Hydroaminomethylation of styrene catalyzed by rhodium complexes containing chiral diphosphine ligands and mechanistic studies: Why is there a lack of asymmetric induction?

Article abstract of DOI:10.1021/cs400906b

Various chiral diphosphine ligands (P-P) have been introduced in the coordination sphere of neutral or cationic rhodium complexes, and the generated species catalyze efficiently the hydroaminomethylation reaction of styrene with piperidine. The diphospholane ligand family is particularly adapted to this tandem reaction leading to the branched amine with good chemo- and regioselectivity. We analyzed in detail the main reasons why the reaction proceeds with no enantioselectivity. Catalytic and HP-NMR experiments reveal the presence of the [Rh(H)(CO)₂(P-P)] species as the resting state. DFT calculations allow us to elucidate the mechanism of the hydrogenation of the branched (Z) or (E)-enamine. From the [Rh(H)(CO)(P-P)] active species, the coordination of the two enamine isomers, the hydride transfer, the H₂ activation, and then the final reductive elimination follow similar energetic pathways, explaining the lack of enantioselectivity for the present substrates. Analysis of the energy-demanding steps highlights the formation of the active species as crucial for this rate-limiting hydrogenation reaction.

Full text of DOI:10.1021/cs400906b

Research Article
pubs.acs.org/acscatalysis
Hydroaminomethylation of Styrene Catalyzed by Rhodium
Complexes Containing Chiral Diphosphine Ligands and Mechanistic
Studies: Why Is There a Lack of Asymmetric Induction?
Delphine Crozet,†,‡ Christos E. Kefalidis,§ Martine Urrutigoïty,*,†,‡ Laurent Maron,*,§
and Philippe Kalck*,†,‡
†CNRS, Laboratoire de Chimie de Coordination, composante ENSIACET, 4 allee
́
Emile Monso, BP 44362, 31030 Toulouse, Cedex
4, France
‡Universite
́
de Toulouse UPS-INPT, F-31030 Toulouse, Cedex 4, France
§LPCNO, UMR 5215, Universite
́
de Toulouse-CNRS, INSA, UPS 135 avenue de Rangueil, 31077 Toulouse Cedex 4, France
S
* Supporting Information
ABSTRACT: Various chiral diphosphine ligands (P−P) have
been introduced in the coordination sphere of neutral or
cationic rhodium complexes, and the generated species catalyze
efficiently the hydroaminomethylation reaction of styrene with
piperidine. The diphospholane ligand family is particularly
adapted to this tandem reaction leading to the branched amine
with good chemo- and regioselectivity. We analyzed in detail the
main reasons why the reaction proceeds with no enantiose-
lectivity. Catalytic and HP-NMR experiments reveal the
presence of the [Rh(H)(CO)2(P−P)] species as the resting
state. DFT calculations allow us to elucidate the mechanism of
the hydrogenation of the branched (Z) or (E)-enamine. From
the [Rh(H)(CO)(P−P)] active species, the coordination of the
two enamine isomers, the hydride transfer, the H2 activation, and then the final reductive elimination follow similar energetic
pathways, explaining the lack of enantioselectivity for the present substrates. Analysis of the energy-demanding steps highlights
the formation of the active species as crucial for this rate-limiting hydrogenation reaction.
KEYWORDS: rhodium, hydroaminomethylation, tandem reaction, chiral diphosphine ligands, DFT calculations
catalytic cycles and is thus often used for HAM. The
mechanisms of rhodium-catalyzed hydroformylation6,7 and
hydrogenation8,9 have been extensively studied, and the active
species involved in each catalytic cycle are presumed to be
different. Neutral rhodium precursors are often used in
hydroformylation, although a few studies are related to cationic
rhodium complexes,10 while cationic precursors are known to
generate active hydrogenation catalysts. Thus, the nature of the
rhodium precursor to be used is an important issue to consider.
Furthermore, to the best of our knowledge, no example of the
asymmetric version of this reaction has been reported up to
now.4,11
The present paper reports on a study on the HAM of styrene
with rhodium/chiral diphosphine (P−P) systems. Few studies
concern the specific HAM of styrene derivatives. Eilbracht et
al.12 reported the first examples, involving the rhodium
precursor [Rh(μ-Cl)(COD)]2, under high pressure and
INTRODUCTION
■
Due to their biological and medicinal properties, amines are of
great importance as building blocks or active reactants in fine
chemistry.1,2 To provide an alternative to multistep classical
organic synthetic routes, the design of efficient catalysts for
their production is of particular interest from an industrial point
of view.3 In that respect, hydroaminomethylation (HAM) is a
promising reaction to synthesize amines from alkenes, carbon
monoxide, and dihydrogen with a high atom economy. This
reaction includes the hydroformylation of an alkene, the
condensation of the produced aldehyde with a primary or a
secondary amine, and the hydrogenation of the resulting imine
or enamine to yield the final amine (Scheme 1). Recent
advances in this reaction have been the subject of several
reviews.4
As HAM is a tandem reaction,5 it is necessary to carefully
design the catalytic system in order to reach high selectivity for
the expected amines. The aim is to combine a high activity for
both the hydroformylation6,7 and hydrogenation8,9 reactions, as
well as a high selectivity in the final amines. Rhodium is able to
complete both the hydroformylation and the hydrogenation
Received: October 11, 2013
Revised: December 16, 2013
Published: December 17, 2013
© 2013 American Chemical Society
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a
Scheme 1. Hydroaminomethylation of Alkenes
a
For clarity reasons, only the linear aldehyde isomer has been represented as product of the hydroformylation step.
