Mechanistically Driven Development of an Iron Catalyst for Selective Syn-Dihydroxylation of Alkenes with Aqueous Hydrogen Peroxide

Article abstract of DOI:10.1021/jacs.7b07909

Product release is the rate-determining step in the arene syn-dihydroxylation reaction taking place at Rieske oxygenase enzymes and is regarded as a difficult problem to be resolved in the design of iron catalysts for olefin syn-dihydroxylation with potential utility in organic synthesis. Toward this end, in this work a novel catalyst bearing a sterically encumbered tetradentate ligand based in the tpa (tpa = tris(2-methylpyridyl)amine) scaffold, [Fe^II(CF₃SO₃)₂(^5-tips3tpa)], 1 has been designed. The steric demand of the ligand was envisioned as a key element to support a high catalytic activity by isolating the metal center, preventing bimolecular decomposition paths and facilitating product release. In synergistic combination with a Lewis acid that helps sequestering the product, 1 provides good to excellent yields of diol products (up to 97% isolated yield), in short reaction times under mild experimental conditions using a slight excess (1.5 equiv) of aqueous hydrogen peroxide, from the oxidation of a broad range of olefins. Predictable site selective syn-dihydroxylation of diolefins is shown. The encumbered nature of the ligand also provides a unique tool that has been used in combination with isotopic analysis to define the nature of the active species and the mechanism of activation of H₂O₂. Furthermore, 1 is shown to be a competent synthetic tool for preparing O-labeled diols using water as oxygen source.

Full text of DOI:10.1021/jacs.7b07909

Subscriber access provided by Queen Mary, University of London
Article
Mechanistically driven development of an iron catalyst for selective
syn-dihydroxylation of alkenes with aqueous hydrogen peroxide
Margarida Borrell, and Miquel Costas
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b07909 • Publication Date (Web): 02 Aug 2017
Downloaded from http://pubs.acs.org on August 2, 2017
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.
Journal of the American Chemical Society 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 11
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Mechanistically driven development of an iron catalyst for selective
synꢀdihydroxylation of alkenes with aqueous hydrogen peroxide
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
Margarida Borrell and Miquel Costas*
Institut de Química Computacional i Catàlisi (IQCC) and Departament de Química, Universitat de Girona, Campus
Montilivi, Girona Eꢀ17071, Catalonia, Spain.
Supporting Information Placeholder
the
traditional
textbook
stoichiometric
synꢀ
ABSTRACT: Product release is the rate determining step
in the arene synꢀdihydroxylation reaction taking place at
Rieske oxygenase enzymes, and is regarded as a difficult
problem to be resolved in the design of iron catalysts for
olefin synꢀdihydroxylation with potential utility in orꢀ
ganic synthesis. Towards this end, in this work a novel
catalyst bearing a sterically encumbered tetradentate
dihydroxylating reagent, but overoxidation is a common
limitation.5 Manganese catalysts have shown promising
activity,6,7 although substrate scope and chemoselectivity
remain critical aspects.
Scheme 1. Proposed catalytic cycle of naphthalene dioxyꢀ
genase (NDO). Red frame indicates the rate determining
step under catalytic conditions.
ligand based in the tpa (tpa
=
trisꢀ(2ꢀ
methylpyridyl)amine scaffold, [FeII(CF3SO3)2(5ꢀtips tpa)],
1 has been designed. The steric demand of the ligand
was envisioned as a key element to support a high cataꢀ
lytic activity by isolating the metal center, preventing
bimolecular decomposition paths, and facilitating prodꢀ
uct release. In synergistic combination with a Lewis acid
that helps sequestering the product, 1 provides good to
excellent yields of diol products (up to 97% isolated
yield), in short reaction times under mild experimental
conditions using a slight excess (1.5 equiv.) of aqueous
hydrogen peroxide, from the oxidation of a broad range
of olefins. Predictable site selective synꢀdihydroxylation
of diolefins is shown. The encumbered nature of the
ligand also provides a unique tool that has been used in
combination with isotopic analysis to define the nature
of the active species and the mechanism of activation of
H2O2. Furthermore 1 is shown to be a competent synꢀ
thetic tool for preparing Oꢀlabeled diols using water as
oxygen source.
3
OH2
His
His
FeII
O2, H+, e-
OH2
FeII
O
O
OH2
His
His
H2O
Asp
H2O
O
O
O
His
His
OH
FeIII
Asp
O
HO
via FeIII(OOH)
O
HO
H+, e-, 2 H2O
Asp
O
His
O
FeIII
O-O cleavage
via FeV(O)(OH)
O
His
O
His
His
OH
O
FeV
Asp
O
O
Asp
Rieske dioxygenases are nonheme iron enzymes that
catalyze the stereo and regiospecific, O2ꢀdependent conꢀ
version of aromatic substrates into cisꢀdihydrodiols
(Scheme 1).8 These enzymes have provided inspiration
for the development of iron based synꢀdihydroxylating
catalysts.9
Introduction. Synꢀdihydroxylation is a very important
reaction in organic synthesis because olefins are readily
available feedstocks and diols are versatile synthetic
intermediates.1 Synꢀdihydroxylation is reliably perꢀ
formed using stoichiometric or catalytic amounts of
1b, 1c
heavy metal oxides, specially OsO4
and RuO4,2 as
well as catalysts based in these metals.3 However, the
cost and toxicity of these metals motivate the developꢀ
ment of more sustainable alternatives such as metalꢀfree
methods4 and catalytic methodologies based on first row
transition metals.1a Along this direction, permanganate is
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 11
genases, diol release is rate determining, and is triggered
1
2
3
4
5
6
7
8
by reduction of the ferric center, which presumably atꢀ
tenuates its oxophilicity.8c, 15 The reaction of the reduced
center with O2 is strictly regulated, and only takes place
once a new substrate molecule enters the active center,
avoiding overoxidation. For synthetic catalysts, an analꢀ
ogous mechanism is not operative, iron (hydrogen) glyꢀ
colate species rapidly accumulate,11j, 12a, 13 and overoxiꢀ
dation of the substrate is difficult to avoid.
Scheme 2. a) Previous iron catalysts employed in synꢀ
dihydroxylation under substrate limiting conditions. b)
Characteristics of the current system.
9
We considered that product release may be facilitated by
making the ligand sterically more demanding, a common
strategy in standard organometallic catalysis. Furtherꢀ
more, this element will also limit formation of oxoꢀ
bridged diferric species, that are catalytically poorly
active thermodynamic sinks. Overall, the activity and
chemoselectivity of the catalyst would be favored. Takꢀ
ing these considerations into account we have designed
an iron catalyst based on the archetypical [Fe(tpa)] arꢀ
chitecture tpa = trisꢀ(2ꢀpyridylmethyl)amine, for which
catalytic synꢀdihydroxylation activity has been thoughtꢀ
fully studied,10, 11j, 12c building sterically demanding trisꢀ
isopropylꢀsilyl (tips) groups in position 5 of the pyridine
rings (Scheme 2b and Figure 1). We have previously
described that incorporation of these bulky groups in
chiral iron and manganese catalysts result in highly acꢀ
tive epoxidation and CꢀH oxidation catalysts, exhibiting
remarkable regio and enantioselective properties.16
Moreover, building on the same mechanistic analysis,
herein we show that addition of Mg(ClO4)2·6H2O imꢀ
proves product yields and chemoselectivities by binding
and sequestering the diol. Overall, this analysis has reꢀ
sulted in an iron based catalytic system that enables fast
and high yield synꢀdihydroxylation of a broad range of
olefins under mild experimental conditions, using H2O2
as oxidant. Remarkably, it is also shown that 1 introducꢀ
es one oxygen atom originating from water in the dihyꢀ
droxylated olefin, as shown by means of isotopic labelꢀ
ing experiments using H218O. Furthermore, analysis of
the isotope distribution of the latter reactions, applied to
unsymmetric olefins, uncovers fundamental aspects of
the nature of the iron active species, and the mechanism
by which they are formed.
