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Citation: Ali, Q.; Chen, Y.; Zhang, R.;
Li, Z.; Tang, Y.; Pu, M.; Lei, M. The
Origin of Stereoselectivity in the
Hydrogenation of Oximes Catalyzed
by Iridium Complexes: A DFT
Mechanistic Study. Molecules 2022,27,
8349. https://doi.org/10.3390/
molecules27238349
Academic Editors: Daoshan Yang
and Zhanhui Yang
Received: 27 September 2022
Accepted: 25 November 2022
Published: 30 November 2022
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molecules
Article
The Origin of Stereoselectivity in the Hydrogenation of Oximes
Catalyzed by Iridium Complexes: A DFT Mechanistic Study
Qaim Ali 1, Yongyong Chen 1, Ruixue Zhang 1, Zhewei Li 1, Yanhui Tang 1,2, Min Pu 1and Ming Lei 1, *
1State Key Laboratory of Chemical Resource Engineering, Institute of Computational Chemistry,
College of Chemistry, Beijing University of Chemical Technology, Beijing 100029, China
2School of Materials Design and Engineering, Beijing Institute of Fashion Technology, Beijing 100029, China
*Correspondence: leim@mail.buct.edu.cn; Tel.: +86-10-6444-6598
Abstract:
Herein the reaction mechanism and the origin of stereoselectivity of asymmetric hydro-
genation of oximes to hydroxylamines catalyzed by the cyclometalated iridium (III) complexes
with chiral substituted single cyclopentadienyl ligands (Ir catalysts
A1
and
B1
) under acidic con-
dition were unveiled using DFT calculations. The catalytic cycle for this reaction consists of the
dihydrogen activation step and the hydride transfer step. The calculated results indicate that the
hydride transfer step is the chirality-determining step and the involvement of methanesulfonate
anion (MsO
−
) in this reaction is of importance in the asymmetric hydrogenation of oximes cat-
alyzed by
A1
and
B1
. The calculated energy barriers for the hydride transfer steps without an
MsO
−
anion are higher than those with an MsO
−
anion. The differences in Gibbs free energies be-
tween
TSA5−1fR
/
TSA5−1fS
and
TSB5−1fR
/
TSB5−1fS
are 13.8/13.2 (
∆∆
G
‡
= 0.6 kcal/mol) and
7.5/5.6 (
∆∆
G
‡
= 1.9 kcal/mol) kcal/mol for the hydride transfer step of substrate protonated oximes
with Econfiguration (
E−2a−H+
) with MsO
−
anion to chiral hydroxylamines product
R−3a
/
S−3a
catalyzed by
A1
and
B1
, respectively. According to the Curtin–Hammet principle, the major products
are hydroxylamines
S−3a
for the reaction catalyzed by
A1
and
B1
, which agrees well with the
experimental results. This is due to the non-covalent interactions among the protonated substrate,
MsO
−
anion and catalytic species. The hydrogen bond could not only stabilize the catalytic species,
but also change the preference of stereoselectivity of this reaction.
Keywords: DFT; non-covalent interactions; stereoselectivity; asymmetric hydrogenation; oxime
1. Introduction
The chiral hydroxylamines are one of the important organic intermediates in pharma-
ceutical and agricultural industries, which could be attributed to the reactive N–O bond
in the structural motif. The molecules owning the N-alkoxy amine group are very com-
mon in a wide range of bioactive and pharmaceutical products [
1
]. Among the syntheses
of chiral amines, the asymmetric hydrogenation of the C=N double bond catalyzed by
transition-metal complexes is one of the most efficient methods to prepare enantiomers at
an industrial scale [
2
]. However, the selective reduction of oximes to the corresponding
chiral hydroxylamine derivatives remains a challenge because the undesired reductive
cleavage of the labile N–O bond leads to undesired primary amines (see Scheme 1a) [
3
].
Chiral hydroxylamine could be obtained by partial oxidation of chiral amines, but this
method could either involve multiple steps or be prone to overreaction [
4
–
7
]. In 2014,
Oestreich et al. reported the reductive hydrogenation of oxime ether catalyzed by B(C
6
F
5
)
3
at room temperature [
8
]. Recently, Zhang et al. realized Ni-catalyzed asymmetric hydro-
genation of oxides to chiral hydroxyl amines via weak attractive interactions between
the catalyst and substrate (Scheme 1b) [
9
]. In 2020, Cramer et al. reported this reaction
catalyzed by cyclometallated iridium (III) complexes with chiral substituted single cy-
clopentadienyl ligands and C,N-bidentate aryl imine ligand (see Scheme 1c) [
10
]. Despite
Molecules 2022,27, 8349. https://doi.org/10.3390/molecules27238349 https://www.mdpi.com/journal/molecules
Molecules 2022,27, 8349 2 of 9
the experimental reports above, the effective strategy of asymmetric hydrogenation of
oxime to hydroxylamine is still relatively scarce. The reaction by Cramer et al. proceeded
at room temperature with 98% ee and the turnover number (TON) reached 4000 before
becoming inactive. This transformation was comprised of the quantitative protonation of
the substrate and subsequent hydride transfer. The hydride could be transferred to the
substrate either directly or with the help of the anion mediation by means of non-covalent
contacts with the transition-metal catalytic species and the protonated substrates. Although
it is obvious that the cyclometallated iridium complexes such as
A1
and
B1
owning chiral
cyclopentadienyl ligand with binaphthyl as backbone and an achiral C,N-bidentate aryl
imine ligand are of importance in the asymmetric hydrogenation of oximes, the reaction
mechanism and the origin of stereoselectivity for this reaction are still unclear. Therefore,
herein a DFT mechanistic study was performed in order to unveil the nature of this reaction
catalyzed by catalysts A1 and B1.
