Anion-dependent switching: Dynamically controlling the conformation of hydrogen-bonded diphenylacetylenes

Article abstract of DOI:10.1002/anie.201100144

With a grain of salt: An anion-dependent switch based on an intramolecularly H-bonded diphenylacetylene is reported. The addition of Cl ^- causes the conformation of the H-bond acceptor to switch from the urea protons to the amide proton (see sc

Full text of DOI:10.1002/anie.201100144

DOI: 10.1002/anie.201100144
Molecular Switches
Anion-Dependent Switching: Dynamically Controlling the
Conformation of Hydrogen-Bonded Diphenylacetylenes**
Ian M. Jones and Andrew D. Hamilton*
Molecules that can switch conformation in a stimulus-
dependent fashion are intriguing chemical species because
of their many potential uses.[1] In particular, switches that
respond to an anionic stimulus[2] have received increasing
attention due to the importance of anions in nature.[3] With
this utility in mind, we now report the development of an
anion-dependent switch based on an intramolecularly H-
bonded diphenylacetylene system.[4]
one amide with a bidentate group, such as a urea, would
considerably bias that equilibrium toward the urea confor-
mer. However, ureas are also known to form strong com-
plexes with anions. In this way a dynamic conformational
switch is possible since addition of anions should preferen-
tially chelate the urea site, causing the H-bond acceptor to
change conformation to the available NH group (Figure 1).
The field of anion recognition has rapidly expanded over
the last 20 years leading to the design and study of many
receptor motifs.[5] A common strategy involves the use of H-
bond donors such as amides and ureas to coordinate a
prospective anion.[6] Of these H-bond donors, complexation
strength follows the trend: amides < ureas < thioureas owing
to the increasing NH acidity[7] and the formation of secondary
H-bond interactions.[8]
This pattern of increasing H-bond potential provides an
entry point in creating a molecular switch using a diphenyl-
acetylene scaffold. We have previously shown that appending
two differentially functionalized benzamides ortho to the
acetylene linkage creates a controllable equilibrium between
two H-bonded conformations[4i] with the more stable confor-
mer formed to the more acidic H-bond donor (Scheme 1).
Another way of controlling that equilibrium is to add
additional secondary H-bond interactions. Thus, replacing
Figure 1. a) The lowest-energy conformation of 1 without added anion.
b) The lowest-energy conformation of 1 with added NBu4Cl (the cation
has been removed for clarity). These minima were found by a
molecular mechanics (MM) conformational search followed by an
AM1 single-point minimization.
To test this hypothesis, compound 1 (Scheme 2) was
designed to juxtapose an acetamide and a phenylurea above a
benzodioxanone carbonyl group. This bicyclic benzodioxa-
none was chosen to provide a less sterically demanding H-
bond acceptor relative to the s-trans methyl ester in Scheme 1.
To gain initial insight on the competency of this system
toward conformational switching, the H-bonded equilibrium
of 1 was modeled in the absence and presence of 1 equiv
NBu4Cl (Figure 1). These studies were carried out using a
molecular mechanics conformational search (MMFF94x
force field) followed by an AM1 single point minimization
using a commercially available software package (see Sup-
porting Information for details).[9] The results show that the
H-bond acceptor of 1 should prefer the urea by À3.4 kcal
molÀ1, but upon addition of NBu4Cl the carbonyl should
switch such that an intramolecular H-bond with the acet-
amide is favored by À9.7 kcalmolÀ1.
Scheme 1. A bisbenzamido–diphenylacetylene scaffold where the con-
formational equilibrium is biased by the differential acidity of the
flanking benzamides.[4i]
[*] I. M. Jones, Prof. A. D. Hamilton
Department of Chemistry, University of Oxford
12 Mansfield Road, Oxford, OX1 3TA (UK)
and
Department of Chemistry, Yale University
P.O. Box 20810, New Haven, CT 06520 (USA)
E-mail: andrew.hamilton@chem.ox.ac.uk
Compound 1 was prepared according to Scheme 2. The
1H NMR spectrum of 1 (5 mm, CDCl3, 298 K), shown in
Figure 2, has three NH peaks at d = 7.89, 8.43, and 8.79 ppm,
which by COSY and NOE experiments (Scheme 2) can be
assigned to NHa, NHc, and NHb, respectively. In addition to
the NH resonances, the spectrum also has a doublet of note at
d = 7.25 ppm that can be assigned to Hd, (Scheme 2) by the 1H
COSY spectrum of 1.
[**] We thank Drs. Sam Thompson, Marc Adler (University of Oxford),
and Andrew Jamieson (University of Leicester) for their insights as
well as the University of Oxford and the NSF (CHE-0750357) for
funding.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201100144.
Angew. Chem. Int. Ed. 2011, 50, 4597 –4600
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anion, shifts downfield the least. Association of 1 with ClÀ
also causes Hd to migrate Dd = 1.10 ppm downfield.
Fitting the equation for a 1:1 binding isotherm (stoichi-
ometry confirmed by Jobꢀs plot) to the shift of NHc gives the
association constant for the binding to ClÀ to 1 as 78mÀ1
(Table 1). Changing the anion from ClÀ to BrÀ gives, in all
Table 1: A comparison of the Ka data obtained from the shift of NHc in 1–
3 upon titration with NBu4Br and NBu4Cl.
Compound
Ka BrÀ [mÀ1
]
Ka ClÀ [mÀ1
]
1
2
3
29Æ6
78Æ6
300Æ100
96Æ3
950Æ60
238Æ5
cases, a weaker downfield shift of the urea NH resonance and
modest decrease in the corresponding Ka value.
To assess the proposed conformational switching mecha-
nism (shown in Figure 1) we prepared a control derivative (2)
