Synthesis of chiral diaza 18-crown-6 ethers from chiral amines and molecular recognition of potassium and sodium salts of amino acids

Article abstract of DOI:10.1016/S0957-4166(03)00594-9

A practical synthesis of chiral amine precursors 3 and 4 and chiral diaza 18-crown-6 ethers 5, 6 and 7 starting from chiral amines are reported. The molecular recognition of these chiral crown ethers for amino acids potassium and sodium salts has been characterized by UV-vis. The selectivity order is Phe>Thr>Ala. In the case of 6 the cavity of the macrocycle plays an important role in recognition.

Full text of DOI:10.1016/S0957-4166(03)00594-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 2633–2637
Synthesis of chiral diaza 18-crown-6 ethers from chiral amines
and molecular recognition of potassium and sodium salts of
amino acids
N. Demirel* and Y. Bulut
University of Dicle, Faculty of Science, Department of Chemistry, 21280 Diyarbakır, Turkey
Received 4 June 2003; accepted 22 July 2003
Abstract—A practical synthesis of chiral amine precursors 3 and 4 and chiral diaza 18-crown-6 ethers 5, 6 and 7 starting from
chiral amines are reported. The molecular recognition of these chiral crown ethers for amino acids potassium and sodium salts
has been characterized by UV–vis. The selectivity order is Phe>Thr>Ala. In the case of 6 the cavity of the macrocycle plays an
important role in recognition.
© 2003 Elsevier Ltd. All rights reserved.
2. Results and discussion
1. Introduction
Molecular recognition has been the focus of
supramolecular chemistry as one of fundamental pro-
cesses in biochemical systems.1 Recent successes in imi-
tating the natural phenomena using synthetic artificial
receptors have shown that biological behavior can be
engineered into relatively simple molecules.2 Crown
ethers, first introduced in 1967 by Pedersen3,4 are
macrocyclic polyethers which are able to form stable
and selective complexes with alkali, alkaline-earth, and
primary ammonium cations. Following this fascinating
discovery, chemists realized that asymmetric derivatives
of these molecules could serve as models for the study
of chiral recognition in enzymatic and other reactions.
Among the artificial carriers previously developed,
macrocyclic polyethers and crown ethers have been
well-recognized as potential carrier models for selective
transport of cations. Gokel et al.5 described the first
enantioselective transport of Z-amino acids and dipep-
tide K+ carboxylates through a bulky chloroform mem-
brane by two lariat ethers bearing N-pivot dipeptide
arms. There has been continuing interest for molecular
recognition of amino acids esters and amino acids
potassium and sodium salts by NMR, UV–vis, extrac-
tion and transport experiment.6–8 Herein we report a
practical synthesis of chiral amine precursors and three
chiral lariat type ethers and molecular recognition of
amino acids potassium and sodium salts.
2.1. Synthesis
The versatile building block, 1, for crown ether synthe-
sis was prepared as shown in Scheme 1. A single step
reaction of catechol with ethylene oxide in the presence
of a catalyst at mild temperature gave 1 in high yield.
In the reaction two catalyst were used, diethylamine
hydrochloride and piperidine hydrochloride, but the
yield of product was similar.11,12
Compound 2 (1 mol equiv.) was allowed to react with
(R)-(+)-1-phenylethylamine (10 mol equiv.) to afford 3
and triethylene glycol ditosylate was allowed to react
with (R)-(+)-1-phenylethylamine (10 mol equiv.) to
afford 4. In the cyclization reaction, although sodium
perchlorate (NaCIO4·H2O) was added to reaction
medium to promote cyclization, the product analysis
revealed that macrocycle 6 existed as the free ligand, no
complexation being observed. On the other hand
macrocycles 5 and 7 were isolated as NaCIO4 com-
plexes. This may be attributed to steric hindrance of the
arene units on the ring of 6 preventing complex forma-
tion (Scheme 2).
