Synthesis and optical characterization of novel enantiopure BODIPY linked azacrown ethers as potential fluorescent chemosensors

Article abstract of DOI:10.1016/j.tet.2009.07.061

Two novel enantiopure BODIPY linked azacrown ether chemosensors were prepared by reacting 3-chloro-5-methoxyBODIPY with new enantiopure monoaza-18-crown-6 ether ligands bearing two methyl and isobutyl groups on their chiral centres, respectively. The latt

Full text of DOI:10.1016/j.tet.2009.07.061

Tetrahedron 65 (2009) 8250–8258
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis and optical characterization of novel enantiopure BODIPY linked
azacrown ethers as potential fluorescent chemosensorsq
a
a,
b
,
c
d,
e
c,d
*
´
´
´
´
´
´ ´
´
´
Ildiko Moczar , Peter Huszthy
, Zita Maidics , Mihaly Kadar , Klara Toth
a Research Group for Alkaloid Chemistry of the Hungarian Academy of Sciences, PO Box 91, H-1521 Budapest, Hungary
b Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, PO Box 91, H-1521 Budapest, Hungary
c Department of Inorganic and Analytical Chemistry, Budapest University of Technology and Economics, PO Box 91, H-1521 Budapest, Hungary
d Research Group of Technical Analytical Chemistry of the Hungarian Academy of Sciences, PO Box 91, H-1521 Budapest, Hungary
e Chinoin Pharmaceutical and Chemical Works Ltd., PO Box 110, H-1325 Budapest, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Two novel enantiopure BODIPY linked azacrown ether chemosensors were prepared by reacting
3-chloro-5-methoxyBODIPY with new enantiopure monoaza-18-crown-6 ether ligands bearing two
methyl and isobutyl groups on their chiral centres, respectively. The latter compounds were synthesized
starting from optically active tetraethylene glycols in six steps. The operation of chemosensors is based
on the intramolecular charge transfer (ICT) process. They exhibit pronounced off–on type fluorescent
Received 25 February 2009
Received in revised form 23 June 2009
Accepted 23 July 2009
Available online 29 July 2009
responses to some metal ions and chiral primary aralkyl ammonium ions, in particular to Ca2þ and Pb2þ
.
Even in the case of 1:1 ratio of Ca2þ and Pb2þ ions to the ionophores, the fluorescence intensities and
quantum yield values increased more than 10-fold, as well as both the absorption and emission bands
were blue-shifted by about 20–30 nm (hipsochromic effect) in acetonitrile. The formation of relatively
stable complexes allowed the determination of log Ks values by the mole-ratio method.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
shifts, ICT sensor molecules show a moderate increase in their
fluorescence intensity with significant shifts in their absorption and
The synthesis and development of sensitive and selective fluo-
rescent sensors for metal ion analysis have gained much research
interest due to the great demand for their application in many fields
such as environmental chemistry, food industry, medical diagnosis
and life sciences.1 Fluorescence spectroscopy is an attractive tool
due to its selectivity, sensitivity and versatility.2,3 Many fluorescent
cation sensors have either a modular structure consisting of a fluo-
rophore and a receptor unit separated by a short alkyl spacer or
fluorescence spectra upon complexation.4–11 In a wider sense,
mostly PET sensor systems besides ICT type ones are extensively
studied also in sensing of anions6,9,12,13 and neutral molecules.8,9,14
Furthermore, many PET sensors have also been developed exploit-
ing the selective quenching of fluorescence upon interactionwith an
analyte.4–7,9,12,13
Enantiomeric recognition is a widespread and important phe-
nomenon in nature. Examples for its action include the metabolism
of single enantiomeric forms of amino acids and saccharides in
biosynthetic pathways. Stereostructure of optically active natural
ion carriers (ionophores) such as valinomycin, monensin, lasalocid,
monactin, dinactin, salinomycin, narasin and nigericin also plays an
important role in the selective transport of metal cations through
biomembranes.15,16
The determination of the enantiomeric composition of organic
compounds is of great importance in drug discovery, food industry,
pesticide chemistry, biological and separation sciences. Enantiomers
may be theoretically distinguished from each other by artificial chiral
host molecules such as crown ethers.17,18 In the past two decades
many efforts have been made on the development of fluorescent
chiral chemosensors.19–24 Among them some crown ethers contain-
ing various fluorescent units were synthesized and their enantio-
meric recognition ability towards amino acid derivatives, amino
a structure wherein the receptor is part of the p-electron system of
the fluorophore. They work on the basis of photoinduced electron
transfer (PET) and internal charge transfer (ICT) processes, re-
spectively. In the absence of analytes such as metal or organic ions,
both types of sensor molecules show reduced fluorescence due to
the efficient quenching process (PET or ICT) in the excited state.
Whereas in PET sensor molecules the binding of the analyte in-
creases the fluorescence intensity to a great extent without spectral
q
Preliminary results presented at the Second International Symposium on
Macrocyclic and Supramolecular Chemistry, Salice Terme, Italy, 24–28 June, 2007.
* Corresponding author. Tel.: þ36 1 463 1071; fax: þ36 1 463 3297.
E-mail address: huszthy@mail.bme.hu (P. Huszthy).
URL: http://www.och.bme.hu/org
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.07.061

´
I. Mo´czar et al. / Tetrahedron 65 (2009) 8250–8258
8251
alcohols and primary amines were studied.25–29 The complexation
properties of some chiral fluorescent crown ether based chemo-
sensors towards metal ions were also investigated.28–30
reacting them with sodium iodide in acetone. Reaction of diiodo
derivatives (S,S)-17 and (S,S)-18 with benzylamine in the presence of
potassium carbonate as a base in acetonitrile resulted in the N-benzyl
derivatives of chiral monoazacrown ethers [(S,S)-19 and (S,S)-20)].
Finally, benzyl protecting groups were removed by catalytic hydro-
genation in methanol to furnish the desired chiral monoazacrown
ethers (S,S)-5 and (S,S)-6 (Scheme 2).
Boron-dipyrromethene (BODIPY,31 4,4-difluoro-4-bora-3a,4a-
diaza-s-indacene) derivatives are useful fluorophores for construct-
ing chemosensors, because of their advantageous characteristics
such as sharp absorption and fluorescence bands, high molar ex-
tinction coefficients, high fluorescence quantum yields, high stability
against light and chemical reactions, and also because they can be
excited in the visible range of light.32–35 A number of chemosensors
containing boradiazaindacenes such as crown ethers,36–48 cal-
ix[4]crown ethers49–52 and podands53 have been synthesized and
their selective metal ion binding abilities have been studied. Fur-
thermore, some of them have been applied for the development of
molecular logic gates.44,51
2.2. UV–vis and fluorescence spectroscopic characterization
The UV–vis spectrophotometric and fluorescence emission
properties of chemosensors 1–(S,S)-3 as well as their metal ion and
NHþ4 complexes are summarized in Table 1. The absorption spectra of
compounds 1–(S,S)-3 in acetonitrile show similar characteristics to
BODIPY chromophores described in the literature.32–35 An intense
band in the 400–600 nm region with a maximum at 527–529 nm
and a shoulder at the shorter wavelength side can be attributed to
a strong S0–S1 transition. Less intense absorption bands (S0–S2) can
also be observed at about 350 nm. The absorption spectra of BODIPY
crown ethers 1–(S,S)-3 are significantly red-shifted (ca. 30 nm)
compared to the reference compound 7 (lmax¼498 nm) due to an
Herein we report the synthesis of two new enantiopure BODIPY
based azacrown ether chemosensors having methyl and isobutyl
groups on their chiral centres and also the studies on their com-
plexation properties towards various metal ions (Liþ, Naþ, Kþ, Agþ,
Mg2þ, Ca2þ, Zn2þ, Cu2þ, Pb2þ, Cd2þ, Hg2þ, Fe3þ), NH4þ ion and the
enantiomers of
a-phenylethylammonium perchlorate (PEA) and
a
-(1-naphthyl)ethylammonium perchlorate (NEA) salts. In addition
extended conjugation of the
p-system of the fluorophore with the
we report our extended complexation studies towards metal ions in
more detail on the achiral analogue described earlier in the
literature.39
imino group of the crown ether. Furthermore, the absorption bands
of ionophores 1–(S,S)-3 are considerably wider and their absorption
coefficients are smaller than those of the reference compound 7
(
3
¼47,700 Mꢀ1 cmꢀ1). The alkyl groups on the chiral centres of
2. Results and discussion
2.1. Synthesis
crown ethers (S,S)-2 and (S,S)-3 hardly influence their spectropho-
tometric properties. Bathochromic shifts (5 nm) can be seen in the
absorption spectra of 1–(S,S)-3 in dichloromethane containing 1%
methanol compared to those recorded in acetonitrile.
