X-ray diffraction and self condensation reaction of thionicotinamide S-oxide

Article abstract of DOI:10.1023/a:1009591819303

Thiobenzamide and thionicotnamide S-oxide were prepared as intermediates in the dimerization of corresponding thioamides to 1,2,4-thiadiazoles and the X-ray crystal structure of thionicotinamide S-oxide water solvate was determined. Crystals belong to orthorhombic Pbca space group with a = 14.129(3), b = 7.299(2), c = 15.277(3)?, and Z = 8. The geometry of the molecule accords well with that found in similar compounds; an intramolecular N-H ? O hydrogen bond is present, while the packing is mainly determined by the hydrogen bond system involving the water molecule and the side-chain of the organic molecule. The contacts between pyridine moieties, stacked along the [010] axis, complete the packing.

Full text of DOI:10.1023/a:1009591819303

Journal of Chemical Crystallography, Vol. 29, No. 1, 1999
X-ray diffraction and self condensation reaction of
thionicotinamide S-oxide
(1)
(2)
(2)
(3)
Anna Bonamartini Corradi, * Carla Boga, Luciano Forlani, and Paolo Sgarabotto
Received May 5, 1997
Thiobenzamide and thionicotnamide S-oxide were prepared as intermediates in the dimeriza-
tion of corresponding thioamides to 1,2,4-thiadiazoles and the X-ray crystal structure of
thionicotinamide S-oxide water solvate was determined. Crystals belong to orthorhombic
˚
Pbca space group with a ϭ 14.129(3), b ϭ 7.299(2), c ϭ 15.277(3)A, and Z ϭ 8. The geometry of
the molecule accords well with that found in similar compounds; an intramolecular N–H и и и O
hydrogen bond is present, while the packing is mainly determined by the hydrogen bond
system involving the water molecule and the side-chain of the organic molecule. The contacts
between pyridine moieties, stacked along the [010] axis, complete the packing.
KEY WORDS: Aminosulphines; thionicotinamide S-oxide; thiobenzamid; X-ray structure.
Introduction
Aminosulphines1,2 (thioamides S-oxide) RS(O)
ence of halide ions. The formation of 3,5-diphenyl-
6
1,2,4-thiadiazoles was reported by us to occur in di-
methylsulfoxide and in the presence of hydrogen
chloride or bromide, or in the presence of other acids
(methanesulfonic, sulfuric acids) and halide salts, as
shown in Scheme 1. A reasonable reaction pathway of
dimerization of the thioamides to 1,2,4-thiadiazoles is
the formation of the thioamide S-oxide as intermedi-
ate. In order to collect some information on the im-
portance of the thioamides S-oxide in the reaction
of Scheme 1, we report the preparation of thiobenz-
amide and thionicotinamide S-oxide and X-ray dif-
fraction of thionicotinamide S-oxide, together with
some indication on the reaction of formation of
1,2,4-thiadiazoles.
NRЈ are interesting compounds because of their re-
2
activity in forming heterocyclic systems with two or
more heteroatoms (mainly sulfur and nitrogen con-
taining, such as thiazoles, dithiazines, thiadiazoles).
Biological interest on thioamides as biomodulators
rises from their administration as biocides. There are
some indications that the biotransformation of thioa-
3
mides, in particular of thionicotinamide, as well as
4
some problems of hepatotoxicity are connected with
3
sulfur oxidation. Thioamide S-oxides are excreted
2
after administration of thioamides.
Our interest is in the reaction of thioamides to
5
form 1,2,4-thiadiazoles with a particular reagent mix-
ture: the dimethylsulfoxide/acid mixture in the pres-
Experimental
(1)
(2)
(3)
Dipartimento di Chimica, Facolt a` d’Ingegneria, Universit a´ di
Modena, via Campi 183, 41100 Modena Italy.
Dipartimento di Chimica Organica ‘‘A. Mangini’’ viale Risorgi-
mento 4, 40136 Bologna Italy.
Dipartimento di Chimica Generale ed Inorganica, Chimica Ana-
litica, Chimica Fisica, Centro di Studio per la Strutturistica Dif-
frattometrica del CNR, Universit a` di Parma, viale delle Scienze,
Oxidation of thioamides was carried out in meth-
2,7
anol with H
2
O
2
.
The thioamide S-oxides were ob-
tained from the reaction mixtures by evaporating the
solvent at 15–20ЊC in vacuum (10 mm/Hg). Thio-
2
1
benzamide S-oxide: m.p. 125–127ЊC. H NMR in
DMSO-d6, internal reference TMS: ͳ ϭ 9.35 (1 Hsb),
4
3100 Parma. Italy.
*
To whom correspondence should be addressed.
8.38 (1 Hsb) (NH
2
); 7.4–7.6 (5 Hm, C
6
5
H ). ␭max 355nm
115
1074-1542/99/0100-0115$16.00/0  1999 Plenum Publishing Corporation

