Selective C-H halogenation over hydroxylation by non-heme iron(iv)-oxo

Article abstract of DOI:10.1039/C8SC02053A

Non-heme iron based halogenase enzymes promote selective halogenation of the sp³-C-H bond through iron(iv)-oxo-halide active species. During halogenation, competitive hydroxylation can be prevented completely in enzymatic systems. However, synthetic iron(iv)-oxo-halide intermediates often result in a mixture of halogenation and hydroxylation products. In this report, we have developed a new synthetic strategy by employing non-heme iron based complexes for selective sp³-C-H halogenation by overriding hydroxylation. A room temperature stable, iron(iv)-oxo complex, [Fe(2PyN2Q)(O)]²⁺ was directed for hydrogen atom abstraction (HAA) from aliphatic substrates and the iron(ii)-halide [Fe^II(2PyN2Q)(X)]⁺ (X, halogen) was exploited in conjunction to deliver the halogen atom to the ensuing carbon centered radical. Despite iron(iv)-oxo being an effective promoter of hydroxylation of aliphatic substrates, the perfect interplay of HAA and halogen atom transfer in this work leads to the halogenation product selectively by diverting the hydroxylation pathway. Experimental studies outline the mechanistic details of the iron(iv)-oxo mediated halogenation reactions. A kinetic isotope study between PhCH₃ and C₆D₅CD₃ showed a value of 13.5 that supports the initial HAA step as the RDS during halogenation. Successful implementation of this new strategy led to the establishment of a functional mimic of non-heme halogenase enzymes with an excellent selectivity for halogenation over hydroxylation. Detailed theoretical studies based on density functional methods reveal how the small difference in the ligand design leads to a large difference in the electronic structure of the [Fe(2PyN2Q)(O)]²⁺ species. Both experimental and computational studies suggest that the halide rebound process of the cage escaped radical with iron(iii)-halide is energetically favorable compared to iron(iii)-hydroxide and it brings in selective formation of halogenation products over hydroxylation.

Full text of DOI:10.1039/C8SC02053A

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Selective C−H Halogenation over Hydroxylation by Non-heme
Iron(IV)-oxo
Received 00th January 20xx,
Accepted 00th January 20xx
Sujoy Rana, † Jyoti Prasad Biswas, † Asmita Sen, † Martin Clémancey, § Geneviève Blondin, Jean-
§
Marc Latour*,§ Gopalan Rajaraman*† and Debabrata Maiti*†
DOI: 10.1039/x0xx00000x
Non-heme iron based halogenase enzymes promote selective halogenation of sp3-C–H bond through iron(IV)-oxo-halide
active species. During halogenation, competitive hydroxylation can be prevented completely in enzymatic systems.
However, synthetic iron(IV)-oxo-halide intermediates often result in a mixture of halogenation and hydroxylation products.
In this report, we have developed a new synthetic strategy by employing non-heme iron based complexes for selective sp3-
C–H halogenation by overriding hydroxylation. A room temperature stable, iron(IV)-oxo complex, [Fe(2PyN2Q)(O)]2+ was
directed for hydrogen atom abstraction (HAA) from aliphatic substrates and the iron(II)-halide [FeII(2PyN2Q)(X)]+ (X,
halogen) was exploited in conjunction to deliver the halogen atom to the ensuing carbon centered radical. Despite
iron(IV)-oxo being an effective promoter of hydroxylation of aliphatic substrates, the perfect interplay of HAA and halogen
atom transfer in this work leads to the halogenation product selectively by diverting the hydroxylation pathway.
Experimental studies outline the mechanistic detail of the iron(IV)-oxo mediated halogenations reactions. Kinetic isotope
study between PhCH3 and C6D5CD3 showed value of 13.5 that supports the initial HAA step as the RDS during halogenation.
Successful implementation of this new strategy led to the establishment of a functional mimic of non-heme halogenase
enzymes with an excellent selectivity for halogenation over hydroxylation. Detailed theoretical studies based on density
functional methods reveal how the small difference in the ligand design lead to large difference in the electronic structure
of the [Fe(2PyN2Q)(O)]2+ species. Both experimental and computational studies, suggest that halide rebound process of
cage escaped radical with iron(III)-halide is energetically favorable compare to iron(III)-hydroxide and it brings in selective
formation of halogenation products over hydroxylation.
www.rsc.org/
differ structurally compared to α-KG dependent
halogenases,2a,4 in a sense wherein halide is coordinated to the
iron centre instead of carboxylate from α-KG. Although these
Introduction
High-valent iron-oxo species serve as the key intermediate for
performing different natural transformation like halogenation,
hydroxylation and olefin epoxidation.1 Several oxygenases
including Cyt P450, Rieske oxygenases, α-keto gluterate-
dependent oxygenases and various halogenases exhibit their
activity via formation of an iron-oxo intermediate.2 Among
these mononuclear iron based enzymes, α-KG-dependent
halogenases carry out biosynthesis of several halogen based
natural products by implementing selective halogenations of
C−
sp3 H bonds by overriding hydroxylation.3 These enzymes
contain α-KG as the key structural motif which is coordinated
to an iron(II) cofactor in a facial triad fashion along with two
histidine moieties. Other halogenases such as CytC3 and SyrB2
enzymes differ structurally, their mode of action towards C−H
halogenation is very much similar. First, iron(II) cofactor
performs O2 activation resulting in a high-spin (S=2) cis-
iron(IV)-oxo-halide species.1a,5 Subsequently, it performs the
hydrogen atom abstraction (HAA) from
C−H bond. The
corresponding nascent radical and iron(III)-halide are placed in
such a way that the radical selectively undergoes rebound with
halide to generate halogenated products.
Biomimetic
[FeIII(TPA)Cl2]+ was first synthesized and judiciously employed
by Que and co-workers for sp3 C H halogenation.4 The iron(V)-
non-heme
iron(III)-halide
complex,
−
oxo-halide, [FeV(TPA)(O)(Cl)]2+ was proposed as the key
intermediate for the halogenation reaction. Recent studies
showed that substrate positioning between halide and
hydroxide is
halogenation.5 Later on Comba reported C
with where iron(IV)-oxo-halide,
[FeII(bispidine)(Cl2)]
[FeIV(bispidine)(O)(Cl))]2+ was proposed as the key
intermediate.6 Subsequently Costas synthesized cis-iron(IV)-
oxo-halide, [FeIV(O)(X)(Pytacn)]+ (X, Cl and Br) for pursuing sp3
a
key factor to ensure selectivity for
−
H halogenations
†Department of Chemistry, IIT Bombay; Powai, Mumbai-400076, India
§University of Grenoble Alpes, LCBM/PMB and CEA, IRTSV/CBM/PMB and CNRS,
LCBM UMR 5249, PMB, 38000 Grenoble, France
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C
−
H halogenation.7 Later Paine and co-workers have reported protocol by overriding hydroxylation chemistry, along with
halogenations of aliphatic and benzylic C H bonds where what is observed in α-KG-dependent halogenases. We planned
−
similar iron(IV)-oxo-halide, [TPPhFeIV(O)(Cl)]2+ was proposed as to employ a room temperature stable pentacoordinated
the key intermediate.8
iron(IV)-oxo species [FeIV(2PyN2Q)(O)]2+
2PyN2Q ligand, (1,1-di(pyridin-2-yl)-N,N-bis(quinolin-2-
(2) supported by
Halogenase Enzymes
ylmethyl)methanamine, Figure 2).10 The corresponding iron(II)-
complex was synthesized by reacting Fe(OTf)2(CH3CN)2 with
the ligand, 2PyN2Q in acetonitrile. The synthesized complex
O
4+
R
H
R
X
LFe
X
Exclusive
Biomimetic studies (Synthetic systems)
[FeII(2PyN2Q)(OTf)2],
(ϵ
1954 M-1L-1) and 470 nm (ϵ
characterized by ESI-MS ([FeII(2PyN2Q)(OTf)]+, m/z
experimental 672.09; calculated = 672.09). Further, showed
paramagnetic shift in H NMR spectroscopy (shift from –60 to
140 ppm). Complex was also characterized by X-ray
crystallography (Figure 2). Synthesis of the reactive iron(IV)-
oxo ([FeIV(2PyN2Q)(O)]2+) complex
was performed by adding
MesI(OAc)2/mCPBA (1.5 equiv.) in acetonitrile and it showed
characteristic UV-vis band at 770 nm (ϵ
250M-1L-1). The
complex was further characterized by FT-IR spectroscopy
where FeIV=O stretching appeared at 832.5 cm-1.10c,11
Further, complex was characterized by Mössbauer
spectroscopy. Figure 3a presents the spectrum recorded at 80
K with a small field (60 mT) applied parallel to the rays. The
1
, showed UV-vis band at 368 nm
O
R
H
4+
887 M-1L-1). Complex
1
was also
R
X
R
R
OH
X
+
∼
∼
LFe
X
=
This Work
1
O
1
4+
LFe
R
H
1
+
[LFeX]X
2
Figure 1. sp3-C
−H halogenation by non-heme complexes
∼
Very recently Que and co-workers have employed high-
spin (S=2) iron(IV)-oxo-halide complexes, [FeIV(TQA)(O)(X)]2+
(X= Cl and Br) for sp3
2
C−
H halogenations.9 These elegant
2
explorations demonstrated that despite having the potential
for promoting selective halogenation chemistry, formation of
hydroxylation product often remained as the bottleneck for
the synthesis of selective halogenated compounds (Figure 1).
