Conformational control of selectivity and stability in hybrid amide/urea macrocycles

Article abstract of DOI:10.1002/chem.200601647

The anion-binding properties of two similar hybrid amide/urea macrocycles containing either a 2,6-dicarboxamidophenyl or a 2,6-dicarboxamidopyridine group are compared. Significant differences in anion affinity and mode of interaction with anions are attr

Full text of DOI:10.1002/chem.200601647

DOI: 10.1002/chem.200601647
Conformational Control of Selectivity and Stability in Hybrid Amide/Urea
Macrocycles
Simon J. Brooks, Sergio E. García-Garrido, Mark E. Light, Pamela A. Cole, and
Philip A. Gale*[a]
Abstract: The anion-binding properties
of two similar hybrid amide/urea mac-
rocycles containing either a 2,6-dicar-
boxamidophenyl or a 2,6-dicarboxami-
dopyridine group are compared. Signif-
icant differences in anion affinity and
mode of interaction with anions are at-
tributed to the presence of intramolec-
ular hydrogen bonds in the pyridine
system. In fact, remarkably, the phenyl
macrocycle undergoes amide hydrolysis
under neutral conditions in DMSO/
water. The anion binding abilities of
the receptors are compared to those of
acyclic analogues of the macrocycles
that show that the phenyl receptor be-
haves in a similar fashion to acyclic
urea-containing receptors (i.e., showing
little selectivity amongst oxo anions),
whilst the pyridine-containing receptor
shows a high affinity and selectivity for
carboxylates.
Keywords: amides · anion binding ·
macrocycles · ureas
Introduction
gen-bonding motifs present in the macrocyclic systems.
These results suggest dramatic differences in the mode of in-
teraction of anions between the two macrocycles, which we
attribute to the pre-organising influence of the pyridine
group in receptor 1.
Amides[1] and ureas[2] have been widely exploited in the
design of receptors for anions.[3] Hybrid receptors containing
both amides and ureas also been synthesised and in some
cases shown to possess remarkably high anion affinities and
high selectivity.[4] Our recent studies have shown that bis-
ureas based on an ortho-phenylenediamine scaffold are par-
ticularly good receptors for carboxylates.[5] We wished to ex-
plore the use of “ortho-phenylenediamine-like” hydrogen-
bond donor arrays in macrocyclic anion receptors. In 2000,
Reinhoudt and co-workers reported the anion-binding abili-
ty of cyclic and acyclic receptors containing two ortho-phe-
nylenediamine-based bis-urea units.[6] This work showed
that these receptors were selective for dihydrogen phos-
phate in DMSO. In this paper, we report the anion-binding
properties of two hybrid macrocycles containing urea and
amide hydrogen bond donors.[7] We have compared the af-
finity of the macrocyclic receptors with a series of “frag-
ments” 3–6 containing various combinations of the hydro-
Results and Discussion
Macrocycle 1 was synthesised in 11% overall yield from 1,3-
bis(2-aminophenyl)urea[8] (Scheme 1). The starting material
was converted to compound 7 by an amide coupling reac-
tion with 3-nitrobenzoic acid; compound 7 was subsequently
reduced by using hydrazine hydrate/palladium on carbon to
give 1,3-bis(2-aminophenyl)urea (8). The bis-amine was con-
densed with pyridine 2,6-dicarbonylchloride in the presence
of 1.6 equivalents of tetrabutylammonium acetate. The
latter reagent was used to solubilise compound 8 in di-
chloromethane and also function as a potential template for
the formation of 1. The macrocycle was purified by column
chromatography on silica gel (60 Š) eluting with 92:8
CH2Cl2/MeOH followed by trituration in boiling ethylace-
tate.
Attempts to prepare macrocycle 2 using this methodology
failed. Fortunately, an alternative route to obtain this recep-
tor was found by the reaction of 8 with 1.1 equivalents of
isophthaloyl dichloride in methanol and in the presence of
2.2 equivalents of concentrated sulfuric acid (Scheme 1).
The macrocycle was purified by filtration and trituration in
[a] Dr. S. J. Brooks, Dr. S. E. García-Garrido, Dr. M. E. Light, P. A. Cole,
Dr. P. A. Gale
School of Chemistry, University of Southampton
Southampton, SO17 1BJ (United Kingdom)
Fax : (+44)23-8059-6805
E-mail: philip.gale@soton.ac.uk
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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FULL PAPER
tion techniques (Table 1). The titration curves were fitted to
1:1 binding models (as confirmed by Job plot[9] analysis in
the case of benzoate and acetate) using the EQNMR com-
puter program.[10] The stability constant data shows that the
Table 1. Stability constants of compound 1 with a variety of anionic
guests added as tetrabutylammonium salts as determined by 1H NMR ti-
tration techniques performed in [D6]DMSO/0.5% water and [D6]DMSO/
5% water at 298 K following NH (or CH)[a] resonances in the recep-
tors.[b]
Stability constants [mÀ1
]
[D6]DMSO/
0.5% water
[D6]DMSO/
5% water
ClÀ
2
1944
10
BrÀ
–
–
51
À
HSO4
H2PO4
NO3
CH3CO2
115
142[a]
<10
À
À
–
À
16500[c]
6430
5170
1830
À
C6H5CO2
selectivity
a(CH3CO2À)/Ka
À
K
A
A
)
116
101
[a] Due to NH broadening titration was conducted by following the shift
of an ArH proton. [b] Errors estimated to be <15%. [c] This value is
greater than 104 mÀ1. As such the stability constant is at the upper limit
that can be determined by this technique and should be treated with cau-
tion.
macrocycle possesses a particularly high affinity for carbox-
A
water, followed by several washes with a mixture of meth-
anol/dichloromethane (1:1).
The stability constants of macrocycle 1 with a variety of
100 more strongly than dihydrogen phosphate both in
[D6]DMSO/0.5% water and in [D6]DMSO/5% water solu-
tion.
