Stereodynamics and conformational chirality of the atropisomers of ditolyl anthrones and anthraquinone

Article abstract of DOI:10.1021/jo800677n

(Figure Presented) Syn and anti conformers in similar proportions were observed at ambient temperature for the title compounds. The conformational assignment of the two anthrones was obtained by the observation of different multiplicity of the methylene N

Full text of DOI:10.1021/jo800677n

Stereodynamics and Conformational Chirality of the Atropisomers
of Ditolyl Anthrones and Anthraquinone
Lodovico Lunazzi, Michele Mancinelli,† and Andrea Mazzanti*
Department of Organic Chemistry “A. Mangini”, UniVersity of Bologna, Viale Risorgimento 4,
Bologna 40136, Italy
mazzand@ms.fci.unibo.it
ReceiVed March 26, 2008
Syn and anti conformers in similar proportions were observed at ambient temperature for the title
compounds. The conformational assignment of the two anthrones was obtained by the observation of
different multiplicity of the methylene NMR signals, whereas that of the anthraquinone derivative was
determined by NOE experiments. The anti-to-syn interconversion barriers were obtained by line-shape
simulation of the temperature-dependent NMR spectra, and by saturation tranfer experiments. In one
case the X-ray diffraction indicated that the syn is the only structure observed in the crystals.
Introduction
appropriate aryl substituents. The interest for synthesizing and
studying these derivatives is due to the fact that they can be
further functionalized quite easily, owing to the presence of the
carbonyl moiety, whereas the compounds investigated so far,
being hydrocarbons,6–11 are less prone to undergo further
modifications. In the present work we report the experimental
detection of atropisomers occurring in the isomeric 1,9-
ditolylanthrones and anthraquinone (1-3 in Chart 1), as well
as the determination of the barrier required for their intercon-
version.
It has been recognized that π-stacking interactions of aromatic
substituents bonded in appropriate positions to planar (or
quasiplanar) frameworks1 play an important role in a great
number of chemical properties, including stereocontrolled
reactions,2 molecular recognitions,3 nucleic acid and protein
structures,4 and crystal packing.5 Depending on the hindrance
of the aryl substituentes and on the type of the planar framework
(e.g., benzene,6 naphthalene,7 phenanthrene,
anthracene,9
8
acenaphthene,10 and acenaphthalene11), the resulting atropiso-
mers can be either stereolabile or configurationally stable. This
type of atropisomer should be also observable when anthrone
or antraquinone are used as a framework to which connect the
(4) (a) Saenger, W. Principles of Nucleic Acid Structures; Springer Verlag:
New York, 1984. (b) Burley, S. K.; Petsko, G. A. Science 1985, 229, 23–28. (c)
Hunter, C. A.; Singh, J.; Thornton, J. M. J. Mol. Biol. 1991, 218, 837–846. (d)
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B. A.; Ren, R. X. F.; Sheils, C. J.; Paris, P. L.; Tanmasseri, D. C.; Kool, E. T.
J. Am. Chem. Soc. 1996, 118, 8182–8183. (g) Ho, T. L.; Liao, P. Y.; Wang,
K. T. J. Chem. Soc., Chem. Commun. 1995, 2437–2438. (h) Ranganathan, D.;
Haridas, V.; Gilardi, R.; Karle, J. L. J. Am. Chem. Soc. 1998, 120, 10793–
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Soc. 2002, 124, 6133–6143. (j) Chelli, F.; Gervasio, F. L.; Procacci, P.; Schettino,
V. Proteins 2002, 48, 117–125.
† In partial fulfilment of the requirements for the Ph.D. degree in Chemical
Sciences, University of Bologna.
(1) Cozzi, F.; Annunziata, R.; Benaglia, M.; Cinquini, M.; Raimondi, L.;
Baldridge, K. K.; Siegel, J. S. Org. Biomol. Chem. 2003, 1, 157–162.
(2) Jones, G. B. Tetrahedron 2001, 57, 7999–8016.
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Smithrud, D. B.; Wyman, T. B.; Diederich, F. J. Am. Chem. Soc. 1991, 113,
5420–5426. (c) Conn, M. M.; Deslongchamps, G.; de Mendoza, J.; Rebek, J.
J. Am. Chem. Soc. 1993, 115, 3458–3557. (d) Philip, D.; Stoddardt., J. F. Angew.
Chem., Int. Ed. Engl. 1996, 35, 1154–1196. (e) Muehldorf, A. V.; Van Egen,
D.; Warner, J. C.; Hamilton, A. D. J. Am. Chem. Soc. 1988, 110, 6561–6562.
