Using the rotaxane mechanical bond to enhance chemical reactivity

Article abstract of DOI:10.1021/ol102132x

Rates of cycloreversion for squaraine rotaxane mono(endoperoxides) were enhanced by structural modifications that increased cross-component steric destabilization of the inward directed 9,10-anthracene endoperoxide group. The largest rate enhancements were obtained when the surrounding macrocycle contained two 2,6-pyridine dicarboxamide bridging units, which induced a cavity contraction effect. The precursor fluorescent, near-IR, squaraine rotaxanes are effectively photostable because the mono(endoperoxide) products, formed by reaction with photogenerated singlet oxygen, rapidly cyclorevert back to the original squaraine rotaxane.

Full text of DOI:10.1021/ol102132x

ORGANIC
LETTERS
2010
Vol. 12, No. 21
4980-4983
Using the Rotaxane Mechanical Bond to
Enhance Chemical Reactivity
Jeffrey M. Baumes, Ivan Murgu, Allen Oliver, and Bradley D. Smith*
Department of Chemistry and Biochemistry, 236 Nieuwland Science Hall, UniVersity of
Notre Dame, Notre Dame, Indiana 46556, United States
smith.115@nd.edu
Received September 7, 2010
ABSTRACT
Rates of cycloreversion for squaraine rotaxane mono(endoperoxides) were enhanced by structural modifications that increased cross-component
steric destabilization of the inward directed 9,10-anthracene endoperoxide group. The largest rate enhancements were obtained when the
surrounding macrocycle contained two 2,6-pyridine dicarboxamide bridging units, which induced a cavity contraction effect. The precursor
fluorescent, near-IR, squaraine rotaxanes are effectively photostable because the mono(endoperoxide) products, formed by reaction with
photogenerated singlet oxygen, rapidly cyclorevert back to the original squaraine rotaxane.
[2]Rotaxanes are interlocked molecules comprised of a
dumbbell-shaped thread encapsulated by a macrocycle.1 The
two components are permanently connected because the
stopper groups at each end of the thread are too large to
pass through the macrocycle. By definition, this mechanical
bond forces the interlocked components into close proximity,
and there are many examples in the literature showing how
one component can sterically protect the other from chemical
attack.2 Here we describe a concept that works in the reverse
manner;the close proximity of the two interlocked com-
ponents induces steric strain in one of them and enhances
chemical reactivity.3
2EP, respectively (Scheme 1), and that both of these products
are very stable at room temperature.4 We have subsequently
discovered that the ability of these macrocycles to capture
and release singlet oxygen is greatly altered if they mechani-
cally encapsulate squaraine dyes and thus exist as squaraine
rotaxanes. For example, irradiation of squaraine rotaxane 3
with red light in air produces singlet oxygen that reacts with
(2) For steric protection of rotaxane thread components, see: (a)
Gassensmith, J. J.; Baumes, J. M.; Smith, B. D. Chem. Commun. 2009,
6329–6338. (b) Parham, A. H.; Windisch, B.; Vo¨gtle, F. Eur. J. Org. Chem.
1999, 1233–1238. (c) Eelkema, R.; Maeda, K.; Odell, B.; Anderson, H. L.
J. Am. Chem. Soc. 2007, 129, 12384–12385. (d) Fernandes, A.; Viterisi,
A.; Coutrot, F.; Potok, S.; Leigh, D. A.; Aucagne, V.; Papot, S. Angew.
Chem., Int. Ed. 2009, 48, 6443–6447. (e) Oku, T.; Furusho, Y.; Takata, T.
Org. Lett. 2003, 5, 4923–4925. (f) D’Souza, D. M.; Leigh, D. A.; Mottier,
L.; Mullen, K. M.; Paolucci, F.; Teat, S. J.; Zhang, S. J. Am. Chem. Soc.
2010, 132, 9465–9470. (g) Sugiyama, J.; Tomita, I. Eur. J. Org. Chem.
