The key role of the latent N-H group in Milstein's catalyst for ester hydrogenation

Abstract

We previously demonstrated that Milstein's seminal diethylamino-substituted PNN-pincer-ruthenium catalyst for ester hydrogenation is activated by dehydroalkylation of the pincer ligand, releasing ethane and eventually forming an NHEt-substituted derivative that we proposed is the active catalyst. In this paper, we present a computational and experimental mechanistic study supporting this hypothesis. Our DFT analysis shows that the minimum-energy pathways for hydrogen activation, ester hydrogenolysis, and aldehyde hydrogenation rely on the key involvement of the nascent N-H group. We have isolated and crystallographically characterized two catalytic intermediates, a ruthenium dihydride and a ruthenium hydridoalkoxide, the latter of which is the catalyst resting state. A detailed kinetic study shows that catalytic ester hydrogenation is first-order in ruthenium and hydrogen, shows saturation behavior in ester, and is inhibited by the product alcohol. A global fit of the kinetic data to a simplified model incorporating the hydridoalkoxide and dihydride intermediates and three kinetically relevant transition states showed excellent agreement with the results from DFT.

Scheme 1. Reversible activation of hydrogen mediated by RuPNN^dearom.

Scheme 2. Dehydroalkylation of Milstein's catalyst and reversible H₂ addition giving RuPNN^HEt.

Scheme 3. Two linked catalytic cycles for ester hydrogenation.

Scheme 4. Species considered as plausible resting states. Energies given represent standard-state free energies in kcal mol⁻¹ at 298.15 K relative to a2.

Fig. 1. Minimum-energy pathway for hydrogen activation to convert the hydrido-ethoxide resting state a2 into dihydride intermediate g1. Throughout this work, atoms in bold and blue represent those atoms principally involved in bond-breaking and bond-forming events in transition states. Atoms shown in turquoise represent neutral ethanol molecules interacting with the main fragment through hydrogen bonds. Small molecules entering or leaving the sequence are in red. Energies given represent standard-state free energies in kcal mol⁻¹ at 298.15 K, relative to a2 and the organic reactants unless otherwise stated.

Fig. 2. MEP for hydrogenolysis of ethyl acetate to acetaldehyde and ethanol, accompanied by conversion of dihydride intermediate g1 into unsaturated intermediate c2, which connects back to the hydrogen-activation pathway shown in Fig. 1. Note that the standard-state free energy of 13.7 kcal mol⁻¹ reported here for c2 corresponds to release of acetaldehyde and binding of ethanol from n, whereas the free-energy of 8.2 kcal mol⁻¹ reported for c2 in Fig. 1 is calculated against the ethyl acetate and dihydrogen reactants.

Fig. 3. MEP for hydrogenation of acetaldehyde to ethanol, accompanied by conversion of dihydride intermediate g1 into unsaturated intermediate c1, which connects back to the hydrogen-activation pathway shown in Fig. 1. For consistency in this energy diagram, the free energy of intermediate g1 (9.1 kcal mol⁻¹) is calculated based on the organic intermediates ethanol, acetaldehyde, and one molecule of hydrogen, whereas the free energy of 2.8 kcal mol⁻¹ shown in Fig. 1 and 4 is based on the organic reactants ethyl acetate and two molecules of hydrogen. This presentation ensures that free energy changes within each figure are correct (e.g. the standard-state free energy change on substituting ethanol for acetaldehyde in converting from g1 to r is 3.2 kcal mol⁻¹ as shown in this figure).

Fig. 4. Simplified energy surface determining the kinetics of ester hydrogenation.

Fig. 5. Simplified kinetic model of the MEP for ester hydrogenation (black), and reasonable alternative pathways including different numbers of explicit ethanol molecules (blue). Numbers given after each species represent standard-state free energies (kcal mol⁻¹) at 298.15 K.

Scheme 5. Synthesis of RuPNN^HEt.

Fig. 6. ORTEP diagram of RuPNN^HEt, showing 50% probability ellipsoids. Hydrogen atoms other than Ru–H and N–H are omitted for clarity. Selected bond lengths (Angstroms) and angles (degrees): Ru(1)–P(2), 2.2536(6); Ru(1)–N(15), 2.1893(19); Ru(1)–N(9), 2.0980(19); Ru(1)–C(22), 1.830(2); C(22)–O(23), 1.164(3); P(2)–Ru(1)–N(9), 82.45(6); N(9)–Ru(1)–N(15), 78.71(7).

Scheme 6. Synthesis of RuPNN^HOEt.

Fig. 7. ORTEP diagram of RuPNN^HOEt, showing 50% probability ellipsoids. Hydrogen atoms other than Ru–H, N–H, and O–H are omitted for clarity. Selected bond lengths (Angstroms) and angles (degrees): Ru(1)–P(2), 2.2671(5); Ru(1)–N(13), 2.1056(14); Ru(1)–N(19), 2.1693(14); Ru(1)–O(22), 2.1980(12); Ru(1)–C(25), 1.8357(19); C(25)–O(26), 1.159(2); H(1)–O(22), 1.725; H(3)–O(22), 2.212; P(2)–Ru(1)–N(13), 82.60(4); N(13)–Ru(1)–N(19), 77.78(5).

Scheme 7. Standard conditions for kinetic experiments.

Fig. 8. Comparison of hexyl hexanoate hydrogenation catalyzed by RuPNN^imine with and without preactivation of the catalyst by incubation under 20 bar hydrogen for 90 minutes. The top plots show [ester] vs. time; dashed lines are merely to guide the eye and do not represent a fit to the data. The bottom plots show ln[ester] vs. time, with linear fits to all data (with preactivation) or to the time points from 45 minutes on (without preactivation).

Fig. 9. Determination of the partial order in RuPNN^imine under the standard conditions. The top plots show the time course of ester conversion using different initial concentrations of RuPNN^imine, along with linear fits to the logarithm of [ester], using data after the induction period of 45 minutes. The bottom plot shows the linear relationship between k_obs and [RuPNN^imine].

Fig. 10. Determination of the partial order in hydrogen under the standard conditions. The top plots show the time course of ester conversion, along with linear fits to the logarithm of [ester], using data after the induction period of 45 minutes. The bottom plot shows the linear relationship between k_obs and hydrogen pressure.

Fig. 11. Optimized kinetic model. The free energies of a2, g2, g1, and g were held fixed at the indicated values. The free energies of f2-g2-TS, m-n-TS, and m1-n1-TS were adjusted to achieve the best global fit to the kinetic data. HH refers to hexyl hexanoate and HA refers to 1-hexanol.

Fig. 12. Data (points) and global fit (lines) for all 18 kinetic experiments. In the standard conditions, [hexyl hexanoate]₀ = 0.25 M, [hexyl alcohol]₀ = 0 M, [RuPNN^imine]₀ = 1.00 mM, and P_hydrogen = 20 bar. The global fit was based on all data from 45 minutes on in each kinetic experiment. Note that the vertical axes are plotted logarithmically.

Fig. 13. Effect of added isopropyl alcohol on the hydrogenation of hexyl hexanoate. The top plots show the time course of ester conversion using different initial concentrations of isopropyl alcohol, along with linear fits to the logarithm of [ester], using data after the induction period of 45 minutes. The bottom plot shows k_obsvs. [isopropyl alcohol].

Scheme 8. Disproportionation of 1-hexanal.