Electrochemical reduction of 1,4-disubstituted phthalazines

Article abstract of DOI:10.1023/A:1013979709884

Electrochemical reduction in dimethylformamide of unsymmetrical 1-Cl-4-X-phthalazines and symmetrical 1,4-X₂-phthalazines (X = Cl, PhO, MeO, EtO, i-PrO) was studied by voltammetry and electrolysis-ESR. The electron trasfer on 1,4-dichlorophthalazine and unsymmetrical 1-Cl-4-X-phthalazines induces anionoid elimination of Cl and X, pyridazine ring cleavage, and phthalonitrile formation. In this previously unknown process the transfer of two electrons induces cleavage of three σ bonds and formation of two new π bonds. The reduction of 1,4-dialkoxy(diaryloxy)phthalazines involves formation of stable radical anions which undergo no heteroring cleavage. Possible mechanisms of the processes studied were discussed. It was assumed that the same mechanism with pyridazine ring cleavage may be realized with other phthalazine derivatives and heteroannelated pyridazines containing readily leaving nucleofuge groups α to nitrogens.

Full text of DOI:10.1023/A:1013979709884

Russian Journal of General Chemistry, Vol. 71, No. 10, 2001, pp. 1636 1646. Translated from Zhurnal Obshchei Khimii, Vol. 71, No. 10, 2001,
pp. 1726 1737.
Original Russian Text Copyright
2001 by Yanilkin, Buzykin, Morozov, Nastapova, Maksimyuk, Eliseenkova.
Electrochemical Reduction of 1,4-Disubstituted Phthalazines
V. V. Yanilkin, B. I. Buzykin, V. I. Morozov,
N. V. Nastapova, N. I. Maksimyuk, and R.M. Eliseenkova
Arbuzov Institute of Organic and Physical Chemistry, Kazan Research Center,
Russian Academy of Sciences, Kazan, Tatarstan, Russia
Received July 6, 2000
Abstract Electrochemical reduction in dimethylformamide of unsymmetrical 1-Cl-4-X-phthalazines and
symmetrical 1,4-X2-phthalazines (X = Cl, PhO, MeO, EtO, i-PrO) was studied by voltammetry and electro-
lysis ESR. The electron trasfer on 1,4-dichlorophthalazine and unsymmetrical 1-Cl-4-X-phthalazines induces
anionoid elimination of Cl and X, pyridazine ring cleavage, and phthalonitrile formation. In this previously
unknown process the transfer of two electrons induces cleavage of three bonds and formation of two new
bonds. The reduction of 1,4-dialkoxy(diaryloxy)phthalazines involves formation of stable radical anions which
undergo no heteroring cleavage. Possible mechanisms of the processes studied were discussed. It was assumed
that the same mechanism with pyridazine ring cleavage may be realized with other phthalazine derivatives
and heteroannelated pyridazines containing readily leaving nucleofuge groups
to nitrogens.
Electrochemical reduction reactions of organohalo-
gen compounds have first been reported by Plamp and
Hammett in 1938 [1], and since that time they have
attracting enduring researcher’s interest. This interest
1,3,5-triazines [12, 13], and various 1-chlorophthal-
azine derivatives, including 1,4-dichlorophthalazine
[14]. In the latter case, the electron transfer induces
a more profound molecular transformation. Recently
is associated with the rather facile electrochemical we found that the electrochemical oxidation of 1-
cleavage of the C Hlg bond, resulting in formation of
highly reactive intermediates, which hold much
promise for solving theoretical problems of electron-
transfer processes, synthetic problems of organic
chemistry, and practical problems of utilization of
chloro-4-X-phthalazines, where X are substituents
capable of anionoid elimination (X = Cl, OPh, OMe),
induces pyridazine ring cleavage with phthalonitrile
formation [15 17]. Unsubstituted phthalazine and
1-alkylphthalazines are initially reduced, like their
organohalogen compounds. As a rule, electrochemical carbocyclic analog, naphthaline, to radical anions in
reduction of alkyl and aryl halides yields the corres-
ponding hydrocarbons. However, some other reaction
directions have been observed, for example, with alkyl
aprotic solvents [18, 19] or undergo hydrogenation
of the pyridazine C=N bond in proton-donor media
[20]. In the latter case, the heteroring cleavage to
1,2-bis(aminomethyl)benzenes to give finally iso-
indole derivatives takes place only on a more pro-
found reduction. We considered it of interest to find
halides having in the
position of readily leaving
groups X. In this case, the transfer of two electrons
gives rise to anionoid elimination of halogen and X
and multiple bond formation. Thus, the electrochemical out which phthalazine derivatives undergo phthalo-
reductions of vicinal dihaloethanes [2 4] and -halo-
ethylsulfones [3] yield ethylenes, and the reduction of
benzoyl chloride hydrazones, benzonitrile and the
nitrile cleavage and to determine conditions for re-
alization of this process which does not fit known
reduction schemes both for organohalogen compounds
corresponding amine (aminonitrile cleavage reac- and for phthalazine or alkylphthalazines. In the
tion) [5].
present communication we present the results of a
thorough study of electrochemical reduction of di-
substituted 1-chloro-4-X-phthalazines I VII, sym-
metrical 1,4-diphenoxy- and 1,4-dialkoxyphthalazines
VIII XI containing two nucleofuge groups. The re-
actions were performed in DMF on the backgroung
of Bu4NI (0.1 M).
