Kinetic and thermodynamic modulation of dynamic imine libraries driven by the hexameric resorcinarene capsule

Article abstract of DOI:10.1021/jacs.0c04705

The composition of dynamic covalent imine libraries (DCL) adapts to the presence of the hexameric resorcinarene capsule. In the presence of the self-assembled capsule, a kinetic and thermodynamic modulation of the imine constituents of the DCLs was observed, which was induced by an unusual predatory action of the capsule on specific imine constituents. More complex 2 × 2 DCLs also adapt to the presence of the hexameric capsule, showing a thermodynamic and kinetic modulation of the constituents induced by the predatory action of the capsule. By cross-referencing experimental data, a good selectivity (up to 66%) for one constituent can be induced in a 2 × 2 DCL.

Full text of DOI:10.1021/jacs.0c04705

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Article
Kinetic and Thermodynamic Modulation of Dynamic Imine
Libraries Driven by the Hexameric Resorcinarene Capsule
Stefania Gambaro, Carmen Talotta, PAOLO DELLA SALA, Annunziata
Soriente, Margherita De Rosa, Carmine Gaeta, and Placido NERI
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c04705 • Publication Date (Web): 07 Aug 2020
Downloaded from pubs.acs.org on August 8, 2020
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Journal of the American Chemical Society
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Kinetic and Thermodynamic Modulation of Dynamic Imine Libraries
Driven by the Hexameric Resorcinarene Capsule
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Stefania Gambaro, Carmen Talotta, Paolo Della Sala, Annunziata Soriente, Margherita De Rosa,*
*
Carmine Gaeta, and Placido Neri
Laboratory of Supramolecular Chemistry, Dipartimento di Chimica e Biologia “A. Zambelli”, Università di Salerno,
Via Giovanni Paolo II, I-84084, Fisciano (SALERNO), Italy.
ABSTRACT: The composition of dynamic covalent imine libraries adapts to the presence of the hexameric resorcinarene
capsule. In the presence of the self-assembled capsule a kinetic and thermodynamic modulation of the imine constituents
of the DCLs was observed, which was induced by an unusual predatory action of the capsule on specific imine
constituents. More complex 2x2 DCLs also adapt to the presence of the hexameric capsule showing a thermodynamic and
kinetic modulation of the constituents induced by the predatory action of the capsule. By cross-referencing experimental
data, a good selectivity (up to 66 %) for one constituent can be induced in a 2x2 DCL.
supramolecular modulation of a DCL was reported by
Sanders and coworkers in which a dynamic library of
Introduction
hydrazone-based pseudopeptides changed in the product
9c
distribution after addition of acetylcholine. In the
presence of the ammonium guest the equilibrium shifted
toward the cyclic trimer which was able to bind
Nature is a continual source of inspiration for those
scientists interested in mimicking the strict level of
selectivity and efficiency that are the basis of living
9c
selectively acetylcholine. Analogously, a dynamic library
1
2,3
systems. Biomimicry starts from the inspiration by
natural processes which include the modus operandi of
the natural enzymes, one of the most amazing
of cyclic pseudopeptide receptors changed its equilibrium
+
distribution in the presence of Li guest, which was able
to convert a complex mixture of about 10 macrocycles
3
phenomena in biological chemistry. Enzymes are able to
+
10
into one that contains 98% of the Li receptor.
work selectively in the presence of complex mixture of
substrates leading to the selective formation of specific
products at once. On these bases, one of the aims of
enzyme-mimicry is the synthesis of artificial systems able
to work selectively in the presence of a complex mixture
of reagents.
Among the major subjects explored in DCC, surely the
1
1
imines attracted a particular attention. Formation of an
imine bond is a dynamic process where a carbonyl
compound reacts in a reversible manner with an amino
group with the loss of water (Figure 1). Usually, upon
response to an external stimulus an imine-based dynamic
library reorganizes the composition of its constituents
and drives it toward the preferential formation of only
selected members (Figure 1).
3
In the past decades, the dynamic covalent chemistry
4
‒6
(DCC) has aroused a particular interest. In DCC, simple
building blocks are held together by reversible covalent
bonds, to form a library of products that under
thermodynamic equilibrium conditions are continuously
Constituents
NH2
NH2
N
N
6
interconverting. Under these conditions, the library is
O
O
usually able to respond to an external stimulus (Figure 1)
by changing its equilibrium composition according to Le
Châtelier principle. Examples were reported in the
literature in which dynamic covalent libraries (DCL)
undergo to reorganization as a response to a physical
N
N
H
H
Components
Adaptation
driven by
Dynamic Covalent Library
6
a
6b,c
stimulus such as temperature,
crystallization,
external stimulus
7
8
distillation, or phase separation. Interesting examples of
supramolecular modulation of DCLs have been also
N
9a
reported in the literature. Sanders and Pantǫȿ pointed
out that a dynamic library of naphthalenediimide-based
macrocycles responded to the presence of different
Figure 1. Adaptation of a dynamic covalent library of imines
to an external stimulus.
