Kinetics and mechanism of methanolysis and cyclization of 1-acyl-3-(2-halo-5-nitrophenyl)thioureas

Article abstract of DOI:10.1002/poc.351

The kinetics of methoxide ion-catalysed solvolysis of 1-acyl-3-(2-halo-5-nitrophenyl)thioureas and cyclization of fluoro derivatives were studied in methanol at 25 deg C. The cyclization involved the substitution of fluorine by sulphur anion of thiourea and proceeded in two steps. With the acetyl derivative, the first step is methanolysis and the second step is much slower cyclization of the 2-fluoro-5-nitrophenylthiourea anion formed to give 2-amino-5-nitro-1,3-benzothiazole. With the benzoyl derivative, the first step involves parallel methanolysis of the benzoyl group and cyclization to 2-benzoylamino-5-nitro-1,3-benzothiazole. At concentrations of sodium methoxide higher than ca. 0.01 mol l^-1 the rates of solvolyses of all the acyl halothioureas decreased and at concentrations higher than ca. 0.01 mol l^-1 the rates of solvolyses of all the acyl halothioureas decreased and at concentrations higher than ca. 0.4 mol l^-1 there was an increase in the formation of other product(s) than the product of cyclization. After the addition of 18-crown-6, the side products were not formed and the cyclization of fluoro derivatives were considerably accelerated. The slowing of the solvolytic reaction and acceleration of the cyclization reaction are most probably due to the formation of dianions.

Full text of DOI:10.1002/poc.351

JOURNAL OF PHYSICAL ORGANIC CHEMISTRY
J. Phys. Org. Chem. 2001; 14: 187–195
Kinetics and mechanism of methanolysis and cyclization of
1-acyl-3-ꢀ2-halo-5-nitrophenyl)thioureas
1
1
2
1
Ï
Ï
Ï
Ï
MilosÏ SedlaÂk, * JirõÂ Hanusek, Michal Holcapek and Vojeslav Sterba
1
Ï
Department of Organic Chemistry, Faculty of Chemical Technology, University of Pardubice, Na m. C s.Legiõ 565, 532 10 Pardubice, Czech
Republic
2
Ï
Department of Analytical Chemistry, Faculty of Chemical Technology, University of Pardubice, NaÂm. C s.LegiõÂ 565, 532 10 Pardubice,
Czech Republic
Received 29 May 2000; revised 9 October 2000; accepted 23 November 2000
ABSTRACT: The kinetics of methoxide ion-catalysed solvolysis of 1-acyl-3-(2-halo-5-nitrophenyl)thioureas and
cyclization of fluoro derivatives were studied in methanol at 25°C. The cyclization involved the substitution of
fluorine by sulphur anion of thiourea and proceeded in two steps. With the acetyl derivative, the first step is
methanolysis and the second step is much slower cyclization of the 2-fluoro-5-nitrophenylthiourea anion formed to
give 2-amino-5-nitro-1,3-benzothiazole. With the benzoyl derivative, the first step involves parallel methanolysis of
the benzoyl group and cyclization tÀo1 2-benzoylamino-5-nitro-1,3-benzothiazole. At concentrations of sodium
methoxide higher than ca 0.01 mol l the rates of solvolyses of all the acyl halothioureas decreased and at
concentrations higher than ca 0.4 mol lÀ1 there was an increase in the formation of other product(s) than the product
of cyclization. After the addition of 18-crown-6, the side products were not formed and the cyclizations of fluoro
derivatives were considerably accelerated. The slowing of the solvolytic reaction and acceleration of the cyclization
reaction are most probably due to the formation of dianions. Copyright  2001 John Wiley & Sons, Ltd.
KEYWORDS: reaction kinetics; cyclization; benzothiazoles; acylthioureas; dissociation constants
INTRODUCTION
was split off either during the cyclization or in the
subsequent slower step.
Phenylthioureas are suitable starting substrates for the
preparation of 2-amino-1,3-benzothiazole derivatives.
The presence of an oxidation agent, which oxidizes the
leaving hydride anion to the proton, leads to ring closure.
The most frequent oxidizing agents involve bromine in
chloroform1 or in acetic acid.2 The reaction is not
regioselective, and the cyclizations of 3-substituted
phenylthioureas usually give mixtures of 5- and 7-
substituted 2-amino-1,3-benzothiazoles.2 Therefore, we
have suggested the regioselective (SNAri) cyclizations
of 1-acyl-3-(2-halo-5-nitrophenyl)thioureas (1a–d), the
mechanism of which we studied in some detail in the
present work.
The aim of this work was to study the kinetics and
mechanism of methoxide-catalysed methanolysis and
intramolecular nucleophilic aromatic substitution of
fluorine in 1-acetyl-3-(2-fluoro-5-nitrophenyl)thiourea
(1a) and substitution of fluorine in 1-benzoyl-3-(2-
fluoro-5-nitrophenyl)thiourea (1b) complemented by the
reactions of analogous chloro derivatives, 1-acetyl-3-(2-
chloro-5-nitrophenyl)thiourea (1c) and 1-benzoyl-3-(2-
chloro-5-nitrophenyl)thiourea (1d), with methoxide.
