Aqueous-Phase Nitrile Hydration Catalyzed by an In Situ Generated Air-Stable Ruthenium Catalyst

Article abstract of DOI:10.1002/chem.201902224

RuCl₂(PTA)₄ (PTA=1,3,5-triaza-7-phosphaadamantane) is an active, recyclable, air-stable, aqueous-phase nitrile hydration catalyst. The development of an in situ generated aqueous-phase nitrile hydration catalyst (RuCl₃?3 H₂O+6 equivalents PTA) is reported. The activity of the in situ catalyst is comparable to RuCl₂(PTA)₄. The effects of [PTA] on the activity of the reaction were investigated: the catalytic activity, in general, increases as the pH goes up, which shows a positive correlation with [PTA]. The pH effects were further explored for both the in situ and RuCl₂(PTA)₄ catalyzed reaction in phosphate buffer solutions with particular attention given to pH 6.8 buffer. Increased catalytic activity was observed at pH 6.8 versus water for both systems with turnover frequency (TOF) up to 135 h^?1 observed for RuCl₂(PTA)₄ and 64 h^?1 for the in situ catalyst. Catalyst loading down to 0.001 mol % was examined with turnover numbers as high as 22 000 reported. Similar to the preformed catalyst, RuCl₂(PTA)₄, the in situ catalyst could be recycled more than five times without significant loss of activity from either water or pH 6.8 buffer.

Full text of DOI:10.1002/chem.201902224

A Journal of
Accepted Article
Title: Aqueous phase nitrile hydration catalyzed by an in-situ generated
air stable ruthenium catalyst
Authors: Whalmany L Ounkham, Jason A Weeden, and Brian J. Frost
This manuscript has been accepted after peer review and appears as an
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content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201902224
Link to VoR: http://dx.doi.org/10.1002/chem.201902224
Supported by

Chemistry - A European Journal
10.1002/chem.201902224
FULL PAPER
Aqueous phase nitrile hydration catalyzed by an in-situ generated
air stable ruthenium catalyst
[
a]
[a]
[a]
Whalmany L. Ounkham, Jason A. Weeden, and Brian J. Frost*
Abstract: [RuCl
2
PTA
4
] (PTA = 1,3,5-triaza-7-phosphaadamantane)
Our group has been interested in the development of water
soluble phosphine ligands for use in catalysis. Our work has
largely focused on ruthenium complexes containing air-stable
and water soluble, air stable 1,3,5-triaza-7-phosphaadamantane
(PTA)23-25 and derivatives for possible aqueous phase
catalysis.26-33 Recently our group published a series of ruthenium
arene complexes containing β-aminophosphine ligands, derived
from PTA which were found to be active catalysts for nitrile
hydration with TOF up to 285 h-1 and TON of up to 97000.31
Unfortunately these aqueous catalysts decomposed under the
reaction conditions (100 °C in the presence of air) and were
unable to be recycled. In 2012 we published a communication
is an active, recyclable, air tolerant, aqueous phase nitrile hydration
catalyst. The development of an in-situ generated aqueous phase
nitrile hydration catalyst (RuCl
reported. The activity of the in-situ catalyst is comparable to
RuCl PTA ]. The effects of [PTA] on activity was investigated;
3 2
•3H O + 6 equivalents PTA) is
[
2
4
catalytic activity, in general, increases as pH increases which
increases with [PTA]. The pH effects were further explored for both
4 2
the in-situ and [RuPTA Cl ] catalyzed reaction in phosphate buffer
solutions with particular attention given to pH 6.8 buffer. Increased
catalytic activitiy was observed at pH 6.8 versus water for both
-
1
-1
2 4
systems with TOF up to 135 h observed for [RuCl PTA ] and 64 h
for the in-situ catalyst. Catalyst loading down to 0.001 mol% was
examined with turnover numbers as high as 22,000 reported. Similar
2 4
on the activity of [RuCl PTA ] as a water soluble and air stable
30
catalyst for the hydration of a wide range of nitriles. In part
because of the high water solubility and air stability this catalyst
was highly recyclable. Due to the relative insolubility of the
product amides in water many of the products of nitrile hydration
could be isolated by filtration away from the catalyst and starting
material containing aqueous solution.
2 4
to the preformed catalyst, [RuCl PTA ], the in-situ catalyst could be
recycled more than five times without significant loss of activity from
both water or pH 6.8 buffer.
RuCl
coworkers,
active and recyclable catalyst for nitrile hydration. Herein we
report the expansion of our previous work on [RuCl PTA
looking at the effects of pH, temperature, salts, and buffers. We
also report that the commercially available RuCl •3H O and PTA
can serve as an in-situ catalyst for the hydration of nitriles
eliminating the need to synthesize and isolate the inorganic
catalyst. The substrate scope, durability and recyclability of the
in-situ catalyst have been explored and compared to
2
PTA
4
,
first
synthesized
by
Darensbourg
and
Introduction
34,35
was reported by our group to be both highly
3
0
Amides are versatile synthetic intermediates in the production of
many commercial (i.e. detergents, lubricants, engineering
plastics) and pharmacological products.1,23 Conventional
methods of nitrile hydration to amides use strong bases or acids
under harsh conditions where undesired overhydrolysis to
carboxylic acids is often observed.1-5 Other drawbacks to
conventional methods include low functional group tolerance
and extensive formation of salts during neutralization that can
lead to contamination, pollution, and separation problems.1,3,4 An
2
4
]
3
2
2 4
[RuCl PTA ].
attractive
heterogeneous
alternative
method
is
homogenous1-4,6
or
7
,8,9-11
metal catalyzed nitrile hydration. With water
Results and Discussion
as a reagent, and many of the product amides having modest
water solubility, nitrile hydration is well suited towards aqueous
phase catalysis.2
2 4 3
Scheme 1. Synthesis of [RuCl PTA ] from RuCl and PTA.
