Kinetics and enantioselectivity of the Baeyer-Villiger oxidation of cyclohexanones by chiral tetrapyridyl oxoiron(IV) complex

Article abstract of DOI:10.1016/j.inoche.2018.04.024

The previously reported oxoiron(IV) complex, [Fe^IV(asN4Py)(O)]²⁺ with chiral pentadentate ligand, asN4Py (asN4Py = N,N?bis(2?pyridylmethyl)?1,2?di(2?pyridyl)ethylamine), is effective for the Baeyer-Villiger oxidation of cyclohexanone derivatives. The reaction is shown to be first order in both cyclohexanone and the oxoiron(IV) species. The second order rate constant is smaller by one order of magnitude than that obtained for the related achiral [Fe^IV(N4Py)(O)]²⁺ complex. Oxidation of 4-substituted cyclohexanone derivatives by the chiral oxoiron(IV) complex attains moderate enantioselectivities up to 45% enantiomeric excess (ee).

Full text of DOI:10.1016/j.inoche.2018.04.024

Accepted Manuscript
Kinetics and enantioselectivity of the Baeyer-Villiger oxidation of
cyclohexanones by chiral tetrapyridyl oxoiron(IV) complex
Ramona Turcas, Dóra Lakk-Bogáth, Gábor Speier, József Kaizer
PII:
DOI:
Reference:
S1387-7003(18)30166-7
doi:10.1016/j.inoche.2018.04.024
INOCHE 6955
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Inorganic Chemistry Communications
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10 April 2018
24 April 2018
Please cite this article as: Ramona Turcas, Dóra Lakk-Bogáth, Gábor Speier, József Kaizer
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ACCEPTED MANUSCRIPT
Kinetics and enantioselectivity of the Baeyer-Villiger oxidation of
cyclohexanones by chiral tetrapyridyl oxoiron(IV) complex
Ramona Turcas, Dóra Lakk-Bogáth, Gábor Speier, József Kaizer*
a
Department of Chemistry, University of Pannonia, 8200 Veszprém, Hungary. Fax: +36 88 624
469; Tel: +36 88 624 720; E-mail: kaizer@almos.vein.hu
______________________________________________________________________________
Abstract
The previously reported oxoiron(IV) complex, [FeIV(asN4Py)(O)]2+ with chiral pentadentate
ligand, asN4Py (asN4Py = N,N-bis(2-pyridylmethyl)-1,2-di(2-pyridyl)ethylamine), is effective for
the Baeyer-Villiger oxidation of cyclohexanone derivatives. The reaction is shown to be first
order in both cyclohexanone and the oxoiron(IV) species. The second order rate constant is
smaller by one order of magnitude than that obtained for the related achiral [FeIV(N4Py)(O)]2+
complex. Oxidation of 4-substituted cyclohexanone derivatives by the chiral oxoiron(IV)
complex attains moderate enantioselectivities up to 45% enantiomeric excess (ee).
Keywords: Biomimetics; Baeyer-Villiger oxidation; Iron(IV)-oxo complex; Enantioselectivity,
Kinetics
______________________________________________________________________________
Baeyer-Villiger (B.-V.) oxidation of ketones into esters or lactones by organic peroxyacids
as stoichiometric oxidants has a wide range of application, from the synthesis of steroids,
antibiotics, pheromones, and herbicides to the synthesis of intermediates for polymerization [1-8].
Since the classical B.-V. reaction lacks of the chemo-, regio-, and enantioselectivity, that are
expected for organic synthesis, and the oxidants which are used are hazardous and expensive,
these limitations led to the application of biocatalytic processes [9-15]. Baeyer-Villiger
monooxygenases (BVMO) are considered highly valuable catalysts for the synthesis of fine
chemicals [16-19]. BVMOs can be classified into three groups: Type I BVMOs contain a flavin
adenine dinucleotide (FAD) as cofactor and use nicotinamide adenine dinucleotide phosphate
(NADPH) as electrons source. Type II BVMOs use flavin mononucleotide (FMN) as flavin
cofactor and nicotinamide adenine dinucleotide (NADH) as electron donor. Type III BVMOs are
specific cytochrome P450s, which are involved in the synthesis of brassinosteroids, steroidal
hormones essential for the growth and development of plants [20,21]. These heme-containing

