Arylbiphenylene atropisomers: Structure, conformation, stereodynamics, and absolute configuration

Article abstract of DOI:10.1021/jo702502n

(Graph Presented) Anti and syn conformers, due to restricted sp ²-sp² bond rotation, were detected in hindered 1,8-diarylbiphenylenes, the aryl moieties being phenyl groups bearing o-alkyl substituents such as Me, Et, i-Pr, and t-Bu.

Full text of DOI:10.1021/jo702502n

Arylbiphenylene Atropisomers: Structure, Conformation,
Stereodynamics, and Absolute Configuration
Lodovico Lunazzi, Michele Mancinelli,1 and Andrea Mazzanti*
Department of Organic Chemistry “A. Mangini”, UniVersity of Bologna, Viale Risorgimento 4,
Bologna 40136, Italy
mazzand@ms.fci.unibo.it
ReceiVed NoVember 21, 2007
Anti and syn conformers, due to restricted sp2-sp2 bond rotation, were detected in hindered
1,8-diarylbiphenylenes, the aryl moieties being phenyl groups bearing o-alkyl substituents such as Me,
Et, i-Pr, and t-Bu. By means of low-temperature NOE experiments, the corresponding structures were
assigned and were found to be in agreement with the results of single-crystal X-ray diffraction. The
interconversion barriers of these conformers were determined by line-shape simulation of the variable-
temperature NMR spectra and the experimental values were reproduced satisfactorily by DFT calculations.
In the case of the bulkiest aryl substituent investigated (i.e., 2-methylnaphthalene), the syn and anti
atropisomers were stable enough as to be separated at ambient temperature. The two enantiomers (M,M
and P,P) of the isomer anti were also isolated by enantioselective HPLC, and the theoretical interpretation
of the corresponding CD spectrum allowed the absolute configuration to be assigned.
Introduction
positions 1,8. In the present work, we have extended the study
to biphenylenes substituted by aryl groups with increasing steric
requirements, with the aim of obtaining sufficiently long-living
isomers (or enantiomers) that could be physically isolated. For
this purpose, a number of aryl moieties bearing, in the ortho
positions, alkyl groups of various sizes were attached to the
positions 1,8 of biphenylene.
Aryl substituents bonded to planar frameworks in sufficiently
close positions adopt a parallel face-to-face arrangement, thus
displaying through-space interactions that, as pointed out by
Cozzi et al.,2 play an important role in a variety of chemical
properties such as molecular recognition,3 stereocontrolled
reactions,4 protein and nucleic acid structures,5 and crystal
packing.6 The stereodynamic processes occurring in many
compounds of this type have been studied mainly by NMR
spectroscopy.7-12 Recently, we reported an unprecedented NMR
detection13 of the exchange processes between stereolabile
conformers and enantiomers that occur in the case of biphe-
nylenes bearing two m-tolyl or two m-xylyl substituents in
(3) (a) Diederich, F. Angew. Chem., Int. Ed. Engl. 1988, 27, 362-386.
(b) Smithrud, D. B.; Wyman, T. B.; Diederich, F. J. Am. Chem. Soc. 1991,
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(1) In partial fulfilment of the requirements for the Ph.D. degree in
Chemical Sciences, University of Bologna.
(2) Cozzi, F.; Annunziata, R.; Benaglia, M.; Cinquini, M.; Raimondi,
L.; Baldridge, K. K.; Siegel, J. S. Org. Biomol. Chem. 2003, 1, 157-
162.
(4) Jones, G. B. Tetrahedron 2001, 57, 7999-8016.
10.1021/jo702502n CCC: $40.75 © 2008 American Chemical Society
Published on Web 02/16/2008
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J. Org. Chem. 2008, 73, 2198-2205

Arylbiphenylene Atropisomers
CHART 1
processes were not observed, even when cooling the sample to
-175 °C). Line shape simulation of the methyl signals as
function of temperature yielded the rate constants for the
interconversion of the major into the minor conformer; from
these values a free energy of activation (∆Gq)17 equal to 10.3
(8) (a) Cozzi, F.; Cinquini, M.; Annunziata, R.; Siegel, J. S. J. Am. Chem.
Soc. 1993, 115, 5330-5331. (b) Cozzi, F.; Ponzini, F.; Annunziata, R.;
Cinquini, M.; Siegel, J. S. Angew. Chem., Int. Ed. Engl. 1995, 34, 1019-
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Steele, M.; Warren, J. E.; Whiting, A. J. Chem. Soc., Perkin Trans. 2 2002,
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2002, 13, 1153-1156. (g) Tumambac, G. E.; Wolf, C. J. Org. Chem. 2004,
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1993, 58, 7516-7523. (c) Lunazzi, L.; Mancinelli, M.; Mazzanti, A. J.
Org. Chem. 2007, 72, 5391-5394.
(11) Cross, W.; Hawkes, G. E.; Kroemer, R. T.; Liedl, K. R.; Loerting,
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(15) Gaussian 03, Revision D.01: Frisch, M. J.; Trucks, G. W.; Schlegel,
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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.;
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Results and Discussion
The compounds synthesized for this investigation are listed
in Chart 1.
As pointed out by Clough and Roberts,14 derivatives resem-
bling compound 1 can exist as three possible conformers,
depending on the relative positions of the two substituted aryl
groups. In the case of 1, DFT computations15 actually predict
the existence of three energy minima,16 corresponding to the
conformers displayed in Figure 1.
