A molecular claw: A dynamic cavitand host

Article abstract of DOI:10.1002/anie.201305761

Up for grabs: A modular receptor comprises a hexaazatriphenylene "platform" and three imide residues on its concave side carrying flexible alkane chains. The chains not only populate the host's cavity but can also extend and can grab an appropriately size

Full text of DOI:10.1002/anie.201305761

Angewandte
Chemie
DOI: 10.1002/anie.201305761
Dynamic Hosts
A Molecular Claw: A Dynamic Cavitand Host**
Keith Hermann, Mina Nakhla, Judith Gallucci, Erdin Dalkilic, Arif Dastan, and
Jovica D. Badji c´ *
The design, synthesis, and study of concave molecules with
Herein, we describe a synthetic method for obtaining
internally functionalized and dynamic cavitands of type 1–3
[1]
enforced cavities have, in the last four decades, revealed
[2]
some benefits of molecular encapsulation. Cavitands can be
(Figure 1). These hosts are modular, comprising intriguing
electronic characteristics, unique topology and remarkable
mode of action: there could be interest for using this type of
molecules as “claws” for selectively “grabbing” small chem-
ical analytes and reporting on their presence.
[
3]
used to promote chemical reactions, stabilize reactive
[
4]
[5]
intermediates, investigate new forms of stereoisomerism,
[
6]
detect important analytes and even resolve the solid-state
[
7]
structure of compounds of interest. The strategy for
obtaining a synthetic host consists of employing methods of
computational chemistry to design a desired receptor fol-
lowed by experimental optimization of its synthesis including
kinetic/thermodynamic templation, dynamic combinatorial
approach, self-assembly
The synthesis of C3v symmetric 1syn–2syn was completed
[25]
following the convergent strategy described in Figure 1A.
In particular, we investigated the condensation of transient
hexaaminobenzene and diketones 5a-c (Figure 1C).
Although hexaaminobenzene 4 decomposes under ambient
[
8]
4
[9]
[10]
[26]
or transition-metal catalyzed
[11]
[27]
macrocyclization. Despite many advances, creating a supra-
molecular receptor/catalyst remains a challenging task requir-
ing time-consuming optimization of both the synthesis and
operation. Furthermore, placing functional groups on the
inner side of cavitandꢀs concave surface is difficult but
conditions, this compound can be generated
in situ and
used in the synthesis of various derivatives of 1,4,5,8,9,12-
[28]
hexaazatriphenylene (HAT). Furthermore, Paquette and
[
29]
co-workers employed diacid 7 in the synthesis of curved
[
30]
[31]
hydrocarbons dodecahedrane
and C -hexaquinacene.
16
[12]
[31]
essential for improving its function. Indeed, self-assembled
cages with functionalized inner face have been investigated
This molecule can now be prepared on large scale
by
a domino Diels–Alder reaction of 9,10-dihydrofulvalene and
dimethyl acetylenedicarboxylate (DMAD, Figure 1A).
[12]
while covalent hosts with such topology remain elusive. The
folding of oligomers into three-dimensional globular or rod-
Importantly, compound 7 can be converted into 5 , which
a-c
[
13]
like structures presents an elegant solution to the problem
yet there remains uncertainty about the nature of the
chemical information embedded in functional oligomers to
is unstable and undergoes decomposition at room temper-
ature.
In the Schiff base condensation of 4 and 5 , combined in
a-c
[14]
ensure folding into desired secondary/tertiary structure.
an approximate 1:3 stoichiometric ratio and at a low temper-
ature, we observed the formation of both syn and anti
diastereomers of 1–3 isolated in overall 7–55% yield (Fig-
ure 1C); note that the yield was estimated since the unstable
reactants ought to be generated in situ. The proportion of
diastereomers was, in these reactions, expected to correlate
The action of biological molecules epitomizes the
synchronized and cooperative motion of molecules and/or
[
15]
their parts to implement the function. In line with natural
[
16]
systems,
elements of design
into artificial structures
forefront of supramolecular chemistry.
gated the action of gated molecular baskets
synthetic hosts could benefit from dynamic
[
17]
yet incorporating such components
[
18]
[32]
is far from trivial and at the
with solvent polarity and the size of appended alkyl groups
[19]
We have investi-
in 5 . That is to say, more polar solvents ought to facilitate the
a-c
[
20]
while self-
formation of compact 1syn–3syn stereoisomers, as assisted by
[
21]
[22]
[23]
[32]
assembled, self-folding as well as switchable cavitands
were studied by others to add to the milieu of hosts with
intriguing dynamic characteristics.
