NO5: 481.2828, Found: 481.2823; Anal.
Calcd for C29H39NO5ꢄ0.5H2O: C, 70.99; H, 8.22; N, 2.85. Found: C,
70.83; H, 8.27; N, 2.57.
Infrared spectra were recorded on a Bruker Alpha-T FT-IR spec-
trometer. Optical rotations were taken on a Perkin–Elmer 241
polarimeter that was calibrated by measuring the optical rotations
of both enantiomers of menthol. 1H (500 MHz) and 13C (125 MHz)
NMR spectra were obtained on a Bruker DRX-500 Avance spec-
trometer. 1H (300 MHz) and 13C (75 MHz) NMR spectra were ob-
tained on a Bruker Avance 300 spectrometer. Mass spectra were
recorded on a Finningan-MAT 95 XP MS instrument (reference
compound: heptacosafluorotributylamine) using EI (70 eV) meth-
od. Elemental analyses were performed in the Microanalytical Lab-
oratory of the Department of Organic Chemistry, Institute for
Chemistry, L. Eötvös University, Budapest, Hungary. Melting points
were taken on a Boetius micro-melting point apparatus and were
corrected. Starting materials were purchased from Sigma–Aldrich
Corporation unless otherwise noted. Silica Gel 60 F254 (Merck)
and aluminum oxide 60 F254 neutral type E (Merck) plates were
4.3.2. Starting from acridono-crown ether (R,R)-7
To a boiling solution of acridono-crown ether (R,R)-7 (58 mg,
0.117 mmol) in propanol (6 mL) was added sodium (80.4 mg,
3.50 mmol) in 5 portions under Ar, and the mixture was refluxed
for 1 h. Water (10 mL) was added to the cooled reaction mixture,
and the pH was adjusted to 7 with 30% aqueous HCl solution.

2800
J. Kertész et al. / Tetrahedron: Asymmetry 20 (2009) 2795–2801
The solvent was removed, and the residue was taken up in a mixture
of water (50 mL) and diethyl ether (50 mL). The aqueous phase was
extracted with diethyl ether (4 ꢂ 20 mL) and the combined organic
phase was shaken with saturated brine (2 ꢂ 50 mL), dried over
MgSO4, filtered, and the solvent was removed.
The hydrogen bromide salt (129 mg, 0.441 mmol) was sus-
pended in water (4 mL), the pH was adjusted to 8 with NaHCO3,
and the crystals were filtered and washed with water. The greenish
yellow solid was recrystallized from aqueous ethanol to give acri-
dinediol 5 (63 mg, 68%) which was identical in every respect to the
reported one.21
The crude product was purified by chromatography on alumina
using ethanol–toluene (1:200) mixture as an eluent to give yellow
crystals (52 mg, 93%).
4.6. (2R,20R)-2,20-Oxybis[(ethane-2,1-diyloxy)decane-2,1-diyl]
bis(4-methylbenzenesulfonate) (R,R)-9
Mp: 115–118 °C; ½a D25
¼ ꢀ35:1 (c 0.50, CH2Cl2). Compound
ꢃ
(R,R)-3 had the same IR and NMR spectra as the one prepared
above from acridinediol 5 and ditosylate (S,S)-6.
