Self-assembly of tris(2-ureidobenzyl)amines with C1 symmetry

Article abstract of DOI:10.1007/s11224-011-9787-y

Tris(2-ureidobenzyl)amines bearing three differentially substituted arms have been synthesized. They possess an asymmetric nitrogen atom, the pivotal one, and thus they feature C₁ symmetry. The self-assembly of these C₁-symmetric tri

Full text of DOI:10.1007/s11224-011-9787-y

Struct Chem (2011) 22:977–981
DOI 10.1007/s11224-011-9787-y
ORIGINAL RESEARCH
Self-assembly of tris(2-ureidobenzyl)amines with C1 symmetry
•
Mateo Alajarin Raul-Angel Orenes
•
Aurelia Pastor
Received: 25 February 2011 / Accepted: 29 March 2011 / Published online: 9 April 2011
Ó Springer Science+Business Media, LLC 2011
Abstract Tris(2-ureidobenzyl)amines bearing three dif-
ferentially substituted arms have been synthesized. They
possess an asymmetric nitrogen atom, the pivotal one, and
thus they feature C1 symmetry. The self-assembly of these
C1-symmetric tris(2-ureidobenzyl)amines may potentially
lead to multiple regio- and diastereoisomeric capsules
coming from the pairing of the four stereoisomeric mono-
mers with configurations (R, P), (S, P), (R, M) and (S, M). The
1H- and 19F{1H}-NMR spectra confirm the presence of
dimeric aggregates, as a mixture of several regio- and dia-
stereoisomeric species.
applications in chemical sensing, drug deliver or catalysis
[4–7].
Tris(2-ureidobenzyl)amines 1 form capsular dimeric
aggregates held together by a seam of six hydrogen-bonded
ureas (Fig. 1) [8]. Although larger and more complex
assemblies are known, capsular aggregates 1ꢀ1 are attrac-
tive and challenging due to their special geometry.
Supramolecular synthons 1 are easily available and have a
great potential for modification [8]. Triureas 1 feature
averaged C3v symmetries in competitive solvents with
hydrogen bonds. However, when two molecules of 1 self-
assemble in non-competitive solvents, their conformations
are frozen into a chiral one of C3 symmetry, with a
propeller arrangement around the tribenzylamine core.
Capsular dimeric aggregates 1ꢀ1 are formed by two
self-complementary and enantiomeric tripods (self-dis-
crimination), offset by 60° each other, resulting in a global
achiral S6 symmetry [8].
Keywords Self-assembly ꢀ Hydrogen bonds ꢀ
Capsular aggregates ꢀ Supramolecular chirality
Introduction
The ability of chemical systems to spontaneously generate
order through self-assembly is one of the most fascinating
phenomena [1–3]. During the last decade, self-assembled
supramolecular systems that provide an internal cavity
have been thoroughly investigated since they may found
Supramolecular chirality involves the nonsymmetric
arrangement of molecules in a noncovalent assembly
[9, 10]. Programming molecules to spontaneously and
selectively assemble into stereochemically predictable
architectures presents a great challenge. A general method
to introduce and control supramolecular chirality is by
attaching stereogenic atoms to the building blocks [10]. In
a preceding work, we investigated the self-assembly of
racemic tris(ureidobenzyl)amines bearing an stereogenic
carbon atom in one of the arms of the tripodal tertiary
amine. This association process is highly diastereoselective
as a consequence of a point-to-helix chirality transfer
mechanism [11]. The self-assembly of triureas with an
overall Cs symmetry has been also investigated [8, 12].
