Designed molecular switches: Controlling the conformation of benzamido-diphenylacetylenes

Article abstract of DOI:10.1021/ol101397y

With the goal of creating a molecular switch, the hydrogen-bonded diphenylacetylene structure has been modified such that an equilibrium now exists between two intramolecular H-bonded states. Through X-ray crystallography and ¹H NMR analysis it

Full text of DOI:10.1021/ol101397y

ORGANIC
LETTERS
2010
Vol. 12, No. 16
3651-3653
Designed Molecular Switches:
Controlling the Conformation of
Benzamido-diphenylacetylenes
Ian M. Jones and Andrew D. Hamilton*
Department of Chemistry, Yale UniVersity, P.O. Box 20810,
New HaVen, Connecticut 06520, and Department of Chemistry, Oxford UniVersity, 12
Mansfield Road, Oxford OX1 3TA, U.K.
andrew.hamilton@chem.ox.ac.uk
Received June 16, 2010
ABSTRACT
With the goal of creating a molecular switch, the hydrogen-bonded diphenylacetylene structure has been modified such that an equilibrium
now exists between two intramolecular H-bonded states. Through X-ray crystallography and 1H NMR analysis it is shown that this equilibrium
can be biased in a predictable manner by modulating the relative acidity of the amide NH’s.
Molecules that can change conformation in a stimulus-
dependent fashion are valued synthetic targets due to their
potential use as logic gates,1-3 information storage systems,4,5
sensors,6 and as stepping stones toward the design of
angstrom scale machines.7 In light of the myriad applications
for switches, many structural motifs have been pursued in
the past 15 years that exhibit a conformational change based
upon a variety of stimuli.7-17
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10.1021/ol101397y  2010 American Chemical Society
Published on Web 07/29/2010

tion.28,29 Accordingly, we should be able to use the ∆σ
between the two benzamides in our system to predict which
NH is the preferred H-bond donor.
Scheme 1. Synthesis of 1
Figure 1. Conceptual transformation of the classical hydrogen
bonded diphenylacetylene into a molecular switch.
Our interest in the design of ꢀ-strand mimetics stabilized
by an intramolecular hydrogen bond across an alkyne
spacer18 prompted us to investigate the use of this system
as a new switching entity. The key feature of this scaffold
is the 10-membered H-bonded ring first described by
Kemp19,20 (Figure 1), which increases the rotational barrier
around the phenyl-alkyne bond from 0.6 to 7.19 kcal/
mol.21,22 The utility of this intramolecular interaction has
been established in the stabilization of helical foldamers,22-24
molecular wires,25 a proteomimetic,18 and an ion sensor.26
Transforming the H-bonded diphenylacetylene unit into a
switch requires that we (i) set up a conformational equilib-
rium between two forms, (ii) demonstrate that the equilibrium
can be biased in a predictable fashion, and (iii) show that
this bias can be altered through the application of a stimulus.
Herein we report our synthetic and analytical stratagem for
accomplishing parts i and ii.
Addition of a second amide, ortho to the alkyne spacer
(Figure 1), opens up the required equilibrium providing two
donors for intramolecular H-bonding. We can potentially bias
the benzoate H-bond acceptor to prefer one amide over the
other by conjugating electron-withdrawing and -donating
groups to the amide carbonyls. If the carbonyl is electron-
rich, the NH bond should be less acidic thus making the
amide a weaker H-bond donor. Conversely, an electron-poor
carbonyl will increase the acidity of the NH making it a
stronger H-bond donor.
To test this idea, compound 1, which balances pNO2-
benzamide with benzamide, was assembled from 2,6-dinitroa-
niline according to Scheme 1. The pNO2-amide has less electron
density than benzamide, as described by ∆σ ) 0.78, and so
the pNO2-amide should be the preferred H-bond donor.
Single crystal X-ray diffraction of 1 (Figure 2) shows that
the preferred H-bond donor is indeed the pNO2-benzamide with
a NH···OC distance of 2.23 Å. There is also a steric clash
between the methyl ester and the pNO2-phenyl that creates a
50° dihedral angle between the ring and the amide carbonyl.
With this result in hand, we expanded our analysis to the
1
solution phase using H NMR. The spectrum of 1 shows
the pNO2-NH at 9.43 and the benzamide NH at 9.07 ppm
(4 mM, CDCl3). These resonances are assigned by the NOE
between these peaks and the aryl protons ortho to each
carbonyl (Scheme 1).
para-Substituted benzoic acids are ideal electron-modulat-
ing groups because of the range of available derivatives with
well characterized σ-Hammett values.27 These values can
be used to quantify the effect of subsitution on acidity and,
in 4-substituted benzamides, the strength of H-bond dona-
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Figure 2. Single crystal X-ray structure of 1.
Org. Lett., Vol. 12, No. 16, 2010
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3652

