"Supramolecular circuitry": Three chemiluminescent, Cucurbit[7]uril-controlled on/off switches

Article abstract of DOI:10.1021/ol201403m

Three Cucurbit[7]uril-controlled chemiluminescent on/off switches based on the lucigenin motif have been synthesized. Light emission is triggered upon addition of sodium peroxide, interrupted or dimmed in the presence of Cucurbit[7]uril, and restored upon

Full text of DOI:10.1021/ol201403m

ORGANIC
LETTERS
2011
Vol. 13, No. 15
3872–3875
“Supramolecular Circuitry”:
Three Chemiluminescent,
Cucurbit[7]uril-Controlled
On/Off Switches
Eric Masson,*,† Yasser M. Shaker,† Jean-Pierre Masson,† Martin E. Kordesch,‡ and
Citra Yuwono†
Department of Chemistry and Biochemistry and Department of Physics and Astronomy,
Ohio University, Athens, Ohio 45701, United States
masson@ohio.edu
Received May 24, 2011
ABSTRACT
Three Cucurbit[7]uril-controlled chemiluminescent on/off switches based on the lucigenin motif have been synthesized. Light emission is
triggered upon addition of sodium peroxide, interrupted or dimmed in the presence of Cucurbit[7]uril, and restored upon injection of a competitive
guest. The process, which can be mimicked by a simple resistor-capacitor circuit, is rationalized by examining the role of the macrocyclic host on
the network of equilibria involved in the chemiluminescent process.
There is an ongoing effort in the supramolecular
community to replicate biological recognition mechanisms
with smaller, less complex organic guests and hosts; one
of these mechanisms is the thermodynamically or kineti-
cally controlled stabilization of reactive species, intermedi-
ates, and otherwise unstable conformations within the
pocket of a larger host.1 While the stabilizations of
cyclobutadiene2a and benzyne2b into hemicarcerands are
now classical supramolecular landmarks, recent examples
of intermediate stabilization also include the controlled en-
capsulation of isoimides,3a hemiaminals,3b and hemiacetals.3c
In this study, we wanted to assess whether a member of
the cucurbituril family of macrocycles (CB[n]) could allos-
terically affect a network of equilibria between several
reactive species, by interacting selectively with subunits
remote from the reaction centers. CB[n]s are pumpkin-
shaped macrocycles that have generated tremendous inter-
est in the past 10 years due to their exceptional recognition
properties;4 they bear n glycoluril motifs linked by methy-
lene bridges, two hydrophilic carbonylated portals, and a
hydrophobic cavity and display the strongest noncovalent
† Department of Chemistry and Biochemistry.
‡ Department of Physics and Astronomy.
(1) For three recent reviews, see: (a) Hooley, R. J.; Rebek, J., Jr.
Chem. Biol. 2009, 16, 255. (b) Uhlenheuer, D. A.; Petkau, K.; Brunsveld,
L. Chem. Soc. Rev. 2010, 39, 2817. (c) Zayed, J. M.; Nouvel, N.;
Rauwald, U.; Scherman, O. A. Chem. Soc. Rev. 2010, 39, 2806.
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Ed. Engl. 1991, 30, 1024. (b) Warmuth, R. Angew. Chem., Int. Ed. Engl.
1997, 36, 1347.
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Hooley, R. J.; Iwasawa, T.; Rebek, J., Jr. J. Am. Chem. Soc. 2007, 129,
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L. Angew. Chem., Int. Ed. 2005, 44, 4844. (b) Liu, S.; Ruspic, C.;
Mukhopadhyay, P.; Chakrabarti, S.; Zavalij, P. Y.; Isaacs, L. J. Am.
Chem. Soc. 2005, 127, 15959. (c) Yang, C.; Ko, Y. H.; Selvapalam, N.;
Kim, H.; Sobransingh, D.; Kaifer, A. E.; Liu, S.; Isaacs, L.; Chen, W.;
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r
10.1021/ol201403m
Published on Web 06/28/2011
2011 American Chemical Society

interaction ever measured toward selected guests4c,d
(see Figure 1 for the structure of CB[7]).
