Synthesis and Enantiomeric Recognition Studies of Optically Active Pyridino-Crown Ethers Containing an Anthracene Fluorophore Unit

Article abstract of DOI:10.1002/chir.22614

Novel enantiopure pyridino-18-crown-6 ether-based sensor molecules containing an anthracene fluorophore unit were synthesized. Their enantiomeric recognition abilities toward the enantiomers of 1-phenylethylamine hydrogen perchlorate (PhEt), 1-(1-naphthyl

Full text of DOI:10.1002/chir.22614

CHIRALITY 28:562–568 (2016)
Synthesis and Enantiomeric Recognition Studies of Optically Active
Pyridino-Crown Ethers Containing an Anthracene Fluorophore Unit
1
BALÁZS SZEMENYEI,1 ILDIKÓ MÓCZÁR,1 DÁVID PÁL,1 IVETT KOCSIS,1 PÉTER BARANYAI2 AND PÉTER HUSZTHY
*
1Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, Budapest, Hungary
2“Lendület” Supramolecular Chemistry Research Group, Institute of Organic Chemistry, Research Centre of Natural Sciences, Hungarian Academy of
Sciences, Budapest, Hungary
ABSTRACT
Novel enantiopure pyridino-18-crown-6 ether-based sensor molecules containing
an anthracene fluorophore unit were synthesized. Their enantiomeric recognition abilities toward
the enantiomers of 1-phenylethylamine hydrogen perchlorate (PhEt), 1-(1-naphthyl)ethylamine
hydrogen perchlorate (NapEt), phenylglycine methyl ester hydrogen perchlorate (PhgOMe),
and phenylalanine methyl ester hydrogen perchlorate (PheOMe) were examined in acetonitrile
using fluorescence spectroscopy. The sensor molecules showed appreciable enantiomeric recog-
nition toward the enantiomers of NapEt, PhEt, and PhgOMe. The highest enantioselectivity was
found in the case of crown ether containing isobutyl groups in the macroring and the enantiomers
of NapEt. Chirality 28:562–568, 2016. © 2016 Wiley Periodicals, Inc.
KEY WORDS: fluorescent sensor molecule; chiral crown ether; complexation; enantioselectivity;
anthracene
Enantiomeric recognition is an important and vital phenom-
enon in Nature. A great number of biologically relevant mole-
cules are chiral, and many biological processes are based on
enantioselective reactions such as the metabolism of amino
acids and sugars in biosynthetic pathways. Since the individ-
ual enantiomers of a biologically active compound may have
different physiological properties, the determination of the
enantiomeric composition of chiral organic compounds has
great importance in drug discovery, the food industry, and
pesticide chemistry.
Considering these results, we designed and synthesized
novel enantiopure pyridino-18-crown-6 ethers [(S,S)-1 and
(S,S)-2] having methyl and isobutyl groups at their stereo-
genic centers, respectively, and an anthracene moiety at posi-
tion 4 of the pyridine ring to provide an extended aromatic
system and also to act as a fluorophore signaling unit. Studies
on the enantiomeric recognition abilities of these fluorescent
sensor molecules toward the enantiomers of protonated chi-
ral primary amines and amino acid esters were performed in
acetonitrile using fluorescence spectroscopy.
The enantioselective sensing based on fluorescence is
attractive due to the selectivity, sensitivity and versatility of
fluorescence spectroscopy.1 In the past three decades many
efforts have been made on the development of chiral fluores-
cent chemosensors.2–11 Among them, chiral crown ethers
containing different fluorophore units have also been synthe-
sized, and their enantiomeric discrimination abilities toward
the enantiomers of various optically active primary ammo-
nium salts such as protonated primary amines, amino acid
esters, and amino alcohols were investigated.12–22
Enantiopure pyridino-18-crown-6 ethers, among them the
ones containing methyl or isobutyl groups at their stereogenic
centers, are effective ligands for enantiomeric recognition.23–32
Their abilities to differentiate the enantiomers of protonated
chiral primary amines, amino acid esters, and amino alcohols
were extensively studied in several solvents and solvent mix-
tures by titration calorimetry and nuclear magnetic resonance
(NMR) spectroscopy,23–28 solvent extraction,29 circular dichro-
ism (CD) spectroscopy,30,31 and molecular modeling.23,24,32
Furthermore, tailored enantiopure pyridino-18-crown-6 ethers
were attached to ordinary and high-performance liquid chroma-
tography (HPLC)-quality silica gels by covalent bonds, and
these chiral stationary phases separated the enantiomers of
protonated chiral primary amines, amino acids, and their deriv-
atives at atmospheric33–36 and high37–39 pressure. It was
observed in our research group that the presence of an aromatic
(phenyl) group at position 4 of the pyridine ring enhanced signif-
icantly the enantiomeric separation ability of such chiral
pyridino-crown ether-based stationary phases.39
MATERIALS AND METHODS
General
Starting materials were purchased from Sigma–Aldrich (St. Louis, MO)
unless otherwise noted. Aluminum oxide 60 F254 neutral type E (Merck,
Darmstadt, Germany) plates were used for thin-layer chromatography
(TLC). Aluminum oxide (neutral, activated, Brockman I) was used for
column chromatography. Ratios of solvents for the eluents are given in volumes
(mL/mL). Solvents were dried and purified according to well-established
methods.40 Evaporations were carried out under reduced pressure.
