Syntheses and complexing ability of α-d-gluco- and α-d-xylofuranoside-based lariat ethers

Article abstract of DOI:10.1007/s10847-016-0601-8

Chiral monoaza-15-crown-5 lariat ethers attached to a 1,2-O-isopropylidene-α-d-glucofuranoside unit (10–13), monoaza-16-crown-5 lariat ethers fused to 1,2-O-isopropylidene-α-d-glucofuranoside- (18) and to 1,2-O-isopropylidene-α-d-xylofuranoside units (23 and 24) have been synthesized. The alkali metal- and ammonium picrate extracting ability of these macrocycles was investigated in dichloromethane–water system. In general, the 15-membered macrocycles (10–13) showed, for almost all cations, a more considerable extracting ability, than the 16-membered lariat ethers (18, 23 and 24). Plasticized PVC membrane electrodes (ISEs) were prepared from the α-d-glucofuranoside-based triphenylmetyl (trityl) ether derivative (18), and its potentiometric selectivities and complex formation constants were determined with the segmented sandwich membrane method. Furthermore, the binding affinities of ionophores to different metal ions were also measured by competitive ESI–MS experiments. One of the 1,2-O-isopropylidene-α-d-glucofuranoside-based lariat ethers (13) exhibited a high selectivity for silver ion (Ag⁺).

Full text of DOI:10.1007/s10847-016-0601-8

J Incl Phenom Macrocycl Chem (2016) 85:19–32
DOI 10.1007/s10847-016-0601-8
ORIGINAL ARTICLE
Syntheses and complexing ability of a-D-gluco-
and a-D-xylofuranoside-based lariat ethers
2
1
3
•
Zsolt Rapi1 Oliver Ozohanics2 Gabor Toth Peter Bako Lajos Hofler
•
•
•
•
´
•
´
Tamas Nemcsok Nandor Kanya Gyorgy Keglevich
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´
¨
1
1
1
•
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Received: 14 October 2015 / Accepted: 18 February 2016 / Published online: 10 March 2016
Ó Springer Science+Business Media Dordrecht 2016
Abstract Chiral monoaza-15-crown-5 lariat ethers
attached to a1,2-O-isopropylidene-a-D-glucofuranoside unit
(10–13), monoaza-16-crown-5 lariat ethers fused to 1,2-O-
isopropylidene-a-D-glucofuranoside- (18) and to 1,2-O-iso-
propylidene-a-D-xylofuranoside units (23 and 24) have been
synthesized. The alkali metal- and ammonium picrate
extracting ability of these macrocycles was investigated in
dichloromethane–water system. In general, the 15-mem-
bered macrocycles (10–13) showed, for almost all cations, a
more considerable extracting ability, than the 16-membered
lariat ethers (18, 23 and 24). Plasticized PVC membrane
electrodes (ISEs) were prepared from the a-D-glucofura-
noside-based triphenylmetyl (trityl) ether derivative (18),
and its potentiometric selectivities and complex formation
constants were determined with the segmented sandwich
membrane method. Furthermore, the binding affinities of
ionophores to different metal ions were also measured by
competitive ESI–MS experiments. One of the 1,2-O-iso-
propylidene-a-D-glucofuranoside-based lariat ethers (13)
exhibited a high selectivity for silver ion (Ag?).
Introduction
Lariat ethers are designed to achieve strong and selective
binding of metal cations via the cooperative binding pro-
vided by the crown ether moiety and the side-arm incor-
porating a heteroatom [1–3]. An important advantage of
azacrown ethers over oxacrown ethers is the presence of
soft nitrogen donor atoms which may offer characteristic
complexing and transporting abilities. A lot of thermody-
namic studies have been performed on the complexation of
lariat crown ethers in an effort to elucidate the factors that
influence the cation-ligand complexation [4, 5]. Many
research groups have investigated the influence of the side
arms on the complex forming abilities. Recently, the effect
of the side arm on the complexation of metal ions was
studied by Bredikhin et al. using lariat ethers of 15-crown-5
type [6] and by Bartsch et al. with monoaza-15-crown-5
lariat ethers as the models [7].
Chiral macrocycles containing different carbohydrate
units form a special group of the crown ethers. The
incorporation of the carbohydrate scaffold is advantageous
in the synthesis of macrocycles: a part of the starting car-
bohydrates is inexpensive and easily available commercial
product. They are biocompatible, and available in enan-
tiomerically pure form. The basic chemistry of these
compounds is well-explored. Carbohydrates are well-en-
dowed with functionalities which enable them to establish
secondary binding sites, as well as catalytic sites. These
compounds can be used in two main fields: one is the
separation of racemic ammonium salts; the other is the
application as chiral phase transfer catalyst in asymmetric
syntheses. Both applications are related to the complex
forming ability of the macrocycles. Many optically active
crown ethers and cryptands have been synthesized from
monosaccharides [8–12]. Earlier, the complexation of a
Keywords Complexing ability Á Crown ethers Á
Extracting property Á Ionselectivity
´
´
& Peter Bako
pbako@mail.bme.hu
1
2
3
Department of Organic Chemistry and Technology, Budapest
University of Technology and Economics, PO Box 91,
1521 Budapest, Hungary
Institute of Organic Chemistry, Research Centre for Natural
Sciences, Hungarian Academy of Sciences, 1117 Budapest,
Hungary
Department of Inorganic and Analytical Chemistry, Budapest
University of Technology and Economics, 1525 Budapest,
Hungary
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J Incl Phenom Macrocycl Chem (2016) 85:19–32
few sugar-based derivatives with alkali metal-, ammonium-
and t-butylammonium picrates were investigated and dis-
cussed by Stoddart et al. [8, 12]. Formerly, the alkali metal
binding selectivity of chiral macrocycles derived from D-
mannitol and L-threitol were studied by Jurczak et al. [13].
Chiral lariat ethers fused to different monosaccharides,
such as D-glucose, D-galactose, D-mannose etc. were
introduced and investigated by us in the last decades [14,
15]. A part of the sugar-based lariat ethers was applied
successfully as chiral phase transfer catalyst in asymmetric
reactions [16–20].
O
O
O
Ph3CO
O
O
O
O
O
O
O
R1
O
O
O
O
N
O
N
R2
R2
A
B
O
O
The phase transfer catalysts can be characterized well by
the extracting ability (EA %) of picrate salts from water into
the organic phase. The EA values describe well the cation
binding ability of crown ethers and lariat ethers in liquid–
liquid two phase systems [10, 21–23]. The extracting ability
of the macrocycles depends mainly on the complex forming
ability influenced by the size of the cavity, the type and
number of heteroatoms, and also on the lipophilicity. These
characteristics determine the distribution of a cation between
the water and the organic phases. Earlier, we found that
hydroxypropyl and methoxypropyl substituents on the
nitrogen atom of the sugar-based macrocycles of type
monoaza-15-crown-5 increased strongly the cation extract-
ing ability [10]. For this reason, this structural element of the
lariat ethers was retained in our new experiments.
O
O
O
O
O
N
R2
C
R1 = Pr, Bn; R2 = (CH2)3OH, (CH2)3OCH3
Fig. 1 Structures of gluco- and xylofuranoside-based lariat ethers
interactions and by competitive experiments, several target
ions can be tested at the same time [24–35].
Experimental
General
In the present paper, complexing abilities of a-D-glu-
cofuranoside- and xylofuranoside-based lariat ethers con-
taining hydroxypropyl and methoxypropyl side arms on the
nitrogen atom of the hetero ring were investigated. Two
types of macrocycles were synthesized. In the first group,
the glucofuranoside moiety is connected to the monoaza-
15-crown-5 ring by a flexible bond (A), while in the other
group, the furanoside unit is annulated to the macro ring
(B and C) (Fig. 1).
Melting points were determined using a Bu¨chi 510 apparatus
and are uncorrected. The specific rotation was measured on a
Perkin-Elmer 241 polarimeter at 22 °C. NMR spectra were
obtained on a Bruker DRX-500 or Bruker-300 instrument in
CDC13 with Me4Si as an internal standard. Mass spectra
were obtained from m-nitrobenzyl alcohol matrix on a Var-
ian MAT312 instrument. Ionselectivity experiments by
direct infusion from water–methanol 2:8 solution were per-
formed on a Micromass Quattro Micro QQQ mass spec-
trometer with ESI ionization. Analytical and preparative thin
layer chromatography was performed on silica gel plates (60
GF-254, Merck), while column chromatography was carried
out using 70–230 mesh silica gel (Merck). Chemicals were
purchased from Aldrich Chem. Co.
