Synthesis of functionalised macrocyclic compounds as Na+ and K+ receptors: A mild and high yielding nitration in water of mono and bis 2-methoxyaniline functionalised crown ethers

Article abstract of DOI:10.1039/b205299g

The syntheses of the bis-aromatic 15-crown-5 and 18-crown-6-ether derivatives 1 and 2, for the selective recognition of intra- and extracellular concentrations of Na⁺ and K⁺, from o-anisidine are described. These compounds were made

Full text of DOI:10.1039/b205299g

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Synthesis of functionalised macrocyclic compounds as Na؉ and K؉
receptors: a mild and high yielding nitration in water of mono and
bis 2-methoxyaniline functionalised crown ethers
1
Thorfinnur Gunnlaugsson,*a H. Q. Nimal Gunaratne,†b Mark Nieuwenhuyzenb and
Joseph P. Leonarda
a Department of Chemistry, Trinity College Dublin, Dublin 2, Ireland.
E-mail: gunnlaut@tcd.ie; Fax: ϩ(353) 1 671 2826; Tel: ϩ(353) 1 608 3459
b School of Chemistry, Queen’s University Belfast, Belfast, UK BT9 5AG
Received (in Cambridge, UK) 31st May 2002, Accepted 18th July 2002
First published as an Advance Article on the web 9th August 2002
The syntheses of the bis-aromatic 15-crown-5 and 18-crown-6-ether derivatives 1 and 2, for the selective recognition
of intra- and extracellular concentrations of Naϩ and Kϩ, from o-anisidine are described. These compounds were
made with the aim of incorporating them into luminescent sensors. To facilitate their incorporation into such sensors,
the compounds were nitrated. Whereas the use of conventional nitration reagents such as HNO3, HNO3–H2SO4 or
NO2BF4 only gave low yields of the desired products, both mono- and bis-nitration products were formed in good
yield by one-pot synthesis using NaNO2 in a mixture of water and acetic acid (10 : 1). The use of X-ray
crystallography proved the presence of the nitro-substituted products. An investigation into this mild nitration
method revealed that the substitution pattern on the aromatic ring governed the ability of the compounds to undergo
nitration.
have been interested in designing simple hosts for ion and
Introduction
molecular recognition that show good selectivity and sensitivity
The recognition and targeting of ions and neutral molecules are
for physiologically important cations.11 We have used these for
at the heart of supramolecular chemistry.1 Over the past years
there has been great interest in the development of fluorescent
and luminescent sensors and reagents for cations, anions and
the incorporation into both fluorescent and colorimetric
(chromogenic) chemosensors for detecting Naϩ, Mg2ϩ, Ca2ϩ
and Zn2ϩ 12,13
Herein we describe the design and the synthesis of
.
neutral molecules under physiological conditions.1,2 In such
systems the ion or molecular recognition can modulate the
various photophysical properties of the luminescent centre,
e.g. the wavelength, luminescence quantum yield (ΦF) and/or
lifetime.2,3 Furthermore, those which display ‘off–on’ or ‘on–off’
(changes in ΦF) switching of luminescence are particularly
interesting since they can be designed in such a way that the
switching action is governed by more than one ion or molecular
receptor.4 Such a design can give rise to switching actions that
mimic the behaviour of logic gate operations in silicon-based
computing.5–7
several new macrocyclic receptors from aromatic crown ethers
made in high yield from o-anisidine. Of these the macrocyclic
receptors 1 and 2 were designed for incorporation into lumin-
escent sensors for the detection of intracellular concentrations
of Naϩ and Kϩ, respectively.14,15
With the aim of facilitating their incorporation into chemo-
sensors we undertook the nitration of 1 and 2 to give 3 and 4
respectively, which were then reduced to the corresponding
amines. Similarly, 12 and 17, the mono aromatic crown ether
analogues of 1 and 2 were also chosen for such modifications
and incorporation into luminescent chemosensors. Use of the
most common nitration reagents, such as HNO3, HNO3–H2SO4
or NO2BF4, gave very low yields in all cases. To investigate this
further we decided to synthesise the corresponding nitroso
compounds by using NaNO2 in a mixture of (ca. 10 : 1) H2O–
AcOH. However, this method gave in each case the correspond-
ing nitro compound in high or moderately good yield, but not
the nitroso compounds. This was confirmed by NMR, HRMS
(high resolution MS) and IR, and by X-ray crystal structural
analysis. Accordingly we set out to investigate this mild
nitration method further, which is highly specific, gives high
yields of the desired products, is easily scaled up, as well as
being extremely environmentally friendly since it is carried out
in aqueous solution.
Designing such ion-selective receptors can be a challenging
task from a synthetic point of view.8 For an efficient sensor
system the recognition event has to be reversible, selective and
sensitive towards the desired species. Over the years many
elegant examples of macrocyclic syntheses have been reported
for the development of ion-selective receptors, and this field has
been extensively reviewed.9 However, very often such macro-
cyclic systems are designed for use in non-aqueous solutions
which often renders them useless in the physiological environ-
ment. This is an important issue when dealing with ions under
physiological conditions such as sodium and potassium. Nearly
all animal cells maintain a large concentration difference in
their intra- vs. extra-cellular concentrations of these ions.10 For
instance, for blood or serum analysis of Naϩ, the ion concentra-
tion range has an upper limit of 145 mM and a lower limit
of 133 mM, whereas the corresponding upper and lower limits
for Kϩ are much lower at 3.5–4.8 mM.11 In contrast, the intra-
cellular concentration range of Kϩ is much higher than that of
Naϩ, being ca. 135 mM compared to that of 5 mM for Naϩ. We
Results and discussion
Synthesis and crystallographic investigation of 1 and 2 and their
complexes
The two receptors 1 and 2 were synthesised according to
Scheme 1. Both receptors are flanked by the methoxy groups
that function as lariat ethers that will affect both the selectivity
† Current address: Queen’s University Belfast, QUILL Centre, Belfast,
Antrim, Northern Ireland, UK BT9 5AG.
1954
J. Chem. Soc., Perkin Trans. 1, 2002, 1954–1962
This journal is © The Royal Society of Chemistry 2002
DOI: 10.1039/b205299g

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Scheme 1 The synthesis of 1 and 2. Reagents and conditions: i) o-anisidine, pyridine, toluene-p-sulfonyl chloride (TsCl), reflux, giving 5 after
aqueous work-up and crystallisation from ethanol. ii) 5, DMF, KI, K2CO3, (ClCH2CH2OCH2)2, 70 ЊC, 3 days. iii) (3 : 2) AcOH–H2SO4 (98% pure),
60 ЊC, 24 hours. iv) For 8: O(CH2COCl)2, pyridine, benzene, high dilution at 75 ЊC, 36 hours; for 9 (ClCOCH2OCH2)2. v) B2H6, THF. vi) Nitration
(see text). vii) 3 or 4, H2 (atm) 10% Pd/C.
and the sensitivity of the recognition process by providing extra
binding sites and a steric effect.16 Our attempt to make 1 and 2
in a single step from 2-fluoro-1-methoxybenzene was unsuccess-
ful and because of this the longer synthetic route shown in
Scheme 1 was chosen.
synthetic procedures. The two macrocycles were characterised
by conventional methods (see Experimental section). For
instance, the 1H NMR of 2 (in CDCl3) indicated that the
structure had high symmetry in solution, showing two triplets
and two doublets for the aromatic protons, and two triplets at
δ 3.61 and 3.55 ppm respectively and a singlet at δ 3.57 for the
24-crown ether protons. A characteristic singlet at 3.85 ppm
was also observed for the two sets of the aromatic methoxy
groups. We were able to grow crystals of 2 by crystallisation
from CH2Cl2 suitable for X-ray crystallographic investigation.
The structure of 2 is shown in Fig. 1, demonstrating that in the
The starting material, o-anisidine, was treated in refluxing
pyridine with toluene-p-sulfonyl chloride to give the corres-
ponded tosylamide 5, which was poured into ice–water, giving
an off-white powder that was recrystallised from EtOH in 87%
yield. These were allowed to react in a 2 : 1 ratio with 1,2-bis(2-
chloroethoxy)ethane in the presence of two equivalents of KI
and K2CO3 in dry DMF at 70 ЊC for 72 hours. The resulting
solution was treated with a mixture of water and EtOAc giving
6 as an oily resin that was triturated with EtOH to give 6 in 91%
yield as a solid. The podand 6 had three characteristic singlets
1
in its H NMR at δ 3.38 and 3.40 for the methyl ether and the
two sets of methylene groups adjacent to the central oxygen of
the diethyl ether respectively and at δ 2.40 for the methyl groups
of the two tosyl groups.
