Enantioselective arene epoxidation under mild conditions by Jacobsen catalyst: The role of protic solvent and co-catalyst in the activation of hydrogen peroxide

Article abstract of DOI:10.1016/j.apcata.2013.04.025

The epoxidation of arenes was achieved in high yield and with high enantioselectivity using the system Jacobsen catalyst:hydrogen peroxide:co-catalyst, ethanol as reaction solvent at 40 C. The effect on the catalytic performance of the use of protic (etha

Full text of DOI:10.1016/j.apcata.2013.04.025

Accepted Manuscript
Title: Enantioselective arene epoxidation under mild
conditions by Jacobsen catalyst: The role of protic solvent and
co-catalyst in the activation of hydrogen peroxide
Author: Mariana Rocha Susana L.H. Rebelo Cristina Freire
PII:
S0926-860X(13)00229-9
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.apcata.2013.04.025
APCATA 14194
To appear in:
Applied Catalysis A: General
Received date:
Revised date:
Accepted date:
18-10-2012
12-4-2013
13-4-2013
Please cite this article as: M. Rocha, C. Freire, Enantioselective arene epoxidation
under mild conditions by Jacobsen catalyst: The role of protic solvent and co-
catalyst in the activation of hydrogen peroxide, Applied Catalysis A, General (2013),
http://dx.doi.org/10.1016/j.apcata.2013.04.025
This is a PDF file of an unedited manuscript that has been accepted for publication.
As a service to our customers we are providing this early version of the manuscript.
The manuscript will undergo copyediting, typesetting, and review of the resulting proof
before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that
apply to the journal pertain.

*Graphical Abstract (for review)
Graphical Abstract
Page 1 of 31

*Highlights (for review)
Highlights
 Arene epoxidation was obtained by Jacobsen catalyst using H2O2 in ethanol at 40ºC
 Use of co-catalyst combined with protic solvent enhanced catalytic efficiency
 Catalytic reactivity is explained by formation of oxo- or hydroperoxy active species
 Role of protic solvent associated with hydrogen bonding with active species
 Best C % was obtained with ammonium acetate and best ee% with
1-methylimidazole
Page 2 of 31

*Revised manuscript
Enantioselective arene epoxidation under mild conditions by
Jacobsen catalyst: the role of protic solvent and co-catalyst in the
activation of hydrogen peroxide
Mariana Rocha, Susana L.H. Rebelo*, Cristina Freire*
REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade
do Porto, Rua do Campo Alegre, 4169-007, Porto, Portugal
E-mail addresses: acfreire@fc.up.pt (C. Freire)*; susana.rebelo@fc.up.pt (S.L.H. Rebelo)*;
mariana.rocha@fc.up.pt (M. Rocha)
*Corresponding authors: phone: +351 220402590; Fax: +351 220402695
Keywords: Jacobsen catalyst, asymmetric epoxidation, hydrogen peroxide, ethanol,
mechanism.
1
Page 3 of 31

Abstract
The epoxidation of arenes was achieved in high yield and with high enantioselectivity
using the system Jacobsen catalyst:hydrogen peroxide:co-catalyst, ethanol as reaction solvent
at 40ºC. The effect on the catalytic performance of the use of protic (ethanol) and aprotic
solvents and of co-catalysts with different acid-base properties was analyzed, as well as,
different reaction temperatures, using as substrates indene, 6-cyan-2,2’-dimethylchromene,
styrene and α-methylstyrene. The protic solvent showed a positive effect enhancing catalytic
performances when compared with the aprotic solvent. For amphoteric co-catalysts
(ammonium acetate, 2-methylimidazol and imidazol) it was observed the highest substrate
conversions, whereas for basic co-catalysts (1-methylimidazol, 4-methylmorpholine N-oxide
and pyridine), higher ee% and relatively lower C% were observed. Moreover, the reactions at
40ºC showed higher enantiomeric induction than those performed at room or lower
temperatures.
The catalytic data are in accordance with a multi-step mechanism for hydrogen peroxide
activation by the Mn(salen) complex with the formation of two catalytic active intermediates,
existing in different extension depending on the reaction conditions: a hydroperoxy
intermediate or oxo-metallocomplex. The activating effect of the protic solvent ethanol vs
aprotic solvent was explained by the formation of hydrogen bonds between the solvent and
the catalytic active intermediates.
2
Page 4 of 31

1. Introduction
The enantioselective synthesis of chiral arene oxides by Jacobsen-Katsuki catalysis [1-4]
has opened a vast academic and industrial interest and discussion;[5-8] nevertheless,
improved eco-compatible conditions are required and the elucidation of the reaction
mechanism still remains an intense field of research [9].
The use of Mn(salen) complexes as oxidative catalysts is very attractive [10] due to low
cost, easy preparation and handling and high activity, in particular when the Jacobsen and
Katsuki catalysts are considered [11]. They have been applied in association with hydrogen
peroxide which is an environmentally clean and a relatively inexpensive oxidant [12-14], both
in aqueous and anhydrous forms [15,16]. The major drawback of these catalytic systems is the
general use of environmentally unacceptable solvents, such as dichloromethane:methanol
[17,18], dichloromethane:water [6], dichloromethane [19], acetone:methanol [20] or
dichloromethane:N,N’-dimethylformamide [21]; aprotic-low polarity solvents, such as
acetonitrile were also used, although often associated with lower catalytic efficiency [22].
The reaction media is a very pertinent issue, since the solvents play a strong impact on
cost and safety of the catalytic processes. When applicable, ethanol has been considered a
good alternative as green solvent [23,24]: i) it is appropriate for substances with wide range of
polarity; ii) it is inexpensive and can be obtained from biomass, iii) it is biodegradable and it
can be used as a fuel. Water/surfactant or water/ethanol/tamponized media have been reported
as eco-compatible reaction solvents, however green oxidants were not used.[25,26]
Studies on the alkene epoxidation by Mn(salen) complexes have been accompanied by an
intense mechanistic debate that involved the effect of catalyst structure and electronic
properties [27,28], the oxidant used [29] and reaction conditions (e.g. presence of co-catalyst,
solvent and temperature) in the reaction efficiency and enantioselectivity [15,30,31]. Initially,
a [Mn(V)-oxo salen] species was considered to be the unique active species and the oxygen
3
Page 5 of 31

