Short Articles
Bull. Chem. Soc. Jpn. Vol. 86, No. 8, 987-989 (2013)
987
Macrocyclic Compound as NMR
Chiral Solvating Agent for
Determination of Enantiomeric
Excess of Carboxylic Acids
O
H
O
H
N
N
R
NH
O
HN
O
R
1, R = Bn
2, R = Ph
3, R = iPr
O
O
Xiao-feng Yang,* Rui Ning, Li-jun Xie, Yu Cui,
Yong-ling Zhang, and Lu-yi Zheng
Figure 1. Chemical structure of CSAs 1-3.
School of Chemistry and Chemical Engineering,
University of Jinan, 106 Jiwei Road, Jinan,
Shandong 250022, P. R. China
X
Y
4 (R = H, X = OH, Y = H)
5 (R = p-Br, X = OH, Y = H)
6 (R = p-OCH3, X = OH, Y = H)
7 (R = p-CF3, X = OH, Y = H)
8 (R = o-Cl, X = OH, Y = H)
9 (R = H, X = Br, Y = H)
COOH
Received April 3, 2013
E-mail: chm_yangxf@ujn.edu.cn
10 (R = H, X = OCH3, Y = H)
11 (R = H, X = CH3, Y = H)
R
O
NHCOCH3
15 (R = CH3)
16 (R = CH(CH3)2
17 (R = CH2Ph)
12 (R = Cl)
13 (R = Br)
14 (R = OH)
H
1H NMR studies demonstrated that chiral macrocycle
1 was a good chiral solvating agent, and was effective for
the determination of the enantiomeric excess of a wide range
of rac-carboxylic acids. Large nonequivalent chemical shifts
(up to 0.125 ppm) can be achieved in the presence of
1.0 equiv of 1.
OH
R
COOH
R
Figure 2. The structures of the guests used herein.
However, despite the increasing number of papers describing
CSAs for carboxylic acids,2,7 reports about chiral macro-
cyclic compounds as efficient chiral solvating agents to
determine the enantiomeric excess of carboxylic acids are very
scarce.2b,2g,2o,5,8 The macrocyclic compounds 1-3 (Figure 1)
have a pyridine-2,6-biscarboxamide moiety as a binding unit,
which has both hydrogen-bond donor and acceptor sites.9 We
expected that the functional groups would be preorganized well
and that the amide bonds in such environments would provide
effective binding sites. Taking this into account, we envisaged
the possibility of 1-3 as chiral NMR shift reagents for a wide
range of carboxylic acids.
Compounds 1-3 were prepared from the enantiopure L-
amino acid methyl ester according to the reported method.10
1H NMR (400 MHz) spectroscopy was utilized to investigate
the chiral recognition ability of host molecules 1-3, the ¦¦¤
value is the difference of the chemical shifts of corresponding
protons of two enantiomers of the guests in the presence of the
CSAs 1-3.
For our initial studies, the rac-mandelic acid 4 was chosen
as the guest and 1:1 mixtures of 1-3 were examined. When a
solution of rac-4 (10 mM in CDCl3) was gradually added to a
10 mM solution of 1-3 in CDCl3 until the ratio reached 1:1, the
signals for the proton attached to the stereogenic center split into
two doublets, with an upfield chemical shift. The largest ¦¦¤
value (0.091 ppm) of the methine proton was observed when
compound 1 was used as the CSA [The ¦¦¤ value (0.024 ppm)
was observed in the presence of 2; and in case of 3, ¦¦¤ value
(0.025 ppm) was observed]. This showed that compound 1 had
the best enantiomer discriminating ability than 2 and 3.
Next the CSA 1 was used as the receptor for the other
racemic carboxylic acids 5-17 (Figure 2). The ¦¦¤ values
in the 1H NMR spectra for the probe groups of the chiral
carboxylic acids were summarized in Table 1.
Chiral carboxylic acids are structural units of many natural
products and play a key role in the design and preparation of
pharmaceuticals, as they are part of the synthetic process in the
production of a wide range of compounds with biological and
pharmacological activities.1 Due to their importance in bio-
logical systems and usefulness as a source of chirality in organic
synthesis, the chiral recognition of carboxylic acids by artificial
receptors is of critical importance in the preparation, separation,
and analysis of enantiomers. In recent years, considerable effort
has been devoted to the design and synthesis of artificial recep-
tors2 for determination of enantiomeric purity and to understand
the basis of the mechanism of host-guest complexations.
Currently, the enantiomeric excess (ee) is determined by
different independent methods. In most cases, chromatography
(GC and HPLC with a chiral stationary phase) and spectroscopy
(NMR and circular dichroism) are applied. Amongst these
methods, NMR spectroscopy has the advantages of easy perfor-
mance and accessibility,3 with no need for special equipment
apart from the common NMR spectrometers. However, this
technique requires the modification of the substrate with a chiral
auxiliary, which would convert the mixture of enantiomers into
a mixture of diastereomeric molecular (covalent, chiral deriva-
tizing agent, CDA) or supramolecular (noncovalent, chiral
solvating agent, CSA) complexes.4 Ideally, these diastereomeric
species will show chemical shift nonequivalence of some of
their NMR signals, allowing the determination of the enantio-
meric composition of the substrate by the direct integration
of these bands.5 The advantage of using the CSAs relies on
the possibility of carrying out the experiment in situ, without
purification steps.6 Besides, the starting chiral materials, analyte
and CSA, could be easily recovered after the measurement.
Yang, Xiao-Feng
