Hydrogenation of aromatic nitro compounds with an inexpensive and efficient CuSO4/CoCl2 catalyst prepared in situ using NaBH 4 as the hydrogen source

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Hydrogenation of Aromatic Nitro
Compounds with an Inexpensive and
Efficient CuSO4/CoCl2 Catalyst Prepared
in situ using NaBH4 as the Hydrogen
Source
Mario Fickera, Johannes F. Petersena, Jon S. Hansena & Jørn B.
Christensena
a Department of Chemistry, University of Copenhagen,
Thorvaldsensvej 40, DK-1871, Frederiksberg C, Denmark
Published online: 26 Mar 2014.
To cite this article: Mario Ficker, Johannes F. Petersen, Jon S. Hansen & Jørn B. Christensen
(2014) Hydrogenation of Aromatic Nitro Compounds with an Inexpensive and Efficient CuSO4/
CoCl2 Catalyst Prepared in situ using NaBH4 as the Hydrogen Source, Organic Preparations
and Procedures International: The New Journal for Organic Synthesis, 46:2, 176-182, DOI:
10.1080/00304948.2014.884374
To link to this article: http://dx.doi.org/10.1080/00304948.2014.884374
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Organic Preparations and Procedures International, 46:176–182, 2014
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2014.884374
OPPI BRIEFS
Hydrogenation of Aromatic Nitro Compounds
with an Inexpensive and Efficient CuSO4/CoCl2
Catalyst Prepared in situ using NaBH4
as the Hydrogen Source
Mario Ficker, Johannes F. Petersen, Jon S. Hansen,
and Jørn B. Christensen
Department of Chemistry, University of Copenhagen, Thorvaldsensvej 40,
DK-1871, Frederiksberg C, Denmark
Aromatic nitro compounds are in general not reduced by sodium borohydride. A number
of research groups have investigated d-block metal salts reduced in situ to form a finely
dispersed catalyst for such reductions with sodium borohydride.1 However, current systems
have disadvantages such as high catalytic loading, long reaction times and low reactivity
resulting in low to moderate yields. Recently Pogorelic´ et al. reported the use of Raney-
nickel and sodium borohydride to reduce a number of aromatic nitro compounds.2 Although
the reaction proceeded rapidly and very good yields, a large amount of expensive catalyst
had to be employed in comparison to the system reported herein. The combination of
copper(II) sulfate and sodium borohydride has previously been reported to reduce aromatic
nitro compounds3,4 as well as some alkenes.4 We discovered serendipitously that the yields
were dramatically dependent on the batch of copper(II) sulfate employed. Because an
inductively coupled plasma mass spectrometry (ICP-MS) analysis showed the presence of
trace amounts of other metals including nickel in some batches of commercial copper(II)
sulfate, we carried out a systematic screening of the catalytic activity of copper(II) sulfate
in combination with sodium borohydride and small amounts of other transition metals.
Although the cobalt-boride particles produced by reduction of cobalt(II) with sodium
borohydride5 are capable of reducing a number of functional groups,1,6–11 these reduc-
tions suffer from long reaction times, low yields and require very large catalyst loading
(>100 mol%). Ding et al.13 showed that copper-cobalt-boride promotes hydrogen evolution
from sodium borohydride solutions by doping cobalt-boride with other transition metals
such as iron, chromium or copper has also been found to increase the rate of the hydrogen
Submitted by April 10, 2013.
Address correspondence to Jørn B. Christensen, University of Copenhagen, Universitetsparken
5, DK-2100 Copenhagen Ø, Denmark. E-mail: jbc@chem.ku.dk
176

Hydrogenation of Aromatic Nitro Compounds
177
evolution from sodium borohydride.12 However, none of these alloys have so far been tested
for catalytic activity in hydrogenations.
We found the best system turned out to be a copper-cobalt combination. All the
hydrogenations were performed by addition of methanolic solutions of CuSO4 and CoCl2
to a solution of the substrate in methanol. Subsequent addition of NaBH4 generated the
catalyst in situ, and further addition of NaBH4 in small portions led to the generation
of hydrogen and reduction of the substrate. The presence of an inert atmosphere is not
required. Typically 3 mol% Cu and 0.3 mol% Co in methanol were used to perform these
reductions. Reaction times varied from 20 to 45 min. All the reactions were performed
at ambient temperature and are exothermic leading to a slight rise in the temperature to
30–40◦C. Although cooling was not necessary in small-scale (4 mmol) reactions, scale-up
(10 mmol) required the use of a reflux condenser.
