Optical resolution, absolute configuration, and chiroptical properties of three-layered [3.3]paracyclophane

Article abstract of DOI:10.1021/jo801441h

(Figure Presented) A racemic mixture of three-layered [3.3]paracyclophane ([3.3]PCP), 1, has been resolved into two enantiomers, and their absolute configuration was determined from a comparison of experimental chiroptical properties and density functiona

Full text of DOI:10.1021/jo801441h

care: boat-type deformation and transannular interactions of
facing aromatic rings cause AC assignment to be laborious, since
the chiroptical characteristics of cyclophanes are sensitive to
these properties. In recent years, however, computational
methods for predicting chiroptical properties such as electronic
circular dichroism (CD), vibrational CD, optical rotation, and
optical rotatory dispersion (ORD) have been developed and
applied successfully to help assign the absolute configurations
of rigid chiral molecules including cyclophane systems.4
Optical Resolution, Absolute Configuration, and
Chiroptical Properties of Three-Layered
[3.3]Paracyclophane1
Atsuya Muranaka,† Masahiko Shibahara,*,‡
Motonori Watanabe,§,| Taisuke Matsumoto,§
Teruo Shinmyozu,§ and Nagao Kobayashi*,†
Department of Chemistry, Graduate School of Science,
Tohoku UniVersity, Sendai, 980-8578, Japan, Department of
Chemistry, Faculty of Education and Welfare Science, Oita
UniVersity, 700 Dannoharu, Oita 870-1192, Japan, Institute
for Materials Chemistry and Engineering, and Department of
Chemistry, Graduate School of Sciences, Kyushu UniVersity,
6-10-1 Hakozaki, Fukuoka 812-8581, Japan
mshiba@cc.oita-u.ac.jp; nagaok@mail.tains.tohoku.ac.jp
Multilayered paracyclophanes (PCPs) have served as model
compounds for investigating transannular delocalization through
completely overlapping aromatic π-electrons and the relationship
between the magnitude of the delocalization and the number of
layers.5 Otsubo et al. synthesized multilayered [2.2]PCPs (up
to six layers) and studied their structural and electronic properties
in detail.5 Yamamoto et al. accomplished the synthesis of
optically active multilayered [2.2]PCPs (up to six layers) and
reported their chiroptical properties.6 In the previous paper, we
reported the synthesis, structural properties, and transannular
π-π interaction of three- and four-layered racemic [3.3]PCPs.7
However, elucidation of their chiroptical properties and AC
determination are remaining to be resolved. We report here
optical resolution, the AC assignment, and chiroptical properties
of 1 on the basis of a combined experimental and computational
study.
ReceiVed July 16, 2008
A racemic mixture of three-layered [3.3]paracyclophane
([3.3]PCP), 1, has been resolved into two enantiomers, and
their absolute configuration was determined from a com-
parison of experimental chiroptical properties and density
functional theory (DFT) calculations. A simple model
comprising two p-xylenes and 1,2,4,5-tetramethylbenzene
(durene) was used to explain the origin of the chiroptical
properties of the three-layered cyclophane system.
Three-layered [3.3]PCP (()-1, which was first reported by
Otsubo et al.,8 was synthesized by an alternative coupling of
the (p-ethylbenzenesulfonyl)methyl isocyanide (EbsMIC) method
(see Supporting Information).7 Resolution of (()-1 was achieved
(4) (a) Furche, R.; Ahlrichs, R.; Wachsmann, C.; Weber, E.; Sobanski, A.;
Vo¨gtle, F.; Grimme, S. J. Am. Chem. Soc. 2000, 122, 1717–1724. (b) Diedrich,
C.; Grimme, S. J. Phys. Chem. A 2003, 107, 2524–2539. (c) Giorgio, E.; Viglione,
R. G.; Zanasi, R.; Rosini, C. J. Am. Chem. Soc. 2004, 126, 12968–12976. (d)
Autschbach, J.; Jensen, L.; Schatz, G. C.; Electra Tse, Y. C.; Krykunov, M. J.
