Evidence that steric factors modulate reactivity of tautomeric iron-oxo species in stereospecific alkane C-H hydroxylation

Article abstract of DOI:10.1039/c3cc47830k

A new iron complex mediates stereospecific hydroxylation of alkyl C-H bonds with hydrogen peroxide, exhibiting excellent efficiency. Isotope labelling studies provide evidence that the relative reactivity of tautomerically related oxo-iron species responsible for the C-H hydroxylation reaction is dominated by steric factors. This journal is The Royal Society of Chemistry.

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Evidence that Steric Factors Modulate Reactivity of Tautomeric Iron-
Oxo Species in Stereospecific Alkane C-H Hydroxylation†
Mainak Mitra,a Julio Lloret-Fillol,b Matti Haukka,c Miquel Costas,*b Ebbe Nordlander*a
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
A new iron complex mediates stereospecific hydroxylation of
alkyl C-H bonds with hydrogen peroxide, exhibiting excellent
efficiency. Isotope labelling studies provide evidence that the
relative reactivity of tautomerically related oxoiron species
scenario resembling the “peroxide shunt”3 of cytochrome P450
and model systems. A highly electrophilic [FeV(O)(OH)(LN4)]2+
oxidant (O), formed via water-assisted cleavage of
a
hydroperoxide [FeIII(OOH)(OH2)(LN4)]2+ (PB) (Scheme 2) is
10 responsible for the C-H hydroxylation reaction are 50 ultimately responsible for C-H oxidation reactions.8a,8d,9-11
dominated by steric factors.
Intermediate O can exist as two tautomerically related species,
OA and OB, that differ in the relative positions of the oxo and
hydroxide ligands, and are connected through a prototopic oxo-
hydroxo tautomerism. We have also previously studied C-H
55 oxidation reactions with a set of catalysts where electronic
properties of the PyTACN ligand were systematically tuned, and
found that the relative reactivity of OA and OB in C-H oxidations
remain basically the same, irrespective of the catalyst.8d
While the selective functionalization of hydrocarbons remains a
significant challenge for chemists,1 several iron-dependent
oxygenases are able to mediate the hydroxylation of C-H bonds
15 under mild conditions, using dioxygen as the terminal oxidant.2
Examples include the cytochrome P450 enzymes,3 and the family
of non heme iron-dependent Rieske oxygenases.4 In both cases,
C-H hydroxylation occurs with almost complete stereoretention,
and is accomplished via the intermediacy of an electrophilic high
20 valent iron-oxo species that attacks the C-H bond via the so-
called oxygen-rebound mechanism (Scheme 1).5
HO
OH
N
R
OH
H3C
60
N
N
FeV
N
N
O
N
R
H3C
H3C
H2O
N
H3C
H2O2/H2O
N
N
N
H3C
OH
FeII
FeIII
R
H
OA
N
OTf
N
O
R
R
OTf
R = H, 2OTf
R = Me, 3OTf
O
H3C
O
Asp
Asp
N
H
H
H
H3C
H3C
N
N
O
O
FeV
O
NHis
O
PB
HO
OH
NHis
NHis
N
OH
R
OH
R
FeV
R
OH
FeIV
OH
O
65
OB
NHis
25
OH
HO
O
R
R
H
Scheme 2. Mechanism for substrate oxidation by Fe(PyTACN)
complexes
Scheme 1. Schematic mechanism for C-H hydroxylation by a
Rieske oxygenase enzyme.
