A putative monooxygenase mimic which functions via well-disguised free radical chemistry

Article abstract of DOI:10.1021/ja963627j

The hydroxylation of cycloalkanes at 25°C by the syringe pump addition of tert-alkyl hydroperoxides (10 and 1 equiv based on catalyst) to deoxygenated acetonitrile containing cycloalkanes (0.64 M) and 0.61 mM of the catalyst, [Fem(III)₂O(TPA)₂(H₂O)₂]⁴⁺, is demonstrated to be a reaction which involves freely diffusing cycloalkyl radicals, i.e., free alkyl radicals.

Full text of DOI:10.1021/ja963627j

10594
J. Am. Chem. Soc. 1997, 119, 10594-10598
A Putative Monooxygenase Mimic Which Functions via
Well-Disguised Free Radical Chemistry1
Philip A. MacFaul,*,†,2 K. U. Ingold,*,† D. D. M. Wayner,† and Lawrence Que, Jr.‡
Contribution from the Steacie Institute for Molecular Sciences, National Research Council of
Canada, Ottawa, Ontario, Canada K1A 0R6, and the Department of Chemistry, UniVersity of
Minnesota, Minneapolis, Minnesota 55455
ReceiVed October 17, 1996. ReVised Manuscript ReceiVed August 11, 1997X
Abstract: The hydroxylation of cycloalkanes at 25 °C by the syringe pump addition of tert-alkyl hydroperoxides
(10 and 1 equiv based on catalyst) to deoxygenated acetonitrile containing cycloalkanes (0.64 M) and 0.61 mM of
the catalyst, [FeIII2O(TPA)2(H2O)2]4+, is demonstrated to be a reaction which involves freely diffusing cycloalkyl
radicals, i.e., free alkyl radicals.
2Me3COO• f 2Me3CO• + O2
Me3CO• + c-CnH2n f Me3COH + c-CnH•2n-1
c-CnH•2n-1 + O2 f c-CnH2n-1OO•
(7)
(8)
(9)
In recent years there have been many attempts to mimic the
chemistry of monooxygenases such as cytochrome P450 and
methane monooxygenase which can oxidize saturated hydro-
carbons by processes which do not involve free (i.e., freely
diffusing) radicals.3 Following the lead provided by these
enzymes, (ferric) iron has generally been chosen as the
2 c-CnH2n-1OO• f c-CnH2n-1OH + c-CnH2n-2dO + O2
(10)
enzyme
RH + O2
8 ROH + H2O
(1)
+2H+ + 2e-
c-CnH•2n-1 (c-CnH2n-1OO•) + Me3COO• f
c-CnH2n-1OOCMe2 (+O2) (11)
catalytically active metal and two-electron-reduced oxygen, in
the form of H2O2 or tert-butyl hydroperoxide (TBHP), has been
utilized (to avoid the requirement for a sacrificial reductant).
However, FeIII/TBHP systems may not undergo the desired
heterolysis to give a high-valent iron-oxo species (formally
FeVdO) as is believed to occur when monooxygenases react
with hydroperoxides. Instead, a homolysis may occur to form
The oxidation of an alkane to a mixture of alcohol, ketone, and
the mixed peroxide (shown in bold face in the scheme) is a
very clear indication that free-radical chemistry has occurred.
Unfortunately, this signature has all too frequently been ignored.
2-Methyl-1-phenyl-2-propyl hydroperoxide (MPPH) is a
probe capable of distinguishing between free alkoxyl radical
chemistry and radical-free (enzyme mimetic) chemistry in iron/
tert-alkyl hydroperoxide/hydrocarbon oxidation systems.4 This
probe relies on the fact that if the corresponding tert-alkoxyl
radical were formed and diffused from its site of formation into
the bulk solution it would undergo far too rapid a â-scission
(kâ ∼ 2 × 108 s-1) for it to abstract a hydrogen atom from a
FeIII + Me3COOH
9
het8 FeVdO + Me3COH
(2)
free tert-butoxyl radicals which then dominate the subsequent
chemistry (see Scheme 1).
