Ketone hydrogenation with iridium complexes with "non N-H" ligands: The key role of the strong base

Article abstract of DOI:10.1021/acscatal.5b00613

Ferrocenyl phosphine thioether ligands (PS), not containing deprotonatable functions, efficiently support the iridium catalyzed ketone hydrogenation in combination with a strong base cocatalyst. Use of an internal base ([Ir(OMe)(COD)]₂ in place

Full text of DOI:10.1021/acscatal.5b00613

Research Article
pubs.acs.org/acscatalysis
Ketone Hydrogenation with Iridium Complexes with “non N−H”
Ligands: The Key Role of the Strong Base
Joseph M. Hayes,†,⊥ Eric Deydier,‡ Gregori Ujaque,† Agustí Lledos,*,† Raluca Malacea-Kabbara,‡,∥
́
Eric Manoury,‡ Sandrine Vincendeau,‡ and Rinaldo Poli*,‡,§
†Departament de Química, Universitat Auton
̀
oma de Barcelona, 08193 Bellaterra (Barcelona), Spain
̀
par convention a l’Universite Paul Sabatier et a l’Institut National
‡Laboratoire de Chimie de Coordination, UPR CNRS 8241 liee
́
̀
́
Polytechnique de Toulouse, 205 Route de Narbonne, 31077 Toulouse Cedex 4, France
§Institut Universitaire de France, 103, bd Saint-Michel, 75005 Paris, France
S
* Supporting Information
ABSTRACT: Ferrocenyl phosphine thioether ligands (PS),
not containing deprotonatable functions, efficiently support
the iridium catalyzed ketone hydrogenation in combination
with a strong base cocatalyst. Use of an internal base
([Ir(OMe)(COD)]2 in place of [IrCl(COD)]2) is not
sufficient to ensure activity and a strong base is still necessary,
suggesting that the active catalyst is an anionic hydride
complex. Computational investigations that include solvent effects demonstrate the thermodynamically accessible generation of
the tetrahydrido complex [IrH4(PS)]− and suggest an operating cycle via a [Na+(MeOH)3···Ir−H4(PS)] contact ion pair with an
energy span of 18.2 kcal/mol. The cycle involves an outer sphere stepwise H−/H+ transfer, the proton originating from H2 after
coordination and heterolytic activation. The base plays the dual role of generating the anionic complex and providing the Lewis
acid cocatalyst for ketone activation. The best cycle for the neutral system, on the other hand, requires an energy span of 26.3
kcal/mol. This work highlights, for the first time, the possibility of outer sphere hydrogenation in the presence of non
deprotonatable ligands and the role of the strong base in the activation of catalytic systems with such type of ligands.
KEYWORDS: catalyzed transfer hydrogenation, iridium, bifunctional ligands, effect of strong base, DFT calculations
XH function (typically an amine) is transferred to the O atom
and a hydride is transferred to the C atom (Scheme 1, I →
II).43 The invoked role of the base in Noyori’s systems is to
allow the catalyst to remain in a more active neutral form (cycle
B), whereas only the slower cycle A via the protonated form III
would occur without base.44 Indeed, certain isolated amido
INTRODUCTION
■
The reduction of carbonyl compounds and particularly the
enantioselective reduction of prochiral ketones, leading to
optically pure secondary alcohols, has been the topic of a
considerable number of studies because of its significance for
the manufacture of pharmaceuticals and advanced materials.1−4
Remarkable efforts have been devoted to the development of
this method by using organometallic complexes as catalysts.
The majority of the work carried out in this area has employed
ruthenium-based precatalysts in combination with a variety of
phosphine and amine ligands.5−10 Of these, the family of
[RuCl2(diphosphine)(diamine)] molecules developed by
Noyori, Ikariya, Ohkuma, and co-workers stands out.11−14
Efficient enantioselective catalysts based on rhodium,15−17
iridium,18−26 and iron27−36 have also been reported in the
literature. Interest in iridium as a catalytic metal is sparked by
the observation that it outperforms rhodium for the ionic
hydrogenation of particularly difficult substrates such as imines
and industrial processes based on Ir-catalyzed hydrogenation
have been implemented.37−40
Scheme 1. “Classical” Outer Sphere Mechanism for the
Hydrogenation of Ketones
Contrary to olefins, unsaturated oxygenated substrates may
be hydrogenated by the outer sphere mechanism,41,42 without
substrate coordination. These processes are also characterized
by the need of a strong base cocatalyst in order to function. In
the generally accepted view, a proton from a metal coordinated
Received: March 21, 2015
Revised: June 7, 2015
Published: June 10, 2015
© 2015 American Chemical Society
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systems (e.g., complexes of type II) are active catalysts in the
absence of added base.43 Computational explorations of this
mechanism, mostly carried out in the gas phase, have analyzed
the neutral cycle (B) but have not addressed the role of the
