A combined experimental and computational study to decipher complexity in the asymmetric hydrogenation of imines with Ru catalysts bearing atropisomerizable ligands

Article abstract of DOI:10.1039/d0cy02390f

RuCl₂(P-OP)(N-N) complexes (1) containing an atropisomerizable phosphine-phosphite (P-OP) and a chiralC₂symmetric diamine (N-N) are readily prepared astransisomers by successive addition of P-OP and N-N ligands to RuCl₂(PP

Full text of DOI:10.1039/d0cy02390f

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A combined experimental and computational
study to decipher complexity in the asymmetric
hydrogenation of imines with Ru catalysts bearing
atropisomerizable ligands†
Cite this: Catal. Sci. Technol., 2021,
11, 2497
a
Félix León,‡a Aleix Comas-Vives, b Eleuterio Álvarez a and Antonio Pizzano
*
RuCl2(P–OP)(N–N) complexes (1) containing an atropisomerizable phosphine–phosphite (P–OP) and a chiral
2 symmetric diamine (N–N) are readily prepared as trans isomers by successive addition of P–OP and N–N
C
ligands to RuCl2(PPh3)3. For these complexes, fast atropisomerization of the biaryl fragment at room
temperature has been observed. Compound trans-1a cleanly isomerizes into a mixture of cis isomers in
EtOH upon heating. DFT calculations reproduce accurately the ratio of isomers observed as well as the
greater thermodynamic stability of the cis isomers of 1a. Complexes 1 are efficient catalyst precursors for
the asymmetric hydrogenation of N-aryl imines 5 in toluene under very mild conditions using KOtBu as a
base (4 bar H2, room temperature, 5/1/KOtBu = 500/1/10). Among the catalyst precursors, 1f provides good
enantioselectivities in the hydrogenation of a wide range of N-aryl imines (84–96% ee, 16 examples). From
DFT calculations, a mechanism consisting in stepwise transfer of a hydride and a proton from the dihydride
to the imine has been proposed, with the most favourable paths for R and S products involving
cis-dihydrides d1R and d3S, respectively. Among several hydrogen activation pathways examined in the
pro-R route, the most favorable one consists of hydrogen coordination to a Ru–amido/amine adduct,
followed by amine assisted activation of dihydrogen.
Received 14th December 2020,
Accepted 21st January 2021
DOI: 10.1039/d0cy02390f
rsc.li/catalysis
displayed a broad substrate scope for catalytic hydrogenation
beyond ketones, which includes imines, esters, and amides,
Introduction
Chiral Ru complexes bearing P- and N-ligands constitute a
group of catalysts of paramount importance in the area of
asymmetric hydrogenation.1 Fueled by the seminal discovery
by Noyori and coworkers about the outstanding performance
of complexes containing BINAP and DPEN or DAIPEN ligands
in the asymmetric hydrogenation of ketones,2 the field has
grown impressively and
comprising different combinations of ligands can be found in
the literature.3 Moreover, these types of catalysts have
among others.4
The study of the mechanism of the prototypical
asymmetric
hydrogenation
of
ketones
with
the
aforementioned catalysts has deserved considerable attention
as well.5 From this background, it is concluded that the
ketone is reduced by an octahedral dihydride, generated in
the reaction medium from a dihalo or a halo-hydride
complex by the action of a base and hydrogen,5a–c by an outer
sphere pathway. In this regard, computational studies by Dub
and Gordon have shown the prevalence of a stepwise
mechanism over a concerted one.6 Another key mechanistic
aspect regards the stereochemistry of the reducing dihydride.
Due to their octahedral geometry, several isomers are
possible depending on the nature of the ancillary ligands. It
is worthy to note that cis isomers possess an additional
source of chirality due to a stereogenic center located at the
metal.7 In this context, a detailed study by Morris and
coworkers on the Ru(H)2(PPh3)2((R,R)-dach) complex (A,
Fig. 1) has shown that the trans,cis isomer is the active
catalyst in the hydrogenation of acetophenone, while the cis,
cis isomers (two isomers differing in metal configuration;
a
vast diversity of catalysts
a Instituto de Investigaciones Químicas and Centro de Innovación en Química
Avanzada (ORFEO-CINQA), CSIC and Universidad de Sevilla, Avda Américo
Vespucio 49, 41092 Sevilla, Spain. E-mail: pizzano@iiq.csic.es
b Department of Chemistry, Universitat Autònoma de Barcelona, 08193 Cerdanyola
del Vallès, Catalonia, Spain
† Electronic supplementary information (ESI) available: Experimental details of
the synthesis and characterization of Ru complexes and procedures for
asymmetric hydrogenation reactions. X-ray crystallographic data for 1a, 1c, 1i
and cis-1a and computational details. CCDC 2045798 (1a), 2045799 (1c), 2045800
(1i), 2045801 and 2045802 (cis-1a). For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/d0cy02390f
‡ Present address: Nanyang Technological University, Singapore.
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computational study on this catalytic system which explains
the high levels of observed enantioselectivity. In addition,
catalyst screening covering diverse combinations of P–OP
and diamine ligands has detected a practical and versatile
catalyst with the DPEN diamine as the sole chiral ligand,
capable of reducing a variety of N-aryl imines under very mild
conditions with good levels of activity and enantioselectivity.
Fig. 1 Structures of cis and trans dihydride isomers relevant in the
catalytic hydrogenation of ketones and imines.
only the Λ isomer is shown) are precursors of the active
one.5c Aligned with these observations, mechanistic studies
on Ru(H)2((S)-BINAP)((S,S)-DPEN) (B) have considered the
trans isomer as the competent catalyst.5h It is pertinent to
note that Ohkuma and coworkers have otherwise proposed a
cis dihydride catalyst in the asymmetric hydrogenation of
imines catalyzed by cis-Ru(Br)2((S,S)-Xyl-skewphos)((S,S)-
DPEN) (C).8 In connection with this, it should also be noticed
that cis dichloro complexes based on diphosphine and
amino-pyridine ligands are also effective in the asymmetric
transfer hydrogenation of ketones.9
Following our interest in the application of chiral
phosphine–phosphites (P–OP) in hydrogenation reactions, we
preliminarily described the application of Ru(Cl)2(P–OP)
(DPEN) complexes (Fig. 2) in the enantioselective
hydrogenation of N-aryl imines.10a Compared to ubiquitous
diphosphine catalysts, the presence of a phosphite fragment
in these complexes may have a profound influence in the
catalytic system due to its π-acidity. Comparison between
structures of the Ru(Cl)2(P–OP)(DPEN) complexes showed
that both cis and trans isomers can be formed depending on
the structure of the P–OP ligand. Moreover, a remarkable
feature of this catalytic system is that high levels of
enantioselectivity were achieved with P–OP ligands bearing
atropisomerizable phosphite fragments.10a This is an
intriguing observation considering the complexity of the
system, as the combination of two different phosphorus
functionalities, the access to both cis and trans isomers and
the atropisomerizable phosphite fragment can lead up to ten
dihydrides with potential catalytic reactivity. In this
Results and discussion
Synthesis and structural features of Ru(Cl)2(P–OP)(N–N)
complexes
Ru(Cl)2(P–OP)(N–N) complexes (1a–1k, Scheme 1) were
prepared in a one-pot reaction by successive addition of
phosphine–phosphite and diamine ligands to RuCl2(PPh3)3.