Optical rotations were taken on a Perkin–Elmer (Boston, MA) 241 po-
larimeter that was calibrated by measuring the optical rotations of both
enantiomers of menthol. IR spectra were recorded on a Bruker (Billerica,
MA) Alpha-T Fourier transform infrared (FT-IR) spectrometer. 1H
(500 MHz) and 13C (125 MHz) NMR spectra were obtained on a Bruker
DRX-500 Avance spectrometer. 1H (300 MHz) and 13C (75.5 MHz) NMR
spectra were taken on a Bruker 300 Avance spectrometer. Mass spectra
were recorded on an Agilent-6120 (Palo Alto, CA) Single Quadrupole liq-
uid chromatography / mass spectroscopy (LC/MS) instrument using the
electrospray ionization (ESI) method. Elemental analyses were per-
formed at the Microanalytical Laboratory of the Department of Organic
Chemistry, Institute for Chemistry, L. Eötvös University, Budapest,
Hungary.
*Correspondence to: Péter Huszthy, Department of Organic Chemistry and
Technology, Budapest University of Technology and Economics, PO Box
91, H-1521 Budapest, Hungary. E-mail: huszthy@mail.bme.hu
Received for publication 16 February 2016; Accepted 25 May 2016
DOI: 10.1002/chir.22614
Published online in Wiley Online Library
(wileyonlinelibrary.com).
© 2016 Wiley Periodicals, Inc.

ENANTIOPURE PYRIDINO-18-CROWN-6 ETHER-BASED FLUORESCENT SENSOR MOLECULES
563
UV–vis spectra were taken on a Unicam (Cambridge, UK) UV4–100
spectrophotometer. Quartz cuvettes with path length of 1 cm were used.
Fluorescence emission spectra were recorded on a Perkin–Elmer LS 50B
luminescent spectrometer and were corrected by the spectrometer soft-
ware. Quartz cuvettes with path length of 1 cm were used. Fluorescence
quantum yields were determined relative to quinine sulfate (Φf = 0.53 in
0.1 M H2SO4).1 Enantiomers of PhEt, NapEt, PhgOMe, and PheOMe
were prepared in our laboratory.35 The concentrations of sensor
molecules (S,S)-1 and (S,S)-2 were 20 μM during the titrations. In order
to determine the stability constants of complexes by global nonlinear
regression analysis, the SPECFIT/32 software was used.
suspension. The reaction mixture was stirred at 0 °C for 10 min, at RT for
30 min, and refluxed for 3 h. The mixture was cooled to ꢁ60 °C and a solu-
tion of ditosylate 341 (1.81 g, 3.26 mmol) in THF (11 mL) was added, and
the reaction mixture was stirred at ꢁ60 °C for 30 min then at RT for 4 days.
The solvent was evaporated and the residue was triturated with ice-water
(20 mL). The mixture was washed into a separating funnel with ether
(60 mL). The phases were mixed well and separated. The aqueous phase
was extracted with ether (3 × 30 mL). The combined organic phase was
dried over MgSO4, filtered, and the solvent was removed. The residue
was purified by column chromatography on alumina using EtOH–toluene
1:160 mixture as an eluent to give (S,S)-7 (350 mg, 21%) as a colorless oil.
