"Marking" the nitrogen atoms of phenyl-(2-pyridyl)-(3-pyridyl)- (4-pyridyl)-methane. Synthesis and absolute configuration of the corresponding tris(pyridine N-oxide)

Article abstract of DOI:10.1002/chir.20965

To "mark" the nitrogen atoms in phenyl-(2-pyridyl)-(3-pyridyl)- (4-pyridyl)methane (1), we have synthesized the corresponding tris(pyridine N-oxide) 2 by oxidation of 1 with m-chloroperbenzoic acid. The nitrogen atoms of 2 are unequivocally determined by

Full text of DOI:10.1002/chir.20965

CHIRALITY 23:543–548 (2011)
‘‘Marking’’ the Nitrogen Atoms of Phenyl-(2-pyridyl)-(3-pyridyl)-
(4-pyridyl)-methane. Synthesis and Absolute Configuration of the
Corresponding Tris(pyridine N-oxide)
1
1
2
3
1
KOUZOU MATSUMOTO,1 KAORI MIKI, TAKUYA INAGAKI, TATSUO NEHIRA, * GENNARO PESCITELLI, YASUKAZU HIRAO,
*
HIROYUKI KURATA,1 TAKESHI KAWASE,4 AND TAKASHI KUBO1*
1Department of Chemistry, Graduate School of Science, Osaka University, Osaka, Japan
2Graduate School of Integrated Arts and Sciences, Hiroshima University, Higashi-hiroshima, Japan
3Department of Chemistry, University of Pisa, Pisa, Italy
4Department of Materials Science and Chemistry, Graduate School of Engineering, University of Hyogo, Himeji, Hyogo, Japan
ABSTRACT
To ‘‘mark’’ the nitrogen atoms in phenyl-(2-pyridyl)-(3-pyridyl)-(4-pyridyl)-
methane (1), we have synthesized the corresponding tris(pyridine N-oxide) 2 by oxidation of 1
with m-chloroperbenzoic acid. The nitrogen atoms of 2 are unequivocally determined by the X-
ray crystal analysis of a single crystal of rac-2 whereas the nitrogen atoms cannot be assigned at
all in the case of rac-1. N-Oxide 2 can be resolved by chiral high-performance liquid chromatog-
raphy under similar conditions to those used for the resolution of 1. The calculated circular
dichroism (CD) curve for (R)-2 on the basis of time-dependent density functional theory reprodu-
ces the experimental spectra very well to suggest that the second-eluted fraction ([CD(1)283]-
2) is the R isomer, namely (R)-[CD(1)283]-2. The independent absolute configuration determi-
nations for 1 and 2 are in keeping with the chemical correlation between the two compounds by
C
VV
oxidation of (R)-1 into (R)-2. Chirality 23:543–548, 2011.
2011 Wiley-Liss, Inc.
KEY WORDS: chiroptical properties; chiral separation; configuration determination; density
functional calculations; heterocycles
INTRODUCTION
determined by X-ray analysis (Scheme 1). Moreover, the ster-
eochemistry at the chirality center would be preserved during
the oxidation of 1, therefore the absolute configurations of 1
and 2 are easily correlated. If the absolute configuration of 2
is independently assigned by CD calculations, the two assign-
ments of 1 and 2 would reinforce each other. Further evi-
dence for the absolute configuration of 1 is in fact desirable
because of the weakness of its experimental CD spectrum
and the molecular flexibility, which affected the CD calcula-
tions. Furthermore, as a number of chiral derivatives of pyri-
dine N-oxide have been explored for various asymmetric syn-
thesis,26–29 2 might be a useful molecule as an asymmetric
catalyst. We now report the synthesis, enantioseparation, chi-
roptical properties and absolute configuration determination
of 2 by calculation of CD curve by means of TDDFT.
