Regulating signal enhancement with coordination-coupled deprotonation of a hydrazone switch

Article abstract of DOI:10.1039/c4sc02882a

Proton relay plays an important role in many biocatalytic pathways. In order to mimic such processes in the context of molecular switches, we developed coordination-coupled deprotonation (CCD) driven signaling and signal enhancement sequences. This was ac

Full text of DOI:10.1039/c4sc02882a

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Regulating signal enhancement with coordination-
coupled deprotonation of a hydrazone switch†
Cite this: Chem. Sci., 2015, 6, 209
a
b
c
*
Justin T. Foy, Debdas Ray and Ivan Aprahamian
Proton relay plays an important role in many biocatalytic pathways. In order to mimic such processes in the
context of molecular switches, we developed coordination-coupled deprotonation (CCD) driven signaling
and signal enhancement sequences. This was accomplished by using the zinc(II)-initiated CCD of a
hydrazone switch to instigate an acid catalyzed imine bond hydrolysis that separates a quencher from a
fluorophore thus leading to emission amplification. Because CCD is a reversible process, we were able
to show that the catalysis can be regulated and turned “on” and “off” using a metalation/demetalation cycle.
Received 19th September 2014
Accepted 22nd September 2014
DOI: 10.1039/c4sc02882a
www.rsc.org/chemicalscience
in many biological signaling pathways (e.g. GTPases and phos-
pholipases),1 to yield signal enhancement (Scheme 1).11,12
Introduction
Herein, we demonstrate how the proton released in CCD can be
used in mimicking such processes through the acid catalyzed
hydrolysis of anthracen-9-yl-N-(4-nitrophenyl)methanimine13
(ANI). Furthermore, we show that the imine hydrolysis (i.e.,
catalysis) can be toggled “on” and “off” through metalation/
demetalation cycles.
Signal transduction in biological systems relies on receptors
that respond to specic inputs in the environment, and then
use catalytic reactions to amplify the signal into useful infor-
mation.1 This complex signaling network is regulated by
reversible feedback mechanisms that switch their activity “on”
and “off” to maintain homeostasis.2 Recently, there has been
interest in designing multicomponent systems3 that use
signaling cascades, whereupon one molecule acts as the input
to another, as a method towards mimicking the complexity4 of
biological processes. Such research is expected to shed light on
the origins of life,5 and lead to molecular computing,6 and
systems chemistry,7 among other developments. Molecular
switches and machines8 have been pursued in this context as
enzyme mimics that are capable of controlling through their
reversible, stimuli-dependent (mainly light) processes, the
active sites of catalysts.9 In doing so, these systems mimic the
regulatory activity demonstrated by enzymes.
Results and discussion
The 1H NMR spectrum of 1(E) (ref. 14) (Fig. 1b) shows the
presence of two deshielded resonances at d ¼ 15.22 and 11.39
ppm, originating from the intramolecularly H-bonded hydra-
zone and imidazolyl protons, respectively. The crystal structure
of 1(E) (Fig. 2a)15 also shows the existence of the intramolecular
H-bond between the hydrazone NH proton and quinolinyl (N3)
ꢀ
˚
and imidazolyl nitrogens (N5) (H1(N1)/N3, 2.35(1) A, 102.5(1) ,
ꢀ
˚
and H1(N1)/N5, 1.93(1) A, 135.8(1) , respectively). The ester
We have recently developed hydrazone-based rotary
switches10 that undergo congurational switching (i.e., E/Z
isomerization) through a bio-inspired, zinc(II)-initiated coordi-
nation-coupled deprotonation (CCD) process.10d We have also
demonstrated that CCD can be used in activating two different
switches through a sequence of proton relays.10f We reasoned
that the CCD induced reversible acid formation could be used to
drive a catalytic hydrolysis reaction, similar to what is observed
aSAMS Research Group, University of Strasbourg, Institut Charles Sadron, CNRS, 23
rue du Loess, BP84047, 67034, Strasbourg Cedex 2, France
bDepartment of Chemistry, School of Natural Sciences, Shiv Nadar University,
Scheme 1 The imidazolyl containing switch 1(E) undergoes CCD
upon addition of zinc(II) resulting in the release of a proton to the
environment. The acidification of the solution can be used to turn “on”
pH-sensitive dyes (S / P), which lead to fluorescence output. The
coupling of this process to a catalytic cycle leads to signal amplifica-
tion. This process is reversible as the molecular switch 1(Zn-E) can be
deactivated through demetalation.
Chithera, Tehsil Dadri, Gautam Budh Nagar-203207, Uttar Pradesh, India
cDepartment of Chemistry, Dartmouth College, 6128 Burke Laboratory, Hanover, NH,
USA 03755. E-mail: ivan.aprahamian@dartmouth.edu
† Electronic supplementary information (ESI) available. CCDC 862857 and
990962. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c4sc02882a
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between 1(E) and zinc(II), with a binding constant of Ka ¼ 1.6 ꢁ
104 Mꢂ1
.
