A Metalloregulated Four-State Nanoswitch Controls Two-Step Sequential Catalysis in an Eleven-Component System

Article abstract of DOI:10.1002/anie.201604658

The nanomechanical switch 1 with its three orthogonal binding motifs—the zinc(II) porphyrin, azaterpyridine, and shielded phenanthroline binding station—is quantitatively and reversibly toggled back and forth between four different switching states by mea

Full text of DOI:10.1002/anie.201604658

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International Edition: DOI: 10.1002/anie.201604658
German Edition: DOI: 10.1002/ange.201604658
Sequential Catalysis Very Important Paper
A Metalloregulated Four-State Nanoswitch Controls Two-Step
Sequential Catalysis in an Eleven-Component System
Sudhakar Gaikwad+, Abir Goswami+, Soumen De, and Michael Schmittel*
Dedicated to Professor U. Lꢀning on the occasion of his 60th birthday
Abstract: The nanomechanical switch 1 with its three orthog-
onal binding motifs—the zinc(II) porphyrin, azaterpyridine,
and shielded phenanthroline binding station—is quantitatively
and reversibly toggled back and forth between four different
switching states by means of addition and removal of
appropriate metal-ion inputs. Two of the four switching
stages are able to initiate catalytic transformations (ON1,
ON2), while the two others shut down any reaction (OFF1,
OFF2). Thus, in a cyclic four-state switching process the
sequential transformation A + B + C!AB + C!ABC can be
controlled, which proceeds stepwise along the switching states
OFF1!ON1 (click reaction: A + B!AB)!OFF2!ON2
(Michael addition: AB + C!ABC)!OFF1. Two consecutive
cycles of the sequential catalysis were realized without loss in
activity in a reaction system with eleven different components.
Moreover, the concentration of chemical inputs may be
modulated, enabling communication between switches[12] as
well as regulation and feedback control, similar to that in
enzyme networks.[5c]
Inspired by natureꢀs metal switches[1] we present herein
a novel four-state nanoswitch, which is reversibly toggled
back and forth between all switching states. Moreover, the
nanoswitch toggles two distinct catalytic processes (a click
reaction and a Michael addition) that can be applied without
loss of activity over two switching cycles to the sequential
transformation A + B + C!AB + C!ABC requiring largely
full orthogonality of a total of eleven components. Nature also
uses multi-step sequential catalysis to effect transformations
of supreme efficiency and selectivity toward complex bio-
molecules.[13]
For the four-state switch 1 we have chosen a different
architecture[14] than for our previous nanoswitches that have
already demonstrated their ability for ON/OFF regulation in
photochemical processes[10b] as well as in organo-[10a] and
transition-metal catalysis.[10c,e] Switch 1 is based on the highly
versatile tetraphenylmethane scaffold equipped with three
arms and three distinct terminals, a zinc(II) porphyrin
(ZnPor) unit, an azaterpyridine arm that includes two func-
tional ligands, and a shielded phenanthroline. Their exact
position in the scaffold was conceived by molecular modeling
so that three orthogonal binding motifs, a) an intramolecular
Nazaterpy!ZnPor linkage (in state IV), b) an intramolecular
HETTAP copper complex (heteroleptic terpyridine and
phenanthroline;[15] in state I), and c) an intermolecular iron-
(II) bisterpyridine complex (in state III), may form depending
on the chosen metal ion input (Cu+, Fe2+, or none). Moreover,
we hypothesized, based on previous findings,[10c] that the
reaction of [Cu(1)]+ with Fe2+ would afford the dimeric
[Cu2Fe(1)2]4+ (state II). Owing to the copper(I)-loaded phe-
nanthroline, this switching state should have the potential to
catalyze a click reaction, Figure 1.[10e]
Compound 1 with its three switching stations was
synthesized through a multistep synthesis and unambiguously
characterized by elemental analysis and the full arsenal of
spectroscopic techniques. The ESI-MS spectrum displays
a molecular-ion peak at m/z 1076.9 Da for [1 + 2H]2+, an
assignment that is corroborated by the good agreement of
experimental and theoretical isotopic splitting (Supporting
Information, Figure S23). In the 1H NMR spectrum, the
pyrimidine protons a-H and b-H of the azaterpyridine unit
appear as sharp signals in the aliphatic region at d = 3.76 and
2.73 ppm, respectively, confirming immersion of the pyrimi-
M
etalloregulated switches play an important role in many
physiological processes with transition-metal ions acting as
cofactors or as coordination centers for large-amplitude
toggling.[1] Owing to the key role of metals, nature has
designed numerous methods for the selective transport of
transition-metal ions, such as copper(I,II), iron(II),[1] across
membranes into the cytoplasm and to the required protein
sites. For this process, a sophisticated mechanism is used for
intracellular metal-ion metabolism (“metallome”).[1,2] To
fathom out and develop the enormous potential of metal-
loregulated large-amplitude switching[3] also outside of the
biosphere, we have focused in our research on metal-ion-
controlled nanoswitches with a particular emphasis on the
allosteric control[4] of catalytic processes. Although switch-
able catalysis has become a topical issue in the last few
years,[5] most of the switches involved operate on light[6] and
pH control,[7] whereas highly selective chemical inputs
(addition of ligands/anions[8] or metal ions)[9,10] for controlling
catalysis are rare. While light is a common preferred choice
for single switching processes,[11] variable chemical inputs are
more suitable for addressing more than two switching steps.
