Chlorine-atom transfer reactions between chloramine (= chloramide) and piperidine: Kinetic reactivity and characterization in a Raschig medium

Article abstract of DOI:10.1002/hlca.200800223

The kinetics of the Cl-transfer reaction between chloramine (1) and piperidine (2)in a Raschig medium (8 < pH < 9) was studied at various temperatures, with variable concentrations of the two reactants. The influence of the pH on the interaction of 1 and 2 was examined at a pH ranging between 8.25 and 12.89. The Cl-transfer reaction resulted in the formation of 1-chloropiperidine (3), which, in the presence of NaOH, underwent a dehydrohalogenation leading to an endocyclic imine derivative: 2,3,4,5 tetrahydropyridine (4). The kinetics of the dehydrohalogenation was also studied at different temperatures, with variable concentrations of 3 and NaOH. Kinetic and thermodynamic parameters were determined for the Cl-transfer and dehydrohalogenation reactions. Both 3 and 4 were prepared according to efficient synthetic routes; they were isolated, purified, and characterized by elemental analysis, IR, ¹H- and ¹³C-NMR, and MS. Their thermal stabilities were evaluated by differential scanning calorimetry (DSC), and their absorption coefficients at various wavelengths were determined experimentally by UV spectrophotometry.

Full text of DOI:10.1002/hlca.200800223

98
Helvetica Chimica Acta – Vol. 92 (2009)
Chlorine-Atom Transfer Reactions between Chloramine (¼Chloramide)
and Piperidine: Kinetic Reactivity and Characterization in a
Raschig Medium
by Chaza Darwich*a), Mazen Elkhatibb), Georg Steinhauserc), and Henri Delalua)
a
´
´
) Laboratoire Hydrazines et Procedes, UMR 5179 UCBL-CNRS-ISOCHEM (groupe SNPE),
´
ˆ
Universite Claude Bernard Lyon 1, Batiment Berthollet, 22 Avenue Gaston Berger, F-69622
Villeurbanne Cedex
(phone: þ 33-4-72431410; fax: þ 33-4-72431291; e-mail: chaza.darwich@univ-lyon1.fr)
b) Laboratory of Applied Chemistry and Toxicology, Faculty of Sciences, Section 3, Department of
Chemistry, P. O. Box 826, Tripoli, Lebanon
c) Vienna University of Technology, Atominstitut der ꢀsterreichischen Universitꢁten, Stadionallee 2,
A-1020 Vienna
The kinetics of the Cl-transfer reaction between chloramine (1) and piperidine (2) in a Raschig
medium (8 < pH < 9) was studied at various temperatures, with variable concentrations of the two
reactants. The influence of the pH on the interaction of 1 and 2 was examined at a pH ranging between
8.25 and 12.89. The Cl-transfer reaction resulted in the formation of 1-chloropiperidine (3), which, in the
presence of NaOH, underwent a dehydrohalogenation leading to an endocyclic imine derivative: 2,3,4,5-
tetrahydropyridine (4). The kinetics of the dehydrohalogenation was also studied at different
temperatures, with variable concentrations of 3 and NaOH. Kinetic and thermodynamic parameters
were determined for the Cl-transfer and dehydrohalogenation reactions. Both 3 and 4 were prepared
according to efficient synthetic routes; they were isolated, purified, and characterized by elemental
analysis, IR, 1H- and 13C-NMR, and MS. Their thermal stabilities were evaluated by differential scanning
calorimetry (DSC), and their absorption coefficients at various wavelengths were determined
experimentally by UV spectrophotometry.
1. Introduction. – This work is part of a complete study involving the preparation of
an unsymmetrical substituted hydrazine – piperidin-1-amine – in an ammoniacal
hypochlorite (ꢂRaschigꢃ) medium, which is used in the pharmaceutical industry as a
precursor of medicinal drugs.
For the hydrazine preparation, Raschig synthesis [1 – 4] can be considered the most
environmentally friendly route among the various syntheses described in the literature
[5 – 25]. It is also the most suitable synthetic route for a large-scale preparation. In the
case of piperidin-1-amine, Raschig synthesis can be schematized by the two reactions
shown in Scheme 1.
However, the Raschig synthesis presents the major drawback of leading to
numerous by-products. This behavior is particularly due to the pH-dependent reactivity
of NH2Cl (1), which may exhibit, depending on the pH value, an aminating (see
Scheme 1), oxidizing (see Scheme 2) [26], or even chlorinating character (see below,
Scheme 3).
ꢄ 2009 Verlag Helvetica Chimica Acta AG, Zꢅrich