Monitoring the reactions by 31P{1H} NMR showed the
formation of one set of signals, enabling the isolation of
compounds 1 with moderate to high yields (56–76%). This
procedure thus constitutes a substantial improvement over
the reaction of Ru(2-Me-C3H4)2(P–OP) with HCl and diamine
used by us before,10 which led to complexes
1 as
diastereomeric mixtures with rather low yields (ca. 10–40%).
In the case of complexes 1a–1c, characterized by an
oxamethylene backbone, the undesired formation of
Ru(Cl)2(P–OP)2 was observed. Latter complexes are
characterized by triplets in the phosphine and phosphite
regions in the 31P{1H} NMR spectra (e.g. centred at 133.0 and
2
4.5 ppm, JPP = 37 Hz, in the synthesis of 1c). These by-
products result from the reaction of RuCl2(P–OP)(PPh3) with
P–OP and better yields of 1a–1c were obtained in more
diluted reactions. The procedure in Scheme 1 is rather
versatile and allowed us to introduce several chiral 1,2-diaryl-
1,2-ethanediamines (3a–3d) or a 1,2-diisopropyl derivative (4)
as well as P–OP ligands differing in their backbone structure.
In the search for chirally-economic catalysts,9b an
atropisomerizable biaryl fragment in the P–OP ligand has
been maintained as a common element11 in the library of
catalysts. The exploitation of such an element is a rather
powerful strategy in the design of chiral catalysts as it
generates a stereogenic axis from an achiral ligand upon
coordination, with its configuration being potentially
controlled by a chiral ancillary ligand.12 For instance, this
approach has been applied successfully in Ru hydrogenation
catalysts by the combination of chiral diamines (e.g. DPEN)
and atropisomerizable diphosphines.12a,b,e
contribution, we present
a combined experimental and
The structure of some representative complexes 1 was
then examined by X-ray crystallography. It should be recalled
that the preliminary structure determination of complex 1d
displayed the presence of two diastereomeric structures with
a trans stereochemistry, differing in the configuration of the
biaryl fragment.10a,13 Analysis of complex 1i showed an
analogous pattern (Fig. 3a), as well as 1a and 1c (see the
ESI†). This stereochemistry seems associated with the
synthetic route in Scheme 1 and can reasonably be assumed
for the rest of complexes 1. To avoid redundancy, an explicit
mention of the trans stereochemistry of 1 will only be made
Fig. 2 Structures of the trans and cis stereoisomers of Ru(X)2(P–OP)((S,
S)-DPEN) (X Cl, H; for the number of isomers, it should be
considered that there are two possible configurations of the
atropisomerizable biaryl phosphite; P and P′ denote either a phosphine
or a phosphite fragment).
=
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Scheme 1 Synthesis of complexes 1.
Fig. 3 ORTEP views of the Rax and Sax diastereomers of complex 1i observed in the crystal lattice (a; hydrogen atoms have been omitted for
clarity). Comparison of structures of the diastereomers of complexes 1d and 1i (b; numerical values correspond to the PO–Ru–PC–CAr dihedral
angles in degrees; PO and Pc denote the phosphorus atoms of phosphite and phosphine fragments, respectively, while CAr corresponds to the
backbone aryl carbon bonded to PC; diamine aryl substituents and hydrogen atoms have been omitted for clarity).
in selected cases for the sake of clarity. The change in the
configuration of the stereogenic axis is accompanied by an
extensive conformational change of the P–OP ligand
backbone and of the arrangement of the phenylphosphine
substituents, in such a way that both structures would be
mirror images if the diamine backbone were not
considered.13b Another common feature of these structures is
that the axial hydrogens of amino groups display a hydrogen
bond with an adjacent chloro ligand,14 as the corresponding
distances range between 2.7 and 2.8 Å, while the sum of van
der Waals radii lies between 2.9 and 3.0 Å.15 Moreover, these
axial hydrogens exhibit a syn periplanar orientation with
chloro ligands, with torsion angles ranging between ca. 13
and 22 degrees. Finally, an interesting difference between
structures of complexes 1d and 1i regards the different
orientation of the phenylene backbone fragment with regard
to the phosphite biaryl moiety as shown by the opposite signs
of the values of the PO–Ru–PC–CAr dihedral angle (Fig. 3b) in
the Rax and Sax diastereomers.
the fast atropisomerization of the biaryl moiety.16
Confirmation of the existence of a dynamic process comes
from variable temperature 31P{1H} NMR spectroscopy of 1b
(Fig. 4), which shows the existence of two species in a 3 : 1
ratio at −90 °C, characterized by doublets in the phosphine
and phosphite regions (major: 174.5, 69.5 ppm; minor: 175.4,
2
67.6 ppm) with a coincident value of JPP coupling constants
(47 Hz). Coalescence of signals was observed at around −70
°C, while over −50 °C, two sharp doublets were observed. For
this dynamic process, a free activation energy of 9.2 kcal
mol−1 was determined at the coalescence temperature by
lineshape analysis, while an analogous analysis for 1d gave a
value of 10.2 kcal mol−1 (coalescence temperature −65 °C, see
the ESI† for details).
Pertinent to note in this context, Ohkuma and coworkers
have observed that a mixture of cis and trans isomers of
Ru(Br)2((S,S)-Xyl-skewphos)((S,S)-DPEN) can be converted into
i
the cis isomer by treatment with a PrOH/CH2Cl2 mixture.
The aforementioned allyl route led to a mixture of isomers of
According to the presence of two diastereomers of
complexes 1 in the crystal lattice, the observation of one set
of signals in 31P{1H} NMR at room temperature agrees with
Ru(Cl)2(2a)(3a) composed of trans complex 1a and additional
isomers. From this mixture,
a cis isomer could be
characterized by X-ray diffraction (cis-1a; cis-1 type structure,
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mixture, exhibiting two new species in a ca. 3 : 1 ratio by
31P{1H} NMR.
Catalytic studies
In our preliminary study of the hydrogenation of imine 5a
with Ru(Cl)2(P–OP)(N–N) complexes (Scheme 2), we screened
several reaction conditions.10a Among them, the best results
were obtained under very mild conditions in toluene with
Ru(Cl)2(2f)(3a) (4 bar H2, RT, S/C/KOtBu = 500/1/10, full
conversion in 24 h; 93% ee). Examination of the performance
of the series of catalyst precursors 1 under these reaction
conditions (Table 1) showed near complete reactions with the
only exception of 1c (86%, entry 3) and particularly 1k, for
which a poor value was observed (27%, entry 10). Moreover,
good values of enantioselectivity were obtained (89–95% ee),
with 1a and 1f surpassing the p-tolyl catalyst (entries 1 and 5,
respectively). The uniformly high levels of enantioselectivity
Fig. 4 31P{1H} NMR spectra of 1b registered at several temperatures.
with
complexes
1
also
demonstrate
that
the
atropisomerizable phosphite fragment is a valuable element
for the design of chirally economic catalysts. It is worth
noting that no influence of the electronic properties of DPEN
substituents was observed with catalyst precursors 1i and 1j
(entries 8 and 9). For the couple of diastereomeric complexes
1g and 1h, little matching/mismatching effects were
Rax configuration; see Fig. 5a in the Computational studies
section).10b According to this finding, we have examined the
isomerization of trans complex 1a in alcoholic solvents.
