Self-assembly of a hexameric aggregate of a lipophilic calix[4]pyrrole- resorcinarene hybrid in solution: A diffusion NMR study

Article abstract of DOI:10.1021/ol1020114

The lipophilic calix[4]pyrrole-resorcinarene hybrid 1b, the extended analogue of resorcin[4]arene 2b, was synthesized for the first time, and its self-assembly in solution was studied using ¹H and diffusion NMR. It was found that 1b self-assemb

Full text of DOI:10.1021/ol1020114

ORGANIC
LETTERS
2010
Vol. 12, No. 21
4864-4867
Self-Assembly of a Hexameric
Aggregate of a Lipophilic
Calix[4]pyrrole-Resorcinarene Hybrid in
Solution: A Diffusion NMR Study
S. Slovak, T. Evan-Salem, and Y. Cohen*
School of Chemistry, The Sackler Faculty of Exact Sciences, Tel AViV UniVersity,
Ramat AViV, Tel AViV 69978, Israel
ycohen@post.tau.ac.il
Received August 25, 2010
ABSTRACT
The lipophilic calix[4]pyrrole-resorcinarene hybrid 1b, the extended analogue of resorcin[4]arene 2b, was synthesized for the first time, and
its self-assembly in solution was studied using 1H and diffusion NMR. It was found that 1b self-assembles to hexameric aggregates in CDCl3
solution. The interaction of trialkylamine guests with the hexameric aggregate of 1b was explored, and it appears that under the conditions
used in the present study these guests interact with the external faces of the hexameric aggregate of 1b.
Hydrogen bond molecular capsules are of much interest in
the field of supramolecular chemistry because of their
potential to serve as nanoreactors where new chemistry and
catalysis may occur.1 The most extensively investigated
molecular capsules based on hydrogen bond interactions are
those based on substituted calix[4]arenes,2 resorcin[4]arenes,3
and pyrogallol[4]arenes.4 Indeed, it was found that resor-
cinarenes form hexameric capsules in the solid state,3a in
the solution,3b,c and even in the gas phase.3d
Resorcin[4]arene and pyrogallol[4]arene capsules are able
to encapsulate various guests.3b,4d,e,5 Another derivative of
calix[4]arenes is calix[4]pyrrole.6
Calix[4]pyrroles are macrocyclic systems composed of
four pyrrole rings linked through the meso-positions by
carbon atoms. While their synthesis was pioneered by Baeyer
(3) (a) MacGillivray, L. R.; Atwood, J. L. Nature 1997, 389, 469–472.
(b) Shivanyuk, A.; Rebek, J., Jr. Proc. Natl. Acad. Sci. U.S.A. 2001, 98,
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15149. (d) Beyeh, N. K.; Kogej, M.; Åhman, A.; Rissanen, K.; Schalley,
C. A. Angew. Chem., Int. Ed. 2006, 45, 5214–5218
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C. L. D.; Gibb, B. C. J. Am. Chem. Soc. 2004, 126, 11408–11409. (c) Giles,
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Atwood, J. L.; Barbour, L. J.; Jerga, A. Proc. Natl. Acad. Sci. U.S.A. 2002,
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2004, 126, 2939–2943. (b) Dalgarno, S. J.; Tucker, S. A.; Bassil, D. B.;
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10.1021/ol1020114  2010 American Chemical Society
Published on Web 10/08/2010

more than 100 years ago,6a they have attracted much attention
in the past decade due to their ability to bind anions,6b neutral
substrates,6c and metal ions.6d Very recently, it was dem-
onstrated that tetraurea calix[4]pyrroles form dimeric capsules
reminiscent of that of tetraurea calix[4]arenes.7 The Ballester
group recently reported the synthesis and the self-assembly
in the solid state of a new R,R,R,R-isomer of the calix[4]-
pyrrole-resorcinarene system 1a.8 It was found that this
sparingly soluble macrocycle self-assembles in the solid state,
in the presence of tetramethylammonium chloride guest, into
a hexameric structure driven by hydrogen bonding and
electrostatic interactions. This study and the resemblance of
1a to resorcin[4]arene 2a3a prompted us to synthesize
compound 1b, the lipophilic calix[4]pyrrole analogue of
resorcin[4]arene 2b9 (see Figure 1).
Figure 2.
1H NMR spectra (400 MHz, 298 K) of 10 mM solution
of 1b (a) in CD3OD, (b) in CDCl3, in the presence of (c) 5 mM 3,
(d) 5 mM 4, and (e) 5 mM 5 in CDCl3. * indicates residual
protonated solvents.