(a) R = Rꢀ = Rꢀꢀ = H (b) R = Me Rꢀ = Rꢀꢀ = H (c) R = H Rꢀ = Me Rꢀꢀ = H (d) R = Rꢀ =
H Rꢀꢀ = Me (e) R = Rꢀ = H Rꢀꢀ = F (f) R = Rꢀ = H Rꢀꢀ = Cl (g) R = Rꢀ = H Rꢀꢀ = I (h) R = Rꢀ =
H Rꢀꢀ = N-morpholino (i) R = H Rꢀ = Br Rꢀꢀ = NH2 (j) R = Rꢀ = H Rꢀꢀ = CO2Me
As shown in Table 1, a number of substituents are tolerated and most of the yields
(by GC) are nearly quantitative. Because of the poor solubility of p-nitroiodobenzene (1g)
in pure methanol, its reduction required a change in solvent to a mixture of methanol and
toluene which in turn necessitated heating, a higher catalyst loading and extended reaction
times to achieve quantitative conversion to p-iodoaniline (2g). A common problem with
some of the halogen-containing compounds is concurrent reductive dehalogenation (1g
and 1i). Thus although chlorine and fluorine atoms of 1e and 1f survived unscathed, the
bromine and iodine of 1g and 1i were hydrogenolized to a small extent. Although we did
not attempt to purify these hydrochloride salts, it might be possible to obtain pure 2g and
2i prior to conversion to their hydrochloride salts.
In conclusion, we have developed a new system for the hydrogenation of nitro com-
pounds using NaBH4 and inexpensive starting materials. It does not require any specialized
glassware or equipment, and can be performed under ambient conditions. The reaction is
completed in less than an hour and the work-up is rapid and easy.
Experimental Section
General Methods
Standard laboratory glassware was used. All starting materials were obtained from com-
mercial suppliers and used as received. N-(p-Nitrophenyl) morpholine14 was prepared by a

178
Christensen et al.
Table 1
Amines (as HCl salts) from Catalytic Reduction of Nitro Compoundsa
Amineb
(salt)
mp. (◦C)
Lit. mp.
(◦C)
Yieldc
(%)
Catalyst
NaBH4
(equiv.)
GC-MS
(m/z)
2a
2b
2c
2d
2e
2f
190–191
212–214
205–206
231–234
235–237
239–240
197–19915
21416
95
95
3.0 mol% Cu
0.3 mol% Co
3.0 mol% Cu
0.3 mol% Co
3.0 mol% Cu
0.3 mol% Co
3.0 mol% Cu
0.3 mol% Co
3.0 mol% Cu
0.3 mol% Co
3.0 mol% Cu
0.3 mol% Co
9.0 mol% Cu
0.9 mol% Co
1.5 mol% Cu
0.15 mol% Co
3.0 mol% Cu
0.3 mol% Co
4.0 mol% Cu
0.4 mol% Co
3.0
3.0
3.0
3.0
3.5
3.0
6.0
3.0
3.0
3.5
93.2
[M+]
107.2
[M+]
107.2
[M+]
107.2
[M+]
111.2
[M+]
127.1
[M+]
219.0
[M+]
178.1
[M+]
186.1
[M+]
151.2
[M+]
20517
96
232–23218
25319
96
97d
94
249–25118
f
2g
2h
2i
-
86e,f
91d
89e,f
87d
252–254
f
-
2j
252–256
27019
(a) Amines isolated as HCl salts. (b) Time is 25 min unless otherwise noted. (c) Yields of free
amines were nearly quantitative by GC-MS except for 2g and 2i. (d) Time: 30 min. (e) Toluene:MeOH
(1:2) solvent at 65◦C, 45 min. (f) Partial dehalogenation occurs: 2g is contaminated with 10% aniline
and 2i is contaminated with 9% aniline as determined by GC-MS.
published procedure. Solvents were HPLC grade and used as received. Methanol was dried
1
13
˚
over molecular sieves (3 A) and stored under a nitrogen atmosphere. H-NMR and C-NMR
spectra were performed on a 300 MHz NMR (Varian) spectrometer (300 MHz 1H-NMR,
75 MHz 13C-NMR) or on a 500 MHz NMR (Bruker) spectrometer (500 MHz H-NMR,
1
125 MHz 13C-NMR). Chemical shifts are reported in δ (ppm) downfield from TMS, with the
resonance of the hydrogen of the residual undeuterated solvent used as internal standards.
