Synthesis and capsule formation of upper rim substituted tetra-acrylamido calix[4]arenes

Article abstract of DOI:10.1039/b502378e

Upper rim substituted tetraiodo calix[4]arenes are coupled to a variety of acrylamides using the palladium catalysed Heck reaction. Tetra-acrylamido upper rim substituted calix[4]arenes are obtained in good yields with exceptionally high stereoselectivity, to produce the & all-trans isomers. Tetra-acrylamido calix[4]arenes derived from secondary acrylamides are shown to dimerise via eight hydrogen bonds to form dimeric capsules, which are able to include small organic molecules. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b502378e

View Article Online / Journal Homepage / Table of Contents for this issue
A R T I C L E
Synthesis and capsule formation of upper rim substituted
tetra-acrylamido calix[4]arenes
Nikolai Kuhnert* and Adam Le-Gresley
Supramolecular and Biomolecular Chemistry Laboratory, Chemistry, School of Biomedical and
Molecular Sciences, C4, The University of Surrey, Guildford, UK GU2 7XH.
E-mail: n.kuhnert@surrey.ac.uk; Tel: 0044 1483 876837
Received 15th February 2005, Accepted 14th April 2005
First published as an Advance Article on the web 4th May 2005
Upper rim substituted tetraiodo calix[4]arenes are coupled to a variety of acrylamides using the palladium catalysed
Heck reaction. Tetra-acrylamido upper rim substituted calix[4]arenes are obtained in good yields with exceptionally
high stereoselectivity, to produce the all-trans isomers. Tetra-acrylamido calix[4]arenes derived from secondary
acrylamides are shown to dimerise via eight hydrogen bonds to form dimeric capsules, which are able to include small
organic molecules.
in coupling acrylamides to the broader rim of the calix[4]arene.
Using our standard reaction conditions we were able to obtain a
small selection of tertiary tetra-acrylamido calix[4]arenes 3a–d
(Fig. 1) in good yields using Pd(OAc)2 and dppp as the
catalytic system, with NEt3 as the base, in DMF. Yields and
selected spectroscopic data are given in Table 1. All reactions
proceed completely stereoselectively to produce the all-trans
Introduction
The main factor contributing to the stability of secondary pro-
tein structure is hydrogen bonding. In a-helical structures and
b-sheet structures trans-amide moieties form regular hydrogen
=
bond arrays between amide C O and adjacent amide N–H
bonds.1 In order to achieve a sufficient degree of stability, several
hydrogen bonds within a single strand (a-helical) or between
two and more strands (b-sheet) are necessary to maintain
tetra-olefinic calix[4]arenes as a single stereoisomer, as indicated
3
by the large JHC
olefinic coupling constant between 15.5
=
CH
structural integrity.2 A transverse section through both an a-
helix (parallel to the axis isolating a quarter of amide bonds)
or a b-sheet (orthogonal to the strands) reveals a topologically
similar chain of hydrogen bonded amides. This chain motif is,
to our knowledge, not found without the structural context
of a helix or sheet in any structurally characterised peptide
or protein. Thus, we wondered whether such a motif of
single hydrogen bonds forming a chain of isolated interstrand
amide hydrogen bonds would be stable in a synthetic system.
Amide substituted calix[n]arenes could display such an unusual
hydrogen bonding motif by dimerisation, although in a cyclic
and 16 Hz (see Table 1). All products are additionally found
exclusively in the cone conformation. It has to be stressed that
this highly chemo- and stereoselective outcome of the reaction is
remarkable indeed, keeping in mind that a total of 120 reaction
products are possible in this reaction including stereoisomers.16
Furthermore, it is worth noting that only very few examples of
Heck coupling reactions with acrylamides have been reported.17
Secondary acrylamides 4a–d could be coupled successfully un-
der similar conditions used for the tertiary acrylamides (Fig. 2).
Similar to the tertiary acrylamides 3a–d and acrylate series,14
the all-trans isomers of 5a–d could be obtained exclusively. The
structures can be directly deduced from their NMR spectra. As
discussed earlier,14,18 the difference in chemical shift Dd for the
two calx[4]arene methylene protons are a good indication of a
close to parallel arrangement of the four olefinic substituents.
Calix[4]arenes found in this particular type of conformation have
been referred to as deep cavity calix[4]arenes.14 All compounds
were found in the cone conformation, exhibiting NMR spectra in
polar solvents with one set of signals for the four repeating units
as expected for a C4V-symmetric molecule. In all tetra-olefinic
substituted derivatives the stereochemical relationship across the
=
form, by using the structural complementarity of their C O
and N–H moieties. Similar hydrogen bonding motifs have been
described by the groups of Rebek3–5 and Bo¨hmer6 using a self
complementary non-covalent assembly via 16 hydrogen bonds
of tetra-ureido calix[4]arenes. A related dimerisation between
calix[6] substituted dipeptides has recently been described by de
Mendoza et al.7 In this assembly 18 hydrogen bonds are formed
between three sets of dipeptides linked to the calix[6]arene
scaffold. It should be noted that both N-linked and C-linked
peptide calix[4]arenes introduced by the Ungaro group8,9 did
not show dimerisation by self complementary assembly, possibly
due to unfavourable stereoelectronic effects or lack of secondary
interactions stabilising the assembly. Related resorcinarene
molecular capsules have been reported by Atwood and co-
workers.10 Dimeric capsules formed by electrostatic interactions
have been reported by the groups of Reinhardt and Schrader.11,12
In this contribution we like to describe in detail the synthesis and
supramolecular chemistry of tetra-acrylamido calix[4]arenes.
Part of this work has been reported as a short communication.13
Results and discussion
Synthesis of tetra-acrylamido calix[4]arenes
Within our research programme aimed at the synthesis of macro-
cyclic libraries14,15 we have recently reported on the palladium
catalysed Heck reaction of tetra-iodo calix[4]arenes to produce
tri- and tetra-olefinic calix[4]arenes.14 In order to expand the
scope of the C–C bond formation process, we became interested
Fig. 1 Heck coupling of tertiary acrylamides.
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 1 7 5 – 2 1 8 2
2 1 7 5
©

View Article Online
Table 1 Yields and selected spectroscopic data tetra-acrylamido calix[4]arenes 3a–d, 5a–d, 8 and 9
Compound
NR2
Yield (%)
Coupling constant 3JHC CH/Hz
Coupling constant 2JHCH/Hz
Molecular ion m/z
=
3a
3b
3c
3d
5a
5b
5c
5d
8
NEt2
60
74
50
65
75
70
65
65
33
49
16.0
15.1
15.5
NA
15.5
15.5
15.1
15.5
15.5
15.9
13.4
13.2
13.5
13.4
13.5
12.8
13.8
13.9
11.8
12.1
1149
1198
1206
1342
1409
1329
1525
1286
N-Cyclo-C5H10
N-Cyclo-iC4H8O
NMeBn
NH(4-NO2C6H4)
NH(4-CNC6H4)
NH(4-CF3C6H4)
NHBn
NH(4-NH2C6H4)
NH(4-NHAcC6H4)
1289
1481 [M + Na]
9
Fig. 2 Heck coupling of secondary acrylamides.
double bond is trans, as indicated by their large 3JHC
olefinic
=
CH
coupling constants between 14.9 to 15.5 Hz. Yields and selected
spectroscopic data are given in Table 1.