Here, we present a study of the self-assembly of C1-sym-
metric tris(2-ureidobenzyl)amines 2a,b (Fig. 2), differen-
tially substituted at the three arms of the tribenzylamine
M. Alajarin ꢀ R.-A. Orenes ꢀ A. Pastor (&)
Departamento de Quimica Organica, Facultad de Quimica,
Universidad de Murcia, Campus de Espinardo, 30100 Murcia,
Spain
e-mail: aureliap@um.es
M. Alajarin
e-mail: alajarin@um.es
R.-A. Orenes
Servicio Universitario de Instrumentacion Cientifica,
Universidad de Murcia, Campus de Espinardo,
30100 Murcia, Spain
123

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Struct Chem (2011) 22:977–981
a
a
a
b
a
c
b
N
c
N
N
c
N
b
)
N
a
a
a
a
c
)
b
)
N
Ar
Ar
H
H
H
N
H
Ar
O
OAr
N
N
N
O
OH
O
H
Ar
HN
Npiv (R
Npiv
(
S
Npiv
(
R)
Npiv (S
a
N
a
represented by
N
Propeller (P)
Propeller (P)
NNH
H Ar
Propeller (M) Propeller (M)
H
N
N
HO
H
N
Fig. 3 Schematic representation of the four stereoisomeric propeller-
like configurations/conformations of triureas 2 (priority convention
a [ b [ c)
N
1·1
Fig. 1 Structure of capsular dimeric aggregates 1ꢀ1 formed by self-
assembly of two tris(2-ureidobenzyl)amines (left). Schematic top
view of a dimer 1ꢀ1 (right)
skeleton. The association of 2 may lead potentially to
several regio- and diastereoisomeric aggregates. This study
includes the analysis of the regio- and diastereoselectivity
in this association process.
Results and discussion
Fig. 4 1H-NMR spectra (300 MHz, 20 °C) of triurea 2a: a in
[D6]DMSO and b in CDCl3. Residual peaks of water and solvent have
been labelled by an asterisk or a circle, respectively
Tris(2-ureidobenzyl)amines 2a,b were synthesized from
the key triazide 3 [13] in a two-step synthetic sequence
(Fig. 2). The triazide 3 was converted into the triamine 4
by reduction with LiAlH4 (LAH), which was then allowed
to react with the corresponding aryl isocyanate.
[D6]DMSO, exhibit the expected resonances for the
monomers (Fig. 4a). The spectra display three sets of sig-
nals in a 1:1:1 ratio, corresponding to the three differentially
substituted branches of the tripodal molecule. This pattern
is clearly evident in Fig. 5a, where the high-frequency
region of the 1H-NMR spectrum of 2a shows the resonances
for the NHs bearing the terminal Ar groups.
Tris(2-ureidobenzyl)amines 2, bearing three differen-
tially substituted arms, possess an asymmetric nitrogen
atom, the pivotal one. Moreover, triureas 2 can adopt a
propeller arrangement around the tribenzylamine core.
Accordingly, four stereoisomers are conceivable consid-
ering the absolute configuration of the tertiary nitrogen
atom and the two senses of the propeller (Fig. 3).
The self-assembly of 2a,b was subsequently investi-
1
gated by comparing their H-NMR spectra measured in
In competitive solvents with hydrogen bonding, where
the monomeric triureas 2 are present, the four stereoisomers
must be in rapid exchange equilibrium. As a matter of fact,
the 1H-NMR spectra of triureas 2a,b, measured in
[D6]DMSO with those measured in a non-competitive
1
solvent such as CDCl3 (10–20 mM). The H-NMR spectra
of 2a,b in CDCl3 are very complex (Fig. 4b) compared to
those of the C3v-symmetric triureas 1 in the same solvent
[12]. In spite of the complexity, the diagnostic features of
the capsular dimeric aggregates 2ꢀ2 can be clearly distin-
guished. For 2a, the resonances of the NH protons bearing
the pendant aryl groups appeared at d = 7.75–8.05 ppm,
i.e. shifted to higher frequencies respect to those of a ref-
erence urea (diphenylurea), which indicates strong hydro-
gen bonding (Fig. 4b) [12, 14]. Moreover, anisotropic
effects for the protons of the pendant aromatic groups (Ar
in Fig. 2) and those of the methylene groups of the
(ArCH2)3N fragments are apparent. Thus, the benzylic
methylene protons appear as a complex signal centred at
d = 3.0 ppm in CDCl3, the same nuclei resonating as three
singlets at 3.60, 3.63 and 3.64 ppm in [D6]DMSO.