Ruthenium complexes have been utilized as efficient and
versatile catalysts for nitrile hydration to amides.1,12-17
Ruthenium(II) and Ru(IV) complexes with nitrogen-containing
6
phosphine ligands (e.g. [RuCl
2
(η -arene)(P(NMe
2
)
3
)]) have
9,13-22
shown significant activity for nitrile hydration.
The relatively simple synthesis34,35 and high activity of
RuCl PTA ] as a catalyst for the hydration of nitriles prompted
us to investigate utilizing RuCl and PTA as an in-situ generated
catalyst. The synthesis of [RuCl
RuCl
[
2
4
[
a]
Dr. W.L. Ounkham, Dr. J.A. Weeden, Prof. B.J. Frost
Department of Chemistry
University of Nevada, Reno
3
2
PTA
4
] involves the reaction of
1
664 N. Virginia St, Reno, NV 89557-0216 (USA)
27
3
hydrate with 6 equivalents PTA in ethanol (Scheme 1).
E-mail: Frost@unr.edu
The first step in looking at an in-situ generated catalyst based on
RuPTA Cl ] was exploring the effect of [PTA] on activity.
[
4
2
Supporting information for this article is given via a link at the end of
the document.
Optimization for the in-situ catalyzed hydration of nitriles was
carried out at 100 °C in water with 1 mmol benzonitrile in a
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Chemistry - A European Journal
10.1002/chem.201902224
FULL PAPER
culture tube under air utilizing 5 mol% RuCl
3
2
•3H O and varying
[
(
a] Reaction conditions: Benzonitrile (100 μL, 1 mmol), 13.1 mg [RuCl
0.05 mmol), X equivalents PTA, 3 mL water, air, 100 °C. [b] mM PTA = mmol
3 2
•3H O]
the [PTA] from 16.7 to 250 mM (1 – 15 equiv PTA based on
Ru]), Scheme 2. The reaction was monitored using GC-MS
[
PTA/3 mL. [c] 1 equiv PTA= 0.05 mmol, mg PTA in parentheses. [d] %
conversion determined by GC/MS after 7 h, 24 h in parentheses. [e] TOF
calculated between 40-60% conversion. [f] TOF calculated from conversion at
with % conversion calculated after 7 and 24 hours. In general,
as [PTA] increased the % conversion increased, Table 1. A large
jump in conversion from 59% to 90% (7 h) was observed moving
from 5 to 6 equivalents of PTA. Even after a 24 h reaction time
conversion did not reach >99% until at least 6 equiv PTA was
added. The increased reactivity starting at 6 equivalents PTA
7
h. [g] [RuCl
mol% RuCl
RuCl ) 24 h.
2
PTA
4
] used as the catalyst (40 mg, 0.05 mmol, 16.7 mM). [h] 5
3
(13.1 mg, 0.05 mmol) 24 h (no PTA). [i] 0.30 mmol PTA (no
3
(
100 mM) is presumably due to two effects: (a) the change in pH
3+
with [PTA], vide infra; (b) an increased rate of Ru reduction to
Ru2+ and generation of O=PTA with increased [PTA]. Excess
PTA was observed by GC-MS when the >4 equivalents of PTA
was used (> 70 mM). Under our reactions conditions 5 mol%
3
RuCl , and in the absence of PTA, provided a 54% conversion
–1 30
over 24 h at 100 °C (TOF = 0.45 h ). Base is also known to
catalyze the hydration of nitriles;36 however, under our
conditions we observed only ~1% conversion with 100 mM PTA
in the absence of ruthenium over 24 h.
Scheme 2. Nitrile hydration catalysed by an in-situ generated catalyst.
Figure 1. Conversion versus time data for the aqueous phase hydration of 1
mmol benzonitrile by 5 mol% [RuCl PTA ] (blue ▲) or an in-situ catalyst
generated from 16.7 mM RuCl and 4 (red ✻), 6 (black ꢀ), 10 (purple ◆), or
5 (green ●) equivalents of PTA in 3 mL water at 100 °C.
