Ortho -substituted 1,8-diarylnaphthalenes: Conformational thermodynamics and kinetics

Article abstract of DOI:10.1055/s-0033-1339695

1,8-Diarylnaphthalenes show interesting potential as chiral sensors, environment sensors and stereodynamic switches. The kinetics and thermodynamics of the conformational equilibria of two such compounds are described. These compounds, along with others r

Full text of DOI:10.1055/s-0033-1339695

LETTER
▌2365
letter
ortho-Substituted 1,8-Diarylnaphthalenes: Conformational Thermodynamics
and Kinetics
ortho-Substituted 1,8-Diarylnaphthalenes
Dilraj K. Judge, Peter Haycock, Robert D. Richardson, Matthew J. Fuchter*
Department of Chemistry, Imperial College London, South Kensington Campus, London SW7 2AZ, UK
Fax +44(20)75945815; E-mail: m.fuchter@imperial.ac.uk
Received: 17.07.2013; Accepted after revision: 13.08.2013
Abstract: 1,8-Diarylnaphthalenes show interesting potential as
chiral sensors, environment sensors and stereodynamic switches.
The kinetics and thermodynamics of the conformational equilibria
of two such compounds are described. These compounds, along
with others reported previously, show that several features can be
used to tune the conformational behaviour of these compounds, giv-
ing the possibility to design molecules for specific applications in
the future.
Key words: biaryls, atropisomerism, isomerisation, solvent effects,
substituent effects
Compounds bearing the 1,8-diarylnaphthalene motif have
Matthew Fuchter obtained his first class honours degree (MSci)
from the University of Bristol in 2002, where he was awarded the
Richard N. Dixon prize. Following doctoral research under the super-
vision of Professor A. G. M. Barrett, FRS FMedSci at Imperial Col-
lege London he was appointed as a CSIRO Research Fellow at the
Commonwealth Scientific and Industrial Research Organisation,
Australia as well as a visiting fellow at the University of Melbourne,
where he worked with Professor A. B Holmes, FRS. From August
2007 he was the RCUK Academic Fellow at the School of Pharmacy,
University of London, before moving back to Imperial College in
2008 as a Lecturer in Synthetic and Medicinal Chemistry. He was
a venerable history. The peri-aryl rings exhibit a cofacial
orientation almost perpendicular to the naphthalene back-
bone, and therefore these compounds have been used as
model systems of π–π aromatic stacking.1 Significant ste-
ric congestion is present however, with minimisation of
steric interactions and Coulomb repulsion of the peri-aryl
rings resulting in their splaying out from each other; the
extent of this deformation being dependent on the substi-
tution pattern on the peri-arenes.1–3
Clough and Roberts4 first reported the synthesis and anal- promoted to Senior Lecturer in July 2012. His multidisciplinary re-
search group use expertise in chemical synthesis to impact molecular
science in chemistry, materials and medicine.
ysis of the syn/anti isomerisation of 1,8-bis(2-methylphe-
nyl)naphthalene (1, Figure 1). The barrier (∆G‡) for syn to
anti rotation of the tolyl rings is 100 kJ mol–1. Using m-
tolyl in place of the o-tolyl rings lowers this barrier4 to 67
kJ mol–1. Several groups have pursued other substitution
patterns to effectively halt rotation about the aryl–aryl
bond.2,5 For example, 2,7-diisopropoxy-1,8-diarylnaph-
thalene 2a has a barrier (∆G‡) to rotation of 76 kJ mol–1
(syn-to-anti), but introduction of a methyl substituent to
the ortho position of the phenyl group (2b)5 was predicted
to raise this to ca. 170 kJ mol–1.
contrast, trimethylammonium salt 4 shows syn preference
(3:1) in chloroform-d attributed to a through-space cat-
ion–π interaction. Increasing the solvent polarity stabilis-
es the anti-isomer of 4 and an anti:syn ratio of 1:1 was
found in dimethylsulfoxide-d6 (DMSO).8
OMe OMe
R
O
R
Interesting stereochemical possibilities emerge for these
systems when the peri-arenes have ortho or meta substit-
uents; the anti-conformer being C2-symmetric (hence chi-
ral), and the syn-isomer being achiral when symmetrically
substituted (Figure 1). This stereochemical feature has led
to the development of 1,8-diacridyl-, 1,8-diquinolyl-, and
1,8-dipyridylnaphthalenes as potential photoluminescent
sensors, and stereodynamic switches.2,6 A ratio of approx-
imately 3:1 anti:syn has been reported for a series of un-
charged 1,8-diaryl- and 1,8-di(heteroaryl)naphthalenes
showing minimal dependency on solvent polarity.1e,4,7 In
O
1
2a R = H
2b R = Me
NMe3
C2-symmetric
( )-anti-3
SYNLETT 2013, 24, 2365–2369
Advanced online publication: 03.09.2013
4
meso-syn-3
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1339695; Art ID: ST-2013-A0667-L
© Georg Thieme Verlag Stuttgart · New York
Figure 1 Representative examples of 1,8-diarylnaphthalenes