[*] M.Sc. S. Gaikwad,[+] M.Sc. A. Goswami,[+] Dr. S. De,
Prof. Dr. M. Schmittel
Center of Micro and Nanochemistry and Engineering, Organische
Chemie I, Universitꢀt Siegen
Adolf-Reichwein Str. 2, 57068 Siegen (Germany)
E-mail: Schmittel@chemie.uni-siegen.de
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201604658.
dine into the shielding p-zone of the ZnPor. The Nazaterpy
!
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of the Nazaterpy!ZnPor
linkage. The heterodi-
metallic
complex
[Cu2Fe(1)2]4+
(state II) was pre-
pared from both pos-
sible precursors, either
from [Cu(1)]+ (state I)
by
addition
of
0.5 equivalents of Fe-
(BF4)2 or from [Fe-
(1)2]2+ (state III) by
adding one equivalent
of [Cu(CH3CN)4][B-
(C6F5)4] (relative to
1). The identity and
quantitative
forma-
tion
of
switching
states
I–III
were
unambiguously estab-
lished by 1H NMR,
1H-1H COSY, and
UV/Vis spectroscopic
data, and ESI-MS (for
complete data, see
Supporting Informa-
tion) as well as by
elemental
analysis.
Some of the diagnos-
tic changes along the
switching states IV!
I!II!III are high-
lighted in Table 1. For
instance, the UV/Vis
Figure 1. Nanoswitch 1 and its four switching states. TMS=trimethylsilyl.
ZnPor interaction was further validated by the UV/Vis data:
the Soret band of 1 appears at l = 429 nm, whereas the
uncoordinated ZnPor unit typically displays an absorption at
l = 421 nm (Figure S27). The 8 nm shift is well documented
for related pyridine-coordinated zinc(II) porphyrin system-
s.[10a,b] The Nazaterpy!ZnPor coordination is clearly intramo-
lecular as indicated by the concentration independence of the
chemical shifts. Thus, the UV/Vis absorption of the Q-band
stays constant at l = 562 nm over c = 10ꢀ6 to 10ꢀ4 m (Fig-
ure S28). These results show that nanoswitch 1 is self-locked
at the Nazaterpy!ZnPor linkage.
Table 1: Selected data of switching states I–IV.
State
UV/Vis[a]
/nm
Phen[b,c]
t-H
Azaterpyridine[b]
a-H
5,6-H
d-H
f-H
i-H
IV
I
II
429/562
421/549
–/549
6.96
6.30
6.95
6.91
7.91
7.96
8.08
7.91
3.76
7.39
7.26
7.24
7.38
8.10
8.86
8.98
7.36
7.95
8.67
8.81
8.68
7.88
6.90
7.02
III
–/549
[a] Absorption maxima. [b] 1H NMR shifts in ppm. [c] Phenanthroline.
For complete 1H NMR data, see Supporting Information.
Initially, we prepared each of the switching states I, II, and
III individually in analytically pure form. Different from
1 (state IV), the other switching states I–III should be able to
inhibit catalytically active amines, such as piperidine (2), by
strong binding at the free ZnPor unit,[10a] an important
prerequisite for controlling catalysis (see below). First, the
intramolecular complex [Cu(1)]+ (state I) was prepared by
adding one equivalent of [Cu(CH3CN)4]PF6 to nanoswitch
1 (= state IV) in [D2]-dichloromethane. The switching arm
has to move 2.5 nm from the zinc(II) to the copper(I) center.
