Asymmetric epoxidation with H2O2 by manipulating the electronic properties of non-heme iron catalysts

Article abstract of DOI:10.1021/ja4078446

A non-heme iron complex that catalyzes highly enantioselective epoxidation of olefins with H₂O₂ is described. Improvement of enantiomeric excesses is attained by the use of catalytic amounts of carboxylic acid additives. Electronic effects imposed by the ligand on the iron center are shown to synergistically cooperate with catalytic amounts of carboxylic acids in promoting efficient O-O cleavage and creating highly chemo-and enantioselective epoxidizing species which provide a broad range of epoxides in synthetically valuable yields and short reaction times.

Full text of DOI:10.1021/ja4078446

Subscriber access provided by UNIV OF WATERLOO
Article
Asymmetric Epoxidation with H2O2 by Manipulating
the Electronic Properties of Non-Heme Iron Catalysts
Olaf Cusso, Isaac Garcia-Bosch, Xavi Ribas, Julio Lloret-Fillol, and Miquel Costas
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja4078446 • Publication Date (Web): 03 Sep 2013
Downloaded from http://pubs.acs.org on September 4, 2013
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 10
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
Asymmetric Epoxidation with H2O2 by Manipulating the Electronic
Properties of Non-Heme Iron Catalysts.
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
Olaf Cussó, Isaac Garcia-Bosch, Xavi Ribas, Julio Lloret-Fillol and Miquel Costas*.
QBIS ResearchGroup, Institut de Química Computacional i Catàlisi (IQCC) and Departament de Química, Universitat de
Girona, Campus Montilivi, Girona E-17071, Catalonia, Spain.
Supporting Information Placeholder
ABSTRACT: A non-heme iron complex that catalyzes highly enantioselective epoxidation of olefins with H2O2 is described.
Improvement of enantiomeric excesses is attained by the use of catalytic amounts of carboxylic acid additives. Electronic effects
imposed by the ligand on the iron center are shown to synergistically cooperate with catalytic amounts of carboxylic acids in pro-
moting efficient O-O cleavage, creating highly chemo- and enantioselective epoxidizing species which provide a broad range of
epoxides in synthetically valuable yields and short reaction times.
Introduction. Inspired by oxidations taking place at oxy-
genases, the combination of iron-based catalysts and hydrogen
peroxide is an attractive approach for developing oxidation
methods because of availability, low cost and low toxicity
considerations.1 A particularly appealing transformation for
this strategy is asymmetric epoxidation due to its pivotal role
in modern organic synthesis.2 Given its importance, asymmet-
ric epoxidation has been actively pursued and some excellent
metal-based catalytic methods are well established.2a-c Howev-
er, iron-catalyzed asymmetric epoxidations that employ H2O2
and provide product yields and stereoselectivities amenable
for preparative purposes remain scarce and limited in substrate
scope mainly because of the intrinsic complexities of Fe-H2O2
reactions.1f,g,3-5 While mononuclear iron-(hydro)peroxide spe-
cies are common intermediates in heme and non-heme oxy-
genases,6-7 in the absence of the elaborate machinery provided
by enzymatic sites, the rich redox chemistry of iron and hy-
drogen peroxide poses serious problems to control the crucial
O-O bond cleavage event. Basic concepts and strategies need
to be developed for controlling this reaction such that metal-
based oxidants susceptible to engage in selective oxygen atom
transfer reactions are generated, thus avoiding Fenton type of
processes, and non-productive peroxide disproportionation
reactions. As a matter of fact, two recent reports of iron cata-
lyzed asymmetric epoxidation bypass this problem by using
peracetic acid and iodosylbenzene as alternative oxidants.5
Herein we show that electronic effects resembling those op-
erating in Cyt-P450 can be used to design excellent non-heme
iron epoxidation catalysts that make an efficient use of H2O2
to afford epoxides with excellent yields and enantioselectivi-
ties in short reaction times. Synergistic operation of metal, a
powerful electron-donating ligand and a carboxylic acid co-
ligand allows an efficient heterolytic O-O bond cleavage, and
relative stabilization of the electrophilic high valent iron-oxo
species, finally leading to stereoselective oxygen atom trans-
fer. Useful insight for further catalyst development and expan-
sion of substrate scope is disclosed.
s -
A
251
p
s -
p
A
251
H+
H
O
O
O
O
H
H
H
H
O
O
r-
Th 252
H
O
O
H
r-
Th 252
O
O
N
N
N
N
N
eIII
eIV
F
F
N
N
N
S
S
Scheme 1. Schematic diagram of the push-pull effect in assist-
ing O-O breakage in P450 to form ferryl species Compound I
(Cpd-I).
Results and Discussion.
Cytochromes P450 (Cyt-P450) constitute a paradigmatic
example where the powerful electron donating properties of
the apical thiolate, and the H-accepting character of a nearby
threonine residue, assist the O-O cleavage step of ferric hy-
droperoxide species via the so-called “push-pull” effect
(Scheme 1).7 In addition, the dianionic and redox non-innocent
nature of the porphyrin ligand alleviates positive charge from
the iron center and provides stabilization of the high valent
ferryl species (Compound I) responsible for substrate oxida-
tion.
Synthesis and characterization of the catalysts
Selected iron complexes containing aminopyridine tetraden-
tate ligands are emerging as powerful oxidation catalysts.8,9
Among these, the family of bipyrrolidine based complexes
X
[FeII(CF3SO3)2(XPDP)], 1 (x = Me2N, dMM, MeO, Me, H,
Cl, CO2Et, Scheme 2, see SI for experimental details) was
identified as a particularly promising platform to evaluate
putative electronic effects in catalytic asymmetric epoxidation,
owing to the excellent performance of H1 in C-H10 and
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 10
1
2
3
4
5
6
7
8
C=C4e,8e oxidation reactions. In epoxidation reactions, H1 in
Scheme 2. Schematic diagram of the iron complexes stud-
combination with H2O2 and acetic acid (1.1 equiv with respect
to substrate) has been previously shown to elicit good yields,
but moderate enantioselectivities (16-62% ee).4e Structurally
ied. In the bottom right, an ORTEP diagram of the single
crystal X-ray determined structure of MeO1 is shown.
related
complexes
[FeII(CF3SO3)2(QuinPDP)],
Quin1,
Catalytic epoxidation activity
[FeII(CF3SO3)2(PinPDP)], Pin1 and [FeII(CF3SO3)2(dMMMCP)],
dMM2, (Scheme 2) were also prepared in the present work, and
their reactivity studied and compared to X1.
