A chemically-driven molecular information ratchet

Article abstract of DOI:10.1021/ja7102394

A chemically driven molecular information ratchet is described. The equilibrium macrocycle distribution in a [2]rotaxane is driven away from its 50:50 population of thread binding sites to a 33:67 ratio by benzoylation under the influence of a chiral cata

Full text of DOI:10.1021/ja7102394

Published on Web 01/18/2008
A Chemically-Driven Molecular Information Ratchet
Mo´nica Alvarez-Pe´rez,† Stephen M. Goldup,† David A. Leigh,*,† and Alexandra M. Z. Slawin‡
School of Chemistry, UniVersity of Edinburgh, The King’s Buildings, West Mains Road, Edinburgh, EH9 3JJ, U.K.,
and the School of Chemistry, UniVersity of St. Andrews, Purdie Building, St. Andrews, Fife, KY16 9ST, U.K.
Received November 12, 2007; E-mail: david.leigh@ed.ac.uk
An information ratchet1 is a basic class of Brownian ratchet
mechanism2 in which a barrier is raised or lowered according to
Scheme 1. Dynamic Kinetic Resolution of a [2]Rotaxane via an
Information Ratchet Mechanisma
the position of a Brownian particle on a potential energy surface,
resulting in the particle distribution being directionally driven away
from equilibrium.3 More than a century of analysis4 of Maxwell’s
celebrated “demon” thought experiment5 (the information ratchet
in its most fundamental form) has shown that for the information
transfer that triggers the change in barrier height to be useful an
energy input is required to avoid falling foul of the Second Law of
Thermodynamics.6 Finding ways of introducing ratchet mechanisms
into molecular-level structures is central to the invention of
functional synthetic molecular machine systems more complex than
simple switches.3,7 Recently, an information ratchet mechanism was
experimentally demonstrated8 with a rotaxane, using photosensitized
energy transfer between the ring and a stilbene unit on the thread
as the key step in changing the macrocycle distribution between
two thread binding sites (“stations”) from the equilibrium value of
65:35 to 45:55 without the binding affinity of the ring for either
station ever varying. Here we report on a very different approach
to a molecular information ratchet mechanism, in this case fueled
solely by chemical energy. The position of the macrocycle in a
rotaxane-based molecular shuttle is used to affect the rate at which
a bulky ester is introduced between two stations on the thread. Once
in place the ester provides a steric barrier trapping the ring on one
side or the other. For rotaxane 1, with two identical stations, the
macrocycle distribution changes from 50:50 to 33:67 (Scheme 1);
for rotaxane (R)-6, with nonidentical stations, it can be driven from
74:26 to 63:37 (Scheme 2). The former corresponds to a dynamic
kinetic resolution of a rotaxane with 34% ee.
Symmetrical bisfumaramide rotaxane 1 and an isotopomer, (S)-
2, in which one of the fumaramide stations is deuterated to provide
an NMR probe of the macrocycle’s position, were prepared in 12
and 17 steps, respectively, from (S)-3-amino-1,2-propanediol (see
Supporting Information). The X-ray crystal structure of 1 (Figure
1) shows four-point hydrogen bonding between the benzylic amide
macrocycle and a single fumaramide group on the thread.9 The
interstation spacer was chosen to inhibit both folding and macro-
cycle-bridging-two-stations motifs12 so as to favor such macrocycle-
to-one-station binding13 in solution. The short distance between the
a Reagents and conditions: Bz2O (2 equiv), Et3N (2 equiv), DMAP or
(S)-3 or (R)-3 (2 equiv), CH2Cl2, room temp, 8 h.
prochiral hydroxyl and the fumaramide groups ensures that mac-
rocycle occupancy of either station in the rotaxane produces a well-
expressed chiral environment at the OH group (Figure 1).