1H NMR titration in a 50 mM acetate buffer (pD 4.74)
with guests4b having a known affinity toward CB[7]).9 The
characteristic10 upfield shift of hydrogen nuclei located
within the cavity of CB[7] was observed (Figure 1), and
hydrogens located close to the CB[7] rim underwent a
moderate downfield shift.10
To envisage how CB[7] may perturb the chemilumines-
cence of lucigenin derivatives 1 in the presence of alkaline
hydrogen peroxide, one should first address the degrada-
tion pathways of acridinium units, which have been in-
vestigated over the past four decades (Figure 2). Lucigenin
derivatives 1 undergo rapid reversible hydroxide and
hydroperoxide anion additions to their 9- and 90-positions,
affording species such as biacridans 2aꢀ2c, acrylidene
oxide 2d, and 1,2-dioxetane 2e.7 While those intermediates
undergo various complex nonchemiluminescent degrada-
tion processes,7 a very minor pathway is the conversion of
1,2-dioxetane 2e to biradical 3, upon electron transfer from
the nitrogen lone pair to the four-membered ring, and
concomitant OꢀO bond cleavage.11 Subsequent CꢀC
bond cleavage leads to the formation of acridone 5 and
diradical zwitterion 4; intermediate 4 then relaxes to
S1(π,π*) acridone 5* via back electron transfer and finally
to S0(π,π*) acridone 5 with emission of a photon.11
According to previous studies,7 both the rate of consump-
tionoflucigenin and the light emission decayshould follow
pseudo-first-order kinetics, with very similar rate con-
stants. Since the dynamic equilibria between lucigenin
derivatives 1 and intermediates 2 are much faster than
the formation of biradical 3 from dioxetane 2e (a pre-
equilibrium situation),11 we expected that the rate of
formation of acridone 5 could be greatly reduced, and
the light emission dimmed or even interrupted, if lucigenin
derivatives 1 were stabilized to the expense of biacridans 2
upon interaction with CB[7]. It has been reported on
several occasions, in particular by Nau12aꢀc and Maca-
rtney,12d that ammonium cations undergo a significant
pKa shift upon encapsulation by CB[n]s (usually 1.2ꢀ
4.5 pKa units), since the cation displays a greater affinity
than the neutral amine toward CB[n]s (corresponding to a
1.6ꢀ6.1 kcal/mol extra stabilization by CB[n]s). A similar
trend is expected between positively charged biacridiniums
1 and neutral biacridans 2, especially since the latter can
probably accommodate only one CB[7] unit, according to
semiempirical PM6-D optimization (Figure 3h).
Figure 1. Structure of CB[7]. 1H NMR spectra of (a) lucigenin
derivative 1c and (b) [3]pseudorotaxane 1c⊂(CB[7])2.
CB[n]/guest interactions can be readily monitored by
nuclear magnetic resonance spectroscopy (NMR), and in
some cases, these interactions are accompanied by changes
in absorption and fluorescence properties.5 However, to
the best of our knowledge, they have never been monitored
by chemiluminescence, a visually appealing phenomenon
widely applied to analytical chemistry6 in immunoassays,
in the detection of proteins, drugs, and pollutants, as well
as in the assessment of oxidative stress. This prompted us
to test whether a CB[n]-controlled light-on/light-off switch
could be developed, by perturbing the complex equilibria
between the various partners of a chemiluminescent pro-
cess. Lucigenin and their derivatives (N,N0-disubstituted-
9,90-biacridiniums; 1aꢀ1d) happen to be ideal structures
for such a project, since they are expected to interact with
CB[n]s via their N-substituents, the positively charged
acridinium surroundings interacting with the carbonylated
portal of CB[n], and the N-substituent sitting within the
cavity of the macrocycle. Cyan light is emitted upon
addition of hydrogen peroxide under basic conditions.7
Lucigenin derivatives 1bꢀ1d were prepared by N-alky-
lation of acridone, followed by zinc-promoted reductive
coupling, and oxidation of the resulting biacridylidenes
with aqueous nitric acid.8 Substituents were chosen to span
a significant range of binding affinities toward CB[7]
(1.0 ꢁ 105, 1.3 ꢁ 106, and 1.7 ꢁ 109 Mꢀ1 in the case of
guests 1bꢀ1d, respectively, as determined by competitive
As expected, upon addition of an excess amount of
sodium peroxide (total concentration 0.10 M) to a solution
of lucigenin derivatives 1aꢀ1d (1.0 mM), cyan light was
emitted (λmax = 485 nm; chemiluminescence quantum
yields (0.4ꢀ2.7) ꢁ 10ꢀ3 einstein/mol, in accordance with
(5) For two recent examples, see: (a) Wu, J; Isaacs, L. Chem.;Eur. J.