Interestingly, heating a solution of this complex in EtOH for
16 h at 60 °C leads to a mixture of two new species in a 2.5 : 1
ratio with almost complete conversion (95%). These
compounds are characterized by very similar NMR data and
among them, an upfield shift of resonances of NH signals
with respect to those of the starting trans complex can be
remarked, attributable to the proximity of the biaryl
phosphite moiety to the amino fragments and hence
indicative of a cis structure. From the mixture, it was possible
to crystallize the major isomer which was identified as cis-1a
by X-ray analysis (minor cis isomer will be denoted as cis-1a′).
In contrast, 1d is rather unreactive under these reaction
conditions and only a conversion of 10% could be observed
after 3 days at 70 °C in an EtOH–1,2-dichloroethane (1 : 1)
observed, with
a small difference of enantioselectivity
between them and the configuration of the product
determined by that of DPEN (entries 6 and 7). This is general
and for catalyst precursors bearing (S,S)-diamines, the R
product is formed (and conversely the S product from (R,R)-
diamines). Among the complexes examined, 1f showed the
best performance with a complete conversion and 95% ee.
From this satisfactory result, we next screened the
application of this complex in the hydrogenation of a set of
N-aryl imines derived from aryl alkyl ketones (5b–5o). For
these substrates, full conversion and enantioselectivities
between 84 and 96% ee were observed (Table 2). It is worth
Fig. 5 Relative free energies calculated for isomers of Ru(Cl)2(2a)(3a) and Ru(H)2(2a)(3a) (a; ΔG in kcal mol−1, notation in brackets). Ru ligand bond
distances determined by X-ray crystallography and computed (in brackets) for stereoisomers of Ru(Cl)2(2a)(3a) (b).
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noting that the set includes demanding ortho substituted
imines (entries 8 and 9), naphthyl imines (entries 13 and 14)
and a thienyl example (entry 12). In contrast, no conversion
was observed in the hydrogenation of challenging isopropyl
methyl imine 5p.
To examine the practical character of 1f, we have also
prepared for the gram scale hydrogenation of 5h (Scheme 3),
as the resulting product has attracted interest in the
synthesis of the NPS R-568 calcimimetic.18 We were pleased
to note that a reaction using 2.0 g of 5h at S/C/B = 1000/1/10
led to full conversion in 24 h, yielding amine 6h with 96%
isolated yield and 95% ee.
Detailed mechanistic studies by the group of Noyori have
shown that hydride–borohydride complexes Ru(H)(BH4)(tol-
BINAP)(1,2-diamine) (1,2-diamine = DPEN, en, DAIPEN) are
suitable catalyst precursors for the hydrogenation of ketones
in isopropanol without the need of an additional base,19,20
while no catalytic activity was observed in toluene.5b Based
on this background, we have prepared Ru(H)(BH4)(2c)(3b) (7)
by treating 1e with an excess of NaBH4 in a toluene : EtOH
(1 : 1) mixture (Scheme 4).21 An analysis by NMR of the
product showed the existence of two isomers of 7 in a 7 : 3
ratio. A 2D NOESY experiment with the mixture indicates that
the major isomer possesses a trans stereochemistry, while the
minor one, attending to the similarity between the
spectroscopic data of both species, can be assigned as the
alternative trans isomer. We have next analysed the
performance of 7 in the hydrogenation of 5a in the absence
of a base. First, no reaction was observed in toluene, in
accord with the literature precedent mentioned above. On
Scheme 2 Catalytic hydrogenation of imines 5.
Table 1 Hydrogenation of imine 5a with catalyst precursors 1a
Entry
Cat
Conv (%)
ee (%; config)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1e
1f
1g
1h
1i
100
100
86
100
100
100
100
100
95
94 (R)
94 (S)
90 (S)
92 (S)
95 (S)
89 (R)
93 (S)
90 (R)
90 (S)
nd
1j
10
1k
27
i
the other hand, a reaction performed under 20 bar H2 in -
a
Reactions performed under
4 bar H2 in toluene at room
PrOH and 60 °C with an S/C = 100 showed a complete
conversion and 84% ee after 24 h. For comparison, a reaction
prepared with 1e under the same reaction conditions but
with addition of a small amount of KOtBu to guarantee
catalyst activation (S/C/B = 100/1/5) provided 91% conversion
temperature for 24 h with KOtBu as a base; S/C/B = 500/1/10;
conversion was determined by 1H NMR. % ee determined by HPLC.
Configuration was determined by comparison with literature data.17
and 83% ee. These results point to
a
common
enantiodetermining step starting from 1e and KOtBu or 7 in
isopropanol. These observations are analogous to those
reported for the BINAP/DPEN system in the asymmetric
hydrogenation of acetophenone.5b
In addition, we have examined the hydrogenation of 5g
under our standard conditions with trans complex 1a, with
the mixture of cis-1a and cis-1a′ isomers (resulting from
isomerization of 1a) and with cis-1a (obtained by
crystallization of the latter mixture). Full conversion and
coincident enantioselectivities (94.2, 94.2 and 94.6% ee,
respectively) were observed in the three reactions, pointing to
Table 2 Hydrogenation of imines 5b–5o with catalyst precursor 1fa
Entry
Imine
% ee (conf)
1
2
3
4
5
6
7
8
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5ñ
5o
94 (S)
94 (S)
87 (S)
94 (S)
91 (S)
96 (S)
95 (S)
93 (S)
95 (S)
94 (S)
91 (S)
95 (S)
84 (S)
92 (S)
96 (S)
9
10
11
12
13
14
15
a
Reactions performed under
4
bar H2 in toluene at room
temperature for 24 h with KOtBu as a base; S/C/B = 500/1/10; full
conversion (1H NMR) was observed in all reactions. % ee determined
by HPLC. See the ESI† for determination of configuration.
Scheme 3 Gram scale synthesis of 6h.
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in isopropanol point to an outer sphere reduction of 5a by
Ru(H)2(2a)(3a) as the enantioselective step. Although the
nature of the resting catalyst state in toluene and isopropanol
should be different,5b it is reasonable to assume that this
reduction mode should also operate in toluene.24
Scheme 4 Synthesis of hydride borohydride 7.
Structure and stereochemical features of Ru(Cl)2(2a)(3a)
and Ru(Cl)2(2c)(3a). The structures of isomers of dichloro
complex 1a have been optimized to get a deeper insight into
their relative stabilities (Fig. 5a). A good agreement has been
observed between the calculated structures of c1R, ctR and
ctS and the X-ray determined structures of cis-1a, and Rax and
Sax diastereomers of trans complex 1a, respectively (Fig. 5b).
