Flavin-based [2]rotaxanes

Article abstract of DOI:10.1021/ol060620q

We report the synthesis of flavin-stoppered hydrogen bonded [2]rotaxanes 1 and 2. We also report the electrochemically controllable properties of these systems in solution, and for derivative 2, as an electropolymerized thin film.

Full text of DOI:10.1021/ol060620q

ORGANIC
LETTERS
2006
Vol. 8, No. 11
2297-2300
Flavin-Based [2]Rotaxanes
Graeme Cooke,*,† James F. Garety,† Brian Jordan,‡ Nadiya Kryvokhyzha,†
Andy Parkin,† Gouher Rabani,† and Vincent M. Rotello‡
WestCHEM, Department of Chemistry, Joseph Black Building, UniVersity of Glasgow,
Glasgow G12 8QQ, United Kingdom, and Department of Chemistry, UniVersity of
Massachusetts at Amherst, Amherst, Massachusetts 01002
graemec@chem.gla.ac.uk
Received March 14, 2006
ABSTRACT
We report the synthesis of flavin-stoppered hydrogen bonded [2]rotaxanes 1 and 2. We also report the electrochemically controllable properties
of these systems in solution, and for derivative 2, as an electropolymerized thin film.
Molecular machine-like processes are ubiquitous in biological
systems, inspiring chemists to create synthetic mimics that
have the ability to undergo controlled molecular motion.1
For example, hydrogen bonded rotaxanes have become
important systems for the development of chemically,2
photochemically,3 and electrochemically4 controllable mo-
lecular machines. Although a wide range of moieties have
been incorporated into the rotaxane architecture to induce
and detect translational motion, there remains considerable
scope for incorporating new moieties to improve and extend
their functions. A particularly attractive building block for
incorporation into the axle unit is the biologically significant
flavin unit, due to the electrochemically controllable hydro-
gen bonding properties,5 tunable redox and recognition
properties,6 and interesting optical properties of this moiety.
Here, we report the synthesis of flavin-based rotaxanes 1
and 2 and their electrochemical properties in solution, and
in the case of 2, as an electropolymerized thin film.
Rotaxanes 1 and 2 were synthesized in reasonable yield using
standard clipping methodologies as described in Scheme 1
and the Supporting Information. The rotaxanes had limited
solubility in nonpolar solvents (e.g., chloroform, dichlo-
romethane); however, good solubility was observed in more
polar solvents, such as tetrahydrofuran and dimethyl sulfox-
ide. MALDI and low resolution fast-atom bombardment mass
spectrometry, respectively, confirmed rotaxane structure for
1 ([M+] 1254) and 2 ([M+] 1332). Slow crystallization of
rotaxane 2 from methanol provided crystals of sufficient
† University of Glasgow.
‡ University of Massachusetts.
(1) Venturi, M.; Credi, A.; Balzani, V. Molecular DeVices and Ma-
chines: A Journey into the Nanoworld; Wiley-VCH: Weinheim, Germany,
2003.
(2) For examples, see: (a) Lane, A. S.; Leigh, D. A.; Murphy, A. J.
Am. Chem. Soc. 1997, 119, 11092-11093. (b) Gong, C.; Gibson, H. W.
Angew. Chem., Int Ed. Engl. 1997, 36, 2331-2333. (c) Jimonez-Molero,
M. C.; Dietrich-Buchecker, C.; Sauvage J.-P. Angew. Chem., Int. Ed. 2000,
39, 3284-3287.
(3) For examples, see: (a) Wurpel, G. W. H.; Brouwer, A. M.; van
Stockkum, I. H. M.; Farran, A.; Leigh, D. A. J. Am. Chem. Soc. 2001, 123,
11327-11328. (b) Altieri, A.; Bottari, G.; Dehez, F.; Leigh, D. A.; Wong,
J. K. Y.; Zerbetto, F. Angew. Chem., Int. Ed. 2003, 42, 2296-2300. (c)
Brouwer, A. M.; Frochot, C.; Gatti, F. G.; Leigh, D. A.; Mottier, L.;
Paolucci, F.; Roffia, S.; Wurpel, G. W. H. Science 2001, 291, 2124-2128.
(4) 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.
(5) Breinlinger, E.; Niemz, A.; Rotello, V. M. J. Am. Chem. Soc. 1995,
117, 5379-5380.
(6) Legrand, Y. M.; Gray, M.; Cooke, G.; Rotello, V. M. J. Am. Chem.
Soc. 2003, 125, 15789-15795.
10.1021/ol060620q CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/28/2006

