Acylhydrazone Subunits as a Proton Cargo Delivery System in 7-Hydroxyquinoline

Article abstract of DOI:10.1002/chem.202101650

The reimagined concept of long-range tautomeric proton transfer using crane subunits is shown by designing and synthesising two new acylhydrazones containing a 7-hydroxyquinoline (7-OHQ) platform. The acylhydrazone subunits attached to the 7-OHQ at the 8t

Full text of DOI:10.1002/chem.202101650

Accepted Article
Accepted Article
Title: Acylhydrazone Sub-Units as a Proton Cargo Delivery System in
7-Hydroxyquinoline
Authors: Liudmil Manolov Antonov, Kosuke Nakashima, Anton Petek,
Yutaro Hori, Anton Georgiev, Shin-ichi Hirashima, Yasuyuki
Matsushima, Dancho Yordanov, and Tsuyoshi Miura
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.202101650
Link to VoR: https://doi.org/10.1002/chem.202101650
01/2020

10.1002/chem.202101650
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Acylhydrazone Sub-Units as a Proton Cargo Delivery System in 7-
Hydroxyquinoline
Kosuke Nakashima,*[a] Anton Petek,[b] Yutaro Hori,[a] Anton Georgiev,*[c][d] Shin-ichi Hirashima,[a]
Yasuyuki Matsushima,[a] Dancho Yordanov,[e,f] Tsuyoshi Miura,[a] and Liudmil Antonov*[e]
[a]
Dr. K. Nakashima, Y. Hori, Dr. S. Hirashima, Dr. Y. Matsushima, Prof. Dr. T. Miura
Department of Medicinal Chemistry
Tokyo University of Pharmacy and Life Sciences
1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
E-mail: knakashi@toyaku.ac.jp
[b]
[c]
A. Petek
Humboldt-Universität zu Berlin
Brook-Taylor-Straße 2, 12489 Berlin, Germany
Dr. A. Georgiev
Department of Organic Chemistry
University of Chemical Technology and Metallurgy
8 St. Kliment Ohridski blvd, 1756 Sofia, Bulgaria
E-mail: antonchem@abv.bg , Personal Twitter: @AntonGeorgiev82
Dr. A. Georgiev
Institute of Optical Materials and Technologies, Bulgarian Academy of Sciences
Acad. G. Bonchev avenue, bldg. 109, 1113 Sofia, Bulgaria
Dr. D. Yordanov, Prof. Dr. L. Antonov
[d]
[e]
Institute of Electronics, Bulgarian Academy of Sciences
72 Tzarigradsko chaussee blvd, 1784 Sofia, Bulgaria
E-mail: lantonov@tautomer.eu
[f]
Dr. D. Yordanov
Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences
Acad. G. Bonchev avenue, bldg. 9, Sofia 1113, Bulgaria
Supporting information for this article is given via a link at the end of the document.
Abstract: The reimagined concept of long-range tautomeric proton
transfer using crane sub-units has been presented by designing and
synthesising two new acylhydrazones containing 7-hydroxyquinoline
(7-OHQ) platform. The acylhydrazone sub-units attached to the 7-
OHQ at 8th position act as a crane arm for proton cargo delivery to
the quinoline nitrogen. Light-induced tautomerization to their keto
tautomers leads to Z/E isomerization of the C=C axle bond, followed
by proton delivery to the quinoline nitrogen by covalent or hydrogen
bond formation. The axle being either imine or ketimine bond is the
structural difference between the studied compounds. The -CH3
group in the latter provides steric strain, resulting in different proton
transport pathway. Both compounds show long thermal stability in
the switched state, which creates a tunable action of bidirectional
proton cargo transport by using different wavelengths of irradiation.