As anticipated, the intermolecular complex [Fe(1)2]2+ (state
III) was afforded quantitatively from switch 1 by addition of
0.5 equivalents of Fe(BF4)2 (Figure S8), again upon cleavage
data unambiguously show that the Nazaterpy!ZnPor linkage is
only present in 1 (state IV) while the 1H NMR downfield shift
at the azaterpyridine unit (d,f-H) indicate that the iron(II)
bisterpyridine complex is realized in both switching states II
and III. The loading of both phenanthroline stations with
copper(I) ions in [Cu2Fe(1)2]4+ (state II) becomes apparent
from the downfield shift of protons 5,6-H when going from
state III!II. Besides, the ESI-MS displays a diagnostic signal
(100%) for the complex [Cu2Fe(1)2]4+ (Figure S26).
Next we investigated the reversibility of toggling between
selected states. Addition of [Cu(CH3CN)4]PF6 to 1 provided
complex [Cu(1)]+, whose low binding constant (logK = 7.42 ꢁ
2
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0.07) reflects the parallel rupture of the Nazaterpy!ZnPor
tion of 1.0 equivalent of cyclam (3) to [Cu2Fe(1)2]4+ (relative
interaction (Figure S48). Addition of one equivalent of
cyclam (3) to a solution of [Cu(1)]+ fully restored 1, as seen
from protons a-H and t-H returning to their original positions
at d = 3.76 and 6.96 ppm, respectively. Further insights were
obtained from a UV/Vis titration of [Cu(1)]+ (1 ꢁ 10ꢀ4 m)
against 3 (2.5 ꢁ 10ꢀ3 m) showing that the Q-band returned
from l = 549 to 562 nm after addition of one equivalent of
cyclam (Figure S30). Thus the UV/Vis and 1H NMR spectro-
scopic studies confirmed quantitative and reversible switching
between states IV and I over three cycles (Figure S11).
to 1) results in the formation of the iron complex [Fe(1)2]2+
(state III). Finally, the Fe2+ ions were removed by adding
1.0 equivalent of 4 affording 1 (reset to state IV; for a com-
plete cycle, see Figure S13). In the course of one cycle,
[Cu(3)]+ and [Fe(4)2]2+ accumulate as waste products that,
however, do not interfere with the switching processes. All the
switching processes IV!I!II!III!IV occurred immedi-
ately upon mixing the components at room temperature as
shown by UV/Vis investigations.[16]
An analysis of the four switching states with their involved
stations reveals two options that are suitable for the
implementation of catalytic reactions: a) The coordinatively
frustrated copper(I) phenanthroline in [Cu2Fe(1)2]4+ is known
for its ability to catalyze click and cyclopropanation reactions.
It is exposed only in state II.[10c,e] b) The ZnPor unit is
intramolecularly unoccupied in three states (I, II, III), so
that a catalytically active species bound to the ZnPor station
will be released only in state IV. These considerations suggest
that the switching states I and III may serve as OFF states
with regard to catalytic activity.
The next step was to select model compounds for
a sequential transformation as a proof of concept. Clearly,
various interferences could show up that need to be avoided:
a) neither the reactant nor the products must intervene in the
switching process that links the four switching states, b) the
second step of the sequential transformation should selec-
tively only convert the product of the first step, as otherwise
side products would form which might intervene in the
switching process. Moreover, c) both catalytic processes
should work at the same temperature and within the same
time. After screening several sequential reactions using
a variety of conditions, we finally came up with the optimized
substrates A, B, and C shown in Figure 2. The most critical
issue was to identify a pair of A and AB in which only AB
reacts in the second catalytic process. As the first catalytic
step in the cycle A + B!AB, we selected a click reaction,
because we expected it to be catalyzed by the coordinatively
frustrated copper(I) phenanthroline available in state II. As
AB contains the ketotriazole group that could act as
a potential chelate complexation unit for metal ions, its
binding ability was lowered with the 4-nitrobenzoyl group. In
the second step of this cascade, an amine released by state IV
should become catalytically active. Actually, an amine such as
piperidine (2) should be strongly bond to the free ZnPor in all
other states (for example, binding of 2 to [Cu(1)]+: logK =
5.37 ꢁ 0.41, Figure S49), whereas it would hardly bind to
1 (logK = 2.66 ꢁ 0.08, Figure S47). Consequently, we chose
a piperidine-catalyzed Michael-type addition for the process
AB + C!ABC.
