Electron-deficient heteroarenium salts: An organocatalytic tool for activation of hydrogen peroxide in oxidations

Article abstract of DOI:10.1021/jo502865f

A series of monosubstituted pyrimidinium and pyrazinium triflates and 3,5-disubstituted pyridinium triflates were prepared and tested as simple catalysts of oxidations with hydrogen peroxide, using sulfoxidation as a model reaction. Their catalytic efficiency strongly depends on the type of substituent and is remarkable for derivatives with an electron-withdrawing group, showing reactivity comparable to that of flavinium salts which are the prominent organocatalysts for oxygenations. Because of their high stability and good accessibility, 4-(trifluoromethyl)pyrimidinium and 3,5-dinitropyridinium triflates are the catalysts of choice and were shown to catalyze oxidation of aliphatic and aromatic sulfides to sulfoxides, giving quantitative conversions, high preparative yields and excellent chemoselectivity. The high efficiency of electron-poor heteroarenium salts is rationalized by their ability to readily form adducts with nucleophiles, as documented by low pK_R+ values (pK_R+ < 5) and less negative reduction potentials (E_red > -0.5 V). Hydrogen peroxide adducts formed in situ during catalytic oxidation act as substrate oxidizing agents. The Gibbs free energies of oxygen transfer from these heterocyclic hydroperoxides to thioanisole, obtained by calculations at the B3LYP/6-311++g(d,p) level, showed that they are much stronger oxidizing agents than alkyl hydroperoxides and in some cases are almost comparable to derivatives of flavin hydroperoxide acting as oxidizing agents in monooxygenases.

Full text of DOI:10.1021/jo502865f

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Article
Electron-deficient Heteroarenium Salts – an Organocatalytic
Tool for Activation of Hydrogen Peroxide in Oxidations
Jiri Sturala, Sona Bohacova, Josef Chudoba, Radka Metelkova, and Radek Cibulka
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo502865f • Publication Date (Web): 06 Feb 2015
Downloaded from http://pubs.acs.org on February 18, 2015
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Electron-deficient Heteroarenium Salts – an Organocatalytic Tool for Activation
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of Hydrogen Peroxide in Oxidations
†
†
‡
§
,†
Jiří Šturala, Soňa Boháčová, Josef Chudoba, Radka Metelková, Radek Cibulka*
†
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Department of Organic Chemistry, University of Chemistry and Technology, Prague, Technická 5,
6628 Prague 6, Czech Republic.
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Central Laboratories, University of Chemistry and Technology, Prague, Technická 5, 16628
Prague 6, Czech Republic
§
Department of Inorganic Chemistry, University of Chemistry and Technology, Prague, Technická
5
, 16628 Prague 6, Czech Republic.
*
Corresponding author: e-mail: cibulkar@vscht.cz
TABLE OF CONTENTS/ABSTRACT GRAFIC:
ABSTRACT
A series of monosubstituted pyrimidinium and pyrazinium triflates and 3,5-disubstituted pyridinium
triflates were prepared and tested as simple catalysts of oxidations with hydrogen peroxide, using
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sulfoxidation as a model reaction. Their catalytic efficiency strongly depends on the type of
substituent and is remarkable for derivatives with electron-withdrawing group showing the reactivity
comparable with flavinium salts which are the prominent organocatalysts for oxygenations. Due to
high stability and good accessibility, 4-trifluoromethylpyrimidinium and 3,5-dinitropyridinium
triflates are the catalysts of choice and were shown to catalyze oxidation of aliphatic and aromatic
sulfides to sulfoxides, giving quantitative conversions, high preparative yields and excellent
chemoselectivity. The high efficiency of electron-poor heteroarenium salts is rationalized by their
ability to readily form adducts with nucleophiles, as documented by low pK values (pK < 5) and
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less negative reduction potentials (E > -0.5 V). Hydrogen peroxide adducts formed in situ during
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catalytic oxidation act as substrate oxidizing agent. The Gibbs free energies of oxygen transfer from
these heterocyclic hydroperoxides to thioanisole, obtained by calculations at the B3LYP/6-
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11++g(d,p) level, showed that they are much stronger oxidizing agents than alkyl hydroperoxides
and in some cases are almost comparable to derivatives of flavin hydroperoxide acting as oxidizing
agents in monooxygenases.
INTRODUCTION
The chemoselective and stereoselective introduction of oxygen into an organic substrate is among
the key transformations in organic synthesis; thus, searching for new effective systems for selective
oxygenations continues to represent an important goal. Currently, oxidation systems have been
studied, especially with respect to sustainability and their environmental impact, which increases the
interest in hydrogen peroxide as an inexpensive and environmentally benign oxidizing agent,
1
producing water as the only byproduct. Despite its high oxidation potential, hydrogen peroxide
requires activation for most reactions with organic substrates due to relatively high activation
2
barriers, which has initiated the development of various catalytic systems for oxidations with
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hydrogen peroxide; the majority of these are based on transition metal complexes forming peroxo
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metal species with significantly higher reactivity. Organocatalytic oxidations with hydrogen
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peroxide remain relatively underdeveloped.
The reactivity of the hydroperoxy function is significantly enhanced by its connection to an
electron-deficient heterocyclic ring, which was demonstrated in metal-free oxidations with several
heterocyclic hydroperoxides of various structures; however, most of these compounds are used as
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stoichiometric oxidants prepared in advance. The use of reactive hydroperoxides generated in a
catalytic cycle remains the domain of organocatalytic oxidations mediated by flavinium salts 1 or 2
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,7
(Scheme 1 and 2). As shown in Scheme 1 in the example of isoalloxazinium derivative 1,
flavinium catalysts react with hydrogen peroxide to form flavin-4a-hydroperoxide 1-OOH. After
oxygen is transferred to a substrate, the catalyst is regenerated by water elimination from a
pseudobase 1-OH. The ability to reversibly add hydrogen peroxide and water, together with the high
reactivity of flavin hydroperoxide (in sulfoxidations, hydroperoxide 1-OOH is more reactive than
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hydrogen peroxide by 4 orders of magnitude ), makes flavinium salts very effective catalysts of
oxidations.