Helvetica Chimica Acta – Vol. 92 (2009)
99
Scheme 1
Scheme 2
In particular, the Cl-transfer reaction (Scheme 3) between chloramine
(¼chloramide; 1) and piperidine (2) is one of the principal side reactions observed
during the synthesis of piperidin-1-amine in the Raschig process [27]. A change of
orientation in the interaction of 1 and 2 is observed on acidification of the reaction
medium, involving the protonation of either 2 or 1 (Scheme 3). In a slightly alkaline
medium, the amount of piperidin-1-amine decreases in favor of 1-chloropiperidine (3).
The latter preponderates at pH ca. 8. Therefore, an accidental lack in the NaOH supply
of our pilot plant resulted in the formation of 3.
Scheme 3
In an alkaline medium, 1-chloropiperidine (3) undergoes a dehydrohalogenation,
leading to the formation of an endocyclic imine derivative, 2,3,4,5-tetrahydropyridine
(4) (Scheme 4). Tetrahydropyridine 4 is likely to precipitate in monomeric, trimeric, or
polymeric form. Hence, when 1-chloropiperidine molecules are surrounded by NaOH
Scheme 4

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Helvetica Chimica Acta – Vol. 92 (2009)
molecules, they are immediately converted into imine derivatives, which, at high
concentrations, precipitate and block up the inlets of the pilot plant unit.
Since these reactions limit the yield of piperidin-1-amine and lead to the
precipitation of by-products, which are difficult to separate during the continuous
extraction of piperidin-1-amine [27], it is necessary to create a kinetic model
quantifying the contribution of main and side reactions involved in the Raschig
medium. Therefore, we have to investigate the kinetics of each of these reactions
separately. Herein, we report on the kinetics of the Cl-transfer reaction (Scheme 3) and
the dehydrohalogenation reaction (Scheme 4) as well as on the efficient syntheses of 3
and 4 and their characterization by several analytical and thermochemical techniques.
2. Results and Discussion. – 2.1. Characterization of 1-Chloropiperidine (3). The UV-absorption
parameters of 3 (e ¼ f(l)) were determined by calibration, with a series of solutions of different
concentrations (1 · 10ꢀ3, 2 · 10ꢀ3, 4 · 10ꢀ3, and 6 · 10ꢀ3 m) prepared from freshly distilled 3 diluted in H2O.
The solutions were titrated by iodometry [28]. Fig. 1 shows a superposition of the UV spectra of 1 and 3.
Another series of solutions was prepared at pH 13 by adding a suitable amount of NaOH, the absorption
parameters obtained were identical to those determined in H2O. UV: (l in nm (e in mꢀ1 · cmꢀ1)): 295
(112), 290 (150), 285 (193), 280 (239), 275 (281), 270 (317), 265 (341), 261 (348), 260 (347), 255 (331),
250 (294), 245 (245), 243 (224), 240 (192), 235 (149), 230 (118). The IR-absorptions (KBr; in cmꢀ1
)
corresponding to the various bonds can be assigned as follows: CꢀH (2940s, 2830s, 1471s, 1452s, 1359s),
CꢀN (1273s, 1215s), CꢀC (1086m, 1056m, 1031m), and NꢀCl (881w, 864w, 823w, 679s, 513m). 1H-NMR
((D6)DMSO, 400.18 MHz, 258; d in ppm rel. to Me4Si): 3.40 (m, 2 HꢀC(2), 2 HꢀC(6)); 1.67 (m,
2 HꢀC(3), 2 HꢀC(5)); 1.40 (m, 2 HꢀC(4)); many 1H,1H couplings were observed, however, it was not
possible to determine the corresponding coupling constants. 13C{1H}-NMR ((D6)DMSO, 100.63 MHz,
258; d in ppm rel. to Me4Si): 63.7 (C(2), C(6)); 27.4 (C(3), C(5)); 22.7 (C(4)). EI-MS (70 eV; in m/z (rel.
%)): 118 (100), 55 (80.2), 42 (75.8), 28 (72.4), 119 (51.4), 84 (37.1), 120 (34.8), 83 (31.8), 78 (23.4), 56
(18.3), 36 (18.2), 121 (16.8), 39 (16.7), 54 (15.6), 29 (15.1), 82 (12.0). The results of the elemental analysis
corroborate the purity grade of 3 determined by differential scanning calorimetry (DSC). Anal. calc. for
C5H10ClN: C 50.21, H 8.43, Cl 29.64, N 11.71; found: C 50.17, H 8.38, Cl 29.51, N 11.84.
Fig. 1. Superposition of UV absorption spectra of chloramine (1) and 1-chloropiperidine (3) in aqueous
solutions. [NH2Cl] ¼ 2.34 · 10ꢀ3 m, [C5H10NCl] ¼ 2.60 · 10ꢀ3 m.

