Manganese catalysts for C-H activation: An experimental/theoretical study identifies the stereoelectronic factor that controls the switch between hydroxylation and desaturation pathways

Article abstract of DOI:10.1021/ja908744w

We describe competitive C-H bond activation chemistry of two types, desaturation and hydroxylation, using synthetic manganese catalysts with several substrates. 9,10-Dihydrophenanthrene (DHP) gives the highest desaturation activity, the final products being phenanthrene (P1) and phenanthrene 9,10-oxide (P3), the latter being thought to arise from epoxidation of some of the phenanthrene. The hydroxylase pathway also occurs as suggested by the presence of the dione product, phenanthrene-9,10-dione (P2), thought to arise from further oxidation of hydroxylation intermediate 9-hydroxy-9,10- dihydrophenanthrene. The experimental work together with the density functional theory (DFT) calculations shows that the postulated Mn oxo active species, [Mn(O)(tpp)(Cl)] (tpp = tetraphenylporphyrin), can promote the oxidation of dihydrophenanthrene by either desaturation or hydroxylation pathways. The calculations show that these two competing reactions have a common initial step, radical H abstraction from one of the DHP sp³ C-H bonds. The resulting Mn hydroxo intermediate is capable of promoting not only OH rebound (hydroxylation) but also a second H abstraction adjacent to the first (desaturation). Like the active Mn^V=O species, this Mn ^IV-OH species also has radical character on oxygen and can thus give H abstraction. Both steps have very low and therefore very similar energy barriers, leading to a product mixture. Since the radical character of the catalyst is located on the oxygen p orbital perpendicular to the Mn ^IV-OH plane, the orientation of the organic radical with respect to this plane determines which reaction, desaturation or hydroxylation, will occur. Stereoelectronic factors such as the rotational orientation of the OH group in the enzyme active site are thus likely to constitute the switch between hydroxylase and desaturase behavior.

Full text of DOI:10.1021/ja908744w

Published on Web 05/18/2010
Manganese Catalysts for C-H Activation: An Experimental/
Theoretical Study Identifies the Stereoelectronic Factor That
Controls the Switch between Hydroxylation and Desaturation
Pathways
†
‡
†
‡
Jonathan F. Hull, David Balcells, Effiette L. O. Sauer, Christophe Raynaud,
,†
,†
,‡
Gary W. Brudvig,* Robert H. Crabtree,* and Odile Eisenstein*
Chemistry Department, Yale UniVersity, P.O. Box 208107, New HaVen, Connecticut 06520, and
UniVersit e´ Montpellier 2, Institut Charles Gerhardt, CNRS 5253, cc 15001, Place Eug e` ne
Bataillon 34095, Montpellier, France
Received October 14, 2009; E-mail: gary.brudvig@yale.edu; robert.crabtree@yale.edu;
odile.eisenstein@univ-montp2.fr
Abstract: We describe competitive C-H bond activation chemistry of two types, desaturation and
hydroxylation, using synthetic manganese catalysts with several substrates. 9,10-Dihydrophenanthrene
(DHP) gives the highest desaturation activity, the final products being phenanthrene (P1) and phenanthrene
9,10-oxide (P3), the latter being thought to arise from epoxidation of some of the phenanthrene. The
hydroxylase pathway also occurs as suggested by the presence of the dione product, phenanthrene-9,10-
dione (P2), thought to arise from further oxidation of hydroxylation intermediate 9-hydroxy-9,10-
dihydrophenanthrene. The experimental work together with the density functional theory (DFT) calculations
shows that the postulated Mn oxo active species, [Mn(O)(tpp)(Cl)] (tpp ) tetraphenylporphyrin), can promote
the oxidation of dihydrophenanthrene by either desaturation or hydroxylation pathways. The calculations
show that these two competing reactions have a common initial step, radical H abstraction from one of the
3
DHP sp C-H bonds. The resulting Mn hydroxo intermediate is capable of promoting not only OH rebound
V
(
hydroxylation) but also a second H abstraction adjacent to the first (desaturation). Like the active Mn dO
IV
species, this Mn -OH species also has radical character on oxygen and can thus give H abstraction.
Both steps have very low and therefore very similar energy barriers, leading to a product mixture. Since
IV
the radical character of the catalyst is located on the oxygen p orbital perpendicular to the Mn -OH plane,
the orientation of the organic radical with respect to this plane determines which reaction, desaturation or
hydroxylation, will occur. Stereoelectronic factors such as the rotational orientation of the OH group in the
enzyme active site are thus likely to constitute the switch between hydroxylase and desaturase behavior.
Introduction
Scheme 1. Reaction Mechanisms Postulated for Hydroxylation and
Desaturation
Iron is the workhorse transition metal element of biology,
commonly employed in metalloenzymes whenever it is ap-
1
plicable. Iron is the typical active site element in oxidoreduc-
tases and, more specifically relevant for this paper, the hydrox-
2
3
ylase and desaturase classes of oxidoreductases. Hydroxylases
and desaturases reduce dioxygen so that one oxygen atom is
converted to water and the other is transferred to iron to form
a highly oxidizing oxo intermediate.
Hydroxylases bring about the conversion of C-H bonds to
C-OH functional groups by incorporating the O atom of the
4
iron oxo intermediate via a rebound pathway (Scheme 1). In
this reaction mechanism, the iron oxo complex first abstracts
2 2
an H atom from the R CH-CHR substrate to give an Fe(OH)
•
2 2
intermediate and a substrate-derived R CH-C R radical. This
radical then abstracts OH from the Fe(OH) intermediate to give
the R CH-C(OH)R product in the rebound step.
Desaturases convert a R CH-CHR alkyl chain to a R
†
Yale University.
Universit e´ Montpellier 2.
2
2
‡
2
2
2 2
CdCR
(
1) Metal Sites in Proteins and Models: Iron Centres (Structure and
chain via introduction of a double bond via a double H
Bonding, Vol. 88); Hill, H. A. O., Sadler, P. J., Thomson, A. J., Eds.;
Springer-Verlag Telos: Emeryville, CA, 1997.
3
abstraction mechanism (Scheme 1). In this case, the iron oxo
10.1021/ja908744w  2010 American Chemical Society
J. AM. CHEM. SOC. 2010, 132, 7605–7616 9 7605