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monooxygenases are supposed to exploit the hydroperoxy heme intermediate (FeIIIOOH) as a
„peracid catalyst”. Iron complexes of meso-tetraphenylporphyrin, FeIII(TPP)Cl [22,23], and N,N-
bis(2-pyridylmethyl)-N-bis(2-pyridyl)methyl-amine [FeII(N4Py)(CH3CN)]2+ (1) [24,25] proved to
be efficient catalysts for the aerobic oxidation of cyclohexanone in the presence of various
aldehydes as sacrificial reductants, wherein, contrary to the heme-containing monooxygenases, a
high-valent iron porphyrin, [FeV(TPP)(O)]Cl and [FeIV(N4Py)(O)]2+ (2) were proposed as key
intermediates in the rate-determining oxygen atom transfer step to generate the -caprolactone.
Much effort has been directed to development of metal-mediated asymmetric B.-V.
reaction. In 1994, Bolm et al. [26] and Strucul et. al. [27] reported the first enantiomer-
differentiating chiral copper and platinium-catalyzed B.-V. reactions. Since then, various optically
active metal complexes including metals, such as Pt [28], Pd [29], Zr [30], Co [31], have been
used as catalysts for asymmetric B.-V. reactions. However, noble metals and their compounds are
expensive, difficult to obtain and hard to recover that cause limitation in industrial production.
Well-characterized and reactive chiral terminal oxo-iron complexes capable of undergoing
oxygen-atom transfer reactions in an enantioselective manner are sparse in the literature.
Recently, we communicated that the chiral oxoiron(IV) complex, [FeIV(asN4Py)(O)]2+ (4)
(asN4Py = N,N-bis(2-pyridylmethyl)-1,2-di(2-pyridyl)ethylamine), generated by the reaction of
[FeII(asN4Py)(CH3CN]2+ (3) with PhIO, can undergo enantioselective sulfoxidation of thioanisole
in 84% enantiomeric excess (ee) [32]. As a continuity of our research, we report herein the
kinetics of the [FeIV(asN4Py)(O)]2+-mediated stoichiometric oxidation of cyclohaxanone
compared to its related oxoiron(IV) derivative, FeIV(N4Py)(O)]2+, and the enantioselectivities
towards 4-substituted cyclohexanone derivatives.

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Scheme 1
It is well-known that oxoiron(IV) complexes are able to oxidize many organic compounds
including various solvents such as toluene and alcohols, but it has been proved that the CH3CN as
solvent is innocent. [FeIV(asN4Py)(O)]2+ (4) is one of the most stable oxoiron(IV) species, its
half-life (t1/2) is ~10 days in acetonitrile (CH3CN) at room temperature. The oxidation potential of
4, compared to FeIV(N4Py)(O)](ClO4)2 (2) has been studied at 25 ˚C in the B.-V. oxidation
process with cyclohexanone. Complex 4 was generated by the reaction of 3 with 1.2 equiv. of
PhIO (<40 min), and the rate of its rapid decomposition, which coincided with the regeneration of
3 (max = 398, 409 nm), and the formation of -caprolactone [33], was measured as a function of
the concentration of added cyclohexanone (Entry 8 in Table 1, and Fig. 1a). No decay process can
be observed in the absence of substrate in CH3CN under this condition. The yield of -
caprolactone was almost quantitative (~80%), proving that the UV-vis spectral change
corresponds to the OAT process. An isosbestic point was observed at 580 nm, indicating that
there were no long-lived intermediates in the conversion of the green species into the FeII product.
The oxoiron(IV) species can be reactivated, and a new stoichiometric cycle can be initiated by the
use of additional 1.2 equiv. of PhIO (~75% yield). The rates in the presence of a large excess of
cyclohexanone (50-350 equiv.) obeyed pseudo-first order kinetics, with respect to 4, and the
pseudo-first order rate constants increased proportionally with the substrate concentration (Entries