2.2. UV–vis
UV–vis spectroscopy is a convenient and widely used
method for the study of binding phenomena. When the
* Corresponding author. E-mail: demireln@dicle.edu.tr
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00594-9

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N. Demirel, Y. Bulut / Tetrahedron: Asymmetry 14 (2003) 2633–2637
Scheme 1. Reagents and conditions: (a) ethylene oxide, piperidine hydrochloride, MeOH, 40°C; (b) TsCl, pyridine, −10°C; (c)
(R)-(+)-1-phenylethylamine (10 equiv.), xylene, 120°C; (d) (R)-(+)-1-phenylethylamine (10 equiv.), xylene, 120°C.
Scheme 2. Reagents and conditions: (a) tripropylamine (10 equiv.), 2, xylene, 120°C, 48 h; (b) tripropylamine (10 equiv.),
triethylene glycol ditosylate, xylene, 120°C, 48 h; (c) tripropylamine (10 equiv.), 2, xylene, 120°C, 48 h.
receptor (or substrate) absorbs light at different wave-
lengths in free and complexed states, the differences in
ultraviolet spectrophotometry may suffice for estima-
tion of molecular recognition. In the UV spectroscopic
titration experiments, addition of varying concentra-
tions of guest molecules resulted in gradual increase or
decrease of characteristic absorptions of the host
molecules. The typical UV spectral changes upon the
addition of ThrNa to 5 are shown in Figure 1.
esi–Hildebrand equation (Eq. (1))10 where [H]o and [G]o
refer to the total concentration of crown ether and
amino acid potassium or sodium salt respectively, Dm is
the change in molar extinction coefficient between the
free and complexed crown ether and DA denotes the
absorption changes of crown ether on addition of
amino acid salt.
[H]o[G]o/DA=1/KaDm+[G]o/Dm
(1)
The binding constants (Ka) and free-energy changes
(−DGo) of these hosts with guest molecules obtained
from usual curve fitting analyses (R>0.9851) of
The association constants of the supramolecular system
formed were calculated according to the modified Ben-

N. Demirel, Y. Bulut / Tetrahedron: Asymmetry 14 (2003) 2633–2637
2635
tion being weak; in acidic medium the amino acid is
bound through the ammonium ion.15 In basic medium
it is complexed through the carboxylate function.16
UV–vis spectroscopic studies indicate that p-stacking
interactions between the aromatic moiety and aromatic
part of the amino acid may contribute further to the
overall binding strength of receptor. Although the
potassium ion forms a stronger complex with 18-crown-
6 than its sodium counterpart, it is very unlikely to find
a correlation between the cation size and selectivity.
ThrNa is recognized better than the respective potas-
sium salt. The situation is reversed for other amino
acids. In the case of Thr, additional hydrogen bonding
between the OH group and the macrocycle is highly
probable. Macrocycle 6 recognizes only PheNa and
PheK, which deserves special attention. This result may
be attributed to the strong p-stacking interaction
between the four aromatic moieties on macrocycle and
aromatic part of the amino acid. The reverse effect may
result from the cavity of 6. The dibenzo substitution on
the diaza crown ether, due to steric hindrance of the
arene units on the ring and p–p interaction between
aromatic moieties on the ring and aromatic moieties on
the side chains may close the cavity. Also the properties
of macrocycle 7 deserve special interest. Macrocycle 7
did not give an absorbance in a mixture of CH3CN–
H2O, it gives good absorbance in CHCI3 at 244.2 nm
but in this case solubility problem of amino acids salts
arise. In MeOH, it gives absorbance at 207.4 nm but,
here MeOH compete with amino acids; so the binding
studies of 7 could not be performed.
Figure 1. UV–vis spectra of 5 (1.33×10−4) in the presence of
ThrNa (4×10−5–14×10−4).
observed absorbance changes are summarized in Table
1. Typical plots are shown for the complexation of 5
with ThrNa in Figure 2.