A clear opportunity for synthetic chemists, therefore, resides
on discovering a selective halogenation protocol by utilizing
the potential of non-heme iron(IV)-oxo complex.
γ
center of the spectrum is dominated by two overlapping
quadrupole doublets and a broad component can be discerned
on both sides and positive velocities. Application of a high
parallel magnetic field (7 T, Figure 3b bottom) turns the latter
component into a sextet extending from −
7.4 to 8 mms-1. By
contrast, the two central features are slightly broadened.
These two spectra can be simulated simultaneously by
considering the presence of three components (Table S1).11
Component A (red line in the simulations), which amounts to
35% of total iron, is a spin S=1 species with an isomer shift
0.043 mms-1, a quadrupole splitting EQ = 0.57 mms-1 and a D
ꢀ
δ =
value ca 26 cm-1. These parameters are consistent with a
FeIV=O species. Component B (blue line in the simulations, 12%
of total iron) is a µ-oxodiferric S=0 species with
and a quadrupole splitting
EQ = 1.5 mms-1. The additional
magnetic component (C, green line) can be accounted for by
considering that it is a high spin FeIII species (53%, S = 5/2,
δ
= 0.5 mm s-1
ꢀ
δ
=
0.56 mms-1, EQ = 0.72 mms-1). These Mössbauer experiments
ꢀ
thus show the formation of a iron(IV)oxo, FeIV=O, species
which is reactive at room temperature forming a µ-oxo diferric
species together with another ferric species.
Figure 2. ORTEP diagram of triflate anion coordinated iron(II)-
complex
iron(IV)-oxo
halide complexes
1
(CCDC 1505984), and DFT optimized structure of
, [FeIV(2PyN2Q)(O)]2+, ORTEP diagram of iron(II)-
(1505989) and (1505986)
2
3
4
Result and Discussion
We have explored a new strategy for the halogenation
reaction involving
a non-heme iron complex with the
expectation to discover a selective sp3-C–H halogenation
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value was found to be 9.6 (Figure 4d). The linearity in BEP plot
and large KIE value suggested that initial HAA step is the rate-
determining step (RDS) during C
0.176 (kcal/mol)-1) of the BEP plot is related with Bronsted
parameter (α) by = [slope.(RT)] and it gives α ∼ −0.10 i.e. the
value is closer to 0. The lower value of Bronsted parameter
suggest reactant like transition state is involved during C
−
H oxidation.13 The slope
(
−
α
−
H
oxidation reactions via HAA step which is further supported by
DFT study.14
18OH
CH3
OAc
CH3
Dissociative
Pathway
+
CH3
86% 18O
enriched
Radical trapped product
[MesI(OAc)2 as oxidant]
Figure 3. a) Mössbauer spectra recorded a 80 K and 60 mT top
and b) at 5.5 K and 7 T (bottom). Experimental spectra:
hatched bars; solid black line: simulation; colored lines:
contributions of species A (red), B (blue) and C (green).
18O
Dissociative
Pathway
N
Me
N
Fe4+
OH
Me
Me
N
N
N
Cis: Trans 3.7:1
Epimerization
Me
2
[FeIV(2PyN2Q)(O)]2+
Initially we opted for demonstrating the feasibility of HAA
step by iron(IV)-oxo species, [FeIV(2PyN2Q)(O)]2+
CH3
(
2
) during
C
−H oxidation. Substrates like ethylbenzene, toluene and
OH
Dissociative
Pathway
Major
cyclohexane yielded the corresponding oxidation products
when reacted with the room temperature stable iron(IV)-oxo
Figure 5. C− 2 (Reactions
H oxidation by [FeIV(2PyN2Q)(O)]2+,
were carried out under N2 atmosphere inside the Glove Box at
species 2.
25 °C)
We moved towards product analysis during C
to gain insights into the mechanistic pathway. When ethyl
benzene was reacted with complex it provided 1-
−H oxidation
2,
phenylethanol (34%), 1-phenylethylacetate (26%) and
acetophenone (5%) under N2 atmosphere. Control reactions
were carried out between 1-phenylethanol and MesI(OAc)2 as
well as between 1-phenylethanol and in situ generated
complex 2. None of these cases, 1-phenyl ethyl acetate was
detected. Therefore, the formation of 1-phenylethylacetate
during the reaction with ethyl benzene could occur via
reaction between cage-escaped radical and acetoxy radical
(•OAc) generated from MesI(OAc)2 during the reaction (Figure
5). This observation suggests that radical could dissociate from
the solvent cage after HAA step. Toluene and cyclohexane (N2
atmosphere) produced 48% of benzyl alcohol and 3% of
benzaldehyde (Figure 5), whereas cyclohexane provided
cyclohexanol (54%) and cyclohexanone (3%). Further,
Figure
4
.
(a) UV-vis change during
at 770 nm (c) bond
dissociation energy (BDE) correlation plot: Bell-Evans-Polyani
plot during C H oxidation by (d) kinetic isotope effect study
C−H oxidation of
ethylbenzene (b) time trace of
2
experiments with O-18 labelled
1-phenylethanol with 86% of O-18 labelling which supported
as the sole oxygen source during C
H oxidation.15
The C H oxidation reactions with ethylbenzene, toluene
2 and ethylbenzene provided
2
−
2
−
(kinetics studies were carried out under N2 atmosphere at 25
−
°C)
and cyclohexane under air was found out to produce
alcohol/ketone (A/K) products with a ratio of 1 or <1.
Additionally, radical trap experiments with CCl3Br were carried
out. Expectedly, cyclohexane and toluene provided exclusive
radical trapped product bromocyclohexane and benzyl
Kinetic study of C−H oxidation reactions were performed
(UV-vis, Figure 4a-b) under pseudo first order conditions. The
second order rate constant (k2) values were found to be 20
times higher when compared to the previously reported rates
of C−H oxidation by penta-coordinated nitrogen containing
bromide, respectively.
Similarly, ethylbenzene provided
iron(IV)-oxo species,15a,16 which could be due to the steric bulk
originating from quinoline moiety.12
radical trapped products (1-chloromoethyl)benzene (20%), (1-
bromoethyl)benzene (10%) and 1-phenylethylacetate (25%).
