Structure and conformational processes of bis(o-cumyl)sulfide, sulfoxide and sulfone

Article abstract of DOI:10.1016/j.tet.2005.04.070

The NMR solution spectra of the title sulfide and sulfone show decoalescence of the geminal methyl signals of the isopropyl groups at low temperature (-178°C for the ¹³C signal of sulfide at 150.8 MHz and -147°C for the ¹H signal of sulfone at 600 MHz). The barriers for the related dynamic processes were measured (4.3 and 7.0 kcal mol ^-1 for the sulfide and sulfone, respectively). The preferred conformer of sulfide has a propeller shape with a C₁ symmetry, as suggested by Molecular Mechanics (MM) calculations. In the case of sulfone the preferred conformer has a propeller shape with a C₂-anti symmetry, as indicated by calculations and supported by X-ray crystallographic determination. The computed contour map of the potential energy shows that in both cases the dynamic processes take place via correlated rotations (cogwheel mechanism) of the two aromatic substituents about the Ar-S bonds. Dynamic processes could not be observed by NMR in the title sulfoxide, which was also found to adopt a propeller shaped conformation, as indicated by MM calculations and X-ray diffraction.

Full text of DOI:10.1016/j.tet.2005.04.070

Tetrahedron 61 (2005) 6782–6790
Structure and conformational processes of bis(o-cumyl)sulfide,
sulfoxide and sulfone
†
*
Lodovico Lunazzi, Andrea Mazzanti and Mirko Minzoni
Department of Organic Chemistry ‘A. Mangini’, University of Bologna, viale Risorgimento 4 Bologna I-40136, Italy
Received 2 March 2005; revised 8 April 2005; accepted 29 April 2005
Abstract—The NMR solution spectra of the title sulfide and sulfone show decoalescence of the geminal methyl signals of the isopropyl
groups at low temperature (K178 8C for the 13C signal of sulfide at 150.8 MHz and K147 8C for the 1H signal of sulfone at 600 MHz). The
barriers for the related dynamic processes were measured (4.3 and 7.0 kcal molK1 for the sulfide and sulfone, respectively). The preferred
conformer of sulfide has a propeller shape with a C1 symmetry, as suggested by Molecular Mechanics (MM) calculations. In the case of
sulfone the preferred conformer has a propeller shape with a C2-anti symmetry, as indicated by calculations and supported by X-ray
crystallographic determination. The computed contour map of the potential energy shows that in both cases the dynamic processes take place
via correlated rotations (cogwheel mechanism) of the two aromatic substituents about the Ar–S bonds. Dynamic processes could not be
observed by NMR in the title sulfoxide, which was also found to adopt a propeller shaped conformation, as indicated by MM calculations and
X-ray diffraction.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
It has been shown that dimesitylsulfide2 and sulfone3 adopt
a propeller-like conformation which entails the existence of
two stereolabile enantiomers that interconvert with a quite
rapid exchange rate. NMR spectra at very low temperatures
allowed the barriers involved in these processes to be
determined (4.25 and 5.0 kcal molK1, respectively).2,3
Molecular Mechanics calculations indicated that the process
occurred via a correlated cogwheel mechanism, according
to a one-ring flip pathway.4,5 If the two mesityl groups are
replaced by two less symmetric aromatic groups bearing
solely one substituent in the ortho position of the phenyl
ring, a number of conformers with different energy can be
generated in principle. Each of these conformational types
comprises a pair of enantiomers. In the present paper we
investigated the ortho-cumyl derivatives 1–3 (Chart 1),
where the isopropyl group was selected as the ortho
substituent because it is a convenient NMR probe (both at
13C and 1H frequencies) for detecting the molecular
dissymmetry.6
In the general case of Ar–X–Ar derivatives (Ar being the
same ortho substituted phenyl moiety) three propeller
conformers can be populated in principle. One such
conformer does not have any element of symmetry (C1
point group), whereas the other two possess a two-fold
symmetry axis (C2 point group). The latter differ for the
relative disposition of the two aryl rings that can have the
ortho substituent either close to (C2-syn), or remote from
(C2-anti), the X atom. These three conformers exist as pairs
of enantiomers, as illustrated in Scheme 1.
In the case of sulfide 1 molecular mechanics calculations7
and ab initio computations (see Section 4) identify three
energy minima, corresponding to the conformers of
Scheme 1 (XZS),8 and indicate that the asymmetric C1 is
more stable than the other two (Table 1). In particular ab
initio computations suggest that the asymmetric conformer
C1 might be, in practice, the only appreciably populated
form experimentally detectable at very low temperature.
Keywords: Dynamic NMR spectroscopy; MM calculations; X-ray
diffraction.
*
Corresponding author. Tel.: C39 51 2093633; fax: C39 51 2093654;
e-mail: mazzand@ms.fci.unibo.it
† See Ref. 1.