In earlier papers we described the kinetics and
reaction mechanisms of intramolecular base-catalysed
reactions3–5 of ureas, thioureas and their benzoyl
derivatives with an ester group in water and methanol.
In all these cases the nitrogen atom reacted with the
carbon atom of the carboxylic group. The benzoyl group
EXPERIMENTAL
The 1-acyl-3-(2-halo-5-nitrophenyl)thioureas (1a–d)
were prepared by reactions of 2-fluoro- or 2-chloro-5-
nitroaniline with acetyl or benzoyl isothiocyanate. The
starting anilines were prepared by known methods.6
*Correspondence to: M. Sedla´k, Department of Organic Chemistry,
ˇ
Faculty of Technology, University of Pardubice, Na´m. Cs. Legiı´ 565,
532 10 Pardubice, Czech Republic.
E-mail: milos.sedlak@upce.cz
General procedure: 1-acyl-3-(2-halo-5-nitrophenyl)-
thioureas (1a–d). A 100 ml flask was charged with
Contract/grant sponsor: Ministry of Education, Youth and Sports of
the Czech Republic; Contract/grant number: CI MSM 253 100 001.
Copyright  2001 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2001; 14: 187–195

´
M. SEDLAK ET AL.
188
40 mmol of 2-halo-5-nitroaniline and 20 ml of dry
acetone. After dissolution, the mixture was treated with
a solution of 45 mmol of acyl isothiocyanate7 in 30 ml of
acetone added in one portion. The reaction mixture was
refluxed on a water-bath for 6 h (1a, c) and then cooled
and left to stand at room temperature 2 h (1b, d). The
separated crystalline solid was collected by filtration and
recrystallized from a suitable solvent.
[Silufol plates/CHCl3–EtOAc(1:1)]: RF = 0.62. 1H NMR
(ꢀ): 8.06 (d, J = 7.27 Hz, 2H, H-o); 7.61 (t, J = 7.66 Hz,
2H, H-m); 7.73 (t, J = 7.32, 1H, H-p); 12.15 (bs, 1H, NH);
12.97 (bs, 1H, NH); 7.96 (d, J = 8.87 Hz, 1H, H3); 8.22
(dd, J = 8.84, 2.63 Hz, 1H, H4); 9.18 (d, J = 2.25 Hz, 1H,
H6). 13C NMR (ꢀ): 131.8 (C-i); 128.5 (C-o); 128.9 (C-m);
133.4 (C-p); 168.7 (C=O); 180.4 (C=S); 136.7 (C–NH);
135.0 (C–Cl); 130.8 (C3); 122.2 (C4); 145.9 (C–NO2);
121.9 (C6). Elemental analysis (% calculated/%
found): C 50.74/50.81; H 3.28/3.21; Cl 11.52/11.63; N
13.65/13.72; S 10.42/10.35.
1-Acetyl-3-/2-¯uoro-5-nitrophenyl)thiourea /1a). The
yield after recrystallization from acetone was 4.9 g
(48%) of white crystals with m.p. 173–175°C (with
decomposition). TLC [Silufol plates/CHCl3-EtOAc
2-Fluoro-5-nitrophenylthiourea /2a). MS (m/z,%):
1
‡
(1:1)]: RF = 0.61. H NMR (ꢀ): 2.24 (s, 3H, CH3); 8.77
[M ‡ H ‡ CH3CN] 256.6, 6.9; [M ‡ H ‡ CH3CN À
‡
‡
‡
(bs, 1H, NH); 12.7 (bs, 1H, NH); 7.31 (m, 1H, H3); 8.14
HF] 236.6, 22.8; [M‡H] 215.5, 49.4; [M ‡ H À HF]
(m, 1H, H4); 9.54 (m, 1H, H6).13C NMR (ꢀ): 24.2 (CH3);
195.4, 100; [M ‡ H À HF À NO] 165.4, 41.1; [M ‡ H
‡
‡
173.9 (C=
O); 180.8 (C
=S); 128.5 (C–NH); 159.3 (d,
À HF À NO2] 149.4, 7.0.
J = 257 Hz, C–F); 117.3 (d, J = 22.6 Hz, C3); 121.5 (d,
2.6, C4); 146.1 (d, J = 254 Hz, C–NO2); 123.5 (d,
2-Chloro-5-nitrophenylthiourea /2b). A 100 ml Erlen-
meyer flask was charged with 1 g (3 mmol) of 1d together
with 60 ml of 0.1 mol lÀ1 sodium methoxide solution.
The yellow-orange solution formed was left to stand at
room temperature overnight, then neutralized with
methanolic hydrogen chloride to pH ꢀ 7. The resulting
yellow solution was treated with 10 ml of water and the
mixture was concentrated to 20 ml by vacuum distilla-
tion. The separated yellow crystalline solid was collected
by filtration. After recrystallization from water–acetone
(2:1), the yield was 0.35 g (45%) of crystals with m.p.
