The biphenyl-monitored effective size of unsaturated functional or fluorinated ortho substituents

Article abstract of DOI:10.1039/c0ob00136h

The size of a series of typical substituents has been probed by dynamic NMR measurements of the barriers to aryl-aryl rotation of the corresponding biphenyls. The resulting B values are meaningful because only mono-ortho substituted compounds were investigated and thus the results are not compromised by the non-additivity of multiple steric effects. On the basis of the chosen model system ethynyl and cyano groups were found to be slightly smaller than a phenyl ring. In contrast, vinyl and, in particular, formyl groups proved to be larger than phenyl. The latter difference is due to the loss of conjugation forces at the planar transition state. α-Hydroxyhexafluoroisopropyl is slightly more bulky than tert-butyl. Pentafluorophenyl and trifluoromethoxy exhibit nearly the same effective size as phenyl and methoxy, respectively. Trifluoromethyl is somewhat smaller than isopropyl.

Full text of DOI:10.1039/c0ob00136h

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
The biphenyl-monitored effective size of unsaturated functional or fluorinated
ortho substituents†‡
Renzo Ruzziconi,*a Sara Spizzichino,a Andrea Mazzanti,*b Lodovico Lunazzib and Manfred Schlosser*c
Received 17th May 2010, Accepted 30th June 2010
DOI: 10.1039/c0ob00136h
The size of a series of typical substituents has been probed by dynamic NMR measurements of the
barriers to aryl-aryl rotation of the corresponding biphenyls. The resulting B values are meaningful
because only mono-ortho substituted compounds were investigated and thus the results are not
compromised by the non-additivity of multiple steric effects. On the basis of the chosen model system
ethynyl and cyano groups were found to be slightly smaller than a phenyl ring. In contrast, vinyl and, in
particular, formyl groups proved to be larger than phenyl. The latter difference is due to the loss of
conjugation forces at the planar transition state. a-Hydroxyhexafluoroisopropyl is slightly more bulky
than tert-butyl. Pentafluorophenyl and trifluoromethoxy exhibit nearly the same effective size as phenyl
and methoxy, respectively. Trifluoromethyl is somewhat smaller than isopropyl.
the a-hydrogens in methoxymethyl or the methyls in isopropyl,
they resonate at different chemical shifts as long as the chirality
of the twisted species is maintained on the NMR time scale.
However, as soon as sufficient thermal energy is supplied, the
chiral conformer enantiomerizes, i.e. is converted it into its mirror
image by rotation about the central inter-ring axis until it passes
through the coplanar transition state (Scheme 1). If this process
occurs rapidly enough the two diastereotopic nuclei become
magnetically equivalent (isochronous). Determination of the so-
called coalescence temperature or, better, full line shape analysis
provides the torsional barrier.
Introduction
It would be of obvious importance to create a reliable set of
substituent parameters in order to predict and rationalize steric
hindrance to chemical reactions. Such data should correlate
reasonably well with the rates of standard transformations that are
impeded to various degrees, but always in a well defined fashion,
by non-bonded (intermolecularly collisional) interactions. Despite
ingenious attempts this goal has not yet been achieved.1
In order to test this correlation, a new benchmark for chemical
bulk is required. We believe that the biphenyl model would best
serve this purpose. The ground state shape of biphenyl itself is
twisted about the central aryl-aryl bond by some 44◦ in order to
alleviate the repulsion between the two pairs of ortho-hydrogen
atoms (at the 2-/2¢- and 6-/6¢-positions).2–5 The twist angle
increases to about 50◦ if one fluorine atom occupies an ortho site
and attains approximately 60◦ with the more voluminous chlorine
and bromine atoms or a methyl group.4,5 At the same time the
energy required for forcing both aryl rings into coplanarity grows
substantially.
Scheme 1 Enantiomerization of a chiral biaryl conformer into its mirror
image by passing through a coplanar transition state.
This energy gap between the twisted ground state and the
coplanar transition state structure can be experimentally assessed
by variable-temperature (“dynamic”) NMR measurements if a
stereolabel Q* is introduced at the 3¢-position in addition to the
substituent R to be probed at the 2-position. If the auxiliary 3¢-
substituent harbors a pair of diastereotopic atoms or groups, e.g.
Our first attempts were aimed at determining the torsional
barriers (“B values”, B standing for biaryl) of methyl, ethyl,
isopropyl, tert-butyl and, in addition, of the most common
heterosubstituents, specifically the halogens, hydroxyl, alkoxy,
nitro, amino, dimethylamino and trimethylammonio.6 Although
most of the project was readily executed (Table 1), the torsional
barriers of the 2-hydroxy and the 2-fluoro compounds proved to
be too small to be measured when our standard diastereotopicity
probes, isopropyl or isopropyldimethylsilyl, were employed. The
minimal energy required for planarization of the unsubstituted
biphenyl (B 2.24 or rather 2.05) was anyway far below experimental
reach so that we had to resort to a computational result.4,5
The problems encountered with the hydroxyl and fluoro-
substituents were eventually solved by attaching a-hydroxyhexa-
fluoroisopropyl as a new diastereotopicity probe to the 3¢-
position. The barriers found in that way amount to 5.4 and
4.4 kcal/mol, respectively (Table 1).7 They can be broken down
into the individual contributions or increments stemming from the
aChemistry Department, University, Via Elce di Sotto 10, I-06100, Perugia,
Italy. E-mail: ruzzchor@unipg.it; Fax: +39 075 5855262; Tel: +39 075
5855543
bOrganic Chemistry Department “A. Mangini”, University of Bologna, Viale
Risorgimento 4, I-40136, Bologna, Italy. E-mail: mazzand@ms.fci.unibo.it;
Fax: +39 051 2093654; Tel: +39 051 2093633
cInstitute of Chemical Sciences and Engineering, Ecole Polytechnique
Fe´de´rale (EPFL – BCh), CH-1015, Lausanne, Switzerland. E-mail:
manfred.schlosser@epfl.ch; Tel: 41 021 6939351
† This article is dedicated to the memory of Professor Carlo Rosini
(Universita` della Basilicata, Potenza) whose untimely demise means a
permanent loss for the entire Italian stereochemical community.
‡ Electronic Supplementary Information (ESI) available: 1H NMR spectra
of 1–12. See DOI:10.1039/c0ob00136h/
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Table 1 B values [in kcal/mol] of hydrogen-, alkyl-, nitrogen-, oxygen-
or halogen-bound substituents as determined by dynamic NMR mea-
surements (in parentheses the numbers resulting from quantum chemical
calculations) and the corresponding substituent increments I2-R/2¢H [again
in kcal/mol] (in parentheses the increments previously reported in ref. 8)
focus on four typical fluorine-containing groups, the pentaflu-
orophenyl, a-hydroxyhexafluoroisopropyl, trifluoromethyl and
trifluoromethoxy substituents (as probed with compounds 9–12).