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1-5 in Table 1, and Fig. 1b). The linear plot of the reaction rate values (V) against the initial
concentration of 4 also states that the reaction is first-order with respect to the oxoiron(IV)
concentration (Entries 5-8 in Table 1, and Fig. 1c). The above results establish a rate law of -
d[4]/dt = k2[4][cyclohexanone], and from these linear plotting, the second order rate constant (k2)
was determined to be 2.06 × 10-4 M-1 s-1 with H≠ = 87 kJ mol-1 and S≠ = -149 J mol-1 K-1 at 25
˚C (Entries 5, 9-11 in Table 1, and Fig. 1d). These results indicate that [FeIV(asN4Py)(O)]2+ (4)
complex is much less reactive than the [FeIV(N4Py)(O)]2+ (2) complex. The second order rate
constant is smaller by one order of magnitude, and the activation enthalpy is two times higher,
than those obtained for the related achiral [FeIV(N4Py)(O)]2+ complex (1.48×10-3 M-1 s-1, 41 87 kJ
mol-1, Table 2). The large negative activation entropies are typical of associative processes, and
indicate that the transition state is better organized than the prior step.
Table 1. Kinetic data for the stoichiometric oxidation of cycklohexanone with
[FeIV(asN4Py)(O)](ClO4)2 [33].
No.
[FeIV(O)]2+
(10-3M)
2.0
Cyclohexanone
V
kobs
k2
T (K)
(M)
0.1
0.4
0.5
0.6
0.7
0.7
0.7
0.7
0.7
0.7
0.7
(10-7 M s-1)
(10-5 s-1)
2.46±0.07
7.2±0.2
(10-4 M-1s-1)
2.46±0.07
1.80±0.05
1.90±0.08
2.10±0.08
2.06±0.06
2.10±0.07
1.97±0.05
1.94±0.05
1.00±0.02
3.37±0.10
6.23±0.24
1
2
298
298
298
298
298
298
298
298
293
303
308
2.0
3
2.0
9.5±0.4
4
2.0
12.6±0.5
14.4±0.4
14.7±0.5
13.8±0.4
13.6±0.4
7.0±0.2
5
2.0
2.88
1.47
2.07
4.08
6
1.0
7
1.5
8
3.0
9
2.0
10
11
2.0
23.6±0.7
43.6±1.7
2.0

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Fig. 1. Reactions of [FeIV(asN4Py)(O)]2+ (4) with cyclohexanone in CH3CN at 298 K. (a) UV-vis
spectral change of 4 (3.0 mM) upon addition of 233 equiv. cyclohexanone. Inset shows time
course of the decay of 4 monitored at 705 nm (Entry 8 in Table 1). (b) Plot of kobs versus
[substrate] for reactions of 4 (2.0 mM) with cyclohexanone (Entries 1-5 in Table 1). (c) Plot of
reaction rate (V) versus [4] for reactions of 4 with cyclohexanone (Entries 5-8 in Table 1). (d)
Eyring plots of log k/T versus 1/T for cyclohexanone (Entries 5, 9-11 in Table 1).
Table 2. Comparison of efficiency of FeIV(asN4Py)(O)]2+ and FeIV(N4Py)(O)]2+complexes
toward the oxidation of cyclohexanone in acetonitrile at 298 K.
H≠
S≠
Complex/Substrate
k2
capcolactone
Ref.
(M-1 s-1)
(%)
80
(kJ mol-1) (J mol-1 K-1)
87
41
[FeIV(asN4Py)(O)]2+ 2.06×10-4
-149
-111
this work
[19]
[FeIV(N4Py)(O)]2+
1.48×10-3
80
Finally, to get direct evidence for the involvement of the high-valent oxoiron(IV) species
in the enantioselective step, the reaction of (R)-(-)-4.(ClO4)2 with 4-Me-cyclohexanone and 4-tert-
butyl-cyclohexanone was investigated at 25˚C in CH3CN [34], and the enantioselectivities were
determined by chiral GC analysis compared to the racemic oxoiron(IV) species (Table 3, and Fig.