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
The first functional model for this class of enzymes was
described by Que and Chen, and performed the synꢀ
dihydroxylation of olefins, using the substrate in large
excess (1000 equiv.) and H2O2 (10 equiv.) as oxidant.10
This work marked the starting point of research efforts
to uncover the reaction mechanism,9, 11 and also to deꢀ
velop catalysts that could have utility in synthesis.12 The
latter aspect has proven particularly challenging; very
few examples exist that could operate under substrate
limiting conditions, potentially amenable for synthesis
(Scheme 2a). Rapid catalyst deactivation and limited
chemoselectivity are critical problems when reactions
are performed under substrate limiting conditions; comꢀ
petitive epoxidation and overoxidation reactions consistꢀ
ently result in modest product yields. Good product
yields and chemoselectivities have been obtained only in
two examples described by Che and are basically limited
to eꢀdeficient (ED) olefins; [FeIII(Cl)2(LN4Me2)]+
(Scheme 2a) employs Oxone® (2 equiv.) to oxidize ED
olefins with excellent yields and chemoselectivities, but
more modest yields and competitive overoxidation are
observed with other types of substrates, specially aliꢀ
phatic olefins. Hydrogen peroxide is a more convenient
oxidant, but only very recently high yielding synꢀ
dihydroxylation of ED olefinic substrates with H2O2 has
been described with the (S,S)ꢀ[FeII(OTf)2(bqcn)] catalyst
(OTf = trifluoromethanesulfonate anion, Scheme 2a).
Interestingly, high enantioselectivities were obtained for
these reactions.12a, 12b
We reasoned that the catalyst deactivation and product
overoxidation commonly observed with iron catalysts
may originate from a rate determining release of the
product, because a strong binding of the diol to the ferric
center is favored by the formation of a fiveꢀmember
chelate ring cycle and the high oxophilicity of the ferric
center.11j, 12a, 13 Indeed, product release appears to be a
critical step not limited to iron but also to rutheniumꢀ
based synꢀdihydroxylation reactions.14 In Rieske dioxyꢀ
Figure 1. ORTEP diagram of [FeII(CF3SO3)2(5ꢀtips3tpa)], 1
(Left) and space filling diagram (Right), showing the different
steric constrains at OA (surrounded by three tips groups) and
2
ACS Paragon Plus Environment

Page 3 of 11
Journal of the American Chemical Society
OB (open to the bulk). Triflate anions are omitted except for
20
12
13
14
2/Mg(ClO4)2·6H2Od 35
3/Mg(ClO4)2·6H2Od 74
4/Mg(ClO4)2·6H2Od 27
4
69
72
ꢀ
1
2
3
4
5
6
7
8
the oxygen atoms directly bound to the iron center; thermal
ellipsoids are set at 50% probability level and hydrogen atoms
omitted for clarity. Selected bond distances; FeꢀN1: 2.192(2),
FeꢀN2: 2.220(2), FeꢀN3: 2.160(2), FeꢀN4: 2.158(2), FeꢀOA:
2.049(2), FeꢀOB: 2.171(2).
42
<1
11
<1
a 1 mol% catalyst, 1.5 equiv H2O2 added by syringe pump during
30’ followed by 30’ stirring at 0ºC, substrate conversion (conv)
and product yields determined by GC, calibrated with
independently prepared products. Mass balance Conditions
employed in ref 12c): 3 mol% catalyst, 4 equiv. H2O2. 2.2
b
c
d
Results and discussion. Synthesis and characterizaꢀ
tion of the catalyst. Standard procedures were used to
assemble the bulky tetradentate 5ꢀtips3tpa ligand (see SI
for details). Towards this end, the silylꢀsubstituted
picolyl chloride and the silylꢀsubstituted picolyl amine
building blocks were conveniently obtained on a gram
scale (see SI) following recently described methods.16a
equiv. e 13 equiv.
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
Catalytic reaction development. Catalytic olefin oxidaꢀ
tion reactions were first performed under air by adding
1.5 equiv. of H2O2 (commercially available 50% w/w
solution diluted in acetonitrile) via syringe pump over 30
minutes at 0ºC to an acetonitrile solution containing 1ꢀ
octene (S1) and 1 mol% of 1 as catalyst. Results are
collected in Table 1. Under these conditions, 1ꢀoctene
was nearly consumed (98% conversion) and the correꢀ
sponding 1,2ꢀdiol (P1b) was obtained in a rewarding
74% yield (entry 1), along with 23% of 1,2ꢀepoxyoctane
(P1c). No significant changes in product yields were
observed when the reaction was performed under argon
or nitrogen atmosphere. Besides the fact that the yield of
diol is the best described for an iron catalyzed dihydroxꢀ
ylation of an aliphatic substrate, it is also extraordinary
the good mass balance of the reaction (99%), even when
substrate conversion was high. The excellent perforꢀ
mance of 1 is best appreciated when compared with
other relevant iron dihydroxylating catalysts (Scheme
2a, and Table 1 entries 2ꢀ5) under analogous conditions;
the simpler [FeII(tpa)(CH3CN)2](ClO4)2 (2) provides a
more modest 47% of diol (entry 2) that can be improved
up to 59% (entry 3) by using a larger catalyst loading
and up to 4 equiv. of H2O2, the triazacyclononane based
catalyst [FeII(CF3SO3)2(Me,MePytacn)] (3, see Scheme 2a)
also provides a modest yield of diol (30%, entry 4), and
[FeII(OTf)2(LN4Me2)] (4, see Scheme 2a left for a diaꢀ
gram of the parent [FeIII(Cl)2(LN4Me2)]+) turns out to be
basically inactive in combination with H2O2 (entry 5). In
sharp contrast to 1, conversion of the substrate into miꢀ
nor amounts of multiple oxidation products was detected
when 2ꢀ4 were employed as catalysts, resulting in less
satisfactory mass balances.
The tetradentate 5ꢀtips3tpa ligand was then reacted with
Fe(CF3SO3)2·2CH3CN in order to prepare the correꢀ
sponding iron complex with formula [FeII(CF3SO3)2(5ꢀ
tips3tpa)], 1 (Figure 1 top) that was obtained as a yellow
crystalline solid in 78% yield. The Xꢀray crystal strucꢀ
ture of 1 shows a distorted octahedral ferrous center,
with the 5ꢀtips3tpa ligand coordinated in a tripodal manner
(Figure 1). Average FeꢀN distances are 2.2 Å, and are
indicative of a high spin ferrous center.17 Two cis labile
positions are occupied by triflate anions. Most interestꢀ
ingly, the sterically demanding tips groups flank these
two positions in a nonꢀequivalent manner (Figure 1).
