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

Article abstract of DOI:10.1039/d1sc00703c

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.

Full text of DOI:10.1039/d1sc00703c

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The key role of the latent N–H group in Milstein's
catalyst for ester hydrogenation†
Cite this: Chem. Sci., 2021, 12, 8477
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have been paid for by the Royal Society
of Chemistry
John Pham,
Thao Kim,
Cole E. Jarczyk,
Tianyi He, Jason M. Keith
Eamon F. Reynolds,
Sophie. E. Kelly,
*
*
and Anthony R. Chianese
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.
Received 3rd February 2021
Accepted 14th May 2021
DOI: 10.1039/d1sc00703c
rsc.li/chemical-science
In the years since the initial reports on RuPNNdearom, many
researchers have studied the effect of catalyst structure on
Introduction
activity in ester hydrogenation, and several highly optimized
catalysts have been discovered that give more than 10 000
turnovers at full substrate conversion.4 Common to almost all of
these elite catalysts is an N–H functional group on the ligand. In
some cases, the N–H group was demonstrated to be essential for
high catalytic activity through the synthesis of control ligands
where N–H was replaced with N–Me, N–Bn, or O.4a,c,e In many
cases, minimum-energy pathways involving deprotonation of
the N–H group have been identied through density functional
theory,4c,f,h,i,5 although recent computational work has suggested
that in some cases, the N–H group may function in catalysis as
a hydrogen-bond donor without being deprotonated on the
catalytic cycle.5b,6 Although many of the most highly active
catalysts for ester hydrogenation feature an N–H functional
group, several structural motifs lacking an N–H group have also
been reported. In particular, several ruthenium catalyst variants
Catalytic transformations relying on metal–ligand-cooperative
hydrogenation or dehydrogenation of polar substrates have
seen a dramatic expansion in development over the past decade
and a half, following the disclosure by Milstein and co-workers
of the PNN-pincer–ruthenium complex RuPNNdearom (Scheme
1), shown to be active under relatively mild conditions for the
hydrogenation of esters to alcohols,1 as well as the reverse
reaction, the acceptorless dehydrogenative coupling (ADC) of
primary alcohols to esters.2 This complex has since been
applied to a wide range of mechanistically related trans-
formations.3 In the original reports, the dearomatized complex
RuPNNdearom was shown to react reversibly with hydrogen at
room temperature to give the rearomatized dihydride complex
RuPNNH2. Based on this observation, a mechanism was
proposed that involved this heterolytic cleavage of hydrogen as
a key step in catalytic ester hydrogenation.
Department of Chemistry, Colgate University, 13 Oak Drive, Hamilton, New York
13346, USA. E-mail: jkeith@colgate.edu; achianese@colgate.edu
† Electronic supplementary information (ESI) available: Computational and
experimental methods. Alternative pathways calculated by DFT and table of
computed energies, images of NMR spectra for RuPNNHOEt, details of kinetic
modeling (PDF). Atomic coordinates (XYZ) for all computed molecular
structures, compiled as one le readable by the free program Mercury32
(compiled.xyz). Animations (GIF) for the imaginary vibrational modes of all
calculated transition states (TS animations.zip). Copasi model (model.cps) and
kinetic data in the format accepted by Copasi (data.txt). CCDC 2057608 and
2057609. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/d1sc00703c
Scheme
1
Reversible activation of hydrogen mediated by
.
RuPNNdearom
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featuring dialkylamino side groups like RuPNNdearom have functional theory to predict the mechanism of ester hydroge-
shown activity.4d,7
nation or the reverse ADC, catalyzed by RuPNNdearom
.
Since
13
During mechanistic studies of our previously reported7c,d,8 these studies rely on the catalytic intermediacy of RuPNNdearom
CNN-pincer–ruthenium catalysts for ester hydrogenation, we or RuPNNH2, they too are unlikely to be correct. More broadly,
made a surprising observation: precatalysts featuring NEt2 or RuPNNdearom has been applied as a catalyst for a wide range of
NiPr2 side groups underwent an unexpected dehydroalkylation related hydrogenation and dehydrogenation reactions,
reaction, releasing an equivalent of ethane or propane early on including amine–alcohol coupling,3a–d couplings of amines3e or
in catalytic reactions.9 The observation of catalytic induction alcohols3f with esters, organic carbonate hydrogenation,3g
periods concomitant with the release of alkane established that carbon dioxide hydrogenation,3h and amide a-alkylation with
dehydroalkylation was a necessary step in formation of the alcohols.3i All of these transformations are conducted at or
active catalyst. Milstein's catalyst RuPNNdearom, which features above 100 ꢀC, where the dehydroalkylation reaction occurs
an NEt2 side group, also showed an induction period for ester rapidly (t ¼ 6 min at 100 ꢀC). As such, it is possible that
1
2
hydrogenation, and released ethane concomitantly with the RuPNNdearom is inactive prior to dehydroalkylation in these
onset of catalytic activity. By heating our CNN- and Milstein's systems as well, which may call into question the DFT studies of
PNN-pincer precatalysts in the presence of tricyclohex- these transformations.13a,14
ylphosphine, we were able to trap the products of dehy-
Kinetic studies have the potential to validate or falsify the
droalkylation as ve-coordinate ruthenium(0) complexes, where ndings from computation, as they show conclusively what
the dialkylamino side group was transformed to an imine species are consumed or released on the pathway from the
functionality (PNN variant shown in Scheme 2). RuPNNimine, the turnover-frequency-determining intermediate (TDI) to the
ruthenium(0) derivative of RuPNNdearom, is dramatically more turnover-frequency-determining-transition state (TDTS).15 For
active as a precatalyst for ester hydrogenation than its example, recent kinetic investigations of metal-catalyzed
precursor, and is by some measures the most efficient catalyst hydroformylation16 and ketone hydrogenation17 have provided
currently known for ester hydrogenation, giving in excess of deep insight into the underlying reaction mechanisms.