Electrochemical reduction of hetaryl halides, too,
most frequently involve dehalogenation [6 9]. At the
same time, the hetaryl radical dimerization [10] and
the preference of hetering saturation over dehalogena-
tion have also been reported [11]. The electrochemical
dehalogenations of halofurans [6], halothiophenes [7],
- or -haloazines [8, 9], as well as -haloazines, such
as 2-chloroquinoline [9], 2-chloro- and 2,4-dichloro-
Phthalazines I XII all are reduced at potentials
ranging from 0.93 to 1.75 V relative to Hg/I
1070-3632/01/7110-1636$25.00 2001 MAIK Nauka/Interperiodica

ELECTROCHEMICAL REDUCTION OF 1,4-DISUBSTITUTED PHTHALAZINES
1637
H
OR
Cl
Cl
N
N
N
N
N
N
N
NH
i, A
H
OR
VIII XI
X
O
4
0
4
I VI
VII
XII
1
3
X = Cl (I), OPh (II), OMe (III), OEt (IV), i-PrO (V),
HMe (VI); R = Ph (VIII), Me (IX), Et (X), i-Pr (XI).
4
(Table 1). The potentials E1/2 are 0.6 V lower than
the reduction potentials of corresponding naphthaline
derivatives (for example, the E1/2 values for phthala-
zine and naphthalene are 1.36 and 2.00 V, respec-
tively), and, consequently, the substitution of two
carbon atoms in naphthalene by two nitrogens in-
creases electron affinity by 0.6 eV. Values of E1/2,
polarogram patterns, and, consequently, reduction
direction are much dependent on the nature of sub-
stituents in the 1 and 4 positions. Thus, 1-chloro-
phthalazine derivatives I VII are reduced easier than
phthalazine XII and 1,4-diethers VIII XI.
2
0
0.5
1.0
1.5
2.0 E, V
Fig. 1. (1) Classical and (2 4) commutated by the
Kalousek circuit scheme II polarograms of 1,4-dichloro
phthalazine (I) (C 1 10 M) in DMF/Bu NI (0.1 M).
3
4
ox
E
, V: (2) 0.8, (3) 1.0 V, and (4) 1.7 (here and here-
inafter, relative to Hg/I ).
The polarograms of 1,4-dichlorophthalazine (I)
which is the easiest reduced in DMF of all the com-
pounds studied show three reduction waves. The first
wave, according to switching polarography (Fig. 1)
and cyclic voltammetry (Fig. 2), is irreversible, and its
limiting current corresponds to transfer of two elec-
trons per one molecule. At the potentials of the second
(one-electron) and third (two-electron) waves by
switching polarography we detected intermediates
whose oxidation potentials are in the same region
(Table 1). The reversibility of the second stage is con-
firmed by cyclic voltammetry (Fig. 2). The value of
commutated anodic current, recorded with the
Kalousek circuit II, depends on oxidation potential
Eox (Fig. 1). If the oxidation is performed at a
potential of 0.8 V, the anodic currents are much
lower that those obtained in the oxidations at first-
and second-wave potentials. Such relations are
characteristic of hidden limiting current phenomena.
The reduced values of commutated anodic currents
are explained by consumption of intermediates in
homogeneous reduction of the easier reducible starting
compound and reaction product. Upon electrolysis at
second-wave potentials directly in an ESR resonator
(a)
3
i, A
5
0
2
1
5
(b)
i, A
10
2
0
1
10
0
0.4
0.8
1.2 E, V
Fig. 2. Cyclic voltammograms of (a) 1,4-dichlorophthal-
azine and (b) 1-chloro-4-methoxyphthalazine in
DMF/Bu NI (0.1 M) on a glassy carbon electrode.
4
1
Potential sweep rate , mV s : (1) 20, (2) 50, and
3
6,7
we detected a single paramagnetic product (aH 0.417,
(3) 100. C 1 10 M, 25 C.
5,7
aN 0.173, aH 0.42 mT) identified as phthalonitrile
radical anion XIIIa [21]. The formation of radical
anions XIIIa suggests that in aprotic conditions at
first-wave potentials in DMF on the background of
Bu4NI (0.1 M) a new reaction direction takes place,
involving pyridazine ring cleavage and phthalonitrile
XIII formation. The overall process involves transfer
of two electons, cleavage of three bonds (N N and
two C Cl) and formation of two new bonds in the
nitrile groups. These stages all are fast, as evidenced
by the diffusion nature of the limiting current (the
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 71 No. 10 2001

1638
YANILKIN et al.
Table 1. Characteristics of the reduction waves of 1-X-4-Y-phthalazine and phthalonitrile derivatives in DMF/Bu4NI
3
(0.1 M); C 1 10 M, 25 C
2
DMF
tan ,
DMF + 1 10 M PhOH
Comp.
no.
