Conformation and stereodynamics of symmetrically ortho-disubstituted aryl carbinols and aryl ethers

Article abstract of DOI:10.1021/jo062289u

(Chemical Equation Presented) By making use of low-temperature dynamic NMR spectroscopy, the rotation barriers about the sp³-sp² bond have been determined in a number of hindered benzyl alcohols symmetrically substituted in the ortho

Full text of DOI:10.1021/jo062289u

Conformation and Stereodynamics of Symmetrically
Ortho-Disubstituted Aryl Carbinols and Aryl Ethers
Daniele Casarini,† Lodovico Lunazzi,‡ Michele Mancinelli,‡,1 and Andrea Mazzanti*,‡
Department of Chemistry, UniVersity of Basilicata, Potenza, Italy, and Department of Organic Chemistry
“A. Mangini”, UniVersity of Bologna, Viale Risorgimento, 4 Bologna 40136, Italy
mazzand@ms.fci.unibo.it
ReceiVed NoVember 6, 2006
By making use of low-temperature dynamic NMR spectroscopy, the rotation barriers about the sp3-sp2
bond have been determined in a number of hindered benzyl alcohols symmetrically substituted in the
ortho positions, the substituents being F, Cl, Br, and Me. The free energies of activation covered the
range 4.6-10.1 kcal mol-1. Ab initio computations matched satisfactorily the trend of these values and
predicted the conformation adopted by these compounds. In one case, this result could be also confirmed
by the X-ray diffraction structure. In the case of the corresponding methyl ethers two barriers could be
measured, corresponding to the passage across two distinguishable transition states: the higher barriers
covered the range 5.0-8.1 kcal mol-1 and the lower ones the range 4.7-6.2 kcal mol-1.
Introduction
detected and their structure assigned.3,8 In the case of very
crowded derivatives bearing, as substituents, the tert-butyl or
the adamantyl groups, the atropisomers could be also separated.5-8
The majority of the compounds studied so far had the aryl
moiety substituted by one or by two different groups. Here we
present an investigation about aryl carbinols bearing two equal
substituents in the ortho positions, as those shown in Chart 1.
In this type of derivative, four possible situations could, in
principle, be considered: in Scheme 1 are displayed, as an
example, the possible conformers one might expect in the case
of compounds 1-4 (R ) Me). In order to decide whether they
actually correspond to ground-state structures, theoretical cal-
culations were employed. The theoretical approach is also
helpful for providing indications about the relative stability of
these conformers.
Restricted rotation about the bond connecting the aryl groups
with the sp3 carbon atoms has been observed in a variety of
aryl carbinols, and the corresponding barriers were determined
by means of variable-temperature NMR spectroscopy.2-10 In
particular, when the aryl moiety does not exhibit a 2-fold
symmetry axis two atropisomers with different populations were
† University of Basilicata.
‡ University of Bologna.
(1) In partial fulfillment for the Ph.D. in Chemical Sciences, University
of Bologna.
(2) Newsoroff, G. P.; Sternhell, S. Tetrahedron Lett. 1967, 8, 2539. Baas,
J. M. A.; Sinnema, A. Recl. TraV. Chim. Pays-Bas 1973, 92, 899. Baas,
J. M. A.; van der Toorn, J. M.; Wepster, B. M. Recl. TraV. Chim. Pays-
Bas 1974, 93, 173.
(3) Landman, D.; Newsoroff, G. P.; Sternhell, S. Aust. J. Chem. 1972,
25, 109. 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.; Vaissermann, 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.
(7) Anderson, J. E.; Bru-Capdeville, V.; Kirsch. P. A.; Lomas, J. S. Chem.
Commun. 1994, 1077. 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.; Pranatharthiharan, L.; Ramagosa, R. B. Tetrahedron Lett.
2002, 43, 8563.
(10) Casarini, D.; Coluccini, C.; Lunazzi, L.; Mazzanti, A. J. Org. Chem.
2005, 70, 5098.