BODIPY linked azacrown ether chemosensor 1 was prepared
according to the literature.39 Enantiopure BODIPY linked monoaza-
18-crown-6 ether ligands (S,S)-2 and (S,S)-3 were obtained by
reacting the new chiral monoazacrown ethers (S,S)-5 and (S,S)-6
with BODIPY derivative 7 in acetonitrile in the presence of trie-
thylamine as a base adopting the procedure39 described for the
synthesis of achiral analogue 1 (Scheme 1). BODIPY derivative 7
was also prepared by following the previously reported method.39
The synthesis of enantiopure monoazacrown ethers (S,S)-5 and
(S,S)-6 was started from chiral tetraethylene glycols (S,S)-854 and
(S,S)-9,55 which were obtained as described in the literature. First, the
latter tetraethylene glycols were elongated with two ethylene glycol
units by reacting their disodium derivatives with 2-(benzyloxy)-
ethylmethanesulfonate (10)56 in THF to give chiral hexaethylene
glycol dibenzyl ethers (S,S)-11 and (S,S)-12. Benzyl protecting groups
were removed by catalytic hydrogenation in methanol to obtain
chiral hexaethylene glycols (S,S)-13 and (S,S)-14. The latter glycols
were treated with tosyl chloride in triethylamine to produce chiral
hexaethylene glycol ditosylates (S,S)-15 and (S,S)-16, which were
transformed to chiral diiodo derivatives (S,S)-17 and (S,S)-18 by
Similar trends can be observed in the fluorescence behaviour
of BODIPY linked crown ethers 1–(S,S)-3 (Table 1). They show
red-shifted (ca. 50 nm) and wider emission bands in acetonitrile
compared to the reference compound 7 (lmax¼525 nm). The
quantum yields of 1–(S,S)-3 are only two times lower than that of
7 (Ff¼0.0088). The low quantum yield values of 1–(S,S)-3 can be
attributed to an intramolecular charge transfer (ICT) process in
the excited state leading to a strong quenching of the fluores-
cence.4–7,9,36–40,44–47,50 Whereas the BODIPY derivative having
methyl substituents at position 1,3,5,7 and a phenyl group at the
meso position of the BODIPY core has a relatively large quantum
yield (Ff¼0.6 in acetonitrile),36,37 our reference compound 7 has
quite a low quantum yield value compared to the former one. On
the one hand this can be explained by the lack of the steric
hindrance of the methyl groups at position 1 and 7 in compound
7, which results in a more extended
p-system leading to fluo-
rescence reduction.34 On the other hand, it has been found that
the quantum yields tended to be reduced by electron donating
substituents at position 3 and 5 relative to unsubstituted BODI-
PYs.34,57,58 It is important to note that the measured
Scheme 1. Preparation of chiral BODIPY linked azacrown ether chemosensors (S,S)-2 and (S,S)-3 and achiral analogue 1.

´
8252
I. Mo´czar et al. / Tetrahedron 65 (2009) 8250–8258
Scheme 2. Preparation of chiral monoazacrown ethers (S,S)-5 and (S,S)-6.
Table 1
Absorption and emission data of 1–(S,S)-3 and their metal ion and NHþ4 complexes in MeCN
1
(S,S)-2
(S,S)-3
l
(abs) nm
3a
l
(em) nm
Ff
l
(abs) nm
3a
l
(em) nm
Ff
l
(abs) nm
3a
l
(em) nm
Ff
Mnþ/L
Free
Ca2þ
Pb2þ
Hg2þ
Cu2þ
Fe3þ
Agþ
529
510
507
419
475
478
529
510
512
537
531
531
505
527
2.96
3.13
3.01
2.23
1.26
0.85
2.95
2.74
2.51
3.28
3.01
2.99
3.30
2.66
571
553
546
532
534
537
570
553
557
571
571
569
542
562
0.0049
0.050
0.056
527
509
509
418
476
479
525
512
510
537
528
529
510
527
2.96
3.53
3.37
2.29
1.53
1.61
2.93
2.84
2.90
3.08
2.98
3.11
3.08
2.97
572
550
548
535
532
534
572
552
555
575
574
570
574
564
0.0049
0.051
0.053
527
508
507
416
475
478
527
509
513
537
528
531
526
526
2.95
3.34
3.30
2.59
1.40
1.36
2.98
2.95
2.69
3.28
2.97
3.13
3.13
2.97
572
550
546
541
534
538
572
551
561
574
571
568
572
565
0.0045
0.047
0.054
d
2
2
2
2
0.020
0.039
0.013
0.0029
0.0015
0.0048
0.039
0.014
0.011
0.0052
0.0055
0.036
0.0066
0.0040
0.0047
0.0099
0.013
0.0080
0.0048
0.0064
0.0062
0.0055
0.0011
0.0010
0.0045
0.015
0.010
0.010
0.0045
0.0048
0.0044
0.0047
20
20
200
200
200
200
200
200
200
Mg2þ
Zn2þ
Cd2þ
Liþ
Naþ
Kþ
NHþ4
0.0072
a
ꢁ104
M .
ꢀ1 cmꢀ1
spectrophotometric data (absorption and emission maxima as
well as fluorescence quantum yield) of achiral analogue 1 were
found to be very similar to those determined by Baruah et al.
obtained for chemosensor 1. The stability constants and stoichiom-
etries of ionophore–metal ion complexes determined by the mole-
ratio59 or Benesi–Hildebrand60–62 method are shown in Table 2.
Repeating the titration experiment with Kþ in the case of che-
mosensor 1, our result was in good agreement with that described
in the literature,39 namely the absorption and emission spectra of
ionophore 1 have been considerably changed upon addition of an
excess of Kþ. This means that chemosensor 1 forms a relatively
stable complex with Kþ. In contrast, the absorption and fluores-
cence spectra of ligand (S,S)-3 bearing isobutyl groups on its chiral
centres remained unchanged under the same experimental con-
ditions (Fig. 1). Therefore complexation with Kþ does not occur at
all in this case, which can be explained by the conformational
changes of the crown ether ring owing to the bulky isobutyl groups.
(
labs¼529 nm, lem¼565 nm, Ff¼0.006).39
2.3. Stoichiometry and stability of ionophore–metal
ion complexes
Based on the previous results of Baruah et al.39 achiral analogue 1
was proved to be Kþ selective over other alkaline ions (Liþ, Naþ, Csþ)
in acetonitrile. We extended the complexation studies in more detail
on achiral ligand 1 and compared the binding properties of chiral
analogues (S,S)-2 and (S,S)-3 towards metal ions (Liþ, Naþ, Kþ, Agþ,
Mg2þ, Ca2þ, Zn2þ, Cu2þ, Pb2þ, Cd2þ, Hg2þ, Fe3þ) and NH4þ ion to those

´
I. Mo´czar et al. / Tetrahedron 65 (2009) 8250–8258
8253
Addition of 1 equiv of Ca2þ and Pb2þ ions induced more than
10-fold fluorescence enhancement in acetonitrile. Both absorption
and emission bands were blue-shifted by about 18–26 nm (hipso-
chromic effect, Fig. 2 and Table 1). The formation of relatively stable
complexes allowed the calculation of log Ks values by the mol-ratio
method.59 (The log Ks values of other ligand–metal ion complexes
were determined from the Benesi–Hildebrand plots60–62 valid for
1:1 stoichiometry.) Unlike the expected 1:1 ligand to metal ion ra-
tio,39 the complex stoichiometries of ionophores 1–(S,S)-3 with Ca2þ
and Pb2þ were found to be 2:1. The only exception was the ligand 1–
Pb2þ complex, which has 1:1 stoichiometry (Table 2). Nevertheless,
increasing concentration of Pb2þ shifts the chemical equilibrium to
the formation of 1:1 stoichiometric complexes in the case of (S,S)-2
and (S,S)-3 as well and therefore the titration curves contain two
breaking points (not shown). Because of the unexpected stoichio-
metry of the complexes with Ca2þ, the equilibrium constants were
also determined by fitting the data using the nonlinear least-squares
regression program SPECFIT. The values of overall stability constants
Table 2
Stability constants and stoichiometries of metal ion and NHþ4 complexes of 1–(S,S)-3
in MeCNa–c
1
(S,S)-2
log Ks
(S,S)-3
log Ks
log Ks
L:Mnþ
L:Mnþ
L:Mnþ
Ca2þ
Pb2þ
Pb2þ
Hg2þ
Mg2þ
Zn2þ
Cd2þ
Kþ
12.82
7.20
d
2:1
1:1
2:1
1:1
1:1
1:1
1:1
1:1
1:1
11.07
6.68
12.30
5.95
2.34
2.05
3.05
2.03
d
2:1
1:1
2:1
1:1
1:1
1:1
1:1
1:1
d
11.92
6.32
14.61
5.82
2.08
1.58
2.14
d
2:1
1:1
2:1
1:1
1:1
1:1
1:1
d
5.84
3.18
2.86
2.28
3.17
2.79
NHþ4
d
d
a
No complexation could be observed in the case of Liþ, Naþ and Agþ. The stability
constants of complexes with Cu2þ and Fe3þ could not be calculated because of their
complicated behaviour.
b
In the case of 2:1 stoichiometric complexes, Ks denotes the overall equilibrium
constant
b
defined as [ML2]/[M][L]2.
c
In the case of Ca2þ, Pb2þ and Hg2þ, the stability constants could be determined
by the mole-ratio method and those of other ligand–metal ion complexes were
calculated from the Benesi–Hildebrand plots valid for 1:1 stoichiometry.
