Switchable dual binding mode molecular shuttle

Article abstract of DOI:10.1021/ol062284j

Protonation controls the location of a dual binding mode macrocycle in a [2]rotaxane. In the neutral form, amide-amide hydrogen bonds hold the macrocycle over a dipeptide residue; when the thread is protonated, polyether-ammonium cation interactions domin

Full text of DOI:10.1021/ol062284j

ORGANIC
LETTERS
2006
Vol. 8, No. 23
5377-5379
Switchable Dual Binding Mode
Molecular Shuttle
David A. Leigh* and Andrew R. Thomson
UniVersity of Edinburgh, School of Chemistry, The King’s Buildings,
West Mains Road, Edinburgh EH9 3JJ, U.K.
daVid.leigh@ed.ac.uk
Received September 16, 2006
ABSTRACT
Protonation controls the location of a dual binding mode macrocycle in a [2]rotaxane. In the neutral form, amide
−amide hydrogen bonds hold
the macrocycle over a dipeptide residue; when the thread is protonated, polyether
changes position.
−ammonium cation interactions dominate and the macrocycle
Rotaxanes in which the position of the macrocyclic compo-
nent can be changed by an external stimulus are among the
simplest of molecular-scale mechanical devices.1 Various
stimuli have been employed to induce such switching,
including metal binding,2 configurational changes,3 and
alteration of the oxidation state4 or protonation level2f,4a,5 of
the molecule. Here we report on the synthesis and operation
of a pH-switchable molecular shuttle that uses different sets
of intercomponent interactions to achieve distinct and dif-
fering coconformations in the neutral and protonated states.
Amide-amide hydrogen bonding of short peptide units
with isophthalamide macrocycles is a well-established tem-
plate route for the synthesis of rotaxanes.6 Recently, the Loeb
group, inspired by the ammonium cation-crown ether
rotaxane system originally introduced by Busch7 and Stod-
dart,8 demonstrated9 that a protonated N-benzylaniline group
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10.1021/ol062284j CCC: $33.50
© 2006 American Chemical Society
Published on Web 10/11/2006

can be complexed as a pseudorotaxane by a crown ether.
We wondered whether these two recognition motifs could
be combined to generate a new type of dual binding mode,
protonation-switched, molecular shuttle.
4 and [2]rotaxane 5 in 65 and 31% yields, respectively (see
Supporting Information).
1
The H NMR spectra (Figure 1) of thread 4, rotaxane 5,
and macrocycle 1 confirm the interlocked nature of 5 and
A target rotaxane incorporating glycylglycine and N-
benzylaniline “stations” in the thread and an isophthalamide
group and polyether chain in the macrocycle was synthesized
using reductive amination to simultaneously generate the
interlocked architecture and install the N-benzylaniline
moiety (Scheme 1).10 In CH2Cl2, macrocycle 1 hydrogen
Scheme 1. Synthesis of Thread 4 and [2]Rotaxane 5
Figure 1. Partial 1H NMR spectra (400 MHz, CD3CN, 298 K) of
(a) thread 4, (b) rotaxane 5, and (c) macrocycle 1. The lettering
corresponds to the proton assignments shown in Scheme 1.
show that in the neutral form of the rotaxane the macrocycle
is largely localized on the peptide region of the thread
(Scheme 2). The upfield shifts of the methylene resonances
of the peptide station (Ha 0.20, Hc 0.32, and He 0.46 ppm,
cf. Figure 1b and Figure 1a) in 5 are characteristic6 of
aromatic shielding by the encapsulating macrocycle. The
greater shielding of He suggests the macrocycle hydrogen
bonds primarily to the central glycylglycine carbonyl unit
and only to a lesser extent to the comparatively hindered
amide carbonyl adjacent to the stopper (Scheme 2).6e The
ester carbonyl is a weaker hydrogen bond acceptor than the
amides11 and does not appear to contribute significantly to
the intercomponent binding.
The thread amide resonances, Hb and Hd, are shifted
upfield (0.13 ppm) and downfield (0.10 ppm), respectively,
in the rotaxane as a result of the collective influences of (i)
aromatic shielding (upfield shift), (ii) hydrogen bonding to
the macrocycle polyether oxygens (downfield shift), and (iii)
inductive effects of the hydrogen bonding to the thread
carbonyl groups (downfield shift). There is no evidence of
bonds to the monostoppered glycylglycine thread 2, forming
a pseudorotaxane.6e Covalent capture of the threaded inter-
mediate by imine formation with bulky amine 3, followed
by in situ reduction with NaBH(OAc)3, afforded the thread
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S. J. Am. Chem. Soc. 2002, 124, 2939-2950. (d) Brancato, G.; Coutrot,
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Z.; Stitchell, S. G. Angew. Chem., Int. Ed. 2004, 43, 3260-3264. (h) Leigh,
D. A.; Morales, M. A. F.; Pe´rez, E. M.; Wong, J. K. Y.; Saiz, C. G.; Slawin,
A. M. Z.; Carmichael, A. J.; Haddleton, D. M.; Brouwer, A. M.; Buma,
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2005, 44, 3062-3067.
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Menzer, S.; Philp, D.; Spencer, N.; Stoddart, J. F.; Tasker, P. A.; Williams,
D. J. Angew. Chem., Int. Ed. Engl. 1995, 34, 1865-1869. (b) Glink, P. T.;
Schiavo, C.; Stoddart, J. F.; Williams, D. J. Chem. Commun. 1996, 1483-
1490.
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Commun. 1995, 1289-1291.
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5378
Org. Lett., Vol. 8, No. 23, 2006

