One-step ring condensation of hydrazine derivatives and cyclic anhydrides

Article abstract of DOI:10.1016/j.molstruc.2014.12.050

Hydroxypyridazinone and pyrroledione rings condensation in the reactions of hydrazine hydrate with citraconic, 2,3-dimethylmaleic, succinic and cis-cyclohexanedicarboxylic anhydrides have been conducted in the HCl aqueous solution. The pyridazine-ring condensation yields products unexpected for these conditions. They have been identified by ¹H/¹³C NMR and X-ray diffraction. The course of the reaction toward the five- and six-membered ring condensation strongly depends on methyl and other substituents in the anhydrides and in hydrazine. The obtained products indicate that the ring condensation is controlled by the molecular strains and steric hindrances between the substituents in anhydrides and pyridazinone products. The condensation of cyclic anhydrides with hydrazines has been reduced to one-step reaction and its yield significantly increased.

Full text of DOI:10.1016/j.molstruc.2014.12.050

Journal of Molecular Structure 1085 (2015) 28–36
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
One-step ring condensation of hydrazine derivatives
and cyclic anhydrides
b
Anna Katrusiak a, , Andrzej Katrusiak
⇑
a Department of Organic Chemistry, Poznan University of Medical Sciences, 60-780 Poznan´, Poland
b Department of Materials Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89b, 61-614 Poznan´, Poland
h i g h l i g h t s
g r a p h i c a l a b s t r a c t
ꢀ
ꢀ
ꢀ
ꢀ
Ring-condensation.
Pyridazinone.
Over-accommodation effects.
Molecular and crystal structure.
a r t i c l e i n f o
a b s t r a c t
Article history:
Hydroxypyridazinone and pyrroledione rings condensation in the reactions of hydrazine hydrate with
citraconic, 2,3-dimethylmaleic, succinic and cis-cyclohexanedicarboxylic anhydrides have been con-
ducted in the HCl aqueous solution. The pyridazine-ring condensation yields products unexpected for
these conditions. They have been identified by 1H/13C NMR and X-ray diffraction. The course of the reac-
tion toward the five- and six-membered ring condensation strongly depends on methyl and other substit-
uents in the anhydrides and in hydrazine. The obtained products indicate that the ring condensation is
controlled by the molecular strains and steric hindrances between the substituents in anhydrides and
pyridazinone products. The condensation of cyclic anhydrides with hydrazines has been reduced to
one-step reaction and its yield significantly increased.
Received 24 September 2014
Received in revised form 28 November 2014
Accepted 15 December 2014
Available online 23 December 2014
Keywords:
Ring-condensation
Pyridazinone
Over-accommodation effects
Molecular and crystal structure
Ó 2014 Elsevier B.V. All rights reserved.
Introduction
feature of hydroxypyridazinone has been used as a growth inhibitor
in agriculture [6].
Pyridazine derivatives exhibit numerous biological activities
desired for pharmaceutical applications. The pyridazine ring is a
fragment of many biologically active compounds of broad activity,
for example analgesic, anti-inflammatory, anticonvulsant, antitu-
mor, antiviral, antibacterial, antifungal [1–5]. Likewise, the growing
interest in hydroxypyridazinone originates from its biological prop-
erties. This molecule can act either as purine or pyrimidine analog,
forming base pairs with uracil and thymine, or with adenine. This
Pyridazine can by synthesized in the reactions of hydrazine
with cyclic anhydrides. These reactions were described in the liter-
ature several decades ago, however they afford only low yields of
pyridazine products [7–13]. Therefore we have undertaken this
systematic study aimed at understanding the mechanism of pyrid-
azine ring condensation and at optimizing the conditions for this
reaction. In particular, the effect of substituents has been investi-
gated in the reactions of citraconic, 2,3-dimethylmaleic, succinic
and cis-cyclohexanedicarboxylic anhydrides with hydrazine
hydrate and its methyl and phenyl derivatives. Three products
are obtained in the condensation facilitated to one-step reaction
⇑
Corresponding author.
E-mail address: akatrus@ump.edu.pl (A. Katrusiak).
http://dx.doi.org/10.1016/j.molstruc.2014.12.050
0022-2860/Ó 2014 Elsevier B.V. All rights reserved.

A. Katrusiak, A. Katrusiak / Journal of Molecular Structure 1085 (2015) 28–36
29
Fig. 1. The molecular structure of compound 2a, as present in the crystal structure.
The thermal ellipsoids are drawn at the 50% probability level. The methyl H-atoms
were refined each in two disordered sites. Torsion angle C2-N1-N10-C20 is 89.7(2)°
and C5-N1-N1’-C50 70.1(3)°.
(a)
illustrated in Scheme 1, their yield depending on the substituents
in substrates.
Results and discussion
The reaction of citraconic anhydride (1) with hydrazine dihy-
drochloride in aqueous solution was first described in 1954 by
Mizzoni and Spoerri [8a]. The obtained product was identified as
4-methyl-3,6-pyridazinediol. In 1966 Hedaya et al. confirmed that
citraconic hydrazide is the only product of this reaction conducted
in glacial acetic acid [9]. Instead of conducting the reaction of
hydrazine dihydrochloride in glacial acetic acid we used hydrazine
hydrate in 10% HCl. This reaction produced a mixture of 6-
hydroxy-5-methylpyridazin-3-one (2), as the main product, and
3,30-dimethyl-1,10-bipyrrole-2,20,5,50-tetraone (2a), as a byproduct
(Fig. 1). Compound 2 was obtained as precipitate, and compound
2a was found in the filtrate. In the 1H NMR spectrum of compound
2 two broad peaks originating from ‘acidic’ protons at nitrogen or
oxygen appear at 10.82 ppm and 11.79 ppm. The 1H NMR spec-
trum of compound 2a contains the signal of two methyl groups
at 2.18 ppm, and the signal of the hydrogen atoms at pyrrole
carbon atoms at 6.55 ppm. The low magnitude of the coupling
constant (J = 1.4 Hz) testifies to a long-range coupling between
the C-methyl group and hydrogen atom at C-4(40).
