Mn(i) organometallics containing the iPr2P(CH2)2PiPr2 ligand for the catalytic hydration of aromatic nitriles

Article abstract of DOI:10.1039/c8cy00416a

The first example of a homogeneous hydration of aromatic nitriles catalyzed by manganese molecular compounds is reported. The Mn(i) organometallics fac-[(CO)₃Mn(dippe)(Z)]^1-nX_1-n (n = 0, 1; Z = Br, OTf, PhCN; X = OTf) were synthesized and characterized, and their reactivity was studied. The species fac-[(CO)₃Mn(dippe)(OTf)] (2) was used as a catalyst precursor for the selective hydration of benchmark benzonitrile (2 mol% 2, THF/H₂O 1:2 v/v, 18 h, 100 °C) to produce benzamide in 90% isolated yield. A series of (hetero)aromatic nitriles were hydrated to synthesize the corresponding amides in very good to excellent yields (88-94%). Isotopic labeling studies accounted for a proton transfer as the rate-determining step.

Full text of DOI:10.1039/c8cy00416a

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Page 1 of 32
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Mn(I) Organometallics Containing the iPr2P(CH2)2PiPr2 Ligand for
the Catalytic Hydration of Aromatic Nitriles
Jorge A. Garduño, Alma Arévalo, Marcos Flores-Alamo and Juventino J. García*
Facultad de Química, Universidad Nacional Autónoma de México, Mexico City, 04510, Mexico.
Abstract
The first example of a homogeneous hydration of aromatic nitriles catalyzed by manganese
molecular compounds is reported. The Mn(I) organometallics fac-[(CO)3Mn(dippe)(Z)]1-nX1-n (n
= 0, 1; Z = Br, OTf, PhCN; X = OTf) were synthesized and characterized, and their reactivity
was studied. Species fac-[(CO)3Mn(dippe)(OTf)] (2) was used as a catalyst precursor for the
selective hydration of benchmark benzonitrile (2 mol% 2, THF/H2O 1:2v/v, 18 h, 100 ºC) to
produce benzamide in 90% isolated yield. A series of (hetero)aromatic nitriles were hydrated to
synthesize the corresponding amides in very good to excellent yields (88-94%). Isotopic labeling
studies accounted for a proton transfer as the rate-determining step.
Keywords: Manganese, Nitrile, Hydration, Amide, Catalysis.
Introduction
The hydration of nitriles is the reaction with the highest atom economy to synthesize amides, an
important functional group found in pharmaceuticals, biomolecules, and polymeric materials.1,2
Molecules such as nicotinamide and acrylamide are of interest in pharmacy and polymers, and
are synthesized at a commercial scale through enzymatic catalysis with NHase from
1

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Rhodococcus rhodochrous J1.3 Compared to the use of enzymes, the methodologies based on
transition metals, exhibiting also a high selectivity, allow for the use of a wider variety of
reaction conditions (i.e. temperature, pH, solvents), and in general show an increased tolerance to
functional groups.2,3 Thus, the use of transition metals has been well documented,4 and only in
the last year, palladium,5a,b ruthenium,5c and osmium5d based catalytic methodologies for the
hydration of nitriles have appeared in literature.
Among d-block elements, manganese is an attractive candidate to develop new catalysts for
organic reactions because is the third most abundant transition metal in the Earth’s crust as well
as a biocompatible element.6a,b The use of manganese in molecular catalysis is currently a very
active field and has been reviewed recently.6a-d Nevertheless, to the best of our knowledge there
are no reports on the use of well-defined manganese complexes in the homogeneous hydration of
nitriles. There are a few examples of other Mn-catalyzed nitrile hydration reactions, notably, yet
heterogeneous, the use of a continuous-flow system through a MnO2 stationary phase allowed for
the preparation of amides in excellent yields,7 and in the homogeneous arena, the use of simple
Mn(II) salts (10 mol%) and stoichiometric amounts of acetaldoxime produced amides in fair to
good yields along with the formation of stoichiometric amounts of acetonitrile.8 Based on this,
new contributions on the hydration of nitriles, which generate no residues, using catalytic
amounts of manganese-based soluble complexes is not undesirable. Herein we report the
synthesis and characterization of new Mn(I) organometallics containing iPr2P(CH2)2PiPr2 (dippe)
as ancillary ligand, namely fac-[(CO)3Mn(dippe)(Z)]1-nX1-n (n = 0, 1; Z = Br, OTf, PhCN; X =
OTf), and their use as catalytic precursors in the synthesis of amides from nitriles and water.
2

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Results and Discussion
Synthesis and characterization of Mn(I) organometallics bearing the dippe ligand
The synthesis of Mn(I) compounds bearing the iPr2P(CH2)2PiPr2 (dippe) ligand was carried out
from commercial [MnBr(CO)5] as depicted in Scheme 1.
Scheme 1. Synthesis of Mn(I) organometallics bearing the dippe ligand
The methodology for the synthesis fac-[(CO)3Mn(dippe)(Br)] (1) in 84% yield (Scheme 1) was
adapted from the reports on the preparation of the parent complexes fac-
[(CO)3Mn(R2P(CH2)2PR2)(Br)] (R = Me (dmpe),9 Ph (dppe)10, 11). The infrared spectrum for 1
showed three signals of strong intensity in the metal carbonyl region consistent with a Cs
symmetry arrangement (2A’ + A’’). According to the –donor character of dippe, the infrared
data for 1 fit into a trend for bidentate phosphine ligands of the type R2P(CH2)2PR2 (R = alkyl or
3

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aryl group), for which lower wavenumber values are observed when increasing such donor
character (Table 1).
Table 1. Comparison between νCO values for fac-[(CO)3Mn(P-P)(Br)] compounds. a
νCOb /cm-1
A’
A’’
A’
Entry
1
fac-[Mn]
dppec depec dipped dppec depec dipped dppec depec dipped
[(CO)3Mn(P-P)(Br)]
2023 2017
2001
1955 1948
1922
1916 1897
1886
i
12
(a) P-P = R2P(CH2)2PR2; R = Ph (dppe), Et (depe), Pr (dippe). (b) For comparison: ν
2155 cm-1. (c)
(free CO)
Data from Ref. 13. (d) Data from this work.
