Dimeric self-assembling capsules derived from the highly flexible tribenzylamine skeleton

Article abstract of DOI:10.1021/jo025852r

Tris(m-ureidobenzyl)amines dimerize both in solid state and in solution to give molecular capsules which are able to encapsulate small molecules. The self-assembly was confirmed by crystal X-ray analysis and NMR spectroscopy. The X-ray structure showed the encapsulation of one molecule of CH₂Cl₂. This new type of capsules presents a propeller-like topology and a belt of six hydrogenbonded ureas. Encapsulation studies in solution and heterodimerization processes are also disclosed.

Full text of DOI:10.1021/jo025852r

Dim er ic Self-Assem blin g Ca p su les Der ived fr om th e High ly
F lexible Tr iben zyla m in e Sk eleton †
Mateo Alajar´ın,*,‡ Aurelia Pastor,‡ Rau´l-AÄ ngel Orenes,‡ and J onathan W. Steed*,§
Departamento de Quı´mica Orga´nica, Facultad de Qu´ımica, Universidad de Murcia, Campus de
Espinardo, Murcia-30.100, Spain and Department of Chemistry, King’s College London, Strand,
London, UK WC2R 2LS, United Kingdom
alajarin@um.es.
Received April 24, 2002
Tris(m-ureidobenzyl)amines dimerize both in solid state and in solution to give molecular capsules
which are able to encapsulate small molecules. The self-assembly was confirmed by crystal X-ray
analysis and NMR spectroscopy. The X-ray structure showed the encapsulation of one molecule of
CH2Cl2. This new type of capsules presents a propeller-like topology and a belt of six hydrogen-
bonded ureas. Encapsulation studies in solution and heterodimerization processes are also disclosed.
In tr od u ction
showed that the dimers exist as “empty” capsules prob-
ably due to their small internal cavities. This pattern of
self-assembly is well-known for the poliureidocalixarenes
studied by Rebek,7 Bo¨hmer,8 and de Mendoza.9 However,
a particular value of our new type of capsules is that no
guest is needed for the nucleation of the assembly, in
stark contrast to the ureidocalixarenes capsules previ-
ously described.
Following our investigations directed toward the design
of new self-assembling capsules based on the tribenzyl-
amine skeleton, we decided to synthesize the structurally
related tris(m-ureidobenzyl)amines. We took into account
that tris(m-ureidobenzyl)amines have all the structural
and functional features necessary for self-assembly like
their ortho counterparts, but they should form dimers
with larger internal cavities. Both types of subunit ortho
and meta share a highly flexible skeleton. Thus, at least
twelve rotations per dimer considering bonds a and b
(eighteen taking into account bonds a, b, and c) and the
inversion of the pivotal nitrogen atom must be restricted
in the assemblies.
The fascinating world of the molecule-within-molecule
complexes (molecular capsules) is one of the most attrac-
tive fields in supramolecular chemistry, not only because
of the need of significant creativity to design the final
target but because of their great number of direct
applications.1 If these applications are to expand, the
accessibility of the capsules, especially with regard to
more diverse shapes, must improve. In particular, self-
assembling capsules are formed by self-complementary
units held together by reversible noncovalent interac-
tions, of which hydrogen bonding is the favorite by virtue
of its directionality, specificity, and biological relevance.2
These self-complementary units are generally based on
conformationally restricted systems such as calixarenes,3
resorcinarenes,4 or glycoluryl5 derivatives.
In a previous communication,6 we reported on the self-
assembly of tris(o-ureidobenzyl)amines. These tris(ureas)
associate forming dimeric aggregates in which two mono-
mers interact by intercalation of their arms, forming a
belt of six hydrogen-bonded ureas. Crystal X-ray analysis
† Dedicated to Professor Waldemar Adam on the occasion of his 65th
birthday.
‡ Universidad de Murcia.
§ King’s College London.
(1) (a) Rebek, J ., J r. Chem. Soc. Rev. 1996, 255-264. (b) Conn, M.
M.; Rebek, J ., J r. Chem. Rev. 1997, 97, 1647-1668. (c) de Mendoza, J .
Chem. Eur. J . 1998, 4, 1373-1377. (d) Rebek, J ., J r. Acc. Chem. Res.
1999, 32, 278-286. (e) Rebek, J ., J r. Heterocycles 2000, 52, 493-504.