The detosylation of 6 was achieved by stirring in a 3 : 2
mixture of glacial AcOH and H2SO4 (98% pure) at exactly 60
ЊC for 24 hours. The resulting mixture was neutralised with
KOH and extracted several times with diethyl ether to give the
detosylated product 7 in 32% yield. This reaction was extremely
sensitive to temperature changes and the quality and ratio of
acid used. For example, temperature changes of 2–3 ЊC led on
many occasions to the isolation of mixtures of products, or no
product at all. Similar results were observed upon changing the
quality of the sulfuric acid. For instance, using 95% pure H2SO4
reduced the overall yield of 7 to less than 20%. Analysis of the
remaining residues indicated that the mono-tosylated product
was the main product formed, but changing the reaction time
did not result in the conversion of this product into 7.
The diamide 15-crown-5 and the 18-crown-6 derivatives 8
and 9 were formed using classical macrocyclic high dilution
synthesis,17 by reacting 7 in an equimolar amount with either
oxydiacetyl dichloride, or 2-(chlorocarbonylmethoxyethoxy)-
acetyl chloride, to give 8 and 9 respectively in dry benzene and
in the presence of dry pyridine at 75 ЊC. The two acid chlorides
were made by a published procedure from the corresponding
acids.17 The resulting macrocycles 8 and 9 were isolated as oils,
that were further purified by trituration with EtOH and diethyl
ether for 8 and 9 respectively to give off-white solids in 66 and
73% yields respectively. These were finally treated with B2H6
(formed in situ from NaBH4 and BF3–Et2O in dry THF) to yield
1 and 2 as oils after aqueous work-up in ca. 90% yield.
Fig. 1 Diagram of 2 showing the relative orientation of the aromatic
methoxy units relative to the crown ether. Hydrogen atoms have been
omitted for clarity.
solid state the molecule adopts C2v symmetry where the two
aromatic methoxy groups are on opposite sides of a plane
cutting through the centre of the crown ether.18,19 The dihedral
angle between the methoxy group and the aromatic amine
C1Ј–N9–C10–C11 is Ϫ16.8Њ. The dihedral angle for the C8Ј–
N9Ј–C1Ј–C2Ј was measured to be 154.5Њ. The crown ether,
possessing the four oxygen and the two amino moieties, has
a cavity with an N9 ؒ ؒ ؒ N9Ј distance of 6.75 Å, whereas the
distances between O6 ؒ ؒ ؒ O6Ј and O3 ؒ ؒ ؒ 03Ј are 7.03 and 4.43
Å respectively. We were also able to obtain crystals of the
sodium receptor 1. We have previously reported these results.9
The Kϩ(PF6Ϫ) complex of 2, 2–K was also obtained by slow
evaporation from 95 : 5 CH2Cl2–MeOH solution. The unit cell
of 2–K contains two unique Kϩ complexes A and B, located
about inversion centres. Of these two complexes, A is shown in
Fig. 2, where the Kϩ is coordinating to the four oxygens and
the two nitrogen moieties of the crown ether. Both of the
complexes A and B showed disorder within the crown ether
backbone adjacent to the nitrogens of the ring. In both com-
pounds the aromatic methoxy groups participate in the Kϩ
binding, with the MeO ؒ ؒ ؒ K distances between 2.5 and 2.8 Å
(for A the methoxy group is also disordered), giving an overall
coordination geometry of eight. The bond lengths for
N9 ؒ ؒ ؒ K1 were measured to be 2.95 and 2.93 Å for A and B
The sodium receptor 1 produced low melting crystals upon
prolonged standing, whereas the potassium receptor 2 gave a
crystalline solid upon trituration with diethyl ether. All the
synthetic steps were easily scaled up without any changes to the
J. Chem. Soc., Perkin Trans. 1, 2002, 1954–1962
1955

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Fig.
2
Diagram of the Kϩ complex of 2, showing the eight
coordination geometry of complex A. Hydrogen atoms and disorder
have been omitted for clarity.
respectively, whereas the O3A ؒ ؒ ؒ K1 distances were found to
be 2.66 and 2.65 Å for A and B respectively. These values
indicate that the ion is sitting almost in the centre of the crown
cavity. The interaction of the methoxy group with the metal ion
has a dramatic effect upon the overall structure; the dihedral
angles C8–N9–C10–C11 are now 50.3 and 77.6Њ for complexes
A and B respectively, indicating that the lone pair of the
nitrogen has been deconjugated to a great extent from the
aromatic ring. This is an important observation for the future
incorporation of these receptors into luminescent sensors since
the oxidation potential of the receptor is greatly increased upon
Kϩ complexation. This in turn could be used to modulate the
rate of energy or electron transfer from the receptor, upon ion
recognition, to the emitting moiety of such a sensor. Similar
results were observed for the Naϩ complex of 1 (giving 1–Na).13
Scheme 2 Synthesis of 3, 4, 10 and 11 by the use of NaNO2 in a
mixture of (10 : 1) H2O–AcOH.
Scheme 3 The one-pot nitration method of 12 and 17 to give 13 and
18.
1
The formation of 1–Na and 2–K was also observed by H
NMR and ESMS. For 2–K the 1H NMR (CDCl3) showed that
both the aromatic and the crown ether protons were sub-
stantially affected upon Kϩ complexation. The largest effect
was seen in the resonances of the crown ether protons and
for the aromatic methoxy groups that participate directly in
the complexation (as seen in the crystal structure above). In the
ESMS, the addition of Kϩ to 2 in CH3CN gave exclusively the
mass for the 2–K mass peak.
analysis of Naϩ.9 The first step involved the nitroso formation
in water using glacial acetic acid (HOAc) at room temperature.
However, the only product obtained was the mono-nitrated
derivative 13, in over 80% yield after work-up and column
chromatographic purification using aluminium oxide. Though
it is known that the nitro compound can be formed under
such experimental conditions, it is usually formed as a minor
product. We noticed that the addition of NaNO2 (in water) to a
solution of 12 in aerated water and glacial acidic acid solution
immediately gave an orange-coloured solution, which suggested
that the nitro derivative was formed instantly and the colour
change was due to the formation of an ICT (internal charge
transfer) excited state in these compounds, where the aniline
and the nitro moieties act as electron donor and receptors
respectively. To ensure that the reaction was complete the
resulting orange solution was stirred at room temperature
overnight, followed by extraction using CH2Cl2. On all
occasions an equimolar amount of the crown ether and NaNO2
was used. Furthermore, the reaction did not proceed below 0
ЊC. The reaction times for these reactions were also short, and
we were able to obtain high yields of products after only 10
minutes.
All characterisation techniques indicated that the nitro
compound was the sole product, for instance the IR spectra of
13 showed only the nitro group at 1500 and 1350 cmϪ1 for the
asymmetric and symmetric stretches, and ESMS showed two
peaks for 13 at 371.8 for the molecular ion (M ϩ 1) and at 392.7
for the Naϩ complex (M ϩ Na). Examination of the crude
product by ESMS did not show the presence of the nitroso
compound. This reaction was also repeated in the absence of
oxygen. The solution of 12 was stirred and purged with argon
before addition of the NaNO2 solution. A deeply orange-
coloured solution was formed, indicating the formation of the
nitro compound 13. We were able to grow crystals from CH2Cl2,
which were suitable for crystallographic investigation. Indeed,
as shown in Fig. 3, the product obtained was 13, with the nitro
group para to the amino moiety.
Synthesis of nitro compounds
With the aim of preparing the two receptors 1 and 2 for
possible incorporation into luminescent chemosensors the two
compounds were nitrated, followed by reduction to the corres-
ponding aromatic amines. We have previously shown that 1
undergoes Vilsmeier–Haack formylation to give the mono
aldehyde derivative of 1.13 However, we were unsuccessful in
making the bis-formylated product. From this experience we
anticipated that we could possibly mono-nitrate the two
receptors. With this in mind the attempted nitration of 1 and 2
was undertaken using conventional nitration reagents such as
HNO3, HNO3–H2SO4, HNO3–AcOH or NO2BF4. For all of
these, a mixture of the mono- and the bis-nitration products
was observed, but in ca. 5–10% overall yield. Other combin-
ations and reaction conditions, such as changing the solvent,
acid ratio, temperature and reaction times, did not significantly
increase the yield of these products.