Molecules 2022, 27, x FOR PEER REVIEW 2 of 9
at room temperature [8]. Recently, Zhang et al. realized Ni-catalyzed asymmetric hydro-
genation of oxides to chiral hydroxyl amines via weak attractive interactions between the
catalyst and substrate (Scheme 1b) [9]. In 2020, Cramer et al. reported this reaction cata-
lyzed by cyclometallated iridium (III) complexes with chiral substituted single cyclopen-
tadienyl ligands and C,N-bidentate aryl imine ligand (see Scheme 1c) [10]. Despite the
experimental reports above, the effective strategy of asymmetric hydrogenation of oxime
to hydroxylamine is still relatively scarce. The reaction by Cramer et al. proceeded at room
temperature with 98% ee and the turnover number (TON) reached 4000 before becoming
inactive. This transformation was comprised of the quantitative protonation of the sub-
strate and subsequent hydride transfer. The hydride could be transferred to the substrate
either directly or with the help of the anion mediation by means of non-covalent contacts
with the transition-metal catalytic species and the protonated substrates. Although it is
obvious that the cyclometallated iridium complexes such as A1 and B1 owning chiral cy-
clopentadienyl ligand with binaphthyl as backbone and an achiral C,N-bidentate aryl
imine ligand are of importance in the asymmetric hydrogenation of oximes, the reaction
mechanism and the origin of stereoselectivity for this reaction are still unclear. Therefore,
herein a DFT mechanistic study was performed in order to unveil the nature of this reac-
tion catalyzed by catalysts A1 and B1.
S
O
OH3C
O
Ir N
O
O
O
MeO
OMe
S
O
OH3C
O
Ir N
O
MeO
OMe
O
NOH
RH2,AcOH
ClCl
Cl
Me
NOtBu
Ar Me
NOtBuH
E2a H+
Ar Me
HN OtBu
H
Ir, H2
23 oC, 20 h
MsOH
B1
>99 %, 89:11 er
A1
41 %, 70:30 er
(b) The Nickel-catalysed asymmetric hydrogenation of oximes
S3a
E1a
(c) The acid-assisted stereoselective hydrogenation of oximes catalyzed by chiral Ir catalysts
M
NOR3
R2
R1
HN
R2
R1
NH2
R2
R1H
H2
N-O
reduction
H
OR3
(a) The transition-metal-catalyzed hydrogenation of oximes deliver undesired amines
over reduction
lack of reactivity
Ni(OAc)2
PhPBE(L*) HN OH
R
Scheme 1. (a) The transition-metal-catalyzed hydrogenation of oximes deliver undesired amines [3],
(b) the Nickel-catalyzed asymmetric hydrogenation of oximes [9] and (c) the acid-assisted stereose-
lective hydrogenation of oximes catalyzed by chiral Ir catalysts [10].
As shown in Scheme 2, the catalytic cycle of this reaction consists of the dihydrogen
activation (DA) step and the hydride transfer (HT) step. In the dihydrogen activation step,
Scheme 1.
(
a
) The transition-metal-catalyzed hydrogenation of oximes deliver undesired amines [
3
],
(
b
) the Nickel-catalyzed asymmetric hydrogenation of oximes [
9
] and (
c
) the acid-assisted stereoselec-
tive hydrogenation of oximes catalyzed by chiral Ir catalysts [10].
As shown in Scheme 2, the catalytic cycle of this reaction consists of the dihydrogen
activation (DA) step and the hydride transfer (HT) step. In the dihydrogen activation step,
one molecular hydrogen interacts with
1
by replacing the weakly coordinated methanesul-
fonate anion (MsO
−
) ligand to afford intermediate
2
, then the dihydrogen is heterolytically
split with the assistance of the MsO
−
anion via the transition state
TS2−3
to form in-
termediate
3.