Hydrogen bonding and dimerisation
In solvents competing for hydrogen bonding, such as DMSO
and acetone, the 1H-NMR spectra of compounds 3a–d and 5a–
d revealed one set of signals per repeating unit in agreement
with their overall C4V-symmetry. In non-polar solvents, such
as CDCl3, CD2Cl2, C2D2Cl4 and C6D6, however, the spectra
changed completely for compounds 5a–c. For compounds 5a, 5b
and 5c in CDCl3 two sets of signals for the aromatic calix[4]arene
protons were apparent. For a detailed description we limit
ourselves to compound 5b. A new sharp set of signals displaying
two aromatic signals at unusual high-fields at 5.88 ppm and
6.76 ppm and a N–H proton signal at 11.20 ppm was observed.
This observation is indicative of a dimerisation process involving
hydrogen bonding that reduces the rotational barrier around the
=
CAr–C C bond, hence giving rise to a pair of non-equivalent
aromatic protons (see Fig. 3). Both H1H-COSY and H13C-
HMQC spectra confirmed this assignment. The 1H15N-HMQC
revealed one cross peak corresponding to the H-bonded N–
H of 5b·5b at 136 ppm. Compounds 3a–d, as tertiary amides
lacking the ability to form hydrogen bonds, and compound 5d,
lacking the ability to form a dimer presumably due to a lack
of favourable aromatic p–p interactions that further stabilise a
dimeric structure, did not show the behaviour described above.
Experimental evidence for aromatic p–p interactions can be
found in the chemical shifts in the 1H-NMR spectra of the
dimeric species in CDCl3. The ESI-mass spectra for the dimeric
compounds 5a·5a, 5b·5b and 5c·5c in methanol recorded in
the negative ion mode show the dimeric compound with one
molecule of methanol included, presumably in the centre of
the capsule. As a representative example, the ESI spectra of
5b·5b·MeOH with a molecular ion at m/z 2689.2 is shown in
Fig. 4. In contrast, the FAB mass spectra show the molecular
ion of the monomeric calix[4]arene exclusively.
1
1
Fig. 3 Expanded 500 MHz 1H-NMR spectra of (a) 5b (in DMSO) with
=
low barrier of rotation around CAr–C C; (b) 5b·5b (in CDCl3) restricted
=
around CAr–C C.
We propose structure 5b·5b (Fig. 5 and Fig. 6) for the hydrogen
bonded dimer, that is in full agreement with semi-quantitative
NOE data and the ASIS effects based on the McConnell
equation.20 The detailed hydrogen bonding is shown in Fig. 6.
Dimerisation occurs via only eight hydrogen bonds, half the
number reported for most previous examples,4–6 between C O
=
and N–H moieties of opposing acrylamides. The amide occupies
the trans geometry in all cases. The capsule geometry resembles
topologically the tetra-ureido hydrogen bonded capsules
reported by Bo¨hmer and Rebek,4,6 with a seam of hydrogen
bonds in the “equatorial” position. The two halves of the
capsules are enantiomeric and the hydrogen bond array forms
a cyclic stereogenic element. The electron deficient p-CN–aryl
2 1 7 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 1 7 5 – 2 1 8 2

View Article Online
group interacts “face to face” with the electron rich aromatic
moiety of the calix[4]arene, adding a further element of stability.
This interaction follows from the ASIS shift induced on to the
ꢀ
high field aromatic calix[4]arene proton Ha at 5.89 ppm (see
Fig. 3). The hydrogen bonding array resembles topologically a
transverse slice through a b-sheet structure, as discussed above,
in which a single amide in one strand binds to a single amide in
a second strand in a cyclic manner.
Further evidence for the dimeric capsule structure comes from
two classic experiments devised by the Bo¨hmer group.19,20 The
addition of benzene to a CDCl3 solution of 5b·5b results in
1
the appearance of a high field signal at 4.52 ppm in the H-
NMR spectrum. A signal at a comparable chemical shift was
assigned to a benzene molecule encapsulated in a tetra-ureido
calix[4]arene dimer by Bo¨hmer and Cohen.21 A similar inclusion
complex could be observed with the pesticides tetramethyl-
thiuram-disulfide 6 or triazine 7 as a guest (Fig. 7). The two
methyl resonances of 6 are shifted towards higher field on
encapsulation, from e.g. 3.52 ppm to 3.21 ppm. The uptake
of this guest is relatively slow (t1/2 ∼ 36 h in CDCl3 at 4.1 mM
of 6 and 5b·5b) as estimated by 1H-NMR spectroscopy. Further
evidence for the encapsulation of 6 results from diffusion NMR
experiments. On encapsulation the diffusion coefficient of 6
changes from 2.08 × 10−10 m2 s−1 to 7.89 × 10−11 m2 s−1.
The latter diffusion coefficient corresponds to the value found
for 5b·5b. Similar changes in diffusion coefficient, along with
chemical shift changes in the 1H-NMR spectrum, are observed
for the inclusion complex with triazine 5b·5b·7 accompanied by
a change of diffusion coefficient from 2.2 × 10−10 m2 s−1 to 7.90 ×
10−11 m2 s−1 on encapsulation. Change in a diffusion coefficient
is in line with encapsulation, as discussed by Cohen et al.21,22
Encapsulation appears to be irreversible. If inclusion complex
5b·5b·7 is treated with an excess of 6 no exchange of the included
guest is apparent after 400 h by 1H-NMR spectroscopy and the
same was observed for the reverse experiment, in which inclusion
complex 5b·5b·6 was treated with an excess of 7.
Fig. 4 Expanded region of ESI-mass spectrum of 5b·5b·MeOH
(recorded in the negative ion mode).
Fig. 7 Encapsulated guest molecules.
Heterodimerisation
Finally, and most importantly, an equimolar mixture of 5a and
5b in CDCl3 gives rise to the formation of heterodimeric capsules.
1
In the H-NMR spectrum four N–H signals corresponding to
the four different N–H protons of the three species present in
solution 5a·5a, 5a·5b and 5b·5b are observed in a statistical ratio
Fig. 5 Proposed 3D structure of dimeric capsule 5b·5b obtained by
ASIS and NOE data (Hs, n-Bu and aromatic residues have been omitted
for clarity).13
Fig. 6 2D representation of schematic hydrogen-bonding array in dimeric capsule 5b·5b (note that C–C bonds completing the macrocyclic structure
have been omitted for clarity).