(f) Zimmermann, S. C.; Zeng, Z.; Wu, W.; Reichert, D. E. J. Am. Chem. Soc.
1991, 113, 183–196. (g) Newcomb, L. T.; Gellman, S. H. J. Am. Chem. Soc.
1994, 116, 4993–4994. (h) Cochran, J. E.; Parrott, T. J.; Whitlock, B. J.; Whitlock,
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Acc. Chem. Res. 1993, 26, 593–598. (c) Anderson, H. L.; Bashall, A.; Henrick,
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Nishimura, J. Liebigs Ann./Recl. 1997, 1769–1776.
5354 J. Org. Chem. 2008, 73, 5354–5359
10.1021/jo800677n CCC: $40.75 2008 American Chemical Society
Published on Web 06/21/2008

Atropisomers of Ditolyl Anthrones and Anthraquinone
CHART 1
SCHEME 1. DFT Computed Structuresa of the Two
Conformers of 1 (top) and Experimental X-ray Structure
(bottom)
1
FIGURE 1. (Top) H methylene spectrum (600 MHz in CD2Cl2 at
-40 °C) of 1. (Bottom) In a chiral environment the splitting of the
single line (blue) of the anti (chiral) conformer but not of the four line
spectrum (red) of the syn (achiral) conformer is observed.
a The relative energies (E) and enthalpies (H) are in kcal mol-1
.
spectrum (Jgem ) -24.0 Hz) along with a single line, due to
the chiroptic methylene of the syn and to the achiroptical
methylene of the anti conformer, in a 50:50 ratio, respectively.
An analogous spectrum is also observed for the CH2 hydrogens
DFT computations predict for each compound the existence
of two energy minima, corresponding to the syn and anti
atropisomers generated by the restricted sp2-sp2 rotation. As
an example, the syn and anti forms computed (at the B3LYP/
6-31G(d) level) for compound 1 are displayed in Scheme 1:
they are predicted to have essentially the same energy. From
this picture it is evident that the two methylene hydrogens of
the anti conformer experience the same environment, being
related by the 2-fold symmetry axis of the molecule (C2 point
group), whereas the two methylene hydrogens (labeled Ha and
Hb) of the syn conformer (Cs point group) experience different
environments, and are therefore diastereotopic.12
of 2 (i.e., a single line and an AB-type spectrum with Jgem
-20.7 Hz, as in Figure S-1 of the Supporting Information).
)
In the case of compound 1 we could also obtain the X-ray
structure (Scheme 1), which shows that solely the syn form is
populated in the solid state.13 From Scheme 1 it is evident that
the central ring of anthrone is bent in the crystalline structure,
while is planar in both the anti and syn calculated structures.
This finding is apparently anomalous, because in the cases of 2
and 3 the DFT calculations indicate that the corresponding
ground states have the central ring bent (see Figure S-2 of the
Supporting Information). To check whether the discrepancy
depends upon the inadequacy of the theoretical approach,
calculations at higher levels (PBE1PBE/6-31+G(d,p), HF/6-
31+G(d,p), and B3LYP/6-31++G(d,p)) were carried out on
the 1-syn conformation: in all cases, however, the central ring
results invariably planar.
Results and Discussion
The 1H NMR signal of the CH2 hydrogens of 1 (upper trace
of Figure 1) displays, in fact, the four lines of an AB-type
(6) (a) Mitchell, R. H.; Yan, J. S. H. Can. J. Chem. 1980, 58, 2584–2587.
(b) Lunazzi, L.; Mazzanti, A.; Minzoni, M.; Anderson, J. E. Org. Lett. 2005, 7,
1291–1294. (c) Mazzanti, A.; Lunazzi, L.; Minzoni, M.; Anderson, J. E. J. Org.
Chem. 2006, 71, 5474–5481.
Two experimental observations in solution actually support
the theoretical prediction of a planar structure of the anthrone
ring in 1:
(7) (a) Clough, R. L.; Roberts, J. D. J. Am. Chem. Soc. 1976, 98, 1018–
1020. (b) Cozzi, F.; Cinquini, M.; Annunziata, R.; Siegel, J. S. J. Am. Chem.