Scheme 1
Me3COOH + (XFeIII) a Me3COO(FeIII) + XH (3)
kâ
•
f PhCH2CMe2O• 98 PhCH2 + Me2CO
PhCH CMe OOH
2
2
(MPPH)
+
(12)
Me3COO(FeIII) f Me3CO• + Od(FeIV) {+H } HO-(FeIV)
-H+
(4)
saturated hydrocarbon, i.e., the equivalent of reaction 8 cannot
occur. MPPH has been employed at the NRC in Ottawa to
demonstrate that cycloalkane oxidations using TBHP and two
tris(2-pyridinylmethyl)amine (TPA) complexes,5 [FeIIICl2-
(TPA)]+ and [FeIII2O(OAc)(TPA)2]3+, and a FeIII picolinate/
pyridine complex6 all occurred via straighforward free radical
Me3COOH + Od(FeIV) f Me3COO• + HO-(FeIII) (5)
Me3CO• + Me3COOH f Me3COH + Me3COO• (6)
(4) Arends, I. W. C. E.; Ingold, K. U.; Wayner, D. D. M. J. Am. Chem.
Soc. 1995, 117, 4710-4711.
† SIMS, NRC.
‡ University of Minnesota.
(5) (a) Leising, R. A.; Norman, R. E.; Que, L., Jr. Inorg. Chem. 1990,
29, 2553-2555. (b) Leising, R. A.; Zang, Y.; Que, L., Jr. J. Am. Chem.
Soc. 1991, 113, 8555-8557. (c) Kojima, T.; Leising, R. A.; Yan, S.; Que,
L., Jr. J. Am. Chem. Soc. 1993, 115, 11328-11335. (d) Leising, R. A.;
Kim, J.; Pe´rez, M. A.; Que, L., Jr. J. Am. Chem. Soc. 1993, 115, 9524-
9530.
X Abstract published in AdVance ACS Abstracts, September 15, 1997.
(1) Issued as NRCC No. 40837.
(2) NRCC Research Associate 1995-97.
(3) For the most recent discussion of the mechanism(s) of such reactions,
see: Newcomb, M.; Le Tadic-Biadatti, M.-H.; Chestney, D. L.; Roberts,
E. S.; Hollenberg, P. F. J. Am. Chem. Soc. 1995, 117, 12085-12091.
(6) Barton, D. H. R.; Chavasiri, W. Tetrahedron 1994, 50, 19-30.
S0002-7863(96)03627-X CCC: $14.00 Published 1997 by the American Chemical Society

Monooxygenase Mimic
J. Am. Chem. Soc., Vol. 119, No. 44, 1997 10595
Table 1. Product Yields (in equiv, Based on Catalyst)a after 10
min Oxidation of Cycloalkanes (0.64 M) by tert-Alkyl
chemistry.4,7-9 This work led to both implicit10 and explicit11
suggestions that MPPH is not “a competent substitute” for TBHP
(apparently because it is particularly subject to, and hence,
induces free radical chemistry). However, MPPH has very
recently been demonstrated to be a competent substitute for
TBHP in hydrocarbon oxidations which are genuine two electron
processes.12
Hydroperoxides (6.1 mM) Catalyzed by [FeIII2O(TPA)2(H2O)2]4+ (1,
0.61 mM) at 25 °C in Acetonitrile Prepurged with Argona
TBHP
syringe
CnH2n-1OO-
CMe3
entry
alkane
pumped CnH2n-1OH CnH2n-2O
The question as to whether or not simple (i.e., nonenzyme)
FeIII/tert-alkyl hydroperoxide systems oxidize alkanes via freely
diffusing alkoxyl radicals or via a metal-based intermediate was
reopened in 1996 with work on a new iron TPA catalyst,
[FeIII2O(TPA)2(H2O)2]4+ (1).11 When 10 equiv (based on 1)
of TBHP was added continuously by syringe pump to cyclo-
hexane in acetonitrile at 25 °C under argon, cyclohexanol was
the only product.11 This was an exciting result because
cyclohexanol would also be the sole product expected from a
genuine monooxygenase mimic. On the other hand, the syringe
pump addition of 10 equiv of MPPH gave no cyclohexane
oxidation products.11,13 To some of us this implied that the
1/TBHP couple, like other FeIII(TPA)/TBHP couples,4,8,9 oxi-
dized alkanes by a free-radical mechanism, i.e., via freely
diffusing tert-butoxyl radicals. Thus, iron/alkyl hydroperoxide
chemistry was faced with an intriguing mechanistic conun-
drum: does catalyst 1 do radical-free or free-radical chemistry?
