Hydration of Aliphatic Nitriles Catalyzed by an Osmium Polyhydride: Evidence for an Alternative Mechanism

Evidence for an Alternative Mechanism

Article

Hydration of Aliphatic Nitriles Catalyzed by an Osmium Polyhydride:

Juan C. Bab ó n, Miguel A. Esteruelas,* Ana M. L ó pez, and Enrique Onate

Cite This: https://doi.org/10.1021/acs.inorgchem.1c00380

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sı Supporting Information

ABSTRACT: The hexahydride OsH (P Pr ) competently catalyzes

3 2

the hydration of aliphatic nitriles to amides. The main metal species

under the catalytic conditions are the trihydride osmium(IV) amidate

derivatives OsH {κ -N,O-[HNC(O)R]}(P Pr ) , which have been

3 2

isolated and fully characterized for R = Pr and Bu. The rate of

hydration is proportional to the concentrations of the catalyst

precursor, nitrile, and water. When these experimental ﬁndings and

density functional theory calculations are combined, the mechanism of

catalysis has been established. Complexes OsH {κ -N,O-[HNC(O)-

R]}(P Pr ) dissociate the carbonyl group of the chelate to aﬀord κ -

N-amidate derivatives, which coordinate the nitrile. The subsequent

attack of an external water molecule to both the C(sp) atom of the

nitrile and the N atom of the amidate aﬀords the amide and regenerates the κ -N-amidate catalysts. The attack is concerted and takes

place through a cyclic six-membered transition state, which involves C ···O−H···N interactions. Before the attack, the free

nitrile

amidate

carbonyl group of the κ -N-amidate ligand ﬁxes the water molecule in the vicinity of the C(sp) atom of the nitrile.

INTRODUCTION

the product to the carboxylic acid, and exhibits a notable

functional group tolerance.

Aromatic nitriles have been mainly used in a ratio of about

■

Amide functional groups are present in natural and synthetic

products, including some drugs. In addition, amide compounds

ﬁnd industrial application in the production of detergents,

2:1 with respect to aliphatic ones (Table S1). The reactions

have been in an overwhelming preponderance performed in

lubricants, or polymers, among other manufactured goods.

water as the solvent and, to a lesser extent, in alcohols,

Amides have been traditionally prepared by procedures

involving carboxylic acids and amines. However, these

methods generate large quantities of waste, resulting in an

unfavorable environmental proﬁle. As a consequence, alter-

native approaches are being developed using surrogates of both

ethers, or their mixtures with water. Although complexes of

d,10

6a,f,h,j,7a,9,11

metals of groups 6

and 8−11

have proven to be

active for nitrile hydration reactions, more than half of the

r e p o r t e d c a t a l y s t s a r e r u t h e n i u m c o m -

6d,h,j−l,7b,c,8,9a,11b,12

substrates. In this context, nitriles have been proven to serve

pounds,

and the vast majority of them bear

as carboxylic acid alternatives. Thus, several eﬃcient reactions

speciﬁc ligands that enhance the solubility of the complex in

for construction of the amide function have been described

water by means of the formation of hydrogen bonds with

6g,k,8a,b,11e,12b,d,e,g,w

starting from them.

solvent molecules.

The improvement of

Homogeneous catalysts of platinum group metals are

particularly eﬃcient for developing atom-economical pro-

cesses. This fact converts them into one of the most powerful

tools of modern selective organic synthesis, being therefore

catalysts and reaction conditions have mainly been based on

empirical data obtained from trial-and-error methods. Kinetic

a,13

analysis of the reactions,

isolation of the reaction

9a,e,14

intermediates,

study of the catalysis

and a density functional theory (DFT)

especially relevant from an environmental point of view.

9a,12a,15

the three legs of the mechanistic

Among the reactions developed for the synthesis of amides,

nitrile hydration, which leads to primary amides in an atom-

economical manner (eq 1 ), is one of the most elegant reactions

investigationhave received scarce attention. As far as we

know, mechanistic proposals based on the three legs together

Received: February 5, 2021

promoted by this class of catalysts. It works under reasonable

conditions, presents ﬁne control of subsequent hydrolysis of

XXXX American Chemical Society

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Inorganic Chemistry

Article

have not been reported. There is consensus on the enhance-

ment of the electrophilicity of the C(sp) atom of the nitrile, as

a result of coordination to the metal center of the catalyst,

which makes it more susceptible to undergoing the

nucleophilic attack of the hydroxide group of a water molecule,

to form metal amidate intermediates via iminolate species

hydration of aliphatic nitriles (the least studied) in a

conventional organic solvent, we decided to explore its

performance. It bears a usual commercially available ligand,

particularly useful for mechanistic studies, is easily prepared

from OsCl ·xH O, in two steps, in high yield, and is much

more stable and handy than its ruthenium counterpart, the

(Scheme 1). The hydroxide attack can be, however, intra- (a)

dihydride bis(dihydrogen) derivative RuH (η -H ) (P Pr ) .