10.1021/jo062289u CCC: $37.00 © 2007 American Chemical Society
Published on Web 01/12/2007
998
J. Org. Chem. 2007, 72, 998-1004

Symmetrically Ortho-Disubstituted Aryl Carbinols and Aryl Ethers
CHART 1
SCHEME 1
FIGURE 1. Temperature dependence (left) of the 19F NMR signal
(564.3 MHz) of compound 1 in CHF2Cl/CHFCl2. The shifts are referred
to the signal of C6F6 at -163 ppm. On the right is displayed the
simulation obtained with the rate constants indicated.
SCHEME 2. Schematic Energy Profile of 1 (E in kcal
mol-1) as a Function of the Dihedral Angle T between the
Aromatic Ring and the Plane of the C1-C-O Moiety
Results and Discussion
Ab initio11 computations (and Molecular Mechanics12 as well)
of 1 (X ) F, R ) Me) indicate that the conformations of type
C (anticlinal13) and D (synclinal13) do not correspond to energy
minima (actually they represent transition states14) and that the
minimum corresponding to conformation A (synperiplanar13)
has an energy higher (by 0.65 kcal mol-1, according to ab initio)
than that of conformation B (synclinal13), indicating that the
latter should be the more populated species at low temperature.
The asymmetry of the most stable conformer B implies the
existence of two enantiomeric forms (+sc and -sc), but the
barrier for their interconversion, involving the passage through
the scarcely populated conformer A (sp), is predicted to be very
low: for instance, the ab initio computed value for 1 is 3.15
kcal mol-1, as shown in Scheme 2.15
Such a low barrier does not allow the corresponding enan-
tiomerization process to be frozen in an NMR experiment in
the case of 1, so that, even at the lowest attainable temperature,
a dynamic Cs symmetry (i.e., the same type of symmetry
displayed by the syn periplanar conformer A) will be actually
observed. Thus, the two methyl groups of 1 will appear
equivalent (enantiotopic) in the NMR time scale, even when
the atoms in the ortho and meta positions become diastereotopic.
The low-temperature 19F spectra of 1 (Figure 1) show indeed
how the single signal of the two ortho fluorine atoms broadens
on cooling and eventually decoalesces at -169 °C into a pair
of partially overlapping signals exhibiting a quite different line
width:16 their integrated intensities indicate that the ratio is 1:1.14
From the rate constants derived from line shape simulation,17
the free energy of activation (∆Gq ) 4.6 ( 0.3 kcal mol-1) for
the rotation that makes the ortho positions equivalent (homo-
topic) could be obtained.18 The corresponding ab initio calcu-
lated barrier is 5.0 kcal mol-1 (Scheme 2), a value in good
agreement with the experiment. These calculations indicate that
(11) Program 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.
(12) MMX force field as in PC Model v 7.5, Serena Software,
Bloomington, IN.
(13) Eliel, L. E.; Wilen, S. H.; Stereochemistry of Organic Compounds;
John Wiley and Sons: New York, 1994; p 21.
(14) This result is at variance with the hypothesis of Schaefer et al.,
which arbitrarily assumed conformation C to be the ground state. See:
Schaefer, T.; Sebastian, R.; Penner, G. H.; Salman, S. R. Can. J. Chem.
1986, 64, 1602.
(15) As shown in Scheme 2, the computed dihedral angle between the
aromatic ring and the plane defined by the C1-C-O moiety of 1 is 48°
for the most stable conformer B and 28° for the transition state intercon-
verting B into A, i.e., the process which is responsible for the too fast
interconversion of the +sc and -sc enantiomers.
(16) Also, the ortho and meta 13C signals of 1 should likewise split into
a pair of lines: this feature, however, was not observed since the
corresponding shift separations were smaller than the line width, which is
very broad below -160 °C.
(17) PC version of QCPE program DNMR 6 no. 633, Indiana University,
Bloomington, IN.
(18) The relatively large experimental error of the barrier of 1 ((0.3
kcal mol-1) is a consequence of the great uncertainty in determining the
intrinsic line width of the two 19F lines at such low temperatures.
J. Org. Chem, Vol. 72, No. 3, 2007 999

Casarini et al.
the conformer B (sc),19 a result in agreement with the corre-
sponding 13C spectrum (Supporting Information, Figure S-1).