Cl
Me
Cl
Me
N
(b)
N
N
H
H
X
O
O Ar
N
N
O
N
H
H
X
X
H
N
N
H
Ar
Ar
X = N3 (3)
X = NH2 (4)
(a)
2a (Ar = 4-MeC6H4)
2b (Ar = 4-CF3C6H4)
Fig. 2 Synthesis of the triamine 4 and the triureas 2a,b. Reagents and
reaction conditions: a LAH, Et2O, 0 °C ? 20 °C, 6 h; b ArNCO,
CH2Cl2, 20 °C, 18 h
123

Struct Chem (2011) 22:977–981
979
may potentially lead to multiple dimeric capsules coming
from the pairing of the four stereoisomeric monomers with
configurations (R,P), (S,P), (R,M) and (S,M) (Fig. 3). On the
basis of previous observations, dimers 2ꢀ2 only form by
assembly of monomers possessing propellers of opposite
sense, i.e. (S,P)/(S,M), (S,P)/(R,M), (R,P)/(R,M) or (S,M)/
(R,P). Within each pair of stereoisomeric dimers, regioiso-
meric assemblies may be formed depending on the relative
position of the six arms. A global view is schematically
represented in Fig. 6. Thus, a maximum of five regioiso-
meric aggregates may result from the self-dimerization of
triureas 2. Regioisomer 1 may exist as two chiral diastereo-
isomeric aggregates (A/B and C/D in Fig. 6). Regiosiomers
2, 3 and 4 are also chiral (structures E/F, G/H and I/J in
Fig. 6). Finally, regioisomer 5 may exist as two diastereo-
isomeric aggregates of Ci symmetry (K and L). Regio- and
diastereoisomers A-L may interconvert each other by dis-
sociation/recombination of the two subunits. For aggregates
A/C, B/D and K/L, the interconversion is also possible by
inversion of the sense of the tribenzylamine propellers and
the ureas’ belt. Both, the dissociation/recombination process
and the inversion of the urea moieties are usually slow on the
NMR time scale, thus separated signals for every species
would be observed [12].
Fig. 5 High-frequency regions of the 1H-NMR spectra of 2a
(300 MHz, 20 °C): a in [D6]DMSO and b in CDCl3, where the
NHs bearing the pendant aryl groups resonate
The aromatic protons of the pendant p-tolyl groups afford
two multiplets centred at 6.15 and 6.45 ppm, the same
protons resonating around 7.03 and 7.28 ppm in
[D6]DMSO. These observations are of diagnostic value for
the interdigitated arrangement [12]. As expected, the res-
onances for the monomeric species are not observed at the
measured concentrations. On the basis of previous work,
this fact would be consistent with a value higher than
9 9 104 M-1 for Kas [12]. An analogous conclusion was
The relative proportion of isomeric species in CDCl3
solutions of 2a and 2b was investigated by analyzing the
resonances of the NHs bearing the pendant Ar substituents
appearing in the region of 7.5–8.5 ppm. The spectra of 2
show a complex signal at higher frequencies. Thus, the
NHs bearing the pendant Ar substituents resonate at d =
7.75–8.05 ppm for 2a (Fig. 5b) and at d = 7.96–8.32 ppm
for 2b. The 19F{1H}-NMR spectrum of 2b in CDCl3 also
1
reached by analyzing the H-NMR spectrum of 2b.
