Synergic Interplay Between Halogen Bonding and Hydrogen Bonding in the Activation of a Neutral Substrate in a Nanoconfined Space

Article abstract of DOI:10.1002/anie.201909865

The principle of amplified halogen bonding (XB) in a small space is exploited as a catalytic tool for the activation of an XB acceptor substrate in a nanoconfined environment. The inner cavity of the resorcinarene capsule has been equipped with an XB cata

Full text of DOI:10.1002/anie.201909865

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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International Edition
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Accepted Article
Title: Synergic Interplay Between Halogen Bond and Hydrogen Bond in
the Activation of a Neutral Substrate in a Nanoconfined Space
Authors: Carmine Gaeta, Pellegrino La Manna, Margherita De Rosa,
Carmen Talotta, Antonio Rescifina, Giuseppe Floresta,
Annunziata Soriente, and Placido Neri
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201909865
Angew. Chem. 10.1002/ange.201909865
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10.1002/anie.201909865
Angewandte Chemie International Edition
RESEARCH ARTICLE
Synergic Interplay Between Halogen Bond and Hydrogen Bond in
the Activation of a Neutral Substrate in a Nanoconfined Space
Pellegrino La Manna, Margherita De Rosa, Carmen Talotta,* Antonio Rescifina,* Giuseppe Floresta,
Annunziata Soriente, Carmine Gaeta,* Placido Neri
Dedication ((optional))
Abstract: The principle of the “amplified halogen bonding (XB) in a
small space” is here exploited as a catalytic tool for the activation of
an XB acceptor substrate in a nanoconfined environment. The inner
cavity of the resorcinarene capsule has been equipped with an XB
catalyst bearing an ammonium unit acting as a Trojan horse to drive
the catalyst inside the capsule. In the presence of the XB catalyst 5,
the capsule is able to catalyze a Michael reaction between N-
methylpyrrole and methyl vinyl ketone. In the bulk medium, in the
absence of the resorcinarene capsule, the XB catalyst 5 was
compounds,[7] activation of substrates by halides abstraction,[8]
and activation of neutral substrates.[9]
In the last decades, many efforts have been devoted to the
study of reactions catalyzed in nanoconfined spaces.[10] Cram [11]
and Rebek[12] earlier showed that when the molecules are
confined inside a capsule, their chemical behavior can diverge
from the usual one observed in the bulk medium. When the
substrates are confined in the restricted space inside a molecular
capsule, the proximity effect between them, and their hyper
concentration due to the nano-confinement, induce a reaction rate
acceleration, thus mimicking the modus operandi of natural
enzymes.[10] The most impressive aspect of the catalysis in
nanoconfined spaces is that the reactivity of the molecules can be
smartly driven to disobey classical behavior.[13] Recently, in an
elegant work by Fujita, Metrangolo, and Resnati,[3b] the authors
highlighted that the confined space inside a self-assembled cage
enhances the halogen bonding between XB donors and XB
acceptors. Previously, Rebek[3c] also showed that the
encapsulation of both XB partners into the nanoconfined space of
a dimeric capsule amplified the halogen bonding interaction and
allowed its NMR characterization.
catalytically
ineffective.
Quantum-mechanical
investigations
highlighted that the Michael reaction proceeds through the activation
of the carbonyl by synergistically enhanced halogen/hydrogen
bonding interactions, and takes place in an open pentameric capsule.
Introduction
The halogen bonding (XB)[1] interaction is considered as an useful
tool in supramolecular chemistry[2] for engineering new
materials[3] and for the self-assembly of supramolecules and
interpenetrated architectures.[2,3] XB is a secondary interaction
between a covalently bound halogen atom in a R–X compound
(the “XB donor”, where X = I, Br, Cl, F, and R = C or any other
atom including even I, for example) and a Lewis base (the “XB
acceptor”).[4] This interaction is highly directional, and its strength
strictly depends on the structures of the XB donor and acceptor
partners.[4] Thus, the presence of electron-withdrawing groups in
R, which are able to polarize the X atom, increases its XB donor
ability and consequently the strength of XB interaction.
