Revisiting the Stereodetermining Step in Enantioselective Iridium-Catalyzed Imine Hydrogenation

Article abstract of DOI:10.1021/acscatal.7b02386

The mechanism for the iridium-catalyzed asymmetric hydrogenation of prochiral imines has been investigated for an experimentally relevant ligand-substrate combination using DFT calculations. The possible stereoisomers of the stereodetermining hydride tran

Full text of DOI:10.1021/acscatal.7b02386

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Article
Revisiting the Stereodetermining Step in
Enantioselective Iridium-Catalyzed Imine Hydrogenation
Brandon Tutkowski, Sutthichat Kerdphon, Elaine Lime, Paul
Helquist, Pher G. Andersson, Per-Ola Norrby, and Olaf Wiest
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b02386 • Publication Date (Web): 01 Dec 2017
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Revisiting the Stereodetermining Step in Enantioselective Iridium-Catalyzed Imine
Hydrogenation
[
a]
[b]
[c]
[a]
Brandon Tutkowski,
Sutthichat Kerdphon,
Elaine Limé,
Paul Helquist,
Pher G.
[b]
[a,d]
[a,c]
Andersson, Olaf Wiest*,
PerꢀOla Norrby
a
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Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana
46556. Email: owiest@nd.edu
b
Arrhenius Laboratory, Department of Organic Chemistry, and Berzelii Centre EXSELENT on
Porous Materials, Department of Materials and Environmental Chemistry, Stockholm University,
SEꢀ106 91 Stockholm, Sweden. Email: Pher.Andersson@su.se
c
Pharmaceutical Development, AstraZeneca, Pepparedsleden 1, SEꢀ431 80 Mölndal, Sweden.
Email: perꢀola.norrby@astrazeneca.com
d
Laboratory of Computational Chemistry and Drug Design, School of Chemical Biology and
Biotechnology, Peking University, Shenzhen Graduate School, Shenzhen 518055, China
Keywords
Imine hydrogenation, iridium, phosphineꢀoxazoline, mechanistic studies, stereoselectivity,
density functional theory
Table of Contents Graphic
Abstract
The mechanism of the iridiumꢀcatalyzed asymmetric hydrogenation of prochiral imines
has been investigated for an experimentally relevant ligandꢀsubstrate combination using DFT
calculations. The possible stereoisomers of the stereodetermining hydride transfer transition
state were considered for four possible hydrogenation mechanisms starting from the recently
disclosed active catalyst consisting of iridium phosphineꢀoxazoline with cyclometalated imine
substrate. The hydrogenation was found to proceed via an outer sphere pathway. The transition
state accurately describes the experimental observations of the active catalyst and provides a
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structural rationale for the high stereoinduction despite the lack of direct interaction points in the
outerꢀsphere mechanism. The predicted enantioselectivity was consistent with experimental
observations. Experimental studies support the hypothesis that the iridacycle forms
spontaneously and functions as the active catalyst in the hydrogenation.
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Introduction
The asymmetric hydrogenation of imines is an important method in the field of
asymmetric synthesis. The chiral amine products of such a reaction are widely used as building
1
blocks in the fine chemical and pharmaceutical industries. Based on the seminal work of
2
Crabtree in the late 1970’s, Pfaltz and coworkers developed an iridium complex with a
3
chelating phosphineꢀoxazoline, or PHOX, ligand. Since their initial utilization by Pfaltz, PHOX
ligands have been used extensively in the asymmetric hydrogenations of both imine and olefin
1b,4
substrates.
In subsequent work, Pfaltz and coworkers used NMR and DFT studies of
Ir(phosphineꢀoxazoline)dihydride complexes to show that the complexes preferred a
configuration with the hydrides cis to each other and one of them trans to the coordinating
5
nitrogen in the oxazoline ring. These studies also emphasized the importance of calculating the
complete chiral ligand, rather than smaller model complexes, as the structure of the ligand
controls the outcome of the enantiomeric product by both steric and electronic factors.