Scheme 2. Hydroaminomethylation of Styrene with Piperidine
temperature (110 bar, 110 °C) giving for instance with an
equivalent mixture of iPrNH2 and (iPr)2NH an iso/n ratio of
5:1 for a 96% yield. Alper et al. have tested a zwiterrionic
complex [Rh+(COD)(η6-PhBPh3)−], under milder conditions
(<80 bar, 80 °C) and obtained, still with iPrNH2, a higher
11.5:1 iso/n ratio.13 A promising rhodium−diphosphine system
was developed by Beller et al.14 that allows the formation of the
branched amine with a good iso/n ratio in the presence of
aniline. Several diphosphine ligands were used, and the couple
[Rh(COD)2]BF4/dppf (dppf: diphenylphosphinoferrocene)
shows the best results in the presence of HBF4, with a 96%
yield and an amine iso/n ratio of 88:12. Recently, introduction
of monophosphine ligands containing electron-withdrawing
substituents, particularly the tris(3,4,5-trifluorophenyl)-
phosphine, led Clarke et al. to obtain 92% of the branched
amine.15
calculations were also carried out in order to get further insights
into the mechanism of the reaction, particularly to explain the
absence of any enantioselectivity.
RESULTS AND DISCUSSION
■
Catalysis. In order to develop the asymmetric version of the
reaction, we decided to investigate the HAM of styrene
(Scheme 2), which provides a chiral branched amine. We chose
to use piperidine as the secondary amine coreactant to avoid
the imine/enamine isomerization reaction (Scheme 1).
First, we analyzed from the literature the separate perform-
ances of various rhodium−phosphine catalytic systems either
for hydroformylation or for hydrogenation of functionalized
−CC− bonds. The ligand donor/acceptor properties
required seem to be opposite to get a good activity for each
step of the tandem process. It is well-known that the more π-
acceptor the phosphine ligand is, the more efficient is the
hydroformylation reaction.6,18,19 In this case, the electron-
withdrawing character of the ligand plays a crucial role for the
system activity, since the alkene double bond coordination as
well as the migratory CO insertion are favored by an
electrophilic metal center. On the other hand, the necessary
In line with preliminary studies,16,17 we investigated the
influence of the nature of the rhodium precursor, starting either
from the cationic rhodium preformed precursors [Rh(COD)-
(P−P)]+ and [Rh(CO)2(P−P)]+ or from the neutral [Rh-
(acac)(CO)2]/diphosphine system. Combination of catalytic
experiments and high-pressure NMR studies allowed us to
identify some key species formed during the reaction. DFT
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σ-donor properties of the diphosphine ligand involved in the
carbon−carbon double bond hydrogenation are often high-
lighted.20 An electron-rich diphosphine ligand favors the
oxidative addition of H2, or the migratory insertion step
leading to the alkyl−rhodium species, which are often described
as the rate-determining steps.21 However, the exact influence of
the ligands on the whole HAM process remains difficult to
rationalize. Kinetics of each elementary step of a catalytic cycle
depends not only on a complex equilibrium between the
ligands σ-donor and π-acceptor properties but also on the
nature of the unsaturated substrate involved.
Scheme 3. Chiral Diphospholane Ligands Examined in the
Present Study
As relative rates of the successive reactions are of crucial
importance, we decided to choose efficient ligands for
hydroformylation. This catalytic reaction has to operate very
fast, in order to avoid competitive reactions such as alkene
hydrogenation. The enamine 5 (Scheme 2), obtained from the
branched aldehyde is conjugated and is expected to be more
difficult to hydrogenate with regard to the linear enamine 4.
Furthermore, in this case, the key step for enantioselectivity is
the hydrogenation of the enamine 5, which produces the
asymmetric center. The chirality of the carbon atom of the
aldehyde 3 is lost during the condensation reaction of
piperidine with the branched aldehyde but leads to the
formation of the prochiral double −CC−N− bond (Scheme
2). The design of the catalyst requires taking these points into
account. Thus, we identified some promising diphosphine
ligands (Scheme 3) for this tandem reaction,22,23 especially the
phospholane-type ligands24 such as the Ph-BPE25 and Duphos-
type ligands26,27 or the P-chirogenic ligands such as
Tangphos,28 Duanphos,29 and Binapine,30 which provide high
enantioselectivities31 for both reactions. Other diphosphine
ligands known to be efficient in hydrogenation but with σ-
donor and π-acceptor properties adapted to hydroformylation
requirements can be of interest in this reaction as well. First,
atropoisomeric ligands32 with a biphenyl backbone, such as
MeO-BIPHEP33 and Synphos,34 (ligand kindly provided by Pr
̂
Genet J.-P., from the Laboratoire Charles Friedel at Chimie
Paris Tech ENSCP) or as the binaphtyl Tol-BINAP ligand were
35
tested. The Josiphos-type ligand (R)-(S)-PPF-PXyl2 and the
foreseen as part of the most efficient ligands. Then, we
compared them with the neutral [Rh(acac)(CO)2]/Ph-BPE
system for styrene/piperidine HAM (see SI, Tables S1 and S2).