Kemp-type diphenylacetylenes show proton spectra with
non-H-bonded amide resonances around 8 ppm and H-
bonded amide resonances from ∼9 to 9.2 (CDCl3).22,24 That
both amides in our compound resonate around this latter
range suggests that each could be involved in a hydrogen
bond. Intermolecular H-bonding, a concentration-dependent
phenomenon, is ruled out by the fact that the NH shifts of 1
stay constant as the solution is diluted from 16 to 0.063 mM
(CDCl3). Thus, the downfield shift of both NH’s must be
due to an equilibrium between the conformations of the
benzoate acceptor.
that the conformational equilibrium is biased toward the
pNO2-benzamide.
This analysis also determines the magnitude of the
conformational bias from the degree to which the benzamide
NH has shifted upfield. Dividing the difference in chemical
shift between 3 and 1 by the difference in chemical shift
between 3 and 4, we find that this initial system has a
preference of 30.6% for the NO2-NH.
Figure 4. Comparison of the % H-bond preference for compounds
1-3. The ∆σ values appear at the top of each bar.
Having shown that the solid-state and solution-phase
conformations can be biased in a predictable manner, we
next investigated the sensitivity of conformational preference
toward a varying ∆σ. Toward this end, compound 2 (Figure
1, R1 ) H, R2 ) Cl) was prepared and analyzed in the same
fashion as 1. Comparison of 2 with its appropriate control
molecules (Figure S2 in Supporting Information) shows that
decreasing ∆σ from 0.78 to 0.23 attenuates the H-bond
preference from 30.6% to 14.2% (Figure 4).
In summary, we have shown (i) evidence of a conforma-
tional equilibrium in these bis(benzamido)-diphenylacetylene
molecules and (ii) that electronic modulation can be used to
attenuate or enhance benzamide H-bond donation strength,
resulting in a measurable conformational bias. Indeed, the
sensitivity of the conformational equilbrium toward a varying
∆σ suggests the utility of this scaffold for dynamic switching,
and we are currently working to develop this facet.
Figure 3.
1H NMR amide resonances of compounds 3, 1, and 4
from top to bottom (4 mM in CDCl3). The benzamide resonances
are denoted by 4, ], and O for 3, 1, and 4, respectively, and the
chemical shifts are also reported.
To determine the position of that equilibrium, two refer-
ence compounds were designed. The first reference positions
an unsubstituted benzamide on both sides (3, Figure 3) and
has a ∆σ ) 0. As such, the methyl ester must partition
equally between the amides, providing a definition of the
benzamide NH chemical shift in a system where no confor-
mational preference exists (50/50 definition). The second
reference compound (4, Figure 3) juxtaposes pNO2-benza-
mide with benzamide; however, in this molecule the ester is
para to the acetylene linker. Because the ester cannot
influence the amide chemical shifts (again intermolecular
association is ruled out by the same dilution assay), these
values represent the resonances of 1 if they are not H-bonded
(100/0 definition).
Acknowledgment. The authors would like to thank Dr.
Christopher D. Incarvito at Yale University for X-ray
crystallographic analysis, Drs. Marc Adler and Andrew
Jamieson at Oxford University for helpful insights, and the
NSF (CHE-0750357) and Oxford University for funding.
We expect that if the pNO2-NH is preferred in solution,
then the other NH will be more shielded, as the result of a
decrease in H-bonding, and will resonate between our two
definitions. Figure 3 shows that the benzamide resonance
for 1 does appear between that of 3 and 4, demonstrating
Supporting Information Available: General experimental
methods, procedures, NMR spectra, and X-ray crystal-
lographic data in CIF format. This material is available free
of charge via the Internet at http://pubs.acs.org.
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