Exciton chirality method in vibrational circular dichroism

Article abstract of DOI:10.1021/ja3001584

The interaction of two IR chromophores yields a strong vibrational circular dichroism couplet whose sign reflects the absolute configuration of the molecule. We present a method to determine absolute configuration of a chiral molecule based on this couplet without need of theoretical calculation. Not only can this method analyze various molecules whose absolute configuration is difficult to determine by other spectroscopic methods, but also it can significantly enhance VCD signals.

Full text of DOI:10.1021/ja3001584

Communication
pubs.acs.org/JACS
Exciton Chirality Method in Vibrational Circular Dichroism
Tohru Taniguchi* and Kenji Monde*
Faculty of Advanced Life Science, Frontier Research Center for Post-Genome Science and Technology, Hokkaido University,
Kita 21 Nishi 11, Sapporo 001-0021, Japan
S
* Supporting Information
rise to electric transition moments whose direction is virtually
ABSTRACT: The interaction of two IR chromophores
parallel to the CO bond. Moreover, carbonyl groups can be
yields a strong vibrational circular dichroism couplet whose
routinely installed to a desired part of the molecule, e.g., by
sign reflects the absolute configuration of the molecule. We
present a method to determine absolute configuration of a
chiral molecule based on this couplet without need of
esterification of a hydroxyl group. The exciton approach based on
CO stretching has been successfully applied in VCD studies of
biomacromolecules.4b,7
theoretical calculation. Not only can this method analyze
To test the feasibility of this approach in determining
various molecules whose absolute configuration is difficult to
absolute configuration, we examined the VCD spectra of chiral
determine by other spectroscopic methods, but also it can
α-hydroxylactone 1a, a common structural motif found in
significantly enhance VCD signals.
natural products such as ginkgolides,8 and its derivatives 1b and
1c (Figure 1a). Each sample was dissolved in CDCl3 at a
hirality plays fundamental roles in numerous biological
and nonbiological phenomena. The determination of
C
absolute configuration of chiral molecules is an essential step in
various research fields including pharmacological science, drug
development, biosynthesis, asymmetric reaction, total synthesis,
and supramolecular chemistry. Chiroptical spectroscopy is the
sole technique that can nonempirically determine molecular
chirality without need of crystallization. One of the most widely
used is the exciton chirality method using electronic circular
dichroism (ECD), developed by Harada and Nakanishi,1 for its
high sensitivity and the ease of spectral interpretation; however,
the requirement for two or more appropriate UV−vis chro-
mophores with proper orientation restricts its applicability. In
the past decade, vibrational circular dichroism (VCD) spectros-
copy using ab initio theoretical calculation has been established as a
reliable and convenient approach.2 Although its application to
middle-sized molecules3 and even peptides and nucleic acids4 was
successful in some cases, VCD technique has been hampered by
the low sensitivity of vibrational absorption and by the computa-
tional demand. In exploration of a more universal, sensitive method,
we envisioned the potential of an exciton coupling approach in VCD,
also classically known as a coupled oscillator model.5 So far, no study
has reported its use for the assignment of absolute configuration, in
stark contrast to the well-established ECD exciton chirality
method. Here we demonstrate the utility of the VCD exciton
coupling approach as a versatile method to determine absolute
configuration through a systematic study on small molecules.
The through-space interaction of two electric transition
moments yields a split-type bisignate CD signal that reflects the
absolute sense of the twist of the two moments:6 the positive twist
generates a positive first Cotton effect (Δε1, lower in wavenumber)
and a negative second Cotton effect (Δε2, higher in wavenumber),
and vice versa (Supporting Information (SI), Figure S1).1 The
carbonyl functional groups are promising chromophores for the
VCD exciton coupling approach because of their strong, sharp,
isolated absorption band around 1650−1800 cm−1 and because of
their well-localized CO stretching vibrational mode that gives
Figure 1. Comparison of VCD spectra of mono- and biscarbonyl
compounds. VCD (top) and IR (bottom) spectra and the arrangement
of the electric transition moments (red arrows parallel to CO
bonds) of (a) α-substituted lactones 1 and (b) mannose derivatives 2.
