Mechanism of Selective C-H Hydroxylation Mediated by Manganese Aminopyridine Enzyme Models

Article abstract of DOI:10.1021/cs5013206

The mechanism of selective oxidation of aliphatic C-H groups with H₂O₂ in the presence of aminopyridine Mn complexes, modeling the reactivities of natural oxygenases of the cytochrome P450 superfamily, has been examined. The oxygenation of C-H groups proceeds via hydrogen atom abstraction by the electrophilic metal site; the logarithm of C-H oxidation rates correlates linearly with bond dissociation energies for homolytic C-H bond cleavage. Hammett correlations and stereospecificity studies reflect the formation of a short-lived electron-deficient radical intermediate. Isotopic labeling studies confirm the incorporation of ¹⁸O from added H₂¹⁸O, thus providing so far lacking evidence for the oxomanganese(V)-mediated oxidation mechanism. (Figure Presented).

Full text of DOI:10.1021/cs5013206

Subscriber access provided by ONDOKUZ MAYIS UNIVERSITESI
Article
Mechanism of Selective C-H Hydroxylation Mediated
by Manganese-Aminopyridine Enzyme Models
Roman V. Ottenbacher, Evgenii P. Talsi, and Konstantin P. Bryliakov
ACS Catal., Just Accepted Manuscript • Publication Date (Web): 10 Nov 2014
Downloaded from http://pubs.acs.org on November 10, 2014
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
ACS Catalysis is published by the American Chemical Society. 1155 Sixteenth Street
N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 18
ACS Catalysis
1
Mechanism of Selective C-H Hydroxylation Mediated by Manganese-
Aminopyridine Enzyme Models
2
3
4
5
6
7
8
Roman V. Ottenbacher,a,b Evgenii P. Talsi,a,b and Konstantin P. Bryliakov a,b*
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a Novosibirsk State University, Pirogova 2, Novosibirsk 630090, Russian Federation
b Boreskov Institute of Catalysis, Pr. Lavrentieva 5, Novosibirsk 630090, Russian Federation
Eꢀmail: bryliako@catalysis.ru
Abstract
The mechanism of selective oxidation of aliphatic CꢀH groups with H2O2 in the presence of
aminopyridine Mn complexes, modeling the reactivities of natural oxygenases of the cytochrome
P450 superfamily, has been examined. The oxygenation of CꢀH groups proceeds via hydrogen atom
abstraction by the electrophilic metal site; the logarithm of CꢀH oxidation rates correlates linearly
with bond dissociation energies for homolytic CꢀH bond cleavage. Hammett correlations and
stereospecificity studies reflect the formation of a shortꢀlived electronꢀdeficient radical
intermediate. Isotopic labeling studies confirm the incorporation of 18O from added H218O, thus
providing so far lacking evidence for the oxomanganese(V) mediated oxidation mechanism.
Keywords
CꢀH hydroxylation; biomimetic catalysis; enzyme models; hydrogen peroxide; manganese;
mechanism
1
ACS Paragon Plus Environment

ACS Catalysis
Page 2 of 18
1
2
Introduction
3
4
5
6
7
8
9
Ironꢀcatalyzed oxidations of aliphatic CꢀH groups has been considered an area of paramount
significance, partly owing to their relevance to the problem of modeling the catalytic cycle of
monoiron enzymes of the cytochrome P450 superfamily,1ꢀ14 as well as giving credit to potential
impact of direct preparative CꢀH oxofunctionalization processes on synthetic chemistry.15ꢀ25 In
contrast, though various naturally manganeseꢀcontaining enzymes are known,26ꢀ28 Mn based
enzyme models have so far been much less extensively studied in the context of biomimetic
selective CꢀH oxidations.29ꢀ39 In particular, until a couple of years ago there have been only two
reports on predictably selective CꢀH oxidations with H2O2 in the presence of mononuclear
biomimetic manganese complexes;40,41 in none of those cases the turnover numbers exceeded 10.
In 2012, we reported the first example of highly efficient, predictably regioselective, and
stereospecific oxidation of unactivated aliphatic CꢀH groups with H2O2 in the presence of
mononuclear manganese complexes 1ꢀ3 (Figure 1).42 The turnover numbers approached 970; high
sensitivity of the oxidation selectivity to electronic effects was documented. Notably,
aminopyridine Mn complexes in some cases demonstrated better characteristics (i.e. activity,
efficiency, selectivity) than structurally related nonꢀheme iron complexes,42 thus representing an
attractive platform for solving the two major challenges with development of practical catalysts, i.e.
generating sufficiently reactive metal complexes and controlling the oxidation selectivity.24
Particularly promising is the ability of direct and selective oxofuntionalizing organic substrates of
natural origin, which may further be exploited for further derivatization. Two examples of this kind
are presented in Figure 1.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Although the high selectivity (adamantane oxidation: 3°/2°= 40ꢀ49) and stereospecificity
(cisꢀ1,2ꢀdimethylcyclohexane oxidation: > 99 % retention of cisꢀconfiguration)42 ruled out nonꢀ
selective free radical driven reaction pathways, the nature of true active sites and the reaction
mechanism remained unestablished, which essentially inspired this work. Herein, we report the
experimental insight into the mechanism of regioꢀ and stereoselective bioinspired CꢀH oxidations
2
ACS Paragon Plus Environment

