Kinetics of the highly selective liquid-phase oxidation of side chain alkyl groups in 2-methylpyrazine and picolines by selenium dioxide

Article abstract of DOI:10.1021/op990042b

Kinetics of the liquid-phase oxidation of alkyl groups in 2-methylpyrazine and picolines with selenium dioxide at moderate conditions were studied. Thus, 2-methylpyrazine was oxidized to pyrazinoic acid with selenium dioxide in pyridine at 115 °C with 99% selectivity at a 2-methylpyrazine conversion of 100% in 8 h. It was deduced that the reaction follows secondorder kinetics and the activation energy was found to be 35 kcal/mol. The same reaction-scheme was found to hold for picolines oxidation to obtain picolinic acids. The byproduct selenium, formed in the reaction, was converted back to selenium dioxide by nitric acid oxidation with 100% selectivity.

Full text of DOI:10.1021/op990042b

Organic Process Research & Development 1999, 3, 455−459
Kinetics of the Highly Selective Liquid-Phase Oxidation of Side Chain Alkyl
Groups in 2-Methylpyrazine and Picolines by Selenium Dioxide
,
†
Sudip Mukhopadhyay* and Sampatraj B. Chandalia
Chemical Engineering DiVision, UniVersity Department of Chemical Technology, UniVersity of Mumbai,
Mumbai - 400 019, India
Abstract:
tiality of selenium dioxide towards these oxidations. Thus,
Kinetics of the liquid-phase oxidation of alkyl groups in
the isolation becomes easier, and the process looks attractive.
The selenium dioxide oxidation could be performed in an
ordinary stainless steel stirred tank reactor at moderate to
low temperatures. Another advantage of using selenium
dioxide is that the precipitated selenium metal after the
oxidation reaction can be easily recycled back as selenium
dioxide after simple oxidation with very high selectivity.
Thus, the raw material cost for the expensive selenium
dioxide is reduced only to its operational losses plus nitric
acid consumption to convert the selenium metal back to
selenium dioxide.
2-methylpyrazine and picolines with selenium dioxide at moder-
ate conditions were studied. Thus, 2-methylpyrazine was
oxidized to pyrazinoic acid with selenium dioxide in pyridine
at 115 °C with 99% selectivity at a 2-methylpyrazine conversion
of 100% in 8 h. It was deduced that the reaction follows second-
order kinetics and the activation energy was found to be 35
kcal/mol. The same reaction-scheme was found to hold for
picolines oxidation to obtain picolinic acids. The byproduct
selenium, formed in the reaction, was converted back to
selenium dioxide by nitric acid oxidation with 100% selectivity.
1
2
Although the chemistry of selenium dioxide oxidation is
well-known, the information regarding the kinetics and im-
portant process parameters such as initial concentration, tem-
perature, and solvent effect is inadequate and needs to be
well-documented. Hence, the present work (Scheme 1) was
undertaken to ascertain the suitable process conditions and
kinetics for the manufacture of the desired products, pyrazi-
noic acid and picolinic acids, from the viewpoint of process
research and development for large-scale production. The
stoichiometric equation of 2-methylpyrazine oxidation is
Introduction
Pyrazinoic acid and picolinic acids are important phar-
maceutical intermediates. They are commonly synthesized
by the oxidation of 2-methylpyrazine, 3-picoline, 4-picoline,
and 2-picoline, respectively. Different oxidizing agents such
1-3
4,5
6-11
as air, nitric acid, and selenium dioxide
can be used
for this type of oxidation. In air-oxidation the use of costly
catalysts and highly corrosive promoters such as bromide
salts in acetic acid solvent at elevated temperature makes
the process somewhat complicated from both cost and design
points of view. In the nitric acid process, the use of higher
temperature leads to a higher rate of residue formation. Thus,
the separation of the product from the reaction mixture
becomes expensive. The molar excess of nitric acid certainly
adds to the waste disposal problem. In this aspect it is worth
considering the use of the highly selective oxidizing poten-
Experimental Section
The experiments were carried out in an autoclave of 300-
mL capacity, made of Hastelloy. The autoclave was equipped
with a four-bladed magnetically driven impeller and an
internal cooling system. The autoclave was heated externally
by a heating element, and the temperature of the reaction
was regulated by a temperature indicator controller. The
pressure gauge, pressure release valve, and sampling valve
were all situated on the reactor cover.
