Novel capsular aggregates from flexible tripodal triureas with C s symmetry

Article abstract of DOI:10.1002/chem.201102246

Tris(2- and 3-ureidobenzyl)amines with C_s symmetry self-assemble in solution forming mixtures of regioisomeric capsular aggregates, one of which is chiral and the other centrosymmetric. Under certain conditions, a predominance of the centrosymmetric regioisomer is found before equilibrium, that is, a mixture close to the statistical ratio of the two species is reached. In the solid state, there is a preference for the centrosymmetric capsules. Molecular models of both regioisomeric aggregates have been built and analyzed for comparison. Guests inside capsules formed by self-assembly of desymmetrized tris(3-ureidobenzyl)amines feel different magnetic environments, depending on whether they are inside a chiral or an achiral regioisomeric container. Of special significance are the experiments with a more flexible triurea endowed with an ureidopropylic arm, which self-assembles with the same efficiency as the more rigid tris(ureidobenzyl)amines. Copyright

Full text of DOI:10.1002/chem.201102246

FULL PAPER
DOI: 10.1002/chem.201102246
Novel Capsular Aggregates from Flexible Tripodal Triureas
with Cs Symmetry
Mateo Alajarin,*[a] Raul-Angel Orenes,[a, b] Judith A. K. Howard,[c] Elinor C. Spencer,[c]
Jonathan W. Steed,[c] and Aurelia Pastor*[a]
Abstract: Tris(2- and 3-ureidobenzyl)-
amines with Cs symmetry self-assemble
preference for the centrosymmetric
capsules. Molecular models of both re-
gioisomeric aggregates have been built
and analyzed for comparison. Guests
inside capsules formed by self-assembly
of desymmetrized tris(3-ureidobenzyl)-
amines feel different magnetic environ-
ments, depending on whether they are
inside a chiral or an achiral regioiso-
meric container. Of special significance
are the experiments with a more flexi-
ble triurea endowed with an ureidopro-
pylic arm, which self-assembles with
the same efficiency as the more rigid
tris(ureidobenzyl)amines.
ACHTUNGTRENNUNG
in solution forming mixtures of regioi-
someric capsular aggregates, one of
which is chiral and the other centro-
symmetric. Under certain conditions, a
predominance of the centrosymmetric
regioisomer is found before equilibri-
um, that is, a mixture close to the stat-
istical ratio of the two species is
reached. In the solid state, there is a
Keywords: host–guest systems · hy-
drogen bonds
· self-assembly ·
supramolecular chemistry · triureas
Introduction
In recent years much attention has been paid to self-as-
sembled capsules, nanoscale structures made up of several
synthetic subunits and connected through noncovalent inter-
actions.[8–10] These systems exhibit the key properties of se-
The ability of molecules to spontaneously generate order
through self-assembly is one of the most attractive phenom-
ena investigated in the last decade.[1,2] The design of self-as-
sembling systems with potential applications needs a pro-
found knowledge of the rules that govern supramolecular
chemistry.[3] Organizational rigidity has been frequently in-
voked for the design of efficient supramolecular assemblies
to minimize entropy losses.[4] However, that the efficiency of
molecular recognition processes suffers less than generally
assumed from the presence of single bonds has been proved
in supramolecular systems based on hydrogen bonds[5,6] or
electrostatic interactions.[7]
lective guest recognition and reversible encapsulation.[11]
A
range of capsules have been constructed from modules with
rigid and preformed concave geometries, such as resorcar-
enes,[12,13] calixarenes[14,15] and calixpyrroles.[16,17] Tris(2- and
3-ureidobenzyl)amines 1 and 2 have proved to be useful
scaffolds in supramolecular chemistry despite their flexibili-
ty. They form capsular dimeric aggregates held together by
a seam of six hydrogen-bonded urea groups (Figure 1).[18]
Whereas assemblies 1·1 exist as solvent-free capsular aggre-
gates,[19,20] assemblies 2·2 are able to encapsulate guests of
appropriate size and shape.[21,22] The tribenzylamine core
provides a high degree of flexibility to triureas 1 and 2,
which adopt averaged C3v symmetry in competitive solvents
with hydrogen bonds. In non-competitive solvents, aggre-
[a] Prof. Dr. M. Alajarin, Dr. R.-A. Orenes, Dr. A. Pastor
Departamento de Quimica Organica, Facultad de Quimica
Universidad de Murcia, Campus de Espinardo, Murcia-30.100 (Spain)
E-mail: alajarin@um.es
aureliap@um.es
[b] Dr. R.-A. Orenes
Servicio Universitario de Instrumentacion Cientifica
Universidad de Murcia, Campus de Espinardo, 30.100 Murcia (Spain)
[c] Prof. Dr. J. A. K. Howard, Dr. E. C. Spencer, Prof. Dr. J. W. Steed
Department of Chemistry, University of Durham
University Science Laboratories, South Road
Durham DH13LE (UK)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102246 or from the author. It
contains experimental procedures and spectroscopic and analytical
1
data of precursors 7–12 and 14 and of triureas 3c–e, H NMR spectra
of 1a,b, 2, 3a, 4a and 5a in [D6]DMSO and CDCl3, high-frequency
region of the H NMR spectra of 4a–c (CDCl3) and 5a (CD2Cl2) and
electrospray ionization mass spectra of 5a and 6.
Figure 1. Structure and schematic representation of capsular aggregates
1·1 and 2·2 formed by self-assembly of tris(2- and 3-ureidobenzyl)amines
1 and 2.
1
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gates 1·1 or 2·2 are formed by assembly of two self-comple-
mentary and enantiomeric tripods of C3 symmetry offset by
608 to each other, resulting in a global achiral S6 symmetry
for the supermolecule (self-discrimination).