Chart 1.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.04.070

L. Lunazzi et al. / Tetrahedron 61 (2005) 6782–6790
6783
an internal motion has been made slow in the NMR
timescale, with molecules in a conformation where the
geminal methyl groups are diastereotopic.9 From a complete
line shape simulation (Fig. 1) the rate constants for the
dynamic process were obtained and the free energy of
activation10 (DGsZ4.3G0.15 kcal molK1) derived. No
evidence was found of significant presence of minor signals
due to a second conformer, hence the single conformer
observed at K178 8C should conceivably correspond to the
C1 structure which has the lowest computed global energy
(Table 1).
In the asymmetric conformer C1, however, the two aryl
substituents bonded to sulfur are not equivalent, so that
different NMR signals should have been detected for all the
pairs of atoms, including the CH isopropyl carbons. To
Scheme 1.
Table 1. Computed relative energy values (kcal molK1) for the ground and transition states of sulfide 1
C1
C2-syn
C2-anti
TS-A
2.5
TS-B
11.0
TS-C
2.2
TS-D
1.6
MMFF-94
Force field
Ab-initio
0.0
0.26
1.35
0.0
0.70
0.98
See Scheme 2 for the meaning of TS-A, TS-B, TS-C, TS-D.
The aliphatic region of the 150.8 MHz 13C NMR spectrum
of 1 displays a single sharp line for the methine and for the
methyl carbons from ambient temperature down to
K150 8C. On further cooling, the isopropyl methyl line
broadens considerably more than that of the corresponding
methine carbon (Fig. 1) and eventually decoalesces into a
pair of equally intense signals at K178 8C. This proves that
understand why this was not the case and why only the
geminal methyl signals are split, the whole rotation pathway
of 1 has to be analyzed.
Figure 2 shows the contour map of the potential energy as
function of the Ar–S dihedral angles q and f, computed
using the MMFF 94 force field,7 with the three energy
minima8 corresponding to the conformers of Scheme 1.
In Scheme 2 are sketched the expected transition states, and
in Scheme 3 are also displayed the possible connections
between the various ground states described according to
the terminology proposed by Mislow4 and followed by other
authors:5 the reader is referred to these papers for the
meaning of the terms employed.
In the case of sulfide 1 (XZS) calculations suggest that the
two-ring flip pathway interconverting the asymmetric
conformer C1 with its enantiomer C1 (Scheme 3) through
the transition state TS-C is a motion too fast to be frozen in a
dynamic NMR experiment, as indicated by the computed
barrier of only 2.2 kcal molK1 (Table 1). Such a fast process
(described by the blue lines of Fig. 2 and of Scheme 3)
exchanges the positions of the two rings and creates, in
practice, a dynamic plane of symmetry perpendicular to the
C–S–C plane, which makes the signals of all the pairs of
carbons isochronous, with the exception of those of the
geminal methyl groups. This is because the local symmetry
plane of the isopropyl substituent is not coincident with the
dynamic plane of the whole molecule, thus making the
geminal methyl groups diastereotopic:6,11 such an interpret-
ation accounts for the NMR spectrum at K178 8C. From the
NMR experimental point of view the pairs of rapidly
interconverting C1, C1 enantiomers can be thus considered
as an average conformer having a dynamic plane of
symmetry perpendicular to the C–S–C plane. Support for
this model is offered by the observation that in the
Figure 1. Experimental (left) and simulated (right) 13C NMR spectra
(150.8 MHz) of the aliphatic region of sulfide 1 in CHF2Cl/CHFCl2 as
function of temperature.

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L. Lunazzi et al. / Tetrahedron 61 (2005) 6782–6790
groups (see Scheme 3), thus accounting for the single 13C
line observed above K175 8C in Figure 1.13 In other words,
this interconversion creates a dynamic plane of symmetry
coincident with the C–S–C plane, thus also coincident with
the local plane of symmetry of the isopropyl substituents: a
condition6 which renders equivalent (enantiotopic) the
geminal0 methyl groups.14 It is the passage through TS-
A/TS-A which corresponds therefore to the experimental
barrier of 4.3 kcal molK1
.
Although the C2-syn conformer must be visited in the course
of this pathway in order to account for the exchange of the
geminal methyl groups, the corresponding NMR signal is
invisible since, as mentioned, its higher energy makes the
corresponding population too low to be experimentally
detected. For the same reason it is also invisible the
spectrum of C2-anti (Scheme 2) which is expected to
exchange with C2-syn with an even lower barrier (Table 1) via
the TS-D/TS-D0 transition states (the corresponding pathways
have been represented by the green lines of Fig. 2).
