Azodicarboxamides as template binding motifs for the building of hydrogen-bonded molecular shuttles

Article abstract of DOI:10.1021/ja101151t

Azodicarboxamides (R₂NCON-NCONR₂) are shown to act as new templates for the assembly of unprecedented azo-functionalized hydrogen-bond-assembled [2]rotaxanes. Moreover, these binding sites can be reversibly and efficiently interconverted with their hydrazo forms through a hydrogenation-dehydrogenation strategy of the nitrogen-nitrogen bond. This novel chemically switchable control element has been implemented in stimuli-responsive molecular shuttles that work through a reversible azo/hydrazo interconversion, producing large amplitude net positional changes with a good discrimination between the binding sites of the macrocycle in both states of the shuttle. These molecular shuttles are able to operate by two different mechanisms: in a discrete mode through two reversible and independent chemical events and, importantly, in a continuous regime through a catalyzed ester bond formation reaction in which the shuttle acts as an organocatalyst. In this latter, the incorporation of both states of the shuttle into this simple chemical reaction network promotes a dynamic translocation of the macrocycle between two nitrogen and carbon-based stations of the thread allowing an energetically uphill esterification process to take place.

Full text of DOI:10.1021/ja101151t

Published on Web 07/19/2010
Azodicarboxamides as Template Binding Motifs for the
Building of Hydrogen-Bonded Molecular Shuttles
Jose´ Berna´,*,† Mateo Alajar´ın,† and Rau´l-Angel Orenes‡
Departamento de Qu´ımica Orga´nica, Facultad de Qu´ımica, UniVersidad de Murcia, Campus de
Espinardo, E-30100 Murcia, Spain, and SerVicio de Apoyo a la InVestigacio´n (SAI), UniVersidad
de Murcia, Campus de Espinardo, E-30100 Murcia, Spain
Received February 8, 2010; E-mail: ppberna@um.es
Abstract: Azodicarboxamides (R2NCONdNCONR2) are shown to act as new templates for the assembly
of unprecedented azo-functionalized hydrogen-bond-assembled [2]rotaxanes. Moreover, these binding sites
canbereversiblyandefficientlyinterconvertedwiththeirhydrazoformsthroughahydrogenation-dehydrogenation
strategy of the nitrogen-nitrogen bond. This novel chemically switchable control element has been
implemented in stimuli-responsive molecular shuttles that work through a reversible azo/hydrazo intercon-
version, producing large amplitude net positional changes with a good discrimination between the binding
sites of the macrocycle in both states of the shuttle. These molecular shuttles are able to operate by two
different mechanisms: in a discrete mode through two reversible and independent chemical events and,
importantly, in a continuous regime through a catalyzed ester bond formation reaction in which the shuttle
acts as an organocatalyst. In this latter, the incorporation of both states of the shuttle into this simple chemical
reaction network promotes a dynamic translocation of the macrocycle between two nitrogen and carbon-
based stations of the thread allowing an energetically uphill esterification process to take place.
controlled reactions),13 remain scarce.14 The switching elements
in these shuttles have been used as components of more complex
Introduction
The efficient use of nanomachinery capable of driving linear
and rotary motion is essential to the suitable functioning of living
cells.1 The construction of molecular machines, ubiquitous in
nature, remains, however, a major contemporary challenge.2 The
recent development of molecular-based systems including
rotors,3 muscles,4 switches,5 elevators,6 motors,7 and processive
catalysts8 has brought the prospect of synthetic molecular
machines within sight.9 Among these artificial molecular
systems, stimuli-responsive molecular shuttles2,10 are viewed
as very promising elements for molecular machinery and the
Brownian change in the position of their subunits has been used
as a nanoscale mechanical switch to alter the properties of
certain materials.11 In principle, molecular shuttles can be
considered as synthetic archetypes of biological machines, which
utilize chemical reactions to control mechanical motion. How-
ever, despite the fact that several kinds of external triggers (light,
electrons, temperature, solvent polarity) have been used to
promote these positional changes,12 chemically driven shuttles,
excluding those controlled by acid-base proton transfer (pH
molecular machines that work by Brownian ratchet mechanisms
in which directional transport of a particle is caused by a periodic
or random switching between two or more potential energy
surfaces.15 In order to control this particular switching, biological
machines16 synergistically couple several chemical events for
(3) Kottas, G. S.; Clarke, L. I.; Horinek, D.; Michl, J. Chem. ReV. 2005,
105, 1281–1376.
(4) (a) Collin, J.-P.; Dietrich-Buchecker, C.; Gavina, P.; Jimenez-Molero,
M. C.; Sauvage, J.-P. Acc. Chem. Res. 2001, 34, 477–487. (b) Juluri,
B. K.; Kumar, A. S.; Liu, Y.; Ye, T.; Yang, Y.-W.; Flood, A. H.;
Fang, L.; Stoddart, J. F.; Weiss, P. S.; Huang, T. J. ACS Nano 2009,
3, 291–300. (c) Chuang, C.-J.; Li, W.-S.; Lai, C.-C.; Liu, Y.-H.; Peng,
S.-M.; Chao, I.; Chiu, S.-H. Org. Lett. 2009, 11, 385–388.
(5) (a) Molecular Switches; Feringa, B. L., Ed.; Wiley-VCH: Weinheim,
Germany, 2001. (b) Geertsema, E. M.; van der Molen, S. J.; Martens,
M.; Feringa, B. L. Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 16919–
16924. (c) Spruell, J. M.; Paxton, W. F.; Olsen, J.-C.; Benitez, D.;
Tkatchouk, E.; Stern, C. L.; Trabolsi, A.; Friedman, D. C.; Goddard,
W. A.; Stoddart, J. F. J. Am. Chem. Soc. 2009, 131, 11571–11580.
(6) (a) Badjic´, J. D.; Balzani, V.; Credi, A.; Silvi, S.; Stoddart, J. F. Science
2004, 303, 1845–1849. (b) Badjic´, J. D.; Ronconi, C. M.; Stoddart,
J. F.; Balzani, V.; Silvi, S.; Credi, A. J. Am. Chem. Soc. 2006, 128,
1489–1499.
