Time Programmable Locking/Unlocking of the Calix[4]arene Scaffold by Means of Chemical Fuels

Article abstract of DOI:10.1002/chem.202002574

In this work, we report that 2-cyano-2-phenylpropanoic acid and its p-Cl, p-CH₃ and p-OCH₃ derivatives can be used as chemical fuels to control the geometry of the calix[4]arene scaffold in its cone conformation. It is shown that, under the action of the fuel, the cone calix[4]arene platform assumes a “locked” shape with two opposite aromatic rings strongly convergent and the other two strongly divergent (“pinched cone” conformation). Only when the fuel is exhausted, the cone calix[4]arene scaffold returns to its resting, “unlocked” shape. Remarkably, the duration of the “locked” state can be controlled at will by varying the fuel structure or amount. A kinetic study of the process shows that the consume of the fuel is catalyzed by the “unlocked” calixarene that behaves as an autocatalyst for its own production. A mechanism is proposed for the reaction of fuel consumption.

Full text of DOI:10.1002/chem.202002574

Accepted Article
Accepted Article
Title: Time Programmable Locking/Unlocking of the Calix[4]arene
Scaffold by Means of Chemical Fuels
Authors: Stefano Di Stefano, Daniele Del Giudice, Emanuele Spatola,
Roberta Cacciapaglia, Alessandro Casnati, Laura Baldini, and
Gianfranco Ercolani
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
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
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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.202002574
Link to VoR: https://doi.org/10.1002/chem.202002574
01/2020

10.1002/chem.202002574
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Time Programmable Locking/Unlocking of the Calix[4]arene
Scaffold by Means of Chemical Fuels
Daniele Del Giudice,[a] Emanuele Spatola,[a] Roberta Cacciapaglia,[a] Alessandro Casnati,[b] Laura
Baldini,*[b] Gianfranco Ercolani,*[c] and Stefano Di Stefano*[a]
[a]
[b]
[c]
D. Del Giudice, E. Spatola, Dr. R. Cacciapaglia, Prof. S. Di Stefano
Dipartimento di Chimica
Università di Roma La Sapienza and ISB-CNR Sede Secondaria di Roma - Meccanismi di Reazione,
P.le A. Moro 5, I-00185 Roma, Italy.
E-mail: stefano.distefano@uniroma1.it
Prof. A. Casnati, Prof. L. Baldini
Dipartimento di Scienze Chimiche, della Vita e della Sostenibilità Ambientale
Università degli Studi di Parma
Parco Area delle Scienze 17/A, 43124 Parma, Italy.
E-mail: laura.baldini@unipr.it
Prof. G. Ercolani
Dipartimento di Scienze e Tecnologie Chimiche
Università di Roma Tor Vergata
Via della Ricerca Scientifica, 00133 Roma, Italy
E-mail: ercolani@uniroma2.it
Supporting information for this article is given via a link at the end of the document.
Abstract: Herein we report that 2-cyano-2-phenylpropanoic acid and
its p-Cl, p-CH3 and p-OCH3 derivatives can be used as chemical fuels
to control the geometry of the calix[4]arene scaffold in its cone
conformation. It is shown that, under the action of the fuel, the cone
calix[4]arene platform assumes a “locked” shape with two opposite
aromatic rings strongly convergent and the other two strongly
divergent (“pinched cone” conformation). Only when the fuel is
exhausted, the cone calix[4]arene scaffold returns to its resting,
“unlocked” shape. Remarkably, the duration of the “locked” state can
be controlled at will by varying the fuel structure or amount. A kinetic
study of the process shows that the consume of the fuel is catalyzed
by the “unlocked” calixarene that behaves as an autocatalyst for its
own production. A mechanism is proposed for the reaction of fuel
consumption.
