Primary Anion-π Catalysis and Autocatalysis

Article abstract of DOI:10.1021/jacs.8b11788

Epoxide-opening ether cyclizations are shown to occur on π-acidic aromatic surfaces without the need of additional activating groups and with autocatalytic amplification. Increasing activity with the intrinsic π acidity of benzenes, naphthalenediimides (NDIs) and perylenediimides (PDIs) support that anion-π interactions account for function. Rate enhancements maximize at 270 for anion-π catalysis on fullerenes and at 5100 M^-1 for autocatalysis. The occurrence of anion-π autocatalysis is confirmed with increasing initial rates in the presence of additional product. Computational studies on autocatalysis reveal transition state and product forming a hydrogen-bonded noncovalent macrocycle, like holding their hands and dancing on the active π surface, with epoxide opening and nucleophile being activated by anion-π interactions and hydrogen bonds to the product, respectively.

Full text of DOI:10.1021/jacs.8b11788

Communication
Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
pubs.acs.org/JACS
Primary Anion−π Catalysis and Autocatalysis
#
#
#,†
#
ez-Andarias, Antonio Frontera,‡
#
Xiang Zhang, Xiaoyu Hao, Le Liu, Anh-Tuan Pham, Javier Lop
́
#
,#
Naomi Sakai, and Stefan Matile*
#
Department of Organic Chemistry, University of Geneva, Geneva CH 1211, Switzerland
Department de Química, Universitat de les Illes Balears, Palma de Mallorca 07122, Spain
‡
*
S Supporting Information
ABSTRACT: Epoxide-opening ether cyclizations are
shown to occur on π-acidic aromatic surfaces without
the need of additional activating groups and with
autocatalytic amplification. Increasing activity with the
intrinsic π acidity of benzenes, naphthalenediimides
(
NDIs) and perylenediimides (PDIs) support that
anion−π interactions account for function. Rate enhance-
ments maximize at 270 for anion−π catalysis on fullerenes
and at 5100 M− for autocatalysis. The occurrence of
anion−π autocatalysis is confirmed with increasing initial
rates in the presence of additional product. Computational
studies on autocatalysis reveal transition state and product
forming a hydrogen-bonded noncovalent macrocycle, like
holding their hands and dancing on the active π surface,
with epoxide opening and nucleophile being activated by
anion−π interactions and hydrogen bonds to the product,
respectively.
1
he idea of anion−π catalysis is to stabilize anionic
T
transition states on π-acidic aromatic surfaces. Since the
1
beginning, this has been realized for enolate, enamine and
iminium chemistry, cascade cyclizations and concerted cyclo-
additions, also in the context of more advanced systems such as
artificial enzymes, π-stacked foldamers, fullerene-centered
2
triads, or electric-field-mediated catalysis. All these results
have been achieved with at least bifunctional systems, usually
3
with the π-acidic surface for anion−π interactions together
with a Brønsted base to initiate the transformation by
generating a negative charge on the substrate. Different from
these initial studies, we here report functional systems that (i)
operate with anion−π interactions as primary interactions and
Figure 1. Epoxide opening ether cyclization of 3 into THF and THP
products 4 and 5 according to the Baldwin rules, with plausible
‡
mechanisms for primary anion−π catalysis (CS ) and substrate
(
ii) show autocatalysis.
‡
activation by product (CPS, CPS ) and substrate (CSS), and with
Epoxide opening polyether cascade cyclizations are classics
examples for anti-Baldwin (1) and Baldwin (2) cascade cyclizations in
biology.
4
in chemistry and biology. They account, for example, for the
biosynthesis of cyclic polyether natural products such as
5
brevetoxin B 1, a THP oligomer, or monensin A 2, a THF
In hexafluorobenzene 6, the cis-epoxide 3b was transformed
into the THF product 4 within hours (Figures 2a, 3a red ◆;
Table 1, entry 4). In pentafluorobenzene 7, no reaction was
observed. Traces of product appeared after 5 days in
pentafluorobromobenzene 8 and pentafluoroiodobenzene 9
6
oligomer (Figure 1). The selectivity of cyclization of epoxides
as simple as 3 into THF and THP products 4 and 5,
7
respectively, is described by the Baldwin rules. They predict
that the 5-exo-tet or “spiro” transition state should be favored
over the 6-endo-tet or “fused” transition state. Usually catalyzed
by Brønsted acids, Baldwin and anti-Baldwin epoxide-opening
ether cyclizations have attracted extensive attention during the
(entries 2, 3). Used as a catalyst in CD
Cl rather than as a
2
2
Received: November 1, 2018
4
last seven decades.