To enable the scale up of the synthesis of 1 and 2 an alter-
native way of nitrating 1 and 2 was chosen (Scheme 2). Our
original idea was to react 1 and 2 with NaNO2 under acidic
aqueous conditions to form the corresponding nitroso com-
pounds, which could be converted to 3 and 4 (or 10 and 11)
using HNO3 (Scheme 2), or the corresponding amines (25 and
26 from 3 and 4 respectively). To investigate these reactions we
initially carried out nitrosation on 12 (Scheme 3), the mono-
substituted 2Ј-methoxyaniline derived 15-crown-5 receptor
which we have previously used for incorporation into colori-
metric and fluorescent chemosensors for blood and serum
1956
J. Chem. Soc., Perkin Trans. 1, 2002, 1954–1962

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Fig. 3 Diagram of the structure of 13 showing the nitro group in the
para position to the crown amino moiety. Hydrogen atoms have been
omitted for clarity.
Scheme 4 The proposed mechanism for the nitration of 14. The same
mechanism is expected in the nitration of 1 and 2.
When the reactions were carried out using 1 and 2, a mixture
of mono- and bis-substituted nitro products, 3 and 4, and 10
and 11 respectively, were isolated in over 80% overall yield. On
both occasions the mono-nitrated product was easily isolated
from the bis product by trituration or by chromatography. We
were able to increase the yield of the mono-nitrated product
substantially by carrying out the reaction in larger volumes. For
instance, when the reaction was carried out on a 4.5 g scale of 1,
in 500 ml of water with the addition of NaNO2 in 80 ml of
HOAc over four hours, 4 was formed in over 70% yield.
which breaks down to give the radical cation 15. This reactive
intermediate reacts with NO2 in an irreversible manner to give
ؒ
the nitro adduct 16, which gives the desired product 13, upon
aromatisation. Other researchers have proposed similar
mechanisms involving radical cations for the nitration of N,N-
substituted anilines.23 Nitration of 17, the potassium receptor
analogue of 12, was also achieved under the same experimental
conditions, giving 18 in 67% yield (Scheme 3).
The interesting difference between our work and that of
Loeppky et al.21 is the fact that in all of our reactions the
nitrated products are formed exclusively, and the nitroso
products are not observed at all by us either in the crude
mixture or after work-up. We also carried out the nitration of
12 in the presence of a 10-fold excess of NaNO2. However, the
nitro product 13 was the only product isolated. The ESMS
showed only two peaks for the crude reaction mixture after 12
hours: for the (M ϩ 1) and the (M ϩ Na) ions respectively.
To investigate this mild nitration method further we carried
out a more detailed examination. For instance, we chose to
nitrate several intermediates from Scheme 1, e.g. 5, 6, 7, and
several other aniline based compounds. Some of these results
are summarised in Fig. 5. It can been seen that when the amino
As for 13, the presence of the nitro groups in 11 was
established by X-ray crystallography, as shown in Fig. 4. As
Fig. 4 Diagram of the structure of 11 showing the two nitro groups in
the para position to the crown amino moiety. Hydrogen atoms have
been omitted for clarity.
before, the crystal structure showed C2v symmetry. The 1H
NMR also indicated the presence of C2 symmetry.
The use of NaNO2 in a mixture of H2O and AcOH is a very
mild method for obtaining nitro-based compounds, and is
extremely attractive since it is carried out in a large excess of
water and as such is environmentally friendly. To the best of our
knowledge only a few examples of such a nitration method have
been reported previously, and many of these used stronger acids
such as HCl, H2SO4 or HNO3 in the presence of NaNO2.20
Loeppky et al. have recently investigated in detail the mechan-
ism behind the nitrosamine formation of N,N-dialkyl aromatic
amines.21 In the synthesis of these nitrosamines the authors
used NaNO2 (in a 3–15-fold excess) in either HOAc or 60%
HOAc–H2O solution buffered to pH 3.8 with NaOAc. The
authors observed that in most cases the nitrosamines were
formed in high yields (up to 86%). However, on several
occasions a minor product was identified as the nitro-
substituted N,N-dimethylaniline derivatives. The authors also
reported that on occasion the ratio between the two products
could be dramatically altered, in favour of the nitro product,
by slight changes in the reactions conditions. The authors
proposed that the mechanism for these reactions involved the
formation of a nitrosammonium ion which could undergo
reversible homolysis to generate NO and a radical cation or,
alternatively, lose NOH to give the nitrosamine. In both cases
the source of NO is N2O3.22 The proposed analogous mechan-
ism for the nitration of 12 to give 13 is shown in Scheme 4.
Here the first intermediate is the nitrosammonium ion 14,
Fig. 5 The observed products and yields using NaNO2 in AcOH and
H2O (1 : 10 v/v). All products were isolated after 12 hours.
moiety is tertiary, with the methoxy group in the ortho position,
an acceptable yield of the corresponding nitro compound is
obtained, e.g. examples 19–21. When the group is in the para
position, good yields were also obtained, as for 22. However,
this method failed to produce the desired nitro compounds
J. Chem. Soc., Perkin Trans. 1, 2002, 1954–1962
1957

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Table 1 Data collection and structure refinement details for 2, 2–K, 11 and 13
Empirical formula
Compound
M
C26H38N2O6
2
474.58
C26H38N2O6KPF6
2–K
658.65
C26H36N4O10
11
564.59
C17H26N2O6
13
370.40
Crystal size/mm
Crystal system
Space group (Z)
a/Å
b/Å
c/Å
α/Њ
β/Њ
0.65 × 0.54 × 0.16
Monoclinic
P21/c (2)
7.218(2)
7.852(2)
21.449(6)
90
93.011(4)
90
1213.9(6)
1.298
0.28 × 0.18 × 01.6
Triclinic
P1 (2)
0.66 × 0.60 × 0.42
Triclinic
P1 (1)
0.52 × 0.30 × 0.12
Triclinic
P1 (2)
¯
¯
¯
11.908(3)
12.219(3)
12.268(3)
86.206(3)
70.910(3)
64.190(3)
1512.5(6)
1.446
688
0.308
3–58
6681
7.4201(17)
8.1588(19)
11.055(3)
99.130(3)
100.381(3)
93.595(3)
647.1(3)
1.449
300
0.112
3.5–57
2884
8.696(3)
8.943(4)
12.098(5)
83.932(6)
71.217(6)
76.937(6)
876.1(6)
1.419
396
0.110
3.5–58
3838
γ/Њ
U/Å3
Dc/g cmϪ3
F(000)
512
0.092
3.5–57
2810
µ(Mo-Kα)/mmϪ1
ω scans; 2θ range/Њ
Unique reflections
wR2 (R1)
0.1052 (0.0483)
0.1924 (0.0593)
0.1317 (0.0460)
0.1939 (0.0640)
when the amino unit was secondary, such as in the attempted
nitration of 7, or in the case of 23, which lacks the methoxy
functionality. Furthermore, the tosylamide derivatives 5 and 6
gave no nitrated products, but the solubility of these starting
materials is poor in aqueous solution. Nitration of benzo-
15-crown-5 and benzo-18-crown-6, which lack the amino
moieties, was also unsuccessful, whereas nitration of N,N-
dimethyl-4-bromoaniline gave the corresponding nitro com-
pound 24.24 On all occasions an equimolar amount of NaNO2
was used. The effect of the solvent and choice of acid on the
nitration product was also investigated using 21. Using a
mixture of water and glacial acetic acid and HCl or H2SO4
gave on all occasions the desired product under either aerated
or degassed conditions. However, no nitration occurred if
MeOH was used instead of water. It is apparent from these
results that the substitution pattern of the starting material is
very important and that the reaction only yields the nitro
compounds when the amino moiety is tertiary. This is in
agreement with the observations of Loeppky et al.21 However,
whenever the desired nitro compounds were formed, they
were formed in good yield and the procedure could be
scaled up.
Of these nitrated products, 3, 4, 13 and 18 were all reduced to
the corresponding aromatic amines 25, 26, 27 and 28 in good
yields using 10% Pd on carbon and an atmospheric pressure of
H2. Even though these products were found to be stable to
oxidation in air over a long period of time (weeks) they were
nevertheless stored under argon. We did not think it necessary
to protect them in any other way. We are currently incorporat-
ing these aromatic amines as recognition sites in luminescent
chemosensors.
Experimental
Melting points were determined using GallenKamp melting
point apparatus. Infrared spectra were recorded on a Mattson
Genesis II FTIR spectrophotometer equipped with a Gateway
2000 4DX2-66 workstation. Oils were analysed using NaCl
plates, solid samples were dispersed in KBr and recorded as
clear pressed discs. 1H NMR spectra were recorded at 400 MHz
using a Bruker Spectrospin DPX-400 instrument. Tetra-
methylsilane (TMS) was used as an internal reference standard,
with chemical shifts expressed in parts per million (ppm or δ)
downfield from the standard. 13C NMR were recorded at 100
MHz using a Bruker Spectrospin DPX-400 instrument. Mass
spectra were determined by detection using Electrospray on a
Micromass LCT spectrometer, using a Waters HPLC. The
whole system was controlled by MassLynx 3.5 on a Compaq
Deskpro workstation.