10 000 catalytic turnovers at room temperature with no added Although catalytic ester hydrogenation and its microscopic
base. Several catalysts have been reported to operate at4d,10 or reverse, ADC, have been studied intensively through computa-
near4b,c,5a,11 room temperature, but require signicant quantities tional methods, detailed experimental mechanistic investiga-
of strongly basic additives such as NaOtBu and KOtBu. tions, especially kinetic studies, are scarce. In studies of an
Conversely, several catalysts operate without the need for added iridium–bipyridine catalyst system, Brewster, Sanford, and
base, but require temperatures of 80 C or higher.1,5g,12
Goldberg determined the dependence of turnover number at
ꢀ
To further probe the catalyst speciation under operating low conversion on the concentrations of catalyst, hydrogen, and
conditions, we monitored the reaction of RuPNNimine with ester.12h However, as reactions were not monitored over time,
hydrogen at room temperature. Under 10 bar H2, RuPNNimine this study did not probe for potential activation of catalyst
converts quantitatively to the dihydride complex RuPNNHEt
,
observed as an induction period, and did not probe for potential
involving a net hydrogenation of the imine functional group and product inhibition. Filonenko, Pidko and coworkers reported
a net oxidative addition of H2 to the ruthenium center (Scheme 2). time-course studies of ester hydrogenation catalyzed by CNC-
As RuPNNHEt contains a ruthenium hydride and N–H group, we pincer–ruthenium complexes, but did not determine the
proposed9 that it may be an active catalytic intermediate in reac- detailed dependences of the rate on concentrations.4e O and
tions initiated by RuPNNimine and RuPNNdearom, operating by Morris also reported time-course studies for ester hydrogena-
a
metal–ligand-cooperative mechanism analogous to that tion catalyzed by ruthenium complexes of NHC–amine ligands,
proposed for other elite N–H-containing catalysts.
but also did not determine a rate law.5a
The discovery of the dehydroalkylative activation of
In this paper, we describe a computational and experimental
RuPNNdearom has potentially broad mechanistic implications. mechanistic study of ester hydrogenation catalyzed by RuPN-
Because we have demonstrated that RuPNNdearom is not
N
imine. We report the crystallographic characterization of the
a kinetically competent intermediate and must undergo dehy- key dihydride intermediate RuPNNHEt, and the synthesis and
droalkylation prior to being catalytically active for ester hydro- characterization of the ruthenium-hydrido-alkoxide RuPNN-
genation, it is unlikely that the originally proposed mechanism1 HOEt, which represents the catalytic resting state and TDI.
is correct. Three reports in the literature apply density Detailed kinetic studies show an induction period at room
Scheme 2 Dehydroalkylation of Milstein's catalyst and reversible H2 addition giving RuPNNHEt
.
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temperature during which RuPNNimine is converted to the active effect of hydrogen-bonded product ethanol molecules (Scheme
form, and aer which the reaction shows rst-order depen- 4). Dihydride species g, g1, and g2 were identied, and we found
dence on [catalyst] and [hydrogen], rst-order saturation a small (<2.0 kcal molꢁ1) effect of binding to ethanol on the
behavior in [ester], and a transition from inverse second-order standard-state free energy. The calculated structure of g very
to inverse-rst-order inhibition by the product alcohol. All of closely matches the crystal structure of RuPNNHEt, described
this kinetic behavior, as well as the overall rate of reaction, is below. We found that unsaturated intermediates c, c1, and c2,
consistent with the minimum-energy pathway calculated using related to the dihydride compounds by formal loss of H2, were
density functional theory.
approximately 4–5 kcal molꢁ1 higher in energy than their
dihydride counterparts. We also considered hydridoalkoxide
species a1 and a2. Although the “free” species a1 is similar in
energy to its unsaturated counterpart c1, the hydridoalkoxide a2
with an additional hydrogen-bonded ethanol molecule is much
more stable than c2, and is identied as the catalyst resting
state. As described below, the calculated structure of a2 closely
matches the crystal structure of RuPNNHOEt, and the experi-
mental kinetics are consistent with a2 as the catalyst resting
state.
Computational mechanistic analysis
Background
Previous computational studies of the mechanism of ester
hydrogenation catalyzed by transition-metal complexes with
a pendant N–H functional group have converged on a bicyclic
pathway,4c,f,h,i,5 which can be separated into three linear
sequences (Scheme 3). In the hydrogen-activation sequence, the
H–H bond is cleaved heterolytically, placing a hydride on the
metal center and a proton on the basic nitrogen center. In ester
hydrogenolysis, these hydrogen atoms are transferred to the
ester substrate, and cleavage of the C–O bond facilitated by the
catalyst produces an aldehyde intermediate and one product
alcohol molecule. In the aldehyde-hydrogenation sequence, the
intermediate aldehyde is reduced to alcohol by the hydroge-
nated form of the catalyst. In one important variation on this
scheme, it is possible that the nitrogen remains protonated
throughout catalysis if an exogenous alkoxide base participates
in hydrogen cleavage directly.5b,6
We chose ethyl acetate as an appropriate model ester for
computational study, for several reasons: (1) its use is well-
precedented in both experimental and computational work;
(2) it is small enough to minimize issues resulting from a large
number of potential conformations; (3) it is large enough to
appropriately model the steric interactions of common ester
substrates with the catalyst. In particular, we expected the
energetics of ethyl acetate hydrogenation to closely mimic those
of hexyl hexanoate, which we employed in the kinetic studies
described below.
Pathway for hydrogen activation
We began by probing a range of possible pathways for the
activation of H2, informed by the rich history of prior work on
related reactions. Our search for the MEP for H2 activation
covered metal–ligand-cooperative heterolytic cleavage involving
the N–H functional group, as proposed by Noyori and co-
workers for their seminal carbonyl hydrogenation catalysts,18
both with and without explicit ethanol molecules to serve as
proton shuttles. Noyori-type mechanisms for H2 activation have
been identied for a range of catalysts for ester hydrogenation
or ADC.4c,f,h,i,5a,c–j,6d We also carefully searched for pathways
involving cooperative activation of H2 through the ruthenium
center and an ethoxide anion, which Dub et al. showed can
Consideration of plausible resting states
We began our study by comparing the relative free energies of
plausible catalyst resting states, in each case considering the
Scheme 4 Species considered as plausible resting states. Energies
given represent standard-state free energies in kcal molꢁ1 at 298.15 K
relative to a2.
Scheme 3 Two linked catalytic cycles for ester hydrogenation.
