Absolute configuration assignment of inherently chiral calix[4]arenes using DFT calculations of chiroptical properties

Article abstract of DOI:10.1021/ol101098x

The racemate of an inherently chiral meta-substituted calix[4]arene derivative 3 has been resolved via enantioselective HPLC. Measured optical rotation dispersion and electronic circular dichroism have been compared with DFT theoretical predictions. The comparison indicates that the absolute configuration of the dextrorotatory enantiomer (+)-3 is cS. The procedure has been successfully tested against a literature precedent confirming the validity of the method.

Full text of DOI:10.1021/ol101098x

ORGANIC
LETTERS
2010
Vol. 12, No. 13
2912-2915
Absolute Configuration Assignment of
Inherently Chiral Calix[4]arenes using DFT
Calculations of Chiroptical Properties
Carmen Talotta,† Carmine Gaeta,† Francesco Troisi,† Guglielmo Monaco,†
Riccardo Zanasi,*,† Giuseppe Mazzeo,‡ Carlo Rosini,‡,§ and Placido Neri*,†
Dipartimento di Chimica, UniVersita` di Salerno, Via Ponte don Melillo, I-84084
Fisciano (Salerno), Italy, and Dipartimento di Chimica, UniVersita` della Basilicata,
Via N. Sauro 85, 85100 Potenza, Italy
rzanasi@unisa.it; neri@unisa.it
Received February 11, 2010
ABSTRACT
The racemate of an inherently chiral meta-substituted calix[4]arene derivative 3 has been resolved via enantioselective HPLC. Measured optical
rotation dispersion and electronic circular dichroism have been compared with DFT theoretical predictions. The comparison indicates that the
absolute configuration of the dextrorotatory enantiomer (+)-3 is cS. The procedure has been successfully tested against a literature precedent
confirming the validity of the method.
Inherently chiral calixarenes,1,2 whose fascinating chirality
is due to an asymmetric substitution pattern coupled to their
nonplanar molecular geometry, have attracted the attention
of several research groups over the past two decades because
of their potential applications in several enantiodiscrimination
processes such as recognition,3 catalysis,3a,4 and sens-
ing.5
Their practical exploitation has been somewhat delayed
by a difficult optical resolution, which usually has been
achieved by enantioselective HPLC methods.6 However, as
recently demonstrated by Huang and co-workers, appropriate
procedures can be devised to obtain gram-scale quantities
(3) For typical representative examples, see: (a) Araki, K.; Inada, K.;
Shinkai, S. Angew. Chem., Int. Ed. Engl. 1996, 35, 72. (b) Narumi, F.;
Hattori, T.; Matsumura, N.; Onodera, T.; Katagiri, H.; Kabuto, C.;
Kameyama, H.; Miyano, S. Tetrahedron 2004, 60, 7827. (c) Luo, J.; Zheng,
Q.-Y.; Chen, C.-F.; Huang, Z.-T. Tetrahedron 2005, 61, 8517. (d)
Shirakawa, S.; Moriyama, A.; Shimizu, S. Org. Lett. 2007, 9, 3117. (e)
Shirakawa, S.; Moriyama, A.; Shimizu, S. Eur. J. Org. Chem. 2008, 5957.
(4) (a) Dieleman, C.; Steyer, S.; Jeunesse, C.; Matt, D. J. Chem. Soc.,
Dalton Trans. 2001, 2508. (b) Xu, Z.-X.; Li, G.-K.; Chen, C.-F.; Huang,
Z.-T. Tetrahedron 2008, 64, 8668. (c) Shirakawa, S.; Kimura, T.; Murata,
S.-I.; Shimizu, S. J. Org. Chem. 2009, 74, 1288. (d) Shirakawa, S.; Shimizu,
S. Eur. J. Org. Chem. 2009, 1916.
† Universita` di Salerno.
‡ Universita` della Basilicata.
§ Deceased.
(1) For comprehensive reviews on calixarenes, see: (a) Bo¨hmer, V.
