Asymmetric hydrogenation with iridium C,N and N,P ligand complexes: Characterization of dihydride intermediates with a coordinated alkene

Article abstract of DOI:10.1002/anie.201309515

Previously elusive iridium dihydride alkene complexes have been identified and characterized by NMR spectroscopy in solution. Reactivity studies demonstrated that these complexes are catalytically competent intermediates. Additional H₂ is required to convert the catalyst-bound alkene into the hydrogenation product, supporting an Ir^III/Ir^V cycle via an [Ir^III(H)₂(alkene)(H₂)(L)]⁺ intermediate, as originally proposed based on DFT calculations. NMR analyses indicate a reaction pathway proceeding through rapidly equilibrating isomeric dihydride alkene intermediates with a subsequent slow enantioselectivity- determining step. As in the classical example of asymmetric hydrogenation with rhodium diphosphine catalysts, it is a minor, less stable intermediate that is converted into the major product enantiomer. Previously elusive iridium dihydride alkene complexes (see scheme) have been identified and characterized by NMR spectroscopy in solution. Reactivity studies indicated that these complexes are catalytically competent intermediates. Additional H₂ is required to convert the catalyst-bound alkene into the hydrogenation product, supporting an Ir^III/Ir^V cycle via an [Ir ^III(H)₂(alkene)(H₂)(L)]⁺ intermediate. Copyright

Full text of DOI:10.1002/anie.201309515

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DOI: 10.1002/anie.201309515
Reactive Intermediates
Asymmetric Hydrogenation with Iridium C,N and N,P Ligand
Complexes: Characterization of Dihydride Intermediates with
a Coordinated Alkene**
Stefan Gruber and Andreas Pfaltz*
Abstract: Previously elusive iridium dihydride alkene com-
plexes have been identified and characterized by NMR
spectroscopy in solution. Reactivity studies demonstrated that
these complexes are catalytically competent intermediates.
Additional H2 is required to convert the catalyst-bound
alkene into the hydrogenation product, supporting an IrIII/IrV
cycle via an [IrIII(H)2(alkene)(H2)(L)]+ intermediate, as orig-
inally proposed based on DFT calculations. NMR analyses
indicate a reaction pathway proceeding through rapidly
equilibrating isomeric dihydride alkene intermediates with
a subsequent slow enantioselectivity-determining step. As in the
classical example of asymmetric hydrogenation with rhodium
diphosphine catalysts, it is a minor, less stable intermediate that
is converted into the major product enantiomer.
Chen and Dietiker, in contrast, found evidence for an IrI/
IrIII cycle occuring in the gas phase, based on a mass
spectroscopic study of the hydrogenation of styrene with an
Ir/PHOX catalyst (PHOX = phoshinooxazoline).[4] Although
their results indicate that an IrI/IrIII cycle is chemically
feasible, they do not rule out an IrIII/IrV cycle in solution.
In low-temperature NMR experiments in THF we were
able to characterize an [Ir(cod)(PHOX)(dihydride)]+ (cod =
cyclo-1,5-octadiene) complex as the primary product of the
reaction of the corresponding precatalyst [Ir(cod)-
(PHOX)]BArF (BArF = tetrakis[3,5-bis(trifluoromethyl)phe-
nyl]borate) with H2.[5] Upon warming under an H2 atmos-
phere, formation of cyclooctane and two diastereoisomeric
[Ir(PHOX)(dihydride)(solvent)]+ complexes were observed.
Our initial studies were carried out in THF, because the labile
hydride species are stabilized by coordination in this solvent.