Moreover, ctR and ctS are very close in energy, as could be
expected from the behaviour shown by 1a in solution. On the
other hand, c1R and c3S are more stable than the trans
structures, in good agreement with the observed
isomerization of 1a. In addition, the small difference in free
energy between c1R and c3S gives a 1.7 : 1 calculated ratio,
which is in good agreement with the ratio of cis-1a and
cis-1a′ species observed after the isomerization. Finally, c1R
shows the same stereochemistry as that of the predominant
cis isomer in solution (cis-1a), while the minor one (cis-1a′)
should have the structure shown by c3S.
A remarkable result regards differences in energy between
cis structures differing in the configuration of the phosphite
stereogenic axis. Thus, low to negligible differences are
observed between atropisomers of types cis-2 and cis-4, which
contain the phosphite fragment coordinated in a cis position
to one NH2 group. In contrast, there are considerable energy
differences between atropisomers of types cis-1 and cis-3,
characterized by a phosphite cis to both NH2 groups in an
arrangement which favors the interaction between the biaryl
phosphite and the diamine backbone. Most interestingly, the
preferred biaryl configuration depends on that of the metal,
with c1R and c3S being appreciably more stable than their
respective atropisomers c1S and c3R, with free energy
differences of 8.1 and 5.9 kcal mol−1, respectively.
the same catalyst formed independently of the
stereochemistry of the catalyst precursor.
It is worth noting in this context that Bäckvall and
coworkers reported the racemization of some enantiopure
amines 6 in toluene at 110 °C using the Shvo catalyst and 0.5
equivalents of 2,4-dimethyl-3-pentanol, with the racemization
rate being significantly reduced when the reaction
temperature was lowered.22a Moreover, in the presence of a
hydrogen acceptor, imines 5 could be obtained.22b Based on
this background, it seems highly interesting to examine if the
formation of amines 6 is irreversible in the present catalytic
system. To this aim, the hydrogenation of 5g using 1a under
standard reaction conditions was stopped at 25% conversion.
This reaction showed a 93.4% ee, which is very close to the
value obtained at full conversion (94.2% ee). In addition, a
sample of rac-6g was exposed to catalytic reaction conditions
for 24 h and neither a variation of the enantiomeric ratio nor
imine were observed. To discard the idea that any impurity
could inactivate the catalyst generated from 1a in the latter
experiment, a complementary one using a mixture of 5g and
rac-6g (1 : 3.4) was examined under the same reaction
conditions. After 24 h, complete reduction of the imine was
observed and determination of the enantioselectivity of 6g
gave a value of 20.8% ee. For this experiment, a theoretical
value of 21.2% ee can be estimated if the imine were
hydrogenated with a 93% ee. These results therefore indicate
that no reversibility of the reduction step should occur under
the mild catalytic conditions used.
Computational studies
Moreover, we have examined selected structures for
complex 1d. Initially, examination of trans structures with the
backbone orientation shown by X-ray analysis leads to a
couple of diastereomers (ctR′ and ctS′) structurally very close
to the experimental structures, with a minimal free energy
difference between them (0.4 kcal mol−1). In addition,
structures with a backbone orientation shown by 1i were also
investigated. Notably, the corresponding trans diastereomers
(ctR″ and ctS″) were appreciably more stable than ctR′ and
We subsequently did computational studies to complement
the experimental results via DFT-based methods.23 These
comprise the structural and stereochemical features of
complex 1a as well as the study of the mechanism of a
representative imine hydrogenation reaction, with the aim of
understanding the role of the atropisomerizable phosphite
fragment and the high enantioselectivities observed. In
addition, some studies regarding 1d and the corresponding
dihydride will be included for comparative purposes. As
mentioned, outer sphere reduction by Ru(H)2(diphosphine)
ctS′, with free energy differences of 4.5 and 5.6 kcal mol−1
,
respectively. Among the four isomers, ctS″ is the more stable
one, with the ctR″ isomer being 1.5 kcal mol−1 higher in free
energy than the former species. Presumably, easy
interconversion between the four conformers should occur in
solution, while the observation of less stable conformers of
1d by X-ray crystallography should be caused by a better
(diamine) is
a well-established step in the asymmetric
hydrogenation of ketones in both protic and aprotic
solvents.5 Moreover, due to the similarity between the Ru
catalyzed hydrogenation of imines and ketones,1b some
catalysts have been proposed to reduce imines
enantioselectively following an outer sphere mechanism,4a,b,8
although no detailed computational study has been provided.
In this regard, results of reactions performed with 1a and 7
packing in the crystal lattice. On the other hand,
a
comparison between cis-1-R and cis-3-S type structures for 1d
(c1R′ and c3S′, respectively) shows a higher stability for the
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former species (1.6 kcal mol−1 in free energy). However, these
cis structures are slightly less stable than ctS″, with free
energy differences of 0.4 and 2.0 kcal mol−1, respectively.
Therefore, the comparison of energies of isomers 1a and 1d
indicates that the cis/trans preference in dichloro complexes
is rather sensitive to the precise structure of the phosphine–
phosphite ligand.
In addition, the atropisomerization of 1a has also been
studied (Fig. 6). As mentioned, this dynamic process involves
a conformational change not only in the biaryl moiety, but
also in the backbone and in the position of the phosphine
substituents. Starting from ctR, which is characterized by a
biaryl dihedral angle (φ) of −49.1°, a scan of the reduction of
this parameter allowed us to locate a transition state (atrop-
TS1, φ = 1.9°) lying 9.3 kcal mol−1 in free energy above ctR.
This transition state leads to an alternative conformer (conf-
1, ΔG = 5.2 kcal mol−1) characterized by a value of 28.3° for φ,
and thus displaying the Sax configuration. To complete the
dynamic process to reach ctS, a pathway involving two
additional transition states and two conformers has been
found (see the ESI† for further details). Notably, the highest
point along the whole atropisomerization pathway
corresponds to atrop-TS1, in good agreement with the
experimental value obtained by VT-NMR for the energy
barrier of the fluxional process shown by 1a.
ligands.25 Thus, those of the trans dihydrides are in the
1.679–1.685 Å range, while for the hydride ligands trans to
the phosphite, phosphine and amino ligands, ranges of
1.657–1.670, 1.648–1.658 and 1.602–1.615 Å are observed,
respectively. Examination of selected structures of
stereoisomers of Ru(H)2(2c)(3a) (i.e. those corresponding to
1d) showed a similar stability pattern to that shown above,
with the cis-1-Rax type isomer (d1R′) as the most stable one,
while the cis-3-Sax type structure (d3S′) is only 0.1 kcal mol−1
in free energy over d1R′. These cis structures are more stable
than the trans isomers irrespective of the backbone
conformation of ligand 2c. Thus, structures dtR′ and dtS′ are
6.6 and 7.1 kcal mol−1 above d1R′ in free energy, while dtR″
and dtS″ are 3.9 and 4.2 kcal mol−1 higher than d1R′,
respectively. For these structures, the Ru–H distances follow
the trend commented above and have value ranges of 1.675–
1.684, 1.658–1.663 and 1.605–609 Å for hydrides trans to the
hydride, phosphite and amino ligands, respectively. These
values indicate that the significantly higher reactivity of trans
dihydrides, compared to cis ones, characteristic of the well-
studied diphosphine catalysts,5b,h may not be transferable to
the present system due to the phosphite fragment. Thus, the
cis-1 and cis-3 dihydrides may have comparable reactivities to
the trans isomers.