transfer to the substrate was proposed to proceed through a concerted manner, via a radical
intermediate or via a manganaoxetane intermediate [32,33]. The observed differences in the
reaction selectivity were associated with the occurrence of each of these pathways in different
extent. In the last years, the mechanistic debate has been directed towards the formation of
other active species and, in addition to the oxo-species, a catalyst-oxidant adduct species was
proposed to be the active intermediate under specific reaction conditions [34-36]. This debate
assumes particular relevance when hydrogen peroxide is used as oxidant, since the catalytic
activation can take place through multi-step pathways, which are very sensitive to the reaction
conditions [37,38]. Further interest arises from the analogy with enzymatic pathways
described for activation of hydrogen peroxide during catalytic cycles of cytochrome P450
monooxygenases and heme based peroxidases, as well as, their synthetic analogues, the
metalloporphyrins [39]. One challenging issue in these mechanistic studies is the short-live
character of the catalytic active species formed and consequently the proposed structures have
been mainly indirectly inferred [40].
The activation of hydrogen peroxide by metallocomplexes generally requires the
presence of a co-catalyst in order to obtain efficient reactions and sometimes to enhance the
enantioselectivity [15,21,41]. Different classes of compounds have been used as reaction co-
catalysts such as pyridines, imidazoles, N-oxides or carboxylates and in metalloporphyrin
catalysis their role has been considered to be similar to that of proximal and distal histidine
residues during the heterolytic O-O bond cleavage by peroxidase, which act through the so
called “push and pull” mechanism [42]. In a similar way, the activation of hydrogen peroxide
catalyzed by manganese porphyrins was proposed to occur through the initial formation of a
hydroperoxy intermediate [Mn(III)porhyrin-OOH]–, favored in basic conditions, followed by
the heterolysis through the “push and pull” mechanism to form a high valent oxo species
[Mn(V)porhyrin=O] as shown in Figure 1. The axial ligands provide electron density to the
4
Page 6 of 31

O-O bond through the metal center, the “push”, while the co-catalyst mediates the proton
delivery to the terminal oxygen creating a better leaving group, the “pull” [43,44].
Figure 1
Pertinent mechanistic studies on metalloporphyrin catalysis showed that when the
dehydration step is unfavorable, a metallo-hydroperoxy species can also be a plausible
electrophilic oxidant in the alkene epoxidation catalytic cycle, under specific conditions.
Rebelo et al. [44] showed that efficient alkene epoxidation by a metallo-hydroperoxy species
can occur when a protic solvent and a highly electron withdrawing metalloporphyrin were
used in the absence of co-catalyst. In the enzymatic context, it was also shown the
involvement of a proton network during activation of peroxo intermediates [42].
In the present work, the epoxidation of four olefins with synthetic interest: indene (1)
[45], 6-cyan-2,2’-dimethylchromene (2) [46], styrene (3) and α-methylstyrene (4), Figure 2,
was performed using hydrogen peroxide as oxidant and ethanol as the solvent, in the presence
of the Jacobsen catalyst. We intend to investigate the effect, on the catalytic performance, of
co-catalysts with different acid-base properties (1-methylimidazol, 2-methylimidazol, 4-
methylmorpholine N-oxide, pyridine and ammonium acetate), oxidant addition form and
reaction temperature, as well as, to evaluate the effect of protic vs aprotic solvent and other
solvent combinations already used as reaction medium. With these, we endeavor to contribute
to the elucidation of the epoxidation reaction mechanism when hydrogen peroxide is used as
the oxidant in the presence of Jacobsen catalyst.
Figure 2
5
Page 7 of 31

2. Experimental
2.1 Materials and reagents
The indene (98%), 2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (6-cyan-2,2’-
dimethylchromene, CN-Chrom, 97%), styrene (Sty >99%), (R)-(+)-styrene oxide (98%),
α-methylstyrene (Me-Sty, 99%), chlorobenzene (99,5%) (R,R)-(-)-N,N’-bis(3,5-di-tert-butyl-
salicylidene)-1,2-cyclohexane-diaminomanganese(III) chloride (Jacobsen catalyst), urea-
hydrogen peroxide addition compound (UHP, 98%), hydrogen peroxide solution 30 wt.% in
H2O (H2O2(aq)), 1-methylimidazol (1-MeIm, 99%), 2-methylimidazol (2-MeIm, 99%) and 4-
methylmorpholine N-oxide (NMO, 97%) were purchased from Aldrich. Pyridine (Py) and
ammonium acetate (NH4AcO, p.a. grade) were obtained from Merck. Methanol (p.a.) was
supplied by Fisher Chemical, dichloromethane and acetonitrile by Romil (HPLC grade) and
absolute ethanol (analytical grade) from Panreac.
2.2 Analytical methods
Proton nuclear magnetic resonance (1H NMR) spectra of compounds and total reaction
mixtures were recorded using a Brucker Advance III spectrometer at a frequency of 400 MHz
and 22ºC, at Centro de Materiais da Universidade do Porto (CEMUP), Porto, Portugal.
Analysis by gas chromatography with flame ionization detector (GC-FID) were
performed with a Varian CP-3380 gas chromatograph equipped with a FID detector using
helium as carrier gas, a fused silica Varian Chrompack capillary column CP-Sil 8 CB Low
Bleed/MS (30 m × 0.25 mm i.d.; 0.25 µm film thickness) and a chiral column, fused silica
Varian Chrompack capillary column CP-Chiralsil-Dex CB (25m × 0.25mm i.d.; 0.25 µm film
thickness). The temperature program was: 70 ºC (1 min), 20 ºC min-1, 200 ºC (5 min); injector
temperature, 200 ºC; detector temperature, 250 ºC. Each aliquot was injected in both columns;
the first was used to obtain conversion and selectivity percentages and the second to obtain
6
Page 8 of 31