The room temperature 31P{1H} NMR spectrum for 1 displayed a single signal at 80.5 ppm
(Table 2, entry 1), consistent with a Cs symmetry arrangement, where the two phosphorus atoms
are equivalent. Based on this, 1 has the structure of a fac isomer where two carbonyl ligands are
located trans to the phosphorus atoms of the bidentate -donor dippe ligand, forming a
thermodynamically favored equatorial arrangement, with a third carbonyl ligand axially
positioned, trans to a bromide. Because the dippe ligand is sensitive to oxygen, complex 1 was
synthesized under an inert atmosphere, nevertheless, after preparation, 1 turned out to be quite
air-stable as revealed by NMR analyses under an uncontrolled atmosphere (Figure S4).
a
Table 2. δP values for fac-[(CO)3Mn(dippe)(Z)]1-nX1-n
Entry Complex
δP b /ppm
fac-[(dippe)Mn(CO)3(Br)]
80.5
1
2
3
4
5
fac-[(dippe)Mn(CO)3(OTf)]
85.7
87.0
86.8
87.8
fac-[(dippe)Mn(CO)3(PhCN)](OTf)
fac-[(dippe)Mn(CO)3(OH2)](OTf)
fac-[(dippe)Mn(CO)3(PhC(O)NH2)](OTf)
(a) n = 0, 1. (b) 31P{1H} NMR (121 MHz, THF-d8).
4

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Complex fac-[(CO)3Mn(dippe)(OTf)] (2) was prepared in 75% yield by reacting 1 with silver
triflate (Scheme 1), following a methodology adapted from the reports on the synthesis of fac-
[(CO)3Mn(dppe)(X)] (X = OTf,11 OClO3 14, 15). The infrared spectrum for powdered 2 agreed
with a Cs symmetry arrangement, analogous to complex 1 (Table 3, entries 1 and 2). Compared
to 1, metal carbonyl bands for complex 2 appeared at higher wavenumber values, consistent with
a poor coordinating character of the triflate anion. The room temperature 31P{1H} NMR
spectrum for 2 in THF-d8 solution featured a singlet at 85.7 ppm (Table 2, entry 2), which
agreed with fac-isomerism on the coordination sphere.
a
Table 3. νCO values for fac-[(CO)3Mn(dippe)(Z)]1-nX1-n
νCOb /cm-1
Entry
Complex
A’
A’’
A’
fac-[(dippe)Mn(CO)3(Br)]
2001
1922
1886
1
2
3
fac-[(dippe)Mn(CO)3(OTf)]
fac-[(dippe)Mn(CO)3(PhCN)](OTf)
2022
2022
1958
1938
1895
1921
(a) n = 0, 1. For comparison: (b) ν (free CO)12 2155 cm-1.
Additionally, suitable single crystals for XRD were obtained for complex 2 from a toluene
saturated solution stored at -30 ºC for 48 h under an argon atmosphere. The corresponding
ORTEP plot for fac-[(CO)3Mn(dippe)(OSO2CF3)] (2) is depicted in Figure 1.
5

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Figure 1. ORTEP plot (50% probability) for complex 2. Selected bond distances (Å): Mn(1)-
P(1) 2.350(4), Mn(1)-P(2) 2.348(4), Mn(1)-C(15) 1.840(15), Mn(1)-C(16) 1.756(14), Mn(1)-
C(17) 1.825(13), Mn(1)-O(3) 2.103(7), C(15)-O(1) 1.150(15), C(16)-O(2) 1.163(15), C(17)-O(6)
1.125(14). Selected bond angles (deg): P(1)-Mn(1)-P(2) 83.07(12), P(1)-Mn(1)-C(15) 177.5(4),
P(1)-Mn(1)-C(17) 89.8(4), P(1)-Mn(1)-C(16) 92.4(4), P(1)-Mn(1)-O(3) 88.5(2), P(2)-Mn(1)-
C(15) 94.5(4), P(2)-Mn(1)-C(17) 172.9(4), P(2)-Mn(1)-C(16) 92.5(4), P(2)-Mn(1)-O(3) 86.3(2),
C(16)-Mn(1)-O(3) 178.4(5).
In the solid state, complex 2 displays a manganese atom in a slightly distorted octahedral
configuration. The phosphorus atoms from a bidentate dippe ligand and the carbon atoms from
two carbonyl groups define the equatorial plane. Another carbonyl carbon and an oxygen atom
from a triflate ligand complete the coordination sphere in apical positions, forming an angle of
178.4 (5)º. The three carbonyls are in a facial arrangement and the triflate ligand is located trans
to one carbonyl group. The Mn-P [2.350(4) and 2.348(4) Å] and Mn-C(CO) [1.840(15) and
1.825(13) Å] distances in the equatorial plane agree with those in the trans P-Mn-CO moiety in
fac-[(CO)3Mn(dppe)(OTf)], [2.337(2) and 2.348(2); 1.814(9) and 1.815(8) Å].11 The P-Mn-P
bite angle of 83.07(12)º agrees with the value of 83.14(8)º for fac-[(CO)3Mn(dppe)(OTf)].
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Considering the low coordinating character of the triflate anion, compound fac-
[(CO)3Mn(dippe)(1-PhCN)](OTf) (3) was prepared by adding excess benzonitrile to a toluene
solution of 2. The synthesis of 3 was adapted from the methodology reported for the preparation
of fac-[(CO)3Mn(dppe)(PhCN)](BF4),14 and the target compound was obtained in 85% yield
(Scheme 1). The infrared spectrum for powdered 3 displayed signals in the metal carbonyl
region for a Cs symmetry arrangement (Table 3, entry 3), along with a signal of weak intensity
featuring an end-on coordinated nitrile at νCN 2251 cm-1 (for comparison: ν(free PhCN) 2231 cm-1).12,
16 Based on this, benzonitrile end-on coordinates at the apical position of the Mn(I) core in an
analogous fashion to bromide and triflate ligands in species 1 and 2, respectively.
