Catalytic and stoichiometric oxidation of N,N-dimethylanilines mediated by nonheme oxoiron(IV) complex with tetrapyridyl ligand

Article abstract of DOI:10.1016/j.poly.2019.05.025

Nonheme iron(II) complex, [(N4Py^*)Fe^II(CH₃CN)](ClO₄)₂ (1) with pentadentate tetrapyridyl ligand (N4Py^* = N,N-bis(2-pyridylmethyl)-1,2-di(2-pyridyl)ethylamine) has been shown to catalyze the oxidation of N,N-dimethylaniline (DMA) with H₂O₂, tert-butyl hydroperoxide (TBHP), peracetic acid (PAA), meta-chloroperoxybenzoic acid (mCPBA) and PhIO resulting N-methylaniline (MA) as the predominant product with N-methylformanilide (MFA) as a result of a free-radical chain process. The product composition (MA/MFA) is remarkably influenced by the electron density on the substrate, especially in the 1/mCPBA system, and by the co-oxidants used. No formation of MFA occurred when the oxidation of DMA was carried out in the presence of 1 with PhIO as co-oxidants under argon. Based on spectral investigation (UV–Vis) of reaction systems above, oxoiron(IV) intermediate, [Fe^IV(N4Py^*)(O)]²⁺ (2) has been suggested to be the key active species of the N-dealkylation reaction in all catalytic systems. The shift in the λ_max value of the oxoiron(IV) species in the presence of DMA from 705 to 750 nm, and the new intense absorption in the range of 5–600 nm indicates a complexation and charge-transfer (CT) type interactions between the oxidant and substrate. The stoichiometric oxidation of various N,N-dimethylaniline derivatives with 2 provided clear evidence (Hammett correlation with ρ = ?1.99, and the large negative slope (?4.1) from the logk_obs versus E^o_ox (DMAs) plot) for the rate-determining electron transfer (ET) followed by a proton transfer (PT) process.

Full text of DOI:10.1016/j.poly.2019.05.025

Accepted Manuscript
Catalytic and stoichiometric oxidation of N,N-dimethylanilines mediated by
nonheme oxoiron(IV) complex with tetrapyridyl ligand
Dóra Lakk-Bogáth, Balázs Kripli, Bashdar I. Meena, Gábor Speier, József
Kaizer
PII:
S0277-5387(19)30355-9
https://doi.org/10.1016/j.poly.2019.05.025
POLY 13950
DOI:
Reference:
To appear in:
Polyhedron
Received Date:
Accepted Date:
12 April 2019
12 May 2019
Please cite this article as: D. Lakk-Bogáth, B. Kripli, B.I. Meena, G. Speier, J. Kaizer, Catalytic and stoichiometric
oxidation of N,N-dimethylanilines mediated by nonheme oxoiron(IV) complex with tetrapyridyl ligand,
Polyhedron (2019), doi: https://doi.org/10.1016/j.poly.2019.05.025
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Catalytic and stoichiometric oxidation of N,N-dimethylanilines
mediated by nonheme oxoiron(IV) complex with tetrapyridyl
ligand
Dóra Lakk-Bogáth, Balázs Kripli, Bashdar I. Meena, Gábor Speier and József Kaizer*
aDepartment of Chemistry, Universtiy of Pannonia, 8201 Veszprém, Hungary
Abstract
Nonheme iron(II) complex, [(N4Py*)Fe (CH
tetrapyridyl ligand (N4Py* = N,N-bis(2-pyridylmethyl)-1,2-di(2-pyridyl)ethylamine) has been
shown to catalyze the oxidation of N,N-dimethylaniline (DMA) with H , tert-butyl
II
3
CN)](ClO
4
)
2
(1) with pentadentate
2
O
2
hydroperoxide (TBHP), peracetic acid (PAA), meta-chloroperoxybenzoic acid (mCPBA) and
PhIO resulting N-methylaniline (MA) as the predominant product with N-methylformanilide
(MFA) as a result of a free-radical chain process. The product composition (MA/MFA) is
remarkably influenced by the electron density on the substrate, especially in the 1/mCPBA
system, and by the co-oxidants used. No formation of MFA occurred when the oxidation of
DMA was carried out in the presence of 1 with PhIO as co-oxidants under argon.
Based on spectral investigation (UV/Vis) of reaction systems above, oxoiron(IV)
IV
2+
intermediate, [Fe (N4Py*)(O)] (2) has been suggested to be the key active species of the N-
dealkylation reaction in all catalytic systems. The shift in the max value of the oxoiron(IV)
species in the presence of DMA from 705 to 750 nm, and the new intense absorption in the
range of 5-600 nm indicates a complexation and charge-tranfer (CT) type interactions
between the oxidant and substrate. The stoichiometric oxidation of various N,N-
dimethylaniline derivatives with 2 provided clear evidence (Hammett correlation with  = -
1
.99, and the large negative slope (-4.1) from the logkobs versus Eoox (DMAs) plot) for the
rate-determining electron transfer (ET) followed by a proton transfer (PT) process.
Keywords: Bioinspired oxidation, C-H activation, Oxidative N-dealkylation, Nonheme
oxoiron complex, Kinetics.
*Corresponding author. Tel.: +36 88 62 4720; Fax: + 36 88 62 4469.
E-mail address: kaizer@almos.uni-pannon.hu.