ee% values. Substrate conversion (C%) was calculated both by determining the reacted
substrate using the internal standard (i.s.) method, C% = {[A(substrate)/A(i.s.)]t=0h
–
[A(substrate)/A(i.s.)]t=xh} × 100 / [A(substrate)/A(i.s.)]t=0h and based on the chromatographic
peak areas of substrate and products, C% = [ΣA(products)] × 100/[A(substrate) +
ΣA(products)]; the values obtained by the two procedures always agreed within 10%. The
epoxide selectivity (S%) and enantiomeric excess (ee%) were calculated as follows: S% =
[A(epoxide)] × 100/[ΣA(products)], ee% = [A(major enantiomer) – A(minor enantiomer)] ×
100/[ΣA(enantiomers)], where A stands for chromatographic peak area. The turnover
frequency, TOF, was calculated as: TOF = [number of moles of epoxide formed/number
moles of catalyst used]/reaction time; the number of moles of epoxide formed was calculated
taking into account C% and S% values. Confirmation of the catalytic results obtained by GC-
1
FID was done by analysis of a total reaction mixture by H NMR: the reaction mixture was
concentrated, eluted through a small plug of silica, washed with n-hexane:ethyl acetate (20%)
mixture, evaporated to dryness and finally analyzed by 1H NMR in CDCl3.
2.3 Catalytic experiments
Generally, the reactions were performed using 0.3 mmol of substrate; 0.3 mmol of co-
catalyst; 0.2 mmol of chlorobenzene (GC internal standard) and Jacobsen complex (15 mg,
0.024 mmol) as catalyst; in 4 mL of solvent with continuous stirring at the desired
temperature. The oxidant (3 mmol) was added totally at the beginning of the reaction (slowly
to prevent gas evolution) or progressively at a rate of 3 mmol h-1. The progress of the reaction
was monitored by GC-FID, by removing small samples of the reaction mixture every 15 min.
The relative proportions of compounds usually did not change from 30-45 min of reaction
time, when oxidant was totally added at the beginning of the reaction or from 120-135 min
when oxidant was progressively added to the reaction mixture.
7
Page 9 of 31

1
The epoxide stereoselectivity was determined by H NMR in comparison with published
data for (-)-(1R,2S)-1,2-indene oxide [47,48] and (3R,4R)-6-cyan-2,2’-dimethychromene [49]
or by comparison of analytic standards for (R)-(+)-styrene oxide.
(3R,4R)-6-cyan-2,2’-dimethylchromene: 1H NMR (400 MHz, CDCl3, 22°C, TMS): δ=1.45 (s,
6H, H-Me), 3.54 (d, 1H, H-3, J=4.2 Hz), 3.91 (d, 1H, H-4, J=4.2 Hz), 6.86 (m, 1H, H-8), 7,28
(s, 1H, H-5), 7.52 (d, 1H, H-7, J=8.6 Hz).
2.4 Quantification of hydrogen peroxide
The concentration of hydrogen peroxide was quantified using a methodology based on
1H NMR spectroscopy [50] owing to the linear correlation of [H2O2] with the position of the
coalescence peak of hydrogen peroxide and water for concentrations in the range 0.1-10 mol
dm-3 and linear correlation of concentration with peak area for lower concentrations (10-3-0.1
mol dm-3). Calibration samples were prepared by mixing hydrogen peroxide with the
deuterated solvent (CDCl3:CD3OD, 1:1), with [2-MeIm] of 0.075 mol dm-3 and [H2O2] from
0.0-0.75 mol dm-3. The coalescence peak of hydrogen peroxide and water shifted from 5.07 to
4.70 ppm. A reaction of indene oxidation was performed in conditions of section 2.3 but using
the above mixture of solvents (CDCl3:CD3OD, 1:1), 2-MeIm as co-catalyst and the reaction
temperature was 40ºC and the [H2O2] determined at different reaction times, using the CHCl3
peak as reference.
3. Results and Discussion
The effect of different reaction conditions on catalytic performance was evaluated for
indene, CN-chrom, Sty and Me-Sty by analyzing substrate conversion (C%), epoxide
selectivity (S%), enantiomeric excess (ee%) and TOF. The behavior of ethanol as solvent was
compared with other protic (CH2Cl2:MeOH) and aprotic (CH3CN) solvents, the addition form
8
Page 10 of 31

of hydrogen peroxide, as an aqueous solution [H2O2(aq)] or as anhydrous urea adduct (UHP),
the effect of different co-catalysts and the reaction temperature were also analyzed.
3.1 Effect of solvent, oxidant addition form and reaction temperature
The results of catalytic oxidation of indene under different conditions are presented in
Table 1. In the presence of 2-methylimidazole (2-MeIm) as co-catalyst, using hydrogen
peroxide in the form of UHP at 40ºC, the effect of the solvent CH2Cl2:MeOH (1:1) was
compared with EtOH (Table 1, entries 1 and 3). The two catalytic reactions showed similar
performance with high C% = 96 and 98% and ee% =77%; the epoxide selectivity was also
high, 99% and 97%, indicating that epoxide opening pathways have low significance in these
conditions. The TOF was 96.5 and 92.7 h-1, respectively. The previous reactions were
performed using an excess of 10 molar equivalents of oxidant relatively to the substrate.
When the amount of UHP was decreased to 2 molar equivalents, in the same conditions of
entry 1, there was a significant decrease in C% and TOF, Table 1, entry 2.
Table 1
On the other hand, in ethanol and using the hydrogen peroxide in the form of aqueous
solution (totally added at the beginning of the reaction, entry 4), the C% decreased to 91%
with maintenance of ee% (78%), but when the aqueous hydrogen peroxide was progressively
added to the reaction mixture at a rate of 3 molar equivalents.h-1 (entry 5), the conversion
increased again to 96% and ee% was kept constant at 77%. The control of H2O2 concentration
in the reaction mixture was performed by 1H NMR methodology during a catalytic reaction in
conditions of entry 5 [50]. This experiment showed the total consumption of H2O2 at the end
9
Page 11 of 31

