A three-compartment chemically-driven molecular information ratchet

Article abstract of DOI:10.1021/ja302711z

We describe a three-compartment rotaxane information ratchet in which the macrocycle can be directionally transported in either direction along an achiral (disregarding isotopic labeling) track. Chiral DMAP-based catalysts promote a benzoylation reaction that ratchets the displacement of the macrocycle, transporting it predominantly to a particular end compartment determined by the handedness of the catalyst.

Full text of DOI:10.1021/ja302711z

Communication
pubs.acs.org/JACS
A Three-Compartment Chemically-Driven Molecular Information
Ratchet
Armando Carlone,† Stephen M. Goldup,† Nathalie Lebrasseur,† David A. Leigh,*,†,‡ and Adam Wilson†
†School of Chemistry, University of Edinburgh, The King’s Buildings, West Mains Road, Edinburgh, EH9 3JJ, U.K.
‡School of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PL, U.K.
S
* Supporting Information
Scheme 1. Directional Transport of a Macrocycle within a
ABSTRACT: We describe a three-compartment rotaxane
information ratchet in which the macrocycle can be
directionally transported in either direction along an
achiral (disregarding isotopic labeling) track. Chiral
DMAP-based catalysts promote a benzoylation reaction
that ratchets the displacement of the macrocycle, trans-
porting it predominantly to a particular end compartment
determined by the handedness of the catalyst.
[2]Rotaxane Three-Compartment Chemical Information
a
Ratchet
ynthetic chemists have developed many different types of
S
molecular switches.1 However, simple positional changes of
the components of molecular machines are insufficient for
directional transport to occur progressively, or work to be done
cumulatively.1a,2 The advance from switch1b to motor3 requires
a ratchet mechanism1a,2−5 that prevents the work that is done
in one step being undone as the machine is reset. Here we
describe a rotaxane information ratchet system4 that is able to
directionally transport a macrocycle to either end of an
essentially achiral track with three ‘compartments’. The two end
compartments are identical (and the rotaxane thread has a
point of inversion) other than for isotopic labels that are used
to distinguish the compartments for analytical purposes,6 and
yet the macrocycle can be efficiently driven to either end of the
track (>70:1 between the end compartments, with 21−25% of
the rings remaining in the center compartment) by
benzoylation reactions in the presence of a chiral catalyst.
This is fundamentally different1a to rotaxane molecular
shuttles7 that can only switch the ring between chemically
different binding sites (achieved by changing the relative
strengths of the macrocycle-thread interactions at the different
sites).
The design of the three-compartment molecular information
ratchet (1, Scheme 1) is based on a [2]rotaxane in which the
distribution of the macrocycle between two compartments can
be biased using a chiral-catalyst-promoted acylation reaction.4b
The interbinding site spacers of 1 were chosen to inhibit axle
folding and disfavor the macrocycle binding to more than one
fumaramide group at a time.8 In 1, the macrocycle is able to
shuttle freely between the three compartments separated by the
hydroxyl groups. Subsequent benzoylation of the hydroxyl
groups provides steric barriers that the macrocycle cannot pass
over, trapping the ring in one of three compartments (Scheme
1).
a
Reagents and conditions: BzCl (4 equiv), NEt3 (4 equiv), (S)-2 or
(R)-2 or DMAP or 50:50 (S)/(R)-2 mixture (4 equiv), CH2Cl2, 10
mM, rt, 2 h.
When diol 1 was treated with benzoyl chloride and triethyl-
amine in the presence of chiral acylation catalyst (S)-29
(Scheme 1, conditions a), the macrocycle was predominantly
[2]Rotaxane diol 1 was prepared in 13 steps from (R)-3-
amino-1,2-propanediol (see the Supporting Information).
Received: March 20, 2012
Published: April 23, 2012
© 2012 American Chemical Society
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Communication
trapped in the right-hand10 compartment (<1:21:79 left-4/
center-4/right-4) via monobenzolyated intermediates such as 3.
Use of the antipode catalyst, (R)-2, led to an equal and
opposite distribution, showing that the direction of net
transport depends on the handedness of the chiral catalyst
(Scheme 1, conditions b). Benzoylation of 1 with the achiral
acylation catalyst 4-dimethylaminopyridine (DMAP) yielded
the benzoylated rotaxane with the macrocycle trapped
preferentially in the two end compartments (Scheme 1,
conditions c), the sites thermodynamically favored by the
macrocycle in 1. Given that the achiral catalyst favors the end
compartments, it is perhaps somewhat counterintuitive that the
use of racemic 2 (Scheme 1, conditions d) favors the center
compartment.
a
Scheme 2. Benzoylation of [2]Rotaxane 5 at a Single Site
a
Reagents and conditions: BzCl (2 equiv), NEt3 (2 equiv), (S)-2 or
(R)-2 or DMAP or 50:50 (S)/(R)-2 mixture (2 equiv), CH2Cl2, 10
mM, rt, 2 h.
Benzoylation of 5 in the presence of DMAP resulted in a
64:36 left-4/center-4 ratio (Scheme 2, conditions c), again
demonstrating that the macrocycle has a thermodynamic
preference for the end compartments; this bias must be
overcome during the ratcheting process using the chiral catalyst
to directionally transport the macrocycle. Use of (S)-2 and (R)-
2 in the benzoylation of 5 gave left-/center-product ratios that
were oppositely biased but not equal (13:87 and 96:4 left-4/
center-4, respectively, Scheme 2, conditions a and b), high-
lighting that the macrocycle distribution is the result of a