Figure 2. Contour energy map of 1, as function of the dihedral angles
indicated (the contour lines are separated by 1 kcal molK1). The ground
states are identified by circles (hollow for C2-syn and full for C2-syn),
triangles (hollow for C2-anti and full for C2-anti), hollow diamonds (C1)
and full diamonds (C1). The allowed rotation pathways are indicated by the
red lines (one-ring flip via TS-A/TS-A0), by the blue lines (two-ring flip via
TS-C) and by green lines (two-ring flip via TS-D/TS-D0). The crosses
represent the transition states (the brown crosses identifies the TS-B/TS-B0
transition states).
From the saddle points of the map of Figure 2 the theoretical
energies of the four possible transition states could be
estimated and the values are collected in Table 1. As
mentioned, the interconversion barrier (2.2 kcal molK1
)
between the enantiomers C1 and C1 via TS-C, described
by the blue lines of Figure 2 and of Scheme 3, is calculated
to be lower than that (2.5 kcal molK1) for the passage of C1
through C2-syn via TS-A (and of C1 through C2-syn via
TS-A0), described by the red lines of Figure 2 and of
Scheme 3: this result is in agreement with the above
interpretation of the experimental findings. The difference
between these two values (0.3 kcal molK1) is very small,
but in this type of approximate calculation, it is the
relative trend, rather than the absolute value, that should
be considered. Furthermore, the measured barrier of
4.3 kcal molK1 corresponds to the lowest possible value
that can be determined by a dynamic NMR experiment in
solution, sothat an exchange process having a barrier lower by
even a few tenth of kcal molK1 would be undetectable. On the
basis of symmetry considerations and calculations, we
conclude that the direct exchange between the C1 and C1
enantiomers via TS-C is too fast to be detected by NMR in
solution, whereas that involving the intermediacy of C2-syn
(via TS-A/TS-A0) is measured experimentally to be
4.3 kcal molK1. The correspondence with the magnitude of
the computed barrier (2.5 kcal molK1) is quite acceptable
given the intrinsic approximations of the theoretical approach
and the complexity of the dynamic process investigated.15
hydrocarbon of similar structure Ar2C]CH2 (ArZortho-
isopropylphenyl) it was possible to detect, as in 1, the
decoalescence of the methyl signals and, on further
lowering the temperature, also the predicted decoalescence
of the isopropyl methine signals,12 which is invisible in 1.
Due to the greater steric hindrance, in fact, the barrier for the
interconversion of the enantiomers C1 and C1 is higher in
this hydrocarbon than in sulfide 1. Although experimental
evidence for the existence of the mentioned enantiomeriza-
tion process could not be obtained in 1, it was at least
detected in an analogous case.
The C1 conformer (identified by the hollow diamond in
Fig. 2) can undergo a mutual exchange with its homomeric
form by passing twice through the transition state TS-A and
visiting the C2-syn conformer: these pathways are rep-
resented by the red lines of Figure 2. This motion exchanges
the environments of the two diastereotopic geminal methyl
It should be also pointed out that the lines connecting the
energy minima of Figure 2 run diagonally with respect to
the q and f axes. This indicates that the rotation processes
about the two Ar–S bonds are correlated motions, as in a
cogwheel mechanism,4,5 where the rotation of one ring
drives the concomitant rotation of the second one (molecu-
lar gear). If these processes had occurred independently of
each other, the mentioned connections would have appeared
as lines parallel to the Cartesian axes.2,3,16–18
Although sulfone 2 (XZSO2) has the same overall
symmetry as sulfide 1, the corresponding conformational
preferences are quite different. MM computations7 indicate
Scheme 2. Representation of the possible transition states for Ar–X–Ar,
(ArZortho-isopropylphenyl).

L. Lunazzi et al. / Tetrahedron 61 (2005) 6782–6790
6785
Scheme 3. Possible pathways connecting the ground states of sulfide 1 (RZisopropyl). The dashed lines represent processes having too high an energy (see
text).
that there are only two minima of energy, corresponding to a
C1 and to a C2-anti conformer: the C2-syn conformation
does not correspond here to a minimum, most likely owing
to the steric hindrance exerted by the oxygen atoms upon the
isopropyl groups. Computations also predict that the C2-anti
is substantially more stable than the C1 conformer (Fig. 3).
This result is supported by the X-ray structure showing that
solely the C2-anti structure is present in the crystalline state.
In Figure 3 the computed and experimental structures of 2
are reported: the structure that theory predicts to be the most
stable is indeed essentially equal to the experimental one. It
has also to be pointed out that the state TS-A of Scheme 2 is
not a transition state in the case of sulfone 2 (as it was in the
case of sulfide 1): inspection of Figure 3 shows, in fact, that
the conformer C1, which is an energy minimum, corre-
sponds to TS-A of Scheme 2.