A R T I C L E S
Hull et al.
Scheme 2. Postulated Hydroxylation-Desaturation Switches, (1) Formation of a Carbocation and (2) Orientation of the Radical
•
species again abstracts an H atom from R
Fe(OH) intermediate and a substrate-derived R
The desaturation pathway differs from the hydroxylation
pathway in that the Fe(OH) intermediate abstracts a second H
2
CH-CHR
2
to give an
of the R
2
CH-C R
2
radical: if the radical is rapidly oxidized by
•
2
CH-C R
2
radical.
the metal center, the resulting carbocation yields the desaturation
product by deprotonation; otherwise, the radical undergoes OH
rebound, yielding the hydroxylation product. The participation
of a carbocation in the reaction mechanism has been proposed
by Shaik in a DFT study. In the second hypothesis, the
orientation of the radical with respect to the active site plays
the key role. Depending on which carbon of the R
radical approaches the Fe(OH) center, the C (orientation A) or
the CH (orientation B), the major product is either the alcohol
or the alkene, respectively. In this case, no carbocation is
8
atom from the adjacent C-H bond to give R
Fe(OH ). In both pathways, the iron oxo active species is
recovered by reoxidation of the metal center.
2 2
CdCR and
9
2
This mechanistic scenario involves hydroxylation and de-
saturation reactions that are connected by a common initial step.
10
•
2
CH-C R
2
5
•
There are indeed some examples in which desaturase activity
6
has been reported for hydroxylases, and the opposite case has
11
7
been observed as well. The switch between the two reaction
formed in the desaturation pathway and both the first and second
H abstractions involve the transfer of a H radical in a single-
channels is thus critical, but its exact nature remains elusive.
Two different hypotheses have been proposed (Scheme 2).
In the first one, the reaction outcome depends on the properties
•
3
d
step process.
Numerous model compounds have been developed to mimic
1
2
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606 J. AM. CHEM. SOC. 9 VOL. 132, NO. 22, 2010

Manganese Catalysts for C-H Activation
Scheme 3. Catalytic Oxidation of DHP
A R T I C L E S
1
4
in synthetic model catalysts. However, no manganese model
catalysts for desaturase chemistry are known. As a result of our
The singlet is the ground state of the system, but both the triplet
and the quintet states may also be accessible in energy,
1
5
18b,19
interest in the water oxidizing center of Photosystem II,
a
depending on the nature of X.
The calculations suggest
manganese enzyme, we have concentrated our efforts on this
metal.
Like iron, manganese forms a high-valent oxo intermediate
that the singlet, which lacks radical character on oxygen, also
termed oxyl character, is unreactive. In contrast, the spin states
with oxyl character, the triplet and the quintet, promote C-H
bond hydroxylation. Interestingly, the reactive Mn(O) group is
not deactivated by H atom abstraction, since the calculations
16
that can promote not only hydroxylation but also desaturation.
Manganese complexes are often preferred in biomimetic work
because of their higher activity; prior work suggests manganese
complexes can mimic the functional properties of iron oxi-
doreductases. Given that the isolation and characterization of
high-valent oxo species are extremely difficult because of their
high reactivity, computational chemistry is a powerful tool for
18c
showed that the Mn(OH) product is also a potent H abstractor.
These studies thus suggest that the Mn(OH) intermediate
(Scheme 1) may promote either OH rebound, yielding the
hydroxylation product, or a second H abstraction, yielding the
desaturation product.
2
e,17
+
their characterization.
The reactivity of [Mn(O)(por)(X)]
In this paper, we report desaturase activity with three
manganese model catalysts (Scheme 3). Our choice of catalysts
includes [Mn(tpp)(Cl)] (C1), known to have hydroxylase
-
-
2-
(
X ) H
2
O, Cl , OH , or O ) in C-H bond hydroxylation has
18
been theoretically studied by several of us. These studies
1
8a
1
6
showed that the reaction follows the rebound mechanism.
activity, Jacobsen’s catalyst (C2), for which the only previ-
20
ously recognized reaction was epoxidation, and our terpyridine
2
1
(
14) Wu, A. J.; Penner-Hahn, J. E.; Pecoraro, V. L. Chem. ReV. 2004, 104,
03–938.
dimanganese catalyst (C3), capable of oxidizing water. We
now find that all three promote desaturation on suitable
substrates, which were chosen to have two adjacent C-H bonds
that are particularly weak, either by being benzylic, tertiary, or
close to a heteroatom. A number of these compounds undergo
desaturation, with 9,10-dihydrophenanthrene (DHP) being the
best. In this case, not only are both activated C-H bonds
benzylic, but the formation of the CdC bond also generates an
aromatic system, thus providing extra stability. For such a
substrate, analogy with aromatase rather than desaturase is more
appropriate, but it is likely that both reactions proceed by
analogous mechanisms. The oxidation of DHP yields a mixture
of three compounds: the desaturation product, phenanthrene
(P1), which is partially overoxidized to phenanthrene 9,10-oxide
9
(
15) (a) Photosystem II: The Light-DriVen Water-Plastoquinone Oxi-
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(
(
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J. AM. CHEM. SOC. 9 VOL. 132, NO. 22, 2010 7607

