Anion-π catalysis

Article abstract of DOI:10.1021/ja412290r

The introduction of new noncovalent interactions to build functional systems is of fundamental importance. We here report experimental and theoretical evidence that anion-π interactions can contribute to catalysis. The Kemp elimination is used as a classical tool to discover conceptually innovative catalysts for reactions with anionic transition states. For anion-π catalysis, a carboxylate base and a solubilizer are covalently attached to the π-acidic surface of naphthalenediimides. On these π-acidic surfaces, transition-state stabilizations up to ΔΔG_TS = 31.8 ± 0.4 kJ mol^-1 are found. This value corresponds to a transition-state recognition of K_TS = 2.7 ± 0.5 μM and a catalytic proficiency of 3.8 × 10⁵ M^-1. Significantly increasing transition-state stabilization with increasing π-acidity of the catalyst, observed for two separate series, demonstrates the existence of "anion-π catalysis." In sharp contrast, increasing π-acidity of the best naphthalenediimide catalysts does not influence the more than 12 000-times weaker substrate recognition (K_M = 34.5 ± 1.6 μM). Together with the disappearance of Michaelis-Menten kinetics on the expanded π-surfaces of perylenediimides, this finding supports that contributions from π-π interactions are not very important for anion-π catalysis. The linker between the π-acidic surface and the carboxylate base strongly influences activity. Insufficient length and flexibility cause incompatibility with saturation kinetics. Moreover, preorganizing linkers do not improve catalysis much, suggesting that the ideal positioning of the carboxylate base on the π-acidic surface is achieved by intramolecular anion-π interactions rather than by an optimized structure of the linker. Computational simulations are in excellent agreement with experimental results. They confirm, inter alia, that the stabilization of the anionic transition states (but not the neutral ground states) increases with the π-acidity of the catalysts, i.e., the existence of anion-π catalysis. Preliminary results on the general significance of anion-π catalysis beyond the Kemp elimination are briefly discussed.

Full text of DOI:10.1021/ja412290r

Article
pubs.acs.org/JACS
Anion−π Catalysis
Yingjie Zhao, Cesar Beuchat, Yuya Domoto, Jadwiga Gajewy, Adam Wilson, Jiri Mareda, Naomi Sakai,
́
and Stefan Matile*
Department of Organic Chemistry, University of Geneva, Geneva, Switzerland
S
* Supporting Information
ABSTRACT: The introduction of new noncovalent interactions to build functional
systems is of fundamental importance. We here report experimental and theoretical
evidence that anion−π interactions can contribute to catalysis. The Kemp elimination is
used as a classical tool to discover conceptually innovative catalysts for reactions with
anionic transition states. For anion−π catalysis, a carboxylate base and a solubilizer are
covalently attached to the π-acidic surface of naphthalenediimides. On these π-acidic
surfaces, transition-state stabilizations up to ΔΔGTS = 31.8 0.4 kJ mol−1 are found. This
value corresponds to a transition-state recognition of KTS = 2.7 0.5 μM and a catalytic
proficiency of 3.8 × 105 M−1. Significantly increasing transition-state stabilization with
increasing π-acidity of the catalyst, observed for two separate series, demonstrates the
existence of “anion−π catalysis.” In sharp contrast, increasing π-acidity of the best
naphthalenediimide catalysts does not influence the more than 12 000-times weaker substrate recognition (KM = 34.5 1.6 μM).
Together with the disappearance of Michaelis−Menten kinetics on the expanded π-surfaces of perylenediimides, this finding
supports that contributions from π−π interactions are not very important for anion−π catalysis. The linker between the π-acidic
surface and the carboxylate base strongly influences activity. Insufficient length and flexibility cause incompatibility with
saturation kinetics. Moreover, preorganizing linkers do not improve catalysis much, suggesting that the ideal positioning of the
carboxylate base on the π-acidic surface is achieved by intramolecular anion−π interactions rather than by an optimized structure
of the linker. Computational simulations are in excellent agreement with experimental results. They confirm, inter alia, that the
stabilization of the anionic transition states (but not the neutral ground states) increases with the π-acidity of the catalysts, i.e.,
the existence of anion−π catalysis. Preliminary results on the general significance of anion−π catalysis beyond the Kemp
elimination are briefly discussed.
quadrupole moments can vary significantly with the method of
calculation used. However, the relative trends are always the
same.
INTRODUCTION
■
The underappreciation of anion−π interactions is under-
standable.1−9 Classical aromatic rings are characterized by
clouds of π electrons that accumulate above and below the
plane of the atoms in the ring. The resulting negative
quadrupole moments Qzz < 0 are characteristic for π-basic
aromatics and compatible with the interaction with cations
rather than anions (Figure 1a). Benzene, for example, has a
quadrupole moment of −9 Buckinghams (Qzz = −9 B, Figure
1c). To invert the intrinsic negative quadrupole moment of
aromatic rings, strongly withdrawing substituents are needed.