Upon addition of acid, the quinoline nitrogen is protonated, which
results in E/Z configurational switching of the acylhydrazone sub-
units. This was proven by single crystal X-ray structure analysis and
NMR spectroscopy.
rigid platform, they have successfully studied programmable
mono, di- and tri-peptide cargo transport using acid input as a
fuel.[11] Despite the impressive achievement of bidirectional
molecular transport by using
a
hydrazone bond, the
development of new architectures is still a challenging field.10,11
Conditions for a rapid, strictly controlled, and reversible change
to an end state, fuelled by light or chemically can be achieved
through an appropriate molecular design.[16,17] Single isomer in
the initial state is one of the specific requirements for the “ideal”
photoswitch. The developed, up to now, rotary switches,
whether hydrazones[12,13] or enamines, [18–20] exist as a mixture of
E- and Z- isomers in their initial state. Fundamental enol/keto
ground or excited state short range tautomerism [21] has already
being applied in different fields, ranging from photonics[22–26] to
biomedicine.[27–31] However, the development of the long-range
proton cargo transport function could unveil new areas of
application of smart switching materials and reveals a new
horizon for designing cutting-edge architectures tuned to
perform specific functions like controlled cargo transport. The
long-range proton transport from one site of the molecule to
another through intramolecular dynamic covalent bonding is
especially promising for the design of new proton based
switches.
The intramolecular motion triggered by light or chemical fuels is
a driving force of the artificial molecular switches.[1–8] The
concept of controlled E/Z isomerization allows for a challenging
design of molecular architectures performing specific functions
such as unidirectional rotation and intramolecular cargo
transport.[9–13] Recently, Leigh and co-workers[9] have
demonstrated selective small-molecule cargo transport by
repositioning of 3-mercaptopropanehydrazide in either direction
Molecular switches able to transport a proton from one to
another site of the molecule via intramolecular hydrogen
bonding interaction (IMHBI) are promising systems because the
large π-electron rearrangements result in strong changes in their
physicochemical
properties.[32,33]
In
this
fashion,
7-
between two sites
2 nm apart. This was achieved by
hydroxyqiunoline (7-OHQ) is a very promising platform for
designing new architectures for proton cargo delivery, because
direct intramolecular proton transfer from the OH group to the
quinoline nitrogen (Nquin) is unlikely to proceed by itself due to
incorporating a quinoline unit into a rigid platform through a
hydrazone group linkage to the rotor in order to control the
directional movement of the mechanical arm. By using a similar
1
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10.1002/chem.202101650
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the large distance and lack of facilitating IMHBI (Scheme 1A).
Therefore, the long-range intramolecular proton transport can be
facilitated by the incorporation of a crane arm at 8th position in 7-
OHQ. Until now, the design and studies of similar systems are
scarce. Varma and co-workers[34] have studied the photophysical
crane, where the proton transport is achieved by the
photoexcitation and formation of zwitterionic excited state
structure, followed by the rotation around a single C-C axle bond
[35]
with proton delivery to the Nquin
.
The studied compound is
characterized by a short lifetime in the switched keto state
(within 40 ns), which is energetically unfavourable in the ground
state.
properties
of
7-hydroxy-8-(N-morpholinomethyl)-quinoline
representing a non-conjugated and pseudo-tautomeric proton
H
N
H
O
un
e
lik ly
t
O
N
r
p
n r n r
o o a s e
A
)
t
f
e o
K t
no
E
l
v r
e conce on or ro on car o
e
e
Th
pti
f
p
t
d li y
g
-
=
x
un
it
a e
x
un
it
a e
l
C C
l
C C
crane
crane
H
H
H
H
O
v r
o
y f H
e
d li
e
z
n
somer a o
B
)
N
u
i
i
ti
O
N
c
N
O
N
O
pi k p H
K1Z
K2E
K2 H
Q
s a or
t t
no
E
l
Scheme 1. Unlikely intramolecular proton transfer in 7-OHQ (A) and proton transport by crane sub-unit incorporated at 8th position in 7-OHQ (B).
As depicted in Scheme 1B, under suitable stimuli, the
conjugated crane sub-unit, which possesses proton-acceptor
properties and enables six-membered IMHBI, can pick up the
tautomeric H resulting in keto form K1Z, where the axle acquires
double bond character. Further isomerization of the C=C axle by
light to K2E leads to a movement of the attached proton to the
Nquin site, followed by delivery of the tautomeric proton and
formation of a H-Nquin covalent bond in the stable K2QH form.
The release of the proton restores the single C-C character of
the axle indicating the end state of the switching process
(Scheme 1B). The original enol form can be recovered either by
visible light or by thermal relaxation.
parameters such as ground and excited states energy
landscape of proton transport (tautomerization, isomerization
and delivery), providing effective switching through Z/E
isomerization.
