The structure, modelling and dynamics of 2,7-diisopropoxy-1,8-diarylnaphthalenes

Article abstract of DOI:10.1039/b201235a

2,7-Diisopropoxy-1,8-dibromonaphthalene 5 was prepared in two steps from 2,7-dihydroxynaphthalene and was coupled under Suzuki cross-coupling conditions with boronic acids 9 and 10 to provide the corresponding 1,8-diarylnaphthalene systems 12a and 13a res

Full text of DOI:10.1039/b201235a

View Article Online / Journal Homepage / Table of Contents for this issue
The structure, modelling and dynamics of 2,7-diisopropoxy-1,8-
diarylnaphthalenes
Carl Thirsk,a Geoffrey E. Hawkes,b Romano T. Kroemer,b,c Klaus R. Liedl,d Thomas Loerting,d
Rima Nasser,b Robin G. Pritchard,e Melanie Steele,a John E. Warrene and Andrew Whiting*a
2
a Department of Chemistry, University of Durham, Science Laboratories, South Road, Durham,
UK DH1 3LE
b Department of Chemistry, Queen Mary, University of London, Mile End Road, London,
UK E1 4NS
c New address: Molecular Modelling & Design, Discovery Research Oncology, Pharmacia,
Viale Pasteur 10, 20014 Nerviano (MI), Italy
d Institute of General, Inorganic and Theoretical Chemistry, University of Innsbruck,
Innrain 52a, A-6020 Innsbruck, Austria
e Department of Chemistry, U.M.I.S.T., PO Box 88, Manchester, UK M60 1QD
Received (in Cambridge, UK) 4th February 2002, Accepted 12th July 2002
First published as an Advance Article on the web 30th July 2002
2,7-Diisopropoxy-1,8-dibromonaphthalene 5 was prepared in two steps from 2,7-dihydroxynaphthalene and was
coupled under Suzuki cross-coupling conditions with boronic acids 9 and 10 to provide the corresponding 1,8-
diarylnaphthalene systems 12a and 13a respectively. In contrast, attempted coupling of dibromide 5 with o-tolyl-
boronic acid 11 proved unrewarding. Single crystal X-ray structure determination of compounds 12a and 13a
showed that both structures possessed a high degree of structural deformation due to high internal steric repulsions
between the 1,8-diaryl rings and their substituents. Dynamic 1H NMR experiments showed that these two systems
possessed very slow phenyl–naphthalene bond rotation (ca. 2 sϪ1), corresponding to rotation barriers (∆G*) of 16–18
kcal molϪ1. Molecular modelling predicts that such systems have approximately similar rotation barriers and that in
order to completely prevent phenyl–naphthalene bond rotation, an ortho-phenyl substituent is required, with a
barrier to rotation of ca. 40 kcal molϪ1
.
7-positions (R1) of the naphthalene ring, and different sub-
stituents in the ortho-aryl (R3) positions would allow us to
identify how to stabilise this class of atropisomeric system.
The addition of the meta-aryl (R2) and phenol functions
would then provide a suitably asymmetric and metal-chelating
environment for asymmetric catalysis. A suitable synthetic
precursor was identified as 2,7-dihydroxynaphthalene, the
phenol groups of which would allow various ether derivatives
to be readily prepared. In this paper we describe a detailed
examination of the synthesis, structure, dynamics and model-
ling of such systems.
Introduction
Recent studies from our laboratories1 have shown that 1,8-
diphenylnaphthalenes and related 5,6-diphenylacenaphthenes
substituted in the meta-position on the peri-phenyl rings will
always undergo rotation. Further examination of the transition
state model for this process shows that the positions which have
the greatest effect on the rotation barrier if substituted are the
ortho-positions on the peri-phenyl rings or the 2- and 7-
positions on the naphthalene ring. Clough and Roberts2
showed that having a methyl on the ortho-position on the peri-
phenyl ring did increase the rotation barrier (24.1 kcal molϪ1),
but rotation was still not completely halted. Hence, we under-
took a study involving placing substituents in the 2- and
7-positions of the naphthalene ring, i.e. as in structure 1, with
the aim of halting atropisomer interconversion. There is no
precedence for the preparation of 2,7-disubstituted-1,8-diaryl-
naphthalenes such as 1, however, House et al.3 have synthesised
analogous anthracene derivatives such as 2. Such systems do
exhibit stable syn- and anti-atropisomeric forms in solution up
to 200 ЊC.
Results and discussion
Synthesis of 2,7-dialkoxy-1,8-diarylnaphthalene systems
It was therefore our intention to prepare a series of new com-
pounds based upon general structure 1 designed to probe what
actual functionality is required to prevent aryl–naphthalene
bond rotation. In order to achieve the synthesis of systems of
type 1, we chose to use Suzuki methods, as previously reported
in the acenaphthene series1 and therefore required access to a
1,8-dihalonaphthalene such as 5. It was therefore necessary to
carry out a dibromination on either 2,7-dihydroxynaphthalene
or a suitable diether derivative thereof, regioselectively in the
1,8-positions (Scheme 1). However, it is reported that bromin-
ation and chlorination of 2,7-dihydroxynaphthalene derivatives
do not occur with the required regiocontrol.4
It was therefore envisaged that the synthesis of a series
of compounds of type 1, with substituents placed in the 2- and
Various conditions using several brominating agents, solv-
ents and bases were screened in order to achieve the required
1
transformation of 3 to 4, on H NMR scale reactions. It was
found that the only brominating agent to selectively brominate
1510
J. Chem. Soc., Perkin Trans. 2, 2002, 1510–1519
DOI: 10.1039/b201235a
This journal is © The Royal Society of Chemistry 2002

View Article Online
Having prepared the dibromide 5, attempts were made to
carry out Suzuki cross couplings using the boronic acids 9–11.
Identical conditions were used to those reported previously,1 i.e.
10 mol% Pd(PPh3)4, 2.3 equivalents of boronic acid, Ba(OH)2,
H2O and DMA. Cross coupling of boronic acid 9 with
dibromide 5 resulted in the formation of the desired compound
12a but only in 28% yield (eqn. (1)). Other products were
identified as the mono-bromo coupled compound 12b (38%
yield) and the debrominated mono-coupled compound 12c. It
should be noted that in the previous acenaphthene series,1 the
formation of mono-bromo compounds was never observed,
which indicates that 12b must be particularly sterically hindered
and that formation of the 1,8-diaryl coupled product 12a is not
1
particularly favoured. The H NMR spectrum of 12a showed
two sharp single methyl resonances at 300 MHz, which could
indicate the presence of two atropisomers present in solution.
However, such assumptions had proved inaccurate in the
acenaphthene series of compounds,1a,b thus it was necessary
to prove that rotation was either not occurring, or was slow
relative to the NMR timescale (vide infra).
Scheme 1
in the 1,8-positions was N-bromosuccinimide. Upon scale up
and optimisation of the reaction, it was discovered that the best
conditions to prepare 4 were NBS and 30 mol% pyridine in
chloroform; these were in fact the only conditions which pushed
the reaction to completion and produced 4 in a pure form (61%)
by direct crystallisation from dichloromethane–hexane after
work up (attempted silica gel chromatography produced rapid
and complete decomposition of 4).
Following successful bromination, attempts to isopropylate
compound 4 (Scheme 1) under a range of conditions merely
produced black insoluble precipitates from which ether 5 could
not be isolated. It was however possible to acetylate 4
(pyridine–acetic anhydride) to afford the stable diacetate 7.