† Departamento de Qu´ımica Orga´nica.
(7) (a) Koumura, N.; Zijlstra, R. W. J.; van Delden, R. A.; Harada, N.;
Feringa, B. L. Nature 1999, 401, 152–155. (b) Kelly, T. R.; De Silva,
H.; Silva, R. A. Nature 1999, 401, 150–152. (c) Leigh, D. A.; Wong,
J. K. Y.; Dehez, F.; Zerbetto, F. Nature 2003, 424, 174–179.
(8) (a) Thordarson, P.; Bijsterveld, E. J. A.; Rowan, A. E.; Nolte, R. J. M.
Nature 2003, 424, 915–918. (b) Hidalgo Ramos, P.; Coumans,
R. G. E.; Deutman, A. B. C.; Smits, J. M. M.; De Gelder, R.; Elemans,
J. A. A. W.; Nolte, R. J. M.; Rowan, A. E. J. Am. Chem. Soc. 2007,
129, 5699–5702. (c) Miyagawa, N.; Watanabe, M.; Matsuyama, T.;
Koyama, Y.; Moriuchi, T.; Hirao, T.; Furusho, Y.; Takata, T. Chem.
Commun. 2010, 46, 1920–1922.
‡ Servicio de Apoyo a la Investigacio´n (SAI).
(1) Molecular Motors; Schliwa, M., Ed.; Wiley-VCH: Weinheim, Ger-
many, 2002.
(2) (a) Balzani, V.; Credi, A.; Raymo, F. M.; Stoddart, J. F. Angew. Chem.,
Int. Ed. 2000, 39, 3348–3391. (b) Balzani, V.; Venturi, M.; Credi, A.
Molecular DeVices and Machines. A Journey into the Nanoworld;
Wiley-VCH: Weinheim, Germany, 2003. (c) Kinbara, K.; Aida, T.
Chem. ReV. 2005, 105, 1377–1400. (d) Browne, W. R.; Feringa, B. L.
Nat. Nanotechnol. 2006, 1, 25–35. (e) Kay, E. R.; Leigh, D. A.;
Zerbetto, F. Angew. Chem., Int. Ed. 2007, 46, 72–191. (f) Bath, J.;
Turberfield, A. J. Nat. Nanotechnol. 2007, 2, 275–284. (g) Champin,
B.; Mobian, P.; Sauvage, J.-P. Chem. Soc. ReV. 2007, 36, 358–366.
(9) Vicario, J.; Eelkema, R.; Browne, W. R.; Meetsma, A.; La Crois,
R. M.; Feringa, B. L. Chem. Commun. 2005, 3936–3938.
9
10.1021/ja101151t  2010 American Chemical Society
J. AM. CHEM. SOC. 2010, 132, 10741–10747 10741

A R T I C L E S
Berna´ et al.
allowing a crucial but thermodynamically unfavorable process
to work and, at same time, they get recycled back into a
particular chemical reaction network.16b In this issue, catalytic
reactions should be considered as prime candidates in the task
for integrating this type of control into synthetic molecular
machines working via an energy ratchet mechanism.
Here we describe our efforts in the search for new effective
and useful chemical means to incite shuttling in interlocked
hydrogen-bonded systems based on bistation hydrogen-bond-
assembled [2]rotaxanes and how this switching process can be
controlled as part of a simple molecular network represented
by a chemically fueled catalytic cycle as a novel approach to
give access to an enhanced and sophisticated generation of
molecular shuttles.
In this regard, the choice of the hydrogen-bonding template
is essential to the functioning of the system in the aforemen-
tioned way because they not only should be able to assist to
the assembly of the interlocked structure but also should have
encoded into their molecular structure a known reactivity pattern
if one may desire a particular chemical behavior after the
construction of the device. Despite growing interest in the
development of molecular shuttles, the number of available
templates for the formation of benzylic amide rotaxanes remains
limited.17 Bearing in mind the previous considerations, we
reasoned that an azodicarboxamide motif could be an excellent
candidate by playing an interesting dual role: (i) by templating
the assembly of tetrabenzylic amide macrocycles around it to
form [2]rotaxanes, because it is closely related to a fumaramide
binding site, the best reported template for such processes, and
(ii) by providing a macrocycle binding site with a known
reactivity pattern, which could be modulated by the presence
of the macrocycle or be used to alter the binding interaction
between the interlocked components. As an initial approach,
we were interested to investigate whether azodicarboxamides
could act as templates and whether the hydrogenation of its azo
bond could alter the near-ideal hydrogen-bonding structure
between macrocycle and thread provoking a change in the
internal dynamics governed by those interactions. It is remark-
able that whereas azobenzenes are frequently used as threads
of photoisomerizable [2]rotaxanes,18 there are no reports on
azodicarboxamides forming part of an interlocked molecule, and
consequently their chemical azo/hydrazo interconversion con-
stitutes an original approach for promoting positional changes
in such systems.
(10) (a) Tian, H.; Wang, Q. C. Chem. Soc. ReV. 2006, 35, 361–374. (b)
Berna´, J.; Bottari, G.; Leigh, D. A.; Pe´rez, E. M. Pure Appl. Chem.
2007, 79, 39–54. (c) Crowley, J. D.; Kay, E. R.; Leigh, D. A. Intell.
Mater. 2008, 1–47. (d) Balzani, V.; Credi, A.; Venturi, M. Chem. Soc.
ReV. 2009, 38, 1542–1550. (e) Crowley, J. D.; Goldup, S. M.; Lee,
A.-L.; Leigh, D. A.; McBurney, R. T. Chem. Soc. ReV. 2009, 38, 1530–
1541. (f) Rescifina, A.; Zagni, C.; Iannazzo, D.; Merino, P. Curr. Org.
Chem. 2009, 13, 448–481.
