Reactions of the activated, rigid, α-diazomethine group of 1,2,5-thiadiazole 1,1-dioxides with nitrogenated nucleophiles. Part III: Aliphatic monoamines and phenylhydrazine

Article abstract of DOI:10.1002/poc.1022

The reactions of n-butylamine (BuNH₂), 2-aminoethanol (H ₂N(CH₂)₂OH), diethylamine (Et₂NH), and phenylhydrazine (PhN₂H₃) with 3,4-diphenyl-(1a) and phenanthro[9,10-c]-1,2,5-thiadiazole 1,1-dioxide (1b) were studied by cyclic voltammetry (CV) and ¹H- and ¹³C-NMR in aprotic solvent solution. The course of the reactions depended on the substrate-nucleophile combination: Et₂NH added to 1a or 1b, forming the corresponding thiadiazolines in an equilibrium monoaddition reaction. The equilibrium constants were evaluated and compared. With primary amines and PhN ₂H₃, the nucleophile added to both C=N double bonds of 1a and displaced the sulfamide moiety. In the case of the reaction of la with PhN₂H₃, the intermediate monoaddition thiadiazoline, 3-(2-phenylhydrazino)-3,4-diphenyl-1,2,5-thiadiazoline 1,1-dioxide, was also isolated. BuNH₂ and H₂N(CH₂)₂OH reacted with la to give α-bis-imines, while la with PhN₂H ₃ gave the α-bis-hydrazone. The configurations of benzil bis(ethanolimine) and benzilosazone were determined by single crystal x-ray diffraction analysis as Z,Z. BuNH₂ and PhN₂H₃ reduced 1b to the corresponding thiadiazoline compound 1bH₂. Copyright

Full text of DOI:10.1002/poc.1022

JOURNAL OF PHYSICAL ORGANIC CHEMISTRY
J. Phys. Org. Chem. 2006; 19: 229–237
Published online 21 April 2006 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/poc.1022
Reactions of the activated, rigid, a-diazomethine group
of 1,2,5-thiadiazole 1,1-dioxides with nitrogenated
nucleophiles. Part III: aliphatic monoamines and
phenylhydrazine
1
2
3
1,4
*
´
´
´
Jose Alberto Caram, Oscar Enrique Piro, Eduardo Ernesto Castellano, Marıa Virginia Mirıfico
and
Enrique Julio Vasini1
1Instituto de Investigaciones Fisicoquı´micas Teo´ ricas y Aplicadas (INIFTA), Facultad de Ciencias Exactas, Departamento de Quı´mica,
Universidad Nacional de La Plata, Casilla de Correo 16, Sucursal 4, 1900 La Plata, Argentina
2Departamento de Fı´sica, Facultad de Ciencias Exactas, Universidad Nacional de La Plata and IFLP (CONICET), C. C. 67, 1900 La Plata,
Argentina
3Instituto Fı´sica de Sa˜o Carlos, Universidade de Sa˜ o Paulo, C.P. 369, 13560 Sa˜ o Carlos (SP), Brazil
4Facultad de Ingenierı´a, Departamento de Ingenierı´a Quı´mica, Universidad Nacional de La Plata, Calle 47 y 1, 1900 La Plata, Argentina
Received 25 September 2005; revised 2 December 2005; accepted 23 December 2005
ABSTRACT: The reactions of n-butylamine (BuNH2), 2-aminoethanol (H2N(CH2)2OH), diethylamine (Et2NH), and
phenylhydrazine (PhN2H3) with 3,4-diphenyl-(1a) and phenanthro[9,10-c]-1,2,5-thiadiazole 1,1-dioxide (1b) were
1
studied by cyclic voltammetry (CV) and H- and 13C-NMR in aprotic solvent solution. The course of the reactions
depended on the substrate-nucleophile combination: Et2NH added to 1a or 1b, forming the corresponding thiadia-
zolines in an equilibrium monoaddition reaction. The equilibrium constants were evaluated and compared. With
—
primary amines and PhN H , the nucleophile added to both C N double bonds of 1a and displaced the sulfamide
—
2
3
moiety. In the case of the reaction of 1a with PhN2H3, the intermediate monoaddition thiadiazoline, 3-(2-
phenylhydrazino)-3,4-diphenyl-1,2,5-thiadiazoline 1,1-dioxide, was also isolated. BuNH2 and H2N(CH2)2OH reacted
with 1a to give a-bis-imines, while 1a with PhN2H3 gave the a-bis-hydrazone. The configurations of benzil
bis(ethanolimine) and benzilosazone were determined by single crystal x-ray diffraction analysis as Z,Z. BuNH2
and PhN2H3 reduced 1b to the corresponding thiadiazoline compound 1bH2. Copyright # 2006 John Wiley & Sons,
Ltd.
Supplementary electronic material for this paper is available in Wiley Interscience at http://www.interscience.
wiley.com/jpages/0894-3230/suppmat/
KEYWORDS: 1,2,5-thiadiazole 1,1-dioxide; nucleophilic addition; monoamines; benzilimines; benzilosazone
INTRODUCTION
bicyclic compounds (Fig. 1). The stability acquired by
cycle formation and the intramolecular character of the
second addition might justify the increased reactivity.6
We report here the reactions of aliphatic monoamines:
n-butylamine (BuNH2), diethylamine (Et2NH), and 2-
aminoethanol (H2N(CH2)2OH), and of phenylhydrazine
(PhN2H3) with 3,4-diphenyl-(1a) and phenanthro[9,10-
c]-1,2,5-thiadiazole 1,1-dioxide (1b) in aprotic solvent
solution. The reacting systems were followed using cyclic
voltammetry (CV) and 1H- and 13C-NMR. Our CV
method2,4 was used to evaluate the equilibrium constants
of the reactions of 1a and 1b with Et2NH.