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 1 7 5 – 2 1 8 2
2 1 7 7

View Article Online
of 1 : 2 : 1 at 8.2 mM concentration of a mixture of 5a and
5b in CDCl3 (see Fig. 8). The three required molecular ions for
the three heterodimeric species can also be observed in the ESI
spectra of the mixture of 5b·5b in methanol in the negative ion
mode. Similar heterodimers are observable for mixtures of 5b
and 5c as well as 5a and 5c.
A further calix[4]arene assembly spectroscopically similar to
5b·5b (B), characterised by broad signals at roughly identical
1
8
chemical shifts can be observed on addition of mol eq. of
acrylamide or p-CN–Ar–acrylamide to the dimeric structure
=
=
5b·5b in CDCl3 producing 5b·5b·H2NC OHC CH2. Similarily,
addition of acrylamide to the two aggregates in C2D2Cl4
resulted in the disappearance of the signals corresponding
to 5b·5b (A) and a new set of signals corresponding to
=
=
5b·5b·H2NC OHC CH2 appeared.
A diffusion NMR experiment of 5b·5b (B) in CDCl3 and
C2D2Cl4 using two well separated high field CH2 multiplets of
the two aggregates revealed the following diffusion constants:
5.3 × 10−9 m2 s−1 for 5b·5b, 5.3 × 10−9 m2 s−1 for 5b·5b·4b
and 5.4 × 10−9 m2 s−1 for 5b·5b (B). These data clearly
indicate that the hydrodynamic radius of all three components is
virtually identical. All three aggregates must therefore be dimeric
calix[4]arene species, although 5b·5b (B) and 5b·5b·4b with a
reduced symmetry induced by host–guest chemistry.
Fig. 8 Expanded 500 MHz 1H-NMR spectrum in CDCl3 of the amide
region showing four N–H signals corresponding to 5a·5a, 5a·5b and
5b·5b.
The nature of the guest molecule interacting with the hydrogen
bond motif is subject to some speculation.
1H-NMR spectra of 5b·5b (A) in C2D2Cl4 change considerably
with increasing temperature. The non-equivalent two singlets
of the aromatic protons in the 5b·5b (A) dimeric capsule seem
to coalesce into one singlet. Coalescence temperature can be
observed around 320 K. This process can be explained by the
rupture of the dimeric structure at higher temperatures giving
two monomeric 5b. Alternatively, this NMR behaviour can be
Aggregation in C2D2Cl4
Suprisingly, in addition to the dimeric capsule 5b·5b (in this
section referred to as a 5b·5b (A)) we observed a second
calix[4]arene species (referred to here as 5b·5b (B)) in CD2Cl4,
showing almost identical spectral data as compared to 5b·5b in
CDCl3. The second calix[4]arene aggregate displays a full set
=
rationalised by assuming rapid rotation around Ar–CH in an
intact dimeric structure. Similarly, increasing the temperature
of 5b·5b (A) in C2D2Cl4 results in the steady collapse of the
methylene doublet at d 2.70 ppm and the growth of a doublet
at d 3.2 ppm, suggesting the adoption of a more pinched cone
conformation.
1
of broad H- and 13C-signals required for a calix[4]arene (see
Fig. 9). Regarding the second calix[4]arene assembly 5b·5b (B),
we have no unambigious definite structural information but a
vast amount of further data that allows some careful suggestions
with regard to its chemical nature.
Estimation of dimerisation constant
In any supramolecular system the estimation of the dimerisation
constant is important. In the case presented this is not a
straightforward task. In the NMR spectra the chemical shift
for the monomer in the solvents of interest is unknown and,
therefore, a NMR shift titration not feasible. Due to the
success of our diffusion NMR experiments we decided to use
diffusion NMR to estimate the dimerisation constant. It has
been reported that in supramolecular systems the diffusion
constant is dependent on the relative concentration of monomer
and dimer.23 The diffusion constant D was determined for
compound 5b·5b for five different concentrations in CDCl3,
using a 1H-cryoprobe at 500 MHz with z-field gradients. Indeed,
a difference in diffusion constant larger than the estimated error
of the experiment could be observed. The data obtained are
shown in Fig. 10. From the data a dimerisation constant, using
standard curve fitting of the appropriate binding model,23 of
4600 900 M−1 was estimated. Due to the relatively large error of
the diffusion constant measurements ( 10–15%), in particular
at low concentrations, an error of 20% was estimated for the
dimerisation constant.
Fig. 9 1H-NMR spectrum of 5b·5b (A) and 5b·5b (B) in C2D2Cl4
(500 MHz).
It has been argued by Rebek and Bo¨hmer3–5,19 that dimeri-
sation via hydrogen bonds of tetraureido calix[4]arenes is
templated by small guests and that in the absence of these guests
loose hydrogen bonded aggregates are formed, resulting in ill
defined, broad NMR spectra. Careful addition of chloroform
to the mixture did, however, reveal that the ratio of 5b·5b (A)
to 5b·5b (B) remained largely unaffected at low chloroform
concentrations. Only by using a chloroform excess of >1000,
the concentration of 5b·5b (B) was significantly reduced and
the signal intensity of 5b·5b (A) increased. We also considered
that an impurity in our C2D2Cl4 might affect the dimerisation
process, however, no impurities could be detected by GC–MS
1
and NMR spectroscopy. From the H-1H-NOESY spectra we
can conclude that due to the absence of any exchange peaks
between of 5b·5b (A) and 5b·5b (B) the exchange between these
species is very slow on the NMR time scale. The signals in the 1H-
NMR spectrum corresponding to 5b·5b (B) are broad. Possible
explanations for this include a high molecular weight, a d◦ynamic
exchange process or both. At lower temperature (−60 C) the
lines of 5b·5b (B) broaden considerably, suggesting approaching
coalescence and a dynamic exchange process.
Fig. 10 Plot of diffusion constant D versus concentration of 5b in
CDCl3.
2 1 7 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 1 7 5 – 2 1 8 2

View Article Online
Extended Acrylamides
Company. Solvents were dried using the usual procedures
and reagents used without further purification unless stated
otherwise. Calix[4]arenes 1 were prepared according to the
literature procedure.14
Following the observation that tetra-acrylamido calix[4]arenes
derived from secondary acrylamides form dimeric capsules in
solution, we decided to synthesise compounds that display
two such hydrogen bonding motifs. In this case it might be
possible to obtain dimeric capsules of different sizes from the
same monomer and eventually control the size by judicious
choice of conditions. Hence, we reduced nitro compound 5a
using stannous chloride to give tetra-amine 8 in moderate yield.
Acetylation of 8 gave octa-amide 9, displaying two distinct sets
of hydrogen bonding motifs (Fig. 11). However, the purity of 9
was unsatisfactory and we obtained 9 in an alternative synthetic
approach using a direct Heck coupling strategy as before, this
time to obtain 9 in satisfactory purity. The spectroscopic data
of 8 and 9 are as expected and mirror those of 3a–d and 5a–d.