However, as THF inhibits hydrogenation reactions, which
require weakly coordinating solvents such as dichlorome-
thane, the crucial part of the catalytic cycle involving the
olefinic substrate cannot be studied in THF. NMR studies
under hydrogenation conditions in dichloromethane proved
to be difficult because of the high reactivity and multifaceted
aggregation behavior of iridium hydride complexes. Only
recently, we found reliable procedures for the controlled
formation of iridium hydride complexes in dichloromethane
and succeeded in characterizing several hydride-bridged
dinuclear complexes, with C,N and N,P ligands, by NMR
spectroscopy and crystal structure analysis.[6] As a next step,
we decided to investigate reactions of iridium precatalysts
with H2 in the presence of an alkene, with the aim of
identifying catalyst–substrate adducts formed under hydro-
genation conditions. Herein we report the results of this study
which led to the characterization and elucidation of the three-
dimensional (3D) structure of three iridium dihydride alkene
complexes by NMR spectroscopy.
C
ationic iridium complexes derived from chiral C,N or
N,P ligands have emerged as highly efficient catalysts for the
asymmetric hydrogenation of olefins. In contrast to rhodium
and ruthenium diphosphine catalysts, they do not require
a coordinating functional group in the substrate, and there-
fore have a very broad scope ranging from purely alkyl-
substituted alkenes to a variety of functionalized olefins as
well as furans and indoles.[1]
Despite the vast amounts of literature on iridium-cata-
lyzed asymmetric hydrogenation, experimental investigations
of the mechanism and the nature of the catalytic intermedi-
ates are still scarce. So current mechanistic proposals rely
almost entirely on computational studies.[2] Based on DFT
calculations Andersson and co-workers and Burgess and co-
workers postulated a catalytic cycle starting from an iridium-
(III) dihydride complex, which as a first step forms a p com-
plex with the substrate. Subsequent coordination of a H2
molecule then leads to an [IrIII(H)2(alkene)(H2)(L)]+ complex
(L = C,N or N,P ligand) which rearranges to an [IrV(H)3-
(alkyl)(L)]+ intermediate and undergoes reductive elimina-
tion releasing the product and closing the catalytic cycle. An
alternative IrI/IrIII cycle, analogous to the well-established
mechanism for rhodium-catalyzed hydrogenation,[3] was
found to be energetically less favorable.
For our studies, we chose the iridium complexes 1 and 2,
which had proven to be efficient catalysts for the hydro-
genation of alkenes.[7] When a solution of the Burgess catalyst
1 and (E)-1,2-diphenyl-1-propene (3; 3 equiv) in CD2Cl2 was
[*] Dr. S. Gruber, Prof. Dr. A. Pfaltz
University of Basel, Department of Chemistry
St. Johanns-Ring 19, 4056 Basel (Switzerland)
E-mail: andreas.pfaltz@unibas.ch
[**] Financial support by the Swiss National Science Foundation is
gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201309515.
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À
treated with hydrogen gas (1 bar) at 263 K, two-dimensional
(2D) NMR analysis indicated partial formation of a dihydride
iridium alkene complex. However the structure of this new
species could not be firmly established because 1 along with 3
and the hydrogenation product, 1,2-diphenylpropane, were
present as major components, and resulted in complex spectra
with severe signal overlap. To simplify the spectra and
facilitate signal assignments, we synthesized the correspond-
ing deuterated alkenes [D5]-4 and [D7]-4. Under optimized
reaction conditions (see Scheme 1) the reaction of 1 with an
cyclic carbene unit. The C C double bond axis of the alkene
lies approximately in the coordination plane defined by the
atoms Ir, N, and C8. The 3D structure of this complex and in
particular the coordination mode of the alkene were corro-
borated by NMR studies of the analogous reaction of [D7]-4
with 1 and H2, thus leading to complex [D7]-5 (see the
Supporting Information).