The reactants and products discussed in this work (with
the exception of 1bH2, Fig. 8) are summarized in
Scheme 1.
In recent papers, we reported the addition reaction of
several nucleophiles (alcohols, thiols, aromatic mono-
amines, and monocarboxamides)1–5 to the C N double
—
—
bonds of 3,4-disubstituted 1,2,5-thiadiazole 1,1-dioxides.
Only equilibrium monoaddition reactions to give 1a. XH
compounds (Scheme 1) were observed. Coherently, these
nucleophiles do not react with 1,2,5-thiadiazoline 1,1-
dioxides.
However, bifunctional nitrogen nucleophiles such as
—
ureas and thioureas, add to both C N double bonds of
—
some 3,4-disubstituted 1,2,5-thiadiazole 1,1-dioxides yielding
EXPERIMENTAL
Compounds 1a, b were synthesized according to Wright.7
Standard methods8–10 were used for purification of
commercial solvents and nucleophiles. The solvents were
´
*Correspondence to: M. V. Mirıfico, INIFTA C.C. 16, Suc. 4, 1900 La
Plata Argentina.
E-mail: mirifi@inifta.unlp.edu.ar
Copyright # 2006 John Wiley & Sons, Ltd.
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230
J. A. CARAM ET AL.
Ph
Ph
Single crystals for x-ray data were obtained by slow
evaporation of the solvent from ethanol solutions of the
compounds.
N
N
R
R
Ph
N
Ph
N
Ph
N
Ph
X
NEt
2
2a: R = n-Bu
NH
N
N
N
NH
S
S
3a: R = -CH2CH2OH
4a: R = -NHPh
S
S
O
O
O
O
O
O
O
O
1a
N-[1,2-diphenyl-2-
(butylimino)ethylidene]butylamine
(benzil bis (n-butylimine) (2a)
1b
1a.XH
X = RO, RS,
ArNH, RC(O)NH,
ArC(O)NH, NEt2
1b.Et2NH
Scheme 1
One hundred twenty three milligrams (0.46 mmol) of 1a,
and 71 mg (0.97 mmol) of BuNH2 were dissolved in
anhydrous MeCN (6 ml) and kept tightly closed and
protected from light. Two months later the solvent was
removed by rotary evaporation at room temperature. The
residue was extracted three times with 1 ml of CH2Cl2.
The remaining white solid was filtered, dried (40 mg,
0.42 mmol) and identified as sulfamide through its IR
spectrum. Evaporation at reduced pressure and room
temperature of the CH2Cl2 solvent gave the product
(130 mg, 89%) as a colorless unstable liquid, which
turned gradually yellow.
R
Ar
1
H
N
X = O, S; Ri = H, alkyl
N
O
O
S
X
Ar = Ph, p-methoxyphenyl,
Ar,Ar =
N
H
N
Ar
R
2
Figure 1. Products of the addition of bifunctional nitrogen
nucleophiles to the indicated 1a derivatives
dried with molecular sieves and stored under a dry nitrogen
atmosphere in a glove box. Their water content (ca 50 ppm)
was measured by Karl–Fischer coulometric titration.
1H- and 13C-NMR spectra were measured with a
Brucker 200 MHz instrument and IR spectra with a
Shimadzu IR-435 spectrophotometer.
The CVexperiments were performed in a conventional
undivided gas-tight glass cell with dry nitrogen gas inlet
and outlet. The working electrode was a 3 mm diameter
vitreous carbon disk encapsulated in Teflon, the counter-
electrode was a 2 cm2 Pt foil and a Agþ (0.1 M, MeCN)/
Ag reference electrode (to which all potentials reported
are referred) was used. The supporting electrolyte was
0.1 M NaClO4. A LYP-M2 potentiostat, a 3-module LYP
sweep generator and a Houston Omnigraphic 2000 pen
recorder were used. The preparation of solutions, the CV
experiments and other manipulations were made in a
glove box under a dry nitrogen atmosphere.
1H-NMR (d, TMS) in MeCN-d3: 7.72–7.32 (2Ph, 16
—
signals, 10H), 3.32–3.26 ( N—CH —, multiplet, 4H),
—
1.69–1.58 ( N—CH —CH —, multiplet, 4H), 1.44–
2
—
—
2
2
—
1.29 ( N—CH —CH —CH —, multiplet, 4H), and
—
0.88–0.83 ( N—CH —CH —CH —CH , triplet, 6H).
2
2
2
—
—
2
2
2
3
13
—
—
C-NMR (d, TMS) (same solution): 165.5 (C N),
—
137.0–127.8 (2Ph, 4 signals), 54.7 ( N—CH —), 33.7
—
2
—
—
—
N—CH —CH —
—
(
N—CH —CH —),
2
21.4
(
2
2
2
—
—
CH —), and 14.2 ( N—CH —CH —CH —CH ).