Proton couplings are reported as s (singlet), d (doublet), t (triplet), q (quartet), br (broad)
and m (multiplet), coupling constants are given in Hertz (Hz). Gas chromatography-mass
spectrometry (GC-MS) was performed on an Agilent 6890 A (G1530A) gas chromatograph
coupled with an Agilent mass selective detector 5973 Network. The temperature program
was 1 min at 100◦C, then ramp of 50 K/min to 300◦C, then 10 min at 300◦C.
Standard in situ Generation of the Catalyst
In general, the hydrogenation catalyst was prepared by dissolving the required amount
of CuSO4·5H2O and CoCl2·6H2O in methanol, which was added to a solution of the

Hydrogenation of Aromatic Nitro Compounds
179
starting material in methanol. The active catalyst was then generated in situ by addition
of NaBH4 to the reaction mixture leading to the reduction of the metal salts to the black
highly dispersed copper-cobalt-boride catalyst which instantly starts to decompose NaBH4
to form hydrogen gas. Further portionwise addition of NaBH4 over a period of 25–40 min
completes the reduction of the nitro groups.
Since small catalyst amounts were typically used to perform the hydrogenations, a
catalyst stock solution containing 0.04 M CuSO4·5H2O and 0.004 M CoCl2·6H2O was
prepared in methanol by dissolving 100 mg CuSO4·5H2O and 9.5 mg CoCl2·6H2O in
10 ml water-free methanol. Although, the reaction tolerates the presence of small amounts
of water introduced by the precursor salts, larger amounts of water result in aggregation of
the catalyst.
General Procedure for the Reduction of Aromatic Nitro Compounds
The catalyst precursor in form of a 0.04 M CuSO4 and 0.004 M CoCl2 solution (3.0 ml,
3.0 mol% CuSO4, 0.3 mol% CoCl2) was added to a magnetically stirred solution of
the nitro compound (4 mmol) in 25 ml methanol. The reaction was initiated by adding
an initial portion of 210 mg (5.6 mmol) NaBH4, resulting in a color change to black
(catalyst generated in situ) and vigorous gas evolution. Additional portions of NaBH4
(7 × 35 mg, 7 × 0.9 mmol) NaBH4 were added in intervals of 3 min. Although the
reaction was carried out at room temperature and under normal atmosphere, the genera-
tion of heat due to the exothermic character of the reaction usually heated the reaction
mixture to 30–40◦C and cooling is generally not necessary on a small scale. However,
for large scale reactions (10 mmol), a reflux condenser was attached. After 25 min,
the reaction mixture was quenched by adding 30 ml of water and extracted with 3 ×
40 ml of CH2Cl2. The combined organic layers were dried over MgSO4. After removal
of the drying agent, 6 M HCl in ether (10 ml) was added to produce the more stable
hydrochloride, which was freed from excess HCl, CH2Cl2 and Et2O under reduced pres-
1
13
sure (10 mmHg). An aliquot of the amine was analyzed using GC-MS, H-NMR and
C-NMR. The NMR data for the compounds are shown in Table 2.
Aniline Hydrochloride (2a)
Yield: 490 mg (95%), white crystals, mp. 190–191◦C, lit.15 197–199◦C; GC-MS: m/z =
93.2 [M]+.
o-Toluidine Hydrochloride (2b)
Yield: 545 mg (95%), white crystals, mp. 212–214◦C, lit.16 214◦C; GC-MS: m/z = 107.2
[M]+.
m-Toluidine Hydrochloride (2c)
Yield: 550 mg (96%), white crystals, mp. 205–206◦C, lit.17 205◦C; GC-MS: m/z = 107.2
[M]+.

180
Christensen et al.