Although more complex systems are known, capsular ag-
gregates 1·1 and 2·2 are attractive and challenging due to
their special geometry. Moreover, the modular structure of
the tribenzylamine skeleton has great potential for modifica-
tion. The sequential construction “arm-to-arm” of the terti-
ary amine core would provide access to new triureas of Cs
symmetry with variation of both the pendant ureido posi-
tions[20] and the substitution at the tribenzylamine skeleton.
Moreover, triureas with even more flexible branches would
be easily available. Herein we present a detailed study of
the self-assembly of desymmetrized tris(2- and 3-ureidoben-
zyl)amines 3–5. New capsules derived from the 5·5 assembly
have been characterised in solution and the solid state. Of
special significance is the self-assembly of the more flexible
supramolecular tecton 6 endowed with a ureidopropylic
arm. The formation of regioisomeric aggregates from triur-
eas 3–6 has also been examined.
Scheme 1. General procedure for the synthesis of triureas 3. Reagents
and reaction conditions: a) LiAlH4, Et2O, 0 !208C, 6 h; b) R3NCO,
CH2Cl2, 208C, 18 h (R1, R2 and R3 in Table 1).
Table 1. Synthesis of triamines 8 and triureas 3.
Entry
Compound
R1
R2
R3
Yield
1
2
3
4
5
6
7
8
8a
8b
8c
3a
3b
3c
3d
3e
H
Me
H
H
Me
Me
H
–
–
–
92[a]
61[a]
76[a]
84[b]
92[b]
81[b]
71[b]
73[b]
Me
Cl
H
4-MeC6H4
4-CF3C6H4
4-MeC6H4
4-MeC6H4
4-CF3C6H4
H
Me
Cl
Cl
H
H
[a] After chromatography. [b] Precipitated from the reaction mixture.
Figure 2. Schematic representation of a) the exchange equilibrium be-
tween the two enantiomeric conformations of a triurea with Cs symmetry
by inverting the rotation sense of the propeller and b) the three putative
dimeric aggregates derived from the assembly of Cs-symmetric triureas
(the arrows symbolize the directionality of the belt of hydrogen bonds).
Results and Discussion
Tris(2-ureidobenzyl)amines 3a–e, with different substituents
at one of the arylic groups of the tribenzylamine skeleton,
were synthesised from key triazides 7a–c (Scheme 1,
Table 1). Intermediate azides 7 were prepared by following
a synthetic route previously reported by us.[23]
ing to the two differently substituted branches of the tripo-
dal molecules. This pattern is clearly evident in Figure 3a, in
1
which the high-frequency region of the H NMR spectrum
Tris(2-ureidobenzyl)amines 3 feature overall Cs symme-
tries in competitive solvents, and thus are not chiral. Fig-
ure 2a shows the exchange equilibrium by inverting the ro-
tation sense of the propeller of the tribenzylamine skeleton
in Cs-symmetric triureas. Accordingly, 1H, 13C{1H} and
19F{1H} NMR spectra of triureas 3a–e in [D6]DMSO exhibit
the expected resonances for Cs-symmetric monomers. The
spectra display two sets of signals in a 2:1 ratio correspond-
of 3b shows the resonances for the NH protons bearing the
R3 groups (full spectrum of 3a included in the Supporting
Information).
The self-assembly of 3a–e was subsequently investigated
in a non-competitive solvent such as CDCl3 (20–40 mm).
1
The H NMR spectra of 3a–e in CDCl3 are very complex
compared to those of 3a–e in [D6]DMSO and to those of
the C3v-symmetric triureas 1 and 2 in the same halogenated
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Capsular Aggregates of Tripodal Triureas
FULL PAPER
served in this region of the spectra, as illustrated for 3b in
Figure 3b. Six singlets were attributed to the chiral regioiso-
mer and three singlets to the meso aggregate, and the three
assemblies are present in statistical ratio (33:33:33). An
analogous conclusion can be drawn for the self-assembly of
3a and 3c,d although the corresponding high-frequency re-
gions of their NMR spectra display more significant overlap.
The self-assembly of 3b and 3e was further analyzed by
19F{1H} NMR spectroscopy. By analogous reasoning, the
statistical ratio of C1- and Ci-symmetric regioisomers should
give rise to nine signals of equal integration, as in fact is ob-
served in the region around ꢀ62.6 ppm for 3e.
As we previously reported,[20] triureas 4a–c (4a: R1 =4-
nBuC6H4, R2 =4-CF3C6H4; 4b: R1 =4-nBuC6H4, R2 =4-
FC6H4; 4c: R1 =4-MeOC6H4, R2 =4-CF3C6H4), differently
substituted at one of the pendant aryl groups, are easily
available from a common intermediate. Taking into account
that a 66:33 ratio of C1- and Ci-symmetric regioisomers cor-
responds to the statistical arrangement, 4a (57:43) and 4c
(60:40) display some degree of selectivity in favour of the
Figure 3. High-frequency regions of the 1H NMR spectra of 3b
(300 MHz, 208C) in a) [D6]DMSO and b) CDCl3, at which the NH
groups bearing the pendant R3 groups resonate.