Soc. 1993, 115, 5330–5331. (c) Cozzi, F.; Ponzini, F.; Annunziata, R.; Cinquini,
M.; Siegel, J. S. Angew. Chem., Int. Ed. Engl. 1995, 34, 1019–1020. (d)
Zoltewicz, J. A.; Maier, N. M.; Fabian, W. M. F. Tetrahedron 1996, 52, 8703–
8706. (e) Zoltewicz, J. A.; Maier, N. M.; Fabian, W. M. F. J. Org. Chem. 1996,
61, 7018–7021. (f) Thirsk, C.; Hawkes, G. E.; Kroemer, R. T.; Liedl, K. R.;
Loerting, T.; Nasser, R.; Pritchard, R. G.; Steele, M.; Warren, J. E.; Whiting, A.
J. Chem. Soc., Perkin Trans. 2 2002, 1510–1519. (g) Tumambac, G. E.; Wolf,
C. J. Org. Chem. 2005, 70, 2930–2938.
(i) The large geminal coupling has been reported14 to be a
function of the dihedral angle φ, defined as the angle between
the π orbital and an imaginary line passing through both protons
of the methylene group. In the case of the calculated planar
structure of 1-syn, this dihedral angle is exactly 0°, thus this
coupling reaches its maximum value.14 In the case of 2, the
bent geometry of the central ring causes the dihedral angle φ to
become about 23° (according to DFT calculations), thus
reducing the value of the J-coupling, as experimentally observed
(i.e., -20.7 and -24.0 Hz in 2 and 1, respectively).15
(ii) In the case of 2, the low-field hydrogen signal of the AB-
(8) Lai, J.-H. J. Chem. Soc., Perkin Trans. 2 1986, 1667–1670.
(9) (a) House, H.; Hrabie, J. A.; Van Derveer, D. J. Org. Chem. 1986, 51,
920–929. (b) House, H.; Holt, J. T.; Van Derveer, D. J. Org. Chem. 1993, 58,
7516–7523.
(10) Cross, W.; Hawkes, G. E.; Kroemer, R. T.; Liedl, K. R.; Loerting, T.;
Nasser, R.; Pritchard, R. G.; Steele, M.; Watkinson, M.; Whiting, A. J. Chem.
Soc., Perkin Trans. 2 2001, 459–467.
(11) Lai, Y.-H.; Chen, P. J. Chem. Soc., Perkin Trans. 2 1989, 1665–1670.
(12) An opposite situation was reported in the case of the 2,6-diarylbenzoic
acids (aryl being 2-methylnaphthalene), which is chiral in the anti but achiral in
the syn configuration. The NMR showed, in fact, that the methylene hydrogens
of the corresponding propargyl esters are diastereotopic in the anti but
enantiotopic in the syn isomers. See: Chen, C-T; Chadah, R.; Siegel, J. S.;
Hardcastle, K. Tetrahedron Lett. 1995, 36, 8403–8406.
4
system displays a small additional J coupling (0.95 Hz) with
(13) In the analogous case of the 1,8-di(o-tolyl)biphenylene, the syn structure
has been also found to be the preferred form in the crystalline state; see: Lunazzi,
L.; Mancinelli, M.; Mazzanti, A. J. Org. Chem. 2008, 73, 2198–2205.
(14) Renaud, R. N.; Bovenkamp, J. W.; Fraser, R. R.; Capoor, R. Can.
J. Chem. 1977, 55, 2642–2648, and references cited therein.
J. Org. Chem. Vol. 73, No. 14, 2008 5355

Lunazzi et al.
the two hydrogens in positions 4 and 5 of the anthrone ring,
whereas the high-field hydrogen signal does not display such a
coupling (Figure S-1 of the Supporting Information). This
implies that in compound 2, Ha and Hb have different dihedral
angles with the two ortho hydrogens, therefore confirming the
bent geometry of the anthrone ring. These considerations are
further supported by the DFT-calculated J-couplings (including
the Fermi contact term) for the two syn conformers of 1 and 2:
in the case of planar 1, in fact, the calculated Jgem for the syn
conformer is actually predicted to be larger than that of 2 (-28.5
and -22.5 Hz, respectively). In addition, these calculations
predict that Hb of compound 2 (computed to have the lower
field signal) is coupled with the hydrogens in positions 4 and 5
of anthrone (4J ) -1.34 Hz), in agreement with the experi-
mental 0.95 Hz value. On the other hand, Ha is predicted to
4
have a negligible J coupling (-0.02 Hz), as experimentally
observed.
The presence of two enantiomers in the anti form can be
demonstrated by the NMR spectrum taken in a chiral environ-
ment. In these conditions,16 for instance, the single signal of
the CH2 moiety of 1 splits into a pair of lines due to the M,M
and P,P enantiomers,17 whereas the CH2 signals of the achiral
syn conformer are not further split (Figure 1, bottom trace):
these methylene hydrogens, in fact, are already diastereotopic
in the achiral solvent.