Figure 4. Temperature dependence of the 600 MHz 1H NMR methyl signal
Figure 3. MM computed energy minima and experimental crystal structure
of 2 (left) in CHF2Cl/CHFCl2 with the simulations (right) obtained using
the rate constants indicated.
for sulfone 2 (the unit cell in the crystal also contains the enantiomer of the
structure shown). The energy values are in kcal molK1
.

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L. Lunazzi et al. / Tetrahedron 61 (2005) 6782–6790
1
In Fig. 4, the methyl doublet of the 600 MHz H NMR
spectrum is reported as a function of temperature. The signal
broadens on cooling and, below K110 8C, decoalesces into
a pair of lines separated by 590 Hz at K147 8C (at this
temperature the splitting due to the coupling with CH is
invisible due to the viscosity broadened lines). An analogous
behavior is observed in the corresponding 150.8 MHz 13C
NMR spectrum where the methyl signal decoalesces into a
pair of lines separated by 50 Hz at K147 8C, whereas the CH
signal remains a single line at all temperatures. Simulations of
The ground state conformer C2-anti interconverts into the
C1 conformer via the transition state TS-B0 (XZSO2 in
Scheme 2), as indicated by the brown line. According to
MM calculations the energy of the latter transition state is
7.1 kcal molK1 higher than that of the ground state.
Although C1 is visited in the course of this pathway, its
computed energy, as mentioned, is too high to yield an
appreciable population, so the corresponding NMR signals
were not detected. Subsequently C1 interconverts (blue line)
into its enantiomer C1 via a TS-C transition state (the energy
of the latter is computed to be 5.8 kcal molK1 higher with
respect to C1) which finally interconverts into the enantio-
meric C2-anti via TS-B. Thus computations indicate that the
barrier to be overcome in order to accomplish the
stereomutation of C2-anti with its enantiomer C2-anti is
7.1 kcal molK1, a value in good agreement with that
experimentally measured (7.0 kcal molK1).
the H and of 13C spectra provide a DGs value of 7.0G
1
0.15 kcal molK1 for this dynamic process. No evidence was
observed of signals due to a second minor conformer, in
agreement with the theoretical prediction indicating a
negligible population of the C1 conformer.
The symmetry of the C2-anti conformer requires that every
pair of atoms yields isochronous NMR signals, with the
exception of the geminal isopropyl methyl groups that are
diastereotopic because the conformer does not possess a
molecular plane of symmetry:6 this agrees with the observed
1H and 13C NMR spectra at K147 8C. When the
temperature is increased above K110 8C the exchange
rate of the C2-anti conformer with its enantiomer C2-anti
becomes fast on the NMR time scale. Such a process creates
a dynamic plane of symmetry coincident with the C–S–C
plane, thus coincident also with the local plane of symmetry
of the isopropyl groups. This makes the methyl groups
become equivalent (enantiotopic),6 yielding a single NMR
line: the measured barrier thus corresponds to the energy
required for this enantiomerisation process.
As in the case of sulfide 1 also in sulfone 2 the lines
corresponding to the allowed pathways between the ground
states run diagonally to the axes in the contour map of
Figure 5, thus indicating that here too we are in the presence
of a correlated cogwheel process.2–5,16–18
With SO being a prochiral moiety, the geminal methyl
groups of sulfoxide 3 are diastereotopic since, contrary to
the cases of 1 and 2, there is not a molecular plane of
symmetry coincident with the local plane bisecting the
isopropyl substituent.6,11 As a consequence, two aniso-
1
chronous H and 13C signals are observed for these methyl
groups, even at ambient temperature. For this reason the
isopropyl moiety cannot be used as a probe for monitoring
the dynamic processes due to restricted motions, as in the
previous cases of 1 and 2. The only way of observing a
dynamic process in 3 would be the existence of an exchange
between conformers having a different population: such a
feature, however, was not observed at any attainable
temperature, not even below K175 8C. This suggests that
only one conformer is essentially populated, although it is
impossible to identify its structure solely on the basis of the
NMR spectrum.
The details of this pathway can be understood by examining
the contour map of the potential energy reported in Fig. 5.
MM calculations7 predict that the two lowest energy
minima of 3 differ by as much as 3.1 kcal molK1 (Fig. 6),
a result in agreement with the low temperature NMR
experiment indicating that only one conformer is populated
in solution. In addition, X-ray diffraction shows that the
crystal structure of 3 (Fig. 6) corresponds to that of the
conformer predicted by calculations to have the lowest
global energy. It seems thus conceivable to conclude that
Figure 5. Contour energy map (MMFF force field) for compound 2, as
function of the dihedral angles indicated. The ground states are identified by
a hollow triangle (C2-anti), a full triangle (C2-anti), hollow diamonds (C1)
and full diamonds (C1). The allowed rotation pathways are indicated by the
brown lines (one-ring flip via TS-B/TS-B0) and by the blue lines (two-ring
flip via TS-C). The crosses represent the corresponding transition states.
