Confirmation by IR of the preferred conformations of CFTA esters in solution: A highly reliable criterion for the stereochemistry assignment of chiral alcohols

Article abstract of DOI:10.1039/b926793j

Direct confirmation of the preferred conformation of diastereomeric esters derived from a chiral secondary alcohol and a chiral derivatizing agent in solution, which is crucial for reliable NMR-based assignment of absolute stereochemistry of the alcohol, has been attained for the first time by examination of IR spectra of the CFTA esters.

Full text of DOI:10.1039/b926793j

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Confirmation by IR of the preferred conformations of CFTA esters
in solution: a highly reliable criterion for the stereochemistry
assignment of chiral alcoholsw
Kenji Omata,*a Kohsuke Kotani,a Kuninobu Kabuto,a Tomoya Fujiwarab and
Yoshio Takeuchib
Received 21st December 2009, Accepted 19th March 2010
First published as an Advance Article on the web 15th April 2010
DOI: 10.1039/b926793j
Direct confirmation of the preferred conformation of diastereo-
meric esters derived from a chiral secondary alcohol and a
chiral derivatizing agent in solution, which is crucial for reliable
NMR-based assignment of absolute stereochemistry of the
alcohol, has been attained for the first time by examination of
IR spectra of the CFTA esters.
Methods to determine absolute configurations are indispensable
in research on the chemistry and applications of chiral
molecules. Currently, 1H NMR-based procedures using chiral
derivatizing agents (CDAs) such as MTPA (a-methoxy-
a-trifluoromethylphenylacetic acid, Fig. 1) are widely employed
for this purpose.1 In the CDA methods, distributions of the
signs of chemical shift differences between diastereomers (Dd)
are correlated to the absolute configuration of alcohols using
Fig. 2 A correlation model for MTPA and CFTA methods.
an empirical correlation model. Thus the determination is
made by extrapolation and therefore the reliability of the
is actually the expected one. It has been known that each
ester derivative of a common CDA exists as an equilibrium
mixture of two or more conformers including those that
give the opposite arrangement of signs to the observed ones.
The energy differences among major conformers are small
(o1 kcal molÀ1) and vary with the structures of alcohol
moieties.4 Therefore, the possibility cannot be excluded that
the observed signs of Dd values might be due to a different
conformation from the one in the model and the adoption of
the model might lead to the reversed configuration, especially
in the case of the CDA esters of sterically hindered alcohols.
In addition, the procedure has a limitation in practical use.
It becomes less reliable for those esters that have only a few
protons in the alcohol moiety.5
determination strongly depends on whether the model actually
represents a preferred conformation in solution.
A practical procedure to assess the validity of a correlation
model of Mosher’s method2 was reported by Kusumi et al.3
They introduced the following criteria: (a) The signs of Dd
values for all assignable protons should be consistent at each
side of the MTPA ester plane. (b) The signs for protons on one
side should be opposite to those on the other side of the plane
(Fig. 2).2 If these two criteria are satisfied, the correlation
model would be applicable.
It is now common practice to use this type of analysis even
for other CDA methods. However, it must be noted that this
type of procedure is insufficient for strict judgement of applica-
bility because an observed regular arrangement of the signs of
Dd values does not guarantee that the preferred conformation
We present here a simple and direct elucidation of the preferred
conformations for CFTA (a-cyano-a-fluoro-p-tolylacetic acid,
Fig. 1) esters in solution by IR spectroscopy. CFTA has a
unique structure with a fluorine and a cyano group at the
stereogenic center.6,7 For CFTA esters of various chiral
secondary alcohols, a consistent distribution of the signs of
Dd values has so far been observed (Fig. 2).7
Fig. 1 Structures of MTPA, CFTA, and CFPA.
Ab initio calculations on the methyl and menthyl esters of
CFPA (CFPA esters were used as simplified models of CFTA
a Department of Chemistry, Graduate School of Science,
Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai,
Japan 980-8578. E-mail: omata@he.tohoku.ac.jp
b Graduate School of Medicine and Pharmaceutical Sciences for
Research, University of Toyama, 2630 Sugitani, Toyama,
Japan 930-0194
esters) found only two types of conformers with respect to the
7,8
rotation around Ca–CCQO
.
One is the conformation with
the C–F bond synperiplanar (sp) to the CQO bond and the
