Raney nickel-catalyzed hydrogenation of unsaturated carboxylic acids with sodium borohydride in water

Article abstract of DOI:10.1080/00397911.2010.533239

A mild, selective, and green method for the reduction of unsaturated carboxylic acids with sodium borohydride-Raney nickel (W6) system in water is reported. This method is practical and safe and avoids use of organic solvents. Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.533239

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Raney Nickel–Catalyzed Hydrogenation
of Unsaturated Carboxylic Acids with
Sodium Borohydride in Water
Gopal Krishna Rao a , Narendra B. Gowda b & Ramesha A.
Ramakrishna c
a Department of Pharmaceutical Chemistry, Al-Ameen College of
Pharmacy, Bangalore, India
b Department of Pharmaceutical Chemistry, Visveswarapura Institute
of Pharmaceutical Sciences, Bangalore, India
c R L Fine Chem, Bangalore, India
Available online: 30 Aug 2011
To cite this article: Gopal Krishna Rao, Narendra B. Gowda & Ramesha A. Ramakrishna (2012): Raney
Nickel–Catalyzed Hydrogenation of Unsaturated Carboxylic Acids with Sodium Borohydride in Water,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 42:6, 893-904
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Synthetic Communications1, 42: 893–904, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.533239
RANEY NICKEL–CATALYZED HYDROGENATION OF
UNSATURATED CARBOXYLIC ACIDS WITH SODIUM
BOROHYDRIDE IN WATER
Gopal Krishna Rao,1 Narendra B. Gowda,2 and
Ramesha A. Ramakrishna3
1Department of Pharmaceutical Chemistry, Al-Ameen College of Pharmacy,
Bangalore, India
2Department of Pharmaceutical Chemistry, Visveswarapura Institute of
Pharmaceutical Sciences, Bangalore, India
3R L Fine Chem, Bangalore, India
GRAPHICAL ABSTRACT
Abstract A mild, selective, and green method for the reduction of unsaturated carboxylic
acids with sodium borohydride–Raney nickel (W6) system in water is reported. This
method is practical and safe and avoids use of organic solvents.
Keywords Reduction; sodium borohydride; unsaturated carboxylic acids; water
INTRODUCTION
Reduction of olefin is an important transformation in organic chemistry and is
very well reviewed in the literature.[1] The large number of protocols developed for
this transformation indicates the importance and usefulness of this in organic chem-
istry.[1–3] Most of the common procedures for the reduction of olefins use molecular
hydrogen along with metal catalysts such as Pd-C,[1] Pt-C,[4] Ni,[5] and several other
noble metals.[1] Additionally, biochemical and enzymatic methods have also been
employed for the reduction of olefins.[3b–3d] The utility of sodium borohydride for
Received June 23, 2010.
Address correspondence to Ramesha A. Ramakrishna, R L Fine Chem, No. 15, KHB Industrial
Area, Yelahanka Newtown, Bangalore 560106, India. E-mail: drramesha@rlfinechem.com
893