The 1H and 13C NMR spectra were recorded in the same
manner as previously described.6 A typical series of spectra taken
of 2-ethynyl-3¢-(isopropyldimethylsilyl)biphenyl (3) is reproduced
below (Fig. 1).
c
Ra
B b
Bcalc
I2-R/2¢-Hd (Ilit)e
H
CH3
—
7.4
8.7
11.1
15.5
8.1
6.9
18.1
7.6
5.4
5.6
2.0f
7.1
—
1.0 (1.0)
6.4 (9.7)
7.7 (—)
C2H5
CH(CH3)2
C(CH3)3
NH2
N(CH3)2
N(CH3)3
NO2
11.1
15.6
8.4
6.8
18.2
7.8
5.3
4.5
6.1
4.3
7.3
8.5
9.9
10.1 (12.5)
14.5 (—)
7.1 (9.6)
5.9 (7.8)
17.1 (—)
6.6 (7.7)
4.4 (6.5)
4.6 (6.4)
4.7 (—)
3.4 (4.6)
6.7 (9.1)
7.7 (10.2)
9.0 (10.9)
OH
OCH3
OCH2OCH3
F
Cl
Br
5.7
4.4
7.7
8.7
I
10.0
a Substituent at the 2-position of the biphenyl. b Experimentally deter-
mined torsional barriers.6,7 c Computed barriers. d Increments obtained by
subtracting 1.0 kcal/mol5 from the corresponding B value. e Increments
previously published (ref. 8). f Ref. 5
repulsion between the 2-substituent R and the 2¢-hydrogen atom
(I2-R/2¢-H) and the repulsion between the 6- and 6¢-hydrogen atoms
(I6-H/6¢-H). The substituent-specific increments are thus obtained
by subtracting 1.0 kcal/mol (representing the I6-H/6¢-H interaction5)
from the experimental torsional barriers. The discrepancy with
previously reported I2-R/2¢-H increments8 is substantial (e.g. 6.4 vs 9.7
for methyl, 4.3 vs 6.5 for hydroxyl and 3.3 vs 4.6 for fluorine). This
is due to the fact that the values reported by Sternhell et al.8 are
derived from 2,2¢-substituted biphenyls to which a strict additivity
rule was applied. As demonstrated,6,7 this additivity rule is not
valid.
Fig. 1 Compound 3: Temperature dependence of the 13C signal of the
silicon-bound methyl groups (recorded at 150.8 MHz in a 3 : 1 v/v mixture
of chlorodifluoromethane and dichlorofluoromethane) on the left, and the
simulated spectra with the corresponding rate constants on the right.
Results
The present work describes three significant extensions of the
previous studies (Scheme 2). First, we determine the B val-
ues of phenyl, ethenyl (vinyl), ethynyl (acetylide) and the aza-
analogous cyano group (as probed with compounds 1–4). These
substituents incorporate characteristic aromatic (one and a half
bond), olefinic (double bond) and acetylenic (triple bond) struc-
tural entities. Next, we turn to the three oxidation levels of
carbon–oxygen functional groups, especially the hydroxymethyl,
formyl and carboxy groups and include also the ester unit
methoxycarbonyl (as probed with compounds 5–8). Finally, we
The NMR spectra of compounds 1–2 and 4–12 were recorded
analogously. Sample temperatures were varied until the decoales-
cence temperature was detected unequivocally in each case. Line
shape analysis and spectra simulation provided the activation
energies of the aryl–aryl rotation. These numbers are listed as
substituent-specific B values along with the computed barriers and
the substituent increments I2-R/2¢-H (Table 2). The latter increments
were obtained by subtracting 1.0 kcal/mol (i.e. the steric repulsion
approximately existing between one coplanar pair of o- and o¢-
hydrogen atoms) from the B value (i.e. the experimental torsional
energy) and thus represent the repulsive force a substituent R
located at the 2-position experiences from a coplanar o-hydrogen
atom facing it on the neighboring ring.
The synthesis of most model compounds relied on the Suzuki–
Miyaura coupling method.9,10 Such reaction are known to be
straightforward. The fundamental choice is to place the 2-R
substituent next to the dihydroxyboryl group and to let the
Scheme 2 The scope of the present investigation: examining the model
compounds 1–12.
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Table 2 B values (in kcal/mol) of aromatic, olefinic, (aza)acetylenic,
carbon–oxygen functional and fluorine-containing substituents as as-
sessed by dynamic NMR measurements of 2-R substituted biphenyls (in
parentheses, for comparison, the numbers obtained by quantum chemical
calculations) and the corresponding substituent increments I2-R/2¢-H.
silyl)phenylboronic acid (Scheme 4). The latter building block
was made from 1,3-dibromobenzene in two operational steps
(Scheme 4).
c
Cpda
2-R
Bb
Bcalc
I2-R/2¢-Hd (Ilit)e
1
C6H5
CH CH2
7.5
8.2
6.0
5.9
7.9
10.2
7.7
7.7
7.4
8.5
5.3
5.2
7.8
11.0
8.5
8.3
8.1
16.9
9.2
4.8
6.5 (7.9)
7.5 (—)
5.0 (—)
4.9 (6.1)
6.9 (9.8)
9.2 (—)
6.7 (—)
6.7 (8.2)
6.7 (—)
15.5 (—)
9.5 (12.1)
4.5 (—)
2
3
C
C
CH
N
4
5
CH2OH
CH
COOH
COOCH3
C6F5
C(CF3)2OH
CF3
OCF3
6
O
7
8
9
7.7
10
11
12
16.5f
10.5
5.5
a Numbering as in Scheme 2. b Barriers to aryl-aryl rotation (B val-
ues) [in kcal/mol]. c Computed barriers (see Experimental Section)
[in kcal/mol]. d Increments for the 2-R/2¢-H repulsion alone by deduc-
tion of 1.0 (representing the 2-H/2¢-H interaction) from the B values
[in kcal/mol]. e Increments previously published (ref. 8). f Value obtained
by monitoring the 1H signal of the silicon-bonded methyls of Q* and from
the 19F spectra of the CF3 groups.
Scheme 4 Biaryls 2 and 4, prepared by palladium-catalyzed cou-
pling of 2-R-substituted bromobenzenes with 3-(isopropyldimethylsilyl)-
phenylboronic acid.
As triple bonds tend to be labile under Suzuki–Miyaura condi-
tions, the 2-ethynyl biaryl 3 was made according to a Negishi-like
protocol (Scheme 5).11 2-Ethynyl-3¢-(isopropyldimethylsilyl)biaryl
(3) was obtained from 1-bromo-2-(trimethylsilylethynyl)benzene
in 72% yield.
bromoarene or iodoarene component bear the 3-Q* di-
astereotopicity probe or to opt for the opposite combination.