*
Corresponding author.
Present Address : Casali Institute of Applied Chemistry, The Hebrew
†
University of Jerusalem, Givat Ram Campus, Jerusalem, 91904, Israel.
(
(
1) Mukhopadhyay, S.; Chandalia, S. B. Org. Process Res. DeV. 1999, 3, 227.
2) Inoue, T.; Hara, T. Jpn. Kokai Tokkyo Koho 76, 29, 483, 1976; Chem.
Abstr. 1976, 85, 94233.
(
(
(
3) Bhattacharya, D.; Guha, D. K.; Roy, A. N. Ind. Chem. Eng. 1982, 24(1),
4
6; Chem. Abstr. 1984, 100, 34383.
4) Zhdanovich, E. S.; Chekmareva, I. B.; Kaplina, L. I.; Preobrazhenskii, N.
A. USSR Patent 148,411, 1962; Chem. Abstr. 1963, 58, 9031.
5) Gostea, T.; Camarasu, C. Romanian Patent 53,589, 1971; Chem. Abstr. 1972,
Experimental Procedure
Oxidation of 2-Methylpyrazine and Picolines. Prede-
termined quantities of starting material, solvent, and selenium
dioxide were charged into the autoclave. The reaction
temperature was maintained at the desired level by control-
ling the flow rate of cooling water and the heating rate. A
constant temperature was maintained throughout the reaction
period.
7
6, 14348.
(6) Gainer, H. J. Org. Chem. 1959, 24, 691.
(7) Mueller, M. B. (Allied Chemical & Dye Corp.) U.S. Patent 2,586,555, 1952;
Chem Abstr. 1957, 46, 9127.
(8) Jerchel, D.; Baner, E.; Hippchen, H. Chem. Ber. 1955, 88, 156; Chem. Abstr.
1
959, 50, 1808.
9) Levi, M.; Pesheva, I. Farmatsiya (Sofia) 1965, 15(5), 266; Chem Abstr.
966, 64, 17531.
(
1
(10) Ruetgerswerke and Teerverwertung, A. G. Br. Patent 1,132,746, 1968; Chem
Abstr. 1969, 70, 37658.
(
11) Dryuk, V. G.; Kurochkin, A. F.; Galushkin, S. N., USSR Patent SU 1616
(12) Edward, S. R.; Ludurig, J. C. U.S. Patent 3,268,294, 1966; Chem. Abstr.
1966, 65, 16903.
9
10, 1990; Chem Abstr. 1991, 114, 228754.
1
0.1021/op990042b CCC: $18.00 © 1999 American Chemical Society and The Royal Society of Chemistry
Vol. 3, No. 6, 1999 / Organic Process Research & Development
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Published on Web 11/03/1999

Scheme 1. Oxidation of 2-methylpyrazine and picolines by
selenium dioxide
then promptly titrated with standard sodium thiosulphate
solution. When the solution became pale yellow, starch
solution was added, and the titration was continued until a
sharp change from a turbid brown to transparent red end-
point was noted. The free selenium dioxide present in the
reaction mixture was calculated from the titre value.
Estimation of Organo Selenium Compounds. Two mil-
liliters of the filtered reaction mixture and 2 mL of
concentrated sulphuric acid were heated together. Fuming
nitric acid was added dropwise until the mixture became
colorless, and heating was continued for about 5 min. The
mixture was then cooled and diluted with 5 mL of previously
boiled distilled water. Urea was then added to the solution
to destroy nitrous acid. The resulting solution was analyzed
for selenium dioxide as per the method described earlier.
The amount of total selenium dioxide was calculated from
the titre value. The amount of free selenium dioxide
estimated from the previous method was subtracted from the
amount of the total selenium dioxide obtained from this
method to account for the selenium in the form of organo
selenium compounds.
Isolation of the Desired Product. After the stipulated
reaction period, the reaction mixture was filtered to remove
precipitated selenium, and the filtrate was distilled under
reduced pressure to remove the solvent. The residual mass,
after solvent removal, was made basic with 10% sodium
hydroxide and filtered to remove any particulate matter. The
filtrate was then acidified with 10% formic acid, and the
free acids were extracted with toluene. Thereafter, the toluene
was removed by distillation under reduced pressure to obtain
the solid acids with an isolated yield of 92-96%.