Phys. Chem. A 2006, 110, 2461–2473. (e) Muranaka, A.; Asano, Y.; Tsuda, A.;
Osuka, A.; Kobayashi, N. ChemPhysChem 2006, 7, 1235–1240. (f) Brotin, T.;
Cavagnat, D.; Dutasta, J.-P.; Buffeteau, T. J. Am. Chem. Soc. 2006, 128, 5533–
5540. (g) Cere`, V.; Peri, F.; Pollicino, S.; Ricci, A.; Devlin, F. J.; Stephens,
P. J.; Gasparrini, F.; Rompietti, R.; Villani, C. J. Org. Chem. 2005, 70, 664–
669. (h) Abbate, S.; Castiglioni, E.; Gangemi, F.; Gangemi, R.; Longhi, G.;
Ruzziconi, R.; Spizzichino, S. J. Phys. Chem. A 2007, 111, 7031–7040. (i) Mori,
T.; Inoue, Y.; Grimme, S. J. Phys. Chem. A 2007, 111, 7995–8006.
(5) (a) Otsubo, T.; Mizogami, S.; Sakata, Y.; Misumi, S. Tetrahedron Lett.
1971, 12, 4803–4806. (b) Otsubo, T.; Mizogami, S.; Sakata, Y.; Misumi, S.
Tetrahedron Lett. 1973, 14, 2457–2460. (c) Otsubo, T.; Mizogami, S.; Sakata,
Y.; Misumi, S. Tetrahedron Lett. 1972, 13, 2927–2930. (d) Otsubo, T.; Mizogami,
S.; Otsubo, I.; Tozuka, Z.; Sakagami, A.; Sakata, Y.; Misumi, S. Bull. Chem.
Soc. Jpn. 1973, 46, 3519–3530.
Cyclophanes are organic compounds consisting of aromatic
units and aliphatic chains that form bridges between the aromatic
rings.2 One of the most interesting properties of cyclophanes is
that these molecules can orientate themselves as chiral and
helical arrangements. Although studies of chiral cyclophanes
have a long history,3 determination of the absolute configurations
(AC) of chiral cyclophane systems still needs a great deal of
† Tohoku University.
‡ Oita University.
§ Institute for Materials Chemistry and Engineering, Kyushu University.
| Department of Chemistry, Kyushu University.
(1) Multilayered [3.3]cyclophanes, part 2. For part 3, see ref 7.
(2) (a) Modern Cyclophane Chemistry; Gleiter, R., Hopf, H., Eds.; VCH:
Weinheim, Germany, 2004. (b) Vo¨gtle, F. Cyclophane Chemistry: Synthesis,
Structures and Reactions; John Wiley & Sons: West Sussex, England, 1993.
(3) (a) Nugent, M. J.; Weigang, O. E., Jr. J. Am. Chem. Soc. 1969, 91, 4556–
4558. (b) Falk, H.; Reich-Rohrwig, P.; Schlo¨gl, K. Tetrahedron 1970, 26, 511–
527. (c) Harada, N.; Soutome, T.; Nehira, T.; Uda, H. J. Am. Chem. Soc. 1993,
115, 7547–7548.
(6) (a) Nakazaki, M.; Yamamoto, K.; Tanaka, S.; Kametani, H. J. Org. Chem.
1977, 42, 287–291. (b) Nakazaki, M.; Yamamoto, K.; Tanaka, S. J. Chem. Soc.
Chem. Commun. 1972, 433.
(7) Shibahara, M.; Watanabe, M.; Iwanaga, T.; Matsumoto, T.; Ideta, K.;
Shinmyozu, T. J. Org. Chem. 2008, 73, 4433–4442.
(8) (a) Otsubo, T.; Kohda, T.; Misumi, S. Tetrahedron Lett. 1978, 19, 2507–
2510. (b) Otsubo, T.; Kohda, T.; Misumi, S. Bull. Chem. Soc. Jpn. 1980, 53,
512–517.
10.1021/jo801441h CCC: $40.75
Published on Web 10/21/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 9125–9128 9125

FIGURE 3. Molecular structures of (-)-1; top (A) and side (B) views.
FIGURE 1. Chromatogram of HPLC resolution of (()-1 in propan-
2-ol.