1H NMR spectroscopy was used to gain insight into the
structure of rotaxanes 1 and 2 in solution. It has been
previously shown that this technique is a useful tool for
studying translational motion in rotaxanes, as aromatic ring
currents in the p-xylylene rings result in significant upfield
shifts in the portion of the axle covered by the macrocycle.7
Due to their limited solubility in nonpolar solvents, the NMR
spectra of rotaxanes 1 and 2 and their corresponding
macrocycle-free axles 7 and 10 were recorded in d8-THF
and d6-DMSO. For both rotaxanes, the chemical shifts of
the succinyl methylene protons were positioned significantly
more upfield than the corresponding protons of their axles
(1 ∆δH: a-a′ and b-b′ ) -1.4 ppm; 2 ∆δH: c-c′ and
d-d′ ) -1.4 ppm in d8-THF). Furthermore, even in DMSO,
which is a competitive solvent for hydrogen bonding
interactions, significant upfield shifts for the succinyl me-
thylene protons were observed (1 ∆δH: a-a′ and b-b′ )
-1.1 ppm; 2 ∆δH: c-c′ and d-d′ ) -1.1 ppm in
d6-DMSO) (see Supporting Information). Thus the NMR data
are consistent with good positional integrity of the wheel
over the succinyl station in these diverse environments. For
both rotaxanes in d8-THF and d6-DMSO, protons in close
proximity to the succinamide NH protons of the station were
also slightly shielded compared to the spectra of their
corresponding axle units.
Scheme 1. Synthesis of Rotaxanes 1 and 2
One of the attractive rationales for incorporating flavin
derivatives into rotaxane architectures is the ability of this
unit to undergo electrochemically tunable hydrogen bonding
interactions with complementary guests.8 Reduction of the
flavin unit to its radical anion (Fl•-) state results in a
significant increase in hydrogen bonding efficiency of their
complexes, due to an increase in electronegativity of the
oxygens of their carbonyl moieties. Therefore, for rotaxanes
1 or 2, we anticipated that electrochemical generation of the
Fl•- species should result in the redox-driven translocation
of the macrocycle from the succinyl moiety to the reduced
flavin species.
quality for X-ray structure determination. The X-ray structure
of 2 is shown in Figure 1 and clearly proves rotaxane
To test this hypothesis, we recorded the solution electro-
chemistry of rotaxanes 1 and 2 and their corresponding axle
units 7 and 10.9 Comparing the cyclic voltammetry of both
rotaxanes with their axle units revealed similar fairly
complicated electrochemical behavior resulting from multiple
redox waves. However, cycling up to -1.0 V (versus Ag/
AgCl) resulted in clearly defined redox waves for the flavin
moiety. In both cases, square wave voltammetry showed
significant stabilization (+90 mV) of the Fl•- state for
rotaxanes 1 and 2 (compared to the flavin units of the their
corresponding axle), indicating that the flavin moiety be-
Figure 1. X-ray crystal structure of 2.
(7) Johnston, A. G.; Leigh, D. A.; Murphy, A.; Smart, J. P.; Deegan, M.
D. J. Am. Chem. Soc. 1996, 118, 10662-10663.
formation. The macrocycle forms bifurcated hydrogen bonds
to the carbonyl oxygens of the succinamide group of the
axle through three hydrogen bonds. The fourth NH moiety
appears not to participate in hydrogen bonding to this axle
unit; however, hydrogen bonding interactions are observed
to a carbonyl group of an adjacent macrocycle. Interestingly,
the macrocycle appears to adopt a boat-like confirmation,
presumably due to the steric influence of the adjacent 2,5-
dithienylpyrrole stopper.
(8) Rotello, V. M.; Niemz, A. Acc. Chem. Res. 1999, 32, 44-52.
(9) All electrochemical experiments were performed using a CH Instru-
ments 620A electrochemical workstation. The electrolyte solution (0.1 M)
-
was prepared from recrystallized Bu4N+PF6 using either dry THF for
reductive scans or acetonitrile and toluene for electropolymerization
processes. The solution was rigorously purged with nitrogen prior to use,
and all electrochemical data were recorded under a nitrogen atmosphere.
A three-electrode configuration was used with a platinum disk (2 mm
diameter) working electrode, with either a silver wire pseudoreference
electrode or a Ag/AgCl reference electrode. A platinum wire was used as
the counter electrode.
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Org. Lett., Vol. 8, No. 11, 2006

