Communications
ture of the crystal forms channels by stacking the dimers along
between CPs in the crystals (see Supporting Information) and
À
the crystallographic a axis, each dimer making van der Waals
contacts with the next through its g face carbonyl and N-
methyl groups.
by those calculated from the N H stretch frequencies (n˜ =
3304, 3309, and 3300 cmÀ1 in 87a, 10 and 117a–9, respectively;
see Supporting Information). However, further studies might
clarify this issue.
The g-Ach-based 7a analogue cyclo[(d-Phe-(1R,3S)-MeN-
g-Ach)3-] (9) also forms stable homodimers 10 in nonpolar
solvents, with an association constant estimated to be at least
105 mÀ1, as in the case of 7a (Figure 2).[8] The possibility of
heterodimer formation was confirmed upon the addition of
0.8 equivalents of 7a to a solution of 9 (2.1 mm) in chloroform,
which resulted in the appearance of a new species with a
1H NMR spectrum that did not correspond to either of the
possible homodimers. The dimeric nature of the new species,
117a-9, was shown by NOE cross-peaks between the signals of
HgAcp (at d = 4.92 ppm) and HaAch (at d = 2.62 ppm). Defin-
itive evidence of heterodimerization in the solid state was
obtained by X-ray crystallography of the colorless prismatic
single crystals recovered from a 1:1 solution of 7a and 9 in
chloroform. As expected, the monomeric cyclic peptides form
heterodimers in which the two essentially flat rings are
antiparallel, with their a faces linked in b-sheet fashion
through six hydrogen bonds with N···O interatomic distances
of 2.82–2.90 (Figure 3). The dimers stack closely along the
a axis, each making van der Waals contacts with its neighbor
with g-face carbonyl and N-methyl groups. The resulting
channel contains two chloroform molecules per unit, one in
the cavity of the heterodimer and a second at variable sites
between successive dimers.
In conclusion, NMR and FTIR spectroscopy and X-ray
diffraction data show conclusively that cyclic a,g hexapep-
tides containing three g-Acp units can form stable cylindrical
dimers in which antiparallel peptide rings are linked by a b-
sheet-like set of six hydrogen bonds. Even greater stability is
shown by the heterodimers of these g-Acp a,g CPs with g-Ach
a,g CPs. Potential applications for nanotubes developed from
appropriately functionalized a,g CPs include their use as logic
gates, biosensors, catalysts, molecular receptors, and molecule
containers.
Received: May 6, 2005
Revised: June 7, 2005
Published online: August 4, 2005
Keywords: amino acids · dimerization · nanotubes · peptides ·
.
self-assembly
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Notably, the heterodimer 117a–9 was in fact about 30-fold
more abundant than the homodimer if prepared as described
above from a mixture of 7a and 9,87a (0.8:1) which at 298 K
corresponds to an energy difference of 2.0 kcalmolÀ1. To
determine whether this selectivity was derived from inter-
actions between the side chains of the monomers, we
investigated the dimerization of 7a with cyclo[(d-Phe-
(1R,3S)-MeN-g-Acp)3-] (7b).[16] If the stability of 117a–9 were
the result of side-chain–side-chain interactions, the potential
heterodimer 87a–7b, in which the side chains are the same as
those of 117a–9 yet not the two backbones, is expected to be at
least as stable as is 117a–9 relative to 87a. Nevertheless, the
1H NMR spectrum of a 1:1 mixture of 7a and 7b in
chloroform showed the presence of dimers 87a, 87b, and 87a–7b
in almost equal concentrations, which implies that all three
species have similar stabilities. This rules out the possibility of
significant interactions between the side chains of opposing
rings. Consistent with this conclusion, the addition of
0.9 equivalents of 9 to a solution of 7b (4.6 mm) in chloroform
resulted in the formation of heterodimer 117b–9 without any
observable trace of the homodimer 10; this shows an even
greater difference in stability between hetero- and homo-
dimers than in the case of 117a–9 and 10.
The cause of the higher stability of the heterodimers is
unclear. However, inspection of the crystal structures of 87a,
10[8a] and 117a–9 (Figure 3) suggests that the heterodimer is
more stable through an improved alignment of hydrogen-
bond donors and acceptors. This could be due in part to more
favorable packing between cyclopentyl and cyclohexyl than
cyclopentyl–cyclopentyl or cyclohexyl–cyclohexyl ring pack-
ing. This hypothesis is supported by the intradimer distances
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Angew. Chem. Int. Ed. 2005, 44, 5710 –5713