Page 3 of 18
ACS Catalysis
1
2
with H2O2, mediated by manganese aminopyridine synthetic enzyme models, achieved on the basis
3
4
5
of combined Hammett, KIE, stereospecificity, and isotopic labeling studies.
6
7
O
N
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
N
Mn
N
N
Mn
N
N
N
Mn
N
OTf
OTf
N
N
OTf
OTf
OTf
OTf
OTf
OTf
N
N
N
N
N
N
OTf
OTf
N
N
Mn
N
H
Mn
N
O
N
3
2
1
5
4
H
H
H
1 (0.1 mol %)
H
4
(0.1 mol %)
CH3CN / AcOH
H2O
OAc
OAc
H
O
CH3CN / AcOH
H2O2 (1.3 equiv)
H
H
H
O
O
2 (3 equiv)
15 °C
O
H
H
(+)-sclareolide
52 % (isolated)
(-)-ambroxide
(-)-acetoxy-p-menthane
66 %
(SI for Ref. 42)
Figure 1. Examples of manganeseꢀaminopyridine catalysts for CꢀH oxidations with H2O2 (1ꢀ3),42
and catalysts considered in this study (4, 5). Examples of oxidations of substrates of natural origin.
Results and discussion
First of all, the oxidation of substrates with benzylic CꢀH moieties was explored, aiming at
selecting proper substrates for further mechanistic studies. It was found that complex 1 did not
demonstrate so high efficiencies in the benzylic oxidations of ethylbenzene, as well as cumene and
its derivatives (Table 1). On the contrary, novel manganese catalysts 4 and 5 (Figure 1) with
electrophilicities attenuated by introduction of electronꢀdonating substituents43 were much more
efficient, performing up to 760 turnovers (Table 1). Table 1 demonstrates the general trend rather
explicitly: for benzylic oxidations, less reactive catalysts appear more productive. As distinct from
the oxidations of aliphatic CꢀH groups (yielding a mixture of the alcohol and ketone),42,44ꢀ47 the
resulting benzylic alcohols partially converted into the corresponding acetate under the
experimental conditions, owing to the presence of abundant acetic acid.
3
ACS Paragon Plus Environment

ACS Catalysis
Page 4 of 18
1
2
Table 1. Oxidation of cumenes with H2O2 on complexes 1, 4, 5.a
3
4
H
OH
OAc
R
O
R
R
5
6
7
Mn cat.
(0.1 mol. %)
+
+
CH3CN / AcOH
H2O2
8
0 °C
X
X
X
X
9
R= H, CH3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
entry substrate
catalyst conversion (%) yield of alcohol /
(TN)
ketone / acetate
1
ethylbenzene
ethylbenzene
19 (190)
47 (470)
25 (250)
41 (41)
11 / 8 / ꢀ
5 / 41 / ꢀ
1 / 24 / ꢀ
32 / ꢀ / 9
49 / 1 / 12
56 / 3 / 7.5
62 / 2 / 12
41 / 3 / ꢀ
47 / 10 / 7
32 / ꢀ / 7
32 / d
1
4
5
1 b
4
5
5
5
5
5
5
2
3
ethylbenzene
cumene
4
5
cumene
62 (620)
67 (670)
76 (760) c
44 (440)
64 (640)
39 (390)
42 (420)
6
cumene
7
cumene
8
pꢀNO2ꢀcumene
pꢀBrꢀcumene
pꢀMeꢀcumene
pꢀMeOꢀcumene
9
10
11
a
At 0 °C; [substrate]:[H2O2]:[AcOH]:[Mn]= 0.100 mmol : 0.13 mmol : 0.600 mmol : 0.1 ꢀmol,
oxidant added via syringe pump over 1 h and the mixture stirred for an additional 3 h, and analyzed
by GC. b catalyst load: 1 mol. %. c H2O2 0.200 mmol. d unidentified minor products (by GC): 10%.
The higher efficiency of complex 5 in benzylic oxidations was exploited for the competitive
oxidations of pꢀsubstituted cumenes, to evaluate the influence of electronic properties on the rates
+
of CꢀH oxidations. A highly linear Hammett correlation vs. σp was obtained (Figure 2a), giving a
moderately negative slope (ρ+) value of ꢀ1.0. The negative sign of ρ+ reflects an electronꢀdemanding
transition state. Its absolute value is somewhat higher than those documented for hydrogen
abstractions by free radical species (ꢀ0.4 to ꢀ0.6) such as cumyloxyl radical,48 tBuO•,49,50 tBuOO•,51
and benzotriazoleꢀNꢀoxyl52 but is close to the range typical for hydroxylations by electronꢀdeficient
transitionꢀmetal complexes (ꢀ1.1 to ꢀ2.0),53ꢀ58 including cytochrome P450 (ꢀ1.6).48 Thus, the
Hammett study points to a hydrogenꢀatom transfer mechanism, with formation of an electronꢀ
deficient, possibly radical, intermediate.56
4
ACS Paragon Plus Environment