(log
b¼11.81–12.89) are essentially the same as the ones obtained by
the mole-ratio method. Comparing the stepwise stability constants,
the values of log Ks1:1 (2.36–3.71) are significantly smaller than those
of log Ks2:1 (9.12–10.53). Therefore on the speciation distribution
diagrams (not shown) the complexes with 1:1 stoichiometry could
not be practically observed.
A considerable blue-shift of the absorption and emission bands
with large fluorescence intensity decrease can be observed upon the
addition of Cu2þ (0–2 equiv) to ionophores 1–(S,S)-3 (Fig. 3 and
Table 1). The spectral characteristics of Cu2þ in excess cannot be
identified on the UV–vis titration series of spectra as compared to
the absorption spectrum of Cu(ClO4)2 in acetonitrile (3.5 mM
Cu(ClO4)2 in acetonitrile, A¼0.07 at 763 nm). Two breaking (equiv-
alent) points appear on the titration curves in the range of 0–2 metal
ion to ligand ratio (Fig. 3). At first glance, the fluorescence quenching
and the blue-shift of the emission spectra can be explained by the
effect of paramagnetic Cu2þ ions and the deconjugation of the
crown ether nitrogen from the BODIPY moiety, respectively. Our
attempt to determine stability constants using nonlinear regression
analysis by means of the SPECFIT program was unsuccessful. This
can be interpreted by the structural changes of the sensor molecules
upon interaction with Cu2þ. Probably at higher excess, Cu2þ may
bind to the dipyrromethene unit by displacement of the BF2 group.38
In the same experimental conditions (0–2 equiv) both absorption
and emission bands of ionophores 1–(S,S)-3 were significantly blue-
shifted [110 nm and 40 nm (lex¼488 nm), respectively] with an
increase of the emission intensities by the effect of Hg2þ (not
shown). The UV–vis and fluorescence titration experiments of
Figure 1. UV–vis titration spectra of (S,S)-3 (20 mM, 2.5 mL) on increasing addition of
0.1 M Kþ solution (0–40 mM, 0–1 mL) in MeCN.
Addition of Ca2þ, Pb2þ, Mg2þ, Zn2þ, Hg2þ, Cu2þ ions causes re-
markable changes in the absorption and emission spectra of all the
three ligands. The most significant effects appear in the case of
Ca2þ, Pb2þ, Hg2þ and Cu2þ (Figs. 2 and 3).
Figure 2. Absorption (A) and emission (B) series of spectra of (S,S)-3 (20
526 nm (A) and 552 nm (B).
m
M) on increasing addition of Ca2þ (0–2 equiv) in MeCN, lex¼488 nm. Insets: titration curves (0–8 equiv) at

´
I. Mo´czar et al. / Tetrahedron 65 (2009) 8250–8258
8254
Figure 3. Absorption (A) and emission (B) series of spectra of (S,S)-3 (20
and 527 nm (A) and 572 nm (B).
m
M) on increasing addition of Cu2þ (0–8 equiv) in MeCN, lex¼488 nm. Insets: titration curves at 480, 488
ionophores 1–(S,S)-3 with Fe3þ (0–20 equiv) afford similar series of
spectra to those with Cu2þ (not shown).
2.4. Enantiomeric recognition of ionophores
In the case of Mg2þ and Zn2þ ions, approximately 500 and 1000-
fold, respectively, higher metal ion concentration was needed to
generate similar changes in the absorption and emission spectra
than for Ca2þ or Pb2þ (Table 1). No changes of the spectrophoto-
metric properties could be observed in the case of Liþ, Naþ and Agþ.
Upon complexation with Ca2þ, Pb2þ, Mg2þ, Zn2þ and Hg2þ ions,
the maxima of both absorption and emission bands are consider-
ably blue-shifted (about 15–40 nm) and large fluorescence en-
hancement (4–12-fold) is observed with respect to the free
ionophores. These indicate that the interaction of metal ions with
the nitrogen atom of the crown ether decreases the conjugation of
Two of the three ionophores studied [(S,S)-2 and (S,S)-3] are
optically active bearing methyl and isobutyl groups on their chiral
centres, respectively. Therefore enantiomers may be theoretically
distinguished from each other by these enantiopure ligands. Thus
the complexation properties of (S,S)-2 and (S,S)-3 towards the en-
antiomers of primary aralkyl ammonium perchlorate (PEA and
NEA) salts were also examined.
No changes in both absorption and emission spectra were
detected, when the titration experiments were carried out in ace-
tonitrile. Using dichloromethane containing 1% methanol instead of
acetonitrile, however, a significant blue-shift of the absorption and
emission spectra (ca. 15–25 nm) and fluorescence enhancement
could be observed upon addition of the enantiomers of PEA and
NEA. The spectrophotometric signals reached a constant value after
addition of an excess of the enantiomers of ammonium ions. This
means that complexation between the ligands and these organic
ammonium ions takes place, but the complexes have relatively
small stability constants (Table 3).25,28 It can be suggested that the
spectrophotometric properties of the optically active ligands have
not been altered to the same extent by the enantiomers of the or-
ganic ammonium salts. However, these differences in the spectro-
photometric properties (absorption and emission maxima of
complexes, molar absorption coefficients, quantum yields and
stability constants) are not suitable for practical applications (Fig. 5
and Table 3). In our opinion, the lack of enantioselectivity or the
poor one may be attributed to the relatively high flexibility of chiral
ligands (S,S)-2 and (S,S)-3. The isobutyl groups in ligand (S,S)-3
considerably decreased the stability of complexes formed with the
enantiomers of both PEA and NEA compared to achiral analogue 1.
The methyl substituted ligand (S,S)-2 is able to discriminate be-
tween PEA and NEA in terms of stability of their complexes in-
dicating that the steric hindrance of aromatic rings in the guest
molecules also plays an important role besides the alkyl sub-
stitution of the host molecule.
the latter with the
p-system of the fluorophore and efficiently
suppresses the ICT process in the excited state. Cu2þ ions are ca-
pable of facilitating the charge transfer (ICT) mechanism thereby
resulted in quenching of fluorescence as seen in the cases of several
photoinduced electron transfer (PET) sensor molecules.4–7,9 Com-
parison of the complex stability constants of ligands 1–(S,S)-3 with
a selected metal ion shows that the stability of complexes depends
on the conformation of the ionophores changed by the alkyl groups
via decreasing the effective diameter of the crown ether ring. The
most pronounced effect can be observed in the case of Kþ and NH4þ
(Table 2). It is noteworthy to mention that the introduction of alkyl
groups in (S,S)-2 and (S,S)-3 enhances their selectivity towards Ca2þ
and Pb2þ compared to achiral ligand 1 (Fig. 4 and Table 2).
3. Conclusion
The synthesis and characterization of two new enantiopure
BODIPY linked azacrown ethers (S,S)-2 and (S,S)-3 have been ach-
ieved. The preparation of their several unreported precursors is also
performed. BODIPY linked chemosensor (S,S)-3 having isobutyl
groups on its chiral centres shows significant changes in the ab-
sorption and fluorescence spectra upon complexation with Ca2þ
and Pb2þ ions. The isobutyl groups cause improved selectivity
Figure 4. Fluorescence response of (S,S)-3 in the presence of various cations in MeCN.