1
solvent (Supporting Information). In spite of their complexi-
ty, the diagnostic features for the dimeric aggregates 3·3 can
be clearly distinguished: 1) shifts to higher frequencies for
the resonances of the NH protons with respect to those of
diphenylurea used as reference,[24] and 2) anisotropic effects
for the protons of the pendant aromatic groups and the
methylenic protons of the (ArCH2)3N fragments. The reso-
nances for the monomeric species are not observed at the
concentrations used for measurements. The complexity of
the spectra of 3 may be due not only to the loss of symmetry
by formation of dimeric assemblies 3·3, but also to the pres-
ence of two regioisomeric species: one enantiomeric pair of
C1 symmetry, labelled A and B in Figure 4, and one Ci-sym-
metric species, denoted C (Figure 4). Aggregates A and B
are schematically represented in Figure 2b and they feature
supramolecular chirality.[25–27] Since separate signals for the
two regioisomers are observed, their interconversion by a
dissociation/recombination process may be slow on the
NMR timescale. The relative proportions of the two re-
gioisomers was determined by analyzing the resonances of
the NH groups bearing the pendant substituents R3 in the
region of 7.8–8.3 ppm. Nine signals of similar area are ob-
Ci-symmetric dimeric species 4a·4a and 4c·4c. The H NMR
spectra of triureas 4b and 4c remain invariant over time.
Conversely, when a sample of 4a obtained by slow evapora-
tion of a CDCl3 solution was redissolved in the same solvent
1
and its H NMR spectrum immediately recorded, it showed
a 36:64 ratio of C1- and Ci-symmetric regioisomers. After
about 20 min, the mixture of species equilibrated and
reached a 57:43 ratio. After 5 d a value close to the statisti-
cal ratio was reached (Table 2).[20] This result seems to be an
indication of a predominance of the centrosymmetric dimer
in the solid state.
Table 2. Ratio of C1- and Ci-symmetric regioisomers of 4a·4a over time.
Entry
Time[a]
C1:Ci[b]
1
2
3
4
1 min
20 min
2 d
36:64
57:43
59:41
62:38
5 d
[a] From the preparation of the sample (CDCl3, 208C) until the spectrum
was measured. [b] Determined by integration of selected signals in their
1H NMR spectra (400 MHz); error ꢁ5% of the stated value.
The influence of temperature and the solvent on the dis-
tribution of regioisomers was also investigated. Thus, the
1H NMR spectra of triurea 4a in C2D2Cl4 at ꢀ30, 25 and
898C and in [D8]toluene at ꢀ60, 25 and 908C were mea-
sured. However, the effect of these parameters in the aggre-
gates ratio was found to be minimal.
To evaluate subtle differences in the structures of the two
regioisomeric aggregates 4a·4a, we used the program Mac-
roModel 8.1 (AMBER* force field) to build the two molec-
ular models. Molecular modelling in the gas phase and in
chloroform led to similar structures (Figure 5). A detailed
analysis of the two energy-minimized structures reveals that
there are no significant differences. The belt of hydrogen-
bonded urea moieties is very symmetric with N···O=C dis-
Figure 4. Structure of the three isomeric aggregates of C1 and Ci symme-
try of 3·3, labelled as A, B and C (R1, R2 and R3 shown in Table 1).
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A. Pastor, M. Alajarin et al.
Scheme 2. Reagents and reaction conditions for the synthesis of triureas
5a–c: a) NaI, acetone, 208C, 20 h; b) 3-azidobenzylamine, Na2CO3,
MeCN, reflux, 24 h; c) i) PMe3, THF, 08C, 30 min; ii) H2O/THF, 208C,
16 h; d) 4-nBuC6H4NCO, CH2Cl2, 208C, 24 h; e) H2, PtO2, THF, 208C,
16 h; f) RNCO, solvent, temperature, 24 h (see Table 3).
Figure 5. Minimum-energy structures of 4a·4a calculated in chloroform.
Top (a) and side (b) views of the chiral regioisomer. Top (c) and side (d)
views of the centrosymmetric regioisomer. The belt of hydrogen-bonded
urea moieties is indicated by dashed lines.
Table 3. Reaction conditions and yields for the synthesis of triureas 5a–c.
Entry
Compound
R
Solvent
T [8C]
Yield [%]
tances of 2.84–2.89 ꢁ for the urea nitrogen atoms bearing
the pendant aromatic substituents very similar to those of
the urea nitrogen atoms attached to the tribenzylamine skel-
eton (N···O=C 2.82–2.88 ꢁ). The distances between the two
pivotal nitrogen atoms are almost coincident: 5.18 ꢁ and
5.22 ꢁ for the chiral and centrosymmetric regioisomer, re-
spectively. The structural resemblance of the two dimeric su-
prastructures would explain their similar stability and thus
the statistical ratio observed in solution.
The synthesis of the tris(3-ureidobenzyl)amines 5a–c, dif-
fering in the pendant substituents, is depicted in Scheme 2.
Treatment of 3-nitrobenzyl chloride with NaI led to the cor-
responding iodide (99% yield), which was then treated with
3-azidobenzylamine in the presence of Na2CO3 yielding ter-
tiary amine 9 (57%). Formation of the corresponding imino-
phosphorane by reaction of 9 with trimethylphosphine fol-
lowed by hydrolysis in THF/H2O led to amine 10 (96%).
Tribenzylamine 11 was isolated in 97% yield after the reac-
tion of 10 with 4-n-butylphenyl isocyanate. Compounds 5a–c
were obtained from 11 by sequential catalytic hydrogenation
(75%) and reaction with the corresponding isocyanate
(Table 3).
1
2
3
5a
5b
5c
4-CF3C6H4
4-MeOC6H4
Bn
CH2Cl2
CH2Cl2
CHCl3
20
20
reflux
72
92
80
zylamine skeleton (labelled in Scheme 2), the latter shifted
as much as 2 ppm to lower frequencies. Thus, whereas pro-
tons at C2 resonate at 7.5 ppm in [D6]DMSO, they appear
as broad signals at 5.7–5.9 ppm in the halogenated solvent.