(2) J effrey, G. A.; Saenger, W. Hydrogen Bonding in Biological
Structures; Springer-Verlag: Berlin, 1991.
Resu lts a n d Discu ssion
(3) Rebek, J ., J r. Chem. Commun. 2000, 637-643.
(4) (a) Ma, S.; Rudkevich, D. M.; Rebek, J ., J r. J . Am. Chem. Soc.
1998, 120, 4977-4981. (b) Ko¨rner, S. K.; Tucci, F. C.; Rudkevich, D.
M.; Heinz, T.; Rebek, J ., J r. Chem. Eur. J . 2000, 6, 187-195.
(5) (a) Wyler, R.; de Mendoza, J .; Rebek, J ., J r. Angew. Chem., Int.
Ed. Engl. 1993, 32, 1699-1701. (b) Meissner, R. S.; Rebek, J ., J r.; de
Mendoza, J . Science 1995, 270, 1485-1488. (c) Hof, F.; Nuckolls, C.;
Craig, S. L.; Mart´ın, T.; Rebek, J ., J r. J . Am. Chem. Soc. 2000, 122,
10991-10996. (d) Lu¨tzen, A.; Starnes, S. D.; Rudkevich, D. M.; Rebek,
J ., J r. Tetrahedron Lett. 2000, 41, 3777-3780.
The readily available tris(m-azidobenzyl)amine10
(Scheme 1) was converted into the tris(amine) 2 by
reduction with LiAlH4 (LAH) in 74% of yield. Tris(m-
1
(7) (a) Hamann, B. C.; Shimizu, K. D.; Rebek, J ., J r. Angew. Chem.,
Int. Ed. 1996, 35, 1326-1329. (b) Castellano, R. K.; Kim, B. H.; Rebek,
J ., J r. J . Am. Chem. Soc. 1997, 119, 12671-12672. (c) Castellano, R.
K.; Nuckolls, C.; Rebek, J ., J r. J . Am. Chem. Soc. 1999, 121, 11156-
11163.
(6) Alajar´ın, M.; Lo´pez-La´zaro, A.; Pastor, A.; Prince, P. D.; Steed,
J . W.; Arakawa, R. Chem. Commun. 2001, 169-170.
10.1021/jo025852r CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/31/2002
J . Org. Chem. 2002, 67, 7091-7095
7091

Alajar´ın et al.
SCHEME 1
ureidobenzyl)amines 3a -c were obtained from 2 by
treatment with the corresponding isocyanate in yields
ranging 89-98%.
As it was expected, the single-crystal X-ray analysis11,12
of the tris(urea) 3a showed the existence of a hydrogen-
bonded dimer entangled by a belt of six hydrogen-bonded
ureas in a head-to-tail manner (Figure 1), analogously
to the structurally related tris(o-ureidobenzyl)amines.6
In agreement with our initial predictions, the dimer is
large enough to include in its cavity an ordered molecule
of CH2Cl2 (the distance between the two pivotal nitrogen
atoms in the dimer is 9.671/9.896 Å (two independent
pairs), significantly larger than the ortho analogue: 5.511
Å6). There are two unique capsules in the crystal lattice
and each half is related to the other half by a near-perfect
inversion symmetry (broken by the guest molecules
themselves and one n-butyl side chain in one capsule and
implying the space group is actually P112). Such guest
ordering within an essentially symmetric capsule is
remarkable and implies a degree of guest-guest interac-
tions from one capsule to the next.
F IGURE 1. Crystal structure of the tris(urea) dimer 3a ‚3a
(top and axial view) showing the self-assembling capsule with
one enclosed molecule of CH2Cl2.
Every capsule is formed by two enantiomeric tripods
turned 59-61° with respect to each other resulting on
an approximate S6 symmetry for the dimeric core.
Observed along the C3 axis the dimer shows its peculiar
propeller-like topology. The distance N‚‚‚OdC (2.88-3.00
Å) for the urea nitrogen atoms bearing the pendant 4-(n-
butyl)phenyl substituents is shorter than the distance
N‚‚‚OdC (3.03-3.38 Å) for the urea nitrogen atoms
attached to the tribenzylamine skeleton, implying a
rather unsymmetric six-membered hydrogen bonded ring,
also unlike the ortho analogue.6 All these data turned to
be especially valuable due to the fact that only a very
few number of self-assembling capsules have been char-
acterized in solid state by X-ray analysis.