ACHTREUNG
1
putative anionic guests were elucidated using H NMR titra-
Figure 1 shows the shift of each NH group present in the
macrocycle 1 upon addition of one equivalent of a variety of
anions. The molecule contains a C2 axis of symmetry that
simplifies the 1H NMR spectrum of the macrocycle, such
that there are three NH resonances in the NMR spectrum.
Proton NMR spectra of compound 1 in [D6]DMSO/0.5%
water in the absence (top) and presence (bottom) of
1.0 equivalents of tetrabutylammonium acetate are shown in
Figure 2. The spectra show that the urea and 2,6-dicarbox-
amidopyridine NH groups shift significantly downfield upon
addition of acetate, but that the amide groups adjacent to
the urea are hardly influenced by the presence of the oxo
anion.
Similarly Figure 3 shows the shifts of each NH group pres-
ent in the macrocycle upon addition of aliquots of benzoate.
The “linking” amide groups adjacent to the urea (Figure 1)
appear to only interact very weakly with the carboxylate
guests (if at all) as judged by the negligible shift of these
protons. The 1:1 stoichiometry of carboxylate binding was
confirmed by Job plot analysis. This leads us to propose the
binding mode shown in Figure 3 for the interaction of the
macrocycle with carboxylates in which one carboxylate
oxygen atom binds to the two urea NH groups and the
other binds to the 2,6-dicarboxamidopyridine NH groups
leaving the amide NH groups next to the urea free. In con-
trast to these results, addition of one equivalent of dihydro-
Scheme 1. The synthesis of macrocycles 1 and 2. i) 3-nitrobenzoic acid,
PyBOP, Et3N, HOBt, DMF (anhydrous); ii) NH2NH2.H2O, Pd/C 10%
cat., EtOH; iii) 2,6-pyridine dicarbonylchloride, tetrabutylammonium
acetate, Et3N, DMAP, CH2Cl2; iv) isophthaloyl dichloride, H2SO4,
MeOH.
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P. A. Gale et al.
urea NH groups, with the up-
field shift of the pyridine
amides caused presumably by
either a desolvation effect as
DMSO is displaced from the
cavity by the anion or a confor-
mational change in the recep-
tor.
As previously reported[7]
crystals of compound 1 were
obtained by slow evaporation
of a methanol solution of the
macrocycle in the presence of
excess tetramethylammonium
salt. The crystal structure
shown in Figure 4reveals the
acetate anion bound to the
pyridine amide NH groups
À
À
(N4 O7 2.975(5) Š; N6 O7
3.321(5) Š) and, in contrast to
the solution binding evidence,
to one linking amide NH
Figure 1. Shifts of the NH proton resonances in compound 1 in the presence of one equivalent of tetrabutyl-
ammonium anion salt in [D6]DMSO/0.5% water. Downfield shifts are shown as positive numbers and upfield
shifts as negative numbers. The most significant downfield shifts are circled.
A
À
group (N7 O6 2.804(5) Š).
Figure 3. Shift of the NH protons in compound 1 upon addition of ben-
zoate. The amide protons adjacent to the urea group do not shift signifi-
cantly, whilst the 2,6-dicarboxamidopyridine NH groups and the urea NH
groups shift downfield by d=0.63 and 1.41 ppm, respectively, upon addi-
tion of excess tetrabutylammonium benzoate. A potential binding mode
of benzoate to the macrocycle is shown on the left.
Figure 2. Downfield shifts of the NH proton resonances of compound 1
in the presence of 1.0 equivalents of tetrabutylammonium acetate in
[D6]DMSO/0.5% water.
The crystals contain water of crystallisation and it is impor-
tant to note that one of the water molecules is bound to the
À
two urea NH groups within the macrocyclic cavity (N1 O8
À
gen phosphate causes a significant downfield shift of only
the amide groups adjacent to the pyridine ring. The other
NH groups in the macrocycle shift downfield by only ap-
proximately 0.1 ppm (see Figure 1). These results suggest
that the predominant interaction in solution in this case is
between the two convergent NH groups and presumably a
single atom in the anion. Consequently the anion is bound
considerably less strongly than the carboxylate guests. On
the other hand addition of chloride causes a significant
downfield shift of the urea NH groups and an upfield shift
of the pyridine amide groups (Figure 1). These results lead
us to suggest that this anion is bound predominantly by the
2.983(6) Š; N2 O8 2.857(6) Š). Additionally a hydrogen
bond is formed between this water and the bound acetate
(O7 O8 2.668(6) Š). Thus O6 could be regarded as having
been “displaced” from the urea NH groups by the bound
water molecule. Thus, despite acetate being capable of bind-
ing in this mode to a linking amide group, it appears not to
do so in solution.
The stability constants of macrocycle 2 with a variety of
putative anionic guests were also elucidated using H NMR
titration techniques (Table 2). The titration curves were
fitted to 1:1 binding models using the EQNMR computer
program.[10] In contrast with the results obtained for macro-
À
1
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Hybrid Macrocycles
FULL PAPER
Table 2. Stability constants of compound 2 with a variety of anionic
guests added as tetrabutylammonium salts as determined by 1H NMR ti-
tration techniques performed in [D6]DMSO/0.5% water at 298 K follow-
ing NH (or CH)[a] resonances in the receptors.[b]
Stability constants [mÀ1
]
[D6]DMSO/0.5% water
ClÀ
12
<10
<10
609[a]
<10
938
BrÀ
À
HSO4
H2PO4
NO3
CH3CO2
À
À
À
À
C6H5CO2
selectivity
Ka
(CH3CO2À)/Ka
321
À
G
A
)
1.54
[a] Due to NH broadening titration was conducted by following the shift
of an ArH proton. [b] Errors estimated to be < 15%.
to the amide groups adjacent to the urea are greater than
that observed for macrocycle 1.
