Alkylation of aniline with methanol in the presence of FeCl 3·6H2O in carbon tetrachloride

Article abstract of DOI:10.1134/S1070428013100072

The reaction of aniline with methanol in the presence of FeCl ₃·6 H₂O in carbon tetrachloride leads to the formation of N-methyl- and N,N-dimethylanilines and 4,4′-methylenebis(N,N- dimethylaniline).

Full text of DOI:10.1134/S1070428013100072

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2013, Vol. 49, No. 10, pp. 1447–1450. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © R.I. Khusnutdinov, A.R. Bayguzina, R.I. Aminov, 2013, published in Zhurnal Organicheskoi Khimii, 2013, Vol. 49, No. 10,
pp. 1469–1472.
Alkylation of Aniline with Methanol
in the Presence of FeCl3 ·6H2O in Carbon Tetrachloride
R. I. Khusnutdinov, A. R. Bayguzina, and R. I. Aminov
Institute of Petrochemistry and Catalysis, Russian Academy of Sciences,
pr. Oktyabrya 141, Ufa, 450075 Bashkortostan, Russia
e-mail: ink@anrb.ru
Received May 4, 2013
Abstract—The reaction of aniline with methanol in the presence of FeCl3 ·6H2O in carbon tetrachloride leads
to the formation of N-methyl- and N,N-dimethylanilines and 4,4′-methylenebis(N,N-dimethylaniline).
DOI: 10.1134/S1070428013100072
N-Methylaniline is one of the most widely used
aniline derivatives. It exhibits antioxidant and anti-
knock properties and is used as anti-knock additive to
motor fuels. N,N-Dimethylaniline is used in industry in
the manufacture of polyester resins, dyes (Malachite
Green, Methylene Blue), and explosives, as well as in
organic synthesis [1].
The main procedures for the synthesis of N-alkyl
aniline derivatives are based on reactions of anilines
with aliphatic alcohols, in particular with methanol, by
the action of sulfuric acid [2] or copper-containing [3]
or ruthenium catalysts [4].
We have now found that N-mono- and N,N-di-
methylanilines can be obtained from aniline and
methanol in carbon tetrachloride in the presence of
FeCl3·6H2O as catalyst. By varying the conditions, the
reaction can be directed toward N-alkylation of aniline
to obtain either a mixture of N-mono- and N,N-di-
methylanilines I and II or a mixture of compound II
and 4,4′-methylenebis(N,N-dimethylaniline) (III). The
yields and composition of the products strongly
depended on the reaction time and reactant concentra-
tion (Scheme 1).
The reaction at 140°C (ratio CCl4–MeOH 1:2) in
4 h gave approximately equal amounts of N-mono- and
N,N-dimethylanilines I and II. After 8 h, N,N-dimeth-
ylaniline (II) became the major product, and the reac-
tion mixture also contained diarylmethane III (yield
6%). The yield of the latter attained 45% after pro-
longed (16 h) heating in the presence of 4 equiv of
methanol.
No N-alkylation of aniline with methanol occurred
in the absence of carbon tetrachloride, other conditions
being equal. With a view to elucidate the role of CCl4,
Scheme 1.
CCl4–MeOH (1:2)
140°C, 4 h
NHMe
NMe2
+
I, 33%
II, 37%
CCl4–MeOH (1:4)
140°C, 8 h
NH2
FeCl3·6H2O
II
+
+
Me2N
NMe2
92%
III, 6%
CCl4–MeOH (1:4)
140°C, 16 h
II
III
57% 45%
1447