Table 2
1H- and 13C-NMR Spectra Data of Amine Hydrochlorides
Cmpd
Solvent
1H-NMR (δ)
13C-NMR (δ)
2a
MeOD-d4 7.56–7.60 (m, 2 H); 7.51–7.55 (m, 1 131.93; 131.29; 130.26;
H); 7.20–7.45 (m, 2 H);
DMSO-d6 10.39 (br, 3 H); 7.48–7.53 (m, 1 H); 132.02; 131.26; 130.80;
7.27–7.32 (m, 3 H); 2.39 (s, 3 H) 128.07; 126.98; 123.31; 17.15
DMSO-d6 10.38 (br, 3 H); 7.33–7.39 (m, 1 H); 139.35; 131.97; 129.51;
7.16–7.23 (m, 3 H); 2.33 (s, 3 H) 128.50; 123.42; 120.18; 20.83
MeOD-d4 7.33–7.57 (m, 2 H); 7.26–7.30 (m, 2 140.72; 131.75; 129.21;
H); 2.39 (s, 3 H) 123.83; 20.96
DMSO-d6 7.41–7.43 (m, 1 H); 7.09–7.12 (m, 1 131.71; 126.14; 122.70;
H); 6.93–6.99 (m, 1 H) 116.78; 107.91
124.11
2b
2c
2d
2e
2f
DMSO-d6 10.34 (br, 3 H); 7.42–7.46 (m, 2 H); 161.05 (d, J = 255 Hz);
7.30–7.35 (m, 2 H)
128.58; 125.15; 116.47 (d,
J = 27.5 Hz)
2g
2h
MeOD-d4 7.55–7.59 (m, 2 H); 7.37–7.42 (m, 2 136.04; 131.39; 130.96;
H)
125.79
D2O
7.72–7.76 (m, 2 H); 7.58–7.62 (m, 2 142.32; 130.98; 125.09;
H); 4.10–4.14 (m, 4 H); 3.69–3.75
(m, 4 H)
122.32; 64.42; 54.19
2i
2j
MeOD-d4 7.89–7.94 (m, 2 H); 7.17–7.22 (m, 2 140.55; 131.34; 130.33;
H)
126.10
DMSO-d6 7.80 (d, 2 H); 7.61 (br, 3 H); 6.97
165.91; 130.91; 116.93;
99.54; 51.61
(d, 2 H)
p-Toluidine Hydrochloride (2d)
Yield: 550 mg (96%), pale yellow crystals, mp. 231–234◦C, lit.18 232–234◦C; GC-MS:
m/z = 107.2 [M]+.
4-Fluoroaniline Hydrochloride (2e)
The general procedure was adopted, but the reaction time was 30 min and 3.5 eq. Of NaBH4
were used. Yield: 570 mg (97%), pale yellow crystals, mp. 235–237◦C, lit.19 253◦C; GC-
MS: m/z = 111.2 [M]+.
p-Chloroaniline Hydrochloride (2f)
Yield: 620 mg (94%), pale yellow crystals, mp. 239–240◦C, lit.18 249–251◦C; GC-MS:
m/z = 127.1 [M]+.

Hydrogenation of Aromatic Nitro Compounds
p-Iodoaniline Hydrochloride (2g)
181
To a magnetically stirred solution of 1.25 g (5 mmol) p-nitroiodobenzene in 29 ml methanol
and 20 ml toluene was added to 11.2 ml of a methanol stock solution containing 0.04 M
CuSO4 and 0.004 M CoCl2 (9.0 mol% CuSO4, 0.9 mol% CoCl2). The flask was fitted with a
reflux condenser and heated to 65◦C. The reaction was started by adding 300 mg (7.9 mmol)
NaBH4. This led to a color change to black and vigorous gas evolution. Thirteen additional
portions of 65 mg (13 × 1.7 mmol) NaBH4 were added in intervals of 3 min. After 45 min,
the reaction mixture was quenched by an addition of 50 ml of water and extracted with
3 × 60 ml CH2Cl2. The combined organic layers were dried over MgSO4. After removal
of the drying agent, 6 M HCl in ether (10 ml) was added to the CH2Cl2 solution to produce
the more stable hydrochloride, which was freed from excess HCL, CH2Cl2 and Et2O under
reduced pressure (10 mmHg) to yield 1.06 g (2g) (86%), as pale yellow crystals. GC-MS
and NMR analyses showed that 10% of the product underwent reductive cleavage of the
iodine to give aniline.