The complexity of the spectra is not only due to the for-
mation of the dimer but also to the presence of regio- and
diastereoisomeric species. Thus, taking into account that the
tribenzylamine skeleton is conformationally restricted
within dimeric structures 2ꢀ2, the self-assembly of triureas 2
Regioisomer 1
Regioisomer 2
Regioisomer 4
a
b
a
b
b
c
a
b
c
b
b
c
a
c
b
c
c
a
a
N
b
a
N
c
c
N
a
a
N
b
b
N
a
b
N
a
c
c
b
c
a
c
RP/RM
1 (I)
RM/SP
RP/RM
1 (E)
SM/SP
SM/SP
SP/RM
C1 (B)
C
C1 (F)
C
C
1 (J)
C1 (A)
enantiomers
enantiomers
enantiomers
Regioisomer 3
Regioisomer 5
b
a
c
N
b
b
b
b
N
c
b
c
a
a
c
a
b
b
c
a
N
a
a
a
a
N
a
b
N
b
c
N
b
a
c
c
c
c
b
c
c
a
RP/SM
C1 (C)
SM/RP
1 (D)
RP/RM
C1 (G)
SP/RM
i (K)
RP/SM
i (L)
SM/SP
1 (H)
C
C
C
C
enantiomers
enantiomers
Fig. 6 Schematic representation of the five regioisomers which can
be formed by self-assembly of two triureas 2. The triureas 2 feature a
different substituent in every arm of the tripod, which has been
symbolized by a, b or c. The absolute configuration of each monomer
within dimers 2ꢀ2 and the symmetry group of every dimeric species
have been also specified
123

980
Struct Chem (2011) 22:977–981
displays a complex signal in the region nearby -62.7 ppm.
Both observations point to the presence of a large number
of isomeric capsular aggregates. As a matter of fact, the
presence of a statistical distribution of dimeric species A–
L would lead to 36 singlets of similar area: six signals due
to the resonances of the NHs of each chiral regioisomers
(A/B, C/D, E/F, G/H and I/J), and three singlets to each
meso aggregate (K and L).
reaction mixture was cooled to 0 °C and treated with a 10%
aqueous NaOH (10 mL). After filtration over a pad of
Celite, which was further washed with Et2O (3 9 25 mL),
the ethereal phase was separated and the aqueous phase
extracted with CH2Cl2 (3 9 15 mL). The combined
extracts were dried over MgSO4, the solvent evaporated
under reduced pressure, and the residue was purified by
silica-gel chromatography eluting with 1:4 AcOEt/CH2Cl2
(Rf = 0.59); 73% yield. Colourless prisms (an analytical
sample was obtained by recrystallization from 1:1 Et2O/n-
These results indicate that the ratio of isomeric aggre-
gates 2ꢀ2 is only slightly influenced by the electronic nature
of the substituents attached to the aromatic rings of the
tribenzylamine skeleton, pointing to tiny differences in
energy between the potential isomeric aggregates.
1
pentane). M.p. 148–150 °C; H-NMR (300 MHz, CDCl3,
20 °C, TMS): d = 2.21 (s, 3H), 3.40 (s, 2H), 3.41 (s, 2H),
3.44 (s, 2H), 3.94 (br s, 6H), 6.46–6.50 (m, 2H), 6.57 (d,
3J(H,H) = 7.8 Hz, 1H), 6.67 (td, 3J(H,H) = 7.2 Hz,
4J(H,H) = 0.9 Hz, 1H), 6.87-6.90 (m, 2H), 6.99–7.10 ppm
(m, 4H); 13C-NMR (75 MHz, CDCl3, 20 °C): d = 20.3
(q), 56.9 (t), 57.2 (2 9 t), 115.6 (d), 115.8 (d), 116.5 (d),
117.9 (d), 121.6 (s), 121.7 (s), 122.0 (s), 123.5 (s), 127.1
(s), 128.6 (d), 129.0 (d), 129.5 (d), 131.3 (d), 132.0 (d),
132.6 (d), 142.9 (s), 144.3 (s), 145.5 ppm (s); IR (Nujol):
Conclusions
Tris(2-ureidobenzyl)amines differentially substituted at the
three arms of the tribenzylamine skeleton are readily
available from the corresponding triazide. The 1H- and
19F{1H}-NMR spectra in non-competitive CDCl3 confirm
the presence of dimeric aggregates 2ꢀ2, as a mixture of
several regio- and diastereoisomeric aggregates. A low
degree of differentiation between the three arms of the
tribenzylamine skeleton leading to tiny differences in
energy between the potential isomeric aggregates could
explain the observed behaviour. More extensive studies
with other triureas of C1 symmetry are in progress in our
laboratories.
