Self-assembly of small peptidomimetic cyclophanes

Article abstract of DOI:10.1002/chem.200400031

The self-assembly of a series of small peptidomimetic cyclophanes in organic solvents was studied. X-ray diffraction, NMR spectroscopy, and molecular modelling were used to understand the structural features of these self-assembling compounds both at the molecular and supramolecular level. The factors that could influence the formation of gels rather than crystals were studied and a model for the arrangement of molecules in the gel was proposed. Furthermore, scanning electron microscopy revealed that in some cases these compounds undergo a transcription of chirality when going from organogelator to helicoidal gel fibres.

Full text of DOI:10.1002/chem.200400031

FULL PAPER
Self-Assembly of Small Peptidomimetic Cyclophanes
[a]
Jorge Becerril,[a] M. Isabel Burguete,[a] BeatriuEscuder,*
Francisco Galindo,[a]
Raquel Gavara,[a] Juan F. Miravet,[a] Santiago V. Luis,*[a] and Gabriel Peris[b]
Abstract: The self-assembly of a series
of small peptidomimetic cyclophanes in
organic solvents was studied. X-ray dif-
fraction, NMR spectroscopy, and mo-
lecular modelling were used to under-
stand the structural features of these
self-assembling compounds both at the
molecular and supramolecular level.
The factors that could influence the
formation of gels rather than crystals
were studied and a model for the ar-
rangement of molecules in the gel was
proposed. Furthermore, scanning elec-
tron microscopy revealed that in some
cases these compounds undergo a tran-
scription of chirality when going from
organogelator to helicoidal gel fibres.
Keywords: gels ¥ helical structures ¥
peptidomimetics ¥ self-assembly ¥
supramolecular chemistry
Introduction
Unfortunately, in most cases the gelation ability of such
compounds has been discovered serendipitously, and the re-
sults of the structural factors involved in the process seem to
be quite dependent on the studied case. Nowadays, a major
effort is directed towards the controlled design of com-
pounds with the appropriate functionalities to obtain the de-
sired gel. As a result, there is an intriguing question with
regard to the transcription of information from the molecu-
lar level to the microscale supramolecular structure of these
materials. Thus, although there are many techniques such as
electron microscopy and X-ray and neutron scattering tech-
niques (SAXS, SANS, etc.) to study the microscopic features
of the gels, it remains difficult to obtain direct information
about the individual molecular organisation inside the
fibres. One of the most convenient approaches to undertake
this objective is to obtain indirect structural information
through the study of structurally related compounds that
have single crystal structures available.[5]
Among the diverse number of low molecular weight struc-
tures found to form gels in organic solvents, amino acid frag-
ments are one of the most common building blocks.[6] For in-
stance, some time ago the Z-protected acyclic precursors of
1 5 were reported as good organogelators, their gelation
ability being based on the presence of the carbamate group
(Scheme 1).[7] Other examples of low molecular weight orga-
nogelators that contain peptides are found in the literature,
but only a few of these are cyclic peptidomimetic organoge-
lators.[8] Recently, we found that peptidomimetic cyclo-
phanes that contain L-valine such as 8b and 8c were able to
form gels in organic solvents.[9] Here we report on the syn-
thesis and study of those molecules as well as several closely
related analogues. The main aim of this workis to highlight
the structural features responsible for their assembly.
In the last decade a large number of low molecular weight
compounds capable of reversibly forming gels in both organ-
ic liquids and water have been reported.[1,2] This class of
compounds is able to self-assemble into fibres of several mi-
crometer length that further crosslinkand entrap solvent
molecules, thus affording a soft, solid-like material. The sin-
gular physical and chemical properties of these materials
have resulted in studies focussing towards their development
as novel functional materials for use in drug delivery pro-
cesses, responsive materials, catalysis, and so forth.[3] The
synthesis of chiral nano- and microstructures is of great in-
terest in many fields of chemistry and technology. For exam-
ple, organogels have been used as templates for the prepara-
tion of nanotubular materials such as the hollow helicoidal
silicas prepared by Shinkai et al. in which a clear transcrip-
tion of chirality from the molecular to the supramolecular
level was observed. This is not always straightforward and
generally requires precise design of a molecule with appro-
priate functionalities.[4]
[a] J. Becerril, Dr. M. I. Burguete, Dr. B. Escuder, Dr. F. Galindo,
R. Gavara, Dr. J. F. Miravet, Prof. Dr. S. V. Luis
Departament de QuÌmica Inorg‡nica i Org‡nica
Universitat Jaume I, 12071 CastellÛ (Spain)
Fax : (+34)964-728-214
E-mail: escuder@qio.uji.es
[b] Dr. G. Peris
Serveis Centrals d’InstrumentaciÛ CientÌfica
Universitat Jaume I, 12071 CastellÛ (Spain)
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
Chem. Eur. J. 2004, 10, 3879 3890
DOI: 10.1002/chem.200400031
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3879

FULL PAPER
the two amide groups; 3) the
macrocyclic nature of the gela-
tor; and general factors such as
4) the solvent; and 5) the cool-
ing rate.
1) As can be seen in Table 1,
compounds 8b, 8c, 10b and
10c, which are derived from
natural b-methyl substituted
amino acids l-valine and l-
isoleucine, form gels in aro-
matic solvents and ethyl
acetate. In contrast, com-
pounds 9a and 9c, which
Scheme 1. i) N-hydroxysuccinimide, DCC, THF, 08C; ii) H2N(CH2)nNH2, DME, room temperature; iii) HBr in
AcOH (33%, basic work-up; and iv) 1,3-bis(bromomethyl)benzene, tetrabutylammonium bromide, CH3CN,
reflux.
Results and Discussion
contain isobutyl fragments derived from l-leucine, with
a methyl group in the g position, do not form gels in aro-
matic solvents. Instead, they are either soluble or precip-
itate out of solution; this is dependent on the polarity of
the solvent. In general, compounds derived from l-ala-
nine and l-glycine are only slightly soluble in aromatic
solvents.
Synthesis: Peptidomimetic cyclophanes 6 10 were prepared
from a commercially available N-carbobenzyloxy protected
amino acid following previously reported procedures
(Scheme 1).[10] All compounds were purified by column
chromatography and characterised by mass spectrometry as
well as 1H and 13C NMR spectroscopy (see Supporting Infor-
mation).[11]
2) Compounds 8a and 10a, which bear only two methylene
groups as aliphatic spacers, do not form gels.
Gelation behaviour: The gelation behaviour of compounds
6 10 was studied in a series of organic solvents. Typically,
the desired amount of macrocycle was mixed with the sol-
vent in a screw-capped vial, heated to the boiling tempera-
ture of the solvent, and left to cool by standing at room tem-
perature. The formation of a gel was checked by turning the
vial upside down. Transparent gels of different strength
were formed in this manner (Table 1). The critical organoge-
3) The macrocyclic structure plays an important role in the
gelation properties of these compounds. This has been
demonstrated by preparing compound 11b, which is an
open chain benzylated analogue of 8b, as it does not
form gels in any of the studied organic solvents. Substitu-
tion of the aromatic moiety is also a determining factor.
For example, when the m-phenylene unit in 8b is re-
placed by a p-phenylene (12b), or a 1,4-naphthylidene
(13b) fragment, gels do not form.
4) Gels are formed only in low polarity solvents. For exam-
ple, gels are not formed when the solvent is an alcohol,
indicating that hydrogen bonding may play an important
part in the gelation behaviour of these compounds.
5) Transparent gels are formed when the hot solutions are
left to spontaneously cool to room temperature or when
they are cooled to 08C in an ice bath. However, when a
0.5 wt% weight solution of compound 8b in benzene
was cooled at a constant rate of 0.58CminÀ1 in a thermo-
statted bath, a fibrilar coagulated precipitate appeared at
508C rather than a gel.
Table 1. Gelation behaviour of compounds 8, 10b, and 10c in organic
solvents.[a]
Solvent
8b
8c
10b
10c
benzene
toluene
xylene
styrene
anisole
G
G
G
G
G
G
G
G
P
P
G
G
G
wG
wG
wG
wG
wG
G
wG
wG
wG
S
G
G
P
nitrobenzene
EtOAc
wG
[a] G: gel; wG: weakgel; S: soluble; P: precipitate.
lator concentration was in the range of 0.3 0.5 wt% for all
the aromatic solvents and 1 wt% in ethyl acetate. Gels were
only formed by compounds 8b, 8c, 10b and 10c in the sol-
vents studied, and none of the compounds jellified in either
alcohols, THF, chloroform or dichloromethane. The Tg
values of the resultant gels were determined by the ™drop-
ping-ball method∫ and were in the range of 35 408C.[12]
At first glance it was rather surprising to find that only
four of the studied compounds formed gels despite the close
structural resemblance among them. Several factors need to
be taken into account in the study of the relationship be-
tween the molecular structure and the gelation behaviour of
these compounds and include: 1) the amino acid residues
utilised; 2) the length of the aliphatic spacer that separates
Electron microscopy: The microscopic structure of the or-
ganogels formed by compounds 8b, 8c, 10b and 10c was
studied by scanning electron microscopy. In every case, an
entangled networkof fibres of up to 100 mm length was ob-
served. A closer lookrevealed that some of these fibres had
an helicoidal shape, especially in the gels formed by com-
pounds 8b and 10b in benzene. As can be seen in Figure 1,
compounds 8b and 10b form right-handed helicoidal fibres
of about 8 mm pitch and 1.5 mm width. Whereas helices
coiled into larger fibres were observed if cooling was accom-
plished by standing at room temperature, an increase in the
number of isolated helices together with a decrease in their
dimensions was found when a gel of 8b in benzene was
formed by cooling the solution quickly in an ice bath. Simi-
3880
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 3879 3890