The investigation of oxidations catalyzed by flavinium salts was initiated by discovery of the mode
of action of hydroperoxides derived from flavin cofactors (FAD, FMN), which were recognized as
9
oxidizing agents in flavoenzymes. Later, this mild oxidation method became a real alternative to
1
0,11
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other oxidation protocols, mainly in sulfoxidations
and Baeyer-Villiger oxidations. Even some
1
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chiral flavinium salts were shown to catalyze stereoselective oxidation of prochiral sulfides and
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cyclobutanones. Recently, new applications of flavinium-catalyzed oxygenations, i.e., in the
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Dakin oxidation, hydroxylation of boronic acids, oxidation of aldehydes to carboxylic acids
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and insertion of oxygen into methyl-rhenium bonds have also been described. To the best of our
knowledge, except for derivatives of flavinium salts 1 and 2 (both derivatives 1, with an
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isoalloxazinium core, and 2, with an alloxazinium core, are classified as flavin derivatives in the
literature), no example has been given in the literature of the in situ generation of a heterocyclic
hydroperoxide by the addition of hydrogen peroxide to a simple heteroarenium salt simultaneously
with using this adduct in catalytic oxidations. This fact is surprising because heteroarenium salts are
known to form adducts with various nucleophiles; the formation of pseudobases by the addition of
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hydroxide anion to heteroarenium salts is one such example.
Scheme 1 Catalytic cycle of H O -oxidations catalysed by flavinium salts 1.
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In our preliminary investigation, pyrazinium tetrafluoroborates 3 (X = BF in Scheme 2) with an
4
electron-withdrawing substituent were shown to catalyze sulfoxidations with hydrogen peroxide in a
similar way as flavinium salts; i.e., hydrogen peroxide adds to salt 3 to form heterocyclic
hydroperoxide 3-OOH, which oxidizes a substrate. This important finding led us to consider if the
ability to catalyze H O oxygenations is limited to pyrazinium salts, representing simple models of
2
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alloxazinium catalysts 2 with the same diazadiene N=C-C=N grouping (Scheme 2), or if this useful
property is general among nitrogen containing heteroarenium compounds. Therefore, we extended
our study to 2-, 4- and 5-substituted pyrimidinium compounds 4 and disubstituted pyridinium
compounds 5 as suitable representatives of simple heteroarenium compounds. Salts 3-5 are readily
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available by only a one-step synthesis from commercial material, making them attractive for
potential practical applications. To gain insight into the mechanism of action of heteroarenium
catalysts in sulfoxidations, structure vs. catalytic activity relationships were studied using
experimental and theoretical approaches.
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Scheme 2 Simplification of heteroarenium catalysts for H O -oxidations.
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RESULTS AND DISCUSSION
Design and Synthesis of Heteroarenium Catalysts. The pyrimidine ring offers several structural
modifications from the point of view of the relative position of a substituent and the quaternary
nitrogen that is to be introduced. Additionally, the relative position of heteroaromatic nitrogen atoms
in the pyrimidine ring (1,3-) differs from that in pyrazines and flavins (both isoalloxazines and
alloxazines), which belong among 1,4-heterocycles. Therefore, pyrimidinium salts 4 (see Figure 1)
were chosen as suitable probes to determine whether other heteroarenium salts are able to catalyze
H O sulfoxidations and, eventually, to find the characteristics that are required for a heteroarenium
2
2
salt to be an active catalyst. To evaluate the effect of substitution, we prepared 2-, 4-, and 5-
substituted derivatives with various types of substituents involving both electron-withdrawing and
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electron-donating groups. To design suitable derivatives in the pyridine series, we considered the
fact that one substituent is not enough to make the pyridinium function effective in the catalysis of
H O sulfoxidations and the aspect of synthetic availability, which favors symmetrical 3,5-
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2
disubstituted pyridinium salts 5b-5i, derivatives of Hantzsch-type pyridines. Nevertheless, to study
the effect of the relative position of substituents on the pyridinium ring, we also prepared 2,5- and
2,6-disubstituted analogs 5j-l with the strongly electron-withdrawing cyano group. Monosubstituted
pyridinium triflates 6, unsubstituted derivatives 3a, 4a, and 5s, as well as quinolinium and
isoquinolinium analogues 7 and 8, were prepared for comparison. To eliminate the effect of the
counter-anion, all salts were prepared in the form of triflates, since preliminary experiments on
quaternization showed methyl triflate to be superior to corresponding tetrafluoroborate as alkylating
agent. Methyl triflate allowed all quaternary salts to be prepared in relatively high yield and high
purity. Accordingly, a series of pyrazinium triflates 3a-g were prepared as analogs of
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tetrafluoroborates studied in our preliminary communication. In selected cases, tetrafluoroborates
were also prepared to study the effect of the counter-anion on the catalytic activity.
Figure 1. Heteroarenium catalysts studied in this work.
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Most heteroarenium triflates were prepared from the corresponding heteroaromatic compounds by
quaternization with an excess of alkyl triflate (alkyl = methyl or ethyl) at 0 °C in dichloromethane or
chloroform. It is important to avoid any nucleophilic solvents or impurities, including water, during
the entire synthetic procedure, as the majority of salts are prone to formation of the corresponding
adducts; this is especially the case of electron-poor derivatives with cyano and nitro substituents,
which add nucleophiles readily. Relatively pure products were obtained by simple evaporation of
the reaction mixture. Nevertheless, the salts were additionally purified by crystallization or
precipitation from dry acetonitrile solution by the addition of dry diethyl ether to obtain final
products of high purity. In some cases, the salts did not crystallize, and they were isolated as oils. To
remove traces of solvents from the products, they were washed several times with dry diethyl ether.
Quaternization of 4-methylpyrimidine under standard conditions led to a mixture of two
regioisomeric quaternary salts, 1,4-dimethyl- (4i) and 1,6-dimethylpyrimidinium triflates
accompanied by decomposition products. To ensure highest selectivity and to avoid product
decomposition, it was necessary to dilute and cool the reaction mixture by dry ice/ethanol mixture,
which led preferably to 4i, the product of alkylation on the less hindered nitrogen, still containing
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8% of 1,6-isomer. 1-Methyl and 1-ethyl tetrafluoroborates were prepared using trialkyloxonium
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tetrafluoroborates according to the described procedure.
Catalytic Activity. The catalytic activity of the prepared heteroarenium salts was measured by
oxidation of thioanisole 9a as a model substrate under conditions usually used for testing flavinium
10d,10f,11c,11d,20-21
salts,
i.e., with 2 mol% of the catalyst, aqueous hydrogen peroxide (1.5 equiv.) in
deuterated methanol at 25 °C (Scheme 3). The efficiency of the heteroarenium salts was evaluated
using the pseudo-first-order rate constant kobs calculated from conversion vs. time dependences or
estimated from the rates in the early phase of the reactions. To evaluate the effect of substitution in
each group of the catalysts, the values of the rate constants of the oxidations catalyzed by substituted
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heteroarenium salts related to those catalyzed by unsubstituted derivatives (k = k / kobs ) are
rel
obs
given. To assess overall efficiency, the values of the rate constants related to those of the
uncatalyzed reaction (k / k ) are also shown (see Tables 1–5).
