The torsional barriers of 2-hydroxy-and 2-fluorobiphenyl: Small but measurable

Article abstract of DOI:10.1002/chem.200903372

By making use of a novel diastereotopicity probe, namely C(CF ₃)₂OH, it has been possible to measure by very low temperature¹⁹F NMR spectroscopy the elusive aryl-aryl rotation barriers of biphenyls bearing an OH or F group in one ortho position. The experimental values (5.4 and 4.4 kcalmol^-1, respectively) are matched by those from ab initio calculations (5.3 and 4.3 kcalmol^-1, respectively).

Full text of DOI:10.1002/chem.200903372

DOI: 10.1002/chem.200903372
The Torsional Barriers of 2-Hydroxy- and 2-Fluorobiphenyl: Small but
Measurable
[
a]
[a]
[b]
[b]
Andrea Mazzanti,* Lodovico Lunazzi, Renzo Ruzziconi,* Sara Spizzichino, and
[
c]
Manfred Schlosser*
Abstract: By making use of a novel diastereotopicity probe, namely C ACTHUNGTRNEU(GN CF ) OH, it
3 2
1
9
Keywords: ab initio calculations ·
biphenyls · diastereotopicity probes ·
has been possible to measure by very low temperature F NMR spectroscopy the
elusive aryl–aryl rotation barriers of biphenyls bearing an OH or F group in one
À1
NMR spectroscopy
drance
· steric hin-
ortho position. The experimental values (5.4 and 4.4 kcalmol , respectively) are
À1
matched by those from ab initio calculations (5.3 and 4.3 kcalmol , respectively).
Introduction
rather than through parallel contact. The biphenyl core sat-
isfies such geometrical requirements optimally, as the colli-
sion angle of 608 mimics realistically the interference of a
sterically congestive substituent with the trajectory of a re-
agent approaching the reaction center (e.g., a nucleophile in
The most popular scale for quantifying steric bulk is based
[1–5]
on the so-called A values,
which mirror the relative free
energies of axially versus equatorially substituted cyclohex-
anes. Despite its conceptional and experimental appeal, this
model is not free from bias. In particular, axially oriented
monovalent substituents barely touch the axial hydrogen
neighbours at the 3- and 5-positions and thus give rise to
only insignificant repulsive forces. As a consequence, the A
values (hydrogen as reference with A=0.00) of fluorine
A=0.15), chlorine (A=0.43), bromine (A=0.38) and
iodine (A=0.43) are very small compared to methyl (A=
.70) or isopropyl (A=2.15).
an S 2 reaction). Pioneering work in this respect was accom-
N
[6]
plished by Sternhell et al., who assessed the torsional bar-
riers of a large series of 2-substituted biphenyls by variable-
temperature (“dynamic” D) NMR spectroscopy monitoring
the coalescence of a pair of geminal methyl groups at the 3’-
position, incorporated into a dihydroindane ring. Unfortu-
nately, they were unable to decrease the sample temperature
below À658C. In order to operate in the À658C/+1858C
(
À1
1
range (corresponding to barriers of 14–22 kcalmol ) they
To avoid such a dilemma, the two interacting bonds
should encounter each other in a lateral tackling array
were obliged to introduce an extra methyl group at the 6’-
position of all test compounds. To list steric parameters I
X–H
of individual substituents X they had to assume additivity of
the 2-X/2’-H and 6-H/6’-CH3 repulsions. In other words,
CH3–H
they always had to subtract the same constant I
incre-
[
a] Dr. A. Mazzanti, Prof. L. Lunazzi
Department of Organic Chemistry “A. Mangini”
University of Bologna
ment from the experimentally found barrier. The underlying
additivity postulate is incorrect, however.
Viale Risorgimento 4, 40136 Bologna (Italy)
Fax : (+39)051-2093654
E-mail: mazzand@ms.fci.unibo.it
Results and Discussion
[
b] Prof. R. Ruzziconi, S. Spizzichino
Chemistry Department, University of Perugia
Via Elce di Sotto 10, 06100 Perugia (Italy)
E-mail: ruzzchor@unipg.it
By adjusting the temperature to as low as À1738C (100 K)
we were able to determine the torsional barriers (“B
values”) of a representative series of biphenyls having a
single substituent at an ortho position, by employing 3’-iso-
propyldimethylsilyl as diastereotopicity probe. The exam-
ples listed (Table 1) span an unprecedented wide range from
moderate size (methyl: B 7.4; chloro: B 7.7) to fairly bulky
[
c] Prof. M. Schlosser
Institute of Chemical Science and Engineering
Ecole Polytechnique Fꢀdꢀrale (EPFL-BCh)
[7]
1
015 Lausanne (Switzerland)
E-mail: manfred.schlosser@epfl.ch
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200903372.