6-Hydroxy-2,5-dimethylpyridazin-3-one (3) was the only prod-
uct of the reaction of 1 with methyl hydrazine in 10% HCl. In the 1H
NMR spectrum of 3 a broad signal of the acidic proton is present in
the region of high values of the chemical shifts at 11.22 ppm.
By treating 1 with phenylhydrazine in 10% HCl, two products in
the comparable yields were obtained: 6-hydroxy-5-methyl-2-
phenylpyridazin-3-one (4) and 3-methyl-1-(phenylamino)-1H-
pyrrole-2,5-dione (4a, Fig. 2) have been isolated by column
chromatography. Compound 4a was obtained as the major product
when 1 reacted with phenylhydrazine in acetic acid [10,11]. In the
1H NMR spectrum of compound 4 the broad signal of the acidic
proton appears at about 11.47 ppm. The 1H NMR signal of imino
proton (NH) of compound 4a appears at 8.70 ppm as a sharp peak
(Scheme 2).
(b)
Fig. 2. Molecule 4a (a); and the NHꢁ ꢁ ꢁO hydrogen-bonded cyclic tetramer (b), as
present in the crystal structure. The thermal ellipsoids are drawn at the 50%
probability level. The methyl H-atoms were refined each in two disordered sites.
In the reaction of 2,3-dimethylmaleic anhydride (5) with hydra-
zine hydrate in 10% HCl 6-hydroxy-4,5-dimethylpyridazin-3-one
(6) and 3,30,4,40-tetramethyl-1,10-bipyrrole-2,20,5,50-tetraone (6a,
Fig. 3) precipitated. Compounds 6 and 6a have been isolated by col-
umn chromatography. Derivative 6a was found also in the filtrate.
It was obtained as the only product when 5 reacted with hydrazine
hydrate in acetic acid [9]. In the 1H NMR spectrum of compound 6
the signal of two methyl groups was found at 3.36 ppm and the
broad signals of hydrogen atoms appear at 10.83 ppm and
11.73 ppm. The 1H NMR spectrum of compound 6a consists of
one signal at 2.05 ppm of four equivalent methyl groups
(Scheme 2).
Only one product, 6-hydroxy-2,4,5-trimethylpyridazin-3-one
(7, Fig. 4) was formed when 5 was treated with methylhydrazine.
In the 1H NMR spectrum a broad signal at about 10.98 ppm was
O
OH
O
O
O
H2NNHR
N
N
O
NH
R
N
N
N
+
+
R
O
O
O
O
O
4a,8a,12,14a,15a,16
1,5,9,13
2a,6a,10,14
2,3,4,6,7,8,15
R = H, CH3, C6H5
Scheme 1. Substrates and main products of the cyclization reaction between hydrazine and cyclic anhydride derivatives.

30
A. Katrusiak, A. Katrusiak / Journal of Molecular Structure 1085 (2015) 28–36
OH
O
O
R1
R2
R1
R2
R1
R2
N
N
N
+
NH
O
O
O
2a, 6a
2, 6
H NNH
2
2
OH
O
R1
R2
R1
R2
;
R1=CH3, R2=H
R1=R2=CH3
1, 2, 2a, 3, 4, 4a
N
N
H NNHCH
2
3
;
5, 6, 6a, 7, 8, 8a
O
CH3
1, 5
O
O
3, 7
H NNHC H
6 5
OH
2
O
R1
R1
R2
N
N
+
N
NH
R2
O
4a, 8a
O
4, 8
Scheme 2. Products of substrates 1 and 5 reacting with different hydrazine derivatives.
products of the reaction between N-aminosuccinimide and 9 in
acetic acid [13].
Likewise, the reactions of methyl- and phenylhydrazine with
compound 9 in 10% HCl do not proceed toward the pyridazine ring
condensation. In both cases acidum succinicum (11) was obtained.
In the reaction of compound 9 with phenylhydrazine also 1-(phe-
nylamino)pyrrolidine-2,5-dione (12, Fig. 7) was synthesized
(Scheme 2). It was also synthesized by Kornet in 1984 in acetic acid
[14].
cis-Cyclohexane-1,2-dicarboxylic anhydride (13) with hydra-
zine hydrate, methylhydrazine or phenylhydrazine in ethanol gave
cis-N-aminocyclohexane-1,2-dicarboxyimide derivatives 14a, 15a
and 16, respectively. In addition to 14a, also bicyclohexanepyrroli-
dinetetraone (14, Fig. 8) was isolated. Similarly, cis-N-methylcyclo-
hexane[d]pyridazinedione (15) was obtained besides 15a
(Scheme 4). Previously, compound 14a was synthesized as a
hydrolysis product of tert-butyl (2,5-dioxopyrrolidin-1-yl)carba-
mate [15]. The mixture of products 15 and 15a can be also
obtained by treating 13 without solvent by methylhydrazine at
Fig. 3. The molecular structure of compound 6a, as present in the crystal structure
at 90 K. Thermal ellipsoids are drawn at the 50% probability level. Torsion angle C2-
N1-N10-C20 is 93.3(2)° and C5-N1-N10-C50 61.2(3)° at 90 K, and 89.9(3) and 72.7(3)°
at 295 K, respectively.