To a vigorously stirred solution of diol (R,R)-8 (4.19 g, 10 mmol)
in CH2Cl2 (80 mL) were added successively tosyl chloride (4.2 g,
22 mmol) and 50% (w/w) aqueous KOH (12 mL) at 0 °C. The reac-
tion mixture was stirred vigorously at 0 °C for 5 min then at rt
for 4 h. After 4 h tosyl chloride (3.0 g, 16 mmol) and 50% (w/w)
aqueous KOH (8 mL) were added to the reaction mixture and stir-
ring was continued for 24 h. After that time, TLC analysis showed
the total consumption of diol (R,R)-8 and tosyl chloride and also
the formation of a new compound (R,R)-9. Water (80 mL) and
CH2Cl2 (50 mL) were added to the mixture and the phases were
shaken thoroughly. The phases were separated, and the organic
phase was shaken with water (2 ꢂ 30 mL), dried over MgSO4,
filtered, and the solvent was removed. The crude product was puri-
fied by chromatography on silica gel using toluene then toluene–
EtOAc mixture (20:1) as eluents to give ditosylate (R,R)-9 (6.1 g,
4.4. (8R,16R)-8,16-Dioctyl-6,9,12,15,18-pentaoxa-25-azatetra-
cyclo[21.3.1.05,26.019,24]heptacosa-1(26),2,4,19,21,23(27),24-
heptaene (R,R)-4
Macrocycle (R,R)-4 was prepared as described above for (R,R)-3
(see entry 4.3.2.) starting from acridono-crown ether (R,R)-11
(58 mg, 0.0952 mmol), sodium (65.6 mg, 2.85 mmol), and propanol
(6 mL). Chromatography on alumina using ethanol–toluene
(1:250) mixture as an eluent gave a dark yellow oil (54 mg,
96%).Rf:
0.52
(alumina
¼ þ1:0;
TLC,
ethanol–toluene
1:15);
20
578
20
½
a 2D0
ꢃ
¼ þ1:2; ½
a
ꢃ
½aꢃ
¼ þ1:7 (c 0.58, CH2Cl2); IR
546
(neat) mmax 2922, 2853, 1625, 1561, 1463, 1405, 1320, 1273,
1260, 1188, 1129, 1106, 802, 743 cmꢀ1; 1H NMR (500 MHz, CDCl3)
d (ppm) 0.90 (t, J = 7 Hz, 6H), 1.28–1.71 (m, 28H), 2.05 (broad s, half
mol of complexed H2O, 1H), 3.77–3.87 (m, 6H), 4.01–4.11 (m, 4H),
4.31–4.39 (m, 4H), 6.94 (d, J = 7.5 Hz, 2H); 7.44 (t, J = 8 Hz, 2H);
7.56 (d, J = 8.5 Hz, 2H) 8.68 (s, 1H); 13C NMR (75.5 MHz, CDCl3) d
(ppm) 14.32, 22.88, 25.87, 29.50, 29.78, 29.90, 29.94, 32.09,
70.72, 71.54, 73.19, 78.45, 107.16, 119.74, 126.23, 128.25, 135.37,
141.39, 154.86; MS Calcd for C37H55NO5: 593.4080, Found:
593.4063; Anal. Calcd for C37H55NO5ꢄ0.5H2O: C, 73.72; H, 9.36; N,
2.32. Found: C, 73.34; H, 9.21; N, 2.05.
84%) as a pale yellow oil. Rf: 0.75 (silica gel TLC, toluene–
18
365
EtOAc = 9:2); ½
aꢃ
¼ þ15:7 (c 1.12, CHCl3); IR (neat) mmax 2928,
2856, 1600, 1450, 1354, 1192, 1184, 1176, 1096, 976, 816,
668 cmꢀ1 1H NMR (500 MHz, CDCl3) d 0.88 (t, J = 7 Hz, 6H),
;
1.20–1.50 (m, 28H), 2.44 (s, 6H), 3.46–3.65 (m, 10H), 3.94–4.04
(m, 4H), 7.34 (d, J = 8 Hz, 4H), 7.79 (d, J = 8 Hz, 4H); 13C
NMR (125 MHz, CDCl3) d 14.06, 21.59, 22.62, 25.06, 29.21, 29.44,
29.54, 31.39, 31.83, 69.71, 70.71, 71.57, 77.73, 127.93, 129.82,
133.07, 144.75; Anal. Calcd for C38H62O9S2: C, 62.78; H, 8.60;
S, 8.82. Found: C, 62.64; H, 8.71; S, 8.77.
4.5. Acridine-4,5-diol 5
4.7. (8R,16R)-8,16-Dioctyl-6,9,12,15,18-pentaoxa-25-azatetra
cyclo[21.3.1.05,26.019,24]heptacosa-1(26),2,4,19,21,23-hexaene-
27-one (R,R)-11
4.5.1. Starting from 4,5-dihydroxyacridone 10
Acridinediol 5 was prepared as described above for (R,R)-3 (see
entry 4.3.2.) starting from dihydroxyacridone 10 (300 mg,
1.32 mmol), sodium (900 mg in 6 portions, 39.15 mmol), and propa-
nol (12 mL). The work-up was modified as follows: 20 mL water was
added to the cooled reaction mixture, and the pH was adjusted to 7
with 30% aqueous HCl solution. The volatile compounds were re-
moved, and the residue was taken up in a mixture of water
(50 mL) and dichloromethane (50 mL). The aqueous phase was ex-
tracted with dichloromethane (4 ꢂ 50 mL). The combined organic
phase was dried over MgSO4, filtered, and the solvent was removed.