2
2
2
2
3
IR (film; cmꢀ1): 3015 (CAr—H), 2990–2980 (CAliph—H),
—
1625 (C N), 1590 (Ar), 1575 (Ar), 1485, 1450, 1370,
—
1350, 1310, 1280, 1230, 1175, 1025, 925, 900, 770, and 695.
Anal. Calcd for C22H28N2: C, 82.45; H, 8.81; N, 8.74.
Found: C, 84.09; H, 8.69; N, 9.15, S, 0.00%.
Single crystal x-ray data of 3a were collected with
COLLECT11 program on a KappaCCD diffractometer,
using w and v scans. The data were reduced with DENZO
and SCALEPACK.12 A complete data set for 4a was
collected with EXPRESS13 on an Enraf-Nonius CAD-4
diffractometer, using the v-2W scan technique. The data
were reduced with XCAD4.14 A graphite monochromated
2-({(1Z,2Z)-2-[(2-hydroxyethyl)imino]-1,2-
diphenylethylidene}amino) ethanol (benzil
bis(ethanolimine)) (3a)
Two hundred twenty milligrams (0.82 mmol) of 1a and
187 mg (3.06 mmol) of H2N(CH2)2OH were dissolved in
anhydrous MeCN (1.7 ml). Twenty days after solution
preparation, the solvent was removed by rotary evapora-
tion at room temperature. The residue was extracted three
times with CH2Cl2 (total volume: 5 ml). A white solid
remained and was identified as sulfamide. The CH2Cl2
solution was dried with anhydrous Na2SO4, concentrated
by evaporation at reduced pressure, and cooled overnight.
The solid obtained was filtered, recrystallized from hot
CH2Cl2 and dried under vacuum at room temperature.
Yield: 172 mg, 0.58 mmol (71%).
˚
MoKa radiation (l ¼ 1.54184 A) was used in both cases.
The experimental ranges were 3.15–25.008 (3a), and
3.86–67.878 (4a).
The structures were solved by direct and Fourier
methods with SHELXS-9715 and the non-H atoms in the
final molecular model were refined anisotropically by full-
matrix least-squares on F2 employing SHELXL-97.16
All hydrogen atoms were found in a difference Fourier
map. However, they were positioned stereochemically
and refined with the riding model. The positions of the
HO-hydrogen atoms in 3a were optimized by allowing
them to rotate around the corresponding C—O bond. The
molecular plots of compounds 3a (Fig. 3) and 4a (Fig. 6)
were drawn with ORTEP.17
The Z,Z configuration of the compound was deter-
mined by x-ray diffraction analysis (Fig. 3).
1H-NMR (d, TMS) in DMSO-d6: 7.70–7.37 (2Ph, 9
—
signals, 10H), 5.76 (OH), 4.69–4.65 ( N—CH —,
—
2
Copyright # 2006 John Wiley & Sons, Ltd.
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ALIPHATIC MONOAMINES AND PHENYLHYDRAZINE
231
—
triplet, 4H), 3.72–3.00 ( N—CH —CH —OH, broad
1a.PhN2H3: In a separate synthesis, only the filtered
solid was worked-up: it was, washed with MeCN, H2O,
EtOH (50:50) and EtOH, and dried under vacuum at
60 8C. The solid was identified as the thiadiazoline
1a.PhN2H3, (i.e., a thiadiazoline as those represented in
Scheme 1 as 1a.XH, with X: PhN2H2), mp 130–131 8C
(dec). The identification was based on its IR, 1H- and 13C-
RMN spectra and CV behavior and the comparison of
these results with those of numerous thiadiazolines
derived from 1a synthesized in our laboratory4,5,18 or
reported in the literature.19 As it also happened with many
of those thiadiazolines, recrystallization attempts from
hot EtOH or MeCN produced only 1a, presumably
because the addition is an equilibrium reaction and 1a is
less soluble than the addition product 1a.PhN2H3.
1H-NMR (d, TMS) in DMSO-d6: 9.01 (O2S—NH, 1
signal), 8.07–6.34 (2Ph, 20 signals).
—
2
2
doublet, 4H).
13
C-NMR (d, TMS) (same solution): 165.0 (C N),
—
—
—
—
135.2–126.8 (2Ph, 4 signals), 61.1 ( N—CH —), 56.5
2
—
—
(
N—CH —CH —OH).
2 2
IR (KBr, cmꢀ1): 3250 (OH), 3010 (CAr—H), 2980
—
(CAliph—H), 1620 (C N), 1560 (Ar), 1495, 1450, 1400,
—
1260, 1220, 1205, 1170, 1050, 930, 850, 770, and 680.
Anal. Calcd for C18H20N2O2: C, 72.95; H, 6.80; N,
9.45; O: 10.80. Found: C, 73.26; H, 6.78; N, 9.97, S,
0.00%.
Crystal dimensions 0.14 ꢁ 0.28 ꢁ 0.34 mm, orthor-
˚
˚
hombic, Pbca, a ¼ 9.3075(1) A, b ¼ 11.1683(3) A,
3
˚
˚
c ¼ 30.5917(7) A, V ¼ 3180.0(1) A , Z ¼ 8, rcalc ¼
1.238 g ꢂ cmꢀ3, 21801 reflections measured, 2686 inde-
pendent [R(int) ¼ 0.0442], R1 ¼ 0.0666 [2145 reflections
with I > 2s(I)], wR2 ¼ 0.1842, 201 parameters, residual
electron density 0.291/ꢀ0.314 e.Aꢀ3. Crystallographic
13C-NMR (d, TMS) (same solution): 177.5 (C ¼ N),
˚
data for the structure of 3a were deposited with the
Cambridge Crystallographic Data Center as supplemen-
tary publication number CCDC: 290220.
