One-pot synthesis of helical aromatics: Stereoselectivity, stability against racemization, and assignment of absolute configuration assisted by experimental and theoretical circular dichroism

Article abstract of DOI:10.1021/jo048858k

Helical aromatics (1) were synthesized via one step in good quantity by solvent-free condensation of N,N′-p-phenylenediamine (2) and various carboxylic acids in the presence of a Lewis acid. Microwave irradiation greatly facilitated the condensation react

Full text of DOI:10.1021/jo048858k

One-Pot Synthesis of Helical Aromatics: Stereoselectivity,
Stability against Racemization, and Assignment of Absolute
Configuration Assisted by Experimental and Theoretical Circular
Dichroism
Masashi Watanabe,† Hiroshi Suzuki,† Yasutaka Tanaka,*,† Toshimasa Ishida,‡
Tatsuo Oshikawa,§ and Akiyoshi Tori-i
Department of Materials Science, Shizuoka University, Hamamatsu, Shizuoka 432-8561, Japan,
Institute for Molecular Science, Okazaki, Aichi 444-8585, Japan, Numazu College of Technology,
3600 Ooka Numazu 410-8501, Japan, and Saga University, Honjo-machi 1, Saga 840-8502, Japan
tcytana@ipc.shizuoka.ac.jp
Received July 6, 2004
Helical aromatics (1) were synthesized via one step in good quantity by solvent-free condensation
of N,N′-p-phenylenediamine (2) and various carboxylic acids in the presence of a Lewis acid.
Microwave irradiation greatly facilitated the condensation reaction to furnish 1 with a 100%
diastereo- and a 50% enantioselectivity, when a chiral carboxylic acid was utilized. 1f, derived
from 2-methylglutaric acid, was quite stable, no racemization taking place even at 200 °C. The
assignment of the absolute configurations to the helical aromatics has been achieved by experimental
and theoretical CD spectra calculated by time-dependent density functional theory.
Introduction
asymmetric molecular recognition, synthesis, sensors,
and polymer fields.3 Recently, their self-assembled struc-
tures have also drawn attention because of their unique
physical properties, including liquid crystallinity and
nonlinear optical responses.4 The potential use of such
aromatics largely depends on obtaining them in good
quantity and in an enantiomerically pure form. Once
isolated, the homochiral forms should strongly resist
racemization. However, the synthetic complexity of these
aromatics, involving multistep reactions and the chiral
resolution, still impedes their production in quantity. In
addition such helical conjugated aromatics racemize
easily especially at high temperatures. We have previ-
ously demonstrated that 1 (R ) CH3) was synthesized
via a solvent-free one-pot condensation reaction of N,N’-
diphenyl-p-phenylenediamine (2) with carboxylic acids (3)
in the presence of ZnCl2 as Lewis acid.5 Here we report
that a variety of derivatives of 1 possessing different alkyl
substituents at the 13 and 14 positions have also been
obtained in one pot by conventional heating as well as
by microwave irradiation. Microwave irradiation drasti-
cally shortened the reaction time and brought about
stereoselectivity. We have also revealed that several
13,14-dialkyldibenzo[b,j][4,7]-phenanthroline (1) pos-
sesses a twisted conjugated aromatic plane due to steric
hindrance from two alkyl groups at the 13 and 14
positions giving rise to helical chirality.1 Thus, 1 and its
derivatives could be considered as a new class of helical
aromatics.
On one hand, the helical aromatics such as helicenes,
which also present left- and right-handed chiral helical
structure, have been intensively studied for their chir-
optical and photochromic properties,2 as well as in
* To whom correspondence should be addressed. Phone: +81-53-
478-1164. Fax: +81-53-478-1199.
† Shizuoka University.
‡ Institute of Molecular Science.
§ Numazu College of Technology.
(3) (a) Murguly, E.; McDonald, R.; Branda, N. R. Org. Lett. 2000, 2,
3169. (b) Sato, I.; Yamashima, R.; Kadowaki, K.; Yamamoto, J.;
Shibata, T.; Soai, K. Angew. Chem., Int. Ed. 2001, 40, 1096. (c) Reetz,
M. T,; Sostman, S. Tetrahedron 2001, 57, 2515. (d) Schmuck, C. Angew.
Chem., Int. Ed. 2003, 42, 2448. (e) Urbano, A. Angew. Chem., Int. Ed.
2003, 42, 3986.
(4) (a) Katz, T. J. Angew. Chem., Int. Ed. 2000, 39, 1921. (b) Verbiest,
T.; Sioncke, S.; Persoons, A.; Vyklicky, L.; Katz, T. J. Angew. Chem.,
Int. Ed. 2002, 41, 3882.
(5) (a) Tanaka, Y.; Sekita, A.; Suzuki, H.; Yamashita, M.; Oshikawa,
T.; Yonemitsu, T.; Torii, A. J. Chem Soc., Perkin Trans. 1 1998, 2471.
(b) Tanaka, Y.; Sekita, A.; Suzuki, H.; Torii, A. U.S. Patent 5973151,
1999.
Saga University.
(1) 5,8-Diazapentaphene rings (dibenzo[b,j][4,7]-phenanthroline)
have been known since the 1950s; see: (a) Badger, G. M.; Pettit, R. J.