Self-Assembly of Small Peptidomimetic Cyclophanes
3879 3890
haviour of compounds 6 10, we
conducted a detailed study of
the conformational features of
those compounds. For this pur-
pose, analysis of data from X-
ray diffraction, NMR spectros-
copy, and molecular modelling
was very helpful. Molecular
mechanics calculations for com-
pounds 6 10 were performed,[13]
and the results revealed a high
conformational
variabiblity.
Several features such as tor-
sional angles involving the
amide and amine groups, the
relative disposition of the aro-
matic unit, as well as the pres-
ence of intramolecular hydro-
gen bonds were very sensitive
to subtle structural modifica-
tions.
Especially interesting is the
variability of the torsional
angles in which the amide
groups are involved, as they are
the most likely to be involved
in hydrogen bonding interac-
tions in the supramolecular ag-
gregates. For example, com-
Figure 1. Scanning electron micrographs of the gels formed by: compound 8b in benzene (A), styrene (B), and
nitrobenzene (C); by compound 10b in benzene (D); and by compound 10c in benzene (E) and ethyl acetate
(F).
pound 9b shows
a
lowest
lar, but less defined twisted fibres were observed in toluene,
styrene, xylene, anisol, and ethyl acetate gels, while in nitro-
benzene only straight fibres were found. On the other hand,
as noted above, the slow cooling of a 0.5 2.0 wt% hot solu-
tion of compound 8b in benzene at 0.58CminÀ1 in a thermo-
statted bath led to the precipitation of the gelator. For the
most concentrated solutions (2 wt%), a coagulated gel
(coagel) was formed at about 508C. Scanning electron mi-
crographs revealed a networkof straight fibres of several
micrometer length in which expression of chirality had not
occurred (see Supporting Information).
CD spectroscopy: To obtain information on the chirality of
Figure 2. Temperature variable CD spectra of compound 8b in benzene.
the organogel formed by compound 8b in benzene, circular
dichroism (CD) spectra were recorded at different tempera-
tures during the gelation process, and an aggregation-in-
duced increase on the CD signal was observed. As can be
seen in Figure 2, formation of the organogel was accompa-
nied by an increase in the negative CD band centred at
about 277 nm. As clear exciton-coupling bands were not
found, we could not obtain any further information on the
supramolecular chirality of the gel. Similar results were
found in other solvents such as ethyl acetate and dichloro-
methane.
À
À
energy conformation in which the O=C Ca H torsional
angles are both in a syn-type conformation (0.38, 16.78) and
one C=O group is intramolecularly hydrogen bonded to an
À
amine and an amide N H. However, the lowest energy con-
formation found for the closely related compound 8b is re-
markably different. In particular, the above mentioned tor-
sional angles are in an anti-type disposition (À124.98,
À157.28) and only one intramolecular hydrogen bond is
found (Figure 3). Moreover, structures that differed signifi-
cantly from the global minimum were found in a narrow
À1
Structural studies: To understand the large influence that
energy range (<5 k Jmol ), and molecular dynamic simula-
small changes in molecular structure had on the gelation be-
tions showed that these structures could easily be intercon-
Chem. Eur. J. 2004, 10, 3879 3890
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3881

B. Escuder, S. V. Luis et al.
FULL PAPER
Figure 3. Calculated structures for compounds 8b (top) and 9b (bottom).
À
À
verted. For example, conformations with both O=C Ca
H
torsional angles in a syn-type disposition as well as in an
anti-type were found within a 1 kJmolÀ1 range for com-
pound 9b, and within a 3 kJmolÀ1 range for compound 8b.
The flexibility of these macrocycles is consistent with the
different self-assembling properties they display upon small
structural variations. These variations could shift the confor-
mational preferences of the different molecules and influ-
ence the efficiency of the aggregation processes.
Although the best approach toward understanding the
fibre structure at the molecular level is by studying single
crystals of the organogelator in the gel medium, this is only
possible in a limited number of cases.[14] However, if one
considers gelation as an incomplete crystallisation, it is feasi-
ble that in some cases a subtle change in the crystallisation
conditions or a small structural modification may lead to
single crystals that are suitable for X-ray diffraction studies.
With this information, and keeping in mind that aggregate
assembly in the gel and solid state may be different, it is
possible to propose a model for the manner in which the
molecules packinto fibres. Although in our studies we were
not able to obtain single crystals for compounds 8b, 8c, 10b
or 10c in any of the solvents in which they formed gels, we
were able to grow single crystals of the closely related com-
pounds 6c, 7c, 9a, 9b and 13b. It should be noted that the
crystal structures of compounds 8a and 12a in dichlorome-
thane have recently been reported.[10,15]
Figure 4. Three-dimensional packing found in the crystal structures of
compounds 6c (top) and 8a (bottom).
the construction of a one-dimensional hydrogen-bonded net-
workin which the intercolumnar pacikng is achieved
through van der Waals interactions (Figure 5A).
Compound 9a crystallises in the monoclinic crystal system
and P21 space group. A columnar hydrogen bond assembly
is also formed, but as can be seen in Figure 5B, two differ-
ent parallel arrays of hydrogen bonds are present. One of
them is formed by an interaction between an amide C=O
À
group and an amide N H of a neighbouring molecule
(2.17 ä, 158.48), while the other hydrogen-bonded chain
comes from an interaction between the second amide C=O
group, which is disposed in a slightly tilted parallel orienta-
À
tion to the first one, and an amine N H group of the vicinal
Compound 6c crystallises in benzene in the orthorhombic
crystal system and Pna21 space group. Each molecule is con-
nected to their neighbours by multiple hydrogen bonds that
form a three-dimensional network(Figure 4). Poorly direc-
tional intramolecular hydrogen bonds with distances of 2.2
molecule (2.35 ä, 159.58). The intercolumnar packing arises
from van der Waals interactions between the leucine side
chains, and the contact distances of about 4 ä are similar to
those found in examples reported for some natural and syn-
thetic leucine-containing peptides.[17]
À
2.4 ä are found between the amide N H and the amine ni-
Compound 9b crystallises in benzene in the triclinic crys-
tal system and P1 space group. The unit cell is composed of
two molecules that correspond to two different conformers
trogen lone pairs.[16]
Compound 7c crystallises in the monoclinic crystal system
and P21 space group. In this case, molecules are assembled
into columns by four hydrogen bonds between the amide
groups (C=O¥¥¥H N amide) with distances of about 2.1 ä.
The anti-parallel orientation of the amide groups favours
À
of 9b, and displays five intermolecular N H¥¥¥O=C hydro-
gen bonds per molecule that have distances in the range of
1.9 2.2 ä (Figure 5C and 6). The crystal packing reveals a
columnar assembly through hydrogen bonds and an interco-
À
3882
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 3879 3890

Self-Assembly of Small Peptidomimetic Cyclophanes
3879 3890
gen-bonded array. Two intermolecular hydrogen bonds arise
À
between the C=O group and the amide N H of a neigh-
bouring molecule (2.06 and 2.26 ä). The aromatic fragments
are stacked parallel to each other at a distance of about
3.6 ä (Figure 5D).
The conformations found in the crystal structures are in
agreement with the conformational variability determined
by the previously described molecular mechanics calcula-
tions. For example, compound 9b contains two different
À
conformers in its unit cell. One displays two anti-type O=C
À
Ca H torsional angles (conformer A, Figure 6), while the
other one contains two syn-type angles (conformer B,
Figure 6).
A comparison of the crystal packing in these structures
revealed significant differences. These were found to be de-
pendent on both the nature of the amino acid residue and
the length of the aliphatic spacer. Thus, the crystal structure
of compound 6c, which was derived from amino acid l-gly-
cine (R=H), shows a three-dimensional packing through
hydrogen bonding, whereas compound 7c, which was de-
rived from l-alanine (R=CH3), stacks into columns with a
one-dimensional hydrogen-bonded networkin which addi-
tional intercolumnar van der Waals interactions are respon-
sible for the final structure. In the latter compound, interco-
lumnar hydrogen bonds were not found probably because of
steric effects associated with the presence of an a-methyl
group. Compounds 9a and 9b, which are derived from l-
leucine (R=CH2CH(CH3)2), also form a columnar, one-di-
mensional hydrogen-bonded networksimilar to compound
7c. In contrast, the length of the aliphatic spacer appears to
influence the crystal structure of compounds 8a and 9a. An
ethylenic spacer increases the rigidity of the ring system and
leads to the formation of strong intramolecular hydrogen
bonds. In compound 9a columnar packing is still main-
tained, but in compound 8a, which was derived from l-
valine (R=CH(CH3)2), the presence of multiple intramolec-
ular hydrogen bonds prevents the formation of columns and
leads to a two-dimensional hydrogen-bonded arrangement.
It appears that both factors, namely the higher accessibility
of the hydrogen bonding centres in 6c, and the presence of
groups that introduce strain in the ring system in 8a (shorter
spacer length, b-methyl substituent) are responsible for their
non-columnar packing.
Figure 5. Columnar arrangement found in the crystal structures of com-
pounds 7c (A), 9a (B), 9b (C), and 13b (D). Carbon-bound hydrogen
atoms have been omitted for clarity.
As we were not able to obtain single crystals for organo-
gelators 8b, 8c, 10b or 10c, X-ray powder diffraction experi-
ments were used to investigate their xerogels and precipi-
tates (Figure 7 and 8). From the results it can be seen that
they are polycrystalline, as there is a high degree of order
inside the fibres. Moreover, as already revealed from the
electron microscopy studies, the solvent used and the cool-
ing rate also influence the observed diffraction patterns. For
example, a similar diffractogram was obtained for xerogels
of compound 8b in benzene and ethyl acetate, in contrast
with that of the xerogel formed in nitrobenzene. It should
also be noted that the diffraction pattern of the precipitate
obtained by slow cooling of 8b in benzene was different to
that of the xerogel of 8b. The former is similar to the one
obtained for compound 9b when the solid was precipitated
under the same conditions, and is therefore, in agreement
Figure 6. X-ray single crystal structure of compound 9b. Two different
conformers (A and B) are found in the unit cell.
lumnar assembly through cooperative van der Waals interac-
tions (Figure 5C). The anti-parallel orientation of the amide
groups favours the construction of a one-dimensional hydro-
gen-bonded networkin which the leucine side chains are or-
thogonal to the column axis. The intercolumnar packing is
similar to that found in 9a, whereby the inter-residue distan-
ces are relatively short (ca. 3.8 ä).
Compound 13b crystallises in chloroform in the monoclin-
ic crystal system and P21 space group. The amide groups are
in an anti-parallel arrangement and form a columnar hydro-
Chem. Eur. J. 2004, 10, 3879 3890
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3883

