Bidentates versus monodentates in asymmetric hydrogenation catalysis: Synergic effects on rate and allosteric effects on enantioselectivity

Article abstract of DOI:10.1021/ja800858x

C₁-Symmetric phosphino/phosphonite ligands are prepared by the reactions of Ph₂P(CH₂)₂P(NMe₂) ₂ with (S)-1,1′-bi-2-naphthol (to give L_A) or (S)-10, 10′-bi-9-phenanthrol (to give L_B). Racemic 10,10′-bi-9-phenanthrol is synthesized in three steps from phenanthrene in 44% overall yield. The complexes [PdCl₂(L_A,B)] (1a,b), [PtCl₂(L_A,B)] (2a,b), [Rh(cod)(L_A,B)]BF ₄ (3a,b) and [Rh(L_A,B)₂]BF₄ (4a,b) are reported and the crystal structure of 1a has been determined. A ³¹P NMR study shows that M, a 1:1 mixture of the monodentates, PMePh₂ and methyl monophosphonite L_1a (based on (S)-1,1′-bi-2-naphthol), reacts with 1 equiv of [Rh(cod) ₂]BF₄ to give the heteroligand complex [Rh(cod)(PMePh ₂)(L_1a)]BF₄ (5) and homoligand complexes [Rh(cod)(PMePh₂)₂]BF₄ (6) and [Rh(cod)(L _1a)₂]BF₄ (7) in the ratio 2:1:1. The same mixture of 5-7 is obtained upon mixing the isolated homoligand complexes 6 and 7 although the equilibrium is only established rapidly in the presence of an excess of PMePh₂. The predominant species 5 is a monodentate ligand complex analogue of the chelate 3a. When the mixture of 5-7 is exposed to 5 atm H₂ for 1 h (the conditions used for catalyst preactivation in the asymmetric hydrogenation studies), the products are identified as the solvento species [Rh(PMePh₂)(L_1a)(S)₂]BF₄ (5′), [Rh(S)₂(PMePh₂)₂]BF₄ (6′) and [Rh(S)₂(L_1a)₂]BF₄ (7′) and are formed in the same 2:1:1 ratio. The reaction of M with 0.5 equiv of [Rh(cod)₂]BF₄ gives exclusively the heteroligand complex cis-[Rh(PMePh₂)₂(L_1a) ₂]BF₄ (8), an analogue of 4a. The asymmetric hydrogenation of dehydroamino acid derivatives catalyzed by 3a,b is reported, and the enantioselectivities are compared with those obtained with (a) chelate catalysts derived from analogous diphosphonite ligands L_2a and L_2b, (b) catalysts based on methyl monophosphonites L_1a and L _1b, and (c) catalysts derived from mixture M. For the cinnamate and acrylate substrates studied, the catalysts derived from the phosphino/ phosphonite bidentates L_A,B generally give superior enantioselectivities to the analogous diphosphonites L_2a and L _2b; these results are rationalized in terms of δ/λ- chelate conformations and allosteric effects of the substrates. The rate of hydrogenation of acrylate substrate A with heterochelate 3a is significantly faster than with the homochelate analogues [Rh(L_2a)(COd)]BF ₄ and [Rh(dppe)(cod)]BF₄. A synergic effect on the rate is also observed with the monodentate analogues: the rate of hydrogenation with the mixture containing predominantly heteroligand complex 5 is faster than with the monophosphine complex 6 or monophosphonite complex 7. Thus the hydrogenation catalysis carried out with M and [Rh(cod)₂]BF₄ is controlled by the dominant and most efficient heteroligand complex 5. In this study, the heterodiphos chelate 3a is shown to be more efficient and gives the opposite sense of optical induction to the heteromonophos analogue 5.

Full text of DOI:10.1021/ja800858x

Published on Web 05/03/2008
Bidentates versus Monodentates in Asymmetric
Hydrogenation Catalysis: Synergic Effects on Rate and
Allosteric Effects on Enantioselectivity
David W. Norman,† Charles A. Carraz,† David J. Hyett,†,§ Paul G. Pringle,*,†
Joseph B. Sweeney,‡ A. Guy Orpen,† Hirrahataya Phetmung,† and
Richard L. Wingad†
School of Chemistry, UniVersity of Bristol, Cantocks Close, Bristol BS8 1TS, U.K., and
Department of Chemistry, UniVersity of Reading, Reading RG6 6AD, U.K.
Received February 3, 2008; E-mail: paul.pringle@bris.ac.uk
Abstract: C1-Symmetric phosphino/phosphonite ligands are prepared by the reactions of
Ph2P(CH2)2P(NMe2)2 with (S)-1,1′-bi-2-naphthol (to give LA) or (S)-10,10′-bi-9-phenanthrol (to give LB).
Racemic 10,10′-bi-9-phenanthrol is synthesized in three steps from phenanthrene in 44% overall yield.
The complexes [PdCl2(LA,B)] (1a,b), [PtCl2(LA,B)] (2a,b), [Rh(cod)(LA,B)]BF4 (3a,b) and [Rh(LA,B)2]BF4 (4a,b)
are reported and the crystal structure of 1a has been determined. A 31P NMR study shows that M, a 1:1
mixture of the monodentates, PMePh2 and methyl monophosphonite L1a (based on (S)-1,1′-bi-2-naphthol),
reacts with 1 equiv of [Rh(cod)2]BF4 to give the heteroligand complex [Rh(cod)(PMePh2)(L1a)]BF4 (5) and
homoligand complexes [Rh(cod)(PMePh2)2]BF4 (6) and [Rh(cod)(L1a)2]BF4 (7) in the ratio 2:1:1. The same
mixture of 5-7 is obtained upon mixing the isolated homoligand complexes 6 and 7 although the equilibrium
is only established rapidly in the presence of an excess of PMePh2. The predominant species 5 is a
monodentate ligand complex analogue of the chelate 3a. When the mixture of 5–7 is exposed to 5 atm H2
for 1 h (the conditions used for catalyst preactivation in the asymmetric hydrogenation studies), the products
are identified as the solvento species [Rh(PMePh2)(L1a)(S)2]BF4 (5′), [Rh(S)2(PMePh2)2]BF4 (6′) and
[Rh(S)2(L1a)2]BF4 (7′) and are formed in the same 2:1:1 ratio. The reaction of M with 0.5 equiv of
[Rh(cod)2]BF4 gives exclusively the heteroligand complex cis-[Rh(PMePh2)2(L1a)2]BF4 (8), an analogue of
4a. The asymmetric hydrogenation of dehydroamino acid derivatives catalyzed by 3a,b is reported, and
the enantioselectivities are compared with those obtained with (a) chelate catalysts derived from analogous
diphosphonite ligands L2a and L2b, (b) catalysts based on methyl monophosphonites L1a and L1b, and (c)
catalysts derived from mixture M. For the cinnamate and acrylate substrates studied, the catalysts derived
from the phosphino/phosphonite bidentates LA,B generally give superior enantioselectivities to the analogous
diphosphonites L2a and L2b; these results are rationalized in terms of δ/λ-chelate conformations and allosteric
effects of the substrates. The rate of hydrogenation of acrylate substrate A with heterochelate 3a is
significantly faster than with the homochelate analogues [Rh(L2a)(cod)]BF4 and [Rh(dppe)(cod)]BF4. A
synergic effect on the rate is also observed with the monodentate analogues: the rate of hydrogenation
with the mixture containing predominantly heteroligand complex 5 is faster than with the monophosphine
complex 6 or monophosphonite complex 7. Thus the hydrogenation catalysis carried out with M and
[Rh(cod)2]BF4 is controlled by the dominant and most efficient heteroligand complex 5. In this study, the
heterodiphos chelate 3a is shown to be more efficient and gives the opposite sense of optical induction to
the heteromonophos analogue 5.
shown in eq 1. Moreover, we suggested1 an explanation for
Introduction
In 2000, it was shown1,2 that optically active monophospho-
nites based on 1,1′-bi-2-naphthol (binol), such as L1a, gave
superior enantioselectivities to their bidentate analogues L2a
(Chart 1) in the rhodium-catalyzed asymmetric hydrogenations
† University of Bristol.
this phenomenon in terms of (i) restricted M-P rotations; (ii)
the different orientation of the P-C bond in the monodentate
and bidentate phosphonites; (iii) the cis preference of phospho-
nite ligands. These results overturned 25 years of dogma that
bidentate phosphorus ligands consistently outperform their
monodentate analogues.3
‡ University of Reading.