(8) (a) Mogck, O.; Bo¨hmer, V.; Vogt, W. Tetrahedron 1996, 52, 8489-
8496. (b) Vysotsky, M. O.; Bo¨hmer, V. Org. Lett. 2000, 2, 3571-3574.
(c) Vysotsky, M. O.; Thondorf, I.; Bo¨hmer, V. Angew. Chem., Int. Ed.
2000, 39, 1264-1267.
(9) Gonza´lez, J . J .; Ferdani, R.; Albertini, E.; Blasco, J . M.; Arduini,
A.; Pochini, A.; Prados, P.; de Mendoza, J . Chem. Eur. J . 2000, 6, 73-
80.
(10) Alajar´ın, M.; Vidal, A.; Lo´pez-Leonardo, C.; Berna´, J .; Ram´ırez
de Arellano, M. C. Tetrahedron Lett. 1998, 39, 7807-7810.
(11) Diffraction quality crystals were obtained from 3a by recrys-
tallization from CH2Cl2/Et2O.
F IGURE 2. (a) 1H NMR spectrum (300 MHz) of the tris(urea)
3a measured in DMSO-d6; (b) H NMR spectrum (300 MHz)
measured in CDCl3 showing the dimer 3a ‚3a ; (b) signal for
residual water; (*) peaks corresponding to NH resonances
1
(12) Crystallographic data for 3a ‚CH2Cl2‚3a : Formula C54.5H64
-
ClN7O3, triclinic crystal, space group P1, a ) 14.6398(5), b ) 15.8871-
(5), c ) 22.5512(7) Å, R ) 90.280(2), â ) 91.939(2), γ ) 112.538(2)°. T
) 120(2) K, U ) 4840.8(3) Å3, Dc 1.236 mg m-3, 20540 independent
reflections used in refinement, 2360 parameters, R1 (I > 2σ(I)) )
0.0622, ωR2 (all data) 0.1599. CCDC 172793. The possibility that the
crystal might be the more common P-1 was investigated. The centric
solution obtained (two-half capsules) resulted in disorder to one of the
sidearms and both guest species which is absent in P1.
In regard to the solution behavior of tris(ureas) 3a -c,
they showed dramatic differences in their 1H NMR
spectra when recorded in CDCl3, CD2Cl2, and C6D6
compared to the competitive solvent DMSO-d6 (Figure
2). While the spectra of 3a -c in DMSO-d6 displayed the
expected patterns for the monomers 3 (Figure 2a) con-
7092 J . Org. Chem., Vol. 67, No. 20, 2002

Dimeric Self-Assembling Capsules
sistent with averaged C3v symmetries, only a less sym-
metric species, assigned to the dimeric aggregates 3‚3
was observed on changing the solvent to CDCl3, CD2Cl2,
or C6D6. No indication of the monomer was observed in
all these solvents (Figure 2b).
The dimeric species featured two well-separated dou-
blets assigned to the diastereotopic methylenic protons
of the (ArCH2)3N fragment (J gem ) 10.5-11.7 Hz in
CDCl3), instead of the singlet observed for the same
nuclei in DMSO-d6. The signals assigned to the NH
protons (6.67-6.76 and 8.07-8.11 ppm) in CDCl3 ap-
peared significantly sharp and also shifted to lower field
when compared to the reference compound N-(4-butyl-
phenyl)-N′-(4-methylphenyl) urea (δ ) 6.65 ppm). The
significant differences in the δ values for both NH protons
in 3‚3 indicate that the two hydrogen bonds are rather
different in strength, in agreement with that observed
in the X-ray structure. Additionally, the involvement of
the urea carbonyl groups as hydrogen bonding acceptors
was supported by the δ values of their carbon atoms in
the 13C NMR spectra. These signals were shifted to
downfield in CDCl3 (∆δ ) 2.6-2.8 ppm) compared to the
spectra recorded in DMSO-d6 (only ∆δ ) 1.2 ppm was
found for the reference urea). Indeed, FT-IR of 3a (12.6
mM) in CHCl3 solutions revealed typical hydrogen-
bonded NH-stretching bands at 3318 cm-1. All these data
pointed out to a highly ordered, hydrogen-bonded struc-
ture (3‚3) for compounds 3a -c in noncompetitive solvents
which perfectly fits with the conformation found in the
solid state.