894
G. K. RAO, N. B. GOWDA, AND R. A. RAMAKRISHNA
the reduction of olefins was discovered by Brown and coworkers in 1962.[6a] In this
reduction, the in situ–generated hydrogen gas from sodium borohydride is con-
sumed. Subsequently, there were several other reports on the modification of this
approach for the reduction of olefins using sodium borohydride.[6b–6i] Many of these
strategies use sodium borohydride in the presence of metals and their derivatives
such as Pd, Rh, In, and NiCl2 to bring about this reduction.[7b–7h]
Sodium borohydride, a very well-known metal hydride, have been extensively
used in the organic transformation.[7a] This is known to be a safe, relatively stable
hydride and is commercially available in powder form and aqueous alkaline solution
in various concentrations below 30% w=w (Montgomery Chemicals, Conshohocken,
PA, USA). Sodium borohydride is widely used for the reduction of carbonyl func-
tional groups such as aldehyde, ketone, and ester.[7a] While a considerable amount
of work has been reported to improve the utility of sodium borohydride–metal–
catalyzed hydrogenation, one of the major disadvantages in these methods is the
requirement for a large amount of sodium borohydride.[7,8] This is mainly because
of competing decomposition of sodium borohydride (Scheme 1), thereby and a
amount of hydrogen is wasted.
The recent reports on the use of RuCl3-catalyzed sodium borohydride hydro-
genation of mono- and disubstituted olefins in tetrahydrofuran (THF) and water[9]
and sodium borohydride–Pd catalyst for reduction of alkenes and alkynes in isopro-
pyl alcohol in the presence of acetic acid[10] is a slight improvement of the reaction
conditions in these directions. Compared to the earlier reports, the sodium
borohydride=Pd-C method appears to be more general and can be used for the
reduction of alkenes and alkynes. Although this method works well in many sol-
vents, including water, the general applicability of this procedure in the presence
of other functional groups has not been demonstrated.
Sodium borohydride–nickel chloride is known to accomplish the reduction of
olefins.[7] However, application of this method for reduction of unsaturated car-
boxylic acids did not give a clean product in our laboratory. While carrying out
the reaction, we observed that the carboxylic acid reacted with sodium borohydride
to form borate ester, which precipitates from the reaction medium, thereby blocking
further reduction. This prompted us to develop an alternative reaction condition.
While a considerable amount of work has been carried out to use noble metal
catalysts in combination with sodium borohydride for the reduction of olefins, sur-
prisingly, there are no reports on the use of commercially available Raney nickel.
Therefore, we decided to explore the reduction of unsaturated carboxylic acid by
using commercially available Raney nickel (W6 grade) in water.
Scheme 1. Competing decomposition of sodium borohydride.

UNSATURATED CARBOXYLIC ACIDS
895
RESULTS AND DISCUSSION
Development of new methodology in organic synthesis based on green chem-
istry is an important goal toward a sustainable future.[11a–f] In our continuing efforts
to develop new methodologies in water, we were interested in developing an alternate
practical method for the reduction of unsaturated carboxylic acids in water. We have
selected sodium borohydride as hydrogen source and Raney nickel (W6 grade) as
catalyst for all our experiments.
Our initial experiments to reduce cinnamic acid with sodium borohydride–
Raney nickel in water did not yield any product (Table 1, entry 1). Attempts to
change the solvents to methanol and tetrahydrofuran (THF) also gave poor yield
(Table 1, entries 2 and 3). Even nickel chloride as catalyst did not furnish a reduced
product in good yield (Table 1, entries 4 and 5).
While carrying out these reactions, we observed two main problems. The first
one is the solubility issue of the substrates, and the second one is the rapid decompo-
sition of sodium borohydride under the reaction condition. The solubility issue has
been addressed by converting the substrates into their corresponding sodium salt in
water. This would also address the unintended reactivity of sodium borohydride with
the carboxylic group. Additionally, sodium borohydride is known to be more stable
under a basic reaction condition.
When sodium salt of cinnamic acid 1 (Table 2, entry 1) was subjected to
reduction in water in the presence of Raney nickel, the reduction proceeded to fur-
nish phenylpropionic acid 1a with good yield. During the reaction, we observed that
the decomposition of sodium borohydride has been slowed considerably. Based on
this result, it is evident that sodium borohydride is slowly liberating hydrogen gas
in the presence of Raney nickel under basic conditions, which is consumed during
hydrogenation. An attempted control experiment in the absence of Raney nickel
did not give any reduced product. In the general optimized reaction conditions,
the substrates are made soluble in water by converting them to corresponding
sodium salt at room temperature. Then Raney nickel (W6) about 30–40% by weight
is added, followed by sodium borohydride (normally a molar equivalent) at room
temperature, and then the mixture is heated at 50–60 ꢀC for 1 h. After the completion
of the reaction as monitored by thin-layer chromatography (TLC), the crude
Table 1. Attempted reduction with sodium borohydride and Raney nickel
Catalyst
(30%wt)
Yield
(%)
Entry
Solvent
1
2
3
4
5
Water
Ra-Ni
Ra-Ni
Ra-N
NiCl2
NiCl2
0
10
22
0
Methanol
THF
Water
Methanol
15

896
G. K. RAO, N. B. GOWDA, AND R. A. RAMAKRISHNA
Table 2. Raney nickel–catalyzed hydrogenation with alkaline aqueous borohydride
Entry
1
Substrate
Product
Yielda (%)
89
2
3
92
90
4
92
5
6
7
90
90
75
8
9
92
86
10
11
91
89
(Continued )