comes hydrogen bonded to the macrocycle unit upon
reduction of the flavin (Figure 2). Due to the fairly rigid
Figure 3. Cyclic voltammogram showing electropolymerization
of 2 (from a ∼1 × 10-4 M solution in toluene/acetonitrile, 1:1)
onto a platinum working electrode (versus Ag/AgCl). Scan rate )
500 mV s-1; 4 cycles.
Figure 2. Square wave voltammograms of 2 (s) and 10 (‚ ‚ ‚)
(∼1 × 10-4 M) recorded in THF (0.1 M Bu4NPF6) (versus Ag/
AgCl).
decided to limit the number of potentiodynamic scans to 4
cycles to both encourage clearly defined electropolymeriza-
tion processes and help prevent multilayer architectures
occurring in the resulting polymer films.
nature of the axle moieties, it is likely that the electrochemical
data arise from the redox-induced translocation of the
macrocycle from the succinyl moiety to the Fl•- moiety,4
rather than a bending of the axle unit to accommodate Fl•--
macrocycle hydrogen bond formation.10
After washing the flavin-functionalized working electrodes
with copious amounts of acetone and allowing the polymer
films to dry in air, the electrodes were placed into a 0.1 M
-
solution of Bu4N+PF6 in THF and their cyclic and square
With electrochemically tunable interactions confirmed for
rotaxanes 1 and 2 in solution, we next turned our attention
onto whether we could exploit the ability of the 2,5-
dithienylpyrrole unit of 2 and 10 to produce flavin-func-
tionalized electrodes,11 as the transferal of solution-based
molecular machines to the solid state is a vital next step for
the development of pragmatic functional systems.12 Flavin-
functionalized electrodes were formed by the dynamic
electropolymerization of 2 or 10 onto a platinum disk
electrode (see Figure 3 and Supporting Information). The
electropolymerizations from a solution in CH3CN/toluene
(1:1) resulted in the appearance of a new redox wave centered
around +0.15 V. Interestingly, the presence of the macro-
cyclic wheel did not significantly influence the electro-
polymerization process, as the half-wave potential of the
developing polymer backbones were essentially the same.
In accordance with previously reported data for the electro-
polymerization of 2,5-dithienylpyrroles, polymer growth
appeared to stop after a few redox cycles.13 Therefore, we
wave voltammetries were recorded between 0.2 and -0.9
V (see Figure 4 and Supporting Information). The poly-
(10) Experiments are underway in our laboratory on related compounds
to investigate whether redox-induced shuttling occurs in rotaxanes of this
type. The results from these investigations will be reported in due course.
(11) For examples of flavins electropolymerized onto electrode surfaces,
see: (a) Cosnier, S.; De´cout, J.-L.; Fontecave, M.; Frier, C.; Innocent, C.
Electroanal. 1998, 10, 521-525. (b) Ivanova, Y. N.; Karyakin, A. A.;
Electrochem. Commun. 2004, 6, 120-125. (c) Cooke, G.; Garety, J. F.;
Mabruk, S.; Rotello, V. M.; Surpateanu, G.; Woisel, P. Chem. Commun.
2004, 2722-2723.
Figure 4. CVs of electropolymerized 10 (following four elec-
tropolymerization cycles from acetonitrile/toluene) recorded in THF
(0.1 M Bu4NPF6). Scan rate ) 1 (largest current), 0.8, 0.6, 0.4, 0.2
(smallest current) Vs-1. ∆Efwhm ) 0.15 V, 9.5 × 10-7 C, Γ ) 9.8
× 10-12 mol cm-2 (using 1 Vs-1 scan rate) (versus Ag/AgCl).
(12) (a) Chia, S.; Cao, J.; Stoddart, J. F.; Zink, J. I. Angew. Chem., Int.
Ed. 2001, 40, 2447-2451. (b) Cooke, G. Angew. Chem., Int. Ed. 2003, 42,
4860-4870.
merization process gave rise to a single redox wave in their
cyclic voltammograms (between these voltages), presumably
Org. Lett., Vol. 8, No. 11, 2006
2299