B. Escuder, S. V. Luis et al.
FULL PAPER
and 6.7 ä, corresponding to the (10), (11) and (21) reflec-
tions of a columnar hexagonal packing. This difference in
packing could explain their different aggregation behaviour.
The results infer two possible conclusions. Firstly, it could
be argued that the molecular conformation of 8b is different
in the precipitate and gel. Although it is not possible to
completely discard this hypothesis, NMR data suggest that
1
this is not the case. In particular, the H NMR spectra of the
gel formed by 8b in [D6]benzene at both 30 and 508C are
almost identical (aside from the shift in the amide signal),
suggesting that the conformational preference does not sig-
nificantly change within this temperature range.[18] In view
of this, it could be argued that although the molecules ini-
tially have the same conformation, they form superaggre-
gates in different ways. As a result, a gel is formed at 208C,
while a polycrystalline precipitate occurs at 508C. This ex-
planation is perfectly reasonable if one considers gelation to
be a supramolecular polymerisation in which the main dif-
ference at 20 and 508C is the length of the supramolecular
aggregates formed. Indeed, NOE measurements obtained
by irradiation of the amide resonance showed positive en-
hancements at 508C but negative ones for the gels at 208C.
This behaviour is the result of the increased correlation
times obtained upon aggregation and, accordingly, as point-
ed out previously by Feringa and co-workers, the average
molecular weight is expected to be at least around 1500,
which in our case is in accordance with the presence of tet-
ramers or larger aggregates in solution.[2i] In the studied case
it seems that by slow cooling, at 508C the molecules super-
aggregate in a crystalline way that results in precipitation
and that the faster cooling till 208C leads to aggregates long
enough to drive the system towards a columnar hexagonal
packing that forms the fibres of the gel. These two packing
modes have a dramatic effect on the shapes observed by
electron microscopy. In one case, straight fibres are ob-
served, while in the other case, helices arise.
Figure 7. X-ray powder diffraction of the xerogels obtained for 8b (A)
and 10b (B) in benzene, and 8b (C) in ethyl acetate.
The diffractogram of a dried gel of 8b obtained from ni-
trobenzene was very similar to that obtained from the pre-
cipitate of the same compound in benzene. This solvent
probably represents a borderline situation in that the self-as-
sembly interactions are strong enough to promote physical
gelation, but the seminal supramolecular aggregates are not
long enough to yield the hexagonal superaggregation mode.
The above results can subsequently be used to provide a
tentative model for the supramolecular arrangement of com-
pounds 8b, 8c, 10b and 10c that leads to gel formation. It is
generally accepted that the formation of one-dimensional
assemblies is an essential requirement for the obtention of
long fibres. In our case it seems reasonable that compounds
8b, 8c, 10b and 10c could assemble into columns in a
manner that is similar to the way that their crystalline ana-
logues form. Furthermore, IR and NMR spectroscopy con-
firm the formation of strong hydrogen bonds during the ge-
lation process. As can be seen in Figure 9, the gelation pro-
Figure 8. X-ray powder diffraction of the solids obtained for 9b (A) and
8b (B) after slow precipitation in benzene, and the xerogel from 8b in ni-
trobenzene (C).
with the microscopic structure described above. This sug-
gests that compound 8b has at least two different packing
modes at the supramolecular level, and that these lead to
the two different diffraction patterns shown in Figure 7 and
8, respectively. The diffraction peaks shown in Figure 8A
are in agreement with those obtained after the single crystal
structure simulation of compound 9b, and thus, correspond
to a similar columnar arrangement of molecules. On the
other hand, the diffraction patterns displayed by the xero-
gels in Figure 7 show three sharp reflections at 17.7, 10.2,
cess for compound 8b is accompanied by an increase in the
À1
À
associated N H stretching peaks at 3330 and 3310 cm , the
appearance of a shifted C=O (amide I) band at 1625
1635 cmÀ1, and a decrease in the initial C=O band at
1680 cmÀ1. On the other hand, the H NMR spectra show a
1
3884
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 3879 3890

Self-Assembly of Small Peptidomimetic Cyclophanes
3879 3890
dihedral angle, that in 8a these angles have a syn-type dis-
position, while in 13b both are anti-type angles. It can be
seen in Table 2 that the measured NOE enhancements cor-
À
À
relate well with the O=C Ca H dihedral angles present in
À
À
Table 2. Dihedral angle O=C Ca H and Ha¥¥¥HN distances versus NOE
at 508C.
Compound
q [8]
Distance [d]
NOE [%]
H¥¥¥HN [ä]
À
Figure 9. IR spectra collected during the gelation process of the N H
stretching region (top) and C=O stretching amide I band (bottom) of
compound 8b in benzene. Arrows indicate the evolution of the band
upon gelation.
8a
30.42, 41.55
65.90, À172.10
À172.08, 177.40
128.5, À158.6
À4.7, 12.7
3.29, 3.25
3.07, 2.17
2.18, 2.22
2.47, 2.27
3.57, 3.61
2.38, 2.20
1.9
3.4
2.9
3.1
1.7
3.2
12a
13b
8b[a]
8c[a]
10b[a]
135.7, À170.9
downfield shift of the amide hydrogen signal upon gelation
(not shown). All the data concur with the observations that
gel formation does not occur in polar solvents because the
hydrogen-bond interactions are less intense.
[a] Values determined from model structures.
To gain information about molecular arrangement in the
supramolecular aggregates it is valuable to know the confor-
mation of the molecules in solution. NOE experiments were
particularly helpful in identifying the presence of conforma-
the different structures. In particular, they were around 3%
for those molecules with anti-type conformations and less
than 2% in the syn-type conformations. When compounds
8b and 10b, which behave as organogelators in benzene
were studied, NOE enhancements higher than 3% were
measured. This strongly suggests that anti-type dihedral
angles are present in these compounds.
Altogether, these data support the hypothesis that confor-
mations such as conformer A in crystal structure of 9b
(Figure 6) are the main constituents present for compounds
8b and 10b in benzene. This is also in agreement with the
conformation found in the crystal structure of the valine de-
rivative 13b. Most likely, the formation of aggregates from
these type of conformers should be responsible for the gel
formation. Indeed, as can be seen in Figure 10A, a mini-
À
À
tions with syn-type or anti-type O=C Ca H torsion angles.
It should be noted that in the anti-type conformations the
amide hydrogen atom and the proton attached to the chiral
carbon atom are in close proximity. As a result, the NOEs
between these two protons should be greater than those ob-
served for the syn-type conformations. Indeed, this was con-
firmed by the NOE enhancements observed for compounds
8a, 12a and 13b upon irradiation of the amide protons.[19]
The crystal structures of these three compounds showed that
À
À
12a contains one anti-type and one syn-type O=C Ca
H
Figure 10. Calculated model for the columnar arrangement of 8b (A) and
8c (B). Hydrogen atoms bonded to carbon atoms have been omitted for
clarity.
Chem. Eur. J. 2004, 10, 3879 3890
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3885