2 2 2 3 2

We were inspired by the previous reactivity of complex 1

with nitriles. This polyhydride inserts aromatic nitriles to form

trihydride osmium azavinylidene compounds, which activate

molecular hydrogen, pinacolborane, and water to give

Scheme 1. Nucleophilic Attack of the Hydroxide Group to

Coordinated Nitriles

orthometalated phenylaldimine derivatives (Scheme 2a). In

Scheme 2. Reactions of Complex 1 with Aromatic and

Aliphatic Nitriles

contrast, aliphatic nitriles undergo C(sp)−C(sp ) bond

or intermolecular (b and c). In the second case, the water

molecule is activated through hydrogen-bonding interaction

with a ligand of the metal coordination sphere (b) or a remote

heteroatom present in the ligand backbone (c).

activation to yield binuclear complexes (P Pr ) H Os(μ-

CN)OsH (RCN)(P Pr ) (Scheme 2b). Under a hydrogen

atmosphere or in the presence of boranes, C(sp)−C(sp ) bond

activation of the aliphatic nitriles is inhibited, and the catalytic

formation of secondary amines and diborylamines is

observed as a consequence of the respective hydrogenation−

condensation and dihydroboration of the substrates (Scheme

3). We now show that C(sp)−C(sp ) cleavage is also inhibited

in the presence of water. In addition, the catalytic formation of

aliphatic amides takes place according to eq 1.

3 2

Catalysis by complexes of platinum group metals has been

traditionally dominated by 4d elements. However, one of the

most active and versatile catalysts for nitrile hydration is the

platinum complex PtH{(PMe O) H}(PMe OH), reported by

Parkins and co-workers in 1995 and improved by Virgil,

Grubbs, and co-workers for cyanohydrins in 2018. Recently,

Yao and co-workers have also discovered half-sandwich iridium

catalysts, which display excellent activity, under mild

conditions, for a broad scope of nitriles. Osmium is the

less used element in catalysis from the six platinum group

metals, although it has proven to be particularly useful in the

asymmetric dihydroxylation of oleﬁns and reactions similar to

that, some reductions, C−C and C−heteroatom

couplings, and acceptorless dehydrogenation of liquid organic

hydrogen carriers and boranes, whereas complexes [Os-

OH)(η -p-cymene)IPr]OTf [IPr = 1,3-bis(2,6-

Scheme 3. Catalytic Transformations of Aliphatic Nitriles

Promoted by Complex 1

(

diisopropylphenyl)imidazolydene; OTf = CF SO ] and

OsCl (η -p-cymene)(PMe OH) promote nitrile hydration

in water/2-propanol and water, respectively.

The osmium chemistry is rich in hydride complexes, which

This paper reports a catalyst for the hydration of a wide

range of aliphatic nitriles, which works with high eﬃciency

under reasonable conditions, and the catalytic mechanism

based on kinetic analysis of the catalysis, isolation of the key

intermediate, and a DFT study. In addition, it demonstrates

that sophisticated ligands favoring the formation of hydrogen

bonds with water molecules are not necessary because the true

are further playing a relevant role in catalysis. Among them,

the d hexahydride species OsH (P Pr ) (1) occupies a

3 2

prominent place because of its ability to activate σ bonds,

which converts it in one of the keystones in the development

of the modern osmium organometallic chemistry. In the search

for a catalyst that could work with high eﬃciency for the

Inorg. Chem. XXXX, XXX, XXX−XXX

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Article

catalysts of the hydration are amidate species generated in situ,

under the reaction conditions, and they can generate the

hydrogen bonds.

Scheme 4. Hydration of Aliphatic Nitriles Catalyzed by 1

Reaction Conditions and Scope. Initially, we looked for

the optimal reaction conditions to obtain the amides with a

high yield in a general manner, using 0.31 M solutions of

acetonitrile, in deuterated tetrahydrofuran (THF-d ) under an

argon atmosphere, contained in a NMR tube. Results of the

optimization involving the catalyst loading, water amount, and

temperature are collected in Table 1.

Table 1. Optimization of the Catalytic Hydration of

Aliphatic Nitriles

entry

1 (mol %)

T (°C)

H O (equiv)

yield (%)

100

Reaction conditions: acetonitrile (0.14 mmol) in THF-d (450 μL)

for 3 h. Yields were calculated by H NMR spectroscopy using

mesitylene as an internal standard.

Acetonitrile was transformed in acetamide in 43% yield after

h in the presence of 1 mol % complex 1 and 20 equiv of

water at 100 °C (entry 1). The raising of the catalyst loading

up to 2 mol % increases the yield of the reaction to 52% (entry

2), which undergoes a new increment up to 72% by increasing

the amount of catalyst precursor to 5 mol % (entry 3).

Lowering the temperature just to 80 °C results in a drastic

decrease in the amount of acetamide down to 34% (entry 4).

Similarly, reduction of the number of water equivalents to 10

lowers the yield of the reaction to 55% (entry 5), whereas the

increment of the water amount up to 50 equiv increases the

yield of amide up to 80% (entry 6). Under these conditions,

the reaction does not progress in the absence of a catalyst

precursor (entry 7). Thus, we decided to carry out the

hydration of nitriles under the conditions of entry 6, i.e., using

Reaction conditions: Corresponding nitrile (0.14 mmol), water (125

μL, 7.0 mmol), 1 (3.6 mg, 0.007 mmol, 5 mol %) in THF-d (450 μL)

at 100 °C. Yields were calculated by H NMR spectroscopy using

mesitylene as an internal standard. Isolated yields are in parentheses.

