Catalytic hydration of cyanopyridines using nickel(0)

Article abstract of DOI:10.1016/j.ica.2009.07.002

The homogeneous catalytic hydration of 2-, 3- and 4-cyanopyridines using 0.5 mol% of [(dippe)Ni(μ-H)]₂ as catalyst precursor was achieved under heating. In the case of 4-cyanopyridine, production of isonicotinamide was observed at temperatures in the range of 80-120 °C. Heating to 180 °C resulted in formation of isonicotinic acid. In the case of 2- and 3-cyanopyridines the quantitative formation of their corresponding amides was achieved at 100 °C. The catalytic hydration of 2,6-dicyanopyridine was also undertaken in this work, in its case resulting in the synthesis of the mixed cyano/amide product, 2-cyanopyridine-6-carboxamide, at short reaction times.

Full text of DOI:10.1016/j.ica.2009.07.002

Inorganica Chimica Acta 363 (2010) 1092–1096
Contents lists available at ScienceDirect
Inorganica Chimica Acta
journal homepage: www.elsevier.com/locate/ica
Catalytic hydration of cyanopyridines using nickel(0)
*
Carmela Crisóstomo, Marco G. Crestani, Juventino J. García
Facultad de Química, Universidad Nacional Autónoma de México, México, D.F. 04510, Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
The homogeneous catalytic hydration of 2-, 3- and 4-cyanopyridines using 0.5 mol% of [(dippe)Ni(l-H)]2
Received 28 April 2009
Received in revised form 27 June 2009
Accepted 5 July 2009
as catalyst precursor was achieved under heating. In the case of 4-cyanopyridine, production of isonico-
tinamide was observed at temperatures in the range of 80–120 °C. Heating to 180 °C resulted in forma-
tion of isonicotinic acid. In the case of 2- and 3-cyanopyridines the quantitative formation of their
corresponding amides was achieved at 100 °C. The catalytic hydration of 2,6-dicyanopyridine was also
undertaken in this work, in its case resulting in the synthesis of the mixed cyano/amide product, 2-cya-
nopyridine-6-carboxamide, at short reaction times.
Available online 9 July 2009
Dedicated to Prof. Jonathan R. Dilworth.
Ó 2009 Elsevier B.V. All rights reserved.
Keywords:
Homogeneous
Catalysis
Heterocyclic nitrile
Cyanopyridines
Hydration
Nickel
1. Introduction
of these substrates has been investigated to some extent using
homogeneous [8–11] and heterogeneous transition-metal based
Nitriles play an important role in laboratory and in industry
provided that the products that can be obtained from them exhibit
several relevant applications [1]. In organic chemistry the addition
of nucleophiles or electrophiles to a –CN bond is a way to form new
C–C, C–N, C–O and C–S bonds [2]. The nitrile hydration reaction in-
volves the nucleophilic addition of OHꢀ moieties to the CN carbon
and the electrophilic addition of H+ to the nitrogen atom in order to
produce amides [3]. Under certain conditions, these may undergo
subsequent hydrolysis to the corresponding carboxylic acid and
ammonia in the case of primary amides, or alternatively to the
NR0R00 amine (R0, R00 = H, alkyl or aryl) if the hydrolysis reaction is
to take place over N-substituted amides. When undergone selec-
tively, hydrolysis reactions may also yield important by-products
for which industrial applications are also known and this indeed
the case for amino acids [4]. Usually however, the selective prepa-
ration of amides is preferred for most industrial processes and this
is exemplified by the synthesis of acrylamide from acrylonitrile [5]
or the preparation of nicotinamide from 3-cyanopyridine (3-Cypy)
[6].
catalysts [6,12] as well as enzymes [13], yet the ultimate applica-
bility of these catalysts remains uncertain.