F IGURE 3. Schematic representation of the dimer 3a ‚3a in
which some chemical shifts differences (1H NMR spectra)
respect to the same signals for the monomer 3a are reflected.
The most significant observed ROE effects are also represented
F IGURE 4. 1H NMR spectra (-60 °C; 300 MHz) of 3a ‚3a after
addition of CH2Cl2 in CDCl3; (encapsulated CH2Cl2 is indicated
by *).
Supporting Information) with 3a ‚3a (CDCl3) that are only
possible in a dimer but not in a monomer (Figure 3).
The dimeric assembly of 3b was further detected by
ESI-MS14 experiments. The spectrum measured in CHCl3
showed the corresponding molecular ion for the proto-
nated dimer 3b‚3b (1464.7).
Encapsulation studies in solution were performed with
3a . After dissolving the sample (10.8 mg) in CDCl3 (0.6
1
mL) and adding CH2Cl2 (30 µL), the H NMR spectrum
(300 MHz) was recorded at room temperature but only
the signal of “nonencapsulated” CH2Cl2 (δ ) 5.30 ppm)
was observed, besides those corresponding to the capsule
which showed only minor changes in their chemical
shifts. Interestingly, on cooling to -60 °C a new signal
appeared at δ ) 4.96 ppm, integrating in a 1:1 ratio with
those of the dimeric capsule, which was attributed to
encapsulated CH2Cl2 (Figure 4). At room temperature the
exchange rate between free and encapsulated CH2Cl2
should be fast on the NMR time scale leading to a time-
averaged spectrum.
Further comparisons on the 1H NMR spectra of the
dimer 3a ‚3a (CDCl3) and the monomer 3a (DMSO-d6)
strongly support that the conformation shown by the
X-ray structure in solid-state persists in solution (Figure
3). Large shifts13 to upfield were observed for the pendant
aryl protons (-0.54, -0.68 ppm), the protons at the
n-butyl chain placed nearest to the aromatic ring (-0.43,
-0.54 ppm), and the protons at the tribenzylamine
skeleton which are directed to the internal cavity (-1.73
ppm). These shifts may be rationalized in terms of the
shielding effect between the aromatic rings from the
tribenzylamine skeleton and the pendant aromatic sub-
stituents placed alternatively due to the interpenetration
of the six arms in the dimeric structure. Finally, ROE
contacts were detected from a ROESY experiment (cf.
Further addition of CD2Cl2 (30 µL) to the same sample
led to a half-decreasing of the intensity for the signal at
4.96 ppm when the 1H NMR spectrum was measured
under the same conditions (i.e. -60 °C). This may be
(14) (a) Schalley, C. A.; Mart´ın, T.; Obst, U.; Rebek, J ., J r. J . Am.
Chem. Soc. 1999, 121, 2133-2138. (b) Schalley, C. A.; Castellano, R.
K.; Brody, M. S.; Rudkevich, D. M.; Siuzdak, G.; Rebek, J . J r. J . Am.
Chem. Soc. 1999, 121, 4568-4579.
(13) Since
a few signals are overlapped these differences are
approximated.
J . Org. Chem, Vol. 67, No. 20, 2002 7093

Alajar´ın et al.
for ureidocalixarenes.8 In our case, the 1H NMR spectrum
of an equimolecular mixture of 3a and 3c revealed the
appearance of signals attributable to the heterodimer 3a ‚
3c, besides those of homodimers 3a ‚3a and 3c‚3c. In this
experiment the regions of the aryl-NH protons (8.00-
8.20 ppm) and of the methoxy substituents (3.20-3.30
ppm) were especially informative (Figure 5). Thus, four
NH singlets appeared (1:1:1:1 relative intensities), two
of them due to the homodimers 3a ‚3a (8.12 ppm) and
3c‚3c (8.07 ppm) and the other two to both aryl-NH
protons of the heterodimer 3a ‚3c (8.02, 8.16 ppm).
Similarly, two singlets of nearly the same intensity
appeared, corresponding to both methoxy groups in the
homodimer 3c‚3c (3.26 ppm) and in the heterodimer 3a ‚
3c (3.23 ppm). The relative intensities revealed a nearly
statistical mixture of the three aggregates (2:1:1 for the
heterodimer and both homodimers respectively).
