Hydrolysis of Aliphatic Bis-isonitriles in the Presence of a Polar Super Aryl-Extended Calix[4]pyrrole Container

Article abstract of DOI:10.1002/anie.202101499

We report binding studies of an octa-pyridinium super aryl-extended calix[4]pyrrole receptor with neutral difunctional aliphatic guests in water. The guests have terminal isonitrile and formamide groups, and the complexes display an inclusion binding geom

Full text of DOI:10.1002/anie.202101499

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How to cite: Angew. Chem. Int. Ed. 2021, 60, 10359–10365
International Edition: doi.org/10.1002/anie.202101499
German Edition: doi.org/10.1002/ange.202101499
Host-Guest Systems
Hydrolysis of Aliphatic Bis-isonitriles in the Presence of a Polar Super
Aryl-Extended Calix[4]pyrrole Container
+
+
Qingqing Sun , Luis Escobar , and Pablo Ballester*
th
Dedicated to Professor Placido Neri on the occasion of his 60 birthday
Abstract: We report binding studies of an octa-pyridinium
super aryl-extended calix[4]pyrrole receptor with neutral
difunctional aliphatic guests in water. The guests have terminal
isonitrile and formamide groups, and the complexes display an
inclusion binding geometry and 1:1 stoichiometry. Using
Generally, such mixtures arising from the reaction makes the
purification and isolation of the desired mono-reacted (non-
symmetric) product challenging and troublesome. The im-
provement of the selectivity in desymmetrization reactions
should increase their application in synthetic strategies.
Molecular containers featuring non-polar cavities have been
used as reaction flasks to address the mono-functionalization
1
H NMR titrations and ITC experiments, we characterized
the dissimilar thermodynamic and kinetic properties of the
complexes. The bis-isonitriles possess independent reacting
groups, however, in the presence of 1 equiv of the receptor the
hydrolysis reaction produces mixtures of non-statistical com-
position and a significant decrease in reaction rates. The
selectivity for the mono-formamide product is specially
enhanced in the case of the bis-isonitrile having a spacer with
five methylene groups. The analysis of the kinetic data suggests
that the observed modifications in reaction rates and selectivity
are related to the formation of highly stable inclusion
complexes in which the isonitrile is hidden from bulk water
molecules. The concentration of the reacting substrates in the
bulk solution is substantially reduced by binding to the
receptor. In turn, the hydrolysis rates of the isonitrile groups
for the bound substrates are slower than in the bulk solution.
The receptor acts as both a sequestering and supramolecular
protecting group.
[9]
problem. For example, Rebek and co-workers employed
a water-soluble octa-methyl tetra-benzimidazolone resorcin-
[4]arene cavitand for increasing the selectivity of: the
[13]
reduction of a,w-bis-azides to mono-amines, the hydrolysis
of a,w-bis-esters to mono-acids, in both acid and basic
[14]
[15]
media, and obtaining mono-epoxides from a,w-bis-enes.
In all cases, the product distributions were exceptional,
containing the mono-functionalized or mono-reacted com-
pound in significantly larger extents than the statistically
predicted upper limit (36.8%) assuming identical rate con-
[
14]
stants, k = k , for each site.
1
2
In these applications, the function of the molecular
container doubles as supramolecular water-solubilizing and
protecting group. The binding of the water-insoluble sym-
metric substrates to the cavitand produces soluble 1:1
inclusion complexes. The bound symmetric guests adopt
folded J-conformations, which interconvert rapidly on the
1
Introduction
H NMR chemical shift time scale, most likely, through a “yo-
[16,17]
yo” motion.
The J-shape of the bound guest provokes an
Molecular containers have been used to mediate and
catalyze chemical transformations, as well as to alter the
alternative exposure of only one of the two reactive ends to
the bulk solution. The exposed end reacts at the interface of
the inclusion complex and water. Subsequently, the equilib-
rium between the reacted and unreacted ends of the bound
guest is modified owing to their different hydrophobicities.
Typically, the unreacted site (being less polar) is prefer-
entially hidden from the water/cavitand interface, and its
further reaction is inhibited. The selectivity for the mono-
functionalization reaction, compared to that in the absence of
the container, is increased.