At a temperature of -172 °C, in fact, the methylene carbon
signal of 5 appears as a single line superimposed to a pair of
equally intense lines, the single line being more intense (about
80%) than the other ones (10% each). The single major line
thus corresponds to the two CH2 carbons of the equivalent
(enantiotopic) ethyl groups of conformer A (sp), whereas the
two distinct lines with lower intensity are due to the two CH2
carbons of the diastereotopic ethyl groups of conformer B (sc)
of Scheme 1.20
In the case of compounds without fluorine substituents, the
exchange process was followed by monitoring the decoalescence
of the 13C signals of the quaternary ortho and CH meta carbons:
21
Figure 3 displays, for instance, the temperature dependence
of these lines in the case of derivative 2 (X ) Cl, R ) Me). In
Table 1 are collected the barriers,22 measured by line shape
simulation,17 for all of the compounds investigated.
As in the case of 1 and 2, also in the other methyl alcohols
investigated (3 and 4), the 13C signals of the methyl groups
bonded to the COH moiety remained equivalent (enantiotopic)
at any attainable temperature, in agreement with the mentioned
expectation of the related enantiomerization process having a
barrier too low to be experimentally detected.
It should be pointed out that, according to calculations, the
ground state (i.e., the B-type conformer of Scheme 1) of
compounds 3 and 4 (X ) Br and Me, respectively) has a value
for the dihedral angle ϑ between the aryl ring and the C1-
(19) The inversion of the relative stability of two conformers when the
ethyl groups substitute the methyl groups had been well documented in
analogous cases (see ref. 10).
FIGURE 2. Temperature dependence of the 19F NMR signal (564.3
MHz) of compound 5 in CHF2Cl/CHFCl2. The shifts are referred to
the signal of C6F6 at -163 ppm.
(20) The interconversion between the two conformers of type A and B
also involves a simultaneous rearrangement of the two ethyl groups: such
a rearrangement contributes to determine the value of the measured barrier
of 5 kcal mol-1 (the corresponding ab initio computed barrier of 4.4 kcal
mol-1 agrees well with the experiment). In the more stable conformer of
type A, in fact, the two ethyl groups adopt a symmetric relative disposition
(see the computed structure in the Supporting Information, Figure S-2), in
agreement with the observation of a single CH2 line in the mentioned 13C
spectrum at the -172 °C. In the less stable conformer of type B, on the
other hand, one of the two ethyl groups adopts a disposition different form
that of its companion (also this the computed structure is displayed in the
Supporting Information, Figure S-2). The existence of symmetric and
asymmetric conformers due to the relative disposition of two ethyl groups
has been also detected by supersonic jet mass resolved excitation spectros-
copy (see: Breen, P. J.; Bernstein, E. R.; Seeman, J. I. J. Chem. Phys.
1987, 87, 3269). A situation analogous to the present one had been also
observed in the case of 3-(1-naphthyl)pentan-3-ol.8
the transition state for this process corresponds to the structure
C (anticlinal), as shown in the rotation pathway reported in
Scheme 2.
The larger width observed at -169 °C (Figure 1) for one of
the two 19F signals might suggest that the process which
interconverts the unequally populated conformers A (sp) and
B (sc) of Scheme 1 has a rate sufficiently slow for broadening
this line, but still too fast to show the expected decoalescence,
in agreement with the quite low computed barrier of 3.15 kcal
mol-1 predicted for 1 (Scheme 2). According to this interpreta-
tion, the greater steric hindrance of the corresponding ethyl
derivative 5 should make possible the detection of this second
process at an attainable temperature. Indeed, Figure 2 shows
that at -120 °C the two fluorine atoms of 5 display two equally
intense lines, due to the freezing of the same rotation process
observed in 1, the corresponding barrier being higher than that
of 1, as anticipated (6.9 rather than 4.6 kcal mol-1). On further
cooling, these lines broaden selectively, as observed in the case
of 1, but now they split into a pair of unequally populated peaks
at -163 °C (Figure 2). These signals correspond, therefore, to
the conformers B (sc) and A (sp) of derivative 5, their relative
proportion being approximately 80:20. Line shape simulation
yields the free energy of activation required to interconvert the
major into the minor conformer (5.0 kcal mol-1).