Recently, an increasing attention has been devoted to
exploiting the XB interaction in solution, where the polarity of the
medium has a crucial role. In this regard, the potential application
of XB donor derivatives in organocatalysis,[5,6] is attracting more
interest in the scientific community. Thus, for example, the XB
interaction has been exploited for the activation of carbonyl
(1R)6•(H2O)8 (CR6
)
Figure 1. Chemical drawing of C-undecylresorcin[4]arene 1 (left) and a reduced
model (R = Me) of the hexameric capsule (1R)6•(H2O)8 (CR6) (right).
On these bases, we have envisioned that the “halogen bonding
amplification in a small space”, can be exploited as a tool for XB
catalysis inside a self-assembled resorcinarene capsule. The
hexameric capsule (1)6•8H2O (C6), originally reported by
Atwood,[14] is obtained by self-assembly of six resorcinarene 1
units and eight water molecules (Figure 1), and has been largely
exploited as nanoreactor[10a,c,e,f,j,k] thanks to its capacity to host
selectively the substrates and to accelerate the organic reactions
with excellent chemo-, regio-, and stereoselectivity. The
advantage of using such nanocontainers as a catalyst, with
respect to smaller macrocycles, is that the larger cavity can be
easily engineered, for example, by introducing specific artificial
Dr. P. La Manna, Dr. C. Talotta, Dr. M. De Rosa, Prof. Dr. A.
Soriente, Prof. Dr. C. Gaeta, Prof. Dr. P. Neri
Laboratory of Supramolecular Chemistry,
Dipartimento di Chimica e Biologia “A. Zambelli”
Università di Salerno
Via Giovanni Paolo II, 132, I-84084, Fisciano (Salerno), Italy
E-mail: cgaeta@unisa.it; ctalotta@unisa.it
Dr. G. Floresta, Prof. A. Rescifina,
Dipartimento di Scienze del Farmaco, Università di Catania, viale
Andrea Doria, 6, 95125 Catania, Italy.
E-mail: arescifina@unict.it
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201909865
Angewandte Chemie International Edition
RESEARCH ARTICLE
cofactors. [15] Commonly, the π-electron-rich cavity of C6 shows a
high affinity for cationic ammonium groups,[10] which can be
considered as an ideal recognition motif useful to drive the
molecular encapsulation of appropriate guests inside the
hexameric capsule. Based on these considerations, we here
report the first example of a halogen bonding catalysis in a
nanoconfined environment synergistically enhanced by hydrogen
bonding interactions. In particular, we have focused our attention
on the Michael reaction reported in Scheme 1, employing p-
iodophenyltrimethyl-ammonium salts 5 as XB-catalysts. Our
design is prompted by the idea that the trimethylammonium group
is able to establish cation···π interactions with the electron-rich
aromatic cavity of C6, while the p-iodophenyl moiety is the active
XB donor. In addition, the Me3N+ moiety could act as an electron-
withdrawing group able to polarize the I atom, thus increasing its
XB donor ability.
iodophenyltrimethylammonium iodide 5a is crucial for the
catalysis of the Michael reaction (Scheme 1) between 2 and 3.
Also, these data strongly indicate that the reaction reported in
Scheme
1 occurs in the nanoconfined space inside a
resorcinarene capsule through an XB activation of the substrate
3, which is ineffective in the bulk medium in the absence of 1.
Table 1. Halogen bonding catalyzed Michael reaction between N-methylpyrrole
2 and methylvinylketone 3 in the presence of 1.
Entry[a] T (°C)
Halogen
bonding
catalyst
(20%)
Capsule
amount
(mol%)
Yield of 4 (%)[b]
1
2
30
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
5a
5a
—
26
26
26
—
26
26
26
26
—
26
—
26
—
26
—
26
26
26
82
98
12
—
88
1
3
4
5a
5a
5a
5a
5b
5b
5c
5c
5d
5d
5e
5e
5f
Results and Discussion
5[c]
6[d]
7[e]
8
Initially, we investigated the reaction between N-methylpyrrole 2
and methyl vinyl ketone 3 in the presence of resorcinarene 1
(Scheme 1), in water-saturated CDCl3 as the solvent, in order to
form the C6 capsule. When the reaction mixture (Table 1, entry 3)
was stirred at 50 °C for 16 h, the product 4 was obtained in 12%
yield, whereas no product was obtained in the absence of 1 (entry
4). Interestingly, when p-iodophenyltrimethylammonium iodide 5a
was added to the mixture of 1, 2, and 3 in water-saturated CDCl3,
a 98% yield of product 4 was obtained after 16 h at 50 °C (Table
1, entry 2). These results confirm the crucial role played by the p-
iodophenyltrimethylammonium iodide in the catalysis of the
Michael reaction reported in Scheme 1.
