Highly diastereoselective self-assembly of chiral tris(m-ureidobenzyl)amino capsules

Article abstract of DOI:10.1039/b809835b

The self-assembly of chiral tris(m-ureidobenzyl)amines to give dimeric capsules is a highly diastereoselective process in solution, while in the solid state, the formation of the corresponding capsules is not only diastereoselective but also regioselective. The Royal Society of Chemistry.

Full text of DOI:10.1039/b809835b

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COMMUNICATION
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Highly diastereoselective self-assembly of chiral
tris(m-ureidobenzyl)amino capsulesw
Mateo Alajarı
Jonathan W. Steedb
n,*a Aurelia Pastor,*a Raul-Angel Orenes,a Andres E. Goetab and
´ ´
Received (in Cambridge, UK) 13th June 2008, Accepted 8th July 2008
First published as an Advance Article on the web 25th July 2008
DOI: 10.1039/b809835b
The self-assembly of chiral tris(m-ureidobenzyl)amines to give
dimeric capsules is a highly diastereoselective process in solu-
tion, while in the solid state, the formation of the corresponding
capsules is not only diastereoselective but also regioselective.
The supermolecule is composed of two clockwise–anticlock-
wise tripods determining an overall S6 symmetry.8,10
We were interested in the design of chiral tribenzylamine
monomers to examine the feasibility of diastereoselective self-
assembling processes. Prediction and switching between
self-assembled supramolecular diastereomers are relevant to
diverse applications.2,12,13 Triureas 2a–c (Fig. 2) bearing a
stereogenic carbon atom in one of the benzylic arms were easily
synthesized from the corresponding a-methyl substituted
tris(m-azidobenzyl)amines, previously reported14 (see ESI for
synthetic detailsw).
In the frozen conformation present in the capsules, triureas
2 may exist in two chiral diastereomeric forms, R,M/S,P and
S,M/R,P, resulting from combining the stereogenic carbon
atom and the propeller-like helicity (Fig. 2). There is a sub-
stantial difference in these two diastereomeric structures re-
garding the arrangement of the methyl group at the benzylic
carbon atom, which is placed either in a pseudoaxial position
in the R,M/S,P enantiomeric pair, or in a pseudoequatorial
arrangement in the S,M/R,P pair (Fig. 2a and b).
Self-assembled capsules are supramolecular structures made
up of molecular bricks which are held together by weak
intermolecular forces.1–3 A great deal is known about the
useful applications of capsules4 as nanovessels,5 as spaces
inside where reagents are stabilized and new forms of stereo-
chemistry can emerge.2,6 We have recently recognized the role
of tris(ureidobenzyl)amines as modular subunits in supra-
molecular chemistry.7–11 Thus, two self-complementary
tris(m-ureidobenzyl)amine molecules 1, identical or not, as-
sociate by hydrogen bonding between their six urea units
forming self-assembled capsules, wherein molecules of ade-
quate size and shape are included (Fig. 1).8,10 Although free
monomers feature averaged C3v-symmetries, the two tripodal
modules adopt a chiral propeller arrangement in the capsule.
Previous studies of our group on the preparation of macro-
bicyclic triphosphazides by tripod–tripod coupling of a-methyl
substituted tris(m-azidobenzyl)amines, with tris(phosphanes) con-
cluded that the configuration of the stereogenic benzylic carbon
Fig. 1 Structure and schematic representation of capsules 1ꢀ1.
a
´
´
´
Departamento de Quımica Organica, Facultad de Quımica,
Universidad de Murcia. Campus de Espinardo, 30.100 Murcia,
Spain. E-mail: alajarin@um.es; aureliap@um.es
Fax: +34 968 364149; Tel: +34 968 367497
b Department of Chemistry, University of Durham, University Science
Laboratories, South Road, Durham, UK DH1 3LE
w Electronic supplementary information (ESI) available: Instruments,
software and procedures used for data collection, structure solution
and refinement of the crystal structure of 2b. Experimental procedures
for the synthesis of 2a–c and 3. Spectroscopic and analytical data for
2a–c and 3 and their precursors. Schematic representation of all
potential isomeric capsules 2ꢀ2 and their symmetry properties. 1H
NMR spectra of 3 in DMSO-d6 and CDCl3, electrospray ionization
mass spectra of 2a and 3 in CHCl3. CCDC reference number 691454.
