Tuning the anion binding properties of calixpyrroles by means of p-nitrophenyl substituents at their meso-positions

Article abstract of DOI:10.1016/j.tet.2007.07.060

Extended cavity calix[4]pyrroles and a calix[6]pyrrole were synthesized by cyclization of 5-methyl-5-(4-nitrophenyl)dipyrromethane with acetone in the presence of acid. The solid-state structures of the novel macrocycles were determined by X-ray crystallo

Full text of DOI:10.1016/j.tet.2007.07.060

Tetrahedron 63 (2007) 10003–10010
Tuning the anion binding properties of calixpyrroles by means
of p-nitrophenyl substituents at their meso-positions
ꢀa
Giuseppe Bruno,a Grazia Cafeo,b Franz H. Kohnkeb, and Francesco Nicolo
*
aDipartimento di Chimica Inorganica, Chimica Analitica e Chimica Fisica, Universitaꢀ di Messina,
Salita Sperone 31, 98166 Messina, Italy
bDipartimento di Chimica Organica e Biologica, Universitaꢀ di Messina,
Salita Sperone 31, 98166 Messina, Italy
Received 20 March 2007; revised 5 July 2007; accepted 19 July 2007
Available online 26 July 2007
Abstract—Extended cavity calix[4]pyrroles and a calix[6]pyrrole were synthesized by cyclization of 5-methyl-5-(4-nitrophenyl)dipyrro-
methane with acetone in the presence of acid. The solid-state structures of the novel macrocycles were determined by X-ray crystallography.
The host–guest chemistry of these receptors towards halide ions was investigated in solution by 1H NMR titration techniques and compared
with those of the meso-octamethylcalix[4]pyrrole and meso-dodecamethylcalix[6]pyrrole. The binding of chloride anions was observed to
occur with different affinities on the two faces of the novel calix[6]pyrrole derivative described here.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Calixpyrroles are a topic of considerable current interest in
supramolecular chemistry because of their ability to act as
receptors for anions.1 These macrocycles bind anions by
means of hydrogen-bonding interactions between the polar
NH units and the electron-rich guests.2 The simplest mem-
ber of this family is calix[4]pyrrole 1, which has been known
since 1886,3 but used as a receptor for anions only since
1996.4 Over the last decade, studies on calixpyrroles as
anion receptors have proliferated and a large number of
derivatives have been reported. These include expanded
calixpyrroles containing more than four pyrrole units,5
‘hybrid’ calixpyrroles6 in which the macrocyclic structure
also contains aromatic units other than pyrrole, calixpyrroles
in which all or some of the pyrrole units have substituents
other than hydrogen at their 3,4-positions,7 meso-functional-
ized calixpyrroles (i.e., having substituents other than the
methyl groups at the quaternary carbon atoms connecting
the pyrrole units),8 ‘strapped calixpyrroles’ in which an
meso-Substituted calixpyrroles are in principle especially
easy to prepare because they can be assembled by the acid
promoted condensation of pyrrole with the appropriate
ketone. However, different ketones exhibit different reactiv-
ities towards condensation with pyrrole, and the initially
formed ‘meso-substituted’ dipyrromethanes also show dif-
ferent behaviours when subjected to macrocyclization with
ketones under acidic conditions, depending on the nature
of the meso-substituent(s).
Some elegant and well-exploited examples of this ‘tuning’
of the reactivity of the dipyrromethane moiety as a function
of the meso-substituent(s) are the syntheses of expanded
meso-substituted calix[6]pyrroles achieved by Eichen.5d
additional chain of atoms joins two meso-positions.9
A
number of calixpyrroles that have a combination of the
above-mentioned features have also been reported.10 These
modifications of the basic calix[4]pyrrole structure produce
a vast range of macrocycles having different and varied
anion binding abilities.
Previous studies have highlighted that the presence of elec-
tron-withdrawing substituents at the meso-positions of calix-
pyrroles enhances their ability to bind anions.8e Moreover,
the use of the calixpyrrole structure as a means to ‘hold’
aryl units in a calixarene-like arrangement was explored
by Floriani8f and Sessler,8b,d,g who also demonstrated the
formation of various stereoisomers of tetra-meso-substituted
calix[4]pyrrole from the condensation of unsymmetrical
ketones (e.g., p-hydroxyacetophenone) and pyrrole.8g
Keywords: Extended calixpyrrole; Anions; Receptors; Complexation.
* Corresponding author. Tel.: +39 090 6765171; fax: +39 090 393895;
e-mail: franz@unime.it
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.07.060

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G. Bruno et al. / Tetrahedron 63 (2007) 10003–10010
Inspired by these studies, we decided to synthesize the calix-
pyrroles that can be formed from 4-nitroacetophenone, pyr-
role and acetone and to study their properties as receptors for
anions. The p-nitrophenyl unit was selected for having elec-
tron-withdrawing character that would enhance the anion
binding properties of the calixpyrroles to be synthesized,8e
and for its potential to provide rather acidic CH units capable
of forming additional hydrogen bonds11 with anionic guests
besides those provided by the pyrrole NH units. The p-nitro-
phenyl unit also has the potential to be involved in anion–p
interactions with the selected (vide infra) substrates.12
In the case of 4a and 4b their structures were also confirmed
by X-ray crystallography, whilst to date we have been unable
to obtain crystals of 5b suitable for X-ray analysis.