1
16
Corradi, Boga, Forlani, and Sgarabotto
Scheme 1
(
␧ ϭ 6,500) (in DMSO with 5% of H
spectrum (m/z) (relative intensities): M ϭ 153(5),
37(40), 135(100), 121(5) 105(7), 77(79). The spec-
2
O by vol.). Mass
3,5-di-(3-pyridyl)-1,2,4-thiadiazole 6 respectively (to-
gether with elemental sulfur).
ϩ
1
ϩ
trum shows the presence of M (238) of 3,5-diphenyl-
(
1,2,4)-thiadiazole.
Thionicotinamide S-oxide: m.p. 128–129ЊC
1
(
MeOH). H NMR in DMSO-d6 ͳ ϭ 9.35 (1 Hsb),
8
.38 (1 Hsb) (NH
2
); 8.8 (2 Hm), 7.5 (1 Hm, C
5
H N).
4
␭
max 360 nm (␧ ϭ 4,500) (in DMSO with 5% of H O
2
by vol.). Mass spectrum (m/z) (relative intensities):
ϩ
M ϭ 154(24), 138(11), 122(7), 105(100), 78(10). The
ϩ
spectrum shows the presence of M (240) of 3,5-
dipyridyl-(1,2,4)-thiadiazole.
Data collection, structure determination and re-
finement are given in Table 1.
Both thiobenzamide S-oxide and thionicotinam-
ide S-oxide show in the H NMR spectrum (in
1
DMSO-d6) with two different N-H signals (see Ex-
perimental). The sulfur oxidation does not change
the geometry and, consequently, the hybridization of
Results and discussion
the nitrogen atom of the thioamide group [C(S)-
8
When H
2
O
2
is added dropwise to a solution of
NH
2
]. As observed in thioamides, the hindered rota-
thionicotinamide in methanol and the solvent is elim-
inated in vacuum without heating, a crystalline solid
tion around the C-N double bond (in DMSO-d6) is
also observed for the respective sulfinimides.
From preliminary kinetic measurements, it is ob-
served that, under the same experimental conditions
and in the presence of HCl or other acids, the reactiv-
ity of thiobenzamide S-oxide is lower than that of
thiobenzamide. The presence of halide ions strongly
enhanced the reactivity of both 1 and 4.
(
the thionicotinamide S-oxide, 5 of Scheme 2) is ob-
tained. When the hydrogen peroxide is added to thio-
benzamide and to thionicotinamide (in methanol) in
the presence of appropriate amounts (ȁ0.3 M) of
HCl, or the reaction mixtures are gently warmed; the
only recovered compounds from the reaction mix-
tures are 3,5-diphenyl-1,2,4-thiadiazole 2 and the
Addition of small amounts (from 0.1 to 0.5
Scheme 2