Figure 6. MM computed energy minima and experimental crystal structure
for sulfoxide 3 (the unit cell in the crystal also contains the enantiomer of
the structure shown). The energy values are in kcal mol.K1
.

L. Lunazzi et al. / Tetrahedron 61 (2005) 6782–6790
6787
the only conformation populated by sulfoxide 3 in solution
is the same propeller shaped structure observed in the solid
state.
of CH2Cl2 was added meta-chloroperbenzoic acid
(MCPBA, 690 mg 2 mmol 77% w/w). After 4 h at
room temperature the reaction was quenched with
aqueous Na2SO3, extracted with Et2O, washed with
NaCl, dried (Na2SO4) and the solvent removed at
reduced pressure. The crude (271 mg 0.9 mmol) was
purified by chromatography on silica gel (Pet. ether/
Et2O 3/2). Single crystal suitable for X-ray diffraction
were obtained by slow crystallisation from hexane.
3. Conclusions
The observation of anisochronous NMR geminal methyl
signals in the solution spectrum of sulfide 1 at K178 8C is
due to the presence of a pair of rapidly interconverting
enantiomers (C1 point group symmetry) having a propeller-
like structure. This rapid motion, occurring via a two-ring
flip correlated pathway, creates a dynamic plane of
symmetry orthogonal to the C–S–C plane which renders
equivalent the two aromatic rings, but leaves diastereotopic
the methyl groups of the isopropyl substituents. The methyl
signals coalesce above K175 8C allowing the measurement
of an interconversion barrier of 4.3 kcal molK1. This
process corresponds to the exchange between the two
homomeric forms of conformer C1 according to a one-ring
flip correlated pathway involving the intermediacy of the
C2-syn conformer (the same occurs for C1 via C2-syn). The
MM computed barrier for this process (2.5 kcal molK1) is
compatible with the experimental value. The aniso-
chronicity of the isopropyl methyl signals of sulfone 2,
observed at K147 8C, is due, on the other hand, to the
presence of the C2-anti conformer, as also confirmed by single
crystal X-ray diffraction. The coalescence of these signals,
occurring above K110 8C, allowed the determination of a
7.0 kcal molK1 interconversion barrier. This process corre-
sponds to the exchange between the C2-anti and its C2-anti
enantiomeric form, and takes place according to a one-ring
flip pathway involving the intermediacy of the C1 conformer.
1
White solid, MpZ148.5–149.5 8C. H NMR (600 MHz,
CDCl3, 22 8C, TMS): dZ1.06 (d, 12H, Me, JZ6.9 Hz),
3.77 (septet, 2H, CH, JZ6.9 Hz), 7.35–7.41 (m, 4H,
Ph), 7.53–7.58 (t, 2H, Ph, JZ8.2 Hz), 8.2 (d, 2H, Ph,
JZ7.7 Hz); 13C NMR (150.8 MHz, CDCl3, 22 8C,
TMS): dZ22.6 (CH3), 29.2 (CH), 126.4 (CH), 128.3
(CH), 128.7 (CH), 134.0 (CH), 139.3 (q), 149.2 (q).
Anal. Calcd for C18H22SO2: C, 71.48; H, 7.33; S, 10.60;
O, 10.58 Found: C, 71.52; H, 7.38; S, 10.56; O, 10.50.
4.1.3. Bis(ortho-cumyl)sulfoxide or bis(2-isopropyl-
phenyl)sulfoxide (3). Thionyl chloride 1.5 (12.5 mmol)
was added dropwise, under stirring, to an ice-cooled
solution of imidazole 3.5 g (51.0 mmol) in 40 ml of
anhydrous tetrahydrofuran. A white precipitate formed
immediately. After cooling for several minutes, the reaction
mixture was rapidly filtered by suction under a nitroge0n
atmosphere. The resulting solution, containing N,N -
thionyldiimidazole, was added at K78 8C to a solution of
1-bromo-2-isopropylbenzene–lithium, obtained by addition
of n-butyl-lithium (30 mmol, 1.6 M in hexane) to 1-bromo-
2-isopropylbenzene (5 g, 25 mmol in 20 ml of THF). After
3 h the mixture was allowed to warm and quenched with
cooled aqueous HCl. The product was extracted with Et2O,
washed with Na2CO3, dried (Na2SO4) and the solvent
removed at reduced pressure. The crude (4.65 g, 16.2 mmol)
was purified by chromatography on silica gel (Pet. ether/
Et2O 1/1). Crystal suitable for X-ray diffraction was
obtained by slow crystallisation in hexane. White solid,
Mp 78.5–79.5 8C. 1H NMR (600 MHz, CDCl3, 22 8C,
TMS): dZ1.15 (d, 12H, Me, JZ6.9 Hz), 3.65 (septet,
2H, CH, JZ6.9 Hz), 7.32–7.36 (m, 4H, Ph), 7.42–7.46
(ddd, 2H, Ph, JZ7.5, 7.4, 1.2 Hz), 7.65–7.67 (dd, 2H,
Ph, JZ7.8, 1.4 Hz); 13C NMR (600 MHz, CDCl3, 22 8C,
TMS): dZ22.1 (CH3), 23.9 (CH3), 29.6 (CH), 126.0
(CH), 126.5 (CH), 127.3 (CH), 131.8 (CH), 141.6 (q),
147.7 (q).
