Mechanistic Insights into the Enantioselective Epoxidation of Olefins by Bioinspired Manganese Complexes: Role of Carboxylic Acid and Nature of Active Oxidant

Article abstract of DOI:10.1021/acscatal.8b00874

Bioinspired manganese and iron complexes bearing nonporphyrinic tetradentate N4 ligands are highly efficient catalysts in asymmetric oxidation reactions by hydrogen peroxide (H₂O₂), in which carboxylic acid is employed as an essentia

Full text of DOI:10.1021/acscatal.8b00874

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Mechanistic Insights into the Enantioselective Epoxidation
of Olefins by Bioinspired Manganese Complexes:
Role of Carboxylic Acid and Nature of Active Oxidant
Junyi Du, Chengxia Miao, Chungu Xia, Yong-Min Lee, Wonwoo Nam, and Wei Sun
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b00874 • Publication Date (Web): 12 Apr 2018
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ACS Catalysis
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†
,‡
†
†
§
,†,§
,†
Junyi Du, Chengxia Miao, Chungu Xia, Yong-Min Lee, Wonwoo Nam,* and Wei Sun*
†
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Center for Excellence in Molecular Synthesis, Suzhou Research In-
stitute of LICP, Lanzhou Institute of Chemical Physics (LICP), Chinese Academy of Sciences, Lanzhou, 730000, P. R. China
‡
University of Chinese Academy of Sciences, Beijing 100049, P. R. China
§
Department of Chemistry and Nano Science, Ewha Womans University, Seoul 03760, Korea
ABSTRACT: Bioinspired manganese and iron complexes bearing nonporphyrinic tetradentate N4 ligands are highly efficient catalysts in asym-
metric oxidation reactions by hydrogen peroxide (H
and stereo-, regio-, and enantioselectivities. The metal catalysts should possess two cis-binding sites for oxidant (e.g., H
2
O
2
), in which carboxylic acid is employed as an essential additive to improve product yields
) and carboxylic acid
2
O
2
to generate high-valent metal-oxo species as active oxidants via “carboxylic acid-assisted” mechanism. In the present study, we have investigated
the role(s) of carboxylic acid and the nature of reactive intermediate(s) in the manganese complex-catalyzed enantioselective epoxidation of
N4
olefins, by employing nonheme manganese catalysts, such as 1 bearing a tetradentate N4 ligand (L ) and 2 bearing a pentadentate N5 ligand
N5
(
L ), and using various oxidants, such as H
2
2
O , alkyl hydroperoxides, and iodosylbenzene (PhIO). As expected, 1 possessing two cis-binding
sites is an effective catalyst irrespective of the oxidants in the presence of carboxylic acid. In contrast, 2 possessing only one binding site is not
an effective catalyst in the reactions of H and alkyl hydroperoxides even in the presence of carboxylic acid. However, unexpectedly, 2 turns
2
O
2
out to be an effective catalyst in the asymmetric epoxidation of olefins by PhIO in the presence of carboxylic acid. The latter result indicates
that a manganese complex, which cannot bind carboxylic acid as an auxiliary ligand, can afford a high enantioselectivity, probably through a
second-sphere coordination interaction between carboxylic acid and the oxo group of a presumed manganese-oxo oxidant. We have also pro-
vided indirect evidence supporting that a high-valent Mn(V)-oxo species is the active oxidant in the catalytic asymmetric epoxidation reactions.
KEYWORDS: Asymmetric Epoxidation, Manganese Catalyst, Carboxylic Acid Additive, Mechanism, Manganese-Oxo
9
oxidation reactions by White and co-workers. Shul’pin and co-
workers also reported that manganese complexes catalyzed the
1
0
The selective oxidation of hydrocarbons under mild conditions is of
great current interest in enzymatic reactions as well as in synthetic
epoxidation of olefins by H O in the presence of acetic acid. Later,
2
2
Que and co-workers invoked a carboxylic acid-assisted O-O bond
cleavage mechanism, in which a highly reactive nonheme Fe(V)-oxo
species was generated via a heterolytic O-O bond cleavage of an
1,2
organic chemistry. In enzymatic reactions, metalloenzymes, such
as heme and nonheme iron enzymes, catalyze a diverse array of
important oxidative transformations, including olefin epoxidation
Fe(III)-OOH precursor in the presence of acetic acid (Scheme
2
5b,11
and alkane hydroxylation reactions. Inspired by the high reactivity
1).
The catalytic systems (e.g., nonheme iron and manganese
and selectivity shown by heme and nonheme iron enzymes,
synthetic iron porphyrins, nonheme iron complexes, and related
manganese complexes have been employed as catalysts in the
oxidation of organic substrates. One notable example is the recent
development in the (asymmetric) epoxidation of olefins and the C-
catalysts/H O /carboxylic acid) were then successfully developed
2
2
in asymmetric oxidation reactions by the groups of Bryliakov/Talsi,
6
,7,12-14
Costas, and Sun.
