Macrocycle-Enabled Counteranion Trapping for Improved Catalytic Efficiency

Article abstract of DOI:10.1002/chem.201800326

The tight host–guest binding enabled by functional macrocycles can be utilized to tune catalysis. While the strong crown ether–cation complexation has been widely applied on enhancing the reactivity of the paired anion, the complementary strategy by applying a macrocyclic anion receptor to trap a counteranion to improve the cation catalytic activity remains unexplored. To realize this strategy, a macrocycle incorporating multiple cooperative H-bonding sites was synthesized and shown to tightly trap ethanedisulfonate anion in crystals and in acetonitrile solution (K>10⁶ m^?1). With the strong binding tendency, the presence of as low as 0.25 mol % of the macrocycle can significantly improve the ethanedisulfonic acid-catalyzed Povarov reaction efficiency, while the acyclic analogues had diminished effect. Catalysis outcomes and binding studies taken together suggested the macrocycle promotion was through favoring the substrate protonation by trapping the counteranion of the acid catalyst.

Full text of DOI:10.1002/chem.201800326

A Journal of
Accepted Article
Title: Macrocycle-Enabled Counteranion Trapping for Improved
Catalytic Efficiency
Authors: Rui Ning, Yu-Fei Ao, De-Xian Wang, and Qi-Qiang Wang
This manuscript has been accepted after peer review and appears as an
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To be cited as: Chem. Eur. J. 10.1002/chem.201800326
Link to VoR: http://dx.doi.org/10.1002/chem.201800326
Supported by

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COMMUNICATION
Macrocycle-Enabled Counteranion Trapping for Improved
Catalytic Efficiency
Rui Ning,[a,b] Yu-Fei Ao,[a] De-Xian Wang,[a,b] and Qi-Qiang Wang*[a,b]
Abstract: The tight host-guest binding enabled by functional
macrocycles can be utilized to tune catalysis. While the strong crown
ether-cation complexation has been widely applied on enhancing the
reactivity of the paired-anion, the complementary strategy by
applying a macrocyclic anion receptor to trap a counteranion to
improve the cation catalytic activity remains unexplored. To realize
this strategy, a macrocycle incorporating multiple cooperative H-
bonding sites was synthesized and shown to tightly trap
ethanedisulfonate anion in crystals and in acetonitrile solution (K >
106 M-1). With the strong binding tendency, the presence of as low
as 0.25 mol% of the macrocycle can significantly improve the
ethanedisulfonic acid-catalyzed Povarov reaction efficiency, while
the acyclic analogues had diminished effect. Catalysis outcomes and
binding studies taken together suggested the macrocycle promotion
was through favoring the substrate protonation by trapping the
counteranion of the acid catalyst.
cation can be simply a proton). Stimulated by the recent
progress on anion coordination chemistry,[11] we envisioned that
if we can design and incorporate a macrocyclic anion receptor
with high binding affinity in a catalysis system to realize this
strategy, and specifically to improve catalytic efficiency through
trapping an indirect counteranion. Herein we reported the
synthesis, binding studies and significant promotion effect of a
bi-thiourea macrocycle on acid-catalyzed Povarov reactions.
With a strong binding (up to 106 M-1) towards ethanedisulfonate
counteranion, the presence of as low as 0.25 mol% of the
macrocycle can improve the reaction yields from <10% to over
90% in most cases, while the acyclic mono-thiourea analogue
has little effect.
In the past decades the tremendous development of
supramolecular
chemistry
has
provided
abundant
supramolecular scaffolds and noncovalent tools to boost
catalysis process, and has led to the emergence of
supramolecular catalysis.[1] Among which various macrocyclic
compounds have been widely used and played a vital role. On
one hand, many cavity-containing macrocycle and cage
compounds including cyclodextrin,[2] cucurbiturils,[3] cavitands,[4]
calixarenes[5] and hemicryptophanes[6] can serve as a catalysis
vessel to accommodate reaction substrates within their confined
cavitties and facilitate otherwise unfavored transformations in
bulk solutions. On the other hand, the macrocycle-enabled high
binding affinity towards certain guests can be utilized to mediate
a catalysis process through tightly binding an “indirect” catalytic
species, e.g. counterions. In this context, the strong crown ether-
cation complexation has been widely used not only on phase-
transfer catalysis[7] by bringing the inslouble alkali metal salts
across the phase interface, but also to yield activated anions
(e.g. “naked” F-) with increased nucleophilicity,[8] and even to
realize stereoselectivity control[9,10] (Scheme 1a). Surprisingly,
Scheme 1. Macrocycle-enabled counterion trapping strategies for tuning
(catalytic) reactivity.
