2,5-dihalothiophenes in the reaction with chlorosulfonic acid

Article abstract of DOI:10.1134/S1070363207050192

The mixtures of mono-and dihalothiophenesulfonyl chlorides, formed in the sulfochlorination reaction of 2,5-dichlorothiophene and 2,5-dibromothiophene, were treated with aqueous ammonia and thus converted into mixtures of the corresponding stable thiophenesulfonamides. The structure and composition of the latter were studied by physicochemical methods: GC-MS and ¹H, ¹³C, ¹H-¹³C HSQC, ¹H-¹³C HMBC, and NOESY NMR spectroscopy. As a result of the above chemical transformations, 2,5-dichlorothiophene afforded a mixture of 5-chlorothiophene-2-sulfonamide and 4,5-dichlorothiophene-3-sulfonamide in a roughly 70:30 ratio. In the case of 2,5-dibromothiophene, a mixture of 5-bromothiophene-2-sulfonamide, 4,5-dibromothiophene-3-sulfonamide, and 3,5-dibromothiophene-2-sulfonamide (3:54:43) was formed. Nauka/Interperiodica 2007.

Full text of DOI:10.1134/S1070363207050192

ISSN 1070-3632, Russian Journal of General Chemistry, 2007, Vol. 77, No. 5, pp. 926 931.
Pleiades Publishing, Ltd., 2007.
Original Russian Text I.B. Rozentsveig, Yu.A. Aizina, K.A. Chernyshev, L.V. Klyba, E.R. Zhanchipova, E.N. Sukhomazova, L.B. Krivdin,
G.G. Levkovskaya, 2007, published in Zhurnal Obshchei Khimii, 2007, Vol. 77, No. 5, pp. 831 836.
2,5-Dihalothiophenes in the Reaction with Chlorosulfonic Acid
I. B. Rozentsveig, Yu. A. Aizina, K. A. Chernyshev, L. V. Klyba,
E. R. Zhanchipova, E. N. Sukhomazova, L. B. Krivdin, and G. G. Levkovskaya
Favorskii Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences,
ul. Favorskogo 1, Irkutsk, 664033, Russia
e-mail: i_roz@irioch.irk.ru
Received November 9, 2007
Abstract The mixtures of mono- and dihalothiophenesulfonyl chlorides, formed in the sulfochlorination
reaction of 2,5-dichlorothiophene and 2,5-dibromothiophene, were treated with aqueous ammonia and thus
converted into mixtures of the corresponding stable thiophenesulfonamides. The structure and composition of
1
1
1
the latter were studied by physicochemical methods: GC MS and H, 13C, H 13C HSQC, H 13C HMBC,
and NOESY NMR spectroscopy. As a result of the above chemical transformations, 2,5-dichlorothiophene
afforded a mixture of 5-chlorothiophene-2-sulfonamide and 4,5-dichlorothiophene-3-sulfonamide in a roughly
70: 30 ratio. In the case of 2,5-dibromothiophene, a mixture of 5-bromothiophene-2-sulfonamide, 4,5-di-
bromothiophene-3-sulfonamide, and 3,5-dibromothiophene-2-sulfonamide (3:54:43) was formed.
DOI: 10.1134/S1070363207050192
Developing expedient synthetic approaches to
prospective biologically active thiophene derivatives
and proceeding with systematic development of the
methods of synthesis of polyhaloethylidene- and
ethylamides of thiophenesulfonic acids [1, 2], based
on the reaction of N,N-dihaloamides with polyhalo-
ethenes and acetylenes [3], we attempted to prepare
dihalothiophenesulfonamides. We planned to perform
sulfochlorination of 2,5-dichloro(bromo)thiophene,
to convert the resulting sulfonyl chlorides into the
corresponding sulfonamides and then to N,N-dichloro-
amides, and, finally, to react the latter with polyhalo-
ethenes. Earlier we successfully used this route to
synthesize the first representative of chloral heteryl-
sulfonylimines, N-(2,2,2-trichloroethylidene)-5-chlo-
rothiophene-2-sulfonamide [1, 2].
In the present work, when studying the reaction of
2,5-dichloro- and 2,5-dibromothiophenes with a 4 6-
fold molar excess of chlorosulfonic acid at 25 to
30 C and in the reaction mixture diluted with CCl4,
we found that sulfochlorination involves both halogen
substitution in position 2 and halogen migration from
position 2 to 3 or 4.