The X-ray crystal structure of 4a (Fig. 1) confirmed the
a,a-configuration assigned by means of NMR spectroscopy.
The calix[4]pyrrole adopts a 1,3-alternate conformation as
observed for calix[4]pyrrole 1 when this is not binding a neg-
atively charged guest.13 The meso-carbon atoms have an rms
˚
deviation from their mean plane of only 0.08 A. The two
diametrically placed pyrrole units N3 and N6 rings are tilted
with their NH units towards the macroring centre, their
planes forming dihedral angles of 59ꢀ with the macroring
mean plane defined bythe four meso-carbon atoms. The other
two pyrrole rings N2 and N5 have their planes almost perpen-
dicular to the macroring plane (dihedral angles 94ꢀ, the NH
units pointing away from the macroring centre). The mole-
cule is helically twisted along the axis C1–C20, hence the
aryl units are skewed by an angle of 51ꢀ. Unlike the a,b-
isomer 4b (vide infra), here the aryl groups have their planes
almost facing the macroring centre (these planes, pivoting
about the C1–C2 and C20–C21 meso-bonds, are tilted by
77ꢀ and 74ꢀ, respectively, with respect to the macroring
2. Results and discussion
Treatment of a solution of 4-nitroacetophenone 2 in pyrrole
(used as the solvent) with trifluoroacetic acid (TFA) gave the
5-methyl-5-(4-nitrophenyl)dipyrromethane (3), which was
easily isolated (40%) by flash chromatography followed by
crystallization from AcOEt (Scheme 1). Condensation of 3
with acetone (also used as the solvent) in the presence of
TFA gave, after chromatographic separation, the a,a- and
a,b-stereoisomeric calix[4]pyrroles 4a and 4b in compara-
ble yields (18%) and the a,a,b-tris-4-nitrophenyl calix[6]-
pyrrole 5b in low yield (5%). We were unable to find
evidence for the presence of the ‘all a’ stereoisomer 5a in
the reaction mixture.
The stereochemistries of 4a, 4b and 5b were evident from
their H NMR spectra, which contained a number of reso-
1
nances consistent with the symmetries of each macrocycle
according to conformations averaged on the NMR time-
scale. Thus the methyl protons of 4a (in CDCl3) resonate as
three signals of equal intensity, whilst those of 4b appear as
two resonances having1:2 intensities. The 1H NMR spectrum
of 5b shows three resonances for the NH protons and three
ABX systems (partially overlapping) for the b-CH protons
of the pyrrole units, and two different resonances (1:2 inten-
sities) for the meso-methyl protons adjacent to the aryl units.
These spectral features are consistent with an a,a,b-configu-
ration of the p-nitrophenyl units at the meso-positions.
Figure 1. The X-ray crystal structure of macrocycle 4a showing the labels of
some key atoms. The two acetone solvent molecules are omitted for clarity.
Thermal ellipsoids are drawn at 25% of probability level while H atom size
is arbitrary.
Scheme 1.

G. Bruno et al. / Tetrahedron 63 (2007) 10003–10010
10005
centroid). The two benzo rings define a wedge-shaped cleft,
which at its narrow end (i.e., the two diametrically placed
anti-parallel orientation with their C1–N1 or C10–N10 vec-
tors forming angles of 136ꢀ with the C1–C10 vector. These
aryl rings have an edge-on orientation with respect to the
macroring centre, and their planes form dihedral angles of
61ꢀ with the mean plane of the macrocycle defined by the
four meso-carbon atoms. The pyrrole units adopt a 1,2-alter-
nate conformation, their planes forming dihedral angles of
53ꢀ with the plane of the macrocycle. The molecule has
a centrosymmetric conformation and lies on a crystallo-
graphic centre of inversion. This conformation differs from
the 1,3-alternate conformation observed for the a,a-isomer
4a. There is no solvent included in the crystal lattice. The
supramolecular structure of the crystal is stabilized by a net-
work of hydrogen bonds involving the pyrrole NH units and
the oxygen atom of the nitro group of an adjacent molecule
at the equivalent position: ꢁx+1/2, y+1/2, ꢁz+1/2: Nꢀ2–H2/
˚
meso-carbon atoms C1 and C20) is 7.1 A wide, whilst the
distance between the centroids of the two benzo rings is
˚
11.26 A. The latter distance can become considerably shorter
by means of conformational changes of the calix[4]pyrrole
moiety that can occur in solution and the aryl units can easily
approach putative anionic substrates either with their p-sys-
tems or by means of their CH units.
The structure contains acetone solvent, two molecules for
each macrocycle. Each acetone molecule is hydrogen
bonded with its carbonyl oxygen atom to one of the NH units
of either pyrrole N5 or N2. The acetone molecule hydrogen
ꢀ
˚
bonded to N5 [N5–H/O distances (A) and angle ( ) 3.01,
2.25, 171] also inserts one of its methyl groups into the cleft
formed by the pyrrole rings N3 and N6: there are two CH–p
interactions between this methyl group and the heterocyclic
˚
O2 and N3–H3/O2 bond lengths (A) and angles ( ): 3.30,
2.46, 166.8 and 3.21, 2.36, 170.8, respectively.