Before the addition of oxime substates in the catalytic cycle, the original
oxime substrate
E−1a
is protonated by MsOH to achieve protonated adduct
E−2a−H+
Molecules 2022,27, 8349 3 of 9
without MsO
−
anion or
E−2a
with MsO
−
anion. In the subsequent hydride transfer step,
the methanesulfonic acid (MsOH) is released to produce intermediate
4
; the protonated
substrates (
E−2a−H+
or
E−2a
) could interact with
4
to achieve the chiral hydroxylamine
product
3a
and regenerate
1
completing the catalytic cycle. In this work, the reaction mech-
anism of the asymmetric hydrogenation of oximes to hydroxylamines was discussed, the
origin of the stereoselectivity was unveiled, and the important role of the MsO
−
anion in
this reaction was described. This might shed lights on the development of transition-metal
catalysts based on the mechanism of the asymmetric hydrogenation of oximes in the future.
Molecules 2022, 27, x FOR PEER REVIEW 3 of 9
one molecular hydrogen interacts with 1 by replacing the weakly coordinated me-
thanesulfonate anion (MsO−) ligand to afford intermediate 2, then the dihydrogen is het-
erolytically split with the assistance of the MsO− anion via the transition state TS2−3 to
form intermediate 3. Before the addition of oxime substates in the catalytic cycle, the orig-
inal oxime substrate E−1a is protonated by MsOH to achieve protonated adduct E−2a−H+
without MsO− anion or E−2a with MsO− anion. In the subsequent hydride transfer step,
the methanesulfonic acid (MsOH) is released to produce intermediate 4; the protonated
substrates (E−2a−H+ or E−2a) could interact with 4 to achieve the chiral hydroxylamine
product 3a and regenerate 1 completing the catalytic cycle. In this work, the reaction
mechanism of the asymmetric hydrogenation of oximes to hydroxylamines was dis-
cussed, the origin of the stereoselectivity was unveiled, and the important role of the MsO−
anion in this reaction was described. This might shed lights on the development of tran-
sition-metal catalysts based on the mechanism of the asymmetric hydrogenation of ox-
imes in the future.
H2
Direct hydride
transfer
MsO
ClCl
Cl
NOtBu
Me
Ar
N
OtBu
Me
H
N-protonation
E1a
MsO
Ar
N
OtBu
Me
H
E2a
MsOH
E2a H+
Ir
CN
H
4
MsO
Ir
CN
H
Ar
N
OtBu
Me
H
5f
Ir
CN
H
Ar
N
OtBu
Me
H
5u
Ir
CN
6
IrMsO
CN
1
Ir
CN
H
H
MsO
2
3
Ir
CN
H
H
MsO
3a
Ar
N
OtBu
Me
H
H
TS5 1f
TS2 3
MsOH
3
a
TS5 1u
MsO
Anion assisted
hydride transfer
Dihydrogen activation
Scheme 2. Proposed reaction mechanism for the asymmetric hydrogenation of oximes to hydroxyl-
amines catalyzed by iridium complexes.
2. Results and Discussion
The catalytic cycle of the asymmetric hydrogenation of oxime to hydroxyamine cat-
alyzed by Ir catalysts (A1 and B1) includes the dihydrogen activation step and the hydride
transfer step. In this work, the (S)-Ir catalysts bearing a chiral binaphthyl-derived cyclo-
pentadienyl ligand was used as the catalytic species for this reaction, which was reported
by experiments [10]. Figure 1 presents the Gibbs free energy profiles for the asymmetric
hydrogenation of E-oxime (E−1a) catalyzed by A1; the energies of the stationary points
are relative to corresponding starting point A1 (see that of hydrogenation of Z-oxime in
Figure S1 of SM). E-oxime was used because it is more stable than Z-oxime. In the dihy-
drogen activation step, one molecule hydrogen coordinates with Ir center by replacing the
weakly coordinated MsO− anion to form intermediate A2, which is endergonic by 14.7
Scheme 2.
Proposed reaction mechanism for the asymmetric hydrogenation of oximes to hydroxy-
lamines catalyzed by iridium complexes.
2. Results and Discussion
The catalytic cycle of the asymmetric hydrogenation of oxime to hydroxyamine cat-
alyzed by Ir catalysts (
A1
and
B1
) includes the dihydrogen activation step and the hydride
transfer step. In this work, the (S)-Ir catalysts bearing a chiral binaphthyl-derived cyclopen-
tadienyl ligand was used as the catalytic species for this reaction, which was reported
by experiments [
10
]. Figure 1presents the Gibbs free energy profiles for the asymmetric
hydrogenation of E-oxime (
E−1a
) catalyzed by
A1
; the energies of the stationary points
are relative to corresponding starting point
A1
(see that of hydrogenation of Z-oxime in
Figure S1 of SM). E-oxime was used because it is more stable than Z-oxime. In the dihy-
drogen activation step, one molecule hydrogen coordinates with Ir center by replacing
the weakly coordinated MsO
−
anion to form intermediate
A2
, which is endergonic by
14.7 kcal/mol. Then the coordinated dihydrogen causes a heterolytic splitting with the
assistance of the MsO
−
anion. The free energy barrier from
A1
to
A3
is 14.5 kcal/mol via
TSA2−3
.