The difference in line shape can be attributed, inter alia,
to different conformations that 1b adopts in different solvents,
a different dynamic, or even the formation of not very well-
defined aggregates in the CDCl3 solution. It is well-known
that calix[4]pyrrole conformation, for example, depends on
the polarity of the solvents used. For example, it was found
that the 1,3-alternate conformation is the most populated
conformation of calix[4]pyrroles in most of the solvents, but
the population of the 1,3-alternate conformer was found to
decrease as the polarity of the solvent increases.11 In the
presence of small anions, the cone form is the major
conformation as a result of anion-π binding between the
anion and NHs of calix[4]pyrrole.
To verify which of the options is responsible for the
peculiar line shape of 1b in CDCl3 solution, we reverted to
diffusion NMR12 which has been used for characterization
of supramolecular assemblies in solution and was found to
be extremely useful in studying both dimeric2c,13 and
hexameric capsules.3c,4c-e,14 Interestingly, the diffusion
coefficient found for the peaks of 1b in CDCl3 (see Figure
2b) was 0.22 ( 0.01 × 10-5 cm2 s-1. This diffusion
coefficient is somewhat smaller than that found for the
Figure 1. Structures of calix[4]pyrroles 1, resorcin[4]arenes 2,
trioctylamine (3), tridodecylamine (4), and trioctadecylamine (5).
Compound 1b was synthesized by the acid-catalyzed
condensation of 1-(3,5-dimethoxyphenyl)dodecan-1-one with
pyrrole and was isolated as the R,R,R,R-isomer after puri-
fication.10 The 1H NMR spectrum of 10 mM of 1b in CD3OD
is shown in Figure 2a. The spectrum contains sharp and well-
defined peaks of the R,R,R,R-isomer of 1b. The presence of
1
only three types of protons in the downfield part of the H
NMR spectrum (δ ) 5.80, 6.15, 6.17 ppm) of 1b suggests
that 1b is locked in the cone conformation or is in fast
1
exchange between different conformations on the H NMR
time scale.
Compound 1b was also found to be soluble in CDCl3, and
1
the H NMR spectrum of 10 mM 1b in CDCl3 is shown in
Figure 2b. Clearly, a different line shape is observed in
CDCl3 as compared to CD3OD (compare Figure 2b to 2a).
(11) (a) Wu, Y.-D.; Wang, D.-F.; Sessler, J. L. J. Org. Chem. 2001, 66,
3739–3746. (b) Blas, J. R.; Lo´pez-Bes, J. M.; Ma´rquez, M.; Sessler, J. L.;
Luque, F. J.; Orozco, M. Chem.sEur. J. 2007, 13, 1108–1116.
(12) Cohen, Y.; Avram, L.; Frish, L. Angew. Chem., Int. Ed. 2005, 44,
520–554.
(6) (a) Baeyer, A. Ber. Dtsch. Chem. Ges. 1886, 19, 2184–2185. (b)
Gale, P. A.; Sessler, J. L.; Kral, V.; Lynch, V. J. Am. Chem. Soc. 1996,
118, 5140–5141. (c) Gale, P. A.; Sessler, J. L.; Kral, V.; Lynch, V. J. Am.
Chem. Soc. 1996, 118, 12471–12472. (d) Floriani, C. Chem. Commun. 1996,
1257–1263.
(13) (a) Frish, L.; Vysotsky, M. O.; Matthews, S. E.; Bohmer, V.; Cohen,
Y. J. Chem. Soc., Perkin Trans. 2 2002, 88–93. (b) Frish, L.; Vysotsky,
(7) Ballester, P.; Gil-Ramirez, G. Proc. Natl. Acad. Sci. U.S.A. 2009,
106, 10455–10459.
M. O.; Bohmer, V.; Cohen, Y. Org. Biomol. Chem. 2003, 1, 2011–2014
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(8) Gil-Ramirez, G.; Benet-Buchholz, J.; Escudero-Adan, E. C.; Ball-
ester, P. J. Am. Chem. Soc. 2007, 129, 380–382.
(14) (a) Avram, L.; Cohen, Y. Org. Lett. 2002, 4, 4365–4368. (b) Avram,
L.; Cohen, Y. Org. Lett. 2006, 8, 219–212. (c) Avram, L.; Cohen, Y. Org.