(21) Owing to the poor solubility of 4 and 11 at temperatures lower than
1
-120 °C, these barriers were measured by monitoring the H signal (600
MHz) of the o-methyl substituents.
(22) As often observed in conformational process, the ∆Gq value was
found independent of temperature within the experimental uncertainty of
the NMR measurements. 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. 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.
Contrary to the case of 1, ab initio computations predict that
the conformer A (sp) of 5 is 0.47 kcal mol-1 more stable than
1000 J. Org. Chem., Vol. 72, No. 3, 2007

Symmetrically Ortho-Disubstituted Aryl Carbinols and Aryl Ethers
is lower than that of the chlorine atom. This is in a qualitative
agreement with the trend recently reported24 for a pair of ortho-
substituted biphenyl derivatives, where the Ar-Ar rotation
barrier was found slightly lower for the methyl than for the
chlorine substituent (i.e., 7.4 vs 7.7 kcal mol-1, respectively).25
The present finding is at variance with the trend of the van
der Waals radii indicated by Bondi,23 who proposed a larger
value for methyl with respect to chlorine (i.e., 2.0 vs 1.75), but
is in keeping with that proposed by Charton,26 if the minimum
van der Waals radius for methyl is taken into account (i.e., 1.715
for methyl vs 1.75 for chlorine).
As previously mentioned, the process that would make
diastereotopic the methyl groups is too fast in the alcohols 1-4
to be experimentally observed. However, if the OH is substituted
by the OMe group (as in compounds 9-12 of Chart 2), the
greater steric requirement should increase the corresponding
barrier, making this process amenable to an experimental
detection. This prediction is supported by Molecular Mechanics
calculations12 of the energy surface as function of the previously
defined dihedral angle ϑ (related to the torsion about the Ar-
C(Me2) bond, and of the dihedral angle æ formed by the C1-
C(Me2)-O and (Me2)C-O-Me planes (this angle is related to
the torsion about the C-OMe bond). As an example, such a
surface is displayed in Figure 5 for the case of 10 (X ) Cl).
The computed barrier involving the transition state which
renders diastereotopic the ortho and meta positions (full square
in Figure 5) is larger than that involving the transition state
which renders diastereotopic the two methyl groups (full circle
in Figure 5): the more accurate ab initio computations (Table
FIGURE 3. Left: temperature dependence of the 13C signals (150.8
MHz in CHF2Cl/CHFCl2) of the two quaternary ortho and of the two
CH meta carbons of 2. Right: simulation obtained with the rate
constants indicated.
2) indicate these two values to be 9.4 and 5.5 kcal mol-1
,
respectively.27 These calculations therefore support the hypoth-
esis that even the lower of these two barriers should be
sufficiently high for obtaining an experimental determination
(barriers larger than 4 kcal mol-1, in fact, are amenable to NMR
measurements28).
C-O plane smaller than 30°. Rather than 48° as in 1 or 40° as
in 2, this angle is predicted to be 18° in 3 and 27° in 4: for this
reason, the corresponding conformer B should be indicated, in
these cases, as syn periplanar (sp) rather than synclinal (sc).13
Single-crystal X-ray diffraction of 4 (Figure 4, left) shows
indeed that the dihedral angle ϑ between the average plane
defined by the aryl group (the shape of the aromatic ring deviates
from a perfect planarity by 6° in the crystal) and that identified
by the C1-C-O moiety is 24°, a value very close to that (ϑ )
27°) computed for the isolated molecule (Figure 4, right).
In the case of compounds 3 and 4, computations also indicate
that the A-type conformer of Scheme 1 (i.e., that having ϑ )
0°) corresponds to a low energy transition state rather than a
ground state, as in 1 and 2. Consequently, the corresponding
energy profile is of the type displayed, as an example, in Scheme
3 for the case of 4 (R ) X ) Me).
