An efficient ruthenium(iv) catalyst for the selective hydration of nitriles to amides in water under mild conditions

Article abstract of DOI:10.1039/c4cc04058a

A Ru(iv) catalyst able to promote the selective hydration of nitriles to amides in water, at low metal loadings and under mild conditions, is presented. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc04058a

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An efficient ruthenium(IV) catalyst for the selective
hydration of nitriles to amides in water under mild
conditions†
Cite this: Chem. Commun., 2014,
50, 9661
Received 27th May 2014,
Accepted 7th July 2014
Eder Tomas-Mendivil, Francisco J. Suarez, Josefina Dıez and Victorio Cadierno*
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DOI: 10.1039/c4cc04058a
www.rsc.org/chemcomm
A Ru(IV) catalyst able to promote the selective hydration of nitriles to
amides in water, at low metal loadings and under mild conditions, is
presented.
Amide bond forming reactions are among the most important and
widely studied transformations in organic chemistry,1 but they also
present a contemporary challenge because of the industrial need
for cleaner and more atom-economical protocols.2 Nitrile hydration
ideally represents the simplest method for the sustainable prepara-
tion of primary amides. However, strong acids and bases combined
Scheme 1 Synthesis of the bis(allyl)-Ru(IV)-phosphinous acid complexes
2a,b.
As shown in Scheme 1, the new complexes [RuCl2(Z3:Z3-
C
10H16){PR2(OH)}] (R = Ph (2a), Me (2b)) were synthesized in
with harsh reaction conditions have been traditionally employed to high yield by treatment of the commercially available dimer
promote the process, lowering its selectivity and applicability.1,3 {RuCl(m-Cl)(Z3:Z3-C10H16)}2 (1) with two equivalents of the corres-
In the search of more attractive and selective protocols, great ponding secondary phosphine oxide R2P(QO)H, via tautomeriza-
improvements have been achieved using enzymes4 and metal tion of R2P(QO)H into the phosphinous acids R2P(OH) and
catalysts.5 In this context, significant efforts have been devoted in cleavage of the chloride bridges of 1.11,12 Compounds 2a,b were
recent years to the search of homogeneous catalysts able to characterized by means of elemental analysis and multinuclear
promote the selective conversion of nitriles to amides directly NMR spectroscopy, the data obtained being fully consistent with
employing water as a solvent.6 We must note down this point that, the proposed formulations (see ESI†). In particular, coordination
although water is the most obvious solvent for this transformation, of the phosphinous acids in the equatorial position was readily
the vast majority of catalysts reported to date operate in organic evidenced in the 1H and 13C{1H} NMR spectra by the appearance
media on grounds of solubility and stability.5
of a single set of signals for the two allylic moieties of the
Ruthenium complexes are particularly effective nitrile hydration 2,7-dimethylocta-2,6-diene-1,8-diyl ligand, i.e. the two halves of
catalysts, and promising results in water have been described with the hydrocarbon chain are in equivalent environments.12 This
the help of hydrophilic phosphine ligands.7 However, high tempera- point was further confirmed by means of a single-crystal X-ray
ture regimes (Z100 1C) and metal loadings (5 mol%) are typically diffraction study on complex 2a (Fig. 1).† An intramolecular
needed to achieve good conversions.8 As a significant improvement, H-bonding interaction of moderate intensity (mostly electro-
herein we present a new Ru(IV) complex able to catalyze the selective static)13 between the OH unit of the phosphinous acid and one
hydration of a large number of organonitriles in water under of the chloride ligands was found in the crystal structure of this
remarkably milder conditions (60 1C), and featuring a high activity complex (distance and angle of the O1–H1OÁ Á ÁCl2 contact of
at a low metal loading (1 mol%).9,10
2.00(3) Å and 163.9(2)1, respectively).14
The ability of complexes 2a,b to promote the catalytic
hydration of nitriles in water was evaluated employing benzo-
nitrile (3a) as a model substrate (Table 1). Thus, using 5 mol%
of 2a, quantitative formation of benzamide (4a) was observed
by GC after only 15 min of heating at 100 1C (entry 1). Reduction
of the catalyst loading to 1 mol% still produced 4a in 98% yield
without a drastic increase in the reaction time (2 h; entry 2).