During the titration of 1(E) with zinc(II) (Fig. S8 in ESI†) we
observed that CCD was accompanied by the protonation of non-
coordinated 1(E). In order to put the released proton to better
use (and simplify the characterization process), the CCD initi-
ated process was coupled with a newly developed pH-responsive
uorophore17 (morpholinyl-containing BODIPY (MBD)), which
resulted in the turn “on” of its uorescence emission (Fig. 1a).18
1H NMR spectroscopy analysis showed that the addition of 1
equiv. of zinc(II) to a 1 : 1 mixture of 1(E) and MBD (Fig. 1b)
yields 1(Zn-E) and the protonated MBD compound (MBD-H+)
(Fig. 1c). The formation of the former was conrmed by
comparing the spectrum obtained via CCD to the one obtained
by the dissolution of crystals used in the X-ray crystallographic
analysis of 1(Zn-E) (Fig. 1d). The formation of MBD-H+, on the
other hand, was conrmed by protonating MBD separately with
TFA (Fig. 1e). As can be seen in Fig. 1c protonation causes a
downeld shi of the phenyl signals of MBD; from d ¼ 7.17
(H11) and 7.05 (H10) ppm in the neutral form, to d ¼ 7.63 (H11)
and 7.78 (H10) ppm in the protonated one. No such shis are
observed when zinc(II) is added to MBD (Fig. S32 in ESI†) con-
rming that protonation results from CCD.
Fig. 1 (a) The compounds involved in the CCD initiated signaling event
1
that turns “on” the emission of MBD. The H NMR spectra (500 MHz,
CD3CN) of (b) 1(E) and MBD (1 : 1 mixture); (c) 1(Zn-E) and MBD-H+
obtained after the addition of 1 equiv. of zinc(II); (d) dissolved crystals of
1(Zn-E); and (e) MBD-H+ obtained after addition of TFA (8 equiv.) to
MBD.
This intermolecular proton relay was also probed using
uorescence spectroscopy (Fig. 3). Initially, the uorescence is
quenched most likely because of twisted intramolecular charge
transfer.17 Upon titration of zinc(II) into a 1 : 1 mixture of MBD
and 1(E), a steady ratiometric increase in uorescence intensity
(l ¼ 522 nm) was observed as a result of the protonation of
MBD. The effect reached saturation when 1 equiv. of zinc(II) was
added to the solution (Fig. 3, inset), resulting in a 1000-fold
increase in emission intensity.19 A limit of detection (LOD) of
3.9 mM was determined using this CCD initiated signaling
mechanism (Fig. S28 in ESI†).20
pH-Responsive uorophores17 have been extensively used in
sensing and molecular logic applications, and hence, the above
Fig. 2 ORTEP drawings (50% probability ellipsoids) of (a) 1(E) and (b)
1(Zn-E). The protons are placed in calculated positions, except for
those of the hydrazone N(1) atom, the imidazolyl nitrogen atoms N(4)/
N(5), and the water molecule, which were refined. The counter ion of
1(Zn-E) is not shown for clarity.
carbonyl oxygen also forms an intramolecular hydrogen bond
˚
with the imidazolyl NH proton (H4(N4)/O2, 2.21(1) A,
117.9(1)ꢀ). This additional intramolecular H-bond changes the
outcome of zinc(II)-initiated CCD in 1(E): instead of an instan-
taneous E / Z isomerization upon coordination to zinc(II)10d,f
the intramolecular H-bond locks the system in its E congura-
tion to form 1(Zn-E). This process was monitored and charac-
terized using 1H NMR spectroscopy (Fig. S5 in ESI†), which
shows the disappearance of the hydrazone NH proton, and an
up-eld shi of the imidazolyl NH signal (d ¼ 11.93 ppm) upon
coordination with zinc(II). Analysis of the crystal structure of
1(Zn-E) (Fig. 2b)16 reveals a shorter intramolecular H-bond
between the imidazolyl NH proton and ester oxygen (H5(N5)/O1,
ꢀ
˚
2.03(1) A, 123.9(1) ). The binding of zinc(II) with 1(E) was also
studied using UV/Vis spectroscopy (Fig. S25–S27 in ESI†). A
Job's plot analysis showed a 1 : 1 binding stoichiometry
Fig. 3 Fluorescence spectra (5 ꢁ 10ꢂ5 M, CH3CN) of a 1 : 1 mixture of
1(E) and MBD as a function of zinc(II) equivalents. The inset shows the
1000-fold increase in emission intensity.
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mentioned results are not unexpected.6 However, in most cases
the signaling event in such processes relies on one input
leading to one output, which is not suitable for designing
multicomponent signaling networks.3 In order to expand the
scope of our system (i.e., using a single input in generating
multiple outputs) and show its ability to reversibly control a
catalytic process we explored the potential of coupling the CCD
initiated signaling event with an amplication mechanism. We
hypothesized that the acid catalyzed hydrolysis of an imine
bond could be used to detach a quencher group from a uo-
rophore. For this purpose, we chose the weakly uorescent dye
ANI, which we speculated will undergo catalytic hydrolysis that
will detach the p-nitrophenyl quencher21 and yield the more
uorescent anthraldehyde emitter (Fig. 4a).