In the past years our group has intensively studied the chemis-
try of nickel compounds with a rigid backbone described by the
general formula [(P–P)Ni(
g
2-N,C-R)] (P–P = chelating alkyl diphos-
phine), that exhibit a
g
2-coordinated aryl-, heteroaryl- or alkyl-ni-
trile [14]. These were probed to be active catalysts for the
hydration of benzo (BN) and acetonitrile (AN) [14c] and more re-
cently also, for the hydration of benzo- [14b] and alkyl-dinitriles
[14a]. Herein, we report on the catalytic hydration of the 2-, 3-
and 4-Cypys.
2. Results and discussion
2.1. Catalytic hydration of CyPys
The catalytic hydration of 2-, 3- and 4-Cyp was achieved under
heating using 0.5 mol percent (mol%) of the nickel(I) compound,
[(dippe)Ni(l-H)]2 (1). Hydrations were performed using water at
the 50:1 mol proportion of water to nitrile. Table 1 summarizes
the results that were obtained with the three substrates in the
range of 80 to 180 °C.
The results in Table 1 suggest that the hydration reactions are
affected by the temperature at which the processes are performed
as well as by the relative position of the nitrile in the correspond-
ing Cypy. In the case of 4-Cypy, hydration at 180 °C resulted in
Among the cyclic heterocyclic nitriles, cyanopyridines (CyPys)
are usually the preferred substrates for the catalytic hydration
reaction due to their small steric hindrance and overall greater
reactivity [7]. To the best of our knowledge, the catalytic hydration
* Corresponding author. Tel.: +52 55 56223514; fax: +52 55 56162010.
E-mail address: juvent@servidor.unam.mx (J.J. García).
0020-1693/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.ica.2009.07.002

C. Crisóstomo et al. / Inorganica Chimica Acta 363 (2010) 1092–1096
1093
Table 1
Catalytic hydration of CyPys using nickel(0).
Entry
Substrate
T (°C)
Product
Yield (%)
TONa
TOF (TON/h)
1
2
4-Cypy
4-Cypy
4-Cypy
4-Cypy
3-Cypy
2-Cypy
80
100
120
180
100
100
isonicotinamide
isonicotinamide
isonicotinamide
isonicotinic acid
nicotinamide
75
80
81
74
88
87
150
160
163
149
177
174
2.08
2.22
2.26
2.06
2.45
2.41
3
4b
5
6
picolinamide
All entries in this table correspond to 72 h heating.
a
Turnover numbers are calculated with respect to the amount of nickel(I) catalyst precursor.
Formation of ammonia was confirmed in this experiment as a result of hydrolysis of isonicotinamide.
b
formation of isonicotinic acid and ammonia (entry 4) whereas
catalytic cycle. The latter compound can follow two pathways
depending on the particular temperature that is used for the pro-
cess, the first one of which is proposed as the productive tautomer-
ization of the coordinated iminic moiety that yields a free amide
and regenerates the nickel(0) catalyst. We propose this route to oc-
cur at temperatures 6120 °C, in accordance to results in Table 1.
Analogous pathways are proposed for the hydrations of 2-Cypy
and 3-Cypy by analogy. Heating the system with 4-Cypy over
120 °C resulted in hydrolysis of isonicotinamide and thus, coordi-
nation of the carbonyl from this amide to [(dippe)Ni] is proposed
as the second possible outcome of catalysis that in such case
heating to lower temperatures (80–120 °C, entries 1–3) yielded
isonicotinamide, only. The catalytic activity increased slightly with
a greater temperature, although heating to 180 °C changed the
selectivity. In the case of 2- and 3-Cypy (entries 5 and 6) the quan-
titative formation of their corresponding amides (nicotinamide and
picolinamide) was also achieved at 100 °C.