Angew. Chem., Int. Ed. Engl. 1995, 34, 713. (b) Ikeda, A.; Shinkai, S. Chem.
ReV. 1997, 97, 1713. (c) Gutsche, C. D. Calixarenes ReVisited; Royal Society
of Chemistry: Cambridge, 1998. (d) Calixarenes 2001; Asfari, Z., Bo¨hmer,
V., Harrowfield, J., Vicens, J., Eds.; Kluwer: Dordrecht, 2001
.
(2) For reviews on inherently chiral calixarenes, see: (a) Bo¨hmer, V.;
Kraft, D.; Tabatabai, M. J. Inclusion Phenom. Mol. Recognit. 1994, 19,
17. (b) Otsuka, H.; Shinkai, S. Supramol. Sci. 1996, 3, 189. (c) Vysotsky,
(5) Luo, J.; Zheng, Q.-Y.; Chen, C.-F.; Huang, Z.-T. Tetrahedron 2005,
61, 8517.
(6) For typical examples of enantioselective HPLC resolution of
inherently chiral calixarenes, see ref 2 in the Supporting Information.
M.; Schmidt, C.; Bo¨hmer, V. AdV. Supramol. Chem. 2000, 7, 139
.
10.1021/ol101098x  2010 American Chemical Society
Published on Web 06/07/2010

of enantiopure inherently chiral calix[4]arene derivatives to
be used for subsequent applications.7
The absolute configuration of inherently chiral calixarenes
has been rarely assigned, usually by single-crystal X-ray
diffractometry.8 Considering the intrinsic difficulties com-
monly associated with this method, we wish to apply here a
more general and practical approach based on DFT calcula-
tions and solution measurements of chiroptical properties.
We have found workable, within reasonable computational
limits, the prediction of optical rotation at several experi-
mental wavelengths, that is a portion of the optical rotation
dispersion (ORD) curve,9 as well as the calculation of the
electronic circular dichroism (ECD) spectrum.10
Figure 1.
Methylene region of the 1H NMR spectrum (CDCl3, 400
MHz, 298 K) of 1 before (bottom) and after (top) addition of
Pirkle’s reagent.
Very recently, we have evidenced that inherently chiral
meta-substituted calix[4]arenes11 can be easily obtained by
exploiting the so-called “p-bromodienone route”12 with
highly activated aromatic substrates.13 In this case, the key
event that leads to chiral meta substitution is a clockwise or
counterclockwise dienone-phenol rearrangement of the
p-aryldienone intermediate 2 (Scheme 1). In this way, among
A definitive proof was obtained by enantioselective HPLC
on Chiralpak ADH stationary phase that, by using 2-pro-
panol/n-hexane (2:98) as mobile phase, led to a good
resolution (resolution factor Rs ) 3.47) of the two enantio-
meric peaks.14 The two enantiomers were obtained after
repeated injections and collection of the eluates correspond-
ing to the two chromatographic peaks. Analytical HPLC
reruns of these peaks gave values of enantiomeric excess
(ee) > 99.9% and of 98.6% for the first and second one,
respectively.14 The ECD spectra of both eluates were
measured and they were mirror images of each other
indicating their enantiomeric nature (Figure 2).
Scheme 1
different other aromatic moieties, a phloroglucinol ring was
introduced at the meta position of a calix[4]arene macrocycle
leading to inherently chiral derivative 3 (Scheme 1).13
The racemic nature of 3 was evidenced by the doubling
of several resonances in its 1H NMR spectrum upon addition
of Pirkle’s reagent [(S)-(+)-(9-antryl)-2,2,2-trifluoroethanol]
(Figure 1).
Figure 2
fractions, corresponding to (+)-3 and (-)-3, respectively. ∆ε in
M-1 cm-1
. ECD spectra of first (green) and second (red) HPLC
.