Chem. Soc. 1952, 1874. (b) Hellwinkel, D.; Ittemann, P. Liebigs Ann.
Chem. 1985, 1501.
(2) For a review of aromatic helical molecules, see: (a) Wynberg,
H. Acc. Chem. Res. 1971, 4, 65. (b) Martin, R. H. Angew. Chem., Int.
Ed. Engl. 1974, 13, 649. (c) Laarhoven, W. H.; Prinsen, W. J. C. Top.
Curr. Chem. 1984, 125, 63. (d) Meurer, K. P.; Vo¨gtle, F. Top. Curr.
Chem. 1985, 127, 1. For a review of chiroptical properties, see: (e)
Grimme, S.; Harren, J.; Sobanski, A.; Vo¨gtle, F. Eur. J. Org. Chem.,
1998, 1491.
10.1021/jo048858k CCC: $27.50 © 2004 American Chemical Society
Published on Web 10/20/2004
7794
J. Org. Chem. 2004, 69, 7794-7801

Stereoselective Formation of Helical Aromatics
SCHEME 1. Formation of 1 from 2 and (a) Carboxylic Acid or (b) Dicarboxylic Acid
TABLE 1. Reaction Time and Yields of Helical
Aromatics (1) from 2 and Carboxylic Acid (3)
condenser, was placed in a domestic microwave oven
(2.45 GHz, 500 W) and irradiated. The reaction progress
was monitored by thin-layer chromatography (SiO2,
CHCl3/ethyl acetate ) 8/1). For example, 1d was provided
in a 83% yield by microwave irradiation for 5 min, while
conventional heating for 9 h afforded a 73% yield (Table
1). However, carboxylic acids possessing low boiling
points such as acetic (3a) and propionic (3b) acids caused
bumping upon microwave irradiation resulting in de-
creased chemical yields (Table 1). Only trace amounts of
condensation products of 1c and 1g were obtained from
lauric (3c) and adipic (3g) acids probably because of the
higher bulkiness of alkyl or methylene groups.
reaction time (min)
micro-
yield (%)
carboxylic
acid
micro-
heating
wave
heating
wave
product
3a
3b
3c
3d
3e
3f
540
540
540
540
540
540
540
30
30
30
5
56
50
0
78
80
18
0
35
0
<1
83
84
34
<1
1a
1b
1c
1d
1e
1fa
1g
5
5
5
3g
a When started with optically pure (S)-3f and 2, both conven-
tional heating and microwave irradiation gave the same yields as
those starting with racemic 3f.
derivatives of 1 could be resolved into their respective
enantiomers, some of which are quite stable as such. No
racemization takes place even at high temperature, as
the bulkiness of the substituents exerts a large influence
on the racemization barrier. The assignment of the
absolute configurations to the helical aromatics has been
achieved by experimental and theoretical CD spectra
calculated by time-dependent density functional theory.
The mechanism of acridine synthesis from diphenyl-
amine and a carboxylic acid in the presence of Lewis acid
has been established and suggested to account for that
of formation of 1.6 Thus, N-acylation of 2 with carboxylic
acids resulting in mono- and di-N-acylated forms of 6 and
6′, followed by the acyl group transfer to an adjacent
aromatic carbon, provided aryl ketones of 7 and 7′, and
subsequent cyclodehydration gave rise to acridine deriva-
tives of 8 and 8′. 8 readily underwent N-acylation, giving
8′ (Scheme 2). In particular, 6c and 6c′ could be detected
by mass spectrometry in the initial stage of the reaction
(<15 min) and 8c and 8c′ could be isolated, and their
structures were also determined by high-resolution mass
Results and Discussion
Synthesis of Helical Aromatics (1). In a typical
preparation, a mixture of N,N’-diphenyl-p-phenylenedi-
amine (2) and a carboxylic acid such as acetic acid (3a)
in the presence of an excess of ZnCl2 was placed in a
three-necked flask equipped with a mechanical stirrer,
thermometer, and reflux condenser. The mixture was
stirred and heated with an oil bath at 200 °C for 9 h,
giving rise to a dark and viscous resinous substance.
Soxhlet extraction with CHCl3 for 12 h and subsequent
column chromatography (silica gel, CHCl3) of the con-
centrated extract afforded 1a (56%), together with a small
amount of 4a (<1%) and 5a (,1%) (Scheme 1).4 Com-
pounds 4a and 4b can also be quantitatively provided
by the reduction of 1a and 1b with LiAlH4 in diethyl
ether. Microwave irradiation, instead of conventional
heating with an oil bath, greatly reduced the reaction
time. The synthetic procedure is almost identical with
that of conventional heating: the mixture of starting
materials, in a round-bottom flask equipped with reflux
1
spectrometry and H NMR spectroscopy.7 6a′ obtained
from the reaction of 2 with acetic anhydride could be
readily converted into 1a in a 78% yield, also indicating
that the one-pot reaction of 2 with 3 giving 1 proceeds
through N-acyl intermediates (Scheme 3).8 It seems the
second acyl transfer in 8′ occurred preferentially at the
aromatic carbon denoted as R, leading to 9R, and the
(6) For the reaction mechanism for 9-substituted acridines from
diphenylamine and carboxylic acid, see: (a) Tsuge, O.; Nishinohara,
M.; Tashiro, M. Bull. Chem. Soc. Jpn. 1963, 36, 1477. (b) Bernthsen,
A. Justus Liebigs Ann. Chem. 1884, 1, 224.
J. Org. Chem, Vol. 69, No. 23, 2004 7795

Watanabe et al.