On top of that, 2-bromo-3¢-(isopropyldimethylsilyl)biphenyl
has been designated to act as a key intermediate in the
preparation of numerous other 2-R-substituted biphenyls (see
below). Its palladium-catalyzed coupling with phenylboronic
acid turned out to offer the most convenient access to 2-phenyl-
3¢-(isopropyldimethylsilyl)biphenyl
(3¢-isopropyldimethylsilyl-
1,1¢;2¢,1¢-terphenyl, 1) as a practical comparison has revealed
(Scheme 3). Biphenyl 1 can also be readily accessed by
coupling 3-(isopropyldimethylsilyl)phenylboronic acid with
2-bromobiphenyl or by coupling biphenyl-2-ylboronic acid with
1-bromo-3-(isopropyldimethylsilyl)benzene (Scheme 3).
Scheme 5 2-Ethynyl-3¢-(isopropyldimethylsilyl)biphenyl (3), prepared by
nickel-catalyzed coupling of 2-(2-trimethylsilyl)ethynylphenylzinc bromide
with 1-bromo-3-(isopropyldimethylsilyl)benzene.
The inverse combination (with respect to Scheme 4) of the
Suzuki–Miyaura components, 2-R-substituted phenylboronic
acids coupled with 1-bromo-3-(isopropyldimethylsilyl)benzene,
had been explored previously6 in an attempt to get hold of
large amounts of 2-bromo-3¢(isopropyldimethylsilyl)biphenyl
(2-R = Br). Unfortunately this product, conceived to act as a
turntable intermediate on the way to whole a series of model
compounds, was almost more rapidly consumed than formed.
Therefore, we had to resort to the equally unclean coupling
between 1,2-dibromobenzene and 3-(isopropyldimethylsilyl)-
phenylboronic acid.6 A satisfactory result was now achieved
by merely replacing the coupling unit 1-bromo-3-(isopropyl-
dimethylsilyl)benzene by its iodo analog. 2-Bromo-3¢-
(isopropyldimethylsilyl)biphenyl was isolated in 89% yield. It was
Scheme
silyl)biphenyl (1).
3 Three routes leading to 2-phenyl-3¢-(isopropyldimethyl-
The 2-vinyl and 2-cyano biaryls 2 (54%) and 4 (60%) were
prepared by palladium-catalyzed condensation of 2-bromo-
styrene and 2-bromobenzonitrile with 3-(isopropyldimethyl-
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readily converted (see Scheme 6) by consecutive halogen/metal
permutation and electrophilic trapping into the biaryls 5 (directly
with paraformaldehyde or indirectly by reduction of aldehyde
6 with sodium borohydride, 95%), 6 (with dimethylformamide,
after hydrolysis, 62%), 7 (with dry ice, after neutralization, 63%),
10 (with hexafluoroacetone, 67%) and 9 (with hexafluorobenzene,
57%). The methyl ester 8 (89%) was obtained by treatment of the
carboxylic acid 7 with ethereal diazomethane (Scheme 6).
Discussion
No set of parameters is without built-in bias. Inequalities inherent
in the reference system will sooner or later manifest themselves and
delude intuition. The resulting discrepancy between expectation
and reality provides new insight. Whatever test applied, a dimethyl-
amino group bound to a saturated counterpart will score as more
voluminous than a simple amino group. But the latter appears to be
evidently “bigger” when attached to the ortho position of a biaryl.
The reason is a consequence of differences in spatial orientation.
The amino group (B 8.1) has its lone pair aligned in parallel
with the adjacent aromatic p-cloud at the twisted ground state.
The corresponding energy of conjugation is lost at the coplanar
transition state where steric hindrance forces the amino group into
a skew position.6 In contrast, the dimethylamino (B 6.9) entity is
twisted out-of-resonance with respect to the adjacent aryl ring
in both the ground state and the transition state. Therefore, as
there is no conjugation energy from the beginning there is no
penalty for sacrificing it either.6 The dependence of conjugation
on conformation is without doubt the origin of the higher B values
of vinyl (B 8.2) and formyl (B 10.2) in comparison with phenyl (B
7.5) and hydroxymethyl (B 7.9), respectively.
Furthermore, noteworthy are the seemingly identical spacial
requirements of methyl (B 7.4) and phenyl (B 7.5). This suggests
a perpendicular orientation of the (unsubstituted) 2-phenyl group
with respect to the coplanar biaryl unit at the torsional transition
state. In this geometry the distance of the 2¢-hydrogen atom to the
2-methyl group is indeed a bit longer than that to the center of
the 2-phenyl ring. These changes of the conformational landscape
are indeed nicely reproduced by DFT calculations (Fig. 2 and
Experimental). The barrier to 2-phenyl/biphenyl rotation has
been previously derived from the dynamic NMR study of 3,3¢-
diisopropyl-1,1¢;2¢,3¢¢¢-terphenyl.12 The number reported (B 7.7)
coincides with the newly found one (B 7.5) within the limits of
error ( 0.2 kcal/mol, mainly due to uncertainty in the temperature
determination).
Scheme 6 Access to the biaryls 5–10 by palladium-catalyzed cou-
pling of 2-bromo-phenylboronic acid with 1-iodo-3-(isopropyldimethyl-
silyl)benzene followed by halogen–metal permutation and electrophilic
trapping.
1-Bromo-3-(isopropyldimethylsilyl)benzene can be employed
without problems for the coupling with arylboronic acids as long
as the latter do not bear bromo or iodo substituents. In this
way, clean reactions were performed affording 2-formyl (6), 2-
trifluoromethyl (11) and 2-trifluoromethoxy (12) substituted 3¢-
(isopropyldimethylsilyl)biphenyls in 91%, 80% and 88% yield,
respectively (Scheme 7).
Fig. 2 Torsional ground state (structures in the bottom line) and
transition state (structure in the top line) of 3-(isopropropyldimethyl-
silyl)-1,1¢;2¢,3¢¢¢-terphenyl [Q* = Si(CH3)2CH(CH3)2]: correlated motion
of the two lateral aryl rings.
The last four model compounds feature prominent oligofluoro
substituents. The famous quote “...trifluoromethyl is at least as big
as isopropyl...”13 has stirred up emotions. The judgment appears
to be based on a somewhat uncritical appraisal of the pertinent
Scheme
7
Biaryls 6, 11 and 12 by palladium-catalyzed coupling
of 2-R-substituted phenylboronic acids with 1-bromo-3-(isopropyl-
dimethylsilyl)benzene.
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A values14–16 (Scheme 8), the energy differences between the axial
and equatorial conformers of (trifluoromethyl)cyclohexane (A 2.4
– 2.5)17 and isopropylcyclohexane (A 2.15).14,18 The inward leaning
C–H bond of an axial methyl group experiences far more repulsion
by the axial hydrogens at the homovicinal ring position than the
compressed lone pairs of an axial fluorine (A 0.15) do (Scheme 8).
Unlike tert-butyl (A 4.90), isopropyl (A 2.15) can rotate all its
methyl groups outward, away from the cyclohexane chair, even if
this goes at the expense of an increase in order (i.e. an entropy
decrease). If trifluoromethyl is the axial substituent, inevitably
one of its halogen atoms collides with the axial hydrogen atoms
at the 3- and 5-position of the ring. Our B values rank CF3 (B
10.5) a little smaller than CH(CH3)2 (B 11.1) but clearly bigger
than CH3 (B 7.4). By the way, the F–C–F angles of 106.9◦ in
benzotri◦fluoride19 are somewhat narrower than the H–C–H angles
of 108.1 in toluene.20
Fluorine is a favorite tool for engineering molecular properties.