2
4
Table 1. Effects of [PTA] on in-situ catalyst performance to benzonitrile
hydration.[
a]
3
1
equiv PTA[c]
PTA], mM[b]
% Conv.[d]
TOF(h )
–1 [e]
[
(mg PTA)
Plots of benzonitrile conversion to benzamide versus time
utilizing an in-situ generated catalyst of 5 mol% RuCl •3H O with
, 6, 10, and 15 PTA equivalents may be found in Figure 1. An
1
3
4
6
8
6.7
3.3
9.9
6.7
3.4
1 (7.85)
42 (81)
36 (93)
39 (93)
37 (95)
59 (92)
90 (99)
99
1.3
0.5[f]
1.1[f]
1.1[f]
1.7
3
2
2 (15.7)
3 (23.5)
4 (31.4)
5 (39.3)
6 (47.1)
7 (55.0)
8 (62.8)
9 (70.7)
4
induction period was observed for 4, 6 and 15 PTA equivalents
which can be attributed to delayed catalyst assembly. Catalytic
activity of 10 PTA/Ru (along with 8 and 12 PTA/Ru see SI) was
faster than RuCl PTA with 99% conversion after 2-3h. Nitrile
2
4
hydration with 6 equivalents of PTA was slightly slower than
100.0
116.7
133.3
150.1
3.4
[
RuCl
2
PTA
4
] completing at 7h vs 6h. TOFs, measured between
2.8[f]
5.6
-1
4
0-60% conversion, of 7.1, 1.1, 3.4, 5.6, 8.0, 8.1, and 5.3 h
were observed for [RuCl PTA
0[PTA], 12[PTA], and 15[PTA], respectively. The activity of
99
2
4
], 4[PTA], 6[PTA], 8[PTA],
1
99
2.8[f]
8.0
[
RuCl
equivalents of PTA. Since the synthesis of [RuCl
RuCl •3H
2
PTA
4
] in water is similar that that of RuCl
3
with 6-8
] utilizes
1
67
00
50
10 (78.5)
12 (94.8)
15 (117.8)
-----
99
2
PTA
4
3
2
O and 6 equiv PTA we decided to utilize 6 equiv PTA
2
2
99
8.1
for all additional studies below.
99
5.3
][g]
pH Effects
[
RuCl
2
PTA
4
99
7.1
The structure and activity of PTA complexes may also be
impacted by pH.26,37-42 Protonation of PTA at nitrogen leads to
an acid with a pKa of ~5.7.43 When coordinated to a metal center
[
h]
(54)[30]
0 (1)
RuCl
3
-----
0.45
-----
00.0[i]
1
6 (47.1)
(P bound), or oxidized, protonated PTA is reported to have a
pKa between 4.69 and 2.12 the latter of which is the pKa of
protonated O=PTA.26,43 Knowing that pH has an effect on nitrile
hydration, with higher pH levels generally leading to higher rates
of reaction, we looked at how [PTA] with and without RuCl
3
altered the pH of aqueous solutions (Table 2). As the [PTA]
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Chemistry - A European Journal
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FULL PAPER
increased the pH increased from a pH of 6.67 for DI water to
To provide analogous reaction conditions for the comparison of
8
0
.68 for an aqueous solution of 200 mM PTA (12 equivalents,
.60 mmol). The same trend was observed for aqueous
3 2 4
the in-situ catalyst (RuCl + 6 PTA) and [RuCl PTA ] we
evaluated the in-situ catalyst in three phosphate buffer solutions:
pH 4.92, pH 6.8, and pH 9.8, Figures 2. At pH 4.92, catalytic
activity is initially sluggish then steadily increases reaching a
90% conversion after 8h. Catalytic activity increases significantly
at pH 6.8, reaching >99% conversion in 3-4 h with little to no
induction period observed. The fastest catalytic activity is
observed at pH 9.8 where the reaction goes to completion in 10-
solutions containing 16.7 mM RuCl
of PTA (Table 2). Interestingly, the pH of a 16.7 mM aqueous
solution of [RuCl PTA ] was higher (pH = 5.21) than the pH of
the in-situ generated catalyst made with 16.7 mM RuCl and 100
mM PTA (pH = 4.77). This is presumably due to the reduction of
Ru(III) to Ru(II) with PTA generating O=PTA and HCl.
3
•3H
2
O with varying amounts
2
4
3
1
5 minutes. No catalytic hydration of benzonitrile to benzamide
was observed in the absence of the catalyst in the pH 4.92 and
.8 phosphate buffer solutions. Hydration of benzonitrile was
6
Table 2. Effect of [PTA] and RuCl
3
on the pH of water.[a]
observed in pH 9.8 buffer affording a 72% conversion after 2h in
the absence of ruthenium or PTA. The reaction rate is faster at
higher pH, presumably due to increased [OH–].14 Hydration of
benzonitrile proceeds efficiently in pH 6.8 buffer which was
utilized for additional studies. The pH 6.8 phosphate buffer,
absent a catalyst, does not hydrate nitriles under our reaction
conditions.
Similar to the studies conducted in water, we looked at the effect
of [PTA] on the in-situ catalyzed nitrile hydration in pH 6.8 buffer.
Under identical reaction conditions, 2, 3, 4, 6, and 10
equivalents of PTA (33.3 mM – 167 mM) along with 16.7 mM
Equiv PTA
[PTA]
mM
0
RuCl
mM (mmol)
3
pH
[b]
(
mmol)
0
0
0
0
0
0
0
0
0
6.67
8.36
8.45
8.54
8.56
8.61
8.64
8.68
1.56
3.90
4.77
5.41
5.70
6.04
6.20
6.28
5.21
(0.20)
(0.30)
(0.35)
(0.40)
(0.45)
67
100
117
133
150
167
200
0
16.7 (0.05)
16.7 (0.05)
16.7 (0.05)
16.7 (0.05)
16.7 (0.05)
16.7 (0.05)
16.7 (0.05)
16.7 (0.05)
-
4
6
7
8
9
(0.20)
(0.30)
(0.35)
(0.40)
(0.45)
67
3
RuCl (5 mol% cat) were examined in pH 6.8 phosphate buffer,
100
117
133
150
167
200
-
Figure 3. The catalytic activity increased as the [PTA] increased.