UNSATURATED CARBOXYLIC ACIDS
897
Table 2. Continued
Entry
12
Substrate
Product
Yielda (%)
97
13
14
90
85
15
16
89
92
17
18
No reaction
No reaction
aIsolated pure yield based on starting material.
product was neutralized with dilute acid and extracted with CH2Cl2 to furnish the
product.
When cinnamic acid 1 (Table 2, Scheme 2) is subjected to reduction with
sodium borohydride and Raney nickel, it is reduced to phenylpropionic acid 1a with
89% yield. Similarly p-chlorocinnamic acid 2 and methoxy substituted cinnamic
acids 3 and 4 are reduced to the corresponding phenylpropionic acids 2a, 3a, and
4a with yields of 92%, 90%, and 92% respectively. It is interesting to note that the
chloro group is not affected in the reaction. Simple unsaturated acids like a-methy-
lacrylic acid 5 and b-methylacrylic acid 6 were reduced completely to their saturated
acids 5a and 6a with good yield. This method has also been extended to sensitive
substrates having furoic acid groups. b-Furylacrylic acid 7 is reduced to correspond-
ing saturated acid 7a with 75% yield. Other substrates such as coumarin 8 are

898
G. K. RAO, N. B. GOWDA, AND R. A. RAMAKRISHNA
Scheme 2. Reduction of unsaturated acid.
reduced to the corresponding saturated hydroxy acid 8a with good yield. This
method has also been extended to maleic acid 9. Because of the solubility of the suc-
cinic acid, it is isolated as corresponding methyl ester 9a with 86% yield, and the
same methodology has been extended to the synthesis of ibuprofen 10a from the cor-
responding unsaturated acid 10. Even o-styrylbenzoic acid 11 is reduced to 2-pheny-
lethylbenzoic acid 11a in good yield. Similarly, undecylenic acid 12, having an
isolated double bond, is completely reduced to saturated undecanoic acid 12a with
excellent yield (97%). Substrates having allylic ether groups 13 and 14 undergo clean
reduction to corresponding saturated acids 13a and 14a with good yield. In substrate
14 it is interesting to note that both a,b-unsaturated and isolated double bonds are
reduced completely with 85% yield. Substrate 14 required 2 equivalents of sodium
borohydride for the complete reduction.
The generality of this method has also been extended to substrates having pro-
pargylic carboxylic acid. Substrate 15, which is an intermediate in the synthesis of
pargiverine and has an having isolated propargyl group, underwent clean reduction
to the corresponding saturated acid 15a with a good yield. Similarly simple aliphatic
a,b-unsaturated 2-octynoicacid 16 (Scheme 2) is completely reduced to the corre-
sponding saturated octanoic acid 16a in very good yield. Alkyne system also required
2 equivalents of sodium borohydride for the complete reduction. This clearly indi-
cates that this method works very well for isolated and a,b-unsaturated triple bonds.
Simple substrates like stilbine 17 and a-methylstyrene 18 did not give any reduced
product even after adding excess catalyst and sodium borohydride. This clearly indi-
cates solubility of the substrates in water is essential for the successful reduction.
This is in clear contrast to the recently published report where in the reduction works
very well in water when sodium borohydride–palladium catalyst and insoluble sub-
strates are used.[10] Substrate 11 has been scaled up to a kilo batch without any prob-
lems. We have successfully reused Raney nickel 10 times without any appreciable
change in yield or activity for the reduction of substrate 11.
It is interesting to note that in comparison to reported procedure in the litera-
ture for the reduction of olefins[6–8] using sodium borohydride, a large excess of
sodium borohydride is not used in this reaction. A molar equivalent of sodium bor-
ohydride is sufficient to bring about the reduction. This is possibly because the
reported procedures are done either at mild acidic or neutral pH conditions, and
under these conditions decomposition of sodium borohydride is one of the main