Impact of the catalyst in product yield and stereoselec-
tivity. Epoxidation of cis-β-methylstyrene (S1) was taken as a
model reaction. H2O2 (1.6 equiv) was delivered by syringe
pump to an acetonitrile solution at -30 ºC containing AcOH
(140 mol %), catalyst (1-2 mol %) and substrate (see Table 1)
under air.
9
Preparation of the complexes involved straightforward reac-
tion of the corresponding tetradentate ligand and
[Fe(CF3SO3)2(CH3CN)2] in acetonitrile solution. Removal of
the solvent under vacuum and recrystallization by ether diffu-
sion into CH2Cl2 solutions yielded the desired complexes as
crystalline materials (see SI for details). The X-ray structures
of H1,10a and Pin111 have been previously described. An ORTEP
diagram of MeO1 is shown in Scheme 2, and serves to illustrate
the basic structural aspects of the family of complexes with
general formula [FeII(CF3SO3)2(XPDP)], X1. Iron centers
adopt a distorted octahedral coordination geometry. Four
coordination sites are occupied by nitrogen atoms of the tetra-
dentate ligand, and the two remaining sites contain oxygen
atoms from the triflate groups. These are in cis- relative posi-
tion and in the same coordination plane as the two bipyrroli-
dine nitrogen atoms. The two pyridine rings bind trans to each
other. Fe-N/O distances are between 2.1-2.2 Å and are indica-
tive of a high spin ferrous center.12 When dissolved in CD3CN
or CD2Cl2 the full set of complexes retain a common C2-
symmetric cis-α topological geometry, with the iron center in
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 1. Epoxidation of S1 using different iron complexesa.
a a
t l
s
mo
1 l
%
(
t
C
y
)
O
.
e u v.
i
q
)
H
2O2
c
1 6
(
x mo
A
H
l
O
%
)
(
-
m n
i
H
N
30º 30
C
3C
C
,
,
S1
Entry Catalyst
AcOH
Conv.
ee (%)
(x mol %)
140
140
140
140
140
140
140
140
140
140
140
3
(Yield) (%)
61(38)
57(33)
44(22)
44(27)
64(37)
97(81)
100(82)
100(85)
89(69)
80(46)
82(55)
100(87)
45(20)
49(26)
32(15)
31(13)
31(17)
38(26)
82(67)
53(41)
1
2
3
4
5
6
7
H1
21
15
19
31
39
40
60
61
30
20
32
62
46
19
16
21
30
38
38
30
Cl1
CO2Et1
Me1
1
the high spin state, as evidenced in their H-NMR spectra by
the number of signals, their relative integration and the large
spectral window (200 to -20 ppm) corresponding to paramag-
netic molecules (see SI for details).
MeO1
dMM1
Me2N1
8[b] Me2N1
pin1[c]
9
10 iQuin1
11 dMM2
12 Me2N1
13 Me2N1
14 H1
0
3
15 Cl1
3
16 CO2Et1
17 Me1
3
3
18 MeO1
19[b] dMM1
20 pin1[c]
3
3
3
ACS Paragon Plus Environment

Page 3 of 10
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
21 iQuin1
3
34(15)
19
Catalysts that contain the most electron-rich pyridines within
the series retain their chemoselectivity when low CA loadings
are employed. These include Me2N1 but also pin1, dMM1 and
MeO1. On the other hand, H1, Me1, Cl1, iQuin1 and CO2Et1 lose
chemoselectivity at low CA loadings, even though the latter
reactions proceed under a priori more favorable conditions for
selectivity since lower substrate conversions are obtained.
Therefore, the Me2N1, pin1, dMM1 and MeO1 catalysts appear to
generate more selective oxidizing species.
In conclusion, Me2N1 exhibits a unique ability to operate as a
remarkably efficient and selective epoxidation catalyst em-
ploying H2O2 as oxidant and low CA concentration, reflecting
an unusual ability to activate and channel H2O2 reactivity
towards selective epoxidizing species.
aProduct yields, substrate conversions and ee's were determined
by GC (See SI for further details). Unless stated, catalysts em-
ployed have (S,S) chirality at the bipyrrolidine moiety. b 2 mol %
catalyst, H2O2 (1.6 equiv). c (R,R)-catalyst was employed.
Moderate yield (38%) and enantioselectivity (21%) is ob-
tained with the simplest catalyst of the series, H1 (Table 1,
entry 1). When electron-withdrawing groups are introduced at
the para- position (R2) of the pyridine (Table 1, entries 2-3),
both yield and selectivity experience erosion, but they became
very much improved in the presence of electron-donating
substituents (Table 1, entries 4-8). Among the series of cata-
lysts tested, excellent epoxide yield and moderate enantiose-
lectivity was obtained with complex Me2N1 (82% yield and 60-
ee, Table 1, entry 7), which contains strongly donating NMe2
groups in the pyridines, and a further slight improvement in
epoxide yield (85%) and enantioselectivity (61%) can be
gained by using 2 mol % of catalyst (entry 8). On the other
hand, catalysts containing more elaborate pyridine derivatives
such as iQuin1 and Pin1 (Scheme 2) give more modest yields
(46-69%) and enantioselectivities (20-30% ee, entries 10 and
9). For comparison, catalyst dMM2 elicits reduced ee’s (entry
11), thus the bipyrrolidine backbone is better than the cyclo-
hexyldiamine backbone for eliciting optimum stereoselectivi-
ty. Finally, control experiments showed that the Me2NPDP
ligand alone is not an epoxidation catalyst, and also that the
simple addition of 4-dimethylaminopyridine (DMAP) inhibits
the epoxidation activity of H1.
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
Optimization of the catalytic activity with regard to
amount and identity of the carboxylic acid.
Table 2. Asymmetric epoxidation of S1 using different car-
boxylic acids using catalyst Me2N1.a
a a
s
mo
2 l
%
(
t
l
t
C
y
)
.
e u v.
i
q
)
O
H2O2 1 6
(
mo
l
%
RCO2H
3
(
)
-
m n
i
CH CN 30ºC 30
,
,
3
S1
Entry
RCO2H
Conv.(yield) (%)
ee (%)
1
2
CF3CO2H
37(13)
26(6)
36
58
AcONa
O
3
4
5
100(81)
100(88)
100(76)
64
80
67
O
H
5-mha
O
Therefore, from the results collected in Table 1 (entries 1-
11) it can be concluded that yields and stereoselectivities of
the epoxidation reactions appear to be strongly and systemati-
cally dependent on the electron-donating nature of the pyridine
of the ligand, and dMM1 and Me2N1 are identified as the best
catalysts of the series.
H
O
eba
O
OH
cxa
Impact of the carboxylic acid loading required for effi-
cient catalytic activity.