§ Current address: DSM Research, P.O. Box 18, 6160 MD Geleen, The
Netherlands.
(1) Claver, C.; Fernandez, E.; Gillon, A.; Heslop, K.; Hyett, D. J.;
Martorell, A.; Orpen, A. G.; Pringle, P. G. Chem. Commun. 2000,
961.
(2) Reetz, M. T.; Sell, T. Tetrahedron Lett. 2000, 41, 6333.
9
6840 J. AM. CHEM. SOC. 2008, 130, 6840–6847
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2008 American Chemical Society

Asymmetric Hydrogenation Catalysis
A R T I C L E S
Chart 1. S-Binol Derivatives only Shown
Chart 2
In the same year, Reetz et al.4 reported that monophosphites
(LZ, Z ) OR) and de Vries, Feringa et al.5 that monophos-
phoramidites (LZ, Z ) NR2) gave highly enantioselective
hydrogenation catalysts (Chart 1). Both of these groups6 and
others7 have subsequently shown that the design of chiral
monophos ligands LZ is amenable to high throughput screening
techniques. (The term “monophos” is used throughout to mean
a monodentate P-donor rather than the DSM trademarked
“MonoPhos” family of phosphoramidite ligands.) One striking
discovery has been that catalysts based on mixtures of monophos
ligands LZ and achiral PY3 (Y ) alkyl, aryl, or OR) can be
more active and enantioselective than catalysts derived from
monophos ligands LZ alone.8 This implies that, in some cases,
the catalyst containing a Rh(LZ)(PY3) moiety is more active
and selective than one containing a Rh(LZ)2 moiety. This
approach has led to the development by the DSM group of a
commercialized asymmetric hydrogenation process.9
The results of the catalysis with the mixed monodentate ligand
systems are complicated to interpret because they depend on
the proportions of the homoligand {Rh(LZ)2 and Rh(PY3)2} and
heteroligand {Rh(LZ)(PY3)} catalysts present (and, in principle,
the proportions of rhodium complexes with 0–4 P-donors
coordinated10), the rates at which each of these catalyze the
hydrogenation, and their enantioselectivity.11,12 Not surprisingly
therefore, the enantioselectivity is a sensitive function of LZ,
the added PY3, and the prochiral substrate. One advantage that
bidentates have over monodentates is control over complex
stoichiometry and stereochemistry: in general, a single, cis-
chelate complex of stoichiometry M(diphos) is expected upon
the addition of a diphos ligand to a metal catalyst precursor.
Indeed several bidentate phosphine/phosphites13,14 and phos-
phine/phosphoramidites14,15 and a few phosphine/phosphonites16
have been shown to form excellent chelate catalysts. However,
a comparison of the performance of directly analogous hetero-
monophos and heterodiphos systems has not been reported.
In this contribution, the factors that determine the asymmetric
hydrogenation catalytic performance of rhodium complexes of
mixed phosphine/phosphonite bidentate and monodentate ligands
are probed by comparing the results obtained with catalysts
derived from the ligands shown in Chart 2. The efficacy of the
catalysts derived from the new, bidentate, phosphine/phosphonite
ligands LA and LB is compared with the corresponding results
for the catalysts derived from (i) the bis(phosphonites) L2a, L2b,
L3, and L4,1,17 (ii) the monophosphonites L1a and L1b, and (iii)
the mixture (M) of monophosphine PMePh2 and monophos-
phonite L1a.
Results and Discussion
Ligand Synthesis. The phosphine/phosphonite ligands LA and
LB were readily prepared by the route shown in eq 2 which is
an adaptation of King’s method18 for making Ph2PCH2CH2P-
(OMe)2.
(3) (a) Lagasse, F.; Kagan, H. B. Chem. Pharm. Bull. 2000, 48, 315. (b)
Chaloner, P. A.; Esteruelas, M. A.; Joó, F.; Oro, L. A. Homogeneous
Hydrogenation; Kluwer: London, 1994. (c) The Handbook of Homo-
geneous Hydrogenation; de Vries, J. G., Elsevier, C. J.,Eds.; Wiley-
VCH: Weinheim, 2007.
(4) Reetz, M. T.; Mehler, G. Angew. Chem., Int. Ed. 2000, 39, 3889.
(5) van den Berg, M.; Minnaard, A. J.; Schudd, E. P.; van Esch, J.; de
Vries, A. H. M.; de Vries, J. G.; Feringa, B. J. Am. Chem. Soc. 2000,
122, 11539.
(6) (a) de Vries, J. G.; Lefort, L. Chem. Eur. J. 2006, 12, 4722. and refs
therein. (b) Reetz, M. T.; Mehler, G.; Meiswinkel, A. Tetrahedron
Asymmetry 2004, 15, 2165. and refs therein.
The amidophosphine precursor and optically active binol are
commercially available. Racemic 10,10′-bi-9-phenanthrol (bi-
phol) was synthesized as shown in Scheme 1 and resolved by
Toda’s method19,20 (see Experimental Section).
(7) Jäkel, C.; Paciello, R. Chem. ReV. 2006, 106, 2912.
(8) (a) Hoen, R.; Boogers, J. A. F.; Bernsmann, H.; Ninnaard, A. J.;
Meetsma, A.; Tiermersma-Wegman, T. D.; de Vries, A. H. M.; de
Vries, J. G.; Feringa, B. L. Angew. Chem., Int. Ed. 2005, 44, 4208.
(b) Reetz, M. T.; Bondarev, O. Angew. Chem., Int. Ed. 2007, 46, 4523.
(9) de Vries, A. H. M.; Lefort, L.; Boogers, J. A. F.; de Vries, J. G.;
Ager, D. J. Chim. Oggi 2005, 23, 18.
(15) Wassenaar, J.; Reek, J. N. H. Dalton Trans. 2007, 3750 and refs
therein.
(10) An IrP1 complex has been shown to be the significant species in Ir-
monophos-catalyzed asymmetric hydrogenations. Giacomina, F.;
Meetsma, A.; Panella, L.; Lefort, L.; de Vries, A. H. M.; de Vries,
J. G. Angew. Chem., Int. Ed. 2007, 46, 1497.
(16) (a) Schull, T. L.; Knight, D. A. Tetrahedron Asymmetry 1999, 10,
207. (b) Reetz, M. T.; Gosberg, A. Tetrahedron Asymmetry 1999, 10,
2129. (c) Laly, M.; Broussier, R.; Gautheron, B. Tetrahedron Lett.
2000, 41, 1183.
(11) Reetz, M. T.; Mehler, G. Tetrahedron Lett. 2003, 44, 4593.
(12) Reetz, M. T.; Fu, Y.; Meiswinkel, A. Angew. Chem., Int. Ed. 2006,
45, 1412.
(17) (a) Dahlenburg, L. Coord. Chem. ReV. 2005, 249, 2962. and refs
therein. (b) Dahlenburg, L. Eur. J. Inorg. Chem. 2003, 2733. and refs
therein.
(13) Nozaki, K. Chem. Record 2005, 5, 376. and refs therein.
(14) Zhang, W.; Chi, Y.; Zhang, X. Acc. Chem. Res. 2007, 40, 1278 and
refs therein
(18) King, R. B.; Masler, W. F. J. Am. Chem. Soc. 1977, 99, 4001.
(19) Toda, F.; Tanaka, K. J. Org. Chem. 1988, 53, 3607.
9
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A R T I C L E S
Norman et al.
