Synthesis of 1-amino-2-methylindoline by Raschig process: Parallel reactions, modeling, and optimization

Article abstract of DOI:10.1002/kin.10079

The reaction between chloramine and 2-methylindoline was studied at pH 12.89, T = 40°C, and for different initial concentrations of reactants. The interaction includes two concurrent bimolecular mechanisms leading to 1-amino-2-methylindoline and 2-methyli

Full text of DOI:10.1002/kin.10079

Synthesis of
1-Amino-2-methylindoline
by Raschig Process:
Parallel Reactions,
Modeling, and Optimization
M. ELKHATIB, L. PEYROT, R. METZ, R. TENU, F. ELOMAR, H. DELALU
Laboratoire Hydrazines et Proce´de´s, FRE CNRS 2397, Universite´ Claude Bernard Lyon 1, Baˆtiment 731 (Berthollet),
3e`me e´tage, 43 boulevard du 11 novembre 1918, F-69622 Villeurbanne Cedex, France
Received 5 November 2001; accepted 20 May 2002
DOI 10.1002/kin.10079
ABSTRACT: The reaction between chloramine and 2-methylindoline was studied at pH 12.89,
T = 40 C, and for different initial concentrations of reactants. The interaction includes two con-
current bimolecular mechanisms leading to 1-amino-2-methylindoline and 2-methylindole.
The rate laws were determined at the first moments of the reaction by using a differential
method. By considering the totality of the reactions that occur in the medium, an appropri-
ate mathematical model was developed. It permits to follow the evolution of the system over
time and to calculate the final yields of reaction products. An optimization in terms of the
initial contents of 2-methylindoline and chloramine was performed. It indicated that the max-
imum yield of 1-amino-2-methylindoline does not exceed 56%. The results show the limit of
C
the Raschig process for the synthesis of indolic hydrazines in aqueous medium. 2002 Wiley
Periodicals, Inc. Int J Chem Kinet 34: 575–584, 2002
international name is Indapamide.
INTRODUCTION
The heterocyclic compounds including an unsymmet-
rical hydrazino group are used in the pharmaceutical
industry as precursors of medicinal drugs [1–5].
CH
3
N
NH
2
1
(CH )
n
H2NN
2
At present, it is prepared by the Wright and Willette
process [5], which is carried out in two steps:
In particular, 1-amino-2-methylindoline (1, NAMI) is a
precursor of an antihypertensive drug whose common
The nitrosation of 2-methylindoline (2, MI) by ad-
dition of sodium nitrite to an acid solution of amine:
Correspondence to: H. Delalu; e-mail: delalu@univ-lyon1.fr.
2002 Wiley Periodicals, Inc.
c
*
)
2NaNO2 + H2SO4
2HNO + Na SO
2
2
4