Many kinds of chiral molecules having outstanding struc-
tural features have been successfully synthesized, and their
fascinating properties have been disclosed.1–16 These mole-
cules have attracted much attention not only from the view-
point of the elucidation of the structure–chiroptical property
relationship but also in relation to the potential application in
the fields of asymmetric synthesis, host–guest chemistry,
and materials science.17–24 Some of these molecules are im-
portant for the understanding of chirality and the origin of
life, ultimately. We recently reported the synthesis, optical
resolution and chiroptical properties of phenyl-(2-pyridyl)-
(3-pyridyl)-(4-pyridyl)methane (1) as a prototypical chiral
molecule based on tetraarylmethane framework.25 As single
crystals of 1 were obtained suitable for X-ray analysis, we
envisaged a possibility for assigning the absolute configura-
tion of 1 and related compounds. The racemic mixture of 1
(rac-1) crystallized as a racemic compound, that is, equal
amounts of the enantiomers were contained in each single
crystal. More surprisingly, we could not assign the positions
of nitrogen atoms at all; the asymmetric unit was only a half
of the molecule. This uncertainty was attributed not only to a
random orientation of the aryl groups but also to the 1808
rotational disorder of 2- and 3-pyridyl groups in the crystals as
the positions of the nitrogen atoms are different from each
other by 1808 rotation of the corresponding aryl rings. The
absolute configuration of 1 was therefore determined by the
comparison of time-dependent density functional theory
(TDDFT)-calculated CD spectra with the experimental ones.
To circumvent the problem of ambiguous assignment of
the nitrogen atoms in the crystals of 1, we considered the
corresponding tris(pyridine N-oxide) 2, where each nitrogen
is ‘‘marked’’ with an oxygen atom and would be easily
EXPERIMENTAL
General
Melting points were taken on a Yanaco MP 500D apparatus and are
1
uncorrected. H and 13C NMR spectra were recorded on a JEOL EX-270
(270 MHz) or JEOL LA-500 (500 MHz) spectrometer. Heteronuclear
Additional Supporting Information may be found in the online version of this
article.
Contract grant sponsor: Kinki Innovation Center; Contract grant number: 21-4
Contract grant sponsor: Japan Society of the Promotion of Science;
Contract grant number: 21750045
*Correspondence to: Kouzou Matsumoto, 1-1 Machikaneyamacho, Toyonaka,
Osaka 560-0043, Japan. E-mail: kmatsu@chem.sci.osaka-u.ac.jp (or) Takashi
Kubo, 1-1 Machikaneyamacho, Toyonaka, Osaka 560-0043, Japan. E-mail:
kubo@chem.sci.osaka-u.ac.jp (or) Tatsuo Nehira, 1-7-1 Kagamiyama, Higashi-
Hiroshima 739-8521, Japan. E-mail: tnehira@hiroshima-u.ac.jp
Received for publication 16 November 2010; Accepted 22 March 2011
DOI: 10.1002/chir.20965
Published online 26 May 2011 in Wiley Online Library
(wileyonlinelibrary.com).
C
VV
2011 Wiley-Liss, Inc.

544
MATSUMOTO ET AL.
CD (hexane-ethanol (1:1 v/v)) kext 331 nm (De 1 0.1), 306 (–1.0), 283
(13.0), 265 (22.4), 244 (10.5).
COMPUTATIONAL METHODS
All calculations were performed either on a Linux computer or on the
grid server at the Media Information Center of Hiroshima University.
Conformational analysis was performed by CONFLEX5 with the
MMFF94S30–33 force field, in which starting structures selected from a
set within 50 kcal mol21 were converged by applying systematic struc-
tural deviations.34,35
DFT calculations were run with the Gaussian 03 program (Revision
C.02). Geometry optimization of the 12 conformers found by MMFF94S
was performed at the B3LYP/6-31G(d) level.36,37 For each input struc-
ture thus obtained, the first 32 excited states were computed with
TDB3LYP/TZVP.36,38,39 For the conformers that contributed to a greater
extent to the average UV-Vis/CD spectra, we verified that all the 32 com-
puted transitions involve virtual orbitals with negative eigenvalues and
have energies (within 5.21–5.58 eV) well below the computed ionization
potential (5.9–6.1 eV).40 All rotational strengths (dipole length gauge for-
mulation) obtained from the calculations were converted into Gaussian-
type curves adopting a 20-nm band-width value r, and summed to afford
the calculated CD curve for each conformer (see Supporting Informa-
tion).
Scheme 1. Synthesis of rac-2.
multiple-quantum correlation (HMQC) and heteronuclear multiple-bond
correlation (HMBC) spectra were recorded on a VARIAN INOVA 600
(600 MHz) spectrometer. Chemical shifts were recorded in unit of parts
per million downfield from tetramethylsilane as an internal standard and
all coupling constants are reported in Hz. Electronic spectra were taken
in hexane/ethanol (1:1 v/v) solution on a JASCO V-570 spectrophotome-
ter. CD spectra were taken on a JASCO J-720W spectropolarimeter.
Mass spectra were recorded with a Shimadzu GCMS-QP5050 spectrome-
ter by EI method. High resolution mass spectra were recorded with a
QSTAR1 Elite spectrometer by ESI method. Elemental analyses were
performed at the Elemental Analysis Center in Faculty of Science, Osaka
University. Commercially available reagents and solvents were purified
and dried when necessary.