Single crystal X-ray structural analysis provided conclusive
evidence that bromination had indeed occurred in the 1- and 8-
positions (Fig. 1 and Table 1). However, dibromodiacetate 7 was
(1)
The cross coupling of compounds 5 and 10 was also
undertaken (eqn. (2)), in order to see if larger tert-butyl
substituents would influence the rotation barrier in the resulting
diaryl system (i.e. 13a versus 12a). The coupling reaction
again produced a mixture of compounds, with purification and
separation proving more difficult due to the extremely low
polarity of all products. Attempts to separate the crude
reaction mixture using silica gel column chromatography and
pure hexane as the eluent eventually resulted in the isolation of
mono-coupled product 13b (27% yield). However, two further
compounds, thought to be the desired compound 13a and
de-brominated product 13c, could only be isolated as an
inseparable mixture. Separation of 13a and 13c was achieved
using preparative reverse phase HPLC (methanol eluent),
resulting in isolation of the desired pure compounds 13a and
13c, unfortunately only on sufficient scale to carry out dynamic
NMR studies (vide infra).
Fig. 1 X-ray crystal structure of dibromide 7.
not considered to be a suitable candidate for cross coupling
under the basic conditions used for the Suzuki reaction or for
subsequent functionalisations.
Due to the problems associated with isopropylating the
dibromide 4, an alternative approach to 5 was required. Hence,
isopropylation of 3 was carried out prior to 1,8-dibromination
using isopropyl bromide–potassium carbonate in DMF to yield
compound 5 (61%), in addition to the mono-ether 8 (18%).
Dibromination of 6 was then achieved using NBS–pyridine
as before to afford 5 without any obvious sign of unwanted
regioisomeric bromination products. The 1H NMR of the crude
reaction product did however show signs of some mono-
brominated product remaining, which was solved by premixing
the four equivalents of pyridine and NBS before the addition of
diether 6. This procedure resulted in increasing the yield of
desired dibromide 5 to 40% after rapid, short column chroma-
tography and recrystallisation.
(2)
Finally, attempts were made to couple dibromide 5 with
commercially available o-tolylboronic acid 11 under identical
reaction conditions to those used for the synthesis of 12a and
13a. Unfortunately, after several attempts and over extended
J. Chem. Soc., Perkin Trans. 2, 2002, 1510–1519
1511

View Article Online
Table 1 Selected crystallographic data for 7, 12a and 13a
Dibromide 7
anti-12a
anti-13a
Temperature/K
293
293
203(2)
Crystal size/mm3
0.4 × 0.3 × 0.2
C14H10Br2O4
402.04
Monoclinic
C2/c
0.4 × 0.25 × 0.25
C32H36O4
484.61
Monoclinic
C2/c
0.4 × 0.20 × 0.05
C38H48O4
568.76
Orthorhombic
Pna21
Molecular formula
Fw
Crystal system
Space group
a/Å
b/Å
c/Å
β/Њ
21.383(3)
5.411(2)
23.737(2)
96.90
22.097(2)
11.505(2)
34.188(2)
102.19
12
16.808(2)
22.023(2)
9.000(3)
90
Z
8
4
λ/Å
1.959
5.955
1.54178
0.581
0.71073
0.072
µ/mϪ1
Reflections collected
Independent reflections
Reflections observed
2460
2391
1332
10030
6674
2842
6087
3107
1972
a
θ range for data collection/Њ
Restraints (parameters)
R1 (observed reflections)
wR2 (all reflections)b
2–25
(0) 183
0.074
0.195
0.959
3–65
(0) 501
0.082
0.264
1.269
1.5–25
(1) 515
0.049
0.101
1.009
Goodness-of-fit on F 2
a I > 2σ(I). b wR2 = {Σ[w(Fo2 Ϫ Fc2)2]/Σ[w(Fo )2]}1/2
.
2
reaction times no reaction was observed, as was also the case
when alternative bases (BaCO3 and Ag2CO3) were used. The
lack of reactivity encountered in this case is paralleled by many
other reports of the difficulty of achieving Suzuki coupling on
such hindered systems.5 However, having obtained compounds
12a and 13a, dynamic NMR studies were undertaken and com-
pared with single crystal X-ray analysis and molecular model-
ling to give an insight into the energies and likely transition
states involved in the rotation process in these types of systems.
Crystal structure analysis†
Compound 12a was slowly recrystallised from diethyl ether–
methanol to give suitable crystals for X-ray analysis. Similarly,
crystals of 13a were grown by slow evaporation from methanol.
The crystallographic data for compounds 12a and 13a are pre-
sented in Table 1. The asymmetric unit for compound 12a is
shown in Fig. 2, where it can be seen that there are two con-
Fig. 3 Crystal structure of 12a (conformation 1).
Fig. 2 Asymmetric unit of crystal structure of compound 12a
showing two conformations.
formations present, both of which have the anti-configuration
[(conformation 1) and (conformation 2), see Figs. 3 and 4
respectively]. Similarly, compound 13a was also obtained with
Fig. 4 Crystal structure of 12a (conformation 2).
anti-geometry, as shown in Fig. 5. Figs. 6, 7 and 8 also show
crystal structures of 12a and 13a, viewed along the naphthalene
ring plane. From these X-ray data, it is clear that both mol-
† CCDC reference numbers 178815–178817. See http://www.rsc.org/
suppdata/p2/b2/b201235a/ for crystallographic files in .cif or other
electronic format.
1512
J. Chem. Soc., Perkin Trans. 2, 2002, 1510–1519

View Article Online
Table 2 Selected geometrical parameters for 12a and 13a
θ/Њ
ꢀ/Њ
τ1/Њ
X/Å
O–O/Å
anti-12a
(conformation 1)
anti-12a
(conformation 2)
anti-13a
13.50
15.32
12.93
9.11
9.58
9.46a
84.7
89.7
84.7a
2.933
2.959
2.985
4.421
4.392
4.032
7.92
9.42
52.1
53.7
Fig. 7 Side view of 12a (conformation 2).
Fig. 5 Crystal structure of 13a looking onto the naphthalene plane.
Fig. 8 Side view of compound 13a.
adding new steric repulsion to the aryl functions, resulting in
forcing the 1,8-aryl functions closer together. The angle θ and
the distance X measure the amount of splaying in the 2,7-
naphthalene series (Table 2). The average angle for θ is 13.9Њ,
while the average for the acenaphthene series is 19.2Њ.1b The
average for distance X in the two series is 2.95 versus 3.13 for the
acenaphthene series.1b Besides the additional repulsion of the
isopropoxy functions in the 2,7-naphthalene series, it is also
possible that absence of the acenaphthene benzylic bridge
allows the two peri-aryl functions to move closer to each other.
In the Cambridge Crystallographic Database, most structures
with a naphthalene backbone have an X distance of 2.970–
3.107 Å, which is comparable to the X distances observed for
12a and 13a. Hence, it seems more probable that the reduction
in the splaying is due more to having a naphthalene ring, rather
than an acenaphthene backbone.
