Exploring rhodium(I) complexes [RhCl(COD)(PR3)] (COD = 1,5-cyclooctadiene) as catalysts for nitrile hydration reactions in water: The aminophosphines make the difference

Article abstract of DOI:10.1021/cs500241p

Several rhodium(I) complexes, [RhCl(COD)(PR₃)], containing potentially cooperative phosphine ligands, have been synthesized and evaluated as catalysts for the selective hydration of organonitriles into amides in water. Among the different phosphines screened, those of general composition P(NR ₂)₃ led to the best results. In particular, complex [RhCl(COD){P(NMe₂)₃}] was able to promote the selective hydration of a large range of nitriles in water without the assistance of any additive, showing a particularly high activity with heteroaromatic and heteroaliphatic substrates. Employing this catalyst, the antiepileptic drug rufinamide was synthesized in high yield by hydration of 4-cyano-1-(2,6- difluorobenzyl)-1H-1,2,3-triazole. For this particular transformation, complex [RhCl(COD){P(NMe₂)₃}] resulted more effective than related ruthenium catalysts.

Full text of DOI:10.1021/cs500241p

Research Article
pubs.acs.org/acscatalysis
Exploring Rhodium(I) Complexes [RhCl(COD)(PR3)] (COD = 1,5-
Cyclooctadiene) as Catalysts for Nitrile Hydration Reactions in Water:
The Aminophosphines Make the Difference
́
Eder Tomas-Mendivil, Rocío García-Alvarez, Cristian Vidal, Pascale Crochet, and Victorio Cadierno*
́
Laboratorio de Compuestos Organometal
en Química Avanzada, Departamento de Química Organ
“Enrique Moles”, Facultad de Química, Universidad de Oviedo, Julian
́
icos y Catal
́
isis (Unidad Asociada al CSIC), Red ORFEO−CINQA - Centro de Innovacion
ica e Inorganica, Instituto Universitario de Química Organometalica
Clavería 8, E-33006 Oviedo, Spain
́
́
́
́
́
S
* Supporting Information
ABSTRACT: Several rhodium(I) complexes, [RhCl(COD)-
(PR3)], containing potentially cooperative phosphine ligands,
have been synthesized and evaluated as catalysts for the
selective hydration of organonitriles into amides in water.
Among the different phosphines screened, those of general
composition P(NR2)3 led to the best results. In particular,
complex [RhCl(COD){P(NMe2)3}] was able to promote the
selective hydration of a large range of nitriles in water without
the assistance of any additive, showing a particularly high
activity with heteroaromatic and heteroaliphatic substrates.
Employing this catalyst, the antiepileptic drug rufinamide was synthesized in high yield by hydration of 4-cyano-1-(2,6-
difluorobenzyl)-1H-1,2,3-triazole. For this particular transformation, complex [RhCl(COD){P(NMe2)3}] resulted more effective
than related ruthenium catalysts.
KEYWORDS: rhodium complexes, aminophosphines, hydration reactions, nitriles, amides, rufinamide, aqueous catalysis
(PTA) and related cage-like aminophosphines,9 tris-
(dimethylamino)phosphine10 or phosphinites (R2POH).11,12
The excellent activities were in most cases attributed to the
activating effect that the heteroatoms present in the structures
of these P-donor ligands exert on the water molecules by H-
bonding or deprotonation. By this way, the key nucleophilic
attack of water, or the hydroxide anion if deprotonation takes
place, on the coordinated nitrile is favored (Figure 1). Most of
INTRODUCTION
■
The hydration of organonitriles is a relevant transformation in
both academia and industry because the products of the
reaction, i.e. primary amides, are versatile synthetic inter-
mediates, as well as useful building blocks for the manufacture
of pharmaceutical molecules and engineering polymers.1
Conventional protocols for hydrating nitriles involve the use
of highly acidic/basic media under harsh reaction conditions,
methods that usually cause partial overhydrolysis of the amides
into the corresponding carboxylic acids and do not tolerate
many key functional groups.2 Nitrile hydratases (NHases), a
family of biocatalysts comprising non-heme iron and non-
corrinoid cobalt enzymes, have demonstrated great potential to
promote the selective transformation of nitriles into amides
under mild conditions.3 Indeed, NHases are now being used for
the large-scale production of acrylamide, nicotinamide, 5-
cyanovaleramide, and the antiepileptic amide drug levetirace-
tam (marketed under the trade name Keppra).3,4 However,
from a synthetic point of view, the high cost and substrate
specificity of the currently available enzymes severely limit their
use. Given their greater substrate scope and easier handling,
methods based on homogeneous or heterogeneous metal-
catalysts represent more attractive and powerful alternatives.5
In this context, remarkable results have been obtained in recent
years using homogeneous ruthenium catalysts containing as
auxiliary ligands pyridyl-phosphines,6 aminoaryl-phosphines,7
thiazolyl-phosphines,8 1,3,5-triaza-7-phosphaadamantane
Figure 1. Cooperative effects of functionalized phosphines in Ru-
catalyzed nitrile hydrations.
these “bifunctional catalysts”13 are able to operate directly in
water as the reaction medium, and without the assistance of any
acidic or basic additive, showing a wide substrate scope and
high tolerance to common functional groups. Studies by Tyler
and co-workers revealed also the utility of complexes
[RuCl2(η6-p-cymene){P(NMe2)3}] and [RuCl2(η6-p-cymene)-
(PMe2OH)] to promote the challenging hydration of α-
Received: February 24, 2014
Revised: April 29, 2014
Published: May 1, 2014
© 2014 American Chemical Society
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Research Article
hydroxynitriles (cyanohydrins) into the corresponding α-
hydroxyamides.10c,f,11b An extremely low reactivity is usually
observed with this particular type of nitrile due to the poisoning
of the catalysts by cyanide, a species that is generated in
solution by partial decomposition of the cyanohydrins.14
All the facts commented on above support the exploration of
new metal complexes with cooperative phosphine ligands as
potential catalysts for nitrile hydration reactions. Rhodium
compounds are good candidates for such purposes due to the
excellent performances shown by this metal in a multitude of
catalytic processes.15 Our interest in rhodium is also motivated
by the few bibliographic precedents on its use for the catalytic
hydration of CN bonds. Thus, in addition to some early
examples of limited scope employing RhCl3 and trans-
[Rh(OH)(CO)(PPh3)2],16 only three effective and general
rhodium-based systems have been described to date in the
literature: (i) The [{Rh(μ-Cl)(COD)}2]/TPPTS combination
(COD = 1,5-cyclooctadiene; TPPTS = tris(meta-sulfonato-
phenyl)-phosphine trisodium salt), which proved to be active in
pure water at 90 °C under basic conditions (optimal pH =
11.7).17 (ii) The [{Rh(μ-OMe)(COD)}2]/PCy3 system, which
Scheme 1. Synthesis of the Mononuclear Rh(I) Complexes
[RhCl(COD)(PR3)] (3a−l)
i
showed a remarkable activity in a PrOH/H2O solvent mixture
at ambient temperature.18 (iii) The rhodium(I) complex A
(Figure 2), containing a naphthyridyl-substituted N-hetero-
included for comparative purposes, the following potentially
cooperative phosphines were employed: the pyridyl-phosphines
2b−d, the cage-like water-soluble ligands PTA (2e) and
DAPTA (2f), the aminophosphines 2g−k, and the trihydrazi-
nophosphaadamantane derivative 2l (THPA). Most of these
ligands have previously demonstrated their usefulness in the
development of highly effective ruthenium catalysts for nitrile
hydration processes.6,9,10 The chloride bridges cleavage
reactions of dimer 1 with phosphines 2a−l proceeded quickly
and cleanly in tetrahydrofuran at room temperature, affording
complexes [RhCl(COD)(PR3)] (3a−l) which were isolated as
yellow solids (oily material in the case of 3i) in high yields
(80−94%).