´
I. Mo´czar et al. / Tetrahedron 65 (2009) 8250–8258
8255
Table 3
Stability constants of complexes of 1–(S,S)-3 with the enantiomers of aralkyl ammonium ions in CH2Cl2/MeOH (99:1, v/v)
1
(S,S)-2
(S,S)-3
UV–vis
Fluorescence
UV–vis
Fluorescence
UV–vis
Fluorescence
(S)-PEA
(R)-PEA
(S)-NEA
(R)-NEA
4.67ꢂ0.13
4.83ꢂ0.13
4.85ꢂ0.08
4.77ꢂ0.06
4.77ꢂ0.10
4.83ꢂ0.15
4.82ꢂ0.08
4.75ꢂ0.06
4.60ꢂ0.04
4.60ꢂ0.02
4.17ꢂ0.12
4.12ꢂ0.13
4.72ꢂ0.04
4.71ꢂ0.03
4.10ꢂ0.03
3.97ꢂ0.01
3.99ꢂ0.35
4.15ꢂ0.32
3.98ꢂ0.28
4.04ꢂ0.26
4.09ꢂ0.05
4.23ꢂ0.09
4.14ꢂ0.14
4.06ꢂ0.12
Figure 5. Absorption (A) and emission (B) spectra of free ligand (S,S)-3 (20
m
M) and its complexes with (R)- and (S)-PEA (200 equiv) in CH2Cl2/MeOH (99:1, v/v), lex¼488 nm.
towards the latter ions compared to achiral analogue 1 by changing
the conformation of the crown ether ring. As the presence of iso-
butyl groups in the molecule enhances its lipophilicity as well, this
ligand can be a good candidate for a sensing unit of an optode
membrane. It shows only moderate enantioselectivity towards the
UV–vis spectra were taken on a UNICAM UV4-100 spectro-
photometer controlled by VISION 3.4 software (ATI UNICAM,
Cambridge, UK). Fluorescence spectra were recorded on a Perkin–
Elmer LS 50B luminescent spectrometer supplied with a FL Win-
Lab 3.0Ô software (Perkin–Elmer Corp., USA). Both the emission
and excitation spectra were corrected by the spectrometer soft-
ware. Quartz cuvettes with path length of 1 cm were used. Fluo-
rescence quantum yields were determined relative to Rhodamine
6 G (Ff¼0.76 in water, lex¼488 nm).64 Spectrophotometric titra-
tions were carried out according to the literature.65 Titrant metal
ions in MeCN or chiral primary aralkyl ammonium ions in CH2Cl2/
MeOH (99:1, v/v) were employed for the log Ks determination of
the ionophore complexes. Perchlorate salts of ions were used in
general with the exception of KSCN, AgNO3, FeCl3 and NH4SCN. All
of metal ion salts were of analytical grade. Chiral aralkyl ammo-
nium perchlorate salts were prepared in our laboratory.28 The
enantiomers of a-phenylethylammonium perchlorate (PEA), which
may be attributed to the relatively high flexibility of chiral ligand
(S,S)-3. A more rigid system containing fluorescent signalling
moiety is expected to show a higher degree of enantiomeric rec-
ognition making suitable for practical applications.
4. Experimental
4.1. General
Infrared spectra (neat unless otherwise indicated) were recorded
on a Zeiss Specord IR 75 spectrometer. Optical rotations were taken
on a Perkin–Elmer 241 polarimeter that was calibrated by measur-
ing the optical rotations of both enantiomers of menthol. NMR
spectra were recorded in CDCl3 either on a Bruker DRX-500 Avance
spectrometer (at 500 MHz for 1H and 125.8 MHz for 13C spectra) or
on a Bruker 300 Avance spectrometer (at 300 MHz for 1H and
75.5 MHz for 13C spectra) and it is indicated in each individual case.
Mass spectra were recorded on a ZQ2000 MS instrument (Waters
Corp.) using ESI method. Elemental analyses were performed in the
Microanalytical Laboratory of the Department of Organic Chemistry,
Institute of Chemistry, L. Eo¨tvo¨s University, Budapest, Hungary.
Starting materials were purchased from Aldrich Chemical Company
unless otherwise noted. Silica gel 60 F254 (Merck) and aluminium
oxide 60 F254 neutral type E (Merck) plates were used for TLC. Silica
gel 60 (70–230 mesh, Merck) and aluminium oxide (neutral, acti-
vated, Brockman I) were used for column chromatography. Ratios of
solvents for the eluents are given in volumes (mL/mL). Romil Ltd
(Cambridge, UK) SuperPurity Solvent grade THF stored under argon
was used as purchased. All other solvents were dried and purified
according to well-established methods.63 Evaporations were car-
ried out under reduced pressure.
concentration of titrant ions was 0.001 M (Ca2þ, Pb2þ, Mg2þ, Zn2þ
,
Hg2þ, Cu2þ) or 0.01 M (Agþ, Fe3þ and chiral aralkyl ammonium
ions) or 0.1 M (Liþ, Naþ, Kþ, NH4þ, Mg2þ, Zn2þ, Cd2þ). The titrant
was added with a Hamilton syringe to a 2.5 mL ionophore con-
taining (20 mM) MeCN or CH2Cl2/MeOH (99:1, v/v) solution in
a quartz cell. If the spectrophotometric signals reached a constant
value only after addition of a considerable excess of titrant ions,
the Benesi–Hildebrand evaluation60–62 was applied for the cal-
culation of the log Ks values. For the determination of some of the
stability constants by nonlinear regression analysis, SPECFIT/32Ô
program was used.
4.2. General procedure for the synthesis of chiral BODIPY
linked monoazacrown ethers (S,S)-2 and (S,S)-3
Ligands (S,S)-2 and (S,S)-3 were synthesized according to the
procedure described in the literature39 for the achiral analogue 1
with the exception that the molar ratio of crown ethers (S,S)-5 and
(S,S)-6, respectively, to BODIPY derivative 7 was 1:1 instead of 1.5:1.
The crude products were purified as described below for each
compound.

´
I. Mo´czar et al. / Tetrahedron 65 (2009) 8250–8258
8256
4.2.1. (2S,12S)-16-{(2Z)-2-[[1-(Difluoroboryl)-5-methoxy-1H-pyrrol-
2-yl](phenyl)methylene]-2H-pyrrol-5-yl}-2,12-dimethyl-1,4,7,10,13-
pentaoxa-16-azacyclooctadecane [(S,S)-2]. The crude product was
purified by column chromatography on silica gel using 1:2 acetone/
hexane as an eluent to give (S,S)-2 (32 mg, 20%) starting from (S,S)-
5 (80 mg, 0.276 mmol), 7 (92 mg, 0.276 mmol), triethylamine
74.70, 75.60. Anal. Calcd for C14H29NO5: C, 57.71; H, 10.03; N, 4.81.
Found: C, 57.59; H, 10.14; N, 4.73.
4.3.2. (2S,12S)-2,12-Diisobutyl-1,4,7,10,13-pentaoxa-16-azacy-
clooctadecane [(S,S)-6]. Yield: 726 mg (92%). Colourless oil. Rf¼0.41
25
(alumina TLC, 1:10 EtOH/toluene); [
a
]
þ3.1 (c 2.00, EtOH); IR nmax
D
(1 mL) and MeCN (40 mL). Reddish violet oil. Rf¼0.21 (silica gel TLC,
3501, 3342, 2957, 2888, 2872, 1649, 1619, 1581, 1456, 1376, 1352,
1312, 1251, 1129, 1014, 1002, 851, 834 cmꢀ1 1H NMR (300 MHz)
0.90 (d, J¼7 Hz, 12H), 1.07–1.21 (m, 2H), 1.37–1.50 (m, 2H), 1.58–
1.78 (m, 2H), 2.62–2.91 (m, 4H), 3.01 (s, br, 1H), 3.36–3.76 (m, 18H);
13C NMR (75.5 MHz)
22.76, 23.29, 24.69, 24.82, 40.61, 49.81, 68.74,
25
1:2 acetone/hexane); [
a]
ꢀ163 (c 0.240, CH2Cl2); IR (KBr) nmax
;
D
3472, 3072, 2958, 2932, 2872, 1564, 1512, 1460, 1401, 1354, 1309,
1264, 1208, 1152, 1110, 1088, 1032, 991, 971, 882, 851, 722,
d
703 cmꢀ1
;
1H NMR (500 MHz)
d
1.10 (d, J¼6 Hz, 6H), 1.69 (s, br,
d
complexed H2O), 3.41–3.51 (m, 4H), 3.56–3.73 (m, 10H), 3.78–3.86
(m, 2H), 3.90–4.01 (m, 2H), 3.98 (s, 3H), 4.01–4.10 (m, 2H), 4.10–
4.27 (m, 2H), 5.64 (d, J¼4 Hz, 1H), 6.26 (d, J¼4 Hz, 1H), 6.34 (d,
J¼5 Hz, 1H), 6.71 (d, J¼5 Hz, 1H), 7.38–7.48 (m, 5H); 13C NMR
70.83, 71.29, 74.77. Anal. Calcd for C20H41NO5: C, 63.97; H, 11.00; N,
3.73. Found: C, 63.88; H, 11.17; N, 3.62.
4.4. General procedure for the synthesis of chiral
hexaethylene glycol dibenzyl ethers (S,S)-11 and (S,S)-12
(75.5 MHz)
d
16.83, 53.91, 58.27, 68.67, 71.01, 71.13, 75.49, 75.73,
93.31, 113.10, 120.23, 125.56, 128.12, 128.77, 130.79, 131.32, 133.32,
133.86, 135.32, 160.46, 162.15; MS: 588 (Mþ1)þ. Anal. Calcd for
C30H40BF2N3O6$H2O: C, 59.51; H, 6.99; N, 6.94. Found: C, 59.42; H,
7.03; N, 6.86.