Unfortunately, 9 is only soluble in DMSO and not in unpolar
solvents such as chloroform, which thus prevents any detailed
analysis of the dimerisation process in less polar solvents as
discussed above.
General procedure for the preparation of acrylamides
Et3N (8.23 ml) and the amine (27 mmol) were stirred in DCM
75 ml for 10 min at rt. Acryloyl chloride (2.66 ml) was very
slowly added with the temperature being maintained at rt. The
reaction was monitored via TLC or NMR. Upon completion,
the reaction was quenched with iced water (200 ml) and the
organic component extracted with DCM (3 × 50 ml). The
combined organic extracts were washed with HCl (3 × 40 ml,
3 M), water (2 × 50 ml) NaOH (3 × 30 ml, 2 M) and
again with water (2 × 50 ml). The organic extract was dried
(Na2SO4), filtered and evaporated under a reduced pressure.
Solid acrylamides could be recrystalised from hot methanol and
all acrylamides were stored below 0 ◦C or used immediately.
Diethylacrylamide 2a24. Pale yellow oil (78%); dH(270 MHz;
CDCl3) 6.25 (1H, dd, J 17.4, 10.2 Hc), 7.40 (1H, d, J 17.4, He),
5.62 (1H, d, J 10.2, Hd), 3.32 (4H, q, J 5.8, Hh), 1.10 (6H, t, J
5.8, Ha).
Conclusion
We have synthesised tetra-acrylamido upper rim calix[4]arene
derivatives and applied the Heck reaction to the synthe-
sis of functionalised calix[4]arenes. All reactions proceed in
good yield and give stereoselectively the all-trans tetra-olefinic
calix[4]arenes.
Benzylacrylamide 4d24. Pale orange shards (78%);
dH(500 MHz; CDCl3) 7.32–7.24 (5H, m, Ha, Hb, Hc),
6.52 (1H, s (broad), Hg), 6.28 (1H, dd, J 17.8, 1.4 He), 7.40 (1H,
dd, J 17.8, 10.3, Hd), 5.62 (1H, dd, J 10.3, 1.4, Hf), 4.46 (2H, d,
J 5.6, Hh).
Calix[4]arenes derived from secondary acrylamides have been
shown to dimerise in non polar solvents to give molecular
5,11,17,23-Tetrakis[(E)-N-(diethyl)-acrylamido]-25,26,27,28-
tetra-n-butoxycalix[4]arene3a. Triethylamine (0.335 ml, 0.157 g,
1.56 mmol) and diethylacrylamide 2a (0.264 g, 2.08 mmol) was
added to a stirred solution of 5,11,17,23-tetraiodocalixarene-
25,26,27,28-tetra-n-butylether (0.3 g, 0.26 mmol) 1 in DMF
=
capsules using eight N–H–O C hydrogen bonds and a series
of aromatic aromatic interactions.
Experimental
◦
1H- and 13C-NMR spectra were recorded on a JEOL GSX
270 MHz and a Bruker Avance 500 MHz spectrometer, d
values are quoted relative to teramethylsilane (dH 0.00 ppm)
or chloroform (dH 7.23 ppm) for 1H-NMR and relative to
chloroform (dC 77.0 ppm) for 13C-NMR. Coupling constants
J are in Hz. Microanalysis were carried out using a Leeman CE
440 automatic elemental analyser. Due to the hygroscopic nature
of the calix[4]arenes, water inclusion molecules are incorporated
into the microanalytical data. Infrared spectra were determined
on a Perkin Elmer 200 Spectrometer. The FAB and CI mass
spectra were recorded using a ThermoQuest Finnigan MAT
95 XL spectrometer. ESI-MS spectra were recorded on a
ThermoFinnigan DECA CQXP Plus.
Thin layer chromatography (TLC) was carried out on com-
mercially available precoated plates (Merck Kieselgel 60 F254
silica) using 1 : 3 ethylacetate–hexane as a solvent sysytem.
Flash column chromatography at a pressure of 1 bar was
carried out on Merck Kieselgel 60 (230–400 mesh) silica. All
chemicals/reagents were purchased from the Aldrich Chemical
(20 ml). After 10 min of vigorous stirring at 25 C, palladium
acetate (0.006 g, 0.026 mmol) and diphenylphosphinopropane
(0.011 g, 0.026 mmol) were added, the mixture heated to 100 ◦C
and stirred for 300 h.
After addition of 50 ml diethylether the mixture was washed
with HCl (3 × 20 ml, 3 M). The organic extract was dried
(Na2SO4), filtered and evaporated under a reduced pressure. The
residue was further dried in a desiccator (SiO2) under a reduced
pressure for 12 h and purified via column chromatography (SiO2,
EtOAc–hexane 1 : 1) to give the calix[4]arene 3a (0.15 g, 51%) as
off-white cubes; mp 120–122 ◦C; mmax (Nujol)/cm−1 1620 (C C),
=
=
1645 (C O); dH(270 MHz; CDCl3) 7.31 (4H, d, J 16.0, Ar–
=
=
CH ), 6.81 (8H, s, Ar–H), 6.39 (4H, d, J 16.0, Ar–CH CH–
C O), 4.41 (4H, d, J 13.4, CHAHBAr), 3.83 (8H, t, J 6.4, CH2O),
3.4–3.2 (16H, m, NCH2), 3.19 (4H, d, J 13.4, CHAHBAr), 1.90
(8H, m, CH2CH2O), 1.50–1.35 (8H, m, OCHCH2CH2), 1.05–
1.20 (24H, m NCH2CH3), 1.00 (12H, t, J 8.3, CH3CH2); dc
(CDCl3) 164.7, 159.4, 142.6, 126.3, 124.5, 123.2, 119.8, 72.2,
45.6, 40.3, 32.3, 31.2, 19.4, 14.1, 13.2; m/z (EI) 1149 [M+].
=
Fig. 11 Reagents and conditions: (i) SnCl2–HCl; (ii) Ac2O, NEt3; (iii) 1, NEt3–15% Pd(OAc)2, dppp, DMF, 100 ◦C, 275 h.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 1 7 5 – 2 1 8 2
2 1 7 9

View Article Online
Found C, 68.95; H, 8.37; N, 4.56% C72H100O8N4·6H2O requires
EtOAc–Hexane, SiO2) to give the calix[4]arene 3d (0.19 g,
55%) as brown cubes; mp 98–100 ◦C; mmax (Nujol)/cm−1
C, 68.76; H, 8.98; N, 4.50%.
