Efficient and selective hydration of nitriles to amides in aqueous systems with Ru(II)-phosphaurotropine catalysts

Article abstract of DOI:10.1016/j.tetlet.2014.04.118

A simple and efficient synthesis of amides by selective hydration of aromatic and aliphatic nitriles is described. The catalysts are prepared in situ from easily available Ru-precursors and ligands using water as the solvent. The most active catalyst, is obtained from [RuCl₂(dmso)₄] and benzylated 1,3,5-triaza-7-phosphaadamantane. Of the 16 substrates examined, 92-99% conversions of 14 nitriles were achieved in one hour at reflux temperature.

Full text of DOI:10.1016/j.tetlet.2014.04.118

Accepted Manuscript
Efficient and selective hydration of nitriles to amides in aqueous systems with
Ru(II)- phosphaurotropine catalysts
Evelin Bolyog-Nagy, Antal Udvardy, Ferenc Joó, Ágnes Kathó
PII:
S0040-4039(14)00755-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.04.118
TETL 44580
Reference:
Tetrahedron Letters
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16 April 2014
30 April 2014
Please cite this article as: Bolyog-Nagy, E., Udvardy, A., Joó, F., Kathó, Á., Efficient and selective hydration of
nitriles to amides in aqueous systems with Ru(II)- phosphaurotropine catalysts, Tetrahedron Letters (2014), doi:
http://dx.doi.org/10.1016/j.tetlet.2014.04.118
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Tetrahedron Letters
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Efficient and selective hydration of nitriles to amides in aqueous systems with Ru(II)-
phosphaurotropine catalysts
Evelin Bolyog-Nagya, Antal Udvardya, Ferenc Joóa,b, Ágnes Kathóa,*
aDepartment of Physical Chemistry, University of Debrecen, Debrecen, Egyetem tér 1, H-4032 Hungary;
bMTA-DE Homogeneous Catalysis and Reaction Mechanisms Research Group, Debrecen, Egyetem tér 1, H-4032 Hungary
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A simple and efficient synthesis of amides by selective hydration of aromatic and aliphatic
nitriles is described. The catalysts are prepared in situ from easily available Ru-precursors and
ligands using water as the solvent. The most active catalyst, is obtained from [RuCl2(dmso)4]
and benzylated 1,3,5-triaza-7-phosphaadamantane. Of the 16 substrates examined, 92-99%
conversions of 14 nitriles were achieved in one hour at reflux temperature.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Nitrile hydration
Ruthenium
Phosphine
Amides
Selective hydration of nitriles to amides is an important
synthetic reaction.1 Traditionally this process employs strongly
acidic or basic solutions and obviously these cannot be used in
case of acid- or base-sensitive compounds. In several cases the
amides obtained are overhydrolysed to carboxylic acids. In
addition, the acid or base component of the reaction mixture has
to be neutralized at the end of the reaction which leads to the
formation of large quantities of unwanted salts.
Frost et al. applied [RuCl2(pta)4] as a catalyst for the hydration
of various nitriles. In the hydration of benzonitrile the catalytic
activity of this complex (TOF=2.9 h-1) was inferior to the
efficiency of the half-sandwich catalysts mentioned above,
however, it was found that most of the product amides
precipitated from the aqueous reaction mixture. Consequently,
for isolation of the products in these systems there was no need to
use extraction with organic solvents. The catalyst was very stable
and could be recycled seven times with no significant loss of
activity.14 The half-sandwich complexes of β-aminophosphines
derived from pta were also found to be active in the hydration of
benzonitrile (TOF =1.5 - 2.7 h-1). Interestingly, the turnover
frequencies increased with decreasing concentrations of the
catalyst and reached 285 h-1 at 0.001 mol%.15
This short summary of prior results on nitrile hydration shows
that although several catalytic procedures are known for selective
syntheses of amides from nitriles, there is still a considerable
need for improvement of the catalyst activity. Herein, we report
on a new and facile synthetic method based on the use of easily
available catalyst precursors. These Ru(II)-catalysed aqueous-
phase hydrations proceed with unequalled rates and lead to high
conversions of nitriles into amides. Furthermore several of the
products can be isolated in high purity by simple filtration of the
aqueous reaction mixtures.
