Synthesis and structure of aroylamidines and N-arylbenzamidines hydrochlorides

Article abstract of DOI:10.1134/S1070428012020091

Aroylamidines can be obtained as salts in a reaction of the corresponding arylcarbonitriles with anhydrous ethanol in the presence of dry HCl followed by treating intermediate imidoesters with alcoholic solution of ammonia. N-Arylbenzamidines are obtained by reacting benzonitrile with arylamines in the presence of AlCl₃. The structure of arylamines and the reaction conditions signifi cantly affect the yield of the target product, and sometimes the very possibility of its preparation. Pleiades Publishing, Ltd., 2012.

Full text of DOI:10.1134/S1070428012020091

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2012, Vol. 48, No. 2, pp. 209−213. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © E.V. Kuvaeva, E.V. Fedorova, V.V. Zaitsev, I.P. Yakovlev, V.I. Zakharov, T.L. Semakova, 2012, published in Zhurnal Organicheskoi
Khimii, 2012, Vol. 48, No. 2, pp. 221−225.
Synthesis and Structure of Aroylamidines
and N-Arylbenzamidines Hydrochlorides
E. V. Kuvaeva, E. V. Fedorova, V. V. Zaitsev, I. P. Yakovlev,
V. I. Zakharov, and T. L. Semakova
St. Petersburg State Chemico-Pharmaceutical Academy, St. Petersburg,197376 Russia
e-mail: kuvaeva.lena@yandex.ru
Received September 14, 2011
Abstract—Aroylamidines can be obtained as salts in a reaction of the corresponding arylcarbonitriles with
anhydrous ethanol in the presence of dry HCl followed by treating intermediate imidoesters with alcoholic solution
of ammonia. N-Arylbenzamidines are obtained by reacting benzonitrile with arylamines in the presence of AlCl3.
The structure of arylamines and the reaction conditions significantly affect the yield of the target product, and
sometimes the very possibility of its preparation.
DOI: 10.1134/S1070428012020091
Amidines possess a high biological activity. An ami- initial nitriles Ia–Id are solid crystalline substances. The
dine enzyme (usually in the composition of a heterocycle) use of the anhydrous ethanol as solvent is unfavorable,
is included in the structure of many drugs, for instance, for the arising imidoester IIa–IId dissolves in its excess
of naphthisin, halazolin, phentolamine, chlorodiaz- which greatly impedes its isolation from the reaction
epoxide. Amidine bases are often used as disinfectants. mixture. Therefore we used as solvents benzene or ether.
Many among amidinium arylsulfonates are used in
chemotherapy [1–4]. The known methods of amidines
preparation [5–10] do not possess a general character, and
the results of the studies of amidine structure are not, as
we believe, rigorously founded. This is an obvious gap
in the chemistry of this interesting group of compounds
especially considering their application as initial material
in the synthesis of heterocyclic substances.
The reaction progress and the purity of compounds
obtained were monitored by TLC on Sorbfil plates. The
obtained aroylamidines hydrochlorides IIIa–IIId are
solid colorless or light-yellow crystalline substances, well
soluble in water and ethanol. Their structure was proved
by 1H, 13C NMR, IR, and UV spectra.
NH
dry HCl
.
C2H5OH
+
HCl
R C N
R C
It was shown formerly [11] that the reaction of ace-
tonitrile or benzonitrile with anhydrous ethanol in the
presence of dry HCl followed by treating intermediate
imidoesters with alcoholic solution of ammonia led to
the formation of acetamidine and benzamidine hydro-
chlorides respectively. No published information exists
on such reactions with substituted arylcarbonitriles.
OC2H5
IIa_IId
Ia_Id
_
NH
NH3 C2H5OH
.