2007, 4651–4653. (h) Gassensmith, J. J.; Matthys, S.; Lee, J.-J.; Wojcik,
A.; Kamat, P. V.; Smith, B. D. Chem.sEur. J. 2010, 16, 2916–2921. (i)
Mateo-Alonso, A.; Brough, P.; Prato, M. Chem. Commun. 2007, 1412–
1414.
We recently reported that cycloaddition of singlet oxygen
to the homologous anthracene-containing, tetralactam mac-
rocycles 1 and 2 produces the bis(endoperoxides) 1EP and
(1) For recent reviews of rotaxanes, see: (a) Ha¨nni, K. D.; Leigh, D. A.
Chem. Soc. ReV. 2010, 39, 1240–1251. (b) Ma, X.; Tian, H. Chem. Soc.
ReV. 2010, 39, 70–80. (c) Harada, A.; Hashidzume, A.; Yamaguchi, H.;
Takashima, Y. Chem. ReV. 2009, 109, 5974–6023. (d) Balzani, V.; Credi,
A.; Venturi, M. Chem. Soc. ReV. 2009, 38, 1542–1550. (e) Stoddart, J. F.
Chem. Soc. ReV. 2009, 38, 1802–1820. (f) Mullen, K. M.; Beer, P. D. Chem.
Soc. ReV. 2009, 38, 1701–1713. (g) Loeb, S. J. Chem. Soc. ReV. 2007, 36,
226–235.
(3) For rotaxane activation of a functional group, see ref 2f.
(4) The activation barriers for cycloreversion of 1EP and 2EP are so
high that prolonged heating at 120 °C leads to decomposition by alternate
reaction pathways: Gassensmith, J. J.; Baumes, J. M.; Eberhard, J.; Smith,
B. D. Chem. Commun. 2009, 2517–2519.
10.1021/ol102132x  2010 American Chemical Society
Published on Web 10/05/2010

directed 9,10-anthracene endoperoxide group by the encapsu-
lated squaraine dye.6 The series 3EP-8EP tests this hypothesis
by inducing different degrees of cross-component steric strain.
The structures evaluate the effectiveness of two strategies to
modulate the strain: macrocycle cavity contraction and stopper
group crowding of the macrocycle (Figure 1).
Scheme 1
Figure 1. Two structural strategies to modulate cross-component
steric strain in a squaraine rotaxane mono(endoperoxide). In both
cases the structure on the right induces more strain on the
endoperoxide group, which accelerates the rate of cycloreversion
and oxygen release.
The macrocycle contraction effect was achieved by
switching the two bridging units in the surrounding rotaxane
macrocycle from isophthalamide (1) to 2,6-pyridine dicar-
boxamide (2). Published X-ray structures of related squaraine
rotaxanes (plus the three structures described below) dem-
onstrate consistently that internal hydrogen bonding of the
amide NH residues with the adjacent pyridyl nitrogen atoms
contracts the surrounding macrocycle and wraps it more
tightly around the encapsulated squaraine.7 The degree
of macrocycle contraction is reflected by the centroid-to-
centroid distance d between the two cofacial aryl walls
of the macrocycle, and d decreases from 6.91-7.18 Å
when there are two bridging isophthalamides to 6.61-6.78
Å when there are two bridging 2,6-pyridine dicarboxam-
ides (Figure 2).
the rotaxane to form mono(endoperoxide) 3EP in quantitative
yield (Scheme 1). Upon sitting, 3EP undergoes spontaneous
cycloreversion back to the starting squaraine rotaxane with
a half-life of 3.2 h at 38 °C.5 The cycloreversion reaction
releases singlet oxygen and emits near-infrared light that can
pass through skin and tissue. To develop this discovery into
practical applications we have started a systematic investiga-
tion of the structural parameters that control the rate of
squaraine rotaxane mono(endoperoxide) cycloreversion. In
this report, we compare the reactivity of endoperoxides
3EP-8EP and find that the rate of cycloreversion can be
controlled in a systematic manner by making subtle changes
in the rotaxane structure.