In accordance with this result, a specific rotation [R]25
D
of +108 (c 0.16, CH2Cl2) was measured for the first-eluted
sample of compound 3 while the second one afforded an
(7) Miao, R.; Zheng, Q.-Y.; Chen, C.-F.; Huang, Z.-T. J. Org. Chem.
2005, 70, 7662.
(8) (a) Narumi, F.; Hattori, T.; Yamabuki, W.; Kabuto, C.; Kameyama,
H. Tetrahedron: Asymmetry 2005, 16, 793. (b) Xu, Z.-X.; Zhang, C.; Zheng,
Q.-Y.; Chen, C.-F.; Huang, Z.-T. Org. Lett. 2007, 9, 4447. (c) h, M. A.;
Yesypenko, O. A.; Pirozhenko, V. V.; Shishinka, S. V.; Shishkin, O. V.;
Boyko, V. I.; Kalchenko, V. I. Tetrahedron 2009, 65, 7085.
(9) Giorgio, E.; Viglione, R. G.; Zanasi, R.; Rosini, C. J. Am. Chem.
Soc. 2004, 126, 12968, and references therein.
(11) Notwithstanding the special interest for the inherent chirality of
meta-substituted calix[4]arenes, functionalizations at the meta position of
calixarene aromatic rings are relatively uncommon. For some representative
examples, see: (a) Reddy, P. A.; Gutsche, C. D. J. Org. Chem. 1993, 58,
3245. (b) Verboom, W.; Bodewes, P. J.; Essen, G. V.; Timmerman, P.;
Hummer, G. J. V.; Harkema, S.; Reinhoudt, D. N. Tetrahedron 1995, 51,
499. (c) Mascal, M.; Warmuth, R.; Naven, R. T.; Edwards, R. A.;
Hursthouse, M. B.; Hibbs, D. E. J. Chem. Soc., Perkin Trans. 1 1999, 3435.
(d) Barton, O. G.; Neumann, B.; Stammler, H.-G.; Mattay, J. Org. Biomol.
Chem. 2008, 6, 104.
(10) For comprehensive articles on ECD, see: (a) Circular Dichroism,
Principles and Applications; Berova, N., Nakanishi, K., Woody, R. W.,
Eds.; Wiley-VCH: New York, 2000.
Org. Lett., Vol. 12, No. 13, 2010
2913

experimental [R]25D of -106.5 (c 0.12, CH2Cl2), in agreement
with its 98.6% ee.
the H-bond directed either on the left or on the right, using the
starting geometry of the lowest energy MMFF94 conformer.
We end up with the two conformations a and b shown in Figure
3. The B3LYP/6-31G* relative energy of b with respect to a
was 1.12 kcal/mol, corresponding to a mixture of 87% of a
and 13% of b of Boltzmann populations at 298 K.14
The specific rotation of the optical isomer contained in
the first-eluted HPLC fraction (+)-3 was measured for a
number of wavelengths at room temperature (c 0.16, CH2Cl2)
to obtain a portion of its optical rotation dispersion (ORD)
curve (see Figure 4, black line). The OR’s of conformers a
In order to assign the absolute configuration of each eluted
sample we considered the cS configuration15 of 3 for the DFT
calculations.14 A MMFF94/Monte Carlo conformational search
was performed using Spartan 0216 with default parameters and
by fixing the propyloxy tails to a zigzag shape. The resulting
conformations were subjected to geometry optimization using
Gaussian 0317 at the B3LYP/6-31G* level. OR and ECD
calculations were performed at TDDFT/B3LYP level, as
implemented in Gaussian 03, using a number of basis sets of
different composition (see later for a description).