The room temperature H NMR spectrum of (S)-2 (Figure 2b)
confirms that the macrocycle moves rapidly between the two
fumaramide groups on the NMR time scale in 1:1 CDCl3-CD3-
OD and resides on each station with equal frequency and probability
(the shielding of Hh and Hi by the xylylene units of the macrocycle
is half that observed13 in related rotaxanes possessing only one
lation of either 1 or (S)-2 in the presence of chiral catalyst (S)-315
fumaramide unit). Benzoylation (Scheme 1, conditions a) of the
(Scheme 1, conditions b) generated product mixtures with unequal
free hydroxyl group of 1 or (S)-2 with the achiral acylation catalyst
4-dimethylaminopyridine (DMAP) gave the benzoylated rotaxanes
with the macrocycles trapped in equal numbers on either side of
the bulky ester barrier (i.e., 50:50 (R)/(S)-4, as evidenced by chiral
1
HPLC, see Supporting Information; and 50:50 FumH2-(S)-5/FumD2-
1
(S)-5,14 as evidenced by H NMR, Figure 2c). However, benzoy-
populations of macrocycles on the binding sites: 33:67 (R):(S)-
411,16 (see Supporting Information) and 33:67 FumH2-(S)-5/FumD2-
† University of Edinburgh.
‡ University of St. Andrews.
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10.1021/ja7102394 CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Ratcheting a Macrocycle Enthalpically Uphill Using a
Chemically-Driven Information Ratcheta
1
Figure 2. Partial H NMR spectra (400 MHz, 1:1 CDCl3-CD3OD, 300
K) of (a) thread, (b) rotaxane (S)-2, (c) 50:50 FumH2-(S)-5/FumD2-(S)-5
produced with DMAP as catalyst (Scheme 1, conditions a), (d) 33:67
FumH2-(S)-5/FumD2-(S)-5 produced with chiral catalyst (S)-3 (Scheme 1,
conditions b) and (e) 67:33 FumH2-(S)-5/FumD2-(S)-5 produced with chiral
catalyst (R)-3 (Scheme 1, conditions c). Residual solvent peaks are shown
in gray. For full spectral assignments, see the Supporting Information.
the occupancy of the deuterated and nondeuterated fumaramide
stations (Figure 2e).
a Reagents and conditions: Bz2O (2 equiv), Et3N (2 equiv), DMAP or
The difference between the 50:50 (R)/(S)-4 mixture and the 33:
67 (R)/(S)-4 mixture corresponds to a decrease in entropy for the
macrocycle distribution, but the enthalpy of macrocycle-thread
interactions is unaffected in the symmetrical information ratchet
(the fumaramide units are chemically identical in (R)- and (S)-4
and essentially the same in (S)-5). To drive the macrocycle
enthalpically uphill it is necessary to use dissimilar stations and
transport some of the macrocycles from a stronger binding site to
a weaker one. The spatial asymmetry which causes the information
ratchet mechanism to operate in Scheme 1 is not exclusively a
property of enantiomers or pseudoenantiomers; any shuttle in which
the position of the macrocycle enhances asymmetry about a reactive
center can, in principle, be used to alter the macrocycle distribution
between dynamically exchanging co-conformers.19
This was demonstrated (Scheme 2) using nonsymmetrical
molecular shuttle (R)-6,20 a rotaxane containing one fumaramide
group and one succinamide group, a weaker binding station for
the benzylic amide macrocycle because it lacks the preorganization
of the hydrogen-bonding sites imparted by the trans olefin.21 The
shielding of the fumaramide protons in (R)-6 (Figure 3b) compared
to those in the corresponding thread (Figure 3a), suggests that the
equilibrium distribution of the macrocycle between the fumaramide
and succinamide sites is ∼75:25. Consistent with this, benzoylation
of (R)-6 in the presence of DMAP (Scheme 2, conditions a) afforded
a 74:26 Fum-(R)-7/Succ-(R)-7 ratio. Carrying out the reaction in
the presence of (S)-3 (Scheme 2, conditions b), however, whose
efficacy in catalyzing the rate of benzoylation of 1 and (S)-2 had
proven sensitive to the position of the macrocycle, the Fum-(R)-
(S)-3 or (R)-3 (2 equiv), CH2Cl2, room temp, 8 h.
Figure 1. X-ray crystal structure of molecular shuttle 1.9 Macrocycle
occupancy of either fumaramide unit produces a well-expressed chiral
environment at the OH group (in an equal and opposite sense to that
generated by macrocycle occupancy of the other fumaramide). The
enantiomeric co-conformers10 are present in equal amounts in the unit cell.