The room temperature 31P{1H} NMR spectrum for 3 in THF-d8 solution displayed two singlets at
85.7 and 87.0 ppm (Table 2, entries 2 and 3). The signal for 2 had already been assigned (vide
supra), so we reasoned that compound 3 partially dissociates forming back 2 and free
benzonitrile in solution (Figure 2a and c).17 The presence of free benzonitrile was confirmed by
the corresponding 1H NMR spectrum, in which the integral values for both aromatic and
aliphatic regions agreed with the expected values for fac-[(CO)3Mn(dippe)(1-PhCN)](OTf)
(Figure S10), but the individual integral values for the signature signal for the aromatic protons
at the ortho-position (Ha in Figure 2a) and for the rest of the hydrogen atoms (2Ha : 6H : 14H :
40H; lower trace in Figure 2b) did not agree with the expected values for 3 alone (2HAr, ortho-
3HAr, para-, meta- : 8HCH2 : 24HCH3). The dissociation of benzonitrile was reversed by adding an
excess of this ligand (middle and upper traces in Figure 2b and c), after which we observed
complete formation of 3 as a predominant species in solution.18
:
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A
B
C
-
Figure 2. (a) Competence for a vacant site between PhCN and OTf at the “fac-
[(CO)3Mn(dippe)]+” core. (b) 1H (300 MHz, THF-d8) and (c) 31P{1H} (121 MHz, THF-d8) NMR
spectra for the as synthesized complex 3 (lower trace), and the addition of 3 equiv. (middle
trace), and 20 equiv. (upper trace) of fresh PhCN to a THF-d8 solution of complex 3. The actual
integral values in 1H NMR spectra appear in parentheses.
Catalytic Hydration of Benzonitrile with Mn(I) organometallics bearing the dippe ligand
Since the nitrile ligand end-on coordinates to Mn(I) in complex 3 (vide supra), the carbon atom
of the cyanide group becomes more electrophilic so it can undergo nucleophilic attack from
water to initiate a hydration process.19 As a proof of concept, complex 3 was assessed as a
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catalyst precursor to carry out the hydration of benchmark benzonitrile. Relevant results are
displayed in Table 4.
Table 4. Mn(I) catalytic precursor assessmenta
Entry
[Mn]cat
mol%
t /h
24
48
24
24
18
18
24
24
%Yieldb
fac-[(CO)3Mn(dippe)(1-PhCN)] (OTf)
fac-[(CO)3Mn(dippe)(1-PhCN)] (OTf)
fac-[(CO)3Mn(dippe)(1-PhCN)] (OTf)
fac-[(CO)3Mn(dippe)(OTf)]
fac-[(CO)3Mn(dippe)(OTf)]
fac-[(CO)3Mn(dippe)(OTf)]
fac-[(CO)3Mn(dippe)(Br)]
53
54
88
89
90
91
5
1
1
2
2
2
2
2
2
1
2
3
4
5
6c
7
[(CO)5Mn(Br)]
8
n.d.
(a) Reactions under an inert atmosphere. Conditions: PhCN (47.3 mg, 0.46 mmol), H2O (2 mL,
111 mmol), THF (1 mL). (b) Yield for isolated benzamide. (c) Mercury drop test.
Considering the low solubility of both 3 and benzonitrile in water, a mixture of water and THF in
a 2:1 v/v ratio was used as the solvent. Thus, THF allowed for the incorporation of 1 mol% 3 and
benzonitrile in the same phase, to which water was added. With this experimental setup, fair
isolated yields of benzamide were observed either after 24 or 48 h (Table 4, entries 1 and 2). The
yield of benzamide was raised to 88% at a time of 24 h by increasing the catalytic loading of
complex 3 to 2 mol% (Table 4, entry 3). Encouraged by this result we moved to a simpler
catalyst precursor, namely compound 2 at a catalytic loading of 2 mol%, under which conditions
benzamide was obtained in 90% yield after both 24 h and an improved time of 18 h (Table 4,
entries 4 and 5). Attempts to decrease the reaction time by using compound 2 led to lower yields.
Benzamide was the only product observed after catalysis, which demonstrates the high
selectivity of the hydration reported herein. Additionally, the catalytic system proved to be
homogeneous upon the performance of a mercury drop test, after which the yield of benzamide
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remained unchanged (Table 4, entry 6). Finally aiming to know whether a simpler Mn-
compound might catalyze the addition of water to benzonitrile, compounds 1 and [(CO)5MnBr]
were assessed as catalytic precursors but the yield dropped significantly in both cases (Table 4,
entries 7 and 8).
Hydration of aromatic nitriles catalyzed by fac-[(CO)3Mn(dippe)(OTf)] (2)
With a suitable hydration protocol at hand, a study of the scope of the reaction was performed for
a series of aromatic nitriles. Main results are displayed in Table 5.
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Table 5. Substrate scope for the hydration of aromatic nitrilesa
Entry
1
Product
%mol 2
t /h
%Yieldb
90
2
18
2a
2b
2c
2
2
18
18
2
3
88
89
2
2
2
18
18
18
4
5
6
2d
2e
2f
94
90
91
2
4
18
24
7
8
70
79
2g
48c
46c
93
2
2
4
24
72
18
9
10
11
2h
4
4
18
18
12
13
2i
2j
90
93
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88c
14
2
18
2k
(a) Reactions under an inert atmosphere. Conditions: RCN (0.46 mmol), H2O (2
mL, 111 mmol), THF (1 mL), 100 ºC. (b) Yields are for isolated amides. (c)
Chromatographic yield.
Optimized experimental conditions (2 mol% 2, THF/H2O 1:2 v/v, 100 ºC, 18 h) were first used
to carry out the hydration of benzonitriles bearing electron-withdrawing groups, after which very
good to excellent isolated yields (88-94%) were observed for the synthesis of amides 2a-d
(Table 5, entries 2 to 4). Next, -deficient n-cyanopyridines (n = 3, 4) were hydrated to yield
isonicotinamide (2e) and industrially relevant niacinamide (2f) in excellent yields (90-91%)
(Table 5, entries 5 and 6). In the case of 2-cyanopyridine (Table 5, entry 7) the catalytic system
performed less efficiently as only 70% yield of picolinamide (2g) was quantified. A possible
reason for this might be the formation of chelated Mn-complexes bearing the picolinamide
bidentate ligand, causing the catalytic activity to drop because of a product inhibition-type
process. To overcome this, both the amount of precatalyst 2 and the reaction time were raised to
4 mol% and 24 h, respectively, after which an increase in the yield of picolinamide was observed
(Table 5, entry 8).
Different from the electron-deficient substrates, aromatic nitriles containing electron-releasing
groups did not perform well under the very same conditions used for benchmark benzonitrile
(Table 5, entry 1), and only fair yields were observed after 24 or even 72 h for the synthesis of 4-
methoxybenzamide (2h) (Table 5, entries 9 and 10). To address this, we chose p-
methoxybenzonitrile as a model substrate and found a higher catalytic loading of catalyst
precursor 2 (4 mol%) was necessary to achieve an excellent isolated yield of 93% at a time of 18
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h at 100 ºC (Table 5, entry 11). Under these new experimental conditions, we achieved both the
hydration of p-tolunitrile, isolating the corresponding p-toluamide (2i) in 90% yield, and the
synthesis of furan-2-carbamide (2j) in 93% yield from the corresponding -excessive 2-
furonitrile (Table 5, entries 12 and 13).