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Scheme 3 Model sulfoxidation for testing the catalytic efficiency of heteroarenium salts 3 - 8 (Het X ).
A remarkable effect of the heterocyclic nitrogen in the 3-position relative to the quaternary center on
the catalytic activity of heteroarenium salts was observed when comparing the relative rate of
thioanisole oxidation in the presence of unsubstituted salts (Table 1). While a small acceleration was
observed with salts possessing only one heterocyclic nitrogen or with pyrazinium salt 3a,
pyrimidinium triflate 4a accelerated the oxidation remarkably. In contrast only a negligible effect on
the oxidation was observed by substitution with an electron-withdrawing cyano group (cf. data for
6
a and 6b with those for 5a).
Table 1 The observed catalytic activity of non-substituted heteroarenium salts and monosubstituted
pyridinium salts in oxidation of thioanisole 9a to 10a.
3
kobs .10
[
a
Catalyst
-1
k /k0
obs
min ]
3a
4a
5a
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5.2
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Rate enhancement relative to non-catalyzed reaction; k = 0.6 × 10 min
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The effect of substituents on the catalytic efficiency was found to be more significant among
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pyrazinium, and mainly among disubstituted pyridinium, salts achieving maximal kobs / kobs values
of 15 and 35, respectively (cf. Tables 2-4). In the case of pyrimidinium salts, the activating effect of
the second heterocyclic nitrogen acting as an electron-withdrawing group is dominant and further
increase of the catalytic activity caused by substitution reaches the maximum value of only 6.9
(Table 2). The substitution in the 2-position even almost does not affect the efficiency of the
pyrimidinium core, with the exception of the electron-donating methoxy group and, surprisingly, the
cyano function, which both decrease the catalytic activity. Low efficiency of the cyano derivative 4h
is associated with slow and almost irreversible formation of the adduct with both solvent and
hydrogen peroxide (the oxidant), which is unprecedented among quaternary salts studied (see
chapter Reaction Mechanism: Adducts with nucleophiles). Interestingly, the effects of substituents
appear to be additive, as shown by the rate constant of oxidation in the presence of 1-
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methylpyrimidinium salt 4v with a 2-methoxy and a 4-trifluoromethyl group (kobs / kobs = 1.1).
There, a deactivating effect of the 2-methoxy group (see catalyst 4c) is compensated by a positive
effect of the 4-trifluoromethyl substituent (see catalyst 4n). Due to decomposition of the 5-cyano
derivative 4t during oxidation precluding its application in catalysis, 4-trifluoromethyl and 4-cyano
derivatives 4n and 4o appear to be the most promising catalysts among pyrimidinium salts.
Table 2 The observed catalytic activity of 2-,4-, and 5-substituted pyrimidinium salts 4 in oxidation of
thioanisole 9a to 10a.
2-
kobs .10
4-
kobs.10
[min ]
-
4.1
6.2
9.4
13.8
11.3
5-
3
3
3
a
a
kobs.10
a
Substituent
Catalyst
-1
krel
Catalyst
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krel
Catalyst
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krel
[
min ]
[min ]
H
Me
MeO
CONEt2
CONHEt
COOEt
4a
4b
4c
4d
4e
4f
5.2
4.8
1.4
6.7
4.9
5.0
1.0
0.9
0.3
1.3
0.9
1.0
-
4i
4j
4k
4l
-
-
-
4p
-
4q
4r
-
-
-
-
1.2
-
2.6
2.5
0.8
1.2
1.8
2.7
2.2
6.2
-
13.7
12.8
4m
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2
2
2
2
2
2
3
3
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3
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4
4
4
4
4
4
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5
5
5
5
5
5
5
5
5
6
CF3
CN
NO2
4g
4h
-
6.6
1.5
-
1.3
0.3
-
4n
4o
29.0
29.9
-
5.6
5.8
-
4s
4t
4u
8.2 c
35.9
5.5
1.6
6.9
1.1
b
c
a
b
Z
H
krel = kobs / kobs ; rate constant relative to reaction catalyzed by non-substituted derivative.
The reaction mixture was allowed to stand at 25 °C for 3h before starting the oxidation to ensure the
equilibrium between 4h and corresponding adducts with nucleophiles is established.
Decomposition of the catalyst was observed.
c
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
The order of the efficiency of substituted 1-methylpyrazinium triflates 3a-3f corresponds to that
2
0
found for analogous 1-ethylpyrazinium tetrafluoroborates (Table 3), nevertheless, an effect of the
counterion and 1-alkyl group was still observed. The change of a methyl for an ethyl group slightly
increases the reactivity of the pyrazinium catalyst due to a steric effect (cf. catalysts 3f and 3g).
Triflate 3g showed higher catalytic activity than tetrafluoroborate 3h most likely because
trifluoromethanesulfonic acid released during the first step of the catalytic cycle is fully dissociated
due to its high acidity (in contrast to tetrafluoroboric acid) thus maximally supporting the specific-
2
2
acid-catalyzed elimination (cf. Scheme 4).
Table 3 The observed catalytic activity of pyrazinium salts 3 in oxidation of thioanisole 9a to 10a.
3
kobs .10
a
Catalyst
-1
krel
[
min ]
3
3
3
3
3
3
3
3h
a
b
c
d
e
f
g
1.4
1.9
3.0
19.7
8.0
1.0
1.4
2.2
14
5.9
15
20.6
19.7
14
10
14.3
a
Z
H
krel = kobs / kobs ; rate constant relative to reaction catalyzed by non-substituted derivative.
As already mentioned, monosubstituted pyridinium salts 6 do not accelerate sulfoxidation, despite
the presence of a strongly electron-withdrawing cyano group (Table 1). However, if two cyano
functionalities are present, the pyridinium salt exhibits remarkable activity, especially if the
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substituents are located in the 3- and 5-positions (catalyst 5f; see Table 4). An even better result was
observed for the dinitro derivative 5g, which is the best catalyst for H O sulfoxidations among the
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
2
heteroarenium salts investigated. In contrast, the use of substituents other than cyano or nitro has no
effect, or even negative effect, on the reactivity of the pyridinium ring (see results for 5b-e).
Similarly as among pyrazinium salts, a remarkable counterion effect was shown, with triflates
superior to tetrafluoroborates (cf. 5f vs. 5h and 5j vs 5k).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 4 The observed catalytic activity of pyridinium salts 5 in oxidation of thioanisole 9a to 10a.
3
kobs.10
a
Catalyst
-1
krel
[min ]
5a
1.3
1.0
5b
0.7
0.6
5c
0.9
0.7
5d
1.0
0.8
5e
1.0
0.8
5
f
34.2
45.2
21.2
20.0
6.1
26.7
35.3
16.6
15.6
6.8
5g
5h
5
i
5j
5k
5l
4.6
3.6
2.0
2.6
a
Z
H
krel = kobs / kobs ; rate constant relative to reaction catalyzed by non-substituted derivative.
