The enantiomeric recognition of chiral organic ammonium salts by chiral monoaza-15-crown-5 ether derivatives

Article abstract of DOI:10.1016/j.tetasy.2004.03.035

Novel chiral monoaza-15-crown-5 ether derivatives 1 and 2 were prepared from L-phenylalaninol and L-leucinol, respectively. The effect of the substituent at the stereogenic center on chiral recognition and enantioselectivity were investigated. Binding con

Full text of DOI:10.1016/j.tetasy.2004.03.035

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 1583–1588
The enantiomeric recognition of chiral organic ammonium salts by
chiral monoaza-15-crown-5 ether derivatives
*
ꢀ
Yılmaz Turgut, Elif Sahin, Mahmut Togrul and Halil Hosgoren
€
ß
ß
Faculty of Science, Department of Chemistry, University of Dicle, 21280 Diyarbakır, Turkey
Received 3 March 2004; accepted 25 March 2004
Available online 21 April 2004
Abstract—Novel chiral monoaza-15-crown-5 ether derivatives 1 and 2 were prepared from
L-phenylalaninol and L-leucinol,
respectively. The effect of the substituent at the stereogenic center on chiral recognition and enantioselectivity were investigated.
Binding constant (K), free-energy changes (ꢀDG0), enthalpy change (DH), and entropy change (DS) values were determined with
enantiomers of organic ammonium salts by a titration UV–vis method in CHCl3.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
synthesized from amino acids14 and their enantiomeric
recognition properties studied.15;16
Host–guest chiral recognition is important in a variety
of physical, chemical, and biological processes including
sensing, purification, and resolution of enantiomers,
asymmetric catalysis reactions, and single enantiomeric
forms of amino acids and sugars.1 Hence, the design,
synthesis, and the use of molecules capable of enantio-
meric recognition of other molecules are of great interest
to workers in these fields. In particular, optically active
macrocyclic receptors and their enantioselective recog-
nition of chiral compounds have been attracting much
attention.2 Cram et al. first described in 1973 the syn-
theses and characterization of a number of chiral crown
ethers capable of enantiomeric recognition toward pri-
mary ammonium salts.3;4 The rapid development in the
field of molecular recognition as applied to macrocycles
was recognized by the awarding of Nobel Prizes in 1987
to three of its pioneers, Pedersen,5 Lehn,6 and Cram.7
Since their pioneering work, enantiomeric recognition of
chiral organic ammonium salts by chiral crown ethers
has received much attention8 while complexation studies
of these macrocycles have been reviewed.9–13
We report herein the synthesis of chiral amino alcohol
precursors from L-phenylalanine and L-leucine and two
chiral monoaza-15-crown-5 ether derivatives. The host–
guest interactions involving these chiral ligand and chi-
ral organic ammonium salts were characterized. Ka,
ꢀDG0, DH, and DS values for these host–guest interac-
tions are also reported.
2. Result and discussion
2.1. Synthesis
The syntheses of
accomplished in one step from
-leucine according to procedures described in the lit-
L
-phenylalaninol and
L-leucinol were
L
-phenylalanine and
L
erature.17 The conversion of 1a and 1b to N-benzyl
amino alcohol derivatives was carried out using our
previously reported method.18 The conversion of 2a and
2b to 3a and 3b was carried out at ꢀ20 °C, as shown in
Scheme 1.
Chirality derived from the readily accessible a-amino
acids has been incorporated into the side chains of aza
and diaza macrocyclic polyethers. Among the chiral
macrocycles crown ethers, several azacrown ethers were
(R)- and (S)-enantiomers of PhCH(CH3)NHþ3 ClO4ꢀ and
1-NapCH(CH3)NHþ3 ClO4ꢀ
were
prepared
from
PhCH(CH3)NH2 and 1-NapCH(CH3)NH2, respectively.
Tosylates were prepared according to a procedure pre-
viously reported.19 Chiral host 1 was prepared from 3a
and tosylate, using sodium hydride as a base in THF.