[7]
groups (tert-butyl: B 15.5; trimethylammonio: B 18.1).
9186
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 9186 – 9192

FULL PAPER
Table 1. B values of common substituents, as determined by the torsional
phenylboronic acid or phenylboronic acid under the condi-
[
a]
barriers of biphenyl model compounds, with corresponding A values for
[15]
tions of Suzuki–Miyaura cross-coupling in the presence of
[
2–4]
comparison.
[16]
tetrakis(triphenylphosphine)palladium(0)
and subsequent
Substituent
X
A values
exptl
B values
acid cleavage afforded 2-hydroxy-3’-(a-hydroxyhexafluoro-
AHCTUNGERTGiNNUN sopropyl)biphenyl (2), 2-fluoro-3’-(a-hydroxyhexafluoroiso-
propyl)biphenyl (3), 2-bromo-3’-(a-hydroxyhexafluoroiso-
propyl)biphenyl (4) and the ortho-unsubstituted parent com-
pound 3-(a-hydroxyhexafluoroisopropyl)biphenyl (5) in 58,
73, 50 and 70% yield, respectively (Scheme 1).
[
b]
[c]
exptl
–
calcd
[
d]
H
0.0
2.2
7.1
–
[
e]
CH
3
1.70
1.75
2.15
4.90
–
2.10
1.20
1.10
0.60
–
0.52
0.15
0.43
0.38
0.43
7.4 (10.8)
[
e]
C
2
H
5
8.7
[
e]
CH
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(CH
3
)
2
11.1 (13.7)
15.5
11.1
15.6
18.2
C
N
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(CH )
3 3
+
A( CH
C
H
T
U
N
G
T
R
E
N
N
U
N
G
3
)
3
18.1
[f]
[f]
N
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(CH
3
)
2
6.9 (8.9)
6.8
8.4
[f]
[f]
NH
NO
2
2
8.1 (10.7)
7.6 (8.8)
5.6 (7.5)
5.7
7.8
4.5
6.1
5.3
4.3
OCH
OCH
OH
F
3
2
OCH
3
[
g]
[h]
–
–
(7.6)
(5.7)
[
g]
[h]
[
e]
Cl
Br
I
7.7 (10.2)
8.7 (11.3)
7.3
8.5
9.9
[i]
10.0 (12.0)
À1
[
a] B values [kcalmol ] are the torsional barriers of 2-X-biphenyls carry-
ing at the 3’-position generally an isopropyldimethylsilyl group as the dia-
Scheme 1. Preparation of biphenyls 2–5 starting from the common pre-
cursor 1.
stereotopicity probe. [b] The values in parentheses are taken from
[
7]
ref. [6].
[
[c] With
B3LYP/6-311+G AHCNUTGTRENNGNU( 2d,p)//B3LYP/6-311+G ACHTNUGTRENNUNG( 2d,p).
[
9]
d] Ref. [8]. [e] Isopropyl was the diastereotopicity probe; see also
ref. [10]. [f] The reason why 2-dimethylamino seems to be smaller than 2-
amino has to do with the various degrees of n–p conjugative stabilization
in the ground and transition states. [g] No decoalescence of the isopro-
The new diastereotopicity probe met our expectations.
First, the torsional barrier of 2-bromo compound 4 was de-
termined (B=8.3). The coincidence with the values previ-
[
7]
pyldimethylsilyl group down to À1738C. [h] With CCSD(T)/6-31G(d)//
CISD ACHTUNGTRENNUNG( full)/6-31G(d) neglecting the diastereotopicity label at the 3’-posi-
[9]
ously obtained with 3’-isopropyl and 3’-isopropyldimethyl-
tion. [i] With B3LYP/DGDZVP//B3LYP/DGDZVP.
[7]
silyl as probes (B=8.7) lies within experimental uncertain-
ty. Next, 2-hydroxy compound 2 and 2-fluoro compound 3
were examined.
However, the challenge presented by the two smallest
substituents, hydroxy and fluoro, proved insurmountable.
