Stereolabile and configurationally stable atropisomers of hindered aryl carbinols

Article abstract of DOI:10.1021/jo050382x

Carbinols of the Ar-C(OH)R₂ type, Ar being o-isopropylphenyl, exist as stereolabile syn-clinal (sc) and anti-periplanar (ap) atropisomers when R = Me, Et, i-Pr. In the latter compound, the major atropisomer also comprises two enantiomeric forms that interchange with a barrier of 6.4 kcal mol ^-1. X-ray diffraction, NOE experiments, and ab initio calculations indicate that the sc-atropisomer is the more stable form when R = Me, i-Pr, t-Bu but is the less stable one when R = Et. NMR spectra at variable temperature allowed the determination of the barriers for the interconversion of the sc- into the ap-atropisomers (ΔG? = 7.6, 8.8, and 13.5 kcal mol ^-1 for Me, Et, i-Pr, respectively). When R is a tert-butyl group, the two atropisomers are configurationally stable: the ap-atropisomer is obtained as the kinetic controlled compound, which can be transformed into the thermodynamically more stable sc-atropisomer with a free energy of activation of 29.3 kcal mol^-1. Both atropisomers exhibit restricted rotation of the tert-butyl moiety, the corresponding ΔG? values being 9.4 and 8.8 kcal mol^-1 for the sc- and ap-atropisomer, respectively.

Full text of DOI:10.1021/jo050382x

Stereolabile and Configurationally Stable Atropisomers of
Hindered Aryl Carbinols
Daniele Casarini*
Department of Chemistry, University of Basilicata, Potenza, Italy
Carmine Coluccini,1 Lodovico Lunazzi, and Andrea Mazzanti*
Department of Organic Chemistry “A. Mangini”, University of Bologna, Viale Risorgimento,
4 Bologna 40136, Italy
mazzand@ms.fci.unibo.it
Received March 1, 2005
Carbinols of the Ar-C(OH)R2 type, Ar being o-isopropylphenyl, exist as stereolabile syn-clinal (sc)
and anti-periplanar (ap) atropisomers when R ) Me, Et, i-Pr. In the latter compound, the major
atropisomer also comprises two enantiomeric forms that interchange with a barrier of 6.4 kcal
mol-1. X-ray diffraction, NOE experiments, and ab initio calculations indicate that the sc-atropisomer
is the more stable form when R ) Me, i-Pr, t-Bu but is the less stable one when R ) Et. NMR
spectra at variable temperature allowed the determination of the barriers for the interconversion
of the sc- into the ap-atropisomers (∆Gq ) 7.6, 8.8, and 13.5 kcal mol-1 for Me, Et, i-Pr, respectively).
When R is a tert-butyl group, the two atropisomers are configurationally stable: the ap-atropisomer
is obtained as the kinetic controlled compound, which can be transformed into the thermodynami-
cally more stable sc-atropisomer with a free energy of activation of 29.3 kcal mol-1. Both
atropisomers exhibit restricted rotation of the tert-butyl moiety, the corresponding ∆Gq values being
9.4 and 8.8 kcal mol-1 for the sc- and ap-atropisomer, respectively.
Introduction
stability were identified.3,8 In the case of highly hindered
compounds, having as R substituent the tert-butyl or the
adamantyl moieties, the atropisomers are configuration-
Restricted rotation about the sp2-sp3 bond of Ar-
C(OH)R2 carbinols was detected and the corresponding
barrier measured, by variable temperature NMR spectro-
scopy.2-9 When the Ar moieties do not possess a 2-fold
symmetry axis, two stereolabile atropisomers of different
5-8
ally stable and can be physically isolated.
Here we report the structural, conformational, and
stereodynamic properties of a class of carbinols (com-
pounds 1-4 of Chart 1) having substituents of different
dimensions, so that either stereolabile or configuration-
ally stable atropisomers can be obtained.
(1) In partial fulfillment for a Ph.D. in Chemical Sciences, University
of Bologna.
(2) (a) Newsoroff, G. P.; Sternhell, S. Tetrahedron Lett. 1967, 2539.
(b) Baas, J. M. A.; Sinnema, A. Recl. Trav. Chim. Pays-Bas 1973, 92,
899. (c) Baas, J. M. A.; van der Toorn, J. M.; Wepster, B. M. Recl. Trav.
