Conformational consequences of the dynamic processes in the stereolabile atropisomers of acyl-substituted m-terphenyl derivatives

Article abstract of DOI:10.1021/jo062558g

By means of low-temperature NMR spectroscopy, conformers (stereolabile atropisomers) due to the restricted rotation about the Ar-Ar and Ar-C(O)R bonds were detected in a number of acylphenyl derivatives, substituted in positions 2 and 6 by the 3-isopropylphenyl moiety (compounds 1-3, R = H, Me, and t-Bu, respectively). The conformational assignment was accomplished on the basis of the symmetry of the low-temperature ¹³C NMR spectra with the added support of ab initio calculations. The interconversion barriers were also determined by complete line shape simulation of the NMR spectra, and the experimental values were satisfactorily reproduced by ab initio calculations. In the case of the asymmetric derivative 4, two enantiomers, generated by the restricted t-BuC(O)-Ar rotation, were found sufficiently stable to allow their separation by means of the enantioselective HPLC technique at ambient temperature and to obtain the corresponding CD spectra.

Full text of DOI:10.1021/jo062558g

Conformational Consequences of the Dynamic Processes in the
Stereolabile Atropisomers of Acyl-Substituted m-Terphenyl
Derivatives
Lodovico Lunazzi, Andrea Mazzanti,* and Mirko Minzoni1
Department of Organic Chemistry “A. Mangini”, UniVersity of Bologna, Viale Risorgimento 4,
Bologna 40136, Italy
mazzand@ms.fci.unibo.it
ReceiVed December 13, 2006
By means of low-temperature NMR spectroscopy, conformers (stereolabile atropisomers) due to the
restricted rotation about the Ar-Ar and Ar-C(O)R bonds were detected in a number of acylphenyl
derivatives, substituted in positions 2 and 6 by the 3-isopropylphenyl moiety (compounds 1-3, R ) H,
Me, and t-Bu, respectively). The conformational assignment was accomplished on the basis of the symmetry
of the low-temperature 13C NMR spectra with the added support of ab initio calculations. The
interconversion barriers were also determined by complete line shape simulation of the NMR spectra,
and the experimental values were satisfactorily reproduced by ab initio calculations. In the case of the
asymmetric derivative 4, two enantiomers, generated by the restricted t-BuC(O)-Ar rotation, were found
sufficiently stable to allow their separation by means of the enantioselective HPLC technique at ambient
temperature and to obtain the corresponding CD spectra.
Introduction
(Chart 1) were accordingly synthesized for this purpose: the
isopropyl moiety was introduced to take advantage of the
diastereotopicity of its methyl groups under the mode of slow
rotation3 of the Ar or RCdO substituents, when a nonplanar
conformation is adopted.
It has been recently reported2 that p-terphenyl derivatives
bearing equal substituents in the ortho positions of the two
external rings give rise to cis and trans stereolabile diastereo-
isomers (atropisomers) that could be detected by low-temper-
ature NMR spectroscopy. This suggests that analogously
substituted m-terphenyl compounds bearing, in addition, an acyl
group on the central phenyl ring should originate an even greater
number of this type of atropisomers that would be amenable to
NMR detection. In the case of a particularly crowded derivative,
it should also be possible, in principle, to achieve a physical
separation of the two enantiomeric forms. Compounds 1-4
Results and Discussion
Three types of conformers (Scheme 1) are expected to exist
for compounds 1-3 when the substituents (Ar and RCdO) are
not coplanar with the central phenyl group. Ab initio calcula-
tions4 indicate that they do correspond to energy minima and
also that the RCdO and the two external aryl groups are not
(1) In partial fulfillment for the Ph.D. in Chemical Sciences, University
of Bologna.
(3) (a) Mislow, K.; Raban, M. Top. Stereochem. 1967, 1, 1. (b) Jennings,
(2) Lunazzi, L.; Mazzanti, A.; Minzoni, M.; Anderson, J. E. Org. Lett.
2005, 7, 1291.
W. B. Chem. ReV. 1975, 75, 307. (c) Eliel, E. L. J. Chem. Educ. 1980, 57,
52.
10.1021/jo062558g CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/07/2007
J. Org. Chem. 2007, 72, 2501-2507
2501

Lunazzi et al.
CHART 1
SCHEME 1a
FIGURE 1. Left: temperature dependence of the 13C (150.8 MHz)
isopropyl methyl signal of 1 in CHF2Cl/CHFCl2. Right: simulation
obtained with four equally intense lines and with the rate constants
indicated.
a In the two cis atropisomers the position of the isopropyl groups closer
to oxygen identifies the structure as syn, that of the isopropyl groups farther
away from oxygen identifies the structure as anti.