On the other hand addition of one equivalent of dihydro-
gen phosphate to macrocycle 2 causes a significant down-
field shift of the urea NH groups, as well as a moderate
downfield shift of the protons of the amide groups adjacent
to the urea. The other NH groups in the macrocycle only
shift downfield by approximately 0.1 ppm. These results sug-
gest that the predominant interaction in solution in this case
is between the two urea NH groups and the anion, whether
carboxylates or dihydrogen phosphate, together with a small
contribution of the amide groups adjacent to the urea. In all
the cases, the 2,6-dicarboxamidophenyl NH groups do not
appear to interact with the anionic guests to a significant
extent. The addition of one equivalent of chloride to this
Figure 4. The X-ray crystal structure of the hydrated tetramethylammoni-
um acetate complex of macrocycle 1. Counterion, non-acidic hydrogen
atoms and non-cavity bound water are omitted for clarity.
cycle 1 its counterpart 2, which contains the 2,6-dicarbox-
A
with a significant difference between their stability constants
of more than one order of magnitude (see Table 1 versus
Table 2). Moreover, the affinity of macrocycle 2 for dihydro-
gen phosphate increases re-
garding its analogous 1 from
142 to 609mÀ1 (see Tables 1
and 2). As a consequence com-
pound 2 has a much lower se-
lectivity for carboxylates than
macrocycle 1.
Figure 5 shows the shifts of
each NH group present in
macrocycle 2 upon addition of
one equivalent of a variety of
anions. As in the case of com-
pound 1, the urea NH group
resonance shifts downfield sig-
nificantly upon addition of ace-
tate and benzoate. In contrast
to what was observed with
macrocycle 1, the 2,6-dicarbox-
amidophenyl
NH
groups
appear to interact very weakly
with the carboxylate guests as
judged by the small shifts of
these protons (see Figure 1
versus Figure 5). Moreover, the
shifts of the protons belonging
Figure 5. Shifts of the NH proton resonances in compound 2 in the presence of one equivalent of tetrabutyl-
ammonium anion salt in [D6]DMSO/0.5% water. The most significant downfield shifts are circled.
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P. A. Gale et al.
macrocycle does not cause any significant change in the
chemical shifts of the receptor NH groups (Figure 5), (Ka =
12mÀ1; see Table 2).
the presence of 5.0 equivalents of tetrabutylammonium ace-
tate, the rate of decomposition was slowed significantly
(Figure 7). In this case, no changes were observed in the
spectra during the first 6 h, and only after 24h is possible to
detect a small amount of the decomposition product (signals
We observed that macrocycle 2 was not stable in solution
([D6]DMSO/0.5% water) over moderate periods of time.
1
Figure 6 shows the H NMR spectra of a 1.0 mm solution of
Figure 7. Decomposition of
a solution of receptor 2 (1.0 mm) in
Figure 6. Decomposition of
[D6]DMSO/0.5% water at 258C as shown by H NMR spectroscopy. The
marked resonance corresponds to free NH2 shown in structure of 9.
a solution of receptor 2 (1.0 mm) in
[D6]DMSO/0.5% water at 258C as shown by 1H NMR spectroscopy in
the presence of 5.0 equivalents of tetrabutylammonium acetate. Decom-
position is slower than in the absence of tetrabutylammonium acetate.
The marked resonance corresponds to free NH2 shown in structure of 9.
1
macrocycle 2 in [D6]DMSO/0.5% water over the course of
24h. As can be observed after only 2 h in solution, new res-
onances appear (including a resonance at about d=5.3 ppm
corresponding to a free NH2 group). Over time these signals
become more intense and correspond predominantly to hy-
drolysis product 9.[11] It has been shown that twisted amide
at ca. d=10.1, 6.7 and 5.3 ppm). The presence of the anion
appears to increase the stability of macrocycle 2, presumably
due to complex formation conferring extra stability on the
macrocyclic framework.
We then synthesised a series of acyclic fragments 3–6 and
the diphenylurea 10[13] to investigate the interaction between
the NH groups and anions in the acyclic fragments as com-
pared the macrocycles. The syntheses of the fragments are
discussed in the Experimental Section below. The crystal
structure of compound 4 is discussed in the Supporting In-
formation. Compounds 3 and 4 were synthesised as ana-
logues for parts of the macrocycles containing the urea
group. The stability constants with oxo anions show that the
addition of an extra amide group in compound 4 as com-
pared to compound 3 has a small but positive effect on the
stability of the complex formed (Table 3). N,N’-Diphenyl-
groups are susceptible to hydrolysis under neutral condi-
tions[12] leading us to suggest that in solution the hydrolysis-
prone amide groups are significantly twisted. The smaller
shifts of these groups in compound 2 than in the analogous
groups in compound 1 upon addition of carboxylates sug-
gests that the amides are not as predisposed to form a con-
vergent hydrogen-bonding array. Presumably in compound 1
the involvement of the pyridine group in the formation of
intramolecular hydrogen bonds with the amide groups in
the 2- and 6-positions of the ring acts to stabilise a more
linear arrangement of these groups than is possible in com-
pound 2, thus leaving compound 2 more prone to hydrolysis.
When the same experiment was repeated with a 1.0 mm
solution of the macrocycle 2 in [D6]DMSO/0.5% water in
urea 10[13] was also studied under these conditions and
shows a similar affinity for benzoate but a significantly
lower affinity for acetate and dihydrogen phosphate than
compounds 3 or 4 (see Table 3).
This evidence leads us to suggest that the amide NH
groups have a less significant interaction with oxo anions as
compared to the urea. The less significant participation of
the amide NH groups is also illustrated by plotting the
change in chemical shift of the NH groups in the compound
with increasing anion concentration. This is illustrated in
Figure 8, which shows the shifts of the NH groups in com-
pounds 3 and 4 upon addition of aliquots of tetrabutylam-
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Hybrid Macrocycles
FULL PAPER
Table 3. Stability constants [mÀ1] of compounds 3–6 and 10 with a variety
of anionic guests added as tetrabutylammonium salts as determined by
1H NMR titration techniques performed in [D6]DMSO/0.5% water at
298 K following NH (or CH)[a] resonances in the receptors.[b]
the hypothesis that the predominant interaction of oxo
anions with compound 2 is through the urea and adjacent
amide groups.