other is antiperiplanar (ap). The sp conformers are more stable
than the ap conformers by 0.6–0.9 kcal molÀ1. The aromatic
plane in each conformer is facing either the R1 or R2 group of
w Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/b926793j
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Table 1 Absorptions of CQO stretching bands observed for CFTA
esters of chiral secondary alcohols (CFTA-OR*) in CHCl3 solutions
n
CQO/cmÀ1
b
entry alcohol moiety (R*)
R/Sa
band I band II AI/AII
Fig. 3 The predicted conformational equilibrium in CFTA esters.
1
2
3
4
5
6
7
8
(R)-1-phenylethyl
(S)-1-phenylpropyl
(R)-2-(4-methylpentyl)
(R)-2-octyl
S
R
S
R
S
R
S
R
1772 1752
1771 1751
1771 1750
1771 1749
1766 1748
1755 1746
1772 1754
1771 1751
1765 1747
1772 1752
1766 1748
1766 1747
1768 1750
1768 1748
1766 1756
1766 1748
1767 1751
1768 1751
1767 1749
1767 1746
1767 1747
1767 1748
2.3
2.3
4.8
6.6
3.5
4.0
6.6
2.2
3.5
2.8
2.2
2.3
1.6
1.9
3.7
3.4
1.8
1.6
3.3
3.5
2.4
1.8
the alcohol moiety. In the case of the menthyl esters, the C–H
bond on the carbinyl carbon is syn to the CQO bond in
each diastereomer, as is well known for esters of secondary
alcohols. The simple conformational preference (Fig. 3)
suggested by the calculations is consistent with the correlation
model for the CFTA method.
9
(R)-1-(2-methyl-1-phenylpropyl) S
R
(1R,2S,5R)-menthyl
10
11
12
13
14
15
16
17
18
19
20
21
22
S
R
S
R
S
R
S
R
S
R
S
R
In order to examine the preferred conformers, we attempted
to detect the individual conformers of twelve diastereomeric
pairs of CFTA esters by IR spectroscopy9 in CHCl3, taking
into consideration the solvent (CDCl3) that was used for
NMR measurement. The absolute configurations of the alcohol
moieties of all these CFTA esters are in good agreement with
those expected from the signs of Dd values using the corre-
lation model based on the sp conformation. In a typical
example, the CQO stretching band for the (R)-CFTA ester of
(1R,2S,5R)-menthol has a strong absorption around 1765 cmÀ1
with a weaker one as a shoulder around 1750 cmÀ1 (Fig. 4).
The carbonyl absorption with a distinct shoulder represents
a marked difference from the absorption of the MTPA ester
which does not show an apparent shoulder.10 Curve-fitting of
the CQO stretching band for all of the CFTA esters examined
revealed absorptions around 1770 cmÀ1 (band I) and around
1750 cmÀ1 (band II) (Table 1).
(1S,2R,5R)-isomenthyl
(1S,2S,5R)-neomenthyl
(1R,2R)-2-exo-bornyl
(1S,2R)-2-endo-bornyl
3b-5,6-dihydrocholesteryl
a
b
Absolute configuration of CFTA moiety. Ratio of areas of band I
and band II absorptions.
Table 2 Observed and calculated absorption of CQO stretching for
CFTA esters (CFTA-OR*) in CHCl3 solutionsa
n
CQO/cmÀ1
band I sp
It should be noted that the band I absorptions are consis-
tently stronger than the band II absorptions. The band I and II
absorptions were assigned to the sp and ap conformers,
respectively, of three diastereomeric pairs of the CFTA esters
by vibrational analysis.11 The observed and calculated frequen-
cies are summarized in Table 2. The calculated frequencies
band II ap
(obsd) (calcd) (obsd) (calcd)
alcohol
entry moiety (R*)
R/Sb
1
2
3
4
5
6
(R)-1-phenylethyl
(1R,2R)-2-exo-bornyl
S
R
S
R
1772
1771
1767
1767
1767
1768
1783
1777
1775
1775
1774
1773
1752
1751
1749
1746
1751
1751
1749
1755
1750
1751
1749
1750
CQO for the sp conformers were 1773–1783 cmÀ1, while those
(1S,2R)-2-endo-bornyl S
R
n
for the ap conformers were 1749–1755 cmÀ1. These calculated
frequencies for the sp and ap conformers were in fair agree-
ment with those of the observed bands I and II, respectively.
The calculated intensities of the two absorptions were quite
similar, indicating that they have similar molar extinction
coefficients. Therefore, if one absorption band is clearly
stronger than the other, the preferential conformer of the
CFTA ester becomes clear. In the present cases, predominance
of the sp conformers over the corresponding ap conformers in
a
Vibrational analysis was conducted on the sp and ap conformers
calculated at the B3YLP/6-31G(d) level using the Gaussian 03
program.11 Scaling factor 0.9613. Absolute configuration of CFTA
moiety.
b
the equilibrium in chloroform solutions was ensured without
the curve-fitting.
Thus, we have developed a facile confirmation of the
preferred conformer of individual CFTA esters. This is the
first direct solution to the ambiguity of the stereochemistry
assignment using CDAs. This confirmation makes the CFTA
method an even more reliable one than any other conventional
CDA procedures.
Notes and references
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Fig. 4 nCQO band for (S)-CFTA ester of (1R,2S,5R)-menthol.
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