Helvetica Chimica Acta – Vol. 92 (2009)
101
The molar purity and the melting parameters of 3 were determined in a first DSC experiment by
cooling a sample of freshly distilled 3 from 0 to ꢀ 1008 (cooling rate ¼ 58/min): purity ¼ 98.95 ꢁ 403.74 ·
10ꢀ6 mol-% or 99.84%, and m.p. ꢀ 59.038 (DH(melting) ¼ 8.68 kJ/mol). A second experiment was
carried out to determine the thermal stability by heating 3 from ꢀ 30 up to 2508 with a heating rate of 58/
min. The decomposition of 3 started at ca. 1258, became more and more violent and reached its apogee at
ca. 1408. The heat of decomposition released, DH(dec.), was evaluated to ca. 31.55 kJ/mol.
2.2. Characterization of 2,3,4,5-Tetrahydropyridine (4). Imino groups have UVabsorption maxima at
ca. 225 nm (Fig. 2); the absorption parameters of 4 (e ¼ f(l)) were determined by calibration with a
series of solutions of different concentrations (1 · 10ꢀ3, 2 · 10ꢀ3, 3 · 10ꢀ3, and 4 · 10ꢀ3 m) prepared by
dissolving a small amount of 4 in 2 ml of Et2O and diluting in 100 ml of H2O. The UV reference cell
contained 2 ml of Et2O diluted in 100 ml of H2O. UV: (l in nm (e in mꢀ1 · cmꢀ1)): 295 (0), 290 (0), 285 (0),
280 (1.5), 275 (6), 270 (12.5), 265 (23.5), 260 (37.5), 255 (57), 250 (85), 245 (116.5), 240 (146), 235
(165.5), 230 (174), 227.59 (175), 225 (173), 220 (165.5).
Fig. 2. UV Absorption spectrum of an aqueous solution of 2,3,4,5-tetrahydropyridine (4). [C5H9N] ¼
3.61 · 10ꢀ3 m.
Similar IR absorptions (KBr; in cmꢀ1) to those observed for 3 are found for CꢀH (2958s, 2923s,
2846m, 2807m), CꢀN (1372s, 1303m, 1238m), and CꢀC (1108m, 1022m, 1031m, 667m, 507m), besides a
weak absorption for C¼N (1653). Due to the equilibrium between the monomer, dimer, and trimer form
1
of 4, the H- and 13C-NMR spectra were quite complex, and it was not possible to assign the various
peaks and determine coupling constants. Several measurements, at different temperatures, in
(D6)DMSO and CDCl3 were conducted; however, no improvement was observed. D2O was tested as
well, but due to the low solubility of 4 in H2O, the concentration was too low to detect peaks. 1H-NMR
((D6)DMSO, 400.18 MHz, 258; Me4Si): mixture of m. 13C{1H}-NMR ((D6)DMSO, 100.63 MHz, 258;
Me4Si): many peaks. EI-MS (70 eV; in m/z (rel. %)): 166 (100), 55 (98.6), 84 (76.8), 83 (73.0), 82 (60.9),
137 (53.4), 138 (40.5), 41 (30.3), 56 (28.4), 42 (25.1), 85 (24.2), 54 (22.5), 167 (19.2), 123 (18.3), 96 (17.9),
68 (17.3), 81 (14.5), 124 (13.5), 57 (12.9), 39 (12.8), 165 (12.0), 122 (8.3), 249 (4.1). The MS data show
that 4 may exist in its dimer (m/z 166) or even trimer form (m/z 249) (see Scheme 4), which explains the
weak IR absorption at 1653 cmꢀ1 corresponding to the imino group. Moreover, after a short time, the
solid obtained seems to be converted into its polymerized form and that, once dissolved in H2O, it is
hydrolyzed into its monomer form. Anal. calc. for C5H9N: C 72.24, H 10.91, N 16.85; found: C 71.03, H
10.52, N 17.48.
By heating a sample (6.06 mg) of 4 from ꢀ 20 and to 2508 (heating rate 58/min), a sharp peak was
observed at ca. 608, which corresponds to the melting point of 4, followed by a decomposition starting at