UNSATURATED CARBOXYLIC ACIDS
899
side reactions with a large amount of hydrogen liberation. In contrast, the basic pH
of the reaction medium has relatively reduced the decomposition of sodium
borohydride.
CONCLUSION
In brief, we have developed a practical green method for the reduction of
unsaturated carboxylic acids using a sodium borohydride–Raney nickel system in
water. It is very essential that the substrates need to be dissolved in water by convert-
ing them into metal carboxylate salts for successful reduction. Further the method is
environmentally friendly and economically viable to carry out on a large scale.
EXPERIMENTAL
All solvents and reagents were purchased from suppliers and used without
further purification. Yields reported are for isolated yield unless otherwise stated.
1H NMR (400, 300, and 200 MHz) and 13C NMR (100, 75, and 50 MHz) spectra
were recorded in CDCl3 or dimethylsulfoxide (DMSO-d6) at room temperature.
The chemical shift is based on internal tetramethylsilane (TMS). Infrared (IR) spec-
tra were recorded by a Shimadzu FTIR instrument. Analytical thin-layer chromato-
graphy (TLC) was performed on Merck silica-gel (60 GF254) plates (0.25 mm)
and components were visualized with ultraviolet light (254 nm wavelength) and
iodine vapors. Melting points were determined on a Thermonic instrument and
are uncorrected.
General Procedure for the Reaction of Conjugated Olefins:
3-Phenylpropanoic Acid (1a)[12a]
Raney nickel (0.30 g, W6 grade) was added to a stirred a solution of cinnamic
acid (0.740 g, 5 mmol) in 0.52 M aqueous sodium hydroxide (10 mL). To this slurry,
sodium borohydride (0.190 g, 5 mmol) is added in small portions at room tempera-
ture. After 30 min, the reaction mixture was stirred at 50–60 ꢀC until the completion
of the reaction (3 h, monitored by TLC), cooled to room temperature, and filtered to
remove Raney nickel. The filtrate was acidified to pH 2 with dilute HCl and
extracted with dichloromethane (2 ꢁ 40 mL). The combined organic layer was dried
over anhydrous sodium sulfate, and the solvent was removed completely to get the
desired product. The product thus obtained is practically pure by NMR. Colorless
.
solid. Mp 46–48 ꢀC (lit.[12b] 46–47 ꢀC). IR (KBr): 1704, 3250 cmꢂ1 1H NMR
(200 MHz, CDCl3): d 2.68 (t, J ¼ 7.8 Hz, 2H), 2.96 (t, J ¼ 7.8 Hz, 2H), 7.22ꢂ7.26
(m, 5H), 9.86 (s, 1H); 13C NMR (100 MHz, CDCl3): d 31.0, 36.0, 126.8, 128.7,
129.0, 140.6, 179.6.
General Procedure for the Reaction of Unconjugated Olefins:
2-(2-Phenylethyl)benzoic Acid (11a)[13a]
Raney nickel (30 g, W6 grade) was added to o-styrylbenzoic acid[4] (112 g,
0.5 mol) dissolved in aqueous sodium hydroxide solution (20.8 g, 0.52 mol in