X
Y
E1/2
,
Ilim 107,
E1/2
,
Ilim 107, tan ,
ia/ic
nc
n
b
Va
A
mV
V
A
mV
I
Cl
Cl
Cl
Cl
0.930
1.140
2.045
1.065
2.015
35.0
17.9
54.8
52.4
43.0
63
52
128
52
0.0
2.0
1.0
3.0
3.0
2.4
0.930
1.130
2.000
1.055
1.680
2.065
1.180
1.415
1.975
1.235
2.015
1.225
1.430
2.040
1.370
1.970
32.8
15.9
138.0
31.9
29.5
39.7
40.9
17.6
87.5
47.3
68.7
33.8
12.8
89.6
43.4
84.3
73
52
136
31
105
84
63
77
178
63
199
58
47
1.9
0.9
7.5
1.8
1.6
2.2
2.3
1.0
4.8
2.9
4.2
2.2
0.8
5.0
2.4
4.7
0.59
0.41
0.27
0.18
II
PhO
MeO
126
III
1.160
2.030
53.6
44.5
62
115
0.24
0.18
3.0
2.0
IV
V
Cl
Cl
EtO
1.215
2.060
1.220
2.045
52.6
44.0
55.1
36.7
73
105
79
3.0
2.4
3.0
2.0
i-PrO
0.25
0.17
84
120
84
126
VI
Cl
Cl
MeNH
OHd
1.380
1.620
1.805
2.070
1.230
1.580
1.950
2.295
1.425
2.155
41.7
7.7
10.3
9.3
15.3
5.0
2.8
21.0
16.9
66.7
63
110
84
115
73
47
73
105
58
131
2.3
0.4
0.6
0.5
1.0
0.3
1.4
1.3
1.0
3.7
VII
1.260
1.575
1.870
27.0
26.6
36.8
84
68
136
1.7
1.6
2.3
VIII PhO
IX MeO
PhO
1.300
1.770
2.065
1.545
1.910
1.610
1.975
1.625
2.160
1.280
1.485
1.820
49.1
54.4
55.6
51.5
43.4
42.5
50.7
56.4
44.2
18.0
18.8
41.7
79
105
84
68
79
73
100
84
94
63
2.7
3.0
3.1
3.0
2.4
2.5
3.0
3.5
2.7
1.1
1.1
2.4
MeO
EtO
i-PrO
H
1.680
1.740
1.750
28.4
24.6
24.9
68
115
73
1.6
1.5
1.4
X
EtO
XI i-PrO
XII
H
1.360
1.785
2.230
1.110
2.010
25.4
28.6
30.3
15.1
38.3
89
105
121
63
1.5
1.7
1.8
0.9
2.3
84
84
XIII
Phthalonitrile
0.78
0.24
130
a
b
On a dropping mercury electrode relative to Hg/I . The ratio of anodic commutated current to cathodic current for reversible
c
processes under the given conditions (f 10 Hz) is 0.78. The number of electrons measured against the one-electron reduction wave
d
of benzophenone.
In the form of 4-chloro-1,2-dihydrophthalazinone (VII).
1/2
ip
dependence is linear in the
range of 20
benzonitrile radical anions at third-wave potentials. It
is the latter radical anions which were detected by
ESR (aH 0.363, aN 0.215, aH 0.03, aH 0.842 mT),
and they are responsible for the anodic current ob-
served in the commutated curves at third-wave
potentials.
1
200 mV s , Fig. 3). The two further waves whose
characteristics are fully coincident with our (Table 1)
and published data for phthalonitrile [22], relate to
further reduction of the resulting phthalonitrile to
radical anion XIIIa at second-wave potentials and to
2,6
3,5
4
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 71 No. 10 2001

ELECTROCHEMICAL REDUCTION OF 1,4-DISUBSTITUTED PHTHALAZINES
The one-electron level of the limiting current of
1639
the second wave of 1,4-dichlorophthalazine, corres-
8
ilim
,
ponding to phthalonitrile reduction, suggests that in
DMF in the presence of Bu4NI (0.1 M) pyridazine
ring cleavage with elimination of chloride ions and
formation of phthalonitrile occur quantitatively. The
same conclusion follows from the almost equal in-
tensity of the ESR signals of radical anions XIIIa
generated from both from 1,4-dichlorophthalazine and
from phthalonitrile in the same conditions. No de-
halogenation to give 1-chlorophthalazine, as expected
earlier [14], was observed. Phthalonitrile was isolated
and identified as in the preparative electrochemical
reduction of 1,4-dichlorophthalonitrile in DMF on
the background of Bu4NBr (0.1 M). However, upon
passing 2 F/mol we could isolate from the reaction
mixture as little as 12%. During electrolysis the
concentration of 1,4-dichlorophthalazine decreased
much faster than expected for two-electron reduction
(Fig. 4). A possible reason is that the bases generated
in the cathodic space of the diaphragm cell during
long-term (6 h) electrolysis catalyze saponification of
1,4-dichlorophthalazines which is readily saponified
both in acidic and in basic media.
A
6
4
10
20
30
1/2, (mV/s)
Fig. 3. Plot of the first-wave reduction current peak of
1,4-chlorophthalozine i vs. potential sweep rate
C 1 10 M, 25 C.
1/2
.
p
3
C,
M
0.3
0.2
The overall five-electron 1,4-dichlorophthalazine
reduction scheme can be represented as follows
1
0.1
(Scheme 1).
2
Scheme 1.
Cl
1
2
3
4
C N
E11/2
Time, h
N
N
2e
2Cl
C N
Fig. 4. Change in the concentration of 1,4-dichloro-
phthalazine in the course of preparative reduction in
DMF in a mercury electrode. (1) Calculation and
(2) experiment.
Cl
II V
XIII
C N
E12/2
XIII + e
involved in the stage of protonation of phthalonitrile
dianions and benzonitrile radical anions.