As containing two mini-chelating H-bonding donors, thioureas
are good anion binding groups and usually have a greater
binding ability than ureas due to the increased acidity.[12] We
chose to incorporate two diarylthiourea units into a macrocyclic
motif to take advantage of the macrocyclic cooperativity
(Scheme 2). The introduction of electron-withdrawing CF3
groups can further increase the N-H acidity and also the
structural rigidity for better preorganization (via facilitating
intramolecular phenyl C-H∙∙∙S H-bonding formation).[13] The
resorcinol connection could provide additional C-H H-bonding
sites. The synthesis of the macrocycle 5 was straightforward and
gram-scale preparation can be easily realized (Scheme 2). By
reacting resorcinol with two equivalents of 3-nitro-5-
trifluoromethylbenzyl bromide 1 followed by nitro reduction, the
diamine 3 was obtained and can be further converted to
diisothiocyanate 4 in high yields. The macrocyclization between
3 and 4 in pyridine readily provided the macrocycle product 5 in
59% yield. The crystal structure showed the macrocycle
possesses an overall planar conformation (Figure 1a). The two
thiourea groups align in parallel and each forms a pair of
bifurcated H-bonds with a solvent acetone molecule. This
alignment permits only one thiourea group pointing inward the
macrocyclic cavity while the other flipping out. The resorcinol
connections are nonsymmetric as well by inward/outward -
OCH2- orientation on each side. However, the macrocycle
should enjoy the conformation flexibility as in solution only one
simple set of 1H and 13C NMR signals exist.
the complementary strategy, for example, applying
a
macrocyclic anion receptor to trap counteranion and
a
accordingly to tune the cation-directed catalysis process, as far
as we know remains unexplored probably due to the complexity
on anion binding and catalysis intergration (Scheme 1b, the
[a]
Mr. R. Ning, Dr. Y.-F. Ao, Prof. Dr. D.-X. Wang, Prof. Dr. Q.-Q.
Wang
Beijing National Laboratory for Molecular Sciences, CAS Key
Laboratory of Molecular Recognition and Function
Institute of Chemistry, Chinese Academy of Sciences
Beijing 100190, China
E-mail: qiqiangw@iccas.ac.cn
[b]
Mr. R. Ning, Prof. Dr. D.-X. Wang, Prof. Dr. Q.-Q. Wang
University of Chinese Academy of Sciences
Beijing 100049, China
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201800326
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COMMUNICATION
The binding affinities of the macrocycle 5 towards different
sulfonates were then investigated in solution (Table 1). As
shown by 1H NMR titrations in CD3CN (Figure S1), upon addition
of ethanedisulfonate (as TBA+ salt), the thiourea proton signal
underwent large downfield shift (Δδmax = 2.1 ppm), consistent
with strong H-bonding interactions. The signals for the inner
resorcinol protons and one set CF3-phenyl protons also showed
significant downfield shifts, suggesting cooperative or concurrent
H-bonding. Upon complexation a large downfield shift (1.3 ppm)
for ethanedisulfonate CH2 signal was also observed. As the
binding affinity is too large to be measured by NMR, it was then
determined by isothermal titration calorimetry (ITC) with an
apparent binding constant of 2.1 × 106 M-1. The affinity is
extremely high especially considering the competitive polar
solvent acetonitrile was used.[12] The macrocycle shows much
weaker binding towards methylenedisulfonate (26 times weaker)
and methanesulfonate (270 times weaker) (Table 1), once again
showcasing the power of complementary binding enabled by
macrocyclic motif with multiple functionality intergration.