appended units, the properties of calix[4]arene-based receptors
or building blocks depend also on the conformational features of
the scaffold. Even when blocked in one of the four possible
structures (cone, partial cone, 1,2- and 1,3-alternate), the
calixarene scaffold retains a certain degree of flexibility. A
calix[4]arene in the cone geometry, for example, when
functionalized at the lower rim with four alkyl or polyether chains
(Figure 1, with R larger than CH3CH2─) rapidly interconverts
between two equally stable pinched cone conformations where
two distal aromatic rings are parallel to each other and the other
two are tilted outwards.[7] This “breathing” movement is originated
from a partial rotation around the eight Ar─CH2 bonds and, as a
consequence, the distances between the opposite carbon atoms
C1─C3 and C2─ C4 are coupled in such a way that when the former
is at its minimum the latter is at its maximum and vice-versa (see
Figure 1). When the calixarene is functionalized also at the upper
rim, this equilibrium can be shifted towards one of the two possible
Introduction
pinched structures as
a result of attractive or repulsive
interactions between the upper rim distal substituents.[8,9,10] The
consequences of this flexibility can be relevant on the calixarene
properties, such as the availability of the aromatic cavity for guest
complexation,[10] the macrocycle self-assembly properties[11] or
the spectroscopic properties of calixarene-based dyes.[12,13] To
the best of our knowledge, control on the conformational
equilibrium of Figure 1 has been mainly attained through a change
of the solvent,[10,12,14,15] a time-consuming operation that does not
allow a fast switch between the two pinched cone structures. We
Modulation of the conformation of complex molecular
architectures is one of the by-nature most used tool to control the
chemical properties of biomolecules. In particular, chemically
induced conformational changes are conveniently employed to
modify binding capability or catalytic activity of allosteric proteins.
Hemoglobin[1] or aspartate carbamoyltransferase[2] are famous
and recurrently cited examples. In the case of man-made
supramolecular systems, although involving far simpler structures,
remarkable examples of chemically-induced conformational
control of properties and reactivity have been reported, mainly
based on molecular machines.[3,4] Among them our attention was
directed to systems in which conformational changes are driven
by chemical fuels.[5,6] In these cases, the conformational change,
for example from state A to state B (A→B), and the consequent
variation of chemical properties, persists as long as the fuel is
present in solution and ends (B→A) when the fuel is exhausted.
Calix[4]arenes have been widely used as abiotic scaffolds in
Supramolecular Chemistry thanks to the possibility of an easy
functionalization of both rims with a large number of functional
units. Importantly, in addition to the chemical functionalities of the
figured that the use of
a chemical fuel to induce the
conformational change of the calixarene scaffold would be highly
desirable as a convenient way to favour one of the two pinched
cone structures in a time-controlled and programmable fashion
without recurring to a variation of the solvent.
With the aim of controlling the conformational equilibrium of
Figure 1 by means of the chemical fuels 1,X (2-cyano-2-
phenylpropanoic acid and its derivatives), which are known to be
capable of driving the oscillatory movements of acid-base
operated molecular machines,[5a,d,f,h,j,k,6] we hypothesized that 1,3-
distal diaminocalix[4]arene 2, could be a good candidate for our
purpose. The inspiration came from our previous report on the
1
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intramolecular Cannizzaro reaction occurring under basic
conditions within the 1,3-distal diformylcalix[4]arene 3.[16] Here,
the intramolecular hydride transfer between the two aldehyde
functions is strongly favored by the flexibility of the calixarene
scaffold which allows the “Hˉ” donor and acceptor functions to be
in close proximity at transition state level as depicted in 4 (high
Effective Molarity, EM[16a,17]). By the same token, protonation of
compound 2 should result in the conjugate acid 2H+ in which a
strong intramolecular hydrogen bond binds the protonated amino
group to the unprotonated one, forcing the two groups to be close
to each other.
Figure 1. Conformational interconversion of a calix[4]arene in the cone
structure (R > CH3CH2─) between two pinched cone conformations. The C1─C3
distance is at its maximum in conformation a and at its minimum in conformation
b. The reverse holds for the C2─C4 distance.
are shifted towards lower and higher fields, respectively. This
witnesses the formation of ion pair 2H+•ArC(CH3)CNCO2ˉ (state
B’), with the calixarene scaffold assuming a rigid pinched cone
conformation. The observed magnetic anisotropy is indeed typical
of such conformation. The shifts of the signals marked in black
belonging to the 2-ethoxyethoxy groups in the lower rim of the
calixarene structure are also in accordance with the above
conformational change
Our design is illustrated in Figure 2. Reaction between fuels
1,X and the “unlocked” calix[4]arene 2 (state A) would generate
the ion pair 2H+•ArC(CH3)CNCO2ˉ (state B’), which should
possess a “locked” pinched-cone conformation with the two
amino groups fixed in close proximity and the opposite
unsubstituted aromatic nuclei far from each other. Subsequent
decarboxylation and back proton transfer from 2H+ to
ArC(CH3)CNˉ, which are intimately paired in state B”, would
regenerate calixarene 2 in the unlocked resting state with
compound 5 as a waste product closing the “conformational cycle”.