1
. Introduction
Heme and non-heme iron-dependent N-dealkylation reactions play important roles in
numerous biological processes from DNA repair to the metabolism and detoxification of
various xenobiotics such as tertiary amine containing drugs [1-7]. For example, 1-methyl-4-
phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxic byproduct of the heroin synthesis,
which is able to induce a Parkinson’s disease in humans. Its detoxification by P450s can
protect neurons within the central nervous system in humans and in animals [8]. The
mechanism of these important processes has been extensively studied but it is still obscured,

whether the oxoiron-mediated N-dealkylations proceed through a C -H abstraction and/or a
single-electron transfer (SET) mechanism [9-16]. In case of horseradish peroxidase (HRP) the
formation of aminium radicals (EPR, electron paramagnetic resonance spectroscopy) during
the oxidation process can be explained by the involvement of the rate-determining electron-
transfer before the -hydroxylation step [17,18]. However, direct hydrogen atom transfer
(HAT) has been proposed for cytochrome P450 [15,16,19]. 2-Oxoglutarate/Fe(II)-dependent
dioxygenases are also known to catalyze O- and N-demethylation reactions [20]. For example
AlkB-type proteins catalyze the removal of N-linked methyl groups at positions 1 and 3 of
purine and pyrimidine bases, respectively, in DNA and RNA [21]. As a functional models for
the iron-containing proteins several catalytic systems have been examined for N,N-
dimethylaniline (DMA) derivatives. Iron(III)-salen, iron(II, III)-2,2’-bipyridine and iron(III)-
porphyrin complexes, furthermore simple iron salts FeCl
3
and Fe(ClO
4
3
) have been developed
as catalysts for the oxidation of DMAs with various oxygen sources including iodosobenzene,
hydroperoxides and molecular oxygen, resulting a mixture of N-methylformanilide (MFA), N-
methylaniline (MA) and other dimerized products, where the product composition and the
mechanism were remarkably influenced by the nature of the iron catalyst used, although the
active species in each case is unclear [22-26]. It is worth to mention that N-methylformanilide
is an important intermediate in organic synthesis, it is widely used in the Vilsmeier reaction
[
27,28]. Recent reports postulate electron transfer–proton transfer (ET–PT) mechanism for N-
IV
2+
demethylation of N,N-dimethylanilines promoted by [(N4Py)Fe (O)] (N4Py = N,N’-bis(2-
IV
2+
pyridylmethyl)-N-bis(2-pyridyl)methylamine),
[(TMC)Fe (O)]
(TMC,
1,4,8,11-
IV
2+
tetramethyl-1,4,8,11-tetraazacyclotetradecane) and [(TPFPP)Fe (O)]
(TPFPP, meso-
tetrakis(pentafluorophenyl)-porphinato dianion) complexes [29,30], where N-methylanilines
were the exclusive reaction products without formation of N-methylformanilides. These