TABLE 1. Experimental Barriers (kcal mol-1) for the Bond
coplanar with the central ring, although not always exactly
orthogonal, as displayed in Scheme 1. However, the torsion
process about the orthogonal position is predicted to have such
a low barrier (in the case of 1, for instance, this barrier is
computed to be as low as 4.0 kcal mol-1 for the torsion of the
HCdO group and 1.0 kcal mol-1 for the aryl-aryl torsion) that
for most purposes these compounds can be considered as having
the symmetry shown in Scheme 1 (i.e., Cs for the two cis
atropisomers and C1 for the trans atropisomer).
Rotation Processes of 1-4a
Ar-Ar
rotation
Ar-C(O)R
rotation
Ar-Ar
rotation
Ar-C(O)R
rotation
compd
compd
1
2
8.7 (9.4)
7.55 (7.8)
<5 (4.0)
7.55 (8.0)
3
4
9.9 (10.1) 23.1 (22.3)
9.5 (10.1) 23.1 (22.3)
a In parentheses are given the ab initio computed values.
ingly, only a single averaged cis conformer can be experimen-
tally detected. The same fast process occurs in the trans C1
conformer, which thus appears as having a “dynamic” C2
symmetry. In other words, not only the torsion of the CHdO
moiety through the orthogonal transition state is very rapid in
1, but also the rotation process through the coplanar transition
state is rapid (this barrier is computed4 to be about 1 kcal mol-1).
Thus, the lines observed at -141 °C are the result solely of the
restricted rotation about the bonds connecting the aryl rings.
The Ar-C(O)H bond rotation is fast on the NMR time scale
even at such low temperatures, indicating that the corresponding
∆Gq value should be less than 5 kcal mol-1 (this agrees well
with the theoretical prediction of 4.0 kcal mol-1, as in Table
1).
In Figure 1 is reported the 13C NMR signal of the isopropyl
methyl groups of 1 (R ) H) as a function of temperature. At
-141 °C four lines are observed: the spectral simulation
indicates that their relative intensities are essentially the same.
This means that two nearly equally populated conformers are
present, each displaying a pair of diastereotopic methyl groups.
Almost all the other 13C lines of 1 are also split into nearly
equally intense pairs at this temperature (see the Supporting
Information, Figure S-1). Such an observation indicates that
HCdO has a very fast rotation rate on the NMR time scale, so
that the cis (syn) and cis (anti) conformers of Scheme 1
interchange too rapidly to be individually identified. Accord-
(4) Gaussian 03, revision D.01: Frisch, M. J.; Trucks, G. W.; Schlegel,
H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, Jr.,
J. A.; 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 Inc., Wallingford, CT, 2004.
Line shape simulation of the spectrum of Figure 1 allowed
us to obtain the rate constants for the interconversion between
the trans and cis conformers of Scheme 1, the corresponding
free energy of activation being 8.7 kcal mol-1 (Table 1). This
result is further confirmed by the observation that the same ∆Gq
value could also be obtained by line shape simulation of the
two lines (149.4 and 149.8 ppm as in the Supporting Informa-
tion, Figure S-1) due to the quaternary carbons bonded to the
isopropyl substituent (identified by means of the gHMBC pulse
sequence5). The ab initio computed barrier for such an Ar-Ar
(5) Hurd, R. E.; John, B. K. J. Magn. Reson. 1991, 91, 648.
2502 J. Org. Chem., Vol. 72, No. 7, 2007

Dynamic Processes in m-Terphenyl DeriVatiVes
into account that the most populated trans form (58%) can be
obtained by rotation of either of the two external aryl rings;
thus, it is 2-fold degenerate with respect to its cis companions:
in other words, this degeneracy is a consequence of the existence
of two enantiomeric forms, due to the chirality of the trans
conformer. The thermodynamic stability of the trans structure
corresponds, accordingly, to a population of 1/2 × 58% ) 29%,
and if this statistical correction is taken into account, the trans
structure appears to be the second most stable conformer, in
qualitative agreement with its computed relative energy of 0.08
kcal mol-1. On this basis, the cis (syn) structure, computed to
be the most stable, must be assigned to the conformer with the
32% population.7
The line shape simulation (Figure 2) could be performed by
using the same rate constant for both the Ar-Ar and the Ar-
C(O)Me rotation processes. This means that the two barriers
are indistinguishable within the experimental accuracy, their
values being 7.55 ( 0.2 kcal mol-1, as in Table 1. Such a near
identity is confirmed by computations that predict barriers of
7.8 and 8.0 kcal mol-1 for the Ar-Ar and Ar-C(O)Me bond
rotations, respectively. The fact that both these motions become
rapid above -110 °C, as shown in Figure 2, is further confirmed
by the observation that also the isopropyl methyl groups, which
appear diastereotopic3 at -146 °C, become equivalent (enan-
tiotopic) on raising the temperature, eventually displaying a
single 13C line: in these conditions, in fact, the molecule has
achieved a dynamic C2V symmetry.