‡
J = 10, Hz, C6). MS (m/z,%): [M ‡ H ‡ CH3CN À HF]
‡
279, 22.7; [M ‡ H] 258, 0.01; [M ‡ H ‡ CH3CN À
‡
‡
HF À NO] 249, 38.7; [M ‡ H À HF] 238, 100; [M ‡
‡
H À HF À NO] 208, 80.0. Elemental analysis (%
calculated/% found): C 42.02/41.95; H 3.13/3.10; N
16.34/16.22; S 12.46/12.53.
1-Benzoyl-3-/2-¯uoro-5-nitrophenyl)thiourea /1b). The
yield after recrystallization from toluene was 10.2 g
(80%) of yellowish needles with m.p. 199–200°C. TLC
(Silufol plates/CHCl3): RF = 0.47. 1H NMR (ꢀ): 7.92 (m,
2H, H-o); 7.56 (m, 2H, H-m); 7.68(m, 1H, H-p); 9.22 (bs,
1H, NH); 13.04 (bs, 1H, NH); 7.34 (m, 1H, H3); 8.16 (m,
1H, H4); 9.66 (m, 1H, H6). 13C NMR (ꢀ): 131.9 (C-i);
1
167–168°C. H NMR (ꢀ): 9.68 (bs, 1H, NH); 7.73 and
8.35 (2Âbs, 2H, NH2); 7.84 (d, J = 8.87 Hz, 1H, H3);
8.07 (dd, J = 8.87, 2.76 Hz, 1H, H4); 8.86 (d, J = 2.52 Hz,
1H, H6). 13C NMR (ꢀ): 182.2 (C
=S); 138.7 (C–NH);
129.0 (C-o); 128.6 (C-m); 133.5 (C-p); 168.8 (C
=
O);
134.8 (C–Cl); 130.5 (C3); 122.7 (C4); 145.8 (C–NO2);
120.7 (C6). Elemental analysis (% calculated/%
found): C 36.29/36.24; H 2.61/2.55; Cl 15.30/15.38; N
18.14/18.21; S 13.84/13.87.
180.4 (C S); 127.5 (d, J = 13 Hz, C–NH); 158.9 (d,
=
J = 257 Hz, C–F); 117.0 (d, J = 22.6 Hz, C3); 121.8 (d,
J = 2.5 Hz, C4); 144.9 (d, J = 268 Hz, C–NO2); 123.5 (d,
J = 10.1 Hz, C6). Elemental analysis (% calculated/%
found): C 52.66/52.62; H 3.16/3.20; N 13.16/13.21; S
10.04/10.15.
General procedure: 2-acylamino-5-nitro-1,3-benzothia-
zoles (3a and b). A 100 ml Erlenmeyer flask was charged
with 0.5 g (1.94 mmol) of 1a or 1b and 30 ml of tert-butyl
alcohol. After dissolution of the starting compound, the
mixture was heated at 30–40°C, whereupon 30 ml of
0.1 mol lÀ1 potassium tert-butoxide were added within
several seconds. The mixture was stirred for another
5 min and then neutralized with acetic acid to pH ꢀ 7.
The solid substance was collected by filtration on a pre-
heated sintered-glass filter and washed with 15 ml of
methanol.
1-Acetyl-3-/2-chloro-5-nitrophenyl)thiourea /1c). The
yield after recrystallization from toluene was 5.5 g
(50%) of white crystals with m.p. 194–195°C. TLC
[Silufol plates/ CHCl3-EtOAc(1:1)]: RF = 0.49. 1H NMR
(ꢀ): 2.24 (s, 3H, CH3); 11.90 (bs, 1H, NH); 12.87 (bs, 1H,
NH); 7.91 (d, J = 8.87 Hz, 1H, H3); 8.16 (dd, J = 8.87,
2.73 Hz, 1H, H4); 9.21 (d, J = 2.51 Hz, 1H, H6). 13C
NMR (ꢀ): 23.9 (CH3); 173.1 (C=O); 179.9 (C=S);
136.4 (C–NH); 134.5 (C–Cl); 130.7 (C3); 122.1 (C4);
145.8 (C–NO2); 121.4 (C6). Elemental analysis (%
calculated/% found): C 39.50/39.60; H 2.95/2.91; Cl
12.95/13.02; N 15.35/15.20; S 11.71/11.80.
2-Acetylamino-5-nitro-1,3-benzothiazole /3a). Yield
0.37 g (80%). H NMR (ꢀ): 2.24 (s, 3H, CH3); 8.47 (d,
1
J = 2.09 Hz, 1H, H4); 8.12 (dd, J = 8.69, 2.23 Hz, 1H,
H6); 8.23 (d, J = 8.71 Hz, 1H, H7). 13C NMR (ꢀ): 23.6
1-Benzoyl-3-/2-chloro-5-nitrophenyl)thiourea /1d). The
yield after recrystallization from toluene was 10.8 g
(80%) of yellowish needles with m.p. 203–204°C. TLC
(CH3); 171.5 (C=O); 163.0 (C2); 149.2 (C3a); 122.6
(C4); 146.2 (C–NO2); 114.4 (C6); 117.1 (C7); 139.1
‡
(C7a). MS(m/z,%): [M ‡ H ‡ CH3CN] 279, 22.6;
Copyright  2001 John Wiley & Sons, Ltd.