While one of the two cis labile positions (OA), trans to
the aliphatic amine N2, is surrounded and hindered by
the tips groups corresponding to each of the three pyriꢀ
dine rings of the catalyst, the second one (OB), trans to
one of the pyridines (N1), is flanked by only two of the
tips groups, and appears to be spatially quite more acꢀ
cessible.
Table 1. Optimization conditions for oxidation of S1 using
different iron catalysts.a
Yield
Yield
Conv
(%)
of
MBb
(%)
Entry
Cat/additive
of P1c
P1b
(%)
(%)
1
1/ꢀ
98
71
83
66
28
62
99
74
47
59
30
2
23
10
13
15
<1
8
99
80
87
68
ꢀ
We considered the possibility that accumulation of the
diol in the reaction may be compromising the chemoseꢀ
lectivity exhibited by 1, presumably by binding to the
iron center, as previously documented for several iron
catalysts.11j, 13 We envisioned that improved yields may
be obtained if the diol product could be separated,12d or
at least sequestered from the reaction mixture. With this
proposal in mind, reactions were conducted in the presꢀ
ence of different Lewis acids, in order to induce binding
to the diol (see Table S4 for details on the different Lewꢀ
is acids tested). Addition of LiClO4·3H2O (Table 1, entry
6, 2.2 equiv.) improved the selectivity towards the diol
([diol]/[epoxide] ~ 6/1) while retaining an excellent
2
2/ꢀ
3c
2/ꢀ
4
3/ꢀ
5
4/ꢀ
6
1/LiClO4·3H2Od
51
75
87
43
77
26
95
97
>99
>99
>99
64
d
7
1/Zn(OTf)2
1/Mg(ClO4)2·6H2Od 100
21
13
10
17
6
8
d
9
1/Mg(ClO4)2
53
94
50
d
10
11
1/Mg(OTf)2
1/H2Oe
3
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 11
mass balance, but provided an overall reduced yield
ability of Mg2+ was well supported by mass spectromeꢀ
try analysis of the reactions, which revealed spectra
dominated by multiple and intense cluster ions combinꢀ
ing diol and Mg2+ ions (see Figure S1 for spectra).
1
2
3
4
5
6
7
8
(51%). Use of Zn(CF3SO3)2 (entry 7) did not elicit sigꢀ
nificant changes. However, a remarkably high yield of
diol (87%, entry 8) was obtained when Mg(ClO4)2·6H2O
(2.2 equiv.) was used (see Table S5). The epoxide apꢀ
pears as a minor product (13%), and the mass balance of
the reaction remained excellent (99%). Of interest, when
1,2ꢀepoxyoctane (P1c) was subjected to these reaction
conditions (1 mol% catalyst, 1.5 equiv H2O2, 2.2 equiv.
Mg(ClO4)2·6H2O), diol P1b was not formed, indicating
that the diol observed in our reaction does not come
from an epoxide ring opening. Consistent improvements
in yields and selectivities for the diol product were obꢀ
served for different substrates when reactions were conꢀ
ducted in the presence of Mg(ClO4)2·6H2O (see Table
S7). Finally, slightly improved yields (92%) and
chemoselectivities towards the diol were obtained when
reactions were performed in 1 mmol scale and the prodꢀ
uct was isolated. Remarkably, 1 retains excellent perꢀ
formance at low catalyst loadings; a noticeable good
yield (75%) of the corresponding diol (along with 25%
of the epoxide) was obtained with 0.25 mol% catalyst
(1:S1:H2O2 ratio of 1:400:600). This yield translates into
300 turnover numbers (TN) of diol, which to the best of
our knowledge is the largest value described to date for
any iron catalyst.
Further evidence in favor of the diol sequestering role of
Mg2+ ions, and its translation into improved catalytic
performance was obtained by performing the oxidation
of 1ꢀoctene (S1) under standard reaction conditions, but
in the presence of varied amounts (20 and 50 mol%) of
cisꢀcycloocteneꢀ1,2ꢀdiol (Scheme 3). In the absence of
Mg(ClO4)2·6H2O, addition of cycloocteneꢀ1,2ꢀdiol (20
and 50 mol%) produces an inhibition of the reaction, and
diol P1b is produced in small yields (28% and 16%,
respectively). However, addition of Mg(ClO4)2·6H2O
(2.2 equiv.) rescues the catalytic activity and P1b is
obtained in good yield (73ꢀ74%) and improved selectiviꢀ
ty.
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 3. Evidence of the positive role of Mg(ClO4)2·6H2O
by sequestering the diol.
1 (1 mol%)
H2O2 (1.5 equiv)
HO
OH
C6H13
C6H13
C6H13
+
HO
+
O
CH3CN, 0˚C, 30'
OH
P1b
P1c
P1c(%) [P1b]/[P1c]
S1
x mol%
x mol%
Mg(ClO4)2—6H2O
P1b (%)
20 mol%
-
28
74
6
12
4.7
6.2
2.2 equiv.
The impact of Mg(ClO4)2·6H2O in the catalytic activity
of 1 was further investigated. Control experiments
showed that the positive effect of Mg(ClO4)2·6H2O is
not reproduced by adding comparable amounts of water
(13 equiv., entry 11), and use of anhydrous sources of
Mg2+ ions also provided reduced product yields (entries
9ꢀ10).
50 mol%
-
16
73
3
13
4.8
5.6
2.2 equiv.
Comparative analysis of catalysts 1 and 2. A time
course analysis of a catalytic olefin oxidation performed
under the optimized reaction conditions (Figure 2) perꢀ
mits us to elucidate different key aspects of the imꢀ
proved performance of 1 when compared with 2. Analyꢀ
sis of oxidation products at different times shows that
the two catalysts are active during all the time course of
H2O2 addition but 1 consistently exhibits a more effiꢀ
cient use of H2O2, providing higher product yields,
which increase linearly with H2O2 addition.
The activity of catalyst 3 is also improved with the addiꢀ
tion of Mg(ClO4)2·6H2O. A higher yield of diol product
(P1b) and a larger [diol]/[epoxide] ratio is observed
(compare entry 13 with entry 4), but these numbers are
still far from those obtained with 1. On the other hand,
unlike 1 and 3, the activity of catalysts 2 and 4 could not
be improved by the addition of Mg(ClO4)2·6H2O (enꢀ
tries 12 and 14).
For both catalysts, the chemoselectivity towards the diol
(estimated by the [diol]/[epoxide] ratio) is eroded as the
reaction progresses, and diol accumulates in solution; for
1 and 2 [diol]/[epoxide] ratios are very similar at 10
minutes (7.5 and 8.3 respectively), and decrease to 6.6
and 5.5 at 30 minutes. Interestingly, the better chemoseꢀ
lectivity displayed by 1 is attained even when substrate
conversion is basically quantitative, and a large concenꢀ
tration of diol has accumulated in the reaction mixture.