Chim. Pays-Bas 1974, 93, 173.
Results and Discussion
On lowering the temperature, the H and 13C NMR
1
(3) (a) Landman, D.; Newsoroff, G. P.; Sternhell, S. Aust. J. Chem.
1972, 25, 109. (b) Suezawa, H.; Wada, H.; Watanabe, H.; Yuzuri, T.;
Sakakibara, K.; Hirota, M. J. Phys. Org. Chem. 1997, 10, 925.
(4) Anderson, S.; Drakenberg, T. Org. Magn. Reson. 1983, 21, 730.
(5) (a) Lomas, J. S.; Dubois, J.-E. J. Org. Chem. 1976, 41, 3033. (b)
Lomas, J. S.; Luong, P. K.; Dubois, J.-E. J. Org. Chem. 1977, 42, 3394.
(6) Lomas, J. S.; Dubois, J.-E. Tetrahedron 1981, 37, 2273. Lomas,
J. S.; Vaissermsnn, J. J. Chem. Soc., Perkin Trans. 2 1998, 1777.
Lomas, J. S. J. Chem. Soc., Perkin Trans. 2 2001,754. Lomas, J. S.;
Adenier, A. J. Chem. Soc., Perkin Trans. 2 2002, 1264.
signals of 1-3 broaden and eventually split into two
(7) (a) Anderson, J. E.; Bru-Capdeville, V.; Kirsch. P. A.: Lomas, J.
S. Chem. Commun. 1994, 1077. (b) Lomas, J. S.; Anderson, J. E. J.
Org. Chem. 1995, 60, 3246.
(8) Casarini, D.; Lunazzi, L.; Mazzanti, A. J. Org. Chem. 1997, 62,
3315.
(9) Wolf, C.; Pranatharthiaran, L.; Ramagosa, R. B. Tetrahedron
2002, 43, 8567.
10.1021/jo050382x CCC: $30.25 © 2005 American Chemical Society
Published on Web 05/25/2005
5098
J. Org. Chem. 2005, 70, 5098-5102

Atropisomers of Hindered Aryl Carbinols
CHART 1
SCHEME 1
groups of signals of different intensity, indicating the
existence of two conformational isomers (stereolabile
atropisomers as in Scheme 1). As an example of this
behavior, let us examine the 13C lines due to the two
quaternary aromatic carbons of 1 (R ) Me) as displayed
in Figure 1. From ambient temperature to -50 °C these
two lines are still sharp, but broaden considerably in the
-90° to -120 °C range and split below -130 °C, yielding
two pairs of lines, the intensity ratio within each pair
being 77:23. The two spectra correspond to the anti-
periplanar (ap) and syn-clinal (sc) atropisomers of Scheme
1 (R ) Me).
FIGURE 1. (Left) Temperature dependence of the 13C NMR
signals (150.8 MHz in CHF2Cl/CHFCl2) of the two aromatic
quaternary carbons of compound 1 (R ) Me). (Right) Simula-
tion obtained with the rate constants indicated.
A complete conformational search was carried out by
molecular mechanics (MM) calculations:10 on each of the
two atropisomer structures: the ground-state energy for
the sc-atropisomer of 1 is computed to be lower than that
for the ap-atropisomer by 1.9 kcal mol-1. Ab initio
calculations11 confirm that these structures are real
energy minima because of the absence of imaginary
frequencies in the vibrational analysis. These calculations
too predict that the sc-atropisomer has an energy 1.85
kcal mol-1 lower than that of its ap-counterpart (Figure
2), and for this reason the sc structure was tentatively
assigned to the more stable of the two atropisomers in
solution.12 Support of this conclusion is offered by the
FIGURE 2. Ab initio computed structures of the ap- and sc-
atropisomers of 1 (the energy values E are in kcal mol-1). The
experimental structure of the sc-atropisomer, obtained by
X-ray diffraction, is also reported. With the exception of the
CH hydrogen of the o-isopropyl substituent (green), the
hydrogen atoms are omitted for convenience.
X-ray diffraction of 1, which shows how the structure
determined in the crystalline state corresponds to that
of the sc-atropisomer (Figure 2).
(10) MMFF force field, as implemented in Titan 1.0.5, Wavefunction
Inc., Irvine, CA. A Monte Carlo algorithm (version 1.0.3) was used for
locating the global minima.