base,43,45−66 except for occasionally verifying that the base-
promoted HCl removal from a chloride complex precatalyst is
exothermic.67 Only one recent study has addressed the role of
the base, using a solvent model, for the further deprotonation
of the NH donor function in the neutral hydride complex with
generation of a more active anionic complex.68
There are, however, efficient systems that do not contain
active protons and yet a strong base is crucial. For instance, the
iridium complexes [Ir(COD)(1R)Cl] (2R where 1R = {CpFe-
[1,2-C5H3(PPh2)(CH2SR)}, Scheme 2)69 are good precatalysts
(NaOMe, KOH, or KOtBu) under an H2 atmosphere (30 bar)
at room temperature or below (e.g., see run 1 in Table 1). Run
Table 1. Results of Catalytic Runs for the Hydrogenation of
a
PhCOR to PhCH(R)OH
b
run
catalyst
ligand additive
NaOMe
R
time (h) conv (%)
c
1
2Et
CH3
CH3
CH3
CH3
CH3
CH3
5
5
5
5
5
5
>99
>99
0
2
[Ir(COD)Cl]2
2Et
1Et
1Et
1Et
NaOMe
c
3
4
5
6
[Ir(COD)Cl]2
[Ir(COD)Cl]2
7
0
[Ir(COD)
(OMe)]2
7
7
8
9
[Ir(COD)
(OMe)]2
CH3
CH3
CH3
5
5
5
0
[Ir(COD)
(OMe)]2
1Et
1Et
NaOMe
NaOMe
98
Scheme 2. Ligand and Precatalyst Object of This Study
d
e
[Ir(COD)
(OMe)]2
81
10 [Ir(COD)Cl]2
11 [Ir(COD)Cl]2
1Et
1Et
NaOMe
NaOMe
CF3
2
5
42
25
tBu
a
Reaction conditions: racemic catalyst, 6.4 × 10−3 mmol ; additive, 3.2
× 10−2 mmol ; acetophenone, 3.2 mmol; under 30 bar at 27 °C in 2
mL of isopropanol. Conversions determined by GC; 100% selectivity
in (R/S)-PhCH(R)OH. From ref 70. Enantiomerically pure ligand
(S). ee = 67% (S).
b
c
d
e
for aromatic ketone hydrogenation in alcohol solvents,70
although only in the presence of a strong base such as
MeONa or tBuOK. No significant activity was observed in the
absence of H2 or when a weaker base such as NEt3 was used.
This behavior is shared by many other catalysts that are devoid
of active protons, whether they are used in hydrogenation20 or
transfer hydrogenation.71−80 The common view is that the base
is needed to eliminate the acidity generated during the catalyst
activation step. Contrary to other compounds described in the
literature, such as [Ir(BINAP){1,2-c-C6H10(NH2)2}(H)(Cl)]+
and [Ir(COD){Ph2PhCH(Ph)CH(Me)NHMe}]+,20,22 com-
plexes 2R also function quite well in aprotic solvents such as
benzene or acetonitrile (so long as a strong base and H2 are
present),70 demonstrating that hydrogenation, rather than
transfer hydrogenation, takes place at least under these
conditions.
In pursuit of further mechanistic information on the catalytic
action of 2R, we have tested a precatalyst that internally
contains the needed methoxide base as a ligand, [Ir(OMe)-
(COD)]2, leading to the conclusion that the active catalyst
cannot be a neutral complex. We have also carried out
additional experiments on nonenolizable substrates. Finally, a
density functional theory (DFT) analysis provided a ration-
alization of the experimental observations. The key result is that
the hydrogenation cycle requires the generation of anionic
species. This constitutes a new paradigm in the hydrogenation
of carbonyl compounds, where access to an efficient outer
sphere mechanism does not require the presence of
deprotonatable ligands on the catalytic metal.
2 shows that the in situ generated chloride precatalyst yields the
same activity as the isolated complex 2Et,70 thus it is not
necessary to isolate compounds 2R. Runs 3−5 confirm the need
of both the ligand and a strong base for activity. Hence, the
methoxide analogue was also generated in situ from [Ir(OMe)-
(COD)]2 and 1Et, without attempting the isolation of putative
[Ir(OMe)(COD)(1Et)]. Contrary to our expectations, the
[Ir(OMe)(COD)]2/1Et catalyst showed only very small activity
(run 6), comparable to that of the corresponding chlorido
system (run 4) and no activity was recorded in the absence of
ligand (run 7). However, full activity was restored in the
presence of both the ligand and the external base (run 8).
When the enantiomerically pure ligand was used (run 9), the
enantiomeric excess of the hydrogenation product (67%) was
identical to that observed for the reaction catalyzed by 2Et/
NaOMe under the same conditions,70 suggesting generation of
the same active species. Hence, the chlorido ligand in
[IrCl(COD)]2/1Et or 2Et has no active role in catalysis. This
conclusion matches with that of another recent study81 of the
related RhI complexes, where complexes [Rh(COD)-
−
(1tBu)]+BF4 and [RhCl(COD)(1tBu)] were shown to feature
the same catalytic behavior.
1.2. Nonenolizable Substrates. For certain hydrogenation
catalysts, evidence has been advanced in favor of a mechanism
proceeding through a metal-assisted enolization of the ketone,
followed by hydrogenation of the enol CC unsaturation.82,83
Two nonenolizable ketones, PhCOR with R = CF3 and tBu,
have therefore been used as substrates for the hydrogenation
catalyzed by [IrCl(COD)]2/1Et (runs 10 and 11, respectively).