Scheme 1
Scheme 3
Scheme 2
Scheme 4
Ligands LA and LB are moderately air-sensitive solids but
are indefinitely stable in an inert atmosphere. The 31P NMR
spectra of LA and LB were particularly informative of purity:
3
in each case, two doublets were observed with J(PP) ≈ 30
Hz. The individual δ(P) values for LA (-11.8, +211.1) are
similar to the symmetrical analogues, dppe (-12.5) and L2a
(+211.5).1
Coordination Chemistry. The palladium(II) and platinum(II)
complexes 1a,b and 2a,b were made according to the routes
shown in Scheme 2 (see Experimental Section for the character-
izing data). Crystals of 1a suitable for X-ray diffraction were
grown by layering pentane on an acetonitrile solution of the
complex and the crystal structure of 1a as its acetonitrile solvate
has been determined (Figure 1). The crystal system was triclinic,
with two molecules of acetonitrile in the unit cell. In the crystal
structure of 1a, the five-membered chelate ring has a λ
conformation. The Pd-P(binol) bond is significantly shorter than
the Pd-PPh2 bond.21 The phosphonite donor apparently has a
slightly higher trans influence than the phosphine donor in 1a,
since the Pd-Cl bond trans to the P(binol) donor is longer than
the Pd-Cl trans to the PPh2 donor albeit by less than 0.02 Å.22
The rhodium coordination chemistry of the heterodiphos
ligands, LA and LB, and the mixture of monophos ligands M
was investigated because of its relevance to the asymmetric
catalysis described below and is summarized in Schemes 3–5.
The rhodium complexes 3a,b were made by the reaction of 1
equiv of the corresponding LA or LB with [Rh(cod)2]BF4
(Scheme 3). The 31P NMR data for the phosphine (δ 59.0,
J(RhP) 154 Hz) and phosphonite (δ 206.8, J(RhP) 222 Hz)
moieties in 3a are similar to the data for the homochelates
[Rh(cod)(dppe)]BF4 (δ 56.5, J(RhP) 148 Hz)23 and
[Rh(cod)(L2a)]BF4 (δ 205.7, J(RhP) 229 Hz)1 indicating that
the P-environments in the heterochelate 3a are similar to their
homochelate analogues.
When more than 1 equiv of LA or LB was added to
[Rh(cod)2]BF4, in each case a new product formed whose 31P
NMR spectrum was a symmetrical AA′MM′X pattern. The data
(see Experimental Section) are consistent with the formation
of the bis-chelates 4a or 4b in which the phosphine donors are
mutually cis.
The products formed upon treatment of M with 1 equiv of
[Rh(cod)2]BF4 were investigated by 31P NMR spectroscopy. The
spectrum obtained was consistent with the presence of com-
plexes 5-7 (Scheme 4) in approximately the statistical 2:1:1
ratio. Precisely the same mixture of products was obtained after
mixing the homoligand rhodium(I) complexes 624 and 71 in a
1:1 ratio in CH2Cl2. These experiments show that complexes
5-7 are in dynamic equilibrium (Scheme 4). The 31P NMR
data for the heteroligand complex 5 are similar to those for 3a
except the values of δ(P) are, as expected,25 to low frequency
of those for the five-membered chelate 3a.
(20) An alternative procedure for the synthesis of optically active biphol
has recently been reported. Ayudin, J.; Kumar, K. S.; Sayah, M. J.;
Wallner, O. A.; Szabó, K. J. J. Org. Chem. 2007, 72, 4689.
(21) Atherton, M. J.; Fawcett, J.; Hill, A. P.; Holloway, J. H.; Hope, E. G.;
Russell, D. R.; Saunders, G. C.; Stead, R. M. J. J. Chem. Soc., Dalton
Trans. 1997, 1137.
(23) de Wolf, E.; Spek, A. L.; Kuipers, B. W. M.; Philipse, A. P.; Meeldijk,
J. D.; Bomans, P. H. H.; Frederik, P. M.; Deelman, B-J.; van Koten,
G. Tetrahedron 2002, 58, 3911.
(24) Osborn, J. A.; Schrock, R. R. J. Am. Chem. Soc. 1971, 93, 2397.
(25) Appleton, T. G.; Bennett, M. A.; Tomkins, I. B. J. Chem. Soc., Dalton
Trans. 1976, 439.
(22) Martín, A.; Orpen, A. G. J. Am. Chem. Soc. 1996, 118, 1464.
9
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Asymmetric Hydrogenation Catalysis
A R T I C L E S
Scheme 5
Figure 1. Solid-state molecular structure of 1a (S-isomer). Hydrogen atoms
have been omitted for clarity. Selected bond lengths (Å) and angles (deg):
Pd(1)-P(1) ) 2.1933(9), Pd(1)-P(2) ) 2.2525(9), Pd(1)-Cl(1) )
2.3621(9), Pd(1)-Cl(2) ) 2.3790(9), P(1)-O(1) ) 1.607(2), P(1)-O(2)
) 1.601(2), P(1)-C(2) ) 1.807(4), P(2)-C(1) ) 1.845(3), P(2)-C(21) )
1.818(4),P(2)-C(31))1.822(3);P(1)-Pd(1)-P(2))85.40(3),P(1)-Pd(1)-Cl(1)
) 90.50(3), P(2)-Pd(1)-Cl(2) ) 88.62(3), Cl(1)-Pd(1)-Cl(2) ) 95.61(3).
Table 1. Asymmetric Hydrogenations of Substrates A-Fa
substrate/eeb
entry
ligand
catalyst
A
B
C
D
E
F
1
2
3
4
LA
LB
LA
LA
3a
3b
in situ
4a
74
94
53
55
69
96
57
51
>99
>99
78
n.d.
72
92
n.d.
96
It was noted that the equilibrium in Scheme 4 took up to
1 h to be established but was reduced to 5 min by the addition
of PMePh2 which catalyzes the ligand exchange. Thus, in
order to obtain reproducible results in the hydrogenations
with M (see below), the isolated complexes 6 and 7 were
mixed in the presence of 0.1 equiv of PMePh2. In addition,
the catalyst was activated by submitting it to 5 atm of H2
for 1 h to obviate any potential problems in interpreting the
results due to 1,5-cyclooctadiene hydrogenation.26 The 31P
NMR spectrum of the products of hydrogenation of the
mixture of 5–7 showed the presence of three species in the
ratio of 2:1:1 (see Scheme 4). The major component was
assigned the structure 5′ on the basis of the AMX 31P NMR
a Conditions: in CH2Cl2, 5 bar H2, 25 °C, 1 mol % catalyst, 1 h;
conversions were 100% (see Experimental Section for full details). b The
%R enantiomer formed in excess.
Chart 3
1
pattern and the absence of hydride signals in the H NMR
spectrum of the mixture. The two minor products (doublets
in the 31P NMR spectrum) were assigned to the solvento
complexes 6′ and 7′ (see Experimental Section for the data).
It was apparent that the ratio in the 5–7 mixture was similar
to the ratio of the derivatives 5′–7′.
When the mixture M was added to 0.5 equiv of
[Rh(cod)2]BF4 in CH2Cl2, a single species was formed and
assigned the structure 8 (Scheme 5) on the basis of the
AA′MM′X pattern in the 31P NMR spectrum which was
similar to that observed for the bis-chelate analogue 4a. The
same species 8 is also the product of the addition of L1a to
6 or PMePh2 to 7 (Scheme 5). Compound 8 was only detected
when the ratio of mixture M to Rh exceeded 1:1. In the
catalysis experiments below, an excess of M was avoided
since we found that 8 had very low activity and gave
essentially racemic hydrogenation products.
Asymmetric Hydrogenation Catalysis. The chelates 3a,b were
screened for asymmetric hydrogenation of the substrates A-F
(Chart 3), and the results are collected in Table 1.
In general, the biphol-derived catalyst 3b was more selective
for these substrates than the binol-derived catalyst 3a. The
variation in the enantioselectivity with the cinnamic acid
derivatives B-F (entries 1 and 2, Table 1) shows the sensitivity
of the catalysts to subtle changes in the substrate structure. When
the catalyst used was made in situ by addition of LA to
[Rh(cod)2]BF4 rather than preformed 3a, the rates of hydrogena-
tion were slower and the ee was lower (entry 3, Table 1); in
fact the results were similar to those obtained with the preformed
bis-chelate 4a (entry 4, Table 1). The hydrogenation of substrate
B was carried out with preformed 3a and 3b at higher (25 atm)
and lower (1 atm) pressure of H2; this had no effect on the
enantioselectivities, but the rates of hydrogenation were faster
at higher H2 pressure.