30
Rf: 0.44 (alumina TLC, EtOH–toluene 1:90); ½αꢀD = ꢁ8.2 (c = 1.0 in
EtOH); IR (neat): νmax 3082, 3065, 3033, 2952, 2922, 2867, 1596, 1576,
Preparation of Crown Ethers (S,S)-1, (S,S)-2, (S,S)-7, (S,S)-
9, (S,S)-11, and (S,S)-13
1453, 1384, 1349, 1321, 1245, 1149, 1112, 1044, 991, 952, 921, 866, 846,
736, 696 cmꢁ1; H NMR (500 MHz, CDCl3): δ 0.89 (d, J = 7 Hz, 6H, iBu-
1
General procedure for the synthesis of sensor molecules (S,S)-1
CH3), 0.93 (d, J = 7 Hz, 6H, iBu-CH3), 1.16–1.24 (m, 2H, iBu-CH2), 1.47–1.55
(m, 2H, iBu-CH2), 1.72–1.84 (m, 2H, iBu-CH), 3.43–3.63 (m, 12H, OCH2),
3.66–3.74 (m, 2H, OCH), δA 4.76 and δB 4.80 (AB q, JAB = 13 Hz, 4H, ben-
zylic type CH2), 5.10–5.16 (m, 2H, benzylic type CH2), 6.91 (s, 2H, Py-H),
7.31–7.44 (m, 5H, Ar-H); 13C NMR (125 MHz, CDCl3): δ 22.51, 23.56,
24.81, 41.22, 69.93, 70.76, 71.02, 72.34, 75.29, 76.20, 107.20, 127.72, 128.45,
128.87, 136.14, 160.45, 166.16; MS: calcd. For C30H45NO6, 515.3; found
[M + H]+, 516.3. Anal. calcd. For C30H45NO6: C 69.87, H 8.80, N 2.72;
found: C 69.85, H 8.95, N 2.71.
(4S,14S)-4,14-Diisobutyl-3,6,9,12,15-pentaoxa-21-azabicyclo[15.3.1]heneicosa-
17,20-diene-19(21H)-one [(S,S)-9]. (Benzyloxy)pyridino-crown ether
(S,S)-7 (700 mg, 1.36 mmol) was hydrogenated in EtOH (35 mL) in
the presence of Pd/C catalyst (105 mg, 10% palladium on charcoal, ac-
tivated). After the reaction was completed, the catalyst was filtered off
and the solvent was evaporated to give (S,S)-9 (550 mg, 95%) as a pale
yellow oil which was used without purification. Macrocycle (S,S)-9
prepared this way was identical in every aspect to that reported in
the literature.37
and (S,S)-2.
A
mixture of iodopyridino-crown ether (S,S)-1239
(114 mg, 0.252 mmol) or (S,S)-13 (135 mg, 0.252 mmol), anthracen-9-
ylboronic acid (62 mg, 0.277 mmol), Pd(PPh3)4 (7.3 mg, 0.0063 mmol),
powdered K3PO4 (80 mg, 0.378 mmol), and KBr (33 mg, 0.277 mmol)
in dioxane–water 6:1 (4 mL) was stirred at 85 °C under Ar for a day.
The solvent was evaporated, and the residue was dissolved in a mixture
of CH2Cl2 (8 mL) and water (4 mL). The phases were mixed well and sep-
arated. The aqueous phase was extracted with CH2Cl2 (3 × 4 mL). The
combined organic phase was dried over MgSO4, filtered, and the solvent
was removed. The crude products were purified as described below for
each compound.
(4S,14S)-19-(Anthracen-9-yl)-4,14-dimethyl-3,6,9,12,15-pentaoxa-21-azabicyclo
[15.3.1]heneicosa-1(21),17,19-triene [(S,S)-1]. The crude product was purified
by column chromatography on alumina using first DME–hexane 1:4 then
DME–toluene 1:10 mixtures as eluents to give (S,S)-1 (48 mg, 38%) as a yel-
20
low oil. Rf: 0.27 (alumina TLC, DME–toluene 1:10); ½αꢀD = +25.2 (c = 1.0 in ac-
etone); IR (neat): νmax 3546 (br, complexed H2O), 3079, 3049, 3028, 2969,
2866, 1601, 1554, 1444, 1378, 1363, 1347, 1334, 1271, 1106, 1016, 977, 931,
887, 863, 842, 793, 738, 681, 669, 653, 633, 615, 555, 450, 437 cmꢁ1; 1H NMR
(500 MHz, CDCl3): δ 1.14 (d, J = 7 Hz, 6H, Me), 2.18 (br s, 1H, complexed
H2O), 3.35–3.77 (m, 12H, OCH2), 3.85–3.96 (m, 2H, OCH), δA 4.97 and δB
4.99 (AB q, JAB = 14 Hz, 4H, benzylic type CH2), 7.36–7.42 (m, 2H, Ar-H),
7.39 (s, 2H, Py-H), 7.46–7.51 (m, 2H, Ar-H), 7.61 (d, J = 9 Hz, 2H, Ar-H),
8.07 (d, J = 9 Hz, 2H, Ar-H), 8.54 (s, 1H, Ar-H); 13C NMR (75.5 MHz, CDCl3):
δ 17.23, 71.00, 71.19, 72.21, 74.28, 76.46, 123.09, 125.47, 126.08, 126.45, 127.52,
128.66, 129.66, 131.43, 134.51, 148.29, 159.12; MS: calcd. For C31H35NO5,
501.3; found [M + H]+, 502.3. Anal. calcd. For C31H35NO5·0.5 H2O: C 72.92,
H 7.11, N 2.74; found: C 72.69, H 7.20, N 2.58.