the hydrophobic effect, while more sizeable alkyl groups in
5a-c should favor the formation of 1anti–3anti stereoisomers, as
a result of the steric strain. In line with such reasoning, the
greatest quantity of desired syn compound formed in the case
[
24]
´
of 2 in CH OH/H O = 8:2 (Figure 1C). We deduce that the
3 2
[
*] K. Hermann, M. Nakhla, J. Gallucci, Prof. J. D. Badjic
Department of Chemistry and Biochemistry
The Ohio State University
propyl chains are in 5b long enough to permit favorable
desolvation of the syn transition state and at the same time
short enough to avoid adverse interactions, that is, van der
Waals strain in the course of forming 2syn versus 2anti. When
100 West 18th Avenue (USA)
E-mail: badjic@chemistry.ohio-state.edu
E. Dalkilic, Prof. A. Dastan
this same reaction was run with neat CH OH, we only isolated
3
Ataturk University Faculty of Sciences, Erzurum (Turkey)
trace quantities of 2syn, suggesting an important role of the
hydrophobic effect in controlling the outcome of the con-
densation.
[
**] This work was financially supported with funds obtained from the
Department of Defense, Defense Threat Reduction Agency
HDTRA1-11-1-0042). The content of the information does not
necessarily reflect the position or the policy of the federal govern-
ment, and no official endorsement should be inferred.
(
The 1H NMR spectrum of 2syn (400 MHz, 298 K) in
CD Cl2 revealed a set of signals corresponding to a C
2
3v
1
symmetric molecule (Figure 2A); with the assistance of H–
H COSY/NOESY spectroscopic methods, we assigned all
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201305761.
1
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

.
Angewandte
Communications
Figure 1. A) The preparation of C3v symmetric 1syn–3syn can be completed on a large scale using simple starting materials and a convergent
synthetic strategy. B) Energy-minimized structure of 1 (MMFFs, Spartan) and van der Waals surface of this molecule showing its cavity
syn
3
(
V=123 ꢀ ); gray C, red O, blue N. C) The condensation of hexaaminobenzene 4 (in CH OH/H O) and diketone 5 (in CH Cl ) gives syn and anti
3
2
a-c
2
2
diastereomers of 1–3 in different ratios (yields are of isolated products).
1
Figure 2. A) H NMR spectra (400 MHz, 298.0 K) of 2syn in C D Cl (top) and CD Cl (bottom). B) Side and top views of energy-minimized
2
2
4
2
2
structures of 2syn (MMFFs, Spartan) with propyl chains assuming anti (green) and gauche (black) conformation about C –C sigma bond.
1
2
C) Newman projections of anti/gauche conformers of 2syn in dynamic equilibrium.
of the proton resonance signals (Figure S23–24). After plac-
and H (Dd = À0.03 ppm) protons altered as well. To account
c
ing host 2syn in C D Cl , the signal corresponding to CH group
for the observation, we first realized that changing the nature
of bulk solvent caused the perturbation of protons adjacent to
the aromatic “floor”. While the polarity of dichloromethane
(e = 9.1) and tetrachloroethane (e = 8.4) is comparable, the
2
2
4
3
underwent a considerable upfield shift (Dd = À0.39 ppm,
A
Figure 2A). In addition, the resonances of CH (Dd =+
2
B
0
.28 ppm), CH2 (Dd = À0.15 ppm), H (Dd =+ 0.18 ppm),
e
1
1
2
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
size difference between these two solvents is considerable.
3
Presumably, smaller molecules of CD Cl (61 ꢁ , Spartan)
2
2
3
[33]
could fill the pocket in 2syn (190 ꢁ ) and push the propyl
chains to extend out and adopt anti conformation (Figure 2B/
C). On the contrary, sizeable C D Cl (108 ꢁ , Spartan) could
3
2
2
4
not effectively solvate the interior of 2syn to drive the propyl
chains to assume less stable gauche conformation and thereby
[
34]
coil into the hostꢀs cavity (Figure 2B/C). In line with the
B
mechanistic scenario, CH and CH2 groups pivot about the
3
cavitand to reside a) on top of the central HAT ring in the
shielded region of the magnetic field (Figure 2A/B, C D Cl )
2
2
4
or b) further away from the HAT aromatic to experience
reduced anisotropic effects (Figure 2A/B, CD Cl ). Finally,
2
2
A
each CH2 group at the rim is the pivoting point about which
the alkyl chain revolves: the position of the CH2 protons
A
alters to face the inner (CD Cl , Figure 2A) or outer side
2
2
(
C D Cl , Figure 2A) of the hostꢀs cavity (Figure 2B), which
2 2 4
is reflected in the chemical shift of these protons (Figure 2A);
note that similar spectroscopic changes accompanied com-
pound 1syn (Figure S25) upon the same alteration of solvents.