The results clearly show that the cyano group has a positive effect on the reactivity of all types of
heterocycles, regardless of the substitution position, with the exception of 2-cyanopyrimidinium salt
4
h. The positive effect of a trifluoromethyl group was observed mainly for 4-substituted
pyrimidinium salt 4n, showing high reactivity and moreover, very high stability. This is also the
case for dinitropyridinium salt 5g, which is the best simple heteroarenium sulfoxidation catalyst
10d,11c
described today, with efficiency being i) comparable to dihydroalloxazine 2a-H2,
the precursor
of alloxazinium catalyst 2a used, e.g., as a redox-active unit in alloxazine-cyclodextrin
1
3c,13d
conjugates,
efficient catalysts of enantioselective sulfoxidations; ii) almost halved compared to
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1
1
1
1
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1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
8
-trifluoromethylalloxazinium perchlorate 2c, one of the best known alloxazinium catalysts from the
10d
point of view of reactivity and stability; and, iii) one-third compared to the most efficient
1
0d,11d
isoalloxazinium catalyst 1a (Table 5).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 5 The catalytic activity of selected heteroarenium salts in oxidation of thioanisole 9a to 10a.
a
Catalyst k /k0
obs
3
f
34
48
50
57
75
79
18
4
4
n
o
5f
5g
b
b
2
a-H2
2b
b
2c
192b
220
1a
a
b
-3
-1
Rate enhancement relative to non-catalyzed reaction; k = 0.6 × 10 min
Calculated from the data from ref. .
0
10d
Preparative Oxidations. Efficient catalysts 4n and 5g were tested in oxidations of various sulfides
on preparative scale (Table 6). With the exception of p-nitrothioanisole 9e (Entry 5) with catalyst
4
n, all sulfides 9 were quantitatively oxidized to the corresponding sulfoxides 10 within the
maximum period of 24 hours using 5 mol% of the catalyst. Similarly as for flavinium catalyzed
sulfoxidations, no overoxidation to the sulfone was observed in any case. Oxidation of thioanisole
9
a and thioanisoles 9b-d (Entries 1-4) with an electron-donating group were finished within 2-3
hours; interestingly, derivative 9f with a carboxy group was effectively converted to 10f over 14
hours using catalyst 4n, and even over only 4 hours using catalyst 5g (Entries 7 and 8). Substrates
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9
d, 9g and 9h were oxidized chemoselectively without side oxidation of the phenol ring, the double
bond or the benzylic position, respectively (Entries 4 and 9-11). Analogously, 2-
(diphenylmethyl)sulfanyl]acetamide (9l), precursor of the psychostimulant Modafinil 10l, was
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
23
[
chemoselectively oxidized to the active substance in quantitative conversion, while the uncatalyzed
oxidation with hydrogen peroxide is very slow under the same conditions (Entries 18 and 19). In the
case of allylic substrate 9h, which is relatively difficult to oxidize, catalyst loading down to 1 mol%
was shown to be adequate for effective oxidation (Entries 12-13).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 6 Preparative oxidations of sulfides by hydrogen peroxide catalyzed by heteroarenium salts
a
4
n and 5g.
b
c
Time Conversion Yield
Blank conv.
[%]
Entry
1
Substrate
Product
Catalyst
[
h]
[%]
[%]
9a
10a
4n
2
quant.
100
8
2
3
4
4n
4n
4n
2
quant.
quant.
quant.
97
100
75
16
35
13
2.5
3
5
6
4n
5g
4n
5g
4n
24
23
14
4
86
84
89
68
73
98
37
35
8
9e
9f
10e
10f
quant.
quant.
96
d
7
8
9
2
6.5
quant.
8
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
10
4n
5g
6
quant.
98
6
1
1
1
1
2
3
9h
9h
9h
10h
10h
10h
4
9
quant.
86
90
81
90
4
9
e
5g
5g
e
21
quant
22
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
14
4n
5g
4n
4
quant.
quant.
quant.
96
91
99
25
14
35
1
1
5
6
9i
10i
2.25
0.75
1
1
7
8
4n
0.33
quant.
98
49
4n
5g
21.5
16.5
quant.
quant.
98
99
4
3
19
9l
10l
a
Conditions for the oxidations: m (substrate) = 100 mg, 1.5 equiv. H O , 5 mol% of the catalyst, methanol (2
mL), T = 25±0.5 °C, monitored by TLC (dichloromethane-ethyl acetate 10:1).
Isolated yield.
Conversion of the non-catalyzed reaction after the same reaction time.
Performed in 3 mL of methanol.
2
2
b
c
d
e
1
Mol% of the catalyst.
Reaction Mechanism: Adducts with Nucleophiles. The general mechanism of sulfoxidations with
hydrogen peroxide catalyzed by heteroarenium salts was proposed taking into account the
1
0d,11d,21,24
mechanism of flavinium-based oxidations
(cf. Scheme 1) and previous findings on
2
0
oxidations catalyzed by pyrazinium tetrafluoroborates and consists of i) reversible formation of a
hydroperoxide adduct; ii) oxygen transfer from the hydroperoxide to a substrate; and, iii)
regeneration of the catalyst from a pseudobase (Scheme 4).
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34
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42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
-
Scheme 4 The proposed mechanism of H O oxidations catalyzed by heteroarenium salt (Het X ).
2
2
Adducts with O-nucleophiles play an important role in the catalytic cycle. To gain knowledge about
their structure, regioselectivity of nucleophilic addition was investigated using a model reaction of
selected heteroarenium salts with methanol in the presence of sodium carbonate, which provides
quantitative formation of the adduct. Due to their low stability in the form of pure substance,
1
13
adducts were generated in situ in deuterated solvent and characterized by H and C NMR spectra
20
and HR-MS analysis. In the previous communication, 3-cyanopyrazinium tetrafluoroborate was
found to add hydrogen peroxide, water and methanol into the 6-position (Scheme 5A). Now, we
observed formation of analogous adducts also for 3-trifluoromethylpyrazinium triflate (3e) and for
pyrimidinium triflates 4h, 4k, 4n and 4o, regardless of substituent position, showing the nucleophile
to prefer addition into the less hindered side next to the quaternary nitrogen (Scheme 5B). In the
case of 3,5-disubstituted pyridinium salts, two electrophilic positions (2- and 4-) compete in the
1
9a
reaction with nucleophiles, as expected, on the basis of UV-VIS spectroscopic studies.
