Non-heme iron catalysts for the benzylic oxidation: A parallel ligand screening approach

Article abstract of DOI:10.1016/S0040-4039(03)00979-1

Ethylbenzene and 4-ethylanisole were used as model substrates for benzylic oxidation with H₂O₂ or O₂ using a range of non-heme iron catalysts following a parallel ligand screening approach. Effective oxidation was found fo

Full text of DOI:10.1016/S0040-4039(03)00979-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4581–4584
Non-heme iron catalysts for the benzylic oxidation: a parallel
ligand screening approach
Marten Klopstra,a Ronald Hage,b Richard M. Kelloggc and Ben L. Feringaa,*
aDepartment of Organic and Molecular Inorganic Chemistry, Stratingh Institute, University of Groningen, Nijenborgh 4,
9747 AG Groningen, The Netherlands
bUnilever R & D Vlaardingen, Olivier van Noortlaan 120, 3133 AT Vlaardingen, The Netherlands
cSyncom BV, Kadijk 3, 9747 AT Groningen, The Netherlands
Received 20 February 2003; revised 8 April 2003; accepted 16 April 2003
Abstract—Ethylbenzene and 4-ethylanisole were used as model substrates for benzylic oxidation with H2O2 or O2 using a range
of non-heme iron catalysts following a parallel ligand screening approach. Effective oxidation was found for Fe complexes based
on tetra- and pentadentate nitrogen ligands affording the corresponding benzylic alcohol and ketone. © 2003 Published by
Elsevier Science Ltd.
Benzylic oxidation allows the conversion of methylene
and methyl groups flanking an aromatic ring to alco-
hols or ketones.1 Recently catalysts based on Ce and
Mn complexes have been reported to effect benzylic
oxidation.2 Also oxygenases and oxygenase mimics
have been used for benzylic oxidation reactions, e.g.
cytochrome P450 and heme iron complexes were found
to be capable of catalyzing the oxidation of ethylben-
zene with H2O2 to afford a-phenylethanol and ace-
tophenone.3 Also the non-heme iron enzyme, methane
monooxygenase, was used employing oxygen as the
terminal oxidant.4 So far little effort has been devoted
to the use of non-heme iron complexes in the oxidation
of ethylbenzene.5 The development of benign, non-toxic
and catalytic alkane oxidations, based on iron, with
H2O2 and O2 is a major challenge. In this article we
describe novel non-heme iron complexes as effective
catalysts for benzylic oxidation.
dentate (18–20)10 ligands were tested for these oxida-
tions.11 The pentadentate ligands coordinate to the iron
leaving one of the six coordination sites on iron open
for binding of O2 or H2O2.6 With tetradentate ligands
an additional coordination site is open for binding of
the oxidant, which is known to have a significant
influence on the activity and selectivity of the catalyst.12
With one hexadentate or two tridentate ligands on one
iron-core all coordination sites on the iron will be
occupied. For catalytic oxidation by these complexes
one of the iron–ligand bonds should be dissociated
before oxidation can occur.
For a fast screening of the different catalysts a parallel
approach using a Chemspeed ASW 2000 robot was
used. The reactions with hydrogen peroxide were car-
ried out under a nitrogen atmosphere. Each reaction
vessel was charged with 0.9 mL of a stock solution
containing 1.75 mmol of the substrate in acetonitrile.
Next, a solution of 1.75 mmol of the catalyst in 0.6 mL
of acetonitrile was added. The reaction was started by
addition of 87.5 mmol of 30% hydrogen peroxide dis-
solved in 0.5 mL of acetonitrile. The solution was
stirred under vortex (500 rpm) at 30°C for 3.5 h and
then quenched with 115 mg of triphenylphosphine in 2
A series of non-heme iron complexes was tested for the
oxidation of ethylbenzene and 4-ethylanisole with both
H2O2 and O2 as terminal oxidant (Eq. (1)). The struc-
tures of the ligands employed are shown in Figure 1.
Most of these complexes are already known and well-
characterized.5–10 Complexes with pentadentate (1–7,
9),6,7 hexadentate (8),8 tetradentate (10–17),6,9 and tri-
(1)
Keywords: benzylic oxidation; catalysis; non-heme iron; molecular oxygen.
* Corresponding author. Tel.: +31-050-3634235; fax: +31-050-3634296; e-mail: feringa@chem.rug.nl
0040-4039/03/$ - see front matter © 2003 Published by Elsevier Science Ltd.
doi:10.1016/S0040-4039(03)00979-1

