Coupling of the Decarboxylation of 2-Cyano-2-phenylpropanoic Acid to Large-Amplitude Motions: A Convenient Fuel for an Acid-Base-Operated Molecular Switch

Article abstract of DOI:10.1002/anie.201602594

The decarboxylation of 2-cyano-2-phenylpropanoic acid is fast and quantitative when carried out in the presence of 1?molar equivalent of a [2]catenane composed of two identical macrocycles incorporating a 1,10-phenanthroline unit in their backbone. When decarboxylation is over, all of the catenane molecules have experienced large-amplitude motions from neutral to protonated catenane, and back again to the neutral form, so that they are ready to perform another cycle. This study provides the first example of the cyclic operation of a molecular switch at the sole expenses of the energy supplied by the substrate undergoing chemical transformation, without recourse to additional stimuli. Poetry in motion: Carboxylic acid 1 was found to be a convenient fuel for the operation of a molecular switch that moves under the influence of protonation-deprotonation steps. The cyclic motions of the catenane switch were induced solely by the chemical energy supplied by the decarboxylation of 1, without recourse to additional stimuli.

Full text of DOI:10.1002/anie.201602594

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International Edition: DOI: 10.1002/anie.201602594
German Edition: DOI: 10.1002/ange.201602594
Molecular Switches
Coupling of the Decarboxylation of 2-Cyano-2-phenylpropanoic Acid
to Large-Amplitude Motions: A Convenient Fuel for an Acid–Base-
Operated Molecular Switch
JosØ Augusto Berrocal, Chiara Biagini, Luigi Mandolini, and Stefano Di Stefano*
Abstract: The decarboxylation of 2-cyano-2-phenylpropanoic
acid is fast and quantitative when carried out in the presence of
1 molar equivalent of a [2]catenane composed of two identical
macrocycles incorporating a 1,10-phenanthroline unit in their
backbone. When decarboxylation is over, all of the catenane
molecules have experienced large-amplitude motions from
neutral to protonated catenane, and back again to the neutral
form, so that they are ready to perform another cycle. This
study provides the first example of the cyclic operation of
a molecular switch at the sole expenses of the energy supplied
by the substrate undergoing chemical transformation, without
recourse to additional stimuli.
of this reaction is that the catenane is switched “off” and “on”
solely through the protonation–deprotonation steps pro-
moted by the substrate undergoing decarboxylation, without
recourse to additional stimuli.
The addition of 1 molar equivalent of trifluoroacetic acid
(TFA) to a solution of 3 in CD2Cl2 causes significant changes
in the 1H NMR spectrum (Figure 1, compare trace a with
trace b). These changes are very similar to those caused by
complexation with Cu+ (Figure 1, trace c);[4a] notably, the
signals of the methylene protons are shifted upfield, apart
from those which are close to the double bond (see Figure S7
in the Supporting Information), as a result of exposure to the
shielding effect of the phenanthroline unit of the other
macrocycle. A deeper investigation based on COSY and
ROESY 2D NMR spectroscopy (see Figures S1–S4) fully
confirmed the close structural analogy between 3·Cu+ and
T
he wide interest in molecular machines is evident from the
large number of books[1] and review articles[2] that have been
published in recent years. An important role has been played
by catenanes and rotaxanes, in which the relative position of
the components is controlled by the presence of switchable
functions. Numerous examples of catalytic systems, in which
the catalytic activity is triggered and controlled by the motion
of one of the substructures with respect to the other, have
been reported.[3] In all these cases, external stimuli, either
chemical or physical, are required to switch the catalyst from
the active to the inactive form, and vice versa.