—
45
—
53
—
5
9
10
11
12
13
14
15
16
17
18
—
50
—
24[f]
8[g]
33
Now, the question arises whether the resorcinarene capsule plays
still a catalytic role in the presence of 5a.
5g
5h
O
+
N
[a] Reaction conditions: 2 (0.59 M), 3 (0.15 M), 1 (0.0063 M) in 1.1 mL of water-
Me
2
[b]
[c]
[d]
saturated CDCl3, 16 h. Isolated yield. Reaction time: 4 h. The reaction
3
[e]
5a: X = I; Y = I
was performed in the presence of hexamethonium bromide (0.76 M).
reaction was carried out in the presence of DMSO. [f,g] The 25%[f] and 18%[g] of
2,5-disubstituted product was obtained.
The
N
X
5b: X = Br; Y = I
5c: X = Cl; Y = I
5d: X = I; Y = BF4
5e: X = I; Y = B(Ph)4
5f: X = Me; Y = I
5g: X = OMe; Y = I
5h: X = H; Y = I
Y
1
5
water-saturated
CDCl3
This was confirmed by the finding that, when the reaction in
Scheme 1 was performed in the presence of hexamethonium
bromide, a known competitive guest,[16] only traces (1%) of 4 were
detected after 16 h at 50 °C (Table 1, entry 6). Under these
conditions, the hexamethonium bromide occupying the cavity of
capsule C6 acts as an inhibitor lowering the yield. In addition, the
1H NMR spectrum of the reaction mixture in the presence of
hexamethonium bromide featured shielded signals at negative
chemical shifts values attributable to the cation inside the cavity
of C6. Furthermore, product 4 was not observed when the reaction
reported in Scheme 1 was performed in the presence of solvents
that compete for hydrogen bonding (e.g., DMSO, Table 1, entry
7).
5a h
–
N
O
Me
4
Scheme 1. Halogen bonding catalyzed Michael reaction between N-
methylpyrrole 2 and methyl vinyl ketone 3 in the presence of 1.
In addition to what noted in entry 4, when the reaction in Scheme
1 was performed in the presence of the non-halogenated
phenyltrimethylammonium 5h (Table 1, entry 18) a significant
decrease in yield was obtained (−65%), respect to the best
performing reaction. This result highlights the crucial role played
by the halogen-bond in the activation of substrate 3 (vide infra).
Summarizing, these preliminary results indicate that the
Following a standard protocol previously reported,[13,15] evidences
for the encapsulation of the reagents and co-catalyst 5a inside the
C6 capsule were provided by 1D and 2D-NMR studies (see the
Supporting Information). Moreover, when methyl vinyl ketone 3
simultaneous
presence
of
both
1
and
p-
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10.1002/anie.201909865
Angewandte Chemie International Edition
RESEARCH ARTICLE
was added to a water-saturated CDCl3 solution of C6, the 1H NMR
spectrum (see the Supporting Information) of the mixture showed
the presence of signals in the upfield region, at negative values,
indicative of the presence of 3 inside C6. Regarding the
encapsulation of 5d a resorcinarene aggregate was formed,
which was catalytically inactive.
1
encapsulation of 5a, the H NMR spectrum of the 5a/C6 mixture
In Silico Studies
in water-saturated CDCl3 evidenced the presence of a signal at
1.32 ppm which correlates, in the HSQC spectrum, with a carbon
resonance at 55.2 ppm attributable to the methyls of the +N(Me)3
group of 5a.
The shielding of the +N(Me)3 signal in the high-field region of the
1H NMR spectrum by 3.78 ppm (Δδ = δfree − δcomplexed = 4.00 −
1.32) is strongly indicative of the inclusion of 5a inside the
aromatic cavity of C6. Analogously, the aromatic hydrogen atoms
of 5a experienced a complexation induced shift (CIS) of 0.42 (Δδ
In order to study the role of the halogen-bonding interaction in the
activation of 3, we conducted a quantum chemical investigation.