576
ELKHATIB ET AL.
Kinetic law is expressed by
Nitrosation
+ HNO
+ H O
2
2
CH
CH
3
3
N
H
N
d[NAMI]/dt = k20 [NAMI][NH2Cl]
NO
2
3
+ k200[NAMIH+][NH2Cl]
The reduction of 1-nitroso-2-methylindoline (3) by
a chemical or catalytic way:
where k20 and k200 are the rate constants of the above reac-
tions. The interaction exhibits a specific acid catalysis
and the global rate constant is linear as a function of
NAMIH+
5
+
aH (Ka
= 8.51 10 [15]):
Reduction
CH
CH
3
3
N
N
+
k2 = k20 + k200aH KaNAMIH
+
NH
NO
2
[H+]
+
At T = 25 C and for aH
k20 = 3.17 10 3 M 1 s
The nitrosation step leads to a high yield (96%, T =
5 C, [H2SO4] = 2.5 M) but, before reduction, 3 must
always be purified by distillation or recrystallization.
Several methods are proposed to reduce 1-nitroso-2-
methylindoline [5–9]. Nevertheless, it must be handled
with a lot of caution because of its highly carcinogenic
properties [10,11], which cause problems of industrial
exploitation. To avoid the nitrosated intermediates, we
have undertaken a study on the amination of 2 in aque-
ous medium by the Raschig process [12,13]. This most
environmentally sound route can be schematized by the
following two reactions:
k200 = 10.6 103 M 1 s
1
1
The activation parameters were determined at pH 12.89
where the ionic process (NH2Cl–NAMIH+) is negligi-
ble. The values are the following:
#
1
1H2 = 57.2 kJ mol
#
1
1S2
=
100.7 J mol 1 K
k2 = 92.8 106 exp( 59.7/RT) M 1 s
(E2 in kJ mol
1
1
)
NaOCl + NH3 → NH2Cl + NaOH
RR0NH + NH2Cl + OH → RR0NNH2 + Cl + H2O
According to pH, the aminonitrene undergoes a dehy-
drogenation or a dimerization leading to 1-amino-2-
methylindole (4) or azo(2-methyl)indoline (5), respec-
tively [16]:
However, it presents the disadvantage of leading to
several by-products. This behavior is due to the ox-
idation and amination properties of NH2Cl, which
appear simultaneously. In particular, the reaction be-
tween 1 and chloramine is one of the principal side
reactions observed during the synthesis of 1-amino-2-
methylindoline by the Raschig process [14]. This re-
action limits the yield and leads to products, which are
difficult to separate during the continuous extraction of
1-amino-2-methylindoline [15].
pH 13
CH
CH
3
3
+
25°C
N
N
N
−
NH
2
4
The first elementary step involves the neutral and
ionic forms of 1 and leads transiently to an aminoni-
trene:
H C
3
pH 9
5°C
CH
NN
NN=
3
2
+
N
N
−
CH
3
k′
2
CH
3
CH
3
+ NH Cl
2
+ NH Cl
4
+
N
N
N
5
-
NH
2
(1)
k″
Another side reaction consists of an alkaline degrada-
tion of chloramine (pH >11). This reaction has been
studied by several authors [17–20].
2
CH
3
CH
+ NH Cl
2
+ NH Cl
4
3
+
N
N
+
NH
H
2,
NH
(2)

SYNTHESIS OF 1-AMINO-2-METHYLINDOLINE BY RASCHIG PROCESS
577
The first step corresponds to the formation of an hy-
Procedure and Analysis
droxylamine intermediate, which immediately reacts
with a second molecule ofchloramine togive hydroxyl-
hydrazine:
Chloramine shows a UV absorption in water at
=
243 nm (ε = 458 M cm 1). It was analyzed in the
reactionmediumbyHPLCatitsmaximumwavelength.
The instrument used was a HP 1100 chromatograph
equipped with a diode array detector. The column was
a 250 4.6 mm ODS column (dp = 5 ␮m). The mobile
1
k30
NH2Cl + OH
→ NH2OH + Cl
(slow)
(3)
phase was H2O/MeOH (75:25% v/v) with a flow rate
1
k300
of 1 ml min
.