Herein we report the decarboxylation of 2-cyano-2-
phenylpropanoic acid [1, Eq. (1)] promoted by the acid–
base-switchable [2]catenane 3[4] [Eq. (2)], the structure of
which consists of two identical interlocked 28-membered
macrocyclic alkenes (cis and trans) featuring 1,10-phenan-
throline units in their backbone. The unprecedented feature
[*] C. Biagini, Prof. L. Mandolini, Dr. S. Di Stefano
Dipartimento di Chimica, Università di Roma La Sapienza and
Istituto CNR di Metodologie Chimiche (IMC-CNR)
Sezione Meccanismi di Reazione
P. le A. Moro 5, 00185 Roma (Italy)
E-mail: stefano.distefano@uniroma1.it
Figure 1. 1H NMR spectra (CD2Cl2, 258C) of a) 3, b) 3·H+ (trifluoroace-
tate salt), c) 3·Cu+ (hexafluorophosphate salt), and d) 3·(H+)2
Dr. J. A. Berrocal
Institute for Complex Molecular Systems
Eindhoven University of Technology
P.O. Box 513, 5600 MB Eindhoven (The Netherlands)
(trifluoroacetate salt). The spectra show signals of phenanthroline
protons (8.8–7.3 ppm), double-bond protons (5.7–5.5 ppm), and meth-
ylene protons at higher field. The signal at 5.3 ppm is due to CHDCl2.
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201602594.
1
See Figure S7 for the full assignment of H NMR signals.
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3·H+, thus strongly supporting the proton catenate structure
expected for 3·H+ on the basis of the behavior of similar
catenanes.[5] The presence of only one set of signals in the
aromatic region indicates that 3·H+ is a symmetrical species in
which scrambling of the proton among the four nitrogen
atoms is fast on the 1H NMR time scale.[5a] Treatment with an
excess of an aliphatic amine (Et3N, pKa = 10.75; Bu2NH,
pKa = 11.25) failed to restore 3·H+ to the neutral form 3, in
keeping with the notion advanced by Sauvage and co-workers
of the topological enhancement of basicity[5a] in phenanthro-
(step III) leads to the final product 2 and restores the base to
its neutral form. When 1,8-bis(dimethylamino)naphthalene
(proton sponge, pKa = 12.1) was used instead of Et3N,
quantitative conversion into 2 was observed in about
10 min. The much lower effectiveness of Et3N as a promoter
is not surprising, as Et3NH+ is expected to stabilize carbox-
ylate 4À by hydrogen bonding much more strongly than the
protonated proton sponge, in which the proton is covalently
bound to one nitrogen atom and hydrogen bonded to the
other.[7] An experiment in which acid 1 was treated with half
a molar equivalent of Et3N is fully consistent with the idea
that strong H-bonding donors exert a retarding effect on the
rate of CO2 liberation from carboxylate anion 4À (see the
Supporting Information for details).
1
line-based catenanes. Indeed H NMR and UV/Vis spectro-
scopic titrations of 3 with Bu2NH2PF6 (see Figure S9) showed
that 3 is no less than 5 orders of magnitude more basic than
Bu2NH. Consistent with the exceptionally high stability of
3·H+ is the finding that a large excess of TFA (20 equiv) was
required to transform 3·H+ into the dication 3·(H+)2 [Eq. (3)].
When the decarboxylation of 1 (5 mm) was carried out in
the presence of 1 molar equivalent of 3, quantitative con-
1
version into 2 was observed in about 50 min.[8] The H NMR
spectra recorded during the course of the reaction (Figure 2,
Scheme 2) revealed a number of unexpected features, nota-
Comparison of the spectrum of 3·(H+)2 (Figure 1d), in which
the protonated phenanthroline units are presumably held
apart by electrostatic repulsion, with that of 3, strongly
suggests that these catenanes have similar structures. Apart
from the phenanthroline protons, which are shifted to lower
fields in 3·(H+)2, prominent features common to both spectra
are the lack of signals in the high-field region above 1.2 ppm
and the upfield shifts of the double-bond protons (see
Figure S8 for details) as compared to the proton catenate
3·H+. Again, comparison of the COSYand ROESY 2D NMR
spectra of 3·(H+)2 (see Figures S5 and S6) with those of 3
strongly indicates very similar structures.