Catalysis by transition metal complexes may allow selective
synthesis of amides under neutral conditions.2 Water is a
straightforward choice as solvent for hydration reactions,
however, so far, only a few water-soluble catalysts are known for
such transformations which lead to high yields under mild
conditions. There are examples of catalytic hydrations in water
with Pd(II)3 and Rh(I)4 complexes, however, the field is
dominated by the use of ruthenium-based catalysts.2,5 Several of
these catalysts have the general formula [(η6-arene)RuCl2(L)]
with arene= η6-p-cymene (η6-C10H14)6,7 or η6-C6Me6,8,9 and L=
pta (1,3,5-triaza-7-phosphaadamantane),6,7 benzylated pta (pta-
Bn)Cl,6-8 mtppms-Na (sodium salt of meta-monosulfonated
triphenylphosphine),6,7
tris-(5-(2-aminothiazolyl)phosphine,10
P(NMe2)3,8,9 pyrazole,11 or 2-(3-pyrazolyl)pyridine.11 The water-
soluble bis(allyl)-ruthenium(IV) complexes,12 [RuCl2(η3:η3-
C10H16)(L)] were found to be less effective than the
corresponding [(arene)RuCl2(L)] complexes. Catalytic hydration
of a variety of aliphatic and aromatic nitriles (with benzonitrile as
a common substrate) proceeded at room to reflux temperatures
with the complexes discussed above.13 In general, the catalysts
were applied in 1-5 mol% and their typical catalytic activity was
characterized by turnover frequencies TOF ≤20 h-1 (TOF=mol
reacted substrate/mol catalyst×h).
In this study the catalysts for nitrile hydration were obtained
in situ from [RuCl2(dmso)4] (1) or [(η6-p-cymene)RuCl2]2 (2),
and the various water-soluble phosphines (3-8) shown on Figure
1. These Ru(II)-complexes16,17 as well as the ligands18-23 are
readily available, some of them (e.g. 2, 3, 6, 7, 8) can be
obtained from commercial sources.
∗ Corresponding author. Tel.: +36-52512900 ext. 22383; e-mail: katho.agnes@science.unideb.hu

2
good or excellent conversions in three hours (entries 3-8) and the
catalytic activities were higher (entries 4-6 and 8) than or close to
(entry 7) that of trans-[RuCl2(pta)4] (entry 15). Hydrated RuCl3
could also be used as a source of ruthenium, however the
conversions of benzonitrile were low compared to those with
[RuCl2(dmso)4] (entries 16-18). The most active catalyst was
obtained in the reaction of 1 + 3 (pta-Bn)Cl (entry 6) which led to
complete conversion of benzonitrile in one hour (but see also
Figure
S1).
Interestingly,
the
isolated
complexes
[RuCl2(dmso)2(pta)2] and [RuCl2(dmso)2(pta-Bn)2]Cl2 showed
low reactivity (entries 9 and 12). Although addition of 1 further
equivalent of phosphine increased the catalytic activity
substantially (entries 11, 13, 14), the use of in situ mixtures of
1 + 3 pta-Bn is more practical since it does not require prior
isolation of [RuCl2(dmso)2(pta-Bn)2]Cl2 or [RuCl2(dmso)2(pta)2].
The reaction of [(η6-p-cymene)RuCl2]2 (2) and (pta-Bn)Cl in a
[(pta-Bn)Cl]/[Ru]=3 ratio also gave a very active catalyst for
benzonitrile hydration with 99% conversion in one hour (Table
S1). However, the time course of the conversion showed an
induction period and complete conversion was achieved only in
60 minutes (Figure S1). In contrast, the reaction catalyzed by
[RuCl2(dmso)4] + 3 (pta-Bn)Cl started with no induction period
and reached at 98% conversion in 20 minutes. From this
conversion a TOF=58.8 h-1 can be calculated. (The initial
turnover frequency of the latter catalyst is 90 h-1.) This reactivity
compares very favorably to the activities of trans-[RuCl2(pta)4]
(TOF=2.9 h-1),14 [(η6-p-cymene)RuCl2(pta-Bn)]Cl (TOF=5 h-1),7
[(η6-cymene)RuCl2{P(NMe2)3}] (TOF=4 h-1),8 and to Romero’s
catalyst (TOF=26.7 h-1).11 (The catalytic activities at 80 °C and
90 °C are shown in Table S2.)
Figure 1. Ru(II)-sources and water-soluble phosphines used in this
study.
The hydration of benzonitrile was chosen as a model reaction.
The in situ catalysts were prepared by mixing an aqueous
●
solution of [RuCl2(dmso)4] (1) or RuCl3 3H2O and the
appropriate phosphine ligand 3-8 at room temperature. After
addition of a given amount (1 mmol in most cases) of
benzonitrile, the reaction mixture was stirred at reflux
temperature open to air. Samples were withdrawn regularly
and the conversions were determined by gas
chromatography.24 The conversions of benzonitrile into
benzamide are shown in Table 1. No formation of byproducts
(e.g., benzoic acid) was observed. The results obtained with
the
use
of
the
isolated
[RuCl2(dmso)2(pta)2],25
25
[RuCl2(dmso)2(pta-Bn)2]Cl2
and
trans-[RuCl2(pta)4]
catalysts are also shown for comparison.
Table 1.