Compounds 5 and 6 have a lower affinity for anions than
the urea-containing receptors 3 and 4, with the pyridine-con-
taining receptor 5 having a slightly higher affinity for anion-
ic guests than receptor 6, presumably due to the preorganis-
ing influence of the pyridine group on the pendant bis-
amides favouring the formation of a cleft conformation
(Table 3). Figure 9 shows the change in chemical shift of the
NH groups in these compounds upon addition of benzoate.
In these cases both the central and terminal amide NH
groups shift downfield upon addition of benzoate and poten-
tial solution binding modes of this anion with the receptors
are shown in Figure 9 (right). The receptors show a very
weak interaction with chloride in solution binding this anion
in a 1:2 receptor:anion stoichiometry (receptor 6; see
Table 3). Interestingly compound 6 is stable in solution
under the conditions that would lead to the decomposition
of compound 2.
3
4
5
6
10
ClÀ
<10
<10
<10
K1 =38
31
K2 =10
BrÀ
HSO4
H2PO4
NO3
CH3CO2
C6H5CO2
–
–
–
–
–
–
681
–
–
–
–
–
À
À
1290
–
2360
606
1.84
1650
–
2470
784101
1.49
294523
–
137
À
–
1261
À
419
À
71
674
À
Ka
A
(H2PO4
)
0.62
0.47
2.41
[a] Due to NH broadening titration was conducted by following the shift
of an ArH proton. [b] Errors estimated to be <15%.
monium benzoate in [D6]DMSO/0.5% water at 298 K show-
ing a much greater downfield shift for the urea NH groups
than for the amide NH group(s). Potential binding modes
for benzoate with compounds 3 and 4 are shown in Figure 8.
The binding mode of carboxylates to compounds 3 and 4 is
different from the binding mode in macrocycle 1 as the evi-
dence leads us to suggest only one of the oxygen atoms in
the carboxylate binds to this unit in the latter system. How-
ever, as the two oxygen atoms in the anion bind as shown in
Figure 8, there is an interaction with the pendant amides re-
sulting in the small downfield shift of these proton resonan-
ces. The receptors show a slightly higher affinity for oxo
anions than macrocycle 2, but with a similar selectivity for
acetate versus dihydrogen phosphate. This finding supports
Crystals of the tetrabutylammonium benzoate complex of
receptor 6 were grown by slow evaporation of a solution of
the receptor in acetonitrile in the presence of excess anion
salt. In contrast to the results obtained in solution, the re-
ceptor forms a 1:2 complex with benzoate (Figure 10). The
central isophthalamide unit adopts a syn–anti conformation
so forming two binding clefts each consisting of one central
amide and one terminal amide group with each NH forming
À
a
single bond to
a
benzoate oxygen atom: N1 O8
À
3.021(4) Š, N2 O7 2.786(4) Š
À
À
and N3 O5 2.923(4) Š, N4
O6 2.880(4) Š. Interestingly
the binding mode of each ben-
zoate to the receptor in the
solid state is similar to the pro-
posed structure of the solution
complex species in that the
anion is bound to both the cen-
tral and terminal amide NH
groups; however, in the solid
state the syn–anti conformation
of the central isophthalamide
presents the two halves of the
proposed solution binding site
to different anionic guests.
Crystals of the tetrabutylam-
monium chloride complex of
receptor 6 were obtained by
slow evaporation of a solution
of the receptor in acetonitrile
in the presence of excess tetra-
butylammonium
chloride
(Figure 11). One molecule of
the receptor crystallises with
three chloride and three coun-
ter tetrabutylammonium ions.
The central isophthalamide
Figure 8. Shifts of the NH protons in compounds 3 (top) and 4 (bottom) showing downfield shifts upon addi-
tion of benzoate. In both cases the shift of the urea protons is greater than the amide NH groups. Potential
binding modes of benzoate to the receptors (that are consistent with the NMR data) are shown on the right.
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P. A. Gale et al.
unit adopts a syn–syn confor-
mation binding a single chlo-
ride anion by means of two
NH···ClÀ
(N2···Cl3
hydrogen
3.3856(4) Š
bonds
and
N3···Cl3 3.289(4) Š). The other
chloride bound to the receptor
bridges between terminal NH
groups in adjacent receptors
(N1···Cl1
3.325(4) Š
and
N4···Cl1 3.412(4) Š). Another
chloride anion in the structure
forms a hydrated ion pair with
a tetrabutylammonium cation
and does not interact with the
receptor.
Conclusion
Macrocycle 1 forms stable hy-
drogen-bonded complexes with
carboxylate anions and dis-
plays a 100-fold selectivity for
Figure 9. Shifts of the NH protons in compounds 5 (top) and 6 (bottom) showing downfield shifts upon addi-
tion of benzoate. Potential binding modes of benzoate to the receptors (that are consistent with the NMR
data) are shown on the right. In both cases the downfield shift of the central amide groups is higher than that
of the terminal NH groups.
acetate versus
dihydrogen
phosphate in [D6]DMSO/0.5%
or 5% water. In contrast, mac-
rocycle 2 shows a lower affinity
and selectivity for carboxylates than 1 and in addition is un-
stable in [D6]DMSO/water. We believe the difference in sta-
bility is due to the absence of the pre-organising influence
of the pyridine group in compound 1 resulting in a twisted
conformation of the isophthalamide group in compound 2
and consequently a higher propensity for amide hydrolysis
under neutral conditions.[12] Whilst no X-ray structural data
for this unstable compound has been obtained, anion-bind-
ing studies show significant differences in the mode of inter-
action of oxo anions with compounds 1 and 2, data that sup-
ports the hypothesis of a distorted 2,6-dicarboxyamidophen-
yl group in macrocycle 2. The more flexible acyclic receptors
3–6 form significantly less stable complexes with anions
than macrocycle 1 and, like macrocycle 2, do not display sig-
nificant selectivity amongst oxo-anionic guests. These results
show that a single change in a macrocyclic framework can
result not only in significantly improved anion selectivity,
but also in improved stability with macrocycle 1 showing ex-
cellent selectivity for carboxylates under partially aqueous
conditions. We are continuing to explore the complexation
properties of this new family of macrocyclic anion receptors.