Table 1. Typical reaction of the oxidation of selenium to
selenium dioxide by nitric acid
selenium loading
concentration of nitric acid
nitric acid feed
reaction temperature
reaction time
1.26 mol/L
5.6 mol/L
35.3% w/v
100 °C
3 h
reaction volume
conversion of selenium
selectivity to selenium dioxide
1 L
98%
100%
Result and Discussion
Definitions. ConWersion. This is the ratio of the number
of moles of the reactant reacted to the number of moles of
reactant added initially.
SelectiWity. This is the ratio of the moles of reactant
consumed in the formation of the desired acid to the total
number of moles of reactant reacted.
Oxidation of Selenium to Selenium Dioxide. A 2-L
borosilicate glass reactor provided with a stirrer, baffles,
thermometer pocket, and a reflux condenser was used for
this reaction. Predetermined quantities of selenium, nitric
acid, and water were added to the reactor, and it was brought
to the required temperature. After the stipulated reaction
period, the reaction mixture was cooled to room temperature
and filtered to remove unreacted selenium. The filtrate was
distilled under reduced pressure to isolate the selenium
dioxide. The reaction conditions are given in Table 1.
Analysis. Estimation of Unreacted Starting Material.
Samples of 1-2 mL, withdrawn at regular intervals of time,
were analyzed for unreacted starting material by gas chro-
matography on a Chemito 8510 instrument equipped with a
flame ionization detector, connected to an integrator. A 2-m
long, 0.003-m diameter stainless steel column with 10% SE-
Process Parameter Studies. Effect of Period of Reaction
and Initial Concentration of 2-Methylpyrazine on the Rate
of Oxidation in Pyridine. It was observed from Figure 1,
that with an increase in period of reaction, the conversion
of 2-methylpyrazine also increased, as expected.
The reaction was studied over a wide range of initial
concentrations, and it was observed that the rate of reaction
also increased with the initial concentration (Figure 1).
Effect of Temperature on the ConWersion and SelectiWity
of 2-Methylpyrazine in Pyridine. The oxidation of 2-meth-
ylpyrazine in pyridine was studied over a range (105-140
°C) of temperatures. It was found that although the rate of
reaction increased with temperature, (Figure 2), the selectivity
decreased significantly at higher temperature possibly due
to higher rate of formation of organo selenium compounds
and decomposition of ring structure leading to residue
formation (Table 2).
30 on Chromosorb-W was used. The injector and detector
temperatures were maintained at 300 °C, and the oven
temperature programming was: 60 °C, 10 °C/min ramp, 200
°
C, 20 °C/min ramp, 250 °C, 5 min.
Estimation of Unreacted Selenium Dioxide. A known
volume (2 mL) of the reaction mixture was taken after
filtration for the determination of selenium dioxide. To this
solution, 5 mL of 1.5 M potassium iodide was added
followed by 2 mL of 6 N sulphuric acid. The solution was
Effect of Different SolWents on the Rate of Oxidation
of 2-Methylpyrazine. In a view to obtain a faster rate and
higher selectivity, different alternative solvents such as
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Vol. 3, No. 6, 1999 / Organic Process Research & Development

Figure 3. The rate of oxidation of 2-methylpyrazine in various
solvents.
Figure 1. Effect of reaction time and initial concentration on
the rate of oxidation of 2-methylpyrazine in pyridine.
Figure 4. The rate of oxidation of various starting materials
in dibenzylether.
Table 3. Product distribution with overall material balance
for the oxidation of 2-methylpyrazine with selenium dioxide
Figure 2. Effect of temperature on the rate of oxidation of
a
2
-methylpyrazine in pyridine.
