M.C.

White, Chem 153 Hydrogenation -140- Week of October 15, 2002

Wilkinson's original report:

Ph3P
Wilkinson’s Catalyst
PPh3
Rh(I) Investigations into the reactivity of (PPh3)RhCl
P h3P Cl uncovered its high activity as a homogeneous
hydrogenation catalyst. This was the first
cat.
homogeneous catalyst that compared in rates
H2 (1 atm), benzene, rt with heterogeneous counterparts.
quantitative

Functionality tolerated Ph3P PPh3

Rh(I)
Ph3P Cl H
O O O Compatibility with carbonyl cat.
groups indicates that the metal H
hydride intermediate is primarily H2: D2 (1:1)
50% D
OR OH covalent in character (lacks
hydridic properties characteristic Minimal H/D scrambling in the product is D
of strongly ionic M-H). See indicative of formation of a dihydrometal
43.9% H
C N NO2 O R Structure & Bonding pg. 28. intermediate that transfers both of its hydrido
ligands to the unsaturated substrate. D
6.1%
Ethylene is not hydrogenated under these conditions but...stoichiometric hydrogen transfer from preformed dihydride complex occurs.
Data indicates that formation
Ph3P PPh 3
Rh(I) of an ethylene/ Rh(Cl)(PPh3)3
H complex inhibits hydrogen
Ph3P Cl Ph3P Ph3P PPh 3 activation by the complex.
H
cat. rt
Rh(III) + Rh(I) + This implies that dihydride
H2 (1 atm), benzene, rt Cl PPh3 Ph3P Cl formation precedes olefin
PPh 3 complexation in the catalytic
cycle.

The stereochemical outcome of this experiment indicates that the mechanism involves stereospecific cis hydrometallation of the unsaturated substrate
followed by stereospecific reductive elimination from the resulting alkenyl (or alkyl) hydrido species.

Ph3P PPh 3 Ph3P PPh3

H H Rh (I) D D Rh(I)
Ph3P Cl Ph3P Cl H H
C 3H7 CH3 + hexane
HO 2C CO2H D2 (1 atm), benzene H H H 2 (50 atm), benzene C 3H7 CH3
20oC HO 2C CO2H 20oC
cis- hexene: trans-hexene
meso compound (>20:1)
major product observed

Wilkinson J. Chem. Soc. (A) 1966, 1711.

M.C. White, Chem 153 Hydrogenation -141- Week of October 15, 2002

Wilkinson: substrate selectivity

Ph3P PPh3
Rh(I)
rate of hydrogenation of
P h3P Cl competition unsaturated substrate
+ 1 mol% + figure = rate of hydrogenation of
unsaturated saturated 1-octene
H2 (1 atms.), benzene, rt
substrate substrate

unsaturated substrate competition figure

NC
14.7
HO
9.1
HO Unsaturated substrates containing functionality are
hydrogenated more rapidly than their unfunctionalized
3.4
counterparts. The effect is suggested to result from polar
functional group assisted olefin coordination to the
2.6 catalyst.

EtO Terminal alkynes are hydrogenated more rapidly than

1.8 terminal alkenes. This selectivity may be enhanced by use
of acidic alcohol co-solvents (e.g. in benzene/
C 3H7 , 2,2,2-trifluoroethanol, 1-hexyne: 1-octene (12:1).
1.7
also 1-heptyne, 1-octyne
Terminal alkenes between C6-C12 are hydrogenated at the
same rate. The same is observed for terminal alkynes. An
C 4H 9 1.0 increase in carbon chain length does not appear to affect
also, 1-decene, 1-dodecene olefin/catalyst interaction.

cyclohexene 0.92
Conjugated dienes are reduced slower than isolated alkenes.
1,3-cyclooctadiene 0.75
C 2H5 C2H5
0.71
Internal and branched alkenes (alkynes) are hydrogenated
C 2H5 0.69 slower than terminal alkenes (alkynes). These differences are
C 3H7 C3H7 rationalized in terms of steric effects on olefin interaction
0.54 with the catalyst and have been used to effect selective
C3H7 alkene hydrogenations in polyene compounds.
0.17
C 3H7 Candlin Faraday Discuss. Chem. Soc. 1968 (46) 60.
M.C. White, Chem 153 Hydrogenation -142- Week of October 15, 2002