Scheme 2. Synthesis of the macrocycle 5.
Table 1. Binding constants K [M-1] [a] of 5-8 with different sulfonate anions.
-
-
-
With the multiple H-bonding sites existed, the macrocycle
would be suitable to bind polydentate sulfonates, which
represent an important class of anions and serve as
counteranions in many protonic and Lewis acid catalysts.[14] To
CH3SO3
-O3SCH2SO3
-O3SCH2CH2SO3
5
6
7
8
7.8 × 103
2.4 × 103
1.8 × 103
7.7 × 103
7.9 × 104 [b, c]
3.0 × 105 [b]
3.0 × 104
2.1 × 106 [b, c]
9.6 × 104 [b]
4.8 × 103
8.1 × 104
2.9 × 104
-
our delight a complex crystal structure of [5•-O3SCH2CH2SO3
][Et4N+]2 was obtained (Figure 1 b,c). The ethanedisulfonate
anion is tightly trapped within the nearly-planar macrocyclic
cavity. It enjoys mulitiple interactions including two pairs of
strong bifurcated H-bonds with the two now inwardly-orientated
thioureas (N-H∙∙∙O distances of about 2.87 Å) and six weak H-
bonds with the phenyl and methylene protons. This convergent
interaction motif highlights the importance of macrocyclic
cooperativity on binding.
[a] Determined by 1H NMR titrations in CD3CN at 298 K (errors <10 %). Anions
were used as TBA+ salts. [b] Determined by ITC in CH3CN as beyond NMR
detectability. [c] Apparent stepwise binding constant for the 2:1 L:A binding.
With the very strong binding of ethanedisulfonate enabled by
the macrocycle 5, we envisioned this system can be
incorporated with acid-catalyzed reactions, for example, to trap
the counteranion of a acid catalyst and hence improve the
“proton” catalytic efficiency. The acid-catalyzed Povarov reaction
between benzylidene aniline 9a and 2,3-dihydrofuran 10, which
represents one of the most convenient synthetic routes to
various tetrahydroquinolines,[15] was then investigated. Polar
solvent acetonitrile was used as on one hand to ensure the
strong binding as above evaluated, and on the other hand to
inhibit ion-pair formation which may complicate the situation.[15c]
As shown in Table 2, the presence of 0.25 mol%
ethanedisulfonic acid (EDSA) catalyzed the reaction with only
7% yield in 40 min (entry 1). Strikingly, the co-existence of as
low as 0.25 mol% macrocycle 5 dramatically increased the yield
to 94% on the same duration (Table 2, entry 2). The macrocycle
itself, however, didn’t show any catalytic activity within 48 h. To
elucidate the macrocycle effect, acyclic analogues 6 and 7 (for
synthesis, see Supporting Information), and the privileged
Schreiner’s thoiurea 8[16] were also applied in the reactions.
While 7 had little effect, 8 and 6 showed some extent of
promotion but all significantly less than the macrocycle 5 (Table
2, entries 3-5). The reaction kinetics clearly showed the
promotion effect follows the order of 5 > 6 > 8 > 7 (Figure 2), in
line with their binding affinity sequence towards the
Figure 1. Crystal structures of (a) 5•2CH3COCH3 and (b, c) [5•-
-
O3SCH2CH2SO3 ][Et4N+]2. In (b, c) Et4N+ counterions are omitted for clarity. H-
bonding distances: in (a) N1-H∙∙∙O6, 2.842; N2-H∙∙∙O6, 2.902; N3-H∙∙∙O5,
2.960; N4-H∙∙∙O5, 2.968 Å; in (b) N1-H∙∙∙O5, 2.875; N2-H∙∙∙O5, 2.867; C14-
H∙∙∙O3, 3.553; C7-H∙∙∙O3, 3.524; C1-H∙∙∙O4, 3.401 Å.
ethanedisulfonate
counteranion
(Table
1).