NH2OH + NH2Cl → NH2NHOH + HCl (fast)
(4)
The MI solution, adjusted to the desired pH
by addition of sodium hydroxide, was introduced
into the reactor. While the thermal equilibrium is
reached, an aqueous solution of chloramine was pre-
pared and then rapidly treated according to a proce-
dure published elsewhere [14,24]. 2-Methylindoline
Upon contact with oxygen, the reaction leads to NO ,
2
N2O, N2O2 , and ONOO [20]:
exhibits two absorption bands in water at
=
1
238 nm (ε1 = 6940 M 1 cm 1) and
= 288 nm
1
1
2
NH2OH + NH2Cl → N2O + NH4Cl + H2O
1
(ε2 = 2302 M cm 1) [15]. Taking into account the
impossibility of simultaneous determination of MI and
chloramine by UV, the reaction mixture was analyzed
by GC and HPLC. The analytical conditions and the
apparatus were previously described [15,16].
2
2
In any case, the reaction follows a second-order law
( d[NH2OH]/dt = 0) and the rate constant with re-
spect to NH2Cl is found from the relation
d[NH2Cl]/dt = k3[NH2Cl][OH ]
RESULTS AND DISCUSSION
Study of MI-NH2Cl Interaction
where k3 = 2k30 = 6.2 10
M
s
1. A comple-
5
1
mentary study on the temperature effect confirms
1
the proposed activation energy (E3 = 86.9 kJ mol
)
Kinetic Evidence of Competitive Reactions. The ex-
periments were carried out in alkaline medium (pH
12.89) where the formation of 5 is neutralized. The
reactant concentrations were kept lower than 20
[20,21].
In order to define the optimum conditions of the
synthesis of 1, we had to establish a mathematical
model able to describe the totality of the experimental
results. It is first necessary to determine the parame-
ters governing the kinetics of the interaction between
2-methylindoline and chloramine. The overall interac-
tions are then included in a kinetic model in order to
represent the evolution of the system according to the
reactant concentrations, pH, and temperature. It is the
object of this paper.
3
10 M so as to maintain a homogeneous mixture. A
temperature of 40 C allowed to reduce the reaction
time and consequently limits the alkaline-hydrolyzed
percentage of chloramine. The solutions were prepared
in deoxygenated water in order to avoid the oxidation of
MI and NAMI by dissolved oxygen. A nitrogen cover
was also maintained.
Under these conditions, the reactants were stable
+
and in their neutral state (at 25 C, KaMIH = 6.76
+
6
2
10 [15], KaNH Cl = 3.41 10 [25,26]). Figure 1
presents a series of chromatograms recorded at t = 1,
18, and 29 min for a mixture of initial concentrations
3
EXPERIMENTAL
Reagents
3
3
of 10 10 M in NH2Cl and 10.5 10 M in MI.
We observe the decrease of 2 (tR = 1.52 min)
and correlatively the appearance of three signals at
tR = 1.86, 2.88, and 2.13 min. GC–MS analyzes show
that the two first signals correspond to 1-amino-2-
methylindoline (1) (tR = 1.86 min) and its oxida-
tion product (tR = 2.88 min), 1-amino-2-methylindole
(4). The third (tR = 2.13 min) results from an oxida-
tion of 2-methylindoline by chloramine. A structural
Water was passed through an ion-exchange resin,
then twice distilled, deoxygenated, and stored under
nitrogen.
All reagents and salts used were reagent grade prod-
ucts from Aldrich and Prolabo RP.
Chloramine was prepared immediately before use
by reacting an aqueous NH3–NH4Cl solution with
sodium hypochlorite as previously described [22,23].