A3
forms iridium hydride intermediate
A4
with the release of one molecule of
MsOH, which is exergonic by 4.9 kcal/mol. The following hydride transfer step could
be the direct hydride transfer without the involvement of the MsO
−
anion or the MsO
−
-
Molecules 2022,27, 8349 4 of 9
assisted hydride transfer. In the direct hydride transfer step, the substrate tethering with
one molecule MsOH,
E−2a
, could produce the protonated oxime
E−2a−H+
with the
removal of one MsO
−
anion. Then
E−2a−H+
approaches the Ir center of
A4
along the
si-face direction to form intermediate
A5uR
leading to the hydroxylamine product
R−3a
.
If it approaches the Ir center of
A4
along the re-face direction, the intermediate
A5uS
is
generated leading to
S−3a
hydroxylamine. The “u” in the names of stationary points such
as
A5uS
represents stationary points along an unfavorable pathway, the “f” is used for
those along a favorable pathway, and “S” or “R” denotes the reaction pathways leading to
S or R products, respectively. In the direct hydride transfer step from
A5uR
/
A5uS
to
A6
,
the hydride is transferred from an Ir center to the carbon atom of pronated oxime moiety of
A5uR
/
A5uS
directly via
TSA5−6uR
/
TSA5−6uS
. The free energy barriers for this step
are 5.2/8.1 kcal/mol from
A5uR
/
A5uS
to
A6uR
/
A6uS
and hydroxylamines, respectively.
Molecules 2022, 27, x FOR PEER REVIEW 4 of 9
kcal/mol. Then the coordinated dihydrogen causes a heterolytic splitting with the assis-
tance of the MsO− anion. The free energy barrier from A1 to A3 is 14.5 kcal/mol via
TSA2−3. A3 forms iridium hydride intermediate A4 with the release of one molecule of
MsOH, which is exergonic by 4.9 kcal/mol. The following hydride transfer step could be
the direct hydride transfer without the involvement of the MsO− anion or the MsO−-as-
sisted hydride transfer. In the direct hydride transfer step, the substrate tethering with
one molecule MsOH, E−2a, could produce the protonated oxime E−2a−H+ with the re-
moval of one MsO− anion. Then E−2a−H+ approaches the Ir center of A4 along the si-face
direction to form intermediate A5uR leading to the hydroxylamine product R−3a. If it
approaches the Ir center of A4 along the re-face direction, the intermediate A5uS is gener-
ated leading to S−3a hydroxylamine. The “u” in the names of stationary points such as
A5uS represents stationary points along an unfavorable pathway, the “f” is used for those
along a favorable pathway, and “S” or “R” denotes the reaction pathways leading to S or
R products, respectively. In the direct hydride transfer step from A5uR/A5uS to A6, the
hydride is transferred from an Ir center to the carbon atom of pronated oxime moiety of
A5uR/A5uS directly via TSA5−6uR/TSA5−6uS. The free energy barriers for this step are
5.2/8.1 kcal/mol from A5uR/A5uS to A6uR/A6uS and hydroxylamines, respectively.
Ir
0.0
10.0
-10.0
-20.0
20.0
30.0
0.0
14.7 14.5
12.1
7.2
A5uR 21.8
A5uS 21.1
TSA5 6uS 29.2
TSA5 6uR 27.0
9.3
IrMsO
Ir
H
H
MsO
IrH
OMs
H
IrH
OMs
H
IrH
TSA2 3
H2
MsOH
3a
Cp*
C
NH
C
NH
Cp*
Ir
C
NH
C
NH
Dihydrogen activation Hydride transfer
Cp*
Ir
C
N
MsO
E2a
C
N
Me
H
BuO
H
C
N
Me
H
BuO
S
O
O
CH3
O
E2a 3a
A1
A2 A3
A4
Ar
Ar
t
t
A5fR 2.9
A5fS 2.2
TSA5 1fR 13.8
TSA5 1fS 13.2
MsO
Cp*
Ir
C
NH
C
NH
S
O
O
CH3
O
Cp*
Ir
C
NH
C
NH
S
O
O
CH3
O
without anion assistance
with anion assistance
A1
A6
24.3
Figure 1. The Gibbs free energy profiles of asymmetric hydrogenation of oximes to hydroxylamines
catalyzed by Ir complex A1 (unit: kcal/mol). * represents chirality and ‡ means this is a transition
state.
Finally, A6uR/A6uS combine with the MsO− anion to regenerate the active catalytic
species A1 and the catalytic cycle is completed. It should be noted that the energetic span
[11] of generating R−3a/S−3a products are 27.0/29.2 kcal/mol
(A1→TSA5−6uR/TSA5−6uS), respectively. That means that R−3a is the dominant product
instead of S−3a, and the energetic span is high, which is contrary with the conditions for
the experiment to be carried out at room temperature.