2.2. Mechanisms for hydration of CyPys
Similarly to previous results published by our group concerning
the catalytic hydration of mono and dinitriles, the catalytic hydra-
tions of Cypys are thought occur through nickel(0) intermediates
may allow
a g g
2-O,C intermediate, [(dippe)Ni( 2-O,C(NH2)-{4-
py})] (4), to be formed also preceding the formation of the free car-
boxylic acid.
that exhibit a
ety [14a–c]. Scheme 1 illustrates this proposal in the case of 4-
Cypy, in which [(dippe)Ni(
2-N,C-{4-py})] (2) is formed in situ.
g
2-coordination of a –CN bond to a [(dippe)Ni0] moi-
g
2.3. Reactivity of CyPys in hydration reactions at shorter time (12 h)
The synthesis and complete characterization of this compound
has already been reported by our group as part of a series of stoi-
chiometric reactions that preceded the use of these compounds for
the catalytic hydration of nitriles [14e]. The addition of a water
molecule to 2 presumably leads to an N-protonated hydroxy imine
The catalytic hydrations of 2-, 3- and 4-Cypy were assessed at
12 h in an attempt at achieving optimized conditions with respect
to the initial 72 h time that was used for all experiments in Table 1.
Experiments were undertaken at 100 °C using 0.5 mol% of 1. The
results obtained showed an increasing trend in the formation the
corresponding pyridine carboxamides as the –CN substituent occu-
pied a farther position with respect to the nitrogen atom of the par-
ticular pyridine ring, 2-Cypy (38%) < 3-Cypy (63%) < 4-Cypy (75%)
(see Fig. 1).
intermediate, [(dippe)Ni(g
2-N(H)@C(OH)-{4-py})] (3), within the
i-Pr2
P
i-Pr2
P
H
Ni
Ni
Initially, we expected 2- and 4-Cyp to be the more reactive sub-
strates on the basis of the more favourable nucleophilic substitu-
tion reactions that may be effected at these positions as a result
of the inductive effect of the heteroatom [15] and thus, we pre-
dicted 3-Cypy to exhibit the lowest conversion within the series.
The fact that hydration of 3-Cypy was favoured over 2-Cypy after
12 h heating suggests that a certain kinetic difference in reactivity
between these two may operate during the process at short reac-
P
P
H
i-Pr2
i-Pr2
(1)
CN
N
COOH
H2
i-Pr
P 2
NH3
+
N
C
N
H2O
Ni
CN
N
P
i-Pr2
+
H2O
N
(2)
i-Pr2
i-Pr2
CONH2
N
P
P
O
N
C
H
OH
Ni
120 ºC
CN
Ni
C
NH2
P
P
i-Pr2
i-Pr2
N
N
(4)
(3)
N
180 ºC
Scheme 1. Mechanistic proposal for the catalytic hydration of 4-Cypy at 120 and
180 °C, using nickel(0).
Fig. 1. Catalytic hydration of CyPys at 100 °C, for a period of 12 h using 0.5 mol% of
1.

1094
C. Crisóstomo et al. / Inorganica Chimica Acta 363 (2010) 1092–1096
tion times. Alternatively, the hydrolysis product of 2-Cypy may be
chelating to nickel and thus slowing down reactivity. The latter
however is overcome by making use of a longer period of time as
indeed, heating the systems to 100 °C for 72 h showed no signifi-
cant difference in conversion with any of the three substrates,
according to the results already shown in Table 1.
this time by the gradual apparition of two new doublets in the
same spectrum, centered at d 79.9 and 73.1 and displaying 2J(P,P)
coupling constants of 27 Hz. The magnitude of the latter coupling
constant is also consistent with previous data for analogous com-
pounds [14].
3. Conclusions
2.4. Catalytic hydration of 2,6-diCypy
The catalytic hydrations of 2-, 3- and 4-cyanopyridine and 2,6-
dicyanopyridine were achieved under reasonably mild conditions
and in good yields using [(dippe)Ni(l-H)]2 as catalyst precursor.
The catalytic hydration of 2,6-diCypy was undertaken using
0.5 mol% of 1 at 100 °C. The results are showed in Table 2.
