Molecules 2006, 11, 684-692
Synthesis and Characterisation of Eight Isomeric
Brendan J. O’Keefe and Peter J. Steel*
Department of Chemistry, College of Science, University of Canterbury, Christchurch, New Zealand
* Author to whom correspondence should be addressed; E-mail: firstname.lastname@example.org
Received: 31 July 2006; in revised form: 28 August 2006 / Accepted: 29 August 2006 / Published: 13
Abstract: Eight isomeric bis(2-pyridyloxy)naphthalenes have been prepared from reactions
of 2-bromopyridine with the appropriate dihydroxynaphthalene and the products fully
characterised by 1- and 2-D NMR spectroscopy.
Keywords: N-Bridging ligands; pyridines; naphthalenes.
Over the last decade we have reported the synthesis and study of numerous compounds
characterised by the schematic representation 1[1,2]. These are comprised of a central arene core to
which are appended a number (n) of heterocyclic rings attached via spacer groups (X). Variation of the
arene core, the spacer group, the nature of the heterocycle and the number n has led to an extensive
library of bridging ligands that we have used for the construction of a diverse range of 1-, 2- and 3-D
metallosupramolecular assemblies with various topological architectures. For example, the
dimetallocyclophane 2, stabilised by internal π-π stacking of the central benzene rings, was formed by
reaction of silver nitrate with 1,4-bis(2-pyridyloxy)benzene, which has a benzene core, an ether
oxygen as spacer and (n = 2) 2-substituted pyridines as the appended heterocycles . The analogous
3-pyridyl ligand provided access to the first quadruply stranded helicate , whereas the 1,2- and 1,3-
disubstituted analogues led to a range of other interesting assemblies .
Molecules 2006, 11
n = 2-8
Disubstitution of a benzene core allows only three possible orientations (ortho, meta and para) of
the appended heterocycles. In contrast, disubstitution of a naphthalene core leads to ten isomeric
possibilities. Thus, in order to maintain greater control over the exact distance and relative orientations
of the donor substituents, we have extended this design strategy to the preparation of isomers of bis(2-
pyridyloxy)naphthalene (3). By varying the substitution pattern in the naphthalene ring system, we
expected to gain more subtle control of the distances between metal centres bridged by these bidentate
ligands. These isomeric compounds were prepared for use as synthons in metallosupramolecular
chemistry, based on previous work with related bis-ethers [3-7] and bis-thioethers [8-14]. We have
previously reported their use in regioselective double cyclopalladation reactions , but the synthetic
methodology and identification of these compounds had not been published. We now report the
synthesis and NMR characterisation of eight of the ten possible isomers of 3.
Results and Discussion
Initially, all ten isomers of 3 were viewed as targets for synthesis. Our previous syntheses of the
three isomeric bis(2-pyridyloxy)benzenes [3,5] employed a solvent-free procedure for the nucleophilic
aromatic substitution of 2-bromopyridine by the isomeric dihydroxybenzenes. This proved to be
inefficient for the corresponding dihydroxynaphthalenes, thus various experimental conditions (solvent,
base, temperature, reaction time) were explored in an effort to improve yields. No high yielding
general procedure was found for these reactions, principally because of isolation problems of these
somewhat irksome reaction products. In the end, two procedures (both using K2CO3 as base) were
found to be suitable and differed in the solvent employed (Scheme 1): method A was carried out in
DMF, whilst method B used a sulpholane/toluene solvent mixture, which was based on a previously
reported series of reactions of dihydroxynaphthalenes .
(A) K2CO3 / DMF / ∆
or (B) K2CO3 / sulpholane/ toluene / ∆
Table 1. Isolated yields for the various isomers of 3.
Method A (%)
Method B (%)
Molecules 2006, 11
Two of the ten possible isomers proved to be inaccessible; the instability of 1,2-
dihydroxynaphthalene prevented access to this isomer, and reaction of 1,8-dihydroxynaphthalene
failed to produce any evidence of the desired product. In general the sulpholane/toluene procedure
(method B) provided better yields (Table 1).
All eight isomers were fully characterised by elemental analysis and
spectroscopy. Complete assignment of the NMR spectra required a battery of 1- and 2-D techniques.
As a representative example the spectra of 1,6-bis(2-pyridyloxy)naphthalene (3d) are discussed.
Figure 1 shows the 1H-NMR spectrum of 3d, which has fourteen non-equivalent aromatic protons. The
assignments of some protons (e.g. H5 and H3) are immediately obvious from the spin-spin coupling
patterns. The signals were readily grouped into the individual spin systems by means of 1D-TOSCY
experiments . By incremental increase of the mixing times it was possible to readily identify the
individual protons within each ring. This readily identified the signals for the two pyridine rings but
did not allow distinction between the two overlapping sets of signals.
Figure 1. 1H-NMR spectrum of 3d.
* Peak due to the solvent (CDCl3)
A subsequent 2D-GHSQC spectrum allowed assignment of the protonated carbon signals. Finally,
the signals for the non-protonated carbons were assigned by means of a 2D-GHMBC spectrum (Figure
2). For example, the peak at 152.28 ppm correlates to H7, H5 (2JCH) and H8 and therefore can be
assigned to C6, whereas the peak at 150.08 ppm correlates to H2 (2JCH), H7 (4JCH), H3, H5 (4JCH), and
H8 and therefore can be assigned to C1. Similarly, distinction between C4a and C8a was made on the
basis that the former shows correlations to H3, H4 (2JCH) and H8, whereas the latter correlates to H2,
H7, H3 (4JCH), H5, and H4. The other correlations in this spectrum also served to confirm the earlier
assignments of the other protons and carbons. The spectra of the other isomers were assigned by
Molecules 2006, 11
Figure 2. GHMBC spectrum of 3d.
