Mechanism of asymmetric hydrogenation catalyzed by a rhodium complex of (S,S)-1,2-bis(tert-butylmethylphosphino)ethane. Dihydride mechanism of asymmetric hydrogenation

Article abstract of DOI:10.1021/ja000813n

The mechanism of asymmetric hydrogenation catalyzed by a new effective catalyst, viz., a rhodium complex of (S,S)-1,2-bis(tert-butylmethylphosphino)ethane (BisP*), has been studied by multinuclear NMR. Hydrogenation of the precatalyst [Rh(BisP*)(nbd)]BF₄ (8) at -20 °C in deuteriomethanol affords solvate complex [Rh(BisP*)(CD₃OD)₂]BF₄ (9), which is, in turn, hydrogenated at -90 °C producing equilibrium amounts (20% at -95 °C) of [RhH₂(BisP*)(CD₃OD)₂] (10) - the first observable dihydride of a Rh(I) complex with a diphosphine ligand. Dihydride 10 is in equilibrium with 9 and dihydrogen, which was studied in the temperature interval from -100 to -50 °C, yielding thermodynamic parameters ΔH = -6.3 ± 0.2 kcal M^-1 and ΔS = -23.7 ± 0.7 cal M^-1 K^-1. The hydrogenation of 9 is stereoselective: two isomers 10a and 10b are produced in a ratio 10:1. Use of HD for the hydrogenation of 9 yields the isomers with deuterium cis and trans to the phosphine in a ratio 1.3 (±0.1):1. The thermodynamic parameters of the equilibrium between 9, 10^d, and HD are ΔH = -10.0 ± 0.4 kcal M^-1 and ΔS = -20.3 ± 1 cal M^-1 K^-1. Dihydride 10 reacts with the substrate 12 at -90 °C, yielding the monohydride intermediate 17a. The same product is obtained when 13 is hydrogenated at -80 °C. At temperatures above -50 °C monohydride intermediate 17a undergoes reductive elimination, affording the hydrogenation product 15 in equilibrium with the product-catalyst complex 16 in which the catalyst is η⁶-coordinated to the phenyl ring of the product. The experimental data require that the dihydride mechanism is operating in the case of asymmetric hydrogenation catalyzed by 9. This, in turn, suggests that the enantioselective step is the migratory insertion in a dihydride intermediate 18.

Full text of DOI:10.1021/ja000813n

J. Am. Chem. Soc. 2000, 122, 7183-7194
7183
Mechanism of Asymmetric Hydrogenation Catalyzed by a Rhodium
Complex of (S,S)-1,2-Bis(tert-butylmethylphosphino)ethane.
Dihydride Mechanism of Asymmetric Hydrogenation
Ilya D. Gridnev,* Natsuka Higashi, Katsuo Asakura, and Tsuneo Imamoto*
Contribution from the Department of Chemistry, Faculty of Science, Chiba UniVersity, Yayoi-cho,
Inage-ku, Chiba 263-8522, Japan
ReceiVed March 6, 2000
Abstract: The mechanism of asymmetric hydrogenation catalyzed by a new effective catalyst, Viz., a rhodium
complex of (S,S)-1,2-bis(tert-butylmethylphosphino)ethane (BisP*), has been studied by multinuclear NMR.
Hydrogenation of the precatalyst [Rh(BisP*)(nbd)]BF4 (8) at -20 °C in deuteriomethanol affords solvate
complex [Rh(BisP*)(CD3OD)2]BF4 (9), which is, in turn, hydrogenated at -90 °C producing equilibrium
amounts (20% at -95 °C) of [RhH2(BisP*)(CD3OD)2] (10)sthe first observable dihydride of a Rh(I) complex
with a diphosphine ligand. Dihydride 10 is in equilibrium with 9 and dihydrogen, which was studied in the
temperature interval from -100 to -50 °C, yielding thermodynamic parameters ∆H ) -6.3 ( 0.2 kcal M-1
and ∆S ) -23.7 ( 0.7 cal M-1 K-1. The hydrogenation of 9 is stereoselective: two isomers 10a and 10b are
produced in a ratio 10:1. Use of HD for the hydrogenation of 9 yields the isomers with deuterium cis and
trans to the phosphine in a ratio 1.3 ((0.1):1. The thermodynamic parameters of the equilibrium between 9,
10d, and HD are ∆H ) -10.0 ( 0.4 kcal M-1 and ∆S ) -20.3 ( 1 cal M-1 K-1. Dihydride 10 reacts with
the substrate 12 at -90 °C, yielding the monohydride intermediate 17a. The same product is obtained when
13 is hydrogenated at -80 °C. At temperatures above -50 °C monohydride intermediate 17a undergoes
reductive elimination, affording the hydrogenation product 15 in equilibrium with the product-catalyst complex
16 in which the catalyst is η6-coordinated to the phenyl ring of the product. The experimental data require that
the dihydride mechanism is operating in the case of asymmetric hydrogenation catalyzed by 9. This, in turn,
suggests that the enantioselective step is the migratory insertion in a dihydride intermediate 18.
Introduction
hydrogenation10-21 promoted mechanistic studies. In contrast
to the Wilkinson catalyst, no stable hydride complexes were
detected upon hydrogenation of [Rh(dppe)(nbd)]BF4 (1).22
Instead, dimer 2 has been structurally characterized, which
dissociates in solution producing solvate complex 3 (Scheme
1).22 Note, however, that ortho-para hydrogen exchange
experiments indicated the existence of a nondetectable concen-
tration of a dihydride in equilibrium with 3.23
Mechanistic studies in the field of asymmetric hydrogenation
of prochiral olefins have already a three-decade history.1 In 1965
Wilkinson et al. reported that, upon hydrogenation of Wilkinson
catalyst RhCl(PPh3)3, stable dihydride complex RhH2Cl(PPh3)3
is produced.2 It was concluded that hydrogenation of the catalyst
precedes the coordination of the substrate.3 Later studies have
provided experimental evidence for certain stages of the catalytic
cycle4-8 and revealed the complicated nature of the system
consisting of RhCl(PPh3)3, dihydrogen, and olefin.5,7-9
Further work showed that formation of the complexes of the
type 3 upon hydrogenation of a catalytic precursor is a general
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10.1021/ja000813n CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/18/2000

7184 J. Am. Chem. Soc., Vol. 122, No. 30, 2000
GridneV et al.