Such observations implied dissociation of the carbon radical
from the solvent cage,16 following which it undergoes a
The Bell-Evans-Polayni (BEP) plot (logk’2 vs BDE) showed
linear correlation (Figure 4c). Further we studied the kinetic
isotope effect (KIE, kH/kD) between C6H5CH3/C6D5CD3 and the
rebound with iron(III)-hydroxide to provide C−H oxidation
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product. Further the cage escape behaviour of the radical was the halide radical from iron(III)-halide intermediate to yield
confirmed by carrying out a reaction of pure stereoisomer of halogenation product preferably over hydroxylation (Figure 6).
cis-1,2-dimethylcyclohexane with 2. It provided a mixture of
Table 1. Scope for C−H bromination and chlorination
cis/trans-1,2-dimethylcyclohexanol (46% yield, 3.7:1 ratio). The
high-degree of epimerization in the products arises from a
long-lived radical, which could be generated due to the
dissociation of the radical from solvent cage after HAA (Figure
5).17
Although complex
sp3-C
H bond of cyclohexane, our attempts to promote
halogenation of cyclohexane by a combination of complex
and 1 equiv. of halide source Bu4N+Cl− or Bu4N+Br− failed. Such
an observation could be attributed to the inability of to form
reactive iron(IV)-oxo-halide intermediate with the
pentacoordinated 2PyN2Q ligand. Additionally, complex
reacted with halide anion faster compared to abstracting
hydrogen atom from sp3-C H bond of cyclohexane.18 We have
carried out the kinetic study for the oxidation of chloride (Cl−)
and bromide (Br−) by
. We found that second order rate
constant, k2 for Cl− and Br− oxidation are 221 and 938 M-1 s-1
respectively. The complex
oxidizes Br− faster than Cl−, which
in turn is much faster compared to hydrogen atom abstraction
2 was found to be suitable for HAA from
−
2
2
2
−
2
2
process (for C−H oxidation of toluene and cyclohexane the
second order rate constants are k2 0.0242 and 0.011 M-1s-1
respectively).11
With these unsuccessful attempts, our attention returned
to the existing report for the formation of a mixture of
halogenation and hydroxylation products. Notably, halide
rebound of cage escaped radical with metal-halide was well
documented with Mn-catalyzed fluorination reaction by
Groves and co-workers.19 We envisioned that if we can
outcompete iron(III)-hydroxide (formed upon HAA of sp3-C
bond by ) with iron(III)-halide, then the cage-escaping carbon
−H
2
centered radical will undergo rebound with iron(III)-halide. The
iron(III) halide can potentially act as a suitable halide donor
and can be generated in situ via one-electron oxidation (by
oxidant mCPBA) of the corresponding iron(II)-halide complexes
[FeII(2PyN2Q)(X)](X) [X = Cl (
of with and cyclohexane led to the formation of
bromocyclohexane (90%) product selectively (Table 1, entry 1,
as the limiting reagent under N2 atmosphere). Use of excess
amount of was detrimental for the formation of
3) and Br (4)] (Figure 2). Reaction
4
2
4
4
bromocyclohexane. Furthermore, we focussed on the
discovery and implementation of the new strategy for
promoting selective halogenation reaction by overcoming the
hydroxylation chemistry described above. The chlorination
aMinor hydroxylation (
∼5% w.r.t. 3 or 4). Reactions were carried out
reactions with cyclohexane in presence of
2 and 3 gave 52%
under N2 atmosphere inside the Glove Box at 25 °C
yield of chlorocyclohexane with 5:1 selectivity for halogenation
over hydroxylation (Table 1, entry 2).
Further in order to get mechanistic insight, we synthesized
iron(II)-halide complexes with perchlorate as counter anion,
The appreciable levels of selectivity for the synthetic non-
heme iron-oxo mediated halogenation chemistry clearly
suggest that the carbon centered radical, generated upon
HAA, escapes the solvent cage and combines with the free
[FeII(2PyN2Q)(X)](ClO4), X = Cl,
5
(1516453), Br,
and characterized these complexes by X-ray crystallography.
Interestingly, when was used for bromination of
cyclohexane, we selectively obtained bromocyclohexane (7:1).
Similarly, employing complex we obtained selective benzylic
6 (1516421),
6
halide radical generated upon halide oxidation by 2. Similar to
5
non-heme halogenase enzymes, this carbon radical engages
chlorinated product with 4-tertbutyltoluene. Moreover the
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solution of 4 (also 6) with 0.5 (or 1 equiv.) mCPBA provided of halogenated products) can also be accounted for higher
brominated product efficiently and therefore suggested the selectivity.6 The formation of iron(III)-halide complex could
feasibility of one electron oxidation of these halide complexes also occur via substitution by halide anion from iron(II)-halide
to provide iron(III)-halide required for halide rebound step complex (Figure 6). Furthermore, we observed that the use of
(Figure 6).20 Additionally, we have tested the possibility of one mCPBA as an oxidant, instead of MesI(OAc)2, during
electron oxidation of the halide complexes by recording EPR bromination
spectrum of with 0.5 equiv. or 1 equiv. mCPBA (pre-oxidized bromocyclohexane product yield from 18% to 90%. The ease
solution) in acetonitrile at 4 k. The EPR spectra showed of hydroxide substitution by halide ion in presence of H+ from
rhombic signal (g1 1.99, g2 4.38, g3 6.24) which is mCPBA can be accounted for higher yield. Similar substitution
characteristic of a high spin (S 5/2) iron(III)-species (Figure of hydroxide bound to iron centre in presence of proton
7).21 These observations suggested that the halide complexes
source was elegantly described by de Visser, Hillier and Paine
and (also and
) possibly undergo one electron oxidation in groups (Figure 6).11,26
reaction
with
cyclohexane
increases
6
=
=
=
=
5
6
3
4
presence of 2 equiv. mCPBA used in halogenation to provide
iron(III)-halide which would undergo halide rebound with the
cage escaped radical (Figure 6). Moreover, we have measured
the one electron oxidation potential of halide complexes (
by cyclic voltametry study. The halide complexes, showed
FeII/FeIII oxidation potentials around
0.9 1.0 V in acetonitrile
3-6)
3-6
∼
−
vs SCE (saturated calomel electrode). Thus it can be oxidized
by mCPBA as the oxidation potential of peracids are around,
∼1.8-2.0 V.22 However, we have not observed any peak around
770 nm in UV-vis upon portion wise addition of mCPBA to the
[(L)Fe(III)X]X complexes, which indicates that for the system
under study Fe(III)-X might not undergo oxidation by mCPBA
(Figure S38).11 Notably as the iron(II)-halide complexes (
3-6)
undergo rapid one electron oxidation under the halogenation
reaction condition and generate iron(III)-halide species, they
do not participate in the known comproportionation reaction
with
iron(IV)-oxo
2
.
However,
possibility
of
Figure 7. EPR spectrum showing one electron oxidation of 6 using
0.5 of mCPBA (Temperature 4 k, X-band frequency 9.376 GHz,
Modulation Amplitude 4G, Modulation Frequency 100 KHz,
Attenuation 22 dB).
comproportionation reaction cannot be completely ruled out.