B. Escuder, S. V. Luis et al.
FULL PAPER
mum energy structure corresponding to a columnar packing
structure can be built from the mentioned conformations. It
should be noted that each molecule participates in six hy-
drogen bonds that hold the structure together. Similar stud-
ies were carried out for compounds 8c and 10c. The data
obtained indicates that both torsional angles have a syn-type
disposition such as that shown in conformer B in the crystal
structure of 9b (Figure 6). A model for the packing of com-
pound 8c is also proposed in Figure 10B.
Experimental Section
NMR spectroscopy: The NMR experiments were carried out either on a
1
Varian INOVA 500 spectrometer (500 MHz for H and 125 MHz for 13C)
or a Varian MERCURY 300 spectrometer (300 MHz for 1H and 75 MHz
for 13C). Chemical shifts are reported in ppm from tetramethylsilane with
the solvent resonance as the internal standard.
Mass spectrometry: Mass spectra were recorded on a Micromass Quattro
LC spectrometer equipped with an electrospray ionisation source and a
triple-quadrupole analyzer.
Molecular modelling: MonteCarlo conformational searches and molecu-
lar dynamics studies were performed with MACROMODEL 7.0[20a] using
AMBER*[20b] as the force field and GB/SA[20c] simulation of chloroform
as solvent. The MonteCarlo conformational search involved modification
of the torsional angles automatically set-up by the program. One thou-
sand step cycles departing from different conformers in each case were
performed until convergence was found. Molecular dynamics calculations
were carried out using the following conditions: simulation tempera-
ture=300 K; and length of simulation=5 ns with 1.5 fs steps. SHAKE[20d]
was used to constrain the length of bonds to hydrogen.
It should be noted that compounds 7c, 9a, 9b and 13b,
which are capable of self-assembly into columns as occurs in
their respective crystal structures do not gel. Structural dif-
ferences, which lead to conformations that self-assemble less
efficiently, most likely explain why these compounds behave
differently than the organogelators. The NOE measure-
ments described above concur with this fact. In particular,
negative NOEs (and large aggregates) were only observed
for the compounds that form gels. In the case of 13b it
seems that the presence of a 1,4-disubstituted aromatic
spacer makes the molecule rigid in such a way that only
four hydrogen bonds per molecule can be formed in the
supramolecular aggregates. For compounds 7c and 9a, the
presence of an alanine residue in the former, a shorter ali-
phatic spacer in the latter, produces conformations that also
self-assemble by means of only four hydrogen bonds per
unit. It is interesting that compound 9b, which forms colum-
nar aggregates through seven hydrogen bonds per molecule
in the crystal structure does not gel. In this case, the coexis-
tence of two different conformers in the supramolecular ag-
gregate introduces an entropically unfavourable factor that
overcomes the favourable enthalpic contribution of the hy-
drogen bonds. These results clearly identify the two requi-
sites in order for physical gelation to take place, namely the
formation of aggregates in a preferred direction (columns)
and the presence of strong intermolecular interactions.
X-ray powder diffraction: Data collection was performed at room tem-
perature on a Siemens D5000 diffractometer using CuKa radiation. Sam-
ples of the powdered solids were placed on a quartz sample holder and
data were collected for 2q values between 3 and 358 with a step size of
0.058 and a time step of 20 s.
X-ray single crystal diffraction: Data collection was performed at room
temperature on a Siemens Smart CCD 1 K diffractometer using graphite
monochromated MoKa radiation (l=0.71073 ä) with a nominal crystal-
to-detector distance of 4.0 cm. A hemisphere of data was collected based
on three w-scan runs (starting w=À28o) at values f=0, 90, and 180 with
the detector at 2q=288. In each of these runs, frames (606, 435 and 230,
respectively) were collected at 0.38 intervals and 40 s per frame. The dif-
fraction frames were integrated using the SAINT package[21a] and cor-
rected for absorption with SADABS.[21b] Structure solution was per-
formed with SHELXTL[21c] and refinement on F2 was done with
SHELXL-97.[21d] The illustrations shown in Figure 3, 4, and 5 were pre-
pared with MERCURY.[21e]
Electron microscopy: Scanning electron micrographs were taken on a
LEO 440I microscope equipped with a digital camera. Samples of the xe-
rogels were prepared by placing the gel on top of a tin plate, and after
slow drying of the solvent they were sputtered with Au/Pd in a Polaron
SC7610 Sputter Coater from Fisons Instruments.
CD spectroscopy: CD spectra were recorded on a Jasco J-810 spectropo-
larimeter. The gel samples were prepared in a quartz cuvette of 1 cm
path length and the measurement temperature was varied from 20 to
608C.
Conclusion
The self-assembly behaviour of small peptidomimetic cyclo-
phanes 6 10 in organic solvents has been studied in detail.
The transcription of molecular chirality into the supramolec-
ular level has been revealed by scanning electron microsco-
py. As can be seen by the fact that only four of the 15 com-
pounds considered actually form gels, the self-assembly of
such compounds is very sensitive to small structural changes
such as the nature of the amino acid residue or aromatic
moiety, and the length of the aliphatic spacer. These factors
have an important influence on the conformational prefer-
ences of these types of molecules, as well as on their supra-
molecular self-assembly. Other factors such as cooling rate
and solvent have been shown to determine the microscopic
shape of the aggregates. All the results indicate that the
strength of the interaction between organogelator molecules
is the key factor that determines the average length of the
aggregates at a given temperature and their further superag-
gregation. Upon consideration of all the results, models for
the assembly of the organogels have been proposed.
Syntheses: The N-hydroxysuccinimide esters of the amino acids, the
N,N’-bis(N-Cbz-l-aminoacyl)diamines, the N,N’-bis(l-aminoacyl)diamines
(1 5, a c), and the macrocycles (6 10, a c, and 13b) were prepared fol-
lowing previously reported procedures.[7]
Compound CBz-1a: Yield: 89%; 1H NMR (500 MHz, [D6]DMSO): d=
7.88 (brs, 2H), 7.35 (m, 10H), 7.32 (brs, 2H), 5.03 (s, 4H), 3.58 (m, 4H),
3.12 ppm (m, 4H); 13C NMR (125 MHz, [D6]DMSO): d=170.0, 157.2,
137.7, 129.0, 128.5, 66.2, 44.3, 39.0 ppm; IR (KBr): n˜ =3320, 3033, 1987,
1642, 1535 cmÀ1; MS (ESI): m/z (%): 465.6 [M+Na]+; elemental analysis
calcd (%) for C22H26N4O6: C 59.72, H 5.92, N 12.66; found: C 59.93, H
6.48, N 12.64.
Compound CBz-1b: Yield: 76%; 1H NMR (500 MHz, [D6]DMSO): d=
7.84 (m, 2H), 7.41 (m, 2H), 7.35 7.30 (m, 10H), 5.03 (s, 4H), 3.58 (m,
4H), 3.06 (m, 4H), 1.51 ppm (m, 2H); 13C NMR (125 MHz, [D6]DMSO):
d=169.2, 156.6, 137.0, 128.4, 127.9, 127.8, 65.6, 43.6, 36.2, 29.2 ppm; IR
(KBr): n˜ =3320, 3038, 1687, 1646, 1534 cmÀ1; MS (ESI): m/z: 479.6
[M+Na]+; elemental analysis calcd (%) for C23H28N4O6: C 60.52, H 6.18,
N 12.27; found: C 61.05, H 6.88, N 12.36.
Compound CBz-1c: Yield: 91%; 1H NMR (300 MHz, CDCl3): d=7.67
(brs, 2H), 7.30 (m, 12H), 5.02 (s, 4H), 3.57 (m, 4H), 3.04 (m, 4H),
1.38 ppm (m, 4H); 13C NMR (75 MHz, CDCl3): d=168.9, 156.6, 137.2,
128.4, 127.84, 127.75, 62.8, 44.0, 38.6, 26.9 ppm; IR (KBr): n˜ =3317, 3031,
1684, 1640, 1531 cmÀ1; MS (ESI): m/z: 471.3 [M+H]+, 493.3 [M+Na]+,
3886
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 3879 3890

