Mendeleev Commun., 2016, 26, 555–557
100
80
Table 1 Effect of alkali metal cation on performance of the coupling
reaction.a
Base
PEG/Base ratiob Conversion (%) Yield of 1 (%) Yield of 2 (%)
NaOH 8.3
KOH 8.3
97.7
100
<0.2
75.9
<0.2
<0.2
20.3
<0.2
60
KOH
0
92.7
40
a Reaction conditions: inorganic base (95 mmol), PhNH2 (60 ml), PhNO2
(8.85 g), PEG (35 or 0 g), air (60 mbar), 60°C, 2.5 h. b The ratio is expressed
as a number of PEG oxyethylene units per a metal atom.
0
2000
4000
6000
8000
10000
PEG Mw/Da
Figure 1 Dependence of yield of mixture 1 and 2 on Mw of PEG. Reaction
conditions: PhNH2 (60 ml), PhNO2 (8.85 g), KOH (5.9 g), PEG (50 ml), air
(60 mbar), 60°C, 2.5 h.
energy, the potassium cation forms stronger complexes than the
sodium one with respective PEGs or PEG derivatives by the value
up to 1.2–1.3 kcal mol–1.17
industrial process, and higher than that in the best laboratory
protocol using TMAH base (93%).5,9
The mechanism of the main process is apparently the oxidative
nucleophilic aromatic substitution of hydride,‡‡ most probably
involving the formation of anionic s-complex 4, which cannot
give the respective substitution product directly as the cleavage of
hydride-ion cannot take place. Instead, the intermediate complex
is oxidized and aromatized either by dioxygen or nitro group
(Scheme 2), which accounts for the formation of reduced by-
products, such as nitroso derivatives or phenazine. In fact, the
predominate formation of nitroso derivative 1, while 2 is a minor
product, reveals that nitro group, rather than air dioxygen, is the
main operative oxidant. Such a mechanism was considered for
We have observed that a slow addition of nitrobenzene to a
solution of potassium hydroxide in a mixture of PEG 4000 con-
taining an excess of aniline under aerobic conditions immediately
resulted in red coloration of the reaction mixture. Analysis of
the final (2.5 h, 60°C) reaction mixture by HPLC showed that
products 1 and 2 were formed in 76 and 20% yields, respectively
(Scheme 1).§ An additional advantage of this method is an
apparently higher selectivity, as azobenzene and phenazine, com-
mon by-products of the TMAH method, were formed only in
trace amounts not exceeding 0.9%.
Both the amount of PEG and the nature of inorganic base have
been shown to play a critical role for achieving high selectivity
and performance.¶ The optimal loading of PEG was found to be
0.36 g per mmol of KOH, which is equivalent to ca. 8.3 oxygen
atoms (oxyethylene units of PEG) per one K+, close to common
coordination environment of the potassium cation.10,11
s
imilar reactions in the presence of TMAH and ButOK·(18-crown-6)
bases.6,8
H
N
O
O
Ph–NH–
(K+)PEG
para
+
Ph NO2
Ph
N
attack
H
4
ion pair
The effect of alkali metal cation is outlined in Table 1. The
results clearly show that the system NaOH–PEG 4000 gave very
low yields of the target products.†† We assume that the dramatic
difference between potassium and sodium hydroxides in the
coupling reaction can be explained by ability of the PEGs to
more strongly bind potassium cation in comparison with sodium
ion, resulting in increased basicity and reactivity of OH– in KOH–
PEG.13 The higher stability of potassium complexes compared to
sodium ones was established using conductivity measurements,14
calorimetric15 and matrix-assisted laser desorption ionization
(MALDI) measurements.16 For example, in terms of Gibbs free
O
H+
H+
Ph
N
N
1
2
– H2O
O
O
Ph
N
N
– H2
Scheme 2
When similar reactions are performed under anaerobic condi-
tions, azobenzene is often formed as the reduced by-product.18
In our case, aerobic conditions dramatically decrease the forma-
tion of such useless by-products.
§
General procedure for reaction of nitrobenzene and aniline. A 250 ml
The lower amount of phenazine observed for KOH–PEG
binary system compared to TMAH is difficult to explain in this
stage of investigation. This by-product is likely to be formed via
ortho-attack of the anilide anion on nitrobenzene followed by
intramolecular oxidation and ring closure of the formed ortho-
substituted s-complex. One possible explanation of the observed
phenomenon originates from a larger sterical hindrance of the
anilide anion in tight ion pair [PhNH][K·PEG] that makes such a
pathway less favorable.
The 1 + 2 mixture can be easily converted to 3 in almost
quantitative yield by catalytic hydrogenation (see Scheme 1).19
The hydrogenation catalyzed by 10% Pd/C can be carried out in
the presence of PEG directly in the reaction mixture formed after
the coupling of nitrobenzene and aniline. Further, PEG can be
recovered from the residue left after isolation of 3 by vacuum
distillation, and can be further reused for the coupling of the next
portions of aniline and nitrobenzene several times.
reactor with a mechanical stirrer was charged with PEG 4000 (35 g) and
potassium hydroxide (5.88 g, 95 mmol). For dissolving of KOH small
amount of methanol (3 ml) was added and the mixture was heated to
120°C under vigorous stirring for 20 min. The clean homogenous solution
obtained was cooled to 60°C, and aniline (60 ml, 0.65 mol) was added in
one portion. Then the reactor was connected to vacuum line, and under
pressure of 60 mbar dry air was bubbled through the reaction mixture
at flow rate 375 ml min–1, and the air flow was kept at this rate until
the reaction was complete. Using a syringe pump nitrobenzene (8.85 g,
72 mmol) was introduced at the rate 0.1 ml min–1 keeping the temperature
at 60°C. After additional 1 h excess of aniline was removed by distillation
under 0.1 mbar pressure, and the residue was neutralized with HCl solu-
tion (10 n, 10.5 ml) to give a solution of (4-nitrosophenyl)phenylamine
(10.83 g, 76%) and (4-nitrophenyl)phenylamine (3.85 g, 20%) in PEG 4000/
water. For next manipulations and details, see Online Supplementary
Materials.
¶
The optimized loading of PEG is 0.55 g per mmol of nitrobenzene with
PEG–KOH weight ratio 5.6.
†† Also the KOH–PEG system (instead of early used NaOH/15-crown-5)12
was found to allow the convenient synthesis of bis(indenyl)methanes
starting from indenes and ketones to be performed, e.g., acetone and indene
give 2,2'-bis(1-indenyl)propane in one step in 55% yield. Analogously to
the coupling of aniline and nitrobenzene, the application of NaOH does
not afford the target bis(indenyl)methanes.
‡‡ The radical mechanism cannot be fully excluded because the admixture
of 4-ADPA was detected in the reaction mixture after coupling with
PEG–KOH. The amount of 4-ADPA for PEG 4000 was less than 0.4%,
whereas in case of PEG 300 and 400 it was up to 3.6%.
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