The resulting π-acidic aromatics with Qzz > 0 have an electron-
poor surface that should, in principle, attract anions (Figure
1b). The arguably most popular example for π-acidic aromatics
is hexafluorobenzene with Qzz = +10 B (Figure 1d). Early on,
we realized that naphthalenediimides (NDIs)4 would be ideal
to study anion−π interactions because their quadrupole
moments are very large.5 Already the native NDI has with
Qzz = +19 B a quadrupole moment that is in the range of TNT
(Figure 1e).5 The introduction of two cyano groups in the NDI
core gives with Qzz = +39 B the strongest π-acid known today
(Figure 1f).6 Four cyano groups should provide access to Qzz =
+55 B, but the synthesis of these super-π-acids has so far not
been successful, their aromatic core is probably too electron
deficient to exist (Figure 1g).6,7 The magnitude of these
The quadrupole moments of NDIs with sulfides and
sulfoxides in the core have not been calculated so far because
of open questions concerning their axial symmetry.8,9 However,
the higher energy of their LUMO at −3.93 eV compared to
−4.31 eV of unsubstituted NDIs implies that electron-donating
sulfide substituents reduce the π-acidity of these NDIs (Figure
1i).8 Qzz = +8 B with alkoxy and Qzz = +2 B with alkylamino
substituents in the core demonstrate that NDIs with sulfides in
the core remain π-acidic.10 NDIs with sulfides in the core are
interesting because their oxidation to sulfoxides and sulfones
converts the π-donors into π-acceptors.8 The drop of their
LUMO energy level from −3.93 eV to −4.46 eV in response to
sulfide oxidation suggests that the π-acidity with two sulfoxides
in the core should be localized between that of native and
dicyano NDIs (Figure 1j).8 Because the effect of the imide
acceptors is diluted over a larger surface, the LUMO energy
level of native perylenediimides (PDIs)11 is with −4.20 eV
above that of native NDIs at −4.31 eV (Figure 1h).4 This
suggests that compared to NDIs, anion−π interactions with
Received: December 6, 2013
Published: January 23, 2014
© 2014 American Chemical Society
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attention.17 Moreover, reports on catalysis with halogen
bonds12,18 and new aspects of dynamic covalent bonds19
continue to emerge. Building on a recent communication of
preliminary results,20 we here report experimental and
theoretical evidence that anion−π interactions can contribute
to catalysis.
RESULTS AND DISCUSSION
■
Initial Results.20 The Kemp elimination was selected for
initial studies on possible contributions of anion−π interactions
to catalysis. This choice was made because the Kemp
elimination has emerged as an ideal analytical tool to elaborate
on conceptually innovative catalysts.21 Examples include
theoretically designed enzymes, catalytic antibodies, promiscu-
ous proteins, synthetic polymers, macrocyclic model systems,
vesicles, micelles, and nonspecific medium effects. There is
consensus in the field that the Kemp elimination is completely
useless with regard to practical applications in organocatalysis.
However, this concern is obviously irrelevant for the topic of
this study.
Figure 1. Schematic side view of (a) π-basic and (b) π-acidic aromatic
rings (solid lines) with their electron-poor (blue) and -rich (red) π-
clouds, and (c−j) representative examples with their axial quadrupole
moments Qzz in Buckinghams B or their LUMO energy against −5.1
eV for Fc/Fc+.
The key to “anion−π catalysis” was to place a carboxylate
base on the π-acidic surface of catalyst C (Figure 2). With this
architecture, the onset of anion−π interactions could coincide
with the injection of the negative charge into the substrate. In
transition state TS, the negative charge could flow over the π-
acidic surface from the carboxylate base over the carbanion of
the conjugate base to the phenolate oxygen. Moreover, proton
PDIs should be weaker, whereas π−π interactions are much
stronger.
The first explicit theoretical considerations of interactions
between anions and π-acidic aromatics appeared about one
decade ago.1 Considering different ways anions can interact
with π-acidic aromatics, extensive discussions concerning the
exact nature of anion−π interactions continue today.2 Early on,
these theoretical studies could be supported by observations in
crystals, but proximity in the solid can originate from effects
other than anion−π interactions. It was quite difficult to
observe and characterize anion−π interactions in solution, and
they still remain somewhat elusive.3 Even harder to catch them
at work, direct experimental evidence for their functional
relevance was secured only 4 years ago.6 This breakthrough was
possible using synthetic transport systems as unique analytical
tools to elaborate on more elusive interactions such as anion−π
interactions or halogen bonds.6,8,12 Experimental evidence for
anion−π interactions at work in transport implied that they
should also be useful for catalysis. Stabilization of anions in the
ground state suggests that the same process can stabilize
anionic transition states. The perspective to use anion−π
interactions in catalysis was interesting. The complementary,
much more popular cation−π interactions13 have been
implicated in the stabilization of carbocation intermediates in
biosynthetic routes, including terpene cyclizations.14 Cation−π
interactions also have been used quite extensively in organo-
catalysis.15 In sharp contrast, anion−π interactions are
essentially16 unknown in catalysis.
The introduction of new interactions for the design of new
catalysts, or new functional systems in general, is of
fundamental importance. Simply speaking, hydrogen bonds,
hydrophobic interactions, π−π interactions, ion pairing, and
cation−π interactions can be considered as basic set available to
engineer interactions between and within molecules. In
organocatalysis, emphasis is on hydrogen bonds, sometimes
used in concert with hydrophobic contacts and π−π and
cation−π interactions.15 Ion pairing receives much current
Figure 2. Design of anion−π catalysts C emphasizes a carboxylate base
on a π-acidic surface to couple charge injection into the substrate S
with the onset of transition-state (TS) stabilization by anion−π
interactions and to prevent product inhibition (blue = electron
deficient, red = electron rich, CS = catalyst−substrate complex, RI =
reactive intermediate, CP = catalyst−product complex).
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transfer from the carboxylic acid to the phenolate in RI would
prevent product inhibition and regenerate the catalyst C.
Catalysis in its broadest sense is understood as transition-state
stabilization.22 Catalyst C, offers anion−π interactions to
stabilize the anionic transition state TS. Acceleration of the
Kemp elimination by catalyst C would, therefore, prove the
existence of anion−π catalysis.
To elaborate on these expectations, catalyst 1 was
synthesized first (Figure 3). A carboxylate base and a
Figure 4. Optimized structures (IEFPCM/B97-D/6-311G**) of most
significant low energy catalyst−substrate complexes.