Self-Assembly of Small Peptidomimetic Cyclophanes
3879 3890
509.3 [M+K]+; elemental analysis calcd (%) for C24H30N4O6: C 61.26, H
6.43, N 11.91; found: C 61.47, H 7.02, N 12.09.
Compound CBz-5c: Yield: 88%; [a]2D0 =À4.9 (c=0.026 in CHCl3/
CH3OH, 7:3 v/v); 1H NMR (300 MHz, [D6]DMSO): d=7.96 (brs, 2H),
7.34 (m, 12H), 5.02 (s, 4H), 3.80 (m, 2H), 3.03 (m, 4H), 1.65 (m, 2H),
1.37 (m, 6H), 1.08 (m, 2H), 0.78 ppm (m, 12H); 13C NMR (75 MHz,
[D6]DMSO): d=171.0, 155.9, 137.1, 128.3, 127.7, 127.6, 65.3, 59.1, 38.1,
36.2, 26.4, 24.4, 15.3, 10.8 ppm; IR (KBr): n˜ =3295, 3091, 1691, 1647,
1537 cmÀ1; MS (ESI): m/z: 605.9 [M+Na]+; elemental analysis calcd (%)
for C32H46N4O6: C 65.96, H 7.96, N 9.61; found: C 65.44, H 8.52, N 9.22.
Compound 1a¥2HBr: (hygroscopic) Yield: 78%; 1H NMR (300 MHz,
D2O): d=3.68 (m, 4H), 3.28 ppm (m, 4H); 13C NMR (75 MHz, D2O):
d=167.3, 40.5, 38.7 ppm; IR (KBr): n˜ =3362, 3222, 3118, 1676, 1655,
1570, 1509 cmÀ1; MS (ESI): m/z: 335.4 [M+H¥Br2]+.
Compound 1b¥2HBr: (hygroscopic) Yield: 60%; 1H NMR (300 MHz,
D2O): d=3.68 (s, 4H), 3.17 (t, 4H), 1.64 ppm (m, 2H); 13C NMR
(75 MHz, D2O): d=167.0, 40.5, 36.7, 27.9 ppm; IR (KBr): n˜ =3257, 2996,
1648, 1591, 1555 cmÀ1; MS (ESI): m/z: 189.1 [M+H]+.
Compound 1c¥2HBr: (hygroscopic) Yield: 79%; 1H NMR (300 MHz,
D2O): d=3.66 (s, 4H), 3.13 (m, 4H), 1.42 ppm (m, 4H); 13C NMR
(75 MHz, D2O): d=166.9, 40.5, 39.1, 25.7 ppm; IR (KBr): n˜ =3243, 3077,
3009, 1663, 1566 cmÀ1; MS (ESI): m/z: 203.1 [M+H]+.
Compound 2a¥2HBr: (hygroscopic) Yield: 78%; [a]2D0 =+14.8 (c=0.025
in CH3OH/H2O, 8:2 v/v); 1H NMR (500 MHz, CD3OD): d=3.96 (m,
2H), 3.37 (m, 4H), 1.50 ppm (d, J=6.8 Hz, 6H); 13C NMR (75 MHz,
D2O): d=171.0, 49.2, 38.8, 16.6 ppm; IR (KBr): n˜ =3442, 3078, 1676,
1561 cmÀ1; MS (ESI): m/z: 225.1 [M+Na]+.
Compound 2b¥2HBr: (hygroscopic) Yield: 87%; [a]2D0 =+8.9 (c=0.025
in CH3OH/H2O, 8:2 v/v); 1H NMR (500 MHz, CD3OD): d=3.96 (m,
2H), 3.29 (m, 4H), 1.77 (m, 2H), 1.51 ppm (d, J=7.3 Hz, 6H); 13C NMR
(125 MHz, CD3OD): d=171.1, 50.4, 50.3, 37.9, 30.0, 17.7 ppm; IR (KBr):
n˜ =3448, 3252, 1671, 1561 cmÀ1; MS (ESI): m/z: 217.2 [M+H]+.
Compound 2c: Yield: 32%; [a]2D0 =À1.1 (c=0.025 in CHCl3); 1H NMR
(500 MHz, CDCl3): d=7.35 (m, 2H), 3.48 (m, 2H), 3.27 (m, 4H), 1.55
(m, 4H), 1.48 (m, 4H), 1.32 ppm (d, J=6.8 Hz, 6H); 13C NMR
(125 MHz, CDCl3): d=175.7, 50.8, 38.6, 27.1, 21.8 ppm; IR (KBr): 3281,
3084, 1648, 1554, 1535 cmÀ1; MS (ESI): m/z: 231.4 [M+H]+; elemental
analysis calcd (%) for C10H22N4O2: C 52.15, H 9.63, N 24.33; found: C
52.38, H 9.81, N 24.27.
Compound 4a: Yield: 95%; [a]2D0 =À39.0 (c=0.025 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.68 (m, 2H), 3.38 (m, 6H), 1.69 (m, 4H), 1.41
(brs, 4H), 1.32 (m, 2H), 0.92 ppm (m, 12H); 13C NMR (75 MHz,
CDCl3): d=176.6, 53.4, 44.0, 39.3, 24.7, 23.3, 21.2 ppm; IR (KBr): n˜ =
3361, 3278, 3189, 1653, 1609, 1555 cmÀ1; MS (ESI): m/z: 287.2 [M+H]+;
elemental analysis calcd (%) for C14H30N4O2: C 58.71, H 10.56, N 19.56;
found: C 59.05, H 11.26, N 19.31.
Compound CBz-2a: Yield: 98%; [a]2D0 =+14.5 (c=0.025 in CHCl3/
CH3OH, 7:3 v/v); 1H NMR (300 MHz, CDCl3): d=7.31 (m, 10H), 6.73
(brs, 2H), 5.54 (m, 2H), 5.07 (m, 4H), 4.17 (m, 2H), 3.47 (m, 2H), 3.24
(m, 2H), 1.34 ppm (d, J=6.8 Hz, 6H); 13C NMR (125 MHz, CDCl3): d=
173.9, 156.2, 135.9, 128.0, 127.7, 127.5, 66.5, 50.4, 38.5, 17.5 ppm; IR
(KBr): n˜ =3313, 3091, 3033, 1687, 1656, 1538 cmÀ1; MS (ESI): m/z: 493.7
[M+Na]+; elemental analysis calcd (%) for C24H30N4O6: C 61.26, H 6.43,
N 11.91; found: C 61.49, H 6.91, N 11.94.
Compound CBz-2b: Yield: 89%; [a]2D0 =À2.7 (c=0.025 in CHCl3/
CH3OH, 7:3 v/v); 1H NMR (300 MHz, CDCl3): d=7.34 (m, 10H), 6.83
(brs, 2H), 5.37 (m, 2H), 5.10 (m, 4H), 4.19 (m, 2H), 3.40 (m, 2H), 3.15
(m, 2H), 1.60 (m, 2H), 1.37 ppm (d, J=6.8 Hz, 6H); 13C NMR (75 MHz,
CDCl3): d=173.7, 156.2, 135.9, 128.1, 127.7, 127.5, 66.5, 50.4, 36.0, 28.2,
17.7 ppm; IR (KBr): n˜ =3302, 3066, 1690, 1644, 1555, 1535 cmÀ1; MS
(ESI): m/z: 507.7 [M+Na]+; elemental analysis calcd (%) for
C25H32N4O6: C 61.97, H 6.66, N 11.56; found: C 62.19, H 7.28, N 11.59.
Compound CBz-2c: Yield: 88%; 1H NMR (300 MHz, CDCl3): d=7.33
(m, 10H), 6.63 (brs, 2H), 5.54 (m, 2H), 5.07 (m, 4H), 4.26 (m, 2H), 3.32
(m, 2H), 3.09 (m, 2H), 1.44 (m, 4H), 1.36 ppm (d, J=7.3 Hz, 6H);
13C NMR (75 MHz, CDCl3): d=173.4, 156.1, 135.9, 128.1, 127.7, 127.5,
66.5, 50.2, 38.5, 25.8, 17.9 ppm; IR (KBr): n˜ =3303, 3105, 3058, 1690,
1647, 1536 cmÀ1; MS (ESI): m/z: 521.8 [M+Na]+; elemental analysis
calcd (%) for C26H34N4O6: C 62.63, H 6.87, N 11.24; found: C 62.98, H
7.43, N 11.35.
Compound CBz-4a: Yield: 88%; [a]2D0 =+20.7 (c=0.025 in CHCl3/
CH3OH, 9:1 v/v); 1H NMR (300 MHz, [D6]DMSO): d=7.94 (brs, 2H),
7.34 (m, 12H), 5.00 (m, 4H), 3.95 (m, 2H), 3.07 (m, 4H), 1.56 (m, 2H),
1.41 (m, 4H), 0.83 ppm (dd, J=6.4 and J’=5.9 Hz, 12H); 13C NMR
(75 MHz, [D6]DMSO): d=172.4, 155.9, 137.0, 128.3, 127.7, 65.3, 53.1,
40.7, 38.2, 24.2, 24.1, 22.9, 21.4 ppm; IR (KBr): n˜ =3304, 3092, 1687, 1650,
1534 cmÀ1; MS (ESI): m/z: 556.0 [M+H]+; elemental analysis calcd (%)
for C30H42N4O6: C 64.96, H 7.63, N 10.10; found: C 65.23, H 8.29, N
10.18.
Compound CBz-4b: Yield: 89%; [a]2D0 =+4.9 (c=0.025 in CHCl3/
CH3OH, 9:1 v/v); 1H NMR (300 MHz, [D6]DMSO): d=7.90 (brs, 2H),
7.40 (m, 12H), 4.99 (m, 4H), 3.94 (m, 2H), 3.01 (m, 4H), 1.56 (m, 2H),
1.43 (m, 6H), 0.83 ppm (dd, J=7.3 and J’=6.8 Hz, 12H); 13C NMR
(75 MHz, [D6]DMSO): d=172.2, 155.7, 137.0, 128.2, 127.7, 127.6, 65.3,
53.1, 40.7, 36.1, 29.1, 24.2, 22.9, 21.4 ppm; IR (KBr): n˜ =3298, 3078, 1691,
1649, 1535 cmÀ1; MS (ESI): m/z: 570.1 [M+H]+; elemental analysis calcd
(%) for C31H44N4O6: C 65.47, H 7.80, N 9.85; found: C 65.26, H 8.54, N
9.86.
Compound CBz-4c: Yield: 79%; [a]2D0 =À4.7 (c=0.025 in CHCl3/
CH3OH, 9:1 v/v); 1H NMR (300 MHz, [D6]DMSO): d=7.88 (brs, 2H),
7.32 (m, 12H), 4.99 (m, 4H), 3.95 (m, 2H), 3.00 (m, 4H), 1.55 (m, 2H),
1.33 (m, 8H), 0.83 ppm (dd, J=6.8 and J’=6.4 Hz, 12H); 13C NMR
(125 MHz, [D6]DMSO): d=172.9, 156.6, 136.3, 128.5, 128.1, 127.9, 66.9,
53.6, 41.9, 38.9, 26.2, 24.8, 22.9, 21.1 ppm; IR (KBr): n˜ =3299, 3077, 1683,
1650, 1532 cmÀ1; MS (ESI): m/z: 584.1 [M+H]+; elemental analysis calcd
(%) for C32H46N4O6: C 65.96, H 7.96, N 9.61; found: C 65.78, H 8.75, N
9.57.
Compound CBz-5a: Yield: 88%; 1H NMR (300 MHz, [D6]DMSO): d=
7.98 (brs, 2H), 7.28 (m, 12H), 5.00 (s, 4H), 3.76 (t, 2H), 3.07 (m, 4H),
1.65 (m, 2H), 1.40 (m, 2H), 1.05 (m, 2H), 0.77 ppm (m, 12H); 13C NMR
(75 MHz, [D6]DMSO): d=171.3, 156.0, 137.0, 128.3, 127.7, 127.6, 65.3,
59.2, 38.1, 36.1, 24.4, 15.4, 10.9 ppm; IR (KBr): n˜ =3297, 1690, 1645,
1541 cmÀ1; MS (ESI): m/z: 555.9 [M+H]+; elemental analysis calcd (%)
for C30H42N4O6: C 64.96, H 7.63, N 10.10; found: C 65.38, H 8.14, N
10.21.
Compound CBz-5b: Yield: 88%; [a]2D0 =À0.6 (c=0.025 in CHCl3/
CH3OH, 7:3 v/v); 1H NMR (300 MHz, [D6]DMSO): d=7.96 (m, 2H),
7.34 (m, 12H), 5.01 (s, 4H), 3.79 (m, 2H), 3.05 (m, 4H), 1.68 (m, 2H),
1.51 (m, 2H), 1.41 (m, 2H), 1.10 (m, 2H), 0.80 ppm (m, 12H); 13C NMR
(75 MHz, [D6]DMSO): d=171.1, 156.0, 137.0, 128.3, 127.7, 127.6, 65.3,
59.2, 36.2, 36.1, 29.0, 24.4, 15.3, 10.9 ppm; IR (KBr): n˜ =3293, 3089, 1690,
1645, 1541 cmÀ1; MS (ESI): m/z: 570.0 [M+H]+; elemental analysis calcd
(%) for C31H44N4O6: C 65.47, H 7.80, N 9.85; found: C 65.38, H 8.46, N
9.92.
Compound 4b: Yield: 89%; [a]2D0 =À33.3 (c=0.025 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.67 (m, 2H), 3.37 (m, 2H), 3.25 (m, 4H), 1.66
(m, 6H), 1.55 (brs, 4H), 1.31 (m, 2H), 0.90 ppm (dd, J=6.4 and J’=
8.8 Hz, 12H); 13C NMR (125 MHz, CDCl3): d=175.8, 53.5, 44.0, 35.7,
29.6, 24.8, 23.3, 21.4 ppm; IR (KBr): n˜ =3299, 3073, 1652, 1532 cmÀ1; MS
(ESI): m/z: 339.8 [M+K]+; elemental analysis calcd (%) for C15H32N4O2:
C 59.97, H 10.74, N 18.65; found: C 60.13, H 10.98, N 18.71.
Compound 4c: Yield: 79%; [a]2D0 =À35.8 (c=0.025 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.40 (m, 2H), 3.35 (m, 2H), 3.24 (m, 4H), 1.70
(m, 4H), 1.53 (m, 4H), 1.39 (brs, 4H), 1.31 (m, 2H), 0.91 ppm (dd, J=
6.4 and J’=8.8 Hz, 12H); 13C NMR (75 MHz, CDCl3): d=175.6, 53.4,
44.0, 38.5, 27.0, 24.8, 23.4, 21.2 ppm; IR (KBr): n˜ =3343, 3292, 1631, 1550,
1524 cmÀ1; MS (ESI): m/z: 315.5 [M+H]+; elemental analysis calcd (%)
for C16H34N4O2: C 61.11, H 10.90, N 17.82; found: C 61.32, H 11.08, N
17.74.
Compound 5a: Yield: 90%; [a]2D0 =À54.7 (c=0.025 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.69 (m, 2H), 3.33 (m, 4H), 3.17 (d, J=3.9 Hz,
2H), 1.88 (m, 2H), 1.31 (m, 4H), 1.10 (m, 2H) 0.88 (d, J=7.8 Hz, 6H),
0.82 ppm (t, J=7.3 Hz, 6H); 13C NMR (75 MHz, CDCl3): d=175.1, 59.9,
39.4, 37.9, 23.7, 16.1, 11.9 ppm; IR (KBr): 3300, 3077, 1639, 1549 cmÀ1
;
MS (ESI): m/z: 287.4 [M+H]+; elemental analysis calcd (%) for
C14H30N4O2: C 58.71, H 10.56, N 19.56; found: C 58.97, H 11.05, N 19.25.
Compound 5b: Yield: 89%; [a]2D0 =À51.4 (c=0.025 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.61 (t, J=5.6 Hz, 2H), 3.15 (m, 6H), 1.82 (m,
2H), 1.54 (m, 2H), 1.35 (m, 6H), 0.98 (m, 2H), 0.83 (d, J=6.8 Hz, 6H),
Chem. Eur. J. 2004, 10, 3879 3890
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3887