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Helvetica Chimica Acta – Vol. 92 (2009)
ca. 1208 and reaching its highest stage at 1678. From the melting phase, it was possible to determine the
molar purity and melting parameters of 4: purity ¼ 98.19 ꢁ 26.29 · 10ꢀ3 mol-% or 99.60%, and m.p. 60.508
(DH(melting) ¼ 7.07 kJ/mol).
2.3. Kinetics of the Cl-Transfer Reaction between Chloramine (1; NH2Cl) and
Piperidine (2; C5H10NH). 2.3.1. Reaction Order and Stoichiometry. At 8 < pH < 9, 1-
chloropiperidine (3) becomes the exclusive product of the interaction of 1 and 2.
Therefore, to measure the rate constant with the utmost precision, experiments were
conducted at 258 and pH ca. 8. Fig. 3 shows the UV spectrophotometric evolution of a
1/2 mixture in H2O at different times of the reaction ([C5H10NH]0 ¼ 10 · 10ꢀ3 m,
[NH2Cl]0 ¼ 2 · 10ꢀ3 m, pH 8.20, and T 258). While the UV absorption of 1 decreased at
243 nm, the one of 3 increased simultaneously creating an isosbestic point at 257 nm,
which can be expressed by Eqn. 1.
[NH2Cl]0 ꢀ [NH2Cl] ¼ [C5H10NCl]
(1)
Fig. 3. Kinetics of Cl-transfer: UV spectrophotometric evolution of the reaction mixture. [C5H10NH]0 ¼
10 · 10ꢀ3 m, [NH2Cl]0 ¼ 2 · 10ꢀ3 m, pH 8.20, T 258.
Since an overlap of the UV absorption spectra of chloramine (1) and chloropiper-
idine (3) is observed (see Fig. 1), we chose to work at two wavelengths (l1 243 nm and
l2 280 nm), at which absorbencies can be expressed by Eqns. 2 and 3 (l ¼ 1.00 cm).
Instantaneous concentrations of 1 and 3 (Fig. 4) are then given by Eqns. 4 and 5, where
l1¼243
l1¼243
l2¼280
l2¼280
e
¼ 458, e
¼ 224, e
¼ 62, and e
¼ 239 mꢀ1 cmꢀ1.
NH2Cl
C5H10NCl
NH2Cl
C5H10NCl

Helvetica Chimica Acta – Vol. 92 (2009)
103
Fig. 4. Evolution of the concentrations of
1 and 3 with the reaction time. Initial conditions:
[C5H10NHþ2 ]0 ¼ 10 · 10ꢀ3 m, [NH2Cl]0 ¼ 2 · 10ꢀ3 m, T 258, pH 8.25.
Dðl1Þ ¼ el
½NH Clꢂ þ elC1 H
½C H10NClꢂ
(2)
(3)
1
NH2Cl
10NCl
2
5
5
Dðl2Þ ¼ el
½NH Clꢂ þ elC2 H
½C H10NClꢂ
2
NH2Cl
10NCl
2
5
5
½elC2 H
Dðl1;tÞ ꢀ el
Dðl2;tÞꢂ
1
10NCl
C5H10NCl
5
½NH2Clꢂ ¼
(4)
(5)
l1
e
el2 NCl ꢀ el2 el1
NH2Cl C5H10
NH2Cl C5H10NCl
l1
½eNH ClDðl2;tÞ ꢀ el
Dðl1;tÞꢂ
2
NH2Cl
2
½C5H10NClꢂ ¼
l1
e
el2 NCl ꢀ el2 el1
NH2Cl C5H10
NH2Cl C5H10NCl
To represent the Cl-transfer in the 2/1 interaction, two reactions to give 3 are
plausible, Path a and Path b in Scheme 3. The rate law can thus be expressed by Eqn. 6,
with k3a (or k3b) and a and b being the rate constant and partial orders of the reaction,
respectively. Taking the acid-dissociation equilibrium of 1 and 2 into account, this leads
to Eqns. 7 and 8. Hence Eqn. 6 becomes Eqn. 9.
r¼ d[C5H10NCl]/dt ¼ k3a [NH2Cl]a [C5H10NHþ2 ]b ¼ k3b [NH3Clþ]a [C5H10NH]b (6)
[NH2Cl] ¼ x1 [NH2Cl]all
[NH3Clþ] ¼ y1 [NH2Cl]all
(7)
(8)
[C5H10NH] ¼ x2 [C5H10NH]all
[C5H10NHþ2 ] ¼ y2 [C5H10NH]all
with [NH2Cl]all ¼ [NH2Cl] þ [NH3Clþ]; [C5H10NH]all ¼ [C5H10NH] þ [C5H10NHþ2 ] and