To investigate the reactivity of [D7]-5 (Figure 3), the
solvent was evaporated from the reaction mixture at 213 K
and the remaining solid was washed with cold n-hexane. The
1H NMR spectrum of the redissolved material in CD2Cl2
showed that all of dihydro-[D7]-4 and part of alkene [D7]-4
were removed by this procedure (Figure 3b). Upon warming
to room temperature the alkene complex [D7]-5 decomposed
with concomitant release of free alkene, but no conversion
into the corresponding alkane was observed. At the same
time new signals belonging to the previously reported
dinuclear hydride complex [IrH(C,N)(m-H)]22+ (6)[6] appeared
(Figure 3c; Figure S1 in the Supporting Information gives an
overview of the hydride region). In contrast, when the
solution containing [D7]-5 and [D7]-4 was warmed to room
temperature under hydrogen gas (1 bar, 10 min) almost full
conversion of [D7]-4 into the hydrogenation product was
observed, accompanied by the disappearance of [D7]-5 and
the formation of 6[10] (Figure 3d).
Obviously, addition of H2 is required to induce turnover of
the coordinated alkene in complex [D7]-5 to the correspond-
ing alkane. These observations support an IrIII/IrV cycle via an
[IrIII(H)2(alkene)(H2)(L)]+ intermediate, as originally con-
cluded from computational studies.[2] However, no signals of
a dihydride complex with an additional coordinated H2
molecule could be detected in reaction mixtures containing
[D7]-5 under 2 bar of hydrogen pressure at 233 K. The
presence of [D7]-5 as the major species in the reaction
mixture resulting from treatment of the precatalyst 1 with
alkene and H2 indicates that [D7]-5 is the resting state of the
catalyst in the hydrogenation of [D7]-4.
A hydrogenation pathway via intermediate [D5]-5 would
lead to the R-configured enantiomer if the alkene remains
bound to the catalyst with the same enantioface as shown in
Figure 2. In contrast, the major enantiomer formed in the
hydrogenation of the methylstilbene 3 with the catalyst 1 is
known to have an S configuration.[7a] Control experiments
with the deuterated substrate [D7]-4 at room temperature and
under the low-temperature conditions, used for the character-
ization of [D5]-5, confirmed the S configuration of the hydro-
genation product with 1 based on optical rotation and chiral-
phase HPLC analysis (see Table S1 in the Supporting
Information). Consequently, in the course of the hydrogena-
tion reaction, [D5]-5 has to be converted into an intermediate
which coordinates the alkene with the opposite enantioface.
Inspection of the hydride region in the 1H NMR spectrum
revealed that a second dihydride iridium alkene complex
(doublets at d = À17.10 and À45.13 ppm) was present in very
low concentration.[11] At 233 K the NOESY spectrum showed
exchange crosspeaks between this species and [D5]-5 in the
hydride region (see Figure S2 in the Supporting Information).
It is tempting to speculate that this minor species is an isomer
resulting from enantioface exchange, although a rotational
Scheme 1. Reaction of 1 and substrate [D5]-4 in CD2Cl2 at 3 bar
hydrogen gas at 238 K.
excess of [D5]-4 and H2 afforded the new dihydride iridium
alkene species [D5]-5 in greater than 95% yield[8] and was
stable in CD2Cl2 solution at 233 K for several days. In
addition, unreacted [D5]-4 and the hydrogenation product
dihydro-[D5]-4 were present.
1
The H NMR spectrum of the reaction mixture showed
two hydride signals both as doublets [2J(H,H) = 7.5 Hz], one
at d = À15.56 ppm and the other at d = À42.64 ppm. Such
a very low frequency shift of a hydride is characteristic for
a structure with a hydride ligand positioned trans to an empty
À
coordination site which is either vacant or engaged in a C H
agostic interaction.[9] The coordination of the alkene to the
iridium metal was verified by a significant low frequency shift
of the olefinic proton and the chemical shifts of the olefinic
13C atoms (Figure 1).
Figure 1. Olefinic 1H and 13C NMR chemical shifts of the free and
coordinated alkene, respectively.