Thus, fuels 1,X would serve to chemically control the
conformational state of calixarene 2.
Results and Discussion
The four 2-ethoxyethoxy groups at the lower rim of 1,3-distal
diaminocalix[4]arene 2 guarantee that the structure always
maintains its cone conformation. 1H NMR spectrum in CD2Cl2 at
25 °C of 4.0 mM 2 is reported as the first trace from bottom of
Figure 3. The pattern of this spectrum is that of a typical 1,3-
distally disubstituted calix[4]arene in its cone conformation.
Addition of 1 mol equiv of fuel 1,H immediately causes a
series of shifts (compare the bottom trace and the second trace
(t = 3 min), the latter being the first spectrum recorded after the
addition of fuel) due to protonation of 2 (step A→B’ in Figure 2).
Signals marked in red and blue belonging to the aromatic rings
Figure 2. Proposed “conformational cycle” experienced by diaminocalix[4]arene
2 under the action of fuels 1,X (see text).
.
2
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t = 245 min
t = 228 min
t = 159 min
t = 109 min
t = 38 min
t = 3 min
2, 4.0 mM, t = 0
Figure 3. 1H NMR time-monitoring of the reaction between 4.0 mM 2 and 4.0 mM fuel 1,H in CD2Cl2 at 25 °C. The bottom trace is the spectrum of 4.0 mM 2 taken
before addition of the fuel
From 3 min ahead, decarboxylation and fast back proton transfer
from 2H+ to ArC(CH3)CNˉ within the ion pair in state B” (Figure 2)
regenerating the native unlocked cone conformation of 2 are
apparent. At the end of the processes (t = 245 min) the solution
only contains 2 in its native state A and the waste product 5.
Interestingly, proton exchange from 2 to 2H+ and vice-versa
results to be fast on NMR time-scale. This finding contrasts with
that obtained in the case of two previously reported molecular
machines driven by fuel 1,H, one based on a catenane[5a] and the
other on a rotaxane[5e] structure. Moreover, in the present case,
the absence of any signal ascribable to the ion pair
2H+•ArC(CH3)CNˉ (state B”) during the whole 1H NMR monitoring
of the reaction, is in accordance with a very fast back proton
transfer from 2H+ to ArC(CH3)CNˉ.
The overall mechanism of the reaction 1,H + 2 depicted in
Figure 2, which is strongly supported by the NMR data of Figure
3, is definitely demonstrated by the fact that para-anisidine 6, a
monofunctional model compound for calixarene 2, is not able to
act as a base promoter of the decarboxylation of fuel 1,H. A
CD2Cl2 solution of 4.0 mM 1,H and 8.0 mM 6 is recovered
unaltered after 16 h at 25 °C (Figure S1), showing that the
catalytic capability of 2 in promoting the decarboxylation of acid
1,H, is dictated by an enhanced basicity of the amine functions of
2 when compared with that of the amine function of 6. The
possibility to share the proton between the two nitrogen atoms in
the calixarene structure is a source of a basicity increase, which
strongly resembles the topological enhancement of basicity found
by Sauvage et al[18] and later by Di Stefano et al[5a] in the case of
phenanthroline based catenanes.
The significantly higher basicity of 2 with respect to 6 is proved
by the fact that after 2 is protonated with 1 mol equiv of
1
trifluoroacetic acid (TFA) to give 2H+•CF3CO2ˉ, whose H NMR
spectrum (Figure S2 top trace) is practically superimposable to
calixarene signals of 2H+•ArC(CH3)CNCO2ˉ (state B’, trace at
t = 3 min in Figure 3) addition of up to 50 mol equiv 6 (in water
pKa = 5.36), fails in deprotonating 2H+•CF3CO2ˉ (Figure S3).
Deprotonation of 2H+•CF3CO2ˉ is instead complete only after
addition of 100 mol equiv of N,N-diethylaniline 7 (in water
pKa = 6.57) (Figure S4). Remarkably, when 6 is protonated by
TFA to give 6H+•CF3CO2ˉ, all aromatic signals are significantly
3
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that it is a reactive intermediate present at sub-detectable
concentrations. The two kinetic profiles are in strict accordance,
but instead of following the usual first-order behavior expected for
the decarboxylation process,[5a,d,j] they present unusual features
characteristic of a complex kinetics. In particular, it appears that
the rate increases on increasing the extent of reaction with no sign
of slowdown until the fuel is completely consumed, as evidenced
by the sharp cusp in correspondence of the end of the reaction.