We wished to synthesize lariat ethers of monoaza-15-
crown-5 and monoaza-16-crown-5 type based on protected
a-D-glucofuranoside and xylofuranoside. We wished to
alkylate the free 3-hydroxyl group of the furanoside to
increase the lipophylicity of the substrate. Our intention
was to study the effect of the monosaccharides connected
to the macrocycles and that of the N-substituents (side
arms) on the complex forming ability and ion selectivity.
Extracting abilities were measured in liquid–liquid system
towards alkali metal ions and ammonium ion. The cation
selectivities and complex formation constants of one of the
crown compounds (18) were determined using the segmented
sandwich membrane method. In addition, we wanted to test
the relative binding affinities of the sugar-based ionophores
towards the metal ions by means of electrospray ionization
mass spectrometry (ESI–MS). The motivation came from
previous studies on various systems demonstrating that ESI–
MS is relatively well suited for screening the complexation
Preparation of compounds 4–13, 16–18, 21–24
1,2-O-Isopropylidene-3-O-benzyl-a-D-glucofuranoside (4)
[36]
1,2:5,6-Di-O-isopropylidene-3-O-benzyl-a-D-glucofura-
noside (2) (13.60 g, 38.8 mmol) was dissolved in 50 % aq.
acetic acid (280 mL) and the solution was stirred overnight
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J Incl Phenom Macrocycl Chem (2016) 85:19–32
21
at room temperature. After completion of the reaction, the
acid was neutralized with Na2CO3, then extracted with
CHCl3 (3 9 50 mL). The organic phase was dried (Na2-
chloroethyl)ether was removed by vacuum distillation. The
crude product was purified by column chromatography
(silica gel, CHCl3–CH3OH 100:0 ? 100:5).
SO4), then evaporated to give product 4 (11.2 g, 93 %);
22
½aŠ = -45.8 (c = 1, CHCl3); 1H NMR (300 MHz,
1,2-O-Isopropylidene-3-O-benzyl-5,6-bis-O-[(2-
D
chloroethoxy)ethyl]-a-D-glucofuranoside (6)
CDCl3), d (ppm): 7.42–7.31 (m, 5H, ArH), 5.95 (d,
J = 3.6 Hz, 1H, H-1), 4.74 (d, J = 11.7 Hz, 1H, CH2Ph),
4.64 (d, J = 3.6 Hz, 1H, H-2), 4.55 (d, J = 11.7 Hz, 1H,
CH2Ph), 4.17–4.08 (m, 2H, H-5, H-4), 4.06–3.99 (m, 1H,
H-3), 3.82 (dd, J = 11.4, 6 Hz, 1H, H-6a), 3.69 (dd,
J = 11.4, 6 Hz, 1H, H-6b), 2.52 (br s, 2H, 2 9 OH), 1.49
(s, 3H, CCH3), 1.33 (s, 3H, CCH3); 13C NMR (75 MHz,
CDCl3), d (ppm): 137.71, 128.41, 127.85, 127.69, 111.71,
105.20, 82.00, 81.83, 78.82, 72.15, 69.36, 64.41, 26.74,
26.21; HRMS calcd for C16H22O6 310.1416, found
310.1419.
Compound 4 (11.2 g, 36.1 mmol) was treated with bis(2-
chloroethyl)ether (127 mL, 1.08 mol) in the presence of
50 % aq. NaOH (127 mL) and Bu4NHSO4 (12.26 g,
36.1 mmol). Chromatography afforded product 6 (10.77 g,
22
57 %); ½aŠ = -19.8 (c = 1, CHCl3); 1H NMR
D
(300 MHz, CDCl3), d (ppm): 7.39–7.29 (m, 5H, ArH), 5.89
(d, J = 3.6 Hz, 1H, H-1), 4.68 (d, J = 8.7 Hz, 1H, CH2-
Ph), 4.62 (d, J = 8.7 Hz, 1H, CH2Ph), 4.59 (d, J = 3.6 Hz,
1H, H-2), 4.23–4.14 (m, 1H, H-4), 4.13–4.09 (m, 1H,
H-6a), 3.96–3.81 (m, 3H, H-3, H-5, H-6b), 3.80–3.49 (m,
16H, 2 9 OCH2CH2O, 2 9 OCH2CH2Cl, 2 9 CH2Cl),
1.48 (s, 3H, CCH3), 1.31 (s, 3H, CCH3); 13C NMR
(75 MHz, CDCl3), d (ppm): 137.78, 128.44, 127.80,
127.67, 111.73, 105.19, 81.90, 81.78, 78.93, 75.89, 72.33,
72.01, 71.34, 71.21, 70.91, 70.81, 70.58, 70.15, 42.84,
42.82, 26.80, 26.32; Elem anal calcd for C24H36Cl2O8 C,
55.07; H, 6.93; Cl, 13.55. Found C, 55.10; H, 6.90; Cl,
13.53; HRMS calcd for C24H36Cl2O8 522.1787, found
522.1792.
1,2-O-Isopropylidene-3-O-propyl-a-D-glucofuranoside (5)
1,2:5,6-Di-O-isopropylidene-3-O-propyl-a-D-glucofuranoside
(3) (5.67 g, 18.8 mmol) was dissolved in 50 % aq. acetic
acid (140 mL) and the solution was stirred overnight at rt.
After completion of the reaction, the acid was neutralized
with Na2CO3, then extracted with CHCl3 (3 9 50 mL). The
organic phase was dried (Na2SO4), then evaporated to
22
afford product 5 (4.88 g, 99 %); ½aŠ = -44.7 (c = 1,
D
1
CHCl3); H NMR (500 MHz, CDCl3), d (ppm): 5.92 (d,
1,2-O-Isopropylidene-3-O-propyl-5,6-bis-O-[(2-
J = 3.5 Hz, 1H, H-1), 4.57 (d, J = 3.5 Hz, 1H, H-2), 4.13
(dd, J = 7.5, 3.5 Hz, 1H, H-4), 4.05–4.00 (m, 1H, H-5),
3.98 (d, J = 3.5 Hz, 1H, H-3), 3.82 (dd, J = 11.5, 3.5 Hz,
1H, H-6a), 3.82 (dd, J = 11.5, 6 Hz, 1H, H-6b), 3.62 (dt,
J = 9 Hz, 6 Hz, 1H, OCH2CH2), 3.47 (dt, J = 9, 6 Hz,
1H, OCH2CH2), 3.05 (br s, 1H, OH), 2.62 (br s, 1H, OH),
1.61 (sex, J = 6 Hz, 2H, CH2CH3), 1.49 (s, 3H, CCH3),
1.32 (s, 3H, CCH3), 0.93 (t, J = 6 Hz, 3H, CH2CH3); 13C
NMR (75 MHz, CDCl3), d (ppm): 111.82, 105.16, 81.93,
81.70, 78.94, 72.21, 69.47, 64.35, 26.82, 26.33, 23.03,
10.51. HRMS calcd for C12H22O6 262.1416. Found
262.1411.
chloroethoxy)ethyl]-a-D-glucofuranoside (7)
Compound 5 (4.88 g, 18.6 mmol) was treated with bis(2-
chloroethyl)ether (65.4 mL, 558 mmol) in the presence of
50 % aq. NaOH (65.4 mL) and Bu4NHSO4 (6.32 g,
18.6 mmol). Chromatography led to product 7 (6.92 g,
22
78 %); ½aŠ = -24.2 (c = 1, CHCl3) 1H NMR (300 MHz,
D
CDCl3), d (ppm): 5.89 (d, J = 3.6 Hz, 1H, H-1), 4.53 (d,
J = 3.6 Hz, 1H, H-2), 4.12 (dd, J = 9, 3 Hz, 1H, H-4),
4.00–3.40 (m, 22H, H-3, H-5, H-6a, H6b, 2 9 OCH2-
CH2O, 2 9 OCH2CH2Cl, 2 9 CH2Cl, OCH2CH2CH3),
1.60 (sex, J = 7.2 Hz, 2H, CH2CH3), 1.47 (s, 3H, CCH3),
General procedure for preparation of bis-chloro
compounds (6, 7, 16 and 21)
1.31 (s, 3H, CCH3), 0.93 (t, J = 7.2 Hz, 3H, CH2CH3). 13
C
NMR (75 MHz, CDCl3), d (ppm): 111.61, 105.22, 81.93,
81.74, 78.88, 75.81, 72.23, 71.92, 71.27, 71.16, 70.94,
70.80, 70.53, 70.06, 42.80, 42.77, 26.86, 26.39, 23.15,
10.57; Elem. anal calcd for C20H36Cl2O8 C, 50.53; H, 7.63;
Cl, 14.91. Found C, 50.57; H, 7.59; Cl, 14.87; HRMS calcd
for C20H36Cl2O8 474.1787. Found 474.1783.