145.4–114.6 (2Ph, 12 signals), 91.0 (PhCNH).
IR (KBr, cmꢀ1): 3250 (N—H), 3209 (N—H), 3066
—
(C —H), 1605 and 1590 (Ar), 1561 (C N), 1498,
Ar
—
1446, 1357, 1320 (>SO2), 1279, 1255, 1215, 1180
(>SO2), 1117, 1039, 973, 907, 871, 818, 760, and 690.
(1Z,2Z)-1,2-diphenylethane-1,2-dione
bis(phenylhydrazone) (benzilosazone) (4a)
and 3-(2-phenylhydrazino)-3,4-diphenyl-1,2,5-
thiadiazoline 1,1-dioxide (1a.PhN2H3)
Phenanthro [9,10-c]-1,2,5-thiadiazoline
1,1-dioxide (1bH2)
One hundred eighteen milligrams (0.44 mmol) 1b and
163 mg (1.51 mmol) PhN2H3 were dissolved in anhy-
drous MeCN (1.0 ml). A light yellow colored solid
precipitated after one day. The solid was filtered, washed
with toluene, and dried under vacuum at room
temperature. One hundred milligrams (86%) of the pure
product was obtained. It was identified by its IR spectrum,
mixed melting point and CV, as compared with an
authentic sample.201b was also reduced to 1bH2 (Fig. 8)
by BuNH2, as observed by CV. This reaction was not
further investigated.
4a: 140 mg (0.52 mmol) of 1a and 125 mg (1.16 mmol)
PhN2H3 were dissolved in anhydrous MeCN (1.0 ml). A
yellow colored solid precipitated immediately after
solution preparation. The filtered solid, combined with
that obtained by concentration at room temperature of the
mother liquors (1/10), was dried under vacuum at room
temperature and recrystallized from hot ethanol. One
hundred fifty milligrams (0.39 mmol; 74%) of the pure
(TLC) product mp: 234–236 8C were obtained. It was
identified as the 1Z,2Z isomer by x-ray diffraction.
Crystallographic data for the structure of 4a were
deposited with the Cambridge Crystallographic Data
Center as supplementary publication number CCDC
290219.
RESULTS AND DISCUSSION
1H-NMR (d, TMS) in DMSO-d6: 9.58 (PhNH-, 1
A summary of the reactions of 1a and 1b studied in this
work is given in Table 1.
signal, 2H), 7.62–6.77 (2Ph, 15 signals, 20H).
13
C-NMR (d, TMS) (same solution): 153.5 (C N),
—
—
144.9–113.3 (2Ph, 10 signals).
IR (KBr, cmꢀ1): 3306 (N—H), 3020 (CAr—H), 1598
—
(C N), 1577 (Ar), 1535, 1504 and 1488, 1452, 1305,
—
Reactions with primary aliphatic amines
1248, 1163 and 1142, 1066, 740 and 679.
Crystal dimensions 0.10 ꢁ 0.10 ꢁ 0.22 mm, tetragonal,
Reaction of 1a with BuNH2. Only one symmetric
isomer of the benzil bis(n-butylimine) 2a was obtained, as
indicated by the single 13C-NMR signal at 165.5 ppm
assigned to C ¼ N. No further studies to decide if the
product was the E,E or the Z,Z isomer were possible
because the substance was an unstable liquid (Experi-
mental). The E,E configuration is proposed as the most
stable for benzilosazones according to published
˚
˚
I41/a, a ¼ b ¼ 16.441(3) A, c ¼ 15.936(6) A, V ¼
3
4308(2) A , Z ¼ 8, rcalc ¼ 1.204 g ꢂ cmꢀ3, 2232 reflec-
˚
tions measured, 1929 independent [R(int) ¼ 0.0309],
R1 ¼ 0.0491 [1076 reflections with I > 2s(I)],
wR2 ¼ 0.1207, 14ꢀ83parameters, residual electron density
˚
0.151/ꢀ0.141 e.A
.
Copyright # 2006 John Wiley & Sons, Ltd.
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232
J. A. CARAM ET AL.
Ph Ph
Ph Ph
NHBu
NH
Table 1. Summary of studied reactions
1)
BuNH
N
O
N
O
+
N
O
2
Substrate Nucleophile
Products
S
S
O
1a
BuNH2
Benzil bis(n-butylimine)
(2a)
1a.BuNH2
1a
1b
1a
BuNH2
H2N(CH2)2OH Benzil bis(ethanolimine)
1b.H2
Ph
Ph
H2N NH2
S
BuNH2
(3a)
1a.Et2NH (equilibrium reaction)
.BuNH
+
1a
+
2)
2
O
O
1a
1b
1a
Et2NH
Et2NH
PhN2H3
BuHN
NHBu
1b.Et2NH (equilibrium reaction)
Benzilosazone (4a) (intermediate
product: 1a.PhN2H3)
2a
Scheme 2
1b
PhN2H3
1bH2
studies,21 while for monoimines the relative stability of
the E or Z configuration depends on the substituent
groups.22 As reported in the experimental part and
discussed below, a Z,Z configuration was found for benzil
bis(ethanolimine) (3a) and benzilosazone (4a).
