New catalytic reactions of (unsaturated) nitriles via metal-ligand cooperative activation of the
C≡N bond
Guo, Beibei
DOI:10.33612/diss.136481036
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Publication date: 2020
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Guo, B. (2020). New catalytic reactions of (unsaturated) nitriles via metal-ligand cooperative activation of the C≡N bond. University of Groningen. https://doi.org/10.33612/diss.136481036
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Chapter 3
Hydration of Nitriles using a
Metal-Ligand Cooperative Ruthenium Pincer
Catalyst
ABSTRACT: Nitrile hydration provides access to amides that are important
structural elements in organic chemistry. Here we report catalytic nitrile
hydration using ruthenium catalysts based on a pincer scaffold with a
dearomatized pyridine backbone. These complexes catalyze the nucleophilic
addition of H
2O to a wide variety of aliphatic and (hetero)aromatic nitriles in
tBuOH as solvent. Reactions occur under mild conditions (room temperature)
in the absence of additives. A mechanism for nitrile hydration is proposed that
is initiated by metal-ligand cooperative binding of the nitrile.
This chapter was published as: Beibei Guo, Johannes G. de Vries and Edwin Otten
Chem.
Sci., 2019, 10, 10647, DOI: 10.1039/c9sc04624k.3.1 Introduction
Amides are an important class of compounds that occur in a large variety of biologically active compounds, polymers and synthetic intermediates,1-2 and
various synthetic methods have been developed for their formation.3-4 Nitrile
hydration provides an atom-efficient synthesis of amides and is carried out on an industrial scale, for example in the production of acrylamide5 and nicotinamide.6
The direct nucleophilic addition of water to the C≡N bond is kinetically slow, and a variety of catalysts have been developed, but it is often difficult to prevent over-hydrolysis to the corresponding carboxylic acids.7-8 Nitrile hydratase enzymes
yield amides with excellent selectivity,9-11 but the limited substrate scope
prevents their widespread use. There has been significant recent interest in the development of nitrile hydration catalysts based on transition metals, but most systems reported to date still require relatively high temperatures to reach appreciable catalytic turnover.12-16 Recent progress with Rh(I),17 Ru(II),18
Pd(II),19 and Pt(II)20 catalysts has allowed catalytic nitrile hydration under mild
conditions, but additives are often required for high activity (e.g., AgOTf in Grubbs’ Pt(II)/phosphinous acid catalysts,20 or Sc(OTf)3 in Yin’s Pd(II)
catalysts19).
Metal complexes with pincer ligands have found widespread use in a large variety of catalytic reactions,21-22 but the incorporation of a reactive fragment in
the ligand backbone to enable ‘bifunctional’ or ‘cooperative’ substrate binding/activation has only recently started to emerge.23-26 Examples include the
(reversible) binding of unsaturated fragments such as CO2,27-30 SO2,31 carbonyl
compounds,32 or nitriles.33-35 Our group reported that Milstein’s dearomatized Ru
PNN pincer complex APNN (Scheme 1, left) catalyzes the conjugate addition of
alcohols to α,β-unsaturated nitriles via a metal-ligand cooperative (MLC) mechanism by activation of the nitrile CN bond.36-38 Very recently, similar
reactivity was observed with a related Mn catalyst.39 This mode of activation
reduces the bond order from 3 in the nitrile (CN) to 2 in the MLC intermediate (-C=N-Ru), which significantly alters the reactivity profile of the substrate. Having established that conjugate (1,4-) addition of weak alcohol nucleophiles is enabled by metal-ligand cooperation, we hypothesized that also 1,2-additions to MLC-activated nitriles may be feasible. Herein we describe our results on catalytic nitrile hydration using Ru complexes with dearomatized pyridine-based pincer ligands, and demonstrate that a large variety of aliphatic and (hetero)aromatic nitriles is selectively converted to the corresponding amides under very mild conditions.
Scheme 1 MLC activation of nitriles towards addition of O-nucleophiles.
3.2 Results and discussion
3.2.1 Catalyst development and reaction scope
Previously it was found that the direct conjugate addition of H2O to α,β-unsaturated
nitriles was sluggish using catalyst APNN.38 However, for some of the substrates tested
we noticed that amides were obtained in low yield by hydration of the nitrile moiety. Encouraged by these observations, we initiated a screening of reaction conditions for the hydration of acetonitrile. These initial results (Table 3-5 in in the Experimental Section 3.4.2) showed that both PNN complex APNN and the symmetrical PNP analogue APNP are active, and performed best in tBuOH solvent. An optimum in catalyst activity was found when 5 equivalents of H2O were added, which gave 63% conversion to
acetamide after 24h at room temperature (3 mol% catalyst APNP). Repeating these
reactions with either 2 or 8 equiv of H2O present gave lower nitrile conversions of 44
and 42%, respectively, and the reaction is almost completely suppressed in the presence of 20 equiv of H2O (4% conversion after 24h). In view of the propensity of
complexes such as A to heterolytically cleave OH bonds (including H2O) in a reversible
manner,40-41 it is likely that the nitrile, H2O and other components in the reaction
mixture compete for reaction with the dearomatized complexes A, and the presence of increased amounts of water will result in a larger equilibrium concentration of Ru-hydroxides (vide infra). The decrease in catalyst activity at H2O amounts beyond the
optimum (5 equiv) indicates that in the present catalyst system, Ru-hydroxides are likely not the active species. Although a variety of transition metal hydroxide species have been reported to catalyze nitrile hydration, these often require elevated temperatures.42-43 Control experiments carried out in the absence of the dearomatized
(the aromatic (PNP)Ru(H)(Cl)(CO) complex) led to no conversion, indicating that the metal-ligand cooperative character of A is important in this catalytic conversion. We subsequently focused on examining the scope of substrates that underwent hydration to the amide using APNP as catalyst (Table 1). A selection of substrates was
also subjected to catalysis by the nonsymmetrical APNN catalyst, which resulted in
similar results (Table 1, entries in brackets).