Former HAM studies with styrene and piperidine led us to
select 90 °C, 30 bar CO/H2 (1:2) as suitable temperature and
CO/H2 pressure, which are close to those classically used in
this reaction.36b As expected, an increase of either the
temperature or the H2 partial pressure favors the enamine
hydrogenation reaction and allows to get higher selectivity in
amines, but it also influences the regioselectivty, with lower iso/
n ratios (see SI, Tables S1 and S2). In the HAM of alkenes such
as oct-1-ene (see SI, Table S3) or α-methylstyrene with
piperidine (see SI, Table S4), we also observed that for long
reaction times, final product distribution was similar for both
cationic and neutral systems with the Ph-BPE ligand. For these
two latter alkenes, the hydrogenation step is not rate-
determining, since the enamine intermediates are not present
in the reaction mixture. In the case of styrene, however, the
rate-determining step is the hydrogenation of the conjugated
enamine 5, and the influence of the cationic or neutral
precursor can be precisely evaluated. The three following
systems were thus investigated: the neutral precursor [Rh-
(acac)(CO)2] combined to Ph-BPE, the cationic precursor
[Rh(CO)2{(R,R)-Ph-BPE}]BF4, and a mixture of the two
(Table 1).
ferrocenyl ligand Me-Ferrocelane were considered as well.
Comparison between Cationic and Neutral Rhodium
Systems. The importance of the nature (cationic or neutral) of
the rhodium precursor used in the HAM reaction was pointed
out in recent studies. Beller et al. first proposed the use of a
cationic rhodium precursor in combination with phosphine
ligands, in order to favor the formation of cationic species active
in hydrogenation.36 Similar observations were made by Vogt et
al.37 In a study on the oct-1-ene HAM in ionic liquids, this
research group compared the activity of systems with
[Rh(COD)2]BF4 and [Rh(COD)2]BF4/[Rh(acac)(CO)2],
with SulfoXantphos as the ligand.38 The mixed cationic/neutral
system gave a higher rate of oct-1-ene conversion than the only
[Rh(COD)2]BF4 precursor. Whereas a significant difference
between the cationic and cationic/neutral system is observed
during the early stage of the reaction (4h), the product
distribution is similar at the end (18h). The authors noted that,
as expected, the hydroformylation activity was improved since
the [Rh(acac)(CO)2] precursor is known to easily generate the
active hydroformylation species.
Taking into account these recent results, we prepared some
cationic rhodium precursors, typically [Rh(COD){(R,R)-Ph-
BPE}]BF4 (COD = 1,5-biscyclooctadiene) or [Rh-
(CO)2{(R,R)-Ph-BPE}]BF4, with Ph-BPE L1, which was
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Table 1. Hydroaminomethylation of Styrene with Piperidine Catalyzed by Rhodium Cationic and Neutral Systems
product selectivity (%)
conversion of
styrene (%)
amines
(iso/n)
branched
aldehyde
branched
enamine
hydrogenation
c
rhodium precursor
[Rh(CO)2{(R,R)-Ph-BPE}]BF4
products
1
100
100
100
19
(64:36)
12
14
8
69
54
40
traces
b
2
[Rh(acac)(CO)2]/(R,R)-Ph-BPE + [Rh(CO)2{(R,R)-Ph-BPE}]BF4
[Rh(acac)(CO)2]/(R,R)-Ph-BPE
30
(56:44)
traces
3
48
(64:36)
2.5
a
b
Conditions: styrene (10 mmol), piperidine (10 mmol); amine/alkene =1; 90 °C; 30 bar CO/H2; 45 mL THF; 7h; S/Rh = 500; L/Rh = 1.2. S/
c
Rh+ = 1000; S/Rh = 1000. Ethylbenzene and 2-phenyl-propan-1-ol
Table 2. Hydroaminomethylation of Styrene with Piperidine Catalyzed by [Rh(acac)(CO)2]−Chiral Diphosphine Systems
product selectivity (%)
conversion of styrene
(%)
amines
(iso/n)
branched
aldehyde
branched
enamine
hydrogenation
e
ligand combined with [Rh(acac)(CO)2]
products
% ee
1
2
96
89 (66:34)
48 (64: 36)
62 (74:27)
42 (62:38)
86 (70:30)
88 (75:25)
74 (75:25)
87 (73:27)
29 (46:53)
42 (48:52)
7 (43:56)
9
8
1
40
36
48
2
0.3
2.5
1
0
0
0
0
0
0
0
0
0
0
0
0
0
(R,R)-Ph-BPE L1
(R,R)-Ph-BPE L1
100
b
3
100
1
4
(R,R)-Me-Duphos L3
(R,R)-iPr-Duphos L4
(S)-Binapine L5
91
7
2.8
7.4
c
5
>99
0.5
9
6
93
91
1
7
(S,S,R,R)-Tangphos L6
(R,R,S,S)-Duanphos L7
(R)-(S)-PPF-PXyl2 L8
(R,R)-Me-Ferrocelane L9
(R)-MeO-BIPHEP L10
(R)-Synphos L11
8
14
6
2.3
0.5
8
90
7
d
9
85
6
62
10
11
12
13
>99
50
9.5
2
47
traces
0.5
d
86
d
43
3 (32:68)
11
4
80
traces
4
(R)-Tol-BINAP L12
65
5 (41:59)
85
a
Conditions: [Rh(acac)(CO)2], styrene (10 mmol), piperidine (10 mmol), S/Rh = 500, ligand/Rh = 1.2, 90 °C, 30 bar CO/H2 (1:2), 45 mL THF,
b
c
d
e
7h. 24 h. 19 h. Trace amounts of the linear isomer. Ethylbenzene and 2-phenyl-propan-1-ol.