1
Nevertheless, under our conditions, H NMR spectra showed formation of only one set of signals
belonging to 2-methoxy-3,5-dinitro-1,2-dihydropyridine 13a. Similarly, in deuterated methanol
2
5
2
without the presence of a base (Scheme 5C), the formation of the [2- H]methoxy adduct 13b, the
adduct with 3,5-dicyanopyridinium salt (5f), was observed. It should be noted that without the
1
presence of a base, the signals of the adduct in the H NMR spectra are accompanied by signals of
the starting quaternary salt because an equilibrium is established. Accordingly, one should keep in
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
mind that the electron-poor heteroarenium salt appears partly in the form of an adduct after
dissolving it in any nucleophilic solvent; this is also the case in a methanolic solution of the catalyst
before starting the catalytic oxidations. As we found, with the exception of the 2-cyanopyrimidinium
salt 4h forming quantitatively the adduct 11d in the range of several hours, for all heteroarenium
salts in the investigation, the equilibrium between free salt and its methoxy adduct was established
within 3 minutes maximum (for examples of the courses of the methanol adduct formation, see
Figure 2). Analogously, in almost cases methoxy adduct and free salt should be in fast equilibrium
with hydroperoxy adduct (the oxidant) under conditions of sulfoxidation thus allowing oxidation to
proceed without substantial delay.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
00
80
60
4
2
0
0
0
0
100
200
Time (min)
Figure 2. Course of the formation of methanol adduct Het-OCH with 4h (red), 4o (blue) and 4c (green).
3
Salts 4o and 4c were taken as examples of electron-poor and relatively electron-rich salts occurring in
methanol preferably in the form of adduct and free salt, respectively.
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19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 5 Regioselectivity of adducts formation.
Evaluation of Substitution Effect. As evident from the catalytic cycle, the ability to add
nucleophiles is one important factor influencing the catalytic activity of heteroarenium salts. It can
19a
be quantified by pK values representing the heteroarenium salt/pseudobase equilibrium (see
R+
Table 7). Although the pK value is associated with the addition of water, it reflects also the ability
R+
26
to add other O-nucleophiles, such as hydrogen peroxide. The ability of heteroarenium salts to react
with nucleophiles - the electrophilicity - can be characterized also by their reduction potentials
(Table 7).
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6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 7 Comparison of pK values and reduction potentials Ered for heteroarenium salts used in catalysis.
R+
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
b
Ered
pKR+
Series
Catalyst
[V]
f
Pyrazinium
3a
-0.67
-0.60
-0.52
-0.45
-0.37
-0.24
-
-
f
3
b
-
3
c
8.5
6.6
7.5
4.0
4.3
4.5
6.7
8.1
8.5
7.2
5.1
5.7
3.1
3
d
3
e
3f
3
3
g
h
-
2
4
5
-Pyrimidinium
4a
-0.95
-1.04
-0.94
-0.82
-0.74
-0.61
-0.54
-0.40
-1.11
-1.39
-0.61
-0.52
-0.42
-0.44
-0.24
-0.56
-0.84
-0.74
-0.69
-0.62
-0.44
-0.99
-0.88
-0.78
-0.58
-0.41
-0.14
-0.40
-0.43
-0.18
-0.18
-0.85
0.35
4
b
4c
4d
4e
4f
4
4
g
h
f
-
-
f
-Pyrimidinium
4i
4
j
9.6
6.6
7.3
6.8
5.1
4.5
6.6
10.2
6.5
4.8
6.4
4.5
4
k
4
l
4
m
4n
4o
4v
4p
-pyrimidinium
Pyridinium
4
q
4
4
r
s
4
t
f
5b
-
5
c
11.9
9.3
9.5
3.7
5
d
5e
5f
5g
c
<1
5
h
3.7
4.0
5
i
f
5
j
-
5
l
5.9
12.2
2.0
d
6
a
e
Flavinium
1a
2
a
0.10
7.9
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2b
0.18
0.28
6.9
4.8
2
c
a
4
The first formal reduction potentials vs SCE in acetonitrile determined by cyclic voltammetry on platinum
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
electrode. The measured reduction potentials were corrected using ferrocene / ferrocenium as a standard.
b
c
d
e
f
+
+
pK = -log K ; K =[FlOH][H ]/[Fl ]; determined by UV-VIS spectroscopy.
R+
R+
R+
1
Estimated value from the half of titration curve measured by H-NMR (see Supporting Information 1).
19a
Ref.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
10d
All data for flavinium salts taken from ref. were obtained under the same conditions.
Not determined because of instability of the compound or value is out of measurable range.
pK values and values of the first (the most positive) reduction potential clearly show (Table 7)
R+
that, in all series studied, electron-withdrawing groups increase the electrophilicity (less negative
reduction potentials) of the heteroarenium core and its ability to add nucleophiles (lower pKR+
values). The effect of electron-donating groups is reversed. As expected, the effect is especially
pronounced among pyridinium salts, being a result of double substitution. Nevertheless, the effect of
the second group on the pyridinium ring is essential, as evident when comparing the values for 3-
cyanopyridinium triflate 6a and 3,5-dicyanopyridinium triflate 5f. An alkyl chain in the 1-position
influences only the value of pK and not the reduction potential (cf. 5h vs 5i), which corresponds to
R+
the assumption about its dominating steric effect. Similar to the catalytic activity, the pK value is
R+
also significantly influenced by nitrogen in the 3-position, providing evidence about the relatively
easy formation of adducts of the unsubstituted pyrimidinium salt 4a with nucleophiles.
As we already reported, catalytic activity of substituted alloxazinium salts 2 expressed as the
1
0d
logarithm of the rate constant nicely correlates with their pK values and reduction potentials.
R+
The lower the values of pK and the less negative values of reduction potential, the higher catalytic
R+
efficiency was observed. This smooth dependence showed heteroarenium salt/pseudobase or
heteroarenium salt/hydroperoxide equilibria to be the most important steps in the catalytic cycle
1
1c,21
11d
with alloxazinium catalysts. It corresponds with the findings of Bäckvall
and Murahashi that
formation of hydroperoxide or water elimination are rate determining steps in oxidations catalyzed
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6
by alloxazinium or isoalloxazinium salts, respectively. We did not similarly find a close correlation
in any of the series of simple heteroarenium salts 3-5. Nevertheless, a visualized dependence of the
relative rate constants k /k of sulfoxidation of thioanisole on the pK and E values of the
obs
0
R+
red
catalysts (Figure 3) shows a clear trend indicating that higher catalytic efficiency was observed for
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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0
1
2
3
4
5
6
7
8
9
0
heteroarenium salts with lower values of pK and with less negative values of reduction potential.