Additionally, efforts were made to hydrate both aliphatic mononitriles and aromatic dinitriles. In
the case of acetonitrile and acrylonitrile, the use of 4 mol% 2 in a THF/H2O (1:2 v/v) mixture at
100 ºC during 18 h, did not afford the corresponding aliphatic amides. Regarding 1,4-
dicyanobenzene, we observed the hydration of only one nitrile moiety to yield p-
cyanobenzamide in 88% chromatographic yield by using the optimized reaction conditions for
the hydration of electron-deficient aromatic nitriles (Table 5, entry 14).
The scope presented herein for aromatic mononitriles (Table 5, entries 1 to 13) demonstrates the
synthetic utility of this Mn(I)-based methodology, because depending on the electronic features
of the substrate, there are two sets of catalytic conditions to perform the hydration of
(hetero)aromatic nitriles in very good to excellent yields. This contribution comes to light not
only as a new synthetic protocol, but to the best of our knowledge, considering the substrates
assessed herein along with the transition metal-catalyzed methodologies available today, for each
substrate used in this work, this is the first example of the corresponding hydration catalyzed by
a soluble Mn(I)-molecular species.
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Mechanistic proposal for the hydration of aromatic nitriles catalyzed by 2
To shed some light on the reaction mechanism, we first performed a 31P{1H} NMR analysis of
the model reaction mixture after catalysis and found signals for 2,20 and two new singlets at 86.8
and 87.8 ppm [Figure 3a (trace e) and Figure S22e]. Given the reactivity of the “fac-
[(CO)3Mn(dippe)]+” core toward neutral ligands (i.e. benzonitrile, Figure 2), and the presence of
water and benzamide after catalysis, these signals were tentatively assigned to complexes fac-
[(CO)3Mn(dippe)(Z)](OTf) [Z = OH2 (4), and PhC(O)NH2 (5)] (Table 2, entries 4 and 5).
Assignments were further confirmed through independent 31P{1H} NMR experiments in which
either excess water or benzamide were added to THF-d8 solutions of complex 2 [Figure 3a
(traces c and d), and Figures S19, S21, and S22].
The outcome of the experiments shown in Figure 3a agreed with a weak coordinating behavior
for benzamide (Figure 3a, trace d). On the other hand, compound 4 was readily formed from
complex 2 in the presence of excess water (Figure 3a, trace c). Since under the actual reaction
conditions (Table 4, entry 5) the amount of water overpasses the one of benzonitrile in a 242:1
molar ratio, we hypothesized that compound 4 might be a predominating species in the model
reaction. To test the stability of 4, this was subjected to thermolysis conditions at 100 ºC for 18 h
in a THF-d8/H2O (1:2 v/v) solution (Figure S19) after which its signature signal at P 86.8
remained unchanged.
Given the occurrence of 4 in the reaction medium, we inquired whether benzonitrile might
compete with water for a vacant site at the “fac-[(CO)3Mn(dippe)]+” core. For this, a THF-d8
solution of complex 2 with excess benzonitrile (1:50 molar ratio) was prepared. The
corresponding 1H NMR spectrum displayed the signature signal for coordinated benzonitrile at
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H 8.04 (J = 6 Hz) and integral values consistent with the formation of complex 3 [Figure 2b
(upper trace) and Figure 3b (traces a and b)]. To this solution, controlled amounts of water were
added to yield the mixture 2/H2O/PhCN in the 2:3:100 and 1:50:50 molar ratios, respectively.
For both mixtures, room temperature 31P{1H} spectra displayed only a signal corresponding to
complex 3 (Figure S23), and 1H spectra featured the signature signal already assigned to
coordinated benzonitrile (Figure 3b, traces c and d). This signal disappeared upon the addition
of excess water (i.e. H2O/PhCN/2 = 1500:50:1 molar ratio), and only a signal for complex 4 was
observed in the corresponding 31P{1H} spectrum. These observations indicate that coordination
of benzonitrile depends on the amount of water in the medium, namely for a (sub)stoichiometric
water to benzonitrile ratio, coordination of benzonitrile prevailed forming compound 3, but in
excess water, equilibrium was shifted to yield complex 4.
A
B
C
31
Figure 3. (a) P{1H} NMR (121 MHz) spectra of THF-d8 solutions of 2 alone (trace b), 2 with
added ligands [traces: a for benzonitrile (1 equiv), c for water (111 equiv), and d for benzamide
1
(10 equiv)], and a THF-d8 solution of the model reaction after catalysis (trace e). (b) H NMR
(300 MHz) spectra displaying the signature signal for coordinated benzonitrile in THF-d8
solutions of complex 2 to which PhCN was added [20 equiv (trace a), and 50 equiv (trace b)],
and in the mixtures obtained after the addition of water [1.5 equiv (trace c), and 50 equiv (trace
1
d)] to the solution shown in trace b. H values are displayed in each trace. (c) H NMR (300
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MHz) monitoring of the model catalytic reaction displaying signals in the aromatic region for
free benzonitrile and benzamide at heating times of zero (red trace), 3 h (green trace), and 9 h
(blue trace). For the latter trace, integrals of signature signals for benzamide and H values for
the signals of both compounds are displayed.
Then it was performed a NMR monitoring of the actual catalytic reaction during the first 9 h of
heating. For this purpose, a THF-d8/H2O (1:2 v/v) solution of benzonitrile containing 2 mol% of
complex 2 was prepared and heated at 100 ºC. NMR data acquisition was performed at room
temperature, first after preparation, then after 3 and 9 h of heating. The three corresponding
31P{1H} spectra displayed only a signal for complex 4 (Figure S25), but 1H spectra exhibited
differences in the aromatic region after each time interval. First, for the as prepared reaction
mixture we observed only signals for free benzonitrile (Figure 3c, red trace) confirming that,
added in excess, water displaces benzonitrile at the “fac-[(CO)3Mn(dippe)]+” core. During the
following 3 and 9 h at 100 ºC, despite no signals for coordinated benzonitrile were detected, new
signals assigned to benzamide were observed (Figure 3c, green and blue traces). Experimental
integral values for signature signals at H 8.01 (bs, 1HNH2 ), 7.83 (d, 3JH-H = 7 Hz, 2Hortho), and
7.06 (bs, 1H NH2) (Figure 3b, blue trace) were consistent with the values expected for
benzamide.21 These observations described so far are summarized in a mechanistic proposal
depicted in Scheme 2.