Figure 10. The X-ray crystal structure of the tetrabutylammonium ben-
zoate complex of receptor 6. Non-acidic hydrogen atoms and tetrabutyl-
A
Experimental Section
Figure 11. The X-ray crystal structure of the tetrabutylammonium chlo-
ride complex of receptor 6. Non-acidic hydrogen atoms, tetrabuylammo-
nium counter cations, non-bound chloride and water have been omitted
for clarity.
General remarks: All reactions were performed in oven-dried glassware
under a slight positive pressure of nitrogen. 1H NMR (300 or 400 MHz)
and 13C NMR (75 or 100 MHz) spectra were determined on a Bruker
AV300 or Bruker DPX 400 spectrometer, respectively. Chemical shifts
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Hybrid Macrocycles
FULL PAPER
for 1H NMR spectra are reported in parts per million, calibrated to the
residual solvent peak set, with coupling constants reported in Hertz (Hz).
The following abbreviations are used for spin multiplicity: s=singlet, d=
doublet, t=triplet, q=quartet, m=multiplet and br=broad. Chemical
shifts for 13C NMR are reported in ppm, relative to the central line of a
septet at d=39.52 ppm for deuterio-dimethylsulfoxide. Infrared (IR)
spectra were recorded on a Mattson Satellite (ATR) FTIR and are re-
ported in wavenumbers (cmÀ1). Melting points were measured on a Gal-
lenkamp melting point apparatus.
(0.82 g, 2.5 mmol, 97.0%). M.p.=1988C; 1H NMR (300 MHz,
[D6]DMSO): d=9.21 (s, 1H; NH), 8.08 (s, 1H; NH), 8.04(d, J=1.4Hz,
2H; ArH), 8.01 (s, 1H; NH), 7.57 ppm (m, 3H; ArH); 13C{1H} NMR
(75 MHz, [D6]DMSO): d=165.8 (CO), 152.9 (CO), 139.7 (C), 134.5 (C),
134.1 (C), 131.7 (CH), 128.8 (CH), 128.4 (CH), 128.1 (C), 127.8 (CH),
127.3 (CH), 126.3 (CH), 122.7 (CH), 122.1 (CH), 121.8 (CH), 118.2 ppm
(CH); IR (film): n˜ =3350, 3200, 3143, 3044, 2995, 1638, 1565, 1478, 1438,
1322, 1226, 748 cmÀ1; LRMS (ESÀ): m/z: 444.0 [M+TFAÀH]À, 775.1
[2M+TFAÀH]À;
elemental
analysis
calcd
(%)
for
C20H17N3O2·0.05CH2Cl2: C 71.75, H 5.14, N 12.52; found: C 71.99, H
5.17, N 12.57.
Macrocycle 1: An oven-dried 1 L three-necked round-bottomed flask was
filled with dry dichloromethane (500 mL) to which triethylamine
(0.49 mL, 3.43 mmol) and a catalytic quantity 4-dimethylaminopyridine
(0.01 g) was added. Two additional solutions were prepared, the first of 8
(1.50 g, 3.12 mmol) and tetrabutylammonium acetate (1.50 g, 4.97 mmol)
in dry dichloromethane (50 mL), the second of 2,6-pyridinedicarbonyl
chloride (0.64g, 3.12 mmol) in dry dichloromethane (50 mL), with both
solutions were introduced into the reaction vessel by using a motor-
driven syringe pump over a period of 6 h. After the addition the reaction
was left stirring at ambient temperature for a further 72 h, before the
volume of solvent was reduced by approximately 75% and reaction was
extracted with water (3”200 mL). The retained organic phase was dried
with MgSO4 before removal of solvent under rotary evaporator. The
light grey residue was dissolved in a small volume of 92:8 dichloro-
1,3-Bis-(2-benzanilidephenyl)urea (4):[14] A solution of 1,3-bis-(2-amino-
phenyl)urea (0.35 g, 1.5 mmol), triethylamine (0.43 mL, 3.1 mmol) and
DMAP (0.002 g, cat.) in dry dichloromethane (30 mL) was stirred for
15 minutes in an oven-dried 100 mL three-necked round-bottomed flask.