A R T I C L E S
Hull et al.
a
Table 1. Oxidation of DHP Catalyzed by C1, C2, and C3 under Various Reaction Conditions
,
b c
,
b d
e
entry
catalyst
atmosphere
solvent
% hydroxylated
% desaturated
desaturated/hydroxylated
f
1
2
3
4
5
6
7
8
9
C1f
N
air
2
CD
CD
CD
CD
CD
CD
CD
CD
CD
2
2
3
3
2
2
3
3
3
Cl
Cl
CN
CN
2
11
11
26
9
3
0
6
19
0
46
2
4.2
0.2
2.6
3.4
C1f
2
C1
C1
C2
C2
C2
C2
C3
N
2
67
31
18
17
22
0
f
air
g
N
2
Cl
Cl
2
6.0
g
air
2
desaturated only
3.7
hydroxylated only
desaturated only
g
N
2
CN
CN
CN/D
g
air
h
N
2
2
O
20
a
b
All reactions were run with 1% catalyst vs substrate for 14 h. Estimated from the NMR spectra with a trimethoxybenzene internal standard
c
d
e
relative to substrate as the limiting reagent. P2 yield.f P1 + P3 yield; epoxide P3 absent for catalysts C2 and C3. (P1 + P3)/P2 product ratio; the
g
P1/P3 ratios are given in the Supporting Information. Two equivalents of PhIO used as the primary oxidant, with no additives. Two equivalents of
h
Oxone (KHSO
5
) used as the primary oxidant, and 1 equiv of N-methylmorpholine N-oxide (NMO) as the additive. Two equivalents of Oxone
(
KHSO ) used as the primary oxidant, with no additives.
5
a
Table 2. Influence of Solvent Polarity on the Oxidation of DHP Catalyzed by C1 and C2
,
b c
,
b d
e
entry
catalyst
solvent
ε
% hydroxylated
% desaturated
desaturated/hydroxylated
f
1
2
3
4
5
6
7
8
9
C1f
o-dichlorobenzene-d
4
2.8
9.1
35.7
37.5
39.4
2.8
<1
11
6
26
<1
0
3
7
0
0
27
46
26
67
20
2
18
0
17
19
>27
C1
dichloromethane-d
nitrobenzene-d
acetonitrile-d
nitromethane-d
o-dichlorobenzene-d
dichloromethane-d
nitrobenzene-d
acetonitrile-d
nitromethane-d
2
4.2
f
C1f
5
4.3
2.6
>20
C1f
3
C1
3
g
C2
4
desaturated only
6.0
hydroxylated only
desaturated only
desaturated only
g
C2
C2
C2
C2
2
9.1
g
5
35.7
37.5
39.4
g
3
g
1
0
3
a
b
All reactions are run with 1% catalyst for 14 h under a N
2
atmosphere. Estimated from the NMR spectra with a trimethoxybenzene internal
c
d
e
f
g
standard. P2. P1 + P3. (P1 + P3)/P2 product ratio. Two equivalents of PhIO used as the primary oxidant, with no additives. Two equivalents of
Oxone (KHSO ) used as the primary oxidant, and 1 equiv of NMO as the additive.
5
(
(
P3), and the hydroxylation product, phenanthrene-9,10-dione
P2), given by the overoxidation of the corresponding diol.
We also combine experimental studies and DFT calculations
yields. In all cases but two (entries 2 and 8), the majority of
the reaction products result from the desaturation of DHP.
Surprisingly, catalyst C1 is the best for desaturation. We
expected the dinuclear catalyst C3 to be better since it has been
to elucidate the reaction mechanism, the main goal being
understanding why these reactions are competitive. The calcula-
tions show that the reaction outcome depends on the orientation
of the organic radical relative to the OH group, thus supporting
the orientation of the hydroxylation-desaturation switch (Scheme
2
2
reported to be a more potent oxidation catalyst, and it is
3
dinuclear like the desaturase active site. The yields of the
reaction with the different catalysts are highly dependent on
the solvent and the presence of oxygen. For both C1 and C2,
the reaction in CD CN under a nitrogen atmosphere has the
3
2
). This is consistent with literature reports that high levels of
control over the orientation and position of the substrate in the
enzyme active site are required to achieve high selectivity.
highest yield. For all reactions, only the starting material and
the expected products were observed.
1
0
Lack of such control in our model catalysts may explain why
literature examples are rare and why our catalysts have a limited
substrate scope and yield hydroxylation/desaturation product
mixtures.
Changing the reaction conditions affected not only the
reaction yields but also the product ratios. Reactions run in air
give lower yields. Under nitrogen, changing the solvent from
2 2 3
CD Cl to CD CN for catalysts C1 and C2 favors hydroxylation
over desaturation, as shown by the decrease in the desaturated/
hydroxylated ratio (Table 1, entries 1, 3, 5, and 7). However,
the trend is not the same under air because the desaturated/
hydroxylated ratio increases for C1 but decreases for C2, when
Experimental Results
Oxidation of DHP and Other Substrates. To develop a simple
model system for the desaturase enzyme family, three catalysts,
C1, C2, and C3 (Scheme 3), were tested for the oxidation of a
series of substrates with a variety of primary oxidants. The 9,10-
dihydrophenanthrene (DHP) substrate gave the highest yield
and was chosen as the primary substrate for our investigation.
The results for the oxidation of DHP under various reaction
conditions are listed in Table 1.
2 2 3
CD Cl is replaced with CD CN as the solvent. To determine
if the observed change in selectivity is due to changes in the
solvent polarity, reactions were run in a series of solvents with
different dielectric constants, ε (Table 2). Catalyst C3 is only
soluble when water is present and was not used in this set of
experiments.
As shown in Table 2, with porphyrin C1 as the catalyst, both
yield and selectivity are significantly affected by the polarity
of the solvent. The highest yields (entries 2-4) are associated
with the lowest selectivities, whereas the lowest yields (entries
Three products are observed, phenanthrene (P1), phenantrene-
9,10-dione (P2), and phenanthrene 9,10-oxide (P3), as illustrated
in Scheme 3. P1 and P2 are the desaturation and hydroxylation
products, respectively. In a separate experiment, P1 was
epoxidized to P3 using catalyst C1, indicating that P3 is an
overoxidized product of P1. Therefore, we regard the “%
desaturated” values of Table 1 as the sums of the P1 and P3
1
and 5) are associated with the highest selectivities. There is
(
22) Hull, J. F.; Sauer, E. L. O.; Incarvito, C. D.; Faller, J. W.; Brudvig,
G. W.; Crabtree, R. H. Inorg. Chem. 2009, 48, 488–495.
7
608 J. AM. CHEM. SOC. 9 VOL. 132, NO. 22, 2010

Manganese Catalysts for C-H Activation
A R T I C L E S
Scheme 4. Desaturation Reaction with Various Substrates, (1)
Table 3. Oxidation of Various Substrates Catalyzed by C1-C3
with a Variety of Oxidants
1
,3-Cyclohexadiene, (2) 1,4-Cyclohexadiene, (3) Indoline, (4)
N-Methylindoline, and (5) [a,e]Dibenzohexamethyleneimine
a
% hydroxylated % desaturated
a
entry catalyst
substrate
,
b c
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
C1
C2
1,3-cyclohexadiene
1,3-cyclohexadiene
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
n/d
<1
<1
<1
n/d
8
c
e
,
d
12
11
<1
<1
<1
<1
<1
<1
20
n/d
16
<1
6
C3f 1,3-cyclohexadiene
C1
C2
1,4-cyclohexadiene
1,4-cyclohexadiene
g
e
C3f 1,4-cyclohexadiene
C1
C2
indoline
indoline
g
e
C3f indoline
0
1
2
3
4
5
C1
C2
N-methylindoline
N-methylindoline
g
e
h
h
h
h
C3f N-methylindoline
C1
C2
C3
[a,e]dibenzohexamethyleneimine
[a,e]dibenzohexamethyleneimine
[a,e]dibenzohexamethyleneimine
g
e
n/d
a
3
Reactions were run in CD CN to allow direct NMR analysis of
products. Yields are reported relative to starting hydrocarbon and were
determined by using 1,3,5-trimethylbenzene as the internal standard
added after the reaction. Control experiments with PhIO alone give no
b
detectable products. Two equivalents of tetrabutylammonium periodate
used as the primary oxidant, with no additives. Periodate was used to
c
no consistent relationship between ε and the yield and desatu-
rated/hydroxylated ratio. For instance, the two highest selectivi-
ties are observed with both the least, dichlorobenzene, and most,
nitromethane, polar solvents. Interestingly, acetonitrile, which
is most able to coordinate to the metal, leads to the highest
yields. This may be associated with the replacement of
oxidize this substrate, as the product of the reaction with iodosyl-
benzene, iodobenzene, interfered with the interpretation of the NMR
d
spectrum of the product. Two equivalents of tetrabutylammonium
periodate used as the primary oxidant, with 1 equiv of NMO as the
e
additive. Two equivalents of Oxone (KHSO
5
) used as the primary
f
oxidant, with no additives. Two equivalents of PhIO used as the
primary oxidant, with no additives. Two equivalents of Oxone
g
the axial ligand with acetonitrile, which would yield
+
(KHSO ) used as the primary oxidant, with 1 equiv of NMO as the
5
[
Mn(O)(tpp)(CH
3
CN)] . This complex is likely to be highly
h
additive. Unidentifiable product mixture.
reactive because of a small energy difference between the low-
1
8b
spin and high-spin states. The C2 catalyst is less sensitive to
the polarity of the solvent. For the same set of solvents tested
for C2, yields are low, being below 20% in all cases, and
desaturation dominates over hydroxylation. As for C1, there is
no consistent trend relating ε with yield and selectivity.
A variety of small molecules containing secondary vinylic
and benzylic C-H bonds were screened for desaturase and
hydroxylase activity (Scheme 4 and Table 3). 1,3-Cyclohexa-
diene was weakly active for desaturation, while 1,4-cyclohexa-
diene was essentially inactive (entries 1-6). The observed
differences between these substrates could be attributed to the
The results given above show that all three catalysts are
broadly similar in their activity. This is especially remarkable
for Jacobsen’s salen catalyst, C2, which is best known for the
2
0
epoxidation of olefins, and not C-H bond oxidation.
Mechanistic Studies. It is generally accepted that high-valent
MnIV or Mn oxoporphyrin and salen complexes, when PhIO
is used as the primary oxidant, oxidize olefins through a
concerted mechanism, and not via a free radical capable of
V
3
16
adjacent pair of sp C-H bonds only being present in 1,3-
diffusion. To test this hypothesis, N-bromosuccinimide (NBS)
cyclohexadiene. N-Methylindoline showed the highest levels of
desaturase activity for this series of substrates (entries 10-12).
Again, this result could be because, like 1,3-cyclohexadiene, it
and CBrCl were used as scavengers to test for radicals or a
radical chain mechanism in our reaction. Oxidation of DHP in
3
the presence of CBrCl or NBS (1/3:100:200:500 C1/C2/C3:
3
3
has an adjacent pair of sp C-H bonds and gives an aromatic
3
DHP:PhIO:CBrCl /NBS) under atmospheric oxygen yielded no
product. In contrast, indoline itself exhibited essentially no
activity, perhaps because the substrate binds to the catalysts and
deactivates them (entries 7-9). This does not happen in the
case of N-methylindoline perhaps because of the steric effects
introduced by the methyl group. In addition, indoline, unlike
acetonitrile, may undergo deprotonation and act as an anionic
ligand. Lastly, [a,e]dibenzohexamethyleneimine showed mixed
results (entries 13-15). With C2, a small amount of desaturase
product was observed; however, C1 showed no activity at all.
C3 gave consumption of the starting material, although the result
was a complicated mixture of products that could not be
identified. It is noteworthy that for all five of these substrates,
hydroxylation products were not observed. This is in stark
contrast to the reactions of DHP which gave a mixture of both
hydroxylation and desaturation products. All reactions may yield
halogenated products, and no large changes in yield were
observed. These results suggest that no radicals escape the
solvent cage or have a lifetime sufficiently long for the
generation of significant amounts of desaturated products or
ketones via a freely diffusing radical chain mechanism. Similar
evidence is obtained by radical tests with C3 using cis-stilbene,
2
3
where only the cis-epoxide is observed.
These data are consistent with a classical rebound pathway
for hydroxylation, with fast OH rebound, and with a double H
abstraction pathway for desaturation, with a fast second H
abstraction. In either case, this prevents formation of a freely
diffusing radical that can be intercepted by the traps employed.
A mechanistic probe was also synthesized to detect the possible
2
side products, like CO , due to the oxidation of the solvent.
This could perhaps explain the lack of hydroxylation and the
overall low yields obtained with some of the substrates.
(
23) Das, S.; Incarvito, C. D.; Crabtree, R. H.; Brudvig, G. W. Science
2006, 312, 1941–1943.
J. AM. CHEM. SOC. 9 VOL. 132, NO. 22, 2010 7609