Amino acids may interact in four ways to form stable
complexes. In neutral solution the amino acid may be
complexed in its neutral form13 (coordination of the
amino group and hydrogen bonding of the acid part) or
more generally in its zwitterionic form for which ther-
modynamic studies have been undertaken,14 complexa-
Table 1. Binding constants (Ka) and free energy of com-
plexation (−DGo) for 1:1 complexes between 5, 6 and
amino acids potassium and sodium salts
Host
Guest
Ka (dm3 mol−1
)
−DGo (kJ mol−1
)
L
L
L
L
L
L
L
L
L
L
L
L
-PheNa
-PheK
-ThrNa
-ThrK
-AlaNa
-AlaK
-PheNa
-PheK
-ThrNa
-ThrK
-AlaNa
-AlaK
(1 0.06)×104
(4 0.042)×104
5.45×103
6.27×103
5.82×103
5.41×103
4.37×103
5.12×103
4.17×103
5.62×103
3. Experimental
(1.86 0.05)×104
(9.33 0.043)×103
(1.6 0.038)×103
(5.67 0.054)×103
(1.14 0.048)×103
(1.33 0.042)×104
No recognition
No recognition
No recognition
No recognition
3.1. General information
5
All chemicals were grade reagent unless otherwise spe-
cified. Melting points were determined with a GAL-
LENKAMP Model apparatus with open capillaries.
Infrared spectra were recorded on a MIDAC-FTIR
Model 1700 spectrophotometer. The elemental analysis
were obtained with CARLO-ERBA Model 1108
6
apparatus. H (400 MHz) and 13C (100 MHz) NMR
1
spectra were recorded on a BRUKER DPX-400 High
Performance Digital FT-NMR spectrometer, with tet-
ramethylsilane as internal standard for solutions in
deuteriochloroform. J values are given in hertz. Optical
rotations were recorded using a ATAGO DR Model
21949 polarimeter, and [h]D values are in units of 10−1
deg cm2 g−1.
3.2. Spectra measurement
The abilities of crown ethers to coordinate to amino
acids salts were investigated using UV spectroscopic
titration.9 The UV–vis spectra were measured at 25
0.3°C with Shimadzu 160 UV spectrometer. The maxi-
mum wavelengths are 276.4 and 274.2 nm for 5 and 6,
respectively. A solution of CH3CN(HPLC grade)–H2O
(50:1) was used as the solvent. The concentrations of
the hosts are 3.5×10−5–1.33×10−4 M with the increasing
concentration of the added guest.
Figure 2. Typical plot of [H]o[G]o/DA versus [G]o for the
host–guest complexation of 5 and ThrNa in (H2O/CH3CN=
1:50).

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N. Demirel, Y. Bulut / Tetrahedron: Asymmetry 14 (2003) 2633–2637
3.3. 1,10-Di-(R)-(+)-1-phenylethyl-4,7-dioxa-1,10-
1.17–1.19 (d, J 6.70, 6H, CH3); 2.68–2.72 (m, 4H,
ArOCH2CH2N); 2.84–2.87 (t, J 6.28, 4H, NCH2); 3.31–
3.37 (m, 8H, OCH2, Ar-OCH2); 3.66–3.68 (q, J 6.69,
2H, CHN); 3.76–3.81 (m, 4H, OCH2CH2O); 6.54–6.65
(m, 4H, Ar-H); 7.00–7.19 (m, 10H, Ar-H); 13C NMR: l
17.69, 50.35, 51.37, 61.70, 69.03, 71.06, 71.62, 113.63,
121.23, 127.21, 128.11, 128.61, 145.05, 149.35. Anal.
calcd for: C32H42N2O4: C, 74.09; H, 8.16; N, 5.40.