70 In this work we turn our attention to investigation of steric
effects. Towards this end, C-H oxidation reactions catalyzed with
the new iron complex [FeII(CF3SO3)2(Me2,BzImTACN)] (Figure 1),
1OTF, were studied. The new tetradentate ligand Me2,BzImTACN
has been developed by replacing the pyridyl arm of the PyTACN
75 scaffold by an N-methyl benzimidazolyl substituent. The sp2
character and the rigidity of the latter substituent should provide a
well-defined steric demand, intermediate between the α–H and
the α–Me groups of a pyridine (Scheme 2, catalysts 2OTf and
3OTf). On the other hand, the relative donor capacities of pyridine
80 and benzimidazole may be estimated as very similar by
comparing the pKa values of their conjugate acids (5.22 for
pyridine, 5.41 for benzimidazole and 5.57 for α-Me pyridine),
and therefore differences in reactivity among this set of
complexes can be traced to steric factors.
30 A fundamental difference between heme and non-heme sites is
that active sites in the latter contain lower coordination numbers,
and a number of them form reactive intermediates containing a
cis-Fe(O)(X) unit (X = HO(H), Cl, Br). This leads to a versatile
reactivity that opens new mechanistic scenarios. Arene cis-
35 dihydroxylation and aliphatic chlorination constitute unique
examples of the reactivity exhibited by cis-Fe(O)(X) units (X =
OH, Cl, Br).4,5b,6
The reactivity of non-heme oxygenases has inspired the design of
synthetic model complexes as selective C-H oxidation catalysts.7
40 Mechanistic studies have shown that in selected cases reactions
are metal based, involving high-valent oxo-iron species, and are
fundamentally distinct from radical pathway Fenton processes.8
The Fe(PyTACN) family of complexes (Scheme 2) belongs to the
group of catalysts that mediate C-H hydroxylation with retention
45 of configuration.8d We and others have proposed a mechanistic
85 The complexes [FeII(CF3SO3)2(Me2,BzImTACN)], 1OTF and
[FeII(H2O)2(Me2,BzImTACN)](CF3SO3)2, 1H2O were prepared and
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characterized following standard procedures (see SI for details).
hydroxylation, including those of the [Fe(PyTACN)] family.
The X-Ray structures of 1OTf and 1H2O are very similar to 2OTf
and 3OTf and have an iron center in a distorted octahedral
Since these catalysts operate via a [FeV(O)(OH)(LN4)]2+ (O)
oxidant,8a,d,10-11 the same was tentatively inferred for 1OTf. Strong
environment surrounded by the four N atoms of the ligand, with 60 experimental evidence in favor of this scenario arises from olefin
5
10
15
the TACN ring capping one face of the octahedron, and two
oxygen atoms from triflate anions (1OTf) or water molecules
(1H2O) cis to each other (cf. Figure 1 and ESI).8d Average Fe-
NTACN and Fe-OH2O distances are 2.23 Å and 2.13 Å respectively,
characteristic of a high spin distorted ferrous center.12
cis-dihydroxylation reactions. The water assisted cleavage of the
O-O bond (Scheme 2) determines the oxygen atom inventory in
the HO-FeV=O oxidant (O). One of the oxygen atoms originates
from the water molecule, while the second oxygen atom is
65 derived from the peroxide. Cis-dihydroxylation reactions
incorporate both oxygen atoms from O into the product and
consequently syn-diols must contain one oxygen atom that
originates from water and one oxygen from the peroxide.11
Indeed, 1OTf catalyzes the oxidation of cyclooctene
70 (1OTf:H2O2:H218O:cyclooctene, 1:10:1000:1000) affording cis-
cyclooctene epoxide (TON = 2) and syn-cyclooctane-1,2-diol
(TON = 7). The syn-diol is 98% 16O18O labeled, providing strong
support in favor of O as the oxidant.