Since styrene conversion is complete after 2 h of reaction, the
reported selectivities reflect the hydrogenation activity of the
system. The {[Rh(acac)(CO)2]/(R,R)-Ph-BPE} system is the
most efficient.
results are very similar for ligands belonging to the same
family (Figure 1). The biaryl ligands MeO-BIPHEP L10,
Synphos L11 and Tol-BINAP L12 (entries 11, 12, and 13) did
not prove to be efficient for HAM, the styrene conversion being
limited to ≈40−50%, with very low amine selectivity (<8%).
The hydroformylation step does occur but remains slow. The
enamines are the major products so that their hydrogenation is
limitative. The Josiphos type ligand (R)-(S)-PPF-PXyl2 L8
reveals to be more efficient than the biaryl ones, with a 29%
amine selectivity as well as a higher hydroformylation rate,
leading to 85% conversion and no other hydrogenation product
detection (entry 9). The selectivity in amines and enamines
obtained with the diphospholanes Ph-BPE L1, Me-Duphos L3,
and Me-Ferrocelane L9 ligands are about 40−50% after a 7 h
reaction time. Hydroformylation of styrene is almost complete.
Experiments carried out with the Ph-BPE and iPr-Duphos
ligands (entries 2, 3, and 5) show that the amine selectivity
increases with reaction time, consistent with a rate-limiting
hydrogenation step.
The best results in terms of selectivity were obtained with the
P-chirogenic Tangphos, Duanphos, and Binapine ligands
(entries 6, 7, and 8), with a conversion of styrene around
90% and amine selectivity from 74 to 88%. (Figure 1b). This
result is in phase with the performances of these ligands in
hydrogenation.31 In all cases, the final iso/n amine ratio is
affected because of the presence of amounts of non-
hydrogenated branched enamine (Table 2). Surprisingly, no
enantiomeric excess was obtained regardless of the [Rh(acac)-
(CO)2]/diphosphine system used (monitoring of the reaction
The regioselectivity of the hydroformylation reaction and the
final selectivity in amines are independently ruled by the
different reaction parameters, and these latter can have some
opposing effects (see SI, Figure S1 and Figure S2). The
presence of both carbon monoxide and amine in the reaction
mixture can influence the formation of the active species
inherent to the hydrogenation and hydroformylation reactions
and also the rate of each catalytic step. The presence of CO
slows down the hydrogenation step, particularly for the
branched enamine 5 (see SI, Figure S1a). The presence of a
large excess of amine (compared to rhodium) slows down the
rate of the hydroformylation and influences the regioselectivity
of the reaction, regardless of the cationic or neutral rhodium
precursor used (see SI, Figure S2). Finally, it is known that high
temperature or H2 partial pressure favors the formation of the
linear aldehyde instead of the branched isomer of interest in
our case, but on the other hand, it favors the enamine
hydrogenation step and also higher amine selectivity.6 These
antinomic effects are relevant to this tandem reaction and must
be adapted to each couple of substrates and to each peculiar
objective.
Performances of Rhodium−Chiral Diphosphines Sys-
tems. Thanks to these preliminary results, the performances of
a series of diphosphine ligands were investigated with the
{[Rh(acac)(CO)2]/diphosphine} system (Table 2). The
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difference in the final selectivity. Addition of molecular sieves to
favor the displacement of the enamine formation equilibrium
toward the aldehyde consumption by water adsorption, allows a
selectivity in amines up to 62% with [Rh(COD){(R,R)-Ph-
BPE}]BF4. In a toluene/isopropanol solvent system, higher
amounts of hydrogenation products 8 and 9 were observed, still
with no enhancement of the amine enantioselectivity (see SI,
Table S5).
These catalytic experiments demonstrate that the hydro-
genation of the enamines is the rate-determining step,
especially for the branched enamine isomer. The diphosphine
ligand plays a crucial role in controlling the selectivity of the
reaction. The neutral rhodium precursor is more efficient than
the cationic one, even if cationic complexes are known to be
more active for hydrogenation reactions. These results point to
that in HAM, the presence of CO and amine dramatically
influences the course of the reaction and changes the behavior
of species classically observed for both the hydroformylation
and the hydrogenation reactions. However, whatever the
conditions investigated, no enantiomeric excess could be
obtained.
Different explanations can be proposed to rationalize the
absence of enantiomeric excess: (i) a nonsuitable metal−ligand
association leading to an active species with no enantio-
discrimination, (ii) a racemization of the final product due to
the reaction conditions, or (iii) the nature of the hydrogenated
intermediates, since the enantioselection occurs during the
hydrogenation reaction. High-pressure NMR experiments were
performed to determine the most likely active species of the
hydrogenation reaction under the HAM conditions (CO/H2
pressure, amine).
High-Pressure NMR Experiments. First, the HAM
reaction was performed in THF-d8 with [Rh(CO)2{(R,R)-Ph-
BPE}]BF4 in order to analyze the crude mixture during the
1
course of the reaction. H NMR analyses at different reaction
times as well as HP-NMR experiments have shown the
presence of both (Z) and (E) isomers of the 1-(2-phenylprop-
1
1-1-enyl)piperidine 5. These latter are characterized in H
NMR by the signal of their ethylenic proton -PhMe-C
CH(NC5H10) at δ = 5.85 ppm for the (Z)-enamine and δ =
6.14 ppm for the (E)-enamine. The two isomers are
continuously present in the reaction mixture (see SI, Figures
S3 and S4). The condensation reaction between the linear
aldehyde and piperidine occurs very fast since only traces of
linear aldehyde can be detected. In the case of the reaction
between the branched aldehyde and piperidine, the (Z)-
enamine is formed faster than the (E)-one. The proportion of
the (E)-enamine progressively increases along the reaction with
time, temperature, and with the (Z)-enamine isomerization
until being the major enamine product. The simultaneous
presence of the (E)- and (Z)-enamine can be of crucial
influence on the enantioselectivity results or on the hydro-
genation activity during the reaction, since one of the two
isomers can be more quickly hydrogenated. It is well-known
that due to the steric hindrance induced at the metal center,
some diphosphine ligands can be selective for one isomer.39
According to the active species involved in the hydrogenation
catalytic cycle, the coordination of the −CC−N− double
bond can be favored for one of them due to steric hindrance,
influencing both the hydrogenation rate and the enantiose-
lectivity.