O
O
6
7
100(91)
100(73)
73
76
H aca
Acetic acid has been previously shown to play a key posi-
tive role in enhancing yields and chemoselectivity in iron
catalyzed epoxidation reactions.8a Because of that, further
studies were conducted to investigate the role of carboxylic
acids (CAs) in the current reactions. Most remarkably, by
using Me2N1 (2 mol %) the amount of acetic acid could be
lowered down to only 1.5 equiv with respect to the iron cata-
lyst, and these conditions even slightly improved yield and
ee’s (Table 1, compare entry 12 with entries 7-8). However, in
the absence of acetic acid, both yields and stereoselectivities
experience a substantial decrease (Table 1, entry 13). Most
remarkably, a perusal of Table 1 shows that only Me2N1 has the
ability to efficiently operate at nearly stoichiometric acid con-
centration. For the rest of the catalysts (Table 1, entries 14-21)
the use of 1.5 equiv of acetic acid has a small effect on ee’s (<
2% ee), but substrate conversions and epoxide yields were
substantially smaller than in analogous reactions run with 140
equiv. of acetic acid (entries 1-11).
O
H pva
O
O
H
O
8
100(86)
80
2-eha
H
O
9
100(97)
100(87)
100(97)
100(87)
86
63
77
66
O
S-Ibuprofen
S-Ibuprofenb
10
11
12
H
O
O
e
M
O
S-Naproxen
S-Naproxenb
O
13
14
100(84)
100(84)
74
76
OH
Along the same vein, the effect of the carboxylic acid load-
ing on the chemoselectivity towards epoxidation of the reac-
tions is also dependent on the nature of the catalysts (Table 1).
S-2-mbab
S-2-mba
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 10
1
2
3
4
5
6
e
M O CF3
OH
Substrate scope. Substrate scope was then explored under
optimized conditions (Table 3), using S-ibp and 2-eha as the
carboxylic acids of choice.
15
16
62(42)
60(36)
58
63
O
R-Mosher’s acidb
R-Mosher’sacid
Table 3. Substrate scope on the optimized asymmetric epoxi-
dation.a
7
8
9
Conv.(Epox. Isol.
O
O
O
O
Entry
Substrate
CA
ee (%)
86
P
Yield, %)
17
-
-
H
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
S-ibp
S-ibp
100(97)b
Ph
R
R = Me (S1)
1
O
2c
R = CO2Et
18
-
-
91
97
H
O
(S2)
NH
aYields, conversions and ee's were determined by chiral GC (see
SI for details). 5-Mha: 5-methylhexanoic acid, eba: ethylbutyric
acid, cha: cyclohexanoic acid, aca: adamantane carboxylic acid,
pva: pivalic acid and 2-eha: 2-ethylhexanoic acid, S-2-mba: S-
3
R = CO2Et (S2)
2-eha
S-ibp
2-eha
81
84
78
95
96
95
4c
5
R = C(O)N(OMe)(Me) (S3)
methylbutyric acid. bReaction with (R,R)-Me2N
1
R = C(O)N(OMe)(Me) (S3)
R
Further optimization took advantage of a recent report by
Lyakin et al. showing an improvement in epoxidation stere-
oselectivities by using different CA additives (up to 86% ee
for chalcone).4e However, the large acid loading required for
efficient operation (0.5-1.4 equiv with respect to the substrate)
in common iron systems limits the diversity of CAs that could
be employed. Instead, since Me2N1 requires only 1.5 equiv with
respect to the catalyst, rapid screening of different CAs differ-
ing in the electronic and spatial properties could be tested with
the aim of improving the enantioselectivity without requiring
extensive catalyst preparation. This approach was then further
pursued by taking the epoxidation of S1 as a model reaction
(Table 2).
S-ibp
2-eha
S-ibp
100(85)d
95
98(3R,4R)
99(3R,4R)
99(3R,4R)
O
6
7
8
R= CN (S4)
R= CN (S4)
R =
100(90)d
NO2(S5)
9
R =
NO2(S5)
2-eha
S-ibp
2-eha
97
99(3R,4R)
e
M
M
48(21)b
53(32)b
7
Ph
Ph
10
11
(S6)
(S6)
e
19
We noticed that certain criteria were necessary for efficient
and selective epoxidation activity. Firstly, poor activity was
observed when a strong acid such as CF3CO2H was used
(entry 1). In addition, the use of sodium acetate instead of
acetic acid resulted in very small epoxide yields (entry 2). The
combination of the two observations indicates that both the
carboxylate moiety and the proton are important for optimized
epoxidation activity. Improved performance both in terms of
epoxide yield and enantioselectivity with regard to acetic acid
can be gained with the use of a number of aliphatic carboxylic
acids (Table 2, entries 3-8). Of these, as also shown by Lyakin
et al., racemic 2-ethylhexanoic acid (2-eha) provides relatively
high ee’s (80 % ee, entry 8). Chiral carboxylic acids could be
also tested, leading to the discovery that the combination of S-
Ibuprofen (S-ibp) with Me2N1 affords the epoxide with high
yield and good enantioselectivity (97% yield, 86% ee, entry
9). Interestingly, use of (R,R)-Me2N1 in combination with S-
Ibuprofen resulted in smaller enantioselectivity (63% ee, entry
10) indicating that the high stereoselection requires proper
matching of the chirality of the complex with that of the acid.
Analogous results were obtained when other chiral carboxylic
acids were tested (entries 11-16); for example S-Naproxen
provides the epoxide with 77% and 66% ee's when NMe21 and
(R,R)-Me2N1 are employed (entries 10 and 11), respectively.
Unfortunately, examples of quite versatile families of chiral
carboxylic acids such as amino acids, and chiral phosphoric
acids (entries 17 and 18) proved incompatible with this sys-
tem.
S-ibp
100(67)b
82(47)b
45
31
Ph
Ph
12
13
(S7)
(S7)
2-eha
O
O
R
R
R
R11
14
S-ibp
57(38)
90
R = R1 = H (S8)
15
(S8)
R = R1 = H
2-eha
2-eha
99
95
98(2R,3S)
97(2R,3S)
16
(S9)
R = Me = R1 = H
17
18
R = Cl= R1 = H (S10)
2-eha
2-eha
97
94
97(2R,3S)
97(2R,3S)
R = H= R1 = CF3 (S11)
O
2-eha
69
47
Ph
Ph
Ph
19
(S12)
O
R
20
21
2-eha
2-eha
66
91
91(2R,3S)
R = OMe (S13)
R = OEt (S14)
91
ACS Paragon Plus Environment

Page 5 of 10
Journal of the American Chemical Society
1
2
3
4
5
6
7
22
23
24
25
R = OiPr (S15)
R = OBz (S16)
R = Me (S17)
2-eha
2-eha
2-eha
2-eha
94
94
60
95
97(2R,3S)
standing enantioselectivity (entry 25, 99% ee). Epoxidation of
trisubstituted aromatic enones was also accomplished with
varying outcomes. α-Methyl substituted chalcone S12 yielded
moderate ee’s (entry 19, 47% ee), but the cyclic enones S19-
S22 (Table 3, entries 26-29) were epoxidized with excellent
yield (94-97%) and enantioselectivity (90-97% ee).