C N
XIIIa
The electrochemical oxidation of 1-chloro-4-alkoxy-
phthalazines (II V) are reduced by a similar scheme
that involves cleavage of the pyridazine ring, elimina-
tion of two anions, and formation of phthalonitrile. In
this case, too, the corresponding anodic currents are
observed in the cyclic voltammogram (cf. Figs. 1 and
5) and phthalonitrile radical anions are registered by
electrolysis ESR upon electrolysis at first-wave
potentials and benzonitrile radical anions upon elec-
trolysis at second-wave potentials. The E1/2 potentials
C N
E13/2
2e, HD
CN ,
XIIIa
D
The same reaction direction takes place in a proton-
donor medium (DMF EtOH, 2:1) and in the presence
of phenol as proton donor (m = CPhOH/CI = 10 1000).
The first two waves in these cases are identical to
those observed in the absence of proton donor, the
second wave is reversible, and ESR detects radical of the first reduction wave of 1-chloro-4-X-phthala-
anions XIIIa. The effect of proton donor shows up
only in increased limiting current of the last reduction
wave (Table 1). Apparently, phenol and ethanol are
zines I V regularly increase with increasing electron-
donor power of the 4-X group in the following order:
Cl < PhO << MeO < EtO < i-PrO. Compound I is the
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 71 No. 10 2001

1640
YANILKIN et al.
This is actually the case with compound II V
(Table 1). The waves of all the compounds get steeper
in the initial part, and with phenoxy derivative II the
slope is slightly decreased (52 mV at 25 C). Thus,
under the electrochemical reduction of compounds
II V involves concurrent heterogeneous and homo-
geneous reactions (Scheme 2).
4
i, A
10
0
3
Scheme 2.
2
10
1
Cl
C N
E11/2
N
N
2e
Cl ,
X
C N
X
XIII
C N
C N
II V
1.0
1.5
2.0
E, V
E11/2
XIII + e
Fig. 5. Cyclic voltammograms of 1-chloro-4-phenoxy-
phthalazine in DMF/Bu NI (0.1 M). Potential sweep rate
XIIIa
4
1
, mV s : (1) 20, (2) 50, (3) 100, and (4) 200. C 1
3
10 M, 25 C.
Cl
N
N
E11/2
only whose reduction potential is lower than the
reduction potentials of phthalonitrile ( E1/2 200 mV),
and, therefore, separate reduction of these two com-
pounds is observed in this case. The other compounds
are reduced in the same range of potentials as phthalo-
nitrile, and, therefore, the corresponding waves
2XIIIa +
3XIII
Cl ,
X
X
The three-electron level of the limiting current of
the first wave suggests that in DMF in the given con-
coalesce to form a single three-electron reduction ditions pyridazine ring cleavage in compounds II V
wave. 1-Chloro-4-phenoxyphthalazine (II) is reduced
slightly easier than phthalonitrile ( E1/2 90 mV), and
the reduction peak of phthalonitrile can only be ob-
served on the cyclic voltammograms obtained at low
sweep rates (Fig. 5). Compounds III V are slightly
more difficult to reduce compared with phthalonitrile,
and the cyclic voltammograms in the range of first-
wave potentials show one cathodic peak and one
with Cl and RO elimination and phthalonitrile
formation occurs quantitatively. The same conclusion
follows from the fact that the ESR singals of the
phthalonitrile radical anions generated by the electro-
chemical reduction of 1,4-dichlorophthalazine and
compounds II V in identical conditions have equal
intensities. In the presence of phenol (m 10), too,
compounds II V undergo reduction to phthalonitrile,
as evidenced by the cyclic voltammograms and ESR
spectra. However, some other, as yet unknown, reac-
tions take place, as evidenced by the reduced limiting
current of the first wave and the observation of one
more reduction wave between the first and second
waves (Table 1). These findings suggests that in II V
pyridazine ring cleavage with phthalonitrile formation
quantitatively occurs in aprotic medium only.
anodic peak of oxidation of phthalonitrile radical
anions. The icp
dependence is linear. Consequent-
1/2
ly, the reaction rate is limited by the rate of diffusion
of the starting compounds to electrode surface.
It is known that radical anions of organic com-
pounds are effective electron carriers in reductions of
organohalogen compounds [23]. The difference in the
reduction potentials of phthalonitrile and compound
II V is very small or even negative, implying that the
homogeneous reduction of the starting compounds
with the phthalonitile radical anions formed is a very
fast reaction. As soon as radical anions XIIIa appear,
the contribution of the homogeneous reaction in the
overall reduction process sharply increases, i.e., in
essence, autocatalysis takes place. As a result, the
slope and symmetry of the wave may be affected.
The electrochemical reduction of methylamino and
hydroxy 1-chlorophthalazine derivatives VI and VII
occurs in a different way compared with compounds
II V. 1-Chloro-4-methylaminophthalazine (VI) in
DMF solutions give four or two (in the presence of
phenol) reduction waves. Both in the absence and in
the presence of phenol, no phthalonitrile radical
anions are detected. Amino and methylamino groups
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 71 No. 10 2001

ELECTROCHEMICAL REDUCTION OF 1,4-DISUBSTITUTED PHTHALAZINES
1641
are known to be difficultly leaving groups, and, evi-
dently, no heteroring cleavage to give phenol takes
place; in this case, however, the proton-donor ability
of methylamino group may be a factor, too. This
assumption is consistent with the isolation of 1-(1-
methylhydrazino)phthalazine upon controlled-po-
tential electrolysis of 1-chloro-4-(1-methylhydrazino)-
phthalazine [14].