(Figure 4). Already in the early stage of the reaction, i.e., in
catalyst−substrate complex CS1, the carboxylate anion is
positioned so that efficient intramolecular anion−π interactions
with the most π-acidic part of NDI surface can take place. The
coplanar arrangement between the carboxylate and NDI planes,
apart by 3.035 Å, suggests a contribution also from π−π
interactions. The carboxylate anion of the catalyst also plays a
role in anchoring the benzisoxazole substrate above the NDI
surface via two C−H···O interactions (1.887 and 2.218 Å,
respectively), therefore favoring the π−π interactions between
the two coplanar aromatic systems. This perfectly sets the stage
for the proton transfer between the catalyst and the substrate,
leading eventually to early transition state TS1 with the
activation barrier of 62.9 kJ mol−1 (Figure 5a). At this stage the
electron transfer occurring over several atoms from carboxylate
anion to phenolate oxygen is efficiently stabilized by the π-
acidic surface of NDI. In accordance with the anion−π
stabilization, the buildup of negative charge of phenolate
oxygen, which effectively doubles to −0.3672, is accompanied
Figure 3. Structure of catalysts 1 and 2.
solubilizing alkyl tail are attached to a π-acidic surface of NDI
1. Contrary to all controls, catalyst 1 showed saturation
behavior. Michaelis−Menten analysis22 gave a ground-state
stabilization of ΔΔGGS = 6.2 0.2 kJ mol−1 and a transition-
state stabilization of ΔΔGTS = 28.3
corresponds to a transition-state recognition of KTS = 10.9
1.6 μM in MeOH/CHCl3 1:1.
If anion−π interactions indeed stabilize the transition state of
the Kemp elimination, increasing π-acidity should result in
increasing activity. Catalyst 2 is identical with catalyst 1 except
for the two cyano substituents in the NDI core. This increase in
π-acidity without global structural change gave a transition-state
stabilization of ΔΔGTS = 30.3 0.4 kJ mol−1. An increase of
ΔΔΔGTS = 2.0 kJ mol−1 was exactly as expected for
strengthened anion−π interactions in the transition state
stabilized by catalyst 2.
Theoretical Considerations. We have examined the most
important aspects of the anion−π catalyzed Kemp elimination
by theoretical DFT calculations using the well-tested and
dispersion-corrected B97-D functional.23 While B97-D func-
tional provides good geometries, binding energies of complexes
are often overestimated. Therefore for energy calculations we
used M06-2X meta-hybrid functional,24 which provide good
results for both thermodynamics as well as kinetics. For all
calculations the solvation by chloroform was taken into account
with IEFPCM model.25 For modeling purposes, the structures
of catalysts 1 and 2 were simplified by removing the solubilizing
alkyl tails with R1 = CH3, R2 = H (Figure 3). The Leonard
linker connecting the carboxylate base to NDI of catalysts 1 and
2 breaks the symmetry of complexes between the catalyst and
benzisoxazole. Therefore the two different orientations of
benzisoxazole S can occur within the catalyst−substrate
complex, leading to the isomers CS1 and CS1′ where the
orientation of benzisoxazole S is inversed (Figure 4). Because
of asymmetric character of the linker and substrate, one must
also distinguish between two different dicyano-substitution
patterns for the naphthyl core: the formally 3,7-dicyano- and
2,6-dicyano-substituted complexes CS2 and CS2′, respectively
(Figure 4).
0.4 kJ mol−1. This
Figure 5. (a) Free energy diagram (IEFPCM/M06-2X/def2-TZVP//
IEFPCM/B97-D/6-311G**) for the Kemp elimination with anion−π
catalyst 1 (in red) and 2 (in blue). (b) Optimized structure of the
transition state (TS2) for the reaction catalyzed by catalyst 2, negative
charge transfer is highlighted in red. (c) Axial view of TS2 showing
optimal overlap of centers where the electron transfer takes place with
the preferential binding sites (in blue) of π-acidic NDI.
Among all possible structures of the initial catalyst−substrate
complexes, CS1 and CS2 proceed with the lowest-energy
pathways toward the transition state of the Kemp elimination
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by decreasing distance of the oxygen atom from the NDI
surface going from 3.276 to 3.202 Å.
removed keeping only the substrate and the N,N-dimethyl
NDI, as a simplified surrogate for the catalyst. The overall
structure of this model complex was constrained in the
geometry of the corresponding transition state (TS1 or TS2),
while the interaction energy was computed with the BSSE
correction. For the neutral complex between the benzisoxazole
and N,N-dimethyl-3,7-dicyano NDI, the computed binding
energy of −32.4 kJ mol−1 is mostly reflecting the π−π
interactions (Figure 6a, entry 2). When in the neutral complex
The NDI catalyst is ideally suited for the charge injection
into substrate since it can simultaneously accommodate the
carboxylate and the phenolate oxygen, both overlapping with
the distinct preferential binding sites (blue spots in Figure 5c).
Such sites have been identified for NDI−halide anionic
complexes,6 knowing that in general for π-acidic aromatic
systems the totality of their surface can interact favorably with
anions.26 The reaction progresses toward the anionic
intermediate RI1, while the negative charge is fully transferred
to the benzisoxazole substrate. The benzisoxazole oxygen
accumulates most of the charge (−0.6456), while its distance
from the NDI surface further decreases to 2.995 Å. The
conformation of this complex once again favors anion−π
interactions by placing the anionic oxygen right above the
preferential binding site of NDI, therefore stabilizing the
complex.