HCl
R C
NH2
IIIa_IIId
In the course of our research we established that in the
synthesis of aroylamidines hydrochlorides IIIa–IIId the
molar ratio of ethanol and dry hydrogen chloride should
be exactly observed, or the synthesized imidoesters would
not crystallize. The great attention in performing this reac-
tion should be paid to the choice of the solvent since the
R = C6H4CH3-4 (a), C6H4Cl-4 (b), C6H4NO2-4 (c),
C6H4NO2-3 (d).
The most characteristic signals in the 1H NMR spectra
of the solutions of compounds IIIa–IIId in DMSO-d6 are
+
the peaks of the protons of the groups C=NH2 , NH2
209

KUVAEVA et al.
210
(9.0–9.8 ppm) and of the aromatic ring (7.8–8.8 ppm). In
the IR spectra of aroylamidines hydrochlorides IIIa–IIId
an absorption band appears at 1675–1680 cm–1 corre-
sponding to the stretching vibrations of the C=N bond.
The spectrum also contains the characteristic absorption
bands in the region 3255–3265 and 2720–2730 cm–1
belonging to the stretching vibrations of N–H bonds in
NH2 and C=NH2 groups. In the UV spectra of alcoholic
solutions of compounds IIIa–IIId two strong absorption
bands appeared in the region 210–252 nm.
The structure of N-arylbenzamidines Va–Vj was
1
proved by H, 13C NMR, IR, and UV spectra. The IR
spectra of amidines in question contain two absorption
bands in the region 1610–1620 (C=N) and 3410–3500
(NH2) cm–1. In the UV spectra of alcoholic solutions of
compounds Va–Vj two or three absorption bands are
observed in the region 206–333.6 nm.
1H NMR spectra of N-arylbenzamidines Va–Vj
in DMSO-d6 are characterized by the presence of
the resonance signals of the protons of the aro-
matic rings (~6.6–8.1 ppm), of a signal in the region
~2.1–2.3 ppm (CH3–Ar) in the spectra of com-
pounds Ve–Vg, of protons of the OCH3 group at
3.3 ppm (Vj), and also of the broadened signal in the
region ~6.0–6.7 ppm (NH2).
+
N-Arylbenzamidines Va–Vj were prepared by the
reaction of arylamines IVa–IVj with benzonitrile (Ie)
in the presence of anhydrous aluminum chloride [12].
C N
+
NH2
1
The H NMR spectrum of N-4-tolyl-benzamidine
(Vg) in DMSO-d6 is presented in Fig. 1. The presence
of one broadened signal at 6.2 ppm with the integral
intensity ~2H indicates that this compound exists in the
tautomeric form A. In the presence of tautomer B the
1H NMR spectrum should contain two resonance signals,
and the proton signal of the =NH group would appear
downfield (9.0–10 ppm). No such signals are observed
in the 1H NMR spectra of compounds Va–Vj.
The data of the 2D correlation spectroscopy 15N-
HSQC also confirm that compounds Va–Vj exist in the
tautomer form A. In the spectrum 15N-HSQC of N-4-
tolylbenzamidine (Vg) (Fig. 2) a single correlation peak
is present between the atom 15N and the protons linked
to this atom in the 1H NMR spectrum.
The 13C NMR spectra of compounds Va–Vj along-
side the carbon signals of the benzene rings in the region
~122–152 ppm and the signals of the carbon atom of the
methyl groups (~17 and 55.59 ppm) a signal is observed in
the weak field at ~153–155 ppm belonging to the carbon
atom of the group N–C=N. Hence the reported spectral
data prove that the obtained N-arylbenzamidines Va–Vj
exist in the tautomer form A.
R
IVа_IVj
NH2
Ie
C
AlCl3
N
Vа_Vj
R
R = H (a), 2-Cl (b), 3-Cl (c), 4-Cl (d), 2-CH3 (e), 3-CH3
(f), 4-CH3 (g), 3-NO2 (h), 4-NO2 (i), 4-OCH3 (j).
It turned out that the structure of anilines not only
affected the yield of the amidines, but sometimes pre-
vented their formation. The presence of a nitro group in
the ortho-position of the aniline reduced its reactivity to
such extent that we failed to obtain the expected amidine.