(11) (a) Huang, T. J.; Brough, B.; Ho, C. M.; Liu, Y.; Flood, A. H.;
Bonvallet, P. A.; Tseng, H. R.; Stoddart, J. F.; Baller, M.; Magonov,
S. Appl. Phys. Lett. 2004, 85, 5391–5393. (b) Berna´, J.; Leigh, D. A.;
Lubomska, M.; Mendoza, S. M.; Pe´rez, E. M.; Rudolf, P.; Teobaldi,
G.; Zerbetto, F. Nat. Mater. 2005, 4, 704–710. (c) Nguyen, T. D.;
Tseng, H. R.; Celestre, P. C.; Flood, A. H.; Liu, Y.; Stoddart, J. F.;
Zink, J. I. Proc. Nat. Acad. Sci. U.S.A. 2005, 102, 10029–10034. (d)
Fioravanti, G.; Haraszkiewicz, N.; Kay, E. R.; Mendoza, S. M.; Bruno,
C.; Marcaccio, M.; Wiering, P. G.; Paolucci, F.; Rudolf, P.; Brouwer,
A. M.; Leigh, D. A. J. Am. Chem. Soc. 2008, 130, 2593–2601.
(12) (a) Mateo-Alonso, A.; Ehli, C.; Aminur Rahman, G. M.; Guldi, D. M.;
Fioravanti, G.; Marcaccio, M.; Paolucci, F.; Prato, M. Angew. Chem.,
Int. Ed. 2007, 46, 3521–3525. (b) Aucagne, V.; Berna´, J.; Crowley,
J. D.; Goldup, S. M.; Haenni, K. D.; Leigh, D. A.; Lusby, P. J.;
Ronaldson, V. E.; Slawin, A. M. Z.; Viterisi, A.; Walker, D. B. J. Am.
Chem. Soc. 2007, 129, 11950–11963. (c) Saha, S.; Flood, A. H.;
Stoddart, J. F.; Impellizzeri, S.; Silvi, S.; Venturi, M.; Credi, A. J. Am.
Chem. Soc. 2007, 129, 12159–12171. (d) Berna´, J.; Goldup, S. M.;
Lee, A.-L.; Leigh, D. A.; Symes, M. D.; Teobaldi, G.; Zerbetto, F.
Angew. Chem., Int. Ed. 2008, 47, 4392–4396. (e) Coskun, A.;
Friedman, D. C.; Li, H.; Patel, K.; Khatib, H. A.; Stoddart, J. F. J. Am.
Chem. Soc. 2009, 131, 2493–2495.
(13) (a) Bissell, R. A.; Cordova, E.; Kaifer, A. E.; Stoddart, J. F. Nature
1994, 369, 133–137. (b) Mart´ınez-D´ıaz, M.-V.; Spencer, N.; Stoddart,
J. F. Angew. Chem., Int. Ed. 1997, 36, 1904–1907. (c) Ashton, P. R.;
Ballardini, R.; Balzani, V.; Baxter, I.; Credi, A.; Fyfe, M. C. T.;
Gandolfi, M. T.; Gomez-Lopez, M.; Martinez-Diaz, M.-V.; Piersanti,
A.; Spencer, N.; Stoddart, J. F.; Venturi, M.; White, A. J. P.; Williams,
D. J. J. Am. Chem. Soc. 1998, 120, 11932–11942. (d) Elizarov, A. M.;
Chiu, S.-H.; Stoddart, J. F. J. Org. Chem. 2002, 67, 9175–9181. (e)
Keaveney, C. M.; Leigh, D. A. Angew. Chem., Int. Ed. 2004, 43, 1222–
1224. (f) Vella, S. J.; Tiburcio, J.; Loeb, S. J. Chem. Commun. 2007,
4752–4754. (g) Chen, N.-C.; Lai, C.-C.; Liu, Y.-H.; Peng, S.-M.; Chiu,
S.-H. Chem.sEur. J. 2008, 14, 2904–2908.
Results and Discussion
Synthesis and Interconversion of Azo/Hydrazo [2]Rotaxanes.
Azodicarboxamide threads, 1 (R1 ) CH2CHPh2; R2 ) H) and
2 (R1 ) R2 ) CH2Ph), were easily obtained by dehydrogenation
of the hydrazo compounds [2H]-1 and [2H]-2, in turn resulting
from the reaction of diphenyl hydrazodicarboxylate19 with 2,2-
diphenylethylamine and dibenzylamine, respectively. Threads
1 and 2 were able to template the assembly of benzylic amide
[2]rotaxanes 3 and 4 in acceptable yields (43% and 58%,
respectively) (method A, Scheme 1).20 Although such yields
are lower than those obtained using comparable fumaramide
threads17d,21 under the same reaction conditions,22 they are still
(14) (a) Asakawa, M.; Ashton, P. R.; Balzani, V.; Credi, A.; Hamers, C.;
Mattersteig, G.; Montalti, M.; Shipway, A. N.; Spencer, N.; Stoddart,
J. F.; Tolley, M. S.; Venturi, M.; White, A. J. P.; Williams, D. J.
Angew. Chem., Int. Ed. 1998, 37, 333–337. (b) Leigh, D. A.; Pe´rez,
E. M. Chem. Commun. 2004, 2262–2263.
(17) (a) Johnston, A. G.; Leigh, D. A.; Murphy, A.; Smart, J. P.; Deegan,
M. D. J. Am. Chem. Soc. 1996, 118, 10662–10663. (b) Leigh, D. A.;
Murphy, A.; Smart, J. P.; Slawin, A. M. Z. Angew. Chem., Int. Ed.
Engl. 1997, 36, 728–732. (c) Bermudez, V.; Capron, N.; Gase, T.;
Gatti, F. G.; Kajzar, F.; Leigh, D. A.; Zerbetto, F.; Zhang, S. Nature
2000, 406, 608–611. (d) Gatti, F. G.; Leigh, D. A.; Nepogodiev, S. A.;
Slawin, A. M. Z.; Teat, S. J.; Wong, J. K. Y. J. Am. Chem. Soc. 2001,
123, 5983–5989. (e) Brancato, G.; Coutrot, F.; Leigh, D. A.; Murphy,
A.; Wong, J. K. Y.; Zerbetto, F. Proc. Natl. Acad. Sci. U.S.A. 2002,
99, 4967–4971. (f) Arunkumar, E.; Forbes, C. C.; Noll, B. C.; Smith,
B. D. J. Am. Chem. Soc. 2005, 127, 3288–3289.
(15) For rotaxane-based molecular information ratchets, see: (a) Serreli,
V.; Lee, C.-F.; Kay, E. R.; Leigh, D. A. Nature 2007, 445, 523–527.