Many factors have been determined to be involved in the enantioselectivity of the
3
reaction, not the least of these being the choice of substituents on the phosphineꢀoxazoline
ligand. While no clear trends in enantioselectivity have been elucidated for the substituents on
phosphine, the substituent in the 5’ꢀposition on the oxazoline has been shown to control both
enantioselectivity and reactivity. A ligand with an isopropyl (iPr) group at this position was found
to be most selective, while ligands with an isobutyl (iBu) or phenyl group gave both lower
conversion and lower enantioselectivity. The selectivity is also dependent on the imine
substrate, with bulky and flexible substituents generally giving lower enantioselectivities.
Based upon earlier work where similar catalytic systems have been used to hydrogenate
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alkenes, quadrant models have been developed to predict the reaction enantioselectivity. It is
interesting to note that, for a given ligand, similarly substituted alkenes and imines can form
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products of opposite absolute configurations. This indicates that even if there could be parallels
between the mechanisms, the stereodetermining step for the two substrates must differ. Solvent
and additives have also been found to influence the enantioselectivity, with dichloromethane or
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toluene being the best choice for acyclic imines. Strongly coordinating solvents or additives can
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reduce enantioselectivity significantly, with one possible explanation being that these solvents
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block a contact point between substrate and metal. Another factor that might influence the
enantioselectivity is the potential E/Z isomerization of the substrate, a factor that is not easily
controlled. Based on the quadrant models, the Eꢀ and Zꢀisomers should interact differently with
the catalyst, and the E/Z ratio should then be expected to have an effect on the enantiomeric
excess (%ee). However, in studies where isomer mixtures of imines have been used, high
enantioselectivities have still been achieved. This has led to the conclusion that mainly one
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imine isomer is reduced, and that imine isomerization is fast, keeping the E/Z ratio constant.
Because of these different observations, it is clear that the mechanism for the iridiumꢀ
catalyzed imine hydrogenation is different from the Ir(III)/Ir(V) cycle which is widely accepted for
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alkene hydrogenation with P,Nꢀligands. This discrepancy has inspired a number of studies on
a range of different systems. Oro and coworkers have performed detailed studies of a system
with a monodentate phosphine ligand and have found that the active catalyst also incorporates
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a coordinated aniline obtained from hydrolyzed imine substrate. The resulting catalyst follows
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the now accepted pathway common to transfer hydrogenation catalysts, with coupled transfer
of a proton from the aniline and a hydride from iridium. The relationship of this mechanism to the
Pfaltz PHOX system is, however, unclear.
Several other mechanisms have been proposed for Ir catalysts, covering innerꢀ and
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outer sphere mechanisms and Ir(I)/Ir(III), Ir(III), and Ir(III)/Ir(V) cycles.
For the case of P,Nꢀ
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ligands, a detailed DFT study of the Pfaltz PHOX system was performed by Hopmann and
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Bayer.
They investigated several mechanistic proposals for both alkene and imine
hydrogenation at the B3LYP/6ꢀ311G**, LANL2DZ level of theory. For imine hydrogenation, the
preferred rateꢀ and selectivityꢀdetermining step is an outer sphere transfer of a hydride from a
neutral Ir(III) trihydride complex to a cationic iminium ion. This is noteworthy because having
only one strong contact (the IrꢀHꢀC vector), it is different from typical enantioselective catalysts
where multiple strong interactions are generally needed to achieve high selectivity. For
example, the selectivityꢀdetermining step in inner sphere alkene hydrogenations can be a
migratory insertion where the alkene is held rigidly by simultaneous contact with the metal and
11a
the hydride. Likewise, in outer sphere transfer hydrogenation reactions, the substrate is held
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in one position by simultaneous transfer of a proton and hydride from the active catalyst.