Scheme 1
Scheme 2
phenomenon for the rhodium(I) complexes containing various
diphosphine ligands.24-31 Usually, no hydride complexes were
detected in the solutions of solvates 3 under hydrogen; hydride
intermediates or oligomeric solvates have been noticed only
when the diphosphine ligand was capable of trans-coordina-
tion.29,32 Note also the formation of an unusual binuclear
trihydride complex with bridging perchlorate anion.33,34
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occurs after substrate binding in the case of cis-chelating
diphosphine rhodium complexes, and the catalytic cycle for
unsaturated mechanism (Scheme 2) has been proposed.22,26,35-37
This point of view is now generally accepted, although the
alternative mechanisms are considered, at least theoretically.1,38-40
The possibility of the dihydride mechanism in which the catalyst
first reacts with hydrogen has been discussed in the case of
trans-binding ligands41,42 or at high pressures of hydrogen.28
by X-ray analyses.22,26,54 In the case of a chiral diphosphine
ligand, several diastereomers of catalyst-substrate complex 4
are possible (two in the case of C2-symmetrical ligand and four
in the case of unsymmetrical diphosphines), but often only one
diastereomer predominates in solution. Initially, it had been
assumed that the stereochemistry of hydrogenation may be
mainly regulated by the relative thermodynamic stability of one
diastereomer.24,27,28,55 However, X-ray structure26 and compara-
tive study of the solution and solid-state CD spectra56 of the
complex 4 containing CHIRAPHOS as a ligand and ethyl (Z)-
R-acetamidocinnamate as a substrate showed that the config-
uration of the major diastereomer does not correspond to the
configuration of the product, if endo-addition of H2 is assumed.
Moreover, it was found that when the catalyst-substrate
complex 4 of [Rh(DIPAMP)]+ with methyl (Z)-R-acetamido-
cinnamate is hydrogenated at low temperatures, the reactivity
of the minor (less stable) diastereomer toward hydrogen is
notably higher compared to the major (more stable) diastere-
omer.43 These findings led to the conclusion37 that at least in
these two cases (CHIRAPHOS and DIPAMP) the stereochem-
istry of hydrogenation is regulated by the relative reactivity of
two diastereomers of 4 rather than by their relative abundance
in the equilibrium.
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of the diastereomers are very important, since if the rate of
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28,57
Thus, the decrease of ee’s under high pressure of H2
or at
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Dihydride Mechanism of Asymmetric Hydrogenation
J. Am. Chem. Soc., Vol. 122, No. 30, 2000 7185
Scheme 3
Kagan for PHELLANPHOS and NOPAPHOS ligands.64 Later,
a considerable amount of X-ray data was found to be in accord
with this empirical rule.65 Two related rules66,67 apparenly refer
to the same stereochemical regularities.
An alternative approach for the prediction of the stereochem-
ical result of the hydrogenation has been developed by Knowles
et al.68,69 This approach operates with “quardant diagrams” for
representation of the chiral environment of the rhodium atom.
Since in the case of the mostly studied tetraphenyl-substituted
diphosphine ligands with a chiral backbone, all four substituents
are equivalent, the “quadrant rule” regards the edge- and face-
oriented phenyls at the phosphorus atoms in the solid-state
structures of the catalytic precursors as the main stereoregulating
factors.
These rules are not Valid for many of the new catalysts with
electron-rich diphosphine ligands. Thus, the catalytic precursor
[Rh((S,S)-t-Bu-BisP*)(nbd)]BF4 (8) is λ-shaped but gives R-
amino acids with extremely high ee’s.70 The λ,δ rule cannot be
applied to the flat [Rh((R,R)-Me-DuPHOS)(cod)]SbF671 or [Rh-
((R,R)-t-Bu-MiniPHOS)2]PF6,72 but application of the quadrant
rule leads to wrong predictions. The same is valid for the Rh
complexes of the newly designed BPE,71 BIPNOR,73 Cnr-
PHOS,74,75 and BisP*70diphosphine ligands.
study, a mixed mechanism has been actually proposed.50 In
seven-membered ring chelates of rhodium-bis(phosphinites),
both reaction pathways are fast in the NMR time scale at room
temperature; low-temperature experiments have shown, how-
ever, that the intramolecular isomerization proceeds faster.52
Although the hydridoalkyl intermediates 6 (Scheme 2) have
previously been characterized by NMR in 1980,35,43 the reality
of the dihydride intermediates 5 in the asymmetric hydrogena-
tion has been experimentally demonstrated only recently.58
Neither can the twist of the coordinated diene76 in 8 be
correlated with the sense of enantioselection, since the diene
molecule is symmetrically coordinated in 870 despite the
apparent difference in size of the methyl and tert-butyl substit-
uents on phosphorus.
1
However, their structure remains unclear, since from the H
NMR data neither of the hydrides seems to be trans to
phosphorus. This result has been interpreted by the distorted
octahedral geometry of the dihydride intermediates.58
The difference in the reactivity of 4a and 4b toward hydrogen
cannot be adequately rationalized.48,53 Discussions of this
problem are often speculative.49,59 Early computational studies
of the pathways and transition states of H2 oxidative addition
to diastereomers of 460-62 inevitably relied on the solid-state
structures of the catalytic precursors and long remained below
the molecular mechanics level due to the absence of reliable
force field constants for metal complexes. Recently, the DFT
calculations of the model nonchiral complexes were reported.40
Two important modifications of the unsaturated mechanism
follow from these results: (1) the importance of molecular
hydrogen complexes as the intermediates in H2 oxidative
addition to the catalyst-substrate complexes; (2) the rate-turnover
step is the migratory insertion rather than the oxidative addition.
However, the authors admit that the real systems containing
bulky substituents may differ significantly from the model
complexes studied so far.40
Since the exact mechanistic model for the origin of stereo-
selection is still unavailable, empirical rules for the prediction
of the stereochemical outcome of a hydrogenation catalyzed by
a certain Rh(I)-diphosphine complex have been proposed.
Historically Fryzuk and Bosnich noticed at first that the stable
conformations (in which the methyl groups are quasi-equatorial)
of the Rh chelate rings with S,S-CHIRAPHOS21 and R-
PROPHOS63 are chiral and different (δ- and λ-conformations,
respectively). Accordingly, these complexes give in hydrogena-
tion R- and S-amino acids. Similar observations were made by
Almost all mechanistic studies of catalytic asymmetric
hydrogenation have been carried out for the catalysts with bis-
(diarylalkylphosphine) ligands. We are only aware of the work
of Armstrong, Brown, and Burk on the catalyst-substrate
complexes with (S,S)-Me-DuPHOS ligand largely made for Ir
complexes.77 Besides, very recently, Burk et al. have published
some experimental results demonstrating the importance of the
carboxylate function for the effective asymmetric reduction of
a precursor of candoxantril with (R,R)-Me-DuPHOS-Rh cata-
(65) Kagan, H. B. Asymmetric synthesis using organometallic catalysts;
Wilkinson, G., Stone, F. G. A., Abel, E. W., Eds.; Pergamon: Oxford, 1982;
Vol. 8, pp 463-498.
