Extensive re-investigations of pressure effects in rhodium-catalyzed asymmetric hydrogenations

Article abstract of DOI:10.1002/adsc.200700445

The catalytic hydrogenation of three prochiral substrates methyl Z-α-acetamidocinnamate (MAC), methyl 2-acetamidoacrylate (M-Acrylate) and ethyl 4-methyl-3-acetamido-2-propanoate (EEMAP) with rhodium precursors complexed with chiral diphosphines is report

Full text of DOI:10.1002/adsc.200700445

FULL PAPERS
DOI: 10.1002/adsc.200700445
Extensive Re-Investigations of Pressure Effects in Rhodium-
Catalyzed Asymmetric Hydrogenations
Mohamad Alame,a Nathalie Pestre,a and Claude de Bellefona,*
a
Laboratoire de GØnie des ProcØdØs Catalytiques, CNRS-CPE Lyon, 69616 Villeurbanne, France
Fax : (+33)-4-7243-1754; e-mail: claude.debellefon@lgpc.cpe.fr
Received: September 7, 2007; Published online: March 20, 2008
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: The catalytic hydrogenation of three pro- sure effects on ee prevails and that the hydrogen
chiral substrates methyl Z-a-acetamidocinnamate pressure effect on enantioslectivity is not an isolated
(MAC), methyl 2-acetamidoacrylate (M-Acrylate) phenomenon since more than 33% of the reaction
and ethyl 4-methyl-3-acetamido-2-propanoate (E- systems studied are strongly affected. In some case,
EMAP) with rhodium precursors complexed with the enantioselectivity can be improved up to 97%
chiral diphosphines is reported at 1–30 bar hydrogen just by applying a higher hydrogen pressure. Exten-
pressure. A library of 56 chiral diphosphines, includ- sion of these conclusions to other non-chiral reagents
ing 23 BINAP derivatives, 7 JOSIPHOS, 5 BIPHEP, is proposed.
3 DUPHOS derivatives, and 18 other ligands, was
used. While it was generally accepted that high hy-
drogen pressure would result in lower ees, it is now Keywords: asymmetric catalysis; hydrogenation; li-
demonstrated on a statistical basis that an equivalent brary of ligands; pressure effect; rhodium; statistical
distribution between beneficial and detrimental pres- analysis
Introduction
have tried to systematically assess the generality of
hydrogen pressure effect on ee.
Hydrogen pressure effects in asymmetric hydrogena-
Why is this so? One reason could be that Halpern
tions have been known for many years. Knowles had used the particular reaction system Rh/DIPAMP/
reported the first evidence for such effects with a Rh/ MAC, for which 31P NMR spectroscopy is very infor-
DIPAMP catalyst,[1] and the mechanism was studied mative but which gives upon pressure increase a detri-
in detail by Brown and Halpern.[2] Further examples mental effect on the enantioselectivity. It may be that
have been published for Ru/BINAP-catalyzed asym- this particular situation has resulted in a lack of moti-
metric hydrogenations by Noyori,[3] and for heteroge- vation for such investigations. With time and with the
nous catalysis.[4] Later, Halpern has provided a quanti- growing numbers of reports on detrimental[4b,6] rather
tative explanation for the influence of hydrogen on than beneficial[2,3] pressure effects on ee the belief has
the enantioselectivity.[5] The oxidative addition of H2
at the rhodium centre, as the last rate-determining
step, is much faster for one enantiomer than for the
other, which leads to enantioselection (Scheme 1).
Since these early works, many examples of hydrogen
pressure effects have been reported.[6]
The early work of Brown and Halpern has also
lead to an abundant literature in the field of asym-
metric hydrogenations, including mechanistic,[7] kinet-
ic,[8] theoretical calculations,[9] and chemical engineer-
ing aspects.[10] Interestingly, while many of these re-
searches have considerably improved our understand-
ing of the mechanism at the molecular level, none
Scheme 1. Simplified mechanism for the asymmetric hydro-
genation of prochiral olefins with rhodium-based catalysts.