Thiourea and amide functionalities are known to
behave as good hydrogen bond donors and acceptors,15
hence both functionalities are also candidates to construct
molecules that self-assemble by hydrogen-bonding. For
comparison, the behavior in solution of the tris(m-
thioureidobenzyl)amine 4 and the tris(m-amidobenzyl)-
amine 5 was tested. Unfortunately, neither tris(thiourea)
4 nor tris(amide) 5 self-assemble in CDCl3 since the
expected patterns for the corresponding monomers with
1
C3v symmetries were found in their respective H NMR
spectra.
F IGURE 5. (a) 1H NMR (300 MHz) spectrum of 3a ‚3a in
1
1
CDCl3; (b) H NMR spectrum of 3c‚3c in CDCl3; (c) H NMR
spectrum of an equimolecular mixture of tris(ureas) 3a and
3c showing the 2:1:1 mixture of hetero- and homodimers
respectively; (b) signal for residual water.
rationalized by the fact that in this case 50% of the
capsules include CH2Cl2 and the other 50% CD2Cl2 which
1
cannot be observed in the H NMR spectrum.
The encapsulation of CH2Cl2 and CHCl3 by using C2D2-
Cl4 as solvent was also tested. In this case, the peak
corresponding to encapsulated CH2Cl2 was found at δ )
4.95 ppm when the spectrum was measured at -30 °C
(300 MHz). For CHCl3 the signal attributable to the
encapsulated guest was assigned at δ ) 6.80 ppm (-30
°C; 300 MHz) although it was partially overlapped with
other signals in the aromatic region of the spectrum
(further addition of CDCl3 led to a decreasing of this
signal). For CH2Cl2, only the signals for the filled capsule
were found. On the contrary, the spectrum showed two
sets of signals in approximately 1:1 ratio when CHCl3
was used as guest. These two sets of signals were
assigned to filled and empty capsule and reflect that
CHCl3 is not as good guest as CH2Cl2 is.
In conclusion, we have reported a key for accessing a
new class of self-assembling capsules based on the
tribenzylamine skeleton. They present as particular
features: (a) high flexibility of the corresponding mono-
mers, (b) a propeller-like topology, and (c) a belt of six
hydrogen-bonded ureas. Investigations directed to the
synthesis of new structural variations for modulating the
size of the internal cavities are in progress in our
laboratories.
Exp er im en ta l Section
CAUTION: Azido compounds may represent an explosion
hazard when being concentrated under vacuum or stored neat.
A safety shield and appropriate handling procedures are
recommended.
Tr is(3-a m in oben zyl)a m in e 2. The tris(azide) 1 (2.00 g,
4.9 mmol) was dissolved in freshly distilled Et2O (20 mL) and
slowly added to a suspension of LAH (0.56 g, 14.6 mmol) in
the same solvent (50 mL) at 0 °C and under a nitrogen-gas
atmosphere. The mixture was stirred at this temperature for
0.5 h, warmed to 20 °C, and stirred for 4 h more. Then, the
reaction mixture was cooled to 0 °C and treated with 10%
aqueous KOH (100 mL). After filtration over a pad of Celite,
the ethereal phase was separated and the aqueous phase
Finally, encapsulation studies were conducted to elu-
cidate whether C6H6 could be included inside tris(m-
ureidobenzyl)amine dimers. However, no changes were
1
observed in the H NMR spectrum after addition of C6H6
to a solution of 3a in CDCl3 (30 °C and -60 °C) which
indicates that CDCl3 was preferably encapsulated. That
the encapsulation of C6H6 is also possible was confirmed
from the 1H NMR spectrum of 3a in a 1:1 mixture of
C6D6/C2D2Cl6. The spectrum (-30 °C) showed a mixture
of two sets of signals (approximately in 1:1 ratio) assigned
to the empty capsule and the capsule with enclosed C6D6.
The formation of heterodimers by the combination of
two homodimeric species is a well-known phenomenon
(15) (a) Etter, M. C. Acc. Chem. Res. 1990, 23, 120-126. (b) Tobe,
Y.; Sasaki, S.; Mizuno, M.; Hirose, K.; Naemura, K. J . Org. Chem. 1998,
63, 7481-7489.