OH
3+
LFe
+
R
HydrogenAtom
Abstraction
Cage Escaped
RDS step
N
N
R
H
N
N
N
O
L=2PyN2Q
4+
LFe
ArCO3H
2+
LFe
OH
3+
LFe
+
R
2+
LFe
2+
2+
[LFe(X)]X
[LFe(X)]Y
Y= Cl-, Br-,ClO4-, ArCO3
Substitution
of hydroxide
-
ArCO3H
X= Cl, Br
Oxidation
by ArCO3H
R
X
2+
-
X
[LFe(X)][ArCO3 ]
Halide Rebound
3+
+
HOH
R
+
LFe
Figure 6. Plausible mechanism of C
oxo, in presence of iron(II)-halide complex
−
H halogenation by iron(IV)-
or
2
3
4
Figure 8. (a) UV-vis change during bromination of toluene, (b)
inset 770 nm decay plot of 2 during bromination of toluene, (c)
The higher selectivity of bromination over chlorination can
be rationalized by ease of halide rebound of the cage escaped
radical with iron(III)-bromide compared to iron(III)-chloride
(Figure 6). Additionally the ease of formation of Br• from Br−
kinetic isotope effect study during bromination reaction
(kinetics studies were carried out under N2 atmosphere at 25
°C)
(E0
− −
•, 1.07 V vs SHE) compared to Cl• from Cl− (E0 •, 1.36
No halogenation products were obtained in presence of
Br /Br Cl /Cl
air; rather we obtained exclusive C−H oxidation products. This
phenomenon suggested that cage escaped radical was
V vs SHE) from complexes
3 and 4 (which can combine with
the cage escaped radical and can lead to the partial formation
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intercepted by O2 (air).23 Further studies were carried out in N(1)
Journal Name
−
Fe
−
O angle which has been found to be 170.1
°degree
order to get insights about these selective halogenation (for most of the Fe(IV)
reactions. Addition of [FeII(2PyN2Q)Br](Br) ( ) to a solution of to be close to linearity).28a,c Other notable differences in
[FeIV(2PyN2Q)O]2+
) showed the iron(IV)-oxo band at 770 nm species , include two strong C ...O interactions between the
(Figure 8a). This experiment suggests that iron(IV)-oxo exists in C(8) H-atom of the quinoline and ferryl-oxygen atom and the
solution in presence of iron(II) halides. Iron(IV)-oxo is the key distances are noted as 2.016 Å. This interaction likely to
species for the initiation of the halogenation reactions. The weaken the Fe bond in species compared to
=
O species reported this angle is found
3
(
2
2
−H
−
−
O
2
kinetic isotope effect study between C6H5CH3 and C6D5CD3 [FeIV(N4Py)O]2+ species where such interactions are absent.
under standard halogenation reaction conditions gave a value Besides, the steric crowding at the active site offered by the
of 13.5 (Figure 8c), which supported initial HAA step as the quinoline ligand could hinder or facilitate the reactions further.
rate determining step.
The spin density distribution reveals a strong oxyl-radical
character at both the S=1 and S=2 states with the oxygen atom
possessing a significant spin densities. Interestingly, the H-
Following the above protocol, cyclopentane, cycloheptane,
cyclooctane and norbornane were subjected to the same
reaction conditions. Expectedly, selective formation of
halogenation products was encountered in these cases (Table
atoms involved in the C−H...O interactions with the ferryl-
oxygen atoms are strongly polarized with sizable negative spin
density (Figure 9b) and this is similar to the behavior observed
earlier with strong H-bonding ligands.25 The Eigen-value plot of
the S=1 state computed is shown in Figure 9c. Due to two
1, entries 3-6). After successful halogenation of the sp3-C
−H
bond of aliphatic substrates, we decided to explore benzylic
halogenation. Under the standard reaction protocol, toluene
provided benzyl bromide in an excellent yield (97%, Table 1,
entry 7). Differentially substituted benzylic substrates provided
selective brominated products as well (Table 1, entries 8-12).
Interestingly, 4-tertbutyltoluene showed excellent selectivity
towards benzylic chlorination (Table 1, entry 13). By overriding
the hydroxylation reaction, ethyl benzene was chlorinated at
the benzylic position selectively (Table 1, entry 14).
weaker Fe−N bonds in the equatorial plane, the Fe−N anti-
2
bonding interaction diminishes for the σ*x 2 orbital leading to
-y
2
smaller gap between the
π
*
and the σ*x 2orbital
xz/yz
-y
compared to the [FeIV(N4Py)O]2+species and this lead to
smaller triplet-quintet gap. Besides, the degeneracy between
the
π
*
and d
π
*
orbitals is lifted due to weak C−H...O
yz
xz
interactions.With these insights into the electronic structure of
the active species, we turn to study the mechanistic aspect.
The mechanism adapted for DFT calculations is shown in
Computational Study
Figure 10. In the first step, C
species is expected.
−H bond activation by Fe(IV)=O
To fully comprehend the mechanistic proposal based on the
experimental evidences, we have turned to computational
tools where B3LYP/LACVP//B3LYP/TZVP set up has been used
to model the reaction pathway for the halogenation reaction
(see computational details for elaborate discussion on the
methodology employed). To begin with, calculations are
Initially, the Fe(IV)=O moiety abstract the H-atom from the
cyclohexane via ts1 leading to the formation of Fe(III)-
hydroxide and radical intermediate (int1) where carbon
centered radical at the cyclohexane is expected. This radical
species is expected to be in the vicinity of the Fe(III)
stabilized by weak non-covalent interactions (cage-radical
species). For the C H bond activation, the barrier heights are
−OH units
performed on the putative [FeIV(2PyN2Q)O]2+(
2) species.
−
Calculations reveal S=1 as the ground state for this species
with the S=2 and S=0 states lie at 12.7 kJ/mol and 121.2 kJ/mol
higher in energy, respectively. The ground state predicted by
the calculations is consistent with the Mössbauer observations
and in accord with the literature reports for such
pentadentateaminopyridine ligands.15b,28 While the ground
state is same as that of the structurally similar [FeIV(N4Py)O]2+
computed to be 69.4 kJ/mol and 96.0 kJ/mol in the quintet and
triplet surfaces, respectively. For S=0 state on the other hand,
the computed barrier height is prohibitively high (175.2
kJ/mol) and rules out the possibility of S=0 participating in the
reaction mechanism. Although triplet state is the ground state
for the Fe(IV)=
lowest energy barrier for the C
O species, the quintet state is found to have the
H bond activation and this
−
species, the S=2 excited state found to lie closer in species
2
suggest a two-state reactivity scenario as has been witnessed
in several other cases.21a,32
and this is attributed to the steric and electronic differences in
the ligand moiety. Smaller triplet-quintet gap is known to
enhance the reactivity in iron(IV)-oxo species as reported
earlier.29,30
Optimized structure of the transition state corresponding to
S=2 is shown in Figure 11a. In the 5ts1, the Fe
−
O bond is
elongated from 1.626 Å to 1.693 Å whereas the C−H bond is
stretched from 1.101 Å to 1.194 Å. The distance for the newly
The optimized structure of the S=1 state is given in Figure 9(a).
The Fe
consistent with the experimental data reported for other
Fe(IV)
O species.24 Since an asymmetric ligand environment is
maintained at the equatorial plane with two strong pyridine
donors and moderate quinoline donors, two sets of Fe
distances are visible with Fe NQu distances slightly longer than
the Fe Npy distances (Figure 9(a)). Due to the steric hindrance
−O bond length is found to be 1.626 Å which is
developed O...H interaction is 1.432 Å. All these parameters
indicate that the Fe−O double bond and C−H bond are not
broken completely in the transition state suggesting a reactant
5
like transition state. The spin density plot of ts1 (Figure 11b)
=
−
N
clearly suggest transfer of α-electron from the substrate to the
Fe-center and this is also reflected in the enhanced value of
spin densities computed at the Fe centre for the transition
−
−
of the quinoline group, the ferryl oxygen atom found to incline
state revealing
σ
-type pathway (Figure 12a-b) as shown in the
towards the pyridine ring and this is clearly reflected in the
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orbital evolution diagram. In the 5ts1 transition state, the species, except for the fact that the Fe
−O…H angle is
Fe O…H angle is estimated to be 167.3 degrees and this estimated to be 127.4 degrees indicating -type pathway at
−
indicate a -type pathway for the H-atom abstraction reaction. the S=1 surface.