The results show that formation of 2-cyanopyridine-6-carbox-
amide or 2,6-pyridinedicarboxamide favours one product over
the other when undergoing hydration at different reaction times
(6–120 h). At shorter reaction times (6–36 h) production of the rare
mixed cyano/amide compound takes place preferentially. When
compared to the previous work using benzodinitriles, hydration
of isophthalonitrile, which is similar to 2,6-diCypy, yielded the
mixed product, 1,3-cyanobenzamide, at 120 °C after 72 h [14b]. Al-
most complete conversion to 2,6-pyridinedicarboxamide was
achieved after 72 h (entries d and e). To the best of our knowledge,
selective hydration of 2,6-diCypy towards 2-cyanopyridine-6-car-
boxamide and its higher by-products, 2,6-pyridinedicarboxamide
and 2,6-pyridinedicarboxylic acid has only been achieved by an
enzymatic route using nitrile hydratase/amidase from Rhodococcus
erythropolis [16].
The potential use of this catalyst in organic synthesis is envisioned
from these results. In the case of 2,6-dicyanopyridine its hydration
can be tuned to yield either the mixed cyano/amide product, 2-
cyanopyridine-6-carboxamide or the fully hydrated one, 2,6-pyrid-
inedicarboxamide, at different reaction times. The current work
confirms that nickel(0) catalysts used for the nitrile hydration reac-
tion are robust and remain active even after prolongued periods of
heating time. Currently we work on further extending this chemis-
try to other heterocyclic nitriles.
4. Experimental
4.1. General considerations
The synthesis of the catalyst precursor, [(dippe)Ni(l-H)]2 (1)
With the aim of obtaining additional information concerning
coordination of 2,6-diCypy to [(dippe)Ni] that could be comparable
to existing data over CyPys mentioned above, a stoichiometric
reaction of this substrate with compound 1 was examined. Eq.
(1) illustrates the reaction that took place at room temperature
in benzene-d6.
was performed under argon atmosphere in an MBraun glovebox
(<1 ppm H2O and O2) according to the reported procedure [17].
All argon used in this work was supplied in high purity grade
(99.998%) by Praxair. Deuterated solvents for NMR experiments
were purchased from Cambridge Isotope Laboratories and were
stored over 3 Å molecular sieves in the glovebox for at least 24 h
before their use. All regular solvents were purchased from J.T. Ba-
ker in reagent grade. THF and hexanes were dried and distilled
from sodium/benzophenone ketyl, according to standard proce-
dures [18]. Ethanol was used for recrystallisation of hydration
products and was used as received. All substrates for this work,
2-Cypy (99%), 3-Cypy (98%), 4-Cypy (98%) and 2,6-diCypy (97%)
were purchased from Aldrich and were used without any addi-
tional purification. All the other chemicals, filter aids and chro-
matographic materials were reagent grade and were used as
P
H
H
P
P
P
P
2
NC
+
H2
2
Ni
+
Ni
Ni
P
N
N
NC
CN
N
(8)
ð1Þ
Examination of the corresponding 31P{1H} NMR spectrum of the
reaction mixture confirmed the presence of two slightly broadened
doublets centered at 79.2 and 65.8 ppm with 2J(P,P) coupling con-
stants of 62 Hz. The magnitude of the coupling constant is consis-
received. Catalysis experiments were performed either in
a
tent with previous data for nickel(0) compounds that exhibit g2
-
300 mL stainless steel vessel, Parr Series 4560 Bench Top Mini
Reactor, or under reflux using a Schlenk line. All the vessels or
Schlenk flasks that were used for catalysis experiments were
charged inside the glovebox. The water used for all hydrations
was distilled and degassed following the standard freeze–pump–
thaw procedure. Experiments for catalysis were performed by
in situ preparation of the respective nickel(0) catalyst. The total
amount of nitrile used was calculated on the basis of 0.5 mol% of
the nickel(I) catalyst precursor 1 versus the total mol amount of
substrate. NMR spectra of complexes and products were recorded
at ambient temperature on a 300 MHz Varian Unity spectrometer.