Since the mixtures of thiophenesulfonyl chlorides,
formed in the sulfochlorination reaction, proved un-
stable on treatment and storage, we treated them with
aqueous ammonia, thus converting them into mixtures
of the corresponding stable thiophenesulfonamides
whose structure and composition were further studied
by physicochemical methods.
X
X
SO2NH2
(1) HOSO2Cl
(2) NH4OH
+
SO2NH2
X
X
X
X
+ X
SO2NH2
S
S
S
S
I, II
III, IV
V
X = Cl (I, III), Br (II, IV, V).
Analysis of the amination products showed that
the sulfochlorination reaction affords 5-halothiophene-
2-sulfonyl chlorides, as well as 4,5-dihalothiophene-3-
sulfonyl chlorides. The formation of 3,5-dihalothio-
phene-2-sulfonyl chloride was observed only in the
reaction with 2,5-dibromothiophene.
926

2,5-DIHALOTHIOPHENES IN THE REACTION WITH CHLOROSULFONIC ACID
927
It should be added that under the above conditions
2-chlorothiophene is sulfochlorinated without substitu-
tion of chlorine, affording 5-chlorothiophene-2-sul-
fonyl chloride exclusively [1, 2].
Apparently, the presence of such a strong acid as
chlorosulfonic is sufficient for generation of stable
halo-substituted thiophenium cations, cationic com-
plexes, from both the starting dihalothiophenes and
ppm
126
128
130
their sulfochlorinated derivatives. Subsequent trans-
132
formations of these thiophenium cations might form
134
the corresponding sulfochlorinated halo- and dihalo-
136
substituted thiophene derivatives.
138
140
142
144
The disproportionation of 2,5-dichloro(dibromo)-
thiophenium ions, leading eventually to 2-chloro-
(bromo)- and 2,4-dichloro(dibromo)thiophenes in the
presence of strong Brønsted or Lewis acids in organo-
chlorine solvents has been described and discussed in
the literature [4 7]. However, there is no information
on similar transformations of dihalothiophenes under
the action of chlorosulfonic acid.
8.0 7.8 7.6 7.4 7.2 7.0 6.8
ppm
C HMBC NMR spectrum of the mixture of thio-
phenesulfonamide chloro derivatives I and III.
1
13
H
2J(C, H). Further evidence for suggested structures I
and III is provided by the observation in the NOESY
spectrum of cross peaks between H4(I) (7.43 ppm)
and H5(III) (7.31 ppm) and the amino group
(7.79 ppm).
The composition of the mixtures of thiophenesul-
fonamides was determined by NMR spectroscopy and
GC MS. Compound I was prepared by us earlier
[1, 2].
1
1
The H NMR spectrum of the mixture of chloro-
In the H NMR spectrum of the mixture of bromo-
substituted thiophenesulfonamides contain two
doublets at 7.20 and 7.43 ppm [3J(H, H) 4.0 Hz],
belonging to compound I, a singlet at 7.31 ppm cor-
responding to compound III, and a broadened signal
of the amino group at 7.79 ppm, belonging to both
these compounds. In the 13C NMR spectrum, eight
signals are observed, three of which correspond to the
methine carbon atoms and five to quaternary carbon
substituted thiophenesulfonamides, there are two
doublets at 7.29 and 7.38 ppm [3J(H, H) 3.8 Hz],
belonging to compound II, a singlet at 7.40 ppm from
compound IV, a singlet at 7.49 ppm from compound
V, and a broadened signal of the amino group at
7.82 ppm from all the three compounds II, IV, and V.
The assignment of the methine carbon signals was
made on the basis of the 2D HSQC NMR spectrum
which shows cross peaks between the protons at 7.29
and 7.38 ppm of compound II and carbon atoms at
130.87 and 130.58 ppm, respectively, H2 at 7.40 ppm
with carbon at 130.50 ppm of compound IV, and H4
at 7.49 ppm with carbon at 135.08 ppm of compound
V. The quaternary carbon signals were assigned by
1
atoms, which were assigned on the basis of the H
1
13C HSQC and H 13C HMBC spectra.