SCHEME 2. Proposed Mechanism for Formation of 1 from 2 and Carboxylic Acid (3)
SCHEME 3. Stepwise Formation of 1a through 6a
following cyclodehydration affords 1 as the single con-
densation product. In particular, the R carbon among four
aromatic carbons (R, â, γ, and δ) in 8′ possesses the
highest HOMO density (R ) 0.104, â ) 0.014, γ ) 0.020,
δ ) 0.032), which were calculated by a MOPAC/PM5
wave function, indicating that the electrophilic acyl cation
attacks the R position in preference to the others.9 This
is also the reason a flat condensed aromatic of 10 derived
through 9â was not obtained even if 10 is far less strained
as compared with 1. The mechanisms of formation of
dihydro form (4a) of 1a and the monomethyl form (5a)
have remained obscure: presumably, hydrogenation and
the C-C bond cleavage between one of the methyls and
the aromatic carbon in 1a occur to relax the highly
strained conjugated aromatic ring to afford 4a and 5a,
respectively.
Chiral Resolution and Kinetic Parameters for
Racemization. 1a (R ) CH3-) and 1b (R ) CH3CH2-)
were resolved into the respective enantiomers by chiral
HPLC separation. For 1a, the pronounced tailing and
leading of first and second chromatographic peaks,
respectively, showed a tendency toward racemization
during chiral separation, while 1b was fully optically
resolved (Figure 1). 1d and 1e, which contain a trimeth-
ylene bridge between the 13 and 14 positions, could not
be optically resolved under various separation conditions,
probably due to the greater flexibility resulting from the
FIGURE 1. Chiral HPLC separations of 1a, 1b, 1d, 1f, and
4b. Column: DAICEL OJ-R; Solvent: acetonitrile/H2O ) 3/7.
Detector: UV at 254 nm.
bridges. On the other hand, 1f, which also possesses a
trimethylene bridge as well as an sp3 chiral carbon in
the bridge, could be conveniently separated into enan-
tiomers (Figure 1). Optically resolved enantiomers of 1
showed characteristic CD spectra reciprocal to one an-
other: CD spectra of a pair of enantiomers of 1f are
shown in Figure 2. 4b could also be separated into a pair
of enantiomers without racemization during the separa-
tion.10
The rates of racemization of 1a, 1b, 1f, and 4b were
estimated by the time-course of CD spectra at different
temperatures: the spectral change in the first eluate of
1a at 45 °C was shown in Figure 3. The racemization
process in 1a and 1b follows first-order kinetics with
respect to the concentration (eq 1);
(7) Molecular ion peaks (MH+) of 6c, 6c′, 8c, and 8c′ were observed
at 443.3061 (calcd 443.3062), 625.4740 (calcd 625.4733), 425.2953 (calcd
425.2957), and 607.4628 (calcd 607.4627), respectively, under high-
resolution conditions. These mass spectra and 1H NMR spectra of 8c
and 8c′ are shown in Supporting Information.
(8) N1,N4-Diphenyl-1,4-benzenendiamine and N1-[4-methyl(phenyl)-
carboxamidophenyl]-N1-phenylacetamide are in the IUPAC nomen-
clature of 2 and 6a′.
(9) HOMO density is equal to the square of the orbital coefficient of
the pZ component; see also Experimental Section.
[(P) - 1] yk1z [(M) - 1]
(1)
k-1
(10) Experimental as well as theoretical CD spectra of 1a and 4a
have shapes identical to those of 1b and 4b, respectively, which are
not unexpected from close structural similarities.
7796 J. Org. Chem., Vol. 69, No. 23, 2004

Stereoselective Formation of Helical Aromatics
TABLE 2. Experimental and Theoretical Kinetic
Parameters for Racemization of 1, 4, and 5
experimental
theoretical (PM5)
0
helical
aromatics
∆Hq
(kJ/mol)
∆Sq
(kJ/mol)
∆∆Hf
(kJ/mol)
1a
1b
1d
1e
1f
4b
5a
87.5
97.1
a
-24.1
-26.9
a
77.6
100.1
29.0
a
a
40.8
ndb
ndb
a
ndb
ndb
a
47.9
121.8
11.6
a Experimental parameters could not be obtained because
homochiral forms were not available. b Nd means that the race-
mization was not detected in the temperature range of 25-200
°C.