(b) Alvarez-Perez, M.; Goldup, S. M.; Leigh, D. A.; Slawin, A. M. Z.
J. Am. Chem. Soc. 2008, 130, 1836–1838. For a rotaxane-based two
compartment molecular energy ratchet, see: (c) Chatterjee, M. N.; Kay,
E. R.; Leigh, D. A. J. Am. Chem. Soc. 2006, 128, 4058–4073. For
catenane-based rotary molecular motors that operate through energy
ratchet mechanisms, see: (d) Herna´ndez, J. V.; Kay, E. R.; Leigh, D. A.
Science 2004, 306, 1532–1537. (e) See ref 7c. (f) For other Brownian
ratchets and rotary motors, see refs 7a,b. (g) Fletcher, S. P.; Dumur,
F.; Pollard, M. M.; Feringa, B. L. Science 2005, 310, 80–82. (h) von
Delius, M.; Geertsema, E. M.; Leigh, D. A. Nat. Chem. 2010, 2, 96–
101.
(18) For some recent examples see: (a) Qu, D. H.; Wang, Q. C.; Tian, H.
Angew. Chem., Int. Ed. 2005, 44, 5296–5299. (b) Murakami, H.;
Kawabuchi, A.; Matsumoto, R.; Ido, T.; Nakashima, N. J. Am. Chem.
Soc. 2005, 127, 15891–15899. (c) Cheetham, A. G.; Hutchings, M. G.;
Claridge, T. D. W.; Anderson, H. L. Angew. Chem., Int. Ed. 2006,
45, 1596–1599. (d) Dawson, R. E.; Maniam, S.; Lincoln, S. F.; Easton,
C. J. Org. Biomol. Chem. 2008, 6, 1814–1821.
(16) For representative examples of biological molecular machines, see:
(a) Namba, K.; Vonderviszt, F. Q. ReV. Biophys. 1997, 30, 1–65. (b)
Boyer, P. D. Angew. Chem., Int. Ed. 1998, 37, 2296–2307. (c) Von
Hippel, P. H.; Delagoutte, E. Cell 2001, 104, 177–190. (d) Spirin,
A. S. FEBS Lett. 2002, 514, 2–10.
(19) (a) Tsunoda, T.; Otsuka, J.; Yamamiya, Y.; Ito, S. Chem. Lett. 1994,
539–542. (b) Harris, J. M.; McDonald, R.; Vederas, J. C. J. Chem.
Soc.,Perkin Trans. 1 1996, 2669–2674.
9
10742 J. AM. CHEM. SOC. VOL. 132, NO. 31, 2010

Azodicarboxamides as Template Binding Motifs
A R T I C L E S
Scheme 1. Synthesis of Azodicarboxamide [2]Rotaxanes 3 and 4
and Their Corresponding Hydrazodicarboxamide [2]Rotaxanes
[2H]-3 and [2H]-4a
a Reagents and conditions: method A, isophthaloyl dichloride, p-
xylylenediamine, Et3N, CHCl3, 3, 43%; [2H]-3, 6%; 4, 58%, [2H]-4, 11%;
method B, N2H4 ·H2O, CHCl3, [2H]-3, 95%; [2H]-4, quantitative; method
C, NBS (N-bromosuccinimide), pyridine, CH2Cl2, 3, 85%; 4, 94%.
impressive for a five-component kinetically controlled interlock-
ing reaction. Probably, the configurational lability of the azo
bond23 compared with the CdC of the fumaramide-based
threads reduces its preorganization during the five-component
“clipping” reaction. The azo rotaxanes 3 and 4 could be
converted quantitatively into the corresponding hydrazo rotax-
anes [2H]-3 and [2H]-4 by reduction (method B) with
hydrazine.24,25 In both cases, the hydrogenation was complete
in a few minutes while a rapid loss of the initial orange color
of the azo compounds was observed.
Figure 1. 1H NMR spectra (400 MHz, CDCl3, 298 K) of (a) azodicar-
boxamide thread 2, (b) azodicarboxamide rotaxane 4, (c) hydrazodicar-
boxamide thread [2H]-2, and (d) hydrazodicarboxamide rotaxane [2H]-4.
Alternatively, the hydrazodicarboxamide [2]rotaxanes [2H]-
3 and [2H]-4 were obtained in low yields (6% and 11%,
respectively) from the corresponding [2H]-1 and [2H]-2 threads
by the established synthetic protocol17b for the preparation of
the benzylic amide rotaxanes (method A). From these results,
it is clear that hydrazodicarboxamides likely adopt a ground
state conformation26 in which the carbonyl hydrogen bond
acceptors do not adopt the ideal orientation of an efficient
template such as fumaramides.17d On other hand, the azo
rotaxanes could be rapidly restored from their hydrazo partners
by a conventional oxidation with NBS/pyridine in excellent
yields (method C, 85-94%).
As one might expect, the azo/hydrazo reversible coupled
transformation must necessarily alter the nature and strength
of the hydrogen-bond network between macrocycle and thread
and therefore also change the internal dynamics governed by
those interactions such as pirouetting27 of the ring around the
thread. In fact, the components of the more soluble azo/hydrazo
pair, rotaxanes 4 and [2H]-4, display noticeable differences in
their 1H NMR spectra in CDCl3 at room temperature. The most
substantial ones are due to the macrocyclic methylene protons.