A R T I C L E S
Hull et al.
participation of a carbocation in the mechanism, but the results
were inconclusive (see the Supporting Information).
1). The reaction starts by the formation of a prereaction complex,
3
Q-1, in which one of the sp C-H bonds of DHP interacts with
the oxo group of Q through a H-bond with a H · · ·O distance
Computational Studies
of 2.06 Å. Because of the weakness of this interaction, Q-1 is
First H Abstraction. The oxidation of DHP by C1 (Scheme
-1
more stable than Q and DHP by only 1.6 kcal mol . The
3
) was studied as the model reaction since it yields both the
hydrogen interacting with the oxo group undergoes H abstraction
leading to intermediate Q-2, which consists of a Mn hydroxo
complex interacting with the monohydrophenanthrene radical,
hydroxylation, P2, and desaturation, P1 and P3, products with
the highest yields. Our study focuses on the H abstraction and
OH rebound steps. The oxidation of C1, which yields the active
oxo species, [Mn(O)(tpp)(Cl)], is not studied. The full substrate is
included in the calculations, whereas the real tpp ligand of the
catalyst is simplified to porphine (por), via replacement of the four
phenyl rings with hydrogens. We believe that this simplification
of the catalyst, which saves a large amount of computational time,
does not imply any major change in either the reaction mechanism
or the electronic and steric properties of the system. Only the
oxidation of DHP by C1 is considered because the theoretical study
focuses on the hydroxylation-desaturation connection, rather than
on the influence of the nature of the catalyst and the substrate on
the outcome of the reaction.
•
MHP . At the transition state, Q-TS1, the hydrogen involved
in the weak interaction with the oxo group is transferred from
the C of DHP [d(C· · ·H) ) 1.20 Å] to the oxygen of Q
[
d(O· · ·H) ) 1.48 Å]. The H abstraction step, Q-1 f Q-TS1
-1
f Q-2, is exothermic by -15.1 kcal mol and has a low energy
barrier of 1.8 kcal mol . In agreement with previous studies,
-1
18a,b
the energies and geometries associated with the quintet reaction
pathway are similar to those found along the triplet pathway.
For completion of the calculation for the triplet, the reactivity
of the associated open-shell singlet has also been explored by
using the wave functions and geometries of the triplet stationary
points, T-TS1 and T-2, as an initial guess. The geometry
optimization attempts to locate the analogues of T-TS1 for the
open-shell singlet were unsuccessful. Single-point calculation
The hydroxylation of DHP by the singlet, S, triplet, T, and
quintet, Q, states of [Mn(O)(por)(Cl)] was explored. In a
previous study, we showed that Q is less stable than the ground
of the open-shell singlet at the T-TS1 geometry gives an energy
-1
18a
spin state, S, by 11.1 kcal mol .
The main differences
-1
1
4.1 kcal mol above that of the triplet, and more importantly,
between S and Q are associated with the MndO distance (1.57
Å in S and 1.70 Å in Q) and the local spin densities on oxygen
no imaginary frequency associated with the activation of the
C-H bond was observed. Starting now from the product side,
a single-point calculation using the geometry of T-2 for the
open-shell singlet MnOH intermediate gives an energy 31.5 kcal
(
0.00 in S and 0.82 in Q), which indicate that Q has radical
oxyl character. Q is generated from S by promotion of two
electrons to the antibonding π*(MndO) orbitals, one from the
Mn dxy orbital and the other from the porphyrin a2u orbital. The
presence of the singly occupied π*(MndO) orbitals in Q
accounts for its long MndO distance and high oxyl character
-1
mol above that of the triplet. Furthermore, the full optimization
of the T-2 geometry in the open-shell singlet state converged
into a species similar to T-1 and Q-1, which has thus no O-H
-1
bond. This stationary point is 2.3 kcal mol below T-1 and
(
vide infra). In T, only one electron is promoted to an
-1
0
.1 kcal mol above S and DHP. These calculations suggest
antibonding π*(MndO) orbital, and the oxyl character is
therefore significant but lower than that of Q.
When S was considered as a plausible active species, all
attempts to optimize a transition state for abstraction of H from
DHP were unsuccessful. In contrast, both the triplet and quintet
states, T and Q, respectively, which have oxyl character,
undergo exothermic H abstraction through a low energy barrier
that the open-shell singlet state, even if energetically accessible
on the reactant side, is unable to promote H abstraction.
All these calculations show that the singlet cannot initiate
the reaction by H abstraction and that high-spin states with oxyl
character are required. The reaction thus necessitates spin
crossover whose barrier has been evaluated by localization of
the MECP [minimum energy crossing point (see Computational
Details)]. The singlet to triplet transition involves one MECP
(
Figure 1). This suggests that in the absence of oxyl character,
the MndO moiety is not capable of promoting C-H bond
(
S f T), whereas the singlet to quintet transition involves two
oxidation. A similar result was previously found for the
MECPs (S f T and T f Q) and is therefore likely to be
associated with a low quantum yield. The S f T MECP was
1
8a
oxidation of toluene by the same reagent.
The triplet promotes abstraction of H from DHP as shown
24
characterized, whereas the T f Q MECP could not be located.
-
1
in Figure 1. The transition state, T-TS1, is only 3.3 kcal mol
above the ground state reactants, S and DHP, and the reaction
The S f T MECP has a productlike geometry with a MndO
distance of 1.63 Å, quite close to that of T (1.66 Å). This MECP
-1
is exothermic by 7.3 kcal mol . These calculations suggest that
the triplet is able to promote the C-H bond oxidation of the
substrate. As it will appear later, the OH rebound (hydroxylation)
and second H abstraction (desaturation) steps could not be
-1
-1
is only 0.5 kcal mol above T and is 3.9 kcal mol above S.
The proximity in energy between the singlet to triplet MECP
and the triplet state itself suggests that spin crossover does not
involve a significant energy barrier.
2
4
characterized for this spin state. Previous studies on toluene
hydroxylation by Mn oxo species have shown that the reaction
pathways associated with the triplet and quintet states are very
Desaturation versus Hydroxylation. After the initial H
abstraction, the system may undergo OH rebound thus following
the classical oxygen rebound mechanism (Figure 1). The oxygen
rebound transition state, Q-TS2, involves the concerted cleavage
of the Mn-OH bond [d(Mn· · ·O) ) 1.90 Å] and formation of
a new C-OH bond [d(C· · ·OH) ) 2.54 Å]. The relaxation of
Q-TS2 toward reactants and products yields intermediates Q-3
and Q-4, respectively. In Q-4, the final hydroxylation product,
DHPO, is fully formed and coordinated to Mn through oxygen.
The OH rebound pathway (Q-3 f Q-TS2 f Q-4) is exothermic
1
8a,b
similar.
Therefore, the quintet state is now used to model
the reactivity of the high-spin oxyl states. We start by calculating
the H abstraction step for the quintet even though this spin state
is higher in energy than the triplet.
As in the case of the triplet state, the quintet also has radical
oxyl character and promotes abstraction of H from DHP (Figure
(
24) Both geometry scans and direct TS search calculations could not be
completed because we were unable to converge the wave function,
which may be due to the multireference character of the triplet.
-
1
by 28.9 kcal mol and has a very low energy barrier of 0.4
-
1
kcal mol . The final dissociation of Q-4 releases the DHPO
7
610 J. AM. CHEM. SOC. 9 VOL. 132, NO. 22, 2010