FIGURE 2. CD and electronic spectra of (+)- and (-)-1 in THF
(broken line) and CH3CN (solid line). (Inset) CD spectra in the longer
wavelength region.
by high performance liquid chromatography using a Chiralcel
OD column (cellulose tris(3,5-dimethylphenylcarbamate), 10 ×
250 mm) of Daicel Chemical Industries, Ltd. eluting with
propan-2-ol at 1.0 mL/min flow speed. The fractions were
detected by UV (λ ) 254 nm). About 50 mg of (()-1 was
dissolved in ca. 50 mL of propan-2-ol. Each time, 2 mL of the
sample solution was injected and separated. After repeated
separations, enantiomers were combined to give (+)-1 (14.8
FIGURE 4. B3LYP/TZVP structures of possible conformers of three-
layered [3.3]PCP, (R)-1. The relative energies (Erel) are based on total
energies corrected with the zero-point vibrational energies.
of (-)-1 are almost stacked on each other, maintaining its
planarity. It is also noted that the projections of the three
aromatic rings do not completely overlap each other. In this
respect, the molecule takes a left-handed helical conformation.
In the crystal-packing diagram of (-)-1, three kinds of CH/π
interactions are observed along the b-axis [C7-H5 (2.881 Å),
C8-C5 (2.837 Å), and C22-H19 (2.712 Å)] (Figure S1,
Supporting Information), whereas the CH/π interactions of the
benzene rings with the trimethylene protons between (-)-1 and
(+)-1 isomers are observed in (()-1.7
mg, retention time 33 min) and (-)-1 (18.7 mg, retention time
25
47 min) (Figure 1). The first-eluted sample is (+)-1 {[R]D
)
25
+125° (c ) 0.90)}, and the second is (-)-1 {[R]D ) -123°
(c ) 0.95)}. The enantiomeric purity was determined by HPLC
with Chiralcel OD after recrystallization from CH2Cl2/EtOH:
(+)-1 100% e.e.; (–)-1 100% e.e.
The CD spectrum of (+)-1 is a mirror image of that of (-)-1
in both THF and CH3CN solution (Figure 2). Solvent effects
on the CD spectral pattern were not observed under the present
conditions, but the CD signal at ca. 230 nm in the THF solution
becomes larger than that in the CH3CN solution.
It is well-known that [3.3]PCPs are flexible molecules. The
1H NMR data for (()-1 show three aromatic signals (δ 5.90,
6.43, and 6.55) in CDCl3,7 indicative of an effective D2
symmetry in solution. This is in contrast to the crystal structure
of (-)-1 which has approximate C2 symmetry. We therefore
carried out conformational analysis of the three-layered [3.3]PCP
with R-configuration ((R)-1) at the B3LYP/TZVP level, to gain
an insight into the structure in solution. As shown in Figure 4,
seven stable conformations, which can be classified into three
groups by their symmetry (D2, C2, and C1), were obtained. The
The molecular structure of (-)-1 was further confirmed by
X-ray crystallographic analysis.9 In the X-ray structure, the
[3.3]PCP units take on a boat-boat conformation (Figure 3A),
which is comparable to that of (()-1,7 but different from that
of the parent [3.3]PCP10 with a chair conformation. The three
benzene rings are approximately centered with intramolecular
distances of 3.260 and 3.284 Å (Figure 3B), which are shorter
than that of the parent [3.3]PCP (3.31 Å). The benzene rings
9126 J. Org. Chem. Vol. 73, No. 22, 2008

FIGURE 6. (a) Calculated spectra for the crystal structure of (-)-1
and a model benzene trimer comprising two p-xylenes and 1,2,4,5-
tetramethylbenzene. An interplanar distance of 3.3 Å was used.
Calculated optical rotation values (B3LYP/TZVP) are also shown.
Gaussian bands with a half-bandwidth of 2000 cm-1 were used. [R]D
values in deg [dm (g/cm3)]-1. (b) Comparison between the geometry
of the X-ray structure and the model system.
conformations, 30 excited states were needed to simulate the
calculated spectra in the region 205-350 nm. As shown in
Figure 5, all of the seven different conformations have an
intensely negative CD signal at around 230 nm. The Boltzmann-
averaged spectral patterns are in fairly agreement with that
observed for (-)-1, although the calculation seems to overes-
timate the excitation energies to some extent. Judging from the
experimental CD spectrum of (-)-1 (Figure 2 inset), the lowest
positive CD signal calculated at ca. 300 nm can be associated
with the weak positive CD observed at around 310-340 nm.
The intensely negative CD signal around 230 nm can be
predicted when using different basis sets (see Supporting
Information).