Some insight on the reaction steps was obtained from
1
the 13C-, H-NMR spectra and CVs scanned during its
course. The 13C-NMR spectra of a solution of 1a and
BuNH2 in MeCN-d3, in a 1:1 molar ratio, showed, 2 h
after solution preparation, signals assigned to the sp2 and
the sp3 (178.0 and 90.9 ppm, respectively) heterocyclic C-
atoms of 1a.BuNH2 (Scheme 2). The resonances of the n-
butyl radical of 1a.BuNH2 (43.0, 32.2, 20.9, and
14.0 ppm) were also observed. One week later, the
signals at 178.0 and 90.9 ppm remained, but a new signal
at 165.5 ppm, which was assigned to the (equivalent) sp2
C-atoms of the benzil bis(n-butylimine) 2a was also
present. The n-butyl radical signals were observed at 54.6,
33.6, 21.2, and 14.0 ppm. Some signals corresponding to
1a.BuNH2 were still observable, but disappeared com-
pletely in the spectrum scanned 45 days after solution
preparation, which showed only the 2a signals.
Figure 2. Time evolution of the CVs of the 1a/BuNH2 sys-
tem. Scan rate: 0.2 VsS1. 1a: 7.00 mM; BuNH2: 33.0 mM.
Scanned solutions were prepared by dilution (with 0.1 M
NaClO4, DMF) of a stock 1a-BuNH2-DMF solution, as detailed
in the text. CV of 1a (7.30 mM in DMF, dotted line) is
included for reference. (—): CV scanned immediately after
stock solution preparation (t ¼ 0), (- - - ): t ¼ 8 days, (- ꢂ -):
t ¼ 34 days, (- ꢂ ꢂ -): CV of a 7.95 mM 2a solution in 0.1 M
NaClO4, DMF
1H-NMR spectra of the same solution were scanned
2 h, 1 week, and 45 days after solution preparation. When
compared with the 1H-NMR spectra of BuNH2 and 2a in
the same solvent, it was observed that the methyl protons
of the n-butyl radical remained approximately at the same
position (d ca 0.85 ppm), while the complex signal of the
CH3CH2CH2— protons of the BuNH2 (1.37–1.30 ppm)
splitted into two downfield shifted groups (1.69–
1.58 ppm, 10 signals and 1.44–1.29 ppm, 9 signals) in
the 45 days spectrum. A new signal at ca 3.3 ppm,
dissolved immediately and completely, however, as it
happened in the NMR experiments, a white precipitate,
identified as 1a, was observed after a couple of hours. It
was concluded from these observations that reaction 1
(Scheme 2) was a rapid equilibrium reaction, with a
relatively high equilibrium constant. Thus, the fresh
solution of 1a and BuNH2 in 1:1 molar ratio should
contain almost exclusively the thiadiazoline 1a.BuNH2.
The remaining BuNH2, in a low equilibrium concentra-
tion, would slowly react with 1a.BuNH2 forming 2a (Eqn
(2), scheme 2). Since the global reaction is
—
—
assigned to the
NCH of 2a, appeared in the 1-week
2
spectrum. The 45 days spectrum presented all signals of
2a (Experimental) along with other signals probably
arising from remaining 1a.BuNH2 and sulfamide.
The initially clear and homogeneous solution in the
NMR tubes presented, at the end of these experiments, a
white solid precipitate, which was identified as 1a.
To study further this re-precipitation phenomenon, a
very concentrated 1:1 molar ratio solution was prepared:
BuNH2 (0.46 mmol) was added to a suspension of 1a
(0.46 mmol) in 1 ml of anhydrous MeCN (1a is only
slightly soluble in MeCN). Upon amine addition, 1a
1a þ 2 BuNH2 ! 2a þ SO2ðNH2Þ2;
1a is in excess at a molar ratio [1a]/[BuNH2] ¼ 1, and,
owing to its low solubility, should precipitate. The
reprecipitation of 1a was not observed in similar tests
with higher amine concentrations ([1a]/[BuNH2] molar
ratios less than 0.5). The reaction was also followed by
CV (Fig. 2). A stock solution of 1a (0.74 mmol) and
BuNH2 (3.79 mmol) in MeCN (1.9 ml) was prepared. At
Copyright # 2006 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2006; 19: 229–237

ALIPHATIC MONOAMINES AND PHENYLHYDRAZINE
233
selected times, 20–30 ml of the stock solution were
diluted with 1–2 ml of DMF (containing 0.1 M NaClO4 as
supporting electrolyte), and a CV was scanned immedi-
ately thereafter.
A CV was registered as soon as the stock solution was
prepared. The characteristic CV couples of 1a were not
present. Three cathodic peaks (ꢀ1.83, ꢀ2.40 (shoulder),
and ꢀ2.56 V); were observed instead. The peak at
ꢀ2.56 V corresponds to 2a, as concluded by comparison
with the CV of an authentic sample of the compound.
Peaks at ꢀ1.83 and ꢀ2.40 Vare similar to those found for
1,2,5-thiadiazoline 1,1-dioxides,4–6 and were assigned to
1a.BuNH2 (Eqn (1), Scheme 2).