%
overall
material
accounted for accounted for balance
Table 2. Effect of temperature on the conversion and
selectivity to the desired pyrazinoic acid
moles of MP
% MP
a
material
MP (input)
pyrazinoic acid
organo selenium cmpds
residue
%
conversion of
% selectivity to
pyrazinoic acid
1.06
1.049
100
99
100
temperature, °C
2-methylpyrazine
0.0063
0.00424
0.6
0.4
1
1
1
1
1
1
1
05
10
15
20
25
30
40
29
56
83
88
92
94
96
100
99
99
98
97
94
89
a
Reaction conditions: initial concentration of 2-methylpyrazine (MP), 1.06
mol/L; SeO , 1.65 mol/L temperature, 115 °C; solvent, pyridine; reaction volume,
2
1
L.
follows the following order, 4-picoline > 2-picoline >
-methylpyrazine > 3-picoline (Figure 4). It may be con-
cluded that in the rate-determining step the acidity of the
proton of the C-H bond adds to the faster rate of oxi-
dation.
Product Distribution. The product distribution and
overall material balance was determined in a 1-L reactor.
The complete product distribution with overall material bal-
ance on the basis of analytical results is given in Table 3.
Kinetics. Considering the reaction
a
Reaction conditions: initial concentration of 2-methylpyrazine, 1.06 mol/
2
L; SeO
mL.
2
concentration, 1.65 mol/L; reaction time, 2 h; reaction volume, 100
pyridine, dibenzyl ether, and 1,4-dioxane were considered
for this investigation. The rate of oxidation of 2-methylpyra-
zine was much slower in 1,4-dioxane compare to other
solvents under the identical reaction conditions (Figure 3).
This surely indicates that the nature of the solvent plays a
critical role in this sort of oxidation.
The Rate of Oxidation of Different Starting Material in
Dibenzyl Ether. The rate of oxidation of different starting
materials, was examined in dibenzyl ether. It was observed
that under identical reaction conditions, the rate of oxidation
A + B f Product
(1)
the rate of disappearance of 2-methylpyrazine or picolines
can be expressed as
Vol. 3, No. 6, 1999 / Organic Process Research & Development
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Table 5. k values for the oxidation of 2-methylpyrazine at
different temperatures in pyridinea
k × 10 , L mol min-1
2
-1
temperature, °C
1
1
1
1
1
1
1
05
10
15
20
25
30
40
0.1
0.37
2.8
4.7
5.4
6.0
8.3
a
2
Reaction conditions: initial concentration, 1.06 mol/L; SeO , 1.65 mol/L;
solvent, pyridine; reaction volume, 100 mL.
Figure 5. ln[(M - 1.5X
A
A
)/M(1 - X )] vs t at different initial
concentrations of 2-methylpyrazine in pyridine.
Table 4. k values at different initial concentrations of
2
-methylpyrazine in pyridinea
k × 10 , L mol min-1
2
-1
initial concentration, mol/L
1
1
2
.06
.5
.0
2.8
4.1
5.1
a
Reaction conditions: molar ratio of 2-methylpyrazine: SeO
temperature, 115 °C; solvent, pyridine; reaction volume, 100 mL.
2
, 1:1.55;
Figure 7. Arrhenius plot.
Figure 6. ln[(M - 1.5X
A
)/M(1 - X
A
)] vs t at different
temperatures for the oxidation of 2-methylpyrazine in pyridine.
-
r ) -dC /dt ) kC C ) C dX /dt
(2)
(3)
A
A
A
B
A0
A
C dX /dt ) kC (1 - X )C (1 - X )
A0
A
A0
A
B0
B
From stoichiometry, for 1 mol of 2-methylpyrazine or
picolines, 1.5 mol of selenium dioxide is required.
Thus, at any instant, t
Figure 8. ln[(M - 1.5X
A
A
)/M(1 - X )] vs t with different
solvents for the oxidation of 2-methylpyrazine.
1
.5C X ) C X
(4)
A0
A
B0
B
A plot of ln[(M - 1.5X
A A
)/M(1 - X )] vs t at different initial
Thus
concentrations (Figure 5) shows that the oxidation in pyridine
follows second-order kinetics. The k value at different initial
concentrations is given in Table 4.
2
C dX /dt ) kC (1 - X )(M - 1.5X )
(5)
A0
A
A0
A
A
From the respective slopes of the plot of ln[(M - 1.5X
M(1 - X )] vs t at different temperatures in pyridine solvent
Figure 6), k values for the oxidation are determined and
given in Table 5. It is observed that at a temperature below
10 °C, the rate of reaction is very slow and the reaction
does not follow a second-order rate law.
