Structure, conformation, and dynamic processes of the stereolabile atropisomers of hindered terphenyl hydrocarbons

Article abstract of DOI:10.1021/ol050091a

(Chemical Equation Presented) Ortho-substituted p-terphenyl hydrocarbons exist as trans and cis atropisomers that were identified by low-temperature NMR spectroscopy. The interconversion barriers increase with the dimensions of the ortho substituents, the experimental values being matched by ab initio calculations. X-ray diffraction shows that only the trans atropisomer is present in the solids. Spectra of a tert-butyl derivative in nonequilibrium conditions indicate that the cis is more populated than the trans atropisomer in solution, favored by attractive interactions.

Full text of DOI:10.1021/ol050091a

ORGANIC
LETTERS
2005
Vol. 7, No. 7
1291-1294
Structure, Conformation, and Dynamic
Processes of the Stereolabile
Atropisomers of Hindered Terphenyl
Hydrocarbons
Lodovico Lunazzi,† Andrea Mazzanti,*,† Mirko Minzoni,1,† and J. Edgar Anderson‡
Department of Organic Chemistry “A. Mangini”, UniVersity of Bologna,
Viale Risorgimento 4, Bologna I-40136, Italy, and Chemistry Department,
UniVersity College, Gower Street, London, U.K.
mazzand@ms.fci.unibo.it
Received January 17, 2005 (Revised Manuscript Received February 16, 2005)
ABSTRACT
Ortho-substituted p-terphenyl hydrocarbons exist as trans and cis atropisomers that were identified by low-temperature NMR spectroscopy.
The interconversion barriers increase with the dimensions of the ortho substituents, the experimental values being matched by ab initio
calculations. X-ray diffraction shows that only the trans atropisomer is present in the solids. Spectra of a tert-butyl derivative in nonequilibrium
conditions indicate that the cis is more populated than the trans atropisomer in solution, favored by attractive interactions.
A benzene ring bearing two identical ortho-substituted phenyl
groups in para positions is expected to involve two types of
atropisomers because the ortho substituents can adopt either
a trans disposition (with the alkyl groups on the opposite
side of the plane of the para-substituted phenyl ring) or a
cis disposition (with the alkyl group on the same side).2,3
These two forms are unlikely to be configurationally stable
Figure 1.
and would rapidly interconvert at ambient temperature. The
stereodynamic consequences of such an interconversion-
rotation of a biphenyl bond with only one ortho substituent
are investigated here for p-terphenyl compounds (1-4 of
Figure 1) with alkyl groups of increasing dimensions as ortho
substituents.
Owing to the competition between conjugative and steric
effects, the two o-alkylphenyl moieties of compounds 1-3
would display dihedral angles with the para-substituted
phenyl ring somewhat intermediate between 0° (coplanarity)
and 90° (orthogonality). As a consequence, both the trans
and cis atropisomers would comprise a pair of rotational
conformers, since in each atropisomer the o-alkyl groups can
be either in a syn or in an anti relative position. In Figure 2
† University of Bologna.
‡ University College.
(1) In partial fulfillment for the PhD in Chemical Sciences, University
of Bologna.
(2) Whitaker, C. M.; McMahon, R. J. J. Phys. Chem. 1996, 100, 1081.
(3) (a) Grilli, S.; Lunazzi, L.; Mazzanti, A.; Pinamonti, M. J. Org. Chem.
2002, 67, 5733. (b) Grilli, S.; Lunazzi, L.; Mazzanti, A.; Pinamonti, M.
Tetrahedron 2004, 60, 4451.
10.1021/ol050091a CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/03/2005