A solution of dimethyl-substituted tetraethylene glycol (S,S)-854
(3.73 g, 16.8 mmol) or diisobutyl-substituted tetraethylene glycol
(S,S)-955 (5.15 g, 16.8 mmol) in dry THF (50 mL) was added dropwise
under Ar at rt to a well stirred suspension of NaH (2.15 g, 53.8 mmol,
60% dispersion in mineral oil) in dry THF (20 mL). After the addition
was completed, the mixture was stirred at reflux temperature for 2 h.
The reaction mixture was cooled down to ꢀ5 ꢃC and a solution of
mesylate 1056 (8.51 g, 37.0 mmol) in dry THF (80 mL) was added
dropwise, and then it was allowed to warm up to rt. Stirring was
continued atrtfor4 days. Thesolventwasremovedand the unreacted
NaH was destroyed by addition of ice (20 g) and water (10 mL) to the
residue. The mixture was stirred vigorously for 15 min. Ether (80 mL)
was added to the mixture and the phases were mixed well and sep-
arated. The aqueous phase was extracted with ether (3ꢁ40 mL). The
combined organic phase was shakenwith saturated brine (1ꢁ60 mL),
dried over MgSO4, filtered and the solvent was evaporated. The crude
products were purified as described below for each compound.
4.2.2. (2S,12S)-16-{(2Z)-2-[[1-(Difluoroboryl)-5-methoxy-1H-pyrrol-
2-yl](phenyl)methylene]-2H-pyrrol-5-yl}-2,12-diisobutyl-1,4,7,10,13-
pentaoxa-16-azacyclooctadecane [(S,S)-3]. The crude product was
purified by column chromatography on silica gel using 1:3 ace-
tone/hexane as an eluent to give (S,S)-3 (33 mg, 18%) starting
from (S,S)-6 (104 mg, 0.276 mmol), 7 (92 mg, 0.276 mmol), trie-
thylamine (1 mL) and MeCN (40 mL). Reddish violet oil. Rf¼0.43
25
(silica gel TLC, 1:2 acetone/hexane); [
a
]
ꢀ185 (c 0.275, CH2Cl2);
D
IR nmax 3585, 3137, 3058, 2955, 2928, 2870, 1574, 1505, 1466,
1402, 1359, 1312, 1268, 1233, 1159, 1112, 1091, 1023, 994, 969, 885,
847, 737, 709 cmꢀ1
;
1H NMR (500 MHz)
d
0.81 (d, J¼7 Hz, 6H),
0.82 (d, J¼7 Hz, 6H), 1.00–1.10 (m, 2H), 1.30–1.40 (m, 2H), 1.56–
1.68 (m, 2H), 1.75 (s, br, complexed H2O), 3.25–3.67 (m, 14H),
3.81–3.89 (m, 4H), 3.90 (s, 3H), 3.93–4.02 (m, 2H), 4.07–4.17 (m,
2H), 5.55 (d, J¼3 Hz, 1H), 6.17 (d, J¼3 Hz, 1H), 6.31 (d, J¼5 Hz, 1H),
6.62 (d, J¼5 Hz, 1H), 7.31–7.40 (m, 5H); 13C NMR (75.5 MHz)
4.4.1. (6S,16S)-6,16-Dimethyl-1,21-diphenyl-2,5,8,11,14,17,20-hep-
taoxahenicosane [(S,S)-11]. The crude product was purified by col-
umn chromatography on silica gel using 2:3 EtOAc/hexane as an
d
22.61, 23.45, 24.83, 40.94, 54.01, 58.23, 69.30, 71.05, 71.10, 74.87,
78.22, 93.06, 113.66, 119.79, 125.52, 128.10, 128.70, 130.81, 130.93,
133.12, 133.95, 135.42, 160.26, 162.36; MS: 672 (Mþ1)þ. Anal.
Calcd for C36H52BF2N3O6$H2O: C, 62.70; H, 7.89; N, 6.09. Found:
C, 62.62; H, 7.80; N, 5.95.
eluent to give (S,S)-11 (3.13 g, 38%) as a colourless oil. Rf¼0.35 (silica
25
gel TLC,1:1 EtOAc/hexane); [
a]
þ4.9 (c 2.01, CH2Cl2); IR nmax 3080,
D
3064, 3048, 3032, 3016, 2980, 2950, 2872, 1648, 1608, 1536, 1496,
1456, 1376, 1280, 1208, 1116, 1056, 1040, 740, 700 cmꢀ1 1H NMR
(500 MHz)
1.19 (d, J¼6 Hz, 6H), 3.41–3.57 (m, 4H), 3.61–3.78 (m,
18H), 4.60 (s, 4H), 7.25–7.41 (m, 10H); 13C NMR (125.8 MHz)
17.42,
;
d
4.3. General procedure for the synthesis of chiral
d
monoazacrown ethers (S,S)-5 and (S,S)-6
68.82, 69.98, 70.81, 70.98, 73.40, 75.26, 75.44, 127.73, 127.90,
128.53, 138.61. Anal. Calcd for C28H42O7: C, 68.55; H, 8.63. Found: C,
68.46; H, 8.71.
Hydrogenation of N-benzyl-blocked dimethyl-substituted
monoazacrown ether (S,S)-19 (801 mg, 2.1 mmol) or N-benzyl-
blocked diisobutyl-substituted monoazacrown ether (S,S)-20
(978 mg, 2.1 mmol) was carried out in MeOH (40 mL) over Pd/C
catalyst (98 mg, 10% palladium on charcoal, activated) in a similar
way as described above for dibenzyl-protected oligoethers (S,S)-13
and (S,S)-14 to give the desired monoazacrown ethers (S,S)-5 and
(S,S)-6. The crude products were either purified by column chro-
matography or used without purification as described below for
each compound.
4.4.2. (6S,16S)-6,16-Diisobutyl-1,21-diphenyl-2,5,8,11,14,17,20-hep-
taoxahenicosane [(S,S)-12]. The crude product was purified by col-
umn chromatography on silica gel using 2:5 EtOAc/hexane as an
eluent to give (S,S)-12 (4.34 g, 45%) as a colourless oil. Rf¼0.25 (silica
25
gel TLC, 2:5 EtOAc/hexane); [
a
]
ꢀ14.6 (c 2.01, CH2Cl2); IR nmax 3081,
D
3063, 3032, 3016, 2952, 2944, 2864,1496,1456,1368, 1108, 736, 696,
620, 602 cmꢀ1 1H NMR (500 MHz)
;
d
0.89 (d, J¼7 Hz, 6H), 0.91 (d,
J¼7 Hz, 6H), 1.20–1.27 (m, 2H), 1.41–1.49 (m, 2H), 1.73–1.84 (m, 2H),
3.43–3.69 (m, 20H), 3.80–3.87 (m, 2H), 4.55 (s, 4H), 7.23–7.36 (m,
4.3.1. (2S,12S)-2,12-Dimethyl-1,4,7,10,13-pentaoxa-16-azacycloocta-
decane [(S,S)-5]. The crude product was purified by column
chromatography on alumina using 1:20 EtOH/toluene as an eluent to
10H); 13C NMR (75.5 MHz)
d 22.51, 23.56, 24.65, 41.44, 69.69, 70.11,
70.81, 70.98, 73.33, 74.77, 77.75, 127.66, 127.83, 128.47, 138.65. Anal.