To a mechanically stirred solution of carbohydrate
derivative having two free OH groups (4, 5, 15 and 20) in
bis(2-chloroethyl)ether, 50 % aq. NaOH solution and
Bu4NHSO4 were added. The mixture was stirred for 14 h at
rt then poured into a 1:1 mixture of CH2Cl2 and water
(used in a threefold volume of volume of the reaction
mixture). The phases were separated, and the aqueous layer
was extracted with CH2Cl2 twice. The combined organic
layers were washed with water, dried (Na2SO4), and con-
centrated under reduced pressure. The excess of the bis(2-
General procedure for preparation of bis-iodo
compounds (8, 9, 17 and 22)
Bis-chloro compound (6, 7, 16 and 21) was dissolved in dry
acetone and after addition of anhydrous NaI the solution
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was refluxed for 30 h. The reaction mixture was filtered,
then concentrated. The residue was dissolved in CHCl3,
filtered then washed with water three times. The organic
phase was dried (Na2SO4), then evaporated to give the
corresponding product.
and the mixture was refluxed with stirring under Ar. After
the reaction was complete (40–50 h), the mixture was fil-
tered, volatile compounds were removed in vacuum, and
the residue was dissolved in CHCl3, washed with water,
dried (Na2SO4) then concentrated in vacuum. The crude
product was purified by column chromatography.
1,2-O-Isopropylidene-3-O-benzyl-5,6-bis-O-[(2-
iodoethoxy)ethyl]-a-D-glucofuranoside (8)
1,2-O-Isopropylidene-3-O-benzyl-a-D-glucofuranoside-
based monoaza-15-crown-5 lariat ether
with hydroxypropyl side arm (10)
Bis-chloro compound 6 (3.60 g, 6.9 mmol) was treated
with NaI (4.14 g, 27.6 mmol) in acetone (60 mL) to afford
22
D
compound
8
(4.45 g, 91 %); ½aŠ = -15.4 (c = 1,
Bis-iodo compound 8 (2.20 g, 3.1 mmol) was treated with
3-aminopropan-1-ol (0.24 mL, 3.1 mmol) in the presence
of Na2CO3 (1.97 g, 18.6 mmol) in CH3CN (40 mL).
Chromatography on Al2O3 (CHCl3–CH3OH 100:0 ?
1
CHCl3); H NMR (500 MHz, CDCl3), d (ppm): 7.37–7.33
(m, 4H, ArH), 7.32–7.28 (m, 1H, ArH), 5.89 (d,
J = 3.5 Hz, 1H, H-1), 4.68 (d, J = 11.5 Hz, 1H, CH2Ph),
4.62 (d, J = 11.5 Hz, 1H, CH2Ph), 4.59 (d, J = 3.5 Hz,
1H, H-2), 4.17 (dd, J = 9, 3 Hz, 1H, H-4), 4.12 (d,
J = 3 Hz, 1H, H-3), 3.95–3.84 (m, 3H, H-5, H-6a, H-6b),
3.78–3.50 (m, 12H, 2 9 OCH2CH2O, 2 9 OCH2CH2Cl),
3.24 (t, J = 7 Hz, 2H, ICH2), 3.22 (t, J = 7 Hz, 2H,
ICH2), 1.48 (s, 3H, CCH3), 1.31 (s, 3H, CCH3); 13C NMR
(75 MHz, CDCl3), d (ppm): 137.83, 128.40, 127.75,
127.62, 111.79, 105.24, 81.96, 81.84, 78.99, 75.80, 72.27,
72.06, 71.39, 71.14, 70.90, 70.88, 70.62, 70.08, 26.76,
26.30, 3.24, 3.19; Elem anal calcd for C24H36I2O8 C,
40.81; H, 5.14; I, 35.93. Found C, 40.82; H, 5.20; I, 35.90.
HRMS calcd for C24H36I2O8 706.0500. Found 706.0504.
100:3) resulted in lariat ether 10 (1.16 g, 71 %);
22
½aŠ = -26 (c = 1, CHCl3); 1H NMR (300 MHz, CDCl3),
D
d (ppm): 7.38–7.28 (m, 5H, ArH), 5.88 (d, J = 3.6 Hz, 1H,
H-1), 4.67 (d, J = 11.4 Hz, 1H, CH2Ph), 4.59 (d,
J = 3.6 Hz, 1H, H-2), 4.52 (d, J = 11.4 Hz, 1H, CH2Ph),
4.17 (d, J = 9.3 Hz, 1H, H-4), 4.12–4.04 (m, 1H, H-3),
3.98–3.40 (m, 17H, H-5, H-6a, H-6b, 2 9 OCH2CH2O,
2 9 OCH2CH2N,
CH2OH),
2.95–2.63
(m,
6H,
3 9 NCH2), 1.79–1.59 (m, 2H, CH2CH2OH), 1.47 (s, 3H,
CCH3), 1.30 (s, 3H, CCH3); 13C NMR (75 MHz, CDCl3), d
(ppm): 137.40, 128.46, 127.86, 127.73, 111.73, 105.14,
81.80, 81.60, 79.09, 75.86, 75.33, 75.06, 71.90, 70.08,
70.01, 69.07, 68.55, 63.89, 57.05, 54.71, 54.52, 26.82,
26.79, 26.34. FAB-MS, m/z 526 [M??1], 548 [M??Na];
HRMS calcd for C27H43NO9 525.2938. Found 525.2943.
1,2-O-Isopropylidene-3-O-propyl-5,6-bis-O-[(2-
iodoethoxy)ethyl]-a-D-glucofuranoside (9)
Bis-chloro compound 7 (6.92 g, 14.6 mmol) was reacted
with NaI (8.75 g, 58.4 mmol) in acetone (130 mL) to
1,2-O-Isopropylidene-3-O-propyl-a-D-glucofuranoside-
based monoaza-15-crown-5 lariat ether
with hydroxypropyl side arm (11)
22
afford compound 9 (7.90 g, 82 %); ½aŠ = -23.5 (c = 1,
D
1
CHCl3); H NMR (300 MHz, CDCl3), d (ppm): 5.89 (d,
J = 3.6 Hz, 1H, H-1), 4.52 (d, J = 3.6 Hz, 1H, H-2), 4.11
(dd, J = 9, 3 Hz, 1H, H-4), 4.01–3.42 (m, 18H, H-3, H-5,
H-6a, H-6b, 2 9 OCH2CH2O, 2 9 OCH2CH2Cl, OCH2-
CH2CH3), 3.23 (t, J = 7 Hz, 4H, 2 9 ICH2), 1.61 (sex,
J = 7.2 Hz, 2H, CH2CH3), 1.48 (s, 3H, CCH3), 1.31 (s,
3H, CCH3), 0.93 (t, J = 7.2 Hz, 3H, CH2CH3); 13C NMR
(75 MHz, CDCl3), d (ppm): 111.73, 105.24, 81.90, 81.77,
78.93, 75.69, 72.31, 71.86, 71.22, 71.05, 70.91, 70.83,
70.59, 70.12, 26.81, 26.34, 23.11, 10.52, 3.23, 3.14; Elem
anal calcd for C20H36I2O8 C, 36.49; H, 5.51; I, 38.55.
Found C, 36.48; H, 5.56; I, 38.52, HRMS calcd for
C20H36I2O8 658.0500. Found 658.0494.
Bis-iodo compound 9 (3.95 g, 6.0 mmol) was reacted with
3-aminopropan-1-ol (0.46 mL, 6.0 mmol) in the presence
of Na2CO3 (3.82 g, 36 mmol) in CH3CN (80 mL). Chro-
matography on Al2O3 (CHCl3–CH3OH 100:0 ? 100:3)
resulted in the formation of lariat ether 11 (1.72 g, 60 %);
22
½aŠ = -26 (c = 1, CHCl3); 1H NMR (500 MHz, CDCl3),
D
d (ppm): 5.85 (d, J = 3.5 Hz, 1H, H-1), 4.52 (d,
J = 3.5 Hz, 1H, H-2), 4.12 (dd, J = 9.5, 3.5 Hz, 1H, H-4),
3.99 (ddd, J = 11, 8, 3.5 Hz, 1H, H-5), 3.88 (d,
J = 3.5 Hz, 1H, H-3), 3.85–3.77 (m, 4H, H-6a, H-6b,
CH2OH), 3.73–3.53 (m, 13H, 2 9 OCH2CH2O,
2 9 OCH2CH2N, CH2CH2CH3) 3.38 (dt, J = 9 Hz, 7 Hz,
1H, CH2CH2CH3), 2.87–2.63 (m, 6H, 3 9 NCH2), 1.78 (br
s, 1H, OH), 1.75–1.63 (m, 2H, CH2CH2OH), 1.58 (sex,
J = 7 Hz, 2H, CH2CH3), 1.46 (s, 3H, CCH3), 1.30 (s, 3H,
CCH3), 0.92 (t, J = 7 Hz, 3H, CH2CH3); 13C NMR
(75 MHz, CDCl3), d (ppm) 111.62, 105.15, 81.82, 79.11,
General procedure for the preparation of lariat
ethers (10–13, 18, 23–24)
Bis-iodo compound was dissolved in dry CH3CN, then
anhydrous Na2CO3 and the appropriate amine were added,
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23
75.47, 72.22, 71.74, 71.03, 70.29, 70.10, 69.27, 68.74,
54.71, 54.49, 28.45, 26.78, 26.32, 23.12, 10.71. FAB-MS,
m/z 478 [M??1], 500 [M??Na]. HRMS calcd for
C23H43NO9 477.2938. Found 477.2942.