FIGURE 2. Temperature dependence of the 1H NMR methylene signal
(600 MHz in CDCl2-CDCl2) of 2 (left). On the right the simulation
with the rate constants indicated (see Figure S-4 of the Supporting
Information for the details of the exchange matrix).
population as the syn (in fact ∆G0 is 0.40 - 0.41 ) -0.01
kcal mol-1), therefore accounting for the nearly equal population
experimentally observed (if the experimental errors are consid-
ered, the 53:47 ratio does not differ significantly from 50:50).
It should also be outlined that the syn has a Cs and the anti a
static C1 symmetry (assuming it has a bent geometry), and as a
consequence, both have an equal symmetry number (σ ) 1),19
causing this contribution to the entropic factor to be the same,
thus irrelevant.20
The same behavior is also observed in the corresponding 13
C
spectrum of the two CH2 lines: the signal at higher field splits,
in fact, into a pair of lines, due to the M,M and P,P enantiomers,
whereas that at lower field does not (Figure S-3 of the
Supporting Information). This allows one to assign the upfield
line to the anti (chiral) and the downfield line to the syn (achiral)
conformer.
In the spectrum of compound 2 (bottom trace of Figure 2)
the intensity of the single line of the anti is slightly higher than
the intensity of the four-line spectrum of the syn (ratio 53:47).
This result, apparently, is not matched by DFT computations
that predict an energy lower (∆E and ∆H0 ) 0.37 and 0.40
kcal mol-1, respectively)18 for the syn with respect to the anti
(Figure S-2 of the Supporting Information). It has to be taken
into account, however, that the anti form is favored (by RT ln
2) by the entropy of mixing, since the anti comprises two
enantiomers whereas the syn does not.19 Accordingly, the
relative computed enthalpy of the anti has to be corrected, at
ambient temperature, by an entropic factor of RT ln 2 ) 0.41
kcal mol-1 with respect to the syn. When this effect is taken
into account, the anti is expected to have essentially the same
On raising the temperature, the CH2 signals of 2 display a
line-broadening effect due to the exchange of the syn and anti
conformers (Figure 2): eventually these signals merge into a
single line when the interconversion process becomes fast (above
+110 °C). This exchange process also can be followed by
monitoring the temperature dependence of the two single lines
of the methyl groups (Figure 3), where the more intense line of
the anti (53%) is at higher field21 than that of the syn conformer
(47%).
From the rate constants used to simulate the exchange process
of the methyl lines (Figure 3), a ∆Gq value of 18.6 kcal mol-1
is obtained.22 This barrier corresponds to the interconversion
of the anti into the syn conformer that, however, can take place
via a rotation of either of the two tolyl rings. To obtain the
barrier corresponding to the rotation of a single tolyl ring, the
values of the rate constants reported should be divided by two:
(15) The observed difference between these two Jgem-couplings (24.0-20.7
) 3.3 Hz for φ ) 0° and 23°, respectively) is consistent with the differences
reported in ref 14 (e.g., 23.6-18.1 ) 5.5 Hz for φ ) 0° and 45°, respectively).
(16) Use was made of a 10:1 molar excess of enantiopure R-(-)-2,2,2-
trifluoro-1-(9-anthryl)ethanol: Pirkle, W. H.; Sikkenga, D. L.; Pavlin, M. S. J.
Org. Chem. 1977, 42, 384–387. The temperature of-40 °C was used to increase
the separation of the lines (10 Hz at 600 MHz)
(17) Each of the two (blue) lines in the bottom trace of Figure 1 corresponds
to the two identical (isochronous) methylene hydrogens within each enantiomer
of the anti conformer. If the two hydrogens had been anisochronous, an AB-
type spectrum, with a geminal J coupling, would have been observed; see: Fraser,
R. R.; Pettit, M. A.; Miskow, M. J. Am. Chem. Soc. 1972, 94, 3253–3254.
Kainosho, M.; Ajisaka, K.; Pirkle, W. H.; Beare, S. D. J. Am. Chem. Soc. 1972,
94, 5924–5926. This issue has to be addressed in that two enantiotopic groups
of an achiral molecule also split their signal in a chiral environment; see: Casarini,