©
XXXX American Chemical Society
A
DOI: 10.1021/jacs.8b11788
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Figure 2. Structure of catalyst candidates 6−19, with indication of contributions from (a) intrinsic (positive quadrupole moments) and (b)
induced π acidity (polarizability). PDI 16 is a mixture of 1,6- and 1,7-dinitro isomers.
a
Table 1. Anion−π Catalysis and Autocatalysis
g
k /
non
k /
η (%)
−1
cat
ac
f
b
c
d
e
C
S
c (M)
Solvent
k
knon
(M )
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
−
8
9
6
6
6
6
10
11
12
13
14
15
16
17
18
19
18
15
17
3b
3b
3b
3b
3a
3c
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
0
CD Cl2
1
14
17
3736
2058
529
−
4
256
63
220
229
17
113
10
15
−
270
30
7
−
643
571
60964
81248
25770
−
−
4
5
100
100
84
−
1
78
27
69
100
4
67
4
2
≈6.8
≈6.3
≈7.3
≈7.3
≈7.3
0.17
0.17
0.17
0.17
0.17
0.17
0.17
0.085
0.17
0.085
0.17
0.085
0.17
0.17
(neat)
(neat)
(neat)
(neat)
(neat)
h
CD Cl2
2
CD Cl2
−
2
i
CD Cl2
1764
1232
1514
5100
370
2139
462
687
−
1045
−
1102
2
0
1
2
3
4
5
6
7
8
9
0
CD Cl2
2
CD Cl2
2
CD Cl2
2
CD Cl2
2
j
CD Cl2
2
CD Cl2
2
CD Cl2
5
2
Figure 3. (a−c) Reaction kinetics of (a) 3a (green ▲), 3b (red ◆),
and 3c (purple ▼, all 840 mM) in 6 (neat), of (b) 3b (240 mM) in 6
CD Cl2
−
64
6
2
7
7
7
(
red ◆) and 3b (840 mM) in CD Cl with AcOH (100 mol %, +),
2 2
and of (c) 3b (840 mM) in CD Cl with 6 (red ▲), 11 (pink △), 12
2
2
l
4
(
brown ▽), 13 (teal ○) or 14 (blue ●, 20 mol %). (d) Dependence
a
of k /k (red ●○) and k /k (blue ■□) on LUMO energies of
Measured with 840 mM 3 and 170 mM catalyst in CD Cl (unless
stated otherwise: neat, entries 1−6; 85 mM, entries 14, 16, 18), at 20
C. Catalysts, see Figure 2. Substrates, see Figure 1. Catalyst
2
2
cat non
ac non
NDIs (red ● blue ■) and PDIs (red ○ blue □). (e) Kinetics of 3b in
b c d
°
the presence of 4b (blue ●, 0; light-blue ○, 10; blue ▽, 50; light-blue
concentration. Values in entries 2−6 were calculated assuming the
□, 66; teal ■, 174 mol %) and with (blue ●○ light-blue □ teal ■) or
e
density of 3 as 1. Enhancement of initial rate relative to v = 3.57 ×
ini
without (blue ▽) 11. (f−i) Dependence of the conversion of 3b on
the initial concentration of (f) product 4b (with 11, 10 mol %), (g)
substrate 3b (with 6 as solvent), (h) catalyst 11, and (i) inhibitor
−
8
−1
−9 −1
1
0
M s for 3b. knon = 4.25 × 10 s , calculated from high-
a
E /(RT)
−
−1
temperatures measurements using k = Ae
Enhancement of maximal rate relative to v = 3.57 × 10 M s for
b, kac from autocatalysis curve fit. Conversion into 4 after 5 days.
, E = 28.4 kcal mol .
a
f
−8
−1
ini
TBANO (with 11).
3
g
3
h
i
j
40% 4c, 44% 5c. Full conversion in 8 days. Full conversion in 10
l
solvent, hexafluorobenzene 6 was inactive (Figure 3c red ▲,
entry 7; deactivation occurred already in the presence of small
percentages of CD Cl , Figure S5C). With π-acidic benzene
days. Conversion after 7 days.