The choice of the substrate for the present investigation
was suggested by the report[6] that acid 1 undergoes smooth
decarboxylation in the presence of tertiary bases under mild
conditions. In a control experiment, we found that the
decarboxylation of 1 (CD2Cl2, 10 mm, 258C) in the presence
of Et3N (1 equiv) was indeed quantitative and complete in
1
about 5 h (t = = 43 min; see Figure S11). Monitoring of the
2
reaction progress by 1H NMR spectroscopy afforded
a number of spectra (see Figure S12) indicating quantitative
proton transfer from 1 to Et3N (step I in Scheme 1), followed
by rate-determining decomposition of the carboxylate anion,
presumably in the form of a hydrogen-bonded ion pair 4À BH+
(step II). Fast proton transfer to the carbanion intermediate
Figure 2. 1H NMR monitoring of the reaction between 3 (5 mm) and
1 (5 mm) in CD2Cl2 at 258C. Marked signals are assigned to the
protons with the corresponding symbol in Scheme 2. The trace at t=0
is the spectrum of 3. See Figure S13 for full spectra.
bly, the presence of three signals in the range of 4.8–3.8 ppm,
whose intensities corresponded to five protons in a 1:3:1
ratio.[9] No traces of these peaks were detected when the
decarboxylation of 1 was carried out in the presence of Et3N
(see Figure S12) or proton sponge. They must belong to
a reaction intermediate, as their disappearance was paralleled
by an increase in intensity of the signal of the benzylic proton
of 2 at 3.95 ppm, as well by the gradual transformation of 3·H+
Scheme 1. Three-step base-promoted decarboxylation of acid 1.
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3·H+, which acts as a strong p-acceptor.[14] In other words, 5À
acts as a very effective shift reagent towards 3·H+, thus
dramatically affecting its 1H NMR spectrum.
Deeper insight into the reaction mechanism came from
decarboxylation experiments carried out in the presence of
substoichiometric amounts of catenane 3. Excess acid is
expected, on the one hand, to retard the loss of CO2 from the
carboxylate anion, as was found to be the case in the reaction
carried out in the presence of Et3N (see the Supporting
Information). On the other hand, however, excess acid should
accelerate the rate of protonation of the carbanion inter-
1
mediate. H NMR spectra for an experiment in which the
molar ratio between acid 1 and catenane 3 was 2:1 are shown
in Figure 3. Inspection of the spectrum recorded after 3 min,
particularly in the double-bond region around 5.5 ppm, shows
that the reaction mixture is composed of two distinct 3·H+
species, namely, the complex A’ and a new species, whose
Scheme 2. Compounds and ion pairs involved in reactions of 1 with 3.
Key hydrogen atoms for the identification of these species in the
1H NMR spectra in Figures 2 and 3 are marked with the symbols used
to label the corresponding peaks.
À
spectrum displays features very similar to those of CF3CO2 ·
(3·H+) (Figure 1b), notably, the signal at 5.70 ppm and the set
of signals in the high-field region. No trace of the latter
species appears in the spectrum at 8 min. At this time, the
reaction has reached 50% conversion, excess acid is no longer
into 3,[10] as clearly shown by the disappearance of the peak at
5.53 ppm of the double-bond protons of the major geo-
metrical isomer and the concomitant appearance of the
corresponding peak at 5.46 ppm of the neutral catenane 3,
among other indications. The only feasible conclusion is that
the reaction intermediate responsible for the three signals in
the range from 4.8 to 3.8 ppm is carbanion 5À. This conclusion
is corroborated by a previous report[11] on the non-equiv-
alence of the five aromatic protons of a-methylbenzyl
carbanion (K+ salt), as characterized by five distinct chemical
shifts in the range from 6.2 to 4.6 ppm in [D8]THF.[12]
The peculiar features displayed by the decarboxylation of
1 as promoted by 3 arise from the structure of 3·H+, in which
the proton is embedded in the tetrahedral arrangement of the
four N atoms. This structural arrangement has important
consequences: The lack of any stabilizing effect of the
carboxylate anion by H-bonding explains why step II
(Scheme 1) is faster than when the countercation is the
protonated proton sponge, and is complete within the short
time required to record the first spectrum. Furthermore, the
proton of 3·H+ is sterically hindered to such an extent that
proton transfer to 5À becomes rate-determining. Accordingly,
in the early stages of the reaction, the system should be almost
exclusively composed of a 1:1 mixture of 5À and 3·H+.