Page 5 of 18
ACS Catalysis
1
2
3
4
5
6
7
8
Furthermore, the logarithms of relative rate constants (SI) for the oxidations of a series of
hydrocarbons correlated linearly with the homolytic CꢀH bond dissociation energies (BDEs) of the
substrates (Figure 2b). This linear relationship suggests that the reaction occurs in a common
mechanism.59ꢀ62 The sensitivity of the relative rates to BDE(CꢀH)63,64 represented by the slope of ca.
ꢀ0.32 in Figure 2b is similar to those previously reported by Tanaka (ꢀ0.3),65 Que (ꢀ0.35),62
Goldberg (ꢀ0.39),56 Mayer (ꢀ0.4)60 for H abstractions by highꢀvalent oxometal species.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
pꢀМеО
0,8
0,4
X
a
H
pꢀМе
pꢀН
0,0
pꢀBr
ꢀ0,4
ꢀ0,8
y = ꢀ1.005x ꢀ 0.020
R2 = 0.999
pꢀNO2
ꢀ0,8 ꢀ0,6 ꢀ0,4 ꢀ0,2 0,0 0,2 0,4 0,6 0,8 1,0
ꢀ1,0
σ+
p
4ꢀMeOꢀcumene
2,0
b
1,5
1,0
Ph3CH
Ph2CHCH3
0,5
PhꢀEt
cumene
84
0,0
ꢀ0,5
80
82
86
88
BDE / kcal molꢀ1
Figure 2. Hammett plot for the oxidation of pꢀsubstituted cumenes with H2O2 on complex 5 (a).
Correlation between the relative rates for the oxidations of various hydrocarbons with H2O2 on
complex 5 (b). Conditions: (0 °C), [substrate]:[H2O2]:[AcOH]:[Mn]= 0.100 mmol : 0.13
mmol : 0.600 mmol : 0.1 ꢀmol, oxidant added via syringe pump over 1 h and the mixture stirred for
an additional 3 h (see SI for details).
A second informative evidence for an Hꢀatomꢀabstraction mechanism for the oxygenated
products formation comes from the analysis of kinetic isotope effects. Competitive oxidations of
cumene/αꢀDꢀcumene reveal primary kH/kD of 3.5ꢀ3.9 (Table 2); the KIE values for the oxidation of
cyclohexane/d12ꢀcyclohexane falling in the range 3.8ꢀ4.7, thus clearly indicating that the hydrogen
atom lies on the reaction coordinate and participates in CꢀH bond breaking step during the
5
ACS Paragon Plus Environment

ACS Catalysis
Page 6 of 18
1
2
oxygenated product formation. The observed kH/kD values are substantially higher than those
3
4
5
•
documented for Hꢀabstraction from various CꢀH donors by OH radical (1ꢀ2),66ꢀ68 comparable to
KIE for H abstraction by tBuO• radical (ca. 4)69 but lower than by benzotriazoleꢀNꢀoxyl radical (11ꢀ
27).52 In fact, those moderate values are most consistent with the reported kH/kD values for the
oxidations of various CꢀHꢀdonors by electronꢀdeficient metal complexes such as iron (KIE 3.2ꢀ
4.3),70ꢀ73 ruthenium (KIE 4.2ꢀ6.5),55,74 and manganese (KIE 2.2ꢀ4.3).75ꢀ77
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 2. CꢀH oxidations with H2O2 on complexes 1, 4, 5.
a
kH/kD
18O (%)from H218O a,c
RC (%)b cisꢀ1,2ꢀDMCH
Complex
C6H12/C6D12
0 °C
20 °C
30 °C
cisꢀ1,2ꢀDMCH adamantane
H/D
3.5
3.8
3.9
4.1
4.7
3.8
> 99
> 99
98.6
97.1
> 99
98.6
94.3
–
–
1
4
5
> 99
> 99
18 (2.3)
7 (1.5)
27 (9.1)
18 (21.8)
For experimental details see Supporting Information. cisꢀ1,2ꢀDMCH = cisꢀ1,2ꢀdimethylcyclohexane.
a At 0 °C; b For all isomers of 1,2ꢀdimethylcyclohexanꢀ1ꢀol: RC = 100%×[(1R,2R) + (1S,2S)) ꢀ
18
((1R,2S) + (1S,2R))]/ [(1R,2R) + (1S,2S)) + ((1R,2S) + (1S,2R))]. c No AcOH; 20 equiv. H2 O relative to
alkane; yields of the corresponding alcohols given in parentheses as turnover numbers.
The obtained data, in principle, may point to a reaction mechanism similar to the classical
rebound mechanism postulated for the cytochrome P450 reaction cycle, which assumes an aliphatic
hydrogen abstraction by a ferryl intermediate (Cpd I), followed by oxygen rebound to form the
alcohol coordinated to the iron center (Scheme 1).78ꢀ83 Independent experimental evidence for the
formation of carbonꢀcentered radicals could provide additional arguments in favor of viability of
such mechanism in the case of aminopyridine manganese complexes. Indirect information of this
kind has been relatively abundant for nonꢀheme iron based systems, such as either (1) partial
erosion of stereochemistry upon the hydroxylation of alkane substrates containing 3° CꢀH bonds,
such as cis or trans stereoisomers of 1,2ꢀdimethylcyclohexane or decalin (intrinsically coupled with
6
ACS Paragon Plus Environment