No obvious induction period was observed above 3 equivalents
of PTA. The initial rate (at ~ 1 h) of at 4, 6, and 10 equivalents of
-
1
PTA were similar with TOF values of 9.0, 9.7, and 9.5 h ,
respectively. In plain water, the in-situ catalyst with 10
equivalents of PTA demonstrated greater catalytic activity (TOF
1
1
0 (0.50)
2 (0.60)
[
RuCl
2
PTA
4
][c]
-1
-1
=
8.0 h ) than [RuCl
likely due to the pH differences of [RuCl
mixture of RuCl and 10 PTA (Table 2); when under constant pH
using a pH 6.8 buffer solution, RuCl PTA displayed greater
4
catalytic activity. Benzonitrile hydration catalyzed by [RuCl PTA ]
2
PTA
4
] (TOF = 7.1 h ). This difference is
[
[
(
a] Conditions: 3 mL H
RuCl •3H O] (0.05 mmol, 16.7 mM); [c] 40 mg [RuCl
0.05 mmol, 16.7 mM) in 3mL H O.
2
O at room temperature; [b] 13.1 mg
2
PTA ] in water versus a
4
3
2
2
PTA ]
4
3
2
2
4
2
is faster than the in-situ generated catalyst reaching completion
between 1 and 1.5 h with a TOF of 19.1 h-1 at 1 h (95%
conversion).
Figure 2. Conversion versus time data for the hydration of benzonitrile by an
in-situ generated catalyst made from 16.7 mM RuCl and 100 mM PTA carried
3
out in pH 4.92, 6.8, and 9.8 phosphate buffer solution. Each data point is a
separate reaction of 1 mmol benzonitrile in 3 mL pH buffer, 5 mol% catalyst,
under air at 100°C with conversions determined by GC-MS.
Figure 3. Conversion versus time data for the aqueous phase hydration of 1
mmol benzonitrile in pH 6.8 phosphate buffer by 5 mol% [RuCl PTA ] (red ꢀ)
2 4
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Chemistry - A European Journal
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FULL PAPER
3
or an in-situ catalyst generated from 16.7 mM RuCl and 2 (orange ●), 3 (light
blue ✻), 4 (black ●), 6 (green ▲), or 10 (dark blue ◆) equivalents of PTA in 3
mL water at 100 °C in air.
Table 3. Substrate scope of nitrile hydration using the 5 mol% RuCl
3
and
6
PTA in-situ generated catalyst in water and pH 6.8 aqueous phosphate
In all the nitrile hydration reactions described here only the
corresponding amides were observed (e.g. no carboxylic acids
[a]
buffer.
Conv[b]
%)
Yield
(%)
TOF
[e]
Conv[b] Yield TOF
[e]
or other by-products).
A wide synthetic scope has been
-
1
-1
(
(h )
(%)
(%)
(h )
established with our reaction conditions compatible with variety
of functional groups such as nitro, bromo, hydroxyl, pyridyl, and
alkyl, Tables 3 and 4. The conversion of various nitriles to the
corresponding amides in water and pH 6.8 buffer using the in-
situ catalyst was explored and summarized in Table 3. Similar to
Substrate
Water
pH 6.8 buffer
c
c
c
91c
67
71c
[g]
[g]
PhCN
99
93
94
83
82
85
2.8
2.5
2.8
2.8
2.5
2.8
0.97
0.91
99
99
99
99
99
99
99
99
16(48)
78(99)
4.0
4.0
d
o-MeC
m-MeC
p-MeC
p-MeOC
p-NO
p-BrC
p-HOC
py-CN
C H CN
6
H
4
CN
87 (99)
98 (99)
98 (99)
86 (99)
98 (99)
34 (95)
32 (99)
11 (57)
13 (78)
[h]
[h]
[h]
6
H
4
CN
CN
5.0
5.0
5.0
6.6
5.3
previously reported for [RuCl
2
PTA
4
], all nitriles were efficiently
d
d
6
H
4
68
converted to amides in water with 11-99% conversion (TOF =
d
d
6
H
4
CN
CN
CN
CN
80
-
1
0
.5–2.8 h ) in 7 h using the in-situ catalyst. In pH 6.8 buffer,
hydration of nitriles by [RuCl PTA resulted in 37-99%
conversion (TOF = 0.5 - 13.2h ) in 7 h (Table 4) compared to
85c
89c
[i]
[i]
2
C
6
H
4
2
4
]
d
d
6
H
4
69
80
-1
91c
c
c
c
6
H
4
94
29
87
2.8
0.45
2.2
-
1
1
(
[
6-99% conversion (TOF = 0.4 – 6.6 h ) for the in-situ catalyst
Table 3). No decomposition was observed for either
RuCl PTA ] or the in-situ catalyst at 100°C in air. After catalysis
c,f
[f]
2
49
0.5
69c,f
0.65[f]
7
15
2
4
[
3 2
a] Reactions conditions: nitrile (1 mmol), [RuCl •3H O] (13.1 mg, 0.05
the solutions were cooled to 0 °C and, in most cases, the
product amides precipitated out and were isolated in good yield
mmol) + 6 PTA (47.1 mg, 0.3 mmol), 3 mL pH 6.8, in air at 100°C; [b]
conversion (%) calculated by GC-MS at 7h (24 in parentheses); [c]
Isolated by column chromatography; [d] Isolated by decantation; [e] TOF
= mol product/(mol cat. × h) based on % conversion at 7h, [f] 24h, [g] 5 h,
(60-85 %) via decantation or up to 94% isolated by traditional
column chromatography. Slightly more efficient conversion to
the amides was observed with benzonitriles containing electron-
withdrawing group versus electron-donating substituents (Table
[
h] 4 h, [i] 3 h.
