Oxidation of substituted pyridines by dimethyldioxirane: Kinetics and solvent effects

Article abstract of DOI:10.1016/j.tetlet.2004.09.083

The second order rate constants for the oxidation of substituted pyridines by dimethyldioxirane at 23°C in dried acetone were found to correlate with sigma values (ρ = -2.91). The reaction was shown to be very sensitive to protic, polar solvents. The oxidation of a series of substituted pyridines by dimethyldioxirane (1) produced the expected N-oxides in quantitative yields. The second order rate constants (k₂) for the oxidation of a series of substituted pyridines (2a-g) by dimethyldioxirane were determined in dried acetone at 23°C. An excellent correlation with Hammett sigma values was found (ρ = -2.91, r = 0.995). Kinetic studies for the oxidation of 4-trifluoromethylpyridine by 1 were carried out in the following dried solvent systems: acetone (k₂ = 0.017 M^-1 s^-1), carbon tetrachloride/acetone (7:3; k₂ = 0.014 M^-1 s ^-1), acetonitrile/acetone (7:3; k₂ = 0.047 M^-1 s^-1), and methanol/acetone (7:3; k₂ = 0.68 M^-1 s^-1). Kinetic studies of the oxidation of pyridine by 1 versus mole fraction of water in acetone [k₂ = 0.78 M^-1 s^-1 (χ = 0) to k₂ = 11.1 M^-1 s^-1 (χ = 0.52)] were carried out. The results showed the reaction to be very sensitive to protic, polar solvents.

Full text of DOI:10.1016/j.tetlet.2004.09.083

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8295–8297
Oxidation of substituted pyridines by dimethyldioxirane:
kinetics and solvent effects
W. Rucks Winkeljohn, Pedro C. Vasquez, Lucjan Strekowski and Alfons L. Baumstark*
Department of Chemistry, Center for Biotech and Drug Design, Georgia State University, Atlanta, GA 30303-3083, USA
Received 11 August 2004; revised 9 September 2004; accepted 10 September 2004
Abstract—The oxidation of a series of substituted pyridines by dimethyldioxirane (1) produced the expected N-oxides in quantitative
yields. The second order rate constants (k2) for the oxidation of a series of substituted pyridines (2a–g) by dimethyldioxirane were
determined in dried acetone at 23°C. An excellent correlation with Hammett sigma values was found (q = ꢀ2.91, r = 0.995). Kinetic
studies for the oxidation of 4-trifluoromethylpyridine by 1 were carried out in the following dried solvent systems: acetone
(k2 = 0.017Mꢀ1 sꢀ1), carbon tetrachloride/acetone (7:3; k2 = 0.014Mꢀ1 sꢀ1), acetonitrile/acetone (7:3; k2 = 0.047Mꢀ1 sꢀ1), and meth-
anol/acetone (7:3; k2 = 0.68Mꢀ1 sꢀ1). Kinetic studies of the oxidation of pyridine by 1 versus mole fraction of water in acetone
[k2 = 0.78Mꢀ1 sꢀ1 (v = 0) to k2 = 11.1Mꢀ1 sꢀ1 (v = 0.52)] were carried out. The results showed the reaction to be very sensitive to
protic, polar solvents.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
tional groups, such as aldehydic or olefinic substituents,
preferential N-oxidation by 1 has been observed.6a–d
Furthermore, the oxidation of aromatic diazines such
as pyrazines by 1 has been shown to afford the mono-
and in selected cases the di-N-oxides depending on
reaction conditions.6e While relative reactivities for
oxidation of selective substituted pyridines by dime-
thyldioxirane have been determined by product stud-
ies,6d no rate constants for N-oxidation by 1 have
been reported. Furthermore, no solvent effects on N-oxi-
dation by dioxiranes have been reported. We report here
the first kinetic data for the oxidation of a series of sub-
stituted pyridines by 1 in acetone and in mixed solvent
systems.
Dioxiranes are versatile oxidizing agents that efficiently
transfer an oxygen atom to a variety of different sub-
strates.1 Dimethyldioxirane (1) has been extensively
studied, and several methods developed for the formula-
tion of 1 either in situ2 or isolated in solution.3 Oxida-
tion by 1 has been shown to be electrophilic in nature4
as well as quantitative in the majority of cases. The
mechanism of olefin epoxidation by 1 has been exten-
sively investigated.1,3 An area of expanding interest is
the oxidation of heteroatoms by 1, especially nitrogen-
containing substrates. In the presence of excess dime-
thyldioxirane 1, primary amines can be successively
oxidized to the nitro compounds.5a,b,c Secondary amines
have been shown to be oxidized to the hydroxylamines,
but undergo an additional oxidation to the nitroxide.5d–g
Tertiary amines are oxidized cleanly to the correspond-
ing N-oxides.6a Aromatic azines such as pyridines and
quinolines have been reported to quantitatively yield
the corresponding N-oxides upon reaction with dioxira-
nes.6b When given the presence of other oxidizable func-
2. Results and discussion
The reaction of dimethyldioxirane (1) with a series of
substituted pyridines (2a–g)7 produced the correspond-
ing N-oxides (3a–g) as the sole observable products in
all cases as expected (rxn. 1).2c,e,3a A 3-fold excess of
dioxirane was employed for product studies on the less
reactive pyridines, whereas only 1.1equiv of 1 were nec-
essary for the more reactive substrates. Isolated yields
were essentially quantitative (98%). N-Oxides were pro-
ven by comparison of spectral and physical data to those
of authentic samples. The product studies were in
Keywords: Kinetics; N-Oxidation; Solvent effects; Dimethyldioxirane;
Pyridines.
*
Corresponding author. Tel.: +1 404 651 1716; fax: +1 404 651
1416; e-mail: chealb@langate.gsu.edu
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.083