The ground state DFT calculations in acetonitrile (ACN) indicate
enol/K1Z tautomerization, favouring exclusively the enol form
(Scheme 2B). Experimentally, the results were confirmed by the
single peaks around 13 ppm (OH) in 1H-NMR spectra,[38] (see
NMR characterization data in SI) and by an absorption
[39]
maximum around λmax= 360 nm typical for the enol
form
(Figures S1-S3), which proves the existence of
a
single
tautomer in the initial state. Upon photoexcitation, the relatively
stable K1Z* tautomer of 1a is populated by excited state
intramolecular proton transfer (ESIPT) from the enol* tautomer.
Further cascade reactions of K1Z*/K2E* isomerization, followed
by NH-Nquin tautomerization (delivery of H) to the most stable
K2QH* tautomer and its ground state relaxation, enable the
formation of H-Nquin covalent bond in the ground stable K2QH
tautomer (Scheme 2B). The dynamic absorption spectra in ACN
We present a new concept for proton cargo delivery system
using 7-OHQ platform (stator) by incorporation at 8th position of
two types of acylhydrazone crane sub-units, containing axle
imine and ketimine bonds (1a and 2a, respectively in Scheme
2A). The structural feature of 2a provides a sterically hindered
CH3 group in the axle unit in order to facilitate the intramolecular
crane motion compared to the 1a. Their synthesis and
characterization are presented in the Supplementary information. after 365 nm UV light irradiation display a decrease of enol
The corresponding model compounds (1b and 2b, see part 2 in
the Supplementary information), containing simple 2-
hydroxynaphthyl stator instead 7-OHQ, were synthesized and
used for comparison.
absorption and a new red-shifted band, appearing above 400
nm (Figure 1A), which is in agreement with TD-DFT spectra
prediction (Figure S1). The photostationary state (PSS) is
achieved in 150 s (k = 4.90×10-2 s-1 and k = 4.81×10-2 s-1 in
toluene and ACN, respectively) with switching of approximately
50 % (Figure S4 and Table S1). The K2QH isomer is identified
a
It is well known that acylhydrazones are new and promising
photoswitch families, which are characterized by highly effective
working parameters (fatigue resistance and quantum yield) and
tunable photochromic action (from unstable T-type to thermally
stable P-type)[36],[37]. Due to their very good optical bands
separation between Z- and E-isomers, we chose them as crane
sub-units for bidirectional proton transport. Through DFT
molecular design we have evaluated a number of working
1
in the H-NMR spectrum as a new peak at 7.48 ppm for H-Nquin
(Figure 2). The complete reversible switching to the original enol
is favored by visible light at λ=425 nm, taking up to 60 min
(Figure 1C), or by dark relaxation displaying thermal half-lives
approximately 60-70 min (Figure S5) in both solvents, which
means that this is a relative bistable system for proton cargo
delivery, controlled in both directions. A reasonable explanation
2
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of this behaviour is the approximate planarity of the
acylhydrazone crane-sub unit in respect to the quinoline ring in
the initial enol and end K2QH isomer, which are stabilized by
IMHBI (Scheme S4). Acylhydrazone 1a reveals the opportunity
of using a dynamic covalent bonding through a proton cargo
allows for tuneable control of long-range proton transport
triggered by different light wavelengths. For a comparison, the
fundamental enol/keto phototautomerization followed by Z/E
isomerization in 1b containing 2-hydroxynaphthyl stator, leads
only to the thermally unstable K2E isomer (Scheme S6, Figure
S7, Table S1).
transport between both switched states.