898
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 898 – 908

Pressure Effects in Rhodium-Catalyzed Asymmetric Hydrogenations
FULL PAPERS
arisen that, in general, high hydrogen pressures would
lead to bad ees. In this work, it is intended to shed
some light on hydrogen pressure effects in asymmet-
ric hydrogenations, albeit not with respect to the
mechanism and the origin of enantioselection, but to
answer the two basic questions: 1) Do hydrogen pres-
sure effects on enantioselectivity apply to a large di-
versity of asymmetric catalysts or to a very restricted
class of exotic ligands? 2) For what reasons do Rh/ (Scheme 1). The hydrogen pressure effect on ee is
chiral diphsophine-catalyzed asymmetric hydrogena- thus given by the sign of the very simple term a. We
tions generally exhibit detrimental pressure effects?
know that the kR/kS ratio may vary from ca. 500
which would give an ee of 99% (R) down to 0.002
[99% (S)] with the non-desired situation kR/kSffi1
Results and Discussion
leading to very poor enantioselection. The ratio kꢀ1R/
kꢀ1S may thus take a large range of numerical values,
Let us first have a look at the proposed mechanism from 500 to 0.002 and the same holds for k2R/k2S.[9c]
and the underlying kinetic laws. At first sight, the Because these ratios concern two different elementa-
mechanism of Scheme 1 may appear too simple, that ry processes, that is, de-coordination of the pro-chiral
is, the hydrogen addition step and other subsequent substrate and oxidative addition of hydrogen, respec-
in-sphere insertions and eliminations being not de- tively, the term a may, a priori, take any value from
tailed. From a global kinetic point of view this is of ca. ꢀ500 to +500. In other words, this term should
no importance since the derived kinetic laws, obtained statistically give an equivalent repartition of negative
using the steady-state approximation, are functions of and positive signs, that is, an equivalent distribution
substrate/reagent and total Rh concentrations only of beneficial (+ sign) and detrimental (ꢀ sign) pres-
and not of untraceable catalytic species. To proceed sure effects. Conversely, in the case where a non-
further, we must accept here the assumptions of the equivalent distribution of hydrogen pressure effect on
steady-state approximation. The risk of drawing erro- ee is found experimentally, it may mean that an intrin-
neous conclusions is, however, small since the steady- sic relation exists between the two elementary steps
state assumption was the basis of Halpernꢁs work and (ꢀ1) and (2) which may be a key to predictive struc-
others and is well verified for Rh-catalyzed asymmet- ture-enantioselectivity tools.
ric hydrogenations,[6,8] as long as the full derived rate
Let us now analyze literature data on asymmetric
laws are considered, without simplification.[5b] Also, hydrogenations with Rh/asymmetric diphosphine cat-
the double cycle of Scheme 1 is complicated by the alysts likely to follow the mechanism of Scheme 1.
fact that intermediates IR and IS can undergo inter- This analysis, performed on more than 45 publica-
conversion through a direct intramolecular path.[11] tions, is detailed in the Supporting Information.[13]
Last but not least, it is also known that oxidative ad- The ee variation was lumped into the criterion Dee,
dition of hydrogen can occur before substrate bind- that is, the difference between ee obtained at high
ing.[12] This “hydride route” mechanism is sometimes and low pressure (Dee=jeejHPꢀjeejLP). Over 35
evoked to account for hydrogen pressure effect, but it chiral diphosphines and 40 substrates forming 110 re-
cannot lead to a pressure effect on ee.[8b,10c] Thus, the action systems, respectively, 46%, 22% and 32% have
simplified mechanism as depicted in Scheme 1 is just been found to have a detrimental (Dee<ꢀ4), benefi-
useful to understand how the hydrogen pressure cial (Dee>4) and negligible (4ꢁDeeꢁꢀ4) pressure
effect translates in terms of mathematics and does not effect on ee. Furthermore, 47% of the systems exhib-
reflect the complexity of the mechanisms of asymmet- its a Dee above 10% (Figure 1).