Each spectrum was measured using CDCl3 (c = 0.05 M, l = 100 μm)
and corrected by a solvent spectrum obtained under identical
measurement conditions. The ester carbonyls are represented as syn
to the methine hydrogen, and the ester group is in s-trans orientation.
The orientations of two carbonyl groups seen from one carbonyl
carbon to the other are presented in Figure S2.
Received: January 6, 2012
Published: February 2, 2012
© 2012 American Chemical Society
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Communication
a
Table 1. VCD Couplet by Two Carbonyl Chromophores
b
b
bc
,
d
e
Δε1 (ν [cm−1])
Δε2 (ν [cm−1])
A
θ
[deg]
R [Å]
f
(S)-1a (R = OH)
(S)-1b (R = OMe)
+0.011 (1782)
g
ND
h
(S)-1c (R = OAc)
(S)-1d (R = OBz)
−0.19 (1751)
−0.12 (1728)
−0.041 (1678)
+0.28 (1794)
+0.15 (1794)
+0.075 (1782)
−0.27 (1794)
−0.47
−0.27
−0.12
+0.44
−99
3.7
4.1
4.3
3.7
i
−135
−152
+99
h
(S)-1e (R = NHAc)
h
(R)-1c
+0.17 (1751)
g
2a (R1 = Ac, R2 = Me, R3 = Me)
2b (R1 = Me, R2 = Ac, R3 = Me)
ND
+0.025 (1747)
f
h
2c (R1 = Ac, R2 = Ac, R3 = Me)
−0.40 (1747)
+0.42 (1759)
+0.13 (1751)
+0.044 (1747)
+0.37 (1751)
+0.41 (1763)
+0.12 (1747)
−0.088 (1751)
−0.062 (1732)
−0.045 (1755)
+0.19 (1751)
+0.083 (1736)
+0.058 (1736)
+0.75 (1724)
−0.73 (1724)
−0.82
−0.20
−0.06
−0.72
−0.71
−0.23
+0.20
+0.20
+0.09
−0.34
−0.10
−0.07
−1.76
+1.73
−113
−60
−150
−83
5.6
4.8
6.3
5.1
j
2d (R1 = Me, R2 = Ac, R3 = Ac)
−0.072 (1736)
−0.016 (1736)
−0.35 (1732)
−0.30 (1747)
−0.11 (1732)
+0.11 (1740)
+0.14 (1720)
+0.044 (1736)
−0.15 (1736)
−0.020 (1712)
−0.015 (1717)
−1.01 (1697)
+1.00 (1697)
j
2e (R1 = Ac, R2 = Me, R3 = Ac)
j
2f (R1 = Bz, R2 = Ac, R3 = Me)
2g (R1 = Ac, R2 = Ac, R3 = Ac)
j
3
−61
+60
4.8
4.7
4.7
4.4
3.7
7.3
11.0
3.1
3.1
j
4a (R = Ac)
j
4b (R = Bz)
+60
j
5
+176
−61
−59
−120
−100
+100
i
6
j
7
j
8
h
(aS)-9
h
(aR)-9
a
VCD measurement conditions: 45 or 90 min accumulation, in CDCl3, l = 100 μm, c = 0.025 M (for 2f) or 0.05 M (others). Calculation condition
b
to obtain the most stable conformer: MMFF94 MonteCarlo Search or DFT optimization at B3LYP/6-311+g(d,p) or B3LYP/6-31g(d). In M−1 cm−1.
c
d
e
Amplitude of the VCD couplet, Δε1 − Δε2. Dihedral angle defined by the two CO of the most stable conformer. Interchromophoric dis-
f
g
h
tance of the most stable conformer. Only monosignate signal was detected. No significant signal was detected. DFT/B3LYP/6-311+g(d,p).
i
j
DFT/B3LYP/6-31g(d). MMFF94.
concentration of 0.05 M and placed in a 100-μm CaF2 cell. IR
and VCD spectra were measured for 2 and 90 min, respectively.