FIGURE 5. Calculated CD and absorption spectra for the possible
conformers of (R)-1 and their Boltzmann-averaged spectra. Calculated
optical rotation values (B3LYP/TZVP) are also shown. Gaussian bands
with a half-bandwidth of 2000 cm-1 were used to produce the spectra.
Specific rotation at the sodium D line ([R]D) for each
conformer of (R)-1 was calculated at the same level as the CD
calculations. Interestingly, all the conformers have negative [R]D
value (-124.4 to -221.8°), which is in agreement with the
experimental [R]D value (-123°) for (-)-1 in CH2Cl2. This is
in contrast to the results for the barrelenophane system, where
the calculated [R]D sign is negative or positive depending on
the conformation.12 The calculated [R]D sign was unchanged
when the 6-31G* (-164.6°) and 6-31+G* (-189.2°) basis sets
were used instead of TZVP. Thus, the TDDFT prediction is
that [R]D is negative and positive for (R)-1 and (S)-1, respectively.
[R]D values in deg [dm (g/cm3)]-1
.
differences in geometry between the conformations lie pre-
dominantly in the relative orientation of the carbon bridges.
Thus, in all the conformers, the benzene rings are almost stacked
maintaining its planarity, as seen in the crystal structure. The
interplanar distances of these optimized structures (3.39-3.41
Å, see Supporting Information) are, however, somewhat longer
than those of the crystal structure (3.260 and 3.284 Å). This
discrepancy probably results from the missing double excitations
between the HOMO and LUMO in the DFT approaches, since
the geometries of cyclophanes are relatively sensitive to electron
correlation effects.11 It should be noted that the geometrical
parameters of the lowest-energy conformation, C2-a, were
essentially identical to those of the crystal structure.
From these results, we can conclude that the AC of the three-
layered [3.3]PCP is (R)-(-)/(S)-(+). TDDFT calculations
(B3LYP/TZVP) of the crystal structure of (-)-1 with an
R-configuration strongly support this assignment (Figure 6a);
the calculated CD spectral pattern agrees well with the
experimental spectra, and the calculated [R]D value (-172.6°)
of the crystal structure is in fairly good agreement with the
experimental value (-123°). It is noted that the CD sign
corresponding to the lowest-energy transition of (R)-1 is positive,
although the corresponding CD sign of the three-layered
[2.2]PCP with an R-configuration is negative.6a This implies
that direct comparison between the CD spectra of related
systems is insufficient for AC assignment of multilayered
cyclophane systems.
We have predicted the UV and CD spectra of the possible
conformers of (R)-1 at the level of B3LYP/TZVP. For all seven
(9) Single crystals of (-)-1 suitable for X-ray analysis were obtained by
recrystallization from CH3CN. Crystal Data: C30H34, FW ) 394.60, crystal
system: tetragonal, space group: P43212 (#96). Lattice parameters: a ) 10.6091(2)
Å, c ) 39.7099(14) Å, V ) 4469.47(20) Å, Z ) 8, Dcalc ) 1.173 g/cm3, F(000)
1712.00, µ(Mo-KR) 0.655 cm-1. Crystallographic data for the structural analyses
of (-)-1 has been deposited within the Cambridge Crystallographic Data Center
(CCDC) as 644835.
(10) Gantzel, P. K.; Trueblood, K. N. Acta Crystallogr. 1965, 18, 958–968.
(11) Grimme, S. Chem.-Eur. J. 2004, 10, 3423–3429.
(12) Stephens, P. J.; McCann, D. M.; Devlin, F. J.; Cheeseman, J. R.; Frish,
M. J. J. Am. Chem. Soc. 2004, 126, 7514–7521.
Zerner and Canuto reported that the UV spectra of the
paracyclophanes could be considered to arise from dimers of
J. Org. Chem. Vol. 73, No. 22, 2008 9127

p-xylene, as long as the interaction is weak.13 Although they
successfully interpreted the UV spectra of [3.3]PCP using two
parallel p-xylene molecules at 3.3 Å separation, no investigation
to interpret the UV and CD spectra of multilayered cyclophane
systems has been reported so far. A detailed molecular orbital
(MO) analysis was therefore carried out to comprehensively
understand the electronic excited states of the present system.
dependence of the excited states on the inter-ring separation
was also investigated using the model. The energies of the
bonding orbital of the LUMO and antibonding orbital of the
HOMO are stabilized and destabilized, respectively, as the inter-
ring distance decreases. This gives rise to a red-shifted absorp-
tion and CD spectra for the system with shorter inter-ring
separation. From these results, it is evident that stereochemistry
and transannular interactions of substituted benzene units play
a vital role in the chiroptical properties of the present system.