A
well-defined
absorption bands separation between initial and end forms
nm
s
Vi light
425
HN
N
O
o or
R t
nm
365
UV light
H
H
a
f
1
o
H
N
nm
g
UV li ht
,
H 1
365
=
=
y
r
A
a
,
R
R
)
e
v
n
i
n
o
O
i
l
u
e
a
2
-
H
H
C
Nq
i
t
cova en on
n
d
3
l
t b di
e
g
a
z
i
r
N
e
c
u
o
o
pi k p H
f H t th Nq
u n
i
m
o
t
u
a
t
HN
N
O
NH
N
NH
O
O
-
z
i
n
somer a o
K2
Q
H
eno e o
l k t
i
ti
e
R
R
N
R
=
x
a
z
i
n
au omer a o
l
C C
t
t
ti
H
N
H
O
H
O
O
N
N
K1Z
a or
t t
HN
N
O
S
a
2
no
l
H
O
3C
E
H
N
ro en on
n
di
g
hyd
g
b
o
o
e
f H t th Nq
u n
i
nm
254
UV light
K2E
B
)
*
x
e c e s a e
it d t t
S1
.
31 9
*
.
.
.
.
T 2
S
9 5 0 55
(
)
)
F
C
7 7 74
0
(
.
.
.
.
.
.
.
.
2 2
7
0 0 0
8
2 0 0 30
(
0 5
.
(
)
)
)
-
*
*
0 0 0 94
T 1
S
1 1
(
K1Z
-
-
.
.
2 3 0 36
(
)
*
*
no
E
l
T 3
S
.
.
2 9 0 61
(
)
*
K2E
-
-
.
.
.
.
9 5 0 24
(
)
9 8 0 28
(
)
*
K2
H
Q
-
.
.
12 8 0 0
(
)
*
K1Z
.
a
7
33
2
.
23 4
roun s a e
d
t t
S0 g
.
a
T 2
S
1
13 2
.
9 8
.
7
8
T 3
S
.
.
.
.
.
6 9
.
.
6 9 0 24
(
)
)
6 6 0 21
(
)
.
.
6 3 0 14
T 1
S
(
.
.
6 4 0 20
(
)
4 2 0 12
(
)
.
.
K2E
K1Z
4 2 0 11
(
)
.
.
.
.
K2
H
0 0 0 44
Q
(
)
0 0 0 58
(
)
no
E
l
Scheme 2. Representation of bidirectional proton cargo delivery in 7-OHQ platform by acylhydrazone crane sub-units in 1a and 2a (A) and theoretically predicted
energy landscape (black for 1a and blue for 2а) in the S0 and S1 states (B) using implicit solvation ACN. The Franck-Condon (FC) state is given for the enol
tautomers. The relative stabilities are given in kcal mol-1 with corresponding oscillator strength in brackets.
3
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Figure 1. Dynamic absorption changes of 1a and 2a upon 365 nm UV light until PSS in ACN (A, B). Recovery to the initial state of 1a upon 425 nm Vis light (C)
and 2a upon 254 nm UV light (D). The inset graphic represents thermal stability of 2a at PSS up to 12 h. The comparative results for 1b and 2b are shown in
Figures S7 and S8 resp.
Figure 2. 1H-NMR spectra of 1a before irradiation (up, black) and after irradiation with UV-light at λ = 365 nm until PSS (down, red).
4
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The sterically hindered axle in 2а leads to a different proton
transport pathway. Steric strain caused by the CH3 group leads
to spontaneous ESIPT from enol* to the substantially more
stable K1Z* tautomer. In the latter, the acylhydrazone cargo sub-
unit is nearly perpendicular in respect to the quinoline ring
(Scheme S5), resulting in a ground state relaxation through
conical intersection to the more stable K2E state (Scheme 2B).
Such scenario has been theoretically described by
Sobolewski,[40] using ab initio study of various crane sub-units in
7-OHQ platform. Compared to the significantly nonplanar enol
and K1Z tautomers (Scheme S5), the planar and stabilized by
IMHBI K2E structure is responsible for the long thermal stability
of the switched system. The latter exhibits almost the same
absorption as the enol form, but with lower oscillator strength as
the TD-DFT calculations suggest (Figure S1). Indeed, the
theoretical data was confirmed by the dynamic absorption
changes upon 365 nm UV light irradiation, where no new
absorption band above 400 nm was observed (Figure 1B). This
means that the proton is delivered to the Nquin site by formation
of an intramolecular hydrogen bond. Further analysis of the
NMR spectra of 2a at PSS displays downfield of the OHa peak at
13.19 ppm toward the NHa one at 12.90 ppm (Figure S6).