´
room temperature [16]. In 2008, Kaminski et al. used phenylhydr-
observed (Scheme 1). Compound 5 treated with phenylhydrazine
azine for synthesizing compound 16 (Fig. 9) in aqueous solution in
the oil bath [17].
gives
a mixture consisting of two products, 6-hydroxy-4,5-
dimethyl-2-phenylpyridazin-3-one (8, Fig. 5) and 3,4-dimethyl-1-
(phenylamino)-1H-pyrrole-2,5-dione (8a, Fig. 6). They have been
isolated by column chromatography. In the 1H NMR spectrum of
compound 8 a broad signal appears at 11.24 ppm, while in the
spectrum of 8a the signal of ‘imino’ proton (NH) is present at
8.29 ppm as a sharp peak (Scheme 1). When 5 was condensed with
phenylhydrazine in glacial acetic acid, it afforded 8a mainly, apart
from a minor amount of byproduct 8 [11]. Although succinic anhy-
dride (9) is a five-membered anhydride too, its reactions with
hydrazine derivatives have not resulted in six-membered ring con-
densation. The treatment of compound 9 with hydrazine hydrate
in 10% HCl yielded a mixture of two products isolated by column
chromatography and identified as 1,10-bipyrrolidine-2,205,50-tetra-
one, 10, and 4,40-hydrazinebis(4-oxobutanoic acid), 10a. The 1H
NMR spectrum of 10 consists of only one signal at about
1.55 ppm (Scheme 3). Treatment of 9 with hydrazine hydrate in
ethanol 10a was obtained as the only product [12]. Previously,
compound 10 was described by Hedaya et al. in 1967 as one of
Among the products of all above reactions, a group of com-
pounds existing as lactam or lactim tautomers can be distin-
guished. These are compounds 2, 3, 4, 6, 7, 8 and 15. We noticed
that in the 1H NMR spectra of these compounds there is a charac-
teristic broad signal of the acidic proton at about 11 ppm. Com-
pounds 4a, 8a, 12, 14a, 15a and 16 cannot undergo tautomeric
transformations and in their 1H NMR spectra the peak of imino
proton at about 8.00 ppm is sharp. The occurrence of broad 1H
NMR signal at about 11 ppm is a convenient indicator of lactam–
lactim tautomers confirming that pyridazine derivatives have been
obtained. A sharp peak at about 8.0 ppm indicates the presence of
N-aminoimide.
Our study shows clearly that methyl groups in the anhydride
influence the direction of the reaction and the obtained products.
Maleic anhydride in the reaction with hydrazine hydrate gave
the pyridazinedione as the only product [18]. One methyl group
in anhydride promoted the formation of dimethylbipyrroletetra-
one as the reaction byproduct. Two methyl groups at anhydride

A. Katrusiak, A. Katrusiak / Journal of Molecular Structure 1085 (2015) 28–36
31
(a)
(b)
Fig. 5. (a) One molecule of 3-hydroxy-4,5-dimethyl-1-phenyl-6-pyridazinone (8);
and (b) chain interval of four AOHꢁ ꢁ ꢁO@ hydrogen-bonded symmetry-independent
molecules, as present in the crystal structure (cf. Scheme 2).
Fig. 4. Hydrate 7ꢁH2O (a), as present in the crystal structure, and (b) the
centrosymmetric hydrogen-bonded dimers, additionally H-bonded to chains of
water molecules linking the molecules into sheets along planes (ꢂ102).
(a)
changed the reaction direction and N-aminoimides became the
main products. The treatment of five membered anhydrides (1,
5) with methylhydrazine leads to pyridazine derivatives only. In
turn, the use of phenylhydrazine contributes to the mixture of
pyridazinone derivative as the main product and phenylaminopyr-
roledione as the byproduct.
The formation of different products of the reactions can be
explained by their stability. The heats of formation (HoF) of the
reactions products, calculated by the MNDO [19] method, are com-
pared in Table 1. It can be observed that the main products have
the largest heat of formation and hence are most stabile of all prod-
ucts obtained.
These calculations indicate that the number of methyl groups in
anhydrides correlate with the energetic stability of products,
which also includes the interference of the ring substituents in
the course of the reaction. In order to understand the effect of
the methyl substituents, the structure of products 2a, 3, 4a, 6a, 7,
(b)
Fig. 6. (a) The molecule of compound 8a (thermal ellipsoids at the 50% probability
level); (b) autostereographic projection of H-bonded chains along crystal direction
[010]. H-Bonds are drawn as the dashed lines.

32
A. Katrusiak, A. Katrusiak / Journal of Molecular Structure 1085 (2015) 28–36
O
O
O
NH
O
O
N
N
+
NH
HO
OH
O
O
O
10
O
10a
H NNH
2
2
O
OH
H2NNHCH3
O
HO
Fig. 8. The molecule of 2,20-bicyclohexanepyrrolidine-1,10,3,30-tetraone (14), as
present in the crystal structure. Torsion angles C2-N1-N10-C20 and C5-N1-N10-C50 in
two symmetry-independent molecules are 82.0(3) and 77.4(3)°, and 80.9(3) and
81.8(3)°, respectively.
9
O
11
O
H NNHC H
6 5
2
O
11
+
N
NH
do not significantly differ in the six-membered pyridazine rings
unsubstituted at C4 and C5, substituted by one methyl and by
two methyl groups. On the other hand, the methyl substituents
form intramolecular contacts significantly shorter than the sums
of van der Waals radii. The shortest are Cꢁ ꢁ ꢁO contacts, in most
cases between 2.7 and 2.8 Å. Such short contacts involve not only
the methyl groups substituted at C4 and C5 atoms, but also the
methyl and phenyl groups substituted at N atoms. The formation
of 5-membered pyrroledione ring eliminates this strain, as all con-
tacts between adjacent substituents are significantly longer than
3 Å. The correlation between the reactions yield and the number
of methyl substituents at the anhydride 3,4-positions corroborates
this conclusion (Fig. 10).