In other words, the chiroptical properties are little affected by
the position of the bridged carbon atoms, the twist structure,
and deformation of the aromatic rings.
Although a number of excited states in a relatively small
energy window were calculated for the present three-layered
[3.3]PCP system, the low-lying excited states associated with
absorption bands longer than 200 nm consist of π-π* transitions
from six occupied MOs to six unoccupied MOs (see Supporting
Information). The frontier orbitals of 1 consist of linear
combinations of the frontier orbitals of the monomeric benzene
derivatives. Thus, the HOMO, HOMO-1, LUMO+4, and
LUMO+5 are considerably destabilized due to the antibonding
interactions between the three benzene units, whereas the
LUMO, LUMO+1, HOMO-4, and HOMO-5 are stabilized
due to the bonding interactions. The energy shift of the
HOMO-2, HOMO-3, LUMO+2, and LUMO+3 are modest,
since these orbitals have a nonbonding nature. This splitting of
the frontier MOs is responsible for the complicated CD pattern
of the present system. Essentially identical frontier MOs were
calculated for the other conformers.
In summary, resolution of three-layered [3.3]PCP, (()-1, was
completely accomplished by a chiral stationary phase with
propan-2-ol. The CD and [R]D of the possible conformers of
(R)-1 have been calculated using the TDDFT method. The
calculated results for the (R)-isomer achieve a very satisfactory
agreement with the experimental observations for the (-)-
isomer, and therefore the absolute configuration (AC) of the
three-layered [3.3]PCP is determined to be (R)-(-)/(S)-(+). A
simple model consisting of benzene derivatives (p-xylenes and
durene) successfully predicted the observed CD and [R]D. As a
consequence, we conclude that the chiroptical properties of the
three-layered [3.3]PCP system are little affected by the con-
formation of the bridged carbon atoms, twisted structure, and
deformation of the aromatic rings. The present results imply
that the [3.3]PCP system has the potential to facilitate AC studies
and CD analyses compared to the more widely investigated
[2.2]PCP system. The synthesis and AC assignment of more
layered [3.3]PCP systems are in progress.
Since the TDDFT calculations predict that all the possible
conformers have similar chiroptical properties, we have inves-
tigated the chiroptical properties of a p-xylene-durene-p-xylene
system with (R)-configuration as a simple model. In this model,
the benzene rings are stacked while maintaining planarity with
an interplanar distance of 3.3 Å, and the projections of the three
aromatic rings completely overlap each other (Figure 6). The
CD and [R]D of the model were calculated at the level of
B3LYP/TZVP. Interestingly, the calculated spectral pattern for
the model system reproduced very well the experimental spectral
feature of the three-layered [3.3]PCP ((-)-1) and the calculated
spectral pattern for the optimized geometries. The calculated
[R]D value of the model system (-186.3°) was also in fairly
good agreement with the experimental data and the calculated
[R]D value using the optimized geometries. The frontier MOs
of the model system consist of linear combinations of the frontier
orbitals of the monomeric benzene derivatives, and the energy
ordering is almost identical to the optimized structure of three-
layered [3.3]PCP system (see Supporting Information). The
Acknowledgment. T.S. gratefully thanks the financial support
of this work from Institute of Chemistry, Academia Sinica,
Taiwan, and a Grant-in-Aid for Scientific Research (B) (No.
18350025) from the Ministry of Education, Culture, Sports,
Science and Technology, Japan. We thank Dr. Toshiaki Shi-
masaki of the Institute for Materials Chemistry and Engineering,
Kyushu University, for optical rotation measurements. Part of
the computational results were obtained using supercomputing
resources at the Information Synergy Center, Tohoku University.
Supporting Information Available: Crystallographic data,
NMR spectra, and computational data. This material is available
free of charge via the Internet at http://pubs.acs.org.
(13) Canuto, S.; Zerner, M. J. Am. Chem. Soc. 1990, 112, 2114–2120.
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