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A.; Yanovsky, A. I. J. Mol. Catal. 1988, 44, 217-243.
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1991, 2, 597-600.
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C.; Barnstorff, H. D.; Friedman, R. B.; Knowles, W. S.; Stults, B. R.;
Vineyard, B. D.; Weinkauff, D. J. Ann. N.Y. Acad. Sci. 1980, 333, 16-22.
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Tsuruta, H.; Matsukawa, S.; Yamaguchi, K. J. Am. Chem. Soc. 1998, 120,
1635-1636.
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Chem. Soc. 1993, 115, 10125-10138.
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Ed. Engl. 1997, 36, 1103-1105.
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(73) Robin, F.; Mercier, F.; Ricard, L.; Mathey, F.; Spagnol, M. Chem.
Eur. J. 1997, 3, 1365-1369.
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106-107.
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8368.
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1450-1453.
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38, 2947-2950.
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(76) Kyba, E. P.; Davis, R. E.; Juri, P. N.; Shirley, K. R. Inorg. Chem.
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5494.
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34, 879-882.

7186 J. Am. Chem. Soc., Vol. 122, No. 30, 2000
GridneV et al.
2
Scheme 4
experiments. The coupling J(PA,PB) is less than 5 Hz, which
resembles the very small 2J(P, P) couplings in a rhodium cationic
complex [RhH2(PP3)]+ (PP3 ) P(CH2CH2PPh2)3).79-81
Further details of the hydrides spin systems were clarified
by the selective 31P decoupling experiments (Figure 2, Table
S1). Thus, the large 186 Hz coupling of the signal at -7.7 ppm
disappeared when the high-field doublet in the 31P spectrum
was irradiated (Figure 2b). Irradiation of the doublet at δ )
95.0 in the 31P eliminated one of the two equal 19 Hz couplings
in the same multiplet (Figure 2c). The remaining 19 Hz coupling
is, therefore, with rhodium. Similarly, the details of the coupling
patterns were found for the hydride signal at δ ) -23.0 and
for the minor isomer of 10 (Table S1).
Scheme 5
From the known starting concentration of 8 and the integral
intensities of the signals of 9 and 10 (both isomers) in the 31P
NMR spectra, the absolute concentrations of 9 and 10 can be
calculated. The concentration of dihydrogen in the solution
could, in turn, be obtained from the relative intensities of the
hydride signals of 9 and the signal of dihydrogen at δ ) 4.5.
This allows calculation of the equilibrium constant K ) [10]/
[9][H2]. The temperature dependence of ln K versus reverse
temperature was linear in the temperature interval from -95 to
-50 °C. The parameters of equilibrium obtained from these
data are ∆H ) -6.3 ( 0.2 kcal M-1 and ∆S ) -23.7 ( 0.7 cal
M-1 K-1. We were able to observe only equilibrium concentra-
tions of 10 even at -100 °C. Therefore, the rate of equilibration
of 9 and 10 is higher than that reported recently for [Ir((R,R)-
Me-DuPHOS)(cod)]BF4.84
lyst.78 However, neither the reasons for the unusually high
activity of the bis(trialkylphosphine)-based catalysts nor the
above outlined apparent difficulties in application of the
stereoselection rules to these catalysts are understood or even
have been challenged until now. We therefore undertook a
detailed study of the mechanism of catalytic asymmetric
hydrogenation catalyzed by (S,S)-t-Bu-BisP*-Rh catalyst.
Results and Discussion
1. Hydrogenation of the Precatalyst. (a) Formation of
Solvate Complex 9. Like all other known catalytic precursors,
[Rh(BisP*)(nbd)]BF4 8 is easily hydrogenated in deuteriometha-
nol at -20 °C to produce a solvate complex [Rh (BisP*)(CD3-
OD)2]BF4 (9) (Scheme 4). Complex 9 was characterized by its
1H, 13C, and 31P NMR spectra. In the 31P NMR spectrum a
dublet was found (δ ) 89.8, 1JP-Rh ) 204 Hz). In the 13C NMR
spectrum three multiplets with characteristic splitting patterns
for the A parts of the AXYY′ system were observed together
with the intensive singlet of 6 methyls from 2 t-Bu groups (δ
) 27.3). The multiplets are easily attributable to the signals of
the P-methyl groups (δ ) 10.7), CH2 group (δ ) 25.4), and
quartenary carbons (δ ) 32.4), respectively. The positions of
three multiplets corresponding to t-Bu, Me, and CH2 groups in
the 1H NMR spectrum were verified by 2D heteronuclear 13C-
1H and 31P-1H correlations.
(b) Oxidative Addition of H2 to Solvate Complex 9. We
found that solvate complex 9 reacted with dihydrogen reversibly
and stereoselectively, producing two isomers of the dihydride
10 in the ratio 10:1 (Scheme 5). The relatively high concentra-
tions of dihydride 10 (approximately 20 mol %) were obtained
when 9 generated by hydrogenation of 8 at -50 °C was further
hydrogenated at -90 °C for 30 min.
The relative stability of the dihydride 10 is most probably
stipulated for the electron-rich character of the diphosphine
ligand stabilizing the octahedral dihydride complex. This
assumption is in accord with theoretical anticipations.40,82
In the 1H 2D EXSY spectra taken in the temperature interval
from -90 to -60 °C, intensive exchange cross-peaks between
two hydride signals were observed. On the other hand, no
exhange cross-peaks of hydride protons with dihydrogen were
observed. Neither exchange cross-peaks were found in the 31P
2D EXSY spectra taken in the same temperature interval.
Therefore, the hydrides in 10 can interchange their positions
without complete dissociation of the hydrogen. A similar
conclusion has been recently made for a structurally related
[RhH2(PP3)]+ complex.79 The mechanism suggested by Hei-
nekey and van Roon on the basis of evaluated kinetic isototope
effect implies the formation of an intermediate of the type 11
with substantial H-H interactions (Scheme 6). Quantification
of the EXSY data obtained at two different mixing times at
193 K gave the rate constant k ) 1.4 s-1 at this temperature.
The exchange with complete elimination of dihydrogen is at
least 10 times slower.
In the hydride region of the proton spectrum (Figures 1 and
2) two 16-line multiplets were observed at -7.7 and -23.0 ppm.