Crystal data were collected using a Bruker SMART diffract-
ometer with graphite monochromated Mo-Kα radiation at ca.
150 K in a dinitrogen stream (Table 1). Crystal stabilities were
checked and there were no significant variations (< 1%). ωꢀ
scans were employed for data collection and Lorentz and
polarisation corrections were applied. The structures were
solved by direct methods and the non-hydrogen atoms were
refined with anisotropic thermal parameters. Hydrogen-atom
positions were added at idealised positions; a riding model
with fixed thermal parameters [Uij = 1.2Ueq for the atom to
which they are bonded (1.5 for Me)] was used for subsequent
refinements. The function minimised was Σ[ω(|Fo|2 Ϫ |Fc|2)]
with reflection weights ωϪ1 = [σ2|Fo|2 ϩ (g1P)2 ϩ (g2P)] where
P = [max|Fo|2 ϩ 2|Fc|2]/3. The SAINT-NT19 and SHELXTL20
program packages were used for data reduction and structure
solution and refinement.
CCDC reference numbers 186701–186704. See http://
www.rsc.org/suppdata/p1/b2/b205299g/ for crystallographic
files in .cif or other electronic format.
Conclusion
The synthesis of the two receptors 1 and 2 was achieved in
good yield in a few steps and can be easily scaled up. These
compounds can be both formylated and nitrated in good
yield to facilitate their incorporation into chemosensors.
Although conventional nitration reagents failed to give the
desired nitro products, a very mild nitration method, involv-
ing NaNO2 in a mixture of water and mild acid, gave the
desired products in good yields. This is a particularly attrac-
tive nitration method since it is carried out in aqueous solu-
tion, and as such it might be of great relevance to industry.
This method is specific, and works well if the aromatic amino
moiety is tertiary and the benzene ring is electron-rich. Of the
nitrated products synthesised several were reacted further to
give the corresponding amines. We are currently using these
compounds for incorporation into new types of luminescent
chemosensors.
N-(2-Methoxyphenyl)-4-methylbenzenesulfonamide (5)
In a 250 ml round-bottom flask, 2-methoxyaniline (30.00 g,
248.5 mmol) and toluene-4-sulfonyl chloride (47.37 g, 248.5
mmol) in pyridine (120 ml) were refluxed for 45 minutes. The
solution was left to cool to room temperature, then poured
into 100 ml of ice–water and stirred for one hour. The grey
precipitate was filtered and washed with cold water (3 × 50 ml)
and then recrystallised from ethanol and dried under vacuum to
give 5 (59 g, 87.23% yield) as white crystals, mp 146–147 ЊC.
Calculated for C14H15NO3S: C, 60.63; H, 5.45; N, 5.05, found:
C, 60.60; H, 5.40; N, 5.05%; calculated for C14H16NO3S: [M ϩ
H peak] m/z = 278.0851, found: 278.0867; δH(CDCl3, 400 MHz)
7.65 (d, J = 8.0 Hz, 2H, Ar-H ), 7.52 (d, J = 8.0 Hz, 1H, Ar-H ),
7.18 (d, J = 8.0 Hz, 2H, Ar-H ), 7.05 (s, 1H, NH ), 7.02 (t, J = 8.0
1958
J. Chem. Soc., Perkin Trans. 1, 2002, 1954–1962

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Hz, 1H, Ar-H ), 6.89 (t, J = 8.0 Hz, 1H, Ar-H ), 6.74 (d, J = 8.0
Hz, 1H, Ar-H ), 3.64 (s, 3H, Ar-O-CH3), 2.35 (s, 3H, Ar-CH3);
δC(CDCl3, 100 MHz) 149.46, 143.51, 136.29, 129.24, 127.15,
125.98, 125.21, 120.99, 120.96, 110.58, 55.54, 21.35; MS
(MeCN, ESϩ) m/z expected: 277.3, found: 278.2 (Mϩ), 300.2
(M ϩ Na), 316.1 (M ϩ K); IR νmax/cmϪ1 3332, 3010, 1594, 1500,
1467, 1446, 1399, 1334, 1309, 1286, 1257, 1208, 1159, 1114,
1089, 1050, 1025, 932, 916, 823, 781, 754, 707, 661, 626, 582,
556, 536.
(M ϩ Na), 399.2 (M ϩ K); IR νmax/cmϪ1 3413, 3064, 3002, 2937,
2896, 2685, 1602, 1513, 1456, 1430, 1346, 1222, 1178, 1139,
1027, 935, 904, 738.
7,13-Bis(2-methoxyphenyl)-1,4,10-trioxa-7,13-diaza-
cyclopentadecane-8,12-dione (8)
1,10-Bis(2-methoxyphenyl)-4,7-dioxa-1,10-diazadecane (7.0 g,
19.43 mmol) and oxydiacetyl dichloride (95% purity, 3.48 g,
19.4 mmol), each dissolved in dry benzene (300 ml), were placed
into two pressure equalising dropping funnels, and over a
period of 12 hours were simultaneously dripped into a stirred
mixture of dry benzene (800 ml) and dry pyridine (16 ml)
placed in a 2 l, three-neck, round-bottom flask under an inert
atmosphere. The solution was stirred for a further 12 hours at
75 ЊC after addition had been completed. The solvent was
removed under vacuum, and the residues were dissolved in
CH2Cl2. The organic solution was washed twice with HCl (1 M)
and twice with H2O, dried over MgSO4 and removed under
reduced pressure to give an off-yellow residue (8.183 g, 17.85
mmol). The product was recrystallised from ethanol to form a
white solid (5.92 g, 12.91 mmol) in 67% yield, mp 152–153 ЊC;
calculated for C24H30N2O7: C, 62.85; H, 6.60; N, 6.11, found: C,
62.35; H, 6.66; N, 5.93%; calculated for C24H31N2O7: [MHϩ
peak] m/z = 459.2131, found: 459.2132; δH(CDCl3, 400 MHz)
7.3 (m, 8H, Ar-H ), 3.77 (m, 22H, Ar-O-CH3, crown-H);
δC(CDCl3, 125.8 MHz) 170, 169, 155, 154, 132, 130, 129, 128,
127, 121, 120, 119, 112, 111, 76, 70, 69, 68, 66, 55, 47, 45; MS
(MeCN, ESϩ) m/z expected: 458.20, found: 459.2 (Mϩ), 481.1
(M ϩ Na), 497.2 (M ϩ K), 916.76 (M2ϩ), 938.65 (M2Naϩ); IR
νmax/cmϪ1 3449, 2986, 2939, 2346, 1672, 1596, 1500, 1458, 1440,
1414, 1359, 1341, 1290, 1278, 1246, 1219, 1190, 1149, 1120,
1096, 1058, 1044, 1019, 990, 968, 926, 898, 867, 780, 763, 670,
578, 500.
1,10-Bis(2-methoxyphenyl)-1,10-bis(4-methylphenylsulfonyl)-
4,7-dioxa-1,10-diazadecane (6)
N-(2-Methoxyphenyl)-4-methylbenzenesulfonamide (20.00 g,
72 mmol) was placed into a 250 ml round-bottom flask contain-
ing K2CO3 (20.00 g, 144 mmol) and KI (4.00 g, 24 mmol) in
DMF (120 ml). To this solution 1,2-bis(2-chloroethoxy)ethane
(6.77 g, 5.616 ml, 36.05 mmol) was added and the mixture
stirred under dry conditions for 72 hours at 70 ЊC. The mixture
was cooled and poured into a mixture of 1 : 1 water–ethyl
acetate (200 ml each) and the solution was shaken vigorously.
The two layers were separated and the aqueous layer was
washed 3 times with ether. The combined organic layers were
dried over MgSO4 and then the solvent was removed under
reduced pressure to give a yellow oil that was triturated from
ethanol to produce 6 (21.57 g, 90.76% yield) as a white solid,
mp 142–143 ЊC; calculated for C34H40N2O8S2: C, 61.06; H, 6.03;
N, 4.19, found: C, 61.39; H, 5.80; N, 4.42%; calculated for
C34H41N2O8S2: [M ϩ H peak] m/z = 669.2304, found: 669.2305;
δH(CDCl3, 400 MHz) 7.56 (d, J = 8.04 Hz, 4H, Ar-H ), 7.26
(m, 4H, Ar-H ), 7.22 (d, J = 8.0 Hz, 4H, Ar-H ), 6.90 (t, J = 7.52
Hz, 2H, Ar-H ), 6.77 (d, 2H, J = 8.0 Hz, Ar-H ), 3.73 (s, 4H,
CH2), 3.51 (t, J = 6.52 Hz, 4H, CH2), 3.41 (s, 4H, CH2), 3.38
(s, 6H, Ar-O-CH3), 2.41 (s, 6H, Ar-CH3); δC(CDCl3, 100 MHz)
156.37, 142.62, 137.51, 133.19, 129.68, 128.87, 127.57, 127.04,
120.49, 111.53, 70.10, 69.42, 54.79, 49.12, 21.39; MS (MeCN,
ESϩ) m/z expected: 668.2, found: 669.7 (Mϩ), 691.7 (M ϩ Na),
707.6 (M ϩ K); IR νmax/cmϪ1 3463, 2960, 2904, 2867, 1596,
1498, 1459, 1436, 1322, 1284, 1263, 1221, 1160, 1135, 1116,
1091, 1074, 1043, 1024, 960, 914, 860, 811, 782, 757, 709, 657,
586, 553, 528, 511, 489.