In the case of the less hindered m-tolyl biphenylene deriva-
tives13 mentioned above, the 90° torsion barrier interconverting
the anti-in into the anti-out conformers, as well as that
interconverting the two enantiomers of the syn conformer, are
sufficiently high as to allow an experimental NMR detection
of the corresponding exchange process. In the present case, on
the contrary, these barriers are predicted to be significantly lower
(1.7 kcal mol-1, according to DFT computations), so that the
90° torsion processes are much faster and only the 180° rotation,
which interconverts the rapidly exchanging anti conformers into
the rapidly exchanging syn enantiomers, displays a barrier (DFT
computed value of 10.5 kcal mol-1) high enough to make the
corresponding pathway accessible to a direct NMR detection.
1
Indeed, the H methyl signal of 1 broadens on cooling and
eventually splits, at -92 °C, into a pair of lines in a 60:40
proportion (Figure 2), one corresponding to the rapidly inter-
converting anti conformers and the other to the rapidly inter-
converting enantiomers of syn conformers: owing to the fast
90° torsion process mentioned above, both the anti and the syn
conformers display a single methyl line (other exchange
(16) In a theoretical paper describing compounds analogous to 1 only
one of the two possible anti conformers was, inexplicably, considered
(see: Bigdeli, M. A.; Moradi, S.; Nemati, F. J. Mol. Structure Theochem.
2007, 807, 125-135).
(17) 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, for instance: Dondoni, A.; Lunazzi, L.;
Giorgianni, P.; Macciantelli, D. J. Org. Chem. 1975, 20, 2979. Hoogosian,
S.; Bushweller, C. H.; Anderson, W. G.; Kigsley, G. J. Phys. Chem. 1976,
80, 643; Lunazzi, L.; Cerioni, G.; Ingold, K. U. J. Am. Chem. Soc. 1976,
98, 7484. Lunazzi, L.; Dondoni, A.; Barbaro, G.; Macciantelli, D.
Tetrahedron Lett. 1977, 18, 1079. Forlani, L.; Lunazzi, L.; Medici, A.
Tetrahedron Lett. 1977, 18, 4525. Bernardi, F.; Lunazzi, L.; Zanirato, P.;
Cerioni, G. Tetrahedron 1977, 33, 1337. Lunazzi, L.; Magagnoli, C.; Guerra,
M.; Macciantelli, D. Tetrahedron Lett. 1979, 20, 3031. Cremonini, M. A.;
Lunazzi, L.; Placucci, G.; Okazaki, R.; Yamamoto, G. J. Am. Chem. Soc.
1990, 112, 2915. Anderson, J. E.; Tocher, D. A.; Casarini, D.; Lunazzi, L.
J. Org. Chem. 1991, 56, 1731. Gribble, G. W.; Olson, E. R.; Brown, J. H.;
Bushweller, C. H. J. Org. Chem. 1993, 58, 1631. Borghi, R.; Lunazzi, L.;
Placucci, G.; Cerioni, G.; Foresti, E.; Plumitallo, A. J. Org. Chem. 1997,
62, 4924. Garcia, M. B.; Grilli, S.; Lunazzi, L.; Mazzanti, A.; Orelli, L. R.
J. Org. Chem. 2001, 66, 6679. Garcia, M. B.; Grilli, S.; Lunazzi, L.;
Mazzanti, A.; Orelli, L. R. Eur. J. Org. Chem. 2002, 4018. Anderson, J.
E.; de Meijere, A.; Kozhushkov, S. I.; Lunazzi, L.; Mazzanti, A. J. Am.
Chem. Soc. 2002, 124, 6706. Casarini, D.; Rosini, C.; Grilli, S; Lunazzi,
L.; Mazzanti, A. J. Org. Chem. 2003, 68, 1815. Casarini, D.; Grilli, S.;
Lunazzi, L.; Mazzanti, A. J. Org. Chem. 2004, 69, 345. Bartoli, G.; Lunazzi,
L.; Massacesi, M.; Mazzanti, A. J. Org. Chem. 2004, 69, 821. Casarini,
D.; Coluccini, C.; Lunazzi, L.; Mazzanti, A.; Rompietti, R. J. Org. Chem.
2004, 69, 5746.
(5) (a) Saenger, W. Principles of Nucleic Acid Structures; Springer-
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(7) (a) Mitchell, R. H.; Yan, J. S. H. Can. J. Chem. 1980, 58, 2584-
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Chem. 2006, 71, 5474-5481.
J. Org. Chem, Vol. 73, No. 6, 2008 2199

Lunazzi et al.
FIGURE 1. Top: DFT-computed structures of the conformers of 1 with the relative energies (E) in kcal mol-1 (for convenience only one of the
two enantiomeric forms is displayed). Bottom: experimental structure obtained by single-crystal X-ray diffraction.
relative to the more symmetric anti form.20 Actually, the DFT
computations of chemical shifts15 predict that the syn should
1
have the H methyl signal at a field lower (by 0.23 ppm) than
the anti-in. As shown in Figure 2, the more intense methyl line
is 0.28 ppm at lower field with respect to its less intense
companion: this feature seems to support the hypothesis that
the syn is actually the more populated conformer in solution.
For this reason an unambiguous experimental assignment of the
two conformers observed in solution had to be undertaken.
To solve this problem, a NOE experiment was carried out at
a quite low temperature (-118 °C) in order to make negligible
the saturation transfer effects:21 at this temperature, in fact, the
rate constant for the exchange is predicted to be as low as 0.01
s-1. As shown in Figure 3, irradiation of the major methyl signal
(trace b) yields significant enhancements only on two signals
of the major conformer, i.e., those of H3,3′ in the tolyl rings
(18) Dissimilarities between the conformations in solution with respect
to the structures found in the solids have been reported; see: Johansen, J.
T.; Vallee, B. L. Proc. Nat. Acad. Sci. U.S.A. 1971, 68, 2532-2535. Kessler,
H. Fresenius Z. Anal. Chem. 1987, 327, 66-67. Burke, L. P.; DeBellis, A.
D.; Fuhrer, H.; Meier, H.; Pastor, S. D.; Rihs, G.; Rist, G.; Rodebaugh, R.