Figure 2. Structure of the Rh(I)−NHC complex A and the transition
state B.
cyclic carbene (NHC) ligand, which, in combination with a
base (KOtBu), was also able to promote the selective hydration
of a large number of organonitriles at room temperature in
iPrOH/H2O.19 For this latter example, DFT calculations
revealed that the bifunctional activation of the water molecule
by the naphthyridyl group is one of the key steps in the catalytic
cycle (transition state B in Figure 2). To the best of our
knowledge, no general rhodium-based catalysts able to operate
in pure water under neutral conditions are currently known.
That is why, with the aim of filling this gap and on the basis of
the previous findings with ruthenium complexes,6−11 we
decided to carry out a study on the behavior of a series of
rhodium(I) derivatives, [RhCl(COD)(PR3)], with potentially
cooperative phosphine ligands, in this catalytic transformation.
The results from this study are presented herein. Among the
different phosphine ligands employed, aminophosphines of
general composition P(NR2)3 were found to be particularly
useful in the development of catalytic systems with high
activity.
Compounds [RhCl(COD)(PPh3)] (3a),20 [RhCl(COD)-
(PPh2py)] (3b),21 and [RhCl(COD)(THPA)] (3l)22 have
been previously described in the literature.23 The rest of
complexes were fully characterized by means of elemental
analyses, IR, and multinuclear NMR spectroscopy (31P{1H}, 1H
and 13C{1H}), all data being fully consistent with the proposed
formulations (details are given in the Experimental Section). In
particular, their 31P{1H} NMR spectra confirmed the
coordination of the phosphines to the metal center, as doublet
resonances due to P−Rh coupling were observed at chemical
shifts different from those found for the free ligands (Table 1).
1
The values of the J(31P,103Rh) coupling constants are a direct
indicator for the strength of the P−Rh bonds.23b,c In accord,
the measured values for complexes 3a−l showed the expected
increase with the π-accepting nature of the PR3 ligands,23b,c,24
1
the highest J(31P,103Rh) value of 231.9 Hz being observed for
[RhCl(COD){P(N-pyrrolyl)3}] (3k).25 The H and 13C{1H}
1
RESULTS AND DISCUSSION
NMR spectra of the novel derivatives 3c−3k were also in
agreement with the proposed structures, showing the expected
resonances for the corresponding phosphine ligand and the η4-
coordinated 1,5-cyclooctadiene unit. For the latter, the
expected two sets of resonances for the chemically inequivalent
olefinic protons and carbons were observed.
■
Our research began with the preparation of a diverse family of
square-planar [RhCl(COD)(PR3)] complexes 3a−l through
the treatment of dimer [{Rh(μ-Cl)(COD)}2] (1) with 2 equiv
of the corresponding monodentate P-donor ligand (Scheme 1).
Thus, in addition to triphenylphosphine (2a) which was only
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Table 1. 31P{1H} NMR Data for Ligands 2a−l and
Table 2. Hydration of Benzonitrile (4a) into Benzamide (5a)
a
Complexes 3a−l
Catalyzed by the Rhodium(I) Complexes 1 and 3a−n in
a
Water
ligand
δP (ppm)
complex
δP (ppm)
1JRhP (Hz)
b
2a
2b
2c
2d
2e
2f
−6.0
−3.5
−2.0
3a
31.4
28.5
152.0
150.6
149.6
151.8
149.4
153.1
159.7
194.4
196.3
192.5
231.9
199.9
3b
c
3c
30.9
−3.6
3d
3e
3f
29.4
−101.9
−78.8
66.0
−52.9
−29.2
79.0
yield
b
TOF
c
entry
conditions
(%)
(h−1
)
1
[{Rh(μ-Cl)(COD)}2] (1)
4
2
0.1
<0.1
0.3
0.6
<0.1
0.1
0.2
1.5
2.5
0.7
2.2
−
2g
2h
2i
3g
3h
2
[RhCl(COD)(PPh3)] (3a)
123.0
117.1
104.9
79.6
109.3
113.0
90.3
b
3
[RhCl(COD)(PPh2py)] (3b)
10
21
3
3i
b
4
[RhCl(COD){PPh2(py-4-NMe2)}] (3c)
[RhCl(COD){PPh2(py-6-tert-amyl)}] (3d)
[RhCl(COD)(PTA)] (3e)
2j
3j
d
5
2k
3k
3l
90.3
6
4
2l
101.8
116.6
a
b
d
7
[RhCl(COD)(DAPTA)] (3f)
6
Unless otherwise stated the NMR spectra were recorded in CDCl3.
Spectrum recorded in C6D6. Spectrum recorded in CD2Cl2.
Recorded in toluene-d8.
c
8
[RhCl(COD){PPh2(NMe2)}] (3g)
[RhCl(COD){P(NMe2)3}] (3h)
[RhCl(COD){P(NEt2)3}] (3i)
[RhCl(COD){P(N-pyrrolidinyl)3}] (3j)
[RhCl(COD){P(N-pyrrolyl)3}] (3k)
[RhCl(COD)(THPA)] (3l)
54
87
24
78
traces
78
73
12
9
10
11
12
13
14
15
Taking into account the good results previously obtained
with the dinuclear Ru(IV) complex [{RuCl2(η3:η3-
C10H16)}2(μ-THDP)] (C10H16 = 2,7-dimethylocta-2,6-diene-
1,8-diyl; THDP = tris(1,2-dimethylhydrazino)diphosphine
(2m)),9b we also considered the use of the analogous
dirhodium(I) derivative [{RhCl(COD)}2(μ-THDP)] (3m) in
our study. This dinuclear species was synthesized in 95% yield
through a known procedure formerly described by us (Scheme
2).26,27
2.2
2.1
0.3
[{RhCl(COD)}2(μ-THDP)] (3m)
[RhCl(COD){P(OMe)3}] (3n)
a
Reactions performed under a N2 atmosphere at 100 °C using 1 mmol
b
of benzonitrile (0.33 M in water). Substrate/Rh ratio: 100/5. Yields
determined by GC (uncorrected GC areas). Turnover frequencies
((mol product/mol Rh)/time).
c
Scheme 2. Synthesis of the Dinuclear Rh(I) Complex
[{RhCl(COD)}2(μ-THDP)] (3m)
bulkier pyridyl-phosphine PPh2(py-6-tert-amyl), for which the
chelation process would be sterically disfavored, did not result
in any improvement (entry 5).31 All these facts indicate that
cooperative effects of this class of ligands are negligible within
the [RhCl(COD)(PR3)] series. We stress at this point that
solubility grounds (compounds 3a−d are not soluble in water
at rt) are not behind the poor catalytic activities observed, since
similar low yields were also achieved performing the reactions
i
in a PrOH/H2O (1:1 v/v) mixture. Moreover, the highly
water-soluble complexes [RhCl(COD)(PTA)] (3e) and
[RhCl(COD)(DAPTA)] (3f) proved to be almost inactive in
the hydration process (entries 6 and 7).