˚
rings (C–H/pyrrole centroid distances of 3.5 A). The
molecular packing is dominated by the usual weak van der
Waals interactions.
The novel receptors were tested for their ability to bind halide
anions (as their n-Bu4N+ salts) by means of 1H NMR titration
experiments14 based on the complexation induced shifts
(CISs) of the NH resonances upon addition of the salts at
21 ꢀC. Satisfactory fitting of the data was obtained for the
1:1 binding model. In several cases (vide infra) the Ka values
of the macrocycles under investigation towards a given anion
were determined by competitive binding with another recep-
tor having a known Ka for that anion.15 We selected CD2Cl2
as the solvent in order to obtain data that would be compara-
ble with previous studies on calix[4]pyrrole 14 and calix[6]-
pyrrole 6.5b Since water is known to have a dramatic effect on
the Ka values for complexation involving hydrogen bonds,16
titration experiments were conducted both in ‘as dry as
possible conditions’ and in water-saturated CD2Cl2 (D2O
0.18% v/v at 21 ꢀC) hereafter referred to as ‘dry’ and ‘wet’,
respectively. The 1:1 Ka values thus obtained are listed in
The X-ray crystal structure of 4b (Fig. 2) confirmed the a,b-
configuration of the two p-nitrophenyl units, which adopt an
Figure 2. The X-ray crystal structure of 4b showing the labels of some key
atoms. The molecule is placed on a crystallographic centre of symmetry and
only half the unit is independent while the other equivalent half is generated
by the symmetry operation ꢁx, 1ꢁy, ꢁz. Thermal ellipsoids are drawn at
25% of probability level while H atom size is arbitrary.
Table 1. Association constants (Ka Mꢁ1, 21 ꢀC) for the formation of 1:1 complexes of the listed receptors with the indicated halide anions as n-butylammonium
salts
Fꢁ
Clꢁ
Brꢁ
Da
Da
Wa
Da
Wa
4a
4b
5b
3
1
7
ca. 8.4ꢂ105 b
ca. 1.2ꢂ105 b
ca. 8.4ꢂ105 c
5600ꢃ1000
1.1ꢂ104ꢃ388
1.2ꢂ104ꢃ1000
NH disappears
382ꢃ29
2300ꢃ80
163ꢃ25
ca. 2ꢂ105 c
173ꢃ8
380ꢃ24
30ꢃ3
34ꢃ10
Not tested
Not tested
40ꢃ3
NH disappears
59ꢃ3
1.7ꢂ104ꢃ900d
1725ꢃ176
2700ꢃ201e
188ꢃ15
350ꢃ5d
85ꢃ11
46ꢃ8e
10ꢃ0.5d
<10
710ꢃ25
37ꢃ3
6
ca. 1.7ꢂ106 f
ca. 3.2ꢂ105 e
ca. 107 f
1.2ꢂ104ꢃ103 e
a
D and W: dry and water-saturated CD2Cl2, respectively.
Ka measured by competition using 1.
Ka estimated by competition using 4a.
Data from Ref. 4.
Data from Ref. 5b.
Ka measured by competition using 5b.
b
c
d
e
f

10006
G. Bruno et al. / Tetrahedron 63 (2007) 10003–10010
Table 1 and include those of the dipyrromethanes 3 and 7 be-
cause these compounds represent structural subunits of the
receptors 4 and 5. The relevant Ka values for 1 and 6 pub-
lished previously1,5b are also included. Data for the binding
of bromide in wet solvent were not collected because the
Ka values observed in dry solvent were very small and they
appeared to be even smaller in the presence of water. Iodide
did not interact appreciably with any of the new macrocycles.
Macrocycle 4b binds chloride weakly (Ka¼163ꢃ25 and
30ꢃ3 Mꢁ1 in dry and wet CD2Cl2, respectively). With the
exception of the NH resonances, the CISs for all of the
aryl and b-pyrrole protons are marginal.
The addition of fluoride to 5b in both dry and wet CD2Cl2
produced broadening of all of the signals and the disappear-
ance of the NH resonances. In competitive titration 5b and
4a were found to bind fluoride with equal strength, compet-
itive titration of 5b and calix[6]pyrrole 6 (1:1, dry CD2Cl2,
0.005 M) showed that 6 binds fluoride 2.2 times more
strongly than 5b. By correlating the data described so far,
we conclude that the Ka of 5b$Fꢁ is ca. 8.4ꢂ105 Mꢁ1 and
2.1. Complexation studies
The addition of fluoride in ‘dry’ CD2Cl2 to 4a revealed the
formation of a highly stable complex. The Ka was too high
for NMR titration and the value of ca. 8.4ꢂ105 Mꢁ1 was de-
termined by competitive binding with 1. The signals for the
NH protons, which resonate as broad singlets at d¼7.32 ppm
for the free host appear at d¼12.6 ppm after the addition of
1 equiv of salt and the complex appeared to be quantitatively
formed. The NH signal in the complex also exhibited a cou-
pling with fluoride (JH–F¼42 Hz). The aryl protons meta to
the nitro group exhibited larger CISs than the ortho ones
(from d¼7.14 to d¼6.80 ppm and from d¼8.06 to d¼
7.94 ppm, respectively). These spectral changes suggest an
interaction between the meta-aryl protons and the anion,
and hence we believe that fluoride is bound by 4a on the
face that contains the two aryl residues.17 In wet CD2Cl2
the Ka of 6$Fꢁ is ca. 1.7ꢂ106 Mꢁ1
.