(4S,14S)-4,14-Diisobutyl-3,6,9,12,15-pentaoxa-21-azabicyclo[15.3.1]heneicosa-
1(21),17,19-triene-19-yl trifluoromethanesulfonate [(S,S)-11]. To a mixture of
pyridino-crown ether (S,S)-9 (550 mg, 1.29 mmol) and Et3N (262 mg,
0.36 mL, 2.58 mmol) in CH2Cl2 (7 mL) a solution of Tf2O (728 mg, 0.43 mL,
2.58 mmol) in CH2Cl2 (2 mL) was added dropwise under Ar at 0 °C. The reac-
tion mixture was allowed to warm to RT and stirred for 1 h. The reaction mix-
ture was poured into ice-water (20 mL) and the pH of the mixture was adjusted
to 10 with 25% aqueous NMe4OH. The mixture was washed into a separating
funnel with CH2Cl2 (40 mL). The phases were mixed well and separated.
The aqueous phase was extracted with CH2Cl2 (3 × 20 mL). The combined or-
ganic phase was dried over MgSO4, filtered, and the solvent was removed. The
dark purple colored residue was purified by column chromatography on alu-
mina using EtOH–toluene 1:100 mixture as an eluent to give (S,S)-11
(460 mg, 64%) as a pale brown oil.
(4S,14S)-19-(Anthracen-9-yl)-4,14-diisobutyl-3,6,9,12,15-pentaoxa-
21-azabicyclo[15.3.1]heneicosa-1(21),17,19-triene [(S,S)-2]. The crude
product was purified by column chromatography on alumina using first
DME–hexane 1:20 then DME–toluene 1:30 mixtures as eluents to give
(S,S)-2 (77 mg, 52%) as a yellow oil. Rf: 0.29 (alumina TLC, DME–toluene
25
Rf: 0.78 (alumina TLC, EtOH–toluene 1:30); ½αꢀD = ꢁ16.4 (c = 1.0 in
CH2Cl2); IR (neat): νmax 3086, 3069, 3037, 2956, 2925, 2870, 1956, 1581,
1:30); ½αꢀ2D5 = ꢁ13.1 (c = 1.0 in acetone); IR (neat): νmax 3326 (br, complexed
H2O), 3083, 3060, 3032, 2953, 2918, 2867, 1601, 1566, 1457, 1420, 1385, 1366,
1350, 1316, 1263, 1110, 1042, 930, 884, 871, 844, 818, 791, 777, 758, 736, 722,
685, 630, 615, 556 cmꢁ1; 1H NMR (500 MHz, CDCl3): δ 0.81 (d, J = 7 Hz, 6H,
iBu-CH3), 0.82 (d, J = 7 Hz, 6H, iBu-CH3), 1.17–1.24 (m, 2H, iBu-CH2),
1.37–1.45 (m, 2H, iBu-CH2), 1.68–1.78 (m, 2H, iBu-CH), 2.83 (br s, 1H, com-
plexed H2O), 3.35–3.65 (m, 12H, OCH2), 3.79–3.85 (m, 2H, OCH), δA 4.90
and δB 5.01 (AB q, JAB = 13 Hz, 4H, benzylic type CH2), 7.41–7.45 (m, 2H,
Ar-H), 7.43 (s, 2H, Py-H), 7.51–7.55 (m, 2H, Ar-H), 7.63 (dd, J = 9 Hz,
J = 1 Hz, 2H, Ar-H), 8.15 (d, J = 9 Hz, 2H, Ar-H), 8.68 (s, 1H, Ar-H); 13C
NMR (125 MHz, CDCl3): δ 22.67, 23.85, 25.36, 42.26, 71.41, 71.62, 73.17,
75.80, 76.44, 123.67, 126.35, 126.91, 126.98, 128.35, 129.54, 130.36, 132.39,
135.38, 148.84, 160.18; MS: calcd. For C37H47NO5, 585.3; found [M + H]+,
586.3. Anal. calcd. For C37H47NO5·0.5 H2O: C 74.72, H 8.13, N 2.35; found:
C 74.54, H 8.03, N 2.22.