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[Mn]
OTf
(iv)
H2O
N
(ii)
PhCN
iPr
iPr
iPr
CO
CO
Mn
H2O
P
P
Ph
[Mn]
(iii)
=
[Mn]
N
(3)
CO
(i)
[Mn]
[Mn]
H2O
iPr
Ph
OTf
"fac-[(CO)3Mn(dippe)]+" core
OTf
OH2
OTf
OH2
(2)
(4)
(v)
(viii)
PhC(O)NH2
O
[Mn]
[Mn]
NH
Ph
NH2
H2O
OTf
OTf
(vii)
Benzamide
Ph
O
Ph
(vi)
NH2
(5)
OH
Scheme 2. Mechanistic proposal for the Mn(I)-catalyzed hydration of benzonitrile
The generation of the active species occurs from initial reaction of catalyst precursor 2 with
excess water (2/H2O in a 1:12000 molar ratio) yielding complex 4 (Scheme 2, step i), which
subsequently reacts with benzonitrile (2/PhCN in a 1:50 molar ratio) to produce compound 3
(Scheme 2, step ii). The in-situ formation of 3 is proposed to take place through an equilibrium
that, in principle, lies in favor of species 4 (Scheme 2, step iii), nevertheless the long the product
of the forward reaction (i.e. complex 3) is consumed, equilibrium is shifted allowing for the
target process to occur. To test the importance of equilibria and the competence for a vacant site
at the “fac-[(CO)3Mn(dippe)]+” core, PPh3 was added as an explicit ligand in an independent
catalytic assay (2/PhCN/PPh3/H2O = 1:50:55:242 molar ratio). After workup, the yield of
benzamide dropped significantly to 51%. We attributed this partial inhibition to coordination of
the monodentate phosphine to Mn(I). This result is consistent with the previously observed
inhibition with the use of complex 1 (Table 4, entry 7), from which a bromo ligand is not
expected to dissociate from the coordination sphere of Mn to create a vacant site.
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Next steps in the mechanistic proposal are the reaction of an end-on coordinated nitrile in
complex 3 with water via a nucleophilic attack (Scheme 2, step iv) and a proton transfer reaction
(Scheme 2, step v) to yield a coordinated benzimidic acid which plausibly tautomerizes to yield
the corresponding coordinated amide contained in complex 5 (Scheme 2, step vi). To provide
some insight into the addition of water, we performed isotopic labeling assays with the use of
deuterium oxide (Table 6).
Table 6. Isotopic labeling with deuterium oxidea
Entry
R
mol%[Mn]cat
t /h
18
18
%Yield (H2O)b %Yield (D2O)c
H
OMe
OMe
2
4
2
1
2
3
90
93
15
19d
n.d.
48d
24
(a) Reactions under an inert atmosphere. Conditions: p-R-C6H4CN (0.46 mmol), D2O (2 mL, 100 mmol), THF
(1 mL). (b) Yields for isolated amides from reactions with H2O are displayed for comparative purposes. (c)
Yield for isolated amides from reactions with D2O. (d) Chromatographic yield.
Table 6 displays the yields for the isolated amides from reactions both with H2O and D2O. A
significant drop in the yield for benzamide with the use of D2O [%Yield (H2O)/ %Yield (D2O) =
6] (Table 6, entry 1) strongly suggest a proton transfer is taking place as the turnover limiting
step (namely step v in Scheme 2).22 Whether a proton transfer is rate determining under the
model reaction conditions (i.e. using 2 mol% 2), it seemed unreasonable to observe only fair
performances by using the very same experimental conditions for substrates containing electron-
releasing groups, namely p-methoxybenzonitrile (See Table 5, entries 9 and 10). To reach the
best performance for electron-rich substrates it was necessary to increase the catalytic loading to
4 mol% 2 (Table 5, entries 11 to 13). Because electron-rich nitriles are less reactive toward
nucleophilic attack (Scheme 2, step iv), we speculated on the possibility of distinguishing this
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step as rate determining for those substrates. We then performed isotopic labeling tests for p-
methoxybenzonitrile (Table 6, entries 2 and 3) but found a proton transfer was also rate
determining for the hydration of electron-rich nitriles regardless of the initial loading of the
catalyst precursor 2.
The last step in the proposed catalytic cycle is the substitution of a coordinated amide by water to
regenerate complex 4 and yield the corresponding free amide (Scheme 2, step vii). At this point,
regeneration of 4 might compete with the formation of complex 5 (Scheme 2, step viii),23
observed after workup in the model reaction. However, we assume this as an unimportant side
reaction given the poor coordinating character of benzamide observed previously (Figure 3a).
Finally, to perform the next turnover, benzonitrile concentration must be high enough to react
with complex 4 and produce 3. Whether the nitrile concentration is not enough to produce 3, an
increase in [Mn(I)] concentration, leading to an increase in the amount of 4, might drive the
forward reaction (Scheme 2, step ii). This would explain why an increase in the catalytic
loading, not in time, led to better performances on the model catalytic reaction (Table 4, entries
1 to 3).
Conclusions
The Mn(I) complexes fac-[(CO)3Mn(dippe)(Z)]1-nX1-n [n = 1: Z = Br (1), OTf (2); n = 0: Z=
PhCN, X = OTf (3)] were synthesized and characterized. Complex 3 featured and end-on
coordinated nitrile, which dissociated in solution to yield 2 and free benzonitrile. End-on
coordination of benzonitrile to the “fac-[(CO)3Mn(dippe)]+” core allowed for the use of
compounds 2 and 3 as catalytic precursors (2 mol%, 100 ºC, 18 h) to perform a hydration process
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to prepare benzamide in excellent isolated yield (90%). Complex 2 catalyzed the hydration of
both electron-deficient (2 mol% 2) and electron-rich aromatic nitriles (4 mol% 2) yielding the
corresponding amides in very good to excellent yields (88-94%). Mechanistic studies featured an
equilibrium between complex 3 and fac-[(CO)3Mn(dippe)(OH2)](OTf), which has to shift in
favor of 3 to perform a catalytic turnover in which a proton-transfer proved to be rate
determining. Current studies are underway within our group to extend the chemistry of the Mn(I)
organometallics reported herein in nitrile related transformations such as the hydration of
aliphatic nitriles as well as both aliphatic and aromatic dinitriles.