°
°
π
σ
Similar scenario is witnessed also for the high-lying 3ts1
Figure 9. (a) Important structural parameters and (b) spin densities of B3LYP-D2 optimized structures of the [FeIV(2PyN2Q)(O)]2+,
(c) Key orbitals of 3K.
After H-abstraction transition state, int1 formation is expected steeply higher compared to −OH rebound barriers reported for
and this step is computed to be endothermic for all the spin the related [FeIV(N4Py)O]2+ species. The optimized structure of
states. For int1 species, a triplet state arising from S=1 spin 5ts2 species along with selected structural parameters
surface is found to be the lowest lying in energy (10.5 kJ/mol) computed for other spin states are given in Figure 14. At the
followed by the quintet state at 20.7 kJ/mol (5int1hs). Besides transition state, the Fe
−O(H) bond is elongated to 1.920 Å and
3
1
these two states, int1is, 7int1hs, 3int1ls and int1ls states found the newly developed O...C interaction is still longer (3.268 Å).
to lie at 22.4, 27.3, 61.8, and 66.5 kJ/mol higher in energy, The cyclohexane is attempting to approach between the
respectively. Next obvious step from the int1 is −OH rebound pyridine and quinonline ring and this is still a sterically
transition state (ts2) where the hydroxide is expected to hindered position as evidenced from the distortions seen in
rebound to the radical intermediate leading to the the quinonline moiety which lie closer to the cyclohexane
hydroxylated product. We have computed rebound transition substrate. This structural deformation adds an energy penalty
state at the triplet, quintet and septet states. The energetic leading to a very large barrier height for hydroxylation to occur
cost associated with the hydroxylation step is estimated to be (see below for further discussion on this aspect). Due to the
173.0 kJ/mol at the quintet surface (5ts2) and this is the lowest stronger C
−
lying transition state with other two spin surfaces found to lie atom of the
H...O interactions, positioning of the hydrogen
OH group is restricted and this leads to the
−
even higher in energy (35.6 and 117.2 kJ/mol for ts2 and ts2 substrate to approach from a sterically hindered position
3
7
5
respectively, compared to the ts2 species, see Figure 13). The leading to a large barrier. The formation of the hydroxylated
5
barrier heights computed for the hydroxylation step are product is exothermic with the POH lying at -132.5 kJ/mol
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1
3
followed by POH and POH at -82.4 and -80.5 kJ/mol, [FeIV(N4Py)O]2+ species and this is very similar to the one
respectively. The computed OH rebound barrier height for computed for . This clearly reveals that the additional phenyl
[FeIV(N4Py)O]2+ species with cyclohexane substrate is reported ring attached to the ligand in
substantially increase the
−
2
2
to be 55.2 kJ/mol at the quintet surface with a slightly kinetic barrier height to prevent facile hydroxylation reaction,
different computational set up.26 The hydroxylation product albeit the thermodynamics of reactions remain similar.
formation energy is reported to be
−153.5 kJ/mol for
Figure 10. Adopted mechanism for the DFT calculation for the halogenation/hydroxylation of cyclohexane by the putative Fe(IV)-
O species.
Since the hydroxylation step is computed to be kinetically ligand exchange (Figure 10). We have computed the
hindered, in the next step, the cyclohexyl radical species is thermodynamics of this reaction and the formation of int3 is
assumed to leave the proximity of the Fe(III)
leading to the formation of cage-escaped radical and lowest in energy (
Fe(III) OH intermediate (int2). This step is computed to be species at 166.6 kJ/mol and +3.4 kJ/mol respectively. For the
endothermic in energy with the 6int2 species lying at 46.9 2int3 species the Fe
Cl bond distance is estimated to be 2.262
kJ/mol and 4int2 and 2int2 at 64.7 and 68.7 kJ/mol higher in Å and the
Cl atom also found to bend towards the pyridine
energy, respectively. The optimized structure of the 6int2 is ring with the N(1)
Fe Cl bond angle estimated to be 159.4
shown in Figure 14, here the Fe O(H) bond distance is and this is smaller than that found for the corresponding
estimated to be 1.812 Å revealing a Fe O single bond Fe(III) OH species. The Fe atom possess a spin density of 1.048
character and the N(1) Fe O angle is 164.6 revealing further at the ground state with some spin density delocalized to the
−
OH species substantially exothermic with the 2int3 species being the
−
170.7 kJ/mol) followed by 4int3 and 6int3
−
−
−
−
−
−
°
−
−
−
−
−
°
inclination towards the pyridine rings as the Fe
−
O bond
−Cl atom (see Table S6 in supporting information).
Subsequently, the cage-escaped cyclohexyl radical species
strength weakens.
In the next step, addition of Fe(II)
−
expected to generate Fe(III) Cl (also can be generated by one to the formation of {Fe(III)
Cl in the reaction mixture is penetrate into the coordination sphere of int3 species leading
Cl....cage radical} species (int4)
−
−
−
Cl by mCPBA) (int3) species by and this formation is also found to be excessively exothermic
electron oxidation of Fe(II)
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with respect to the Fe(III) Cl formation by
quintet surface (5int4). The 7int4 and 1int4 species are found to vicinity of the complex with the Fe
−
−
72.4 kJ/mol for the 5int4 species. At the ground state, the radical species is in the
C(radical) distance is
−
be 66.0 and 74.8 kJ/mol respectively, higher compared to the estimated to be 3.06 Å and stabilized purely by the dispersion.
Figure 11. (a) Important structural parameters of the B3LYP-D2 optimized structures of the ts1 and (b) spin densities of B3LYP-
D2 computed 5ts1.
(a)
(b)
2
2
2
σ*z
σ*z
2
σ*x
2
2
ꢀy
σ*x
ꢀy
ꢀ*xz/yz
ꢀ*xz/yz
δxy
σCH
σCH
δxy
S=2
S=2
Figure 12. (a) Orbital occupancy diagrams for the H-abstraction process and (b) corresponding orbital selection rules for
predicting Transition-State structures.
Further, the rebound of the –Cl from the {Fe(III)
radical} (int4 via ts3 is expected. Transitions states has a lower-bound barrier of 51.3 kJ/mol, significant gain in
corresponding to the –Cl rebound have been calculated for energy upon replacing the –OH by –Cl lead to overall negative
three different spin surfaces with the 5ts3 found to be the energy for the transition state 5ts3 from the Fe(IV)
−Cl....cage Å to 2.602 at the transition state. Although this transition state
)
=
O
lowest energy transition state with an estimated barrier height reactant, suggesting that the reaction is expected to take place
of 51.3 kJ/mol for –Cl rebound. This is followed by two other very rapidly without any significant kinetic barrier. In the next
3
7
transition states, ts3 and ts3 at 21 kJ/mol and 101.4 kJ/mol step, formation of the chlorinated product takes place and this
5
higher compared to the ts3 transition state. The geometry of is computed to be exothermic in nature with {5P + PCl} being
5
the ts3 transition state is shown in Figure 14, along with the the ground state with the formation energy of
−
61.0 kJ/mol.
structural parameters computed for other two transition The {1P + PCl} and {3P + PCl} spins states of the products are
states. At the 5ts3 transition state, the newly forming higher in energy by 40.9 kJ/mol and 43.0 kJ/mol from the
Cl….C(cyclohexane) distance is estimated to be 2.368 Å and ground state {5P + PCl} species.