Although the catalytic activity is reduced for these systems,
probably because of electronic effects in the former case and
steric hindrance in the latter one, hydrogenation does take
place. Hence, a hydrogenation mechanism without the need of
tautomerization is energetically viable, at least for these two
substrates.
RESULTS AND DISCUSSION
■
1. Experimental Studies. 1.1. Chloride vs Methoxide. In
order to probe the effect of the strong base, we have now tested
a precatalyst that internally contains the needed strong base for
the generation of neutral chloride-free species. As previously
reported,70 compounds 2R (R = Et, Ph, tBu, Bz) display high
activity in the hydrogenation of substituted acetophenones
when used in iPrOH in combination with a strong base
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1.3. Fate of the Cyclooctadiene. Additional information on
the nature of the catalyst activation process was sought by
treating the [IrCl(COD)]2/1Et mixture with H2 in the absence
of substrate. This reaction results in COD elimination
selectively as cyclooctene (observed by gas-chromatography),
with no detectable trace of cyclooctane. Thus, hydrogenation of
the COD ligand takes place at the initial stages of the
hydrogenation catalysis and the cyclooctene product does not
have sufficient binding affinity with the Ir center under these
conditions to be further hydrogenated.
Gibbs energies are greatly dependent on n for small n values
but then converge, remaining essentially unchanged on going
from 5 to 6 (see details in the Supporting Information (SI)).
Only the values for n = 6 will be presented. Views of all
calculated structures are in the SI, and the energy results are
presented in Figure 1. Note that these computational
2. Mechanistic Considerations. In the absence of base,
activation of either [IrCl(COD)]2/1Et or [Ir(OMe)(COD)]2/
1Et with H2 in a coordinating solvent such as iPrOH,
presumably generates [Ir(H)2(1Et)(iPrOH)2]+ after COD
hydrogenation and cyclooctene expulsion. Related species
1
have been observed for the rhodium analogue by H NMR
using para-hydrogen induced polarization.84 Subsequent
deprotonation by the external or internal base could lead for
instance to [IrH(1Et)(iPrOH)] or to the related alkoxide
derivative [Ir(OiPr)(1Et)(iPrOH)], from which a host of
different mechanisms may be imagined. When the reaction is
carried out in an aromatic hydrocarbon solvent, η2-arene
coordination or alkoxide bridge formation can temporarily
saturate the iridium coordination sphere, although the vacant
position can then be saturated by the ketone substrate or by the
alcohol product. This would rationalize the observation of
catalytic activity even in a noncoordinating solvent. However,
this neutral system cannot be the catalytically active species,
because it should be equally accessible also from the
[Ir(OMe)(COD)]2/1Et mixture. The need of additional base
to promote the catalytic activity points to further deprotonation
with the generation of anionic species.
Numerous attempts have been made to identify the nature of
the catalytically active species in solution by generation from
[Ir(OMe)(COD)]2/1Et and strong base in the absence of
substrate, under a variety of different conditions and in different
solvents and notably to find supporting evidence for its anionic
nature, using NMR spectroscopic and mass spectrometric
methods. Because of the compounds extreme sensitivity, we
have so far been unable to isolate or spectroscopically identify
this species. Therefore, we have used computational chemistry
to explore the likely nature and structure of a putative anionic
catalyst.
3. DFT Computational Study. 3.1. Cationic vs Neutral vs
Anionic Systems. Exploratory investigations used a simpler
model of 1, henceforth abbreviated as (PS), generated by
replacing the ferrocene linker with a −CHCH− linker and
the phenyl groups by H atoms (see Scheme 3), but relevant
systems were subsequently calculated with the real ligand. The
calculations included the effect of solvation by optimization in a
Figure 1. Relative energy in methanol solution (ΔGMeOH in
kilocalories per mole) of various species generated from [Ir(COD)-
(PS)]+/H2/[MeO(MeOH)5]−). Only the structures of the lowest
energy isomers are shown. See the SI for the others. Color coding:
green, (a isomers, H trans to P); red (b isomers, H trans to S); blue
(numbers with no letter, primed numbers for isomers), symmetric
systems.
investigations are only meant to assess the relative stability of
various species and do not intend to suggest the mechanism
leading from the precatalyst to the most stable species.
Starting from the cationic [Ir(PS)(COD)]+ (3), COD
removal by hydrogenation coupled to isopropanol coordination
yields [Ir(PS)(iPrOH)2]+ (4). This process is undoubtedly
exothermic, and the formation of cyclooctene has been
experimentally demonstrated; therefore no calculations were
carried out on this step. Complex 4 is 9.3 kcal/mol higher than
the neutral system [Ir(OiPr)(PS)(iPrOH)] (iPrOH trans to P,
isomer 6a), which is taken as the reference point on the G scale.