B. Escuder, S. V. Luis et al.
FULL PAPER
0.76 (t, J=7.3 Hz, 6H) ppm; 13C NMR (75 MHz, CDCl3): d=174.6,
126.1, 59.9, 37.9, 35.5, 29.6, 23.5, 16.0, 11.7 ppm; IR (KBr): n˜ =3291, 3078,
1641, 1546 cmÀ1; MS (ESI): m/z: 301.6 [M+H]+; elemental analysis calcd
(%) for C15H32N4O2: C 59.97, H 10.74, N 18.65; found: C 60.11, H 11.16,
N 18.71.
Compound 5c: Yield: 72%; [a]2D0 =À49.3 (c=0.025 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.40 (m, 2H), 3.17 (m, 6H), 1.87 (m, 2H), 1.45
(m, 4H), 1.29 (m, 6H), 1.00 (m, 2H), 0.85 (d, J=6.8 Hz, 6H), 0.79 ppm
(t, J=7.5 Hz, 6H); 13C NMR (75 MHz, CDCl3): d=174.1, 126.2, 59.7,
38.4, 37.8, 27.0, 23.5, 16.1, 11.8 ppm; IR (KBr): n˜ =3292, 3085, 1637,
1552 cmÀ1; MS (ESI): m/z: 315.6 [M+H]+; elemental analysis calcd (%)
for C16H34N4O2: C 61.11, H 10.90, N 17.82; found: C 61.29, H 11.32, N
17.91.
Compound 6c: Yield: 12%; 1H NMR (300 MHz, CDCl3): d=7.48 (m,
3H), 7.26 (m, 1H), 7.12 (d, J=7.3 Hz, 2H), 3.78 (s, 4H), 3.33 (m, 8H),
2.05 (m, 2H), 1.58 ppm (m, 4H); 13C NMR (75 MHz, CDCl3): d=171.6,
140.0, 128.7, 127.5, 127.2, 53.8, 52.1, 38.0, 26.8 ppm; IR (KBr): n˜ =3315,
1667, 1528 cmÀ1; MS (ESI): m/z: 305.2 [M+H]+; elemental analysis calcd
(%) for C16H24N4O2: C 63.13, H 7.95, N 18.41; found: C 63.28, H 8.21, N
18.53.
Compound 7a: Yield: 27%; [a]2D0 =+16.1 (c=0.03 in CHCl3/CH3OH, 7:3
v/v); 1H NMR (300 MHz, CDCl3): d=7.41 (m, 2H), 7.37 (s, 1H), 7.25
(m, 1H), 7.09 (d, J=7.2 Hz, 2H), 4.05 (d, J=13.2 Hz, 2H), 3.59 (d, J=
13.2 Hz, 2H), 3.19 (m, 6H), 1.79 (m, 2H), 1.35 ppm (d, J=6.6 Hz, 6H);
13C NMR (75 MHz, CDCl3): d=176.0, 140.2, 128.7, 128.6, 127.5, 59.1,
53.6, 38.9, 19.9 ppm; IR (KBr): n˜ =3379, 3304, 3270, 3019, 1670, 1641,
1542, 1524 cmÀ1; MS (ESI): m/z: 305.5 [M+H]+; elemental analysis calcd
(%) for C16H24N4O2: C 63.13, H 7.95, N 18.41; found: C 63.19, H 8.32, N
18.47.
(KBr): n˜ =3315, 3060, 1637, 1543 cmÀ1; MS (ESI): m/z: 209.5 [M+2H]2+
;
elemental analysis calcd (%) for C24H40N4O2: C 69.19, H 9.68, N 13.45;
found: C 68.93, H 10.02, N 13.19.
Compound 10a: Yield: 56%; [a]2D0 =À23.9 (c=0.025 in CHCl3); H NMR
1
(500 MHz, CDCl3): d=7.39 (m, 2H), 7.27 (m, 2H), 7.12 (m, 2H), 4.11 (d,
J=13.2 Hz, 2H), 3.56 (d, J=13.2 Hz, 2H), 3.19 (m, 4H), 3.12 (d, J=
3.9 Hz, 2H), 1.95 (m, 2H), 1.72 (m, 2H), 1.47 (m, 2H), 1.17 (m, 2H),
1.04 (d, J=6.8 Hz, 6H), 0.92 ppm (m, 6H); 13C NMR (125 MHz, CDCl3):
d=174.7, 140.5, 128.9, 128.5, 127.5, 68.8, 54.9, 39.0, 38.4, 24.9, 16.2,
11.8 ppm; IR (KBr): n˜ =3314, 1655, 1509 cmÀ1; MS (ESI): m/z: 389.8
[M+H]+; elemental analysis calcd (%) for C22H36N4O2: C 68.01, H 9.34,
N 14.42; found: C 67.85, H 9.68, N 14.31.
Compound 10b: Yield: 41%; [a]2D0 =+27.0 (c=0.025 in CHCl3);
1H NMR (300 MHz, CDCl3): d=7.46 (m, 2H), 7.33 (s, 1H), 7.27 (m,
1H), 7.12 (d, J=7.2 Hz, 2H), 4.04 (d, J=13.8 Hz, 2H), 3.50 (d, J=
13.8 Hz, 2H), 3.41 (m, 2H), 3.09 3.04 (m, 4H), 1.83 (m, 4H), 1.62 (m,
2H), 1.45 (m, 2H), 1.17 (m, 2H), 0.99 (m, 6H), 0.89 ppm (m, 6H);
13C NMR (75 MHz, CDCl3): d=173.8, 140.6, 128.8, 128.0, 127.1, 68.2,
53.8, 38.2, 35.6, 28.7, 25.0, 16.1, 11.9 ppm; IR (KBr): n˜ =3330, 3072, 1637,
1542 cmÀ1; MS (ESI): m/z: 202.5 [M+2H]2+; elemental analysis calcd
(%) for C23H38N4O2: C 68.62, H 9.51, N 13.92; found: C 68.71, H 9.73, N
14.08.
1
Compound 10c: Yield: 58%; [a]2D0 =À58.4 (c=0.025 in CHCl3); H NMR
(300 MHz, CDCl3): d=7.50 (m, 2H), 7.41 (s, 1H), 7.30 (m, 1H), 7.16 (d,
J=6.8 Hz, 2H), 3.89 (d, J=12.7 Hz, 2H), 3.64 (m, 2H), 3.55 (d, J=
12.7 Hz, 2H), 3.12 (d, J=4.4 Hz, 2H), 2.99 (m, 2H), 1.88 (m, 2H), 1.65
(m, 6H), 1.46 (m, 2H), 1.14 (m, 2H), 0.99 (d, J=6.84 Hz, 6H), 0.90 ppm
(m, 6H); 13C NMR (75 MHz, CDCl3): d=173.4, 140.3, 128.72, 128.67,
126.9, 68.1, 53.9, 38.04, 38.00, 26.8, 24.8, 16.1, 11.8 ppm; IR (KBr): n˜ =
3306, 3058, 1637, 1542 cmÀ1; MS (ESI): m/z: 209.5 [M+2H]2+; elemental
analysis calcd (%) for C24H40N4O2: C 69.19, H 9.68, N 13.45; found: C
69.36, H 10.30, N 13.44.
Compound 7b: Yield: 39%; [a]2D0 =+20.2 (c=0.025 in CHCl3/CH3OH,
1
7:3 v/v); H NMR (500 MHz, CDCl3): d=7.55 (m, 2H), 7.46 (s, 1H), 7.28
(m, 1H), 7.13 (d, J=7.8 Hz, 2H), 4.05 (d, J=13.7 Hz, 2H), 3.65 (d, J=
13.7 Hz, 2H), 3.30 (m, 6H), 1.72 (m, 4H), 1.36 ppm (d, J=6.8 Hz, 6H);
13C NMR (125 MHz, CDCl3): d=175.3, 140.2, 128.7, 127.4, 126.9, 57.9,
52.2, 37.3, 28.9, 19.1 ppm; IR (KBr): n˜ =3317, 3085, 1630, 1541 cmÀ1; MS
(ESI): m/z: 319.2 [M+H]+, 341.2 [M+Na]+; elemental analysis calcd (%)
for C17H26N4O2: C 64.12, H 8.23, N 17.60; found: C 63.92, H 8.61, N
17.51.
Compound 13b: Yield: 65%; [a]2D0 =+89.8 (c=0.006 in CH2Cl2);
1H NMR (300 MHz, CD3OD): d=8.26 (dd, J=3.3 and J’=6.1 Hz, 2H),
7.56 (dd, J=3.3 and J’=6.1 Hz, 2H), 7.39 (s, 2H), 4.62 (d, J=14.8 Hz,
2H), 3.92 (d, J=14.3 Hz, 2H), 2.96 (d, J=6.1 Hz, 2H), 2.58 (m, 2H),
2.33 (m, 2H), 2.03 (m, 2H), 0.99 (d, J=7.2 Hz, 6H), 0.95 (d, J=6.6 Hz,
6H), 0.60 ppm (m, 2H); 13C NMR (75 MHz, CD3OD): d=176.9, 137.2,
133.5, 127.1, 127.0, 125.4, 71.1, 37.8, 32.6, 28.9, 19.8, 18.5 ppm; IR (NaCl):
n˜ =3322, 3075, 1651, 1520 cmÀ1; MS (ESI): m/z: 425.3 [M+H]+, 447.3
[M+Na]+; elemental analysis calcd (%) for C25H36N4O2: C 70.72, H 8.55,
N 13.20; found: C 70.86, H 8.71, N 13.38.
Compound 7c: Yield: 38%; [a]2D0 =À14.6 (c=0.025 in CHCl3/CH3OH,
1
7:3 v/v); H NMR (300 MHz, CDCl3): d=7.47 (m, 2H), 7.35 (s, 1H), 7.22
(m, 1H), 7.10 (d, J=7.8 Hz, 2H), 3.88 (d, J=12.7 Hz, 2H), 3.53 (m, 2H),
3.49 (d, J=12.7 Hz, 2H), 3.24 (m, 2H), 2.94 (m, 2H), 1.95 (m, 2H), 1.53
(m, 4H), 1.29 ppm (d, J=7.3 Hz, 6H); 13C NMR (75 MHz, CDCl3): d=
174.8, 140.2, 128.8, 128.4, 127.0, 58.6, 52.7, 38.2, 26.9, 19.6 ppm; IR (KBr):
Compound 11b: Benzyl bromide (300 mL, 2.4 mmol) was added dropwise
to a refluxing mixture of compound 3b (0.3 g, 1.1 mmol), K2CO3 (0.8 g,
5.7 mmol), and tetrabutyl ammonium bromide (0.05 g) in dry CH3CN
(60 mL). After being refluxed overnight, the mixture was filtered off and
the solvent was evaporated under vacuum. The crude waxy solid was fur-
ther purified by silica-gel column chromatography using CH2Cl2/CH3OH
(40:1 v/v) as eluent. Yield: 45%; [a]2D0 =À47.7 (c=0.025 in CHCl3);
1H NMR (500 MHz, CDCl3): d=7.51 (m, 2H), 7.32 (m, 10H), 3.79 (d,
J=13.2 Hz, 2H), 3.64 (d, J=12.7 Hz, 2H), 3.28 (m, 4H), 2.96 (d, J=
4.4 Hz, 2H), 2.11 (m, 2H), 1.64 (m, 4H), 0.96 (d, J=6.8 Hz, 6H),
0.90 ppm (d, J=6.8 Hz, 6H); 13C NMR (125 MHz, CDCl3): d=174.0,
139.7, 128.5, 128.2, 127.2, 68.0, 53.5, 35.6, 31.3, 30.2, 19.6, 17.9 ppm; IR
(KBr): n˜ =3310, 3064, 3022, 1646, 1520 cmÀ1; MS (ESI): m/z: 453.3
[M+H]+, 475.3 [M+Na]+, 491.3 [M+K]+; elemental analysis calcd (%)
for C27H40N4O2: C 71.65, H 8.91, N 12.38; found: C 71.68, H 9.03, N
12.47.
n˜ =3317, 3296, 3085, 1639, 1629, 1551 cmÀ1
; MS (ESI): m/z: 333.8
[M+H]+; elemental analysis calcd (%) for C18H28N4O2: C 65.03, H 8.49,
N 16.85; found: C 65.18, H 8.76, N 16.88.
Compound 9a: Yield: 49%; [a]2D0 =À2.1 (c=0.025 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.23 7.14 (m, 4H), 7.03 (m, 2H), 4.00 (d, J=
13.2 Hz, 2H), 3.46 (d, J=13.2 Hz, 2H), 3.12 (m, 2H), 2.96 (m, 4H), 1.93
(m, 2H), 1.69(m, 2H), 1.53 (m, 2H), 1.33 (m, 2H), 0.89 ppm (m, 12H);
13C NMR (75 MHz, CDCl3): d=176.2, 140.1, 129.3, 128.5, 127.6, 62.6,
54.5, 43.3, 39.3, 25.0, 23.2, 21.7 ppm; IR (KBr): n˜ =3317, 1653, 1520 cmÀ1
;
MS (ESI): m/z: 195.4 [M+2H]2+; elemental analysis calcd (%) for
C22H36N4O2: C 68.01, H 9.34, N 14.42; found: C 68.00, H 10.57, N 14.29.
Compound 9b: Yield: 40%; [a]2D0 =+14.7 (c=0.025 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.36 7.27 (m, 4H), 7.13 (m, 2H), 4.04 (d, J=
13.8 Hz, 2H), 3.51 (d, J=13.8 Hz, 2H), 3.29 (m, 2H), 3.20 (m, 2H), 3.05
(m, 2H), 1.68 (m, 6H), 1.41 (m, 2H), 0.96 ppm (d, J=6.1 Hz, 12H);
13C NMR (75 MHz, CDCl3): d=175.3, 140.5, 128.8, 128.0, 127.0, 61.9,
53.1, 42.9, 35.9, 28.7, 25.2, 23.2, 21.9 ppm; IR (KBr): n˜ =3317, 3085, 1630,
1544 cmÀ1; MS (ESI): m/z: 202.4 [M+2H]2+; elemental analysis calcd
(%) for C23H38N4O2: C 68.62, H 9.51, N 13.92; found: C 68.68, H 10.22, N
13.60.
CCDC-227044 227048 contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crys-
tallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK;
fax: (+44)1223-336-033; or e-mail: deposit@ccdc.cam.ac.uk).
Compound 9c: Yield: 27%; [a]2D0 =À58.9 (c=0.025 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.46 (m, 2H), 7.41 (s, 1H), 7.30 (m, 1H), 7.18 (m,
2H), 3.90 (d, J=12.7 Hz, 2H), 3.64 (m, 2H), 3.55 (d, J=12.7 Hz, 2H),
3.24 (m, 2H), 2.98 (m, 2H), 1.78 1.58 (m, 8H), 1.39 (m, 2H), 0.97 ppm
(dd, J=2.4 and J’=6.4 Hz, 12H); 13C NMR (75 MHz, CDCl3): d=174.8,
140.3, 128.8, 127.0, 61.9, 53.3, 42.9, 38.3, 26.9, 25.3, 23.2, 21.9 ppm; IR
Acknowledgements
The authors thankthe SCIC of the University Jaume I for technical assis-
tance with microscopy and crystallographic studies, and the Generalitat
3888
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 3879 3890