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Helvetica Chimica Acta – Vol. 92 (2009)
10NHþ2
NH3Clþ
a
½H ꢂ þ KaNH Cl
K
KaC H
5
x1 ¼
þ ; y1 ¼ 1 ꢀ x1; x2 ¼
þ ; y2 ¼ 1 ꢀ x2
þ
½Hþꢂ þ KaC5H10NH
3
2
r¼ k3a [NH2Cl]a[C5H10NH2þ]b ¼ k3b [NH3Clþ]a[C5H10NH]b
¼ c [NH2Cl]aall[C5H10NH]abll
(9)
NH3Clþ
K
a
with c ¼ k3a x1 y2 ¼ k3b x2 y1 and k3b ¼ k3a
10NHþ2
KaC H
5
Furthermore, according to the acid-ionization constant Ka values of the two
þ
C5H10NHþ2
reactants 1 and 2 (KaNH Cl ¼ 3.41 · 10ꢀ2 m [29] and Ka
¼ 7.53 · 10ꢀ12 m [30]), at
3
pH 8.20, the neutral and protonated species have the following percentages: for 1, ca.
100% NH2Cl and 0.18 · 10ꢀ4% NH3Clþ, and for 2, 99.88% C5H10NHþ2 and 0.12%
C5H10NH.
Therefore, at this pH value, Path a is the preferred reaction (Scheme 3). As the
kinetic parameters were determined by the Ostwald method, the corresponding rate
law is given by Eqn. 10.
r¼ k3a [NH2Cl]a [C5H10NH]0 ([C5H10NHþ2 ]0 ꢃ [C5H10NH]0all
)
(10)
b
all
To evaluate the partial order a, a series of three measurements was carried out, with
a constant concentration of 2 (20 · 10ꢀ3 m) and chloramine (1) concentrations ranging
from 1 · 10ꢀ3 to 4 · 10ꢀ3 m (pH 8.20, T 258). The curves Log ([NH2Cl]0/[NH2Cl]) ¼ f(t)
b
came up to be straight lines with the slope y ¼ k3a [C5H10NH]0 all, indicating that a ¼ 1.
Similarly, b was determined by the same method and under the same conditions by
maintaining the concentration of 1 constant (2 · 10ꢀ3 m) and varying the concentration
of 2 (10 · 10ꢀ3 to 60 · 10ꢀ3 m). The curve Log y ¼ f(Log [C5H10NH]0all) was also a
straight line with the slope b ¼ 1.00 and a Y intercept ¼ Log k3a (r2 ¼ 0.997). Results are
shown in Table 1.
Table 1. Kinetics of Cl-Transfer between Chloramine (1) and Piperidine (2): Determination of Partial
Orders a and b and Rate Constants. T 258, pH 8.20.
[NH2Cl]0 [m]
[C5H10NH]0all [m]
y [sꢀ1
]
k3a [mꢀ1 sꢀ1
]
2 · 10ꢀ3
2 · 10ꢀ3
2 · 10ꢀ3
2 · 10ꢀ3
2 · 10ꢀ3
1 · 10ꢀ3
3 · 10ꢀ3
4 · 10ꢀ3
10 · 10ꢀ3
20 · 10ꢀ3
30 · 10ꢀ3
40 · 10ꢀ3
60 · 10ꢀ3
20 · 10ꢀ3
20 · 10ꢀ3
20 · 10ꢀ3
5.13 · 10ꢀ4
1.13 · 10ꢀ3
1.66 · 10ꢀ3
2.24 · 10ꢀ3
3.20 · 10ꢀ3
1.10 · 10ꢀ3
1.10 · 10ꢀ3
1.14 · 10ꢀ3
51.3 · 10ꢀ3
56.6 · 10ꢀ3
55.5 · 10ꢀ3
55.9 · 10ꢀ3
53.3 · 10ꢀ3
54.2 · 10ꢀ3
54.7 · 10ꢀ3
56.8 · 10ꢀ3
The plot D[NH2Cl] ¼ f([C5H10NCl]) (Fig. 5) shows that the amounts ratio of
chloramine consumed and chloropiperidine formed is linear and ca. 1, which establishes

Helvetica Chimica Acta – Vol. 92 (2009)
105
that the stoichiometry of the reaction is 1:1. Consequently, the second-order rate
constant, at pH 8.20 and T 258, was found to be equal to k3a ¼ 54.8 · 10ꢀ3 ꢁ 1.8 · 10ꢀ3 mꢀ1
sꢀ1 (k3b ¼ 24.8 · 107 mꢀ1 sꢀ1).
Fig. 5. D[NH2Cl] vs. [C5H10NCl] Plot. Exper. conditions at t ¼ 0: [C5H10NHþ2 ]0 ¼ 10 · 10ꢀ3 m, [NH2Cl]0 ¼
2 · 10ꢀ3 m, T 258, pH 8.25.
2.3.2. Influence of pH. To study the pH effect on the chloramine (1)/piperidine (2)
interaction, another series of measurements was performed, with constant concen-
trations of 1 and 2 titrating 2 · 10ꢀ3 m and 20 · 10ꢀ3 m, respectively, and varying the pH
value between 8.20 and 12.89. The observed rate constant, kobs, corresponds to the
disappearance of chloramine (1) against the concurrent formations of 1-chloropiper-
idine (3) by Cl-transfer and of piperidin-1-amine by N-amination of piperidine (2). The
values of the observed rate constant were determined from the slopes r0 of the curves
[NH2Cl] ¼ f(t), at t ¼ 0 (Eqn. 11). The values of kobs with respect to the pH values are
summarized in Table 2.
r0
kobs ¼ ꢀ
ð11Þ
½C5H10NHꢂ0 all½NH2Clꢂ0
Table 2. pH Effect on the Rate Constant of the Chloramine (1)/Piperidine (2) Interaction. T 258.
pH
8.20
54.8
9.30
55.6
10.50
57.3
11.50
59.9
12.00
60.8
12.70
61.4
12.89
61.1
kobs [mꢀ1 sꢀ1] · 103
Under these conditions, the rate of the interaction of 1 and 2 can be expressed by
Eqn. 12, where k1a is the rate constant of piperidin-1-amine formation, and x2 and y2 are