Fortunately, much better results were obtained with the
rhodium complexes that contain auxiliary phosphine ligands
with direct P−N bonds. Thus, the substitution of PPh3 by
PPh2NMe2 allowed increasing the benzamide (5a) yield to 54%
(entry 8 vs entry 2). Further improvements were reached with
the tris(amino)phosphine-based complexes [RhCl(COD){P-
(NMe2)3}] (3h) (entry 9) and [RhCl(COD){P(N-pyrrolidin-
yl)3}] (3j) (entry 11), and the hydrazinophosphine-based ones
[RhCl(COD)(THPA)] (3l) (entry 13) and [{RhCl-
(COD)}2(μ-THDP)] (3m) (entry 14). All of them were able
to generate 5a in ≥73% GC-yield after 7 h of heating, with
[RhCl(COD){P(NMe2)3}] (3h) showing the best perform-
ance (87% yield; TOF = 2.5 h−1; entry 9). As previously
proposed for the ruthenium(II) complexes [RuCl2(η6-arene)-
{P(NMe2)3}],10f the enhanced activities of these systems most
probably rely on the effective activation of the incoming water
molecule by H-bonding during its nucleophilic attack to the
coordinated nitrile (Figure 3).
The catalytic potential of the Rh(I) complexes 3a−m for
nitrile hydration reactions was then investigated using
benzonitrile (4a) as model substrate. In a typical experiment,
the corresponding complex (5 mol % of Rh) was added under
N2 atmosphere to a 0.33 M aqueous solution of 4a, and the
mixture was heated in an oil bath at 100 °C for 7 h. The results
obtained are collected in Table 2. Under the neutral conditions
employed, the dimeric precursor [{Rh(μ-Cl)(COD)}2] (1) and
the triphenylphosphine complex [RhCl(COD)(PPh3)] (3a)
were nearly inactive in the hydration process (entries 1−2),
delivering benzamide (5a) in only 2−4% yield as determined
by gas chromatography (GC).28 Slight improvements were
observed when the reaction was performed with the pyridyl-
phosphine complexes [RhCl(COD)(PPh2py)] (3b) and
[RhCl(COD){PPh2(py-4-NMe2)}] (3c), although yields were
still unsatisfactory (entries 3−4). A reason for the low catalytic
activity shown by 3b−c might be related with the chelation of
the ligands to rhodium, that would compete with the activation
of the water molecule by hydrogen bonding with the pyridyl
nitrogen atom.29,30 However, we must note that the use of the
The marked differences in activity observed between
complexes [RhCl(COD){P(N-pyrrolidinyl)3}] (3j) and [RhCl-
(COD){P(N-pyrrolyl)3}] (3k) seem to support this proposal.
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larger size of the tris(diethylamino)phosphine ligand 2i.
However, the differences between the cone angle34 of P(NEt2)3
(2i; 174.0°) and those of P(NMe2)3 (2h; 167.9°), P(N-
pyrrolidinyl)3 (2j; 169.8°), THPA (2l; 165.0°) and THDP
(2m; 165.9°), all calculated following the mathematical
procedure recently described by Allen and co-workers from
the DFT-optimized structures of complexes 3h−3j, 3l, 3m
(included in the SI file),35 seems to be not significant enough to
explain the remarkably lower efficiency of [RhCl(COD){P-
(NEt2)3}] (3i).36 Further studies indicated that stability
grounds are more probably behind this discrepancy. In favor
of this hypothesis is the fact that, while complexes [RhCl-
(COD){P(NMe2)3}] (3h) and [RhCl(COD){P(N-pyrrolidin-
yl)3}] (3j) are perfectly stable in solution, complex [RhCl-
(COD){P(NEt2)3}] (3i) evolves in polar media into a mixture
Figure 3. Proposed activating effect of the amino- and hydrazino-
phosphine ligands.
Thus, while complex [RhCl(COD){P(N-pyrrolidinyl)3}] (3j),
in which the lone pairs of the nitrogen atoms are available to
establish H-bonds with water, showed a respectable activity
(entry 11), complex [RhCl(COD){P(N-pyrrolyl)3}] (3k) was
rendered completely inactive (entry 12), due to the aromatic
delocalization of the nitrogen lone pairs into the pyrrole rings
(resonance structures are shown in Figure 4).32 Full evidence of
1
of uncharacterized products, as assessed by 31P{1H} and H
NMR spectroscopy (CD3CN and CD3NO2 solutions). The
flexibility associated with the ethyl units of the ligand P(NEt2)3,
which allows the approach of the methyl groups to the Rh(I)
center, could lead to the oxidative C−H addition of these
groups to the metal and hence the observed instability.37
On the other hand, analogously to what was previously
observed with ruthenium catalysts,10f replacement of the
tris(amino)phosphine ligands by P(OMe)3 led to a much less
active catalyst, i.e. [RhCl(COD){P(OMe)3}] (3n) (entry 15),
pointing out the key role played by the P−N units, which seems
to establish stronger H-bonds with water in comparison with
the P−O ones.
As commented in the introduction of this article, most of the
known rhodium catalysts usually require basic reaction
conditions to hydrate CN bonds in an effective manner.
This raised the question of whether the addition of a base could
improve the activity of our catalysts. To answer this question
we conducted the hydration of benzonitrile (4a) with the most
active complex [RhCl(COD){P(NMe2)3}] (3h) (5 mol %) in
the presence of variable amounts of KOtBu (from 1 to 5 mol %;
i.e. from 0.2 to 1 equiv per Rh atom). As shown in Figure 5,
slight improvements in activity were observed in the presence
of 1−3 mol % of KOtBu, but a drastic drop occurred when a
larger amount of base was added (4−5 mol % of KOtBu). pH
measurements on these solutions showed a significant increase
Figure 4. Resonance structures for N-pyrrolyl-phosphine ligands.
the aromaticity of the pyrrole rings in 3k was gained through its
computed electrostatic potential map (included along with that
of 3j in the Supporting Information [SI]). In addition, we have
also theoretically studied (DFT calculations) the relative
basicity of the nitrogen atoms of the pyrrolidine/pyrrole
fragments in complexes [RhCl(COD){P(N-pyrrolidinyl)3}]
(3j) and [RhCl(COD){P(N-pyrrolyl)3}] (3k). Protonation of
the pyrrolidine N atom in 3j was found to be favored by 37.12
kcal/mol with respect to that of the pyrrole moiety in 3k. This
fact clearly indicates that the N atoms of P(N-pyrrolidinyl)3 are
much more basic than those of P(N-pyrrolyl)3, and therefore
more prone to establish H-bonds with water (details are
included in the SI).33
During this initial study, a striking result was found with
complex [RhCl(COD){P(NEt2)3}] (3i), which showed a much
lower activity (24% GC yield; entry 10) than that of its peers
3h, 3j, 3l, 3m (≥73% GC yield; entries 9, 11, 13 and 14,
respectively). We initially thought that this could be due to the
Figure 5. Catalytic hydration of 4a into 5a using the Rh(I) complex [RhCl(COD){P(NMe2)3}] (3h) in the presence or absence of KOtBu.
Conditions: reactions performed under N2 atmosphere at 100 °C using 1 mmol of 4a, 0.05 mmol of 3h (5 mol %) and 3 mL of water.