Similar mechanistic proposals for imine hydrogenation using H were invalidated by the
2
surprising finding that upon exposing a dihydride complex of an iridiumꢀPHOX precursor to an
imine substrate under hydrogenation conditions, rapid formation of an iridacycle analogous to
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complex 2 in Scheme 1 (vide infra) occurred. Detailed experiments, including the collection of
crystal structures showing the imine substrate cyclometalated to iridium, demonstrated that this
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iridacycle is the active catalyst in the hydrogenation of acetophenoneꢀderived imines. It was also
shown that cyclometalation with one imine can change the selectivity in the reaction with
another imine. An iridacycle has since been invoked as the active catalyst in an iridiumꢀ
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catalyzed transfer hydrogenation of imines. Current published mechanistic proposals for
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iridiumꢀPHOX catalyzed imine hydrogenations do not include an iridacycle as the active
catalyst. We decided to revisit the proposed reaction mechanisms for the imine hydrogenation in
order to gain an understanding of the pathway for a preꢀcatalyst complex containing an
aminophosphineꢀoxazoline ligand with a 2ꢀazanorbornane backbone developed by Andersson
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and coꢀworkers, 1, which provided high ee values (Figure 1). Because cyclometalation clearly
changes the catalyst, we took a step back from previously published mechanisms and
considered both inner and outer sphere mechanisms involving the iridacycle as the active
catalyst. The goal of these studies was to elucidate the basis of stereoinduction of the imine
hydrogenation catalyzed by 1 involving the iridacycle.
Figure 1. The iridium preꢀcatalyst with phosphineꢀoxazoline ligand studied in this work.
Results and Discussion
We considered the four potential mechanisms involving an iridacycle as the active
catalyst shown in Scheme 1. These mechanisms were an outer sphere Ir(III) pathway, an inner
sphere pathway through a heptacoordinate Ir complex, an inner sphere Cꢀmigration pathway,
and an inner sphere Nꢀmigration pathway all involving iridacycle 2 as the active catalyst. The
mechanisms investigated in this work are analogous to those investigated by Hopmann and
Bayer, but involving an iridacycle complex rather than a diꢀ or trihydride as the active catalyst.
The outer sphere mechanism begins with the binding of H to an open coordination site
2
of the catalyst. Proton transfer to the unbound imine substrate occurs, followed by hydride
transfer and extrusion of product, completing the catalytic cycle. By contrast, the inner sphere
mechanisms all include an imine substrate bound to the metal during the stereodetermining
hydride transfer step. The inner sphere mechanism through a heptacoordinate complex has
proton transfer to the substrate nitrogen occurring before hydride transfer. The Cꢀ and Nꢀ
migration pathways involve hydride transfer to the substrate occurring before proton transfer. In
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the Cꢀmigration pathway, hydride transfer occurs to the imine carbon of the substrate, leading to
a complex with a negatively charged nitrogen bound to iridium. In the Nꢀmigration pathway,
hydride transfer occurs to the nitrogen of the substrate, leading to a complex with a carbanion
bound to iridium. As shown, the active catalyst in all mechanisms is an iridacycle with H πꢀ
2
bound to iridium in what would otherwise be an empty coordination site. Hopmann and Bayer
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found that replacing a molecule of bound solvent with H in this site of their catalyst had little
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impact on the relative energies of the final structures. For the sake of simplicity, we decided to
use structures with H , rather than solvent, bound in this site.
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Scheme 1. Proposed catalytic cycles for imine hydrogenation using complex 2: the outer sphere
mechanism (upper left), the inner sphere mechanism through a heptacoordinated TS (upper right), the
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inner sphere Cꢀmigration mechanism (lower left), and the inner sphere Nꢀmigration mechanism (lower
right). * indicates a chiral center.
We started the investigation by calculating hydride transfer transition structures for a
minimal model system. In this system, the Ir is part of a cyclometalated acrylimine in place of
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the full (E)ꢀN,1ꢀdiphenylethanꢀ1ꢀimine substrate. A PH was used in place of the phosphorus
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moiety of the Andersson ligand while NH was used in place of the nitrogen portion of the
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Andersson ligand. As the small substrate model, we used formaldimine, which was protonated
in some investigated mechanisms. Representative examples of both model and full system
structures are provided in Scheme 2.
Scheme 2. Representative examples of full system structures and their corresponding model system
structures.