3). As found in other nitrile hydration reactions the nitrile carbon
seems to become more susceptible to nucleophilic attack in the
presence of an electron-withdrawing group.13,14,44 Ortho-
4 2
Table 4. Substrate scope of nitrile hydration using 5 mol% [RuPTA Cl ]
catalyst in water and pH 6.8 aqueous phosphate buffer.
[a]
substituted
benzonitriles,
o-tolunitrile,
displayed
lower
Conv[b] Yield TOF
[e]
Conv[b]
(%)
Yield
(%)
TOF
[e]
conversion relative to m- and p-tolunitriles (Tables 3 and 4).
Conversion versus time plots for the hydration of o-, m-, and p-
tolunitrile reveal that for all solvent systems o-tolunitrile reacts at
a slower rate than the meta or para substituted analogues,
Figures 4 and 5 and SI.27 This is attributed to steric hindrance of
o-tolunitrile indicating coordination of nitrile to the metal center is
necessary for activation. For both the in-situ catalyst and
-
1
-1
(
%)
(%)
(h )
(h )
Substrate
Water27
pH 6.8 buffer
91[c]
75[c]
[f]
PhCN
99
2.8
2.4
2.7
2.8
99
99
99
99
4.0
4.0
[d]
[d]
[f]
o-MeC
m-MeC
p-MeC
p-
MeOC
p-NO
p-BrC
p-HOC
py-CN
6
H
4
CN
83 (99)
96 (99)
97 (99)
67
60
84[c]
94[c]
[g]
6
H
4
CN
CN
11.3
11.3
[d]
[d]
[g]
6
H
4
77
81
2
[RuCl PTA
4
]
hydration of cyanopyridine was sluggish,
90 (99)
78[d]
2.6
99
85[d]
13.2[h]
presumably due to the ability of the substrate to coordinate to
the metal center. Slower catalytic activity for the in-situ catalyst
may be attributed to the pyridine nitrogen coordinating to Ru and
inhibiting the catalyst from being assembled in solution.
6
H
4
CN
86[c]
87[c]
[h]
2
C
6
H
4
CN
99
99
89 (99)
43 (81)
72 (99)
2.8
2.8
2.5
1.2
2.1
99
99
99
37(62)
79(99)
13.2
13.2
[d]
[d]
[h]
6
H
4
CN
CN
73
65
[c]
[c]
[c]
[c]
6
H
4
90
72
88
83
57
83
2.8
1.1
2.2
[
c]
c]
2
[
7
C H15CN
[
a] Reactions conditions: nitrile (1 mmol), [RuCl
3 2
•3H O] (13.1 mg, 0.05 mmol)
+
6 PTA (47.1 mg, 0.3 mmol), 3 mL pH 6.8, in air at 100°C; [b] conversion (%)
calculated by GC-MS at 7h (24 in parentheses); [c] Isolated by column
chromatography; [d] Isolated by decantation; [e] TOF = mol product/(mol cat.
×
h) based on % conversion at 7h, [f] 5 h, [g] 1.5 h, [h] 1.75 h.
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Chemistry - A European Journal
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Table 5. Nitrile hydration of benzonitrile catalysed by [RuCl
2 4
PTA ] or the
in-situ catalyst (RuCl + 6 PTA) at 80 °C in water or pH 6.8 phosphate
3
[a]
buffer.
mol%
Cat.
5
5
5
5
1
1
Catalyst
Solvent
% Conv.
24 h
48.5
32.9
99
TOF
% Conv.
48 h
99
99
-
-
99
90
98.9
TOF
(h )
0.4
0.4
-
-
1
-1
(h )
0.4
0.3
0.9
0.8
2.2
1.8
2.4
2.1
2
RuCl PTA
4
4
4
4
water
water
pH 6.8
pH 6.8
water
water
pH 6.8
pH 6.8
in-situ
2
RuCl PTA
in-situ
99
-
2
RuCl PTA
53.1
42.6
56.4
51.4
2.1
1.9
2.1
1.8
in-situ
1
1
2
RuCl PTA
in-situ
86.5
[
a] Reaction conditions: benzonitrile (100 μL, 1 mmol), 3 mL water, in air
at 80 °C.
Figure 4. Conversion versus time data for the hydration of o-, m-, and p-
tolunitrile by [RuCl
2
PTA
4
] in pH 6.8 phosphate buffer solution: 1 mmol nitrile in
The durability and longevity of the in-situ generated catalyst
3
mL solution,
5 mol% catalyst, under air at 100°C with conversions
3
(RuCl + 6 PTA) was evaluated by reducing the catalyst loading
determined by GC-MS.