This latter result could be improved using 2b, which led to the
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Laboratorio de Compuestos Organometalicos y Catalisis (Unidad Asociada al CSIC),
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Centro de Innovacion en Quımica Avanzada (ORFEO-CINQA), Departamento de
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Quımica Organica e Inorganica, IUQOEM, Universidad de Oviedo, 33006 Oviedo,
Spain. E-mail: vcm@uniovi.es
† Electronic supplementary information (ESI) available: Experimental section,
characterization data and copies of the NMR spectra of all compounds. CCDC
989910 (2a). For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c4cc04058a
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Table 2 Catalytic hydration of nitriles to amides in water using the
ruthenium(IV) complex [RuCl2(Z3:Z3-C10H16){PMe2(OH)}] (2b)a
Entry Substrate 3
t (h)
Yield of 4b (%) TOF (hÀ1
)
1
2
3
4
5
6
R = Ph (3a)
R = C6F5 (3b)
3
0.5
7
2
2
499 (89)
98 (85)
98 (80)
499 (74)
97 (75)
98 (80)
99 (75)
89 (71)
95 (87)
97 (81)
95 (73)
99 (75)
97 (74)
98 (84)
98 (90)
99 (71)
97 (79)
499 (72)
499 (76)
499 (83)
97 (65)
499 (87)
499 (80)
99 (92)
33.3
196.0
14.0
50.0
48.5
98.0
198.0
1.8
31.7
12.1
13.6
24.8
16.2
196.0
98.0
198.0
97.0
200.0
200.0
33.3
16.2
16.7
R = 2-C6H4Cl (3c)
R = 3-C6H4Cl (3d)
R = 4-C6H4Br (3e)
R = 4-C6H4(COMe) (3f)
R = 3-C6H4NO2 (3g)
R = 2-C6H4Me (3h)
R = 4-C6H4Me (3i)
R = 4-C6H4OMe (3j)
R = 4-C6H4OH (3k)
R = 4-C6H4SMe (3l)
R = 2-pyridyl (3m)
R = 3-pyridyl (3n)
R = 4-pyridyl (3o)
R = 2-thienyl (3p)
R = 3-thienyl (3q)
R = 5-Me-2-furyl (3r)
R = 3-furyl (3s)
Fig. 1 ORTEP view of the structure of 2a (thermal ellipsoids are drawn at
30% probability level). Hydrogen atoms, except that on O1, have been
omitted for clarity. Selected bond distances (Å) and angles (1): Ru–P1 2.3784(7),
Ru–Cl1 2.4178(6), Ru–Cl2 2.4540(6), P1–O1 1.6040(18), Ru–C* 2.0065(2), Ru–
C** 1.9997(2), Cl1–Ru–Cl2 172.41(2), Cl1–Ru–P1 86.48(2), Cl1–Ru–C* 95.53(2),
Cl1–Ru–C** 88.20(2), Cl2–Ru–P1 86.11(2), Cl2–Ru–C* 88.92(2), Cl2–Ru–C**
93.51(2), P1–Ru–C* 113.33(2), P1–Ru–C** 115.56(2), C*–Ru–C** 131.11(1). C*
and C** denote the centroids of the allyl units (C1, C2 and C4, and C7, C8 and
C9, respectively).