These protons are coupled through the 5 Hz coupling as follows
from the homodecoupling experiments. The same absolute value
of the geminal proton-proton coupling in a Rh dihydride has
been recently reported.79 The minor isomer 10b gives two
multiplets similar to those of 10a at -7.0 and -23.1 ppm. The
31P NMR spectrum of the hydrogenation product (Figure 1)
contains two doublets at δ ) 43.8 (1J(P, Rh) ) 86 Hz) and δ
) 95.0 (1J(P, Rh) ) 145 Hz). Each of these two signals
correlates with both hydride protons in the 2D P, H correlation
The intermediacy of dihydrogen complex 11 in the intramo-
lecular dynamic rearrangement of 10 is also in accord with the
most recent computational study of the oxidative H2 addition
to Rh(I) complexes.40 Landis et al. have shown that the
molecular hydrogen coomplexes are real minima on the potential
energy surface for the hydrogenation of model Rh(I) phosphine
(80) Bianchini, C.; Mealli, C.; Peruzzini, M.; Zanobini, F. J. Am. Chem.
Soc. 1987, 109, 5548-5549.
(81) Biandini, C.; Elsevier, C. J.; Ernsting, J. M.; Peruzzini, M.; Zanobini,
F. Inorg. Chem. 1995, 34, 84-92.
(82) Sargent, A. L.; Hall, M. B.; Guest, M. F. J. Am. Chem. Soc. 1992,
114, 517-522.
(78) Burk, M. G.; Bienewald, F.; Challenger, S.; Derrick, A.; Ramsden,
J. A. J. Org. Chem. 1999, 64, 3290-3298.
(79) Heinekey, D. M.; Roon, M. v. J. Am. Chem. Soc. 1996, 118, 12134-
12140.
(83) Burk, M. J.; McGrath, M. P.; Wheeler, R.; Crabtree, R. H. J. Am.
Chem. Soc. 1988, 110, 5034-5039.
(84) Kimmich, B. F. M.; Somsook, E.; Landis, C. R. J. Am. Chem. Soc.
1998, 120, 10115-10125.

Dihydride Mechanism of Asymmetric Hydrogenation
J. Am. Chem. Soc., Vol. 122, No. 30, 2000 7187
1
Figure 1. Left: hydride region of the H NMR spectrum (600 MHz, CD3OD, -90 °C) of the equilibrium mixture of 9 and 10. Right: 31P NMR
spectrum (162 MHz, CD3OD, -90 °C) of the equilibrium mixture of 9 and 10.
Scheme 6
Scheme 7
The selectivity in hydrogenations of transition metal com-
plexes governed by the electronic properties of different ligands
has been extensively studied.82,83 However, in the hydrogenation
of 9 the stereoselectivity is induced by the steric properties of
the ligands. Similar high diastereoselectivity was recently
observed for the hydrogenation of a series of Ir diphosphine
complexes.84
We could not determine experimentally the structure of the
major diastereomer, since the alkyl groups of 10 resonate very
closely in the 1H NMR spectrum. The molecule of the rhodium
complex is C2-symmetrical, and there are only two possibilities
for the hydrogen molecule to approach it for the oxidative
addition. One of these posibilities is evidently favored due to
the less steric hindrance from the bulky t-Bu groups (Scheme
7). We think, therefore, that the formation of 10a may be
preferred kinetically. However, the relative thermodynamic
stability of one of the diastereomers observed in our experiments
is difficult to rationalize due to the very similar structures of
10a and 10b.
1
Figure 2. Line shape of the hydride signals of 10a in the H NMR
spectra (400 MHz, CD3OD, -70 °C): (a) normal 1H NMR; (b) selective
decoupling from 31P with δ ) 43.5; (c) selective decoupling from 31P
with δ ) 95.0.
(c) Oxidative Addition of HD to the Solvate Complex 9.
The hydrogenation of 9 using HD gave the mixture of four
isomers 10d (Scheme 8). The ratio 10ad:10bd was the same as
for the corresponding dihydrides (10:1). Of interest is the
significantly unequal distribution of deuterium between cis and
complexes and are comparable in energy with further formed
dihydrides.40

7188 J. Am. Chem. Soc., Vol. 122, No. 30, 2000
GridneV et al.
Scheme 8
Scheme 10
correlation and selective decoupling experiments). In the
aliphatic part of the spectrum all four alkyl groups resonate
separately due to lack of symmetry in the molecule of 13. The
four protons of two CH2 groups give complex multiplets; their
positions in the spectrum were found from 2D H-13C cor-
1
Scheme 9
relation experiments. The methyl groups of the diphosphine give
doublets at 1.40 and 1.52 ppm, whereas the signals of two t-Bu
groups are separated for 0.48 ppm (δ ) 0.70 and 1.18). The
considerable high-field shift of one of the t-Bu groups (it is the
t-Bu group attached to high-field phosphorus with δ ) 76.0
ppm according to the 31P-1H correlation) is caused by the well-
known shielding effect of a spatially close phenyl ring. This
conclusion has been confirmed by a comparison of the 1H NMR
1
trans positions (relative to the phosphorus atom): deuterium
prefers to occupy cis position with a factor 1.3 ( 0.1. The ratio
(10ad1 + 10bd1):(10ad2 + 10bd2) remained constant within
experimental error in the temperature interval from -100 to
-50 °C and was reproduced exactly in four independent
hydrogenation experiments. To our knowledge, this is a first
observation of such effect for the oxidative addition of HD to
transition metal complexes.84
The parameters of equilibrium between 9, HD, and 10d (all
isomers) have been found similarly to the equilibrium with H2
(see above). The thermodynamic parameters of this equilibrium
are ∆H ) -10.0 ( 0.4 kcal M-1 and ∆S ) -20.3 ( 1 cal
M-1 K-1. The significant equilibrium isotope effect observed
for the addition of HD is in accord with known regularities.85
Thus, we have detected the reversible and stereoselective
formation of the dihydride complex 10 upon hydrogenation of
the solvate complex 9 in deuteriomethanol. This observation
gives reasons to consider a dihydride mechanism for the
asymmetric hydrogenations catalyzed by 9. To probe further
this possibility, we have studied the asymmetric hydrogenation
of methyl (Z)-R-acetamidocinnamate (12).
spectrum of 13 with the H NMR spectra of the complexes of
9 with (Z)-R-acetamidocinnamic acid (∆δ(t-Bu) ) 0.46),
acetamidoacrylic acid (∆δ(t-Bu) ) -0.08), and dimethyl
itaconate (∆δ(t-Bu) ) -0.08); these results will be reported in
detail elsewhere.
In the phase-sensitive NOESY spectrum of 13, the intensive
NOE cross-peak is observed between the olefinic proton of the
substrate and the methyl group attached to the low-field
phosphorus atom (δ ) 79.3). The intensity of this cross-peak
is the same as for the evident cross-peak of the olefinic proton
with ortho-protons of the adjacent phenyl ring. This NOE and
the shielding of one t-Bu group taken together allow elucidation
of the solution structure of the complex 13 (Scheme 10). Only
in the case of diastereomer 13a it is possible to obtain close
proximity between one of the t-Bu groups and the phenyl ring
under the condition that the methyl group attached to another
phosphorus atom is close enough to the olefinic proton to
produce NOE.