1
The 2D H 13C HSQC NMR spectrum shows cross
peaks between protons at 7.20, 7.43, and 7.31 ppm
and carbons at 127.51, 129.78 and 126.48 ppm,
respectively. To assign the quaternary carbon atoms,
1
n
1
the H 13C HMBC method optimized for J(C, H) of
10 Hz was employed (see figure). In the HMBC spec-
trum, the proton at 7.20 ppm gives three cross peaks:
C2(I): 144.0 ppm, 3J(C, H) 11.1 Hz; C5(I):
the H 13C HMBC NMR. In the HMBC spectrum, the
H4 signal of compound II at 7.29 ppm gives a cross
peak with the more downfield C2 signal at 146.72 ppm
[3J(C, H) 10.7 Hz]. The H3 signal of compound II at
7.38 ppm gives a cross peak with the more upfield C5
133.15 ppm, J(C, H) 2.2 Hz; and C3(I): 129.78 ppm,
2
2J(C, H) 5.5 Hz, which unequivocally proves structure
I. The proton at 7.31 ppm gives three cross peaks:
signal with J(C, H) 15.3 Hz, which unambiguously
3
proves structure II. The H2 signal of compound IV at
7.40 ppm shows three cross peaks: with C3
C3(III): 140.17 ppm, 2J(C, H) 3.2 Hz; C4(III):
2
[143.37 ppm, J(C, H) 3.3 Hz], C4 [112.93 ppm,
126.94 ppm, 3J(C, H) 13.5 Hz; and C5(III):
4
4
125.81 ppm, J(C, H) < 1 Hz, which confirms struc-
3J(C, H) 12.2 Hz], and C5 [111.63 ppm, J(C, H) <
ture III. The assignment was made with due regard
1 Hz], which proves structure IV. The H4 signal of
compound V at 7.49 ppm shows three cross peaks:
1
that vicinal 13C H coupling constants are substantial-
ly larger than geminal ones, that is, 3J(C, H) >
one with C2 [141.26 ppm, J(C, H) 8.3 Hz] and two
3
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 77 No. 5 2007

928
ROZENTSVEIG et al.
with C5 (116.80 ppm) and C3 [111.27 ppm, 2J(C, H)
2 3 Hz], which corresponds to structure V. The final
The direct and long-range coupling constants were
measured by means of 2D 1H 13C HMBC and 1H 13C
HSQC techniques, as well as by analysis of the
assignment of the C5 and C3 signals of compound V
was made by means of B3LYP/cc-pVDZ quantum-
chemical computation of the shielding constants in
this compound.
1
decoupled 13C NMR spectrum. The resulting H 13C
coupling constants (Hz) for compounds I V are
shown in Scheme 1.
Scheme 1.
H5.5
H
5.5 H
Cl
H
H
13.5
SO2NH2
174.7
176.4
3.9
2.2
11.1
3.2
H
14.9
SO2NH2
Cl
SO2NH2
Cl
Cl
S
III
S
S
181.1
I
12.2
Br
Br
SO2NH2
H
Br
H 175.6
176.8
15.3
183.0
3.3
8.3
10.7
Br
Br
SO2NH2
SO2NH2
H
180.8
S
S
S
II
IV
V
The mass-spectra of halogenated thiophenesulfon-
amides I V are characterized by a stable molecular
ion [M]+ (W· 16 20%, see table) whose fragmenta-
tion is typical of arenesulfonamides [8 10]. Actually,
the fragmentation of I V involves the isomerization
of [M]+ prior to its dissociation, leading to skeletal
rearrangement ions arising from C O and C N bond
formation [8 10]. The main fragmentation pathway
of the molecular ion of 5-halo-substituted thiophene-
sulfonamides I, II involves formation of an odd-elec-
tron [M
SO2]+ ion which further expels X and
H2NCS radicals (Scheme 2). A similar fragmentation
pathway is also characteristic of compounds III V
(see table).
Scheme 2.
+
+
O
S
SO2NH2
S
X
X
X
NH2
O
S
M1+
I, II, M+
SO2
NHSO
+
+
SCNH2
[C3H2X]+
NH2
X
OH
S
S
X
HX
X
[C3H2]+
[C4H2SO]+
[C4H4SN]+
m/z 38
m/z 98
m/z 98
The rearranged radical ion [M NHSO]+ charac-
teristic of sulfonamides [11] is more probably formed
from dihalothiophene-3-sulfonamides III V (Sche-
me 2). No elimination of CO from the molecular ions
of sulfonamides I IV was observed.