D.; Davalli, S.; Lunazzi, L.; Macciantelli, D. J. Org. Chem. 1989, 54, 4616–
4619. Casarini, D.; Lunazzi, L.; Verbeek, R Tetrahedron 1996, 52, 2471–2480.
Casarini, D.; Lunazzi, L.; Mazzanti, A. Angew. Chem., Int. Ed. 2001, 40, 2536–
2539. In compound 1, in fact, not only the methyl signal of the anti but also the
methyl signal of the syn conformer splits in this experiment, because the methyl
groups of the latter are enantiotopic in the achiral environment, contrary to the
corresponding CH2 hydrogens that are already diastereotopic (see Figure 2)
23
the corresponding barrier is, accordingly, 0.5 kcal mol-1
higher (∆Gq ) 19.1 kcal mol-1 as in Table 1).
Since the exchange of methylene hydrogens corresponds to
two subsequent single rotations of the tolyl rings, this explains
why the rate constants, introduced in the matrix for simulating
the spectrum of Figure 2, are one-half those of Figure 3 at the
(18) The ratio of the conformers actually depends upon the free energy ∆G°
) ∆H°- T∆S°. DFT computations yield acceptable values for the enthalpy, but
they are known to produce unreliable values for the entropy factor when low-
frequency normal modes (< 900 cm-1) are taken into account, as happens in
the present cases; see, for instance: Ayala, P. Y.; Schlegel, H. B. J. Chem. Phys.
1998, 108, 23142325. For this reason we preferred to estimate the entropy
contribution on the basis of the molecular symmetry, according to ref 19.
(19) Eliel. E. L.; Wilen, S. H. Stereochemistry of Organic Compounds; Wiley:
New York, 1994; pp 97. and 601. See also: Lunazzi, L.; Mazzanti, A.; Minzoni,
M. J. Org. Chem. 2005, 70, 10062–10066.
5356 J. Org. Chem. Vol. 73, No. 14, 2008

Atropisomers of Ditolyl Anthrones and Anthraquinone
FIGURE 4. Saturation transfer experiment (1D-EXSY) for compound
1 at +72 °C (600 MHz in CDCl2-CDCl2). The AB-type CH2 spectrum
(black trace) of the syn conformer grows when raising the mixing time
(in ms), after saturation of the CH2 anti single line (red signal).
for the anti-to-syn interconversion, corresponding to a ∆Gq
value of 20.3 ( 0.2 kcal mol-1. Within the experimental
error, this value agrees with that obtained by the DNMR
technique (Table 1).
Also in compound 3 two atropisomers with different propor-
tions (57:43) are observed at ambient temperature. Line shape
simulation of the two methyl signal as a function of temperature
yields the corresponding interconversion barrier (Figure S-6 of
the Supporting Information).
FIGURE 3. Temperature dependence of the CH3 signals (600 MHz
in CDCl2-CDCl2) of 2 (left). On the right is the spectral simulation
with the rate constants indicated.
TABLE 1. Conformer Ratio and Anti-to-Syn Interconversion
a
Barrier (in kcal mol-1
)
for Compounds 1-3
compd
1
2
3
To establish unambiguously whether in 3 the anti or the syn
is more populated, a NOE experiment was performed (the
temperature of -10 °C was used to avoid the effects of
saturation transfer). Irradiation of the methyl signal of the syn
conformer is expected to enhance two groups of signals, i.e.,
those of the hydrogens in positions 2,7 of the antraquinone
moiety and those of the hydrogens in the position ortho to
the methyl group (indicated as 3,3′ in Figure 5). Irradiation of
the methyl signal of the anti conformer would enhance the same
signals and, in addition, those of the hydrogens in positions 6′
and 6 of the facing ring: in the anti atropisomer, in fact, the
methyl in position 2 of one tolyl ring is close to the hydrogen
in position 6′ of the other tolyl ring (likewise the methyl in
position 2′ is close to the hydrogen in position 6 of the other
tolyl). Since irradiation of the major methyl signal displays three
significant NOE effects (red middle trace of Figure 5), the
corresponding conformation is established to be anti. Again the
DFT computations of 3 predict the syn to have an enthalpy lower
(by 0.19 kcal mol-1) than that of the anti (Figure S-2 of
Supporting Information), but the mentioned correction for the
entropy of mixing (RT ln 2) accounts for the greater population
observed for the anti form: in this case, in fact, the ∆G0 of the
anti results lower (by 0.19 - 0.41 ) -0.22 kcal mol-1) than
that of the syn.
anti:syn ratio
50:50
53:47
18.6 (19.1)
57:43
18.7 (19.2)
anti-to-syn barriera
20.7 (21.2)
20.3b (20.8)
a The values in parentheses refer to the rotation barrier of a single
tolyl ring (see text). b Data obtained from 1D-EXSY experiments.
same temperature. In the case of 1, where the methyl signals
are accidentally coincident, the corresponding anti-to-syn in-
terconversion barrier could be obtained, by dynamic NMR
approach, only by monitoring the methylene signals (Figure S-5
of the Supporting Information).