After this benzoyl chloride (0.34mL, 2.9 mmol) was added to the reac-
tion in a dropwise manner with the reaction then left stirring for 18 h,
after which solvent was removed by a rotary evaporator. The crude prod-
uct was purified by flash column chromatography using dichloromethane/
methanol 95:5 as eluent. The white product obtained was further purified
by recrystalisation from hot ethanol which yielded compound 4 as a
white powder (0.39 g, 0.87 mmol, 49%). M.p.=1948C; 1H NMR
(300 MHz, [D6]DMSO): d=10.00 (s, 2H; NH), 8.61 (s, 2H; NH), 7.99
(m, 4H; ArH), 7.75 (dd, J=7.9, 1.1 Hz, 2H; ArH), 7.50 (m, 8H; ArH),
7.22 (td, J=7.5, 1.5 Hz, 2H; ArH), 7.11 ppm (td, J=7.6, 1.5 Hz, 2H;
ArH); 13C{1H} NMR (75 MHz, [D6]DMSO): d=165.6 (CO), 153.7 (CO),
134.3 (C), 133.5 (C), 131.6 (CH), 129.0 (C), 128.4 (CH), 127.7 (CH),
126.8 (CH), 126.0 (CH), 123.3 (CH), 122.9 ppm (CH); IR (film): n˜ =
A
The white solid was further purified from hot ethyl acetate to give 1 as a
white powder (0.32 g, 0.52 mmol, 17%). M.p.=2358C; 1H NMR
(300 MHz, [D6]DMSO): d=11.26 (s, 2H; amide NH), 9.99 (s, 2H; amide
NH), 8.54(d, J=8.3 Hz, 2H; ArH), 8.50 (s, 2H; urea NH), 8.43–8.32 (m,
3H; ArH), 8.16 (s, 2H; ArH), 7.97 (d, J=8.3 Hz, 2H; ArH), 7.72 (d, J=
8.3 Hz, 2H; ArH), 7.60 (t, J=7.9 Hz, 2H; ArH), 7.31–7.21 (m, 4H;
ArH), 7.07 ppm (t, J=7.5 Hz, 2H; ArH); 13C{1H} NMR (75 MHz,
[D6]DMSO): d=166.9 (CO), 161.6 (CO), 153.2 (CO), 148.5 (C), 140.4
(CH), 138.0 (C), 136.0 (C), 134.9 (C), 129.1 (CH), 128.3 (C), 127.3 (CH),
126.5 (CH), 125.2 (CH), 123.4(CH), 122.9 (CH), 122.8 (CH), 120.8 ppm
3239, 3058, 3027, 1704, 1638, 1593, 1514, 1472, 1437, 1296, 1261 cmÀ1
;
LRMS (ESÀ): m/z: 562.9 [M+TFAÀH]À, 934.9 [2M+Cl]À, 1386.2
[3M+Cl]À; elemental analysis calcd (%) for C27H22N4O3: C 71.99, H 4.92,
N 12.44; found: C 71.75, H 4.87, N 12.36.
Pyridine-2,6-dicarboxylic acid bis-[(3-phenylcarbamoylphenyl)amide)]
(5): In an oven-dried 250 mL three-necked round-bottomed flask, a stir-
ring solution of 3-aminobenzanilide (0.48 g, 2.26 mmol), triethylamine
(0.35 mL, 2.49 mmol) and DMAP (0.004 g, cat.) in dry dichloromethane
(50 mL) was left for 15 minutes before adding 2,6-pyridinedicarbonyl
chloride (0.23 g, 1.13 mmol). The reaction was left stirring at ambient
temperature for 18 h, after which the resulting white precipitated product
was removed by filtration was washed with dichloromethane and water
with 5 isolated as a white solid (0.32 g, 5.80 mmol, 52%). M.p.>3008C;
1H NMR (300 MHz, [D6]DMSO): d=11.25 (s, 2H; NH), 10.34(s, 2H;
NH), 8.47 (m, 2H; ArH), 8.45 (s, 2H; ArH), 8.34 (dd, J=8.7, 6.8 Hz,
1H; ArH), 8.19 (m, 1H; ArH), 8.16 (m, 1H; ArH), 7.80 (m, 6H; ArH),
7.62 (t, J=7.9 Hz, 2H; ArH), 7.37 (m, 4H; ArH), 7.12 ppm (m, 2H;
ArH); 13C{1H} NMR (75 MHz, [D6]DMSO): d=165.4(CO), 162.0 (CO),
148.7 (C), 140.1 (CH), 139.1 (C), 138.3 (C), 135.8 (C), 128.9 (CH), 128.6
(CH), 125.6 (CH), 124.2 (CH), 123.8 (CH), 123.4 (CH), 120.7 (CH),
120.5 ppm (CH); IR (film): n˜ =3235, 3135, 3058, 1646, 2584, 1528, 1422,
1324, 1237, 1142, 1079, 998, 902 cmÀ1; LRMS (ES+): 578.1 [M+Na]+,
1133.4[2 M+Na]+, 1163.7 [2M+MeOH+Na]+; elemental analysis calcd
(%) for C33H25N5O4·0.25MeOH: C 70.86, H 4.65, N 12.43; found: C
70.72, H 4.43, N 12.50.
(CH); IR (film): n˜ =3245, 3056, 1656, 1597, 1530, 1441, 1305, 747 cmÀ1
;
LRMS (ESÀ): m/z: 646.3 [M+Cl]À, 724.4 [M+TFAÀH]À; elemental
analysis calcd (%) for C34H25N7O5·0.50CH2Cl2: C 63.35, H 4.01, N 14.99;
found: C 63.19, H 4.17, N 14.96.
Macrocycle 2: An oven-dried 500 mL three-necked round-bottomed flask
was filled with 8 (1.50 g, 3.12 mmol) and isophthaloyl dichloride (0.70 g,
3.45 mmol) in anhydrous methanol (350 mL) to form a suspension when
stirred. Concentrated sulfuric acid (0.375 mL, 6.870 mmol) was added to
this stirred suspension. Following this addition the reaction was then
heated to reflux under nitrogen for 30 minutes, after which the mixture
was evaporated under low pressure. The resulting residue was then resus-
pended in water (100 mL) and filtered to afford a white solid that was
washed with water (3”10 mL) and diethyl ether (3”10 mL). The white
solid was triturated in MeOH/CH2Cl2 (1:1) to give 2 as a white powder
(0.53 g, 0.87 mmol, 28%). M.p.=2248C; 1H NMR (300 MHz,
[D6]DMSO): d=10.61 (s, 2H; amide NH), 10.05 (s, 2H; amide NH), 8.64
(s, 2H; urea NH), 8.58 (d, J=9.4Hz, 2H; ArH), 8.39 (s, 1H; ArH), 8.18
(d, J=8.1 Hz, 2H; ArH), 8.05 (d, J=8.1 Hz, 2H; ArH), 7.78–7.69 (m,
5H; ArH), 7.49 (m, 4H; ArH), 7.13 ppm (m, 4H; ArH); 13C{1H} NMR
(75 MHz, [D6]DMSO): d=165.3 (CO), 165.1 (CO), 153.9 (CO), 139.3
(C), 134.9 (C), 134.8 (C), 133.2 (C), 130.8 (CH), 129.3 (C), 128.7 (CH),
128.6 (CH), 127.1 (CH), 126.7 (CH), 125.9 (CH), 123.6 (CH), 123.5
(CH), 123.0 (CH), 122.6 (CH), 120.2 ppm (CH); IR (film): n˜ =3260,
1651, 1592, 1530, 1483, 1451, 1303, 1254, 751 cmÀ1; LRMS (ESÀ): m/z:
645.0 [M+Cl]À, 721.1 [M+TFAÀH]À; elemental analysis calcd (%) for
C35H26N6O5·CH2Cl2: C 62.17, H 4.06, N 12.08; found: C 62.39, H 4.27, N
12.06.