Therefore, the direct hydride transfer mode cannot explain well the experimental ob-
servation. The non-covalent interactions have been proposed to be of importance in the
asymmetric reactions, which might stabilize the transition states, accelerate chemical re-
action and regulate the stereoselectivity [9,12,13]. Note that the Gibbs free energy of the
oxime substrate tethering with one molecule MsOH (E−2a) is 17.3 kcal/mol lower than
that of protonated oxime E−2a−H+, which could be more stable to form E−2a for E−2a−H+
Figure 1.
The Gibbs free energy profiles of asymmetric hydrogenation of oximes to hydroxylamines
catalyzed by Ir complex
A1
(unit: kcal/mol). * represents chirality and
‡
means this is a transition state.
Finally,
A6uR
/
A6uS
combine with the MsO
−
anion to regenerate the active catalytic
species
A1
and the catalytic cycle is completed. It should be noted that the energetic
span [
11
] of generating
R−3a
/
S−3a
products are 27.0/29.2 kcal/mol (
A1→TSA5−6uR
/
TSA5−6uS
), respectively. That means that
R−3a
is the dominant product instead of
S−3a
,
and the energetic span is high, which is contrary with the conditions for the experiment to
be carried out at room temperature.
Therefore, the direct hydride transfer mode cannot explain well the experimental
observation. The non-covalent interactions have been proposed to be of importance in the
asymmetric reactions, which might stabilize the transition states, accelerate chemical reac-
tion and regulate the stereoselectivity [
9
,
12
,
13
]. Note that the Gibbs free energy of the oxime
substrate tethering with one molecule MsOH (
E−2a
) is 17.3 kcal/mol lower than that of pro-
tonated oxime
E−2a−H+
, which could be more stable to form
E−2a
for
E−2a−H+
com-
bining with the conjugated base MsO
−
anion. There are non-covalent interactions including
hydrogen bonds formed by
E−2a−H+
, MsO
−
and Ir catalytic species after
E−2a
interacts
with
A4
. It is exergonic by 4.3 and 5.0 kcal/mol to generate
A5fR
and
A5fS
from the
interaction of
E−2a
and
A4
. In the subsequent MsO
−
-assisted hydride transfer step from
A5fR
/
A5fS
to
A1
+
R−3a
/
A1
+
S−3a
, the hydride is transferred from the Ir center to the car-
bon atom of oxime moiety. The free energy barriers for this step are 10.9 and
11.0 kcal/mol
for the formation of
R−3a
and
S−3a
via
TSA5−1fR
/
TSA5−1fS
, respectively. Based on
Molecules 2022,27, 8349 5 of 9
the energetic span model and Curtin–Hammet principle [
14
], the energetic spans of the
reaction pathways to achieve
R-3a
and
S-3a
products adopting the
MsO−-assisted
hydride
transfer mode are 13.8 (
A1→TSA5−1fR
) and 13.2 (
A1→TSA5−1fS
) kcal/mol, respec-
tively. It is obvious that the reaction pathways with the involvement of the MsO
−
anion is
much favorable than those without the MsO
−
anion. The difference of the energetic spans
for the reactions leading to R and S products are 0.6 kcal/mol (
∆∆
G
‡
= 0.6 kcal/mol). The
calculated results show that
S−3a
is the dominant product. The predicted enantioselectiv-
ity is 73:27 e.r., which agrees well with that obtained in the experiment (70:30 e.r.) [
10
]. This
indicates that the non-covalent interactions including hydrogen bonds among
E−2a−H+
,
MsO
−
and Ir catalytic species are very important, as they could not only stabilize the
catalyst but also turn over the stereoselectivity of the reaction.
Meanwhile, the asymmetric hydrogenation of oxime
E−1a
to hydroxylamine cat-
alyzed by Ir catalyst
B1
was also investigated using DFT method in this work. The free
energy profiles for this reaction catalyzed by
B1
are shown in Figure 2. Following the simi-
lar reaction pathways as discussed for catalyst
A1
above, in the dihydrogen activation step
from
B1
to
B4
molecular hydrogen replaces weakly coordinated the MsO
−
anion of
B1
to
afford
B2
at first, which is endergonic by 9.3 kcal/mol. Then
B2
proceeds with a heterolytic
dihydrogen splitting to achieve
B3
via
TSB2−3
with a free energy barrier of 3.0 kcal/mol.