The third explicitly pronounced fragmentation
pathway of the molecular ions of compounds I V
involves rupture of the S N bond and expulsion of an
NH2 radical. The probability of this fragmentation
pathway practically halves with increasing number
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 77 No. 5 2007

2,5-DIHALOTHIOPHENES IN THE REACTION WITH CHLOROSULFONIC ACID
929
Principal characteristic ions in the mass-spectra of thiophenesulfonamide halo derivatives I V, m/z (I, % of total ion
current, mass numbers are given for 35Cl and 79Br)
Compound
Ion
I
II
III
IV
V
M+
[M
[M
197 (16)
181 (16)
133 (10)
134 (13)
117 (3)
105 (6)
98 (1)
82 (4)
73 (18)
79 (1)
38 (4)
(3)
241 (18)
225 (14)
177 (8)
178 (3)
161 (5)
149 (5)
98 (1)
82 (13)
117 (3)
123 ( )
38 (7)
(5)
231 (16)
215 (7)
167 (6)
168 (5)
151 (8)
139 (1)
132 (11)
116 (6)
107 (13)
79 (4)
72 (2)
(6)
319 (18)
303 (9)
255 (8)
256 (4)
239 (4)
227 (3)
176 (2)
160 (10)
195 (1)
123 (1)
116 (1)
(11)
319 (20)
303 (9)
255 (6)
256 (3)
239 (3)
227 (4)
176 (1)
160 (10)
195 (3)
123 (1)
116 (3)
(11)
NH2]+
SO2]+
[M
NHSO]+
NH2)
H2NSO)
H2NSO)
H2NSO2)
H2NSO2)
[(M
[(M
[(M
[(M
[(M
SO2]+
CO]+
a
X]+
X]+
CS]+
[CSX]+
[(M
H2NSO2)
CSX]+
[HOS(O)NH2]+ , m/z 81
[C3HS] +, m/z 69
[H2N=S=O] +, m/z 64
m/z 57
(2)
(6)
(4)
(3)
(4)
(2)
(2)
(6)
(3)
(4)
(7)
(3)
(3)
(6)
(1)
(2)
(1)
(3)
(3)
(9)
(1)
(4)
(1)
(5)
(4)
(7)
(1)
(4)
(1)
(6)
[CHS]+, m/z 45
m/z 38 [C3H2]+
m/z 37 [C3H] +
a
+
+
The [(M
NHSO)
HX] peak overlaps with the [(M
H NSO)
X] peak.
2
of halogen atoms in the molecule. Scheme 3 exem-
plifies this fragmentation pathway by 5-halothio-
phene-2-sulfonamide and illustrates formation of the
most abundant ions in the spectrum.
Scheme 3.
+
O
S
+
SO2
NH2
+
S
X
NH2
X
X
X
O
S
S
O
S
S
O
SO
I, II, M+
SO2
+
S
[C4H2S]+
m/z 82
X
X
XCH
C
CH
C
X
[C4H2SO]+
O+
CS
m/z 98
[C3H2]+
[C3H2X]+
m/z 38
S
CO
HX
+
S
[C3HS]+
[C3H2XS]+
[XCS]+
O
X
m/z 69
It is noteworthy that all spectra contain an intense
odd-electron sulfinic acid ion peak at m/z 81, formed
by rupture of the C S bond and hydrogen migration
(Scheme 4). Subsequent expulsion of the hydroxyl
radical leads to an m/z 64 ion peak.
Therefore, the main fragmentation pathways of the
molecular ions of compounds I V are associated with
C S bond rupture and formation of skeletal rearran-
gement ions arising due to C O and C N bond forma-
tion. As the number of halogen atoms increases, the
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 77 No. 5 2007

930
ROZENTSVEIG et al.
Scheme 4.
H
+
+
O
S
HO
+
OH
H2N=S=O
S
NH2
X
NH2
S
O
O
I, II, M+
m/z 81
m/z 64
contribution of this pathway increases. The nature and
number of halogen atoms in the molecule do not
affect the fragmentation pathway. The processes of
halogen and CO expulsion from the molecular ion
are also not observed.
fonamide (I) (yield 43%) and 30% of 4,5-dichloro-
thiophene3-sulfonamide (III) (yield 15%).