1468, 1426, 1387, 1368, 1350, 1296, 1243, 1211, 1139, 1118, 1044, 965, 874,
819, 765, 605, 572, 516 cmꢁ1 1H NMR (300 MHz, CDCl3): δ 0.90 (d,
;
J = 6 Hz, 6H, iBu-CH3), 0.92 (d, J = 6 Hz, 6H, iBu-CH3), 1.10–1.30 (m, 2H,
iBu-CH2), 1.44–1.58 (m, 2H, iBu-CH2), 1.66–1.86 (m, 2H, iBu-CH),
3.38–3.63 (m, 12H, OCH2), 3.66–3.78 (m, 2H, OCH), δA 4.85 and δB 4.89
(AB q, JAB = 14 Hz, 4H, benzylic type CH2), 7.20 (s, 2H, Py-H); 13C NMR
(75.5 MHz, CDCl3): δ 22.46, 23.41, 24.85, 40.96, 70.77, 71.20, 71.83, 75.68,
76.91, 112.10, 118.79 (q, J = 321 Hz, CF3), 157.43, 163.12; MS: calcd. For
C24H38F3NO8S, 557.2; found [M + H]+, 558.2. Anal. calcd. For C24H38F3NO8S:
C 51.69, H 6.87, N 2.51, S 5.75; found: C 51.50, H 7.01, N 2.39, S 5.61.
(4S,14S)-19-Iodo-4,14-diisobutyl-3,6,9,12,15-pentaoxa-21-azabicyclo[15.3.1]
heneicosa-1(21),17,19-triene [(S,S)-13]. To a solution of triflate (S,S)-11
(460 mg, 0.825 mmol) in toluene (9 mL) was first added NaI (619 mg,
4.13 mmol) followed by concentrated H2SO4 (105 mg, 58 μL, 1.07 mmol),
and the resulting mixture was stirred under Ar at RT for 5 h. The solvent
was evaporated, the residue was triturated with water (12 mL), and the pH
of the mixture was adjusted to 10 with 1 M NaOH. The mixture was washed
into a separating funnel with CH2Cl2 (24 mL). The phases were mixed well
and separated. The aqueous phase was extracted with CH2Cl2 (3 × 12 mL).
The combined organic phase was washed with 5% aqueous Na2S2O3
(4S,14S)-19-Benzyloxy-4,14-diisobutyl-3,6,9,12,15-pentaoxa-21-azabicyclo
[15.3.1]heneicosa-1(21),17,19-triene [(S,S)-7].
A suspension of NaH
(417 mg, 10.4 mmol, 60% dispersion in mineral oil) in pure and dry THF
(6 mL) was stirred under Ar at 0 °C. A solution of tetraethylene glycol
(S,S)-528 (1.00 g, 3.26 mmol) in THF (14 mL) was added dropwise to the
Chirality DOI 10.1002/chir

564
SZEMENYEI ET AL.
(30 mL), 1 M NaOH (30 mL), and water (3 × 30 mL). The organic phase was
dried over MgSO4, filtered, and the solvent was removed. The residue was
purified by column chromatography on alumina using EtOH–toluene 1:300
mixture as an eluent to give (S,S)-13 (221 mg, 50%) as a pale brown oil.