Owing to the rigid calix[4]arene structure and the fixed
propyloxy tails, only four conformations were detected by
MMFF94/Monte Carlo search, which differ mainly for the
different orientation of the three OH groups of the phloro-
glucinol moiety. The ring of the latter was found almost
perpendicular to the linked calixarene aryl ring.14
The orientation of the OH group at the para position of this
ring is of very low importance, conversely the two OH groups
at the meta positions show a markedly preferred orientation
pointing toward the center of the linked calixarene aryl ring,
most likely due to OH-π interactions.18 Considering the
noninfluential orientation of the phloroglucinol OH group in
the para position and discharging all MMFF94 conformations
with a relative energy exceeding 3.5 kcal/mol, that is with
vanishing populations, only one conformation remains (very
similar to conformer a in Figure 3) in which the OH group at
Figure 4. Portion of the ORD curve experimentally measured for
(+)-3 (black line) (c 0.16, CH2Cl2, 298 K) and theoretically
calculated for cS-3 at the TDDFT/B3LYP level using 6-31G* (red),
6-31G(2d,1p) (green), and cc-pVDZ(d) (blue).
and b of cS-3 were computed using the TDDFT/B3LYP
method.19 Solvent was not included.
The choice of the basis set(s) was based on the following
arguments. It is generally agreed that diffuse functions are
necessary for the calculation of chiroptical properties.20 How-
ever, according to some preliminary tests,14 diffuse functions
have to be included on a well balanced basis set. In the present
case, this implies a rather big basis set requiring prohibitively
large computational resources. On the other hand, the inclusion
of polarization functions improves the description of excited
states at higher energy, which could be important for the OR
predictions. Therefore, considering the large size of 3, we
decided to adopt the 6-31G* basis set to compute the OR for
all the wavelengths considered in the experimental measure and
two larger basis sets containing polarization functions, i.e.,
6-31G(2d,1p) and cc-pVDZ(d)21 to compute the OR at 589.3
and 405 nm. The predicted ORD obtained as weighted sum
over the conformations is compared with the experimental data
in Figure 4. As can be observed the agreement, in terms of OR
sign and ORD trend, is fairly good with all the three basis sets
and in particular with the smaller 6-31G* one.
Figure 3. Top view of conformers a and b of cS-3 optimized at
the B3LYP/6-31G* level, showing the different orientation of the
H-bond at the lower rim.
the lower rim establishes a single H-bond with the OPr group
on the left. Any attempt to reorient the H-bond at the lower
rim toward the other OPr group on the right was unsuccessful
after MMFF94 energy minimization. We interpreted this as a
failure of the MMFF94 force field, and we decided to perform
a B3LYP/6-31G* geometry optimization of both structures with
(12) Troisi, F.; Pierro, T.; Gaeta, C.; Neri, P. Org. Lett. 2009, 11, 697.
(13) Troisi, F.; Pierro, T.; Gaeta, C.; Carratu`, M.; Neri, P. Tetrahedron
Lett. 2009, 50, 4416.
(14) See the Supporting Information for further details.
(15) Dalla Cort, A.; Mandolini, L.; Pasquini, C.; Schiaffino, L. New
J. Chem. 2004, 28, 1198.
(19) Stephens, P. J.; Devlin, F. J.; Cheeseman, J. R.; Frisch, M. J. J.
Phys. Chem. A 2001, 105, 5356.
(20) Autcshbach, J. Chirality 2009, 21, E116.
(16) Spartan 02; Wavefunction, Inc., Irvine, CA.
(17) Frisch et al. Gaussian 03, Gaussian, Inc., Pittsburgh, PA, 2003.
(18) Atwood, J. L.; Hamada, F.; Robinson, K. D.; Orr, G. W.; Vincent,
R. L. Nature 1991, 349, 683.
(21) The cc-PVDZ(d) basis set has been obtained from the smaller cc-
PVDZ basis set by adding a single set of d functions to heavy atoms. The
exponents of these diffuse functions are those of the most diffuse d functions
of the standard aug-cc-PVDZ basis set.