with the chiral separation behaviors (Table 2 and Figure
1). These indicated that the bulkiness of the substituents
exerts a large influence on the racemization barrier:
thus, ∆Hq increases as smaller groups at 13 and 14
positions are substituted by larger ones (5a (monomethyl)
< 1a (dimethyl) < 1b (diethyl)). The small differences in
FIGURE 2. CD spectra (top) of optically resolved 1f: first
eluate (solid line), second eluate (dotted line), and 1f synthe-
sized from (S)-2-methylglutaric acid ((S)-3f) by microwave
irradiation (bold, 50.3% enantiomeric excess). Absorption
spectrum (bottom) of 1f. Scale on the right abscissa is for the
absorption spectrum. All spectra were measured at 25 °C in
methanol.
enthalpy (∆Hq and ∆∆Hf ) for both experimental and
0
theoretical values in 1d and 1e have also proven them
to be racemized easily due to the greater flexibility in
their trimethylene bridge. However, the high racemiza-
tion barrier experimentally observed in 1f was entirely
unexpected, although 1f also contains the trimethylene
bridge. The theoretical ∆∆Hf 0 of 47.9 kJ/mol for 1f is too
small to explain the barrier observed: the racemization
of 1f probably proceeded by way of a different transition
conformation from the other 1 derivatives. No racemiza-
tion of 4b took place, even at 200 °C: the presence of a
central hydrocarbon ring in helical aromatics generally
increases the racemization barrier as compared with that
of the parent fully aromatic derivatives.12
1H NMR Spectra and X-ray Single-Crystal Analy-
ses of 1. The pronounced stability of 1f against racem-
ization is quite unique and can be ascribed to its
1
structural characteristics. H NMR spectrum of 1f indi-
cated five independent resonances assigned to five pro-
tons at the 13, 14, and 15 positions in the temperature
range from -45 to 100 °C (Figure 4 and its inset) due to
the immobilized methylene bridge and the conjugated
aromatic ring as well. On the other hand, 1d exhibited
only two resonances for six protons at the 13, 14, and 15
positions in the same temperature range (inset in Figure
4), indicating the occurrence of fast ring inversion (ra-
cemization). The extra methyl group at the 13 position
in 1f appears to exhibit an anchoring effect to immobilize
the methylene bridge, eventually preventing aromatic
ring inversion. The specific NOEs between the protons
at the 12 and 13, CH3 and 14, and 1 and 15 positions
observed in 1f also confirmed restricted flexibility in the
methylene bridge.
FIGURE 3. Time course of CD spectra (top) of the first eluate
of 1a measured at 45 °C in methanol.10 Absorption spectrum
(bottom) of 1a. Scale on the right abscissa is for the absorption
spectrum.
kinetic parameters, ∆Hq and ∆Sq, derived from rate
constants (k1) are summarized in Table 2. In contrast the
obvious alterations in CD intensity at various tempera-
tures up to 200 °C were not observed for 1f and 4b,
indicating that no racemization was occurring even at
elevated temperatures. Table 2 also included theoretical
parameters of ∆∆Hf 0 as an index of racemization barrier
calculated by molecular orbital methods.11
The experimental kinetic parameters were well repro-
duced by the theoretical parameters and also consistent
X-ray single-crystal analyses of the helical aromatics
demonstrated that the conjugated aromatic rings are
indeed twisted. The space-filling representations of ra-
cemic crystals of 1b and 1f are shown in Figure 5. The
(P)- and (M)-enantiomers, which are mirror images of
0
0
(11) Theoretical ∆∆Hf is the difference in ∆Hf between the most
stable and transition state conformations. MOPAC/PM5 calculation
always generated U-shape structures of helical aromatics 1 possessing
Cs symmetry as the transition state conformation for racemization of
1, while 1 in the most stable state took C2 symmetry; see also
Experimental Section. In particular, a racemization mechanism through
the Cs-symmetric conformation in the transition state has been
proposed by molecular orbital methods of AM1, MNDO, and PM3 to
account for racemization of helicenes; see: Janke, R. H.; Haufe, G.;
Wu¨rthwein, E.-U.; Borkent, J. H. J. Am. Chem. Soc. 1996, 118, 6031.
(12) (a) Goedicke, C.; Stegemeyer, H.; Tetrahedron Lett. 1970, 11,
937. (b) Carren˜o, M. C.; Carc´ıa-Cerrada, S.; Urbano, A. J. Am. Chem.
Soc. 2001, 123, 7929.
J. Org. Chem, Vol. 69, No. 23, 2004 7797

Watanabe et al.
FIGURE 4. 1H NMR spectrum of 1f in CDCl3 at 0 °C. The insets show the spectra expansions in the region of 2.50-4.75 ppm
of 1f (bottom) and 1d (top). The numerals under the respective resonances in the insets indicate the proton positions in 1f and
1d. The arrows in the chemical structure stand for proton-to-proton NOEs.
of the sp3 chiral carbon adjacent to carbonyl group in (S)-
3f or in reaction intermediates seemed to take place
through an enol form at elevated temperature. In marked
contrast to conventional heating, microwave irradiation
has achieved a 50.3% enantiomeric excess to give prefer-
ence to one of the 1f enantiomers over the antipode.15
The product exhibited the same signs in the CD as those
of the second eluate on HPLC chiral resolution of 1f
racemates (Figure 2). A shortening of the reaction period
seemed to suppress racemization of the sp3 chiral carbon
and thus brought about enantioselectivity along with
diastereoselectivity. The infrared radiation thermometer
indicated that the temperature of the reaction mixture
reached over 200 °C within 50s after commencing mi-
crowave irradiation. The rapid increase in temperature
led the reactive starting materials and intermediates
readily to the final products without racemization of the
sp3 carbon resulting in stereoselectivity. Repeated re-
crystallization from the enantiomer excess solution readily
provided an enhancement of the optical purity of 1f.