highly selective stoichiometric reactions can be proposed as a possible elementary step of the
catalytic systems mentioned above.
We have recently been successful in obtaining well characterized synthetic analogues
of high-valent non-heme iron species with N4Py-type pentadentate ligands,
IV
2+
[
Fe (N4Py*)(O)] (2) (N4Py* = N,N-bis(2-pyridylmethyl)-1,2-di(2-pyridyl)ethylamine),
which have features in common with non-heme iron-dependent oxygenases [31] with respect
to their structure and oxidative activity. These intermediates are shown to mediate a variety of
monooxygenations, including aliphatic and aromatic hydroxylations [32,33], oxygenation of
sulfides [31] and aldehydes [32], epoxidation of olefins [34], and Baeyer-Villiger oxidations
[
[
35]. Herein, we set out to explore the catalytic reactivity of the complex,
II
(N4Py*)Fe (CH
3
CN)](ClO
4
)
2
(1) towards N,N-dimethylanilines with TBHP, H
2
2
O , PAA and
mCPBA as terminal oxidants, and wanted to get direct evidence for the formation of reactive
intermediates, and their possible role in the oxidation (N-demethylation) process based on
kinetic and spectroscopic studies (Fig.1).
Fig. 1 Oxoiron(IV) mediated N-demethylation reaction in this study.
2
. Experimental section
2
.1. Materials and methods

II
The N
4
Py* ligand, and its [Fe (N
4
Py*)(CH
3
CN)](ClO
4
2
) (1) complex were prepared
according to published procedures [31]. UV/Vis spectra were recorded with an Agilent 8453
diode-array spectrophotometer with quartz cells. GC analyses were performed on Shimadzu
QP2010SE equipped with a secondary electron multiplier detector with conversion dynode
and a 30 m HP-5MS column.
2
.2. Description of the catalytic oxidation reactions
In a typical reaction, 1 mL of H (diluted from 35% solution), mCPBA (77%), PAA
diluted from 38-40% solution) or TBHP (diluted from 70% solution) solution in CH CN was
delivered by syringe pump in air (Ar) to a stirred solution (2 mL) of catalyst 1 or Fe(ClO
salt, and DMA substrate inside a vial. The final concentrations were 3 mM catalyst 1, 150
mM co-oxidant, and 300 mM substrate. The PhIO was added as a solid into the CH CN
solution containing 100 l H O due to the poor solubility of PhIO. The products were
2
O
2
(
3
)
4 2
3
2
identified by GC, GC/MS analysis, and their yields were determined by comparison with
authentic compounds using bromobenzene as an internal standard in the reactions. The HCHO
was identified as 2,4-dinitrophenylhydrazone by GC/MS (M+ =210).
IV
2+
2
.3. Stoichiometric oxidation of N,N-dimethylaniline with [Fe (N4Py*)(O)] (2)
All reactions were carried out under thermostated conditions at different temperature
II
in 1 cm quartz cuvettes with stirring under argon. [Fe (N
4
Py*)(CH
3
CN)](ClO
4
)
2
complex
-3
-3
(
2.00 × 10 M) was dissolved in acetonitrile (1.5 mL), then iodosobenzene (3.00 × 10 M)
was added to the solution. The mixture was stirred for 50 minutes then excess iodosobenzene
was removed by filtration. The rate of substrate oxidation was followed by monitoring the
-1
-1
decrease in absorbance at 705 nm ( = 400 M cm ), under pseudo-first order condition of
excess DMA derivatives.
3
. Results and discussion
3
.1. Catalytic oxidation of N,N-dimethylaniline (DMA) derivatives
As reported earlier, DMA can be oxidized by iron salts via one-electron oxidation to
dimerized product (D) as the predominant product with small amount of demethylated N-
methylaniline (D/MA = 1.7; TON = ~ 40 at 60˚C after 10 h.) under molecular oxygen. In
contrast, in the presence of iron-salen complexes the N-methylformanilide was the major
product with MA (MFA/MA = ~2; TON = 180 at 60˚C after 10 h.). Aminium cation radical

