Stable σh-adducts in the reactions of the acridinium cation with heterocyclic N-nucleophiles

Article abstract of DOI:10.1007/s11172-013-0105-2

A reaction of NH-heterocycles with the 10-methylacridinium cation in the presence of a base led to 9,10-dihydro-10-methyl-9-substituted acridines, which can be considered as stable intermediates in the aromatic nucleophilic substitution reaction of hydrogen. The structure of the intermediates was studied and their oxidation potentials were determined. Generally, the oxidation potential was found to symbatically change with the changes in the energy of HOMO.

Full text of DOI:10.1007/s11172-013-0105-2

Russian Chemical Bulletin, International Edition, Vol. 62, No. 3, pp. 773—779, March, 2013
773
Stable Hꢀadducts in the reactions of the acridinium cation
with heterocyclic Nꢀnucleophiles*
A. V. Shchepochkin,a O. N. Chupakhin,a,b V. N. Charushin,a,b G. L. Rusinov,a
Yu. O. Subbotina,a,b P. A. Slepukhin,a and Yu. G. Budnikovac
aInstitute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
22/20 ul. Akademicheskaya, 620019 Ekaterinburg, Russian Federation.
Fax: +7 (343) 374 1189. Eꢀmail: chupakhin@ios.uran.ru
bUral Federal University,
19 ul. Mira, 620002 Ekaterinburg, Russian Federation.
Eꢀmail: chupakhin@ios.uran.ru
cA. E. Arbuzov Institute of Organic and Physical Chemistry Kazan Scientific Center of the Russian Academy of Sciences,
8 ul. Akad. Arbuzova, 420088 Kazan, Russian Federation.
Eꢀmail: yulia@iopc.ru
A reaction of NHꢀheterocycles with the 10ꢀmethylacridinium cation in the presence of
a base led to 9,10ꢀdihydroꢀ10ꢀmethylꢀ9ꢀsubstituted acridines, which can be considered as stable
intermediates in the aromatic nucleophilic substitution reaction of hydrogen. The structure of
the intermediates was studied and their oxidation potentials were determined. Generally, the
oxidation potential was found to symbatically change with the changes in the energy of HOMO.
H
Key words: aromatic nucleophilic substitution of hydrogen,  ꢀadducts, acridine, NHꢀheteroꢀ
cycles, cyclic voltammetry.
Classic methods for the functionalization of aromatic
rings are based on electrophilic substitution reaction of
hydrogen (SEH Ar) and nucleophilic substitution of groups
readily leaving as anions (SNipso Ar). The last decades are
marked by the really triumphant development of the tranꢀ
sition metal catalyzed crossꢀcouplings at the C—X bond
of arenes (X is the group readily leaving as an anion) with
Cꢀ and heteroatomic nucleophiles (Negishi, Kumada, Suꢀ
zuki, Buchwald reactions, etc.). At the same time, the
contemporary requirements stimulate development of
chemical science in agreement with the "green" chemistry
principles and elaboration of environmentally friendly proꢀ
cesses.1 In the year 2005, the Green Chemistry Institute
(GCI, USA) and global pharmaceutical corporations
prioritized directions of the research and development in
the field of chemistry.2 Among other problems, a direct
functionalization of the C—H bond in arenes was put on
the first place.
reactions leading to the formation of C—C, C—N, C—O,
C—P, C—S, C—Si, and C—Hal bonds in various aromatic
compounds of both carboꢀ and heterocyclic series.5—8 The
first step of the SNHꢀreaction includes a nucleophilic atꢀ
tack of the substrate with the formation of the intermediate
Hꢀadduct (Scheme 1). Then follows the step of its aromꢀ
atization, which is accompanied by the leaving of hydroꢀ
gen and an electron pair (formally, the hydride ion) by the
elimination (AE) or oxidation (AO) SNHꢀmechanism.
Rather frequently, the SNH AO reaction is carried out
as a threeꢀcomponent synthesis, i.e., an oxidant is added
to the system simultaneously with the reaction particiꢀ
pants. Obviously, it is necessary in this case to take into
account the susceptibility of the reagents to oxidation:
first of all of the nucleophile, and sometimes of the subꢀ
strate I, too.
Thus, the choice of a proper oxidant is a crucial factor
in accomplishing the SNHꢀconversions. At the present
time, there are no clearꢀcut criteria of such choice, thereꢀ
fore, chemists at large are usually governed by their expeꢀ
rience, intuition, and some empirical rules.9,10 All of this
does not stimulate development of SNHꢀreactions. An apꢀ
proach to the rational choice of the oxidation agent can
be based on the measurement of oxidation potenꢀ
tials of Hꢀadducts II and on their structure. The studies
of the behavior Hꢀintermediates on the anode is of sepaꢀ
One of the atomꢀsaving variations of crossꢀcoupling,
which does not require the use of halides and transition
metal catalysis, is the aromatic nucleophilic substitution
reaction of hydrogen (SNH).3,4 By the present moment,
a vast body of data is accumulated on the SNHꢀcoupling
* Dedicated to Academician of the Russian Academy of Sciences
I. P. Beletskaya on the occasion of her anniversary.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 0772—0778, March, 2013.
1066ꢀ5285/13/6203ꢀ773 © 2013 Springer Science+Business Media, Inc.

