PH-dependent conformational switching in 2,6-benzamidodiphenylacetylenes

Article abstract of DOI:10.1002/anie.201106241

The conformational equilibrium of a pH-dependent switch based on an intramolecularly H-bonded diphenylacetylene can be predictably biased by using electron-donating or -withdrawing groups (see scheme). Furthermore, protonation of the electron-donating dim

Full text of DOI:10.1002/anie.201106241

DOI: 10.1002/anie.201106241
Molecular Switches
pH-Dependent Conformational Switching in 2,6-Benzamidodiphenyl-
acetylenes**
Ian M. Jones, Hannah Lingard, and Andrew D. Hamilton*
The conformational dynamism of macromolecules in
response to changing pH is essential to the maintenance of
many biological systems.[1] However, due to the complexity of
such systems the elements essential to conformational switch-
ing can be difficult to discern. Molecular switches, which are
relatively easier to prepare and analyze, can help to identify
these essential elements and employ them in new contexts.[2]
With this application in mind we now report a pH-dependent
switch based on our 2,6-benzamidodiphenylacetylene system.
Many structural motifs have been explored that behave as
switches in response to changes in pH.[3] With a notable
exception,[3d] these molecules tend to utilize intramolecular
hydrogen-bonds to stabilize a particular conformation. Direct
protonation of one H-bond acceptor changes that group to a
H-bond donor, forcing the system to reconfigure to a new
conformation.
While these studies characterize direct protonation as a
tool for controlling conformation, an alternative approach
employs remote protonation. The protein rhodopsin, for
example, uses a conjugated p-system to link a basic imine to
the spatially removed photo-switchable olefin. Thus, addition
of a proton to the basic site electronically controls the
absorption wavelength of the switch.[1a] In this way, it should
also be possible to manipulate a H-bonded equilibrium
through electronic modulation. A system of this type would
involve a basic site, such as an electron-donating amine, that is
removed from the H-bond network but linked through
conjugated p-bonds. Addition of a proton to the basic site
could then be communicated electronically to the H-bond
network, causing it to switch conformation.
Scheme 1. Conjugation of electron-withdrawing (EWG) or -donating
groups (EDG) to the H-bonded network can control the conforma-
tional equilibrium by increasing or decreasing the NH acidity.
The strength of a H-bond can be controlled by increasing
or decreasing the acidity of the amide proton. For this task, 4-
substituted benzamides provide a wide variety of electron-
withdrawing or -donating groups spatially separated from the
H-bond donors. Additionally, para substituted benzoic acids
have well characterized Hammett values (sp)[5] that correlate
acidity to the electronegativity of the para-substituent.[6]
To test this idea we prepared compound 1 according to
Scheme 2. This compound compares the electron-donating p-
NMe2-benzamide (sp = À0.83) with benzamide (sp = 0.00).
We have designed a H-bonded 2,6-benzamidodiphenyl-
acetylene system that offers the ability for remote protona-
tion (Scheme 1). Based upon Kempꢀs singly H-bonded b-
sheet mimetic,[4] our scaffold contains two potential H-bond
donors. The balance between the two conformations should
be biased toward the amide NH that offers the strongest
H-bond.
Scheme 2. The synthesis and NOE contacts observed for 1 as well as
the structures of 3 and 4. Reagents and conditions: a) NaNO2, H2SO4,
AcOH then KI and H2O, 708C; b) Fe0, AcOH, reflux; c) benzoyl
chloride, pyr., DMAP, DCM; d) SnCl2·2H2O, EtOAc; e) methyl 5-
alkynyl-benzoate, [PdCl2(PPh3)2], CuI, DMF, NEt3, 808C; f) p-NMe2-
benzoyl chloride, pyr., DMAP, DCM.
[*] I. M. Jones, Dr. H. Lingard, Prof. A. D. Hamilton
Department of Chemistry, Yale University
P.O. Box 20810 New Haven, CT 06520 (USA)
and
The electron-donating character of p-NMe2 should lower the
acidity of its associated amide NH (NHa) rendering it a
weaker H-bond donor relative to the benzamide NH (NHb).
The X-ray crystal structure of 1 (Figure 1a) shows that the
electron-donating p-NMe2 group causes the H-bond acceptor
to prefer the NHb with a CO···N distance of 3.1 ꢁ in the solid
state. This structure also displays a steric interaction between
the methyl benzoate and the benzamide ring causing a
rotation of 498 out of the amide plane.
University of Oxford
12 Mansfield Rd. Oxford, OX1 3TA (UK)
E-mail: andrew.hamilton@chem.ox.ac.uk
[**] The authors would like to thank Dr. Sam Thompson (Oxford) and
Prof. Marc Adler (N.I.U.) for helpful insights; Drs. Amber Thomp-
son and Christopher Incarvito for crystallography; NSF (CHE-
0750357) and the University of Oxford for funding.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201106241.
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
12569