Scheme 2. Principal Intercomponent Binding Modes of 5 in
Its Neutral and Protonated Formsa
Figure 2. Partial 1H NMR spectra (400 MHz, CD3CN, 298 K) of
(a) protonated thread 4‚TsOH, (b) protonated rotaxane 5‚TsOH,
and (c) macrocycle 1. The lettering corresponds to the proton
assignments shown in Scheme 1.
in the protonated unrotaxanated thread. Thus, the presence
of the macrocycle effectively “insulates” the amides of the
thread from the ammonium center.
The ring amide protons appear 0.2 ppm downfield in 5‚
H+ (Figure 2b) with respect to 5 (Figure 1b), which is likely
due to hydrogen bonding to the tosylate counterion.12 When
an alternative, noncoordinating, acid such as HBF4 is used,
the HD resonance appears at the same position as in the free
macrocycle, but the ring still resides over the ammonium
group indicating that the macrocycle-anion interaction is
not crucial for the shuttling process.
In conclusion, rotaxane 5/5‚H+ is a novel type of molecular
shuttle that switches the macrocycle between two distinct
translational forms with high positional integrity by exploit-
ing both amide-amide hydrogen bonding and crown ether-
ammonium cation interactions. The incorporation of multiple
recognition motifs into molecular structures is likely to prove
important for controlling component and substrate motion
in future generations of molecular-level machines.13
a For X- ) TsO-, the macrocycle amides H-bond to the anion;
for X- ) BF4-, they do not.
any interaction between the macrocycle and the secondary
amine group. For the rotaxane macrocycle, the 0.22 ppm
(cf. Figure 1b and Figure 1c) downfield shift of the amide
protons (HD) indicates significant amide-amide hydrogen
bonding with the thread. The polyether protons (HH-HK)
are shifted upfield by roughly 0.1 ppm, confirming that the
polyether oxygens accept hydrogen bonds from the thread
amides. As the thread is unsymmetrical, the faces of the
macrocycle are diastereotopic in the rotaxane. This effect is
seen most clearly in the ABX system of HE (Figure 1b).
Protonation of 5 with 1 equiv of p-toluenesulfonic acid
1
results in significant changes to the H NMR spectrum in
CD3CN (Figure 2b). Aromatic shielding is observed for the
thread protons adjacent to the ammonium unit (Hj) and the
macrocycle benzyl groups (HF and HG), indicating that the
preferred position of the ring is now over the anilide
ammonium station (Scheme 2). Interestingly, the signals for
the thread amide protons in the protonated rotaxane appear
at 6.6 ppm, almost the same as in the neutral thread (4). In
the protonated thread, however, these signals occur at 6.9
and 6.95 ppm, suggesting inter- or intramolecular interactions
exist between the amide carbonyls and the ammonium group
Supporting Information Available: General synthetic
experimental procedure, characterization, and spectroscopic
data for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL062284J
(12) Leigh, D. A.; Lusby, P. J.; Slawin, A. M. Z.; Walker, D. B. Angew.
Chem., Int. Ed. 2005, 44, 4557-4564.
(13) Chatterjee, M. N.; Kay, E. R.; Leigh, D. A. J. Am. Chem. Soc. 2006,
128, 4058-4073.
Org. Lett., Vol. 8, No. 23, 2006
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