The direct anti-to-syn interconversion also can be obtained
by means of an independent method, based upon the use of the
saturation transfer approach (1-D EXSY as in the Experimental
Section), which allows one to perform experiments at lower
temperatures and to achieve rate constants much smaller than
those obtainable by the DNMR method. This was accomplished
by saturating the single CH2 line of the anti conformer whereas
observing the increase of the CH2 lines of the syn conformer.
In this way (see as an example Figure 4 and the Supporting
Information) rate constants of 0.30, 0.44, 0.64, and 0.92 s-1 (at
+59, +63, +67, and +72 °C, respectively) were determined
In Table 1 are summarized the results obtained for compounds
1-3. The barriers of 2 and 3 are equal within the experimental
error ((0.2 kcal mol-1), because in both cases the intercon-
version involves the passage of the tolyl ring across the CdO
moiety. On the other hand the barrier of 1 is significantly higher
because the corresponding interconversion requires the passage
of the ring across the bulkier CH2 moiety.
(20) When the same argument is applied to the case of compound 1, the anti
conformer should be likewise expected to be more populated than the syn, but
in this case the anti has a C2 symmetry, whereas the syn has Cs symmetry. As
a consequence, the former is favored by the entropy of mixing, but it is disfavored
by RT ln 2 because of the different symmetry number (σ ) 1 for Cs and σ ) 2
for C2): the two entropic effects act in opposite directions and therefore cancel
out. The enthalpy difference, accordingly, remains the same as that (-0.01 kcal
mol-1) computed in Scheme 1 and such a negligible difference accounts for the
equal population experimentally observed.
(21) The methyl line of the anti is at higher field than that of the syn because
it lies above the plane of the other aromatic ring, thus experiencing the well-
known effect of the aromatic ring currents. See, for instance: Jackman, L. M.;
Sternhell, S. Applications of NMR Spectroscopy in Organic Chemistry, 2nd ed.;
Pergamon Press: Oxford, UK, 1969; p 95. Jennings, W. B.; Farrell, B. M.;
Malone, J. F. Acc. Chem. Res. 2001, 34, 885–894. Wu¨thrich, K. Angew. Chem.,
Int. Ed. 2003, 42, 3340–3363.
Experimental Section
Materials: 1,8-Di(o-tolyl)anthracene-9,10-dione (3). To a solu-
tion of 1,8-dichloroanthraquinone (0.277 g, 1.0 mmol, in 10 mL
of benzene) were added K2CO3 (2 M solution, 5.0 mL), o-
tolylboronic acid (2.0 mmol, suspension in 2 mL of ethanol), and
Pd(PPh3)4 (0.23 g, 0.2 mmol) at room temperature. The stirred
solution was refluxed for 2-3 h, the reaction being monitored by
(22) As often observed in conformational processes, the free energy of
activation was found independent of temperature within the errors, indicating a
negligible value of ∆Sq. See: Lunazzi, L.; Mancinelli, M.; Mazzanti, A. J. Org.
Chem. 2007, 72, 5391, and references cited therein.
J. Org. Chem. Vol. 73, No. 14, 2008 5357

Lunazzi et al.
reaction. The brown cooled mixture was extracted with Et2O, and
the extracted organic layer was dried (Na2SO4) and evaporated.
The crude was prepurified by chromatography on silica gel (hexane/
Et2O 1:1) to obtain a mixture containing the target compounds (in
a 1:4 ratio, yield 55%) together with the starting product. Analyti-
cally pure samples of 1 and 2 were obtained by semipreparative
HPLC on a C18 column (5 µm, 250 × 10 mm, 5 mL/min, ACN/
H2O; see the Supporting Information for details). Crystals of 1
suitable for X-ray analysis were obtained by slow evaporation of a
CHCl3 solution. Details of X-ray diffraction data are reported in
the Supporting Information.