9
b
complementary naphthalene guests. Another example of
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7a
CR . As stated by J. M. Lehn “changes in expression of the
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different constituents as a factor of external parameters
represent an adaptation of the system to environmental
conditions”. On these bases, we wonder if the
composition of dynamic imine libraries adapts to the
presence of CR , which, in addition to catalytic abilities,
6
usually also shows a substrate and product selectivity.
In particular, the reversible formation of imine bonds
is affected by external factors such as temperature, pH,
and concentration, but also by internal factors such as
steric and electronic features of the substrates. Dynamic
imines have been used in different applications, including
synthesis of complex molecular architectures, such as
12
13
cages, and in self-sorting systems.
Recently, in biomimicry much attention has been
devoted to catalytic processes in a nanoconfined space
Results and Discussion
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using self-assembled capsules. The confined space inside
Adaptation of the DCL of imines A2a and A2b to the
presence of the hexameric capsule
the self-assembled containers looks like to an enzyme
pocket and provides interesting catalytic features. Among
the self-assembled architectures, the hexameric
We start this study by investigating the formation of
imines A2a and A2b in single experiments (Scheme 1) in
the presence or in the absence of the hexameric capsule
resorcinarene capsule CR
increasingly important in catalysis. The formation of an
hexameric resorcin[4]arene capsule CR (Figure 2) in the
6
(Figure 2) has became
15
6
CR .
6
16
solid state was originally reported by Atwood, while
evidences for its formation in water-saturated chloroform
Cl
1
7
or wet benzene solution were provided by Cohen and
coworkers by diffusion NMR experiments. The capsule is
obtained by self-assembly of six resorcinarene 1 and eight
water molecules, sealed by 60 H-bonding interactions.
NH2
CHO
N
+
R
Cl
R
CR6, wet CDCl3
2a) R = H
A
A2a) R = H
The container CR
useful tool in biomimetic catalysis: a) the internal
π···electron rich cavity of 1375 Å is able to recognize
6
shows some features that make it an
2b) R= CF3
A2b) R = CF3
3
3
Scheme 1. Synthesis of imines A2a and A2b in the
presence of capsule CR
neutral and cationic species and to stabilize transition
states, thanks to secondary interactions; b) the capsule
6
.
6
CR behaves as a mild Brønsted acid with a pKa value of
1
8a
about 5.5-6.0; c) four bridging water molecules show an
H-bond donating free valence, which are catalytically
When benzaldehyde 2a and p-chloroaniline A were
mixed in equimolar ratio (42.3 mM), in water saturated
CDCl at 30 °C in the presence of capsule CR (1 equiv),
3 6
then the formation of imine A2a was detected in the
reaction mixture already after 30 min (Figure 3). The
equilibrium was reached after 2 h leading to 34% of A2a
1
8b,19
20
relevant.
that CR
In addition, previously reported data show
capsule is able to exert a substrate selectivity,
6
while a stereo- and regioselectivity toward the products is
also generally observed.
(
Figure 3).
HO
R
OH
R
HO
OH
OH
H2O-saturated
CDCl3
HO R
HO
R
OH
1
; R = n-C H
11 23
CR : 1 (H O)
8
6
6
2
Figure 2. Self-assembly of resorcinarene 1 in water-saturated
CDCl forming the hexameric resorcinarene capsule CR
3
6
.
Tiefenbacher and coworkers reported the first
example of catalysis of formation of iminium group inside
21
6
CR , exploiting its mild acidity and its ability to stabilize
cationic intermediates and transition states. Successively,
our group reported experimental and computational
evidences of the formation of an iminium specie inside
Figure 3. Formation of imines A2a (top) and A2b
bottom) during the single experiments in the presence or
in the absence of capsule CR (Scheme 1).
(
22
6
6
CR .
These considerations prompted us to investigate the
behavior of dynamic imine libraries in the presence of
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When the reaction in Scheme 1 was performed under
the same conditions but in the absence of capsule CR
then the formation of A2a was slowed and only 12 % of it
Figure 4. Distribution of imine constituents A2a and A2b in
the DCL in Scheme 2, without (a) and with (b) capsule CR
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.