Table 2. Hyperfine coupling constants of the ring protons
and 14N nuclei in radical anions generated by electro-
3
chemical reduction of 1 10 M solutions of phthalazine
derivatives at first-wave potentials on a platinum elec-
trode in DMF/Bu4NI (0.1 M); 22 C
R
8
5
1
N2
N 3
7
4-Chloro-1-hydroxyphthalazine (VII) is reduced in
a complicated way. As known, both in crystal and in
solutions 4-chloro-1-hydroxyphthalazines (X = H, Cl,
OAlk, etc.) exist as 4-X-1,2-dihydrophthalazinone
tautomers [24, 25].
6
4
R
Comp.
no.
5
8
6
7
R
aN, mT aH (H ), mT aH (H ), mT
Cl
N
N
VIIIa PhO
0.092
0.105
0.111
0.088
0.515
0.545
0.550
0.460
0.228
0.233
0.237
0.200
VII
IXa
MeO
i-PrO
H
XIa
OH
XIIaa
VII-(OH)
a
1
4
In DMSO, a
= 0.591 mT [18].
H (H )
We expected that in DMF solutions the amide
imdol equilibrium would do occur, and the hydroxy
form [VII-(OH)] would behave like alkoxy deriva-
tives III V. The limiting current of the first irrever-
sible reduction wave of compound VII corresponds
to the transfer of one electron per a molecule (n = 1.0),
which is much lower than the three-electron transfer
observed with II V at a quantitative pyridazine ring
cleavage. No paramagnetic species were detected by
ESR on electrolysis at the potentials of the first and
further waves, until background electrolyte decom-
position. In the presence of phenol (m 10), the limiting
current attains the level n = 1.7, but phthalonitrile
radical anions are not detected, too. The reduction of
4-chloro-1,2-dihydrophthalazinone (VII) either gives
no phthalonitrile or the formation of the latter cannot
be detected by ESR and voltammetry because of auto-
protonation with compound VII which is a fairly
strong acid. That this process may occur we showed
by special experiments on electrochemical reduction
of 1,4-dichlorophthalazine in the presence of 4-chloro-
1,2-dihydrophthalazinone (VII). Here, too, phthalo-
nitrile radical anions were not detected by ESR.
Therefore, the resulting data give us no grounds to
state with assurance that the electrochemical reduction
of compound VII involves no pyridazine ring
cleavage to form phthalonitrile.
chemical reduction only and takes place in the
chemical reduction of the compounds studied with
metallic potassium in DMF. In the latter case, too,
phthalonitrile radical anions were detected by ESR.
Comparing the reduction patterns of 1,4-dichloro-
phthalazine (I) and 1-chloro-4-aryloxy(alkoxy)phtha-
lazines II V in aprotic medium, one can note that
substitution of one chlorine atom by an alkoxy(aryl-
oxy) group in 1,4-dichlorophthalazine hinders electron
transfer but has no effect on the reaction result. At the
same time, substitution of a further chlorine atom by
these groups not only raises the ionization potentials
(Table 1), but also radically changes the reaction
result.
Diethers VIII XI in the first stage irreversibly take
up one electron to form stable radical anions
VIIIa XIa. The latter are detected by cyclic volt-
ammetry and ESR. The heteroring cleavage with
phthalonitrile formation is observed with none of
compounds VIII XI, even on prolonged electrolysis
(30 min) at first-wave potentials (with VIII, at first-
and second-wave potentials), as well as in the pre-
sence of phenol and on the background of LiClO4
(0.1 M) instead of Bu4NI (0.1 M). In [15], we made a
mistake. Apparently, the presence of chlorine in
the phthalazine derivatives is a key factor responsible
for their pyridazine ring cleavage.
Thus, we found that pyridazine ring cleavage with
phthalonitrile formation is the major pathway of elec-
trochemical reduction in aprotic media only for 1-
chloro-4-X-phthalazines (X = Cl, OPh, OMe, OEt,
OPr-i), which contain two groups able to anionoid
elimination. This pathway is not peculiar to electro-
The ESR spectrum of the radical anion obtained
by reduction of 1,4-diphenoxyphthalazine (VIII) is
given in Fig. 6, and the hyperfine coupling constants
of aromatic protons and 14N nuclei in radical anions
VIIIa XIa are given in Table 2. It is known that
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 71 No. 10 2001

1642
YANILKIN et al.
transfer is followed by fast chemical and/or electro-
chemical stages responsible for the irreversibility of
the overall reaction.
Introduction of proton donor (phenol) in a 10-fold
excess in the case of diethers VIII XI which form
stable radicals VIIIa XIa raises the limiting current
to three-electron level and shifts E1/2 to lower values
by 130 mV (Table 1). With easier reducible 1-chloro
derivatives I VII, phenol additives reduce the limit-
ing current but have no effect on E1/2. Consequently,
the rate of further transformations in the latter case is
higher than the rate of protonation of the primary
radical anion, and protons take no part in the potential-
determining stage.