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M. Klopstra et al. / Tetrahedron Letters 44 (2003) 4581–4584
Figure 1. Non-heme ligands used for the iron complexes.
O2 as the oxidant for the benzylic oxidation of ethyl-
benzene a lower activity was found in all cases. The
major product was found to be the ketone instead of
the alcohol. To enhance the conversion the reaction
temperature was increased from 30 to 80°C. The results
are shown in Table 2. The catalytic activity was
increased drastically in almost all cases. The best results
were found for the Fe complexes of the tetradentate
ligands 10 and 11. For the complex of 10, up to 54
mmol of the alcohol and up to 107 mmol of the ketone
were obtained. Also the complexes of the tetradentate
ligand 12 and the pentadentate ligands 1, 2 and 6
showed enhanced turnover numbers. Only with the
imine 15 was a lower activity found at 80°C. This
probably arises from degradation of the catalyst at this
temperature. Again, in all cases the ketone was found
to be the major product with an A/K ratio of 0.5 to 1.0.
Also benzaldehyde was found to be an oxidation
product with up to 56 mmol, whereas at 30°C only
traces of benzaldehyde were observed. The formation
of benzaldehyde can be explained by degradation of
1-phenylethyl hydroperoxide, which might be formed
during the reaction (vide supra).3
mL of acetonitrile. Aliquots were taken from the reac-
tion mixture and analyzed by GC. For the reactions
with oxygen as the oxidant, the reaction vessels were
put under an oxygen atmosphere before addition of the
reagents. In this case the peroxide solution was substi-
tuted for 0.5 mL of acetonitrile. The reactions were
stirred under vortex (1000 rpm) at 30°C overnight and
subsequently quenched with triphenylphosphine. The
results of the oxidations with H2O2 and O2 are summa-
rized in Table 1.
In most cases catalytic activity in the benzylic oxidation
of ethylbenzene was observed, affording both the alco-
hol and ketone. However, some of the catalysts gave
significant higher turnover numbers. For the oxidation
of ethylbenzene with hydrogen peroxide the alcohol
was normally obtained as the major product with an
alcohol/ketone (A/K) ratio of 1.1–3.2. The highest
yields were obtained with the complexes of the penta-
dentate ligands 1, 3, 6, and 7. The most active com-
plexes with tetradentate ligands were derived from the
imines 13 and 15. In the case of ethylanisole as a
substrate, with an electron-donating methoxy group at
the para-position, yields were generally higher. The
highest yields were found for the complexes of the
pentadentate ligands 1, 6, 9, and the tetradentate lig-
ands 13, 14, and 15. For ethylanisole the complexes of
the imines also showed a high A/K ratio of 5.6–6.1. The
complexes of the tridentate ligands showed low or
complete lack of activity for both substrates. On using
The difference in A/K ratios between oxidation with
H2O2 and O2 is indicative of a different mechanism for
the different oxidants. The formation of both alcohol
and ketone with an A/K ratio of approximately 1 in the
O2 oxidation and the formation of benzaldehyde with
O2 are indicative of an autoxidation mechanism, in