Amido–hydride complexes. Another kind of important
complexes in the catalytic system are amido–hydride
complexes Ru(H){(S,S)-NH–CHPh–CHPh–NH2}(2a).5c These
compounds should be formed by the activation of Ru(Cl)2(2a)
(3a) with a base and hydrogen as well as by the reduction of
the imine by Ru(H)2(2a)(3a) (see below). Conversely, the
reaction of amido–hydrides with hydrogen should lead to
dihydrides Ru(H)2(2a)(3a). Considering that the latter
reaction can occur with small structure rearrangement, the
starting structures for amido–hydride compounds can be
generated by the formal abstraction of a hydride and a
pseudo-axial adjacent amine proton from the dihydrides.5a
By optimization of these starting structures, either distorted
trigonal bipyramidal or square pyramidal species were
located, with those of the former type being significantly
more stable than the latter (ca. 30 kcal mol−1 in free energy,
see the ESI†). Amido and amino fragments of the
deprotonated DPEN occupy the equatorial and apical
Dihydrides. The differences in free energy between
isomers of Ru(H)2(2a)(3a) (Fig. 5a) parallel the trend observed
for those of the dichloro complex. Hence, d1R and d3S are
the more stable dihydrides of the series, while the trans
isomers are among the less stable ones. In addition,
compounds d1R and d3S have appreciably lower free energies
than their corresponding atropisomers (7.4 and 6.9 kcal
mol−1, respectively). Moreover, variations in Ru–H distances
are in good accord with the trans influence of ancillary
Fig.
6 Schematic fluxional mechanism computed for the
atropisomerization of 1a (relative free energies in kcal mol−1 in
brackets relative to ctR; diamine ligand has been omitted for clarity).
Fig. 7 Structures of amido–hydride complexes (ΔG relative to a6S in
kcal mol−1 in brackets).
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coordination positions in the bipyramidal complexes
respectively (Fig. 7). In turn, no clear preference of the
remaining ligands for an axial/equatorial position seems
apparent. As expected, the Ru–amido bond distance is
shorter than the Ru–amino one. For instance, for a1R, values
of 1.970 and 2.221 Å have been obtained. For this structure,
the equatorial plane is defined by the amido and P ligands,
covalent interactions (NCI).26 For instance, in the case of
d1R-RP-5a, C–H/aryl interactions,27 a high number of C–H/C–
H
dispersion interactions,28 and
a
N⋯H–N interaction
between the imine nitrogen and a NH fragment of the
diamine ligand have been detected (Fig. 9). This NCI driven
stabilization is a remarkable aspect for an outer-sphere
mechanism, as these weak interactions enable structural
preorganization29 of the substrate–catalyst complex favoring
the reduction.
with
N(amido)–Ru–P(phosphine)
and
N(amido)–Ru–
P(phosphite) angles of 162.5 and 116.0 degrees, respectively.
Finally, relatively small free energy differences are observed
between the atropisomers of each type of amido–hydride (ΔG
= 1.5–4.4 kcal mol−1), if compared with the stabilization
observed for d1R and d3S with regard to their atropisomers.
Imine reduction. An inspection of the structures of d1R
and d3S indicates that the hydride located in the trans
position to the amino group is surrounded by one phenyl
substituent of the phosphine and one of the tBu groups
(Fig. 8a and b), thus blocking the approach of the imine
CN fragment to the corresponding Ru(H)–NH2 moiety. As
mentioned above, the Ru–H distances in the computed
structures indicate an appreciably longer distance for the
hydride trans to the phosphite in comparison with that trans
to the amino ligand in d1R (1.670 vs. 1.604 Å) and d3S (1.666
vs. 1.604 Å). Based on these considerations, we have
reasonably assumed an easier transference of the hydride
trans to the phosphite from either d1R or d3S to 5a,
compared with that trans to the amine.
Considering the presence of two NH2 groups in d1R (trans
to phosphine or to hydride) and two prochiral faces of 5a,
four different approaches of the imine can be considered
(Fig. 8c), as well as in the case of d3S. It is worth noting that
the approximation of the substrate to the dihydride leads to
the formation of loose precomplexes. Among the eight
precomplexes, significant stabilization over their components
is observed in the cases of d1R-RP-5a and d3S-SP-5a, with ΔG
values of −7.1 and −7.0 kcal mol−1, respectively. This
stabilization can be ascribed to diverse substrate–ligand non-
From imine–dihydride precomplexes, the hydride transfer
step to give monohydride–amide ionic pair species was next
investigated. This class of transition states will be referred in
the following as TS1. Among the TS1 transition states for d1R
and d3S (Fig. 10), the most favorable one corresponds to
pro-R precomplex d1R-RP-5a (TS1-d1R-RP-5a, ΔΔG‡ = 0.0 kcal
mol−1; in the following, this transition state will be used as
the reference to compare energies of TS1 transition states).
The most favorable TS1 for the S enantiomer (TS1-d3S-SP-5a)
involves d3S dihydride and has a ΔΔG‡ value equal to 1.6 kcal
mol−1 (see the ESI† for data on TS1 energies for the rest of
the dihydride precomplexes). This is, moreover, the lowest
TS1 transition state for d3S dihydride, followed by a pro-R
one with ΔΔG‡ = 4.9 kcal mol−1. Despite TS1-d1R-RP-5a and
TS1-d3S-SP-5a lying 6.2 and 7.8 kcal mol−1 in free energy
above the corresponding dihydride imine precomplexes, they
are very close in free energy to the starting dihydrides and
free imine (−0.88 and 0.76 kcal mol−1 for TS1-d1R-RP-5a and
TS1-d3S-SP-5a compared with d1R and free 5a, respectively),
due to the stabilization associated with the formation of the
dihydride imine precomplexes.
Based on the literature precedents on the higher reactivity
of trans dihydrides over cis ones5 and considering that
trans-dihydrides have the longest Ru–H bond distances in the
series of Ru(H)2(2a)(3a) dihydrides, it seems pertinent to
study the barrier for the hydride transfer step for dtR and
dtS. An inspection of these structures indicates that one of
t
the hydride ligands is protected by a P–Ph and a Bu group
from the approach of the imine (views for dtR collected in
Fig. 8 Side (a) and top views (b) of d1R (HPO and HN denote hydrides
trans to phosphite and amino ligands, respectively). Possible
orientations of 5a to d1R depending on the substrate face and NH2
fragment approached (c).
Fig. 9 d1R-RP-5a (a). Plot of non-covalent interactions for the latter
precomplex (b, color ranges from strong attractive interactions in blue
to strong repulsive ones in red; distances between interacting atoms
or centroids of aryl rings in Å).30
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Fig. 10 General scheme for the reduction of imine 5a (ΔG relative to d1R + 5a in kcal mol−1 in brackets).