According to calculations, the minor ap-atropisomer
has a molecular plane of symmetry coincident with that
of the phenyl ring (Figure 2, left), thus accounting for
(11) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.;
Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.;
Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson,
G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.;
Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai,
H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken,
V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev,
O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P.
Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.;
Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas,
O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.;
Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov,
B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.;
Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.;
Gonzalez, C.; Pople, J. A. Gaussian 03, Revision C.02; Gaussian, Inc.:
Wallingford, CT, 2004.
1
the observed equivalence at any temperature of the H
and 13C NMR signals due to the enantiotopic methyl
groups bonded to the C-OH moiety. On the contrary, the
major sc-atropisomer (Figure 2, center and right) has the
O-C-C1 plane (C1 being the phenyl carbon ortho to the
isopropyl substituent) twisted with respect to that of the
phenyl ring, the corresponding dihedral angle being 44°
(MM), 46° (ab initio), or 52.2° (X-ray). Such a structure
is therefore asymmetric, thus chiral, and indeed the 16
molecules comprised in the crystal cell (Supporting
Information) have opposite M and P configurations (eight
molecules for each configuration). The methyl groups
bonded to the C-OH moiety are therefore diastereotopic
in the solids, yet they yield a single line in the NMR
solution spectrum, even at -150 °C. This indicates that
the interconversion of the two M and P enantiomers of
(12) According to the calculated energy difference between the two
atropisomers of 1 (and of 3 as well), the population of the minor form
should be negligible: the agreement with the NMR experiment is
therefore only qualitative. On the other hand, the computed energy
difference in the case of 2 and 4 (Table 1) matches the NMR
experiment, since the populations of the minor forms are predicted to
be =30% and 0%, respectively, as observed.
J. Org. Chem, Vol. 70, No. 13, 2005 5099

Casarini et al.
TABLE 1. Interconversion Barriers (∆Gq in kcal mol-1), Atropisomer Ratio, and Ab Initio Computed Energy Difference
(kcal mol-1) for Compounds 1-4
∆Gq
compd (R)
sc/ap ratio
solvent
sc to ap
ap to sc
Eap - Esc
1 (Me)
2 (Et)
3 (i-Pr)
4 (t-Bu)
77/23 (at -131 °C)
35/65 (at -115 °C)
88/12 (at -45 °C)
100/0 (at 100 °C)
CHF2Cl/CHFCl2
CHF2Cl
CHF2Cl/CHFCl2
C2Cl4
7.6
8.8
13.5
-
7.35
9.0
12.6
29.3
1.85
-0.3
2.2
6.75
the sc-atropisomer is very rapid in solution in that the
passage of the OH group across the o-isopropyl substitu-
ent involves a rather low barrier. The corresponding
computed value is indeed too small (3.2 or 3.6 kcal mol-1
according to MM or ab initio calculations, respectively)
to allow detection of different NMR signals for the
mentioned methyl groups at any attainable temperature.
In other words, such a fast motion generates, in practice,
a dynamic plane of symmetry that makes these methyl
groups appear equivalent (enantiotopic) in solution.
The interconversion rates of the more into the less
stable atropisomer of 1 were determined by line shape
simulation at different temperatures, as shown in Figure
1: the corresponding free energy of activation13 could
thus be obtained (∆Gq ) 7.6 ( 0.15 kcal mol-1, as in Table
1). Such a process requires the passage of one methyl
group across the o-isopropyl susbstituent: the energy
calculated for this transition state with respect to the sc
ground state of 1 (7.0 and 7.1 kcal mol-1 in the MM and
ab initio computations, respectively) is in good agreement
with the experiment.
Analogous results were obtained for derivatives 2 (R
) Et) and 3 (R ) i-Pr), where the interconversion barriers
were found to increase regularly because of the larger
steric requirements: the corresponding interconversion
barriers and atropisomer ratios are collected in Table 1.
It should be pointed out that in the case of 2 (R ) Et)
the ratio is reversed, in that to the major atropisomer
the ap structure has been assigned. To understand on
which ground an opposite stability was attributed to the
atropisomers of 2, it is necessary to illustrate how the
experimental assignment was achieved in the case of
compounds 3 and 4.