O
12
Scheme 3. Reactions of succinic anhydride (9) with hydrazine and its methyl and
phenyl derivatives.
Some of the crystal structure determined by X-ray diffraction
(Table 2, shown in Figs. 1–9) exhibit interesting features of the
molecular aggregation. For example, the molecules of compound
4a are NHꢁ ꢁ ꢁO bonded into cyclic tetramers (Fig. 2); molecules 7
are double NHꢁ ꢁ ꢁO hydrogen-bonded into dimers and also OHꢁꢁꢁO
bonded to chains of hydrogen-bonded water molecules (Fig. 4);
four molecules
8 are symmetry-independent in the crystal
(Z0 = 4), and they all are hydrogen bonded in a sequence into one
chain (Fig. 5); in compound 8a the NH group implies the formation
of NHꢁ ꢁ ꢁO bonded chains (Fig. 8); similar NHꢁ ꢁ ꢁO bonded chains are
present in the structure of compound 16 (Fig. 9); despite analogous
hydrogen bonds NHꢁ ꢁ ꢁO in compound 12 (Fig. 7), its structure is
strongly disordered with the molecules present in two orienta-
tions. No strongly hydrogen-bonded aggregates are formed in the
crystal structures of compounds 2a (Fig. 1) and 14 (Fig. 8), both
devoid of H-donors.
Fig. 7. The molecular structure of compound 12: one of two sites of the molecule
disordered in the crystal structure is shown for clarity.
8, 8a, 12, 14 and 16 was determined by single-crystal X-ray diffrac-
tion (Table 2); these determinations were also aimed at confirming
the assignments of products suggested by spectroscopic and chem-
ical methods, as well as the postulated lactam–lactim tautomeric
forms in 3, 7 and 8. The molecular structures of the compounds
determined by X-rays are shown in Figs. 1–9. Two main hypothe-
ses were considered:
Conclusions
It can be concluded that spacious substituents at sites 3 and 4 in
succinic-acid anhydrides reduce the yield of pyridazine products of
the condensation reactions. This effect can be associated with ste-
ric hindrances between the adjacent non-H substituents at carbons
C3 and C4 with the oxygen atoms at the 2,5-locations, respectively.
The distances between the substituents of the 6-membered pyrid-
azine ring are shorter than the sum of van der Waals radii. In the
5-membered pyrroledione ring of alternative products these
contacts are longer than the sums of van der Waals radii of the
hydrogen atoms of the methyl groups and of the oxygen atoms.
Consequently, the steric hindrances in the methylated anhydride
are unfavourable for the pyridazine-ring condensation. It has been
established that the direction of the reactions between the dimeth-
ylmaleic and citraconic anhydrides with the hydrazines can be
optimized by changing the solvents. The glacial acetic acid reac-
tion-environment promoted only one product of the reaction,
(i) That the methyl substituents induced some steric hin-
drances as a consequence of their close location to the oxy-
gen atoms and that this overcrowded accommodation was
reduced in 5-membered rings compared to the 6-membered
ones; consequently, the methyl groups would promote the
formation of the bipyrrole products.
(ii) That the methyl groups induced angular strains in the ring,
which promoted the formation of 5-membered rings with
smaller annular bond angles.
The analysis of the shortest intramolecular distances between
ring substituents (Table S1 in Supplementary Information) sug-
gests that their overcrowding effect may play the important role
for the type of the ring condensation. The annular valence angles

A. Katrusiak, A. Katrusiak / Journal of Molecular Structure 1085 (2015) 28–36
33
Scheme 4. Reactions of cis-cyklohexane-1,2-dicarboxylic anhydride (13) with hydrazine derivatives.
100
80
60
40
Hydrazine
Methylhydrazine
Phenylhydazine
Fig. 9. The molecular structure of compound 16, as present in the crystal structure.
20
0
Table 1
Calculated magnitudes of heats of formation (HoF, in kJ molꢂ1
) of the reaction
0
1
2
products (cf. Schemes 2–4). The main products of the reactions are indicated by the
bold fonts.
Anhydride 3,4-non-H substituents
Comp.
Yield (%)
HOF (kJmolꢂ1
)
Comp.
Yield (%)
20%
HOF (kJmolꢂ1
)
Fig. 10. The pyridazine-ring product yields of the condensation reactions between
anhydrides and hydrazine (red points), methyl-hydrazine (blue), and phenylhydr-
azine (green) plotted against the number of non-H substituents at the 3,4-locations
of the anhydrides. (For interpretation of the references to color in this figure legend,
the reader is referred to the web version of this article.)
2
3
4
6
7
75
78
46
23
63
41
48
59.69
95.63
76.21
6.65
92.64
68.60
ꢂ73.02
2a
ꢂ39.95
4a
6a
40%
72%
82.45
25.18
8
10
8a
10a
49%
40%
73.43
ꢂ105.70
6-Hydroxy-5-methylpyridazin-3-one (2) and 3,30-dimethyl-1,
10-bipyrrole-2,20,5,50-tetraone (2a)
whereas the 10% HCl aqueous solution allows several products, dif-
ficult to synthesize otherwise. The elimination of glacial acetic acid
makes the reaction of pyridazine-ring condensation easier and
safer.
To the stirred and cooled on ice solution of 1.12 g (0.01 mol)
of citraconic anhydride in 50 cm3 of 10% HCl 0.49 g (0.01 mol) of
99% hydrazine hydrate was added dropwise. The precipitate was
filtered, crystallized from EtOH and identified as compound 2.