of reaction and the occurrence of H2O2 decomposition, probably induced by the presence of
the catalyst or due to the lower stability of H2O2 at the reaction temperature.
With both H2O2 oxidant forms, when the reaction temperature was lowered from 40ºC to
room temperature (approximately 20ºC) a decrease on ee% was observed from 77% to 65-
66%, but the C% values were kept at 95-96% (entries 6 and 7).
The oxidation of indene was also performed with a higher quantity of the Jacobsen
catalyst (from 6.7% to 10% mol, Table 1, entry 8). In this case, the C% was complete (100%),
but a decrease of ee% to 69% was observed; since the ratio co-catalyst:catalyst was lower,
this result evidenced the importance of the molar relation between catalyst and co-catalyst on
the observed enantioselectivity and, consequently, the role of the co-catalyst in the catalytic
process.
The use of a similar co-catalyst 1-methylimidazole (Table 1, entries from 9 to 14), when
the oxidant was H2O2(aq) totally added at the beginning of the reaction, also led to similar
catalytic performance when the solvent was ethanol or a mixture of CH2Cl2:MeOH (entries 9
and 10). However, when the protic solvent ethanol was replaced by the aprotic solvent in the
same reaction conditions (entries 11 and 12), a significant decrease in C%, from 85% to 62%
and in ee%, from 94% and 75%, were observed, indicating the importance of the protic
solvent for the catalytic process. With this co-catalyst, the effect of temperature was analyzed
by comparing the catalytic performance at 40ºC to that at room temperature (20ºC) and
keeping the other conditions (entries 11 and 13): in this case, a decrease in ee% from 94% to
86% was observed, although C% was kept at 85%.
The effects of temperature and protic vs aprotic solvent on the catalytic performance
described previously were also tested for the reaction using the co-catalyst ammonium
acetate, Table 1 entries from 15 to 20. On going from the oxidation reaction of indene at 40ºC
to room temperature (entries 15-17), there was a decrease in ee% from 89 to 69%, but in both
10
Page 12 of 31

cases there was a nearly complete substrate conversion of 98-99%; at 0ºC, the ee% was
identical to that observed at r.t. (70%), but the C% slightly decreased to 95%. Furthermore,
the change of EtOH to CH3CN (entries 15 and 19), produced a decrease in C% from 98% to
69% and ee% from 89 to 73%.
The catalytic system was also tested in the absence of Jacobsen catalyst with ammonium
acetate as co-catalyst (entry 20), with no substrate conversion observed.
The oxidation of CN-chrom (2) was screened for the above reaction conditions and, as
can be seen in Table 2, it was possible to epoxidize this alkene in ethanol with 100% epoxide
selectivity.
Table 2
For this substrate the best catalytic performances were obtained using ammonium acetate
or 2-methylimidazole as co-catalysts, in ethanol and hydrogen peroxide as both adduct UHP
or aqueous solution; in the latter case, the oxidant was added progressively to the reaction
mixture (Table 2 entries 2, 3 and 5). Although very high ee% (99%) was observed, the
substrate conversions were moderate, C% = 28-35%, due to the deactivation of the double
bond by the proximity of the CN group. When H2O2(aq) was the oxidant (totally added at the
beginning of the reaction, entry 1), the substrate conversion was very low, C% =14%, and
once more, the reaction at room temperature led to lower ee% (86%, Table 2, entry 4). In the
presence of pyridine the C% and ee% were relatively low (22% and 86%, respectively), but
similar catalytic performance for both protic solvents, ethanol and mixture of CH2Cl2:MeOH
was observed.
3.2 The effect of co-catalyst
11
Page 13 of 31

The effect of the different co-catalysts in the catalytic oxidation of indene (Table 1) and
styrene (Table 3) by adduct UHP in ethanol at 40ºC was analyzed: the use of both amphoteric
co-catalysts (NH4AcO, 2-MeIm, Im) and basic co-catalysts (1-MeIm, NMO and Py) led to
different C% and ee% values that are summarized in Figure 3.
Table 3
Figure 3
For indene oxidation (Figure 3, a), all the amphoteric co-catalysts, NH4AcO, 2-MeIm and
Im, led to high C% values in the range 97-98% and ee% decreased in the order: NH4AcO > 2-
MeIm > Im, from 89% to 70%. The ee% for the reaction in the presence of 2-MeIm and Im
compare with ee% values of the reaction performed without co-catalyst, but all the C% values
are significantly higher than that obtained for the reaction performed in the absence of co-
catalyst.
For the basic co-catalysts, 1-MeIm and Py, the C% values are lower (85% and 74%,
respectively) than those of reactions in the presence of amphoteric co-catalysts. The former is
approximately of the same magnitude as that of the reaction in the absence of co-catalyst, but
the latter shows a negative effect relatively to the absence of co-catalyst. Furthermore, the
reaction in the presence of 1-MeIm showed the highest ee% value observed (94%), whereas
for Py ee% = 84%, which is of the same magnitude as that of the reaction in the absence of
co-catalyst.
In order to test the use of a higher amount of co-catalyst in the catalytic reaction,
NH4AcO and 1-MeIm were chosen as representatives of the amphoteric and basic co-
catalysts, respectively. Indene oxidation was performed doubling the molar quantity of 1-
MeIm (Table 1, entry 14) or NH4AcO (Table 1, entry 18), but keeping the other reaction
12
Page 14 of 31