1
FIGURE 2. Left: experimental NMR H signal (600 MHz in CD2-
K.; P. Shum, S. P. J. Am. Chem. Soc. 1997, 119, 8313-8323. Paulus, E.
Cl2) of the methyl group of 1 as function of temperature (the starred
line is a trace of HDO present in the solvent). Right: line shape
simulation obtained with the rate constants indicated.
F.; Kurz, M.; Matter, H.; Ve´rtesy. L. J. Am. Chem. Soc. 1998, 120, 8209-
8221. Coluccini, C.; Grilli, S.; Lunazzi, L.; Mazzanti, A. J. Org. Chem.
2003, 68, 7266-7273. Perry, N. B.; Blunt, J. W.; Munro, M. H. Magn.
Reson. Chem. 2005, 27, 624-627.
TABLE 1. Experimental and DFT Computed Barriers (kcal
mol-1) for the Interconversion of the Major into the Minor
Conformer in Compounds 1-6a
(19) A situation where it has been unambiguously demonstrated that the
structure observed by X-ray diffraction in the crystal is that of the minor
conformer present in solution has been reported in: Lunazzi, L.; Mazzanti,
A.; Minzoni, M.; Anderson, J. E. Org. Lett. 2005, 7, 1291-1294.
(20) It has to be taken into account that the syn conformer exists as four
degenerate forms (two identical pairs of enantiomers), whereas the anti-in
exists solely as two degenerate forms, corresponding to a pair of enantiomers
(the presence of the anti-out can be, in practice, neglected, since its higher
relative energy of 0.9 kcal mol-1 would correspond to a proportion lower
than 8% at -92 °C). Owing to the greater probability, the actual population
of the syn conformer might be higher than expected solely on the basis of
its computed energy. In fact, both of the anti forms belong to the C2 point
group and are therefore disfavored by RT ln 2 (i.e., 0.24 kcal mol-1 at -92
°C, see: Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds;
Wiley: New York, 1994; pp 97 and 601). Accordingly, when corrected
for this factor the energy difference becomes 0.06 kcal mol-1, a value that
corresponds to an anti/syn ratio of 54/46. When the proportions are so close
to 50/50, the approximations involved in the computed energy do not allow
one to obtain a reliable assignment for the situation in solution because, in
these conditions, even a small solvent effect might cause a reversal of the
assignment.
compd
1
2
3
4
5
6
experimental
(% of anti)
computed
10.3
(40)
10.5
11.4
(60)
11.9
13.9
(87)
13.7
17.0 b)
(80)
16.8
13.0
(62)
13.3
34.5c
(64)c
34.7
a The proportion of the conformer anti in compounds 1-5, measured at
equilibrium in CD2Cl2 at appropriate low temperatures, is shown in
parentheses. b See ref 26. c Determined in DMSO at +140 °C (see text).
( 0.15 kcal mol-1 was obtained, a result which agrees well
with that predicted by DFT computations (Table 1).
Single-crystal X-ray diffraction shows that in the solid state
the structure of compound 1 is essentially equal to that computed
for the syn conformation (Figure 1): this might be due to the
existence of a more stable crystal lattice when the molecule
adopts a syn disposition,18,19 but could also reflect the fact that,
despite the higher computed energy, the syn might have a larger
population in solution as a consequence of its higher entropy
(21) Saunders, J. K.; Bell, R. A. Can J. Chem. 1970, 48, 512-513.
Combrisson, S.; Roques, B.; Rigny, P.; Basselier, J. J. Can J. Chem. 1971,
49, 904-918. Neuhaus, D.; Williamson, M. The Nuclear OVerhauser Effect
in Structural and Conformational Analysis; VCH Publishers Inc.: New
York, 1989; Chapter 5.
2200 J. Org. Chem., Vol. 73, No. 6, 2008

Arylbiphenylene Atropisomers
methyl group in the meta position of the aryl ring produces the
so-called buttressing effect,23 which generates a steric hindrance
more similar to that of the ethyl groups in 2 than to that of the
methyl groups in 1, thus making higher the rotation barrier (∆Gq
) 13.0 kcal mol-1 as in Table 1). The increased steric hindrance
also renders the anti conformer of 5 more stable than the syn
(as proved by the low-temperature NOE experiments24 in Figure
S-2 of the Supporting Information), contrary to the case of the
apparently similar compound 1. This assignment is further
confirmed by the observation that the DFT-computed shifts of
the two methyl groups for the anti conformer of 5 correspond
to the more intense pair of the experimental methyl lines,
whereas the shifts computed for the syn conformer correspond
to the less intense lines of the experimental spectrum.
In the even more hindered derivative 3 (R ) isopropyl), the
proportion of the minor syn conformer25 is further reduced
(13%) and the interconversion barrier, obtained by line shape
simulation (Figure S-3 of the Supporting Information), is
increased (13.9 kcal mol-1, Table 1).
As conceivable, the barrier increases further in the tert-butyl
derivative 4,26 although the proportion of the more stable
conformer anti25 does not increase accordingly in that, surpris-
ingly, it is lower than in the case of 3: solvent effects might be
responsible for this feature.27
Contrary to the case of 1, the single-crystal X-ray diffraction
of 4 shows that the anti conformation is adopted in the solid
FIGURE 3. Trace a: aromatic region (600 MHz at -118 °C in CD2-
1
Cl2) displaying H signals for the major and minor conformers of 1.
(22) When the rotation about the aryl-biphenylene bond is frozen, the
methylene hydrogens are diastereotopic because the conformers adopt a
non planar conformation. For the same reason are diastereotopic at low
temperature the methyl groups of the isopropyl moieties of compound 3.
See: Mislow, K.; Raban, M. Top. Stereochem. 1967, 1, 1. Jennings, W. B.
