Phenazine-1,6-dicarboxamides: Redox-Responsive Molecular Switches

Article abstract of DOI:10.1021/jacs.9b11160

We introduce phenazine-1,6-dicarboxamides as redox-responsive molecular switches. The reduction of their phenazine core transforms them from hydrogen-bond acceptors into hydrogen-bond donors and thus forces the secondary amide substituents to turn around.

Full text of DOI:10.1021/jacs.9b11160

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Communication
Phenazine-1,6-dicarboxamides: redox-responsive molecular switches
Jingwei Yin, Ali N. Khalilov, Pandi Muthupandi, Ruby Ladd, and Vladimir B. Birman
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b11160 • Publication Date (Web): 24 Dec 2019
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Phenazine-1,6-dicarboxamides: redox-responsive molecular switches
Jingwei Yin, Ali N. Khalilov, Pandi Muthupandi, Ruby Ladd, Vladimir B. Birman*
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Washington University Department of Chemistry, Campus Box 1134, One Brookings Drive, Saint Louis, Missouri, 63130.
Supporting Information Placeholder
Our basic design is illustrated in Figure 1a. The phenazine nitro-
ABSTRACT: We introduce phenazine-1,6-dicarboxamides as re-
gens in structure 1 serve as hydrogen bond acceptors and thus de-
termine the orientation of the adjacent carboxamide moieties. The
reduced 5,10-dihydrophenazine form (2), on the other hand, func-
tions as a double hydrogen bond donor, which favors the opposite
orientation of the amide groups.9 Thus, reduction-oxidation of this
system will be accompanied by ca. 180° rotation of the two parallel
bonds shown in blue. A chain composed of such molecular
switches and cisoid spacers (shown in black) is predicted to fold in
a butterfly-coil fashion, i.e., forming loops with regularly alternat-
ing chirality (Figure 1b).10
dox-responsive molecular switches. Reduction of their phenazine
core transforms it from a hydrogen bond acceptor into a hydrogen
bond donor and thus forces the secondary amide substituents to turn
around. The resulting conformational changes are envisioned to
form the basis for butterfly-coil foldamers undergoing reversible
extension and contraction in response to changing their oxidation
state.
Foldamers1 capable of changing their linear dimensions quickly
and reversibly in response to an external stimulus may be viewed
as molecular actuators,2 which could form the basis for designing
artificial muscles and other functional materials.3 Existing stimuli-
responsive foldamer designs incorporate molecular switches that
change their conformation in response to irradiation,4 protonation,5
or introduction of other ions,6 or neutral organic molecules.7,8 How-
ever, from the practical standpoint, the most convenient way to
stimulate a molecular actuator would be via a redox process, which
could be achieved electrochemically and reversed simply by
switching the direction of electric current. Furthermore, it would be
desirable to design a system that would not require the migration of
large ions, but rely only on the flow of electrons and protons. In
this Communication, we describe a new type of molecular switch
that satisfies these requirements.
To test the basic premise of our design, we first synthesized
model bis-amide 6 via the route shown in Scheme 1. Hydrogen
bonding between the amide protons and the adjacent phenazine ni-
trogens and methoxy groups was predicted to favor the desired dou-
bly folded conformation. Indeed, the NOESY spectrum of 6 con-
tained the diagnostic interactions shown in purple (a—d, d—e, e—
a), which confirmed the expected geometry. Next, we set out to
demonstrate the unfolding of model compound 6 under reducing
conditions. To this end, we chose catalytic hydrogenation, so as to
avoid by-products that would complicate the subsequent isolation
and NMR analysis. Stirring 6 under 20 psi of hydrogen in the pres-
ence of palladium on carbon converted it cleanly to the highly air-
sensitive dihydrophenazine 7. To our satisfaction, the NOESY
spectrum of 7 displayed interactions between the amide protons d
and ortho-protons c, indicating that the expected unfolding did in-
deed take place. Upon exposure to air, 7 reverted cleanly to 6.
Scheme 1. Proof-of-principle study
Figure 1. Phenazine-based molecular switch and butterfly-coil
folding geometry.
With these results in hand, we proceeded to design a symmetrical
spacer that would encourage the phenazine moieties to stack in an
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offset, antiparallel orientation, as required by the butterfly coil ge-
Coupling 4 with two equivalents of 2,7,9,9-tetramethylxanthene-
4,5-diamine 9 afforded symmetrical derivative 10. In contrast to 6,
which is essentially flat, the xanthene moieties in compound 10 are
twisted significantly out of the plane of the phenazine nucleus (ca.
33° dihedral angles, according to DFT calculations). Geometry op-
timization predicted two stable conformers of 10: a C2-symmetrical
one, with the two amino groups positioned over the same face of
the phenazine, and a centrosymmetrical one, in which the amino
groups are on the opposite faces. It is the latter conformation that
corresponds to the geometry of each phenazine unit in the proposed
butterfly coil. Computer-assisted modeling indicated that trans-
forming the amines into benzamide moieties, which cannot fit on
the same face of the phenazine nucleus, would effectively ensure
that the product would adopt the desired centrosymmetrical confor-
mation exclusively.11 With this in mind, diamine 10 was subjected
to bis-acylation with 3,4,5-trimethoxybenzoyl chloride 11 to afford