To this purpose, we chose, as a representative model, the
reaction between 2 and 3, using a reduced capsule (CR6) with
methyl feet and ONIOM method (M06-2X:PM6).[13,15,19] The
stabilization energy of the complexes calculated by QM method
suggests that the first species to enter in the capsule is 5a
followed by 3 and then by 2 (Table S1, entries 1, 5, 8).
= δfree − δcomplexed = 7.86 − 7.24) and 1.52 ppm (Δδ = δfree
δcomplexed = 7.62 − 6.10).
−
In conclusion, it is clear that p-iodophenyltrimethylammonium XB-
catalyst 5a is enclosed inside the cavity of C6 driven by cation···
interactions (Scheme 2) and 1D and 2D-NMR studies highlighted
that also the reactants 2 and 3 are confined inside the hexameric
capsule C6.
To corroborate the catalytic role of this halogen bonding
interaction, we studied the reaction reported in Scheme 1 using
p-X-phenyltrimethylammonium salts 5b–d (Table 1, entries 8, 10,
and 12). As it is well established,[1,4] the XB strength increase with
the polarizability of the XB donor atom, that is, F < Cl < Br < I.
Accordingly, when N-methylpyrrole 2 was reacted with 3, in the
presence of 1, and p-bromophenyltrimethylammonium iodide 5b,
then product 4 was obtained in 45% yield (Table 1, entry 8), while
a 53% of 4 was obtained using p-chlorophenyltrimethylammo-
nium iodide 5c (Table 1, entry 10). In addition, in these cases, the
XB catalysts 5b and 5c do not work in the bulk medium, in the
absence of capsule (Table 1, entries 9 and 11).
Figure 2. Full optimized geometries of [5a+2+3]@CR6 (left), and [5a+3]@CR5
(right) complexes. The arbitrary numbers on the selected atoms were introduced
to understand the subsequent analysis employing the second-order
perturbation theory (SOPT).[20]
In addition, the results (SI) clearly indicates that the counteranion
I− prefers to stay inside the capsule, stabilized by hydrogen bond
interactions with a bridging water molecule. QM-calculations
indicate that the halogen-bonding interaction between 5a and 3
inside C6 forces the reagents along the axis that joins two vertexes
of the octahedral capsule (Figure 2, left). In this way, they are able
to engage a halogen bond, but the pyrrole 2 is sterically unable to
interact with the -carbon of 3, and we were not able to locate any
effective TS geometry for the studied Michael addition without the
loss of the halogen bond interaction. Due to this mandatory
requirement for the geometry of the reactants, we supposed to
work with a reduced pentameric capsule (Figure 2 right, CR5) in
which a resorcinarene unit is removed.[21] Interestingly, a recent
report by Schalley and coworkers showed the existence of a
pentameric cluster of resorcin[6]arene units by HR FT ICR mass
spectrometry.[22] In this way, we were able to find a stationary
geometry in which not only the reactants 5a and 3 are able to
engage a halogen bond that is preserved during the Michael
addition, but the carbonyl oxygen of 3 is also able to establish two
supplementary hydrogen bonds with two bridging water
molecules of the pentameric resorcinarene structure (Figure 2,
right); this last event ulterior activate the reaction, synergistically
enhancing the halogen bond effect. In this geometry, three methyl
groups of 5a are symmetrically pointing inside the -electron-rich
cavity of a resorcinarene macrocycle, and the reagents are
located in the same axis that joins two vertexes of the original
octahedral geometry of the capsule, but the methyl vinyl ketone 3
is pointing outside the cavity of the capsule. Even in this case, the
With these results in hand, we investigated the role of the
counteranion of the trimethylammonium cation on the efficiency
−
of the catalytic system. When the BF4 salt of p-
iodophenyltrimethylammonium (5d) was mixed with 1, 2, and 3,
in water-saturated CDCl3, only 5% of product 4 was detected after
−
16 h at 50 °C (Table 1, entry 12). In the presence of B(Ph)4 as
counteranion (5e) (Table 1, entry 14) the product 4 was isolated
in 50% yield, a value significantly lower than that obtained in the
presence of iodide as counteranion (98%).