H2 oxidative addition to 4 to yield [IrH2(PS)(iPrOH)2]+ (5)
can occur in 4 different ways, each one leading to a different
stereoisomer. Indeed, H2 may add along the P−Ir−O or the S−
Ir−O′ vector and in each case the additions either above or
below the coordination plane are diastereotopically related
polarizable continuum (methanol being used as the solvent)
−
and the base was modeled by [MeO(MeOH)n−1
]
clusters,
yielding [(MeOH)n],85 with n up to 6. The proton transfer
Scheme 3. Ligand Simplification Used for the Initial
Computational Investigations
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because of the ligand chirality. Of the four possible isomers, 5a
and 5a′ with a hydride ligand trans to P and 5b and 5b′ with a
hydride ligand trans to S, the two latter ones have lower energy
because the strongest trans labilizing ligand (hydride) is located
trans to the less strongly bonded donor atom (S). Figure 1
illustrates the energy of all isomers but details only the
geometry of the lowest energy one. All chemical drawings are
provided in the SI.
already noted for the cationic and neutral manifolds, the H2
oxidative addition processes are exoergic and the iPrOH
reductive elimination processes are endoergic, though by a
lesser amount. This phenomenon yields a trend of decreasing
energy upon substitution of OiPr ligands with hydrides by the
H2 oxidative addition−iPrOH reductive elimination sequence.
The most important energetic result, however, concerns the
deprotonation. While for certain stoichiometries the most
stable system is the neutral one (e.g., 6a vs 4 and 11; 7b vs 5b
and 12b; 9 vs 14) and the deprotonation of 8b to 13b is nearly
thermoneutral, the tetrahydrido system 16 is much more
stabilized than the protonated neutral version 10 and is by far
the most stabilized species overall. It is therefore likely to
correspond to the catalyst resting state. Note that 16 is
isoelectronic with the [IrH4(PR3)2]− (R = iPr, Ph) anions,86,87
which were isolated and fully characterized as salts of crown-
ether-stabilized alkali metals.86,88
Neutral and anionic systems can be obtained by single and
double deprotonation. In the neutral manifold, two isomers of
[Ir(OiPr)(PS)(iPrOH)] (6a and 6b) are generated by
deprotonation of 4, involving either the isopropanol ligand
located trans to S (isomer 6a) or that trans to P (6b). The
deprotonation process is energetically favorable and the lowest
energy isomer is 6a where the isopropoxide, which is a stronger
donor than isopropanol, is located trans to the weaker donor S
atom. H2 oxidative addition to 6 to generate [IrH2(OiPr)(PS)-
(iPrOH)] (7) is also energetically favorable and may occur in
four different ways, by analogy to the H2 oxidative addition to
the protonated analogue 4 examined above. The lowest energy
isomer (7b) features the strongest donor ligand (hydride) trans
to S. These four compounds can also be generated by
deprotonation of the corresponding isomers of 5. It is now
possible to envisage iPrOH reductive elimination from 7 to
yield two isomers of [IrH(PS)(iPrOH)] (8a and 8b), which
may also be generated by deprotonation of 5 at the metal with
concomitant iPrOH release. Isomer 8b with the hydride ligand
trans to S is the more stable one. The iPrOH reductive
elimination process is endoergic by ca. 7 kcal/mol. It is then
possible to oxidatively add H2 to 8a/b to give [IrH3(PS)-
(iPrOH)] with three fac H ligands (9 and 9′, both generated
from either 8a or 8b). This process is very exothermic, even
when starting from the most stable isomer 8b (ΔG = −17.2
kcal/mol). The two products have a symmetric substitution
pattern trans to the PS ligand, therefore only two isomers are
possible, differing by the placement of the axial H and iPrOH
ligands above and below the enantiomeric equatorial plane.
Putative mer isomers of 9 would be disfavored because of
strong trans influence of the mutually trans H atoms and have
not been considered. Another possible tautomer, the 7-
coordinate [IrH4(OiPr)(PS)] of formally IrV, converged to a
nonclassical octahedral isomer of IrIII, [IrH2(OiPr)(H2)(PS)]
(9″), at much higher energy and is not included in Figure 1.
Substitution of iPrOH with H2 in 9 or 9′ leads to
[IrH3(H2)(PS)], 10. A classical pentahydride tautomer of this
compound (10′) was found higher in energy (see the SI).
Hence, the lowest energy species in the neutral manifold is the
trihydride complex 9. This will be considered as the putative
catalyst resting state in hydrogenation cycles carried out in the
absence of base (vide infra).
After obtaining preliminary indications of the likely identity
of the most stable solution species from the above exploratory
investigations, selected calculations were carried out on the full
system in order to assess the importance of electronic and steric
effects associated with the ligand simplification. The
calculations were carried out using 1Ph as ligand at the full
quantum mechanical level. The relative energies for all systems
investigated did not greatly vary relative to those of the simpler
model: cationic 5bPh is at −1.5 kcal/mol relative to 6aPh (vs
−5.2 kcal/mol for the model system), neutral 7bPh, 9Ph, and
10Ph are respectively at −11.9, −20.4, and −18.0 kcal/mol (vs
−13.5, −21.9, and −19.3 kcal/mol for the model system) and
Ph
anionic 12Ph, 14′ , and 16Ph are respectively at −7.8, −16.2,
and −25.8 kcal/mol (vs −9.1, −17.4, and −28.3 for the model
system) showing a limited effect of the ligand backbone and
substituents. The deprotonation from 10Ph to 16Ph is exoergic
by −7.8 kcal/mol (cf. −9.0 kcal/mol for the model system).