6
The imine A2a, obtained by benzaldehyde 2a and p-
chloroaniline A, was formed faster than A2b, but after 1 h
A2a started to decrease while A2b increased. This trend
continued up to 24 h, when the A2a/A2b ratio reached
the 15/60 value and remained constant (48 h). The results
in Figure 4 showed that A2a was kinetically favored, while
A2b was the thermodynamic product under these
conditions.
was detected in the reaction mixture after 24 h.
When p-trifluoromethylbenzaldehyde 2b was used
with p-chloroaniline A in the presence of capsule CR6,
then imine A2b reached the equilibrium value of 60 %
after 24 h (Figure 3). Also in this case the formation of
6
A2b was slowed in the absence of CR (Figure 3).
With these results in hand, we then investigated an
imine-based DCL of two imine constituents A2a and A2b
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As it is known, in an imine-based DCL, the imines
constituents exchange their components between them,
by reversible formation of chemical bonds. Usually, these
processes are under thermodynamic control and in this
way the most stable constituent prevails. Thus, we have
envisioned a new experiment, reported in Scheme 3, in
which benzaldehyde 2a and p-chloroaniline A were
(
Scheme 2) formed by the three components
benzaldehyde 2a, p-trifluoromethylbenzaldehyde 2b, and
p-chloroaniline (in equimolar ratio, Scheme 2).
Experiments were performed either in the presence or in
A
the absence of capsule CR
using a concentration of 42.3 mM each of 2a/2b/A/CR
6
, in water saturated CDCl
3
,
.
6
The reactions were conducted at 30 °C. The formation of
imine products was monitored as a function of time, by
6
reacted in the presence of CR in order to form only imine
A2a. After 24 h, A2a was formed in 34 % yield (Scheme 3).
At this point, the mixture was added of 1 equiv of
aldehyde 2b and already 1 h later A2b started to increase
as A2a to decrease (Scheme 3 and Figure 5). The
equilibrium was reached 24 h later (Figure 5), showing a
distribution pattern close to that obtained in the
experiment in Figure 4b.
1
quantitative H NMR (qNMR) spectroscopy using 1,1,2,2-
tetracloroethane (TCE) as internal standard. Aliquots of
the reaction mixtures were added of DMSO (SI), in order
to disaggregate CR
integrated with respect to the signal of TCE. In the
absence of CR capsule, the two imine constituents A2a
and A2b were formed in equal quantities up to 48 h
Figure 4a), when the conversion was about 20 % of each
one.
6
, and the imine-signals were
6
Cl
Cl
Cl
(
2b
NH2
CHO
CR6
N
N
N
Cl
Cl
+
CHO
CHO
NH2
CR6
wet CDCl3
+
+
Cl
A
N
+
N
24h
F3C
F3C
Cl
wet CDCl3
2a
A2a
A2a
A2b
2a
2b
A
30 °C
F3C
A2a
A2b
Scheme 2. Dynamic library formed by the three
components 2a, 2b, A and by the two constituents A2a,
A2b, in the presence of CR .
6
Scheme 3.
The evolution of the imine composition in Figure 4
clearly indicates that the capsule CR shows two effects:
6
Interestingly, the DCL in Scheme 2 adapts to the
presence of the capsule CR (Figure 4b). In fact, the
a) CR acts as catalyst by accelerating the
6
a
6
formation of imine constituents A2a and A2b,
thanks to its mild acidity and capability to
stabilize cationic intermediates;
imines A2a and A2b were formed immediately after
mixing with a conversion of 30 % and 10 %, respectively.
6
b) CR acts as an external stimulus because the DCL
composition of A2a and A2b adapts to its
presence. The formation of imine A2a is initially
favored, while A2b prevails in the long time. Thus,
under these conditions A2a and A2b represent the
kinetic and the thermodynamic adducts,
respectively.
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Figure 5. Imine constituents distributions in DCL in
Scheme 3.
into 2a and A was observed. Differently the hydrolysis of
A2b to 2b and A in the presence of CR was slower (Figure
6), in fact the equilibrium was reached after 72 h with a
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In order to get more insights on the mechanism of this
kinetic and thermodynamic modulation of the DCL in
40 % of conversion of A2b to 2b and A.
23
Scheme 2, we performed uptake experiments. In details,
a competition experiment was carried out in which
benzaldehyde 2a and p-trifluoromethylbenzaldehyde 2b
were in competition to occupy the inner cavity of CR
6
.
The uptakes of 2a/2b inside CR , were measured by
6
1
quantitative H NMR experiments, in which the aldehydes
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0
2a and 2b (42.3 mM each one) were mixed in the presence
of 1 equiv of CR in water-saturated CDCl3. The quantity of
6
encapsulated aldehyde was obtained by difference
between its initial concentration and the concentration of
1
the free aldehyde in solution. The H NMR signal of the
free aldehyde was integrated with respect to the signal of
the internal standard (TCE). After equilibration, a 52 %
Figure 6. Hydrolysis of imines A2a and A2b in the
presence of capsule CR .