2
2
derivatives at 20 mol %, only the dinitrobenzoate 10 produced
traces of 4b in the same period of time (entry 8).
surface (Figure 3c teal ○ blue ●; entries 11, 12). Poor activity
of NDI 15 with sulfide donors and inactivity of control 19
supported that contributions from hydrogen bonding with the
amides in the imide substituent are not of primary importance
(entries 13, 17).
NDIs have served well in anion−π catalysis because of their
high intrinsic π acidity, as indicated by their strongly positive
1
,2
quadrupole moments (Figure 2a). At 20 mol % in CD Cl ,
2
2
NDI 11 produced 78% of THF product 4b (Figure 3c pink
; entry 9). This NDI 11 and all other catalyst candidates
△
PDIs have received little attention in anion−π catalysis,
were synthesized by following or adapting previously reported
although they can reach exceptionally positive Q (Figure
zz
8
9
procedures; all details on multistep synthesis of substrates 3
2a). PDI 16 with two nitro acceptors in the core was almost as
and catalyst candidates 11−19 can be found in the SI
active as the best NDI 14, although only 10 mol % catalyst
could be used because of poor solubility (entry 14). Removal
of one nitro acceptor in 17 decreased activity (entry 15).
Overall increasing catalytic activity with increasing intrinsic π
(
Schemes S1−S3). Variation of the solubilizing imide side
chains in 12 reduced activity (Figure 3c brown ▽; entry 10).
Replacement of ethyl sulfones in NDI 11 gave highly active
catalysts 13 and particularly 14, presumably due to interactions
acidity (i.e., LUMO energies, positive Q ) identified for
zz
8
with the π-basic and π-acidic “wings” around the central NDI
various benzenes (6 ≫ 8 ∼ 9 > 7), NDIs and PDIs (Figure
B
DOI: 10.1021/jacs.8b11788
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
d) provided strong experimental support for operational
Communication
3
anion−π catalysis.
Fullerenes have been introduced to anion−π catalysis
because their high polarizability is ideal to explore induced π
acidity (i.e., induced macrodipoles that appear only in the
presence of an anion or anionic transition state, Figure 2b),
10
without complications from intrinsic π acidity (Figure 2a).
The solubility of pristine C was insufficient to study catalysis.
60
With better soluble Bingel products, measurements were
possible at 10 mol % in CD Cl . The activity of fullerenes 18
2
2
(
(
entry 16) was like less performing benzenes, NDIs and PDIs
entries 8, 13, 15). In pentafluorobenzene 7, however,
‡
Figure 4. Structure of transition state CPS for catalyst 11′ (Me
imides), product 4b and substrate 3b (hydrogens and NDI
substituents mostly omitted, distances in Å), and computed energy
fullerenes 18 showed much higher initial velocities (k /k
cat non
−
1
=
270; entry 18). Pentafluorobenzene 7 alone as a solvent was
inactive and failed to activate comparable NDIs and PDIs
entries 19, 20). Pentafluorobenzene 7 was thus likely to
diagram (energies in kcal mol , noninteracting compounds included
in energy estimations listed only for initial S).
(
activate fullerenes 18 by increasing solubility and, perhaps,
extending polarizability with remote donor−acceptor com-
10
interactions to attract and stabilize electron density on the
alcoholate leaving group (Figure 4). The location of the
hydrogen between the two oxygens on the π surface confirmed
that in the transition state, the negative charge accumulating
on this emerging alcoholate oxygen is stabilized by anion−π
interactions rather than neutralized by proton transfer.
Removal of this H bond shortened the O−π distance from
plexes (Figure 2b).
Slow at room temperature, epoxide-opening ether cycliza-
tion of 3b in CD Cl without catalyst was measured at higher
2
2
temperature to extrapolate a knon = 4.25 × 10−9
−1
s
(entry 1).