conditions. No significant variation of the catalytic performance of the catalyst was observed
since the C% and ee% values were of the same magnitude as those described previously.
The oxidation of styrene (3) was also studied in ethanol by the catalytic system
Jacobsen:H2O2 (Table 3). Styrene is less reactive relatively to indene and due to the terminal
position of the double bond the epoxidation reaction is also less selective for styrene epoxide
(S% values in the range of 91-94%), since low amounts of benzaldehyde were formed. The
effect of co-catalysts for styrene oxidation (Table 3 and Figure 3, b) showed the same
reactivity pattern that was typically observed as for indene (Figure 3, a). Although the C%
and ee% values are lower relatively to indene, similarly, the highest C% values are observed
for amphoteric catalysts: NH4AcO (68%), 2-MeIm (66%) and Im (56%) and the ee% values
follow the order NH4AcO (66%) > 2-MeIm (58%) > Im (54%). The basic co-catalyst 1-
MeIm, when compared to the previous ones, led to lower C% (51%), but the highest ee%
value observed for this substrate (72%); NMO gave the second highest ee% (66%) and a
higher conversion relatively to 1-MeIm (62%). As previously, the use of pyridine resulted
almost usefulness, since its presence in the reaction medium did not enhance the catalytic
performance relatively to the reaction in the absence of co-catalyst (Table 3, entry 7).
Finally, higher catalytic efficiency was observed for the epoxidation of α-methylstyrene
by the system Jacobsen catalyst: H2O2: UHP: ethanol: 40ºC (Table 3) when compared to
styrene (79% substrate conversion, 96% epoxide selectivity and 98% ee, due to the higher
activation and steric hindrance of the double bond.
3.3 Mechanistic considerations
The present results showed the pronounced effect of the solvent (protic/aprotic), the co-
catalyst properties and the reaction temperature, in the activity and selectivity of the Jacobsen
catalyst in arene epoxidation by hydrogen peroxide and they are in accordance with a multi-
13
Page 15 of 31

step mechanism for the activation of hydrogen peroxide, where the extension of the different
pathways are highly sensitive to the reaction conditions [37,38].
In agreement with what was already described for the activation of H2O2 by other metal
complexes, namely metalloporphyrins and by peroxidase, [51,52] the activation of H2O2 by
Mn(salen) based complexes can be similarly described through a stepwise reaction, as
schematically represented in Figure 4. Upon addition of hydrogen peroxide to the catalyst (I),
the peroxyl group is activated through formation of a [Mn(III)salen-H2O2] adduct (Figure 5,
II), which by deprotonation leads to a hydroperoxy intermediate, [Mn(III)salen-OOH]- (III).
Then, the hydroperoxy intermediate (III) can undergo protonation and dehydration,
generating the oxo-species [Mn(V)salen=O] (IV). The hydroperoxy species can be able to
epoxidize olefins through a concerted mechanism, as observed for the epoxidation by
peracids, namely m-CPBA, since the electrophilicity of the distal peroxidic oxygen is
enhanced, due to metal bond activation. On the other hand, the activity of the oxo-species was
found to be high and independent of the oxidant used and was considered to be the
intermediate mainly responsible for the high enantioselectivity of Jacobsen catalyst relatively
to other systems, as a consequence of the high proximity of the active oxygen to the non-
planar and hindered salen ligand [53,54].
Figure 4
The effect of the reaction solvent, CH3CN (aprotic solvent) vs EtOH (protic solvent),
observed during the catalytic epoxidation of indene is highlighted in Figure 5, either in the
absence of co-catalyst or in the presence of 1-MeIm or NH4AcO, co-catalysts with basic and
amphoteric character, respectively.
14
Page 16 of 31

Figure 5
In the absence of co-catalyst (Figure 5, a and d), the epoxidation performance was
significantly enhanced when the reaction was carried out in EtOH compared to CH3CN: the
C% was 82% vs 39% and the asymmetric induction was 75% vs 51%. This result can be
related with the possibility of hydrogen bond formation between the protic solvent and the
active oxidizing intermediates, exemplified by intermediate (V) in Figure 4, in analogy with
what was proposed for H2O2 activation by metalloporphyrins and heme peroxidase [44]. This
new adduct will have improved electrophilicity on the distal oxygen of the peroxyl bond and
consequently high reactivity towards epoxidation; concomitantly, the rigidity imposed by the
three dimensional hydrogen bond network in the ethanol-hydroperoxy adduct may lead to the
observed improvement of ee% values.
In the presence of the co-catalysts, the epoxidation performance was further enhanced: 1-
MeIm led to the highest ee% and NH4AcO to the highest C%. This tendency can be also
noticed for the other co-catalysts (Figure 3), where the different reactivity pattern is ascribed
to co-catalysts with amphoteric or basic characters. For both indene and styrene epoxidation,
the amphoteric co-catalysts (NH4AcO, 2-MeIm and Im) always led to the highest substrate
conversions, whereas basic co-catalysts (1-MeIm, NMO and pyridine), produced relatively
higher ee% and relatively lower C%. These results can be explained by the preferential
formation of oxo-species with amphoteric co-catalysts, in accordance with their highest
capability to induce the dehydration step through protonation of the peroxyl bond in
intermediate (III) to afford (IV), as shown in Figure 4 (pull effect). Besides the effect of the
acid-base properties of the co-catalyst in the Jacobsen catalyst performance, discussed above,
they also act as axial ligands and consequently their electronic properties can influence
differently the reactivity of the metal centre in the intermediates (III) and (IV), thus
15
Page 17 of 31

originating a variety of ee% and C% values for each group of co-catalysts (amphoteric vs
basic).
Previous reports on Mn(salen) epoxidation showed that low temperatures tend to induce
higher ee% in comparison with reactions performed at room temperature.[9] However, an
efficient epoxidation of 2-styrylchromones and analogues using Jacobsen catalyst and
hydrogen peroxide at 40ºC was reported [55,56]. In this present work, we observed higher
enantiomeric induction at 40ºC compared to room temperature. The improvements in ee%
with temperature reaction were higher for amphoteric co-catalysts (for 2-MeIm and NH4AcO
the improvements were 17% and 20%, respectively) than for basic co-catalysts (for 1-MeIm
the improvement was 8%). These can be related with the highest extension of the dehydration
reaction and concomitant formation of the oxo-species during the catalytic cycle, in the case
of amphoteric co-catalysts.
4. Concluding remarks
The enantioselective epoxidation of mono- and bicyclic arenes using the system Jacobsen
catalyst: co-catalyst: hydrogen peroxide was achieved using a mild synthetic route comprising
ethanol as reaction solvent at 40ºC. High catalytic performances (very high substrate
conversions and enantiomeric inductions) were obtained, both using the hydrogen peroxide-
urea adduct and aqueous hydrogen peroxide added progressively to the reaction mixture
combined with co-catalysts with amphoteric and basic properties. Typically, better catalytic
performances were observed for the protic solvent compared with the aprotic solvent CH3CN
and the amphoteric co-catalysts (NH4AcO, 2-MeIm and Im) always led to the highest
substrate conversions, whereas the basic co-catalysts (1-MeIm, NMO and pyridine), led to
relatively higher ee% and relatively lower C%. Furthermore, the reactions at 40ºC showed
higher enantiomeric induction than those performed at room or lower temperature.
16
Page 18 of 31

