A R T I C L E S
Han et al.
2′/3′ position (large annular face) with a substituent of proper
size, the cyclodextrin can form either intramolecular (self-
inclusion)8 or intermolecular complexes with the substituent,
where the substituent is inserted in the annular cavity of the
CD.9 For these studies of inclusion complexation of small
molecules, the size of the ensemble of different possible
conformations is often small and negligible.10
Inspired by the ubiquitous folding of biomolecules and
artificially designed foldamers in water,11 we set out to explore
if molecular folding can be designed into the structure of an
amphiphile based on inclusion complexes of cyclodextrin.
Whereas the folding of a protein or a foldamer involves a
backbone of amide bonds, we study the multiple folding
possibility of a ferrocene group with â-cyclodextrin. By
introducing a ferrocene group tethered with an aliphatic chain
at the 5′ position of âCD (Scheme 1), amphiphilic structure 1
can exist in multiple modes of complexation and folding to
arrive at different conformations (Figure 1). The complexation
can be either intramolecular or intermolecular. Two possible
intramolecular complexations exist. One proceeds with direct
complexation leaving the aliphatic chain trailing out of the 5
smaller annular face (structure A in Scheme 1). The other one
involves threading the aliphatic chain into the annular cavity
first to give an intermediate structure B, and then further binds
the ferrocene in the âCD cavity to afford the final structure C.
For intermolecular complexation, three possible pathways exist.
In these pathways, the aliphatic chain and the ferrocene can
either thread through the 5′ small annular face or thread through
Figure 1. Possible modes of inclusion complexes and different folded
conformations of amphiphile 1. Structure A shows a folded conformation
in which both the aliphatic chain and ferrocene are included in the âCD.
Structure B shows an intermediate, in which the aliphatic chain threads
through the âCD. Structure C shows a self-threading complex. Structure D
shows a dimer formed by intermolecular threading. Structures E and F show
different oligomers formed by intermolecular complexation.
the 3′ large annular face to afford dimeric structure D or
oligomeric structures E and F.
Amphiphile 1 offers two new properties that are fundamen-
tally interesting and potentially useful. First, certain molecular
assemblies in the form of both liquid crystals (cubic phase) and
micellar aggregate do not denature protein folding structure.12
In particular, it is well-known that some non-ionic surfactants
such as Brij and Triton are used to stabilize protein structure
and reduce physical adsorption of proteins on surfaces.13
Because cyclodextrin is non-ionic and mildly hydrophilic,
amphiphilic molecules using âCD as part of the hydrophilic
head group have the potential to retain the native folding of a
protein. Second, this inclusion complex has the potential to
exhibit reversible switching in the conformation triggered by
the control of the oxidation states of the ferrocene group. Kaifer
and co-workers demonstrated that by introducing a viologen
group onto the CD, the complexation can be controlled
electrochemically.9c In this work, we derivatize a redox-active
group, ferrocenyl alkene, on the 5′ face of the CD. The control
of the oxidation state of ferrocene can trigger a change in the
conformation of the inclusion complex formed between the
ferrocene and the CD. This oxidation-triggered conformational
change can in turn cause changes at the level of supramolecular
assembly.
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For the formation of intramolecular complexation, the nature
and the geometry of the covalent linkage between the ferrocene
groups and âCD plays a critical role for its stability. While the
ester bond has been previously used to link ferrocene groups
with the âCD covalently,14 we choose the amide bond for
amphiphile 1 because the amide bond is generally more robust
than the ester bond toward hydrolysis in aqueous solutions.
Because the amide and ester bonds are isosteric, as they share
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13914 J. AM. CHEM. SOC. VOL. 128, NO. 42, 2006