Host 2 was synthesized in the same way starting from
3b. To obtain the product in a solid state (for easier
* Corresponding author. Tel.: +90-412-2488550; fax: +90-412-24880-
39; e-mail: yturgut@dicle.edu.tr
0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.03.035

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Y. Turgut et al. / Tetrahedron: Asymmetry 15 (2004) 1583–1588
are powerful tools used for the examination of the rec-
R
H
i
R
H
ognition ability of new chiral macrocycles.1;21–23 UV–vis
spectroscopy is a convenient and widely used method
for the study of binding phenomena. When the receptor
(or substrate) absorbs light at different wavelengths in
the free and complexed states, the differences in the UV–
vis spectra may suffice for the estimation of molecular
recognition thermodynamics. In UV spectroscopic
titration experiments, the addition of a varying con-
centration of guest molecules results in a gradual in-
crease or decrease of characteristic absorptions of the
host molecules. With the assumption of a 1:1 stoichio-
metry, the complexation of ammonium cations (G) with
chiral azacrown ether type molecular (H) is expressed by
Eq. 1:
OH
OH
NH2
NH
ii
2a R = benzyl
2b R = isobutyl
1a R = benzyl
1b R = isobutyl
R
H
OH
OH
N
3a R = benzyl
3b R = isobutyl
K
H þ G ꢀ H ꢁ G
ð1Þ
Scheme 1. Reagents and conditions: (i) PhCH2Cl, Na2CO3, 110 °C, (ii)
ethylene oxide.
Under the conditions employed herein, chiral organic
ammonium perchlorate salts were selected as the guest
molecules. The association constants of the supramo-
lecular systems formed were calculated according to the
modified Benesi–Hilderbrand equation, Eq. 2,24 where
½Hꢂ and ½Gꢂ refer to the total concentration of crown
isolation) NaClO4ÆH2O (toxic) was added to macrocycle
crown 1 and 2. These macrocycles were then recovered
from their complex form by column chromatography to
give yellow oils in 46% and 61% yield, respectively, as
shown in Scheme 2. Our previous studies20 on the fac-
tors governing enantiomeric recognition of chiral
organic ammonium salt by chiral aza-15-crown-5 ethers
showed that the highest enantioselectivity can be
expected when a host involving a benzo unit is on the
ring. As a result, we turned to the synthesis of chiral aza-
0
0
ether and organic ammonium salt, respectively, De is the
change in molar extinction co-efficient between the free
and complexed crown ether and DA denotes the
absorption changes of crown ether on the addition of
organic ammonium salts.
½Hꢂ ½Gꢂ =DA ¼ 1=KaDe þ ½Gꢂ =De
ð2Þ
0
0
0
15-crown-5, 1, and 2, ethers starting from
L
L-phenyl-
alaninol and -leucinol with effect of the substituent at
For all guest molecules examined, plots of calculated
½Hꢂ ½Gꢂ =DA values as a function of ½Gꢂ values gave
0
0
0
the stereogenic center. The structures proposed for these
chiral macrocycles and amino alcohols are consistent
with data obtained from 1H NMR, 13C NMR, IR
spectra, and elemental analyses.
excellent linear relationships, supporting the 1:1 com-
plex formation. The binding constants (Ka) and free-
energy changes (ꢀDG0) of these hosts with guest mole-
cules obtained from usual curve fitting analyses (R > 0,
9834) of observed absorbance changes are summarized
in Table 1. The binding constant, Ka of the complexes of
crown ethers 1 and 2 with organic ammonium salts were
determined by the Benesi–Hilderbrand equation on the
basis of the UV–vis spectrum of the complexes in CHCl3
collected at four different temperatures. The thermo-
dynamic parameters, (ꢀDG0), (DH), and (DS) for the
complex formation were determined from the van’t Hoff
plots of the Ka values with changes summarized in Table
2.2. Molecular recognition and UV–vis
The main purpose of synthesizing these receptors is to
study their molecular recognition for guest molecules.
Molecular recognition can be characterized by various
spectroscopic methods, such as ultraviolet visible
(UV–vis), NMR, fluorescence, and infrared (IR), which
O
O
H
N
R
O
O
TsO
TsO
O
O
OH
OH
H
+
N
1
O
R= benzyl
R= isobutyl
O
H
N
O
O
2
Scheme 2. Reagents and conditions: NaH, THF, reflux, 50 h.