7094 J . Org. Chem., Vol. 67, No. 20, 2002

Dimeric Self-Assembling Capsules
extracted with CH2Cl2 (4 × 50 mL). The combined organic
extracts were dried (MgSO4), the solvent was evaporated (20
°C/75 Torr), and the residue was purified by silica gel chro-
matography eluting first with AcOEt and subsequently with
10:1 AcOEt/MeOH (Rf ) 0.36, AcOEt), 74% yield. An analytical
sample was obtained by recrystallization from 1:1 Et2O/
petroleum ether. Colorless prisms, mp 140-141 °C; IR (Nujol)
H), 3.57 (br s, 6 H), 5.78 (s, 6 H), 6.25 (d, J ) 8.7 Hz, 12 H),
6.73-6.76 (m, 18 H), 7.02 (d, J ) 7.2 Hz, 6 H), 7.28 (t, J ) 7.8
Hz, 6 H), 7.35 (d, J ) 7.8 Hz, 6 H), 8.07 (s, 6 H); 13C NMR
(DMSO-d6, 50 MHz): δ 55.1 (q), 57.1 (t), 114.0 (2×d), 116.7
(d), 118.3 (d), 120.0 (2×d), 121.8 (d), 128.7 (d), 132.7 (s), 139.7
(s), 139.9 (s), 152.7 (s), 154.4 (s); 13C NMR (CDCl3, 75 MHz):
δ 55.3 (q), 58.5 (t), 114.2 (2×d), 119.3 (2×d), 125.5 (2×d), 127.0
(d), 127.4 (d), 132.4 (s), 137.2 (s), 140.1 (s), 154.7 (s), 155.3 (s);
Anal. Found: C, 69.08; H, 5.98; N, 12.77%. Calcd for C45H45N7O6
(779.9): C, 69.30; H, 5.82; N, 12.57%.
Tr is{3-[N′-(ben zyl)th iou r eid o]ben zyl}a m in e (4). The
tris(amine) 2 (0.15 g, 0.45 mmol) was dissolved in dry CHCl3
(10 mL), and benzyl isothiocyanate (0.20 g, 1.36 mmol) was
added. After stirring under reflux for 20 h, the solvent was
removed (20 °C/75 Torr) and the residue was purified by
recrystallization from 1:1 CH2Cl2/Et2O, 72% yield. Colorless
prisms, mp 96-99 °C; IR (Nujol) ν: 3379 (NH), 3217 (NH)
cm-1; 1H NMR (CDCl3, 200 MHz): δ 3.49 (s, 6 H), 4.80 (d, J )
5.2 Hz, 6 H), 6.47 (br s, 3 H), 7.11-7.30 (m, 27 H), 9.04 (s, 3
H); 13C NMR (CDCl3, 50 MHz): δ 49.1 (t), 57.8 (t), 123.1 (d),
124.6 (d), 127.0 (d), 127.6 (3×d), 128.7 (2×d), 129.7 (d), 136.8
(s), 137.3 (s), 141.5 (s), 180.2 (s); Anal. Found: C, 68.64; H,
6.12; N, 12.59%. Calcd for C45H45N7S3‚0.50 H2O: C, 68.50; H,
5.88; N, 12.43%.
1
ν: 3411 (NH), 3336 (NH), 3210 (NH) cm-1; H NMR (CDCl3,
200 MHz): δ 3.47 (s, 6 H), 3.62 (br s, 6 H), 6.55 (dd, J ) 7.7
Hz, J ) 1.5 Hz, 3 H), 6.74 (s, 3 H), 6.80 (d, J ) 7.6 Hz, 3 H),
7.09 (t, J ) 7.7 Hz, 3 H); 13C NMR (CDCl3, 50 MHz): δ 57.9
(t), 113.6 (d), 115.4 (d), 119.1 (d), 129.0 (d), 141.0 (s), 146.3 (s);
Anal. Found: C, 74.68; H, 7.44; N, 16.70%. Calcd for C21H24N4‚
0.25 H2O: C, 74.86; H, 7.33; N, 16.63%. EI-MS: m/z:333 (M+
+ 1, 9), 332 (M+, 20), 226 (99), 106 (100).
Gen er a l P r oced u r e for th e Syn th esis of th e Tr is-
(u r ea s) 3a -c. The tris(amine) 2 (0.05 g, 0.15 mmol) was
dissolved in dry CH2Cl2 (3 mL) and the appropriate isocyanate
(0.45 mmol) was slowly added at 0 °C under a nitrogen-gas
atmosphere. After stirring at 20 °C for 18 h, the solvent was
removed (20 °C/75 Torr) and Et2O (3 mL) was added. The white
solid was filtered off and dried under vacuum.