R+
The most effective catalysts (i.e., those with a k /k value higher than 30) are characterized by both
obs
0
i) a pK value lower than 5 and ii) a reduction potential (E ) less negative than -0.5 V. The
R+
red
exception is the efficient pyrazinium salt 3d, with a slightly higher pK value. On the other hand,
R+
the 2,6-dicyanopyrazinium salt 5l nearly meets the criteria noted above, but its efficiency is low,
most likely due to steric hindrance.
Figure 3. Visualization of the dependence of the catalytic activity of heteroarenium salts expressed by
relative rate of thioanisole oxidation (k /k ) on pK and Ered values. The blue color refers to the space with
obs
0
R+
the most effective catalysts. Only catalysts with all data available are included.
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2
It is interesting to compare the pK and E values of the most efficient heteroarenium salts (4o,
R+
red
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
4
n, 4t, 5f and 5g) with those for the efficient flavinium derivatives 2 and 1a (see Table 7 for pKR+
and E values and Table 5 for catalytic activity). While the pK values are comparable for both
red
R+
groups of catalysts (cf. 5f and 2c or 5g and 1a, for example), the reduction potentials of the simple
heteroarenium salts are more negative by 0.3-0.6 V, even for the most efficient dinitropyridinium
salt 5g. This result means that although some simple heteroarenium salts are able to easily form
adducts, they are not as electron-poor as alloxazines and isoalloxazines. This property may be
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
reflected in the rate of the S 2-like oxygen transfer step (Scheme 6), which was previously found to
N
8
correlate with the ability of the RO group to escape the intermediate. In oxidations with flavin
hydroperoxide (FlOOH), electron-poor flavin skeleton causes FlO subunit to be very good leaving
group which allows oxygen transfer to proceed readily; it means that it does not affect the overall
rate of oxidation. On the other hand, the oxygen transfer step from HetOOH appears to influence the
overall rate of catalytic oxidation since HetO group derived from less electron-poor, simple
heteroarenium salts is not as good leaving group as FlO.
Scheme 6. Simplified S 2-like oxygen transfer step in sulfoxidations with peroxide compounds.
N
Theoretical Calculations on the Oxygen Transfer Step. To gain more insight into the oxidation
step, we decided to estimate the barriers of the oxygen transfer from hydroperoxides to thioanisol
based on quantum calculations. We assumed that the position of the hydroperoxy group in the
heterocyclic hydroperoxide corresponds to that determined by NMR experiments for model
methoxy adducts. From a mechanistic point of view, we considered a generally accepted S 2-like
N
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
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4
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4
4
5
5
5
5
5
5
5
5
5
5
6
2
,27
mechanism, where the sulfur lone pair attacks the terminal oxygen atom (Scheme 7A) or a model
28
with one molecule of methanol participating in the process (Scheme 8A).
For comparison, we calculated the values of the energy barriers and the Gibbs free energies for
oxidation of thioanisole with isoalloxazine-hydroperoxide 1a-OOH and with isomeric
alloxazine-hydroperoxides 2-OOH (Table 8) using a simplified model without participation of a
solvent molecule in the oxygen transfer (Scheme 7A, Het = Fl). The energy barrier (54.6 kJ/mol)
obtained for the isoalloxazine derivative 1a-OOH is in good agreement with the previously reported
value calculated by Bach at the B3LYP/6-31++g(d,p) level of theory for oxidation of dimethyl
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
,27a
sulfide with the biomimetic flavin hydroperoxide 1c-OOH (47.7 kJ/mol),
taking into account
that aromatic thioanisole requires more energetic conditions than aliphatic dimethyl sulfide and also
possible error by using different basis set. Interestingly, while substitution of the benzene ring in
alloxazine had a significant effect on the catalytic efficiency of the corresponding alloxazinium salt
10d
2
(see Table 5), as well as their pK and E values (see Table 7), the calculated oxidation
R+ red
barriers are minimally affected by the substitution (Table 8). This initially surprising result supports
previous findings showing addition of hydrogen peroxide and elimination of water to be the most
important steps for oxidations catalyzed by alloxazinium and isoalloxazinium salts, which are
substantially influenced by substitution.
ǂ
ǂ
Table 8. Reaction energy barriers (E ) and Gibbs free energies (G ) for the oxygen atom transfer
from flavin-hydroperoxides (FlOOH) to thioanisole calculated on B3LYP/6-311++g(d,p) level.
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9
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21
22
23
24
25
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28
29
30
31
32
33
34
35
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37
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46
47
48
49
50
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52
53
54
55
56
57
58
59
60
ǂ
ǂ
FlOOH
E [kJ/mol]
54.6
G [kJ/mol]
1
a-OOH
60.2
60.4
-
64.8
61.3
1
b-OOH
56.2
a
1
c-OOH
2a-OOH
b-OOH
c-OOH
47.7
61.4
59.3
58.6
2
2
61.2
a
2,27a
The value for oxidation of dimethyl sulfide from ref.
calculated on B3LYP/6-31++g(d,p) level.
Energy barriers and Gibbs free energies for hypothetical hydroperoxides derived from substituted
heteroarenium salts show that electron-withdrawing substituents facilitate oxygen transfer (Table 9).
In the pyrimidine and pyrazine series, the effect is less significant, while the second atom of
nitrogen also serves as an electron-withdrawing group. A very strong influence of substitution in the
pyridine and 5-substituted pyrimidine series is most likely caused by the substituent in the ortho
position relative to the hydroperoxy group. The most reactive hydroperoxide, derived from a 1-
methyl-3,5-dinitropyridinium salt, has the Gibbs free energy of oxygen transfer almost the same
(
60.9 kJ/mol) as that for isoalloxazine hydroperoxides 1-OOH (cf. with values in Table 8). The
value, calculated taking in regard hydrogen transfer mediated by one methanol molecule (63.5
kJ/mol), shows this hydroperoxide being somewhat weaker oxidant in comparison with
isoalloxazine hydroperoxides, which corresponds better with its slightly lower catalytic activity.
[29]
B)
C)
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2
2
2
2
2
2
3
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3
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3
3
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3
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5
5
5
5
5
6
0
1
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3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
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7
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9
0
1
2
3
4
5
6
7
8
9
0
Scheme 7 Representation of oxygen transfer step in sulfoxidations with heterocyclic peroxide compounds (A)
and geometry of prereaction complexes (B) of 2-hydroperoxy-1-methyl-1,2-dihydropyrimidine with
thioanisole (9a) and corresponding transition states for oxygen transfer (C) optimized at the B3LYP/6-
3
11++g(d,p) level. Energies are in Hartree, distances are in Å.