2914
Org. Lett., Vol. 12, No. 13, 2010

The ECD spectra of conformers a and b of cS-3 were
computed using the TDDFT/B3LYP method, adopting a
number of different basis sets, i.e., 6-31G*, 6-31G(2d,1p), cc-
pVDZ, and cc-pVDZ(d), using the first 50 rotational strengths.14
Also in this case the solvent was not included. The weighted
sum of the two conformers is compared with the experimental
ECD spectrum of the first-eluted HPLC fraction in Figure 5.
have been also reported.8b Considering its unreliable low value,
we neglected OR calculations.22 We then focused on the ECD
and started our analysis, adopting the cS configuration of 4a
and performing the calculation as in the case of 3. Fixing the
propyloxy tails, the procedure provided one conformer corre-
sponding to the X-ray structure reported by Xu et al.8b A second
conformer, which could be described as the opposite pinched-
cone, with a higher relative energy of 2.02 kcal/mol, was also
taken into account. The weighted TDDFT/B3LYP ECD spectra
calculated using 6-31G* and cc-pVDZ basis sets are reported
in Figure 6.
Figure 5. Comparison of the experimental (black) and TDDFT/
B3LYP predicted ECD spectra.
Figure 6.
TDDFT/B3LYP ECD spectra of compound 4a.8b
Although the computed molar circular dichroism (∆ε) is
significantly underestimated, the agreement between theoretical
and experimental ECD spectra, in terms of form and sign of
the bands with respect to wavelengths, can be considered
satisfactorily. Remarkably, the 6-31G* simulation is very similar
to those obtained with the much more expensive 6-31G(2d,1p)
and cc-pVDZ(d) basis sets. Deviations in ∆ε can be mainly
attributed to the lack of diffuse functions and solvent effect.
In summary, we remark that (i) the OR magnitude at 589.3
nm is large enough to be considered for a reliable ab initio
assignment,22 (ii) the trend of the theoretical ORD curves
match the experimental one,9 and (iii) the sequence of bands
in the ECD spectrum, even if not to scale, is well reproduced.
Recalling that the application of more than one chiroptical
spectroscopic method is recommended to obtain reliable
molecular structural information,23 we feel confident to
conclude that the absolute configuration of (+)-3 is cS-3.
To provide additional support of the validity of the above
conclusion, we decided to perform an additional test of our
method on an inherently chiral calixarene with known absolute
configuration. The case reported by Xu et al.8b appeared to be
appropriate for our purposes. In particular, we focused our
attention on compound 4a of that reference, which is a m-Br-
substituted inherently chiral calix[4]arene, whose absolute
configuration was determined by a single-crystal X-ray diffrac-
Although the molar circular dichroism (∆ε) is not directly
comparable with the mdeg of ellipticity used in Figure 2 of
ref 8b, the agreement with the experimental spectrum (form
and sign of the bands with respect to wavelengths) is
reasonably good. On this basis, the DFT-predicted absolute
configuration is the same as that experimentally determined
by X-ray diffractometry. This result provides further support
for the validity of our approach.
In conclusion, the absolute configuration of the two
enantiomers of inherently chiral, meta-substituted calix[4]arene
3, resolved via enantioselective HPLC, has been determined
using DFT calculations of chiroptical properties measured
in solution. Considering the current reasonable computational
limits, this approach can be easily extended to other
inherently chiral calixarene derivatives, providing a practi-
cable method to assign their absolute configuration.
Acknowledgment. We are grateful for financial support
from the Italian MIUR. We also thank Dr. Amedeo Capo-
bianco for useful discussions.
Supporting Information Available: Details of HPLC
enantioresolution, Cartesian coordinates of conformers (cS)-
3a and (cS)-3b, table of optical rotations, and details of DFT
calculations. This material is available free of charge via the
Internet at http://pubs.acs.org.
tion study as cS.8b A [R]25 of -15.9 and the ECD spectrum
D
(22) Usually, ab initio assignments are considered to be reliable if the
OR magnitude is higher than 28.9: Stephens, P. J.; McCann, D. M.;
Cheeseman, J. R.; Frisch, M. J. Chirality 2005, 17, S52.
(23) Polavarapu, P. L. Chirality 2008, 20, 664.
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