For this reasonit plays a privilegedrole incurrentresearchfocusing
on new pharmaceuticals, agrochemicals and high-performance
materials.24–30 Scaling the size of common fluorinated substituents
may help to promote such practical applications.
Experimental section
Generalities
Starting materials were purchased from Aldrich-Fluka (CH-
9479 Buchs) and Apollo Scientific (UK-SK62QR Stockport)
unless literature sources or details of the preparation are given.
All commercial reagents were used without further purification,
except trimethyl borate which was distilled before use.
Air and moisture sensitive compounds were stored in Schlenk
tubes or Schlenk burettes. They were protected by, and handled
under, an atmosphere of 99.995% pure nitrogen, using appropriate
glassware. Tetrahydrofuran and diethyl ether were stored over
potassium hydroxide pellets in the presence of cuprous chloride,
from which they were distilled, before being redistilled from
sodium wire after the characteristic blue color of in situ generated
sodium biphenyl ketyl (benzophenone-sodium “radical anion”)
had been found to persist. “Petroleum ether” refers to an alkane
fraction having a boiling range of 40–60 ◦C.
Scheme 8 A values and, for comparison, B values of fluorine, methyl,
isopropyl, tert-butyl and trifluoromethyl.
The temperature of liquid nitrogen/methanol and dry
ice/methanol baths are consistently indicated as -90 ◦C and
-75 ◦C, respectively, that of ice baths as 0 ◦C. Ambient temperature
(“room temperature”) translates into +25 ◦C although the real
temperature inthe laboratoryvaries between 22and26 ◦C. Melting
ranges (m.p.) given were found to be reproducible after resolidifi-
cation unless decomposition (“dec.”) is specified. The temperature
readings were corrected using a calibration curve established with
authentic standards.
1H, 13C and 19F NMR spectra were recorded at 400, 100.6
and 376.5 MHz, respectively, samples having been dissolved in
deuterochloroform. Chemical shifts (d) are given in ppm relative
to the internal standards tetramethylsilane and trichlorofluo-
romethane. IR spectra were taken of chloroform solutions in the
4000–625 cm-1 frequency range, mass spectra by electron impact
fragmentation at 70 eV ionization potential and 200 ◦C source
temperature.
The purity of all final products was testified by elemental
analyses (performed by the Redox Company in Monza and
by Dr E. Solari at the Analytic Services of EPFL-ISIC) and
by gas chromatography using two capillary columns of dif-
ferent polarity (30 m ¥ 0.35 mm ¥ 0.25 mm DB 5MS [5%
phenylmethylpolysiloxane] and 30 m ¥ 0.35 mm ¥ 0.25 mm DB23
[50% cyanopropylmethylpolysiloxane]). This holds also for the
highly (17–27%) fluorinated products 9–12, the elemental analyses
of which deviated from the calculated numbers considerably more
than by the ordinary error limits (of 0.3%). This happens often
with samples containing more than 10% of fluorine in weight.
Replacing the 2-phenyl substituent (in compound 1) by a
pentafluorophenyl entity (in compound 9) should raise the barrier
to the corresponding aryl–aryl rotation only moderately (the tor-
sional activation energy of 2,2¢-difluorobiphenyl is approximately
4.8 kcal/mol4) and increase that of the 2-R-phenyl/3¢Q*-phenyl
rotation hardly at all. These assumptions were confirmed by the
experiment (Table 2).
As evidenced by its impressive
B value of 16.5, a-
hydroxyhexafluoroisopropyl undoubtedly belongs to the very
bulky substituents. In drug design it may qualify as a metabolically
stable mimic of the similarly voluminous tert-butyl (B 15.5) or tert-
amyl (1,1-dimethylpropyl) group.
Trifluoromethoxy is a substituent that receives growing atten-
tion in the life sciences arena.21 Having virtually the same dimen-
sions as methoxy (B 5.6) it belongs to the smallest substituents in
our present collection (Table 2, compound 12, B 5.5). Anisole and
(trifluoromethoxy)benzene nevertheless exhibit some structural
differences (Scheme 9). Whereas all heavy atoms occupy the same
plane at the ground state of anisole, its trifluorinated analog favors
the orthogonal orientation of the O–CF3 group with respect to
the ring plane.22,23 This change in conformational preference may
be merely caused by the steric interaction between an ortho-
C–H bond and the CF3 substituent (being bigger than CH3).
Alternatively, it may mirror a stereoelectronic effect (the electron-
withdrawing halogens impeding an effective conjugation between
the OCF3 oxygen and the aromatic p-sextet).
Intermediates and Final Products
(3-Iodophenyl)isopropyldimethylsilane. At -95 ◦C (liquid air/
methanol bath), butyllithium (9.10 mmol) in hexanes (5.7 mL)
and, 5 min later, chloroisopropyldimethylsilane (2.5 g, 18 mmol)
Scheme 9 Relative populations of anisole and (trifluoromethoxy)benzene
conformations.
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were added to a solution of 1,3-diiodobenzene (3◦.3 g, 14 mmol)
in dry tetrahydrofuran (30 mL). After 2 h at -75 C the mixture
was poured into water (0.10 L) and extracted with diethyl ether
(3 ¥ 40 mL). The combined extracts were dried with sodium
sulfate. After evaporation of the solvent, distillation of the residue
afforded a pale yellow liquid product; 2.50 g (90%); b.p. 119–
121 ◦C/0.2 mmHg. 1H NMR: d 7.67 (d, J = 7.9 Hz, 1 H), 7.43 (d,
J = 7.3 Hz, 1 H), 7.08 (t, J = 7.4 Hz, 1 H), 0.93 (s, 7 H), 0.22 (s, 6
H). 13C NMR: 142.4, 142.3, 137.6, 132.7, 129.6, 95.4, 17.4 (2 C),
13.6, -5.5 (2 C). MS: m/z (%) 304 (M+, 36), 289 (2), 261 (100), 247
(11), 134 (23), 119 (55), 43 (17). Anal.: calcd for C11H17ISi (304.24)
C, 43.43; H, 5.63; found: C, 43.74; H, 6.06.
which, when dry, was poured on top of a column filled with
more silica gel (75 mL). Upon elution with hexanes, 2-vinyl-3¢-
(isopropyldimethylsilyl)biphenyl was collected as a colorless oil;
0.14 g (54%). 1H NMR: d 7.7 (m, 1 H), 7.5 (m, 2 H), 7.41 (t, J =
6.6 Hz, 1 H), 7.4 (m, 4 H), 6.74 (dd, J = 17, 11 Hz, 1 H), 5.72 (d,
J = 17 Hz, 1 H), 5.20 (d, J = 11 Hz, 1 H), 1.00 (s, 7 H), 0.29 (s,
6 H). 13C NMR: d 141.1, 139.8, 138.2, 136.1, 135.9, 135.5, 132.7,
130.1, 127.6, 127.4, 127.3, 125.8, 114.5 (2 C), 17.4 (2 C), 13.8, -5.3
(2 C). MS: m/z (%) 280 (M+, 1), 237 (14), 195 (10), 178 (100), 165
(25), 101 (12), 59 (82). Anal.: calcd for C19H24Si (280.48) C, 81.36;
H, 8.62; found: C, 81.43; H, 8.67.