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Russ.Chem.Bull., Int.Ed., Vol. 62, No. 3, March, 2013
Shchepochkin et al.
Scheme 1
W is electronꢀwithdrawing group. A is assisting group.
rate interest as an electrochemical version of SNHꢀreꢀ
actions.
Scheme 2
The choice of the acridinium cation as an object for
this study was made based on the fact that it is a conveꢀ
nient model with only one electrophilic center. Besides,
the acridines with substituents at position 9 are of interest
because of their biological activity. Acridine derivatives
are known to act as antiseptics.11 In the last years, they
were found to exhibit antitumor,12,13 antiviral,14,15 antiꢀ
malarial,16 antiprionic,17 and analgesic properties.18 Meanꢀ
while, only a limited amount of works are devoted to the
synthesis and studies of the properties of Hꢀadducts of
acridine with Nꢀnucleophiles. Thus, the synthesis of stable
Hꢀadducts obtained by the attack of morpholine and pipꢀ
eridine on the acridinium cation was reported in the
work.19 Besides, the formation of unstable Nꢀbound Hꢀadꢀ
ducts in the reaction of primary arylamines with 10ꢀmethꢀ
ylacridinium iodide (1) was detected by NMR and UV
spectroscopy. Such adducts were shown to be unstable
and to exist only in solutions at reduced temperatures.20
The only example of thisꢀtype stable Hꢀadduct, which
was characterized by Xꢀray crystallography, was obtained
when 1,2,3ꢀbenzotriazole was used as the nucleophile.21
In the present work, we used a wide range of heteroꢀ
cyclic Nꢀnucleophiles for the synthesis of 9,10ꢀdihydroꢀ
10ꢀmethylꢀ9ꢀsubstituted acridines. The reaction of 10ꢀmeꢀ
thylacridinium iodide (1) with NHꢀheterocycles gave the
corresponding 9,10ꢀdihydroꢀ10ꢀmethylꢀ9ꢀsubstituted acꢀ
ridines 2—9 in high yields (Scheme 2, Table 1). Physical
and spectral characteristics of compounds 2 and 7 agree
with the corresponding characteristics of compounds deꢀ
scribed earlier.19,22
R =
(2),
(3),
(4),
(5),
(6),
(7),
(8),
(9)
Table 1. Characteristics of compounds 2—9
Comꢀ Molecular
pound
Found
Calculated
M.p./C Yield
(%)
formula
(%)
C
H
N
2
3
4
5
6
7
8
9
С20H16N4
С16H14N4
С21H17N3
С26H20N2
С19H19N3
77.09 4.94 17.94
76.90 5.16 17.94 (PriOH)
73.27 5.48 20.42 182
73.26 5.38 21.36 (EtOH)
80.73 5.63 13.22 190
81.00 5.50 13.49 (EtOH)
169
74
85
83
88
79
91
88
72
86.01 5.55
7.74
7.77 (EtOH)
136
78.86 6.62 14.52 (MeOH)
196
86.64 5.59
The 1H NMR spectra of dihydroacridines 2—9 obꢀ
tained exhibit signals for the protons of the added heteroꢀ
cyclic moieties (Table 2), a singlet for the methyl group in
the region  3.39—3.63 and characteristic signals in the
region  6.90—7.80 corresponding to the aromatic protons
of the acridine framework. The spectra of the Nꢀadducts
with the aromatic NHꢀheterocycles 2—6 are distinguished
by the position of the signal for proton H(9) in the region
78.87 6.80 14.59
С18H20N2O 77.06 7.33
77.11 7.19
С18H20N2S 73.15 6.95
72.93 6.80
9.93
9.99 (EtOH)
9.37 160
9.45 (EtOH)
8.96 129
8.97 (EtOH)
141
С22H20N2
84.07 6.49
84.58 6.45