Page 7 of 18
ACS Catalysis
1
2
3
4
5
6
7
8
trapping of dissolved O2),70,71 or (2) documented existence of alternative reaction pathways, such as
desaturations or secondary transformations ascribed to intramolecular rearrangements of the
initially formed Cꢀcentered radicals.17,18 As for secondary pathways, so far we have not obtained
any experimental evidence for that in Mnꢀaminopyridine mediated oxidations, the reactions
proceeding with high selectivity to alcohols (for 3° CꢀH bonds) or alcohol/ketone mixtures (for 2°
CꢀH bonds).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1. Part of proposed catalytic cycle for hydrocarbon oxidation by cytochrome P450.
The most straightforward evidence in favor of formation of radical intermediates is derived
from partial erosion of stereochemistry in the course of oxidation of cis or transꢀ1,2ꢀ
dimethylcyclohexane), due to the epimerization of tertiary alkyl radicals.70,71 Mn based catalysts of
the types 1, 2, 3, appear to be highly stereoretentive, leading to a >99 % retention of
stereoconfiguration (RC) in the oxidation of cisꢀ1,2ꢀdimethylcyclohexane at 0 °C (cf. also Ref. 42),
which is characteristic of very short lived alkyl radicals with lifetimes less than 10ꢀ10 s.70 One could
expect, however, that attenuation of electrophilicity of the Mn active site might slow down the
rebound step, while increased temperature might accelerate the inversion of tertiary alkyl radicals,
thus leading eventually to lower RC. In full agreement with this prediction, electronꢀrich catalysts 4
and 5 at +30 °C showed only 98.6 and 94.3 % RC, respectively (Table 2), thus providing the first
experimental evidence for the involvement of short lived alkyl radicals and hence, for the viability
of the rebound oxidation mechanism.
Unraveling the nature of the reactive highꢀvalent metalꢀoxo species in biomimetic systems is
a particular challenge. By analogy with the aminopyridine iron based catalyst systems, oxometal(V)
7
ACS Paragon Plus Environment

ACS Catalysis
Page 8 of 18
1
2
3
4
5
6
7
8
complexes were recently proposed as the most likely active species of aminopyridine manganese
catalyzed epoxidations.43,84 For oxidations promoted by structurally similar aminopyridine iron
complexes, the soꢀcalled “waterꢀassisted” mechanism71,78(Scheme 2) had been accepted, which
recently found further experimental support based on VTꢀMS studies.85 Furthermore, the
reactivities of the elusive oxoiron(V) species were monitored by EPR86,87 (we notice that Oloo et al.
have recently challenged88 the oxidation state assignment for the iron centers responsible for the
observed S = ½ signal89). Apparently, those approaches can hardly be directly transferred to Mn
based systems of the types 1ꢀ5, due to EPR invisibility of the expected oxomanganese(V) (d2)
species, and to their higher reactivity (and lower stability) as compared to iron prototypes.
However, some useful evidence can be derived from isotopic labeling studies.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
A characteristic feature of the “waterꢀassisted” mechanism is the incorporation of 18O
isotope from added 18Oꢀlabeled water into the resulting alcohols, which becomes possible due to
participation of water in the heterolysis of the OꢀO bond of the hydroperoxoiron(III) intermediate,90
and to the oxoꢀhydroxo tautomerism70ꢀ72,91,92 in the oxoiron(V) species (Scheme 2, top). Previously,
we noticed the apparent similarities of epoxidation mechanisms operated by aminopyridine
manganese complexes and their iron counterparts.43,84 However, the incorporation of 18O into
hydroxylated hydrocarbons on Mn complexes has never been achieved. The evident reason for that
was the need in the presence of the abundant additive – carboxylic acid – which blocked the H218O
coordination to the Mn site, thus suppressing the isotopic scrambling.43 We are pleased to report
that this restriction can be overcome by the use of catalysts 4 and 5 that turned out capable of
hydroxylating CꢀH bonds even without added carboxylic acid. In particular, a 7ꢀ27 % 18O
enrichment was documented for the oxidation of adamantane and cisꢀ1,2ꢀdimethylcyclohexane
(Table 2), thus providing so far lacking evidence in favor of “waterꢀassisted” mechanism in
manganese catalyzed oxidations. It should be noted that in the absence of AcOH, complexes 4 and 5
demonstrate lower reactivity, which becomes insufficient for activating stronger 2° CꢀH bonds.93
8
ACS Paragon Plus Environment