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bypass the deprotonation of the N–H group on the pincer molecules, both for the low overall barrier and for the stepwise
ligand.5b,6 Lastly, we exhaustively examined pathways for H2 proton-shuttle mechanisms. For comparison, we calculated
activation involving deprotonated CH2 linkers on the pincer analogous pathways involving only one ethanol molecule as
ligand, as originally proposed by Milstein and coworkers,1 and proton shuttle and involving no ethanol molecules. These
identied by DFT in many studies.13a,14a–e,g,19
pathways, both concerted, are described in detail in the ESI
Fig. 1 shows the pathway we identied with the lowest overall (Fig. S3†), and were found to proceed through higher overall
barrier, which we describe as a “proton brigade” because of the barriers of 18.6 and 25.3 kcal molꢁ1, respectively.
involvement of two ethanol molecules in the stepwise cleavage
We also searched exhaustively for pathways involving the
of the H–H bond. Beginning with the resting state a2, whose activation of H2 mediated by deprotonated CH2 linkers of the
experimental characterization is described in the next section, pincer ligand, both with and without explicit ethanol molecules
a double proton transfer through a2-b2-TS (ref. 20) gives the N- as proton shuttles. These pathways, described in detail in the
deprotonated species b2 with a neutral ethanol molecule coor- ESI,† would implicate dearomatized species similar to
dinated to Ru. Then, this ethanol dissociates to give the RuPNNdearom as key intermediates in catalysis. All mechanisms
unsaturated species c2, which transfers a proton back to of this nature were found to proceed through higher barriers for
nitrogen to give d2 before binding H2 in the s-complex f2, in H2 cleavage, with a lowest identied barrier of 25.6 kcal molꢁ1
which the nitrogen is protonated and an ethoxide anion is for mechanisms involving the NCH2 linker and 23.7 kcal molꢁ1
stabilized by two hydrogen bonds. Then, H2 is cleaved through for the PCH2 linker. In summary, our work shows that the
the proton-shuttle transition state f2-g2-TS, resulting in the presence of the N–H functional group is essential for activation
dihydride species g2 (with two associated ethanol molecules) or of hydrogen with a low barrier. The N–H group is temporarily
g1 (with one associated ethanol). Although this pathway does deprotonated in our MEP, but a pathway where the N–H group
involve temporary deprotonation of nitrogen between a2 and remains protonated and instead serves to stabilize intermedi-
d2, the reformation of the N–H bond is not concerted with H2 ates and transition states through hydrogen bonding is ener-
cleavage. We also located a pathway connecting a2 to d2 where getically similar, and cannot be excluded by DFT. Pathways
the N–H bond remains intact (Fig. S1†), and a pathway con- involving deprotonation of CH2 linkers have signicantly higher
necting c2 to f2 where hydrogen coordination occurs before barriers and can be excluded.
proton transfer to nitrogen (Fig. S2†), both with slightly higher
barriers.
Pathway for ester hydrogenolysis
The MEP identied for hydrogen activation requires passing
The ester hydrogenolysis portion of the catalytic cycle involves
the hydrogenation of the carbonyl functional group and
cleavage of the C–O bond, ultimately releasing one product
through f2-g2-TS at 15.0 kcal molꢁ1. Notably, this proton-
brigade pathway relies on the inclusion of two explicit ethanol
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 molꢁ1 at 298.15 K, relative to
a2 and the organic reactants unless otherwise stated.
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alcohol molecule and an aldehyde intermediate. Prior work on through this sequence is limited by both the cleavage of the
many systems has identied the transfer of hydride from the O–H bond in k (essentially barrierless in the forward direction)
metal to the carbonyl carbon as a key initial step, which and the cleavage of the C–O bond in m (essentially barrierless in
generates a hemiacetaloxide intermediate. Two principal path- the reverse direction).20
ways for cleavage of the C–OEt bond have emerged, which have
We also identied a different pathway for C–O cleavage, with
been shown to have similar barriers for related catalysts. These a nearly identical overall barrier of 18.1 kcal molꢁ1, which
pathways differ by the coordination of either the aldehyde directly places the newly formed ethoxide rather than the
oxygen4c,f,i,5d,f,h,6d or the alkoxide oxygen4h,5a,h,i,6d,21 to Ru during aldehyde on ruthenium (Fig. S8†). Similar to the transformation
C–O cleavage. In our system, we nd these mechanisms to have identied by Hasanayn and termed
a hydride-alkoxide
nearly identical barriers, as described below. The pathway metathesis,21 this pathway would predict identical kinetic
shown in Fig. 4 is an example of the former mechanism. behavior as the one shown below in Fig. 2. In the process of
Beginning from the dihydride intermediate g1, the ester establishing the twin minimum-energy pathways described in
replaces the hydrogen-bonded alcohol molecule to give the Fig. 2 and S8,† we characterized diastereomeric sequences
reactant complex h, which transfers hydride from Ru to C to give where the ester initially coordinates to Ru through the opposite
the C–H s-complex i, where the hemiacetaloxide oxygen is face, and pathways involving an explicit ethanol molecule. As
stabilized by hydrogen-bonding to the N–H. Then, proton described in detail in the ESI,† we found slightly higher overall
transfer from N to O gives j,20 which rearranges to place the barriers for the diastereomeric pathways (Fig. S10 and S12†) and
hydroxyl oxygen on Ru in k, followed by reprotonation of similar overall barriers for pathways involving an explicit
nitrogen and subsequent hydrogen bond formation to give the ethanol molecule (Fig. S11 and S14†). We also calculated
Ru-bound hemiacetaloxide complex m. Then, cleavage of the a ruthenium-free pathway for the conversion of the hemiacetal
C–O bond, concerted with proton transfer from N back to O, to ethanol and acetaldehyde (Fig. S15†), and nd a much higher
gives n, a loosely-bound complex of the product ethanol and barrier of 36.4 kcal molꢁ1, in line with previous work.6d,14h In
intermediate acetaldehyde. Replacement of the aldehyde with summary, we nd that ester hydrogenolysis proceeds in our
another ethanol molecule gives c2, which connects back to the system by well-precedented mechanisms for ruthenium–pincer
hydrogen activation pathway in Fig. 1 and completes the rst catalysts possessing an N–H group, and that the decomposition
hydrogenation cycle.
of the hemiacetal is mediated by the ruthenium–pincer catalyst.
The ester hydrogenolysis pathway shown above proceeds
through a highest barrier of 17.4 kcal molꢁ1, which is the free
energy of the intermediate species n. Notably, intermediates k
and n and transition states k-l-TS and m-n-TS all have essen-
tially identical free energies of 17.0–17.4 kcal molꢁ1. Thus, ux
Pathway for aldehyde hydrogenation
The nal portion of the catalytic cycle involves hydrogenation of
the aldehyde intermediate to give the second equivalent of
alcohol product. This sequence, as mediated by a ruthenium
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 molꢁ1 reported here for c2 corresponds to release of acetaldehyde and binding of ethanol from n, whereas the free-energy of
8.2 kcal molꢁ1 reported for c2 in Fig. 1 is calculated against the ethyl acetate and dihydrogen reactants.
