Overriding Intrinsic Reactivity in Aliphatic C?H Oxidation: Preferential C3/C4 Oxidation of Aliphatic Ammonium Substrates

Article abstract of DOI:10.1002/anie.202004242

The site-selective C?H oxidation of unactivated positions in aliphatic ammonium chains poses a tremendous synthetic challenge, for which a solution has not yet been found. Here, we report the preferential oxidation of the strongly deactivated C3/C4 positions of aliphatic ammonium substrates by employing a novel supramolecular catalyst. This chimeric catalyst was synthesized by linking the well-explored catalytic moiety Fe(pdp) to an alkyl ammonium binding molecular tweezer. The results highlight the vast potential of overriding the intrinsic reactivity in chemical reactions by guiding catalysis using supramolecular host structures that enable a precise orientation of the substrates.

Full text of DOI:10.1002/anie.202004242

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Overriding Intrinsic Reactivity in Aliphatic C–H Oxidation:
Preferential C3/C4 Oxidation of Aliphatic Ammonium Substrates
Authors: Melina Knezevic, Michael Heilmann, GiovanniMaria Piccini,
and Konrad Tiefenbacher
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202004242
Link to VoR: https://doi.org/10.1002/anie.202004242

10.1002/anie.202004242
Angewandte Chemie International Edition
COMMUNICATION
Overriding Intrinsic Reactivity in Aliphatic C–H Oxidation:
Preferential C3/C4 Oxidation of Aliphatic Ammonium Substrates
Melina Knezevic,[a] Michael Heilmann,[a] GiovanniMaria Piccini,[b] and Konrad Tiefenbacher*[a][c]
In memory of Rolf Huisgen.
[a]
MSc. M. Knezevic, MSc. M. Heilmann, Prof. Dr. K. Tiefenbacher
Department of Chemistry
University of Basel
Mattenstrasse 24a, 4058 Basel, Switzerland
E-mail: Konrad.tiefenbacher@unibas.ch
[b]
[c]
Dr. GM. Piccini
Department of Chemistry and Applied Biosciences, ETH Zurich, c/o USI Campus, Via Giuseppe Buffi 13, CH-6900 Lugano, Switzerland; Facoltàdi
Informatica, Istituto di Scienze Computazionali, Universitàdella SvizzeraItaliana (USI), Via Giuseppe Buffi 13, CH-6900 Lugano, Switzerland
Prof. Dr. K. Tiefenbacher
Department of Biosystems Science and Engineering,
ETH Zurich
Mattenstrasse 24, 4058 Basel, Switzerland
Supporting information for this article is given via a link at the end of the document.
Abstract: The site-selective C-H oxidation of unactivated positions in
aliphatic ammonium chains poses a tremendous synthetic challenge
for which a solution has not been found yet. Here, we report
preferential oxidation of the strongly deactivated C3/C4 positions of
aliphatic ammonium substrates by employing a novel supramolecular
catalyst. This chimeric catalyst was synthesized by linking the well-
explored catalytic moiety Fe(pdp) to an alkyl ammonium binding
molecular tweezer. The results highlight the vast potential of
overriding the intrinsic reactivity in chemical reactions by guiding
catalysis using supramolecular host structures that enable a precise
orientation of the substrates.