In the 13C NMR spectrum of 13 (Table S3), both signals of
the Rh-coordinated double bond have the expected couplings
with trans-phosphorus, whereas the quarternary carbon atom
is additionally coupled to rhodium (6 Hz). Both amide and
carboxyl carbonyls are coupled to phosphorus as was previously
observed for the DIPAMP complex.27 Additionally a long-range
coupling (3 Hz) with trans-phosphorus is observed for the
quarternary aromatic carbon. In the aliphatic region of the 13C
NMR spectrum, two signals of the t-Bu methyls, two doublets
of P-bonded methyls, and two doublets of quarternary carbons
have the expected chemical shifts and couplings values. The
CH2 groups give multiplets at δ ) 21.1 and 32.6 (Table S3).
2. Binding of the Catalyst with a Substrate and a
Hydrogenation Product. (a) NMR Study of the Solution
Structure of a Catalyst-Substrate Complex. Addition of a
2-fold excess of methyl (Z)-R-acetamidocinnamate (12) to a
solution of solvate complex 9 in deuteriomethanol under argon
resulted in immediate formation of catalyst-substrate complex
13 (Scheme 9).
The 31P NMR spectrum of the complex 13 at room temper-
ature shows two signals at 76.0 and 79.3 ppm (Figure 3h, Table
S2). Each is split by a large heteronuclear Rh-P coupling (158
and 156 Hz, respectively) and a smaller homonuclear P-P
coupling (32 Hz). The results of the heteronucleus 31P-1H
correlation experiments together with the NOESY data indicate
that the high-field signal is trans to the double bond. This is in
accord with the most recent assignments.50
It should be noted that the solution structure of 13, similarly
to the catalyst-substrate complexes studied so far, does not
correspond to the configuration of the hydrogenation product.
Thus, olefin in 13a is coordinated with its re-face, but the
hydrogenation of 12 catalyzed by 9 gives R-amino acid.
Therefore, similarly to the well-studied hydrogenations catalyzed
by bis(diarylalkylphosphine) Rh(I) complexes, we conclude that
the relative abundance in solution of the diastereomers 13a and
13b is not a stereodetermining factor.
In the 1H NMR spectrum of 13 the olefinic proton resonates
as double doublet at 6.08 ppm and has characteristic couplings
2JHRh ) 3.0 Hz and JHP ) 4.9 Hz (confirmed by the 31P-1H
3
(b) Equilibration of Diastereomers of 13. Figure 3 shows
(85) Abu-Hasanayn, F.; Krogh-Jespersen, K.; Goldman, A. S. J. Am.
Chem. Soc. 1993, 115, 8019-8023.
the temperature dependence of the 31P NMR spectrum of the

Dihydride Mechanism of Asymmetric Hydrogenation
J. Am. Chem. Soc., Vol. 122, No. 30, 2000 7189
Scheme 11
intramolecular interconversion of diastereomers of a catalyst-
substrate complex was recently reported.52 By analogy we tend
to conclude that the observed temperature dependence of the
NMR spectra of 13 corresponds to the fast intramolecular
equilibrium between 13a and 13b (Scheme 11).
Intensive exchange cross-peaks were observed in the phase-
sensitive NOESY spectra of 13 taken in the temperature interval
20-45 °C. The cross-peaks were observed for the exchange
between 13 and free substrate 12 and for the pairwise exchange
of two methyl and two t-Bu groups in the diphosphine-rhodium
chelate cycle. Therefore, the EXSY data testify to the reversible
dissociation of 13 producing 12 and nondetectable concentration
of 9 (Scheme 11). The activation parameters for this reaction
(EA ) 17.4 kcal mol-1, ln A ) 29) were found from the
quantitative EXSY experiments.87 Since the intermolecular
interconversion of 13a and 13b involves this dissociation, we
conclude that the barrier for this pathway is much higher than
the barrier of the intramolecular interconversion.
(c) Formation of Binuclear Complexes. More complex
equilibria were observed if less than 2 equiv of 12 was added
to the solution of the solvate complex 9. The 31P NMR spectra
of the samples containing 1, 2, and 0.5 equiv of 12 are compared
in Figure 4. When 1 equiv of 12 was added to 9, then together
with the multiplets of 13 and much less intensive broadened
doublet of 9, additional signals were observed in the 31P NMR
spectrum (Figure 4b). These are the doublet at 87.0 ppm and
two double doublets very close in spectral characteristics to the
signals of 13. The relative intensities of these signals increased
notably when only half of an equivalent amount of 12 was added
Figure 3. Dependence of the line shape in the 31P NMR spectrum
(202 MHz, CD3OD) of 13 on the temperature: (a) at -95 °C; (b) at
-90 °C; (c) at -80 °C, (d) at -72 °C (Tc); (e) at -60 °C, (f) at -50
°C; (g) at 0 °C; (h) at 20 °C.
catalyst-substrate complex 13. At room-temperature two sharp
multiplets of two unequivalent phosphorus atoms were found
in the spectrum. Despite the high signal-to-noise ratio, no signals
of the second diastereomer could be detected. When the
temperature was lowered to -60 °C, a significant broadening
of the high-field multiplet was observed. This broadening
became maximum at -72 °C, whereas at -95 °C this multiplet
sharpened again, and the second signal, apparently of the same
multiplicity, appeared (the low-field doublet component of the
multiplet is overlapped with the signal of major tautomer).
Similar dynamic effects were observed in the 1H and 13C NMR
spectra of 13. These observations indicate the existence of a
second species being in fast equilibrium with the major isomer
13a; equilibrium constant is approximately 10 at -95 °C. This
species may be either second diastereomer 13b or a conformer
of 13a. We cannot distinguish definitely between these two
possibilities. The activation barrier is 9 kcal mol-1 at TC ) 201
K.86 A very close value of the activation barrier for the
1
to the solution of 9 (Figure 4a). In the H and 13C spectra of
the same samples, the signals of an η6-coordinated phenyl ring
were observed (two doublets and three triplets between 5.5 and
1
7.0 ppm in the H spectrum and six signals in the region 90-
100 ppm in the 13C spectrum) together with two sets of aliphatic
signals similar to those of 13 and 9. On the basis of the presented
evidence, we conclude that a binuclear complex 14 is in
equilibrium with 13, 9, and 12 (Scheme 12). A second
diastereomer, 14b, with a concentration approximately 10 times
1
lower than that of 14a was detectable in the H and 31P NMR
spectra of the equilibrium mixture (e.g.Figure 4a). Apparently,
the intramolecular interconversion of 14a and 14b is retarded,
and both diastereomers can be observed even at ambient
temperature.