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Helvetica Chimica Acta – Vol. 92 (2009)
the neutral and protonated fractions of piperidine, respectively. Hence, at t ¼ 0 Eqn. 13
holds. Therefore, at pH 8.20 (y2 ꢃ 1), kobs becomes identical to k3a, whereas at pH 12.89
(y2 ꢃ 0), kobs corresponds to the formation of piperidin-1-amine (k1a). The plot kobs
f(pH) can be determined as well from Eqn. 13.
¼
ꢀ d[NH2Cl]/dt ¼ [x2k1a þ y2k3a] · [NH2Cl] · [C5H10NH]all
kobs ¼ (1 ꢀ y2) k1a þ y2 k3a
(12)
(13)
2.3.3. Influence of Temperature. The temperature effect was studied at pH 8.20
between 15 and 458. Concentrations used for 1 and 2 were equal to 2 · 10ꢀ3 m and 10 ·
10ꢀ3 m, respectively. The variation of k3a with temperature was found to comply with
the Arrhenius law (Eqn. 14). The curve Log k3a ¼ f(1/T) is a straight line of slope ¼
ꢀE3a/R and Y intercept ¼ Log A3a (r2 ¼ 0.999). A3a and E3a/R represent the Arrhenius
factor and activation energy, respectively. The enthalpy and entropy of activation can
be deduced from the Eqns. 15 and 16, where kB is Boltzmannꢃs constant and h is
Planckꢃs constant (kB ¼ 1.38033 · 10ꢀ23 J Kꢀ1 and h ¼ 6.623 · 10ꢀ23 J s). The calculated
values are: DHoz ¼ 58.22 kJ molꢀ1 and DS3oza ¼ ꢀ73.59 J molꢀ1 Kꢀ1.
3a
k3a ¼ 2.38 · 109 exp(ꢀ60.69/RT) (E3a in kJ molꢀ1)
(14)
(15)
(16)
oz
3a
DH ¼ E3a ꢀ RT
oz
3a
DS ¼ Log (A3a h)/(e kB T)
2.4. Kinetics of the Dehydrohalogenation of 1-Chloropiperidine (3) in Alkaline
Media. 2.4.1. Reaction Order and Influence of Temperature. Fig. 6 shows the UV
spectrophotometric evolution of a 1-chloropiperidine (3)/NaOH mixture in H2O at
different times of the reaction ([C5H10NCl]0 ¼ 2 · 10ꢀ3 m, [NaOH]0 ¼ 0.1m, T 258): a
decrease in the intensity of the UV absorption of 3 is occurring simultaneously to an
absorption shift to the shorter wavelengths; the isosbestic point observed at 238 nm
indicates that 3 and the product of its dehydrohalogenation are stoichiometrically
proportional. The UVabsorption spectrum registered at the end of the reaction, with a
maximum at 227 nm, shows that 3 has been completely consumed. To identify the
product resulting from the dehydrohalogenation of 3, further experiments were carried
out (see synthesis (Exper. Part) and characterization (Sect. 2.2) of 4). It was
established that, in alkaline medium, 3 was converted into 4.
Experiments were conducted at 258 with concentrations of NaOH and 3 ranging
from 0.1 to 1m and from 1 · 10ꢀ3 to 4 · 10ꢀ3 m, respectively. The kinetic parameters were
determined by the Ostwald method, and the rate law can be expressed by Eqn. 17, with
k4 and a and b being the rate constant and partial orders of the reaction, respectively.
r¼ ꢀd[C5H10NCl]/dt ¼ k4 [C5H10NCl]a [OHꢀ]0
(17)
b
A first series of measurements was carried out, using a constant concentration of
NaOH (0.1m) and variable concentrations of 3 ranging from 1 · 10ꢀ3 to 4 · 10ꢀ3 m (T