On the basis of extensive 2D NMR analyses the 3D
structure was assigned. Figure 2 shows two segments through
the 2D NOESY spectrum for [D5]-5, in which the NOE
contacts from the hydrides to various protons of the
coordinated alkene and the C,N ligand are visible (for
additional spectra, see the Supporting Information). In
agreement with DFT calculations by Burgess, Hall, and co-
workers[2d,e] the alkene is coordinated trans to the N-hetero-
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Figure 2. Section of the 2D NOESY spectrum for [D5]-5 showing the contacts from the hydrides (Ha and Hb) to various protons of the coordinated
alkene and the C,N ligand (the contacts to the isopropyl group containing C15 are not shown in the structure; 233 K, 500 MHz, CD2Cl2).
À
À
isomer with the alkene C C axis aligned with the axial Ir H
bond cannot be excluded.
In view of these results, demonstrating that substrate
catalyst adducts are indeed observable by NMR spectroscopy,
we decided to extend our studies to N,P ligand complexes.
After initial experiments with various iridium catalysts, the
phosphinooxazoline complex 2, which is a very reactive
hydrogenation catalyst as shown in entries 3 and 4 in Table S1
of the Supporting Information, was chosen as the most
promising candidate for further investigations.
When a CD2Cl2 solution of the iridium complex 2 and
4.5 equivalents of [D5]-4 was treated with 3 bar of hydrogen
gas at 233 K for 35 minutes and then degassed, 2D NMR
analysis revealed the formation of two isomeric dihydride
alkene iridium complexes in a ratio of about 11:1. Coordina-
tion of the alkene to the iridium metal was verified for both
species by a significant low-frequency shift of the olefinic
proton and the 13C chemical shifts (see Figure S3 in the
Supporting Information). The 1H NMR spectra of both
isomers showed a coupling between the olefinic proton and
the phosphorus atom, which was identified by 31P decoupling.
In the 1H NMR spectrum two hydride resonances appear
as doublets of doublets at d = À20.41 and À32.32 ppm for the
major species [2J(H,H) = 5.8 Hz] and at d = À20.75 and
À31.61 ppm for the minor species [2J(H,H) = 6.1 Hz;
2
Figure 4]. The J(H,P) values of 15–20 Hz observed for both
isomers confirm that both hydrides are located cis to the
phosphorus atom.[12] On the basis of additional 2D NMR
studies the 3D structures for [D5]-7a (major) and [D5]-7b
(minor) were assigned as shown in Figure 4.
In agreement with computational studies[2a–c] the alkene is
coordinated trans to the phosphorus atom in both [D5]-7a and
[D5]-7b. In the major isomer the C–C double bond axis of the
alkene is positioned approximately in the coordination plane
defined by the Ir, N, and P atoms, whereas in the minor isomer
it is rotated out of plane by 908.[13] A clear distinction between
[D5]-7a and [D5]-7b can be made based on the absence or
presence of 1H NOE contacts between the proton at the
stereogenic center of the ligand and the protons of the p-tolyl
residue of the alkene (for full characterization, see the
Supporting Information). Notably, the major and the minor
Figure 3. Reactivity studies of [D7]-5 in the absence and presence of
hydrogen gas (233 K, 500 MHz, CD2Cl2).
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analyses is S (72% ee, see Table S1), which requires coordi-
nation of the alkene as determined for minor isomer [D5]-7b.
Thus the major pathway leading to the S-configured product
seems to proceed via a minor intermediate, similar to the
mechanism of the asymmetric hydrogenation of acetamido-
acrylates with rhodium diphosphine catalysts.[3]
The alkene complexes [D5]-7a and [D5]-7b proved to be
less stable than the analogous C,N ligand complex [D5]-5. At
233 K slow formation of additional dihydride species could be
detected and likely arose from complexation of the isomer-
ized cis-alkene [D5]-4, which could be identified after reaction
workup (see Figure S4 in the Supporting Information). The
instability of [D5]-7a and [D5]-7b precluded reactivity studies
as described for complex [D7]-5. Nevertheless, we could show
that under 2 bar of hydrogen gas at 233 K complexes [D5]-7a
and [D5]-7b did not form any hydride species with an
additional coordinated H2 molecule. These findings are
consistent with DFT calculations of Hopmann and Bayer,
according to which coordination of a H2 molecule to an
[Ir(PHOX)(dihydride)(alkene)]+ complex is energetically
unfavorable, mainly as a result of entropic destabilization.