For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/b809835b
Fig. 2 Schematic representation of the two diastereomeric triureas
2a–c, the respective S,P and R,P enantiomeric forms are omitted for
simplicity.
ꢁc
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Fig. 3 Schematic representation of regioisomers 1 and 2 which can
form by self-assembly of 2. The stereogenic carbon atoms are indicated
by circles on the propellers. Chiral capsules have been labelled by ‘‘*’’
(ent-D*–G* have been omitted for simplicity). The configuration of
each monomer and the arrangement of the methyl group, pseudoaxial
(a) or pseudoequatorial (e), have been also specified.
Fig. 5 X-Ray structure of 2bꢀ2b@n-pentane: (a) axial and (b) top
view.
The structure depicted in Fig. 5 clearly shows that the two
methyl groups are in a pseudoaxial arrangement providing an
approximate S6 symmetry for the dimeric core. Since A is
formed by two enantiomeric subunits, the formation of 2bꢀ2b
constitutes a chiral self-discrimination process.15–20
atom at one arm of the triazide dictates the handedness of the
propeller-like helicity of the final macrobicycle (point-to-helix
chirality transfer).14 This stereochemical bias can be traced down
to a marked preference of the methyl group placed at this carbon
atom for the pseudoaxial position to minimize steric crowding
(compare Fig. 2a and b).
The self-assembly of triureas 2a,b in solution was subsequently
tested in noncompetitive solvents. Unfortunately, the low solubi-
lity of 2c in CDCl3, C2D2Cl4 or toluene-d8 hampered analogous
studies. In a strongly hydrogen bonding solvent such as
DMSO-d6 2a exists as a monomeric, non-assembled species
(Fig. 6a). The change to a noncompetitive solvent such as CDCl3
causes significant alterations in the 1H NMR spectrum (Fig. 6b).
These variations concern not only the number of signals but also
the chemical shifts of some resonances. The complexity and line-
width of the signals in this spectrum are indicative of a mixture of
different species. Nevertheless, the spectra possess typical signa-
tures of tribenzylamine-derived capsules such as significant shifts
to lower frequencies of particular resonances, attributed to local
anisotropic effects.8,10 Thus, large shifts to lower frequencies were
observed for the signals of the pendant p-tolyl protons (Fig. 6, in
red) appearing as broad signals at 1.7–1.8, 6.5 and 6.7 ppm in
CDCl3. These protons resonate in DMSO-d6 at 2.2, 7.1 and
7.3 ppm, respectively. Analogously, the aromatic protons located
at the C-2 position (Fig. 2) in the tribenzylamine skeleton were
also shifted around 2 ppm to lower frequencies in CDCl3. Thus,
whereas these protons resonate at 7.5 ppm in DMSO-d6, they
appear as a broad signal around 5.7 ppm in the halogenated
solvent (Fig. 6, in blue). Finally, the broad signal around
8.2–8.3 ppm was assigned, as in capsules 1ꢀ1, to the ureido NH
In principle, the self-assembly of racemic triureas 2 may lead to
multiple dimeric capsules coming from the pairing of the four
monomers (R,M), (S,P), (S,M) and (R,P), along with two
regioisomeric assemblies depending on the relative position of
the two arms bearing the stereogenic carbon atom, i.e. opposite or
adjacent, which have been labelled as regioisomers 1 and 2,
respectively in Fig. 3.9 There are three different diastereomeric
forms for regioisomeric capsule 1, two achiral centrosymmetric
(A and B) and one chiral (C*), schematically represented in Fig. 3
(for a more complete picture see ESIw). Similarly, regioisomeric
capsule 2 may exist as four different chiral diastereoisomers
(D*–G*). Summing up, a maximum of seven regio- and diastereo-
isomeric capsules may result from the self-dimerization of
racemic 2.
Notably, this somewhat puzzling and complex picture could
be simplified by considering the expected preference of the
methyl group for the pseudoaxial position (point-to-helix chir-
ality transfer).14 Taking into account this fact, the formation of
capsules A and D* should be favoured over the rest (Fig. 4).
To our delight, the single-crystal X-ray analysis of 2b
(CHCl3–n-pentane) showed one single regio- and diastereomeric
capsule in the crystal lattice! (Fig. 5).z In the solid state, each
dimer contains a disordered molecule of n-pentane as the guest
species. The capsule is formed by two enantiomeric monomers
with configurations R,M and S,P, and features the two stereo-
genic carbon atoms in opposite arms, that is, capsule A of Fig. 4.