Instead, the selectivity observed with 2 is obtained under
experimentally less demanding conditions with regard to
the latter parameters. The sum of these data suggests that
under optimal conditions (initial points of the reaction
when substrate concentration is large and diol concentraꢀ
tion is small), 1 and 2 show quite similar chemoselecꢀ
tivity in the oxidation of S1, but 1 appears to be more
efficient in activating H2O2 in an effective manner to
perform the dihydroxylation reaction. In addition, as the
A positive effect of H2O in the synꢀdihydroxylation abilꢀ
ity of 3 has been previously observed.12d It was reasoned
that water can help in the activation of H2O2 (see below
for details on the reaction mechanism), and can also
facilitate product release. However, in the case of 1, the
sole addition of water does not improve the overall perꢀ
formance of the catalyst, and Mg2+ ions appear to exert
an important beneficial role, which is best evidenced in
higher product yields and a robust selectivity towards
synꢀdihydroxylation, even when large amounts of diols
accumulate in the reaction mixture. The positive effect
of the Mg2+ ions can actually be rationalized by considꢀ
ering their Lewis acidity and oxophilicity, which must
ensure strong binding to the diol, limiting their interacꢀ
tion to the iron species. Interestingly, the diol binding
4
ACS Paragon Plus Environment

Page 5 of 11
Journal of the American Chemical Society
reaction progresses, 1 is more resistant against deactivaꢀ functional groups including an amide (S5, 72%), an
1
2
3
4
5
6
7
8
tion of the dihydroxylation channel, presumably caused
by diol accumulation and binding to the iron center.
alcohol (S10, 86%), a halide (S11, 76%) and an ester
(S13, 97%). Interestingly, the electron poor dimethyl
fumarate (S14) and dimethyl maleate (S12) are also
oxidized with excellent chemoselectivity to the correꢀ
sponding synꢀdiols (92% and 67%, respectively). Effiꢀ
cient oxidation of maleate (S12) requires that the oxidaꢀ
tion reaction is performed in the absence of Mg2+ ions
presumably because favorable chelation to maleate (as
ascertained by ESIꢀMS analysis, see Figure S2) deacꢀ
tivates the substrate. Oxidation of these very electron
poor substrates finds precedent in Che’s synꢀ
dihydroxylation catalyst [FeIII(Cl)2(LN4Me2)]+ (scheme
2a), which operates with Oxone®,12b and is particularly
remarkable because these substrates are inert towards
iron epoxidation catalysts that use H2O2 and can be seen
as structurally related to 1.16b On the other hand, subꢀ
strates bearing sterically impeded olefins exhibit reduced
reactivity; 3,3ꢀdimethylꢀ1ꢀbutene (S4) is oxidized to the
diol in 53% yield and 2,3ꢀdimethylꢀ3ꢀbutene probed
unreactive, suggesting sensitivity of the catalyst to subꢀ
strate sterics.
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
Interestingly, cyclic aliphatic enones (S17ꢀS22) are also
viable substrates and are oxidized to the corresponding
synꢀdiol with excellent chemoselectivity (>90%) and
moderate to excellent product yields (60ꢀ99%). These
substrates are valuable synthons in the elaboration of
natural products and their cyclic nature makes the synꢀ
diol difficult to obtain by other methods. Of remark, the
reaction proceeds satisfactorily for 6ꢀ8 member ring
substrates (S17ꢀS22). Again, steric hindrance on the
substrate appears to impact in the efficiency of the reacꢀ
tion to a different extent; substrates with gem dimethyl
groups installed in the cyclohexanone ring (S18ꢀS20) are
oxidized with good but reduced yields of synꢀdiol when
compared with S17, but substitutions at the olefinic site
(S20) make the corresponding substrates unreactive.
Therefore, while 1 generates very powerful oxidizing
species, they are remarkably sensitive to steric hinꢀ
drance, a conclusion that can be rationalized because of
the high steric demand imposed by the 5ꢀtips3tpa ligand.
Figure 2. Time course of the catalytic oxidation of 1ꢀoctene
S1 with catalysts 1 (blue dots) and 2 (orange dots). H2O2 (1.5
equiv. delivered by syringe pump at 0ºC) is added to a solution
of substrate, Mg(ClO4)2·6H2O (2.2 equiv.) and catalyst (1
mol%) in acetonitrile. Values in parenthesis correspond to
[diol]/[epoxide] ratio at different reaction times.
Substrate scope. Dihydroxylation of different families
of substrates was then explored under the optimized
conditions (Table 2). For comparison purposes, best
results described so far in the literature with an iron
catalyst are collected in Table S1. In general, the data
shows that 1 yields substantially improved yields when
compared with the stateꢀofꢀtheꢀart iron catalysts. Aliꢀ
phatic substrates with different substitution patterns are
oxidized to the corresponding diol in good to excellent
isolated product yields (up to 97%). This includes termiꢀ
nal olefins (S1ꢀS6, 38ꢀ92%), transꢀolefins (S7ꢀS8 and
S14, 74ꢀ92%), cisꢀolefins (S9ꢀS13, 67ꢀ97%) and cyclic
olefins (S15ꢀS16, 81ꢀ89%). The good mass balance of
these reactions (>95%) compares favorably with the
values attained with any iron catalyst described to date.
In general, substrate conversions are complete, and
epoxides are formed as minor products, accounting for
In the absence of deactivating electronꢀwithdrawing
groups, aromatic olefins are quite delicate substrates for
iron oxidation catalysis.11i, 11j, 12b, 12d, 18,11i However, nonꢀ
deactivated styrenes appear also to be suitable substrates
for the current system, and the corresponding diols are
obtained in moderate to good (S23ꢀS26, 44ꢀ80%) prodꢀ
uct yields. Following the same pattern observed for aliꢀ
phatic substrates a cisꢀaromatic olefin (S23) is oxidized
with a substantially better yield (80%, dr 95:5) than the
corresponding trans isomer (S26), and styrene S21 (a
terminal olefin) is oxidized to the corresponding diol in
58% yield. Aromatic olefins with electron withdrawing
groups (S27ꢀS29 and S31) are oxidized with improved
product yields (57ꢀ99%) and excellent chemoselectivity
towards the corresponding synꢀdiol. Again, as observed
for aliphatic olefins, oxidation of trisubstituted olefins
the rest of the oxidation products.
A
1,1ꢀ
dialkylsubstituted olefin (S6) appears to be a singular
case, because its oxidation produces a 1:1 mixture of
diol and epoxide (which can be readily converted in the
corresponding diol by reaction with an acid), with an
excellent 80% combined yield. A particularly remarkaꢀ
ble feature is that reactions proceed with stereoretention,
forming diol resulting from a synꢀdihydroxylation reacꢀ
tion. Remarkably, the reaction is tolerant to different
5
ACS Paragon Plus Environment

Journal of the American Chemical Society
(S28 and S30) provide reduced yields, an effect that is
most obvious when comparing S28 with the transꢀ
disubstituted analogue (S27).
