Dissipative Catalysis with a Molecular Machine

Article abstract of DOI:10.1002/anie.201905250

We report on catalysis by a fuel-induced transient state of a synthetic molecular machine. A [2]rotaxane molecular shuttle containing secondary ammonium/amine and thiourea stations is converted between catalytically inactive and active states by pulses of a chemical fuel (trichloroacetic acid), which is itself decomposed by the machine and/or the presence of additional base. The ON-state of the rotaxane catalyzes the reduction of a nitrostyrene by transfer hydrogenation. By varying the amount of fuel added, the lifetime of the rotaxane ON-state can be regulated and temporal control of catalysis achieved. The system can be pulsed with chemical fuel several times in succession, with each pulse activating catalysis for a time period determined by the amount of fuel added. Dissipative catalysis by synthetic molecular machines has implications for the future design of networks that feature communication and signaling between the components.

Full text of DOI:10.1002/anie.201905250

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Accepted Article
Title: Dissipative Catalysis with a Molecular Machine
Authors: David Leigh, Chiara Biagini, Stephen D. P. Fielden, Fredrik
Schaufelberger, Stefano Di Stefano, and Dean Thomas
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201905250
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10.1002/anie.201905250
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Dissipative Catalysis with a Molecular Machine
Chiara Biagini[a,b], Stephen D. P. Fielden[a], David A. Leigh[a]*, Fredrik Schaufelberger[a], Stefano Di
Stefano[b] and Dean Thomas[a]
Abstract: We report on catalysis by a fuel-induced transient state of
a synthetic molecular machine. A [2]rotaxane molecular shuttle
containing secondary ammonium/amine and thiourea stations is
converted between catalytically inactive and active states by pulses
of a chemical fuel (trichloroacetic acid) that is, itself, decomposed by
the machine and/or the presence of additional base. The ON-state of
the rotaxane catalyzes the reduction of a nitrostyrene by transfer
hydrogenation. By varying the amount of fuel added, the lifetime of
the rotaxane ON-state can be regulated and temporal control of
catalysis achieved. The system can be pulsed with chemical fuel
several times in succession, each pulse activating catalysis for a
time period determined by the amount of fuel added. Dissipative
catalysis by synthetic molecular machines has implications for the
future design of networks that feature communication and signaling
between the components.
that of (strongly binding) ammonium and (weakly binding) amine
groups.[13e,13j] Since thioureas are also adept at hydrogen
bonding catalysis,[14] we envisaged
1 (Figure 1a) as an
acid/base switchable rotaxane catalyst. Under acidic conditions,
the thiourea moiety should be revealed and the catalytic activity
switched on, while under basic conditions the crown ether
should encapsulate the thiourea unit switching off the catalytic
activity.[13e,13j]
Living systems are complex dissipative cellular networks
capable of advanced functions such as adaptability,
responsiveness and evolution through the consumption of
energy.[1] The design and operation of synthetic dissipative
chemical systems, i.e. out-of-equilibrium assemblies that require
inputs of energy (in the form of light, heat or chemical fuels) to
remain in a functional state, is still in its infancy.[2] Chemical fuels
have been used to self-assemble supramolecular materials with
tunable lifetimes[3], to temporally control host-guest systems,[4]
for both ratcheted directional motion[5] and transient switching,[6]
and to construct transitory signaling systems[7] and self-
replicators[8].
To date the only example of an artificial system where
catalytic activity is turned on by the presence of a chemical fuel
is a vesicle system developed by Prins and co-workers.[9] Given
that dissipative catalysis forms the basis for many signal
transduction events in biology,[2a] it represents a significant ‘next
step’ of functional complexity[10] in bio-inspired approaches[11] to
synthetic molecular machines. Stimuli-responsive rotaxane
molecular shuttles are well-suited for switchable catalysis[12,13]
and chemical fuels have been used to achieve transient co-
conformational changes[5,6] in mechanically interlocked
architectures. We sought to combine these features to make a
dissipative system in which the consumption of a chemical fuel
is coupled to the transient formation of the active state of a
rotaxane catalyst (Figure 1).