ric hydrogenation. A detailed overview on the mecha-
That only 32% of the systems display no pressure
nism has been published recently.[7] Now, considering effects on enantioselectivity answers the first ques-
the underlying rate laws for both enantiomers, it ap- tion: the hydrogen pressure effect on enantioselectivi-
pears that negative and positive pressure effects are ty does indeed apply to most asymmetric hydrogena-
linked to the sign of the derivative of ee with hydro- tion catalysts. The dramatic difference between detri-
gen concentration [Eq. (1)]. The mathematical devel- mental and beneficial hydrogen pressure effects asks,
opment is detailed in the Experimental Section. A however, for further questioning: either the base of
similar treatment as applied to the enantiomer ratio observation composed of the 110 systems is statistical-
R/S leads obviously to the same result.
ly too small or an unknown phenomenon operates
In Eq. (1), kꢀ1R (respectively kꢀ1S) are the constants that mostly leads to negative Dee (see discussion
of the elementary steps of substrate de-coordination above). In fact, almost half of the substrates, that is,
and k2R (respectively k2S) are the constants of the ele- 52 systems out of the 110 reported, are acetamidoci-
mentary steps of oxidative addition of hydrogen namic acid derivatives, which may result in a statisti-
Adv. Synth. Catal. 2008, 350, 898 – 908
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
899

Mohamad Alame et al.
FULL PAPERS
ined the occurrence of beneficial and detrimental hy-
drogen pressure effects in the asymmetric hydrogena-
tion of pro-chiral olefins catalyzed by Rh/chiral di-
phosphine complexes. A library of chiral diphosphines
was selected to ensure no statistical bias. It should be
as diverse as possible while some stepwise structural
changes can be of interest to assess any possible struc-
ture-ee relationships. It should also be as large as pos-
sible in terms of statistics while, from a practical point
of view, the size of the library is restricted by the
availability of the ligands. Thus, 56 chiral diphos-
phines have been collected or synthesized (Figure 2
and Table 1), of which 35 are commercially available.
The library features 23 BINAP derivatives (stepwise
changes), 7 JOSIPHOS, 5 BIPHEP, 3 DUPHOS de-
rivatives, and 18 other ligands. The synthesis of the
BINAP derivatives are published elsewhere.[14]
Figure 1. Distribution of ee variation (Dee=jeeHighPressure jꢀ
jeeLowPressure j) for the 75/110 catalytic systems displaying
jDeej>4 (literature data). The 35 systems displaying negli-
gible pressure effects (jDeej<4) are not shown.
In preliminary studies, 18 of the commercially avail-
able ligands [i.e., (R,R)-DIPAMP, 1, 15, 30, 31, 33, 34,
38, 40, 41, 42, 45, 47, 48, 49, 51, 52, 55] were investi-
gated over the largest range of hydrogen pressure
cal bias, substrate topologies being unequally repre- available with our experimental set-up (1–40 bar) and
sented. for the hydrogenation of only one substrate, methyl
We thus have embarked on a project to verify the Z-a-acetamidocinnamate (MAC). Selected results are
literature survey. On a statistical basis, we have exam- sketched in Table 2. As a general trend, a detrimental
Table 1. Numbering and short names of the 56 chiral diphosphines pictured in Figure 2.[a]
Number
Name
Number
Name
(R,S)-Xylyl-Ph-JOSIPHOS
1
(R)-BINAP
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
ACHTREUNG
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
