A practical solvating agent for the chiral NMR discrimination of carboxylic acids

Article abstract of DOI:10.1002/ejoc.201100692

A bisimidazoline compound has been prepared as a new chiral solvating agent starting from isophthalaldehyde and (S,S)-1,2-diphenylethylenediamine through a single-step synthesis. In the presence of one equivalent of this reagent, carboxylic acid racemates

Full text of DOI:10.1002/ejoc.201100692

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201100692
A Practical Solvating Agent for the Chiral NMR Discrimination of Carboxylic
Acids
Seon-mi Kim[a] and Kihang Choi*[a]
Keywords: Chirality / Chiral auxiliaries / Enantiomeric purity / NMR spectroscopy
A bisimidazoline compound has been prepared as a new chi-
ral solvating agent starting from isophthalaldehyde and
equivalences large enough for the discrimination of the
enantiomers. Studies with related compounds showed that
the 1,3-disubstituted structure is crucial for the acid-solvating
ability of the bisimidazoline compound.
(S,S)-1,2-diphenylethylenediamine through
a single-step
synthesis. In the presence of one equivalent of this reagent,
carboxylic acid racemates show 1H NMR chemical shift non-
mers, preparations of these reagents usually require
multistep syntheses, which greatly limit their practical appli-
cation.
Introduction
With the advent of asymmetric synthesis, there is a grow-
ing demand for the development of simple and fast methods
to determine the enantiomeric purity of chiral compounds.
One of the traditional approaches for this purpose is to uti-
lize chiral reagents in combination with NMR spec-
troscopy: Enantiomers are covalently modified with chiral
derivatizing agents (CDAs) or solvated with chiral solvating
agents (CSAs), and the resulting diastereomeric species are
analyzed by NMR spectroscopy.[1] Although the CDA
method could provide additional information on the abso-
lute configuration of chiral compounds, it requires a
derivatization step. Therefore, the CSA method is generally
preferred for the NMR spectroscopic analysis of enantio-
meric purity.[1] CSAs interact with chiral substrates through
noncovalent bond interactions. Once mixed with a CSA,
two enantiomers of a chiral substrate may show different
NMR chemical shift values because of the difference in
time-averaged solvation environments caused by the CSA.
Various CSAs have been developed for different classes of
compounds, and for the case of carboxylic acid substrates,[2]
many CSAs reported so far consist of either an optically
pure amine or amide because they can form strong ionic or
hydrogen-bonding interactions with the substrate. Although
these amine- or amide-based CSAs can afford relatively
large spectral differences between the substrate enantio-
Herein, we report that bisimidazoline 1 (Figure 1) is an
efficient and readily available CSA for the chiral NMR dis-
crimination of carboxylic acids. It has been known that a
1,3,5-trisubstituted benzene with three imidazoline groups
can form 1:3 complexes with carboxylic acids or tetrazoles
through hydrogen bonding.[3] We envisioned that a closely
related 1,3-disubstituted compound, bisimidazoline 1, de-
rived from a chiral diamine could also form interactions to
solvate carboxylic acids. We also expected that the carbox-
ylic acid enantiomers complexed with the reagent would ex-
perience significantly different magnetic environments be-
cause the substrate binding site is very close to the reagent’s
chirality centers substituted with anisotropic aromatic rings.
[a] Department of Chemistry and Research Institute for Natural
Sciences, Korea University,
Seoul 136-701, Republic of Korea
Fax: +82-2-3290-3121
Figure 1. (a) Interaction between bisimidazoline 1 and carboxylic
acids. (b) Previously reported 1:3 trisimidazoline/carboxylic acid
complex.
E-mail: kchoi@korea.ac.kr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100692.
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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S.-m. Kim, K. Choi
SHORT COMMUNICATION
CSA than other compounds studied and strongly support
the interaction mode suggested (Figure 1), in which the cleft
between the two imidazoline rings is used for substrate
binding.
Results and Discussion
We synthesized designed compound 1 from commercially
available (S,S)-1,2-diphenylethylenediamine (2) and iso-
phthalaldehyde following
a well-established procedure
The structural properties of bisimidazoline 1 were further
investigated by using conformational search and ab initio
calculations.[6] In the lowest-energy conformation (Fig-
ure 2), an N–H bond is projected into the cleft surrounded
by two benzene rings, and on the other side of the cleft
an sp2-hybridized N atom is positioned. Prompted by this
interesting arrangement of the potential hydrogen-bonding
donor and acceptor in close proximity (≈4.5 Å), we tested
1 for the solvation of other classes of compounds with hy-
drogen-bonding abilities like esters, ketones, aldehydes,
alcohols, and nitro compounds. The tested racemates
showed no separation of enantiomer signals under the same
conditions as those listed in Table 1; the only exception was
the case of alcohols, but the ΔΔδ values were very small.[7]
These results suggest that 1 can solvate carboxylic acids se-
lectively, and in addition to hydrogen bonding, the charge–
charge interaction after proton transfer between the imid-
azoline and carboxyl groups is presumably responsible for
this selectivity.