[1–12]
selectivity of reactions occurring in bulk solution.
In
solution the mono-functionalization of symmetric difunc-
tional compounds featuring independent reacting groups, i.e.,
the chemical modification of one group has little effect on the
reactivity of the other, yields statistical mixtures of products.
[
+]
[+]
[
*] Q. Sun, L. Escobar, P. Ballester
Institute of Chemical Research of Catalonia (ICIQ), The Barcelona
Institute of Science and Technology (BIST)
Av. Països Catalans, 16, 43007 Tarragona (Spain)
E-mail: pballester@iciq.es
[18,19]
[20]
[21]
The groups of Gibb,
Nitschke
and Dalcanale,
[22]
among others, have also reported beautiful examples of
molecular containers able to sequester reactive groups from
external reagents. Both polar and steric factors have strong
impacts on the transition stateꢀs energy of reactive groups
sequestered in molecular containers.
We reported the synthesis and binding properties of
[
+]
[+]
Q. Sun, L. Escobar
Universitat Rovira i Virgili, Departament de Química Analítica
i Química Orgµnica
c/Marcel·lí Domingo, 1, 43007 Tarragona (Spain)
[23,24]
P. Ballester
[
25,26]
water-soluble aryl-extended (AE-C[4]P)
and super aryl-
Catalan Institution for Research and Advanced Studies (ICREA)
Passeig Lluís Companys, 23, 08010 Barcelona (Spain)
[27]
extended calix[4]pyrrole (SAE-C[4]P) receptors containing
polar aromatic cavities. We demonstrated that in aqueous
solution an AE-C[4]P binds formamides with high affinity,
+
[
] 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:
https://doi.org/10.1002/anie.202101499.
4
À1
K > 10 M . There is selectivity for the cis-isomer of primary
a
[25]
and secondary formamides, despite the energetic prefer-
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[
28]
ence for a trans-conformation when free in solution. Water-
isonitriles 2a–e in the absence and in the presence of receptor
1 (1 equiv). The results showed that the presence of 1 induces
yield enhancements for the mono-formamides (non-symmet-
ric) 3a–e with respect to the statistical mixture of products
obtained in the absence of the receptor. The largest yield
enhancement was obtained for the mono-formamide 3b. The
modifications in the composition of the reaction mixture and
the observed diminution in reaction rates are related to the
formation of stable inclusion complexes of the reacting
substrates (2 and 3) with receptor 1.
soluble SAE-C[4]Ps were also effective in the binding of polar
neutral substrates such as pyridyl N-oxides, K > 10 M .
The cone conformation of AE-C[4]Ps and SAE-C[4]Ps, i.e.,
(Figure 1a and Figure 3), creates sizeable polar aromatic
cavities. In water, their inclusion complexes are stabilized not
only by the hydrophobic effect and CH-p, NH-p and p-p
but also by the establishment of four con-
vergent hydrogen bonds between the pyrrole NHs of the
calix[4]pyrrole unit of the receptor and the oxygen atom of
5
À1 [27]
a
1
[29]
interactions
[30]
the bound guest.
Results and Discussion
The interaction of SAE-C[4]P 1 with bis-isonitrile 2b and
mono- and bis-formamides, 3b and 4b, in D O solution was
2
1
1
followed using H NMR spectroscopy (see SI). The H NMR
spectrum of a millimolar D O solution of free 1 shows broad
2
proton signals due to aggregation or intermediate dynamics
between conformational changes (cone and alternate). The
addition of 1 equiv of the mono-formamide 3b provoked the
sharpening of the signals of receptor 1. In addition, the five
methylene units of 3b appeared upfield shifted, locating them
within the four aromatic walls of SAE-C[4]P 1. The addition
of more than 1 equiv of 3b produced a separate set of signals
corresponding to the protons of the free guest (Figure 2c).