Fig. 6 Side view of 12a (conformation 1).
ecules 12a and 13a relieve the steric strain by distortion of
the naphthalene plane and the distortion results in splaying of
the phenyl rings. The rings are pushed to opposite sides of the
naphthalene plane and they also twist slightly so that they are
not at 90Њ to the naphthalene plane. Selected measurements of
compounds 12a and 13a are shown in Table 2. Comparison of
the two data sets also reveals further interesting features. The
first observation is that the amount of splaying of the 1,8-diaryl
rings is decreased quite substantially when compared with the
acenaphthene series.1b It appears that substituents in the 2,7-
positions on the naphthalene reduce the splaying effect by
J. Chem. Soc., Perkin Trans. 2, 2002, 1510–1519
1513

View Article Online
Table 3 1H Chemical shifts for 2,7-diisopropoxy-1,8-diphenylnaphthalenes 12a and 13a
Compound
H1/H1Ј
H2/H2Ј
H3/H3Ј
H4/H4Ј
H5/H5Ј
H6/H6Ј
Other signals
anti-12a
7.77
7.17
4.96
6.41
6.16
6.61
1.02 -Me1/Me2
3.75 -OMe
2.01 -Me
syn-12a
anti-13a
syn-13a
7.77
7.78
7.76
7.17
7.19
7.18
4.96
6.49
6.45
6.63
6.42
6.32
6.44
6.51
6.82
6.63
1.07 -Me1/Me2
3.75 -OMe
1.93 -Me
4.15 (4.17)a
4.14 (4.17)a
1.0 (0.95) -Me1/Me2a
3.71 -OMe
1.30 -tButyl
0.97 (0.93) -Me1/Me2a
3.74 -OMe
1.27 -tButyl
a Diastereotopic, hence two peaks.
Comparison of the other measurements, i.e. τ1 and ꢀ, reveals
that the isopropoxy unit does have some effect on the ground
state geometry. Compounds 12a and 13a show some structural
deviation in order to deal with different substituents. Firstly,
12a has compensated for the increase in steric effects by
increasing the movement of the phenyl rings to above and
below the naphthalene plane (average angle ꢀ is 9.38Њ for 12a
versus 7.17Њ for the corresponding acenaphthene system).
Secondly, the rotation angle τ1 is nearly 90Њ, which places the
phenyl rings virtually perpendicular to the naphthalene plane.
In contrast, compound 13a has to compensate for its phenyl
ring substituents by increasing the deformation of the phenyl
rings on either side of the naphthalene plane; ꢀ is almost
identical when comparing 13a (8.7Њ) and the corresponding
acenaphthene system (9.2Њ). The change in the amount of
splaying also results in a change in τ1, where the phenyl rings are
at an angle of approximately 50Њ to the naphthalene plane
(Table 2). However, it is unclear if these deviations are a direct
result of having the isopropoxy substituents in the 2,7-
positions. The X-ray structures only give a reflection of the
ground state configuration and crystal packing forces could
also have a large effect on the observed conformation, as well as
the relative energy of the molecule.
exchange was occurring. In molecule 12a the barriers to inter-
conversion are particularly large and therefore the rates of
interconversion are very slow in comparison to the acenaph-
thene systems1b (0.1 sϪ1 versus 2.4 sϪ1). Due to the very slow
exchange rates observed in 12a, no line broadening effects or
coalescence of the resonances are observed, making it impos-
sible to use line shape analysis as a technique to calculate the
rotation barriers. Instead, selective inversion experiments were
used to obtain the rates of syn–anti interconversion over a
range of temperatures (see Experimental section). The Eyring
activation parameters were calculated from these exchange
rates and the results are shown in Table 4, which gives rates of
exchange and activation parameters.
The 1H NMR spectrum of 13a at 600 MHz showed that two
atropisomers were present in solution with the predominant
form being assigned to the anti-atropisomer. Observation of the
syn-atropisomer was not apparent when the 1H NMR spectrum
was run at 300 MHz due to the high anti : syn ratio. The reson-
ances shown in Table 4 were assigned based on integration,
chemical shifts, couplings and NOEs. Again no line broadening
effects or coalescence of the resonances were observed over a
wide range of temperatures. Due to the slow exchange rates,
selective inversion experiments were performed at various tem-
peratures using the tert-butyl group and the calculation of
exchange rates and activation parameters was carried out as
previously described. However, due to the large ratio of anti :
syn atropisomer these experiments proved to be difficult when
inverting the syn-atropisomer tert-butyl group and only one
inversion was successfully completed. The other rates were
calculated from this rate, so the activation parameters for the
syn-anti interconversion are assumed rather than calculated.
The activation parameters are also shown in Table 4.
The effects of shielding on both compound 12a and 13a are
identical. For the anti–syn interconversion of the substituents,
i.e. for either the methyl or tert-butyl system, the syn-resonance
is shifted upfield relative to the anti-resonance. The same effect
is observed for H6/H6Ј (Table 3). However, the reverse is
observed for H4/H4Ј and H5/H5Ј; the anti-syn interconversion
results in the protons being shifted downfield. This observation
is explained by the shielding effect of the aromatic system on
the protons. When a proton is close to the centre of the aro-
matic system, it is shielded resulting in an upfield shift of the
resonance; when compounds 12a and 13a are in the syn-
geometry, the H4/H4Ј and H5/H5Ј protons are not affected
by the aromatic system. However, rotation due to the anti-
atropisomer places these two protons in close proximity to the
aromatic system, which causes the resonances to shift upfield.
In the case of the substituents on the peri-phenyl rings and the
H6/H6Ј protons, the opposite effect is observed and when 12a
or 13a is in the syn-geometry the phenyl substituents and the
H6/H6Ј hydrogens are shielded by the aromatic system. This
follows the same pattern as that which was observed for the
acenaphthene series,1b although the shielding effects are greater
Dynamic and structural NMR studies
Having isolated compounds 12a and 13a, we employed 1H
NMR spectroscopy to probe the rotational dynamics which
1
operate in such systems. Thus, all dynamic H NMR studies
were measured at 600 MHz and longitudinal relaxation times
were measured using the inversion-recovery technique. ROESY
experiments were used to observe any NOE and exchange
effects caused by rotation of the phenyl rings. The numbering
scheme used for NMR assignment purposes for these molecules
is shown in Fig. 9.
Fig. 9 Numbering scheme for 12a and 13a.
The 1H NMR spectrum of compound 12a showed that both
the syn- and anti-atropisomers were present at ambient tem-
perature, appearing as sharp well defined resonances (vide
supra). The individual resonances were assigned as shown in
Table 3, based upon integration, chemical shifts and couplings,
in addition to NOEs measured from the ROESY experiments.
However, the ROESY spectrum of 12a indicated that slow
1514
J. Chem. Soc., Perkin Trans. 2, 2002, 1510–1519

View Article Online
Table 4 Activation parameters and rates of rotation for 12a and 12b
Activation enthalpy
Activation entropy
Rotation barrier
Compound
(∆H )a /kcal molϪ1
(∆S)a /cal KϪ1 molϪ1
(∆G)a /kcal molϪ1
Rate of rotation/sϪ1 (K)
12a anti-syn
syn-anti
13a anti-syn
syn-anti
15.7
15.6
17.8
17.8a
Ϫ8.07
Ϫ7.56
Ϫ0.42
5.17a
18.2
17.9
17.9
16.3a
0.111 (270 K)
0.138 (270 K)
0.085 (273 K)
—
a Assumed values.
