Mendeleev Commun., 2015, 25, 41–43
Table 1 Screening of the conditions for the synthesis of 3-chlorobenzoic
acid 2b from 4-chloronitrobenzene 1b (4 mmol) by the von Richter reaction
Table 2 Synthesis of benzoic acids 2a,c–f from nitrobezenes 1a,c–f by the
von Richter reaction in the presence of 175 mol% of [bmim]BF4 at 85°C.
in the presence of ILs.
Yield
of 2 (%)
(lit. data)
1
KCN/
EtOH/ H2O/
Yield
of 2 (%)
Entry
t/h
Isolated
T/°C t/h yield of
2b (%)
(4 mmol) mmol
ml
ml
KCN/ EtOH/ H2O/
mmol ml
Entry
IL (mmol)
ml
1
2
3
1a
1a
1a
20
40
80
5
5
7
5
5
7
90 2a (0)
90 2a (26)
90 2a (44)
109(b) a
09(b) b
1
2
20
20
20
20
20
20
40
80
20
20
0.5
3
0.5
3
[bmim]BF4 (14)
[bmim]BF4 (4)
[bmim]BF4 (7)
[bmim]BF4 (7)
[bmim]BF4 (7)
[bmim]BF4 (7)
[bmim]BF4 (7)
[bmim]BF4 (7)
[bmim]PF6 (7)
110 20
0
40
48
85
85
8
9
3
5
5
4
5
6
1c
1c
1c
20
40
80
5
5
7
5
5
7
90 2c (40)
4
5
5
85 13 61
85 18 70
85 20 70
85 20 68
60 2c (67) 379(b) c
5
5
5
12 2c (52)
6
5
5
7
8
9
1d
1d
1d
20
40
80
5
5
7
5
5
7
50 2d (52)
7
5
5
20 — (42)d 09(b) e
8
7
7
85
8
58
8
— (41)d
9
5
5
85 40 34
10
11
12
1e
1e
1e
20
40
80
5
5
7
5
5
7
90 2e (0)
10
5
5
[emim](C2F5)3PF3 (7) 85 50
0
30 2e (61) 409(b) f
20 2e (50)
performed in 4 mmol scale of reactant 1b (Table 1).† Heating
the mixture of nitrobenzene 1b and KCN in [bmim]BF4 in the
presence of little EtOH and H2O amounts at 110°C for 20 h gave
only tar materials (Table 1, entry 1). Therefore, the temperature
was reduced to 85°C, EtOH and H2O were used in larger amounts
and the ratio between of 1b, KCN, EtOH, H2O and IL was varied.
At first, the completion of reaction was monitored by TLC (dis-
appearance of starting nitrobenzene 1b). Prolongation of reaction
time promoted raising the yield of 2b twice (entries 5–7). Since
the outcome of the reactions with the KCN:1b molar ratio 5:1,
10:1 and 20:1 was comparable (entries 5–8), a fivefold KCN
excess was used in the next experiments. The optimum molar ratio
[bmim]BF4 : 1b was found to be 1.75:1 (entries 3–8). Optimum
EtOH and H2O amounts for 4 mmol of 1b proved to be 5 ml of
each solvent (entries 3–7). When the KCN:1b molar ratio was
20:1, EtOH and H2O amounts were increased to 7 ml (entry 8).
Apart from [bmim]BF4, two other ILs – 1-butyl-3-methyl-
imidazolium hexafluorophosphate ([bmim]PF6) and 1-ethyl-
3-methylimidazolium trifluorotris(pentafluoroethyl)phosphate
([emim](C2F5)3PF3) – were tested. Ionic liquid [bmim]PF6 was
less effective than [bmim]BF4 (entry 9), whereas in the case of
[emim](C2F5)3PF3 the reaction did not actually occur (entry 10).
Therefore, [bmim]BF4 was used further on.
13
14
15
1f
1f
1f
20
40
80
5
5
7
5
5
7
90 2f (0)
39(a) g
90 2f (12)
09(d) h
40 2f (15)
a Sealed tube, 180°C, 1.5 h. b Sealed tube, 160°C, 2 h. c 48 h reflux in 48%
EtOH, 8-fold molar excess of KCN. d 4-Ethoxynitrobenzene was a product.
e Sealed tube, 150°C, 1 h, or 5% of 4-ethoxynitrobenzene. f Sealed tube,
150°C, 1 h. g Sealed tube, 170–180°C, 1 h. h 72 h reflux in 48% EtOH.