1
7
0.5
16
3
8
7
4
6
0.5
1
0.5
1
0.5
0.5
3
6
6
0.25
5 min
1
8c
9
10
11
12
13
14
15
Table 1 Catalytic hydration of benzonitrile (3a) to benzamide (4a) in water 16
using the ruthenium(IV) complexes 2a,ba
17
18
19
20
21
22
23
24
25
26
R = CHQCH2 (3t)
R = n-C6H13 (3u)
R = CH3 (3v)
Entry
Cat.
mol% Ru
T (1C)
t (h)
0.25
2
1
3
72
24
Yieldb (%)
TOF (hÀ1
)
R = CH2Cl (3w)
400.0
1188.0
100.0
16.7
R = CH2OPh (3x)
R = CH2-2-thienyl (3y)
R = CH2CH2OPh (3z)
1
2
3
4
5
6
2a
2a
2b
2b
2b
2b
5
1
1
1
1
0.2
100
100
100
60
20
60
499
98
499
499
499
499
80.0
49.0
100.0
33.3
1.4
499 (87)
499 (80)
6
a
Reactions were performed under a N2 atmosphere starting from
b
1 mmol of the corresponding nitrile (0.33 M in water). Determined
20.8
by GC (uncorrected GC areas); isolated yields after the work-up are
given in brackets. Reaction performed with 3 mol% of 2b.
c
a
Reactions were performed under a N2 atmosphere starting from
1 mmol of 3a (0.33 M in water). b Determined by GC (uncorrected GC areas).
result of the higher electrophilicity of the nitrile carbon atom in
quantitative formation of 4a in 1 h (TOF = 100 hÀ1; entry 3). these substrates, due to the inductive effects of the chlorine atom
Even at 60 1C, a rapid conversion of 3a into 4a was observed by and the phenoxy group, respectively. For 3x, an impressive TOF value
employing 1 mol% of 2b (entry 4). The reaction could also be of 1188 hÀ1 was attained at this mild temperature. We would also
completed at r.t., but 3 days were required in this case (entry 5). like to stress that, in no case, traces of the corresponding carboxylic
It is also worthy of note that a respectable TON of 500 could be acids were detected by GC in the crude reaction mixtures.16
achieved using 0.2 mol% of 2b, and performing the hydration
reaction at 60 1C, conditions under which complete transformation
of 3a into 4a was again observed (entry 6).15
The outstanding performance of complex [RuCl2(Z3:Z3-
10H16){PMe2(OH)}] (2b) was further exploited in the catalytic
C
synthesis of the antiepileptic drug rufinamide 4aa (marketed
The scope and functional group tolerance of the most active under the trade name Inovelons),17 which could be generated
catalyst [RuCl2(Z3:Z3-C10H16){PMe2(OH)}] (2b) was subsequently in 83% isolated yield by hydration of 4-cyano-1-(2,6-
explored. Thus, as shown in Table 2, by performing the reactions difluorobenzyl)-1H-1,2,3-triazole 3aa (Scheme 2).18
at 60 1C with 1 mol% of this complex, a large variety of aromatic,
An additional proof of the synthetic utility of [RuCl2(Z3:Z3-
heteroaromatic, a,b-unsaturated and aliphatic organonitriles 3a–z C10H16){PMe2(OH)}] (2b) is its ability to promote the challenging
could be selectively transformed into the corresponding primary hydration of cyanohydrins (a-hydroxynitriles), substrates that are
amides 4a–z without the assistance of any acidic or basic co-catalyst. very difficult to hydrate because they degrade in aqueous media
Concerning the aromatic substrates, a slight influence of the into the corresponding carbonyl compounds and HCN. The vast
electronic properties of the aryl rings was observed, with the majority of nitrile hydration catalysts reported to date are inactive
substrates containing electron-donating groups showing a lower
reactivity (e.g., entry 10 vs. 6). Substitution in the ortho position also
led to a less efficient hydration (e.g., entry 8 vs. 9). The influence of
the electronic properties of the substrates in the activity of 2b was
also evidenced with aliphatic substrates. Thus, in comparison with
acetonitrile 3v (entry 22), chloroacetonitrile 3w (entry 23) and
Scheme 2 Catalytic synthesis of rufinamide 4aa using complex 2b.
phenoxyacetonitrile 3x (entry 24) were hydrated much faster as a
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Scheme 3 Catalytic hydration of cyanohydrins 3ab,ac using complex 2b.
towards cyanohydrins due to their poisoning by cyanide.19 As
shown in Scheme 3, using 5 mol% of 2b and performing the
reactions at r.t. to minimize the decomposition of the substrates,
complete conversion of lactonitrile 3ab and 2-hydroxybutyronitrile
3ac into the corresponding a-hydroxyamides 4ab,ac could be
achieved after 72 h of stirring. In the case of 3ab, a 92% conversion
is already reached after 7 h.20
Fig. 3 Reuse of the aqueous solution containing 2b in the hydration reaction
of pentafluorobenzonitrile (3b). Separation of pentafluorobenzamide (4b)
formed by crystallization at 0 1C in an ice bath. Reaction conditions identical
to those indicated in Table 2 (0.5 h of reaction in each cycle).