An analogous profile is observed when the reaction in CH2Cl2 is
monitored by UV-Vis spectrophotometry, by following the
increase of absorbance at  = 315 nm due to the higher molar
absorptivity of the reaction products (Figure 4c and Figure S11).
A rate increase of the decarboxylation process on increasing
the extent of reaction suggests that the process is catalyzed by
the unprotonated calixarene 2 formed in the course of the reaction,
that, in fact, behaves as an autocatalyst. Moreover, the cusp in
the kinetic profiles is characteristic of a process which is pseudo
zero-order in substrate, because any reaction order larger than
zero would necessarily imply a slowdown of the reaction when the
substrate concentration tends to zero. The operation of an
autocatalytic process requires the presence of a background
reaction capable of producing the initial amount of product that
will then act as an autocatalyst for its own production. Taking into
account the experimental results, it is reasonable to assume that
the background reaction is the first-order decarboxylation process
of the ion pair 2H+•ArC(CH3)CNCO2ˉ (state B’), and that the main
reaction is the calixarene assisted decarboxylation of state B’
which is pseudo zero-order in substrate and first-order in the
product 2 (Scheme 1).
shifted to lower field (+0.23 ppm) as expected (Figure S5), in stark
contrast with what occurs to the aromatic signal of the amino
functionalized rings of 2, which is shifted to higher fields (−0.22
ppm) upon conversion into 2H+•CF3CO2ˉ by protonation. The shift
to higher fields of the 2H+ signal is indeed suggestive of the switch
of the scaffold conformation to a locked, closed pinched cone
state. Indeed, in this structure, the two amino functionalized
aromatic rings are parallel to each other as a consequence of the
+
NH3 ∙∙∙NH2 intramolecular hydrogen bond and experience the
shielding effect of the other two rings pointing outwards.
Eventually, VT NMR experiments performed on 2 and
2H+•CF3CO2ˉ (Figure S6 and S7, respectively) showed minimal
shifts ( < 0.1 ppm) of the signals in the temperature range -50°C
 55°C and a slight broadening only at the low temperatures,
indicating that the conformation of 2 both in the “unlocked” and in
the “locked” state is not modified upon heating nor cooling.
Kinetics and Mechanism of Decarboxylation
The progress of the decarboxylation step B’→B”, which is the
rate determining step of the whole motion cycle, can be monitored
1
by H NMR as shown in Figure 3 (CD2Cl2). The reaction can be
followed over time by monitoring either the disappearance of the
reactant ArC(CH3)CNCO2ˉ, component of state B’, (Figure 4a), or
the formation of the reaction product 5 (Figure 4b). The two
measures are independent from each other since have been
obtained by comparison of the areas of the corresponding methyl
group signals with that of a calix[4]arene signal conveniently
chosen. The carbanion ArC(CH3)CNˉ, component of state B”,
was not detected during the entire reaction course, thus indicating
Scheme 1. Background and calixarene assisted decarboxylation reactions
according to experimental results.
Figure 4. (a) Plot of the concentration of the PhC(CH3)CNCO2ˉ component of state B’ vs. time as monitored by 1H NMR for the reaction between 4.0 mM 2 and 4.0
mM fuel 1,H in CD2Cl2 at 25 °C. The solid curve is the least-squares fit of the experimental points to the integral of Eq. 1 for the disappearance of B’ (Eq. S6). (b)
Plot of the concentration of product 5 vs. time for the same reaction of Figure 4a. The solid curve is the least-squares fit of the experimental points to the integral of
Eq. 1 for product formation (Eq. S7). (c) Plot of the normalized absorbance at  = 315 nm for the reaction between 1.0 mM 2 and 1.0 mM fuel 1,H in CH2Cl2 at 25 °C.
The solid curve is the least-squares fit of the experimental points to the integral of Eq. 1 for product formation (Eq. S7).
4
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Accordingly, the rate equation for such scheme can be
formulated as shown in Eq. 1, where v’ is the rate of the
background reaction, and v’’ is the rate of the autocatalytic
process.