=
=
1607 (C C), 1648(C O); dH(270 MHz; CDCl3) 7.50–7.16
5,11,17,23-Tetrakis[(E)-N -(piperidyl)-acrylamido]-25,26,27,
28-tetra-n-butoxycalix[4]arene 3b. Triethylamine (0.335 ml,
0.157 g, 1.56 mmol) and piperidylacrylamide 2b (0.289 g,
2.08 mmol) were added to a stirred solution of 5,11,17,23-
tetraiodocalixarene-25,26,27,28-tetra-n-butylether (0.3 g,
0.26 mmol) 1 in DMF (20 ml). After 10 min of vigorous
=
(24H, m, Ar–CH and Ar–H (benzyl)), 6.80–6.62 (8H, s,
=
=
Ar–H), 6.41–6.5 (4H, m, Ar–CH CH–C O), 4.69 (4H, m,
CHAHBAr), 4.35 (8H, m, CH2Ar), 4.0–3.6 (8H, m, CH2O), 3.19
(4H, d, J 13.4, CHAHBAr), 3.01 (12H, s, CH3N), 1.90 (8H, m,
CH2CH2O), 1.50–1.35 (8H, m, OCHCH2CH2), 1.00 (12H, t,
J 8.3, CH3CH2). dC (CDCl3) 167.5, 158.1, 143.0, 142.8, 137.2,
129.6, 128.4, 127.7, 127.6, 122.6, 115.3, 75.1, 53.6, 32.7, 32.4,
30.9, 19.4, 14.1; m/z (EI) 1342 [M+]. Found C, 73.20; H, 7.71;
N, 3.75% C88H100N4O8·5H2O requires C, 73.82; H, 7.74; N,
3.91%.
◦
stirring at 25 C, palladium acetate (0.006 g, 0.026 mmol) and
diphenylphosphinopropane (0.011 g, 0.026 mmol) were added,
the mixture heated to 100 ◦C and stirred for 325 h.
After addition of 50 ml diethylether the mixture was washed
with HCl (3 × 20 ml, 3 M). The organic extract was dried
(Na2SO4), filtered and evaporated under a reduced pressure.
The residue was further dried in a desiccator (SiO2) under a
reduced pressure for 12 h and recrystalised from hot methanol
to give the calix[4]arene 3b (0.17 g, 55%) as off-white cubes;
5,11,17,23-Tetrakis[(E)-N-(4-nitrophenyl)-acrylamido]-25,26,
27,28-tetra-n-butoxycalix[4]arene 5a. Triethylamine (0.335 ml,
0.157 g, 1.56 mmol) and 4-nitrophenylacrylamide 4a (0.399 g,
2.08 mmol) were added to a stirred solution of 5,11,17,23-
tetraiodocalixarene-25,26,27,28-tetra-n-butylether
0.26 mmol) 1 in DMF (20 ml). After 10 min of vigorous
mp 88–90 ◦C; mmax (Nujol)/cm−1 1646 (C O), 1605 (C C);
(0.3
g,
=
=
=
dH(270 MHz; CDCl3) 7.28 (4H, d, J 15.1, Ar–CH ), 6.82
◦
stirring at 25 C, palladium acetate (0.006 g, 0.026 mmol) and
=
=
(8H, s, Ar–H), 6.49 (4H, d, J 15.1, Ar–CH CH–C O), 4.41
(4H, d, J 13.2, CHAHBAr), 3.90 (8H, t, J 7.4, CH2O), 3.6–3.4
(16H, m, CH2NCH2), 3.20 (4H, d, J 13.2, CHAHBAr), 1.90
(8H, m, CH2CH2O), 1.70–1.40 (32H, m, OCHCH2CH2 and
CH2CH2CH2CH2NCH2), 1.00 (12H, t, J 8.3, CH3CH2); dC
(CDCl3) 165.9, 158.2, 142.3, 136.1, 130.1, 128.8, 115.9, 75.5,
47.1, 43.3, 32.5, 30.8, 26.7, 24.7, 19.5, 14.1; m/z (EI) 1198 [M+].
Found C, 75.10; H, 8.23; N, 4.52% C76H100N4O8·H2O requires
C, 75.09; H, 8.46; N, 4.61%.
diphenylphosphinopropane (0.011 g, 0.026 mmol) were added,
the mixture heated to 100 ◦C and stirred for 48 hrs.
After addition of 50 ml DCM the mixture was washed
with HCl (3 × 20 ml, 3 M). The organic extract was dried
(Na2SO4), filtered and evaporated under a reduced pressure.
The residue was further dried in a desiccator (SiO2) under a
reduced pressure for 12 h and recrystalised from hot methanol
to give the calix[4]arene 5a (0.15 g, 51%) as off-white cubes;
mp 151–154 ◦C; mmax (Nujol)/cm−1 3384 (N–H), 1748 (C O),
=
5,11,17,23-Tetrakis[(E)-N -(morpholinyl)-acrylamido]-25,26,
27,28-tetra-n-butoxycalix[4]arene 3c. Triethylamine (0.335 ml,
0.157 g, 1.56 mmol) and acryloylmorpholine 2c (0.294 g,
2.08 mmol) were added to a stirred solution of 5,11,17,23-
=
1615 (C C); dH(270 MHz; d6-DMSO) 10.65 (4H, s, NH), 8.05
(8H, d, J 9.0, Ar–H (nitrobenzene)), 7.36 (8H, d, J 9.0, Ar–
=
H (nitrobenzene), 7.37 (4H, d, J 15.5, Ar–CH ), 7.00 (8H, s,
=
=
Ar–H), 6.48 (4H, d, J 15.5, Ar–CH CH–C O), 4.44 (4H, d,
J 13.5, CHAHBAr), 3.96 (8H, t, J 6.8, CH2O), 3.37 (4H, d, J
13.5, CHAHBAr), 1.90 (8H, m, CH2CH2O), 1.50–1.47 (8H, m,
OCHCH2CH2), 1.02 (12H, t, J 8.3, CH3CH2); dc (d6-DMSO)
165.0, 158.9, 146.3, 142.6, 142.3, 135.8, 129.1, 128.8, 125.6,
126.1, 119.7, 75.2, 36.2, 32.5, 19.2, 14.2; m/z (EI) 1409 [M+];
found C, 66.88; H, 5.52; N, 7.60% C80H80N8O16·2H2O requires
C, 66.47; H, 5.86; N, 7.75%.
tetraiodocalixarene-25,26,27,28-tetra-n-butylether
(0.3
g,
0.26 mmol) 1 in DMF (20 ml). After 10 min of vigorous
◦
stirring at 25 C, palladium acetate (0.006 g, 0.026 mmol) and
diphenylphosphinopropane (0.011 g, 0.026 mmol) were added
and the mixture heated to 100 ◦C and stirred for 275 hrs.
After addition of 50 ml diethylether the mixture was washed
with HCl (3 × 20 ml 3 M HCl). The organic extract was
dried (Na2SO4), filtered and evaporated under reduced pressure.