The temperature dependence of the 13C signals of 10 (X )
Cl), reported in Figure 6, shows that at -144 °C the single lines
of the two ortho and of the two meta carbons split into 1:1
pairs, since the same type of process observed in the corre-
sponding alcohol 2 has been frozen. The signal of the two
methyl groups bonded to the C-OMe moiety is still a single
(24) Mazzanti, A.; Lunazzi, L.; Minzoni, M.; Anderson, J. E. J. Org.
Chem. 2006, 71, 5474.
(25) It should be outlined that the present result is at variance with the
report of another pair of biphenyl derivatives, where the o-methyl-substituted
compound displayed a rotation barrier 0.5 kcal mol-1 higher than that of
the corresponding chlorine derivative. See: Bott, G.; Field, L. D.; Sternhell,
S. J. Am. Chem. Soc. 1980, 102, 5618.
(26) Two values were indicated for the van der Waals radii of the methyl
group: a minimum of 1.715 and a maximum of 2.23; see: Charton, M.
J. Am. Chem. Soc. 1969, 91, 615.
(27) Ab inito calculations of the whole energy surface exceeded the
capabilities of our computing facilities; thus, only the optimized singular
points (ground and transition states) were computed (see the Experimental
Section and Supporting Information).
(28) Examples of NMR determinations of very low barriers can be found
in: Anet. F. A. L.; Chmurny, G. N.; Krane, J. J. Am. Chem. Soc. 1973, 95,
4423. Anet, F. A. L.; Yavari I. J. Am. Chem. Soc. 1977, 99, 6752. Lunazzi,
L.; Macciantelli, D.; Bernardi, F.; Ingold, K. U. J. Am. Chem. Soc. 1977,
99, 4573. Brown, J. H.; Bushweller, C. H. J. Am. Chem. Soc. 1992, 114,
8153. Pawar, D. M.; Noe, E. A. J. Am. Chem. Soc. 1998, 120, 41485. Pawar,
D. M.; Wilson, K. K.; Noe, E. A. J. Org. Chem. 2000, 65, 1552. Casarini,
D.; Grilli, S.; Lunazzi, L.; Mazzanti, A. J. Org. Chem. 2001, 66, 2757.
Anderson J. E.; de Meijere, A.; Kozhushkov, S. I.; Lunazzi, L.; Mazzanti,
S. J. Am. Chem. Soc. 2001, 124, 6706. Lunazzi, L.; Mazzanti, A.; Minzoni,
M. Tetrahedron 2005, 61, 6782. Lunazzi, L.; Mazzanti, A.; Minzoni, M.
J. Org. Chem. 2005, 70, 456. Pawar, D. M.; Brown, J., II; Chen, K.-H.;
Allinger, N. L., Noe, E. A. J. Org. Chem. 2006, 71, 6512.
In the aryl carbinols with two ethyl substituents bonded to
the COH moiety (compounds 5-8), the interconversion barrier
was found to be consistently larger (by 2.45 ( 0.15 kcal mol-1
)
than in the analogous methyl-substituted derivatives 1-4. This
is a consequence of the greater bulkiness of the ethyl with
respect to the methyl group. In addition, in derivatives 1-3 and
5-7 the barriers increase with the dimension of the halogen
substituent: this parallels the trend of the corresponding van
der Waals radii (1.47, 1.75, 1.85 for F, Cl, Br, respectively).23
As shown in Table 1, the barriers measured for compounds
4 and 8 (having two methyl groups as ortho substituents) are
lower than those of the corresponding derivatives 2 and 6 that
have two chlorine atoms as ortho substituents (the average
difference is 0.7 kcal mol-1). This trend suggests that the steric
hindrance exerted by the methyl group upon the rotation process
(23) Bondi, A. J. Phys. Chem. 1964, 68, 441.
J. Org. Chem, Vol. 72, No. 3, 2007 1001

Casarini et al.