1
The H spectrum of 2 shows that the line representing the
À1
Their torsional barriers can not exceed 5 kcalmol , as not
phenolic hydroxyl group splits into two signals with 65:35 in-
even the beginning of decoalescence was observed at
tensity ratio below À1508C (Figure 1, left). This is due to re-
[7]
À1738C.
stricted rotation around the arylÀC
ACHTUNGTNERNUN(G CF ) OH bond, which
3 2
The only hope to solve the problem was to replace the so-
far top-performing isopropyldimethylsilyl probe by an even
better diastereotopicity sensor, in other words by one show-
ing wider signal splitting of the diastereotopic nuclei. We
makes visible, at this temperature, two different OH signals
for two unequally populated conformers. In fact, as ob-
[17,18]
served formerly with similarly bulky 3’-substituents,
the
hydroxyl group of the HOF iPr entity will be accommodated
6
chose the a-hydroxyhexafluoroisopropyl (HOF iPr) group,
in the ring plane either facing the neighbouring aryl (syn
conformer sp-2, Scheme 2) or looking away from it (anti
conformer ap-2, Scheme 2). The syn/anti interconversion
6
which we planned to attach to the biphenyl core by nucleo-
philic addition of a suitable aryl lithium to anhydrous hexa-
fluoroacetone. The sparse literature reports available were
contradictory, and thus cast doubt on the practicability of
the envisaged approach. Phenylethynylsodium was found to
°
process requires an activation free energy (DG ) of
À1
6.1 kcalmol , as obtained from the rate constants used for
the line-shape simulation (Figure 1, dashed lines).
[11]
19
combine cleanly with hexafluoroacetone (in 76% yield),
whereas sodium acetylide provided only 16% of impure
This process is NMR-invisible in the F spectrum of 2,
since the chemical shift difference between the ap and sp
conformers is much smaller than the line widths of the CF3
signals, which are quite large due to the increased viscosity
at such low temperatures. However the effects of two other
[12]
product. 1,1-Dichloroallyllithium reacted with hexafluoro-
[13]
acetone readily and regioselectively, but 2-(dimethylami-
no)phenyllithium gave the expected ortho-substituted
adduct contaminated with considerable amounts of the cor-
1
9
dynamic processes are detected in the
F spectrum
[14]
responding meta isomer. Despite such inconsistencies, 3-
bromophenyllithium, generated from 1,3-dibromobenzene
by halogen/metal permutation with n-butyllithium, com-
bined smoothly with hexafluoroacetone to afford, after hy-
drolysis, 1-bromo-3-(a-hydroxyhexafluoroisopropyl)benzene
(Figure 1, right), since the chemical shift separations in-
volved are much larger. These other processes are restricted
CÀCF rotation (which yields three 1:1:1 lines for the three
3
fluorine atoms) and restricted aryl–aryl rotation (which
makes the two CF3 groups diastereotopic). As a conse-
quence, six lines of equal integrated intensity are expected.
These lines, however, are not completely resolved. There-
(
1). Reaction of aryl bromide 1 with 2-methoxymethoxy-
phenylboronic acid, 2-fluorophenylboronic acid, 2-bromo-
Chem. Eur. J. 2010, 16, 9186 – 9192
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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9187

A. Mazzanti, R. Ruzziconi, M. Schlosser et al.
relation of the two stereomutations by a common “gear” (or
[20–22]
“
cogwheel”) effect.
1
9
Analogous behaviour was observed in the F spectrum of
3
, in which the signal of the ortho-fluorine atom splits below
À1508C into a pair of lines with 60:40 intensity ratio
(
Figure 2, left) due to the presence of the sp and ap
1
Figure 1. Temperature dependence of the H signal of the phenolic OH
1
9
group (left) and F spectrum of the CF
3 3
groups of 2 in CBrF together
with the line-shape simulation obtained with the rate constants indicated
2
(
dashed lines). The JFF couplings are smaller than the line width.
1
9
Figure 2. Temperature dependence of the F signal of the single phenyl-
bound fluorine atom (left) and of the CF groups (right) of 3 in CBrF to-
3
3
Scheme 2. syn and anti Conformers of biphenyls 2 and 3.
gether with the line-shape simulation obtained with the rate constants in-
dicated (dashed lines). The JFF couplings are smaller than the line width.