The residue was further dried in a desiccator (SiO2) under
reduced pressure for 12 hrs and recrystalised from methanol
to give the calix[4]arene 3c (0.14 g, 40%) as light brown cubes;
5,11,17,23-Tetrakis[(E)-N-(4-cyanophenyl)-acrylamido]-25,26,
27,28-tetra-n-butoxycalix[4]arene 5b. Triethylamine (0.335 ml,
0.157 g, 1.56 mmol) and 4-cyanophenylacrylamide 4b (0.33 g,
2.08 mmol) were added to a stirred solution of 5,11,17,23-
tetraiodocalixarene-25,26,27,28-tetra-n-butylether
0.26 mmol) in DMF (20 ml). After 10 min of vigorous
mp 254–256 ◦C; mmax (Nujol)/cm−1 1645 (C C) 1620 (C O);
=
=
1 (0.3 g,
=
dH(270 MHz; CDCl3) 7.32 (4H, d, J 15.5, Ar–CH ), 6.82 (8H,
=
=
J 13.4, s, Ar–H), 6.46 (4H, d, J 15.5, Ar–CH CH–C O), 4.42
(4H, d, J 13.5, CHAHBAr), 3.90 (8H, t, J 7.5, CH2O), 3.73–3.56
(16H, m, H2COCH2), 3.72–3.70 (16H, m, H2CN(CO)CH2), 3.19
(4H, d, J 13.5, CHAHBAr), 1.90–1.88 (8H, m, CH2CH2O), 1.50–
1.44 (8H, m, OCHCH2CH2), 1.00 (12H, t, J 8.3, CH3CH2); dC
(CDCl3) 165.7, 158.3, 143.1, 135.3, 129.4, 128.0, 114.3, 75.2,
66.8, 45.5, 42.1, 32.3, 30.9, 19.3, 14.1; m/z (EI) 1206 [M+].
Found C, 65.49; H, 7.35; N, 4.13% C72H92N4O12·6H2O requires
C, 65.83; H, 7.98; N, 4.27%.
◦
stirring at 25 C, palladium acetate (0.006 g, 0.026 mmol) and
diphenylphosphinopropane (0.011 g, 0.026 mmol) were added,
the mixture heated to 100 ◦C and stirred for 24 h. After addition
of 50 ml DCM the mixture was washed with HCl (3 × 20 ml,
3 M). The organic extract was dried (Na2SO4), filtered and
evaporated under a reduced pressure. The residue was further
dried in a desiccator (SiO2) under a reduced pressure for 12 h
and purified via column chromatography (SiO2, EtOAc–hexane
1 : 2) to give the calix[4]arene 5b (0.19 g, 55%) as off-white
cubes; mp 180–183 ◦C; mmax (Nujol)/cm−1 3312 (N–H), 2228
5,11,17,23-Tetrakis[(E)-N-(methylbenzyl)-acrylamido]-25,26,
27,28-tetra-n-butoxycalix[4]arene 3d. Triethylamine (0.335 ml,
0.157 g, 1.56 mmol) and methylbenzylacrylamide 2d (0.364 g,
2.08 mmol) were added to a stirred solution of 5,11,17,23-
=
=
(CN), 1686 (C O), 1604 (C C); dH(500 MHz; d6-DMSO)
10.43 (4H, s, NH), 7.72 (8H, d, J 8.8, Ar–H (benzenenitrile)),
7.61 (8H, d, J 8.8, Ar–H (benzenenitrile)), 7.32 (4H, d, J
=
tetraiodocalixarene-25,26,27,28-tetra-n-butylether
(0.3
g,
15.5, Ar–CH ), 6.97 (8H, s, Ar–H), 6.42 (4H, d, J 15.5,
=
=
0.26 mmol) 1 in DMF (20 ml). After 10 min of vigorous
stirring at 25 ◦C, palladium acetate (0.006 g, 0.026 mmol)
and diphenylphosphinopropane (0.011 g, 0.026 mmol) were
added, the mixture heated to 100 ◦C and stirred 325 h. After
addition of 50 ml diethylether the mixture was washed with
HCl (3 × 20 ml, 3 M). The organic extract was dried (Na2SO4),
filtered and evaporated under a reduced pressure. The residue
was further dried in a desiccator (SiO2) under a reduced
pressure for 12 h and purified via column chromatography (1 : 5
Ar–CH CH–C O), 4.41 (4H, d, J 13.8, CHAHBAr), 3.93 (8H,
t, J 6.4, CH2O), 3.31 (4H, d, J 13.8, CHAHBAr), 1.90 (8H, m,
CH2CH2O), 1.50–1.38 (8H, m, OCHCH2CH2), 1.00 12H, t, J
8.3, CH3CH2); dH (500 MHz; CDCl3) 11.20 (8H, s, NH), 8.21
(8H, d, J 8.7, Ar–H (benzenenitrile)), 7.72 (8H, d, J 8.7, Ar–H
=
(benzenenitrile)), 7.05 (4H, d, J 15.5, Ar–CH ), 6.84 (4H, s,
=
=
Ar–H), 6.42 (4H, d, J 15.5, Ar–CH CH–C O), 5.77 (4H, s,
Ar–H), 4.22 (4H, d, J 11.8, CHAHBAr), 3.74 (8H, dd, J 12.7
J 8.1, CH2O), 2.63 (4H, d, J 11.8, CHAHBAr), 1.92 (8H, m,
2 1 8 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 1 7 5 – 2 1 8 2

View Article Online
CH2CH2O), 1.44–1.20 (8H, m, OCHCH2CH2), 1.00 (12H, t,
J 8.3, CH3CH2); dc (d6-DMSO) 167.4, 155.2, 139.9, 139.2,
134.6, 133.9, 127.1, 122.7, 120.3, 119.9, 116.2, 96.3, 76.6, 32.5,
33.0, 19.7, 15.1; m/z (LSIMS) 1329 [M+]; m/z (ESI, negative
with DCM (2 × 100 ml) and the organic layer stirred with
distilled water (300 ml) for 5 h. Separation of the organic layer
preceded the removal of the solvent under a reduced pressure.
The residue was further dried in a desiccator (SiO2) under a
reduced pressure for 12 h to give the calix[4]arene 8 (60 mg,
33%) as light brown shards; mp 120–123; mmax (Nujol)/cm−1
−
ion mode in MeOH) 2689.2 [M2 + CH3OH] C165H164N16O17;
found C, 75.79; H, 6.37; N, 8.29% C84H80N8O8 requires C,
75.88; H, 6.06; N, 8.43%.
=
=
3501 (N–H), 3384 (N–H (amide)), 1748 (C O), 1615 (C C);
dH(270 MHz; d6-DMSO) 9.62 (4H, s, NH), 7.33 (8H, d, J 7.8,
5,11,17,23-Tetrakis[(E)-N -(4-trifluoromethylphenyl)-acryl-
amido]-25,26,27,28-tetra-n-butoxycalix[4]arene 5c. Triethyl-
amine (0.335 ml, 0.157 g, 1.56 mmol) and 4-trifluoromethyl-
phenylacrylamide 4c (0.399 g, 2.08 mmol) were added to a
stirred solution of 5,11,17,23-tetraiodocalixarene 25,26,27,28-
tetra-n-butylether (0.3 g, 0.26 mmol) 1 in DMF (20 ml).