The monocarbonyl (S)-1a and (S)-1b showed a strong IR
absorption band around 1780 cm−1 with no significant VCD
features in the CO stretching region, while a simple
introduction of an acetate group ((S)-1c) resulted in a sharp
bisignate VCD signals whose intensity was amplified by more
than a factor of 25 (Table 1). A similar phenomenon was
observed for mannose derivatives 2. As shown in Figure 1b, the
bisacetate derivative 2c exhibited a VCD couplet that is more
than ∼20 times stronger than the signals of monoacetate
derivatives 2a and 2b. Comparison of the VCD spectra of
2a−2c suggests that the observed couplets were not the sum of
the signals from each CO group but should be ascribed to a
through-space and/or through-bond interaction of the two
carbonyl chromophores. Importantly, the signs of these
couplets are consistent with the absolute twist of the two
CO bonds (defined by the sign of the dihedral angle θ of two
CO groups, see Figure S1) estimated from the s-trans
conformation of the ester groups and the syn relationship
between the ester carbonyl and the methine hydrogen.1
Namely, negative−positive (from lower to higher frequency)
signals were observed for (S)-1c and 2c, both of which display a
counterclockwise chromophoric orientation (Figure 1). Density
functional theory (DFT) calculation of 1c and 2c at the
B3LYP/6-311G+(d,p) level well reproduced the observed VCD
couplets, including their signs (SI, Figure S2).
Figure 2. Structures of the biscarbonyl compounds prepared and
measured in this study.
most stable conformers of each compound calculated either by
MMFF94 MonteCarlo search or by DFT optimization (see the
SI for details). Expectedly, all compounds with a clockwise twist
(0° < θ < +180°) exhibited a positive−negative couplet (a positive
A value), while a counterclockwise screw sense (−180° < θ < 0°)
showed a negative−positive signal (a negative A value), probing
the reliability of this methodology for determination of absolute
configuration.
Furthermore, the set in Table 1 was designed to evaluate the
influence of the spatial arrangement and the nature of the chro-
mophores on the amplitude A. Although a precise correlation of
these factors could be obscured by the presence of other
conformers that contributed to the observed A value, these data
suggested some practical aspects of this approach. (1) An
increase in the energy difference between two chromophores
lowered the A value (1c−1e; 2c and 2f); it is striking that two
chromophores that differ by over 100 cm−1 yielded a couplet
(1e). (2) A dihedral angle close to 0° and 180° resulted in a
decrease in A (e.g., 2e and 5). (3) A longer interchromophoric
To bolster the generality of the relationship between the chro-
mophoric orientation and the sign of the couplets, we prepared a
series of biscarbonyl compounds (Figure 2) and measured their
VCD spectra. Table 1 lists the observed values of Δε1 and Δε2, the
amplitude of the couplet A (defined as Δε1 − Δε2), and θ of the
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distance, R, attenuated the coupling (e.g., 6 and 7). A coupling
over as far as 11 Å can be detectable unless intrinsic VCD
signals interfere, as seen in 8. In contrast, two carbonyls in the
close vicinity (∼3 Å) in 9 exhibited a huge VCD couplet that
reached to the Δε value of 1. (4) Last, the additivity rule1b
may be applied: the spectral shape of the couplet in a trischromo-
phoric system 2g was well approximated by the sum of the com-
ponent bischromophoric combinations 2c−2e (SI, Figure S3).
Although the degree of the contributions from the through-
space (excitonic) and through-bond interactions to the origin
of the VCD couplet is yet to be discussed,5b,7c this approach
shares the same features (1)−(4) with the ECD exciton chirality
method.1 In this regard, we feel it appropriate to call this
method a VCD exciton chirality method.