The efficiency of the heterochelate catalyst 3a for hydrogena-
tion of substrate A was compared with those of the homochelates
[Rh(cod)(L2a)]BF4 and [Rh(cod)(dppe)]BF4 by monitoring the
substrate conversion as a function of time. Under the same
reaction conditions (see Experimental Section), after 3 min,
the conversion of substrate A using 3a as catalyst was 95%,
using [Rh(cod)(L2a)]BF4 as catalyst was 33%, and using
[Rh(cod)(dppe)]BF4 as catalyst was 8%. These experiments
show that having a mixed P-donor set in this case leads to a
significant enhancement in rate; we27,28 and others13 have
previously noted a synergic effect on the rates of catalysis with
mixed P-donor catalysts.
(27) Carraz, C. A.; Ditzel, E. J.; Orpen, A. G.; Ellis, D. D.; Pringle, P. G.;
Sunley, G. J. Chem. Commun. 2000, 1277.
(28) Basra, S.; de Vries, J. G.; Hyett, D. J.; Harrison, G.; Heslop, K. M.;
Orpen, A. G.; Pringle, P. G.; von der Luehe, K. Dalton Trans. 2004,
1901.
(26) Cobley, C. J.; Lennon, I. C.; McCague, R.; Ramsden, J. A.; Zanotti-
Gerosa, A. Tetrahedron Lett. 2001, 42, 7481.
9
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A R T I C L E S
Norman et al.
Table 2. Comparison of Asymmetric Hydrogenations of Substrates
A and Ba
the mismatched S,S-λ species (entries 3 and 6, Table 2). It appears
that the conformation (or shape) of the catalyst responds to the
substrate, i.e., an allosteric effect.32 Support for the suggestion that
the substrate can influence the chelate conformation comes from
the crystal structures of complexes of the type [Rh(diphos)(η4-
diene)]+ which show that the adoption of a δ or λ chelate
conformation depends on the diene.33
There is a striking contrast between the high enantioselec-
tivities obtained with biphol-heterochelate [Rh(cod)(LB)]BF4
(entry 2, Table 2) and the low enantioselectivities obtained with
biphol-homochelate [Rh(cod)(L2b)]BF4 (entry 4, Table 2). As
above, we suggest that at least part of the explanation for this
is the difference in populations and/or activities of the matched
and mismatched conformers.
Inspection of the enantioselectivities obtained with the
catalysts derived from analogous monophosphonite and diphos-
phonite catalysts reveals complicated behavior. The catalyst
derived from the binol-monodentate L1a gave higher ee’s (entry
7, Table 2) than the analogous diphos L2a (entry 3, Table 2),
whereas the biphol-derived monodentate L1b and diphos L2b
both gave poor ee’s (entries 4 and 8, Table 2). The greater
conformational flexibility of monodentate P-complexes (via
Rh-P rotation) than analogous diphos complexes coupled with
an incomplete understanding of the mechanism of the hydro-
genation with monodentate P-catalysts10,34,35 makes interpreta-
tion of these enantioselectivities fraught with difficulties.
The distinction is clearer when the unsymmetrical diphos LA
(entry 1, Table 2) is compared with the mixture of monodentates
M (entry 9, Table 2). The catalyst derived from the mixture M
not only gives lower ee’s than LA but the sense of optical
induction is opposite. Reetz et al. reported a similar inversion
of optical induction with catalysts derived from mixtures of
chiral phosphites and achiral phosphines.11 Assuming the
catalysts 5–7 act independently, the net S-selectivity must be
due to the mixed monodentate complex 5 since 6 is achiral and
7 gives R-product (Entry 7, Table 2). To probe this further, the
hydrogenation of A catalyzed by 6, 7, and the 2:1:1 mixture of
5–7 derived from M was monitored by measuring the conver-
sions to product as a function of time. Under the same reaction
conditions (see Experimental Section), with the same Rh
concentrations, after 3 min, the conversions were, 95% using
mixture 5–7 as catalyst, 50% using [Rh(cod)(PMePh2)2]BF4 (6)
as catalyst, and 60% using [Rh(cod)(L1a)2]BF4 (7) as catalyst.
Thus, as with the heterodiphos catalyst 3a, the heteromonophos
catalyst 5 shows a synergic effect of the mixed donors on the
rate of catalysis. This kinetic advantage offers the prospect of
phosphonite/phosphine mixtures being discovered that yield
efficient and selective catalysts.
eec
entry
ligandb
A
B
ref
1
2
3
4
5
6
7
8
9
LA
LB
L2a
L2b
L3
74
94
90
23
89
26
93
29
-40
69
96
19
14
85
36
92
-14
-27
this work
this work
1
1
17
17
this work
1
this work
L4
L1a
L1b
Md
a Conditions in this work: 5 bar H2, 25 °C, CH2Cl2 (unless otherwise
stated), 1 mol % catalyst (see Experimental Section for full details).
b Preformed rhodium complexes were used unless otherwise stated.
c The %R-enantiomer formed in excess; a negative number indicates that
the S-enantiomer was in excess. d This catalyst was generated by mixing
complexes 6 and 7 (see Experimental Section ) in a 5:1 mixture of
EtOAc/CH2Cl2. In pure CH2Cl2, the ee was -14% with substrate A and
-11% with substrate B.
The data collected in Table 2 will be used to discuss the results
obtained for the asymmetric hydrogenations of substrates A and
B with catalysts derived from the ligands shown in Chart 2.
The bidentate ligands LA, LB, L2a, and L2b all contain the
flexible PCH2CH2P unit which allows the metal chelate rings
to adopt chiral δ and λ conformations (Figure 2a). Rapid ring
inversion would be expected,29 but these conformers will not
be equally populated in solution because they are diastereoi-
somers, by virtue of the S-binol or S-biphol substitutents. In
terms of the catalyst enantioselectivity, one of the diastereoi-
somers will be the matched isomer, and the other, the mis-
matched isomer. The ee obtained will depend on the relative
abundance of the two diastereoisomers and their catalytic activity
and enantioselectivity.
Dahlenburg17 has convincingly demonstrated, with evidence
from the S-binol-derived ligands L3 and L4 which have enforced
δ and λ conformations (Figure 2b), that the δ chelate is the
matched isomer, i.e. for the hydrogenation of substrates A and
B, the catalyst derived from L3 gave higher R-enantioselectivity
than the catalyst derived from L4 (see entries 5 and 6). They
argued that upper-left/lower-right quadrant blocking (which
favors R-enantioselectivity30) by the S-binol substituents was
reinforced by the δ conformation of the chelate which puts the
blocking groups in a more effective pseudoaxial site. The crystal
structures of [PdCl2(LA)] and [PtCl2(L2b)]1 reproduced in Figure
3 corroborate this explanation: in the δ conformer [PdCl2(LA)]
(Figure 3a) the upper-left quadrant is clearly more blocked than
in the λ conformer [PtCl2(L2b)] (Figure 3b).
We suggest that solutions of the catalysts derived from L2a and
Conclusion
L
2b contain mixtures of matched (S,S-δ) and mismatched (S,S-λ)
chelates (Figure 2a).31 The high ee obtained in the hydrogenation
of substrate A with the catalyst derived from L2a is consistent with
the catalyst behaving as the matched S,S-δ species (compare entries
3 and 5, Table 2) whereas the low ee obtained for substrate B
with the same catalyst is consistent with the catalyst behaving as
Monodentate P-ligands have made a great impact on asymmetric
hydrogenation catalysis in recent years. From the discovery of
(32) (a) Allosteric effects are normally associated with enzyme catalysts
although synthetic catalysts are known that show allosteric effects;
see: Merlau, M. L.; Mejia, M. P.; Nguyen, S. T.; Hupp, J. T. Angew.