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METHANOLYSIS AND CYCLIZATION OF ACYLTHIOUREAS
189
‡
‡
[M ‡ H ‡ CH3CN À NO] 249, 27.3; [M ‡ H] 238,
methoxide concentration of 0.1 mol lÀ1. The separated
white crystals of 3b (0.21 g; 45%) were collected by
filtration. The filtrate was evaporated until dry and the
residue was washed with water. Yield 0.15 g (50%) of
yellow crystals of 4.
‡
100; [M ‡ H À NO] 208, 55.3; 196, 17.6; 166, 21.3.
Elemental analysis (% calculated/% found): C 45.57/
45.49; H 2.97/2.80; N 17.71/17.84; S 13.51/13.64.
2-Benzoylamino-5-nitro-1,3-benzothiazole /3b). Yield
0.35 g (75%) of yellowish crystals, sublimation point at
ambient pressure 233–235°C lit.2(m.p. 239–240°C). H
1
NMR (ꢀ): 8.17 (m, 3H, H-o); 7.59 (m, 2H, H-m); 7.69 (m,
1H, H-p); 13.21 (bs, 1H, NH); 8.51 (d, J = 2.12 Hz, 1H,
Measurements. 1H and 13C NMR spectra were measured
at 360.14 and 90.57 MHz, respectively, on a Bruker
AMX 360 spectrometer at 25°C. Compounds 1a and b
were measured as saturated solutions in CDCl3, and the
chemical shifts were referenced to hexamethyldisiloxane
[ꢀ(1H) = 0.05] and to the solvent signal [ꢀ(13C) = 77.0].
Compounds 1c and 1d, 2a, 3a and 3b and 4 were
measured as saturated solutions in hexadeuteriodimethyl
sulfoxide, and the chemical shifts were referenced to
tetramethylsilane [ꢀ(1H) = 0] and the solvent signal
[ꢀ(13C) = 39.6]. The CH, CH3 and Cquart groups in the
13C NMR spectra were distinguished by the APT method.
Mass spectra of compounds 1a, 2a, 3a and 4 were
measured on a VG Platform II mass spectrometer
(Micromass, Manchester, UK) with chemical ionization
at atmospheric pressure (APCI) and a quadrupole
analyser (0–3000 Da). The mass spectrometer was
equipped with a preliminary separation unit composed
of a Waters 616, high-pressure pump, Waters 717
autosampler Waters 996 UV detector (all from Waters,
Milford, MA, USA) and a Separon SGX C18 HPLC
column (Tessek, Prague, Czech Republic). For the
mobile phase we used a 1:1 mixture of acetonitrile
(Merck, Darmstadt, Germany) and redistilled water.
Kinetic measurements were carried out on an HP UV/
VIS 8453 diode-array apparatus. A 1 cm quartz cell was
charged with 2 ml of methanolic sodium methoxide or
phenolate buffer. At 25°C, 50 ml of a methanolic solution
of substrate were injected and the absorbance was
measured at the selected wavelength. In the experiment
with 18-crown-6, the concentration of the latter was
always 2 Â 10À3 mol lÀ1 higher than that of sodium
methoxide. The stability constant10 for complexation of
H4); 8.17 (m, 3H, H6); 8.30 (d, J = 8.71 Hz, 1H, H7). 13
C
NMR (ꢀ): 131.8 (C-i); 128.5 (C-o); 128.7 (C-m); 133.1
(C-p); 166.5 (C O); 162.5 (C2); 148.7 (C3a); 122.9
=
(C4); 146.4 (C-NO2); 114.9 (C6); 117.8 (C7); 139.1
(C7a).
2-Amino-5-nitro-1,3-benzothiazole /4).
A
100 ml
Erlenmeyer flask equipped with a CaCl2 closure was
charged with 0.5 g (1.94 mmol) of 1a and 40 ml of
methanol. After dissolution of the starting compound,
13 ml of 0.5 mol lÀ1 sodium methoxide were added
within several seconds. The yellow solution formed was
left to stand at room temperature overnight to separate
yellow crystals, which were collected by filtration on a
sintered-glass filter. Yield 0.37 (97%), m.p. 308–310°C
lit.8 (m.p. 308–309°C).
A 100 ml Erlenmeyer flask equipped with a reflux
condenser was charged with 0.5 g (2.16 mmol) of 2b or
0.5 g (2.10 mmol) of 3a and 50 ml of 0.5 mol lÀ1 sodium
methoxide. The reaction mixture was refluxed for 2 h and
then neutralized with methanolic hydrogen chloride to
pH ꢀ 7, whereupon 15 ml of water were added, and
30 ml of distillate were distilled off from the mixture. The
residue on cooling separated 0.2 g (47% from 2b) or 0.3 g
(70% from 3a) of product 4 with m.p. 310°C.