6
uptake of benzaldehyde 2a inside CR
value significantly higher than that obtained for the
aldehyde 2b (5 %). Thus the hexameric capsule CR shows
6
was measured, a
6
On these bases we can explain the origin of the kinetic
and thermodynamic modulation of the DCL in Scheme 2
(Figure 4b). The imine A2a is accumulated preferentially
during the early stage of the reaction in Scheme 2 (Figures
7 and 8), thanks to the preferential encapsulation of 2a
a higher affinity for benzaldehyde 2a with respect to p-
CF3-benzaldehyde 2b. Clearly, this result is in accord with
the finding that A2a is preferentially formed in the early
stage of the reaction, where the capsule is filled to a
greater extent with benzaldehyde 2a.
inside the cavity of CR (Figures 5-8), which catalyzes the
6
formation of A2a. In the presence of a significant
quantity of A2a then its hydrolysis starts quickly inside
Proofs of the encapsulation of benzaldehyde 2a inside
CR were obtained by 1D and 2D NMR studies and in
6
particular by HSQC experiments (SI, Figures S48-S54). By
these studies emerges that the benzaldehyde is
6
CR capsule (Figure 8), catalyzed by the inherent
Brønsted acidity of the capsule and its ability to stabilize
24
cationic intermediates and transition states. Differently,
the hydrolysis of the imine A2b inside CR is less favored,
encapsulated inside CR
to the NMR time scale (600 MHz). Analogously, the
encapsulation of the aldehyde 2b inside CR was studied
6
with a slow kinetic with respect
6
probably because of the lower affinity of the capsule for
the imine A2b. In fact, qNMR experiments revealed a very
6
by 1D and 2D NMR experiments (SI, Figures S55-S59).
Analogous studies were reported in SI in order to show
the encapsulation of p-chloroaniline A inside CR (SI,
6
low-level of uptake of A2b inside CR
6
of 5 %, immediately
after mixing of A2b and CR , while the imine A2a is
6
encapsulated to a greater extent (45 %). In Silico
calculations were in accord with these results (Figure 7
and SI). Quantum-mechanical calculations (SI) indicate
an enthalpic stabilization of ‒22.14 kcal/mol and a Gibbs
Figures S60-S63).
It remains to understand the fate of the two imines
A2a and A2b. In detail, we wonder why A2b prevails in
the long time while A2a decreases with respect to its
initial percentage.
free energy stabilization of ‒8.08 kcal/mol for the
25
formation of the A2a  CR
6
complex. Differently, the
is unfavoured in
When A2a, was dissolved in water saturated CDCl
solution in the presence of CR (1 equiv) then after 30 min
3
formation of the complex A2b  CR
enthaplic as well as Gibbs free energy terms.
6
6
25
a 62 % of A2a was hydrolyzed to 2a and A (Figure 6).
After 4 h the hydrolysis of A2a was close to the
equilibrium (Figure 6) with a 65 % of conversion of A2a to
constituents 2a and A. Interestingly, with respect to the
total quantity of benzaldehyde 2a obtained by hydrolysis
26
Natural Bond Orbital (NBO) and Non-Covalent
27
Interaction (NCI) (see SI) analyses were performed on
complexes A2a  CR and A2b  CR to identify the
6
6
second order interactions between the capsule and the
imine. Second-order perturbation theory (SOPT) analysis
of the FOCK matrix in NBO basis clarified that the better
binding affinity of A2a is principally due to a strong
hydrogen bonding interaction (Figure 7e) between the
nitrogen atom of the imine moiety of A2a and a bridged
of A2a after 4 h, a 29 % uptake of 2a inside CR
measured. The uptake of 2a inside CR suggests that
probably, the benzaldehyde 2a behaves like a reversible
inhibitor for the capsule CR slowing down its catalytic
activity. Under the same conditions but in the absence of
CR , the imine A2a was stable over the time and no
6
was
6
6
28
water molecule of CR
interaction shows a N···OH
6
.
2
This strong
H-bonding
6
distance of 2.81 Å (Figure 7e)
hydrolysis products were detected (SI). These data
strongly indicate that the hydrolysis of A2a occurs inside
and a N···H‒OH angle of 167° and accounts for the 49 % of
the total stabilization energy of the A2a  CR complex
(51 % represents the Van der Waals interactions).