0.5 mT
The difference in the reduction potentials of
phthalazine derivatives I XI is accounted for by the
electronic effects of substituents on the first electron-
transfer stage (electron affinity of the starting mole-
cule) and the subsequent chemical reaction. Electron-
acceptor substituents commonly facilitate electron
transfer and hinder subsequent chemical reactions
(Mairanovskii antibasis rule [26]). This rule surely
applies to the heterocyclic system in hand. The sta-
bility of diether radical anions VIIIa XIa (electron-
donor substituents) suggests that pyridazine ring
cleavage and alkoxide(aryloxide) ion elimination in
1-chlorophthalazines I V (electron-acceptor substi-
tuents) is not a primary act induced by the first elec-
tron transfer. Obviously, 1-chlorophthalazines I VII
are first reduced with chloride ion elimination, and
this is a key stage that triggers the overall mechanism
involving heteroring cleavage and, finally, phthalo-
nitrile formation. Relying on the present notion of
reduction of organohalogen compounds as ESE [22]
or EED processes [27, 28] with conjugate elimination,
we can propose a number of possible reduction
schemes for 1-chlorophthalazines I VII (Schemes 3 5).
H
Fig. 6. ESR spectrum of the 1,4-diphenoxyphthalazine
radical anions generated by electrolysis of a 1 10
solution at a potential of 1.4 V in DMF/Bu NI (0.1 M).
4
3
M
hyperfine coupling constants are directly related to
excess spin density. As follows from data in Table 2,
the unpaired electron in radical anions VIIIa XIa is
mostly delocalized over four carbon atoms in the 1,
4, 5, and 8 positions of the phthalazine moiety. In
going from the most readily reducible unsubstituted
phthalazine (XIII) to more difficultly reducible di-
ethers VIII XI, i.e. with increasing electron-donor
power of the substituents in the 1 and 4 positions, the
spin density on the ring nitrogen atoms and protons
appreciably increases.
Mechanism of electrochemical reduction of 1-
chloro-4-X-phthalazines. The overall electrochemical
reduction process of 1-chloro-4-X-phthalazines I V
(X = Cl, PhO, MeO, EtO, i-PrO) with phthalonitrile
formation involves transfer of two electrons, cleavage
of three bonds, and formation of two new bonds.
The electron transfer induces a profound multistage
transformation of 1-chlorophthalazines I V. In the
absence of halogen, like in unsubstituted phthalazine
(XII) and symmetrical 1,4-disubstituted phthalazines
VIII XI, the one-electron transfer gives rise to
primary radical anions. In these compounds, the
electron transfer is accompanied by reorganization
of the solvation shell and only slightly affects the
reacting species. Extrapolating these results on the
reduction of 1-chlorophthalazines I VII, one can
suggest that here, too, the first stage involves rever-
sible one-electron transfer to form radical anions Ia
VIIa. This suggestion is consistent with the slope of
the wave, which is characteristic of reversible one-
electron transfers (60 mV at 25 C). The first electron
According to Scheme 3, the transfer of two elec-
trons by the ECE or EED mechanism [27, 28] gives
rise to a carbanion which further undergoes cascade
ring cleavage and X elimination reactions.
According to Scheme 4 (both the ECE and EED
mechanisms are possible), the second electron transfer,
dissociation of the N N bond, and formation of a
nitrile bond occur synchronously in one elementary
act, resulting in formation of an imide ion whose
further transformations are similar to those proposed
by Scheme 3.
Finally, it can be proposed (Scheme 5) that the
second electron transfer occurs synchronously with
dissociation of the N N bond, elimination of group
X, and formation of two new C N bonds in one
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 71 No. 10 2001

ELECTROCHEMICAL REDUCTION OF 1,4-DISUBSTITUTED PHTHALAZINES
1643
Scheme 3.
Cl
Cl
X
N
N
N
N
N
N
+ e
Cl
X
X
e
H
X
N
N
e
HD
N
N
Cl
X
quickly
C N
C N
C N
C N
HD
X
C=N
X
C=NH
X
Scheme 4.
geneous electrode reduction, concurrently by the ECE
and EED mechanisms, the latter prevailing. With
1,4-dichlorophthalazine (I), we consider Scheme 5
more probable. The molecule is symmetric, and in
radical anion Ia the N N band and both C Cl bonds
should be loosened (the latter two, to equal extent),
Cl
X
N
N
N
N
Cl
and simultaneously two new
bonds should be
X
formed. Dissociative (C Cl and N N bonds) asso-
ciative (C N) transfer of the second electron com-
pletes N N and C Cl bond cleavages and C N bond
formation. Evidence for this scheme comes from the
fact that even at very high concentrations of proton
donor (phenol, m 10 10000) no new reduction waves
appear in the polarograms, expected by Schemes 3
and 4.
e
C N
C=N
e
Cl
X
Scheme 5.
Vice versa, the appearance of additional waves in
the presence of phenol with 1-chlorophthalazines II V
argues in favor of Schemes 3 and 4. Good evidence
for Scheme 4 might be provided by the observation
of a reduction wave due to dechlorinated 1-X-phthala-
zines in the presence of phenol at potentials in the
range from phthalazine to diethers VIII XI. Com-
pounds II V in the presence of phenol give additional
waves but in another potential range (Table 1). This
may imply either that the intermediate carbanion
undergoes fast heteroring cleavage at a rate higher
than the protonation rate or that the reduction occurs
by Scheme 4. Probably, these additional waves are
associated with protonated products of pyridazine ring
cleavage. Hence, we cannot decide between
Schemes 3 and 4 with the evidence in hand.
Cl
X
N
N
N
N
Cl
X
e
X
C N
C N
e
Cl ,
X
elementary act (here, too, both the ECE and EED
can be operative).