Subsequently,
B3
releases MsOH to form iridium hydride
intermediate B4
. This step is
exergonic by 4.6 kcal/mol. In the following hydride transfer step (the chirality-determining
step), the hydride of metal center of B4 could be stereoselectively transferred to the proto-
nated substrate with or without MsO
−
anion assistance. Similarly, MsOH tethered substrate
E−2a releases the MsO−anion to afford protonated substrate E−2a−H+before the inter-
action with the iridium hydride intermediate
B4
. In the situation without the participation
of the MsO
−
anion,
E−2a−H+
interacts with
B4
along its Si/Re face to form
B5uR
/
B5uS
intermediates, which could achieve the final chiral hydrogenated products. Instead, the
intermediate
B5fR
/
B5fS
could be formed by the combination of
B4
and
E−2a
with the
participation of the MsO
−
anion. Similarly, the intermediates
B5fR
/
B5fS
are more stable
than
B5uR
/
B5uS
due to the formation of hydrogen bonds among
E−2a−H+
and MsO
−
anion in the former ones. The calculated free energy barriers of the MsO
—
assisted hydride
transfer step of this reaction to achieve
R-3a
and
S-3a
products are 6.6 (
B5fR→TSB5f−1R
)
and 9.4 (
B5fS→TSB5f−1S
) kcal/mol, respectively. Compared to the MsO
−
-assisted hy-
dride transfer, those adopting the direct hydride transfer mode without the involvement
of the MsO
−
anion are 18.7 (
B1→TSB5−1uR
) and 22.8 (
B1→TSB5−1uS
) kcal/mol, re-
spectively. It is obvious that the MsO
−
-assisted hydride transfer with MsO
−
anion is
much more favorable than the direct hydride transfer without MsO
−
anion. In addition,
according to the Curtin–Hammet principle, the difference in relative free energies between
TSB5−1fS
and
TSB5−1fR
is 1.9 kcal/mol (
∆∆
G
‡
=
1.9 kcal/mol
). This implies that the hy-
droxylamine
S−3a
is the favorable product and the predicted enantioselectivity is 96:4 e.r.,
this also agrees well with the result reported by experiment (89:11 e.r.) [10].
In general, the calculated results above for the asymmetric hydrogenation of oximes
to hydroxylamines catalyzed by iridium complexes
A1
and
B1
could predict that the final
favorable product would be
S−3a
, which is consistent with experimental results. The
stereoselectivity of
B1
is better than that of
A1
. The hydride transfer step is the chirality-
determining step and the MsO
−
anion is proposed to be of importance in this asymmetric
hydrogenation of oximes. The MsO
−
-assisted hydride transfer mode is superior to the
direct hydride transfer mode.
In order to explore the origin of stereoselectivity of asymmetric hydrogenation of
oximes to hydroxylamines catalyzed by chiral Ir catalysts (
A1
and
B1
), the independent
gradient model based on Hirshfeld partition of molecular density (IGMH) analysis were
employed using Multiwfn software and were visualized using VMD software [
15
]. IGMH
analysis could characterize and visualize the non-covalent interactions of key structures
along reaction pathways for this reaction. IGMH analysis of key transition state structures
TSB5−1fR
/
TSB5−1fS
for the hydride transfer step in the asymmetric hydrogenation
Molecules 2022,27, 8349 6 of 9
of oximes to hydroxylamines catalyzed by
B1
are shown in Figure 3. It could be seen
that there existed a strong hydrogen bond interaction between the MsO
−
anion and the
substrate in the anion-assisted hydride transfer step. This hydrogen bond interaction
could stabilize the catalyst and make the MsO
−
anion-assisted hydride transfer mode
superior to the direct hydride transfer. In addition, we found that the distance between
the hydrogen atom of benzene ring moiety of catalyst
B1
and the hydrogen atom of
the substrate is close (marked by a red cycle in Figure 3). The distance between the
two hydrogen atoms in
TSB5−1fR
/
TSB5−1fS
is 1.904 Å/2.191 Å, respectively. IGMH
analysis visualized this van der Waals repulsion, and the distance in
TSB5−1fR
is closer
than that in
TSB5−1fS
, implying that the repulsion interaction in
TSB5−1fR
is greater
than that in
TSB5−1fS
. This might be the origins of stereoselectivity of this reaction and
the instability of
TSB5−1fR
compared to
TSB5−1fS
. However, this recognition effect is
weakened in the catalyst
A1
due to the smaller ligand and could not be visualized by
IGMH analysis (see
Figure S4 of SM
). The distances between the two hydrogen atoms of
TSA5−1fR
and
TSA5−1fS
are 2.221 Å and 2.291 Å, respectively, which are longer than
those of corresponding TSB5−1fR and TSB5−1fS.
Molecules 2022, 27, x FOR PEER REVIEW 6 of 9
Figure 2. The Gibbs free energy profiles of asymmetric hydrogenation of oximes to hydroxylamines
catalyzed by Ir complex B1 (unit: kcal/mol). * represents chirality and ‡ means this is a transition
state.