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2). Oxidation of 4-substituted-cyclohexanone derivatives by the chiral oxoiron(IV) complex
attains moderate enantioselectivities up to 39% enantiomeric excess (ee) at 25˚C (Table 3).
Significantly better value can be observed at lower temperature, namely 45% ee for 4-Me-
cyclohexanone at 5˚C compared to that observed at 25˚C (ee 30%).
In the present work, we carried out B.V. oxidation reactions with spectroscopically well
characterized chiral mononuclear nonheme iron(IV) complex. The reactivity of chiral and achiral
nonheme oxoiron complexes has been briefly compared as well. To the best of our knowledge,
this study provides the first details of enantioselective 4-substituted-cyclohexanone oxidations
with oxoiron(IV) complexes generated in situ, which bear nonheme chiral ligand. Our results
demonstrate that the iron(IV)-oxo complex with a chiral moiety can significantly affect the
enantiomeric selectivity, therefore the oxidation must be bound to the metal-based oxidant. In
conclusion, we have reported the first example of a chiral nonheme iron(IV)-oxo intermediate
that is capable of the stereoselective B.-V. reaction of cyclohexanone derivatives, suggesting that
iron(II) compexes with chiral ligands may serve as a good candidates for an efficient and selective
catalyst for the B.-V. reactions.
Table 3. Stoichiometric 4-tert-butyl-cyclohexanone oxidations by racemic and (R)-(-)-
FeIV(asN4Py)(O)]2+ complexes, [4]0 = 5.90 × 10-3 M, [substrate]0 = 2.06 × 10-1 M. [33]
no.
1
oxidant
(R,S)-(+/-)-4
substrate
4-tert-butyl-
cyclohexanone
4-tert-butyl-
cyclohexanone
4-methyl-
ee (%) yield (%)a
T (K)
298
0
50
48
54
25
2
3
4
39 (R)
30 (R)
45 (R)
298
298
278
(R)-(-)-4
(R)-(-)-4
(R)-(-)-4
cyclohexanone
4-methyl-
cyclohexanone
aBased on [4]; IS = PhBr.

