1. In our molecular recognition program with synthetic receptors, we use Rebek imide scaffolds to develop model receptors for nucleobases. We investigate the preferences of purine bases for Hoogsteen and Watson-Crick hydrogen-bonding (1) asking the question, how this hydrogen bonding preference is changed by additional non-covalent bonding interactions. These studies, that include database mining, calculations, liquid-phase binding titrations, and X-ray crystallography, focus on the following issues at the center of interest in contemporary molecular recognition:
p-p-stacking and edge-to-face interactions on hydrogen-bonding arrays
sulfur-aromatic interactions
cation-p interactions (see 2)
interactions with perfluorinated aromatic rings.
In this work, we also develop versatile new platforms and scaffolds for future molecular recognition studies.
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2. In another avenue of molecular recognition research, we investigate the
energetics of the newly discovered orthogonal dipolar interactions such as
C–F...C=O
in synthetic model systems. Thus we have quantified the C–F...C=O
interactions in chemical double mutant cycles using new derivatives of the
Wilcox torsional
balance.
In collaboration with the Nanoscale Science Center (NCCR) in Basel, we prepare and study dynamic receptors that function as molecular grippers. These compounds undergo conformational switching between a vase form, capable of complexation of guests in a deep cavity, and a kite form, with a large flat surface. We have shown that this conformational switching can be done both by temperature and pH change and imaged the receptors anchored to gold surfaces at molecular resolution using STM. Furthermore, we recently demonstrated that Langmuir films of the grippers can be switched from the vase to the kite conformation driven by stoichiometric zinc(II) ion complexation. These systems are now investigated to induce very large molecular motions between two bistable states.
Another objective includes investigation of the vase-kite switching mechanism
at the level of single molecules using confocal fluorescence microscopy
(in collaboration with Prof.
B. Hecht, Univ. Basel. For this purpose, dyes are attached to the walls
of the molecular grippers as shown below. Ultimately, we wish to integrate
the grippers into suitable devices such as scanning probe microscopy tips:
they should be able to capture (by complexation) a single molecule in the
vase form and hold it during translation, while releasing it upon switching
to the non-bonding kite conformation.
3. In our program on functional dendrimers, we position iron heme co-factors
as initiator cores into the center of spherical dendrimers. The dendritic
iron porphyrins such as 3 are outstanding, reversible O2-binders,
displaying much higher activity than human hemoglobin, besides a very small
CO-binding
activity. We are actively investigating the origin of this gas binding selectivity.
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In a major effort in collaboration with Prof.
H. P. Merkle from the Institute
of Pharmaceutical Sciences, D-CHAB, ETHZ), we prepare and test small self-assembling
amphiphilic dendrimers such as 4 as transfection agents for gene delivery.
These compounds display excellent DNA binding and transport activities with
low toxicity, matching the best vectors reported in the literature. In the
frame of the Nanoscale Science Center Basel (NCCR Basel), the packing of
plasmids by the self-assembling dendrimers has been demonstrated using STM-imaging.
Comprehensive structure-activity relationships are pursued in future work
with the objective to develop optimal vectors for gene therapy. .
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