In all the three schemes, apparently, the homo-
geneous reduction involving one-electron carriers
occurs by the ECE mechanism, while the hetero-
As already noted, 1-chloro-4-X-phthalazines II V
can be homogeneously reduced by phthalonitrile
radical anions XIIIa. The homogeneous one-electron
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 71 No. 10 2001

1644
YANILKIN et al.
Were the latter reaction quantitative, the limiting
current of the first reduction wave of 1-chlorophtha-
lazines II V would correspond to n = 1.5, and a
reduction wave of the corresponding diether VIII XI
would be observed with n = 0.5.
ilim
A
,
(a)
50
40
30
3e
2II V
XIIIa + VIII XI
2Cl
We failed to obtain any experimental evidence for
the SRN1 reaction. The limiting current of the first
reduction waves of 1-chloro-4-phenoxyphthalazine
(II) and 1-chloro-4-methoxyphthalazine (III) is linear
20
10
3
2
in concentration over the range 10 10 M (Fig. 7)
and corresponds to tree-electron transfer, but the
polarograms lack the reduction wave of diethers VIII
and, correspondingly, IX. Obviously, the SRN1 reac-
tion does not occur under these conditions. A possible
reason may lie in that pyridazine ring cleavage occurs
not only in the anion-formation, but also in the ra-
dical-formation stage.
0
2
4
6
8
10
103, M
C
ilim
A
,
(b)
20
10
Summarizing the resulting data, we can note that
at any reduction mechanism the tendency of phthal-
azines I V for phthalazine ring cleavage with phthalo-
nitrile formation depends on the ability of substi-
tuents in the 1 and 4 positions to anionoid elimination.
Qualitatively, chloride ion is a better leaving group
than RO. Therefore, 1-chlorophthalazines I V un-
dergo ring cleavage, while diethers VIII XI not.
2
4
6
8
C
103, M
Fig. 7. Plots of the limiting currents of the first reduction
waves of (a) 1-chloro-4-methoxyphtalazine and
(b) 1-chloro-4-phenoxyphthalazine vs. concentration in
In conclusion it may be said that our present results
allow certain predictions as to the possibility of pyri-
dazine ring cleavage with phthalonitrile formation in
reduction of other 1-chlorophthalazine derivatives
having a nucleofuge group, such as PhS , AlkS ,
RSe , etc., in the 4 position. Knowing that C Br and
C I are better cleaved than C Cl, we can propose that
the nitrile pyridazine ring cleavage is also character-
istic of 1-bromo(iodo)-4-X-phthalazines and annelated
heteropyridazines with similar substituents, where X
is a readily leaving group. These questions will be
considered in our subsequent publications.
DMF/Bu NI (0.1 M).
4
transfer can initiate an SRN1 reaction (Scheme 6)
leading to diethers IX XII.
Scheme 6.
Cl
X
Cl
C N
C N
N
N
N
N
XIII +
+
X
EXPERIMENTAL
XIIIa
II V
IIa Va
Compounds I, III, VI IX, XII, and XIII were
synthesized by known procedures [24, 29 32]. The
melting points were determined on a Boetius hot stage,
C: I 163 164 (published data: 164 [24, 29]); III
105 108 (108 [30]); VI 223 224 (223 224 [24]); VII
270 272 (273, 274 [24,29]); VIII, 220 222 (222 [31]);
IX 89 92 (93 [31]); XII 89 90 (90 [24,29]); and XIII
138 140 (139 141 [32]). The NMR spectra were
measured on a Varian T-60 spectrometer, reference
TMS.
X
X
N
N
N
N
X
IIa Va
Cl
X
VIIIa XIa
VIIIa XIa + II V
IIa Va + VIII XI
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 71 No. 10 2001

ELECTROCHEMICAL REDUCTION OF 1,4-DISUBSTITUTED PHTHALAZINES
1645
1-Chloro-4-phenoxyphthalazine (II). To a solu-
tion of 0.65 g of phenol in 20 ml of dry dioxane we
added 0.15 g of Na, and the mixture was heated until
sodium had dissolved completely. After cooling, 1.3 g
of 1,4-dichlorophthalazine was added, the solution
was heated under reflux for 1 h and then filtered while
hot. The solvent was evaporated until crystallization
had began, the crystals that formed were filtered off,
washed with water, and recrystallized from benzene
to obtain 0.96 g (59%) of compound II as colorless
was studied by classical and switching polarography,
cyclic voltammetry, preparative electrolysis, and elec-
trolysis ESR in DMF on the background of Bu4NI
(0.1 M). The deporizer concentration was 1 10 M,
temperature 25.0 C. The solutions were deoxygenated
with argon or nitrogen.
3
The polarograms were obtained on a PU-1 polaro-
graph in a two-electrode mode using a PDA-1 two-
coordinate recorder. Potential sweep rate 10 mV/s.
1
Capillary parameters: m 1.07 mg s , t1 0.5 s. Switch-
1
crystals (prisms), mp 120 122 C. H NMR spectra
ing frequency 10 Hz. The reference electrode was
bottom mercury in the presence of iodide ions (Hg/I ),
potential 0.5 V relative to a saturated calomel
electrode.
(F3CCOOH), , ppm: 7.36 m (5H, Ph), 8.50 asym.m
(4H, H5 H8). Found Cl, %: 14.25. C12H14N2O2.
Calculated Cl, %: 13.84.