Thionicotinamide S-oxide
117
a
Table 1. Experimental Data for the Crystallographic Analysis
Formula
6 8 2 2
C H N O S
CCDC deposit no.
Temperature (K)
Crystallographic system
Space group
CCDC-1003/5481
294
Orthorhombic
Pbca
14.129(3)
7.299(2)
15.277(3)
1575.5(6)
8
Scheme 3
˚
a (A)
˚
b (A)
˚
c (A)
˚
3
V (A )
On the other hand, the thionicotinamide S-oxide
shows the direct formation of thiadiazole spectrum.
Under our experimental conditions, no evidence for
protonating equilibrium of the thionicotinamide S-
oxide are obtained. The spontaneous cyclization
pathway of thioamide S-oxide is depicted in
Scheme 4.
All attempts to crystallize the S-oxide from
warmed alcohols, afforded mixtures of thiadiazole 2
or 6 and sulfur. Crystals of 2 were obtained by slow
evaporation of solvent (methanol) at room tempera-
ture. Attempts to obtain crystals suitable for X-ray
diffraction of 3 failed. Injection of S-oxide into a
gaschromatographic apparatus with a mass detector,
showed the signals related to thiadiazole 2 and 6
and sulfur; the mass ion signal may be obtained by
introducing the sample with moderate heat. Clearly,
the thioamides S-oxides dimerize to 1,2,4-thiadiazole
quickly and spontaneously when heated or slowly by
acid catalysis. It is of interest to note that in our
reaction mixtures the presence of dithiadiazines
(which are obtained in different experimental condi-
Z
D
(g cmϪ3)
1.45
c
Reflections for lattice parameters
Number
30
␪
range (Њ)
21.1–38.4
720
Siemens AED
0.31 ϫ 0.14 ϫ 0.47
32.8
CuKͰ 1.54178
3.0–12.0
1.2 ϩ 0.35 tan ␪
3–70
F(000)
Diffractometer
Crystal size (mm)
Ϫ1
Ȑ (cm )
Radiation, ␭ (A)
˚
Ϫ1
Scan speed (Њmin )
Scan width (Њ)
␪
range (Њ)
h, k, l range
Scan mode
No. of reflections measured
No. of reflections used in the
refinement [I Ͼ 2 ␴(I)]
No. of refined parameters
0–17, 0–8, 0–18
Ͷ–2␪
1708
1278
132
R ϭ ͚͉⌬F͉/͚͉F
Rw ϭ [͚w(⌬F )/͚wF
k, g in w ϭ k[␴ (F
0
2
͉
0.048
0.050
2.403, 1.11 ϫ 10
2.59
2
0
]1/2
2
2
]Ϫ1
Ϫ3
0
) ϩ gF
0
GOF
˚
Ϫ3
Max., min. height in final ⌬F map (eA) )
0.63, Ϫ0.38
a
10
The structure was solved by direct methods using SHELXS86
and refined by SHELX7611 with cycles of full-matrix anisotropic
9
least-squares. All hydrogen atoms were located in the difference-
Fourier map and refined isotropically. The study of the molecular
geometry was carried out by the PARST93 program on an
ENCORE E91 computer.
tions) was not observed. If the equilibrium of scheme
12
3 is wholly shifted toward the protonated species,
this cannot be transformed in the thiadiazole deriva-
tive by the pathway of Scheme 4, which involves a
tautomer of the unprotonated thioamide S-oxide.
equivalent with respect to thiobenzamide) of HCl to
the solution of thiobenzamide S-oxide in DMSO-d6
does not change the phenyl chemical signals in its H
1
NMR spectrum, but changes the two N-H signals to
a single signal at ͳ about 8.4. In the UV/VIS spec-
trum, the addition of HCl to a solution of thiobenz-
amide S-oxide in DMSO produces the immediate
disappearance of the absorption band at 360 nm
related to the S-oxide compound, without the appear-
ance of the absorption band of the 3,5-diphenyl-1,2,4-
thiadiazole. Also, several hours after mixing the re-
agents, the neutralization of HCl with NaHCO
3
produces the return of the thiobenzamide S-oxide
spectrum. Thiobenzamide S-oxide is probably pro-
tonated by the strong acid to form a poorly reactive
species (at room temperature), Scheme 3.
Scheme 4