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Fig. 2. The GC chromatogram of the reaction of racemic 4 and 4-tert-butyl-cyclohexanone (a);
and (R)-(-)-4 and 4-tert-butyl-cyclohexanone (b) in MeCN at 298 K. [(R)-(-)-4)]0 = 5.90 × 10-3 M,
[PhIO]0 = 1.18 × 10-2 M, [4-tert-butyl-cyclohexanone]0 = 2.06 × 101 M.
Acknowledgements
This work was supported by a grant from The Hungarian Research Fund (OTKA) K108489,
GINOP-2.3.2-15-2016-00049, and the New National Excellence Program of the Ministry of
Human Capacities-2016-3-IV. (D. Lakk-Bogáth).
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[33] [FeII (asN4Py)(CH3CN)](ClO4)2 (3) complex (2.0 × 10-3 M) was dissolved in acetonitrile
(1.5 mL), and then iodosobenzene (2.4 × 10-3 M) was added to the solution. The mixture
was stirred for 40 minutes then the excess of iodosobenzene was removed by filtration.
Substrate (0.1 – 0.7 M) was added to the solution and the reaction was monitored with
UV-vis spectrophotometer (Agilent 8453 diode-array spectrophotometer) at 705 nm ( =
400 M-1 cm-1) (Table 1). Product analysis of the resulting solution was performed by GC
and GC/MS (Shimadzu QP2010SE equipped with a secondary electron multiplier detector
with conversion dynode and a 30 m HP-5MS column): Product: -caprolactone (80%);
m/z (%) 114 (M+; 12.6); 84 (24.1); 70 (15.3); 56 (39.6); 55 (100); 42 (99.8); 41 (49.6);
39 (23.5).
[34] (R)-(-)-FeII(asN4Py) complex (5.90 × 10-3 M) was dissolved in acetonitrile (1.0 mL), then
iodosylbenzene (1.18 × 10-2 M) was added to the solution. The mixture was stirred for 50
minutes then the excess iodosylbenzene was removed by filtration. 4-tert-butyl-
cyclohexanone (4-methyl-cyclohexanone) (2.06 × 101 M) was added to the solution and
the mixture was stirred at 25°C for 5 hours. The products were identified by GC (Agilent
6850 gas chromatograph equipped with a flame ionization detector), and the yield of 4-
tert-butyl--caprolactone (4-methyl--caprolactone) were calculated based on the amount
of iron(IV)-oxo using bromobenzene as an internal standard in the reactions. Enantiomeric
excess was determined with GC analysis on chiral CHIRASIL-L-VAL column: ([R] - [S])
/ ([R] + [S]). 4-tert-butyl-- caprolaktone: m/z (%) 170 (M+; 4.1); 114 (69.2); 86 (79.6);
83
(12.7); 69 (12.5); 68 (16.8); 57 (100); 56 (12.1); 55 (75.8); 54 (12.8); 43 (9.5); 42 (6.8);

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41 (46.8); 39 (14.0); 4-methyl--caprolactone: m/z (%) 128 (M+ , 8.1); 98 (13.2); 70 (9.5);
69 (51.3); 57 (6); 56 (100); 55 (51.4); 43 (11.3); 42 (20.7); 41 (41.4); 39 (14.4).

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List of Schemes and Figures
Scheme 1.
Scheme 2
Fig. 1. Reactions of [FeIV(asN4Py)(O)]2+ (4) with cyclohexanone in CH3CN at 298 K. (a) UV-vis
spectral change of 4 (3.0 mM) upon addition of 233 equiv. cyclohexanone. Inset shows time
course of the decay of 4 monitored at 705 nm (Entry 8 in Table 1). (b) Plot of kobs versus
[substrate] for reactions of 4 (2.0 mM) with cyclohexanone (Entries 1-5 in Table 1). (c) Plot of
reaction rate (V) versus [4] for reactions of 4 with cyclohexanone (Entries 5-8 in Table 1). (d)
Eyring plots of log k/T versus 1/T for cyclohexanone (Entries 5, 9-11 in Table 1).
Fig. 2. The GC chromatogram of the reaction of 4 and 4-tert-butyl-cyclohexanone (a); and (R)-(-
)-4 and 4-tert-butyl-cyclohexanone (b) in MeCN at 298 K. [(R)-(-)-4)]0 = 5.90 × 10-3 M, [PhIO]0
= 1.18 × 10-2 M, [4-tert-butyl-cyclohexanone]0 = 2.06 × 101 M.

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Graphical abstract
Kinetics and enantioselectivity of the Baeyer-Villiger oxidation of
cyclohexanones by chiral tetrapyridyl oxoiron(IV) complex
Ramona Turcas, Dóra Lakk-Bogáth, Gábor Speier, József Kaizer*
The reactivity of oxoiron(IV) complex, [FeIV(asN4Py)(O)]2+ with chiral pentadentate
ligand, has been investigated in the Baeyer-Villiger oxidation of cyclohexanone
derivatives.

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Highlights
 Reactivity of chiral oxoiron(IV) complex towards cyclohexanone
 Reaction kinetics with UV-Vis spectroscopy
 Enantioselective Baeyer-Villiger reactions