Tr is{3-[N′-(4-bu tylp h en yl)u r eid o]ben zyl}a m in e (3a ):
89% yield. Colorless prisms (from 1:1 CHCl3/Et2O), mp 185-
1
208 °C; IR (Nujol) ν: 3317 (NH), 1660 (CdO) cm-1; H NMR
Tr is[3-(4-m eth ylben za m id o)ben zyl]a m in e (5). The tris-
(amine) 2 (0.15 g, 0.45 mmol) and triethylamine (0.14 g, 1.36
mmol) were dissolved in dry CH2Cl2 (15 mL). After cooling to
0 °C, a solution of 4-methylbenzoyl chloride (0. 21 g, 1.36 mmol)
in the same solvent (8 mL) was slowly added. The reaction
mixture was warmed to 20 °C and stirred at this temperature
for 20 h. Then, the mixture was washed with saturated
aqueous NaHCO3 solution (15 mL) and the organic phase was
dried with MgSO4. After removal of the solvent (20 °C/75 Torr),
the residue was purified by silica gel chromatography eluting
with 2:3 AcOEt/hexanes (Rf ) 0.36), 95% yield. An analytical
sample was obtained by recrystallization from 1:1 CH2Cl2/
Et2O. Colorless prisms, mp 210-215 °C; IR (Nujol) ν: 3325
(DMSO-d6, 300 MHz): δ 0.89 (t, J ) 7.2 Hz, 9 H), 1.28 (m, J
) 7.3 Hz, 6 H), 1.51 (m, J ) 7.5 Hz, 6 H), 2.48 (t, J ) 7.7 Hz,
6 H), 3.50 (s, 6 H), 7.04-7.08 (m, 9 H), 7.25 (t, J ) 7.7 Hz, 3
H), 7.33-7.39 (m, 9 H), 7.50 (s, 3 H), 8.52 (s, 3 H), 8.59 (s,
3H); 1H NMR (CDCl3, 300 MHz): δ 0.83 (t, J ) 7.1 Hz, 18 H),
0.97 (m, 12 H), 1.07 (m, 12 H), 2.05 (t, J ) 7.7 Hz, 12 H), 2.62
(d, J ) 11.4 Hz, 6 H), 3.57 (d, J ) 11.7 Hz, 6 H), 5.77 (s, 6 H),
6.52 (d, J ) 8.1 Hz, 12 H), 6.67-6.70 (m, 18 H), 7.00 (d, J )
7.2 Hz, 6 H), 7.27 (t, J ) 7.7 Hz, 6 H), 7.35 (d, J ) 8.1 Hz, 6
H), 8.11 (s, 6H); 13C NMR (DMSO-d6, 50 MHz): δ 13.7 (q),
21.6 (t), 33.2 (t), 34.1 (t), 57.1 (t), 116.7 (d), 118.3 (3×d), 121.9
(d), 128.4 (2×d), 128.6 (d), 135.6 (s), 137.3 (s), 139.7 (s), 139.8
(s), 152.5 (s); 13C NMR (CDCl3, 50 MHz): δ 14.1 (q), 22.4 (t),
33.5 (t), 34.7 (t), 58.3 (t), 118.1 (2×d), 125.7 (2×d), 127.2 (2×d),
128.4 (2×d), 136.5 (s), 136.7 (s), 136.9 (s), 139.7 (s), 155.3 (s);
Anal. Found: C, 75.35; H, 7.67; N, 11.72%. Calcd for C54H63N7O3
(858.1): C, 75.58; H, 7.40; N, 11.43%.
(NH), 1658 (CdO), 1652 (CdO) cm-1 1H NMR (CDCl3, 200
;
MHz): δ 2.34 (s, 9 H), 3.63 (s, 6H), 6.97 (d, J ) 7.8 Hz, 6 H),
7.06 (d, J ) 7.5 Hz, 3 H), 7.26 (t, J ) 7.8 Hz, 3 H), 7.61-7.64
(m, 9 H), 8.12 (br s, 3 H), 8.30 (s, 3 H); 13C NMR (CDCl3, 50
MHz): δ 21.4 (q), 57.4 (t), 118.8 (d), 120.8 (d), 124.7 (d), 127.3
(2×d), 128.7 (d), 129.2 (2×d), 132.5 (s), 138.5 (s), 140.9 (s),
141.7 (s), 166.2 (s); Anal. Found: C, 77.29; H, 6.60; N, 8.06%.