TABLE 1. Experimental Rotation Barriers (kcal mol-1)a for Compounds 1-8 and ab Initio Computed Barriers for Compounds 1-4
1
2
3
4
5b
6
7
8
R ) Me
R ) Me
R ) Me
R ) Me
R ) Et
R ) Et
R ) Et
R ) Et
compd
exptl
computed
(X ) F)
(X ) Cl)
(X ) Br)
(X ) Me)
(X ) F)
(X ) Cl)
(X ) Br)
(X ) Me)
4.6
6.8
7.4
6.2
6.9
9.4
10.1
8.6
5.0c
7.0d
7.9d
7.8c
a In CHF2Cl/CHFCl2. b In 5 a second barrier of 5.0 kcal mol-1 has been also measured (see text). c B3LYP/6-31G(d) level. d B3LYP/6-311+G(2df,p)//
B3LYP/6-31G(d) level.
FIGURE 4. Experimental (left) and computed (right) structure of
compound 4.
SCHEME 3. Schematic Energy Profile of 4 (E in kcal
mol-1) as a Function of the Dihedral Angle T between the
Aromatic Ring and the Plane of the C1-C-O Moiety
FIGURE 5. MM-computed energy (kcal mol-1) surface of 10 as
function of the dihedral angles ϑ and æ defined in the text. The solid
line describes the passage across the higher energy transition state (full
square) and the dashed line that across the lower energy transition state
(full circle). The ground states are indicated as +sc and -sc.
TABLE 2. Experimental Values of the Two Barriers (kcal mol-1
)
Measureda for the Rotation Processes Occurring in Ethers 9-12
(the Computed Values Corresponding to the Transitions States TS-1
and TS-2 Are Shown in Parentheses)
9
10
11
12
compd
(X ) F)
(X ) Cl)
(X ) Br)
(X ) Me)
higher barrier (TS-1) 5.0 (5.5b) 6.9 (9.4c) 8.1 (10.2c) 7.0 (10.0b)
lower barrier (TS-2)
4.7 (4.9b) 4.8 (5.5c) 5.0 (5.9c) 6.2 (5.5b)
CHART 2
a In CHF2Cl/CHFCl2. b B3LYP/6-31G(d) level. c B3LYP/6-311+G(2df,p)//
B3LYP/6-31G(d) level.
initio calculations predicting quite similar values for these two
barriers (5.5 and 4.9 kcal mol-1, respectively, as in Table 2).
The higher of the two barriers measured in the ethers 9-11
increases regularly (5.0, 6.9, 8.1 kcal mol-1 as in Table 2) with
the dimension of the halogen substituent, as already observed
in the corresponding alcohols 1-3 and 5-7 (Table 1): this trend
is also predicted by the computed values of Table 2. The
pathway responsible for this effect is due to the restriction of
the Ar-C bond rotation that drives the C-OMe bond into a
perpendicular position to the aryl ring (i.e., a situation analogous
to that of type C of Scheme 1): the corresponding ab initio
computed transition states (indicated as TS-1) are reported in
Figure S-3 of the Supporting Information. On the contrary, the
values of the lower barriers measured for the ethers 9-11 are
equal within the experimental uncertainty (4.7-5.0 kcal mol-1
as in Table 2) and do not depend, therefore, on the dimension
of the halogen substituents. This suggests that the lower barriers
measured by NMR are essentially determined by the rotation
process about the C-OMe bond (i.e., that indicated by the angle
line at -144 °C, but on further lowering the temperature to
-178 °C splits into a 1:1 pair of lines, because also the second
process, with the lower barrier, has been frozen at this
temperature. Analogous results were obtained for 11 and 12
(X ) Br and Me, respectively): the corresponding barriers are
collected in Table 2.
Also in the case of 9 (X ) F), the methyl groups become
diastereotopic at low temperature, as predicted by calculations:
within the experimental uncertainty ((0.15 kcal mol-1), how-
ever, the corresponding barrier was found equal to that measured
by monitoring the 19F signals of the ortho fluorine substituents
(5.0 and 4.7 kcal mol-1, respectively, as in Table 2). This means
that in compound 9 the barrier for rendering diastereotopic the
ortho and meta positions is very close to that required to make
diastereotopic the two methyl groups. This agrees with the ab
1002 J. Org. Chem., Vol. 72, No. 3, 2007

Symmetrically Ortho-Disubstituted Aryl Carbinols and Aryl Ethers
the suspension of the resulting lithiate29 was treated either with
acetone (for compounds 1-3, 40 mmol, neat) or diethyl ketone
(for compounds 5-7, 40 mmol, neat). The temperature was
immediately raised to ambient temperature, and the mixture treated
with aqueous NH4Cl, extracted with Et2O, and dried (Na2SO4). After
removing the solvent, the crude was prepurified by a silica gel
chromatography column (petroleum ether/Et2O 8/2). Yields: 73%
for 130, 52% for 2, 8% for 3, 66% for 5, 44% for 6, 10% for 7.