1H NMR (ꢀ): 7.99 (bs, 2H, NH2); 8.06 (d, J = 2.20 Hz,
1H, H4); 7.88 (dd, J = 8.62, 2.27 Hz, 1H, H6); 7.94(d,
J = 8.62 Hz, 1H, H7). 13C NMR (ꢀ): 169.2 (C2); 153.2
(C3a); 121.6 (C4); 146.2 (C-NO2); 111.5 (C6); 115.5
‡
(C7); 139.2 (C7a). MS (m/z,%): [M ‡ H ‡ CH3CN]
‡
‡
237, 68.0; [M ‡ H] 196, 100; [M ‡ H À NO] 166,
33.3.
‡
18-crown-6 with Na at 25°C is log K = 4.36.
The data given agree with those given in the literature9.
The percentages of individual products formed by the
reactions 1b → 3b and 1b → 2a → 4 were determined
spectrophotometrically using an HP UV/VIS 8453
diode-array apparatus and 1 cm closeable cells placed
in the cell compartment of the apparatus kept at 25°C.
The following procedure was used: 10 ml calibrated
flasks were charged with 5 ml of methanolic sodium
methoxide (0.1–0.7 mol lÀ1) (added from a pipette) and
placed in a thermostat; after attaining a temperature of
Balance experiment in 0.1 mol lÀ1 CH3ONa. A 250 ml
Erlenmeyer flask was charged with 0.5 g (1.6 mmol) of
1b and 50 ml of 0.1 mol lÀ1 sodium methoxide. After
mixing, the reaction mixture was left to stand for 15 h,
whereupon 0.26 g (85%) of 4 was collected by filtration.
The filtrate was neutralized with acetic acid, whereupon
0.07 g (15%) of white crystals of 3b separated.
25°C, 1 ml of
a
methanolic solution of 1b
Balance experiment in 1.0 mol lÀ1 CH3ONa. A 250 ml
Erlenmeyer flask was charged with 0.5 of (1.6 mmol) of
1b and 50 ml of 1.0 mol lÀ1 sodium methoxide. After
mixing, the reaction mixture was left to stand for 15 h,
whereupon it was neutralized with acetic acid to the final
(c = 2.11 Â 10À4 mol lÀ1) was added and the flask
contents were thoroughly mixed and left to stand at
25°C for 6–7 h. Thereafter, the samples were taken and
their absorbance was measured at 313 nm. The popula-
tion of individual solvolysis and cyclization products
Copyright  2001 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2001; 14: 187–195

´
M. SEDLAK ET AL.
190
was calculated from Eqns (1) and (2):
mixtures was estimated after the reactions 1a → 3a and
1a → 2a → 4 carried out in sodium methoxide solutions
with added 18-crown-6. In this case, the measurements
were carried out at 268 and 291 nm. The molar
absorption coefficients of 3a were e268 nm = 1290
l molÀ1 cmÀ1 and e291 nm = 4000 l molÀ1 cmÀ1. The
molar absorption coefficients of 4 changed with changing
sodium methoxide concentration, and its values are given
in Table 3.
313nm
3b
313nm
A3113nm
ˆ
c
Á l ‡
Ác4 Á l
ꢁ1†
ꢁ2†
"
"
4
3b
c1b ˆ c3b ‡ c4
where A is the absorbance of the reaction mixture after
the completed reaction, e3b and e4 are the molar
absorption coefficients of the respective substances and
l is the optical pathlength.
1
The measurement was carried out at a wavelength of
313 nm, at which only the products in question absorb
light.
The molar absorption coefficients at 313 nm were
determined with the use of standards of substances 3b
and 4: e3b = 22 600 l molÀ1 cmÀ1 and e4 = 5000
l molÀ1 cmÀ1. Similarly, the composition of reaction
RESULTS AND DISCUSSION
The reaction of 1a with 0.1 mol lÀ1 sodium methoxide
gives 2-amino-5-nitro-1,3-benzothiazole (4) in an almost
quantitative yield. With 2-acetylamino-5-nitro-1,3-ben-
zothiazole (3a) prepared by the reaction of 1a with t-
Scheme 1
Table 1. Rate constants kobs /sÀ1) of the methanolysis of 1-acyl-3-/2-halo-5-nitrophenyl)thioureas /1a, c, d) in methanolic
solutions of p-bromophenoxide buffers /1:4±4:1) and the K1/1a, c, d) /l molÀ1), pKa and km /l molÀ1 sÀ1) values of 1a, c and d in
the same medium
kobs  103 (sÀ1
)
[CH3ONa] Â104 (mol lÀ1
)
1a
1c
1d
1.24
2.28
3.30
2.06
2.83
0.71
0.82
1.65
2.47
5.14
4.13
0.96
4.94
7.42
6.99
1.10
9.90
11.4
8.79
1.23
14.8
12.1
9.45
1.40
19.8
12.4
9.61
1.34
K1 (1a, c, d)
pKa
km
1658 Æ 262
13.70 Æ 0.07
27.99 Æ 2.91
2086 Æ 342
13.60 Æ 0.07
26.05 Æ 2.97
7257 Æ 620
13.06 Æ 0.04
10.77 Æ 0.76
Copyright  2001 John Wiley & Sons, Ltd.