7,16-Bis(2-methoxyphenyl)-1,4,10,13-tetraoxa-7,16-diaza-
cyclooctadecane-6,17-dione (9)
The synthesis of compound 9 is identical to that for compound
8 using 1,10-bis(2-methoxyphenyl)-4,7-dioxa-1,10-diazadecane
(7.00 g, 19.43 mmol) and (2-chlorocarbonylmethoxyethoxy)-
acetyl chloride (4.176 g, 19.42 mmol). After reaction, the
organic layer was dried over MgSO4 and removed under
reduced pressure to give a yellow–white residue (7.09 g, 14.10
mmol) of a mixture of the cis and trans forms of 9, which
solidified on standing to give a white solid in 72.64% yield.
Calculated for C26H35N2O8: [M ϩ H peak] m/z = 503.2393,
found: 503.2383; δH(CDCl3, 400 MHz) 7.58 (d, 2H, J = 8.04 Hz,
Ar-H ), 7.32 (t, 2H, J = 8.30 Hz, Ar-H ), 7.06 (t, 2H, J = 8.04 Hz,
Ar-H ), 6.90 (d, 2H, J = 8.04 Hz, Ar-H ), 4.03 (s, 1H, CH2), 3.99
(s, 1H, CH2), 3.89 (s, 1H, CH2), 3.86 (s, 1H, CH2), 3.87 (s, 6H,
Ar-O-CH3), 3.61–3.56 (m, 8H, CH2), 3.42–3.37 (m, 6H, CH2),
2.98 (t, 1H, J = 4.52 Hz, CH2), 2.95 (t, 1H, J = 4.52 Hz, CH2);
δC(CDCl3, 100 MHz) 169.85, 154.92, 132.26, 129.72, 127.75,
121.28, 111.21, 71.05, 70.50, 69.91, 67.63, 55.26, 45.72; MS
(MeCN, ESϩ) m/z expected: 502.56, found: 503.37 (Mϩ),
525.42 (M ϩ Na), 549.48 (M ϩ K); IR νmax/cmϪ1 3434, 2928,
2876, 1648, 1596, 1500, 1459, 1438, 1399, 1347, 1290, 1260,
1159, 1098, 1022, 769, 584.
1,10-Bis(2-methoxyphenyl)-4,7-dioxa-1,10-diazadecane (7)
To a 3 : 2 mixture of glacial acetic acid and sulfuric acid (70 ml :
46.6 ml) at 60 ЊC (exactly), 1,10-bis(2-methoxyphenyl)-1,10-
bis(4-methylphenylsulfonyl)-4,7-dioxa-1,10-diazadecane (5.00
g, 7.24 mmol) was added and the suspension stirred for 24
hours. The mixture was then poured hot into 400 ml of H2O
and the pH brought up to 7, by adding KOH pellets. The
aqueous solution was extracted three times with ether, and the
combined ether layers were washed twice with K2CO3 (0.1 M)
solution and twice with H2O. The salt was also washed with
ether and combined with the organic layer. The organic layers
were then dried over MgSO4 and the solvent removed under
reduced pressure, to give a thick brown oil (1.85 g) which was
purified by flash column chromatography using 25 : 75, ethyl
acetate–hexane to yield 7 (0.85 g, 31.6% yield) as a pale yellow
oil that was triturated and later recrystallised from ethanol, mp
216–217 ЊC; calculated for C20H28N2O4: C, 66.64; H, 7.83; N,
7.77, found: C, 66.09; H, 7.78; N, 7.68%; calculated for
C20H29N2O4: [M ϩ H peak] m/z = 361.2127, found: 361.2126;
δH(CDCl3, 400 MHz) 6.89 (t, J = 7.52 Hz, 2H, Ar-H ), 6.79 (d,
J = 7.52 Hz, 2H, Ar-H ), 6.70 (t, J = 7.56 Hz, 2H, Ar-H ), 6.65
(d, J = 7.52 Hz, 2H, Ar-H ), 4.62 (br s, 2H, N-H), 3.85 (s, 6H,
CH2), 3.77 (t, J = 5.00 Hz, 4H, CH2), 3.70 (s, 4H, CH2), 3.37 (t,
J = 5.00 Hz, 4H, CH2); δC(CDCl3, 100 MHz) 147.07, 138.15,
121.16, 116.56, 109.91, 109.49, 70.31, 69.80, 55.32, 43.24; MS
(MeCN, ESϩ) m/z expected: 360.2, found: 361.2 (Mϩ), 383.2
7,13-Bis(2-methoxyphenyl)-1,4,10-trioxa-7,13-diazacyclo-
pentadecane (1)
7,13-Bis(2-methoxyphenyl)-1,4,10-trioxa-7,13-
diazacyclopentadecane-8,12-dione (4.905 g, 10.7 mmol) was
added to a stirred solution of dry THF (60 ml). To this stirred
solution, at room temperature, a six-fold equivalent of NaBH4
(2.524 g, 66.7 mmol) was added, and then over a period of two
hours, an eight-fold equivalent of boron trifluoride–diethyl
ether (12.519 g, 88.2 mmol) in dry THF (60 ml) was added.
J. Chem. Soc., Perkin Trans. 1, 2002, 1954–1962
1959

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After addition the suspension was refluxed for 4 hours and then
poured into 30 ml of H2O and the pH brought to 7 using KOH.
The aqueous solution was extracted twice with CH2Cl2. The
organic layer washed several times with H2O, and then dried
over MgSO4. The solvent was removed under reduced pressure
to give a colourless oil, which crystallised upon standing to give
a 97.67% yield (4.502 g, 10.4 mmol) of 1. Calculated for
C24H34N2O5: C, 66.94; H, 7.96; N, 6.51, found: C, 66.08; H,
7.96; N, 6.35%; calculated for C24H35N2O5: [M ϩ H peak] m/z =
431.2546, found: 431.2538; δH(CDCl3, 400 MHz) 7.05 (d, 2H, J
= 7.56 Hz, Ar-H ), 6.95 (t, 2H, J = 6.04 Hz, Ar-H ), 6.87 (m, 4H,
Ar-H ), 3.84 (s, 6H, Ar-O-CH3), 3.72 (t, 4H, J = 5.52 Hz, CH2),
3.66 (m, 8H, CH2), 3.51–3.44 (m, 8H, CH2); δC(CDCl3, 100
MHz) 152.96, 140.55, 122.21, 121.01, 120.75, 111.90, 71.20,
70.78, 69.80, 53.38, 53.21, 52.51; MS (MeCN, ESϩ) m/z
expected: 430.2, found: 431.3 (Mϩ), 453.3 (M ϩ Na), 861.6 (M2
ϩ H), 883.7 (M2 ϩ Na); IR νmax/cmϪ1 3059, 2927, 2856, 1725,
1593, 1499, 1461, 1353, 1238, 1180, 1108, 1028, 795, 744.
Ar-H ), 7.67 (d, 1H, J = 2.52 Hz, Ar-H ), 6.99 (d, 1H, J = 8.04
Hz, Ar-H ), 6.94 (d, 1H, J = 7.52 Hz, Ar-H), 6.93–6.83 (m, 3H,
Ar-H), 3.87 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 3.77 (t, 2H, J =
5.0 Hz, OCH2CH2), 3.71–3.61 (m, 14H, OCH2CH2), 3.46
(t, 2H, J = 5.48 Hz, OCH2CH2), 3.38 (t, 2H, J = 4.52 Hz,
OCH2CH2); δC(CDCl3, 100 MHz) 153.19, 149.56, 146.30,
140.43, 139.46, 122.53, 121.42, 120.70, 118.34, 115.54, 111.92,
107.32, 71.44, 70.85, 70.75, 69.73, 69.38, 55.82, 55.33, 53.68,
55.35, 53.14, 52.24; MS (MeCN, ESϩ) m/z expected: 475.23,
found: 476.1 (M ϩ H); IR νmax/cmϪ1 3431 (H2O), 2922, 2857,
1585, 1509, 1458, 1322, 1276, 1240, 1183, 1096, 1025, 862, 798,
745.