(Scheme 1).[4] This one-pot condensation/oxidation reaction
proceeded smoothly and provided the desired compound in
high yield.
Scheme 1. Synthesis of bis- and monoimidazoline compounds.
Next, we tested the chiral discrimination ability of 1 with
a racemic mixture of 2-methylbutyric acid (R = CH3, RЈ =
CH2CH3 in Figure 1). Addition of 1 (1 equiv.) produced a
chemical shift nonequivalence (ΔΔδ) of 0.07 ppm for the α-
methyl protons of the acid, showing that this structurally
simple CSA can provide chiral environments to acid sub-
strate enantiomers and induce chemical shift differences
comparable with those obtained with previously reported
receptors.[2]
To investigate the relationship between the receptor
structure and the chiral discrimination ability, we also syn-
thesized imidazoline 3 and 4, the para- and monosubsti-
tuted analogues of bisimidazoline 1, respectively
(Scheme 1).[5] Addition of these imidazoline analogues to 2-
methylbutyric acid (1 equiv.) induced small upfield shifts in
the NMR signals of the substrate, but the separation of the
enantiomer signals is almost negligible (Table 1). A similar
result was obtained when chiral diamine 2 was added to the
acid substrate. The ΔΔδ values summarized in Table 1
clearly show that bisimidazoline 1 is a much more efficient
Figure 2. Calculated structure (left; C, gray; H, white; N, blue) and
electrostatic potential plot (right; blue, positive; red, negative) of
bisimidazoline 1.
Having demonstrated that the 1,3-disubstituted structure
is crucial for the solvation and chiral discrimination ability
of the carboxylic acid, we investigated the utility of 1 as
a versatile CSA with a variety of acid racemates. Figure 3
summarizes the obtained results in the presence of 1
(1 equiv. with respect to the racemates) at 5 mm concentra-
tion. In all cases, the separation of at least one signal is
large enough to have baseline resolution in the NMR spec-
tra (400 MHz), and the ΔΔδ values are comparable to the
values previously reported with other CSAs. The C2H pro-
ton of 1 exhibited large downfield shifts (0.4–1.0 ppm) upon
complexation, whereas the C4H and C5H protons were
shifted upfield (0.1–0.2 ppm), confirming that the substrate
interaction occurs close to the C2H proton.
Table 1. Chemical shift nonequivalences of the methyl protons of
2-methylbutiric acid induced by compounds 1–4.[a]
CH3CH–
δ (ppm)
CH3CH–
ΔΔδ
CH3CH2CH– CH3CH2CH–
δ (ppm)
ΔΔδ
None
1.19
0.89/0.82
1.16
1.14
1.15
–
0.07
Ͻ0.005
Ͻ0.005
Ͻ0.005
0.95
–
0.02
0.005
0.005
Ͻ0.005
To reduce the chance of accidental signal overlap, it is
preferred to use structurally simple CSAs in chiral NMR
discrimination studies. Addition of 1 to the substrate does
1
2
3
4
0.69/0.67
0.936/0.931
0.917/0.912
0.92
1
not make it more complicated to analyze the aliphatic H
signals of the substrates; because of the molecular sym-
metry, there is only one aliphatic signal due to 1, and this
singlet signal from the four protons attached to the CSA
[a] 1H NMR (400 MHz) spectra of 2-methylbutyric acid (5 mm in
CDCl3 at 25 °C) were recorded in the presence of compounds 1–4
(1 equiv.).
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Solvating Agent for the Chiral NMR Discrimination of Carboxylic Acids
7.28–7.38 (m, 20 H), 5.53 (br. s, 2 H), 4.94 (br. s, 4 H) ppm. 13C
NMR (100 MHz, CDCl3, TMS): δ = 162.4, 143.2, 130.4, 129.9,
128.9, 128.7, 127.5, 126.6, 126.1 ppm (the signal of the sp3 carbon
atoms of the imidazolidine rings was not detected owing to tauto-
merization). HRMS (FAB): calcd. for C36H31N4 [M + H]+
519.2549; found 519.2557.
1,4-Bis[(4S,5S)-4,5-diphenyl-4,5-dihydro-1H-imidazol-2-yl]benzene
(3): The procedure described for compound 1 was followed except
that terephthalaldehyde was used instead of isophthalaldehyde.
Yield: 87%. M.p. 266–271 °C. [α]2D1 = –8.4 (c = 0.5, CHCl3). 1H
NMR (400 MHz, CDCl3, TMS): δ = 8.06 (s, 4 H), 7.30–7.40 (m,
20 H), 5.43 (br. s, 2 H), 4.92 (br. s, 4 H) ppm. 13C NMR (100 MHz,
CDCl3, TMS): δ = 162.6, 143.2, 132.4, 128.7, 127.59, 127.55,
126.6 ppm (the signal of the sp3 carbon atoms of the imidazolidine
rings was not detected owing to tautomerization). HRMS (FAB):
calcd. for C36H31N4 [M + H]+ 519.2549; found 519.2546.