Only the peak at ꢀ2.56 V was observed in the CV
registered at a reaction time t ¼ 8 days. CVs registered at
intermediate times (not shown) revealed a continuous
decrease in the current intensity of the thiadiazoline peaks
and an increase of the peak at ꢀ2.56 V.
It was also observed that the current intensity of the
ꢀ2.56 V signal continued to increase even after the
disappearance of the thiadiazoline peaks (see 34 days CV,
Fig. 2), reaching a level that remained constant in time.
This behavior suggested the presence of a nonelectror-
educible intermediate that decomposed to give 2a. A 3,4-
n-butylamino disubstituted thiadiazolidine might be this
intermediate, as we have observed that thiadiazolidine
compounds do not present voltammetric electroreduction
signals in the experimental potential range used.6 If this
were the case, 2a would be formed by the separation of a
sulfamide molecule from the intermediate, as indicated in
Eqn (3).
Figure 3. Molecular diagram of 3a showing the labeling of
the non-H atoms and their displacement ellipsoids at the
30% probability level
The 13C-NMR spectrum of 3a showed only four signals
for both phenyl rings, one signal for both sp2 C-atoms and
two signals for the sp3 C-atoms, thus confirming the
presence of only one symmetric isomer in solution.
The time evolution of the CVs of the reacting system,
followed using the same procedure detailed above for the
reaction of 1a with BuNH2, is shown in Fig. 4.
Ph
Ph
An initial CV did not show the 1a couples. Three
cathodic peaks (ꢀ1.87, ꢀ2.38 (shoulder), and ꢀ2.50 V)
were observed instead. Their current intensities changed
with time and after 60 days only the peak at ꢀ2.38 V
remained. The peaks at ꢀ1.87 and ꢀ2.50 V were assigned
to the thiadiazoline 1a.H2N(CH2)2OH. The peak at
ꢀ2.38 V corresponded to 3a by comparison with the CV
of an authentic sample of the compound (Experimental).
Unlike the case of the 1a/BuNH2 system, the voltammetric
peak of 3a reached its highest current intensity simulta-
neously with the disappearance of the peaks of the
thiadiazoline intermediate 1a.H2N(CH2)2OH. Therefore, if
the reactions paths were similar, the decomposition of the
intermediate (reaction 3) must be faster. Apparently
neighboring group (HO) participation must be operating.
RHN
NHR
H2N NH2
S
2a
3)
HN
O
NH
O
+
O
O
S
Reaction of 1b with BuNH2. Compound 1b was
reduced to 1bH2 by BuNH2 as well as by PhN2H3 (see
below ‘reactions of 1b with PhN2H3,’), but a separate
synthesis of 1bH2 from 1b and BuNH2 was not attempted.
The reduction product was only identified in the final CV
of the reaction mixture, which was coincident with that
found for the 1b/PhN2H3 system and with the CV of a
sample of 1bH2.20
Reaction of 1a with H2N(CH2)2OH. Stereoselec-
tive synthesis of 2-({(1Z,2Z)-2-[(2-hydroxyethyl)i-
mino]-1,2-diphenylethylidene} amino) ethanol
(benzil bis(ethanolimine)) (3a). The reaction of 1a
with H2N(CH2)2OH in MeCN solution gave a white solid
identified as the 1Z,2Z isomer of 3a. Figure 3 shows a
molecular diagram of this isomer as determined by single
crystal x-ray diffraction.
Reactions with secondary aliphatic amines:
equilibrium systems
Reactions of 1a and 1b with Et2NH. These reactions
were studied using CV. A typical experiment consisted in
the addition of Et2NH (to obtain an initial concentration
in the 0.1–2.7 M concentration range) to a solution of 1a
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234
J. A. CARAM ET AL.
Figure 4. Time evolution of the CVs of the 1a/
H2N(CH2)2OH system. Scan rate: 0.2 VsS1, 1a: 7.16 mM;
H2N(CH2)2OH: 0.143 M. Solutions prepared by dilution of
a stock, as indicated in the text. (—): CV scanned immedi-
ately after stock solution preparation (t ¼ 0), (- - - ): t ¼ 10
days, (- ꢂ -): t ¼ 60 days, (ꢂ ꢂ ꢂ ): CV of a 6.12 mM 3a solution in
0.1 M NaClO4, DMF
Figure 5. CVs of the 1a/Et2NH system. Scan rate: 0.2 VsS1
.
(- - - ): CV of a 7.30 mM solution of 1a; (—) equilibrium CV of
the same solution after addition of Et2NH to a 0.29 M final
concentration. DMF solvent, supporting electrolyte: 0.1 M
NaClO4
equilibrium CV, equal quantities of 1a and of the addition
thiadiazoline 1a.Et2NH are consumed at peak Ic by the
reactions:
or 1b (ca 6 mM) in DMF solvent, with 0.1 M NaClO4 as
supporting electrolyte. CVs of the solutions were
registered initially and at convenient times during the
course of the reactions.
The rate of change of the CV signals increased with the
increase in the concentration of added Et2NH, and a final
equilibrium CV was obtained in all cases. The changes, as
below described and shown in Fig. 5 for 1a/Et2NH
system, followed a well-known sequence, already
reported by us when the mono-addition of alcohols3,4
or amides5,6 were studied. Therefore, we concluded that
the reactions corresponded to the mono-addition of
Et2NH to 1a or 1b (reaction 4).