Y. Turgut et al. / Tetrahedron: Asymmetry 15 (2004) 1583–1588
1585
Table 1. Binding constants (K), the Gibbs free-energy changes (ꢀDG0), enantioselectivities KR=KS, and ꢀDG0 calculated from ꢀDG0 for the com-
plexation of (RS)-guest with the chiral host 1 and host 2 in CHCl3 at 25 °C
Guesta
K (dm3 molꢀ1
)
KR=KS
ꢀDG0 (kJ molꢀ1
24.50
23.67
22.60
24.30
)
DDG0 (kJ molꢀ1
ꢀ0.83
)
b
Host
1
(R)-PhEt
(S)-PhEt
1.97 ꢃ 104
1.41 ꢃ 104
9.22 ꢃ 103
1.82 ꢃ 104
1.40
(R)-NapEt
(S)-NapEt
0.51
1.70
2
(R)-PhEt
(S)-PhEt
9.53 ꢃ 103
4.77 ꢃ 103
4.00 ꢃ 103
3.00 ꢃ 103
4.76
1.33
22.71
20.98
20.52
20.20
ꢀ1.73
ꢀ0.32
(R)-NapEt
(S)-NapEt
a PhEt: a-phenylethylamine perchlorate salts. NapEt: a-(-1-naphthyl)ethylamine perchlorate salts.
b DDG0 ¼ ꢀDG0ðRÞ ꢀ DG0ðSÞ
.
1. The typical UV spectral changes upon the addition of
(S)-PhCH(CH3)NHþ3 ClO4ꢀ salt to 2 are shown in Figure
1 while typical plots are shown for the complexation of 2
with (S)-PhCH(CH3)NHþ3 ClO4ꢀ salt in Figure 2.
the degree of chiral recognition. Therefore, determina-
tion of DH and DS for crown ether-chiral ammonium
salt interactions is desirable. A general trend among
these values is that both DH and DS favor the formation
of the complex, if one enantiomer of the guest is favored
over the other by the chiral host in terms of both DH
(more negative in value) and DS (less negative in value).
Sometimes, the entropic contribution seemed to be more
important than the enthalpy contribution. Among chiral
host–guest systems, the ideal candidates would be those
that showed relatively strong interaction and yet are
sufficiently simple that synthetic modifications can be
made easily. The choice of such systems should allow us
to examine in a systematic manner the effect on the
enantiomeric recognition of altering various structural
features and environmental factors. We have shown that
1 and 2 azacrown ethers formed complexes of appre-
ciable stability with primary ammonium cations and
displayed good chiral recognition toward enantiomers
of these guests. It has been found that20 the highest
enantioselectivity can be seen when the host containing
a benzo unit on the ring of the chiral aza-15-crown-5
ethers. As a result, we synthesized the chiral aza-15-
crown-5 ethers 1 and 2, which include a benzo unit on
Figure 1. UV–vis spectra of 2 (2.0 ꢃ 10ꢀ4 mol dmꢀ3) in the presence of
(S)-PhCH(CH3)NH3þClO4ꢀ salt (5.0 ꢃ 10ꢀ5–7.5 ꢃ 10ꢀ4 mol dmꢀ3).
the ring starting from L-phenylalaninol and L-leucinol,
respectively. Macrocycle 1 differed from 2 in that
the benzyl substituent on 1 is replaced by an isobutyl
40
30
20
10
0
in 2. From Table
1
and Figure 3, both
1-NapCH(CH3)NHþ3 ClO4ꢀ and PhCH(CH3)NH3þClOꢀ4
salts form stable complexes with 1. The stability con-
stants of 1 wiþth the (R)- and (S)-enantiomers of
PhCH(CH3)NH3 ClOꢀ4 were found to be 1.97 ꢃ 104 and
1.41 ꢃ 104, respectively, the (R) form, 1.40 times more
0
20
40
60
80
[G]o/10-5 mol dm-3
Figure 2. Typical plot of ½Hꢂ ½Gꢂ =DA versus ½Gꢂ for the host–guest
0
0
0
25
complexation of 2 and (S)-PhCH(CH3)NHþ3 ClO4ꢀ salt in CHCl3.
20
15
10
5
R
S
Determination of K values for chiral host–guest inter-
actions provides information about the capability of the
chiral hosts to recognize enantiomers of the chiral host
under given sets of conditions. The correlation of the
degree of recognition with the structural features of
recognition with the structural features of the host–guest
complexes is essential in understanding the origin of the
chiral recognition. The thermodynamic data in Table 2
provides information that makes possible the identifi-
cation and evaluation of the relationship between the
chiral ligand and the ammonium cation structures and
0
PhEt
NapEt
enantioselective recognition
Figure 3.
Barþ plots
of
of
PhCH(CH3)NH3 ClO4ꢀ(PhEt) and 1-NapCH(CH3)NH3þClOꢀ4 (NapEt)
for 1.