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METHANOLYSIS AND CYCLIZATION OF ACYLTHIOUREAS
191
BuOK in t-BuOH, the methanolysis takes place to only a
slight extent under the same conditions. This means that
the reaction goes in two steps. The first consists in
methanolysis of 1a giving 2-fluoro-5-nitrophenylthiourea
(2a), and the second involves cyclization of 2a to 4
(Scheme 1).
The reaction of 1b with 0.1 mol lÀ1 sodium methoxide,
after completion on a preparative scale, gave 15% 2-
benzoylamino-5-nitro-1,3-benzothiazole (3b) and 85% 4,
whereas the analogous reaction in 1.0 mol lÀ1 sodium
methoxide gave 45% 3b and 50% 4 (as isolated without
further purification).
Since 3b (prepared also from 1b by reaction with t-
BuOK in t-BuOH) reacts with methoxide even more
slowly than 3a, the reaction must take two steps again:
the first produces a mixture of 2a and 3b and the second
involves cyclization of 2a to 4 (in analogy with the
reaction of 1a; see Scheme 1).
Figure 2. Dependence of observed rate constants kobs /sÀ1
of the cyclization reaction of 2-¯uoro-5-nitrophenylthiourea
)
Kinetics of methanolysis of 1a,c and d
/2a) on sodium methoxide concentration c/CH3ONa) /mol
l
À1) in the absence /*) and presence /*) of 18-crown-6.The
inset represents the best ®t of the measured data in the
(a) The methanolysis kinetics were measured at 340 nm
in p-bromophenoxide buffers at a constant concentration
of sodium p-bromophenoxide (0.05 mol lÀ1; see Table 1).
The reactions exhibited pseudo-first-order kinetics up to
90% of reaction.
range 0.002±0.1 mol lÀ1 obtained by means Eqn./7)
calculated from Eqn. (3):
pKaꢁp À bromophenol† ˆ pKsꢁCH3OH† ‡ log‰CH3OÀŠ
The p-bromophenol/p-bromophenoxide ratio varied
from 1:4 to 4:1. The concentration of methoxide ion was
‰p À bromophenoxideŠ
À log
ꢁ3†
‰p À bromophenolŠ
where the value of pKa(p À bromophenol) is 13.61 in
methanol11 and the autoprotolytic constant of methanol12
is pKS(CH3OH) = 16.916.
The reaction mechanism is presented in Scheme 2. The
methanolysis rate constants km (l molÀ1 À1) and the
s
equilibrium constants K (l molÀ1) were calculated from
Eqn. (4) and the pKa values from Eqn. (6) (Table 1). The
methanolysis rate constant km is defined by Eqn. (5).
km Á ‰CH3OÀŠ
vm ˆ kobs Á c1a ˆ
Á c1a
ꢁ4†
1 ‡ K Á ‰CH3OÀŠ
k1k2
km ˆ
ꢁ5†
ꢁ6†
ꢁ7†
k
‡ k2
À1
pKa ˆ pK ‡ pKsꢁCH3OH†
kc Á K Á ‰CH3OÀŠ
Figure 1. Dependence of observed rate constants kobs /sÀ1
)
of methanolysis of 1-acyl-3-/2-halo-5-nitrophenyl)thioureas
1a /squares) c /diamonds) and d /circles) in sodium
methoxide solution /concentration in mol lÀ1), without
addition /solid symbols) and with addition /open symbols)
of 18-crown-6.The curves represent only the nature of the
dependence
vc ˆ kobs Á c2a ˆ
Á c2a
1 ‡ K Á ‰CH3OÀŠ
There are only very small differences in pKa and km
values between the chloro- and fluoroacetyl derivatives
Copyright  2001 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2001; 14: 187–195

´
192
M. SEDLAK ET AL.
Scheme 2
1a and c. The methanolysis rate of acetyl derivative
1c at sodium methoxide concentrations above 5 Â
10À3 mol lÀ1 is about one order higher than that of the
benzoyl derivative 1d at the same sodium methoxide
concentrations. We suppose that the difference between
the methanolysis rates of the fluoro derivatives 1a and 1b
is also the same.