(86) Sandstro¨m, J. Dynamic NMR-Spectroscopy; Academic Press:
London, 1984
(87) Perrin, C. L.; Dwyer, T. J. Chem. ReV. 1990, 90, 935-967.

7190 J. Am. Chem. Soc., Vol. 122, No. 30, 2000
GridneV et al.
Scheme 13
indicate that 16 is a catalyst-product complex in which the
product is η6-coordinated to rhodium by the phenyl ring (Scheme
13).
Such η6-aryl Rh complexes are not unusual88-90 and are also
known for the chelate diphosphine Rh(I) complexes.89-92
Surprisingly, this seems to be a first observation of such a
complex in the course of the asymmetric hydrogenation. Note
that Bargon recently employed PHIP method to detect otherwise
nondetectable intermediates similar to 16.93
The equilibrium between 9, 15, and 16 was studied in the
temperature interval from -80 to +30 °C. The temperature
dependence of the equilibrium constant gives for the formation
of 16 ∆H ) -0.7 ( 0.1 kcal M-1 and ∆S ) 6.2 ( 0.3 cal M-1
K-1. Binding of the product 16 is notably weaker than binding
of the substrate 12: in the presence of double excess of 15 a
detectable concentration of 9 was observed even at -80 °C.
3. Simulation of the Dihydride Mechanism of Asymmetric
Hydrogenation. (a) Reaction of 12 with Dihydride 10.
Addition of a 2-fold excess of 12 to a solution of dihydride 10
in equilibrium with 9 at -100 °C under hydrogen resulted in
immediate disappearance of the signals of 10 from the NMR
spectra and appearance of a new hydride species. In the hydride
Figure 4. 31P NMR spectra (162 MHz, CD3OD, -20 °C) of the
samples obtained by adding various amounts of 12 to a solution of 9
in deuteriomethanol: (a) 0.5 equiv of 12; (b) 1 equiv of 12; (c) 2 equiv
of 12.
1
region of the H NMR spectrum (Figure 5, compare to Figure
Scheme 12
1a) a single multiplet was observed at -23.0 ppm. It correlated
to a pair of double doublets at δ ) 60.2 and δ ) 70.4 in the
31P NMR spectrum. At -50 °C these signals disappeared from
the spectra with t1/2 ≈ 8 min and the signals of the hydrogenation
product 15, solvate complex 9, and η6-arene complex 16
appeared simultaneously (e.g., Figure 6).
The 1H, 13C, and 31P NMR spectra of this monohydride
species 17 (Tables S1-S3) are almost equal to those reported
previously for monohydride intermediates.35,43 The chemical
shift of the hydride signal (δH ) -23.0) indicates its trans-
disposition to an oxygen atom. The values 2JH,P (16 and 28 Hz)
are in agreement with the presence of two cis-phosphorus atoms
respective to hydride. The signal of the quarternary R-C carbon
bound to the rhodium atom has the expected large coupling with
trans-phosphorus (80 Hz) and a smaller coupling with Rh (20
1
Hz). The CH2Ph group resonates at δ ) 4.09 in the H NMR
spectrum and at δ ) 43.7 in the 13C NMR. Both carbonyls are
approximately 10 ppm downfield-shifted relative to the free
ligand (Figure 7) indicating that they both are coordinated to
rhodium.43
The enantiomeric excess of 15 produced in this experiment
was 99% (R). Since the migratory insertion step of the
(d) A Catalyst-Product Complex. The solvate complex 9
is capable of coordinating reversibly a molecule of the hydro-
genation product 15 (Scheme 13) giving in the 31P NMR
spectrum a doublet at δ ) 87.0 (1JRh-P ) 202 Hz). The structure
of this new species 16 follows from the 1H and 13C NMR spectra
containing the signals of the coordinated phenyl ring (5 signals
(88) Green, M.; Kuc, T. A. J. Chem. Soc., Dalton Trans. 1972, 832-
839.
(89) White, C.; Thompson, S. J.; Maitlis, P. M. J. Chem. Soc., Dalton
Trans. 1977, 1654-1661.
(90) Muetterties, E. L.; Bleeke, J. R.; Wucherer, E. J. Chem. ReV. 1982,
82, 499-525.
(91) Townsend, J. M.; Blount, J. F. Inorg. Chem. 1981, 20, 269-271.
(92) Singewald, E. T.; Slone, C. S.; Stern, C. L.; Mirkin, C. A.; Yap, G.
P. A.; Liable-Sands, L. M.; Rheingold, A. L. J. Am. Chem. Soc. 1997, 119,
3048-3056.
(93) Hu¨bler, P.; Giernoth, R.; Ku¨mmerele, G.; Bargon, J. J. Am. Chem.
Soc. 1999, 121, 5311-5318.
1
in the H NMR in the area 6-7 ppm and 6 signals in the 13C
NMR in the region 90-110 ppm), together with the signals of
the CH2CH(NHCOMe)(CO2Me) moiety very close in spectral
characteristics to the hydrogenation product 15 (see Supporting
Information for complete NMR data). These spectral data

Dihydride Mechanism of Asymmetric Hydrogenation
J. Am. Chem. Soc., Vol. 122, No. 30, 2000 7191
Figure 5. 1H NMR spectrum (600 MHz, CD3OD, -95 °C) of the
sample obtained by addition of a 2-fold excess of 12 to the equilibrium
mixture of 9 and 10 at -100 °C. Insets show the appearance of the
hydride multiplet with and without selective decoupling from phos-
phorus.
asymmetric hydrogenation catalyzed by Rh(I) complexes was
recently shown to be irreversible,94 we conclude that the
configuration of the R-C in the observed monohydride corre-
sponds to the R-hydrogenation product 15. Furthermore, the
structural conclusions based on the NMR data (cis-hydride to
both phosphorus, R-C trans to phosphorus) give reasons to
exclude from consideration all possible isomers of 17 except
four, viz. 17a-d (Scheme 14). We consider the structures 17c
and 17d less probable, since neither of them can form directly
by the transfer of the equatorial hydride to the coplanar double
bond, that is considered to be the nessesary requirement for a
successful migratory insertion step.40,95 The isomers 17a and
17b (as well as 17c and 17d) can interconvert via dissociation
of the Rh-O bond, rotation around the Rh-C bond and
recoordination of the carbonyl. The significant low-field shift
of both carbonyl carbons in the 13C NMR spectrum of 17 (Figure
7) suggests that they both are coordinated; therefore the isomer
17a is most probably observed (in 17b the coordination of the
second carbonyl is impossible due to spatial reasons). A
ruthenium complex with a very similar coordination of the same
substrate was recently characterized by X-ray.96
Thus, the reaction of dihydride 10 with 12 proceeds very fast
at -100 °C, producing the monohydride intermediate 17a, which
further transforms to the hydrogenation product 15 with 99%
ee. This experiment demonstrates the reality of the dihydride
mechanism in asymmetric hydrogenation of 12. Apparently, the
dihydride 10 coordinates a molecule of the substrate producing
an extremely unstable dihydride intermediate 18 (Scheme 15),
which undergoes migratory insertion to produce monohydride
17b. In 17b coordination of the second carbonyl is impossible
due to geometry reasons and it rearranges to a more stable 17a
by rotation around the Rh-C bond.