1586
Y. Turgut et al. / Tetrahedron: Asymmetry 15 (2004) 1583–1588
stable than the (S)-PhCH(CH3)NHþ3 ClO4ꢀ (KR=KS ¼
1:40). In the same way, 1 exhibited chiral recognition
toward the enantiomers of 1-NapCH(CH3)NHþ3 ClO4ꢀ
salt by forming a complex with the (S)-form of the guest,
which was 0.51 times more stable than that formed with
the (R) and DDG0 ¼ 1:70 kJ molꢀ1 in CHCl3. In the case
of 2, from Table 1 and Figure 4, it can be seen that 2 has
salts with 1 and 2 in CHCl3 are given in Table 2.
Complexation of the chiral ammonium salts with 1 and
2 was exothermic in each case while the DS value was
negative except in the case of (R)-PhCH(CH3)NHþ3 ClO4ꢀ
for þ1, (R)-PhCH(CH3)NHþ3 ClO4ꢀ, (S)-PhCH(CH3)-
NH3 ClOꢀ4 , and (S)-1-NapCH(CH3)NH3þClOꢀ4 for 2.
These facts indicate that the interaction of (S)-PhCH-
(CH3)NHþ3 ClO4ꢀ (DR–SDH ¼ 15:22), (RS)-1-NapCH-
a
greater enantioselectivity toward þ (R)-PhCH-
(CH3)NHþ3 ClO4ꢀ than (S)-PhCH(CH3)NH3 ClOꢀ4 , which
was 4.76 times more stable than that formed with the
(S)- form (DDG0 ¼ ꢀ1:73 kJ molꢀ1). This discrimination
could be due to the different interaction modes of the
substituent on the guest with chiral barriers on the host.
(CH3)NHþ3 ClO4ꢀ (DR–SDH ¼ 8:60) with the
1 are
enthalpy driven. The enthalpy discrimination values for
2 can be seen in Table 2, and are as follows: DR–SDH of
(RS)-PhCH(CH3)NHþ3 ClO4ꢀ 7.97 and DR–SDH of (RS)-
1-NapCH(CH3)NH3þClOꢀ4 ꢀ17.37 kJ molꢀ1 for 2. These
results indicate that the increased negative enthalpy
discrimination arises from the interaction between 2 and
guest cations. On the other hand, both enthalpy and
entropy changes þcontribute to the increased (R)-1-
NapCH(CH3)NH3 ClOꢀ4 binding constant with 2, the
much larger negative DH values probably arise from a
strong interaction between guest and the nitrogen atoms
of the hosts.
R
S
12
10
8
6
4
2
0
PhEt
NapEt
enantioselective
The reason behind entropy values being positive with
certain guests while negative with others can be
explained by the reaction enthalpy. As the difference
between enthalpy increases, the reaction entropy will
become negative. As for enantiomeric recognition, both
enthalpy and entropic changes contribute. In the case of
host 1, the entropy for the formation of the complexes is
negative in the most cases, indicating unfavorable
entropic contribution to the formation of complexes. As
in the case of host 2, the entropy for the formation of the
complexes is positive in the most cases, indicating
favorable entropic contribution to the formation of
complexes.
Figure 4.
Barþ plots
of
recoþgnition
of
PhCH(CH3)NH3 ClO4ꢀ (PhEt) and 1-NapCH(CH3)NH3 ClOꢀ4 (Na-
pEt) for 2.
The presence of a benzyl substituent on the stereogenic
center as in the case of macrocycle 1, results in recog-
nition of (R)-PhCH(CH3)NHþ3 ClO4ꢀ, (S)-PhCH(CH3)-
NHþ3 ClOꢀ4 , and (S)-1-NapCH(CH3)NH3þClOꢀ4 salts in
good order but the observed enantioselectivity was low.