96
94
99
R = N(OMe)(Me) (S18)
8
9
Encouraged by the results in the epoxidation of aromatic
enones, we turned our attention to the challenging cyclic ali-
phatic enones.14 Initial epoxidation reactions using catalyst
Me2N1 provided poor yields (12%) and moderate enantioselec-
tivity (76% ee) in the epoxidation of 2-cyclohexen-1-one
(S23). The poor performance of Me2N1 in the epoxidation of
these cyclic enones is most likely due to the rapid deactivation
of this catalyst that occurs when the substrate is not rapidly
oxidized under the standard oxidation conditions. Competitive
epoxidation of chalcone (S8) and cyclic enone (S23) with
Me2N1 indeed shows that the former is epoxidized preferentially
(ratio of epoxides >10:1) than the later. Instead, dMM1 is more
tolerant to the oxidative conditions, giving improved yields
and ee’s in the epoxidation of 2-cyclohexen-1-one (S23),
(Table 3, entry 30, 99% yield, 84 % ee) and 2-cyclopenten-1-
one (S24) (Table 3, entry 31, 79% yield, 87% ee), albeit 140
mol % of 2-eha co-ligand was required. Trisubstituted aliphat-
ic cyclic enones were also convenient substrates for the system
and were epoxidized with good yields and enantioselectivity
(Table 3, entry 32, 79% yield, 80 % ee). In conclusion, these
catalysts exhibit a very remarkable broad substrate scope,
which is substantially more extended than any other iron based
system described so far.
O
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
2-eha
94
90(2R,3S)
R
26
R = H (S19)
R = Me (S20)
R = F (S21)
27
28
29
2-eha
2-eha
2-eha
97
96
96
97(2R,3S)
97(2R,3S)
95
R = tBu (S22)
100(99)b
92(79)b
84 (R)
O
2-eha
2-eha
30e
31e
(S23)
O
87
(S24)
94(79)b
80
O
2-eha
32e
(S25)
aUnless stated, reaction conditions are Me2N1 (2 mol%), H2O2
(1.6 equiv) and CA (3 mol %) in CH3CN at -30 ºC during 30 min.
Yields refer to isolated yields of pure epoxide. ee’s and configura-
tion was determined by chiral GC and HPLC (see SI for details).
Mechanistic studies.
bEpoxide yields and substrate conversions determined by GC. 5
c
Precedents. The positive role of acetic acid in iron cata-
lyzed oxidations has been documented for some years,8a but
mechanistic interpretation has not been provided until more
recently.15 The original mechanism proposed by Que and co-
workers for the Fe-catalyzed AcOH assisted epoxidation of
olefins with H2O2 involves the intermediacy of oxo-
carboxylate-iron(V) species (Ib, Scheme 3) as the oxygen
atom delivering agent. Species Ib is formed via acid assisted
heterolytic cleavage of the O-O bond in a FeIII(OOH)(HOAc)
(Ia) precursor.15 Experimental spectroscopic evidence in favor
of this mechanistic scenario has been also recently provided
by Talsi, Briakov and co-workers,16 and further computational
support for the formation and oxidative competence of these
species has been built by Rajaraman et al in a study of the
ortho-hydroxylation of aromatic compounds by non-heme Fe
complexes.17
d
mol % catalyst, and 3 equiv. of H2O2. Epoxide yields and sub-
1
e
strate conversions determined by H-NMR. Reaction conditions
are: dMM1 (1 mol %), H2O2 (1.2 equiv) and 2-eha (140 mol %) in
CH3CN at -30 ºC during 30 min.
For both carboxylic acids, good yields and excellent enanti-
oselectivities were obtained with cis-cinnamic esters (S2,
Table 3, entries 2 and 3), an amide derivative (S3, Table 3,
entries 4 and 5), and with electron-deficient chromenes (Table
3, entries 6-9). We conclude that this catalyst constitutes a rare
example of an iron-based system which effectively epoxidizes
cis-aromatic substrates with high enantioselectivity.13 On the
other hand, trans-β-methyl styrene (S6) and the terminal aro-
matic olefin α-methyl styrene (S7) were epoxidized with mod-
est chemoselectivity and only low ee’s (entries 10-13). Further
scope of the catalyst includes the epoxidation of aromatic
enones. Initial experiments employing S-ibuprofen as a co-
ligand did elicit good stereoselectivities in the epoxidation of
chalcone, but only moderate yields (entry 14). However, ex-
cellent yields (99%) and stereoselectivitives (98%) were ob-
tained in the epoxidation of chalcone when employing 2-eha
(Table 3, entry 15, S8), which are the highest reported for an
iron-based system.1f,4 Introduction of electron-donating (S9) or
electron-withdrawing (S10 and S11) groups in the aromatic
rings retains the excellent performance (Table 3, entries 16-
18). Most interestingly, trans-cinnamic esters (S13-S16) are
also a suitable family of substrates and are epoxidized with
excellent yields and selectivities (entries 20-23, ee’s 91-97%),
and the same applies to an alkylstyrylketone S17 (entry 24,
94% ee). The amide derivative S18 is epoxidized with out-
On the other hand, Shaik, Que et al have recently proposed
on the basis of DFT analyses that the carboxylate may play a
role as a redox non-innocent ligand, sharing one electron with
the iron site.18 The electronic structure of this intermediate
(Ib’, Scheme 3) will bear obvious similarities with that of
Compound I in P450.7
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 10
1
2
3
4
5
6
7
8
9
H
2O2
sion is in agreement with recent studies by Nam et al showing
eII
+
LN4
F
F
R
H
CO2
C
(
3SO3 2
[
]
)
that ferric hydroperoxide and alkylperoxide species are slug-
gish oxygen atom transfer agents.20 Furthermore, since enanti-
oselection is affected by both the nature and the chirality of
the carboxylic acid, it could be deduced that the latter remains
as a ligand in the oxygen delivering species.