E1
C1 1a:ꢀ þ 1a:Et2NH , 1aH: þ 1a:Et2NHꢀ
1a þ eꢀ , 1a:ꢀ
E2
1aH: þ eꢀ , 1aHꢀ
Thus, peak IIc, associated with the electroreduction of
1a.ꢀ to 1a2ꢀ, is no longer present (under the experimental
conditions chosen, see below) because 1a.ꢀ is completely
consumed by reaction C1. Cathodic peak IIIc is
associated with the electroreduction of the addition
thiadiazoline that has not been consumed at peak Ic by
reaction C1:
E3 1a:Et2NH þ eꢀ , 1a:Et2NH:ꢀ
C2 1a:Et2NH:ꢀ , 1a:H:þEt2NH:ꢀ
Ar
Ar
Ar
Ar
NEt
followed immediately by the electroreduction of 1aH. to
1aHꢀ (E2). The anions 1aHꢀ and 1a.Et2NHꢀ are further
reduced at peak IVc.
2
4)
Et NH
N
O
N
O
+
N
O
NH
2
S
S
In the presence of a sufficient excess of the nucleophile
(i.e., [Et2NH]equilibrium ꢃ [Et2NH]0), and if peak IIc is
absent from the equilibrium CV (i.e., peak Ic corresponds
to the E1C1E2 mechanism above), a function of the
current intensity of peaks Ic and IIIc in the equilibrium
CV and the voltage sweep rate (n), (Eqn (5)),2,4 can be
used to estimate the equilibrium constant of the addition
reaction.
O
The CV changes observed were the following: the
current intensity of both cathodic peaks of the thiadiazole
(Ic and IIc) decreased simultaneously. Peak IIc dis-
appeared from the final equilibrium CV for all experi-
mental Et2NH nucleophile concentrations used, but the
current intensity of peak Ic decreased and reached a final
equilibrium intensity that was inversely proportional to
the nucleophile concentration. Two cathodic peaks (IIIc
and IVc) at more negative potentials appeared and
increased in current successively: peak IVc, when peak
IIc started to decrease, and peak IIIc, after the
disappearance of peak IIc.
n
o
iðIcÞ
2 ꢁ iðIIIcÞ þ
n1=2
2ꢁn1=2
K ꢁ ½Nuꢄ0 ¼
(5)
iðIcÞ
n1=2
where [Nu]0 is the initial Et2NH concentration, and K is
the equilibrium constant of reaction 4.
The linear dependence of the peak current intensity of
As already discussed,2,4 these changes are coherent
with the following mechanism, illustrated for 1a: in the
Ic and IIIc with n , a requisite for the validity of Eqn (5),
was verified for these systems in the range of experi-
½
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ALIPHATIC MONOAMINES AND PHENYLHYDRAZINE
235
Figure 6. Different views of the ORTEP diagram of 4a. The view on the left shows that one half of the molecule is symmetry
related the other half through a crystallographic two-fold axis
mental sweep rates (0.05–0.30 Vsꢀ1). The estimated
equilibrium constants were 23 ꢅ 2 and 3.6 ꢅ 0.5 Mꢀ1 for
the formation of 1a.Et2NH and 1b.Et2NH, respectively.
The relatively smaller equilibrium constant for
1b.Et2NH might be related to the molecular geometry
Reaction with PhN2H3
Reaction of 1a with PhN2H3. 1a reacted with PhN2H3
in MeCN solution yielding 4a (Experimental).
13
Only one C-NMR signal assigned to C N (at
—
—
of the parent thiadiazole.23 In 1b, the —N C—C
153.5 ppm) was observed. This indicated that a symme-
trical isomer was obtained. Single crystal x-ray diffrac-
tion showed the Z,Z isomer. Figure 6 shows its highly
symmetric structure, with the phenyl rings arranged in a
tetrahedral geometry.
—
—
—
N— group is in the plane of the aromatic system and the
—
—
—
C
N double bonds participate of the delocalized
electronic system. Thus, the formation of the 1b.Et2NH
—
—
thiadiazoline not only involves the opening of the C
N
double bond, but also decreases the extent of this
resonance system. This does not happen in the case of
1a, for their phenyl rings are out (by ca 428) of the
The reaction was followed by the changes in the CVs of
the reacting solution. A stock solution of 1a and PhN2H3
(1a: 0.59 mmol; 0.293 M; PhN2H3: 1.42 mmol; 0.713 M;
DMF: 2.0 ml, supporting electrolyte: 0.1 M NaClO4) was
prepared. At selected times, 50 ml of the stock solution
were diluted with 1.6 ml of DMF (containing 0.1 M
NaClO4 as supporting electrolyte), and a CV scan was
registered immediately thereafter.
heterocyclic plane and only weakly conjugated with the
24
—
—
C
N bonds.
The resulting CVs are shown in Fig. 7. The changes
with time were similar to those observed in the 1a-
BuNH2-MeCN system described above: the initial CV,
scanned immediately after PhN2H3 addition, did not
show 1a peaks Ic and IIc, but two irreversible signals
(IIIc: ꢀ1.90 V, IVc: ꢀ2.45 V), assigned to the thiadia-
zoline 1a.XH (Scheme 1 with X ¼ PhN2H2) initially
formed by the fast nucleophilic monoaddition of
PhN2H3 to 1a. As the reaction proceeded, the
thiadiazoline voltammetric signals decreased gradually
and after 390 min an almost featureless (only a very low
intensity peak is observed at ꢀ2.45 V) CV was
registered. Finally, peaks at ꢀ2.40 and ꢀ2.90 V
appeared and increased with time. The CV remained
unchanged thereafter. The final CV corresponds with
that of an authentic benzilosazone sample. The reaction
mechanism, judging by the similarity of the CV
responses, might be that proposed above for the
reaction of 1a with BuNH2.