Chem. ReV. 1975, 75, 307. Eliel, E. L. J. Chem. Ed. 1980, 57, 52. Casarini,
D.; Lunazzi, L.; Macciantelli, D. J. Chem. Soc., Perkin Trans 1992, 2, 1363.
(23) (a) Westheimer, F. H. In Steric Effects in Organic Chemistry;
Newman, M. S., Ed.; John Wiley and Sons, Inc.: New York, 1956; Chapter
12. (b) Karnes, H. A.; Rose, M. L.; Collat, J. W.; Newman, M. S. J. Am.
Chem. Soc. 1968, 90, 458-461. (c) Decouzon, M.; Ertl, P.; Exner, O.; Gal,
J.-F.; Maria, P.-C. J. Am. Chem. Soc. 1993, 115, 12071-12078. (d) Heiss,
F.; Marzi, E.; Schlosser, M. Eur. J. Org. Chem. 2003, 4625-4629. (e)
Gorecka, J.; Heiss, C.; Scopelliti, R.; Schlosser, M. Org. Lett. 2004, 6,
4591-4593. (f) Heiss, C.; Leroux, F.; Schlosser, M. Eur. J. Org. Chem.
2005, 5242-5247. (g) Schlosser, M.; Cottet, F.; Heiss, C.; Lefebvre, O.;
Marull, M.; Masson, E.; Scopelliti, R. Eur. J. Org. Chem. 2006, 729-734.
(24) Irradiation (Figure S-2 of the Supporting Information) of the major
signal of the methyls in position 3,3′ of the xylyl rings (1.67 ppm) of 5,
yields enhancement for the major signal of the corresponding hydrogens in
position 4,4′ (6.90 ppm) of the same xylyl rings and for the major signal of
the hydrogens in positions 5′,5 (6.96 ppm) of the other ring, as expected
for an anti conformer, where the latter distance is short enough to produce
NOE effects. On the contrary irradiation of the minor signal (1.86 ppm) of
the methyls in position 3,3′ of the xylyl rings, enhances solely the minor
signal of the corresponding hydrogens in position 4,4′ of the same ring
(6.74 ppm). Likewise irradiation of the major signals of the methyl in
positions 2,2′ of the xylyl rings (1.37 ppm) enhances the corresponding
signals of the hydrogens in positions 2,7 of the biphenylene moiety (6.59
ppm) and also that of the hydrogens in positions 6′,6 of the other xylyl
ring (6.96 ppm). On the contrary, irradiation of the minor signal of the
methyl groups (1.76 ppm) enhances solely the corresponding H2,7 minor
signal of biphenylene (6.60 ppm), as expected for a syn conformer where
the distance between the hydrogens of the methyl in position 2 of one ring
and the hydrogen in position 6′ of the other ring is too large to yield a
NOE effect.
Trace b: NOE due to irradiation of the major methyl signal (1.87 ppm),
showing significant enhancement for two aromatic signals of the major
conformer (syn). Trace c: NOE due to irradiation of the minor methyl
signal (1.59 ppm), showing significant enhancements for three aromatic
signals of the minor conformer (anti).
and of H2,7 in the biphenylene ring. On the other hand,
irradiation of the minor methyl signal (trace c) yields significant
enhancement on three signals of the minor conformer: in
addition to the H3,3′ signal in the tolyl rings and the H2,7 signal
in the biphenylene ring, also the signal of the hydrogens in
positions 6,6′ in the tolyl rings is significantly enhanced. The
latter effect can only occur in the anti conformer because the
methyl in position 2 of one tolyl ring is close to the H6′ in the
second tolyl ring (and likewise the methyl in position 2′ is close
to H6 in the second ring). Thus the minor conformer, displaying
three large NOE enhancements, must have the anti structure
whereas the major, displaying only two large NOE enhance-
ments, must have the syn structure. There is no doubt, therefore,
that the syn is the more populated conformer of 1 in solution,
as it is in the crystalline state.
When the dimension of the ortho substituent is increased, as
in derivative 2 (R ) Et), the situation is reversed in that the
more stable conformer in solution appears to be the less hindered
anti form (about 60%). This was proved by an analogous low-
temperature NOE experiment (Figure S-1 of the Supporting
Information) where opposite effects, with respect to the case of
1, were observed. In fact, simultaneous irradiation of the two
major signals of the diastereotopic methylene hydrogens yields
enhancement on three aromatic signals of the more intense
spectrum, whereas only two aromatic signals of the less intense
spectrum are enhanced when irradiating the two minor signals
of the diastereotopic methylene hydrogens.22
(25) The conformational assignment in compounds 3 and 4 was obtained
by means of the mentioned low temperature NOE experiments.
(26) For the NMR determination of the larger barrier of 4 it was necessary
to use a solvent (tetrachloroethane-d2) with a higher boiling point than the
solvent (CD2Cl2) employed for measuring the barriers of compounds 1-3
and 5.
(27) The lower proportion of the conformer anti observed in compound
4 with respect to 3 might be also interpreted as the consequence of a statistic
effect, due to the possibility of having both the anti-in and anti-out situations
in the case of 3, whereas solely a single anti form occurs in 4.
The effect of steric hindrance in controlling the relative
stability of the anti and syn conformers was also noticed in the
case of derivative 5. Here the introduction of an additional
J. Org. Chem, Vol. 73, No. 6, 2008 2201

Lunazzi et al.
FIGURE 5. Left: methyl signal of 6a (600 MHz in CDCl3 at 0 °C)
with the amplified 13C satellites (red) in the inset of the lower trace.
The NOE effect, obtained by irradiating the 13C satellites, is displayed
in the top trace (red). Right: methyl signal of 6b (600 MHz in acetone-
d6 at 0 °C) with the amplified 13C satellites (blue) in the inset of the
lower trace. The absence of NOE effect, on irradiation of the 13C
satellites, is clearly evident in the top trace (blue).