At room temperature in hexafluorobenzene 6, the initial rate
enhancement with 3b was k /k = 3.7 × 10 (entry 4). The
dependence of product formation on time was sigmoidal
3
cat non
‡
S (2.57 → 2.36 Å) and the H bond from the nucleophile
(
Figure 3a,b, red ◆). Similar behavior was observed with most
(
1.87 → 1.64 Å), indicating the release of some tension in the
anion−π catalysts (Figure 3c), but not with a simple acid
catalyst, AcOH (Figure 3b+). Using NDI 11 as an example,
the occurrence of autocatalysis was supported by the
increasing initial rate of the substrate conversion with
increasing concentration of product 4b from the beginning
supramolecular macrocycle “dancing” on the π surface (Figure
S23). As a result, the loss of a H bond is nearly compensated
by stronger anion−π interactions to activate the leaving group
and stronger H bonds to activate the nucleophile.
1
1
In the computed energy diagram, rate enhancements
(
EC50 = 530 mM, Figure 3e,f). Controls confirmed that
E (CPS) ∼ E (CSS) < E (CS) < E (S) were consistent with
without anion−π catalysts, product 4b alone does not
a
a
a
a
both anion−π catalysis and autocatalysis (Figures 4, S18−
S23). Ternary complexes with either an additional product
(autocatalysis) or an additional substrate gave similar
activation energies but differed on the level of ground-state
accelerate the reaction (Figure 3e blue ▽). Applying the
11
analysis of autocatalytic reactions, we obtained maximal kac/
4
−1
knon = 6.1 × 10 M (entry 4). Anion−π autocatalysis was
inhibited by nitrate due to the interruption of anion−π
‡
‡
(
CPS > CSS) and transition-state recognition (CPS > CSS ),
12,13
interactions between transition state and NDI surface (IC
=
5
0
i.e., catalytic efficiency and proficiency.
4
70 mM, Figure 3i). The dependence of initial rate on the
The Baldwin products were obtained exclusively except for
the dimethylated substrate 3c (Figure 1). Product ratios
inverted from PDI 16 (THP/THF (5c/4c) = 0.7) over NDI
substrate concentration followed a second-order power law,
implying cooperative substrate activation (Figure 3g). The
dependence on the concentration of catalyst 11 was linear,
indicating that the catalysts function as monomers (Figure 3h.
For 6, highly superlinear dependence on catalyst concentration
supported that more than one π surface is needed to
accommodate substrate and product in close proximity (Figure
S5C); at very high substrate concentrations, decreasing
concentrations of the solvent catalyst resulted in decreasing
activities for the same reason (Figure S5D)). Controls in the
dark confirmed independence from light.
1
1 without selectivity (THP/THF = 1.0) to NDI 14, the most
active anion−π catalyst (THP/THF = 1.2). These first
indications of anti-Baldwin behavior encourage further
investigation, together with studies on asymmetric catalysis,
ring expansion and contraction as well as cascade cyclizations
into higher oligomers (Figure 1). Preliminary results are
available up to trimers.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.8b11788.
Decreasing rates with increasingly substituted epoxides from
a to 3c (Figure 3a) supported a concerted mechanism with
■
*
S
3
the displacement of partial negative charges along the molecule
to the intramolecular alcoholate leaving group and the
complementary partial positive charges accumulating on
Detailed experimental procedures (PDF)
‡
‡
hydrogens but not on carbons, as outlined in CS and CPS
(
‡
‡
Figure 1). In CPS computed for catalyst 11′, S and P are
AUTHOR INFORMATION
Corresponding Author
*stefan.matile@unige.ch
■
connected with two H bonds and form a noncovalent
macrocycle on the π surface (Figure 4, B3LYP/6-31+G*,
‡
CH Cl continuum). Both S and P contact the π surface with
2
2
‡
ORCID
one oxygen. The shorter O−π distance with S (2.57 Å)
compared to P (2.79 Å) was consistent with a more advanced
transition from lone pair (lp)−π interactions to anion−π
Antonio Frontera: 0000-0001-7840-2139
Stefan Matile: 0000-0002-8537-8349
C
DOI: 10.1021/jacs.8b11788
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Present Address
Communication
Stereoselective and Ring Selective Synthesis of Tetrahydrofuran and
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(
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Notes
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(
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■
2
́
́
́
We thank NMR and MS platforms for services, and the
University of Geneva, the Swiss National Centre of
Competence in Research (NCCR) Chemical Biology, the
NCCR Molecular Systems Engineering and the Swiss NSF for
financial support. A.F. thanks the MINECO/AEI (project
CTQ2017-85821-R, FEDER funds) of Spain for financial
support. J.L.-A. is a Curie Fellow.
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