The geometry of 16Ph, the lowest energy system calculated by
this study, is depicted in Figure 2. To conclude, the DFT
Figure 2. View of the optimized geometry for the anionic complex
[IrH4(1Ph)]− (16Ph).
Concerning the anionic species, [Ir(OiPr)2(PS)]− (11) is
obtained by deprotonation of 6a or 6b, [IrH2(OiPr)2(PS)]−
(12, four isomers) by H2 oxidative addition to 11 or by
deprotonation of 7, [IrH(OiPr)(PS)]− (13, two isomers) by
iPrOH reductive elimination from 12 or by deprotonation of 8,
[IrH3(OiPr)(PS)]− (14, two isomers) by H2 oxidative addition
to 13 or by deprotonation of 9, [IrH2(PS)]− (15) by iPrOH
reductive elimination from 14, and finally [IrH4(PS)]− (16) by
H2 oxidative addition to 15 or by deprotonation of 10.
Wherever there are isomeric possibilities, as noted above for the
cationic and for the neutral systems, the most stable isomer is
always the one placing the stronger σ donor ligand trans to S
and the weaker one trans to P. Also parallel to the trends
calculations suggests a thermodynamically favorable trans-
formation of the iridium precatalysts 2R to the octahedral
anionic tetrahydride complex 16R in the presence of H2 and a
strong base in alcohol solvents.
3.2. Relevance of Anionic Hydrides in Hydrogenation
Catalysis. Quite some time ago, Pez et al. proposed the role of
anionic hydride species in the catalytic hydrogenation of several
oxygenated substrates, following the isolation and character-
ization of ortho-metalated [K(Ln)][RuH2(κ2:C,P-o-C6H4PPh2)-
(PPh3)2] salts (Ln = solvent or crown ether).89−92 However,
detailed investigations by Halpern et al. subsequently
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demonstrated that the Pez complex, which yields
[RuH3(PPh3)3]− under H2,93,94 is reversibly protonated to
[RuH2(H2)(PPh3)3] in alcohol solvents and that the latter
“tetrahydride” complex is the real catalyst.95 It seems that, after
these debated contributions, the catalytic activity of anionic
hydride complexes has no longer been considered.
This Pez/Halpern contribution on the protonation state of
the ruthenium-phosphine-hydride catalyst gives us the oppor-
tunity to benchmark our computational system. We have
therefore computed the [RuH3(PPh3)3]−/[RuH2(H2)(PPh3)3]
system using the same base and solvent models and level of
theory as for the above iridium study. Three isomeric structures
were optimized for the neutral system, one nonclassical
ruthenium(II) complex with a dihydrogen ligand, [RuH2(H2)-
(PPh3)3], and two classical ruthenium(IV) tetrahydride
complexes (see Figure 3). The lowest energy isomer is the
elimination events and an outer-sphere mechanism where the
catalyst provides a hydride and a proton to the substrate
without the need of substrate coordination, either concertedly
(e.g., as in Scheme 1) or stepwise. The fundamental problem of
system 16 is that neither a coordination site for a ketone
coordination/insertion pathway nor a transferrable proton for
the outer sphere pathway are available. A possible pathway,
however, follows that recently presented by Dub et al. to
reappraise the hydrogenation mechanism in the presence of
Noyori’s catalyst,68 concluding that the base (tBuOK) serves to
deprotonate the amine in [RuH2(BINAP)(NH2CHPhCH-
PhNH2)]. The operating cycle occurs on a [K]+[RuH2-
(BINAP)(NHCHPhCHPhNH2)]− system with stepwise hy-
dride transfer, H2 coordination, and proton transfer, whereas II
(Scheme 1) is only an off-loop species.
Exploratory calculations (see Figure 4) were initially run on
the simpler model and then repeated for the best cycle on the
Figure 3. Relative energy in methanol solution (ΔGMeOH in
kilocalaries per mole) of three “RuH4(PPh3)3” isomers and of the
deprotonated complex [RuH3(PPh3)3]−.
nonclassical one, in agreement with NMR evidence96,97 and
with the solid state structure of a related complex.98 The next
lowest isomer has a 1:3:3 (capped octahedron) geometry, an H
atom capping the fac (PPh3)3 face (3.2 kcal/mol higher than
the nonclassical minimum). The less stable geometry can be
described as a pentagonal bipyramid with two axial and one
equatorial PPh3 ligands (4.3 kcal/mol higher than the
minimum). The anionic trihydride complex [RuH3(PPh3)3]−
has a regular octahedral geometry with a fac arrangement of the
hydrides and PPh3 ligands, as in the experimentally determined
structures of [K(18-crown-6)][RuH3(PPh3)3]99 and [Li-
(THF)3][RuH3(PPh3)3].100
Using the same base and conjugate acid models also
employed to calculate the deprotonation energetics of the
iridium system, namely the [MeO(MeOH)5]− and (MeOH)6
clusters, the deprotonation of the tetrahydride complex was
found nearly thermoneutral (−0.7 kcal/mol). This result is in
good agreement with the experimental evidence of an
equilibrated process for the [RuH3(PPh3)3]−/[RuH2(H2)-
(PPh3)3] system (the experimental study used cyclohexanol
in THF-D8)95 and confirms that the Ir system has greater
tendency to be anionic in basic alcohol relative to the Pez/
Halpern Ru system.