CH2CH3); 13C NMR (75 MHz, CDCl3), d (ppm): 111.65,
105.12, 81.87, 79.06, 75.54, 72.26, 71.71, 71.09, 70.33,
70.06, 69.29, 59.04, 54.70, 54.48, 28.45, 27.52, 26.30,
23.18, 10.75. FAB-MS, m/z 492 [M??1], 514 [M??Na];
HRMS calcd for C24H45NO9 491.3094. Found 491.3090.
1,2-O-Isopropylidene-3-O-benzyl-a-D-glucofuranoside-
based monoaza-15-crown-5 lariat ether
with methoxypropyl side arm (12)
1,2-O-Isopropylidene-6-O-trityl-a-D-glucofuranoside (15)
[37]
Bis-iodo compound 8 (2.10 g, 3.0 mmol) was reacted with
3-methyoxypropylamine (0.31 mL, 3 mmol) in the pres-
ence of Na2CO3 (1.91 g, 18 mmol) in CH3CN (40 mL).
Chromatography on silica gel (CHCl3–CH3OH
100:0 ? 100:5) resulted in the formation of lariat ether 12
1,2-O-Isopropylidene-a-D-glucofuranoside (14) (6.40 g,
29 mmol) was dissolved in pyridine (60 mL) and tri-
phyenlmethylchloride (10.44 g, 37.5 mmol) was added.
The resulting solution was allowed to stand at rt. with
occasional stirring for 48 h. Then, water was added until
permanent turbidity has been observed. After 2 h, the
mixture was poured into ice-water (1000 mL). The white
precipitate was filtered, washed with water three times, and
dissolved in CHCl3. The solution was washed with 3 % aq.
acetic acid until the pH of the aqueous phase became
acidic, after that the organic phase was washed with water
until neutrality, and dried (Na2SO4). After evaporation of
the solvent, the crude product was crystallized from diethyl
22
1
(0.74 g, 46 %); ½aŠ = -32.5 (c = 1, CHCl3); H NMR
D
(500 MHz, CDCl3), d (ppm): 7.37–7.29 (m, 5H, ArH), 5.88
(d, J = 3.5 Hz, 1H, H-1), 4.67 (d, J = 11.5 Hz, 1H,
CH2Ph), 4.59 (d, J = 3.5 Hz, 1H, H-2), 4.52 (d,
J = 11.5 Hz, 1H, CH2Ph), 4.16 (dd, J = 9, 3 Hz, 1H,
H-4), 4.08 (d, J = 3.5 Hz, 1H, H-3), 3.96 (ddd, J = 10, 8,
3.5 Hz, 1H, H-5), 3.90–3.85 (m, 1H, H-6a), 3.86–3.82 (m,
1H, H-6b), 3.67–3.44 (m, 12H, 2 9 OCH2CH2O,
2 9 OCH2CH2N), 3.40 (t, J = 6 Hz, 2H, CH2CH2OCH3),
3.31 (s, 3H, OCH3), 2.98–2.54 (m, 6H, 3 9 NCH2),
1.78–1.69 (m, 2H, CH2CH2OCH3), 1.47 (s, 3H, CCH3),
1.31 (s, 3H, CCH3); 13C NMR (75 MHz, CDCl3) d (ppm):
137.48, 128.48, 127.92, 127.72, 111.76, 105.16, 81.76,
81.61, 79.19, 75.46, 72.50, 71.88, 71.12, 70.96, 70.33,
70.23, 70.14, 70.10, 58.59, 54.79, 54.46, 53.83, 27.51,
26.80, 26.33. FAB-MS, m/z 540 [M??1], 562 [M??Na];
HRMS calcd for C28H45NO9 539.3094. Found 539.3099.
ether to provide compound 15 (7.88 g, 61 %); m.p. 137–
22
139 °C; ½aŠ = -19.9 (c = 2, CH3OH); 1H NMR
D
(300 MHz, CDCl3), d (ppm): 7.46 (d, J = 8.1 Hz, 6H,
ArH), 7.36–7.20 (m, 9H, ArH), 5.95 (d, J = 3.3 Hz, 1H,
H-1), 4.51 (d, J = 3.3 Hz, 1H, H-2), 4.34–4.27 (m, 1H,
H-3), 4.25–4.16 (m, 1H, H-5), 4.15–4.08 (m, 1H, H-4),
3.47–3.41 (m, 1H, H-6a), 3.38–3.29 (m, 2H, H-6b, OH),
2.73 (br s, 1H, OH), 1.47 (s, 3H, CCH3), 1.31 (s, 3H,
CCH3); 13C NMR (75 MHz, CDCl3), d (ppm): 144.02,
128.86, 127.91, 127.35, 111.86, 105.24, 86.46, 82.11,
81.74, 78.76, 69.45, 64.62, 26.83, 26.25; HRMS calcd for
C28H30O6 462.2042, found 462.2048.
1,2-O-Isopropylidene-3-O-propyl-a-D-glucofuranoside-
based monoaza-15-crown-5 lariat ether
with methoxypropyl side arm (13)
1,2-O-Isopropylidene-3,5-bis-O-[(2-chloroethoxy)ethyl]-6-
Bis-iodo compound 9 (3.95 g, 6.0 mmol) was treated with
3-methyoxypropylamine (0.61 mL, 6 mmol) in the pres-
ence of Na2CO3 (3.82 g, 36 mmol) in CH3CN (80 mL).
Chromatography on silica gel (CHCl3–CH3OH
O-trityl-a-D-glucofuranoside (16)
Compound 15 (7.88 g, 17.1 mmol) was reacted with bis(2-
chloroethyl)ether (60.0 mL, 513 mmol) in the presence of
50 % aq. NaOH (60 mL) and Bu4NHSO4 (5.81 g,
17.1 mmol). Chromatography furnished product 16
100:0 ? 100:3) gave lariat ether 13 (1.24 g, 42 %);
22
D
½aŠ = -22.2 (c = 1, CHCl3); 1H NMR (500 MHz,
22
1
(9.20 g, 80 %); ½aŠ = -11.9 (c = 1, CHCl3); H NMR
CDCl3), d (ppm): 5.85 (d, J = 3.5 Hz, 1H, H-1), 4.53 (d,
J = 3.5 Hz, 1H, H-2), 4.11 (dd, J = 9.5, 3.5 Hz, 1H, H-4),
3.99 (ddd, J = 11, 8, 3.5 Hz, 1H, H-5), 3.87 (d,
J = 3.5 Hz, 1H, H-3), 3.86–3.78 (m, 2H, H-6a, H-6b),
3.72–3.53 (m, 13H, 2 9 OCH2CH2O, 2 9 OCH2CH2N,
CH2CH2CH3), 3.41 (t, J = 6 Hz, 2H, CH2CH2OCH3), 3.37
(dt, J = 9, 7 Hz, 1H, CH2CH2CH3), 3.31 (s, 3H, OCH3),
2.88–2.62 (m, 6H, 3 9 NCH2), 1.74–1.62 (m, 2H, CH2-
CH2OH), 1.57 (sex, J = 7 Hz, 2H, CH2CH3), 1.47 (s, 3H,
CCH3), 1.31 (s, 3H, CCH3), 0.91 (t, J = 7 Hz, 3H,
D
(500 MHz, CDCl3), d (ppm): 7.47 (d, J = 7.5 Hz, 6H,
ArH), 7.28 (t, J = 7.5 Hz, 6H, ArH), 7.21 (t, J = 7.5 Hz,
3H, ArH), 5.83 (d, J = 3.5 Hz, 1H, H-1), 4.58 (d,
J = 3.5 Hz, 1H, H-2), 4.26 (dd, J = 9.5, 3 Hz, 1H, H-4),
3.97 (d, J = 3 Hz, 1H, H-3), 3.90 (ddd, J = 9.5, 5, 3 Hz,
1H, H-5), 3.80–3.55 (m, 16H, 2 9 OCH2CH2O,
2 9 OCH2CH2Cl, 2 9 CH2Cl), 3.49–3.43 (m, 1H, H-6a),
3.27 (dd, J = 9.5, 6 Hz, 1H, H-6b), 1.46 (s, 3H, CCH3),
1.30 (s, 3H, CCH3); 13C NMR (75 MHz, CDCl3), d (ppm):
123

24
J Incl Phenom Macrocycl Chem (2016) 85:19–32
144.10, 128.90, 127.83, 127.39, 111.83, 105.19, 86.41,
82.13, 81.66, 78.84, 75.41, 71.27, 71.16, 70.83, 70.72,
70.51, 70.04, 64.90, 42.75, 42.73, 26.77, 26.19; Elem. anal
calcd for C36H44Cl2O8 C, 64.00; H, 6.56; Cl, 10.49. Found
C, 64.06; H, 6.60; Cl, 10.45; HRMS calcd for C36H44Cl2O8
674.2413. Found 674.2419.
26.35; FAB-MS, m/z 678 [M??1], 700 [M??Na]; HRMS
calcd for C39H51NO9 677.3564. Found 677.3571.