Fig. 11); therefore, participation of this hydride should only
be possible after atropisomerization of the P–OP ligand (i.e.
conversion of dtR in dtS and vice versa). Accordingly, only the
transference of the less encumbered hydride needs to be
examined for these dihydrides. As mentioned above for d1R
and d3S, there are four possible imine approaches for both
dtR and dtS, leading to eight precomplexes and
corresponding TS1 transition states. For those leading to the
R product, the ΔΔG‡ values range between 3.9 and 18.2 kcal
mol−1, while for the pro-S ones, we found ΔΔG‡ values that
range between 8.7 and 18.6 kcal mol−1. Presumably, steric
effects associated with the bulky phosphite fragment in the
equatorial plane should be responsible for the higher barriers
observed for the trans-dihydrides. Likewise, an examination
of the structures of dihydrides of types cis-2 and cis-4
RP-5a by 3.4 and 5.5 kcal mol−1, respectively. On the other
hand, d2S-SH-5a is 2.8 kcal mol−1 over TS1-d3S-SP-5a, while
d2S-SP-5a is only 0.8 kcal mol−1 more stable in free energy
than the latter transition state, with TS1-d2S-SP-5a being 11.8
kcal mol−1 higher in free energy than TS1-d3S-SP-5a.
Considering that TS1 possess the highest free energy in the
reduction pathway of 5a by d1R and d3S (Fig. 10), the values
of transition states of type TS1 for d2S, dtR and dtS point to
cis-dihydrides d1R and d3S as the actual catalysts in the
present system.
A remarkable feature of precomplexes d1R-RP-5a and d3S-
SP-5a is that they show the substrate appropriately arranged
for the hydride transfer step and a minimal structural
variation from the precomplexes to the corresponding TS1 is
required (Fig. 12). Moreover, TS1-d1R-RP-5a and TS1-d3S-SP-
5a are stabilized by a hydrogen bond between the imine
nitrogen and a N–H of the diamine, with N⋯H distances of
indicates
a substantial steric encumbrance around the
hydride located in the trans coordination position to the
phosphine ligand (i.e. that characterized by a longer Ru–H
bond) because of the orientation of the biaryl phosphite, with
the exception of d2S. For this dihydride, the corresponding
set of four precomplexes was calculated, with d2S-RP-5a and
d2S-RH-5a being already higher in free energy than TS1-d1R-
Fig. 12 Structures of the preferred pro-R (TS1-d1R-RP-5a, top right)
and pro-S (TS1-d3S-SP-5a, bottom right) hydride transfer transition
states (H atoms bonded to carbons have been omitted for clarity). Key
structural distances involved in the transformation from dihydride–
imine precomplexes to hydride-transfer transition states are given in Å
in the corresponding schemes.
Fig. 11 Side view of dtR (a), and top (b) and bottom (c) space filling
views of the same compound.
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1.827 and 1.963 Å, respectively.31 On the other hand, the
distances between the hydride and the iminic carbon have
values of 1.477 and 1.441 Å, respectively. In addition,
expected elongations of the Ru–H and the C–N imine bonds
are observed from the imine adducts to TS1 structures. In
is 4.2 kcal mol−1 lower in free energy than ip-pro-R, although
the magnitude of the stabilization is not as pronounced as
reported for an N-(phenyl)phenylmethylamide compound.33
Thus, a1R-R-6a is 1.8 kcal mol−1 more stable than N1R in free
energy.34
both transition states, the substrate displays
a
similar
Hydrogen activation. Although it has received less
attention than the enantioselective reduction of the
substrate, hydrogen activation constitutes a key mechanistic
aspect in asymmetric hydrogenations performed by
bifunctional catalysts. It is pertinent to note in this context
that computational studies by Dub and Gordon about the
hydrogenation of acetophenone catalyzed by trans-Ru(H)2((S)-
BINAP))((S,S)-DPEN) have shown that hydrogen activation by
an ion pair species (assisted by the alkoxide fragment
resulting from hydride transfer to the ketone) is a more
favorable route than the direct activation by an amido–
hydride complex.5h The involvement of the imine in the
orientation, with the iminic nitrogen interacting with the
amino ligand located in a trans coordination position to the
phosphine, while the pseudoaxial Ph phosphine and the C–
Ph imine substituents point to opposite directions.
The hydride transfer step from TS1-d1R-RP-5a and TS1-
d3S-SP-5a next leads to ion pairs ip-pro-R and ip-pro-S,
respectively.32 These species are stabilized by a hydrogen
bond, with N⋯H distances of 1.788 Å and 1.821 Å for ip-pro-
R
and ip-pro-S, respectively, as well as by an agostic
interaction provided by the new C–H bond, with Ru–H
distances of 2.031 Å and 2.033 Å, respectively. From the
respective ion pair intermediates, a very easy proton transfer
(TS2) via TS2-pro-R and TS2-pro-S can take place, lying 1.3
and 0.4 kcal mol−1 above the corresponding ion-pairs,
respectively. The proton transfer step leads to adducts formed
by an amido complex and enantiomers of amine 6a (a1R-R-6a
and a3S-S-6a, respectively). It is worth noting that this step
also displays the completion of the hydride transfer step, as
shown by a shortening of the corresponding C–H distance
(e.g. from 1.201 Å in ip-pro-R to 1.119 Å in a1R-R-6a) with a
concomitant lengthening of the C–N bond of the product
(e.g. from 1.394 to 1.462 Å in the pro-R route). Complexes
a1R-R-6a and a3S-S-6a are stabilized as well by a hydrogen
bond between the amido ligand and 6a with N⋯H distances
of 2.011 Å and 1.969 Å for a1R-R-6a and a3S-S-6a, respectively.
The proton transfer step raises an important difference with
the hydrogenation of acetophenone, as the deprotonation of
the DPEN ligand by N-(phenyl)-1-phenylethylamide should be
easier than that by 1-phenylethoxide, due to the higher
basicity of the former. In addition, amido–amino complexes
are significantly more stable than the parent ion pair species,
with respective gains of free energy equal to 6.0 and 9.1 kcal
mol−1 for a1R-R-6a and a3S-S-6a, respectively. It is worth
noting in this context that the evolution of ionic pair species
to the corresponding amido (or alkoxo complexes in ketone
activation of hydrogen can therefore be
a point of
considerable interest in the present system that deserves
study. Attending to the pathway described for the reduction
of 5a by d1R, hydrogen coordination and further activation
by a1R-R-6a seems a plausible route for the second part of
the catalytic cycle. Nevertheless, alternative pathways from
ion pair ip-pro-R as well as direct activation by amido
complex a1R have also been considered attending to
aforementioned precedents.
Hydrogen interaction with a1R-R-6a started with
a
sequence of steps for H2 coordination (Fig. 13). Approach of
the H2 molecule to the amido complex shows a first
transition state (TS3a) with Ru–H distances of 2.812 and
2.662 Å, while the H–H distance in the complex is 0.749 Å,
indicating a minimal interaction with the metal center (0.744
Å computed for free hydrogen). From TS3a, the reaction
sequence first produces a loose dihydrogen complex h1R-R-
6a-l (d(Ru–H) = 2.106, 2.160 Å, d(H–H) = 0.779 Å) and then a
tight one h1R-R-6a-t characterized by shorter Ru–H distances
of 1.779 and 1.746 Å and a H–H distance of 0.839 Å, as well
as the corresponding transition state between them (TS3b). It
is worthy to note that both dihydrogen complexes as well as
transition states along the pathway are stabilized by a
hydrogen bond to (R)-6a. TS4a connects the tight H2 bound
complex with a hydrogen bonded adduct between d1R and
(R)-6a (d1R-R-6a). However, TS4a mainly shows proton
hydrogenation) is typically
a
very thermodynamically
favorable step.5h,33 In the present case, amido complex N1R
Fig. 13 Hydrogen activation by a1R-R-6a (ΔG and ΔE values in kcal mol−1 referenced to a1R + (R)-6a + H2, bond distances in Å).