It might seem quite surprising that the Ar-Ar rotation barrier
of 2 is somewhat lower (by 1.2 kcal mol-1) than that of 1 (Table
1). This feature is most likely a consequence of the different
dihedral angles adopted by the RCdO moieties with respect to
the central aryl ring. In the case of 1 (R ) H) this angle is
computed to be only 28°, whereas in 2 (R ) Me) it is 88°. Due
to its orthogonal arrangement, the MeCdO moiety exerts a steric
interaction smaller than that of the nearly coplanar HCdO group
toward the external isopropylphenyl rings: for this reason the
HCdO moiety behaves, in practice, as a bulkier group as far
as the Ar-Ar rotation is concerned.
The low-temperature (-115 °C) 13C spectrum of the methyl
groups of the tert-butyl moiety of 3 (Figure 3) displays three
signals with a 48:40:12 peak surface ratio that coalesce into a
single line above -74 °C. As in the case of 2 all three possible
conformers are NMR visible in that both the Ar-Ar and the
t-BuC(O)-Ar bond rotations are locked at this temperature.
The pair of quaternary carbons bonded to the isopropyl groups
display four lines at -125 °C, their peak surface ratio being
12:20:48:20 (Supporting Information Figure S-3). The pair of
equally intense lines (20% each) must thus be assigned to the
trans conformer, which, accordingly, is present in a 40%
proportion. By analogy with the methyl derivative 2, the cis
FIGURE 2. Left: temperature dependence of the 13C (150.8 MHz)
signal of the quaternary carbons bonded to the isopropyl groups of 2
in CHF2Cl/CHFCl2. Right: simulation obtained with the rate constants
indicated.
rotation process (9.4 kcal mol-1) is in good agreement with the
experiment.6
The 13C carbonyl signal of 2 (R ) Me) at -146 °C shows
three lines, with 32:58:10 relative integrated intensities (Sup-
porting Information, Figure S-2). This means that all three
possible conformers of Scheme 1 appear to be populated, a
situation which requires that both the Ar-Ar and the Ar-C(O)-
Me bond rotations are locked on the NMR time scale at this
temperature. Information on the symmetry of the conformers
can be obtained from the signals of the pairs of carbons. For
instance, the spectrum due to the pair of quaternary carbons
bonded to the isopropyl group (identified by the gHMBC pulse
sequence5) displays four lines with relative integrated intensities
of 32:29:10:29 (Figure 2). Thus, the two equally intense lines
(29 ( 1% each) must be assigned to the asymmetric trans
conformer (C1 point group), whereas the other two (32 ( 1%
and 10 ( 1%) belong to the cis conformers, because both have
a plane of symmetry (Cs point group). It was impossible for us
to identify which is the more stable of the two cis conformers
solely on experimental grounds, so we made use of the ab initio
computations to help in the assignment. The values of the
relative energies calculated in this way are 0, 0.08, and 0.16
kcal mol-1 for the cis (syn), trans, and cis (anti) conformers,
respectively. The cis (anti) structure is the least stable and should
be thus assigned to the conformer displaying the 10% population
in the experimental spectrum. These computations match the
experimental trend of the populations since it has to be taken
(7) The analysis of the population distribution might also be performed
by taking into account the entropy of mixing the conformational enantiomers
(see: Eliel, L. E.; Wilen, S. H. Stereochemistry of Organic Compounds;
John Wiley and Sons: New York, 1994; pp 97 and 601. Collet, A. In
Problems and Wonders of Chiral Molecules; Simonyi, M., Ed.; Akade´miai
Kiado´: Budapest, 1990; p 93). The computed energy (0.08 kcal mol-1) of
the chiral trans conformer is thus lowered by RT ln 2 (i.e., 0.175 kcal mol-1
at -146 °C), becoming, therefore, 0.08-0.175 ) -0.095 kcal mol-1. On
the basis of this correction, the previously computed relative energies of
the three conformers (i.e., 0, 0.16, and 0.08 kcal mol-1) become 0.095,
0.255, and 0 kcal mol-1 for cis (syn), cis (anti), and trans, respectively.
These values correspond to theoretical populations of 33%, 18%, and 49%,
respectively, a trend which parallels the experimental ratio of 32%, 10%,
and 58%.
(6) Since the cis to trans interconversion can be accomplished by the
rotation of either of the two external aryl rings, the rate for the rotation of
a single aryl ring corresponds to half of the measured rate constants. The
corresponding barrier thus becomes 0.2 kcal mol-1 higher, and it is this
value that, in principle, should be compared to the theoretical barrier.