The revolution of the alkyl groups within 2syn must be fast
on the NMR time scale to average the observed proton
resonance signals (Figure 2). In fact, the folded state of 2syn is
C symmetric with gauche alkyl chains forming right (P) or
3
left-handed (M) stereoisomers and therefore including dia-
A
B
[35]
stereotopic CH /CH protons (Figure 2B).
Variable-
2
2
Figure 3. A) Energy-minimized structure of folded and unfolded
1
temperature NMR study of 2syn in both C D Cl (298–248 K,
(MMFFs, Spartan) forms of 2syn trapping CBr guest. B) H NMR
2
2
4
4
Figure S26) and CD Cl (298–177 K, Figure S27) did not show
any decoalescence but a consistent shift of the alkyl resonance
spectra (400 MHz, 298.0 K) of 2syn (1.0 mm) in C D Cl obtained upon
2 2 4
2
2
incremental addition of CBr (0–1.1m) and the nonlinear least-square
4
1
analysis of the H NMR chemical shifts of CH (ppm) in 1 (1.0 mm,
3
syn
signals: in particular, triplet corresponding to CH moved
3
red) and 2syn (1.0 mm, black) as a function of CBr concentration (m).
4
upfield at higher temperatures. Apparently, a low activation
barrier must be characterizing the folded/unfolded dynamic
equilibrium (Figure 2C) with the folded state of 2syn being
preferred at higher temperatures. We reason that the
formation of folded 2syn is, in both solvents, accompanied by
a release of solvent molecules (DS8 > 0) for which the
equilibrium free energy is more favorable (DG8 < 0) at
higher temperatures.
À1
A 1:1 stoichiometric model gave association constants K (m ) at
a
298.0 K.
displace shorter ethyl groups from the interior of 1syn than
longer propyl groups in 2syn. Furthermore, it could be argued
that less polarizable and shorter ethyl groups are forming less
[
38]
favorable contacts with the HAT “floor”; note that chang-
ing the nature of bulk solvent might improve the stability of
the host–guest complex.
Since the solvation of the inner space of 2 is a form of
syn
[
36]
molecular recognition we decided to titrate CH Cl to this
2
2
host in noncompeting C D Cl and quantify the interaction.
The solid-state structure of 3anti shows a pairwise assembly
of these compounds in the unit cell besides multiple and
2
2
4
As larger quantities of the guest could not saturate 2
syn
3
(
Figure S28), we tested more sizeable CHCl (75 ꢁ ,) and
disorganized molecules of CHCl (Figure 4). The distance
3
3
3
CCl (89 ꢁ , Figure S29). The binding affinity improved, but it
between the two HAT rings is 3.5 ꢁ (middle region, Fig-
4
1
was still difficult to quantify the interaction with H NMR
ure 4A), with a slipped geometry of such p-stacked aromatics
[
39]
spectroscopy. Ultimately, we completed an incremental
(Figure 4B). Interestingly, two molecules of 3anti face each
other with one imide moiety, while the remaining two imide
groups point away. The butyl chain of the facing imides
(bottom region, Figure 4A) assumes the anti conformation
about the C –C /C –C bonds: with the aromatic ring pop-
3
addition of CBr (108 ꢁ , Figure 3B) to 2syn: the nonlinear
4
least-square fitting of the experimental data to a 1:1 stoichio-
2
metric model (R = 0.99, Figure 3B) gave the association
À1 [37]
constant of K = 1.77 Æ 0.02m . Evidently, the formation of
a
1
2
2
3
the 1:1 complex was accompanied with downfield shift of CH3
ulating the space next to 3anti, the alkyl chain extends out. In
contrast, two alkyl groups on the remaining imides (top
region, Figure 4A) are disordered but clearly coiled to fill the
space above each HAT ring.
(
Figure 3B) resonances, which is in line with the “opening” of
the host to accept the guest (Figure 3A). We reasoned that
the small binding energy (DG8) for the formation of
[
2 ꢀCBr ] is, in part, due to relatively stable ground state
Novel hosts of type 1syn–2syn comprise a unique topology
and also employ an intriguing mode of action in trapping
guests. Importantly, the organic framework of these com-
pounds can be modified to give functional molecules and
materials with tunable electrochemical or optical character-
syn
4
of the folded host having its cavity already populated with
three alkyl chains. In fact, the affinity of 1syn toward
complementary CBr was somewhat greater with K =
4
a
À1
2
3
.73 Æ 0.02m (R = 0.99, Figure 3B): it costs less energy to
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

.