Yield 65%, mp: 282–285 °C (286.5–287 °C [8]); 1H NMR
(400 MHz; DMSO; TMS): d = 2.02 (d, J = 1.4 Hz, 3H), 6.87 (q,
J = 1.4 Hz, 1H), 10.82 (br s, Oꢁ ꢁ ꢁHꢁ ꢁ ꢁN, 1H), 11.79 (br s, Oꢁ ꢁ ꢁHꢁ ꢁ ꢁN,
1H); 13C NMR (100 MHz, DMSO, TMS): d = 129.88, 139.49,
158.48, 159.32.
The filtrate was extracted with CH2Cl2. The extracts were
washed with water, dried (MgSO4) and evaporated. The residue
was crystallized from H2O and identified as 2a. Yield 20%, mp:
139–140 °C; 1H NMR (400 MHz, CDCl3, TMS): d = 2.18 (d,
J = 1.9 Hz, 6H), 6.55 (q, J = 1.9 Hz, 2H); 13C NMR (100 MHz, CDCl3,
TMS): d = 132.32, 150.21, 163.92, 166.28.
Experimental section
General
Melting points were determined on a Boetius apparatus and are
uncorrected. 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra
were recorded in CDCl3 or DMSO with TMS as internal standard;
chemical shifts are given in d (ppm) and J-values in Hz. The prod-
ucts were separated by column chromatography using an acetone/
hexane mixture (3:2) as mobile phase, with silica gel (0.040–
0.063 mm, 23-400 ASTM, Merc).

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A. Katrusiak, A. Katrusiak / Journal of Molecular Structure 1085 (2015) 28–36
6-Hydroxy-2,5-dimethylpyridazin-3-one (3)
NMR (100 MHz, CDCl3, TMS): d = 9.99, 114.78, 122.70, 126.86,
134.79, 141.33, 165.49.
To 1.12 g (0.01 mol) of citraconic anhydride in 50 cm3 of 10%
HCl 0.46 g (0.01 mol) of methylhydrazine was added dropwise.
The mixture was heated under reflux for 3 h. After cooling the mix-
ture was poured into water and extracted with CH2Cl2. The extracts
were washed with water, dried (MgSO4) and evaporated. The resi-
due was crystallized from EtOH and identified as 3. Yield 73%, mp:
265 °C (262–263 °C [20]); 1H NMR (400 MHz, CDCl3, TMS): d = 2.03
(d, J = 1.4 Hz, 3H), 3.44 (s, 3H), 6.74 (q, J = 1.4 Hz, 1H), 11,22 (br s,
Oꢁ ꢁ ꢁHꢁ ꢁ ꢁN, 1H); 13C NMR (100 MHz, CDCl3, TMS): d = 22.94, 32.39,
129.50, 139.64, 158.97, 163.92.
1-(Phenylamino)pyrrolidine-2,5-dione (12)
From 1.00 (0.01 mol) of succinic anhydride and 1.09 g
(0.01 mol) of phenylhydrazine. After cooling the precipitate was
filtered, crystallized from EtOH and identified as 12. Yield 76%,
mp: 159–160 °C (160–161.5 °C [14]); 1H NMR (400 MHz, DMSO,
TMS): d = 2.58 (s, 4H), 4.03 (s, 1H), 6.70–7.19 (m, 5H); 13C NMR
(100 MHz, CDCl3, TMS): d = 28.98, 112.96, 122.68, 126.71, 142.85,
171.08.
Similarly were obtained:
6-Hydroxy-4,5-dimethylpyridazin-3-one (6) and 3,30,4,40-
tetramethyl-1,10-bipyrrole-2,20,5,50-tetraone (6a)
6-Hydroxy-2,4,5-trimethylpyridazin-3-one (7)
From 1.26 (0.01 mol) of dimethylmaleic anhydride and 0.46 g
(0.01 mol) of methylhydrazine. Yield 63%, mp: 167–168 °C; 1H
NMR (400 MHz, DMSO, TMS): d = 2.02 (s, 6H), 3.37 (s, 3H), 10.98
(br. s, Oꢁ ꢁ ꢁHꢁ ꢁ ꢁN, 1H); 13C NMR (100 MHz, CDCl3, TMS): d = 9.94,
10.16, 33.96, 120.14, 120.75, 158.66, 161.56.
To 1.26 g (0.01 mol) of dimethylmaleic anhydride in 50 cm3 of
10% HCl 0.49 g (0.01 mol) of 99% hydrazine hydrate was added
dropwise. The mixture was heated under reflux for 3 h. After cool-
ing the precipitate was filtered and purified by column chromatog-
raphy. Isolated compounds were identified as 6 and 6a. Compound
6a was found also in filtrate. Therefore the filtrate was extracted
with CH2Cl2. The extracts were washed with water, dried (MgSO4)
and evaporated. The residue was crystallized from H2O and identi-
fied as 6a.
1,10-Bipyrrolidine-2,205,50-tetraone (10) and 4,40-hydrazinebis(4-
oxobutanoic acid) (10a)
From 1.00 (0.01 mol) of succinic anhydride and 0.49 g
(0.01 mol) of 99% hydrazine hydrate. The CH2Cl2 extracts were
evaporated and purified by column chromatography. Isolated com-
pounds were identified as 10 and 10a.
Compound 6; Yield 23%, mp: 348 °C (347–351 °C [8b]); 1H NMR
(400 MHz, CDCl3, TMS): d = 3.36 (s, 6H), 10.83 (br s, Oꢁ ꢁ ꢁHꢁ ꢁ ꢁN, 1H),
11.73 (br s, Oꢁ ꢁ ꢁHꢁ ꢁ ꢁN, 1H); 13C NMR (100 MHz, CDCl3, TMS):
d = 10.31, 122.66, 150.92.
Compound 10; Yield 48%, mp: 309 °C (309–310 °C [16]); 1H
NMR (400 MHz, CDCl3, TMS): d = 1.55 (s, 8H); 13C NMR
(100 MHz, CDCl3, TMS): 26.73, 162.14.