In the initial stages of the titration of 5b with chloride in dry
CD2Cl2 all of the resonances broadened considerably. The
NH resonances that appeared in the free receptor as three dif-
ferent signals of equal intensity at d¼7.58, 7.69 and
7.60 ppm (Fig. 3a) disappeared and became visible as two
different signals (1:1 intensities) at d¼10.25 and 10.49 ppm
(Fig. 3b) after the addition of a slight excess (1.3 equiv) of
salt. This behaviour prevented the determination of a Ka
value by direct titration at room temperature (21 ꢀC). A com-
petitive titration of 5b and 4a (1:1, dry CD2Cl2, 0.005 M)
showed that 4a begins to bind chloride only after 5b is fully
complexed by the addition of just over 1 equiv of salt. This
behaviour is consistent with 5b binding fluoride ca. 100
times more strongly than 4a, hence we entered the value of
ca. 2ꢂ105 in Table 1. In a competitive binding of 5b and
6, the latter appeared fully complexed after the addition of
1 equiv of salt, while 5b was still unaffected. This sets the
minimum value of ca. 107 Mꢁ1 for the Ka of 6$Clꢁ.
the complex 4a$Fꢁ had a Ka value of 1.1ꢂ104ꢃ388 Mꢁ1
.
Chloride was complexed by 4a with Ka values of 2300ꢃ80
and 380ꢃ24 Mꢁ1 in dry and wet CD2Cl2, respectively. In
4a$Clꢁ the signals of the aryl protons were only marginally
affected with respect to the free receptor. Therefore, we
believe that, unlike fluoride, chloride interacts with this re-
ceptor on the face that does not contain the aryl units. This
difference of the mode of interaction seems reasonable on
the basis of steric considerations (chloride is larger than fluo-
ride). However, the mechanism by which the p-nitrophenyl
units in 4a boost (compared to 1) the affinity of the calix[4]-
pyrrole moiety towards chloride although they are not conju-
gated with the pyrrole units and remote from the anion in the
complex is rather puzzling and would require additional
investigation.
Upon cooling to ꢁ50 ꢀC the spectrum of the 1:1 mixture of
5b with chloride became sharp (Fig. 3c) showing two dis-
crete sets of signals for the NH, the aryl and the pyrrole pro-
tons. We ascribe these spectral features to the slow exchange
of the bound chloride between the two different faces of the
macroring (see diagrams in Fig. 3). At this temperature the
two complexes are formed in a 1:2 proportion (each set of
resonances is in a 1:2 intensity ratio with the other). Inspec-
tion of the CISs and intensities of the aryl protons indicates
that the most favoured complex is that in which the chloride
ion is bound to the face containing two aryl residues. The as-
signments indicated in Figure 3 for the aryl protons were
confirmed by means of a COSYexperiment at the same tem-
perature.
Bromide was complexed by 4a only weakly (Ka¼34ꢃ
10 Mꢁ1 in dry CD2Cl2).
The Ka of 4b with fluoride in dry CD2Cl2 could not be deter-
mined by direct titration because it was too high. Moreover
the NH resonances disappeared in the initial stages of the
experiment. In a competitive experiment 4b was found to
bind fluoride with a Ka value (1.2ꢂ105 Mꢁ1) seven times
larger than that of calix[4]pyrrole 1. A competitive titration
of 4a and 4b (1:1 in dry CD2Cl2, 0.005 M) showed that 4a
binds fluoride with a Ka value that is larger than that of 4b.
In fact, during this titration the NH resonances of 4b show
significant CISs only after the addition of over 0.5 equiv of
salt. The broadening of the resonances and the fact that
some of them disappeared during the titration prevented an
accurate evaluation of the relative strengths of the two Kas,
which appeared to differ by a factor of 5–8. However, the
two receptors 4a and 4b had very similar affinities for fluo-
This modest preference for the chloride to complex 5b with
the face having the two aryl substituents indicates that the
meta-aryl and the pyrrole NH protons interact with the anion
synergically. This mode of binding differs from that de-
scribed above for 4a and we believe that it is made possible
by the larger size of receptor 5b in which there is enough
space for the chloride ion to approach in this way.
3. Conclusions
ride in wet CD2Cl2 (Ka values 1.1ꢂ104 and 1.2ꢂ104 Mꢁ1
,
Comparing the Ka values of the receptors having meso-p-
nitrophenyl groups with those having only meso-methyl
respectively).