The observed effects of solvent, co-catalyst and reaction temperature were explained by a
multi-step mechanism for activation of hydrogen peroxide with the formation of different
active species, Mn(III)salen hydroperoxy- and oxo- intermediates, depending on the reaction
conditions. The positive effect of protic solvent on the reaction performance was explained by
the establishment of hydrogen bonding between the protic solvent and the active oxidizing
intermediates enhancing both the electrophilicity and steric hindrance.
The development of heterogeneous catalysts by immobilization of chiral Mn(III)salen
complexes onto solid inorganic supports and their catalytic performance in these optimized
conditions are currently being studied [57]: these will add the advantages of using mild
reaction conditions and the inherent advantages of easy separation and recycling of the
catalyst.
Acknowledgments
This work was funded by Fundação para a Ciência e a Tecnologia (FCT) and FEDER,
through grant no. PEst-C/EQB/LA0006/2011 and projects ref. PTDC/QUE-
EQU/110825/2009 and PTDC/QUI-QUI/105304/2008. M. Rocha thanks FCT for a grant.
17
Page 19 of 31

References
[1] E.N. Jacobsen, A. Pfaltz, H. Yamamoto (Ed.), Comprehensive Asymmetric Catalysis, Vols. I–III,
Springer, Berlin, 1999.
[2] C. Baleizão, H. Garcia, Chem. Rev. 106 (2006) 3987-4043.
[3] W. Zhang, J.L. Loebach, S.R. Wilson, E.N. Jacobsen, J. Am. Chem. Soc. 112 (1990) 2801-2803.
[4] R. Irie, K. Noda, Y. Ito, N. Matsumoto, T. Katsuki, Tetrahedron Lett. 31 (1990) 7345-7348.
[5] E.M. McGarrigle, D.G. Gilheany, Chem. Rev. 105 (2005) 1563–1602.
[6] L. Chen, F. Cheng, L. Jia, L. Wang, J. Wei, J. Zhang, L. Yao, N. Tang, J. Wu, Appl. Catal. A: Gen.
415-416 (2012) 40-46.
[7] A.R. Silva, V. Budarin, J.H. Clark, C. Freire, B. de Castro, Carbon 45 (2007) 1951-1964.
[8] A.R. Silva, C. Freire, B. de Castro, Carbon 42 (2004) 3027-3030.
[9] R.I. Kuresky, T. Roy, N. Khan, S.H.R. Abdi, A. Sadhukhan, H.C. Bajaj, J. Catal. 286 (2012) 41-
50.
[10] T. Katsuki, J. Mol. Catal. A Chem. 113 (1996) 87-107.
[11] T.C. Leod, V.P. Barros, A.L. Faria, M.A. Schiavon, I.V. Yoshida, M.E. Queiroz, M.D. Assis, J.
Mol. Catal. A Chem. 273 (2007) 259-264.
[12] T. Katsuki, Coord. Chem. Rev. 140 (1995) 189-214.
[13] B.S. Lane, K. Burgess, Chem. Rev. 103 (2003) 2457–2473.
[14] T. Schwenkreis, A. Berkessel, Tetrahedron Lett. 34 (1993) 4785-4788.
[15] R.I. Kureshy, N.H. Khan, S.H.R. Abdi, S. Singh, I. Ahmed, R.S. Shukla, R.V. Jasra, J. Catal. 219
(2003) 1-7.
[16] B. Rhodes, S. Rowling, P. Tidswell, S.Woodward, S.M. Brown, J. Mol. Catal. A: Chem. 116
(1997) 375-384.
[17] N.C. Maity, S.H.R. Abdi, R.I. Kureshy, N.H. Khan, E. Suresh, G.P. Dangi, H.C. Bajaj, J. Catal.
277 (2011) 123-127.
[18] R.I. Kureshy, N.H. Khan, S.H.R. Abdi, S.T. Patel, R.V. Jasra, Tetrahedron-Asymmetry 12 (2001)
433-437.
[19] H. Shitama, T. Katsuki, Tetrahedron Lett. (2006) 3203-3207.
[20] A.Stamatis, C. Vartzouma, M. Louloudi, Catal. Commun. 12 (2011) 475-479.
[21] S.-Y. liu, D.G. Nocera, Tetrahedron Lett. (2006) 1923-1926.
[22] G. De Faveri, G. Ilyashenko, M. Watkinson, Chem. Soc. Rev. 40 (2011) 1722-1760.
[23] C. Capello, U. Fischer, K. Hungerbühler, Green Chem. 9 (2007) 927-934.
[24] P.G. Jessop, Green Chem. 13 (2011) 1391-1398.
[25] F.P. Ballisteri, L. Brinchi, R. Germani, G. savelli, G.A. Tomaselli, R.M. Toscano, Tetrahedron 64
(2008) 10239-43.
18
Page 20 of 31