2
fore, only five overlapping lines of different width, and of
1
:1:1:1:2 intensity, were detected in the À1678C spectrum of
conformers (Scheme 2) although the separation of the corre-
sponding signals is as small as 0.1 ppm. The rate constants,
obtained by line-shape simulation (dashed lines), lead to a
Figure 1 (right). The experimental intensity distribution, in
which the fifth line at d=À72.9 ppm is twice as intense as
the others, was confirmed by the excellent agreement with a
°
À1
syn/anti interconversion barrier of DG =6.4 kcalmol ,
[19]
line-shape simulation (Figure 1, right, dashed traces).
which is essentially equal, within experimental error
À1
The rate constants for the aryl–aryl and CÀCF rotation
(Æ0.2 kcalmol ), to that measured for compound 2.
3
appeared to be essentially equal, so that only a single rate
The splitting due to sp and ap conformers is invisible in
constant k results from the simulation. The corresponding
the CF spectral region, where the signals have line widths
3
barriers for aryl–aryl and CÀCF rotations are 5.4Æ
larger than the chemical shift separation. At sufficiently low
3
À1
0
.3 kcalmol . The equality of these two barriers might just
temperatures restricted aryl–aryl and restricted CÀCF bond
3
be a coincidence, but it is not unreasonable to assume a cor-
rotation should lead to six equally intense lines, as discussed
9188
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Chem. Eur. J. 2010, 16, 9186 – 9192

Torsional Barriers of 2-Hydroxy- and 2-Fluorobiphenyl
FULL PAPER
À1
for 2. These six lines partially overlap, whereby three of
them yield the line at d=À75.2 ppm, and two others that at
d=À77.2 ppm. A third isolated single line appears at d=
À80.6 ppm. Consequently three lines having a 3:2:1 integrat-
ed intensity ratio are observed at À1738C (Figure 2, right).
The intensity and the varying line widths are perfectly
matched by the simulation (dashed trace). Simulations at
higher temperatures also correctly reproduce the experi-
mental traces and again suggest that, presumably owing to
0.3 kcalmol ). This value is equal to that measured for 2
[24]
and quite similar to that of 3.
In view of the complexity of our low-temperature spectra
we verified the experimental findings by quantum chemical
calculations. The torsional barriers of biaryls essentially rep-
resent the energy difference between the twisted ground
state and the coplanar transition state (where both the steric
repulsion of colliding atoms or groups in the ortho positions
and the stabilizing p conjugation of the parallel-aligned p or-
[20–22]
[25]
the above mentioned “gear effect”,
aryl–aryl and
bitals attain their maximum) Even when a large basis set
CÀCF rotation have the same rate constant and the same
is used, the B3LYP functional tends to underestimate the
steric barrier with respect to the experimental values, espe-
cially in the case of small substituents. For this reason, we
optimised the geometries of the ground states and transition
states of model compounds 2 and 3 (i.e., 2-hydroxybiphenyl
3
°
À1
[8]
barrier (DG =4.4Æ0.3 kcalmol ).
To confirm the interpretation of the low-temperature
spectra of 2 and 3 we investigated compound 5, which lacks
an ortho substituent, so that the aryl–aryl rotation is fast on
the NMR timescale at any temperature because the barrier
and 2-fluorobiphenyl) at the higher ab initio CISD ACHTUNGTRENNUNG( full)/6-
[8]
À1
is exceedingly small (2.2 kcalmol , Table 1). The dynamic
31G(d) level. Single-point energies were eventually obtained
at the even higher CCSD(T)/6-31G(d) level. This gave cal-
symmetry due to this fast rotation makes compound 5 achi-
À1
ral, and the two CF groups will be enantiotopic and thus
culated energy barriers of 5.3 and 4.3 kcalmol , in excellent
3
equivalent in the NMR spectrum. As a consequence, when
agreement with the experimental values (5.4 and
4.4 kcalmol , respectively). This is a strong support for the
1
9
À1
CÀCF rotation is frozen the F single signal would split
3
only into three (rather than six) lines due to the non-equiva-
fact that we actually measured the aryl–aryl rotation barrier.
The smallest barriers ever assessed by dynamic NMR are
[23]
lence of the three fluorine atoms within each CF group.