Given its highly simplified nature, this model system does not describe sterics or
stereoselectivity, but rather it is designed to provide general insights on the metal coordination
and to potentially limit the number of coordination possibilities around the metal for each
mechanism. Using this model system, all possible geometries of the hydride transfer transition
states in each of the four mechanisms were calculated. This model data is referenced to a
model version of low energy intermediate 7, Table 1 (vide infra), where the amine product is
coordinated to Ir. This is the product formed after the full hydrogenation of the substrate. One
representative hydride transfer transition state geometry in each mechanism, except for the
inner sphere through a heptacoordinated intermediate, is shown in Figure 2. Data for the
remaining geometries calculated for each mechanism can be found in Table S1 in the
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Supporting Information. A few basic trends can be noticed immediately from these model
system data. First, the mechanism with the lowest energy hydride transfer transition states is
the Cꢀmigration mechanism involving transition structures 5, the lowest of which is structure 5a
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at 82 kJ/mol. This stands in contrast to the previous results of Hopmann and Bayer, who
discounted a Cꢀmigration pathway due to high energy transition states. The second lowest
energy transition structures are in the outer sphere pathway. The lowest energy transition
structure of this pathway is 3d, which is 26 kJ/mol higher than 5a. The Nꢀmigration pathway
proceeds via transition structures that are at least 60 kJ/mol higher in energy than the Cꢀ
migration pathways. The energies for the few converged transition structures 4 that could be
located for the inner sphere pathway through a heptacoordinated iridium intermediate were
prohibitively high, as expected for a formal d20 complex. Therefore, this mechanism was not
further explored.
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For the other three mechanisms, we chose the two structures with the lowest energy or
which mirrored the geometry around iridium of the crystal structures collected by Schramm and
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coworkers, to calculate the diastereomeric transition structures of the experimentally studied
system. For the outer sphere mechanism, these were structures 3a and 3d. For the Cꢀmigration
mechanism, these were structures 5a and 5b. For the Nꢀmigration mechanism, these were
structures 6a and 6b. Based on the model system results, these were determined to be the
transition states most likely to match with experimental results and provide insight into the
mechanism. Two coordination modes were observed by Schramm and coworkers for plausible
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intermediates. Both fulfilled the expected requirement that ligands with strong trans
influence/effect (carbanion, hydride, or phosphine) should not be trans to each other in a low
energy complex. The same is true for all intermediates considered in our full systems, with the
exception of the dihydride species in the outer sphere mechanism which has four ligands with
high trans influence. We note that the “Halpern effect”, the preferences for some pathways to go
via high energy intermediates, in several examples can be traced to a strong trans effect that is
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relieved in the subsequent transition state, as is the case for the currently proposed outer
sphere mechanism. Since the hydride transfer is the stereodetermining step for all mechanisms,
the mechanism with the lowest energy hydride transfer transition state and that correctly
reproduces the enantiomeric excess observed experimentally should be the overall favored
pathway.
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Figure 2. Representative examples of model system hydride transfer transition states
The possibility of crossovers between the proposed mechanisms was also considered.
Of the four proposed mechanisms, the inner sphere mechanism through a heptacoordinated
intermediate has already been rejected based on high energy transition structures in the model
system and will not be discussed further here. Of the three remaining mechanisms, all three
have the same starting structure: an Ir P,N complex with one hydride and cyclometalated imine
substrate as shown in Scheme 3. The empty coordination site of this starting structure can be
occupied by either H or the πꢀbound substrate following the outer sphere or inner sphere
2
pathways, respectively. These structures can only interchange by reverting to the initial starting
structure that is common to all mechanisms, as can be shown by considering the possible
pathways for crossover. In the outer sphere pathway, a proton transfer occurs with unbound
substrate after coordination of H . The next step in the inner sphere pathways is, conversely, a
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hydride transfer to either the imine carbon or the imine nitrogen for the Cꢀ and Nꢀmigration
pathways, respectively. At this stage, the intermediates have either a positively or a negatively
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charged substrateꢀderived group on the Ir and are not directly in equilibrium with each other.
The products of the Cꢀ and Nꢀmigration, both of which have negatively charged groups, have
that charge localized on the nitrogen or on the carbon and are not directly in equilibrium either.
After a hydride transfer in the outer sphere pathway and a proton transfer in the Cꢀ and Nꢀ
migration pathways, the products obtained are the same for all three mechanisms. This analysis
shows that it is highly unlikely, and likely impossible, for there to be crossover between the three
proposed mechanisms midꢀway through any pathway.