Substrates with halogen substituents (1b-f) as well as electron-withdrawing trifluoromethyl (1g) or aldehyde groups (1h) at the para-position all afforded the corresponding amides in quantitative isolated yields. In case of aldehyde 1h, its poor solubility in tBuOH resulted in slow conversion under the standard conditions, but addition of THF as co-solvent afforded a homogeneous solution and resulted in facile amide formation. For the three bromo-substituted substrates (1d-f), conversion of the hindered ortho-isomer was sluggish at room temperature, but at 50 °C the reaction went to completion within 2 days. The hydration reaction also occurred with naphtylnitriles (1j,k). The presence of an electron-withdrawing para-nitro substituent completely suppressed the reaction at room temperature; heating to 80 °C restored some catalytic activity, but the reaction stalled at ca. 25% conversion under those conditions. Catalyst deactivation by the nitro-group does not seem to take place, as hydration of 1b in the presence of an equimolar amount of nitrobenzene gives full conversion to 2b at a rate that is similar to that in the absence of nitrobenzene (see 3.4 Experimental Section). A likely explanation is that the p-nitro benzamide product, which has a relatively acidic N-H bond, competes with the nitrile substrate for binding with the catalyst and leads to product inhibition (vide infra). Benzonitriles with electron-donating substituents (p-Me, -OMe, -NR2) are also hydrated, although the
aniline derivatives required heating to achieve full conversion (1n: 50 °C for 20h; 1o: 80 °C for 16h). In the case of the free aniline 1o, this may be due to competing (reversible) N-H bond activation to form Ru-anilido species.44 Consistent with this
hypothesis is the observation that 4-hydroxybenzonitrile is not converted even at 80 °C, indicating that the acidic Ar-OH moiety deactivates the catalyst in an irreversible manner.36, 45
Table 1 Scope of nitrile hydration catalyzed by Ru pincer complex APNP.a
a Isolated yield after reaction at room temperature for 1 day, unless noted otherwise. Conversions using
catalyst APNN under the same conditions are given in square brackets. b Reaction at 50 °C for 2 days. c Reaction
in a 1:1 mixture of THF/tBuOH due to poor solubility of the starting material. d Reaction at 50 °C for 20 hours. e Reaction at 80 °C for 16 hours. f Reaction at room temperature for 1 day with 0.5 mol% catalyst loading. g
Unhindered esters such as 4-acetoxybenzonitrile and ethyl 4-cyanobenzoate also do not form the amide products, likely because of competing ester hydrolysis to the carboxylic acids. For more hindered esters, however, the reaction works well as demonstrated by full conversion of tert-butyl 4-cyanobenzoate (1i).
Heteroaromatic nitriles are also converted, with even shorter reaction times under the standard conditions (< 1 h with 3 mol% catalyst APNP). Consequently, this class of
substrates reaches full conversion within a day at room temperature using a catalyst loading of 0.5 mol% (TON = 200). The ortho-, meta- and para-isomers of cyanopyridine (1p-r), as well as the pyrazine derivative (1s) are converted to the amide products in quantitative yields. Moreover, substrates with oxygen- (furan, 1t,u) or sulfur-containing rings (thiophenes, 1v,w), structural motifs that are often considered catalyst poisons, underwent this ruthenium-catalyzed process with remarkable ease.
Substrates with sp3-C substituents adjacent to the C≡N group react more slowly but
nevertheless are converted with complete selectivity to the amide. For example, benzyl cyanide (1x) and its α-methylated analogue (1y) show full conversion to the amide within 1 day at room temperature, and the same applies to 3-phenylpropionitrile (1z) and the sp2-substituted cinnamonitrile (1aa). While purely aliphatic nitriles also react
at room temperature, these substrates require longer reaction times to reach synthetically useful conversions (65-83% after 2 days). However, gentle heating of the reaction mixtures to 50 °C for 1 day affords amide products in >99% isolated yield for primary, secondary as well as tertiary alkylnitriles (1ab-ae). Substrates with two nitrile moieties were selectively converted to the corresponding diamides (1af/1ag). The substrates shown in Table 1 are converted by catalysts A already at room temperature (and many reach full conversion within 24 h), but, with the exception of heteroaromatic nitriles, turnover numbers (TONs) for the majority of entries are only modest due to the presence of 3 mol% catalyst (maximum TON = 33). To examine whether higher turnover numbers can be obtained, we tested the reaction at elevated temperature (70 C) for aromatic nitrile 1b and aliphatic dinitrile 1af. For 1b, hydration is initially fast (63% conversion in 1 h), but then gradually slows down to reach 98% conversion in 20 h under those conditions (TON = 196). Dinitrile 1af also gave >98% conversion of the starting material in 24 h at 70 C to afford a mixture of mono- and diamide products in a 57:43 ratio, which corresponds to a total nitrile TON of 307. Moreover, with 3-cyanopyridine (1q) the catalyst reaches 1000 turnovers within a day at 70 C, demonstrating the robustness of the catalyst at elevated temperature.
Table 2 Selection of nitrile hydration catalyzed by Ru pincer complex APNP at 70oC
3.2.2 Mechanistic considerations
To obtain insight in the species present during turnover, we monitored a catalysis reaction mixture (3 mol% APNP, 5 eq H2O in tBuOH) with the fluoro-substituted benzonitrile 1b by 19F NMR spectroscopy. This showed the presence of three distinct 19F-containing species. Two of these correspond to the nitrile starting material and the
amide product by comparison to authentic samples. A third species was present throughout the course of the reaction in minor amount (19F NMR: δ -118 ppm, ca. 2.5%
based on integration; Figure 1). This resonance was also observed in the 19F NMR of a
catalysis mixture with APNN, suggesting that APNP and APNN lead to similar speciation
under the reaction conditions.
To characterize this species and develop an understanding of the individual steps that might be involved in the catalysis, we carried out stoichiometric NMR scale experiments in THF-d8 between the dearomatized pincer complexes A and the components present
in the catalysis reaction mixture. Analysis of a 1:1 mixture of complex APNP and nitrile 1b by 1H NMR spectroscopy (Figure 2). showed a substantial broadening of the Ru-H
exchanging equilibrium between the starting materials and the Ru-nitrile adduct BPNP
(Scheme 2).37
Figure 1 19F NMR spectrum of 4-flourobenzonitrile hydration by APNP.
Scheme 2 Stoichiometric reactions between A and the components present in the reaction mixture.