The benzylic protons of the (ArCH2)3N fragment resonate
as two multiplets at d=2.6–2.7 and d=3.2–3.6 ppm. Finally,
the broad signals around 7.9–8.6 ppm were assigned, as in
capsules 2·2, to the ureido NH protons bearing the pendant
aromatic groups. The dimeric assembly 5a·5a was also de-
tected by ESI-MS experiments. The spectrum measured in
CHCl3 shows the corresponding molecular ion of the pro-
tonated dimer at m/z 1764 (Supporting Information).
Molecular models of both regioisomeric aggregates 5a·5a
(Figure 7) were computed in both gas phase and chloroform
by using MacroModel 8.1 (AMBER* force field). The two
energy-minimized structures reveal no significant differen-
ces. The separations between the two pivotal nitrogen atoms
are 10.11 and 10.12 ꢁ for the chiral and the centrosymmetric
species, respectively. The N···O=C distances (2.77–2.79 ꢁ)
for the urea nitrogen atoms bearing the pendant aromatic
substituents are slightly shorter than the N···O=C distances
(2.90–3.00 ꢁ) for the urea nitrogen atoms attached to the
tribenzylamine skeleton.
Subsequently, the self-assembly of triureas 5a–c in CDCl3
was tested. The complexity and line width of the signals
once more indicate the presence of a mixture of species.
Whereas the spectrum of 5c is too complex to extract any
1
conclusion, the H NMR spectra of 5a–b show typical signa-
tures of tribenzylamine-derived capsules (Figure 6).[21,22]
Large shifts to lower frequencies were observed for the sig-
nals of the protons of the pendant aromatic substituents as
well as the protons located at the C2 position of the triben-
The regioselectivity in the self-assembly of triureas 5a
and 5b was examined by analyzing the region in which the
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Capsular Aggregates of Tripodal Triureas
FULL PAPER
exists (Supporting Information).
The observed ratio for C1- and
Ci-symmetric regioisomers was
62:38, very close to the statisti-
cal distribution.
Tris(3-ureidobenzyl)amines 2
(Figure 1) form dimeric aggre-
gates with cavities that are able
to encapsulate guests of appro-
priate shape and size.[21,22] The
resemblance of the spectra of
triureas 5 with those of triureas
2 in CDCl3 suggests the pres-
ence of capsules 5·5@CDCl3.
Previously, we demonstrated
that dimeric aggregates 2·2 are
excellent containers for MeI,
CH2Cl2 and MeNO2.[22] At
1
ꢀ158C, the H NMR spectra of
Figure 6. 1H NMR spectra (400 MHz, 258C) of 5a in a) [D6]DMSO and b) CDCl3. *) Water and ) residual
peaks of the solvent.
5a in the presence of an excess
of MeI, CH2Cl2 and MeNO2,
show the resonances for the
*
capsules
5a·5a@MeI,
5a·5a@CH2Cl2, 5a·5a@MeNO2 as well as the encapsulated
guests, shifted 0.3–0.4 ppm to lower frequencies with respect
to those of the free ones (Figure 8). The high-frequency re-
1
gions of the H NMR spectra support a distribution of re-
gioisomers close to statistical (Figure 8, left), which indicates
that the presence of these guests inside the cavity may not
influence the regioselectivity of the self-assembly process.[27]
Interestingly, the spectra reveal two different resonances for
MeI and MeNO2 inside 5a·5a, with slightly different chemi-
cal shifts in a 2:1 ratio (Figure 8a and 8c, right). The most
intense signals were assigned to the guests inside the chiral
capsules, since they exist as a 50:50 mixture of two enantio-
mers, and the less intense signal to the guest inside the achi-
ral one. Clearly, the guests feel a different magnetic environ-
ment depending on whether they are inside the chiral con-
tainer or the achiral one.
We succeeded in growing single crystals of 5a suitable for
X-ray analysis (CHCl3/n-pentane). The structure comprises
two independent molecules 5a·5a, each of which forms a
unique capsule by symmetry, as we have described previous-
ly (Figure 9).[21,28] The belt of hydrogen-bonded urea resi-
dues is rather symmetrical, as expected from the computed
structures, with N···O=C distances ranging from 2.86 to
3.09 ꢁ. Inside the capsule, a disordered molecule of n-pen-
tane was found as guest species. Notably, the crystal shows
the exclusive presence of the Ci-symmetric regioisomeric
capsule. The preference for the centrosymmetric arrange-
ment in the solid state suggests that crystal packing forces
must play a significant role.[28,29]
Figure 7. Minimum-energy structures of 5a·5a calculated in the gas
phase. Top (a) and side (b) views of the chiral regioisomer. Top (c) and
side (d) views of the centrosymmetric regioisomer. The belt of hydrogen-
bonded urea moieties is indicated by dashed lines.
NH protons bearing the terminal substituents resonate. Nev-
ertheless, the broadness and overlap of these signals ham-
pered this analysis. The spectrum of 5a in CDCl3 recorded
at ꢀ10 and ꢀ608C, as well as that measured in [D8]toluene
also at low temperatures, did not provide a better resolution.
The resonances were resolved as nine peaks by using
CD2Cl2 as solvent, in which the capsule 5a·5a@CD2Cl2
Intrigued by the self-assembly abilities of more flexible
triureas, we designed triurea 6 with an ureidopropylic arm.
Rigid molecules have been frequently designed to minimize
entropy losses and favour their self-assembly processes.[4]
However, the presence of flexible regions is less of a disad-
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A. Pastor, M. Alajarin et al.
Figure 8. Selected regions of the 1H NMR spectra (400 MHz, CDCl3, ꢀ158C) of a) 5a·5a@MeI, b) 5a·5a@CH2Cl2 and c) 5a·5a@MeNO2, at which the
NH moieties bearing the pendant aryl groups (left part) and the encapsulated guest (right part) resonate.