G. Bruno et al. / Tetrahedron 63 (2007) 10003–10010
10007
Figure 3. Partial 1H NMR spectrum in CD2Cl2 of (a) 5b at 21 ꢀC; (b) a mixture of 5b and TBACl (1:1) at 21 ꢀC; (c) the same sample as in (b) at ꢁ50 ꢀC; the
expanded aromatic region shows the spectral assignments obtained by means of a COSY experiment at this temperature.
groups (Table 1) one can conclude that the presence of
the electron-poor aromatic rings has a positive effect on
the anion binding as previously reported for other calix-
pyrrole derivatives with electron-withdrawing groups at
the meso-positions.8e This effect is clearly seen by com-
paring the Ka values of the dipyrromethane components 3
and 7. However, when these become part of the macrocyclic
structures the stereochemistry at the meso-centres plays
a crucial role. Thus the anion binding behaviour of 4a
and 4b differ substantially, this difference being more
pronounced for the complexation of the larger chloride
anion with respect to fluoride. Considering the Ka values
of 4b, 3 and 7 for chloride, one is led to conclude that
4b is probably interacting with chloride by means of just
one of its dipyrromethane moieties, i.e., using only two
NH units.
Compared to calix[4]pyrrole 1, which exhibits fluoride/
chloride preference factors of ca. 50 and 7 in dry and wet
CD2Cl2, respectively, 4a and 4b are considerably more se-
lective, the corresponding factors being ca. 360 and 30 for
4a, and ca. 730 and 400 for 4b. It is also noteworthy that cal-
ix[6]pyrrole 6 is the strongest chloride ligand among those
listed in Table 1. We speculate that compound 5a could be
an even better ligand for chloride than calix[6]pyrrole.
Moreover, should it become available, it would provide
a means to gain additional insight into the role of the p-nitro-
phenyl groups in the anion recognition process. Unfortu-
nately in our laboratory 5a still remains an elusive prey.
We believe that the results outlined in this paper provide
information that is relevant to evaluate the use of the p-nitro-
phenyl substituents at the meso-position of calixpyrroles as
a means to tune their anion binding properties.

10008
G. Bruno et al. / Tetrahedron 63 (2007) 10003–10010
4. Experimental
application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK [fax: +44 (0)1223 336033 or e-mail: deposit@
ccdc.cam.ac.uk].
4.1. General methods and instrumentation
Acetone was distilled from dry CaCO3. Pyrrole was distilled
before use. All other chemicals were of standard reagent
grade and were used without further purification. All
air-sensitive and/or moisture-sensitive reactions were con-
ducted under a dry argon atmosphere. Thin layer chromato-
graphy (TLC) was conducted on Merck SiO2 60 F254 plastic
plates. Compounds were visualized with iodine, vanillin, or
4.3. 1H NMR titrations
The n-tetrabutylammonium salts were dried in a vacuum
oven for at least 24 h. For measurements in ‘dry’ CD2Cl2
this was stored on dry alumina and care was taken to mini-
mize exposure to the atmosphere during sample preparation
and titration. Wet CD2Cl2 was obtained by vigorous stirring
with D2O for 1 h at 21 ꢀC (see Ref. 5b). The anions were
added as measured volumes of solutions (ca. 0.035 M) in
CD2Cl2 to the solution of the macrocycle under investigation
(0.005 M) in the same solvent (0.7 mL). The sample volume
was kept constant by evaporating the excess solvent with
a flow of dry nitrogen. After each addition the stoichiometric
ratios between the salt and macrocycle were also re-deter-
mined from the intensities of the resonance of the pyrrole
protons of the host versus those of the n-tetrabutyl-
ammonium cation. Quantitative 1H NMR integrations were
obtained by the use of appropriate pulse delays in all cases.
Processing the data with the WinEQNMR14b program pro-
duced the reported Ka values for the 1:1 complexation
model.
by examination under UV light. Column chromatography
1
˚
was conducted on Aldrich Silica gel 230–400 mesh, 60 A. H
and 13C NMR spectra were recorded on a Varian Gemini-
300 at 300 and 75 MHz, respectively, using the residual
proton resonances of the solvents (CDCl3 and CD2Cl2)
as d reference. Melting points were determined on a Kofler
hot stage apparatus, and are not corrected. Electron impact
(EI) mass spectra were measured on a Finnigan Mat 90 spec-
trometer operated by Dr. Marcello Saitta.
Accurate mass measurements were recorded in reflector
mode using an APPLIED BIOSYSTEMS 4800 MALDI
TOF/TOFÔ instrument. Samples were diluted in 500 mL
acetonitrile. This solution (1 mL) was mixed with the same
volume of the matrix (3 mg/mL a-cyano-4-hydroxycin-
namic acid in TFA 0.1%/CH3CN 2:1), directly spotted
onto a 384-well MALDI plate (APPLIED BIOSYSTEMS)
and allowed to dry at room temperature. Resolution was
better than 16,000. Internal calibration was used so that
mass accuracy was better than 20 ppm. Comparisons be-
tween measured and calculated isotopic patterns were also
performed.