M. Klopstra et al. / Tetrahedron Letters 44 (2003) 4581–4584
4583
Table 1. Catalytic activity of non-heme iron complexes in benzylic oxidation at 30°C expressed as mmol yield from 1.75
mmol of substrate
Catalyst
Ethylbenzene H2O2
Ketone
Ethylbenzene O2
Ketone
Ethylanisole H2O2
Alcohol Ketone
Alcohol
Alcohol
Blank
1
2
3
4
5
6
7
8
1.8
16.5
10.5
15.6
6.7
0
4.7
8.4
7.7
7.5
6.5
6.1
7.4
0.9
4.6
6.5
6.8
6.0
7.5
2.6
2.5
2.8
3.5
2.8
1.8
5.3
2.8
0.5
11.4
1.6
10.3
5.3
1.8
3.7
2.3
10.7
4.9
12.6
12.3
13.0
7.4
7.5
7.5
8.9
1.2
0.5
11.0
8.2
0
32.4
7.2
9.5
9.8
7.7
26.1
9.5
0
9.3
3.3
11.9
4.6
2.5
6.3
15.9
6.7
4.4
4.2
4.0
5.4
4.0
3.7
3.7
12.1
1.2
6.3
2.3
1.2
18.0
3.2
3.7
5.3
2.1
9.6
2.3
1.6
20.0
11.6
3.5
4.9
4.8
4.8
4.0
13.8
0
6.7
14.7
24.7
7.5
5.6
6.7
2.8
8.9
10.7
6.1
10.7
7.0
3.2
9
25.4
17.2
5.8
14.7
24.7
26.6
23.3
18.6
1.4
10
11
12
13
14
15
16
17
18
19
20
0.7
9.1
8.1
2.1
1.2
1.2
1.2
0
3.9
0
Table 2. Catalytic activity of non-heme iron complexes
with O2 in mmol at 80°C expressed as mmol yield from
1.75 mmol of ethylbenzene
In conclusion, we have discovered that a number of
non-heme iron complexes are capable of benzylic oxida-
tion both with H2O2 and O2. In oxidations with O2 the
most active catalysts are the complexes derived from
the pentadentate ligands 1 and 7 and the tetradentate
ligands 10 and 11, and with ethylbenzene at 80°C up to
107 mmol was obtained. With H2O2 the most active
catalysts are the complexes of the pentadentate ligands
1 and 6 and of the imines 13, 14, and 15. Up to 25 mmol
alcohol formation was observed. Using the imine lig-
ands the highest A/K ratios, up to 6 for ethylanisole,
were reached. The alcohol was formed as the major
product by the use of H2O2 and the ketone by O2, the
latter mainly resulting from a catalytic autoxidation
mechanism.
Catalyst
Alcohol
Ketone
Benzaldehyde
Blank
1
2
3.5
65.1
54.8
39.4
53.6
43.4
40.8
0.7
0.4
83.5
53.2
26.4
107.1
90.5
39.4
1.8
0.2
59.3
48.0
7.4
56.0
54.3
32.6
0.4
6
10
11
12
15
which the Fe catalyst reacts with 1-phenylethyl
hydroperoxide to afford the observed products.3 How-
ever, in the oxidations with H2O2 this will not be the
only source of product formation as indicated by con-
siderably higher A/K ratios. Most of the catalysts are
already known to form an active species with H2O2 that
could participate in oxidation reactions.7,9,12 To obtain
further insight into the origin of ketone formation,
1-phenylethyl alcohol was used as a substrate with the
complexes of 2, 10, 12, and 15 at 30°C. With O2 as the
oxidant almost no ketone was formed, indicating that
the ketone is directly formed from ethylbenzene and
not from oxidation of the alcohol. This is in agreement
with the expected autoxidation mechanism with O2.
With H2O2 some of the alcohol was converted into the
ketone. In this case, at least part of the ketone formed
during the oxidation of ethylbenzene will originate
from the corresponding alcohol formed during the reac-
tion. This can be due to an iron-oxo species formed
from the iron complexes with H2O2.
Acknowledgements
Financial support from NRSC-Catalysis and the
Netherlands Foundation for Scientific Research NWO-
CW is gratefully acknowledged.
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