Figure 1. a) Dissipative translocation of the macrocycle in [2]rotaxane 1,
revealing and hiding a thiourea catalyst. Reagents and conditions for fuel
pulse: CCl3CO2H, CD2Cl2 or toluene-d8, RT, quantitative. b) Partial 1H NMR
spectra (600 MHz, CD2Cl2, 298 K) showing the two states of rotaxane switch
Thioureas can be used in the axles of rotaxanes as
macrocycle binding sites with an affinity intermediate between
-
1/1H+ and the corresponding non-interlocked thread 2H+. i) [1H+][CF3CO2 ]. ii)
-
[2H+][CF3CO2 ]. iii) 1.
Rotaxane [1H+][CF3CO2 ] was prepared in six synthetic steps
-
[a]
[b]
Prof. D. A. Leigh, C. Biagini, S. D. P. Fielden,
Dr. F. Schaufelberger, D. Thomas.
School of Chemistry, University of Manchester
Oxford Road, M13 9PL, Manchester, United Kingdom.
E-mail: david.leigh@manchester.ac.uk
from commercially available materials through a threading-and-
capping strategy (see Supporting Information). Deprotonation of
the rotaxane was achieved with polymer supported 2-tert-
butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-
diazaphosphorine (BEMP) phosphazene base in CH2Cl2 to form
neutral 1. The translocation of the macrocycle between the
different sites in 1 and 1H+ was established by comparison of
their 1H NMR spectra in CD2Cl2 (Figure 1b).[15] Among the
signals characteristic of the ring position on the axle, the
benzylic amine protons Hc and He are shifted from 4.48 and 4.67
C. Biagini, Prof. S. Di Stefano,
Edificio Cannizzaro (VEC), Dipartimento di Chimica, Università degli
Studi di Roma “La Sapienza”,
Piazzale Aldo Moro 5, 00185, Roma, Italy.
Supporting information for this article is given via a link at the end of
the document.
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in 1H+ to 3.71 and 3.72 ppm in 1. Concomitantly, the urea
protons Hl and Hm move from 11.44 and 11.77 ppm to 9.19 and
9.52 ppm. Confirmation that these shifts are caused by shielding
from the crown ether and not just protonation of the ammonium
moiety comes from comparison with the protonated non-
interlocked thread 2H+ (Figure 1bii, see Supporting Information
return to its original state. The addition of triethylamine
significantly accelerated the fuel decomposition[5b] and this could
be used to tune the fuel lifetime, and thereby the lifetime of the
active state of the rotaxane, to shorter timescales.
We next addressed the coupling of the dissipative
switching to catalysis by the rotaxane. Thiourea hydrogen
bonding activates nitrostyrenes to various types of nucleophilic
-
for synthesis of [2H+][CF3CO2 ]). Similar chemical shift changes
occur in toluene-d8, which proved a more convenient solvent for
subsequent experiments with the chemical fuel.
attack.[14] The biomimetic reduction of nitrostyrene
3 via
Hantzsch ester-based transfer hydrogenation[18] is an attractive
transformation in this context, given that it is catalyzed by
hydrogen bond donors but not by strong acids such as
CCl3CO2H.[19] We selected tert-butyl ester 4 as the Hantzsch
ester hydrogen donor (Scheme 1), as its good solubility in
toluene-d8 allowed for the in situ monitoring of the reaction via
1H NMR. Nitrostyrene concentrations between 0.025 and 0.05 M
were found to give reaction rates suitable for studying the effects
of fuel pulses.
We next investigated the operation of 1 under transient
protonation conditions. Amongst the recently reported chemical
fuels for artificial dissipative systems, base-catalyzed
decarboxylative acids such as 2-cyano-2-arylpropanoic acids[6c-f]
and trichloroacetic acid (CCl3CO2H)[5d,6b] have the ability to
temporarily switch the global pH of the reaction medium from
basic to acidic for definable periods of time. Trichloroacetic acid
has the additional advantage that the only waste products of the
fuel are carbon dioxide and chloroform, a volatile solvent.