When
methylenedisulfonic acid (MDSA) was used as acid catalyst, the
macrocycle still showed the most pronounced promotion, albeit
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10.1002/chem.201800326
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100%
80%
60%
40%
20%
0%
a longer period required to complete the reactions (Table 2,
entries 6-10). As from the binding studies the macrocycle
showed some weaker binding towards methylenedisulfonate
than the acyclic bi-thiourea 6 (Table 1), the outstanding
promotion effect could be due to the macrocyclic motif can
provide a tighter surrounding to accommodate the counteranion
to minimize its interference on the catalytic process. For
methanesulfonic acid (MSA) catalyzed reactions, both the
macrocycle 5 and acyclic analogues 6-8 showed little promotion
effects (Table 2, entries 11-15). This was not difficult to
understand as all of them displayed significantly weaker and no
much difference of binding towards the counteranion
methanesulfonate (Table 1).
5
6
7
8
none
0
10
20
30
40
Time (min)
Figure 2. Reaction progress for the conversion of 9a monitored by 1H NMR for
EDSA-catalyzed Povarov reactions in the presence of 5-8 in CD3CN. For the
reaction conditions, see Table 2 (entries 1–5).
Table 2. Macrocycle promotion on acid-catalyzed Povarov reactions
comparing with acyclic analogues.[a]
improved the catalytic efficiency, while the acycle 7 had little
effects (Table 3). The macrocycle-promoted catalytic reactions
can be scaled-up as shown for one case 10-times scaling-up
went smoothly without loss of efficiency (Table 3, entry 3). The
supramolecular catalysis system can be also applied to three-
component Povarov reactions[17] where the macrocycle
promotion also stood out (Table S3).
Table 3. Macrocycle promotion on EDSA-catalyzed Povarov reactions with
different imine substrates.[a]
Entry
Acid[b]
Thiourea
Time
Yield [%][c]
1
2
3
4
5
EDSA
EDSA
EDSA
EDSA
EDSA
-
40 min
40 min
40 min
40 min
40 min
7
5 (0.25 mol%)
6 (0.25 mol%)
7 (0.5 mol%)
8 (0.5 mol%)
94
53
9
Yield of 11 [%][b]
Entry
9
R1, R2
Time
20
None
With 5
With 7
6
7
8
9
10
MDSA
MDSA
MDSA
MDSA
MDSA
-
1.5 h
1.5 h
1.5 h
1.5 h
1.5 h
9
5 (0.25 mol%)
6 (0.25 mol%)
7 (0.5 mol%)
8 (0.5 mol%)
87
45
13
49
1
2
3
4
5
6
7
8
9b
9c
9d
9e
9f
H, Br
0.5 h
3 h
6
89
8
H, CH3
H, NO2
H, OCH3
Br, H
19
2
95
95, 92[c]
30
3
0.25 h
8 h
14
9
75
25
11
29
16
23
11
12
13
14
15
MSA
MSA
MSA
MSA
MSA
-
1 h
1 h
1 h
1 h
1 h
77
86
85
81
88
0.5 h
2 h
90
5 (0.25 mol%)
6 (0.25 mol%)
7 (0.5 mol%)
8 (0.5 mol%)
9g
9h
9i
CH3, H
NO2, H
OCH3, H
17
15
13
90
3 h
50
5 h
81
[a] All the reactions were carried out at rt with 9a (0.2 mmol) and 10 (0.4
mmol). [b] Acid loading: EDSA (0.25 mol%), MDSA (0.25 mol%), MSA (0.5
mol%). [c] Determined by 1H NMR using 1,3,5-trimethoxybenzene as an
internal standard. Endo- and exo-forms of products were obtained in ca. 1:1
ratios.
[a] All the reactions were carried out at rt with 9b-i (0.2 mmol) and 10 (0.4
mmol) unless otherwise stated. [b] Determined by 1H NMR using 1,3,5-
trimethoxybenzene as an internal standard. Endo- and exo-forms of products
were obtained in ca. 1:1 ratios. [c] Isolated yield for 10-times scaling-up
reaction.