Self-Assembly of Small Peptidomimetic Cyclophanes
3879 3890
Valenciana (Project CTDIA/2002/123) and the Spanish Ministry of Sci-
ence and Technology (Project BQ2003-09215) for financial support.
Langmuir 2000, 16, 7558 7561; f) K. Sakurai, Y. Ono, J. H. Jung, S.
Okamoto, S. Sakurai, S. Shinkai, J. Chem. Soc. Perkin Trans. 2 2001,
108 112; g) J. -L. Pozzo, J. -P. Desvergne, G. M. Clavier, H. Bouas-
Laurent, P. G. Jones, J. Perlstein, J. Chem. Soc. Perkin Trans. 2 2001,
824 826.
[1] a) P. Terech, R. G. Weiss, Chem. Rev. 1997, 97, 3133 3159; b) D. J.
Abdallah, R. G. Weiss, Adv. Mater. 2000, 12, 1237 1247; c) J. van
Esch, B. L. Feringa, Angew. Chem. 2000, 112, 2351 2354; Angew.
Chem. Int. Ed. 2000, 39, 2263 2266; d) O. Gronwald, E. Snip, S.
Shinkai, Curr. Opin. Colloid Interface Sci. 2002, 7, 148 156.
[6] a) H. Hidaka, M. Murata, T. Onai, J. Chem. Soc. Chem. Commun.
1984, 562 564; b) K. Hanabusa, K. Okui, K. Karaki, T. Koyama, H.
Shirai, J. Chem. Soc. Chem. Commun. 1992, 1371 1373; c) K. Hana-
busa, J. Tange, Y. Taguchi, T. Koyama, H. Shirai, J. Chem. Soc.
Chem. Commun. 1993, 390 392; d) K. Hanabusa, Y. Naka, T.
Koyama, H. Shirai, J. Chem. Soc. Chem. Commun. 1994, 2683
2684; e) H. T. Stock, N. J. Turner, R. McCague, J. Chem. Soc. Chem.
Commun. 1995, 2063 2064; f) K. Hanabusa, K. Hiratsuka, M.
Kimura, H. Shirai, Chem. Mater. 1999, 11, 649 655; g) R. Jayaku-
mar, M. Murugesan, C. Asokan, M. A. Scibioh, Langmuir, 2000, 16,
1489 1496; h) G. Mieden-Gundert, L. Klein, M. Fischer, F. Vˆgtle,
K. Heuzÿ, J. -L. Pozzo, M. Vallier, F. Fages, Angew. Chem. 2001,
113, 3266 3267; Angew. Chem. Int. Ed. 2001, 40, 3164 3166; i) X.
Luo, B. Liu, Y. Liang, Chem. Commun. 2001, 1556 1557; j) J. Ma-
karevic, M. Jokic, B. Peric, V. Tomisic, B. Kojic-Prodic, M. Zinic,
Chem. Eur. J. 2001, 7, 3328 3341; k) A. Carrÿ, P. Le Grel, M.
Baudy-Floc’h, Tetrahedron Lett. 2001, 42, 1887 1889; l) N. Yamada,
T. Imai, E. Koyama, Langmuir 2001, 17, 961 963; m) J. Makarevic,
M. Jokic, L. Frkanec, D. Katalenic, M. Zinic, Chem. Commun. 2002,
2238 2239; n) L. Frkanec, M. Jokic, J. Makarevic, K. Wolsperger,
M. Zinic, J. Am. Chem. Soc. 2002, 124, 9716 9717; o) I. Ihara, T. Sa-
kurai, T. Yamada, T. Hashimoto, M. Takafuji, T. Sagawa, H. Hachi-
sako, Langmuir 2002, 18, 7120 7123; p) S. K. Maji, D. Haldar, A.
Banerjee, A. Banerjee, Tetrahedron 2002, 58, 8695 8702; q) S.
Malik, S. K. Maji, A. Banerjee, A. K. Nandi, J. Chem. Soc. Perkin
Trans. 2 2002, 1177 1186; r) S. A. Ahmed, X. Sallenave, F. Fages, G.
Mieden-Gundert, W. M. M¸ller, U. M¸ller, F. Vˆgtle, J. -L. Pozzo,
Langmuir 2002, 18, 7096 7101; s) S. Kiyonaka, S. Shinkai, I. Hama-
chi, Chem. Eur J. 2003, 9, 976 983.
[7] a) S. Bhattacharya, S. N. Ghanashyam Achayra, A. R. Raju, Chem.
Commun. 1996, 2101 2102; b) K. Hanabusa, R. Tanaka, M. Suzuki,
M. Kimura, H. Shirai, Adv. Mater. 1997, 9, 1095 1097; c) S. Bhatta-
charya, S. N. Ghanashyam Achayra, Chem. Mater. 1999, 11, 3121
3132.
[8] a) E. J. de Vries, R. M. Kellogg, J. Chem. Soc. Chem. Commun.
1993, 238 240; b) K. Hanabusa, Y. Matsumoto, T. Miki, T. Koyama,
H. Shirai, J. Chem. Soc. Chem. Commun. 1994, 1401 1402; c) K.
Hanabusa, Y. Matsumoto, M. Kimura, A. Kakehi, H. Shirai, J. Col-
loid Interface Sci. 2000, 224, 231 244.
[9] J. Becerril, M. I. Burguete, B. Escuder, S. V. Luis, J. F. Miravet, M.
Querol, Chem. Commun. 2002, 738 739.
[10] a) F. Adriµn, M. I. Burguete, S. V. Luis, J. F. Miravet, M. Querol, Tet-
rahedron Lett. 1999, 40, 1039 1040; b) J. Becerril, M. I. Burguete, F.
Galindo, E. GarcÌa-EspaÊa, S. V. Luis, J. F. Miravet, J. Am. Chem.
Soc. 2003, 125, 6677 6686.
[2] See for example: a) Y. Lin, B. Kachar, R. G. Weiss, J. Am. Chem.
Soc. 1989, 111, 5542 5551; b) R. Oda, I. Huc, S. J. Candau, Angew.
Chem. 1998, 110, 2835 2838; Angew. Chem. Int. Ed. 1998, 37, 2689
2691; c) G. M. Clavier, J. F. Brugger, H. Bouas-Laurent, J. -L. Pozzo,
J. Chem. Soc. Perkin Trans. 2 1998, 2527 2534; d) K. Yoza, N. Ama-
nokura, Y. Ono, T. Akao, H. Shinmori, M. Takeuchi, S. Shinkai,
D. N. Reinhoudt, Chem. Eur. J. 1999, 5, 2722 2729; e) N. Amano-
kura, Y. Kanekiyo, S. Shinkai, D. N. Reinhoudt, J. Chem. Soc.
Perkin Trans. 2 1999, 1995 2000; f) D. J. Abdallah, L. Lu, R. G.
Weiss, Chem. Mater. 1999, 11, 2907 2911; g) R. J. H. Hafkamp,
M. C. Feiters, R. J. M. Nolte, J. Org. Chem. 1999, 64, 412 426; h) J.
van Esch, F. Schoonbeek, M. de Loos, H. Kooijman, A. L. Spek,
R. M. Kellogg, B. L. Feringa, Chem. Eur. J. 1999, 5, 937 949; i) F.
Schoonbeek, J. van Esch, R. Hulst, R. M. Kellogg, B. L. Feringa,
Chem. Eur. J. 2000, 6, 2633 2643; j) M. de Loos, A. G. J. Ligtenbarg,
J. van Esch, H. Kooijman, A. L. Spek, R. Hage, R. M. Kellogg, B. L.
Feringa, Eur. J. Org. Chem. 2000, 3675 3678; k) D. J. Abdallah,
R. G. Weiss, Langmuir 2000, 16, 352 355; l) M. Kˆlbel, F. M.
Menger, Langmuir 2001, 17, 4490 4492; m) A. Ajayaghosh, S. J.
George, J. Am. Chem. Soc. 2001, 123, 5148 5149; n) U. Beginn, B.
Tartsch, Chem. Commun. 2001, 1924 1925; o) O. Gronwald, S. Shin-
kai, Chem. Eur. J. 2001, 7, 4328 4334; p) G. Wang, A. D. Hamilton,
Chem. Eur. J. 2002, 8, 1954 1961; q) J. J. van Gorp, J. A. J. M. Veke-
mans, E. W. Meijer, J. Am. Chem. Soc. 2002, 124, 14759 14769;
r) M. George, R. G. Weiss, Langmuir 2002, 18, 7124 7135; s) M.
George, R. G. Weiss Langmuir 2003, 19, 1017 1025; t) C. Wang, A.
Robertson, R. G. Weiss, Langmuir 2003, 19, 1036 1046; u) C. Wang,
R. G. Weiss, Chem. Commun. 2003, 310 311; v) G. B¸hler, M. C.
Feiters, R. J. M. Nolte, Angew. Chem. 2003, 115, 2599 2602; Angew.
Chem. Int. Ed. 2003, 42, 2494 2497.
[3] a) N. W. Fadnavis, A. Deshpande, Curr. Org. Chem. 2002, 6, 393
410; b) I. Sato, K. Kadowaki, H. Urabe, J. H. Jung, Y. Ono, S. Shin-
kai, K. Soai, Tetrahedron Lett. 2003, 44, 721 724; c) J. C. Tiller,
Angew. Chem. 2003, 115, 3180 3183; Angew. Chem. Int. Ed. 2003,
42, 3072 3075.
[4] a) J. H. Jung, Y. Ono, S. Shinkai, J. Chem. Soc. Perkin Trans. 2 1999,
1289 1291; b) J. H. Jung, Y. Ono, S. Shinkai, Chem. Eur. J. 2000, 6,
4552 4557; c) J. H. Jung, M. Amaike, S. Shinkai, Chem. Commun.
2000, 2343 2344; d) J. H. Jung, S. Shinkai, J. Chem. Soc. Perkin
Trans. 2 2000, 2393 2398; e) J. H. Jung, Y. Ono, S. Shinkai, Lang-
muir 2000, 16, 1643 1649; f) J. H. Jung, H. Kobayashi, M. Masuda,
T. Shimizu, S. Shinkai, J. Am. Chem. Soc. 2001, 123, 8785 8789;
g) Y. Ono, K. Nakashima, M. Sano, J. Hojo, S. Shinkai, J. Mater.
Chem. 2001, 11, 2412 2419; h) J. H. Jung, S. Shinkai, J. Incl. Phen.
Macroc. Chem. 2001, 41, 53 59; i) K. Sugiyasu, S. Tamaru, M. Take-
uchi, D. Berthier, I. Huc, R. Oda, S. Shinkai, Chem. Commun. 2002,
1212 1213; j) J. H. Jung, S. Shinkai, T. Shimizu, Nano Lett. 2002, 2,
17 20; k) J. H. Jung, H. Kobayashi, K. J. C. van Bommel, S. Shinkai,
T Shimizu, Chem. Mater. 2002, 14, 1445 1447; l) J. H. Jung, K. Yosh-
ida, T. Shimizu, Langmuir 2002, 18, 8724 8727; m) S. Kobayashi, N.
Hamasaki, M. Suzuki, M. Kimura, H. Shirai, K. Hanabusa, J. Am.
Chem. Soc. 2002, 124, 6550 6551; n) A. M. Seddon, H. M. Patel, S.
Burkett, S. Mann, Angew. Chem. 2002, 114, 3114 3117; Angew.
Chem. Int. Ed. 2002, 41, 2988 2991; o) K. J. C. van Bommel, A.
Friggeri, S. Shinkai, Angew. Chem. 2003, 115, 1010 1030; Angew.
Chem. Int. Ed. 2003, 42, 980 999.
[11] Compounds 6a and 6b were obtained in less than 10% yield and
were not isolated from the oligomeric mixture.
[12] H. M. Tan, A. Moet, A. Hiltner, E. Baer, Macromolecules 1983, 16,
28 34.
[13] MACROMODEL 7.0, AMBER*, GB/SA solvent simulation.
[14] a) F. M. Menger, Y. Yamasaki, K. K. Catlin, T. Nishimi, Angew.
Chem. 1995, 107, 616 618; Angew. Chem. Int. Ed. Engl. 1995, 34,
585 586; b) P. Babu, N. M. Sangeetha, P. Vijaykumar, U. Maitra, K.
Rissanen, A. R. Raju, Chem. Eur. J. 2003, 9, 1922 1932; c) J. Makar-
evic, M. Jokic, Z. Raza, Z. Stefanic, B. Kojic-Prodic, M. Zinic,
Chem. Eur. J. 2003, 9, 5567 5580; d) S. Kiyonaka, K. Sada, I. Yoshi-
mura, S. Shinkai, N. Kato, I. Hamachi, Nat. Mater. 2004, 3, 58 64.
[15] The same structural parameters were found when crystals of com-
pound 8a were grown in benzene.
[16] Positional disorder was found in the crystal structure of compound
6a for atoms C11 and C12 (see Supporting Information). This could
be explained as a consequence of the conformational mobility of the
butylenic chain at room temperature. This effect has been omitted
in Figure 5 for the sake of clarity.
[5] a) E. Ostuni, P. Kamaras, R. G. Weiss, Angew. Chem. 1996, 108,
1423 1425; Angew. Chem. Int. Ed. Engl. 1996, 35, 1324 1326;
b) F. M. Menger, K. L. Caran, J. Am. Chem. Soc. 2000, 122, 11679
11691; c) P. Terech, D. Pasquier, V. Bordas, C. Rossat, Langmuir
2000, 16, 4485 4494; d) D. C. Duncan, D. G. Whitten, Langmuir
2000, 16, 6445 6452; e) D. J. Abdallah, S. A. Sirchio, R. G. Weiss,
[17] D. T. Bong, M. R. Ghadiri, Angew. Chem. 2001, 113, 2221 2224;
Angew. Chem. Int. Ed. 2001, 40, 2163 2166.
Chem. Eur. J. 2004, 10, 3879 3890
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3889