These data clearly indicate that the catalytic efficiency of the p-
iodophenyltrimethylammonium co-catalyst is strongly affected by
the counteranion. The two salts 5a and 5d show different solubility
in the reaction medium, in fact, when the p-
iodophenyltrimethylammonium 5a was mixed with 2 and 3, in the
presence of 1 in water-saturated CDCl3, then a homogenous
solution was obtained, while the analogous experiment in the
presence of 5d (BF4− salt of p-iodophenyltrimethylammonium) led
to the formation of a suspension of the salt. Besides, data
previously reported by Rebek,[17] highlighted that the
tetraalkylammonium salts of I– and BF4− both form a resorcinarene
1
aggregate but the H NMR spectra of the two complexes differ
starkly. In accord with this, DOSY studies reported by Cohen[18]
showed
that
the
tetraethylammonium
iodide
and
tetraethylammonium BF4− are encapsulated inside resorcinarene
aggregate that haven’t the same structure for the two different
anions. These results suggest that probably after the
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10.1002/anie.201909865
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RESEARCH ARTICLE
counteranion establishes hydrogen bond interactions with a
bridging water molecule. The calculated energies suggested an
enthalpic and a free Gibbs energy stabilization for the reactants 2,
3, and 5a after the complexation.
Furthermore, to assess the solvent effect on the most crucial rate-
determining step of this reaction, the activation energies for the
investigated TSs were further calculated in chloroform (Table S1).
The results are substantially in line with those obtained in the gas
phase; substantially, there was only an increase in the free
activation energies in the range 1.71–3.34 kcal/mol.
Figure 4. Selected principal orbital interactions for [5a+3]@CR5 as derived by
Figure 3. Schematic representation of the two alternative mechanistic routes
the SOPT analysis.
proposed for the supramolecular catalyzed Michael addition.
To further validate and elucidate the obtained results on the
reactivity of this system, especially on the contributions due by H-
bond, halogen-bond, and other non-covalent interactions (NCI),
we indagate on the geometries of selected stationary points with
some of the powerful tools of the conceptual density functional
theory. For this purpose, we have selected the local
electrophilicity (k), according to the recently improved definition
of Domingo),[23] the interaction energies [E(2)] arising from the
SOPT analysis of the Fock matrix in NBO basis, according to the
definition of delocalization energy given by Weinhold,[20] and the
non-covalent interactions (NCI) index proposed by Yang’s group.
Interestingly, the SOPT analysis (Figure 4) conducted on the
[5a+3]@CR5, [5b+3]@CR5, and [5c+3]@CR5 complexes (Table
S2) indicates that they are stabilized, also, by a dense network of
H-bond and halogen-bond interactions.
In particular, for the investigated complexes, we calculated the
n* interaction between the carbonyl O1 (n) and the antibonding
orbitals (*) of the O2–H2 and O3–H3 (Figure 4, refer to Figure 2
for the numeration) single bonds of the two water molecules.
These interactions account for total energy of 14.13, 13.13, and
14.26 kcal/mol for [5a+3]@CR5, [5b+3]@CR5, and [5c+3]@CR5
complexes, respectively (Table S2, entries 4–6).