Calcd for C45H42N4O3‚0.50 H2O: C, 77.67; H, 6.23; N, 8.05%.
Tr is{3-[N′-(4-m eth ylp h en yl)u r eid o]ben zyl}a m in e (3b):
98% yield. Colorless prisms (from 4:1 CHCl3/Et2O), mp 193-
195 °C; IR (Nujol) ν: 3374 (NH), 3292 (NH), 1664 (CdO) cm-1
;
1H NMR (DMSO-d6, 200 MHz): δ 2.21 (s, 9 H), 3.49 (s, 6 H),
7.03-7.07 (m, 9 H), 7.25 (t, J ) 7.9 Hz, 3 H), 7.31-7.39 (m, 9
1
Ack n ow led gm en t. This work was supported by
MCYT (Project BQU2001-0010) and Fundacio´n Se´neca-
CARM (Project PI-1/00749/FS/01). J . W. S. thanks the
EPSRC and King’s College London for the funding of
the diffractometer system. A.P. and R.-A.O. thank the
European Commission (contract HMPF-CT-1999-00126)
and the Spanish Ministerio de Educacio´n, Cultura y
Deporte, respectively, for a fellowship. We also thank
Prof. Ryuichi Arakawa (Kansai University, Osaka,
J apan) and Dr. H. G. Degen (University of Wu¨rzburg,
Germany) for ESI-MS and ROESY spectra measure-
ments, respectively.
H), 7.47 (s, 3 H), 8.52 (s, 3 H), 8.60 (s, 3H); H NMR (CDCl3,
300 MHz): δ 1.71 (s, 18 H), 2.65 (d, J ) 10.5 Hz, 6 H), 3.55 (d,
J ) 10.5 Hz, 6 H), 5.72 (s, 6 H), 6.47 (d, J ) 8.1 Hz, 12 H),
6.68-6.71 (m, 18 H), 7.02 (d, J ) 6.6 Hz, 6 H), 7.27 (t, J ) 7.7
Hz, 6 H), 7.34 (d, J ) 8.1 Hz, 6 H), 8.08 (s, 6 H); 13C NMR
(DMSO-d6, 50 MHz): δ 20.3 (q), 57.1 (t), 116.8 (d), 118.2 (3×d),
121.9 (d), 128.7 (d), 129.2 (2×d), 130.5 (s), 137.1 (s), 139.7 (s),
139.8 (s), 152.5 (s); 13C NMR (CDCl3, 75 MHz): δ 20.1 (q), 58.4
(t), 118.0 (2×d), 125.6 (2×d), 126.9 (d), 127.2 (d), 129.1 (2×d),
131.5 (s), 136.5 (s), 137.0 (s), 139.8 (s), 155.3 (s); Anal. Found:
C, 73.71; H, 6.35; N, 13.47%. Calcd for C45H45N7O3 (731.9): C,
73.85; H, 6.20; N, 13.40%.
Tr is{3-[N′-(4-m eth oxyph en yl)u r eido]ben zyl}am in e (3c):
98% yield. Colorless prisms (from 1:1 CHCl3/ Et2O), mp 145-
1
245 °C; IR (Nujol) ν: 3314 (NH), 1659 (CdO) cm-1; H NMR
Su p p or tin g In for m a tion Ava ila ble: ROESY spectrum
of the tris(urea) 3a in CDCl3 (600 MHz). This material is
available free of charge via the Internet at http://pubs.acs.org.
(DMSO-d6, 300 MHz): δ 3.49 (s, 6 H), 3.69 (s, 9 H), 6.84 (d, J
) 9.0 Hz, 6 H), 7.04 (d, J ) 7.5 Hz, 3 H), 7.24 (t, J ) 7.7 Hz,
3 H), 7.32-7.38 (m, 9 H), 7.46 (s, 3 H), 8.42 (s, 3 H), 8.55 (s,
3H); 1H NMR (CDCl3, 300 MHz): δ 2.70 (br s, 6 H), 3.27 (s, 18
J O025852R
J . Org. Chem, Vol. 67, No. 20, 2002 7095