The crude product was recrystallized from aqueous ethanol to
give acridinediol 5 as yellow crystals (255 mg, 91%). Acridinediol
5 had the same physical properties and spectroscopic data as
reported.21
A mixture of acridonediol monohydrate 10 (490 mg, 2 mmol),
ditosylate (R,R)-9 (1.6 g, 2.2 mmol), finely powdered anhydrous
K2CO3 (2.76 g, 20 mmol) was stirred in dry and pure DMF
(45 mL) vigorously under Ar at rt for 10 min then at 50 °C for 6
days. The solvent was removed and the residue was taken up in
a mixture of water (150 mL) and EtOAc (150 mL). The phases were
shaken well and separated. The aqueous phase was extracted with
EtOAc (2 ꢂ 20 mL). The combined organic phase was shaken with
water (2 ꢂ 50 mL), dried over MgSO4, filtered, and the solvent
was removed. The crude product was purified by chromatography
on silica gel using CH2Cl2–EtOAc mixture (20:1) as an eluent to
give macrocycle (R,R)-11 (130 mg, 10 %) as
Mp: 72–73 °C; Rf: 0.36 (silica gel TLC, toluene–iPrOH 10:1);
¼ ꢀ28:9 (c 1.0, CHCl3); IR (KBr) mmax 3424, 2928, 2856,
1624, 1600, 1560, 1532, 1454, 1272, 1224, 1136, 1128, 1112,
1104, 1084, 746, 592 cmꢀ1 1H NMR (500 MHz, CDCl3) d 0.88 (t,
a semihydrate.
½ ꢃ
a 2D3
4.5.2. Starting from 4,5-dimethoxyacridine 14
A mixture of dimethoxyacridine 14 (184 mg, 0.769 mmol) and
48% aqueous HBr (4 mL) was stirred vigorously under Ar at reflux
temperature for 2 days. The reaction mixture was filtered to
give the hydrogen bromide salt of 14 as maroon crystals
(129 mg, 57%). Mp: 253–254.5 °C; Rf: 0.35 (silica gel TLC, MeOH–
CH2Cl2 1:20); IR (KBr) mmax 3383, 3328, 2965, 1627, 1590, 1507,
1474, 1466, 1419, 1328, 1119, 800, 789, 743, 712, 576, 555, 530,
;
J = 7 Hz, 6H), 1.24–1.53 (m, 24 H), 1.59–1.66 (m, 2H), 1.69–1.75
(m, 2H), 2.03 (broad s, half mol of complexed water, 1H), 3.70–
3.84 (m, 8H), 3.87–3.90 (m, 2H), 4.19–4.28 (m, 4H), 7.05 (d,
J = 8 Hz, 2H), 7.16 (t, J = 8 Hz, 2H), 8.05 (d, J = 8 Hz, 2H), 9.29 (broad
s , NH, 1H); 13C NMR (125 MHz, CDCl3) d 14.24, 22.78, 25.67, 29.33,
29.65, 29.89, 31.61, 31.97, 70.18, 71.00, 71.93, 77.81, 111.84,
118.28, 120.50, 121.93, 131.17, 146.35, 177.60; MS Calcd for
C37H55NO6: 609.4024. Found: 609.4012; Anal. Calcd for
C37H55NO6ꢄ0.5H2O: C, 71.81; H, 8.96; N, 2.26. Found: C, 71.70; H,
9.18; N, 2.06.
402 cmꢀ1
; d 4.17 (broad s,
1H NMR (300 MHz, DMSO-d6)
2OH, NH+, absorbed H2O), 7.15 (d, J = 7 Hz, 2H), 7.47 (t, J = 8 Hz,
2H), 7.59 (d, J = 9 Hz, 2H), 9.07 (s, 1H); 13C NMR (75.5 MHz,
DMSO-d6) d 111.90, 119.18, 127.69, 128.34, 137.17, 139.45, 151.57.

J. Kertész et al. / Tetrahedron: Asymmetry 20 (2009) 2795–2801
2801
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4.8. 4,5-Dimethoxy-9,10-dihydroacridine 13
4. Trojanowicz, M.; Wcisło, M. Anal. Lett. 2005, 38, 523–547.
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Heterocycl. Chem. 1994, 31, 1–10.
Compound 13 was prepared as described above for (R,R)-3 (see
entry 4.3.2.) starting from dimethoxyacridone 12 (0.5 g,
1.96 mmol), sodium (1.5 g in 6 portions, 65.2 mmol), and propanol
(20 mL). The work-up was modified as follows: 30 mL water was
added to the cooled reaction mixture, and the pH was adjusted
to 7 with acetic acid. The volatile compounds were removed and
the crude product was filtered and dried over KOH in a desiccator
under reduced pressure to give 13 as yellow crystals (0.407 g, 86%).