Whereas in 4 these protons appear as two very broad signals at
5.02 and 3.64 ppm, the same protons in [2H]-4 emerge as a
sharp and well-resolved signal (δ ) 4.42 ppm) at room
temperature (Figure 1). A comparable NMR change was
observed for the macrocyclic methylene protons during the
isomerization of fumaramide rotaxanes28 into their maleamide
(20) Whereas N,N′-disubstituted hydrazo rotaxane 3 proved to be very
insoluble in common non-hydrogen-bond-disrupting deuterated sol-
vents, rotaxane 4 was readily soluble probably because it cannot form
intermolecular hydrogen bonds with other rotaxane molecules, see:
Altieri, A.; Gatti, F. G.; Kay, E. R.; Leigh, D. A.; Martel, D.; Paolucci,
F.; Slawin, A. M. Z.; Wong, J. K. Y. J. Am. Chem. Soc. 2003, 125,
8644–8654.
(21) Altoe, P.; Haraszkiewicz, N.; Gatti, F. G.; Wiering, P. G.; Frochot,
C.; Brouwer, A. M.; Balkowski, G.; Shaw, D.; Woutersen, S.; Buma,
W. J.; Zerbetto, F.; Orlandi, G.; Leigh, D. A.; Garavelli, M. J. Am.
Chem. Soc. 2009, 131, 104–117.
(22) Altieri, A.; Bottari, G.; Dehez, F.; Leigh, D. A.; Wong, J. K. Y.;
Zerbetto, F. Angew. Chem., Int. Ed. 2003, 42, 2296–2300.
(23) (a) Fantazier, R. M.; Herweh, J. E. J. Am. Chem. Soc. 1974, 96, 1187–
1192. (b) Herweh, J. E.; Fantazier, R. M. J. Org. Chem. 1974, 39,
786–793.
(24) Zhang, C.-R.; Wang, Y.-L. Synth. Commun. 2003, 33, 4205–4208.
(25) Koppes, W. M.; Moran, J. S.; Oxley, J. C.; Smith, J. L. Tetrahedron
Lett. 2008, 49, 3234–3237.
(27) Pirouetting, a 180° rotation of the macrocycle about its orthogonal
axis and formal chair-chair flip of the macrocycle, is the simplest
process that must occur to translate the equatorial macrocyclic
methylene protons onto the axial sites. See ref 17c.
(28) Gatti, F. G.; Leo´n, S.; Wong, J. K. Y.; Bottari, G.; Altieri, A.; Morales,
M. A. F.; Teat, S. J.; Frochot, C.; Leigh, D. A.; Brouwer, A. M.;
Zerbetto, F. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 10–14.
(26) Ab initio calculations on the three possible configurations (Z,Z; Z,E,
and E,E) of diformylhydrazine (OHCNHNHCHO) indicate that the
minimum energy rotamers all have dihedral angles between the
nitrogen lone-pairs of approximately 90°. Reynolds, C. H.; Hormann,
R. E. J. Am. Chem. Soc. 1996, 118, 9395–9401.
9
J. AM. CHEM. SOC. VOL. 132, NO. 31, 2010 10743

A R T I C L E S
Berna´ et al.
2.268 Å) with the CO groups of the hydrazo29,30 thread in [2H]-
3, two NH groups of the macrocycle of 3 establish strong
hydrogen bonds (2.091 Å) with the carbonyl groups of the thread
and the other two NH groups of the same ring interact with the
2
nitrogen atoms of the azo function through weak NH · · ·Nsp
hydrogen bonds (2.547 Å).31,32 It should be realized that all
the electronegative atoms in the structure33 are involved in the
formation of at least one hydrogen bond, which in turn modifies
the acceptor/donor capability of their nearby heteroatoms
through electronic (inductive/mesomeric) effects to form other
hydrogen bonds.34 This fact could have a significant influence
in the establishment of other nonbonding interactions during
the crystal lattice formation, and it must be considered as a
plausible cause of the formation, in 3, of a hydrogen-bond
network different from the preferred double set of bifurcated
hydrogen bonds that predominates in solution of nonpolar
solvents for this [2]rotaxane class.35
It is also worth noting that the observed conformation for
the hydrazocarboxamide moiety notably differs from the
structure of the related biurea (H2NCONH)2 in the solid state
in which the strong repulsion of the lone pairs on the adjacent
N atoms is the origin of the observed rotation about the N-N
bond. In fact, biurea shows a folded conformation with an angle
of 84.02° between the planes defined by the two NCN
connectivities.36 In stark contrast, the same value for [2H]-3 is
negligible. We reasoned that this unfavorable planar arrangement
of the CO-N-N-CO framework is only possible thanks to
the stability gained as a result of the hydrogen bond saturation
of the system.26
Synthesis and Chemical Switching of Azo/Hydrazo Molecular
Shuttles. It is conceivable that tuning the binding affinity of a
nitrogenated station for a benzylic amide macrocycle in a
molecular shuttle, mediated by a chemical transformation as
the one described above, can be exploited for the building of
synthetic molecular machines. To test this idea, we have
investigated the ring-shuttling processes in a two-station [2]ro-
taxane in chloroform solution. The rotaxane is composed of a
dumbbell component, containing an azodicarboxamide and a
succinic amide ester binding site, threaded through a tetraben-
zylic amide macrocycle.
Figure 2. X-ray structures of (a) azodicarboxamide [2]rotaxane 3 and (b)
hydrazodicarboxamide [2]rotaxane [2H]-3 crystallized from DMF/H2O. For
clarity, carbon atoms of the macrocycles are shown in gray and the carbon
atoms of the threads in green; oxygen atoms are depicted in red, nitrogen
atoms are depicted in blue, and selected hydrogen atoms are white. Also
for clarity, solvent molecules have been omitted. Intramolecular hydrogen-
bond lengths [Å] (and angles [deg]): (a) O1HN3/O1AHN3A 2.09 (158.5);
N2HN4/N2AHN4A 2.55 (149.4); (b) O3HN1/O3AHN1A 2.27 (174.8);
O3HN2/O3AHN2A 2.16 (176.7).