After 10 min of vigorous stirring at 25 ◦C, palladium acetate
(0.006 g, 0.026 mmol) and diphenylphosphinopropane (0.011 g,
0.026 mmol) were added, the mixture heated to 100 ◦C and
stirred for 175 h.
=
Ar–H (aminobenzene)), 7.22 (4H, d, J 15.5, Ar–CH ), 7.04
(8H, s, Ar–H), 6.48 (8H, d, J 7.8, Ar–H (aminobenzene)), 6.39
=
=
(4H, d, J 15.5, Ar–CH CH–C O), 4.80 (8H, s, NH2), 4.38
(4H, d, J 11.8, CHAHBAr), 3.92 (8H, t, J 6.4, CH2O), 3.22 (4H,
d, J 11.8, CHAHBAr), 1.90 (8H, m, CH2CH2O), 1.46–1.39 (8H,
m, OCHCH2CH2), 1.00 (12H, t, J 8.3, CH3CH2); dc (d6-DMSO)
151.4, 143.9, 143.5, 138.1, 134.7, 127.1, 126.9, 122.7, 120.7,
120.3, 113.9, 75.2, 36.2, 32.5, 19.2, 14.2; m/z (LSMIS) 1289
[M+]; found C, 71.75; H, 6.95; N, 8.00% C80H88N8O8·2H2O
requires C, 72.48; H, 7.00; N, 8.45%.
After cooling to rt and addition of HCl (50 ml, 2 M) the
mixture was filtered and the residue washed with water (100 ml)
and methanol (100 ml). The organic extract was dried (Na2SO4),
filtered and evaporated under a reduced pressure. The residue
was further dried in a desiccator (SiO2) under a reduced pressure
for 12 h and recrystalised from methanol to give the calix[4]arene
5c; mp 235–240 ◦C; dH(300 MHz; d6-DMSO) 10.34 (4H, s,
HNCO), 7.69 (8H, d, J 10.0, Ar–H (triflouromethylaniline)),
7.43 (8H, d, J 10.0, Ar–H (triflouromethylaniline), 7.25 (4H, d,
5,11,17,23-Tetrakis[(E)-N-(4-acetamidophenyl)-acrylamido]-
25,26,27,28-tetra-n-butoxycalix[4]arene
9. Triethylamine
(0.335 ml, 0.157 g, 1.56 mmol) and 4-acrylamidephenylacet-
amide (0.428 g, 2.10 mmol) were added to a stirred solution of
5,11,17,23-tetraiodocalixarene-25,26,27,28-tetra-n-butylether
(0.3 g, 0.26 mmol) 1 in DMF (20 ml). After 10 min of vigorous
◦
stirring at 25 C, palladium acetate (0.006 g, 0.026 mmol) and
diphenylphosphinopropane (0.011 g, 0.026 mmol) were added,
the mixture heated to 100 ◦C and stirred for 275 h.
=
J 15.10, Ar–CH ), 6.92 (8H, s, Ar–H), 6.27 (4H, d, J 15.20,
=
CH–C O), 4.35 (4H, d, J 13.8, CHAHBAr), 3.89 (8H, q, J 6.3,
After addition of 50 ml HCl (2 M) the mixture was filtered and
washed with water (100 ml) and methanol (100 ml). The organic
extract was dried (Na2SO4), filtered and evaporated under a
reduced pressure. The residue was further dried in a desiccator
(SiO2) under a reduced pressure for 12 h and recrystalised from
hot methanol to give the calix[4]arene 9 (0.15 g, 49%) as dark
brown microcrystals; mp 219–221 ◦C; mmax (Nujol)/cm−1 3398
OCH2CH2), 3.30 (4H, d, J 13.8, CHAHBAr), 1.89–1.72 (8H, m,
CH2CH2O), 1.47–1.37 (8H, m, OCH2CH2CH2), 0.94 (12H, t, J
8.2, CH3CH2); dC (d6-DMSO) 164.5, 143.3, 141.4, 136.7, 135.7,
129.3, 129.1, 128.1, 126.7, 126.4, 126.3, 119.2, 74.9, 32.0, 30.5,
18.9, 14.0; m/z (LSIMS) 1525 [M + 1H + Na)]; found C, 64.63;
H, 5.53; N, 4.59% C84H80F12O8N4·2DMF requires C, 65.60; H,
5.75; N, 5.10%.
=
=
=
(N–H), 3384 (N–H), 1748 (C O), 1732 (C O), 1615 (C C);
dH(300 MHz; d6-DMSO) 10.33 (4H, s, CH3CONH), 9.89 (4H, s,
5,11,17,23-Tetrakis[(E)-N-(benzyl)-acrylamido]-25,26,27,28-
tetra-n-butoxycalix[4]arene 5d. Triethylamine (0.314 ml,
0.210 g, 2.083 mmol) and benzylacrylamide 4d (0.251 g,
1.56 mmol) were added to a stirred solution of 5,11,17,23-
tetraiodocalixarene-25,26,27,28 tetra-n-butylether (0.3 g,
0.26 mmol) 1 in DMF (20 ml). After 10 min of vigorous
=
C CHCONH), 7.50 (8H, d, J 8.3, Ar–H (anilide)), 7.40 (8H,
d, J 8.3, Ar–H (anilide)), 7.38 (4H, d, J 15.9, Ar–CH ), 7.00
=
=
=
(8H, s, Ar–H), 6.49 (4H, d, J 15.9, Ar–CH CH–C O), 4.39
(4H, d, J 12.1, CHAHBAr), 3.93 (8H, t, J 6.8, CH2O), 3.37 (4H,
d, J 12.1, CHAHBAr), 2.02 (12H, s, CH3CON), 1.90 (8H, m,
CH2CH2O), 1.50–1.47 (8H, m, OCHCH2CH2), 1.02 (12H, t, J
8.3, CH3CH2); dc (d6-DMSO) 169.2, 165.0, 158.9, 146.3, 142.6,
135.8, 129.1, 129.0, 128.8, 125.6, 126.1, 119.7, 75.2, 36.2, 32.5,
24.8, 19.2, 14.2; m/z (EI) 1481[M + Na]; found C, 69.86; H,
6.20; N, 6.61% C88H96N8O12·4H2O requires C, 69.09; H, 6.85; N,
7.32%.
◦
stirring at 25 C, palladium acetate (0.006 g, 0.026 mmol) and
diphenylphosphinopropane (0.011 g, 0.026 mmol) were added,
the mixture heated to 100 ◦C and stirred for 48 h.
After addition of 50 ml DCM the mixture was washed
with HCl (3 × 20 ml, 3 M). The organic extract was dried
(Na2SO4), filtered and evaporated under a reduced pressure.