These results indicated the formation of a 1:1 inclusion
complex, 3bꢀ1, for which we can estimate a stability constant
4
À1
value (K ) larger than 10 M , with a binding process
a
1
displaying slow exchange dynamics on the H NMR chemical
shift time scale. The five methylene signals of bound 3b
showed quite different upfield shifts (Dd < 0), which reflect
the dissimilar anisotropic shielding provided by the four walls
of 1 along its aromatic cavity. In contrast to the observations
Figure 1. a) Chemical structure of SAE-C[4]P 1; b) Stepwise reaction
scheme of the acid-catalyzed hydrolysis of bis-isonitrile 2 to give mono-
formamide 3 and bis-formamide 4. c) Line-drawing structure of 4-
phenylpyridine N-oxide 5 used as competitive binding guest.
[31]
In bulk solution, the acid-catalyzed hydrolysis of long-
chain aliphatic a,w-bis-isonitriles provides the mono-hydro-
lyzed formamide-isonitrile as a statistical mixture with the
unreacted starting material and the doubly-hydrolyzed com-
pound (Figure 1b). Formamide and isonitrile (isocyanide)
functional groups display orthogonal reactivity. Isonitriles
[32]
participate in multi-component reactions,
and are easily
attached to biomolecules, making long-chain aliphatic a,w-
formamide-isonitriles valuable intermediates in organic and
bio-organic synthesis. The efficient binding of primary
formamides exhibited by water-soluble calix[4]pyrrole recep-
tors and their supramolecular sequestering and protecting
abilities suggested an improved selectivity in the hydrolysis
reaction of symmetric aliphatic a,w-bis-isonitriles; we report
on these developments here.
1
Figure 2. Selected region of the H NMR spectra (500 MHz with cryop-
robe, D O, 313 K) registered for the titration of SAE-C[4]P 1 with bis-
isonitrile 2b: a) 0.5 and b) 1 equiv added. Panels c) and d) display the
identical region of the H NMR spectra (298 K) of mixtures containing
with 2 equiv of mono-formamide 3b and bis-formamide 4b, respec-
2
Initially, we examined the binding of SAE-C[4]P 1 in
water to a series of difunctional aliphatic guests: bis-isonitriles
1
1
2, mono-formamides 3 and bis-formamides 4 (Figure 1b). We
tively. Primed numbers correspond to the proton signals of bound
investigated the acid-catalyzed hydrolysis of a series of bis-
species: 2b (in red), 3b (in blue) and 4b (in orange).
1
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[
9]
5
made in inclusion complexes of resorcin[4]arene cavitands,
specially the one alpha to the isonitrile end (H ), although
being less deep in the cavity of 1, experienced more intense
shielding (Dd = À2.42 ppm). These larger CIS derive from the
placement of the methylene groups in the upper non-polar
aromatic cavity of 1. In this location, they are exposed to the
strong shielding effect exerted by the four terminal phenyl
substituents of the receptor.
the magnitudes of the upfield shifts are not directly related to
the various depth of the guestꢀs alkyl chain included in the
SAE-C[4]P 1. For example, the formyl proton of bound 3b
appeared at d = 4.39 ppm (Dd = À3.60 ppm) (see SI, Fig-
ure S59).
We observed analogous complexation-induced shifts (CIS,
Dd) in the binding of the cis-isomers of phenyl and alkyl
formamides with a water-soluble AE-C[4]P. This places the
We did not observe additional signals that could be
assigned to the hydrogen atoms of the “reverse” binding
geometry of the 3bꢀ1 complex (Figure 3c). Remarkably, the
chemical exchange between free and bound 3b was fast on the
EXSY time scale (tmix = 0.3 s). The observed chemical ex-
change cross-peaks were used for unequivocal assignment of
the proton signals of bound 3b. The exclusive observation of
i + 2 NOE peaks between the methylene proton signals of
bound 3b supports the extended conformation of its alkyl
chain.
[25]
cis-formamide group of 3b in the closed and polar aromatic
[33]
cavity of calix[4]pyrrole 1. In turn, this arrangement fixes
the geometry of the 3bꢀ1 complex by placing the isonitrile
end of 3b close to the open rim of the receptor (Figure 3b).