578
ELKHATIB ET AL.
Figure 1 Kinetics of the formation of NAMI. GC analyses recorded as a function of time, A: t = 1 min, B: t = 18 min, C:
3
3
t = 29 min, (pH 12.89, [NH2Cl]0 = 10 10 M, [MI]0 = 10.5 10 M, T = 40 C).
characterization leads to 2-methylindole (6).
(Table II):
t
t
Z
Z
CH
3
I1 = d([NAMI] + [4]) I2 = d[6]
N
H
0
0
6
where I1 and I2 are the instantaneous material balance
of the reaction products.
Complementary trials carried out under the same
conditions of pH and temperature but at different
Table I indicates the variation of the concentrations
of 1, 2, 4, and 6 according to time. In particular,
we note that I1/I2 ratio is constant and close to 1.3

SYNTHESIS OF 1-AMINO-2-METHYLINDOLINE BY RASCHIG PROCESS
579
I
Table I Study of NH2Cl–MI Interaction; Variation of
1
the Concentrations of 1, 2, 4, and 6 with Respect to
Time
4
3
2
1
0
Experimental points
Time
[MI]
[NAMI]
[4]
[6]
(min) ( 103 M) ( 103 M) ( 103 M) ( 103 M)
0
1
17
29
41
65
97
136
196
10.46
10.11
8.48
7.53
6.84
5.60
5.08
4.53
4.30
0.00
0.05
1.02
1.41
1.74
2.13
2.50
2.66
2.82
0.00
0.05
0.19
0.21
0.31
0.40
0.55
0.66
0.81
0.00
0.10
0.82
1.18
1.54
1.94
2.40
2.69
2.90
0
1
2
3
3
3
[NH2Cl]0 = 10 10 M, [MI]0 = 10.5 10 M, pH 12.89,
T = 40 C.
I
2
Figure 2 Study of MI–NH2Cl interaction. Kinetic evi-
dence of a competitive mechanism (T = 40 C, pH 12.89):
(a) [NH2Cl]0 = 10 10 3 M, [MI]0 = 10.5 10 3 M; (b)
concentrations of MI and NH2Cl lead to results that
are identical. In all cases, the plots I1 = f (I2) are lines
with a slope about 1.30 (r2 = 0.994) (Fig. 2). These
results confirm the existence of a competitive process
to the formation of 1-amino-2-methylindoline.
3
3
[NH2Cl]0 = 5 10 M, [MI]0 = 14.8 10 M.
Thus, by deriving with respect to time, we obtain
The system is then reduced to the reactions (5) and
(6) (k11 = k1/p) the mechanistic details of which were
d([1] + [4])/dt = p d[6]/dt
previously published ( = 1) [16].
1
where p is the I1/I2 ratio. The oxidation of 2-
methylindoline could not be avoided, and the rate laws
of appearance of 1 and 4 are written as
k
1
CH
CH
3
3
+ NH Cl
+ HCl
2
N
N
H
NH
2
d[1]/dt = 1k1[MI] [NH2Cl]
2k2[NAMI][NH2Cl]
(5)
k
11
CH
CH
3
3
+ NH Cl
+ NH Cl
4
2
d[4]/dt = 2k2[NAMI][NH2Cl]
N
H
N
H
(6)
Knowing that = 1 [14], we deduce
2
d[6]/dt = 1[MI] [NH2Cl] k1/p
Partial Orders and Rate Constants. Taking into ac-
count the oxidation of 1 by chloramine, the rate laws
were determined at the first instants of the reaction
by using a differential method. The identity between
initial and current partial orders was controlled by nu-
meric resolution of the kinetic model. The initial rates
of formation of 1 and 6 are written as
Table II Study of NH2Cl–MI Interaction; Kinetic
Evidence of a Competitive Mechanism
[NH2Cl]0 = 0.01 M,
[MI]0 = 0.0105 M
Time (min) ([1] + [4])/[6]
[NH2Cl]0 = 0.005 M,
[MI]0 = 0.0148 M
Time (min) ([1] + [4])/[6]
V10 = (d[NAMI]/dt)t=0 = k1[MI]0 [NH2Cl]0
(7)
(8)
0
0
17
29
41
65
97
1.48
1.37
1.33
1.30
1.27
1.23
1.25
15
28
49
65
77
1.49
1.40
1.37
1.30
1.31
1.30
1.24
0
0
0
0
0
V11 = (d[6]/dt)t=0 = k11[MI]0 [NH2Cl]0
0
0
where
,
,
0
,
and V10, V101 are respec-
0
0
0
136
196
106
171
tively the initial partial orders and the initial rates
of reactions (5) and (6). The slopes of the curves
[NAMI] = f (t) and [6] = f (t) determined at different
pH 12.89, T = 40 C.