Of particular note is the report by
3
-5
Bryliakov/Talsi and co-workers that the steric bulk of carboxylic
acid additives affects the epoxidation enantioselectivity, implying
that the carboxylic acid molecule is involved in the
enantioselectivity-determining step, presumably acting as an
H bond hydroxylation of alkanes by hydrogen peroxide (H
2
O )
2
6,7
catalyzed by nonheme iron and manganese complexes. In the
catalytic oxidation reactions, carboxylic acid (e.g., acetic acid) is an
essential component for high product yields and stereo-, regio-, and
1
2a
auxiliary ligand. Very recently, we succeeded in using a catalytic
amount of sulfuric acid (H SO ), instead of using a large amount of
2
4
6,7
enantioselectivities. Indeed, Jacobsen and co-workers reported for
carboxylic acid, to achieve the asymmetric oxidation of organic
15
the first time that the catalytic epoxidation of aliphatic olefins by a
substrates by nonheme manganese complexes and H O . These
2
2
nonheme iron complex and H
2
O
2
afforded high product yields in the
presence of acetic acid, followed by using the catalytic system (e.g.,
nonheme iron catalysts/H /carboxylic acid) in C-H selective
results demonstrate unambiguously that carboxylic acid (and
sulfuric acid) plays an important role in improving the catalytic
activity as well as the enantioselectivity in the asymmetric oxidation
8
2
O
2
1
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Table 1. Summary of Asymmetric Epoxidation Reactions by
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Manganese Complexes and Various Oxidants in the Presence of
a
Carboxylic Acid
oxidant
H
2
O
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
alkyl hydroperoxides
PhIO
aThe square represents the binding site(s) for oxidant and carboxylic
acid. The tick and cross stand for excellent and poor reactivity, respec-
tively.
Scheme 1. Proposed Carboxylic Acid-Assisted Heterolytic O-O
Bond Cleavage Mechanism
reactions by nonheme metal catalysts and H
Another important factor, which is crucial to achieve the efficient
asymmetric olefin epoxidation by metal complexes and H in the
2
O
2
.
2
O
2
presence of carboxylic acid, is the structure (and topology) of the
iron and manganese catalysts. The metal catalysts bearing
tetradentate N4 ligands should possess two cis-labile sites for the
binding of both oxidant (e.g., H
2
2
O ) and carboxylic acid to facilitate
the heterolytic O-O bond cleavage of metal(III)-hydroperoxo
intermediates (Scheme 1, red-colored structure) and form
metal(V)-oxo species as active oxidants (Scheme 1, blue-colored
5
-7
Scheme 2. Structures of Ligands and Manganese Complexes Used
in This Study
structure). Indeed, mononuclear nonheme Fe(V)-oxo species
have been trapped and characterized using various spectroscopic
1
2,16-18
techniques,
stopped-flow UV−vis, and variable-temperature mass spectrometry
VT-MS), along with density functional theory (DFT)
such as electron paramagnetic resonance (EPR),
oxidants, such as H
2
2
O , alkyl hydroperoxides, and iodosylbenzene
(
PhIO). We now report that the manganese complex bearing the
(
N4
1
9
tetradentate N4 (L ) ligand, 1 (Scheme 2, left structure), is an
effective catalyst irrespective of the oxidants in the presence of
carboxylic acid additive, whereas the manganese complex bearing
the pentadentate N5 (L ) ligand, 2 (Scheme 2, right structure), is
not an effective catalyst in the reactions of H and alkyl
calculations, supporting the intermediacy of the Fe(V)-oxo species
in the catalytic oxidation reactions. Thus, the availability of two cis-
binding sites in nonheme metal catalysts is crucial for the generation
N5
21
of high-valent metal(V)-oxo intermediates by activating H
presence of carboxylic acid additive.
2
2
O in the
2
O
2
hydroperoxides under the identical reaction conditions (see Table 1
for the summary of the asymmetric epoxidation of olefins by various
oxidants catalyzed by 1 and 2). Interestingly, 2 turns out to be a
highly efficient catalyst giving high product yields with a high
enantioselectivity in the asymmetric epoxidation of olefins by PhIO
in the presence of carboxylic acid (Table 1). Other mechanistic
aspects, such as the nature of the active manganese oxidant and the
formation mechanism of the manganese oxidant, are also discussed
in the present study.
As mentioned above, it is clear that carboxylic acid (or sulfuric
acid) plays a key role in generating high-valent metal-oxo
intermediates for the selective oxidation reactions (Scheme 1, red-
and blue-colored structures). However, the carboxylic acid effect on
the enantioselectivity in the epoxidation reactions is still unclear and
remains elusive. Moreover, the nature of the active oxidant(s)
responsible for the catalytic epoxidation reactions needs to be
clarified, especially in nonheme manganese systems; there has been
a controversy on the structure of the active oxidant, such as M(V)-
16c,20
oxo versus M(III)-(acyl)hydroperoxo (M = Mn and Fe) species.
As our ongoing efforts to develop and understand the catalytic
asymmetric oxidation reactions using earth-abundant metal
catalysts and environmentally benign oxidants, we have investigated
the manganese complex-catalyzed enantioselective epoxidation of
olefins, by employing nonheme manganese catalysts bearing
Synthesis and Characterization of Manganese Catalysts. We used
two manganese(II) catalysts in this study, such as 1 with a
N4
N4
tetradentate N4 ligand (denoted as L , L = (S)-N,N’-bis(2-
picolinyl)-N’-benzyl-2-pyrrolidinemethanamine) and 2 with a
N5
N5
N4
N5
pentadentate N5 ligand (denoted as L , L = (S)-N,N’,N’-tris(2-
tetradentate N4 (L ) and pentadentate N5 (L ) ligands (see Table
for the Mn core structures of catalysts and Scheme 2 for the
structures of ligands and Mn(II) complexes) and using various
picolinyl)-2-pyrrolidinemethanamine) (see Scheme 2 for the
1
N4
N5
structures of L , L , 1, and 2). The ligands were synthesized by
2
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N4
introducing one benzyl and two 2-picolinyl groups for L and three
Table 2. Asymmetric Epoxidation of Chalcone by Mn Catalysts
under Various Conditions
N5
a
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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4
4
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4
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5
5
5
5
5
5
5
5
5
6
2-picolinyl groups for L to the L-proline-derived chiral skeleton
(S)-2-pyrrolidinemethanamine.