The syntheses of compounds 3a-3h, corresponding to eight of the ten possible isomers of bis(2-
pyridyloxy)naphthalene (3) have been carried out and the compounds fully characterized by 1- and 2-
D NMR spectroscopy. Whereas the 1,4-isomer 3b proved to be unaccommodating, due to its
insolubility in common reaction solvents, the other isomers have been found to be useful functional
reactants for the assembly of an intriguing and diverse array of metal complexes that will be reported
elsewhere in the near future.
NMR spectra were recorded on a Varian 300 Unity spectrometer with a 3mm probe operating at
300 MHz and 75 MHz for 1H- and 13C-, respectively. Spectra were recorded in CDCl3 and referenced
relative to internal Me4Si. When required, nOe, 1-D TOCSY, GHSQC and GHMBC experiments
were performed using standard pulse sequences and parameters available with the Unity 300 system.
In the 1H-NMR spectra listed below only 3J coupling constants are listed, which is useful for
assignment purposes due to the following characteristic values  H3 (d, J = 8 Hz), H4 (t, J = 8 Hz),
H5 (dd, J = 8, 5 Hz), H6 (d, J = 5 Hz). Mass spectra were recorded using a Kratos MS80RFA
spectrometer with a Mac 3 data system. Electron Impact spectra were obtained at 70eV with a source
temperature of 150 ºC (C20H14N2O2 requires M+., 314.1055). Melting points were determined using an
Electrothermal melting point apparatus and are uncorrected. Elemental analyses were performed by the
Molecules 2006, 11
Chemistry Department, University of Otago, Dunedin, (C20H14N2O2 requires C, 76.42; H, 4.49; N,
General procedures for the preparation of the bis(2-pyridyloxy)naphthalenes
Method A: A mixture of the dihydroxynaphthalene (1 equiv.), 2-bromopyridine (3 equiv.) and
potassium carbonate (4 equiv.) was refluxed in DMF for 72 hours. The mixture was added to a
solution of aqueous sodium hydroxide (10%) and this was repeatedly extracted with chloroform. The
chloroform was removed in vacuo and the resulting DMF solution was added to acetone. This solution
was heated, treated with decolourising charcoal, then filtered. The solvent was then removed to give
the crude product, which was purified by recrystallisation and/or column chromatography.
Method B: A mixture of the dihydroxynaphthalene (1 equiv.) and potassium carbonate (4 equiv.) was
stirred in sulpholane/toluene (2:1) with nitrogen bubbling through it for 30 min. To this was added 2-
bromopyridine (3 equiv.). The mixture was heated under nitrogen for 40 hours then added to a solution
of aqueous sodium hydroxide (10%) and this was repeatedly extracted with chloroform. The
chloroform was removed in vacuo and the resulting sulpholane solution was added to acetone. This
solution was heated, treated with decolourising charcoal, then filtered. The acetone was removed in
vacuo and water was added to the sulpholane solution to precipitate the crude product which was
filtered off and redissolved with acetone. The product was allowed to crystallise from this solution.
Method B. Reaction of 1,3-dihydroxynaphthalene (0.800 g, 4.99 mmol),
2-bromopyridine (1.63 g, 10.3 mmol), potassium carbonate (2.91 g, 21.1
mmol) in sulpholane/toluene gave crude 3a, which was recrystallised from
acetone/water to give the title compound as colourless crystals (0.391 g,
24%), m.p. 105-106 ºC; Anal. Found: C, 76.46; H, 4.44 N, 9.04; MS: found
M+., 314.1047; 1H-NMR δ: 6.94-7.02 (4H, m, H3', H3", H5', H5"), 7.10 (1H,
m, H2), 7.40 (1H, t, H7), 7.46 (1H, s, H4), 7.49 (1H, t, H6), 7.68 (2H, m , H4', H4"), 7.81 (1H, d, H5),
8.01 (1H, d, H8), 8.20 (2H, m, H6', H6"); 13C-NMR δ: 111.17, 111.69, C3', C3"; 112.76, C2; 114.28,
C4; 118.75, C5', C5"; 122.16, C8; 125.09, C8a; 125.30, C7; 127.07, C6; 127.56, C5; 135.02, C4a;
139.48, 139.56, C4', C4"; 147.80, 147.97, C6', C6"; 151.12, C1; 151.59, C3; 163.50, 163.90, C2', C2".
Method A. A mixture of 1,4-dihydroxynaphthalene (1.10 g, 6.9 mmol),
2-bromopyridine (2.17 g, 13.7 mmol) and potassium carbonate (1.89 g, 13.7
mmol) was refluxed in DMF (10 mL) for 22 hours. Removal of solvent and
subsequent washing of the residue with water, then methanol, gave 3b (0.60 g,
28%), m.p. >130°C (dec.); Anal. Found: C, 76.04; H, 4.18; N, 8.60; 1H-NMR
δ: 6.99 (2H, d, H3’), 7.01 (2H, t, H5’), 7.25 (2H, s, H2,3), 7.48 (2H, d, H6,7),
7.71 (2H, t, H4’), 8.01 (2H, d, H5,8), 8.19 (2H, d, H6’); 13C-NMR δ: 110.88,