8296
W. R. Winkeljohn et al. / Tetrahedron Letters 45 (2004) 8295–8297
excellent agreement with those reported for several of
the pyridines.6b
Despite the difference in type of correlation, the results
are mechanistically consistent due to a lack of direct
conjugation of the nitrogen lone pair in the aromatic
azines. A study by Adam and Golsch6d looked at com-
petitive N-oxidation of substituted pyridines by 1 in
comparison to N-methylation. Their data of relative
reactivity ratios showed that the oxidation of substituted
pyridines occur via an SN2 mechanism rather than an
electron transfer mechanism. Comparison of ratios of
appropriate k2Õs for N-oxidation of selected pyridines
in the current study are in good agreement with the ratios
of relative reactivities reported by Adam and Golsch.6d
X
X
O
O
O
k2
23 o
C
N
acetone
N
O
1
[a X = 4-CN; b X = 4-CF ;
c X = 3-Br; d X = H; e X = 4-Ph
f X = 4-Me; g X = 4-OMe]
2
3
3a-g
ð1Þ
The kinetics for rxn. 1 was determined using UV tech-
niques.8 As expected the reaction was found to be of
the first order with respect to each of the reagents; sec-
ond order overall. The second order rate constants
(k2Õs) determined in dried acetone under equimolar or
pseudo first order conditions were within experimental
error ( 15%). All k2 values are the average of at least
three determinations. The k2 values (Mꢀ1 sꢀ1) in dried
acetone at 23 0.3°C were determined for the reaction
of 1 with: 4-cyanopyridine (2a, k2 = 0.014 0.001),
The effect of solvent polarity on the oxidation of 2b by 1
was studied under pseudo first order conditions at 23°C.
The kinetic experiments were conducted in acetone with
70% (v/v) of either carbon tetrachloride, acetonitrile or
methanol (Table 1). The second order rate constant
obtained in 70% carbon tetrachloride was found to be
0.014 0.002Mꢀ1 sꢀ1, slightly slower than that of the
more polar solvent, acetone (0.017 0.002Mꢀ1 sꢀ1),
while addition of 70% of the more polar solvent, aceto-
nitrile (0.048 0.017Mꢀ1 sꢀ1), resulted in a 2.8-fold
increase in the second order rate constant over that of
acetone. In contrast, addition of 70% methanol resulted
in a rate constant of 0.68 0.07Mꢀ1 sꢀ1, a 40-fold
increase over that in acetone.11 A study by Gilbert et al.
reported a 3.3-fold decrease in the magnitude of the rate
constant for epoxidation of cis-stilbene by dimethyldi-
oxirane 1 in 100% carbon tetrachloride compared to
that of acetone.12a Previous work in this lab has shown
that oxidation of 2-methyl-2-pentene has a similar rate
constant in 90% dried carbon tetrachloride/acetone to
that of dried acetone.12b In addition, it was shown that
the epoxidation of 2-methyl-2-pentene by 1 in a 90%
methanol/acetone solution had a 27-fold increase in
the magnitude of the rate constant from that of acetone.
Subsequently, the effect of added water on the oxidation
of 2d by 1 was examined. The second order rate con-
stants were determined at 23°C in acetone versus mole
fraction of water. Kinetic runs were carried out under
4-trifluoromethylpyridine
3-bromopyridine (2c, k2 = 0.041 0.006), pyridine (2d,