Chem., Int. Ed. 2001, 40, 4239. (b) Gianneschi, N. C.; Bertin, P. A.;
Nguyen, S. T.; Mirkin, C. A.; Zakharov, L. N.; Rheingold, A. L. J. Am.
Chem. Soc. 2003, 125, 10508. (c) We have previously suggested an
allosteric effect with an asymmetric hydrogenation catalyst; see: Baber,
A.; de Vries, J. G.; Orpen, A. G.; Pringle, P. G.; von der Luehe, K.
Dalton Trans. 2006, 4821.
(29) Fernandez, E.; Gillon, A.; Heslop, K.; Horwood, E.; Hyettt, D. J.;
Orpen, A. G.; Pringle, P. G. Chem. Commun. 2000, 1663.
(30) Gridnev, I.; Imamoto, T. Acc. Chem. Res. 2004, 37, 633.
(31) The 31P NMR spectrum of [Rh(cod)(L2a)]BF4 and [Rh(cod)(LA)]BF4
in CH2Cl2 solution showed only one set of signals even at-80°C;
this could be because only one conformer is present at NMR-detectable
levels or, more likely, that the λ and δ conformers are in rapid
equilibrium with a low-energy barrier to ring inversion.
(33) Tsuruta, H.; Imamoto, T.; Yamaguchi, K.; Gridnev, I. D. Tetrahedron
Lett. 2005, 46, 2879.
(34) Gridnev, I. D.; Fan, C.; Pringle, P. G. Chem. Commun. 2007, 1319.
9
6844 J. AM. CHEM. SOC. VOL. 130, NO. 21, 2008

Asymmetric Hydrogenation Catalysis
A R T I C L E S
Figure 2. (a) Schematic of the δ/λ conformer equilibrium for a ligand with a flexible C2-backbone; (b) Dahlensburg’s ligands which give δ and λ chelate
conformers respectively enforced by the rigid C2-backbone.17
more difficult to predict, with the rotationally less constrained
monodentate P-ligands, as implied by the opposite sense of
induction observed with the heterodiphos and analogous het-
eromonophos systems described here. Further mechanistic
studies aimed at deepening the understanding of these important
features are in progress.34
Experimental Section
Unless otherwise stated, all work was carried out under a dry
nitrogen atmosphere, using standard Schlenk line techniques. Dry
N2-saturated solvents were collected from a Grubbs system37 in
flame- and vacuum-dried glassware. Anhydrous methanol and
pentane were purchased from Aldrich and were degassed prior to
use by bubbling with dry nitrogen. 2,2-Dimethoxypropane was
freshly distilled prior to use. [PtCl2(cod)],38 [PdCl2(NCPh)2],39 and
[Rh(cod)2]BF4,40 were prepared by literature methods. (S)-(-)-1,1′-
bi-2-naphthol was purchased from Syncom BV, Groningen and
Ph2P(CH2)2P(NMe2)2 was purchased from EPP Ltd. (Edinburgh).
Substrates C-F were supplied by DSM chemicals. All other starting
materials were purchased from Aldrich. Unless otherwise stated,
1H, 13C, and 31P NMR spectra were recorded at 300, 75, and 121
Figure 3. Crystal structures of (a) [PdCl2(LA)] (1a) and (b) [PtCl2(L2b)]1
(with phenanthrene fragments truncated for ease of comparison) showing
the δ and λ chelate conformations and their effect on the upper-left quadrant
blocking.
MHz respectively at +23 °C on a Jeol ECP 300 spectrometer. Mass
spectra were recorded on a Fisons MD800 (FAB), a VG Analytical
Quattro (ESI) or a VG Analytical Autospec (EI). Elemental analyses
were carried out by the Microanalytical Laboratory of the School
of Chemistry, University of Bristol.
effective combinations of achiral and optically active monodentates
has emerged a powerful high throughput protocol for tailoring
catalysts to a particular substrate. The comparison of the hetero-
bidentate phosphino/phosphonite LA and the monophosphonite/
monophosphine analogue M presented in this article has revealed
that the greater activity of the heteroligand catalysts compared to
that of the homoligand catalysts is true for the bidentate and
monodentate systems. The synergic effect of the heteroligands on
the rate explains why the heteromonodentates dominate the catalysis
in mixed monodentate systems.
It is well-known that the performance of many asymmetric
hydrogenation catalysts is sensitive to the substrate,36 and here
we have argued that chelate catalysts with flexible backbones
will be particularly prone to this sensitivity because of substrate-
induced conformational changes, i.e. allosteric effects. For
example, the observation of the contrasting performances of the
five-membered chelates formed by the diphosphonites L2a, L2b
and the phosphine/phosphonites LA, LB can be partly explained
by differences in populations and activities of matched (δ) and
mismatched (λ) conformers of the chelate catalysts. Conforma-
tional preferences will certainly be important, but inevitably
9-Hydroxyphenanthrene. This precursor was prepared in pure
form for the coupling reaction to racemic 10,10′-bi-9-phenanthrol
described below since the commercially available technical grade of
9-hydroxyphenanthrene was found to be unsuitable for the coupling
reaction. Magnesium turnings (2.08 g, 86 mmol) were activated
overnight by vigorous stirring under nitrogen. A dropping funnel was
charged with a solution of 9-bromophenanthrene (20.04 g, 78 mmol)
in tetrahydrofuran (65 cm3). Enough of this solution was added to
cover the magnesium turnings followed by the rest of the solution
dropwise. After the addition, the mixture was refluxed for 20 h followed
by cooling to room temperature to give the Grignard reagent. In a
separate flask a solution of trimethylborate (9.6 cm3, 86 mmol) in
tetrahydrofuran (65 cm3) was cooled to -10 °C, and the Grignard
was added dropwise while maintaining the temperature below 0 °C.
The solution was stirred for 1 h at -5 °C and then recooled to -10
°C. Glacial acetic acid (7 cm3) was added followed by a solution of
30% aqueous hydrogen peroxide (8.7 cm3) in water (7.9 cm3) while
maintaining the solution at <0 °C. The resulting brown solution was
allowed to warm to room temperature while stirring for an additional
40 min. Saturated aqueous ammonium chloride solution was added
(100 cm3) followed by tetrahydrofuran (50 cm3), and the organic layer
(37) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.;
Timmers, F. J. Organometallics 1996, 15, 1518.
(38) McDermott, J. X.; White, J. F.; Whitesides, G. M. J. Am. Chem. Soc.
1976, 98, 6521.
(35) Reetz, M. T.; Meiswinkel, A.; Mehler, G.; Angermund, K.; Graf, M.;
Thiel, T.; Mynott, R.; Blackmond, D. G. J. Am. Chem. Soc. 2005,
127, 10305.
(39) Doyle, J. R.; Slade, P. E.; Jonassen, H. B. Inorg. Synth. 1960, 6, 218.
(40) Schenk, T. G.; Downes, J. M.; Milne, C. R. C.; MacKenzie, P. B.;
Boucher, H.; Whelan, J.; Bosnich, B. Inorg. Chem. 1985, 24, 2334.
(36) Tang, W.; Zhang, X. Chem. ReV. 2003, 103, 3029.
9
J. AM. CHEM. SOC. VOL. 130, NO. 21, 2008 6845

A R T I C L E S
Norman et al.
1
2
was separated. The organic layer was washed with saturated aqueous
sodium bicarbonate solution (100 cm3), water (100 cm3), and brine
(3 × 100 cm3), dried with magnesium sulfate, and filtered. The solvent
was removed in vacuo to yield a brown oil. This oil was dissolved in
toluene, and the solvent was removed in vacuo to give 9-hydrox-
yphenanthrene as a light-brown powder (13.77 g, 71 mmol, 91%).
The product can be recrystallized from toluene. Melting point: 134–136
°C; MS(EI): m/z ) 194 (M+); 1H (270 MHz, CDCl3) δ: 5.30 (s, 1H,
OH), 7.02 (s, 1H, ArH), 7.47–7.57 (m, 2H, ArH), 7.62–7.73 (m, 3H,
ArH), 8.30–8.33 (m, 1H, ArH), 8.58–8.70 (m, 2H, ArH).