Analytically pure samples were obtained by semipreparative HPLC
on a Synergi Polar-RP column (4 µm, 250 × 10 mm, 4 mL/min,
MeOH/H2O 80:20 v:v). See the Supporting Information for details.
2-(2,6-Dimethylphenyl)propan-2-ol (4) and 3-(2,6-Dimeth-
ylphenyl)pentan-3-ol (8). A 12.5 mL portion of BuLi (20 mmol,
1.6 M in hexane) was added to a solution of 1-bromo-2,6-
dimethylbenzene (20 mmol in 15 mL of dry THF) at -78 °C. The
solution was stirred for 60 min and then treated with acetone or
diethyl ketone (40 mmol in 5 mL of dry THF). After being stirred
for 10 min, the mixture was warmed to 25 °C, treated with aqueous
NH4Cl, extracted with Et2O, and dried (Na2SO4). The crude obtained
after removal of the solvent was purified by a silica gel chroma-
tography column (petroleum ether/Et2O 8/2) to give 4 (65%)31 and
8 (58%). Analytically pure samples were obtained by semiprepara-
tive HPLC on a Synergi Polar-RP column (4 µm, 250 × 10 mm,
4 mL/min, MeOH/H2O 80:20 v/v). In the case of compound 4,
crystals suitable for X-ray diffraction were obtained by slow
evaporation from CHCl3. See the Supporting Information for details.
FIGURE 6. Temperature dependence of 13C signals (150.8 MHz) of
the two ortho, two meta, and two methyl carbons (bonded to the
C-OMe moiety) of 10 in CHF2Cl/CHFCl2.
General Procedure for 9, 10, and 12. To a suspension of NaH
(95% powder, about 10 mmol in 5 mL of dry THF), kept at 0 °C,
was added dropwise a solution of the appropriate alcohol (2 mmol
in 2 mL of dry THF). After 10 min, the stirred suspension was
treated with excess MeI (1 mL). After being warmed to ambient
temperature, the reaction was cautiously quenched with aqueous
NH4Cl, extracted with Et2O, and dried (Na2SO4). After removal of
the solvent, the crude was prepurified by a silica gel chromatography
column (petroleum ether/Et2O 20/1) to give 9 (72%), 10 (65%),
and 12 (58%). Analytically pure samples were obtained by
semipreparative HPLC on a Synergi Polar-RP column (4 µm, 250
× 10 mm, 4 mL/min, MeOH/H2O 80:20 v/v) in the case of
compound 10, and on a Luna C18(2) column (5 µm, 250 × 10
mm, 4 mL/min, ACN/H2O 95:5) in the case of compounds 9 and
12. See the Supporting Information for details.
1,3-Dibromo-2-(2-methoxypropan-2-yl)benzene (11). A solu-
tion of LDA was prepared in 1 h by addition of 12.5 mL of
n-butyllithium (20 mmol, 1.6 M in hexane) to a stirred solution of
2.02 g of diisopropylamine (20 mmol in 12.5 mL of anhydrous
THF) kept at -5 °C. The solution was then slowly transferred into
a solution of 1,3-dibromobenzene (20 mmol in 12.5 mL of
anhydrous THF) kept at -78 °C. After 1.5 h, the suspension of
the resulting lithiate was treated with acetone (40 mmol, neat). The
temperature was immediately raised to 25 °C, and the mixture
transferred into a solution of MeI (1 mL) in anhydrous DMF (10
mL). After 1 h, the solvents and DMF were removed by distillation
at reduced pressure and the crude was prepurified by a silica gel
chromatography column (petroleum ether/Et2O 20/1) to obtain 11
(overall yield: 3%, ∼30% on the intermediate alcohol). Analytically
pure samples were obtained by semipreparative HPLC on a Luna
C18(2) column (5 µm, 250 × 10 mm, 4 mL/min, ACN/H2O 80:20
v:v). See the Supporting Information for details.