CR
the finding that in the presence of DMSO, as a solvent
6
thanks to its catalytic activity. This was confirmed by
6
15
Regarding the A2b  CR complex, because of the steric
able to break down the capsule, no conversion of A2a
6
demand imposed by the trifluoromethyl group, A2b is
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Journal of the American Chemical Society
details, in the presence of CR
forced to stay on the axis that joins two vertexes of the
6
an adaptation of
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5
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7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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4
4
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5
5
5
5
5
6
capsule (Figures 7c and 7d), with the –CF3 group pointing
inside the cavity of a resorcinarene macrocycle (Figures 7c
and 7d). In this position the imine moiety of A2b is too far
from the bridged water molecules of CR and cannot
6
establish any H-bonding interactions.
constituents was thermodynamically driven by the
hexameric capsule toward the imine A2c derived by
aldehyde bearing an electron-withdrawing group on the
phenyl ring, while the constituent A2a remained the
kinetically favored one (S20-S23).
CHO
CHO
NH2
+
F3C
+
Cl
2a
2b
A
CR6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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1
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0
1
2
3
4
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0
1
2
3
4
5
6
7
8
9
0
CR6
O
O
O
O
H
H
H
CHO
H
H
H
H
CHOH
NH2
NH2
F3C
H
H
O
H
H
H
O
O
O
H
Cl
H
Cl
H
O
Cl
O
H
H
H
H
A2b + CR6
A2a
CR6
+
N
H
H
O
O
H
H
O
O
H
H
H
H
CR6
H
H
H
O
O
H
2
a + A + CR6
Figure 8. The “predatory” mechanism proposed for
the adaptation of imines constituents in the DCL in
Scheme 1 and Figure 3b.
Figure 7. Different views of the optimized geometries of
complexes: (a and b) A2a  CR ; (c and d) A2a  CR . (e)
6
6
Particular of the H-bonding interaction of A2a with the
bridged water molecule of CR6.
Differently, when the p-OMe-benzaldehyde 2d was
used together with 2a and A as component of the DCL,
then the formation of imines A2a and A2d was observed
In summary, these results show that this is a rare
example of kinetic and thermodynamic adaptation of a
DCL, in which the intraspecific “predatory” effect29 of the
catalyst (CR ) on one of the constituents (A2a) plays a
6
crucial role.
6
in very low yields in the presence of CR .
Now, in order to corroborate this assumption, we
studied the distribution of the constituents A2a and A2b
in the presence of lower quantities of “predator” CR
6
(
Figure 9). When the reaction in Scheme 2 was performed
6
in the presence of a lower quantity of CR (0.5 equiv) then
the kinetically favored imine A2a was prevalent up to 2 h
Figure 9), a time significantly longer than that observed
in the presence of 1 equiv of CR (0.5 h). Under these
(
6
Figure 9. Evolution of the distribution of A2a and A2b
with different amounts of capsule CR
conditions the thermodynamic imine A2b began to
prevail at 4 h and finally the quantity of A2a after 48 h
was slightly higher than that obtained in the presence of 1
equiv of capsule (see Figure 9). Lowering the quantity of
6
.
Interestingly, in this case, the imine A2a was favored
capsule CR
6
at 0.1 equiv, the imine A2a prevailed up to
over the time (Figure S24-S27).
about 20h, with a yield of about 40 %, higher than that
observed in the presence of 0.5 (23 %) and 1.0 equiv (15 %)
of CR6. This result clearly indicates that the stability of
the imine A2a in the DCL increases by lowering the
Adaptation of the 2x1 DCL of imines B2a and B2b to the
presence of the hexameric capsule
quantity of capsule CR
effect on A2a.
6
showing in this way its predatory
Next, we investigated a DCL starting by aniline B and
aldehydes 2a and 2b (R
= CF3) (Scheme 4) as
components. The imine constituents B2a and B2b were
formed immediately after mixing (Figure 10b), while in
the absence of capsule the reaction proceeded more
Interestingly, when the p-nitrobenzaldehyde 2c was
used instead of 2b then the DCL of the components
A/2a/2c showed an analogous behavior (see SI). In
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Journal of the American Chemical Society
Page 6 of 12
slowly (Figure 10a). As concerns the imines distribution,
Figure 10. Distribution of imine constituents B2a and
B2b in the DCL in Scheme 4, without (a) and with (b)
capsule CR
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
B2a was kinetically favored, reaching 20 % of conversion
after 0.5 h (Figure 10b). After 30 min B2a started to
decrease as B2b increased, while the equilibrium was
reached after 6 h with a B2b/B2a ratio of 52/10. In
summary, even changing the aniline components the
benzaldehyde-derived imine B2a results the kinetically
favored product while the imine obtained by 2b results
the thermodynamic one.
6
.