Table 5 Calculated biaryl rotational energy barriers for compounds
12a, 13a and 14 (enthalpy difference between the anti-conformer and
the transition state of the aryl–aryl rotation)
etry optimisations were carried out for each of these points on
the pathway of naphthyl–aryl rotation. These calculations were
carried out for 25 points (or one-degree increments) before and
after the transition state on this pathway and resulted in smooth
and continuous energy profiles. It turned out that initially the
energetically preferred orientation of the adjacent methoxy
group was as shown for the anti-conformation of compound
14a in Fig. 10 (herewith referred to as “below” the naphthyl
plane when viewing the structure in Fig. 10 from the left-hand
side). Fourteen points (or degrees) before the transition state for
the naphthyl–aryl torsion is reached, the energetic preference of
the adjacent methoxy group is shifted to “above” the naphthyl
plane, as shown for the transition state of 14a in Fig. 10. At this
point of the pathway, calculation of the rotational barrier of the
methoxy group to move from one conformation “below” to the
other conformation “above” the naphthyl plane gave a value of
0.98 kcal molϪ1. The corresponding value for the isopropoxy
group was very similar, and these calculations included location
of the transition state for alkoxy rotation and characterization
by frequency analysis. The associated activation energies are low
compared to the energy that is still required to overcome the
remaining energy barrier (ca. 8 kcal molϪ1) on the naphthyl–aryl
torsional pathway. Transition state location for methoxy rota-
tion in the local minimum of the anti-conformer of 14a gave an
activation barrier of 2.19 kcal molϪ1. Summarizing these data,
the minimum energy pathway for anti–syn interconversion
could be described as follows. Starting from the anti-conformer
with the alkoxy group “below” the plane, via a transition state
with respect to alkoxy rotation, an anti-conformer with the
alkoxy group above the plane can be generated. This intermedi-
ate rotamer is slightly higher in energy, and the process that
leads to it requires very little activation energy (ca. 2 kcal molϪ1).
This implies that this intermediate rotamer is easily accessible
throughout the process. The other transition state on the path-
way corresponds to rotation about the naphthyl–aryl bond and
the transition requires much more activation energy (ca. 20 kcal
molϪ1). Therefore, the overall energy barrier is determined by
the transition state on the naphthyl–aryl torsional pathway
(Table 5). Taken together, one can consider the anti- to syn-
interconversion in compounds 12a, 13a and 14 as the interplay
of two linked rotors, i.e. rotation of both the alkoxy and the
diaryl moieties, where the rotamers with respect to alkoxy rota-
tion are energetically easily accessible.
Compound
HF/3-21G*/kcal molϪ1
14a
12a
13a
14b
18.82
20.89
20.90
37.69
in these molecules, with some aromatic resonances being shifted
as far upfield as 6.16 ppm.
It is also worth noting that the energy barriers for 12a and
13a are essentially identical within experimental error; a phe-
nomenon which was also previously observed in the acenaph-
thene series of compounds.1b The explanation for the rotation
barriers being similar is the fact that during rotation of a phenyl
ring, the less hindered side of one ring is projected towards the
flat face of the other phenyl ring and rotation can always occur
away from the meta-substituent.
Molecular modelling
In order to probe the structural and dynamic features which
operate in general systems 1, we used ab initio molecular model-
ling methods to understand what processes control rotational
dynamics. Hence, structures 12a, 13a and 14 were examined
using quantum chemical calculations and the GAUSSIAN98
programme at the HF/STO-3G and HF/3-21G* levels of the-
ory. Only the HF/3-21G* results were used for prediction of the
heights of the energy barriers, as our earlier studies indicated
better agreement between the results at this level and experi-
ments.1b Also in the present study the agreement between this
method and the experimental measurements is rather good,
indicating a reasonable compromise between accuracy and
computational costs. The calculated energy barriers for struc-
tures 12a, 13a and 14 are displayed in Table 5. The correspond-
ing structures (anti-conformations and transition states) are
shown in Fig. 10.
The energies for biaryl rotation (see Table 5) indicate that the
size of the substituents in the 2,7-positions (methoxy or isopro-
poxy in this study) has only a minor influence on the activation
energy. Replacing the methoxy substituent with an isopropoxy
group (14a versus 13a) increases the activation enthalpy by 2.08
kcal molϪ1. The value of 20.90 kcal molϪ1 for compound 13a is,
however, too low to prevent the molecule from undergoing anti-
to syn-interconversion at room temperature. Substituting a
hydrogen atom in the ortho-position of the aryl moiety for a
methyl group (i.e. 14a versus 14b) has a much more significant
effect and increases the energy required for interconversion by
almost 20 kcal molϪ1. Analysis of the geometry of the corres-
ponding transition state (see Fig. 10) indicates that not only the
naphthyl moiety deviates significantly from planarity (as in the
other transition states), but the aryl ring itself is also severely
distorted. The reason for this distortion is that the rotating ring
When we studied the rotation about the naphthyl–aryl tor-
sion, we also investigated the influence of the conformations of
the methoxy/isopropoxy groups adjacent to the rotating aro-
matic ring. To this end, the naphthyl–aryl torsion in molecule
14a was changed in one-degree increments. The corresponding
dihedral angle was fixed and the rest of the molecule fully
relaxed with the adjacent methoxy group being located above
and below the plane defined by the naphthyl ring, i.e. two geom-
J. Chem. Soc., Perkin Trans. 2, 2002, 1510–1519
1515

View Article Online
Fig. 10 Geometries of anti conformations and transition states of molecules 12a, 13a, and 14.
becomes “wedged” between the adjacent aryl ring (distance
there is still a clear need to develop new coupling protocols
ortho-H to ortho-C of adjacent ring: 2.68 Å) and the adjacent
methoxy substituent (distance ortho-methyl C–oxygen of the
methoxy group: 2.66 Å). As a consequence the activation
energy rises to nearly 40 kcal molϪ1 for 14b, which should be
sufficient to prevent this molecule from interconverting at room
temperature.
which can be applied to such systems. However, it was possible
to access compounds 12a and 13a and study both these
compounds by both X-ray and NMR methods. Unfortunately,
similar coupling reaction methods could not be applied to
access a corresponding ortho-substituted 2,7-diisopropoxy-1,8-
diphenylnaphthalene system. X-ray crystallographic studies on
both 12a and 13a do however shed considerable light upon the
extreme steric repulsions which operate in these systems, mak-
ing preparation of the corresponding ortho-substituted-phenyl
systems very challenging. The severe distortions shown by the
X-ray structures are also mirrored by the dynamic NMR
Summary and conclusion
The synthesis of highly hindered 1,8-diaryl-2,7-dialkoxy-
naphthalene systems is far from straightforward, showing that
1516
J. Chem. Soc., Perkin Trans. 2, 2002, 1510–1519

View Article Online
spectroscopy, which shows extremely slow interconversion
between syn- and anti-atropisomers, i.e. two orders of magni-
tude greater than we have observed before in systems which do
not possess 2,7-dialkoxy functions on the naphthalene ring.1b
However, despite the success of the two dialkoxy functions in
slowing rotation, these substituents are not sufficient to prevent
the rotation process at room temperature; rotation barriers are
in agreement with those of corresponding 2,7-unsubstituted
systems1b and those systems reported by Cozzi et al.,17 and
reasonably well reproduced by ab initio calculations. The
question therefore remains as to whether it is possible to ever
stop the rotation process in systems of type 1. Ab initio calcula-
tions perhaps provide the answer to this question; it is predicted
that the addition of an ortho-methyl function onto the two
1,8-diphenyl rings in addition to 2,7-dialkoxynaphthalene
substituents (i.e. to provide structure 14b), would result in a
rotation barrier of the order of 40 kcal molϪ1, which should be
sufficient to completely prevent all biaryl rotation at room
temperature. In the light of this prediction, we are working
towards the synthesis of such a system.
ively inverted using a soft ‘sinc’ pulse.12 A separate experiment,
inverting one of the syn aromatic signals, was not attempted
because of their low intensity relative to the corresponding anti
signal. Intensity changes of the anti signal during the return to
equilibrium would therefore have been very small and derived
exchange rates would include a large uncertainty. A relaxation
delay of 12 s was used in these experiments, and during the
return to equilibrium the intensities of the signals from the
exchanging sites were monitored at 36 time intervals between 10
ms and 12 s. The analysis of the intensities, to give exchange
rates, used the program CIFIT, derived13 from the earlier
work of Muhandiram and McClung.14 Input to the CIFIT
program includes approximate values for the spin-lattice
relaxation times (T 1) of the exchanging sites, and these were
obtained experimentally using the non-selective inversion-
recovery technique. The dynamic NMR measurements were
repeated at five temperatures in the range 270 to 330 K for 12a,
and six temperatures in the range 255 to 330 K for 13a.