due to the formation of the flavin radical anion species, 2rad
-
or 10rad-, respectively, within the polymer films. The CVs
of electropolymerized thin films of 2 or 10 recorded at
different scan rates displayed a linear increase in current with
scan rate for the flavin reduction process, which is indicative
of surface-confined behavior. The monolayers proved to be
reasonably stable, displaying a similar current/voltage re-
sponse for more than 10 scan cycles. The estimated surface
coverages of the electropolymerized films of 2 (Γ ) 2.5 ×
10-12 mol cm-2) or 10 (Γ ) 9.8 × 10-12 mol cm-2)
(polymerized from a 1 × 10-4 M solution in CH3CN/
toluene), calculated from the average charge recorded under
the reduction wave of the flavin, are consistent with a
submonolayer coverage.
We have investigated the redox properties of the films
using square wave voltammetry (SWV). The data for the
surface-confined 2 and 10 are consistent with their square
wave data recorded in solution (Figure 5); however, only a
+20-30 mV shift of the redox wave corresponding to the
2rad- state was observed (compared to data obtained for the
formation of 10rad-), indicating that the electropolymeriza-
tion process diminishes hydrogen bond-mediated stabilization
of 2rad-, presumably due to steric effects within the film.
Furthermore, the polymerization process seems to promote
the formation of a second redox wave at -0.25 V, which is
presumably due to inter- or intramolecular proton transfer.5
In summary, we have described a new class of electro-
chemically tunable rotaxanes incorporating a flavin moiety.
We have shown that electrochemical reduction of the flavin
unit results in significant stabilization of the flavin radical
anion state of the axle moiety in the solution state, and to a
lesser extent at the solid-liquid interface of an electro-
polymerized thin film. We are currently exploiting the
Figure 5. Square wave voltammograms of electropolymerized thin
films of 2 (s) and 10 (‚ ‚ ‚) (versus Ag/AgCl).
tunable electrochemical properties and interesting fluores-
cence properties of the flavin unit to synthesize the next
generation of flavin rotaxanes. Our endeavors in these areas
will be reported in due course.
Acknowledgment. G.C. acknowledges the EPSRC and
ORS for funding this work. B.J.J. thanks the NSF for an
IGERT fellowship (DUE-044852), and V.R. acknowledges
the NSF (CHE-0518487).
Supporting Information Available: Synthetic procedures
and characterization of all new compounds. Electrochemical
data and X-ray crystal structure data. This material is
available free of charge via the Internet at http://pubs.acs.org.
(13) Audebert, P.; Sadki, S.; Miomandre, F.; Hapiot, P.; Chane-Ching,
K. New J. Chem. 2003, 27, 798-804.
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