The two methylene groups alpha (H ) and beta (H ) with
respect to the formamide end of 3b are significantly less
shielded (Dd = À0.99 and À0.62 ppm, respectively). This is
due to their location in the cavity region of 1 surrounded by
the alkynyl linkers, which impart a reduced magnetic shield-
ing. In striking contrast, the remaining three methylene units,
1
2
The binding of the symmetric bis-formamide 4b with the
SAE-C[4]P 1 produced identical results (see Figure 2d and SI
for details). That is, a 1:1 inclusion complex of 4b with K >
a
4
À1
1
0 M , and its slow bound/free exchange dynamics on the
1
H NMR chemical shift time scale. Fast exchange with the
free counterpart on the EXSY time scale was detected, but
not tumbling of the bound guest on the same time scale. We
observed five separate signals for the methylene protons of
bound 4b. The lack of symmetry and the magnitude of the
upfield shifts experienced by the methylene signals in the
4
bꢀ1 complex indicated that a cis-formamide end is bound by
the calix[4]pyrrole unit of 1 while the other formamide end, in
cis (15%) and trans (85%) conformation, occupies the upper
non-polar aromatic cavity. We performed the assessment of
the binding constant values for the 3bꢀ1 and 4bꢀ1 com-
plexes using ITC experiments (Table 1).
Table 1: Binding constant values (K ) determined using ITC experiments
a
for the 1:1 complexes of receptor 1 with guests 2b–4b in water at 313 K
and their corresponding free energies (DG). Error values in K are
a
reported as standard deviations and propagated to DG. The heat
capacities (DC ) were calculated using the DH values of ITC experiments
p
performed at 298 and 313 K.
5
À1
À1
À1 À1
Guest
K (”10 M
)
DG (kcalmol
)
DC (calmol
K
)
a
p
2
3
4
b
b
b
1.3Æ0.1
6.9Æ0.9
9.2Æ0.1
À7.3Æ0.1
À8.3Æ0.1
À8.5Æ0.1
À240
À193
À233
[
[
a]
a]
[
a] The reported K values are apparent (Kapp) because only the cis-isomer
a
of the guests binds the receptor. K and K have similar magnitudes
a
app
when the percentage of the cis-isomer in solution is significant, as is the
case here. See ref. [25] for a more detailed analysis of the ratio between
these constant values.
[
36,37]
Figure 3. Gas-phase energy-minimized structures at the BP86
-
[
38]
A bound symmetric difunctional guest, having five
methylene groups and experiencing fast tumbling on the
Def2SVP-D3 level of theory of simplified 1:1 inclusion complexes:
a) 2bꢀ1; b) 3bꢀ1; c) “reverse” binding geometry for 3bꢀ1 and
d) 3cꢀ1. The complexation-induced shifts (CIS, Dd) experienced by all
the non-polar proton signals of the bound guests, 2b and 3b, and the
1
H NMR chemical shift time scale inside the cavity of 1,
should lead to the observation of only three signals. At 313 K,
1
dynamics of their in/out chemical exchange process on the H NMR
1
we observed only three upfield shifted signals in the H NMR
spectrum of mixtures of the symmetric bis-isonitrile 2b (0.5-
chemical shift time scale are indicated. Receptor 1 is shown in line-
stick representation with non-polar hydrogen atoms omitted for clarity.
Bound guests are depicted as CPK models. The water-solubilizing
groups at the upper and lower rims of 1 are pruned to methyl groups.
See Figure 1 for the line-drawing structures of the compounds.
1
equiv) with 1 (Figure 2a,b). In this case, however, the
binding process displayed fast exchange dynamics on the
chemical shift time scale. This latter characteristic serves to
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explain the symmetric pattern of the proton signals of bound
b without the need to invoke fast tumbling of the bound
(1 mM) of 2b and 1 in 0.5 mL of D O (final pD ꢁ 3). We
2
2
monitored the progress of the reaction at 313 K using
1
guest. The addition of more than 1 equiv of 2b did not induce
further changes in the proton signals of 1 (Figure S45). This
observation allows us to estimate that the binding constant
H NMR spectroscopy (see SI, Figure S129). The distribution
of the species as a function of time was determined using the
integral values of the guestsꢀ methylene proton signals in the
4
À1
[40]
value of the 2bꢀ1 complex is also larger than 10 M . The
CIS of the methylene protons of bound 2b were calculated by
extrapolating the fit of its chemical shift changes experienced
in the titration of 1 using a theoretical 1:1 binding model
corresponding inclusion complexes. Alternatively, we add-
ed 1.2 equiv of 4-phenylpyridine N-oxide 5 (Figure 1c) to the
reaction mixture at different time intervals (Figure S132). N-
[27]
oxide 5 is a competitive guest that displaces the reacting
species bound in the cavity of 1 to the bulk solution. Next, we
used the integral values of the proton signals of the displaced
guests to determine their concentrations. The two method-
ologies produced similar results.