B. Escuder, S. V. Luis et al.
FULL PAPER
[18] As the gel fibres are in a solid state they do not contribute to the
[20] a) F. Mohamadi, N. G. J. Richards, T. Hendrickson, W. C. Still, J.
Comput. Chem. 1990, 11, 440; b) S. J. Weiner, P. A. Kollman, D.
Case, U. C. Singh, G. Alagona, S. Profeta, P. Weiner, J. Am. Chem.
Soc. 1984, 106, 765; c) W. C. Still, A. Tempczyk, R. C. Hawley, T.
Hendrickson, J . Am. Chem. Soc. 1990, 112, 6127; d) J.-P. Ryckaert,
G. Ciccotti, H. J. C. Berendsen, J. Comput. Phys. 1977, 23, 327.
[21] a) SAINT version 6.26 A Bruker Analytical X-ray Systems, Madi-
son, WI; b) G. M. Sheldrick, SADABS empirical absorption pro-
gram, V 2.03, University of Gottingen, 1996; c) G. M. Sheldrick,
SHELXTL. 5.1 ed. Bruker Analytical X-Ray Systems, Madison WI.
1997; d) G. M. Sheldrick, SHELX-97: A program for the refinement
of crystal structures; University of Gˆttingen, Germany, 1997;
e) MERCURY 1.1.2, CCDC, 2002.
1
solution phase H NMR spectra. Most likely, only monomers or sol-
ution phase pre-gel aggregates are observed.
[19] It is known that steady state NOE enhancement values are sensitive
to different spin relaxation mechanisms, which in turn depend on
factors such as solvent, the molecular weight of the molecules, as
well as the concentration and influence of neighbouring nuclei (see
T. D. W. Claridge, High Resolution NMR Techniques in Organic
Chemistry, Pergamon, 1999). However, all these factors are expected
to be almost equivalent for the experiments described below be-
cause the molecules are very closely related analogues, the protons
involved in the NOE present analogous spin systems, and all the ex-
periments were recorded using the same concentration and solvent.
Therefore, a comparison of the observed NOE enhancements of the
different molecules should be possible.
Received: January 13, 2004
Published online: June 24, 2004
3890
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 3879 3890