The
Mn(II)
] (1) and [Mn (L )(OTf)](OTf) (2), were
synthesized by treating the ligands with an equimolar amount of
complexes,
II
N4
II
N5
[Mn (L )(OTf)
2
−
−
Mn(OTf)
2
(OTf = CF
3
SO
3
) in CH CN under an Ar atmosphere
3
(
Experimental Section for the synthesis and characterization of
N4
ligand L and 1; see also Supporting Information (SI), Figure S1 for
the schematic drawings for the synthesis of ligands and Mn
catalysts). The crystal structure of 1 exhibits a hexa-coordinated
manganese complex in cis-α topology with two triflate ligands,
indicating that two labile sites are available for the binding of oxidant
and carboxylic acid (Scheme 2, left structure; also see SI, Tables S1
and S2 for crystallographic data and Figure S2 the X-ray crystal
structure). In contrast, 2 contains a single triflate ligand bound to the
manganese center, implying that only one labile site is available for
the binding of either oxidant or carboxylic acid (Scheme 2, right
EHA
conv.
(%)
yield
(%)
ee
entry
cat.
1
oxidant
(
equiv)
(%)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
H
2
O
2
0
5
0
5
0
5
0
5
0
0
5
0
5
0
5
0
5
0
<1
75
46
99
39
99
33
99
99
<1
<1
15
16
7
<1
71
43
97
33
96
30
97
94
<1
<1
11
12
5
n. d.
89
TBHP
CHP
19
90
21
structure).
5
Catalytic Reactions by 1 and 2 under Various Conditions. The
catalytic activity of 1 possessing two cis-binding sites was compared
with that of 2 possessing only one binding site, by carrying out the
asymmetric epoxidation of chalcone with various oxidants, such as
90
PhIO
32
H
(
2
O
2
, tert-butyl hydroperoxide (TBHP), cumyl hydroperoxide
CHP), and PhIO, in the absence and presence of 2-ethylhexanoic
acid (EHA), which is a frequently used carboxylic acid in the
oxidation of organic substrates by H catalyzed by nonheme Fe
The reaction conditions are described in the
89
2
O
2
PhI(OAc)
2
75
12a,22
and Mn complexes.
schematic diagram and footnote in Table 2, and the product yields
as well as the enantiomeric excess (ee) values of the epoxide product
are listed in Table 2. The results are divided into two sub-sections
for discussion, such as one with H
the other with PhIO.
1
0
2
H
2
O
2
n. d.
n. d.
n. d.
n. d.
n. d.
n. d.
25
11
12
2
2
O and alkyl hydroperoxides and
TBHP
CHP
(i) Reactions with H
epoxidation of chalcone by 1 and H
2
O
2
and Alkyl Hydroperoxides. The
did not yield the epoxide
1
1
1
3
4
5
2
O
2
product in the absence of carboxylic acid (i.e., EHA; Table 2, entry
1). However, when the identical reaction was carried out in the
presence of EHA, chalcone oxide was produced with a high yield and
a good enantioselectivity (Table 2, entry 2; see also SI, Figures S3
and S4 for NMR and HPLC analyses). The carboxylic acid effect was
also observed in the catalytic epoxidation of chalcone by 1 and alkyl
hydroperoxides, such as TBHP and CHP (Table 2, entries 3 and 4
for TBHP and entries 5 and 6 for CHP). Thus, as demonstrated
11
41
72
76
7
16
17
18
PhIO
37
70
71
78
6,7,12,13
previously,
in the olefin epoxidation reactions by H
2
O
2
and
PhI(OAc)
2
66
alkyl hydroperoxides catalyzed by 1, the binding of carboxylic acid at
the manganese center promotes the heterolytic O-O bond cleavage
of the manganese-hydro(alkyl)peroxo precursors, resulting in the
formation of a high-valent manganese-oxo species as an active
oxidant via the “carboxylic acid-assisted” mechanism (Scheme 3,
aReaction conditions: chalcone (0.20 mmol), catalyst (2.0 mol%), oxi-
dant (2 equiv to substrate), and 2-ethylhexanoic acid (EHA; 0 or 5 equiv
to substrate) in CH CN at 0 °C for 2 h.
3
5b,11
pathways a and c).
results are rationalized with the roles of protic solvent and carboxylic
acid for the efficient formation of an active Mn-oxo species and the
enhanced epoxidation enantioselectivity, respectively. That is, a
When the catalytic epoxidation of chalcone by 1 and H
2
2
O was
carried out in protic solvent (i.e., trifluoroethanol (TFE)) in the
absence of the carboxylic acid additive, chalcone oxide was produced
with a high yield but the ee value was low (Scheme 4). Interestingly,
when the epoxidation reaction was carried out in the presence of
EHA under the identical conditions, we observed the formation of
chalcone oxide not only with a high product yield but also with a
good enantioselectivity (Scheme 4); the ee value was increased from
31% in the absence of EHA to 86% in the presence of EHA. These
Mn(III)-hydroperoxo species is converted to
a Mn-oxo
intermediate via an “alcohol-assisted” heterolytic O-O bond
cleavage; this “alcohol-assisted” mechanism is similar to the “water-
assisted” mechanism proposed previously by Que and co-
Indeed, it has been shown in iron porphyrin systems
that the O-O bond of iron(III)-hydroperoxo porphyrin species is
heterolytically cleaved in protic solvents (e.g., methanol), thereby
5
b,23
workers.
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9
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
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4
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4
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5
5
5
5
5
5
5
6
a
Scheme 4. Epoxidation of Chalcone by 1 and H
2
O in Protic Solvent
2
aReaction conditions: chalcone (0.20 mmol), 1 (2.0 mol%), H
mmol), and EHA (0 or 1.0 mmol) at 0 °C for 2 h.