Lett. 2008, 10, 1505–1508. (d) Evan-Salem, T.; Cohen, Y. Chem.sEur. J.
2007, 13, 7659–7663. (e) Wirtheim, E.; Avram, L.; Cohen, Y. Tetrahedron.
2009, 65, 7268–7276. (f) Slovak, S.; Avram, L.; Cohen, Y. Angew. Chem.,
(9) Tunstad, L. M.; Tucker, J. A.; Dalcanale, E.; Tunstad, L. M.; Tucker,
J. A.; Dalcanale, E.; Wieser, J.; Bryant, J. A.; Sherman, J. C.; Helgeson,
R. C.; Knobler, C. B.; Cram, D. J. J. Org. Chem. 1989, 54, 1305–1312.
(10) See Supporting Information for the synthesis of 1b.
Int. Ed. 2010, 49, 428–431
.
Org. Lett., Vol. 12, No. 21, 2010
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hexameric capsule of 2b at the same concentration in CDCl3
solution (0.25 ( 0.01 × 10-5 cm2 s-1). The 1H NMR signal
decay as a function of gradient strength (G) of 1b and of 2b
is presented in Figure S4 (Supporting Information). This
finding is to be expected as the molecular weight of 1b is
slightly higher than that of 2b (molecular weights of 1365
g/mol and 1104 g/mol for the monomers of 1b and 2b,
respectively). Since it is well-known that 2b molecules self-
assemble into hexameric capsules in CDCl3 solution,3c,4d it
is reasonable to conclude that 2b also forms a hexameric
assembly. To corroborate this conclusion further, we added
increasing amounts of CD3OD, a solvent which disrupts
hydrogen bonding, to the solution of 1b in CDCl3. The
addition of CD3OD resulted in a significant increase in the
diffusion coefficient of 1b (Figure 3) as in the case of 2b.3c,4e
indicates that 1b is locked in the cone conformation, a
conformation needed for the formation of hexameric cap-
sules.
Figure 4 presents the diffusion coefficients of 1b, 5, and
mixtures of 1b and 5 in CDCl3 solutions. The diffusion
Figure 4. Diffusion coefficients (D) (298 K, CDCl3) of 1b and 5
in different samples and of mixtures of 1b and 5 at the indicated
ratios. The concentration of 1b was 10 mM in all samples.
coefficients of 1b and 5, for the 6:1, 6:2, and 6:3 solutions
of 1b/5, were 0.22 ( 0.01 × 10-5 and 0.24 ( 0.01 × 10-5
cm2 s-1, respectively. Interestingly, the diffusion coefficient
of 5 was much lower than that found for free 5 in the same
CDCl3 solution (0.55 ( 0.01 × 10-5 cm2 s-1). These results
indicate that 1b and 5 in that solution diffuse as a single
molecular entity. Further addition of 5 to the same solution
resulted in an increase in the diffusion coefficient of 5, which
means that the “bound” 5 and “free” 5 molecules are in fast
exchange on the NMR time scale. These results suggest that
the hexameric structure of 1b interacts with three molecules
of 5. For 1b in the presence of 3 or 4, similar results were
observed (see Figure S6 and S7, Supporting Information).
The next step was to determine whether the formed
hexameric aggregate of 1b is indeed a hexameric capsule as
in the case of 2b with other trialkylamines.4e It should be
noted that in the case of 2b encapsulated guests are
characterized by upfield chemical shifts, slow exchange, and
low diffusion coefficient which is identical to that of the host.
On one hand, since the guests 3, 4, and 5 show only one set
of peaks, downfield chemical shifts, and diffusion coefficient
which increases with the increase of the guest/host ratio, it
is not clear that the formed hexameric aggregate of 1b is a
hexameric capsule as in the case of 2b. On the other hand,
however, 1b forms hexameric aggregates in which all six
monomers are equivalent as in the case of the hexameric
capsule of 2b, and Ballester showed that 1a forms hexameric
capsules in the solid states.8 Therefore, it seems that the most
plausible explanation for all the results presented here is that
1b self-assembles into hexameric capsules, with relatively
leaky faces, to which the trialkylamine guests (3, 4, and 5)
Figure 3. Effect of methanol titration on the diffusion coefficient
(D) of 1b (10 mM) in CDCl3 at 298 K.
At 200 equiv of CD3OD, a plateau was reached for the
diffusion coefficient of 1b which was found to be 0.39 (
0.01 × 10-5 cm2 s-1. These observations are in accordance
with the formation of hexameric aggregates of 1b in
chloroform solution which disaggregate upon addition of
CD3OD.