FIGURE 3. NOE experiments (600 MHz at -80 °C in CD2-
Cl2) carried out by excitation of the CH multiplet of the o-
isopropyl group of the minor and major atropisomer of
compound 3 (traces b and c, respectively). The control spectrum
in the region 1.6-4.6 ppm (trace a) is also reported.
fact expected that these atropisomers are sufficiently long
living at -80 °C to prevent the occurrence of saturation
transfer effects.14 Excitation of the CH multiplet of the
o-isopropyl substituent in the major atropisomer en-
hances the corresponding OH line (trace c of Figure 3).
Excitation of the same hydrogen signal in the minor
atropisomer enhances the corresponding CH multiplet
of the two isopropyl groups bonded to C-OH (trace b of
Figure 3). This means that for the major atropisomer the
structure must be of the sc type and in the minor of the
ap type.
As a consequence of the proximity of the OH group,
the shift of the CH multiplet of the o-isopropyl substitu-
ent of 3 is at lower field in the major sc-atropisomer (4.45
ppm) than in the minor ap-atropisomer (3.38 ppm). The
same trend had been also observed in the case of 1 (R )
Me), where the assignment of the sc-atropisomer relied
on the X-ray diffraction data (the corresponding o-
isopropyl CH hydrogen has the shift of the sc-atropisomer
at 4.7 and that of the ap-atropisomer at 3.8 ppm). Again
in the case of 4 (see further), the unambiguously assigned
(NOE experiments15,16) sc-atropisomer has the signal of
the mentioned CH hydrogen downfield (4.56 ppm) with
respect to that of the ap-atropisomer (3.54 ppm). The
trend of these shifts can thus be used as a criterion for
Unambiguous assignment of the structure of the two
atropisomers could be obtained in the case of 3 (R ) i-Pr)
by making use of NOE experiments carried out at -80
°C. On the basis of the measured barrier of 3, it is in
(13) In the restricted temperature range where this dynamic process
could be monitored, the free energy of activation was found to be
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.
(14) At -50 °C there is still a saturation transfer effect, since
irradiation of the o-isopropyl CH signal of the major atropisomer affects
also the corresponding signal of the minor atropisomer and vice versa.
On the contrary, at -80 °C this effect had disappeared, as clearly
evident from Figure 3, where saturation of the major CH signal leaves
unaffected the minor one (trace c) and likewise saturation of the minor
leaves the major signal unaffected (trace b).
5100 J. Org. Chem., Vol. 70, No. 13, 2005

Atropisomers of Hindered Aryl Carbinols
FIGURE 5. Ab initio computed structures of the two enan-
tiomeric forms of the sc-atropisomer of compound 3. With the
exception of the CH hydrogen of the three isopropyl substit-
uents (green), the hydrogen atoms are omitted for convenience.
FIGURE 4. (Left) Temperature dependence of the 13C NMR
(150.8 MHz in CHF2Cl/CHFCl2) signals of the methine carbons
of the two isopropyl groups bonded to the C-OH moiety of 3.
(Right) Simulation obtained with the rate constants indicated.
Compound 4, which bears two tert-butyl substituents,
is hindered enough as to yield, in principle, two configu-
rationally stable atropisomers. The reaction (see Experi-
mental Section) produced, however, only one atropisomer
(indicated as 4b), to which the ap configuration was
unambiguously assigned by means of NOE experiments
(Supporting Information).15 When a tetrachloroethylene
solution of 4b is kept overnight at 100 °C, a complete
interconversion into the sc-atropisomer 4a was obtained
(the sc-configuration was also confirmed by means of
NOE experiments16). This indicates that the latter is the
thermodynamically more stable atropisomer, whereas
the ap-atropisomer 4b is the result of a kinetic prefer-
ence.
The transformation rate of the ap- into the sc-atropi-
somer (i.e. 4b into 4a) was followed at 100 °C by
monitoring the time-dependent variation of the relative
intensities of the NMR spectra in C2Cl4. From the rate
constant obtained in this way (k ) 5 × 10-5 s-1) a ∆Gq
value of 29.3 kcal mol-1 (Table 1) was derived.
Both the sc- (4a) and ap-atropisomers (4b) exhibit
restricted rotation of the tert-butyl groups. For example,
the single 13C line of the methyl carbons broadens on
cooling and finally splits into three equally intense
signals below -130 °C (Supporting Information). The
rotational barriers derived by line shape simulation are
slightly different, being 9.4 and 8.8 kcal mol-1 for 4a and
4b, respectively.