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transfer from (R)-6a to the complex to generate an ionic-pair
type species along with incipient activation of the
coordinated H2, assisted by deprotonated (R)-6a. Further
activation of the coordinated H2 is easy and IRC analysis
from TS4a leads to d1R-R-6a in the product direction. It is
worthy to note that the free energy of TS4a is only 1.8 kcal
mol−1 above that of h1R-R-6a-t, indicating that ionization
induced by the proton transfer step enables very easy
hydrogen activation. Notwithstanding that, this is the step
with the highest barrier in the coordination-activation of H2
by a1R-R-6a.
Analysis of H2 coordination to ip-pro-R led to a high
energy transition state (TS3c, ΔG‡ = 16.4 kcal mol−1, Fig. 14).
It seems that separation in toluene of the tightly bonded
ionic components of the pair due to the uncompleted hydride
transfer and the agostic interaction has a considerable
energetic cost. TS3c shows a dissimilar interaction between
Ru and both atoms of the H2 molecule, with Ru–H distances
of 2.161 and 2.548 Å, while the H–H distance (0.761 Å)
indicates the scarce activation of dihydrogen. In addition, the
N–H distances reflect the ionic-pair character of TS3c. Based
on the comments made above, one might expect that H2 is
quite ready to be activated from TS3c and indeed, an IRC
analysis from this transition state directly leads in the
product direction to a hydrogen bonded adduct between (R)-
6a and d1R, which differs from d1R-R-6a in the orientation
of the amine.
of the coordination of the hydrogen molecule to the a1R
complex displayed an analogous pathway to that described
for a1R-R-6a, with loose and tight H2 complexes and
corresponding transition states (see the ESI† for further
details). Activation of the coordinated hydrogen in the tight
complex h1R-t leads to TS4b (ΔG‡ = 16.6 kcal mol−1) and then
to d1R. It is worthy to note that most of the energetic cost of
the hydrogen activation process corresponds to the
coordination of the H2 molecule, since reaching the h1R-t
species has an energetic cost of 12.1 kcal mol−1 with respect
to a1R and H2, while the subsequent step (TS4b) has a low
relative ΔG‡ value (4.5 kcal mol−1) with respect to h1R-t. The
comparison between the activation schemes by a1R-R-6a and
a1R indicates hydrogen bond stabilization from (R)-6a along
the pathway in the first case, leading to a more favorable
hydrogen activation route. Moreover, loose interaction
between a1R and (R)-6a in a1R-R-6a compared with ionic
fragments in ip-pro-R enables easier H2 coordination. Finally,
an analysis of the reaction profile using the energetic span
model35 indicates that the turnover determining intermediate
(TDI) is a1R-R-6a, while the turnover determining transition
state (TDTS) is TS4a, with an energetic span (δE) of 17.5 kcal
mol−1, which is an affordable free energy barrier at room
temperature.
Although the results described above point to hydrogen
activation as the turnover-limiting step, it should be noticed
that the determination of the lowest hydrogen activation
route in the present system is an exceedingly difficult task.
For instance, a1R-R-6a should easily exchange amine with its
A third possible H2 activation pathway corresponds to
non-assisted activation by amido complex a1R. Examination
Fig. 14 General scheme for the hydrogen activation pathways. ΔG values in brackets in kcal mol−1 referred to a1R + (R)-6a + H2.
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S
enantiomer. In addition, hydrogen bond interaction
each type (i.e. d1R, d3S, dtR and dtS with d1R′, d1S′, dtR″
and dtS″, respectively) shows rather coincident structures. In
addition, from the Ru–H distances of the Ru(H)2(2c)(3a)
complexes, a comparable reactivity between cis and trans
dihydrides can be expected. Based on these considerations, a
pathway involving cis-dihydrides seems also plausible for
between 6a and the amido complex generates a stereogenic
center at nitrogen for which two configurations are possible
resulting from easy nitrogen inversion in 6a. In addition,
proton transfer between amido and amino fragments of the
DPEN ligand assisted by 6a should also be a feasible step. As
already mentioned, easy atropisomerization of the biaryl
fragment in pentacoordinate amido complexes is an
additional variable to consider. Recalling, finally, the
fluxional nature described for RuH(NHCMe2CMe2NH2)
catalysts with
stabilization
a
of
phenylene backbone. However, as the
imine–dihydride precomplexes and
corresponding TS1 depend on a precise substrate–complex
recognition, this possibility cannot be ascertained without a
detailed analysis of all possible pathways, which is further
complicated by the conformational properties of the
phosphine–phosphite ligand.
5a
(PPh3)2 and considering the existence of several amido–
hydride complexes in a narrow interval of energy (Fig. 7),
isomerization of a1R may be an additional factor to consider.
Product configuration and enantioselectivity. The
irreversible formation of amine observed experimentally
points to the hydride insertion as the enantiodetermining Conclusions
step.36 Thus, the general scheme drawn for the reduction of
5a explains the configuration of the amine product obtained
experimentally (i.e. (R)-6a from 1a). It is worthy to note that
the chiral diamine induces a strong preference in product
configuration. Thus, in addition to the favored formation of
(R)-6a from d1R, trans dihydrides dtR and dtS also show a
significant preference for (R)-6a, as the most favorable pro-R
TS1 is 3.8 kcal mol−1 lower in free energy than the most
favorable pro-S TS1 for the trans isomers. In contrast, metal
configuration prevails in d3S over that of DPEN favouring the
formation of (S)-6a (3.3 kcal mol−1 difference in free energy
between most favourable pro-S and pro-R TS1).
There is extensive information in the literature about
fluxionality and isomerization of ruthenium dihydrides.37
Particularly relevant in this context, Morris has studied in detail
the behavior of complex A, observing the isomerization between
trans,cis and cis,cis isomers (with the latter being more stable),5c
pointing to a non-dissociative trigonal twist mechanism for the
exchange.38 Due to the complexity introduced by the
atropisomerization of the phosphine–phosphite ligand, we have
not investigated the exchange between d1R and d3S, but
considering that coincident enantioselectivities were obtained
independent of the stereochemistry of Ru(Cl)2(2a)(3a), such an
exchange may also be operative in the present system. Following
this assumption, the value of ΔΔG‡ of 1.6 kcal mol−1 between
TS1-d1R-RP-5a and TS1-d3S-SP-5a gives an estimation of 88% ee
for the enantioselectivity, while the value of ΔΔE‡ of 1.9 kcal
mol−1 corresponds to 92% ee. Using a more extended basis set
(def2QZVP for Ru and 6-311++g(2d,p) for main group atoms), a
value of ΔΔE‡ equal to 1.9 kcal mol−1 was obtained (91% ee).