FIGURE 4. DFT-computed structures of the syn and anti conformers
of 4 with the relative energies (E) in kcal mol-1 (top). Experimental
structure obtained by single-crystal X-ray diffraction (the hydrogen
atoms are omitted for convenience) (bottom).
state, a result which agrees with the computations predicting
the anti to be more stable by 1.1 kcal mol-1 than the syn (Figure
4): also the DFT calculations of chemical shifts confirm such
an assignment. According to computations the dihedral angle
between the aryl rings and the biphenylene moiety (81°) is very
close to 90°; thus, only one type of conformer anti occurs in 4,
because the anti-in and anti-out conformations of Figure 1
become essentially indistinguishable when the planes are nearly
orthogonal: the same value for this dihedral angle was also
found in the X-ray structure.27
irradiation of the two satellite lines of the isomer having the
lower field methyl signal at 2.08 ppm (6a) yields a NOE effect,
indicating that this signal must be that of the isomer syn, where
the hydrogens of the two methyl groups are sufficiently close
to experience a reciprocal NOE enhancement. On the other hand,
irradiation of the satellites of the compound having the higher
field methyl signal at 1.52 ppm (6b) does not produce any NOE
effect, indicating that this signal corresponds to the isomer anti,30
where the hydrogens of the two methyl groups are too far apart
to experience a reciprocal NOE enhancement. In this way, an
unambiguous assignment could be achieved for the isomers 6a
(syn) and 6b (anti).
The process leading to the interconversion of the configura-
tionally stable isomers of 6 was followed by monitoring the
time dependence of the NMR methyl signal of the pure syn
isomer (6a) in DMSO at +140 °C. The intensity of the original
methyl line of 6a decreases, while that of the anti isomer 6b
begins to appear at higher field with an intensity which increases
until an equilibrium, corresponding to a syn/anti ratio of 36:64
(Table 1), is reached (as in the case of compounds 2-5 the
anti is more stable than the syn in equilibrium conditions). From
the first-order kinetics equation for a process at the equilibrium,
the appropriate rate constants were obtained (details in Figure
S-4 of the Supporting Information), and the barrier for exchang-
ing the more (anti, 6b) into the less (syn, 6a) stable isomer was
derived (∆Gq ) 34.5 kcal mol-1). The result agrees well with
the DFT computed value (34.7 kcal mol-1) reported in Table
1.
The barrier measured for 4 (17.0 kcal mol-1) indicates that
even the presence of the large tert-butyl group in the ortho
position of the benzene rings is not sufficient to allow a physical
separation of the anti and syn forms at ambient temperature, in
that the lifetime of the corresponding conformers is exceedingly
short (t1/2 ≈ 0.3 s at +25 °C).
Such a separation could be, however, achieved in the case
of compound 6, were two â-methylnaphthyl rings are bonded
to the biphenylene moiety in the 1,8 positions: computations
predict, in fact, a barrier as high as 34.7 kcal mol-1 (Table 1)
for the corresponding naphthylbiphenylene rotation process. The
two isomers, indicated as 6a and 6b, were isolated at ambient
temperature by HPLC, and their structural assignment was
carried out with an alternative NOE approach, which was found
more appropriate for the present case.
Following the procedure reported28 for the assignment of
symmetric isomers, the 13C satellites of the methyl signals of
6a and of 6b (both with JCH ) 126.7 Hz) were irradiated at a
temperature of 0 °C.29 As shown in Figure 5, simultaneous
(28) Lunazzi, L.; Mazzanti, A. J. Am. Chem. Soc. 2004, 126, 12155-
12157. See also ref 10c.
(30) The isomer anti (6b) displays a methyl signal at a substantially higher
field than the methyl signal of the isomer syn (6a) owing to the effect of
the aromatic ring currents, since in the anti situation the methyl groups lie
above the plane of the naphthalene rings, see: Jackman, L. M.; Sternhell,
S. Applications of NMR Spectroscopy in Organic Chemistry, 2nd ed.;
Pergamon Press: Oxford, 1969; p 95. Jennings, W. B.; Farrell, B. M.;
Malone, J. F. Acc. Chem. Res. 2001, 34, 885. Wu¨thrich, K. Angew. Chem.,
Int. Ed. 2003, 42, 3340.
(29) The temperature of 0 °C was selected in order to obtain a better
signal to noise ratio in the DPFGSE-NOE experiment. In order to avoid
the interference of the HDO signal (present as an impurity in our CDCl3)
with the signals of 6b, the spectrum of the latter was obtained in acetone-
d6 (the impurity of HDO in our acetone-d6 lies in a position that does not
interfere with the signals of 6b).
2202 J. Org. Chem., Vol. 73, No. 6, 2008

Arylbiphenylene Atropisomers
SCHEME 1. Schematic Representation of the Syn (Meso),
6a, and Anti (Racemic), 6b, Isomers of Compound 6
The syn isomer 6a (Cs point group), having two equal
stereogenic axes with opposite (M,P) handedness, corresponds
to a meso form, whereas the anti isomer 6b (C2 point group)
exists as a pair of enantiomers (M,M and P,P),31,32 as illustrated
in Scheme 1. The two enantiomers of 6b were separated by
enantioselective HPLC, and the corresponding CD spectra
display the two opposite signed traces shown in Figure 6. The
intense band at ∼215 nm is due to the 1B transition of
naphthalene, and that at ∼255 nm is that of the biphenylene
moiety (these bands are also observed at the same wavelengths
in the experimental UV spectrum as in Figure S-5 of the
Supporting Information). In order to assign the absolute con-
figuration (AC), the CD spectrum of one enantiomer is
calculated by theoretical methods and its shape (and intensity)
compared with that of the experimental spectrum. If they match,
the AC assumed in the calculations should then be assigned to
the enantiomer whose experimental spectrum has been recorded.