N-Arylbenzamidines Va–Vj are solid colorless or red-
brown crystalline substances, sparingly soluble in water
and ethanol, well soluble in benzene. The homogeneity
of ь N-arylbenzamidines Va–Vj was proved by TLC.
N-Arylbenzamidines may exist in two tautomeric
forms A and B.
The quantum-chemical calculation of the heat of for-
mation of tautomers A, B carried out by the semiempirical
methods AM1, PM3, MNDO, MINDO/3 using program
package GAMESS show that the energetically preferred
tautome form is form A (see the table).
NH2
N
NH
NH
C
C
А
B
EXPERIMENTAL
In [13, 14] the prevalence of tautomer B was stated but
we thought this statement insufficiently confirmed. The
conversion of tautomer B into tautomer A was performed
using a catalyst of a complex structure [14].
1H, 13C, 15N-HSQC were registered on a spectrometer
BrukerAM-400 (400 MHz) from solutions of compounds
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SYNTHESIS AND STRUCTURE OF AROYLAMIDINES
211
9
8
7
6
5
4
3
2
1
ppm
Fig. 1. 1H NMR spectrum of solution of N-4-tolylbenzamidine (Vg) in DMSO-d6.
δ, ppm
0
20
40
60
79 ppm
80
100
120
140
12 11 10
9
8
7
6
5
4
3
2
1
0 δ, ppm
Fig. 2. 15N-HSQC spectrum of solution of N-4-tolylbenzamidine (Vg) in DMSO-d6.
Heat of formation of N-arylbenzamidines Va and Vi in
a vacuum at 0 K
in DMSO-d6. IR spectra were recorded on a Fourier spec-
trophotometer FSM -1201 from crystalline substances
pelletized with KBr. Electron absorption spectra were
taken on a spectrophotometer SF-2000 in quartz cells
1 cm thick from solution of compounds in 96% ethanol,
concentration of solutions 10–4–10–5 mol l−1.
Heat of formation, kJ mol−1
Compd. Tautomer
no.
form
AM1
PM3 MNDO MINDO/3
Va
A
B
A
B
79.58 73.55
83.20 74.91
81.04 62.94
80.48
85.64
94.76
61.32
66.67
41.52
47.03
The homogeneity of compounds obtained and the reac-
tion progress were monitored by TLC on Silufol UV-254
and Sorbfil plates, development under UV irradiation or in
Vi
85.36 64.76 100.98
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KUVAEVA et al.
212
C 41.2; H 4.3; N 20.7. C7H8ClN3O. Calculated, %:
C 41.8; H 4.0; N 20.9.
iodine vapor. Melting points were detemined by capillary
method, and no corrections were done.
N-Arylbenzamidines Va–Vj. To a mixture of
0.34 mol of arylamine IVa–IVj and 0.33 mol of benzo-
nitrile (Ie) was added at stirring within 20 min 0.34 mol
of anhydrous AlCl3. The mixture was heated for 30 min
at 200°C and in the molten form it was slowly poured
into 1.2% HCl solution, 10.0 g of activated carbon was
added, and the reaction mixture was filtered. The filtrate
was poured into 15.5% solution of NaOH. The separated
precipitate was filtered off, dried, and recrystallized from
benzene.
Aroylamidinium chlorides IIIa–IIId. To a solution
of 1 mol of arylcarbonitrile Ia–Id in anhydrous benzene
was added 1 mol of anhydrous ethanol. The mixture was
cooled by ice bath, and dry HCl was passed through it
to saturation. The reaction mixture was left standing in
a refrigerator for 2–3 days. The precipitate of imidoester
hydrochloride IIa–IId was filtered off. To 0.5 mol of salt
IIa–IId was added a solution of 0.8 mol of ammonia in
anhydrous alcohol. The mixture was stirred for 40–48 h,
the precipitate of NH4Cl was filtered off. From the filtrate
the solvent was distilled off, the precipitated amidine
hydrochloride was recrystallized from alcohol.