Wilkinson hydrogenation: classic dihydride mechanism

H
oxidative
PPh3 addition
P h3P PPh3 H PPh3
Rh (I) H2 solution structure
Rh(I) Rh(III) determined by NMR.
Ph3P Cl Ph3P Cl Ph3P Cl
strong π-acids (e.g. ethylene) bind PPh3
tightly to the electron rich Rh
center and inhibit hydrogenation
+PPh 3 -PPh3 +PPh 3 -PPh3

catalytic cycle oxidative H H

addition
S PPh3 H PPh3 H PPh3
Ph3P Cl PPh3 H2
Rh(I) Rh(III) Rh(III)
Rh(I) Rh(I)
Ph3P Cl Ph3P Cl Ph3P Cl
Ph3P Cl PPh 3
coordinatively unsaturated
S
complex reacts w/ H2 10 4 x
faster than Rh(Cl)PPh3 R
H2
H
PPh3
reductive R migratory
Ph3P Cl H elimination PPh3 insertion
Rh(I) Rh(III) Rh (III) RDS
Ph3P Cl H Ph3P Cl
PPh3 S

Intermediates observed by NMR or as isolated Halpern Chem. Comm. 1973 629.

solids in the reaction system. Formation of Halpern J. Mol. Catal. 1976 (2) 65.
these "side-products" results in a reduction in Halpern Inorg. Chim. Acta. 1981 (50) 11.
the rate of hydrogenation.
M.C. White, Chem 153 Hydrogenation -143- Week of October 15, 2002

Site selective hydrogenation: sterics

Wilkinson: site selectivity
O
ketone activated Pd/C O
cis-disubstituted acetone, H2 (1 atm), rt Ph3P PPh3
75% O highly active heterogeneous
O H Rh(I)
catalysts often cannot achieve
O high levels of selectivity. Ph3P Cl

O Ph3P PPh3 Chlorotris(triphenylphosphine)rhodium I

Rh(I)
tetrasubstituted O Strem catalog 2001-2003
Ph3P Cl 1g = $42
1 mol% O
H2 (1 atm), benzene/EtOH, rt
95% O
Pedro JOC 1996 (61) 3815.
Site selective hydrogenation: sterics and electronics
H3 CO H3 CO
O H CH(CH3 )C2 H5 O H CH(CH3 )C2H5
O O
O trisubstituted O
HO H HO H
O O O O
MeO MeO
cis-disubstituted
only site of
Ph3P PPh3 hydrogenation
conjugated O O Rh (I) O O
diene Ph3P Cl
OH H OH H
~30 mol%
trisubstituted H 2 (1 atm), tol, rt
92%
O O
H H
Fisher J. Med. Chem. 1980 (23) 1134. Ivermectin OMe OMe

cis vs. trans-disubstituted olefins:

O cis-disubstituted O
Ph3P PPh3 CO2Me
CO2Me Rh(I)
Ph3P Cl
cat.
H2 (1 atm), benzene/acetone, rt
HO 80% HO
trans-disubstituted OAc OAc
PGE 2 PGE 1 Schneider JOC 1973 (38) 951.
M.C. White, Chem 153 Hydrogenation -144- Week of October 15, 2002