furnished pyridono-crown ether (S,S)-9. Another route for
the preparation of pyridono-crown ether (S,S)-9 starting from
its THP protected form (which was isolated as a crude prod-
uct) has already been reported in the literature.37 Pyridono-
crown ether (S,S)-9 was converted to triflate (S,S)-11 by
reacting the former with trifluoromethanesulfonic anhydride
in dichloromethane using triethylamine as a base. Triflate
(S,S)-11 was reacted with sodium iodide in toluene in the
presence of sulfuric acid to yield iodopyridino-crown ether
(S,S)-13. Its methyl analog (S,S)-12 was synthesized accord-
ing to the literature procedure,39 which uses sodium iodide
and 30% aqueous hydrochloric acid in acetonitrile. The
change of 30% aqueous hydrochloric acid to sulfuric acid in
the case of iodo derivative (S,S)-13 was made to eliminate
the nucleophile water from the reaction mixture, which can
provide a better yield.43
Sensor molecules (S,S)-1 and (S,S)-2 were prepared from
iodopyridino-crown ethers (S,S)-12 and (S,S)-13, which
were reacted with anthracen-9-ylboronic acid in Suzuki–
Miyaura cross-coupling reactions (Scheme 1). First, we used
dioxane as a solvent for the synthesis of ligand (S,S)-1 ac-
cording to an analogous procedure39 described for the reac-
tion of iodo derivative (S,S)-12 and 4-(methoxycarbonyl)
phenylboronic acid, but in our case the total consumption of
iodo derivative (S,S)-12 could not be achieved according to
the TLC analysis. It is known that the yields of Suzuki–
Miyaura reactions carried out with sterically hindered bo-
ronic acids can be improved by adding water as a cosolvent
25
Rf: 0.52 (alumina TLC, EtOH–toluene 1:40); ½αꢀD = ꢁ26.8 (c = 1.0 in
CH2Cl2); IR (neat): νmax 3083, 3066, 3034, 2953, 2921, 2867, 1560, 1446,
1385, 1366, 1350, 1332, 1263, 1114, 1042, 943, 863, 804, 747, 659, 637,
514 cmꢁ1; 1H NMR (300 MHz, CDCl3): δ 0.91 (d, J = 7 Hz, 6H, iBu-CH3),
0.93 (d, J = 7 Hz, 6H, iBu-CH3), 1.11–1.28 (m, 2H, iBu-CH2), 1.45–1.58
(m, 2H, iBu-CH2), 1.69–1.89 (m, 2H, iBu-CH), 3.36–3.63 (m, 12H,
OCH2), 3.63–3.77 (m, 2H, OCH), δA 4.76 and δB 4.79 (AB q, JAB = 14 Hz,
4H, benzylic type CH2), 7.66 (s, 2H, Py-H); 13C NMR (75.5 MHz, CDCl3):
δ 22.49, 23.54, 24.83, 41.17, 70.82, 71.14, 71.91, 75.54, 76.59, 106.56, 129.51,
159.79; MS: calcd. For C23H38INO5, 535.2; found [M + H]+, 536.2. Anal.
calcd. For C23H38INO5: C 51.59, H 7.15, N 2.62; found: C 51.65, H 7.17,
N 2.59.
RESULTS AND DISCUSSION
Synthesis
The synthesis of pyridino-crown ethers (S,S)-7, (S,S)-9,37
(S,S)-11, and (S,S)-13 containing isobutyl groups at the ste-
reogenic centers of their macrorings was carried out in a sim-
ilar way as published for their methyl analogs (S,S)-6,42 (S,S)-
8,42 (S,S)-1039 and (S,S)-1239 (Scheme 1).
(Benzyloxy)pyridino-crown ether (S,S)-7 was prepared by
a macrocyclization reaction starting from ditosylate 341 and
optically active tetraethylene glycol (S,S)-528 in THF using so-
dium hydride as a strong base. The removal of the benzyl
protecting group by catalytic hydrogenation in ethanol
Scheme 1. Synthesis of sensor molecules (S,S)-1 and (S,S)-2.
Chirality DOI 10.1002/chir

ENANTIOPURE PYRIDINO-18-CROWN-6 ETHER-BASED FLUORESCENT SENSOR MOLECULES
565
to the reaction mixture.44 In our case the change of dioxane to
a dioxane–water 6:1 mixture resulted in the total conversion
of iodopyridino-crown ether (S,S)-12 and the formation of
only one main product according to the TLC analysis, thus we
carried out the synthesis of both sensor molecules [(S,S)-1
and (S,S)-2] applying the latter solvent mixture.
with NapEt, which contains a more extended aromatic system
relative to a phenyl group, and smaller degrees of enantio-
meric recognition were observed in the cases of PhEt and
PhgOMe containing a phenyl group at their stereogenic cen-
ters. The presence of a methoxycarbonyl group in PhgOMe
had an adverse effect on the enantiomeric recognition relative
to the methyl group in PhEt. The enantioselectivity prefer-
ences in these cases [(R)-enantiomer for NapEt and PhEt,
and (S)-enantiomer for PhgOMe] are the same considering
the spatial arrangements of the amino group, the aromatic
moiety (naphthyl or phenyl), and the third group (methyl or
methoxycarbonyl), which are similar in (R)-NapEt, (R)-PhEt,
and (S)-PhgOMe. In the case of PheOMe containing a phenyl
group attached by a methylene spacer to its stereogenic cen-
ter, none of the sensor molecules showed enantiomeric
discrimination.