N-Phenylbenzamidine (Va). Yield 35.6 g (55%).
Colorless crystals, mp 116–118°C, Rf 0.50 (ethyl ac-
etate–hexane, 7:4). IR spectrum, ν, cm–1: 3480 (NH2),
4-Methylbenzamidinium chloride (IIIa). Yield
60.5 g (71%). Colorless crystals, mp 227–229°C, Rf 0.609
(ethyl acetate–hexane, 7:4). IR spectrum, ν, cm–1: 3250
1
1620 (C=N). H NMR spectrum, δ, ppm: 6.02 s (2H,
NH2), 6.86–7.98 m (10H, Ph). 13C NMR spectrum, δ,
ppm: 122.05–136.33 (Ph), 154.14 (N–C=N). Found, %:
C 64.8; H 13.5; N 21.7. C13H12N2. Calculated, %: C 65.0;
H 13.3; N 21.7.
+
1
(NH2), 2720 (NH2 ), 1680 (C=N). H NMR spectrum,
δ, ppm: 2.36 s (3H, Me), 9.29 s (2H, NH2), 9.49 s (2H,
+
NH2 ), 7.36–7.38 d (2H, Ph), 7.78–7.80 d (2H, Ph).
13C NMR spectrum, δ, ppm: 21.56 (Me), 123.17–129.92
(Ph), 165.92 (N–C=N). Found, %: C 56.8; H 6.1; N 15.9.
C8H11ClN2. Calculated, %: C 56.3; H 6.4; N 16.4.
N-2-Chlorophenylbenzamidine (Vb). Yield 37.3 g
(49%). Colorless crystals, mp 116–119°C, Rf 0.84 (ethyl
acetate–hexane, 7:4). IR spectrum, ν, cm–1: 3470 (NH2),
1
1615 (C=N). H NMR spectrum, δ, ppm: 6.18 s (2H,
4-Chlorobenzamidinium chloride (IIIb). Yield
56.3 g (59%). Colorless crystals, mp 242–244°C,
Rf 0.625 (ethyl acetate–hexane, 7:4). IR spectrum, ν,
NH2), 6.91–7.99 m (9H, Ph). 13C NMR spectrum, δ,
ppm: 120.50–149.70 (Ph), 154.40 (N–C=N). Found,
%: C 67.2; H 5.0; N 12.4. C13H11ClN2. Calculated, %:
C 67.6; H 4.8; N 12.1.
cm–1: 3260 (NH2), 2730 (NH2 ), 1675 (C=N). 1H NMR
+
+
spectrum, δ, ppm: 9.40 s (2H, NH2), 9.66 s (2H, NH2 ),
7.56–7.67 d (2H, Ph), 7.89–7.91 d (2H, Ph). 13C NMR
spectrum, δ, ppm: 128.40–134.27 (Ph), 166.45 (N–C=N).
Found, %: C 43.7; H 4.3; N 14.9. C7H8Cl2N2. Calculated,
%: C 44.0; H 4.2; N 14.7.
N-3-Chlorophenylbenzamidine (Vc). Yield 38.0 g
(50%). Colorless crystals, mp 119–121°C, Rf 0.73 (ethyl
acetate–hexane, 7:4). IR spectrum, ν, cm–1: 3500 (NH2),
1
1610 (C=N). H NMR spectrum, δ, ppm: 6.28 s (2H,
NH2), 6.77–7.96 m (9H, Ph). 13C NMR spectrum, δ,
ppm: 114.07–150.71 (Ph), 153.86 (N–C=N). Found,
%: C 67.4; H 4.6; N 12.3. C13H11ClN2. Calculated, %:
C 67.6; H 4.8; N 12.1.