Compound 6a; Yield 72%, mp: 241 °C (237–238 °C [13]); 1H
NMR (400 MHz, TMS): d = 2.05 (s, 12H); 13C NMR (100 MHz, CDCl3,
TMS): d = 138.93, 166.28.
Compound 10a; Yield 40%, mp: 225 °C (225.5 °C [12]); 1H NMR
(400 MHz, CDCl3, TMS): d = 2.33–2.35 (t, J = 6.0 Hz, 4H), 2.37–2.44
(t, J = 6.0 Hz, 4H), 9.78 (s, 2H), 12.12 (br s, 2H); 13C NMR
(100 MHz, CDCl3, TMS): d = 29.96, 31.77, 168.99, 175.30.
2,20-Bicyclohexanepyrrolidine-1,10,3,30-tetraone (14) and cis-N-
aminocyclohexane-1,2-dicarboxyimide (14a)
6-Hydroxy-5-methyl-2-phenylpyridazine-3-one
(4)
and
1.54 g of cyclohexane-1,2-dicarboxylic anhydride was dissolved
in 50 cm3 of ethanol at room temperature. Stirring 0.49 g
(0.01 mol) of 99% hydrazine hydrate was added dropwise. After
refluxing for 1 h the solvent was evaporated. The residue was puri-
fied by column chromatography. Isolated compounds were identi-
fied as 14 and 14a.
3-methyl-1-(phenylamino)-1H-pyrrole-2,5-dione (4a): To 1.12 g
(0.01 mol) of citraconic anhydride in 50 cm3 of 10% HCl 1.09 g
(0.01 mol) of phenylhydrazine was added dropwise. The mixture
was heated under reflux for 3 h. After cooling the precipitate was
filtered and purified by column chromatography. Isolated com-
pounds were identified as 4 and 4a.
Compound 14; Yield 47%, mp: more then 325 °C; 1H NMR
(400 MHz, CDCl3, TMS): d = 1.39–1.52 (m, 4H), 1.74–1.99 (m, 8H),
2.59–2.71 (m, 8H); 13C NMR (100 MHz, CDCl3, TMS): d = 21.71,
22.33, 38.58, 168.66.
Compound 4; Yield 55%, mp: 225 °C (220–221 °C [8a]); 1H NMR
dH (400 MHz, DMSO, TMS): d = 2.11(d, J = 1.3 Hz, 3H), 6.87 (q,
J = 1.3 Hz, 1H), 7.32–7.57 (m, 5H), 11.47 (br s, Oꢁ ꢁ ꢁHꢁ ꢁ ꢁN, 1H); 13C
NMR (100 MHz, CDCl3, TMS): d = 22.02, 125.15, 126.62, 132.31,
141.30, 158.91, 162.95.
Compound 4a; Yield 40%, mp: 158–160 °C (155–157 °C [12]);
1H NMR (400 MHz, DMSO, TMS): d = 2.11(d, J = 1.3 Hz, 3H), 7.08
(q, J = 1.3 Hz, 1H), 7.33–7.56 (m, 5H), 8.70 (s, 1H); 13C NMR
(100 MHz, CDCl3, TMS); d = 11.21, 114.36, 122.84, 125.86, 126.87,
142.01, 143.83, 165.43, 168.66.
Compound 14a; Yield 32%, mp: 60–61 °C (60–63 °C [15]); 1H
NMR (400 MHz, DMSO, TMS): d = 1.24–1.36 (m, 2H), 1.63–2.09
(m, 4H), 2.49–2.59 (m, 4H), 10.08 (s, 2H); 13C NMR (100 MHz,
CDCl3, TMS): d = 22.43, 24.77, 39.43, 173.46.
Similarly were obtained:
cis-N-Methylcyclohexane[d]pyridazine-1,4-dione (15) and cis-N-
(methylamino)cyclohexane-1,2-dicarboxyimide (15a)
Similarly were obtained:
6-Hydroxy-4,5-dimethyl-2-phenylpyridazin-3-one(8) and 3,4-
dimethyl-1-(phenylamino)-1H-pyrrole-2,5-dione (8a)
From 1.54 g of cyclohexane-1,2-dicarboxylic anhydride and
0.46 g (0.01 mol) of methylhydrazine.
Compound 15; Yield 21%, mp: 173 °C (171–172 °C [16]); 1H
NMR (400 MHz, CDCl3, TMS): d = 1.24–1.29 (m, 2H), 1.61–1.94
(m, 4H), 2.72–2.80 (m, 4H), 3.25 (s, 3H), 10.23 (br s, Oꢁ ꢁ ꢁHꢁ ꢁ ꢁN,
1H); 13C NMR (100 MHz, CDCl3ßTMS): d = 22.19, 24.50, 25.34,
36.27, 37.95, 38.79, 171.60, 173.08.
From 1.26 (0.01 mol) of dimethylmaleic anhydride and 1.09 g
(0.01 mol) of phenylhydrazine.
Compound 8; Yield 41%, mp: 135–137 °C; 1H NMR (400 MHz,
DMSO, TMS): d = 2.09 (s, 6H), 7.32–7.56 (m, 5H), 11.24 (br s,
Oꢁ ꢁ ꢁHꢁ ꢁ ꢁN, 1H); 13C NMR (100 MHz, CDCl3, TMS): 9.55, 10.33,
119.52, 121.52, 124.34, 127.04, 132.64, 158.68, 167.56.
Compound 8a; Yield 49%, mp: 123–124 °C; 1H NMR (400 MHz,
DMSO, TMS): d = 1.96 (s, 6H), 6.61–7.18 (m, 5H), 8.29 (s, 1H); 13C
Compound 15a; Yield 62%, mp: 93 °C (94–95 °C [16]); 1H NMR
(400 MHz, CDCl3, TMS): d = 1.38–1.47 (m, 2H), 1.72–1.95 (m, 4H),
2.69–2.73 (m, 4H), 5.32 (s, 1H); 13C NMR (100 MHz, CDCl3, TMS):
d = 22.30, 25.03, 35.51, 40.22, 174.14.