Fig. 1. Molecular structure of [FeII(H2O)2(Me2,BzImTACN)]2+
(1H2O) with 30% probability ellipsoids; H-atoms have been 75 same mechanism as 2OTf and 3Otf, we proceeded to investigate the
Having obtained positive evidence that 1OTf operates through the
20 omitted for clarity.
relative reactivity of the OA/OB tautomers in C-H hydroxylation
reactions. Since the origin of the oxygen atoms is determined in
the peroxide precursor (PB), the relative reactivity of OA and OB
in C-H hydroxylation can be probed using isotopically labeled
Complex 1OTf was found to be an outstanding catalyst in C-H
oxidation reactions with H2O2. Catalytic oxidation of
cyclohexane was chosen for proper comparison with literature 80 water and hydrogen peroxide (Scheme 2). The oxidation of
25 precedents.8,13 Syringe pump addition of 10 equivalents (w.r.t. the
complex) of H2O2 together with 1000 equivalents of H2O§ to a
CH3CN solution containing 1 and substrate (1000 equivalents)
over 30 min in air at room temperature resulted in the formation
cyclohexane by 1OTf in the presence of 10 equivalents of H218O2
and 1000 equivalents of H2O afforded 45% 18O-labeled
cyclohexanol. Complementary experiments with 10 equivalents
of H2O2 and 1000 equivalents of H218O afforded 48% 18O-labeled
of cyclohexanol (A) with turnover numbers (TON) of 8.5 and a 85 cyclohexanol (Table 1).
30 small amount of cyclohexanone (K) with TON of 0.8, giving an
alcohol/ketone (A/K) ratio of 10.6. The efficiency w.r.t.
consumption of oxidant was around 99-100%, and remains
unusually high (54%) when 100 equiv. of H2O2 are employed.
Interestingly, when followed over time, the A/K product ratio in
Table 1. Comparison of percentage of 18O incorporation into alcohol
products by different Fe-catalysts using 1000 equivalents of H218O
35 oxidation of cyclohexane showed that the initial value for A/K
was around 35, which gradually decreased to 10.6 (cf. Figure S5,
ESI†). This provides strong evidence that cyclohexanol is the
almost exclusive primary product of the alkane oxidation
reaction, and cyclohexanone is a result of further oxidation of the
40 alcohol, thereby eliminating the significant implication of a
Russell-type termination mechanism initiated by hydroxyl
radicals and producing equal amounts of alcohol and ketone.
Several mechanistic probes further substantiate that the reactions
are metal-based. The intermolecular kinetic isotope effect was
45 determined for the formation of cyclohexanol from a mixture
(1:3) of cyclohexane and its deuterated isotopomer cyclohexane-
d12, and was found to be 5. Also, complex 1OTf oxidizes
adamantane with a large C3/C2 normalized selectivity (14)
towards the tertiary C-H bond. The oxidation of cis-1,2-
50 dimethylcyclohexane (DMCH) leads to the corresponding tertiary
alcohol product with 97% retention of configuration. These data
are consistent with the implication of selective oxidants whose
relative reactivities against C-H bonds are modulated by their
bond strengths and steric properties.7a The reactivity of 1OTf
55 against these mechanistic probes is thus in good accordance with
that described for iron catalysts that mediate stereospecific C-H
Substrate
Cyclohexane
Cyclohexane-d12
Cyclooctane
Cis-DMCH
Adamantane
Cis-cyclooctenea
epoxide
1OTf
48
48
41
26
28
24
2OTf
45
40
44
79
74
77
3OTf
11
-
-
2
Fe(TPA)b
29
35
23
6
6
9
3
5
Syn-cyclooctane-
98
97
78
86
1,2-diola
a Cyclooctene was employed as substrate. b reference 8a
Similar levels of 18O-label incorporation from H218O were
90 observed in the case of cyclooctane (41%) and cyclohexane-d12
(48%). These levels of water incorporation are unusually high,
only bypassed in the literature by 2OTf 8d-e
and constitute strong
,
evidence that OA and OB are roughly equally reactive against
secondary C-H bonds. Most interestingly, when the substrates
95 contain tertiary C-H bonds (e.g. DMCH and adamantane), the
percentages of 18O incorporation from H218O were found to be in
the range 25-29%, indicating a preferential oxidation via OA.