As is plausible, MM and ab initio calculations predict
that one tert-butyl group is not eclipsed but staggered
with respect to the other; in other words, the three Me-C
bonds of one tert-butyl group are rotated by 30° with
respect to those of the other. When the rotation is frozen,
such an arrangement would yield six 13C methyl lines
(and two quaternary carbon lines as well) for each
atropisomer, contrary to the experimental evidence. To
account for the experimental observation, a fast oscilla-
tory motion (libration process) that exchanges the recip-
rocal positions of the two tert-butyl methyl groups must
take place. It is reasonable to expect that the barrier for
such a motion is much lower than that for the rotation
required to exchange the three methyl groups within each
of the two tert-butyl moieties, and thus is NMR invisible.
Indeed MM calculations confirm that the barriers for this
libration process are as low as 3.9 and 3.5 kcal mol-1 for
the sc- and ap-atropisomers, respectively.
identifying the atropisomers: in the case of 2, the major
(65%) signal of the o-isopropyl CH multiplet is, on the
contrary, upfield (3.3 ppm) with respect to the minor one
(4.2 ppm), indicating that the more stable atropisomer
of 2 has the ap structure. Furthermore, the same ab initio
computations that had indicated the sc-atropisomer to
be the more stable form in 1, 3, and 4 predict that the
ap-atropisomer has an energy lower by 0.3 kcal mol-1
than that of the sc-atropisomer of 2 (Table 1). What
causes the inversion of the stability of the atropisomers
of 2 with respect to those of 1, 3, and 4 is still unclear.
The major sc-atropisomer of 3 undergoes a second
dynamic process, which was detected by cooling the
sample at even lower temperatures. The 13C signals of
the CH3 and CH carbons of the two isopropyl groups
bonded to the C-OH moiety broaden and eventually
split, displaying four lines of equal intensity for the
methyl and two lines of equal intensity for the methine
carbons at -149 °C (Figure 4). This proves that the
rotation of the two isopropyl groups has been frozen
and, in addition, that the molecule has adopted an
asymmetric, thus chiral, conformation. Ab initio calcula-
tions11 confirm that the global energy minimum for the
sc-atropisomer of 3 corresponds to a structure where the
C-H bonds of the two isopropyl groups point into
opposite directions (Figure 5), thus making all six cor-
responding carbons diastereotopic. The temperature
dependence of the 13C signals of the two isopropyl CH
carbons is displayed in Figure 4, and from the measured
rate constants the barrier for the interconversion of the
two enantiomers of Figure 5, brought about by the
rotation of the isopropyl groups, was determined (∆Gq )
6.4 ( 0.15 kcal mol-1).13
(15) Excitation of the tert-butyl line enhances, in addition to the OH
line, the methine and methyl signals of the o-isopropyl substituent,
and likewise, excitation of the methine signal of the latter substituent
enhances the line of the tert-butyl groups but not that of the OH. On
the other hand, excitation of the OH line enhances the tert-butyl line
and also one CH aromatic signal, but does not have any effect on the
signals of the o-isopropyl substituent. This proves that the OH group
is directed away from the o-isopropyl substituent (hence ap-atropiso-
mer).
(16) Excitation of the OH line enhances, in addition to the tert-butyl
line, both the methine and methyl signals of the o-isopropyl substituent
(but does not have any effect on any aromatic hydrogen signals), and
likewise, excitation of the CH multiplet enhances the OH line. This
indicates that the OH group is directed toward the o-isopropyl
substituent (hence the sc-atropisomer).
J. Org. Chem, Vol. 70, No. 13, 2005 5101

Casarini et al.
8.03 (1H, m); 13C NMR (CDCl3, 150.8 MHz) δ 26.0 (CH3), 30.3
(CH3), 31.4 (CH), 42.6 (Cq), 87.4 (Cq), 125.1 (CH), 126.5 (CH),
127.7 (CH), 129.8 (CH), 144.4 (Cq), 146.8 (Cq). Anal. Calcd
for C18H30O: C, 82.38; H, 11.52. Found C, 82.03; H, 11.45.