Page 6 of 11
1
2
3
Previous mechanistic studies have revealed that iron
catalyzed synꢀdihydroxylation can involve electrophilic
and nucleophilic species, depending on the nature of the
catalyst.11i To address this question the competitive oxiꢀ
dation of cyclooctene (S15) and cyclohexanone (S17)
with 1 was performed (see Table S2 for details), revealꢀ
ing exclusive oxidation of the former. This observation
is in agreement with the exclusive site selective oxidaꢀ
tion of S13 at the most electron rich site (Table 2), and
overall evidence an electrophilic nature of the oxidizing
species. Further studies were directed towards stablishꢀ
ing the relative reactivity of 1 against aliphatic olefins
bearing different substitution patterns. Competitive oxiꢀ
dation of pairs of aliphatic olefins (see Table S2) permits
the establishment of the following pattern of relative
reactivity; cis and terminal olefins are more reactive than
trans (cisꢀ2ꢀoctene S9 and 1ꢀoctene S1 are roughly three
and two times more reactive than transꢀ2ꢀoctene S8,
respectively). Moreover cisꢀ2ꢀoctene S9 is 1.5 times
more reactive than cyclooctene S15. These competitive
studies reveal a preferential reactivity for cisꢀolefins, and
most significantly the relatively high reactivity of a terꢀ
minal olefin, which are recognized as a more difficult
class of substrates to oxidize by electrophilic oxidants
than internal olefins,18ꢀ19 suggests that the steric demand
of the substrate is a major component in dictating relaꢀ
tive reactivity.
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
Table 2. Substrate scope of different alkenes using catalyst 1
and H2O2. Isolated yield (%)a ([diol]/[epoxide] ratio) b
a Reaction conditions: 1 equiv. of substrate (1 mmol), 1mol%
catalyst, 1.5 equiv. of H2O2 (50% w/w solution), added via
syringe pump during 30 min, 10 mL of CH3CN, at 0ºC, plus
b
30 min stirring. [diol]/[epoxide] ratio determined by GC in 1
d
mmol substrate reactions. c Yields determined by GC. Two
additions of 1 mol% catalyst and 1.5 equiv. of H2O2. e Epoxide
f
is not formed. Isolated yields using standard conditions;
S10(77), S12(57), S17(75), S19(55), S27(82), S29(56),
S31(53).g Oxidation performed without Mg(ClO4)2·6H2O. h 2
i
j
mol% of catalyst. 1 equiv. H2O2. 2 mol% of catalyst in the
first addition. n.r.=not reactive. Stereoselectivities were deterꢀ
mined by GC analyses of the crude reaction mixtures. Stereoꢀ
chemistry of diols resulting from oxidation of S7, S8, S9, S17,
6
ACS Paragon Plus Environment

Page 7 of 11
Journal of the American Chemical Society
S23 and S32 was determined by comparison to diols prepared
by Sharpless dihydroxylation, and by epoxide ring opening.1b,
1
2
20
Stereochemistry of diols resulting from oxidation of S12,
3
4
5
S14, S15, S16 and S22 was determined by comparison with
spectroscopic and GC retention time of commercially availaꢀ
ble diols.
Scheme 5. a) Mechanistic typology of ironꢀbased synꢀ
dihydroxylation catalysts.11i,11j b) Results from isotopic
labeling analysis of the oxidation of a series of substrates
by 1. Relative 18O incorporation into the two oxygen atoms
of the diol is displayed. c) Schematic model rationalizing
the favorable and disfavorable approach of the olefin to
the catalyst on the basis of steric interactions. The proꢀ
posed site of H2O2 and H2O binding to the catalysts derived
from the isotopic labeling study is also shown.
Understanding the selectivity properties of 1 permits its
use in the predictable selective oxidation of more comꢀ
plex substrates such as small natural products, bearing
more than one olefinic site (Scheme 4). Oxidation of cisꢀ
jasmone (S32, contains 8% trans isomer) proceeds with
an excellent 94% isolated yield of the diol (92:8 dr, see
SI section 11) resulting from oxidation at the most elecꢀ
tron rich site. More significantly, oxidation of the steroiꢀ
dal substrate (S33), bearing a fatty acid derived chain,
takes place with excellent selectivity towards the steriꢀ
cally less congested cisꢀsite in 81% isolated yield, withꢀ
out any detectable oxidation at the more electron rich
double bond, but congested trisubstituted site. These
results underscore the potential utility of 1 in organic
synthesis.
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
Scheme 4. Site selective synꢀdihydroxylation of natural
products.
Mechanistic studies. Regioselective labeling. Previous
mechanistic studies in the reaction of synꢀ
dihydroxylation catalyzed by iron coordination comꢀ
plexes have led to the organization of catalysts in two
classes (Scheme 5a).11i,11j For Class A catalysts the reꢀ
sulting diol contains one oxygen atom that originates
from H2O2 and the second one from H2O, while diols
formed with class B catalysts contain two oxygen atoms
derived from the same molecule of H2O2. Class A cataꢀ
lysts contain tetradentate strong field ligands, while
Class B bear weak field ligands.11i It can be expected
that the introduction of the bulky silyl groups at the 5th
position of the pyridines will not perturb in a substantial
manner the crystal field and electronic properties of the
iron center in 1 when compared with 2, and therefore
both catalysts will likely operate via a common mechaꢀ
nism. Indeed, the latter can be seen as the prototypical
example of a Class A catalyst. Isotopic labeling analysis
confirms this prediction. Catalytic oxidation of a series
of olefins by 1 with H2O2 in the presence of H218O (7.5
equiv.) produces the corresponding synꢀdiol that is 90%
singly 18Oꢀlabeled (Scheme 5b).
Class A catalysts operate via a FeV(O)(OH) species
formed via water assisted OꢀO cleavage of a FeIIIOOH
species (Scheme 5a).11j Most interestingly, 1 is unique
because its two labile sites possess quite different strucꢀ
tural constraints (see Scheme 5c). It was envisioned that
this structural feature may permits us to interrogate at
which position (OA or OB) is located the oxygen atom
from H2O2 and H2O in the FeV(O)(OH) oxidant. Since
OA is sterically more hindered than OB, it is expected
that an unsymmetric olefin will react by approaching the
sterically less demanding olefin carbon site to OA, and
the sterically more congested carbon site to OB.
In order to test this model, oxidations of a series of subꢀ
strates were performed under standard catalytic condiꢀ
7
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 11
12c
tions in the presence of 7.5 equiv. of H218O, and the
3).11j,
A systematic improvement of the selectivity
1
2
3
4
5
6
7
8
resulting diols were analyzed by GCꢀMS (Scheme 5b
and Table S8). Ionization by electron impact fragments
the diol and allows us to interrogate the position of the
18O oxygen atom. Almost a 1:1 ratio between the two
positions is measured for erythroꢀvicꢀ2,3ꢀoctanediol
(43:57) resulting from oxidation of cisꢀ2ꢀoctene (S9),
but most interestingly, preferential introduction of the
18O atom at the less congested carbon is observed as the
difference between the steric demand of the two olefinic
carbon sites is accentuated (from 33:66 to 16:84). For
example, dihydroxylation of vinyl cyclohexane (S3)
yields predominantly the diol where the terminal carbon
atom is regioselectively 18Oꢀlabeled with a 19:81 ratio.
