From DNA to catalysis: A thymine-acetate ligated non-heme iron(III) catalyst for oxidative activation of aliphatic C-H bonds

Article abstract of DOI:10.1039/c5cc07597a

A non-heme, iron(iii)/THA(thymine-1-acetate) catalyst together with H₂O₂ as an oxidant is efficient in oxidative C-H activation of alkanes. Although having a higher preference for tertiary C-H bonds, the catalyst also oxidizes aliphatic secondary C-H bonds into carbonyl compounds with good to excellent conversions. Based on the site selectivity of the catalyst and our mechanistic studies the reaction proceeds via an Fe-oxo species without long lived carbon centered radicals.

Full text of DOI:10.1039/c5cc07597a

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From DNA to Catalysis: Thymine-acetate ligated non-heme
iron(III) catalyst for oxidative activation of aliphatic C-H bonds
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
a*
A. Al-Hunaiti, M. Räisänen and T. Repo
DOI: 10.1039/x0xx00000x
www.rsc.org/
[7]
Abstract A non-heme, iron(III)/THA(thymine-1-acetate) catalyst oxidation reactions.
together with H as an oxidant is efficient in oxidative C-H
O
N
2 2
O
activation of alkanes. Although having a higher preference for
tertiary C-H bonds the catalyst oxidizes also aliphatic secondary C-
H bonds into carbonyl compounds with good to excellent
conversions. Based on the site selectivity of the catalyst and our
mechanistic studies the reaction proceeds via a Fe-oxo species
without long lived carbon centered radicals.
N
O
THA
COOH
H
R
H
FeCl (5mol%), THA(10mol%)
3
O
R
1
R1
n
n
2
2
R
H O , MeCN, 10 h
2 2
R
R
1
:alkyl, aryl, ester, acid
:Methyl,ethyl,Propyl
2
C-H activation is a fundamental chemical transformation and
highly valuable in the functionalization of alkanes and aliphatic
Scheme1. Oxidative activation of aliphatic C-H bonds by the thymine-acetate
[1,2]
hydrocarbons. Although extensively studied, the topic ligated non-heme iron(III) catalyst.
remains one of the significant challenges in modern chemistry;
3
inactivated sp C-H bonds have high dissociation energy (90-
We reported recently in-situ prepared Fe(III)/thymine-1-
[
3]
acetate catalyst for the oxidation of primary and secondary
aliphatic alcohols and diols into corresponding carbonyl
compounds. Characteristic for the Fe(III)/THA catalyst is high
1
00kcal/mol) and low acidity (pK = 45-60). To be practical in
a
synthesis, a catalyst has to sustain a very high reactivity
combined with predictable site selectivity. Necessity of a
catalytic system which comprises these two conflicting
demands into one species, keeps the challenge high and alive.
The majority of recent studies is devoted to routes using
biologically inspired iron catalysts and hydrogen peroxide as an
[9]
reactivity. During the reaction optimization for alcohol
oxidation, an oxidation of a some solvent residue (hexane) was
also observed. This observation prompted us further studies
along the oxidative activation of aliphatic C-H bonds. Herein
we report the novel highly active iron based system Fe(III)/THA
with predictable selectivity among aliphatic secondary C-H
[4–5]
oxidant.
Fe-based catalytic methods are also particularly
appealing due to the availability, lack of toxicity of this element
and because iron-based reagents are very reactive, capable to
hydroxylate not only 3° C−H groups, but also 2° alkyl sites, thus
complementing existing oxidizing methodologies without the
bonds when H
After optimizing reaction conditions, we investigated the
substrate scope under similar reaction conditions using H
2 2
O is used as a terminal oxidant (Scheme 1).
2 2
O
[6–8]
as a terminal oxidant. A variety of cyclic alkanes are oxidized
with good to excellent yields to ketones (Table 1, entries 1 and
2). Oxidation of trans-decalin shows preferential oxidation at
the secondary site than sterically and more protected tertiary
implication of free-diffused radicals are attempting.