2
O (0.40
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 3. cis-Binding Sites Required for the Formation of Active
Manganese-Oxo Species in the Reactions of H
Hydroperoxides
2
2
O and Alkyl
affording high product yields in the catalytic epoxidation of olefins
2
4
by iron(III) porphyrin complexes and H
2
O . More importantly,
2
the observation that the ee value was increased dramatically in the
presence of carboxylic acid is the direct evidence that carboxylic acid
plays an important role in tuning the epoxidation enantioselectivity
via either coordinated or non-coordinated carboxylic acid (vide
infra).
In the epoxidation reactions using 2 as a catalyst, product yields
were low in the reactions of H
2
2
O and alkyl hydroperoxides even in
Scheme 5. Formation of Active Manganese-Oxo Species in the
Reactions of 1 and 2 with PhIO
the presence of carboxylic acid (Table 2, entries 10 – 15), probably
due to the single binding site available at the Mn center in 2 (Scheme
3
, pathway b; see also the structure in Table 1 and Scheme 2). These
results demonstrate again the importance of the two cis-binding sites
to form an active Mn-oxo intermediate via the “carboxylic acid-
assisted” mechanism (Schemes 1 and 3). In addition, the present
results lead us to propose that a pyridyl group coordinating at the
manganese center in 2 cannot be replaced by carboxylic acid (vide
infra). If carboxylic acid can coordinate to Mn center by replacing a
out in the presence of carboxylic acid, not only the product yields but
also the ee values increased dramatically in the reactions of 1 and 2
(Table 2, entries 8 and 17). These results demonstrate that highly
reactive and enantioselective manganese-oxo intermediates were
formed in the reactions of 1 and 2 with PhIO in the presence of
carboxylic acid (Scheme 5). In addition, there are several important
points that should be addressed here: First, in the catalytic
epoxidation of chalcone by 1, the ee value obtained in the reaction
of PhIO was virtually the same as those obtained in the reactions of
N5
pyridyl group in L , the reactivity of 2 would be similar to that of 1
in the epoxidation of olefins by H
2
2
O and alkyl hydroperoxides;
however, 2 is not an effective catalyst in these reactions (Table 2,
entries 11, 13, and 15). We therefore conclude that the low catalytic
H
2
O and alkyl hydroperoxides (Table 2, entries 2, 4, and 6 for
2
activity of 2 in the epoxidation reactions by H
2
O
2
and alkyl
peroxides and entry 8 for PhIO), suggesting that a common
intermediate (e.g., Mn-oxo species) was generated as an active
oxidant in all of the reactions. If different oxidants (e.g., Mn-oxidant
adducts such as Mn-OOH(R) or Mn-OIPh) were involved in the
catalytic epoxidation reactions, the ee values of the epoxide product
would be different depending on the terminal oxidants. Second, it is
notable that the ee value obtained in the reaction of 2 and PhIO was
high. It has been shown above that carboxylic acid cannot bind to 2
hydroperoxides even in the presence of carboxylic acid additive is
due to the lack of two cis-binding sites for oxidant and carboxylic
acid at the Mn center in 2 (Scheme 3, pathway b)
(ii) Reactions with PhIO. Iodosylbenzene (PhIO) is a single oxygen
atom donor, which does not require the O-O bond cleavage step in
generating high-valent metal-oxo intermediates. Therefore,
different from the reactions of H
2
2
O and alkyl hydroperoxides, the
N5
by replacing one of the pyridyl groups in L . Nonetheless, the ee
catalytic activities of 1 and 2 bearing tetradentate N4 and
pentadentate N5 ligands, respectively, would be similar in the
reactions using PhIO as a terminal oxidant. In order to verify this
hypothesis, we carried out the epoxidation of chalcone by PhIO
catalyzed by 1 and 2 in the absence and presence of carboxylic acid.
First, in the absence of carboxylic acid, the product yields and the ee
values were low in the reactions of 1 and 2 (Table 2, entries 7 and
value was increased from 25% in the absence of carboxylic acid to 78%
in the presence of carboxylic acid. The latter result implies that the
enantioselectivity can be affected by non-coordinated carboxylic
acid molecule(s), probably via a second-sphere hydrogen-bonding
interaction between the H-atom(s) of the carboxylic acid and the
oxo group of the manganese-oxo species (Scheme 6). It has been
shown previously that secondary coordination sphere effects play an
important role in selectivity and reactivity in a number of catalytic
1
6). The low ee values were not unexpected, since carboxylic acid
plays an important role in tuning epoxidation enantioselectivity
vide supra). Interestingly, when the identical reactions were carried
2
5
and enzymatic reactions. However, to the best of our knowledge,
this is the first example showing that the epoxidation
(
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Table 3. Epoxidation of cis-Stilbene (Gray Area) and Competitive
1
2
3
4
5
6
7
Epoxidation of cis- and trans-Stilbenes (Orange Area)
a,c
(1) Epoxidation of cis-stilbene
b,c
Scheme 6. Proposed Second-Sphere Hydrogen-Bonding
Interaction That Controls the Epoxidation Enantioselectivity
(2) Competitive epoxidation of cis- vs trans-stilbenes
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
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7
8
9
0
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2
3
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
enantioselectivity can be affected by the non-coordinated carboxylic
acid(s); as discussed briefly above, carboxylic acid molecule(s)
modulates the enantioselectivity of Mn-oxo species through a
hydrogen-bonding interaction with the manganese-oxo moiety.