The Kemp elimination in the presence of the 3,7-dicyano-
substituted catalyst 2 follows a similar pathway as with catalyst
1. However, the increased π-acidity enhances the TS2
transition-state stabilization by 4.4 kJ mol−1 when compared
to TS1 (Figure 5a). While the energy differences are quite
small, this stabilization is only about 2.4 kJ mol−1 stronger than
what was experimentally measured for catalyst 220 and the
sulfoxide-substituted catalyst 4 (see below). Convincing
stabilization enhancement of TS2 by more π-acidic NDI
surface of 2 confirms that anion−π interactions contribute
significantly to this reaction. As was the case for TS2, the
reaction is again favored by perfect alignment of the negative
charge transfer between the carboxylate base and substrate and
preferential binding sites of the π-acidic surface of NDI in the
TS2 (Figure 5c). The evolution of certain geometric
parameters during the reaction mechanism involving catalyst
2 also reflects enhanced anion−π implication; namely the more
pronounced decrease of the distance between benzisoxazole
oxygen and NDI plane from 3.154 Å in CS2 to 3.046 Å in TS2
to contract finally to 2.804 Å in RI2 and is correlated with the
negative charge buildup of −0.455 on the phenolate oxygen.
When compared to mechanism involving less π-acidic catalyst
1, yet another structural difference is the slight reduction of
interplanar distances between the two π-systems; for transition
states by 0.032 Å and for reactive intermediates by 0.026 Å.
It is also noteworthy to mention that the potential energy
surfaces showed slightly higher activation barriers for Kemp
elimination in case of structures where benzisoxazole was
inverted in substrate−catalyst complexes (see the conformer
CS2′ in Figure 4). Nevertheless, the transition-state stabiliza-
tion of 1.7 kJ mol−1, upon dicyano substitution of the naphthyl
core, was also detected in such alternate conformation.
Interestingly enough the majority of conformers displayed
better overlap of benzisoxazole phenyl ring with NDI π-system
but only at the expense of slightly disfavoring the interactions of
benzisoxazole oxygen with the preferential binding site of NDI.
This could explain the slightly higher energy pathways for these
conformers since improved π−π interactions do not fully
compensate for weaker anion−π interactions. For the 2,6-
dicyano-substituted substrate−catalyst complex CS2′ (Figure
4), the activation barrier is also higher than for the 3,7-
disubstituted complex CS2 discussed above.
Figure 6. Model for transition-state complexes of (a) neutral and (b)
negatively charged complexes of benzisoxazole with N,N-dimethyl
NDI. For both unsubstituted and dicyano-substituted substrates the
BSSE corrected binding energies are computed with the IEFPCM/
M06-2X/Def2-TZVP method.
cyano substituents on the NDI are removed, the binding energy
increases by 1.9 kJ mol−1 (Figure 6a, entry 1). Remarkably,
upon dicyano NDI substitution of anionic complexes a
substantial increase of binding energy is noted. It increases
from −51.0 to −69.2 kJ mol−1, highlighting the anion−π
interaction enhancement with increased π-acidity of NDI
surface (Figure 6b, entries 3 and 4). This simplified model
confirms in a more prominent way the transition-state
stabilization occurring via anion−π interactions in a subtler
manner during the Kemp elimination catalyzed by 1 and 2.
Dependence of Anion−π Catalysis on π-Acidity. The
most convenient method to increase π-acidity without global
structural changes uses sulfide oxidation chemistry.8,9 With m-
chloroperbenzoic acid (MCPBA), sulfide donors can be
converted in situ into sulfoxide and sulfone acceptors. This
strategy has been used to build voltage-gated ion channels27
and to produce NDIs with maximal π-acidity under mild
conditions.8 To apply this strategy to anion−π catalysis, the
weakly π-acidic NDI 3 with two sulfides in the core was
envisioned (Figure 7). Oxidation under mild conditions will
afford the strong π-acid 4 with two sulfoxides in the core,
further oxidation would give two sulfones. Compared to the
introduction of cyano groups in catalyst 2, this approach was
attractive because the increase in π-acidity occurs with minimal
global structural change.
The synthesis of catalyst 3 from naphthalenedianhydride
(NDA) 5 was mostly straightforward (Scheme 1). Building on
experience with related systems, NDA 5 was brominated
first.4,28 The reaction mixture including the desired 2,6-
dibromo NDA 6 was used without further purification.
Reaction with the two amines 7 and 8 gave mixed NDI 9
together with the symmetrical side products. The bromo
substituents in the NDI core of 9 were finally replaced by
sulfides. This nucleophilic aromatic substitution with thioetha-
nol nicely illustrates the intrinsic π-acidity of the NDI core.
In order to appreciate binding energies at the transition state
of the Kemp elimination catalyzed by 1 or 2, we designed a
model system, where the carboxylate base and the linker were
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Figure 7. Structure of the catalysts 3 and 4. R1 and R2 as in Figure 3.
(a) MCPBA, CH2Cl2, 0 °C; and (b) MCPBA, CH2Cl2, room
temperature.
Figure 8. Initial velocity of product formation as a function of the
○
concentration of substrate S in the presence of 8.3 mM 3 ( ) and 4
●
( ); 5.0 mM TBAOH, CD3OD/CDCl3 1:1, room temperature; with
Michaelis−Menten curve fit.
a
Scheme 1. Synthesis of catalyst 3
formal dissociation constants of the transition states TS, i.e.,
KTS, were approximated with eq 2:
KTS = knonKM/kcat
(2)
where knon is the rate constant of the uncatalyzed Kemp
elimination under identical conditions (i.e., knon = (7.1 0.1) ×
10−8 s−1).20 From the dissociation constants of the transition
states KTS, the transition-state stabilizations ΔΔGTS were
readily approximated with eq 3:
ΔΔGTS = −RTln KTS
(3)
The ground-state stabilizations ΔΔGGS were approximated
analogously from KM. The results of the Michaelis−Menten
analysis for catalysts 3 and 4 are summarized in Table 1 and
Figure 9.
a
(a) Dibromoisocyanuric acid, H2SO4, rt, 12 h, 76%;4,28 (b) AcOH, 80
°C; (c) EtSH, 18-crown-6, K2CO3, CHCl3, 75 °C; (d) TFA, CH2Cl2.