(R)-5,5’-Br2-BINAP
(R)-5,5’-CN2-BINAP
(R)-5,5’-(CH2NH2)2-BINAP
(R)-5,5’-(C8F17)2-BINAP
(R)-5,5’-Me2-BINAP
(R)-5,5’-Ph2-BINAP
(R)-5,5’-(COOH)2-BINAP
(R)-4,4’-Br2-BINAP
(R)-4,4’-CN2-BINAP
(R)-4,4’-(CH2NH2)2-BINAP
(R)-4,4’-(C10F21)2-BINAP
(R)-4,4’-Me2-BINAP
(R)-4,4’-Ph2-BINAP
(R)-Tol-BINAP
(R)-(S)-t-Bu-Ph-JOSIPHOS
(R)-(S)-JOSIPHOS
(R)-(S)-Cy-p-OMe-Xylyl-JOSIPHOS
(R)-(S)-Ph-Cy-JOSIPHOS
(R)-(S)-Cy-Cy-JOSIPHOS
(R)-(S)-P(t-Bu)3-Cy-JOSIPHOS
G
(R)-Ph-CTH-P-PHOS
(R)-Xylyl-CTH-P-PHOS
(R)-PHANPHOS
CTH-(S)-3,5-Xylyl-PHANPHOS
AHCTREUNG
AHCTREUNG
A
ACHTREUNG
AHCTREUNG
(R)-p-OMe-BINAP
(R)-p-OH-BINAP
ACHTREUNG
AHCTREUNG
(R)-p-NMe2-BINAP
ACHTREUNG
(R)-p-Oꢀ-BINAP
+
(R)-p-NMe3 -BINAP
ACHTREUNG
(R)-6,6’-(C12H25)2-p-OH-BINAP
(R)-6,6’-(C12H25)2-p-Oꢀ-BINAP
(R)-3,5-Xylyl-BINAP
(R)-Cy-SONIPHOS
(R)-C3-TUNEPHOS
(R)-DifluoroPHOS
ACHTREUNG
AHCTREUNG
AHCTREUNG
(R)-BINAPHANE
(S)-BINAPINE
(R)-SYNPHOS
(R)-Cl-OMe-BIPHEP
ACHTREUNG
ACHTREUNG
[a]
Full names and CAS numbers are given in the Supplementary Informations.
900
asc.wiley-vch.de
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 898 – 908

Pressure Effects in Rhodium-Catalyzed Asymmetric Hydrogenations
FULL PAPERS
Figure 2. The library of 56 chiral diphosphines used in this work.
effect is observed, the extreme situation being en- 42) give the same major enantiomer (R) as report-
countered with JOSIPHOS (31) for which a dramatic
decrease of ee from 92% to 8% is observed
(Figure 3).
ACHTREUNG
This confirms that a risk of a statistical bias exists docinnamate (MAC), methyl 2-acetamidoacrylate (M-
when the size of the chiral diphosphine library is too Acrylate) and ethyl 4-methyl-3-acetamido-2-propa-
small (ca. 30 references). It is also quite clear that noate (E-EMAP) were used. The influence of hydro-
substrates derived from acetamidocinamic acid tend gen pressure on the enantioselectivity was evaluated
to favour detrimental hydrogen pressure effects. Ben- for the library of 56 chiral diphosphines and with the
eficial pressure effects that improve the ee from a rhodium precursor [Rh
fairly good (>80%) up to very high ees (97%) have of the 56”3=168 ligand/substrate systems was inves-
been observed for (S,S)-i-Pr-DUPHOS (42) or (S,S)-i- tigated under two different pressures (5 and 30 bar),
(COD)2]BF4 (Scheme 2). Each
AHCTREUNG
Pr-CNRPHOS (Table 2, entries 7 and 8). This obser- each experiment being performed twice to ensure a
vation outlines the practical impact of the pressure good reproducibility. The results of these ca. 700 ex-
effect. Note that all DUPHOS derivatives (40, 41 and periments are given in Table 3. For each data set, the
Adv. Synth. Catal. 2008, 350, 898 – 908
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
901

Mohamad Alame et al.
FULL PAPERS
Figure 2 (cont.)
ee variation upon pressure increase, that is, Dee being observed for 5,5’-(CN)2-BINAP (3)/E-EMAP
(Dee=jeej30barꢀjeej5bar) was computed and catego- and JOSIPHOS (31)/MAC, respectively.
rized. Only 25 catalysts exhibit significant, that is,
Out of the 168 catalyst/substrate systems investigat-
jDeejꢂ15%, variations and very few systems exhibit ed, 13 display very low ee values (ꢀ4 <ee<4) and
large Dee, the highest values (+44% and ꢀ33%) are not used for the statistical analysis. This threshold
Table 2. Chiral diphosphines leading to significant hydrogen pressure effects for asymmetric hydrogenation of MAC with a
[Rh(COD)2]BF4 precursor and comparison with literature data.
N
Entry
Diphosphine
(R,R)-DIPAMP
Number
eeLP
eeHP
Dee
Ref.