3
19
[26]
Indeed, the F spectrum of compound 5 at À1608C displays
two lines (d=À76.0 and À78.4 ppm) with a 4:2 intensity
ratio, as expected if two of the three predicted lines overlap
at d=À76.6 ppm (Figure 3). The line-shape simulations, ob-
tained by taking into account three lines with 1:1:1 intensity
those of the ring inversions of cyclohexanone, 1,5-cyclooc-
[26]
[28]
À1
tadiene
and cis-cyclononene
(4.1–4.2 kcalmol ) and
those of the rotations around the single bonds of 2,3-dime-
[
29]
[30]
thylbutane, chloromethyl methyl ether and 2,2’,6,6’-tet-
[21]
À1
ramethyldiphenyl sulfide (4.2–4.3 kcalmol ). Work in the
biphenyl series is hampered by several adverse effects in-
cluding solubility problems. The smallest torsional barrier so
°
ratio, provides the CÀCF3 rotation barrier (DG =5.4Æ
far experimentally assessed in this class of compounds is
À1 [7]
5
.6 kcalmol . The HOF iPr group now made it possible to
6
venture to still lower barriers and to establish a new record
À1
at 4.4 kcalmol . The potential of the new diastereotopicity
probe may not yet be exhausted with this success.
Although unintentionally, the present data may stir up
once again the old dispute about whether fluorine, as far as
its bulkiness is concerned, should be compared to hydrogen
[31,32]
À1
or rather to hydroxy.
If 1.1 kcalmol for the interaction
of the 6-H/6’-H pair is subtracted from the experimental
À1
barriers of 2-hydroxybiphenyl (2: 5.4 kcalmol ) and 2-fluo-
À1
robiphenyl (3: 4.4 kcalmol ), the remaining 4.3 and
À1
3
.3 kcalmol account for the 2-OH/2’-H and 2-F/2’-H repul-
sions, respectively. In other words, fluorine lies between hy-
drogen and oxygen, but closer to the latter element. On the
basis of mere size, fluorine and hydrogen are nevertheless
indistinguishable for biological detectors such as enzymes or
receptors. In principle one may use the same argument to
claim bioisosterism also for hydrogen and hydroxy. Howev-
er, the recognition pattern of proteins with respect to hy-
droxylated compounds is generally dominated by the pro-
nounced hydrogen-bond donor and acceptor capacities of
the hydroxyl group rather than just by its van der Waals
radius.
1
9
Figure 3. Left: temperature dependence of the F signal of the CF
groups of 5 in CBrF at 564 MHz. Right: line-shape simulation obtained
with the rate constants indicated. The JFF couplings are smaller than the
3
3
2
[
23]
line width (ca. 350 Hz).
Chem. Eur. J. 2010, 16, 9186 – 9192
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9189

A. Mazzanti, R. Ruzziconi, M. Schlosser et al.
0
.41 g (58%) of product 2 was collected as a colourless oil. Hickmann
Experimental Section
distillation gave biphenyl 2 (0.10 g) as an opalescent gel. B.p. 125–1278C/
0
2
1
.2 mmHg; H NMR: d=7.86 (s, 1H), 7.73 (d, J=7.8 Hz, 1H), 7.6 (m,
H), 7.3 (m, 2H), 7.02 (t, J=7.4 Hz, 1H), 6.97 (d, J=8.0 Hz, 1H), 5.07
1
13
19
Unless stated otherwise, H, C and F NMR spectra were recorded of
samples dissolved in CDCl at 400, 100 and 376 MHz, respectively. Chem-
3
1
3
(
s, 1H), 3.69 ppm (s, 1H); C NMR: d=152.3, 137.8, 130.9, 130.4, 130.2,
ical shifts are given relative to the internal standards tetramethylsilane
and trichlorofluoromethane. The purity of all products used in dynamic
NMR experiments was tested by gas chromatography on two capillary
columns of different polarity [30 mꢂ0.35 mmꢂ0.25 mm DB 5MS (5%
phenylmethylpolysiloxane) and 30 mꢂ0.35 mmꢂ0.25 mm DB23 (50% cy-
anopropylmethylpolysiloxane)]. A Waters 600 apparatus (with 2487 UV
detector) was available for semi-preparative HPLC purification. Elemen-
tal analyses of compounds containing more than 10% of fluorine in
weight tend to be afflicted with standard deviations exceeding the ordina-
ry error limits of Æ0.3%.
Reagents and solvents: Trimethyl borate, 1,3-dibromobenzene, 2-bromo-
phenol, 2-fluorophenylboronic acid, 2-bromophenylboronic acid, chloro-
methyl methyl ether, tetrakis(triphenylphosphine)palladium and other
commercial products were used as received. Tetrahydrofuran and diethyl
ether were distilled from KOH pellets in the presence of CuCl and redis-
tilled from sodium wire in the presence of the violet-blue benzophenone/
sodium ketyl. All reactions were carried out under an atmosphere of
1
29.5, 129.3, 127.4, 127.3, 125.8, 122.6 (q, J=286 Hz, 2C), 121.1, 116.1,
1
9
8
3.0 ppm (sept, J=28 Hz); F NMR: d=À75.8 ppm (s); elemental analy-
: C 53.58, H 3.00; found: C 53.27, H 2.51.