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hydride complex with a pendent N–H functional group on the intermediate s. As proton transfer from N to O through s-t-TS is
ligand, has been studied extensively through DFT in the context barrierless20 and strongly exergonic in our system, we did not
of ester hydrogenation, but also has a longer history dating back search extensively for additional pathways for conversion of the
to the original Noyori catalysts, which were highly efficient for aldehyde to ethanol.
aldehyde and ketone hydrogenation.18 For ester hydrogenation
catalysts, the aldehyde hydrogenation step is generally found to
have a lower barrier than the ester hydrogenolysis step, which
Summary and predicted kinetics
along with the thermodynamic instability of the aldehyde with
respect to reactants, is consistent with the lack of buildup of
aldehyde in catalytic reactions. For our catalytic system, we
identied the pathway shown in Fig. 3, beginning with coordi-
nation of the aldehyde to form r. This is followed by stepwise
transfer of hydride and proton to the substrate from the
ruthenium and nitrogen centers, respectively, giving interme-
diates s and t. Dissociation of the C–H s-complex gives c1,
which connects back to the hydrogen activation pathway.
In some recent studies,6,13c,22 proton transfer from the ligand
to the alkoxide oxygen was calculated to have a higher barrier
than proton transfer from an exogenous alcohol molecule,
which enables the construction of a pathway for hydrogenation
where the ligand N–H group (or CH2 linker) is never deproto-
nated. Pathways like this may have been missed in earlier work
because of the optimization of structures without a solvent
model, which can favor concerted proton/hydride transfer
pathways and disfavor ion-pair intermediates such as s. In our
work, conducting geometry optimizations using a toluene
continuum solvent model allowed the identication of the
In summary, we have identied MEPs for hydrogen activation,
ester hydrogenolysis, and aldehyde hydrogenation in ester
hydrogenation catalyzed by RuPNNHEt, which forms in situ from
RuPNNimine as we have shown experimentally.9 Fig. 4 shows
a simplied energy diagram depicting key intermediates and
transition states relevant in predicting the kinetics of hydroge-
nation through the energetic span model.15 The hydrido-
alkoxide complex a2 is predicted to be the turnover-frequency-
determining intermediate (TDI). The highest-energy transition
states in the hydrogen activation and ester hydrogenolysis
sequences are f2-g2-TS and m-n-TS, respectively. Although
intermediate n is calculated to be higher than m-n-TS by
0.3 kcal molꢁ1 20 we have used m-n-TS in our kinetic analysis for
,
consistent application of transition-state theory to calculate rate
constants. The 2.1 kcal molꢁ1 free-energy difference between f2-
g2-TS and m-n-TS is likely within the error of the DFT method,
especially considering the changes in molecularity involved:
between a2 and f2-g2-TS, a hydrogen molecule is consumed,
and between f2-g2-TS and m-n-TS, two ethanol molecules are
released and ethyl acetate is consumed.
Fig. 3 MEP for hydrogenation of acetaldehyde to ethanol, accompanied by conversion of dihydride intermediate g1 into unsaturated inter-
mediate c1, which connects ꢁb1ack 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 ) is calculated based on the organic intermediates ethanol, acetaldehyde, and one molecule of hydrogen, whereas
the free energy of 2.8 kcal molꢁ1 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 molꢁ1 as shown in this figure).
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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 molꢁ1) at
298.15 K.
Fig. 4 Simplified energy surface determining the kinetics of ester
hydrogenation.
energy pathway for hydrogen activation goes through f2-g2-TS
and includes two ethanol molecules as a “proton brigade”,
although a pathway through e1-g1-TS, with only one ethanol
molecule as a proton shuttle, is only 3.6 kcal molꢁ1 higher.
Third, as the energies of g, g1, and g2 – the dihydride inter-
mediates with 0, 1, and 2 ethanol molecules included – are
above the energy of a2 and below the energies of the transition
states, their specic energies and relative ordering are not
kinetically relevant. Last, ester hydrogenolysis proceeds
through a very similar free-energy barrier whether an explicit
ethanol molecule is included (m1-n1-TS, 17.4 kcal molꢁ1) or not
(m-n-TS, 17.1 kcal molꢁ1). This model formed the basis for our
kinetic analysis, described below.
The energetic span model allows a prediction of the rate of
catalysis based on the free-energy difference between the TDI
and the TDTS, which is an effective barrier for catalytic turn-
over.15 Taking our DFT results at face value, the TDTS is m-n-TS
when the reactants, EtOAc and H2, as well as the product EtOH,
are at their standard states of 1 M. In this scenario, the energetic
span is 17.1 kcal molꢁ1, which is qualitatively consistent with
a catalytic system that turns over rapidly at room temperature.
The predicted rate law, based on the species consumed and
released between the TDI and TDTS, is represented by eqn (1).
In our experimental kinetic analysis described below, we have
taken the above simplied model as a starting point, and
additionally we nd saturation behavior at high [ester],
consistent with a switch to f2-g2-TS as TDTS under these
conditions.
Synthesis of proposed intermediates
RuPNNHEt. The computational studies described above
predict that the catalyst resting state will be a hydrido-alkoxide
species such as a2, stabilized by hydrogen-bonding to a product
alcohol molecule. Dihydride species such as g, g1, and g2 are
predicted to be key intermediates, but are less stable by
several kcal molꢁ1 and are expected to have low steady-state
concentrations once even small amounts of alcohol product
build up in ester hydrogenation reactions. We previously
demonstrated (Scheme 2) that the precatalyst RuPNNimine
converts quantitatively to the dihydride RuPNNHEt under
hydrogen pressure,9 although the reversibility of this reaction
½Ruꢂ½H2ꢂ½EtOAcꢂ
rate ¼ k
(1)
2
½EtOHꢂ
Effect of explicit ethanol on kinetics
Motivated by past work showing the key involvement of protic
solvent in heterolytic hydrogen cleavage23 and by the compli-
cated dependence of our catalytic rate on alcohol concentration
(as described below), we examined the effect of including
explicit ethanol molecules in the hydrogen activation and ester
hydrogenolysis pathways described above. The complete path-
ways are included in the ESI.† Fig. 5 shows a summary of the
effect of explicit ethanol molecules on the free energies of key
intermediates and transition states that determine the kinetics.
Taking the computed free energies at face value, several
predictions can be made about the kinetics. First, the hydrido-
alkoxide intermediate a2 interacts strongly with an ethanol
molecule from solution, so the “free” complex a1 does not
represent a signicant fraction of the resting catalyst speciation,
even at very low ethanol concentration. Second, the minimum-
on removal of hydrogen prevented easy isolation of RuPNNHEt
.