The decreasing of the quantity of imine B2a in the
experiment in Figure 10b suggests a possible predatory
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
action of the capsule CR
by this hypothesis we evaluated the stability of B2a in
water-saturated CDCl in the presence or in the absence
of capsule CR (Figure 11). The imine B2a was hydrolyzed
in the presence of capsule CR and the reaction reached
the equilibrium with a 73 % of conversion of B2a already
after 1h (Figure 11), while in the absence of capsule CR the
at room
6
on the imine B2a. Encouraged
3
Figure 11. Hydrolysis of imine B2a in the presence and in
the absence of capsule CR6.
6
6
On the other hand, the reaction without capsule
progressed more slowly and gave an equimolar mixture of
imines C2a and C2b along the reaction time (Figure 12a).
6
imine B2a was stable in water-saturated CDCl
3
temperature.
Adaptation of the 2x1 DCL of imines C2a and C2b to the
presence of the hexameric capsule
Starting from p-methoxyaniline C, which shows a
higher basicity (pKa = 5.36) than A and B, and aldehydes
2
a/2b in Scheme 4, the DCL adapts in the presence of CR
6
(
Figure 12), but smaller kinetic effects were observed.
R
R
CHO
CHO
NH2
CR6
+
+
N
+
N
F3C
R
wet CDCl3
2a
2b
A) R = Cl
B) R = H
C) R = OMe
A-C2a
A-C2b
F3C
Scheme 4. Dynamic library of three components 2a, 2b, A-C
and two constituents in the presence of CR
Figure 12. Distribution of imines C2a and C2b in the
dynamic system generated by aldehydes 2a and 2b and
6
.
aniline C without (a) and with (b) capsule CR
A close inspection of the kinetics in Figure 12a and 12b,
indicates that in the absence of CR the imine C2a
increases over the time until to reach an equilibrium
value of 55 % after 24 h. Differently, when the capsule CR
6
.
A comparison of the distribution over the time of the
constituents C2a and C2b (Figure 12), with and without
capsule, clearly shows that in the presence of CR
2b), the equilibrium was reached already after 1 h with a
C2b/C2a ratio of 67/32.
6
(Figure
6
1
6
was present, then a conversion of 36 % of C2a was
obtained after 30 min, but already after 1 h C2a started to
decrease until to reach an equilibrium value of 32 % after
6
h. Again, this behavior, suggests a predatory action of
the capsule CR on C2a. Thus, in order to confirm this
assumption, we evaluated the stability of C2a in water-
saturated CDCl in the presence or in the absence of
capsule CR (Figure 13).
The imine C2a was rapidly hydrolyzed in the presence
of capsule CR and the reaction reached the equilibrium
with a 59 % of conversion of C2a already after 1h, while in
the absence of capsule CR the imine C2a was stable in
water-saturated CDCl at room temperature.
6
3
6
6
6
3
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Journal of the American Chemical Society
Scheme 6. Dynamic library of three components 2a, A, E in
1
2
3
4
5
6
7
8
9
6
the presence of CR . p-Chloroaniline vs. n-butylamine
substrate selectivity.
Thus, these results indicate that the capsule depresses
the reactivity of an aliphatic amine such as the n-
butylamine E toward the aldehydes 2a and 2b. This
conclusion can be explained on the basis of the data
18a
previously reported by Tiefenbacher.
In fact, n-
Figure 13. Hydrolysis of imine C2a in the presence and in
the absence of capsule CR
butylammine E is protonated by the capsule to an extent
of 80 %, and the resulting n-butylammonium cation is
6
.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
18a,
stabilized inside the capsule by cation···π interactions.
20a
In summary, these results (Figures 12 and 13) indicate
that also the DCL of imines C2a and C2b adapts in the
Consequently, the percentage of free neutral n-
butylamine is low and the imine formation (Scheme 5) is
presence of capsule CR
6
by a predatory effect of the
depressed. Differently, p-chloroaniline A, which shows a
1
8a
capsule on one of the imine constituent.
lower basicity (pKa = 3.8), is not protonated by CR6 and
consequently shows a remarkable reactivity when co-
confined with aldehydes.
Adaptation of 2x1 DCLs of imines E2a/E2b and A2a/E2a
to the presence of the hexameric capsule. Substrate
selectivity: aromatic vs. aliphatic amine
With these results in hand, we performed
competition experiment (Scheme 6) in which p-
chloroaniline and n-butylamine compete for
benzaldehyde 2a. In details, A, E, and 2a were mixed in
/1/1 ratio (42.3 mM) in wet CDCl3, in the presence or in
the absence of CR . As reported in SI (Table S10 and
Figures S38-S40) and Scheme 6, in the absence of capsule
a
A
E
One of the aims of the enzyme mimicry is to achieve
the substrate selectivity typical of natural systems. Thus,
we envisioned to study the substrate selectivity of the
1
6
hexameric capsule in the presence of
a mixture
constituted by aromatic and aliphatic amines. First we
analyzed the modulation of the DCL in Scheme 5 starting
by benzaldehyde 2a, p-trifluoromethylbenzaldehyde 2b
and n-butylamine E in the presence or in the absence of
CR
%
6
the imines E2a and A2a were formed in 50 % and 25
yield, respectively (Figure 14). Differently, in the
, the selectivity order was reversed to
presence of CR
6
15/25 in favor of A2a (Figure 14).