In
general, the catalysts have promising hydroxylation reactivity
[7]
with unactivated tertiary C–H bonds. The challenge remains
to develop facile and high reactive catalytic systems for
secondary C–H bonds, which are less reactive than the tertiary
C–H bonds. Fortunately, some of these unique catalysts were
very recently demonstrated as a powerful synthetic tool in C-H
(Table 1, entry 3). Further on, π-activated C-H bonds, both
tertiary and secondary ones, were also oxidized with good to
excellent conversions and with excellent selectivity (Table 1,
entries 4 - 9). The low yield of 2-benzylpyridine presumably
due to coordination of pyridine to the iron center (Table 1,
entry 10).
Next we examined the effect of electron-withdrawing groups
on the site selectivity of oxidation using simple substrates
(Table 1, entries 11 and 12). The carboxylate group on the
substrate such as 4-methylvaleric acid directed the C–H
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oxidation site towards the remote site (up to four carbons [Fe(THA)
Journal Name
+
Cl]H . The catalyst can also be prepared in situ using
2
away from carboxylic group). A five-membered lactone ring Fe:THA ratio 1:2. .
a
Table 1. Oxidation of substituted aliphatic alkanes
formed in 53% yield, whereas a terminal ester group formed a
ketoester at C as the major product. Surprisingly the absence
4
selectivity
(%):
of directing groups, aliphatic hydrocarbons such as n- octane
and n-decane were oxidized into ketones in a normalized 8:5:1
Total
Main
Time
(h)
Run
Substrate
yield
b
product
(Isolated
c
Yield)
[%]
C
3
:C
shows that C
conditions, than C
oxidation of C
2
:C
4
mixture and remarkable 62-68% combined yields. This
and C are more reactive, under these
. However, a slight preference towards the
2
3
d
1
10
10
86
83
68:(65)
83
4
4
carbon was observed (Table 1, entries 13 and
2
1
4). Very limited examples with similar selectivity are found in
[10,11]
literature.
The results above highlight the substantial
1
0
46
68
67
80
85
90
scope for Fe(III)/THA catalyzed oxidation of alkanes.
d,g
3
Although the main product in these reactions is ketone, which
formally indicates the involvement of freely diffusing carbon-
centered radicals, low alcohol amounts are likely due to over-
oxidation of alcohol intermediates. In fact, monitoring the
oxidation of ethyl benzene under limited oxidant and at room
temperature shows a rise of alcohols via GC-MS. Noteworthy,
peroxides tend decompose in oxidation which complicate
6
98:(61)
99
4
1
0
f
5
mechanistic interpretations. Therefore, the Ph P treatment of
3
f
8
80:(70)
99:85
6
the reaction samples prior GC indicated that the product
[12]
distribution was unchanged.
We further investigated the oxidation of substituted
7
12
7
o
o
cycloalkanes with different 2 and 3 C-H bonds to assist the
selectivity of our iron-based catalyst (Table 2). Various mono
and substituted cyclohexane derivatives were employed in this
study. The reactivity of 1,1-dimethylcyclohexane and tert-
butylcyclohexane were investigated using the same condition
95
95:(91)
8
9
(Table 2 entries 15 and 16). With tert-butylcyclohexane,
8
6
89
91
99:88
oxidation is observed at the C carbons with a 3:1 ratio to the
4
C2 carbons. With 1,1-dimethylcyclohexane, the oxidation
occurs mainly at C4 and C2 carbons with a 2:1 ratio.
Noteworthy, oxidation of the primary carbon is not noted in
any of those substrates. Furthermore, the catalyst shows a
preferential oxidation to the more accessible secondary site
when tertiary C-H bonds are sterically hindered. Nevertheless,
a good preference for tertiary C−H bonds over secondary ones
90:(88)
1
1
0
1
g
1
1
0
0
60
90
59
72
h
1
2
[10]
f,
f,
g
g
was observed with adamantane (Table 2 entry 17).
ratio of tertiary/secondary C-H bond activation ( 9:1) indicates
the involvement of highly selective metal centered oxidant.