H
1
/
2 H
2O2
O
R
O
H
O
C
eIII
LN4
F
O
O
Evidence in favor of the implication of an electrophilic oxi-
dant species is derived from a competitive epoxidation of S1
and ethyl cis-cinnamic ester S2. Epoxidation of the most elec-
tron rich alkene S1 (Scheme 4) is favored roughly 9 times with
regard to S2. This result is also significant because it provides
solid evidence against epoxidation taking place though a nu-
cleophilic Weitz-Scheffer-type epoxidation mechanism.2e,21
O
O
-
2
F
3SO3
C
C
R
LN4
F
eIII
a
I
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
c
I
R
R'
O
e
2N1
M
O
mo
l
%
)
O
5
(
H
O
C
H
e
u v.
i
)
H2O2
3
(
q
LN4
F
eV
O
-
u
. mo
S Ib 7 5
l
%
(
)
+
O
R
+
-
m n
i
CH CN 30ºC 30
R
,
,
R'
3
Ib
Et
CO2
Et
CO2
or
O
:
e
:
i ld 7
:
S1 S2
3% 8 %
:
y
O
:
:
ee
4
8 %
87
%
1 1
LN4
F
eIV
Scheme 4. Competitive epoxidation experiment of substrates
S1 and S2.
Ib'
O
R
Scheme 3. Original mechanistic scheme proposed by Que et al
The sum of these observations, namely the identical enanti-
oselectivity irrespective of the oxidant, as well as the electro-
philic character of the oxidizing species, in combination with
the literature precedents for poor oxygen atom transfer reactiv-
ity of iron peroxides provides thus experimental evidence that
O-O breakage in Me2N1 precedes formation of the oxidizing
species. The cleavage of the O-O bond in iron peroxide spe-
cies can occur through homolysis or heterolysis. Homolysis is
discarded in the present case because it implies formation of
poorly selective hydroxyl radicals, and oxo-iron(IV) species,
which are relatively modest O-atom transfer agents.22 There-
fore, heterolysis must be the operating path, leading to an
electrophilic FeV(O)(O2CR) species (Ib, Scheme 3), which is
then responsible for the O-atom transfer.
for the carboxylic acid assisted O-O cleavage.15
The mechanistic picture that emerges from analyzing the re-
activity of Me2N1 is in good agreement with that originally
proposed by Que et al. This mechanistic scheme provides a
rationale for the efficient H2O2 activation mediated by Me2N1,
and for the origin of the high stereoselectivity observed for
this catalyst.
Mechanistic studies into the nature of the oxidizing spe-
cies. Insight into the O-delivering species could be deduced by
comparing the epoxidation of S1 with catalyst Me2N1 and acetic
acid as co-ligand but employing different oxidants including
t
H2O2, BuOOH and peracetic acid (Table SI.1). Substrate
e
M
2N1
mo
2
.
l
%
(
)
conversion and epoxide yields are dependent on the oxidant;
32% conversion and 20% epoxide yield for tBuOOH, and 85%
conversion and 63% epoxide yield for peracetic acid, to com-
pare with quantitative conversion and 87% epoxide yield with
H2O2. But the most significant aspect with regard to the nature
of the O-delivering species is that the enantiomeric excess in
the corresponding epoxide is virtually the same (61±1% ee)
when any of three different oxidants are employed. Particular-
ly interesting is the observation that tBuOOH is also a compe-
tent oxidant to engage in an enantioselective epoxidation be-
cause, unlike in the present reactions, its combination with non
heme iron complexes has been shown to produce unselective
free-diffusing radical reactions initiated by homolytic O-O
cleavage of FeIII(OOtBu) intermediates.19 The ability of Me2N1
to avoid this free radical reactivity and engage in metal cen-
tered stereoselective chemistry is therefore notable. Enantio-
meric excesses are quite sensitive indicators of the differences
in energy between the transition states associated with the
oxygen atom transfer reaction, leading to the two enantiomeric
epoxides, and are usually finely dependent on the nature of the
reagents. Because of that, the observation of virtually identical
ee’s strongly suggests that oxygen atom transfer is performed
by the same species, irrespective of the oxidant, discarding
iron-peroxides such as Ia as possible oxidants. This conclu-
a
H218O2 0 05
e u v
i
q
)
)
(
16O
c
mo
l
%
A OH
3
(
)
-
m n
i
CH CN 30ºC 30
,
,
3
1
8O
91
%
e
2N1
M
mo
2
(
l
%
)
.
e
e
u v.
i
q
)
u v
i
q
)
H2O2 1 6
(
b
)
H218O
1
(
16O
c
mo
l
%
A OH
3
(
)
-
m n
i
CH CN 30ºC 30
,
,
3
0 4 18O
.
%
Scheme 5. Isotopic analysis studies. H218O2 reagent is a 2%
solution in H216O.
Isotopic analyses were also employed as mechanistic tools
(Scheme 5), and conform to the same mechanistic picture,
providing insight into the mechanism of O-O lysis. Epoxida-
tion of S1 with Me2N1 using H218O2 (90% 18O enrichment) as
oxidant provided the corresponding epoxide 91(±1)% 18O-
labelled (Scheme 5a), and virtually no 18O was incorporated
(0.4(±1)%) when H216O2/H218O was used (Scheme 5b), indi-
cating that the oxidant is the source of oxygen atoms incorpo-
rated into the epoxide, and also that oxygen from water is not
incorporated. This isotopic pattern argues against the implica-
tion of a water-assisted O-O lysis that results in FeV(O)(OH)
ACS Paragon Plus Environment

Page 7 of 10
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
species,8b,22 and instead points towards the carboxylic acid
same analysis was done for substrates S1, S4 and S13, show-
mediated pathway that leads to Ib, in line with the previous
ing analogous correlations. The consistent linear nature of the
Hammett correlation for four different substrates strongly
suggests that this linear free energy relationship is general and
has mainly an electronic origin which can be straightforward
analyzed with the previously proposed mechanistic frame
(Scheme 3). As the ligand becomes more electron rich, the
electrophilicity of the metal-oxo species is attenuated, and the
transition state is displaced towards a more product-like com-
plex, characterized by a tighter substrate/metal oxo-species,
with more specific non-bonding interactions. However, elec-
tron-poorer systems result in a more electrophilic and less
discriminatory oxidant, exhibiting lower stereochemical dif-
ferentiation.27a This scenario indeed finds precedent in Mn-
salen epoxidation systems27 but its application in non-heme
iron chemistry is, to the best of our knowledge, unprecedented.