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in the basicity of the reaction medium (from 7.9 in the absence
of KOtBu to 12.1 in the presence of 5 mol % of KOtBu), which
is accompanied by a rapid decomposition of 3h (31P{1H} NMR
measurements). The sudden change in activity observed in the
presence of 4−5 mol % of KOtBu seems therefore associated
with the low stability of complex [RhCl(COD){P(NMe2)3}]
(3h) in highly basic media.38 Similar observations were made
when employing the related complex 3j. Since the addition of a
base did not result in significant improvements, we decided to
study the scope of the catalytic reaction with [RhCl(COD)-
{P(NMe2)3}] (3h) under neutral conditions. To this end, a
variety of nitriles were subjected to the action of 3h (5 mol %)
in pure water (0.33 M solutions) at 100 °C. Selected results are
collected in Table 3.
ortho position also resulted in a less efficient hydration (entry 3
vs 4). Remarkably, in no case were traces of the corresponding
benzoic acids detected by GC in the crude reaction mixtures.
Complex [RhCl(COD){P(NMe2)3}] (3h) was particularly
effective with heteroaromatic nitriles (entries 9−17). In
addition, for this particular class of substrates, marked
differences in activity were observed, depending on the relative
position of the heteroatom and the CN unit. Thus, while 2-
cyanopyridine (4i) and 4-cyanopyridine (4k) were almost
quantitatively converted into picolinamide (5i) and isonicoti-
namide (5k), respectively, after only 2−3 h of heating (entries
9 and 11), a much longer reaction time (24 h) was needed to
generate nicotinamide (5j) from 3-cyanopyridine (4j) in high
yield (entry 10). Resonance effects could be responsible for the
different reactivity observed since in 4j the nitrile carbon has a
reduced electrophilicity (negative charges always located on the
carbon atoms of the py ring vs N atoms in the case of 4i and
4k), and therefore the nucleophilic addition of water at this
position is disfavored.
Table 3. Catalytic Hydration of Nitriles into Amides in
a
Water Using [RhCl(COD){P(NMe2)3}] (3h) as Catalyst.
Extremely fast reactions were also observed with 2-
pyrimidinecarbonitrile (4l) and pyrazinecarbonitrile (4m)
(entries 12 and 13). In particular, hydration of 4m allowed
the isolation of pure pyrazinamide (5m), a drug used to treat
tuberculosis,39 in 82% yield. Also worthy of note is that,
similarly to the case of cyanopyridines, a much higher reactivity
was observed with 2-thiophenecarbonitrile (4n) and 5-methyl-
2-furanecarbonitrile (4p) in comparison with the related
systems 3-thiophenecarbonitrile (4o) and 3-furanecarbonitrile
(4q) (entries 14 vs 15 and 16 vs 17). Resonance effects can be
again evoked to rationalize these observations. It must be
stressed in this point that the higher reactivity of [RhCl-
(COD){P(NMe2)3}] (3h) toward heteroaromatic vs simple
aromatic substrates clearly differentiates this catalysts from the
other rhodium-based systems previously described in the
literature, where such differences were not noted.16−19 For
example, using the [{Rh(μ-OMe)(COD)}2]/PCy3 system,
benzonitrile and 2-thiophenecarbonitrile were hydrated with
an identical TOF of 8 h−1.18 Similar TOF values of around 90
h−1 were also reached in the hydration of benzonitrile and 2-
furanecarbonitrile with the rhodium(I)-NHC complex A
(Figure 2).19 Indeed, to our knowledge, such behavior has no
precedents with any homogeneous catalyst.40 Only heteroge-
neous systems, such as Au/TiO2, CeO2, or Ni0.7Mn0.3O, have
shown a comparatively higher effectiveness with heteroaromatic
nitriles.41 The preferred anchoring of the substrates to the
catalysts surface through the heterocyclic ring, instead of the
nitrile function, was in these cases proposed to explain the
differences in activity observed. This raised the possibility that
rhodium nanoparticles could be the real catalytically active
species in our hydration reactions, a fact that was ruled out
performing the catalytic experiments in the presence of
elemental mercury.42a No major differences in activity were
observed when some drops of Hg(0) were added to the
reaction media (see entries 25 and 26 in Table 3).42b The
enhanced reactivity of [RhCl(COD){P(NMe2)3}] (3h) toward
heteroaromatic substrates must therefore be related to the
electronic nature of these nitriles, the strong activating effect of
the heterocycles being probably responsible for the differences
in reactivity found. However, we can not totally disregard the
participation of the heteroatom in an extended H-bonded
network with the water molecules that can also be facilitating
the nucleophilic addition of water to the CN bond.
b
c
entry
substrate
R = Ph (4a)
time (h)
yield (%)
TOF (h−1
)
1
24
24
24
24
24
7
5a; 94 (91)
5b; 96 (88)
5c; 79 (55)
5d; 96 (79)
5e; 94 (91)
5f; 99 (92)
5g; 87 (73)
5h; 92 (71)
5i; 99 (87)
5j; 90 (75)
5k; 98 (84)
5l; 99 (89)
5m; 96 (82)
5n; 99 (87)
5o; 86 (56)
5p; 99 (90)
5q; 96 (77)
5r; 12
0.8
0.8
0.6
0.8
0.8
2.8
0.7
0.7
9.9
0.7
6.5
19.8
12.8
9.9
0.7
9.9
0.8
0.1
0.04
3.8
38.8
19.8
0.8
2.8
0.8
9.9
2
R = C6F5 (4b)
3
R = 2-C6H4F (4c)
R = 4-C6H4F (4d)
R = 4-C6H4Cl (4e)
R = 3-C6H4NO2 (4f)
R = 4-C6H4Me (4g)
R = 3-C6H4OMe (4h)
R = 2-pyridyl (4i)
R = 3-pyridyl (4j)
R = 4-pyridyl (4k)
R = 2-pyrimidyl (4l)
R = pyrazyl (4m)
R = 2-thienyl (4n)
R = 3-thienyl (4o)
R = 5-Me-2-furyl (4p)
R = 3-furyl (4q)
4
5
6
7
24
24
2
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
24
3
1
1.5
2
24
2
24
24
24
5
R = n-C6H13 (4r)
R = CH3 (4s)
5s; 5
R = CH2Cl (4t)
5t; 95 (80)
5u; 97 (79)
5v; 99 (94)
5w; 98 (73)
5x; 98 (86)
5a; 93
R = CCl3 (4u)
0.5
1
R = CH2OPh (4v)
R = CH2OMe (4w)
R = CH2−2-thienyl (4x)
R = Ph (4a)
24
7
d
25
d
24
2
26
R = 2-pyridyl (4i)
5i; 99
a
Reactions performed under a N2 atmosphere at 100 °C using 1 mmol
of the corresponding nitrile (0.33 M in water). Substrate/Rh ratio:
100/5. Yields determined by GC (uncorrected GC areas). Isolated
yields after appropriate workup are given in brackets. Turnover
b
c
d
frequencies ((mol product/mol Rh)/time). Reactions performed in
the presence of Hg(0).