Assignment of Absolute Configuration of Helical
Aromatics. The absolute configurations of helical aro-
matics were assigned on the basis of CD exciton chirality
method (exciton-coupled CD) as well as comparison
between experimental and theoretical CD spectra gener-
ated by Gaussian 03. Exciton-coupled CD is based on
interacting choromophores, which bring about the exciton
splitting of electric transition of the chromophores.16
When the two choromophores are oriented with clockwise
movement from front to back (positive chirality), the first
and second halves (the longer and shorter wavelength
FIGURE 5. Space-filling renderings from the single-crystal
X-ray diffraction data of racemic (a) 1b and (b) 1f consisting
of pairs of (P)- and (M)-forms and (S)-(M)- and (R)-(P)-forms,
respectively. Hydrogen atoms are omitted for clarify.
each other, were aligned alternately so as to form the
racemic crystal. Only two isomers, a pair of enantiomers
of (S)-(M)- and (R)-(P)-1f, were found to exist out of four
possibilities, the other two being (S)-(P)- and (R)-(M)-
1f (Figure 5b).13 Therefore, the synthetic reaction of 1f
from racemic 2-methylglutaric acid (3f) and 2 proceeded
diastereoselectively, and thus the point chirality at the
terminal of the methyl group determines the helicity. The
X-ray analysis of 1f also indicated that the protons
between 12 and 13 and between 1 and 15, respectively,
are in close proximity.
Enantioselective Formation of 1f Assisted by
Microwave Irradiation. Microwave-assisted reactions
take place when a polar molecule coexists as solvents,
catalysts, or reactants themselves. It is known that the
frequency of the microwave radiation (2.45 GHz) does not
activate specific bonds in an organic molecule. Neverthe-
less the coupling of microwaves with the dipolar molecule
leads to a dielectric heating effect to directly heat the
reactants and eventually accelerate a chemical reaction.
Therefore, it has been argued that conventional heating
and microwave-activated reactions share in general the
identical reaction mechanism.14 When started with opti-
cally pure (S)-3f and 2 in the presence of ZnCl2, the
conventional heating reaction gave a racemic mixture of
1f as in the case starting with racemic 3f; racemization
(14) For a recent review of microwave-assisted organic synthesis,
see: (a) Microwave-Enhanced Chemistry; Kingston, H. M., Haswell,
S. J., Eds.; American Chemical Society: Washington, DC, 1997. (b)
Microwaves in Organic Synthesis; Loupy, A. Eds.; Wiley-VCH: Wein-
heim, 2002. (c) Caddick, S. Tetrahedron 1995, 51, 10403. Loupy, A.;
Perreux, L.; Liagre, M.; Burle, K.; Moneuse, M. Pure Appl. Chem. 2001,
73, 161. (d) Varma, R. S. Pure Appl. Chem. 2001, 73, 193. (e) Lidstrom,
P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron, 2001, 57, 9225.
(f) Leadbeater, N. E.; Marco, M. J. Org. Chem. 2003, 68, 5662.
(15) 9-Substituted acridines were recently synthesized by microwave
irradiation; see: (a) Vevekova´, E.; M. Noskova´, M.; Toma, S. Synth.
Commun. 2002, 32, 729. (b) Koshima, H.; Kutsunai, K. Heterocycles
2002, 57, 1299. (c) Seijas, J. A.; Vazquez-Tato, M. P.; Martinez, M.
M.; Rodriguez-Parga, J. Green Chem. 2002, 4, 390.
(13) In (S)-(M)-1f, (S) stands for the absolute configuration of the
sp3 carbon at the 13 position, which was derived from the chiral carbon
in 3f, and (M) denotes the helicity of the conjugated aromatic plane.
7798 J. Org. Chem., Vol. 69, No. 23, 2004

Stereoselective Formation of Helical Aromatics
FIGURE 6. (a) Molecular geometry of (P)-4b: two green arrows represent electric transition dipole moments along the long axes
of the quinoline chromophores, and a red arrow refers to the negative exciton chirality or the left-handed screwness between the
two long axes of chromophores. (b) CD spectra (top) of optically resolved 4b: first eluate (solid), second eluate (dotted).10 Absorption
spectrum (bottom) of 4b. (c) Theoretical CD spectra (top) of (P)-4b (solid line) and (M)-4b (dotted line). Theoretical absorption
spectrum (bottom) of 4b. Scale on the right abscissa is for the absorption spectrum.
halves) of the split CD curve are positive and negative,
respectively. With negative chirality, the first and second
halves are negative and positive, respectively. The CD
exciton chirality method seems to be applicable to 4 since
4 comprises two independent and equivalent quinoline
moieties.17 CD and UV-vis spectra of a pair of enanti-
omers of 4b are shown in Figure 6b. Absorption of
moderate intensity around 330 nm and a very intense
absorption at 263 nm were distinguishing features of the
UV-vis spectrum. These two are attributable to two
transitions that are polarized along the short and long
axes of the quinoline chromophore, respectively, and
correspond to La and Bb transitions in a naphthalene
ring. The latter is suited for observing the exciton
coupling Cotton effect due to the large molecular extinc-
tion coefficient (ꢀ) and the established assignment of the
polarization of the transition. The strong negative Cotton
effect at 265 nm for the first eluate of 4b, depicted in
Figure 6b as the solid line, may be assignable to the
negative first split CD at the long-axis transition band.