It is important to mention that manipulation of the electronic
properties of heme ferryl species has been used to modulate
the chemoselectivity of their oxidation reactions,28 but transla-
tion into asymmetric oxidations has not been described so far.
proposals.15-16
On the bases of these mechanistic considerations, the ability
of Me2N1 to efficiently and selectively operate at low CA load-
ings most likely indicates that the heterolytic cleavage of the
O-O bond in FeIII(OOH)(HOAc) (Ia) to form FeV(O)(O2CR)
(Ib) is exceptionally facilitated for this catalyst. We propose
that the mechanism of O-O cleavage in this case is facilitated
by the assistance of a proton of the carboxylic acid (pull-
effect, as early proposed by Que et al) and also by a push
effect exerted by the powerful electron donating character of
the dimethyl amino pyridine ligand. This synergistic operation
may then provide an efficient channel for controlling the O-O
cleavage event, and prevent from otherwise energetically
competitive alternative paths. Interestingly, this scenario bears
strong resemblance to that operating in the mechanism of
formation of Cpd I in Cyt P450 (Scheme 1).7
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
Mechanistic insights in the O-atom transfer reaction.
Stereospecificity and linear free energy correlation. Re-
markably, epoxidation with the present iron-based catalysts is
stereospecific and takes place with stereoretention even in the
cases of substrates that can easily undergo epimerization dur-
ing epoxidation with other reagents. For example, epoxidation
of S1 and of the sterically congested disubstituted β,β’-enone
S12 yields a single diastereomer. This indicates that oxygen
atom transfer occurs through concerted formation of the two
new C-O bonds, or alternatively, sequential C-O bond for-
mation occurs very fast, without scrambling. That constitutes a
difference with respect to Mn-salen systems,24 and Weitz-
Scheffer-type epoxidations, where some degree of epimeriza-
tion takes place.2e,21
Conclusion and future remarks
In conclusion, the present work illustrates how electronic
effects can be used as powerful tools for controlling the activa-
tion of H2O2 and O-atom transfer in non-porphyrinic iron
complexes, leading to excellent catalysts for highly asymmet-
ric epoxidation of olefins with H2O2. Efficient activation of
H2O2 is proposed to occur via facile heterolytic O-O bond
cleavage in electron rich iron complexes. Although the exact
details by which this reaction is exceptionally facilitated by
Me2N1 remains to be clarified, a resemblance to the so-called
push-pull effect operating in P450 can be drawn.7 Even more
exciting analogies could be also suggested between the well-
established redox active non-innocent nature of porphyrins7,29
and dimethylaminopyridine ligands,30 and how these electron-
ic structures may facilitate stabilization of highly electrophilic
high oxidation states. From a more synthetic perspective, this
work provides directions for future rational design of catalysts,
fine tuning of enantioselection and for expanding substrate
scope, without the need for elaborate catalyst development,
but by taking advantage of cooperative catalysis effects be-
tween aminopyridine and carboxylic acid ligands. Expansion
of substrate scope, extension towards other oxygen atom trans-
fer reactions and clarification of the reaction intermediates
involved in these reactions are currently being explored.
O
O
Ph
Ph
Ph
Ph
Supporting Information. Experimental details for the prepa-
ration and characterization of ligands and metal complexes.
Experimental details of catalytic reactions, and spectroscopic
data for product characterization. Crystallographic information
file for MeO1. This material is available free of charge via the
Internet at http://pubs.acs.org.
Figure 1. Hammett analysis of stereoselectivity as a function of
catalyst employed in the epoxidation of S8 (for analogous analysis
with S1, S4 and S13 see Figures SI.1-SI.2). Catalyst x1 (1 mol %),
AcOH (140 mol %), H2O2 (1.2 equiv) in CH3CN at 0 ºC. Ham-
mett’s values are taken from reference 25.
Finally, this mechanistic scenario provides a rational mech-
anistic frame for understanding the electronic effects of the
catalysts in the enantioselectivity. A plot of the log (ee) (ratio
of enantiomers) corresponding to chiral induction in epoxida-
tion of S8 as a function of the Hammett parameter of the x
Corresponding Author
* Dr. M. Costas. QBIS Research Group, Institut de Química
Computacional i Catàlisi (IQCC), and Departament de Química,
Universitat de Girona, Campus Montilivi, Girona E-17071, Cata-
lonia, Spain. Tel: +34-972419842, email: miquel.costas@udg.edu.
X
group in 1 (Figure 1) shows a linear correlation. The enanti-
oselectivity ranges from 51% to 90% ee for epoxidation of S8
X
ACKNOWLEDGMENT
with the series of 1 complexes, which corresponds to a nota-
ble improvement in selectivity of ∆∆G≠ ~ 1.0 kcal·mol-1. The
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 10
1
2
3
4
5
6
7
8
9
(9) For pioneering work with Mn systems see; a) Murphy, A.;
We acknowledge financial support from European Research
Council (ERC-2009-StG-239910), MINECO of Spain (CTQ2012-
37420-C02-01/BQU, Consolider-Ingenio CSD2010-00065) and
the Catalan DIUE of the Generalitat de Catalunya (2009SGR637).
J.Ll.F thanks MICINN for a RyC contract. X.R. and M.C. thank
ICREA-Academia awards. X.R. is grateful for financial support
from INNPLANTA project IPN-2011-0059-PCT-42000-ACT1.
I.G.-B. thanks the European Community for an IOF Marie Curie
fellowship. We thank STR’s from UdG for technical support.
Dubois, G.; Stack, T. D. P. J. Am. Chem. Soc. 2003, 125, 5250. And
further evolution of the this type of Mn catalysts; b) Gómez, L.;
Garcia-Bosch, I.; Company, A.; Sala, X.; Fontrodona, X.; Ribas, X.;
Costas, M. Dalton Trans. 2007, 5539. c) Wu, M.; Wang, B.; Wang,
S.; Xia, C.; Sun, W. Org. Lett. 2009, 11, 3622; d) Garcia-Bosch, I.;
Gómez, L.; Polo, A.; Ribas, X.; Costas, M. Adv. Synth. & Catal.
2012, 354, 65.; e) Lyakin, O. Y.; Ottenbacher, R. V.; Bryliakov, K.
P.; Talsi, E. P. Acs Catal. 2012, 2, 1196; f) Wang, B.; Miao, C.;
Wang, S.; Xia, C.; Sun, W. Chem. Eur. J. 2012, 18, 6750.
(10) a) Chen, M. S.; White, M. C. Science 2007, 318, 783; b) Chen,
M. S.; White, M. C. Science 2010, 327, 566; c) Bigi, M. A.; Reed, S.
A.; White, M. C. Nat. Chem. 2011, 3, 216; d) Bigi, M. A.; Reed, S.