has been suggested for the former, and -amino radical for the latter case as key species, but
the iron-based intermediates are still unclear [24,25]. To get more insight into the mechanism
II
2+
of this curious reaction the catalytic activity and selectivity of [Fe (N4Py*)(CH
3
CN] (1),
IV
where the possible reactive high-valent intermediate (Fe O) is known and spectroscopically
well characterized, was studied in the oxidation of DMA derivatives, utilizing TBHP, H
2
2
O ,
II
PAA and mCPBA as co-oxidants compared to the corresponding Fe (ClO
4
2
) /co-oxidant
system (Table 1). Reactions were carried out under standard catalytic conditions (1 : 100 : 50
for the catalyst : DMA : co-oxidant) in acetonitrile at room temperature under air (Ar). Co-
oxidants were added by syringe, and the excess of DMA was used to minimize the over-
oxidized products. The catalytic activity and selectivity of 1 and the iron(II) salt appeared to
II
be dependent on the co-oxidants used for oxidation. The Fe (ClO
4
)
2
salt together with H
2
O
2
oxidizes DMA to MA and MFA, and a turnover number (TON) of 2.9 and 0.8 was obtained
with an overall yield of 7.5% (the sum of both MA and MFA; based on co-oxidant),
respectively. Almost identical result has been observed by the use of TBHP as co-oxidant (3.3
and 0.8 TON, respectively), with a similar MA to MFA ratio (3.7 vs. 4.4 for TBHP). When
mCPBA and PAA were used as co-oxidants significantly higher activities were observed
(
TON of 10 vs. 16 with MA/MFA = 4.2 vs. 6.5 for PAA). The increased reactivity of peracids
compared to H and TBHP may be explained by the in situ formed [Fe O(OAc)
]+ and
Fe O(mCBA)
]+ complexes with a remarkably higher catalytic activities compared to the
parent Fe(ClO salt [25]. The catalytic activity of 1 was also examined including the same
2
O
2
3
3
[
3
3
4 2
)
co-oxidants, and conditions used above, facilitating direct comparison with results obtained
with the parent iron(II) salt. Table 1 and Fig. 2 show that there is an increase of the overall
yield when the oxidants employed are PhIO, H
9%), albeit with moderate product selectivity, significantly lower MA/MFA ratios (2.2, 2
and 2.5 for H , TBHP and PAA, respectively) except of 1/mCPBA system (MA/MFA = 6).
2
2
O , TBHP, mCPBA, and PAA (from 11 to
6
2
O
2
The result of PhIO-containing system was not included in Fig. 2 due to the observed
inhomogeinity. The low MA/MFA ratio indicates an autooxidation process via Russel-type
termination mechanism involving reaction of the PhC(Me)CH
equimolar amount of PhC(Me)CH OH and PhC(Me)CHO, and finally MA and CH
the former hydroxy intermediate. The formation of PhC(Me)CH • radical may be explained
2
• radical with dioxygen to form
2
2
O from
2
by the appearance of hydroxyl (tert-butoxy) radical during the formation of oxoiron(IV)
species. In case of mCPBA and PhIO the presence of highly reactive hydroxyl radical can be
excluded, but the formation of MFA could occur via reaction between cage-escaped
PhC(Me)CH • radical (derived from the reaction of 2 with DMA) and dioxygen. In summary,
2