Figure 7. Time evolution of the CVs of the 1a/PhN2H3
system. Scan rate: 0.2 VsS1
1a: 7.83 mM; PhN2H3:
.
19.0 mM. Scanned solutions were prepared by dilution (with
0.1 M NaClO4, DMF) of a stock 1a-PhN2H3-DMF solution, as
detailed in the text. (—): CV scanned immediately after stock
solution preparation (t ¼ 0), (- - - ): t ¼ 48 h, (- ꢂ -): t ¼ 364 h,
(ꢂ ꢂ ꢂ): CV of a 7.51 mM 4a solution in 0.1 M NaClO4, DMF
Copyright # 2006 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2006; 19: 229–237

236
J. A. CARAM ET AL.
line was actually isolated. A rationale for the practical
lack of diaddition of alcohol nucleophiles has been
given,4 based on the structure of 1a24 and its thiadiazoline
derivatives.25 However, the stronger nitrogen nucleo-
—
philes can react further, attacking the remaining >C N-
—
double bond of the substrate to yield thiadiazolidines.
The displacement of a sulfamide molecule gave the
final reaction product. In the case of the H2N(CH2)2OH
nucleophile the departure of the leaving group was easier
than for BuNH2 or PhN2H3. This suggests an influence of
the HO neighboring group in the reaction parameters.
The products obtained from the systems 1a/
H2N(CH2)2OH and 1a/PhN2H3 (3a and 4a, respectively)
were the Z,Z isomers. 4a presented a remarkably
symmetric crystalline structure with the phenyl rings
arranged in a tetrahedral geometry.
Figure 8. 1bH2:phenanthro[9-10-c]-1,2,5-thiadiazoline1,
1-dioxide
The CV detected intermediate thiadiazoline
1a.PhN2H3 (1a.XH; Scheme 1 with X ¼ PhN2H2) was
isolated in a synthetic assay performed in similar
conditions (Experimental).
The differences in the reaction path and products were
rationalized considering the electronic delocalization
possibilities of both compounds. This structural differ-
ence also explained the considerable smaller equilibrium
constant for the monoaddition of Et2NH to 1b as
compared with the same addition to 1a.
Reaction of 1b with PhN2H3. 1b reacted with PhN2H3
yielding the reduction product 1bH2, which was identified
by its IR spectrum, mixed melting point and CV, as
compared with an authentic sample.201bH2 was also
obtained in the reaction of 1b with BuNH2, as above
mentioned.
The differences between the reactions of 1a and 1b
with these nucleophiles can be related to the structure of
the substrates. The thiadiazole heterocycle in 1b is
substituted at the 3,4 positions by a connected p-system
Supplementary information
which is in the same plane of the heterocycle.23 This
—
A blank CV of the 0.1 M NaClO4 supporting electrolyte
solution in DMF and a series of 13C-NMR spectra for the
1a–n-BuNH2 system, including the synthesized 2a
product, and the spectra scanned after the following
reaction times: 2 h, 1 week, and 45 days, as described in
‘Results and Discussion.’
allows the inclusion of the two C N double bonds in an
—
extended delocalized p-system. Also, as we have
observed,6 thiadiazoline 1bH2 differs from the typical
1,2,5-thiadiazole structure, since both carbon–nitrogen
bonds are single. In the formation of the thiadiazoline
1bH2, resonance stability is preserved by replacing the
original delocalized system of 1b by a phenanthrene
group (Fig. 8).
Acknowledgements
On the contrary, in 1a the plane of each phenyl ring is
rotated out of the heterocyclic plane by ca 428 and their
—
This work was financially supported by the Consejo
´
resonance coupling with the C N bonds is weak.24 In a
—
´
Nacional de Investigaciones Cientıficas y Tecnicas
´
´
(CONICET), the Comision de Investigaciones Cientıficas
de la Provincia de Buenos Aires (CIC Pcia. Bs.As.) and
the Universidad Nacional de La Plata (UNLP), Facultad
hypothetical 1aH2, with the same structure of 1bH2, the
—
—
C
C double bond would only worsen the steric
repulsion between the phenyl rings by bringing them
closer together without providing additional delocaliza-
tion energy.
´
de Ciencias Exactas, Departamento de Quımica and
´
´
´
Facultad de Ingenierıa, Departamento de Ingenierıa Quı-
mica. M. V. M, J. A. C. and O. E. P. are researchers of
CONICET and UNLP, E. J. V. is researcher of CIC Pcia.
Bs. As. and UNLP.
CONCLUSIONS
Primary aliphatic monoamines and phenylhydrazine
reacted almost instantaneously with 1a, to form the
corresponding thiadiazolines, which were unstable in the
reaction media. The reactions involved the initial, very
fast, nucleophilic attack of the N atom of the nucleophile
to only one of the identical electron-deficient heterocyclic
carbon atom of the substrate. This initial thiadiazoline
formation was observed by CV and NMR experiments,
and, in the case of the 1a/PhN2H3 system, the thiadiazo-
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