These values therefore show a good agreement with the
experimental value of 94% ee. A remarkable difference between
these transition states regards metal configuration.39 Thus, in
the case of d1R, there is a matched combination of diamine
and metal configurations which enables a better fitting of the
substrate in the pocket generated by the dihydride, therefore
allowing a shorter N(imine)⋯HN hydrogen bond40 in TS1-d1R-
RP-5a than in TS1-d3S-SP-5a.
Complexes 1 have selectively been obtained as trans isomers
by subsequent treatment of RuCl2(PPh3)3 with P–OP and N–N
ligands. In the case of 1a, a clean trans to cis isomerization
has been observed by heating in EtOH. DFT calculations
performed with Ru(Cl)2(2a)(3a) reproduce the higher stability
of the cis isomers over the trans isomers as well as the low
energy difference between atropisomers of trans-1a observed
experimentally. Moreover,
a
strong bias on biaryl
configuration caused by metal and diamine chirality is
observed in cis-1 and cis-3 type isomers. Complexes 1 are
effective catalyst precursors for the enantioselective
hydrogenation of N-aryl imines 5 under very mild conditions
with satisfactory enantioselectivities (84–96% ee, 16
examples). The catalyst performance is also suitable for
multigram hydrogenation as shown in the case of the
synthesis of 6h. Complex Ru(H)(BH4)(2c)(3b) hydrogenates 5a
in iPrOH without the need of an additional base, giving
i
nearly coincident enantioselectivity with 1e in PrOH using 5
equiv. of base, pointing to a common enantiodetermining
step in both reactions. Likewise, the enantioselectivity in the
hydrogenation of 5g under standard conditions did not
depend on the stereochemistry of starting Ru(Cl)2(2a)(3a),
while additional experiments pointed to the irreversible
reduction of this substrate.
In addition, the mechanism of the reduction of 5a by
Ru(H)2(2a)(3a) has been calculated by DFT methods. Results
obtained from the latter are in accord with a stepwise
reduction of the imine,41 with the hydride transfer being
enantiodetermining, while the pro-R and the pro-S routes are
generated by d1R and d3S dihydrides, respectively.
Calculations rationalize the configuration of the preferred
product enantiomer and show
a good agreement with
experimental enantioselectivity. From the examination of
several hydrogen activation pathways, the most favourable
one is initiated by hydrogen coordination to hydrogen
bonded adduct a1R-R-6a, followed by activation of the η2-H2
assisted by the amine. In the latter, proton transference from
the amine to the amido ligand, leading to an ion pair species,
has been observed before an easy hydrogen activation step.
Despite the different backbones in dihydrides Ru(H)2(2a)
(3a) and Ru(H)2(2c)(3a), a comparison between isomers of
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Conflicts of interest
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Kong and Q.-L. Zhou, J. Am. Chem. Soc., 2007, 129, 1868; (e)
T. Li, I. Bergner, F. N. Haque, M. Z. De Iuliis, D. Song and
R. H. Morris, Organometallics, 2007, 26, 5940; ( f ) J. M. John
and S. H. Bergens, Angew. Chem., Int. Ed., 2011, 50, 10377.
5 (a) K. Abdur-Rashid, S. E. Clapham, A. Hadzovic, J. N.
Harvey, A. J. Lough and R. H. Morris, J. Am. Chem. Soc.,
2002, 124, 15104; (b) C. A. Sandoval, T. Ohkuma, K. Muñiz
and R. Noyori, J. Am. Chem. Soc., 2003, 125, 13490; (c) R.
Abbel, K. Abdur-Rashid, M. Faatz, A. Hadzovic, A. J. Lough
and R. H. Morris, J. Am. Chem. Soc., 2005, 127, 1870; (d) A.
Hadzovic, D. Song, C. M. MacLaughlin and R. H. Morris,
Organometallics, 2007, 26, 5987; (e) M. Z.-D. Iuliis and R. H.
Morris, J. Am. Chem. Soc., 2009, 131, 11263; ( f ) A. Comas-
Vives, G. Ujaque and A. Lledós, Inner- and Outer-Sphere
There are no conflicts to declare.
Acknowledgements
This work was supported by the Spanish Ministry of Science
and Innovation (projects CTQ2016-75193-P; AEI/FEDER, UE,
RED2018-102387-T, PID2019-110856GA-I00 and PGC2018-
100818-A-I00). The Mass Spectrometry Service of the
Universidad de Sevilla (CITIUS) is acknowledged for technical
assistance as well as the Supercomputing Center of Galicia
(CESGA) for the access to computing facilities. Dr. Joaquín
López-Serrano is also gratefully acknowledged for providing
valuable comments. A. C.-V. also thanks the Spanish MEC
and the European Social Fund (Ramón y Cajal Fellowship:
RyC-2016-19930). We acknowledge support of the publication
fee by the CSIC Open Access Publication Support Initiative
through its Unit of Information Resources for Research
(URICI). This work is dedicated to Prof. Antonio Otero on the
occasion of his retirement.
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attempted using procedures described in the literature for
the synthesis of ruthenium hydrides (e.g. treatment with H2
in the presence of a base or reaction with hydride reagents),
obtaining complex reaction mixtures in all cases. Moreover,
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well due to phosphite decomposition under reaction
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phosphine–phosphite ligands.
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of ketones (ref. 5h). In reactions prepared without an added
base or with a low concentration of base, ketone reduction
by Ru(H)2(diphosphine)(diamine) is proposed. In contrast,
under high base concentration, alkaline dihydride–amidate
complexes resulting from deprotonation of the diamine
ligand are proposed as the key reductive species.
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using the B3PW91 functional, with the SDD basis set for Ru
and 6-31g(d,p) for main group atoms, including D3
dispersion corrections and the use of the SMD continuum
solvent model. For the latter, toluene was used for all
32 A detailed analysis of the hydride transfer step shows the
participation of intermediate ion pair species ag-pro-R and
ag-pro-S, respectively, with Ru–H distances of 1.903 and
1.899 Å, respectively, while the C–H ones amount to 1.228
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34 A considerable effort has been dedicated to find TS
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estimated (see the ESI† for details).
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39 An analogous reaction scheme with cis dihydrides differing
in metal configuration leading to opposite product
enantiomers has been previously proposed by Morris5c to
explain
low
enantioselectivities
observed
in
the
a
stoichiometric hydrogenation of acetophenone with
mixture of Δ-cis,cis and Λ-cis,cis-A dihydrides.
40 For other examples of transition states in bifunctional catalysis
stabilized by hydrogen bonds, see: (a) J. F. Sonnenberg, K. Y.
Wan, P. E. Sues and R. H. Morris, ACS Catal., 2017, 7, 316; (b)
C. S. G. Seo, T. Tannoux, S. A. M. Smith, A. J. Lough and R. H.
Morris, J. Org. Chem., 2019, 84, 12040.
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Yamakawa, H. Ito and R. Noyori, J. Am. Chem. Soc.,
2000, 122, 1466; (b) Ref. 4e.
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