2009, 15, 11675. (b) Nau, W. M.; Ghale, G.; Hennig, A.; Bakirci, H.;
Bailey, D. M. J. Am. Chem. Soc. 2009, 131, 11558.
(6) For two recent reviews, see: (a) Powe, A. M.; Das, S.; Lowry, M.;
El-Zahab, B.; Fakayode, S. O.; Geng, M. L.; Baker, G. A.; Wang, L.;
McCarroll, M. E.; Patonay, G.; Li, M.; Aljarrah, M.; Neal, S.; Warner,
I. M. Anal. Chem. 2010, 82, 4865. (b) Gamiz-Gracia, L.; Garcia-
Campana, A. M.; Huertas-Perez, J. F.; Lara, F. J. Anal. Chim. Acta
2009, 640, 7.
(10) (a) Moon, K.; Kaifer, A. E. Org. Lett. 2004, 6, 185. (b) Lu, X.;
Masson, E. Org. Lett. 2010, 12, 2310. (c) Mock, W. L.; Shih, N. Y.
J. Org. Chem. 1986, 51, 4440.
(7) (a) Maskiewicz, R.; Sogah, D.; Bruice, T. C. J. Am. Chem. Soc.
1979, 101, 5347. (b) Maskiewicz, R.; Sogah, D.; Bruice, T. C. J. Am.
Chem. Soc. 1979, 101, 5355.
(8) (a) Papadopoulos, K.; Nikokavouras, J. J. Prakt. Chem. 1993,
335, 633. (b) Amiet, R. G. J. Chem. Educ. 1982, 59, 163.
(9) We did not detect any positive or negative binding cooperativity;
the binding constant thus represents the interaction between one CB[7]
macrocycle and any free acridinium substituent.
(11) Ciscato, L. F. M. L.; Bartoloni, F. H.; Weiss, D.; Beckert, R.;
Baader, W. J. J. Org. Chem. 2010, 75, 6574.
(12) For recent examples, see: (a) Shaikh, M.; Choudhury, S. D.;
Mohanty, J.; Bhasikuttan, A. C.; Nau, W. M.; Pal, H. Chem.;Eur. J.
2009, 15, 12362. (b) Saleh, N.; Koner, A. L.; Nau, W. M. Angew. Chem.,
Int. Ed. 2008, 47, 5398. (c) Praetorius, A.; Bailey, D. M.; Schwarzlose, T.;
Nau, W. M. Org. Lett. 2008, 10, 4089. (d) Wyman, I. W.; Macartney,
D. H. Org. Biomol. Chem. 2010, 8, 247.
Org. Lett., Vol. 13, No. 15, 2011
3873

Figure 2. Plausible chemiluminescent pathway for the decomposition of biacridiniums 1aꢀ1d, and their stabilization by CB[7]. Structure
of competitive guests 6a and 6b (trifluoromethanesulfonate as the counteranion).
previous characterizations of similar structures).13 The
emission intensity was monitored at 510 nm, at which
wavelength acridiniums 1 barely absorb the emission of
acridone 5*(Figure3a), and anexponentialintensitydecay
was observed as a function of time, at least in the case of
biacridiniums 1aꢀ1c; the decomposition of lucigenin deri-
vative 1d is clearly more complex (see Figure 3b for a
logarithmic plot of the emission intensity vs time and the
corresponding linear regressions; rates of light emission
decays are 1.8 ꢁ 10ꢀ3, 2.0 ꢁ 10ꢀ3, and 5.8 ꢁ 10ꢀ3 sꢀ1 in the
case of acridiniums 1aꢀ1c, respectively). As mentioned on
several occasions,7b,13 reaction quantum yields of acri-
dones 5 are very low (4ꢀ38%).
bilization of lucigenin derivatives 1 by CB[7] over the
transition state of the slow electron transfer from dioxe-
tane 2e to diradical 3; since the geometry of the transition
state is expected to resemble dioxetane 2e, we consider that
the stabilization of the latter by CB[7] likely mimics the
stabilization of the transition state; in other terms, rates
of electron transfers from dioxetane 2e, 2e⊂CB[7], and
2e⊂(CB[7])2 to the corresponding biradicals 3 are con-
sidered to be similar.