J. Org. Chem, Vol. 72, No. 7, 2007 2503

Lunazzi et al.
FIGURE 4. Bottom: 13C NMR (150.8 MHz) signals of the isopropyl
methyl groups of 3 at -115 °C in CHF2Cl/CHFCl2. The two lines
labeled “a” belong to the cis (syn) conformer, the four lines labeled
“b” to the trans conformer, and the two lines labeled “c” to the cis
(anti) conformer. Top: same spectrum recorded at 105 °C in toluene-
d8.
FIGURE 3. Left: temperature dependence of the tert-butyl methyl
signal (13C NMR at 150.8 MHz in CHF2Cl/CHFCl2) of 3. Right:
simulation obtained with the rate constants indicated.
(syn) structure should be assigned to the most populated (48%)
conformer and the cis (anti) structure to the least populated
(12%) conformer. This assignment is further supported by
calculations that indicate how the trend for the relative computed
energies is 0.0, 0.03, and 0.09 kcal mol-1 for the cis (syn), trans,
and cis (anti) conformers, respectively.8
The spectrum of the isopropyl methyl groups of 3 at -115
°C (Figure 4, bottom) displays seven out of the expected eight
lines, owing to the accidental coincidence of two peaks.9 On
raising the temperature, these lines coalesce into a doublet, but
even at 105 °C (Figure 4, top) do not exchange any further to
yield a single line, contrary to the case of 2. The plane of the
t-BuCdO moiety is twisted with respect to the central aryl ring,
but the corresponding rotation process has a barrier so high10
that the molecule cannot achieve the mentioned dynamic C2V
symmetry, even when warmed well above ambient tempera-
ture: for this reason the isopropyl methyl groups of 3 always
appear diastereotopic.3 Accordingly, the barrier determined by
means of the rate constants of Figure 3 (∆G ) 9.9 kcal mol-1
)
is due solely to the Ar-Ar bond rotation:6 the corresponding
computed value of 10.1 kcal mol-1 is in very good agreement
with this value (Table 1).
The absence of a noticeable broadening of the isopropyl
methyl lines of 3 (as shown in the top trace of Figure 4)
prevented the determination of the t-BuC(O)-Ar rotation barrier
by the coalescence method.10 As an alternative technique we
made use of a monodimensional EXSY experiment, which was
performed at 107 °C on the 1H isopropyl methyl lines (see the
Experimental Section). This approach allows one to achieve
meaningful measurements of rate constants smaller than those
obtainable by the other method, and in this way (Supporting
Information Figure S-4) a rate constant of 0.4 s-1, corresponding
to a ∆Gq value of 23.1 kcal mol-1 (Table 1), was derived for
the rotation about the t-BuC(O)-Ar bond:11 again the computed
value (22.3 kcal mol-1) matches reasonably well the experi-
mental measurement.
The highly restricted rotation about the t-BuC(O)-Ar bond
of 3 suggests that, in the analogous derivative 4, where only
one of the two external aryl rings bears the isopropyl substituent
(Scheme 2), two enantiomers with a stability sufficient for
allowing a physical separation should occur: a ∆Gq value of
23.1 kcal mol-1 implies, in fact, a half-life of about 21/2 h at 21
°C (an analogous type of enantiomers, generated, as in the
present case, by the restricted rotation about the sp2-sp2 bond,
could be separated, for instance, in the case of hindered
naphthylimines12).
(8) Further support for this assignment was obtained by means of the
computations of the 13C chemical shifts (see the Experimental Section) of
the trans conformer of 3. These calculations indicate that the upfield shift
of the quaternary carbon bonded to the isopropyl moiety corresponds to
that in the ring having a syn relationship to CdO, the downfield shift being
that in the anti relationship. The experimental signal of the same carbon of
the major (48%) cis conformer is very close to the upfield shift of the trans
conformer, whereas the experimental signal of the minor (12%) cis
conformer is close to the downfield shift of the trans conformer (Supporting
Information Figure S-3). On this basis, it is thus conceivable to assign the
cis (syn) structure to the major conformer and the cis (anti) structure to the
minor conformer, in agreement with the trend of the computed energies.
(9) The integrated intensity distribution of the isopropyl methyl lines
matches the ratio 47:40:13 derived from the other signals. In particular,
the four lines expected for the trans isomer correspond to the 40% intensity.