Moreover, the rotamer signals of CH3 at 2.80 and 2.16 ppm
significantly decrease and a new single peak at 1.66 ppm
appears at PSS, indicating a nearly planar structure of K2E. As
expected from DFT calculations, the switched system shows
long thermal stability. Even after 12 h it remains unrecovered
confirming the bistable P-type photochromic behaviour (Figure
1D inset graphic). By applying 254 nm UV light irradiation, full
recovery to the initial state takes up to 150 s (k = 6.07×10-2 s-1)
(Figure 1D). The kinetics of enol/K2E switching in toluene is
similar as in ACN, but the recovery of the initial state takes up to
60 min by dark relaxation (Figure S4 and Table S1), which
compared to the long thermal stability in ACN indicates T-type
photochromism. The results of the photodynamic study of 2a
reveal the influence of solvent polarity on bidirectional proton
cargo transport. The polar stabilization of IMHBI of K2E in ACN
compared to the less favourable stabilization in toluene is the
reason for this behaviour. The structural differences in the two
acylhydrazone crane sub-units show two distinct light-fueled
pathways by exploiting dynamic covalent (1a) and hydrogen (2a)
bonding for proton cargo transport to the Nquin site in 7-OHQ,
operating in both directions. Moreover, the structural feature of
2a in the sterically hindered axle suggests not only light-driven
proton transport, but also solvent-driven control in the switched
state over the kinetics of thermal relaxation to the initial state.
switching under acid input by trifluoroacetic acid (TFA), because
they exist as single enol tautomers in the initial state and the
protonation of Nquin induces configurational switching by rotation
around the C-C single bond axle to the most stable Z-HQH
isomer (Scheme 3A). Inherently, external acid input, represents
proton delivery to the Nquin and forces the acylhydrazone sub-
units into the switched state due to the formation of stable IMHBI.
Ground state proton exchange to the Z-H form is obviously
unlikely due to the positive charge formation on the C=N group
with restricted π-delocalization, compared to the extended one
in quinoline ring of Z-HQH tautomer. We assume that two
factors play a substantial role in the acid switching: (i) Nquin
protonation and concomitant rotation of acylhydrazone units to
the Z-HQH enables stabilization of the cation by IMHBI; (ii)
breaking the IMHBI in the enol form and intermolecular H-
bonding with the TFA anion. According to the ground state
theoretical predictions, the Z-HQH isomer, obtained from the
protonated enol-H via barrierless transition, was found to be the
most stable one (Scheme 3B). The predicted switched form of
1a, stabilized by intermolecular hydrogen bonding between the
OH group and the TFA anion was confirmed by single crystal X-
ray structure analysis (Scheme 3C). The TD-DFT (Figure S9)
and experimental absorption spectra (Figure 3A, B), in
agreement, demonstrate red-shifted bands, at λmax = 378 nm
(1a) and 363 nm (2a), upon acid input. The process is
accompanied by rising red-shifted emission with large Stokes
shifts, corresponding to ESIPT towards the azomethine nitrogen
as suggested by Scheme 3A. The acid-switched state is fully
reversible to the original enol by triethylamine (TEA) stepwise
titration and demonstrates
a bidirectional chemically-driven
switching system. Due to the availability of pure forms in the
initial and end states the studied 7-OHQ acylhydrazones are
close to the ideal switch. Indeed, the comparison of the 1H-NMR
spectra of neutral and protonated 1a unequivocally proves the
process (Figures 3C). Through fast proton exchange with the
TFA anion, the OH signal of the switched form disappears, while
the protonated quinoline ring is characterized by a new peak at
7.77 ppm and downfield quinoline Hf at 8.83 ppm compared to
the neutral form (8.23 ppm). Moreover, a strong upfield of the
azomethine proton (9.34 ppm) is observed (compared to the
neutral form at 9.85 ppm) as a result of the rotation and the lack
of interaction with the protonated Nquin, which makes this signal
specific for monitoring the process. For structure elucidation of
the switched system in CD3CN, the 2D COSY and NOESY NMR
are presented in Figure S11. The corresponding results of 2a
are shown in Figure S12. For comparison, the protonated
acylhydrazones containing a 2-hydroxynaphthyl stator (1b and
2b) do not show switching under the same conditions (Figure
S13).