Interpretation of these values can be done by considering those
obtained with 2OTf and 3OTf in analogous reactions. Table 1
2
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DOI: 10.1039/C3CC47830K
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50 aChemical
Physics,
Department
of
Chemistry,
Lund
shows that hydroxylation of tertiary C-H bonds mediated by 2Otf
University,Lund,P.O.Box-124,SE-22100, Sweden. Fax: +46-46-22 24119;
Tel: +46-46-22 28118; E-mail: Ebbe.Nordlander@chemphys.lu.se.
bQBIS Group, Department of Chemistry, University de Girona, Campus
Montilivi, 17071 Girona, Catalonia, Spain. Fax: +34 972 41 81 50; Tel:
55 +34 972 41 98 42; E-mail: miquel.costas@udg.edu.
is predominantly performed by OB as shown by the large extent
of oxygen atoms originating from water in the alcohol product
(up to 79%, cf. Table 1). Instead, hydroxylation of secondary C-H
bonds occurs with incorporation of ~ 40% of oxygen atoms from
water, suggesting comparable reactivity of both tautomers. In
sharp contrast, hydroxylations catalyzed by 3OTf exhibit a
relatively small extent (~ 10%) of water incorporation in
hydroxylation of secondary C-H bonds, and negligible (< 3%)
5
cDepartment of Chemistry,University of Jyväskylä, Jyväskylä, Finland.
† Electronic Supplementary Information (ESI) available: Ligand
synthesis, complex synthesis, proton NMR spectra, ESI-MS and IR
60 spectra of the complex, crystallographic data for complexes 1OTf and
1H2O, catalysis experiments and results, details of isotope labelling
experiments. CCDC no 960138 and 960139. For ESI and crystallographic
data in CIF format see DOI: 10.1039/b000000x/.
10 incorporation in the hydroxylation of tertiary C-H sites,
indicating that hydroxylation is almost exclusively performed by
OA.
§Analogous product yields and A/K selectivity values were obtained
65 when H2O (1000 equiv.) was not specifically added.
Therefore, the relative reactivity of the two tautomeric forms of
the [FeV(O)(OH)(LN4)]2+ (O) intermediate is finely tuned among
15 the series of catalysts (1OTf-3OTf), a fact that contrasts with the
small effects exerted when the electronic properties of the
pyridine in a series of catalysts is altered.8d Trends observed for
1OTf-3OTf may thus be rationalized on the basis of steric effects.
The benzylimidazole ring introduces steric bulk in the proximity
20 of position B at the iron center that is intermediate between that
set by pyridine and 6-Me-pyridine arms (Fig. 2). Accordingly,
when secondary C-H bonds are hydroxylated, 1OTf behaves as
2OTf, i.e. tautomers OA and OB are equally implicated in the C-H
oxidation reaction. Instead, oxidation of sterically more
25 demanding tertiary C-H bonds yield levels of water incorporation
that suggest predominant participation of OA as in the case of
3OTf, although unlike in the latter case, implication of OB remains
significant (~25%) because steric hindrance at position B induced
by the C- C-sp2 benzylimidazol moiety is smaller than the one
30 caused by a C-sp3 methyl substituent.
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85
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95
5
6
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8
Figure 2. Comparative analysis of the steric bulk in proximity to
site B.
In conclusion, the present work adds to the growing evidence that 100
35 the coordination environment at non heme sites opens reactivity
scenarios unattainable by hemes. Here we have shown that
systematic tuning of the steric properties of the two sites in the
cis-Fe(O)(X) unit translates into systematic differences in relative
reactivity of the two iron-oxo tautomers. We postulate that
40 analogous steric conditions may influence the relative reactivities
of putative tautomers in non-heme iron oxygenases.
9
DFT calculations indicate that isomeric peroxide PA is not implicated
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This work has been supported by the European Union (the
Erasmus Mundus program), the International Research Training
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Mechanisms (www.biometals.eu), COST Action CM1003. We
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Notes and references
120
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