it can be concluded that the moderate selectivity can be explained by the parallel selective
metal-based, and non-selective radical processes resulting in MA and MFA-MA as main
products, respectively. In the 1/H
2
2
O /DMA reaction system, 2,6-di-tert-butyl-4-methylphenol
as a radical trap was used, and it was found that the reaction was inhibited by its presence (12
vs. 4 TON with significantly higher MA to MFA ratio MA/MFA = 2.2 vs. 4.1), suggesting
that the oxidation of DMA catalyzed by 1 should really involve radical species, and the MFA
derives from its reaction. Similar result has been observed for the anaerob 1/PhIO/DMA
system in the presence of radical trap. Further evidence for this assumption, that no formation
of MFA occurred when the oxidation of DMA was carried out in the presence of 1 with PhIO,
PAA, mCPBA and TBHP as co-oxidants under argon, whilst the MA was the exclusive
product with 10.9, 29, 26.3 and 10.9 yields. In case of the H
2
O
2
the presence of dioxygen can
. Para-substituted N,N-
be explained by the metal-based disproportionation of H
2
O
2
dimethylanilines were observed to produce corresponding secondary anilines where anilines
with electron-donating groups on the phenyl ring gave better yields and selectivity than those
with electron-withdrawing groups, suggesting a metal-based oxidant with electrophilic
character (Fig. 3). It can also be seen that the product composition (MA/MFA ratio) being
remarkably influenced by the electron density on the substrate (Fig. 4), especially in the
1
/mCPBA system.
Table 1
a
Iron-catalyzed oxidation of N,N-dimethylanilines with various co-oxidants under air and
argonb.
[
1]:[DMA]:[Co-oxidant]a Yield (%)c TONMA Yield (%)c TONMFA MA/MFA TON
4
R-MA
4R-MFA
4.2H
19.7H
-
1c:100:50 (PAA)a
27.3H
48.9H
29H
13.8
24.5
14.3
8.5
2.1
9.8
-
6.5
2.5
16
34
14
10
25
22
13
19
15
1
. 100 :50 (PAA)a
. 100 :50 (PAA)b
1
1d:100:50 (mCPBA)a
17H
3.9H
6.6Me
6.2H
-
1.8
3.3
3.1
-
4.2
6.7
6
1
1
1
1
1
. 100 :50 (mCPBA)a
. 100 :50 (mCPBA)a
. 100 :50 (mCPBA)b
. 100 :50 (mCPBA)a
. 100 :50 (mCPBA)a
43.9Me
36.9H
26.3H
31.6Br
23.2CN
21.9
18.5
13.2
15.8
11.6
6.5Br
6.0CN
3.2
3
4.9
3.9

1d . 100 :50 (TBHP)a
6.6H
3.3
10.6
5.5
2.9
10.2
8
1.5H
10.3H
1>
0.8
5.2
0.5>
0.8
3.7
3.5
1.2
0.8
4
4.4
2.0
4
1
. 100 :50 (TBHP)a
. 100 :50 (TBHP)b
21.3H
10.9H
5.9H
16
1
6
1d . 100 :50 (H
O
2
)a
1.58H
7.4Me
7.1H
2.5H
1.6H
8.0Br
8.3CN
1.0H
-
3.7
2.8
2.2
4.5
4.1
1.4
0.9
4
2
1
1
1
1
1
1
1
1
. 100 :50 (H
. 100 :50 (H
. 100 :50 (H
. 100 :50 (H
. 100 :50 (H
. 100 :50 (H
2
2
2
2
2
2
O
O
O
O
O
O
2
2
2
2
2
2
)a
)a
)b
)e
)a
)a
20.4Me
15.9H
11.2H
6.1H
14
12
5.6
3.1
5.6
3.9
5.4
5.4
0.3
7
4
11.3Br
7.82CN
10.9H
10.9H
0.6H
10
4.2
0.5
-
8
. 100 :50 (PhIO)a
. 100 :50 (PhIO)b
. 100 :50 (PhIO)b,e
4
-
5
0.3
1
-
-
a
c
d
Reaction conditions: see Experimental section. Based on oxidant. Fe(ClO
4
)
2
was used as
e
catalyst. Reaction in the presence of 2,6-di-tert-butyl-4-methylphenol (15 equiv.).

Fig. 2 Comparison of the product formation in the iron-catalyzed (Fe(ClO
of N,N-dimethylaniline to N-methylaniline (blue) and N-methylformanilide (red) with various
co-oxidants in CH CN at 25°C under air.
4
2
) vs. 1) oxidation
3
Fig. 3 Comparison of the product formation in the iron-catalyzed (1) oxidation of substituted
N,N-dimethylanilines to N-methylaniline (blue) and N-methylformanilide (red) derivatives
with mCPBA (A) and H
2
O
2
(B) in CH CN at 25°C under air.
3