isomers, which was ascribed to an acceleration in the
rotational motion of the ring. Consequently these NMR data
seem to point out that pirouetting of the ring is slower in the
azo rotaxane 4 than in the hydrazo partner [2H]-4. Further-
more, this fact also indicates that a hydrazodicarboxamide
moiety is a weaker binding site than its azo partner confirming
our explanation on why the yields obtained in the assembly
of both rotaxanes are so different. Therefore the postassembly
chemical reduction of the azo rotaxanes promotes a structural
mismatch between the recognition binding sites of the
interlocked subcomponents, reducing the intercomponent
interaction and thus decreasing the energy barrier for the
macrocycle pirouetting of the rotaxane. Such unprecedented
chemical control can be added to those previously reported
involving the use of external oscillating electrical fields27 or
photochemical stimuli.28
(29) The hydrazodicarboxamide group can be considered as two adjacent
urea functions. For some examples of urea-template synthesis of
[2]rotaxanes see: (a) Biscarini, F.; Cavallini, M.; Leigh, D. A.; Leo´n,
S.; Teat, S. J.; Wong, J. K. Y.; Zerbetto, F. J. Am. Chem. Soc. 2002,
124, 225–233. (b) Huang, Y.-L.; Hung, W.-C.; Lai, C.-C.; Liu, Y.-
H.; Peng, S.-M.; Chiu, S.-H. Angew. Chem., Int. Ed. 2007, 46, 6629–
6633.
(30) For an example of a hydrazopyridinium-containing [2]catenane see:
Ashton, P. R.; Brown, C. L.; Cao, J.; Lee, J.-Y.; Newton, S. P.; Raymo,
F. M.; Stoddart, J. F.; White, A. J. P.; Williams, D. J. Eur. J. Org.
Chem. 2001, 957–965.
2
(31) For a representative study of the N-H· · ·Nsp hydrogen interaction
see: Llamas-Saiz, A. L.; Foces-Foces, C. J. Mol. Chem. 1990, 238,
367–382.
(32) For some examples of intermolecular CONH · · ·NdN hydrogen bonds
see: (a) Cromer, D. T.; Larson, A. C. J. Chem. Phys. 1974, 60, 176–
184. (b) Blaton, N. M.; Peeters, O. M.; De Ranter, C. J.; Willems,
G. J. Acta Crystallogr. 1979, B35, 2629–2634. (c) Okabe, N.; Kisaichi,
H. Acta Crystallogr. 1992, C48, 2047–2049. (d) Klapo¨tke, T. M.; Miro´
Sabate´, C. New J. Chem. 2009, 33, 1605–1617.
Interlocked Structures in the Solid State. X-ray crystal
structures of rotaxanes 3 and [2H]-3 (Figure 2) crystallized from
DMF/H2O demonstrate a good fit between thread and macro-
cycle. However, the nature of the established noncovalent
interactions between thread and macrocycle were found to be
different in both interlocked structures. Whereas the NH groups
of the macrocycle form two bifurcated hydrogen bonds (2.158,
(33) Multiple hydrogen bonds are established between the solvating water
molecules and the rotaxanes. Detailed information on these interactions
is given in the Supporting Information.
(34) Steiner, T. Angew. Chem., Int. Ed. 2002, 41, 48–76.
(35) For other examples of [2]rotaxanes with the same binding site but
showing a different hydrogen bonding pattern in solution and in the
solid state, see refs 17d, e, 20, and 29a.
(36) Brown, D. S.; Russell, P. R. Acta Crystallogr. 1976, B32, 1056–1058.
9
10744 J. AM. CHEM. SOC. VOL. 132, NO. 31, 2010

Azodicarboxamides as Template Binding Motifs
A R T I C L E S
Scheme 2. Synthesis of Bistable Molecular Shuttles Based on
Azodicarboxamide Binding Sites 7 and 8 and Their Corresponding
1,2-Hydrazodicarboxamides [2H]-7 and [2H]-8a
Figure 3. 1H NMR spectra (400 MHz, CDCl3, 298 K) of (a) azodicar-
boxamide thread 5, (b) azodicarboxamide rotaxane 7, (c) hydrazodicar-
boxamide thread [2H]-5, and (d) hydrazodicarboxamide rotaxane [2H]-7.
The assignments correspond to the lettering shown in Scheme 2.
a Reagents and conditions: (a) Ph2CHCH2NH2 or (PhCH2)2NH, Et3N,
CHCl3; (b) Ph2CHCH2O2C(CH2)2CONH(CH2)12NH2 (2,2-diphenylethyl
3-(12-aminododecylcarbamoyl)propanoate), Et3N, CHCl3, [2H]-5, 35%;
[2H]-6, 54%; (c) NBS, pyridine, CH2Cl2, 5, 91%; 6, 95%; 7, 86%; 8, 93%;
(d) isophthaloyl dichloride, p-xylylenediamine, Et3N, CHCl3, 7, 34%; 8,
45%; (e) N2H4 ·H2O, CHCl3, [2H]-7, 88%; [2H]-8, 92%. Full experimental
procedures can be found in the Supporting Information.
to its isolated thread 5 due to the polarization caused by
hydrogen bonding of the azodicarboxamide carbonyl groups
with the macrocycle. Accordingly, we conclude that the
macrocycle in 7 is located mainly over the azodicarboxamide
unit (>94% of the time in CDCl3, 298 K).37
Using identical reaction conditions as for the hydrogenation
of 3 and 4 (Scheme 1), molecular shuttle 7 was quickly (less
than 5 min), cleanly, and quantitatively converted into its
hydrazo derivative [2H]-7, this reduction concomitantly activates
the translocation of the macrocycle to the succinic amide ester
station. The hydrazodicarboxamide protons (Hc, Hf, Hd, and He,
purple) resonate at nearly identical chemical shifts in rotaxane
and thread (compare Figure 3c,d), whereas the succinic amide
ester methylene groups (Hm and Hl, orange) are each shielded
by >1.5 ppm in the rotaxane. In the latter, the succinic amide
ester NH (Hk, orange) appears shifted 1.3 ppm downfield
compared with its thread. These spectroscopic data confirm that
rotaxane [2H]-7 adopts the coconformation where the ring sits
around the succinic amide ester binding site.37 A comparable
Molecular shuttles 7 and 8 were prepared as outlined in
Scheme 2. Threads 5 and 6 were prepared by standard
procedures starting from diphenyl hydrazodicarboxylate,19 which
was sequentially aminated, first with the commercially available
2,2-diphenylethylamine or dibenzylamine and then with 2,2-
diphenylethyl 3-(12-aminododecylcarbamoyl)propanoate,22 which
already contains the succinic amide ester station. The obtained
hydrazo compounds [2H]-5 and [2H]-6 were dehydrogenated
with NBS/pyridine leading finally to the azo threads 5 and 6 in
32% and 51% overall yield, respectively. Compounds 5 and 6
were subjected to rotaxane-forming conditions (p-xylylenedi-
amine, isophthaloyl dichloride, triethylamine, chloroform, 4 h,
high dilution) furnishing the molecular shuttles 7 and 8 in 34%
and 45% yield, respectively.