2-Cyano-3¢-(isopropyldimethylsilyl)biphenyl (4). Analogously,
2-Bromo-3¢-(isopropyldimethylsilyl)biphenyl6. Ethanol
(5.0
from
(3-bromophenyl)(isopropyl)dimethylsilane
(0.35
g,
mL), benzene (10 mL), (3-iodophenyl)isopropyldimethylsilane
(0.50 g, 1.6 mmol), 2.0 M aq. potassium carbonate (1.6 mL),
tetrakis[triphenylphosphine]palladium(0) (0.040 g, 0.034 mmol)
were added consecutively to 2-bromophenylboronic acid (0.36 g,
1.8 mmol). The mixture was kept at reflux for 3 h. After cooling,
water was added and the mixture was extracted with diethyl
ether (20 mL). After drying with sodium sulfate the solvent
was evaporated. Elution of the residue from silica gel (0.12 L)
with petr◦oleum ether afforded a colorless oil; 0.49 g (90%); b.p.
1.4 mmol) and 2-bromobenzonitrile (0.16 g, 0.88 mmol),
biphenylnitrile 4 was obtained as a colorless oil; 0.147 g (60%).
1H NMR: d 7.79 (dd, J = 7.7, 0.8 Hz, 1 H), 7.7 (m, 1 H), 7.65 (td,
J = 7.8, 1.4 Hz, 1 H), 7.5 (m, 5 H), 0.99 (s, 7 H), 0.30 (s, 6 H).
13C NMR: d 145.8, 139.4, 137.3, 134.2 (2 C), 133.7, 132.7, 130.1,
129.0, 127.9, 127.4, 118.7, 111.4, 17.5 (2 C), 13.7, -5.3 (2 C). IR
(chloroform): nmax 3016, 2958, 2874, 2227 cm-1. MS: m/z (%) 279
(M+, 1), 264 (2), 236 (100), 220 (23), 206 (16). Anal.: calcd for
C18H21NSi (279.45) C, 77.36; H, 7.57; found: C, 77.41; H, 7.66.
1
171–173 C/0.2 mmHg. H NMR: d 7.67 (d, J = 8.0 Hz, 1 H),
7.55 (s, 1 H), 7.52 (d, J = 6.7 Hz, 1 H), 7.4 (m, 4 H), 7.20 (ddd, J =
9.1, 7.3, 2.4, 1 H), 0.97 (s, 7 H), 0.27 (s, 6 H) ppm. 13C NMR: d
142.8, 140.1, 138.3, 135.0, 133.1, 133.1, 131.3, 129.6, 128.6, 127.3,
127.2, 122.7, 17.6 (2 C), 13.8, -5.3 (2 C) ppm. MS : m/z (%) =
334 (M+ + 1, 2), 332 (M+ - 1, 2), 291 (100), 289 (100), 211 (14),
152 (35), 43 (33). Anal.: calcd for C17H21BrSi (333.34) C, 61.25;
H, 6.35; found: C, 61.30; H, 6.80.
2-Ethynyl-3¢-(isopropyldimethylsilyl)biphenyl (3). At -75 ◦C,
butyllithium (0.81 mmol) in hexanes (0.50 mL) was added to
(2-bromophenylethynyl)trimethylsilane (0.20 g, 0.80 mmol) in
tetrahydrofuran. At 0 ◦C, zinc bromide (0.20 g, 0.89 mmol),
and after stirring for 15 min, 3-bromophenylisopropyl-
dimethylsilane (0.20 g, 0.78 mmol) and tetrakis[triphenyl-
phosphine]palladium(0) were consecutively added. The mixture
was kept under reflux for 12 h before being absorbed on silica gel
(10 mL). Elution with petroleum ether from a column filled with
more silica (0.10 L) gave a viscous colorless oil; 0.160 g (72%). 1H
NMR: d 7.78 (m, 1 H), 7.64 (broad d, J = 7.8 Hz, 1 H), 7.56 (ddd,
J = 7.6, 1.9, 1.4 Hz, 1 H), 7.53 (dt, J = 7.3, 1.3 Hz, 1 H), 7.4 (m, 3
H), 7.32 (ddd, J = 7.7, 6.6, 2.2 Hz, 1 H), 3.03 (s, 1 H), 0.84 (s, 7 H),
0.27 (s, 6 H). 13C NMR: d 144.7, 139.2, 138.1, 135.0, 133.9, 133.4,
133.1, 129.6, 129.4, 128.9, 127.3, 126.9, 120.4, 83.2, 80.0, 17.6 (2
C), 13.8, -5.3 (2 C). IR: nmax 3308, 3012, 2957, 2881 cm-1. MS: m/z
(%) 278 (M+, 5), 235 (99), 219 (100), 165 (8), 43 (6). Anal.: calcd
for C19H22Si (278.46) C, 81.95; H, 7.96; found: C, 81.79; H, 8.00.
3¢-(Isopropyldimethylsilyl)-2-phenylbiphenyl
[3-(isopropyl-
dimethylsilyl)-1,1¢;2¢,1¢¢terphenyl] (1). Ethanol (3.0 mL),
benzene (5.0 mL), 2-bromo-3¢-(isopropyldimethylsilyl)biphenyl
(0.14 g, 0.42 mmol), 2.0 M aq. potassium carbonate (1.6 mL),
tetrakis[triphenylphosphine]palladium(0) (0.040 g, 0.034 mmol)
were added consecutively to phenyl boronic acid (0.056 g,
0.46 mmol). After refluxing the mixture for 3 h, water (10 mL) was
added and the mixture was extracted with diethyl ether (20 mL).
The dried organic layer was evaporated. Elution of the residue
with petroleum ether from silica gel (90 mL) afforded a viscous
colorless oil; 0.98 g (71%). 1H NMR: d 7.45 (m, 4 H), 7.3 (m, 3 H),
7.2 (m, 6 H), 0.79 (s, 7 H), 0.05 (s, 6 H). 13C NMR: d 141.6, 140.8,
140.7, 140.3, 137.8, 136.0, 131.9, 130.6, 130.5, 129.9, 129.8 (2 C),
127.8 (2 C), 127.4, 127.3, 127.3, 126.4, 17.5 (2 C), 13.6, -5.6 (2
C). MS m/z (%) 330 (M+, 27), 287 (100), 271 (25), 59 (33). Anal.:
calcd for C23H26Si (330.54) C, 83.57; H, 7.93; found C, 83.34; H,
8.00.