Angewandte
Communications
[
18] C. R. Benson, A. I. Share, A. H.
Flood, Bioinspiration Biomimicry
Chem. 2012, 71 – 119.
[
19] L. C. Palmer, J. Rebek, Jr., Org.
Biomol. Chem. 2004, 2, 3051 – 3059.
20] S. Rieth, K. Hermann, B.-Y. Wang,
J. D. Badjic, Chem. Soc. Rev. 2011, 40,
[
1609 – 1622.
[
21] a) J. L. Atwood, L. J. Barbour, A.
Jerga, Proc. Natl. Acad. Sci. USA
2002, 99, 4837 – 4841; b) P. Ballester,
G. Gil-Ramirez, Proc. Natl. Acad. Sci.
USA 2009, 106, 10455 – 10459.
[
22] U. Lꢂcking, F. C. Tucci, D. M. Rudke-
vich, J. Rebek, Jr., J. Am. Chem. Soc.
2
000, 122, 8880 – 8889.
Figure 4. Stick representations of the solid-state structure of 3anti showing the orientation of two
molecules within the unit cell. See text for details.
[23] I. Pochorovski, M.-O. Ebert, J.-P. Gis-
selbrecht, C. Boudon, W. B. Schwe-
izer, F. Diederich, J. Am. Chem. Soc.
2
012, 134, 14702 – 14705.
[40]
istics. In particular, we are investigating the functionaliza-
tion of the inner amides as well as an extension of the outer
olefins for optimizing the recognition characteristics of
molecular claws.
[
24] T. Ishi-i, M. Crego-Calama, P. Timmerman, D. N. Reinhoudt, S.
Shinkai, J. Am. Chem. Soc. 2002, 124, 14631 – 14641.
[25] S. M. Grayson, J. M. J. Frechet, Chem. Rev. 2001, 101, 3819 –
3867.
[
[
[
26] D. A. Dixon, J. C. Calabrese, J. S. Miller, Angew. Chem. 1989,
01, 79 – 81; Angew. Chem. Int. Ed. Engl. 1989, 28, 90 – 92.
27] J. Mahmood, D. Kim, I.-Y. Jeon, M. S. Lah, J.-B. Baek, Synlett
013, 246 – 248.
28] a) J. J. Wolff, A. Zietsch, B. Nuber, F. Gredel, B. Speiser, M.
Wuerde, J. Org. Chem. 2001, 66, 2769 – 2777; b) R. Juꢃrez, M. M.
Oliva, M. Ramos, J. L. Segura, C. Aleman, F. Rodriguez-Ropero,
D. Curco, F. Montilla, V. Coropceanu, J. L. Bredas, Y. Qi, A.
Kahn, M. C. Ruiz Delgado, J. Casado, J. T. Lopez Navarrete,
Chem. Eur. J. 2011, 17, 10312 – 10322.
1
Received: July 3, 2013
Published online: && &&, &&&&
2
Keywords: cavitands · dynamic hosts ·
.
molecular encapsulation · NMR spectroscopy ·
supramolecular chemistry
[
1] a) D. J. Cram, Science 1983, 219, 1177 – 1183; b) D. J. Cram,
Science 1988, 240, 760 – 767.
[29] M. J. Wyvratt, L. A. Paquette, Tetrahedron Lett. 1974, 15, 2433 –
2436.
[
2] a) Molecular Encapsulation: Organic Reactions in Constrained
Systems (Eds.: U. H. Brinker, J.-L. Mieusset), J. Wiley & Sons
LTD, Chichester, UK, 2010; b) F. Hof, S. L. Craig, C. Nuckolls, J.
Rebek, Jr., Angew. Chem. 2002, 114, 1556 – 1578; Angew. Chem.
Int. Ed. 2002, 41, 1488 – 1508.
[30] L. A. Paquette, Chem. Rev. 1989, 89, 1051 – 1065.
[31] R. T. Taylor, M. W. Pelter, L. A. Paquette, Org. Synth. 1990, 68,
198 – 205.
[32] R. Breslow, K. Groves, M. U. Mayer, Pure Appl. Chem. 1998, 70,
1933 – 1938.
[
3] a) Z. J. Wang, K. N. Clary, R. G. Bergman, K. N. Raymond, F. D.
Toste, Nat. Chem. 2013, 5, 100 – 103; b) Supramolecular Catalysis
[33] N. R. Voss, M. Gerstein, Nucleic Acids Res. 2010, 38, W555 –
W562.
(
Ed.: P. W. N. van Leeuwen), Wiley-VCH, Weinheim, 2008.