In order to explore the origin of stereoselectivity of asymmetric hydrogenation of ox-
imes to hydroxylamines catalyzed by chiral Ir catalysts (A1 and B1), the independent gra-
dient model based on Hirshfeld partition of molecular density (IGMH) analysis were em-
ployed using Multiwfn software and were visualized using VMD software [15]. IGMH
analysis could characterize and visualize the non-covalent interactions of key structures
along reaction pathways for this reaction. IGMH analysis of key transition state structures
TSB5−1fR/TSB5−1fS for the hydride transfer step in the asymmetric hydrogenation of
oximes to hydroxylamines catalyzed by B1 are shown in Figure 3. It could be seen that
there existed a strong hydrogen bond interaction between the MsO− anion and the sub-
strate in the anion-assisted hydride transfer step. This hydrogen bond interaction could
stabilize the catalyst and make the MsO− anion-assisted hydride transfer mode superior
to the direct hydride transfer. In addition, we found that the distance between the hydro-
gen atom of benzene ring moiety of catalyst B1 and the hydrogen atom of the substrate is
close (marked by a red cycle in Figure 3). The distance between the two hydrogen atoms
in TSB5−1fR/TSB5−1fS is 1.904 Å/2.191 Å, respectively. IGMH analysis visualized this
van der Waals repulsion, and the distance in TSB5−1fR is closer than that in TSB5−1fS,
implying that the repulsion interaction in TSB5−1fR is greater than that in TSB5−1fS. This
might be the origins of stereoselectivity of this reaction and the instability of TSB5−1fR
compared to TSB5−1fS. However, this recognition effect is weakened in the catalyst A1
due to the smaller ligand and could not be visualized by IGMH analysis (see Figure S4 of
SM). The distances between the two hydrogen atoms of TSA5−1fR and TSA5−1fS are
2.221 Å and 2.291 Å, respectively, which are longer than those of corresponding TSB5−1fR
and TSB5−1fS.
Figure 2.
The Gibbs free energy profiles of asymmetric hydrogenation of oximes to hydroxylamines
catalyzed by Ir complex
B1
(unit: kcal/mol). * represents chirality and
‡
means this is a transition state.
Molecules 2022, 27, x FOR PEER REVIEW 7 of 9
Figure 3. The IGMH analysis of the transition states of the MsO−-assisted hydride transfer step of
the reaction by catalyst B1 (δginter = 0.008 a.u.).
3. Computational Methods
Being consistent with our previous research on the mechanisms of hydrogenation
reaction catalyzed by transition-metal complexes [16–24], all the calculations were per-
formed using the ωB97X-D/BSI method employing the Gaussian 09 program [25,26]. BSI
indicates that the LANL2DZ basis set was used for Ir atom and 6-31G* basis set for all
other non-metal atoms [27–29]. Additionally, single point energies were calculated with
ORCA package at the ωB97M-V/def2-TZVP level using optimized geometries at the
ωB97X-D/BSI level [30–33]. The solution model based on the density (SMD) solvation
model using tert-amyl alcohol as the solvent (ε = 5.78) was employed in calculations [34].
The frequency analyses were performed to verify that all transition states have one and
only one imaginary frequency. The intrinsic reaction coordinate (IRC) calculations were
performed for key steps to confirm transition states connecting two desired minima [35].
The quasi-rigid-rotor harmonic oscillator was used to consider low-frequency contribu-
tions utilizing the Shermo code [36,37]. To correct the overestimations of entropy contri-
butions due to using the ideal gas phase model in the Gaussian program, we applied a
correction of (n-m)*1.9 for a process from m components to n components according to the
reference [38]. The non-covalent interactions were observed by mapping the independent
gradient model based on Hirshfeld partition (IGMH) surfaces using Multiwfn [39,40]. Un-
less otherwise stated, all energies of stationary points are the Gibbs free energies calcu-
lated at 298.15 K, 1.0 atm and compared to A1 or B1. Total energies, Cartesian coordinates
of all optimized structures and the calculation formula for enantioselectivity ratios (e.r.)
are given in the Supplementary Materials (SM).
4. Conclusions
In summary, the reaction mechanism and the origin of stereoselectivity of asymmet-
ric hydrogenation of oximes to hydroxylamines catalyzed by the cyclometalated iridium
(III) complexes (A1 and B1) with chiral substituted single cyclopentadienyl ligand were
investigated using DFT method. The hydride transfer step is proposed to be the chirality-
determining step. The reaction could proceed via the direct hydride transfer or the MsO−-
assisted hydride transfer. The calculated results showed that the major product should be
the hydroxylamines S−3a along the MsO−-assisted hydride transfer pathway, and that the
involvement of the MsO− anion be of importance in this asymmetric hydrogenation of
oximes catalyzed by A1 and B1. This agrees well with experimental results and implies
that the non-covalent interactions including hydrogen bonds formed by the protonated
Figure 3.
The IGMH analysis of the transition states of the MsO
−
-assisted hydride transfer step of
the reaction by catalyst B1 (δginter = 0.008 a.u.).