2-Formyl-3¢-(isopropyldimethylsilyl)biphenyl {2-[3-(isopropyl)-
dimethylsilylphenyl]benzaldehyde} (6). At -75 ◦C, tert-
butyllithium (0.66 mmol) in pentanes (0.33 mL) and
azeotropically (using benzene) dried dimethylformamide
(0.10 mL, 0.094 g, 1.4 mmol) were added consecutively to
2-bromo-3¢-(isopropyldimethylsilyl)biphenyl6 (0.22 g, 0.66 mmol)
in tetrahydrofuran (10 mL). The mixture was absorbed on silica
gel (5 mL) and eluted with a 1 : 9 (v/v) mixture of diethyl ether
and petroleum ether from a column filled with more silica gel
3¢-Isopropyldimethylsilyl-2-vinylbiphenyl (2). At -75 ◦C, butyl-
lithium (1.4 mmol) in hexanes (0.84 mL) and,
5 min
later, trimethyl borate (0.62 g, 6.0 mmol) were added to
3-bromophenylisopropyldimethylsilane (0.35 g, 1.4 mmol) in
tetrahydrofuran (10 mL). The hexanes were stripped off and
replaced by toluene (10 mL). 2-Bromostyrene (0.16 g, 0.90 mmol),
ethanol (8.0 mL), water (3.0 mL), potassium carbonate
(0.10 g, 0.94 mmol), and tetrakis[triphenylphosphine]palladium(0)
(0.074 g, 0.064 mmol) were added. The mixture was heated to
reflux for 2.5 h before being absorbed on silica gel (5.0 mL)
1
(50 mL) to give a colorless oil; 0.105 g (62%). H NMR: d 9.98
(s, 1 H), 8.05 (d, J = 7.8 Hz, 1 H), 7.64 (td, J = 7.6 and 1.4 Hz,
1 H), 7.56 (dd, J = 7.2, 0.8 Hz, 1 H), 7.5 (m, 4 H), 7.38 (dd, J =
7.5, 1.3 Hz, 1 H), 0.99 (s, 7 H), 0.27 (s, 6 H). 13C NMR: d 192.4,
146.3, 139.2, 136.8, 135.5, 133.8, 137.7, 133.5, 130.8, 130.4, 127.7,
127.6, 127.5, 17.5 (2 C), 13.7, -5.4 (2 C). IR: nmax 3020, 2957,
2865, 1691 cm-1. MS: m/z (%) 282 (M+, 3), 239 (14), 165 (100).
4468 | Org. Biomol. Chem., 2010, 8, 4463–4471
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Anal.: calcd for C18H22OSi (282.45) C, 76.54; H, 7.85; found: C,
76.40; H, 7.94.
b.p. 180–185 ◦C/0.2 mmHg (Hickmann flask); 0.115 g (57%).
1H NMR: d 7.5 (m, 3 H), 7.3 (m, 5 H), 0.83 (s, 7 H), 0.14 (s, 6
H); 13C NMR: d 144.0 (broad d, J = 241 Hz), 143.3, 140.5 (bd,
J = 252 Hz, 2 C), 139.4, 138.3, 137.3 (dt, J = 251, 16 Hz), 133.9,
132.9, 131.0, 130.3, 129.7, 128.9, 127.5, 127.4, 125.0, 116.0 (t, J =
22 Hz), 17.2 (2 C), 13.7, -5.6 (2 C). 19F NMR: d -140.58 (dd, J =
23 and 8.0 Hz, 2 F), -156.27 (t, J = 22 Hz, 1 F), -163.28 (td, J =
22, 7.0 Hz, 2 F). MS: m/z (%) 420 (M+, 15), 377 (100), 280 (79),
262 (32), 77 (43), 43 (10). Anal.: calcd for C23H21F5Si (420.49) C,
65.70; H, 5.03; found: C, 66.62; H, 5.18.
2-Hydroxymethyl-3¢-(isopropyldimethylsilyl)biphenyl
{2-[3-
(isopropyldimethylsilyl)phenyl]benzyl alcohol} (5). Aldehyde 6
(0.20 g, 0.71 mmol) was treated with sodium borohydride (0.027 g,
0.71 mmol) in methanol (10 mL) at +25 ◦C for 1 h. Diethyl ether
(10 mL) was added and the solution was washed with 0.1 M
sulfuric acid (5.0 mL). Absorption of the organic layer on silica
gel (10 mL) and elution with a 1 : 4 (v/v) mixture of diethyl ether
and hexanes from a column filled with more silica (0.10 L) to
give a colorless oil; 0.192 g (95%). 1H NMR: d 7.57 (dd, J = 7.0,
1.5 Hz, 1 H), 7.51 (dt, J = 7.1, 1.3 Hz, 1 H), 7.5 (m, 1 H), 7.4 (m,
4 H), 7.30 (dd, J = 7.2, 1.7 Hz, 1 H), 4.62 (s, 2 H), 0.96 (s, 7 H),
0.26 (s, 6 H). 13C NMR: d 141.6, 139.6, 138.7, 138.1, 134.6, 132.8,
130.1, 129.4, 128.3, 127.6 (2 C), 127.5, 63.2, 17.6 (2 C), 13.7, -5.33
(2 C). IR: nmax 3315, 2953, 2880, 1209 cm-1. MS: m/z (%) 284 (M+,
3), 165 (20), 75 (100), 43 (10). Anal.: calcd for C18H24OSi (284.47)
C, 76.00; H, 8.50; found C, 75.99; H, 8.69.
2-(Hexafluoro-a-hydroxyisopropyl)-3¢-(isopropyldimethylsilyl)-
biphenyl {2-[3-(isopropyldimethylsilyl)phenyl]-1-[2,2,2-trifluoro-1-
(trifluoromethyl)ethanol} (10). Gaseous hexafluoroacetone was
generated by adding cautiously the trihydrate to concentrated
(98% aq.) sulfuric acid at +50 ◦C and it was condensed, through
Teflon tubing, into a 50 mL Schlenk tube cooled to -75 ◦C. In
a second Schlenk tube, butyllithium (0.60 mmol) in hexanes
(0.37 mL) was added dropwise, in 15 min, to a solution of 2-
bromo-3¢-(isopropyldimethylsilyl)biphenyl (0.20 g, 0.60 mmol) in
tetrahydrofuran (10 mL) at -95 ◦C. Warming the Schlenk tube
2-Carboxy-3¢-(isopropyldimethylsilyl)biphenyl
pyldimethylsilyl)phenyl]benzoic
acid}
{2-[3-(isopro-
(7). Butyllithium
◦
slowly to +25 C made the hexafluoroacetone stream through a
(0.81 mmol) in hexanes (0.50 mL) was added to 2-bromo-
3¢-(isopropyldimethylsilyl)biphenyl (0.27 g, 0.81 mmol) in
tetrahydrofuran (5.0 mL) at -75◦. The mixture was immediately
poured onto an excess of freshly crushed dry ice, the cold bath was
removed and the temperature was allowed to rise to +25 ◦C. The
pale yellow solid left behind after evaporation of the solvent was
washed with diethyl ether (3 ¥ 5 mL) and 0.1 M sulfuric acid
(10 mL). The colorless solid was recrystallized from petroleum
ether to give white needles; mp 89–91 ◦C; 0.152 g (63%). 1H
NMR: d 7.92 (dd, J = 7.7, 1.2 Hz, 1 H), 7.57 (td, J = 7.5, 0.9 Hz,
1 H), 7.4 (m, 6 H), 0.93 (s, 7 H), 0.24 (s, 6 H); 13C NMR: d
173.3, 143.5, 140.0, 138.3, 134.2, 132.9, 131.9, 131.2, 130.5, 129.5,
128.7, 127.3, 127.0, 17.5 (2 C), 13.7, -5.4 (2 C). IR : nmax 3013
(very broad), 2957, 2865, 1722 cm-1. Anal.: calcd for C18H22O2Si
(298.45) C, 72.44; H, 7.43; found C, 72.89; H, 8.03.