Addition of CCl3CO2H (1.1 equiv.) to
1 in toluene-d8
immediately protonated the amine group, 1H NMR showing
-
similar shifts to [1H+][CF3CO2 ] confirming translocation of the
macrocycle from the thiourea to the newly-formed ammonium
-
group (Figure 2). The protonated shuttle [1H+][Cl3CCO2 ]
persisted over ca. 9 h, during which time decarboxylation of
1
excess acid occurred (evidenced by the only change in the H
NMR spectrum being the emergence of a signal at 6.10 ppm
corresponding to CHCl3). After 9 h the amount of 1H+ present
started to decline, gradually converting back[15] to 1 over the
course of 7 h.[16] Upon completion of the fuel cycle, and the
1
return of the system to thermodynamic equilibrium, the H NMR
spectrum of the reaction mixture was identical to that of the
starting material apart from the additional presence of the CHCl3
waste product. To demonstrate the robustness of the dissipative
cycling, a series of fuel pulses were made to the same sample
(Figure S1). Each time (for at least seven fuel cycles) rotaxane 1
underwent switching, with no decomposition of 1 nor any fuel-
induced fatigue apparent by 1H NMR spectroscopy.
Scheme 1. Reaction network for dissipative catalysis with [2]rotaxane 1/1H+.
The reaction between 3 and 4 to give reduced product 5 was
monitored in the presence of a range of additives (Figure S2).
With a starting concentration (c0) of 3 of 0.05 M the background
initial rate was 0.20 mM/h (~0.05 mM/h at c0 = 0.025 M), giving
8 % conversion of 3 and 4 to 5 over 24 h (2 % with c0 = 0.025 M).
The presence of NEt3 or CCl3CO2H caused negligible rate
The lifetime of the 1H+ state could be varied by pulsing with
different amounts of CCl3CO2H.[17] Toggling the shuttling with 1.3
equiv. of fuel led to decay back to 1 in less than 72 h, whilst
addition of 1.9 equiv. extended the time required to 7 days. With
2.5 equiv. of fuel >2 weeks were needed for the rotaxane to
enhancements.[20] However, addition of
significantly increased the reaction rate, with 5 being formed in
a model thiourea
Figure 2. Partial 1H NMR spectra (600 MHz, toluene-d8, 298 K) showing the evolution of 1/1H+ (1 mM) in toluene-d8 upon addition of a fuel pulse.[15] Conditions: i)
CCl3CO2H (1.1. equiv), added at t = 0.1 h.
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50 % yield after 24 h (Figure S2a versus S2b).
The catalytic activity of 1 and 1H+ was then examined
(Figure S3). A reaction rate of 0.044 mM/h between 3 and 4 (c0
[3] = 0.025 M) was measured in the presence of 15 mol% OFF-
state catalyst 1, virtually the same as the background. Under
similar conditions the ON-state, 1H+, induced a 6× increase in
reaction rate to 0.28 mM/h.[21] The catalysis was then performed
under dissipative conditions (Scheme 1 and Figure 3). In a
typical experiment the OFF-state molecular machine 1 (15
mol%) and Et3N (0-1 equiv., used to determine the fuel lifetime)
were added to 3 and 4 in toluene-d8. After 20 h, a pulse of
CCl3CO2H (0.20 equiv.) was added, switching 1 to the ON-state
(1H+). 1H NMR was used to confirm translocation of the
macrocycle from the thiourea to the dibenzylammonium site.
After the fuel had fully decarboxylated (after an additional 21 h,
41 h in total, when 0.6 equiv. Et3N used) 1H NMR again
confirmed the rotaxane catalyst had reverted back to the inactive
state. The effect on the fuel-induced catalysis of the reaction
between 3 and 4 by the rotaxane is shown over one cycle under
conditions that optimize the conversion to 5 in a single pulse
(Figure 3a and 3b) and over multiple cycles of fuel pulses
(Figure 3c and 3d).