The MM computed value for this process (7.1 kcal molK1
agrees well with the experimental observation.
)
4. Experimental
4.1. Synthesis
4.1.1. Bis(ortho-cumyl)sulfide or bis(2-isopropylphenyl)-
sulfide, (1). To a suspension of LiAlH4 (2.2 mmol in 12 ml
of Et2O) were added 233 mg (0.74 mmol) of bis(2-
isopropylphenyl)sulfoxide 3 in 10 ml of THF at ambient
temperature. When the addition was terminated the reaction
was refluxed for 2 h and then cautiously quenched with
aqueous NH4Cl. The product was extracted with Et2O, dried
(Na2SO4) and the solvent removed at reduced pressure. The
crude (189 mg 0.7 mmol) was purified by chromatography
on silica gel (Pet. ether/Et2O 10/1) colourless oil. 1H NMR
(600 MHz, CDCl3, 22 8C, TMS): dZ1.46 (d, 12H, Me, JZ
8.2 Hz), 3.65 (septet, 2H, CH, JZ8.2 Hz), 7.05–7.07 (m,
4H, Ph), 7.21–7.24 (m, 2H, Ph), 7.32 (d, 2H, Ph, JZ8.2 Hz);
13C NMR (150.8 MHz, CDCl3, 22 8C, TMS): dZ22.8
(CH3), 30.6 (CH), 126.0 (CH), 126.7 (CH), 127.6 (CH),
131.8 (CH), 134.0 (q), 149.5 (q). Anal. Calcd for C18H22S:
C, 80.02; H, 8.20; S, 11.78. Found: C, 79.88; H, 8.16; S,
11.74.
4.2. Computations
A conformational search, using a Molecular Mechanics
(MMFF 94 Force Field7) approach, was performed to locate
the potential minima of 1 and 2. For each of the mentioned
structures C1, C2-syn and C2-anti, other local minima can be
also reached by rotation of the isopropyl groups. The latter
minima, however, have energies quite higher than that
corresponding to the ground states appearing in Table 1 and
in Figure 3, so that their populations can be considered
negligible. An analogous conformational search, using the
same approach, was performed to locate the potential
minima of sulfoxide 3. The potential energy maps of 1 and 2
were obtained using the dihedral drive option of the
software.7 The two dihedral angles were simultaneously
driven by 108 steps, leading to a matrix composed by 1296
4.1.2. Bis(ortho-cumyl)sulfone or bis(2-isopropylphenyl)-
sulfone, (2). To a cooled (0 8C) solution of 286 mg
(1 mmol) of bis(2-isopropylphenyl)sulfoxide 3 in 10 ml

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L. Lunazzi et al. / Tetrahedron 61 (2005) 6782–6790
2
optimised structures. The transition states were located by
identifying the saddle points of the energy map, as in
Figures 2 and 5. To better localize the transition states, the
dihedral drive was then restricted to a 108!108 range
around the saddle region, using a step angle of 18. Ab initio
computations on compound 1 were carried out at the RHF/
6-31G* level by means of the Gaussian 03 series of
programs.19 Harmonic vibrational frequency were calcu-
lated in order to ascertain the nature of the stationary
points: for each optimised ground state the frequency
analysis showed the absence of imaginary frequencies.
The search and the computations of the transition states
by the same ab initio approach exceeded the capabilities
of our computing facilities. For this reason in Table 1 only
the barriers computed by MM are indicated.
O2s(I), weighting scheme wZ1=½s2ðFo2ÞCð0:0695PÞ C
1:2582Pꢀ where PZðFo2 C2Fc2Þ=3, largest difference peak
and hole 0.372 and K0.502 e AK3. Crystallographic data
˚
(excluding structure factors) have been deposited with
the Cambridge Crystallographic Data Centre as supple-
mentary publication no. CCDC-264520. Copies of the
data can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge CB21EZ, UK (fax:
C44 1223 336 033; e-mail: deposit@ccdc.cam.ac.uk).