propionamide, and hexanamide are formed in similar yields,

about 80% after 2−3 h. The hydration is slightly sensitive to

the steric hindrance on the C(sp) atom of unfuctionalized

substrates; 2-methylpropionitrile and cyclohexanecarbonitrile

are converted into the corresponding amides with the same

eﬃciency as that of linear nitriles; however, the trisubstituted

pivalonitrile needs 24 h to reach a conversion similar to

pivalamide. Although the presence of aromatic substituents at

mol % of the hexahydride complex and 50 equiv of water at

00 °C. Under these conditions, the eﬃciency of complex 1 to

promote the hydration of acetonitrile to acetamide is higher

than those of the majority of the reported catalysts so far,

whereas it compares well with the eﬃciencies of a few

d,l,12m,o,r,w

ruthenium precursors

and the osmium complex

OsCl (η -p -cymene)(PMe OH), which work in water as the

the C atom with respect to the CN function generally delays

solvent (Tables S2 −S5 ). Scheme 4 shows the amides isolated

the reaction, the corresponding amides are formed in almost

quantitative yield after 24 h. In this context, noteworthy is the

preparation in high yields of branched chain amide derivatives

of ketoprofen and ibuprofen, which are nonsteroidal

antiinﬂammatory drugs widely employed as advanced inter-

mediates in the preparation of several prodrugs and preclinical

under the selected conditions.

Complex 1 displays good tolerance to functional groups.

Consequently, it promotes the hydration of a remarkable

variety of aliphatic nitriles, including unfunctionalized sub-

strates of linear and branched chains, among others the deﬁant

trisubstituted pivalonitrile, cyclic nitriles as cyclohexanecarbo-

nitrile, and functionalized aliphatic nitriles with methoxide,

keto, R-aryl (R = MeO, Br, CF , R, CO Me, NO , and COPh),

6c,12g

candidates.

Main Species under the Catalytic Conditions. The H

NMR spectra of the catalytic solutions contain a broad triplet

and pyridyl groups.

The length of the aliphatic chain does not have a noticeable

inﬂuence on the yield of the obtained amide. Thus, acetamide,

at about −13.6 ppm ( J

≈ 13 Hz), corresponding to a new

H−P

class of species, in addition to the signals due to the reagents,

amide products, and phosphine ligands of the catalyst. The

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

X-ray di ﬀ raction analysis (2b ).

Article

high-ﬁeld resonance ﬁts with a singlet at about 36 ppm in the

P{ H} NMR spectra. Resonances due to 1 are not observed.

the ¹³C{ H} NMR spectra, the presence of the amidate ligand

is strongly supported by a singlet close to 181 ppm.

The new species are rapidly and quantitatively formed and

remain while the nitrile is present in the solution and also once

it is consumed. To gain information about their nature, we

decided to prepare them at a Schlenk tube scale, with two

model nitriles: 2-methylpropanenitrile and pivalonitrile. The

treatment of THF solutions of 1 with 2.0 equiv of the nitriles

and 2.0 equiv of water at 100 °C for 3 h aﬀorded 1.0 equiv of

the corresponding amide and the trihydride osmium(IV)

Once the nature of the main metal species was established

under the catalytic conditions, we investigated their catalytic

performance. Thus, hydration of 2-methylpropanenitrile and

pivalonitrile was carried out using the isolated complexes 2a

and 2b , respectively, as catalysts. Figure 2 shows the course of

amidate derivatives OsH {κ -N,O-[HNC(O)R]}(P Pr ) [R =

3 2

Pr (2a), Bu (2b)], according to eq 2. These compounds were

isolated as a colorless oil (2a) and colorless crystals suitable for

Figure 2. Hydration of 2-methylpropanenitrile (0.24 M) catalyzed by

−

(blue ●) or 2a (red ◆) (both 1.2 × 10 M) in THF-d at 100 °C.

Figure 1 shows a view of 2b. The structure proves the

formation of the amidate group, which acts as a N,O-chelate

the hydration of 2-methylpropanenitrile in the presence of 1

and 2a. According to the observed reaction proﬁles, it is clear

that both compounds display the same activity; i.e., under the

catalytic conditions, complex 1 reacts with 1.0 equiv of nitrile

and 1.0 equiv of water to give trihydride osmium(IV) amidate

species, such as 2a and 2b, and to release two hydrogen

molecules. The formed osmium(IV) amidate compounds are

catalyst precursors closer to the true catalyst of hydration than

. Each hydration has a speciﬁc catalyst that is generated with

the nitrile substrate itself.

Complex 1 is saturated, and, consequently, its trans-

formation into amidate derivatives needs the previous creation

of a coordination vacancy, which occurs by the dissociation of

a hydrogen molecule. The resulting unsaturated tetrahydride

OsH (P Pr ) (A) has been trapped by several types of Lewis

3 2

8e,31−35

bases.

Once A is generated, the formation of amidate

complexes could take place via two diﬀerent paths: (a) nitrile

or (b) water (Scheme 5). The ﬁrst route should involve the

initial coordination of the nitrile to the unsaturated metal

center of A. The coordination would give B, with the

coordinated substrate activated for the attack of an external

water molecule. The attack should aﬀord the amidate ligand

and the release of a second hydrogen molecule. In the second

one, the tetrahydride A would be trapped by a water molecule.

Then, the subsequent reaction of the resulting intermediate C

with the nitrile could yield the amidate complexes and the

second hydrogen molecule. To gain information on the

intimate details of the routes and to compare their energetic

cost, we carried out DFT calculations at the dispersion-

corrected PCM(THF)-B3LYP-D3//SDD(f)-6-31G ** level

(see computational details in the Supporting Information)

using propionitrile as a model of the substrate. The variations

in free energy (ΔG) were calculated in THF at 298.15 K and 1

atm.