1,2-O-Isopropylidene-a-D-xylofuranoside (20) [38]
D-Xylose 19 (10.0 g, 67 mmol) was dissolved in acetone
(260 mL) containing H2SO4 (10 mL, 96 %) by stirring
over 30 min. A solution of Na2CO3 (13.0 g, 123.0 mmol)
in water (112 mL) was added dropwise applying external
cooling to keep the internal temperature below 20 °C. The
mixture was stirred for 2.5 h, then solid Na2CO3 (7.0 g,
66 mmol) was added. The mixture was filtered, the filter
cake was washed with acetone and the combined filtrates
were concentrated in vacuum. The crude product was
purified by column chromatography (silica gel, CHCl3–
1,2-O-Isopropylidene-3,5-bis-O-[(2-iodoethoxy)ethyl]-6-
O-trityl-a-D-glucofuranoside (17)
Bis-chloro compound 16 (9.10 g, 13.8 mmol) was treated
with NaI (8.27 g, 55.4 mmol) in acetone (150 mL) to give
22
compound 17 (10.12 g, 91 %); ½aŠ = -16.8 (c = 1,
D
1
CHCl3); H NMR (500 MHz, CDCl3), d (ppm): 7.47 (d,
J = 7.5 Hz, 6H, ArH), 7.28 (t, J = 7.5 Hz, 6H, ArH), 7.21
(t, J = 7.5 Hz, 3H, ArH), 5.84 (d, J = 3.5 Hz, 1H, H-1),
4.58 (d, J = 3.5 Hz, 1H, H-2), 4.26 (dd, J = 9.5, 3 Hz, 1H,
H-4), 3.98 (d, J = 3 Hz, 1H, H-3), 3.94–3.88 (m, 1H, H-5),
3.87–3.54 (m, 12H, 2 9 OCH2CH2O, 2 9 OCH2CH2I),
3.46 (d, J = 9.5 Hz, 1H, H-6a), 3.27 (dd, J = 9.5, 6 Hz,
1H, H-6b), 3.26 (t, J = 6.5 Hz, 2H, CH2I), 3.02 (t,
J = 6.5 Hz, 2H, CH2I), 1.46 (s, 3H, CCH3), 1.30 (s, 3H,
CCH3); 13C NMR (75 MHz, CDCl3), d (ppm): 144.03,
128.82, 127.76, 127.42, 111.77, 105.25, 86.50, 82.18,
81.74, 78.80, 75.36, 71.22, 71.18, 70.78, 70.73, 70.50,
70.11, 64.82, 26.79, 26.22, 3.24, 3.18; Elem anal calcd for
C36H44I2O8 C, 50.36; H, 5.17; I, 29.56. Found C, 50.38; H,
5.19; I, 29.55; HRMS calcd for C36H44I2O8 858.1126.
Found 858.1130.
CH3OH 100:0 ? 100:3) to afford compound 20 (10.81 g,
22
D
85 %); ½aŠ = -19.4 (c = 1, CHCl3); 1H NMR
(300 MHz, CDCl3), d (ppm): 5.98 (d, J = 3.3 Hz, 1H,
H-1), 4.52 (d, J = 3.3 Hz, 1H, H-2), 4.30–4.26 (m, 1H,
H-4), 4.20–4.17 (m, 1H, H-3), 4.10 (m, 2H, H-5a, H-5b),
1.48 (s, 3H, CCH3), 1.32 (s, 3H, CCH3); 13C NMR
(75 MHz, CDCl3), d (ppm): 111.64, 105.26, 82.73, 82.30,
79.37, 70.36, 26.77, 26.29; HRMS calcd for C8H14O5
190.0841, found 190.0840.
1,2-O-Isopropylidene-3,5-bis-O-[(2-chloroethoxy)ethyl]-a-
D-xylofuranoside (21)
Compound 20 (5.40 g, 28.4 mmol) was reacted with bis(2-
chloroethyl)ether (100.0 mL, 853 mmol) in the presence of
50 % aq. NaOH (100 mL) and Bu4NHSO4 (9.64 g,
1,2-O-Isopropylidene-6-O-trityl-a-D-glucofuranoside-
based monoaza-15-crown-5 lariat ether
with hydroxypropyl side arm (18)
28.4 mmol). Chromatography led to product 21 (5.60 g,
22
49 %); ½aŠ = -32.2 (c = 1, CHCl3); 1H NMR
D
(500 MHz, CDCl3), d (ppm): 5.91 (d, J = 3.5 Hz, 1H,
H-1), 4.59 (d, J = 3.5 Hz, 1H, H-2), 4.37 (td, J = 6,
3.5 Hz, 1H, H-4), 3.91 (d, J = 3.5 Hz, 1H, H-3), 3.81–3.60
(m, 18H, H-5a, H-5b, 2 9 OCH2CH2O, 2 9 OCH2CH2Cl,
2 9 CH2Cl), 1.49 (s, 3H, CCH3), 1.31 (s, 3H, CCH3). 13C
NMR (75 MHz, CDCl3), d (ppm): 111.73, 105.17, 82.64,
82.23, 79.44, 75.56, 72.11, 71.39, 71.23, 70.83, 70.79,
70.54, 42.80, 42.77, 26.84, 26.33; Elem anal calcd for
C16H28Cl2O7 C, 47.65; H, 7.00; Cl, 17.58. Found C, 47.68;
H, 7.02; Cl, 17.55. HRMS calcd for C16H28Cl2-
O7 402.1212. Found 402.1219.
Bis-iodo compound 17 (4.90 g, 6.0 mmol) was treated with
3-aminopropan-1-ol (0.46 mL, 6.0 mmol) in the presence
of Na2CO3 (3.82 g, 36 mmol) in CH3CN (100 mL).
Chromatography on Al2O3 (CHCl3) afforded lariat ether 18
22
(1.84 g, 49 %); ½aŠ = -9.8 (c = 1, CHCl3); 1H NMR
D
(500 MHz, CDCl3), d (ppm): 7.47 (d, J = 7.5 Hz, 6H,
ArH), 7.27 (t, J = 7.5 Hz, 6H, ArH), 7.20 (t, J = 7.5 Hz,
3H, ArH), 5.82 (d, J = 3.5 Hz, 1H, H-1), 4.53 (d,
J = 3.5 Hz, 1H, H-2), 4.33 (dd, J = 9.5, 3 Hz, 1H, H-4),
4.04 (d, J = 3 Hz, 1H, H-3), 3.73–3.53 (m, 15H, H-5,
2 9 OCH2CH2O, 2 9 OCH2CH2N, CH2OH) 3.45 (dd,
J = 10.5, 2 Hz, 1H, H-6a), 3.25 (dd, J = 10.5, 5 Hz, 1H,
H-6b), 2.96–2.83 (m, 2H, NCH2), 2.76–2.46 (m, 4H,
2 9 NCH2), 1.66–1.54 (m, 2H, CH2CH2OH), 1.48 (s, 3H,
CCH3), 1.30 (s, 3H, CCH3); 13C NMR (75 MHz, CDCl3), d
(ppm): 144.20, 128.84, 127.65, 126.77, 111.50, 104.92,
86.37, 82.31, 75.86, 70.23, 70.04, 69.48, 69.22, 69.18,
68.88, 64.17, 63.23, 56.00, 54.45, 54.18, 30.91, 26.71,
1,2-O-Isopropylidene-3,5-bis-O-[(2-iodoethoxy)ethyl]-a-D-
xylofuranoside (22)
Bis-chloro compound 21 (5.60 g, 13.9 mmol) was treated
with NaI (8.33 g, 55.6 mmol) in acetone (150 mL) to
22
provide compound 22 (7.31 g, 90 %); ½aŠ = -21.2
D
1
(c = 1, CHCl3); H NMR (300 MHz, CDCl3), d (ppm):
123

J Incl Phenom Macrocycl Chem (2016) 85:19–32
25
5.91 (d, J = 3.3 Hz, 1H, H-1), 4.59 (d, J = 3.3 Hz, 1H,
H-2), 4.36 (td, J = 6, 3.3 Hz, 1H, H-4), 3.92 (d,
J = 3.3 Hz, 1H, H-3), 3.81–3.60 (m, 14H, H-5a, H-5b,
2 9 OCH2CH2O, 2 9 OCH2CH2I), 3.26 (t, J = 6.9 Hz,
2H, CH2I), 3.25 (t, J = 6.9 Hz, 2H, CH2I), 1.49 (s, 3H,
CCH3), 1.32 (s, 3H, CCH3); 13C NMR (75 MHz, CDCl3), d
(ppm): 111.81, 105.26, 82.60, 82.27, 79.40, 75.49, 72.02,
71.47, 71.11, 70.86, 70.85, 70.50, 26.77, 26.31, 3.29, 3.16;
Elem anal calcd for C16H28I2O7 C, 32.78; H, 4.81; I, 43.30.