The sterically less hindered PNN analogue APNN reacts with nitrile 1b to an equilibrium
mixture of CPNN and C’PNN according to NMR spectroscopy(Figure 3). In this mixture, a
characteristic 1H NMR resonance is observed at 11.65 (singlet) for the NH fragment
in C’PNN. Additionally, signals at -10.47/-13.75 ppm (doublets, JPH = 25.7/32.8 Hz)
appear for the Ru-H groups in CPNN/C’PNN. The NMR features are very similar to those
observed previously by us for the reaction of APNN and benzonitrile,37 and confirm that
the former products arise from MLC binding of the CN bond. The different outcomes of the reaction between 1b and APNN or APNP indicates that the divergent steric demands
of the PNP vs. PNN ligand affects the equilibria between species A, B and C. Although a detailed comparison between PNN- and PNP-based catalysts is beyond the scope of this research, preliminary DFT calculations indicate that MLC-binding of benzonitrile is exergonic at the N-arm (-2.7 kcal/mol) whereas it is endergonic at the P-arm (PNN: +9.4 kcal/mol; PNP: +7.2 kcal/mol). It should be noted that, even though the relative stability of the various intermediates is sensitive to steric effects, metal-ligand cooperative reaction pathways are involved in complexes with both these ligands.46-47
Regardless of the different equilibrium compositions, addition of H2O (1 equiv) to a
THF-d8 solution of both the PNN- or PNP-based mixture resulted in the slow appearance
of a new species (D) with a 19F NMR shift (ca. δ -118 ppm) that agrees well with the one
observed during catalysis in tBuOH. Compounds D were also obtained cleanly by treatment of the dearomatized Ru pincer complexes A with amide 2b, and are formulated as Ru-carboxamides (DPNN/DPNP, Scheme 2) on the basis of their NMR
Figure 3 1H NMR spectrum of stoichiometric reaction of APNN with 4-fluorobenzonitrile.
The observation that D is the dominant Ru-containing species during turnover suggests that it may be a dormant catalyst state, and that catalysis could be subject to product inhibition. Indeed, when a mixture of nitrile substrate and amide product (33 and 10 equiv, respectively, relative to APNP) is present at the start, the reaction rate is decreased
but full conversion is still obtained (Figure 4). Also, when DPNP is prepared
independently and tested in catalysis, hydration of 1b occurs with a rate that is qualitatively similar to that with APNP.
Figure 4 Conversion vs. time plot for hydration of 4-fluorobenzonitrile (3mol% APNP catalyst); left) standard reaction was followed with addition of a second batch of nitrile substrate;right)reaction wasinhibited by extra 4-fluorobenzamide (2b)
These observations indicate that the coordinatively saturated complex D is able to generate the active species via a rapid equilibrium with A. This was further confirmed by the observation that DPNN reacts with nitrile 1b to regenerate the equilibrium
mixture of CPNN and C’PNN (Figure 5), a reaction that presumably involves APNN as an
upon addition of H2O, and NMR resonances attributable to the free amide 2b
increase(water: 0→20 eq., DPNP: 95% → 88%) (Figure 6). From these data it is clear that
the catalyst speciation in this system is complex: the dearomatized pincer complexes A are involved in dynamic equilibria with H2O, nitrile, as well as amide. Thus, even though
under the reaction conditions most of the Ru is present in a coordinatively saturated, inactive form (D), access to catalytically active species is kinetically facile and allows turnover of the nitrile substrate.
Figure 5 1H NMR spectrum of stoichiometric reaction of DPNN with 4-fluorobenzonitrile.
Figure 6 Effect of water amount on the equilibrium of DPNP with APNP and 4-fluorobenzamide (2b) followed by 19F NMR.
Mechanistic proposals for catalytic nitrile hydration in the literature often involve Lewis acid activation of the nitrile, sometimes in conjunction with ligand-mediated (‘bifunctional’) deprotonation of H2O,48-53,54-56 or nucleophilic attack of a reactive
ligand-OH fragment (e.g., in catalysts with phosphinous acid ligands).57-59 For bimetallic
complexes, a reactive hydroxide group can be generated adjacent to a metal-nitrile adduct, which provides a low-energy pathway to hydration.60-63
On the basis of the results discussed above, we propose that the mechanism of nitrile hydration by A is distinct and follows the steps illustrated in Scheme 3. Under the reaction conditions, complexes A react reversibly with amide or H2O to form the
off-cycle species D and E, respectively. Although these species are not catalytically relevant, a rapid equilibrium between these dormant states and A ensures an entry into the catalytic cycle. We propose that catalysis is initiated by MLC binding of the nitrile substrate (1) to form C. The MLC mode of CN bond activation results in a reduced CN bond order of 2, and transfers the basicity ‘stored’ in the pincer framework in A onto the nitrile-derived Ru-N moiety in C. This allows deprotonation of the pro-nucleophile H2O and attack at the electrophilic C-atom of the activated nitrile to form F, either
directly or facilitated by a hydrogen-bond network involving additional H2O or tBuOH
as proton-shuttles.64-66,58 The coordinated hydroxyamido fragment in intermediate F
may be liberated from the metal complex by a retro-cycloaddition to form the iminol, which tautomerizes in solution to the final amide product (2). Alternative pathways that directly convert F to the Ru-carboxamide D cannot be ruled out at present. The proposed reaction pathway accounts for several key experimental observations, including (i) the requirement for a reactive ligand site for catalytic activity, (ii) an optimum in catalyst activity as function of the amount of water added, (iii) and the occurrence of product inhibition.
3.3 Conclusions
In summary, this work describes an efficient homogeneous catalyst for the hydration of nitriles. Complexes based on dearomatized PNP or PNN ligands are shown to be active under very mild reaction conditions (ambient temperature, additive-free). The PNP Ru pincer catalyst is tolerant to a variety of functional groups, and allows the hydration of a broad range of aliphatic, aromatic and heteroaromatic nitriles. On the basis of stoichiometric experiments, a mechanism is proposed that involves metal-ligand cooperative activation of the nitrile CN bond. The results suggest that the generation of intermediates with a C=N moiety (i.e., a reduced bond order in comparison to the nitrile starting material) via this mode of nitrile activation significantly increases its reactivity and leads to facile attack by (pro)nucleophiles as weak as H2O. We anticipate
that this strategy may be more broadly applicable and lead to novel reactivity of nitriles and other unsaturated organic compounds.
Scheme 3 Proposed catalytic cycle.