Experimental Section
General Considerations
Unless otherwise noted, all manipulations were performed using standard Schlenk techniques in
an inert-gas/vacuum double manifold or under an argon atmosphere (Praxair 99.998) in an
MBraun Unilab Pro SP glovebox (1 ppm H2O and O2). All liquid reagents were purchased as
reagent grade and degassed before use. Anhydrous benzonitrile, the rest of the nitriles, and silver
triflate were purchased from Aldrich and stored in the glovebox before use. Regular toluene (J.
T. Baker, reagent grade) was dried and distilled from sodium/benzophenone. Regular THF and
hexanes (J. T. Baker) were dried and degassed in a MB-SPS-800. Solvents and degassed distilled
water were stored in the glovebox before use. Deuterated solvents (THF-d8, DMSO-d6,
CD3C6D5) were purchased from Cambridge Isotope Laboratories and stored over 3 Å molecular
sieves inside the glovebox before use. NMR spectra were recorded at room temperature on the
following spectrometers: Varian Unity 300 MHz, Bruker Avance 300 MHz, and Varian VNMRS
400 MHz. Wilmad (0.38 mm) NMR tubes equipped with a J. Young valve were used for
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analyzing air-sensitive samples. NMR signals were processed using the Mnova 8.1 software
(MestreLab Research). 1H chemical shifts (δH) are reported in ppm and relative to the residual
proton resonance of the solvent: THF-d8 3.58 (1), 1.73 (1); CD3C6D5 2.09 (5); CDCl3 7.26 (1);
DMSO-d6 2.50 (5). 31P{1H} NMR chemical shifts (δP) are reported in ppm and relative to
external 85% H3PO4. 19F NMR chemical shifts (δF) are reported in ppm and relative to external
F3CC(O)OH. Coupling constants (J values) are given in Hz. The following abbreviations are
used for the NMR data: s = singlet; d = doublet; t = triplet, m = multiplet; and br = broad.
Elemental analysis experiments were performed on a Thermo Scientific Flash 2000 and on a
Perkin Elmer 2400 (oven temperature 950 ºC). FTIR (ATR) analyses were performed on a
Perkin-Elmer Spectrum 400 (4000-400 cm-1). GC-MS determinations were performed using an
Agilent Technologies G3171A equipped with the following column: 5 % phenylmethylsilicone,
ꢀ0 푚 × 0.ꢁ5 푚푚 × 0.ꢁ5 휇푚. The iPr2P(CH2)2PiPr2 (dippe) ligand was synthesized from
Cl2P(CH2)2PCl2 (Aldrich) and a 2.0 M THF solution of iPrMgCl (Aldrich).24 [MnBr(CO)5]
(Strem Chemicals) was purified by sublimation under reduced pressure and stored in the
glovebox before use.
Synthesis and characterization of fac-[(CO)3Mn(dippe)(Br)] (1)
In a Schlenk flask, 0.36 mmol (100 mg) of freshly sublimed [MnBr(CO)5] were suspended in
toluene (5 mL). To this mixture, a solution of dippe (105 mg, 0.40 mmol) in toluene (5 mL) was
added dropwise via syringe, allowing the evolved CO to vent to the inert gas/ vacuum double
manifold. Then, a condenser was adapted to the Schlenk flask and the reaction mixture was
refluxed for 20 minutes. After that, the yellow solution was evaporated under reduced pressure.
The solid residue was washed with hexanes (2 x 2 mL) at room temperature and dried under
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vacuum for 6 h. 1 was obtained as a yellow powder (146.2 mg, 84%). 1H (300 MHz, THF-d8)
3.58 (s, THF), 2.90-2.69 (m, 1H), 2.38-2.22 (m, 1H), 2.18-1.88 (m, 2H), 1.73 (s, THF), 1.47-1.16
(m, 12H). 31P{1H} (121 MHz) 80.45 (s). FTIR (ATR) νC-H (cm-1) 2960.77 m, 2934.09 w,
2898.91 w, 2874.40 w; νC-O (cm-1) 2001.29 s, 1921.98 s, 1885.76 s. Anal. Calcd for 1,
C17H32BrMnO3P2: C, 42.43; H, 6.70. Found: C, 42.46; H, 6.83.
Synthesis and characterization of fac-[(CO)3Mn(dippe)(OSO2CF3)] (2)
In the glovebox, AgOSO2CF3 (29.8 mg, 0.12 mmol) was suspended in toluene (3 mL) and added
dropwise to a solution of 1 (50.8 mg, 0.11 mmol) in toluene (5 mL). The reaction mixture was
protected from light and stirred for 60 min at room temperature. After that, the suspension
formed was filtered through a Celite® 545 (Merck) pad, which was previously dried under
vacuum at 100 ºC for 4 h, to obtain a yellow solution. Evaporation under reduced pressure
yielded a yellow powder, which was dried under vacuum for 6 h. 2 (43.4 mg, 75%). 1H (300
MHz, THF-d8) 2.53-2.27 (m, 1H), 2.18-2.00 (m, 1H), 1.47-1.30 (m, 6H). 31P{1H} (121 MHz)
85.74 (s). 19F NMR (282 MHz) -78.19 (s). FTIR (ATR) νC-H (cm-1) 2968.39 m, 2941.35 w,
2881.54 w; νC-O (cm-1) 2021.57 s, 1957.71 s, 1895.22 s. Anal. Calcd for 2, C18H32F3MnO6P2S: C,
39.28; H, 5.86; S, 5.82. Found: C, 38.44; H, 5.88; S, 5.75.
Synthesis and characterization of fac-[(CO)3Mn(dippe)(κ1-PhCN)](OSO2CF3) (3)
In the glovebox, a toluene colorless solution of benzonitrile (16.9 mg, 0.16 mmol) was added
dropwise to a toluene yellow solution of 2 (30 mg, 0.05 mmol) using a total solvent volume of 5
mL. The reaction mixture was stirred at room temperature for 60 min, after which a pale-yellow
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solution was obtained. Solvent was removed under reduced pressure and the pale yellow oily
residue was dried under vacuum for 2 h. After that, the oil was washed with hexanes (5 x 1 mL)
to yield an almost colorless powder, which was dried under vacuum for 6 h. 3 (30.9 mg, 85%).