Thereafter, reversible toggling between nanoswitch
1 (state IV) and [Fe(1)2]2+ (state III) was evaluated. After
addition of 0.50 equivalents of Fe(BF4)2 to 1, the azaterpyr-
idine protons a-H, d-H, and f-H shifted from d = 3.76, 7.38,
and 7.36 ppm to 7.24, 8.98, and 8.81 ppm, respectively. The
concomitant unlocking of the azaterpyridine arm at the
ZnPor binding site was additionally corroborated by a UV/
Vis titration of switch 1 (1 ꢁ 10ꢀ4 m) against Fe(BF4)2 (2.75 ꢁ
10ꢀ3 m) with the Q band shifting from l = 562 to 549 nm upon
addition of 0.50 equivalents of Fe2+. This resulted in logK =
10.06 ꢁ 0.29 for the formation of [Fe(1)2]2+ (Figure S50). To
reverse the process, we added 4-N,N-dimethylamino-
2,2’:6’,2’’-terpyridine (4) because of its higher affinity for
Fe2+ ions. After addition of 1 equivalent of 4, protons a-H and
i-H emerged at d = 3.76 and 8.68 ppm, respectively. Equally,
the Nazaterpy!ZnPor coordination was regained. When a solu-
tion of [Fe(1)2]2+ (1 ꢁ 10ꢀ4 m) in dichloromethane was titrated
against 4 (2.5 ꢁ 10ꢀ3 m), the band at l = 549 nm was fully
shifted to 562 nm (Figure S32) after addition of one equiv-
alent of 4 (relative to 1). Quantitative and reversible switching
between states IV and III was checked up to two cycles by
1H NMR spectroscopy as well (Figure S12).
After the successful demonstration of reversible toggling
between distinct states of nanoswitch 1, we evaluated the
unidirectional cyclic switching along the states IV!I!II!
III!IV (Figure S13). As shown above, addition of 1.0 equiv-
alent of copper(I) ions to a solution of switch 1 (state IV)
produced the HETTAP complex [Cu(1)]+ (state I). Further
addition of 0.50 equivalents of Fe2+ ions destroyed the
HETTAP complexation and yielded the “dimeric” complex
[Cu2Fe(1)2]4+ (state II). All the spectroscopic data confirm
that [Cu2Fe(1)2]4+ (state II) is equipped with two identical
coordinatively frustrated copper(I) complexation sites. Addi-
Prior to developing the switchable catalysis in presence of
1, we optimized the conditions for the sequential catalysis in
presence of model catalysts. In presence of 10 mol% of
[Cu(5)]+ (as a model for [Cu2Fe(1)2]4+) the click reaction
between A and B (1:1) at 558C for 2 h furnished click product
AB in 54% yield (Figure S33), while in presence of 10 mol%
of the HETTAP complex [Cu(5)(6)]+ as a mimic of [Cu(1)]+
no product AB was afforded (Figure S34). Secondly, the
catalytic reaction between AB and Michael acceptor C (1:1)
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mino-2,2’:6’,2’’-terpyridine (4)
was added to trap the Fe2+ ions
and to generate the nanoswitch
1 (state IV). At this point, the
switching arm moved to the
ZnPor station, which conse-
quently should release piperi-
dine (2). Indeed, the heating of
state IV at 558C for 2 h afforded
the Michael addition product
ABC in 14% absolute yield
(28% yield relative to AB, Fig-
ures 3d and Figure S45). The
reactant for the Michael addi-
tion step, AB, is used up consis-
tently (ꢀ26%; catalysis ON2 in
state IV). Then, the second cycle
was started after replacing the
used-up reactants A + B to
create identical starting condi-
tions as for the first cycle
(1H NMR data for 2nd cycle,
Figure S46e-i). After addition of
one equivalent of Cu+ ions and
the generation of [Cu(1)(2)]+
(state I), the product yields
Figure 2. Schematic representation of the switching cycle of nanoswitch 1 with the catalytic trans-
formation of A+B+C!AB+C!ABC occurring in switching states II (ON1) and IV (ON2). For the
molecular structures of states I–IV, see Figure 1. Note that in switching states I–III piperidine (2) is
firmly bound to the ZnPor unit of 1 and thus is not available in solution as a catalytically active species.
in presence of 10 mol% of piperidine provided the Michael
addition product ABC in 33% yield (Figure S35), while in
presence of the piperidine-ZnTPP complex[17] the product
ABC did not arise (Figure S42).