4-Nitrobenzamidinium chloride (IIIc). Yield 74.5 g
(74%). Light-yellow crystals, mp 201–203°C, Rf 0.716
(ethyl acetate–hexane, 7:4). IR spectrum, ν, cm–1: 3265
(NH2), 2720 (NH2 ), 1690 (C=N). 1H NMR spectrum, δ,
+
+
ppm: 9.62 s (2H, NH2), 9.90 s (2H, NH2 ), 8.23–8.26 d
N-4-Chlorophenylbenzamidine (Vd). Yield 39.6 g
(52%). Colorless crystals, mp 114–116°C, Rf 0.76 (ethyl
acetate–hexane, 7:4). IR spectrum, ν, cm–1: 3500 (NH2),
(2H, Ph), 8.36–8.38 d (2H, Ph). 13C NMR spectrum, δ,
ppm: 129.34–136.01 (Ph), 166.54 (N–C=N). Found,
%: C 41.2; H 3.7; N 20.5. C7H8ClN3O. Calculated, %:
C 41.8; H 4.0; N 20.9.
1
1610 (C=N). H NMR spectrum, δ, ppm: 6.22 s (2H,
NH2), 6.80–7.95 m (9H, Ph). 13C NMR spectrum, δ,
ppm: 114.07–136.17 (Ph), 154.66 (N–C=N). Found,
%: C 67.8; H 4.8; N 12.1. C13H11ClN2. Calculated, %:
C 67.6; H 4.8; N 12.1.
3-Nitrobenzamidinium chloride (IIId). Yield
64.5 g (65%). Light-yellow crystals, mp 254–256°C,
Rf 0.710 (ethyl acetate–hexane, 7:4). IR spectrum, ν,
cm–1: 3255 (NH2), 2730 (NH2 ), 1680 (C=N). 1H NMR
+
N-2-Methylphenylbenzamidine (Ve). Yield 43.7 g
(63%). Colorless crystals, mp 102–104°C, Rf 0.67 (ethyl
acetate–hexane, 7:4). IR spectrum, ν, cm–1: 3450 (NH2),
1620 (C=N). 1H NMR spectrum, δ, ppm: 2.10 s (3H, Me),
+
spectrum, δ, ppm: 9.61 s (2H, NH2), 9.85 s (2H, NH2 ),
7.25–7.97 m (4H, Ph). 13C NMR spectrum, δ, ppm:
128.50–135.30 (Ph), 165.94 (N–C=N). Found, %:
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 2 2012

SYNTHESIS AND STRUCTURE OF AROYLAMIDINES
213
5.88 s (2H, NH2), 6.71–7.99 m (9H, Ph). 13C NMR spec-
trum, δ, ppm: 17.54 (Me), 121.30–149.57 (Ph), 153.40
(N–C=N). Found, %: C 79.5; H 6.5; N 13.0. C14H14N2.
Calculated, %: C 80.0; H 6.7; N 13.3.
N-4-Methoxyphenylbenzamidine (Vj). Yield 50.7 g
(68%). Colorless crystals, mp 86–88°C, Rf 0.56 (ethyl
acetate–hexane, 7:4). IR spectrum, ν, cm–1: 3410 (NH2),
1
1620 (C=N). H NMR spectrum, δ, ppm: 3.30 s (3H,
OMe), 6.04 s (2H, NH2), 6.80–7.94 m (9H, Ph). 13C NMR
spectrum, δ, ppm: 55.59 (OMe), 115.03–143.86 (Ph),
154.67 (N–C=N). Found, %: C 73.8; H 6.8; N 12.1.
C14H14N2O. Calculated, %: C 74.2; H 6.2; N 12.4.
N-3-Methylphenylbenzamidine (Vf). Yield 42.3 g
(61%). Colorless crystals, mp 110–113°C, Rf 0.61 (ethyl
acetate–hexane, 7:4). IR spectrum, ν, cm–1: 3460 (NH2),
1620 (C=N). 1H NMR spectrum, δ, ppm: 2.30 s (3H, Me),
5.99 s (2H, NH2), 6.63–7.96 m (9H, Ph). 13C NMR spec-
trum, δ, ppm: 17.98 (Me), 121.30–149.57 (Ph), 153.38
(N–C=N). Found, %: C 80.1; H 6.7; N 13.3. C14H14N2.