(b) The methanolysis kinetics were measured in
sodium methoxide solutions with concentrations from
0.01 to 1.4 mol lÀ1. With all the three acyl derivatives
(1a, c, and d), increasing methoxide concentration at first
causes a drop in the observed rate constant but then,
starting from about 0.4 mol lÀ1 methoxide concentration
(for 1-acetyl derivatives 1a and c) or 0.2 mol lÀ1
methoxide concentration (for 1-benzoyl derivative 1d),
the reaction rate shows an increase (Fig. 1), a new
reaction product being gradually formed (ꢁmax = 260 and
360 nm for the 1-acetyl derivatives and ꢁmax = 328 and
455 nm for the 1-benzoyl derivative).
formed from 1c and d at high methoxide concentrations
contains a chlorine atom. However, the spectra in
2.0 mol lÀ1 methoxide (for 1c) and 1.0 mol lÀ1 methox-
ide (for 1d) [a further increase in methoxide concentra-
tion brings about only small changes in the spectra] differ
substantially from those of the cyclizates 3a and b and 4,
and also from those of 2-chloro-5-nitrophenylthiourea
(2b) and 2-mercapto-5-nitro-1,3-benzoimidazole (the last
being a conceivable cyclization product formed by the
reaction of nitrogen atom) in the given medium. These
products seem to be stable only in the given medium and
their structures have not been determined. The formation
of these products cannot involve methanolysis as the first
step because the methanolysis product obtained from 2b
is stable under these conditions.
Kinetics of cyclization of 2a
Within the whole methoxide concentration range used,
the reaction is pseudo-first order, but the isosbestic points
are not sharp at the higher concentrations, obviously
owing to the formation of side product(s). From the mass
spectra it was found out that neither of the chief products
The cyclization kinetics were measured in sodium
methoxide solutions. The kinetic experiments showed
that the subsequent cyclization of 2a is about two orders
of magnitude slower than the methanolysis of 1a, hence
the kinetics of both the reactions can be measured
Copyright  2001 John Wiley & Sons, Ltd.
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METHANOLYSIS AND CYCLIZATION OF ACYLTHIOUREAS
193
methanolysis and cyclization of 1b (Scheme 1). Their
values are almost one order of magnitude higher than the
rate constants of subsequent cyclization of thiourea 2a,
and the absorbance changes were measured at isosbestic
points of the products from the first and the second steps.
The dependence of the calculated constants km and kc on
the concentration of sodium methoxide is shown in Fig.
3. At methoxide concentrations above 0.7 mol lÀ1
,
increasing amounts of side products were formed, hence
it was impossible to determine the observed rate
constants of cyclization and methanolysis in the first
step.
The subsequent cyclization of thiourea 2a was usually
measured at the ꢁmax of the cyclizate formed, i.e. at
263 nm. The observed rate constants of the second step
were the same as those of the second step of reaction of
1a, but the error of measurement gradually increased as
the proportion of thiourea 2a in the first step decreased
with increasing methoxide concentration.
Figure 3. Dependence of rate constants of methanolysis km
/sÀ1) /*) and cyclization kc /sÀ1) /*) of 1-benzoyl-3-/2-
¯uoro-5-nitrophenyl)thiourea /À11b) in sodium methoxide
Study of reactions of 1a±d and 2a in the presence
of 18-crown-6
solution /concentration in mol l
)
The decrease in the observed rate constant kobs in the
reactions of 1a–1d with methoxide at concentrations
above 1 Â 10À2 mol lÀ1 (Fig. 1) may be due to the fact
that the anions formed in the acid-base reactions of 1a–1d
with sodium methoxide are stabilized by interaction with
sodium cation, which shifts the acid-base equilibrium.
The concentrations of starting thioureas are lower than
corresponds to the methoxide concentrations, and the
methanolysis rate decreases with increasing concentra-
tion of sodium methoxide. The subsequent increase can
independently of each other starting from 1a. [Note:
attempts to isolate 2a failed. Even at concentrations of 1a
as low as about 0.1 mol lÀ1 a rather small amount of 2a
besides the starting compound 1a and cyclizate 4 was
detected by means of HPLC in the reaction products. The
decrease in the rate of methanolysis of 1a is probably due
to its association at higher concentrations. The formation
of 2a in kinetic runs was proved by combining HPLC
with MS. After about seven half-lives of the methanolysis
of 1a at a concentration of sodium methoxide of
2 Â 10À3 mol LÀ1 there was virtually only one compound
detected by HPLC, which was proved by MS to be 2a.
The reaction exhibited pseudo-first-order kinetics within
the whole range measured (six half-lives). At concentra-
tions higher than 0.05 mol lÀ1 the observed rate constant
kobs of the cyclization reaction increases slowly and
approximately linearly, although almost all thiourea 2a is
transformed into anion (Fig. 2).
‡
be caused by a reaction of the ion pair CH3OÀNa with
the complexes of thiourea anions and sodium cation.