With this macrocycle contraction effect in mind, we
reasoned that the strain energy in mono(endoperoxide) 4EP
(6) For discussions of conventional intramolecular steric effects on
addition and release of oxygen to aromatic compounds, see: (a) Aubry,
J.-M.; Pierlot, C.; Rigaudy, J.; Schmidt, R. Acc. Chem. Res. 2003, 36, 668–
675. (b) Fudickar, W.; Linker, T. Chem.sEur. J. 2006, 12, 9276–9283. (c)
Wasserman, H. H.; Wiberg, K. B.; Larsen, D. L.; Parr, J. J. Org. Chem.
2005, 70, 105–109. (d) Schmidt, R.; Brauer, H.-D. J. Photochem. 1986,
34, 1–12. (e) Lapouyade, R.; Desvergne, J. P.; Bouas-Laurent, H. Bull. Soc.
Chim. Fr. 1975, 9, 2137–2142.
(7) (a) Fu, N.; Baumes, J. M.; Arunkumar, E.; Noll, B. C.; Smith, B. D.
J. Org. Chem. 2009, 74, 6462–6468. (b) Gassensmith, J. J.; Arunkumar,
E.; Barr, L.; Baumes, J. M.; DiVittorio, K. M.; Johnson, J. R.; Noll, B. C.;
Smith, B. D. J. Am. Chem. Soc. 2007, 129, 15054–15059. (c) Arunkumar,
E.; Forbes, C. C.; Noll, B. C.; Smith, B. D. J. Am. Chem. Soc. 2005, 127,
3288–3289. (d) The relevant structural data from refs 7a-7c have been
deposited with the Cambridge Crystallographic Data Centre using the CCDC
numbers 258547, 736493, 736495, 258548, 677692, 736492, 736494, and
736496. These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre, 12 Union Rd., Cambridge CB2 1EZ, UK or
via www.ccdc.cam.ac.uk/conts/retrieving.html.
Rates of aromatic endoperoxide cycloreversion are known
to be sensitive to steric effects, and we attributed the facile
cycloreversion of 3EP to steric destabilization of its internally
(5) Baumes, J. M.; Gassensmith, J. J.; Giblin, J.; Lee, J.-J.; White, A. G.;
Culligan, W. J.; Leevy, W. M.; Kuno, M.; Smith, B. D. Nature Chem. 2010.
DOI: 10.1038/nchem.871.
Org. Lett., Vol. 12, No. 21, 2010
4981

component, steric crowding of the macrocycle by the bulky
stopper groups at each end of the encapsulated squaraine
thread. We reasoned that this effect would be maximized
by shortening the length of the encapsulated squaraine and
making it harder for the macrocycle to avoid steric interaction
with the stopper groups (Figure 1). Support for the idea was
gained by comparing the conformationally different X-ray
crystal structures of two separate samples of 7 (Figure 4).
Figure 2. The centroid-to-centroid distance d between the two
cofacial aryl walls in the surrounding macrocycle of squaraine
rotaxane crystal structures depends on the two macrocycle bridging
units. When the bridging units are 2,6-pyridine dicarboxamides there
is internal hydrogen bonding of the amide NH residues with the
adjacent pyridyl nitrogen atoms (see insert), which contracts the
macrocycle cavity.7
would be greater than that in 3EP, and we were pleased when
preliminary kinetic studies at room temperature indicated that
the cycloreversion of 4EP was so fast that accurate measure-
ments could not be made. To enable a direct comparison,
we employed an NMR method to determine the rates of
mono(endoperoxide) cycloreversion at the same low tem-
perature of 10 °C. Briefly, an NMR tube containing a sample
of the parent squaraine rotaxane in aerated CDCl3 was
maintained at 0 °C and irradiated with red light for enough
time to photogenerate the corresponding mono(endoperoxide)
in sufficient amounts to allow accurate kinetic measurements.