this is slightly lower than that found for the corresponding It is worth comparing the computed mechanistic aspects to the
intermediate. Similarly the Fe−Cl bond is elongated from 2.439 experimental findings. To begin with, the triplet-quintet gap
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for species
2
is drastically lower compared to the [FeIV(N4Py)O]2+ species. Secondly, upon H-atom abstraction, a
[FeIV(N4Py)O]2+species due to the difference in the geometry cage-radical formation takes place, which is slightly
as discussed earlier. The
computed at S=2 surface for species
step of the halogenations reaction. This barrier is estimated to correlated to the difference in the ligand structure (both steric
be 69.4 kJ/mol for species , while the same is computed to be and electronic effects). Although significant barrier for –OH
79.9 kJ/mol for [FeIV(N4Py)O]2+species.26 As the Fe N bonds rebound has also been computed for [FeIV(N4Py)O]2+,26 in our
present in the equatorial planes are unsymmetrical and longer case the barrier is much larger suggesting a possibility of cage-
C
−
H
bond activation barrier endothermic in nature. However there is a substantial barrier
2
is the rate determining for the –OH rebound from the Fe(III) OH species. This is
−
2
−
for species
barrier for C
2
compared to [FeIV(N4Py)O]2+, the estimated escape. This is also supported by the control experiments
H bond activation is lower. This is also reflected performed with species and cyclohexane,toluene and ethyl
−
in the control experiments performed with cyclohexane where benzene as substrates.
2
species 2 is found to react 20 times faster compared to the
Figure 13. Depiction of B3LYP-D2-computed potential energy surface (∆G in kJ/mol) for the C
rebound process b) the cage escape and subsequent halogenation pathway. Horizontal lines represent the spin state: high spin
by green color, low spin state by blue and intermediate state by red. The C H bond activation pathway is shown in black, with
the –OH rebound leading to hydroxylation in pink and –Cl rebound leading to halogenations pathway in orange.
−H activation followed by a) O−H
−
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The radical escaping from the Fe(III)
−
OH species is computed Fe(III)
−
Cl
and
Fe(III)
−
OH.
The
formation
of
to be slightly endothermic (by 46.9 kJ/mol) and suggest that {cyclohexylradical….Fe(III)
such an event is certainly possible with species
essentially due to the fact that, the additional quinoline
present in the ligand moiety exerts steric repulsion to the 72.4 kJ/mol. Thus the energetic gain associated with the
radical species and the phenyl rings of the quinoline are also formation of {cyclohexylradical….Fe(III) Cl} is more than
not in favorable orientation for a C H… interaction with the compensated by the energetic loss due to the cage-escape
radial species. Thus strong anchoring of the radical species process from the {cyclohexylradical….Fe(III) OH}. The
with the Fe(III) OH species is absent leading to the cage- stabilization of {cyclohexylradical….Fe(III) Cl} compared to the
escape being the favored pathway. In such scenario, the corresponding Fe(III) OH is also correlated to the variation in
radical is expected to have longer life time leading to the electronic structure. The cyclohexylradical in the
stereochemical scrambling and this is also witnessed in the {cyclohexylradical….Fe(III) Cl} caged species lie in closer
control experiments performed with species . Addition of proximity to the complex and the carbon radical found to
Fe(II) Cl complex into the solution, however, changes possess a smaller spin density suggesting a long range
drastically the scenario as the exchange between –OH and –Cl electron-transfer from the radical to the {Fe(III) Cl} complex
is found to an energetically favourable exothermic process. leading to a variation in the electronic structure and hence the
Besides the radical cage formation with the Fe(III) Cl is found energetic gain. This electron transfer is supported by the high
−
OH} from the Fe(III)
−
OH is
2. This is exothermic by 36.4 kJ/mol while the formation of
{cyclohexylradical….Fe(III) Cl} from Fe(III) Cl is exothermic by
−
−
−
−
π
−
−
−
−
−
2
−
−
−
to be further exothermic suggesting the clear possibility of the electron affinity difference between the two species {EA[Fe(III)-
cage-escaped radical to preferably penetrate in to the Cl]=-122.95 kCal/mol and EACy•=-47.43 kCal/mol).This is also in
coordination sphere of Fe(III)
informative to compare the cage-radical species the highest occupied molecular orbital of Fe(III)-Cl complex is
−
Cl species. It is highly agreement with the ionization potential of the two.27 Again
{cyclohexylradical….Fe(III)
{cyclohexylradical….Fe(III)
−
−
Cl}
and lying lower in energy than that of the radical system, indicative
OH} from the corresponding of the feasibility of electron transfer.
Figure 14. B3LYP-D2-optimized structures with selected structural parameters: (a) 5,5,3int1, (b) 2,4,6int2, (c) 3,5,7ts2, (d) 1,3,5P+POH
(e) 2,4,6int3 (d) 3,5,7int4 (f) 3,5,7ts3, (g) 1,3,5P+PCl
Now we turn to analyze the transition state corresponding to barrier for –OH rebound from Fe(III)
−
the hydroxylation and halogenation reaction to ascertain why while for –Cl rebound from the Fe(III)
OH species is 173 kJ/mol
Cl is estimated to be
−
. The lower-bound 51.3 kJ/mol. Both the lower-bound barriers are for the quintet
halogenation is favoured with species
2
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surface and hence the difference due to the nature of spin-
states can be ruled out. Particularly, the –OH rebound barrier
is substantially higher and this is correlated to the approach of
cyclohexyl radical towards the hydroxyl group. Strong
deformation at both the complexes and the substrate is noted
for this transition state with the total deformation energy is
computed to be 111.1 kJ/mol for the quintet transition state.
As the barrier computed is 173 kJ/mol, the difference of 61.6
kJ/mol is due to electronic contribution to the transition state.
The deformation energy clearly reveals that the steric factor
dominates the barrier height and is the primary reason for
such a large barrier height. The deformation energy computed
for the –Cl rebound transition state is much lower (40.0
kJ/mol), although here as well the steric factor seems to
dictate the terms of the kinetic outcome. A careful look at the
geometries of both the transition state reveals that the
cyclohexyl radical needs to approach closer to the Fe centre in
Experimental Section
Materials and Methods.
All 1H NMR spectra were reported in units of parts per million
(ppm) and measured relative to the signals for residual
chloroform (7.26 ppm) in CDCl3/ and for residual CH3CN in
CD3CN at 1.96 ppm, unless otherwise stated. All 13C NMR
spectra were reported in ppm relative to CDCl3 (77.23 ppm),
unless otherwise stated and were obtained with 1H
decoupling.
Acetonitrile, CD3CN, FeIICl2, FeIIBr2,
trimethylsillyltriflate (TMSOTf) were purchased from Sigma
Aldrich. Diethyl ether was procured from Spectrochem
chemicals. Ethylbenzene was bought from TCI. H218O was
purchased from Sigma Aldrich and ICON-isotope. 2-
(Chloromethyl)quinoline hydrochloride was purchased from
TCI and di(2-pyridyl)ketone were purchased from alfa aeser.
All the products were analyzed by GC-MS analysis. GC-MS was
performed on a Thermo Scientific ISQ QD Mass Spectrometer
attached with Thermo Scientific TRACE 1300 gas
chromatograph using an HP-5ms capillary column (30 m×0.25
mm×0.25 μm, J&W Scientific) with helium as the carrier gas.
The product yields were calculated from GC trace by
comparing with the area percentage of standard products.
Fe(III)
are estimated to be 1.920 Å at the transition state. For the –Cl
rebound transition state, however, the Fe(III) Cl distances are
−OH rebound transition state as the Fe(III)−OH distance
−
much longer (2.602 Å). Therefore, the very close approach
(causing steric repulsion with the bulky quinonline ligand) is
avoided. This leads to a lower barrier height. Additionally, the
energetic gain upon exchanging the –OH by –Cl ease out the
energetic cost of the chlorination, since the –Cl rebound is a
barrier-less process. A facile chlorination is likely happening
Kinetics study.