1
2
3
4
5
6
7
c-C6H12
c-C6H12
c-C6H12
c-C6H12
c-C8H16
c-C8H16
c-C8H16
yes
2.6; 3.6
4.0
0.5; 0.9
0; 0
2.4; 2.8
0.9; 0.9
1.1; 0.8
0; 0
0
0; 0
0; 0
0; 0
0.4; tr
0.3; 0.5
0
1.0; 1.8
2.1; 2.3
tr; tr
0.2; tr
1.4; 0.9
b
yes
dropc
no
yesd
dropc
no
1.0; 0.8
MPPH
syringe
PhCH2OO-
entry
alkane
pumped PhCH2OH (PhCH2)2 CMe2CH2Ph
e
b
e
e
8
9
10
11
c-C8H16
c-C6H12
c-C8H16
c-C8H16
yes
yes
dropc
no
3.0; 3.0
not reported
0.9; 0.6
tr; tr
0; 0
tr; 0
tr; tr
0.2; 0.2
0.2; tr
1.0; 0.9
aReactions were carried out under argon. Yields are from duplicate
runs with the first number referring to the same reaction; tr ) trace,
too small to quantify. All analyses were by GC-FID. b From ref 11.
c Dropwise addition of TBHP. d Cyclooctene (0.1 equiv) was also
formed in both runs. e There were no cyclooctane-derived products and
no benzaldehyde.
Results
and 0.35 equiv). Finally, and in agreement with the earlier
report (entry 9),11 the 1/10 equiv of MPPH catalyst system gave
no cycloalkane oxidation products. However, products were
detected and they were clearly derived from benzyl radicals
(entries 8, 10, and 11), the main product under syringe pump
conditions being benzyl alcohol (3.0 equiv, entry 8). Interest-
ingly, the 1/1 equiv of MPPH catalyst system gave only bibenzyl
(0.1 and 0.15 equiv, i.e., 0.2 and 0.3 equiv of benzyl radicals)
and no benzyl alcohol. We attribute the difference in product
type between the 1 equiv of TBHP and 1 equiv of MPPH
experiments to the lower reactivity of the resonance-stabilized
benzyl radicals.
To distinguish unequiVocally between free-radical and radical-
free processes, the following critical experiments were designed
and the reactions were carried out under (otherwise) normal
conditions, viz., 0.64 M cycloalkane(s) and 0.61 mM 1 in
acetonitrile preflushed with argon. The TBHP (6.1 mM, 10
equiv in argon-flushed acetonitrile) was added by syringe pump
directly into the stirred solution over the 10 min course of a
reaction which was run at 25 °C under argon.
1. Addition of a low concentration of CCl3Br (30.5 mM) to
a cyclohexane oxidation gave only cyclohexyl bromide (3.4 and
3.6 equiv in duplicate runs). A similar experiment with
cyclooctane gave only cyclooctyl bromide (2.5 and 2.9 equiv).
(Control experiments carried out in the absence of TBHP gave
no cycloalkyl bromides.) Dropwise addition of the TBHP to a
cyclohexane oxidation carried out in the presence of 30.5 mM
CCl3Br also gave only cyclohexyl bromide (3.9 and 4.1 equiv).
Even if the trapping of alkyl radicals by CCl3Br is diffusion-
controlled, the time scale for bromine atom transfer is about 2
orders of magnitude slower than the time scale for the reaction
of a caged radical pair. Thus CCl3Br cannot capture cycloalkyl
radicals while they are still in the solvent cage in which they
were formed. This result demonstrates that the overall process
yields freely diffusing cycloalkyl radicals exclusiVely.