Brudvig,[7] and Bach.[8] The oxidation of unactivated positions
remains problematic.[4d] Longer alkyl chains comprise one of the
most challenging substrate classes for selective oxidation, as the
methylene C–H bonds hardly differ in their reactivity.[9] For
instance, oxidation of a decyl ammonium substrate (Fig. 1)
2d, 10]
utilizing the White-Chen[1a,
catalyst 1 yields mixtures of
ketone products with a preference for oxidation at carbons C6 and
higher.[11] Remarkably, the Costas group recently reported a novel
method for selective oxidation of alkyl ammonium substrates
Previous work
Costas[10]
C-H oxidation
intrinsic reactivity
C8/C9
Fe/Mn(pdp)-crown-ether complex 3
H3N
C4
C8
C3
C9
C8/C9
site-selectivity for
Over the last decades, synthetic methodology has progressed
enormously. However, the site-selective oxidation of unactivated
C(sp3)–H bonds still poses a remarkable challenge.[1] While it is
possible to predict and exploit differences in the intrinsic reactivity
of the C–H bonds in a given molecule, the oxidation of less
reactive positions generally remains elusive.[2] Arguably, such
methodology would considerably simplify the synthesis of
complex oxygenated organic molecules. Nature, in many cases a
role model for chemists, clearly demonstrates the potential of
such methodology utilizing complex cytochrome P450 enzymes.[3]
The optimized binding pocket of the active site is crucial in
orienting a specific C–H bond towards the oxidant that is not
necessarily the most reactive one. Mimicking such selective
binding modes with synthetic catalysts has been very
challenging.[4]
Fe(pdp) 1
(intrinsic reactivity)
product distribution
slightpreference for C6-C9
This work
Fe(pdp)-Tweezer complex 4
preference for
C3/C4
O
O
O
O
O
N
O
N
OTf
OTf
Fe
N
N
M
N
N
N
OTf
OTf
3
N
(M = Fe, Mn)
R
1 (R = H)
2 (R = Br)
N
O
O
O
O
N
N
N
O
Fe
OTf
O
OTf
Fe
One promising approach is the covalent merger of a well-
developed oxidation catalyst with a supramolecular binding
R
R
O
O
N
N
OMe
OMe
N
N
N
5]
motif.[4b-d,
For instance, seminal work by Breslow involved
O
O
R
O
N
R
N
R
N
N
R
R
N
N
N
O
N
cyclodextrin(CD)-modified metalloporphyrin complexes.[4b,
Several covalently modified substrates (to enable binding to the
CD-moieties of the catalyst) were selectively oxidized using this
strategy. The selective oxidation without the covalent attachment
of recognition moieties to the substrate has been less successful,
although remarkable examples were reported by Crabtree and
6]
R
N
N
N
O
MeO
OMe
MeO
OMe
O
OMe
4
OMe
R = COOEt
Figure 1. C–H Oxidation catalysts with different selectivities for alkylammonium
chains.
1
This article is protected by copyright. All rights reserved.

10.1002/anie.202004242
Angewandte Chemie International Edition
COMMUNICATION
O
O
O
O
I
Br
X
Br
OMe
OMe
X
OMe
OMe
X
N
N
N
N
N
N
N
N
a, b
c
Tweezer
R
R
R
R
O
O
OMe
OMe
9
Br
Br
5
N
N
NH
R
NH
(X =
)
H
R
6 (X =
TBS )
8a (X =
9 (X =
TBS )
d
)
H
[8b (X = H)]
7
R
COOEt
=
N
N
N
N
N
N
N
O
N
N
N
N
Fe
O
N
N
N
12
H
N
OTf
N
Br
14
OTf
N
10
Br
f-h
e
i
9
Tweezer
Tweezer
Tweezer
11
13
4
Scheme 1. Synthesis of the Fe(pdp)-functionalized tweezer Fe-Twe 4. a) TBS-acetylene, PdCl2(PPh3)2, CuI, Et2NH, 50 °C, 16 h, 97%. b) NBS, AIBN, CCl4, 95 °C,
72 h, 58%. c) 7, KOtBu, 6, DMSO, rt, 16 h, 44%. d) TBAF, THF, 0 °C, 2 h, 80%. e) 10, PdCl2(PPh3)2, CuI, PPh3, THF, µw, 120 °C, 90 min, 76%. f) NaCNBH3, TFA,
MeOH, CH2Cl2, rt, 4 h, 96%. g) PBr3, CH2Cl2, 0 °C → rt, 16 h, 75%. h) 11, K2CO3, TBAB, MeCN, 90 °C, 16 h, 97%. i) Fe(OTf)2(MeCN)2, MeCN, rt, 2.5 h, 58%.AIBN:
azobis-iso-butyronitrile, TBS: (tert-butyldimethylsilyl), TBAB: tetra-n-butylammonium bromide, TBAF: tetra-n-butylammonium fluoride, TFA: trifluoroacetic acid, NBS:
N-bromosuccinimide.
