Unique cation binding capability of cyclic oligo(l-lactic acid) (l-COLA)

Article abstract of DOI:10.1016/j.tetlet.2015.02.037

Cyclic l-lactic acid octamer (l-COLA-8) shows a unique complexing capability towards alkali and alkali earth metal cations in acetonitrile-d₃/chloroform-d (9/1). The valence of the cation affects the stoichiometry of the complexes between l-COLA-8 and the cation; l-COLA-8 forms a 2:1 complex with alkali metal cations, but forms a 1:1 complex with alkali earth metal cations. Additionally, l-COLA-8 shows a binding selectivity for Rb⁺ and Ba²⁺, which have a diameter about 3 ?.

Full text of DOI:10.1016/j.tetlet.2015.02.037

Accepted Manuscript
Unique Cation Binding Capability of Cyclic Oligo(L-lactic acid) (L-COLA)
Chizuru Kogame, Toshiyuki Kida, Tomoko Fujiwara, Mitsuru Akashi
PII:
S0040-4039(15)00307-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.02.037
TETL 45905
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
6 January 2015
4 February 2015
10 February 2015
Please cite this article as: Kogame, C., Kida, T., Fujiwara, T., Akashi, M., Unique Cation Binding Capability of
Cyclic Oligo(L-lactic acid) (L-COLA), Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.
2015.02.037
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Unique Cation Binding Capability of Cyclic
Oligo(L-lactic acid) (L-COLA)
Chizuru Kogame, Toshiyuki Kida, Tomoko Fujiwara, Mitsuru Akashi*
alkali earth metal cation
alkali metal cation
2:1 complex
L-COLA-8
1:1 complex
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O

1
Tetrahedron Letters
journal homepage: www.els evier.com
Unique Cation Binding Capability of Cyclic Oligo(L-lactic acid) (L-COLA)
Chizuru Kogame, a Toshiyuki Kida, a Tomoko Fujiwara, b Mitsuru Akashi *a
a Department of Applied Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamada-oka, Suita, Osaka 565-0871, Japan
b Department of Chemistry, The University of Memphis, 213 Smith Chemistry Bldg. Memphis, TN 38152, United States
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
.
Cyclic L-lactic acid octamer (L-COLA-8) shows a unique complexing capability towards alkali
and alkali earth metal cations in acetonitrile-d3/chloroform-d (9/1). The valence of the cation
affects the stoichiometry of the complexes between L-COLA-8 and the cation; L-COLA-8 forms
a 2:1 complex with alkali metal cations, but forms a 1:1 complex with alkali earth metal cations.
Additionally, L-COLA-8 shows a binding selectivity for Rb+ and Ba2+, which have a diameter
about 3 Å.
Available online
Keywords:
Cyclic lactic acid
Oligomer
Macrocyclization
Cation binding
Size selectivity
Since Pedersen’s discovery of the binding capability of
crown ethers towards metal cations,1 the development of host
molecules bearing unique molecular recognition capabilities,
such as calixarenes,2,3 cyclodextrins,4,5 cyclic oligopeptides,6-8
cucurbiturils,9,10 and crown ether derivatives11 have attracted
much attention in diverse fields, including biomedical and
pharmaceutical fields as well as analytical and separation
sciences. Macrocyclization of linear oligomers or polymers with
repeating interaction sites for a guest ion or molecule is a
powerful approach to construct host molecules with high guest
new type of macrocyclic host molecule towards alkali metal and
alkali earth metal cations.
(a)
binding capabilities and selectivities.
For instance,
macrocyclization of oligo(ethylene glycol)s with electron-
donating oxygen atoms yields crown ethers with high cation
binding capabilities and selectivities through ion-dipole
interactions.11 On the other hand, macrocyclization of malto-
oligosaccharides produces cyclodextrins bearing unique cavities
into which appropriately sized and shaped guest molecules can
be selectively incorporated mainly through hydrophobic and van
der Waals interactions.4,5
(b)
Figure 1. Chemical structure of (a) L-COLA-8 and (b)
monobenzylated L-LOLA-8.
Oligo or poly(lactic acid)s are composed of several or many
lactic acid units with an electron-dense carbonyl oxygen. Thus,
their macrocyclization should afford unique host molecules with
a cation binding capability through ion-dipole interactions.
Moreover, they should have wide use in biomedical and
pharmaceutical fields due to the potential biodegradability and
biocompatibility of the resulting cyclic lactic acids. Except for
one report on the crystal structure of a complex between a cyclic
lactic acid hexamer and sodium cation,12 the cation binding
We chose L-COLA-8, which is composed of eight L-lactic acid
units, as the host (Fig. 1a). Alkali metal cations and alkali earth
metal cations, including Mg2+ ions, were used as the guest cations.
According to a previously reported method, L-COLA-8 was
synthesized in ten steps from L-lactide (Scheme S1).13-15
capability of cyclic lactic acids has yet to be reported. We report
herein the cation binding capability of a cyclic lactic acid as a
———
1
Figure 2a shows the changes of the H NMR signals of L-
COLA-8 in acetonitrile-d3/chloroform-d (9/1) upon the addition
* Corresponding author. Tel.: +81 6 6879 7356; fax: +81 6 6879 7359.
E-mail address: akashi@chem.eng.osaka-u.ac.jp (M. Akashi).