The experimental conditions and results with 10 equiv of
TBHP and 10 equiv of MPPH14 are given in Table 1 together
with the original results.11 With cyclohexane and syringe pump
addition of 10 equiv of TBHP directly into the solution
containing the other reagents, only alcohol (4.0 equiv) was
observed originally (entry 2).11 The present results (entry 1)
using the same experimental procedure, i.e., syringe needle
below the surface of the solution containing the other reagents
combined with vigorous stirring, essentially confirm the earlier
report although slightly less alcohol was obtained. However,
a small amount of the mixed peroxide was also detected, which
is a sign that free-radical chemistry may be occurring. Interest-
ingly, when the TBHP solution was added dropwise at the same
rate (by holding the needle from the syringe pump over the
solution), the mixed peroxide became the major product (entry
3), and when the TBHP was added “all at once”, the mixed
peroxide became the only product (entry 4). Similar results
and product yields were obtained using cyclooctane as substrate
(entries 5-7). When cyclohexane was oxidized with 1 equiv
of TBHP added by syringe pump, only cyclohexanol was
observed originally (0.55 equiv)11 and in the present work (0.43
(7) Snelgrove, D. W.; MacFaul, P. A.; Ingold, K. U.; Wayner, D. D. M.
Tetrahedron Lett. 1996, 37, 823-826.
(8) Arends, I. W. C. E.; MacFaul, P. A.; Snelgrove, D. W.; Ingold, K.
U.; Wayner, D. D. M. NATO ASI Conf. 1996.
(9) MacFaul, P. A.; Arends, I. W. C. E.; Ingold, K. U.; Wayner, D. D.
M. J. Chem. Soc., Perkin Trans. 2 1997, 135-145.
(10) Traylor, T. G.; Kim, C.; Richards, J. L.; Xu, F.; Perrin, C. L. J.
Am. Chem. Soc. 1995, 117, 3468-3474.
(11) Kim, J.; Harrison, R. G.; Kim, C.; Que, L., Jr. J. Am. Chem. Soc.
1996, 118, 4373-4379.
(12) With two TiIV on MCM-41 silica catalysts MPPH was found to be
an even better alkene epoxidizing agent than TBHP, see: Oldroyd, R. D.;
Thomas, J. M.; Maschmeyer, T.; MacFaul, P. A.; Snelgrove, D. W.; Ingold,
K. U.; Wayner, D. D. M. Angew. Chem., Int. Ed. Engl. 1996, 35, 2787-
2790.
(13) The presence or absence of the products expected from any benzyl
radicals produced via reaction 12 was not remarked upon.11
(14) Use of 140 equiv of TBHP gave the usual free-radical-derived
products (alcohol, ketone, mixed peroxide plus traces of olefin); similarly
140 equiv of MPPH gave the usual benzyl radical-derived products (benzyl
alcohol, benzaldehyde, bibenzyl, and mixed peroxide): see Supporting
Information. Cyclooctane was used in all the MPPH experiments because
it is more reactive than cyclohexane.7-9
c-CnH•2n-1 + CCl3Br f c-CnH2n-1Br + •CCl3 (13)
2. In duplicate competitive oxidations with [c-C8H16] )
[c-C6H12] ) 0.32 M in the presence of 30.5 mM CCl3Br, only

10596 J. Am. Chem. Soc., Vol. 119, No. 44, 1997
MacFaul et al.
Table 2. Product Ratios from Competitive Oxidation of Cycloalkanes (0.32 + 0.32 M) by 1 (0.61 mM) and tert-Butyl Hydroperoxide (6.1
mM) under Argon or Di-tert-butyl Hyponitrite (BONNOB) under Vacuum in Acetonitrile at 25 °Ca
entry
competition
conditions
products
ratio
1
2
3
4
5
6
7
8
9
c-C8H16/c-C6H12
c-C8H16/c-C6H12
c-C8H16/c-C6H12
c-C6H12/c-C6D12
c-C6H12/c-C6D12
c-C6H12/c-C6D12
c-C6H12/c-C6D12
c-C6H12/c-C6D12
c-C6H12/c-C6D12
1 + TBHP + CCl3Br
BONNOB + CCl3Br
1 + TBHP
c-C8H15Br/c-C6H11Br
c-C8H15Br/c-C6H11Br
c-C8H15OX/c-C6H11OXe
c-C6H11Br/c-C6D11Br
c-C6H11Br/c-C6D11Br
c-C6H11OX/c-C6D11OXe
c-C6H11OX/c-C6D11OXe
c-C6H11OH/c-C6D11OH
c-C6H11OH/c-C6D11OH
2.05:1b,c
2.2:1d
2.05:1b
4.35:1b,f
4.9:1d
1 + TBHP + CCl3Br
BONNOB + CCl3Br
1 + TBHP
4.5:1b,g
6.55:1b,h
6.3:1b,i,j
5.7:1b,k,l
1 + TBHP
1 + TBHP
1 + TBHP
a TBHP in argon-purged acetonitrile was added via syringe pump over the 10 min course of the reaction to a stirred argon-purged acetonitrile
solution of the reagents. BONNOB was added all-at-once, and the reagents were degassed by the freeze-pump-thaw method, following which
they were sealed under vacuum and the reactions were allowed to proceed for 5 days. All analyses were by GC-FID except for the extra data given
in the footnotes. b Duplicate runs. c Dropwise addition of TBHP gave a mean ratio of 2.0:1. d Single run. e Mainly X ) H plus traces of X )
Me3CO. f Dropwise addition of TBHP gave a mean ratio of 4.7:1. g Dropwise addition of TBHP gave a mean ratio of 6.0:1. h GC-MS/SIM mean
ratio for alcohols only ) 6.0. i Using catalyst prepared at the University of Minnesota. j GC-MS/SIM mean ratio ) 5.7. k Competitive oxidation
of c-C6H12 and c-C6D12 in a 1:5 molar ratio. l GC-MS/SIM mean ratio ) 6.5.