down to 0.001 mol% (Table 6) in both water and pH 6.8
phosphate buffer. Studies were conducted in pH 6.8 buffer with
[
2 4
RuCl PTA ] and compared to the previously reported data in
Temperature studies: One way to further improve the greenness
of the reaction was to reduce the temperature. We explored the
water, Table 7. For both catalytic systems the TOF were higher
in pH 6.8 buffer versus plain water and the TOF increased as
the catalyst loading was reduced from 5 to 1 to 0.1 mol %. The
effect of lower temperature (80 °C) using both [RuCl
the in-situ catalyst (RuCl + 6 PTA) in both water and pH 6.8
phosphate buffer at 1 and 5 mol % catalysts loading, Table 5. At
0 °C the reactions take 24-48 h to reach completion (versus < 7
h at 100 °C). Hydration in pH 6.8 buffer at 80°C with 5 mol %
catalyst reached 99% conversion after 22 h for [RuCl PTA
TOF = 0.9 h ) and 24 h for in-situ (TOF = 0.8 h ). The reaction
2 4
PTA ] and
3
[RuCl
2 4
PTA ] catalyst reacts faster than the in-situ generated
-1
catalyst in water or pH 6.8 buffer. A TOF of 39 h in water and
8
1
34.5 h-1 in pH 6.8 buffer was observed for [RuCl
2 4
PTA ]
hydration and a TOF of 36.2 h in water and 63.5 h-1 in pH 6.8
-1
2
4
]
buffer was observed for the in-situ catalyst at 0.1 mol % catalyst
1
1
(
loading. With the TOF mentioned above [RuCl
situ catalyst (RuCl /6PTA) are not as active as some other
catalysts. High TOF for other metal complexes like [cis-
Ru(acac) (PPh py) have been observed for hydration of
benzonitrile in 1,2-dimethoxyethane (DME) under an inert
atmosphere of argon (TOF = 20,900 h at 180 °C). The
hydration of acetonitrile in tetrahydrofuran (THF)/water was
reported to have a TOF of 318 h-1 at 40 °C (TON 12,712)
2 4
PTA ] and the in-
-1
took close 48 h to reach completion in water (TOF = 0.4 h ).
With 1 mol % catalyst the TOF were higher, but only 42–56 %
conversion was obtained after 24 h for either catalyst or solvent
system.
3
2
2
2
]
-1
45
4
6
utilizing [(DPPF)PtCl(PMe
reported that [(η -arene)RuCl(κ -PTA-CPh
2
OH)]OTf as the catalyst. We have
6
2
2
NHPh)]Cl can reach
TOF of 285 h-1 at 100 °C for the hydration of benzonitrile;
however, this catalyst sustained significant decomposition under
our reactions conditions.31 Other systems such as [(η6-
2 2 3
arene)RuCl P(NMe ) ] have shown impressive reactivity and are
synthesized from commercially available materials with TOF up
to 11,400 h-1 utilizing MW irradiation (150 °C).12,47 In our view the
utility of the catalyst systems described in this paper are
simplicity of the reactions, air tolerance, commercial availability
of all reagents, and the facile separation of the product.
Figure 5. Conversion versus time data for the hydration of o-, m-, and p-
tolunitrile in pH 6.8 buffer by an in-situ generated catalyst made from 16.7 mM
3
RuCl and 100 mM PTA: 1 mmol nitrile in 3 mL solution, 5 mol% catalyst,
under air at 100°C with conversions determined by GC-MS.
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Chemistry - A European Journal
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(90% yield with excess product versus 99% yield) on the
Table 6. Summarized results of reduced catalyst loading for benzonitrile
hydration catalyzed by the in-situ generated catalyst from RuCl
water and pH 6.8 phosphate buffer.
3
+ 6 PTA in
2 4
hydration of p-methozybenzonitrile with [RuCl PTA ] and little to
no effect on the activity of the in-situ catalyst (See SI for further
details).
Nitrile hydration catalysts often display a reduction in activity in
the presence of cyanide, a particular problem with the hydration
of cyanohydrins.1,46 Tyler and coworkers conducted a potassium
cyanide (KCN) poisoning study with a variety of nitrile hydration
[a]
Time
Conv.[b]
(%)
TOF[d]
Catalyst
TON[c]
Solvent
(mol %)
-1
(h)
(h )
water
pH 6.8
water
5
5
7
99
98
19
19
2.8
4
4
1
4
85
83.7
20.9
24
1
5,21
catalysts.
[
In the case of acetonitrile hydration catalyzed by
(P(NMe )] the reaction rate increased
pH 6.8
water
1
4
98
96.3
6
(η -p-cymene)RuCl
when 1 equiv of CN was added and decreased with increasing
CN–].15 This rate increase was attributed to the formation of [(η6-
2
2 3
)
0.1
0.1
0.001
0.001
23.5
7
85
951
36.2
63.5
4.5[f]
9.1[f]
–
pH 6.8
water
44
444.8
10100[f]
20500[f]
[
2250
2250
10.1[e]
20.5[e]
2 3
p-cymene)RuCl(CN)(P(NMe ) )] altering the electronics of the
metal center and increasing the electrophilic nature of the metal
coordinated nitrile.21 The effect of cyanide on the catalytic
pH 6.8
[
a] Reaction conditions: benzonitrile (1 mmol, 0.33 M; 20 mmol nitrile for 0.1
2 4 3
activity of [RuCl PTA ] and the in-situ catalyst [RuCl + 6 PTA]
and 0.001 catalyst loading), solvent (3 mL), 100°C, in air; [b] Determined by
GCMS (isolated yields in parentheses); [c] TON = (moles product)/(moles
catalyst); [d] TOF = (moles product)/(moles catalyst x h); [e] Isolated by
column chromatography; [f] based on isolated yield.
was examined. KCN was added into the solution prior to heating
the reaction at 100°C. If the cyanide was binding to the metal
center, rate inhibition and eventual cease of activity should be
observed since cyanide coordination is irreversible in
solution.15,21 No decrease in % conversion was observed with up
to 6 equivalence KCN (30 mol %) demonstrating the ability of
these catalysts to tolerate excess cyanide and possibly other
salts in solution without significant activity lost (see supporting
information for more detail). The tolerance for cyanide makes
Table 7. Summarized results of reduced catalyst loading for benzonitrile
30
[a]
hydration catalyzed by [RuCl
2
PTA
4
] in water and pH 6.8 phosphate buffer.