This anticipates the left-handed screwness between the
two long axes of the chromophores and the provisional
absolute configuration of (P)-helicity.17 However, the
distinct second split CD at this band could not be
observed: obviously there are other transitions over-
lapping with the long-axis transition of quinoline chro-
mophores. Therefore, considerable ambiguity remains in
determining the absolute configuration of 4 by the CD
exciton chirality method.18
Theoretical simulations reproducing CD spectra were
accomplished to prove the above.19 The molecular geom-
etries obtained from single-crystal X-ray analyses (1a,
1b, and 1f) and from the geometry optimization with
MM3 followed by MOPAC/PM5 (4b, Figure 6a) were
adopted for the following calculations. The rotatory
strengths for all excited states were calculated using the
time-dependent density functional theory (TDDFT) with
the B3LYP hybrid functional and the 6-31G(d,p) basis
set. Calculations were carried out using the Gaussian 03
suite of programs.20 We obtained the rotatory strengths
from the dipole-length expression as well as the dipole-
velocity expression for all the molecules.19 Both rotatory
strengths are the same for the exact wave functions for
the ground and excited states concerned and should be
close to each other for good wave functions. We used the
former strengths to simulate spectra because the former
strengths are essentially the same values as the latter
strengths. Theoretical CD spectra were synthesized with
the sum of Gaussian bands with the width of 0.18 eV.
All calculated excitation energies are blue-shifted by 0.28
eV, and the intensities have been scaled by a factor of
0.5.21 The theoretical CD spectra for a pair of enantiomers
of 4b are illustrated in Figure 6c. The theoretical UV-
1
1
(16) (a) Harada, N.; Nakanishi, K. In Circular Dichroic Spectros-
copy: Exciton Coupling in Organic Stereochemistry; University Science
Books: Mill Valley, CA, 1983. (b) Berova, N.; Nakanishi, K. In Circular
Dichroism, Principles and Applications; Nakanishi, K.; Berova, N.;
Woody, R., Eds.; VHC: New York, 1994. (c) Rodger, A.; Norde´n, B. In
Circular Dichroism and Linear Dichroism; Oxford, Oxford, New York,
1997.
(17) Provisional assignment of absolute configuration of 4a in our
previous communication (ref 4) was incorrect. We previously misjudged
the direction of screwness between two long axes of the chromophores.
For CD spectra of molecules possessing identical orientation of two
chromophores to 4a, see: (a) Imajo, S.; Nakamura, A.; Shingu, K.; Kato,
A.; Nakagawa, M. J. Chem. Soc., Chem. Commun. 1979, 867. (b) Imajo,
S.; Kato, A.; Shingu, K.; Kuritani, H. Tetrahedron Lett. 1981, 22, 2179.
(c) Shingu, K.; Imajo, S.; Kato, A.; Kuritani, H. J. Am. Chem. Soc. 1982,
104, 4272.
(18) For a review of the limitations of the CD exciton chirality
method, see: Superchi, S.; Giorgio, E.; Rosini, C. Chirality 2004, 16,
422.
(19) (a) Grimme, S.; Harren, J.; Sobanski, A.; Vo¨gtle, F. Eur. J. Org.
Chem. 1988, 53, 1. (b) Furche, F.; Ahlrichs, R.; Wachsmann, C.; Weber,
E.; Sobanski, A.; Vo¨gtle, F. Grimme, S. J. Am. Chem. Soc. 2000, 122,
1717.
J. Org. Chem, Vol. 69, No. 23, 2004 7799

Watanabe et al.
FIGURE 7. (a) Theoretical CD spectra (top) of (P)-1a (solid line) and (M)-1a (dotted line). Experimantal CD spectrum of the first
eluate of 1a (red). Theoretical absorption spectrum (bottom) of 1a. (b) Theoretical CD spectra (top) of (R)-(P)-1f (solid line) and
(S)-(M)-1f (dotted line). Experimantal CD spectrum of the first eluate of 1a (red). Theoretical absorption spectrum (bottom) of
1f. Scale on the right abscissa is for the absorption spectrum.
vis and CD spectra are highly resolved as compared with
experimental ones and thus consist of several isolated
bands. However, the theoretical CD spectrum of (P)-4b
is approximately composed of three areas as in the
experimental CD of the first eluate of 4b: a positive band
at 338 nm followed by intense negative bands around 277
nm and positive bands around 234 nm. Therefore, the
experimental CD spectra are well reproduced by the
calculation, and thus we have finally assigned the
absolute configuration of the first eluate of 4b as (P)-
helicity. In this way we have also compared experimental
and theoretical CD spectra of 1a, 1b, and 1f and found
that all experimental spectra were well described by
calculation. Theoretical CD spectra of 1b and 1f along
with the experimental ones are shown in Figures 7a and
7b, respectively.