Scheme 3. Synthesis of triamine 14 and triurea 6. Reagents and reaction
conditions: a) i) PMe3, THF, 08C, 5 h; ii) H2O/THF, 208C, 18 h; b) 4-
MeC6H4NCO, CHCl3, 208C, 20 h.
Figure 9. X-ray structure of 5a·5a@n-pentane. a) Top and b) side view.
The belt of hydrogen-bonded urea moieties is indicated by dotted lines.
A molecule of pentane is located inside the cavity.
(Figure 11). The resonances appearing around 7.5–8.5 ppm
were assigned to the NH groups bearing the pendant aro-
matic groups. Additionally, the signals around 6.10-7.00 ppm
vantage than previously supposed, since single bonds can
better accommodate strain.[3,5,6] The synthesis of 6 was con-
ducted from triazide 13[30] by reduction to triamine 14 and
subsequent reaction with 4-methylphenyl isocyanate
(Scheme 3).
were attributed to the arylic protons of the pendant 4-meth-
ylphenyl groups, and those appearing at 1.89-2.28 ppm to
the methyl protons of the same fragments. The lack of a sin-
glet around 3.6 ppm points to an undetectable amount of
monomeric species at this concentration (40 mm). The di-
meric assembly 6·6 was also detected by ESI-MS experi-
ments. The spectrum measured in CHCl3 shows the corre-
sponding molecular ion of the protonated dimer at m/z 1505
(Supporting Information).
1
The pattern of signals in the H NMR spectrum of 6 in
[D6]DMSO is consistent with the presence of an averaged
Cs-symmetric monomer (Figure 10a). However, a more
1
complex picture is present in CDCl3. The H NMR spectrum
of 6 in this solvent reveals a large number of sharp signals,
ruling out the presence of oligomeric associations (Fig-
ure 10b). The spectrum was interpreted as being due to an
equilibrium mixture of C1- and Ci-symmetric regioisomers
The appearance of nine signals with a similar integration
in the high-frequency region of the H NMR spectrum of 6
(CDCl3) would be in agreement with the presence of the
two regioisomeric aggregates in 66:33 (statistical) ratio
1
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Capsular Aggregates of Tripodal Triureas
FULL PAPER
1
*
Figure 10. H NMR spectra (400 MHz, 258C) of 6 in a) [D6]DMSO and b) CDCl3; *) Water and ) residual peak of the solvent.
(Figure 11). In fact, this is the overall picture, although only
seven signals are clearly visible; the two missing resonances
may be overlapped by the aromatic region (Figure 12a).
The analysis of the region between 1.86 and 2.30 ppm is
even more revealing (Figure 12b). Thus, the spectrum dis-
plays eight singlets, one of them of double intensity, for the
resonances of the methyl groups of the pendant 4-methyl-
phenyl substituents. Compared to the resonances of the C3v-
symmetric aggregates 1·1, the resonances attributed to these
protons are spread out over a wider region. This fact can be
rationalized on the basis of a more different environment
experienced by the six methyl groups within 6·6 depending
on their location, that is, either between two ureidobenzylic
branches or between one ureidopropylic and one ureidoben-
zylic arms (Figure 11).
Conclusion
Flexible tris(2- and 3-ureidobenzyl)amines with Cs symmetry
are synthetically accessible and able to self-assemble to
form capsular dimeric aggregates. In solution, the dimeric
aggregates exist as a mixture of regioisomers, one chiral and
one centrosymmetric. Under certain conditions, predomi-
nance of the centrosymmetric dimers is observed before the
equilibrium, that is, a distribution close to the statistical
ratio of the two regioisomers, is reached. Computed molecu-
lar models point to the two regioisomeric structures having
a similar stability. Interestingly, the guests inside capsules
derived from desymmetrized tris(3-ureidobenzyl)amines feel
different magnetic environments depending on whether they
are inside a chiral or an achiral container. Moreover, there
is a preference for the centrosymmetric capsule in the solid
state, probably due to crystal packing effects. Finally, a triur-
ea endowed with an ureidopropylic arm has the ability to
self-assemble with the same efficiency as the tris(ureidoben-
zyl)amines do. These results further authenticate the use of
tris(ureidobenzyl)amines and their derivatives as versatile
frameworks for the rational design of more sophisticated
supramolecular systems in the foreseeable future.
Figure 11. Structure of the three isomeric aggregates of C1 and Ci symme-
try of 6·6 labelled as A, B and C (Ar=4-MeC6H4).
Chem. Eur. J. 2012, 18, 2389 – 2397
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2395

A. Pastor, M. Alajarin et al.
wR2 =0.2201, R indices based on 5164 reflections with I>2s(I) (refine-
ment on F2), 1227 parameters, 0 restraints. Lp and absorption corrections
applied, m=0.182 mmꢀ1. CCDC 813383 (5a) contains the supplementary
crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
General procedure for synthesis of triureas 3a–e: The corresponding iso-
cyanate (0.90 mmol) was added to a solution of the corresponding tria-
mine 8 (0.30 mmol) in dry CH2Cl2 (8 mL) under N2. After stirring at
208C for 18 h, the solvent was removed under reduced pressure and the
residue triturated with Et2O (5 mL). The white solid was filtered and
dried under vacuum. Further purification was carried out by recrystalliza-
tion.