Subsequently, obtained the correct geometry with the pyrrole
conveniently placed to carry out the Michael addition, the effect of
three different halogens (iodine, bromine, and chlorine) was
evaluated by measuring the activation energies attributable to the
transition states for the reaction inside the capsule, considering
the halogen bond donors 5a–c and the reactants 2 and 3. The
free Gibbs activation energy involved in the first step of the
addition of the N-methylpyrrole 2 to the -unsaturated enone 3
justify the trend of experimentally observed yields (Table S1,
entries 12–14). Although this result seems to go against the
classical trend linked to the strength of the halogen bond (I > Br >
Cl), we will see that it is not so (see the discussion on the SOPT
analysis). Moreover, we studied the Michael reaction between 2
and 3 in the presence of 5a but in the absence of halogen-bonding
interactions between 5a and 3. Differently from the geometry in
Figure 3 (left), when the carbonyl group of 3 did not establish
halogen-bonding interactions with 5a, then a hydrogen bonding
interaction was found with a bridging water molecule (Figure 3,
right). Significantly, in this geometry (Figure 3, right) the carbonyl
group of 3 was located close to the positively charged nitrogen of
5a. The pyrrole 2 was located in a position able to interact with
the -carbon of 3. The activation energy for this reaction resulted
in 26.44 kcal/mol (Table S1, entry 9), which is 6.28 kcal/mol higher
than that of the reaction catalyzed through halogen bonding,
suggesting again that the effects of the halogen interaction can
lower the energy barrier. Finally, the calculated activation energy
for the reaction in the absence of the catalyst resulted in 28.28
kcal/mol (Table S1, entry 15), confirming the pivotal role of the
capsule in this reaction. Thus, these results are entirely in
accordance with the experimental ones; in fact, when 2 and 3
were reacted in the presence of 1, under the conditions reported
Moreover, the n* interactions of the carbonyl O1 lone pairs with
the antibonding orbital of the C4–X1 single bond, that highlight the
formation of an halogen bond, have a value of 1.70, 1.66, and
1.33 kcal/mol for the iodine, bromine, and chlorine-containing
complexes, respectively (Table S2, entries 8,9, and Figure 4 for
iodine), that is in accord with the classical trend linked to the
strength of the halogen bond. Based on these and others[24]
(Table S2, entries 1–3, 7, and 10–12) energy analyses (Table S2),
emerges that the stability order for the complexes at hand is
[5a+3]@CR > [5c+3]@CR > [5b+3]@CR5 (21.30 > 19.85 > 19.78
5
5
in Scheme
1
and Table 1, in the presence of
kcal/mol, Table S2, total energy) due to a complex synergistic
balance between H-bonds, halogen-bond, and non-covalent
interactions (see Supporting Information, #9.2 and Figure S54).
phenyltrimethylammonium 5h (Table 1, entry 18) then 33% of 4
was obtained, according to the calculated activation free energy
of 27.06 kcal/mol (Table S1, entry 17). Analogously, lower yields
of 4 were obtained in the presence of 5f (p-Me, Table 1 entry 16)
and 5g (p-MeO, Table 1 entry 17) confirming the crucial role
played by the halogen atom in the para-position of 5 for the
Michael reaction reported in Scheme 1.
Since the electron density transfer taking place in the transition
states
[5a+2+3]@CR5-TS,
[5b+2+3]@CR5-TS,
and
[5c+2+3]@CR5-TS, in terms of the residual charge of N-
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10.1002/anie.201909865
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RESEARCH ARTICLE
methylpyrrole 2 fragment, is high (0.428, 0.431, and 0.437 au,
respectively) the process can be considered polar and the
reactivity directly correlated to the local electrophilicity of the C3 -
carbon atom of the reagent 3 (C ). The values obtained for the
3
C (Table S3) are consistent with the efficiency of the above
3
described catalytic ensemble exerted on the generation of a most
potent electrophilic C3 center; in fact, the highest value of C3 has
been registered for the [5a+3]@CR complex followed by the
5
[5a+3]@CR , [5c+3]@CR , [5b+3]@CR5, and [5a+3] ones (Table
6
5
S3, entries 1,4,3,2, and 5, respectively), according to the
experimental results. In particular, it is evident that the competition
between the halogen bond activated pentameric complex and the
non-halogen bond activated hexameric complex is in favor of the
former (Table S3, entry 1 vs. entry 4). Finally, the halogen bond
activated complex without the presence of the capsule shows the
smallest C value (Table S3, entry 5), whose magnitude is not
3
sufficient to support an efficient nucleophilic attack.
Thus, the SOPT analysis and, mostly, the electrophilic indices
account for the striking higher activity of the XB catalyst 5c with
respect to 5b. In fact, even if Br is an XB donor group more strong
than the Cl one, the XB catalyst 5c is moderately more active than
5b, because the former shows a higher local electrophilicity value
(Table S3, entries 2 and 3). Moreover, from the examination of
Table S3, comparing the entries 1 and 5, it can be deduced that
the halogen bond, for iodine, affects approximately 50% on the
value of electrophilicity; the remaining is attributable to all the
other interactions. Therefore, presumably, the halogen bond that
involves iodine affects 50% of the activation of the reaction
studied here.