4.4. Syntheses
4.4.1. 5-Methyl-5-(4-nitrophenyl)dipyrromethane 3. TFA
(2.77 mL, 36 mmol) was added to a solution of p-nitroaceto-
phenone (2.0 g, 12 mmol) in pyrrole (21 mL), at 0 ꢀC. The
mixture was stirred under argon atmosphere at room temper-
ature for 3 h, then neutralized (NaOH 1 M) and extracted
(2ꢂ25 mL CH2Cl2). The organic phase was dried (MgSO4)
and concentrated to fractionally remove CH2Cl2 and excess
pyrrole under reduced pressure. The crude brown oil was
subjected to column chromatography (SiO2, hexane/EtOAc
3:1) and crystallized from EtOAc to give 3: 1.27 g, 40%,
4.2. Crystal data
Crystal data for compound 4a [4b]. Chemical formu-
la¼C44H50N6O6 [C38H38N6O4]; crystal system¼triclinic
[monoclinic]; space group¼P-1 [P21/n]; cell parameters:
1
mp 141–142 ꢀC; H NMR (CDCl3): d 2.07 (s, 3H, CH3),
˚
˚
a¼10.530(2) [11.778(3)] A, b¼14.019(2) [10.390(2)] A,
5.95 and 6.19 (2ꢂm, 2ꢂ2H, pyrrole b-CH), 6.72 (m, 2H,
c¼15.092(2) [13.322(3)] A, a¼96.528(3) [90]ꢀ, b¼
pyrrole a-CH), 7.25 and 8.10 (2ꢂ2H, AA0BB0 system,
˚
1
105.524(3) [94.400(6)]ꢀ, g¼96.820(3) [90]ꢀ; V¼2106.4(6)
Ar-H), 7.88 (br s, 2H, NH); H NMR (CD2Cl2): d 2.06 (s,
3
˚
[1625.5(6)] A ; Z¼2 [2]; collected refls¼12,155 [10,894];
3H, CH3), 5.92 and 6.16 (2ꢂm, 2ꢂ2H, pyrrole b-CH),
6.72 (m, 2H, pyrrole a-CH), 7.27 and 8.10 (2ꢂ2H, AA0BB0
system, Ar-H), 7.94 (br s, 2H, NH); 13C NMR (CDCl3):
d 28.4 (CH3), 45.0 (Cq), 106.9, 108.4, 117.7, 123.2, 128.4
(CH), 135.7, 146.5, 155.0 (Cq); EIMS, m/z (%): 281 (M+
31), 266 (100), 220 (23), 159 (13).
unique refls¼5975 [2075]; refls with I>2s(I)¼gt¼
2024 [1194]; refined params¼516 [220]; R (all)¼0.1202
[0.1477]; R(gt)¼0.0500 [0.1111]; wR (all)¼0.1111 [0.3385];
wR(gt)¼0.1018 [0.3231]; GOF¼0.676 [1.178]; max resi-
ꢁ3
˚
dual¼0.164 [0.625] eA
.
Diffraction data were collected at room temperature for both
compounds on a Bruker single crystal diffractomer APEX 8
by using graphite monochromated Mo X-ray radiation. Both
structures were solved by using standard direct methods18
and refined by the combination of the Fourier difference
maps and weighted least square technique with all the inde-
pendent intensities and no constraints.19 In both structural
models all non-H atoms were refined anisotropically while
the hydrogens were included by the SHELX ‘reading model’
method. Crystallographic data (excluding structure factors)
for compounds 4a and 4b have been deposited with the Cam-
bridge Crystallography Data Centre as supplementary publi-
cation numbers CCDC 639715 and 639716, respectively.
Copies of the data can be obtained free of charge on
4.4.2. 5,10,15,20,22,24-Hexahydro-5,5,10,15,15,20-hexa-
methyl-10a,20a-bis(4-nitrophenyl)-calix[4]pyrrole 4a,
5,10,15,20,22,24-hexahydro-5,5,10,15,15,20-hexamethyl-
10a,20b-bis(4-nitrophenyl)-calix[4]pyrrole 4b and
2,2,7,12,12,17,22,22,27-nonamethyl-7a,17a,27b-tris(4-
nitrophenyl)-calix[6]pyrrole 5b. TFA (5.4 mL, 7.1 mmol)
was added to a solution of 3 (2.0 g, 0.71 mmol) in dry ace-
tone (50 mL), at 0 ꢀC. The mixture was stirred under argon
atmosphere at room temperature for 4 h, then neutralized
(NaOH 1 M) and then concentrated to 15 mL and extracted
(2ꢂ50 mL CH2Cl2). The organic phase was dried (MgSO4),
concentrated and the brown oil was subjected to column
chromatography (SiO2, PhCH3/EtOAc, 92:8) to give in order
of elution (Rf values 0.6, 0.5, 0.4, respectively).

G. Bruno et al. / Tetrahedron 63 (2007) 10003–10010
10009
Compound 4b: 416 mg, orange solid, 18%, mp 250 ꢀC dec
from EtOH; H NMR (CDCl3): d 1.56 (s, 12H, CH3), 1.93
2. (a) Gale, P. A.; Anzenbacher, P.; Sessler, J. L. Coord. Chem.
Rev. 2001, 222, 57–102; (b) Gale, P. A.; Sessler, J. L.; Kral,
V. Chem. Commun. 1998, 1–8.
3. Baeyer, A. Ber. Dtsch. Chem. Ges. 1886, 19, 2184–2185.
4. Gale, P. A.; Sessler, J. L.; Kral, V.; Lynch, V. J. Am. Chem. Soc.
1996, 118, 5140–5141.