A. Katrusiak, A. Katrusiak / Journal of Molecular Structure 1085 (2015) 28–36
35
Table 2
Selected crystal information of 6-hydroxy-2,4,5-trimethylpyridazin-3-one (7); 6-hydroxy-4,5-dimethyl-1-phenylpyridazin-3-one (8); 1-(phenylamino)pyrrolidine-2,5-dione
(12); 2,20-bicyclohexanepyrrolidine-1,10,3,30-tetraone (14) and cis-N-(phenylamino)cyclohexane-1,2-dicarboxyimide (16).
Code
7
8
12
14
16
Empirical formula
Formula weight
Temperature (K)
Crystal system
Space group
Unit cell: a(Å)
b(Å)
C7H12N2O3
172.19
293(2)
Monoclinic
P21/c
10.0515(8)
4.8853(4)
17.6438(13)
92.883(7)
865.30(12)
4, 1.322
C12H12N2O2
216.24
293(2)
Monoclinic
C2/c
27.0591(14)
15.5011(7)
20.6945(10)
92.288(4)
8673.3(7)
32, 1.325
C10H7N2O2
187.18
293(2)
Orthorhombic
P212121
8.8116(9)
18.3590(15)
5.8617(8)
90
C16H20N2O4
304.34
293(2)
Monoclinic
Pc
11.9142(13)
10.3244(6)
12.7381(12)
105.319(11)
1511.2(2)
4, 1.338
C14H16N2O2
244.29
293(2)
Orthorhombic
Pbca
10.6133(9)
10.0001(9)
23.5473(19)
90
c(Å)
b(°)
Volume (Å3)
Z, density (g cmꢂ3
948.26(18)
4, 1.311
0.094
2499.2(4)
8, 1.299
0.088
)
Absorption (mmꢂ1
F(000) (e)
)
0.104
368
0.092
3648
0.097
648
388
1040
Crystal size (mm)
h range of data (°)
Max/min. indices h, k, l
Reflections all/unique
Rint
0.40ꢁ0.30ꢁ0.12
2.31–28.9
ꢂ13/13, ꢂ3/6, ꢂ23/23
5391/2114
0.0258
0.30ꢁ0.21ꢁ0.15
1.51–26.63
ꢂ34/33, ꢂ11/19, ꢂ25/26
31413/9021
0.0331
0.45ꢁ0.35ꢁ0.15
2.56–26.44
ꢂ8/11, ꢂ17/22, ꢂ6/6
2403/1297
0.0221
0.34ꢁ0.30ꢁ0.22
2.58–27.82
ꢂ14/14, ꢂ13/13, ꢂ12/16
5422/3318
0.0281
0.40ꢁ0.30ꢁ0.15
2.58–28.13
ꢂ13/13, ꢂ13/9, ꢂ30/31
16896/2911
0.1563
hMax(°)/completeness (%)
Data/restraints/parameters
Goodness-of-fit on F2
28.91/92.9
2114/0/121
1.008
26.63/98.9
9021/0/613
1.045
26.44/ 83.6
1297/36/180
1.053
27.82/75.0
3318/2/397
1.189
28.13/95.4
2911/0/163
0.998
Indices R1/R2 [I > 2rI
R1/R2 indices (all data)
Max./min.
F (eÅꢂ3
]
0.0460/0.1073
0.0700/0.1281
0.219/ꢂ0.168
0.0370/0.1177
0.0499/ 0.1366
0.217/ꢂ0.205
0.0495/0.1204
0.0608/0.1416
0.251/ꢂ0.180
0.0560/0.1818
0.0849/0.1941
0.313/ꢂ0.199
0.0412/ 0.1018
0.0832/0.1321
0.180/ꢂ0.149
D
)
Table 3
Selected crystal information of 3,30-dimethyl-1,10-bipyrrole-2,20,5,50-tetraone (2a); 3-methyl-1-(phenylamino)-1H-pyrrole-2,5-dione (4a); 3,30,4,40-tetramethyl-1,10-bipyrrole-
2,20,5,50-tetraone (6a); 3,4-dimethyl-1-(phenylamino)-1H-pyrrole-2,5-dione (8a).