Indeed, it has been shown recently that the reactivity of high-valent
metal-oxo species is greatly influenced by the presence of protons,
probably through a hydrogen-bonding interaction between metal-
(1) ratio of cis- to (2) ratio of cis- to
entry cat. oxidant
trans-stilbene
trans-stilbene
oxide products
oxide productsd
e
1
2
3
4
5
1
H
2
O
2
40/1
40/1
40/1
40/1
40/1
1/4
1/4
1/4
1/4
1/4
26,27
oxo moiety and proton(s). Finally, the increased product yields
in the reactions of 1 and 2 with PhIO in the presence of carboxylic
acid are due to the increased solubility of the polymeric PhIO by the
carboxylic acid (eq 1) (see the data in the columns of conversion and
yield in Table 2, entries 7 and 8 for 1 and entries 16 and 17 for 2).
TBHP
CHP
This speculation is evidenced by using PhI(OAc)
2
, which is soluble
in CH CN, as a terminal oxidant (Table 2, entries 9 and 18); the
3
PhIO
product yields as well as the ee values were high in these reactions.
2
PhIO
In this section, we have discussed the carboxylic acid effect in the
asymmetric epoxidation of chalcone by various oxidants, such as
a
b
Reaction conditions: cis-Stilbene (0.20 mmol), oxidant (2 equiv); cis-
stilbene (0.10 mmol) + trans-stilbene (0.10 mmol), oxidant (0.040
H
2
2
O , alkyl hydroperoxides, and` PhIO, catalyzed by two
c
mmol, 0.2 equiv); catalyst (2.0 mol%), EHA (5 equiv), in
mononuclear nonheme manganese complexes bearing tetradentate
N4 and pentadentate N5 ligands; one of the significant observations
is that the enantioselectivity in epoxidation can be affected by non-
coordinated carboxylic acid molecule(s), probably via a second-
sphere coordination interaction between carboxylic acid and the oxo
group of a manganese-oxo oxidant. The carboxylic acid effect was
also shown in the epoxidation of other olefins, such as cyclooctene,
styrene, and 1-octene, in which the product yields were dependent
significantly on the presence of carboxylic acid and the availability of
two cis-binding sites in the Mn catalysts (SI, Tables S3 – S5).
d
CH
3
CN/CH
2
Cl
2
(3:1 v/v) at 0 °C for 2 h. Products from epoxidation
e
of cis-stilbene; products from the competitive epoxidation of cis- and
trans-stilbenes.
error (e.g., ~90%) when the reactions were carried out in the
presence of carboxylic acid (Table 2, entries 2, 4, 6, and 8). These
results suggest that a common intermediate was generated as an
active oxidant in all of the reactions. Herein, we carried out the
epoxidation of cis-stilbene and the competitive epoxidation of cis-
and trans-stilbenes and compared the ratios of cis- and trans-stilbene
oxide products,to support that one oxidant is indeed responsible for
the epoxidation reactions (see the reaction Schemes shown in Table
3).
Nature of Reactive Intermediate(s). There has been a long-
standing debate on one oxidant (e.g., high-valent metal-oxo species)
versus multiple oxidants (e.g., high-valent metal-oxo plus metal-
2
8,29
oxidant adducts) in the catalytic oxidation of organic substrates.
The mechanism of the O-O bond cleavage of metal-
hydro(alkyl)peroxo intermediates for the formation of high-valent
metal-oxo species (e.g., homolysis versus heterolysis) has also been
of great interest in the community of bioinorganic/biomimetic
First, in the oxidation of cis-stilbene, cis-stilbene oxide was
produced predominantly with a trace amount of trans-stilbene oxide
and the ratio of cis- to trans-stilbene oxide products was 40:1 in all of
the reactions (see Table 3, the gray-colored column; SI, Figure S5
for NMR analysis); it was shown previously that cis-olefin oxides
were produced in the epoxidation of cis-olefins by nonheme
3
0
chemistry. In this section, we report the nature of active oxidant(s)
and the O-O bond cleavage mechanism in the catalytic epoxidation
of olefins by manganese catalysts, 1 and 2, with various oxidants in
the presence of carboxylic acid.
20a
manganese catalysts in the presence of carboxylic acid additive. In
the epoxidation of trans-stilbene, trans-stilbene oxide was
exclusively produced in all of the reactions (SI, Table S6). These
results demonstrate that the epoxidation of olefins is highly
stereospecific. We then performed a competitive epoxidation
reaction with cis- and trans-stilbenes, since it has been often used as
a mechanistic probe to propose one oxidant versus multiple oxidants
(
i) Mechanistic Studies in Olefin Epoxidation. We have shown
above that the ee values of epoxide product formed in the catalytic
epoxidation of chalcone by 1 with various oxidants, such as H
alkyl hydroperoxides, and PhIO, were the same within experimental
2
2
O ,
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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
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9
0
1
2
3
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 7. Heterolytic vs Homolytic O–O Bond Cleavage
Mechanisms
3
1
in catalytic oxidation reactions. Interestingly, the ratios of cis- to
trans-stilbene oxide products were the same irrespective of the
oxidants and catalysts used (see Table 3, the orange-colored column;
SI, Figure S6 for NMR analysis), providing strong evidence that one
oxidant is responsible for the olefin epoxidation by manganese
catalysts with PhIO, H
2
2
O , TBHP, and CHP in the presence of
carboxylic acid. We presume that a Mn-oxo species is generated as
an active oxidant in the epoxidation reactions, although we cannot
distinguish Mn(IV)-oxo versus Mn(V)-oxo from the mechanistic
studies (vide infra). As discussed above, if Mn-oxidant adducts are
involved in the competitive epoxidation reactions, then the ratio of
cis- to trans-stilbene oxides would be different depending on the
terminal oxidants.