2366
D. K. Judge et al.
LETTER
1
formers was determined by integration of the H NMR.
I
I
The free energy of isomerisation of diether 6 varies little
with temperature or with solvent. The error margins for
these measurements combined with the small temperature
effect make it difficult to conclude whether the anti pref-
erence is a result of enthalpic or entropic factors. The con-
formation of diphenol 7 is strongly influenced by the
solvent with the anti-conformer always favoured, but
more strongly in DMSO. To investigate this further, the
equilibrium anti:syn ratio of diphenol 7 was measured in
a selection of solvents covering a wide range of polarities
and hydrogen bonding properties (Table 2).
MeO
OMe
Pd2(dba)3/SPhos
Cs2CO3
DMF–H2O
125 °C, 3 h
OMe
B(OH)2
5
6 (93%)
i) BBr3, CH2Cl2
0 °C to r.t., 1 h
HO
OH
ii) H2O
At first glance, the preference for the anti-conformer of
diether 6 appears to be steric. While the extra steric con-
gestion between the two methoxy groups in the syn-con-
former is likely to be partly responsible for this
observation, closer inspection suggests a more complicat-
ed picture. Comparing the energy difference for the con-
formers of diether 6 (ca. 5.7 kJ mol–1) with the A-value of
a methoxy group on a cyclohexane ring (2.5 kJ mol–1)11
suggests that the conformational preference of this system
is more sensitive to the group than is the case for cyclo-
hexane conformations. However, Clough4 reports that the
anti-conformer of ditolyl compound 1 is more stable than
the syn by only 3 kJ mol–1 in chloroform-d. The A-value
of a methyl group is 7.1 kJ mol–1,11 indicating a lower sen-
sitivity for the diarylnaphthalene in this case. It seems that
either the steric bulk further along the substituent is more
relevant in this case than it is in cyclohexane substituents,
or that the electronic effects of the methoxy group might
affect the π-stacking interactions, but a further systematic
study is necessary to fully understand the effects here. The
small solvent dependence of the conformational prefer-
ence of diether 6 can be explained by the fact that the me-
thoxy group will be weakly solvated in all cases so both
the size and the electronic properties are not substantially
affected by solvent.
7 (73%)
Scheme 1 Synthesis of 1,8-bis(2-methoxyphenyl)naphthalene (6)
and 1,8-bis(2-hydroxyphenyl)naphthalene (7)
We felt that 1,8-bis(2-methoxyphenyl)naphthalene (6)
and 1,8-bis(2-hydroxyphenyl)naphthalene (7) would be
useful comparative molecules for this series, in light of
their lower steric bulk and differences in the electronic
properties of their peri-aryl substituents when compared
to the majority of other systems studied. It was envisaged
that such atropisomeric substrates might exhibit interest-
ing rotational dynamics and conformational preferences.
Diether 6 was prepared by a Suzuki–Miyaura cross-cou-
pling of 1,8-diiodonaphthalene and boronic acid 5
(Scheme 1). After screening a range of catalysts, ligands,
bases, solvents and reaction temperatures for this transfor-
mation we achieved an excellent yield (93%) using
Pd2(dba)3/SPhos which compares favourably to the previ-
ous synthesis of this compound using 1,8-dibromonaph-
thalene and an N-heterocyclic benzhydrylamine-based Pd
complex,9 giving a moderate yield (64%).10 Deprotection
with boron tribromide afforded diphenol 7 in 73% yield.
The anti-preference of diphenol 7 in DMSO (6.7 ± 0.8 kJ
mol–1) is close to that of diether 6 under a range of condi-
tions, but much smaller (0.88 ± 0.18 kJ mol–1) in benzene.
The steric and electronic properties of a hydroxyl group
are weakly solvent dependent12 but similar to that of a me-
thoxy group so, while the steric properties might explain
the behaviour of diphenol 7 in DMSO, it is insufficient to
explain the full solvent dependence. A likely explanation
for this solvent dependence is that the anti preference of
diphenol 7 in DMSO has the same origin as that for the di-
ether 6, however this is partially balanced by an attractive
interaction between the two hydroxyl groups in the syn-
conformer. This interaction must be reduced by increased
solvent polarity or hydrogen bonding properties. DFT cal-
culations at the M06-2X/6-311G(2d,p)//B3LYP/6-
31G(d,p) level using a PCM model for benzene identify
several low energy conformers for both 6 and 7 (Figure 2).
The energy differences between the conformers appear
overestimated when compared to experiment, but the
structures serve to highlight possible stabilising inter-
actions.
Table 1 Conformational Preferences of Diether 6 and Diphenol 7
Compound Solvent
T
(K)
Ksyn-anti
∆Gsyn-anti
(kJ mol–1)
6
6
6
6
6
7
7
7
benzene-d6
333
338
353
333
373
298
338
298
8.3 ± 1.6
7.7 ± 1.4
7.1 ± 1.2
6.7 ± 1.1
6.7 ± 1.1
1.4 ± 0.1
1.4 ± 0.1
14.8 ± 4.8
−5.9 ± 0.5
−5.7 ± 0.5
−5.8 ± 0.5
−5.3 ± 0.4
−5.9 ± 0.5
−0.9 ± 0.2
−1.0 ± 0.2
−6.7 ± 0.8
benzene-d6
benzene-d6
DMSO-d6
DMSO-d6
benzene-d6
benzene-d6
DMSO-d6
The conformational equilibrium of diether 6 and diphenol
7 was studied at several temperatures in two solvents of
different polarity (Table 1). The ratio of syn to anti con-
Synlett 2013, 24, 2365–2369
© Georg Thieme Verlag Stuttgart · New York