Bis{5-methyl-2-[N’-(4-methylphenyl)ureido]benzyl}{2-ACTHUNRTGNEUNG[N’-(4-methylpheny-
l)ureido]benzyl}amine (3a): Colourless prisms (from 1:1 CHCl3/Et2O),
84% yield. M.p. 234–2368C; 1H NMR (300 MHz, [D6]DMSO, 208C): d=
2.13 (s, 6H), 2.21 (s, 9H), 3.59 (s, 6H), 6.91–6.97 (m, 3H), 7.01–7.04 (m,
3
6H), 7.12 (t, J
N
(d, 3J(H,H)=8.1 Hz, 2H), 7.43 (d, 3J
ACTHNUGTRENNUGN ACHTUNGTRENNNUG
AHCTUNGERTG(NNUN H,H)=8.1 Hz, 1H), 7.83 (s, 2H), 7.98 (s, 1H), 8.60 (s, 2H), 8.66 ppm (s,
1H); 13C NMR (50 MHz, [D6]DMSO, 208C): d=20.4 (q), 20.6 (q), 54.8
(t), 118.3 (d), 123.2 (d), 123.4 (d), 124.3 (d), 127.1 (d), 127.8 (d), 129.1
(d), 129.5 (s), 129.9 (d), 130.2 (s), 130.5 (s), 132.8 (s), 134.5 (s), 137.2 (s),
~
137.3 (s), 153.0 (s), 153.4 ppm (s); IR (Nujol): n=3319 (s), 1665 (vs),
1607 (vs), 1557 (vs), 1516 (s), 1316 (m), 1287 (m), 1244 (m), 1208 (m),
819 (s), 746 (w), 721 (w), 695 cmꢀ1 (w); elemental analysis calcd (%) for
C47H49N7O3 (760.0): C 74.28, H 6.50, N 12.90; found: C 73.91, H 6.84, N
12.99.
Bis{5-methyl-2-[N’-(4-trifluoromethylphenyl)ureido]benzyl}{2-ACTHUNTGRNEUNG[N’-(4-tri-
fluoromethylphenyl)ureido]benzyl}amine (3b): Colourless prisms (from
1:1 CHCl3/Et2O) 92% yield. M.p. 248–2518C; 1H NMR (300 MHz,
Figure 12. Selected regions of the 1H NMR spectrum (400 MHz, CDCl3,
258C) of triurea 6 where a) the NH moieties bearing the pendant aryl
groups and b) the methyl groups of the 4-methylphenyl substituents reso-
nate.
[D6]DMSO, 208C): d=2.11 (s, 6H), 3.61 (s, 6H), 6.90 (dd, 3J
ACHTUNGTRENNUNG
8.1 Hz, 4J
A
(H,H)=1.5 Hz, 2H), 6.96 (t, 3J
ACHUTGTNRENNUG CAHTUNGTRENNUNG
3
3J(H,H)=7.2 Hz, 1H), 7.50 (d, 3J
ACHTNUTRGENNUG HCATUNGTRENN(NGU H,H)=7.2 Hz, 1H), 7.53–7.62 (m,
12H), 8.01 (s, 2H), 8.16 (s, 1H), 9.12 (s, 2H), 9.18 ppm (s, 1H); 13C NMR
(75 MHz, [D6]DMSO, 208C): d=20.4 (q), 54.7 (t), 117.9 (d), 121.6 (q, 2J-
Experimental Section
ACHUTNGRENNUG CAHTUNGTRENNUNG
(C,F)=31.6 Hz) (s), 123.8 (d), 123.9 (d), 124.5 (q, 1J
124.8 (d), 125.9 (q, 3J
ACHTUNGTRENNUNG
General: See the Supporting Information for experimental procedures
and spectroscopic and analytical data of precursors 7–12 and 14 and of
triureas 3c–e, 1H NMR spectra of 1a,b, 2, 3a, 4a and 5a in [D6]DMSO
and CDCl3, high-frequency region of the 1H NMR spectra of 4a–c
(CDCl3) and 5a (CD2Cl2) and electrospray ionization mass spectra of 5a
and 6.
130.1 (d), 130.3 (s), 130.9 (s), 133.4 (s), 134.0 (s), 136.8 (s), 143.5 (s), 152.8
(s), 153.2 ppm (s); 19F NMR (188 MHz, [D6]DMSO, 208C): d=
~
ꢀ59.8 ppm; IR (Nujol): n=3329 (s), 1666 (vs), 1605 (vs), 1563 (vs), 1410
(w), 1325 (vs), 1249 (m), 1168 (s), 1125 (vs), 1068 (s), 850 (m), 833 cmꢀ1
(w); elemental analysis calcd (%) for C47H40F9N7O3 (921.9): C 61.24, H
4.37, N 10.64; found: C 61.17, H 4.47, N 10.68.
Molecular mechanics calculations: All molecular mechanics calculations
were carried out by using the AMBER* force field as implemented
within Maestro/MacroModel 8.1. Standard potentials and atomic charges,
as provided by the AMBER* force field, were employed without modifi-
cations. AMBER* and OPLAA force fields produce essentially the same
results in related structures. Calculations were initially performed under
vacuum and then in chloroform solution (GB/SA solvation model). Most
complex structures were virtually identical under both conditions. Energy
minimizations were conducted over 500 iterations on a Silicon Graphics
Computer. Minimized structures were then subjected to conformational
searches with 5000-step Monte Carlo multiple minimum simulations. All
conformations within 15 kJmolꢀ1 of the computed global minimum were
stored and the representative lowest-energy structure was analyzed.
General procedure for the synthesis of triureas 5a,b: The corresponding
isocyanate (1.10 mmol) was added to a solution of 12 (0.28 g, 0.55 mmol)
in dry CH2Cl2 (10 mL) under N2. After stirring at 208C for 24 h, the sol-
vent was removed under reduced pressure and Et2O (5 mL) was added.
The white solid was filtered and dried under vacuum.
Bis{3-ACTHNUGRTENNUG[N’-(4-trifluoromethylphenyl)ureido]benzyl}{3-ACHTUNGTERN[NUGN N’-(4-butylpheny-
l)ureido]benzyl}amine (5a): Colourless prisms (an analytical sample was
obtained by recrystallization from 1:3 CHCl3/n-pentane), 72% yield. M.p.