Figure 4. Computed cycle for acetone hydrogenation catalyzed by
[Na(MeOH)3][IrH4(1Ph)] (17Ph). For each species the Gibbs
energies (optimized geometry with BS1/fixed geometry with BS2)
in kilocalories per mole are given in parentheses below the compound
symbol.
full system. Only the energies related to the full system are
presented in Figure 4; once again, they do not substantially
differ from those of the simpler model (see the SI for the
details). In addition, single-point calculations on all fixed
optimized geometries were also repeated with a larger basis set
(BS2, see Computational Details). The calculations used
acetone as model substrate, methanol as model solvent, and
Na(MeOH)n+ (n = 3) as counterion, while using cation models
with n > 3 yielded higher G values for all systems. The cycle
starts with a [Na+(MeOH)3···16Ph] ion pair (17Ph). The Na+
cation anchors the ketone substrate in the first step (17Ph−
18Ph). A very recent paper has also highlighted the role of the
alkali metal cation, modeled as [Na(H2O)6]+, in the formate
decarboxylation catalyzed by an iron pincer complex.101 The
acetone adduct 18Ph is only slightly more stable, by 0.4 kcal/
mol, than the precursor 17Ph, but becomes less stable after
recalculation with BS2. Hydride transfer follows to generate a
Na+-anchored alkoxide (19Ph) held in the Ir coordination
sphere by σ C−H coordination, which then rearranges to a
3.3. Exploration of the Hydrogenation Mechanism from
the Anionic Complex 16. The hydrogenation of polar
substrates may in principle occur by several different
mechanisms. The most common ones are the inner-sphere,
or coordination/insertion mechanism, which can be further
classified into monohydride and dihydride mechanisms
depending on the number of available hydrides on the catalytic
metal and on the order of the insertion/H2 activation/reductive
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more stable μ2-O isomer (20Ph). In the next step, H2 displaces
OiPr from the Ir coordination sphere to yield 22Ph through a
van der Waals adduct (21Ph) as a local minimum. The H2
ligand in 22Ph then delivers a proton to the Na+-bonded OiPr
ligand to yield an isopropanol adduct 23Ph, and the cycle is
completed by product expulsion. The resting state is the
acetone adduct 18Ph (or the tetrahydrido complex 17Ph at the
BS2 level) and the rate determining transition state, TS(21−
22)Ph, corresponds to the isopropoxide substitution by H2.
Therefore, the hydrogenation is in essence an outer sphere
process with stepwise H−/H+ transfer to the sodium-activated
ketone, but the proton is not initially present on the catalyst; it
is only provided in a later step after H2 activation. The cycle
energy span is 18.2 kcal/mol (or 17.3 kcal/mol at the BS2
level), in good agreement with the observed high TOF at room
temperature.70 Indeed, for a TON of 500 in 2 h at 298 K, a
span of 19.0 kcal/mol can be calculated using the Eyring
equation, but the initial TOF is greater for an estimated span
closer to the computed value. Note that the alkali metal cation
plays a crucial role in this mechanism, ensuring the ketone
activation in intermediate 18. Evidence in favor of an active role
played by the alkali cation has been documented for RuII-
diamine-based hydrogenation catalyst.102,103
It is of interest to compare the energy profile of this cycle
with that recently presented by Dub et al. for the related
[K]+[RuH2(BINAP)(NHCHPhCHPhNH2)]− species.68 For
the deprotonated Noyori catalyst, where a naked K+ cation
was used as opposed to our more realistic MeOH-solvated Na+
cation, the calculated rate-determining transition state was the
ketone insertion step. This step yields an intermediate where
the alkoxide ligand is not coordinated to the alkali metal but
rather forms a hydrogen bond with the N−H group and a very
weak σ C−H coordination to the Ru center. In this way, there
is no need to displace a strongly bonded anionic ligand to
coordinate H2, as opposed to our calculated cycle in which the
alkoxide rearranges to bridge the Ir and Na metals.
3.4. Exploration of the Hydrogenation Mechanism from
the Neutral Complex 9. The next question to be addressed is
why catalysis is not efficient in the absence of a strong base.
This means that the best available cycle from a neutral iridium
complex must have a higher energy span than the anionic
system presented above. The lowest energy species calculated
within the neutral manifold (which is accessed from [Ir(OMe)-
(COD)]2/1Et when no strong base is added) is the trihydride
complex 9. Therefore, this species is likely the resting state of
any putative operating cycle under base-free conditions. Species
9 has an easily accessible vacant position for a coordination/
insertion mechanism, made available by isopropanol dissocia-
tion, and also a proton (on the coordinated alcohol) for an
outer sphere pathway.