B)
C)
Scheme 8. Representation of oxygen transfer step in sulfoxidations with heterocyclic peroxide compounds
(A) with participation of solvent (methanol) and geometry of prereaction complexes (B) of 2-hydroperoxy-1-
methyl-1,2-dihydropyrimidine with thioanisole (9a) and corresponding transition states for oxygen transfer
(
C) optimized at the B3LYP/6-311++g(d,p) level. Energies are in Hartree, distances are in Å.
ǂ
ǂ
Table 9. Effect of substituents on reaction energy barriers (E ) and Gibbs free energies (G ) of
oxygen atom transfer to thioanisol from heterocyclic hydroperoxides.
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ǂ a,c
ǂ a,c
ǂ
b,c
Heterocycle
Pyrimidine
Position and
substituent R
2-COOEt
E
G
G
rel
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
[kJ/mol]
84.5 (82.1)
80.0 (78.9)
77.3 (77.0)
84.7 (83.1)
85.3 (83.7)
90.8 (86.2)
88.0 (84.6)
91.4 (86.2)
76.1 (76.1)
78.0 (78.5)
82.7 (81.9)
80.8 (76.1)
85.5 (81.4)
91.1 (86.6)
88.0 (84.6)
91.7 (86.1)
81.2 (80.1)
69.1 (71.7)
71.9 (73.5)
71.5 (80.0)
76.8 (77.6)
81.3 (81.5)
83.8 (80.3)
88.0 (84.6)
71.5 (73.3)
76.3 (75.7)
75.4 (76.8)
78.1 (77.1)
80.2 (78.6)
85.9 (82.9)
58.8 (67.6)
66.2 (71.1)
61.8 (67.4)
74.7 (76.9)
79.6 (80.6)
84.8 (83.5)
86.8 (86.5)
102.6 (90.0)
[kJ/mol]
83.1 (90.8)
83.2 (86.7)
83.3 (78.8)
85.8 (95.0)
87.8 (90.2)
94.0 (94.5)
94.6 (100.0)
95.6 (94.5)
81.9 (82.7)
82.4 (78.0)
84.1 (79.2)
84.3 (79.5)
88.4 (85.4)
94.0 (93.0)
94.6 (100.0)
94.6 (91.9)
86.9 (88.6)
72.9 (71.9)
75.1 (75.1)
75.3 (86.7)
80.5 (84.6)
85.4 (84.5)
87.4 (88.4)
94.6 (100.0)
77.1 (74.9)
78.3 (79.4)
79.6 (80.6)
79.9 (82.4)
82.3 (83.5)
89.6 (88.0)
60.9 (63.5)
67.7 (76.5)
68.9 (72.2)
75.7 (82.9)
83.4 (84.9)
87.7 (86.7)
90.8 (92.3)
104.6 (97.7)
[kJ/mol]
-11.5 (-9.3)
-11.3 (-13.4)
-11.2 (-21.2)
-8.8 (-5.0)
-6.8 (-9.8)
-0.6 (-5.6)
0
1.1 (-5.5)
-12.7 (-17.3)
-12.2 (-22.0)
-10.5 (-20.8)
-10.2 (20.5)
-6.2 (-14.6)
-0.5 (-7.0)
0
2
-CF3
2-CN
2-CONEt2
2-CONHEt
2
-MeO
H
2
-Me
Pyrimidine
4-CN
4
4
4
4
4
-CF3
-CONHEt
-COOEt
-CONEt2
-MeO
H
4-Me
4-CF3--2MeO
5-NO2
0 (-8.2)
-7.7 (-11.4)
-21.7 (-28.1)
-19.5 (-24.9)
-19.3 (-13.4)
-14.0 (-15.4)
-9.2 (-15.6)
-7.2 (-11.6)
0
-12.5 (-13.1)
-11.3 (-8.7)
-10.0 (-7.4)
-9.7 (-5.6)
-7.3 (-4.5)
0
-43.7 (-34.2)
-36.9 (-21.2)
-35.7 (-25.5)
-28.9 (-14.8)
-21.2 (-12.8)
-16.9 (-11.0)
-13.8 (-5.4)
0
Pyrimidine
5
5
5
5
5
-CN
-CONHEt
-CF3
-COOEt
-MeO
H
Pyrazine
Pyridine
3-CN
3-COOEt
3-CF3
3
3
-CONHEt
-CONEt2
H
3,5-NO2
3
2
3
3
3
,5-CN
,6-CN
,5-CF3
,5-COOEt
,5-CONHEt
3,5-CONEt2
H
a
b
c
Calculated on B3LYP/6-311++g(d,p) level.
ǂR
ǂH
Values relative to non-substituted heterocyclic hydroperoxide (G -G ).
Values calculated taking into account participation of methanol on hydrogen transfer are given in
parentheses.
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2
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3
4
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5
5
5
5
5
5
5
6
The calculated values for the energies of oxygen transfer from heterocyclic hydroperoxides are
important to understand their intrinsic reactivity, as the experimental data are hard to achieve due to
their low stability. It is necessary to realize that the data, which are certainly useful for the
comparison of hydroperoxides with similar cores, may serve to compare the hydroperoxides of
different structure only on a qualitative level. Nevertheless, taking into account the good correlation
between the experimental and calculated data observed by Bach for sulfoxidations with various
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
7a
peroxide species, we used our data to estimate the relative oxidizing power of simple heterocyclic
ǂ
ǂ
hydroperoxides. The G and E values for the oxidation of thioanisole with simple heterocyclic
-1
-1
hydroperoxides are within the 61–105 kJ mol and 59–103 kJ mol interval, respectively which
means that i) the best hydroperoxides from our series achieve the reactivity of flavin hydroperoxides
ǂ
-1
1
-OOH and 2-OOH (G = 60–65 kJ mol ), and ii) all of our hydroperoxides appear to be stronger
2
,27a
ǂ
-1
agents than tert-butyl hydroperoxide
(E = 114 kJ mol for oxidation of dimethyl sulfide).
Noteworthy, all hydroperoxides derived from flavines and simple heterocycles still remain less
2
ǂ
-1
reactive in comparison with peroxy acids (E = 15.5 kJ mol for oxidation of dimethyl sulfide).
Nevertheless this “tuned” reactivity (between alkyl hydroperoxide and peroxy acids) can for
example explain the extremely high chemoselectivity of sulfides oxidations mediated by
heterocyclic hydroperoxides, which usually lead to sulfoxides without overoxidation to sulfones.