(10) Not even at 130 °C (in tetrachloroethane-d2 as solvent) could we
detect any appreciable broadening of the 1H isopropyl methyl lines of 3,
thus suggesting that the t-BuC(O)-Ar rotation barrier must be larger than
22.5 kcal mol-1. This lower limit derives from the consideration that a rate
constant of at least 5 s-1 is usually needed to obtain a clearly noticeable
broadening caused by an exchange process (see, for instance, Figures 2
and 3). Since in the present case the rate constant at 130 °C is certainly
lower than 5 s-1, the ∆Gq value should be consequently higher than 22.5
As shown in Scheme 2, two conformers (syn and anti) might
be populated in 4, each exhibiting a pair of M and P
enantiomers. Owing to the fast syn to anti exchange13 and to
the mentioned slow M to P interconversion, the two “syn/anti
kcal mol-1
.
2504 J. Org. Chem., Vol. 72, No. 7, 2007

Dynamic Processes in m-Terphenyl DeriVatiVes
SCHEME 2
averaged” enantiomers were actually observed at ambient
temperature by NMR in a chiral environment,14 as displayed in
Figure 5.
1
FIGURE 5. Top: ambient-temperature H NMR signals (600 MHz
in CDCl3) of the CH and of the diastereotopic Me groups of the
isopropyl moiety of 4. Bottom: same spectrum in a chiral environment14
exhibiting a splitting of all the lines, due to the M and P enantiomers.
These enantiomers could even be separated by HPLC at 21
°C using an enantioselective column (Experimental Section):
the oppositely phased CD spectra of these enantiomers (recorded
at 10 °C to avoid racemization) are displayed in Figure 6.
The kinetics of the racemization process was followed by
monitoring the decrease of the HPLC peak of the second eluted
isolated enantiomer, accompanied by a simultaneous increase
of the peak of its first eluted companion, until the two peaks
again reached the same intensity: in this way a rate constant
of 4 × 10-5 s-1 was obtained at 21 °C (Supporting Information
Figure S-5). This rate corresponds to a free energy of activation
of 23.1 kcal mol-1 (Table 1), a value equal, as conceivable,15
to that obtained via NMR for the extremely similar derivative
3.
Experimental Section
Materials. 2,6-Dibromobenzaldehyde16 and 3-Isopropyl-phenyl-
boronic acid17 were prepared according to the literature. Phenyl-
boronic acid was commercially available.
1-(2,6-Dibromophenyl)-2,2-dimethylpropan-1-one. A solution
of lithium diisopropylamide was prepared in 1 h by addition of 6.3
mL of n-butyllithium (10 mmol, 1.6 M in hexane) to a stirred
solution of 1.08 g of diisopropylamine (10 mmol in 40 mL of
anhydrous THF) kept at -5 °C. The solution was then slowly
transferred into a solution of 1,3-dibromobenzene (1.87 g, 8 mmol
in 30 mL of anhydrous THF) kept at -78 °C. After 1 h the
suspension of the resulting lithiate was treated with trimethyl-
acetaldehyde (1.72 g, 20 mmol in 10 mL of THF). After 1 h at
-78°, the mixture was warmed to ambient temperature and
quenched with aqueous NH4Cl. The extracted organic layer (Et2O)
was dried (Na2SO4) and evaporated, and the crude was treated with
pyridinium chlorochromate (3.45 g, 16 mmol in 20 mL of CH2-
Cl2) at room temperature for about 1 h, following the reaction by
GC-MS. The suspension was then filtered on silica and purified
by chromatography on silica gel (hexane/Et2O, 10:1) to obtain 2.27
g (7.1 mmol, 88%) of a white solid. Mp: 79-80 °C. 1H NMR (400
MHz, CDCl3, 25 °C, TMS): δ 1.38 (9H, s) 7.08 (1H, t, J ) 8.1
Hz), 7.53 (2H, d, J ) 8.1 Hz). 13C NMR (100.6 MHz, CDCl3, 25
°C, TMS): δ 28.7 (CH3), 44.2 (q), 118.1 (q), 130.4 (CH), 131.9
(2CH), 144.0 (q), 211.5 (CO).
(11) This value can still be compared to those obtained at lower
temperatures since the conformational processes have free energies of
activation nearly independent of temperature, due to the negligible contribu-
tion of the ∆Sq values. See, for instance: 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. 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,
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. 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. 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.
2,6-Bis(3-isopropylphenyl)benzaldehyde (1). To a solution of
2,6-dibromobenzaldhyde (0.264 g, 1 mmol in 6 mL of benzene)
were added K2CO3 (2 M solution, 1.25 mL), 3-isopropylphenyl-
boronic acid (0.410 g, 2.5 mmol, suspension in 6 mL of ethanol),
and Pd(PPh3)4 (0.231 g, 0.2 mmol) at room temperature. The stirred
(12) Casarini, D.; Lunazzi, L.; Macciantelli D. J. Chem. Soc., Perkin
Trans. 2 1992, 1363
(13) Low-temperature NMR spectra of 4 show that the syn (65%) to
anti (35%) interconversion has a barrier (9.5 ( 0.2 kcal mol-1) equal, within
the uncertainity, to that of the very similar compound 3 (Table 1). Again
calculations predict that the conformer with the less crowded syn structure
is more stable (by 0.1 kcal mol-1) than the anti structure.