580
ELKHATIB ET AL.
Table III Kinetics of NH2Cl–MI Interaction;
Determination of the Rate Constants of the Formation
of 1 and 6
initial concentrations of reactants permit the access to
the kinetic parameters. Each curve was adjusted by the
least-squares method and then extrapolated at t = 0.
To evaluate 0, three series of experiments were re-
[NH2Cl]0
[MI]0
k1
M
k11
M
3
1
1
1
( 103 M) ( 103 M) ( 103
s
1) ( 103
s
)
alized at constant concentration of MI (15 10 M)
and for NH2Cl contents ranging between 5 10 3 and
15 10 3 M. 0 was determined according to the same
procedure but while varying the titre of 2 between
10.0
5.00
8.22
14.6
5.03
5.09
4.98
10.5
14.8
14.8
14.8
7.32
11.4
15.1
12.6
12.2
12.7
12.9
13.1
12.7
12.5
9.95
9.84
9.80
9.91
9.73
9.87
9.74
7
10 3 and 15 10 3 M ([NH2Cl]0 = 5 10 3 M,
T = 40 C, pH 12.89).
At constant concentration of one of the reagents and
for two different initial contents of the other (ci and cj ),
the relations (7) and (8) lead to the following equations:
T = 40 C, pH 12.89.
V10
V10
V10 = [MI]0
[MI]0
0
0
ci
ci
cj
ci
cj
Modeling of NH2Cl–MI Interaction
V10 = [NH2Cl]0
[NH2Cl]0
0
0
cj
ci
cj
To determine the instantaneous concentrations of dif-
ferent species, it is necessary to take into account the
overall reactions that intervene in the medium. The sys-
tem of differential equations was defined from the rate
laws of the interactions (1)–(6). Let us indicate respec-
tively by x, a, u, y, z, and g the instantaneous contents
of NH2Cl, 2, 1, 6, 4, and NH2OH. At constant values of
pH and temperature, the differential system is written
(b = [OH ]) as
0
0
V101
V101
V11 = [MI]0
[MI]0
0
0
0
ci
cj
ci
cj
0
0
V101 = [NH2Cl]0
[NH2Cl]0
0
0
ci
cj
ci
cj
We deduce
= Log V10
V10
cj
0
ci
Log([MI]0)c ([MI]0)c
i
j
dx/dt = (k1 + k11)xa k2ux k3bx
da/dt = (k1 + k11)xa
du/dt = k1xa k2ux
dy/dt = k11xa
(9)
(10)
(11)
(12)
(13)
= Log V10
V10
cj
0
ci
Log([NH2Cl]0)c ([NH2Cl]0)c
i
j
= Log V101
V101
cj
0
0
ci
dz/dt = k2ux
Log([MI]0)c ([MI]0)c
i
j
= Log V101
V101
cj
0
0
ci
with the initial conditions t = 0, x = x0, a = a0, b =
b0, and u = y = z = g = 0.
Log([NH2Cl]0)c ([NH2Cl]0)c
i
j
The above system can be resolved by the numeri-
cal method of Runge–Kutta according to a fourth-order
procedure step. However, in order to simplify the math-
ematical treatment, an algebric solution was developed.
It makes it possible to describe the evolution of the sys-
tem over time from one implicit equation and analytical
relations. Moreover, it allows access to the final yields
without applying a step-by-step procedure.
Thus, by eliminating t from Eqs. (9) and (10), we
deduce:
k1 = V10 [MI]0 [NH2Cl]0
0
0
0
0
0
0
0
k11 = V11 [MI]0 [NH2Cl]0
The overall results are consigned in Table III. In the
above concentration range, the partial orders are sit-
uated between 0.95 and 1.10, which confirm that the
two competitive reactions are bimolecular. At pH 12.89
and T = 40 C, the rate constants are k1 = 12.7
3
1
1
3
1
10
M
s
and k11 = 9.83 10
M
s
1. In ad-
dx/da = 1 + {k2/(k1 + k11)}(u/a)
dition, we verified that the rate of disappearance of
2 is equal to the sum of the appearance rates of 1
and 6:
+ {k3b0/(k1 + k11)}(1/a)
(14)
where k2/(k1 + k11) is a function of pH and tempera-
(d[MI]/dt)t=0 = (k1 + k11)[MI]0[NH2Cl]0
ture. To integrate Eq. (14), it is necessary to express

SYNTHESIS OF 1-AMINO-2-METHYLINDOLINE BY RASCHIG PROCESS
581
u = f (a). From the Eqs. (10) and (11) we obtain
du/da = k1/(k1 + k11) + {k2/(k1 + k11)}(u/a)
In particular, at the end of the reaction (x = 0), the final
content of 2 can be found via the relation (18):
x0 (a0 a ){1 + r1r2/(r2 1)}
∞
(15)
+ {1 (a /a0)r2 }r1/(r2 1)
∞
b0 Log(a /a0)r3 = 0
(18)
Let us designate by r1 and r2 the following reports:
r1 = k1/(k1 + k11) r2 = k2/(k1 + k11)
The Eq. (15) becomes
∞
It then becomes possible to access the instantaneous
concentration and the yield of 1:
u = a{1 (a/a0)r2 }r1/(r2 1)
1
du/da = r1 + r2(u/a)
= u(a0, a , r1, r2)/x0
1
∞
By introducing an auxiliary variable u = ϕ(t)a, we ob-
tain a differential equation where u and a are separated:
By eliminating t from Eqs. (10) and (12), we obtain an
expression of y = f (a):
d(Log a) = dϕ/{r1 ϕ(r2 1)}
dy/da = k11/(k1 + k11) = r1
1
Its integration (t = 0, a = a0) leads to
which, after integration (t = 0, a = a0, y = 0), allows
to express the variation of y according to a:
Log a/a0
= {Log[r1 ϕ(r2 1)] Logr1}/(r2 1)
y = (1 r1)(a0 a)
(19)
which is also written in the form
At t = ∞, it becomes easy to calculate the yield in
2-methylindole:
1
u = a{1 (a/a0)r2 }r1/(r2 1)
(16)
= y(a0, a , r1)/x0
6
∞
after reconsidering of the initial variable u = ϕ(t)a.
The substitution of u in Eq. (14) leads to a differential
equation, which is a function of x and a:
In a similar way, we established a relation between z
and a:
1
dx/dt = 1 + r3 b0/a + r1r2{1 (a/a0)r2 }/(r2 1)
dz/da = r2(u/a)
(20)
where r3 = k3/(k1 + k11).
From Eqs. (16) and (20), we deduce
Its integration leads to the final expression (at t = 0,
x = x0, a = a0)
z
a
Z
Z
r2
1
a
dz = r1r2/(1 r2)
1
da
a0
x0 x = (a0 a) + r1r2(a0 a)/(r2 1)
a0
0
{1 (a/a0)r2 }r1/(r2 1)
which leads to z and
:
4
3
b0 Log(a/a0)r
(17)
z = r1a0 a{r2 (a/a0)r2 }r1/(r2 1)
1
For a given value of x ∈ [0, x0], the concentration of
= z(a0, a , r1, r2)/x0
4
∞
MI is the root of the implicit equation
z can also be calculated from the relations (16), (19),
and the material balance relative to 2-methylindoline:
(x0 x) (a0 a){1 + r1r2/(r2 1)}
+ {1 (a/a0)r2 }r1/(r2 1)
b0 Log(a/a0)r3 = 0
a0 a = u + y + z