1
18
Corradi, Boga, Forlani, and Sgarabotto
4
Table 2. Fractional Atomic Coordinates (ϫ 10 ) and Equivalent
˚
2
4
Isotropic Thermal Parameters (A ϫ 10 ) for non-H-atoms with
esd’s in parentheses
a
x
y
z
U
eq
S(1)
8734(0)
9589(1)
9817(1)
6611(1)
8993(1)
8260(1)
7304(1)
6866(2)
7792(2)
8506(1)
9541(1)
1684(1)
2462(3)
2598(3)
1285(3)
1971(3)
1481(3)
1688(3)
660(3)
3721(0)
3217(1)
5026(1)
5812(1)
4787(1)
5437(1)
5250(1)
6599(1)
6849(1)
6262(1)
3308(1)
487(2)
574(6)
421(5)
433(6)
351(6)
332(6)
377(6)
438(7)
423(7)
389(7)
556(6)
O(1)
N(1)
N(4)
C(1)
C(2)
C(3)
C(5)
C(6)
C(7)
O(2w)
Fig. 1. Perspective view of thionicotinamide S-oxide water solvate.
405(3)
801(3)
6296(3)
the pyridine ring dimensions are not different with
respect to the thioamidopyridine derivatives and free
a
U
eq ϭ 1/3͚
i
j ij i j i j
͚ U a иa ).
* a*(a
1
3, 14
the pyridine molecule.
In the side chain, the C(1)-
˚
C(2) distance, 1.479(2) A, is significantly longer than
˚
2
2
Molecular geometry
1.466 A, corresponding to a Csp -Csp bond, but is
comparable with that found in previous work
˚
The final atomic coordinates and equivalent iso-
tropic thermal parameters are quoted in Table 2,
while bond distances and angles are reported in Table
(1.488(5) A) and interpreted in terms of conjugation
between the side chain and the pyridine molecule.
Also, the reduction of the C(1)-S(1) and C(1)-N(1)
bonds compared with the corresponding values in
3
. Figure 1 shows the perspective view of the molecule
1
5
with labeling scheme.
Bond distances and angles are regular and agree
with those found in similar compounds. In particular,
thioacetamide agrees with conjugation in the pyri-
dine-side chain, which induces a withdrawal of elec-
tron density from C(1)-C(2) into the side chain. In
˚
Table 3. Bond Distances (A) and Angles (deg), Selected Torsion Angles (deg), and Hydrogen
Bonds with esd’s in Parentheses
S(1)UO(1)
S(1)UC(1)
N(1)UC(1)
N(4)UC(3)
1.541(2)
1.682(2)
1.303(2)
1.335(2)
1.336(2)
C(1)UC(2)
C(2)UC(3)
C(2)UC(7)
C(5)UC(6)
1.479(2)
1.389(2)
1.398(2)
1.376(4)
1.380(3)
N(4)UC(5)
C(6)UC(7)
O(1)US(1)UC(1)
C(3)UN(4)UC(5)
S(1)UC(1)UN(1)
N(1)UC(1)UC(2)
S(1)UC(1)UC(2)
C(1)UC(2)UC(7)
C(1)US(1)UC(1)UN(1)
N(1)и и иO(1) 2.784(2)
N(1)UH(12)и и иO(1) 107(3)
O(2w)и и иO(1) 2.803(3)
O(2w)UH(1w)и и иO(1) 175(4)
105.5(1)
C(1)UC(2)UC(3)
C(3)UC(2)UC(7)
N(4)UC(3)UC(2)
N(4)UC(5)UC(6)
C(5)UC(6)UC(7)
C(2)UC(7)UC(6)
N(1)UC(1)UC(2)UC(7)
121.1(1)
117.2(2)
120.6(1)
121.5(1)
117.9(1)
121.1(1)
Ϫ5.2(2)
117.8(1)
123.9(1)
123.6(2)
119.1(2)
118.6(1)
Ϫ31.8(3)
N(1)UH(12) 0.84(3)
H(12)и и иO(1) 2.42(3)
O(2w)UH(1w) 0.89(5)
O(2w)UH(2w) 0.88(4)
H(1w)и и иO(1) 1.91(5)
i
a
i
O(2w)и и иO(1) 2.768(2)
H(2w)и и иO(1) 1.89(4)
i
O(2w)UH(2w)и и иO(1)
75(3)
1
ii
ii
N(1)и и иO(2w) 2.820(2)
N(1)UH(11) 0.94(3)
N(1)UH(12) 0.84(3)
H(11)и и иO(2w) 1.89(3)
ii
N(1)UH(11)и и иO(2w) 168(3)
iii
H(12)и и иN(4)iii 2.16(3)
N(1)и и иN(4) 2.954(2)
iii
N(1)UH(12)и и иN(4) 159(3)
a
i ϭ 2 Ϫ x, 1/2 ϩ y, 1/2 Ϫ z; ii ϭ 2 Ϫ x, 1 Ϫ y, 1 Ϫ z; iii ϭ 1/2 ϩ x, 1/2 Ϫ y, 1 Ϫ z.

Thionicotinamide S-oxide
119
(
2.1(5)Њ) of the torsion angle O-S-C-N. As depicted
in the projection along the [010] axis reported in Fig.
, the pyridine rings are stacked in the y direction at
2
a distance of b/2 between them.
Acknowledgments
The authors thank the Ministero dell’Universita`
e della Ricerca Scientifica e Tecnologica and the Uni-
versity of Bologna (Progetto d’Ateneo: Biomodula-
tori Organici: sintesi, propriet a` ed applicazioni).
Fig. 2. Packing of thionicotinamide S-oxide along [010], water
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