For comparison, the oxidation of vinyl cyclohexane was
also studied with 2 in the presence of H218O, yielding a
55:45 ratio of 18Oꢀlabeled that denotes a modest, oppoꢀ
site regioselectivity.
towards the diol (usually studied in the oxidation of
cyclooctene) can be gained by introducing methyl
groups in α position of the pyridines in the ligand, but
this modification results in catalysts with weaker NPyꢀFe
bonds, which are labile and exhibit poor stability against
demetalation, which in turn translates into poor activiꢀ
ty.11d, 11j, 11k, 12c On the other hand, the introduction of
alkyl groups in β position does not compromise the staꢀ
bility of the catalyst, but has a modest effect in the selecꢀ
tivity towards cisꢀdihydroxylation.11j,12c The high
chemoselectivity towards synꢀdihydroxylation exhibited
by 1, which can be regarded as a βꢀtrialkylsilyl substitutꢀ
ed version of 2, while retaining high catalytic perforꢀ
mance is unprecedented and suggests that epoxidation is
minimized by the steric crowding of the catalyst. This
behavior may be tentatively explained on the basis of at
least two factors; a) the steric isolation of the iron center
is envisioned to promote product release and also to
limit oligomerization reactions, in turn facilitating the
retention, during catalysis, of the two labile sites reꢀ
quired for dihydroxylation activity, and b) steric isolaꢀ
tion is attained without compromising the strength of the
FeꢀNpy bonds and therefore the stability of the catalyst.
Both of these aspects find strong experimental support in
the catalytic behavior exhibited by 1 over time, illustratꢀ
ed in Figure 2.
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
Therefore, the distinct structural constraints of the two
labile sites in 1 translate into a distinctive isotopic labelꢀ
ing, strongly pointing out that the oxygen atoms from
water and hydrogen peroxide occupy positions OA and
OB respectively in the [FeV(O)(OH)(5ꢀtips3tpa)]2+ active
species (Scheme 5c). Identification of the latter brings
novel insights into the mechanism of H2O2 activation
operating at this catalyst, and in particular on the nature
of the ferric hydroperoxide species that evolves into the
FeV(O)(OH) oxidant.11j The isotopic labeling data indiꢀ
cates that the oxygen atom derived from H2O2 binds at
the spatially more exposed site of the catalyst, trans to a
pyridine, forming [FeIII(OBOH)(OAH2)(5ꢀtips3tpa)]2+, that
then evolves into [FeV(OB)(OAH)(5ꢀtips3tpa)]2+ via a water
assisted OꢀO cleavage.11j Fast oxoꢀhydroxo tautomerism
can then result in the formation of the tautomeric isomer
[FeV(OBH)(OA)(5ꢀtips3tpa)]2+.
Table 3. Comparison between the [diol]/[epoxide] ratio exhibꢀ
ited by different iron catalysts with tpa type of ligands.
A tentative rationale for the dominant H2O2 activation at
OB may be put forward by considering the relative labilꢀ
ity of the two available binding sites. Pyridine is a πꢀ
acceptor ligand and exerts a stronger trans effect than an
aliphatic amine. This should translate into a higher labilꢀ
ity of the transꢀsite to the pyridine (OB), facilitating
H2O2 binding. On the other hand, the corresponding
terminal oxo ligand is expected to be thermodynamically
less stable, also because of the stronger trans effect exꢀ
erted by the pyridine. Therefore, it is likely that the domꢀ
inant activation of H2O2 at position OB during catalysis
results from a kinetically preferred peroxide binding,
along with the formation of a more reactive high valent
ironꢀoxo isomer.
[diol]/[epoxide]
1a
6.6
3.8
24
ꢀ
2b
5c,d
3.3
3.5
ꢀ
6e,b
Substrate\Catalyst
1ꢀoctene
2.4
2.0
ꢀ
ꢀ
Vinyl cyclohexane
Cisꢀ2ꢀoctene
ꢀ
ꢀ
Cisꢀ2ꢀheptene
Transꢀ2ꢀoctene
Transꢀ2ꢀheptene
1.4
ꢀ
3.0
ꢀ
10
8
ꢀ
ꢀ
2.2
1.2
4.3
ꢀ
10
7ꢀ14c
Cyclooctene
4
a
b
c
This work.
Data from ref. 11j).
5Me3tpa
5 corresponds to
tris(5ꢀmethylꢀ2ꢀ
[Fe(CF3SO3)2(5Me3tpa)],
=
pyridylmethyl)amine. d Data from ref. 12c). e 6 corresponds to
Finally, the chemoselectivity towards the synꢀ
dihydroxylation reaction exhibited by 1 deserves considꢀ
eration. In general, iron catalysts react with H2O2 oxidizꢀ
ing aliphatic olefins to mixtures of epoxides and diols.11j
The parent catalyst 2 constitutes a prototypical case that
yields a modest preference for the diol ([diol]/[epoxide]
~ 3ꢀ1, representative examples are collected in Table
[Fe(6Me3tpa)(CH3CN)2](ClO4)2, 6Me3tpa
pyridylmethyl)amine.
=
tris(6ꢀmethylꢀ2ꢀ
However, comparison of our data with the literature
precedents (Table 3) also strongly suggests that the
FeV(O)(OH) oxidant in 1 and 2 must exhibit an innate
8
ACS Paragon Plus Environment

Page 9 of 11
Journal of the American Chemical Society
Supporting Information. The Supporting Information is
different chemoselectivity, the former being similar to
1
available free of charge on the ACS Publications website.
Experimental details in the preparation and characterization
of the catalysts, of the experimental procedures for the
catalytic reactions and spectroscopic data for the products.
CIFꢀfile corresponding to 1.
that attained with 6. A rationale for this effect can be
found in computational studies in the epoxidation and
cisꢀdihydroxylation reaction performed by [FeV(O)(OH)
(tpa)]2+.20 These studies indicate that epoxidation is iniꢀ
tiated by an attack of the oxo ligand over the olefin,
while synꢀdihydroxylation is initiated by an attack of the
hydroxide. In this scenario, since the Fe=O bond is
shorter than the FeꢀOH bond, it can be proposed that
epoxidation, when compared with synꢀdihydroxylation,
will require a closer approach of the substrate to the iron
center. Therefore, introduction of sterically demanding
groups in either α or β position of the pyridine, can favor
the synꢀdihydroxylation reaction. It is interesting to note
that this is actually a topological effect, meaning that
different substitution patterns or shape of the olefin subꢀ
strate must also affect their approach to the reactive ironꢀ
oxo species, translating into different [diol]/[epoxide]
ratios. Results collected in Tables 2 and 3 provide experꢀ
imental evidence in favor of this hypothesis. It is also
important to notice that this effect is independent of the
one that occurs when the catalyst changes from Class A
to Class B by weakening of the crystal field.11i It is enviꢀ
sioned that manipulation of both elements may serve in
the near future to design catalysts with improved
chemoselectivities.