Calculated, %: C 80.0; H 6.7; N 13.3.
REFERENCES
1. Short, F. and Oxley, P., US Patent 2433489, 1947.
2. Fulton, J.D., Ann. Tropical, Med. Parasitol., 1942, vol. 36,
N-4-Methylphenylbenzamidine (Vg). Yield 41.6 g
(60%). Colorless crystals, mp 101–103°C, Rf 0.56 (ethyl
acetate–hexane, 7:4). IR spectrum, ν, cm–1: 3450 (NH2),
1615 (C=N). 1H NMR spectrum, δ, ppm: 2.28 s (3H, Me),
6.20 s (2H, NH2), 6.75–7.97 m (9H, Ph). 13C NMR spec-
trum, δ, ppm: 16.98 (Me), 120.09–135.40 (Ph), 154.05
(N–C=N). Found, %: C 79.7; H 6.5; N 13.1. C14H14N2.
Calculated, %: C 80.0; H 6.7; N 13.3.
p. 131.
3. Shriner, R.L., Chem. Rev., 1944, vol. 35, p. 360.
4. Evans, D.G., Lancet, 1944, p. 523.
5. Houben, J., Die Methoden der organischen Chemie,
Leipzig: Georg Thieme, 1930.
6. Oxley, P. and Short, W., J. Shem. Soc., 1946, p. 147.
7. Short, F. and Oxley, P., US Patent 2451779, 1948.
8. Franklin, J., J. Am. Chem. Soc., 1933, vol. 55, p. 4912.
9. Franklin, J., Nitrogen, System of Compounds, 1935, p. 271.
N-3-Nitrophenylbenzamidine (Vh). Yield 40.4 g
(50%). Light-yellow crystals, mp 135–137°C, Rf 0.58
(ethyl acetate–hexane, 7:4). IR spectrum, ν, cm–1: 3480
(NH2), 1615 (C=N). 1H NMR spectrum, δ, ppm: 6.60 s
(2H, NH2), 7.25–7.97 m (9H, Ph). 13C NMR spectrum,
δ, ppm: 116.60–151.78 (Ph), 154.90 (N–C=N). Found,
%: C 64.3; H 4.5; N 17.6. C13H11N3O2. Calculated, %:
C 64.7; H 4.6; N 17.4.
10. Grivas, J.C. and Taurins, A., Can. J. Chem., 1961, vol. 39,
p. 761.
11. Organic Synthesis: An Annual Publication of Satisfactory
Methods for the Preparation of Organic Chemicals, New
York, 1949, no. 1, p. 66.
N-4-Nitrophenylbenzamidine (Vi). Yield 42.9 g
(53%). Red-brown crystals, mp 165–167°C, Rf 0.81
(ethyl acetate–hexane, 7:4). IR spectrum, ν, cm–1: 3510
(NH2), 1610 (C=N). 1H NMR spectrum, δ, ppm: 6.73 s
(2H, NH2), 6.76–8.14 m (9H, Ph). 13C NMR spectrum,
δ, ppm: 123.90–137.40 (Ph), 155.45 (N–C=N). Found,
%: C 64.4; H 4.5; N 17.4. C13H11N3O2. Calculated, %:
C 64.7; H 4.6; N 17.4.
12. Organic Synthesis: An Annual Publication of Satisfactory
Methods for the Preparation of Organic Chemicals, New
York, 1958. no. 8, p. 62.
13. Zhou, L. and Zhang, Y., Synth. Commun. 1998, vol. 28,
p. 3249.
14. Wang, J., Xu F., Cai, T., and Shen, Q., Org. Lett. 2008,
vol. 20, p. 445.
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