7,13-Bis(2-methoxy-4-nitrophenyl)-1,4,10-trioxa-7,13-diaza-
cyclopentadecane (10)
Isolated in 17% yield as a yellow solid. Mp 130–131 ЊC. Calcu-
lated for C24H32N4O9: C, 55.38; H, 6.20; N, 10.76, found: C,
55.63; H, 6.20; N, 10.46%; calculated for C24H33N4O9: [M ϩ H
peak] m/z = 521.2248, found: 521.2260; δH(CDCl3, 400 MHz)
7.81 (dd, 2H, J1 = 9.00, J2 = 2.52 Hz, Ar-H ), 7.68 (d, 2H, J =
2.52 Hz, Ar-H ), 6.86 (d, 2H, J = 9.04 Hz, Ar-H ), 3.87 (s, 6H,
OCH3), 3.73 (t, 4H, J = 5.0 Hz, OCH2CH2), 3.68 (m, 8H,
OCH2CH2), 3.62 (s, 8H, OCH2CH2); δC(CDCl3, 100 MHz)
149.76, 146.32, 139.79, 118.28, 115.72, 107.37, 71.35, 70.90,
69.50, 55.88, 53.67, 52.68; MS (MeCN, ESϩ) m/z expected:
520.5, found: 521.2 (M ϩ H); IR νmax/cmϪ1 2927, 2885, 2862,
1584, 1491, 1319, 1278, 1242, 1095, 1062, 1025, 967, 872, 798,
746, 721, 643, 593, 556.
7,16-Bis(2-methoxyphenyl)-1,4,10,13-tetraoxa-7,16-diazacyclo-
octadecane (2)
The synthesis of compound 2 is identical to that for 1 using
7,16-bis(2-methoxyphenyl)-1,4,10,13-tetraoxa-7,16-diazacyclo-
octadecane-6,17-dione (6.077 g, 12.1 mmol), which was added
to a stirred solution of dry THF (60 ml). To this stirred
solution, at room temperature, a six-fold equivalent of NaBH4
(2.852 g, 75.3 mmol) was added, and then over a period of
two hours, an eight-fold equivalent of boron trifluoride–diethyl
ether (14.142 g, 99.6 mmol) in dry THF (60 ml) was added.
After work-up, a colourless oil was isolated that crystallised
upon standing to give a 91.59% yield (5.256 g, 11.07 mmol) of
2. A small sample of this material was crystallised by slow
evaporation from DCM. Mp 206–208 ЊC; calculated for
C26H38N2O6ؒCH2Cl2: C, 57.96; H, 7.21; N, 5.01, found: C,
57.89; H, 6.91; N, 5.04%; calculated for C26H39N2O6: [M ϩ H
peak] m/z = 475.2808, found: 475.2798; δH(CDCl3, 400 MHz)
7.18 (d, 2H, J = 7.52 Hz, Ar-H ), 6.98 (t, 2H, J = 7.56 Hz,
Ar-H ), 6.91 (t, 2H, J = 7.56 Hz, Ar-H ), 6.87 (d, 2H, J = 8.04
Hz, Ar-H ), 3.85 (s, 6H, Ar-O-CH3), 3.61 (t, 8H, J = 5.52 Hz,
CH2), 3.56 (s, 8H, CH2), 3.49 (t, 8H, J = 6.04 Hz, CH2);
δC(CDCl3, 100 MHz) 153.07, 139.28, 122.45, 121.45, 120.72,
111.78, 70.54, 69.90, 55.37, 52.65; MS (MeCN, ESϩ) m/z
expected: 474.2, found: 475.3 (Mϩ), 497.3 (M ϩ Na), 513.3
(M ϩ K); IR νmax/cmϪ1 3446, 3069, 3002, 2889, 2859, 1579,
1499, 1458, 1436, 1368, 1336, 1285, 1266, 1243, 1209, 1187,
1170, 1129, 1103, 1088, 1050, 1022, 994, 915, 880, 824, 799, 744,
718, 612, 584, 542, 479, 410.
7-(2-Methoxy-4-nitrophenyl)-16-(2-methoxyphenyl)-1,4,10,13-
tetraoxa-7,16-diazacyclooctadecane (4)
Isolated in 43% yield as
a yellow oil. Calculated for
C26H37N3O8: C, 60.10; H, 7.18; N, 8.09, found: C, 60.49; H,
7.41; N, 7.58%; calculated for C26H38N3O8: [M ϩ H peak] m/z =
520.2659, found: 520.2676; δH(CDCl3, 400 MHz) 7.82 (dd, 1H,
J1 = 6.52, J2 = 2.52 Hz, Ar-H ), 7.68 (d, 1H, J = 2.0 Hz, Ar-H ),
7.11 (d, 1H, J = 6.04 Hz, Ar-H ), 6.97–6.84 (m, 4H, Ar-H), 3.89
(s, 3H, OCH3), 3.83 (s, 3H, OCH3), 3.73–3.71 (m, 8H,
OCH2CH2), 3.62–3.57 (m, 12H, OCH2CH2), 3.53–3.48 (m, 4H,
OCH2CH2); δC(CDCl3, 100 MHz) 153.12, 149.76, 146.16,
139.77, 139.94, 122.58, 121.41, 120.66, 118.19, 116.05, 111.84,
107.27, 70.73, 70.57, 70.08, 69.82, 55.82, 55.34, 52.70, 52.67;
MS (MeCN, ESϩ) m/z expected: 519.6, found: 520.7 (M ϩ H);
IR νmax/cmϪ1 3434 (H2O), 2921, 2863, 1579, 1508, 1457, 1321,
1275, 1242, 1181, 1095, 800, 746, 669.
7,16-Bis(2-methoxy-4-nitrophenyl)-1,4,10,13-tetraoxa-7,16-
diazacyclooctadecane (11)
General procedure for the nitration
Isolated in 36% yield) as a yellow solid. Mp 147–149 ЊC. Calcu-
lated for C26H36N4O10: C, 55.31; H, 6.43; N, 9.92, found: C,
55.37; H, 6.45; N, 9.61%; calculated for C26H37N4O10: [M ϩ H
peak] m/z = 565.2510, found: 565.2507; δH(CDCl3, 400 MHz)
7.82 (dd, 2H, J1 = 6.52, J2 = 2.52 Hz Ar-H ), 7.68 (d, 2H, J = 2.48
Hz, Ar-H ), 6.91 (d, 2H, J = 9.04 Hz, Ar-H ), 3.89 (s, 6H,
OCH3), 3.70 (s, 12H, OCH2CH2), 3.60 (s, 12H, OCH2CH2);
δC(CDCl3, 100 MHz) 149.84, 146.11, 139.94, 118.19, 115.97,
107.34, 70.80, 70.07, 55.88, 52.76; MS (MeCN, ESϩ) m/z
expected: 564.2, Found: 565.2 (M ϩ H), 586.7 (M ϩ Na), 602.7
(M ϩ K); IR νmax/cmϪ1 3434 (H2O), 2922, 2886, 2856, 1582,
1509, 1484, 1453, 1328, 1280, 1249, 1127, 1094, 1026, 991, 910,
873, 801, 728, 528, 554, 483, 431.
To
a 250 ml single-necked round-bottom flask 13-(2-
methoxyphenyl)-1,4,7,10-tetraoxa-13-azacyclopentadecane
(0.585 g, 1.89 mmol) was added along with 60 ml of distilled
water and 6 ml of glacial acetic acid (100%). The solution was
stirred at room temperature. Over a ten minute period 10 ml
of deionised water containing NaNO2 (0.144 g, 2.09 mmol,
97%) was added. The solution turned bright orange during this
addition. The solution was then left to stir overnight. The
orange solution was washed with DCM (4 × 50 ml). The
organic phases were combined and dried over K2CO3, and the
resulting solution was reduced to a yellow oil. This was purified
by column chromatography through alumina using 99 : 1
diethyl ether–MeOH, or by trituration.