LETTER
ortho-Substituted 1,8-Diarylnaphthalenes
2367
Diether 6 has a clear preference to have the methoxy tropic cost of bringing two species into a complex and is
groups oriented away from the naphthalene but diphenol not relevant for the work discussed here.
7 has more flexibility. Hydrogen bonded structure 7syn1 is
the lowest energy syn-conformer, 4 kJ mol–1 above the an-
ΔGH bond = (α–αs) (β–βs) + ΔGrestricting motion)
ti, with 7syn2, stabilised by an opposed-dipole, a further 0.7
Equation 1
kJ mol–1 higher. Using a PCM model for dimethyl sulfox-
ide does not predict the large changes in the relative ener-
Plotting the ΔG values (Table 2) against the first term of
the Hunter equation taking α = 3.8 (kJ mol–1)1/2 and β = 2.7
(kJ mol–1)1/2, determined for phenol, as estimates for the
solute properties,12 gives a linear relationship with gradi-
ent 0.27 (Figure 3). The Hunter equation predicts the
strength of a hydrogen bond in a complex (here: the syn-
conformer) and how it may be weakened in stronger hy-
drogen bonding solvents, thus how such solvents can
break apart the complex (here: stabilise the anti-conform-
er). From the definition of the Hunter parameters,12 the
gradient should be unity. The reduced gradient in this case
may be a result of steric effects in the syn-conformer, or
the fact that the hydrogen bond is formed in a suboptimal
geometry. Plotting the ∆G values against 1/ε or (1/ε)2 does
not result in a linear relationship (see Supporting Informa-
gies of the conformers, suggesting the solvent-dependent
conformation of diphenol 7 results from discrete solvent–
solute molecular interactions, consistent with a hydrogen
bonding interpretation. The syn-conformers have the
arene units distorted substantially from the geometry usu-
ally seen in these peri-diarylnaphthalenes (maximises the
π-stacking interactions), to bring the phenol groups closer
together.
ΔG values from Table 1 can be compared to the function
used by Hunter12 to study the solvent effect on bimolecu-
lar hydrogen bonding (Equation 1). α and αs are hydrogen
bond donating parameters for the solute and solvent, re-
spectively, while β and βs are hydrogen bond accepting
parameters. The ΔGrestricting motion term accounts for the en-
Table 2 Conformational Preferences of Diphenol 7 at 298 K
c
Ksyn→anti
Solvent
εa
2.3
αsb (kJ mol–1)1/2
βsb (kJ mol–1)1/2
ΔG°syn→antic (kJ mol–1)
benzene-d6
CDCl3
1.0
2.2
1.9
1.4
1.5
1.2
0.8
2.2
0.8
1.1
7.0
5.8
8.3
8.9
1.4 ± 0.1
1.5 ± 0.1
1.6 ± 0.1
4.5 ± 0.5
4.7 ± 0.6
11.6 ± 2.9
14.8 ± 4.8
−0.88 ± 0.18
−1.00 ± 0.17
−1.23 ± 0.18
−3.7 ± 0.3
4.8
8.9
CD2Cl2
pyridine-d5
acetone-d6
DMF-d7
12.4
20.7
36.7
46.7
−3.8 ± 0.3
−6.1 ± 0.6
DMSO-d6
−6.7 ± 0.8
a Relative dielectric constant.
b Hunter’s hydrogen bonding parameters.
c Errors are quoted as ± 1 standard deviation; DMF = N,N-dimethylformamide.
Figure 2 DFT calculated structures of 6 and 7 with energies in kJ mol–1
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2365–2369