(15) The identity of the two ∆Gq values measured at temperatures as
different as 21 and 107 °C (for the nearly equal compounds 4 and 3,
respectively) further supports the consideration that the term ∆Sq is
negligible in the majority of conformational processes, as reported in ref
11.
(14) Use was made of a 60:1 molar excess of the 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).
(16) Lulinski, S.; Serwatowski, J. J. Org. Chem. 2003, 68, 5384.
(17) Mazzanti, A.; Lunazzi, L.; Minzoni, M.; Anderson, J. E. J. Org.
Chem. 2006, 71, 5474.
J. Org. Chem, Vol. 72, No. 7, 2007 2505

Lunazzi et al.
FIGURE 6. Top: HPLC resolution of the two enantiomers of 4 at 21 °C. Bottom: CD spectra (at 10 °C) of the first (red) and second (blue) eluted
enantiomers.
solution was refluxed for 2-3 h, the reaction being monitored by
GC-MS. Then CHCl3 and H2O were added, and the extracted
organic layer was dried (Na2SO4) and evaporated. The crude was
purified by chromatography on silica gel (hexane/Et2O, 20:1) to
yield 0.270 g (0.79 mmol, 79%). Analytically pure samples were
obtained by semipreparative HPLC (5 µm, 250 × 10 mm column,
and quenched with acqueous NH4Cl, and the organic layer was
extracted with Et2O and dried (Na2SO4). The crude was then treated
with pyridinium chlorochromate (0.77 g, 3.0 mmol in 10 mL of
CH2Cl2) at room temperature for about 1 h, following the reaction
by GC-MS. The suspension was then filtered on silica and purified
by chromatography on silica gel (hexane/Et2O, 10:1) to obtain 0.340
g (0.85 mmol, 85%) of the product. Analytically pure samples were
obtained by semipreparative HPLC (5 µm, 250 × 10 mm column,
1
5 mL/min, ACN/H2O, 95:5, v/v). H NMR (600 MHz, CDCl3, 25
°C, TMS): δ 1.28 (12H, d, J ) 6.8 Hz), 2.95 (2H, septet, J ) 6.8
Hz), 7.17-7.58 (11H, m). 13C NMR (150.8 MHz, CDCl3, 25 °C,
TMS): δ 24.0 (CH3), 34.0 (CH), 125.7 (CH), 127.0 (CH), 127.9
(CH), 128.0 (CH), 130.2 (CH), 131.3 (CH), 133.4 (q), 139.6 (q),
144.5 (q), 148.7 (q), 193.8 (CO). HRMS (EI): m/z calcd for
C25H26O 342.19836, found 342.19761.
1
5 mL/min, ACN/H2O, 95:5, v/v). H NMR (600 MHz, CDCl3, 25
°C, TMS): δ 0.30 (9H, s), 1.25 (6H, d, J ) 6.9 Hz), 1.27 (6H, d,
J ) 6.9 Hz), 2.92 (2H, septet, J ) 6.9 Hz), 7.16-7.22 (4H, m),
7.27-7.31 (4H, m), 7.33 (2H, d, J ) 7.6 Hz), 7.45 (1H, dd, J )
8.1, 7.3 Hz). 13C NMR (150.8 MHz, CDCl3, 25 °C, TMS): δ 23.9
(CH3), 24.0 (CH3), 27.0 (CH3), 34.1 (CH), 44.2 (q), 125.6 (CH),
127.8 (CH), 127.99 (CH), 128.01 (CH) 128.6 (CH), 129.2 (CH),
138.2 (q), 140.5 (q), 141.0 (q), 148.6 (q), 216.4 (CO). HRMS
(EI): m/z calcd for C29H34O 398.26097, found 398.26031.