7-(2-Methoxy-4-nitrophenyl)-13-(2-methoxyphenyl)-1,4,10-
trioxa-7,13-diazacyclopentadecane (3)
13-(2-Methoxy-4-nitrophenyl)-1,4,7,10-tetraoxa-13-azacyclo-
pentadecane (13)
Isolated in 48% yield as
C24H34N3O7: [M ϩ H peak] m/z = 476.2397, found: 476.2420;
δH(CDCl3, 400 MHz) 7.81 (dd, 1H, J1 = 6.52, J2 = 2.48 Hz
a
yellow oil. Calculated for
Isolated as yellow oil that solidified upon standing for a few
days in 89% yield. Mp 75–76 ЊC. Calculated for C17H26N2O7: C,
55.13; H, 7.08; N, 7.56, found: C, 55.35; H, 7.09; N, 7.26%;
1960
J. Chem. Soc., Perkin Trans. 1, 2002, 1954–1962

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calculated for C17H27N2O7: [M ϩ H peak] m/z = 371.1818,
found: 371.1817; δH(CDCl3, 400 MHz) 7.77 (dd, 1H, J1 = 9.04,
J2 = 2.52 Hz, Ar-H ), 7.63 (d, 1H, J = 2.52 Hz, Ar-H ), 6.86 (d,
1H, J1 = 9.04 Hz, Ar-H ), 3.83 (s, 3H, OCH3), 3.70 (t, 4H, J =
5.52 Hz, OCH2CH2), 3.64–3.59 (m, 16H, OCH2CH2);
δC(CDCl3, 100 MHz) 149.36, 145.96, 139.25, 118.24, 115.37,
107.21, 70.97, 70.30, 70.17, 69.72, 55.72, 53.64; MS (MeCN,
ESϩ) m/z expected: 370.4, found: 371.8 (M ϩ H), 392.7 (M ϩ
Na); IR νmax/cmϪ1 2940, 2885, 2856, 1585, 1512, 1497, 1319,
1292, 1269, 1239, 1223, 1120, 1096, 1051, 1025, 992, 940, 891,
857, 800, 742, 669, 615.
[Ethoxycarbonylmethyl(4-methoxy-2-nitrophenyl)amino]acetic
acid ethyl ester (22)
Isolated in 79% as a yellow oil. Calculated for C13H17N2O7: [M
ϩ H peak] m/z = 313.1036, found: 313.1038; δH(CDCl3, 400
MHz) 7.46 (d, 1H, J = 8.76 Hz, Ar-H ), 7.23 (d, 1H, J = 2.92 Hz,
Ar-H ), 7.03 (dd, 1H, J1 = 9.36, J2 = 2.92 Hz, Ar-H ), 4.06 (s, 4H,
CH2), 3.81 (s, 3H, OCH3), 3.68 (s, 6H, COOCH3); δC(CDCl3,
100 MHz) 171.00, 156.16, 147.10, 136.34, 127.88, 119.59,
109.21, 55.83, 55.40, 51.74; MS (MeCN, ESϩ) m/z expected:
312.3, found: 313.2 (M ϩ H), 335.2 (M ϩ Na); IR νmax/cmϪ1
3432, 3006, 2955, 2847, 1751, 1530, 1438, 1355, 1292, 1203,
1174, 1029, 849, 808, 624, 562.
16-(2-Methoxy-4-nitrophenyl)-1,4,7,10,13-pentaoxa-16-aza-
cyclooctadecane (18)
3-Methoxy-4-[13-(2-methoxyphenyl)-1,4,10-trioxa-7,13-diaza-
cyclopentadecan-7-yl]phenylamine (25)
Isolated in 68% yield as
a yellow oil. Calculated for
C19H30N2O8: C, 55.06; H, 7.30; N, 6.76, found: C, 54.57; H,
7.20; N, 6.42; calculated for C19H31N2O8: [M ϩ H peak] m/z =
415.2080, found: 415.2066; δH(CDCl3, 400 MHz) 7.81 (dd, 1H,
J1 = 9.36, J2 = 2.32 Hz, Ar-H ), 7.66 (d, 1H, J = 2.92 Hz, Ar-H ),
6.93 (d, 1H, J1 = 9.32 Hz, Ar-H ), 3.88 (s, 3H, OCH3), 3.70–3.66
(m, 16H, OCH2CH2), 3.65–3.63 (m, 4H, OCH2CH2), 3.61–3.60
(m, 4H, OCH2CH2); δC(CDCl3, 100 MHz) 149.85, 146.20,
139.81, 118.20, 116.36, 107.26, 70.77, 70.68, 70.53, 69.76, 55.85,
52.81; MS (MeCN, ESϩ) m/z expected: 414.4, found: 415.2 (M
ϩ H), 437.2 (M ϩ Na), 453.2 (M ϩ K); IR νmax/cmϪ1 2914,
2870, 1584, 1509, 1458, 1321, 1275, 1243, 1176, 1096, 1024, 923,
800, 748.
Compound 3 (0.7643 g, 1.61 mmol) was placed in a 250 ml
round-bottom flask. To this was added 10% Pd–C (0.10 g) and
ethanol (100 ml). The solution was stirred under a H2 atmos-
phere until no more H2 was consumed. The resulting solution
was passed through a Celite filter, and the resulting solution
reduced under vacuum to produce a colourless resin, which
slowly turned light purple over time. The resin was purified by
acid/base extraction to yield 25 (0.4228 g, 59.0%). Calculated
for C24H36N3O5: [M ϩ H peak] m/z = 446.2655, found:
446.2655; δH(CDCl3, 400 MHz) 7.04 (d, 1H, J = 7.52 Hz,
Ar-H ), 6.92 (m, 2H, Ar-H ), 6.87 (d, 1H, J = 7.52 Hz, Ar-H ),
6.82 (d, 1H, J = 8.04 Hz, Ar-H ), 6.19 (m, 2H, Ar-H ), 3.80
(s, 3H, OCH3), 3.74 (s, 3H, OCH3), 3.70 (t, 2H, J = 5.52 Hz,
OCH2CH2O), 3.62 (m, 8H, OCH2CH2O), 3.54 (t, 2H, J = 6.0
Hz, OCH2CH2O), 3.46 (m, 4H, OCH2CH2O), 3.41 (m, 4H,
OCH2CH2O); δC(CDCl3, 100 MHz) 155.15, 152.70, 143.20,
140.36, 131.52, 125.10, 121.93, 120.72, 120.56, 111.73, 106.49,
100.50, 70.83, 70.78, 70.52, 69.66, 69.54, 55.20, 55.03, 53.91,
53.39, 53.27, 52.96, 52.49; MS (MeCN, ESϩ) m/z expected:
445.56, found: 446.23 (M ϩ H), 468.28 (M ϩ Na); IR νmax/cmϪ1
3426, 2927, 2858, 1617, 1509, 1458, 1353, 1239, 1212, 1171,
1110, 1028, 950, 830, 748, 568.
[Ethoxycarbonylmethyl(2-methoxy-4-nitrophenyl)amino]acetic
acid ethyl ester (19)
Isolated in 44% yield as
a yellow oil. Calculated for
C13H17N2O7: [M ϩ H peak] m/z = 313.1036, found: 313.1038;
δH(CDCl3, 400 MHz) 7.80 (dd, 1H, J1 = 9.04, J2 = 2.52 Hz,
Ar-H ), 7.69 (d, 1H, J = 2.48 Hz, Ar-H ), 6.67 (d, 1H, J = 9.0 Hz,
Ar-H ), 4.20 (s, 4H, CH2), 3.85 (s, 3H, OCH3), 3.78 (s, 6H,
COOCH3); δC(CDCl3, 100 MHz) 170.90, 149.55, 144.97,
141.21, 118.06, 115.77, 107.50, 56.11, 54.17, 52.07; MS (MeCN,
ESϩ) m/z expected: 312.3, found: 313.2 (M ϩ H), 335.2 (M ϩ
Na); IR νmax/cmϪ1 3448, 3000, 2953, 2852, 1750, 1685, 1588,
1515, 1458, 1329, 1289, 1249, 1207, 1176, 1101, 1011, 946, 863,
804, 745, 721, 627, 560.
3-Methoxy-4-[16-(2-methoxyphenyl)-1,4,10,13-tetraoxa-7,16-
diazacyclooctadecan-7-yl]phenylamine (26)
Same procedure as for compound 25: from compound 4 (0.7643
g, 1.61 mmol), giving 26 in 74.47% yield (0.487 g). Calculated
for C26H40N3O6: [M ϩ H peak] m/z = 490.2917, found:
490.2912; δH(CDCl3, 400 MHz) 7.10 (dd. 1H, J1 = 7.52, J2 = 1.52
Hz, Ar-H ), 6.96 (d, 1H, J = 8.04 Hz, Ar-H ), 6.91 (t, 1H, J =
7.52 Hz, Ar-H ), 6.85 (t, 1H, J = 7.54 Hz, Ar-H ), 6.80 (d, 1H, J
= 7.54 Hz, Ar-H ), 6.20 (m, 2H, Ar-H ), 3.96 (br s 2H, N-H),
3.77 (s, 3H, OCH3), 3.72 (s, 3H, OCH3), 3.54 (t, 4H, J = 5.04 Hz,
OCH2CH2O), 3.50 (m, 16H, OCH2CH2O), 3.35 (t, 4H, J = 6.04
Hz, OCH2CH2O); δC(CDCl3, 100 MHz); 154.82, 152.89,
143.03, 139.06, 130.08, 124.40, 122.27, 121.32, 120.49, 111.63,
106.56, 99.98, 70.27, 70.23, 69.71, 69.26, 55.15, 55.04, 53.28,
52.47; MS (MeCN, ESϩ) m/z expected: 489.61, found: 490.16
(M ϩ H); IR νmax/cmϪ1 3463, 3341, 3208, 2932, 2870, 1620,
1509, 1463, 1349, 1249, 1213, 1174, 1139, 1116, 1032, 992, 927,
874, 819, 751, 635, 613, 548, 477.