Found C, 32.80; H, 4.84; I, 43.28; HRMS calcd for
C16H28I2O7 585.9924. Found 585.9928.
27.55, 26.84, 26.35; FAB-MS, m/z 420 [M? ?1], 442 [M?
?Na]; HRMS calcd for C20H37NO8 419.2519. Found
419.2523.
Extraction ability [39]
Equal volumes (5 mL) of a dichloromethane solution of the
crown ether (c = 0.01 mol L-1) and of the aqueous alkali
metal picrate (c = 0.005 mol L-1) were introduced into an
Erlenmeyer flask which was then stoppered and shaken for
40 min at 22 °C. The mixture was then allowed to stand for
at least 2 h in order to allow complete phase separation.
The picrate concentration in the aqueous phase
was determined from its absorption at 354 nm
(e = 14600 mol-1 cm-1). The extraction ability is given
as % of the picrate extracted into the organic phase. In the
control experiments carried out in the absence of azacrown
ethers, no detectable amounts of picrates were extracted
into the organic phase.
1,2-O-Isopropylidene-a-D-xylofuranoside-based monoaza-
16-crown-5 lariat ether with hydroxypropyl side arm (23)
Bis-iodo compound 22 (3.60 g, 6.1 mmol) was treated with
3-aminopropan-1-ol (0.47 mL, 6.1 mmol) in the presence
of Na2CO3 (3.90 g, 36.8 mmol) in CH3CN (100 mL). The
chromatography on Al2O3 (CHCl3) gave lariat ether 23
22
D
1
(1.46 g, 59 %); ½aŠ = -20.2 (c = 1, CHCl3); H NMR
(500 MHz, CDCl3), d (ppm): 5.91 (d, J = 3.5 Hz, 1H,
H-1), 4.53 (d, J = 3.5 Hz, 1H, H-2), 4.34 (td, J = 6 Hz,
3 Hz, 1H, H-4), 3.98 (d, J = 3 Hz, 1H, H-3), 3.91 (dd,
J = 10, 6 Hz, 1H, H-5a), 3.82–3.52 (m, 15H, H-5b,
2 9 OCH2CH2O, 2 9 OCH2CH2N, CH2OH), 2.78–2.63
(m, 6H, 3 9 NCH2), 1.72–1.63 (m, 2H, CH2CH2OH), 1.48
(s, 3H, CCH3), 1.31 (s, 3H, CCH3); 13C NMR (75 MHz,
CDCl3), d (ppm): 111.62, 105.06, 82.81, 82.34, 79.37,
72.02, 70.83, 70.33, 69.81, 69.50, 69.14, 69.07, 64.09,
55.89, 54.40, 54.10, 28.39, 26.83, 26.37; FAB-MS, m/z 406
[M??1], 429 [M??Na]; HRMS calcd for C19H35NO8
405.2363. Found 405.2368.
Calculation of lipophilicity [40, 41]
Membrane and electrode preparation, and potentiometric
measurements [42]
Membranes with and without the crown compound (18) as
ionophore were prepared. Both types of membranes con-
tained 0.41 mg (5 mM) lipophilic salt additive (potassium
tetrakis[3,5-bis(trifluoromethyl)phenyl]borate,
60 mg
dioctyl sebacate (DOS) plasticizer and 30 mg high
molecular weight poly(vinyl chloride). The membrane with
ionophore contained 0.44 mg (6.7 mM) of the lariat ether
(18). The membrane components were dissolved in ca.
1 mL of tetrahydrofuran. This solution was cast into a
24 mm diameter glass ring. After evaporation of the sol-
vent, a 7 mm disk (thickness ca. 200 lm) cut from the
membrane was mounted into a Philips IS-561 electrode
body (Eindhoven, The Netherlands). The inner solution
was either 1 mM KCl for selectivity experiments or
0.01 M NaCl solution, which was buffered to pH 9.5 with
1 mM glycine buffer to keep (18) in its neutral form for the
segmented sandwich membrane experiments. Membranes
were conditioned overnight in the respective solution. The
prepared ion-selective electrodes (ISE) were used with a
Ag/AgCl double-junction reference electrode. The elec-
tromotive force (EMF) was measured at ambient temper-
ature in magnetically stirred solutions using a 16-channel
electrode voltmeter (Lawson Lab Inc., Malvern, Pa. 19355,
USA). Unbiased potentiometric selectivity coefficients [40]
were determined from the EMF data measured in metal
chloride salts by performing a two-point calibration.
Complex formation constant of the crown compound (18)
1,2-O-Isopropylidene-a-D-xylofuranoside-based monoaza-
16-crown-5 lariat ether with methoxypropyl side arm (24)
Bis-iodo compound 22 (3.4 g, 5.9 mmol) was treated with
3-methyoxypropylamine (0.6 mL, 5.9 mmol) in the pres-
ence of Na2CO3 (3.7 g, 35.1 mmol) in CH3CN (100 mL).
The chromatography on silica gel (CHCl3–CH3OH
100:0 ? 100:3) furnished compound 24 (1.0 g, 41 %);
22
D
½aŠ = -27.6 (c = 1, CHCl3); 1H NMR (300 MHz,
CDCl3), d (ppm) 5.90 (d, J = 3.6 Hz, 1H, H-1), 4.53 (d,
J = 3.6 Hz, 1H, H-2), 4.34 (td, J = 6, 3.3 Hz, 1H, H-4),
4.05-3.95 (m, 2H, H-3, H-5a), 3.80–3.50 (m, 13H, H-5b,
2 9 OCH2CH2O, 2 9 OCH2CH2N), 3.41 (t, J = 6.3 Hz,
2H, CH2OCH3), 3.32 (s, 3H, OCH3), 2.83–2.70 (m, 4H,
2 9 NCH2), 2.58 (t, J = 6.3 Hz, 2H, NCH2CH2CH2), 1.72
(qui, J = 6.3 Hz, 2H, CH2CH2OCH3), 1.49 (s, 3H, CCH3),
1.31 (s, 3H, CCH3); 13C NMR (75 MHz, CDCl3), d (ppm):
111.63, 105.03, 82.71, 82.38, 79.28, 71.88, 70.86, 70.78,
70.58, 69.85, 69.58, 68.90, 58.60, 54.25, 54.15, 52.73,
123

26
J Incl Phenom Macrocycl Chem (2016) 85:19–32
was determined with the segmented sandwich membrane
method in 0.01 M NaCl, 1 mM glycine buffer (pH 9.5).
82 %, respectively. These compounds were then cyclized
with two kinds of primary amines, 3-aminopropanol and
3-methoxypropylamine in the presence of dry Na2CO3 in
boiling acetonitrile, to afford azacrown ethers 10-13 after
purification by column chromatography. As the lariat
ethers with the hydroxypropyl group (10 and 11) were
obtained in somewhat higher yields than the methox-
ypropyl derivatives (12 and 13) (71 vs 60 % and 46 vs
42 %) a more efficient template affect can be assumed for
the previous cases [47].
ESI–MS measurements [43]
The ESI–MS experiments were performed on a commer-
cial Micromass Quattro Micro triple quadrupole instrument
equipped with an electrospray ionization source. The ions
were generated by direct infusion of the target molecules in
MeOH–H2O 8:2 solutions and a series of metal ions as
nitrate, chloride or bromide salts. The spray capillary
voltage was set to 3 kV, the cone voltage to 20 V and the
extractor to 5.5 V. The ESI source was operated at 130 °C.