-Fluoro-3’-(hexafluoro-a-hydroxyisopropyl)biphenyl (3):
5 mL), benzene (10 mL), bromoarene 1 (0.50 g, 1.5 mmol), 2.0m aq.
CO (1.5 mL) and [Pd(PPh ] (0.040 g, 0.034 mmol) were added con-
sis calcd for C15
10 6 2
H F O
2
(
K
Ethanol
2
3
A
H
U
G
R
N
U
3 4
)
secutively to 2-fluorophenylboronic acid (0.26 g, 1.9 mmol). The mixture
was kept at reflux for 3 h. After cooling, water was added and the mix-
ture extracted with diethyl ether (20 mL). The organic layer was dried
with Na SO and the solvent evaporated. Chromatography of the residue
2 4
on silica gel (eluent: diethyl ether/petroleum ether 95/5) afforded a col-
ourless oil. Hickmann distillation gave pure biphenyl 3 (0.370 g, 73%).
B.p. 121–1238C/0.2 mmHg; H NMR: d=7.91 (s, 1H), 7.72 (d, J=7.9 Hz,
1
1
H), 7.68 (dsept, J=7.7 and 1.0 Hz, 1H) 7.54 (t, J=7.9 Hz, 1H), 7.45 (td,
J=7.7 and 1.8 Hz, 1H), 7.35 (symm. m, 1H), 7.23 (td, J=7.5 and 1.2 Hz,
1
3
1
H), 7.17 (ddd, J=10, 8.2 and 1.1 Hz, 1H), 3.51 ppm (s, 1H); C NMR:
d=159.7 (d, J=247 Hz), 136.3 (2C), 130.8 (d, J=20 Hz), 129.5 (d, J=
.3 Hz), 128.7 (2C), 128.1 (d, J=13 Hz), 127.2, 125.7, 124.5 (d, J=
3.6 Hz), 122.6 (q, J=286 Hz, 2C), 116.2 (d, J=22 Hz), 83.1 ppm (sept,
9
9.999% pure nitrogen or argon. The aryl–aryl coupling protocols em-
8
ployed for the preparation of products 1–5 were elaborated in analogy to
[
33–35]
literature precedents.
-(3-Bromophenyl)hexafluoroisopropanol (1): Gaseous hexafluoroace-
tone was produced by cautious addition of its trihydrate to 98% aq.
SO at 508C and was condensed, through Teflon tubing, into a 50 mL
Schlenk tube cooled at À758C. In a second Schlenk tube, n-butyllithium
1.6m in hexanes, 13 mL, 21 mmol) was added dropwise over 15 min to a
1
9
J=28 Hz); F NMR: d=À75.9 (s, 6F), À118.6 ppm (brs, 1F); MS: m/z
2
+
(
%): 338 ([M ], 100), 269 (100), 251 (36), 199 (100), 172 (92), 152 (28),
9
9 (38), 85 (32), 69 (16); elemental analysis calcd for C15
H 2.68; found: C 53.37, H 1.98.
-Bromo-3’-(hexafluoro-a-hydroxyisopropyl)biphenyl (4) was obtained in
9 7
H F O: C 53.27,
H
2
4
2
(
the same way starting from bromoarene 1 (0.50 g, 1.5 mmol) and 2-bro-
mophenylboronic acid (0.62 g, 3.1 mmol). Upon chromatography of the
crude product on silica gel (eluent: petroleum ether/diethyl ether 9/1)
impure bromobiphenyl 4 (0.48 g) was isolated. According to mass spec-
troscopy, it was contaminated mainly by 2-(2-bromophenyl)-3’-(hexa-
fluoro-a-hydroxyisopropyl)biphenyl. A sample (0.14 g) was subjected to
solution of 1,3-dibromobenzene (5.0 g, 21 mmol) in THF (40 mL) at
À958C. After 5 min hexafluoroacetone was transferred from the first
tube, now kept at +258C, through a Teflon cannula, ending 5 mm above
the liquid surface, into the mixture. After 10 min at À958C, the cold bath
2 4
was removed and the temperature raised to 258C. Aq. 5% H SO
(
2
50 mL) was added and the mixture was extracted with diethyl ether (3ꢂ
5 mL). The extracts were dried with Na SO and the solvent evaporated.