Another remarkable aspect of complex [RuCl2(Z3:Z3-C10H16)-
{PMe2(OH)}] (2b) is that it can be easily separated from the reaction
products. Thus, in most cases, after completion of the reaction,
selective crystallization of the amide takes place by cooling the
mixture at r.t., or at 0 1C in an ice bath, remaining 2b completely
dissolved in water.21 As an illustrative example, the reaction mixture
resulting from the hydration of the model benzonitrile substrate 3a
before and after cooling is shown in Fig. 2. Clean and extensive
crystallization of the formed benzamide readily took place at r.t.
This easy catalyst/product separation allowed us to evaluate the
lifetime and level of recyclability of 2b, which are the key factors for
practical applications of this catalyst.22 To our delight we found
that, using the hydration of pentafluorobenzonitrile (3b) into
pentafluorobenzamide (4b) as a model (entry 2 in Table 2), the
aqueous phase containing 2b could be reused 10 consecutive times,
with loss of activity being observed only after the sixth cycle
(cumulative TON after the 10 cycles = 853; see Fig. 3).
In summary, we have designed a new metal catalyst for the
selective hydration of nitriles into primary amides in water, displaying
a broad substrate scope and functional compatibility. The following
features of complex [RuCl2(Z3:Z3-C10H16){PMe2(OH)}] (2b) merit high-
lighting: (i) it is readily accessible in high yield from a commercially
available ruthenium precursor. (ii) It operates in pure water without
the assistance of any acidic or basic co-catalyst.23 (iii) The reactions
proceed efficiently and cleanly under remarkably mild conditions
Fig. 4 The activating effect of the phosphinous acid ligand Me2P(OH)
during catalysis.
(60 1C) and with low metal loadings (1 mol%). (iv) It is able to hydrate
the challenging cyanohydrins. And (v) it can be easily recycled. In
short, complex [RuCl2(Z3:Z3-C10H16){PMe2(OH)}] (2b) represents the
most active homogeneous catalyst reported to date for the catalytic
hydration of nitriles employing environmentally friendly water as the
solvent. Although studies to elucidate the mechanism of action of 2b
are still in progress in our lab, we can assume, based on previous
studies by Tyler,20 that the excellent activity shown by this complex is
related to the activating effect that the OH group of the phosphinous
acid ligand Me2P(OH) exerts on the water molecules by H-bonding. In
this way, the key nucleophilic attack of water on the coordinated
nitrile is favoured (see Fig. 4).
Financial support from MINECO of Spain (CTQ2010-14796/
BQU) is acknowledged. E.T.-M. also thanks the Spanish Govern-
ment and the ESF for the award of a FPU fellowship.
Notes and references
1 (a) The Chemistry of Amides, ed. J. Zabicky, Wiley-Interscience, New York,
1970; (b) The Amide Linkage: Structural Significance in Chemistry, Bio-
chemistry and Materials Science, ed. A. Greenberg, C. M. Breneman and
J. F. Liebman, John Wiley & Sons, New York, 2000.
2 For reviews highlighting this point, see: (a) D. J. C. Constable, P. J. Dunn,
J. D. Hayler, G. R. Humphrey, J. L. Leazer Jr., R. J. Linderman, K. Lorenz,
J. Manley, B. A. Pearlman, A. Wells, A. Zaks and T. Y. Zhang, Green
Chem., 2007, 9, 411; (b) V. R. Pattabiraman and J. W. Bode, Nature, 2011,
480, 471; (c) C. L. Allen and J. M. J. Williams, Chem. Soc. Rev., 2011,
40, 3405.