Helvetica Chimica Acta – Vol. 92 (2009)
107
Fig. 6. Kinetics of dehydrohalogenation of 1-chloropiperidine (3): UV spectrophotometric evolution of
the reaction mixture. [C5H10NCl]0 ¼ 2 · 10ꢀ3 m, [NaOH]0 ¼ 0.1m, T 258.
258). The curves Log ([C5H10NCl]0/[C5H10NCl]) ¼ f(t) came up to be straight lines with
the slope f ¼ k4 [OHꢀ]0 , indicating that a ¼ 1. A second series of measurements was
b
performed at the same temperature by maintaining the concentration of 3 constant (4 ·
10ꢀ3 m) and varying the concentration of NaOH from 0.1 to 1m. The curves Log f ¼
f(Log [OHꢀ]0) were straight lines with the slope b ¼ 1.00 (r2 ¼ 0.999) and Y
intercept ¼ Log k4. All results are summarized in Table 3. In consequence of this, the
rate constant of the dehydrohalogenation of 3 at T 258 can be expressed by Eqn. 18.
ꢀ d½C5H10NClꢂ=dt
k4 ¼
¼ 34.2 · 10ꢀ6 ꢁ 0.64 · 10ꢀ6 mꢀ1 sꢀ1
(18)
½C H10NClꢂ½OHꢀꢂ
5
Table 3. Kinetics of Dehydrohalogenation of 1-Chloropiperidine (3) in Alkaline Medium: Determination
of Partial Orders a and b and Rate Constants. T 258.
[C5H10NCl]0 [m]
[NaOH]0 [m]
f [sꢀ1
]
k4 [mꢀ1 sꢀ1
]
4 · 10ꢀ3
3 · 10ꢀ3
2 · 10ꢀ3
1 · 10ꢀ3
4 · 10ꢀ3
4 · 10ꢀ3
4 · 10ꢀ3
4 · 10ꢀ3
0.10
0.10
0.10
0.10
1.00
0.75
0.50
0.25
3.37 · 10ꢀ6
3.42 · 10ꢀ6
3.51 · 10ꢀ6
3.45 · 10ꢀ6
33.7 · 10ꢀ6
24.97 · 10ꢀ6
17.50 · 10ꢀ6
8.52 · 10ꢀ6
33.7 · 10ꢀ6
34.2 · 10ꢀ6
35.1 · 10ꢀ6
34.5 · 10ꢀ6
33.7 · 10ꢀ6
33.3 · 10ꢀ6
35.0 · 10ꢀ6
34.1 · 10ꢀ6

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Helvetica Chimica Acta – Vol. 92 (2009)
The influence of temperature was studied between 15 and 458; with concentrations
of 3 and NaOH equal to 2 · 10ꢀ3 m and 0.1m, respectively. Fig. 7 shows that Log k4 ¼ f(1/
T) is a straight line of slope ¼ ꢀE4/R and Y intercept ¼ Log A4 (r2 ¼ 0.995). A4 and E4/R
represent the Arrhenius factor and activation energy of the reaction, respectively (E4 in
kJ molꢀ1). Thus, one deduces Eqn. 19 for the rate constant; and the following values for
the enthalpy and entropy of activation (see Eqns. 15 and 16): DHo4z ¼ 90.98 kJ molꢀ1 and
DSo4z ¼ ꢀ23.29 J molꢀ1 Kꢀ1.
k4 ¼ 1.02 · 1012 exp(ꢀ 93.45/RT) mꢀ1 sꢀ1
(19)
Fig. 7. Kinetics of dehydrohalogenation of 1-chloropiperidine (3): influence of temperature.
[C5H10NCl]0 ¼ 2 · 10ꢀ3 m, [NaOH]0 ¼ 0.1m.
2.4.2. Mechanism. To suggest a mechanism for the dehydrohalogenation of 1-
chloropiperidine (3), an overview of the reactivity of similar chloramines is worthy of
mention. The reactivity of chloramine (1) in alkaline medium has been the subject of
previous studies [31 – 34]. The suggested mechanism involves the formation of
NH2OH, which reacts with another molecule of 1 to form an unstable hydroxyhy-
drazine (Scheme 5). The latter might be oxidized to nitrite and peroxonitrite ions with
N2 (g) emission.
Scheme 5