favoring the positions C8/C9 (Fig.1).[11] The catalyst utilized in
their work features a catalytic center (Mn- or Fe-N,N’-bis(2-
pyridylmethyl)-2,2’bipyrrolidine (Mn- / Fe(pdp)) attached to two
18-benzocrown-6 ether (BC) receptors (3) able to bind primary
aliphatic ammonium ions.[11]
coupled with TBS acetylene under Sonogashira coupling
conditions. Subsequent tetrabromination with NBS and AIBN
yielded compound 6, which was linked via alkylation with two
equivalents of 7[14] to produce tweezer 8a. TBS deprotection using
TABF resulted in tweezer 9, which subsequently was coupled with
5-bromo-2-pyridine carboxaldehyde (10). Surprisingly, reductive
amination with 12 resulted in low yields under a variety of
conditions. Therefore, the desired ligand 13 was constructed via
alkylation (after reduction of the aldehyde and Appel-like
bromination). The final complex 4 was obtained via coordination
of 13 with Fe(OTf)2(MeCN)2.[11] As a reference oxidation catalyst
lacking the tweezer binding motif but carrying a substituent at the
pyridine 5-position, catalyst 2 (Figure 1) was also synthesized
(see Supporting Information).
Surprisingly, the determination of the binding constant of
decyl ammonium tetrafluoroborate and Fe-Twe 4 resulted in
rather weak binding (Ka = 29.5 ± 1.9 M M ± 2.2 mM).
–1, Kd = 34.0 m
Subsequent dilution titration experiments, however, revealed that
Fe-Twe 4 displays a relatively large dimerization constant
(Kdim = 160 ± 2.2 M
–1) in contrast to tweezer 8b which did not
Our recent interest in molecular tweezers,[12] combined with
their ability to bind alkyl ammoniums prompted us to investigate
their potential for selective C–H oxidation. Molecular tweezers are
host molecules with an open cavity defined by two rigid arms.[13]
Specifically, we decided to utilize a framework similar to the
glycoluril-based tweezer 8b (Scheme 1) originally developed by
Isaacs.[14] We speculated that it may bind alkylammonium cations
more rigidly than the flexible crown ethers in catalyst 3; potentially
delivering an increased oxidation selectivity. Here we report the
synthesis of the chimeric tweezer-oxidation catalyst 4, and its
unprecedented selectivity for the deactivated positions C3/C4.
Although the ability of tweezer 8b (R = COOH, Scheme 1)
to bind alkyl ammonium species in water was documented,[14] this
project depended on binding in acetonitrile, the standard solvent
for oxidations utilizing catalyst 1 and its derivatives.[2e, 10-11, 15] The
binding constant of decyl ammonium tetrafluoroborate (C10-
show significant aggregation (see Supporting information’s, p
S94-99).
+
NH3 ) to 8b (R = COOEt) in acetonitrile was determined via NMR
titration experiments (see Supporting Information, p. S95-96) and
Initially, decyl ammonium tetrafluoroborate was chosen as
a model substrate and investigated in the oxidation reactions with
indicated reasonably strong binding (Ka = 210 ± 7.6 M–1
,
Kd = 4.77 m
M
± 0.17 m
M
). Under the general oxidation
+
2
concentrations adapted from Costas (1.0 eq. substrate, 74 m
MeCN; 5 mol% Fe-Twe 8b; vide infra),[11] > 93% of tweezer 8b
M
in
Oxidation of C10-NH3 with Fe-Br
K9
K9
K7
K6
K5
K5
K4
K4
would be occupied with substrate.
Oxidation of C10-NH3+ with Fe-Twe 4
Encouraged by these initial results, we decided to explore a
synthetic route towards the tweezer-catalyst 4, which comprises
10]
the well-explored catalytic moiety Fe(pdp)[1a,
linked to the
K3
K7
tweezer binding motif by an alkyne residue. Initially, we
envisioned a convergent approach based on the coupling of
tweezer 9 and ligand 14 (Scheme 1). However, attempts to
achieve such a coupling failed which led us to develop a more
linear approach. Commercially available iododurene (5) was
+
Figure 2. GC Chromatograms of the oxidation of C10-NH3 with Fe-Br 2 (top)
resp. Fe-Twe 4 (bottom).
2
This article is protected by copyright. All rights reserved.

10.1002/anie.202004242
Angewandte Chemie International Edition
COMMUNICATION
Table 1. Oxidation of aliphatic ammonium salts by catalyst Fe-Br 2 and Fe-Twe 4.
1) Cat.
H2O2, AcOH
90 min, 0 °C
O
K1
O
NH3BF4
N
n
2) NEt3, Ac2O
1 h, 0 °C
(MeCN)
n
K2
H
n = 1 - 6, 8
Entry
Substrate
Catalyst
Conv.