preparative HPLC (LiChrospher 100 RP18, 250ꢂ25 mmꢂ5 mm column, a
2
4
À1
mixture of CH
3
CN/H
2
O (3/2) as eluent, 10 mLmin ) followed by Hick-
For purification, the raw material was converted into the methoxymethyl
1
mann distillation, to afford pure bromobiphenyl 4 (0.087 g, 50%). B.p.
ether [ H NMR: d=7.77 (brs, 1H), 7.62 (ddd, J=8.0, 1.9, 1.0 Hz, 1H),
1
1
43–1458C/0.2 mmHg; H NMR: d=7.76 (m, 3H), 7.59 (m, 2H), 7.47
7
.57 (brd, J=8.0 Hz, 1H), 7.34 (t, J=8.0 Hz, 1H), 4.85 (s, 2H), 3.55 ppm
+
+
(td, J=7.6 and 1.1 Hz, 1H), 7.39 (dd, J=7.6 and 1.6 Hz, 1H), 7.32 (td,
(
(
s, 3H); MS: m/z (%): 368 ([M +1], 2), 366 ([M À1], 2), 308 (65), 306
1
3
J=7.8 and 1.7 Hz, 1H), 5.99 ppm (s, 1H); C NMR: d=141.6, 141.4,
67), 227 (100), 253 (99), 207 (80), 157 (59), 61 (54), 45 (100)] and the
1
2
33.4, 131.6, 131.4, 129.2, 129.1, 128.3, 128.0, 126.3, 125.7, 123.3 (q, J=
latter subjected to chromatography (silica gel, eluent 9:1 petroleum
ether/diethyl ether mixture) followed by acid cleavage (1:4 v/v trifluoro-
acetic acid/CH Cl , 1 h at 258C). Upon distillation through a 5 cm Vig-
2 2
1
9
90 Hz, 2C), 122.5, 83.2 ppm (sept, J=29 Hz); F NMR: d=À75.8 ppm
+
+
(
s); MS m/z (%) 400 ([M +1], 79), 398 ([M À1], 78), 331 (21), 329 (21),
13 (13), 311 (13), 250 (24), 181 (91), 152 (100), 76 (33); elemental analy-
sis calcd for C H BrF O: C 45.14, H 2.27; found: C 44.89, H 2.43.
3
reux column, 4.82 g (71%) of bromoarene 1 were collected as a colour-
1
1
5
9
6
less liquid. B.p. 119–1218C/14 mmHg; H NMR: d=7.91 (s, 1H), 7.6 (m,
1
3
2
1
2
(
(
H), 7.33 (t, J=8.0 Hz, 1H), 4.06 (s, 1H); C NMR: d=133.4, 131.5,
3-(Hexafluoro-a-hydroxyisopropyl)biphenyl (5): Analogously, biphenyl 5
was obtained by allowing bromoarene 1 (0.48 g, 1.5 mmol) to react with
phenylboronic acid (0.23 g. 1.9 mmol). Chromatography on silica gel
(eluent: diethyl ether/petroleum ether 95/5), followed by Hickmann dis-
tillation, gave pure biphenyl 5 (0.336 g, 70%) as a colourless viscous oil.
30.0, 129.9, 125.2, 122.8, 122.4 (q, J=286 Hz, 2C), 83.3 ppm (sept, J=
1
9
+
8 Hz); F NMR: d=À75.8 ppm (s); MS m/z (%) 324 ([M +1], 97), 322
+
[M À1], 98), 285 (2), 283 (2), 255 (99), 253 (99), 204 (38) 185 (100), 183
100), 157 (33), 155 (31), 145 (31), 69 (48); elemental analysis calcd for
1
C
9
H
5
BrF
6
O: C 33.46, H 1.56; found: C 32.89, H 1.58.
B.p. 117–1198C/0.2 mmHg; H NMR: d=7.96 (s, 1H), 7.7 (m, 2H), 7.6
(
3
m, 2H), 7.54 (t, J=7.6 Hz, 1H), 7.5 (m, 2H), 7.39 (t, J=7.5 Hz, 1H),
.49 ppm (s, 1H); C NMR: d=141.8, 140.3, 129.8, 129.0 (2C), 128.9
2
-Hydroxy-3’-(hexafluoro-a-hydroxyisopropyl)biphenyl (2): At À758C, n-
1
3
butyllithium (3.9 mL, 1.6m in hexanes, 6.4 mmol) and, 5 min later, freshly
distilled trimethyl borate (1.4 mL, 1.2 g, 12 mmol) were added to 1-
bromo-2-(methoxymethoxy)benzene (0.67 g, 3.1 mmol) in THF (50 mL).