Manganese Catalysts for C-H Activation
A R T I C L E S
Figure 1. Potential energy profiles, in kilocalories per mole, for the first H abstraction (above) and OH rebound (below) steps. The dashed and solid lines
stand for the triplet and quintet pathways, respectively.
product and recovers the catalyst in its quintet state, Q-5. This
-1
step is endothermic by only 2.6 kcal mol . The overall
-
1
hydroxylation process is exothermic by 32.0 kcal mol .
Overoxidation of DHPO, which is not studied, will lead to the
formation of the dione product observed experimentally, P2
(
Scheme 3).
Interestingly, the MnOH intermediate resulting from the first
H abstraction, Q-2, and the one leading to OH rebound, Q-3,
have different orientations of the OH group as expressed by
the θ(N′-Mn-O-H) dihedral angle (Figure 2). In Q-2, θ )
6
9.1° and the OH group points toward the carbon that has
undergone H abstraction, whereas in Q-3, θ ) 246.0° and the
OH group points in the opposite direction.
Figure 2. Optimized geometries of the Q-2 (left) and Q-3 (right)
intermediates.
J. AM. CHEM. SOC. 9 VOL. 132, NO. 22, 2010 7611

A R T I C L E S
Hull et al.
Figure 4. Desaturation pathway. The potential energies, in parentheses,
are given in kilocalories per mole.
•
Figure 3. Rotation of the Mn-OH bond in the presence of the MHP
values and all other geometrical parameters are optimized (see
the Supporting Information). As expected, C-H bond cleavage
prompts O-H bond formation and yields the desaturation
product, Q-6. Nevertheless, no energy maximum suggesting the
presence of a transition state is observed in this scan. All these
results show that the second H abstraction involves one or more
very low energy barriers, similar to that found for OH rebound.
Further optimization of the θ ) 150°, θ ) 170°, and θ )
radical. For each θ orientation of the OH group, all other structural
parameters are optimized. Q-2, Q-3, and Q-6 are the first H abstraction
product, OH rebound reactant, and desaturation product, respectively.
Since Q-2 does not lead to OH rebound, a rotation of the
Mn-OH bond is required to reach the reactive Q-3 conforma-
25
tion and force the reaction to proceed. We explore this rotation
by performing a relaxed energy scan, in which the dihedral angle
θ is frozen at different values, whereas all other geometrical
parameters are optimized (Figure 3). The scan confirms that
the optimal orientations of the OH group correspond to Q-2
and Q-3, which are associated with the θ ) 70° and θ ) 250°
minima, respectively. The potential energy surface is very flat,
and therefore, Q-2 and Q-3 are separated by very low energy
1
90° structures, in which all geometrical parameters, including
θ, are optimized, converges into the same complex, Q-6 (Figure
). This species, which is a van der Waals complex of the aqua
complex [Mn(OH )(por)(Cl)], Q-7, with the desaturation prod-
4
2
-1
uct, P1, dissociates with an energy cost of only 2.7 kcal mol .
Partial oxidation of P1, which is not studied, will yield the oxide
observed experimentally, P3 (Scheme 3).
-1
barriers, <1 kcal mol .
2
7
Interestingly, the scan reveals a set of θ values at which the
MnOH complex is not stable in the presence of the MHP•
radical. For these θ values (150-190°), the geometry optimiza-
tion yields a Mn aqua complex weakly bound to the desaturation
product, phenanthrene (P1). This clearly identifies a window
of OH orientations in which the second H abstraction is
achieved.
The triplet state pathway has also been explored. The
hydroxylation and desaturation products are optimized by using
the geometries and wave functions of the corresponding quintet
products, Q-4 and Q-6, as an initial guess. These calculations
yield the T-4 (hydroxylation) and T-6 (desaturation) triplet
products, whose structures are very similar to Q-4 and Q-6,
respectively. The energy difference between the triplet and
The desaturation reaction is likely to involve two consecutive
energy barriers associated with the following processes: (1)
Mn-OH bond rotation and (2) C-H bond cleavage in the
reactive θ ) 150-190° window. We could not locate the
transition states of these processes because of the complexity
and flatness of the potential energy surface. Nevertheless, the
(
26) We found a transition state for the rotation of the Mn-OH bond in
the isolated [Mn(OH)(por)(Cl)] complex on the high-spin quartet
surface. The values of θ for the reactant, transition state, and product
are 51.0°, 89.7°, and 123.2°, respectively. The energies associated with
-1
q
-1
this reaction (∆E ) 0.0 kcal mol , and ∆E ) 0.5 kcal mol ) confirm
that this process is essentially isothermic and barrier-free, as suggested
by the relaxed energy scan of Figure 3. See the Supporting Information
for further details.
θ ) 110° and θ ) 210° energy maxima, which are less than 1
kcal mol-1 above Q-2, suggest the presence of a very flat and
(
27) The OH rebound transition state could not be located, because of
convergence problems associated with the multireference character
of the triplet. Nevertheless, when the O · · ·C distance is shortened to
26
low energy barrier for Mn-OH bond rotation. The C-H bond
cleavage is further investigated by means of a relaxed energy
scan in which the d(C-H) distance is kept frozen at different
2
.00 Å, subsequent full optimization yields the hydroxylation product,
T-4. The transition state for desaturation on the triplet surface could
not be located either. However, the optimization of the θ ) 150°
conformation yields the desaturation product, T-6. These results
suggest that the triplet state promotes either hydroxylation or desatu-
ration depending on the orientation of the OH group, as found for the
quintet.
(
25) (a) Ogliaro, F.; Harris, N.; Cohen, S.; Filatov, M.; de Visser, S. P.;
Shaik, S. J. Am. Chem. Soc. 2000, 122, 8977–8989. (b) Sch o¨ neboom,
J. C.; Cohen, S.; Lin, H.; Shaik, S.; Thiel, W. J. Am. Chem. Soc. 2004,
1
26, 4017–4034.
7
612 J. AM. CHEM. SOC. 9 VOL. 132, NO. 22, 2010

