Enantioselective complexation of chiral lariat crown ethers and chiral primary alkylammonium perchlorates

Article abstract of DOI:10.3906/kim-1008-844

In order to investigate the enantiomeric recognition abilities toward 2 chiral alkylammonium perchlorates (AmI, AmII) by ¹ H-NMR titration method in CDCl₃, 4 chiral lariat ethers 8-11 with a (p-methoxyphenoxy) methyl flexible side arm were used. The most effective enantiomeric recognition was obtained by LCEs 9 and 11 toward AmII, by K _R/K_S 6.58 and K_S/K_R 6.63, respectively. The effect of macroring size, subunit of macroring, and side arm appeared to have strong influence on the binding ability of these alkylammonium ions. TUeBITAK.

Full text of DOI:10.3906/kim-1008-844

Turk J Chem
35 (2011) , 171 – 179.
¨
˙
c
ꢀ TUBITAK
doi:10.3906/kim-1008-844
Enantioselective complexation of chiral lariat crown
ethers and chiral primary alkylammonium perchlorates
1
2
2,∗
¨
¨
M. Zafer KOYLU , Tarık ARAL , Mehmet KARAKAPLAN
,
2
2
¨
¨
S¸afak Ozhan KOCAKAYA , Halil HOS¸GOREN
1Department of Physics, Faculty of Science, Dicle University, Diyarbakır-TURKEY
e-mail: mkkaplan@dicle.edu.tr
2Department of Chemistry, Faculty of Science, Dicle University, Diyarbakır-TURKEY
Received 17.08.2010
In order to investigate the enantiomeric recognition abilities toward 2 chiral alkylammonium perchlorates
(AmI, AmII) by 1 H-NMR titration method in CDCl3, 4 chiral lariat ethers 8-11 with a (p-methoxyphenoxy)
methyl flexible side arm were used. The most effective enantiomeric recognition was obtained by LCEs 9
and 11 toward AmII, by KR /KS 6.58 and KS /KR 6.63, respectively. The effect of macroring size, subunit
of macroring, and side arm appeared to have strong influence on the binding ability of these alkylammonium
ions.
Key Words: Chiral lariat crown ethers, enantioselectivity, complexation properties, molecular recognition,
NMR titration
Introduction
Lariat crown ethers (LCEs) are usually depicted as crown ethers with side arms containing donor atoms located
at their end.1 Such lariat ethers are designed to enhance the cation binding ability or selectivity of crown ethers
by providing the potential of 3-dimensional complexation. This can lead to the mimicking of the dynamic
complexation processes exhibited by natural macrocyclic ionophores.2 The structural and chemical similarities
between lariat crown ethers and a number of enzymes, where nearly 10% of amino acid side chains are terminated
by the aromatic residues benzene (in phenylalanine), phenol (in tyrosine), and indole (in tryptophan), make
this type of compound a favored model for biochemists as well as chemists. Side arm participation in metal
cation complexation by lariat ether was demonstrated in solid state structures3−5 and inferred by increased
∗Corresponding author
171