A high
13
12
12
60
52
37
35
∼
1
4
[
10]
Interestingly, when we tested 3 mol% of the catalyst for the
oxidation of terpenoid (−)-ambroxide, which contains two
tertiary C−H sites and 14 methylenic sites, the acꢀvated
methylenic C−H bond adjacent to the ether moiety was
preferentially oxidized affording sclareolide in 30% yield (Table
a)
Reaction conditions: substrate 2.0 mmol, iron(III) chloride 5 mol%,
THA 10mol%, H O 6.5 mmol (30% in water), MeCN 1 mL and 60 °C.
2
2
b)
1
The results were based on substrate conversion collected with
H
NMR using dichlorobenzene as an internal standard and GC-MS (all
experiments were repeated at least 3 times) and all products were
based on and identified by comparison of their analytical data with
those of previous reports or commercial materials. Selectivity toward the
main product, isolated yield after purification in
c)
2, entry 19). The catalyst was also applied to oxidize cyclic
a
column
alkenes such as cyclooctene and cyclohexene, were both
found to undergo formation of carbonyl compounds together
with small amount of epoxidation (Table 2, entries 20, 21).
For mechanistic studies, the pre-made complex powder was
analyzed using electrospray ionization mass spectra (ESI-MS),
d)
chromatography. Other products entry 1: 1,2- cycloctanedione(20%) and
1,2-cycloctanediol(13%);
entry3:
1-decalone:15%,
e)
5
%(octahydronaphthalenol and decahydro-2-naphthol Other products
g)
h)
we found 10% lactone. The normalized C
Other products 4% 3-keto-4-methyl pentanoic acid and 4-methyl-3-ene-
pentanoic acid H O 6.5 mmol (30% solution in water) was used as
2 2
oxidant at 80 C, Cat:H O :Substrate 5:360:100.
2
/C
3
/C
4
selectivity ratio (5:8:1).
f)
2
2
o
IR spectroscopy and elemental analysis and all analysis data
III
confirm Fe (THA)
2
Cl as a structure of the complex (see
supporting information). In the ESI-MS spectrum the major
peak at m/z=457.99 corresponds to the protonated complex,
The yellow in-situ prepared catalyst shows no free ligand in
ESI-MS studies, but a prominent ion peak at m/z=457.99
2
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assigned above
A
second prominent peak appears at
Yield [%]b
Entry
Substrate
products yields
2
m/z=493.96 and according to isotope analysis, it is [Fe(THA) -
O
O
+
] where THA coordinates as a neutral ligand to the iron
1
5
(Cl)
2
33
center (Figure 6-7 in SI.). Furthermore, UV-vis analysis of the
complex solution shows dominant maximum at 364 nm which
22%
O
OH
HO
(
is characteristic for Fe complexes and magnetic studies using
III)
36
16
18%
8%
10%
[11]
the Evans’ NMR method show that in the solution the iron
complexes are in a low-spin state with S=1/2 (effective
magnetic moment µeff=1.65 B.M.). Despite of our efforts,
unfortunately all attempts to obtain single crystals of the
complex for X-ray analysis failed.
OH
OH
O
1
1
7
5
9
2%
4%
53%
OAc
OAc
OAc
8
43
The characterized complex solution was monitored after
addition of H O and n-hexane (as a substrate). ESI-MS studies
O
OH
O
10%
33%
2
2
O
O
in the MeCN/H O show disappearance of the above described
2
19
30
Fe complexes and the appearance of new iron species. A peak
at m/z=298.06 is worth to note, as the peak is assigned to di-
3
0%
IV 2+
cationic [Fe (THA) (C H O)(OOH)H] complex, where the
OH
OH
O
O
20
2
6
11
O
73
85
oxidized substrate has coordinated to a high valent iron
peroxo center (Figures 10-12 in SI). Additional complementary
evidence for these species is obtained by in-situ IR
spectroscopy studies of the complex containing solution as a
new band representing the stretching vibration of Fe–O bond
OH
2
5%
28%
7%
O
13%
63%
OH
OH
OH
21
O
6%
16%
a)
-1
[13]
Reaction conditions: substrate 2.0 mmol, iron(III) chloride 5 mol%, THA
0mol%, H 6.5 mmol (30% in water), MeCN 1 mL and temperature 60°C.