[%]
Total Yield a
Yield
K3-4 [%]
Yield
K3-5 [%]
Selectivity b Selectivity b
[%]
K3-4 [%]
K3-5 [%]
+
1 vs 2c
3 vs 4
5 vs 6
C10-NH3
C10-NH3
Fe-Br 2 vs Fe-Twe 4 75 vs 47
Fe-Br 2 vs Fe-Br 2 + 8b 75 vs 52
Fe-Br 2 vs Fe-Twe 4 57 vs 43
34 vs 25
34 vs 19
27 vs 18
32 vs 14
3.8 vs 6.4
17 vs 8.2
30 vs 16
42 vs 24
28 vs 10
33 vs 18
1.8 vs 7.0
1.8 vs 1.5
1.9 vs 2.9
1.7 vs 0.9
1.8 vs 5.1
3.2 vs 4.2
2.9 vs 6.6
1.6 vs 5.7
1.0 vs 2.4
0.7 vs 3.8
5.9 vs 11
5.9 vs 3.4
5.5 vs 5.6
5.3 vs 2.4
2.7 vs 5.9
6.1 vs 5.2
7.3 vs 8.7
5.0 vs 8.7
2.8 vs 3.8
2.9 vs 6.1
5.3 vs 28
5.3 vs 7.8
7.1 vs 16
5.2 vs 6.2
46 vs 80
19 vs 51
10 vs 40
3.9 vs 24
3.8 vs 23
2.1 vs 21
17 vs 43
17 vs 18
20 vs 32
17 vs 17
70 vs 92
36 vs 64
24 vs 53
12 vs 37
9.9 vs 37
8.8 vs 34
+
+
C10-NMeH2
7d vs 8d C10-NMe2H+
"
"
"
"
"
"
"
60 vs 41
34 vs 34
37 vs 22
49 vs 39
57 vs 36
63 vs 39
77 vs 68
+
9 vs 10
11 vs 12
13 vs 14
15 vs 16
17 vs 18
19 vs 20
C7-NH3
C8-NH3
C9-NH3
+
+
+
+
+
C11-NH3
C12-NH3
C14-NH3
General reaction conditions:[11] substrate (18.5 µmol, 1.0 equiv.), catalyst (925 nmol, 5 mol%), AcOH (148 µmol, 8.0 equiv.), H2O2 (278 µmol,
15 equiv., addition via a syringe pump over 90 min), MeCN, 0 °C. After 15 min, internal standard (biphenyl, 9.25 µmol, 0.5 equiv.), NEt3
(100 µL), Ac2O (150 µL), 0 °C. After 1 h, washing with H2O, 2
M H2SO4, NaHCO3, H2O, dried (Na2SO4) and analyzed by GC. [a] Total yield
refers to mixture of all isomers. [b] Selectivity refers to yield of selected ketones/total yield. [c] 5 mol% of Tweezer 8b was added additionally.
[d] Different work-up, see SI.
a)
b)
binding mode 1
(inside)
binding mode 2
(outside)
Figure 3. a) Reaction selectivities of the possible ketone products for the oxidation of different aliphatic ammonium ions with Fe-Br 2 resp. Fe-Twe-4. b) Binding
modes 1 and 2 of Fe-4 and decyl ammonium (optimized at the PM3 level).
Fe-Br 2 (intrinsic reactivity) and Fe-Twe 4 (Figure 2). As
expected,[11] the non-directed oxidation with Fe-Br 2 resulted in
mixtures of ketone products (K4-K9, ketones at C4-C9). Oxidation
at the more proximal positions (K3/K4) was hardly detectable due
to deactivation by the nearby ammonium moiety.[16] The main
products were K6-K9 in nearly equal amounts. Employing catalyst
3
This article is protected by copyright. All rights reserved.

10.1002/anie.202004242
Angewandte Chemie International Edition
COMMUNICATION
Fe-Twe 4 also led to mixtures but resulted in an inversed
selectivity. Interestingly, the deactivated positions K3-K5 were
those preferred by the supramolecular catalyst 4, overriding the
intrinsic reactivity of the substrate (Table 1, entry 1 vs 2).
substrate to the tweezer (see Supporting Information, p. S101-
107). According to the calculations, the two binding modes are
relatively close in energy indicating that C6-9 oxidation not only
stems from a background reaction but also from binding mode 1.