Recently, Gusev reported a clever method to isolate the dihy-
dride product RuPNNH2 formed by reaction of Milstein's orig-
inal precatalyst RuPNNdearom with hydrogen: a solution of the
dearomatized species was placed under hydrogen in an
unstirred pressure vessel, in a solvent mixture that dissolved
RuPNNdearom completely but allowed the product dihydride to
crystallize.13c Gratifyingly, we found that the same procedure
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allowed us to successfully isolate RuPNNHEt in crystalline form hydrogenation reactions,5h,13a,24 our calculations indicate that
(Scheme 5). RuPNNHEt is isolated as yellow crystals, which are alkoxide a2 is more stable than the dihydride g1 by
moderately stable at room temperature, but can be stored under 2.9 kcal molꢁ1. In recent work, Gusev demonstrated experi-
argon at ꢁ37 C for extended periods without decomposition. mentally that RuPNNH2 converts rapidly to alkoxide species on
ꢀ
Although RuPNNHEt is stable even under air as a solid, it addition of alcohols, and showed computationally that the
decomposes rapidly when dissolved in degassed benzene-d6 at ethoxide species was more stable than the dihydride by
room temperature. As we previously characterized RuPNNHEt 0.4 kcal molꢁ1
.
We observed analogous reactivity for
13c
fully in solution under H2 pressure,9 we did not attempt to RuPNNHEt: although it decomposes in benzene-d6 with no other
repeat the spectroscopic characterization in the absence of H2. additives, RuPNNHEt rapidly converts to the hydrido-alkoxide
The crystals of RuPNNHEt formed by the method described species RuPNNHOEt when dissolved in benzene-d6 containing
above were suitable for characterization by X-ray crystallog- ethanol, with visible evolution of hydrogen gas (Scheme 6).
raphy. Fig. 6 shows the molecular structure in the solid state. As NMR spectra taken immediately aer reaction show one clean
was concluded based on our previous spectroscopic character- species. RuPNNHOEt was fully characterized by NMR spectros-
ization,9 RuPNNHEt features a nearly octahedral ruthenium(II) copy at 25 ꢀC in benzene-d6. The hydride signal appears as
center bound to two hydride ligands, carbon monoxide, and a doublet at ꢁ15.8 ppm. At room temperature, broad signals are
a PNN-pincer ligand with an aromatic pyridine fragment observed for the methylene and hydroxyl hydrogens of free
anked by CH2P(tBu)2 on one side and CH2NHEt on the other. ethanol. Signals for the bound ethoxide, N–H, and the PCH2
The structure is closely analogous to that of RuPNNH2 as hydrogen syn to the ethoxide are not observed, as they are in
recently reported by Gusev,13c except for the change from NEt2 to rapid exchange with hydrogens from free ethanol. To charac-
NHEt. The mechanism of double hydrogenation from RuPN- terize RuPNNHOEt in the absence of this chemical exchange, 1H
N
imine to give RuPNNHEt is not obvious, and is the subject of an NMR spectra were recorded from ꢁ90 ꢀC to 20 ꢀC in toluene-d8
ongoing experimental and computational study.
(see the ESI† for spectral images). At ꢁ50 ꢀC, the above chemical
RuPNNHOEt. Although dihydride species such as RuPNNH2 exchanges are slow on the NMR time scale, and distinct reso-
have been proposed as the resting states in catalytic nances are observed for free ethanol, bound ethoxide, the N–H,
and all four CH2 linker hydrogens.
Single crystals of RuPNNHOEt suitable for X-ray crystallog-
raphy were obtained by slow evaporation of a pentane solution
containing a small amount of ethanol. Although crystals could
be reproducibly obtained in this manner, the instability of
RuPNNHOEt in the absence of an excess of ethanol coupled with
its high solubility in solvents with a wide range of polarities
have thus far prevented its bulk isolation as a solid. Fig. 7 shows
the structure of RuPNNHOEt. In the solid state, the ethoxide
ligand is syn to the N–H group, which is pseudo-axial and is 2.21
Scheme 5 Synthesis of RuPNNHEt
.
ꢀ
A from the ethoxide oxygen, indicating a weak intramolecular
hydrogen bond. A molecule of ethanol is present in the asym-
metric unit, and the O–H hydrogen interacts with the ethoxide
ꢀ
oxygen through hydrogen-bonding with a distance of 1.73 A.
The solid-state geometric parameters for RuPNNHOEt are
remarkably similar to the computationally optimized structure
a2, which was the lowest-energy hydrido-alkoxide conformation
we were able to locate that included one explicit ethanol
molecule.
The rapid conversion of RuPNNHEt to RuPNNHOEt at room
temperature is consistent with our DFT study above. This
transformation is the reverse of the hydrogen activation shown
in Fig. 1, which is predicted to proceed in the reverse direction
Fig. 6 ORTEP diagram of RuPNNHEt, showing 50% probability ellip-
soids. 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 RuPNNHOEt
.
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saturation behavior is possible. Third, because alcohol
product is released between the TDI and TDTS, the reaction
should be inhibited by the buildup of alcohol. The precise
dependence of the rate on [alcohol] is not unambiguously
predicted by computation, because of the multiple pathways
available as shown in Fig. 5 above. Lastly, and very impor-
tantly, the overall rate of reaction should be approximately
consistent with the overall barrier predicted by DFT, which is
17.1 kcal molꢁ1 in our system.
Although the hydrogenation of ethyl acetate to ethanol was
ideal for our computational study and for the isolation of the
hydrido-alkoxide intermediate RuPNNHOEt, we chose to conduct
detailed kinetic studies using hexyl hexanoate as substrate,
because both the ester reactant and alcohol product have very
low volatilities at room temperature, which minimizes the
possibility of evaporation of reactant or product at any point
during the setup, reaction, or analysis. As both RuPNNHEt and
RuPNNHOEt were unstable in solution, we conducted kinetic
studies using RuPNNimine as precatalyst. We previously deter-
mined that isopropyl alcohol was an ideal solvent for obtaining
Fig. 7 ORTEP diagram of RuPNNHOEt, showing 50% probability ellip-
soids. 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).
high catalytic rates and turnover numbers in practical ester
hydrogenation catalyzed by RuPNNimine
,
but we decided to
9
conduct kinetic studies in toluene for two reasons: (1) the
RuPNNimine precatalyst is only sparingly soluble in isopropyl
alcohol, posing difficulties with the preparation of stock solu-
tions and occasionally causing clogging in the stainless-steel
tubing used for removing aliquots from the reaction mixture;
and (2) as described below, the hexanol product was found to
inhibit turnover, and the analysis of this observed product
inhibition was most straightforward if no other alcohols were
present in solution.
with a free-energy barrier of 12.1 kcal molꢁ1, proceeding from
g1 through f2-g2-TS. The complete formation of RuPNNHOEt
from RuPNNHEt suggested that, as predicted by computation,
the alkoxide species might be more stable under catalytic
conditions, and would hence represent the resting state and
TDI. To conrm this, we placed a solution of RuPNNHOEt
formed in situ from RuPNNHEt and ethanol under 10 bar H2 in
a high-pressure NMR tube. No conversion back to the dihydride
species was observed, consistent with the prediction from
computation that RuPNNHOEt is the dominant resting state
throughout the catalytic reaction.