3-(2-Isopropylphenyl)-2,2,4,4-tetramethylpentan-3-ol
(4a), sc-Atropisomer. A tetrachloroethylene solution of 4b
was kept overnight at 100 °C to yield quantitatively the
sc-atropisomer 4a: mp 60 °C; 1H NMR (CDCl3, 600 MHz) δ
1.14 (18H, s, t-Bu), 1.20 (6H, d, J ) 6.9 Hz), 1.97 (1H, s, OH),
4.56 (1H, eptet, J ) 6.9), 6.99 (1H, m), 7.16 (1H, m), 7.35 (1H,
m), 7.47 (1H, m); 13C NMR (CDCl3, 150.8 MHz) δ 25.2 (CH3),
29.2 (CH), 30.0 (CH3), 43.4 (2Cq), 88.6 (Cq), 122.2 (CH), 125.9
(CH), 127.6 (CH), 129.8 (CH), 141.3 (Cq), 149.6 (Cq). Anal.
Calcd for C18H30O: C, 82.38; H, 11.52. Found C, 82.17; H,
11.41.
NMR Measurements. NMR spectra were recorded at 300,
400, or 600 MHz for 1H and 75.4, 100.6, or 150.8 MHz for 13C.
The assignments of the 13C signals were obtained by DEPT
and 2D experiments (gHSQC sequence). The NOE experiments
were obtained by means of the DPFGSE-NOE sequence18 using
a “rsnob” selective pulse (typically 37 ms) and a mixing time
of 2.0 s at ambient temperature or 0.8 s at -80 °C. The samples
for the 13C NMR low-temperature measurements were pre-
pared by connecting to a vacuum line the NMR tubes contain-
ing the compound and some C6D6 for locking purpose and
condensing therein the gaseous CHF2Cl and CHFCl2 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 substitut-
ing the sample with a precision Cu/Ni thermocouple before
the measurements. Complete fitting of dynamic NMR line
shapes was carried out using a PC version of the DNMR-6
program.19 At least five different temperature spectra were
used for the simulations.
Computations. A complete conformational search, using
molecular mechanics (MMFF force field10), was performed to
locate the global minima of the two atropisomers of 1-4; ab
initio computations were carried out on these structures at
the B3LYP/6-31G(d) level by means of the Gaussian 03 series
of programs11 (the standard Berny algoritm in redundant
internal 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 optimized structures are re-
ported in the Supporting Information.
Experimental Section
Materials. 2-(2-Isopropylphenyl)propan-2-ol (1).17 1-Bro-
mo-2-isopropylbenzene (5 mmol in 15 mL of dry THF) was
added to a suspension of Mg (5 mmol) and I2 in 15 mL of dry
THF. After warming for 30 min, the solution was stirred for
additional 60 min at room temperature and then treated with
propan-2-one (5 mmol in 15 mL of dry THF). After stirring
for 3 h, the mixture was treated with H2O, extracted with
ether, and dried (Na2SO4). After removing the solvent, the
crude product was purified by a silica gel chromatography
column (petroleum ether/Et2O 9/1) to give 1 (2.9 mmol, overall
yield 58%). Crystals suitable for X-ray diffraction were ob-
tained from absolute ethanol: mp 65 °C; 1H NMR (CDCl3, 400
MHz) δ 1.25 (6H, d, J ) 6.9 Hz), 1.68 (6H, s), 1.75 (1H, s, OH),
3.88 (1H, eptet, J ) 6.9 Hz), 7.10 (1H m), 7.26 (1H, m), 7.38
(1H, m), 7.42 (1H, m); 13C NMR (CDCl3, 100.6 MHz) δ 24.7
(2CH3), 29.2 (CH), 31.6 (CH3), 73.5 (Cq), 124.8 (CH), 125.2
(CH), 127.3 (CH), 127.7 (CH), 144.2 (Cq), 148.0 (Cq). Anal.
Calcd for C12H18O: C, 80.85; H, 10.18. Found. C, 80.05; H,
10.07.