As observed for benzonitrile (4a), which was converted into
benzamide (5a) in 94% GC yield after 24 h of heating (entry
1), other aromatic nitriles 4b−h could be transformed into the
corresponding primary amides 5b−h in high yields (≥79% GC
yield) after 7−24 h (entries 2−8). A slight influence of the
electronic properties of the aryl rings was observed, with those
substrates containing electron-donating groups showing, in
general, a lower reactivity (e.g., entry 8 vs 6). Substitution in the
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ACS Catalysis
Research Article
The hydration of aliphatic nitriles was also examined with
complex 3h. Very poor conversions were obtained with
heptanenitrile (4r) and acetonitrile (4s) after 24 h (entries
19 and 20 in Table 3). The low activity is probably due to the
increased electron density of the nitrile carbon atom in these
substrates, which makes the nucleophilic attack of water less
favorable than in the preceding cases. However, the
introduction of heteroatoms in the β-position with respect to
the CN unit was beneficial, and the hydration processes
proceeded in these cases to completion. Thus, chloroacetoni-
trile (4t), trichloroacetonitrile (4u), phenoxyacetonitrile (4v),
and methoxyacetonitrile (4w) were converted to the
corresponding primary amides 5t−w in ≥95% GC yield after
1−24 h of reaction (entries 20−23).43 This may again be
understood in terms of the enhancement of the electrophilicity
of the nitrile carbon atom by the substituents. The higher
inductive effects of the chlorine atoms and the phenoxy group
vs the methoxy group are fully consistent with the reaction
times observed.44 For trichloroacetonitrile (4u) a significant
TOF value of 38.8 h−1 could be attained (entry 21). A good
result was also obtained with 2-thienylacetonitrile (4x) (98%
conversion after 7 h; entry 24).
Scheme 4. Catalytic Synthesis of Rufinamide (5z) by
Hydration of Nitrile 4z
The subtle sensitivity of [RhCl(COD){P(NMe2)3}] (3h) to
the electronic characteristics of the nitrile substituents was
clearly evidenced in the reaction of the dinitrile 4y, which could
be selectively transformed into the monoamide 5y, in which the
less activated nitrile group remains intact (Scheme 3).
CONCLUSION
■
In summary, different rhodium(I)−phosphine complexes
[RhCl(COD)(PR3)] have been evaluated as potential catalysts
for the selective hydration of organonitriles into amides in
water. Among the different ligands screened, aminophosphines
of general composition P(NR2)3 were found to be particularly
useful to develop catalytic systems featuring a high activity.
Indeed, one of the complexes synthesized with this type of
ligand, namely [RhCl(COD){P(NMe2)3}], was able to
promote efficiently the selective hydration of a large range of
organonitriles, representing the first rhodium-based catalyst
able to operate in pure water without the assistance of any
acidic or basic additive. In addition, complex [RhCl(COD){P-
(NMe2)3}] has proved to be very sensitive to the electronic
nature of the substrates, showing a particularly high reactivity
with different series of heteroaromatic and heteroaliphatic
nitriles. The synthetic utility of [RhCl(COD){P(NMe2)3}] was
also fully demonstrated in the high-yield preparation of the
antiepileptic drug rufinamide by catalytic hydration of 4-cyano-
1-(2,6-difluorobenzyl)-1H-1,2,3-triazole, reaction in which
complex [RhCl(COD){P(NMe2)3}] proved to be more
effective than a number of related ruthenium-based nitrile
hydration catalysts.
Scheme 3. Selective Monohydration of the Dinitrile 4y Using
[RhCl(COD){P(NMe2)3}] (3h)
It should also be noted that, although the catalytic activity
shown by complex [RhCl(COD){P(NMe2)3}] (3h) is in
general lower than those recently described for related
ruthenium complexes with cooperative phosphine ligands,
such as [RuCl2(η6-C6Me6){P(NMe2)3}] (6),10b [RuCl2(η6-p-
cymene)(L)] (L = PMe2OH (7),11b tris(5-(2-aminothiazolyl))-
phosphinetrihydrochloride (8)8), and [RuCl2(η3:η3-C10H16)-
(THPA)] (9)9b (TOF values within the range 9.9−26.4 h−1 for
the hydration of benzonitrile (4a) under reaction conditions
identical to those indicated in Table 3), for the particular case
of heteroaromatic nitriles its effectiveness is comparable or even
higher. A proof of this is, for example, the greater activity found
for [RhCl(COD){P(NMe2)3}] (3h) in the catalytic hydration
of 4-cyano-1-(2,6-difluorobenzyl)-1H-1,2,3-triazole (4z) into
rufinamide (5z) (Scheme 4), a relevant amide used as drug in
the treatment of the Lennox−Gastaut syndrome (a severe form
of epilepsy) and other seizure disorders.45,46 Using complex
[RhCl(COD){P(NMe2)3}] (3h), and our standard reaction
conditions, an almost quantitative formation of rufinamide (5z)
was observed by GC after 3 h of heating (83% isolated yield
after appropriate workup). Among the various ruthenium
catalysts tested in this work, only [RuCl2(η6-C6Me6){P-
(NMe2)3}] (6) showed a comparable reactivity (Scheme 4).
To the best of our knowledge this is the first time that metal
catalysts are involved in the preparation of rufinamide.
EXPERIMENTAL SECTION
■
Synthetic procedures were performed under an atmosphere of dry
nitrogen using vacuum-line and standard Schlenk techniques. Organic
solvents were dried by standard methods and distilled under nitrogen
before use. All reagents were obtained from commercial suppliers and
used without further purification with the exception of the phosphine
ligands PPh2py (2b),47 PPh2(py-4-NMe2) (2c),48 PPh2(py-6-tert-
amyl) (2d),49 PTA (2e),50 DAPTA (2f),51 PPh2(NMe2) (2g),52 P(N-
pyrrolidinyl)3 (2j),53 P(N-pyrrolyl)3 (2k),53 THPA (2l)54 and THDP
(2m),55 the Rh(I) complexes [{Rh(μ-Cl)(COD)}2] (1),56 [RhCl-