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8
9
0
Scheme 3 Diagram of possible points of crossover between three proposed mechanisms. IS stands for
‘inner sphere,’ OS stands for ‘outer sphere.’
We optimized the transition structures identified from the model system data for the
three mechanisms using the full structures of an experimentally examined substrate and
catalyst. The final energies for the lowest energy stereoisomers of each transition structure are
shown in Table 1 and are reported relative to the energy of the structure of the resting state of
the catalyst with amine product bound to iridium, 7.
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 1. Structures and free energies for the full system catalyst resting state 7 and selected full system
hydride transfer transition structures. Blue = N, orange = P, red = O, gold = Ir, dark grey = C, white = H.
CꢀH hydrogens omitted for clarity.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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5
6
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8
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5
6
7
8
9
0
Outer Sphere
Hydride
Transfer
TS
Geometry
3
as
3dr
3ar
3ds
2
98 K,DCM
∆G
[kJ/mol]
14
22
82
112
Inner Sphere C-Migration
Hydride
Transfer
TS
Geometry
5ar
5as
5br
5bs
298 K,DCM
∆
G
89
108
104
119
[
kJ/mol]
Inner Sphere N-Migration
Hydride
Transfer
TS
Geometry
6ar
6as
6br
6bs
298 K,DCM
∆G
[kJ/mol]
157
177
225
225
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Reference
2
98 K,DCM
∆G
= 0 kJ/mol
7
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
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9
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2
3
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5
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9
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2
3
4
5
6
7
8
9
0
In order to gain insight into which of the three proposed pathways is the most favorable,
the lowest energy diastereomeric transition structures for each of the three proposed
mechanisms were compared. The lowest energy transition state of the outer sphere mechanism
is the pro R, isomer 3ar shown in Figure 3a. In comparison, the lowest energy structure of the
inner sphere Cꢀmigration mechanism, the pro R, stereoisomer 5ar shown in Figure 3b, is higher
ꢀ1
in energy by 75 kJ mol . The lowest energy transition state of the inner sphere Nꢀmigration
mechanism is the pro R, stereoisomer 6ar shown in Figure 3c. Compared to 3ar, the inner
ꢀ1
sphere Nꢀmigration mechanism is higher by 143 kJ mol than the outer sphere alternative.
These results suggest that the most favored mechanism has an iminium unbound to the iridium
15
during the hydride transfer step in analogy to the results for the nonꢀiridacycle pathway.
A
3
ar
4 kJ mol
ꢀ1
1
B
5
ar
ꢀ
1
89 kJ mol
C
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ar
ꢀ
1
1
57 kJ mol
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2
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7
8
9
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Figure 3. Calculated structures for the lowest energy hydride transfer transition states of the three
proposed mechanisms, a) outer sphere 3ar, b) inner sphere Cꢀmigration 5ar, and c) inner sphere Nꢀ
migration 6ar. CꢀH hydrogens omitted for clarity.
We next compared the lowest energy transition state in the outer sphere pathway, which
results in an R product amine, 3ar (Figure 4), to the lowest energy transition state in the same
pathway which results in an S amine, 3as. The transition state 3as is 8 kJ/mol higher in energy
than 3ar. This leads to a prediction of 90% ee in favor of the R amine product, which is in
excellent agreement with the experimental value of 90%. This agreement between calculation
and experiment suggests that the outer sphere pathway via a cyclometalated Ir(III) complex is a
good model for the reaction mechanism that can provide insights into the origin of the
stereoselectivity.
A
3
ar
ꢀ
1
1
4 kJ mol
Major
B
3as
22 kJ mol
Minor
ꢀ
1
Figure 4. Calculated structures for the lowest energy hydride transfer transition states yielding a) R and
b) S amine products in the iridium(III) inner sphere mechanism. CꢀH hydrogens omitted for clarity.
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The finding that a reaction with good stereoselectivity proceeds via an outer sphere
mechanism where the substrate is not coordinated to Ir and has only a single point of contact
with the catalyst is surprising. Without multiple points of contact in the binding pocket of the
catalyst, it would seem unlikely that the iPr substituent on oxazoline could direct
enantioselectivity by as much as it does (90%).