Figure 1. Conversions and selectivity obtained with rhodium
complexes bearing (a) phospholane ligands, (b) P-chirogenic
phospholane ligands, (c) biaryl diphosphine ligands.
and analysis at the end of the reaction by chiral gas
chromatography).
In order to check if it could arise from a problem during the
formation of the postulated starting precursor [RhH(CO)2(P−
P)], the latter was prepared in situ before the introduction of
the substrates (details are given in the Experimental Section.
For both HAM and reductive amination reactions, no
enantiomeric excess was obtained with either the (R,R)-Ph-
BPE or (S)-Binapine ligands. Additionally, the use of preformed
cationic precursors [Rh(COD){(R,R)-Ph-BPE}]BF4, [Rh-
(COD)(R,R,S,S)-Duanphos)]BF4, [Rh(COD)((S,S,R,R)-
Tangphos)]BF4 does not result in any enantiomeric excess
(see SI, Table S5). The influence of some parameters was
investigated in an attempt to get better insights. Thus, changing
−
−
the counterion BF4 to NTf2 in the cationic complex
In order to get a first insight into the rhodium species
[Rh(COD){(R,R)-Ph-BPE}]+ did not show any significant
involved in the reaction, high-pressure 31P and 1H NMR
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Scheme 4. Rhodium Complexes Detected during HP-NMR Experiments
Figure 2. 31P NMR of the solution of C1 with 100 equiv piperidine and styrene after 5 min under 30 bar CO/H2 (1:2), in THF-d8, at 298K.
experiments were performed under conditions close to those of
catalysis (30 bar CO/H2 (1:2), styrene/Rh = 100, piperidine/
Rh = 100) with both [Rh(acac)(CO)2]/Ph-BPE, and [Rh-
(CO)2{(R,R)-Ph-BPE}]BF4 systems.
to a fast exchange phenomenon of the two phosphorus atoms
on the NMR time scale and the two doublet of doublets of C3
at 73.7 and 80.2 ppm.16 Complex C4 is still observed, but it
rapidly disappears to lead to C2. The signals of some other
unidentified species, probably related to the fast reactivity with
styrene under HP-NMR conditions, were also observed (Figure
3b). Studies are under investigation in order to assign the
signals of these minor species.
These high-pressure NMR experiments showed that what-
ever the precursor, two common species are formed at the very
beginning of the reaction (30 bar CO/H2 (1:2), 298K): the
monohydride complex C2 and the pentacoordinated cationic
complex C3 in different proportions. Complexes C2 and C3
were obtained with a 40:60 ratio starting from the [Rh(acac)-
(CO)2] precursor and with a 5:95 ratio from [Rh(CO)2{(R,R)-
Ph-BPE}]BF4 (Figure 4). We believe that the difference of
activity between the cationic and neutral systems could be
related to their ability to generate the [RhH(CO)2(P−P)]
species, which appears as the main key species of the HAM
reaction.
Previous studies16,17 have shown that under these conditions,
the cationic complex [Rh(CO)2{(R,R)-Ph-BPE}]BF4 C1 reacts
immediately to give small amounts of the neutral monohydride
species [RhH(CO)2{(R,R)-Ph-BPE}] C2 and the amino
pentacoordinated complex [Rh(NHC5H10)(CO)2{(R,R)-Ph-
BPE}]BF4 C3 formed due to the large excess of amine
(Scheme 4 and Figure 2).
31P NMR experiments performed from [Rh(acac)(CO)2]
without syngas pressure (Figure 3a) showed [Rh(acac){(R,R)-
Ph-BPE}] C4 as the major species,16 characterized by a doublet
at 105.7 ppm (1JRh−P = 201 Hz) as well as the presence of the
cationic complex [Rh(CO)2(NHC5H10){(R,R)-Ph-BPE}]+ C3.
In this case, the acetylacetonato entity plays the role of
counteranion. The formation of rhodium cationic species with
diphosphine ligands and acac− as counterion was already
described.40,41 Attempts to isolate the complex [Rh-
(CO)2(NHC5H10){(R,R)-Ph-BPE}]acac C3 were unsuccessful,
since the stabilization of the rhodium cation by acac− is
This hypothesis is reinforced by results of a reported study
describing the use of the [RhH(CO)2(Chiraphos)] complex in
the enone hydrogenation reaction.42 In this study, the complex
is prepared under hydroformylation conditions ([Rh(acac)-
(CO)2]/Chiraphos, 80 bar CO/H2, 2h, 60 °C) before
16
−
somewhat less efficient than by BF4 . 31P NMR analyses
under 30 bar CO/H2 (1:2) revealed after 15 min the presence
of the doublet of the monohydride species C2 at 97.9 ppm due
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Figure 3. 31P NMR spectra of a solution of [Rh(acac)(CO)2]/(R,R)-Ph-BPE in the presence of piperidine (100 equiv) and styrene (100 equiv) in
THF-d8 at 298K (a) without pressure, under argon atmosphere (b) under 30 bar CO/H2 (1:2) after 15 min.