1-Chloro-4-ethoxyphthalazine (IV). To a solution
of sodium ethylate (obtained from 0.12 g of sodium)
in 30 ml of ethanol we added 1.0 g of 1,4-dichloro-
phthalazine, and the mixture was heated under reflux
for 0.5 h. The solution was filtered while hot, the
alcohol was evaporated to dryness, and the residue
was recrystallized from aqueous alcohol to obtain
0.73 g (70 %) of compound IV as colorless crystals
The cyclic voltammograms were obtained using a
PI-50-1 potentiostat, a PR-8 programmer, and an
N307/2 two-coordinate recorder. Potential sweep rate
20, 50, 100, 200 mV/s. The working electrode was a
glassy carbon disc electrode 2 mm in diameter,
embedded into fluoroplasic. The reference electrode
was an Ag/AgNO3, 0.1 M acetonitrile solution, po-
tential +0.3 V relative to a saturated calomel electrode.
The auxiliary electrode was a platinum wire. The
potentials in the work are given relative to bottom
mercury.
1
(prisms), mp 72 73 C. H NMR spectrum (CCl4),
, ppm (J, Hz): 1.78 t (3H, CH3, J 7.0), 4.6 q (2H,
CH2, J 7.0), 8.27 asym.m (4H, H5 H8). Found, %: C
54.73; H 4.32; Cl 16.47; N 13.23. C10H9ClN2O2.
Calculated, %: C 55.05; H 4.31; Cl 16.87; N 13.45.
Electrolysis ESR studies were performed on a
system combining a Radiopan SE/X-2544 ESR spec-
trometer and a potentiostat, that allows the electro-
chemical process to be performed directly in an ESR
resonator. The working electrode was a platinum plate,
the auxiliary electrode was a platinum wire, and the
reference electrode was a silver wire.
1-Chloro-4-isopropoxyphthalazine (V) was ob-
tained similarly to product IV. Yield 81%, colorless
prisms, mp 107 109 C (i-PrOH H2O). 1H NMR
spectrum (F3CCOOH), , ppm (J, Hz): 1.62 d (3H,
CH3, J 7.0), 1.75 d (3H, CH3, J 7.0), 5.53 septet (1H,
CH, J 7.0), 8.45 asym.m (4H, H5 H8).
Preparative electrochemical reduction of 1,4-di-
chlorophthalazine was performed in a diaphragm
(ceramics) cell in a galvanostatic mode in DMF using
Bu4NBr as background electrolyte. The dc source was
a B5-49 power pack. The working electrode was
bottom mercury with a working surface area of
63 cm2. The anode was a graphite cylinder. In the
course of electrolysis the solution was purged with
argon. The temperature was 20 C. The quantity of
electricity passed through the solution was determined
as a product of current strength on electrolysis time.
1,4-Diethoxyphthalazine (X) was obtained si-
milarly monosubstitution product III using doubled
fraction of sodium ethylate. Yield 55%, colorless
prisms, mp 122 124 C (first from EtOH H2O, then
from MeCN). 1H NMR spectrum (F3CCOOH), , ppm
(J, Hz): 1.72 m (6H, CH3, J 7.0), 4.76 q (4H, CH2, J
7.0), 8.30 sym.m (4H, H5 H8). Found, %: C 65.23;
H 6.47; N 13.27. C12H14N2O2. Calculated, %: C 65.05;
H 6.42; N 12.84.
1,4-Diisopropoxyphthalazine (XI) was obtained
similarly to monosubstitution product V using
doubled fraction of sodium isopropylate. Yield 30%,
colorless crystals, mp 66 68 C (two times from i-
The working solution (70 ml) was prepared by dis-
solving in DMF of 4 g of 1,4-dichlorophthalazine and
2.25 g of Bu4NBr. In the course of electrolysis,
samples of the reaction mixture were taken at certain
intervals (1 h) and analyzed by polarography. The
reaction progress was followed by the consumption
of the starting compound. The quantity of electricity
required for complete reduction was 2 F/mol (6 h).
The solution was stirred with a magnetic stirrer. After
1
PrOH H2O, 9:1). H NMR spectrum (CCl4), , ppm
(J, Hz): 1.48 d (6H, CH3, J 7.0 ), 1.58 d (6H, CH3, J
7.0), 5.53 m (1H, CH, J 7.0). Found, %: C 68.42; H
7.32; N 11.64. C14H18N2O2. Calculated, %: C 68.29;
H 7.30; N 11.36.
Electrochemical reduction of compounds I XIII
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 71 No. 10 2001

1646
YANILKIN et al.
the electrolysis had been complete, ether and water
(50 ml each) were added to the catholyte. The aqueous
layer was extracted with ether (2 50 ml). The organic
layer was washed with water and dried with Na2SO4.
The solvent was removed, and the residue was re-
crystallized from water to obtain 0.3 g (12%) of
phthalonitrile. The IR spectrum and melting point
(138 141 C) of the product are consistent with
published data [32].
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(Int. Sci. Conf. Organic Synthesis and Combinatorial
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16. Buzykin, B.I., Yanilkin, V.V., Morozov, V.I., Maksi-
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17. Buzykin, B.I., Yanilkin, V.V., Morozov, V.I., Eli-
seenkova, R.M., and Maksimyuk, N.I., Izv. Ross.
Akad. Nauk, Ser. Khim., 2000, no. 1, p. 181.
18. Stone, E.W. and Maki, A.H., J. Chem. Phys., 1963,
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