1H and 13C{1H} NMR spectra of hydration products were obtained
using concentrated solutions of these dissolved in DMSO-d6.1H and
31P{1H} NMR spectra of complex 8 was obtained using a concen-
trated solution of the nickel compound prepared in situ, in an inert
solvent such as benzene-d6. The sample was handled under argon,
using a thin wall ꢀ0.38 mm WILMAD NMR tube equipped with a J.
Young valve. 1H and 13C{1H} chemical shifts (d, ppm) are reported
relative to either the residual proton or deuterated-carbon reso-
nances of the solvent, respectively. 31P{1H} NMR spectra were re-
corded relative to external 85% H3PO4. All hydration products
were purified by recrystalization and column chromatography
and their characterization was made by direct comparison of the
coordination of a CN bond to the metal center [14]. As such, we
have assigned the doublets in the spectrum to the two asymmetric
phosphorus environments in the compound, [(dippe)Ni(g
2-N,C-
{2,6-(CN)2-pyridine})], which was observed to be stable at room
temperature and in deoxygenated solution for a period of 16 h.
Evolution of this compound to the C–CN oxidative addition deriv-
ative, [(dippe)Ni(CN)(6-Cypy)] (9), was observed on standing after
Table 2
Catalytic hydration of 2,6-diCypy using 0.5 mol% nickel(0) at 100 °C.
Entry
t (h)
Isolated products (%)
CONH2
CONH2
NC
N
H2NOC
N
2-cyanopyridine-6-carboxamide
2,6-pyridinedicarboxamide
A
B
C
D
E
6
68
37
11
9
30
48
55
65
82
12
36
72
120
6

C. Crisóstomo et al. / Inorganica Chimica Acta 363 (2010) 1092–1096
1095
1H and 13C{1H} NMR spectra to expressly prepared standards and
available literature [19]. Melting points of the products were ob-
tained using an Electrothermal Digital Melting Point Apparatus,
also compared to a standard whenever possible. Calculated 1H
and 13C{1H} NMR spectra were obtained using the ACD/HNMR
and ACD/CNMR Predictors [20]. Elemental analyses and mass spec-
tra (MS-EI+) of the purified organic products were carried out by
USAI-UNAM using an EA 1108 FISONS Instruments analyzer and
a Jeol SX-102A mass spectrometer, respectively. Infrared spectra
were obtained using a Perkin–Elmer 1600 FT spectrophotometer.
All turnover numbers (TON) for the catalytic hydrations in this
work were calculated as moles of isolated product over moles of
nickel(I) catalyst precursor. Turnover frequencies (TOF) were cal-
culated as TON over reaction time.
white solid (1.1 g, 0.0088 mol) with a TON of 163 and a TOF of
two cycles per hour.
4.3.3. Hydration of 4-Cypyat 180 °C, formation of isonicotinic acid
A reactor vessel was charged in the glovebox with 1 (0.035 g,
0.054 mmol), 4-Cypy (1.14 g, 0.010 mol) and water (10 mL,
0.55 mol). The mixture was heated to 180 °C under vigorous stir-
ring for 72 h, after which time the reactor vessel was left to cool
down. All the ammonia (NH3) generated in the vessel during the
reaction was bubbled into concentrated hydrochloric acid produc-
ing NH4Cl. After complete venting of the gas, the vessel was opened
and a white solid residue recovered and subjected to purification.
The product was purified by sublimation. Yield of isonicotinic acid,
after work-up: 74% white solid (0.995 g, 0.008 mol) with a TON of
149 and a TOF of two cycles per hour. M.p. of isonicotinic acid:
200–250 °C (sublimes). MS-EI+: m/z = 123 (molecular ion). Losses:
m/z = 106 (–OH), 78 (–COOH). Anal.Calc. for C6H5N1O2 (isonicotinic
acid): C, 58.4; H, 4.1; N, 11.3. Found: C, 58.9; H, 4.5; N, 11.2. NMR
spectra for isonicotinic acid in DMSO-d6: 1H, d 8.77–8.76 (d, 2H,
CH), 7.82–7.80 (d, 2H, CH). 13C{1H}, d 166.4 (carbonyl), 150.7 (s,
CH), 138.4 (s, C), 122.9 (s, CH).