Wilkinson: diastereoselectivity
Ph3P PPh3
Rh(I)
Ph3P Cl
1 mol% H Me
H2 (1 atm.), benzene/EtOH, rt R = H : 73% endo
R = Me : 92% endo
Me
R R R
endo exo
Rationale for observed diastereoselectivity:
Olefin binds the catalyst from the least
sterically hindered exo face. Subsequent cis H H
hydrometallation of the exo face followed
by stereospecific reductive elimination of Ph3P H Ph3P H
the alkyl metal hydrido intermediate results Rh(III) Rh(III)
Cl PPh3 ClR PPh3
in overall cis addition of H2 to the least
sterically hindered exo face of the olefin.
vs.
Rousseau J. Mol. Cat. 1979 (5) 163.
Jardine Prog. Inorg. Chem. 1981 (28) 63.
R

olefin complexation and

hydrogenation from sterically
less hindered face
Ph3P PPh 3
BnO Rh(I) BnO
OMOM P h3P Cl OMOM
30 mol%
H2 (1 atm.), tol, rt
83%
BnO OBn BnO OBn Lowary OL 2000 (2) 167.
M.C. White, Chem 153 Hydrogenation -145- Week of October 15, 2002

Wilkinson: directing group effects

Ph3P PPh3
Rh(I)
Ph3P Cl
OH OH
0.04 mol%
H 2 (6.8 atm, 100psi), benzene, 50oC
no reaction note: when Pd/C was used
a mixture of cis and trans
Ph3P PPh3 isomers resulted
Rh(I)
H
trisubstituted K+ B - Ph3P Cl
0.04 mol%
MeO MeO
H 2 (6.8 atm, 100psi), benzene, 50oC cis isomer (exclusive)
68%

The slow reaction without the alkoxide is

O -K+ PPh3 attibuted to the steric hinderance of the
O PPh3 tri-substituted double bond, which renders it less
Rh H able to coordinate to the Rh. The protonated
H alcohol is not a strong enough nucleophile to
associatively displace the anionic chloride ligand.
Base-assisted formation of the alkoxide results in
H effective displacement of the chloride ligand and
trisubstituted thus directs olefin complexation from the same
face.
MeO
Thompson JACS 1974 (96) 6232.
Jardine Prog. Inorg. Chem. 1981 (28) 63.
M.C. White, Chem 153 Hydrogenation -146- Week of October 15, 2002

Schrock- Osborn /Crabtree: Cationic catalysts

Diene ligated cationic catalysts mode of activation:
+ H +
PCy3 PCy3
(PF 6-) (PF 6- )
Ir(I) Ir(III)
N H2 H
cis-oxidative N cis-migratory +
addition insertion
PCy3
diene ligated Ir(III) (PF 6- )
catalyst precursor H

N
+ +

S PCy3 PCy3
Ir(I) (PF 6- ) repeat Ir(I) (PF 6- )
S N S N cis-reductive
elimination

solvated active catalyst

Crabtree Acc Chem Res 1979 (12) 331.

Turnover Frequency (TOF)

P h3P PPh3
Wilkinson's catalyst Rh (I)
Ph3P Cl
650 700 13 ---- "Coordinatively" unsaturated
benzene/EtOH, 25oC cationic hydrogenation catalysts
+ are the most active homogeneous
hydrogenation catalysts
PPh3 developed thus far. Use of
Schrock-Osborn catalyst Rh (I) (PF 6- )
weakly coordinating solvents
PPh3 4000 10 ---- ---- provides the olefin substrate
CH2Cl2, 25oC with relatively free access to the
metal's reactive site. These
+ cationic catalysts are also
remarkably selective....
PCy3
Crabtree's catalyst Ir(I) (PF 6- )
6400 4500 3800 4000
N
CH2Cl2, 25oC
TOF = mol reduced substrate/mol catalyst/h
 M.C. White, Chem 153 Hydrogenation -147- Week of October 15, 2002