Figure 4. Rhodium species observed after 15 min under 30 bar CO/H2 (1:2), at 25 °C, THF-d8, in the presence of piperidine (100 equiv) and
styrene (100 equiv).
introducing the enone and performing its hydrogenation under
80 bar H2. The key point is that under similar preformation
conditions, the [Rh(COD)2]BF4/Chiraphos system did not
catalyze the hydrogenation of the enone substrate, whereas the
[Rh(acac)(CO)2]/Chiraphos system was active. Our observa-
tions are consistent with these results. In the case of the
cationic system, the difference between this latter study and our
own work is the presence of the amine in the mixture. We
recently showed that under CO/H2 pressure, [Rh(COD)2]-
BF4/P−P or [Rh(COD)(P−P)]BF4 lead only to the formation
of the cationic complex [Rh(CO)2(P−P)]+, and that the
presence of a base such as THF or an amine allows us to
generate the [RhH(CO)2(P−P)] species.16
order to get insight on the mechanism of the reaction and to
explain the absence of enantioselectivity.
Computational Study. The purpose of the computational
study is to give insights on two critical points of the present
experimental work. First, we investigated the relative high
temperature needed in order for the catalysis to proceed as well
as the observed lack of enantioselectivity of the hydrogenation
step. In this respect, free energy profiles were computed using
DFT for the hydrogenation of the 1-(2-phenylprop-1-enyl)-
piperidine (5). The rhodium complexes were modeled using
Me-BPE as ligand rather than Ph-BPE. This modeling was
shown to be adequate in a previous study involving similar
species16 as the computed free energies were found to be
consistent with the two systems (full experimental and reduced
one).
All these observations led us to identifiy the [RhH(CO)2(P−
P)] complex C2 as the most likely precursor for the active
species of the hydrogenation, so that it was chosen as the
starting complex in the following DFT studies performed in
First, the dissociation of one carbonyl group from the initial
complex [RhH(CO)2{(R,R)-Me-BPE}], E1, yields the “active
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Figure 5. Optimized geometries and comparisons between Gibbs free energies for the isomers E2 vs E2′ and E3 vs Z3. Most of the hydrogen atoms
were omitted for clarity.
Figure 6. Possible Gibbs free energy (kcal·mol−1) profiles for the hydrogenation of (E)-enamine catalyzed by E2.
catalyst” [RhH(CO){(R,R)-Me-BPE}] E2, which adopts a
square planar geometry (Figure 5). The relatively high
endoergicity of this dissociation (18.7 kcal·mol−1), is the result
of the loss of a strong interaction between the metal and the
good σ-donor and π-acceptor CO ligand. Another isomer, E2′,
was also found as local minimum on the potential energy
surface but 18.6 kcal.mol−1 higher in energy than the global
minimum E2. The former adopts a distorted trigonal pyramidal
geometry, as is shown in Figure 5. However, the estimated high
energy difference between E2 and E2′ indicates that the
isomerization E2 → E2′ is thermodynamically unfavorable. The
formation of the intermediate E2 (already proposed in the
literature)6 is thus thermodynamically disfavored at room
temperature. This correlates with the high temperature needed
for the reaction to proceed so that one key step for
hydrogenation is already the formation of the active species.
Therefore, E1 can be considered as a dormant species and
could represent the catalyst resting state.
The unsaturated 16e− monomeric species E2 could react
with the enamine to yield the catalytically competent 18e−
species formulated as [Rh(H)(CO){(R,R)-Me-BPE}(η2-enam-
ine)]. Considering the stereochemistry of the full rhodium−
enamine complexes along with the chirality induced by the
diphosphine ligand, it results in the hypothetical existence of
four different isomers for both (E)- and (Z)-enamine (see SI,
Figure S5). For the former, the most stable complex is E3 with
the enamine occupying the equatorial position of the distorted
trigonal bipyramid along with the BPE ligand, while the
remaining axial positions are occupied by a carbonyl and a
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Figure 7. Possible Gibbs free energy (kcal·mol−1) profiles for the hydrogenation of (Z)-enamine catalyzed by E2.
hydride. The same also holds true for complex Z3 for the
rhodium−(Z)-enamine complex (Figure 5).
used in the latter studies (triphenylphosphine) rather than the
rigid chelating one, which is used in the present work. The
following process in the reaction sequence corresponds to the
coordination of H2 to form a dihydrogen intermediate and the
subsequent oxidative addition of the latter to form the
dihydrido species. The coordination of H2 is endoergic for
both pathways (10.9 and 18.4 kcal·mol−1, respectively, due to
entropy loss upon coordination) while the oxidative addition
corresponds to a barrierless process. The corresponding
complexes adopt an octahedral geometry, with the hydride
and the carbonyl group lying in the axial positions. It should be
noted that the oxidative addition of dihydrogen is an
endergonic process in both cases (3.7 and 9.3 kcal·mol−1,
respectively), being in line with a previous joined experimental/
theoretical study on catalytic hydrogenation of enamides using
cationic complexes of rhodium.43 Finally, in the last step,
migration of a hydride to the alkylamine takes place, allowing
the formation of the S-product along with catalyst regeneration.