In kinetic experiments, we monitored the conversion of hexyl
ꢀ
hexanoate to 1-hexanol at 25 C by gas chromatography, with
tetradecane as an internal standard. We began with the stan-
dard conditions shown in Scheme 7, then varied the initial
concentrations of RuPNNimine, hexyl hexanoate, and hexanol, as
well as the hydrogen pressure in independent experiments. The
plots labeled “without preactivation” in Fig. 8 shows a typical
kinetic trace under our standard conditions. Over approxi-
mately the rst 45 minutes of the reaction, the rate increases,
aer which apparent pseudo-rst-order consumption of ester is
Kinetics
As we noted in the introduction, DFT studies of catalytic ester observed, as the plot of ln[ester] vs. time is linear aer this
hydrogenation are widespread but kinetic studies are rare. point. During the 45 minute induction period, aliquots are dark
Because the computed mechanism and energies make clear purple, indicating the presence of the strongly absorbing pre-
predictions about the kinetics, the latter provide an important catalyst RuPNNimine, and become pale yellow as the precatalyst
check on the former. Based on our computed mechanism, the is converted to the resting state, which we propose is a hydrido-
following predictions can be made. First, because hydrogen hexyloxide species analogous to RuPNNHOEt
.
activation occurs between the TDI and TDTS, the reaction
To determine if the observed induction period can be
should be rst-order in hydrogen. If a dihydride intermediate explained by the activation of RuPNNimine with hydrogen, we
such as g1 were more stable than the intermediate preceding
hydrogen activation (a2 in our work), the reaction would
follow zero-order kinetics in hydrogen. Second, because an
ester molecule is consumed between the TDI and TDTS, the
reaction should be rst-order in ester. If the barrier for
hydrogen activation were much higher than the barrier for
ester hydrogenolysis, the reaction would follow zero-order
kinetics in ester. If these two barriers are similar in energy, Scheme 7 Standard conditions for kinetic experiments.
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To determine the partial order in catalyst concentration
under the standard conditions, we repeated the experiment
with a range of initial concentrations of RuPNNimine (Fig. 9). The
same initial induction period followed by pseudo-rst-order
behavior was observed, and kobs was taken as the slope of the
linear portion of the plot of ln[ester] vs. time. A plot of kobs vs.
[RuPNNimine]0 is linear with an intercept of zero, indicating that
the reaction is rst-order in [ruthenium] aer the induction
period is complete.
To determine the partial order in hydrogen, we repeated the
standard experiment varying the hydrogen pressure (Fig. 10). In
all experiments, a constant hydrogen pressure was maintained
as aliquots were removed. Again, kobs was determined based on
the linear portion of the plot of ln[ester] vs. time, and again
a plot of kobs vs. hydrogen pressure gave a line with an intercept
of zero, indicating that the reaction is rst-order in hydrogen
under these conditions.
We then repeated the experiment with initial ester (hexyl
hexanoate) concentrations varied over a wide range from 0.05 M
to 0.75 M. At high [ester]0, we observed a change from pseudo-
rst-order to pseudo-zero-order behavior, consistent with satu-
ration kinetics. When [ester]0 is 0.25 M or less, apparent rst-
order kinetic behavior is observed in each individual
Fig. 8 Comparison of hexyl hexanoate hydrogenation catalyzed by
RuPNNimine with and without preactivation of the catalyst by incuba-
tion 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).
conducted a preactivation experiment where we rst pressur-
ized a solution of RuPNNimine with hydrogen (20 bar) for 90
minutes, which results in formation of the dihydride complex
RuPNNHEt
.
Then, the hexyl hexanoate substrate was trans-
9
ferred into the pressure reactor and its conversion to 1-hexanol
was monitored at 25 ꢀC. As the plots labeled “with pre-
activation” in Fig. 8 demonstrate, the reaction follows apparent
rst-order kinetics without an induction period, giving a nearly
identical kobs value to what is observed without pre-activation of
the catalyst. Importantly, this experiment rules out the possi-
bility that sigmoidal kinetics come from acceleration of the
reaction by the product alcohol, as proposed by O and Morris
for their catalyst.5a We also attempted to use RuPNNHEt directly
as a precatalyst, but partial decomposition prior to the intro-
duction of hydrogen pressure hindered our attempts to obtain
reliable kinetic data. Because it was much more operationally
convenient to assemble kinetic experiments in parallel without
a catalyst preactivation step, we elected to conduct further
kinetic trials using RuPNNimine as the precatalyst, using only the
data aer the 45 minute induction period to develop the kinetic
model for the activated catalyst.
Fig. 9 Determination of the partial order in RuPNNimine under the
standard conditions. The top plots show the time course of ester
conversion using different initial concentrations of RuPNNimine, 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 kobs and [RuPNNimine].
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the time course for ester hydrogenation, given the initial
concentrations of ruthenium catalyst (a2), hexyl hexanoate,
hexanol, and hydrogen. Hydrogen concentration, calculated
from its known solubility in toluene at 25 ꢀC and the appro-
priate pressure,27 was held xed in the model. Because the
activity coefficients of alcohols are known to vary signicantly
over the range of 0 to 1.0 M in non-polar solvents,28 we used the
activity of 1-hexanol rather than its molarity, as estimated
following a model developed by Li and coworkers for 1-hexanol
in benzene.29
In attempting to reproduce the kinetic data with our model,
we set the relative free energy of a2 to zero and compared
a range of scenarios adjusting the remaining energies, in an
attempt to achieve the best overall t while including the
smallest number of adjustable parameters. We found no better
t by allowing the free energies of a1, e1-g1-TS, g2, g1, or g to be
adjusted. On the other hand, allowing adjustment of f2-g2-TS,
m-n-TS, and m1-n1-TS was essential to obtaining a good global
t. Further, entirely excluding the pathway through e1-g1-TS
had no detrimental effect on the t. Our optimized model is
depicted in Fig. 11, and the global t to the kinetic data is
shown in Fig. 12. The free energies of the dihydride species g,
g1, and g2 were taken from the DFT results and held constant.