Compared to the original NDI 1, the introduction of sulfide
π-donors in the core of NDI 3 increased the ground-state
stabilization by +2.1 kJ mol−1 (Table 1, entries 1 and 3). This
anticatalytic effect suggested that hydrophobic contacts with the
ethyl groups at the periphery are sufficient to overcompensate
weakened π−π interactions. This was the first indication that
changes in π-acidity influence π−π interactions much less than
anion−π interactions. The validity of this important conclusion
was nicely confirmed by the observation that, compared to NDI
1, the stabilization of the transition state by NDI 3 was with
+1.6 kJ mol−1 slightly weaker than that of the ground state
(Table 1, entries 1 and 3).
The increase in π-acidity upon oxidation of catalyst 3 to 4
caused an increase in transition-state stabilization by +1.9 kJ
mol−1 (Table 1, entries 3 and 4, Figure 9). In other words, the
recognition of the transition state increased from KTS = 5.7
0.4 μM for 3 to KTS = 2.7 0.5 μM for 4. This increase was
nearly the same as the one observed previously with catalysts 1
and 2 (+2.0 kJ mol−1, Table 1, entries 1 and 2). This finding
provided powerful corroborative evidence for the existence of
anion−π catalysis.
Most importantly, the increase in π-acidity from catalyst 3 to
4 did not cause an increase in ground-state stabilization (Table
1, entries 3 and 4, Figure 9). This finding was in sharp contrast
to the previously reported catalysts 1 and 2. In that system,
increasing transition-state stabilization by +2.0 kJ mol−1
coincided with increasing ground-state stabilization by +0.9 kJ
mol−1 (Table 1, entries 1 and 2). This ground-state stabilization
could originate from increasing π−π interactions with
increasing π-acidity or peripheral contacts with the added
Deprotection of the acid in NDI 10 afforded catalyst 3, which
could be oxidized to catalyst 4 with MCPBA at 0 °C. MCPBA
oxidation at room temperature lead directly to the correspond-
ing sulfone 11. Unfortunately, the NDI 11 with maximal π-
acidity could not be used for catalysis because of the onset of
competing, unidentified side reactions.
The influence of the π-acidic NDIs 3 and 4 on the kinetics of
1
the Kemp elimination was followed by H NMR spectroscopy
(Figure S1). This choice was important because one of the
advantages of the Kemp elimination is that it can be followed
1
by absorption spectroscopy. However, H NMR spectroscopy
was preferable because the higher concentrations needed under
routine conditions revealed saturation kinetics also for systems
with weak ground-state stabilization, i.e., Michaelis constants
KM in the millimolar range. The conditions developed to
characterize catalysts 1 and 2 were used without change to
ensure comparability, i.e., solutions of catalysts (8.3 mM),
TBAOH (5.0 mM), and substrate S (0−180 mM) in CD3OD/
CDCl3 1:1, stirred at room temperature.
The initial velocities of product formation vini were
determined as a function of the substrate concentration [S].
The catalytic activity clearly increased with increasing π-acidity
from catalyst 3 (Figure 8, ○) to catalyst 4 (Figure 8, ●). Curve
fit to eq 1:
vini/[C] = kcat[S]/(KM + [S])
(1)
gave the rate constants kcat and the Michaelis constants KM. The
latter correspond to the dissociation constants in the ground
states, i.e., the catalyst−substrate complexes CS (Figure 2). The
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a
Table 1. Characteristics of Anion−π Catalysts
b
c
d
e
f
entry
catalyst
KTS (μM)
KM (mM)
(kcat/KM)/knon (M−1
)
ΔΔGTS (kJ mol−1
)
ΔΔGGS (kJ mol−1
)
g
1
1
10.9 1.6
5.0 0.8
5.7 0.4
2.7 0.5
5.4 1.4
82.5 7.8
56.5 6.2
34.5 1.6
35.9 4.5
31.0 5.4
92000
200000
176000
384000
197000
28.3 0.4
30.3 0.4
29.9 0.2
31.8 0.4
30.1 0.6
6.2 0.2
7.1 0.3
8.3 0.1
8.3 0.3
8.6 0.4
g
2
2
3
4
5
3
4
12
13
14
15
16
17
18
20
21
22
h
h
h
h
h
h
6
na
na
na
na
na
7
10.6 2.2
19.3 3.5
5.1 1.2
5.6 2.1
3.9 1.0
63.4 8.5
99000
53000
28.5 0.4
26.9 0.5
30.2 0.6
30.2 1.0
30.9 0.6
6.9 0.3
5.4 0.3
8.2 0.4
8.0 0.5
9.0 0.5
8
115.9 12.7
37.6 6.3
41.5 11.3
26.6 5.0
9
205000
208000
270000
10
11
12
13
14
h
h
h
h
h
na
na
na
na
na
20.8 4.0
142.8 16.2
50000
26.8 0.5
4.8 0.3
h
h
h
h
h
na
na
na
na
na
a
b
From Michealis−Menten analysis, compare Figures 8, 9, 11, and 13 and eqs 1−3. Dissociation constant of the transition state TS (Figure 2) from
c
d
eq 2. Michaelis constant, comparable to the dissociation constant of the catalyst−substrate complex CS (Figure 2) from eq 1. Catalytic proficiency,
from eq 1, knon = 7.1 × 10−8 s−1.20 Transition-state stabilization from eq 3. Ground-state stabilization, from ΔΔGGS = −RT ln KM. Data from ref
e
f
g
h
20. na = not applicable; these catalysts did not show saturation kinetics.
doubled from (kcat/KM)/knon = 1.8 × 105 M−1 for 3 to (kcat/
KM)/knon = 3.8 × 105 M−1 for 4.