II
Fig. 4 Reactions of [Fe (N
4
Py*)(CH
3
CN)](ClO
)
4 2
with DMAs by the use of mCPBA and
of para-
H
2
O
2
in CH CN at 25°C under air. (A) Plot of MA to MFA ratio against the 
3
p
substituted DMAs. (B) Plot of MA to MFA ratio against the ˚ox of para-substituted DMAs.
Anaerobic spectral investigations were also performed to trap the possible intermediates. The
UV-Vis measurements in the absence of DMA using various co-oxidants (mCPBA, PAA,
TBHP, and H
2
O
2
) have confirmed the formation of oxoiron(IV) species 2 (Fig. 5A) [31]. We
have shown earlier that the complex 1 forms very stable high valent oxoiron(IV) species (2)
-1
-1
with PhIO in CH CN (t1/2 = 233 h at R.T.; max = 705 nm,  = 400 M cm ) (Fig. 5A) [31]. Its
3

yield and the observed red shift on the max values (from 703 to 730 nm) can be explained by
the reaction and/or interaction (H-bridge) of the oxoiron(IV) with the oxidant (PAA, mCPBA,
TBHP, H
2
O
2
) and/or the solvent (tert-BuOH, AcOH, H
2
O…) used during the generation. In
case of the H
2
O
2
, its reaction with 1 in CH CN resulted in the formation of a transient purple
3
-1
-1
species with a characteristic absorbance maximum at max 535 nm ( = 630 M cm ). It has a
half-life of about 3 min at 25°C. These values are identical with those reported for low-spin
III
2+
N4Py-type [(N3PyBim)Fe (OOH)] systems with one 1-methyl-2-benzimidazolyl arm [36].
Its decay resulted in the formation of 2 (Fig. 5B). These results may suggest that a high-valent
oxoiron(IV) species is one of the possible intermediate which is responsible for the
demethylation reaction of DMA. However, we have to expect the presence of free radicals
such as HO•, tBuO•, and dioxygen which may compete with the metal-based oxidation.

Fig. 5 The UV-Vis spectral change of 1 upon addition of various co-oxidants (PAA, mCPBA,
III
TBHP and H
derived from the reaction of 1 with H
0. ([1] = 3 mM) in CH CN at 25°C (B).
The UV-Vis experiments in the presence of DMA under the preveously used standard
catalytic conditions (1/H /DMA = 1 : 50 : 100) have also confirmed the formation of
oxoiron(IV) species 2, that undergoes a decay, which is affected by the substrate, DMA (Fig.
A). The shift in the max value of the oxoiron(IV) species in the presence of DMA from 705
2
O
2
at room temperature (A), and time courses of the decay of Fe OOH species
2
2
O , during the formation of 2. [1] : [ co-oxidant] = 1 :
5
3
2
O
2
6
to 750 nm, and the new intense absorption in the range of 5-600 nm indicates a complexation
and charge-tranfer (CT) type interaction between the oxidant and the substrate, albeit their

nature is not known. The same spectral changes can be observed when the substrate, DMA
was added to the oxoiron(IV) species generated by the reaction of 1 and PhIO.
Fig. 6 The UV-Vis spectral changes of 1 and 2 (inset) species in the presence of DMA upon
addition of H
2
O
2
at room temperature, [1] : [H
2
2
O ] : [DMA] = 1 : 50 : 100. ([1] = 3 mM) in
CH CN at 25°C (A), and the UV-Vis spectral change after addition of DMA to 2 (derived
3
from the reaction of 1 with PhIO), [2] : [DMA] = 1 : 100. ([2] = 3 mM, l = 0.5 cm) in CH
3
CN
at 25°C (B).
3
.1. Stoichiometric oxidation of N,N-dimethylaniline (DMA) derivatives with 2
In the iron-catalyzed oxidation of DMA with terminal oxidants two processes can be proposed
as rate-controlling step, namely the formation of high-valent oxoiron(IV) species from the
reaction of precursor complex with the correspondent co-oxidant, or the reaction of oxometal
species with the substrate. To avoid this difficulty, and to get more insight into the mechanism