the two cycloalkyl bromides were produced (total 4.1 and 3.6
equiv) with [c-C8H15Br]/[c-C6H11Br] ) 1.9 and 2.2 (Table 2,
entry 1). Triplicate analogous competitive experiments with
dropwise addition of the TBHP gave only the two bromides
(total yields 3.9-5.6 equiv) with [c-C8H15Br]/[c-C6H11Br] )
1.8, 2.1, and 2.1. All of these values are consistent with the
independently measured rate constant ratio of 2.2:1.0 for
hydrogen atom abstraction from c-C8H16 and c-C6H12 by
authentic tert-butoxyl radicals (Table 2, entry 2).15
3. Duplicate analogous competitive experiments in the
absence of CCl3Br gave ∑c-C8H16 oxidation products ) 1.64
and 2.35 equiv and ∑c-C6H12 oxidation products ) 0.78 and
1.19 equiv. These data yield C8/C6 reactivity ratios of 2.1 and
2.0 (Table 2, entry 3). These values are in satisfactory
agreement with the reactivity ratio of 2.2 obtained with authentic
tert-butoxyl radicals (Table 2, entry 2).
4. The magnitude of the c-C6H12/c-C6D12 deuterium kinetic
isotope effect (DKIE) in FeIII(TPA)/TBHP oxidations has been
employed as a probe of reaction mechanism.5c,d,11 In duplicate
competitive oxidations with [c-C6H12] ) [c-C6D12] ) 0.32 M
in the presence of 30.5 mM CCl3Br only, the two bromides
were formed (total 4.5 and 3.4 equiv) and the calculated DKIE’s
were 4.3 and 4.4 (Table 2, entry 4). Dropwise addition of the
TBHP gave, in duplicate experiments, total bromide yields of
2.8 and 2.3 equiv and DKIE’s of 4.6 and 4.8. The independently
measured DKIE using authentic tert-butoxyl radicals was 4.9
(Table 2, entry 5).16
5. Duplicate analogous competitive experiments in the
absence of CCl3Br gave (∑c-C6H12 oxidation products)/(∑c-
C6D12 oxidation products) ) 4.95 and 4.05 (Table 2, entry 6).
Duplicate runs with dropwise addition of the TBHP gave ratios
of 5.65 and 6.33. These DKIE’s (overall mean 5.25) are in
excellent agreement with the (expected) DKIE of 4.9 for
authentic tert-butoxyl radicals (Table 2, entry 5), but they are
considerably smaller than the DKIE of ∼10 originally reported11
although the product yields are similar. Additional duplicate
sets of experiments were performed using both a sample of
catalyst 1 prepared at the NRC in Ottawa (Table 2, entry 7)
and a sample of 1 prepared in Minnesota (Table 2, entry 8).