Found: C, 74.12; H, 8.12; N, 5.46.
diazadecane 4
Triethylene glycol ditosylate (11.45 g, 25 mmol) and
(R)-(+)-1-phenylethylamine (30.25 g, 250 mmol) was
stirred at 120°C under dry nitrogen for 16 h in xylene
(400 ml). The mixture was cooled to the rt and then
white precipitate filtered off and xylene evaporated. The
product distilled under reduced pressure to afford 4
(7.65 g) in yield 86% as yellow oil had a bp 176–178°C/
0.2 mmHg. [h]2D0 +25.5 (c 1, EtOH); IR: w 3330, 3084,
3061, 3023, 2953, 2865, 1600, 1492, 1446, 1372, 1349,
3.6. N,N%-Di-(R)-(+)-1-phenylethyl-7,16-diaza-1,4,10,13-
tetraoxa-2,3,11,12-dibenzo-cyclooctadeca-2,11-diene 6
1
1303, 1123, 1029, 757, 702, 589; H NMR: l 1.34 (d, J
6.60, 6H, CH3); 1.67 (bs, 2H, NH); 2.56–2.69 (m, 4H,
NCH2); 3.50–3.56 (m, 8H, OCH2CH2O, OCH2); 3.74–
3.76 (q, J 6.57, 2H, NCH); 7.18–7.33 (m, 10H, Ar-H);
13C NMR: l 24.94, 47.61, 58.69, 70.62, 71.09, 127.05,
127.27, 128.81, 146.03. Anal. calcd for: C22H32N2O2 : C,
74.12; H, 9.05; N, 7.86. Found: C, 74.23; H, 9.12; N,
7.76.
To a mixture of tripropylamine (14.3 g, 100 mmol) in
xylene (500 ml) 1,2-bis-(2-p-tolylsulphonylethoxy)-
benzene 2 (5.06 g, 10 mmol) and 1,2-bis-[2-(N-(R(+)-1-
phenylethylamino)ethoxy] benzene 3 (4.04 g, 10 mmol)
was added simultaneously. The mixture was stirred for
2 days at 120°C. The mixture was then cooled to the rt.
The xylene was then evaporated. The concentrated
crude product was washed with hot water and extracted
with CHCl3 (3×50 ml) and dried (Na2SO4). The chloro-
form was then evaporated. The product crystallized
from ethyl acetate to afford 6 (2.54 g) in yield 45% as
white solid had a mp 137–138°C. [h]2D0 +23.2 (c 0.05,
CH2Cl2); IR;w 3066, 3058, 3035, 2963, 2925, 2863, 1585,
1500, 1453, 1351, 1249, 1225, 1210, 1171, 1117, 1017,
921, 810, 779, 748, 701, 663, 547; 1H NMR: l 1.40–1.42
(d, J 6.65, 6H, CH3); 3.18–3.25 (m, 10H, NCH2, NCH);
3.91–3.96 (m, 8H, OCH2); 6.67–6.79 (m, 8H, Ar-H);
7.23–7.41 (m, 10H, Ar-H); 13C NMR: l 17.14, 50.69,
61.82, 68.91, 112.12, 120.75, 127.26, 128.07, 128.64,
145.00, 148.85. Anal. calcd for: C36H42N2O4: C, 75.76;
H, 7.95; N, 3.68. Found: C, 75.43; H, 7.81; N, 3.72.
3.4. (R)-(+)-1,2-Bis-[2-(N-1-phenylethylamino)-
ethoxy]benzene 3
1,2-Bis-(2-p-tolylsulphonylethoxy)benzene (12.65 g, 25
mmol) and (R)-(+)-1-phenyl-ethylamine (30.25 g, 250
mmol) was stirred at 120°C under dry nitrogen for 16 h
in xylene (400 ml). The mixture was cooled to rt and
then white precipitate filtered off and xylene evapo-
rated. The product distilled under reduced pressure to
afford 3 (6.36 g) in yield 63% as yellow oil had a bp.