The observed enantioselectivity toward (R)-PhCH-
(CH3)NHþ3 ClOꢀ4 increases in the case isobutyl sub-
stituent. In conclusion, it has been demonstrated that
the substituent on the stereogenic center play a very
important effect on the chiral recognition. It is also
known that for enantiomeric recognition, the steric
repulsion between the substituent on the stereogenic
center and the substituent of ammonium cation has been
found to be an important factor.25 It is expected that the
extent of enantiomeric recognition could be improved
upon due to the bulkiness of the substituent at the ste-
reogenic center.1
3. Experimental
3.1. General information
All chemicals were reagent grade unless otherwise
specified. L-Phenylalanine, L-leucine, and (RS)-a-phenyl
Thermodynamic parameters (DH, DS, DR–SDH, and
DR–SDS) for the interaction of (RS)-a-phenylethylamine
perchlorate and a-(1-naphthyl)ethylamine perchlorate
ethylamine and a-(1-naphthyl)ethylamine were pur-
chased from Fluka chemical company. Silica gel 60
(Merck, 0.040–0.063 mm) and silica gel/TLC-cards
Table 2. Thermodynamic parameters for complexation of host 1 and host 2 with (RS)-guest in CHCl3
Host
1
Guesta
DH (kJ molꢀ1
)
DR–SDHb
DS (J molꢀ1Kꢀ1
)
DR–SDSc
(R)-PhEt
(S)-PhEt
ꢀ9.69
ꢀ24.91
ꢀ31.79
ꢀ40.39
15.22
49.58
ꢀ4.16
53.74
(R)-NapEt
(S)-NapEt
8.60
ꢀ30.54
ꢀ53.84
23.30
2
(R)-PhEt
(S)-PhEt
ꢀ19.67
ꢀ14.27
ꢀ23.00
ꢀ5.63
ꢀ5.40
10.13
15.87
ꢀ8.21
48.90
ꢀ5.74
(R)-NapEt
(S)-NapEt
ꢀ17.37
ꢀ57.11
a Same as a in Table 1.
b DR–SDH ¼ DHR ꢀ DHS .
c DR–SDS ¼ DSR ꢀ DSS.

Y. Turgut et al. / Tetrahedron: Asymmetry 15 (2004) 1583–1588
1587
(F254) were used for flash column chromatography and
TLC. Melting points were determined with a Gallenk-
amp Model apparatus with open capillaries. Infrared
spectra were recorded on a Mattson 1000 FTIR model
spectrometer. Elemental analyses were performed with a
Carlo–Erba 1108 model apparatus. Optical rotations
were taken on a Perkin Elmer 341 model polarimeter.
1H (400 MHz) and 13C (100 MHz) NMR spectra were
recorded on a Bruker DPX-400 high performance digital
FT-NMR spectrometer.
970, 880, 841, 783, 746, 707, 617 cmꢀ1
;
1H NMR
(CDCl3) d 0.90–0.96 (dd, 6H), 1.25–1.31 (m, 1H), 2.40–
1.67 (m, 2H), 2.76–2.78 (m,1H) 3.28–3.70 (m, 2H), 3.77–
3.85 (dd, 2H), 7.26–7.38 (m, 5H); 13C NMR (CDCl3) d
23.13, 25.37, 41.65, 56.62, 63.58, 77.81, 77.46, 127.53,
128.56, 128.90, 140.46. Anal. Calcd for C13H21NO: C,
75.44; H, 10.20; N, 6.60. Found: C, 75.36; H, 10.36; N,
6.76.
3.5. (S)-N-Benzyl-4-benzyl-3-aza-1,5-propanediol 3a
3.2. UV spectral measurements
A solution of 2a (10 g, 0.04 mol) in 250 mL methanol
was cooled to ꢀ20 °C in a 100 mL flask. Ethylene oxide
(2 mL, 0.04 mol) in 10 mL of methanol at 20 °C was
added to the solution dropwise at ꢀ20 °C. The mixture
was kept at ꢀ20 °C during addition in deepfreeze. After
addition the mixture was stirred for 24 h at ꢀ20 °C and a
further 24 h at þ4 °C. The mixture was kept for 1 day at
room temperature in a closed flask. Methanol was
evaporated in rotary evaporator. The product was
The abilities of crown ethers to coordinate to chiral
organic ammonium salts were investigated using UV
spectroscopic titration.26 The UV–vis spectra were
measured at 288, 298, 308, and 318 K with a thermo-
stated cell compartment by Shimadzu 160 UV spec-
trometer. The same concentrations of guest solution
were added to the sample cell and reference cell. The
maximum wavelength was 242 and 277 nm for 1 and 2 in
CHCl3. The concentrations of the host are
2.0 ꢃ 10ꢀ4 mol dmꢀ3 with the increasing concentration of
the added guest.
purified by distillation under reduced pressure to
give 11 g of 3a (94%), bp 188–192 °C/0.8 mmHg; ½aꢂ
20
D
¼
ꢀ13:2 (c1, MeOH); IR (KBr) 3363, 3087, 3064, 3026,
2941, 1602, 1491, 1453, 1369, 1135, 1033, 916, 869, 745,
698 cmꢀ1 1H NMR (CDCl3) d 2.46–3.92 (m, 11H),
;
7.14–7.36 (m, 10H); 13C NMR (CDCl3) d 33.31, 51.40,
55.67, 60.46, 61.77, 63.35, 126.63, 127.64, 128.93,
128.99, 129.26, 129.51, 139.92, 140.18. Anal. Calcd for
C18H23NO2: C, 75.70; H, 8.00; N, 4.89. Found: C, 75.79;
H, 8.07; N, 4.91.