(
Figure S46). The calculated values represent average chem-
ical shifts of the two separate signals expected for both alpha-
and beta-methylene protons in a 2bꢀ1 complex experiencing
slow dynamics on the chemical shift time scale for its binding
and tumbling processes (see CIS for 2bꢀ1 in Figure 3a). The
calculated average CIS values for the two separate alpha- and
beta-methylene proton signals observed for 3bꢀ1 or the
symmetric bis-formamide 4b in the 4bꢀ1 complex are in line
with those of the bis-isonitrile 2b in the 2bꢀ1 complex. This
result suggests that 2b also adopts an extended conformation
when included in the cavity of 1. In this conformation, one of
the two isonitrile groups of 2b is more accessible to water
molecules in the interface between the open end of the SAE-
C[4]P 1 and the bulk solution. ITC experiments provided
The formation of the mono-formamide 3b was evident
from the loss of symmetry of its inclusion complex. Please
note that we assigned a preferred binding geometry for the
3bꢀ1 complex fixing the formamide group in the calix-
[4]pyrrole unit and having an extended conformation for the
alkyl spacer (vide supra). After ca. 2 h, the composition of the
reaction mixture contained the mono-formamide 3b in an
amount close to 80% (Figure 4a). This result suggests that the
remaining isonitrile group in the 3bꢀ1 complex is less
accessible to bulk water. It also represents a significant
improvement of the theoretical 36.8% predicted by Rebek
and co-workers in the mono-functionalization of symmetrical
difunctional substrates having independent reacting
a more accurate value for K (2bꢀ1) (Table 1). We calculated
a
large and negative heat capacity values (DC ) for all binding
p
processes. This result indicates that the formation of the
[14]
complexes, 2b-4bꢀ1, is mainly driven by the hydrophobic
groups.
The isolation of the mono-formamide 3b was
[
34,35]
effect.
possible by extracting it from the neutralized aqueous
solution using ethyl acetate (Figure S139).
Based on the above, we hypothesized that in the 2bꢀ1
complex, the rate of the hydrolysis reaction producing the
mono-formamide 3b should be different from that in the bulk
solution.
[14]
In analogy to the Rebekꢀs report,
we fit the exper-
imental concentration data vs. time to a theoretical kinetic
model of two consecutive first-order irreversible reaction
Assuming that the reaction occurs preferentially at the
water/SAE-C[4]P interface (isonitrile end located at the open
cavity of the container), the resulting mono-formamide 3b
will locate the non-reacted isonitrile end buried in the polar
cavity of 1 protected from bulk water. This would result in the
“
reverse” binding geometry of the 3bꢀ1 complex (Figure 3c).
1
However, as mentioned above, the H NMR spectrum of the
3
bꢀ1 complex (Figure 2c) did not show additional proton
signals hinting to the presence of this isomer in solution.
Nevertheless, we cannot rule out its existence to a reduced
extent (< 10 M). Our expectations were that the inclusion of
À4
the bis-isonitrile 2b and the mono-formamide 3b in the cavity
of 1 might produce a reduction in the hydrolysis reaction rates
of their isonitrile ends exposed at the water/container inter-
face in comparison to the bulk solution. Possible reasons of
this putative effect include: a limited exposure to bulk water
molecules and a reduced solvation of the transition state. It is
worth mentioning that the superior binding properties of
SAE-C[4]P 1 for the mono-formamide 3b will reduce its
[39]
concentration in solution to a large extent.