We then analyzed products derived from the CHP reactions to
understand the mode of the O-O bond cleavage of the presumed
Mn(III)-alkylperoxo precursor; CHP has been often used as an
oxidant probe to propose the O-O bond homolysis versus
32
heterolysis mechanisms. As shown in Scheme 7, cumyl alcohol is
the product in the heterolytic O−O bond cleavage pathway (SI,
Figure S7 for HPLC analysis), whereas the homolytic O−O bond
cleavage pathway affords acetophenone as a product. Since cumyl
alcohol was formed quantitatively in the epoxidation of chalcone
and other olefins by CHP catalyzed by 1 in the presence of carboxylic
acid, we conclude that the O-O bond of Mn-(hydro)alkylperoxo is
cleaved heterolytically.
Figure 1. (a) UV-vis absorption spectral changes showing the formation
of 3 (red line) observed in the reaction of 1 (0.50 mM, blue line) and
PhIO (2.5 mM) in CH CN at –40 °C. Inset shows the time course
monitored at 590 nm for the formation of 3. (b) CSI-TOF MS spectrum
3
(ii) Reactivity of a Synthetic Mn(IV)-Oxo Complex. Two high-
valent Mn-oxo complexes, such as Mn(IV)-oxo and Mn(V)-oxo, can
be considered as the intermediate generated in the reactions of 1
16
of 3. Inset shows the isotope distribution patterns of 3- O (blue line)
1
8
and 3- O (red line). (c) X-band CW-EPR spectrum of 3 recorded at 5
K. The signal at g = 3.7 is characteristic of S = 3/2 high-spin
manganese(IV) species. The signals around at g = 2.0 with impurity
scale (<3%) are assignable to the dimanganese(III,IV) species.
with PhIO, H
Mn(IV)-oxo complexes have been successfully synthesized
2
2
O , TBHP, and CHP. Since mononuclear nonheme
3
3-36
recently,
by following the literature procedues. Addition of 5 equiv of PhIO
to 1 in CH CN at –40 °C resulted in the formation of a yellowish-
green intermediate (3), with a broad absorption band at λmax = 590
we attempted to synthesize a Mn(IV)-oxo species of 1
3
3b
that 3 contains one oxygen atom. The X-band CW-EPR spectrum of
3
3
, recorded in a frozen solution at 5 K, exhibits signals corresponding
IV
33-35
to high-spin (S = 3/2) Mn species (Figure 1c).
Based on the
−1
−1
nm (ε = ~500 M cm ) (Figure 1a; see also SI, Figure S8 for natural
decay). The intermediate 3 was characterized with coldspray
ionization time-of-flight mass spectrometer (CSI-TOF MS) and
electron paramagnetic resonance (EPR) spectroscopy. The CSI-
TOF MS of 3 exhibits a prominent peak at m/z = 474.2, whose mass
spectroscopic characterization, the intermediate 3 is assigned as
IV
N4 2+
[Mn (O)(L )] .
Then, the reactivity of 3 was examined in olefin epoxidation
reactions, by adding substrates to the solution of 3 generated in situ
in CH CN at –40 °C. The UV-vis spectrum of 3 was intact upon
3
and
isotope
distribution
pattern
correspond
to
N4
IV
+
addition of chalcone or cyclooctene (25 mM; 50 equiv to 3) (SI,
Figure S9), suggesting that 3 is not capable of epoxidizing olefins at
[(L )Mn (O)(OCH
3
)] (calculated m/z = 474.2) (Figure 1b).
18
18
When 3 was prepared with an isotopically O-labeled PhI O, a mass
shift from 474.2 to 476.2 was observed (Figure 1b, inset), indicating
o
–40 C. Further, 3 even in the presence of carboxylic acid (e.g., EHA)
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incompetent in epoxidizing olefins, leading us to exclude Mn(IV)-
did not react with olefins (SI, Figure S9). In contrast, under the
identical reaction conditions, the catalytic epoxidation of chalcone
by H in the presence of carboxylic acid (EHA) in CH CN at –40
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
oxo as an active oxidant and propose Mn(V)-oxo species as the most
plausible active oxidant in the catalytic olefin epoxidation reactions.
2
O
2
3
o
C afforded the epoxide product with 67% yield (see Experimental
Section for detailed reaction procedures). Based on the results of the
stoichiometric and catalytic reactions, we are able to exclude the
Mn(IV)-oxo species as a potent intermediate responsible for the
olefin epoxidation, since the synthetic Mn(IV)-oxo complex was not
reactive with olefins. The remaining candidate that can be
considered as an active oxidant is a Mn(V)-oxo species, although
such a mononuclear nonheme Mn(V)-oxo species bearing neutral
tetradentate N4 and pentadentate N5 ligands has never been
detected in any stoichiometric and catalytic reactions. Nonetheless,
In future studies, it will be of great interest if mononuclear
nonheme Mn(V)-oxo species bearing neutral tetradentate N4 and
pentadentate N5 ligands are synthesized and their chemical
37
properties are unveiled in (asymmetric) oxidation reactions.
Materials. All chemicals were purchased from commercial sources
with the maximum purity available and used as received unless
mentioned otherwise. Anhydrous solvents were purified using
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
38
standard methods. 2 was prepared according to published
6,7,12,14,16-20,22,23
as proposed in a number of cases,
we believe that a
21
procedures (see SI, Figure S1 for the synthetic method).
Mn(V)-oxo species is the active oxidant that effects the olefin
epoxidation reaction.
Manganese catalysts were purified before use by recrystallization
with acetonitrile and ether.