RESULTS AND DISCUSSION
The target tris(pyridine N-oxide) rac-2 was obtained by ox-
idation of rac-1 with MCPBA in excellent yield (see Scheme
1) as colorless, hygroscopic solid. (We adopted some modifi-
cation to the synthetic procedure of rac-1 as described in
Preparation of Rac-(1-oxy-pyridin-2-yl)-(1-oxy-pyridin-3-yl)-
(1-oxy-pyridin-4-yl)-phenyl-methane (rac-2)
m-Chloroperbenzoic acid (MCPBA) (248 mg, 1.44 mmol) was added
in small portions to a solution of rac-1 (40 mg, 0.12 mmol) in CH2Cl2
(10 mL) at 08C. The reaction mixture was stirred for 90 min at 08C, then
at room temperature overnight. After concentration of the reaction mix-
ture the residue was purified by column chromatography on alumina
eluted with CH2Cl2–MeOH (4:1 v/v) to give rac-2 (> 99%) as pale yellow
solid. M.p. > 3158C (dec.). UV/Vis (in EtOH) kmax/nm (log e) 276
(4.39). 1H NMR (500 MHz, CDCl3): d 5 8.15 (ddd, J 5 6.5, 1.5, 0.5 Hz,
1H), 8.13 (dd, J 5 5.0, 1.5 Hz, 2H), 8.12 (ddd, J 5 5.5, 1.5, 1.0 Hz, 1H),
7.98 (t, J 5 2.0 Hz, 1H), 7.40 (ddd, J 5 8.0, 2.0, 0.5 Hz, 1H), 7.37–7.33
(m, 4H), 7.29 (td, J 5 8.5, 1.5 Hz, 1H), 7.25 (dd, J 5 8.0, 6.5 Hz, 1H),
7.08 (ddd, J 5 8.0, 2.0, 0.5 Hz, 1H), 7.06–7.04 (m, 2H), 7.03 ppm (dd, J 5
5.0, 1.5 Hz, 2H) ppm. 1H NMR (600 MHz, methanol-d4): d 5 8.25–8.24
(m, 4H, 4PyNO-2,6H, 3PyNO-6H), 8.22 (dd, J 5 6.0, 1.2 Hz, 1H, 2PyNO-
6H), 8.10 (s, 1H, 3PyNO-2H), 7.64 (dd, J 5 7.8, 3.0 Hz, 1H, 2PyNO-3H),
7.63–7.55 (m, 2H, 2PyNO-4,5H), 7.48 (t, 1H, J 5 7.2 Hz, 3PyNO-5H),
7.41–7.38 (m, 3H, 3PyNO-4H, Ph-metaH), 7.35 (t, J 5 7.2 Hz, 1H, Ph-
paraH), 7.32 (d, J 5 7.2 Hz, 2H, 4PyNO-3,5H), 7.17 ppm (d, J 5 7.8 Hz,
2H, Ph-orthoH) ppm. 13C NMR (67.8 MHz, CDCl3): d 5 151.40, 141.20,
140.19, 140.03, 139.86, 138.40, 138.25, 137.21, 129.72, 128.84, 128.10,
127.61, 127.41, 127.04, 126.01, 124.79, 124.70, 60.83 ppm. 13C NMR (150
MHz, methanol-d4): d 5 152.60, 143.84, 142.34, 142.00, 141.68, 141.54,
139.80, 138.69, 132.38, 131.31, 130.18, 129.86, 129.39, 129.12, 128.87,
128.28, 127.04, 62.58 ppm. MS (FAB) m/z 372 [M1H]1. HRMS (ESI):
m/z calcd for C22H18N3O3 372.1342 [M1H]1; found 372.1346, calcd for
1
Ref 25. See Supporting Information.) The H NMR chemical
shifts of rac-2 are on the whole observed at higher field than
the corresponding ones of rac-1. In particular, the high field
shifts of the ortho- and para-protons with respect to the N-ox-
ide groups are relatively large. These high field shifts are
also observed in the parent pyridine N-oxide and ascribed to
C
22H17N3NaO3 394.1162 [M1Na]1; found 394.1159. C22H17N3O3ꢀ3.2H2O
(429.04): C 61.59, H 5.50, N 9.79; found C 61.70, H 5.45, N 9.57.
Resolution of Rac-2
Fig. 1. ORTEP drawing of tris(pyridine N-oxide rac-2 (50% probability).