However, binding mode 2 (the cavity is filled with a acetonitrile
solvent, not shown in Fig. 3) is preferred by approx. 5 kJ/mol, in
accordance with the experimental results. Since binding mode 2
depends on the guest molecule acetonitrile, the observed
selectivity for K3-5 should be solvent dependent. Indeed, the
selectivity is greatly reduced with trifluoroethanol, and disappears
completely with the larger hexafluoro isopropanol as solvent (see
Supporting information, p. S35-36). These results provide further
evidence that the observed oxidation of the unactivated positions
C3-5 stem from substrate binding to the tweezer moiety of catalyst
4.
Several control experiments were carried out to elucidate
the role of the supramolecular recognition motif. First an
experiment in which the two parts of Fe-Twe 4 were added as
separate entities (tweezer 8b (5 mol%), and Fe-Br 2 (5 mol%))
was performed (Table 1, entry 4). The selectivity was significantly
reduced and similar to the results of Fe-Br 2, demonstrating that
the tweezer has to be covalently linked to the oxidation catalyst to
achieve high selectivity. In separate experiments, we tried to
reduce the binding ability of the substrate via methylation of the
+
amine residue. The oxidation of C10-NMeH2 already delivered
reduced selectivities (entry 5 vs 6) while with dimethylated C10-
NMe2H+ as substrate, the selectivity was almost completely lost.
These results strongly indicate that the substrate binds to the
tweezer via hydrogen bonds. The yields in these two cases
(entries 6 and 8) were only slightly reduced in comparison to entry
2 which suggest that oxidation without specific binding to the
tweezer is taking place as a background reaction. This is also
indicated by the oxidation of cyclohexane by both catalysts (see
Supporting Information, p. S37). In a competition experiment,
decylammonium and cyclohexane were subjected to the oxidation
reactions with Fe-Br 2 and Fe-Twe 4 in equal amounts which
resulted in only slightly increased selectivity for decylammonium
with Fe-Twe 4. The background reaction was much less
pronounced with 3,[11] presumably due to the oxidant being
blocked from two sides by the crown ether moieties. A third series
of control experiments was performed with the aim of inhibiting
substrate binding inside Fe-Twe 4. As Inhibitors, NH4PF4, NaOTf
and methyl viologen dichloride hydrate were explored. The yields
of the oxidation products, as well as the selectivity for C3-4
decreased. However, these results are difficult to interpret since
the inhibitor, also inhibits oxidation of the regular catalyst Fe-Br 2
devoid of a tweezer moiety. However, due to the reduced
selectivity these experiments also indicate some background
oxidation with regular “solution” selectivity at C6-9.
In summary, we reported the synthesis of a supramolecular
oxidation catalyst capable of overriding the intrinsic reactivity in
aliphatic C–H oxidation of alkyl ammonium salts. The main
products formed were ketones at carbons C3 and C4, positions
that are intrinsically strongly deactivated and therefore not formed
to a significant degree with other catalysts. Although the
selectivities have clearly to be improved to achieve synthetically
useful yields, these results augur well for the selective oxidation
of unactivated C–H positions on complex carbon frameworks.
Acknowledgements
This work was supported by the Swiss National Science
Foundation as part of the NCCR Molecular Systems Engineering
program. The authors thank Fabian Bissegger for VT-NMR
experiments, Dr. Michael Pfeffer for HR-MS analysis, and Dr.
Joan Serrano Plana for helpful discussions. Calculations were
carried out on the ETH Euler cluster.
Keywords: C–H oxidation • molecular recognition •
Subsequently, we studied the oxidation of several aliphatic
ammonium salts with different chain lengths (Table 1, Figure 3).
For all oxidation reactions with Fe-Twe 4 a pronounced selectivity
increase for the C3–C4 positions was observed compared to the
non-directed oxidations. In fact, with most substrates, ketones K3
or K4 were the favored products for Fe-Twe 4 oxidation reactions.