KHUSNUTDINOV et al.
1448
Scheme 4.
the reaction mixture was analyzed by HPLC/MS, and
the presence of chloroform, methyl formate (m/z 60
[M]+), and methyl chloride (gas phase, m/z 50 [M]+)
was revealed.
NH2
+
BuCl
IV
According to published data, N-alkylanilines can be
prepared by reaction of aniline with alcohols using
iridium and ruthenium complexes as catalysts [5].
N,N-Dialkylanilines were synthesized by alkylation of
aniline with alkyl halides [6]. Taking into account that
the products of the reaction of aniline with methanol in
the presence of FeCl3·6H2O are N-mono- and N,N-di-
methylanilines I and II, we presumed that the alkylat-
ing agent in the reaction under study is methyl chloride
which may be generated according to Scheme 2.
FeCl3·6H2O
NHBu
NBu2
140°C, 6 h
+
V, 65%
VI, 28%
[BuOH]:[PrCl] = 1:100:100:100, 140°C, 6 h). Ac-
cording to the HPLC/MS data, the product mixture
contained 52% of N-propylaniline (VII), 18% of
N-butylaniline (VIII), 26% of 3-ethyl-2-propylquino-
line (IX), 3% of N-butyl-N-propylaniline (X), and
1% of N,N-dipropylaniline (XI), which were identified
using NIST/EPA/NIH Mass Spectral Library Version
2008 (Scheme 5). The predominant formation of
N-propylaniline (VII) may be rationalized by facile
alkylation of aniline with 1-chloropropane. 2,3-Disub-
stituted quinoline is likely to be formed via oxidation
of butan-1ol with carbon tetrachloride to butyl hypo-
chlorite and butyraldehyde [7] and condensation of the
latter with aniline to produce the corresponding Schiff
base PhN=CHPr which undergoes cyclization by the
action of FeCl3 ·6H2O [9]. These findings confirmed
that methyl chloride acts as alkylating agent in the
reaction of aniline with methanol.
Scheme 2.
[Fe]
MeOH
+
CCl4
MeOCl
CH2O
–CHCl3
[MeOH2]+ Cl–
–HCl
MeOH + HCl
MeCl + H2O
NMe2
NH2
2MeCl
–2HCl
In the first step, methanol is oxidized with carbon
tetrachloride under catalysis by FeCl3 ·6H2O to pro-
duce formaldehyde through intermediate formation of
methyl hypochlorite which decomposes into CH2O and
HCl [7]. Hydrogen chloride thus formed reacts with
methanol to form methyl chloride [8]. The overall
reaction may be represented by Scheme 3.
4,4′-Methylenebis(N,N-dimethylaniline) (III) also
known as Arnolds base is used as indicator in the
determination of medicines, narcotics [10], and hypo-
chlorite ions, as well as building block for the syn-
thesis of tetraazacyclophanes and bis(tetraazacyclo-
phanes) which are widely used in pharmaceutical
chemistry [11].
Scheme 3.
5MeOH PhNMe2
PhNH2
+
2CCl4
+
+ HCl
+
2CHCl3
+
3H2O + MeCl + 2CH2O
Diarylmethane III was formed in quantitative yield
in the reaction of N,N-dimethylaniline (II) with excess
methanol in CCl4 in the presence of FeCl3 ·6H2O
([Fe]:MeOH:CCl4 = 1:400:100; 100°C, 7 h). No re-
action occurred in the absence of methanol. A known
method of synthesis of compound III is based on the
condensation of N,N-dimethylaniline with CH2O in the
presence of HCl, H2SO4, FeCl3, or FeCl3·6H2O [12].
Presumably, in our experiments formaldehyde is
also responsible for the formation of III. In keeping
with published data, in our case generation of formal-
dehyde in situ is possible via catalytic oxidation of
methanol with carbon tetrachloride through interme-
diate methyl hypochlorite (Scheme 2) [7]. The pres-
ence of methyl hypochlorite in the reaction mixture
was confirmed by iodometric titration; the concentra-
In 1 h after the reaction started, the concentration of
HCl was estimated at 163 mg/ml by mercurimetric
titration, while it decreased to 1–3 mg/ml by the end of
the process as a result of consumption for the forma-
tion of methyl chloride which reacted with aniline.
In order to verify the possibility for alkylation of
aniline with methyl chloride generated in situ (taking
into account its high volatility), we carried out model
experiments with butyl chloride (IV). The reaction of
IV with aniline in the presence of FeCl3 ·6H2O afford-
ed N-butyl- and N,N-dibutylanilines V and VI in 65%
and 28% yields, respectively (Scheme 4).
Interesting results were obtained in experiments
utilizing a mixture of butan-1-ol and 1-chloropropane
as alkylating agent ([FeCl3 ·6H2O]:[PhNH2]:[CCl4]:
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 10 2013