3
capsule in water saturated CDCl , using a concentration
6
of 42.3 mM each of 2a/2b/E/CR , at 30 °C.
In summary, is clear that the CR capsule is able to
6
host the scarcely basic p-chloroaniline A in its neutral
form, thus promoting the formation of the corresponding
imine in the presence of an aldehyde. Differently, when
the more basic n-butylammine is used, then the
corresponding ammonium form is obtained after
protonation inside the capsule where is stabilized by
cation···π interactions. In this way, the formation of imine
is depressed. This is an intriguing example of substrate
N
N
CHO
CHO
a,b)
+
+
NH2
+
wet-CDCl3
4 h, 30 °C
F3C
2
F3C
E2b
2a
2b
E
E2a
a) 17%
b) 3%
40% without CR6
13% with CR6
Scheme 5. Dynamic library of three components 2a, 2b, E
and two constituents in the presence or in the absence of
CR .
6
6
selectivity that the capsule CR exerts towards aliphatic
vs. aromatic amines, by lowering the reactivity of the
former towards the formation of imines.
The results in Table S9 and Scheme 5, clearly show
that the formation of imines E2a and E2b is favored in the
absence of CR , with 17% and 40 % yield, respectively,
after 24 h. Differently, in the presence of CR , E2a and
6
6
E2b were obtained in 3 % and 13 % yield, respectively.
This is in contrast to the results reported in Figure 4, in
which the formation of imines A2a and A2b starting by an
aromatic amine such as p-chloroaniline A and aldehydes
2
6
a and 2b, is favored in the presence of CR .
Cl
CR6
CHO
NH2
N
+
N
+
+
NH2
Cl
Wet
CDCl3
24 h, 30 °C
2a
A
E
E2a
A2a
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Figure 14. Distribution of imine constituents A2a and
E2a in the DCL, without (a) and with (b) capsule CR
components (Figure 15a). Performing the reaction in
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
.
Scheme 7 in the presence of a lower quantity of CR (0.5
6
equiv, Figure S42), then the kinetically favored imine A2a
survived longer, thus also in this case the predatory effect
of the capsule toward A2a was depressed (Figure S42).
Adaptation of the 2x2 DCL of imines A2a, A2b, B2a, and
B2b to the presence of the hexameric capsule
OMe
OMe
At this point our attention was focused on a more
complex DCL formed by four constituents derived by four
components (Scheme 7). We mixed equimolar amounts of
aldehydes 2a and 2b with anilines A (p-Cl) and B (p-H)
N
+
N
CHO
CHO
NH2
MeO
F3C
CF3
MeO
MeO
F3C
F3C
C2d
C2b
CR6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2d
2b
D
(
Scheme 7) and we monitored the adaptation of the DCL
+
wet CDCl3
CF3
NH2
of the four imine constituents to the presence of CR
6
.
C
N
+
N
Cl
Cl
MeO
F3C
N
+
N
D2D
D2b
CHO
NH2
CHO
NH2
Scheme 8. Dynamic library of four components 2d, 2b, C,
D and four constituents in the presence of CR
F3C
CR6
F3C
A2a
A2b
2
a
2b
B
6
+
wet CDCl3
Cl
N
+
N
A
In accordance with one of the aims of enzyme-
3
mimicry, to work selectively in the presence of a complex
F3C
B2a
B2b
mixture of reagents, the results reported in Figure 15
clearly show that the hexameric capsule CR is able to
6
Scheme 7. Dynamic library of four components 2a, 2b, A,
B and four constituents in presence of CR6.
work selectively in the presence of complex mixtures of
substrates, thanks to a fine control of the encapsulated
species leading to the selective formation of specific
imines. In order to further corroborate this result, we
performed a new 2x2 experiment, changing the amine and
aldehyde components.
In the presence of capsule (Figure 15b), a mixture of all
four imines was formed immediately after mixing. The
imine constituents A2a and B2b were the main
components, followed by B2a and A2b in a distribution of
25 %, 20 %, 17 %, and 11 %, respectively (Figure 15b).
Already 2 h later, the imine A2b and B2b started to
increase as A2a and B2a decreased. Thus the imines A2a
and B2a resulted the kinetic products, while the products
A2b and B2b emerged under thermodynamic conditions.