′
[
]
[ ]
푑 ퟓ
[ ]
푑 ퟐ
푑 퐁
′
= 푣′ + 푣′′= 푘1
(1)
[
퐁
]
[ ]
+ 푘2 ퟐ
−
=
=
푑푡
푑푡
푑푡
The curves shown in Figures 4a-c were obtained by fitting the
experimental points to the integrated rate equations, obtained as
detailed in SI (pages S16-S18). The adherence of the calculated
curve to the experimental points is very good, thus lending
support to the above kinetic analysis.
Although Scheme
1 is in good agreement with the
Scheme 2. Proposed kinetic mechanism involving the cationic impurity in the
experimental data, the mechanism of the autocatalytic process is
puzzling and needs to be clarified. The observation of a pseudo
zero-order substrate dependency for a reaction occurring in
homogeneous solution typically arises due to one of two possible
mechanisms: i) the autocatalyst is involved in a rate-limiting
process preceding the reaction with the substrate (the fuel); ii) the
substrate is involved in a strong pre-equilibrium binding that
saturates a catalytic species present in minute amounts, the
resulting complex then reacts with the autocatalyst in the rate-
limiting product formation. If mechanism i were operating, the rate
of the autocatalytic process would be independent of the nature
of the fuel. However, investigation of the kinetics of the reaction
with different fuels 1,X showed that the rate of the autocatalytic
process is fuel-dependent (vide infra), thus ruling out mechanism
i, and leaving mechanism ii as a viable option. The latter
mechanism implies the presence of a catalytic species which, in
all probability, can be attributed to an impurity of the solvent, since
normalized kinetic profiles of reactions carried out at different
dilution are practically superimposable (Figure S18). If the
impurity had belonged to the reactants, its dilution would have
slowed down the reaction. All commercial samples of methylene
chloride are known to contain small amounts of metal ions of
various charge, mostly present as chlorides. In such a low
dielectric solvent, the anionic substrate ArC(CH3)CNCO2ˉ is
necessarily paired with a cation, and any of the resulting ion pairs
must have a specific reactivity. It is reasonable to think that among
the many cations present in solution, one or more of them not only
displays a high affinity for the substrate but also gives an ion pair
more reactive than 2H+•ArC(CH3)CNCO2ˉ (state B’). Since the
autocatalytic reaction is first-order in the product 2, the following
mechanism can be envisaged for any cationic species, say M+,
present in solution (Scheme 2). The free calixarene 2 interacts
with the ion pair ArC(CH3)CNCO2ˉ•M+ by coordinating the metal
ion with the two aminic nitrogens. The coordination makes the
carboxylate freer thus favoring the rate-limiting decarboxylation.
The formed ion pair ArC(CH3)CNˉ•M+ quickly takes the proton
from state B’ giving the product 5 and the reactants, which begin
a new catalytic cycle. Interestingly, when the reaction is carried
out in the presence of trifluoroacetic acid (TFA) in the proportions
2 : 1,H : TFA = 1 : 0.9 : 0.1, the kinetic profile changes as shown
in Figure 5 where it appears that the autocatalytic reaction is
slowed down, especially in the final part of the reaction where the
product asymptotically approaches its final value. This evidence
autocatalysis.
Figure 5 Plot of the normalized absorbance at  = 315 nm for the reaction
between 1.0 mM 2 and 0.9 mM fuel 1,H in the presence of 0.1 mM TFA in CH2Cl2
at 25.0 °C. The points are experimental data, the dashed line has been
calculated by the integral of Eq. 1 (Eq. S7) with k1 and k2 values obtained from
the data in Figure 4c, and the solid line is the least-squares fit of the
experimental points to the integral of Eq. 2 for product formation (Eq. S13).
suggests that now the autocatalytic process is first-order in
substrate and first-order in the product 2. Indeed, the
experimental points have been successfully fitted by the integral
rate equation obtained from Eq. 2 (SI, pages S19-S20).
′
[
]
[ ]
푑 ퟓ
[ ]
푑 ퟐ
푑 퐁
′
[
]
[ ]
+ 푘2[퐁′] ퟐ
−
=
=
= 푘1
퐁
(2)
푑푡
푑푡
푑푡
This result can be explained by considering that both the
conjugate bases of 1,H and of TFA, initially in a 9:1 ratio, are
present in solution. It is reasonable to assume that the two anions
have similar chelating abilities toward metal ions, thus initially
most of the catalytically active metal ion is ion paired with the
conjugate base of 1,H, and displays the usual catalytic
mechanism. However, towards the end of the reaction, the
conjugate base of TFA sequesters most of the catalytically active
ion, and the mechanism of autocatalysis changes as it would be
in the absence of catalytic impurities (Scheme 3), i.e. free
calixarene 2 interacts by hydrogen bond with the ion pair
2H+•ArC(CH3)CNCO2ˉ (state B’) loosening the ion pair and
favoring the rate-limiting decarboxylation.