Page 9 of 18
ACS Catalysis
1
2
3
4
5
6
7
8
In the presence of acetic acid, the mechanism of formation of oxometal(V) is diverted to the
“carboxylicꢀacidꢀassisted” pathway (Scheme 2, bottom) which has been previously invoked in
studies of nonꢀheme Fe and Mn catalyzed oxidations to explain the coꢀcatalytic effects of
carboxylic acid additives.5,13,14,43,84 The accelerating effects of carboxylic acids in biomimetic
systems was also previously reported in Refs. 30ꢀ34, 37ꢀ39.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 2. “Waterꢀassisted” mechanism (top) and “carboxylicꢀacidꢀassisted” mechanism for the
formation of oxometal(V) active species. 18Oꢀlabeled oxygen atoms are coloured blue.
Conclusions
Insight into the mechanism of direct oxofunctionalization of CꢀH groups performed by highly
efficient and selective manganese based synthetic enzyme models has been achieved. Hammett
analysis, correlation of oxidation rates with CꢀH BDEs, and KIE data witness that the oxygenated
product formation proceeds via hydrogen atom abstraction from the CꢀH bond by the electrophilic
metal center. At the same time, Hammett data and analysis of stereospecificity of 3° CꢀH bond
hydroxylations reflect the formation of an electronꢀdeficient radical intermediate, which is
consistent with the rebound mechanism postulated for oxidations by cytochrome P450 enzymes.
Isotopic labeling studies confirm the incorporation of 18O from added H218O, thus bearing so far
lacking evidence for the viability of “waterꢀassisted” oxidation mechanism mediated by highꢀvalent
9
ACS Paragon Plus Environment

ACS Catalysis
Page 10 of 18
1
2
3
4
aminopyridine manganese oxo complex. We foresee further studies aimed at developing methods
for direct in situ detection of the elusive oxometal active species by spectroscopic techniques.
5
6
7
8
9
Associated content
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Supporting information, including materials and methods, synthetic procedures, general procedures
for CꢀH oxidations, KIE experiments, supplementary catalytic results, NMR data, examples of
NMR and MS spectra, and GCꢀMS chromatograms. This information is available free of charge via
the Internet at http://pubs.acs.org/.
Author information
Corresponding author
Eꢀmail: bryliako@catalysis.ru.
Notes
The authors declare no competing financial interest.
Acknowledgments
Financial support from the Russian Scientific Foundation (grant 14ꢀ13ꢀ00158) is gratefully
acknowledged. The authors thank Mr. M. V. Shashkov for the GCꢀMS measurements.
References
(1) Solomon, E. I.; Brunold, T. C.; Davis, M. I.; Kemsley, J. N.; Lee, S. K.; Lehnert, N.;
Neese, F.; Skulan, A. J.; Yang, Y. S.; Zhou, J. Chem. Rev. 2000, 100, 235ꢀ350.
(2) Costas, M.; Mehn, M. P.; Jensen, M. P.; Que, Jr., L. Chem. Rev. 2004, 104, 939ꢀ986.
(3) Meunier, B.; de Visser, S. P.; Shaik, S. Chem. Rev. 2004, 105, 3947ꢀ3980.
10
ACS Paragon Plus Environment

Page 11 of 18
ACS Catalysis
1
2
(4) Krebs, C.; Fujimori, D. G.; Walsh, C. T.; Bollinger, Jr., M. Acc. Chem. Res. 2007, 40,
3
4
5
484ꢀ492.
6
7
(5) Que, Jr., L. Acc. Chem. Res. 2007, 40, 493ꢀ500.
8
9
(6) Que, Jr., L.; Tolman, W. B. Nature, 2008, 455, 333ꢀ340.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(7) Bruijnincx, P. C. A.; van Koten, G.; Klein Gebbink, R. J. M. Chem. Soc. Rev. 2008, 37,
2716ꢀ2744.
(8) Company, A.; Gόmez, L.; Fontrodona, X.; Ribas, X.; Costas, M. Chem. Eur. J. 2008, 14,
5727ꢀ5731.
(9) Ortiz de Montellano, P. R. Chem. Rev. 2010, 110, 932ꢀ948.
(10) Costas, M. Coord. Chem. Rev. 2011, 255, 2912ꢀ2932.
(11) McDonald, A. R.; Que, Jr., L. Coord. Chem. Rev. 2013, 257, 414ꢀ428.
(12) Groves, J. T. Nat. Chem. 2014, 6, 89ꢀ91.
(13) MasꢀBallesté, R.; Que, Jr., L. J. Am. Chem. Soc. 2007, 129, 15964ꢀ15972.
(14) MasꢀBallesté, R.; Fujita, M.; Que, Jr., L. Dalton Trans. 2008, 1828ꢀ1830.
(15) Chen, M. S.; White, M. C. Science 2007, 318, 783ꢀ787.
(16) Chen, M. S.; White, M. C. Science 2010, 327, 566ꢀ571.
(17) Bigi, M. A.; Reed, S. A.; White, M. C. J. Am. Chem. Soc. 2012, 134, 9721ꢀ9726.
(18) Bigi, M. A.; Reed, S. A.; White, M. C. Nat. Chem. 2011, 3, 216ꢀ222.
(19) Gómez, L.; Canta, M.; Font, D.; Prat, I.; Ribas, X.; Costas, M. J. Org. Chem. 2013, 78,
1421ꢀ1433.
(20) Company, A.; Gómez, L.; Costas M. In Iron containing enzymes: versatile catalysts of
hydroxylation reactions in Nature; de Visser, S. P.; Kumar D., Eds.; RCS publishing: Cambridge,
2011, pp. 148ꢀ208.
(21) Talsi, E. P.; Bryliakov, K. P. Coord. Chem. Rev. 2012, 256, 1418ꢀ1434.
(22) Prat, I.; Gόmez, L.; Canta, M.; Ribas, X.; Costas, M. Chem. Eur. J. 2013, 19, 1908ꢀ1913.
11
ACS Paragon Plus Environment