of the N-demethylation process we have synthesized the oxoiron(IV) complex 2 by in situ
reaction of 1 with PhIO, and investigated the stoichiometric oxidation of DMA with it. In this
way, the formation of hydroxyl and tert-butoxy radicals and their non-selective reactions with
the substrate in the stoichiometric reaction can be excluded, and the role of the oxoiron(IV)
species can be directly investigated. Complex 2 is able to oxidize the N,N-dimethylanilines
under mild anaerob conditions, at 15˚C, in CH
product indicated the formation of MA (yields ~80% based on 2) as the main product with
CH O. The kinetics of N-demethylation of DMAs with 2 were followed under pseudo-first-
3
CN, and the GC and GC/MS analysis of the
2
order conditions in the presence of 10-30-fold excess of substrate over the oxidant by
measuring the change in the absorbance maximum at max 705 nm of 2 with time at 5-20˚C.
The reaction shows 1st-order dependence on both the oxoiron(IV) and the substrate
-2
-1 -1
≠
-1
≠
concentration with k = (9.8 ± 0.4)×10 M s (Fig. 7a), H = 68 kJ mol and S = -121 J
2
-1
mol K for DMA (Table 2). Reaction rate obtained for the oxidation of DMA is smaller by
one order of magnitude than those observed for oxoiron(IV) complexes with N4Py and TMC
-1
-1
ligands (k = 1.4 ± 0.1 and 1.2 ± 0.1 M s , respectively [30]), but larger by two order of
2
IV
-4
-1 -1
magnitude than that observed for Fe O/TPFPP system ((3.0 ± 0.2)×10 M s ). The
relatively large negative entropy is typical of associative processes (Fig. 7b). Based on
previous catalytic results above, it can be expected that the N-demethylation reaction is
sensitive to the nature of the substituent in the phenyl ring of DMAs. Upon using para-
substituted DMA derivatives with electron donating groups the rate of the stoichiometric
reactions were increased remarkably (Table 3, Fig. 7c). Based on the competitive reactions,
the Hammett correlation (r = 0.98, n = 5,  = -1.99) demonstrates that the rate constant for the
N-demethylation of DMA by 2 is much more sensitive to changes in the electronic properties
of the DMA compared to the 2/PhCH
2
OH and 2/PhCH systems including rate-determining
3
HAT process ( = -0.32, and  = -0.98, respectively) [38]. Furthermore this  value almost
IV
2+
identical to that measured in the [Fe (N4Py)(O)] /DMA system ( = -2.1), where electron
transfer (ET) and concomitant proton transfer (PT) was proposed with a rate-determining PT
step (Table 2 and 3) [29,30]. The correlation of log k
2
values with the one-electron oxidation
potentials of DMAs (E˚ox) is good, and the slope (-4.1) is comparable to those obtained for the
IV
2+
IV
2+
[
[
Fe (N4Py)(O)] /DMA
(-3.3),
[Fe (TMC)(O)] /DMA
(-4.0)
and
IV
2+
Fe (TPFPP)(O)] /DMA (-5.0) systems (Fig. 7d, Table 2 and 3). The magnitude of these
values is also in a good agreement with the previously suggested ET-PT mechanism.

Table 2
Kinetic parameters determined in the oxidation of N,N-dimethylanilines by oxoiron(IV)
complexes in acetonitrile at 25°C.
IV
≠
≠
≠
[
(L)Fe (O)]
k
2

slope
H
S
G
Refs.
-
1 -1
(logk vs.˚ ) (kJmol-1) (Jmol K ) (kJmol-1)
-1 -1
L
(M s )
1.4 ± 0.1
1.2 ± 0.1
2
ox
N4Py
TMC
-2.2
-2.6
-3.3
-4.0
-5.0
[30]
[30]
[30]
t. w.
TPFPP
N4Py*
(3.0 ± 0.2)×10-4 -3.3
(9.8 ± 0.4)×10-2 -1.99 -4.1
68
-121
103
Table 3
Kinetic parameters determined in the oxidation of p-X-N,N-dimethylanilines by
IV
2+
[
Fe (N4Py*)(O)] (2) in acetonitrile at 10°C.
a
-1 -1
X
p
˚ (vs SCE, V)
k (M s )
2
ox
NMe
Me
H
2
-0.83 n.a.
-0.17 0.69
(14.5 ± 0.5)×10-1
(9.21 ± 0.3)×10-2
(7.45 ± 0.1)×10-2
(1.95 ± 0.04)×10-2
(1.35 ± 0.04)×10-3
0
0.76
0.92
1.15
Br
0.23
CN
0.66
aData from [37]