directional, kinetic, bias being applied by the chiral catalyst
reaction conditions to the thermodynamic preference for the
end compartments. The bias is added to (‘matched’) in the case
of catalysis by (R)-2, resulting in very effective macrocycle
transport, or is opposed (‘mis-matched’), in the case of catalysis
by (S)-2, resulting in transport that is less effective.
With the use of a 50:50 (racemic) mixture of (S)-2/(R)-2 in
the benzoylation reaction of 5, it is possible to overcome the
thermodynamic preference of the macrocycle for the end
compartments and afford a 45:55 mixture of left-4/center-4
(Scheme 2, conditions d).
Further insight into the mechanism of directional transport
can be gained by treating the double benzoylation of 1 as a
hidden Markov process,11 in which 1 is converted in a stepwise
fashion into the kinetically trapped products, passing through a
set of four singly benzoylated intermediates (see the Supporting
Information, Section 7). Although the individual steps of the
process cannot be observed, analysis of the benzoylation
products of 5 allows the probabilities of the various transitions
1
Figure 1. Partial H NMR spectra (500 MHz, DMSO, 300 K) of (a)
center-4, (b) thread, (c) left-4. Residual solvent peaks are shown in
gray. The lettering corresponds to the proton labeling shown in
Scheme 1. For full spectral assignments see the Supporting
Information.
Each of the isomers of 4 were isolated and characterized
unambiguously by H NMR spectroscopy and high-resolution
mass spectrometry. As expected, the H NMR spectrum of
center-4 is highly symmetrical (Figure 1a), while left-4 and right-
1
1
1
4 have identical H NMR spectra apart from the influence of
one of the fumaric groups being deuterated (the spectrum of
left-4 is shown in Figure 1c).6 The relative shielding of protons
by the aromatic rings of the macrocycle enables the position of
the ring in each rotaxane to be deduced by comparing the
chemical shift in the rotaxane to the equivalent signal in the
dibenzoylated thread (Figure 1b). The relative amounts of the
different products in the crude ratcheting reaction mixtures
1
were determined by H NMR (see Supporting Information,
Section 6).
The mechanism of the directional transport process was
probed by investigating the reaction of putative intermediates
in the ratcheting reaction, such as the mono-OH rotaxane 5
(Scheme 2, see Supporting Information for the synthesis of 5).
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Communication
from 1, via intermediates, to be determined, and thus, an
understanding of how the product distribution is built up: With
a chiral catalyst, the first benzoylation reaction of 1 occurs
preferentially far from the macrocyclethis can be deduced
from little macrocycle being trapped in one of the end
compartments (Scheme 1, conditions a and b). This is probably
due to the steric requirements of the bulky chiral catalyst, since
using DMAP itself the macrocycle ends up trapped to a
significant extent in both end compartments (Scheme 1,
conditions c). Directional transport with the individual chiral
catalysts ((S)-2 or (R)-2) is a result of two ratcheting1a,2−4
steps. There is selectivity in which hydroxyl group of 1 is first to
be benzoylated (which occurs without trapping the ring in the
end compartment, as discussed above), as the macrocycle spends
significant time in each compartment and can influence the rate of
reaction of the chiral reactive intermediates with the different
hydroxyl groups on the thread.12 The second benzoylation
reaction then discriminates between the center and the remaining
accessible end compartment according to the match between the
position of the macrocycle, the stereochemistry of the hydroxyl
group and the handedness of the catalyst. The result is highly
efficient transport of the macrocycle in 1 to an end compartment
determined by the handedness of the chiral catalyst.
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reactive intermediates, resulting in acylation taking place
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ASSOCIATED CONTENT
* Supporting Information
■
(11) For other examples of hidden Markov models being used to
probe chemical processes, see: (a) Venkataramanan, L.; Sigworth, F. J.
Biophys. J. 2002, 82, 1930−1942. (b) Messina, T. C.; Kim, H.; Giurleo,
J. T.; Talaga, D. S. J. Phys. Chem. B 2006, 110, 16366−16376.
(c) Zhou, Y.; Zhuang, X. J. Phys. Chem. B 2007, 111, 13600−13610.
S
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.
(d) Mullner, F. E.; Syed, S.; Selvin, P. R.; Sigworth, F. J. Biophys. J.
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AUTHOR INFORMATION
Corresponding Author
David.Leigh@manchester.ac.uk
Chem. Phys. 2011, 13, 16912−16927.
■
(12) Although the hydroxyl groups on the thread are enantiomeric,
the chirality of each is likely to be poorly expressed (the enantiomers
only differ in structure eight bonds from the chiral center) other than
when the macrocycle is on an adjacent fumaramide residue. The
benzoylation reactions do not alter the absolute configuration of the
asymmetric carbon atoms.
Notes
The authors declare no competing financial interest.
(13) Gouaux, E.; MacKinnon, R. Science 2005, 310, 1461−1465.
ACKNOWLEDGMENTS
■
We thank Professor Stephen J. Connon (Trinity College
Dublin) for the generous donation of (S)-2. This research was
supported by the EPSRC. AC is a Marie Curie IntraEuropean
Fellow. We thank the EPSRC National Mass Spectrometry
Service Centre (Swansea, U.K.) for accurate mass data.
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