ACS Catalysis
Page 12 of 18
1
2
3
4
(23) Prat, I.; Font, D.; Company, A.; Junge, K.; Ribas, X.; Beller, M.; Costas, M. Adv. Synth.
Catal. 2013, 355, 947ꢀ956.
5
6
7
8
9
(24) Gunnoe, T. B. In Alkane C–H Activation by SingleꢀSite Metal Catalysis; Pérez, P. J., Ed.
Springer: Dordrecht, 2012, p. 13.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(25) Shul’pin, G. B. Dalton Trans. 2013, 42, 12794ꢀ12818.
(26) Including the oxygen evolving complex of photosystem II, manganese superoxide
dismutases and hydrogen peroxide catalases, oxidoreductases, transferases, hydrolases, lyases,
isomerases, ligases, lectins, and integrins, Refs. 27, 28.
(27) Law, N. A.; Caudle, M. T.; Pecoraro, V. L. Adv. Inorg. Chem. 1999, 46, 305ꢀ440.
(28) Tanase, S.; Bowman, E. In Advances in Inorganic Chemistry; van Eldik, R.; Reedijk, J.,
Eds., Academic Press: Amsterdam, 2006, p. 34.
(29) Essentially, CꢀH oxidations catalyzed by dinuclear Mnꢀtrimethyltriazacyclononane
complex were explored, that mostly displayed characteristics of a radicalꢀdriven processes, i.e. low
siteꢀselectivity, erosion of stereoconfiguration in oxidation of cisꢀ and transꢀ1,2ꢀ
dimethylcyclohexane, etc., see Refs. 30ꢀ39.
(30) Lindsay Smith, J. R.; Shul’pin, G. B. Tetrahedron Lett. 1998, 39, 4909ꢀ4912.
(31) Shul’pin, G. B.; SüssꢀFink, G.; Lindsay Smith, J. R. Tetrahedron 1999, 55, 5345ꢀ5358.
(32). B. Shul’pin, G. B.; SüssꢀFink, G.; Shul’pina, L. S. J. Mol. Catal. A: Chem. 2001, 170,
17ꢀ34.
(33) Shul’pin, G. B.; Nizova, G. V.; Kozlov, Y. N.; Pechenkina, I. G. New J. Chem. 2002, 26,
1238ꢀ1245.
(34) Nizova, G. V.; Bolm, C.; Ceccarelli, S.; Pavan, C.; Shul’pin, G. B. Adv. Synth. Catal.
2002, 344, 899ꢀ905.
(35) Bennur, T. H.; Sabne, S.; Desphande, S. S.; Srinivas, D.; Sivasanker, S. J. Mol. Catal. A:
Chem. 2002, 185, 71ꢀ80.
12
ACS Paragon Plus Environment