13C{1H} (CDCl3) δ: 19.53 (dd, J(CP) ) not resolved, J(CP) )
1
2
14.9 Hz, CH2PPh2), 31.72 (dd, J(CP) ) 37.4 Hz, J(CP) ) 13.3
Hz, CH2P(biphol)), 121.25 (d, J(CP) ) 3.4 Hz), 121.91 (d, J(PC)
) 5.8 Hz), 123.06 (s), 123.10 (d, J(PC) ) 1.7 Hz), 125.48 (s),
125.84 (s), 125.88 (s), 126.69 (s), 126.77 (s), 127.24 (d, J(PC) )
1.2 Hz), 127.36 (s), 127.41 (s), 127.87 (s), 127.93 (s), 128.01 (s),
128.10 (s), 128.40 (s), 128.51 (s), 128.56 (s), 128.60 (s), 128.65
(s), 128.78 (s), 128.85 (s), 129.21 (s), 131.46 (d, J(PC) ) 1.2 Hz),
131.64 (d, J(PC) ) 1.2 Hz), 131.72 (d, J(PC) ) 1.7 Hz), 132.07
(s), 132.59 (s), 132.68 (s), 132.83 (s), 132.94 (s), 137.66 (d, J(PC)
) 13.3 Hz), 137.97 (d, J(PC) ) 13.3 Hz), 146.05 (d, J(PC) ) 8.1
Hz, C-O), 147.06 (d, J(PC) ) 3.5 Hz, C-O′).
Racemic 10,10′-Bi-9-phenanthrol. Copper(II) nitrate trihydrate
(5.00 g, 21 mmol) was added to a stirred solution of 9-hydrox-
yphenanthrene (2.01 g, 10 mmol) in methanol (50 cm3) at room
temperature. Benzylamine (6.8 cm3, 62 mmol) was added to the
deep-blue solution to give a thick brown suspension. The reaction
mixture was stirred under nitrogen overnight and then quenched
with a 2 M solution of hydrochloric acid (40 cm3) to afford a thick
blue-white suspension. The layers were partitioned by the addition
of brine (50 cm3) and CH2Cl2 (50 cm3). The organic layer was
separated and washed with 2 M aqueous ammonium hydroxide
solution until the aqueous layer remained colorless. The organic
layer was then washed with brine (2 × 100 cm3), dried with
magnesium sulfate, and filtered, and the solvent was removed in
vacuo to give racemic 10,10′-bi-9-phenanthrol as a yellow solid
(1.78 g, 4.6 mmol, 89%). Melting point: 231–233 °C; MS(EI): m/z
) 386 (M+), 368 (M - 18+);1H (CDCl3) δ: 5.50 (2H, s, OH),
7.27 (2H, dd, 3J(HH) ) 8.4 Hz, 4J(HH) ) 1.2 Hz, ArH), 7.35
(2H, ddd, 3J(HH) ) 8.2 Hz, 3J′(HH) ) 6.9 Hz, 4J(HH) ) 1.2 Hz,
ArH), 7.54 (2H, ddd, 3J(HH) ) 8.3 Hz, 3J′(HH) ) 6.8 Hz, 4J(HH)
[PdCl2(LA)] (1a). To a solution of [PdCl2(NCPh)2] (90 mg, 0.23
mmol) dissolved in CH2Cl2 (2 cm3) was added a solution of LA
(124 mg, 0.23 mmol) in CH2Cl2 (2 cm3). After stirring the mixture
for 1 h the volatiles were removed in vacuo. The residue was
redissolved in CH2Cl2 (2 cm3) and filtered through Celite. The Celite
was washed with CH2Cl2 (10 cm3), and the volume of the resultant
solution was concentrated to ∼2 cm3. Diethyl ether (10 cm3) was
added to precipitate an orange solid. The solid was filtered, washed
with diethyl ether (2 × 10 cm3), and dried in vacuo to give 1a as
a pale-orange solid (96 mg, 0.14 mmol, 61%). Elemental analysis
(calcd): C, 57.98 (57.86); H, 3.83 (3.71); MS(FAB): m/z ) 706
(M+), 671 (M+
-
35Cl);31P{1H} (CDCl3) δ: 65.5 (2J(PP) ) 12.1
Hz, PPh2), 182.3 (2J(PP) ) 12.1 Hz, P(binol)); H (CD2Cl2) δ:
1
1.84–2.61 (4H, m, CH2CH2), 7.04–8.21 (22H, m, ArH).
[PdCl2(LB)] (1b). The complex was prepared similarly to 1a
from LB to give 1b as a white powder (43 mg, 0.05 mmol, 70%).
Elemental analysis (calcd 1b·2CH2Cl2): C, 53.99 (54.16); H, 3.59
3
3
) 1.5 Hz, ArH), 7.72 (2H, ddd, J(HH) ) 8.2 Hz, J′(HH) ) 7.0
Hz, 4J(HH) ) 1.2 Hz, ArH), 7.82 (2H, ddd, 3J(HH) ) 8.3 Hz,
3J′(HH) ) 7.0 Hz, 4J(HH) ) 1.4 Hz, ArH), 8.46 (2H, dd, 3J(HH)
) 8.1 Hz, 4J(HH) ) 1.1 Hz, ArH), 8.75 (2H, d, 3J(HH) ) 8.3 Hz,
ArH), 8.81 (2H, d, 3J(HH) ) 8.3 Hz, ArH). The 10,10′-bi-9-
phenanthrol was resolved using Toda’s procedure.19
(3.51); MS(FAB): m/z ) 805 (M+), 770 (M+ - Cl), 735 (M+
-
2Cl);31P{1H} (D6-dmso) δ: 69.2 (2J(PP) ) 14.9 Hz, PPh2), 192.8
1
(2J(PP) ) 14.9 Hz, P(biphol)); H (D6-dmso) δ: 2.35–3.15 (4H,
m, CH2CH2), 7.10 (1H, d, J ) 8.1 Hz, ArH), 7.18 (1H, d, J ) 8.4
Hz, ArH), 7.30–7.37 (2H, m, ArH), 7.53–7.77 (10H, m, ArH),
7.80–7.92 (4H, m, ArH), 7.95–8.04 (2H, m, ArH), 8.07 (1H, d, J
) 8.1 Hz, ArH), 8.41 (1H, d, J ) 8.2 Hz, ArH), 8.91–8.97 (3H,
m, ArH), 9.01 (1H, d, J ) 8.4 Hz, ArH).
Preparation of LA. Ph2P(CH2)2P(NMe2)2 (1.15 g, 3.46 mmol)
was dissolved in toluene (50 cm3), and (S)-(-)-1,1′-bi-2-naphthol
(0.99 g, 3.46 mmol) was added. The reaction mixture was refluxed
for 16 h, and the solvent was removed in vacuo to give a white
foamy solid. Trituration with pentane afforded LA as a white solid
(1.74 g, 3.29 mmol, 95%). MS(EI): m/z ) 528 (M+); HRMS(EI):
calculated for C34H26O2P2: 528.1408, found 528.1401; 31P{1H}
[PtCl2(LA)] (2a). To a solution of [PtCl2(cod)] (88 mg, 0.23
mmol) dissolved in CH2Cl2 (4 cm3) was added a solution of LA
(124 mg, 0.23 mmol) in CH2Cl2 (3 cm3). After stirring the mixture
for 1 h, the solution was concentrated to ∼2 cm3, and diethyl ether
(10 cm3) was added to precipitate a white solid. The solid was
filtered, washed with diethyl ether (2 × 10 cm3), and dried in vacuo
to give 2a as a white solid (151 mg, 0.19 mmol, 83%). Elemental
analysis (calcd 2a·Et2O): C, 52.73 (52.60); H, 3.99 (4.07);
3
3
(CDCl3) δ: -11.8 (d, J(PP) ) 28 Hz, PPh2), 211.1 (d, J(PP) )
28 Hz, P(binol)); 1H (CDCl3) δ: 1.56–1.74 (2H, m, CH2PPh2),
2.10–2.27 (2H, m, CH2P(binol)), 7.04–7.44 (18H, m, ArH),
7.70–7.97 (4H, m, ArH); 13C{1H} (100 MHz, CDCl3) δ: 19.63
(dd, 1J(PC) ) 16.9 Hz, 2J(PC) ) 14.6 Hz, CH2PPh2), 29.94
MS(FAB): m/z ) 759 (M+
-
35Cl); 31P{1H} (CD2Cl2) δ: 43.3
(1J(PtP) ) 3500 Hz,2J(PP) ) 1.9 Hz, PPh2), 153.3 (1J(PtP) ) 5031
Hz,2J(PP) ) 1.9 Hz, P(binol));1H (CD2Cl2) δ: 1.83–2.59 (4H, m,
CH2CH2), 7.15–8.06 (22H, m, ArH).