900
G. K. RAO, N. B. GOWDA, AND R. A. RAMAKRISHNA
600 mL) and stirred for 15 min. To this aqueous slurry, sodium borohydride (19 g,
0.5 mol) is added in small portions over a period of 20 min at room temperature
and stirred until the frothing stopped. Then the reaction mixture was stirred at
50–60 ꢀC until the completion of the reaction (monitored by TLC), cooled to room
temperature, and filtered to remove Raney nickel. Filtrate was acidified to pH 2 with
concentrated HCl and extracted with dichloromethane (3 ꢁ 400 mL). The combined
organic layer was dried over anhydrous sodium sulfate; solvent was evaporated to
get 2-(2-phenyl ethyl) benzoic acidꢂa1s a white solid. Mp 130ꢂ132 ꢀC (lit.[13b]
130 ꢀC). IR (KBr): 1685, 3155 cm
.
1H NMR (200 MHz, CDCl3): d 2.94
(t, J ¼ 8.0 Hz, 2H), 3.35 (t, J ¼ 8.0 Hz, 2H), 7.15ꢂ7.51 (m, 8H), 8.09 (d, J ¼ 9.0 Hz,
1H); 13C NMR (100 MHz, CDCl3): d 37.6, 38.6, 126.4, 126.7, 128.6, 128.8, 129.0,
132.0, 132.3, 133.5, 142.4, 145.3, 173.9.
Selected Data
3-(4-Chlorophenyl)propanoic acid (2a).[12a] White solid. Mp 122–124 ꢀC
1
(lit.[12c] 119–121 ꢀC). IR (KBr): 1695, 3207 cmꢂ1. H NMR (300 MHz, DMSO-d6):
d 2.49 (t, J ¼ 7.6 Hz, 2H), 2.7 7(t, J ¼ 7.6 Hz, 2H), 7.14ꢂ7.30 (m, 4H).
3-(4-Methoxyphenyl)propanoic acid (3a).[12a] White solid. Mp 98ꢂ100 ꢀC
1
(lit.[12b] 101–102 ꢀC). IR (KBr): 1703, 3217 cmꢂ1. H NMR (300 MHz, CDCl3): d
2.64 (t, J ¼ 7.5 Hz, 2H), 2.90 (t, J ¼ 7.5 Hz, 2H), 6.83 (d, J ¼ 8.4 Hz, 2H), 7.12
(d, J ¼ 9.0 Hz, 2H).
3-(3,4-Dimethoxyphenyl)propanoic acid (4a).[15] Cream solid. Mp
96–98 ꢀC (lit.[14] 96–97 ꢀC). IR (KBr): 1701, 3205 cmꢂ1. 1H NMR (300 MHz, CDCl3):
d 2.66 (t, J ¼ 7.5 Hz, 2H), 2.91 (t, J ¼ 7.5 Hz, 2H), 3.85 (s, 3H), 3.86 (s, 3H), 6.71ꢂ
6.81 (m, 3H).
2-Methylpropanoic acid (5a).[16] Colorless liquid. IR (neat): 1707,
3205 cmꢂ1
1H), 10.65 (s, 1H).
.
1H NMR (200 MHz, CDCl3): d 1.15ꢂ1.21 (m, 6H), 2.53ꢂ2.62 (m,
1
Butanoic acid (6a).[17] Brown liquid. IR (neat): 1711, 3191 cmꢂ1. H NMR
(400 MHz, CDCl3): d 0.9 7(t, J ¼ 7.2 Hz, 3H), 1.62–1.71 (m, 2H), 2.34 (t, J ¼ 7.4 Hz,
Hz, 2H), 9.93 [s (broad), 1H]; 13C NMR (100 MHz, CDCl3): d 13.9, 18.5, 36.4, 180.8.
3-(2-Furyl)propanoic acidꢂ1(7a).[18a] White solid. Mp 56–58 ꢀC (lit.[18b]
56 ꢀC). IR (KBr): 1701, 3213 cm
.
1H NMR (300 MHz, DMSO-d6): d 2.49 (t,
J ¼ 7.6 Hz, 2H), 2.78 (t, J ¼ 7.6 Hz, 2H), 6.04 (s, 1H), 6.29 (s, 1H), 7.45 (s, 1H);
13C NMR (100 MHz, DMSO-d6): d 23.8, 32.8, 106.0, 111.2, 142.2, 155.2, 174.3.
3-(2-Hydroxyphenyl)propanoic acid (8a).[19] Solid. Mp 84–86 ꢀC (lit.[19]
.
83–85 ꢀC). IR (KBr): 1686, 3389 cmꢂ1 1H NMR (400 MHz, CDCl3): d 2.76 (t,
J ¼ 7.8 Hz, 2H), 2.91 (t, J ¼ 7.8 Hz, 2H), 6.81–6.89 (m, 2H), 7.11 (q, J ¼ 8.0 Hz, 2H).
Dimethylbutandioic acid (9a).[20] Yellow liquid. IR (neat): 1711, 3191 cmꢂ1
.
1H NMR (400 MHz, CDCl3): d 2.60 (s, 2H), 3.66 (s, 3H); 13C NMR (100 MHz,
CDCl3): d 28.9, 51.8, 173.0.