Addition of CB[7] to lucigenin (1a), which lacks the host
binding site, does not interrupt the chemiluminescent
reaction. To the contrary, CB[7] enhances its rate by a
factor of 1.3 (Figure 3c); unfortunately, the complexity of
the process prevents us from offering any justification for
this phenomenon.
After 2 min, CB[7] (2.0 equiv) was added to the reaction
cuvette, and light emission was immediately interrupted in
the case of lucigenin derivatives 1c and 1d and dimmed
approximately 10-fold when using biacridinium 1b, which
displaysthe weakest affinity toward CB[7] (Figure 3dꢀ3g).
Yet a series of complications prevent us from providing a
quantitative relationship between the intensity attenuation
and the binding affinity ofprecursors1 and intermediates 2
toward CB[7]: (1) binding affinities of biacridiniums 1
cannot be measured under the conditions leading to their
chemiluminescence and will differ, at least partly, from
those determined in the reference acetate buffer; (2) while
lucigenin derivatives 1c and 1d are both expected to be
doubly encapsulated by CB[7], biacridinium 1b probably
coexists as a time-dependent mixture of free, [2]-, and
[3]pseudorotaxane 1b, 1b⊂CB[7], and 1b⊂(CB[7])2; (3)
biacridans 2 are likely to be present as time-dependent
mixtures of free and monoencapsulated structures;
(4) CB[7] may also complex acridones 5 as well as various
intermediates and side products along the reaction path-
way, albeit weakly. Overall, the rate retardation of the
chemiluminescent reaction is caused by a preferential sta-
After an additional 6 min period, a competitive guest
with a very high affinity toward CB[7] was added to release
lucigenin derivatives 1bꢀ1d (xylylene 6a, binding affinity
1.5 ꢁ 1010
M
ꢀ1; adamantylpyridinium (6b), binding
affinity4b 2.0 ꢁ 1012
M
ꢀ1). The rate of the dissociationꢀ
association guest exchange process is expected to depend
on the overall free Gibbs energy difference between CB[7]-
encapsulated biacridinium 1 and the transition state of the
dissociation or the association step, whichever is at higher
energy. Consequently, (1) CB[7] was immediately ejected
from pseudorotaxanes 1b⊂CB[7] and 1b⊂(CB[7])2, and
light emission was fully restored with no intensity loss
(Figure 3d); (2) the same process was slightly slower with
[3]pseudorotaxane 1c⊂(CB[7])2 (Figure 3e and the
rounded section of the intensity profile between 480 and
500 s); (3) guest exchange with assembly 1d⊂(CB[7])2 was
significantly slower, due to the stronger affinity of CB[7]
toward thetrimethylsilyl substituent. Theeffectisparticularly
pronounced when the competitive bulky adamantyl unit
slips through the portal of CB[7], and this association is
likely the rate-determining step. One should stress that this
onꢀoffꢀon switch, which shows no intensity loss after
the 6-min long “off” period (at least in the case of
(13) Papadopoulos, K.; Spartalis, S.; Nikokavouras, J. Anal. Chim.
Acta 1994, 290, 179.
3874
Org. Lett., Vol. 13, No. 15, 2011

biacridinium 1d (Figure 3f), thereby indicating that the
latter may undergo side reactions even while encapsulated.