The desolvation temperature was set to 220 °C with
800 L h-1 gas flow. Spectra were acquired in the
125–800 m/z mass range. The binding preference order of
the ionophores to various metal ions was calculated from
the area ratio of the corresponding adduct species. The
concentration of the ionophores was set such that the
protonated peak intensity was in the middle of the dynamic
range of the MS.
Scheme 2 shows the preparation of another type of
16-membered macrocycle (18), where the azacrown ring is
fused to the a-D-glucofuranoside moiety. The macro-ring
contains three stereogenic centers.
The starting 1,2-O-isopropylidene derivative (14) was
obtained by the partial hydrolysis of 1,2:5,6-di-O-iso-
propylidene-a-D-glucofuranose (1) [44]. The trihydroxy
compound 14 was alkylated selectively on the primary
hydroxyl group with triphenylchloromethane in pyridine as
the solvent to furnish ether 15 in a yield of 61 % [37]. The
free hydroxyl groups 3 and 5 served as the connecting
points to establish the crown ring in the fashion described
above. The double alkylation of intermediate 15 with bis(2-
chloroethyl) ether gave bischloro-podand 16 in a yield of
80 %. The halogen exchange with NaI led to the bisiodo
compound 17 in a yield of 91 %, finally, the ring closing
reaction with 3-aminopropanol afforded target macrocycle
18 in a 49 % yield.
Results and discussion
Synthesis
One part of the molecules comprised lariat ethers con-
necting to a protected glucofuranoside unit by a covalent
bond and containing a 3-hydroxypropyl or 3-methox-
ypropyl side arm (10–13) (Scheme 1).
The xylofuranoside-based 16-membered macrocycles 23
and 24 were synthesized employing similar approach
(Scheme 3).
The starting 1,2:5,6-di-O-isopropylidene-a-D-glucofura-
noside 1 was prepared from D-glucose using literature
procedure [44]. The alkylation of protected 1 with benzyl
bromide in the presence of NaH in THF gave benzyl ether
2 in a yield of 75 % [45]. The propyl derivative (3) was
prepared in a similar way in a yield of 39 % [46]. The 5,6-
O-isopropylidene-acetal moiety of intermediates 2 and 3
was removed by selective hydrolysis using 50 % acetic
acid to afford compounds 4 and 5 in the yield of 93 and
99 %, respectively [36]. The 5,6-vicinal hydroxyl groups
of the glucofuranoside derivatives so obtained (4, 5) were
utilized to establish the crown ring according to an earlier
described protocol [10].
1,2-O-Isopropylidene-a-D-xylofuranoside (20) was pre-
pared from D-xylose (19) by treatment with sulfuric acid in
acetone [38]. The 3- and 5-hydroxyl groups were alkylated
with bis(2-chloroethyl)ether to yield 21 in moderate yield
(49 %). Next, chlorine atoms were exchanged by iodine
yielding 22 (90 %). Finally, the azacrown ring was formed
by reaction with 3-aminopropanol and 3-methoxypropy-
lamine in good yields (59 %) for 23 and 41 % for 24,
respectively.
Extracting properties
The liquid–liquid phase transfer catalytic properties of the
chiral lariat ethers 10–13, 18, 23 and 24 were characterized
by the extraction of lithium, sodium, potassium, rubidium,
cesium, and ammonium picrate salts, from water into
dichloromethane following the procedure described by
Kimura et al. [39]. The concentration of the picrates in the
aqueous phase was measured by UV spectroscopy. The
data were collected in Table 1. The amount of the salts
transferred to the organic phase is expressed as the per-
centage of the initial amount of salt (extractability %) in
The vicinal hydroxyl groups of compounds 4 and 5 were
alkylated with bis(2-chloroethyl)ether in the presence of
50 % aq. NaOH as the base and tetrabutylammonium
hydrogensulfate as the catalyst in a liquid–liquid two-phase
system to give intermediate 6 and 7 in 57 and 78 % yield,
respectively, after purification by chromatography. The
exchange of chlorine to iodine in intermediates 6 and 7 was
accomplished by reaction with NaI in boiling acetone to
afford bis-iodo derivatives 8 and 9 in a yield of 91 and
123

J Incl Phenom Macrocycl Chem (2016) 85:19–32
27
BnBr
or
O
O
O
50% aq.
CH3COOH
O
O
O
O
nPrBr
(ClCH2CH2)2O
O
O
THF
NaH
50 % NaOH
Bu4NHSO4
O
O
OH
O
R1
O
O
HO
O
R1
OH
1
2 R1 = Bn (75%)
4 R1 = Bn (93%)
5 R1 = nPr (99%)
3 R1 = nPr (39%)
O
O
O
O
O
O
O
O
O
H2N(CH2)3OR2
NaI
acetone
O
O
O
O
O
R1
R1
O
R1
O
O
O
CH3CN
Na2CO3
O
O
O
O
O
O
R2 = H, CH3
N
Cl
I
R2O(H2C)3
Cl
I
6 R1 = Bn (57%)
7 R1 = nPr (78%)
8 R1 = Bn (91%)
9 R1 = nPr (82%)
10 R1 = Bn, R2 = H (71%)
11 R1 = nPr, R2 = H (60%)
12 R1 = Bn, R2 = CH3 (46%)
13 R1 = nPr, R2 = CH3 (42%)
Scheme 1 Synthesis of glucofuranoside-based lariat ethers
O
O
Ph3CO
O
O
O
O
TrCl
(ClCH2CH2)2O
O
O
O
O
O
O
pyridin
50 % NaOH
Bu4NHSO4
O
HO
Ph3CO
OH
OH
OH
OH
Cl
Cl
14
15 (61%)
16 (80%)
O
O
O
O
O
O
O
Ph3CO
Ph3CO
O
O
H2N(CH2)3OH
NaI
acetone
O
O
O
CH3CN
Na2CO3
O
O
N
I
HO(H2C)3
I
17 (91%)
18 (49%)
Scheme 2 Synthesis of glucofuranoside-based lariat ether containig a trityl group
123

28
J Incl Phenom Macrocycl Chem (2016) 85:19–32
O
O
OH
OH
O
O
O
OH
OH
(ClCH2CH2)2O
acetone
H2SO4
O
O
O
O
O
50 % NaOH
Bu4NHSO4
O
OH
OH
Cl
Cl
19
20 (85%)
21 (49%)
O
O
O
O
O
O
O
O
O
H2N(CH2)3OR
NaI
acetone
O
O
O
CH3CN
Na2CO3
O
O
N
I
R = H, CH3
RO(H2C)3
I
22 (90%)
23 R = H (59%)
24 R = CH3 (41%)
Scheme 3 Synthesis of xylofuranoside-based lariat ethers
the water phase. The differences between the alkali metal
picrate extraction abilities of the host molecules refer to the
selectivity. The extracting ability of the macrocycles
depends mainly on the complex forming ability, but also on
the lipophilicity. Lipophilicity of the lariat ethers (10–13,
18, 23–24) was calculated using substructure-based parti-
tioning coefficient estimation with the MarvinSketch
(ChemAxon) software [40, 41]. For comparison purposes,
properties of the unsubstituted monoaza-15-crown-5 (25)
were also measured [14].
complexation is also influenced by the side arms, and the
lipophilicity will also be modified. Comparing the com-
plexing ability of macrocycles 10–13, 18, 23 and 24, it can
be seen that, in general, the 15-membered macrocycles
(10–13) show, for almost all cations, a higher extracting
ability than the 16-membered lariat ethers (18, 23, 24).
Stoddart et al. proved that 18-crown-6 forms the stron-
gest complex with a variety of cations in the ‘‘all-gauche’’
conformation, and that any changes distorting the ideal
conformation result in a weaker coordinating ability [8].
This must be true also for the derivatives of monoaza-15-
crown-5 (25). Comparing the complexing ability of
macrocycles 10 and 11 with N-hydroxypropyl side arm,
one can see that the benzyl and propyl substituent on the
sugar moiety has not much effect on the complexing ability
(50–77 %). Both compounds (10 and 11) show a certain
extent of selectivity (74 and 77 %) for the K? cation. Lariat
ethers 12 and 13 with N-methoxypropyl side arm revealed,
with one exception, a weaker complex forming ability, than
species 10 and 11 with with N-hydroxypropyl substituents.
It is noted that the increased lipophilicity of lariat ethers 12
and 13 does not justify the tendency mentioned.