N,N’-Bis-(3-phenylcarbamoylphenyl)isophthalamide (6): A solution of 3-
aminobenzanilide (1.00 g, 4.7 mmol), triethylamine (0.72 mL, 5.2 mmol),
DMAP (0.003 g, cat.) in dry dichloromethane (30 mL) was placed in an
oven-dried 100 mL three-necked flask. The solution was then stirred for
30 minutes before slow portion wise addition of isophthaloyl dichloride
(0.48 g, 2.3 mmol). Following the addition the reaction was left stirring
for 16 h before precipitated white product was removed by filtration and
subsequently washed with dichloromethane (2”10 mL) followed by
water (2”10 mL). The precipitate was dried under high vacuum; howev-
er, 1H NMR analysis revealed approximately 10% of mono-substituted
isophthalic acid side product. The crude product was further purified by
suspending in acidic MeOH (100 mL) and refluxing for 18 h. After this
time reaction suspension was filtered hot and washed with MeOH (2”
20 mL). Compound 6 was obtained as a white solid (0.65 g, 1.17 mmol,
54%). M.p. >3008C; 1H NMR (300 MHz, [D6]DMSO): d=10.63 (s, 2H;
N-[2-(3-Phenylureido)phenyl]benzamide (3): N-(2-aminophenyl)benza-
mide (0.54g, 2.5 mmol) dissolved in dry dichloromethane (40 mL) was
placed into an oven-dried 100 mL three-necked round-bottomed flask
and phenyl isocyanate (0.28 mL, 2.5 mmol) was then added dropwise.
The reaction was left stirring for 16 h, after which time the resulting
white precipitate was removed by filtration and washed with dichloro-
A
Chem. Eur. J. 2007, 13, 3320 – 3329
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3327

P. A. Gale et al.
NH), 10.28 (s, 2H; NH), 8.33 (t, J=1.8 Hz, 2H; ArH), 8.21 (dd, J=8.0,
1.8 Hz, 2H; ArH), 8.07 (m, 2H; ArH), 7.78 (m, 4H; ArH), 7.72 (m, 3H;
ArH), 7.54(t, J=7.7 Hz, 2H; ArH), 7.36 (m, 4H; ArH), 7.10 ppm (m,
2H; ArH); 13C{1H} NMR (75 MHz, [D6]DMSO): d=165.5 (CO), 165.1
(CO), 139.2 (C), 139.1 (C), 135.7 (C), 134.9 (C), 130.8 (CH), 128.7 (CH),
128.6 (CH), 127.1 (CH), 123.7 (CH), 123.3 (CH), 122.7 (CH), 120.4
(CH), 120.0 ppm (CH); IR (film): n˜ =3288, 3061, 1689, 1645, 1534, 1451,
1326, 1253 cmÀ1; LRMS (ES+): 555.0 [M+H]+; elemental analysis calcd
(%) for C34H26N4O4: C 73.19, H 4.65, N 10.35; found: C 73.24, H 4.68, N
9.97.
SADABS.[17] The structures were solved by direct methods[18] and refined
by full-matrix least-squares methods on F2. Non-hydrogen atoms were re-
fined anisotropically and hydrogen atoms were treated using a riding
model.
Crystal data for 6(TBAbenzoate)
: C80H108N6O8, Mr =1281.72, T=
2
120(2) K, monoclinic, space group P21/n, a=8.5260(2), b=20.8328(11),
c=41.390(2) Š, b=94.690(3)8, V=7327.1(6) Š3, 1calcd =1.162 gcmÀ3, m=
0.075 mmÀ1, Z=4, reflections collected: 41713, independent reflections:
13190 (Rint =0.0973), final
0.2018, R indices (all data): R1=0.1767. wR2=0.2511.
Crystal data for (TBACl) 3·H2O: C82H136N7O5Cl3, Mr =1406.33, T=
120(2) K, orthorhombic, space group P212121, a=8.2548(3), b=
20.2938(9), c=48.724(2) Š, V=8162.3(6) Š3, 1calcd =1.144 gcmÀ3
m=
0.165 mmÀ1, Z=4, reflections collected: 42045, independent reflections:
16936 (Rint =0.1239), final indices [I>2s(I)]: R1=0.0956, wR2=
R indices [I>2s(I)]: R1=0.0845, wR2=
1,3-Bis-(2-(3-nitro)benzanilidephenyl)urea (7): A solution of 3-nitroben-
zoic acid (3.13 g, 18.73 mmol), triethylamine (2.81 mL, 20.60 mmol),
PyBOP (9.75 g, 18.73 mmol) was placed in an oven-dried 100 mL three-
necked round-bottomed flask. HOBt (0.01 g) in anhydrous dimethylfor-
mamide (40 mL) with 1,3-bis-(2-aminophenyl)urea[8] (2.27 g, 9.37 mmol)
was slowly added. Following the addition the reaction was left stirring at
ambient temperature for 72 h, after which the solvent was removed using
reduced pressure distillation to produce a brown solid residue. The resi-
due was resuspended in methanol (50 mL) and filtered to afford a white
solid 7 (3.70 g, 6.84mmol, 73%) that was further washed with diethyl
ether. M.p.=2178C; 1H NMR (300 MHz, [D6]DMSO): d=10.37 (s, 2H;
NH), 8.78 (s, 2H; NH), 8.52 (s, 2H; NH), 8.39 (m, 4H; ArH), 7.84 (dd,
J=8.3, 1.5 Hz, 4H; ArH), 7.75 (t, J=7.9 Hz, 2H; ArH), 7.40 (dd, J=7.5,
1.1 Hz, 2H; ArH), 7.25 (m, 2H; ArH), 7.10 ppm (m, 2H; ArH);
13C{1H} NMR (75 MHz, [D6]DMSO): d=163.6 (CO), 153.3 (CO), 147.7
(C), 135.7 (C), 134.1 (CH), 130.0 (CH), 128.1 (C), 127.1 (CH), 126.5
(CH), 126.1 (CH), 123.1 (CH), 122.6 (CH), 122.4ppm (CH); IR (film):
n˜ =3260, 1651, 1592, 1530, 1483, 1451, 1303, 1254, 751 cmÀ1; LRMS
(ESÀ): m/z: 653.1 [M+TFAÀH]À, 1193.7 [2M+TFAÀH]À, 1733.4
[3M+TFAÀH]À; elemental analysis calcd (%) for C27H20N5O7: C 60.00,
H 3.73, N 15.54; found: C 59.70, H 3.83, N 15.60.