Manganese Catalysts for C-H Activation
A R T I C L E S
Figure 5. Possible reaction pathways in the catalytic oxidation of DHP.
-
1
quintet products is <3 kcal mol . These results suggest that
the triplet and quintet pathways are close in terms of structure
and energy, and therefore, both states can promote the reaction.
From the thermodynamic point of view, desaturation (∆E )
The alcohol is quantitatively overoxidized to the dione P2,
whereas P1 is overoxidized to a small extent to the oxide P3
(see the Supporting Information). Therefore, P2 is the hydroxy-
lation product, and P1 and P3 are the desaturation products.
Our experiments show that the oxidation of DHP catalyzed by
C1 leads to mixtures of these three products (Table 1), which
demonstrates that the reaction involves both hydroxylation and
desaturation pathways, as previously observed with some
hydroxylase and desaturase enzymes. Catalysts C2 and C3
give similar results, except that no epoxide P3 is formed, and
the three catalysts can be thus regarded as models for desaturase
activity.
-1
-
)
40.6 kcal mol ) is clearly favored over hydroxylation (∆E
-32.0 kcal mol ) (Figures 1 and 4). Nevertheless, the high
energy barriers associated with the reverse reactions (>25.0 kcal
-1
-1
mol ) indicate that both desaturation and hydroxylation are not
reversible. The selectivity of the overall reaction is, thus, not
under thermodynamic control.
Once the first H abstraction is completed, the rotation of the
Mn-OH bond of Q-2 generates unstable conformations, which
yield either the desaturation product by the second H abstraction
or the hydroxylation product by OH rebound. The extremely
low and similar energy barriers associated with these reactions
6
,7
The mechanistic picture of Figure 5 indicates that desaturation
and hydroxylation diverge from a common radical intermediate.
Therefore, some sort of switch has to control the final outcome
•
3d
have two consequences. (1) Once the MHP radical is generated,
of the reaction. The nature of this switch has been debated.
it reacts immediately so it does not have time to diffuse away
and initiate radical chain reactions, and (2) the reaction gives a
mixture of the hydroxylation and desaturation products. Both
predictions are in good agreement with our experiments (vide
supra). Furthermore, both hydroxylation and desaturation start
from a common radical intermediate, and therefore, selectivity
is not determined by the initial H abstraction step.
One proposal is that the switch consists of the formation of a
8,9,28
carbocation
which, depending on the nature of the substrate,
is yielded by the oxidation of the radical intermediate. This
carbocation leads to desaturation by loss of a proton.
Previous reports of the dehydrogenation of saturated carbo-
and heterocycles use heterogeneous catalysts that form a
2
9
carbocation on the substrate directly. However, in explaining
the mechanism, the prior authors propose a single reaction path
with a carbocation intermediate that does not resemble the
biological transformation of interest here. Our experimental and
theoretical studies do not provide evidence supporting the
formation of a carbocation intermediate in the oxidation of DHP.
In contrast, the lower yield and altered product ratios of reactions
run in the presence of atmospheric oxygen suggest that a radical
may be involved in the mechanism (Table 1, entries 2, 4, 6,
The calculations suggest that the catalytic oxidation of DHP
by C1 is straightforward because all steps involved in the
reaction mechanism are exothermic and have very low energy
barriers. Nevertheless, our experiments show that under mild
conditions the yield of this reaction is low (Tables 1-3). This
suggests that the critical step is neither H abstraction nor OH
rebound. In line with this, experimental studies by Newcomb
showed that the overall rate of the process may be controlled
1
6e
by the generation and stability of the active Mn oxo species.
3
and 8). However, tests using NBS and CBrCl indicate that such
A detailed study of kinetic isotope effects (KIE) may clarify
this point. However, the determination of KIE in our system is
challenging both at the experimental and at the theoretical levels,
and it is beyond the scope of this paper. Eyring KIE plots are
therefore not provided.
a radical is not long-lived, preventing radical trapping. These
observations are in good agreement with the calculations that
show that both OH rebound and H abstraction in the radical
intermediate involve extremely low energy barriers, <1 kcal
-1
mol (Figures 1 and 3).
Discussion
(
(
28) Bassan, A.; Blomberg, M. R. A.; Siegbahn, P. E. M. J. Biol. Inorg.
Chem. 2004, 9, 439–452.
The oxidation of DHP starts with H abstraction by the
manganese oxo active species derived from C1 (Figure 5). The
resulting radical undergoes either OH rebound, yielding an
alcohol, or a second H abstraction, yielding phenanthrene (P1).
29) (a) Khenkin, A. M.; Neumann, R. J. Am. Chem. Soc. 2002, 124, 4198–
4
199. (b) Kamata, K.; Kasai, J.; Yamaguchi, K.; Mizuno, N. Org.
Lett. 2004, 6, 3577–3580. (c) Neumann, R.; Lissel, M. J. Org. Chem.
1989, 54, 4607–4610.
J. AM. CHEM. SOC. 9 VOL. 132, NO. 22, 2010 7613