10ꢀMethylꢀ9ꢀsubstituted dihydroacridines
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 3, March, 2013
775
Table 2. 1H NMR spectra of compounds 2—9 in solutions in DMSOꢀd6
Compound

2
3
4
3.63 (s, 3 H, NCH3); 6.96 (s, 2 H, Ar); 7.29—7.55 (m, 9 H, Ar); 7.74 (s, 1 H, H(9)); 7.96 (m, 1 H, Ar)
3.50 (s, 3 H, NCH3); 6.95 (s, 1 H, H(9)); 7.00—7.46 (m, 8 H, Ar); 7.80 (s, 1 H, HAz); 8.14 (s, 1 H, HAz
3.60 (s, 3 H, NCH3); 6.95 (m, 2 H, Ar); 7.14 (m, 2 H, Ar); 7.18 (s, 1 H, H(9)); 7.27 (m, 2 H, Ar);
)
7.36 (m, 4 H, Ar); 7.51 (m, 1 H, Ar); 7.60 (m, 1 H, Ar); 8.00 (s, 1 H, HAz
)
5
6
3.56 (s, 3 H, NCH3); 6.58—6.69 (m, 4 H, Ar); 7.18—7.39 (m, 10 H, Ar); 7.54 (s, 1 H, H(9)); 8.20 (m, 2 H, Ar)
2.02 (s, 3 H, CH3); 2.11 (s, 3 H, CH3); 3.45 (s, 3 H, NCH3); 5.8 (s, 1 H, HAz); 6.73 (s, 1 H, H(9)); 6.92 (m, 4 H,
Ar); 7.13 (m, 2 H, Ar); 7.30 (m, 2 H, Ar)
7
2.13 (m, 4 H, N(CH2)2); 3.35 (m, 4 H, O(CH2)2); 3.39 (s, 3 H, NCH3); 4.64 (s, 1 H, H(9)); 7.00 (m, 2 H, Ar);
7.11 (m, 2 H, Ar); 7.30 (m, 4 H, Ar)
8
9
2.42 (s, 8 H, CH2), 3.39 (s, 3 H, NCH3), 4.78 (s, 1 H, H(9)), 6.99 (m, 2 H, Ar); 7.10 (m, 2 H, Ar); 7.29 (m, 4 H, Ar)
2.66 (m, 2 H, CH2); 2.77 (m, 2 H, CH2); 3.44 (s, 3 H, NCH3); 6.13 (s, 1 H, H(9)); 6.51 (m, 1 H, Ar); 6.93 (m, 3 H,
Ar); 7.03—7.12 (m, 4 H, Ar); 7.27—7.33 (m, 4 H, Ar)
 6.7—7.7, whereas for similar Cꢀadducts, the signal for
this proton is found in the region  5.0—5.5 (see Ref. 23),
while in the case of addition of cycloalkylimines (comꢀ
pounds 7 and 8), the signal for proton H(9) is in the region
 4.64—4.78 (see Table 2).
for the understanding of the transition state structure of
both the addition step and the aromatization of adducts
2—9. Single crystals of compound 3—5, 7, and 8 were
studied by Xꢀray cristallography. The principal crystalꢀ
lographic parameters are given in Table 3. The molecular
structures of compounds and the atom numbering scheme
accepted in the structural experiments are given in Fig. 1.
The studies of geometric configuration of the geminal
center at atom C(9) of the acridine fragment is important
Table 3. Principal crystallographic data and parameters of refinement for the structures of compounds 3—5, 7, and 8
Parameter
3
4
5
7
8
Formula
Temperature/K
Crystal system
Space group
a/Å
b/Å
c/Å
/deg
C16H14N4
295(2)
Monoclinic
P21/n
9.0097(3)
10.4927(4)
14.1909(5)
90
C21H17N3
295(2)
Monoclinic
P21/c
15.0541(13)
10.4942(6)
10.5119(7)
90
C26H20N2
295(2)
Orthorhombic
Pbca
9.1049(8)
17.6977(12)
23.693(2)
90
C18H20N2O
295(2)
Tetragonal
Pꢀ421c
19.4503(12)
19.4503(12)
7.8538(12)
90
C18H20N2S
Monoclinic
P21/n
15.8091(10)
5.6004(5)
17.701(2)
90
/deg
90.958(3)
90
1341.36(8)
4
1.299
0.081
103.436(7)
90
1615.2(2)
4
1.280
0.077
90
90
90
90
103.380(8)
90
1524.7(2)
4
1.291
0.207
/deg
3
V/Å
3817.8(6)
8
1.254
2971.2(5)
8
1.253
Z
dcalc/g cm–3
/mm–1
0.073
0.078
Region of measurements, /deg 2.70 <  < 30.52
2.78 <  < 26.34
7255
2.66 <  < 26.38
16189
2.80 <  < 26.34
6812
3.12 <  < 26.38
5569
Number of observed
9619
reflections
Number of independent reflections
Rint
Number of reflection with
4023
0.0168
2137
3217
0.0298
1452
3900
0.0398
1809
1642
0.0382
927
2999
0.0323
1671
(I > 2(I))
Completeness of
reflection massif (%)
QꢀFactor F2
98.2%
97.3%
99.7%
95.8%
96.6%
1.001
0.0366
1.005
0.0356
1.004
0.0378
1.001
0.0309
1.008
0.0580
R1 (I > 2(I))
wR2 (I > 2(I))
0.0846
0.0758
0.0884
0.0792
0.1946
R1 (on all the parameters)
wR2 (on all the parameters)
Residual electron
0.0700
0.0889
0.137/–0.163
0.0893
0.0798
0.129/–0.150
0.0934
0.0943
0.167/–0.213
0.0660
0.0830
0.146/–0.146
0.0996
0.2047
0.412/–0.238
–3
density (max/min)/e Å