ALKYLATION OF ANILINE WITH METHANOL
1449
Scheme 5.
NHPr
NPr2
PrCl
PrCl
VII
XI
NBu2
BuOH
PrCl
140°C, 6 h
BuOH
NH2
NHBu
BuCl
+
CCl4 + FeCl3·6H2O
NPrBu
VIII
BuOH
X
N
Et
Pr
PrCHO
CHPr
N
IX
tion of MeOCl increased in parallel with the methanol
concentration (0.1 mg/ml at a CCl4–MeOH ratio of 1:2
and 0.3 mg/ml at a CCl4–MeOH ratio of 1:4). How-
ever, we failed to detect formaldehyde among gaseous
reaction products; nevertheless, its formation was
indirectly confirmed by the presence in the reaction
mixture of methyl formate as product of its further
oxidation.
Commercially available initial reagents were dis-
tilled prior to use. The reactions were carried out under
continuous stirring in a 10-ml ampule which was
placed into a 17-ml stainless steel high-pressure
reactor with controlled heating.
N-Methylaniline (I). An ampule was charged
under argon with 1 mmol of FeCl3 ·6H2O, 100 mmol
of aniline, 100 mmol of carbon tetrachloride, and
200 mmol of methanol. The ampule was sealed and
heated for 4 h at 140°C under continuous stirring. The
ampule was cooled to room temperature and opened,
the mixture was treated with 5 ml of 10% aqueous
HCl, and the aqueous phase was separated, neutralized
with 10% aqueous sodium hydroxide, and extracted
with methylene chloride (3 ×5 ml). The combined
extracts were filtered and evaporated, and the residue
was distilled under reduced pressure. Yield 33%, light
yellow oily liquid, bp 195–197°C, 76–77°C (10 mm),
nD20 = 1.570; published data [13]: bp 196°C, nD20 = 1.571.
N,N-Dimethylaniline (II) was isolated in a similar
way in the reaction of 100 mmol of aniline with
400 mmol of methanol in 100 mmol of carbon tetra-
chloride in the presence of 1 mmol FeCl3·6H2O (reac-
tion time 8 h). Yield 92 %, yellow oily liquid, bp 193–
194°C, 73–74°C (10 mm), nD20 = 1.555; published data
[13]: bp 194°C, nD20 = 1.557.
EXPERIMENTAL
1
The H and 13C NMR spectra were recorded on
a Bruker Avance-400 spectrometer at 400.13 and
100.62 MHz, respectively, using CDCl3 as solvent; the
chemical shifts were measured relative to tetramethyl-
silane. The mass spectra were obtained on a Shimadzu
GCMS-QP2010Plus instrument (SPB-5 capillary
column, 30 m×0.25 mm; carrier gas helium; oven tem-
perature programming from 40 to 300°C at a rate of
8 deg/min; injector temperature 280°C; ion source
temperature 200°C; electron impact, 70 eV). Chro-
matographic analyses were carried out on Shimadzu
GC-9A and GC-2014 instruments (2-m×3-mm column
packed with 5% of SE-30 on Chromaton N-AW-
HMDS; oven temperature programming from 50 to
270°C at a rate of 8 deg/min; carrier gas helium, flow
rate 47 ml/min). Gaseous products were analyzed
using a Shimadzu GCMS-QP2010Ultra instrument
(Supel-Q PLOT capillary column, 30 m×0.53 mm;
oven temperature programming from 37 to 250°C at
a rate of 10 deg/min; carrier gas helium, flow rate
3 ml/min; ion source temperature 200°C; electron
impact, 70 eV).
4,4′-Methylenebis(N,N-dimethylaniline) (III) was
synthesized in a similar way by reaction of 100 mmol
of N,N-dimethylaniline (II) with 100 mmol of carbon
tetrachloride and 200 mmol of methanol in the pres-
ence of 1 mmol of FeCl3 ·6H2O (reaction time 8 h).
Yield 45%, mp 89–90°C; published data [14]: mp 89–
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 10 2013