1a
1b
2
G
-
-
ꢀ961
ꢀ961
921
901
921
951
971
>991
822
ꢀ6540
ꢀ7410
840
4241
5441
9020
9230
8815
9720
90100
ꢀ3140
ꢀ2210
ꢀ8440
ꢀ4840
ꢀ3840
ꢀ520
This work
[5]
This work
This work
This work
[6a]
This work
This work
This work
[6b]
[a]
-
(R)-(S)-JOSIPHOS
(R,R)-Me-BPE
(S,S)-BPPM
31
43
49
-
40
41
42
-74
3
R
4a
4b
5
6
7
U
[b]
-
N
ꢀ530
R
ꢀ1115
+1518
+1695
ACHTREUNG
8
ACHTREUNG
5
[a]
[Rh
[Rh
[Rh
U
G
ACHTREUNG
[b]
[c]
ACHTREUNG
ACHTREUNG
902
asc.wiley-vch.de
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 898 – 908

Pressure Effects in Rhodium-Catalyzed Asymmetric Hydrogenations
FULL PAPERS
Figure 4. Distribution of Dee for the 82 catalytic systems
(over 155) displaying jDeej> 4 within a restricted pressure
range (5–30 bar). The 73 systems (i.e., 47%) with negligible
pressure effects are not shown.
47% of catalytic systems as observed in the literature
survey (see Figure 1), but still significant.
The lower number of catalytic systems exhibiting a
large Dee in this work is likely due to the restricted
pressure range used here (5 to 30 bar) compared to
literature data (1 to 100 bar). It is obvious than the
larger the pressure range, the higher Dee could be.
Some of the results depicted in Table 2 have been
also been investigated at 1 bar hydrogen pressure and
the results confirm this view. For example, 83% ee is
observed for the system Xylyl-BINAP(23)/E-EMAP
at 1 bar which gives a Dee of ꢀ55%. Concerning the
second question about the distribution of beneficial
and detrimental effects, it is almost equal which
breaks the general belief that a detrimental hydrogen
pressure effect on enantioselectivity is expected with
Figure 3. Selected examples of influence of hydrogen pres-
sure (or concentration in the liquid phase) on the enantiose-
lectivity. Top : detrimental pressure effect. Bottom: benefi-
cial pressure effect.
value of jeej=4 is chosen considering experimental most of the known chiral diphosphines.[6b,8b]
error such as GC analysis. The number of 155 systems
Are these results of practical interest? We still do
left is still statistically significant. In Figure 4, the bar not have tools to predict the beneficial or detrimental
diagram shows the distribution of hydrogen pressure hydrogen pressure influence on ee. However, two
effect on ee (Dee). Note that a threshold value of propositions are made. First, screening must be per-
jDeej>4 has been used to categorize detrimental, formed systematically at higher hydrogen pressure to
beneficial and negligible effects. Setting the threshold detect those catalysts displaying higher ee. Those cata-
at higher or lower values does not change the conclu- lysts will also be more active since rates of hydrogena-
sion (see Supporting Information). Concerning the tions are generally of positive order with hydrogen.
first question about the general character of hydrogen Second, in the literature, most of the chiral ligands
pressure influence, 36% of the systems exhibit a sig- have been investigated under ambient hydrogen pres-
nificant ee variation (Deeꢂ10%), that is, 64% are not sure or higher. Many catalysts may display good but
much influenced (Figure 4). This is much less than the insufficient ees in the range 60–80% under such con-
ditions. In the case where these catalysts exhibit detri-
mental hydrogen pressure effects, higher ees are ex-
pected at sub-atmospheric pressures. Performing sub-
atmospheric asymmetric hydrogenations in the range
0.5–0.1 bar H2 will certainly offer a convenient way to
extend the scope of application of widely used li-
Scheme 2. Target substrates.
gands, albeit at the expense of activities.
Adv. Synth. Catal. 2008, 350, 898 – 908
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
903

Mohamad Alame et al.