Molecular modelling
Quantum chemical calculations were carried out using the
program Gaussian98.15 Initial geometry optimisations were
performed at the HF/STO-3G level.16 The structures were then
optimised further at the HF/3-21G* level.18 The geometries of
stationary points were fully optimised without symmetry con-
straints. Harmonic vibrational frequencies were computed in
order to characterize stationary points. Energy minima were
confirmed as such by having no imaginary frequencies. Transi-
tion states were confirmed as first order saddle points by
possessing exactly one imaginary frequency. Animation of the
imaginary frequencies of the transition states indicated that
the negative vibrational mode corresponded to the correct
pathway of conformational transition. The energy barriers
were calculated as the difference between minima and saddle
point energies.
Experimental
General procedures and reagents
THF was freshly distilled under argon from benzophenone–
sodium. Dichloromethane was freshly distilled under argon
from calcium hydride. All other solvents were either purchased
as anhydrous or used directly without further purification. 5,6-
Dibromoacenaphthene,6 TBABr3 and Pd(dba)2/Pd2(dba)3ؒ
7
CHCl3 were prepared8 as reported in the literature. Pd(PPh3)4
was prepared as reported in the literature9 and sealed under
argon in glass ampoules for storage. All other reagents were
purchased from Aldrich or Lancaster and were used without
further purification unless stated otherwise.
Chromatography
General characterisation
Column chromatography was performed under medium pres-
sure on silica gel (Merck, pore size 60 Å, 230–400 mesh). All
anhydrous, low temperature reactions were carried out in
glassware, which was dried prior to use in an oven at 140 ЊC
and cooled under a stream of argon. All Suzuki coupling
reactions were performed under strictly anaerobic conditions
with all solvents being thoroughly degassed prior to use. All
evaporations were carried out by partial evaporation on a Büchi
rotary evaporator, followed by solvent drying in vacuo at
approximately 0.5 mmHg. TLC was performed using Merck
Kieselgel 60F254 plastic backed plates or Fluka Kieselgel 60F254
aluminium backed plates.
All melting points are uncorrected and were measured on a
capillary melting point apparatus. Low resolution Fast Atom
Bombardment (FAB) mass spectra were recorded on a Kratos
MS50 mass spectrometer using an m-nitrobenzyl alcohol
matrix. High-resolution electron impact (EI) mass spectra were
recorded on a Kratos Concept IS spectrometer. Infrared spectra
were recorded on a Perkin-Elmer 298 spectrometer as thin films
on KBr plates or as KBr discs. UV–Vis spectra were recorded
on a Perkin-Elmer 115 spectrometer. Microanalyses were
performed using a Carlo-Erba 1106 elemental analyser. For
1
compounds characterised without microanalysis, H and 13C
NMR were used to assess purity.
NMR spectroscopy
Preparation of 1,8-dibromonaphthalene-2,7-diol 4
Room temperature 1H NMR spectra were recorded at 300, 400
or 600 MHz on Bruker AC300, AC400 or AMX600 spectro-
meters respectively. 13C NMR spectra were recorded at 75.5 or
100 MHz on Bruker AC300 or AC400 spectrometers respect-
ively. Both 1H and 13C NMR spectra used residual incompletely
deuterated solvent as the internal standard.
A mixture of 2,7-dihydroxynaphthalene 3 (1.0 g, 6.24 mmol),
NBS (2.22 g, 12.4 mmol), CHCl3 (100 cm3) and pyridine (0.148
g, 1.87 mmol) was stirred at room temperature for 4 hours. The
resulting solution was washed with 10% HCl, water, dried
(MgSO4) and evaporated. The crude solid was recrystallised
from ether–hexane to give compound 4 (1.2 g, 61%) as light
brown crystals: mp 125 ЊC (Found: C, 38.0; H, 1.8; Br, 50.0.
C10H6Br2O2 requires C, 37.8; H, 1.9; Br 50.2%); λmax (EtOH)/
nm 312 (ε/dm3 molϪ1 cmϪ1 5855) and 241.5 (48993); νmax/cmϪ1
(KBr disc) 3400 (OH), 1610 and 1510 (aromatics), 1350 (OH),
1180 (C–O), 840 (para-substituted aromatics) and 500 (C–Br);
δH (300 MHz; DMSO) 7.09 and 7.71 (each 2 H, d, J 8.8, 2 × Ar-
H), 10.58 (2 H, s, 2 × OH) (addition of D2O causes signal at δ
10.58 to disappear); δC (75.5 MHz; DMSO) 101.6, 125.5, 131.7
and 155.3 (Ar-C), 115.3 and 131.7 (Ar-CH); m/z (FAB) 318/
316 (Mϩ, 30), 238 (Mϩ Ϫ Br, 8), 207 (Mϩ Ϫ O2Br, 12%); m/z
(EI) 315.8733 (Mϩ, C10H6Br2O2 requires 315.8736).
The samples of 12a and 13a used for 1H NMR kinetic
1
analysis were dissolved in CDCl3, and all dynamic H NMR
measurements were made at 600 MHz. The assignments of the
resonances were confirmed by 2-dimensional ROESY and
1
TOCSY spectra, and H–13C HSQC spectra. Exchange rates
were measured by monitoring signal intensity changes follow-
ing selective inversion of one of the two exchanging sites.10 For
12a, in two separate experiments the peri-ring CH3 signals of
the syn and anti atropisomers were selectively inverted using the
π
π/2 – t1 – /2 sequence of Robinson et al.,11 whereas for 13a the
anti ortho aromatic proton signal due to H2 (6.82 δ) was select-
J. Chem. Soc., Perkin Trans. 2, 2002, 1510–1519
1517

View Article Online
Preparation of 2,7-diacetoxy-1,8-dibromonaphthalene 7
of 2,7-diisopropoxynaphthalene 6 (1.70 g, 6.97 mmol) in
chloroform (∼5 cm3) was added dropwise, followed by heating
at reflux for 9 hours. After cooling to room temperature and
evaporation, the crude reaction mixture was purified by silica
gel chromatography (petroleum ether : ethyl acetate, 50 : 1 as
eluent) to provide a solid which was re-crystallised from DCM–
petroleum ether to yield the product 5 (1.096 g, 40%) as a
brown–orange crystalline solid: mp 113 ЊC (Found: C, 47.5; H,
4.6; Br 40.0. C16H18Br2O2 requires C, 47.8; H, 4.5; Br 39.8%);
λmax (Et2O)/nm 311 (ε/dm3 molϪ1 cmϪ1 6070) and 246.5 (66069);
νmax/cmϪ1 (KBr disc) 2980 and 2920 (CH3), 1610 and 1510
(aromatic), 1380 and 1370 (CH3), 1260 (Ar–C–O), 1105 (C–O–
C), 830 (two adjacent aromatic H’s) and 620 (C–Br); δH (300
MHz; CDCl3) 1.43 and 1.45 [each 6 H, s, CH(CH3)2], 4.69 (2 H,
sept, J 6.0, 2 × CH(CH3)2], 7.13 and 7.68 (each 2 H, d, J 9.0, 2 ×
Ar-H); δC (75.5 MHz; CDCl3) 22.8 (CH3), 74.0 [CH(CH3)2],
109.4, 128.3 and 155.8 (Ar-C), 116.1 and 129.9 (Ar-CH); m/z
(FAB) 402 (Mϩ, 100), 318 (Mϩ Ϫ C6H12, 95), 43 (C3H7ϩ, 100%);
m/z (EI) 399.9675 (Mϩ, C16H18Br2O2ϩ requires 399.9675).