2
(dd,1J(PC) ) 36.9 Hz, J(PC) ) 14.6 Hz, CH2P(binol)), 121.39
(d, J(PC) ) 1.5 Hz), 122.00 (s), 123.62 (d, J(PC) ) 3.1 Hz), 124.71
(d, J(PC) ) 5.4 Hz), 125.03 (d, J(PC) ) 6.9 Hz), 126.39 (s), 126.98
(d, J(PC) ) 3.8 Hz), 128.40 (s), 128.50 (s), 128.56 (s), 128.65 (d,
J(PC) ) 2.3 Hz), 128.72 (s), 128.84 (s), 129.02 (s), 129.16 (s),
129.94 (s), 130.79 (s), 131.15 (s), 131.61 (s), 132.65 (s), 132.83
(s), 132.92 (s), 132.97 (s), 133.15 (s), 137.93 (d, J(PC) ) 1.5 Hz),
138.06 (d, J(PC) ) 1.5 Hz), 148.41 (d, J(PC) ) 6.9 Hz, C-O),
150.30 (d, J(PC) ) 3.1 Hz, C-O′).
[PtCl2(LB)] (2b). The complex was prepared similarly to 2b from
LB to give 2b as a white powder (107 mg, 0.12 mmol, 63%).
Elemental analysis (calcd 2b·CH2Cl2): C, 52.29 (52.72); H, 3.41
(3.29); MS(FAB): m/z ) 894 (M+), 859 (M+ - Cl);31P{1H} (D6-
dmso) δ: 44.8 (1J(PtP) ) 3465 Hz, J(PP) not observed, PPh2),
2
160.9 (1J(PtP) ) 5066 Hz, 2J(PP) not observed, P(biphol)); 1H
(D6-dmso) δ: 2.23–2.41 (2H, m, CH2PPh2), 2.67–3.09 (2H, m,
CH2P(biphol)), 7.19 (1H, d, J ) 7.7 Hz, ArH), 7.27 (1H, d, J )
8.1 Hz, ArH), 7.39 (1H, d, J ) 8.4 Hz, ArH), 7.44 (1H, d, J ) 7.7
Hz, ArH), 7.59–8.10 (16H, m, ArH), 8.18 (1H, d, J ) 7.9 Hz, ArH),
8.46 (1H, d, J ) 8.1 Hz, ArH), 8.97–9.04 (3H, m, ArH), 9.06 (1H,
d, J ) 8.2 Hz, ArH).
Preparation of LB. Prepared similarly to LA from (S)-(-)-10,10′-
bi-9-phenanthrol to give LB as a pale-yellow solid (0.578 g, 0.92
mmol, 97%). MS(EI): m/z ) 628 (M+); HRMS(EI): calculated for
C42H30O2P2: 628.1721, found 628.1723; 31P{1H} (CDCl3) δ: -11.9
3
3
(d, J(PP) ) 28 Hz, PPh2), 216.2 (d, J(PP) ) 28 Hz, P(biphol));
1H (CDCl3) δ: 1.67–1.79 (2H, m, CH2PPh2), 2.06–2.18 (1H, m,
CHH′P(biphol)), 2.30–2.40 (1H, m, CHH′P(biphol)), 7.14–7.39
[Rh(cod)(LA)]BF4 (3a). To a solution of [Rh(cod)2]BF4 (321
mg, 0.79 mmol) dissolved in CH2Cl2 (2 cm3) was added a solution
of LA (418 mg, 0.79 mmol) in CH2Cl2 (10 cm3) dropwise over 5
min. The resulting yellow solution was stirred for a further 30 min,
and then the solution was concentrated to ∼5 cm3, and the orange
solid product 3a precipitated by the addition of Et2O (∼15 cm3).
The product 3a was filtered off and dried in vacuo (500 mg, 0.61
mmol, 77%). Elemental analysis (calcd): C, 61.30 (61.04); H, 5.05
3
(14H, m, ArH), 7.35–7.62 (2H, m, ArH), 7.66 (1H, td, J(HH) )
4
3
7.6 Hz, J(HH) ) 1.0 Hz, ArH), 7.73 (1H, td, J(HH) ) 7.6 Hz,
4J(HH) ) 1.0 Hz, ArH), 7.75–7.81 (2H, m, ArH), 8.19 (1H, dd,
3J(HH) ) 8.1 Hz, J(HH) ) 1.1 Hz, ArH), 8.35 (1H, dd, J(HH)
4
3
4
3
) 7.8 Hz, J(HH) ) 1.4 Hz, ArH), 8.76 (2H, dd, J(HH) ) 8.2
Hz, 4J(HH) ) 2.5 Hz, ArH), 8.79 (2H, d, 3J(HH) ) 8.2 Hz, ArH);
9
6846 J. AM. CHEM. SOC. VOL. 130, NO. 21, 2008

Asymmetric Hydrogenation Catalysis
A R T I C L E S
(4.63); MS(FAB): m/z ) 739 (M+ - BF4), 631 (M+ - BF4 -
under 5 atm of H2 for 10 min in a 50 cm3 glass autoclave. The
pressure was then reduced to 1 atm H2, a solution of substrate A
(50.0 mg, 0.35 mmol) in ethyl acetate (4.0 cm3) was added and
the mixture stirred. Samples were taken at 0.5, 1, 3, 10, and 20
min and the conversions measured by GC analysis. All runs were
done in duplicate.
2
cod); 31P{1H} (CDCl3) δ: 59.0 (dd,1J(RhP) ) 154 Hz, J(PP) )
27 Hz, PPh2), 206.8 (dd,1J(RhP) ) 222 Hz, 2J(PP) ) 27 Hz,
1
P(binol)); H (CDCl3) δ: 2.07–2.70 (12H, m, CH2CH2 and 4 CH2
groups from cod), 4.43 (1H, br, cod-CH), 5.09 (1H, br, cod-CH),
5.42 (1H, br, cod-CH), 5.74 (1H, br, cod-CH), 7.13–8.19 (22H, m,
ArH). In the presence of an excess of LA complex 3a reacts to
form a new species assigned the bis-chelate structure 4a. 31P{1H}
(CH2Cl2) analyzed as an AA′MM′X spin system: δA: 218.7 (1J(RhP)
) 191.8 Hz, P(binol)), δM: 53.6 (1J(RhP) ) 127.5 Hz, PPh2),
J(AM) ) 333.1, J(AM′) ) -30.7 Hz, J(AA′) ) 31.9, J(MM′) )
22.6 Hz.
Asymmetric Hydrogenation of Substrates B-F. The catalyst
(preformed complexes 3a, 3b, 4a, 5–7 or ligands LA or LB with
equimolar amounts of [Rh(cod)2]BF4 (0.010 mmol)) and the
substrates B-F (1.0 mmol) were mixed in glass vessels in air. Up
to eight vessels were placed in an Endeavor parallel screening
apparatus and flushed with nitrogen. CH2Cl2 was added (5 cm3),
and the apparatus was sealed. The vessels were then purged 10
times with nitrogen and once with hydrogen. The autoclave was
pressurized with hydrogen (1, 5, or 25 bar), and gas uptake was
monitored. After hydrogen uptake was complete (usually within
1 h), the reaction solutions were filtered through a small plug of
silica to remove the catalyst. Volatiles were removed on a rotary
evaporator, and the conversion was measured by 1H NMR
spectroscopy. The products were characterized by GC for substrate
B and HPLC for C-F using the following conditions. For substrate
B, Varian Chiracel-L-Val column (25 m × 0.25 mm × 0.12 µm),
He (carrier) 1.5 cm3/min, 160 °C; for substrate C, Chiracel OJ
column (250 mm × 4.6 mm), hexane/iPrOH, 80:20; for substrates
D and E, Chiralpak-AD (250 mm × 4.6 mm), hexane/iPrOH, 70:
10; for substrate F: HPLC, Chiralpak-AD (250 mm × 4.6 mm);
hexane/iPrOH, 90:10.