Here, again, initial explorations were run on the simpler
model system. Figure 5 shows the best cycle, while full details
are provided in the SI. The first step is dissociative replacement
of the isopropanol ligand to yield the acetone complex 25 via
the coordinatively unsaturated trihydride complex 24. Iso-
propanol dissociation has a very small energy cost (3.8 kcal/
mol) because of the strong trans labilizing effect of the hydride
ligand. The next step is hydride insertion to yield the alkoxide
complex 26, of which two isomers are possible (26a with the
alkoxide trans to S, represented in Figure 5, and 26b with the
alkoxide trans to P). Isomer 26b is actually lower in energy (at
3.8 kcal/mol relative to 9) because the two strongest trans
labilizing ligands (the hydride and the P donor) are not
Figure 5. Best cycle for acetone hydrogenation catalyzed by
[IrH4(1Ph)(iPrOH)] (9). For each species the Gibbs energy in kcal/
mol is given in parentheses below the compound symbol.
mutually trans. However, isomer 26a leads to the lowest span
cycle. Note that the isopropoxide ligand in 26a occupies the
same equatorial position previously occupied by the hydride
ligand: the axial ketone moves toward the equatorial plane
concertedly with the insertion process. Therefore, this is an
example of a real insertion, as opposed to a migratory insertion
which characterizes the alkyl migration toward carbonyl groups
in carbonylation processes or toward coordinated olefins in
coordination polymerization processes. The catalytic cycle is
then closed by H2 coordination yielding the adduct 27a′ and
heterolytic activation, to transfer a proton to the coordinated
isopropoxide and regenerate the hydride ligand via the rate-
determining transition state TS(27a′-9). This pathway involves
coordination of H2 to the equatorial position with concomitant
rearrangement of the isopropoxide ligand, which migrates
toward the axial position. The alternative H2 coordination to
the vacant axial site trans to the hydride ligand in 26a, while
yielding a lower energy dihydrogen complex 27a, leads to a
higher energy TS for the final heterolytic activation step. It is
also possible to envisage an alternative outer sphere pathway for
the concerted transfer of a proton from the coordinated
isopropanol and a hydride ligand from 9 to the outer sphere
acetone (indicated as the dashed pathway in Figure 5). This,
however, would generate the same dihydro-isopropoxide
complex 26. The coordination/insertion pathway that has
already been found for this transformation is not the cycle rate-
determining process. Therefore, even if the outer sphere H+/
H− transfer were competitive with the coordination/insertion
pathway, the cycle would remain limited by the rate of H2
activation and catalyst regeneration and the cycle energy span
would not change.
The catalyst regeneration step from 26 to 9 can also be
envisaged in another way, by inverting the H2 addition and
iPrOH formation steps. Isopropoxide-hydride coupling could
take place first, to generate the [IrH(PS)(iPrOH)] system (8),
followed by H2 oxidative addition. Thus, the mechanism would
operationally become a “dihydride coordination/insertion”
mechanism, as opposed to that shown in Figure 5 which is
operationally a “monohydride coordination/insertion” mecha-
nism. This possibility has also been explored on the model
system, as shown in Figure 6. In this case, the best pathway
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bis(phosphine) systems, is the catalyst resting state and yields a
cycle with an energy span consistent with the observed catalytic
activity. The base has the dual role of generating the anionic
complex and providing the Lewis acid cocatalyst for ketone
activation. The cycle is similar to that recently presented by
Dub et al. for the Noyori catalyst.68 However, we have
demonstrated here for the first time that an outer sphere
mechanism for ketone hydrogenation can be accessed also in
the presence of “non-deprotonatable” supporting ligands, with
the strong base playing a crucial role in the generation of
anionic species through a sequence of H2 addition and
deprotonation steps. Current work aims at studying the catalyst
resting state by experimental methods. The role of the cation in
the ketone activation will also be investigated in further
combined experimental and computational work.
EXPERIMENTAL SECTION
■
All operations were carried out under an atmosphere of argon
with standard glovebox and Schlenk-line techniques. Isopropa-
nol was purified by distillation over CaH2. Ligand 1Et and
complex 2Et were prepared as previously described.69,104
Compounds [Ir(OMe)(COD)]2 (Strem), acetophenone (Al-
drich, 99%), 2,2,2-trifluoroacetophenone (Lancaster, 98%), and
phenyl tert-butyl ketone (Alfa Aesar, 98%) were used as
received.
Figure 6. Alternative O−H coupling/H2 oxidative addition pathway
for the regeneration of the resting state 9 from 26b.
involves the lower energy isomer 26b. A direct transfer of the
axial H atom from Ir to the isopropoxide ligand requires a very
high activation barrier, but the involvement of an additional
solvent molecule, modeled with methanol, makes the process
easier through a proton shuttle mechanism. 26b forms an H-
bonded adduct with MeOH, 26b·MeOH, which leads to 8b·
MeOH via TS(26b−8b)·MeOH. While this TS is at lower
energy relative to the non-MeOH assisted mechanism, it still
remains at higher energy than the alternative rate-determining
TS for the monohydride mechanism in Figure 5. Once arrived
at the IrI hydride complex 8b, the cycle is completed by H2
oxidative addition. The TS of this final step was not calculated
since the high energy of TS(26b−8b)·MeOH already makes
this pathway less viable than the monohydride coordination/
insertion mechanism of Figure 5.