Crystal data for rac-2: Molecular formula C22H17N3O3, M 5 371.39, triclinic,
space group P—1 (No. 2), a 5 7.2706(10) A, b 5 9.1391(14) A, c 5 14.682(2)
The optical resolution of rac-2 was performed by a high-performance
liquid chromatography (HPLC) system consisting of a JASCO PU-2080
plus intelligent HPLC pump, a DG-2080-53 3-Line-Degasser, a CO-2060
plus intelligent column thermostat, a UV-2075 plus intelligent UV/VIS
detector, and a CD-2095-K1 plus chiral detector. An HPLC separation
was performed by using Chiralcel OD (4.6 or 10 mm f 3 25 cm) under
the conditions described in the captions of Figures (See below). Fraction
1; [CD(–)281]-2 CD (hexane-ethanol (1:1 v/v)) kext 333 nm (De 20.2),
306 (10.9), 281 (–2.7), 264 (11.2), 244 (–0.7). Fraction 2; [CD(1)283]-2
˚
˚
˚
˚
A, a 5 78.731(4)8, b 5 77.960(4)8, g 5 63.316(4)8, V 5 846.7(2) A3, Z 5 2,
Dc 5 1.457 g cm–3, T 5 200 K, total reflections collected 5 8438, unique
reflections 5 3865 (Rint 5 0.033), final R1 5 0.0649 (Rw 5 0.2306 for all data)
for 2399 reflections (I > 2r(I)), GOF 5 1.105. The structure was solved by
direct method and refined by full-matrix least squares by using the SHELXL-
97 program. CCDC-790313 contains the supplementary crystallographic data
for this article. These data can be obtained free of charge from The Cam-
bridge
Crystallographic
Data
Centre
via
ccdc.cam.ac.uk/data_
request.cif.
Chirality DOI 10.1002/chir

CHIRAL TETRAARYLMETHANE DERIVATIVE
545
Fig. 2. Chromatograms for the optical resolution of rac-2. Top: UV detec-
tion (k 5 275 nm). Bottom: CD detection (k 5 275 nm). Column: Chiralcel
OD (diameter; 4.6 mm), eluent: hexane/ethanol 5 1:1 (v/v), flow rate: 1.0
mL min21, temperature: 358C. After five cycles, the two enantiomers were
well-resolved.
Fig. 3. Top: UV spectrum of rac-2 in hexane/ethanol (1:1 v/v). Bottom:
CD spectra of the enantiomeric pair of 2 in hexane/ethanol (1:1 v/v). The
curves of the first and second eluted fractions are shown by solid and dotted
lines, respectively.
electron-donating effect of the N-oxide group toward the
ring. The 13C NMR chemical shift of the central carbon in
rac-2 is observed at d 60.83 ppm (in CDCl3), slightly higher
field than that of rac-1 (d 64.73 ppm in CDCl3). A similar
high field shift is observed in the central carbon in tetra-
kis(2-pyridyl)methane (d 72.36 ppm) by oxidation to the cor-
responding tetra(pyridine N-oxide) (d 59.63 ppm).41 Full
assignment of the 1H and 13C NMR chemical shifts in metha-
nol-d3 was achieved by the acquisition of HMQC and HMBC
spectra (see Supporting Information).
TABLE 1. Calculated stability of 12 comformers of (R)-2 by DFT method (B3LYP/6–31G(d) level)
Codea Relative energy (kcal mol21
Optimized energy (Hartree) Population at 298 K (%)
conf_01 21238.2892945 0.0000
Stability order
)
1
2
3
4
5
6
7
8
9
26.6
14.8
13.8
8.9
6.2
5.7
5.5
5.4
4.6
3.3
2.8
2.4
conf_02
conf_03
conf_04
conf_11
conf_10
conf_09
conf_07
conf_08
conf_06
conf_12
conf_05
21238.2887409
21238.2886799
21238.2879730
21238.2879256
21238.2878397
21238.2878002
21238.2877843
21238.2876458
21238.2873230
21238.2871734
21238.2870424
0.3474
0.3857
0.8292
0.8590
0.9129
0.9376
0.9477
1.0346
1.2371
1.3310
1.4132
10
11
12
aThe code name ‘‘conf_xx’’ is based on the order of appearance in the CONFLEX search using MMFF94S.
Chirality DOI 10.1002/chir

546
MATSUMOTO ET AL.