A.; White, M. C. J. Am. Chem. Soc. 2012, 134, 9721; e) White, M. C.
Science 2012, 335, 807.
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
REFERENCES
(1) a) Que, L.; Tolman, W. B. Nature 2008, 455, 333; b) Enthaler,
S.; Junge, K.; Beller, M. Angew. Chem. Int. Ed. 2008, 47, 3317. c)
Correa, A.; Mancheño, O. G.; Bolm, C. Chem. Soc. Rev. 2008, 8,
1108; d) Liu, L.-X. Curr. Org. Chem. 2010, 14, 1099. e) Chang-Liang
Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev. 2011, 111, 1293-1314.; f)
Darwish, M.; Wills, M. Catal. Sci. Technol. 2012, 2, 243.; g)
Gopalaiah, K. Chem. Rev. 2013, 113, 3248
(2) a) Katsuki, T. In Catalytic Asymmetric Synthesis; 2nd ed.;
Ojima, I., Ed.; Wiley-VCH: New York, 2000, p 287; b) De Faveri, G.;
Ilyashenko, G.; Watkinson, M. Chem. Soc. Rev. 2011, 40, 1722; c)
Chatterjee, D. Coord. Chem. Rev. 2008, 252, 176; d) Wong, O. A.;
Shi, Y. Chem. Rev. 2008, 108, 3958; e) Diez, D.; Nunez, M. G.;
Anton, A. B.; Garcia, P.; Moro, R. F.; Garrido, N. M.; Marcos, I. S.;
Basabe, P.; Urones, J. G. Curr. Org. Synth. 2008, 5, 186.
(3) Fe systems showing moderate stereoselectivity, a) Marchi-
Delapierre, C.; Jorge-Robin, A.; Thibon, A.; Ménage, S. Chem.
Commun. 2007, 11, 1166; b) Yeung, H.-L.; Sham, K.-C.; Tsang, C.-
S.; Lau, T.-C.; Kwong, H.-L. Chem. Commun. 2008, 3801. c) Oddon,
F.; Girgenti, E.; Lebrun, C.; Marchi-Delapierre, C.; Pecaut, J.;
Menage, S. Eur. J. Inorg. Chem. 2012, 85.
(11) Gomez, L.; Canta, M.; Font, D.; Prat, I.; Ribas, X.; Costas, M.
J. Org. Chem. 2013, 78, 1421.
(12) a) Diebold, A.; Hagen, K. S. Inorg. Chem. 1998, 37, 215; b)
Blakesley, D. W.; Payne, S. C.; Hagen, K. S. Inorg. Chem. 2000, 39,
1979; c) Simaan, A. J.; Döpner, S.; Banse, F.; Bourcier, S.;
Bouchoux, G.; Boussac, A.; Hildebrandt, P.; Girerd, J.-J. Eur. J.
Inorg. Chem. 2000, 1627; d) Chen, K.; Que, L., Jr. J. Am. Chem. Soc.
2001, 123, 6327; e) Britovsek, G. J. P.; England, J.; White, A. J. P.
Inorg. Chem. 2005, 44, 8125; f) Zang, Y.; Kim, J.; Dong, Y.;
Wilkinson, E. C.; Appelman, E. H.; Que, L., Jr. J. Am. Chem. Soc.
1997, 119, 4197.
(13) For a single previous precedent see ref 4f
(14) a) Lee, A.; Reisinger, C. M.; List, B. Adv. Synth. & Catal.
2012, 354, 1701; b) Wang, X.; Reisinger, C. M.; List, B. J. Am.
Chem. Soc. 2008, 130, 6070.; c) Lifchits, O.; Mahlau, M.; Reisinger,
C. M.; Lee, A.; Fares, C.; Polyak, I.; Gopakumar, G.; Thiel, W.; List,
B. J. Am. Chem. Soc. 2013, 135, 6677.
(15) Mas-Balleste, R.; Que, L., Jr. J. Am. Chem. Soc. 2007, 129,
15964.
(4) a) Gelalcha, F. G.; Anilkumar, G.; Tse, M. K.; Brückner, A.;
Beller, M. Chem. Eur. J. 2008, 14, 7687; b)
Gelalcha,
F.
G.;
(16) a) Lyakin, O. Y.; Bryliakov, K. P.; Britovsek, G. J. P.; Talsi,
E. P. J. Am. Chem. Soc. 2009, 131, 10798; b) Lyakin, O. Y.;
Bryliakov, K. P.; Talsi, E. P. Inorg. Chem. 2011, 50, 5526.
(17) Ansari, A.; Kaushik, A.; Rajaraman, G. J. Am. Chem. Soc.
2013, 135, 4235.
Bitterlich, B.; Anilkumar, G.; Tse, M. K.; Beller, M. Angew Chem.
Int. Ed. 2007, 46, 7293; c) Wu, M.; Miao, C.-X.; Wang, S.; Hu, X.;
Xia, C.; Kühn, F. E.; Sun, W. Adv. Synth. & Catal. 2011, 353, 3014;
d) Wang, B.; Wang, S.; Xia, C.; Sun, W. Chem. Eur. J. 2012, 18,
7332; e) Lyakin, O. Y.; Ottenbacher, R. V.; Bryliakov, K. P.; Talsi, E.
P. Acs Catal. 2012, 2, 1196.; f) Cheng, Q. F.; Xu, X. Y.; Ma, W. X.;
Yang, S. J.; You, T. P. Chin. Chem. Lett. 2005, 16, 1467.
(5) Fe systems employing other oxidants; a) Nishikawa, Y.;
Yamamoto, H. J. Am. Chem. Soc. 2011, 133, 8432; b) Niwa, T.;
Nakada, M. J. Am. Chem. Soc. 2012, 134, 13538.
(6) a) Kovaleva, E. G.; Lipscomb, J. D. Nat. Chem. Biol. 2008, 4,
186; b) Abu-Omar, M. M.; Loaiza, A.; Hontzeas, N. Chem. Rev.
2005, 105, 2227; c) Costas, M.; Mehn, M. P.; Jensen, M. P.; Que, L.,
Jr. Chem. Rev. 2004, 104, 939.
(7) a) Shaik, S.; Cohen, S.; Wang, Y.; Chen, H.; Kumar, D.; Thiel,
W. Chem. Rev. 2010, 110, 949; b) Meunier, B.; de Visser, S. P.;
Shaik, S. Chem. Rev. 2004, 104, 3947; c) Meunier, B.; de Visser, S.
P.; Shaik, S. Chem. Rev. 2004, 104, 3947.
(8) a) White, M. C.; Doyle, A. G.; Jacobsen, E. N. J. Am. Chem.