1,8-Dibromo-2,7-dihydroxynaphthalene 4 (2.0 g, 9.44 mmol),
pyridine (3.73 g, 47.1 mmol), acetic anhydride (4.82 g, 47.1
mmol) and diethyl ether (100 cm3) were stirred at room
temperature for 8 hours. The mixture was washed with dilute
HCl (75 cm3), water (75 cm3), dried (MgSO4) and evaporated.
The resulting crude solid was recrystallised from chloroform–
hexane to yield the product 7 (3.04 g, 82%) as pale brown
crystals: mp 179–182 ЊC (Found: C, 42.0; H, 2.6; Br 39.5.
C14H10O4Br2 requires C, 41.8; H, 2.5; Br, 39.7%); λmax (Et2O)/
nm 297.5 (ε/dm3 molϪ1 cmϪ1 7476) and 232.5 (69426); νmax/cmϪ1
(KBr disc) 2940 (CH3), 1765 [C(O)–O], 1610 and 1505
(aromatic), 1460 (CH3), 1375 [O–C(O)–CH], 1200 (C–O) and
845 (C–Br); δH (300 MHz; CDCl3) 2.44 (6 H, s, 2 × CH3), 7.28
and 7.85 (each 2 H, d, J 8.8, 2 × Ar-H); δC (75.5 MHz; CDCl3)
21.4 (CH3), 114.15, 131.2, 133.3 and 149.7 (Ar-C), 122.8 and
130.4 (Ar-CH) and 169.0 (C᎐O); m/z (FAB) 402 (Mϩ, 79), 361
᎐
(Mϩ Ϫ C2H2O, 100), 318 (Mϩ Ϫ C4H5O2, 98), 43 (C2H6O2
35%); m/z (EI) 399.8943 (Mϩ, C14H10O4Br2 requires 399.8947).
ϩ
,
Cross coupling of 1,8-dibromo-2,7-diisopropoxynaphthalene 5
with 4-methoxy-3-methylphenylboronic acid 9
Preparation of 2,7-diisopropoxynaphthalene 6 and 7-isopropoxy-
2-naphthol 8
A mixture of 1,8-dibromo-2,7-diisopropoxynaphthalene 5 (0.6
g, 1.49 mmol), 4-methoxy-3-methylphenylboronic acid 9 (0.54
g, 3.27 mmol), barium hydroxide octahydrate (1.88 g, 5.96
mmol), DMA (15 cm3) and water (3 cm3) in a Rotaflo tube
was degassed using a freeze–pump–thaw method (3 cycles).
After the addition of Pd(PPh3)4 (0.17 g, 0.149 mmol) and
repeated degassing (3 cycles), the mixture was heated under
argon at 70–80 ЊC for 72 hours. After cooling to room tempera-
ture, the mixture was diluted with DCM (15 cm3), washed with
10% HCl (4 × 20 cm3), dried (MgSO4) and evaporated. The
crude product was purified using silica gel chromatography
(petroleum ether : ethyl acetate, 75 : 1 as eluent) to give 3 frac-
tions. The first fraction was 2,7-diisopropoxy-1-(4-methoxy-3-
methylphenyl)naphthalene 12c (0.056 g, 10%): δH (300 MHz;
CDCl3) 1.16 and 1.29 [each 6 H, d, J 6.0, CH(CH3)2], 2.29 (3 H,
s, CH3), 3.93 (3 H, s, OCH3), 4.36 and 4.45 [each 1 H, sept, J
6.0, CH(CH3)2], 6.93 (1 H, d, J 7.2, Ar-H), 6.94 (1 H, s, Ar-H),
7.01 (1 H, dd, J 9.0 and 2.0, Ar-H), 7.17 (3 H, m, 3 × Ar-H) and
7.84 (2 H, d, J 7.8, 2 × Ar-H); δC (300 MHz; CDCl3) 16.6, 22.1
and 22.3 [CH(CH3)2], 22.8 (CH3), 55.7 (OCH3), 69.9 and 73.0
[CH(CH3)2], 107.6, 109.8, 116.7, 117.4, 128.4, 129.7, 129.8 and
133.8 (Ar-CH), 125.4, 126.1, 127.2, 128.9, 135.7, 153.5, 156.2
and 156.9 (Ar-C); m/z (FAB) 364 (Mϩ, 100), 280 (Mϩ Ϫ C6H12,
60) and 43 (C3H7ϩ, 20%); m/z (EI) 364.2025 (Mϩ, C24H28O3
requires 364.2038). The second fraction was 1-bromo-2,7-
diisopropoxy-8-(4-methoxy-3-methylphenyl)naphthalene 12b
(0.25 g, 38%): mp 135-137 ЊC; λmax (Et2O)/nm 311 (ε/dm3 molϪ1
cmϪ1 6205), 247 (48085) and 202.5 (31763); νmax/cmϪ1 (KBr disc)
3000–2840 (CH3, CH), 1610, 1580 and 1500 (aromatic), 1390
and 1370 (CH3)2, 1260 (Ar–O–C), 1110 (C–O), 1030 (Ar–O–C),
830 (para substituted aromatic) and 560 (C–Br); δH (300 MHz;
CDCl3) 1.11 and 1.13 (each 3 H, s, CH3), 1.36 and 1.39 (each 3
H, d, J 2.0, CH3), 2.25 (3 H, s, CH3), 3.90 (3 H, s, OCH3), 4.39
and 4.60 [each 1 H, sept, J 6.0, CH(CH3)2], 6.83 (1 H, d, J 8.7,
Ar-H), 7.00 (1 H, d, J 3.0, Ar-H), 7.01 (1 H, s, Ar-H), 7.11 (1 H,
d, J 8.7, Ar-H), 7.21 (1 H, d, J 8.7, Ar-H) and 7.73 (2 H, dd, J
8.7 and 3.0, 2 × Ar-H); δC (75.5 MHz; CDCl3) 16.5 [CH(CH3)2],
22.7 (CH3), 55.7 (OCH3), 73.0 and 73.9 [CH(CH3)2], 109.1,
116.0, 116.8, 129.4, 129.5, 130.4 and 134.6 (Ar-CH), 110.3,
125.0, 127.7, 128.3, 133.3, 154.9, 155.8 and 157.0 (Ar-C);
m/z (CI) 443 (Mϩ, 100), 363 (Mϩ Ϫ Br, 95%); m/z (ES)
443.1220 (M ϩ H, C24H27BrO3 requires 443.1222). The third
fraction was 2,7-diisopropoxy-1,8-bis(4-methoxy-3-methyl-
phenyl)naphthalene 12a (0.204 g, 28%): mp 121–125 ЊC
(Found: C, 79.5; H, 7.7. C32H36O2 requires C, 79.3; H, 7.5%);
λmax (hexane)/nm 305 (ε/dm3 molϪ1 cmϪ1 8484), 248 (55484) and
201 (42272); νmax/cmϪ1 (KBr disc) 2980–2840 (CH3, CH), 1610
A solution of 2,7-dihydroxynaphthalene 3 (10 g, 62 mmol),
potassium carbonate (25.88 g, 0.187 mol), tetrabutylam-
monium iodide (2.3 g, 6.24 mmol) and DMF (150 cm3) under
argon was stirred for 1 hour. 2-Bromopropane (46 g, 0.374 mol)
was added and the solution heated at 70 ЊC for 9 hours. After