2
Tetrahedron
of K+. Adding K+ shifts both the methine and methyl proton
d3/chloroform-d (9/1) at 25 °C estimated from the 1H NMR
spectral changes of L-COLA-8 upon adding alkali metal cations.
The binding capability of L-COLA-8 increases in the following
order: Li+ << Na+ < Cs+ < K+ < Rb+. This trend differs from those
of 18-crown-6 (Li+ < Na+ < Cs+ < Rb+ < K+),16 21-crown-7 (Li+ <
Na+ < K+ < Rb+ < Cs+),16 and dibenzo-24-crown-8 (K+ < Rb+ =
Cs+)17 in methanol. Additionally, L-COLA-8 (host : guest = 2 : 1)
and these crown ethers (host : guest = 1 : 1) form complexes with
different stoichiometries, suggesting that they have different
coordination modes with the alkali metal cations.
signals of L-COLA-8. Similarly, adding Na+, Rb+, or Cs+ shifts
the proton signals of L-COLA-8, whereas adding Li+ only slightly
shifts these proton signals. These observations suggest L-COLA-
8 forms a complex with Na+, K+, Rb+, and Cs+, but complexation
with Li+ is negligible. Job plots for the complexes of L-COLA-8
with Na+, K+, and Rb+ using an NMR method show a maximum
at a [L-COLA-8]/[cation] ratio of 2:1, indicating that L-COLA-8
forms
a 2:1 complex with these cations in acetonitrile-
d3/chloroform-d (9/1) (Fig. 3, S19, S20). In the case of the
complex between L-COLA-8 and Cs+, it is difficult to determine
the stoichiometry by the Job plots because the shift of the proton
signals of L-COLA-8 upon adding one or less equivalent of Cs+ is
only a little. On the other hand, in the ESI-MS spectrum of a
mixture of L-COLA-8 (1.0 × 10-4 M) and CsClO4 (1.0 × 10-3 M)
in acetonitrile/chloroform (9/1), a strong peak corresponding to
the 2:1 complex ([2COLA + Cs]+, m/z = 1286) is observed along
with a slight peak corresponding to the 1:1 complex ([COLA +
Cs]+, m/z = 709) (Fig. S22). This observation strongly suggests
that L-COLA-8 forms a 2:1 complex with Cs+, similar to the
complexes with Na+, K+, and Rb+.
Table 1. Binding constants (K) between L-COLA-8 and alkali
metal cations in acetonitrile-d3/chloroform-d (9/1) at 25 °C.
K
2
+
L-COLA-8
alkali metal cation
2:1 complex
CH
CH3
[K+]/
(a)
cation diameter (Å)
stability constant (M-2)
~0
[L
-COLA-8]
Li+
Na+
K+
Rb+
Cs+
1.2
1.9
2.7
3.0
3.3
0.0
(6.5 0.4) × 105
(8.0 1.1) × 106
(3.1 1.3) × 107
(2.6 1.0) × 106
4.0
16
32
5.3
5.2
5.1
1.5
1.4
ppm
CH
CH3
[Li+]/
[L-COLA-8]
(b)
Figure 4, S10, and S11 shows the 1H NMR spectral changes of
L-COLA-8 upon the addition of alkali earth metal cations. Upon
adding Ca2+, Sr2+, or Ba2+ ions, the proton signals of L-COLA-8
shift remarkably. In contrast, adding Mg2+ ion hardly induces a
shift. These results indicate that L-COLA-8 has a negligible
binding capability towards Mg2+ as well as Li+ in acetonitrile-
d3/chloroform-d (9/1). In addition, the results imply that unlike
crown ethers, which have a more flexible ring structure that
allows binding with the smaller cations,20 L-COLA-8 has a rigid
ring structure.
0.0
4.0
16
128
5.3
5.2
5.1
1.5
1.4
ppm
1
Figure 2. H NMR spectral changes observed for L-COLA-8
(1.0 × 10-4 M) in acetonitrile-d3/chloroform-d (9/1) upon the
addition of (a) KClO4 and (b) LiClO4 at 25 °C.
CH
CH3
[Ba2+]/
[L-COLA-8]
(a)
0.0
4.0
16
30
20
10
0
32
5.3
5.2
5.1
1.5
1.4
ppm
[Mg2+]/
[L-COLA-8]
(b)
CH
CH3
0.0
4.0
16
0.67
0
0.5
-COLA-8]
L
-COLA-8]+[K+]
1
[
L
32
[
5.3
5.2
5.1
1.5
1.4
ppm
Figure 3. Job plot for the complex between L-COLA-8 and
KClO4 in acetonitrile-d3/chloroform-d (9/1) at 25 oC.
1
Figure 4. H NMR spectral changes observed for L-COLA-8
(1.0 × 10-4 M) in acetonitrile-d3/chloroform-d (9/1) upon the
addition of (a) Ba(ClO4)2 and (b) Mg(ClO4)2 at 25 °C.
Table 1 shows the binding constants (K) between two COLA
molecules and one alkali metal cation in acetonitrile-