1H NMR (300 MHz, THF-d8) 8.06-7.49 (m, 5H), 3.58 (s, THF), 2.78-1.94 (m, 8H), 1.73 (s,
THF), 1.53-1.23 (m, 24 H). 31P{1H} NMR (121 MHz) 3, 87.03 (s); 2, 85.74 (s). 19F NMR (282
MHz) -78.17. FTIR (ATR) νC-H (cm-1) 2965.79 w, 2939.65 w, 2878.40 w, 2903.02 w; νC-N (cm-1)
2250.91 vw; νC-O (cm-1) 2021.53 s, 1937.65 s, 1921.16 s. Anal. Calcd for 3, C25H37F3MnNO6P2S:
C, 45.95; H, 5.71; N, 2.14; S, 4.91. Found: C, 44.06; H, 5.77; N, 2.00; S, 5.03.
Synthesis of benzamide (2a) via benzonitrile hydration catalyzed by complex 2
In the glovebox, a THF solution of benzonitrile (47.3 mg, 0.46 mmol) was added dropwise to a
yellow THF solution of 2 (5 mg, 0.0092 mmol). The pale-yellow solution was transferred to a 25
mL Schlenk tube (Synthware Glass) (1 mL THF total volume), to which water (2 mL, 111
mmol) was added to form an emulsion, which evolved to a solution upon heating. The reaction
mixture was stirred into an oil bath at 100 ºC during 18 h. After that, the solvent and volatiles
were removed under reduced pressure in the inert gas/ vacuum double manifold. The residue was
exposed to air and chromatographed on a silica gel column with hexanes/ethyl acetate as eluent.
Once the solvents were evaporated under vacuum, the remaining solid were recrystallized from
acetone and finally washed with fresh hexanes. 2a was obtained as a white crystalline powder
(50 mg, 90%); m.p. 126-128 ºC. 1H (400 MHz, DMSO-d6) 7.97 (bs, 1H), 7.87 (dt, 3JHH = 7 Hz,
4JHH = 2 Hz, 2H), 7.51 (tt, 3JHH = 7.3 Hz, 4JHH = 2 Hz, 1H), 7.44 (tdd, 3JHH = 7.6 Hz, 4JHH = 2 Hz,
5JHH = 1 Hz, 2H), 7.35 (bs, 1H). 13C{1H} (100 MHz) 167.9, 134.3, 131.2, 128.2, 127.4. MS (EI)
m/z 121 [M+ (100)], 122 [M+1 (9  0.5)], 123 [M+2 (<1)].
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General procedure for the synthesis of aromatic amides bearing electron-withdrawing
substituents (2b-g) catalyzed by complex 2.
In the glovebox, THF solutions of p-CF3-C6H4CN, p-F-C6H4CN, C6F5CN, 4-Cypy, 3-Cypy, or 2-
Cypy (0.46 mmol), were added dropwise to yellow solutions of 2 (5 mg, 0.0092 mmol). The
solutions were transferred to 25 mL Schlenk tubes (Synthware Glass) (1 mL THF total volume),
to which water (2 mL, 111 mmol) was added. The resulting mixtures were stirred into an oil bath
at 100 ºC during 18 h. Workup of each reaction was carried out as described in the procedure for
the synthesis of benzamide (2a). Amides were obtained as white crystalline powders. 2b (77 mg,
88%); m.p. 184-185 ºC. 1H (400 MHz, CDCl3/DMSO-d6) 8.04 (bs, 1H), 8.01 (d, J = 8.2 Hz, 2H),
7.63 (d, J = 8.1 Hz, 2H), 7.25 (bs, 1H). 13C{1H} (100 MHz) 167.3, 137.5, 131.8 (q, 1JCF = 32.2
Hz), 128.1, 124.8 (q, 3JCF = 3.7 Hz), 122.2. 19F (376 MHz) -60.3 (s). MS (EI) m/z 189 (M+). 2c
(57 mg, 89%); m.p. 154-156 ºC. 1H (400 MHz, CDCl3/DMSO-d6) 7.92 (dd, 3JHH = 8.6 Hz, 4JHF
=
5.6 Hz, 2H), 7.89 (bs, 1H), 7.22 (bs, 1H), 7.14 (t, 3JHH = 3J HF = 8.7 Hz, 2H). 13C{1H} (100 MHz)
165.1, 162.6, 130.4, 129.9 (d, 3JCF = 8.9 Hz), 114.7 (d, 1JCF = 21.5 Hz). 19F (376 MHz) -107.5 (tt,
3JFH = 8.6 Hz, 4JFH = 5.5 Hz). MS (EI) m/z 139 (M+). 2d (91 mg, 94%); m.p. 152-153 ºC. 1H (400
MHz, CDCl3/DMSO-d6) 8.05 (bs, 1H), 7.84 (bs, 1H). 13C{1H} (100 MHz) 158.5, 144.4-144.0
(m), 142.3-141.6 (m), 139.7-139.4 (m), 138.2-137.7 (m), 135.7-135.2 (m), 113.0-112.4 (m). 19F
(376 MHz) -139.3 (dtd, 3JFF = 22 Hz, 4JFF = 6.2 Hz, 5JFF = 2.5 Hz), -151.7 (t, 3JFF = 21.2 Hz), -
159.5 (tdd, 3JFF = 21.4 Hz, 4JFF = 6.6, 5JFF = 2.7 Hz). MS (EI) m/z 211 (M+). 2e (50 mg, 90%);
m.p. 154-156 ºC. MS (EI) m/z 122 (M+). 2f (51 mg, 91%); m.p. 130-132 ºC. MS (EI) m/z 122
(M+). 2g (39 mg, 70%); m.p. 106-108 ºC. 1H (400 MHz, DMSO-d6) 8.62 (d, J = 4.4 Hz, 1H),
8.11 (bs, 1H), 8.04 (d, J = 7.7 Hz, 1H), 7.97 (td, J = 7.6 Hz, 1.6 Hz, 1H), 7.64 (bs, 1H), 7.58
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(ddd, J = 7.4 Hz, 4.7 Hz, 1.3 Hz, 1H) 13C{1H} (100 MHz) 166.0, 150.3, 148.4, 137.6, 126.4,
121.9. MS (EI) m/z 122 (M+). 2k MS (EI) m/z 146 (M+).
General procedure for the synthesis of aromatic amides bearing electron-releasing substituents
(2h-j) catalyzed by complex 2.