~
m = 3463 (vs), 3353 (vs), 1628 (s), 1506 (m), 1497 (s),
1421 (m), 1315 (m), 1290 (m), 1099 (m), 963 (w), 817 (w),
760 (w) cm-1; MS (70 eV, EI): m/z (%): 382 (1) [M??2],
380 (3) [M?], 274 (14), 260 (21), 240 (16), 222 (14), 155
(16), 142 (13), 140 (46), 135 (40), 120 (94), 106 (100), 103
(21), 93 (9), 91 (15), 77 (49); elemental analysis calcd (%)
for C22H25ClN4 (380.9): C 69.37, H 6.62, N 14.71; found:
C 69.48, H 6.51, N 14.79.
General procedure for the synthesis of triureas 2a,b
Experimental
To a solution of 4 (0.10 g; 0.26 mmol) in dry CH2Cl2
(10 mL) the corresponding isocyanate (0.78 mmol) dis-
solved in the same solvent (5 mL) was added under N2.
After stirring at 20 °C for 18 h the solvent was removed
under reduced pressure and Et2O (5 mL) was added. The
white solid was filtered and dried under vacuum. Triurea 2a
was purified by recrystallization. Due to its low solubility
in all common organic solvents, triurea 2b was thoroughly
washed with CH2Cl2.
1H- and 13C-NMR spectra were measured on Varian Unity-
300 (1H: 300 MHz, 13C: 75 MHz) and Bruker AVANCE
400 (1H: 400 MHz, 13C: 101 MHz) spectrometers with
TMS (d 0.00 ppm) or the solvent residual peak as internal
standards. IR spectra were recorded on a FT-IR Nicolet
Impact 400 infrared spectrometer and melting points were
taken on a Reichert apparatus and are not corrected.
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.
{5-Chloro-2-[N0-(4-methylphenyl)ureido]benzyl}{5-
methyl-2-[N0-(4-methylphenyl)ureido]benzyl}{2-[N0-
(4-methylphenyl)ureido]benzyl}amine (2a)
(2-Aminobenzyl)(2-amino-5-chlorobenzyl)(2-amino-5-
45% yield; colourless prisms (an analytical sample was
obtained by recrystallization from 1:1 CHCl3/Et2O). M.p.
262–263 °C; 1H-NMR (300 MHz, [D6]DMSO, 20 °C):
d = 2.14 (s, 3H), 2.21 (s, 9H), 3.60 (s, 2H), 3.63 (s, 2H),
3.64 (s, 2H), 6.93–7.05 (m, 8H), 7.12 (d,
3J(H,H) = 7.8 Hz, 1H), 7.17 (dd, 3J(H,H) = 8.0 Hz,
4J(H,H) = 2.4 Hz, 1H), 7.25–7.31 (m, 7H), 7.37 (d,
3J(H,H) = 8.1 Hz, 1H), 7.48–7.49 (m, 2H), 7.56–7.59 (m,
methylbenzyl)amine (4)
The triazide 3 [13] (0.73 g; 1.6 mmol) was dissolved in dry
Et2O (15 mL) and slowly added to a suspension of LiAlH4
(0.18 g; 4.8 mmol) in the same solvent (15 mL) at 0 °C
under N2. The mixture was stirred at this temperature for
1 h, warmed to 20 °C, and stirred for 5 h more. Then, the
123

Struct Chem (2011) 22:977–981
981