Isolated [(η6-p-cymene)RuCl2(pta-Bn)]Cl was less active than
the in situ [(η6-p-cymene)RuCl2]2 + 6 (pta-Bn)Cl catalyst and
afforded only 23% conversion in hydration of benzonitrile in one
hour (Table S1). However, addition of 1 or 2 further equivalents
of (pta-Bn)Cl increased the catalytic activity substantially,
leading to 86% and 98% conversions, respectively.
Conversions of benzonitrile into benzamide catalyzed by various
water-soluble Ru(II)-phosphine catalystsa
Conversionb (%)
The scope of the hydration with the most active new catalysts,
1+3 (pta-Bn)Cl and 2+6 (pta-Bn)Cl, was studied with 16
aromatic and aliphatic nitriles.
Entry
Catalyst
1 + 3 mtppms-Na
1 + 3 mtppts-Na3
1 + 2 pta
1 h
0
2 h
0
3 h
0
1
2
3
4
5
6
7
8
9
Table 2.
0
0
0
Hydration of various nitriles into amides catalyzed by the in situ
catalysts [RuCl2(dmso)4] (1) + 3 (pta-Bn)Cl and [(η6-p-
20
45
75
99
16
51
0
43
78
90
99
36
69
13
56
62
93
95
100
78
91
46
79
cymene)RuCl2]2 (2) + 6 (pta-Bn)Cla.
1 + 3 pta
1 + 2 (pta-Bn)Cl
1 + 3 (pta-Bn)Cl
1 + 3 (pta-Me)CF3SO3
1 + 3 dapta
1 + 3 (pta-Bn)Cl 2 + 6 (pta-Bn)Cl
Entry
Substrate
[Ru]:[P]= 1 : 3
99 (90) {42}
99 (65) {64}
[Ru]:[P]= 1 : 3
99 (80) {18}
98 (91) {49}
1
2
Benzonitrile
4-Tolunitrile
4-Chlorophenyl-
acetonitrile
4-Chlorobenzonitrile
4-(Trifluoromethyl)-
benzonitrile
3
4
5
98 {56}
96 {51}
[RuCl2(dmso)2(pta)2]
10 [RuCl2(dmso)2(pta)2] + pta
11 [RuCl2(dmso)2(pta)2] +
(pta-Bn)Cl
2
98 (86) {59}
95 (72) {47}
98 (68) {60}
90 (47) {43}
99
6
7
8
9
3-Phenylpropionitrile
1,3-Dicyanobenzene
1,4-Dicyanobenzene
4-Nitrobenzonitrile
97 (90) {16}
99 (91)
99 (99)
98 {77}
99
99
10
95
92{32}
97{47}
0
98 (93) {27}
99 (99)
99 (99)
98 {49}
95{86}
97{66}
20
12 [RuCl2(dmso)2(pta-Bn)2]Cl2
13 [RuCl2(dmso)2(pta-Bn)2]Cl2 + pta
14 [RuCl2(dmso)2(pta-Bn)2]Cl2 +
(pta-Bn)Cl
15
99
34
99
62
99
99
10 3-Pyridinecarbonitrile
11 4-Pyridinecarbonitrile
12 2-Pyridinecarbonitrileb
13 Propionitrileb
14 Butyronitrile
15 i-Butyronitrile
15 trans-[RuCl2(pta)4]
35
0
21
4
70
0
46
14
87
0
55
24
16 RuCl3·3H2O + 3 pta
17 RuCl3·3H2O + 5 pta
18 RuCl3·3H2O + 5 (pta-Bn)Cl
85
82{25}
92{89}
0
aReaction conditions: 5 mol% Ru, 1 mmol benzonitrile, 3 mL H2O, reflux,
bDetermined by GC
16 Acetonitrile
aReaction conditions: 5 mol% Ru, 1 mmol substrate, 3 mL H2O, reflux, 1 h.
bNo solid product separated.
[RuCl2(dmso)4] (1) or its mixtures with sulfonated
triphenylphosphines (7 or 8) did not catalyze the hydration of
benzonitrile (entries 1 and 2). In contrast, the use of
phosphaurotropines 3-8 allowed the hydrations to proceed with

3
Table
2
shows the conversions determined by gas
TÁMOP-4.2.2.A-11/1/KONV-2012-0043 (ENVIKUT). The
chromatography together with isolated yields following ethereal
extraction (in round brackets), and isolated yields by simple
filtration and aqueous washing (in curly brackets). With the
exception of acetonitrile, the substrates were poorly soluble in
water and the reactions take place in aqueous-organic biphasic
media. A very advantageous feature of aqueous systems is that
upon cooling, several of the products precipitate or crystallize
from the reaction mixtures.14 In some cases, however, partial
dissolution or incomplete crystallization of the product may lead
to lower isolated yields compared to the conversion of the
substrate nitrile and extraction using a suitable solvent as a more
efficient method of work-up may be necessary.