Analyses by GC-FID of all four samples gave (∑c-C6H12
oxidation products)/(∑c-C6D12 oxidation products) values of 4.9
and 8.2 (NRC’s catalyst) and 6.4 and 6.2 (Minnesota’s catalyst),
overall mean 6.43. To reduce the rather large errors associated
with the GC-FID. analyses of the small yields of the deuterated
products the samples were also analyzed by GC-MS. operated
in the single ion monitoring (GC-MS/SIM.) mode for m/z 82
and 92, i.e., the dehydration products of the nondeuterated and
the deuterated alcohols. After a correction for the deuterium
isotope effect of the dehydration (1.25), the DKIE values for
alcohol formation were calculated to be 5.0 and 6.9 (NRC’s
catalyst) and 6.2 and 5.1 (Minnesota’s catalyst), overall mean
5.8.
6. The relatively small yield of the deuterated alcohol makes
the measurement of the c-C6H11OH/c-C6D11OH ratio rather
imprecise by any method; we therefore carried out a competitive
oxidation of c-C6D12 and c-C6H12 in a 5:1 ratio. If the correct
DKIE is around 5 this should yield GC peaks for the deuterated
and nondeuterated alcohols of similar size which will reduce
the errors arising from the measurement of small peak areas
relative to much larger peak areas (as in the 1:1 c-C6H12/c-
C6D12 oxidations). GC-FID and GC-MS/SIM analyses of
duplicate experiments gave peaks of similar size. The calculated
DKIE values for alcohol formation by GC-FID were 5.5 and
5.9 (Table 2, entry 9), and by GC-MS/SIM, 6.4 and 6.6, overall
mean 6.1.
7. With cyclohexene (0.68 M) as the substrate, the syringe
pump addition of 10 equiv of TBHP gave no cyclohexene oxide.
This result stands in sharp contrast to genuine two-electron-
oxidation catalysts which readily epoxidize cyclohexene using
TBHP in acetonitrile at 25 °C.12 The failure of other FeIII(TPA)
catalysts to epoxidize cyclohexene has been observed previously.5c
Mechanistic Considerations
We have demonstrated that the addition, even by syringe
pump, of 10 equiv of a tert-alkyl hydroperoxide to 1 in
acetonitrile at 25 °C generates the corresponding freely diffusing
tert-alkoxyl radical which is the agent responsible for product
formation. In the case of MPPH these products are derived
from the benzyl radical formed in reaction 12. With 10 equiv
of TBHP, all that remains to be explained is why different
mixtures of products are obtained by syringe pump and by
dropwise or all-in-at-once addition of the hydroperoxide and
why none of these product slates resembles those found with
140 equiv of TBHP (see Supporting Information).
(15) Determined in a competitive experiment carried out in the presence
of CCl3Br by measuring, the relative yields of c-C8H15Br and c-C6H11Br
formed in degassed acetonitrile using tert-butoxyl radicals generated over
5 days at 25 °C by the thermal decomposition of di-tert-butyl hyponitrite.
(16) A competitive experiment carried out over 5 days in the presence
of CCl3Br in degassed acetonitrile using di-tert-butyl hyponitrite at 25 °C
as the tert-butoxyl source and measurement of the relative yields of c-C6H11-
Br and c-C6D11Br gave a DKIE ) 4.9. Absolute rate measurements by
laser flash photolysis using the cumyloxyl radical gave a DKIE ) 5.1.
The explanation is simple once it is recognized that there is
virtually no oxygen present at the beginning of an experiment
and, furthermore, that very little oxygen will be formed (reaction

Monooxygenase Mimic
J. Am. Chem. Soc., Vol. 119, No. 44, 1997 10597
7, Scheme 1) as the reaction progresses (see Scheme 2). With
syringe pump addition the TBHP concentration will always be
very low. As a consequence, the formation of tert-butylperoxyl
radicals via reactions 5 or 6 will be less important than for 10
equiv of TBHP added all-at-once and very much less important
than for 140 equiv of TBHP (whether added by syringe pump
or all-at-once). With reaction 9 “shut down” the cycloalkyl
radicals are forced to react with the most available reagent.17
For the all-at-once procedure this will be the tert-butylperoxyl
radicals and, hence, the mixed peroxide (reaction 11′)18 will be
the major (c-C8H16) or sole (c-C6H12) product. Even for the
dropwise addition of TBHP by syringe pump there is a reduction
in the yield of alcohol and an enhancement in the yield of mixed
peroxide (and for cyclooctane, ketone) relative to the normal
syringe pump addition (see Table 1). For dropwise addition, it
is clear that relatively high local concentrations of TBHP and
tert-butylperoxyl radicals are present. In the virtual absence
of oxygen and tert-butylperoxyl radicals the only available trap
for the cycloalkyl radicals is the original catalyst, 1, and its
likely products, viz., HO-(FeIV) and HO-(FeIII) formed in
reactions 4 and 5, respectively. A simple HO-ligand transfer
with one of these three iron species might yield alcohol (which
is by far the major product under syringe pump conditions for
both cycloalkanes). To check on the possibility of a direct
reaction of cyclohexyl radicals with 1, these radicals were
generated by the thermal decomposition of (c-C6H11CO2)2 in
degassed acetonitrile at 25 °C in the presence of 1. No
cyclohexanol could be detected. We suggest, therefore, that
the most likely trap for the cycloalkyl radicals is HO-(FeIV)
(see reaction 14, Scheme 2).