Adaptation of the 2x2 DCL of imines C2b, C2d, D2b, and
D2d to the presence of the hexameric capsule
Finally, we focused our attention toward a 2x2 DCL
starting by components bearing an electron-donating
OMe group (2d/C) and an electron-withdrawing
trifluoromethyl group (2b/D) (Scheme 8). As in all the
above cases, the formation of imines was more efficient in
6
the presence of CR capsule (Figure 16).
Figure 15. Distribution of imines in the dynamic systems
from 2a, 2b, A and B without (a) and with (b) capsule CR .
6
When the reaction was performed without the
capsule, the composition of the library showed no
substantial preference in the distribution of the
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1
Figure 16. Distribution of imines in the dynamic
systems from 2b, 2d, C, and D without (a) and with (b)
aldehydes by 1D and 2D experiments, H NMR experiments
as proofs of the predatory effect of the capsule.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
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3
3
3
3
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5
5
5
5
5
5
6
6
capsule CR .
AUTHOR INFORMATION
Corresponding Author
After 0.5 h, the imine constituents C2b and C2d from
p-methoxyaniline were detected as the main
C
components of the mixture in a C2b/C2d ratio of 47/19,
while the imines D2b and D2d, obtained from the less
reactive p-trifluoromethylaniline D, were present in
almost negligible quantities. Over the time, an increase in
the quantity of C2b was observed, which after 24 h was
the most abundant constituent of the mixture, with a
composition of C2b, D2b, C2d, and D2d of 66 %, 12 %, 5
*C.G.: cgaeta@unisa.it.
*M.D.: maderosa@unisa.it.
Author Contributions
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All authors have given approval to the final version of the
manuscript.
ACKNOWLEDGMENT
This work was supported by the University of Salerno (FARB
%, and 5 %, respectively. In summary, by cross
referencing the data in Figures 12 and 15 it becomes clear
that no kinetic preference was observed in DCL systems
in which are present as component the p-OMe-
benzaldehyde 2d or p-OMe-aniline C.
2018 and PhD funding).
REFERENCES
(
1) Berg, J. M. ; Stryer, L.; Tymoczko, J.; Gatto, G.
th
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(
2) (a) Benyus, J. M. Biomimicry: Innovation Inspired by
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New Jersey, 2012.
In conclusion, we have demonstrated that dynamic
covalent libraries of imine constituents are able to adapt
their composition in response to the presence of the
hexameric resorcinarene capsule CR
A2a and A2b formed by benzaldehyde 2a, p-CF
benzaldehyde 2b, and p-chloroaniline A, adapts its
composition in the presence of CR showing a kinetic and
thermodynamic preference of the constituents. In
particular, the kinetically favored constituent A2a,
obtained by benzaldehyde 2a, is preferentially formed
immediately after mixing, thanks to the preferred
inclusion of 2a inside CR6. Surprisingly, the capsule shows
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quickly hydrolyzed to components A and 2a inside the
capsule. Differently, the imine constituent A2b, obtained
(
3) (a) Breslow, R. Biomimetic Chemistry and Artificial
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John Wiley & Sons Ltd., Chichester (UK), 2018
3
by p-CF -benzaldehyde 2b, is hydrolyzed slower than A2a.
Uptake studies show that after the hydrolysis of the imine
A2a, the benzaldehyde component 2a remains included
in the capsule CR
6
. Interestingly, the hexameric capsule
CR , shows an analogous predatory action on other
6
benzaldehyde-based imines such as B2a and C2a derived
from aniline B and p-OMe-aniline C, respectively. Finally,
also more complexes 2x2 DCL systems adapt to the
presence of the hexameric capsule showing
a
thermodynamic and kinetic modulation of the
constituents and leading to a good selectivity (up to 66 %)
for one of them.
(
(
5) (a) Giuseppone, N.; Lehn, J.-M. Protonic and
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a Dynamic Combinatorial
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Dynamers: Thermally Induced, Reversible Chain
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Chem. Soc. 2011, 133, 10966-10973
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(
I) architectures and solid-state stabilization of the
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imines as function of time, proofs of encapsulation of
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2
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Dynamic Libraries and Networks from Kinetic to
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metallosupramolecular
DCLs
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2
(
7) (a) Osowska, K; Miljanić, O. Š. Self-Sorting of Dynamic
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Self-Sorting of Dynamic Ester Libraries. J. Org. Chem.
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Molecular Behaviour in Small Spaces, World Scientific,
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(
25) Due to the high computational cost derived from the
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in silico investigation using the ONIOM method on a
6
reduced model of CR , substituting the undecylic
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capsule with the methyl ones. This approach was
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