179–1818C; 1H NMR (401 MHz, [D6]DMSO, 208C): d=0.86 (t, 3J-
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
Data collection, structure solution and refinement of the crystal structure
AHCTUNGERTG(NNUN H,H)=8.6 Hz, 4H), 8.54 (s, 1H), 8.61 (s, 1H), 8.79 (s, 2H), 9.08 ppm (s,
2H); 13C NMR (101 MHz, [D6]DMSO, 208C): d=13.7 (q), 21.7 (t), 33.2
of 5a: C53H57.5Cl1.5F6N7O3; Mr =1007.74; 0.17ꢂ0.11ꢂ0.10 mm; triclinic,
¯
space group P1 (No. 2); a=14.7822(6), b=18.1191(7), c=18.4515(7) ꢁ;
a=94.795(2), b=93.989(2), g=98.372(2)8; V=4855.5(3) ꢁ3; Z=4; 1cald
1.379 gcmꢀ3
000 =2112; Bruker SMART 1000, MoKa radiation, l=
(t), 34.1 (t), 57.0 (t), 57.1 (t), 116.8 (d), 117.1 (d), 117.8 (d), 118.26 (d),
118.33 (d), 118.7 (d), 121.7 (q, 2J
G
=
1
3
;
F
124.5 (q, J
(C,F)=269.4 Hz) (s), 126.0 (q, J
0.71073 ꢁ; T=120(1) K; 2qmax =46.68; 25611 reflections collected, 13904
of which were unique (Rint =0.0758). The structure was solved and re-
fined by using the programs SHELXS-97[31] and SHELXL-97,[31] respec-
tively. The program X-Seed[32] was used as an interface to the SHELX
programs and to prepare the figures. Final GOF=0.865, R1 =0.0861,
128.7 (d), 135.7 (s), 137.3 (s), 139.3 (s), 139.7 (s), 139.8 (s), 143.5 (s), 152.2
~
(s), 152.6 ppm (s); IR (Nujol): n=3329 (s), 1668 (vs), 1608 (vs), 1565 (vs),
1488 (m), 1415 (m), 1331 (vs), 1251 (s), 1165 (s), 1118 (vs), 1076 (s), 853
(m), 778 (w), 703 cmꢀ1 (m); MS (FAB+): m/z (%): 882 (74) [M+1]+, 881
(34) [M]+, 880 (63), 600 (27), 588 (32), 294 (26), 293 (100), 237 (26); ele-
2396
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ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 2389 – 2397

Capsular Aggregates of Tripodal Triureas
FULL PAPER
mental analysis calcd (%) for C48H45F6N7O3 (881.9): C 65.37, H 5.14, N
11.12; found: C 64.91, H 5.13, N 11.11.
Acknowledgements
This work was supported by the Ministerio de Educacion y Ciencia of
Spain (project nos. CTQ2008-05827 and CTQ2009-12216) and Fundacion
Seneca-CARM (project no. 08661/PI/08). J.W.S. is grateful to Durham
University and the EPSRC for funding. The photograph of the “Danza-
trice” on the TOC is used with the kind permission of the Egyptian
Museum of Turin, for which we are very grateful.
Bis{3-ACHTUNGTRENNUNG[N’-(4-methoxyphenyl)ureido]benzyl}{3-ACHUTNGTREN[NUGN N’-(4-butylphenyl)ureido]-
benzyl}amine (5b): Colourless prisms (an analytical sample was obtained
by recrystallization from 10;1 CHCl3/Et2O), 92% yield. M.p. 141–1468C;
1H NMR (401 MHz, [D6]DMSO, 208C): d=0.89 (t, 3J
ACHTUNGTRENNUNG
3H), 1.29 (sext, 3J
(H,H)=7.4 Hz, 2H), 1.50 (quint, 3J
E
3
3
2H), 2.49 (t, J
N
ACHTUNGTRENNUNG(H,H)=6.8 Hz, 4H), 7.06–7.08 (m, 5H), 7.25–7.28 (m, 3H), 7.36–7.38 (m,
9H), 7.50–7.52 (m, 3H), 8.47 (s, 2H), 8.56 (s, 1H), 8.60 (s, 2H), 8.64 ppm
(s, 1H); 13C NMR (101 MHz, [D6]DMSO, 208C): d=13.8 (q), 21.7 (t),
33.3 (t), 34.2 (t), 55.1 (q), 57.1 (t), 114.0 (d), 116.8 (d), 118.3 (d), 120.0
(d), 121.8 (d), 121.9 (d), 128.5 (d), 128.7 (d), 132.7 (s), 135.7 (s), 137.3 (s),
139.7 (s), 139.8 (s), 139.9 (s), 152.6 (s), 152.7 (s), 154.4 ppm (s); IR
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10455–10459.
~
(Nujol): n=3326 (s), 1654 (vs), 1606 (vs), 1555 (vs), 1511 (vs), 1489 (vs),
1311 (s), 1247 (vs), 1181 (m), 1113 (w), 1036 (w), 834 (m), 780 (w),
700 cmꢀ1 (m); MS (FAB+): m/z (%): 806 (42) [M+1]+, 805 (20) [M]+,
804 (33), 550 (21), 255 (45), 237 (28), 133 (22), 132 (100), 124 (37), 123
(78), 122 (32), 120 (20); elemental analysis calcd (%) for C48H51N7O5
(806.0): C 71.53, H 6.38, N 12.17; found: C 71.90, H 6.42, N 12.47.