N4
Synthesis of L and Its Manganese Complex. The precursor
N4
compound of L , (S)-2-(benzylaminomethyl)pyrrolidine, was
In bioinspired catalytic systems (e.g., nonheme iron and manganese
3
9
N4
synthesized according to a literature method. Then, ligand L was
synthesized by reacting (S)-2-(benzylaminomethyl)pyrrolidine
catalysts/H
2
2
O /carboxylic acid) for the (asymmetric) epoxidation
of olefins, carboxylic acid is an essential additive that improves the
catalytic activity and enantioselectivity of the metal complexes. In
this work, we have performed mechanistic studies to understand the
carboxylic acid effect and the nature of the active intermediate(s) in
the manganese complex-catalyzed enantioselective epoxidation of
olefins, by employing nonheme manganese catalysts (e.g., 1 and 2)
with 2-picolylchloride hydrochloride in the presence of KI and
o
triethylamine (Et
3
N) in CH
3
CN at 25 C, as reported previously
1
13
21
(
see SI, Figure S10 for H and C NMR spectra). Finally,
II
N4
[Mn (L )(OTf)
2
] (1) was synthesized by reacting Mn(OTf)
2
with
CN at 25 C (see SI, Figure S1).
Crystals of 1 suitable for X-ray diffraction were obtained by diffusing
ether into the CH CN solution. CCDC 1587411 (in the Cambridge
N4
o
equimolar amounts of L in CH
3
and various oxidants (e.g., H
results obtained herein are summarized as follows:
1) The catalytic systems of 1/H -TBHP-CHP/carboxylic
acid afford high product yields with good enantioselectivities,
whereas the catalytic systems of 2/H -TBHP-CHP/carboxylic
2
O
2
, TBHP, CHP, and PhIO). The
3
Crystallographic Data Centre) contains the supplementary
crystallographic data for 1.
(
2
O
2
1
13
Instruments and Analysis Methods. H and C NMR spectra
2
O
2
1
were recorded using a Bruker Avance III 400MHz spectrometer. H
acid are inefficient. Given that 1 has two cis-binding sites but 2 has
only one binding site, the results demonstrate the significance of two
cis-binding sites to form an active Mn-oxo oxidant via the
1
3
and C NMR spectroscopic chemical shifts (ppm) were referenced
to the residual solvent peaks. High resolution mass spectra (HRMS)
were recorded on an Agilent 6530 Q-TOF mass spectrometer with
an ESI source. Optical rotation was recorded with a Perkin-Elmer
“
carboxylic acid-assisted” mechanism.
(2) In protic solvent, the product yield is high in the catalytic
3
41 polarimeter (sodium lamp, 1-dm cuvette, c in g/100 ml, 20 °C).
system of 1/H
2
2
O even in the absence of carboxylic acid (e.g., an
X-ray crystallographic data were collected at 173 K on a Bruker
Smart APEX II diffractometer equipped with Cu Kα radiation (λ =
“alcohol-assisted” heterolytic O-O bond cleavage), but the
enantioselectivity is low. The enantioselectivity is increased upon
addition of carboxylic acid, demonstrating that carboxylic acid
modulates the epoxidation enantioselectivity.
1
.54184 Å). GC-MS analyses were performed with Agilent
7890A/5975C GC-MS system with an HP-5 MS column. HPLC
analysis for measuring ee values was performed with a SHIMADZU
system (SHIMADZU LC-20AT pump, SHIMADZU LC-20A
Absorbance Detector) with a Chiralpak OD-H column (Daicel
Chemical Industries, LTD). HPLC analysis for product(s) derived
from the decomposition of the cumyl hydroperoxide was performed
using an Agilent 1260 infinity instrument with an Agilent Zorbax SB-
C18 column. GC analysis for ee values, conversion and yields were
performed with an Agilent 7890 GC instrument with a CP-Chirasil-
Dex CB column. UV-vis spectra were recorded on an Agilent 8454
spectrophotometer equipped with a variable-temperature liquid-
nitrogen cryostat (UNISOKU Scientific Instruments). X-band CW-
EPR spectra were recorded at 5 K using an X-band Bruker EMX-plus
spectrometer equipped with a dual mode cavity (ER 4116DM). Low
temperatures were achieved and controlled with Oxford
Instruments ESR900 liquid Helium quartz cryostat fitted with an
Oxford Instruments ITC503 temperature and gas flow controller
(3) The enantioselectivity in the catalytic system of 2/PhIO is
dramatically increased upon addition of carboxylic acid. Since
carboxylic acid cannot bind to the manganese center in 2, we
propose that the epoxidation enantioselectivity can be modulated by
the non-coordinated carboxylic acid molecule(s), probably through
a second-sphere hydrogen-bonding interaction between the non-
coordinated carboxylic acid molecule(s) and the Mn-oxo moiety.
(4) Irrespective of the oxidants, the catalytic systems of 1/H
2
2
O -
TBHP-CHP-PhIO/carboxylic acid afford virtually the same ee
values in the asymmetric epoxidation of olefins. In addition, the
ratios of cis- to trans-stilbene oxide products are the same in the
competitive epoxidation of cis- versus trans-stilbenes as well as in the
cis-stilbene epoxidation. These results demonstrate that a common
intermediate (e.g., Mn-oxo) is generated as an active oxidant in all of
the catalytic systems.
[experimental parameters; microwave frequency = 9.647 GHz,
(
5) A synthetic Mn(IV)-oxo complex of 1 is shown to be
microwave power = 1.0 mW, modulation amplitude = 10 G, gain =
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× 10 , modulation frequency = 100 kHz, time constant = 40.96 ms,
Page 8 of 11
4
1
The authors declare no competing financial interest.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
conversion time = 85.00 ms]. CSI-TOF MS spectra were collected
on a JMS-T100CS (JEOL) mass spectrometer equipped with a CSI
source. Typical measurement conditions were as follows: needle
voltage: 2.2 kV, orifice 1 current: 50-500 nA, orifice 1 voltage: 0 to
20 V, ring lens voltage: 10 V, ion source temperature: 5 °C, spray
We acknowledge financial support of this work from the National Natu-
ral Science Foundation of China (21473226 and 21773237 to W.S.)
and the NRF of Korea through CRI (NRF-2012R1A3A2048842 to
W.N.), GRL (NRF-2010-00353 to W.N.), and Basic Science Research
Program (2017R1D1A1B03029982 to Y.M.L.).