5
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the neutral calixarene 2, increasing the life time of the pinched
cone conformation of 2H+.[20]
Scheme 3. Proposed mechanism of autocatalysis in absence of catalytic
impurities.
Support for this mechanism is provided by the structures of
models of the ion pair 2H+•ArC(CH3)CNCO2ˉ (state B’) and of the
ternary complex 2•2H+•ArC(CH3)CNCO2ˉ, fully optimized at the 2-
layer ONIOM (B97XD/6-311+G(2d,p):HF/3-21G*) level of theory,
including IEFPCM solvation in CH2Cl2, as implemented in
Gaussian 16,[19] showing that the length of the hydrogen bond
between the carboxylate anion and the ammonium ion changes
from 1.547 Å to 1.614 Å on passing from the ion pair to the ternary
complex (SI, Figure S19 pages S21-S26).
Figure 6. Plot of the concentration of the product 5 vs. time as monitored by 1H
NMR for the reaction between 4.0 mM 2 and 4.0 mM fuel 1,p-Cl (red trace), 4.0
mM 2 and 4.0 mM fuel 1,H (black trace), 4.0 mM 2 and 4.0 mM fuel 1,p-CH3
(blue trace) and 3.6 mM 2 and 3.6 mM fuel 1,p-OCH3 (green trace), in CD2Cl2
at 25 °C. The solid curve is the least-squares fit of the experimental points to
the integral of Eq. 1 for product formation (Eq. S7). Since protonation of 2 by
ArC(CH3)CNCO2H (A→B’) and re-protonation of ArC(CH3)CNˉ by 2H+ (B”→A)
are very fast reactions, each trace describes the corresponding, complete
A→B’→B”→A cycle. For the corresponding sequences of 1H NMR spectra see
SI, pages S8-S10.
Controlling the rate of the conformational cycle
In spite of the above mechanistic complications, the rate with
which the conformational cycle of the calix[4]arene scaffold
occurs can be easily controlled by changing the nature of the
para-substituent in the fuel aromatic moiety. As previously stated,
the decarboxylation is the rate limiting step of the entire cycle of
the conformational motion. Electron-withdrawing groups that
stabilize the developing negative charge on the benzyl carbon
atom in the decarboxylation transition state (TS), are indeed
expected to accelerate the motion cycle, whereas electron-
donating groups should retard it. This expectation is confirmed by
the results obtained when acids 1,p-Cl, 1,p-CH3 and 1,p-OCH3 are
Table 1. First-order rate constants k1 and k2 for the reactionof different fuels 1,X
according to Scheme 1 and Eq. 1
X
p-Cl
H
p-CH3
p-OCH3
k1, s-1
k2, s-1
1
(2.9  0.4)  10-4
(3.2  0.1)  10-5
(1.6  0.1)  10-5
(3.3  0.1)  10-6
(1.2  0.1)  10-3
(1.2  0.1)  10-4
(3.8  0.1)  10-5
(7.3  0.1)  10-6
used as fuels to drive the conformational cycles of 2. H NMR
(Figure 7 and SI, pages S8-S10) and UV-Vis monitoring (SI, page
S10) show exactly the same features of those related to the
parent acid 1,H, but the time needed to complete the cycle
increases in the order 1,p-Cl < 1,H <1,p-CH3 < 1,p-OCH3 (28, 250,
610, and 3200 min, respectively). Thus, a simple variation of the
fuel structure allows to control the rate of the conformational
motions of 2 exactly as in the case of the oscillating motions of
acid-base operated molecular machines based on catenane or
rotaxane structures.5d,h,6
Fit of the experimental points in Figure 6 to the integral of Eq. 1
for product formation (Eq. S7) gave the first-order rate constants
k1 and k2 reported in Table 1.
Hammett plots of the rate constants k1 and k2 are linear with
 values equal to 3.6 and 4.2, respectively (Figure S20). The high
 values indicate that a significant fraction of the negative charge
is developing on the benzylic carbon in both the transition states
for the background and autocatalytic decarboxylation reactions.
The slightly higher sensitivity observed for the autocatalytic
process is in line with the formation of a looser ion pair.