Cationic catalysts: substrate-directed hydrogenations +

PCy3 OH OH
OH (PF6 -)
Ir(I)
N

2.5 mol% H H
CH2Cl2, H 2 (1 atm), rt
Me Me Me
The availability of a second "open" coordination 98% 64:1
site on the catalyst now makes it possible to bind a Pd/C (EtOH), 1:5 (sterics)
ligating group on the substrate in addition to the H +
olefin. This "two-point" binding has important Py
Cy3P (PF6-)
implications on the selectivity of product formation. Ir(III)
The ability of a late metal complex to effectively
H OH
bind hard functionality (hydroxyls, ketones, etc...)
is attributed to the lewis acidic properties imparted
on the complex by the overall positive charge. Me
i-Pr Crabtree JOC 1986 (51) 2655.
Other functionalities with lewis basic sites also direct:
Esters: Ketones: Ethers
O Me O Me Me Me
CO2Me CO2Me O O

above above above

97% >99% >99%

Me Me H Me Me H Me Me H
(±) 56:1 (±) 124:1 999:1
Pd/C 1.35:1 Pd/C 1.26:1 (±)
Pd/C 1:4

Amides: O Me H O

N above N
5 mol%

For a comprehensive review of cyclic and acyclic

N N
substrate-directed hydrogenations see: Hoveyda, H O H O
Evans, and Fu Chem. Rev. 1993 (93) 1307 and >99:1
D.A. Evans; Chem 206 notes. Pd/C 1:9 (steric approach control)
 M.C. White/Q. Chen Chem 153 Hydrogenation -148- Week of October 15, 2002

High catalyst loadings: diminished yields and selectivities

+

PCy3
OH (PF6 -) OH OH
Ir( I)
N

H H
CH2Cl2, H2 (1 atm), rt
Me Me Me
A B

A decrease in selectivity is observed at higher catalyst selectivity

loadings. It is possible that higher catalyst loadings yield (ratio A:B)
promote the formation of dimeric (Crabtree suggested
M-H-M) species that no longer have the "open" 2.5 mol% 99% 139:1
coordination site necessary for providing effective
directing effects in olefin hydrogenation. No 20 mol% 48% 74:1
experimental data exists thus far to support this
hypothesis. Stork JACS 1983 (105) 1072.
Crabtree JOC 1986 (51) 2655.

Dimished yields are observed with higher catalyst loadings. This can be
rationalized on the basis that higher catalyst loadings promote the irreversible
trimerization of the coordinatively unsaturated catalysts to yield inactive triiridium
hydride bridged complexes. Such complexes have been isolated by Crabtree from
reaction mixtures of more sterically hindered olefins that did not proceed to
completion.

Crabtree Acc. Chem. Res. 1979 (12) 331.

M.C. White, Chem 153 Hydrogenation -149- Week of October 15, 2002

Synthetic applications of directed hydrogenations

+

Ph2 (BF4-)
P
OH Rh (I) OH
P ()n= 3
MOMO MOMO
Ph2
O O
[Rh(NBD)(DIPHOS-4)]+BF4-
O O
H H H
NaH, THF
MOMO Me OSEM O H2 (800 psi), rt MOMO Me OSEM O

68%

Paquette OL 2002 (4) 937.

+
PCy3
Ir(I) (PF 6-)
N Me
H H H H
Me
Me 10
[Ir(COD)(py)(PCy3)]+PF6- Me

Me O H Me
HO H2, CH2Cl2 O
O HO HO O HO
OH OH
HO HO
99% Yield,
d.r. 11:1 at C10
Barriault OL 2001 (3) 1925.
 M.C. White, Chem 153 Hydrogenation -150- Week of October 15, 2002

Mechanism of hydrogenation:bidentate cationic complexes

nbd diphos
(norbornadiene) +
+ ring strain results
Ph 2
in more facile (PF 6-)
PPh 3 P
(PF 6- ) hydrogenation
Rh(I) Rh(I)
P () n= 3
PPh3
Ph 2

Schrock-Osborn type catalyst

Schrock-Osborn catalyst most commonly used:
[Rh(nbd)(diphos-4)]BF4

Halpern's mechanism for cationic Rh(I) catalysts with bidentate +

Ph2
phosphine ligands: P
Rh(I)
P
Ph2
H2
MeOH
Ph CO 2Me + Ph CO 2Me (R)
Ph2
NHAc P S NHAc
stereospecific Rh(I)
reductive P S
elimination Ph2
+ observed by NMR +
H H Ph
Ph
H
H Ph2
Ph 2 P
P R Rh(I) R NH
(III)
Rh NH + P O
P O Ph2
H Ph
Ph2
S H
Ph 2 observed by NMR
observed by NMR
P
Rh (III) R H2 oxidative addition (OA)
stereospecific P H RDS
cis-migratory Ph 2 NH (rate determining step)
insertion O
Halpern Science 1982 (217) 401.
M.C. White, Chem 153 Hydrogenation -151- Week of October 15, 2002