The free energies of the transition states f2-g2-TS, m-n-TS, and
m1-n1-TS were allowed to vary; tted values are shown in
Fig. 11.
Overall, the kinetic data are very well-reproduced by this
simplied model, with minimal adjustment of the free energies
obtained from DFT. Interestingly, the free energy of the
hydrogen activation transition state f2-g2-TS was adjusted
upward by 2.4 kcal molꢁ1, while the energies of the ester
hydrogenolysis transition states were adjusted downward by 1.2
and 1.4 kcal molꢁ1, indicating that the standard-state activation
barrier for hydrogen cleavage is the higher of the two, in
contrast to the prediction from DFT. The model correctly
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 kobs and hydrogen pressure.
experiment, but kobs increases dramatically at lower [ester]0,
consistent with inhibition by the product 1-hexanol. Although it
may be counterintuitive that pseudo-rst-order kinetic behavior
in [ester] is observed when the buildup of alcohol product
inhibits the reaction, in our system the increasing product
inhibition is roughly cancelled out by saturation in [ester],
resulting in apparent rst-order behavior in each experiment.
To directly probe for inhibition by the product hexanol, we
repeated the experiment with a range of initial 1-hexanol
concentrations, and we found that the rate decreases as
[hexanol]0 is increased, consistent with product inhibition.
To deconvolute the effects of saturation in [ester] and inhi-
bition by the product alcohol, we developed a numerical model
of the reaction progress using the program Copasi.25 Numerical
modeling is seeing increased use in the analysis of kinetics in
catalytic systems.16b,26 When used in combination with DFT,
kinetic modeling offers the potential to validate mechanisms
and rene the energies predicted by DFT.16b,26e In developing
our model, we included the data aer the 45 minute induction
period from a total of 18 kinetic experiments, where the initial
ester, alcohol, and ruthenium concentrations were varied, as
well as the hydrogen pressure. Our model takes the standard-
state free energies of the kinetically relevant intermediates
and transition states as inputs (see Fig. 5 above), and computes
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.
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Fig. 12 Data (points) and global fit (lines) for all 18 kinetic experiments. In the standard conditions, [hexyl hexanoate]0 ¼ 0.25 M, [hexyl alcohol]0 ¼
0 M, [RuPNNimine
]
¼ 1.00 mM, and Phydrogen ¼ 20 bar. The global fit was based on all data from 45 minutes on in each kinetic experiment. Note
0
that the vertical axes are plotted logarithmically.
reproduces the rst-order dependence on hydrogen pressure, effect of isopropyl alcohol further, we repeated our standard
the rst-order dependence on [Ru], and the saturation kinetics kinetic experiment with varying amounts of isopropyl alcohol
in [ester]. The inclusion of two similar-barrier pathways for ester added, up to 0.75 M. For comparison, pure isopropyl alcohol is
hydrogenolysis allows a transition from second-order inhibition 13.1 M. As shown in Fig. 13, we observe moderate but clear
by alcohol at low [alcohol] to rst-order inhibition at higher acceleration of the reaction with added isopropyl alcohol,
[alcohol], consistent with the data. Importantly, the relatively consistent with our prior ndings and in contrast with the
small adjustment of the transition-state energies, less than inhibiting effect of added 1-hexanol. Although we have not tried
3 kcal molꢁ1 in each case, indicates that the barriers from DFT to probe this effect further, it likely originates from a different
calculations are consistent with overall rate of the catalytic balance of stabilization of the resting state and transition-states
reaction. The above model satisfactorily reproduces the effect of by the two alcohols, potentially through specic interactions
[hexanol] on the rate of reaction essentially by assuming strong and/or medium polarity effects. For example, the activity coef-
hydrogen bonding to the resting state a2 and weaker interaction cient of 1-hexanol is expected to decrease with increasing
with the transition states for ester hydrogenation. However, we [isopropyl alcohol], which should reduce 1-hexanol inhibition
do not claim that this model fully accounts for the behavior of and accelerate the catalytic reaction. We note that the detailed
the alcohol in the system, which likely includes medium rate dependence determined above for hexyl hexanoate, espe-
polarity effects and more complicated interactions with the cially the effect of the alcohol, does not necessarily extend to the
reacting species.
hydrogenation of all other esters.
Effect of added isopropyl alcohol
Disproportionation of aldehydes to esters
Although we have conducted the above kinetic experiments in As Gusev has reported recently,30 catalysts for ester hydrogena-
toluene, we determined previously9 that isopropyl alcohol was tion that produce an aldehyde intermediate can also be active
an ideal solvent for the reaction, giving rates approximately 2–3 for the catalytic disproportionation of aldehydes to esters,
times faster than toluene and THF. To probe the accelerating which effectively operates by running the ester hydrogenolysis
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an NHEt group that is essential for catalytic activity.9 In this
work, we have presented a plausible minimum-energy pathway,
identied through computation and validated experimentally
through kinetic characterization and isolation of two key
intermediates, RuPNNHEt and RuPNNHOEt. Our computations
demonstrate that the N–H functional group plays a key role in
the exceptional room-temperature activity of this catalyst. The
N–H group is deprotonated and re-protonated in our MEPs for
hydrogen activation, ester hydrogenolysis, and aldehyde
hydrogenation, although in the rst two cases we identied
nearly isoenergetic pathways where the N–H group acts only as
a hydrogen-bond donor without being deprotonated. A thor-
ough search for alternative pathways where a CH2 linker is
involved in hydrogen activation identied a minimum barrier of
23.7 kcal molꢁ1, compared to 15.0 in our MEP.
Because of the widespread application of RuPNNdearom in
catalytic transformations and the corresponding widespread
study of its reactivity by DFT prior to our disclosure of its facile
dehydroalkylative activation, this system provides a unique case
study in how the application of DFT in the absence of comple-
mentary experimental data can lead to the proposal of incorrect
reaction mechanisms. Three studies we are aware of report
a complete pathway for ester hydrogenation catalyzed by
RuPNNdearom. In 2017, Zhang and coworkers reported a mech-
anism for the hydrogenation of ethyl benzoate catalyzed by
RuPNNdearom
.