Following this preliminary exploration and given the general
fidelity of the relative energies found for the real system to
those of the simpler model (vide supra), the cycle energy span
for the real system was assessed by calculating only the resting
state 9Ph, the key intermediate 27a′Ph for the best cycle (found
at 19.6 kcal/mol from 9Ph), and the rate determining transition
state TS(27a′-9)Ph, which was found at 26.3 kcal/mol from 9Ph.
The energy span of this cycle is therefore 26.3 kcal/mol, i.e. 8.1
kcal/mol higher than that afforded by the anionic hydride 17Ph.
This result agrees with the experimental evidence that
hydrogenation is efficient only when a strong base in present.
The rate determining transition state for the neutral cycle is
unfavorable because it involves heterolytic H2 activation in a
structure with two mutually trans strong ligands (H and OiPr),
whereas in the anionic cycle of Figure 4 the trans influence of
these two ligands is alleviated by the alkoxide coordination to
sodium and by the incipient substitution with H2.
General Procedure for Asymmetric Hydrogenation. In
a glovebox, a solution of 6.4 × 10−3 mmol of catalyst (6.4 ×
10−3 mmol of 2Et or 6.4 × 10−3 mmol of 1Et and 6.4 × 10−3
mmol of metallic precursor), 3.2 × 10−2 mmol of NaOMe (5
equiv, if appropriate), and 0.37 mL of acetophenone (381 mg,
3.2 mmol, 500 equiv) in 2 mL of iPrOH was transferred into a
5 mL glass ampule which was then placed into a stainless steel
autoclave. The reaction vessel was pressurized to the required
H2 pressure (30 bar) and stirred with a magnetic bar for the
desired time at 27 °C). The reaction was stopped by release of
pressure and the solution was filtered on silica with CH2Cl2
elution at room temperature. The product was finally analyzed
by chiral GC (Supelco BETA DEX 225).
Computational Details. The calculations were carried out
within the DFT approach with the M06 functional,105 including
an ultrafine integration grid, as implemented in Gaussian 09.106
All geometry optimizations were carried out using a basis set
BS1, which consisted of the SDD basis set and ECP for the Ir
and Fe atoms,107 augmented with f polarization functions (α =
0.938 and 2.462, respectively),108 the 6-31G(d) basis set for all
other heavy atoms, and the 6-31G(d,p) basis set for all H
atoms.109 All molecules involved in the best catalytic cycle (see
Results and Discussion) were also recalculated at their fixed
geometries with a more extended basis set BS2 (same SDD
functions for Ir and Fe, plus the 6-311++G(d,p) functions for
all other atoms). The effect of the solvent was included by the
SMD polarizable continuum110 in methanol (ε = 35.688)
during the geometry optimizations with BS1 and single point
calculations with BS2. All of the energies presented in the text
are Gibbs energies in methanol (ΔGMeOH). A correction of 1.95
kcal/mol was applied to all G values to change the standard
state from the gas phase (1 atm) to solution (1 M).111
CONCLUSION
■
We have experimentally demonstrated that the Ir ketone
hydrogenation catalyst generated by activation of 2 cannot be a
neutral iridium complex; the need of additional strong base
suggests the generation of an anionic active complex.
Calculations with the inclusion of implicit and explicit solvation
ASSOCIATED CONTENT
■
+
S
* Supporting Information
effects and of the Na(MeOH)3 counterion suggest that the
contact ion pair [Na+(MeOH)3···Ir−H4(PS)], containing an
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.5b00613.
anionic tetrahydride complex similar to already described
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Additional details of the DFT calculations, Cartesian
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AUTHOR INFORMATION
Corresponding Authors
*Fax: +34-935912477. E-mail: agusti@klingon.uab.es (A.L.).
*Fax: +33-561553003. E-mail: rinaldo.poli@lcc-toulouse.fr
(R.P.).
■
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Present Addresses
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⊥J.M.H.: Division of Chemistry, Centre for Materials Science,
University of Central Lancashire, Maudland Building, MB 50,
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We thank the European Commission through the HYDRO-
CHEM program (contract HPRN-CT-2002-00176) for sup-
port of this work. Additional bilateral support (LEA, Toulouse-
Barcelona) and National support from the CNRS (France),
from the Institut Universitaire de France, and from the
MINECO (project CTQ2014-54071-P, Spain) is also gratefully
acknowledged. This work was granted access to the HPC
resources of CINES and IDRIS under the allocation (2006
through 2015)-086343 made by GENCI (Grand Equipement
National de Calcul Intensif) and to the resources of the CICT
(Centre Interuniversitaire de Calcul de Toulouse, project
CALMIP).
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DOI: 10.1021/acscatal.5b00613
ACS Catal. 2015, 5, 4368−4376