12 as a bright-red crystalline solid.
ometry represented schematically in Figure 1b. With the help of
computer-assisted modeling, we identified xanthene-4,5-diamines
as promising candidates for this role. For example, tetramer 8 (de-
picted in Figure 2 in extended form for ease of illustration) was
predicted to fold as shown below.
1
2
3
4
5
6
7
8
Me Me
Me Me
Me
Me
Me
Me
O
O
H
H2
N
O
O
N
N
H
O
O
N
NH2
H
N
N
N
N
N
9
N
N
N
H
H
H
H
O
N
N
O
O
N
N
O
10
11
12
13
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8
O
O
Me
Me
Me
Me
Me Me
Me Me
X-ray crystallography confirmed that compound 12 adopted the
expected folded conformation in solid state (Figure 3). The tri-
methoxyphenyl groups were found in a parallel, slightly offset
face-to-face orientation relative to the central pyrazine ring, with
ca. 3.7 Å distance between the centers, consistent with π-stacking.
The C1/C6 carboxamide groups formed hydrogen bonds to the
phenazine nitrogens and the xanthene oxygens, estimated at ca. 1.9
Å and 2.3 Å, respectively, in complete agreement with computer
modeling.
Figure 2. Predicted folded structure of tetramer 8.
h
h
Me
Me
f
g
i
j
Me
Me
Me
Me
O
Me
Me
e
k
MeO
MeO
O
d
Cl
11
l
O
N
NH2
O
H
NH2
NH2
a
N
b
c
OMe
c
9
(2 equiv)
DMF (79%)
4
b
Py, CH2Cl2
N
a
Figure 3. X-ray structure of 12.
l
H
O
e
NH2
d
N
The folded conformation was found to be favored in solution as
O
k
1
10
well. The H NMR spectrum of 12 in CDCl3 revealed that ortho-
j
f
protons m/m′ were strongly shifted upfield (δ 5.8 ppm vs. δ 7.3
ppm in simple 3,4,5-trimethoxybenzamides), presumably due to
shielding by the phenazine nucleus. The shielding effect persisted
in the presence of protic and polar solvents (80% CD3OD-20%
CDCl3, DMSO-d6). Moreover, the chemical shifts of m/m′ were
not affected appreciably by temperature changes when heated up to
75 °C in DMSO-d6 or cooled down to –75 °C in CD2Cl2. A NOESY
spectrum of 12 confirmed the proximity of both sets of amide pro-
tons (d and l) to each other and to the a protons on the phenazine
nucleus.
Me
Me
g
i
Me
Me
h
h
h'
g
h
Me
Me
i
f
j
Me
e
Me
k
O
m'
o
d
l
N
O
N
O
MeO
n
H
OMe
H
a
MeO
m
b
N
H
H
c
It should be noted that the point symmetry of the folded structure
of 12 is expected to render geminal methyl groups h and h′ on the
xanthene moieties diastereotopic. However, at ambient temperature
they produce one sharp singlet in 1H NMR, and only begin to sep-
arate into a diastereotopic pair at –42 °C (Figure 4), which trans-
lates into an energy barrier of 10.9 Kcal/mol, according to the
Eyring-Polanyi equation.12 This observation indicates that the
folded conformation, although thermodynamically favored, is ki-
netically quite mobile. This allows the xanthene moieties to flip
rapidly on NMR timescale resulting in the interconversion of two
degenerate centrosymmetrical conformers X and X′, as illustrated
m
H
n'
n
b
NMeO
H
a
OMe
H
OMe
O
O
d
N
l
N
o
O
12
k
e
j
f
Me
Me
i
g
Me
h'
Me
h
Scheme 2. Synthesis of single unit model 12.
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schematically in Figure 5. As an aside, it may also be observed that
Our next objective was to demonstrate the opening of the single
unit model in response to reduction. Catalytic hydrogenation of 12
was carried out similarly to that of 6 to give rise to the expected
dihydrophenazine 13 (Scheme 3). As the first sign of its conforma-
tional change, we observed that aromatic protons m shifted from
5.8 to 7.0 ppm, which was consistent with the expected structure
with diminished shielding. Furthermore, the two sets of amide pro-
tons (Hd and Hl) no longer displayed NOE with protons a. Instead,
NOESY indicated the proximity of amide protons d to aromatic
proton c on the dihydrophenazine nucleus. As with the simpler
model (cf. 7 above), dihydrophenazine 13 quickly oxidized back to
12 on exposure of its solution to air.
the signals due to aromatic protons m/m′ and methyl groups n/n′
broaden around –65 °C as the rotation of the trimethoxyphenyl
groups slows down.
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In conclusion, we have demonstrated the feasibility of using phen-
azine-1,6-dicarboxamides as redox-responsive molecular switches.
Our current efforts are focused on optimizing the design of the
cisoid linkers and the phenazine building blocks and assembling
them into short oligomers. We are also exploring electrochemical
methods for their reduction-oxidation.13 Our studies in these direc-
tions will be published in due course.
ASSOCIATED CONTENT
Supporting Information
Figure 4. Variable-temperature experiment (300 MHz).
The Supporting Information (experimental procedures, computa-
tional studies, characterization data, NMR spectra, and X-ray crys-
tallographic data for 12) is available free of charge on the ACS
Publications website.
AUTHOR INFORMATION
Corresponding Author
birman@wustl.edu
ORCID
Vladimir B. Birman: 0000-0003-0299-358X
Present Addresses
Figure 5. Double flip
Dr. Ali N. Khalilov, (a) Organic Chemistry Department, Baku State
University, Z. Xalilov str. 23, Az, 1148 Baku, Azerbaijan and (b)
Department of Physics and Chemistry, "Composite Materials" Sci-
entific Research Center, Azerbaijan State Economic University
(UNEC), H. Aliyev str. 135, Az 1063, Baku, Azerbaijan.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank our colleagues Prof. John-Stephen Taylor and Kevin
Moeller for helpful discussions on this project and Dr. Jeff L.-F.
Kao for his kind assistance with NMR analysis. Bureau of Educa-
tional and Cultural Affairs (Fulbright Scholarship to Dr. Ali N.
Khalilov) and National Science Foundation (CHE 1566588) are
gratefully acknowledged for their sponsorship of this study.
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