3.3. (S)-N-Benzyl-2-amino-3-phenyl-1-propanol 2a
(S)-Phenylalaninol (33 g, 0.218 mol), benzyl chloride
(6.96 g, 0.055 mol), and anhydrous Na2CO3 (5.8 g,
0.055 mol) were placed in a 250 mL two-necked round
bottomed flask. The mixture was stirred at 110 °C for
12 h under dry N2. The mixture was then cooled and
CHCI3 (150 mL) added to the mixture and refluxed for
2 h. The CHCl3 layer was separated from the solid
phase. The solid phase was re-extracted with CHCI3
(3 ꢃ 150 mL). The combined organic phases were dried
over anhydrous MgSO4, filtered, and evaporated. The
product was then distilled under reduced pressure and
the residue recrystallized from toluene to give 10 g of 2a
3.6. (S)-N-Benzyl-4-hydroxymethyl-3-aza-6-methyl-hep-
tane-1-ol 3b
Prepared as described for 3a, using 2b (10 g, 0.049 mol),
ethylene oxide (2.2 mL, 0.049 mol). Yield 10 g (83%), bp
20
D
(KBr) 3358, 3060, 3024, 2960, 1599, 1496, 1478, 1458,
168–170 °C/0.8 mmHg; ½aꢂ ¼ þ35:6 (c 1, MeOH), IR
1362, 1162, 1112, 1066, 918, 867, 732, 701 cmꢀ1 1H
;
(77%), bp 165–167 °C/0.8 mmHg, mp 54–56 °C;
D
3057, 3026, 2919, 1495, 1451, 1379, 1344, 1114, 1060,
1028, 959, 919, 885, 854, 742, 696 cmꢀ1 1H NMR
;
(CDCl3) d 2.04 (br, 2H), 2.76–3.00 (m, 3H), 3.35–3.80
(m, 4H), 7.17–7.34 (m,10H); 13C NMR (CDCl3) d 38.51,
51.55, 59.84, 62.95, 126.85, 127.50, 128.44, 128.88,
128.99, 129.62, 138.92, 140.42. Anal. Calcd for
C16H19NO: C, 79.67; H, 7.88; N, 5.81. Found: C, 79.60;
H, 7.80; N, 5.78.
NMR (CDCl3) d 0.88–0.92 (dd, 6H), 1.08–1.13 (m, 1H),
1.38–1.44 and 1.52–1.56 (m, 2H), 2.54–2.58 (m, 1H),
2.77–2.87 (m, 2H), 3.37–3.59 (m, 6H) 7.28–7.40 (m, 5H);
13C NMR (CDCl3) d 22.77, 24.06, 25.82, 35.60, 51.42,
55.19, 59.14, 60.50, 62.37, 127.57, 128.86, 129.24,
140.37. Anal. Calcd for C15H25NO2: C, 71.71; H, 9.96;
N, 5.58. Found: C, 71.70; H, 9.89; N, 5.60.
20
½aꢂ ¼ ꢀ11:1 (c 1.2, MeOH); IR (KBr) 3355, 3289, 3084,
3.7. (S)-2-Benzyl-N-benzyl-4,7,10,13-tetraoxa-8,9-benzo-
1-azacyclopentadec-8-ene 1
3.4. (S)-N-Benzyl-2-amino-4-methyl-1-pentanol 2b
To a suspension of NaH (1.46 g, 0.048 mol, %80 in
mineral oil) in 100 mL dry THF at 0 °C was added a
solution of diol 3a (3.5 g, 0.012 mol) in 250 mL of THF.
The reaction mixture was refluxed for 2 h. After the
reaction had cooled to 0 °C, a solution of tosylate
(6.19 g, 0.012 mol) in 250 mL of THF was slowly added.
The suspension was refluxed for 50 h. The solvent was
evaporated and 100 mL of water was added to the resi-
due. The mixture was extracted with CH2Cl2 (3 ꢃ 150).
The combined organic layers were washed with 100 mL
This compound was prepared as described above for 2a,
using 1b (21 g, 0.181 mol), benzyl chloride (5.72 g,
0.045 mol), and anhydrous Na2CO3 (4.65 g, 0.045 mol).