cooling to room temperature, DCM (150 cm3) was added
followed by washing with 5% NaOH solution (150 cm3), water
(5 × 200 cm3), drying (MgSO4) and evaporation. The resulting
crude product was purified by silica gel chromatography (pet-
roleum ether : ethyl acetate, 50 : 1 as the eluent) to give two
fractions. The first fraction was identified as 2,7-diisopropoxy-
naphthalene 6 (9.29 g, 61%) and obtained as a colourless solid:
mp 49–51 ЊC (Found: C, 78.9; H, 8.3. C16H20O2 requires C, 78.8;
H, 8.3%); λmax (hexane)/nm 327 (ε/dm3 molϪ1 cmϪ1 4051), 319
(2145), 312.5 (2521), 299.0 (2299), 277.0 (3461), 268.5 (3276)
and 235 (37179); νmax/cmϪ1 (KBr disc) 3030 (Ar-H), 3000–2860
(CH3, CH2), 1620 and 1510 (aromatic), 1390 and 1370 (CH3),
1210 and 1110 (Ar–O–C) and 820 (para-substituted aromatic);
δH (300 MHz; CDCl3) 1.41 and 1.43 (each 6 H, s, 2 × CH3), 4.71
(2 H, sept, J 6.0, 2 × CH), 6.98 (2 H, dd, J 9.0 and 2.3, 2 ×
Ar-H), 7.05 (2 H, d, J 2.3, 2 × Ar-H) and 7.66 (2 H, d, J 9.0, 2 ×
Ar-H); δC (75.5 MHz; CDCl3) 22.5 (CH3), 70.2 [OCH(CH3)2],
108.2, 117.5 and 129.5 (Ar-CH), 124.5, 136.4 and 156.7 (Ar-C);
m/z (FAB) 244 (Mϩ, 100), 160 (Mϩ Ϫ C6H12, 83), 43 (C3H7
,
ϩ
21%); m/z (EI) 244.1464 (Mϩ, C16H20O2 requires 244.1463). The
second fraction was 7-isopropoxy-2-naphthol 8 (2.26 g, 18%)
and obtained as a colourless solid: mp 96–98 ЊC; λmax (Et2O)/nm
328 (ε/dm3 molϪ1 cmϪ1 3615), 320 (2153), 313.5 (2500), 282
(3369) and 234.5 (97564); νmax/cmϪ1 (KBr disc) 3460 br (OH),
2990–2880 (CH3, CH), 1610 and 1510 (aromatic), 1390 (CH3),
1270 (OH), 1200 (C–O) and 840 (para-substituted aromatic); δH
(300 MHz; CDCl3) 1.40 and 1.42 (each 3 H, s, CH3), 4.70 [1 H,
sept, J 6.0, CH(CH3)2], 5.01 (1 H, br s, OH) (signal disappears
on addition of D2O), 6.91–6.98 (2 H, m, 2 × Ar-H), 7.00 (1 H, s,
Ar-H), 7.04 (1 H, d, J 2.6, Ar-H), 7.67 (2 H, d, J 8.7, 2 × Ar-H);
δC (75.5 MHz; CDCl3) 22.4 (CH3), 70.2 [O-CH(CH3)2], 107.6,
109.0, 115.5, 117.7, 129.7 and 129.9 (Ar-CH), 124.7, 136.4,
154.3 and 156.2 (Ar-C); m/z (FAB) 202 (Mϩ, 95), 160 (Mϩ
Ϫ
C3H6, 100), 43 (C3H7ϩ, 19%); m/z (EI) 202.0992 (Mϩ, C13H14O2
requires 202.0994).
Preparation of 1,8-dibromo-2,7-diisopropoxynaphthalene 5
A solution of NBS (4.96 g, 27.9 mmol) in CHCl3 (68 cm3) under
argon was treated with pyridine (2.21 g, 27.9 mmol). The
mixture was heated at reflux for 1 hour (all NBS had dissolved
and the solution turned from colourless to orange). A solution
1518
J. Chem. Soc., Perkin Trans. 2, 2002, 1510–1519

View Article Online
and 1500 (aromatic), 1450 (C–H), 1390 and 1370 (CH3), 1250
(Ar–O–C), 1140 and 1110 (C–O), 1040 (Ar–O–C) and 800 (para
substituted aromatic); δH (300 MHz; CDCl3) 0.98–1.05 [12 H,
m, 2 × CH(CH3)2], 1.95 (3 H, s, CH3), 2.02 (3 H, s, CH3), 3.77 (6
H, s, 2 × OCH3), 4.21 [2 H, dsept, J 6.0 and 1.9, 2 × CH(CH3)2],
6.32 (1 H, d, J 8.3, Ar-H), 6.40–6.57 (4 H, m, 4 × Ar-H), 6.63 (1
H, dd, J 8.3 and 2.3, Ar-H), 7.19 (2 H, d, J 9.0, 2 × Ar-H), 7.78
(2 H, d, J 9.0, 2 × Ar-H); δC (75.5 MHz; CDCl3) 16.2 and 16.3
(CH3), 22.7 (CH3), 55.5 (OCH3), 73.3 and 73.4 (OCH), 108.0,
109.0, 117.2, 117.3, 129.3, 130.2, 130.3 and 134.4 (Ar-CH),
124.0, 124.3, 127.4, 129.4, 130.7, 130.9, 155.1, 155.2, 155.4 and
155.5 (Ar-C); m/z (FAB) 484 (Mϩ, 100), 400 (Mϩ Ϫ C6H12, 25),
279 (C18H15O2ϩ, 11), 43 (C3H7ϩ, 15%); m/z (EI) 484.2619 (Mϩ,
C32H36O4 requires 484.2613).
and 130.9 (Ar-CH); m/z (CI) 487.4/485.4 (M ϩ H, 100), 405.5
(Mϩ Ϫ Br, 50%); m/z (ES) 485.1689 (M ϩ H, C27H33O3Br
requires 485.1691).
Acknowledgements
We thank the EPSRC for studentships (to MS, GR/97311210
and RN, GR/98700139) and Dr H. Toms (QMUL) for
assistance and advice with the selective inversion experiments.
We thank Professor A. D. Bain (McMaster University, Canada)
for advice and for providing the CIFIT software, and the
University of London Intercollegiate Research Service
(ULIRS) for access to the AMX600 spectrometer. We also wish
to acknowledge the use of the EPSRC’s Chemical Database
Service at Daresbury.19
Cross coupling of 1,8-dibromo-2,7-diisopropoxynaphthalene 5
with 3-tert-butyl-4-methoxyphenylboronic acid 10
References
A mixture of 1,8-dibromo-2,7-diisopropoxynaphthalene 5 (1.0
g, 2.49 mmol), 3-tert-butyl-4-methoxyphenylboronic acid 10
(1.08 g, 5.22 mmol), barium hydroxide octahydrate (3.14 g, 9.94
mmol), water (5 cm3) and DMA (25 cm3) in a Rotaflo tube
was degassed using the freeze–pump–thaw method (cycles).