A R T I C L E S
Hull et al.
As the experiments, the calculations do not indicate the
participation of a carbocation in the mechanism. The initial H
abstraction step yields intermediate Q-2, in which the organic
fragment generated from DHP interacts with a Mn hydroxo
complex (Figure 2). The local spin densities and charges of Q-2
indicate that the organic monohydrophenanthrene fragment, with
a total charge of 0.01 and a total spin density of 0.97, is a neutral
•
radical, MHP . A large part of this spin density, 0.57, is located
on the carbon which has undergone H abstraction. These data
show that the radical is not spontaneously transformed into a
carbocation by reduction of the metal center to Mn(III). The
organometallic part of Q-2, [Mn(OH)(por)(Cl)], with a total
charge of -0.01, is neutral and has a total spin density of 3.03,
mostly located on the metal (2.60). This local spin density
suggests that the metal center has been reduced to Mn(IV) in
the hydroxo intermediate. All these results point to the radical
nature of the initial H abstraction step. In addition, the radical
product of this reaction undergoes a second H abstraction
induced by the rotation of the Mn-OH bond (Figures 3 and
4
), yielding the desaturation product without the participation
of a carbocation.
•
The dissociation of Q-2 may yield the MHP radical and the
hydroxo complex, [Mn(OH)(Cl)(por)]. Transfer of a single
electron between both species would lead to the formation of
the monohydrophenanthrene cation, MHP , and the anionic
hydroxo complex, [Mn(OH)(Cl)(por)] (eq 1).
Figure 6. SOMO orbitals of intermediate Q-2. Spin density is plotted in
Figure 7.
+
-
•
+
MHP + [Mn(OH)(Cl)(por)] f MHP +
[
Mn(OH)(Cl)(por)]- (1)
The spin states are doublet, quartet, singlet, and quintet for
•
+
-
MHP , [Mn(OH)(Cl)(por)], MHP , and [Mn(OH)(Cl)(por)] ,
respectively. The energy change associated with this reaction,
∆GCPCM(1), was computed by considering acetonitrile as a
solvent with the continuum CPCM method, to account for the
presence of charged species. The value of ∆GCPCM(1) (18.1 kcal
-
1
mol ) shows that the radical intermediate is clearly favored
over the cationic one for the system under study. Nevertheless,
both the radical and cationic mechanisms may be relevant, and
the preference for one or the other is likely to depend strongly
on the specific nature of the substrate, catalyst, and solvent in
each case.
Figure 7. Spin density of Q-2. The excess R and ꢀ spin densities are
colored blue and green, respectively. Local spin densities are given in
parentheses.
The shape of the π*(MndO) and π(O,Cl) orbitals suggests
that the spin density on oxygen is located along an axis
perpendicular to the MnOH plane. This is confirmed by the plot
of the total spin surface of Q-2 (Figure 7). Right after the first
H abstraction, in Q-2, this axis points neither to the radical
The calculations support the hypothesis in which the orienta-
tion of the substrate with respect to the reactive center constitutes
the hydroxylation-desaturation switch. The electronic structure
of Q-2 was further explored via analysis of its four singly
occupied molecular orbitals. The highest-energy SOMO, π(C),
which lies at the HOMO level, is a nonbonding π orbital located
on the aromatic rings of the organic fragment (Figure 6). π(C)
accounts for the radical character of the organic fragment, and
the most relevant contribution to this orbital comes, indeed, from
the carbon with the strongest radical character. Deeper in energy,
we found two other SOMOs: an antibonding π orbital of the
MndO bond, π*(MndO), and the nonbonding dxy Mn orbital.
These two orbitals contribute to the local Mn spin density. The
fourth SOMO, π(O,Cl), is a nonbonding combination of the
oxygen and chloride lone pairs. The π*(MndO) and π(O,Cl)
orbitals contribute to the significant local spin density on the O
atom (0.20). This spin density implies that Q-2 has radical
character on oxygen and is, therefore, capable of promoting not
only OH rebound but also the second H abstraction leading to
3
carbon nor to the vicinal sp C-H bonds, and therefore, this
species does not react. Nevertheless, the free rotation of the
Mn-OH bond yields the Q-3 conformation, in which the spin
vector on oxygen points toward the radical C of the organic
fragment. This orientation promotes the hydroxylation of the
radical by OH rebound. In contrast, when the Mn-OH bond
rotates in the opposite sense, the spin vector on oxygen points
3
toward one of the sp C-H bonds. This induces a second H
abstraction from the organic radical, which yields the desatu-
ration product.
These results show that the Mn hydroxo intermediate will
promote either desaturation or hydroxylation, depending on how
the organic radical is oriented with respect to the OH group. In
our computational model, these reactive orientations are achieved
by rotation of the Mn-OH bond. In the real system, these
orientations may be controlled by more complex mechanisms.
For instance, the organic radical can move around the MnOH
group. The orientation of the substrate in its initial approach to
18c
the desaturation product. However, not only the presence but
also the orientation of the spin density on oxygen is crucial.
7
614 J. AM. CHEM. SOC. 9 VOL. 132, NO. 22, 2010