Enantiomeric Recognition Studies
The enantiomeric recognition abilities of pyridino-crown
ethers (S,S)-1 and (S,S)-2 toward the enantiomers of 1-
phenylethylamine hydrogen perchlorate (PhEt), 1-(1-naphthyl)
ethylamine hydrogen perchlorate (NapEt), phenylglycine
methyl ester hydrogen perchlorate (PhgOMe), and phenylala-
nine methyl ester hydrogen perchlorate (PheOMe) (Fig. 1)
were studied in acetonitrile by UV–vis and fluorescence
spectroscopies.
The largest degree of enantiomeric recognition was experi-
enced in the case of pyridino-crown ether (S,S)-2 and NapEt
(Table 1, Fig. 3). This can be explained by the presence of
the extended aromatic system in the chiral ammonium salt
and the bulky isobutyl groups at the stereogenic centers of
the macrocycle. It seems to be that a stronger π–π interaction
in the complex is needed for the bulkiness of the substituents
in the macroring to play an important role in enantiomeric
discrimination.
The absorption spectra of crown ethers (S,S)-1 and (S,S)-2
showed no (in the cases of the enantiomers of PhEt and
NapEt) or small (in the cases of the enantiomers of PhgOMe
and PheOMe) spectral changes upon addition of the various
optically active primary ammonium salts (Fig. 2).
However, the addition of these protonated aralkyl amines
and amino acid esters to sensor molecules (S,S)-1 and
(S,S)-2 having fluorescence quantum yields of 0.60 and 0.58,
respectively in acetonitrile, caused significant fluorescence
quenching with 93.5–99.4% decreases of emission intensities
during the titrations (Fig. 3A–C). All the fluorescence spectral
changes were evaluated using global nonlinear regression
analysis. The titration series of spectra could be fitted satisfac-
torily by assuming 1:1 complex formation, and the stability
constants were calculated (Table 1).
Based on these results, it can be seen that the stabilities of
complexes are lower in the case of crown ether (S,S)-2 be-
cause of the steric effect of the bulky isobutyl groups attached
to the macroring. However, the trends for the enantiomeric
recognition abilities of macrocycles (S,S)-1 and (S,S)-2 are
similar. Namely, the highest enantioselectivities were found
Since the complexation with the chiral ammonium salts has
a fluorescence quenching effect, the Stern–Volmer equation
(Eq. 1)1 can be applied for the titration processes (Fig. 3D).
I0=I ¼ 1 þ KSV ½Qꢀ
(1)
where I0 and I are the fluorescence intensities of the sensor
molecule in the absence and the presence of a quencher (which
is a chiral ammonium salt in our case), respectively, [Q] is the
concentration of the quencher, and KSV is the Stern–Volmer
constant. In the case of the highest enantioselectivity observed
[(S,S)-2 and NapEt] we recorded the fluorescence intensity
versus the enantiomeric composition of added chiral salt.
Fig. 1. Optically active primary ammonium salts used in the enantiomeric recognition studies.
Fig. 2. Series of absorption spectra upon titration of (S,S)-2 (20 μM) with (R)-PhEt (0, 0.5, 1, 2, 10, 20 equiv.) (A) and (S,S)-1 (20 μM) with (S)-PhgOMe (0, 0.5, 1,
2, 10, 20 equiv.) (B) in MeCN.
Chirality DOI 10.1002/chir

566
SZEMENYEI ET AL.
Fig. 3. Series of fluorescence emission spectra upon titration of (S,S)-2 (20 μM) with (R)-NapEt (A) and (S)-NapEt (B) (0, 0.2, 0.4, 0.8, 1.4, 2.2, 4, 8, 20, 120
equiv.) in MeCN, λex = 337 nm. Titration curves (0–20 equiv., solid lines: fitted curves) (C) and Stern–Volmer plots (0–4 equiv., 0–80 μM) (D) at 410 nm for the
titrations with (R)-NapEt and (S)-NapEt.