1
series of shifts occur in the H NMR spectra of the molecular
1
shuttle 8/[2H]-8 (for stacked H NMR spectra, see Supporting
Information). The translocation of the macrocycle is fully
reversed upon oxidation with the chemical pair NBS/pyridine,
which regenerates the azodicarboxamide site and triggers the
ring motion to this station by biased Brownian motion.
The 1H NMR spectra (CDCl3, 400 MHz, 298 K) of thread 5
and rotaxane 7 are shown in Figure 3. The position of the
macrocycle could be determined by comparing these two
spectra. The succinic amide ester signals (Hm, Hl, and Hk,
orange) appear at nearly identical chemical shifts in both thread
and rotaxane, thus proving that this station remains unoccupied
in 7, whereas the NH azodicarboxamide protons (Hc and Hf,
red) are deshielded by 0.7 ppm in the azo rotaxane with respect
(37) (a) The occupancy level of the preferred station in both molecular
shuttle states was estimated using the method described in ref 22. (b)
For an alternative method see: Gu¨nbas¸, D. D.; Zalewski, L.; Brouwer,
A. M. Chem. Commun. 2010, 46, 2061–2063.
9
J. AM. CHEM. SOC. VOL. 132, NO. 31, 2010 10745

A R T I C L E S
Berna´ et al.
Scheme 3. Proposed Cyclic Chemical Functioning of the Shuttle 8 by Means of an Ester Bond Formation Reaction between an Acid,
ArCO2H (Where Ar is 4-O2NC6H4), and an Alcohol, ROH (Where R is C6H5CH2) Mediated by a Classical Mitsunobu Protocol with
Triphenylphosphane Followed by an in Situ Oxidation of the Hydrazo Generated Shuttle [2H]-8
Pleasantly, hydrogenation and dehydrogenation of both shuttles
Table 1. Stoichiometric and Substoichiometric Mitsunobu
are fast, high yielding, and preparatively simple and generate
large amplitude net positional changes, with excellent discrimi-
nation between the binding sites exhibited by the macrocycle
in both chemical states of the shuttles. Remarkably, this
chemically induced shuttling processes in these bistable [2]ro-
taxanes should add to the scarce number of examples of
molecular shuttles using a chemical stimulus under mild reaction
conditions.14
Organocatalytic Function of the Molecular Shuttle 8. In
recent years, the realization of energy ratchet mechanisms in
molecular-level structures has become essential to the develop-
ment of functional molecular machines more complex than
simple switches.2,5 We turned our attention toward the design
of a chemically driven molecular shuttle able to work in cyclic
manner for generating synthetically useful covalent bonds as a
novel strategy to incorporate a new type of control over the
switching periodicity of the potential energy surface of a bistable
[2]rotaxane. In particular, we reasoned that having an azodi-
carboxamide function integrated in the thread, a feasible
transformation could involve the catalytic formation of ester
bonds by a Mitsunobu protocol,38,39 focusing on shuttles
8/[2H]-8.19a,40 During this process, the macrocycle will be
continuously translocated between the nitrogen and carbon-based
stations assisted by triphenylphosphane, which acts a chemical
activator of the azo group, and iodosobenzene diacetate41 as
stoichiometric oxidant of the resulting hydrazo unit (Scheme
3).
Esterification of 4-Nitrobenzoic Acid with Benzylic Alcohol by
Azodicarboxamide Rotaxanes and Threadsa
azo
(equiv)
PPh3b
(equiv)
PhI(OAc)2
(equiv)
temp
(°C)
yield
(%)
entry
solvent
1
2
3
4
5c
6
7
8
2 (1)
1
2
2
2
2
2
2
2
THF
THF
THF
THF
CH3CN
CH3CN
CH3CN
CH3CN
25
25
25
50
50
50
50
50
61
53
42
67
71
16
69
65
2 (0.1)
2 (0.3)
2 (0.1)
2 (0.1)
4 (0.1)
6 (0.1)
8 (0.1)
2
2
2
2
2
2
2
a Reactions were carried out at 0.1 M concentrations of the azo
compound using 1 equiv of carboxylic acid and 2 equiv of alcohol, in
anhydrous degassed solvents and protected from moisture (see
Supporting Information). b Except entry 1, triphenylphosphane was
slowly added via syringe pump. c An additional experiment carried out
in the absence of PPh3 yielded the ester but in only 9% yield.
this transformation, obtaining benzyl 4-nitrobenzoate in a good
yield (Table 1, entry 1). Using reaction conditions similar to
those described by Toy,41 we next performed the organocatalytic
Mitsunobu reaction with 2 to obtain the ester in 53% yield
(Table 1, entry 2), which was increased to 71% by changing
the solvent to acetonitrile and raising the temperature to 50 °C
(Table 1, entries 3-5). The two-station thread 6 also behaved
similarly in these substoichiometric conditions (Table 1, entry
7). Having achieved an efficient substoichiometric version of
the Mitsunobu reaction with the thread 6, we next tested
[2]rotaxane 4 and proved that the reactivity of its azo function
is nearly extinguished by the steric shielding caused by the
surrounding macrocycle, which apparently precludes the initial
triphenylphosphane attack (Table 1, entry 6). Delightfully, the
molecular shuttle 8 served as a successful organocatalyst of the
ester bond formation giving the product in 65% yield (Table 1,
entry 8) thus proving that if a second station is available for
hosting the macrocycle, initially over the azo function, the ring
movement then allows the catalytic esterification to take place.