4.2. Reaction of 1 with 2,6-diCypy, preparation of [(dippe)Ni(
{2,6-(CN)2-py})] (8)
g
2-N,C-
To
a
dark red benzene-d6 solution (1 mL) of
1 (0.020 g,
0.030 mmol) was added
2
equiv. of 2,6-diCypy (0.008 g,
0.062 mmol), at room temperature. After mixing, extensive forma-
tion of H2(g) was observed; all of which was vented away into the
glovebox. The mixture was left to stir for 1 h, after which time it
was examined by NMR. After of 16 h stirring at room temperature,
complex 8 evolved into its respective nickel(II) derivative [(dip-
pe)Ni)(CN)(6-CN-py)] (9). NMR spectra of 8 in benzene-d6 solution:
1H, d 7.82 (s, 1H, CH), 6.54 (s, 2H, CH), 2.2–1.9 (m, 4H, CH), 1.85–1.6
4.3.4. Hydration of 3-Cypy at 100 °C, formation of nicotinamide
A Schlenk flask was charged in the glovebox with 1 (0.035 g,
0.054 mmol), 3-Cypy (1.14 g, 0.010 mol) and water (10 mL,
0.55 mol). The mixture was heated to 100 °C in an oil bath under
inert atmosphere, connected to an inert-gas/vacuum double man-
ifold, for 72 h. A white solid residue was progressively formed dur-
ing this time and recovered from the flask by dissolving it in hot
ethanol. The product was recrystallised by dropwise addition of
cold hexane. Yield of nicotinamide at 100 °C, after work-up: 88%
of white crystals (1.18 g, 0.0096 mol), with a TON of 177 and a
TOF of two cycles per hour. M.p. of nicotinamide: 129–131 °C. Anal.
Calc. for C6H6N2O1 (nicotinamide): C, 59.0; H, 4.9; N, 22.9. Found:
C, 59.4; H, 4.9; N, 22.2%. NMR spectra for nicotinamide in DMSO-
d6: 1H, d 9.0 (s, H, CH), 8.69–8.68 (d, H, CH), 8.22–8.20 (m, br, 2H,
CH and NH2), 7.6. (s, br, H, NH2), 7.6–7.4 (m, H, CH). 13C{1H}, d
166.5 (carbonyl), 151.9 (s, CH), 148.7 (s, CH), 135.1 (s, CH), 129.7
(s, C), 123.4 (s, CH).
2
(m, 4H, CH2), 1.2–0.92 (m, 24H, CH3). 31P{1H}, d 79.2 (d, JP–
2
P = 62 Hz), 65.8 (d, JP–P = 63 Hz). NMR spectra of 9 in benzene-d6:
1H, d 6.3–6.1 (m, 3H, CH), 2.2–1.9 (m, 4H, CH), 1.85–1.6 (m, 4H,
CH2), 1.2–0.92 (m, 24H, CH3). 13C{1H}, d 139.1 (d, JC–P = 7.2 Hz, C),
137.9 (s, CH), 135.1 (s, coordinated CN), 130.3 (s, CH), 122.8 (s,
CH), 119.8 (s, C), 116.3 (s, CN), 32.3 (s, CH), 30.5 (s, CH), 25.7–
21.8 (m, CH2), 20.1 (s, CH3), 19.2 (s, CH3), 19.6 (s, CH3), 18.9 (s,
2
2
CH3). 31P{1H}, d 79.9 (d, JP–P = 27 Hz), 73.1 (d, JP–P = 27 Hz).