3.4 Experimental Section
3.4.1 General considerationsThe chemicals 2,6-bis(di-tert-butylphosphinomethyl)pyridine (Strem Chemicals, 99%), carbonylchlorohydridotris(triphenylphosphine)ruthenium(II) (Strem Chemicals,
99%),
[2-(di-tert-butylphosphinomethyl)-6-(diethylaminomethyl)pyridine]ruthenium(II) chlorocarbonyl hydride (precatPNN,
Sigma-Aldrich, 99%), potassium tert-butoxide (Sigma-Aldrich, ≥98%), 2-fluorobiphenyl (Sigma-Aldrich, 96%), 4-fluorobenzonitrile (1b, Sigma-Aldrich, 99%), 4-chlorobenzonitrile (1c, Aldrich, 99%), bromobenzonitrile (1d-f, Sigma-Aldrich, 99%), (trifluoromethyl)benzonitrile (1g, Sigma-Sigma-Aldrich, 99%), 4-formylbenzonitrile (1h, TCI, >98%), tert-butyl 4-cyanobenzoate (1i, Enamine Ltd, 95%), 1-naphthonitrile (1j, TCI, >95%), 2-naphthonitrile (1k, TCI, >98%), 4-methylbenzonitrile (1l, Aldrich, 98%), 4-methoxybenzonitrile (1m, Sigma-Aldrich, 99%), 4-(dimethylamino)benzonitrile (1n, TCI, >98%), 4-aminobenzonitrile (1o, Sigma-Aldrich, 98%), pyridinecarbonitrile (1p-r, Sigma-Aldrich, 98%), 2-furonitrile (1v,TCI, >98%), 3-2-furonitrile (1w, Sigma-Aldrich, >97%), terephthalonitrile (1ag, Sigma-Aldrich, 98%), 4-acetoxybenzonitrile (Fisher Scientific, 97%), 4-nitrobenzonitrile (Sigma-Aldrich, 97%), 4-hydroxybenzonitrile (Fluka, 98%) and ethyl 4-cyanobenzoate (TCI, >98%) were obtained commercially and used without further
purification. The substrates benzonitrile (1a, Sigma-Aldrich, 99%), pyrazinecarbonitrile (1s, Aldrich, 99%), 2-thiophenecarbonitrile (1t, Aldrich, 99%), 3-thiophenecarbonitrile (1u, TCI, >98%), benzyl cyanide (1x, Sigma-Aldrich, 98%), 2-phenylpropanitrile (1y, Sigma-Sigma-Aldrich, 96%), 3-phenylpropanitrile (1z, Sigma-Aldrich, 99%), cinnamonitrile (1aa, Sigma-Aldrich, 97%), n-pentanenitrile (1ac, Sigma-Aldrich, 99.5%), cyclohexanecarbonitrile (1ad, Sigma-Aldrich, 98%), pivalonitrile (1ae, Sigma-Aldrich, 98%), adiponitrile (1af, TCI, >98%), were obtained commercially, degassed and passed over columns of Al2O3 prior to use. The complex
[2,6-Bis(di-tert-butylphosphinomethyl)pyridine]ruthenium(II) chlorocarbonyl hydride (precatPNP)67-68 was prepared according to a literature procedure. Toluene was
passed over columns of Al2O3 (Fluka), BASF R3-11-supported Cu oxygen scavenger, and
molecular sieves (Aldrich, 4 Å). THF (Aldrich, anhydrous, 99.8%) was dried by percolation over columns of Al2O3 (Fluka). Tert butanol (Boom, >99%),isopropanol
(Boom, >99%), 1,4-dioxane (Boom, >99%) and acetonitrile (1ab, Boom, >99%) were dried with calcium hydride and distilled under N2 atmosphere prior to use. Doubly
distilled water was obtained from the Microanalytical Department of the University of Groningen and degassed prior to use. d8-THF and d8-toluene (Aldrich) were vacuum transferred from Na/K alloy and stored in the glovebox. The reactions for which isolated yields are reported were carried out at least twice, which led to similar results (within 5 %); the values reported are the average. NMR spectra were recorded on Varian 400, Agilent 400 or Varian Inova 500 spectrometers and referenced using the residual solvent resonance. Gas chromatography measurements were performed on HP6890 series equipped with a Rxi-5Sil column for GC/MS and HP5890 series II equipped with Rtx-1701 column for GC-MS/FID. Enantiomeric excess (ee) was determined by chiral HPLC analysis using a Shimadzu LC-20AD HPLC equipped with a Shimadzu SPD-M20A diode array detector. Elemental analysis and high resolution mass spectra (HRMS) were performed at the Microanalytical Department of the University of Groningen.
Table 3: Solvent screening for hydration of acetonitrile. Conditions: 3 mol% of catalyst APNP at room temperature in the presence of 5 equiv. of water.
Table 5: Influence of catalyst structure and reaction temperature on the hydration of acetonitrile
3.4.3 Synthetic procedures
3.4.3.1 Preparation of stock solutions of catalysts and reagents
APNP catalyst (stock solution 1): In the glovebox, the catalyst precursor
(PNP)Ru(Cl)(H)(CO) (precatPNP, 28.0 mg, 0.050 mmol) was dissolved in 5 mL of toluene
in a 20 ml vial, and then cooled in the freezer to -32 oC. Subsequently, tBuOK (5.6 mg,
0.050 mmol, 1 eq.) was added and the vial was stored at -32 oC for 1 hour, after which
it was allowed to warm to room temperature and stirred for another 3 hours. The solution was filtered and toluene was added to achieve a total volume of 10 mL. This stock solution (0.0050 mol/L) was stored at -32 oC for later use.
APNP catalyst (stock solution 2, used for reactions on larger scale): In the glovebox, the
catalyst precursor (PNP)Ru(Cl)(H)(CO) (precatPNP, 0.375 mmol, 213.0 mg) was
dissolved in 25 mL of toluene in a 25 ml vial, and then cooled in the freezer to -32 oC.
Subsequently, tBuOK (42.0 mg, 0.375 mmol, 1 eq.) was added and the vial was stored at
-32 oC for 1 hour, after which it was allowed to warm to room temperature and stirred
for 1 hours. Then the green solid was dissolved in 25 ml tBuOH and the stock solution (0.0150 mol/L) was used immediately.