1
(s, 6H, CH3), 5.76 and 5.96 (2ꢂm, 2ꢂ4H, pyrrole CH),
7.24 (br s, 4H, NH), 7.30 and 8.12 (2ꢂ2H, AA0BB0 system,
Ar-H); 1H NMR (CD2Cl2): d 1.54 (s, 12H, CH3), 1.91 (s, 6H,
CH3), 5.75 and 5.95 (2ꢂm, 2ꢂ4H, pyrrole CH), 7.22 (br s,
4H, NH), 7.28 and 8.10 (2ꢂ2H, AA0BB0 system, Ar-H);
13C NMR (CD2Cl2): d 29.0, 29.2 (CH3), 35.3, 45.0 (Cq),
103.6, 106.3, 123.1, 128.3 (CH), 135.0, 139.0, 146.7,
154.2 (Cq); EIMS, m/z (%): 642 (M+ 100), 627 (93), 612
(10), 597 (10), 520 (8), 453 (12), 321 (9), 306 (20).
5. (a) Cafeo, G.; Kohnke, F. H.; Parisi, M. F.; Nascone, R. P.; La
Torre, G. L.; Williams, D. J. Org. Lett. 2002, 4, 2695–2697; (b)
Cafeo, G.; Kohnke, F. H.; La Torre, G. L.; Parisi, M. F.;
Nascone, R. P.; White, A. J. P.; Williams, D. J. Chem.—Eur.
J. 2002, 8, 3148–3156; (c) Turner, B.; Shterenberg, A.;
Kapon, M.; Suwinska, K.; Eichen, Y. Chem. Commun. 2002,
404–405; Turner, B.; Shterenberg, A.; Kapon, M.; Suwinska,
K.; Eichen, Y. Chem. Commun. 2001, 13–14; (d) Turner, B.;
Botoshansky, M.; Eichen, Y. Angew. Chem., Int. Ed. 1998,
37, 2475–2478.
6. (a) Sessler, J. L.; An, D.; Cho, W.-S.; Lynch, V.; Yoon, D.-W.;
Hong, S.-J.; Lee, C.-H. J. Org. Chem. 2005, 70, 1511–1517; (b)
Song, M. Y.; Na, H. K.; Kim, E. Y.; Lee, S. J.; Kim, K. I.; Baek,
E. M.; Kim, H. S.; An, D. K.; Lee, C. H. Tetrahedron Lett. 2004,
45, 299–301; (c) Sessler, J. L.; Cho, W.-S.; Lynch, V.; Kral, V.
Chem.—Eur. J. 2002, 8, 1134–1143.
7. (a) Levitskaia, T. G.; Marquez, M.; Sessler, J. L.; Shriver, J. A.;
Vercouter, T.; Moyer, B. A. Chem. Commun. 2003, 2248–2249;
(b) Anzenbacher, P., Jr.; Jursikova, K.; Shriver, J. A.; Miyaji,
H.; Lynch, V. M.; Sessler, J. L.; Gale, P. A. J. Org. Chem.
2000, 65, 7641–7645; (c) Gale, P. A.; Sessler, J. L.; Allen,
W. E.; Tvermoes, N. A.; Lynch, V. Chem. Commun. 1997,
665–666.
8. (a) Ji, X. K.; Black, D. St. C.; Colbran, S. B.; Craig, D. C.;
Edbey, K. M.; Harper, J. B.; Willett, G. D. Tetrahedron 2005,
61, 10705–10712; (b) Woods, C. J.; Camiolo, S.; Light,
M. E.; Coles, S. J.; Hursthouse, M. B.; King, M. A.; Gale,
P. A.; Essex, J. W. J. Am. Chem. Soc. 2002, 124, 8644–8652;
(c) Shao, S. J.; Wang, A. Q.; Yang, M.; Jiang, S. X.; Yu,
X. D. Synth. Commun. 2001, 31, 1421–1426; (d) Camiolo, S.;
Gale, P. A. Chem. Commun. 2000, 1129–1130; (e) Sessler,
J. L.; Anzenbacher, P., Jr.; Miyaji, H.; Jursikova, K.;
Bleasdale, E. R.; Gale, P. A. Ind. Eng. Chem. Res. 2000, 39,
3471–3478; (f) Bonomo, L.; Solari, E.; Toraman, G.;
Scopelliti, R.; Latronico, M.; Floriani, C. Chem. Commun.
1999, 2413–2414; (g) Anzenbacher, P., Jr.; Jursikova, K.;
Lynch, V. M.; Gale, P. A.; Sessler, J. L. J. Am. Chem. Soc.
1999, 121, 11020–11021.
Compound 4a: 416 mg, yellow solid, 18%, mp 290 ꢀC dec
from acetone; 1H NMR (CDCl3): d 1.55 (s, 6H, CH3), 1.64
(s, 6H, CH3), 1.93 (s, 6H, CH3), 5.61 and 5.96 (2ꢂm,
2ꢂ4H, pyrrole CH), 7.15 and 8.09 (2ꢂ4H, AA0BB0 system,
1
Ar-H), 7.25 (br s, 4H, NH); H NMR (CD2Cl2): d 1.64 (s,
6H, CH3), 1.92 (s, 6H, CH3), 2.12 (s, 6H, CH3), 5.64 and
5.96 (2ꢂm, 2ꢂ4H, pyrrole CH), 7.14 and 8.07 (2ꢂ4H,
AA0BB0 system, Ar-H), 7.33 (br s, 4H, NH); 13C NMR
(CDCl3): d 27.6, 27.8, 30.0 (CH3), 35.1, 44.9 (Cq), 103.6,
106.4, 122.9, 128.3 (CH), 135.1, 138.8, 146.6, 155.3 (Cq);
EIMS, m/z (%): 642 (M+ 100), 627 (93), 612 (10), 597
(10), 520 (8), 453 (12), 321 (9), 306 (20).