3 P. D. Bailey, T. J. Mills, R. Pettecrew and R. A. Price, in Comprehen-
sive Organic Functional Group Transformations II, ed. A. R. Katritzky
and R. J. K. Taylor, Elsevier, Oxford, 2005, vol. 5, pp. 201–294.
4 For selected reviews, see: (a) M. Kobayashi and S. Shimizu, Curr.
Opin. Chem. Biol., 2000, 4, 95; (b) S. Prasad and T. C. Bhalla,
Biotechnol. Adv., 2010, 28, 725.
5 For reviews, see: (a) V. Y. Kukushkin and A. J. L. Pombeiro, Inorg.
Chim. Acta, 2005, 358, 1; (b) T. J. Ahmed, S. M. M. Knapp and
Fig. 2 Hydration of benzonitrile (3a) to benzamide (4a) in water using
complex [RuCl2(Z3:Z3-C10H16){PMe2(OH)}] (2b) as the catalyst. After com-
pletion of the reaction at 60 1C (left) and after cooling the mixture at r.t.
(right). Reaction conditions identical to those indicated in Table 2.
D. R. Tyler, Coord. Chem. Rev., 2011, 255, 949.
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6 For
a
specific review, see: R. Garcıa-Alvarez, P. Crochet and
V. Cadierno, Green Chem., 2013, 15, 46.
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7 (a) For a specific review, see: R. Garcıa-Alvarez, J. Francos, E. Tomas-
Mendivil, P. Crochet and V. Cadierno, J. Organomet. Chem., 2014,
DOI: 10.1016/j.organchem2013.11.042, in press: (b) For a recent
example not included in this review, see: E. Bolyog-Nagy,
loading of 5 mol%). The higher activity of 2b may be reasoned in
terms of the more effective activation of the CRN bond upon
coordination to the stronger Lewis acid Ru(IV) center. See:
S. M. M. Knapp, T. J. Sherbow, R. B. Yelle, J. J. Juliette and
D. R. Tyler, Organometallics, 2013, 32, 3744(b) Complex 2b proved
to be also more active than analogous [RuCl2(Z3:Z3-C10H16)(PR3)]
(PR3 = ‘‘cage-like’’ water-soluble phosphine) species previously
described by us (TOF up to 20 hÀ1 at 100 1C). This fact points out
the key role played by the phosphinous acid ligand in the catalytic
reaction, which could establish H-bonds with water facilitating its
approach and addition to the coordinated nitrile. See: V. Cadierno,
´
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´
A. Udvardy, F. Joo and A. Katho, Tetrahedron Lett., 2014, 55, 3615.
8 Some examples showing a remarkable activity in water at 100 1C and
at 1 mol% of Ru loading have been described: (a) W.-C. Lee and
B. J. Frost, Green Chem., 2012, 14, 62; (b) W.-C. Lee, J. M. Sears,
R. A. Enow, K. Eads, D. A. Krogstad and B. J. Frost, Inorg. Chem.,
2013, 52, 1737.
9 Only the homogeneous systems [PtH{(PMe2O)2H}(PMe2OH)], [{Rh-
(m-OMe)(cod)}2]/PCy3 and [RhBr(PIN)(cod)] (cod = 1,5-cycloctadiene;
´
J. Dıez, J. Francos and J. Gimeno, Chem. – Eur. J., 2010, 16, 9808.
PIN
=
1-isopropyl-3-(5,7-dimethyl-1,8-naphthyrid-2-yl)imidazol-2- 16 Despite the high functional group tolerance shown by complex 2b,
ylidene), based on more expensive transition metals, have shown
high activity and scope below 100 1C. All of them operate in organic
attempts to hydrate 4-aminobenzonitrile and 6-aminohexanenitrile
failed (up to 11% conversion after 24 h).
media. See: (a) T. Ghaffar and A. W. Parkins, J. Mol. Catal. A: Chem., 17 See, for example: G. Coppola, Neuropsychiatr. Dis. Treat., 2011,
2000, 160, 249; (b) A. Goto, K. Endo and S. Saito, Angew. Chem., Int. 7, 399, and references cited therein.