3-(2-Isopropylphenyl)pentan-3-ol (2). BuLi (3.1 mL, 1.6
M) in hexane was added to solution of 1-bromo-2-isopropyl-
benzene (5 mmol in 15 mL of dry THF) at -78 °C. The solution
was stirred for 60 min and then treated with pentan-3-one (5
mmol in 15 mL of dry THF). After stirring for 10 min, the
mixture was warmed to 25 °C and treated with H2O, extracted
with ether, and dried (Na2SO4). After removing the solvent,
the crude was purified by a silica gel chromatography column
(petroleum ether/Et2O 19/1) to give 2 (2.5 mmol, overall yield
50%): 1H NMR (CDCl3, 300 MHz) δ 0.78 (6H, t), 1.21 (6H, d,
J ) 6.9 Hz), 1.89 (2H, m), 2.01 (2H, m), 3.67 (1H, eptet, J )
6.9 Hz), 7.14 (1H, m), 7.22 (1H, m), 7.33 (1H, m), 7.42 (1H,
m); 13C NMR (CDCl3, 75.4 MHz) δ 8.3 (CH3), 22.5 (Cq), 24.7
(CH3), 29.4 (CH2), 33.9 (CH3), 78.5 (Cq), 125.0 (CH), 126.9 (CH),
127.0 (CH), 127.4 (CH), 141.2 (Cq), 147.0 (Cq). Anal. Calcd
for C14H22O: C, 81.50; H, 10.75. Found. C, 80.67; H, 10.63.
3-(2-Isopropylphenyl)-2,4-dimethylpentan-3-ol (3). BuLi
(3.1 mL, 1.6 M) in hexane was added to solution of 1-bromo-
2-isopropylbenzene (5 mmol in 15 mL of dry THF) at -78 °C.
The solution was stirred for 60 min and treated with 2,4-
dimethylpentan-3-one (5 mmol in 15 mL of dry THF). After
stirring for 10 min, the mixture was warmed to 25 °C, treated
with H2O, extracted with ether, and dried (Na2SO4). After
removing the solvent, the crude was purified by a silica gel
chromatography column (petroleum ether/Et2O 9/1) to give 3
(1.9 mmol, overall yield 38%): 1H NMR (CDCl3, 600 MHz) δ
0. 78 (6H, bd), 0.94 (6H, bd), 1.21 (6H, d, J ) 6.8 Hz), 1.59
(1H, s, OH), 2.38 (2H, bs), 4.48 (1H, bs), 7.07 (2H, bs), 7.18
(1H, bt), 7.37 (1H, bd); 13C NMR (CDCl3, 150.8 MHz) δ 16.8
(CH), 17.9 (CH), 25.3 (2 CH3), 29.2 (CH), 35.5 (CH3), 85.2 (Cq),
124.0 (CH), 126.3 (CH), 127.4 (CH), 127.9 (CH), 138.2 (Cq),
150.6 (Cq). Anal. Calcd for C16H26O: C, 81.99; H, 11.18. Found
C, 81.16; H, 11.07.
Acknowledgment. Financial support from the Uni-
versity 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.
3-(2-Isopropylphenyl)-2,2,4,4-tetramethylpentan-3-ol
(4b), ap-Atropisomer. t-BuLi (3.1 mL, 1.5 M) in pentane was
added to a solution of 1-bromo-2-isopropylbenzene (5 mmol in
15 mL of dry THF) at -78 °C. The solution was stirred for 60
min and then treated with 2,2,4,4-tetramethylpentan-3-one (5
mmol in 15 mL of dry THF). After stirring for 10 min, the
mixture was warmed to 25 °C, treated with H2O, extracted
with ether, and dried (Na2SO4). After removing the solvent,
the crude was purified by a silica gel chromatography column
(petroleum ether/Et2O 9/1) to give 4b (2.2 mmol, overall yield
Supporting Information Available: Crystal data for
compound 1, temperature dependence of the 13C NMR spectra
and NOE experiments for 4a and 4b, and computational data
for compounds 1-4. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO050382X
(18) (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.
1
44%): mp 58 °C; H NMR (CDCl3, 600 MHz) δ 1.15 (18H, s,
t-Bu), 1.30 (6H, d, J ) 6.7 Hz), 1.98 (1H, s, OH), 3.54 (1H,
eptet, J ) 6.7 Hz), 7.13 (1H, m), 7.21 (1H, m), 7.37 (1H, m),
(17) Brown, H. C.; Brady, J. D.; Grayson, M.; Bonner, W. H. J. Am.
Chem. Soc 1957, 79, 1897.
(19) PC version of the QCPE program no. 633, Indiana University,
Bloomington, IN.
5102 J. Org. Chem., Vol. 70, No. 13, 2005