GC-MS: m/z = 219.0 [M]+.
p-(N-Morpholino)aniline Hydrochloride (2h)
To a magnetically stirred solution of 5.0 g (24 mmol) N-(p-nitrophenyl)morpholine in
180 ml methanol was added to 7.5 ml methanol stock solution containing 0.04 M CuSO4
and 0.004 M CoCl2 (3.0 mol%, CuSO4, 0.3 mol% CoCl2). The flask was equipped with
a reflux condenser for this large scale procedure. The reaction was started by the careful
portionwise addition of 1.26 g (33.3 mmol) NaBH4. This led to a color change to black
and vigorous gas evolution. Nine additional portions of 160 mg (9 × 4.2 mmol) NaBH4
were added in intervals of 3 min. After 30 min, the reaction mixture was quenched by
cautious addition of 240 ml water and extracted with 3 × 200 ml CH2Cl2. The combined
organic layers were dried over MgSO4. After removal of the drying agent, 6 M HCl in ether
(10 ml) was added to the CH2Cl2 solution to produce the more stable hydrochloride, which
was freed from excess HCl, CH2Cl2 and Et2O under reduced pressure (10 mmHg) to yield
5.47 g (91%) (2h) as a pale pink solid, mp. 252–254◦C (dec.) MS: m/z = 178.1 [M]+.
Anal. Calcd for C10H16N2OCl2: C, 47.78; H, 6.43; N, 11.14. Found: C, 47.30; H, 6.41;
N, 10.97.
Bromo-p-phenylenediamine Hydrochloride (2i)
Yield: 935 mg (89%), pale pink crystals. GC-MS: m/z = 186.1 [M]+. GC-MS and NMR
analysis showed that 9% of the product had undergone reductive bromine removal, resulting
in benzene-1,4-diamine.
Methyl 4-Aminobenzoate Hydrochloride (2j)
650 mg (87%) as pale white crystals, mp. 252–256◦C (decomposition), lit.19 270◦C. The
general procedure was adopted. The reaction time was 30 min, 4.0 mol% CuSO4, 0.4 mol%
CoCl2 and 3.5 eq. of NaBH4 were used.

182
Christensen et al.
References
1. R. C. Wade, J. Mol. Catal., 18, 273 (1983).
2. I. Pogorelic´, M. Filipan-Litvic´, S. Merkasˇ, I. Cepanec and M. Litvic´, J. Mol. Catal. A: Chem.,
274, 202 (2007).
3. J. Drouin, S. Gauthier, O. Patricola, P. Lante´ri and R. Longeray, Synlett, 791 (1993).
4. S. Yoo and S. Lee, Synlett, 419 (1990).
5. H. I. Schlesinger, H. C. Brown, A. E. Finholt, J. R. Gilbreath, H. R. Hoekstra and E. K. Hyde,
J. Am. Chem. Soc., 75, 215 (1953).
6. J. W. Chen and C. Q. Qin, React. Polym., 16, 287 (1991).
7. Y. Z. Chen and K. J. Wu, Appl. Catal., 78, 185 (1991).
8. C. A. Brown, J. Org. Chem., 35, 1900 (1970).
9. S. W. Heinzman and B. Ganem, J. Am. Chem. Soc., 104, 6801 (1982).
10. N. Satyanarayana and M. Periiasanz, Tetrahedron Lett., 25, 2501 (1984).
11. S. K. Chung, J. Org. Chem., 44, 1014 (1979).
12. X. L. Ding, X. Yuan, C. Jia and Z. F. Ma, Int. J. Hydrogen Energy, 35, 11077 (2010).
13. N. Patel, R. Fernandes and A. Miotello, J. Catal., 271, 315 (2010).
14. T. Ibata, Y. Isogami and J. Toyoda, Bull. Chem. Soc. Jpn, 64, 42 (1991).
15. L. Pehlivana, E. Metay, S. Laval, W. Dayouba, P. Demonchaux, G. Mignani and M. Lemaire,
Tetrahedron, 67, 1971 (2011).
16. J. R. Reasenberg, E. Lieber and G. B. L. Smith, J. Am. Chem. Soc., 61, 384 (1939).
17. G. Singh, J. P. S. Kapoor and J. Kaur, Indian J. Chem. Sec. B., 38, 56 (1999).
18. G. B. Wang, L. F. Wang, C. Z. Li, J. Sun, G. M. Zhou and D. C. Yang, Res. Chem. Intermed., 38,
77 (2012).
19. H. Rinderknecht and C. Niemann, J. Am. Chem. Soc., 72, 2296 (1950).