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Enantioselective complexation of chiral lariat crown ethers and..., M. Z. KOYLU, et al.,
stability constant in solution compared with corresponding crown ethers ligand.6 In other words, the side arm
of the LCEs can lead to significant changes in the complexation behavior of the host molecules.7
The enantiomeric recognition of primary alkylammonium salts by chiral macrocyclic receptors is helpful in
developing new methods of asymmetric synthesis and chromatographic resolution of enantiomers.8 In particular,
chiral crown ethers are known to be chiral solvating agents (CSA) toward protonated primary amines and
amino acid methyl ester salts.9−13 Among these macrocycles, optically active 18-crown-6 ethers have been well
investigated.14−20 So far, there have been a few reports on the use of the C -pivot type of chiral crown ethers
as CSAs for metal cations,21−24 primary alkylammoniums,25,26 and amino acid methyl esters.27 The use of
CSAs is one of the most effective and convenient methods for the assessment of the binding constants with
guest molecules in NMR spectroscopy. Awareness of the conformational preference of LCE is important for
predicting its 3-dimensional properties of molecular structures and binding affinities with guest molecules. This
is important in the field of supramolecular chemistry and molecular recognition.28
Our previous study showed that LCEs 8-11 exhibited good chiral recognition toward amino acid methyl
esters27 and an excellent enantioselective transport of amino acids and their sodium and potassium salts through
the chloroform membrane phase.29 An investigation of the effect of the side arm on the complexation of a solid-
state structure of LCE 8 sodium perchlorate complex has also been reported.30
In this study, 4 chiral lariat crown ethers bearing (p-methoxyphenoxy) methyl moiety (8-11) were de-
signed in order to investigate their complexation ability and molecular recognition with chiral α-phenylethylam-
monium perchlorate (AmI) and α-(1-naphtyl)ethylammonium perchlorate (AmII) by 1 H-NMR titration method
(Scheme). The introduction of aromatic π and n donor side arms into chiral crown ether is regarded as a useful
strategy for new types of crown ethers because such aromatic side arms should affect enantiomeric discrimina-
tion by the combination of steric and electronic factors. Macrocycles 8-11 were synthesized by ring closure of
chiral subunit diol 1 prepared from (S)-glycidol and p-methoxyphenol as described in our previous report.27
Macrocycles 10 and 11 bear benzo and naphtho units as rigid and lipophilic groups, respectively.
Experimental section
General information
1 H-NMR (400 MHz) and 13 C-NMR (100 MHz) spectra were recorded on a Bruker Avance-400 MHz high
performance digital FT-NMR spectrometer, with tetramethylsilane as the internal standard solution in deuteri-
ochloroform. Hosts 8-11 were synthesized as described in a previous report.27
Evaluation of the stoichiometry of the host-guest complex (Job plots)
The stoichiometric host-guest complexes were determined according to Job’s method of continuous variations.
Equimolar amounts of host and guest compound were dissolved in CDCl3 (Figure 1). These solutions were
distributed among 9 NMR tubes in such a way that the molar fractions X of host and guest in the resulting
solutions increased (or decreased) from 0.1 to 0.9 (and vice versa). The complexation-increased shifts were
multiplied by X and plotted against X itself (Job plot).
172

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Enantioselective complexation of chiral lariat crown ethers and..., M. Z. KOYLU, et al.,
RO
RO
O
O
O
O
O
O
i
ii
ROH
+
OH
+
O
O
HO
OH
1
OTs
TsO
O
4
+
8
TsO
OTHP
2
RO
RO
RO
O
O
O
O
O
O
O
O
O
O
O
ii
ii
O
O
+
+
O
O
O
O
OH
HO
OTs TsO
O
OTs TsO
3
+
7
6
OTs
O
TsO
O
10
5
11
ii
Guest:
O
O
O
O
OR
O
O
NH3+ClO4-
NH3+ClO4-
AmII
9
AmI
Scheme. R: p-MeOPh-, reagents and condition, i) piperidine hydrochloride, 70-80 ◦ C, 4 h, ii) NaH, THF, reflux, 56 h.
10.0
8.0
6.0
4.0
2.0
0.0
0.2
0.4
0.6
0.8
1.0
X
Figure 1. Job plots of compound (S)-11 with (S)-AmI (X = molar fraction of the guest, Δδ = chemical shift change
of diastereotopic side arm and macroring protons of (S)-11).
173

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¨
Enantioselective complexation of chiral lariat crown ethers and..., M. Z. KOYLU, et al.,
NMR host-guest titration
The host compound was dissolved in an appropriate amount of solvent (CDCl3) and the resulting solution was
evenly distributed among 9 NMR tubes. The first NMR tube was sealed without any guest. The guest compound
was also dissolved in the appropriate amount of solvent and added in increasing amounts to the NMR tubes, so
that solutions with the following relative amounts (equiv.) of guest versus host compound (concentration was
4.16 × 10−3 M) were obtained: 0.00 0.125, 0.25, 0.375, 0.50, 1,00, 2.00, 4.00, and 6.00. K was calculated for
compounds 8-11 from the observed Δδ values and the respective host and guest concentrations by the NMR
version of the Benesi-Hildebrand equation.31,32 The chemical shift change of diastereotopic protons of host 11
toward (S)- and (R)-AmI can be seen in Figure 2.
A
B
6.000
4.000
2.000
1.000
0.500
0.375
0.250
0.125
0.000
[G/H]
ppm
4.3
4.2
ppm
4.3
4.2
Figure 2. Diastereotopic proton signals of host 11 (4.16 × 10−3 M) by addition of guest compounds (A: (S)-AmI, B:
(R)-AmI) in CDCl3 at 25 ◦ C.
Results and discussions
It is known that the nature, rigidity, and quality of side arms of hosts are all expected to play an important role in
enantiomeric recognition. 1 H-NMR titration is the most reliable method in order to determine the association
complex. For inclusion phenomena, chemical shift changes or the appearance of a separate NMR peak are
indicative of the formation of the host-guest complex. In the present study, the complexation phenomena
between the C -pivot type of chiral LCEs 8-11 and alkylammonium perchlorates (AmI and AmII) in CDCl3
were investigated by 1 H-NMR titration method. Therefore, the 1 H-NMR spectra of pure LCEs 8-11 and their
perchlorate complexes were collected. It was observed that the peak at about 4.3-4.2 ppm was considerably
174