(4S,5S)-2,4,5-Triphenyl-4,5-dihydro-1H-imidazole (4): The pro-
cedure described for compound 1 was followed except that benzal-
dehyde was used instead of isophthalaldehyde and the amount of
diamine 2 was adjusted to one equivalent. Yield: 92%. M.p. 160 °C.
1
[α]2D3 = –79 (c = 0.5, CHCl3). H NMR (400 MHz, CDCl3, TMS):
Figure 3. ΔΔδ values of carboxylic acid racemates measured in the
presence of bisimidazoline 1 (1 equiv.). Conditions as those listed
in Table 1 were used.
δ = 7.95–7.98 (m, 2 H, o-CH), 7.46–7.54 (m, 3 H), 7.29–7.38 (m,
10 H), 5.35 (br. s, 1 H), 5.12 (br. s, 1 H), 4.74 (br. s, 1 H) ppm. 13
C
NMR (100 MHz, CDCl3, TMS): δ = 163.0, 143.5, 131.0, 130.2,
128.7, 128.6, 127.5, 127.4, 126.6 ppm (the signal of the sp3 carbon
atoms of the imidazolidine ring was not detected owing to tauto-
merization). HRMS (FAB): calcd. for C21H19N2 [M + H]+
299.1548; found 299.1544.
chiral centers can be easily distinguished from the substrate
signals on the basis of the multiplet pattern and the integral
value.
Supporting Information (see footnote on the first page of this arti-
cle): NMR spectra of carboxylic acid racemates in the presence of
compound 1.
Conclusions
We have presented a bisimidazoline-based CSA for the
chiral discrimination of carboxylic acids. The reagent could
be prepared through an efficient, one-step synthesis from
commercially available starting materials. Unlike previously
reported CSAs, our reagent with highly symmetric structure
displays very simple NMR signals reducing the probability
of accidental overlap with substrate signals. The separation
of substrate enantiomer signals is large enough to have
baseline resolution in the presence of one equivalent of the
CSA. Combining its simple structure and facile synthesis, 1
could provide a practical NMR spectroscopic method to
discriminate carboxylic acid enantiomers.
Acknowledgments
This work was supported by the National Research Foundation of
Korea funded by the Ministry of Education, Science and Technol-
ogy through a grant (No. 2010–0000176) and Priority Research
Centers Program (No. 2010–0020209).
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Experimental Section
1,3-Bis[(4S,5S)-4,5-diphenyl-4,5-dihydro-1H-imidazol-2-yl]benzene
(1): Isophthalaldehyde (0.10 g, 0.76 mmol) and (1S,2S)-1,2-diphen-
ylethylenediamine (2; 0.33 g, 2.0 equiv.) were dissolved in CH2Cl2
(10 mL). After 1 h of stirring, N-bromosuccinimide (NBS, 0.27 g,
2.0 equiv.) was added to the solution at 0 °C, and then the mixture
was stirred overnight at room temperature. After adding saturated
NaHSO3 and 5% KOH aqueous solutions, the mixture was ex-
tracted with CH2Cl2. The organic layer was dried with anhydrous
Na2SO4 and concentrated under reduced pressure. The residue was
purified by SiO2 chromatography to give the product as a white
1
solid (0.38 g, 95%). M.p. 134 °C. [α]2D0 = –46 (c = 0.5, CHCl3). H
NMR (400 MHz, CDCl3, TMS): δ = 8.52 (s, 1 H, C2-H), 8.12 (d,
3JH,H = 7.9 Hz, 2 H, C4-H), 7.58 (t, JH,H = 7.9 Hz, 1 H, C5-H),
3
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S.-m. Kim, K. Choi
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shima, S. Hayashi, Y. Takahara, H. Fujioka, Org. Lett. 2010,
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[5] Our attempts to synthesize the ortho-substituted analogue from
phthalaldehyde only yielded complex, inseparable product mix-
tures.
MMFF force field to find the lowest-energy conformation,
which was then used as an initial structure for the ab initio
geometry optimization (RHF/6-31G*). The electrostatic poten-
tial map was calculated at the same level of theory.
[7] For example, the CH3 proton signals of sec-butyl alcohol were
resolved in the presence of bisimidazoline 1 with ΔΔδ values
less than 0.005 ppm.
[6] Spartan06 (Wavefunction, Inc.) was used for the calculation. A
Monte Carlo conformation search was performed by using the
Received: May 18, 2011
Published Online: July 18, 2011
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Eur. J. Org. Chem. 2011, 4747–4750