quantities of TBHP involve freely diffusing radicals even when
the hydroperoxide is added by syringe pump. It must, however,
be admitted that the radical nature of these reactions was
extremely well disguised. Thus the conundrum presented by
the apparently contradictory results originally reported11 and
herein confirmed when using 1 and adding TBHP or MPPH by
syringe pump is resolved. To our knowledge, no simple (i.e.,
nonenzyme) complex of FeIII has been described which really
can use tert-alkyl hydroperoxides to mimic the monooxygenase-
catalyzed oxidation of alkanes. We hope that any future claim
for such an important scientific breakthrough will have been
subjected to all of the tests described herein and in earlier
publications.4,7-9
Experimental Section
Materials. [FeIII2O(TPA)2(H2O)2]4+ (1),19 di-tert-butyl hyponitrite
(BONNOB),20 2-methyl-1-phenyl-2-propyl hydroperoxide (MPPH),21
and dicyclohexylformyl peroxide22 (1H NMR (200 MHz, CDCl3): δ
1.10-1.55 (12 H, m), δ 1.60-2.05 (8H, m), and δ 1.25 (2H, m)) were
all prepared according to referenced literature procedures. tert-Butyl
hydroperoxide (90% Aldrich) was extracted into ether and dried with
sodium sulfate, and the solvent was removed and the pure, dried
material made up to the required concentration in acetonitrile (Omni-
solve), which itself was distilled prior to use. The (CH3)3CO18OH was
synthesized by Dr. E. H. Appelman.23 All other chemicals were
commercially available and used as received.
Instrumentation. UV-visible spectra were recorded on a Varian
Cary 3 spectrophotometer. 1H NMR were recorded on a Bruker AM200
spectrometer. GC analyses were performed on a Hewlett-Packard 5890
gas chromatograph using a HP methyl silicone Ultra 1 column. Data
analyses were performed using a Hewlett-Packard chemstation. GC-
MS analyses were carried out on a Hewlett-Packard 5890 gas
chromatograph connected to a 5970 series mass selective detector
operated in the single ion monitoring mode. Liquid chromatography
was performed on a HP 1090 liquid chromatograph equipped with a
reverse phase ODS Hypersil column using a water/methanol solvent
system. Syringe pump additions were achieved using a Sage instru-
ments 341A syringe pump.