582
ELKHATIB ET AL.
3
The concentration of hydroxylamine is determined by
[conc.] × 10 (M)
integration of the ratio dg/da:
10
8
dg/da = {k3/(k1 + k11)}b0/a = r3b0/a
g = r3b0 Log a0/a
Calculated points
Experimental points
= g(a0, a , r3, b0)/x0
NH2OH
∞
6
The instantaneous contents a, x, u, y, z, and g are ex-
pressed in terms of time by numeric resolution of the
following integral obtained from the relations (10) and
(17):
2
4
1
2
4
a
Z
da
t = 1/(k1 + k11)
a[s(a) x0]
0
0
50
100
150
200
a0
time (min)
Figure 3 Kinetics of the formation of NAMI. Variation
of the concentrations of 1, 2, and 4 according to time
where s(a) is the second term of the equality (17).
From the above algebraic treatment, we obtained a
series of mathematical expressions allowing the com-
plete characterization of the reaction mixture. An opti-
mization of the process is then necessary to define the
optimum conditions of synthesis.
3
3
([NH2Cl]0 = 10 10
M, [MI]0 = 10.5 10
M, pH
12.89, T = 40 C).
at the end of the reaction whereas NH2Cl has com-
pletely disappeared. The final contents of 6 and 4 are
high and reach 106% and 36% of the total quantity of
1 respectively.
Optimization of the Synthesis
of 1-Amino-2-methylindoline
The Figs. 5 and 6 present the influence of the
concentration of 2. [MI]0/[NH2Cl]0 ratio was fixed
The synthesis of 1 must be carried out under strict con-
ditions of concentration and pH. Indeed, in slightly al-
kaline medium, the quantity of 6 increases rapidly at
the expense of 1-amino-2-methylindole. Moreover, the
oxidation of 1 by chloramine is accelerated accord-
ing to a specific acid-catalyzed process [14]. At pH
9, this interaction leads principally to a brown solid
5 [16], which makes the development of a continuous
process impossible. These difficulties are enhanced by
the instability of 1 and 2, which increases in acidic
medium. A sufficient concentration of sodium hydrox-
ide is thus essential to support the formation of 1-
amino-2-methylindoline. An increase of the concen-
tration of chloramine does not improve the yield of 1
because of its implication in the side reactions (1)–(4),
and (6). A more concentrated medium in 2 allows the
increase in the quantity of 1-amino-2-methylindoline
formed by enhancing the reactions (5) and (6) to the
detriment of reactions (1)–(4). Finally, the temperature
has little influence to favor the yield of 1 [15].
3
at 3 (T = 40 C, [NH2Cl]0 = 5 10 M, [MI]0 =
14.8 10 3 M, pH 12.89). We note an increase of 15%
3
[conc.] × 10 (M)
2
6
Calculated points
Experimental points
1
Hydroxylamine
4
0
The Figs. 3 and 4 show the variation of the concen-
trations of NH2Cl, NH2OH, 1, 2, 4 and 6 in the follow-
ing experimental conditions: pH 12.89, [NH2Cl]0 =
10 10 3 M, [MI]0 = 10.5 10 3 M, and T = 40 C.
The calculated curves are in good agreement with the
experimental points with a maximum error lower than
7%. Inparticular, weobservethat73%of 2isconsumed
0
50
100
150
200
time (min)
Figure 4 Kinetics of the formation of NAMI. Variation of
the concentrations of 6, NH2Cl, and NH2OH as a function of
time ([NH2Cl]0 = 10 10 M, [MI]0 = 10.5 10 M,
pH 12.89, T = 40 C).
3
3