Manganese Catalysts for C-H Activation
A R T I C L E S
3
0
31
the catalyst, the dynamics of the system, and the weak
Representative duplicate experiments were performed in the key
cases with consistent results.
3
2
interactions among the catalyst, substrate, and solvent may
also have a critical influence on the final outcome of the reaction.
Therefore, the accurate prediction of the final desaturation/
hydroxylation ratio, which is not the goal of this paper, will
require extremely computationally demanding calculations. In
addition, there will be no general rules for predicting the
selectivity of the reaction, which will depend on the nature of
each species participating in the reaction.
In summary, the mechanistic picture of the reaction reveals
that the relative orientations of both the metal catalyst and the
organic radical need to be precisely defined, to favor only one
of the two possible reactions and obtain high selectivity. In
agreement with this scenario, high desaturation/hydroxylation
selectivity ratios are achieved only by enzymes in which the
position of the reactive center is fixed and the orientation of
the substrate is precisely set by the protein environment.
Oxidation by Catalyst C1. A suspension of substrate (0.10
mmol) and C1 (0.005 mmol) in 1 mL of solvent was degassed
with three freeze-pump-thaw cycles. Before the mixture thawed
in the final cycle, iodosobenzene (0.20 mmol) was added under a
flow of nitrogen and the flask was sealed, evacuated, and refilled
with nitrogen. Upon warming to room temperature, the reaction
mixture was stirred at ambient temperature for the time indicated
(
12-16 h), at which point 1,3,5-trimethoxybenzene was added as
an internal standard. The reaction mixture was then filtered over a
pad of Celite, and the crude mixture was immediately analyzed by
1
H NMR.
Oxidation by Catalyst C2. A suspension of substrate (0.10
mmol), tetrabutylammonium oxone (0.20 mmol), and N-methyl-
morpholine N-oxide (0.11 mmol) in 1 mL of solvent was degassed
with three freeze-pump-thaw cycles. After the last cycle, Jacob-
sen’s catalyst (0.005 mmol) was added under a flow of nitrogen
and the flask was sealed. The reaction mixture was stirred at ambient
temperature for the time indicated (12-16 h), at which point 1,3,5-
trimethoxybenzene was added as an internal standard. The reaction
mixture was then filtered over a pad of Celite, and the crude mixture
Conclusions
We have conducted the first model study of desaturase
chemistry using synthetic manganese catalysts and several
substrates. DHP gives the highest desaturase activity, and the
presence of the dione product P2 indicates the close relationship
between hydroxylation and desaturation. Other reactive sub-
strates for desaturation included N-methylindoline and 1,3-
1
was immediately analyzed by H NMR. Only catalyst C1 showed
a modest degree of overoxidation of P1 to P3 (see the Supporting
Information).
Oxidation by Catalyst C3. A mixture of substrate (0.10 mmol)
and tetrabutylammonium oxone (0.20 mmol) in 1 mL of solvent
was degassed with three freeze-pump-thaw cycles. After the last
cycle, catalyst C3 (0.001 mmol) was added under a flow of nitrogen
and the flask was sealed. The reaction mixture was stirred at ambient
temperature for the time indicated (12-16 h), at which point 1,3,5-
trimethoxybenzene was added as an internal standard; the reaction
mixture was filtered over a pad of Celite, and the crude reaction
3
hexadiene, both of which contain two adjacent sp CH bonds,
and both also give aromatic species on desaturation. The
experimental work is supported by the calculations and shows
that the postulated Mn oxo active species, [Mn(O)(por)(Cl)],
promotes the oxidation of dihydrophenanthrene by either
hydroxylation or desaturation. These two competing reactions
1
mixture was immediately analyzed by H NMR.
have a common initial step, which is radical H abstraction from
one of the sp3 C-H bonds. The resulting Mn hydroxo
Computational Details
intermediate is capable of promoting not only OH rebound
Unrestricted DFT calculations were performed by using the BP86
33
(
hydroxylation) but also a second H abstraction (desaturation)
functional. All geometries were fully optimized for each spin state,
without any symmetry or geometry constraints. The nature of all
stationary points was confirmed by the analytical calculation of their
frequencies. The vibrational data were used to relax the geometry
of each transition state toward reactants and products, to confirm
because, in parallel with the active oxo species, it has radical
character on oxygen. Both steps have very low and similar
energy barriers, leading to a product mixture. Since the radical
character of the catalyst is located on the oxygen p orbital
perpendicular to the MnOH plane, the orientation of the organic
radical with respect to this plane determines which reaction will
occur. Substrate orientation in the enzyme active site is, thus,
likely to constitute the switch between hydroxylation and
desaturation.
its nature. The geometries were optimized with basis set I
34
(
Stuttgart-Bonn scalar relativistic ECP with associated basis set
35
for Mn and the 6-31G basis set for O, N, C, and H). The energies
given in the text were computed by single-point calculations with
3
6
basis set II (basis set I and polarization functions on all atoms),
on the stationary points obtained with basis set I. The effect of the
solvent, acetonitrile, was modeled by single-point calculations with
Experimental Section
37
the CPCM method with basis set II. Free energies were obtained
from the vibrational calculations with basis set I. The solvent,
entropy, and zero-point energy corrections did not alter to a great
extent the energy profiles. All these corrections are given in the
Supporting Information. The molecular orbitals and the spin
General. All reagents were purchased from Sigma-Aldrich,
unless otherwise noted. The epoxide standard for P3 was prepared
when 1 equiv of phenanthrene (P1) was stirred with 1.5 equiv of
4
-chloroperoxybenzoic acid (m-CPBA) for 3-20 h and purified
using column chromatography (230-400 mesh silica gel, gradient
of 30/70 to 60/40 EtOAc/hexanes). Solvents were degassed using
standard Schlenk techniques. All yields for manganese-catalyzed
reactions were measured by NMR using 1,3,5-trimethoxybenzene
as an internal standard on a Bruker spectrometer running at 400 or
(33) (a) Perdew, J. P. Phys. ReV. B 1986, 33, 8822–8824. (b) Perdew, J. P.
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5
00 MHz, and gas chromatography and mass spectrometry on a
Hewlett-Packard 5971A spectrometer.
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The following typical reaction conditions were used for each
catalyst, unless otherwise noted in the footnotes of the tables.
2257–2261.
(
36) (a) Ehlers, A. W.; B o¨ hme, M.; Dapprich, S.; Gobbi, A.; Höllwarth,
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(
(
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J. AM. CHEM. SOC. 9 VOL. 132, NO. 22, 2010 7615

A R T I C L E S
densities were obtained from NPA (natural population analysis)
Hull et al.
3
8
give the same qualitative picture in which, regardless of the stability
ordering, all the spin states are close in energy and therefore
accessible.
3
9
calculations. All calculations were conducted with Gaussian03.
The optimization of MECP (minimum energy crossing point)
between different spin surfaces was conducted by using the code
4
0
Acknowledgment. We thank the National Science Foundation
Grant 0614403) for financial support. E.L.O.S. thanks the NSERC
developed by J. N. Harvey.
(
The pure BP86 functional has been successfully used by us in
and DOE grant DE-FG02-84ER13297. D.B. thanks Sanofi-Aventis
for a postdoctoral fellowship. O.E., C.R., and D.B. thank the CNRS
and the French Ministry of National High Education and Research
for funding. We also thank Siddhartha Das for initial observations
in this area.
previous studies of C-H bond oxidation by manganese oxo
1
8
species. The DFT calculations for these catalytic systems should
be assessed with caution, since some results may depend on the
nature of the functional chosen. Test calculations at the DFT(B3LYP)
level have shown that this hybrid functional predicts a different
energy ordering of the spin states, in which the quintet is the ground
state. In contrast, the BP86 calculations indicate that the ground
state is the singlet. This result is in better agreement with several
experimental studies on manganese oxo complexes, which suggest
Supporting Information Available: A table of all substrates
that were screened for activity; details of the mechanistic
experiments, including the synthesis of a substrate to probe the
proposed mechanistic pathways; P1/P3 ratios for entries 1-4
of Table 1; optimized geometries of all stationary points together
with their potential, zero-point, entropy, and CPCM energies;
relaxed energy scan for C-H bond cleavage in the second H
abstraction step; reaction pathway for the rotation of the
Mn-OH bond in the isolated [Mn(OH)(por)(Cl)] complex; and
a complete list of authors for ref 39. This material is available
free of charge via the Internet at http://pubs.acs.org.
16
that the ground state is a diamagnetic singlet species. In a previous
study, we have also shown that the electronic structure of the
manganese oxo species may depend on the nature of the
1
8c
functional. Nevertheless, both the BP86 and B3LYP functional
(
(
(
38) Reed, A. E.; Curtiss, L. A.; Weinhold, F. Chem. ReV. 1988, 88, 899–
9
26.
39) Frisch, M. J.; GAUSSIAN 03, revision D.01; Gaussian, Inc.: Walling-
ford, CT, 2004.
40) Harvey, J. N.; Aschi, M.; Schwarz, H.; Koch, W. Theor. Chem. Acc.
1
998, 99, 95–99.
JA908744W
7
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