Bis{3-ACHTUNGTRENNUNG[N’-ACHTUNGTRENNUNG(benzyl)ureido]benzyl}{3-ACHTNGUTREN[NUGN N’-(4-butylphenyl)ureido]benzyl}a-
mine (5c): Benzyl isocyanate (0.05 g, 0.40 mmol) was added to a solution
of 12 (0.10 g, 0.20 mmol) in dry CHCl3 (10 mL) under N2. After stirring
at reflux for 24 h, the solvent was removed under reduced pressure and
n-pentane (5 mL) was added. The white solid was collected by filtration
and dried under vacuum to give 5c in 80% yield; colourless prisms (an
analytical sample was obtained by recrystallization from 1/1 acetone/n-
pentane). M.p. 155–1588C; 1H NMR (401 MHz, [D6]DMSO, 208C): d=
0.88 (t, 3J
(quint, 3J(H,H)=7.2 Hz, 2H), 2.45 (br s, 2H), 3.43 (s, 6H), 4.28 (d, 3J-
(H,H)=5.5 Hz, 4H), 6.57 (t, 3J
(H,H)=6.0 Hz, 2H), 6.97–7.08 (m, 5H),
ACHTUNGTRENNUNG ACHTUNGTNER(NUGN H,H)=7.2 Hz, 2H), 1.50
(H,H)=7.2 Hz, 3H), 1.28 (sext, 3J
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
7.12–7.41 (m, 22H), 8.54 (s, 2H), 8.60 ppm (s, 1H); 13C NMR (75 MHz,
[D6]DMSO, 208C): d=13.8 (q), 21.7 (t), 33.3 (t), 34.2 (t), 42.7 (t), 57.05
(t), 57.13 (t), 116.4 (d), 116.7 (d), 118.0 (d), 118.3 (d), 121.3 (d), 121.9 (d),
126.7 (d), 127.0 (d), 127.1 (d), 128.3 (d), 128.5 (d), 128.6 (d), 135.7 (s),
137.3 (s), 139.6 (s), 139.8 (s), 140.3 (s), 140.4 (s), 152.6 (s), 155.2 ppm (s);
[17] G. Gil-Ramꢃrez, M. Chas, P. Ballester, J. Am. Chem. Soc. 2010, 132,
2520–2521.
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2010, 46, 1394–1403.
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R. Arakawa, Chem. Commun. 2001, 169–170.
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~
IR (Nujol): n=3312 (s), 1647 (vs), 1606 (s), 1552 (vs), 1490 (s), 1315 (s),
1239 (s), 1131 (w), 1083 (w), 888 (w), 784 (w), 696 cmꢀ1 (s); MS (FAB+):
m/z (%): 774 (100) [M+1]+, 773 (29) [M]+, 772 (50), 534 (42), 492 (26),
147 (26), 132 (78), 108 (23); elemental analysis calcd (%) for C48H51N7O3
(774.0): C 74.49, H 6.64, N 12.67; found: C 74.70, H 6.71, N 12.77.
[21] M. Alajarꢃn, A. Pastor, R.-A. Orenes, J. W. Steed, J. Org. Chem.
2002, 67, 7091–7095.
Preparation of bis{5-chloro-2-[N’-(4-methylphenyl)ureido]benzyl}{3-ACTHNUTRGENUG[N N’-
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Rꢆegger, P. S. Pregosin, Chem. Eur. J. 2007, 13, 1559–1569.
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(4-methylphenyl)ureido]propyl}amine (6): 4-Methylphenyl isocyanate
(0.06 g, 0.48 mmol) was added to a solution of 14 (0.06 g, 0.16 mmol) in
dry CHCl3 (15 mL) under N2. After stirring at 208C for 20 h, the solvent
was removed under reduced pressure and Et2O (2 mL) was added. The
white solid was collected by filtration and dried under vacuum. The cor-
responding triurea was purified by recrystallization from CHCl3/Et2O
(2:1) (yield: 77%). M.p. 218–2208C; 1H NMR (400 MHz, [D6]DMSO,
208C): d=1.65 (quint, 3J
2.49 (m, 2H), 3.01 (q, 3J
(H,H)=6.0 Hz, 1H), 6.97–7.03 (m, 6H), 7.16 (dd, 3J
(H,H)=2.1 Hz, 2H), 7.23 (d, 3J(H,H)=8.2 Hz, 2H), 7.29 (d, 3J
8.2 Hz, 4H), 7.39 (d, 4J(H,H)=1.9 Hz, 2H), 7.65 (d, 3J
(H,H)=8.7 Hz,
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
2H), 8.31 (s, 2H), 8.32 (s, 1H), 8.96 (s, 2H); 13C NMR (100 MHz,
[D6]DMSO, 208C): d=20.35 (q), 20.39 (q), 26.4 (t), 37.4 (t), 51.9 (t), 54.4
(t), 118.0 (d), 118.8 (d), 124.3 (d), 127.0 (s), 127.1 (d), 129.0 (d), 129.1 (d),
129.8 (s), 130.8 (s), 131.5 (s), 136.7 (s), 137.1 (s), 137.9 (s), 152.9 (s), 155.6
~
(s); IR (Nujol): n=3340 (s), 1656 (vs), 1599 (vs), 1555 (s), 1514 (s), 1410
(w), 1318 (m), 1289 (m), 1247 (m), 1184 (w), 1116 (w), 823 cmꢀ1 (m); MS
(FAB+): m/z (%): 754 (21) [M+3]+, 753 (15) [M+2]+, 752 (27) [M+1]+,
373 (17), 308 (28), 290 (18), 275 (26), 274 (21), 273 (79), 271 (34), 266
(17), 241 (30), 219 (26); HRMS (ESI): m/z calcd for C41H43Cl2N7O3 +H+:
752.2877; found: 752.2883 [M+H]+.
Received: October 4, 2011
Published online: January 19, 2012
Chem. Eur. J. 2012, 18, 2389 – 2397
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2397