In their work, RuPNNdearom was identied as
13b
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 kobs vs. [iso-
propyl alcohol].
the resting state, and the highest barrier occurred in ester
hydrogenolysis, giving an energetic span of 27.2 kcal molꢁ1. In
2011, Wang and coworkers reported a study comparing the
activity of RuPNNdearom for the acceptorless dehydrogenative
coupling (ADC) of alcohols to give esters against the coupling of
amines and alcohols to give amides, rationalizing the prefer-
ence for the latter pathway over the former.13a Reversing the
ADC process predicts an overall energetic span of
38.5 kcal molꢁ1 for ester hydrogenation, from a dihydride
resting state aer hydrogen activation to a proton-transfer TDTS
along the ester hydrogenolysis pathway. In 2020, Gusev reported
a revised mechanism for ester hydrogenation and the reverse
ADC, aided by the experimental identication of a hydridoalk-
oxide species as the proposed resting state.13c In that study, the
energetic span from the hydridoalkoxide TDI to the TDTS,
a Hasanayn-like21 hydride-alkoxide metathesis transition state,
pathway in reverse and the aldehyde hydrogenation pathway in
the forward direction. Rearranging the pathways in Fig. 2 and 3
gives the MEP shown in Fig. S16 in the ESI,† with an overall
barrier of 12.9 kcal molꢁ1. Therefore, our calculations predict
that aldehyde disproportionation should be rapid at room
temperature. To test this prediction, we dissolved 1-hexanal in
benzene-d6 with 0.2 mol% RuPNNHEt at room temperature, and
monitored by 1H NMR. Aer 10 minutes, the aldehyde was
completely consumed and hexyl hexanoate was the major
product (Scheme 8). Further studies of this disproportionation
reaction are in progress.
was 31.8 kcal molꢁ1
As all three of the above studies rely on the on-cycle inter-
mediacy of either RuPNNdearom RuPNNH2
or both, the
.
,
,
proposed mechanisms cannot be correct, as we have shown that
RuPNNdearom, which converts rapidly to RuPNNH2 under
hydrogen pressure,1 is inactive in ester hydrogenation prior to
undergoing dehydroalkylation.9 With our present demonstra-
tion that the experimental free-energy barrier to catalytic turn-
over is only 17.4 kcal molꢁ1, the computed pathways above can
also be excluded because the barriers they predict are implau-
sibly high. Although it is not always explicitly stated, a common
lter for the plausibility of reaction mechanisms calculated by
DFT or other quantum-chemistry methods is a qualitative
agreement of the overall reaction barrier with the observed rate
of reaction. When detailed kinetic information is not available,
Discussion
We previously demonstrated that the ubiquitous RuPNNdearom
is not kinetically competent as a catalyst for ester hydrogena-
tion, instead converting from an inactive precatalytic form with
an NEt2 side group to an active form RuPNNHEt, which features
Scheme 8 Disproportionation of 1-hexanal.
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reaction barriers must be estimated knowing only the catalyst determined by experiment are in agreement with the mecha-
loading, reaction time, and temperature. In the case of ester nism predicted by DFT.
hydrogenation catalyzed by RuPNNdearom, Milstein's initial
disclosure reported a turnover number of 100 in 4 h at 115 ꢀC.1
If one assumes that catalyst induction is rapid and the turnover
Author contributions
frequency is constant over the reaction time course, an overall J. Pham: kinetic experiments, Copasi modeling, writing of
barrier (energetic span) of 26.7 kcal molꢁ1 can be estimated. manuscript. C. Jarczyk: DFT calculations, synthesis. E. Rey-
However, the barrier for turnover can be substantially over- nolds: DFT calculations, synthesis. S. Kelly: DFT calculations. T.
estimated if the catalyst undergoes a slow activation followed by Kim: DFT calculations. T. He: kinetic experiments, synthesis,
very rapid turnover, as we showed is the case for this system.9 DFT calculations. J. Keith: funding acquisition, supervision of
This overestimation makes the above mechanisms, especially computational work, review and editing of manuscript. A.
those proposed by Gusev and Zhang, appear plausible even Chianese: conceptualization, funding acquisition, and super-
though they predict barriers that are much higher than the vision; writing, review, and editing of manuscript.
actual barrier for catalytic turnover.
It is worth revisiting a broader implication of the ndings we
report here. As we described in the introduction, the majority of
Conflicts of interest
elite catalysts for ester hydrogenation and the reverse ADC of The authors declare no competing nancial interest.
alcohols feature an N–H group with a key role in promoting
catalysis. In this work and in a prior study,9 we demonstrated
Acknowledgements
that Milstein's catalyst RuPNNdearom and NEt2-substituted CNN-
pincer analogs developed in our group7d are initially inactive, We thank the National Science Foundation (CHE-1665144 and
and must convert to an NHEt form to be catalytically active. CHE-1954924) for support of the research project, and (CHE-
Recently, Khaskin, Gusev, and coworkers22 have shown that the 1726308) for the acquisition of an upgraded NMR spectrometer.
same is true for a related bipyridyl PNN-pincer catalyst origi-
nally reported by Milstein and coworkers.31 In this case, a pyri-
dine ring is hydrogenated to a piperidine, again providing
References
a latent N–H functional group with a key role in catalysis. Before
these reports, initial proposals1,2,31 and many computational
studies13a,14 pointed to the reversible deprotonation of a CH2
linker as a key step in catalysis, but these proposals should
potentially be reevaluated in light of the new ndings. Impor-
tantly, our work does not completely rule out the potential
involvement of CH2 linkers in other processes. It is experi-
mentally known that the addition of H2 to RuPNNdearom occurs
reversibly at room temperature (Scheme 1).1 Our calculations
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(Fig. S7†) indicate that this process has
a barrier of
23.7 kcal molꢁ1 under the conditions of ester hydrogenation,
which is too high to account for the fast room-temperature
turnover the activated catalyst exhibits in this process, but
could be accessible at a higher temperature in a different
process. We are continuing to probe these possibilities in
computational and experimental studies of related catalytic
transformations.
Conclusion
We previously demonstrated that Milstein's pincer–ruthenium
catalyst for ester hydrogenation and related reactions is acti-
vated by dehydroalkylation to give the active form, which
contains an NH functional group that is essential for catalysis.9
In this work, we have presented a detailed computational and
experimental study of the mechanism of ester hydrogenation
catalyzed by this activated form, and conclude that participa-
tion of the N–H functional group is key in hydrogen activation,
ester hydrogenolysis, and aldehyde hydrogenation. The catalyst
speciation, the overall rate of reaction, and the dependence of
the rate on the concentrations of reactants and products
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8492 | Chem. Sci., 2021, 12, 8477–8492
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