From each of the two intermediates E6a and E6b, there are two
possibilities for the final hydrogenation of the alkylamine, as
shown in the Gibbs free energy reaction profile in Figure 6.
Indeed, from intermediate E6a the reductive elimination of the
Apart from these configurations, we also examined the other
possibility of coordination isomers. For instance, a distorted
tetrahedral geometry is possible. However, energetically all the
other configurations lie above the most stable intermediate E3
or Z3 respectively (see SI, Figure S5). It should be noticed that
profiles involving slightly higher in energy intermediates than
E3 and Z3 were computed and were found not to be kinetically
competitive with those described hereafter (see SI). Thus, the
latter complexes (E3 and Z3) will be the references throughout
this study.
All the considered free energy pathways for the hydro-
genation of (E)-enamine catalyzed by the E2 isomer are
depicted schematically in Figure 6.
Coordination of the enamine to the catalytically active
complex E2 results in the formation of intermediate E3 and is
an exoergic process (−5.4 kcal·mol−1). From intermediate E3,
insertion of the enamine to Rh−H bond can be achieved
through two different cyclic four-membered transition states,
namely, TSE3‑E4a and TSE3‑E4b, yielding intermediate E4a and
E4b, respectively. The corresponding activation barriers for the
insertion process are 17.3 and 21.2 kcal·mol−1, respectively.
The energy difference of almost 4.0 kcal·mol−1 between the
activation barriers highlights the kinetic preference for the
hydride (denoted as H1) to migrate at the carbon (denoted as
Ca) bearing the cyclic amine group (Figure 6). The associated
intermediates (according to IRC calculations) of this process lie
at 1.5 and 2.3 kcal·mol−1 with respect to the initial complex E2,
leading to an endoergic step by 6.9 and 7.7 kcal·mol−1,
respectively. Intermediate E4a adopts geometry closer to a
tetrahedral one, in contrast with E4b, which adopts an almost
square planar geometry. It should be noted that all attempts to
locate an intermediate in which a secondary interaction
between the nitrogen and the rhodium exists failed, ruling
out any possible existence of such a species on the potential
energy surface, in contrast to related computational studies.15
This can be attributed to the different type of phosphine that is
final product can be achieved either via TSE6a‑E2′ or TSE6a‑E2
,
overcoming an activation barrier of 15.2 or 13.2 kcal·mol−1,
respectively. The first case corresponds to the migration of the
axial hydride (H2 in Figure 6), while in the second one,
corresponds to the migration of the equatorial hydride (H3) to
the alkylamine group. The energy difference between these
transition states is 2.0 kcal·mol−1 in favor of TSE6a‑E2. While the
outcome of TSE6a‑E2 is directly E2 along with the formation of
the S-product, in contrast TSE6a‑E2′ gives the relatively unstable
intermediate E2′ and S-product, which upon isomerization
forms the active catalyst E2. A similar situation applies in the
case of intermediate E6b. The corresponding activation barriers
are lower than in previous case by almost 11 kcal·mol−1. This
can be explained by the energy difference between
intermediates E6a and E6b (6.4 kcal·mol−1 in favor of E6a)
and the kinetic preference for the migration of hydride to the
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Figure 8. Comparison between the two most favorable pathways for (E)- and (Z)-enamine cases (in kcal·mol−1).
Ca over Cb (3.9 kcal·mol−1, leading to a difference of 10.3 kcal·
mol−1). Overall, the catalytic reaction is found to be exoergic by
−12.5 kcal·mol−1.
The same mechanistic scenario applies in the case of Z-
enamine, as depicted in Figure 7, and is very similar to the (E)-
case.
observations and taking into account the DFT error, which is
in general in the range of 2 kcal·mol−1, all profiles can be
considered as equivalent in energy, and these considerations
explain the lack of enantiomeric excess observed experimentally
when using this particular catalytic system.
The only difference occurs in the reductive elimination step.
Indeed, the energetic stability of the two intermediates (Z6a
and Z6b) matches the energy ordering of the four
corresponding transition states (no energetic crossing is
observed). Thus, the general energetic trend is maintained for
all the stationary points of the pathways. In addition, it is worth
noting that the energy gap between the two transition states of
the insertion step decreases substantially with respect to the
analogues in the (E)-enamine case (1.1 vs 3.9 kcal·mol−1).
Finally, while the pathway corresponding to (E)-enamine leads
to the (S)-product, the (Z)-enamine one gives the (R)-product.
In order to shed light to the experimental observed lack of
enantioselectivity of the reaction when a racemic mixture of
enamine is used, a comparison between the two most
energetically favorable corresponding pathways is required
and displayed in Figure 8.