Calcd for C34H54O7: C, 71.05; H, 9.47. Found: C, 70.97; H, 9.61.
give (S,S)-5 (263 mg, 43%) as a colourless oil. Rf¼0.21 (alumina TLC,
25
1:10 EtOH/toluene); [
a
]
þ35.7 (c 2.01, EtOH); IR nmax 3504, 3345,
4.5. General procedure for the synthesis of chiral
hexaethylene glycols (S,S)-13 and (S,S)-14
D
3072, 2872,1648,1624,1584,1456,1376,1352,1320,1248,1128,1016,
1000, 852, 836 cmꢀ1 1H NMR (500 MHz)
1.05 (d, J¼6 Hz, 6H),
2.70–2.79 (m, 4H), 2.92 (s, br, 1H), 3.35–3.45 (m, 4H), 3.49–3.71
(m, 14H); 13C NMR (75.5 MHz)
16.34, 49.66, 68.02, 70.77, 71.19,
;
d
Dibenzyl-blocked dimethyl-substituted hexaethylene glycol (S,S)-
11 (3.68 g, 7.5 mmol) or dibenzyl-blocked diisobutyl-substituted
d

´
I. Mo´czar et al. / Tetrahedron 65 (2009) 8250–8258
8257
hexaethylene glycol (S,S)-12 (4.31 g, 7.5 mmol) was hydrogenated in
MeOH (175 mL) in the presence of Pd/C catalyst (0.86 g, 10% palla-
dium on charcoal, activated) until the theoretical volume of hydrogen
was consumed. After the reaction was completed, the catalyst was
filtered off and the solvent was evaporated to give the desired
hexaethylene glycols, which were used without purification.
2H), 1.60–1.71 (m, 2H), 2.44 (s, 6H), 3.35–3.63 (m, 14H), 3.64–3.70
(m, 2H), 3.84–3.90 (m, 2H), 4.13 (t, J¼5 Hz, 4H), 7.33 (d, J¼8 Hz, 4H),
7.79 (d, J¼8 Hz, 4H); 13C NMR (125.8 MHz)
d 21.81, 22.37, 23.51,
24.51, 41.12, 67.94, 69.90, 70.76, 70.93, 75.04, 78.02, 128.17, 129.95,
133.36, 144.85. Anal. Calcd for C34H54O11S2: C, 58.10; H, 7.74. Found:
C, 58.03; H, 7.82.
4.5.1. (4S,14S)-4,14-Dimethyl-3,6,9,12,15-pentaoxaheptadecane-1,17-
4.7. General procedure for the synthesis of chiral
diol [(S,S)-13]. Yield: 2.14 g (92%). Colourless oil. Rf¼0.33 (silica gel
hexaethylene glycol diiodo derivatives (S,S)-17 and (S,S)-18
25
TLC, 1:4 MeOH/EtOAc); [
a]
þ26.8 (c 2.00, CH2Cl2); IR nmax 3400,
D
2981, 2948, 2872, 1460, 1376, 1352, 1256, 1112, 976, 956, 916,
880 cmꢀ1; 1H NMR (500 MHz)
1.10 (d, J¼6 Hz, 6H), 3.27 (s, br, 2H),
3.41–3.48 (m, 4H), 3.51–3.58 (m, 2H), 3.60–3.74 (m, 16H); 13C NMR
(125.8 MHz) 17.05, 62.08, 70.66, 70.77, 70.81, 75.12, 75.52. Anal.
A mixture of dimethyl-substituted hexaethylene glycol ditosy-
late (S,S)-15 (1.30 g, 2.1 mmol) or diisobutyl-substituted hexa-
ethylene glycol ditosylate (S,S)-16 (1.48 g, 2.1 mmol), NaI (1.26 g,
8.4 mmol) and dry acetone (20 mL) was stirred under Ar at reflux
temperature for 16 h. The solvent was removed and the residue was
dissolved in a mixture of ether (80 mL) and water (10 mL). The
phases were mixed well and separated. The aqueous phase was
extracted with ether (3ꢁ40 mL). The combined organic phase was
shaken with saturated brine (1ꢁ60 mL), dried over MgSO4, filtered
and the solvent was removed. The crude products were purified as
described below for each compound.
d
d
Calcd for C14H30O7: C, 54.18; H, 9.74. Found: C, 54.06; H, 9.82.
4.5.2. (4S,14S)-4,14-Diisobutyl-3,6,9,12,15-pentaoxaheptadecane-
1,17-diol [(S,S)-14]. Yield: 2.78 g (94%). Colourless oil. Rf¼0.75 (silica
25
gel TLC, 1:4 MeOH/EtOAc); [
a
]
D
þ4.1 (c 2.12, CH2Cl2); IR nmax 3440,
2952, 2888, 2872, 1560, 1536, 1468, 1368, 1116, 972, 940, 908,
884 cmꢀ1 1H NMR (500 MHz)
;
d
0.92 (d, J¼7 Hz, 6H), 0.93 (d,
J¼7 Hz, 6H), 1.15–1.22 (m, 2H), 1.40–1.48 (m, 2H), 1.68–1.80 (m, 2H),
3.31 (s, br, 2H), 3.42–3.53 (m, 4H), 3.58–3.76 (m, 18H); 13C NMR
4.7.1. (4S,14S)-1,17-Diiodo-4,14-dimethyl-3,6,9,12,15-pentaox-
aheptadecane [(S,S)-17]. The crude product was purified by column
chromatography on silica gel using 1:6 acetone/hexane as an eluent
(75.5 MHz)
d 22.56, 23.50, 24.68, 41.48, 62.43, 70.65, 70.83, 72.08,
74.95, 77.75. Anal. Calcd for C20H42O7: C, 60.88; H, 10.73. Found: C,
60.74; H, 10.85.
to give (S,S)-17 (0.73 g, 66%) as a pale yellow oil. Rf¼0.51 (silica gel
25
TLC, 1:6 EtOH/toluene); [
a]
þ3.0 (c 2.00, CH2Cl2); IR nmax 2968,
D
4.6. General procedure for the synthesis of chiral
2952, 2872, 1560, 1456, 1376, 1344, 1264, 1112, 1000, 924 cmꢀ1; 1H
hexaethylene glycol ditosylates (S,S)-15 and (S,S)-16
NMR (500 MHz)
d
1.18 (d, J¼6 Hz, 6H), 3.21–3.30 (m, 4H), 3.43–3.54
(m, 4H), 3.64–3.74 (m, 10H), 3.81 (t, J¼7 Hz, 4H); 13C NMR
To stirred dimethyl-substituted hexaethylene glycol (S,S)-13
(2.95 g, 9.5 mmol) or diisobutyl-substituted hexaethylene glycol
(S,S)-14 (3.75 g, 9.5 mmol) a solution of tosyl chloride (3.98 g,
20.9 mmol) in dry triethylamine (50 mL) was added dropwise under
Ar at rt. After the addition was completed, the reaction mixture was
stirred at rt for 2 days. Excess triethylamine was evaporated, and the
residue was dissolved in a mixture of ether (100 mL) and water
(30 mL). The pH of the aqueous phase was adjusted to 2 by addition
of 5% aqueous HCl solution and the phases were mixed well and
separated. The aqueous phase was extracted with ether (3ꢁ50 mL).
The combined organic phase was shaken with saturated brine
(1ꢁ80 mL), dried over MgSO4, filtered and the solvent was removed.
The crude products were either purified bycolumn chromatography
or used without purification as described below for each compound.
(125.8 MHz) d 3.84, 17.30, 70.24, 70.63, 70.85, 75.09, 75.40. Anal.
Calcd for C14H28I2O5: C, 31.72; H, 5.32. Found: C, 31.68; H, 5.41.
4.7.2. (4S,14S)-1,17-Diiodo-4,14-diisobutyl-3,6,9,12,15-pentaox-
aheptadecane [(S,S)-18]. The crude product was purified by column
chromatography on silica gel using 1:7 acetone/hexane as an eluent
to give (S,S)-18 (1.02 g, 79%) as a pale yellow oil. Rf¼0.61 (silica gel
25
TLC, 1:6 EtOH/toluene); [
a
]
ꢀ9.3 (c 2.01, CH2Cl2); IR nmax 2952,
D
2944, 2872, 1464, 1408, 1352, 1264, 1116 cmꢀ1; 1H NMR (300 MHz)
d
0.91 (d, J¼7 Hz, 6H), 0.92 (d, J¼7 Hz, 6H), 1.15–1.28 (m, 2H), 1.38–
1.51 (m, 2H), 1.73–1.91 (m, 2H), 3.17–3.31 (m, 4H), 3.42–3.52 (m,
4H), 3.52–3.69 (m, 10H), 3.69–3.81 (m, 2H), 3.86–3.98 (m, 2H); 13C
NMR (75.5 MHz)
71.35, 75.21, 77.77. Anal. Calcd for C20H40I2O5: C, 39.10; H, 6.56.