[26] B. Bahramian, V. Mirkhani, M. Moghadam, S. Tangestaninejad, Catal. Commun. 7 (2006) 289-
96.
[27] M. Palucki, N.S. Finney, P.J. Pospisil, M.L. Güller, T. Ishida, E.N. Jacobsen, J. Am. Chem. Soc.
120 (1998) 948-954.
[28] A. Zsigmond, A. Horváth, F. Notheisz, J. Mol. Catal. A: Chem. 172 (2001) 95-102.
[29] A.R. Rosa, C. Freire, B. de Castro, New J. Chem. 28 (2004) 253-260.
[30] D.L. Hughes, G.B. Smith, J. Liu, G.C. Dezeny, C.H. Senanayake, R.D. Larsen, T.R. Verhoeven,
P.J. Reider J. Org. Chem. 62 (1997) 2222-2229.
[31] J. Cubbillos, S. Vásquez, C.M. de Correa, Appl. Catal. A: Gen. 373 (2010) 57-65.
[32] C. Linde, M. Arnold, P.-O. Norrby, B. Akermark, Angew. Chem. Int. Ed. 36 (1997) 1723-1725.
[33] N.S. Finney, P.J. Pospisil, S. Chang, M. Palucki, R.G. Konsler, K.B. Hansen, E.N. Jacobsen,
Angew. Chem. Int. Ed. 36 (1997) 1720-1723.
[34] J.P. Collman, Li Zeng, J.I. Brauman, Inorg. Chem. 43 (2004) 2672-2679.
[35] W. Adam, K.J. Roschmann, C.R. Saha-Möller, D. Seebach, J. Am. Chem. Soc. 124 (2002) 5068-
5073.
[36] K. Bryliakov, E.P. Talsi, Chem Eur. J. 13 (2007) 8045-8050.
[37] G.Yin, M. Buchalova, A.M. Danby, C.M. Perkins, D. Kitko, J.D. Carter, W.M. Scheper, D.H.
Busch, Inorg. Chem. 45 (2006) 3467-3474.
[38] S.-Y. Liu, J.D. Soper, J.Y. Yang, E.V. Rybak-Akimova, D.G. Nocera, Inorg. Chem. 45 (2006)
7572-7574.
[39] A. Chellamani, N.I. Alhaji, S. Rajagopal, J. Phys. Org. Chem. 20 (2007) 255-263.
[40] R. Zhang, M. Newcomb, J. Am. Chem. Soc. 125 (2003) 12418-12419.
[41] C. Vartzouma, E. Evaggelou, Y. Sanakis, N. Hadjiliadis, M. Louloudi, J. Mol. Catal. A: Chem.
263 (2007) 77-85.
[42] Y. Watanabe, “High Valent Intermediates”, in K.M. Kadish, K.M. Smith, R. Guilard (Ed.), The
Porphyrin Handbook, Academic Press, San Diego, 2000, Vol. 4, pp 97-99.
[43 N.Jin, D.E. Lahaye, J.T. Groves, Inorg. Chem. 49 (2010) 11516-11524.
[44] S.L.H. Rebelo, M.M. Pereira, M.M.Q. Simões, M.G.P.M.S Neves, J.A.S. Cavaleiro, J. Catal. 234
(2005) 76-87.
[45] B.D. Dorsey, R.B. Levin, S.L. McDaniel, J.P. Vacca, J.P. Guare, P.L. Darke, J.A. Zugay, E.A.
Emini, W.A. Schleif, J.C. Quintero, J.H. Lin, I.W. Chen, M.K. Holloway, P.M.D. Fitzgerald, M.G.
Axel, D. Ostovic, P.S. Anderson, J.R. Huff, J. Med. Chem. 37 (1994) 3443-3451.
[46] N.H. Lee, A.R. Muci, E.N. Jacobsen Tetrahedron Lett. 32 (1991) 5055-5058.
[47] P. Pietikäinen, Tetrahedron 54 (1998) 4319-4326.
[48] D.R. Boyd, N.D. Sharma, A.E. Smith, J. Chem. Soc. Perkin Trans. I (1982) 2767-2770.
19
Page 21 of 31

[49] W. Adam, J. Jekő, A. Lévai, C. Nemes, T. Patonay, P. Sebők, Tetrahedron Lett. 36 (1995) 3669-
3672.
[50] N.A. Stephenson, A.T. Bell, Anal. Bioanal. Chem. 381 (2005) 1289-1293.
[51] S.L.H. Rebelo, M.M. Pereira, P.V. Monsanto, H.D. Burrows, J. Mol. Catal. A: Chem. 297 (2009)
35-43.
[52] S.L.H. Rebelo, M.M.Q. Simoes, M.G.P.M.S. Neves, A.M.S. Silva, J.A.S. Cavaleiro, A.F.
Peixoto, M.M. Pereira, M.R. Silva, J.A. Paixão, A.M. Beja, Eur. J. Org. Chem. 23 (2004) 4778-4787.
[53] H. Jacobsen, L. Cavallo, Chem. Eur. J. 7 (2001) 800-807.
[54] L. Kürti, M.M. Blewett, E.J. Corey, Org. Lett. 11 (2009) 4592-4595.
[55] C.M.M. Santos, A.M.S. Silva, J.A.S. Cavaleiro, T. Patoney, A. Lévai, J. Heterocycl. Chem. 43
(2006) 1316-1326.
[56] C.M.M. Santos, A.M.S. Silva, J.A.S. Cavaleiro, A. Lévai, T. Patonay, Eur. J. Org. Chem. (2007)
2877-2887.
[57] H. Gaspar, M. Andrade, C. Pereira, A.M. Pereira, S.L.H. Rebelo, J.P. Araújo, J. Pires, A.P.
Carvalho, C. Freire, Catal. Today (2012), http://dx.doi.org/10.1016/j.cattod.2012.04.018.
20
Page 22 of 31