For this approach, use was made of the TDDFT method
(implemented in the Gaussian 03 program15), since such a
technique has been successfully employed several times33 to
predict CD spectra (the geometry had been already optimized
at the B3LYP/6-31G(d) level). As shown in Figure 6, the CD
FIGURE 6. Enantioselective HPLC trace of the two enantiomers of
the anti isomer 6b (top). CD spectra of the two enantiomers (middle).
Computed CD spectrum (blue-shifted by 7 nm, dashed trace) for the
M,M configuration, compared with the experimental spectrum (green)
of the first eluted enantiomer (bottom).
spectrum calculated by assuming the M,M configuration has a
shape analogous to that of the spectrum of the first eluted
enantiomer, with a significant positive Cotton effect at lower
wavelengths (∼220 nm), as well as a significant negative effect
at higher wavelengths (∼255 nm). Accordingly, the first eluted
enantiomer has the M,M configuration and, as a consequence,
the P,P configuration must be assigned to the second eluted
enantiomer. (In the Supporting Information, the velocity rota-
tional strengths are plotted in Figure S-6 and the transitions
energies, oscillator strengths and rotational strengths of the
absolute configuration M,M for the lowest 60 states are collected
in Table S-1.)
(31) Dell’ Erba, C.; Gasparrini, F.; Grilli, S.; Lunazzi, L.; Mazzanti, A.;
Novi, M.; Pierini, M.; Tafani, C.; Villani, C. J. Org. Chem. 2002, 67, 1663-
1668.
(32) Grilli, S.; Lunazzi, L.; Mazzanti, A.; Pinamonti, M. Tetrahedron
2004, 60, 4451-4458.
(33) For the assignments made by TDDFT-CD calculations see: (a)
Diedrich, C.; Grimme, S. J. Phys. Chem. A 2003, 107, 2524. (b) Autschbach,
J.; Ziegler, T.; van Gisbergen, S. J. A.; Baerends, E. J. J. Chem. Phys.
2002, 116, 6930. (c) Pecul, M.; Ruud, K.; Helgaker, T. Chem. Phys. Lett.
2004, 388, 110. (d) Grimme, S.; Bahlmann, A. Modern Cyclophane Chem.
2004, 311. (e) Braun, M.; Hohmann, A.; Rahematpura, J.; Buehne, C.;
Grimme, S. Chem. Eur. J. 2004, 10, 4584. (f) Furche, F.; Ahlrichs, R.;
Wachsmann, C.; Weber, E.; Sobanski, A.; Voegtle, F.; Grimme, S. J. Am.
Chem. Soc. 2000, 122, 1717. (g) Stephens, P. J.; McCann, D. M.; Butkus,
E.; Stoncius, S.; Cheeseman, J. R.; Frisch, M. J. J. Org. Chem. 2004, 69,
1948. (h) Stephens, P. J.; McCann, D. M.; Devlin, F. J.; Cheeseman, J. R.;
Frisch, M. J. J. Am. Chem. Soc. 2004, 126, 7514. (i) Neugebauer, J.;
Baerends, E. J.; Nooijen, M.; Autschbach, J. J. Chem. Phys. 2005, 122,
234305/1-234305/7. (j) Pecul, M.; Marchesan, D.; Ruud, K.; Coriani, S.
J. Chem. Phys. 2005, 122, 024106/1-024106/9. (k) Giorgio, E.; Tanaka,
K.; Ding, W.; Krishnamurthy, G.; Pitts, K.; Ellestad, G. A.; Rosini, C.;
Berova, N. Bioorg. Med. Chem. 2005, 13, 5072. (l) Mori, T.; Inoue, Y.;
Grimme, S. J. Org. Chem. 2006, 71, 9797. (m) Stephens, P. J.; McCann,
D. M.; Devlin, F. J.; Smith, A. B., III. J. Nat. Prod. 2006, 69, 1055. (n)
Salam, Y. M. A. Chem. Phys. 2006, 324, 622-630. (o) Bringmann, G.;
Gulder, T.; Reichert, M.; Meyer, F. Org. Lett. 2006, 8, 1037-1040. (p)
Stephens, P. J.; Pan, J.-J.; Devlin, F. J.; Urbanova, M.; Hajicek, J. J. Org.
Chem. 2007, 72, 2508. (q) Casarini, D.; Lunazzi, L.; Mancinelli, M.;
Experimental Section
Materials. 2-Methylphenylboronic acid, 2-ethylphenylboronic
acid, 2-isopropylphenylboronic acid, and 2,3-dimethylphenylboronic
acid were commercially available. 1,8-Dibromobiphenylene,34 1,3-
Mazzanti, A.; Rosini, C. J. Org. Chem. 2007, 72, 7667-7676. (r) Goel,
A.; Singh, F. V.; Kumar, V.; Reichert, M.; Goulder, T. A. M.; Bringmann,
G. J. Org. Chem. 2007, 72, 7765-7768. (s) Berova, N.; Di Bari, L.;
Pescitelli, G.; Chem. Soc. ReV. 2007, 36, 914-931.
(34) Humayun Kabir, S. M.; Hasegawa, M.; Kuwatani, Y.; Yoshida, M.;
Matsuyama, H.; Iyoda, M. J. Chem Soc., Perkin Trans. 2001, 1, 159-165.
For the preparation of the intermediate 2,2′,6,6′-tetrabromobiphenyl, see:
Rajca, A.; Safronov, A.; Rajca, S.; Ross, C. R., II; Stezowski, J. J. J. Am.
Chem. Soc. 1996, 118, 7272-7279.