Compound 5b: 114 mg, orange solid, 5%, mp 167–168 ꢀC
from toluene; H NMR (CDCl3): d 1.45 (s, 12H, CH3),
1
1.50 (s, 3H, CH3), 1.52 (s, 3H, CH3), 1.82 (s, 3H, CH3),
1.92 (s, 6H, CH3), 5.55, 5.70 and 5.83 (3ꢂm, 2H, 4H, 6H,
pyrrole CH), 7.19 and 8.04 (2ꢂ6H, AA0BB0 system,
1
Ar-H), 7.53, 7.66, 7.68 (3ꢂbr s, 3ꢂ2H, NH); H NMR
(CD2Cl2): d 1.49 (br s, 18H, CH3), 1.86 (s, 3H, CH3), 1.92
(s, 6H, CH3), 5.56, 5.64, 5.74 (3ꢂm, 2H, 4H, 6H, pyrrole
CH), 7.20 and 8.07 (2ꢂm, 2ꢂ6H, Ar-H), 7.46 and 7.55
(2ꢂbr s, 2H, 4H, NH); 13C NMR (CDCl3): d 29.1, 29.1,
29.2, 29.2, 29.3, 29.3 (CH3), 35.5, 35.5, 44.9, 45.0 (Cq),
103.8, 103.9, 104.1, 106.7, 106.7, 106.8, 123.3, 123.3,
128.1, 128.1 (CH), 134.7, 135.0, 138.9, 139.0, 139.2,
146.6, 154.7, 155.0 (Cq); EIMS, m/z (%): 963 (M+ 100),
948 (90), 933 (20), 918 (37), 453 (27), 322 (25), 306 (43).
Acknowledgements
9. (a) Miyaji, H.; Kim, H.-K.; Sim, E.-K.; Lee, C.-K.; Cho, W.-S.;
Sessler, J. L.; Lee, C.-H. J. Am. Chem. Soc. 2005, 127, 12510–
12512; (b) Lee, C.-H.; Lee, J.-S.; Na, H.-K.; Yoon, D.-W.;
Miyaji, H.; Cho, W.-S.; Sessler, J. L. J. Org. Chem. 2005, 70,
2067–2074; (c) Lee, C.-H.; Na, H.-K.; Yoon, D.-W.; Won,
D.-H.; Cho, W.-S.; Lynch, V. M.; Shevchuk, S. V.; Sessler,
J. L. J. Am. Chem. Soc. 2003, 125, 7301–7306.
We acknowledge financial support from Messina University.
We thank Dr. Domenico Garozzo and Dr. Angela Messina at
CNR, ICTP, Viale Regina Margherita 6, I-95125 Catania
(Italy) for providing high resolution MALDI-TOF measure-
ments of the novel macrocycles.
References and notes
10. For some recent examples of these macrocycles, see: (a) Cafeo,
G.; Kaledkowski, A.; Kohnke, F. H.; Messina, A. Supramol.
Chem. 2006, 18, 273–279; (b) Sessler, J. L.; Cho, W.-S.;
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1. A selection of recent key papers on this topic includes: (a)
Sessler, J. L.; Gross, D. E.; Cho, W.-S.; Lynch, V. M.;
Schmidtchen, F. P.; Bates, G. W.; Light, M. E.; Gale, P. A.
J. Am. Chem. Soc. 2006, 128, 12281–12288; (b) Nishiyabu,
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Chem. Soc. 2006, 128, 11496–11504; (c) de Namor, A. F. D.;
Shehab, M.; Abbas, I.; Withams, M. V.; Zvietcovich-Guerra,
J. J. Phys. Chem. B 2006, 110, 12653–12659; (d) Nishiyabu,
R.; Anzenbacher, P. J. Am. Chem. Soc. 2005, 127, 8270–
8271.

10010
G. Bruno et al. / Tetrahedron 63 (2007) 10003–10010
12. (a) Berryman, O. B.; Hof, F.; Hynes, M. J.; Johnson, D. W.
Chem. Commun. 2006, 506–508; (b) Garau, C.; Frontera, A.;
Ballester, P.; Quinonero, D.; Costa, A.; Deya, P. M. Eur. J.
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Garau, C.; Quinonero, D.; Frontera, A.; Ballester, P.; Costa,
A.; Deya, P. M. New J. Chem. 2003, 27, 211–214.
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J. L. J. Am. Chem. Soc. 1996, 118, 12471–12472.
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16. Blas, J. R.; Marquez, M.; Sessler, J. L.; Luque, F. J.; Orozco, M.
J. Am. Chem. Soc. 2002, 124, 12796–12805.
17. For a similar facial selectivity on different calix[4]pyrrole
derivatives, see Ref. 8b.
18. Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G.;
Giacovazzo, C.; Guagliardi, A.; Moliterni, A. G. G.;
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€
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€
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