Code
2a
4a
6a
6a
8a
Empirical formula
Formula weight
Temperature (K)
Crystal system
Space group
Unit cell:
C
10H8N2O4
C11H10N2O2
202.21
293(2)
Tetragonal
P41/a
C12H12N2O4
248.24
91(1)
Monoclinic
P21/c
C12H12N2O4
248.24
293(2)
Monoclinic
P21/c
C12H12N2O2
216.24
293(2)
Monoclinic
P21/c
220.18
293(2)
Monoclinic
C2/c
a(Å)
b(Å)
c(Å)
b(°)
9.924(2)
9.089(2)
11.911(3)
102.82(2)
1047.6(4)
4, 1.396
13.65699(15)
13.65699(15)
22.3911(3)
90
4176.25(9)
16, 1.286
10.597(2)
13.615(3)
8.084(2)
98.28(3)
1154.2(4)
4, 1.429
10.967(2)
13.849(3)
8.090(2)
98.78(3)
1214.3(5)
4, 1.358
7.9689(4)
10.3352(5)
13.2468(7)
94.058(4)
1088.27(10)
4, 1.320
Volume (Å3)
Z, density (g cmꢂ3
)
)
Absorption (mmꢂ1
F(000) (e)
0.110
456
0.091
1696
0.109
520
0.104
520
0.092
456
Crystal size (mm)
h range of data (°)
Max/min. indices h, k, l
Reflections all/unique
Rint
0.35ꢁ0.30ꢁ0.10
3.07–29.81
ꢂ10/13, ꢂ11/12, ꢂ16/11
4204/1353
0.0389
0.30ꢁ0.30ꢁ0.20
2.98–29.19
ꢂ18/18, ꢂ18/18, ꢂ30/30
100273/2729
0.0293
0.30ꢁ0.20ꢁ0.05
3.57–29.35
ꢂ14/14, ꢂ17/18, ꢂ6/11
7905/2928
0.0868
0.3ꢁ0.2ꢁ0.05
3.70–29.53
ꢂ14/14, ꢂ18/18, ꢂ6/11
8694/3071
0.0593
0.32ꢁ0.30ꢁ0.14
2.50–29.62
ꢂ6/10, ꢂ14/13, ꢂ17/18
10551/2795
0.0298
hMax(°)/completeness (%)
Data/restraints/parameters
Goodness-of-fit on F2
29.81/89.7
1353/0/75
1.097
29.19/96.4
2729/0/136
1.087
29.35/92.4
2928/0/74
1.185
29.53/90.6
3071/0/163
1.221
29.62/91.0
2795 / 0 / 193
1.018
Indices R1/R2 [I > 2rI
R1/R2 indices (all data)
Max./min.
F (eÅꢂ3
]
0.0334/0.1040
0.0517/0.1284
0.118/ꢂ0.138
0.0371/0.1082
0.0661/0.1229
0.248/ꢂ0.248
0.0410/0.0822
0.0621/0.1132
0.243/ꢂ0.212
0.0451/0.0914
0.0677/0.1210
0.296/ꢂ0.234
0.0398/0.0962
0.0997/0.1206
0.171/ꢂ0.166
D
)
cis-N-(Phenylamino)cyclohexane-1,2-dicarboxyimide (16)
CCD four-circle diffractometer and Mo K
a
radiation (0.71073 Å)
was used. The structures were determined by direct methods and
refined by full-matrix least squares. In most cases the hydrogen
atoms were located from the molecular geometry, except for the
hydroxyl groups where the H-atoms were located from the differ-
ence Fourier map. Program SHELXS was used for structures solu-
tion and SHELXL for their refinements [21]. The structures were
refined by full-matrix least-squares on F2. The experimental and
crystallographic data are listed in Tables 2 and 3, whereas detailed
crystallographic information files (CIFs) have been deposited in the
Cambridge Crystallographic Database Centre (CCDC). Deposits
numbered CCDC-995574 to CCDC-995583 contain the supplemen-
tary crystallographic data for structures 2a, 4a, 6a at 293 K, 6a at
From 1.54 g of cyclohexane-1,2-dicarboxylic anhydride and
1.09 g (0.01 mol) of phenylhydrazine. Yield 71%, mp: 158 °C
(156–158 °C [17]); 1H NMR (400 MHz, CDCl3, TMS): d = 1.49–1.51
(m, 2H), 1.79–197 (m, 4H), 2.95–3.03 (m, 4H), 6.16 (s, 1H), 6.76–
7.27 (m, 5H); 13C NMR (100 MHz, CDCl3, TMS): d = 22.46, 25.09,
37.61, 112.51, 122.60, 126.64, 141.98, 180.34.
X-ray diffraction
The structures of selected compounds, 2a, 4a, 6a, 7, 8, 8a, 12, 14
and 16, was determined by single-crystal diffraction. A KuMa KM-4

36
A. Katrusiak, A. Katrusiak / Journal of Molecular Structure 1085 (2015) 28–36
[4] H. Frank, G. Heinisch, in: G.P. Ellis, G.B. West (Eds.), Progress in Medicinal
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[6] P.D. Cradwick, Nature 258 (1975). 774-774.
91 K, 7, 8a, 8, 12, 14 and 16, respectively. These data can be
obtained free of charge from the CCDC via www.ccdc.cam.ac.uk/
data_request/cif.
[7] (a) R.H. Mizzoni, P.E. Spoerri, J. Am. Chem. Soc. 73 (1951) 1873–1874;
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510–523.
Acknowledgement
We are grateful to Mr. Marcin Znamirowski for his assistance in
part of this project carried out in the Department of Organic Chem-
istry, Poznan University of Medical Sciences, during his M.Sc. thesis
preparation.
[11] K. Mori, Yakugaku Zassh 82 (1962) 1161–1170.
[12] H. Feuer, G.B. Bachman, E. White, J. Am. Chem. Soc. 73 (1951) 4716–4719.
[13] E. Hedaya, R.L. Hinman, V. Schomaker, S. Theodoropulos, L.M. Kyle, J. Am.
Chem. Soc. 89 (1967) 4875–4884.
Appendix A. Supplementary material
[14] M.J. Kornet, J. Pharm. Sci. 73 (1984) 405–406.
[15] J.G. Krause, S. Kwon, B. George, J. Org. Chem. 37 (1972) 2040–2042.
[16] S. Kasina, J. Nematollahi, J. Org. Chem. 42 (1977) 159–161.
[17] K. Kamin´ ski, J. Obniska, Bioorg. Med. Chem. 16 (2008) 4921–4931.
[18] J. Druey, K. Meier, K. Eichenberger, Helv. Chim. Acta 37 (1954) 121.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.molstruc.2014.12.
050.
[19] MOPAC is
a
semi-empirical quantum-mechanical method: Quantum
Chemistry Program Exchange, No. 455, Indiana University, USA J.J.P. Stewart,
J. Comput. Chem. 10 (1983) 209–221.
References
[20] T. Tsuchiya, H. Arai, M. Hasebe, H. Igeta, Chem. Pharm. Bull. 22 (1974) 2301–
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