k2 = 0.78 0.02), 4-phenylpyridine (2e, k2 =
(2b,
k2 = 0.017 0.002),
1.01 0.06), 4-methylpyridine (2f, k2 = 2.36 0.26),
and 4-methoxypyridine (2g, k2 = 5.36 0.27). The reac-
tion mixtures from the kinetics experiments were
checked by GC/MS for product formation. In all cases,
a signal for the appropriate amount of the correspond-
ing pyridine N-oxide was observed.
The Hammett plot of the substituted pyridines yielded
an excellent fit with sigma values (Fig. 1) with a rho of
ꢀ2.91 0.13 (r = 0.995). The rho value is in agreement
with that previously reported in the Hammett study of
substituted pyridine N-oxidation by peroxybenzoic acid
(q = ꢀ2.35, 25°C) in 50:50 dioxane/water.9 The rho
value for the oxidation of pyridine by 1 is consistent with
an electrophilic mechanism, and also shows that oxida-
tion is very sensitive to substituent effects. In contrast,
the analogous studies for the epoxidation of olefinic
compounds by 1 have been shown to correlate with
sigma plus values to give rho plus values of ꢀ0.90 for
4-substituted styrenes,3b ꢀ1.53 for substituted ethyl
cinnamates,10a and ꢀ1.03 for 4-substituted chalcones.10b
equimolar conditions, with vH O60.5 to avoid solubility
2
problems. The value of the rate constant was found to
increase significantly as the mole fraction of water
(vH O) increased (Fig. 2).
2
Interestingly, the magnitude on the effect of pyridine
oxidation is found to be substantially greater than that
seen for the epoxidation of 4-methoxystyrene.3b Substi-
tution of deuterium oxide for water in a 0.30mole
1
0.5
0
4-OMe
fraction experiment yielded
a
k2 value of
4-Me
5.42 0.32Mꢀ1 sꢀ1, similar to that obtained for water
(5.90 0.15Mꢀ1 sꢀ1). Within experimental error, the
kH O/kD O ratio is close to unity, indicating that proton
4-Ph
H
-0.5
-1
2
2
-1.5
-2
Table 1. Second order rate constants for the oxidation of 2b by 1 in
various solvents at 23°C
3-Br
0.4
4-CN
4-CF3
Solvent (v/v)
k2 (Mꢀ1 sꢀ1
)
krel
-2.5
-0.4
-0.2
0
0.2
σ
0.6
0.8
Dried acetone (100%)
Acetone/CCl4 (30:70)
0.017 0.002
0.014 0.002
0.048 0.017
0.68 0.07
ꢁ1
0.8
Acetone/acetonitrile (30:70)
Acetone/methanol (30:70)
2.8
40
Figure 1. Hammett plot of logk2 for the oxidation of pyridines 2a–g by
dimethyldioxirane (1) at 23°C in acetone.

W. R. Winkeljohn et al. / Tetrahedron Letters 45 (2004) 8295–8297
8297
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catalysis is not a primary factor in the enhancement of
pyridine oxidation.
3. Conclusions
The first kinetic data for N-oxidation by dimethyldioxi-
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that N-oxidation by 1 is significantly enhanced by pro-
tic, polar solvents.
Acknowledgements
7. Compounds 2a–g are commercially available.
1
8. The loss of
(e = 5.1Mꢀ1 cmꢀ1
was monitored at k = 370nm
rather than at 330nm (normally
Acknowledgment is made to the US Army ERDEC
(DAAA 12-94-K-004) SEAS subcontract and to the
Georgia State University Research Fund for the support
of this work.
)
employed for epoxidation kinetics) to avoid complications
due to adsorption by the product(s).
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