A
)/
where M ) CB0/CA0. By integrating and simplification the
final form will be where M * 1.5 and
A
(
ln[(M - 1.5X )/M(1 - X )] ) C (M - 1.5)kt
(6)
(7)
A
A
A0
1
ln[(M - 1.5X )/M(1 - X )] ) (C - 1.5C )kt
A
A
B0
A0
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Vol. 3, No. 6, 1999 / Organic Process Research & Development

complicated bubble column reactor design make it somewhat
inferior to selenium dioxide oxidation. The recycling of
costly cobalt, manganese, and zirconium acetate catalysts is
still problematic in air oxidation, but the selenium can be
easily converted to selenium dioxide with very high selectiv-
ity, thus reducing the operating cost.
The material of construction is not as exotic as in air or
nitric acid oxidation because of the use of a low to moderate
reaction temperature and a common noncorrosive solvent.
The major disadvantage of this process-scheme is in the
handling of poisonous selenium metal. With proper industrial
practice, this problem could be overcome.
Conclusions
Figure 9. ln[(M - 1.5X
A
A
)/M(1 - X )] vs t for different starting
The oxidation of 2-methylpyrazine and picolines with
selenium dioxide follows second-order kinetics with respect
to the starting materials. The activation energy was found
to be 35 kcal/mol.
The valuable data obtained in this study could enable one
to formulate the optimum process conditions and to design
an appropiate reactor for plant level production.
Above all, the high selectivity of this process is an added
advantage in comparison to the other processes, but strict
precautions must be taken for large-scale production while
handling the poisonous selenium metal.
materials in dibenzylether.
Table 6. k values for different solvents for the oxidation of
2
-methylpyrazinea
k × 10 , L mol min-1
2
-1
solvent
dibenzyl ether
pyridine
3.8
2.8
0.6
1,4-dioxane
a
Reaction conditions: 2-methylpyrazine:SeO
2
ratio, 1:1.55; temperature, 115
°
C; solvent, pyridine; reaction volume, 100 mL.
Table 7. k values for the oxidation of different starting
materials in dibenzyl ether at 120 °Ca
Notations
C 0
A
initial concentration of 2-methylpyrazine or picolines at
time, t ) 0, mol/L
k × 10 , L mol min-1
2
-1
starting material
B
C 0
initial concentration of selenium dioxide at time, t ) 0,
mol/L
2
-methylpyrazine
3.8
5.3
0.4
7.0
2
3
4
-picoline
-picoline
-picoline
C
A
B
concentration of 2-methylpyrazine or picolines at time,
t ) t, mol/L
a
2
Reaction conditions: initial concentration, 1.06 mol/L; SeO , 1.65 mol/L;
temperature, 120 °C; solvent, dibenzyl ether; reaction volume, 100 mL.
C
concentation of selenium dioxide at time, t ) t, mol/L
X
A
fractional conversion of 2-methylpyrazine or picolines at,
t ) t.
From the Arrhenius plot, (Figure 7), the energy of
activation was found to be 35 kcal/mol (r ) 0.86).
-
r
A
-dC /dt ) rate of disappearance of substrate
A
2
M
molar ratio of the initial concentration of selenium dioxide
to the substrate
rate constant, L mol- min-1
k values for 2-methylpyrazine oxidation in different
solvents and for different starting materials in dibenzyl ether
were determined from Figure 8 and Figure 9 and are given
in Tables 6 and 7, respectively. Although best-fit lines for a
second-order rate equation were obtained for the oxidation
of 2-methylpyrazine in pyridine and dibenzyl ether, they were
not obtained in dioxane. This means that the solvent has a
specific role in this oxidation.
Comparison of this Process with Other Existing
Processes. The very high selectivity obtained in this oxi-
dation reaction, permits the simple isolation of the de-
sired products unlike that obtained in air and nitric acid
oxidation.
1
k
t
time, min
Acknowledgment
One of the authors (S.M.) is grateful to the University
Grants Commissions, New Delhi, for the award of a Senior
Research Fellowships and acknowledges the active support
of Professor Yoel Sasson during preparation of this manu-
script.
Received for review May 6, 1999.
OP990042B
Although air oxidation is commercially preferred to
chemical oxidation, the use of costly catalysts and the
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