1
1
1
1
1
1
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1
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3
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5
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7
8
9
0
Before a more detailed analysis of the factors favoring the outer sphere pathway and the
factors controlling stereoselectivity, control experiments to ensure that the same cyclometalated
Ir complex forms and is the active species with the Andersson ligand, used in the comparison of
the stereoselectivity, were performed. Using an oꢀTol derivative of the ligand studied
computationally, with (oꢀTol) in place of Ph on phosphorus, the hydrogenation reaction was
2
2
run using cyclohexyl imine substrate 8. This substrate was chosen as one for which
cyclometalation would be difficult, if not impossible. A 0.5 mol% loading of CODꢀligated catalyst
precursor was added to a vial along with substrate and H gas at either 20 or 50 bars pressure.
2
The experiment was run twice at each of the two pressures, once without any additive and once
with 5 mol% (E)ꢀN,1ꢀdiphenylethanꢀ1ꢀimine. This additive was chosen as an imine implicated by
17
Schramm and coworkers to cyclometalate to Ir and form an active catalyst for hydrogenation.
When no imine additive was included in the reaction mixture, conversion was low at both 20 bar
(
(
4% conversion) and 50 bar (5% conversion) after reaction at room temperature for 15 hours
Table 2, entries 1 and 2). Enantioselectivities were also quite low for these hydrogenations
without additive, 18% and 15% ee at the two pressures, respectively. When the imine capable
of forming the iridacycle catalyst was included as an additive (5 mol%), yields and
enantioselectivities dramatically improved (Table 2, entries 3 and 4). This improvement strongly
suggests the involvement of the iridacycle as the active catalyst for hydrogenation in the case of
the Andersson ligand 1. The cyclometalation of the additive is much faster than hydrogenation,
given that the improvement of yield and stereoselectivity is observed when both additive and
substrate are added at the same time. Additionally, a hydrogenation product derived from the
additive was not observed along with hydrogenated substrate in reactions run with additive,
providing further evidence for cyclometalation of the additive occurring to provide reaction
improvement. Taken together, the results provide strong evidence that the mechanism involving
the iridacycle is capable of explaining the high reactivity and stereoselectivity observed in the
19
15
previous experiments while the previously studied mechanisms lacking its involvement are
not. The previously proposed trihydride is conformationally labile in the presence of excess H2,
allowing a switch between two facial coordination geometries. Furthermore, the steric influence
of the hydrides is negligible, allowing multiple approach vectors. Conversely, the configuration
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5
6
around the metal in the iridacycle is locked analogous to the “chiralꢀatꢀmetal” systems that lead
to high stereoselectivities in a range of reactions by constraining possible approaches of the
21
substrate.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
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9
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1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 2. Experimental results for hydrogenation run with and without cyclometalating imine additive.
a
b
Entry
p(H ) (bar)
Additive
Conversion (%)
ee (%)
2
1
2
3
4
20
50
20
ꢀ
ꢀ
4
5
18 (R)
16 (R)
74 (R)
70 (R)
31
50
24
5
mol%
a
b
Determined by NMR.
Determined by HPLC analysis on a ChiralcelꢀOJH column, 254 nm,
hexane/iPrOH 98/2 or 99/1, 0.5 mL/min flow rate.
Having shown that the iridacycle mechanism is also applicable to the reaction under
study here, the origin of the preference for the outer sphere mechanism and the origin of the
surprisingly high stereoselectivity were analyzed in more detail. It can be noted that, for the
iridacycle, an inner sphere mechanism involving proton transfer before hydride transfer would
inevitably lead through a heptacoordinated intermediate. While such heptacoordinated Ir
22
structures are precedented, in the case of this mechanism, a heptacoordinated intermediate
would be a sterically crowded, unfavorable 20ꢀelectron complex. Additionally, any inner sphere
pathway would have the substrate held rigidly in place by the combination of the isopropyl group
of the oxazoline ligand on one side and the cyclometalated imine on the other, thus restricting
the ability of the substrate to relieve steric strain. In the outer sphere mechanism, the substrate
can relieve this source of strain. This model is supported by an analysis of the C(Ph)ꢀC=NꢀC(Ph)
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dihedral angle of the iminium between the TSs of each mechanism (Table 3). The conjugated
iminium system should have this dihedral at or close to 180°. Angles near 180° are observed for
outer sphere TSs 3ar, 3as, 3dr, and 3ds (entries 1ꢀ4) but differ significantly from 180° for inner
sphere mechanism structures (Table 3, entries 5ꢀ12). This indicates that, in the inner sphere
mechanisms, the iminium must distort to relieve steric strain, something which is not necessary
in the outer sphere pathway.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 3. C(Ph)ꢀCꢀNꢀC(Ph) dihedral angles for reported TSs in each mechanism.