Teflon cannula, ending at 5 mm above the liquid surface, into the
second Schlenk tube containing the reaction intermediate. When
the add◦ition was complete, the mixture was kept for further 10 min
at -95 C. Upon chromatography on silica gel (70 mL), using a
1 : 20 (v/v) mixture of diethylether and hexanes as the eluent, a
viscous colorless oil was collected; 0.169 g (67%). 1H NMR: d 7.76
(broad d, J = 3.9 Hz, 1 H), 7.58 (dd, J = 6.1, 1.2 Hz, 1 H), 7.4 (m,
4 H), 7.35 (d, J = 7.5 Hz, 1 H), 7.2 (m, 1 H), 3.52 (s, 1 H), 0.94 (s,
7 H), 0.25 (s, 3 H), 0.24 (s, 3 H). 13C NMR: d 141.6, 139.8, 138.7,
134.2 (2 C), 133.3, 129.3, 129.1, 128.0 (sept, J = 3.1 Hz), 127.9,
127.8, 126.5, 122.6 (q, J = 285 Hz, 2 C), 80.1 (q, J = 29 Hz), 17.3
(2 C), 13.6, -5.5 (2 C). 19F NMR: d -75.14 (q, J = 8.3 Hz, 3 F),
-75.71 (q, J = 8.3 Hz, 3 F). MS: m/z (%) 420 (M+, 1), 377 (15), 233
(100), 214 (47), 183 (78), 165 (28), 77 (60), 43 (17). Anal.: calcd for
C20H22F6OSi (420.46) C, 57.13; H, 5.27; found: C, 56.33; H, 5.48.
2-Methoxycarbonyl-3¢-(isopropyldimethylsilyl)biphenyl {methyl
2-[3-(iso-propyldimethylsilyl)phenyl]benzoic acid} (8). Ethereal
diazomethane was addeddropwise to the acid 7 (0.10 g 0.33 mmol),
dissolved in diethyl ether (5 mL), until the yellow color persisted.
Elution with a 1 : 9 (v/v) mixture of diethyl ether and hexanes from
2-Formyl-3¢-(isopropyldimethylsilyl)biphenyl {2-[3-(isopropyl)-
dimethylsilylphenyl]benzaldehyde} (6). Ethanol (3.0 mL), ben-
zene (5.0 mL), (3-bromophenyl)isopropyldimethylsilane6 (0.20 g,
0.78 mmol), 2.0
M
aq. potassium carbonate (1.6 mL),
1
tetrakis[triphenylphosphine] palladium(0) (0.040 g, 0.034 mmol)
were added consecutively to 2-formylphenylboronic acid (0.13 g,
0.86 mmol). After reflux for 3 h, the mixture was eluted with
petroleum ether from silica gel (50 mL) to furnish a viscous
colorless oil; 0.200 g (91%). Spectroscopic and analytical data
are given in the appropriate section above.
silica gel (90 mL) gave a viscous colorless oil; 0.093 g (89%). H
NMR: d 7.81 (dd, J = 7.2, 1.4 Hz, 1 H), 7.52 (td, J = 7.3, 1.1 Hz, 1
H), 7.48 (dt, J = 7.4, 1.2 Hz, 1 H), 7.4 (m, 4 H), 7.33 (dt, J = 7.6,
1.4 Hz, 1 H), 3.61 (s, 3 H), 0.96 (s, 7 H), 0.25 (s, 6 H). 13C NMR: d
169.3, 142.6, 140.3, 138.3, 133.8, 132.8, 131.6, 131.1, 130.7, 129.6,
128.6, 127.3, 127.0, 51.9, 17.5 (2 C), 13.7, -5.3 (2 C). MS: m/z (%)
312 (M+, 7), 269 (53), 237 (57), 195 (44), 89 (100), 59 (25). Anal.:
calcd for C19H24O2Si (312.48) C, 73.03; H, 7.74; found, C, 72.94;
H, 7.77.
3¢-Isopropyldimethylsilyl-2-(trifluoromethyl)biphenyl (11). (3-
Bromophenyl)isopropyldimethylsilane (0.20 g, 0.78 mmol) and
2-trifluoromethylboronic acid (0.18 g, 0.95 mmol) were subjected
to the same procedure as described above for the preparation
of aldehyde 6. Hickmann distillation of the residue provided a
colorless oil; b.p. 151–153 ◦C/0.2 mmHg; 0.201 g (80%). 1H NMR:
d 7.76 (d, J = 7.8 Hz, 1 H), 7.4 (m, 7 H), 0.96 (s, 7 H), 0.26 (s, 6 H).
13C NMR: d 141.8, 138.9, 138.0, 134.4, 133.1, 132.0, 131.2, 129.2,
128.5 (q, J = 29 Hz), 127.2, 126.9, 126.0 (q, J = 5.3 Hz), 124.1 (q,
J = 272 Hz), 17.5 (2 C), 13.8, -5.4 (2 C). 19F NMR: d -57.19 (s).
MS: m/z (%) 322 (M+, 67), 279 (99), 201 (64), 183 (100), 163 (58),
3¢-(Isopropyldimethylsilyl)-2-(pentafluorophenyl)biphenyl {3¢-
(isopropyl)dimethylsilyl-2,3,4,5,6-pentafluoro-1,1¢;2¢,1¢terphenyl}
◦
(9). At -75 C, butyllithium (0.49 mmol) in hexanes (0.30 mL)
and, 5 min later, pentafluorobenzene (0.10 g, 0.54 mmol) were
added to 2-bromo-3¢-(isopropyldimethylsilyl)biphenyl (0.16 g,
0.48 mmol) in tetrahydrofuran (10 mL). The mixture was kept
for 1 h at +25 ◦C before being absorbed on silica (5 mL). Elution
with petroleum ether from silica gel (50 mL) gave a colorless oil;
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133 (20), 77 (100), 43 (34). Anal.: calcd for C18H21F3Si (322.44) C,
67.05; H, 6.56; found C, 67.21; H, 6.60.
as that used during the acquisition of the spectra. The uncertainty
in temperature measurements can be estimated as 2 ◦C.