The tube was transferred to a spectrometer whose probe was
precooled to 10 °C and the rate of cycloreversion was
determined by monitoring the changes in NMR signal
intensities. As illustrated in Figure 3, the kinetic plots
Figure 4. X-ray structures of 5 and two separate crystalline samples
of squaraine rotaxane 7. See Figure 2 for the definition of d.
In one structure (Figure 4b), the macrocycle adopts a
flattened chair conformation with d ) 6.91 Å, whereas the
other structure (Figure 4c) shows the macrocycle as a bent
chair conformation with d ) 7.16 Å. Moreover, a third
independent crystal structure of squaraine rotaxane 5 (Figure
4a), with the same surrounding macrocycle but slightly
different thread component, also exhibited a flattened chair
with d ) 6.95 Å. These structures suggested to us that
squaraine rotaxane endoperoxides with shortened thread
components and bulky stopper groups might force the
surrounding macrocycle to adopt a flattened chair with
decreased distance d. This in turn might increase putative
cross-component strain on the internally directed endoper-
oxide group and accelerate the rate of cycloreversion.
Therefore, we prepared squaraine rotaxanes 5, 6, and 7 with
the shortened encapsulated squaraine threads 10, 11, and 12,
respectively, and converted them to the corresponding
mono(endoperoxides). This allowed direct comparison of the
cycloreversion rates for 3EP, 5EP, 6EP, and 7EP, with each
rotaxane having exactly the same reactive macrocyclic
mono(endoperoxide) component (i.e., mono(endoperoxide)
of 1) but different encapsulated squaraine threads. Compared
to 3EP (with relatively long squaraine thread) we found that
cycloreversion for 5EP, 6EP, and 7EP (each with a different
shortened squaraine thread) was faster by factors of 1.7, 1.1,
and 2.2, respectively. These modest enhancements indicate
that stopper group crowding has only a minor effect on the
stability and reactivity of the surrounding macrocycle mo-
no(endoperoxide).8
Figure 3. First-order kinetic data for cycloreversion of squaraine
rotaxane mono(endoperoxides) at 10 °C in CDCl3.
exhibited first-order behavior. The derived rate constants
show that mono(endoperoxide) 4EP, with a surrounding
macrocycle containing two bridging 2,6-pyridine dicarboxa-
mide units, undergoes cycloreversion 250 times faster than
3EP.
In principle, another way to increase strain energy in the
surrounding endoperoxide macrocycle is to induce cross-
4982
Org. Lett., Vol. 12, No. 21, 2010

As a final kinetic test of our [2]rotaxane cross-component,
steric strain hypothesis we measured the rate of cyclorever-
sion for mono(endoperoxide) 8EP whose structure combines
the large macrocycle cavity contraction effect in 4EP (which
produced a cycloreversion rate enhancement of 250) with
the small stopper group crowding effect in 5EP (which
produced a cycloreversion rate enhancement of 1.7). The
parent squaraine rotaxane 8 was readily synthesized, and as
expected, extended irradiation of an aerated NMR sample
at room temperature produced negligible accumulation (<5%)
of the corresponding mono(endoperoxide) 8EP. However,
at low temperature the cycloreversion was slowed sufficiently
and 8EP accrued in sufficient amount for unambiguous NMR
characterization of its structure and kinetics. As shown in
Figure 3, 8EP undergoes cycloreversion 540 times faster than
3EP at 10 °C. Thus, the two simultaneous structure-induced
changes in cross-component steric strain combine in additive
fashion to reduce the activation barrier for mono(endoper-
oxide) cycloreversion.
To summarize the conclusions and practical implications
of this work, we find that fluorescent squaraine rotaxanes
with 1 as the surrounding macrocycle (having two isoph-
thalamide bridging units) react with singlet oxygen to form
relatively stable squaraine rotaxane mono(endoperoxides).