The interconversion between the “dynamic” trans (C2h)
and cis (C2V) atropisomers, defined as above, requires that
in the transition state an o-alkylphenyl group becomes
coplanar with the central para-substituted phenyl ring. In the
case of 1 this energy has been calculated4 to be 6.7 kcal
mol-1 higher than that of the ground state (Table 1), a value
which should be amenable to an experimental verification.
In Figure 3 a few selected NMR spectra (1H at 600 MHz)
of the aliphatic region of 1 are reported as a function of
temperature. Below -120 °C the methyl signal begins to
broaden and eventually decoalesces into a pair of lines with
a 48:52 intensity ratio at -150 °C,6 making the existence of
cis and trans atropisomers experimentally observable.
From the rate constants derived by line shape simulation,7
the free energy of activation (∆Gq ) 6.8 ( 0.2 kcal mol-1,
as in Table 1) was determined:8 the experimental value is
essentially equal to that predicted by calculations.
When the dimension of o-alkyl substituent R increases,
the measured barriers become progressively higher owing
to the larger steric effects, as anticipated by calculations
(Table 1). Also the population of the more stable atropisomer
increases regularly with the dimension of the substituents
(Table 1).
The tert-butyl group is large enough as to make the
adjacent phenyl rings essentially orthogonal, the dihedral
angle predicted by calculations4 being, in this case, 93°. For
this reason, compound 4 has only two energy minima (rather
than the four minima of 1-3), indicating that the cis and
Figure 2. Representation of the four rotamers of 1 as derived by
ab initio calculations (for convenience only the methyl hydrogens
are reported). The carbons of the para-substituted phenyl group are
green, and those of the o-methylphenyl group are blue when directed
toward the observer and red when away from the observer. The
shape of the two atropisomers (trans on the left and cis on the right)
resulting from the rapid interconversion of the corresponding pair
of rotamers is sketched underneath. On the top is also shown the
structure obtained by X-ray diffraction in the solids, which is very
similar to that of the computed trans-anti rotamer.
(4) (a) Ab initio computations were carried out at the B3LYP/6-31G(d)
level by means of the Gaussian 03 programs4b (the standard Berny algoritm
in redundant internal coordinates, and default criteria of convergence were
employed). Harmonic vibrational frequency were calculated in order to
ascertain the nature of all the stationary points. For each optimized ground
state the frequency analysis showed the absence of imaginary frequencies,
whereas for each transition state the frequency analysis showed a single
imaginary frequency. The corresponding optimised structures are reported
in the Supporting Information. (b) Gaussian 03, Revision C.02: 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, Inc.,
Wallingford, CT, 2004.
(5) Also in the cases of 2 (R ) Et) and 3 (R ) i-Pr) the four rotamers
have essentially the same computed energies, their differences lying within
0.03 and 0.04 kcal mol-1, respectively. The dihedral angles between the
aromatic rings were computed to be 64° for the four rotamers of 2 and 60°
for those of 3.
(6) 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 purpose 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 a spectrometer operating at 600 MHz. The
temperatures were calibrated by substituting the sample with a Cu/Ni
thermocouple before the measurements.
these four rotamers, which correspond to the four energy
minima resulting from ab initio computations,4 are displayed
for compound 1 (R ) Me), the mentioned dihedral angles
being 55° for all the rotamers. The corresponding energies
can be considered essentially equal within the computing
approximations because their differences are less than 0.01
kcal mol-1.5
Single-crystal X-ray diffraction shows that the structure
of 1 is of the trans-anti type (Figure 2, top); the measured
dihedral angle of 54.9° matches that anticipated by calcula-
tions (55°). Since this rotamer has essentially the same
computed energy as the other three, the preference for this
structure in the solids should be attributed to a particularly
stable crystal packing.
The barrier for the mutual interconversion between the
trans-syn and trans-anti rotamers (as well as between the cis-
syn and cis-anti) is expected to be very small, since
corresponds to the passage of one o-alkylphenyl group across
the plane perpendicular to that of the central, para-substituted
phenyl ring. Computations4 predict that this barrier is as low
as 0.63 kcal mol-1 in the case of 1 and is therefore too low
to be determined by dynamic NMR measurements. This fast
motion generates, consequently, a dynamic symmetry, so that
the trans atropisomer should display the time averaged
symmetry of the C2h point group: likewise, the cis atropi-
somer has the symmetry of the C2V point group.
(7) PC version of QCPE program no. 633, Indiana University, Bloom-
ington, IN.
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Org. Lett., Vol. 7, No. 7, 2005

Table 1. Experimental and Computed Barriers (in kcal mol-1) for the Interconversion of the More into the Less Stable Atropisomer
of Compounds 1-4
compd
solvent
atropisomer ratio
∆Gq (exptl)
∆E (computed)
1 (R ) Me)
2 (R ) Et)
3 (R ) i-Pr)
4 (R ) t-Bu)
CHF2Cl/CHFCl2
CHF2Cl/CHFCl2
CD2Cl2
52/48 (at -150 °C)
53/47 (at -125°C)
55/45 (at -90 °C)
67/33 (at -30 °C)
6.8 ( 0.2
7.9 ( 0.15
9.9 ( 0.15
14.6 ( 0.15
6.7
8.1
10.7
14.8
CD2Cl2
trans atropisomers adopt structures (Figure 4) that correspond
to static C2V and C2h symmetries, respectively. The energies
calculated (ab initio) for the two atropisomers are very
similar, the cis being more stable than the trans by only 0.1
kcal mol-1.9
(Supporting Information), the difference with respect to the
computed value of 93° being due to a slight structural
distortion occurring in the crystal.
Figure 4. Ab initio computed structures of the trans (left) and cis
(right) atropisomers of 4. The relative energies (E) obtained by ab
initio computations are in kcal mol-1. On the top is also displayed
the structure (trans) of 4, as obtained by X-ray diffraction.
1
Figure 3. Experimental (left) and computer-simulated (right) H
NMR spectrum (600 MHz) of the methyl signal of 1 as a function
of temperature in CHF2Cl/CHFCl2.
Whereas in compounds 1-3 the two atropisomers have
very similar populations, in derivative 4 there is a substan-
tially difference in their relative proportions. To achieve a
structural assignment in the latter case, the following ex-
periment was performed.
Single-crystal X-ray diffraction of 4 shows that the crystal
cell comprises two identical molecules (actually four-half
molecules related by a center of symmetry) having the
structure trans. The mentioned dihedral angle is 99.5°
A few crystals of 4, known by X-ray diffraction to contain
only the trans atropisomer, were dissolved at -80 °C in
CD2Cl2 and the spectrum recorded at -90 °C without ever
raising the temperature. From the measured value of the
interconversion barrier (14.6 kcal mol-1, as in Table 1) the
half-life of the atropisomers of 4 is predicted to be almost 2
h at this temperature. Under these conditions, the system has
not had enough time to reach the conformational equilibrium
in solution, so that the observed NMR signals should mainly
correspond to those of the trans form. The relative proportion
of the two NMR signals measured in these conditions (0.51)
is indeed reversed with respect to the value observed at the
equilibrium (2.03, Table 1). In other words, the major signal
(8) In the restricted temperature range where this dynamic process could
be monitored, the free energy of activation was found essentially constant
within the experimental errors, suggesting a negligible value for the
activation entropy, as often observed in conformational processes. See:
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. 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.
(9) Also, Molecular Mechanics calculations (MMX force field as in PC
Model v 7.5, Serena Software, Bloomington, IN) indicate that the cis should
be more stable than the trans atropisomer by 0.2 kcal mol-1
.
Org. Lett., Vol. 7, No. 7, 2005
1293