All the kinetics studies were carried out at 25 °C under N2
atmosphere. First order rate constants (k1) were calculated
based on non-linear exponential fit in OriginPro8 software. All
the kinetics were carried out in pseudo-first-order conditions.
The rate constant (k1) was calculated based on the decay
pattern of iron(IV)-oxo complex at 770 nm by nonlinear curve
once the C
note that the cyclohexyl radial species formed upon hydrogen
atom abstraction needs to escape from the Fe(III) OH cage
Cl species to complete the
−H bond abstraction completes. It is important to
−
and penetrate back in to the Fe(III)
chlorination.
−
*
fitting, [y = y0 + A*exp(R0 x)], (where x is time, t and R0 is rate
The cage-escaped radical could choose to react via other
possible routes. This is consistent with the experimental
observations that in the presence of air, due to auto-oxidation
process, other product such as ketone and alcohol are
witnessed.
constant, k1, y is absorbance) and showed good fit in rate
constant value within 10% error. Resulting k1 values
corroborated linearly with substrate concentration to give
second-order rate constant k2. All the sp3 C-H oxidation and
halogenations reactions were carried out at 25 °C under N2
atmosphere inside the Glove Box.
As steric congestion of the quinoline at the rebound barrier
determines the rate of the reaction, one can rationalize the
faster bromination reactions compared to chlorination that
Instrumentation
.
NMR spectra were recorded on a Bruker 400 /500 /750 MHz.
ESI-MS spectra were performed in Bruker QTOF ESI-MS
instrument. UV-vis kinetics studies were performed in
Agilent 8453 diode array based UV-vis Spectrophotometer.
Single crystals were diffracted in Rigaku X-ray single crystal
diffractometer. GC-MS was performed on a Thermo Scientific
ISQ QD Mass Spectrometer attached with Thermo Scientific
TRACE 1300 gas chromatograph using an HP-5ms capillary
column (30 m×0.25 mm×0.25 μm, J&W Scientific) with helium
as the carrier gas and Agilent 7890A GC system connected
with 5975C inert XL EI/CI MSD (with triple axis detector). EPR
was recorded in Bruker EMX plus series instrument using X-
band at 4 K. Mössbauer spectra were recorded at 5.5 Kor 80 K
on a lowfield Mössbauer spectrometer equipped with a Janis
CCR cryostat and at 5.5 K on a strong-field Mössbauer
spectrometer equipped with an Oxford Instruments
are witnessed in the experiments. As the Fe(III)−Br distances
are expected to be longer than the Fe(III) Cl bond, therefore
−
rebound of –Br at the transition state is expected to have less
steric repulsion than the corresponding –Cl rebound transition
state. This is expected to reduce the barrier even further
leading to faster reactivity for bromination compared to
chlorination.
Conclusions
In summary we have developed a new strategy for selective
halogenation by using a room-temperature stable non-heme
iron(IV)-oxo complex in presence iron(II)-halide complex. The
interplay of non-heme iron(IV)-oxo and iron(II)-halide
complexes provided selective halogenation. The present
strategy and detailed theoretical investigations are expected
to have immense importance for further development of
selective halogenations methods.
Spectromag 4000 cryostat containing an
8 T split-pair
superconducting magnet. Both spectrometers were operated
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in a constant acceleration mode in transmission geometry. mmol, 2.2 g) was added to an aqueous solution of sodium
The isomer shifts were referenced against that of a metallic hydroxide (NaOH) (5 mL, 5 M) at 0 °C. After stirring for 10
iron foil at room temperature. Analysis of the data was minutes, the solution was added to bis(2-pyrimidyl)
performed with the program WMOSS (WMOSS4 Mössbauer methylamine (0.97 g; 5.23 mmol) and another portion of
Spectral Analysis Software, www.wmosss.org, 2009-2015) and aqueous solution of NaOH (5 M, 5 mL).30 The solution was
a home-made program.28
allowed to stir for 36 hours at room temperature and then
concentrated perchloric acid (HClO4) was added dropwise to
get a sticky brownish precipitate, which was recrystallized
from hot water. Treatment of this perchlorate salt with 2.5
(M) NaOH solutions and extraction with dichloromethane
yielded yellowish solid 2PyN2Q in 40% yield. The synthesized
Computational details.
All calculations are performed using the Gaussian 09 suite of
program. The geometries are optimized using B3LYP-D2
functional which incorporates the dispersion proposed by
Grimme et al.29 The geometry optimization is performed using
LACVP basis set, comprising the LanL2DZ double ζ-quality basis
set with the Los Alamos effective core potential for Fe and 6-
31G* basis set for the other atoms. Single point energy
calculations are performed on the optimized geometries using
a TZVP basis set on all atoms. PCM model is used to
incorporate solvent effects on the geometries using include
the role of solvent on the geometries and energies of the
optimized structures. Here we have used acetonitrile as a
solvent for our computation. We have computed frequency
for all the geometries and confirmed the minima/transition
state nature. All the transition states are characterized by one
imaginary frequency corresponding to the expected reaction
coordinate and verified by animating the vibration mode using
Chemcraft. All the other species possess only positive
frequencies. All the energies reported are free energies
including the zero-point, enthalpy and entropic contributions
unless specified otherwise.
1
ligand was thoroughly characterized by H, 13C NMR and ESI-
MS analysis. The obtained NMR data for ligand, 2PyN2Q: 1H
NMR (500 MHz, CDCl3, δ): 4.21 (s, 4H), 5.452 (s, 1H), 7.11 (2H),
7.45 (2H), 7.60-7.68 (6H, m), 7.73 (2H), 7.80 (2H), 8.01 (4H),
8.58 (2H). 13C NMR (125 MHz, CDCl3): δ 58.40, 72.69, 121.51,
122.40, 124.51, 126.20, 127.36, 127.55, 129.06, 129.44,
136.33, 136.57, 147.60, 149.44, 160.54, 160.02. ESI-MS
([M+Na]: observed, 490.197 calculated for C31H25N5Na:
490.20).
Synthesis and characterization of iron(II)-complex 1,
[FeII(2PyN2Q)](OTf)2.31
The ligand 2PyN2Q (1.2 mmol) and iron(II)-precursor complex
Fe(OTf)2.2CH3CN32 (1.0 mmol) were reacted for overnight in
excess amount of acetonitrile (40 mL) inside the glove box.
The reaction mixture was concentrated by applying vacuum.
Then excess dry diethyl ether was added to the reaction
mixture and the schlenk was shaken vigorously to get
precipitate of complex. The mixture was kept undisturbed to
settle down the precipitate of complex at the bottom of the
schlenk flask. The clear solution part above the precipitate was
decanted off. Then the precipitate was dried properly by
applying vacuum and kept under N2 atmosphere of glove box.
Resultant complex was crystallized from dichloromethane and
diethyl ether solvent mixture. The corresponding triflate anion
coordinated single crystal was grown from acetonitrile-
toluene or acetonitrile-diethylether solvent combination. The
obtained complex was characterized spectroscopically. UV−vis
(MeCN): 368 nm (ϵ~1954 Lmol−1cm−1) and 470 nm (ϵ~1954
Lmol−1cm−1). ESI-MS (observed, 688.090 calculated, 688.093),
Elemental Anal. (Calculated for C33H25F6FeN5O6S2,) C, 48.25; H,
3.07; N, 8.52; S, 7.80; found: C, 48.145, H, 3.30, N, 8.256, S,
7.65.
Synthesis and characterization of 2PyN2Q ligand.