Similarly, from 2,5-dibromothiophene, 1.83 g of a
mixture was obtained containing, according to 1H
NMR data, 3% of 5-bromothiophene-2-sulfonamide
(II) (yield <2%), 54% of 4,5-dibromothiophene-3-sul-
fonamide (IV) (yield 30%), and 43% of 3,5-dibromo-
thiopene-2-sulfonamide (V) (yield 25%).
5-Chlorothiophene-2-sulfonamide (I). 1H NMR
spectrum (DMSO-d6), , ppm: 7.20 d (1H, H4),
7.43 d (1H, H3), 7.79 s (2H, NH2). 13C NMR spectrum
(DMSO-d6), , ppm: 127.51 (C4), 129.78 (C3), 133.15
(C5), 144 (C2).
EXPERIMENTAL
1
The H and 13C NMR spectra were registered on a
Bruker DPX-400 spectrometer at 400.6 (1H) and
100.61 MHz (13C) in 5-mm tubes for 5 10% DMSO-
1
d6 solutions against internal HMDS. The 13C H
coupling constants were measured by 2D HSQC and
HMBC techniques with the following parameters:
spectrum width 800 Hz (1H) and 5 kHz (13C), pulse
duration 6 (1H) and 14 s (13C), relaxation delay 2.5 s,
time of reading of the free induction decay signal 2 s,
digital resolution 0.1 (1H) and 0.5 Hz/point (13C).
1
5-Bromothiophene-2-sulfonamide (II). H NMR
spectrum (DMSO-d6), , ppm: 7.29 d (1H, H4), 7.38 d
(1H, H3), 7.82 s (2H, NH2). 13C NMR spectrum
(DMSO-d6), , ppm: 116.81 (C5), 130.58 (C3), 130.87
(C4), 146.72 (C2).
The mass spectra were recorded on a QP5050A
GC MS instrument (Shimadzu) at 70 eV. Chromato-
graphic separation was performed on an SPBTM
5MS capillary column (60 m 0.25 mm 0.25 m).
Injector temperature 250°C, ion source temperature
220°C. The oven temperature was programmed from
4,5-Dichlorothiophene-3-sulfonamide (III). 1H
NMR spectrum (DMSO-d6), , ppm: 7.31 s (1H, H2),
7.79 s (2H, NH2). 13C NMR spectrum (DMSO-d6), ,
ppm: 125.81 (C5), 126.48 (C2), 126.94 (C4), 140.17
(C3).
1
60 to 250°C at a rate of 10 deg min .
4,5-Dibromothiopene-3-sulfonamide (IV). 1H
NMR spectrum (DMSO-d6), , ppm: 7.40 s (1H, H2),
7.82 s (2H, NH2). 13C NMR spectrum (DMSO-d6), ,
ppm: 111.63 (C5), 112.93 (C4), 130.50 (C2), 143.37
(C3).
Reaction of 2,5-dihalothiophenes with chlorosul-
fonic acid. To a solution of 2.67 4.01 ml (40
60 mmol) of a freshly distilled chlorosulfonic acid in
5 ml of CCl4, 10 mmol of 2,5-dichloro- or 2,5-dibro-
mothiophene was added dropwise with vigorous stir-
ring and cooling to 30 C. The reaction mixture was
stirred for another 30 min at 25 C and 30 min at
room temperature, and then poured on ice. The or-
ganic layer was separated, the solvent was removed
under reduced pressure, the residue was mixed with
50 ml of 25% aqueous ammonia with intermittent
shaking, kept for 3 h, and then neutralized with 10%
HCl. The precipitate of thiophenesulfonamide formed
was filtered off, dried, and investigated by physico-
chemical methods.
3,5-Dibromothiophene-2-sulfonamide (V). 1H
NMR spectrum (DMSO-d6), , ppm: 7.49 s (1H4, H),
7.82 s (2H, NH2). 13C NMR spectrum (DMSO-d6), ,
ppm: 116.80 (C5), 111.27 (C3), 135.08 (C4), 141.26
(C2).
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