After the successful implementation of sequential catal-
ysis, the ability of the eleven-component-system (nanoswitch
1, piperidine (2), the four inputs for switching, reactants A +
B + C, and products AB + ABC) to function in a one-pot
process was tested in two consecutive switching cycles. For
this purpose (1H NMR data for the 1st cycle, Figure S45a–d),
an NMR tube containing [Cu(1)]+ (1.97 mm), piperidine (2),
A, B, and C in a 1:1:10:10:10 ratio in CDCl3 was heated to
558C for 2 h. By NMR spectroscopy, no product formation
was found (catalysis OFF1 in state I, see Figure 3a), which is
Figure 3. Evolution of the yield (black numbers) of AB and ABC in the
various switching states (S=State) over the course of two cycles. The
yields (or losses) for each step are given in brackets (%) with regard
to the quantity (or consumed amount) of the starting material.
readily rationalized on the basis that piperidine (2) is firmly
bound to the ZnPor site of [Cu(1)(2)]+ and copper(I) is buried
in the HETTAP complexation site. Addition of 0.50 equiv-
alents of Fe2+ ions transformed [Cu(1)(2)]+ to [Cu2Fe(1)2-
(2)2]4+ (state II, Figure 2). Heating at 558C for 2 h afforded
the click reaction product AB in 50% yield (Figure 3b),[18]
while no Michael addition product was detected (catalysis
ON1 in state II). Notably, the catalytic activity of [Cu2Fe(1)2-
(2)2]4+ was almost the same as that seen in the model reaction
in the presence of [Cu(5)]+. After addition of one equivalent
(relative to 1) of cyclam (3) to remove the Cu+ ions from
phenanthroline binding site, the complex [Fe(1)2(2)]2+ (state
III) was afforded. As expected, heating at 558C for 2 h did not
produce any further click reaction product AB (total yield of
AB = 50%, see Figure 3c). Moreover, no Michael addition
product was detected in the NMR spectrum, attesting
a complete shutdown of both catalytic reactions (catalysis
OFF2 in state III). Now 1.0 equivalent of 4-N,N-dimethyla-
remained almost unaltered after a repeated heating at 558C
for 2 h (click product AB = 37%, Michael addition product
ABC = 15%, Figure 3e), which corresponds to OFF1. Addi-
tion of 0.50 equivalents of Fe2+ ions and heating of the
mixture (state II) at 558C for 2 h furnished the click product
AB in 48% yield (Figure 3 f: 85% is the total yield in the 2nd
cycle with regard to one equivalent of A). At the same time,
no additional Michael addition product ABC was afforded
(ON1). Trapping of Cu+ ions by 1.0 equivalent of cyclam and
subsequent heating under similar conditions turned off both
reactions (OFF2; Figure 3g). The addition of 1.0 equivalent
of 4 restored compound 1. Now heating at 558C for 2 h
4
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(Figures 3h and Figure S46).[19] Finally, the addition of one
equivalent of Cu+ ions turned off both catalyses (OFF1;
Figure 3i).
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Both, the formation of the two catalytically generated
products and the mass balance of all steps are remarkably
reproducible over two cycles. In both cycles the conversion of
A + B!AB is 50% (see Figure 3b,f; relative to A), while that
of AB!ABC is 28% and 34% (relative to consumed AB).[19]
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corresponds in both cycles to the production of ABC (+ 28
and + 34%) within the errors of integration. These yields are
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and the Michael addition product ABC in 33% yield (using
piperidine). Thus, all features demonstrate a remarkable
reproducibility in the twice repeated cyclic ON/OFF switch-
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was hampered by the partial precipitation of ABC from the
reaction mixture.
Switchable catalysis is no end in itself. As recently
highlighted by Leigh et al.,[5b] it is a key challenge to switch
several subsequent processes by a distinct sequence of stimuli.
With the system presented herein, the first four-state nano-
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can be commanded with high reproducibility over the course
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interferences (see Figure 2). Thus, the present work enlarges
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We are grateful to the DAAD (Deutscher Akademischer
Austauschdienst), the DFG Deutsche Forschungsgemein-
schaft (Schm-647/19-1), and the Universitꢂt Siegen for
financial support.
Keywords: allosteric control · coordination chemistry ·
molecular switches · nanomechanical motion ·
sequential catalysis
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[16] To obtain reliable kinetic data, stopped-flow investigations
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Received: May 12, 2016
Published online: && &&, &&&&
6
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ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 7
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Sequential Catalysis
Connect four: The first nanoswitch with
four states can control a sequential
transformation A+B+C!AB+C!ABC
with 11 components over two complete
cycles. The cycle proceeds stepwise along
the switching states OFF1!ON1 (click
reaction: A+B!AB)!OFF2!ON2
(Michael addition: AB+C!ABC)!
OFF1 (see scheme). The system’s pre-
formance is superior to that of systems
with only two switching states.
S. Gaikwad, A. Goswami, S. De,
M. Schmittel*
&&&& — &&&&
A Metalloregulated Four-State
Nanoswitch Controls Two-Step
Sequential Catalysis in an Eleven-
Component System
Angew. Chem. Int. Ed. 2016, 55, 1 – 7
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7
These are not the final page numbers!