I0=I ¼ 1 þ KSV
;
½ðRÞ-NapEtꢀ
TABLE 1. Stability constants for complexes of (S,S)-1 and (S,S)-2
with the enantiomers of optically active primary ammonium salts
and the degrees of enantiomeric recognition in MeCN
ðRÞ
þKSV
;
½ðSÞ-NapEtꢀ ¼
ðRÞ
ðSÞ
h
ꢀ
ꢁ
i
¼ 1 þ KSV þ KSV
;
– KSV
x
½NapEtꢀ
(2)
ðSÞ
ðSÞ
ðRÞ
(S,S)-1
log K
(S,S)-2
log K
where [NapEt] is the sum of concentrations of (R)- and (S)-
Δ log K
Δ log K
NapEt, x(S) is the molar fraction of (S)-NapEt, KSV (R)
,
and
KSV (S) are the Stern–Volmer constants for the quenching pro-
,
(R)-PhEt
(S)-PhEt
5.29 0.02
5.03 0.02
5.55 0.03
5.17 0.03
5.38 0.04
5.56 0.04
5.09 0.04
5.05 0.03
0.26
4.60 0.02
4.34 0.02
5.08 0.02
4.48 0.02
5.02 0.04
5.19 0.03
4.66 0.04
4.61 0.04
0.26
cesses with (R)- and (S)-NapEt, respectively. Since the NapEt
concentration was kept constant (4 equiv.) during the experi-
ment, I0/I varied linearly with x(S) giving a calibration curve
(Fig. 4), which can provide an opportunity45–49 for the deter-
mination of the enantiomeric composition of NapEt.
(R)-NapEt
(S)-NapEt
(R)-PhgOMe
(S)-PhgOMe
(R)-PheOMe
(S)-PheOMe
0.38
ꢁ0.18
0.04
0.60
ꢁ0.17
0.05
CONCLUSION
Novel enantiopure pyridino-crown ether-based fluorescent
sensor molecules [(S,S)-1 and (S,S)-2] containing an anthra-
cene unit were synthesized, and their enantiomeric recogni-
tion abilities toward various primary ammonium salts in
acetonitrile were investigated by fluorescence spectroscopy.
The sensor molecules showed a remarkable “turn-off” fluo-
rescence response upon addition of the ammonium salts,
with an almost total quenching of the fluorescence during
the titrations. The largest degree of enantiomeric recognition
(Δ log K = 0.60) was observed in the case of pyridino-crown
ether (S,S)-2 containing isobutyl groups in the macroring
and the enantiomers of 1-(1-naphthyl)ethylamine hydrogen
perchlorate (NapEt). It can be explained by the presence of
both the bulky substituents in the macroring and the ex-
tended aromatic system in the ammonium salt. Based on the
Stern–Volmer equation a linear relationship was found as a
function of the enantiomeric composition of NapEt, providing
an opportunity for the determination of the latter.
Fig. 4. Stern–Volmer calibration curve for (S,S)-2 (20 μM) and different en-
antiomeric compositions of NapEt (4 equiv.) in MeCN.
Because of the good linearity of the Stern–Volmer plots for both
enantiomers of NapEt (Fig. 3D), the Stern–Volmer equation
can be used in the following form (Eq. 2).1,45
Chirality DOI 10.1002/chir
Because of the significant role of the bulkiness of the sub-
stituent at the stereogenic centers in enantiomeric

ENANTIOPURE PYRIDINO-18-CROWN-6 ETHER-BASED FLUORESCENT SENSOR MOLECULES
567
recognition,25,26 we plan to synthesize the analogous fluores-
cent pyridino-crown ether containing tert-butyl groups at
those places to achieve higher enantioselectivity.
19. Móczár I, Huszthy P, Mezei A, Kádár M, Nyitrai J, Tóth K. Synthesis and
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or an N-methylacridinone unit as potential fluorescent chemosensors. Tet-
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20. Kertész J, Móczár I, Kormos A, Baranyai P, Kubinyi M, Tóth K, Huszthy
P. Synthesis and enantiomeric recognition studies of dialkyl-substituted
18-crown-6 ethers containing an acridine fluorophore unit. Tetrahedron:
Asymmetry 2011; 22: 684–9.
ACKNOWLEDGMENTS
Financial support of the Hungarian Scientific Research
Fund / National Research, Development and Innovation Of-
fice (OTKA / NKFIH No. K 112289 and PD 104618), the
New Széchenyi Development Plan (TÁMOP-4.2.1/B-09/1/
KMR-2010-0002), and the Zsuzsanna Szabó Research Fellow-
ship are gratefully acknowledged. The authors thank Dr.
György Tibor Balogh and Dr. Eszter Riethmüller for taking
mass spectra.
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