Hydroxylamine hydrochloride (750.5 mg, 10.8 mmol) and
sodium acetate (NaOAc) (886 mg, 10.8 mmol) were heated in
10 mL of distilled water at 60 °C for one hour. After heating
the solution for one hour, a solution of di(2-pyridyl)ketone (1g,
5.43 mmol) in 5 mL MeOH was added. The resulting mixture
was stirred at 80°C overnight. Consequently the pink color
solidified oxime was obtained. The product oxime was washed
with methanol (MeOH) and the solvent was dried over rotary
evaporator. The crude oxime, a pink solid, was used in the
next step without further purification. The above prepared
oxime (1 g, 5 mmol), ammonium acetate (NH4OAc, 655 mg,
8.5 mmol), ammonia (NH3, 25% aqueous solution, 15 mL),
ethanol (20 mL) were mixed along with 10 mL of water heated
at 80 °C. Activated Zn dust (1.47 g, 22.5 mmol) was then
added to the reaction mixture in small amounts for over a
durarion of 30 minutes. The resulting mixture was refluxed for
4 hours and then stirred at room temperature for overnight.
The mixture was filtered and the residue was washed with
methanol (MeOH) and water. The filtrate was concentrated
and the resulting aqueous solution was made strongly alkaline
with 10 (M) sodium hydroxide (NaOH) solution. The amine
was then extracted with dichloromethane and the organic
phase was then washed with brine, dried over Na2SO4 and
concentrated in ratory evaporator and vacuum to afford
brown oil. 1H NMR (400 MHz, CDCl3, δ): 8.48 (m, 2H, Py), 7.55
(m, 2H, Py), 7.31 (d, 2H), 7.04 (m, 2H), 5.25 (s, 1H, CH), 2.43 (s,
2H, NH2). 2-(Chloromethyl)-quinoline hydrochloride (9.9
Synthesis and characterization of iron(IV)-oxo-complex, 2,
[FeIV(2PyN2Q)(O)]2+.
The complex
with 1.5-2 equiv. of MesI(OAc)2 or mCPBA in acetonitrile. The
resulting solution forms iron(IV)-oxo complex , within 1
1 (1.21 mM solution in acetonitrile) was reacted
2
minute of addition of the oxidant. The corresponding iron(IV)-
oxo complex showed UV-vis band at 770 nm (d-d transition)
with a molar extinction coefficient, ϵ~250 Lmol−1cm−1. The
formation of the iron(IV)-oxo complex
vis. The complex showed the half-life around ~30 minutes.
The iron(IV)-oxo species was characterized by ESI-MS
2 was monitored by UV-
2
2
(Calculated for [FeIV(2PyN2Q)(O)(OTf)]+, m/z
obtained 688.090).
688.093,
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Synthesis and characterization of iron(II)-complex 3,
[FeII(2PyN2Q)(Cl)]Cl.33
558.103 calculated, 558.115), Elemental Anal. (Calculated for
C31H25Cl2FeN5O4) C, 56.56; H, 3.83; N, 10.64; found: C, 56.46,
H, 3.70, N, 10.50. For complex 6, UV−vis (MeCN): λmax = 355
The ligand 2PyN2Q (1 mmol) and iron(II)-chloride, FeCl2 (1.2
mmol) were reacted for 12 h in tetrahydrofuran (THF) and
acetonitrile inside the glove box at 25 °C. The reaction mixture
was concentrated by applying vacuum. Excess dry hexane was
added to the reaction mixture and shaken to get precipitate of
nm, 445 nm, ESI-MS (observed, m/z 602.056 calculated,
602.064), Elemental Anal. (Calculated for C31H25BrClFeN5O4) C,
52.98; H, 3.59; N, 9.97; found: C, 52.75, H, 3.47, N, 9.73.
General procedure for sp3 C
−H oxidation reactions.
complex. The mixture was allowed to settle down. The clear From stock solution of complex
1, (1.21 mM acetonitrile
solution above the precipitate was decanted off. Then the solution), 1.5 mL was taken in a 20 mL vial along with stir bar.
precipitate was dried properly by applying vacuum and kept 1.5 equiv. of MesI(OAc)2 was added under stirring condition.
under N2 atmosphere of glove box. The single crystal of the After 1 minutes excess amount (>100 equiv.) of substrate was
corresponding chloro complex was obtained from acetonitrile. added to the reaction mixture and the reaction was stirred for
Crystallized complex was characterized spectroscopically. 30 min. Finally, the reactions mixtures were analyzed by
UV−vis (MeCN): λmax = 358 nm, 454 nm, ESI-MS (observed, GC/GC-MS studies. Yield of the hydroxylation products were
558.10 calculated, 558.11), Elemental Anal. (Calculated for calculated based on area of the standard products.
C31H25Cl2FeN5) C, 62.65; H, 4.24; N, 11.78; found: C, 62.50, H, General procedure for 18-O labelling study for sp3 C
−H
4.20, N, 11.71.
oxidation reactions.
Synthesis and characterization of iron(II)-complex 4,
[FeII(2PyN2Q)(Br)]Br:
To a solution of complex
2
(1.21 mM), MesI(OAc)2 (2 equiv.)
inside glove
was added to generate the iron(IV)-oxo complex
2
The ligand 2PyN2Q (1.2 mmol) and iron(II)-bromide, FeBr2 (1.0 box. Subsequently 50 μL of H218O was added to this solution.
mmol) were reacted for 12 in excess amount of The resulting solution was kept at -35 °C freezer inside the
h
tetrahydrofuran (40 mL) and acetonitrile inside the glove box. glove box for 40 minutes. The solution was taken out from the
The reaction mixture was concentrated by applying vacuum. fridge, ethylbenzene was added and the reaction was
Then excess dry hexane was added to the reaction mixture continued for 30 minutes. Reaction mixtures were analyzed by
and shaken to get precipitate of Fe complex. The mixture was GC-MS to detect the percentage of 18-O labelling in the
left undisturbed to settle down the precipitate of complex at
the bottom of the schlenk flask. The clear solution part above General procedure for sp3 C
the precipitate was decanted off. Then the precipitate was From a stock solution of complex
products.
−
H halogenations reactions.
1, (4 mM in acetonitrile), 1
dried properly by applying vacuum and kept under N2 mL of solution was taken in a 20 mL vial with a stir bar.
atmosphere of glove box. UV−vis (MeCN): λmax = 352 nm, 460 Subsequently 2 equiv. of mCPBA was added under stirring
nm, ESI-MS (observed, m/z, 558.10 calculated, 558.11), condition. Immediately
a
solution of halide complex
, [Fe(2PyN2Q)(Br)](Br) was added to it
(40 mol% w.r.t. complex concentration). Substrate was
3,
Elemental Anal. (Calculated for C31H25Br2FeN5) C, 54.50; H, [Fe(2PyN2Q)(Cl)](Cl) or
4
3.69; N, 10.25; found: C, 54.41, H, 3.60, N, 10.10.
2
added to the reaction mixture and the reaction was stirred for
30 minutes.
Synthesis and characterization of iron(II)-complex
[FeII(2PyN2Q)(X)](ClO4) (5 and 6).34
Conflicts of interest
The above-synthesized complexes
3 and 4 were reacted with
There are no conflicts to declare.
2.5 equiv. of NaClO4 in MeOH-MeCN (20 mL). The resulting
solution was stirred for 4 hours. This process was repeated for
second time. The complex solution was dried to get orange
powder complex. Then the residue was dissolved in
dichloromethane (DCM) to get complex in the solution. The
remaining white residue remained at the bottom of the
schlenk flask. The solution was kept idle for 1 hour to settle
down the white precipitate. Then the clear red solution was
decanted off and filtered through Whatman filter paper fitted
in sintered funnel. The filtrate was dried to get orange
powdered [FeII(2PyN2Q)(X)](ClO4). The complexes were
crystallized from chloroform/hexane and used for
halogenations reactions. The anion exchanges were carried
Acknowledgements
This activity is supported by SERB, India (EMR/2015/000164).
Financial support has been received from CSIR-India
(fellowship to S.R., J.P.B. and A.S.).
Notes and references
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