Helvetica Chimica Acta – Vol. 92 (2009)
109
As for N-chlorodimethylamine, the formation of N-hydroxydimethylamine may
correspond to the first elementary step (SN2) of Scheme 6. To confirm this hypothetic
scheme, a precise amount of N-hydroxydimethylamine hydrochloride (¼ N,N-dime-
thylhydroxylamine hydrochloride; 99%; Aldrich) was dissolved in alkaline medium
(addition of NaOH), and the solution was analyzed by GC/MS. Neither the
corresponding imino derivative nor its hydrolyzed form was detected in the chromato-
gram [35]. Moreover, by reacting equimolar solutions (10 · 10ꢀ3 m) of N-hydroxydi-
methylamine and N-chlorodimethylamine at pH 12.89 (T 258), a gas emission was
observed, and new derivatives, which were not observed in the dehydrohalogenation of
N-chlorodimethylamine, were detected [35].
Scheme 6
These results exclude the hypothetic formation of a substituted hydroxylamine
compound from 1-chloropiperidine (3). Since OHꢀ ions have both basic and
nucleophilic properties, there exists a competition between an SN2 and E2 process.
Furthermore, when bulky substituents are present next to the electrophilic site, they
create sterical limitations for an SN2 reaction, and hence the E2 process becomes
preponderant (Scheme 7).
Scheme 7
We are thankful to ISOCHEM (groupe SNPE) for financial support. Claude Bernard University of
Lyon and Lebanese University are also gratefully acknowledged. C. D. would like to express gratefulness
to the Centre National FranÅais de la Recherche Scientifique for a Ph.D. scholarship and to truly thank Dr.
Antoine Ollagnier for his valuable help in preparation of the figures.
Experimental Part
Reagents. All reagents and salts used were reagent-grade products from Aldrichꢆ and Prolabo RPꢆ.
H2O was passed through an ion-exchange resin, and then distilled twice.
Chloramine (1). NH2Cl is unstable in H2O, thus it was prepared in situ at ꢀ 108 by reacting 2m
sodium hypochlorite (25 ml) and aq. NH3/NH4Cl soln. ([NH4Cl] ¼ 2.3m, [NH3] ¼ 3.6m; 20 ml) in the
presence of Et2O (40 ml). The org. layer (0.8 – 1m of NH2Cl) was shaken and washed several times with
aliquots of dist. H2O. An aq. soln. of 1 was obtained by re-extraction from the Et2O phase. Its conc. was
determined by UV spectroscopy at l 243 nm (e ¼ 458 mꢀ1 cmꢀ1) [36].
1-Chloropiperidine (3). At 08, 2.4m aq. piperidine soln. (100 ml) was treated with 2.25m sodium
hypochlorite (100 ml). The chlorination was instantaneous and gave a mixture of two phases. The upper

110
Helvetica Chimica Acta – Vol. 92 (2009)
yellow phase was distilled under 0.05 bar leading to a pure fraction of 3 at 658. Purity as determined by
DSC: 99.84%.
2,3,4,5-Tetrahydropyridine (4). At 258, dist. 1-chloropiperidine (3); 5 g was treated with KOH (10 g)
in MeOH (90 g). The mixture was stirred overnight, and a white precipitate of KCl was formed and
filtered off. The filtrate was concentrated and then treated with 0.1m aq. HCl soln. which resulted in the
precipitation of the product that was filtered off and washed with small amounts of cold H2O: 1.8 g (52%)
of 4.
Kinetic Apparatus. The apparatus consisted of two thermostated vessels of borosilicate glass, one on
the top of the other and joined by a conical fitting. The lower reactor (200 ml) had inlets allowing the
measurement of pH and temperature, and removal of aliquots for analysis. This set-up allowed a quick
introduction of the ampoule contents into the reactor, and hence a precise definition of the start of the
reaction. A slightly reduced pressure was maintained throughout the reaction, and the reactor temp. was
kept constant to ꢁ 0.18 (thermocouple). A glass electrode (Tacussel TB/HS) and a calomel reference
electrode connected to a Tacussel-Isis-20000 pH meter were used for pH control.
Cl-Transfer Reaction. Reactant solns. were prepared at the same pH, and piperidine (2) was
introduced into the lower reactor. The pH value was adjusted by addition of an aq. KH2PO4/K2HPO4
buffer soln. As soon as the thermal equilibrium was reached, the aq. soln. of chloramine (1; prepared
according to the above-mentioned procedure) of identical pH was added from the upper vessel.
The conc. of 1 consumed and of 1-chloropiperidine (3) formed were monitored by their UV
absorptions, analyzed with a Cary-1E double-beam UV-spectrophotometer.
Dehydrohalogenation. As described for the Cl transfer, but 3 was introduced into the lower reactor,
and its disappearance with respect to time was monitored by UV spectrophotometry (e3 ¼ 348 mꢀ1 cmꢀ1 at
l 261 nm).
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Received June 5, 2008