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Shchepochkin et al.
C(17)
C(18)
C(17)
C(19)
C(16)
C(15)
C(18)
C(19)
N(4)
C(15)
N(3)
C(22)
C(20)
C(15)
N(3)
C(16)
C(9)
C(16)
C(21)
C(26)
C(23)
C(24)
C(20)
N(2)
N(2)
C(14)
C(9)
N(2)
C(5)
C(7)
C(10)
C(7)
C(8)
C(25)
C(5)
C(7)
C(5)
C(4)
C(6)
N(1)
C(10)
C(8)
C(9)
C(12)
C(11)
C(2)
C(1)
C(13)
C(8)
C(4)
C(6)
C(3)
C(10)
C(6)
C(13)
N(1)
C(11)
C(12)
C(1)
C(3)
C(13)
C(4)
N(1)
C(12)
C(1)
C(11)
C(14)
C(3)
C(2)
C(21)
C(2)
C(14)
3
4
5
S(1)
O(1)
C(16)
C(17)
C(18)
C(16)
C(15)
N(2)
C(18)
C(17)
N(2)
C(15)
C(7)
C(9)
C(5)
C(7)
C(9)
C(5)
C(10)
C(11)
C(8)
C(13)
C(8)
C(10)
C(11)
C(13)
C(6)
C(3)
C(1)
C(6)
C(3)
C(4)
C(12)
C(1)
C(12)
C(4)
N(1)
N(1)
C(2)
C(14)
C(2)
C(14)
7
8
Fig. 1. Molecular structures of compounds 3—5, 7, and 8.
The Xꢀray diffraction analysis data show that the comꢀ
pounds under study crystallize in the centrosymmetric
space groups of symmetry. The molecular packing of
the compounds is nonspecific, any essential shortened
contacts are absent. As it was already mentioned, the
sp3ꢀhybridized atom at position 9 is the most important
structural element of the molecule (in the structural exꢀ
periment atom C(7)), which causes a distortion of the
acridine system. The conformation of the dihydropyridine
ring in compounds under consideration can be characterꢀ
ized as a pseudoboat, with atoms C(7) and N(1) deviating
from the plane of the ring and the axial position of the
added NHꢀheterocycle. As a result, the dihydropyridine
ring experiences a bend along the axis N(1)—C(7), with
the dihedral angle between the phenylene rings being able
to reach a considerable value (29.67 for compound 7,
Table 4). The bond distances in the phenylene fragments
are generally in good agreement with the standard values,
the spread of the corresponding bond distances does not
exceed 0.01 Å with respect to the average values. The length
of the C(7)—N(2) bond increases in the sequence of comꢀ
pounds 5 < 8 < 4 < 7 < 3, however, the difference between
the maximal and the minimal bond distances is slightly
more than 0.02 Å, which does not allow one to consider
these changes as significant. At the same time, this value
correlates well with the change in the dihedral angle beꢀ
tween the plane of the Nꢀnucleophilic fragment and the
plane determined by atoms N(1)C(7)N(2) (see Table 4).
Especially note that the dihedral angles between the
phenylene rings correlate with the measured oxidaꢀ
tion potentials (see Tables 4 and 5). Thus, as the distorꢀ
tion angle of the acridine system increases in the sequence
of compounds 5, 3, 4, 7, their oxidation potentials deꢀ
crease.
The oxidation potentials of 9,10ꢀdihydroꢀ10ꢀmethylꢀ
9ꢀsubstituted acridines 2—9 were determined by cyclic
voltammetry (see Table 5).
Note that in the earlier works devoted to the study of
electrochemical oxidation of dihydroacridines A on a platꢀ
inum disk electrode with a ring, it was shown that the
oxidation process included the electron transfer leading to
the formation of radical cationic particles B, with their