1
However, the H NMR spectrum recorded 3 min after the
start of the reaction (Figure 2) bears little resemblance to the
À
À
spectra of the CF3CO2 (Figure 1b) and PF6 salts (see
Figure S10) of 3·H+, notably in the high-field region, in which
the highly structured signal pattern of the methylene protons
is replaced with a broad signal at 1.2–0.7 ppm. As a possible
explanation, we suggest that the driving force for the
association of 5À with 3·H+ is not a simple cation–anion
attraction as that involved in the ion pairs of 3·H+ with
À
À
CF3CO2 and PF6 anions. It seems likely that the pair
5À·(3·H+), A’ in Scheme 2, is better described as an electron-
donor–acceptor (EDA) complex[13] between the presumably
strong p-donor 5À and the protonated phenanthroline core of
Figure 3. 1H NMR monitoring of reaction between 1 (4 mm) and 3
(2 mm) in CD2Cl2 at 258C. Marked signals are assigned to the protons
with the corresponding symbol in Scheme 2. The trace at t=0 is the
spectrum of 3. See Figure S15 for full spectra.
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present, and free catenane 3 begins to reappear, as shown by
the tiny peak at 5.56 ppm. From then onwards, the second half
of the reaction proceeds exactly as in the case in which the 1:1
molar ratio was set from the start (Figure 2). Excess acid in
the first half of the reaction is clearly responsible for the
appearance of the transient species. The observed phenomena
are accounted for by the reaction pathways in Scheme 3:
Figure 4. 1H NMR spectra (CD2Cl2, 258C; peaks in the range 2.8–
5.8 ppm) showing the results of three cycles of the reaction of 1 with
3. Trace 0 is the spectrum of 5 mm catenane in the neutral form 3 and
shows the signals of the double-bond protons and the triplet of the
CH2 groups bound to the phenanthroline moieties. Each cycle was
started by the addition of 1 molar equivalent of acid 1, and the
corresponding spectrum was recorded after a reaction time of 50 min.
The quartet centered at 3.95 ppm is due to the benzylic proton of 2.
Scheme 3. Reaction pathways for the reaction of 1 with 3. The reaction
sequence in Scheme 1 is shown on the left-hand side from top to
bottom. An alternative pathway involving the rate-limiting liberation of
CO2 from the ternary adduct B is made available by excess acid.
Consequently, the switchable catenane undergoes large-
amplitude motions at the expense of the chemical energy
supplied by the substrate undergoing decarboxylation.
In conclusion, we have shown that the mechanical
motions experienced by an acid–base switchable catenane
between two distinct states do not require the intervention of
additional stimuli, but are intrinsically associated with the
ability of the catenane itself to act as an effective base
promoter of the decarboxylation of acid 1. In general, we
believe that any molecular switch[3] or motor that moves
between two states under the influence of protonation/
deprotonation could utilize acid 1, or any other acid that
undergoes base-promoted decarboxylation at a convenient
rate, as a fuel.
Excess acid transforms adduct A into the ternary complex B,
thus causing a diversion of the reaction mechanism from
a sequence in which the rate-determining step is the intra-
molecular proton transfer within A’, to one in which the rate-
determining step is the liberation of CO2 from the ternary
complex B, which is the transient species detected in the
1H NMR spectrum recorded after 3 min (Figure 3).
Consistent results were obtained from a reaction with
1
a 10-fold molar excess of acid (see Figure S16 for H NMR
1
spectra). In this case, the H NMR signals of B were clearly
visible during a much longer period of time. After 102 min,
the concentration of B was still larger than that of A’, and it
was still significant after 110 min, thus showing that only in
the very late stages of reaction A’ is the predominant
1
intermediate. The H NMR spectra clearly indicate that the
fractional contribution of the pathway proceeding via B was
much larger in this case than in the reaction in which a twofold
excess of acid was used.[15]
Acknowledgements
We thank the Ministero dell’Istruzione, dell’Università e della
Ricerca (MIUR) for financial support (PRIN 2010CX2TLM).
This research was also partially supported by Università di
Roma La Sapienza (Progetti di Ricerca 2014). We thank
Flaminia Di Pietri for technical assistance.