2,6-Bis(3-isopropylphenyl)acetophenone (2). To a solution of
2,6-bis(3-isopropylphenyl)benzaldehyde (0.342 g, 1 mmol in 10
mL of THF) kept at -78 °C was added a solution of MeLi (1.6
mL, 2.4 mmol in Et2O). After 1 h at -78 °C, the stirred solution
was warmed to ambient temperature and quenched with aqueous
NH4Cl, and the organic layer was extracted with Et2O and dried
(Na2SO4). The crude was then treated with pyridinium chlorochro-
mate (0.77 g, 3.0 mmol in 10 mL of CH2Cl2) at room temperature
for about 1 h, following the reaction by GC-MS. The suspension
was then filtered on silica and purified by chromatography on silica
gel (hexane/Et2O, 10:1) to obtain 0.310 g (0.87 mmol, 87%) of the
product. Analytically pure samples were obtained by semiprepara-
tive HPLC (5 µm, 250 × 10 mm column, 5 mL/min, ACN/H2O,
95:5, v/v). 1H NMR (600 MHz, CDCl3, 25 °C, TMS): δ 1.26 (12H,
d, J ) 6.9 Hz), 1.86 (3H, s), 2.93 (2H, septet, J ) 6.9 Hz), 7.18-
7.47 (11H, m). 13C NMR (150.8 MHz, CDCl3, 25 °C, TMS): δ
23.9 (CH3), 32.8 (CH3), 34.0 (CH), 125.7 (CH), 126.4 (CH), 127.4
(CH), 128.3 (CH), 128.5 (CH), 129.0 (CH), 139.4 (q), 140.3 (q),
141.4 (q), 148.9 (q), 206.4 (CO). HRMS (EI): m/z calcd for
C26H28O 356.21402, found 356.21358.
1-[2′-(3-isopropylphenyl)-6′-phenylphenyl]-2,2-dimethylpro-
pan-1-one (4). To a solution of 1-(2,6-dibromophenyl)-2,2-di-
methylpropan-1-one (0.320 g, 1 mmol, in 6 mL of benzene) were
added K2CO3 (2 M solution, 1.25 mL), 3-isopropylphenylboronic
acid (0.164 g, 1.0 mmol, suspension in 3 mL of ethanol), and Pd-
(PPh3)4 (0.231 g, 0.2 mmol) at room temperature. The stirred
solution was refluxed for 2-3 h, the reaction being monitored by
GC-MS. After the solution was cooled to room temperature,
phenylboronic acid (0.244 g, 2.0 mmol, suspension in 6 mL of
ethanol) and Pd(PPh3)4 (0.231 g, 0.2 mmol) were then added, and
the solution was refluxed again for 2 h. Then 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, 20:1) to yield a fraction containing the title
compound together with compound 3 and 1-[2′-bromo-6′-(3-
isopropylphenyl)phenyl]-2,2-dimethylpropan-1-one. Analytically
pure samples of 4 were obtained by semipreparative HPLC (5 µm,
250 × 10 mm column, 5 mL/min, ACN/H2O, 95:5, v/v). 1H NMR
(600 MHz, CDCl3, 25 °C, TMS): δ 0.31 (9H, s), 1.254 (6H, d, J
) 6.9 Hz), 1.270 (6H, d, J ) 6.9 Hz), 2.92 (2H, septet, J ) 6.9
Hz), 7.16 7.22 (4H, m), 7.28-7.38 (7H, m), 7.40-7.42 (2H, m),
1-[2′,6′-Bis(3-isopropylphenyl)phenyl]-2,2-dimethylpropan-1-
one (3). To a solution of 2,6-bis(3-isopropylphenyl)benzaldehyde
(0.342 g, 1 mmol in 10 mL of THF) kept at -78 °C was added a
solution of t-BuLi (1.7 mL, 2.5 mmol in pentane). After 1 h at
-78 °C, the stirred solution was warmed to ambient temperature
2506 J. Org. Chem., Vol. 72, No. 7, 2007

Dynamic Processes in m-Terphenyl DeriVatiVes
7.46 (1H, t, J ) 7.7 Hz). 13C NMR (150.8 MHz, CDCl3, 25 °C,
TMS): δ 23.8 (CH3), 24.0 (CH3), 27.1 (CH3), 34.1 (CH), 44.2 (q),
125.7 (CH), 127.5 (CH), 127.8 (CH), 127.9 (CH), 128.02 (CH),
128.06 (CH), 128.7 (CH), 129.3 (CH), 130.7 (CH), 137.9 (q), 138.3
(q), 140.4 (q), 140.6 (q), 140.9 (q), 148.6 (q), 216.4 (CO). HRMS
(EI): m/z calcd for C26H28O 356.21402, found 356.21321.
NMR Spectroscopy. The spectra were recorded at 400 and 600
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 right 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,21 was used as a reference to scale the absolute
shielding value.
Enantioselective HPLC. Separation of the two atropisomers of
4 was obtained at 21 °C on a 250 × 4.6 mm column, at a flow rate
of 0.5 mL/min, using hexane/i-PrOH, 98:2, v/v, as the eluent. UV
detection was fixed at 225 nm. To avoid racemization, the two
fractions were collected directly into refrigerated (-20 °C) contain-
ers.