C(Ph)-C-N-C(Ph)
Angle (°)
C(Ph)-C-N-C(Ph)
Angle (°)
Entry Structure
Entry
7
Structure
5br
3ar
134.2
1
175.4
2
3
4
5
6
3as
3dr
3ds
5ar
5as
168.6
176.8
172.5
116.3
125.3
8
9
10
11
12
5bs
6ar
6as
6br
6bs
114.4
135.4
126.2
131.9
46.6
Analysis of the relevant transition structures 3ar and 3as can provide insights into the
structural original of the Gibbs free energy difference between them of 8 kJ/mol. Both 3ar and
ꢁ
.
3as have a similarly favorable CꢀH π interaction between the iPr CꢀH and the Nꢀ(Ph) group of
the substrate (Figure 5a and c). The HꢀPh(C) distance in 3ar is 2.86 Å and in 3as is 2.59 Å.
However, 3ar exhibits stacking interactions not present in 3as (Figure 5b). The phenyl rings of
the iminium substrate (CꢀPh), the cyclometalated imine, and ligand stack in 3ar, but not in 3as
(
Figure 5b and c). Finally, in 3ar the methyl group on the iminium carbon points towards the
oxazoline, while in 3as the phenyl group on the iminium carbon points towards the oxazoline,
leading to additional steric strain in 3as.
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3ar
B
3ar
C
3as
Figure 5. a) 3ar sideꢀon view showing distance (in Å) between oxazoline iPr and substrate. b) 3ar direct
view showing distance (in Å) between phenyl groups aligned for aromatic stacking. c) 3as sideꢀon view
showing distance (in Å) between oxazoline iPr and substrate.
Conclusions
The iridiumꢀcatalyzed hydrogenation of imines is a powerful method for the generation of
chiral amines. DFT calculations of the mechanism of imine hydrogenation using a realistic
model of the Andersson iridium phosphineꢀoxazoline iridacycle catalyst suggest that the
reaction proceeds through an outer sphere pathway. Experimental studies of a system that does
not allow for the formation of the iridacycle lead to low reactivity and stereoselectivity, whereas
substrates or additives that allow cyclometalation display significantly improved performance.
The lowest energy hydride transfer transition structure for our outer sphere pathway is 75 kJ
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ꢀ
1
mol lower in energy than the lowest energy hydride transfer transition structure for the inner
ꢀ1
sphere Cꢀmigration pathway, and 143 kJ mol lower in energy than the lowest energy hydride
transfer transition state for the inner sphere Nꢀmigration pathway. The outer sphere pathway
‡
model predicts a 90% ee of R amine (∆∆G = 8 kJ/mol) in excellent agreement with experiment
for catalyst 2. The origin of the stereoselectivity is traced to aromatic stacking interactions in the
favored pathway.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
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4
4
4
5
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5
5
5
5
5
5
5
6
0
1
2
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0
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0
1
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0
1
2
3
4
5
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9
0
1
2
3
4
5
6
7
8
9
0
The ability of the mechanism for hydrogenation proposed here to reconcile the
contradictions found in the literature provides the basis for the development of improved chiral
catalysts for the enantioselective hydrogenation of imines guided by a sound mechanismꢀguided
analysis of candidate substrates and ligands. Previous work from our groups using the
23
quantumꢀguided molecular mechanics (Q2MM) method for the quantitatively accurate
prediction of stereoselectivity of hydrogenation reactions provides a clearly defined roadmap for
a highꢀthroughput virtual screening of substrate/catalyst combinations for optimization of
reaction outcomes. The transition structures elucidated in the present study provide the basis
for the application of the Q2MM method to a catalytic reaction of significant interest in the
pharmaceutical industry and other sectors of academia and industry.