SYNTHESIS OF 1-AMINO-2-METHYLINDOLINE BY RASCHIG PROCESS
583
3
Table IV Modelling of MI–NH2Cl Interaction;
[conc.] × 10 (M)
Variation of the Yields of 1, 4, 6, and NH2OH According
to the [MI]0/[NH2Cl]0 Ratio
16
12
8
Experiment
(%)
(%)
(%)
(%)
NH2OH
1
6
4
2
a
b
29.8
44.6
31.5
37.6
10.7
3.8
17.3
10.2
Calculated points
3
T = 40 C, pH 12.89; (a) [NH2Cl]0 = 10 10 M, [MI]0 =
3
3
Experimental points
10.5 10 M; (b) [NH2Cl]0 = 5 10 M, [MI]0 = 14.8
3
10 M.
Chloramine
4
1
also occur. Let us examine how
p = a0/x0 grows (p → ∞):
/
6 ratio varies when
1
0
0
20
40
60
80
100 120 140 160 180 200 220
1
/
= r1a {1 (a /a0)r2 }/
time (min)
1
6
∞
∞
Figure 5 Kinetics of the formation of NAMI. Variation
of the concentrations of 1, 2, and NH2Cl according to
{(1 r1)(r2 1)(a0 a )}
(21)
∞
3
3
time ([NH2Cl]0 = 5 10
M, [MI]0 = 14.8 10
M,
Taking into account the stoichiometry of MI–NH2Cl
interaction, the final content in 2 can be written in the
form
pH 12.89, T = 40 C).
in the yield of NAMI whereas undergoes a signifi-
4
a
= a0 mx0 (m 1)
∞
cant diminution. The yield in 2-methylindole does not
exceed 84% of 1. The overall yields are consigned in
Table IV.
The substitution of a by its value in Eq. (21) leads to
∞
1
The experimental yields show that the final content
in NAMI is affected by three interactions: the hydrol-
ysis of NH2Cl, the oxidation of NAMI by chloramine,
and the formation of 2-methylindole. In concentrated
solution and for a fixed pH, the term Log(a/a0)r3 rel-
ative to the hydrolysis of chloramine becomes negligi-
ble. While the oxidation of NAMI can be neutralized by
using a great excess of 2, the concurrent process could
/
= r1(1/h 1){1 (1 h)r2 }/
1
6
{(1 r1)(r2 1)}
(22)
where h = m/p(h → 0).
By applying the development of Mac-Laurin (h →
0), we prove that
(1 h)r2
1
(r2 1)h
1
The Eq. (22) depending only on r1 and
equal to
/
is then
6
1
3
[conc.] × 10 (M)
11
/
= r1/(1 r1) = k1/k11
1
6
10
Chloramine
Calculated points
9
Knowing that
exceed:
+
= 1, the yields in 1 and 6 cannot
1
6
Experimental points
8
7
6
5
4
3
2
1
0
= r1 = k1/(k1 + k11)
= 1 r1 = k11/(k1 + k11)
1
6
6
At pH 12.89 and T = 40 C,
56% and
44%.
1
6
The preceding results show the limit of the Raschig
process for the synthesis of indolic hydrazines. This
phenomenon is due to the partial positive character
of nitrogen atom, which supports the concurrent re-
action leading to 2-methylindole [16]. For example,
experiments carried out on the synthesis of 1-amino-2-
methylindole by reaction between 2-methylindole and
NH2Cl show that the 3-chloro-2-methylindole is the
Hydroxylamine
150
0
50
100
200
250
time (min)
Figure 6 Kinetics of the formation of NAMI. Variation
of the concentrations of 4, 6, and NH2OH with respect to
3
time (pH 12.89, [NH2Cl]0 = 5 10 M, [MI]0 = 14.8
3
10 M, T = 40 C).

584
ELKHATIB ET AL.
principal product. To obtain a higher yield of NAMI, it
is necessary to operate in a new reaction medium where
its formation is favored. A similar study conducted in
water–alcohol and water–acetonitrile mixtures is cur-
rently in progress.
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