4.4.2. Crystal data of bis(2-isopropylphenyl)sulfoxide,
(3). Molecular formula: C18H22OS, Mr Z286.42, mono-
clinic, space group P21/c (No. 14), aZ13.994(4), bZ
3
˚
˚
8.031(2), cZ15.948(4) A, bZ114.9588; VZ1625.0(7) A ,
TZ295(2) K, ZZ4, rcZ1.171 g cm–3, F(000)Z616,
graphite-monochromated
Mo Ka
radiation
(lZ
0.71073 A), m (Mo Ka)Z0.193 mmK1, colourless plate
(0.60 !0.60!0.20 mm3), empirical absorption correction
with SADABS (transmission factors: 0.8928–0.9624), 1800
frames, exposure time 10 s, 1.61%q%30.12, K19%h%19,
K11%k%11, K22%l%22, 19,743 reflections collected,
4769 independent reflections (RintZ0.0497), 4066 reflec-
tions with IO2s(I), solution by direct methods (SHELXS)
and subsequent Fourier syntheses, full-matrix least-squares
on Fo2 (SHELXTL), hydrogen atoms refined with a riding
model, data/parametersZ4769/181, S(F2)Z1.045, R(F) Z
0.0462 and wR(F2)Z0.1140 on all data, R(F)Z0.0384 and
wR(F2)Z0.1067 for reflections with I O2s(I), weighting
˚
4.3. NMR measurements
The samples for the low temperature measurements were
prepared by connecting to a vacuum line the NMR tubes
containing the compound and some C6D6 for locking
purpose and condensing therein the gaseous CHF2Cl and
CHFCl2 (4:1 v/v) under cooling with liquid nitrogen. The
tubes were subsequently sealed in vacuo and introduced into
the precooled probe of a spectrometer (Varian Inova,
equipped with a variable temperature device where the
nitrogen gas was precooled to K40 8C before entering in the
liquid nitrogen heat exchanger) operating at 600 MHz for
1H and 150.8 MHz for 13C. The temperatures were
calibrated by substituting the sample with a precision
Cu/Ni thermocouple before the measurements. Complete
fitting of dynamic NMR line shapes was carried out using a
PC version of the DNMR-6 program.20 Since the isopropyl
methine 13C signal of 1 does not undergo exchange
broadening, its width at any temperature was assumed as
intrinsic line width also for the methyl 13C signals. The
separation of the latter, obtained by spectral simulation
(Fig. 1), was estimated as 250G20 Hz (at 150.8 MHz). The
signals of the aromatic region of 1–3 were not clearly
detectable being overlapped by the much more intense
signals of the non deuteriated solvents needed to reach such
low temperatures.
scheme wZ1=½s2ðFo2ÞCð0:0607PÞ C0:4870Pꢀ) where
2
PZðFo2 C2Fc2Þ=3, largest difference peak and hole 0.510
and K0.299 e AK3. Crystallographic data (excluding
˚
structure factors) have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
no. CCDC-264698. Copies of the data can be obtained free
of charge on application to CCDC, 12 Union Road,
Cambridge CB21EZ, UK (fax: C44 1223 336 033;
e-mail: deposit@ccdc.cam.ac.uk).
Acknowledgements
The authors gratefully thank Professor J. E. Anderson,
University College, London, UK for reading the manuscript
and for many helpful comments. Financial support from the
University of Bologna (Funds for selected research topics
and RFO) and from MIUR-COFIN 2003, Rome (national
project ‘Stereoselection in Organic Synthesis’) was received
by L.L. and A.M.
4.4. X-ray diffraction
4.4.1. Crystal data of bis(2-isopropylphenyl)sulfone, (2).
Molecular formula: C18H22O2S, Mr Z302.42, ortho-
rhombic, space group Pbca (No. 61), aZ11.4062(17), bZ
3
˚
˚
13.43(2), cZ21.909(3) A, VZ3356.2(9) A , TZ295(2) K,
ZZ8, rcZ1.197 g cmK3, F(000)Z1296, graphite-mono-
chromated Mo Ka radiation (lZ0.71073 A), m (Mo Ka)Z
˚
0.195 mmK1, colourless block (0.40!0.40!0.40 mm3),
empirical absorption correction with SADABS (trans-
mission factors: 0.9261–0.9263), 1800 frames, exposure
time 20 s, 1.86%q%30.02, K16%h%15, K18%k%18,
K30%l%30, 41,300 reflections collected, 4906 inde-
pendent reflections (Rint Z0.0700), 3022 reflections with
IO2s(I) (RsZ0.0482), solution by direct methods
(SHELXS) and subsequent Fourier syntheses, full-matrix
least-squares on Fo2 (SHELXTL), hydrogen atoms refined
with a riding model, data/parametersZ4906/185, S(F2)Z
1.009, R(F)Z0.0932 and wR(F2)Z0.1599 on all data,
R(F)Z0.07519 and wR(F2)Z0.1236 for reflections with I
References and notes
1. In partial fulfillment for the PhD in Chemical Sciences,
University of Bologna.