CONCLUSION
We showed that the ability to activate hydrogen peroxide for oxidations is not only the domain of
flavinium salts, already established organocatalysts of H O oxygenations and models of flavin
2
2
5
,7b,7c
cofactors in monooxygenases,
but it is most likely a general property of all electron-poor
heteroarenium salts. Structure vs. reactivity studies of a series of pyrazinium, pyrimidinium and
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pyridinium salts led us to the conclusion that, to be an effective catalyst of H O oxidations, a
2
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
heteroarenium salt should be electron-poor enough to be able to readily add hydrogen peroxide,
providing a high concentration of heterocyclic peroxide, which is the oxidizing agent in the catalytic
cycle. The ability to form adducts can be simply quantified by the pK values and reduction
R+
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
potentials, which were found to be lower than 5 and more positive than -0.5 V, respectively, for the
outstandingly efficient heteroarenium catalysts. Moreover, the heterocyclic core of the efficient
catalyst should be electrophilic enough to ensure that the corresponding hydroperoxide behaves as a
strong oxidant because the S 2-like oxygen transfer step to a substrate from a hydroperoxide derived
N
from simple heteroarenium salts appears to be significant for the overall rate of catalytic oxidation
beside addition and elimination step (unfortunately, elucidation of the rate determining step is not
possible based on current knowledge). This is in contrast to oxidations catalyzed by flavinium
(isoalloxazinium and alloxazinium) salts, where oxygen transfer takes place readily and formation of
hydroperoxide or regeneration of the catalyst by water elimination from the pseudobase are the rate
1
1c,11d,24
ǂ
determining steps.
This difference was supported by the Gibbs free energy values (G ) of
the oxygen transfer step from a hydroperoxide to a substrate being strongly dependent on the
substituent in the case of simple heterocyclic hydroperoxides and almost independent of the
substitution for alloxazine and isoalloxazine derivatives.
The idea to simplify the structure of flavinium salts led us to some very active pyrazinium,
pyrimidinium and pyridinium salts, which are accessible by one- or two-step syntheses from
commercially available material. The catalytic efficiency of the heteroarenium core can be easily
tuned by substitution. It should be noted that not only the type but also the position of the substituent
is important for the activity of the catalyst, as the substitution effect is not fully transferred through
the heterocyclic nitrogen. It is especially pronounced for the trifluoromethyl substituent. For
pyridinium salts, two electron-withdrawing groups are necessary to ensure sufficient activity. The
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5
5
6
relative position of heterocyclic nitrogens influencing the reactivity of the heteroarenium core is the
most advantageous in pyrimidinium derivatives. The effect of the counter-anion was also observed,
with higher efficiency for triflates over tetrafluoroborates.
In summary, 3-(ethoxycarbonyl)pyrazinium (3d), 3-cyanopyrazinium (3f), 4-cyanopyrimidinium
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(4o), 4-trifluoromethylpyrimidinium (4n), and 5-cyanopyrimidinium triflates (4t), as well as
Hantzsch-type 3,5-dicyano- (5f) and 3,5-dinitropyridinium triflates (5g), showed significant
catalytic activity; salt 5g, today the most efficient among simple heteroarenium salts, even achieved
the efficacy of the original flavinium salts 1 and 2. Additionally, 3,5-dinitropyridinium (5g) and 4-
trifluoromethylpyrimidinium triflates (4n) showed very high stability. Therefore, the use of these
derivatives, which were shown to mediate oxidations of various types of sulfides, is also
recommended for other types of oxygenations or as redox-active units for the construction of
catalysts for stereoselective oxidations. Our conclusions, in terms of structure vs. activity studies,
offer a tool in the search for further efficient heteroarenium catalysts for oxygenations.
EXPERIMENTAL SECTION
General Comments: All reagents were analytical grade, obtained from commercial suppliers, and
used without further purification, or prepared according to known procedures (see Supporting
Information 2 for further details). Dry dichloromethane, chloroform and acetonitrile were distilled
from P O , diethyl ether from sodium. Silica gel (0.040-0.063 mm) from Merck or RediSep Rf Gold
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Reversed-phase C18 column was used in preparative column chromatography. H and C NMR
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spectra are reported relative to residual solvent signal, F NMR spectra are reported relative to
CCl F. High resolution mass spectra (HRMS) were acquired in electrospray (ESI) or atmospheric-
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pressure chemical ionization (APCI) mode using orbitrap mass analyzer.
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The Journal of Organic Chemistry
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General Procedure 1 for Synthesis of Heteroarenium Salts: A solution of heterocycle (1 eq.) in
dry dichloromethane or chloroform was cooled to 0 °C under argon atmosphere. Methyl
trifluoromethanesulfonate (1.0 – 1.1 eq.) was added drop wise. The reaction mixture was allowed to
stir for specified reaction time. Precipitated solid was collected by filtration or the reaction mixture
was evaporated. The crude product was purified by dissolving in small amount of dry acetonitrile
and precipitation by the addition of dry diethyl ether (2 times). The final product was washed with
small amount of dry diethyl ether, and dried in vacuo.
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General Procedure 2 for Synthesis of Heteroarenium Salts: Heterocycle (1 eq.) was dissolved in
dry dichloromethane or chloroform and trialkyloxonium tetrafluoroborate (1.0 – 1.5 eq.) was added
under argon atmosphere. The mixture was allowed to stir at specified temperature and time.
Precipitated solid was collected by filtration. The solid was washed with small amount of dry
dichloromethane or chloroform and purified by dissolving in small amount of dry acetonitrile and
precipitation by the addition of dry diethyl ether (2 - 3 times). The final product was washed with
small amount of dry diethyl ether, and dried in vacuo.
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-Methylpyrazinium trifluoromethanesulfonate (3a): Prepared according to general procedure 1
from pyrazine (200 mg, 2.530 mmol), methyl trifluoromethanesulfonate (436 mg, 2.650 mmol) in
dry dichloromethane (4 mL), reaction time 6 h, to give product as a white solid (391 mg, 64 %
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yield); mp 58 – 60 °C. H NMR (500 MHz, Acetonitrile-d )  9.37 (dt, J = 4.9, 2.8 Hz, 2H), 8.75 (d,
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J = 3.1 Hz, 2H), 4.39 (s, 3H). C NMR (126 MHz, Acetonitrile-d )  152.0, 138.9 (t, J = 9.4 Hz),
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23.4 (q, J = 320.6 Hz), 50.2 (t, J = 5.1 Hz). F NMR (282 MHz, Acetonitrile-d )  -78.17 (s, 3F).
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Anal. Calcd for C H F N O S: C, 29.51; H, 2.89; F, 23.34; N, 11.47; S, 13.13. Found C, 29.29; H,
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.82; F, 23.19; N, 11.24; S, 12.85.
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-(Diethylcarbamoyl)-1-methylpyrazinium trifluoromethanesulfonate (3b): Prepared according
to general procedure 1 from N,N-diethylpyrazine-2-carboxamide (14a) (400 mg, 2.232 mmol),
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