[Rh(cod)(LB)]BF4 (3b). The complex was prepared similarly to
3a from LB to give 3b as an orange powder (145 mg, 0.16 mmol,
90%). Elemental analysis (calcd for 3b·CH2Cl2 ·Et2O): C, 60.44
(60.85); H, 4.73 (5.01); MS(EI): m/z ) 838 (M+ - BF4); 31P{1H}
2
(CDCl3) δ: 57.3 (dd,1J(RhP) ) 154 Hz, J(PP) ) 27 Hz, PPh2),
209.3 (dd,1J(RhP) ) 223 Hz, 2J(PP) ) 27 Hz, P(biphol)); 1H
(CDCl3) δ: 1.46–1.79 (12H, m, CH2CH2 and 4 CH2 groups from
cod), 3.86 (1H, br, cod-CH), 5.28 (2H, br, 2 cod-CH), 5.93 (1H,
br, cod-CH), 7.30–7.98 (19H, m, ArH), 8.24 (1H, d, J ) 8.5 Hz,
ArH), 8.53 (1H, d, J ) 8.5 Hz, ArH), 8.77–8.86 (4H, m, ArH),
8.87 (1H, d, J ) 7.8 Hz, ArH). In the presence of an excess of LB
complex 3b reacts to form a new species assigned the bis-chelate
structure 4b. 31P{1H} (CH2Cl2) the AA′MM′X pattern was not fully
analyzed: δ: 53.8 (1J(RhP) ) 125 Hz, |J(AM) + J(AM′)| ) 306
Hz,PPh2), 223.0 (1J(RhP) ) 190 Hz, P(biphol)).
[Rh(cod)(L1a)(PMePh2)]BF4 (5). Ligand mixture M was pre-
pared by combining a solution of PMePh2 (11 mg, 0.055 mmol) in
CH2Cl2 (0.3 cm3) with a solution of L1a (18 mg, 0.055 mmol) in
CH2Cl2 (0.3 cm3) and was added to a NMR tube charged with
[Rh(cod)2]BF4 (22 mg, 0.055 mmol) to give a light-orange solution
of the products. 31P{1H} (CH2Cl2), major species 5, δ: 14.8
(dd,1J(RhP) ) 146 Hz, 2J(PP) ) 40 Hz, PMePh2), 192.4
(dd,1J(RhP) ) 211 Hz, 2J(PP) ) 40 Hz, PMe(binol)); minor species
[Rh(cod)(PMePh2)2]BF4 (6), δ: 11.4 (d,1J(RhP) ) 144 Hz) and
[Rh(cod)(L1a)2]BF4 (7), δ: 190.5 (d,1J(RhP) ) 208 Hz). The relative
ratio of complexes 5, 6, and 7 remained constant after 1 h at 2:1:1.
The same mixture of 5–7 was also made by mixing a solution of
6 (15 mg, 0.022 mmol) in CH2Cl2 (0.3 cm3) and 7 (21 mg, 0.022
mmol) in CH2Cl2 (0.3 cm3); with this method, equilibration took
1 h unless a trace (5–10%) of PMePh2 was added when equilibrium
was achieved in less than the time required to obtain an NMR
spectrum of the reaction mixture (∼5 min).
X-ray Experimental. X-Ray diffraction experiments on crystals
of 1a as its MeCN solvate were carried out at 193(2) K on a Bruker
SMART diffractometer using Mo KR X-radiation (λ ) 0.71073
Å) and a single crystal coated in paraffin oil mounted on a glass
fiber.41 Diffracted intensities were integrated42 from several series
of exposures, each exposure covering 0.3° in ω. Absorption
corrections were based on multiple and symmetry-equivalent
measurements SADABS,43 and structures were refined using
2
SHELXTL44 against all Fo data with hydrogen atoms riding in
calculated positions, with isotropic displacement parameters equal
to 1.2 times the Uiso for their attached carbon. Complex neutral-
atom scattering factors were used.45 The crystal structure contained
residual electron density which could not be fully identified and
was modeled using the SQUEEZE algorithm incorporated into the
PLATON suite.
Acknowledgment. We thank Prof. J. G. de Vries, Dr. A. H. M.
de Vries, and Dr. J. A. F. Boogers of DSM Chemicals for useful
discussions, assistance with the catalytic experiments and ee
determinations. D.W.N. thanks the Natural Sciences and Engineer-
ing Research Council of Canada (NSERC) and The Royal Society
for Postdoctoral Fellowships.
[Rh(L1a)2(PMePh2)2]BF4 (8). Ligand mixture M was prepared
by combining a solution of PMePh2 (22 mg, 0.11 mmol) in CH2Cl2
(0.3 cm3) with a solution of L1a (36 mg, 0.11 mmol) in CH2Cl2
(0.3 cm3) and was added to a NMR tube charged with
[Rh(cod)2]BF4 (22 mg, 0.055 mmol) to give a light-orange solution
of the products. 31P{1H} (CH2Cl2) showed that cis-8 was the
product; the AA′MM′X pattern was not fully analyzed: δ: 13.0
(1J(RhP) ) 123.8 Hz, PMePh2), 203.8 (1J(RhP) ) 187.0 Hz,
|J(AM) + J(AM′)| ) 294 Hz, PMe(binol)).
Supporting Information Available: Crystallographic informa-
tion in CIF format. This material is available free of charge via
the Internet at http://pubs.acs.org.
Asymmetric Hydrogenation of Substrate A. The catalyst
(preformed complexes 3a, 3b, 4a, 5–7 (0.0035 mmol)) and substrate
A (0.35 mmol) were mixed in glass vessels under nitrogen; up to
10 vessels were placed in a parallel screening apparatus. CH2Cl2
was added (5 cm3), the apparatus purged three times with hydrogen,
and the autoclave then sealed and pressurized with hydrogen (5
bar). After 1 h of stirring the reaction mixtures, the autoclave was
depressurised, and the reaction solutions were filtered through a
small plug of silica and submitted for GC analysis using a Varian
Chiracel-L-Val column (25 m × 0.25 mm × 0.12 µm) with He
(carrier) at 1.5 cm3/min, 112 °C.
JA800858X
(41) SMART diffractometer control software. SMART collections: Version
5.054; Bruker-AXS Inc.: Madison, WI, 1997–1998; SMART APEX
collections: Version 5.628; Bruker-AXS Inc.: Madison, WI, 2005;
PROTEUM collections: Version 5.625; Bruker-AXS Inc.: Madison,
WI, 1997–2001.
(42) SAINT V6.02–7.06A integration software; Siemens Analytical X-ray
Instruments Inc.: Madison, WI, 2003.
(43) Sheldrick, G. M. SADABS V2.10; University of Göttingen: Göttingen,
Germany, 2003.
(44) SHELXTL program system, version 5.1; Bruker Analytical X-ray
Instruments Inc.: Madison, WI, 1998.
Comparison of Rates of Asymmetric Hydrogenation of
Substrate A. A stirred solution of the preformed catalyst (3a,
[Rh(cod)(dppe)]BF4, [Rh(cod)(L2a)]BF4, 5, 6 or a mixture of 5–7)
(0.0035 mmol) in CH2Cl2 (1.0 cm3) was preactivated by putting it
(45) International Tables for Crystallography: Kluwer: Dordrecht, 1992;
Vol. C.
9
J. AM. CHEM. SOC. VOL. 130, NO. 21, 2008 6847