Ed., 2008, 47, 3607; (c) P. Daw, A. Sinha, S. M. W. Rahaman, S. Dinda 18 We have recently described the hydration of 3aa with different Rh(I)
and J. K. Bera, Organometallics, 2012, 31, 3790.
and Ru(II) catalysts. Higher metal loadings (5 mol%) and tempera-
10 The heterogeneous systems CeO2 and MnO2 have also shown a
remarkable reactivity below 100 1C. See: (a) M. Tamura,
H. Wakasugi, K.-I. Shimizu and A. Satsuma, Chem. – Eur. J., 2011,
ture (100 1C) were needed to generate rufinamide 4aa in high yields.
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See: E. Tomas-Mendivil, R. Garcıa-Alvarez, C. Vidal, P. Crochet and
V. Cadierno, ACS Catal., 2014, 4, 1901.
17, 11428; (b) C. Battilocchio, J. M. Hawkins and S. V. Ley, Org. Lett., 19 T. J. Ahmed, B. R. Fox, S. M. M. Knapp, R. B. Yelle, J. J. Juliette and
2014, 16, 1060.
D. R. Tyler, Inorg. Chem., 2009, 48, 7828, and references cited
therein.
11 For reviews dealing with the use of secondary phosphine oxides as
precursors of phosphinous acids and related P-donor ligands, see: 20 Only two metal catalysts capable of effectively hydrating cyano-
(a) L. Ackermann, Synthesis, 2006, 1557; (b) T. M. Shaikh, C.-M.
Weng and F.-E. Hong, Coord. Chem. Rev., 2012, 256, 771.
12 For reviews on the coordination chemistry and catalytic applications
hydrins, namely [RuCl2(Z6-p-cymene){PMe2(OH)}] and [RuCl2(Z6-
p-cymene){P(NMe2)3}] are currently known. Under identical reaction
conditions to those employed herein, the former was able to convert
3ab into 4ab in 94% yield (by 1H NMR) after 17.5 h, and the latter
in 499% (by 1H NMR) after 112 h. See ref. 15a and: S. M. M. Knapp,
T. J. Sherbow, R. B. Yelle, L. N. Zakharov, J. J. Juliette and D. R. Tyler,
Organometallics, 2013, 32, 824.
´
of dimer 1, see: (a) V. Cadierno, P. Crochet, S. E. Garcıa-Garrido and
J. Gimeno, Curr. Org. Chem., 2006, 10, 165; (b) C. Bruneau and
M. Achard, Coord. Chem. Rev., 2012, 256, 525.
13 (a) G. A. Jeffrey, An Introduction to Hydrogen Bonding, Oxford
University Press, Oxford, 1997; (b) T. Steiner, Angew. Chem., Int. 21 Although complex 2b presents by itself a low solubility in water at
Ed., 2002, 41, 48.
r.t. (0.1 mg mLÀ1) or even at 60 1C (0.5 mg mLÀ1), under the catalytic
conditions employed, i.e. in the presence of a large excess of nitrile,
it readily dissolves in water at r.t.
14 Metal-bound chlorine atoms are well-known H-bond acceptors:
´
G. Aullon, D. Bellamy, L. Brammer, E. A. Bruton and A. G. Orpen,
Chem. Commun., 1998, 653.
22 Recoverable and Recyclable Catalysts, ed. M. Benaglia, John Wiley &
Sons, Chichester, 2009.
15 (a) A TOF of 10 hÀ1 in the hydration of 3a was recently described
using the related Ru(II) complex [RuCl2(Z6-p-cymene){PMe2(OH)}] in 23 We must note that, when dissolved in water, complex 2b generates
pure water (quantitative formation of 4a after 2 h at 100 1C with a Ru
an acidic solution (pH of 2.8 at r.t.).
9664 | Chem. Commun., 2014, 50, 9661--9664
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