Table(s)
Table 1. Catalytic data for the oxidation of indene (1) in the presence of Jacobsen catalyst with
hydrogen peroxide and UHP in different reaction conditions.
Reaction Conditionsa
Entry Solvent
Oxidantb
Catalytic results (%)
TOFf
(h-1)
Co-cat
T(ºC) Other
Cc
Sd
eee
1
CH2Cl2:MeOHg UHP
2-MeIm
2-MeIm
2-MeIm
2-MeIm
2-MeIm
2-MeIm
2-MeIm
2-MeIm
1-MeIm
1-MeIm
1-MeIm
1-MeIm
1-MeIm
1-MeIm
40ºC
40ºC
40ºC
40ºC
40ºC
r.t.
98
37
96
91
96
96
95
100
75
77
85
62
85
84
98
99
95
99
99
97
97
97
98
99
94
97
96
97
96
97
96
96
96
96
91
98
-
77
78
77
78
77
66
65
69
93
90
94
75
86
94
89
69
70
89
73
-
96.5
36.4
92.7
87.8
92.7
93.6
93.6
62.7
72.4
73.6
82.0
59.2
82.0
80.2
93.6
94.6
90.7
90.5
67.3
-
h
2
CH2Cl2:MeOHg UHP2eq
3
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
UHP
4
H2O2(aq)
5
H2O2(aq) prog
UHP
6
7
H2O2(aq) prog
H2O2(aq) prog
CH2Cl2:MeOHg H2O2(aq)
r.t.
8
40ºC
40ºC
40ºC
40ºC
40ºC
r.t.
Cat. 10%
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
EtOH
EtOH
CH3CN
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
CH3CN
EtOH
EtOH
EtOH
EtOH
CH3CN
H2O2(aq)
UHP
UHP
UHP
UHP
UHP
UHP
UHP
UHP
UHP
UHP
UHP
UHP
UHP
UHP
40ºC
+1-MeIm
NH4AcO 40ºC
NH4AcO r.t.
NH4AcO 0ºC
NH4AcO 40ºC
NH4AcO 40ºC
NH4AcO 40ºC
+NH4AcO 100
69
no cat.
0
Im
Py
-
40ºC
40ºC
40ºC
40ºC
97
74
82
39
97
96
87
95
70
84
75
51
93.6
70.7
71.0
36.9
-
aReaction conditions unless otherwise said: substrate (0.3 mmol), chlorobenzene - GC internal standard (0.2 mmol), co-
catalyst (0.3 mmol), Jacobsen catalyst at 6.7 molar %, hydrogen peroxide (3 mmol), solvent (4 mL), results after 30 min of
reaction time. bThe hydrogen peroxide was added in two forms: anhydrous adduct with urea (UHP) or 30% aqueous solution
[H2O2(aq)], the addition was performed totally at the beginning or progressively (prog) at a rate of 3 mmol h-1, in this last
case the catalytic results are reported after 1h of reaction time; cConversion; dEpoxide selectivity; eEnantiomeric
excess;fTurnover frequency; gmixture (1:1); hreaction in the same conditions as in a) but using 2 molar equivalents of oxidant.
1
Page 23 of 31

Table 2. Catalytic data for the oxidation of chromene (2) in the presence of Jacobsen catalyst with
hydrogen peroxide and UHP in different reaction conditions.
Reaction Conditionsa
Entry Solvent
Oxidantb
Catalytic results (%)
Co-cat
2-MeIm
2-MeIm
2-MeIm
2-MeIm
NH4AcO
Py
T(ºC)
40ºC
40ºC
40ºC
r.t.
Cc
14
30
28
23
35
22
23
Sd
eee
99
99
99
95
99
86
84
TOF (h-1)f
13.9
1
2
3
4
5
6
7
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
H2O2(aq)
H2O2(aq) prog
UHP
100
100
100
100
100
100
100
29.9
27.9
UHP
22.9
UHP
40ºC
40ºC
40ºC
34.8
UHP
21.9
CH2Cl2:MeOHg UHP
Py
22.9
aReaction conditions unless otherwise said: substrate (0.3 mmol), chlorobenzene - GC internal standard (0.2mmol), co-
catalyst (0.3 mmol), Jacobsen catalyst at 6.7 molar %, hydrogen peroxide (3 mmol), solvent (4 mL), results after 30 min of
b
reaction time. The hydrogen peroxide was added in two forms: anhydrous aduct with urea (UHP) or 30% aqueous solution
[H2O2(aq)], the addition was performed totally at the beginning or progressively (prog) at a rate of 3 mmol h-1, in this last
c
d
e
case the catalytic results are reported after 1h of reaction time; conversion; Epoxide selectivity; Enantiomeric excess;
fTurnover frequency; gmixture (1:1).
2
Page 24 of 31

Table 3. Catalytic data for the oxidation of styrene (3) and α-methylstyrene (4) by Jacobsen catalyst
with UHP in ethanol.a
Catalytic results
C (%)b
68
66
S (%)c
ee (%)d
66
58
TOF (h-1)e
61.6
61.7
-
Entry Substrate
Co-cat
NH4AcO
2-MeIm
Im
1-MeIm
Py
1
2
3
4
5
6
7
91
94
f
56
-
54
51
43
62
42
93
93
92
91
72
47
66
48
47.2
39.8
56.8
38.0
NMO
-
75.5
8
2-MeIm
79
96
98
aReaction conditions: substrate (0.3 mmol), chlorobenzene - GC internal standard (0.2 mmol), co-catalyst (0.3 mmol),
Jacobsen catalyst at 6.7 molar %, hydrogen peroxide (UHP, 3 mmol), ethanol (4 mL), results after 1h of reaction time;
bconversion; cEpoxide selectivity; dEnantiomeric excess; eTurnover frequency; fNot determined.
3
Page 25 of 31

Figure(s)
Captions to Figures
Figure 1. “Push and pull” mechanism: B corresponds to histidine residues on
peroxidase active site or to the co-catalyst used in metalloporphyrin
catalyzed oxidation reactions.
Figure 2. Jacobsen catalyst and benzylic olefins used in this work: indene (1), 6-cyan-
2,2’-dimethylchromene (CN-chrom) (2), styrene (3) and α-methylstyrene
(4).
Figure 3. Effect of the co-catalyst on substrate conversion and enantioselectivity of
epoxidation of a) indene (1); b) styrene (3).
Figure 4. Mechanism proposal for arene epoxidation by hydrogen peroxide/UHP in
the presence of Jacobsen catalyst
Figure 5. Comparison of catalytic efficiency and enantioselectivity for indene
epoxidation in protic/aprotic solvents in the presence and absence co-
catalyst.
1
Page 26 of 31

Figure 1
2
Page 27 of 31

Figure 2
3
Page 28 of 31

Figure 3
a)
b)
4
Page 29 of 31