Although the hydrogen bonds between the azodicarboxamide
station and the macrocycle can survive even in relatively polar
Initially we ran a stoichiometric ester bond formation reaction
to ascertain the ability of the monostation thread 2 to carry out
(38) (a) Mitsunobu, O.; Yamada, M.; Mukaiyama, T. Bull. Chem. Soc. Jpn.
1967, 40, 935–939. (b) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc.
Jpn. 1967, 40, 2380–2382.
(39) For selected recent general reviews dealing with Mitsunobu reactions,
see: (a) Dandapani, S.; Curran, D. P. Chem.sEur. J. 2004, 10, 3130–
3138. (b) But, T. Y. S.; Toy, P. H. Chem.sAsian J. 2007, 2, 1340–
1355. (c) Swamy, K. C. K.; Kumar, N. N. B.; Balaraman, E.; Kumar,
K. V. P. P. Chem. ReV. 2009, 109, 2551–2651.
(40) Ito, S.; Tsunoda, T. Pure Appl. Chem. 1999, 71, 1053–1057.
(41) But, T. Y. S.; Toy, P. H. J. Am. Chem. Soc. 2006, 128, 9636–9637.
9
10746 J. AM. CHEM. SOC. VOL. 132, NO. 31, 2010

Azodicarboxamides as Template Binding Motifs
A R T I C L E S
solvents such as THF or acetonitrile,22 these solvents may
compete with the hydrogen bond donors of the thread. In such
case, Brownian macrocycle escape from the azo station allows,
in some extension, the phosphane attack to form the corre-
sponding Morrison-Brunn-Huisgen42 betaine, like I (Scheme
3).43 This betaine was detected by high-resolution mass
spectrometry. Thus, in its mass spectrum, peaks at m/z )
1554.7446, and 777.8780, corresponding to [M + H]+ and [M
+ 2H]2+, respectively, were observed, and their isotopic
resolutions are in excellent agreement with the theoretical
distributions (see Supporting Information). Triphenylphosphane
addition to the azodicarboxamide station alters its affinity for
the macrocycle and notably increases the steric bulk between
the amide groups. In fact, Corey-Pauling-Koltun space-filling
models show that a tetrabenzylic amide macrocycle would be
unlikely to wrap the azophosphonium moiety of the betaine and
therefore the succinic amide ester becomes the positional
minimum energy. This intermediate then follows the well-known
mechanistic pathway44 of the Mitsunobu reaction to give the
ester and the hydrazo [2]rotaxane [2H]-8, which, after in situ
reoxidation, recycles the coconformer 8 by an excess of
bis(acetoxy)iodobenzene, and it is ready to start again the
catalytic wheel of the ester bond formation. This particular
functioning provides an original method to trigger a continuous
ring translocation ruled by the esterification and oxidation
reactions, which could be employed in the tuning of distance-
or time-dependent properties of other interlocked systems
designed to this purpose. From a thermodynamic point of view,
it should be noted that although the esterification reaction is an
endergonic process, the oxidation of phosphane promoted by
the reduction of the azodicarboxamide binding site makes the
overall process exergonic. In these reaction conditions, this
molecular shuttle operates in a cyclic manner as long as the
fueling chemicals are accessible into this dynamic system, which
is able to move a threaded macrocycle between two nitrogen-
and carbon-based stations of a programmed track to make an
esterification process going downhill.
Conclusions
In summary, we have described the ability of different
azodicarboxamides to act as new templates for the assembly of
unprecedented azo-functionalized [2]rotaxanes. Moreover, they
can be reversibly and efficiently interconverted with their
hydrazo forms by very well-known chemical methods in fast
and clean manners. This novel, chemically switchable binding
site class has been used for the building of bistable, stimuli-
responsive molecular shuttles that work through reversible
hydrogenation-dehydrogenation of the nitrogen-nitrogen bond,
producing large amplitude net positional changes with a good
discrimination between the binding sites of the macrocycle in
both states of the shuttle. These molecular shuttles are able to
operate by two different mechanisms: in a discrete mode through
two reversible and independent chemical events triggering
reduction and oxidation reactions and in a continuous mode
through a catalyzed ester bond formation reaction in which the
shuttle acts as an organocatalyst. We believe such features open
a new expectation for the elaboration of more complex molec-
ular machines by enabling them to participate inside of a
chemical reaction network and so giving rise to controllable
dynamic systems closer to those operating in nature.
Acknowledgment. This work was supported by the MICINN
(Project CTQ2009-12216/BQU) and Fundacio´n Se´neca-CARM
(Project 08661/PI/08). J.B. thanks the MICINN for a Ramo´n y Cajal
contract.
Supporting Information Available: Experimental procedures
and spectroscopic data for all new compounds and full crystal-
lographic details of rotaxanes 3 and [2H]-3 including cif files.
This material is available free of charge via the Internet at http://
pubs.acs.org.
(42) (a) Morrison, D. C. J. Org. Chem. 1958, 23, 1072–1074. (b) Brunn,
E.; Huisgen, R. Angew. Chem., Int. Ed. Engl. 1969, 8, 513–515.
(43) It should be noted that the phosphane attack could occur at the nitrogen
in R or ꢀ position to the Bn2NC(O)- group of 8. For simplicity, we
have depicted the betaine derived from the attack to the R nitrogen.
(44) For a DFT computational study of the Mitsunobu reaction, see: Schenk,
S.; Weston, J.; Anders, E. J. Am. Chem. Soc. 2005, 127, 12566–12576.
JA101151T
9
J. AM. CHEM. SOC. VOL. 132, NO. 31, 2010 10747