APNN catalyst stock solution: In the glovebox, the catalyst precursor (PNN)Ru(Cl)(H)(CO)
(precatPNN, 14.7 mg, 0.030 mmol) was dissolved in 4 mL of toluene in a 20 ml vial, and
then cooled in the freezer to -32 oC. Subsequently, tBuOK (3.4 mg, 0.030 mmol, 1 eq.)
was added and the vial was stored at -32 oC for 1 hour, after which it was allowed to
warm to room temperature and stirred for another 3 hours. This stock solution (0.0075 mol/L) was stored at -32 oC for later use.
4-fluorobenzonitrile stock solution: A stock solution (0.30 mol/L) was prepared by
dissolving 18.2 mg of 4-fluorobenzonitrile in 0.5 ml d8-THF.
4-fluorobenzamide stock solution: A stock solution (0.24 mol/L) was prepared by
dissolving 16.7 mg of 4-fluorobenzamide in 0. 5ml d8-THF.
Water stock solution: A stock solution (1.70 mol/L) was prepared by dissolving 9.2 μl of
H2O in 300 μl of anhydrous d8-THF.
3.4.3.2 General procedure for catalytic nitrile hydration experiments
In the glovebox, 1.5 mL of a 0.0050 mol/L stock solution of APNP catalyst (0.0075 mmol)
was added to a 20 mL vial. After removal of all volatiles under vacuum, 0.5 ml tBuOH
was added to dissolve catalyst again. After ca. 2 min, water (22.5 μl, 1.25 mmol) was added to the catalyst solution, and then the mixture was transferred into a 2 mL GC vial (equipped with a Teflon-lined screw cap and additionally sealed with parafilm) containing the nitrile (0.25 mmol). The reaction mixture was taken out of glovebox and stirred for 16 h to 1 day at rt or 50/80oC. After this time, the reaction mixture was
exposed to air to deactivate the catalyst. The procedure for subsequent workup depended on the nature of the reaction mixture:
Procedure a) If precipitated solid product was precipitated during the reaction, 3 mL of ether was added into the vial and the solid product was isolated by filtration and washed with ether. The filtrate was concentrated under vacuum to a viscous oil, then washed with ether/pentane (5:1, 3x2 ml) precipitating the second portion; collecting all the white solid and drying under vacuum gave >99% yield;
Procedure b) If no solid was precipitated during the reaction, the solvent was removed under vacuum to give a viscous oil and the residue was washed with ether/pentane (5:1 or 10:1) to precipitate a solid product; collecting all the white solid and drying under vacuum gave 90-99% yields.
3.4.3.3 Reactions performed on larger scale
Catalytic hydration reactions for a series of representative nitriles were performed on 2.5 mmol scale. For nitriles 1a, 1b, 1i and 1ad, 5 mL of a 0.0150 M stock solution of APNP
catalyst (0.0750 mmol, 3 mol%) was added to a 20 mL vial containing the nitrile. For nitrile 1r, 0.8 mL of a 0.0150 M stock solution of APNP catalyst (0.0120 mmol, 0.5 mol%)
was diluted with 4.2 mL of tBuOH and added to a 20 mL vial containing the nitrile. Water
(225 μl, 5 equiv relative to nitrile) was added to each of the vials and the mixtures were stirred at 50oC (1ad) or rt (1a, 1b, 1i and 1r) inside the glovebox. To monitor reaction
progress, samples for GC analysis were taken at regular time intervals from each of these reaction mixtures. After the reaction went to completion, workup was carried out as described above.
benzonitrile (1a): 257.5 mg (2.5 mmol) of 1a afforded 287.4 mg (2.38 mmol, 95%) of
benzamide (2a). Elemental analysis for C7H7NO: Calculated: C, 69.41; H, 5.82; N, 11.56;
Found: C, 69.44; H, 5.75; N, 11.42.
4-fluorobenzonitrile (1b): 302.5 mg (2.5 mmol) of 1b afforded 336 mg (2.42 mmol,
97%) of 4-fluorobenzamide (2b). Elemental analysis for C7H6FNO: Calculated: C, 60.43;
H, 4.35; N, 10.07; Found: C, 60.64; H, 4.44; N, 9.97.
4-methylbenzonitrile (1i): 292.5 mg (2.5 mmol) of 1i afforded 335.8 mg (2.49 mmol,
99%) of 4-methylbenzamide (2i). Elemental Analysis for C8H9NO: Calculated: C, 71.09;
H, 6.71; N, 10.36; Found: C, 71.26; H, 6.67; N, 10.24.
Cyclohexanecarbonitrile (1ad): 272.5 mg (2.5 mmol) of 1ad afforded 305.0 mg (2.40
mmol, 96%) of cyclohexanecarboxamide (2ad). Elemental Analysis for C7H13NO:
Calculated: C, 66.11; H, 10.30; N, 11.01; Found: C, 66.09; H, 10.18; N, 10.83.
4-pyridinecarbonitrile (1r): 260.0 mg (2.5 mmol) of 1r afforded 304.0 mg (2.49 mmol,
99%) of 4-pyridinecarboxamide (2r). Elemental Analysis for C6H6N2O: Calculated: C,
59.01; H, 4.95; N, 22.94; Found: C, 58.87; H, 4.84; N, 22.93.
Figure 7. Conversion vs. time plot for hydrdation of nitriles using APNP as catalyst in tBuOH (3 mol%, 5 eq of
H2O). Reaction progress monitored at room temperature, except for cyclohexane carbonitrile (Cy), which was
3.4.3.4 Characterization of amide products 4-bromobenzamide (2d)
1H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H, NH), 7.81 (d, J = 8.2 Hz, 2H, Ph), 7.66 (d, J =
8.2 Hz, 2H, Ph), 7.45 (s, 1H, NH); 13C NMR (101 MHz, DMSO-d6) δ 166.9(CONH2), 133.4
(1-Ph), 131.2 and 129.6 (o, m-Ph), 125.0 (p-Ph). HRMS (ESI) calcd. for C7H6BrNO [M+H+]
199.97055, found 199.97005.