It should be noted that in order to make the direct
comparison between the two isomers, we had to shift all the
values of the (E)-enamine pathway by 0.3 kcal·mol−1. The latter
value corresponds to the energy difference between the two
organic isomers, in favor of (Z)-enamine. Perusal of Figure 8
reveals that both pathways almost overlap. First, the highest
activation barrier for (E)-enamine pathway is 17.3 kcal·mol−1
being very close to the analogous case for (Z)-enamine, with
the latter being 17.6 kcal·mol−1, both corresponding to the
hydride migration. This is the rate-limiting step of the
mechanism, as already pointed out in previous theoretical
works on hydride transfer on alkenes.44 More importantly for
the catalytic activity, the highest point in both pathways
corresponds to the final reductive elimination transition state,
being identical in terms of energy (∼18.8 kcal·mol−1 with
respect to E2). It should be noted that reaction profiles starting
from other enamine adducts (different enantiofaces coordi-
nated, namely E3-rot-ef and Z3-ef, see SI, Figures S6 and S7)
involve much higher relative energy for the reductive
elimination step (more than 22.7 kcal·mol−1) than those
reported above and are thus not competitive. In terms of
thermodynamics, both pathways have overall the same energy
(−12.2 and −12.8 kcal·mol−1 for (E)- and (Z)-enamine case,
respectively). On the basis of the aforesaid theoretical
CONCLUSION
■
In this study, we have analyzed the rhodium-catalyzed HAM
reaction involving mainly styrene and piperidine. Among the
considered chiral diphosphine ligands, the diphospholane
ligands allow reaching a higher reaction rate and selectivity in
1-(2-phenylpropyl)piperidine. The reactivity of both neutral
[Rh(acac)(CO)2]/diphosphine and cationic [Rh(CO)2(P−
P)]+ systems have been studied. The catalytic results and HP
NMR data show that although the neutral complex
[RhHCO)2(P−P)], considered to be the precursor of the
active species for both hydroformylation and hydrogenation
reactions, can be formed from either the neutral or cationic
precursors, it is the neutral [Rh(acac)(CO)2]/diphosphine
system that is the more efficient, probably due to a higher
concentration in the active species. This result highlights that
under HAM conditions (presence of CO/H2 and amine), the
catalytic activity of a given system cannot be easily anticipated
only on the basis of the intrinsic activity for hydroformylation
and hydrogenation.
A surprising result of this study is the complete lack of
enantioselectivity, whatever the {rhodium−chiral ligand}
system involved. Catalytic experiments have shown that a
mixture of (Z) and (E)-enamines is produced during the one-
pot reaction. DFT calculations revealed that the formation of
the [RhHCO(P−P)] active species from the [RhH(CO)2(P−
P)] precursor is energy demanding (18.7 kcal·mol−1). From
this active species, the rate-determining-step of the HAM is the
migration of a hydride to the alkylamine ligand. The pathways
for the (E)- and (Z)-enamine cases have overall the same
energy (−12.2 and −12.8 kcal·mol−1), explaining the lack of
enantioselectivity in the present case. Hydroaminomethylation
is a complex tandem reaction, and this study constitutes the
first attempt of an asymmetric one-pot reported version of this
reaction. Although our results show the absence of
enantioselectivity for a given system, we believe that additional
efforts should be devoted. As far as the catalytic system is
concerned, the use of larger bite-angle diphosphines might
orientate the enamine coordination mode and change the
energy difference between the transitions states. Another
couple of amine/alkene starting substrates might also favor
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the formation of only one enamine isomer and its coordination
in an enantiofacial discrimination mode. This study shed light
on catalytic species involved in the reaction and opens new
perspectives for further investigations on this challenging
reaction.
ASSOCIATED CONTENT
* Supporting Information
Text, tables for experimental details, and DFT calculations data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Authors
*E-mail: philippe.kalck@ensiacet.fr.
*E-mail: martine.urrutigoity@ensiacet.fr.
*E-mail: laurent.maron@irsamc.ups-tlse.fr.
EXPERIMENTAL SECTION
■
■
General Considerations. All NMR spectra data were
recorded on Bruker DRX 300 or Avance 300−500
spectrometers with TMS as internal reference for H and 13C,
1
85% phosphoric acid as external reference for 31P. Chemical
shifts are reported in ppm, and coupling constants (J) are given
in Hertz. All experiments were carried out under argon using
Schlenk techniques or glovebox. Solvents were obtained from a
Solvent Purification System (MB SPS-800) or were previously
distilled. Rhodium complexes were prepared according to
previously described procedures.16,17 Products were charac-
terized by gas chromatography (GC, chiral GC, and GC-MS)
and NMR (see SI).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
L.M. is a member of the Institut Universitaire de France.
CALMIP and CINES are acknowledged for generously granting
computing time. L.M. would like to thank the Humboldt
Foundation. The authors thank CNRS and UPS for the
financial support of this work. Pr. Carmen Claver and her group
are gratefully acknowledged for the opportunity given to
perform some HP NMR experiments and for fruitful
discussions.
General Procedure for Hydroaminomethylation Ex-
periments. All experiments were performed following the
same procedure in a 90 mL stainless-steel autoclave purchased
from TOP Industrie. The gas mixture was previously prepared
in the desired pCO/pH2 ratio. The alkene (10 mmol) and the
amine (10 mmol) were introduced in the reactor, followed by
the rhodium complex and the ligand solubilized in the solvent.
The closed reactor was then purged three times with the CO/
H2 gas mixture. The reaction mixture was placed under 10 bar
CO/H2 and heated until the desired temperature with a 1000
rpm stirring rate. The pressure was then completed until 30 bar
CO/H2. The experiment was running under a continuous feed
of gas mixture. Samples were taken during the experiment in
order to follow the reaction course by gas chromatography (see
SI) or NMR. The autoclave was cooled to room temperature
and then slowly depressurized. The crude mixture was analyzed
by gas chromatography.
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NOTE ADDED AFTER ASAP PUBLICATION
■
This paper was published on the Web on January 6, 2014. The
Abstract graphic was revised, and minor changes made to the
footnotes of Table 1, and the paper was reposted on January 9,
2014. An error in the title of the paper was discovered, and the
paper was reposted on January 13, 2014.
447
dx.doi.org/10.1021/cs400906b | ACS Catal. 2014, 4, 435−447