Figure 6. Evolution of the 31P NMR spectrum (202 MHz, CD3OD)
of the sample obtained obtained by hydrogenation of the CD3OD
solution of 13 for 2 h at -80 °C: (a) at -90 °C; (b) at -60 °C; (c) at
-50 °C immediately; (d) at -50 °C after 25 min; (e) at 30 °C.
asymmetric hydrogenation.94,97 The reaction of the mixture of
isomers 10d in CD3OD gave the isomers 17ad1 and 17ad2 (the
ratio was not determined, since the signal of CH2 group was
obscured by the intensive peaks of 12 and 13); the ratio of the
hydrogenation products obtained after raising the temperature
15d1:15d2 was 1.18 ((0.05):1 (Scheme 16).
(b) Experiments Using HD. Use of HD has been shown to
provide valuable information on the mechanism of catalytic
Catalytic hydrogenation of 12 in CH3OH using HD with 8
as a catalyst precursor afforded the mixture of two isomers 15d1
and 15d2 in a 1.17 ((0.05):1 ratio (the mean value from the
(94) Brauch, T. W.; Landis, C. R. Inorg. Chim. Acta 1998, 270, 285-
297.
(95) Seebach, D.; Plattner, D. A.; Beck, A.; Wang, Y. M.; Hunziker,
D.; Petter, W. HelV. Chim. Acta 1992, 75, 2171-2209.
(96) Wiles, J. A.; Bergens, S. H.; Young, V. G. J. Am. Chem. Soc. 1997,
119, 2940-2941.
2
1H, H, and 13C data). Use of THF as a solvent gave the ratio
1.22 ((0.05):1, which is only slightly higher, and therefore the
(97) Brown, J. M.; Parker, D. Organometallics 1982, 1, 950-956.

7192 J. Am. Chem. Soc., Vol. 122, No. 30, 2000
GridneV et al.
Scheme 15
Figure 7. Carbonyl region of a 13C NMR spectrum of a sample
containing the mixture of 12, 13, and 17a (100 MHz, CD3OD, -70
°C).
Scheme 14
NMR spectra of thus obtained sample (e.g. Figure 6a) showed
the high concentration of the monohydride 17a. Besides, the
signals of 9, 10, and 13 were found in the NMR spectra.
Therefore, the migratory insertion occurs to some extent under
the specified conditions, and the liberated catalyst is again
hydrogenated producing dihydride 10, which remains untouched
in the absence of additional substrate. When the same experi-
ment was carried out in the presence of 2-fold excess of 12, a
31P NMR spectrum containing only the signals of 13 and 17a
was obtained. The enantiomeric excess of the hydrogenation
product 15 obtained from either of these experiments was 97%
(R).
It should be mentioned that the formation of the monohydride
17a upon hydrogenation of 13 was relatively slow: in the
reaction between 10 and 12 monhydride 17 was obtained
immediately at -100 °C, whereas about 1 h at -80 °C was
nessesary to obtain the same concentration of 17a by hydro-
genating 13 under 2 atm of H2.
isotopic exchange with the protons of methanol94 does not affect
significantly the observed results. The values of deuterium
partitioning for the hydrogenations of 12 catalyzed by
DIPHOS,94,97 DIOP,97 and DIPAMP97 are somewhat higher
(1.33-1.37); a value close to our results was obtained for the
catalytic hydrogenation of methyl acetamidoacrylate.94
It is noteworthy that the catalytic hydrogenation and the
experiment simulating the dihydride mechanism afforded almost
the same value of isotope partitioning. These data suggest that
the dihydride pathway is really operating in the catalytic
conditions.
Another interesting result is that the preferential occupation
of the apical position by deuterium in 10d is roughly conserved
throughout the whole catalytic cycle (Scheme 16). A straight-
forward explanation of this result is that the partitioning of
deuterium on the coordination step and migratory insertion step
compensate each other. Calculations predict the partitioning of
about 1.5 in favor of R-deuteration for the migratory insertion
step.40 Therefore, to accommodate the observed partitioning to
this possibility, the coordination step must give the partitioning
order of about 0.6. Besides, the equilibrium between 18d1 and
18d2 should be faster than the migratory insertion step.
Another possibility to explain the experimental partitioning
of deuterium is to suppose that the consequence of substrate
coordination and migratory insertion proceeds much faster than
the interconversion of 10d1 and 10d2.
Thus, the results of low-temperature hydrogenation of 13 can
be also rationalized in terms of dihydride mechanism. In this
case the reaction proceeds by reversible dissociation of 13
producing 9 (see above), which is hydrogenated to 10, which
immediately reacts with the substrate. The relatively slow rate
of hydrogenation is explained by the slow dissociation step.
On the other hand, nothing speaks against the possibility of
a direct hydrogenation of 13. The rate of equilibration of 13a
and 13b at -80 °C is high enough to allow the usual explanation
of the generation of “correct” monohydride intermediate 17a
from the equilibrium mixture of 13a and 13b. Therefore, the
simultaneously proceeding unsaturated pathway cannot be ruled
out in the asymmetric hydrogenation of 12 catalyzed by 9.
However, the most important fact is the formation of the same
monohydride intermediate 17a and high (R)-stereoselection in
all three experiments.
4. Mechanism of Asymmetric Hydrogenation Catalyzed
by t-Bu-BisP* Catalyst and Origin of the Stereoselection. It
is possible to rationalize why the different reaction conditions
produce the same result in the reaction under study. Indeed,
the relative stability of the dihydride 10 implies that a dihydride
18 formed either by reaction between 10 and 12 or by
hydrogenation of 13 can easily dissociate to 10 and 12 and
produce another diastereomer of 18 in the next association step
(Scheme 17). In other words, either complexation of 10 and 12
(c) Hydrogenation of the Catalyst-Substrate Complex 13.
To simulate more closely the conditions of a catalytic reaction,
we have studied the low-temperature hydrogenation of the
catalyst-substrate complex 13. The solution of 13 was hydro-
genated under 2 atm of H2 at -80 °C for 2 h. Analysis of the

Dihydride Mechanism of Asymmetric Hydrogenation
J. Am. Chem. Soc., Vol. 122, No. 30, 2000 7193
Scheme 16
Scheme 17
Scheme 18
with deuteration experiments94 and computation results40 suggest
that the migratory insertion is a turnover limiting irreversible
step of asymmetric hydrogenation. Therefore, the TS of the
migratory insertion should have a geometry similar to that of
starting dihydride (Hammond’s postulate). Thus, estimating the
relative stabilities of 18a and 18b, one can roughly compare
the barriers of the migratory insertion step.