2-[(2-Hydroxyethyl)(2-methoxy-4-nitrophenyl)amino]ethanol
(20)
Isolated in 59% yield as
a yellow oil. Calculated for
C11H17N2O5: [M ϩ H peak] m/z = 257.1137, found: 257.1137;
δH(CDCl3, 400 MHz) 7.82 (dd, 1H, J1 = 9.04, J2 = 2.52 Hz,
Ar-H ), 7.71 (d, 1H, J = 2.52 Hz, Ar-H ), 7.0 (d, 1H, J = 8.52 Hz,
Ar-H ), 3.93 (s, 3H, OCH3), 3.77 (t, 4H, J = 5.04 Hz, CH2), 3.56
(t, 4H, J = 5.0 Hz, CH2), 2.96 (br s, 2H, OH); δC(CDCl3, 100
MHz) 150.84, 145.42, 141.07, 117.98, 117.82, 107.39, 60.43,
55.94, 55.15; MS (MeCN, ESϩ) m/z expected: 256.2, found:
257.1 (M ϩ H); IR νmax/cmϪ1 3387, 2957, 2928, 2873, 1584,
1509, 1321, 1274, 1241, 1093, 1068, 1024, 799, 745.
Dibutyl(2-methoxy-4-nitrophenyl)amine (21)
13-(2-Methoxy-4-aminophenyl)-1,4,7,10-tetraoxa-13-azacyclo-
pentadecane (28)
Isolated in 55% yield as
a yellow oil. Calculated for
C15H25N2O3: [M ϩ H peak] m/z = 281.1865, found: 281.1879;
δH(CDCl3, 400 MHz) 7.82 (dd, 1H, J1 = 9.04, J2 = 2.0 Hz,
Ar-H ), 7.68 (d, 1H, J = 2.52 Hz, Ar-H ), 6.72 (d, 1H, J = 9.04
Hz, Ar-H ), 3.89 (s, 3H, OCH3), 3.32 (t, 4H, J = 7.52 Hz, CH2),
1.54 (m, 4H, CH2), 1.30 (quartet, 4H, J = 7.04 Hz, CH2), 0.92
(t, 6H, J = 7.52 Hz, CH3); δC(CDCl3, 100 MHz) 149.93, 146.51,
139.31, 118.31, 115.72, 107.37, 55.81, 55.24, 29.86, 20.28, 13.88;
MS (MeCN, ESϩ) m/z expected: 280.3, found: 281.3 (M ϩ H);
IR νmax/cmϪ1 2958, 2930, 2871, 1585, 1509, 1465, 1323, 1285,
1241, 1099, 1029, 932, 864, 801, 746.
Same procedure as for 25, using 18 (3.052 g, 7.36 mmol).
Isolated as a coloured oil that was purified by column chroma-
tography through alumina using DCM to yield 28 (1.923 g,
67.85%) as a purple resin. Calculated for C19H33N2O6: [M ϩ H
peak] m/z = 385.2339, found: 385.2349; δH(CDCl3, 400 MHz)
7.28 (s, 2H, N-H), 6.73 (d, 1H, J = 8.52 Hz, Ar-H ), 6.33 (s, 1H,
Ar-H ), 6.19 (d, 1H, J = 8.04 Hz, Ar-H ), 3.56 (s, 3H, OCH3),
3.41 (s, 8H, OCH2CH2), 3.36 (br s, 4H, OCH2CH2), 3.21 (br s,
4H, OCH2CH2), 3.10 (br s, 4H, OCH2CH2), 2.92 (br s, 4H,
J. Chem. Soc., Perkin Trans. 1, 2002, 1954–1962
1961

View Article Online
6 A. P. de Silva, H. Q. N. Gunaratne and C. P. McCoy, Nature, 1993,
364, 42; A. P. de Silva and N. D. McClenaghan, J. Am. Chem. Soc.,
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7 F. A. Raymo, Adv. Mater., 2002, 14, 401; F. A. Raymo and
S. Giordani, J. Am. Chem. Soc., 2002, 124, 2004.
OCH2CH2); δC(CDCl3, 100 MHz) 155.25, 127.50, 125.40,
124.02, 108.67, 99.84, 69.23, 69.06, 69.02, 68.74, 66.76, 55.14,
55.02; MS (MeCN, ESϩ) m/z expected: 384.8, found: 385.12
(M ϩ H), 407.1 (M ϩ Na); IR νmax/cmϪ1 3427, 2897, 1610, 1513,
1468, 1350, 1285, 1258, 1215, 1106, 1029, 956, 834, 602.
8 J. V. Mello and N. S. Finney, Angew. Chem., Int. Ed., 2001, 40, 1536;
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16-(2-Methoxy-4-aminophenyl)-1,4,7,10,13-pentaoxa-16-aza-
cyclooctadecane (27)
Same procedure as for 25, using 13 (0.464 g, 1.25 mmol). The
resulting oil was purified by column chromatography through
alumina using DCM to give 27 in 98% yield (0.419 g). Calcu-
lated for C17H29N2O5: [M ϩ H peak] m/z = 341.2076, found:
341.2070; δH(CDCl3, 400 MHz) 7.00 (d, 1H, J = 6.80 Hz,
Ar-H ), 6.30 (s, 1H, Ar-H ), 6.22 (d, 1H, J = 8.28 Hz, Ar-H ),
5.46 (br s 2H, N-H), 3.78 (s, 3H, OCH3), 3.70 (s, 4H,
OCH2CH2), 3.64 (t, 4H, J = 3.28 Hz, OCH2CH2), 3.53 (t, 4H, J
= 4.52 Hz, OCH2CH2), 3.42 (s, 4H, OCH2CH2), 3.26 (s, 4H,
OCH2CH2); δC(CDCl3, 100 MHz) 173.35, 154.78, 145.96,
125.05, 106.85, 98.65, 68.88, 68.80, 68.83, 67.01, 54.95, 54.89;
MS (MeCN, ESϩ) m/z expected: 340.4, found: 340.9 (M ϩ H),
362.9 (M ϩ Na); IR νmax/cmϪ1 3433, 3208, 2917, 2874, 1610,
1513, 1458, 1352, 1294, 1258, 1214, 1122, 1027, 941, 829, 631.
10 U. E. Spichiger-Keller, Chemical Sensors and Biosensors for Medical
and Biological Applications, Wiley-VCH, Weinheim, Germany, 1998.
11 T. Gunnlaugsson, M. Nieuwenhuyzen, L. Richard and V. Thoss,
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12 T. Gunnlaugsson and D. Parker, Chem. Commun., 1998, 511;
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13 A. P. de Silva, H. Q. N. Gunaratne, T. Gunnlaugsson and
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Acknowledgements
This work was supported by the National Pharmaceutical
Biotechnology Center, Bio Research Ireland, Enterprise Ireland
(postgraduate scholarship to JPL), Kinerton Ltd and Trinity
College Dublin. We thank Drs John E. O’Brien, Hazel M.
Moncrieff and Thomas J. McDonald and for their help and
discussions, and Dr Margaret Woods (NPBC, BioResearch
Ireland) and Professor Clive Williams (Biochemistry, TCD) for
their continuous support and help. Finally we would like to
thank Professor A. P. de Silva, Queen’s University Belfast for
his help and support over the years. He has been a great
support, and inspiration to all of us.
16 R. A. Schultz, B. D. White, K. A. Dishong, W. Arnold and
G. W. Gokel, J. Am. Chem. Soc., 1985, 107, 6659.
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18 SAINT-NT, Bruker AXS Madison, Wisconsin, 1998.
19 G. M. Sheldrick, SHELXTL, University of Göttingen, Göttingen,
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J. Am. Chem. Soc., 1998, 120, 5193 and references therein;
A. H. Clemens, P. Helsby, J. H. Ridd, F. Al-Omran and J. J. P.
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J. Chem. Soc., Perkin Trans. 1, 2002, 1954–1962