FULL PAPERS
904
asc.wiley-vch.de
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 898 – 908

Pressure Effects in Rhodium-Catalyzed Asymmetric Hydrogenations
FULL PAPERS
Let us now comment further on the general impor-
tance of the fact that hydrogen pressure variation
does have a quite general impact on ee. Although we
cannot predict (yet) the beneficial or detrimental in-
fluence of hydrogen pressure, we can extend the con-
cept of the influence of a non-chiral reagent on ee as
an inexpensive tool to increase the enantioselectivity.
Let us first introduce the graph theory as applied to
chemical kinetics.[15] The graph for the mechanism of
Scheme 1 is easily derived (Figure 5, a). In the graphs,
Figure 5. (a) Graph corresponding to mechanism of
Scheme 1. (b) Generalized graph for asymmetric catalysis.
h are pseudo kinetic constants (h=kC where C is the
concentration of any reagent, solvent or ligand, enter-
ing the catalytic cycle) and X are the catalytic sites.
Two limitations are worth mentioning. First, the
steady-state principle is used to calculate the rates of
reactions. Second, only those elementary steps involv-
ing terminal products are used to build the mecha-
nism and the graph.[??] From the graph, the rate laws
for the enantiomer products R and S may be conven-
iently derived as well as their ratio [Eq. (2a)]. The ap-
plication of the graph theory allows an easy access to
a more general conclusion for any mechanism pos-
sessing an associated graph exhibiting the same topol-
ogy (Figure 5, b). Indeed, the generalized version of
graph (a) leads to an analytical expression of the in-
stantaneous enantioselectivity, conveniently expressed
as the ratio between the rates of reactions leading to
products R and S [Eq. (2b)]. Eq. (2b) might look
complicated but reduces to Eq. (2a) for j=1, i.e.,
Adv. Synth. Catal. 2008, 350, 898 – 908
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
905

Mohamad Alame et al.
FULL PAPERS
methyl-3-acetamido-2-pentanoate) were prepared according
to a published procedure.[1,20] Synthesis of the new BINAP
derivatives are published elsewhere.[14]
when the R and S loops display only two elementary
steps (mechanism of Scheme 1).
The ratio rR/rS does not depends on the hi,ꢀi which
are the constants involved in the common segment
pathway, but only on the hjR,ꢀjR and hjS,ꢀjS, that is, the
kinetic constants and reagent concentrations of ele-
mentary steps forming the R and S loops. This dem-
onstrates that any reagents (Ci) entering the cycle
before the “splitting” are of no importance for the
enantioselectivity while those (Cj) entering after the
splitting but before the RDS may affect the enantio-
slectivity. This demonstration is of course valid for
those mechanisms having associated graphs of the
same topology compared to that of Figure 5. Several
experimental facts support this idea. The kinetic anal-
ysis of the effect of acetone concentration on ee has
been published,[16] and reports on the effect of other
achiral reagents such as KBr,[17] NEt3,[18] or anions,[19]
on ee may also well represent examples of this con-
cept. Might this concept be more general? The
answer is perhaps, but most of enantioslective reac-
tions display coupled cycles with a common pathway
segments (i.e., intermediates) and thus are prone to a
reagent effect on enantioselectivity.
Mathematical Derivation of the Sign of Derivative of
ee withHydrogen Concentration
Two parallel reactions are competing for the formation of
enatiomers R and S and the reaction scheme writes as:
Each of the reactions (R) and (S) decomposes in the fol-
lowing six elementary steps according to the proposed
mechanism:
Conclusions
In this report, it has been demonstrated using a 168
chiral diphosphines/subtrates library that equivalent
distribution between beneficial and detrimental pres-
sure effects on ee prevails. Furthermore, it is also
shown that the hydrogen pressure influence is quite
general, more than 33% of the reaction systems inves-
tigated being influenced. In some cases, hydrogen
pressure may clearly be a practical an inexpensive
tool to considerably improve ees up to 97%! The
graph theory was used to show how this conclusion
may apply to the effect of other non-chiral reagents
on enantioselectivity. Although predictive tools are
not given, screening of potential achiral reagents may
lead to a large improvement of enantioselectivity.
Application of the steady-state approximation leads to
the following rate laws for reaction (R). The rate for reac-
tion (S) is obtained by exchange of the R and S indices.