Found: C, 39.01; H, 6.70.
d 4.23, 22.46, 23.61, 24.62, 41.41, 70.88, 71.06,
4.6.1. (4S,14S)-4,14-Dimethyl-3,6,9,12,15-pentaoxaheptadecane-1,17-
diyl bis(4-methylbenzenesulfonate) [(S,S)-15]. The crude product
was purified by column chromatography on silica gel using 1:8
4.8. General procedure for the synthesis of N-benzyl
derivatives of chiral monoazacrown ethers (S,S)-19
and (S,S)-20
acetone/toluene as an eluent to give (S,S)-15 (2.70 g, 46%) as a col-
25
ourless oil. Rf¼0.40 (silica gel TLC, 1:6 EtOH/toluene); [
a]
þ6.4 (c
D
2.03, CH2Cl2); IR nmax 3082, 3058, 3032, 2957, 2882, 2872, 1600,
A mixture of dimethyl-substituted hexaethylene glycol diiodide
(S,S)-17 (689 mg, 1.3 mmol) or diisobuyl-substituted hexaethylene
glycol diiodide (S,S)-18 (799 mg, 1.3 mmol), benzylamine (139 mg,
1.3 mmol), K2CO3 (719 mg, 5.2 mmol) and dry MeCN (15 mL) was
stirred under Ar at reflux temperature for 24 h. The solvent was
evaporated and the residue was dissolved in a mixture of CH2Cl2
(40 mL) and water (40 mL). The phases were mixed well and sep-
arated. The aqueous phase was extracted with CH2Cl2 (3ꢁ20 mL).
The combined organic phase was dried over MgSO4, filtered and the
solvent was removed. The crude products were purified as de-
scribed below for each compound.
1568, 1560, 1496, 1456, 1360, 1296, 1176, 1160, 1096, 1016, 920, 816,
776, 664, 552, 540 cmꢀ1; 1H NMR (500 MHz)
2.44 (s, 6H), 3.34–3.43 (m, 4H), 3.56–3.63 (m, 10H), 3.67–3.76 (m,
d
1.07 (d, J¼6 Hz, 6H),
4H), 4.13 (t, J¼5 Hz, 4H), 7.33 (d, J¼8 Hz, 4H), 7.79 (d, J¼8 Hz, 4H);
13C NMR (75.5 MHz)
d 17.20, 21.80, 66.98, 69.81, 70.75, 70.95, 75.48,
75.53, 128.15, 129.97, 133.33, 144.90. Anal. Calcd for C28H42O11S2: C,
54.35; H, 6.84. Found: C, 54.20; H, 6.91.
4.6.2. (4S,14S)-4,14-Diisobutyl-3,6,9,12,15-pentaoxaheptadecane-
1,17-diyl bis(4-methylbenzenesulfonate) [(S,S)-16]. Yield: 4.27 g
(64%). Pale yellow oil. Rf¼0.49 (silica gel TLC, 1:6 EtOH/toluene);
25
[
a]
ꢀ10.7 (c 2.18, CH2Cl2); IR nmax 3080, 3058, 3029, 2960, 2888,
4.8.1. (2S,12S)-16-Benzyl-2,12-dimethyl-1,4,7,10,13-pentaoxa-16-
azacyclooctadecane [(S,S)-19]. The crude product was purified by
column chromatography on alumina using 1:200 EtOH/toluene as an
eluent to give (S,S)-19 (263 mg, 53%) as a colourless oil. Rf¼0.61
D
2872, 1600, 1572, 1560, 1496, 1460, 1360, 1296, 1176, 1168, 1120,
1012, 920, 816, 772, 664, 552, 544 cmꢀ1; 1H NMR (500 MHz)
0.84
(d, J¼7 Hz, 6H), 0.86 (d, J¼7 Hz, 6H), 1.10–1.17 (m, 2H), 1.29–1.37 (m,
d

´
8258
I. Mo´czar et al. / Tetrahedron 65 (2009) 8250–8258
25
21. Costero, A. M.; Colera, M.; Gavin˜a, P.; Gil, S.; Kubinyi, M.; Pa´l, K.; Ka´llay, M.
(alumina TLC,1:20 EtOH/toluene); [
a
]
þ5.9 (c 2.03, acetone); IR nmax
D
Tetrahedron 2008, 64, 3217–3224.
3081, 3042, 3016, 2964, 2910, 2872,1624,1496,1456,1376,1296,1120,
736, 700 cmꢀ1; 1H NMR (300 MHz)
1.10 (d, J¼6 Hz, 6H), 2.66–2.90
(m, 4H), 3.37–3.56 (m, 4H), 3.60–3.80 (m,16H), 7.19–7.39 (m, 5H); 13C
NMR (75.5 MHz) 17.11, 54.13, 60.21, 67.86, 71.01, 71.05, 74.91, 75.93,
22. Liu, S.; Pestano, J. P. C.; Wolf, C. J. Org. Chem. 2008, 73, 4267–4270.
23. Chen, Z.-H.; He, Y.-B.; Hu, C.-G.; Huang, X.-H. Tetrahedron: Asymmetry 2008, 19,
2051–2057.
24. Han, F.; Chi, L.; Liang, X.; Ji, S.; Liu, S.; Zhou, F.; Wu, Y.; Han, K.; Zhao, J.; James,
T. D. J. Org. Chem. 2009, 74, 1333–1336.
25. Prodi, L.; Bolletta, F.; Montalti, M.; Zaccheroni, N.; Huszthy, P.; Samu, E.;
Vermes, B. New J. Chem. 2000, 24, 781–785.
26. Wong, W.-L.; Huang, K.-H.; Teng, P.-F.; Lee, C.-S.; Kwong, H.-L. Chem. Commun.
2004, 384–385.
27. Upadhyay, S. P.; Pissurlenkar, R. R. S.; Coutinho, E. C.; Karnik, A. V. J. Org. Chem.
2007, 72, 5709–5714.
28. Dolci, L. S.; Huszthy, P.; Samu, E.; Montalti, M.; Prodi, L.; Zaccheroni, N. Collect.
Czech. Chem. Commun. 2004, 69, 885–896.
29. Kim, K. S.; Jun, E. J.; Kim, S. K.; Choi, H. J.; Yoo, J.; Lee, C.-H.; Hyun, M. H.; Yoon, J.
Tetrahedron Lett. 2007, 48, 2481–2484.
30. Gunnlaugsson, T.; Bichell, B.; Nolan, C. Tetrahedron 2004, 60, 5799–5806.
31. BODIPYÒ is a registered trademark of Molecular Probes, Inc., Eugene, OR, USA.
32. Karolin, J.; Johansson, L. B.-A.; Strandberg, L.; Ny, T. J. Am. Chem. Soc. 1994, 116,
7801–7806.
d
d
126.80, 128.14, 128.93, 139.88. Anal. Calcd for C21H35NO5: C, 66.11; H,
9.25; N, 3.67. Found: C, 65.97; H, 9.39; N, 3.48.
4.8.2. (2S,12S)-16-Benzyl-2,12-diisobutyl-1,4,7,10,13-pentaoxa-16-
azacyclooctadecane [(S,S)-20]. The crude product was purified by
column chromatography on alumina using 1:200 EtOH/toluene as
an eluent to give (S,S)-20 (297 mg, 49%) as a colourless oil. Rf¼0.82
25
(alumina TLC, 1:20 EtOH/toluene); [
a
]
ꢀ13.9 (c 2.01, EtOH); IR
D
nmax 3084, 3046, 3016, 2960, 2907, 2872, 1648, 1564, 1496, 1456,
1368, 1112, 952, 736, 696 cmꢀ1 1H NMR (500 MHz)
;
d
0.87 (d,
J¼7 Hz, 6H), 0.89 (d, J¼7 Hz, 6H), 1.08–1.15 (m, 2H), 1.35–1.42 (m,
33. Ziessel, R.; Ulrich, G.; Harriman, A. New J. Chem. 2007, 31, 496–501.
34. Loudet, A.; Burgess, K. Chem. Rev. 2007, 107, 4891–4932.
35. Ulrich, G.; Ziessel, R.; Harriman, A. Angew. Chem., Int. Ed. 2008, 47, 1184–1201.
36. Kollmannsberger, M.; Rurack, K.; Resch-Genger, U.; Daub, J. J. Phys. Chem. A
1998, 102, 10211–10220.
2H), 1.63–1.76 (m, 2H), 2.64–2.84 (m, 4H), 3.43–3.84 (m, 20H), 7.16–
7.36 (m, 5H); 13C NMR (125.8 MHz)
d 22.51, 23.51, 24.73, 41.29,
54.40, 60.76, 68.94, 71.21, 71.30, 75.66, 77.59, 126.93, 128.26, 129.13,
139.97. Anal. Calcd for C27H47NO5: C, 69.64; H, 10.17; N, 3.01. Found:
C, 69.51; H, 10.25; N, 2.98.