1,8-Di(o-tolyl)anthracen-9(10H)-one (2). 1H NMR (600 MHz,
CDCl3, 25 °C, TMS) δ 1.94 (3H, s), 2.08 (3H, s), 4.23 (0.5H, d, J
) -20.7 Hz), 4.34 (s, 1H), 4.39 (0.5H, d, J ) -20.7 Hz), 6.85
(1H, d, J ) 7.6 Hz), 6.98-7.18 (9H, m), 7.40-7.50 (4H, m); 13C
NMR (150.8 MHz, CDCl3, 25 °C, TMS) δ 20.51 (CH3), 20.54
(CH3), 34.3 (CH2), 34.4 (CH2), 124.84 (CH), 124.87 (CH), 126.56
(CH), 126.57 (CH), 126.6 (2CH), 126.8 (2CH), 128.0 (CH), 128.7
(CH), 129.2 (CH), 129.6 (CH), 129.8 (CH), 129.9 (CH), 130.2 (CH),
130.8 (CH), 133.3 (q), 134.1 (q), 134.9 (q), 135.2 (q), 139.6 (q),
139.8 (q), 140.9 (q), 141.5 (q), 141.8 (q), 142.2 (q), 185.9 (CO),
187.2 (CO); HRMS(EI) m/z calcd for C28H22O 374.16707, found
374.1674
4,5-Di(o-tolyl)anthracen-9(10H)-one (1). 1H NMR (600 MHz,
CDCl3, 25 °C, TMS) δ 1.907 (3H, s), 1.911 (3H, s), 3.14 (0.5H, d,
J ) -24.0 Hz), 3.34 (s, 1H), 3.51 (0.5H, d, J ) -24.0 Hz), 6.94
(2H, m), 7.06-7.18 (6H, m), 7.40 (2H, dt, J ) 7.3, 1.7 Hz), 7.52
(2H, t, J ) 7.7 Hz), 8.40 (2H, d, J ) 8.4 Hz); 13C NMR (150.8
MHz, CDCl3, 25 °C, TMS) δ 19.57 (CH3), 19.59 (CH3), 29.6 (CH2),
29.8 (CH2), 125.6 (CH), 125.7 (CH), 126.6 (CH), 126.8 (CH), 127.6
(2CH), 128.6 (CH), 128.7 (CH), 129.8 (CH), 129.9 (CH), 132.03
(q), 132.04 (q), 133.4 (2CH), 135.0 (q), 135.2 (q), 138.7 (q), 138.8
(q), 139.04 (q), 139.05 (q), 141.45 (q), 141.47 (q), 184.79 (CO),
184.83 (CO); HRMS(EI) m/z calcd for C28H22O 374.16707, found
374.1672.
FIGURE 5. Aromatic spectral region (600 MHz at -10 °C in CDCl3)
of compound 3 (bottom trace, black). NOE experiments are due to the
irradiation of the major methyl signal at 1.98 ppm (middle trace, red)
and of the minor methyl signal at 2.08 ppm (top trace, blue).
GC-MS to confirm the first coupling had been achieved. After
cooling to room temperature, a second amount of K2CO3 (2 M
solution, 5.0 mL), o-tolylboronic acid (2.0 mmol, suspension in 2
mL of ethanol), and Pd(PPh3)4 (0.12 g, 0.1 mmol) were added,
and the mixture was refluxed again and monitored by GC-MS, until
the monochloro intermediate disappeared. To the cooled mixture
CHCl3 and H2O were added and the extracted organic layer was
dried (Na2SO4) and evaporated. The crude was prepurified by
chromatography on silica gel (hexane/Et2O 10:1) to obtain a mixture
containing the target compound contaminated by 1-(o-tolyl)an-
thraquinone and 1-chloro-8-(o-tolyl)anthraquinone. Analytically
pure 3 was obtained by semipreparative HPLC on a C18 column
(10 µm, 250 × 21.2 mm, 24 mL/min, ACN/H2O; see the Supporting
Information for details).