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Mislow, K. J. Am. Chem. Soc. 1973, 95, 1535–1547. (e)
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(g) Borghi, R.; Lunazzi, L.; Placucci, G.; Cerioni, G.; Foresti,
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11. A situation analogous to that of 1 at K178 8C is, for instance,
that of (Me2CH)2PPh at ambient temperature, where the
methyl groups are diastereotopic whereas the methine
hydrogens are equivalent (enantiotopic) because the molecular
plane of symmetry is not coincident with the local plane of
symmetry of the isopropyl substituents, see: McFarlane, W.
Chem. Commun. 1968, 229–230.
5. (a) Glaser, R. In Acyclic Organonitrogen Stereodynamics;
Lambert, J. B., Takeuchi, J., Eds.; VCH: New York, 1992. (b)
Rappoport, Z.; Biali, S. E. Acc. Chem. Res. 1997, 30, 307–314.
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Biali, S. E.; Nugiel, D. A.; Rappoport, Z. J. Am. Chem. Soc.
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Chem. Soc. 1984, 106, 477–496. (g) Biali, S. E.; Rappoport,
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12. Lunazzi, L.; Mazzanti, A.; Minzoni, M. J. Org. Chem. 2005,
70, 456–462.
13. The same type of interconversion might occur through the
transition state TS-B of Scheme 2, but calculations show that
the corresponding energy (Table 1) is much higher than that of
TS-A, so that this rotation process can be considered as not
allowed. For this reason this pathway has not been indicated in
Figure 2 and only the positions corresponding to TS-B/TS-B0
(brown crosses) are displayed.
6. (a) Mislow, K.; Raban, M. Top. Stereochem. 1967, 1, 1–38. (b)
Jennings, W. B. Chem. Rev. 1975, 75, 307–322. (c) Eliel, E. L.
J. Chem. Ed. 1980, 57, 52–55.
14. Above K174 8C the situation of 1 becomes analogous, for
instance, to that of (Me2CH)2CO, where the methyl groups are
enantiotopic and exhibit, therefore, a single line in the 13C
NMR spectrum because the molecular plane of symmetry is
coincident with the local plane of symmetry of the isopropyl
substituents.
7. MMFF-94 force field as implemented in the computer
package PC Model v 7.5, Serena Software, Bloomington,
IN.
8. These conformers can be also classified on the basis of the
value and of the sign of dihedral angles C2–C1–S–C10 (q) and
C20–C10S–C1 (f) indicated in Scheme 1. In the case of the
sulfide 1 the values of these angles (MM computed) are: qZC
708, fZK1308 for conformer C1 and qZK1308, fZC708
for its identical (homomeric) form: in Figure 2 they are
identified by hollow diamonds. The angles qZC1308, fZK
708 correspond to the enantiomer C1 and qZK708, fZC1308
to its homomeric form: in Figure 2 they are identified by full
diamonds. The angles for C2-syn, identified by a hollow circle
in Figure 2, are qZfZC1158 (the enantiomer C2-syn has qZ
fZK1158 and is identified by a full circle). The angles for
C2-anti, identified by a hollow triangle in Figure 2, are qZ
fZC658 (the enantiomer C2-anti has qZfZK658 and is
identified by a full triangle).
9. This motion cannot be due to a slow Ph–Pri rotation since the
corresponding barrier is too low to yield separate signals at any
accessible temperature in a liquid phase NMR experiment:
examples of such an occurrence, in fact, have never been
reported. The observed anisochronicity of the methyl signals
must be therefore a consequence of the molecular dissymmetry
(see, for instance: Kessler, H.; Rieker, A.; Rundel, W. Chem.
Commun. 1968, 475–476.
15. It cannot be excluded, in principle, that the chemical shift
difference of the methine isopropyl carbons of sulfide 1 might
be smaller than the line width (about 110 Hz) at K178 8C, so
that the observed spectrum might actually correspond to that of
the static asymmetric C1 conformer. This hypothesis would
also require that four lines be observed for the methyl groups:
again the corresponding shift difference should be assumed to
be lower than 110 Hz in order to explain why only two methyl
signals are resolved. Also the aromatic lines should be split in
this case but, unfortunately, they are overlapped by the intense
signals of the solvents needed to reach such extremely low
temperatures and cannot be used to check whether the
aromatic rings are different, as expected for the static C1
conformer. If all these assumptions are accepted, the two
mentioned interconversion processes would be, in practice,
undistinguishable: in other words, the interconversion through
the TS-C and the TS-A transition states should be considered
as having essentially the same barrier. In view of the similarity
between these two computed barriers (2.2 and 2.5 kcal molK1
,
respectively) we feel that this alternative explanation cannot
be unambiguously rejected.
16. Grilli, S.; Lunazzi, L.; Mazzanti, A. J. Org. Chem. 2001, 66,
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10. As often observed in conformational processes, the DGs
values are essentially independent of temperature (indicating
negligible DSs values) since the corresponding variations lie
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)
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