Figure 1. Molecular structure of 2b with ellipsoids at the 50%

probability level. H atoms are omitted for clarity (except for the

hydride ligands and NH group). Selected bond distances (Å) and

angles (deg): Os−N1 = 2.185(3), Os−O1 = 2.245(2), O1−C1 =

.289(4), N1−C1 = 1.285(4), Os−P1 = 2.3373(6), Os−P2 =

.3372(6); N1−Os−O1 = 57.47(10), P1−Os−P2 = 171.79(2).

ligand with a bite angle of 57.47(10)°. The polyhedron around

the metal center is the expected pentagonal bipyramid for a

seven-coordinated d derivative, with the phosphine ligands

occupying axial positions [P−Os−P = 171.79(2)°], whereas

the chelate and hydride ligands lie at the perpendicular plane.

The H and P{ H} NMR spectra of 2a and 2b are consistent

with the spectra of the respective catalytic solutions involving

-methylpropanenitrile and pivalonitrile. Furthermore, the H

A nitrile route was previously proposed by Lin, Lau, and co-

workers to rationalize the hydration of nitriles with an

indenylruthenium hydride catalyst. The presence of a Ru−

H···H−OH dihydrogen-bonding interaction in the transition

state lowers the barrier for nucleophilic attack of an external

NMR spectra of these compounds in toluene-d as a function

of the temperature reveal that the hydride ligands undergo a

thermally activated position site exchange process, typical for

28f,g,31

OsH (XY)(P Pr ) complexes.

Thus, the hydride reso-

nance at about −13.6 ppm splits into three signals at about

10, −14, and −15 ppm at temperatures lower than 213 K. In

3 2

12a

water molecule to the coordinated nitrile. Although the drop

−

is signiﬁcant (19.3 kcal mol ), the barrier remains too high

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

Article

Scheme 5. Possible Routes for the Formation of Amidate Complexes

Figure 3. Relative Gibbs energies for formation of the κ -amidate OsH {κ -N,O-[HNC(O)R]}(P Pr ) (2; R = Et) via intramolecular (blue lines)

3 2

or intermolecular (red lines) attack.

Scheme 6. Intermediates in the Formation of κ -Amidate Complexes 2

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Article

−

(

40.0 kcal mol ). A similar attack involving an Os−H ···H −

hydroxo group at the nitrile, in the intermolecular one, it is the

OH dihydrogen bonding is also possible in our case (Figure

S93 ); the activation energy is even lower than that for the half-

sandwich ruthenium catalyst. However, it is still very high

heterolytic activation of the water molecule. The diﬀerence

⧧

−1

between the barriers (ΔΔG ) is small, 1.3 kcal mol , and both

barriers are low and experimentally accessible.

−

(

32.5 kcal mol ). Thus, we discarded the nitrile route as a

Kinetics and Mechanism of the Catalysis. Once the

main metal species under the hydration conditions was

established and its method of generation was analyzed, we

investigated the mechanism of catalysis. To this end, the

kinetics of hydration of 2-methylpropanenitrile promoted by 1

feasible pathway for the formation of amidate compounds.

Once the nitrile route was discarded, we analyzed the water

route. Figure 3 shows the energetic proﬁle of the trans-

formation, whereas Scheme 6 collects the calculated reaction

intermediates. Coordination of the water molecule to the metal

center of A to give C is slightly exergonic (2.3 kcal mol ). The

formation of C is the previous step to the hydride-mediated

heterolytic activation of the water molecule. The cleavage

occurs with an activation energy of 12.9 kcal mol , with

respect to A, and leads to the trihydride hydroxo Kubas-type

dihydrogen osmium(IV) species D (d_H₋_H= 0.839 Å).

Subsequent dissociation of the coordinated hydrogen molecule

aﬀords the unsaturated six-coordinate osmium(IV) derivative

E, which lies 4.2 kcal mol⁻below A. Although hydride

hydroxo derivatives of the platinum group metals are very rare

was studied in THF-d under pseudo-ﬁrst-order conditions.

−

The reactions were followed by H NMR spectroscopy and

carried out in the 373−348 K temperature range with

concentrations of the catalyst precursor 1 between 2.4 ×

−

−2

10 and 1.2 × 10 M and concentrations of water between

12.2 and 4.9 M, starting from an initial concentration of nitrile

of 0.24 M.

The decrease of the nitrile concentration with a correspond-

ing increase of the amide concentration is an exponential

function of time under the selected conditions, in agreement

obs

with a pseudo-ﬁrst-order process. The rate constant k for

and their chemistry is underdeveloped, the trihydride

hydroxoosmium(IV) complex OsH (OH){xant(P Pr ) }

xant(P Pr ) = 9,9-dimethyl-4,5-bis(diisopropylphosphino)-

xanthene], related to E, was recently reported and a part of

each concentration of the catalyst precursor and water used

and each temperature was calculated by graphing the

expression shown in eq 3, as exempliﬁed in Figure 4 for the

reactions performed at 373 K, with a concentration of water of

12.2 M. The obtained values are collected in Table 2.

2 2

[

2 2

23g,37

its reactivity studied.