4-formylbenzamide (2h)
1H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H, CHO), 8.17 (s, 1H, NH), 8.05 (d, J = 8.0 Hz,
2H, Ph), 7.98 (d, J = 8.0 Hz, 2H, Ph), 7.60 (s, 1H, NH).13C NMR (101 MHz, DMSO-d6) δ
192.9 (CHO), 167.1 (CONH2), 139.3 and 137.8 (Ph, quaternary C), 129.4 and 128.2 (o,
m-Ph). HRMS (ESI) calcd. for C8H7NO2 [M+H+] 150.05496, found 150.05477.
tert-butyl 4-cyanobenzoate (2i)
1H NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H, NH), 7.97(d, J = 9.1 Hz, 2H, Ph), 7.95(d, J =
9.1 Hz, 2H, Ph), 7.55 (s, 1H, NH), 1.55 (s, 9H, tBu); 13C NMR (101 MHz, DMSO-d6) δ
167.1(CONH2), 164.4(COOtBu), 138.0 and 133.5 (Ph, quaternary C), 128.9 and 127.7 (o,
m-Ph), 81.2 (C(CH3)3), 27.7 (C(CH3)3). HRMS (ESI) calcd. for C12H15NO3 [M+H+]
222.11247, found 222.11229.
1H NMR (400 MHz, DMSO-d6) δ 7.74 (d, J = 8.7 Hz, 2H,o-Ph ), 7.63 (s, 1H, NH), 6.93 (s,
1H, NH), 6.67 (d, J = 8.7 Hz, 2H, m-Ph), 2.95 (s, 6H, N(CH3)2); 13C NMR (101 MHz,
DMSO-d6) δ 168.0 (CONH2), 152.1 (p-Ph), 128.9 (o-Ph), 121.0 (1-Ph), 110.7 (m-Ph), 39.7(CH3).
HRMS (ESI) calcd. for C9H12N2O [M+H+] 165.10224, found 165.10172.
3-furanamide (2w)
1H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H, 1-furan), 7.69 (dd, J = 1.7 Hz, 1H, 4-furan),
7.64 (s, 1H, NH), 7.18 (s, 1H, NH), 6.80 (d, J = 1.9 Hz, 1H, 3-furan); 13C NMR (101 MHz,
DMSO-d6) δ 163.4 (CONH2), 145.3 (1-furan), 143.9 (4-furan), 122.9 (2-furan), 109.3
(3-furan). HRMS (ESI) calcd. for C5H5NO2 [M+H+] 112.03930, found 112.03902.
Acetamide (2ab)
1H NMR (400 MHz, D2O) δ 2.01 (s, 1H, CH3); 13C NMR (101 MHz, D2O) δ 180.0(CO),
23.9(CH3).
3.4.3.5 Stoichiometric NMR scale reactions for PNP complexes Reaction of APNP with 4-fluorobenzonitrile (1b)
A solution of APNP was prepared as described above from precatPNP (15.6 mg, 0.028
mmol) and tBuOK (3.1 mg, 0.028 mmol, 1 eq.) in 5 mL of toluene. After the toluene was
4-fluorobenzonitrile stock solution (0.028 mmol, 1 eq.), and the solution was transferred into a J. Young NMR tube. Analysis of the NMR spectral data shows the formation of an equilibrium mixture of BPNP in rapid exchange with the starting
materials APNP + 4-fluorobenzonitrile.37
NMR data for the equilibrium mixture [APNP + 1b ⇄ BPNP]:
19F NMR (376 MHz, THF-d8) δ -102.8;
31P NMR (162 MHz, THF-d8) δ 84.8 (d, J = 219.9 Hz), 78.7 (d, J = 219.9 Hz).;
1H NMR (500 MHz, THF-d8) δ 7.73 (dd, J = 8.8, 5.0 Hz, 2H, o-Ph), 7.29 (dd, J = 8.3 Hz,
2H, m-Ph), 6.23 (t, J = 7.7 Hz, 1H, Py-4H), 6.01 (d, J = 8.8 Hz, 1H, Py-5H), 5.39 (d, J = 6.4 Hz, 1H, Py-3H), 3.43 (d, J = 4.0 Hz, 1H, Py-2-CH), 3.16 (d, J = 8.7 Hz, 2H, Py-5-CH2), 1.37
– 1.27 (m, 36H, tBu), -19.06 (s, 1H, RuH).
Reaction of APNP with 4-fluorobenzonitrile (1b) and water
Subsequent addition of 16.4 μl of H2O stock solution (1.70 mol/L, 0.028 mmol, 1 eq.)
to the mixture described above resulted in the slow appearance of a new set of NMR signals that is attributed to the Ru-carboxamide species DPNP as the major product.
NMR data for DPNP:
19F NMR (376 MHz, THF-d8) -118.3 (DPNP);
31P NMR (162 MHz, THF-d8) 82.3(DPNP);
1H NMR (500 MHz, THF-d8) δ -13.05 (t, J = 19.8 Hz, 8H, RuH of DPNP). Characterization of DPNP
Assignment of the major product from the above NMR scale reaction (APNP+ 1b + H2O)
In a glovebox, 1 ml of APNP stock solution (0.017 mol/L, 0.017 mmol) was added to a
vial. After removal of all volatiles, 0.5 mL of d8-THF was added to dissolve the catalyst. Then 70 μl of 4-fluorobenzamide (2b) stock solution (0.24 mol/L, 0.017 mmol) was added. The solution was transferred into a J. Young NMR tube and taken out of the glovebox. NMR characterization data are consistent with formation of DPNP as the major
species (> 90%). In addition to compound DPNP, the Ru-H resonance of APNP as well as
amide 2b are visible, which shows that these are in equilibrium. NMR data for DPNP: 19F NMR (376 MHz, THF-d8) δ -118.3. 31P NMR (162 MHz, THF-d8) δ 82.3. 1H NMR (400 MHz, THF-d8) δ 7.56 (dd, J = 8.8, 5.9 Hz, 2H, o-Ph), 7.51 (t, J = 7.7 Hz, 1H, Py-4H), 7.21 (d, J = 7.7 Hz, 2H, Py-3,5H), 6.82 (dd, J = 8.8 Hz, 2H, m-Ph), 4.66 (s, 1H, NH), 4.16 (d, J = 16.3 Hz, 2H, py-2,6-CH2), 3.52 (dt, J = 16.3, 3.9 Hz, 2H, py-2,6-CH2), 1.35 (dd, J = 6.4 Hz, 18H, PtBu2), 1.29 (t, J = 6.4 Hz, 18H, PtBu2), -13.04 (t, J = 19.9 Hz, 1H, RuH). 13C NMR (101 MHz, THF-d8) δ 209.8 (RuCO), 172.3 (CONH), 165.3 (py-2,6C), 163.45 (d,
J = 243.7 Hz, 4C), 140.9 (1C), 137.7 (py-4C), 129.32 (d, J = 8.1 Hz,
p-F-ph-oC), 120.1 (py-3,5C), 114.17 (d, J = 21.0 Hz, p-F-ph-pC), 39.4 (py-2,6-CH2), 37.50 (dd, J
= 5.3 Hz, C(CH3)3), 36.56 (dd, J = 10.6 Hz, C(CH3)3), 30.5 and 30.0 C(CH3)3).