Since 1b is an extended analogue of 2b, we assumed that
in the case of hexameric capsule formation the cavity of 1b
would be significantly larger than that found for 2b. Our
next step was to explore the relative affinity of 1b to different
long-chain trialkylamine guests such as trioctylamine (3),
tridodecylamine (4), and trioctadecylamine (5) (Figure 1).
Addition of 3 to the solution of 1b in CDCl3 resulted in a
dramatic change in the 1H NMR spectrum of 1b (Figure 2c).
1
We found much sharper peaks in the H NMR spectrum of
1b after the addition of 3. Appearance of five singlets (in a
1:1:1:1:1 ratio) in the region of 5-7 ppm, which were
assigned to the aromatic protons of 1b (δ ) 5.87, 5.92, 6.01,
6.13, 6.41 ppm), indicates that a molecular species with a
lower symmetry is formed following the addition of 3. In
addition, a small downfield shift was observed for the peaks
of compound 3. Similar spectra were obtained after the
addition of 4 or 5 to 1b (Figure 2d and 2e, respectively).
The NOESY spectrum of 1b in the presence of 3 in CDCl3
solution shown in Figure S5 (Supporting Information)
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Org. Lett., Vol. 12, No. 21, 2010

are attached to the external faces of the hexameric aggregate
of 1b. Such interactions have been documented very recently
for the hexameric capsule of 2b with trialkylamine guests.15
To explore the strength of the interaction between 1b and
4, for example, we titrated the 6:3 solution of 1b/4 with
CD3OD. The graph showing the changes in the diffusion
coefficients of 1b and of 4 upon the addition of CD3OD is
shown in Figure 5. For 4, the initial addition of 10-20 equiv
CD3OD. These results show that the interactions between 4
and 1b are easily disrupted even when a small amount of
CD3OD is added which does not disaggregate the aggregate
of 1b. These results are similar to the results obtained recently
for the hexameric capsule of 2b.4e
To conclude, we prepared, for the first time, a chloroform
soluble derivative of a calix[4]pyrrole-resorcin[4]arene
hybrid (1b), having a structure reminiscent to 2b. 1H NMR
and more specifically diffusion NMR spectroscopy showed
that 1b self-assembles into hexameric aggregates both in the
absence and in the presence of trialkylamine guests. These
aggregates can be disrupted by addition of polar solvents
such as methanol. Addition of trialkylamine (3-5) resulted
1
in a complex for which the H NMR spectrum has a lower
symmetry. We found that the guest molecules are in fast
exchange between their free and bound states on the NMR
time scale. The absence of the high-field peaks of the guest
1
in the H NMR spectrum seems to suggest that no guest
encapsulation occurred. Due to the recent findings that
indicate that 1a self-assembles into the hexameric capsules
in the solid state8 and the fact that 2b, the resorcin[4]arene
analogue of 1b, forms hexameric capsules in solution,3c,4e
we expected 1b to form extended hexameric capsules in the
solution capable of encapsulating extremely large guests. It
seems that 1b forms hexameric capsules and that 3, 4, and
5 interact inter alia with the external faces on this relatively
leaky hexameric capsule. Further studies with various guests
are currently in progress.
Figure 5. Effect of CD3OD titration on the diffusion coefficient
(D) of 1b and of 4 in the 6:3 CDCl3 solution of 1b (10 mM) in the
presence of 4 at 298 K.
Acknowledgment. We gratefully acknowledge the finan-
cial support from the Israel Science Foundation (ISF, Grant
No. 301/07), Jerusalem, Israel.
of CD3OD resulted in the increase in the diffusion coefficient.
Further titration of the solution of 4 with CD3OD resulted
in an increase in the diffusion coefficient until a plateau was
reached when 80-100 equiv of CD3OD was added. For 1b,
the diffusion coefficient, however, remained constant upon
the addition of the first 20 equiv of CD3OD, and here again
a plateau was reached after addition of 80-100 equiv of
Supporting Information Available: Experimental pro-
cedure, characterization data, NMR spectra for all new
compounds, and diffusion coefficients of 1b, 3, and 4 and
mixtures thereof. This material is available free of charge
via the Internet at http://pubs.acs.org.
(15) Slovak, S.; Cohen, Y. Supramol. Chem. 2010, DOI: 10.1080/
10610278.2010.506549.
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