A fine control of the rate of the conformational cycle of 2 can be
obtained by controlling the amount of fuel added in solution. This
trick was previously applied by Leigh et al[5i] to modulate the time
in which a rotaxane-based machine, working as a dissipative
catalyst, persists in one of the two available co-conformations. As
an example, Figure 7 reports the 1H-NMR monitoring of the
1,H + 2 reaction progress at different relative concentrations of
the two reactants. Concentration of 2 is fixed at 4.0 mM while
concentration of 1,H is 4.0 mM (black trace), 5.4 mM (red trace),
or 8.0 mM (green trace). It is evident that excess of fuel with
respect to 2 retards the recovery of the resting conformation of
As also observed in the case of a catenane based molecular
machine,[5a,f,j] when an excess of fuel is present, the latter is very
probably associated with the carboxylate forming a ternary
complex RCO2ˉ•HO2CR•2H+, whose structure is analogous to a
solvent separated ion pair. The latter association weakens the ion
pairing with 2H+, and this is very likely the reason why, at the
beginning of the reaction, the signal related to the protons of
amino substituted aromatic rings in 2H+ are found at lower fields
than expected (5.82 and 5.85 ppm for the red and green trace,
respectively, to be compared with 5.80 for the black trace; Figure
8).
The kinetic behavior of the reaction in the presence of an
excess of fuel is not trivial and requires some comment. It is
evident that free calixarene 2 cannot be present with an excess
of fuel because it would be immediately protonated by the latter
as soon as it forms. Accordingly, under this condition the
autocatalytic reaction cannot work because there is no free
calixarene 2 available. On the other hand, depending on the
amount of excess fuel, two first-order decarboxylation reactions
can be envisaged, one due to the ion pair 2H+•RCO2ˉ (state B’),
and the other due to the ternary complex RCO2ˉ•HO2CR•2H+. In
both
cases,
immediately
after
decarboxylation
of
ArC(CH3)CNCO2ˉ, the just formed carbanion ArC(CH3)CNˉ will
take the proton from the stronger acid RCO2H in excess rather
than from 2H+, which will persist in its protonated form (pinched
6
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10.1002/chem.202002574
Chemistry - A European Journal
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cone conformation). Thus, the result of both the two
decarboxylation reactions consists of the depletion of the ternary
complex in favor of state B’ (Eq. 3) until all the fuel RCO2H in
excess is consumed. This point corresponds to the minimum of
ranging from molecular receptors to sensing devices whose
active state could be switched on at will.[21]
Experimental Section
RCO−2 • HO2CR • ퟐH+
→
RH + CO2 + ퟐH+ • RCO−2
(3)
Instrument and methods: 1H NMR spectra were recorded on a 300 MHz
spectrometer. The spectra were internally referenced to the residual
proton signal of the solvent at 5.30 ppm. VT 1H NMR spectra were
recorded on a 600 MHz spectrometer. All the experiments were carried out
in thermostated NMR tubes. UV–Vis measurements were performed on a
Perkin Elmer Lambda 18 spectrophotometer.
Materials: All reagents and solvents were purchased at the highest
commercial quality and were used without further purification, unless
otherwise stated. CH2Cl2 and CD2Cl2 were dried over molecular sieves (3
Å) for 24 h and stored in a desiccator loaded with activated silica gel Rubin.
Before use the molecular sieves were activated at 300 °C for 24 h. Fuels
1,X[5d] and 1,3-diaminocalix[4]arene 2[22] were available from previous
investigations.
NMR decarboxylation experiment of fuel 1,X in the presence of 4.0
mM calix[4]arene 2: In a typical NMR decarboxylation experiment, 1.78
mg of calix[4]arene 2 were weighed into an NMR tube and diluted with
CD2Cl2 giving a solution ~ 4.0 mM. The t = 0 1H NMR spectrum was
recorded and then an aliquot of a stock solution of 1,X was added so that
the final volume of the solution was 600 µl. Thus, concentration of
calix[4]arene 2 was 4.0 mM, that of fuel 1,X was 4.0 mM or higher for the
experiments with excess of fuel.
Figure 7. Controlling the duration of the conformational cycle of the
calix[4]arene scaffold of 2 (4.0 mM) by regulating the excess of fuel 1,H (4.0 mM
black trace, 5.4 mM red trace, 8.0 mM green trace). 1H NMR monitoring of the
chemical shift of protons on the amino-substituted aromatic rings (CD2Cl2 25 °C).