37. Kollmannsberger, M.; Rurack, K.; Resch-Genger, U.; Rettig, W.; Daub, J. Chem.
Phys. Lett. 2000, 329, 363–369.
38. Rurack, K.; Kollmannsberger, M.; Resch-Genger, U.; Daub, J. J. Am. Chem. Soc.
2000, 122, 968–969.
Acknowledgements
´
39. Baruah, M.; Qin, W.; Vallee, R. A. L.; Beljonne, D.; Rohand, T.; Dehaen, W.;
Boens, N. Org. Lett. 2005, 7, 4377–4380.
Financial support of the Hungarian Scientific Research Fund
(OTKA No. K 62654, T 46403) is gratefully acknowledged. The au-
thors express their appreciation to Dr. Pe´ter Baranyai for helpful
discussions.
40. Bricks, J. L.; Kovalchuk, A.; Trieflinger, C.; Nofz, M.; Bu¨ schel, M.; Tolmachev, A. I.;
Daub, J.; Rurack, K. J. Am. Chem. Soc. 2005, 127, 13522–13529.
41. Yamada, K.; Nomura, Y.; Citterio, D.; Iwasawa, N.; Suzuki, K. J. Am. Chem. Soc.
2005, 127, 6956–6957.
42. Ka´lai, T.; Hideg, K. Tetrahedron 2006, 62, 10352–10360.
43. Coskun, A.; Akkaya, E. U. J. Am. Chem. Soc. 2006, 128, 14474–14475.
44. Rurack, K.; Trieflinger, C.; Kovalchuck, A.; Daub, J. Chem. Eur. J. 2007, 13, 8998–
9003.
References and notes
45. Yuan, M.; Li, Y.; Li, J.; Li, C.; Liu, X.; Lv, J.; Xu, J.; Liu, H.; Wang, S.; Zhu, D. Org. Lett.
2007, 9, 2313–2316.
1. Chemosensors of Ion and Molecule Recognition; Desvergne, J. P.; Czarnik, A. W.,
Eds.; NATO ASI Series C: Vol. 492, Kluwer: Dordrecht, The Netherlands, 1997.
2. Lakowicz, J. R. Principles of Fluorescence Spectroscopy, 2nd ed.; Kluwer: New
York, NY, 1999.
3. Valeur, B. Molecular Fluorescence: Principles and Applications; Wiley-VCH:
Weinheim, Germany, 2002.
46. Blakemore, J. D.; Chitta, R.; D’Souza, F. Tetrahedron Lett. 2007, 48, 1977–1982.
47. Qin, W.; Baruah, M.; Sliwa, M.; Van der Auweraer, M.; De Borggraeve, W. M.;
Beljonne, D.; Van Averbeke, B.; Boens, N. J. Phys. Chem. A 2008, 112, 6104–6114.
48. Kim, H. J.; Kim, S. H.; Kim, J. H.; Lee, E.-H.; Kim, K.-W.; Kim, J. S. Bull. Korean
Chem. Soc. 2008, 29, 1831–1834.
49. Cha, N. R.; Moon, S. Y.; Chang, S.-K. Tetrahedron Lett. 2003, 44, 8265–8268.
50. Malval, J.-P.; Leray, I.; Valeur, B. New J. Chem. 2005, 29, 1089–1094.
51. Yuan, M.; Zhou, W.; Liu, X.; Zhu, M.; Li, J.; Yin, X.; Zheng, H.; Zuo, Z.; Ouyang, C.;
Liu, H.; Li, Y.; Zhu, D. J. Org. Chem. 2008, 73, 5008–5014.
52. Csokai, V.; Ka´da´r, M.; Ha Mai, D. L.; Varga, O.; To´th, K.; Kubinyi, M.; Gru¨n, A.;
Bitter, I. Tetrahedron 2008, 64, 1058–1063.
4. de Silva, A. P.; Gunaratne, H. Q. N.; Gunnlaugsson, T.; Huxley, A. J. M.; McCoy, C.
P.; Rademacher, J. T.; Rice, T. E. Chem. Rev. 1997, 97, 1515–1566.
5. Valeur, B.; Leray, I. Coord. Chem. Rev. 2000, 205, 3–40.
6. de Silva, A. P.; McClean, G. D.; Moody, T. S.; Weir, S. M. In Handbook of Photo-
chemistry and Photobiology; Nalwa, H. S., Ed.; American Scientific: Stevenson
Ranch, CA, 2003; Vol. 3, Chapter 5.
53. Coskun, A.; Akkaya, E. U. J. Am. Chem. Soc. 2005, 127, 10464–10465.
7. Montalti, M.; Prodi, L.; Zaccheroni, N. In Handbook of Photochemistry and Pho-
tobiology; Nalwa, H. S., Ed.; American Scientific: Stevenson Ranch, CA, 2003;
Vol. 3, Chapter 6.
8. Bell, T. W.; Hext, N. M. Chem. Soc. Rev. 2004, 33, 589–598.
9. Callan, J. F.; de Silva, A. P.; Magri, D. C. Tetrahedron 2005, 61, 8551–8588.
10. Parkesh, R.; Lee, T. C.; Gunnlaugsson, T. Org. Biomol. Chem. 2007, 5, 310–317.
11. Peng, X.; Du, J.; Fan, J.; Wang, J.; Wu, Y.; Zhao, J.; Sun, S.; Xu, T. J. Am. Chem. Soc.
2007, 129, 1500–1501.
´
54. Horvath, G.; Huszthy, P. Tetrahedron: Asymmetry 1999, 10, 4573–4583.
´
}
55. Samu, E.; Huszthy, P.; Horva´th, G.; Szo¨llosy, A.; Neszme´lyi, A. Tetrahedron:
Asymmetry 1999, 10, 3615–3626.
56. Scribner, A. W.; Haroutounian, S. A.; Carlson, K. E.; Katzenellenbogen, J. A. J. Org.
Chem. 1997, 62, 1043–1057.
57. Rohand, T.; Baruah, M.; Qin, W.; Boens, N.; Dehaen, W. Chem. Commun. 2006,
266–268.
´
´ ˜
´
58. Li, L.; Nguyen, B.; Burgess, K. Bioorg. Med. Chem. Lett. 2008, 18, 3112–3116.
59. Incze´dy, J. Analytical Application of Complex Equilibra; Akade´miai Kiado´ /Ellis
Horwood Ltd. Coll House: Budapest/Chichester, 1976.
60. Benesi, H. A.; Hildebrand, J. H. J. Am. Chem. Soc. 1949, 71, 2703–2707.
61. Takeshita, M.; Shinkai, S. Chem. Lett. 1994, 23, 125–128.
12. Martınez-Manez, R.; Sancenon, F. J. Fluoresc. 2005, 15, 267–285.
13. Gunnlaugsson, T.; Ali, H. D. P.; Glynn, M.; Kruger, P. E.; Hussey, G. M.; Pfeffer, F.
M.; dos Santos, C. M. G.; Tierney, J. J. Fluoresc. 2005, 15, 287–299.
14. James, T. D. Top. Curr. Chem. 2007, 277, 107–152.
15. Gokel, G. W.; Nakano, A. In Crown Compounds: Toward Future Applications;
Cooper, S. R., Ed.; VCH: New York, NY, 1992, Chapter 1.
16. Tsukube, H.; Yamada, T.; Shinoda, S. Ind. Eng. Chem. Res. 2000, 39, 3412–3418.
17. Lehn, J.-M. Supramolecular Chemistry; VCH: Weinheim, Germany, 1995.
18. Ariga, K.; Kunitake, T. Supramolecular Chemistry-Fundamentals and Applications
(Advanced Textbook); Springer: Heidelberg, Germany, 2006.
´
´
´
62. Martın, L.; Leon, A.; Olives, A. I.; del Castillo, B.; Martın, M. A. Talanta 2003, 60,
493–503.
63. Riddick, J. A.; Bunger, W. B.; Sakano, T. K. In Techniques of Chemistry, 4th ed.;
Weissberger, A., Ed.; Wiley-Interscience: New York, NY, 1986; Vol. 2.
64. Olmsted, J. J. Phys. Chem. 1979, 83, 2581–2584.
´
´
´
´
65. Kadar, M.; Biro, A.; Toth, K.; Vermes, B.; Huszthy, P. Spectrochim. Acta, Part A
2005, 62, 1032–1038.
19. Pu, L. Chem. Rev. 2004, 104, 1687–1716.
20. Liang, X.; James, T. D.; Zhao, J. Tetrahedron 2008, 64, 1309–1315.