In the glovebox, THF solutions of p-MeO-C6H4CN, p-Me-C6H4CN, or 2-CN-C4H3O (0.46
mmol), were added dropwise to yellow solutions of 2 (10 mg, 0.0184 mmol). The solutions were
transferred to 25 mL Schlenk tubes (Synthware Glass) (1 mL THF total volume), to which water
(2 mL, 111 mmol) was added. The resulting mixtures were stirred into an oil bath at 100 ºC
during 18 h. Workup of each reaction was carried out as described in the procedure for the
synthesis of benzamide (2a). Amides were obtained as white crystalline powders. 2h (65 mg,
93%); m.p. 166-168 ºC. 1H (400 MHz, CDCl3/DMSO-d6) 7.83 (ddd, 3JHH = 8.8 Hz, 4JHH = 3.6
Hz, 5JHH = 1.6 Hz, 2H), 7.70 (bs, 1H), 6.93 (bs, 1H), 6.87 (ddd, 3JHH = 8.8 Hz, 4JHH = 3.6 Hz,
5JHH = 1.6 Hz, 2H), 3.78 (s, 3H). 13C{1H} (100 MHz) 167.8, 161.5, 129.2, 126.2, 112.9, 54.9.
MS (EI) m/z 151 (M+). 2i (56 mg, 90%); m.p. 160-162 ºC. MS (EI) m/z 135 (M+). 2j (47 mg,
93%); m.p. 136-138 ºC. 1H (400 MHz, DMSO-d6) 7.78 (s, 1H), 7.75 (bs, 1H), 7.36 (bs, 1H), 7.09
(s, 1H), 6.58 (s, 1H). 13C{1H} (100 MHz) 159.4, 147.9, 144.9, 113.5, 111.7. MS (EI) m/z 111
(M+).
Isotopic labeling in the synthesis of benzamide (2a) via benzonitrile hydration with deuterium
oxide catalyzed by complex 2.
In the glovebox, a THF solution of benzonitrile (47.3 mg, 0.46 mmol) was added dropwise to a
yellow THF solution of 2 (5 mg, 0.0092 mmol). The pale-yellow solution was transferred to a 25
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mL Schlenk tube (Synthware Glass) (1 mL THF total volume), to which deuterium oxide (2 mL,
100 mmol) was added. The reaction mixture was stirred into an oil bath at 100 ºC during 18 h.
After that, the solvent and volatiles were removed under reduced pressure in the inert gas/
vacuum double manifold. Taking care to not expose the residue to the air, this was dissolved in
anhydrous THF inside the glovebox and analyzed by GC-MS. The incorporation of deuterium to
the resulting amide 2a was observed by MS [(EI) 121 {M+ (100)}, 122 {M+1 (28)}, 123 {M+2
(3)}]. Compare to MS data displayed in the procedure for the synthesis of benzamide (2a).
Finally, workup was performed as described in the procedure above for the synthesis of 2a (8.3
mg, 15%).
Isotopic labeling in the synthesis of p-methoxybenzamide (2h) via p-methoxybenzonitrile
hydration with deuterium oxide catalyzed by complex 2.
In the glovebox, a THF solution of p-methoxy benzonitrile (61.2 mg, 0.46 mmol) was added
dropwise to a yellow THF solution of 2 (5 mg, 0.0092 mmol, or 10 mg, 0.0184 mmol). The
solution was transferred to a 25 mL Schlenk tube (Synthware Glass) (1 mL THF total volume),
to which deuterium oxide (2 mL, 100 mmol) was added. The reaction mixture was stirred into an
oil bath at 100 ºC during 18 or 24 h. After that, the solvent and volatiles were removed under
reduced pressure in the inert gas/ vacuum double manifold. The residue was exposed to air,
dissolved in acetone, and analyzed by GC-MS.
X-Ray structure determination
A crystal for 2 mounted on a glass fiber was studied with Oxford Diffraction Gemini "A"
diffractometer with a CCD area detector (MoK = 0.71073 Å, monochromator: graphite) source
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equipped with a sealed tube X-ray source at 130 K. Unit cell constants were determined with a
set of 15/3 narrow frame/runs (1° in ) scans. A data set consisted of 192 frames of intensity
data collected, and a crystal-to-detector distance of 80.00 mm. The double pass method of
scanning was used to exclude any noise. The collected frames were integrated by using an
orientation matrix determined from the narrow frame scans. CrysAlisPro and CrysAlis RED
software packages 25 were used for data collection and data integration. Analysis of the
integrated data did not reveal any decay. Final cell constants were determined by a global
refinement of 6815 reflections ( < 25.347° ). Collected data were corrected for absorbance by
using Analytical numeric absorption correction 26 using a multifaceted crystal model based on
expressions upon the Laue symmetry using equivalent reflections. Structure solution and
refinement were carried out with the SHELXS-201427 and SHELXL-2014 28, WinGX v2014.1
software was used to prepare material for publication 29. Full-matrix least-squares refinement
was carried out by minimising (Fo2–Fc2)2. All non-hydrogen atoms were refined anisotropically.
H atoms attached to C atoms were placed in geometrically idealized positions and refined as
riding on their parent atoms, with C–H = 0.98– 1.00 Å and with Uiso(H) = 1.2Ueq(C) for
methyne and methylene groups, and Uiso(H) = 1.5Ueq(C) for methyl groups.
Details of the X-ray studies for compound 2 are summarized in Table S1. Crystallographic data
have been deposited at the Cambridge Crystallographic Data Center as supplementary material
number CCDC 1818178. Copies of the data can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK. E-mail:deposit@ccdc.cam.ac.uk.
ASSOCIATED CONTENT
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Supporting Information
Featuring detailed multinuclear NMR spectra of the synthesized compounds and of the
monitoring of reactions described in the main text. Also includes mass spectra for isolated
amides and crystallographic data for complex 2.
AUTHOR INFORMATION
*Corresponding author
E-mail: juvent@unam.mx
ACKNOWLEDGMENTS
Authors thank CONACyT (178265) and DGAPA-UNAM (IN-202516) for their financial
support. J. A. G. also thanks CONACyT for a graduate studies grant (335811).
REFERENCES
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(c) R. García-Álvarez, J. Francos, E. Tomás-Mendivil, P. Crochet and V. Cadierno, J.
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