The yields, however, were generally lower for catalyst 4, which is
presumably due to catalyst decomposition during the oxidation
reaction (see Supporting Information, p. S39-42). The only
exception is the oxidation of C7-NH3+ in which almost all positions
are deactivated.[16] Moreover, substrates with longer alkyl chains
mostly resulted in higher yields compared to the short ones, a
trend also observed with 3.[11] Regarding the selectivities, in
principle, two different binding motifs can be envisioned for
catalyst 4 (Figure 3b): (1) The binding of the aliphatic chain inside
the cavity of the tweezer. This binding mode is observed in
aqueous solution, presumably due to the hydrophobic effect.[14] It
would expose positions C6-C8 to the oxidant. (2) Without the
hydrophobic effect, the sole binding to the polar end groups (urea
carbonyl and methoxy oxygen) of the tweezer would be feasible,
favoring the oxidation of positions C3-C5. The oxidation results
obtained clearly suggest that the second binding mode is the
predominant one. Molecular modeling was performed to
investigate the suggested binding modes of the ammonium
regioselectivity • catalysis • supramolecular chemistry
[1]
[2]
a) M. C. White, J. Zhao, J. Am. Chem. Soc. 2018, 140, 13988-14009; b)
W. R. Gutekunst, P. S. Baran, Chem. Soc. Rev. 2011, 40, 1976-1991.
a) T. Brückl, R. D. Baxter, Y. Ishihara, P. S. Baran, Acc. Chem. Res.
2012, 45, 826-839; b) J. F. Hartwig, M. A. Larsen, ACS Cent. Sci. 2016,
2, 281-292; c) T. Newhouse, P. S. Baran, Angew. Chem. Int. Ed. 2011,
50, 3362-3374; d) M. S. Chen, M. C. White, Science 2010, 327, 566-
571; e) P. E. Gormisky, M. C. White, J. Am. Chem. Soc. 2013, 135,
14052-14055; f) K. Chen, J. M. Richter, P. S. Baran, J. Am. Chem. Soc.
2008, 130, 7247-7249; g) B. Li, M. Driess, J. F. Hartwig, J. Am. Chem.
Soc. 2014, 136, 6586-6589; h) M. A. Bigi, S. A. Reed, M. C. White, J.
Am. Chem. Soc. 2012, 134, 9721-9726.
[3]
[4]
a) P. R. Ortiz de Montellano, Chem. Rev. 2010, 110, 932-948; b) R.
Fasan, ACS Catal. 2012, 2, 647-666.
a) P. Dydio, J. N. Reek, Chem. Sci. 2014, 5, 2135-2145; b) R. Breslow,
S. D. Dong, Chem. Rev. 1998, 98, 1997-2012; c) S. Das, G. W.
Brudvig, R. H. Crabtree, Chem. Commun. 2008, 413-424; d) D. Vidal,
G. Olivo, M. Costas, Chem. Eur. J. 2018, 24, 5042-5054; e) F. Burg, T.
Bach, J. Org. Chem. 2019, 84, 8815-8836; f) N. R. Mote, S. H. Chikkali,
Chem. Asian J. 2018, 13, 3623-3646; g) M. Raynal, P. Ballester, A.
Vidal-Ferran, P. W. van Leeuwen, Chem. Soc. Rev. 2014, 43, 1660-
1733; h) S. Carboni, C. Gennari, L. Pignataro, U. Piarulli, Dalton Trans.
2011, 40, 4355-4373.
[5]
examples of similar approaches concerning C-H borylation:a) Y.
Kuninobu, H. Ida, M. Nishi, M. Kanai, Nat. Chem. 2015, 7, 712; b) H. J.
Davis, M. T. Mihai, R. J. Phipps, J. Am. Chem. Soc. 2016, 138, 12759-
12762; c) M. E. Hoque, R. Bisht, C. Haldar, B. Chattopadhyay, J. Am.
Chem. Soc. 2017, 139, 7745-7748; examples of similar approaches
concerning olefin functionalization: d) P. Thordarson, E. J. Bijsterveld,
A. E. Rowan, R. J. Nolte, Nature 2003, 424, 915-918; e) T. Šmejkal, B.
Breit, Angew. Chem. Int. Ed. 2008, 47, 311-315; f) P. Dydio, W. I. Dzik,
4
This article is protected by copyright. All rights reserved.

10.1002/anie.202004242
Angewandte Chemie International Edition
COMMUNICATION
M. Lutz, B. de Bruin, J. N. Reek, Angew. Chem. Int. Ed. 2011, 50, 396-
400; g) S. a. Korom, P. Ballester, J. Am. Chem. Soc. 2017, 139, 12109-
12112; h) P. Fackler, C. Berthold, F. Voss, T. Bach, J. Am. Chem. Soc.
2010, 132, 15911-15913.