We should note here that every step of the preparation was carried
out under an inert atmosphere. The crude product was used with-
out further purification. A small amount of crude product was
recrystallized from ethanol to give an analytical sample as pale yel-
low crystals.
Mp: 80–80.5 °C (ethanol) (lit.32 mp: 91–92.5 °C (ethanol)); Rf:
0.88 (silica gel TLC, MeOH–CH2Cl2 1:60); IR (KBr)
mmax 3424, 3055,
3001, 2958, 2933, 2852, 2833, 1613, 1576, 1510, 1492, 1478, 1449,
1408, 1335, 1268, 1253, 1105, 1074, 925, 759, 727, 697, 668 cmꢀ1
;
1H NMR (500 MHz, CDCl3) d (ppm) 3.93 (s, 6H), 4.13 (s, 2H), 6.73
(d, J = 8 Hz, 2H); 6.76 (d, J = 8 Hz, 2H); 6.82 (t, J = 8 Hz, 2H) 6.97 (s,
1H, NH); 13C NMR (125 MHz, CDCl3) d (ppm) 31.06, 55.58, 107.98,
119.59, 119.80, 120.60, 129.75, 145.98.
21. Huszthy, P.; Samu, E.; Vermes, B.; Mezey-Vándor, G.; Nógrádi, M.; Bradshaw, J.
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Vermes, B. New J. Chem. 2000, 24, 781–785.
4.9. 4,5-Dimethoxyacridine 14
24. Szarvas, S.; Majer, Z.; Huszthy, P.; Vermes, B.; Hollósi, M. Enantiomer 2002, 7,
241–249.
25. Farkas, V.; Szalay, L.; Vass, E.; Hollósi, M.; Horváth, G.; Huszthy, P. Chirality
2003, 15, S65–S73.
26. Samu, E.; Huszthy, P.; Somogyi, L.; Hollósi, M. Tetrahedron: Asymmetry 1999,
10, 2775–2796.
27. Szalay, L.; Farkas, V.; Vass, E.; Hollósi, M.; Móczár, I.; Pintér, Á.; Huszthy, P.
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28. Huszthy, P.; Farkas, V.; Tóth, T.; Székely, G.; Hollósi, M. Tetrahedron 2008, 64,
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29. Albert, A. The Acridines, 2nd ed.; Edward Arnold Publishers: London, 1966. pp
25–27.
30. Kovács, I.; Huszthy, P.; Bertha, F.; Sziebert, D. Tetrahedron: Asymmetry 2006, 17,
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32. Sherlin, S. M.; Braz, G. I.; Yakubovich, A. Y.; Vorobjeva, E. I.; Rabinovich, F. E.
Zhurnal Obshchei Khimii, 1938, 8, 884–97. (Chem. Abstr. 1939, 33, 1330; Chem.
Zentralbl. 1939, 110, 4324).
Dimethoxyacridane 13 (0.448 g, 1.86 mmol) in acetic acid
(20 mL) was stirred under oxygen atmosphere at reflux tempera-
ture for 5 h. The solvent was removed and the brown solid was trit-
urated with water, filtered, and washed with water. The pH of the
aqueous phase was adjusted to 9 with 25% aqueous Me3N solution
and shaken with dichloromethane (4 ꢂ 10 mL). The combined
organic phase was dried over MgSO4, filtered, and the solvent
was removed.
The combined crude product (the filtered solid and the crystals
obtained from the organic phase) was recrystallized from metha-
nol to give 14 (0.357 g, 80%) as yellow crystals.
Dimethoxyacridine 14 had the same physical properties and
spectral data as reported.31
33. Albert, A. The Acridines, 2nd ed.; Edward Arnold Publishers: London, 1966. pp.
14–16.
34. Morf, W. E. The Principles of Ion-Selective Electrodes and of Membrane Transport;
Elsevier: New York, 1981.
Acknowledgment
35. Boles, J. H.; Buck, R. P. Anal. Chem. 1973, 45, 2057–2062.
36. Izatt, R. M.; Wang, T.; Hathaway, J. K.; Zhang, X. X.; Curtis, J. C.; Bradshaw, J. S.;
Zhu, C. Y.; Huszthy, P. J. Inclusion Phenom. 1994, 17, 157–175.
37. Riddick, J. A.; Bunger, W. B.; Sakano, T. K. In: Techniques of Chemistry, 4th ed.;
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Horwood Ltd: Chichester, 1978.
Financial support of the Hungarian Scientific Research Fund
(OTKA No. K62654) is gratefully acknowledged.
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