In conclusion, we were able to identify and characterize
previously elusive iridium dihydride alkene complexes which
were generated under hydrogenation conditions. Reactivity
studies indicated that these complexes are catalytically
competent intermediates which represent the resting state
of the catalyst. The observation that H2 is required to convert
the catalyst-bound alkene into the hydrogenation product
supports an IrIII/IrV cycle via an [IrIII(H)2(alkene)(H2)(L)]+
intermediate, as originally proposed by Andersson and co-
workers. The 3D structures of the two major alkene com-
plexes derived from the Burgess catalyst and an Ir/PHOX
Figure 4. Section of the 1H NMR spectrum showing the hydride
signals for [D5]-7a and [D5]-7b and their 3D structures (233 K,
500 MHz, CD2Cl2).
isomer coordinate the alkene with the opposite enantioface.
These assignments and the 3D structures were fully confirmed
by analogous NOE studies of reaction mixtures of alkene
[D7]-4 and iridium complex 2.
The NOESY spectrum of the reaction mixture at 253 K
showed an exchange process between the alkene ligands in
[D5]-7a and [D5]-7b (Figure 5). In addition, an exchange
between the bound alkene in [D5]-7a and [D5]-7b and the free
alkene [D5]-4 was observed, thus indicating fast equilibration
of the major and minor isomer by alkene dissociation/
association. The configuration of the product obtained from
hydrogenation under the conditions used for the NMR
=
precursor revealed that the C C bond enantioface which
coordinates to the catalyst does not correlate with the
absolute configuration of the major product enantiomer
formed in the corresponding preparative hydrogenation. In
case of the Ir/PHOX complex we observed a second minor
hydride complex, which is bound to the opposite enantioface
of the alkene and is in rapid equilibrium with the major
isomer. These findings imply a reaction pathway proceeding
through rapidly equilibrating isomeric dihydride alkene
intermediates with a subsequent slow enantioselectivity-
determining step. As in the classical example of asymmetric
hydrogenation with rhodium diphosphine catalysts, it is
a minor, less stable intermediate which is converted into the
major product enantiomer.
Received: November 1, 2013
Published online: January 21, 2014
Keywords: hydrogenation · iridium · reaction mechanisms ·
.
reactive intermediates · structure elucidation
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Figure 5. Section of the phase-sensitive 2D NOESY spectrum for the
reaction mixture containing [D5]-7a and [D5]-7b showing only the
exchange crosspeaks between the protons M-8 and m-8, M-8’ and m-8’
as well as between M-7a and m-7a (253 K, 500 MHz, CD2Cl2).
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[9] We have recently reported two structures with the formula
[IrH(C,N)(m-H)]2(BArF)2 with a hydride shift trans to an empty
cooridnation site appearing at d = À36.85 and À34.45 ppm,
respectively; See Ref. [6]. See also: a) H. E. Selnau, J. S. Merola,
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[10] We have shown that the dinuclear hydride complex 6 is not an
active catylst at 1 bar hydrogen pressure; see Ref. [6].
[11] Four additional hydride signals at d = À22.24, À24.17, À28.19,
and À36.55 ppm were present. However, COSY data indicate
that they are correlated with each other and they were also
present in hydrogenations of complex 1 in the absence of alkene
[D5]-4.
[12] For an orientation trans to a phosphorus atom a coupling
constant of 100 – 200 MHz would be expected: see P. S. Pregosin,
NMR in Organometallic Chemistry, Wiley-VCH, Weinheim,
2012.
[13] The effective rotation of the complexed alkenes were drawn on
the basis of preliminary calculations.
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