detected in this experiment corresponds to the minor signal
observed at equilibrium and Vice Versa. On raising the
temperature, the minor signal increases its proportion,
becoming the major one (and the major diminishes becoming
the minor signal) until the equilibrium is eventually attained
(Figure 5). Thus, the cis structure should be assigned to the
The preference for the cis with respect to the trans
atropisomer in solution can be explained on the basis of the
attractive interactions,10,11 which have been observed to affect
conformational equilibria when many-atom groups such as
pairs of tert-butyl groups12 are so distant that they do not
repel each other (in the present case the smallest distance
between the tert-butyl hydrogens is computed to be as large
as 3.4 Å in the cis conformer of 4).
Hindered rotation about biphenyl bonds is the founding
epitome for atropisomerism,13 and since 1922, many ex-
amples have been studied by a range of techniques.14 Sur-
prisingly, the present series represents the first systematic
study of such bonds in compounds with a single ortho
substituent hindering rotation.
Acknowledgment. Financial support from the University
of Bologna (Funds for selected research topics and RFO)
and from MIUR-COFIN 2003, Rome (national project
“Stereoselection in Organic Synthesis”) was received by L.L.
and A.M.
Supporting Information Available: Experimental pro-
cedures and computational data for compounds 1-4. Crystal
data for compounds 1 and 4. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL050091A
Figure 5. 1H NMR (600 MHz in CD2Cl2 at -90 °C) single lines
due to the four equivalent hydrogens of the para-substitued phenyl
group of the cis and trans atropisomers of 4 (at this temperature
the line at 7.162 ppm overlaps some of other aromatic hydrogens
signals). Trace a: spectrum obtained by dissolving 4 at -80 °C
and recorded without ever raising the temperature. Trace b:
spectrum recorded after having raised the temperature for a few
minutes at -70 °C. Trace c: spectrum obtained after equilibration
at room temperature.
(10) (a) Baas, J. M. A.; van der Toorn, J. M.; Wepster, B. M. Recl. TraV.
Chim. Pays-Bas 1974, 32, 133. (b) Lyttle, M. H.; Streitwieser, A., Jr.; Kluttz,
R. Q. J. Am. Chem. Soc. 1981, 103, 3232. (c) Nishio, M.; Hirota, M.
Tetrahedron 1989, 45, 7201.
(11) (a) Anderson, J. E.; Pearson, H.; Rawson, D. J. Chem. Commun.
1973, 95. (b) Anderson, J. E.; Pearson, H. J. Chem. Soc., Perkin Trans. 2
1977, 699. (c) Anderson, J. E.; Bru-Capdeville, V.; Kirsch. P. A.; Lomas,
J. S. Chem. Commun. 1994, 1077. (d) Marzabadi, C. H.; Anderson, J. E.;
Gonzalez-Outeirino, J.; Gaffney, P. R. J.; White, C. G. H.; Tocher, D. A.;
Todaro, L. J. J. Am. Chem. Soc. 2003, 125, 15163.
(12) (a) Carter, R. E.; Nilsson, B.; Olsson, K. J. Am. Chem. Soc. 1975,
97, 6155. (b) Carter, E. R.; Stilbs, P. J. Am. Chem. Soc. 1976, 98, 7515.
(13) Christie, G. H.; Kenner, J. H. J. Chem. Soc. 1922, 121, 614.
(14) Leading references are given in: Eliel, E. L.; Wilen, S. H.
Stereochemistry of Organic Compounds; Wiley-Interscience: New York,
1994; Chapter 14.5.
more stable atropisomer in solution. That the crystal con-
formation is trans implies a more stable crystal lattice when
molecules are in that conformation.
1294
Org. Lett., Vol. 7, No. 7, 2005