UNSATURATED CARBOXYLIC ACIDS
901
2-(4-Isobutylphenyl)propanoic acid (10a).[21] White solid. Mp 74–76 ꢀC
1
(lit.[21] 75–77 ꢀC). IR (KBr): 1706, 3189 cmꢂ1. H NMR (400 MHz, CDCl3): d 0.9
(d, J ¼ 8.0 Hz, 6H), 1.49 (d, J ¼ 8.0 Hz, 2H), 1.83–1.86 (m, 1H), 2.45 (d, J ¼ 8.0 Hz,
Hz, 2H), 3.71 (q, J ¼ 8.0 Hz 1H), 7.10 (d, J ¼ 8.0 Hz, 2H), 7.24 (d, J ¼ 8.0 Hz, 2H);
13C NMR (100 MHz, CDCl3): d 18.6, 22.9, 30.7, 45.5, 127.8, 129.9, 137.4, 141.3,
182.0.
1
Undecanoic acid (12a).[22] Viscous liquid. IR (neat): 1702, 3205 cmꢂ1. H
NMR (200 MHz, CDCl3): d 0.87–2.33 (m, 21H); 13C NMR (50 MHz, CDCl3): d
14.0, 22.6, 25.1, 29.3, 29.5, 29.6, 31.9, 34.4, 35.3, 37.3, 180.0.
2-Propoxybenzoic acid (13a).[23] Yellow oil. IR (neat): 1703, 3215 cmꢂ1. 1H
NMR (300 MHz, CDCl3): d 1.10 (t, J ¼ 7.5 Hz, 3H), 1.90–2.01 (m, 2H), 4.22 (t,
J ¼ 6.6 Hz, 2H), 7.03–7.15 (m, 2H), 7.52–7.58 (m, 1H), 8.18 (dd, J ¼ 9.6 Hz, 1H);
13C NMR (75 MHz, CDCl3): d 10.2, 22.2, 71.6, 112.5, 121.9, 133.5, 134.9, 157.5,
165.4.
3-(3-Methoxy-4-propoxyphenyl)propanoic acid (14a).[24] Cream solid.
1
Mp 66–68 ꢀC. IR (KBr):1718, 3219 cmꢂ1. H NMR (300 MHz, CDCl3): d 1.02 (t,
J ¼ 7.5 Hz, 3H), 1.81–1.88 (m, 2H), 2.67 (t, J ¼ 7.5 Hz, 2H), 2.89 (t, J ¼ 7.5 Hz,
2H), 3.86 (s, 3H), 3.95 (t, J ¼ 6.6 Hz 2H), 6.71–6.82 (m, 3H); 13C NMR (75 MHz,
CDCl3): d 10.3, 22.4, 30.2, 35.8, 55.9, 70.6, 112.2, 113.3, 120.1, 132.8, 147.1, 149.4,
179.0.
2,2-Diphenyl-2-propoxyethanoic acid (15a).[25] White solid. Mp
1
118–120 ꢀC (lit.[25] 120–121 ꢀC). IR (KBr):1706, 3155 cmꢂ1. H NMR (300 MHz,
CDCl3): d 0.83 (t, J ¼ 7.5 Hz, 3H), 1.55 (q, J ¼ 6.6 Hz, 2H), 3.05 (t, J ¼ 6.9 Hz,
2H), 7.19–7.39 (m, 10H); 13C NMR (75 MHz, CDCl3): d 10.4, 23.0, 67.0, 86.5,
127.6, 127.9, 128.2, 128.6, 139.3, 175.1.
1
Octanoic acid (16a).[26] Yellow oil. IR (neat): 1709, 3201 cmꢂ1. H NMR
(300 MHz, CDCl3): d 0.88 (t, J ¼ 7.5 Hz, 3H), 1.26 (s, 8H), 1.63 (t, J ¼ 7.5 Hz,
2H), 2.35 (t, J ¼ 7.2 Hz, 2H); 13C NMR (75 MHz, CDCl3): d 14.0, 22.6, 24.7, 29.0,
29.1, 31.7, 34.3, 180.3.
ACKNOWLEDGMENTS
The authors thank B. G. Shivananda, principal, Al-Ameen College of Phar-
macy and Management, Visveswarapura Institute of Pharmaceutical Sciences, Ban-
galore, for providing facilities and constant support. This work was also generously
supported by Anjan Roy, managing director, R L Fine Chem, Bangalore, India.
Also we thank K. R. Prabhu, Indian Institute of Science, Bangalore, India for useful
discussion.
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