Intermediate E displays the typical

structure with C symmetry of complexes OsH X(PR ) . In

3 2

[

RCN]

order to be diamagnetic, these compounds undergo distortion

from the octahedral geometry, which involves destabilization of

an orbital of the t₂_gset and the simultaneous stabilization of

some occupied ones. This distortion partially cancels the

electron deﬁciency of the metal center, which receives electron

density through σ bonds with the hydride ligands and from a

obs

= −k t

[RCN]₀

(3)

lone pair of X via a π bond. In agreement with the partially

saturated character of the metal center of E, coordination of

−

the nitrile is slightly endergonic (1.6 kcal mol ). The resulting

seven-coordinate species F has two pathways to evolve into the

amidate complex, one intramolecular and the other inter-

molecular. The former would involve the attack of the

coordinated hydroxo group to the C(sp) atom of the nitrile,

while in the second one, the attack should proceed from the

hydroxo group of an external water molecule. The intra-

molecular attack has to overcome an activation energy of 14.2

Figure 4. Plot of eq 3 for hydration of 2-methylpropanenitrile (0.24

M) with diﬀerent concentrations of 1 in THF-d at 373 K. [H O] =

2.2 M; [1] = 1.2 × 10 M (purple ); 1.5 × 10 M (yellow );

1.7 × 10 M (blue ■); 1.9 × 10 M (red ◆); 2.4 × 10 M (green

●).

−

kcal mol with respect to A, which is experimentally

−

−2

accessible, and leads to the κ -iminolate derivative G.

▲

●

−

−2

Dissociation of the coordinated OH group of the iminolate

aﬀords the hydroxoazavinylidene species H, a thermodynami-

cally disfavored tautomer of the κ -N-amidate I. Coordination

of the carbonyl group of the amidate ligand of the latter yields

the experimentally observed κ -amidate species 2 in an

exergonic overall process by 22.8 kcal mol⁻with respect to

A. The barrier for the intermolecular attack is lower than that

for the intramolecular one (5.1 kcal mol⁻with regard to A).

The reason is that the external water molecule forms a HO···

H−OH hydrogen bond with the coordinated hydroxo group,

which provides slight stabilization of the system. The resulting

adduct J lies 9.1 kcal mol⁻¹below A. The attack leads to the κ -

N-iminolate K, which coordinates a water ligand. Its

dissociation regenerates the external water molecule and

aﬀords the hydroxoazavinylidene intermediate H, a common

intermediate for both pathways. A comparison of the overall

proﬁle for both routes reveals that the main diﬀerence between

them is the rate-determining step of the process. While, for the

intramolecular pathway, it is the attack of the coordinated

The rate constant k^o^b^sis a function of the concentrations of

the catalyst precursor and water, according to eqs 4 and 5:

_kobs = k₁[Os]

obs

(4)

(5)

k₁^o^b^s= k[H O]

obs

A plot of log k versus log [Os], for a water concentration

of 12.2 M, yields a straight line of slope 1.1 (Figure 5),

revealing that the hydration is ﬁrst-order also in the catalyst

obs

concentration and therefore the values of k₁given in Table 2

were obtained from eq 4 for a = 1. Similarly, the plot of log

obs

k₁versus log [H O], for a concentration of the catalyst

−

precursor of 2.4 × 10 M, aﬀords a straight line of slope 1.0

(Figure 6), proving that the reaction is also ﬁrst-order in the

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Table 2. Kinetic Data for Hydration of 2-

Methylpropanenitrile (0.24 M) in THF-d Catalyzed by 1

k^o^b^s(×10

k₁(×10

obs

k (×10

−2 −1

[1]

[H O]

−1

−1 −1

(

K) (×10 M)

(M)

)

s )

373

363

358

353

348

2.4

1.9

1.7

1.5

1.2

2.4

12.2

9.7

8.5

7.3

6.1

4.9

13.0 ± 2.0

10.6 ± 0.7

9.1 ± 0.4

7.3 ± 0.7

6.2 ± 0.4

10.6 ± 0.4

8.6 ± 0.5

7.6 ± 0.4

6.9 ± 0.3

5.0 ± 0.3

5.3 ± 0.4

4.0 ± 0.3

2.8 ± 0.2

1.9 ± 0.1

5.3 ± 0.5

5.5 ± 0.6

5.4 ± 0.5

5.1 ± 0.5

4.4 ± 0.4

3.5 ± 0.4

3.1 ± 0.3

2.8 ± 0.3

2.1 ± 0.2

2.2 ± 0.2

1.7 ± 0.2

1.1 ± 0.1

0.8 ± 0.1

4.4 ± 0.4

4.5 ± 0.5

4.4 ± 0.4

4.2 ± 0.4

4.5 ± 0.5

4.1 ± 0.4

4.3 ± 0.4

4.6 ± 0.5

4.2 ± 0.4

1.8 ± 0.2

1.4 ± 0.1

0.9 ± 0.1

0.6 ± 0.1

Figure 7. Plot of k₁^o^b^sversus [H O] for hydration of 2-

methylpropanenitrile (0.24 M) with water catalyzed by 1 (2.4 ×

12.2

−

M) in THF-d at 373 K.

because the concentration of metal introduced in the catalysis

is approximately equal to the concentration of the κ -amidate

complex generated during hydration, such a rate-determining

step should yield a second-order reaction, independent of the

nitrile concentration.

The obtained rate law indicates that both nitrile and water

are involved in the rate-determining step of hydration. To gain

information about it, we extended the previous DFT

calculations to the catalytic cycle (Scheme 7). Figure 8

shows the calculated proﬁle for propionitrile as the model

nitrile.

The κ -N,O to κ -N transformation of the coordination

mode of the amidate ligand of 2 aﬀords the necessary

coordination vacancy for entry of the nitrile molecule.

Coordination of the nitrile to the κ -N-amidate complex I

Figure 5. Plot of log k^o^b^sversus log [Os] for hydration of 2-

methylpropanenitrile (0.24 M) catalyzed by 1 in THF-d at 373 K.