The volatile substances were replaced by toluene (30 mL), bromoarene 1
(
(
1
2C), 127.7, 127.2 (2C) 125.3, 125.2, 122.6 (q, J=286 Hz, 2C), 83.5 ppm
1
9
+
sept, J=28 Hz); F NMR: d=À75.9 ppm (s); MS: m/z (%): 320 (]M ,
00), 281 (7), 251 (100), 233 (59), 181 (100), 154 (100), 152 (100), 90
47), 76 (49); elemental analysis calcd for C15 O: C 56.26, H 3.15.
(
10 6
H F
(
0.68 g, 2.1 mmol), ethanol (30 mL),
2 2 3
H O (20 mL), Na CO (1.0 g,
found: C 56.12, H 2.35.
9
.4 mmol) and [Pd(PPh (0.074 g, 0.064 mmol). The mixture was
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
3 4
) ]
heated to 1108C for 4 h. After cooling, the organic layer was separated
Variable-temperature NMR spectroscopy: Variable-temperature NMR
and the aqueous phase extracted with diethyl ether (3ꢂ20 mL). The com-
spectra were recorded by using a Varian INOVA spectrometer operating
at a field of 14.4 T (600 MHz for H). Samples for experiments below
1
bined organic phases were dried with Na
and the crude biphenyl treated with trifluoroacetic acid/CH
0 mL). Saturated aq. NaHCO (50 mL) was added with vigorous stirring.
The organic phase was separated and dried with Na SO . After evapora-
tion of the solvent the resulting yellow oil was absorbed on silica gel
5 mL), which, when dry, was poured on top of a column filled with more
silica gel (75 mL). Upon elution with diethyl ether/petroleum ether (9/1),
2
SO
4
, the solvent was evaporated
2
Cl (1/4,
À1008C were prepared at a vacuum line. First a small amount of C
[D ]acetone (ca. 0.05 mL) was introduced by means of a microsyringe for
locking purposes. Next the NMR tube was immersed in liquid nitrogen
and evacuated in order to condense about 0.65 mL of CBrF (Freon
6 6
D or
2
1
3
6
2
4
3
(
13B1), which was transferred as gas from a commercial lecture bottle.
The tubes were subsequently sealed under reduced pressure (0.01 Torr)
9190
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Chem. Eur. J. 2010, 16, 9186 – 9192

Torsional Barriers of 2-Hydroxy- and 2-Fluorobiphenyl
FULL PAPER
with a methane/oxygen torch. Avoiding any rapid temperature change,
they were cautiously warmed to +258C, where the Freon develops a
pressure of about 12 atm. After 24 h at ambient temperature, the samples
can be safely introduced into the probe head of the spectrometer, already
Acknowledgements
This work was supported by the Universities of Perugia and Bologna, the
Ministero dell’Istruzione, Universitꢃ e Ricerca (MIUR, COFIN contracts
nr. 2004033322 and 2005035330) and the Schweizerische Nationalfonds
zur Fçrderung der wissenschaftlichen Forschung, Bern (grant 20-100’336-
02).
1
cooled to À508C. Low-temperature H spectra were acquired without
spinning by using a 5 mm dual direct probe with a 9000 Hz sweep width,
2
.0 ms (208 tip angle) pulse width, 3 s acquisition time and 1 s delay time.
F spectra were acquired with 90000 Hz sweep width, 2.5 ms (308 tip
1
9
angle) pulse width, 0.75 s acquisition time and 1 s delay time. A shifted
[
36]
sine bell weighting function equal to the acquisition time was applied
before the Fourier transform. Usually 32 to 128 scans were acquired.
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5
[
38]
°
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3
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04.
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3
the CF spectral region.
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[
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DNMR data. Therefore, the computed values have not been corrected
for zero-point energy contributions or other thermodynamic parameters.
This avoids artefacts that might result from the inevitably ambiguous
choice of an adequate reference temperature, from empirical scaling fac-
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À
the C CF
3
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Chem. Eur. J. 2010, 16, 9186 – 9192
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9192
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ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 9186 – 9192