Reaction of DPNP with water
An NMR solution of DPNP, prepared as described above, was treated with increasing
amounts of water by sequential addition of a 1.70 mol/L stock solution (0.5, 1, 2, 5, 10, 20 eq). After each addition, NMR spectra were recorded.
Before addition of water, the mixture of APNP + amide 2b shows the formation of DPNP
as the major product, with a small amount of APNP left in the equilibrium mixture.
Addition of water results in broadening and ultimately disappearance (> 10 equiv H2O)
of the signals due to APNP, with concomitant appearance of a new Ru-H triplet at -14.68
ppm. In the 31P NMR spectrum, a new resonance at 86.3 ppm appears. These signals are
attributed to the Ru-hydroxide species shown in the scheme (RuOH) by comparison to the literature values reported this compound.69-70 The changes in the 19F NMR spectrum
upon addition of increasing amounts of water show that the amount of free amide 2b in solution (relative to that bound in DPNP) increases ca. twofold upon addition of 20
equiv of water, and the data indicate that the deromatized species APNP is involved in
dynamic equilibria with nitrile, amide and water.
Figure 8. Effect of water amount on the equilibrium of DPNP with APNP and 4-fluorobenzamide (2b) followed by 1H NMR
3.4.3.6 Stoichiometric NMR scale reactions for PNN complexes Reaction of APNN with 4-fluorobenzonitrile (1b)
In a glovebox, 2 ml of APNN stock solution (0.0075 mol/L, 0.015 mmol) was added to a
vial. After removal of all volatiles, 0.5 mL of d8-THF was added to dissolve the catalyst. Then 50 μl of 4-fluorobenzonitrile stock solution (0.30 mol/L, 0.015 mmol) was added. The solution was transferred into a J. Young NMR tube and taken out of glovebox. NMR characterization data are consistent with formation of an equilibrium mixture of CPNN
and C’PNN in a ratio of 1 : 3.84. In addition, resonances due to the equilibrium [APNN + 1b
⇄ BPNN] were observed (e.g., Ru-H at -25.24) that account for ca. 7% of the total Ru-H
concentration.
selected NMR data for CPNN and C’PNN:
19F NMR (376 MHz, THF-d8) δ -109.6(C’ PNN), -118.0(CPNN).
31P NMR (162 MHz, THF-d8) δ 117.6 (CPNN), 102.1 (C’PNN).
1H NMR (500 MHz, THF-d8) δ 11.65 (s, 3.2H, NH of C’PNN), -10.47 (d, J = 25.7 Hz, 1H, RuH
of CPNN), -13.75 (d, J = 32.8 Hz, 3.8H, RuH of C’PNN). Reaction of APNN with 4-fluorobenzonitrile (1b) and water
Subsequent addition of 8.8 μl of a H2O stock solution (1.7 mol/L, 0.015 mmol) to the
mixture described above resulted in the slow appearance of a new set of NMR signals that is attributed to the Ru-carboxamide species DPNN as the major Ru-containing
product.
NMR data for DPNN:
19F NMR (376 MHz, THF-d8) δ -117.7 31P NMR (162 MHz, THF-d8) δ 105.3
1H NMR (400 MHz, THF-d8) δ -13.06 (d, J = 26.9 Hz, RuH)
Characterization of DPNN
Assignment of the major product from the above NMR scale reaction (APNN + 1b + H2O)
as compound DPNN was corroborated by an independent synthesis as described below.
In glovebox, a small vial was added with 2 ml of 0.0075 mol/L APNN stock solution
(0.0150 mmol, 1 eq.). After under vacuum for 0.5 hour, 0.5 ml d8-THF was added to dissolve the catalyst (dark red). Then 63 μl of 0.24 mol/L 4-fluorobenzamide (0.0150 mmol, 1 eq.) was added forming amide adduct DPNN (light yellow). The solution was
then transferred into a J. Young NMR tube and taken out of glovebox to characterize by NMR spectroscopy, which shows full conversion to DPNN.
19F NMR (376 MHz, THF-d8) δ -117.7. 31P NMR (162 MHz, THF-d8) δ 105.3.
1H NMR (400 MHz, THF-d8) δ 7.70 – 7.64 (m, 2H,p-F-Ph-oH ), 7.61 (t, J = 7.7 Hz,
1H,Py-4H), 7.32 (d, J = 7.8 Hz, 1H, py-3H), 7.14 (d, J = 7.2 Hz, 1H, py-5H), 6.92 – 6.81 (m, 2H,
p-F-Ph-mH), 5.21 (s, 1H, NH), 4.75 (d, J = 14.3 Hz, 1H,py-6-CH2), 3.87 (dd, J = 14.4, 2.6 Hz,
1H, py-6-CH2), 3.81 (dd, J = 16.8, 9.5 Hz, 1H, py-2-CH2), 3.41 – 3.19 (m, 3H, py-2-CH2 and
N(CH2CH3)2), 2.96 – 2.85 (m, 2H, N(CH2CH3)2 ), 1.29 (d, J = 12.9 Hz, 9H,PtBu2), 1.28 (t, J
= 7.0 Hz, 3H, N(CH2CH3)2), 1.23 (d, J = 12.9 Hz, 9H, PtBu2), 1.06 (t, J = 7.2 Hz, 3H,
N(CH2CH3)2), -13.06 (d, J = 26.9 Hz, 1H, RuH).