J. Org. Chem, Vol. 73, No. 6, 2008 2203

Lunazzi et al.
dibromo-2-iodobenzene,35 and 2-methylnaphthylboronic acid36 were
prepared according to the literature. 2-tert-Butylphenylboronic acid
was prepared following known procedures37 (see the Supporting
Information for details).
of the anti isomer 6b (first eluted) and 0.005 g of the syn isomer
6a (second eluted) were obtained.
1,8-Bis(2-methylnaphthalen-1-yl)biphenylene, Syn Isomer
1
(6a). H NMR (600 MHz, CDCl3, 25 °C, TMS): δ 2.09 (6H, s),
6.51 (2H, d, J ) 8.2 Hz), 6.75-6.84 (10H, m), 7.17-7.23 (6H,
m). 13C NMR (150.8 MHz, CDCl3, 25 °C, TMS): δ 20.5 (CH3),
115.9 (CH), 123.8 (CH), 125.0 (CH), 125.05 (CH), 127.1 (CH),
127.2 (CH), 127.3 (CH), 128.3 (CH), 129.9 (q), 130.98 (q), 131.0
(q), 131.4 (CH), 131.8 (q), 133.1 (q), 150.8 (q), 151.3 (q). HRMS-
(EI): m/z calcd for C34H24 432.18780, found 432.1876.
1,8-Bis(2-methylnaphthalen-1-yl)biphenylene, Anti Isomer
(6b). 1H NMR (600 MHz, acetone-d6 25 °C): δ 1.55 (6H, s), 6.33
(2H, d, J ) 8.4 Hz), 6.50 (2H, d, J ) 8.1 Hz), 6.87 (2H, d, J ) 6.7
Hz), 6.92 (2H, dd, J ) 8.1, 6.9 Hz), 7.27 (2H, d, J ) 8.4 Hz),
7.31-7.37 (4H, m), 7.44 (2 H, d, J ) 8.2 Hz), 7.67 (2H, d, J )
8.0 Hz). 13C NMR (150.8 MHz, acetone-d6, 25 °C): δ 19.7 (CH3),
116.5 (CH), 124.3 (CH), 125.2 (CH), 125.5 (CH), 127.3 (CH), 127.6
(CH), 128.1 (CH), 128.9 (CH), 130.2 (q), 131.0 (CH), 131.72 (q),
131.74 (q), 132.5 (q), 133.1 (q), 150.8 (q), 151.6 (q). HRMS(EI):
m/z calcd for C34H24 432.18780, found 432.1877.
General Procedure for 1-5. To a solution of 1,8-dibromobi-
phenylene (0.062 g, 0.2 mmol, in 2 mL of benzene) were added
K2CO3 (2 M solution, 1.0 mL), the appropriate boronic acid (0.5
mmol, suspension in 2 mL of ethanol), and Pd(PPh3)4 (0.046 g,
0.04 mmol) at room temperature. The stirred solution was refluxed
for 2-3 h, and the reaction was monitored by GC-MS to confirm
the first coupling. After the mixture was cooled to room temper-
ature, a second amount of boronic acid (0.5 mmol, suspension in
2 mL of ethanol) and Pd(PPh3)4 (0.046 g, 0.04 mmol) were added,
and the solution was refluxed again for 2 h. Subsequently, CHCl3
and H2O were added, and the extracted organic layer was dried
(Na2SO4) and evaporated. The crude products were prepurified by
chromatography on silica gel (hexane/Et2O 10:1) to obtain mixtures
containing the target compounds, together with biphenylene,
1-bromobiphenylene, 1-aryl-biphenylene, and 1-aryl,8-bromobi-
phenylene as impurities. Analytically pure samples of 1-5 were
obtained by semipreparative HPLC on a C18 column (5 µm, 250
× 10 mm, 5 mL/min, ACN/H2O; see the Supporting Information
for more details). Crystals suitable for X-ray analysis were obtained
from chloroform, by slow evaporation, in the cases of 1 and 4.
Detailed spectroscopic data for compounds 2-5 are reported in
the Supporting Information.
Enantioselective HPLC and CD Spectra. Separation of the two
enantiomers of 6b was achieved at 25 °C on a Chiralcel OJ-H 250
× 4.6 mm column, at a flow rate of 1.0 mL/min, using hexane/
iPr-OH 95:5 v/v as eluent. In order to have the sufficient amount
to record the CD spectra, 10 injections (50 µg each one) were
collected. UV detection was fixed at 225 nm. UV absorption spectra
were recorded at 25 °C in hexane on the racemic mixture, in the
190-400 nm spectral region. The cell path length was 0.1 cm,
concentration was 1.43 × 10-4 mol L-1. Maximum molar absorp-
tion coefficient was recorded at 218 nm (ꢀ ) 66670). CD spectra
were recorded at 25 °C in hexane, with the same path lengths of
0.1 cm, in the range 190-400 nm; reported ∆ꢀ values are expressed
1,8-Di(o-tolyl)biphenylene (1). 1H NMR (600 MHz, CDCl3, 25
°C, TMS): δ 1.89 (6H, s), 6.66 (6H, m), 6.80 (6H, m), 6.93 (2H,
td, J ) 7.4, 1.6 Hz). 13C NMR (150.8 MHz, CDCl3, 25 °C, TMS):
δ 19.7 (CH3), 115.6 (CH), 124.8 (CH), 127.1 (CH), 128.2 (CH),
128.2 (CH), 129.4 (CH), 130.3 (CH), 132.5 (q), 135.0 (q), 137.6
(q), 149.6 (q), 150.8 (q). HRMS(EI): m/z calcd for C26H20
332.15650, found 332.1564.
as L mol-1cm-1
NMR Spectroscopy. The spectra were recorded at 600 MHz
for 1H and 150.8 MHz for 13C. The assignments of the 1H and 13
.