Molecules 2022,27, 8349 7 of 9
3. Computational Methods
Being consistent with our previous research on the mechanisms of hydrogenation
reaction catalyzed by transition-metal complexes [
16
–
24
], all the calculations were per-
formed using the
ω
B97X-D/BSI method employing the Gaussian 09 program [
25
,
26
]. BSI
indicates that the LANL2DZ basis set was used for Ir atom and 6-31G* basis set for all
other non-metal atoms [
27
–
29
]. Additionally, single point energies were calculated with
ORCA package at the
ω
B97M-V/def2-TZVP level using optimized geometries at the
ωB97X-D/BSI level
[
30
–
33
]. The solution model based on the density (SMD) solvation
model using tert-amyl alcohol as the solvent (
ε
= 5.78) was employed in calculations [
34
].
The frequency analyses were performed to verify that all transition states have one and
only one imaginary frequency. The intrinsic reaction coordinate (IRC) calculations were
performed for key steps to confirm transition states connecting two desired minima [
35
].
The quasi-rigid-rotor harmonic oscillator was used to consider low-frequency contributions
utilizing the Shermo code [
36
,
37
]. To correct the overestimations of entropy contributions
due to using the ideal gas phase model in the Gaussian program, we applied a correction of
(n-m)*1.9 for a process from mcomponents to ncomponents according to the reference [
38
].
The non-covalent interactions were observed by mapping the independent gradient model
based on Hirshfeld partition (IGMH) surfaces using Multiwfn [
39
,
40
]. Unless otherwise
stated, all energies of stationary points are the Gibbs free energies calculated at 298.15 K,
1.0 atm and compared to
A1
or
B1
. Total energies, Cartesian coordinates of all optimized
structures and the calculation formula for enantioselectivity ratios (e.r.) are given in the
Supplementary Materials (SM).
4. Conclusions
In summary, the reaction mechanism and the origin of stereoselectivity of asymmetric
hydrogenation of oximes to hydroxylamines catalyzed by the cyclometalated iridium (III)
complexes (A1 and B1) with chiral substituted single cyclopentadienyl ligand were inves-
tigated using DFT method. The hydride transfer step is proposed to be the chirality-
determining step. The reaction could proceed via the direct hydride transfer or the
MsO−-assisted
hydride transfer. The calculated results showed that the major product
should be the hydroxylamines
S−3a
along the MsO
−
-assisted hydride transfer pathway,
and that the involvement of the MsO
−
anion be of importance in this asymmetric hydro-
genation of oximes catalyzed by
A1
and
B1
. This agrees well with experimental results
and implies that the non-covalent interactions including hydrogen bonds formed by the
protonated substrate, MsO
−
anion and Ir catalytic species could not only stabilize the
catalyst but also turn over the stereoselectivity of the reaction. This work might provide
theoretical insights for the mechanism-based development of transition-metal catalysts for
the asymmetric hydrogenation of oximes in the future.
Supplementary Materials:
The following supporting information can be downloaded at: https:
//www.mdpi.com/article/10.3390/molecules27238349/s1. Figure S1: The Gibbs free energy profiles
of asymmetric hydrogenation of Z-oximes to hydroxylamines catalyzed by Ir complex
A1
(unit:
kcal/mol). * represents chirality and
‡
means this is a transition state. Figure S2: The Gibbs
free energy profiles of asymmetric hydrogenation of Z-oximes to hydroxylamines catalyzed by Ir
complex B1
(unit: kcal/mol). * represents chirality and
‡
means this is a transition state. Figure
S3: Several possible forms of
E−2a
. Figure S4: The IGMH analysis of the transition states of the
MsO
−
-assisted hydride transfer step of the reaction by catalyst
A1
and
B1
(
δ
g
inter
= 0.008 a.u.). Figure
S5: The Gibbs free energy profiles for the hydride transfer step of the asymmetric hydrogenation of
oximes to hydroxylamines catalyzed by Ir complex
A1
using different functional (unit: kcal/mol).
* represents chirality and
‡
means this is a transition state. Table S1: The calculated absolute electronic
energies (
E, in a.u.
), thermal free energies (G, in a.u.), and relative Gibbs energies (
∆
G, in kcal/mol)
(Calculated at 298.15 K and 1 atm). Table S2: Calculated imaginary frequencies of transition states at
ω
B97X-D/BSI level. Table S3: Atomic cartesian coordinates of intermediates and transition states
(presented in Å). References [41–43] are cited in the Supplementary Materials.
Molecules 2022,27, 8349 8 of 9
Author Contributions:
The manuscript was written through contributions of all authors. M.L.
designed this work; Q.A., Y.C., R.Z. and Z.L. performed the DFT calculations; Z.L., Y.T., M.P. and M.L.
co-wrote the manuscript; M.L. supervised the whole research. All authors have read and agreed to
the published version of the manuscript.
Funding:
This research was funded by National Natural Science Foundation of China (Grant number
22073005).
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: All data is available in the main text or the Supplementary Materials.
Acknowledgments:
We thank the National Supercomputing Center in Tianjin and the High Per-
formance Computing (HPC) Platform at Beijing University of Chemical Technology (BUCT) for
providing part of the computational sources.
Conflicts of Interest: The authors declare no competing financial interests.
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