The tentative to computationally rationalize the observed effects
for the different studied counterions failed; however, this is in
accord with other studied reactions which involve the halogen
bond catalysis: the effects vary both with the type of reaction and
with the type of solvent used, and it is not predictable. [25]
Figure 5. a) Overlapped DOSY spectra of the mixture of 1, 2, 3 and 5a in water-
saturated CDCl3 (600 MHz, 298 K), after: I) 1h, II) 5h and III) 14h. b) Diffusion
coefficients of the resorcinarene capsule measured during the reaction between
2 and 3 in the presence of 5a; c) The conversion of the reaction in Scheme 1 in
the presence of different catalysts.
High-Resolution FT-ICR ESI-MS and DOSY
Studies
Experimental evidences of the presence of a pentameric
resorcinarene capsule C5 under the catalytic reaction conditions
were collected by DOSY studies and HR FT-ICR ESI MS (Figures
5 and 6). As reported in Figures 5a,b when the reactants 2 and 3
were added to a solution of the complex 5a@C6 then a strong
increasing of the diffusion coefficient of the capsule was observed
(from –10.57 to –9.70 m2/sec, Figure 5a (I and II) and Figure 5b)
in accord with the variation of the molecular size of the
supramolecular complex in solution. Of course, this is compatible
with the loss of a resorcinarene unit (5a@C6 − 1105.7 Da). Very
significantly, the diffusion coefficient remains practically constant
during the reaction progress (Figure 5b,c), while it returns to the
initial value (about −10.35 m2/sec, see Figure 5a,b) after 14 h,
when the conversion of the reactants to product 4 was 95%
(Figure 5c), and no reactants were left over to form the pentameric
capsule. At this point, the hexameric complex 5a@C6 was formed
back again.
Kinetic studies (Figure 5c) were performed for the reaction
in Scheme 1 using the catalyst 5a, 5b and the non-halogenated
catalyst 5h, used as reference compounds. We aimed to assess
the efficiency of the two alternative mechanistic routes proposed
in Figure 3 for the halogenated and non-halogenated catalysts in
Scheme 1. In fact, using catalyst 5h the catalytic mechanism in
Figure 3 (left) should be operative in which an H-bond, with a
bridging water molecule, and ion-dipole interactions should be
accountable for the activation of the substrate 3. In the presence
of derivatives 5a,b, the H-bonding interaction should be again
catalytically active, but also the halogen-bonding interaction with
the catalyst should be established (Figure 3 left). In this way, by
comparing the catalytic performance of 5a and 5h we could
evaluate the role of the halogen-bonding interactions in the
catalysis of the reaction in Scheme 1. In the presence of non-
halogenated catalyst 5h we observed a slight activity (Figure 6c,
green line), in the initial part of the reaction, which does not evolve
in the complete transformation of reagents into the products;
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10.1002/anie.201909865
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RESEARCH ARTICLE
probably, the observed reactivity is due to the mechanistic route
in Figure 3 (right).
templates the formation of pentameric (5a)2@15 and hexameric
(5a)2@16 aggregate, which were detected at 3024.613 m/z and
3579.024 m/z, and in which two units of 5a were present inside
the capsules. Significantly, when the reactants 2 and 3 were
added to the mixture in Figure 6b then the mass spectrum in
Figure 6c was obtained, in which a peak at 5787.24 m/z was
revealed attributable to the pentameric aggregate containing a
single unit of catalyst 5a, (5a@15). Under these conditions no
hexameric capsule was detected. In conclusion, MS studies
confirm the presence of a pentameric capsule, in addition they
provide an useful suggestion to explain the initial lag-phase in the
kinetic profile of 5a (and 5h). Probably, because of the greater
affinity of the cationic guests for the resorcinarene capsule, after
the initial addition of 5a a complex (5a)2@C6 was formed (Scheme
2) in which two units of 5a were included into the cavity of the
hexameric capsule. Consequently, time was required for the
formation of the heterocomplex [5a+3+2]@C5.