Time
Conv.[b]
(%)
TOF[d]
Catalyst
TON[c]
Solvent
(mol %)
-1
(h)
(h )
2
[RuCl PTA
4
]
potentially appealing for the hydration of
water
pH 6.8
water
5
5
7
99
99
87
99
19.8
20
2.8
6.6
cyanohydrins used for the synthesis of methacrylates.
3
Mechanism
1
7
87
12.4
24.5
39
The induction period observed in the in-situ catalysed reactions
and the similarity in reactivity to [RuCl PTA) ] (and the
2 4
straightforward synthesis) leads us to the conclusion that the
active catalyst for both catalyst systems is very similar (if not the
same). Based on previous reports and discussion on the
pH 6.8
water
1
4
97.8
916.4
0.1
0.1
0.001
0.001
91.2[e]
2
3.5
7
pH 6.8
water
94[e]
941
134.5
(22)[e]
(22)[e]
22000[f]
9.5[f]
2
2
328
250
behaviour of [RuCl
are many species likely present at 100 °C such as
RuCl(H O)(PTA O)(OH)(PTA (PTA )],
)]+, [Ru(H )]+, [Ru(OH)
and a series of [Ru(H
)]2+ substitutional isomers.
Nitrile hydration is often proposed to proceed with initial
2 4
PTA) ] and related complexes in water there
pH 6.8
22000[f]
9.8[f]
[
2
4
2
4
2
4
[
a] Reaction conditions: benzonitrile (1 mmol, 0.33 M; 20 mmol nitrile for 0.1
O)6-n(PTA
2 n
and 0.001 catalyst loading), solvent (3 mL), 100°C, in air; [b] Determined by
GCMS (isolated yields in parentheses); [c] TON = (moles product)/(moles
catalyst); [d] TOF = (moles product)/(moles catalyst x h); [e] Isolated by
column chromatography; [f] based on isolated yield.
27,30,48,49
nitrile coordination to the metal center,1 in these systems
coordination is proposed to occur through ligand substitution of a
chloride. The slower reactivity of o-tolunitrile (Figures 4-5)
We utilized
homogeneous catalysed nitrile hydration reaction catalysed by
either [RuCl PTA ] or the in-situ generated catalyst. Metallic
mercury (~1 g) was added to the reaction vessel prior to heating
to 100 °C. Any colloidal ruthenium was expected to be absorbed
by the mercury and if heterogeneous a reduction in the
conversion of benzonitrile to amide would be expected. There
was no decrease in % conversion observed for either catalyst in
water or pH 6.8 phosphate buffer indicating that both systems
are likely classified as homogeneous catalysts.
a mercury test to provide evidence for a
2 4
supports this mechanism. Reaction of [RuCl PTA) ] with
benzonitrile resulted in the isolation of a yellow powder with
multiple 31P{ H} NMR signals, but consistent with a series of
2
4
1
complexes
of
Ru(OH)(PhCN)PTA)
RuCl(H O)(PhCN)(PTA
the
type
4
[RuCl(PhCN)PTA) ]Cl,
2
+
[
[
4
]Cl,
[Ru(H
2
O)(PhCN)(PTA
4
)] ,
)]+ etc. Products observed by P{ H}
31
1
2
3
NMR spectroscopy from nitrile hydration reaction solutions
catalysed by [RuCl PTA) ] include or are consistent with O=PTA,
PTA, [Ru(PTA) (H O)
PTAH+, (PhCN)3-n)]2+,
Ru(PTA) (PhCN)2-n)] , [Ru(PTA) (H O)
(PhCN)4-n)]2+
see supporting information).
Recyclability
Recyclability of the in-situ generated catalyst was comparable
with the previously reported [RuCl PTA
].30 The in-situ catalyst
was recyclable up to seven times without significant loss of
2
4
3
2
n
2
+
[
(
4
(H
2
O)
n
2
2
n
2 4
The catalyst activity for both the in-situ and [RuCl PTA ] catalyst
3
0
was further studied with a product inhibition experiment. The
effects of excess product in the system was investigated by
adding benzamide to the reaction vial for the hydration of p-
methoxybenzonitrile. The presence of excess product
2
4
(benzamide) in the reaction mixture had a slight negative impact
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Chemistry - A European Journal
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FULL PAPER
2 4
Figure 6. Kinetic plot of benzonitrile hydration by [RuCl PTA ] and in-situ
catalytic activity or selectivity for benzonitrile hydration, Table 8.
The recycling experiments were conducted by cooling down the
generated catalyst in water and pH 6.8 phosphate buffer over time.
Conversions were determined by GC-MS. Each data point is a separate
reaction. Reaction conditions: benzonitrile (100 μL, 1 mmol) with in-situ
7h reaction overnight, carefully transferring the aqueous
supernatant containing the catalyst to another reaction tube and
adding fresh nitrile. The precipitated amide product was washed
with cold water and isolated. Conversion was >99% in all cases.
Isolation of the product, after the first cycle afforded, low yields
3 2
catalyst: [RuCl •3H O] (13.1 mg, 0.05 mmol) and PTA (47.1 mg, 0.3 mmol) or
preformed catalyst: [RuCl
air.
2 4
PTA ] (40 mg, 0.05 mmol), solvent (3 mL), 100°C, in
(
18%) for both preformed and in-situ generated catalyst in water.