2
3
4
5
6
7
8
9
AUTHOR INFORMATION
Corresponding Author
*miquel.costas@udg.edu
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
ACKNOWLEDGMENT
We acknowledge financial support from MINECO of Spain
(CTQ2015ꢀ70795ꢀP) and the Catalan DIUE of the Generalꢀ
itat de Catalunya (2009SGR637). M.C. thanks an ICREAꢀ
Academia award. We thank Teodor Parella for assistance in
the NMR assignment of products. We thank Anna Compaꢀ
ny, Massimo Bietti and Xavi Ribas for helpful discussions,
and L. Gómez by the GCꢀMS isotopic analyses. STR of
UdG are acknowledged by experimental support.
REFERENCES
(1) (a) Bataille, C. J. R.; Donohoe, T. J., Chem. Soc. Rev. 2011, 40, 114; (b)
Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B., Chem. Rev. 1994, 94,
2483; (c) Zaitsev, A. B.; Adolfsson, H., Synthesis 2006, 1725.
(2) (a) Shing, T. K. M.; Tam, E. K. W.; Tai, V. W. F.; Chung, I. H. F.; Jiang,
Q., Chem. Eur. J. 1996, 2, 50; (b) Shing, T. K. M.; Tai, V. M. F.; Tam, E. K.
W., Angew. Chem. Int. Ed. 1994, 33, 2312.
(3) (a) Sugimoto, H.; Kitayama, K.; Mori, S.; Itoh, S., J. Am. Chem. Soc.
2012, 134, 19270; (b) Yip, W.ꢀP.; Ho, C.ꢀM.; Zhu, N.; Lau, T.ꢀC.; Che, C.ꢀ
M., Chem. Asian J. 2008, 3, 70; (c) Yip, W. P.; Yu, W. Y.; Zhu, N. Y.; Che, C.
M., J. Am. Chem. Soc. 2005, 127, 14239.
Conclusion
In conclusion, this work describes the development of a
sterically encumbered iron catalyst that permits the high
yield, selective synꢀdihydroxylation of a broad range of
olefins at short reaction times using aqueous H2O2 as
oxidant. The combination of its excellent performance as
a synthetic tool in combination with the fact that it emꢀ
ploys water as an oxygen source can make this catalyst a
valuable tool for a convenient Oꢀlabeling of organic
substrates. For example, considering the interest of 17Oꢀ
labeled compounds in biological sciences,21 along with
the fact that H217O is by far the most economically acꢀ
cessible source of 17O, this catalyst may be of interest to
these fields. Furthermore, besides providing a novel tool
that can enable more sustainable synthetic organic
chemistry, the work discloses new mechanistic perspecꢀ
tives. The structure of this bulky catalyst is uniquely
suitable to provide details of the molecular and topologiꢀ
cal composition of the active species, which could only
be previously proposed on the basis of computational
analyses.11h, 22 The improved understanding of the cataꢀ
lytically active species that emerges from the current
work may also represent a valuable tool to rationally
design, in the nearly future, the catalytic active site in
order to pursue selectivity on the basis of structural asꢀ
pects such as molecular shape or olefin substitution
patterns.
(4) (a) Rawling, M. J.; Tomkinson, N. C. O., Org. Biomol. Chem. 2013, 11,
1434; (b) Colomer, I.; Barcelos, R. C.; Christensen, K. E.; Donohoe, T. J.,
Org. Lett. 2016, 18, 5880; (c) Griffith, J. C.; Jones, K. M.; Picon, S.;
Rawling, M. J.; Kariuki, B. M.; Campbell, M.; Tomkinson, N. C. O., J. Am.
Chem. Soc. 2010, 132, 14409; (d) Giglio, B. C.; Schmidt, V. A.; Alexanian,
E. J., J. Am. Chem. Soc. 2011, 133, 13320; (e) Schmidt, V. A.; Alexanian, E.
J., Angew. Chem. Int. Ed. 2010, 49, 4491; (f) Emmanuvel, L.; Shaikh, T. M.
A.; Sudalai, A., Org. Lett. 2005, 7, 5071; (g) Fujita, M.; Wakita, M.;
Sugimura, T., Chem. Commun. 2011, 47, 3983; (h) Kang, Y.ꢀB.; Gade, L.
H., J. Am. Chem. Soc. 2011, 133, 3658; (i) Zhong, W.; Yang, J.; Meng, X.;
Li, Z., J. Org. Chem. 2011, 76, 9997.
(5) Dash, S.; Patel, S.; Mishra, B. K., Tetrahedron 2009, 65, 707.
(6) (a) De Vos, D. E.; de Wildeman, S.; Sels, B. F.; Grobet, P. J.; Jacobs, P.
A., Angew. Chem. Int. Ed. 1999, 38, 980; (b) Saisaha, P.; Pijper, D.;
Summerren, R. P. v.; Hoen, R.; Smit, C.; Boer, J. W. d.; Hage, R.; Alsters,
P. L.; Feringa, B. L.; Browne, W. R., Org. Biomol. Chem. 2010, 8, 4444; (c)
de Boer, J. W.; Browne, W. R.; Harutyunyan, S. R.; Bini, L.; Tiemersmaꢀ
Wegman, T. D.; Alsters, P. L.; Hage, R.; Feringa, B. L., Chem. Commun.
2008, 3747; (d) de Boer, J. W.; Browne, W. R.; Brinksma, J.; Alsters, P. L.;
Hage, R.; Feringa, B. L., Inorg. Chem. 2007, 46, 6353; (e) Boer, J. W. d.;
Brinksma, J.; Browne, W. R.; Meetsma, A.; Alsters, P. L.; Hage, R.;
Feringa, B. L., J. Am. Chem. Soc. 2005, 127, 7990.
(7) Chow, T. W.ꢀS.; Liu, Y.; Che, C.ꢀM., Chem. Commun. 2011, 47, 11204.
(8) (a) Karlsson, A.; Parales, J. V.; Parales, R. E.; Gibson, D. T.; Eklund, H.;
Ramaswamy, S., Science 2003, 299, 1039; (b) Barry, S. M.; Challis, G. L.,
ACS Catal. 2013, 3, 2362; (c) Wolfe, M. D.; Parales, J. V.; Gibson, D. T.;
Lipscomb, J. D., J. Biol. Chem. 2001, 276, 1945; (d) Kovaleva, E. G.;
Lipscomb, J. D., Nat. Chem. Biol. 2008, 4, 186.
(9) Feng, Y.; Ke, C.ꢀy.; Xue, G.; Que Jr., L., Chem. Commun. 2009, 50.
(10) Chen, K.; Que Jr., L., Angew. Chem. Int. Ed. 1999, 38, 2227.
(11) (a) GarciaꢀBosch, I.; Codolà, Z.; Prat, I.; Ribas, X.; LloretꢀFillol, J.;
Costas, M., Chem. Eur. J. 2012, 18, 13269; (b) Feng, Y.; England, J.; Que
Jr., L., ACS Catal. 2011, 1, 1035; (c) Oldenburg, P. D.; Feng, Y.; Pryjomskaꢀ
ASSOCIATED CONTENT
9
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 10 of 11
Ray, I.; Ness, D.; Que Jr., L., J. Am. Chem. Soc. 2010, 132, 17713; (d)
1116; (c) Plietker, B.; Niggemann, M., Org. Biomol. Chem. 2004, 2, 2403;
Suzuki, K.; Oldenburg, P. D.; Que Jr., L., Angew. Chem. Int. Ed. 2008, 47,
1887; (e) Barry, S. M.; Rutledge, P. J., Synlett 2008, 2172; (f) Bautz, J.;
Comba, P.; Laorden, C. L. d.; Menzel, M.; Rajaraman, G., Angew. Chem.