Such an increase in reaction rate necessitates that the
transition state of this reaction be stabilized more than
methoxide anion with sodium cation.13,14 In that case, the
presence of a reagent forming firm complexes with
sodium cation (e.g. 18-crown-6) should substantially
change the reaction course. With the acyl derivatives 1c
and d the only reaction in the presence of 18-crown-6 was
methanolysis of both substrates (Fig. 1), and even at the
highest sodium methoxide concentrations neither the
increase in the observed rate constant kobs nor the
formation of the products as in the absence of 18-crown-6
were observed. The most likely interpretation of the drop
in observed rate constant kobs is the increasing content of
the dianion with increasing concentration of sodium
methoxide and the corresponding drop in concentration
of neutral starting substrate. In order to verify this
presumption, we measured the spectra of 1a immediately
after mixing its solution with a solution of sodium
methoxide and 18-crown-6. With increasing methoxide
concentration, the absorbance of the solution gradually
increased at ꢁ >297 nm and decreased at ꢁ <297 nm,
The mechanism of the reaction is also presented in
Scheme 2. The cyclization rate constant kc =
(2.31 Æ 0.05) Â 10À4 l molÀ1 sÀ1 and the equilibrium
constant K(2a) = 284 Æ 27 were calculated from Eqn. (7).
The value of pKa(2a) = 14.46 Æ 0.04 was calculated from
Eqn. (6).
Kinetics and mechanism of solvolysis and cycliza-
tion of 1b
The methoxide-catalysed reaction of 1b takes place in
two steps again. However, the measured rate constants of
the first step are equal to km ‡ kc, i.e. the sum of parallel
Copyright  2001 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2001; 14: 187–195

´
M. SEDLAK ET AL.
194
Table 2. Rate constants of methanolysis and cyclization of 1a and of those of cyclization of 2a in the presence of 18-crown-6
and molar absorption coef®cients of 4 in the presence of 18-crown-6
4
[CH3ONa]
kobs  103 (sÀ1
)
km  103 (sÀ1
)
kc  103 (sÀ1
)
kc  103 (sÀ1
)
(mol lÀ1
)
268 nm
291 nm
(1a)
(1a)
(1a)
(2a)
0.7
0.8
0.9
1.0
1.2
19000
18400
16500
14600
12400
9800
10900
12950
14500
18450
9.80
9.35
8.70
8.70
9.10
5.80
4.40
3.20
2.60
1.40
4.00
4.95
5.50
6.10
7.70
0.96
1.10
1.44
1.70
2.50
Scheme 3. /a) Upper part of the scheme is in the presence of 18-crown-6./b) CH 3ONa is the sum of solvated ions and ion pair./c)
1a, bÀ means anions of 1a, b and similarly for other anions./d) We have no idea about the mechanism of formation of other
products but from the steep increase in Kobs of 1c and d with increase in concentration of sodium methoxide /Fig.1) we suggest
‡
that there are two sodium cations in the activated complex of the rate-limiting step. 1aÀ Na ÁCH3ONa is the possible structure
‡
of the encounter complex, and similarly for 2aÀ Na ÁCH3ONa
which is characteristic of an acid–base equilibrium. In
further experiments, we tried to find out the effect of 18-
crown-6, and hence also increasing concentration of
dianion, on the observed rate constants of cyclization in
the two-step reaction of 1a and in the first reaction step of
1b. With 1b we only used 18-crown-6 at a concentration
of 0.8 mol lÀ1; under these conditions, the cyclization to
3b was almost the only reaction, so the whole reaction
proceeded virtually in one step with observed rate
At higher concentrations of methoxide ion, the
cyclization of 1a to 3a gradually started to make itself
felt (Table 2). In 0.8 mol lÀ1 sodium methoxide the rate
of cyclization is already higher than the rate of
methanolysis. In the absence of 18-crown-6 the ratio of
cyclization to methanolysis rates and its increase with
increase in sodium methoxide concentration is much
smaller because the formation of complexes of anions
with sodium cations decreases the rates of both
methanolysis and cyclization reactions. The rate constant
constant kobs = 4.1Â10À3
s
À1, i.e. ca 50% higher than
that in the absence of 18-crown-6.
kc = 4.95 Â 10À3
s
À1, of 1a in 0.8 mol lÀ1 sodium
In the reaction of sodium methoxide with 1a, the effect
of 18-crown-6 on both the reaction steps at concentra-
tions of sodium methoxide from 0.7 to 1.2 mol lÀ1 was
studied (Figs 1 and 2 and Table 2). In the first step the
observed rate constant kobs decreased except for the
highest methoxide concentration (Table 2) whereas the
rate of cyclization of thiourea 2a in the second step
increased rapidly (Fig. 2), hence at the highest methoxide
concentration the second reaction step was only about
four times as fast as the first step (Table 2).
methoxide is almost the same as the observed rate
constant of cyclization of benzoyl derivative 1b
(kobs = 4.3 Â 10À3
s
À1) measured under the same condi-
tions. The 15% yield of benzoyl cyclizate 3b and, on the
other hand, the almost exclusive solvolysis of acetyl
derivative 1a at a sodium methoxide concentration of
0.1 mol lÀ1 in the absence of 18-crown-6 are obviously
largely due to the fact that the solvolysis rate of 1a is ca
10 times higher than that of 1b.
The absence of cyclization reactions of chloro
Copyright  2001 John Wiley & Sons, Ltd.
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METHANOLYSIS AND CYCLIZATION OF ACYLTHIOUREAS
195
derivatives 1c and d, both with and without 18-crown-6,
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Copyright  2001 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2001; 14: 187–195