In order to test our hypotheses, we studied the hydrolysis
reaction of bis-isonitrile 2b chaperoned by the synthetic
container 1 in water. In doing so, we also wanted to evaluate
the potential application of 1 in addressing the mono-
functionalization problem of 2b. We performed the hydrolysis
reaction by adding 5 equiv of citric acid as a solution (0.5 M in
Figure 4. Plots of the concentration of the species vs. time for the
acid-catalyzed hydrolysis of bis-isonitrile 2b: a) with 1 equiv of 1;
b) without container; c) with 1 equiv of 1 and d) with 1.5 equiv of 1.
Dashed lines represent fit/simulation of the kinetic data to model 1 in
a) and d). Solid lines represent fit/simulation of the kinetic data to
model 2 in b) and model 3 in c) and d). Error bars are standard
deviations.
D O) to a NMR tube containing an equimolar mixture
2
1
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steps, Equations (1) and (2) (model 1), using COPASI kinetic
modeling software.
Fixing k and k to the values determined in the absence of
3
4
1
, and K (2bꢀ1), K (3bꢀ1) and K (4bꢀ1) to the measured
a
a
a
From the fit of the data, we obtained the rate constant
magnitudes (Table 1), within experimental error, also pro-
duced a reasonable fit to the experimental distribution of the
species for the time course of the hydrolysis reaction of 2b
chaperoned by 1 (Figure 4c, solid lines).
À2
À1
À3
À1
values k = 1.7 ” 10 min and k = 2.3 ” 10 min (Fig-
1
2
ure 4a, dashed lines). Based on this model, the determined
rate constant values for the hydrolysis reactions in the water/
container interface show that the first step [Eq. (1)] is seven-
fold faster than the second one [Eq. (2)]. This result is difficult
to reconcile with the experimental observation made for the
Remarkably, the theoretical kinetic models 1 and 3
produced quite different results in the simulations of the
time course for the hydrolysis reaction of 2b chaperoned by
1.5 equiv of 1. Model 1 considers that the hydrolysis reactions
take place exclusively in the bound substrates and forecasts
no changes in reaction rates. Conversely, model 3 assuming
that only the free species are hydrolyzed in the bulk aqueous
solution projects a significant reduction in reaction rates
owing to the increased sequestering effect of the free reacting
species by complexation with the additionally added contain-
er.
3
bꢀ1 complex, which preferentially locates the reactive
isonitrile end at the open cavity of the container not providing
an increased protection for its hydrolysis.
[41]
Moreover, model 1 disregards that the reactions can also
take place in the bulk solution by assuming that the rates are
very slow and the concentration of the free substrates
negligible. However, the bis-isonitrile 2b and the mono-
formamide 3b are perfectly soluble in water at millimolar
concentrations.
In order to evaluate which of the two models was most
reliable, we experimentally undertook the hydrolysis of 2b in
the presence of 1.5 equiv of 1. Figure 4d displays the
experimental time course of the reaction (points). The dashed
and solid lines represent the simulated kinetic profiles using
models 1 and 3, respectively. The simulation of the exper-
imental data to model 3 is good, suggesting that it better
explains the observed selectivity enhancement in the acid-
catalyzed hydrolysis of 2b. In short, container 1 sequesters 2b
and 3b offering protection to their isonitrile end groups
towards the hydrolysis reaction. The hydrolysis of the
substrates occurs mainly as the free species present in the
bulk solution. Because the concentrations of the free reac-
tants are very low, their hydrolysis reaction rates are reduced.
This is specially the case for the mono-formamide 3b, whose
concentration free in solution becomes relevant when close to
80% of 2b has reacted.
To evaluate the scope and generality of the sequestering
and protection effect delivered by the synthetic chaperone
1 in improving the selectivity for the acid-catalyzed hydrolysis
of symmetric aliphatic a,w-bis-isonitriles, we used a series of
shorter and longer homologues of 2b (Figure 1b). In the case
of the bis-isonitrile 2a, having a spacer with three methylene
groups, the reaction selectivity for the mono-formamide 3a
was reduced to 70% and the reaction rate was just slightly
diminished compared to that in the absence of 1. The
maximum percentage of 3a was obtained after 40 min of
reaction instead of ca. 2 h required for 3b. Taking into
account the smaller binding affinities of the shorter substrates
2a and 3a for 1 (see SI), compared to the longer counterparts
2b and 3b, the obtained results can be simply explained by
invoking an attenuation in the sequestering effect of the
container. Also in this case, model 3 provides a good fit to the
obtained hydrolysis kinetic data (see SI, Figure S128).