excess of KCN was transformed to 4-ethoxynitrobenzene instead
of 3-fluorobenzoic acid 2d (entries 8, 9). Therefore, KCN amount
was screened for nitrobenzenes 1a,e,f. The fivefold KCN molar
excess was insufficient for these compounds to react even at
90 h heating (see Table 2, entries 1, 10, 13), while the 10-fold and
20-fold KCN molar excess provided positive results. Benzoic
acid 2a was prepared in 26% yield with 10-fold and 44% yield
with 20-fold molar excess of KCN (entries 2, 3). 3-Iodobenzoic
acid 2e was obtained in 61% yield with 10-fold and in 50% yield
with 20-fold molar excess of KCN (entries 11, 12). 3-Methoxy-
benzoic acid 2f was merely yielded in 12% with 10-fold and
15% with 20-fold molar excess of KCN on heating for 90 and
40 h, respectively, on full conversion of initial nitrobenzene 1f
(entries 14, 15). Structures of compounds obtained were estab-
lished by a comparison of their melting points, IR, 1H, 13C NMR
and mass spectra with published data.
In summary, the von Richter reaction of nitroarenes 1a–f in
the presence of ILs provided results which were inaccessible
under previously described conditions (Table 2, the last column).
We found that the increase in electron-donating properties of
substituents in nitrobenzenes decelerated the reaction. Our results
represent the first example of nucleophilic aromatic cine-sub-
stitution of hydrogen promoted by ionic liquids.
Other nitrobenzenes 1a,c–f (Table 2) were treated similarly
under the optimized conditions (see Table 1, entries 5, 6). How-
ever, under these conditions, only 4-fluoronitrobenzene 1d gave
the expected 3-fluorobenzoic acid 2d in 52% yield (Table 2,
entry 7). Heating for 90 h was needed to prepare 3-bromobenzoic
acid 2c from 4-bromonitrobenzene 1c in 40% yield (entry 4).
Raising KCN amount to 10 or 20 mol per 1 mol of 1c rose the
yield of 2c to 67% (60 h, entry 5), or to 52% (12 h, entry 6).
Interestingly, 4-fluoronitrobenzene 1d with 10 and 20-fold molar
References
†
General procedure. A mixture of nitrobenzene 1 (4 mmol), KCN (20,
1 (a) F. Terrier, Modern Nucleophilic Aromatic Substitution, Wiley-VCH,
Weinheim, 2013, ch. 6; (b) F. Terrier, Nucleophilic Aromatic Displace-
ment, Verlag Chemie, Weinheim, 1991; (c) O. N. Chupakhin, V. N.
Charushin and H. C. van der Plas, Nucleophilic Aromatic Substitution of
Hydrogen, Academic Press, San Diego, 1994.
40 or 80 mmol), EtOH (5 or 7 ml), water (5 or 7 ml) and [bmim]BF4
(7 mmol, 175 mol%) was heated on the oil bath with stirring at 85°C (see
Tables 1 and 2). Then 10 ml of water was added and the mixture was
extracted with CH2Cl2 (3×10 ml) and diethyl ether (3×20 ml). The aqueous
layer was acidified with HCl to pH 1–2 and extracted with diethyl ether
(3×20 ml). Magnesium sulfate (~5 g) and absorbent carbon (~1 g) were
added to the ether layer and this was stirred for 5 h. The solid was filtered
off, the filtrate was evaporated and the residue was crystallized from the
corresponding solvent to give product 2.
2 M. Ma˛kosza, Chem. Soc. Rev., 2010, 39, 2855.
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4 M. Ma˛kosza and J. Winiarski, Acc. Chem. Res., 1987, 20, 282;
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(c) M. Ma˛kosza and A. Kwast, J. Phys. Org. Chem., 1998, 11, 341.
5 (a) V. von Richter, Chem. Ber., 1871, 4, 21; (b) V. von Richter, Chem.
Ber., 1875, 8, 1418; (c) M. J. Rosenblum, J. Am. Chem. Soc., 1960, 82,
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(e) S. Blazej, A. Kwast and M. Ma˛kosza, Tetrahedron Lett., 2004, 45, 3193.
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(b) Z. Wrobel, Eur. J. Org. Chem., 2000, 521.
Benzoic acid 2a: mp 121–122°C (H2O) (lit.,13 121–123°C).
3-Chlorobenzoic acid 2b: mp 154–156°C (EtOH) (lit.,14 154–158°C).
3-Bromobenzoic acid 2c: mp 156–157°C (EtOH) (lit.,15 156–158°C).
3-Fluorobenzoic acid 2d: mp 122–123°C (H2O) (lit.,16 122–123°C).
3-Iodobenzoic acid 2e: mp 184–185°C (PriOH) (lit.,17 185–186°C).
3-Methoxybenzoic acid 2f: mp 106–107°C (H2O) (lit.,18 107–108°C).
4-Ethoxynitrobenzene: mp 55–56°C (light petroleum) (lit.,19 55–56°C).
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