4] Z. Lin, J. Sun, B. Efremovska, R. Warmuth, Chem. Eur. J. 2012,
8, 12864 – 12872.
[34] J. W. Park, S. Y. Lee, H. J. Song, K. K. Park, J. Org. Chem. 2005,
70, 9505 – 9513.
[35] A. Scarso, L. Trembleau, J. Rebek, Jr., J. Am. Chem. Soc. 2004,
126, 13512 – 13518.
[
1
[
5] J. Rebek, Acc. Chem. Res. 2009, 42, 1660 – 1668.
[
6] A. P. Umali, E. V. Anslyn, Curr. Opin. Chem. Biol. 2010, 14,
[36] A. Shivanyuk, J. Rebek, Chem. Commun. 2002, 2326 – 2327.
[37] Frontiers in Supramolecular Organic Chemistry and Photo-
chemistry (Eds.: H. J. Schneider, H. Duerr), Wiley-VCH,
Weinheim, 1991.
685 – 692.
[
7] Y. Inokuma, S. Yoshioka, J. Ariyoshi, T. Arai, Y. Hitora, K.
Takada, S. Matsunaga, K. Rissanen, M. Fujita, Nature 2013, 495,
4
61 – 466.
8] J. D. Badji c´ , S. Stojanovi c´ , Y. Ruan, Adv. Phys. Org. Chem. 2011,
5, 1 – 37.
9] S. R. Beeren, J. K. M. Sanders, Dyn. Comb. Chem. 2010, 1 – 22.
[38] a) C. Zhao, R. M. Parrish, M. D. Smith, P. J. Pellechia, C. D.
Sherrill, K. D. Shimizu, J. Am. Chem. Soc. 2012, 134, 14306 –
14309; b) N. J. Zondlo, Acc. Chem. Res. 2013, 46, 1039 – 1049.
[39] a) C. A. Hunter, J. K. M. Sanders, J. Am. Chem. Soc. 1990, 112,
5525 – 5534; b) S. E. Wheeler, Acc. Chem. Res. 2013, 46, 1029 –
1038.
[
[
4
[
[
10] D. Ajami, J. Rebek, J. Org. Chem. 2009, 74, 6584 – 6591.
11] F. Fabris, C. Zonta, G. Borsato, O. De Lucchi, Acc. Chem. Res.
2
011, 44, 416 – 423.
[40] a) J.-M. Herrera, S. J. A. Pope, A. J. H. M. Meijer, T. L. Easun,
H. Adams, W. Z. Alsindi, X.-Z. Sun, M. W. George, S. Faulkner,
M. D. Ward, J. Am. Chem. Soc. 2007, 129, 11491 – 11504; b) S.
Furukawa, T. Okubo, S. Masaoka, D. Tanaka, H.-C. Chang, S.
Kitagawa, Angew. Chem. 2005, 117, 2760 – 2764; Angew. Chem.
Int. Ed. 2005, 44, 2700 – 2704; c) D. Hanifi, D. Cao, L. M.
Klivansky, Y. Liu, Chem. Commun. 2011, 47, 3454 – 3456; d) Y.
Zhang, D. Hanifi, S. Alvarez, F. Antonio, A. Pun, L. M.
Klivansky, A. Hexemer, B. Ma, Y. Liu, Org. Lett. 2011, 13,
6528 – 6531.
[
[
12] S. Kubik, Top. Curr. Chem. 2012, 319, 1 – 34.
13] a) G. Guichard, I. Huc, Chem. Commun. 2011, 47, 5933 – 5941;
b) Y. Zhao, J. S. Moore, Foldamers 2007, 75 – 108.
14] S. H. Gellman, Acc. Chem. Res. 1998, 31, 173 – 180.
15] J. Huang Tony, K. Juluri Bala, Nanomedicine 2008, 3, 107 – 124.
16] C. Fahrenbach Albert, J. Bruns Carson, D. Cao, J. F. Stoddart,
Acc. Chem. Res. 2012, 45, 1581 – 1592.
17] H.-J. Schneider, Angew. Chem. 2009, 121, 3982 – 4036; Angew.
Chem. Int. Ed. 2009, 48, 3924 – 3977.
[
[
[
[
4
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Dynamic Hosts
K. Hermann, M. Nakhla, J. Gallucci,
E. Dalkilic, A. Dastan,
J. D. Badji c´ *
&&&& — &&&&
A Molecular Claw: A Dynamic Cavitand
Host
Up for grabs: A modular receptor com-
prises a hexaazatriphenylene “platform”
and three imide residues on its concave
side carrying flexible alkane chains. The
chains not only populate the host’s cavity
but can also extend and can grab an
appropriately sized and shaped guest in
solution.
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!