Not only can the VCD exciton chirality method be used as
conveniently as the ECD method, but also it can analyze
molecules that are outside of the coverage of ECD and other
spectroscopic techniques. For example, spirobicarbonyl com-
pounds such as 2,2′-spirobiindane-1,1′-dione (9), azaspirene,
and biyouyanagins9 may be categorized in such a class. This
advantage was further pronounced in our next study on
biologically and therapeutically important molecules that
include α-hydroxyketone, α-amidelactam, and dilactone
difficult targets by other methods (Figure 3). N-Tetradecanoyl
homoserine lactone 10 (a signaling molecule in bacterial
quorum sensing), picrotoxinin 11 (a GABAA receptor chloride
channel blocker), and diltiazem 12 (an antianginal and
antiarrhythmic drug) exhibited a bisignate VCD signal with
its sign corresponding to the structure. Such a couplet was also
recognized in the VCD spectrum of penicillin G 13 (SI, Figure S4).
The couplets in 12 and 13 were not perturbed by other
chromophores. In the case of taxifolin 14 (a flavanonol with a
potential chemopreventive effect), an acetate chromophore was
strategically introduced to observe a VCD coupling with the
pre-existing ketone chromophore, which led to a couplet
consistent with their clockwise chromophoric orientation. Such
bisignate strong signals were seen also in previous DFT-based
VCD studies on natural products,8b,10 although no attempt was
made to correlate the spectral shape and their molecular
structure without computation. Structural determination using
the VCD exciton chirality method does not require theoretical
calculation, and therefore it should be amenable to the analysis
of further bigger, more complex systems, which will be done in
due course.
Figure 3. VCD (top) and IR (bottom) spectra and arrangement of
two carbonyl chromophores of natural products and drugs. The
spectra were measured for 2 and 90 min, respectively, in CDCl3
(l = 100 μm) at a concentration of 0.075 M (10 and 12) or 0.05 M
(11 and 14). Each spectrum was corrected by a solvent spectrum
obtained under identical measurement conditions. Each wave-
number at the extrema is labeled in italic. The alkyl chain in the
model of 10 is omitted for clarity. The derivatization scheme of 14
is shown in (d).
The utility of this method as a signal intensifier has not
escaped our interest. Indeed, 1c exhibited a clearly observable
VCD couplet at a concentration of 2.5 mM (180-min accumula-
tion, l = 100 μm), where less than 20 μg of the sample was used,
or within a 2-min VCD accumulation (c = 0.05 M, l = 100 μm)
(SI, Figure S5). Such measurement would be impossible for the
unmodified 1a.
It should be reminded that a VCD coupling phenomenon is
not limited to carbonyl groups, although CO stretching
vibration is by far easier to analyze than absorption in a lower
frequency region. Properly used, other chromophores such as
C−O groups (data not shown) could offer useful stereostructural
information. It is intriguing to consider any of a propitious pair
of electric transition moments associated with up to 3N − 6
fundamental vibrational modes (where N is the number of the
atoms in the molecule) could be used for the exciton approach
in VCD.
originating from two IR chromophores. This technique can
analyze molecules whose absolute configuration would otherwise
be difficult to determine. Moreover, it can significantly enhance
the signals by a factor of ∼20 in the case of 1 and 2, while an
even stronger signal was observed for 9. This property would
redeem the low sensitivity of VCD spectroscopy. Supported by
the recent development of more sensitive VCD instruments,2b,11
this method should find various usages in future, e.g., analysis of
minuscule molecules with or without using theoretical
calculation or time-dependent VCD measurement.
ASSOCIATED CONTENT
■
S
* Supporting Information
Selected experimental and theoretical spectra; procedures for
experiment and calculation, synthesis, and characterization.
This material is available free of charge via the Internet at
http://pubs.acs.org.
In summary, we present a new approach for the analysis of
chiral molecules based on the bisignate VCD couplet
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AUTHOR INFORMATION
Corresponding Author
ttaniguchi@sci.hokudai.ac.jp; kmonde@sci.hokudai.ac.jp
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was partially supported by the Hoansha Foundation
and a Grant-in Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
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