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¨
Enantioselective complexation of chiral lariat crown ethers and..., M. Z. KOYLU, et al.,
shifted to the higher magnetic field by the addition of alkylammonium salts for all of the LCEs. The peak
belonging to the diastereotopic protons of the side arm and macroring, shown by the DEPT and HETCOR
spectra of host 11, is an example (Figures 3 and 4). This means that the electronic structure of both the
macroring and side arm was perturbed by the complexation, indicating that the aromatic group of guests
AmI and AmII overlapped the macroring’s side arm site. This overlapping caused a magnetic shielding effect,33
resulting in upfield shifts of 1 H-NMR signals. These findings are in agreement with LCE carboxylate-alkali metal
complexes in solution.21 Upfield shifts of the macroring proton signals were also observed upon complexation
with AmII enantiomers in the solution.34,35
DEPT 135
DEPT 90
13C
150 140 130 120 110 100 90
80
70
60
50
40
30
20
10
ppm
Figure 3. 13 C, DEPT 90, and 135 spectra of host 11.
ppm
0
20
40
60
80
100
120
140
ppm
9
8
7
6
5
4
3
2
1
0
Figure 4. HETCOR spectrum of host 11.
175

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Enantioselective complexation of chiral lariat crown ethers and..., M. Z. KOYLU, et al.,
The binding constants of LCEs 8-11 were determined by the chemical shift differences of this signal at
4.3-4.2 ppm (Table). In each association experiment, 1:1 binding stoichiometry was assumed as the observation
for the 1:1 instantaneous complex between host 11 and (S)-AmI by Job plots (Figure 1). In addition to this,
the titration curves of LCEs 8-11 showed that the changes of this signal difference significantly decreased after
formation of the 1:1 complex. These changes were clearly seen from the diastereotopic proton signals of host
11 by addition of guest compounds (S)-AmI and (R)-AmI (Figure 2).
Table. Binding constants (K), enantioselectivities (KS /KR), and Gibbs free energy changes (ΔG ◦ ) for the complex-
ation of chiral guests AmI and AmII with chiral hosts (S)-8-11 in CDCl3 (4.16 × 10−3 M) at 25 ◦ C.
LCEs
Guest
K (dm3/mol) KS/KR -ΔG◦ (kJ/mol)
(S)-AmI
(R)-AmI
(S)-AmII
(R)-AmII
(S)-AmI
(R)-AmI
(S)-AmII
(R)-AmII
(S)-AmI
(R)-AmI
(S)-AmII
(R)-AmII
(S)-AmI
(R)-AmI
(S)-AmII
(R)-AmII
265 40
78
13.827
10.796
16.283
14.487
13.365
11.285
11.461
16.129
13.365
11.532
15.420
16.411
11.648
10.796
15.111
10.419
3.39
2.06
2.31
0.15
2.10
0.67
1.50
6.63
5
(S)-8
714 114
346 45
220 20
95
3
(S)-9
(S)-10
(S)-11
102
6
671 174
220 18
105
4
504 150
752 188
110
73
5
3
445 40
67
2
Taking into account the binding constants, host 8 exhibited stronger complex ability toward AmI than
AmII, by KS /KR 3.39 and 2.06, respectively. Crown ethers with 15-crown-5 and 18-crown-6 rings had average
21
cavity sizes of 1.84and 2.90 A, respectively. Therefore, host 8 probably formed perching complexes21 rather
˚
than 3 hydrogen bonds with polyether ring oxygens, in which the predominant geometry of diastereomeric com-
plexes causes the change of the electronic environment of the side arm. This picture is helpful in understanding
the formation of complexes between ammonium ions and the side arm of the macroring.
In the case of host 9, a higher binding constant and enantioselectivity were obtained for AmII than
AmI, by KR/KS 6.58 and 2.31, respectively. The enantioselectivity of AmII may be assessed with effective
noncovalent interactions and appropriate steric hindrance, which is caused a specific conformational binding
including favorable π stacking interaction between the flexible side arm of the host and the aromatic moiety of
AmII.
Generally, host 10 has relatively strong binding ability but lower enantioselectivity toward Am II, by
KR/KS 1.5, than AmI, byKS/KR 2.1, due to greater rigidity and the π − π stacking interaction of the benzo
176