Page 13 of 18
ACS Catalysis
1
2
(36) Ryu, J. R.; Kim, S. O.; Nam, W.; Heo, S.; Kim, J. Bull. Korean Chem. Soc. 2003, 24,
3
4
5
1835ꢀ1837.
6
7
8
9
(37) Nizova, G. V.; Shul’pin, G. B. Tetrahedron 2007, 63, 7997ꢀ8001.
(38) Shul’pin, G. B.; Matthes, M. G.; Romakh, V. B.; Barbosa, M. I. F.; Aoyagi, J. L. T.;
Mandelli, D. Tetrahedron 2008, 64, 2143ꢀ2152.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(39) Romakh, V. B.; Therrien, B.; SüssꢀFink, G.; Shul’pin, G. B. Inorg. Chem. 2007, 46,
1315ꢀ1331.
(40) Nakayama, N.; Tsuchiya, S.; Ogawa, S. J. Mol Catal. A: Chem. 2007, 277, 61ꢀ71.
(41) Gómez, L.; GarciaꢀBosch, I.; Company, A.; BenetꢀBuchholz, J.; Polo, A.; Sala, X.;
Ribas, X.; Costas, M. Angew. Chem. Int. Ed. 2009 48, 5720ꢀ5723.
(42) Ottenbacher, R. V.; Samsonenko, D. G.; Talsi, E. P.; Bryliakov, K. P. Org. Lett. 2012,
14, 4310ꢀ4313.
(43) Ottenbacher, R. V.; Samsonenko, D. G.; Talsi, E. P.; Bryliakov, K. P. ACS Catal. 2014,
4, 1599ꢀ1606.
(44) Although the formation of alkyl hydroperoxides has been previously reported in
biomimetic systems (e.g. Refs. 45ꢀ47), the Shul’pin’s triphenylphosphineꢀaddition test did not
reveal the presence of alkyl hydroperoxides in our catalyst systems.
(45) Shul’pin, G. B. J. Mol. Catal. A: Chem. 2002, 189, 39ꢀ66.
(46) Shul’pin, G. B.; Kozlov, Y. N.; Shul’pina, L. S.; Kudinov, A. R.; Mandelli, D. Inorg.
Chem. 2009, 48, 10480ꢀ10482.
(47) Shul’pin, G. B.; Kozlov, Y. N.; Shul’pina, L. S.; Petrovsky, P. V. Appl. Organomet.
Chem. 2010, 464ꢀ472.
(48) Blake, II, R. C.; Coon, M. J. J. Biol. Chem. 1981, 256, 12127ꢀ12133.
(49) Sakurai, H.; Hosomi, A. J. Am. Chem. Soc. 1967, 89, 458ꢀ460.
(50) Walling, C.; McGuinness, J. A. J. Am. Chem. Soc. 1969, 91, 2053ꢀ2058.
13
ACS Paragon Plus Environment

ACS Catalysis
Page 14 of 18
1
2
(51) Russell, G. A. Free Radicals; Kochi, J. K., Ed.; Wiley: New York, 1973; Vol. 1, pp. 275ꢀ
3
4
5
331.
6
7
8
9
(52) Coniglio, A.; Galli, C.; Gentili, P.; Vadalà, R. Org. Biomol. Chem. 2009, 7, 155ꢀ160.
(53) Murahashi, S. I.; Komiya, N.; Oda, Y.; Kuwabara, T.; Naota, T. J. Org. Chem. 2000, 65,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
9186ꢀ9193.
(54) Farrer, B. T.; Pickett, J. S.; Thorp, H. H. J. Am. Chem. Soc. 2000, 122, 549ꢀ553.
(55) Wang, C.; Shalyaev, K. V.; Bonchio, M.; Carofiglio, T.; Groves, J. T. Inorg. Chem.
2006, 45, 4769ꢀ4782.
(56) Lansky, D. E.; Goldberg, D. P. Inorg. Chem. 2006, 45, 5119ꢀ5125.
(57) Lykakis, I. N.; Tanielian, C.; Seghrouchini, R.; Orfanopoulos, M. J. Mol. Catal. A:
Chem. 2007, 262, 176ꢀ184.
(58) Yi, C. S.; Kwon, K. H.; Lee, D. W. Org. Lett. 2009, 11, 1567ꢀ1569.
(59) Cook, G. K.; Mayer, J. M. J. Am. Chem. Soc. 1995, 117, 7139ꢀ7156.
(60) Gardner, K. A.; Kuehnert, L. L.; Mayer, J. M. Inorg. Chem. 1997, 36, 2069ꢀ2078.
(61) Mayer, J. M. Acc. Chem. Res. 1998, 31, 441ꢀ450.
(62) Kaizer, J.; Klinker, E. J.; Oh, N. Y.; Rohde, J. U.; Song, W. J.; Stubna, A.; Kim, J.;
Munck, E.; Nam, W.; Que, Jr., L. J. Am. Chem. Soc. 2004, 126, 472ꢀ473.
(63) Luo, Y. R. Handbook of Bond Dissociation Energies in Organic Compounds. CRC Press
LLC: Boca Raton, 2003.
(64) Bietti, M.; Capone, A. J. Org. Chem. 2008, 73, 618ꢀ629.
(65) Furukawa, S.; Shishido, T.; Teramura, K.; Tanaka, T. J. Phys. Chem. C 2011, 115,
19320ꢀ19327.
(66) TrotmanꢀDickenson, A. F. Adv. Free Radical Chem. 1965, 1, 1ꢀ38.
(67) Buxton, G. V.; Greenstock, C. L.; Helman, W. P.; Ross, A. B. J. Phys. Chem. Ref. Data
1988, 17, 513ꢀ886.
(68) Miyajima, S.; Simamura, O. Bull. Chem. Soc. Jpn. 1975, 48, 526ꢀ530.
14
ACS Paragon Plus Environment