Communications
Figure 1. a) The solid-state structure of 1 depicting the methyl ben-
zoate H-bonded to the benzamide NH; b) The solid-state structure of
2 depicting the methyl benzoate H-bonded to the p-NO2-benzamide
NH. The ORTEP ellipsoids are shown at the 50% probability level.
Blue N, grey C, red O, white H.
We have previously reported that electron-withdrawing
groups can be used to control the H-bonded conformation of
our diphenylacetylene system. Compound 2, which juxtaposes
p-NO2-benzamide (sp = 0.78) with benzamide (sp = 0.00),
should prefer to form a H-bond with the more acidic p-
NO2-benzamide. Figure 1b shows that the benzoate carbonyl
is H-bonded to the p-NO2-amide NH in the solid state, with a
CO···N distance of 3.1 ꢁ.[4i]
It is also possible to determine the position of the
conformational equilibrium in solution.[4i] By this procedure
(see Supporting Information for details) we find that the
conformational equilibrium of 1 in solution (CD2Cl2, 8 mm,
298 K) is biased toward the benzamide NH in a ratio of 1.3:1.
The conformational equilibrium of 2 in solution is biased
toward the p-NO2-benzamide in a ratio of 1.9:1.
Having demonstrated the ability to predictably influence
the H-bonded equilibrium by modulating spatially removed
functional groups we returned to remote protonation. Com-
pound 1 provides a basic dimethylamine (pKb ꢀ 11 in MeCN/
H2O)[7] that is conjugated to the H-bond network. When
deprotonated, electron donation from the p-NMe2 biases the
conformation toward the benzamide NH in the solid state and
the solution phase. However, protonation to form the
dimethyl-ammonium ion should transform it into an elec-
tron-withdrawing group, leading to a conformational switch
(Scheme 3).
Figure 2. 1H NMR spectra of 1 (8 mm, CD2Cl2) with 0–6 equiv of TFA.
The peak labels correspond to the assignments in Scheme 3.
0.43 ppm downfield. The resonance corresponding to NHb
shifts Dd = 0.04 ppm upfield after 3 equiv then begins to move
downfield again upon addition of 4–6 equiv. The resonances
of the aryl protons Hc and Hd also shift downfield by 0.31 and
0.94 ppm, respectively. NOE and COSYexperiments after the
addition of 0, 2, and 3 equiv of TFA confirm the identity of the
salient peaks.
The downfield shift of Hc and Hd suggests that the
dimethyl-ammonium ion is acting as an electron-withdrawing
group whose influence is distance dependent, as demon-
strated by the greater shift of Hd compared with Hc. The shift
of NHa beyond NHb suggests that a conformational switch
may be occurring. Further analysis of the amide resonances is
complicated by the competing influences of the changing H-
bond equilibrium and the electronic effect of protonating the
NMe2 group.
Titration of compound 3 (Scheme 2) serves to isolate the
electronic effect of protonation by removing the intramolec-
ular H-bond. Addition of 0–6 equiv of TFA causes the p-
NMe2-benzamide and benzamide NH signals in 3 to migrate
0.04 and 0.05 ppm downfield (See Supporting Information).
Figure 3 compares the shift of the amide resonances in 1
and 3. Subtracting the shift of the p-NMe2-NH of 3 from that
of 1 yields the migration of NHa due only to the changing
conformational equilibrium (triangular markers, Figure 3).
The line in Figure 3 at d = 9.00 ppm corresponds to the amide
resonance of 4 in the absence of TFA (Scheme 2). Compound
4 balances two p-NMe2-benzamides and as such its amide
resonance should approximate the shift of NHa when the
conformational equilibrium ratio is 1:1. After 1 equiv of TFA,
NHaꢀs corrected resonance has moved downfield of the line,
indicating that the H-bonded equilibrium is now biased
Scheme 3. The proposed pH-dependent molecular switch based upon
compound 1.
+
toward the p-N(H)Me2 -benzamide. Using a similar method
The 1H NMR spectra of 1 (8 mm, CD2Cl2) in the presence
of 0–6 equiv of trifluoracetic acid (TFA) are shown in
Figure 2. The spectrum in the absence of acid depicts two
singlets at 9.26 and 8.95 ppm that can be assigned to NHb and
NHa in Scheme 3. Additionally the two doublets assigned to
Hc and Hd in Scheme 3 resonate at 7.87 and 6.72 ppm. Upon
addition of 6 equiv of TFA, the NHa resonance migrates Dd =
as in the neutral case the equilibrium ratio in the presence of
6 equiv of TFA is calculated to be 99:1 toward the dimethy-
lammonium-benzamide.
These results in solution and the solid state support the
presence of a conformational equilibrium between two H-
bonded configurations. The position of this equilibrium can
be predictably biased by conjugating electron-donating or
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^
*
Figure 3. The change in chemical shift of NHa ( ) and NHb ( ) of 1
^
*
as well as that for p-NMe2-NH ( ) and p-H-NH ( ) of 3 upon addition
~
of 0–6 equiv of TFA (8 mm, CD2Cl2). The markers represent the shift
of NHa minus the shift of p-NMe2-NH of 3. The line at d=9.00 ppm
represents the amide resonance of 4 in the absence of TFA.
-withdrawing groups to the H-bond network. Furthermore,
we show that the pH-dependent conversion of a donating
group to a withdrawing group is communicated to the remote
H-bond network, triggering a conformational switch.
Received: September 2, 2011
Keywords: conformational dynamics · diphenylacetylene ·
hydrogen bonding · molecular switch · pH dependence
.
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