(COD)(PPh3)] (3a),20 [RhCl(COD)(PPh2py)] (3b),21 [RhCl-
(COD)(THPA)] (3l),22 [{RhCl(COD)}2(μ-THDP)] (3m),26 and
[RhCl(COD){P(OMe)3}] (3n)20 and the organonitriles 4-cyanophe-
noxyacetonitrile (4y)57 and 4-cyano-1-(2,6-difluorobenzyl)-1H-1,2,3-
triazole (4z)58 and the ruthenium complexes [RuCl2(η6-C6Me6){P-
(NMe2)3}] (6),10b [RuCl2(η6-p-cymene)(L)] (L = PMe2OH (7),11b
tris(5-(2-aminothiazolyl))phosphinetrihydrochloride (8)8), and
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ACS Catalysis
Research Article
[RuCl2(η3:η3-C10H16)(THPA)] (9),9b which were prepared by
following the methods reported in the literature. Infrared spectra
were recorded on a PerkinElmer 1720-XFT spectrometer. GC
measurements were made on Hewlett-Packard HP6890 equipment
using a Supelco Beta-Dex 120 column (30 m length; 250 μm
diameter). NMR spectra were recorded on a Bruker DPX-300 or
AV400 instruments. The chemical shift values (δ) are given in parts
per million and are referred to the residual peak of the deuterated
solvent employed (1H and 13C) or an external 85% aqueous H3PO4
solution (31P). DEPT experiments have been carried out for all the
compounds reported. Elemental analyses were provided by the
497 (w), 469 (w) cm−1. 31P{1H} NMR (CDCl3) δ −29.2 (d, JRhP
=
1
153.1 Hz). 1H NMR (CDCl3) δ 2.08 (s, 3H, CH3), 2.10 (s, 3H, CH3),
2.11 (m, 4H, CH2), 2.45 (m, 4H, CH2), 3.35 (d, 1H, 2JHH = 19.5 Hz,
PCH2N), 3.75 (br, 2H, CH), 3.78−4.55 (m, 6H, PCH2N and
NCH2N), 4.92 (d, 1H, 2JHH = 15.8 Hz, NCH2N), 5.36 (d, 1H, 2JHH
=
19.5 Hz, NCH2N), 5.50 (br, 2H, CH), 5.76 (d, 1H, 2JHH = 15.8 Hz,
NCH2N). 13C{1H} NMR (CDCl3) δ 21.3 (s, CH3), 21.6 (s, CH3),
28.2 (d, 2JRhC = 6.1 Hz, CH2), 33.4 (d, 2JRhC = 9.6 Hz, CH2), 36.6 (d,
1
1JPC = 17.2 Hz, PCH2N), 42.4 (d, JPC = 15.2 Hz, PCH2N), 47.2 (d,
2
1JPC = 20.9 Hz, PCH2N), 62.0 (d, JPC = 3.8 Hz, NCH2N), 67.3 (d,
1
2
2JPC = 4.5 Hz, NCH2N), 68.4 (dd, JRhC = 11.3 Hz, JPC = 6.0 Hz, 
CH), 108.5 (br, CH), 169.5 (s, CO), 170.0 (s, CO). (3g):
Yield: 0.305 g (87%). Anal. Calcd for C22H28ClNPRh: C, 55.54; H,
5.93; N, 2.94. Found: C, 55.42; H, 6.19; N, 2.89. IR (KBr): ν 3060
(w), 2994 (w), 2942 (m), 2867 (m), 2839 (m), 2796 (m), 1480 (w),
1432 (s), 1334 (w), 1279 (m), 1195 (s), 1097 (vs), 1070 (m), 985
(vs), 862 (m), 816 (w), 747 (w), 697 (vs), 671 (s), 545 (s), 502 (s),
́
Analytical Service of the Instituto de Investigaciones Quımicas (IIQ-
CSIC) of Seville.
Synthesis of complexes [RhCl(COD)(PR3)] (PR3 = PPh2(py-4-
NMe2) (3c), PPh2(py-6-tert-amyl) (3d), PTA (3e), DAPTA (3f),
PPh2(NMe2) (3g), P(NMe2)3 (3h), P(NEt2)3 (3i), P(N-pyrrolidinyl)3
(3j), P(N-pyrrolyl)3 (3k)). A solution of the Rh(I) dimer [{Rh(μ-
Cl)(COD)}2] (1) (0.197 g, 0.400 mmol) and the corresponding
phosphine ligand (0.820 mmol) in tetrahydrofuran (20 mL) was
stirred at room temperature for 1.5 h. The solvent was then removed
under reduced pressure to give a yellow solid residue (oily residue in
the case of 3i), which was washed twice with 15 mL of a hexane/
diethyl ether mixture (1:1 v/v) and dried in vacuo. (3c): Yield: 0.353 g
(80%). Anal. Calcd for C27H31N2ClPRh: C, 58.65; H, 5.65; N, 5.07.
Found: C, 58.79; H, 5.57; N, 5.20. IR (KBr): ν 3051 (w), 2921 (m),
2824 (w), 1589 (m), 1536 (w), 1480 (w), 1435 (s), 1376 (m), 1266
(w), 1187 (m), 1027 (w), 985 (s), 829 (w), 746 (w), 698 (m), 554
1
466 (m) cm−1. 31P{1H} NMR (CDCl3) δ 79.0 (d, JRhP = 159.7 Hz).
1H NMR (CDCl3) δ 1.98 (m, 4H, CH2), 2.37 (m, 4H, CH2), 3.05 (br,
2H, CH), 3.06 (d, 6H, 3JPH = 9.3 Hz, NMe), 5.53 (br, 2H, CH),
7.43 (m, 6H, CHarom), 7.65 (m, 4H, CHarom). 13C{1H} NMR (CDCl3)
δ 28.7 (s, CH2), 33.1 (s, CH2), 43.3 (d, 2JPC = 6.2 Hz, NMe), 70.0 (d,
1JRhC = 14.0 Hz, CH), 105.9 (dd, 1JRhC = 12.8 Hz, 2JPC = 6.7 Hz, 
2
CH), 127.9 (d, JPC = 9.6 Hz, CHarom), 129.9 (s, CHarom), 132.8 (d,
1
3JPC = 11.5 Hz, CHarom), 133.3 (d, JPC = 44.2 Hz, Carom). (3h):23
Yield: 0.285 g (87%). Anal. Calcd for C14H30N3ClPRh: C, 41.04; H,
7.38; N, 10.26. Found: C, 41.19; H, 7.25; N, 10.41. IR (KBr): ν 2996
(w), 2879 (m), 2791 (w), 1480 (w), 1457 (m), 1425 (w), 1279 (m),
1196 (s), 1066 (m), 986 (s), 961 (s), 757 (w), 710 (m), 660 (s), 514
(m), 486 (m) cm−1. 31P{1H} NMR (CDCl3) δ 109.3 (d, 1JRhP = 194.4
1
(w), 533 (m) cm−1. 31P{1H} NMR (CD2Cl2) δ 30.9 (d, JRhP = 149.6
1
Hz). H NMR (CD2Cl2) δ 2.04 (m, 4H, CH2), 2.42 (m, 4H, CH2),
2.97 (s, 6H, N(CH3)2), 4.44 (br, 2H, CH), 5.36 (br, 2H, CH),
6.48 (m, 1H, CHarom), 7.43 (m, 7H, CHarom), 7.84 (m, 4H, CHarom),
8.27 (d, 1H, 3JHH = 5.7 Hz, CHarom). 13C{1H} NMR (CD2Cl2) δ 28.3
1
Hz). H NMR (CDCl3) δ 1.97 (m, 4H, CH2), 2.34 (m, 4H, CH2),
1
3
(br, CH2), 31.0 (br, CH2), 38.8 (s, N(CH3)2), 68.0 (d, JRhC = 13.9
2.77 (d, 18H, JPH = 8.1 Hz, NMe), 3.81 (br, 2H, CH), 5.37 (br,
2
2H, CH). 13C{1H} NMR (CDCl3) δ 28.3 (d, 2JRhC = 1.7 Hz, CH2),
Hz, CH), 106.1 (s, CHarom), 107.4 (br, CH), 116.5 (d, JPC
=
2
2
2
32.2 Hz, CHarom), 127.7 (d, JPC = 10.1 Hz, CHarom), 129.9 (s,
33.5 (d, JRhC = 3.2 Hz, CH2), 39.5 (d, JPC = 8.1 Hz, NMe), 65.2 (d,
1JRhC = 13.9 Hz, CH), 106.0 (dd, 1JRhC = 15.1 Hz, 2JPC = 6.0 Hz, 
CH). (3i): Yield: 0.332 g (84%). Anal. Calcd for C20H42N3ClPRh: C,
48.64; H, 8.57; N, 8.51. Found: C, 48.91; H, 8.70; N, 8.69. IR (KBr): ν
3197 (w), 2966 (s), 2931 (s), 2868 (s), 2830 (m), 1456 (m), 1378 (s),
1334 (m), 1294 (w), 1181 (s), 1101 (m), 1076 (w), 1053 (w), 1013
(s), 931 (s), 869 (w), 855 (w), 797 (m), 650 (m) cm−1. 31P{1H} NMR
(C6D6) δ 113.0 (d, 1JRhP = 196.3 Hz). 1H NMR (C6D6) δ 1.16 (t, 18H,
3JHH = 7.1 Hz, CH3), 1.89 (m, 4H, CH2), 2.31 (m, 4H, CH2), 3.30
1
3
CHarom), 132.0 (d, JPC = 51.3 Hz, Carom), 135.1 (d, JPC = 11.1 Hz,
3
3
CHarom), 149.5 (d, JPC = 15.1 Hz, CHarom), 153.5 (d, JPC = 15.1 Hz,
1
Carom), 156.2 (d, JPC = 61.4 Hz, Carom). (3d): Yield: 0.394 g (85%).