So far our attention has been concentrated on the peculiar
features of the decarboxylation of 1 as promoted by 3. We
now focus on the large-amplitude motions experienced by 3 in
going from the neutral catenand to the proton catenate state
when the reaction is carried out with a 1:1 molar ratio. These
motions are coupled to decarboxylation in such a way that
each time a reactant molecule is transformed into the product,
a catenane molecule switches from the neutral to the
protonated state, and back again to the neutral state
(Scheme 3, left). Thus, if another molar equivalent of acid
1 is added to the system, catenane 3 performs another cycle,
and so on. The results of three full cycles are shown by the
1H NMR spectra in Figure 4. It is apparent that the sole
difference in the composition of the solutions obtained in the
various cycles is the accumulation of the reaction product 2.
Keywords: catenanes · chemical fuels · decarboxylation ·
molecular devices · molecular motions
How to cite: Angew. Chem. Int. Ed. 2016, 55, 6997–7001
Angew. Chem. 2016, 128, 7111–7115
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[5] a) M. Cesario, C. O. Dietrich-Buchecker, A. Edel, J. Guilhem, J.-
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A. Livoreil, L. PØrez-García, J.-P. Sauvage, J. F. Stoddart, J. Am.
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[6] H. Brunner, P. Schmidt, Eur. J. Org. Chem. 2000, 2119 – 2133.
[7] F. Hibbert, Adv. Phys. Org. Chem. 1986, 22, 113 – 212.
[8] In a control experiment, a 5 mm solution of acid 1 was treated
with 10 mm neocuproine (2,10-dimethyl-1,9-phenanthroline,
pKa = 6.15) in CD2Cl2 at 258C. After a reaction time of 50 min,
the yield of product 2 did not exceed 1%. The poor effectiveness
of neocuproine can be ascribed to its low basicity and contrasts
sharply with the behavior of 3, which arises from the topological
enhancement of basicity.
À
the aromatic signals of C6H5CH2 in [D8]THF were shifted
upfield when the high-charge-density countercation Li+ (peaks
in the range from 6.30 to 5.50 ppm) was replaced by lower-
charge-density K+ (peaks from 5.59 to 4.79 ppm). An even
stronger upfield-shifting effect is expected for a much bigger
countercation, such as 3·H+.
[13] M. B. Smith, J. March, Marchꢀs Advanced Organic Chemistry,
6th ed., Wiley, Hoboken, 2007, p. 155.
[14] The non-equivalence of the two subunits of 3·H+ in 5À·(3·H+) is
particularly evident in the aromatic proton region (see Fig-
ure S13, trace at 3 min) and contrasts with the perfect equiv-
alence revealed by the spectrum of the trifluoroacetate salt
(Figure 1b; see also Figure S7). This difference indicates that
À
3·H+ interacts with 5À much more strongly than with CF3CO2
,
and that any rearrangement within the complex that would
produce a time-averaged equivalence of the subunits is slow on
1H NMR time scale.
[15] A catalyst can be defined as a substance which accelerates the
rate of a chemical reaction without itself undergoing any
chemical change. There is no doubt that the bases used in this
study strictly comply with that definition from an operational
point of view, independent of whether they are used in
stoichiometric or substoichiometric amounts. From a mechanistic
point of view, however, the situation is more complex, as shown
by the experiment in which 10 mol % of catenane 3 was used. In
this case, catenane 3 is not a catalyst in a strict sense, because it
does not turn over. It rather behaves as the initiator of the
secondary pathway proceeding via ternary adduct B, which is
a chain reaction. Admittedly, catenane 3 is a very peculiar
initiator, as it is recovered unchanged when the reaction has
come to an end.
[9] Identical results were observed when the concentration of both
reactants was raised to 10 mm (see Figure S14).
[10] Proton exchange between 3 and 3·H+ is slow on the H NMR
1
time scale.
[11] K. Takahashi, M. Takaki, R. Asami, Org. Magn. Reson. 1971, 3,
539 – 543.
[12] The chemical shifts of the K+ salt of a-methylbenzyl carbanion
cannot be directly compared with those of the reaction
intermediate for a number of reasons: 1) the structure of the
two carbanions is not the same, 2) the 1H NMR spectra were
Received: March 14, 2016
Published online: April 26, 2016
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