4.3. Catalysis
4.3.1. Hydration of 4-Cypy at 80 and 100 °C, formation of
isonicotinamide
In a glovebox, Schlenk flasks were charged in different runs
with 1 (0.035 g, 0.054 mmol), 4-Cypy (1.14 g, 0.010 mol) and water
(10 mL, 0.55 mol). The mixtures were heated in a silicon oil bath
under argon, connected to an inert-gas/vacuum double manifold,
during 72 h. A white solid residue was recovered from the flasks
and was recrystallised from hot ethanol using hexanes. Yield of iso-
nicotinamide at 80 °C, after work-up: 75% of white solid (0.99 g,
0.008 mol) with a TON of 150 and a TOF of two cycles per hour.
Yield of isonicotinamide at 100 °C, after work-up: 80% of white so-
lid (1 g, 0.0087 mol) with a TON of 160 and a TOF of two cycles per
hour. M.p. of isonicotinamide: 155–157 °C. MS-EI+: m/z = 122
(molecular ion). Losses: m/z = 106 (–NH2), 78 (–CONH2). Anal. Calc.
for C6H6N2O1 (isonicotinamide): C, 59.0; H, 4.9; N, 22.9. Found: C,
59.2; H, 5.1; N 22.8%. NMR spectra for isonicotinamide in DMSO-
d6: 1H, d 8.71–8.70 (d, 2H, CH), 8.2 (s, br, H, NH2), 7.77–7.75 (d,
3H, CH and NH2). 13C{1H}, d 166.6 (carbonyl), 150.3 (s, CH), 141.4
(s, C), 121.5 (s, CH).
4.3.5. Hydration of 2-Cypy at 100 °C, formation of picolinamide
A Schlenk flask was charged in the glovebox with 1 (0.035 g,
0.054 mmol), 2-Cypy (1.14 g, 0.010 mol) and water (10 mL,
0.55 mol). The mixture was heated to 100 °C following the proce-
dure described above, for 72 h. Yield of picolinamide at 100 °C,
after work-up: 87% of white solid (1.15 g, 0.0094 mol), with a
TON of 174 and a TOF of two cycles per hour. M.p. of picolinamide:
105–108 °C. Anal.Calc. for C6H6N2O1 (picolinamide): C, 59.0; H, 4.9;
N, 22.9. Found: C, 57.7; H, 5.0; N, 22.1%. NMR spectra for picolina-
mide in DMSO-d6: 1H, d 8.63–8.61 (m, H, CH), 8.1 (br s, H, NH2),
8.0–7.9 (m, 2H, CH), 7.6. (s, br, H, NH2), 7.6–7.5 (m, H, CH).
13C{1H}, d 166.0 (carbonyl), 150.2 (s, C), 148.4 (s, CH), 137.6 (s,
CH), 126.4 (s, CH), 121.9 (s, CH).