(S)-5 (Figure 2d).17 Clearly the chiral catalyst, through its N-ben-
zoylated reactive intermediate, is able to discriminate between the
two enantiomeric co-conformers of 1 which interconvert through
the macrocycle shuttling between the fumaramide stations, and
acylates the hydroxyl group more rapidly when the macrocycle is
on the pro-S fumaramide group (and the equivalent FumD2 site in
(S)-2).18 Use of the antipode catalyst for the benzoylation of (S)-2
(Scheme 1, conditions c), afforded equal and opposite biasing of
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C O M M U N I C A T I O N S
Supporting Information Available: Experimental details and
spectroscopic data for the rotaxanes, their precursors, and the operation
of the molecular information ratchets. This material is available free
of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Astumian, R. D.; Dere´nyi, I. Eur. Biophys. J. 1998, 27, 474-489. (b)
Parmeggiani, A.; Ju¨licher, F.; Ajdari, A.; Prost, J. Phys. ReV. E 1999, 60,
2127-2140. (c) Parrondo, J. M. R.; De Cisneros, B. J. Appl. Phys. A
2002, 75, 179-191.
(2) The other basic class of Brownian ratchet mechanism is an energy ratchet
(see ref 3), in which directional transport of a Brownian particle is caused
by periodic or random switching (irrespective of the particle position)
between two or more potential energy surfaces. For a rotaxane-based two-
compartment molecular energy ratchet, see: (a) 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: (b) Leigh, D. A.; Wong, J. K. Y.; Dehez, F.; Zerbetto,
F. Nature 2003, 424, 174-179. (c) Herna´ndez, J. V.; Kay, E. R.; Leigh,
D. A. Science 2004, 306, 1532-1537. For other types of small molecule
ratchets and rotary motors, see: (d) Kelly, T. R.; De Silva, H.; Silva, R.
A. Nature 1999, 401, 150-152. (e) Koumura, N.; Zijlstra, R. W. J.; van
Delden, R. A.; Harada, N.; Feringa, B. L. Nature 1999, 401, 152-155.
(f) Fletcher, S. P.; Dumur, F.; Pollard, M. M.; Feringa, B. L. Science
2005, 310, 80-82.
1
Figure 3. Partial H NMR spectra (400 MHz, 1:1 CDCl3-CD3OD, 300
K) of (a) thread, (b) rotaxane (R)-6, (c) mixture of Fum-(R)-7 and Succ-
(R)-7 produced with (S)-3 (Scheme 2, conditions b). Residual solvent peaks
are shown in gray. For full spectral assignments of purified samples of
Fum-(R)-7 and Succ-(R)-7, see the Supporting Information.
(3) (a) Kay, E. R.; Leigh, D. A.; Zerbetto, F. Angew. Chem., Int. Ed. 2007,
46, 72-191. (b) Astumian, R. D. Phys. Chem. Chem. Phys. 2007, 9,
5067-5083.
(4) Maxwell’s Demon 2. Entropy, classical and quantum information,
computing; Leff, H. S., Rex, A. F., Eds.; Institute of Physics Publishing:
Bristol, U.K., 2003.
(5) Maxwell, J. C. Theory of Heat; Longmans, Green and Co.: London, U.K.,
1871; Chapter 22.
(6) Bennett, C. H. Int. J. Theor. Phys. 1982, 21, 905-940.
(7) Kay, E. R.; Leigh, D. A. Nature 2006, 440, 286-287.
(8) Serreli, V.; Lee, C.-F.; Kay, E. R.; Leigh, D. A. Nature 2007, 445, 523-
527.
(9) Details of the X-ray crystal structure of 1 are provided in the Supporting
Information.
(10) “Co-conformers” differ in the relative positions of mechanically interlocked
and/or noncovalently bonded components, see: Fyfe, M. C. T.; Glink, P.
T.; Menzer, S.; Stoddart, J. F.; White, A. J. P.; Williams, D. J. Angew.
Chem., Int. Ed. Engl. 1997, 36, 2068-2070.
(11) In assigning (R)- and (S)-4 we follow the conventions [(a) Schill, G.
Catenanes, Rotaxanes, and Knots; Academic Press: New York, 1971.
(b) Safarowsky, O.; Windisch, B.; Mohry, A.; Vo¨gtle, F. J. Prakt. Chem.
2000, 342, 437-444] that (i) covalent bonding takes precedence over
mechanical bonding and (ii) the region of the thread to which a macrocycle
is localized is higher priority than one that it is not.