[6]
a) R. Breslow, X. Zhang, Y. Huang, J. Am. Chem. Soc. 1997, 119,
4535-4536; b) R. Breslow, Y. Huang, X. Zhang, J. Yang, Proc. Natl.
Acad. Sci. USA 1997, 94, 11156-11158; c) J. Yang, R. Breslow, Angew.
Chem. Int. Ed. 2000, 39, 2692-2695; d) J. Yang, B. Gabriele, S.
Belvedere, Y. Huang, R. Breslow, J. Org. Chem. 2002, 67, 5057-5067.
a) S. Das, C. D. Incarvito, R. H. Crabtree, G. W. Brudvig, Science 2006,
312, 1941-1943; b) S. Das, G. W. Brudvig, R. H. Crabtree, J. Am.
Chem. Soc. 2008, 130, 1628-1637.
a) J. R. Frost, S. M. Huber, S. Breitenlechner, C. Bannwarth, T. Bach,
Angew. Chem. Int. Ed. 2015, 54, 691-695; b) F. Burg, M. Gicquel, S.
Breitenlechner, A. Pöthig, T. Bach, Angew. Chem. Int. Ed. 2018, 57,
2953-2957; c) F. Burg, S. Breitenlechner, C. Jandl, T. Bach, Chem. Sci.
2020, 11, 2121-2129.
[7]
[8]
[9]
X.-S. Xue, P. Ji, B. Zhou, J.-P. Cheng, Chem. Rev. 2017, 117, 8622-
8648.
[10] M. S. Chen, M. C. White, Science 2007, 318, 783-787.
[11] G. Olivo, et al., Angew. Chem. 2017, 129, 16565-16569.
[12] M. Heilmann, K. Tiefenbacher, Chem. Eur. J. 2019, 25, 12900-12904.
[13] Reviews: a) M. Hardouin–Lerouge, P. Hudhomme, M. Salle, Chem.
Soc. Rev. 2011, 40, 30-43; b) F.-G. Klärner, T. Schrader, Acc. Chem.
Res. 2013, 46, 967-978; c) V. Valderrey, G. Aragay, P. Ballester,
Coord. Chem. Rev. 2014, 258, 137-156; d) A. E. Rowan, J. A. Elemans,
R. J. Nolte, Acc. Chem. Res. 1999, 32, 995-1006; e) F.-G. Klärner, B.
Kahlert, Acc. Chem. Res. 2003, 36, 919-932; f) S. Ganapati, L. Isaacs,
Isr. J. Chem. 2018, 58, 250-263; g) J. Rebek, Science (Washington, D.
C.) 1987, 235, 1478-1484; h) S. C. Zimmerman, in Top. Curr. Chem.,
Springer, 1993, pp. 71-102; i) S. C. Zimmerman, Beilstein J. Org.
Chem. 2016, 12, 125-138; early contributions: j) C. Chen, H. Whitlock
Jr, J. Am. Chem. Soc. 1978, 100, 4921-4922; k) J. Rebek Jr, et al., J.
Am. Chem. Soc. 1985, 107, 6736-6738; l) C. S. Wilcox, L. M. Greer, V.
Lynch, J. Am. Chem. Soc. 1987, 109, 1865-1867; m) S. C. Zimmerman,
C. M. VanZyl, J. Am. Chem. Soc. 1987, 109, 7894-7896.
[14] C. A. Burnett, D. Witt, J. C. Fettinger, L. Isaacs, J. Org. Chem. 2003,
68, 6184-6191.
[15] R. V. Ottenbacher, D. G. Samsonenko, E. P. Talsi, K. P. Bryliakov, Org.
Lett. 2012, 14, 4310-4313.
[16] a) M. Lee, M. S. Sanford, J. Am. Chem. Soc. 2015, 137, 12796-12799;
b) J. M. Howell, K. Feng, J. R. Clark, L. J. Trzepkowski, M. C. White, J.
Am. Chem. Soc. 2015, 137, 14590-14593.
5
This article is protected by copyright. All rights reserved.

10.1002/anie.202004242
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
We report the synthesis of a supramolecular tweezer catalyst capable of oxidizing aliphatic ammonium salts at the deactivated
methylene positions C3/C4. The catalyst is able to override the intrinsic reactivity in C–H oxidation of these substrates.
Twitter username: @TiefenbacherLab
6
This article is protected by copyright. All rights reserved.