Line shape simulations were performed using a PC version
of the QCPE DNMR6 program.32 Electronic superimposition
of the original spectrum and of the simulated one enabled
the determination of the most reliable rate constant. The rate
constants, thus obtained at various temperatures, afforded the free
energy of activation DG‡ or bond rotation by applying the Eyring
equation.33 In all cases investigated, the activation energy DG‡ was
found to be virtually invariant in the given temperature range, thus
implying a negligible activation entropy DS‡.34
3¢-Isopropyldimethylsilyl-2-(trifluoromethoxy)biphenyl
(12).
Analogously prepared from 3-bromophenylisopropyldimethyl-
silane (0.19 g, 0.75 mmol) and 2-(trifluoro-methoxy)phenyl-
boronic acid (0.18 g, 0.90 mmol); b.p. 156–158 ◦C/0.2 mmHg;
0.223 g (88%). 1H NMR: d 7.62 (broad s, 1 H), 7.45 (m, 1 H), 7.37
(m, 3 H), 0.99 (s, 7 H), 0.28 (s, 6 H). 13C NMR: d146.3, 138.6,
135.9, 135.6, 134.8, 133.2, 131.5, 129.5, 128.5, 127.5, 127.0, 121.2,
120.4 (q, J = 256 Hz), 14.4 (2 C), 13.7, -5.4 (2 C). 19F NMR: d
-57.47 (s). MS: m/z (%) 338 (M+, 10), 199 (100), 165 (50), 152
(44), 77 (89), 43 (14). Anal.: calcd for C18H21F3OSi (338.44) C,
63.88; H, 6.25; found: C, 64.03; H, 6.38.
Computational Work
A complete conformational search was preliminarily carried out
by means of the Molecular Mechanics Force Field (MMFF),35
using the Monte-Carlo method implemented in the package
TITAN 1.0.5.36 The most stable conformers thus identified were
subsequently energy-minimized by Density Functional Theory
(DFT) computations. Those were performed by the Gaussian
Variable Temperature NMR Studies
NMR spectra were performed using a Varian INOVA spectrom-
eter operating at a field of 14.4 Tesla. The variable temperature
experiments of compound 10 were recorded in acetonitrile-d3.
In the other◦ cases, where the temperature was to be decreased
below -100 C, the NMR tubes containing the compound were
manipulated at a vacuum line. First a small amount (approx.
0.05 mL) of hexadeuterobenzene (or acetone-d6 in the case
of compound 7) was introduced by means of a microsyringe
for locking purposes. The NMR tube was immersed in liquid
nitrogen and evacuated in order to condense about 0.45 mL
of chlorodifluoromethane (Freon 22) and about 0.15 mL of
dichlorofluoromethane (Freon 21) transferred as gases from
lecture bottles. The tubes were subsequently sealed under reduced
pressure (0.01 mbar) using a methane/oxygen torch. Avoiding any
rapid temperature change, the samples were cautiously warmed to
+25 ◦C, where the Freons develop a pressure of about 8 atm. After
a few hours at ambient temperature, the samples can be safely
introduced into the probe head of the spectrometer, already cooled
to -30 ◦C. Low temperature 600 MHz 1H spectra (compounds 2,
5, 6, 7, 8, 9, 10, 11) were acquired without spinning using a 5 mm
dual direct probe with a 9000 Hz sweep width, 2.0 ms (20◦ tip
angle) pulse width, 3 s acquisition time and 1 s delay time. A
shifted sine bell weighting function31 equal to the acquisition time
(i.e., 3 s) was applied before the Fourier transformation. Usually
32 to 64 scans were collected. Low temperature 150.8 MHz 13C
spectra (compounds 1, 3, 4, 7, 12) were acquired without spinning
and under proton decoupling conditions with a 38000 Hz sweep
width, 4.2 ms (60◦ tip angle) pulse width, 1 s acquisition time and
1 s delay time. A line broadening function of 1–2 Hz was applied
before the Fourier transformation. Usually 128 to 512 scans were
collected.
03 rev E.01 series of programs37 on multi-core Xeonꢀ servers,
R
the operating system being the Red Hat Enterprise Linux 5.1. The
standard geometry optimization included in Gaussian 03 is the
“Berny algorithm”.38 This algorithm uses the various forces acting
on the atoms of a given structure along with the Hessian to predict
energetically more favorable structures and thus to optimize
the molecular structure towards the nearest local minimum
on the potential energy surface. To avoid the computationally
expensive explicit calculation of the second derivative matrix,
the Berny algorithm constructs an approximate Hessian at the
beginning of the optimization procedure through application of
a simple valence force field, and then uses the energies and first
derivatives calculated along the optimization pathway to upgrade
the approximate Hessian matrix. All the calculations employed the
B3LYP hybrid HF-DFT method39 and the 6–31G(d) basis sets.
Harmonic vibrational frequencies were calculated for all sta-
tionary points. As revealed by the frequency analysis, imaginary
frequencies were absent in all ground states whereas just one
imaginary frequency was associated with each transition state.
Visual inspection of the corresponding normal modes40 validated
the identification of the transition states.
The listed energy values (see Table 2) represent total electronic
energies. In general, these give the best fit with experimental
DNMR data.41 Therefore, the computed numbers have not been
corrected for zero-point energy contributions or other thermo-
dynamic parameters. This avoids artifacts that might result from
the ambiguous choice of an adequate reference temperature, from
empirical scaling factors to which one has often to resort for a
better matching of experimental and theoretical numbers42 and
from the idealization of low-frequency vibrators as harmonic
oscillators (particularly important in the present case, where one
third of the calculated frequencies fall in the 500–600 cm-1 range).43
When operating the NMR apparatus at low temperature, a flow
of dry nitrogen first passed through a precooling unit adjusted to
-50 ◦C. Then the gas entered into an inox steel heat-exchanger
immersed in liquid nitrogen and connected to the NMR probe
head by a vacuum-insulated transfer line. Gas flows of 10 to
40 L min-1 were required to descend to the desired temperature.
Temperature calibrations were performed before the experiments,
using a digital thermometer and a Cu/Ni thermocouple (models
C9001 and KX2384, respectively, Comark Ltd., Hertfordshire,
UK) placed in an NMR tube filled with isopentane. The conditions
were kept as identical as possible with all subsequent work. In
particular, the sample was not spun and the gas flow was the same
Acknowledgements
The authors are indebted to the University of Bologna (RFO funds
2008), the Ministerodell’Universita` e Ricerca, Roma (MUR PRIN
2004 contract 033322), and the Schweizerische Nationalfonds zur
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The Royal Society of Chemistry 2010
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Fo¨rderung der Wissenschaftlichen Forschung, Bern (grant 20–
100¢336-02) for financial support.
27 P. Maienfisch and R. G. Hall, Chimia, 2004, 58, 93–99.
28 J. D. Dunitz, ChemBioChem, 2004, 5, 614–621.
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