Soc. 2001, 123, 7194; b) Chen, K.; Costas, M.; Kim, J.; Tipton, A. K.;
Que Jr., L. J. Am. Chem. Soc. 2002, 124, 3026; c) Mikhalyova, E. A.;
Makhlynets, O. V.; Palluccio, T. D.; Filatov, A. S.; Rybak-Akimova,
E. V. Chem. Commun. 2012, 48, 687; d) Wang, B.; Miao, C.-X.;
Wang, S.-F.; Kuehn, F. E.; Xia, C.-G.; Sun, W. J. Organomet. Chem.
2012, 715, 9; e) Talsi, E. P.; Bryliakov, K. P. Coord. Chem. Rev.
2012, 256, 1418. For other representative Fe-based epoxidation
systems see; f) Dubois, G.; Murphy, A.; Stack, T. D. P. Org. Lett.
2003, 5, 2469; g) Anilkumar, G.; Bitterlich, B.; Gelalcha, F. G.; Tse,
M. K.; Beller, M. Chem. Commun. 2007, 3, 289. h) Schroeder, K.;
Enthaler, S.; Bitterlich, B.; Schulz, T.; Spannenberg, A.; Tse, M. K.;
Junge, K.; Beller, M. Chem. Eur. J. 2009, 15, 5471. i) Schröder, K.;
Join, B.; Amali, A. J.; Junge, K.; Ribas, X.; Costas, M.; Beller, M.
Angew Chem. Int. Ed. 2011, 50, 1425.
(18) Wang, Y.; Janardanan, D.; Usharani, D.; Han, K.; Que, L.;
Shaik, S. ACS Catal. 2013, 3, 1334.
(19) a) MacFaul, P. A.; Ingold, K. U.; Wayner, D. D. M.; Que, L.
J. Am. Chem. Soc. 1997, 119, 10594; b) Ingold, K. U.; MacFaul, P. A.
In Biomimetic Oxidations Catalyzed by Transition Metal Complexes;
Meunier, B., Ed.; Imperial College Press: London, 2000, p 45.
(20) a) Seo, M. S.; Kamachi, T.; Kouno, T.; Murata, K.; Park, M.
J.; Yoshizawa, K.; Nam, W. Angew. Chem. Int. Ed. 2007, 46, 2291; b)
Park, M. J.; Lee, J.; Suh, Y.; Kim, J.; Nam, W. J. Am. Chem. Soc.
2006, 128, 2630.
(21) a) Bunton, C. A.; Minkoff, G. J. J. Chem. Soc. 1949, 665; b)
Christian, C. F.; Takeya, T.; Szymanski, M. J.; Singleton, D. A. J.
Org. Chem. 2007, 72, 6183; c) House, H. O.; Ro, R. S. J. Am. Chem.
Soc. 1958, 80, 2428; d) Kelly, D. R.; Caroff, E.; Flood, R. W.; Heal,
W.; Roberts, S. M. Chem. Commun. 2004, 2016; e) Kelly, D. R.;
Roberts, S. M. Pept. Sci. 2006, 84, 74; f) Meerwein, H. J. Prakt.
Chem. 1926, 113, 9; g) Weitz, E.; Scheffer, A. Chem. Ber. 1921, 54,
2344.
(22) A single case of well-defined FeIV(O) species has been shown
to be kinetically competent to mediate epoxidation of olefins, albeit at
relatively low reaction rates. See Ye, W. H.; Ho, D. M.; Friedle, S.;
Palluccio, T. D.; Rybak-Akimova, E. V. Inorg. Chem. 2012, 51, 5006.
(23) a) Prat, I.; Mathieson, J. S.; Güell, M.; Ribas, X.; Luis, J. M.;
Cronin, L.; Costas, M. Nat. Chem. 2011, 3, 788; b) Oloo, W. N.;
Fielding, A. J.; Que, L., Jr. J. Am. Chem. Soc. 2013, 135, 6438.
(24) Jacobsen, E. N.; Zhang, W.; Muci, A. R.; Ecker, J. R.; Deng,
L. J. Am. Chem. Soc. 1991, 113, 7063.
(25) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91(2), 165-
195.
ACS Paragon Plus Environment

Page 9 of 10
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
(26) A significant deviation has only been observed for the relative
enantioselectivities obtained with CO2Et1 and Cl1 in the epoxidation of
S1 (Figure S1), showing that in specific cases other factors can alter
the LFER. The importance of these deviations could be estimated by
traslating the corresponding ee’s into differences in energy. At -30 ºC,
∆∆G≠ corresponding to ee’s obtained in the epoxidation of S1 with
CO2Et1 and Cl1 differ by < 0.07 kcal·mol-1. Therefore the significance
of this deviation should be considered small.
(27) a) Jacobsen, E. N.; Zhang, W.; Muci, A. R.; Ecker, J. R.;
Deng, L. J. Am. Chem. Soc. 1991, 113, 7063; b) Cavallo, L.;
Jacobsen, H. J. Org. Chem. 2003, 68, 6202. c) For the opposite
scenario see b) Liao, S.; List, B. Angew. Chem. Int. Ed. 2010, 49, 628.
(28) a) Traylor, T. G.; Miksztal, A. R. J. Am. Chem. Soc. 1989,
111, 7443; b) Groves, J. T.; Watanabe, Y. J. Am. Chem. Soc. 1986,
108, 507.
(29) Praneeth, V. K. K.; Ringenberg, M. R.; Ward, T. R. Angew.
Chem. Int. Ed. 2012, 51, 10228.
(30) Rycke, N. D.; Couty, F.; David, O. R. P. Chem. Eur. J. 2011,
17, 12852.
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
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 10 of 10
1
2
3
TOC
4
5
N
6
7
8
9
e
2N1
l
M
-
mo
S S
2
,
%
(
)
(
)
OH
.
e u v.
i
q
mo
l %
)
H
2O2 (1 6
)
O
R''
R''
RCO2
H
3
(
O
R
R
N
OTf
OTf
N
R'
O
R'
RCO2H
-
m n
i
CH3CN, 30ºC, 30
e
F
su s ra es
25
b
t
t
N
OH
u
o
o
e
i ld
t
t
99
%
p
u
p
y
%
N
ee
99
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
O
e
2N1
M
-
S S
,
)
O
O
(
O
O2N
N
R
t
CO2E
O
=
=
=
ee
ee
R
R
R
Ph 99 98
ee
ee
)
,
,
%
%
91%
9
7
(
%
90% 99%
(
(
)
)
e
% %
60 94
M
(
)
r
ee
)
OiP 94 97
%
,
%
(
ACS Paragon Plus Environment