1
This catalytic process was studied using H NMR spectros-
copy (Fig. S22 in ESI†) with 10 mol% of 1(E). Upon adding
Fig. 5 The fluorescence spectra (5 ꢁ 10ꢂ5 M, CH3CN) obtained
through the CCD mediated catalytic hydrolysis of ANI.
10 mol% of zinc(II) a catalytic amount of acid is produced
through CCD that results in complete hydrolysis of ANI within
20 minutes. The maximum turnover number under these
conditions is 10, which means that at best each proton is now
leading to 10 outputs! This signal enhancement process was
also followed using uorometry (Fig. 5). Upon the addition of
10 mol% of zinc(II) to a 1 : 1 mixture of 1(E) and ANI a steady
increase in uorescence was observed (l ¼ 522 nm), which
reached saturation aer 180 minutes.22
Next we took advantage of the reversible nature of CCD
(Fig. S17 in ESI†) to regulate the catalysis and toggle it between
the “on” and “off” states. To follow this process we focused on
the diagnostic imine and aldehyde proton signals of ANI and
the anthraldehyde product, respectively (Fig. 4a). The initial
mixture (Fig. 4b) shows the characteristic imine signal of ANI at
d ¼ 9.77 ppm, and the hydrazone and imidazole NH proton
signals of 1(E) (catalytic amount)23 at d ¼ 15.25 and 11.38 ppm,
respectively. The addition of Zn(ClO4)2 to the mixture affords
1(Zn-E), with its characteristic imidazolyl resonance at d ¼ 11.93
ppm (Fig. 4c). The concomitant release of acid results in the
hydrolysis of the imine bond and production of anthraldehyde,
which results in a signal at d ¼ 11.50 ppm that grows over
time.24 The catalysis was turned “off” with the addition of excess
CNꢂ (5 equiv.), which effectively demetalates 1(Zn-E) and
restores 1(E), thus stopping the catalytic cycle (Fig. 4d).25 This
mixture was monitored for an additional 10 minutes to ensure
1
that the H NMR spectrum does not change during the “off”
state (Fig. 4e). The hydrolysis can then be turned back “on” with
the reintroduction of excess Zn(ClO4)2 (7 equiv.), which results
in the complete hydrolysis of ANI within a few minutes.
Fig. 4 (a) The on/off hydrolysis of ANI using reversible CCD of a
catalytic amount of 1(E); the 1H NMR spectra (500 MHz, CD3CN)
showing the imine and NH region of (b) ANI and 1(E); (c) hydrolysis of
ANI and formation of anthraldehyde after the addition of Zn(ClO4)2; (d)
hydrolysis turn “off” and restoration of 1(E) by addition of excess CNꢂ;
(e) mixture 10 min after the addition of CNꢂ, demonstrating that
catalysis is deactivated; and (f) the complete hydrolysis of ANI after the
re-introduction of zinc(II).
Conclusions
We have demonstrated how coordination-coupled deprotona-
tion can be used in signaling and catalysis driven signal
amplication. These processes are possible because CCD in 1(E)
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leads to the acidication of the solution, which when coupled
with pH sensitive uorophores leads to uorescence turn “on”.
This was demonstrated with the activation of a new BODIPY dye
(MBD) that led to a 1000-fold increase in emission intensity.
More importantly, the reversible CCD process was used in
regulating signal enhancement by turning the catalytic hydro-
lysis of ANI “on” and “off” using a metalation/demetalation
cycle. We plan to continue with the development of multicom-
ponent switchable systems, and further complicate the
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Acknowledgements
We would like to acknowledge the support of the National
Science Foundation CAREER program (CHE-1253385), and the
Donors of the American Chemical Society Petroleum Research
Fund (51842-DNI4). We gratefully acknowledge Prof. Richard
Staples (Michigan State University) for X-ray data.
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˚
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˚
˚
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ꢀ
ꢀ
˚
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212 | Chem. Sci., 2015, 6, 209–213
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´
space group C2/c, Z ¼ 8, 18054 reections measured, 4252
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(I > 2s(I)). The nal R1 values were 0.1222 (all data). The
nal wR(F2) values were 0.1888 (all data).
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19 When zinc(II) is added to MBD (Fig. S33 in ESI†) no 24 The addition of zinc(II) to ANI resulted in no changes in the
appreciable increase in emission is observed conrming
1H NMR spectrum (Fig. S29 in ESI†) indicating that the CCD
that protonation results from CCD. Having the morpholinyl
is required for the hydrolysis to occur.
group is important as replacing it with a dimethyl amino 25 The addition of a high concentration of CNꢂ leads to a side
group results in a false turn “on” with zinc(II).
(addition) reaction with the imine (Fig. S23 in ESI†). In order
to obtain a cleaner transformation we used TREN as the
demetalation agent. This yielded a clean and reversible
catalysis (Fig. S24 in ESI†); however, the partial
consumption of the released proton by TREN upon
reintroduction of zinc(II) to the mixture, signicantly
slowed down the reaction rate (i.e., hydrolysis completes in
6 h). This also means that now we have a larger turnover
number, because less protons are available for catalysis.
20 This value is comparable to those obtained with various
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´
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