KHUSNUTDINOV et al.
1450
1
Watanabe, Y., Morisaki, Y., Kondo, T., and Mitsudo, T.,
91°C. H NMR spectrum, δ, ppm: 2.92 s (12H, CH3),
3.86 s (2H, CH2), 6.84 d (4H, m-H, J = 8.2 Hz), 7.11 d
(4H, o-H, J = 8.4 Hz). 13C NMR spectrum, δC, ppm:
38.82 (CH2), 40.97 (CH3), 113.14 (Cm), 129.45 (Co),
130.42 (Ci), 149.10 (Cp). Mass spectrum, m/z (Irel, %):
254 [M]+ (100), 253 (68), 210 (30), 134 (24), 126 (17),
118 (16).
J. Org. Chem., 1996, vol. 61, p. 4214.
6. Mohri, K., Suzuki, K., Usui, M., Isobe, K., and
Tsuda, Y., Chem. Pharm. Bull., 1995, vol. 43, p. 159;
Hayat, S., Rahman, A., Choudhary, M.I., Khan, K.M.,
Schumann, W., and Bayer, E., Tetrahedron, 2001,
vol. 57, p. 9951; Dehmlow, E.V. and Thieser, R., Tetra-
hedron Lett., 1985, vol. 26, p. 297; Saikia, G. and
Iyer, P., J. Org. Chem., 2010, vol. 75, p. 2714.
7. Khusnutdinov, R.I., Shchadneva, N.A., Bayguzina, A.R.,
Mukminov, R.R., Mayakova, Yu.Yu., Smirnov, A.A.,
and Dzhemilev, U.M., Neftekhimiya, 2008, vol. 48,
p. 467.
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 12-03-00183-a).
REFERENCES
8. Rozanov, V.N. and Treger, Yu.A., Kinet. Katal., 2011,
1. Stytsenko, V.D., Khyu, T.D., and Vinokurov, V.A., Kinet.
Katal., 2005, vol. 46, p. 402.
2. Lebedev, N.N., Khimiya i tekhnologiya osnovnogo
organicheskogo i neftekhimicheskogo sinteza (Chemistry
and Technology of Large-Scale Organic and Petro-
chemical Synthesis), Moscow: Khimiya, 1975.
3. Golovachev, V.A. and Dogadaev, V.N., Russian Patent
no. 2270187, 2004; Mitin, N.A., Slepov, S.K., Merzlya-
kova, N.V., and Utrobin, A.N., Russian Patent
no. 2232749, 2002.
4. Watanabe, Y., Tsuji, Y., Ige, H., Ohsugi, Y., and Ohta, T.,
J. Org. Chem., 1984, vol. 49, p. 3359; Huh, K.-T.,
Tsuji, Y., Kobayashi, M., Okuda, F., and Watanabe, Y.,
Chem. Lett., 1988, vol. 17, p. 449.
vol. 52, p. 670
9. Khusnutdinov, R.I., Bayguzina, A.R., Aminov, R.I., and
Dzhemilev, U.M., Russ. J. Org. Chem., 2012, vol. 48,
p. 690; Khusnutdinov, R.I., Bayguzina, A.R., and
Aminov, R.I., Izv. Akad. Nauk, Ser. Khim., 2013, p. 134.
10. Volf, K. and Pitr, K., Soud. Lek., 1992, vol. 37, p. 62.
11. Lai, C.-F., Odashima, K., and Koga, K., Chem. Pharm.
Bull., 1989, vol. 37, p. 2351.
12. Carr, R.H., US Patent no. 7943724, 2011; Li, Z.X.,
Duan, Z., and Wu, Y.J., Chin. Chem. Lett., 2009, vol. 20,
p. 511.
13. Rabinovich, V.A. and Khavin, Z.Ya., Kratkii khimi-
cheskii spravochnik (Brief Chemical Handbook),
St. Petersburg: Khimiya, 1994, pp. 159, 178.
5. Naskar, S. and Bhattacharjee, M., Tetrahedron Lett.,
2007, vol. 48, p. 3367; Fujita, K., Li, Z., Ozeki, N., and
Yamaguchi, R., Tetrahedron Lett., 2003, vol. 44, p. 2687;
14. Matsubara, Y., Matsuda, T., Kato, A., Kakedai, Y., and
Yamaguchi, Y., Synth. Commun., 2003, vol. 33, p. 1885.
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