191–193°C at 0.2 mmHg. [h]2D0 +42.6 (c 1, EtOH); IR: w
3328, 3066, 3027, 2963, 2933, 2871, 2831, 1591, 1499,
1452, 1398, 1367, 1252, 1221, 1120, 1042, 759, 744, 704;
1H NMR: l 1.14–1.16 (d, J 6.59, 6H, CH3); 2.2 (bs, 2H,
NH); 2.6–2.67 (m, 4H, NCH2); 3.61–3.62 (q, J 6.58, 2H,
NCH); 3.82–3.86 (m, 4H, OCH2); 6.66–6.67 (s, 4H,
Ar-H); 6.99–7.14 (m, 10H, Ar-H); 13C NMR: l 25.00,
47.16, 58.52, 69.32, 115.03, 122.09, 127.18, 127.50,
128.99, 145.76, 149.45. Anal. calcd for: C26H32N2O2: C,
77.19; H, 7.92; N, 6.93. Found: C, 77.06; H, 7.86;
N,6.95.
3.7. N,N%-Di R-(+)-1-phenylethyl-1,7,10,16-tetraoxa-
4,13-diaza-cyclooctadecane 7
To a mixture of tripropylamine (14.3 g, 100 mmol) in
xylene (500 ml) triethylene glycol ditosylate (4.58 g, 10
mmol) and 1,10-di-R-(+)-1-phenylethyl-4,7-dioxa-1,10-
diazadecane 4 (3.56 g, 10 mmol) was added simulta-
neously. The mixture was stirred for two days at 120°C.
The mixture was then cooled to the rt. The xylene was
then evaporated. The concentrated crude product was
washed with hot water to remove tripropylamine salt,
was then extracted with CHCl3 (3×50 ml) and dried
(Na2SO4). The residue was purified by column chro-
matography (200 mesh Si-gel, ethyl acetate:petroleum
ether:triethylamine 17:80:3) to afford 7 (2.25 g) in yield
48% as yellow oil. [h]2D0 +19.2 (c 0.05, CH2CI2 ), IR; w
3091, 3053, 3029, 2972, 2931, 2869, 1605, 1478, 1455,
1376, 1352, 1298, 1201, 1121, 1067, 1034, 980, 911, 833,
3.5. N,N%-Di-(R)-(+)-1-phenylethyl-7,16-diaza-1,4,10,13-
tetraoxa-2,3-benzo-cyclooctadec-2-ene 5
To a mixture of tripropylamine (14.3 g, 100 mmol) in
xylene (500 ml) 1,2-bis-(2-p-tolylsulphonylethoxy)-
benzene 2 (5.06 g, 10 mmol) and 1,10-di-(R)-(+)-1-
phenylethyl-4,7-dioxa-1,10-diazadecane 4 (3.56 g, 10
mmol) was added simultaneously. The mixture was
stirred for 2 days at 120°C. The mixture was then
cooled to the rt. The xylene was evaporated. The
concentrated crude product was washed with hot water
then extracted with CHCI3 (3×50 ml) and dried
(Na2SO4). The chloroform was then evaporated and the
residue purified by column chromatography (200 mesh
Si-gel, ethyl acetate:petroleum ether:triethylamine
17:80:3) to afford 5 (2.80 g) in 54% yield as a yellow oil.
[h]2D0 +27.4 (c 0.05, CH2CI2 ), IR: w 3068, 3029, 2974,
2926, 2872, 1597, 1496, 1441, 1371, 1348, 1325, 1261,
1215, 1122, 1053, 1029, 776, 745, 699; 1H NMR: l
1
770, 731, 708; H NMR: l 1.38–1.40 (d, J 6.76, 6H,
CH3); 2.78–2.86 (m, 8H, NCH2); 3.56–3.61 (m, 16H,
OCH2CH2O, OCH2); 3.86–3.88 (q, J 6.72, 2H, NCH);
7.23–7.40 (m, 10H, ArH); 13C NMR: l 17.65, 51.24,
61.48, 71.15, 71.38, 127.09, 128.10, 128.48, 144.81.
Anal. calcd for: C28H42N2O4: C, 71.46; H, 8.99; N, 5.95.
Found: C, 71.38; H, 8.76; N, 5.87.

N. Demirel, Y. Bulut / Tetrahedron: Asymmetry 14 (2003) 2633–2637
2637
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