The dissipative catalysis is more pronounced at higher
concentrations (≥0.05 M, 15 mol% 1, Figure 3a and 3b), where a
single fuel pulse allows ca 60 % yield of 5 to be achieved within
48 h. However, the effect of further pulses diminishes if the
starting materials are not replenished, reflecting the decrease in
reactant concentration, and also 1 precipitates slowly over
time.[22] To alleviate the latter issue, we used more dilute
solutions (0.025 M, 10 mol% catalyst loading) to study the effect
of multiple fuel pulses. Stepwise increases in the amount of 5
formed were apparent over three successive fuel pulse cycles,
each lasting 12-18 h (Figure 3c and 3d, see also Supporting
1
information). H NMR confirmed that the retardation of catalysis
during each cycle correlated with the rotaxane returning to the
OFF-state. The time taken for the pulse to decay decreases
slightly with each addition. As no precipitation of rotaxane occurs
at these concentrations, and the reaction cleanly forms 5 with no
side products other than CHCl3 and CO2, the decrease appears
to be due to the build up of relatively polar CHCl3 in the reaction
medium. Addition of a fourth and fifth pulse of fuel also produced
rate increases, but these were less pronounced unless the
consumed reactants were replenished (see Supporting
information, section S4.3.3).
In conclusion,
a rotaxane can be switched between
Figure 3. Dissipative catalysis with [2]rotaxane 1/1H+. a) Formation of 5 over a
single fuel pulse (raw data; c0 [3] = 0.05 M). b) Catalyst-enhanced formation of
5 over a single fuel pulse (background subtracted; c0 [3] = 0.05 M). c)
Formation of 5 over multiple fuel cycles (raw data; c0 [3] = 0.025 M). d)
catalytically active and inactive states using pulses of a chemical
fuel, delivering temporal control of catalysis by the synthetic
molecular machine. The amount of fuel controls the lifetime of
the catalyst ON-state and hence the amount of product formed.
This corresponds to a chemical fuel regulating the kinetics of a
reaction in which it does not directly participate via coupling to a
molecular machine in a connected reaction network. The ability
to construct catalysts requiring a continuous consumption of
energy to remain in a functional state has implications for the
future design of systems that can imitate advanced biological
functions, including signal transduction.[10]
Catalyst-enhanced formation of
5 over multiple fuel pulses (background
subtracted; c0 [3] = 0.025 M). Conditions: Nitrostyrene 3 (1 equiv.), Hantzsch
ester 4 (1.1 equiv.), rotaxane 1 (0.15 equiv. for a and b, 0.10 equiv. for c and
d), NEt3 (0.60 equiv.), toluene-d8, RT. Pulses of CCl3CO2H (0.20 equiv.) were
added at the start of each green band and complete decarboxylation occurred
by the end of the green band. Volume of all experiments 1 mL. †Background
subtracted. Error bars indicate estimated experimental errors in
measurements and analysis. Reactions monitored by 1H NMR integration
versus trimethylphenylsilane or 1,3,5-trimethoxybenzene internal standards.
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Acknowledgements
We thank the Engineering and Physical Sciences Research
Council (EPSRC; EP/P027067/1), the EU (European Research
Council (ERC) Advanced Grant no. 786630; Marie Skłodowska-
Curie Individual Postdoctoral Fellowship to F.S., EC 746993),
the CESaRe project from La Sapienza for funding to C.B., and
the University of Manchester Mass Spectrometry Service Centre
for high-resolution mass spectrometry. We are grateful to Dr.
Daniel Tetlow for useful discussions. D.A.L. is a Royal Society
Research Professor.
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COMMUNICATION
[21] Thread 2H+ gave a similar rate enhancement to the ON-state of
rotaxane catalyst 1H+ (Figure S4).
Mika, A. Csámpai, T. Holczbauer, G. Kardos, T. Soós, RSC Adv. 2015,
5, 95079–95086.
[22]
A
small amount of product inhibition may also contribute to the
diminished catalytic activity from later pulses of fuel, see: E. Varga, L. T.
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10.1002/anie.201905250
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
An out-of-equilibrium state of
synthetic molecular machine is used
to control catalysis. A rotaxane is
a
Chiara Biagini, Stephen D. P. Fielden,
David A. Leigh*, Fredrik Schaufelberger,
Stefano Di Stefano and Dean Thomas.
transiently
converted
from
a
catalytically inactive state to an active
form by CCl3CO2H. The acid
Page No. – Page No.
decarboxylates,
promoted
by
Dissipative Catalysis with a Molecular
Machine
deprotonation by the rotaxane,
returning the system to its original
state and stopping catalysis. The
process allows temporal control of a
coupled biomimetic reduction reaction.
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