The enantiomers of 2 were successfully separated by chi-
ral HPLC under conditions similar to the resolution of rac-1
(Fig. 2). We expected that the resolution of rac-2 might be
easier than those of rac-1 as the differences among the four
aryl groups are increased by oxidation. However, recycling
was again needed for the optical resolution of rac-2. The CD
spectra of the two fractions in n-hexane–ethanol (1:1 v/v)
show the typical mirror-image relationship for a pair of enan-
tiomers (Fig. 3). As expected, the shape of CD spectra of 2
was quite different from those of 125 because of the change
in the electronic structure due to the oxidation.
To determine the absolute configuration of 2, we calcu-
lated the electronic CD curve of (R)-2 by a quantum-mechan-
ical method for comparison with the experimental ones.44–48
As was observed for (R)-1, the 12 stable conformers, which
had been expected considering the three orientations for the
phenyl group and two distinct directions for both 1-oxo-
pyridin-2-yl and 3-yl groups, were all obtained. They were
subjected to optimization with the density functional theory
(DFT) method at the B3LYP/6-31G(d) level, which also
afforded relative internal energies used to estimate the Boltz-
mann populations at 298 K (Table 1). The incentive to oxida-
tion of 1 was originally to alter the molecular polarity to
induce crystallization and to reduce the number of stable
conformations, and it resulted in a more biased population of
all 12 conformers (The population of the most stable con-
former of 1 and 2 were 14.8 and 26.6%, respectively). The
twelve calculated CD curves, where the rotational strengths
were converted to Gaussian curves with a r value of 20 nm
(equivalent to 2900 cm21 at 250 nm, see Supporting Informa-
tion), were Boltzmann-weighted and summed to afford the
theoretical CD curve for (R)-2 (Fig. 4). The calculated aver-
age spectrum was in good agreement, in terms of sign, posi-
tion and relative intensity of bands, with the experimental
CD recorded for the second eluted enantiomer of 2. Conse-
quently, we could determine the absolute configuration of 2
as (R)-[CD(1)283]-2.
Fig. 4. Boltzmann-weighted average of calculated CD curves for (R)-2 at
B3LYP/TZVP level (dotted line) and experimental CD spectrum for the sec-
ond-eluted enantiomer [CD(1)283]-2 (solid line).
Single crystals of rac-2 were obtained from a solution in
methanol by vapor diffusion with ether. The molecular struc-
ture of rac-2 in the crystal (Fig. 1) was in good correlation
with the most stable conformation of 2 calculated by the
DFT method (vide infra). It is apparent from the space group
P–1 that 2 crystallizes as a racemic compound; each crystal
is composed of the same amounts of (R)- and (S)-enantiom-
ers. Interestingly, there were several short contacts between
adjacent molecules causing a mutual arrangement which can-
cels the molecular dipole moments. Heterochiral pairs are
held together by two appreciable CꢁꢁHꢀꢀꢀO interactions42,43
˚
(C9–H6ꢀꢀꢀO3 3.289(5) A, \C9–H6–O3 150.7(2)8). A further
˚
CꢁꢁHꢀꢀꢀO interaction (C6–H4ꢀꢀꢀO2 3.449(4) A, \C6–H4–O2
166.8(2)8) is observed between homochiral pairs. There is a
˚
strong CꢀꢀꢀC contact (C6ꢀꢀꢀC6i 3.122(5) A, symmetry code: i
This assignment of absolute configuration was further con-
firmed by the oxidation of a sample of enantiopure 1. Thus,
6.3 mg of (R)-1 (first-eluted, configuration assigned by
TDDFT method)25 were converted to (R)-2 (9.1 mg, > 99%).
No racemization occurred during the oxidation according to
a chiral HPLC analysis (Fig. 5). The retention time (con-
firmed using the same conditions as described in Fig. 1) and
the CD sign of the product were comparable with those of
the second-eluted one, which was finally confirmed by its
5 2x 1 1, 2y, 2z 1 1), which would be the reason for the
cancellation of the dipole moments of 1-oxo-pyridin-2-yl
groups.
Fig. 5. Chromatogram for the analysis of optically pure 2 obtained by the
oxidation of the optically pure 1 (first-eluted fraction). Detection: CD at 275
nm, Column: Chiralcel OD (diameter 10 mm), flow rate: 3.0 mL min21, elu-
ent: hexane/ethanol 5 1:1 (v/v), temperature 358C.
Fig. 6. Molecular structure of (R)-[CD(1)283]-2.
Chirality DOI 10.1002/chir

CHIRAL TETRAARYLMETHANE DERIVATIVE
547
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