2H), 7.84 (s, 1H), 7.97 (s, 2H), 8.62 (s, 1H), 8.68 (s, 1H),
8.70 ppm (s, 1H); 13C-NMR (75 MHz, [D6]DMSO,
20 °C): d = 20.3 (q), 20.5 (q), 54.3 (t), 54.65 (t), 54.70 (t),
118.35 (d), 118.39 (d), 123.4 (d), 123.5 (d), 124.4 (d),
124.6 (d), 126.8 (d), 127.1 (d), 127.2 (s), 127.8 (d), 128.2
(d), 128.7 (d), 129.0 (d), 129.5 (d), 129.6 (s), 130.3 (s),
130.45 (s), 130.52 (s), 130.7 (s), 131.8 (s), 132.9 (s), 134.4
(s), 136.1 (s), 136.9 (s), 137.08 (s), 137.13 (s), 152.7 (s),
143.3 (s), 143.50 (s), 143.54 (s), 152.6 (s), 152.9 (s),
153.2 ppm (s); 19F-NMR (188 MHz, [D6]DMSO, 20 °C):
~
d = -59.7, -59.6 ppm; IR (Nujol): m = 3330 (vs), 1668
(vs), 1605 (s), 1557 (vs), 1409 (w), 1325 (s), 1250 (w),
1168 (m), 1130 (s), 1070 (m), 847 (w), 750 (w) cm-1
;
elemental analysis calcd (%) for C46H37ClF9N7O3 (942.3):
C 58.63, H 3.96, N 10.41; found: C 58.38, H 4.33, N 10.49.
Acknowledgments This work was supported by the Ministerio de
Educacion y Ciencia of Spain (Projects CTQ2008-05827/BQU and
CTQ2009-12216/BQU) and Fundacion Seneca-CARM (Project
08661/PI/08).
~
153.1 (s), 153.4 ppm (s); IR (Nujol): m = 3325 (s), 1660
(vs), 1605 (s), 1568 (vs), 1517 (m), 1314 (m), 1245 (w),
975 (w), 820 (m), 746 (w), 715 (w) cm-1; elemental
analysis calcd (%) for C46H46ClN7O3 (780.4): C 70.80, H
5.94, N 12.56; found: C 70.71, H 6.22, N 12.66.
References
{5-Chloro-2-[N0-(4-trifluoromethylphenyl)
ureido]benzyl}{5-methyl-2-[N0-(4-trifluoromethylphenyl)
ureido]benzyl}{2-[N0-(4-trifluoromethylphenyl)ureido]
benzyl}amine (2b)
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1
83% yield; colourless prisms. M.p. 235–236 °C; H-NMR
(300 MHz, [D6]DMSO, 20 °C): d = 2.13 (s, 3H), 3.62 (s,
2H), 3.65 (s, 2H), 3.66 (s, 2H), 6.93 (d, 3J(H,H) = 7.5 Hz,
3
1H), 7.02 (t, J(H,H) = 7.2 Hz, 1H), 7.11–7.17 (m, 2H),
7.24 (s, 1H), 7.34 (d, 3J(H,H) = 8.1 Hz, 1H), 7.47-7.58 (m,
16H), 8.03 (s, 1H), 8.15 (s, 1H), 8.16 (s, 1H), 9.15 (s, 1H),
9.21 (s, 1H), 9.23 ppm (s, 1H); 13C-NMR (101 MHz,
[D6]DMSO, 20 °C): d = 20.6 (d), 54.1 (t), 54.6 (t), 54.7
2
(t), 117.85 (d), 117.93 (d), 121.6 (q, J(C,F) = 31.7 Hz)
2
2
(s), 121.7 (q, J(C,F) = 31.7 Hz) (s), 121.8 (q, J(C,F) =
31.7 Hz) (s), 124.1 (d), 124.2 (d), 124.6 (q, 1J(C,F) =
268.7 Hz) (s), 124.7 (d), 125.2 (d), 126.0 (q,
3J(C,F) = 3.6 Hz) (d), 127.0 (d), 127.3 (d), 127.9 (s),
128.0 (d), 128.3 (d), 128.9 (d), 129.6 (d), 130.4 (s), 130.9
(s), 132.7 (s), 133.6 (s), 133.9 (s), 135.6 (s), 136.7 (s),
123