Using identical conditions, we performed the hydrolysis
experiment of the bis-isonitrile 2b in the absence of container
1. The reaction profile showed also a good fit to two
consecutive first-order irreversible reactions, Equations (3)
À2
À1
and (4) (model 2), with k = 7.0 ” 10 min and k = 3.5 ”
3
4
À2
À1
1
0
min (Figure 4b, solid lines).
The selectivity of the reaction for the mono-formamide 3b
reached a maximum of 50%, in agreement with the theoret-
ical statistical distribution for identical microscopic reaction
rate constants. As could be expected from a protective/
sequestering effect of the container, the calculated rate
constant values in the absence of 1 increased more than
four-fold with respect to those determined above. For this
reason, the 50% maximum concentration of 3b was obtained
after 20 min of reaction compared to ca. 2 h needed to
produce 3b in an extent of 80% in the presence of 1.
Having determined the rate constants for the hydrolysis
reaction of 2b in the bulk solution and the binding constants
of the inclusion complexes of 1 with all the species at 313 K,
we decided to mathematically analyze the hydrolysis data in
the presence of 1 using a more elaborate kinetic model. This
model includes two consecutive irreversible reactions occur-
ring in the bulk solution, Eqs. 3 and 4, and the reversible
formation of three complexes: 2bꢀ1, 3bꢀ1 and 4bꢀ1,
Equations (5)–(7) (model 3). It also assumes that the rates
of the hydrolysis reaction of the bound substrates are
negligible.
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Longer bis-isonitriles 2c–e, having seven to nine methyl-
ene groups as spacers, and their corresponding mono-
formamides 3c–e (Figure 1b) display higher affinity for
receptor 1 (Tables S12 and S13). As mentioned above, the
hydrophobic effect is an important component in the binding
cavity (1), on the chemical selectivity of a desymmetrization
reaction in water solution and its proposed function mecha-
[44]
nism are unprecedented.
of the homologous series of difunctional aliphatic guests by 1. Acknowledgements
The selectivity of the mono-formamides 3c–e in the hydrol-
[
42]
ysis reactions of 2c–e (1% DMSO/D O) reaches values of
5
We thank Gobierno de EspaÇa MICIN/AEI/FEDER, UE
(projects CTQ2017-84319-P and CEX2019-000925-S), the
CERCA Programme/Generalitat de Catalunya, and
AGAUR (2017 SGR 1123) for financial support. Q. S. thanks
the Chinese Research Council for a predoctoral fellowship
(2017–06870013). L. E. thanks MECD for a predoctoral
fellowship (FPU14/01016).
2
5–65%. The achievement of these selectivities require
extensive reaction times (3–8 h). On the other hand, the
hydrolysis reactions of 2c–e in the absence of 1 (see SI)
produced similar results to those discussed above for 2b.
Taking together, these results suggest that the longer sym-
metric difunctional substrates being more hydrophobic are
present in reduced concentrations in the bulk solution. On the
other hand, the formed inclusion complexes with 1 might
[43]
provide a decrease in the hydrolysis rate of the bound Conflict of interest
isonitrile end group that is located close to the open cavity of
the container but not inhibition (total protection). This is due
to the increased protrusion of the isonitrile end groups of
these complexes into the water/container interface (see
Figure 3d for the energy-minimized structure of the 3cꢀ1
complex).
The authors declare no conflict of interest.
Keywords: amides · host-guest systems · isonitriles ·
molecular containers · mono-functionalization
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2
[
In summary, we demonstrated that, in water solution, the
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Manuscript received: January 31, 2021
Accepted manuscript online: February 17, 2021
Version of record online: March 22, 2021
Angew. Chem. Int. Ed. 2021, 60, 10359 – 10365
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