The instantaneous enantioselectivity ratio is given by:
Experimental Section
General Procedure for the Catalytic Hydrogenations
Hydrogenation experiments were performed in a stainless
steel mini-autoclave of 15 cm3 equipped with a magnetic stir-
rer (2200 rpm). All reactions were carried out at 358C at
Knowing that the mass balances for species R and S in a
batch reactor with no limitations by mass transfer are:
substrate and catalyst [Rh(COD)2]BF4 concentrations of
G
0.1M and 10ꢀ3–10ꢀ4 M, respectively, under hydrogen pres-
sure (1–40) bar in degassed MeOH (4 cm3). A ligand/Rh
ratio of 1 was used. Yields are all >96%. Conversions,
yields and enantioselectivities (eeꢃ1%) were determined by
GC on a lipodex A (25 m”0.25 mm) and CHIRASILVAL
(25 m”0.25 mm) column. MAC and E-EMAP (ethyl 4-
It follows that:
906
asc.wiley-vch.de
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 898 – 908

Pressure Effects in Rhodium-Catalyzed Asymmetric Hydrogenations
FULL PAPERS
[5] a) C. R. Landis, J. Halpern, J. Am. Chem. Soc. 1987,
109, 1746–1754; b) C. R. Landis, J. Halpern, J. Am.
Chem. Soc. 1987, 109, 6217.
[6] a) I. Ojima, T. Kogure, N. Yoda, J. Org. Chem. 1980,
45, 4728–4739; b) A. Marinetti, S. Jus, J.-P. GenÞt, Tet-
rahedron Lett. 1999, 40, 8365–8368; c) D. Heller, J.
Holz, I. V. Komarov, H. J. Drexler, J. You, K. Drauz,
A. Boerner, Tetrahedron: Asymmetry 2002, 13, 2735–
2741; d) Y. Sun, J. Wang, C. LeBlond, R. N. Landau, J.
Laquirada, J. R. Sowa Jr. , D. G. Blackmond, J. Mol.
Catal. A: 1997, 115, 495–502.
Under constant hydrogen concentration (or constant hy-
drogen pressure in a mass transfer free reactor), this ratio is
constant and can be integrated to give the integral enantio-
selectivity ratio:
[7] J. M. Brown, in: Handbook of Homogeneous Hydroge-
nation, (Eds.: J. G. de Vries, C. J. Elsevier), Wiley-
VCH, Weinheim, 2007, vol 3, chap 31, pp 1073–1103.
[8] a) H.-J. Drexler, A. Preetz, T. Schmidt, D. Heller, in:
Handbook of Homogeneous Hydrogenation, (Eds.:
J. G. de Vries, C. J. Elsevier), Wiley-VCH, Weinheim,
2007, vol 1, chap 10, pp 257–293; b) H.-J. Drexler, J.
You, S. Zhang, C. Fischer, W. Baumann, A. Spannen-
berg, D. Heller, Org. Proc. Res. Dev. 2003, 7, 355–361.
[9] a) J. M. Brown, P. L. Evans, Tetrahedron 1988, 44,
4905–4916; b) P. L. Bogdan, J. J. Irwin, B. Bosnish, Or-
ganometallics 1989, 8, 1450–1453; c) S. Feldgus, C. R.
Landis, J. Am. Chem. Soc. 2000, 122, 12714–12727;
d) S. Feldgus, C. R. Landis, Catalysis by Metal Com-
plexes 2002, 25, 107–135, and references cited therein.
[10] a) Y. Sun, R. N. Landau, J. Wang, C. LeBlond, D. G.
Blackmond, J. Am. Chem. Soc. 1996, 118, 1348–1353;
b) N. Pestre, V. Meille, C. de Bellefon, J. Mol. Catal. A:
Chem. 2006, 252, 85–89; c) C. de Bellefon, N. Tan-
choux, D. Schweich, Recents Prog. Genie Procedes
1999, 13, 237–246.