6
ACHTREUNG
,
R
0.1666, R indices (all data): R1=0.2121. wR2=0.2149.
CCDC-609225 and CCDC-609227 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
Acknowledgements
P.A.G. would like to thank the EPSRC for a DTA studentship (S.J.B.)
and for access to the crystallographic facilities at the University of South-
ampton. S.E.G.-G. would like to thank the Ministerio de Educacion y
Ciencia of Spain for the award of a Postdoctoral grant.
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1,3-Bis-(2-(3-amino)benzanilidephenyl)urea (8): A suspension of 1,3-bis-
(2-(3-nitro)benzanilidephenyl)urea (0.50 g, 0.93 mmol) in ethanol
(150 mL) was place in an oven-dried three-necked round-bottomed flask
and the suspension was stirred. Pd/C 10% (0.01 g, cat.) and hydrazine
monohydrate (0.50 mL) were added dropwise to this suspension. The re-
action was then heated to reflux and left stirring for 16 h, after which the
reduced product was removed by filtration. The product was dissolved in
dimethylformamide and filtered to remove Pd/C, after which the solvent
was removed by reduced pressure distillation, resuspended in dichloro-
methane and washed with water to remove remaining dimethylforma-
mide. The white precipitated product 8 was removed by filtration (0.40 g,
0.83 mmol, 89%). M.p.=2378C; 1H NMR (300 MHz, [D6]DMSO): d=
9.79 (s, 2H; amide NH), 8.62 (s, 2H; urea NH), 7.65 (dd, J=7.9, 1.5 Hz,
2H; ArH), 7.49 (dd, J=7.5, 1.5 Hz, 2H; ArH), 7.22–7.09 (m, 10H; ArH),
6.75 (m, 2H; ArH), 5.27 ppm (s, 4H; NH2); 13C{1H} NMR (75 MHz,
[D6]DMSO): d=166.1 (CO), 153.9 (CO), 148.8 (C), 135.1 (C), 132.9 (C),
129.7 (C), 128.8 (CH), 126.4(CH), 125.7 (CH), 123.5 (CH), 123.1 (CH),
116.9 (CH), 114.5 (CH), 113.2 ppm (CH); IR (film): n˜ =3312, 3285, 1641,
1509, 1441, 1308, 1293, 1275, 1233 cmÀ1; LRMS (ESÀ): 515.2 [M+Cl]À,
542.1 [M+2MeOHÀH]À, 559.1 [M+Br]À, 593.3 [M+TFAÀH]À, 995.4
[2M+Cl]À, 1041.4 [2M+Br]À, 1073.6 [2M+TFAÀH]À; elemental analysis
calcd (%) for C27H24N5O3·0.25CH3OH: C 67.00, H 5.16, N 17.20; found:
C 66.80, H 5.11, N 17.06.
1H NMR spectroscopic titrations: A Bruker AV300 NMR spectrometer
1
was used to measure the H NMR shifts of the NH protons of the recep-
tors. Solutions of 1–6 and 10 were titrated with ꢀ10 mm anion salt in a
ꢀ1 mm solution of the compounds in [D6]DMSO/0.5% water or
[D6]DMSO/5% water at 258C. The titration data was plotted Dppm
versus concentration of guest and fitted to a binding model using the
EQNMR computer program.[10]
X-ray structure determinations: Cell dimensions and intensity data were
recorded at 120 K, using a Bruker Nonius KappaCCD area detector dif-
fractometer mounted at the window of a rotating Mo anode (l(MoKa)=
G
0.71073 Š). The crystal-to-detector distance was 30 mm and f and W
scans were carried out to fill the asymmetric unit. Data collection and
processing were carried out using the programs COLLECT,[15] and
DENZO[16] and an empirical absorption correction was applied using
3328
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 3320 – 3329

Hybrid Macrocycles
FULL PAPER
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[7] Aspects of this work have been communicated see: S. J. Brooks,
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[11] The hydrolysis product 9 was also detected in the mixture by mass
spectrometry (LRMS (ESÀ): 626.1 [MÀH]À, 663.3 [M+Cl]À; see
Supporting Information).
[12] The hydrolysis of highly twisted amides promoted by water has
been previously studied using density functional theory in conjunc-
tion with a continuum dielectric method: J. I. Mujika, J. M. Mercero,
X. Lopez, J. Am. Chem. Soc. 2005, 127, 4445–4453.
[13] M. E. Sitzmann, W. H. Gilligan, J. Org. Chem. 1985, 50, 5879–5881.
[14] This compound has been reported previously synthesised by a differ-
ent procedure: W. I. Awad, M. H. Nosseir, N. L. Doss, E. A. Ishak, J.
Prakt. Chem. 1973, 315, 1152–1160.
[15] B. V. Nonius, COLLECT, Data Collection Software, 1998.
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Received: November 16, 2006
Published online: February 16, 2007
Chem. Eur. J. 2007, 13, 3320 – 3329
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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