1,8-Bis(2-methylnaphthalen-1-yl)biphenylene (6). To a solution
of 1,8-dibromobiphenylene (0.062 g, 0.2 mmol, in 2 mL of benzene)
were added K2CO3 (2 M solution, 1.0 mL), 2-methylnaphtylboronic
acid (0.5 mmol, suspension in 2 mL of ethanol), and Pd(OAc)2
(0.009 g, 0.04 mmol) at room temperature. The stirred solution
was refluxed for 48 h, and the reaction was monitored by GC-
MS to confirm the first coupling had achieved. Subsequently, CHCl3
and H2O were added, and the extracted organic layer was dried
(Na2SO4) and evaporated. The crudes was prepurified by chroma-
tography on silica gel (hexane/Et2O 10:1) to obtain a mixture that
was further purified by preparative HPLC on a C18 column (10
µm, 250 × 21.2 mm, 24 mL/min, ACN/H2O 90:10 v/v), to obtain
0.052 g (60%) of 1-bromo-8-(2-methylnaphthalen-1-yl)biphenylene.
To a solution of this intermediate, (0.052 g, 0.12 mmol, in 2 mL
of benzene) were added K2CO3 (2 M solution, 1.0 mL), 2-meth-
ylnaphtylboronic acid (0.5 mmol, suspension in 2 mL of ethanol),
and Pd(PPh3)4 (0.046 g, 0.04 mmol), the solution was stirred for
48 h, and the reaction was monitored by GC-MS. Subsequently,
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 purified
mixtures containing the title compound and 1-(2-methylnaphthalen-
1-yl)biphenylene as impurity. Separation of the two isomers 6a and
6b was obtained in two steps: the pair was first separated from
the impurity by preparative HPLC on a C18 column (10 µm, 250
× 21.2 mm, 24 mL/min, ACN/H2O 95:5 v/v), then the separation
of the two isomers was obtained by joining a C18 and a C8
semipreparative HPLC columns (first column: Kromasil C18, 5
µm, 250 × 10 mm; second column: Luna C8(2), 5 µm, 250 × 10
mm, 5 mL/min, ACN/H2O 90:10 v/v). A total amount of 0.015 g
C
signals were obtained by bi-dimensional experiments (edited-
gHSQC38 and gHMBC39 sequences). Temperature calibrations were
performed before the experiments, using a Cu/Ni thermocouple
immersed in a dummy sample tube filled with isopentane, and under
conditions as nearly identical as possible. The uncertainty in the
temperatures was estimated from the calibration curve to be (1
°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. Kinetic equilibration of compound 6 was obtained
by heating a NMR sample of pure 6a in DMSO-d6 into a
thermostatic oil bath, kept at +140 °C. NMR spectra were then
recoded at regular times until the equilibrium was reached (see
Figure S4 of the Supporting Information.)
Calculations. Geometry optimizations were carried out at the
B3LYP/6-31G(d) level by means of the Gaussian 03 series of
programs15 (see the Supporting Information): the standard Berny
algorithm in redundant internal coordinates and default criteria of
convergence were employed. The reported energy values are not
ZPE corrected. Harmonic vibrational frequencies were calculated
for all the stationary points. For each optimized ground state the
frequency analysis showed the absence of imaginary frequencies,
whereas each transition state showed a single imaginary frequency.
Visual inspection of the corresponding normal mode was used to
confirm that the correct transition state had been found. NMR
chemical shift calculations were obtained with the GIAO method
at the B3LYP/6-311++G(2d,p)//B3LYP/6-31G(d) level. TMS,
calculated at the same level of theory, was used as reference to
scale the absolute shielding value. TDDFT calculations on the M,M
enantiomer of 6b were obtained at the B3LYP/6-31+G(d,p)//
(35) Leroux, F.; Schlosser, M. Angew. Chem., Int. Ed. 2002, 41, 4272-
4274.
(36) Pathak, R.; Nhlapo, J. M.; Govender, S.; Michael, J. P.; Van, Otterlo,
W. A. L.; De Koning, C. B. Tetrahedron 2006, 62, 2820-2830.
(37) Thompson, W. J.; Gaudino, J. J. Org. Chem. 1984, 49, 5237.
(38) Bradley, S. A.; Krishnamurthy, K. Magn. Reson. Chem. 2005, 43,
117-123. Willker, W.; Leibfritz, D.; Kerssebaum, R.; Bermel, W. Magn.
Res. Chem. 1993, 31, 287-292.
(39) Hurd, R. E.; John, B. K. J. Magn. Reson. 1991, 91, 648-653.
2204 J. Org. Chem., Vol. 73, No. 6, 2008

Arylbiphenylene Atropisomers
B3LYP/6-31G(d) level. In order to cover the whole 190-400 nm
range, 60 transitions were calculated. The CD spectrum was then
obtained by applying a 0.3 eV Gaussian band shape.40
Supporting Information Available: Low-temperature NOE
spectra of compounds 2 and 5; VT-NMR spectra of 3; kinetic data
for compound 6; calculated and experimental UV spectrum of 6b;
calculated velocity rotational length and CD spectrum of (M,M)-
6b; X-ray data of compounds 1 and 4 (CIF); experimental procedure
for the preparation of 2-tert-butylphenylboronic acid; spectroscopic
data of compounds 2-5; 1H and 13C NMR spectra and HPLC traces
of 1-6; chemical shift calculations and computational data of 1-6.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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”).
(40) (a) O’Boyle, N. M. GaussSum 2.1.3, 2007. Available at http://
gausssum.sf.net. (b) O’Boyle, N. M.; Tenderholt, A. L.; Langner, K. M. J.
Comput. Chem. 2007, DOI 10.1002/jcc.20823
JO702502N
J. Org. Chem, Vol. 73, No. 6, 2008 2205