The product was distilled and crystallized from petro-
leum ether–benzene to give 8 g of 2b (88%), bp 123–
20
D
125 °C/0.8 mmHg, mp 72–73 °C; ½aꢂ ¼ þ33:5 (c 1,
MeOH); IR (KBr) 3294, 3070, 3024, 2960, 2928, 2909,
1503, 1464, 1387, 1348, 1271, 1208, 1092, 1060, 1022,

1588
Y. Turgut et al. / Tetrahedron: Asymmetry 15 (2004) 1583–1588
4. Stoddart, J. F. Chiral Crown Ethers. In Topics in
Streochemistry; Eliel, E. L., Wilen, S. H., Eds.; Wiley:
New York, 1988; Vol. 17, p 207.
of water again, dried on anhydrous Na2SO4, and the
solvent evaporated. The crude product was purified by
flash column chromatography on silica gel (eluent: tri-
5. Pedersen, C. J. J. Inc. Phenom. 1988, 6, 337.
6. Lehn, J.-M. J. Inc. Phenom. 1988, 6, 351.
7. Cram, D. J. J. Inc. Phenom. 1988, 6, 397.
8. Zhang, X. X.; Bradshaw, J. S.; Izatt, R. M. Chem. Rev.
1997, 97, 3313–3361.
9. Pedersen, C. J. In Synthetic Multidentate Macrocyclic
Compounds; Izatt, R. M., Christensen, J. J., Eds.; Aca-
demic: New York, 1978; p 21.
10. Izatt, R. M.; Bradshaw, J. S.; Nielsen, S. A.; Lamb, J. D.;
Christensen, J. J.; Sen, P. Chem. Rev. 1985, 85, 271.
11. Izatt, R. M.; Pawlak, K.; Bradshaw, J. S.; Bruening, R. L.
Chem. Rev. 1991, 91, 1721.
12. Izatt, R. M.; Pawlak, K.; Bradshaw, J. S.; Bruening, R. L.
Chem. Rev. 1995, 95, 2559.
ethylamine/ethyl
acetate/petroleum
ether
60–
20
D
80 ¼ 3:17:80) to give 2.5 g (46%) of an oil; ½aꢂ ¼ ꢀ33 (c
1, CHCl3), IR: m 3064, 3030, 2926, 2865, 1649, 1601,
1497, 1458, 1370, 1251, 1133, 1045, 927, 748, 702 cmꢀ1
;
1H NMR (CDCl3) d 2.81–2.93 (m, 3H), 3.15–3.28 (m,
2H), 3.63–3.91 (m, 10H), 4.15–4.21 (m, 4H), 6.95–6.99
(m, 4H) 7.19–7.30 (m, 10H); 13C NMR (CDCl3) 34.52,
50.66, 57.01, 62.35, 69.13, 69.82, 69.93, 70.04, 72.02,
72.86, 120.53, 121.69, 126.16, 127.03, 128.49, 128.62,
128.87, 129.77, 141.06, 141.34. Anal. Calcd for
C28H33NO4: C, 75.00; H, 7.43; N, 3.30. Found: C, 75.02;
H, 7.62; N, 3.34.
13. Bradshaw, J. S.; Huszthy, P.; Mcdaniel, C. W.; Oue, M.;
Zhu, C. Y.; Izatt, R. M. J. Coord. Chem. 1992, 27, 105–
114; Izatt, R.M.; Zhu, C.Y.; Huszthy, P.; Bradshaw, J. S.
Enantiomeric Recognition in Macrocycle-Primary Ammo-
nium Cation Systems. In Crown Ethers: Toward Future
Applications; Cooper. S. R., Ed.; New York, 1993;
Chapter 12.
3.8. (S)-2-Isobutyl-N-benzyl-4,7,10,13-tetraoxa-8,9-benzo-
1-azacyclopentadec-8-ene 2
This compound was prepared in similar manner to 1
using NaH (2.15 g, 0.0715 mol), 3b (4 g, 0.021 mol), and
tosylate (10.62 g, 0.021 mol). The crude product was
purified by flash column chromatography on silica gel
(eluent: triethylamine/ethyl acetate/petroleum ether 60–
€
14. Joly, J. P.; Schroder, G. Tetrahedron Lett. 1997, 38, 8197–
8198.
15. Chadwick, D. J.; Cliffe, I. A.; Sutherland, I. O. J. Chem.
Soc., Chem. Commun. 1981, 992–994.
16. Chadwick, D. J.; Cliffe, I. A.; Sutherland, I. O. J. Chem.
Soc., Perkin Trans. 1 1984, 1707–1717.
