Shuttling through reversible covalent chemistry

Article abstract of DOI:10.1039/b412570c

The first stimuli-responsive molecular shuttle that functions through reversible C-C bond formation is reported.

Full text of DOI:10.1039/b412570c

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Shuttling through reversible covalent chemistry{
David A. Leigh* and Emilio M. Pe´rez
School of Chemistry, University of Edinburgh, The King’s Buildings, West Mains Road, Edinburgh UK
EH9 3JJ. E-mail: David.Leigh@ed.ac.uk; Fax: 144 131 6679085; Tel: 144 131 650 4721
Received (in Cambridge, UK) 16th August 2004, Accepted 7th September 2004
First published as an Advance Article on the web 23rd September 2004
The first stimuli-responsive molecular shuttle that functions
through reversible C–C bond formation is reported.
Biological machines utilize chemical reactions to control mechan-
ical motion1 and establishing methods for generating large
amplitude changes in the relative positions of the components of
[2]rotaxanes (so-called ‘stimuli-responsive molecular shuttles’) is of
interest for producing synthetic analogues of such systems.2
Molecular shuttles that undergo well-defined positional changes
in response to redox processes,3 ion exchange,4 polarity changes,5
and photochemical6 and thermal7 stimuli have all been described
but, somewhat surprisingly, the use of covalent bond-forming
reactions in this regard has been limited to simple acid–base proton
transfers.8 Here we describe the first example of shuttling through
the formation (and breaking) of C–C bonds, using the well-
established Diels–Alder9 (‘‘DA’’) and retro-Diels–Alder9,10
(‘‘r-DA’’) reactions.
Rotaxane E-1 (Scheme 1) has previously been investigated as a
photo-switchable molecular shuttle.11 The trans double bond holds
the two amide carbonyls of the fumaramide (green) station in a
close-to-ideal arrangement for forming four strong H-bonds with
the benzylic amide macrocycle.12 The succinic amide-ester station
(orange) contains a poorly hydrogen bonding ester group and lacks
preorganisation. Accordingly, the macrocycle in E-1 is located
primarily over the fumaramide unit (w95% of the time in CDCl3 at
298 K and w85% even in d6-DMSO, a powerful hydrogen bond-
disrupting solvent). Photo-isomerization of fumaramide to male-
amide ‘switches off’ the binding affinity of the olefin station,13
resulting in the macrocycle translocating to the succinic amide-ester
site.11 However, the double bond also opens up the possibility of
utilising DA and r-DA chemistry to trigger the shuttling response.
Addition of a diene to the fumaramide station would both change
its H-bonding geometry and increase the steric bulk between the
amide groups. Indeed, CPK models suggest that a benzylic amide
macrocycle would be unlikely to hydrogen bond simultaneously to
both amide groups of a station derivatised as the cyclo-adduct
with cyclopentadiene and the succinic amide-ester station should
consequently become the positional energy minimum. Since
stereochemistry is conserved through a DA–r-DA sequence (E
dienophile results in trans adduct, which in turn yields E educt
upon r-DA), the change in position of the macrocycle should be
reversible through a r-DA reaction.
Accordingly, E-1 was treated with cyclopentadiene in d6-DMSO
at 80 uC for 16 h affording Cp-1 as a 1 : 1 mixture of diastereomers
in 90% yield (Scheme 1). The 1H NMR spectra (CDCl3, 400 MHz,
298 K) of rotaxanes E-1 and Cp-1 and the corresponding threads
E-2 and Cp-2 are shown in Fig. 1. In Cp-1 and Cp-2, the bicyclic
adduct signals (H1–H7, dark blue, and H1’–H7’, red) appear at near-
identical chemical shifts in both thread and rotaxane, while the
succinic amide ester signals (Hc and Hd, orange) are shifted
y1.2 ppm upfield in Cp-1 with respect to Cp-2 due to the shielding
effect of the xylylene rings of the macrocycle. Moreover, the NH
fumaramide protons (Hh and Hk, green) are deshielded by
Scheme 1 Shuttling through reversible covalent bond formation.{ Absolute
stereochemistry for Cp-2 and Cp-1 is depicted arbitrarily. Reaction
conditions: i) isophthaloyl dichloride, p-xylylenediamine, Et3N, CHCl3,
57%; ii) cyclopentadiene, d6-DMSO, 80 uC, 16 h, 90%; iii) 250 uC, 1022
Torr, 20 min, y100%; iv) cyclopentadiene, d6-DMSO, 80 uC, 8 h, 93%; v)
250 uC, 1022 Torr, 20 min, y100%.
y1.5 ppm in E-1 with respect to E-2 through polarisation of the
thread N–H bonds caused by the macrocycle H-bonding to the
fumaramide carbonyl groups, but in Cp-1 it is the succinic amide-
ester NH (He, orange) that is shifted 0.8 ppm downfield compared
to its thread, with Hh and Hk not significantly affected. The
spectroscopic data confirm that the translocation of the macrocycle
from the fumaramide unit in E-1 to the succinic amide-ester station
in Cp-1 proceeds with excellent positional integrity.
The covalent chemistry shuttling system proved perfectly
reversible; the r-DA reaction could be accomplished by heating
Cp-1 at 250 uC under reduced pressure (1022 Torr) for 20 minutes
using the inlet oven of a flash vacuum pyrolysis (FVP) apparatus to
quantitatively regenerate E-1.
An interesting consequence of the encapsulated architecture of
the rotaxane is the effect the macrocycle has on the reactivity of the
fumaramide station in the DA reaction.14 E-2 reacts with
cyclopentadiene approximately twice as fast as E-1 in d6-DMSO
{ Electronic supplementary information (ESI) available: experimental
procedures and physical data for Cp-1 and Cp-2. See http://www.rsc.org/
suppdata/cc/b4/b412570c/
2 2 6 2
C h e m . C o m m u n . , 2 0 0 4 , 2 2 6 2 – 2 2 6 3
T h i s j o u r n a l i s ß T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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Fig. 1 1H NMR (CDCl3, 400 MHz, 298 K ) of a ) thread E-2; b ) rotaxane
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In conclusion, we have described the first example of a bistable
stimuli-responsive molecular shuttle that functions through
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preparatively simple and generate large amplitude net positional
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This work was supported by the European Union FET
Programme ‘MechMol’. The authors thank Dr G. Priimov for
preliminary studies on the DA reaction and Dr H. McNab and
S. Wharton for the use of FVP equipment and advice on the r-DA
reaction.
Notes and references
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C h e m . C o m m u n . , 2 0 0 4 , 2 2 6 2 – 2 2 6 3
2 2 6 3