NMR Spectroscopy. The spectra were recorded at 600 MHz
1
for H and 150.8 MHz for 13C. Variable-temperature spectra of 1
1
were obtained at 400 MHz. The assignments of the H and 13C
signals were obtained by bidimensional experiments (edited-
gsHSQC25 and gsHMBC26). The NOE experiments on 3 were
obtained by means of the DPFGSE-NOE27 sequence. To selectively
irradiate the desired signal, a 50 Hz wide shaped pulse was
calculated with a refocusing-SNOB shape28 and a pulse width of
37 ms. Mixing time was set to 1.5 s. Saturation transfer experi-
ments29 (1D-EXSY) of 1 were obtained by using the same
DPFGSE-NOE pulse sequence,27 raising the mixing time from 25
to 500 ms. Temperature calibrations were performed before the
experiments, using a Cu/Ni thermocouple immersed in a dummy
sample tube filled with 1,1,2,2-tetrachloroethane, and under condi-
tions as nearly identical as possible. The uncertainty in the
temperatures was estimated from the calibration curve to be (1
1,8-Di(o-tolyl)anthracene-9,10-dione (3). 1H NMR (600 MHz,
CDCl3, 25 °C, TMS) δ 1.95 (3.66H, s), 2.05 (2.76H, s), 6.90 (0.88H,
d, J ) 6.9 Hz), 7.00 (1.23H, m), 7.07 (2.12H, m), 7.15 (4.25H,
m), 7.47 (1.14H, dd, J ) 7.6, 1.3 Hz), 7.50 (0.86H, dd, J ) 7.6,
1.2 Hz), 7.69 (0.86H, t, J ) 7.6 Hz), 7.72 (1.14H, t, J ) 7.6 Hz),
8.27 (0.86H, dd, J ) 7.7, 1.2 Hz), 8.30 (1.14H, dd, J ) 7.7, 1.2
Hz); 13C NMR (150.8 MHz, CDCl3, 25 °C, TMS) δ 20.27 (CH3),
20.31 (CH3), 125.2 (CH), 125.3 (CH), 126.2 (CH), 126.4 (CH),
127.1 (CH), 127.2 (CH) 127.8 (CH), 128.6 (CH), 129.6 (CH), 129.8
(CH), 131.8 (CH), 132.3 (CH), 133.89 (q), 133.91 (q) 134.2 (q),
134.4 (q), 134.6 (q), 134.8 (q), 137.21 (CH), 137.27 (CH), 140.3
(q), 140.6 (q), 142.48 (q), 141.54 (q), 184.0 (CO), 184.1(CO), 184.6
(CO), 185.5 (CO); HRMS(EI) m/z calcd for C28H20O2 388.14633,
found 388.1462.
4,5-Di(o-tolyl)anthracen-9(10H)-one (1) and 1,8-Di(o-tolyl)-
anthracen-9(10H)-one (2). 1 and 2 were obtained by the Wolf-
Kishner reduction24 of 3: Hydrazine hydrate (1 mL) and KOH (50
mg, solid) were added to a solution of 1,8-di(o-tolyl)anthracene-
9,10-dione (100 mg, 0.257 mmol) in a flask equipped with a
Dean-Stark apparatus. The stirred solution was refluxed in a oil
bath kept at 200 °C for about 3 h, removing the water during the
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5358 J. Org. Chem. Vol. 73, No. 14, 2008

Atropisomers of Ditolyl Anthrones and Anthraquinone
°C. The line shape simulations were performed by means of a PC
version of the QCPE program DNMR 6 no. 633, Indiana University,
Bloomington, IN.
Calculations. Geometry optimizations were carried out at the
B3LYP/6-31G(d) level by means of the Gaussian 03 series of
programs30 (see the Supporting Information). In the case of 1-syn,
geometry optimization was also carried out at the B3LYP/6-
31++G(d,p), PBE1PBE/6-31+G(d,p), and HF/6-31+G(d,p) level.
The standard Berny algorithm in redundant internal coordinates and
default criteria of convergence were employed in all calculations.
Reported energies include unscaled ZPE and thermal correction to
enthalpy. Harmonic vibrational frequencies were calculated for all
the stationary points. For each optimized ground state the frequency
analysis showed the absence of imaginary frequencies. Chemical
shift and J-coupling calculations were obtained at the B3LYP/6-
31+G(d,p) level by using the option that includes the Fermi contact
contribution.
Acknowledgment. L.L. and A.M. received financial support
from the University of Bologna (RFO) and from MUR-COFIN
2005, Rome (national project “Stereoselection in Organic
Synthesis”).
(30) 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.; Bakken, V.; 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.; Challacombe, M.; Gill,
P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A.
Gaussian 03, Revision D.01; Gaussian, Inc.: Wallingford CT, 2004.
Supporting Information Available: DFT optimized geom-
1
etry of 2 and 3, high-resolution H spectrum of 2, 13C spectra
of 1 in chiral medium, VT spectra and simulation of 1-3, X-ray
1
diffraction data of 1, 1D-EXSY kinetic data, copy of H, 13C
NMR spectra, and HPLC traces of 1-3, and computational data
of 1-3. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO800677N
J. Org. Chem. Vol. 73, No. 14, 2008 5359