Intramolecular motion, triggered not only by light, but also by
chemical fuels is one of the advantages of using acylhydrazone
units in the 7-OHQ platform. The compounds are suitable for
5
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COMMUNICATION
,
H 1
=
=
a
,
R
R
A
)
a
2
H
C
3
NH
N
NH
N
O
HN
N
HN
N
O
O
O
-
-
>
=
N
C
H Nq
u n
i
R
R
R
R
-
TFA
TEA
z
n
au omer a o
ro a on aroun
t ti
ax e
l
H
N
t
t
i
ti
H
O
H
N
H
N
d
C C
N
O
O
O
O
O
O
H
O
H
O
H
O
-
-
-
no
Z H
no
F
F
E
l H
E
l
F
F
Z H
H
F
Q
F
F
F
F
B
)
roun s a e
t t
S0
g
d
.
.
0 1
0 0
-
T
S
no
l H
E
a
1
-
.
5 1
a
2
-
Z H
-
.
-
.
11 1
-
11 5
-
Z H
Z H
H
Q
-
.
17 1
-
Z H
H
Q
C
)
TFA
TEA
Scheme 3. Reversible acid/base switching of 1a and 2a upon addition of TFA/TEA (A), ground state energy landscape of the possible isomers (B), and ORTEP
drawings of 1a enol and switched Z-HQH state at the 50 % probability level (C).
6
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Figure 3. Absorption and emission spectra of 1a and 2a in ACN before (black) and after 1 eq. TFA addition (red). Restoration of the original form by stepwise
titration with 1 eq. (grey lines) TEA (A, B). NMR spectra of 1a in CD3CN before (black) and after 1 eq. TFA (red) addition (C).
In summary, light- and acid-initiated switching was exploited in
two new acylhydrazones containing 7-OHQ stator. Their
structural differences in the axle bond allow for light-fuelled site-
to-site proton transport by intramolecular dynamic covalent
bonding to the K2QH form in the 1a imine acylhydrazone crane
sub-unit, while the 2a CH3 steric strained crane demonstrates
proton delivery to the Nquin site stabilized by IMHBI in K2E form.
Long thermal stability of the switched states allows for
bidirectional light-driven long-range proton transport control. The
sterically hindered axle in 2a features not only light-driven proton
transport, but also solvent-driven control over the kinetics of
thermal relaxation to the initial state. The selective proton
delivery pathways suggest expanding the range for using the
tautomerism phenomenon in light- and solvent-driven artificial
proton based switches. Configurational E/Z switching upon acid
input demonstrates external proton delivery by protonation of
Nquin resulting in rotation of the acylhydrazone units followed by
formation of stable intramolecular hydrogen bonding with the
protonated quinoline ring. The chemically-driven switching
provides a clean, reversible and controlled transition between
the initial and end states and was proven by NMR spectroscopy
and single crystal X-ray structure analysis. The designed
acylhydrazone proton based switches using 7-OHQ platform
give а reason for reimagining and expanding the vision of
fundamental enol/keto tautomerization toward long-range proton
transport as cutting-edge switching materials with highly
tuneable action environment.
Acknowledgements
The authors thank the Bulgarian National Science Fund,
National Research Program VIHREN by project T-Motors
(contracted as KP-06-DV-9/2019), for the financial support for
this investigation. AG thanks the project КП-06-Н38/15 of
Bulgarian National Science Fund. The research equipment of
Distributed Research Infrastructure INFRAMAT, part of
Bulgarian National Roadmap for Research Infrastructures,
supported by Bulgarian Ministry of Education and Science was
used in this investigation.
7
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Chemistry - A European Journal
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Keywords: Acylhydrazones, density functional theory
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10.1002/chem.202101650
Chemistry - A European Journal
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Entry for the Table of Contents
Two structurally different acylhydrazones containing imine (1a) and ketimine (2a) functions have been evaluated as proton cargo
delivery sub-units in the 7-hydroxyquinoline platform. The tautomeric OH proton was delivered to the quinoline nitrogen by covalent
(1a) and hydrogen (2a) bonding. The system is characterized by long stability in the switched state, enabling for control of
bidirectional proton motion under different light energy.
9
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