Anal. Calcd for C30H36ClNPRh: C, 62.13; H, 6.26; N, 2.42. Found: C,
61.92; H, 6.40; N, 2.61. IR (KBr): ν 3053 (w), 2961 (m), 2878 (m),
2830 (w), 1575 (m), 1557 (s), 1480 (m), 1434 (s), 1387 (m), 1333
(w), 1310 (w), 1185 (w), 1169 (w), 1093 (s), 1028 (w), 992 (m), 960
(w), 858 (w), 807 (m), 742 (s), 700 (s) cm−1. 31P{1H} NMR (CDCl3)
δ 29.4 (d, 1JRhP = 151.8 Hz). 1H NMR (CDCl3) δ 0.62 (t, 3H, 3JHH
=
3
3
(dq, 12H, JPH = 14.2 Hz, JHH = 7.1 Hz, NCH2), 3.83 (br, 2H, 
CH), 5.85 (br, 2H, CH). 13C{1H} NMR (C6D6) δ 14.7 (s, CH3),
28.5 (s, CH2), 33.6 (s, CH2), 41.8 (d, 2JPC = 8.8 Hz, NCH2), 65.5 (d,
1JRhC = 14.1 Hz, CH), 104.4 (dd, 1JRhC = 16.0 Hz, 2JPC = 6.2 Hz, 
CH). (3j): Yield: 0.363 g (93%). Anal. Calcd for C20H36N3ClPRh: C,
49.24; H, 7.44; N, 8.61. Found: C, 49.48; H, 7.44; N, 8.33. IR (KBr): ν
3185 (w), 2931 (s), 2859 (s), 2826 (s), 1457 (w), 1340 (w), 1194
(m), 1124 (s), 1067 (vs), 1001 (vs), 954 (m), 910 (w), 868 (w), 813
(w), 756 (m), 668 (w), 562 (s), 537 (m), 520 (s) cm−1. 31P{1H} NMR
(C6D6) δ 90.3 (d, 1JRhP = 192.5 Hz). 1H NMR (C6D6) δ 1.68 (m, 12H,
NCH2CH2), 1.90 (m, 4H, CH2), 2.31 (m, 4H, CH2), 3.37 (m, 12H,
NCH2CH2), 3.96 (br, 2H, CH), 5.88 (br, 2H, CH). 13C{1H}
6.0 Hz, CH2CH3), 1.27 (s, 6H, C(CH3)2), 1.71 (q, 2H, 3JHH = 6.0 Hz,
CH2CH3), 2.00 (m, 4H, CH2), 2.42 (m, 4H, CH2), 3.39 (br, 2H, 
CH), 5.59 (br, 2H, CH), 7.24−7.78 (m, 13H, CHarom). 13C{1H}
NMR (CDCl3) δ 9.1 (s, CH2CH3), 27.3 (s, C(CH3)2), 28.9 (s, CH2),
1
33.0 (s, CH2), 35.7 (s, CH2CH3), 41.2 (s, C(CH3)2), 70.5 (d, JRhC
=
1
2
13.6 Hz, CH), 104.9 (dd, JRhC = 12.1 Hz, JPC = 7.5 Hz, CH),
2
3
120.1 (s, CHarom), 127.7 (d, JPC = 9.5 Hz, CHarom), 128.7 (d, JPC
=
26.5 Hz, CHarom), 130.0 (s, CHarom), 132.0 (d, 1JPC = 43.0 Hz, Carom),
2
3
132.1 (d, JPC = 9.7 Hz, CHarom), 135.4 (d, JPC = 11.8 Hz, CHarom),
155.7 (d, 1JPC = 62.6 Hz, Carom), 167.9 (d, 3JPC = 12.1 Hz, Carom). (3e):
Yield: 0.290 g (90%). Anal. Calcd for C14H24N3ClPRh: C, 41.65; H,
5.99; N, 10.41. Found: C, 41.78; H, 5.90; N, 10.65. IR (KBr): ν 2995
(w), 2938 (m), 2874 (w), 1470 (w), 1418 (m), 1334 (w), 1290 (m),
1278 (s), 1241 (s), 1157 (m), 1055 (m), 1015 (m), 971 (s), 947 (s),
898 (m), 867 (w), 801 (m), 743 (m), 502 (s), 481 (m) cm−1. 31P{1H}
3
NMR (C6D6) δ 26.3 (d, JPC = 6.0 Hz, NCH2CH2), 28.4 (s, CH2),
33.8 (s, CH2), 48.5 (d, 2JPC = 6.3 Hz, NCH2CH2), 64.6 (d, 1JRhC = 14.2
1
2
Hz, CH), 106.1 (dd, JRhC = 15.9 Hz, JPC = 5.9 Hz, CH). (3k):
Yield: 0.357 g (94%). Anal. Calcd for C20H24N3ClPRh: C, 50.49; H,
5.08; N, 8.83. Found: C, 50.30; H, 5.33; N, 8.84. IR (KBr): ν 3129
(w), 3089 (w), 3028 (w), 2946 (w), 2867 (w), 2824 (w), 1454 (s),
1426 (w), 1336 (w), 1288 (m), 1238 (m), 1101 (vs), 1087 (s), 1063
(vs), 1051 (vs), 1040 (vs), 977 (m), 932 (w), 867 (m), 815 (w), 784
1
1
NMR (CDCl3) δ −52.9 (d, JRhP = 149.4 Hz). H NMR (CDCl3) δ
2.06 (m, 4H, CH2), 2.35 (m, 4H, CH2), 3.59 (br, 2H, CH), 4.17 (s,
6H, PCH2N or NCH2N), 4.49 (m, 6H, PCH2N or NCH2N), 5.40 (br,
2H, CH). 13C{1H} NMR (CDCl3) δ 28.2 (s, CH2), 33.4 (s, CH2),
1
1
50.4 (d, JPC = 11.1 Hz, PCH2N), 67.4 (d, JRhC = 14.1 Hz, CH),
73.2 (d, 2JPC = 7.0 Hz, NCH2N), 107.3 (br, CH). (3f): Yield: 0.315
g (83%). Anal. Calcd for C17H28N3O2ClPRh: C, 42.92; H, 5.93; N,
8.83. Found: C, 43.09; H, 6.10; N, 8.61. IR (KBr): ν 3004 (w), 2938
(w), 2879 (m), 2830 (w), 1636 (vs), 1465 (m), 1409 (s), 1350 (m),
1302 (w), 1236 (m), 1207 (m), 1121 (w), 1100 (m), 1048 (s), 995
(s), 958 (w), 892 (s), 871 (w), 797 (m), 705 (w), 629 (w), 565 (m),
(w), 756 (s), 734 (vs), 716 (m), 632 (m), 615 (s), 574 (m), 540 (s),
1
523 (s), 478 (w) cm−1. 31P{1H} NMR (CDCl3) δ 90.3 (d, JRhP
=
1
231.9 Hz). H NMR (CDCl3) δ 2.20 (m, 4H, CH2), 2.45 (m, 4H,
CH2), 3.36 (br, 2H, CH), 5.99 (br, 2H, CH), 6.37 (m, 6H,
NCHCH), 7.10 (m, 6H, NCHCH). 13C{1H} NMR (CDCl3) δ 28.5
(s, CH2), 33.1 (s, CH2), 73.8 (d, JRhC = 13.0 Hz, CH), 113.0 (d,
1
1907
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Research Article
3JPC = 7.4 Hz, NCHCH), 114.9 (dd, 1JRhC = 15.1 Hz, 2JPC = 5.6 Hz, 
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2
CH), 124.8 (d, JPC = 8.5 Hz, NCHCH).