17. Marc, J.; McKennon, A.; Meyers, I. J. Org. Chem. 1993,
80 ¼ 3:17:80), yield was obtained as an oil 4 g (61%);
20
D
½aꢂ ¼ ꢀ11:6 (c 1.4, CHCl3), IR: m 3070, 3031, 2940,
2877, 1592, 1503, 1458, 1362, 1259, 1227, 1131, 1053,
938, 783, 739, 707 cmꢀ1; 1H NMR (CDCl3) 0.88–0.95 (m,
6H), 1.21–1.81 (m, 3H), 2.86–3.13 (m, 3H), 3.62–3.88 (m,
10H), 4.12–4.20 (m, 4H), 6.90–6.98 (m, 4H), 7.22–7.40
(m, 5H); 13C NMR (CDCl3) d 22.99, 23.71, 25.39, 38.47,
50.63, 55.99, 58.34, 69.32, 69.88, 69.97, 70.95, 71.93,
73.80, 113.85, 121.63, 126.99, 128.48, 129.00, 141.71,
149.43. Anal. Calcd for C25H35NO4: C, 72.64; H, 8.47; N,
3.30. Found: C, 72.40; H, 8.10; N, 3.10.
58, 3568–3571.
€
€
18. Ozbey, S.; Hoßsgoren, H.; Turgut, Y.; Topal, G. J. Inc.
Phenom. Macrocycl. Chem. 2001, 39, 315–320.
ꢀ
€
19. Topal, G.; Demirel, N.; Togrul, M.; Turgut, Y.; Hoßsgo-
ren, H. J. Heterocycl. Chem. 2001, 38, 281.
€
20. Turgut, Y.; Hoßsgoren, H. Tetrahedron: Asymmetry 2003,
14, 3815–3818.
21. Samu, E.; Huszthy, P.; Horvath, G.; Szollosy, A.;
€
Neszmelyi, A. Tetrahedron: Asymmetry 1999, 10, 3615–
3626.
22. Pietraszkiewicz, M.; Kozbial, M.; Pietraszkiewicz, O.
J. Membr. Sci. 1998, 138, 109–113.
23. Yuan, Y.; Gao, G.; Jiang, Z.-L.; You, J.-S.; Zhou, Z.-Y.;
Yuan, D.-Q.; Xie, R.-G. Tetrahedron 2002, 58, 8993–8999.
24. (a) Polster, J.; Lachman, H. Spectrometric Titrations;
VCH: Wienheim, 1989; (b) Connors, K. A. Binding
Constants. The Measurement of Molecular Complex;
Wiley: New York, 1987; (c) Benesi, H. A.; Hildebrand,
J. H. J. Am. Chem. Soc. 1949, 71, 2703.
Acknowledgement
The financial support from the University of
Dicle (Project No: DUAPK-03-FF-92) is greatly
appreciated.
25. Davidson, R. B.; Bradshaw, J. S.; Jones, B. A.; Dalley,
N. K.; Christensen, J. J.; Izatt, R. M.; Morin, F. G.;
Grant, D. M. J. Org. Chem. 1984, 49, 353.
References and notes
26. Examples of the UV–vis titremetric method being used in
molecular recognition: (a) Pietraszkiewicz, M.; Kozbial,
M.; Pietraszkiewicz, O. J. Membr. Sci. 1998, 138, 109–113;
(b) Peng, X.-b; Huang, J.-W.; Li, T.; Ji, L.-N. Inorg. Chim.
Acta 2000, 305, 111–117; (c) Chen, X.; Du, D.-M.; Hua,
W.-T. Tetrahedron: Asymmetry 2003, 14, 999–1007; (d)
Yuan, Y.; Gao, G.; Jiang, Z.-L.; You, J.-S.; Zhou, Z.-Y.;
Yuan, D.-Q.; Xie, R.-G. Tetrahedron 2002, 58, 8993–8999,
and references cited therein.
1. Izatt, R. M.; Wang, T.; Hathaway, J. K.; Zhang, X. X.;
Curtis, J. C.; Bradshaw, J. S.; Zhu, C. Y. J. Inc. Phenom.
Mol. Recognit. Chem. 1994, 17, 157–175.
2. Zhau, H. W.; Hua, W. T. J. Org. Chem. 2000, 65, 2933–
2938.
3. Kyba, E. P.; Koga, K.; Siegel, M. G.; Sousa, L. R.; Cram,
D. J. J. Am. Chem. Soc. 1973, 95, 2692.