In NDI 4, the sulfoxides exist as mixtures of stereoisomers.
The possibility to separate these stereoisomers has been
demonstrated previously, and the anion-transport activity of
individual stereoisomers differed significantly.9 These results
imply that enantiopure anion−π catalysts 4 would be even
better catalysts. Moreover, they identify catalysts 4 with achiral
π-surfaces as attractive starting point for developments toward
asymmetric anion−π catalysis.
Dependence of Anion−π Catalysis on Solubilizers. In
the original anion−π catalyst 1, one imide of the NDI carries
the carboxylate base, whereas the other is equipped with a
branched alkyl substituent in racemic form (Figure 3). This
partial “swallowtail” is essential to solubilize the catalyst. To
evaluate possible contributions to anion−π catalysis, alternative
solubilizers had to be explored. In NDI 12, the original
solubilizer was replaced by a π-basic phenyl group with two
solubilizing alkoxy substituents in meta and para position
(Figure 10).
Figure 9. Energy diagram for the Kemp elimination catalyzed by
anion−π catalysts 3 and 4 (compare Figure 8 and Table 1).
Compared to original anion−π catalyst 1, the presence of the
aromatic solubilizer in NDI 12 increased the ground-state
stabilization by +2.4 kJ mol−1 (Table 1, entries 1 and 5). This
substrate recognition conceivably originated from hydrophobic
contacts between the benzisoxazole and the aromatic
solubilizer. A significant C−H···O bond to the benzisoxazole
oxygen is less likely because the increase in transition-state
stabilization ΔΔGTS by anion−π catalysts 1 and 12 was the
about same as for the ground state (Table 1, entries 1 and 5).
The stabilizing contributions of the new aromatic solubilizer in
anion−π catalyst 12 were more prevalent in the ground state
than the transition state and thus anticatalytic.
Dependence of Anion−π Catalysis on the Leonard
Linker. In anion−π catalysts 1−4, the carboxylate base is
placed on the π-acidic surface with a Leonard linker (Figure
3).29 This fully flexible propylene or trimethylene bridge has
been identified early on as privileged structure to position
motifs of interest on aromatic surfaces. The perfect topological
matching offered by the Leonard linker has been used
successfully to explore intramolecular π−π interactions,29,30
cation−π interactions,31,32 and arene-templated ion pair-
cyano groups. The insensitivity of the ground-state stabilization
to increasing π-acidity of catalysts 3 and 4 with nearly identical
global structure supported that the latter is the case. This
finding was important because it confirmed that the impact of
increasing π-acidity on anion−π interactions exceeds that on
π−π interactions by far. The key conclusion that increasing
transition-state stabilization with increasing π-acidity demon-
strates the existence of anion−π catalysis therefore holds.
Results from computational studies are in agreement with this
conclusion (see above).
The new anion−π catalyst 4 is the most performant anion−π
catalyst prepared so far. The ΔΔGTS = 31.8
0.4 kJ mol−1
corresponds to a recognition of the anionic transition state with
KTS = 2.7 0.5 μM. This quite remarkable transition-state
recognition by anion−π interactions exceeds the recognition of
the neutral substrate by a factor of more than 12000 (KM = 35.9
4.5 mM). The transition-state stabilization ΔΔGTS = 31.8
kJ mol−1 by the so far best anion−π catalyst 4 corresponds to a
catalytic proficiency (kcat/KM)/knon = 3.8 × 105 M−1 (Table 1).
With increasing π-acidity, the catalytic proficiency more than
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activity. It also confirmed that the catalytic inactivity of
pyrenebutyrate 19 originates from anion−π repulsion with
the π-basic pyrene and not from lacking substituents on the
Leonard linker.20
Catalysis of the Kemp elimination by the NDI propionic acid
13 did not exhibit saturation kinetics (Figure 11, ○, Table 1,
entry 6). This finding suggested that the propionate linker is
too short to position the carboxylate on the π-acidic surface.
The homologous NDI valeric acid 15 followed Michaelis−
Menten kinetics (Figure 11, △). However, compared to the
ideal NDI butyric acid 14, ground-state stabilization ΔΔGGS by
the NDI valeric acid 15 dropped by −1.5 kJ mol−1 and
transition-state stabilization ΔΔGTS by −1.6 kJ mol−1 (Table 1,
entries 7 and 8). This finding suggested that the valerate linker
is too long to position the carboxylate correctly on the π-acidic
surface.
These interpretations were well supported by molecular
models (Figure 12). With the Leonard linker in butyrate 14, the
Figure 10. Structure of the catalysts 12−18 and 20−22 and of the
cation−π control 19. R1 and R2 are as in Figure 3.
ing,32,17e and the lessons learned have been applied to sensing31
and cellular uptake.32,17e The robustness of the unusual U-motif
of the Leonard linker has been confirmed in computational
models, crystal structures, and in many variations.29,30
Figure 12. Optimized geometries (IEFPCM/B97D/6-311G**) of the
deprotonated anion−π catalysts (a) 13, (b) 14, and (c) 15; side views.