Scheme 7. Catalytic Cycle for Nitrile Hydration

Figure 6. Plot log k ^o^b^sversus log [H O] for hydration of 2-

−

methylpropanenitrile (0.24 M) catalyzed by 1 (2.4 × 10 M) in

THF-d at 373 K.

water concentration, i.e., b = 1 in eq 5. Thus, the rate law is

obs

described by eq 6, where k[H O] = k₁and k₁[Os] = k .

d[RC(O)NH₂]

d[RCN]

−

= k[Os][RCN][H O]

(6)

obs

The plot of k₁versus [H O] (Figure 7) provides a value of

−2 −1

(

4.4 ± 0.4) × 10⁻

for k at 373 K.

The rate law described in eq 6 excludes the reaction of κ -

amidate complexes with water as the rate-determining step of

nitrile hydration. In this context, it should be noted that,

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

Article

The concentration of the intermediate M can be determined as

follows:

[

Os] = [2] + [I] + [L] + [M]

(8)

Because [L] = [M]/K [H O] and [I] = [M]/K K [RCN]-

2 3

[

H O], we have [2] = [M]/K K K [RCN][H O] and ﬁnally

K K K [Os] [RCN][H O]

[

^M^]⁼1

+ K + K K [RCN] + K K K [RCN][H O]

(

Amidate complexes 2 are the only spectroscopically observed

species during the course of hydration. As a consequence, we

Figure 8. Computed energy proﬁle for the catalytic cycle shown in

Scheme 7 (R = Et).

can assume that K + K K [RCN] + K K K [RCN][H O] ≪

1, and therefore [M] can be described as follows:

leads to the seven-coordinate intermediate L, which is the key

species of the catalysis. It undergoes the attack of an external

water molecule in the rate-determining step, as expected

[

M] = K K K [Os] [RCN][H O]

(10)

Combining eqs 7 and 10, we obtain eq 11, where [Os] is the

concentration of the catalyst precursor complex 1.

according to eq 6. The free carbonyl group of the κ -N-amidate

ligand ﬁxes the water molecule in the vicinity of the C(sp)

atom of the nitrile. Once placed, the water molecule of adduct

M attacks the C atom of the nitrile and the N atom of the

amidate in a concerted manner. The attack takes place through

a six-membered cyclic transition state, TS_M_-_N, which involves

C _n _i _t _r _i _l _e ···O −H ···N _a _m _i _d _a _t _e interactions (Figure 9 ). This transition

^d^[^R^C⁽^O⁾^N^H2^]

k K K K [Os] [RCN][H O]

(11)

Inspection of eq 11 shows that the rate of hydration is

proportional to the concentrations of the catalyst precursor,

nitrile, and water, in good agreement with the rate law

obtained experimentally (see eq 6), where k = k K K K .

1 2 3

CONCLUDING REMARKS

■

This study has discovered that the d hexahydride 1, which is

easily prepared from OsCl ·xH O in high yield and bears a

usual commercially available ligand, eﬃciently catalyzes the

hydration of alkyl nitriles to amides. Furthermore, it displays a

good tolerance to functional groups, including methoxide,

benzoyl, functionalized aryl, and pyridyl groups, while also

being active with substrates of a branched chain as the

challenging trisubstituted pivalonitrile. The main metal species

under the catalytic conditions are the trihydride osmium(IV)

amidate derivatives OsH {κ -N,O-[HNC(O)R]}(P Pr ) ,

3 2

which are formed in a stoichiometric process involving three

main steps: heterolytic O−H bond activation of water, nitrile

coordination, and nucleophilic attack of a hydroxo group at the

C(sp) atom of the coordinated nitrile.

Evidence obtained by combining isolation of the main metal

species under the catalytic conditions, kinetic analysis of the

hydration, and DFT calculations strongly supports an

alternative mechanism to those previously reported. Each

reaction has its own catalyst. The trihydride osmium(IV)

Figure 9. Transition state (TS_M₋_N) between intermediates M and N.

H atoms of the ethyl group and triisopropilphosphine ligands have

been omitted for clarity. Selected bond distances (Å) and angles

(

deg): Os−N(1) = 2.363, Os−N(2) = 2.118, H(1)−N(1) = 1.231,

H(1)−O(1) = 1.272, C(1)−O(1) = 1.952, C(1)−N(2) = 1.186;

N(1)−Os−N(2) = 81.6.

amidate complexes OsH {κ -N,O-[HNC(O)R]}(P Pr ) re-

3 2

lease the carbonyl group of the chelate to aﬀord κ -N-amidate

derivatives, which are the true catalysts of hydration, one

diﬀeent for each nitrile. These catalysts coordinate the nitrile

to give the key intermediates of the catalysis, which undergo

the attack of an external water molecule in the rate-

determining step. The water molecule attacks the C atom of

the nitrile and the N atom of the amidate in a concerted

manner, through a six-membered cyclic transition state, which

involves Cnitrile···O−H···Namidate interactions. The attack

state lies 24.1 kcal mol⁻above the κ -amidate complex and

ends up in the κ -N-iminolate N, which resembles K bearing a

κ -N-amide instead of a water ligand. The amide dissociation

from N aﬀords the hydroxoazavinylidene intermediate H,

which tautomerizes into the κ -N-amidate complex I, closing

the cycle.