1
MHz for H and 100.6 and 150.8 MHz for 13C. The assignments
of the 13C signals were obtained by bidimensional experiments
(edited gHSQC18 and gHMBC5 sequences). The samples for
obtaining spectra at temperatures lower than -100 °C were prepared
by connecting to a vacuum line the NMR tubes containing the
compound and some C6D6 for locking purposes and condensing
therein the gaseous CHF2Cl and CHFCl2 (4:1, v/v) under cooling
with liquid nitrogen. The tubes were subsequently sealed in vacuo
and introduced into the precooled probe of the spectrometer. The
temperatures were calibrated by substituting the sample with a Cu/
Ni thermocouple before the measurements. Low-temperature 13C
spectra were acquired with a 5 mm dual probe, without spinning,
with a sweep width of 38000 Hz, a pulse width of 4.9 µs (70° tip
angle), and a delay time of 2.0 s. Proton decoupling was achieved
with the standard Waltz-16 sequence. A line broadening function
of 1-5 Hz was applied to the FIDs before Fourier transformation.
Usually 512-1024 scans were acquired. Both peak integration and
spectra deconvolution were used to determine the intensity ratios.
The line shape simulations were performed by means of a PC
version of the QCPE program DNMR 6 no. 633, Indiana University,
Bloomington, IN. The monodimensional EXSY experiments were
obtained in toluene-d8 at 107 °C by means of the DPFGSE-NOE19
sequence, raising the mixing time from 20 to 500 ms. To selectively
irradiate the upfield doublet of the isopropyl methyl group, a 10
Hz wide shaped pulse was calculated with a refocusing SNOB
shape20 and a pulse width of 185 ms.
CD Spectra. UV/vis absorption spectra of compound 4 in
hexane/i-PrOH, 98:2, were recorded at 25 °C on the racemic mixture
in the 350-190 nm spectral region. The cell path length was 0.1
cm. A concentration of compound 4 of 2.6 × 10-3 mol L-1 was
used. CD spectra were recorded at 10 °C with the same path lengths
of 0.1 cm, in the range 310-205 nm (the absorbance of the HPLC
solvents obscured the region under 205 nm). Reported ∆ꢀ values
are expressed as L mol-1 cm-1
.
Acknowledgment. Thanks are due to Dr. L. Giorgini,
University of Bologna, Italy, for the acquisition of the CD
spectra. L.L. and A.M. received financial support from the
University of Bologna (funds for selected research topics and
RFO) and from MIUR-COFIN 2005, Rome (national project
“Stereoselection in Organic Synthesis”).
Supporting Information Available: 13C NMR (at -141 °C)
of the quaternary carbon spectral region of 1, 13C NMR (at -146
°C) of the carbonyl carbon spectral region of 2, 13C NMR signal
of the isopropyl-bonded quaternary carbons of 3, monodimensional
EXSY spectra and kinetic data for 4, time dependence of the
Calculations. Computations were carried out at the B3LYP/6-
31G(d) level by means of the Gaussian 03 series of programs4 (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.
1
enantioselective HPLC traces of 4, H NMR, 13C NMR, and EI
mass spectra of compounds 1-4 and of the precursor of 4, HPLC
traces of compounds 1-4, and computational data for compounds
1-4. This material is available free of charge via the Internet at
http://pubs.acs.org.
(18) Bradley, S. A.; Krishnamurthy, K. Magn. Reson. Chem. 2005, 43,
117. Willker, W.; Leibfritz, D.; Kerssebaum, R.; Bermel, W. Magn. Reson.
Chem. 1993, 31, 287.
(19) (a) Stott, K.; Stonehouse, J.; Keeler, J.; Hwand, T.-L.; Shaka, A. J.
J. Am. Chem. Soc. 1995, 117, 4199. (b) Stott, K.; Keeler, J.; Van, Q. N.;
Shaka, A. J. J. Magn. Reson. 1997, 125, 302. (c) Van, Q. N.; Smith, E. M.;
Shaka, A. J. J. Magn. Reson. 1999, 141, 191. (d) See also: Claridge, T. D.
W. High Resolution NMR Techniques in Organic Chemistry; Pergamon:
Amsterdam, 1999.
JO062558G
(21) Use was made of the absolute shielding value reported for
tetramethylsilane in the following: Foresman, J. B.; Frisch A. E. Exploring
Chemistry with Electronic Structure Methods, 2nd ed. (errata corrige);
Gaussian Inc.: Wallingford, CT, 1996.
(20) Kupcˇe, E.; Boyd, J.; Campbell, I. D. J. Magn. Reson., Ser. B 1995,
106, 300.
J. Org. Chem, Vol. 72, No. 7, 2007 2507