For related sequences of 1H NMR spectra see Figure 3 and SI, pages S13-S14.
the curves shown in Figure 7, that in turn corresponds to the
chemical shift of the signal of the ion pair 2H+•RCO2ˉ, state B’ (δ
= 5.80 ppm for both red and green traces). Note that from this
point on, the reaction proceeds according to Scheme 1, where the
first-order decarboxylation reaction of state B’ is accompanied by
the autocatalytic process. Indeed, the ascending portions of the
curves are parallel to each other, indicating that after the minimum
the same process is occurring. Since the excess fuel can be
controlled at will, one has a full control over the time spent by the
calixarene scaffold in the pinched cone conformation.
UV-vis decarboxylation experiments of fuel 1,X in presence of 0.30
mM calix[4]arene 2: In a typical UV-vis decarboxylation experiment, 200
µl of a 3.0 mM stock solution of calix[4]arene 2 and an aliquot of a stock
solution of fuel 1,X were mixed in a 1.0 cm path length cuvette at 25 °C.
Then, the solution was diluted with CD2Cl2 so that the final volume was
2.00 mL, fixing the concentration of calix[4]arene 2 to 0.30 mM and that of
fuel 1,X to 0.30 mM for equimolar experiments, or higher for the
experiments with excess of fuel.
NMR titrations of 2H+•CF3CO2ˉ: Calix[4]arene 2 (0.89 mg) was weighed
into an NMR tube and diluted with 575 µl CD2Cl2 to give a 2.1 mM solution.
Then, 20 µl of a 0.06 M stock solution of TFA were added to the solution
giving a ~ 2.0 mM solution of 2H+•CF3CO2ˉ. At this point, subsequent
aliquots of 5.0 µl of a 0.06 M stock solution of p-anisidine 6 were added up
to 50 mol equiv NMR spectra of the solution were recorded at each titrant
addition. In another experiment, aliquots of a stock solution of N,N-
diethylaniline 7 were added to a ~ 2.0 mM 2H+•CF3CO2ˉ solution in the
NMR tube, prepared as described before, until 100 mol equiv of the titrant
were added.
Conclusion
In this report we have shown that the shape of a calix[4]arene
scaffold in its cone conformation can be controlled by the use of
chemical fuels. In particular, the cone 1,3-distal isomer of the
upper rim functionalized diaminocalix[4]arene 2 offers a unique
solution for this purpose. The basicity of the system is indeed
enhanced by the chance of the two amino functions to share the
proton in the conjugate acid. This basicity enhancement enables
the diaminocalix[4]arene to promote the decarboxylation of a
series of activated acids 1,X, which act as chemical fuels. During
the decarboxylation reaction the vast majority of the calixarene
molecules persists in the closed pinched cone conformation with
the two amino groups convergent and the two opposite distal
positions strongly divergent (locked state). The time spent by the
calix[4]arene scaffold in the locked state can be regulated by the
choice of the fuel used to drive the conformational cycle, and
finely modulated by controlling the amount of added fuel.
Acknowledgements
This work was supported by University of Roma La Sapienza
(Progetti di Ricerca Grandi 2018, prot. n. RG1181641DCAAC4E)
and by the Italian Ministry of Instruction, University and Research
programmes (COMP-HUB initiative, Departments of Excellence
Program and PRIN 2017E44A9P). “Centro Interfacoltꢀ di Misure”
(CIM) of the University of Parma is acknowledged for VT-NMR
experiments.
We believe that the possibility to fine-tune the
conformational interconversion of the calixarene in a time
dependent fashion and without recurring to solvent changes
opens the way to new perspectives in calixarene chemistry,
Keywords: Calixarene • Chemical Fuel • Molecular Motions •
Conformational Control • Molecular Machine
7
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Entry for the Table of Contents
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The shape of the cone
Daniele Del Giudice, Emanuele
Spatola, Roberta Cacciapaglia,
Alessandro Casnati Laura
Baldini,* Gianfranco Ercolani,*
and Stefano Di Stefano*
calix[4]arene scaffold can be
controlled by means of
chemical fuels. The time in
which the calix[4]arene
platform persists in the
“locked” shape is controlled
by varying nature and amount
of the chemical fuel.
Page No. – Page No.
Time Programmable
Locking/Unlocking of the
Calix[4]arene Scaffold by
Means of Chemical Fuels
9
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