Page 15 of 18
ACS Catalysis
1
2
3
4
5
6
7
8
(69) Kim, J.; Harrison, R. G.; Kim, C.; Que, Jr., L. J. Am. Chem. Soc. 1996, 118, 4373ꢀ4379.
(70) Chen, K.; Que Jr., L. J. Am. Chem. Soc. 2001, 123, 6327ꢀ6337.
(71) Costas, M.; Que Jr., L. Angew. Chem. Int. Ed. 2002, 41, 2179ꢀ2181.
(72) Company, A.; Gómez, L.; Güell, M.; Ribas, X.; Luis, J. M.; Que, Jr., L.; Costas, M. J.
Am. Chem. Soc. 2007, 129, 15766ꢀ15767.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(73) Ligtenbarg, A. G. J.; Oosting, P.; Roelfcs, G.; La Crois, R.; Lutz, M.; Spek, A. L.; Hage,
R.; Feringa, B. L. Chem. Commun. 2001, 385ꢀ386.
(74) Russell, G. A. In Free Radicals; Kochi, J., Ed.; WileyꢀInterscience: New York, 1973;
Vol. II, pp. 689ꢀ690.
(75) Campestrini, S.; Cagnina, A. J. Mol. Catal. A: Chem. 1999, 150, 77ꢀ86.
(76) Hoffmann, P.; Robert, A.; Meunier, B. Bull. Soc. Chim. Fr. 1992, 129, 85ꢀ97.
(77) Brinksma, J.; Rispens, M. T.; Hage, R.; Feringa, B. L. Inorg. Chim. Acta 2002, 337, 75ꢀ
82.
(78) Chen, K.; Costas, M.; Que Jr., L. J. Chem. Soc. Dalton Trans. 2002, 672ꢀ679.
(79) Groves, J. T.; McGlusky, G. A.; White, R. E.; Coon, M. J. Biochem. Biophys. Res.
Commun. 1978, 81, 154ꢀ160.
(80) Groves, J. T.; Marla, S. S. J. Am. Chem. Soc. 1995, 117, 9578ꢀ9579.
(81) Groves, J. T. In Cytochrome Pꢀ450. Structure, Mechanism and Biochemistry, 3rd Ed.;
Ortiz de Montellano, P. R., Ed.; Plenum Press: New York, 2005, pp. 1ꢀ46.
(82) J. T. Groves, J. T. J. Inorg. Biochem. 2006, 100, 434ꢀ447.
(83) Ortiz de Montellano, P. R.; De Voss, J. J. In Cytochrome Pꢀ450. Structure, Mechanism
and Biochemistry, 3rd Ed.; Ortiz de Montellano, P. R., Ed.; Plenum Press: New York, 2005, pp.
183ꢀ246.
(84) Lyakin, O. Yu.; Ottenbacher, R. V.; Bryliakov, K. P.; Talsi, E. P. ACS Catal. 2012, 2,
1196ꢀ1202.
15
ACS Paragon Plus Environment

ACS Catalysis
Page 16 of 18
1
2
3
4
(85) Prat, I.; Mathieson, J. S.; Güell, M.; Ribas, X.; Luis, J. M.; Cronin, L.; Costas, M. Nat.
Chem. 2011, 3, 788ꢀ793.
5
6
7
8
9
(86) Lyakin, O. Yu.; Prat, I.; Bryliakov, K. P.; Costas, M.; Talsi, E. P. Catal. Commun. 2012,
29, 105ꢀ108.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(87) Lyakin, O. Y.; Bryliakov, K. P.; Britovsek, G. J. P.; Talsi, E. P. J. Am. Chem. Soc. 2009,
131, 10798ꢀ10799.
(88) Oloo, W. N.; Meier, K. K.; Wang, Y.; Shaik, S.; Münck, Que, L. Nat. Commun. 2014, 5,
article number: 3046.
(89) The EPR active, presumably oxoiron(V) species with the rhombically anisotropic spectra
(g1 ≈ 2.7, g2 = 2.4, g3 = 1.5ꢀ1.7) reported by Lyakin et al. were extremely unstable and decayed
within minutes even at ꢀ80…ꢀ85 °C.86,87 On the contrary, the studies of Oloo et al.88 were conducted
at much higher temperature (ꢀ40 °C), thus suggesting that Lyakin and Oloo monitored and assigned
species of different types.
(90) Oloo, W. N.; Fielding, A. J.; Que, Jr., L. J. Am. Chem. Soc. 2013, 135, 6438ꢀ6441.
(91) Bernadou, J.; Fabiano, A. S.; Robert, A.; Meunier, B. J. Am. Chem. Soc., 1994, 116,
9375ꢀ9376.
(92) Bernadou, J.; Meunier, B. Chem. Commun. 1998, 2167ꢀ2173.
(93) Indeed, while the attempted oxidation of cyclohexane under the conditions as in
footnotes for Table 2 has yielded small amounts of cyclohexanol and cyclohexanone (total yield 43
TN), the alcohol/ketone ratio (1.0) and level of 18O incorporation into the alcohol (0 %) point to a
different (apparently radical) oxidation pathway dominating in this case
.
16
ACS Paragon Plus Environment

Page 17 of 18
ACS Catalysis
1
2
TOC graphic
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
17
ACS Paragon Plus Environment

ACS Catalysis
Page 18 of 18
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
TOC graphic
43x10mm (300 x 300 DPI)
ACS Paragon Plus Environment