(12) Bottari, G.; Dehez, F.; Leigh, D. A.; Nash, P. J.; Pe´rez, E. M.; Wong, J.
K. Y.; Zerbetto, F. Angew. Chem., Int. Ed. 2003, 42, 5886-5889.
(13) (a) 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. (b) Kay,
E. R.; Leigh, D. A. Top. Curr. Chem. 2005, 262, 133-177.
(14) The italicized prefixes Fum-, Succ-, FumH2- and FumD2- denote the
position of the macrocycle on the thread.
(15) Da´laigh, C. OÄ .; Hynes, S. J.; O’Brien, J. E.; McCabe, T.; Maher, D. J.;
Watson, G. W.; Connon, S. J. Org. Biomol. Chem. 2006, 4, 2785-2793.
(16) Absolute configurations assigned by analogy to the FumH2:FumD2 ratio
found for (S)-5.
7/Succ-(R)-7 ratio was reduced to 63:37 (Figure 3c).22 In other
words, approximately 15% of the net number of macrocycles that
were positioned on the fumaramide site in (R)-6 at equilibrium were
transported enthalpically uphill to the succinamide unit by the
chemically driven information ratchet. Unlike an energy ratchet
mechanism performing a similar task,2a at no stage does a
thermodynamic driving force exist for the Fum/Succ ring ratio to
be decreased. It happens solely through the kinetics of the chemical
reaction selectively trapping the macrocycle in a thermodynamically
unfavorable position. Conversely, use of the “mismatched” enan-
tiomer of catalyst 3 with (R)-6 (Scheme 2, conditions c) results in
an increase in the macrocycle occupancy of the fumaramide station
(from 74% to 80%).
In conclusion we have demonstrated a functioning molecular
information ratchet mechanism fueled by the energy that comes
from an acylation reaction that is sensitive to the position of a
dynamically exchanging substrate. The ratchet is exemplified by
driving the macrocycle distribution away from its equilibrium
position in both symmetrical and unsymmetrical rotaxane-based
molecular shuttles. The former corresponds to a dynamic kinetic
resolution of the rotaxane, the latter to driving macrocycles
enthalpically uphill; in both cases the change occurs without the
binding affinity of the macrocycle for the different regions of the
thread ever varying and the net direction of the ring movement is
determined by the handedness of the catalyst used. Such a
mechanism could be used as the “engine” for an autonomous
molecular motor which moves a substrate directionally as long as
a chemical fuel is available.
(17) For asymmetric synthesis of a rotaxane (4.4% ee), see: Makita, Y.; Kihara,
N.; Nakakoji, N.; Takata, T.; Inagaki, S.; Yamamoto, C.; Okamoto, Y.
Chem. Lett. 2007, 36, 162-163.
(18) Variation of catalyst loading and lowering the temperature did not alter
the selectivity of the process while necessitating longer reaction times.
(19) Note that the consumption of a chemical fuel is required to drive the
macrocycle distribution away from its equilibrium value. Treatment of 4,
(S)-5, or (R)-7 solely with a reversible chiral transesterifcation catalyst
would not lead to a decrease in the entropy of the macrocycle distribution.
(20) For the synthesis of (R)-6, see Supporting Information.
(21) Altieri, A.; Bottari, G.; Dehez, F.; Leigh, D. A.; Wong, J. K. Y.; Zerbetto,
F. Angew. Chem., Int. Ed. 2003, 42, 2296-2300.
(22) For diastereomeric co-conformers such as Fum-(R)-6 and Succ-(R)-6, the
position-discriminating reagent or catalyst does not necessarily have to
be chiral. However, the steric and chemical space around the hydroxyl
group in the two macrocycle translational co-conformers of (R)-6 is
obviously very similar to that of 1. Since (S)-3 discriminates well between
the macrocycle positions in 1, and with the desired directional bias, it
was also expected to do so for (R)-6.
Acknowledgment. This work was supported by the EPSRC.
We thank the Principado de Asturias government for a Fellowship
(to M.A.-P.), Regis Technologies Inc. (MA) for chiral HPLC
analyses, the EPSRC National Mass Spectrometry Service Centre
(Swansea, U.K.) for accurate mass data, and Dr. E. R. Kay for
many useful discussions.
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