The complexing ability of the macrocycles synthesized
(10–13, 18, 23 and 24) should be compared very carefully,
as the ring size, the N-substituents and the connecting
carbohydrate moieties are different. These all may have a
significant effect on the complex forming ability and on the
lipophilicity. Macrocycles 10–13 have the same monoaza-
15-crown-5 hetero ring as reference crown 25. It can be
seen that lariat ethers 10–13 possess, with the exception for
Cs? ion, a significantly more considerable extent of
extracting ability as compared to reference crown 25. On
the basis of the ratio of the ring/cation diameter, the
complexation should be the best for Na? ion. However, the
123

J Incl Phenom Macrocycl Chem (2016) 85:19–32
29
Table 1 Alkali metal and
Host molecule
Percent of picrate extracteda
Lipophilicity log P
ammonium picrate extraction
data and lipophilicity of chiral
lariat ethers
Li?
Na?
K?
Rb?
Cs?
NH4
?
10
50
52
47
52
36
39
38
25
60
54
43
75
41
33
29
26
74
77
22
45
36
25
20
15
51
49
24
46
37
27
20
21
55
52
20
40
30
26
20
49
57
64
41
59
41
30
33
13
1.54
0.70
11
12
13
18
23
24
25
a
2.19
1.34
5.24
-0.20
0.45
-0.82
Room temperature; aqueous phase (5 mL); [picrate] = 5 9 10-3 M; organic phase (CH2Cl2, 5 mL);
[crown ether] = 1 9 10-2 M; defined as % picrate extracted into the organic phase, determined by UV
spectroscopy, error = 1 %
ꢀ
ꢁ
Macrocycle 13 exhibits a rather high extent of selectivity
(75 %) for Na? cation. The 16-membered lariat ethers (18,
23 and 24) show weak/medium extracting abilities, and
they do not reveal striking selectivity toward any cations. It
is worth mentioning that although macrocycle 18 with a
trityl substituent exhibits the highest value for lipophilicity
(5.24), there is practically no selectivity (30-41 %) for the
different cations. In the case of the xylofuranoside-based
macrocycles (23 and 24) the N-substituents did not have
much effect on the extracting ability; the range of the latter
for derivatives 23 and 24 was 25–39 and 20–38 %,
respectively. Both lariat ethers (23 and 24) extracted best
lithium picrate (39 and 38 %).
EISM
RT
F
bIL ¼ ðLT À RTÞ exp
where LT and RT are the concentrations of ionophore and
lipophilic anion, respectively. R, T and F are gas constant,
absolute temperature, and Faraday constant, respectively.
The complex formation constant for the crown compound
(18)—sodium complex is log bIL = 5.14 0.05, which is
a few order of magnitudes lower, than the log bIL of
commercially available ionophores. This explains the rel-
atively poor selectivity of the ISE toward interfering ions.
Binding affinities of ligands (10–13, 18, 23–24)
to metal ions measured by ESI–MS
Potentiometric experiments with ion-selective
electrodes incorporating ionophore 18
During the ESI MS measurements, aqueous solutions of
LiCl, KBr, CsCl, CaCl2, ZnCl2, Mg(NO3)2, Pb(NO3)2,
Hg(NO3)2, Cu(NO3)2 were used. All experiments were
carried out in positive ion mode, with ionophore concen-
tration of 10-3 M in MeOH/H2O 8/2 solvent and the metal
ions at 10-4 M. The halides were measured in a separate
injection. Compared to proton affinity, the studied iono-
phores’ affinity towards most metal ions is low. In most
cases, no metal adduct peak was observed, as the ring N is
easily protonated, even in pure water. The relative areas of
the ionophores ? metal peaks were summarized in
Tables 3 and 4.
The most lipophilic lariat ether 18 was selected as iono-
phore in plasticized polymer membrane based ion-selective
electrode. The selectivity coefficients of ion-selective
membranes prepared with macrocycle 18 was determined
for selected alkali and alkaline earth metals (Table 2).
In accordance with the extraction studies, the sodium
ion was preferred. The selectivity coefficient depends on
the composition of the membrane (ionophore, lipophilic
anion concentration), stoichiometry and stability constants
of the formed complexes. To investigate further the com-
plex of crown 18 and sodium, potentiometric segmented
sandwich membrane experiments were performed. The
membrane containing the ionophore (18) was mechanically
pressed together with the membrane that did not contain
ionophore. The complex formation constants for single
charged ions with 1:1 stoichiometry of ion-ionophore
complex can be calculated from the resulting membrane
potential (EISM) with the following equation:
Table 2 Unbiased potentiometric selectivity coefficients for selected
alkali and alkaline earth metals
Pot
Naþ;Mþ
Host molecule
log K
Li?
K?
Mg2?
Ca2?
18
-0.3
-0.7
-0.7
-1.1
123

30
J Incl Phenom Macrocycl Chem (2016) 85:19–32
Table 3 Relative peak areas of
various metal ion adducts with
reference to the protonated
molecular ion
10 (%)
11 (%)
12 (%)
13 (%)
18 (%)
23 (%)
24 (%)
25 (%)
Li?
K?
Cs?
Zn??
Ag?
0.8
0.0
1.0
0.0
0.8
0.0
0.1
0.0
73.5
0.7
0.1
0.0
0.0
0.0
0.0
0.0
0.0
4.0
0.0
0.0
0.0
0.0
8.7
0.7
1.8
0.0
0.8
2.3
0.0
0.0
0.4
0.0
0.0
0.0
0.0
0.0
64.9
61.1
80.0
14.1
Table 4 Relative peak areas of Na? and Ag? cation adducts with
reference to the protonated molecular ion and to each other
significantly the complex forming ability and the
lipophilicity. The lariat ethers 10–13 possess, with the
exception for Cs? ion, a significantly higher extent of
extracting ability as compared to reference crown 25.
Comparing the complexing ability of macrocycles 10–13,
18, 23 and 24, it can be seen that, in general, the
15-membered macrocycles (10–13) reveal, for almost all
cations, a more considerable extracting ability, than the
16-membered lariat ethers (18, 23, 24).
10
11
12
13
Na?/H?
Ag?/H?
Ag?/Na?
0,10679
1,21827
11,41
0,13898
0,70872
5,10
0,06279
1,03509
16,49
0,03804
1,17246
30,82
Potentiometry was used to determine the ion-selectivity
coefficients of crown compound 18, and to assess the 18
crown–sodium complex formation constant. The resulting
low selectivity values could be explained by the relatively
low complex formation constant of the 18 crown– sodium
complex.
The Ag? affinity was studied in a separate experiment.
The affinity of compound 25, the underivatized azacrown
was comparable towards Ag? and to K? affinity. Surpris-
ingly, derivatives 10–13, 18, 23 and 24 all show increased
Ag? affinity. Comparative Na?/Ag? measurements were
also carried out for compounds 10–13; the Ag? concen-
tration was kept constant 10-3 M, and the Na? concen-
tration was varied in the range of 10-6–10-2 M.
As with the potentiometric measurements, the ESI–MS
experiments indicate that 15-membered rings show higher
metal affinity. The ion selectivity of the 1,2-O-isopropyli-
dene-a-D-glucofuranoside-based lariat ether (13) for Ag?
was 30 times higher than that for the Na? cation. The
surprising Ag? binding effect is greatly enhanced by the N-
substitution which stabilizes the Ag? coordination.
The best result was observed for compound 13. Using
the same salt concentration for Na? and Ag?, the ratio of
the area for Na?/Ag? was 0.03 (0.09 for 10, 0.20 for 11
and 0.06 for 12). The selectivity towards Ag? is more
pronounced, when the ring size is smaller and when the N-
substituent is methylated. The substituent on the tetrahy-
drofuran (furanoside) ring has a little effect on the Na?/H?
and Ag?/H? selectivities. The outstanding selectivity of
macrocycle 13 for Ag? cation is to be examined further.
Our experience is rather surprising, as the selective iono-
phores described earlier were macrocycles/lariat ethers
typically with one or two sulphur atoms. However, there
are also similar other cases, Williams et al. found, for
example, that the presence of nitrogen atoms in the
macrocyclic ring is essential for silver selectivity over
other transition metals and alkali metal ions [48]. Overall,
we can say that Ag? binds to the azacrown ring, and the
binding strength is greatly modulated by the N-substitution.
Acknowledgments This work was financially supported by the
Hungarian Scientific Research Found (OTKA PD No. 112166) and
´
´
the New Szechenyi Development Plan (TAMOP-4.2.1/B-09/1/KMR-
2010-0002). L.H. gratefully acknowledges the support of the Bolyai
´
Janos Fellowship. The support of the Lendu¨let program of the Hun-
garian Academy of Sciences (LP2013-63/2013) is gratefully
acknowledged.
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