13C NMR (101 MHz, THF-d8) δ 209.2 (d, J = 16.3 Hz, RuCO), 172.3 (CONH), 163.3 (d, J =
244.1 Hz, F-ph-4C), 162.4 (d, J = 3.9 Hz, py-2C), 161.6 (py-6C), 140.2 (d, J = 2.9 Hz, p-F-ph-1C), 137.0 (py-4C), 129.2 (d, J = 8.0 Hz, p-F-ph-oC ), 120.3 (d, J = 9.7 Hz, py-3C), 119.1 (py-4C), 114.0(d, J = 21.1 Hz, p-F-ph-mC), 66.5 (py-6-CH2), 55.6 and 50.6
(N(CH2CH3)2), 38.1 (d, J = 20.1 Hz, py-2-CH2), 36.7 (d, J = 12.6 Hz, C(CH3)3), 36.4 (d, J =
25.5 Hz, C(CH3)3), 29.9 (d, J = 3.1 Hz, C(CH3)3), 29.5 (d, J = 4.5 Hz, C(CH3)3), 11.6 and 8.6
(N(CH2CH3)2).
To a NMR solution of DPNN, prepared as described above, was added 50 μl of a 0.30
mol/L stock solution of 4-fluorobenzonitrile (0.015 mmol, 1 eq.), resulting in a color change to light brown. Analysis of the NMR spectral data showed immediate conversion (ca. 13%) of DPNN to the CN addition products CPNN and C’PNN. This demonstrates that
compounds CPNN are kinetically accessible from DPNN and nitrile.
19F NMR (376 MHz, THF-d8) δ-109.7(C’PNN), -117.7(DPNN), -118.0(CPNN);
31P NMR (162 MHz, THF-d8) δ 117.6(CPNN), 105.3(DPNN), 102.1(C’ PNN);
1H NMR (400 MHz, THF-d8) δ 11.65 (s, 1H, NH of C’PNN), -10.47 (d, J = 25.8 Hz, 0.22H,
RuH of CPNN), -13.06 (d, J = 26.9 Hz, 8H, RuH of DPNN), -13.76 (d, J = 32.8 Hz, 1H, RuH of C’PNN).
3.4.3.7 Catalyst inhibition
Hydration of 4-fluorobenzonitrile (1b) under standard conditions, with addition of a new batch of substrate after completion
In a glovebox, 0.5 mL of a stock solution of APNP (0.0015 mol/L, 0.0075 mmol, 3 mol%)
was added to a vial. After removal of volatiles under vacuum for 0.5 hour, 0.5 mL of
tBuOH and 22.5 ul of water (5 eq.) were added to dissolve the catalyst. The solution was
then transferred into another vial containing 4-fluorobenzonitrile (30.3 mg, 121, 0.25 mmol) and an internal standard (2-fluorobiphenyl, 5 mg). The solution was quickly transferred to a J. Young NMR tube and measured by 19F NMR spectroscopy for 10h.
After this time, 19F NMR spectroscopy indicated > 98% conversion of nitrile 1b to the
corresponding amide 2b. The tube was taken into the glovebox and another batch of 4-benzonitrile (30.3 mg, 1 eq.) and water (5.4 ul, 1eq.) were added into the J. Young NMR tube. The reaction was monitored by 19F NMR again for another 15h. Figure S10 shows
the conversion vs. time plot of the two sequential nitrile hydration reactions, indicating that a second batch of substrate is converted with a somewhat lower reaction rate.
Catalysis with additional amide present from the start.
To test whether the decreased rate in experiment (a) above is due to decomposition of the catalyst, or due to product inhibition, we subsequently carried out a catalytic nitrile
hydration reaction under identical conditions, but now with 0.075 mmol amide 2b present at the start (0.3 equiv. with respect to nitrile 1b).
The catalyst solution in tBuOH (prepared as described above, 3 mol% APNP + 5 eq. of
water) was transferred into a vial containing a mixture of 4-fluorobenzonitrile (30.3 mg, 121, 0.25 mmol), 4-fluorobenzamide (10.4 mg, 139, 0.075 mmol, 0.3 eq.) and internal standard (2-Fluorobiphenyl, 5 mg). The solution was quickly transferred to a J. Young NMR tube and measured by 19F NMR spectroscopy for 10 h. A comparison of the
data with and without amide 2b added at the start (Figure S11) shows that product inhibition takes place.
Effect of nitro group on hydration of nitrile
To test whether the catalyst is deactivated by nitro-groups (as suggested by the lack of catalytic turnover for p-nitrobenzonitrile), the hydration of 1b was carried out in the presence of an equimolar amount of nitrobenzene.
In a glovebox, a small vial was charged with 0.0015 mol/L APNP stock solution (0.5 ml,
0.0075 mmol, 3 mol%). After removal of the volatiles under vacuum for 0.5 hour, 0.5 ml of tBuOH and 22.5 ul of water (5 eq.,) were added to dissolve the catalyst. The solution
was transferred into another vial containing a mixture of 4-fluorobenzonitrile (30.3 mg, 0.25 mmol), nitrobenzene (30.8 mg, 0.25 mmol, 1 eq.) and internal standard (2-Fluorobiphenyl, 5 mg). The solution was quickly transferred to a J. Young NMR tube and measured by 19F NMR spectroscopy for 10 h. A comparison of the data collected in the
presence/absence of nitrobenzene is shown in Figure S12, indicating that the catalyst is not deactivated by the -NO2 functional group.
Figure 9. Conversion vs. time plot for hydration of 4-fluorobenzonitrile (1b) with additive of nitrobenzene
0 10 20 30 40 50 60 70 80 90 100 0 100 200 300 400 500 600
con
v/
%
t/min
standard condition nitrobenzene3.4.4 Preliminary DFT calculations
Geometry optimizations were carried out using density functional theory with the TPSS functional71 and def2-TZVP basis set72 on all atoms. The W06 density fitting set
was employed. Calculations were carried out with a SMD solvation model73 with
isopropanol, and an empirical dispersion correction using Grimme’s D3 damping function.74 The calculations converged on minima on the potential energy surface, as
confirmed by a frequency analysis (no imaginary frequencies). Gibss free energies of the nitrile-MLC activation products C (all with PhCN bound) shown below are relative to the dearomatized precursors A and PhCN computed at the same level of theory.
CPNP CPNN (addition to P-arm) CPNN (addition to N-arm)
G 7.2 kcal/mol 9.4 kcal/mol -2.7 kcal/mol
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