Finally, like many supramolecular chemists who enjoy
linking nanoscopic phenomena to macroscopic devices
(molecular “plugs and sockets”, “shuttles”, “elevators”,
and “muscles” being just a few examples),14 we found
it didactically appealing to design the simplest electro-
nic circuit possible, which would mimic our light-emitting
chemical system (Figure 3i), with one general rule: one
chemical action (addition of a reagent, for example) must
correspond to one user action on the circuit: (1) adding
sodium peroxide to a solution of biacridiniums 1 is
mimicked by activating switch P1 and charging capacitor C1
(the small resistor R1 prevents the shortcircuit of capacitor
C1 upon charging and can mimic the duration of the
sodium peroxide injection that is nonzero). When switch
S1 is in position “1”, capacitor C1 discharges through
resistor R3 and diode D1; the exponential voltage decay
at capacitor C1 is equivalent to the pseudo-first-order
intensity decay of our chemiluminescent system. (2) Add-
ing CB[7] is mimicked by switching S1 to position “2”. In
the case of a perfect switch (biacridiniums 1c and 1d), bus
B1 is open and the circuit is interrupted; to mimic the
imperfect switch with acridinium 1b, bus B1 is closed and
capacitor C1 is discharged over a large resistor R2 in addi-
tion to R3 and the diode. (3) Switching S1 to position “3”
corresponds to the injection of competitive guest 6a or 6b
to the reaction cuvette; if the guest exchange is fast
(lucigenin derivatives 1b and 1c), bus B2 is set as closed,
and capacitor C1 discharges through resistor R3 and diode
D1 again; if the exchange is relatively slow (acridinium 1d),
the progressive increase in light intensity (Figure 3f) can be
mimicked by the charge of a smaller capacitor C2 through
resistor R4 (buses B3a and B3b are closed and bus B2 is
open; resistor R5 is added to counterbalance the added
capacity and also mimics the intensity loss observed with
this switch). As long as diode D1 is replaced by a light
source with a voltage-independent resistance, red and blue
dashed lines in Figure 3dꢀ3f represent the voltage profiles
best fit to our chemiluminescence intensity measurements,
and the overlap is pleasantly satisfactory.
Figure 3. (a) Absorption (50 μM; dashed) and chemilumines-
cence spectra of biacridinium 1c (0.25, 2, 3, 5, 7, and 10 min after
peroxide injection). (b) Logarithmic plot of the light intensity
decay vs time, with linear regressions indicating pseudo-first-
order kinetics. Light emission decays of lucigenin derivatives
(c) 1a, (d) 1b, (e) 1c, and (f) 1d. CB[7] is added at t = 120 s and
competitive guests 6a (red profiles, noted ‘I’) or 6b (blue profiles,
noted ‘II’) at t = 480 s. Reference profiles (dashed, and noted
“III”) are recorded in the absence of CB[7] and competitive
guest. (g) Photographs of the on/off/on switch obtained with
lucigenin derivative 1c and competitive guest 6a. (h) PM6-D
optimized structure of dioxetane 2e⊂CB[7] (obtained from bia-
cridinium 1c). (i) Resistor-capacitor circuit mimicking the lumi-
nescence profiles of biacridiniums 1bꢀ1d.
Acknowledgment. This work was supported by the
Dept of Chemistry and Biochemistry, the College of Arts
and Sciences and the Vice President for Research at Ohio
University. We are grateful to Prof. J. J. Rack (Dept of
Chemistry and Biochemistry) and Prof. F. N. Castellano
(Dept of Chemistry, Bowling Green State University) for
allowing us to use their fluorimeter at no cost. We also
thank Prof. Castellano’s graduate student, V. Prusakova,
for her practical advice.
biacridiniums 1b and 1c; Figure 3d and 3e), is operational
only because the various nonchemiluminescent degra-
dation pathways do not target encapsulated (i.e., thermo-
dynamically stabilized) lucigenin derivatives 1 as long as
pseudobases 2 are depleted from the reaction mixture.7
Some moderate intensity loss is observed in the case of
Supporting Information Available. Preparation and
characterization of lucigenin derivatives 1bꢀ1d, their
precursors 5bꢀ5d, and their interlocked assemblies
with CB[7]; kinetic procedures, binding affinity mea-
surements, and circuit diagram. This material is avail-
able free of charge via the Internet at http://pubs.acs.
org.
(14) (a) Ishow, E.; Credi, A.; Balzani, V.; Spadola, F.; Mandolini, L.
ꢀ
Chem.;Eur. J. 1999, 5, 984. (b) Bissell, R. A.; Cordova, E.; Kaifer,
ꢀ
A. E.; Stoddart, J. F. Nature 1994, 369, 133. (c) Badjic, J. D.; Balzani, V.;
Credi, A.; Lowe, J. N.; Silvi, S.; Stoddart, J. F. Chem.;Eur. J. 2004, 10,
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