As can be seen from Scheme 18, the only structural feature
discriminating 18a and 18b is the nature of the alkyl group being
in a close contact with the chelate cycle made by the enamide.
In the diastereomer 18a the chelate ring interacts with the methyl
substituent, and in 18bswith the bulky tert-butyl group. It is
clear, therefore, that the transition state of the migratory insertion
produced from 18a would be much lower in energy compared
to 18b, and the R-stereoselection should be predicted. This
corresponds to the experimental findings. Note also that a similar
approach was used previously by Seebach et al.95
or hydrogenation of 13 produces the same equilibrium mixture
of all eight possible diastereomers of 18. The stereoselection,
therefore, must occur at a later step of the catalytic cycle. The
same conclusion has been recently made on the basis of
computational results for the model systems.40
There are eight possible diastereomers of 18. Only two of
these, viz. 18a and 18b (Scheme 18) are precursors of the
observed R-alkyl monohydride intermediate with trans-posi-
tioned hydride and oxygen atoms. As can be seen from Scheme
18, the migratory insertion in these intermediates must lead to
different stereoisomers of 17. Our experimantal data together

7194 J. Am. Chem. Soc., Vol. 122, No. 30, 2000
GridneV et al.
It is interesting to note that coordination of 12 to 10a produces
18a, whereas reaction of 10b and 12 yields 18b. Therefore, if
our assumption of the structure of 10a is correct, the diaste-
reoselectivity of the hydrogenation of 9 may facilitate the
enantioselection in the migratory insertion step.
Formulated like this, the quadrant rule remains valid for all
catalysts with backbone chirality and is also in accord with the
sense of stereoselection demonstrated by new P-chirogenic
catalysts for asymmetric hydrogenation.
5. Quadrant Rule. The above considerations on the mech-
anism of enantioselection are independent of the exact nature
of the catalyst. Therefore, following the classification of
Knowles et al.,68,69 we can conclude that any catalyst possesing
bulky substituents in the upper-left and lower-right quadrants
would produce R-hydrogenation products (Scheme 18). The
opposite arrangement of substituents would give S-products.
This conclusion contradicts the original formulation of the
“quadrant rule” made by Knowles for catalysts with backbone
chirality and four equivalent or almost equivalent in size phenyl
substituents on the phosphorus atoms. It is important to underline
that in 1983 Knowles had established the correlation between
the spatial arrangement of the substituents and the stereochem-
ical outcome of the reaction. This correlation itself works well:
the catalysts with backbone chirality produce R-amino acids if
in the stable conformation of the rhodium complex upper left
and lower right quadrants are occupied with axial phenyls. The
opposite arrangement of phenyls gives S-amino acids. However,
the mechanistic explanation of the quadrant rule proposed in
1983 may be changed in view of the new results obtained
recently by us and other workers.
The sense of enantioselection demonstrated by the Rh(I)
complexes of P-chirogenic diphosphines, in which the difference
in size between four substituents surrounding Rh atom is
apparent, is the same as in the case of BisP*. This is valid for
the catalysts with BPE,71 DuPHOS,71 BIPNOR,73 CnrPHOS,74,75
and MiniPHOS72 ligands. In the case of these ligands the
arrangement of substituents in the quadrants is independent of
the conformation of the chelate cycle. Therefore, a bulky
substituent in the upper left corner (and automatically bottom
right for C2 symmetrical ligand) provokes R-stereoselection.
If we apply the latter conclusion for the catalysts with
backbone chirality (and accordingly with equal substituents on
two phosphorus atoms), we must conclude that axial phenyls
are recognized as larger ones by the substrate. The relative
bulkiness of the quasi-axial substituents is understandable in
view of Scheme 18, since in the case of octahedral complexes
the axial interactions are more important for the stereoselection
than the equatorial interactions. The same conclusion has been
already made by Nagel in 1989.59
Conclusions
The profound mechanistic study of the asymmetric hydro-
genation catalyzed by BisP*-Rh catalyst revealed several
important features of this reaction. The most important finding
is the detection and characterization of the dihydride 10. Because
of the lack of experimental evidence on the stability of such
dihydrides in the case of diphosphine ligands, the dihydride
pathway of the asymmetric hydrogenation was rarely regarded
as a serious alternative to the unsaturated mechanism. We have
shown, however, that the dihydride mechanism can be success-
fully simulated at low temperatures by fast and quantitative
reaction of the dihydride 10 with substrate 12, producing the
monohydride intermediate 17a. The same monohydride inter-
mediate 17a is obtained upon hydrogenation of the catalyst-
substrate complex 13, and the same sense of enantioselection
is observed. Our results are completely consistent with the
dihydride mechanism of asymmetric hydrogenation catalyzed
by [Rh(BisP*)S2]BF4- (9). The enantiodetermining step, there-
fore, must be the migratory insertion, since on all previous stages
of the catalytic cycle the intermediates providing different
stereoselection are in equilibrium. We suggest that the main
stereodetermining factor is the relative order of steric repulsion
between the chelate ring made by the substrate and the alkyl
substituent on phosphorus in two isomers of a dihydride
intermediate (18a and 18b). The proposed mechanism of
stereoselection is consistent with the sense of enantioselectivity
demonstrated by the catalysts with P-chirogenic ligands. The
generally applicable quadrant rule may be formulated by
accepting the larger steric hindrance of the quasi-axial phenyls
for the catalysts with backbone chirality
Acknowledgment. This work was supported by “Research
for the Future” Program, the Japan Society for the Promotion
of Science, the Ministry of Education, Japan.
Supporting Information Available: Experimental proce-
dures for 8-10, 13, 14, 16, and 17; Tables S1-S3 of NMR
We suggest, therefore, that the quadrant rule can be refor-
mulated in a following way: (a) Bulky substituents on
phosphorus atoms in the top-left and bottom-right quadrants give
R-hydrogenation products (Scheme 18); opposite orientation
gives S-hydrogenation products. (b) If the substituents are the
same or very near in size, more steric hindrance is given by
quasi-axial substituents.
data for 9, 10, 13, 14, 16, and 17; charts of H, 13C, and 31P
1
NMR spectra and 2D NMR of 8-10, 13, 15-17, 10d, and 15d;
linearized dependencies of equilibrium constants versus tem-
perature for 10, 10d, and 16; kinetic data for 13. This material
is available free of charge via the Internet at http://pubs.acs.org
JA000813N