Fig. 6 1H NMR spectra of 2b: (a) in DMSO-d6 and (b) in CDCl3. The
signals of water and residual solvent have been labelled with an
asterisk and a circle, respectively.
Fig. 4 Schematic representation of the two expected regioisomeric
dimers from the self-assembly of 2.
ꢁc
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‘‘ortho’’ triurea 3 (see ESI for synthetic detailsw) for testing its
dimerization ability. However, the triurea 3 has a low tendency to
assemble in CDCl3 (Fig. 8). Thus, the spectrum of 3 recorded in
this solvent shows a mixture of monomer : dimer in a 84 : 16 ratio
(see ESI for 1H NMR and electrospray ionization mass spectraw).
This behaviour has been rationalized taking into account the
severe steric interactions in the putative aggregates 3ꢀ3 bearing
pseudoaxial methyl groups. This steric hindrance would originate
from the location of these methyl groups inside the small cavity of
the dimeric aggregates 3ꢀ3 (Fig. 8).21
Fig. 7 Region of the 1H NMR spectrum of 2bꢀ2b@MeI where NH
protons of the p-butylamino fragments resonate (CDCl3, ꢂ15 1C).
protons bearing the tolyl group.10 The resemblance of the spectra
of triureas 2 to those of triureas 1 in CDCl3 suggests that capsules
2ꢀ2, analogously to 1ꢀ1, exist in solution and they contain a
molecule of solvent inside the cavity.10 A dimeric assembly 2aꢀ2a
was also detected by electrospray ionization-MS experiments. The
spectrum measured in CHCl3 showed the corresponding mole-
cular ion of the protonated dimer at m/z = 1491.4 (ESIw).
Subsequently, the regio- and diastereoselectivity for the self-
assembly of 2 were scrutinized by analyzing the region where
the NH protons of the p-tolylamino fragments resonate
(8–9 ppm).9 In principle, a statistical mixture of all the species
would lead to 36 singlets of similar integration value in this
region of the spectrum. On the contrary, the exclusive presence
of capsule A, as observed in the solid state, would give only
three peaks of similar intensity. Unfortunately, the broadness
of the signals of the spectra of both 2a and 2b in CDCl3,
probably due dynamic processes within the capsule, hampered
further analysis. The spectrum of 2b recorded at low tempera-
ture (ꢂ10 and ꢂ60 1C) and measured in toluene-d8 (also at low
temperatures) did not provide a better resolution. To our
delight, these resonances could be resolved into nine peaks
of similar intensity (two of them overlapped, see Fig. 7) at
ꢂ15 1C in the presence of an excess of MeI, where the capsule
2bꢀ2b@MeI is formed (the signal for encapsulated MeI was
observed at 1.9 ppm).10 We have applied Occam’s razor to
rationalize our findings for the assembly of triureas 2 in
solution. Thus, the marked preference of the methyl group
for being at the pseudoaxial position could direct the prefer-
ence formation of capsules A and D, probably in a statistical
ratio. In this case, three singlets may appear due to the
resonances of the terminal NH protons of the centrosymmetric
capsule A, and six due to those of the chiral capsules D* and
In summary, chiral tris(m-ureidobenzyl)amines 2 self-assem-
ble in solution in a highly diastereoselective manner selecting
only two isomeric capsules out of the seven possible by a
double point-to-helix chirality transfer mechanism. In the
crystal, a second level of discrimination occurs resulting in a
highly regio- and diastereoselective process.
We thank the ‘‘Ministerio de Educacio
(MEC) of Spain and FEDER funds (Project CTQ2005-
02323/BQU) as well to the ‘‘Fundacion Seneca-CARM’’
´
n y Ciencia’’
´
´
(Project 08661/PI/08) for funding.
Notes and references
z Crystal data for compound 2b: C57.5H71N7O3, M = 908.21 g cmꢂ3
,
ꢀ
T = 120 K. Triclinic, space group P1, unit cell dimensions: a =
14.856(2) A, b = 16.166(3) A, c = 22.046(4) A, V = 4855.1(13) A3, Z
= 4. Reflections collected/unique 42 719/17 078 [R(int) = 0.0392].
Final R indices [I 4 2s(I)] R1 = 0.0572, wR2 = 0.1417. CCDC
691454.
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ꢁc
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3994 | Chem. Commun., 2008, 3992–3994