Conclusions
A higher isolated yield (64%) was recovered from the in-situ
generated and preformed catalyst in pH 6.8 buffer solution for
the initial reaction cycle presumably due to a salting out effect of
the amide by the phosphate buffer. Overall, the in-situ generated
catalyst demonstrated similar recyclability abilities as the
preformed catalyst as observed by the isolated yields.
The nitrile hydration catalysis described here incorporates many
green chemistry principles; it is catalytic, recyclable, utilizes a
benign solvent (water), 100 % atom efficient, and minimizes the
use of auxiliary solvents (e.g. product can in many cases be
separated via decantation). The efficient and recyclable in-situ
3 2
catalytic system (RuCl •3H O and 6 PTA) converts nitriles to
amides with tolerance of air and a broad substrate scope. The
advantages of the in-situ catalyst include no prior catalyst
preparation, use of commercially available materials, catalyst
recyclability, use of a benign solvent (water), and in some cases,
easy product separation (decantation). The in-situ catalyst
exhibited comparable catalytic activity, substrate scope,
durability, and recyclability to the “preformed” catalyst
Table 8. Recycling of [RuCl
for the hydration of benzonitrile in water and pH 6.8 buffer.
2 4 3
PTA ] and in-situ (RuCl + 6 PTA) catalysts
[a]
catalyst
Recycling experiment[b]
1
2
3
4
5
6
7
[
2
RuCl PTA
4
]
2 4
[RuCl PTA ], figure 6. Both catalyst systems were found to be
behave as homogeneous catalysts with highest activity
observed in pH 6.8 buffer. The in-situ catalyst did exhibit a slight
induction period.
9
18)
9
99
(53)
99
99
99
99
99
99
H
2
O27
[
c]
(
(89) (55) (61) (52) (66)
99 99 99 99 99
(80) (78) (81) (64) (76)
9
9
pH 6.8 buffer
(63)
(75)
3
RuCl + 6 PTA (in-situ catalyst)
Experimental Section
9
6
99
(79)
99
99
(86) (75) (83) (69) (75)
99 99 99 99 99
(80) (77) (74) (73) (71)
99
99
99
99
2
H O
(
9
18)
9
Materials and Methods: All manipulations were preformed in air.
Solvents (water, dichloromethane, diethyl ether, ethyl acetate, methanol)
were used as received without further purification or degassing. All
commercially available reagents: benzonitrile, o-tolunitrile, m-tolunitrile,
p-tolunitrile, methoxybenzonitrile, p-cyanophenol, p-nitrobenzonitrile, p-
bromobenzonitrile, cyanopyridine, heptyl cyanide, ruthenium trichloride
trihydrate, and deuterated NMR solvents were used as received. 1,3,5-
pH 6.8 buffer
(64)
(64)
[
a] Reaction conditions: Benzonitrile (100 μL, 1 mmol), 5 mol % catalyst,
solvent (3 mL), 7 h, 100°C, air; [b] % conversion determined by GCMS
isolated yields obtained via decantation in parentheses); [c] A 93 %
isolated yield can be obtained by extracting with CH
evaporating to dryness.
(
2 2
Cl (3 mL x 5) and
triaza-7-phosphaadamantane (PTA)50
synthesized as reported in the literature.
and
[RuCl
PTA
]27
were
2
4
Instrumentation and Procedures: GC-MS analyses were obtained
using Varian CP 3800 GC (DB5 column) equipped with a Saturn 2200
MS and a CP 8410 auto-injector or an Agilent 7890A GC equipped with
an Agilent 5975C inert MSD with triple axis detector and Agilent 7693
autosampler. NMR spectra were recorded with Varian Unity Plus 500 FT-
NMR or Varian NMR System 400 spectrometer. 1H and 13C{ H} NMR
spectra were referenced to residual solvent relative to tetramethylsilane
1
(TMS). pH measurements were made using a Mettler Toledo pH meter.
General procedure for the catalytic nitrile hydration: All hydration
reactions were prepared under air in a Telfon-sealed screw cap culture
tube. To a typical culture tube 1 mmol nitrile, 3 mL water or pH 6.8
phosphate buffer solution, 5 mol% [RuCl
2 4
PTA ] (40 mg) or RuCl
3 2
•3H O
(13.1 mg) and 47.1 mg PTA (6 equiv) was added to a Telfon-sealed
screw-cap culture tube along with a magnetic stir bar. The tubes were
heated in an oil bath and stirred at 100 C for 7h. GC yields were
obtained by removing a small aliquot (~50 μL) from the hot solution and
extracting with CH
2 2
Cl (2 mL × 3) and analysing by GC-MS. Isolated
yields were obtained by either decanting the aqueous layer from the
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Chemistry - A European Journal
10.1002/chem.201902224
FULL PAPER
product crystals or by evaporation of the solvent followed by column
chromatography over silica gel using ethyl acetate as eluent. Amide
confirmation was assessed by comparison to their 1H and 13C{ H} NMR
spectroscopic data reported in literature as well as their retention time
and fragmentation from GC-MS with an authentic sample.
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[
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FULL PAPER
The activity of an in-situ
Nitrile hydration
generated catalyst from the
commercially available RuCl
and PTA is compared to
Whalmany L. Ounkham, Jason,
A. Weeden, Brian J. Frost*
3
[
2 4
RuCl PTA ] in both water and
Page No. – Page No.
pH 6.8 buffer. Both are active,
air stable, recyclable, cyanide
tolerant aqueous phase nitrile
hydration catalysts
Aqueous phase nitrile
hydration catalyzed by an in-
situ generated air stable
ruthenium catalyst
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