Experimental Procedures
To an ovenꢀdried pressure vial with magnetic stir bar, the imine (0.1mmol), additive (5
mol%) and iridium complex (0.5 mol%) in DCM (0.5 ml) were added. The vial was placed in a
hydrogenation apparatus, purged three times with nitrogen then pressurized to 20 or 50 bar with
hydrogen gas. After stirring 15 h, the pressure was released, and the solvent was evaporated to
1
obtain yellow residual oil. The conversions were determined by H NMR spectroscopy, and the
ee values were determined by HPLC using a ChiralcelꢀOJH column, 254 nm, hexane/iPrOH
9
8/2 or 99/1, 0.5 mL/min flow rate.
Computational Methods
24
All calculations were performed using Gaussian 09. All energies reported are Gibbs
free energies, unless otherwise noted. Unconstrained geometry optimizations in the gas phase
25
26
were performed using the M06 functional with the sdd basis set with effective core potentials
27
(
ECPs) for Ir and the 6ꢀ31G(d,p) basis set for the other atoms. Grimme’s D3 dispersion
28
29
corrections were included as a part of all calculations. The singleꢀpoint energies and solvent
effects in DCM were computed based on the gasꢀphase optimized structures at the M06 level of
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theory with the sdd basis set and ECPs for Ir and the 6ꢀ31G(d,p) basis set for the other atoms.
Optimization in solution phase (DCM) resulted in no significant differences from the gasꢀphase
calculations (see Supporting Information). Solvation energies were evaluated for the optimized
30
geometries by a selfꢀconsistent reaction field (SCRF) using the SMD model. Frequency
calculations performed in the gas phase confirmed the stationary points as transition states (one
imaginary frequency) or minima (no imaginary frequencies). Transition states were further
0
1
2
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5
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2
3
4
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8
9
0
31
characterized by intrinsic reaction coordinate (IRC) calculations. In the case of small energy
differences between transition states and related intermediates, IRC calculations systematically
32
failed. In such situations, ‘quick reaction coordinate’ (QRC) calculations were performed. This
method involves performing a small manual displacement (0.25 bohr) of the geometry on the
vibration of the imaginary frequency followed by optimization to a minimum. The final free
energies were calculated by adding the singleꢀpoint energies of the structures calculated with
the implicit solvent model to the thermal corrections from the gas phase optimizations. The
results for all of the structures are presented in Table S2. The final free energies from the
optimizations are reported in kJ/mol. Figures 2 ꢀ 5 and the structures in Table 1 were created
33
using CYLview.
Supporting Information
All energies (electronic, free energies, ZPE), single imaginary frequencies, and Cartesian
coordinates for all complexes and transition states discussed. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgments
We would like to thank the National Science Foundation (CHEꢀ1565669), the Swedish
Research Council (VR), the Stiftelsen Olle Engkvist Byggmästare, and the Swedish Energy
Agency for support of this research, and the National Science Foundation for providing B.T. with
financial support through the IRES program (OISEꢀ1261033).
References
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1
(
a) Chiral Amine Synthesis: Methods, Developments, and Applications. (Ed.: Nugent, T. C.) WileyꢀVCH,
Weinheim, 2010. (b) Xie, J.ꢀH.; Zhu, S.ꢀF.; Zhou, Q.ꢀL. Chem. Rev. 2011, 111, 1713ꢀ1760.
2
(
a) Crabtree, R. H.; Felkin, H.; Morris, G. E. J. Organomet. Chem., 1977, 141, 205ꢀ215. (b) Crabtree, R.
H.; Morris, G. E. J. Organomet. Chem., 1977, 135, 395ꢀ403. (c) Crabtree, R. H.; Felkin, H.; Fillebeenꢀ
Khan, T.; Morris, G. E. J. Organomet. Chem., 1979, 168, 183ꢀ195. (d) Crabtree, R. Acc. Chem. Res.,
1
1
1
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2
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4
4
5
5
5
5
5
5
5
5
5
5
6
0
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6
7
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9
0
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