In the original anion−π catalyst 1, L-glutamic acid is used to
build a Leonard linker that places the carboxylate base on the π-
acidic NDI surface (Figure 3). The second acid of L-glutamic
acid is transformed into an amide that continues with a long,
linear alkyl chain. The possible influence of the nature of this
linker on solubility and activity of anion−π catalysts required
clarification. Anion−π catalysts 13−18 contain simple alkyl
linkers of increasing length (Figure 10).
Corresponding to the original NDI glutamic acid 1, the NDI
butyric acid 14 with a pure Leonard linker29 gave nearly
identical ground- and transition-state stabilizations (Figure 11,
●, Table 1, entries 1 and 7). This result demonstrated that the
hexylamide branching in anion−π catalyst 1 is irrelevant for
carboxylate anion resides comfortably on top of the most π-
acidic pyridinedione heterocycle of the NDI (Figure 12b).
Their separation by 2.88 Å is as expected for strong
intramolecular anion−π interactions. The orientation of the
carboxylate parallel to the NDI surface is consistent with the
occurrence of π−π enhanced anion−π interactions. Similar
observations have been made previously to explain the nitrate
selectivity of anion transport with anion−π interactions.3,6,12
A
carboxylate lying parallel 2.88 Å above the π-acidic surface is
ideal to contribute to the recognition of the benzisoxazole
substrate. Dominated by π−π interactions, the proximal
carboxylate has one oxygen lone pair in place for an important
O···H−C bond to the benzene carbocycle and a second oxygen
lone pair perfectly positioned to accept the proton from the
isoxazole heterocycle and initiate the reaction (Figures 2 and
4).
Molecular models of mismatched NDI propionate 13
confirm that this linker is too short for π−π enhanced anion−π
interactions with the π-acidic surface. As a result, the
carboxylate reorients perpendicular to the NDI plane to
position one lone pair for interaction with the π-surface
(Figure 12a). This position of the carboxylate is obviously less
suited to support substrate recognition and initiate the reaction.
Molecular models of mismatched NDI valerate 15 confirm
that this linker is too long. The carboxylate has to bend down
to the anion−π surface to establish intramolecular anion−π
interactions (Figure 12c). These interactions misorient and
partially use the lone pairs involved in catalysis.
Figure 11. Initial velocity of product formation as a function of the
concentration of substrate S in the presence of 8.3 mM catalyst 13
Comparison with the mismatched 13 and 15 suggested that
the Leonard linker in anion−π catalyst 14 is important for
function (Table 1, entries 6−8). However, further elongation of
○
●
△
( ), 14 ( ), and 15 ( ), 5.0 mM TBAOH, CD3OD/CDCl3 1:1,
○
room temperature; with linear ( ) and Michaelis−Menten curve fit
●
△
( , , compare Table 1).
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the linker restored catalytic activity to the fullest. With the NDI
caproic acid 16, ΔΔGGS and ΔΔGTS recovered by +2.8 and
+3.3 kJ mol−1, respectively (Table 1, entries 8 and 9).
Compared to Leonard catalyst 14, ΔΔGGS and ΔΔGTS of
NDI caproic acid 16 were also clearly higher, although the
increases mostly concerned counterproductive substrate
recognition (Table 1, entries 7 and 9). Further linker
elongation gave practically identical results with NDI enanthic
acid 17 (Table 1, entry 10). The NDI lauric acid 18 with 11
carbons in the linker gave even slightly better activity, although
the anticatalytic contributions from ground-state stabilization
increased as well (Table 1, entry 11). Linker elongation also
gradually decreased the solubility of the catalysts in the reaction
mixture. The overall poor sensitivity of the anion−π catalysts to
linker elongation beyond the critical length of five carbons in
NDI caproic acid 16 indicated that the correct positioning of
the carboxylate base on the π-acidic surface is mainly controlled
by intramolecular anion−π interactions, whereas structural
changes of the linker can hurt more than help. Shorter tails that
interfere with this perfect positioning of the carboxylate reduce
activity significantly (propionate 13, valerate 15). However, the
perfect length of the Leonard liker in butyrate 14 does not have
a pre-organizing effect, longer flexible chains give similar results
(caproate 16 and beyond).
This interpretation was fully supported by catalysts with
rigidified linkers. In catalyst 20, the linker length is with four
atoms identical with that of NDI valeric acid 15 (Figure 10).
Already at full flexibility, this mismatched linker could not
properly fold into a conformation that would allow for
convincing intramolecular π−π enhanced anion−π interactions
between carboxylate and π-acidic surface (Figure 12c). As a
result, ground- and transition-state stabilization by anion−π
catalyst 15 decreased (Table 1, entry 8). Further rigidification
of this mismatched linkers in catalyst 20 gave very weak
catalytic activity without saturation behavior, although pre-
organization by the ortho substitution of the phenyl ring as such
would point into the right direction (Table 1, entry 12).
Addition of one carbon in homologue 21 improved the
situation. The Kemp elimination proceeded with saturation
behavior, although ground- and transition-state stabilization
remained comparably weak (Table 1, entry 13). The rigidified
catalyst 21 was the weakest of all catalysts prepared, even
catalyst 15 with a flexible but mismatched linker showed
slightly better transition-state stabilization (Table 1, entry 8).