IV
Fig. 7 Reactions of [Fe (N4Py*)(O)] (2) with DMAs in CH
3
CN. (a) Plot of kobs versus
[
substrate] for reactions of 2 (2mM) with DMA at 288 K. Inset shows time course of the
decay of 2 monitored at 705 nm with DMA ([2]
0
= 2 mM, [DMA]
= 40 mM). (c) Hammett plot of log krel
of para-substituted DMAs. (d) Plot of log k against the ˚ox of para-
substituted DMAs.
0
= 40 mM). (b) Eyring plot
of logk/T versus 1/T for DMA ([2]
against the 
0
= 2 mM, [DMA]
0
p
2
4
. Summary and conclusions
Efforts have been made to work out a highly efficient and highly selective iron(II)-
catalyzed N-demethylation reactions by the use of various co-coxidants such as PhIO,
mCPBA, PAA, TBHP and H
2
O
2
, as well as their detailed mechanistic aspects. As a catalyst
complex was chosen, where the possible reactive high-
II
the [(N4Py*)Fe (CH
3
CN)](ClO
4
)
2
IV
valent intermediate (Fe O) is known and spectroscopically well characterized. The order of
efficacy for the co-oxidants was found to be PAA > mCPBA > TBHP > H
2
2
O > (PhIO) in the
presence of the iron(II) catalyst, which can be explained by the different mechanism of the
oxoiron(IV) formation and the presence/absence of hydroxyl (tert-butoxy) radicals. In case of
PAA, mCPBA and PhIO the reaction procceds via oxene transfer, where the stoichiometry of
II
III
II
Fe /oxidant = 1, whilst with H
2
O and TBHP via Fe -intermediates (Fe /oxidant = 1.5),
2

resulting hydroxyl (tert-butoxy) radicals. It was also found that the selectivity, the product
composition (MA/MFA) ramarkably depends on the electron density on the substrate and the
nature of the co-oxidants used. The highest selectivities have been found for mCPBA
(MA/MFA = ~6) and PhIO, where no formation of MFA occurred during the oxidation. To
get a plausible mechanism for the catalytic reaction, the capture and characterization of the
possible intermediates, and their test against the substrate are the most important tasks. Based
on spectroscopic and kinetic investigations on the 1/co-oxidant/DMA systems we have found
a direct and convincing proof for the formation of high-valent oxoiron(IV) species in all cases
and for its key role in the catalytic cycle. Based on experimental observations derived from
the catalytic and stoichiometric experiments the following mechanisms can be proposed (Fig.
8
). In the peracid and PhIO-based systems the formation of oxoiron(IV) can be explained by
II
direct oxygen atom transfer from the co-oxidant to the Fe(II) precursor: Fe + PhIO (mCPBA)
IV
=
Fe O + PhI (mCBA), while in the H
2
2
O -based system as a result of the decomposition of
III
2+
III
2+
IV
the transient [Fe (OOH)] species: [Fe (OOH)] → Fe O + HO• (tBu•). In the former,
clearly metal-based process only the oxoiron(IV) is responsible for the N-methylation reaction
via ET-PT mechanism with a rate determining PT step (Path a in Fig. 8) [29], but in the latter
case the reaction can be explained by the parallel selective metal-based and non-selective
radical processes (Path a + b in Fig. 8) [39,40].

Fig. 8. Proposed mechanism in the iron(II)-catalyzed N-demethylation reaction.
Acknowledgements
Financial support of the Hungarian National Research Fund (OTKA K108489), and
GINOP-2.3.2-15-2016-00049 are gratefully acknowledged.
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Catalytic and stoichiometric oxidation of N,N-dimethylanilines mediated by
nonheme oxoiron(IV) complex with tetrapyridyl ligand
Dóra Lakk-Bogáth, Balázs Kripli, Bashdar I. Meena, Gábor Speier and József Kaizer
*
II
2+
Catalytic activity and selectivity of [Fe (N4Py*)(CH
3
CN] , where the possible reactive high-
IV
valent intermediate (Fe O) is known and spectroscopically well characterized, was studied in
the oxidation of DMA derivatives, utilizing PhIO, TBHP, H
oxidants.
2
2
O , PAA and mCPBA as co-
*Corresponding author. Tel.: +36 88 62 4720; Fax: + 36 88 62 4469.
E-mail address: kaizer@almos.uni-pannon.hu.