Reduction of 1b with LiAlH4 seems possible to take
place to produce 4b with retention of helicity due to the
high racemization barriers for 1b and 4b (Table 2). The
first eluate of 1b, which possesses the same CD signs as
those of the first eluate of 1a illustrated in Figure 3,10
was collected (% ee g 80%) and reduced by LiAlH4 at
room temperature to selectively yield the first eluate of
4b (% ee ≈ 80%). These indicated that the absolute
configrations of the first and second eluates of 1b were
(P)- and (M)-helicity, respectively. We have concluded
from experimental and theoretical results that all of the
first and second eluates in Figure 1 have absolute
configurations of (P)- and (M)-, respectively.
Conclusion
We have demonstrated that novel helical aromatics
were readily synthesized from commercially available
compounds via one step. Microwave irradiation achieved
shortening of the reaction period as well as brought about
stereoselectivity in the synthesis of the helical aromatics.
Of particular importance is also that the unusual stability
against racemization in the helical aromatic formed from
2-methylglutaric acid is comparable to those of more
widely known helicenes.22 We have proven that theoreti-
cal CD generated by TDDFT derived the identical
absolute configuration for helical aromatics. Thus, the
theoretical CD spectra are reliable and will aid in the
assignment of absolute configurations of not only helical
molecules but also chiral molecules possessing sp3 chiral
genetic centers.
Experimental Section
General Procedure for Microwave-Assisted and Con-
ventional Heating Reactions. We adopted a domestic
microwave oven of MARUMAN MD-668 (2.54 GHz, 500 W
fixed, 100 V, 60 Hz) produced in Japan in 1993. The microwave
oven has been modified according to the literature.23 Thus, we
bore a hole of 2 cm in diameter at the very center of the top
plate of the oven for the condenser fitting or measurement of
the infrared radiation as an index of the reaction temperature.
No leakage of microwaves has been detected using an elec-
tromagnetic field meter. A mixture of N,N′-p-phenylenedi-
amine (2) (0.795 mmol), carboxylic acid (3.00 mmol), and zinc
chloride (11.63 mmol) in a rounded-bottom flask equipped with
or without a reflux condenser was placed in a domestic
microwave oven (2.45 GHz, 500 W), and the sample was
(20) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.;
Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.;
Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson,
G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.;
Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai,
H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Adamo,
C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin,
A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma,
K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.;
Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.;
Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui,
Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.;
Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challa-
combe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.;
Gonzalez, C.; Pople, J. A. Gaussian 03, revision B.01; Gaussian, Inc.:
Pittsburgh, PA, 2003.
(22) [6]Helicene exhibits kinetic parameters of τ1/2 ) 106 min and
∆Gq ) 156.3 kJ mol-1 at 200 °C. [7]- and [8]helicenes showed ∆Gq
)
174.5 and 177.4 kJ mol-1 at 27 °C, respectively; see: (a) Martin, R.
H.; Marchant, M. J. Tetrahedron 1974, 30, 347. (b) Janke, R. H.; Haufe,
G.; Wu¨rthwein, E.-U.; Borkent, H. J. Am. Chem. Soc. 1996, 118, 6031.
(c) Meier, H.; Schwertel, M.; Schollmeyer, D. Angew. Chem., Int. Ed.
1998, 37, 2110.
(21) Difference in wavelength and absorption coefficient between
theoretical and experimental CD and absorption spectra was partly
rationalized by solvent effects and the systematic underestimation of
higher excitation energies in TDDFT; see ref 18 and: Bauernschmitt,
R.; Ahlrichs, R. Chem. Phys. Lett. 1996, 256, 454.
(23) Ni-i, T.; Matsumura, T.; Oka, T. Kagaku to Kyouiku 1993, 41,
278.
7800 J. Org. Chem., Vol. 69, No. 23, 2004

Stereoselective Formation of Helical Aromatics
irradiated. The reaction mixture obtained was neutralized with
aqueous ammonia followed by extraction with chloroform and
subsequent column chromatography on silica gel with CHCl3-
ethyl acetate as the eluant gave 1. The synthetic procedure of
conventional heating reactions was almost identical with those
of the microwave-assisted reactions described above, except
for the use of an oil bath for heating.
Chiral Resolution and Kinetic Measurements. The
chiral resolution was accomplished by passing the acetonitrile
solution of racemic 1 through a HPLC chiral column (DAICEL,
CHIRALCEL OJ-R, solvent ) 3/7 acetonitrile/H2O) in both
analytical and preparative scales. Kinetic measurements for
the racemization of optically pure 1a were taken in 3/7
acetonitrile/H2O by means of CD spectroscopy, ∆ꢀ at 308.5 nm
being utilized for estimating the time course of [(P)- or (M)-
1a] and [racemic-1a]. The conversion of optically pure (P)-1a
into its racemate followed first-order kinetics of d[(P)-1a]/dt
) -k1[(P)-1a] + k-1[racemic-1a]. The rate constant of racem-
ization (k1 ) 8.55 × 10-5 s-1 at 20 °C) gave kinetic parameters
of τ1/2 and ∆Gq from the equations of τ1/2 ) ln 2/k1 and -∆Gq )
RT ln(k1h/kBT) where h and kB referred to the Planck and
Boltzmann constants, respectively.