The residue was further dried in a desiccator (SiO2) under a
reduced pressure for 12 h and recrystalised from hot methanol
to give the calix[4]arene 5d (0.21 g, 65%) as pale brown cubes;
Diffusion NMR spectra
Diffusion NMR spectra were obtained following the procedure
of: E. J. Cabrita and S. Berger, Magn. Reson. Chem., 2001,
39, 142. Typical conditions for diffusion NMR spectra using
a Bruker AMX 500 Avance instrument with standard Bruker
diffusion software were as follows: d = 3 ms, D = 35 ms, ten
gradients from 98% to 2% using 256 scans each, using a field
gradient tritium/proton cryoprobe.
mp 151–154 ◦C; mmax (Nujol)/cm−1 3275 (N–H), 1656 (C O),
=
=
1542 (C C); dH(270 MHz; CDCl3) 7.31–7.19 (24H, m, Ar–
=
CH & Ar–H (benzyl)), 6.74 (8H, s, Ar–H), 6.09 (4H, d, J
=
=
15.5, Ar–CH CH–C O), 4.51 (8H, d, 5.7, CH2NH), 4.41 (4H,
d, J 13.9, CHAHBAr), 3.88 (8H, t, J 7.8, CH2O), 3.12 (4H, d, J
13.9, CHAHBAr), 1.90 (8H, m, CH2CH2O), 1.46–1.39 (8H, m,
OCHCH2CH2), 1.00 (12H, t, J 8.3, CH3CH2); dC (CDCl3) 165.0,
157.2, 138.3, 134.7, 128.9, 128.2, 128.1, 128.0, 127.5, 127.3,
126.6, 76.6, 43.7, 32.2, 30.1, 19.7, 14.1. m/z (EI) 1286 [M+];
found C, 75.95; H, 7.17; N, 4.26% C84H92N4O8·2H2O requires C,
76.33; H, 7.32; N, 4.24%.
Acknowledgements
We would like to thank the EPSRC for a studentship for A. L. G.
and the European Union for further financial support (project
“Pesticide”; No. ICA2-CT-2000-10002). Furthermore, N. K.
would like to thank Prof. A. Danil de Namor, Prof. P. Sammes
and Dr S. Faulkner for helpful discussions and Ms J. Peters,
Mr R. Chaundy, Ms N. Walker and Mr J. Bloxsidge for
their excellent technical support. We acknowledge the excellent
service of the EPSRC National Mass Spectrometry Service in
Swansea.
5,11,17,23-Tetrakis[(E)-N-(4-aminophenyl)-acrylamido]-25,26,
27,28-tetra-n-butoxycalix[4]arene 8. SnCl2·2H2O (0.478 g,
2.2 mmol) was added to a stirred solution of 5,11,17,23-
tetranitrophenylacrylamidocalixarene-25,26,27,28-tetra-n-butyl-
ether 5a (0.15 g, 0.12 mmol) in ethanol (25 ml). After 6 h of
vigorous reflux, the mixture was poured onto ice 100 g and the
pH adjusted to 8 with NaOH (2 M). The product was extracted
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 1 7 5 – 2 1 8 2
2 1 8 1

View Article Online
14 N. Kuhnert and A. Le-Gresley, J. Chem. Soc., Perkin Trans. 1, 2001,
3393.
References
1 A. M. Lesk, Introduction to Protein Architecture, Oxford University
Press, Oxford, 1st edn, 2001.
2 L. J. Prins, D. N. Reinhoudt and P. Timmerman, Angew. Chem., Int.
Ed., 2001, 40, 2382.
3 C. Hamann, K. D. Shimizu and J. Rebek, Jr., Angew. Chem., Int. Ed.
Engl., 1996, 37, 1526.
4 K. D. Shimizu and J. Rebek, Jr., Proc. Natl. Acad. Sci. USA, 1995,
92, 12403.
5 (a) J. Rebek, Jr., Chem. Commun., 2000, 637; (b) F. Hof, S. L. Craig,
C. Nuckolls and J. Rebek, Jr., Angew. Chem., Int. Ed., 2002, 41, 1488.
6 O. Mogck, V. Bo¨hmer and W. Vogt, Tetrahedron, 1996, 52, 8489.
7 A. M. Rincon, P. Prados and J. de Mendoza, Eur. J. Org. Chem.,
2002, 640.
15 N. Kuhnert, A. Lopez-Periago and G. M. Rossignolo, Org. Biomol.
Chem., 2003, 1, 1157.
16 The number of 120 possible isomers uses the assumption that mon-,
di-, tri- and tetra-substitution products are possible as a- or b-
insertion products, in cis or trans stereochemistry and in various
calix[4]arene conformations such as cone, 1,2-alternate and 1,3-
alternate.
17 H. C. Zhao, P. Ming-Zhong, Y. Chun; and C. S. Song, J. Chem. Res.,
2002, 28.
18 C. D. Gutsche, Aldrichim. Acta, 1995, 28, 7.
19 O. Mogck, M. Pons and V. Bo¨hmer, J. Am. Chem. Soc., 1997, 119,
5706.
20 C. W. Haigh and R. B. Mallion, Progr. Nucl. Magn. Reson. Spectrosc.,
8 L. Frish, F. Sansone, A. Casnati, R. Ungaro and Y. Cohen, J. Org.
Chem., 2000, 65, 5026.
9 M. Lazzarotto, F. Sansone, L. Baldini, A. Casnati, P. Cozzini and R.
Ungaro, Eur. J. Org. Chem., 2001, 66, 595.
1980, 33, 303.
21 L. Frish, M. O. Vysotsky, S. E. Mathews, V. Bo¨hmer and Y. Cohen,
J. Chem. Soc., Perkin Trans. 2, 2002, 88.
22 L. Frish, S. E. Mathews, V. Bo¨hmer and Y. Cohen, J. Chem. Soc.,
Perkin Trans. 2, 1999, 669.
10 L. R. MacGillivray and J. L. Atwood, Nature, 1997, 389, 469.
11 F. Carbellini, L. Di Constanzo, M. Crego-Calama, S. Geremia and
D. N. Reinhoudt, J. Am. Chem. Soc., 2003, 125, 9946.
12 R. Zadmard, M. Junkers, T. Schrader, T. Grawe and A. Kraft, J. Org.
Chem., 2003, 68, 6511; R. Zadmard, A. Kraft, T. Schrader and U.
Linne, Chem. Eur. J., 2004, 10, 4233.
23 C. E. Atkinson, A. E. Aliev and W. B. Motherwell, Chem. Eur. J.,
2003, 9, 1714; Y. Cohen, L. Avram and L. Frish L., Angew. Chem.,
Int. Ed., 2005, 44, 520 (and references cited therein).
24 J. A. Brunink, W. Verboom, J. F. Engbersen, S. Harkema and
D. N. Reinhoudt, Recl. Trav. Chim. Pays-Bas, 1992, 111, 511
(acrylamides).
13 N. Kuhnert and A. Le-Gresley, Chem. Commun., 2003, 2426–2427.
2 1 8 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 1 7 5 – 2 1 8 2