For example, extended irradiation of squaraine rotaxane 3
in air leads to quantitative formation of the mono(endoper-
oxide) 3EP, which subsequently undergoes clean but rela-
tively slow spontaneous cycloreversion with a half-life of
3.2 h at 38 °C (Scheme 1). The propensity to react with
singlet oxygen means that squaraine rotaxanes incorporating
macrocycle 1 will not act as inert fluorescence imaging
probes; however, the unusual ability of the mono(endoper-
oxide) products to slowly release singlet oxygen produces a
potentially valuable chemiluminescent effect.5 The new
information in this report is that subtle structural changes
can create modified squaraine rotaxanes that are effectively
photostable. The mono(endoperoxide) product that is formed
by reaction with photogenerated singlet oxygen undergoes
a rapid cycloreversion to release the trapped oxygen and
restore the original squaraine rotaxane. Most notably,
squaraine rotaxane mono(endoperoxides) with 2 as the
precursor surrounding macrocycle (containing two bridging
2,6-pyridine dicarboxamides) exhibit a 250-fold enhancement
in cycloreversion compared to analogues that have 1 as the
precursor surrounding macrocycle. The enhanced reactivity
is attributed to the increased cross-component steric strain
that is induced by contraction of the rotaxane macrocyclic
cavity. Because of this effect, the steady state fraction of
mono(endoperoxide) 4EP that is formed by extended ir-
radiation of squaraine rotaxane 4 at room temperature in air
is never more than a few percent.9 In other words, squaraine
rotaxanes, with macrocycles composed of anthracene wall
units and bridging 2,6-pyridine dicarboxamides are remark-
ably resistant to photobleaching. These extremely bright,
near-infrared fluorophores also exhibit an unusually large
Stokes shift of >40 nm, a highly desired technical feature
that facilitates many types of fluorescence applications.10
Indeed, we have already produced a useful fluorescence
bioimaging probe based on 4 as a highly photostable
substitute fluorophore for the commonly used near-infrared
cyanine dye Cy-5.5.11 From a broader perspective, it will
be interesting to see if other strain-sensitive reactions can
be accelerated by strategies that harness the energy of the
mechanical bond.12
Acknowledgment. This work was supported by the Notre
Dame Integrated Imaging Facility, the University of Notre
Dame, and the NSF.
Supporting Information Available: Synthesis, spectral
data, X-ray structure details, and kinetic studies. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL102132X
(9) The very low photochemical conversion of 4 into 4EP at room
temperature is not due to an inability of 4 to photogenerate singlet oxygen.
Chemical trapping experiments, using 1,3-diphenylisobenzofuran to react
with photogenerated singlet oxygen, showed that irradiation of separate
samples of squaraine rotaxanes 3 or 4 produced about the same amounts of
singlet oxygen (see the Supporting Information).
(10) Valeur, B., Molecular Fluorescence, Principles and Applications;
Wiley-VCH: Weinheim, Germany, 2002.
(11) (a) Lee, J.-J.; White, A. G.; Baumes, J. M.; Smith, B. D. Chem.
Commun. 2010, 46, 1068–1069. (b) White, A. G.; Fu, N.; Leevy, W. M.;
Lee, J.-J.; Blasco, M. A.; Smith, B. D. Bioconjugate Chem. 2010, 21, 1297–
1304.
(8) It is not clear if the minor rate effect induced by the bulky stopper
groups in 5EP, 6EP, and 7EP is because they do not force the surrounding
macrocycle to adopt a flattened chair or, alternatively, the flattened chair is
not strained enough to exhibit a high rate of cycloreversion.
(12) For a discussion of how mechanical bonding can induce functional
groups to adopt high-energy conformations, see: Leigh, D. A.; Lusby, P. J.;
Slawin, A. M. Z.; Walker, D. B. Angew. Chem., Int. Ed. 2005, 44, 4557–
4564.
Org. Lett., Vol. 12, No. 21, 2010
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