3
Interestingly, the Job plots (Fig. 5, S21) and the ESI-MS
spectrum (Fig. S23)21 indicate that the stoichiometry of the
complexes between L-COLA-8 and alkali earth metal cations is
1:1, in sharp contrast to the complexes between L-COLA-8 and
alkali metal cations, which have a 2:1 stoichiometry. Table 2
summarizes the binding constants between L-COLA-8 and alkali
earth metal ions. L-COLA-8 shows a binding selectivity for Ba2+,
to L-COLA-8, an NMR titration method was used to evaluate
the cation binding capability of L-LOLA-8.
CH
CH3
[Rb+]/
(a)
[
L-LOLA-8]
0.0
4.0
8.0
and the increasing order of the binding constants (Mg2+ << Ca2+
<
Sr2+ < Ba2+) is consistent with that of the complex between
dibenzo-24-crown-8 and alkali earth metal cations,22 although the
stability constants for the former are lower.
5.4
5.2
5.0
4.8
4.6
4.4
ppm
4.2
1.5
1.4
1.3
CH
CH3
[Ba2+]/
(b)
[
L-LOLA-8]
0.0
15
10
5
4.0
8.0
5.4
5.2
5.0
4.8
4.6
4.4
ppm
4.2
1.5
1.4
1.3
Figure 6. 1H NMR spectral changes for monobenzylated L-
LOLA-8 (1.0 × 10-4 M) in acetonitrile-d3/chloroform-d (9/1)
upon the addition of (a) RbClO4 and (b) Ba(ClO4)2 at 25 °C.
0
6
shows the 1H NMR spectral change of
0
0.5
1
Figure
[L-COLA-8]
[L-COLA-8]+[Ba2+
monobenzylated L-LOLA-8 upon the addition of Rb+ or Ba2+ in
acetonitrile-d3/chloroform-d (9/1). Even upon adding eight-times
the molar amounts of these cations, the proton signals of
monobenzylated L-LOLA-8 are not shifted, indicating that L-
LOLA-8 hardly forms a complex with these cations. These
results clearly demonstrate that the macrocyclic structure is
necessary for the cation binding by oligo(lactic acid)s.
]
Figure 5. Job plot for the complex between L-COLA-8 and
Ba(ClO4)2 in acetonitrile-d3/chloroform-d (9/1) at 25 oC.
In conclusion, cyclic L-lactic acid octamer (L-COLA-8)
effectively forms a complex with alkali and alkali earth metal
ions in acetonitrile-d3/chloroform-d (9/1). L-COLA-8 forms a 2:1
complex with alkali metal cations, but forms a 1:1 complex with
alkali earth metal cations. L-COLA-8 selectively binds to metal
cations with a diameter about 3 Å, such as Rb+ and Ba2+. In sharp
contrast to L-COLA-8, the linear oligo(L-lactic acid)s, L-LOLA-8,
hardly forms a complex with these metal cations. These results
confirm that macrocyclization is important to prepare a cation-
binding host molecule from oligo(L-lactic acid)s. It is expected
that various combinations of L- and D-lactic acids will realize
cyclic oligo(lactic acid)s with higher cation binding capabilities
and selectivities. Further studies along these lines are now in
progress in our laboratory.
Table 2. Binding constants (K) between L-COLA-8 and alkali
earth metal cations in acetonitrile-d3/chloroform-d (9/1) at
25 °C.
K
+
L-COLA-8
alkali earth metal cation
1:1 complex
cation diameter (Å) stability constant (M-1)
Mg2+
1.3
2.0
2.3
2.7
~0
(9.5 1.6) × 102
(4.1 0.1) × 103
(5.3 0.5) × 103
Ca2+
Sr2+
Ba2+
Acknowledgments
This work was partially supported by a Grant-in-Aid for Sci-
entific Research (S) (A23225004) from the Japan Society for the
Promotion of Science.
Supplementary Material
Linear oligo(ethylene glycol)s that are composed of several
oxyethylene units have a cation binding capability, but their
binding constants are much lower than those of the
corresponding macrocyclic crown ethers. For instance,
heptaethylene glycol dimethyl ether forms complexes with alkali
metal cations in methanol. The binding constants with Na+, K+,
and Cs+ are 47, 741, and 257 M-1, respectively.23 Thus, we
compared the cation binding capability between L-COLA-8 and
the corresponding linear lactic acid octamer (L-LOLA-8). Similar
Supplementary data associated with this article can be found,
in the online version, at---------- Experimental details, spectral
data, titration curves for complex formation, and Job plots for
complexes.
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×
10-3 M) in
acetonitrile/chloroform (9/1), peaks corresponding to a 1:1
complex ([COLA + Ca]2+, m/z = 308; [COLA + Ca +
ClO4]+, m/z = 715) were observed, whereas there was no
peak corresponding to a 2:1 complex, indicating that L-
COLA-8 forms a 1:1 complex with Ca2+ in this solvent.
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