10ꢀMethylꢀ9ꢀsubstituted dihydroacridines
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 3, March, 2013
777
Table 4. Selected bond distances, bond and dihedral angles for compounds 3—5, 7, and 8
Parameter
Bond
3
4
5
7
8
d/Å
С(7)—Н(7)
С(7)—N(2)
C(6)—C(7)
C(7)—C(8)
N(1)—C(1)
N(1)—C(13)
N(1)—C(14)
C(1)—C(6)
C(8)—C(13)
C(3)—C(4)
C(10)—C(11)
0.970(9)11
1.4929(11)
1.4951(13)
1.4974(12)
1.3979(12)
1.3956(12)
1.4578(12)
1.4001(13)
1.4000(12)
1.3795(17)
1.3715(16)
1.003(13)
1.4860(19)
1.498(2)
1.498(2)
1.395(2)
1.4015(19)
1.465(2)
1.399(2)
1.395(2)
1.368(3)
1.382(3)
0.969(13)
1.4701(19)
1.500(2)
1.495(2)
1.390(2)
1.395(2)
1.454(2)
1.388(2)
1.388(2)
1.363(3)
1.362(3)
1.01(3)1
1.489(3)
1.516(4)
1.505(4)
1.401(4)
1.405(5)
1.465(4)
1.393(4)
1.388(4)
1.365(4)
1.382(6)
0.92(4)1
1.479(4)
1.509(4)
1.495(5)
1.396(4)
1.407(4)
1.465(5)
1.393(5)
1.383(5)
1.351(7)
1.376(6)
Angle
/deg
a