The above results clearly illustrated the macrocycle 5 had a
dramatic promotion effect on the EDSA-catalyzed reactions. To
demonstrate the generality of this strategy, a series of N-aryl
imine substrates with versatile electron-demanding properties
were applied (Table 3). For each substrate, three parallel
reactions in the absence of any thiourea, in the presence of 0.25
mol% macrocyle 5 and 0.5 mol% acyclic mono-thiourea 7 were
performed. Although the intrinsic reactivity for each substrate
varies (Table S2), in all cases the macrocycle 5 significantly
Further experiments were performed to shed more light on the
macrocycle promotion effect. Firstly, the effect of the macrocycle
binding on the pKa of ethanedisulfonic acid was investigated.
Ethanedisulfonic acid itself showed a moderate acidity (pKa1
=
7.6, pKa2 = 12.0) as measured in the reaction solvent acetonitrile
(Supporting Information). The strong binding tendancy of the
counteranionic species specially ethanedisulfonate dianion by
the macrocycle caused significant supramolecular complexation-
induced pKa shifts[18] as large as ‒1.6 (ΔpKa1 ) and ‒3.0 (ΔpKa2)
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10.1002/chem.201800326
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(Supporting Information). Hence the trapping of the counteranion
led to an unusual large acidity enhancement. Secondly, the
effect of the counteranion trapping-induced acidity enhancement
on substrate imine protonation was explored. Based on NMR
studies, the protonation of the imine 9a in CD3CN is fast but
incomplete with equivalent proton source existed (0.5 eq.
ethanedisulfonic acid). The presence of the macrocycle
promoted the imine protonation to a more significant extent
under the same condition while accompanied by the
ethanedisulfonate counteranion trapping within the macrocyclic
cavity (Supporting Information). On the other hand, however, the
presence of acyclic mono-thiourea 7 didn’t show any significant
influence on the imine protonation. As the protonated imine is
the catalytic resting state for the reaction[15c] and hence its
enrichment by the supramolecular counteranion trapping would
promote the conversion (Figure 3).
Keywords: supramolecular catalysis • macrocyclic compounds •
anion binding • counteranion trapping • Povarov reactions
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Figure 3. Schematic representation of macrocycle-enabled counteranion
trapping for promoting the EDSA-catalyzed Povarov reaction by favoring the
imine protonation.
In conclusion, a macrocycle-enabled counteranion trapping
supramolecular catalysis strategy has been demonstrated.
Taking advantage of the very strong binding enabled by the
designed bi-thiourea macrocycle with multiple and convergent
H-bonding sites, the counteranion of ethanedisulfonic acid can
be tightly trapped and led to a significant complexation-induced
acidity enhancement. When the supramolecular binding system
was integrated with the acid-catalyzed Povarov reactions as
shown in the current example, the use of as low as 0.25 mol%
macrocycle dramaticly improved the catalytic efficiency. The
acyclic mono-thiourea analogue, however, had little effect, thus
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believe this macrocycle-enabled counteranion trapping strategy
could be also general and can find applications on boosting
many cation-directed catalytic transformations. The utilization of
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Acknowledgements
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Financial supports from National Natural Science Foundation of
China (21502200, 91427301, 21521002) and Chinese Academy
of
Sciences
(QYZDJ-SSW-SLH023)
are
gratefully
acknowledged. Q.-Q. Wang also thanks the Thousand Young
Talents Program for the support.
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10.1002/chem.201800326
Chemistry - A European Journal
COMMUNICATION
COMMUNICATION
Rui Ning, Yu-Fei Ao, De-Xian Wang, and
Qi-Qiang Wang*
Page No. – Page No.
Macrocycle-Enabled Counteranion
Trapping for Improved Catalytic
Efficiency
A macrocycle-enabled counteranion trapping supramolecular catalysis strategy was
developed as demonstrated by using as low as 0.25 mol% of a high-binding
macrocycle to significantly promote acid-catalyzed Povarov reactions. The
macrocycle promotion was through favoring the imine protonation pre-equilibrium
by tightly trapping the counteranion of the acid catalyst.
This article is protected by copyright. All rights reserved.