2368
D. K. Judge et al.
LETTER
tion). This suggests that hydrogen bonding within the syn- between the phenol groups prohibits selective inversion of
conformer (in non-polar solvents) and of the anti-con- the OH resonances.
former with the solvent (in polar solvents) dominates the
conformational preference of diphenol 7.
The Eyring plots show small solvent dependence for the
activation parameters for the biaryl rotation, just as there
was little solvent dependence on the conformational pref-
erence of diether 6. At 298 K, the predicted activation free
energy for the syn–anti rotation in benzene is 88 kJ mol–1.
This predicts a lifetime of about six minutes at room tem-
perature for syn-6 or about 75 minutes for anti-6. This is
consistent with our observation that these conformers can
be separated on a TLC plate and the anti-isomer can be
isolated by rapid column chromatography, but intercon-
version is seen shortly afterwards.
The predicted activation free energy in either solvent
[∆G‡syn–anti (313 K) = 89 ± 6 kJ mol–1] is slightly lower
than that reported by Clough4 (100 kJ mol–1 in chloro-
form-d) for the same rotation in ditolyl compound, 1, con-
sistent with the smaller size of the methoxy substituent as
assessed by cyclohexane A-values (2.5 kJ mol–1 cf. 7.1 kJ
mol–1 for a methyl group). However, given that the con-
formational preference cannot be explained by A-values
alone, we are tentative to draw too strong a conclusion on
the origin of this difference from the data presented here.
So far, we have been unable to replicate these enthalpies
of activation computationally. It may be that functionals
with high quality dispersion corrections than those tried to
date are necessary to describe the kinetics of these sys-
tems satisfactorily.
Figure 3 Linear free energy relationship between the free energy of
isomerisation and the Hunter equation
The rotational dynamics of diether 6 were measured using
selective peak inversion NMR spectroscopy13 in benzene-
d6 and DMSO-d6. The rate constants for syn–anti inter-
conversion were obtained by selectively inverting the 1H
NMR resonance of the methyl group in both the syn- and
anti-conformers. The peak recovery and magnetisation
transfer data from both experiments were fitted separately
using the CIFIT program13 to extract the syn-anti rate con-
stant for peak inversion. The average from both peak in- In conclusion, the conformational preferences of 1,8-dia-
version experiments was taken. The anti–syn rate rylnaphthalenes are more complicated than previously
constants were calculated from this value and the equilib- thought. They are affected by the steric size of the substit-
rium constant, determined by integration of the 1H NMR uents on the aryl groups and the electronics of that group
spectrum. The Eyring equation (Figure 4) was used to de- even when solvation does not seem to play a significant
termine the entropy and enthalpy of activation for both role. With the right substituents, hydrogen bonding can
processes. Unfortunately, the conformational dynamics of stablise the syn-conformer, but in diphenol 7 this is not
diphenol 7 could not be studied by this technique. The enough to overcome the preference for the anti-form. For
NMR frequencies of the aromatic protons are too close for diether 6, the anti-conformer is preferred over the syn by
selective inversion and fast intermolecular proton transfer approximately 5.7 kJ mol–1, essentially independent of
solvent or temperature. The free-energy difference in di-
phenol 7 varies from about 6 kJ mol–1 in strongly hydro-
gen bonding solvents to less than 1 kJ mol–1 in weakly
hydrogen bonding solvents. This, coupled to a fairly rapid
interconversion between the conformers could lead to
interesting uses as sensors for hydrogen bonding.2,6
Acknowledgment
We thank the Leverhulme Trust (grant F/07058/BG) for funding
this work.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
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Synlett 2013, 24, 2365–2369
© Georg Thieme Verlag Stuttgart · New York

LETTER
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