The derivative of this ratio with hydrogen concentration is
written as:
Because kinetic constants and concentrations are always
positive, the sign of this derivative, which indicates the in-
crease or decrease of enantioselectivity with hydrogen con-
centration writes as:
[11] a) H. Bircher, B. R. Bender, W. Von Philipsborn,
Magn. Reson. Chem. 1993, 31, 293–298; b) J. A. Rams-
den, T. D. W. Claridge, J. R. Brown, J. Chem. Soc.,
Chem. Commun. 1995, 2469–2471.
[12] I. D. Gridnev, N. Higashi, T. Imamoto, J. Am. Chem.
Acknowledgements
Soc. 2000, 122, 10486–10487.
[13] a) N. Pestre, PhD thesis, UniversitØ Claude Bernard
Lyon 1, 2004; b) M. AlamØ, PhD thesis, UniversitØ
Claude Bernard Lyon 1, 2007.
Funding from the CNRS and the Ecole SupØrieure de Chimie
Physique Electronique de Lyon (ESCPE) is acknowledged.
Many thanks to Mr. Bilal Nehmeh and Betrand Bobet for ex-
perimental work.
[14] a) M. Berthod, C. Saluzzo, G. Mignani, M. Lemaire,
Tetrahedron: Asymmetry 2004, 15, 639–645; b) M. Ber-
thod, G. Mignani, M. Lemaire, Tetrahedron: Asymme-
try 2004, 15, 1121–1126; c) A. Hu, H. L. Ngo, W. Lin,
Angew. Chem. 2004, 116, 2555–2558; Angew. Chem.
Int. Ed. 2004, 43, 2501–2504; d) M. AlamØ, M. Jahjah,
M. Berthod, M. Lemaire, V. Meille, C. de Bellefon, J.
Mol. Catal. A: Chem. 2007, 268, 205–212; e) M.
AlamØ, M. Jahjah, S. Pellet-Rostaing, M. Lemaire, V.
Meille, C. de Bellefon, J. Mol. Catal. A: Chem. 2007,
271, 18–24; f) M. Berthod, G. Mignani, G. Woodward,
M. Lemaire, Chem. Rev. 2005, 105, 1801–1836.
[15] a) C. Kuo-Chen, R. E. Carter, S. ForsØn, Chemica
Scripta 1981, 18, 82–86; b) F. G. Helfferich, in: Kinetics
of Homogeneous Multistep Reactions, (Eds.: R. G.
Compton, G. Hancock), Elsevier, Amsterdam, 2001,
vol. 38.
References
[1] B. D. Vineyard, W. S. Knowles, M. J. Sabacky, G. L.
Bachman, D. J. Weinkauff, J. Am. Chem. Soc. 1977, 99,
5946–5952.
[2] a) J. M. Brown, P. A. Chaloner, Tetrahedron Lett. 1978,
1877–1880; b) A. C. S. Chan, J. J. Pluth, J. Halpern,
Inorg. Chim. Acta 1979, 37, L477.
[3] R. Noyori, in: Asymmetric Catalysis in Organic Synthe-
sis, John Wiley & Sons, New York, 1994, pp 16–94.
[4] a) H.-U. Blaser, H.-P. Jalett, M. Garland, M. Studer, H.
Thies, A. Wirth-Tijani, J. Catal. 1998, 173, 282–294;
b) B; Minder, M. Schurch, T. Mallat, A. Baiker, T.
Heinz, A. Pfaltz, J. Catal. 1996, 160, 261–268.
[16] C. de Bellefon, N. Tanchoux, Tetrahedron: Asymmetry
1998, 9, 3677–3686.
Adv. Synth. Catal. 2008, 350, 898 – 908
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
907

Mohamad Alame et al.
FULL PAPERS
[17] Q. Jiang, Y. Jiang, D. Xiao, P. Cao, X. Zhang, Angew.
Chem. 1998, 110, 1203–1207; Angew. Chem. Int. Ed.
1998, 37, 1100–1103.
[19] J. M. Buriak, J. C. Klein, D. G. Herrington, J. A.
Osborn, Chem. Eur. J. 2000, 6, 139–150.
[20] S.-G. Lee, Y. J. Zhang, Org. Lett. 2002, 4, 2429–2431.
[18] K. Achiwa, J. Am. Chem. Soc. 1976, 98, 8266–8267.
908
asc.wiley-vch.de
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 898 – 908