0.325
42.43
21.74
0.376
25.94
28.36
0.101
5.45
6.66
0.352
24.071
29.671
0.344
27.49
24.14
b
c
a Angle  is the deviation of atom C(7) from the plane C(1)C(6)C(8)C(13).
b Angle  is the turn of the plane of Nꢀnucleophile with respect to the plane N(1)C(7)N(2).
c Angle  is the dihedral angle between the phenylene rings in dihydroacridines.
subsequent deprotonation and oxidation of radicals C to
products D of the SNHꢀreaction (Scheme 3).24,25
It is obvious that the step of the singleꢀelectron transꢀ
fer initiating this process should correlate with the HOMO
energies of dihydroacridines. In fact, the calculations
showed that the HOMO energies correlated well enough
with the oxidation potentials of Hꢀadducts under studies.
Quantum chemical calculations of the energies of HOMO,
as the orbitals directly "involved" in the oxidation (see
Table 5), were performed using the GAUSSIAN 09 softꢀ
ware.26 The correlation between the HOMO energy and
the oxidation potential (Fig. 2) allows us to draw a conꢀ
Scheme 3
Table 5. The calculated energies of HOMO and the
experimentally found oxidation potentials
Epox/V
5
1.25
1.05
0.85
0.65
Compound
EHOMO/eV
Epox/V
3
2
2
3
4
5
6
7
8
9
–5.26540
–5.29615
–5.46894
–5.20091
–5.15248
–5.04771
–5.12064
–5.23656
1.01
1.05
0.88
1.28
0.84
0.84
0.82
0.53
4
6
7
8
9
–5.40
–5.30
–5.20
EHOMO/eV
Fig. 2. The correlation dependence between the HOMO enerꢀ
gies and the oxidation potentials Epox of compounds 2—9.

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Russ.Chem.Bull., Int.Ed., Vol. 62, No. 3, March, 2013
Shchepochkin et al.
clusion that the oxidation potentials of compounds, exꢀ
cept 5 and 9, change symbatically with the changes of the
HOMO energies.
It can be suggested that the development of this apꢀ
proach will allow one to use quantum chemical calculaꢀ
tions for the evaluation of stability of forming Hꢀadducts
and their oxidation potentials, that, in turn, will suggest
a more rational choice of synthetic methods and selection
of oxidants for aromatization.
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 12ꢀ03ꢀ90705ꢀ
mob_st.) and the Council on Grants at the President of
the Russian Federation (Program of State Support for
Leading Scientific Schools of the Russian Federation,
Grant NShꢀ55052012.3).
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Experimental
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served as a working electrode, a glass graphite rod as a auxiliary
electrode, Ag/AgCl was a reference electrode. The scanning
rate 100 mV s–1. The concentration of the samples 10–3 M.
Elemental analysis was performed on a Carlo Erba 1108 autoꢀ
1
matic CHNO analyzer. H NMR spectra were obtained on an
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AVANCE DRXꢀ400 spectrometer (Bruker BioSpin) (solvent
DMSOꢀd6), using Me4Si as an internal standard.
Xꢀray diffraction studies were performed on a Xcalibur 3
automatic fourꢀcircle diffractometer, using a standard proceꢀ
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/2ꢀscan technique). The structure was solved and refined using
the SHELX software.27 All the nonhydrogen atoms were refined
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solved and refined independently in isotropic approximation.
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Structural Database (CCDC 929423, 929424, 929426—929428).
Acridine was commercially available from Aldrich. 10ꢀMeꢀ
thylacridinium iodide was synthesized according to the known
procedure.28
9,10ꢀDihydroꢀ10ꢀmethylꢀ9ꢀsubstituted acridines 2—9 (genꢀ
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droxide (38 mg, 0.685 mmol) and the corresponding NHꢀheteroꢀ
cycle (0.685 mmol) were added to a suspension of 10ꢀmethylꢀ
acridinium iodide (1) (200 mg, 0.623 mmol) in ethanol (3 mL).
The reaction mixture was stirred at room temperature for
40—50 min, then diluted with water (15 mL). A precipitate
formed was filtered off, washed with water, and recrystallized
from the corresponding solvent.
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The authors are grateful to Professor A. Rauk (Univerꢀ
sity of Calgary), WestGrid and Compute/Calcul Canada,
for the providing us with the calculation resources and
O. S. El´tsov with coꢀworkers of the NMR spectroscoꢀ
py group of of the Collective Center of the Ural Federal
University for their help in carrying out the NMR exꢀ
periments.

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Received December 17, 2012;
in revised form February 15, 2013