From the data in Table 2 it can be seen that most of the nitriles
were hydrated efficiently in one hour with both catalysts. With
1 + 3 (pta-Bn)Cl all but two of the substrates reacted with
conversions higher than 90%, and in 11 cases the conversions
were in the 97-99% range. (This catalyst led to high conversions
after only 30 min; Table S3). The use of 2 + 6 (pta-Bn)Cl gave
approximately the same results with the exception of
propionitrile and butyronitrile (entries 13 and 14) which gave
slightly lower conversions with this catalyst in one hour. Both in
situ catalysts showed low catalytic activity in the case of 2-
pyridinecarbonitrile (entry 12), while acetonitrile was not
hydrated at all (entry 16). Strong coordination of both
substrates5,14 to Ru(II) may be the reason for the poor or zero
conversion. The products of hydration of both 1,3- and 1,4-
dicyanobenzene (entries 7 and 8) were so insoluble in water that
they precipitated at reflux temperature and only traces of
unreacted dinitriles could be observed by gas chromatography
after one hour. The 1H and 13C NMR spectra of the products (see
Supporting Material) showed exclusive formation of diamides.
Over the one hour reaction time 2 + 6 (pta-Bn)Cl catalyzed the
hydration of several substrates with greater conversions than [(η6-
p-cymene)RuCl2(pta-Bn)]Cl (see Table S4).
authors are grateful for the support of the National Research
Fund of Hungary (OTKA 101372).
References and notes
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Methoden Der Organischen Chemie (Houben-Weyl); Müller, E.
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1024-1031
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The recovery and recycling of the catalyst was studied with
1 + 3 (pta-Bn)Cl in the hydration of benzonitrile under standard
conditions (Table 2). After one hour, the conversion was
determined by gas chromatography. The reaction mixtures were
kept at ice-water temperatures for a few hours and then the
precipitated benzamide was filtered out. A new batch of
benzonitrile was added and the procedure was repeated.24 In the
6th cycle the conversion was 95% (compared to 99% in the 1st
cycle) and the yield of the isolated amide was 48% (57% in the
1st cycle). It can be concluded that the catalyst can be efficiently
recovered from the aqueous phase, shows high stability, and
retains its activity over several repeated cycles (detailed data are
reported in Table S5).
In summary, we have developed a simple and efficient
catalytic method for the selective hydration of aliphatic and
aromatic nitriles to the corresponding amides. The catalysts are
prepared in situ from easily available Ru-precursors and ligands.
The most active catalyst was obtained from [RuCl2(dmso)4] and
benzylated 1,3,5-triaza-7-phosphaadamantane (pta-Bn)Cl. The
reactions take place in aqueous reaction mixtures in air at reflux
temperature in short reaction times and are characterized by
excellent conversions and isolated yields. In several cases the
product amides precipitated or crystallized from the aqueous
mixture upon cooling and could be isolated in high purity by
filtration and aqueous washing. This latter feature makes the
procedure operationally simple and more environmentally
friendly.
14. Lee, W.-C.; Frost, B. J. Green Chem. 2012, 14, 62-66.
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1977, 32, 499-506.
20. Mena-Cruz, A.; Lorenzo-Luis, P.; Romerosa, A.; Saoud, M.;
Serrano-Ruiz M. Inorg. Chem. 1997, 46, 6120-6128.
21. (a) Siele, V. I.; J. Heterocycl. Chem., 1977, 14, 337-339; (b)
Darensbourg, D. J.; Ortiz, C. G.;
Kamplain, J. W.
Organometallics, 2004, 23, 1747-1754.
22. (a) Ahrland, S.; Chatt, J.; Davies, N. R.; Williams, A. A.; Chatt, J.;
Davies, N. R.; Williams, A. A. J. Chem. Soc. 1958, 264-276; (b)
Joó, F.; Kovács, J.; Kathó, Á.; Bényei, A. Cs.; Decuir, T.;
Darensbourg, D. J. Inorg. Synth. 1998, 32, 1-8.
23. Herrmann W. A.; Kohlpaintner C. W. Inorg. Synth. 1998, 32, 8-
25.
24. For detailed experimental procedures and analytical methods see
the Supplementary Material.
25. Udvardy, A.; Bényei, A. Cs.; Kathó, Á. J. Organomet. Chem.
2012, 717, 116-122.
Supplementary Material
Synthetic procedures and product analysis (GC method);
Tables of conversions of the nitriles as a function of time,
temperature, catalyst composition; Figure of the time course of
benzonitrile hydration; spectroscopic characterization of
products.
Acknowledgements
This work was supported by the European Union and Hungary
and co-financed by the European Social Fund through the grant
∗ Corresponding author. Tel.: +36-52512900 ext. 22383; e-mail: katho.agnes@science.unideb.hu