General Procedure for the Catalytic Hydration of Nitriles
Employing Complex [RhCl(COD){P(NMe2)3}] (3h). Under a
nitrogen atmosphere, the corresponding nitrile 4a−z (1 mmol),
water (3 mL), and the rhodium complex 3h (0.02 g, 0.05 mmol) were
introduced into a Teflon-capped sealed tube, and the reaction mixture
was stirred at 100 °C for the indicated time (see Table 3 and Schemes
3 and 4). The course of the reaction was monitored by regularly taking
samples of ∼20 μL, which, after extraction with CH2Cl2 (3 mL), were
analyzed by GC. Once the reaction completed, two different
procedures were applied to isolate the primary amide product
depending on its solubility. For amides which partially precipitate in
the reaction medium, they were extracted with EtOAc (3 × 3 mL), the
combined organic extracts were dried over anhydrous MgSO4, filtered,
and evaporated to dryness. The crude product was then purified by
flash chromatography over silica gel using diethyl ether as the eluent.
For those amides that do not precipitate, isolation was carried out as
follows. After elimination of the water solvent under reduced pressure,
the crude reaction mixture was pulverized in diethyl ether and the
resulting solid filtered, washed, and dried in vacuo. In some cases
additional purification by column chromatography was required (silica
gel with CH2Cl2 as the eluent). The identity of the amide products was
assessed by comparison of their NMR spectroscopic data with those
reported in the literature (copies of the spectra of all the amides are
included in the SI).
(5) For reviews, see: (a) Parkins, A. W. Platinum Metals Rev. 1996,
40, 169−174. (b) Kukushkin, V. Y.; Pombeiro, A. J. L. Chem. Rev.
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L. Inorg. Chim. Acta 2005, 358, 1−21. (e) Ahmed, T. J.; Knapp, S. M.
M.; Tyler, D. R. Coord. Chem. Rev. 2011, 255, 949−974. (f) García-
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Alvarez, R.; Crochet, P.; Cadierno, V. Green Chem. 2013, 15, 46−66.
(6) (a) Utsunomiya, M.; Takahashi, K.; Oshiki, T.; Takai, K. Jpn.
Kokai Tokkyo Koho JP 2004269522, 2004. (b) Oshiki, T.; Yamashita,
H.; Sawada, K.; Utsunomiya, M.; Takahashi, K.; Takai, K. Organo-
metallics 2005, 24, 6287−6289. (c) Oshiki, T.; Takai, K. Jpn. Kokai
Tokkyo Koho JP 2008088153, 2008. (d) Oshiki, T.; Hyodo, I.;
̌
Ishizuka, A. J. Synth. Org. Chem. Jpn. 2010, 68, 41−51. (e) Smejkal, T.;
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ASSOCIATED CONTENT
* Supporting Information
■
Hyodo, I.; Okumura, W.; Oshiki, T. Catal. Today 2011, 164, 552−555.
S
́
(g) García-Alvarez, R.; García-Garrido, S. E.; Díez, J.; Crochet, P.;
Details on DFT and cone angles calculations, copies of the
NMR spectra of the new Rh(I) complexes and all the amides
synthesized in this work. This material is available free of charge
via the Internet at http://pubs.acs.org.
Cadierno, V. Eur. J. Inorg. Chem. 2012, 4218−4230.
́
(7) García-Alvarez, R.; Díez, J.; Crochet, P.; Cadierno, V.
Organometallics 2010, 29, 4955−3965.
́
(8) García-Alvarez, R.; Zablocka, M.; Crochet, P.; Duhayon, C.;
Majoral, J.-P.; Cadierno, V. Green Chem. 2013, 15, 2447−2456.
(9) (a) Cadierno, V.; Francos, J.; Gimeno, J. Chem.Eur. J. 2008, 14,
6601−6605. (b) Cadierno, V.; Díez, J.; Francos, J.; Gimeno, J.
Chem.Eur. J. 2010, 16, 9808−9817. (c) Lee, W.-C.; Frost, B. J. Green
Chem. 2012, 14, 62−66. (d) Lee, W.-C.; Sears, J. M.; Enow, R. A.;
Eads, K.; Krogstad, D. A.; Frost, B. J. Inorg. Chem. 2013, 52, 1737−
1746. (e) Frost, B. J.; Lee, W.-C. US Pat. Appl. US 2013/0096344.
AUTHOR INFORMATION
Corresponding Author
*E-mail: vcm@uniovi.es.
Notes
■
The authors declare no competing financial interest.
́
(10) (a) García-Alvarez, R.; Francos, J.; Crochet, P.; Cadierno, V.
ACKNOWLEDGMENTS
́
■
Tetrahedron Lett. 2011, 52, 4218−4220. (b) García-Alvarez, R.; Díez,
This work was financially supported by MINECO (project
CTQ2010-14796/BQU) of Spain. E.T.-M. thanks MECD of
Spain and the European Social Fund (ESF) for the award of a
FPU fellowship. We also thank Dr. Dimas Suarez for his help
́
with the DFT calculations.
J.; Crochet, P.; Cadierno, V. Organometallics 2011, 30, 5442−5451.
(c) Knapp, S. M. M.; Sherbow, T. J.; Juliette, J. J.; Tyler, D. R.
́
Organometallics 2012, 31, 2941−2944. (d) García-Alvarez, R.; Díaz-
́
Alvarez, A. E.; Borge, J.; Crochet, P.; Cadierno, V. Organometallics
́
́
2012, 31, 6482−6490. (e) García-Alvarez, R.; Díaz-Alvarez, A. E.;
Crochet, P.; Cadierno, V. RSC Adv. 2013, 3, 5889−5894. (f) Knapp, S.
M. M.; Sherbow, T. J.; Yelle, R. B.; Zakharov, L. N.; Juliette, J. J.; Tyler,
D. R. Organometallics 2013, 32, 824−834.
(11) (a) Oshiki, T.; Muranaka, M. PCT Int. Appl. WO 2012/017966.
(b) Knapp, S. M. M.; Sherbow, T. J.; Yelle, R. B.; Juliette, J. J.; Tyler,
D. R. Organometallics 2013, 32, 3744−3752.
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