N
O
O
O
O
H
H
H
I
H
H
H
N
H
O
H
+
N
I
I
3
Me
2
H
I
I
O
I
H
H
H
H
H
O
O
O
H
H
1+5a
O
N
N
Me
(5a)2@C6
[5a+2+3]@C5
2 + 3
N
O
Me
O
H
H
N
1
H
4
O
I
H
Figure 6. ESI‐FTICR mass spectra of: a) a 250 μM solution of 1 in water-
saturated CHCl3, b) after addition of stoichiometric amounts of 5a, c) mixture in
(b) in the presence of 2 and 3 (same reaction conditions), Experimental patterns
I
H
H
O
5a@C5
of d) [(5a)2@15]2+, e) [(5a)2@16]2+, and f) [5a@15]2+
.
Scheme 2. Proposed mechanism for the Michael reaction in Scheme 1 through
the formation of the pentameric capsule C5 as extrapolated by QM calculations,
DOSY, and HR FTICR ESI MS studies in Figure 6.
The kinetic profile in the presence of catalysts 5a,b shows
different reaction courses. In detail, bromine-based catalyst 5b
led to a conversion of 45% after 16 hours (Figure 5c, blue line).
Regarding catalyst 5a, the kinetic profile of the reaction (Figure
5c, orange line) shows a sigmoidal shape (analogously for 5h) in
which an initial lag-phase (for the first 2 h) is followed by a strong
increase in the reaction rate. Thus, an 80% conversion in product
was observed after 4 h, while during the remaining 12 h another
18% of conversion was collected. Probably, the formation of a
stable, catalytically less active complex (e.g.: 5a+2@C5 or 4@C5)
could be envisioned in order to explain the plateau observed after
4h in the kinetic profile of 5a (Figure 5c, orange line). In conclusion,
in accord with the QM calculations, the halogen bonding
interaction plays a pivotal role in the activation of the carbonyl
group of 3.
Conclusion
In conclusion, by analyzing both the experimental and in-
silico results, we can conclude that the studied Michael reaction
can occur in a nanoconfined space through the activation of the
electrophile 3 by XB interactions with the p-iodophenyltrimethyl-
ammonium co-catalyst, with the additional assistance of HB
interactions with the bridging water molecules. Quantum-
mechanical calculations strongly corroborated the presence of an
XB interaction between 5a–c and 3 in the nanoconfined space of
an open pentameric capsule. Here, the XB co-catalyst 5a is kept
inside through cation···π interactions with the π-electron-rich
cavity. Finally, evidences or the formation of a pentameric
resorcinarene capsule were obtained by DOSY studies and HR
FTICR ESI mass spectra.
As concerns the presence of the pentameric capsule, useful
insights in this aspect have been obtained by HR-FTICR-ESI
mass spectrometry (Figure 6). When resorcinarene 1 was ionized
with an ESI source in the absence of catalyst 5a, then only the
molecular peak of 1 at 1104.835 m/z was detected (Figure 6a).
Differently, when an equimolar mixture of resorcinarene 1 and
catalyst 5a was ionized with an ESI source according to the
conditions reported previously by Schalley and coworkers[22] then
the mass spectrum reported in Figure 6b was obtained. The
results in Figure 6b suggested that the organic cation of 5a
Halogen Bonding • Catalysis • Nanoconfined • Resorcinarene
Capsule
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Angewandte Chemie International Edition
RESEARCH ARTICLE
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Keywords: Halogen Bonding • Catalysis • Nanoconfined •
Resorcinarene Capsule
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Angewandte Chemie International Edition
RESEARCH ARTICLE
RESEARCH ARTICLE
Closer
and
stronger.
The
Pellegrino La Manna, Margherita De
Rosa, Carmen Talotta,* Antonio
Rescifina,* Giuseppe Floresta,
Annunziata Soriente, Carmine Gaeta,*
and Placido Neri
amplification of the halogen bonding in
a small space introduced by Rebek in
2013 is here exploited for the activation
of the methyl vinyl ketone in a Michael
reaction. The reaction occurs in the
Page No. – Page No.
nano-confined
space
of
a
recorcinarene capsule where the XB
catalyst is effective. No reaction occurs
in the bulk medium in absence of
capsule.
Synergic Interplay Between Halogen
Bond and Hydrogen Bond in the
Activation of a Neutral Substrate in a
Nanoconfined Space
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