4.3.6. Hydration of 2,6-diCypy, formation of 2-cyanopyridine-6-
carboxamide and 2,6-pyridinedicarboxamide
Schlenk flasks were charged in separate runs with 1 (0.0024 g,
0.0037 mmol), 2,6-diCypy (0.1 g, 0.774 mmol) and water (10 mL,
0.55 mol), in the glovebox. The mixtures were refluxed at 100 °C
under argon atmosphere for different periods of time, being 6,
12, 36, 72 and 120 h. The crude mixtures were purified by column
chromatography eluting over silica gel with an 80:20 (v/v) mixture
of ethyl acetate and hexane. 2-cyanopyridine-6-carboxamide was
eluted as the first fraction; elution with ethanol allowed recovery
of 2,6-pyridinedicarboxamide as the second one. The two products
were vacuum dried for 4 h. Yield of 2-cyanopyridine-6-carboxam-
4.3.2. Hydration of 4-Cypy at 120 °C, formation of isonicotinamide
In a glovebox, a reactor vessel was charged with 1 (0.035 g,
0.054 mmol), 4-Cypy (1.14 g, 0.010 mol) and water (10 mL,
0.55 mol). The mixture was heated to 120 °C for 72 h. After this
time, heating was stopped and the vessel allowed to cool down
to room temperature. A white solid residue was recovered from
the reactor vessel and recrystallised from hot ethanol as described
above. Yield of isonicotinamide at 120 °C, after work-up: 81% of

et al. / Inorganica Chimica Acta 363 (2010) 1092–1096
C. Crisóstomo
1096
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Chem. 19 (2008) 1143;
ide produced after 6 h, after work-up: 68% of a white crystalline so-
lid (0.0771 g, 0.052 mmol). Yield of 2-cyanopyridine-6-carboxam-
ide produced after 12 h, after work-up: 37% of a white crystalline
solid (0.042 g, 0.28 mmol). Yield of 2-cyanopyridine-6-carboxam-
ide produced after 36 h, after work-up: 11% of a white crystalline
solid (0.012 g, 0.081 mmol). Yield of 2-cyanopyridine-6-carboxam-
ide produced after 72 h, after work-up: 9% of a white crystalline so-
lid (0.0104 g, 0.068 mmol). Yield of 2-cyanopyridine-6-
carboxamide produced after 120 h, after work-up: 6% of a white
crystalline solid (0.0064 g, 0.043 mmol). M.p. of 2-cyanopyridine-
6-carboxamide: >200 °C (sublimes). NMR spectra for 2-cyanopyri-
dine-6-carboxamide in DMSO-d6: 1H, d 8.8–8.2 (m, 3H, CH), 7.7 (s,
br, 2H, NH2). 13C{1H}, d 164.5 (carbonyl), 151.8 (s, C), 139.7 (s, CH),
131.4 (s, C), 131.3 (s, CH), 125.8 (s, CH), 117.1 (s, CN). IR (KBr disc,
cmꢀ1): 3399 and 3201 (NH2), 2238 (CN), 1709 (carbonyl), 836–450
(Ar). Yield of 2,6-pyridinedicarboxamide produced after 6 h, after
work-up: 30% of a white crystalline solid (0.0383 g, 0.023 mmol).
Yield of 2,6-pyridinedicarboxamide produced after 12 h, after
work-up: 48% of a white crystalline solid (0.060 g, 0.38 mmol).
Yield of 2,6-pyridinedicarboxamide produced after 36 h, after
work-up: 55% of a white crystalline solid (0.070 g, 0.42 mmol).
Yield of 2,6-pyridinedicarboxamide produced after 72 h, after
work-up: 65% of a white crystalline solid (0.0829 g, 0.50 mmol).
Yield of 2,6-pyridinedicarboxamide produced after 120 h, after
work-up: 82% of a white crystalline solid (0.1051 g, 0.63 mmol).
M.p. of 2,6-pyridinedicarboxamide: >250 °C (sublimes). Anal. Calc.
for C7H7N3O2 (2,6-pyridinedicarboxamide): C, 50.9; H, 4.2; N, 25.4.
Found: C, 50.2; H, 4.3; N, 24.6. NMR spectra for 2,6-pyridinedicarb-
oxamide in DMSO-d6: 1H, d 8.8 (br s, H, NH2), 8.2–8.1 (m, 3H, CH),
7.7 (br s, H, NH2). 13C{1H}, d 165.6 (carbonyl), 149.1 (s, C), 139.4 (s,
CH), 124.4 (s, CH). IR (KBr disc, cmꢀ1): 3420 and 3244 (NH2), 1686
(carbonyl), 843–548 (Ar).
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Acknowledgements
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54 (1988) 1766;
We thank CONACYT (Grant 080606) and DGAPA-UNAM (Grant
IN202907-3) for their support to this work. CC and MGC also thank
CONACYT for an M.Sc. and a Ph.D. grant, respectively.
.
For other examples of enzymatic hydration of heterocyclic nitriles,
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Appendix A. Supplementary data
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Supplementary data associated with this article can be found, in
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