Int. Ed. 2007, 46, 8067; (g) Oldenburg, P. D.; Shteinman, A. A.; Que Jr., L.,
J. Am. Chem. Soc. 2005, 127, 15672; (h) Bassan, A.; Blomberg, M. R. A.;
Siegbahn, P. E. M.; Que Jr., L., Angew. Chem. Int. Ed. 2005, 44, 2939; (i)
Fujita, M.; Costas, M.; Que Jr., L., J. Am. Chem. Soc. 2003, 125, 9912; (j)
Chen, K.; Costas, M.; Kim, J.; Tipton, A. K.; Que Jr., L., J. Am. Chem. Soc.
2002, 124, 3026; (k) Costas, M.; Tipton, A. K.; Chen, K.; Jo, D.ꢀH.; Que Jr.,
L., J. Am. Chem. Soc. 2001, 123, 6722; (l) Bruijnincx, P. C. A.; Buurmans, I.
L. C.; Huang, Y.; Juhasz, G.; VicianoꢀChumillas, M.; Quesada, M.; Reedijk,
J.; Lutz, M.; Spek, A. L.; Muenck, E.; Bominaar, E. L.; Gebbink, R. J. M. K.,
Inorg. Chem. 2011, 50, 9243; (m) Bruijnincx, P. C. A.; Buurmans, I. L. C.;
Gosiewska, S.; Moelands, M. A. H.; Lutz, M.; Spek, A. L.; van Koten, G.;
Gebbink, R. J. M. K., Chem. Eur. J. 2008, 14, 1228; (n) Folkertsma, E.; de
Waard, E. F.; Korpershoek, G.; van Schaik, A. J.; Miron, N. S.; Borrmann,
M.; Nijsse, S.; Moelands, M. A. H.; Lutz, M.; Otte, M.; Moret, M. E.;
Gebbink, R., Eur. J. Inorg. Chem. 2016, 1319; (o) Chatterjee, S.; Paine, T.
K., Angew. Chem. Int. Ed. 2015, 54, 9338; (p) Kejriwal, A.; Biswas, S.;
Biswas, A. N.; Bandyopadhyay, P., J. Mol. Cat.. A: Chem. 2016, 413, 77.
(12) (a) Zang, C.; Liu, Y.; Xu, Z.ꢀJ.; Tse, C.ꢀW.; Guan, X.; Wei, J.; Huang, J.ꢀ
S.; Che, C.ꢀM., Angew. Chem. Int. Ed. 2016, 55, 10253; (b) Chow, T. W.ꢀ
S.; Wong, E. L.ꢀM.; Guo, Z.; Liu, Y.; Huang, J.ꢀS.; Che, C.ꢀM., J. Am. Chem.
Soc. 2010, 132, 13229; (c) Ryu, J. Y.; Kim, J.; Costas, M.; Chen, K.; Nam,
W.; Que Jr., L., Chem. Commun. 2002, 12, 1288; (d) Prat, I.; Font, D.;
Company, A.; Junge, K.; Ribas, X.; Beller, M.; Costas, M., Adv. Synth.
Catal. 2013, 355, 947.
(d) Plietker, B.; Niggemann, M., Org. Lett. 2003, 5, 3353.
1
2
3
4
5
6
7
8
(15) (a) Neibergall, M. B.; Stubna, A.; Mekmouche, Y.; Munck, E.;
Lipscomb, J. D., Biochemistry 2007, 46, 8004; (b) Wolfe, M. D.; Altier, D.
J.; Stubna, A.; Popescu, C. V.; Münck, E.; Lipscomb, J. D., Biochemistry
2002, 41, 9611.
(16) (a) Font, D.; Canta, M.; Milan, M.; Cusso, O.; Ribas, X.; Gebbink, R.;
Costas, M., Angew. Chem. Int. Ed. 2016, 55, 5776; (b) Cusso, O.;
Cianfanelli, M.; Ribas, X.; Gebbink, R.; Costas, M., J. Am. Chem. Soc. 2016,
138, 2732; (c) Milan, M.; Bietti, M.; Costas, M., ACS Central Sci. 2017, 3,
196.
(17) (a) Prat, I.; Company, A.; Corona, T.; Parella, T.; Ribas, X.; Costas, M.,
Inorg. Chem. 2013, 52, 9229−9244; (b) Zang, Y.; Kim, J.; Dong, Y.;
Wilkinson, E. C.; Appelman, E. H.; Que Jr., L., J. Am. Chem. Soc. 1997,
119, 4197; (c) Diebold, A.; Hagen, K. S., Inorg. Chem. 1998, 37, 215.
(18) White, M. C.; Doyle, A. G.; Jacobsen, E. N., J. Am. Chem. Soc. 2001,
123, 7194.
(19) Murphy, A.; Pace, A.; Stack, T. D. P., Org. Lett. 2004, 6, 3119.
(20) Wang, Z.; Cui, Y.ꢀT.; Xu, Z.ꢀB.; Qu, J., J. Org. Chem. 2008, 73, 2270.
(21) (a) Antzutkin, O. N.; Iuga, D.; Filippov, A. V.; Kelly, R. T.; Beckerꢀ
Baldus, J.; Brown, S. P.; Dupree, R., Angew. Chem. Int. Ed. 2012, 51,
10289; (b) Wu, G., Solid State Nucl. Magn. Reson. 2016, 73, 1; (c) Young,
R. P.; Caulkins, B. G.; Borchardt, D.; Bulloch, D. N.; Larive, C. K.; Dunn, M.
F.; Mueller, L. J., Angew. Chem. Int. Ed. 2016, 55, 1350; (d) Wong, A.;
Poli, F., SolidꢀState Oꢀ17 NMR Studies of Biomolecules. In Annual Reports
on NMR Spectroscopy, Webb, G. A., Ed. Elsevier Academic Press Inc: San
Diego, 2014; Vol. 83, pp 145.
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
(22) (a) Bassan, A.; Blomberg, M. R. A.; Siegbahn, P. E. M.; Que Jr., L.,
Chem. Eur. J. 2005, 11, 692; (b) Bassan, A.; Blomberg, M. R. A.; Siegbahn,
P. E. M.; Que Jr., L., J. Am. Chem. Soc. 2002, 124, 11056.
(13) Prat, I.; Mathieson, J. S. J. S.; Güell, M.; Ribas, X.; Luis, J. M. J. M.;
Cronin, L.; Costas, M., Nat. Chem. 2011, 3, 788.
(14) (a) Plietker, B.; Niggemann, M., J. Org. Chem. 2005, 70, 2402; (b)
Plietker, B.; Niggemann, M.; Pollrich, A., Org. Biomol. Chem. 2004, 2,
10
ACS Paragon Plus Environment

Page 11 of 11
Journal of the American Chemical Society
TOC
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
11
ACS Paragon Plus Environment