æ in Figure 5), the related transition state (TS-2) being described
by the O-Me bond eclipsing one of the two C-Me bonds (this
situation corresponds to the point identified by the full dot in
Figure 5 for compound 10). It is quite evident that this process
cannot be affected by the dimension of the halogen groups in
the ortho position, thus accounting for the observed invariance
of the lower barriers in 9-11: these TS-2 transition states,
resulting from ab initio computations, are displayed in Figure
S-3 of the Supporting Information.
Such an interpretation also accounts for the fact that in the
alcohols 1-4 the diastereotopicity of the two methyl groups
could not be observed in the NMR spectra, even at the same
low temperatures where it was detected in the corresponding
methyl ethers 9-12: the rotation barrier about the C-OH bond
of the alcohols is in fact conceivably lower than that about the
CO-Me bond of the corresponding ethers.
Conclusion
As anticipated by computations, the low-temperature NMR
spectra of symmetrically ortho disubstituted aryl carbinols
display a barrier due to the restricted rotation about the sp2-
sp3 Ar-C bond, the threshold mechanism being that where the
C-OH bond becomes perpendicular to the aryl ring: this barrier
increases with the increasing dimension of the halogen substit-
uents. In the corresponding methyl ethers a second additional
barrier, due to the C-OMe bond rotation, could be also
measured, the latter barrier being independent, as conceivable,
of the type of the halogen groups in the ortho positions.
NMR Spectroscopy. The spectra were recorded at 300, 400,
1
and 600 MHz for H and 75.45, 100.6, and 150.8 MHz for 13C,
Experimental Section
and 564.3 MHz for 19F. The external standard C6F6 (neat, set at
-163.0 ppm) in the 19F spectra was used as reference. The
assignments of the 13C signals were obtained by DEPT and
Materials: General Procedure for 1-3 and 5-7. A solution
of lithium diisopropylamide (LDA) was prepared in 1 h by addition
of 12.5 mL of n-butyllithium (20 mmol, 1.6 M in hexane) to a
stirred solution of 2.02 g of diisopropylamine (20 mmol in 12.5
mL of anhydrous THF) kept at -5 °C. The solution was then slowly
transferred into a solution of the appropriate 1,3-dihalobenzene (20
mmol in 12.5 mL of anydrous THF), kept at -78 °C. After 1.5 h,
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J. Org. Chem, Vol. 72, No. 3, 2007 1003

Casarini et al.
bidimensional experiments (gHSQC32 and gHMBC33 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 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 the spectrom-
eter. The temperatures were calibrated by substituting the sample
with a Cu/Ni thermocouple before the measurements.
Calculations. Computations were carried out at the B3LYP/6-
31G(d) or at the B3LYP/6-311+G(2df,p)//B3LYP/6-31G(d) level
by means of the Gaussian 03 series of programs11 (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.
Acknowledgment. Thanks are due to Prof. W. B. Jennings,
University College, Cork, Ireland, for useful comments and to
Dr. G. Bianco, CIRCOVA Center, University of Basilicata, Italy,
for the ESI-HRMS 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: Variable-temperature NMR
spectra of compound 5, optimized structures of the two ground-
state conformations of 5, optimized TS-1 and TS-2 transition-state
structures for compounds 9-11, X-ray diffraction data of compound
1
4, analytical and spectroscopic data of compounds 1-12, H and
13C NMR spectra of compounds 1-12, mass spectra of compounds
3, 7, and 11, HPLC traces of compounds 1-12, and computational
data for compounds 1-5 and 9-12. This material is available free
of charge via the Internet at http://pubs.acs.org.
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JO062289U
1004 J. Org. Chem., Vol. 72, No. 3, 2007