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Enantioselective complexation of chiral lariat crown ethers and..., M. Z. KOYLU, et al.,
unit and the aromatic moiety of AmII (Table). Ammonium ions probably bind with the same side of the
macroring; therefore, the steric hindrance of the side arm does not significantly influence the enantiomers of
guests leading to enantioselectivity.
It is known that the rotation about the single bonds in the side arm is facile and that the diastereotopic
side arm protons are magnetically equivalent, leading to a singlet absorption in the 1 H-NMR spectrum. In
Figure 2, the diastereotopic side arm proton signals of (S)-AmI are seen to be shifted to the higher field
together with splitting to 2 signals, but (R)-AmI is seen to have shifted without any splitting peaks. This
indicates that the diastereotopic side arm protons are nonequivalent, producing an AB pattern by restricts of
the side arm. Docking studies (molecular docking) were obtained via MD studies for 1 ns for the hosts and
100 ps for the guests by using AMBER (v. 9).36 Docking of the guests was carried out using the program
DOCK (v. 6.0). Structures estimated by the docking study for complexes formed between host 11 and the
enantiomers of AmI showed different interactions (Figure 5). While (S)-AmI preferred cation-π interaction in
complexation, (R)-AmI preferred π − π interaction. On the other hand, host 11 exhibited better enantiomeric
recognition toward AmII, by KS/KR 6.63, than AmI, by KS/KR 1.5, due to the favorable cation-π and π −π
stacking interaction between an enantiomer of AmII and the macroring. Thus, the greater enantioselectivity
of AmII may also be explained by the specific binding of (S)-AmII by appropriate π − π stacking interaction
between the side arm and guest. Host 11 also exhibited good enantioselectivity toward amino acid methyl ester
by the UV-titration method, according to our previous report.27 This result shows that the presence of the
naphtho unit on the macroring not only gives rise to the best environment for complexation but also increases
enantiomeric recognition due to the specific conformational binding. Consequently, LCEs 8-11 form reasonably
stable complexes with guest enantiomers, indicating that the low conformational flexibility of diastereomeric
complexes results in a high degree of enantiomeric recognition.
Figure 5. Structures estimated by docking study for the complexes formed between host 11 and (S)-AmI (left) and
(R)-AmI (right), respectively.
177

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Enantioselective complexation of chiral lariat crown ethers and..., M. Z. KOYLU, et al.,
Conclusion
C1 symmetric C-pivot chiral LCEs 8-11 not only exhibit appreciable complexation constants but also show good
enantiomeric recognition toward primary alkylammonium perchlorates AmI and AmII. In particular, despite
their small cavities, LCE 8 forms stable enantioselective complexes and LCE 9 forms favorable enantioselective
complexes with macroring oxygens. On the other hand, LCE 10 has relatively high binding constants and
low enantioselectivity due to its planar structure, and LCE 11 forms a stable enantioselective complexation
by a specific conformational binding with effective π − π and cation-π interaction. It was found that the
electron donor characters of the side arm appeared to have a strong influence on the binding ability of these
alkylammonium ions.
Acknowledgement
¨
This research was supported by the Research Project Council of Dicle University (DUAPK) (Project No.
¨
DUAPK-09- FF-13).
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