This result supported the interpretation that catalytic activity is
mainly governed by the correct positioning of the carboxylate
above the π-acidic surface through intramolecular anion−π
interactions and that any strain added in the linker hinders this
positioning and thus reduces activity.
solubilities nicely illustrate that the π−π interactions in PDIs
are much stronger than in NDIs.11 Catalysis of the Kemp
elimination with PDI catalyst 22 did not exhibit saturation
kinetics (Figure 13, ●; Table 1, entry 14). This incompatibility
Figure 13. Initial velocity of product formation as a function of the
○
concentration of substrate S in the presence of 8.3 mM catalyst 16 ( )
●
and 22 ( ), 5.0 mM TBAOH, CD3OD/CDCl3 1:1 or 1:20, room
●
○
temperature; with linear ( ) and Michaelis−Menten curve fit ( ,
compare Table 1).
with Michaelis−Menten kinetics was in sharp contrast to the
operational NDI catalyst 16 with the same caproate linker
(Figure 13, ○; Table 1, entry 9). The dose response curve of
the original NDI catalyst 1 is similar to that of 16.20 The
relevant initial velocities at high dilution before the onset of
saturation were clearly better for NDI catalyst 16 (or 1) than
for PDI catalyst 22 (Figure 13, left side). The poor
performance of PDIs provided additional support that the
contributions of π−π interactions to anion−π catalysis are
nearly irrelevant. This finding was in agreement with insights
from theory (Figures 4-6) as well as the independence of
ground-state stabilization on increasing π-acidity (Figure 9).
CONCLUSIONS
■
In this study, compelling experimental evidence for the
existence of catalysis with anion−π interactions is provided.
The Kemp elimination is used as an established tool to
elaborate on conceptual innovation in catalysis. Already very
simple catalysts composed of a carboxylate base on top of a π-
acidic naphthalenediimide (NDI) surface can accelerate this
reaction. The best anion−π catalysts exhibit saturation behavior
and are thus compatible with Michaelis−Menten analysis. This
analysis reveals that the stabilization of the anionic transition
state of the Kemp elimination increases with the π-acidity of the
new catalysts. This finding, observed in two independent series,
is very important because it demonstrates that anion−π
interactions indeed contribute to catalysis. Computational
studies support the key conclusion that transition-state
recognition increases with increasing π-acidity of the catalyst.
This conclusion holds independent of the exact mode of
anion recognition in the transition state. The intrinsic charge
delocalization in any transition state implies that anion−π
interactions in anion−π catalysis are necessarily beyond the
strict definition of pure anion−π interactions. This situation
stimulates continuing discussion on the nature of anion−π
interactions and calls conceptual evolutions similar to the ones
made in the perception of cation−π interactions, particularly
when applied to catalysis.13−15
Perylenediimides. The inclusion of perylenediimides
(PDIs)11 in this study was of interest to better dissect
contributions from π−π and anion−π interactions to catalysis.
With an expanded π-surface, π−π interactions with PDIs are
naturally stronger than with NDIs. In clear contrast, PDIs are
less π-acidic than NDIs because the withdrawing effect of the
two imides is diluted over the expanded π-surface. This
decrease in π-acidity is illustrated by the increase of the energy
of the LUMO (Figure 1).
In catalyst 22, the PDI was equipped with a caproic acid as in
the operational NDI catalyst 16 and a swallowtail solubilizer on
the other side (Figure 10). This most powerful solubilizer was
needed because the simpler solubilizer that was sufficient for
the NDI catalysts failed to solubilize the PDI catalyst. Different
Contributions of π−π interactions to anion−π interactions
were considered first to explain nitrate selectivity.3,6,12 The
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contributions from anion−π and π−π interactions to the
acceleration of the Kemp elimination on π-acidic surfaces are
not easily dissected. However, this study provides several
surprising insights on this topic. Most importantly, anion−π
catalysts were introduced that could change π-acidity without
global structural changes (i.e., the oxidation of π-donating
sulfides into π-accepting sulfoxides in the NDI core). With
these catalysts, the stabilization of the neutral ground state is
independent of the π-acidity of the catalyst, whereas that of the
anionic transition state increases. Moreover, PDIs, character-
ized by stronger π−π and weaker anion−π interactions
compared to NDIs, give catalysts that do not follow
Michaelis−Menten kinetics. Computational studies confirm
that π−π interactions are nearly insensitive to changes in π-
acidity, whereas anion−π interactions with a virtual carbanion
intermediate increase dramatically with increasing π-acidity of
the catalyst. Taken together, these findings rule out significant
contributions from π−π interactions and provide compelling
corroborative experimental evidence for the existence of
anion−π catalysis.
Evidence that anion−π interactions can contribute to
organocatalysis could influence the field in the broadest
sense. Focused heavily on hydrogen bonds, the ongoing shift
of attention toward other established interactions, such as ion
pairing17 or cation−π interactions,16 as well as toward the more
innovative halogen bonds12,18 provides marvelous examples
how the introduction of new interaction can inspire the field
beyond incremental progress. Catalysis with anion−π inter-
actions is entirely new. The Kemp elimination is obviously not
interesting for organocatalysis and used in this study as the
(ideal) tool rather than the (irrelevant) topic. However,
stabilization of the anionic transition state of the Kemp
elimination implies that anion−π interactions can stabilize
anionic transition states in the broadest sense. Enolate
chemistry is particularly interesting for anion−π catalysis.
Claisen condensations with anionic transition states dominate
polyketide biosynthesis33 as carbocation chemistry dominates
terpenoid and steroid biosynthesis,13,14 and it would certainly
be intriguing if anion−π interactions could complement the
central role cation−π interactions play in stabilizing carbocation
intermediates. Intense studies to expand anion−π catalysis
beyond the Kemp elimination are ongoing, and the first results
will be reported soon.
(NCCR) Chemical Biology, and the Swiss NSF for financial
support.
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Corresponding Author
stefan.matile@unige.ch
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We thank D. Jeannerat, A. Pinto, and S. Grass for NMR
measurements, the Sciences Mass Spectrometry (SMS) plat-
form for mass spectrometry services, and the University of
Geneva, the European Research Council (ERC Advanced
Investigator), the National Centre of Competence in Research
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