The results were collected via H NMR using dichlorobenzene as an internal
standard and GC-MS (all experiments were repeated at least 3 times) and all
products were identified by comparison of their analytical data with those of
previous reports or commercial materials.
gradually accumulates with time at 837 cm (Figure 1). The
UV-vis analysis of the solution shows two new, distinct
absorption maxima at 436 nm and 591 nm which corresponds
1
2 2
O
b)
1
(IV)
to Fe (Figure13 in SI). Furthermore, Evans’ method gave
magnetic moment µeff 6.25 B.M, which has previously been
(
IV)
(V)
assigned for a binuclear Fe -Fe high-spin state complex.
[7,8]
The Evans’ method confirms the UV-vis and ESI-MS results
concerning the presence of high valent iron species but the lack of a
(IV)
(V)
m/z feature corresponding to the Fe -Fe dimer should not be
considered infallible proof of its absence and responsibility for
catalytic activity via O–O bond homolysis mechanism (see below).
1
8
O labeling experiments were used for deducing whether the
peroxide O-O bond cleavage occurs prior to the attack of substrates
by establishing the source of oxygen atoms incorporated into the
[
10]
Figure 1
.
FTIR spectra recorded after the interaction of the in-situ prepared
in a 3 hour interval.
products.
By carrying out isotopic labeling experiments using
complex with H
2
O
2
cyclohexane as a model substrate. First the oxidation reaction was
18
carried out in presence of H2 O, using H O as terminal oxidant.
2
2
6 6 12
The oxidation rate of C D12 is significantly lower relative to C H
The compositions of cyclohexanol were determined from the
1
6
18
relative abundances of the peaks at m/z=100 ( O) and 102 ( O) in indicating that H-atom abstraction is an important component of a
GC-MS. After a 5 min. reaction time 34% of the cyclohexanol rate determining step (see supporting information). The pseudo-
product contains 18O-labeled. Secondly, when the oxidation was
done with H218O2 a 42% of the oxygen atoms in the cyclohexanol
were 18O-labeled. The results support the mechanism where the
iron-oxo species are formed via water-assisted homolysis of O-O
bond, and the carbonyl bond formed via either the oxygen from
-
first-order rate constants (kobs) for c-C
6
H
12 and c-C
and 1.15 × 10 S , respectively. The KIE obtained (kobsH/kobsD)
.9 ±0.4, is in good agreement with the value of 2.2 ±0.4 from
6
D12 are 2.26 × 10
2
-1
-2 -1
S
1
competition experiments (see Figure S3 and Table 3 in SI). A series
of substrates used in excess shows that the catalyst decay follows
[14]
H2O2 or the oxygen from H2O.
first–order kinetics.
substrate concentration in all cases. This permits us to define the
comparable second-order rate constants k (Figures S1-4 in SI).The
(calculated based on the number of equivalent
kobs values were linearly dependent on
We studied the kinetic isotopic effect (KIE) using cyclohexane (c-
C H ) and D -cyclohexane (c-C D ) as substrates to gain further
insight into the mechanism of the reaction and nature of an active
species.
6
12
12
6 12
2
’
linear plot of k
2
target C–H bond of the substrate) against the C–H bond dissociative
energy (BDE) of different alkanes (Figure 2). The kinetic study
strongly suggests that reactions proceed through the iron-oxo
a
Table 2. Aliphatic alkanes substrates for selectivity studies.
[14]
assisted H-atom abstraction mechanism.
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Journal Name
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2
2
1
8
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oxo species are formed via water-assisted heterolysis of O−O
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2
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2
2
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cyclohexane substrates. Because of easy catalyst preparation,
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1
1
Notes and references
1
3
The Research was supported by the Finnish Funding Agency for
Innovation TEKES (project number 40099) and the Graduate
School of Inorganic Materials Chemsitry.
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4
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