1
8
temperature: –40 °C. The CSI-TOF mass spectra of 3 and 3- O
were obtained by infusing the reaction solution directly into the ion
source through pre-cooled tube under high N gas pressure.
2
Typical Procedure for Catalytic Olefin Epoxidations. Substrate
(0.20 mmol), carboxylic acid additive (1.0 mmol, 5 equiv to
substrate), and manganese catalyst (4.0 µmol, 2.0 mol% to substrate)
(
1) (a) Que, L., Jr.; Tolman, W. B. Biologically Inspired Oxidation Ca-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
talysis. Nature 2008, 455, 333–340. (b) Newhouse, T.; Baran, P. S. If C–H
Bonds Could Talk: Selective C–H Bond Oxidation. Angew. Chem. Int. Ed.
2011, 50, 3362–3374. (c) Hartwig, J. F.; Larsen, M. A. Undirected, Homo-
geneous C–H Bond Functionalization: Challenges and Opportunities. ACS
Cent. Sci. 2016, 2, 281–292.
(2) (a) Abu-Omar, M. M.; Loaiza, A.; Hontzeas, N. Reaction Mecha-
nisms of Mononuclear Non-Heme Iron Oxygenases. Chem. Rev. 2005, 105,
227–2252. (b) Krebs, C.; Galonić Fujimori, D.; Walsh, C. T.; Bollinger, J.
were dissolved in CH CN (2 mL), and the mixture was
3
thermostated at 0 °C. Then the desired oxidant (0.40 mmol, 2 equiv
to substrate) was added in one portion for TBHP, CHP and PhIO
or over 0.5 h via a syringe pump for H
for 2 h, saturated NaHCO and Na
added to quench the reaction. For cis-, trans-stilbene, and chalcone,
the mixture was dried over anhydrous Na SO and filtered through
a short column of silica gel, which was subsequently rinsed with ethyl
acetate. After evaporation, internal standard CH Br was added to
2
O
2
upon stirring. After stirring
3
2
S
2
O
3
aqueous solutions were
2
M., Jr. Non-Heme Fe(IV)–Oxo Intermediates. Acc. Chem. Res. 2007, 40,
484–492. (c) Ortiz de Montellano, P. R. Hydrocarbon Hydroxylation by Cy-
tochrome P450 Enzymes. Chem. Rev. 2010, 110, 932–948. (d) Solomon, E.
2
4
2
2
I.; Goudarzi, S.; Sutherlin, K. D. O
Biochemistry 2016, 55, 6363–6374.
3) (a) Liu, W.; Groves, J. T. Manganese Catalyzed C–H Halogenation.
2
Activation by Non-Heme Iron Enzymes.
1
the residue. Products were analyzed by H NMR to determine the
conversion and yield. For cyclooctene and styrene, the resulting
solution was extracted with ether before GC analysis. Products were
analyzed by GC in the presence of decane as the internal standard. It
(
Acc. Chem. Res. 2015, 48, 1727–1735. (b) Engelmann, X.; Monte-Pérez, I.;
Ray, K. Oxidation Reactions with Bioinspired Mononuclear Non-Heme
Metal–Oxo Complexes. Angew. Chem. Int. Ed. 2016, 55, 7632–7649. (c)
Groves, J. T.; Myers, R. S. Catalytic Asymmetric Epoxidations with Chiral
Iron Porphyrins. J. Am. Chem. Soc. 1983, 105, 5791–5796. (d) Liu, W.;
Cheng, M.-J.; Nielsen, R. J.; Goddard, W. A., III; Groves, J. T. Probing the
C–O Bond-Formation Step in Metalloporphyrin-Catalyzed C–H Oxygena-
tion Reactions. ACS Catal. 2017, 7, 4182–4188.
should be noted that the CH
3
CN-CH
2
2
Cl (v/v 3:1) mixed solvent
was used for cis- and trans-stilbene because of the solubility of
substrates. Besides, to compare with stoichiometric reactions by
IV
Mn (O) species, catalytic epoxidation of chalcone by 1 was also
performed at –40 °C (reaction conditions: [chalcone] = 25 mM,
[EHA] = 125 mM, [1] = 0.50 mM, and [H
2
2
O ] = 50 mM).
(
4) (a) Che, C.-M.; Lo, V. K.-Y.; Zhou, C.-Y.; Huang, J.-S. Selective
Product Analysis for the Oxidation of Chalcone by Cumyl
Hydroperoxide. Chalcone (0.20 mmol), EHA (1.0 mmol; 5 equiv to
substrate) and 1 (4.0 µmol, 2.0 mol% to substrate) were dissolved in
Functionalisation of Saturated C–H Bonds with Metalloporphyrin Catalysts.
Chem. Soc. Rev. 2011, 40, 1950–1975. (b) Costas, M. Selective C–H Oxi-
dation Catalyzed by Metalloporphyrins. Coord. Chem. Rev. 2011, 255,
912–2932. (c) Lu, H.; Zhang, X. P. Catalytic C–H Functionalization by
Metalloporphyrins: Recent Developments and Future Directions. Chem.
Soc. Rev. 2011, 40, 1899–1909.
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CH CN (2.0 mL) and thermostated at 0 °C. Then cumyl
3
hydroperoxide (40 µmol) was added to reaction solution in one
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by HPLC (Agilent Zorbax SB-C18 column; H
2
O : CH
3
CN (v/v
-1
5
0:50); flow rate 1.0 ml min ; monitoring at 215 nm; 30 °C).
Quantitative analysis was conducted on the basis of comparison
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Crystallographic data for [Mn (L )(OTf) ] (1) (CIF)
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