The rate of formation of the amide is described by eq 7

according to the proﬁle shown in Figure 7 and the rate-

determining step approximation.

liberates the amide and regenerates a new κ -N-amidate to

continue the hydration. The group κ -N-amidate is not only an

intermediate in the formation pathway of the amide but also a

noninnocent ligand, which cooperates in the external attack of

the water molecule. Its free carbonyl group ﬁxes the water

d[RC(O)NH₂]

k_c[M]

(7)

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

The Supporting Information is available free of charge at

Article

molecule in the vicinity of the C(sp) atom of the nitrile, before

the attack.

the time indicated on Scheme 4, the solvent and remaining water were

removed under vacuum, yielding a silvery oil or a white solid. The

addition of pentane (1 mL) induced the precipitation of a white solid,

which was washed with further portions of pentane (3 × 1 mL) and

The electron density of the metal center of the precursor is

responsible of the formation of these amidate catalysts; direct

participation of the ligands of the precursor does not take

place. Once the amidate complexes are formed, the steps

involved in the catalytic cycle are also mainly governed by the

amidate itself and the electron density of the metal center; the

role of the ligands of the precursor is reduced to that typical in

homogeneous catalysis: to modulate the electron density of the

metal center and the space around it. According to this, it

seems to be clear that the hydration of nitriles with catalyst

precursors bearing only innocent ligands is possible.

dried under vacuo. The amides were characterized by H and

C{ H} NMR and IR spectroscopy.

Kinetic Experiments. All kinetic experiments were performed in

THF-d₈solutions contained in NMR tubes under an argon

atmosphere. The NMR tubes were charged with 2-methylpropaneni-

trile (0.14 mmol, 0.24 M), water (50.4−125 μL, 2.8−7.0 mmol, 4.9−

−

−3

−2

12.2 M), complex 1 (7.0 × 10 −14.0 × 10 mmol, 1.2 × 10 −2.4

−

× 10 M), and mesitylene (0.14 mmol, 0.24 M; internal standard),

and the ﬁnal volume was brought to 575 μL using THF-d . Then H

NMR spectra were recorded every 5 min for 1 h or until the

conversion was over 90%.

EXPERIMENTAL SECTION

■

ASSOCIATED CONTENT

sı Supporting Information

https://pubs.acs.org/doi/10.1021/acs.inorgchem.1c00380.

■

General details including X-ray analysis, instrumental methods, and

computational information are given in the Supporting Information.

Chemical shifts are expressed in parts per million. Coupling constants

are given in hertz (N = J

+ J

for H and J

+ J

for

H−P

H−P′

C−P

C−P′

C).

General information, structural analysis, computational

details, analytical data of the isolated amides, NMR

spectra, energies of computed structures, and compara-

tive tables of metal-catalyzed nitrile hydration (PDF)

Preparation of OsH {κ -N,O-[HNC(O)CH(CH ) ]}(P Pr ) (2a).

3 2

-Methylpropanenitrile (35.9 μL, 0.4 mmol) and water (7.2 μL, 0.4

mmol) were placed in a Schlenk tube with a solution of 1 (100 mg,

.19 mmol) in THF (2 mL). The Schlenk tube was heated at 100 °C

for 3 h. The solvent was eliminated in vacuo to give a yellow oil. The

Cartesian coordinates of calculated structures (XYZ)

oil was washed with several portions of cold pentane (3 × 2 mL at

Accession Codes

−

78 °C) and dried in vacuo. Yield: 60 mg (50%). HR-MS

CCDC 2057271 contains the supplementary crystallographic

data for this paper. These data can be obtained free of charge

via www.ccdc.cam.ac.uk/data_request/cif , or by emailing

data_request@ccdc.cam.ac.uk , or by contacting The Cam-

bridge Crystallographic Data Centre, 12 Union Road,

Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

(

electrospray). Calcd for C H NOOsP ([M − H] ): m/z

00.3101. Found: m/z 600.3133. H NMR (300.13 MHz, C D ,

98 K): δ 5.30 (br, 1H, NH), 1.99 (m, 7H, CHP Pr + CH Pr), 1.22

7 8

dvt, J = 6.7, N = 12.6, 36H, CH P Pr ), 0.98 (d, J_H₋_H= 7.0, 6H,

H−H 3 3

i 1

CH Pr), −13.26 (br, 3H, OsH ). H NMR (300.13 MHz, C D , 183

K): δ 5.30 (br, 1H, NH), 1.91 (br, 7H, CHP Pr + CH Pr), 1.23 (br,

−

(

6H, CH P Pr ), 1.00 (br, 6H, CH Pr), −10.28 (br, 1H, OsH),

13.80 (br, 1H, OsH), −15.14 (br, 1H, OsH). P{ H} NMR

AUTHOR INFORMATION

Corresponding Author

13 1

■

121.50 MHz, C D , 298 K): δ 36.5. C{ H} APT NMR (75.48

MHz, CDCl , 298 K): δ 181.2 (NCO), 37.6 (CH Pr), 26.6 (vt, N =

3, CH Pr), 20.3 (CH P Pr ), 18.5 (CH Pr).

Miguel A. Esteruelas − Departamento de Química Inorgánica,

Instituto de Síntesis Química y Catálisis Homogénea

(ISQCH), Centro de Innovación en Química Avanzada

Preparation of OsH {κ -N,O-[HNC(O)C(CH ) ]}(P Pr ) (2b).