in which the H-bond accepting carbonyl group is shifted to the
para position of the lower phenyl ring. This derivative
maintains the electronic characteristics of 1 while removing
the potential for intramolecular H-bonding. This molecule
should assay the relative contributions of anion binding and
conformational switching on the downfield shift of NHa in 1.
Figure 3 shows that, upon addition of 12 equiv of ClÀ, the
amide NH resonance in 2 shifts Dd = 0.89 ppm, which is
significantly less than that for NHa in 1. This confirms that the
downfield shift of NHa is affected both by anion binding and a
Scheme 2. The synthesis and observed NOE contacts in 1 and 3 as
well as the structures of 2 and 4. Reagents and conditions: a) NaNO2,
AcOH, and H2SO4, then KI and H2O, 64%; b) Fe0 and AcOH, reflux
51%; c) AcCl, pyr., DMAP, DCM, 67%; d) SnCl2·2H2O, EtOAc, 68%;
e) 5-alkynylbenzodioxinone,[10] [PdCl2(PPh3)2], CuI, DMF, NEt3, 71%;
f) 4-R-PhNCO, pyr., DCM, 61%. DMAP=dimethylaminopyridine;
DCM=dichloromethane, pyr.=pyridine.
Figure 2. The 1H NMR spectra of 1 (5 mm, 298 K, CDCl3) upon
addition of 0–12 equiv of NBu4Cl. Peaks at d=7.25, 7.89, 8.43, and
8.79 ppm correspond to Hd, NHa, NHc, and NHb (Scheme 2), respec-
tively.
Figure 3. The change in chemical shift of the acetamide NH protons
~
~
*
*
upon titration of 1 ( ), 2 ( ), 3 ( ), and 4 ( ) with an increasing
number of equivalents of NBu4Cl. All titrations are at 500 MHz with
5 mm solutions of 1, 2, 3, or 4 in CDCl3 at 298 K.
The molecular modeling results suggest that anion binding
should result in strong downfield shifts of the NHc and Hd
1H NMR signals because of a direct interaction with the
halide. The NHa peak should also experience a downfield
migration due to interaction with the HB acceptor carbonyl.
Indeed, Figure 2 shows that titration of 1 with NBu4Cl
causes the resonances corresponding to NHa, NHb, and NHc
to shift downfield by Dd = 1.35, 0.40, and 2.03 ppm, respec-
tively. It is noteworthy that NHb, which swaps an intra-
molecular H-bond for an intermolecular interaction with the
change in the conformation of the molecule. The increased Ka
for ClÀ binding to 2 (Table 1) shows that removing the
energetic cost of breaking the intramolecular H-bond
increases anion affinity by more than an order of magnitude
over compound 1.
Further evidence for the proposed switching mechanism
came from compounds 3 and 4, which are analogous to 1 and 2
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but incorporate a p-nitro group onto the phenylurea. This
electron-withdrawing substituent should increase the acidity
and thus the H-bond donation capability of the urea. The
resulting increase in affinity should stabilize both the intra-
molecular H-bond as well as association of anion with the
urea. Correspondingly, this stabilization should be reflected in
the shift of the acetamide-NH resonance if a conformational
switch is present.
In fact, the 1H NMR spectrum of 3 shows that the
acetamide resonance is shifted by Dd = 0.1 ppm upfield
compared to that of 1 (see 0 equiv, Figure 3). This change is
indicative of a shift of the H-bonded equilibrium away from
NHa toward the urea protons. Furthermore, addition of the p-
nitro group increases the anion affinity, determined from the
urea resonances, by two- to three-fold compared to 1
(Table 1), and causes an increased downfield shift of the
acetamide NH signal at lower equivalents of ClÀ (see 2–
6 equiv, Figure 3). It is also noteworthy that both NHa signals
in 1 and 3 appear to saturate at the same point, indicating that
they are experiencing the same H-bond interaction.
Solubility problems in CDCl3 precluded the measurement
of spectra for 4 with 0 and 1 equiv of BrÀ or ClÀ. However, the
p-nitro group in 4 causes increased anion affinity as evidenced
by a larger downfield shift of the urea resonances compared
to those of 2 (see 1.5–12 equiv, Figures S16 and S19). Despite
this increase in affinity, Figure 3 shows a reduced downfield
shift of the acetamide resonance in 4 compared to that of 2,
indicating that a conformational shift, and not direct anion
binding, is the cause of the increased shift of NHa in 3. These
differences in the downfield shifts of the acetamide signals of
1–4 confirm that molecules 1 and 3 are anion-dependent
molecular switches.
It is possible to quantify the magnitude of the conforma-
tional shift by comparing dNHa at a given [ClÀ] with the
corresponding chemical shifts of NHa when it is completely H-
bonded and not H-bonded. The value of the fully H-bonded
NHa can be obtained by fitting the titration data to the
equation for the 1:1 binding isotherm and is estimated to be
d = 9.49 ppm. The chemical shift of NHa when it is not H-
bonded is estimated as the acetamide shift in 2, which is d =
7.74 ppm. From these values the equilibrium position at a
given [ClÀ] is determined by dividing the difference between
dNHa and 7.74 ppm by the difference between 9.49 and
7.74 ppm. By this method we find that in the absence of
anion the H-bond acceptor prefers the urea in a ratio of 9:1.
Upon addition of 12 equiv of ClÀ, that ratio becomes nearly
5:1 in favor of the acetamide (Figure 4).
Figure 4. The change in the equilibrium position upon increasing the
number of equivalents of NBu4Cl from 0 to 12. Light gray bars
correspond to the percent of molecules adopting the urea H-bonded
conformation, while the dark gray bars represent the percent of the
population in the acetamide H-bonded state.
Received: January 8, 2011
Published online: April 14, 2011
Keywords: anion binding · diphenylacetylene · molecular switch
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