Crystal Structures. Crystal structures of 1a, 4a, and 5a
have been reported previously.4 Crystallographic data of 1b
and 1f were collected on a Rigaku Mercury/CCD AXIS-4
diffractometer with graphite monochromated Mo KR radiation
[γ(Mo KR) ) 0.71070 Å]. Data were collected and processed
using CrystalClear (Rigaku).24 All calculations were performed
using the CrystalStructure crystallographic software pack-
age.25 Structures were solved by direct methods and expanded
using Fourier techniques.26,27 The non-hydrogen atoms were
refined anisotropically. Hydrogen atoms were refined using
the riding model. The full-matrix least-squares refinement on
F2 was carried out.
Crystal data and structure refinement for 1b (C24H20N2):
crystal size ) 0.30 × 0.20 × 0.05 mm, fw ) 336.42, temper-
ature ) -120 °C, monoclinic, C2/c, a ) 23.220(6) Å, b )
9.111(2) Å, c ) 16.230(4) Å, â ) 90.176(7)°, V ) 3433.6(14) Å3,
Z ) 8, Fc ) 1.30 Mg/m3, R1 ) 0.057, wR2 ) 0.131, GOF ) 1.005.
For 1f (C24H18N2): crystal size ) 0.15 × 0.20 × 0.05 mm, fw
) 334.42, temperature ) -100 °C, monoclinic, P21/n, a )
7.980(3) Å, b ) 12.096(5) Å, c ) 17.014(7) Å, â ) 90.122(11)°,
V ) 1642.4(12) Å3, Z ) 4, Fc ) 1.352 Mg/m3, R1 ) 0.082, wR2
) 0.2000, GOF ) 1.000.
General Procedure for Obtaining HOMO Densities
and Theoretical Racemization Barriers (∆∆Hf0). We have
confirmed that the orbital coefficients, the most stable con-
Supporting Information Available: 1H NMR spectra of
1a-e, 1g, 4a, 4b, 5a, 6a′, 8c, and 8c′; high-resolution mass
spectra of 1a-g, 4a, 4b, 5a, 6a′, 8c, and 8c′; elemental
analyses of 1a, 1d, 1f, and 4a; the Z-matrix and the total
energy for 1a, 1b, 1d-f, 4b, 5a, and 8a′ generated by an
optimized geometry calculation in MM/MOPAC using MM3/
PM5 parameters; crystallographic information file (CIF) for
1b and 1f. This material is available free of charge via the
Internet at http://pubs.acs.org.
0
formations, and ∆Hf values generated by three different
methods of MOPAC/AM1, MOPAC/PM5, and the time-depend-
ent density functional theory (B3LYP/6-31G*) were almost
identical, so MOPAC/PM5 was utilized unless otherwise noted.
The most stable conformation was thus primarily generated
by MM3 followed by MOPAC/PM5, resulting in the orbital
coefficients. The HOMO density is equal to the square of the
orbital coefficient of the pZ component. The most stable
conformation generated was adopted as the initial conforma-
tion for the following calculations for obtaining the theoretical
JO048858K
0
∆∆Hf as an index of racemization barrier. A dihedral angle
consisting of four atoms denoted by R, 13, 14, and R in the
chemical structures of (P)-1 of (M)-1 in the Introduction was
defined. We decreased the dihedral angle by 5° from the initial
conformation, immobilized the angle, and then calculated the
(24) CrystalClear; Rigaku Corporation: 1999. CrystalClear Soft-
ware User’s Guide; Molecular Structure Corporation: 2000. Pflugrath,
J. W. Acta Crystallogr. 1999, D55, 1718-1725.
(25) (a) CrystalStructure 3.6.0: Crystal Structure Analysis Package;
Rigaku and Rigaku/MSC: The Woodlands, TX, 2004. (b) Watkin, D.
J.; Prout, C. K.; Carruthers, J. R.; Betteridge, P. W. CRYSTALS Issue
10; Chemical Crystallography Laboratory: Oxford, UK, 1996.
(26) Sheldrick, G. M. SHELX97; 1997.
(27) Beurskens, P. T.; Admiraal, G.; Beurskens, G.; Bosman, W. P.;
de Gelder, R.; Israel, R.; Smits, J. M. M.; The DIRDIF-99 Program
System, Technical Report of the Crystallography Laboratory; University
of Nijmegen: Nijmegen, The Netherlands, 1999.
0
most stable conformation and its ∆Hf using MOPAC/PM5.
0
We continued this procedure until the largest ∆Hf was
0
obtained. When the dihedral angle was 0° the largest, ∆Hf
was always provided in which the conformations of the helical
0
aromatics take the Cs symmetry.11 The difference in ∆Hf
values between the initial and final conformations was taken
as the theoretical racemization energy (∆∆Hf 0).
J. Org. Chem, Vol. 69, No. 23, 2004 7801