Cycloalkane Oxidations. Cyclooctane oxidations by 1 with Me3-
COOH and MPPH were performed by adding the cyclooctane to a
solution of the catalyst in acetonitrile and deoxygenating the solution
by purging the solution with oxygen-free argon for 10 min. In the
case of the cyclohexanes, a known volume of the deoxygenated
cycloalkane was added to the deoxygenated catalyst solution. A known
volume of deoxygenated oxidant solution was then added all at once
to start the reaction or delivered via syringe pump over the course of
the reaction (10 min). The reaction product mixtures were quenched
with excess triphenylphosphine to reduce all unreacted hydroperoxides
to the corresponding alcohols. 1,4-Dibromobenzene was then added
as an internal standard, and either the solution was combined with an
equal volume of aqueous sodium sulfate, followed by extraction into
diethyl ether and injection of the ethereal solution onto the GC column,
or the acetonitrile solutions were analyzed directly by GC. Both
methods gave similar results. Response factors for the GC-FID and
the GC-MS single ion monitoring (m/z 82 and 92) analyses were
calculated using authentic samples of the alcohols. Injection of a 1:1
ratio of c-C6H11OH:c-C6D11OH gave 1:1 ratio of peak areas in the GC-
FID but gave a 1.25:1 ratio in the GC-MS/SIM mode. The results
from the GC-MS/SIM analyses were adjusted to account for the DKIE
of the dehydration. For experiments involving CCl3Br, a known volume
of the oxygen-free trapping agent was added prior to the addition of
the oxidant. For the reactions involving the thermal decomposition of
Scheme 2
+
Me3COO(FeIII) f Me3CO• + Od(FeIV) {+H } HO-(FeIV)
-H+
(4)
Me3COOH + Od(FeIV) N Me3COO• + HO-(FeIII) (5)
Me3CO• + Me3COOH N Me3COH + Me3COO• (6)
Me3CO• + c-CnH2n f Me3COH + c-CnH•2n-1
(8)
c-CnH•2n-1 + Me3COO• f c-CnH2n-1OOCMe3 (11′)
c-CnH•2n-1 + HO-(FeIV) f c-CnH2n-1OH + (FeIII) (14)
The “hydroxyl” oxygen atom in TBHP appeared to be the
most likely source of the oxygen atom in the cycloalkanols
produced under syringe pump conditions with 10 equiv (or less)
of TBHP. This was confirmed by oxidizing cyclooctane in
acetonitrile under argon using 1 and 10 equiv of (CH3)3CO-
18OH (96% 18O) added by syringe pump. The incorporation of
18O into the cyclooctanol was 93%. A control experiment using
cyclooctane, 1, and 10 equiv of unlabeled TBHP added by
syringe pump to the acetonitrile solution containing 100 mM
H218O gave cyclooctanol with no 18O incorporation. It is clear
that the CsO bond-forming step must be significantly faster
than solvent water exchange with the HO-(FeIV) species.
Conclusion
We believe that the present results prove beyond any
reasonable doubt that alkane oxidations catalyzed by 1 and small
(19) Dong, Y.; Fujii, H.; Hendrich, M. P.; Leising, R. A.; Pan, G.;
Randall, C. R.; Wilkinson, E. C.; Zang, Y.; Que, L., Jr.; Fox, B. G.;
Kauffmann, K.; Mu¨nck, E. J. Am. Chem. Soc. 1995, 117, 2778-2792.
(20) Mendenhall, G. D. Tetrahedron Lett. 1983, 24, 451-452.
(21) Footnote 16 in ref 4.
(22) Hart, H.; Wyman, D. P. J. Am. Chem. Soc. 1959, 81, 4891-4896.
(23) Zang, Y.; Kim, J.; Dong, Y.; Wilkinson, E. C.; Appelman, E. H.;
Que, L. Jr. J. Am. Chem. Soc. 1997, 119, 4197-4205.
(17) Indeed, when a 1/20 equiv of TBHP syringe pump experiment was
performed under air without prior deoxygenation of the solvent the “usual”
free-radical-derived product slate was obtained.11
(18) This cross-radical-radical reaction is strongly favored by the
Ingold-Fischer “persistent radical effect”.9

10598 J. Am. Chem. Soc., Vol. 119, No. 44, 1997
MacFaul et al.
BONNOB or the diacyl peroxide, all of the reagents were mixed
together and then degassed by performing four freeze-pump-thaw
cycles. The samples were then sealed and left at room temperature
for 5 days, after which they were subjected to the usual workup
procedures.
ments on an earlier version of this paper. This work was
supported by the Association for International Cancer Research,
the National Foundation for Cancer Research, and the National
Institutes of Health (Grant GM-38767).
Acknowledgment. We thank Mrs. S. Lin for synthesizing
the dicyclohexylformyl peroxide, Mr. R. Kolt for recording the
Supporting Information Available: Four tables giving the
complete product analyses for 82 individual experiments with
140, 10, or 1 equiv of hydroperoxide (6 pages). See any current
masthead page for ordering and Internet access instructions.
NMR spectra, Dr. E. H. Appelman for synthesizing (CH3) -
3
CO18OH, and Drs. C. Kim and H. Miyake for carrying out the
experiments with the 18O-labeled TBHP and water. We also
thank several anonymous reviewers for their thoughtful com-
JA963627J