Tetrakis(triphenylphosphine)palladium() (0.286 g, 0.249
mmol) was added, the mixture was degassed as before (3 cycles)
and heated to 80 ЊC for 72 hours. After cooling to room tem-
perature, it was diluted with DCM (30 cm3), washed with 10%
HCl (5 × 30 cm3) and evaporated. The resulting solid was
purified by silica gel chromatography (petroleum ether : ethyl
acetate, 100 : 1 as the eluent) to give a first fraction which was a
mixture of 13c mono-substituted product and 13a doubly
coupled product. Further purification of this mixture was
achieved employing preparative HPLC using a Dynamax 60A
reverse phase C18 preparative column (internal diameter 41.5
mm) with methanol (100%) as the eluent with a flow rate of 10
ml minϪ1. The first fraction was 13c: δH (300 MHz; CDCl3) 0.96
and 1.01 [each 6 H, d, J 6.0, CH(CH3)2], 1.30 [18 H, s, 2 ×
C(CH3)3], 3.72 (6 H, s, 2 × OCH3), 4.16 [2 H, sept, J 6.0, 2 ×
CH(CH3)2], 6.33 (2 H, d, J 8.3, 2 × Ar-H), 6.45 (2 H, dd, J 8.3
and 1.9, 2 × Ar-H), 6.82 (2 H, d, J 1.9, 2 × Ar-H), 7.20 and 7.79
(each 2 H, d, J 8.7, 2 × Ar-H); δC (100 MHz; CDCl3) 22.6 and
22.7 [CH(CH3)2], 30.1 [C(CH3)2], 34.8 [C(CH3)3], 54.8 (OCH3),
73.2 [OCH(CH3)2], 110.3, 117.5, 129.1, 130.3 and 130.5
(Ar-CH), 127.5, 130.1, 130.6, 134.9, 155.1 and 155.9 (Ar-C);
m/z (FAB) 568 (Mϩ, 100%); m/z (EI) 568.3566 (Mϩ, C38H48O2
568.3721). The second fraction obtained from column chroma-
tography was 1-bromo-8-(3-tert-butyl-4-methoxyphenyl)-2,7-
diisopropoxynaphthalene 13b (0.32 g, 27%): mp 113 ЊC (Found:
C, 67.0; H, 6.8; Br, 16.2. C27H33O3Br requires C, 66.8; H, 6.85;
Br 16.5%); λmax (Et2O)/nm 310 (ε/dm3 molϪ1 cmϪ1 7,719), 245
(59,351) and 210 (31,098); νmax/cmϪ1 (KBr disc) 3000–2820
(CH3, CH), 1610 and 1500 (aromatic), 1390 and 1360 (CH3),
1230 (Ar–O–C), 1110 (C–O), 850 and 820 (para-substituted
aromatics) and 630 (C–Br); δH (300 MHz; CDCl3) 1.10, 1.14,
1.37 and 1.38 [each 3 H, d, J 6.0, CH(CH3)2], 1.40 [9 H, s,
C(CH3)3], 3.91 (3 H, s, OCH3), 4.38 and 4.61 [each 1 H, sept, J
6.0, CH(CH3)2], 6.88 (1 H, d, J 8.3, Ar-H), 6.99 (1 H, dd, J 8.3
and 2.3, Ar-H), 7.12 (1 H, d, J 8.7, Ar-H), 7.17 (1 H, d, J 2.3,
Ar-H), 7.23 (1 H, d, J 8.8, Ar-H), 7.74 and 7.75 (each 1 H, d, J
8.7, Ar-H); δC (75.5 MHz; CDCl3) 22.7 and 22.8 [CH(CH3)2],
30.3 [C(CH3)3], 35.1 [C(CH3)3], 55.5 (OCH3), 73.0 and 74.0
[CH(CH3)2], 110.5, 127.8, 129.0, 130.1, 133.3, 136.8, 154.9,
155.8 and 157.9 (Ar-C), 110.8, 116.2, 116.9, 129.4, 129.5, 130.4
1 (a) M. Steele, M. Watkinson and A. Whiting, Perkin Trans. 1, 2000,
588; (b) W. Cross, G. E. Hawkes, R. T. Kroemer, K. R. Liedl, T.
Loerting, R. Nasser, R. G. Pritchard, M. Steele, M. Watkinson and
A. Whiting, Perkin Trans. 2, 2000, 459; (c) R. G. Pritchard, M.
Steele, M. Watkinson and A. Whiting, Tetrahedron Lett., 2000, 41,
6915; (d ) N. C. Edge, J .J. James, C. A. McAuliffe, B. Beagley, N.
Jaiboon, M. Thorpe, M. Watkinson, A. Whiting and D. Wright,
Tetrahedron, 1996, 52, 10193; (e) M. Watkinson, A. Whiting and C.
A. McAuliffe, J. Chem. Soc., Chem. Commun., 1994, 2141.
2 R. L. Clough and J. D. Roberts, J. Am. Chem. Soc., 1976, 98, 1018.
3 H. O. House, J. T. Holt and D. VanDerveer, J. Org. Chem., 1993, 58,
7516.
4 (a) R. D. Wilson, Tetrahedron, 1958, 3, 236; (b) R. D. Wilson,
J. Chem. Soc., 1965, 3304; (c) F. Bell, J. A. Gibson and R. D. Wilson,
J. Chem. Soc., 1956, 2335.
5 (a) T. Watanabe, N. Miyaura and A. Suzuki, Synlett., 1992, 207; (b)
M. G. Johnson and R. J. Foglesong, Tetrahedron Lett., 1997, 38,
7001; (c) J. C. Anderson, H. Namli and C. A. Roberts, Tetrahedron,
1997, 53, 15123.
6 N. Tanaka and T. Kasai, Bull. Chem. Soc. Jpn., 1981, 54, 3020.
7 C. K. Mihir, K. T. Abu, P. K. Bhisma, D. Deepa and K. Wancydora,
Tetrahedron Lett., 1998, 39, 8163.
8 L. Hegedus, B. Lipshutz, H. Nozoki, M. Reetz, P. Rittmeyer, K.
Smith, F. Totter and H. Yamamoto, Organometallics in Synthesis: A
Manual, Wiley, Chichester, 1995.
9 D. R. Coulson, Inorg. Synth., 1972, 13, 121.
10 T. Beringhelli, G. D’Alfonso, H. Molinari, G. E. Hawkes and K. D.
Sales, J. Magn. Reson., 1988, 80, 45.
11 G. Robinson, P. W. Kuchel, B. E. Chapman, D. M. Doddrell and
M. G. Irving, J. Magn. Reson., 1985, 63, 314.
12 (a) M. S. Silver, M. I. Joseph and D. I. Hoult, J. Magn. Reson., 1984,
59, 347; (b) R. Freeman, Chem. Rev., 1991, 91, 1397.
13 A. D. Bain and J. A. Cramer, J. Magn. Reson., Ser. A, 1996, 118, 21.
14 D. R. Muhandiram and R. E. D. McClung, J. Magn. Reson., 1987,
71, 187.
15 K. Raghavachari, J. B. Foresman, J. Cioslowski, J. V. Ortiz, A. G.
Baboul, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I.
Komaromi, R. Gomperts, R. L. Martin, D. J. Fox, T. Keith, M. A.
Al-Laham, C. Y. Peng, A. Nanayakkara, C. Gonzalez, M.
Challacombe, P. M. W. Gill, B. Johnson, W. Chen, M. W. Wong, J. L.
Andres, C. Gonzalez, M. Head-Gordon, E. S. Replogle and J. A.
Pople, Gaussian, Inc., Pittsburgh PA, 1998.
16 J. B. Collins, P. V. R. Schleyer, J. S. Binkley and J. A. Pople, J. Chem.
Phys., 1976, 64, 5142.
17 F. Cozzi, M. Cinquini, R. Annuziata and J. S. Siegel, J. Am. Chem.
Soc., 1993, 115, 5330.
18 J. S. Binkley, J. A. Pople and W. J. Hehre, J. Am. Chem. Soc., 1980,
102, 939.
19 (a) D. A. Fletcher, R. F. McMeeking and D. Parkin, J. Chem. Inf.
Comput. Sci., 1996, 36, 746; (b) F. H. Allen and O. Kennard, Chem.
Des. Autom. News, 1993, 8, 1–31.
J. Chem. Soc., Perkin Trans. 2, 2002, 1510–1519
1519