3 3

3 2

Complex 1 (100 mg, 0.19 mmol) in THF (2 mL) was treated with

pivalonitrile (44.2 μL, 0.4 mmol) and water (7.2 μL, 0.4 mmol) for 3

h at 130 °C. The solvent was eliminated under vacuum, obtaining a

yellow oil. The addition of cold pentane (1 mL at −78 °C) caused the

precipitation of a white solid. The solid was washed with further

portions of cold pentane (3 × 2 mL) and dried in vacuo. Yield: 35 mg

(

ORFEO-CINQA), Consejo Superior de Investigaciones

Cientíﬁcas (CSIC)Universidad de Zaragoza, Zaragoza

0009, Spain; orcid.org/0000-0002-4829-7590;

Email: maester@unizar.es

(

30%). Colorless single crystals suitable for X-ray diﬀraction analysis

Authors

were obtained from a saturated solution of 2b in pentane at −30 °C.

Juan C. Babón − Departamento de Química Inorgánica,

Instituto de Síntesis Química y Catálisis Homogénea

HR-MS (electrospray). Calcd for C H NOOsP ([M − H] ): m/z

14.3291. Found: m/z 614.3302. Anal. Calcd for C H NOOsP : C,

23 55 2

(

ISQCH), Centro de Innovación en Química Avanzada

5.00; H, 9.03; N, 2.28. Found: C, 44.78; H, 8.85; N, 2.46. IR (ATR,

−

cm ): ν(NH) 3432 (w), ν(Os−H) 2126 (s). H NMR (300.13

MHz, C D , 298 K): δ 5.42 (br, 1H, NH), 1.99 (m, 6H, CHP Pr ),

(ORFEO-CINQA), Consejo Superior de Investigaciones

Cientíﬁcas (CSIC)Universidad de Zaragoza, Zaragoza

50009, Spain; orcid.org/0000-0001-9815-9383

Ana M. López − Departamento de Química Inorgánica,

Instituto de Síntesis Química y Catálisis Homogénea

1.20 (dvt, J

= 5.6, N = 12.5, 36H, CH P Pr ), 1.02 (s, 9H,

H−H 3 3

CH Bu), −13.36 (br, 3H, OsH ). H NMR (300.13 MHz, C D , 193

K): δ 5.45 (br, 1H, NH), 1.89 (br, 6H, CHP Pr ), 1.26 (br, 36H,

CH P Pr ), 1.06 (s, 9H, CH Bu), −10.33 (br, 1H, OsH), −13.77 (br,

C D , 298 K): δ 37.0. C{ H} APT NMR (75.48 MHz, CDCl , 298

K): δ 182.5 (NCO), 39.9 (C Bu), 26.8 (CH Bu), 26.4 (vt, N = 23.1,

CHP Pr), 20.3 (CH P Pr ).

(

ISQCH), Centro de Innovación en Química Avanzada

H, OsH), −14.94 (br, 1H, OsH). P{ H} NMR (121.50 MHz,

13 1

(ORFEO-CINQA), Consejo Superior de Investigaciones

Cientíﬁcas (CSIC)Universidad de Zaragoza, Zaragoza

50009, Spain; orcid.org/0000-0001-7183-4975

Catalytic Hydration of Nitriles. All reactions were performed in

NMR tubes under an argon atmosphere. Nitrile (0.14 mmol),

deoxygenated water (125 μL, 7.0 mmol), and mesitylene (19.5 μL,

Enrique Onate − Departamento de Química Inorgánica,

Instituto de Síntesis Química y Catálisis Homogénea

(ISQCH), Centro de Innovación en Química Avanzada

.14 mmol), used as an internal standard, were added to a solution of

(

ORFEO-CINQA), Consejo Superior de Investigaciones

Cientíﬁcas (CSIC)Universidad de Zaragoza, Zaragoza

0009, Spain; orcid.org/0000-0003-2094-719X

(3.6 mg, 0.007 mmol, 5 mol %) in THF-d (450 μL). The mixture

was heated at 100 °C, and the reaction was monitored by H NMR.

The yields were determined by comparing the integration areas of the

characteristic signals of the amides with those of the mesitylene. After

Complete contact information is available at:

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

https://pubs.acs.org/10.1021/acs.inorgchem.1c00380

Article

catalytic behaviour. Dalton Trans. 2016, 45, 3163 −3174. (i) Gonzá-

lez-Fernández, R.; Crochet, P.; Cadierno, V. Cymene-Osmium(II)

Complexes with Amino-Phosphane Ligands as Precatalysts for Nitrile

Hydration Reactions. ChemistrySelect 2018, 3, 4324 −4329. (j) Gonzá-

lez-Fernández, R.; Crochet, P.; Cadierno, V. Synthesis of β -

hydroxyamides through ruthenium-catalyzed hydration/transfer hy-

drogenation of β -ketonitriles in water: Scope and limitations. J.

Organomet. Chem. 2019 , 896 , 90 −101. (k) Ounkham, W. L.; Weeden,

J. A.; Frost, B. J. Aqueous-Phase Nitrile Hydration Catalyzed by an In

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25, 10013−10020. (l) Vyas, K. M.; Mandal, P.; Singh, R.; Mobin, S.

M.; Mukhopadhyay, S. Arene-ruthenium(II)-phosphine complexes:

Green catalysts for hydration of nitriles under mild conditions. Inorg.

Chem. Commun. 2020, 112, 107698.

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

Financial support was provided by MINECO of Spain

CTQ2017-82935-P (AEI/FEDER, UE) and RED2018-

■

[

02387-T], Gobierno de Aragón (E06_20R and

LMP148_18), FEDER, and the European Social.

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