Mechanism of monodentate cationic complexes

Halpern notes that the hydrogenation mechanism for bidentate ligated cationic complexes where olefin substrate coordination precedes oxidative addition of H 2 may
not be operating for cationic catalysts with monodentate ligands. Schrock-Osborn invoke involvement of the dihydride complex (below) in the principle hydrogenation
pathway for their catalyst. Halpern notes some significant differences in the reactivities towards H2 of the catalysts w/ bidentate and monodentate phosphine ligands.

+ + H +
Ph 2 Ph2 Ph 2
In the absence of olefin substrate, no P S P S P
Rh(I) H2 k1 Rh(I)
further uptake of H 2 can be Rh (I)
detected. The only species observed P S P H P
by NMR is the cationic, Ph 2 Ph 2 k-1 Ph 2
S
4-coordinate solvated species.
only species
observed by NMR

H +
+ +
Treatment of the monodentate
PPh3 PPh3 S PPh 3
catalyst with H 2 resulted in detection S k1 Rh (III)
Rh(I) H2 Rh (I)
of the Rh(III)-dihydride complex. P h3P H
PPh3 Ph3P S
k-1
S
only species
observed by NMR
Halpern JACS 1977 (99) 8055. Schrock & Osborn JACS 1976 (98) 2135.
The Trans Effect:

To explain the difference in reactivities towards H2 of the catalysts, Halpern invokes the trans effect. The trans effect is defined as the
labilization of ligands trans to certain other ligands. The trans effect often arises when a ligand shares an orbital with another ligand of strong
σ-bonding character. Because phosphine forms a strong σ bond with Rh, trans Rh-H bonds formed will be weak because the orbital is not as
available for bonding to H. In the case of the bidentate complex, cis addition of H2 requires that one hydride share an orbital with a phosphine.
Since both hydride and phosphine are strong σ-bonding ligands, the dihydride adduct, once formed, is highly unstable and thus rapidly reverts
back via reductive elimination to the solvated 4-coordinate species. In the case of the monodentate phosphine complex, a H2 adduct can form
where neither H ligand is trans to a phosphine.
Classic example of the trans effect: synthesis of "cis-platinum" a chemotherapeutic agent

2- - 2+ +
Cl NH3 Cl Cl NH3 NH3 Cl Cl
Cl Cl NH3 (II) H 3N H 3N H 3N
Pt(II) Pt(II) Pt Pt(II) Cl Pt(II) Cl Pt(II)
Cl Cl Cl NH3 Cl NH3 H 3N NH3 H 3N NH3 Cl NH3
Cl has a stronger "trans only the cis Cl has a stronger "trans only the trans
influence" than NH3 isomer is formed influence" than NH3 isomer is formed
M.C. White, Chem 153 Hydrogenation -152- Week of October 15, 2002

Asymmetric Hydrogenation
A bidentate, C2 symmetric version of the cationic Schrock-Osborn catalyst affords extraordinarily high levels of
enantioselectivity in the hydrogenation of achiral enamides. This was the first demonstration that a chiral
transition metal complex could effectively transfer chirality to a non-chiral substrate with selectivities that rival
those observed in enzymes. Recall that this led to the 1st commericalized asymmetric process using a chiral
transition metal complex: Monsanto Process for the industrial production of L-DOPA (see Structure and
Bonding, pg. 4)

+ +
MeO
PPh3 P
(PF 6- ) Rh(I) (PF 6-)
Rh(I)
PPh 3 P
DIPAMP (common name for
OMe this bidentate chiral phosphine
ligand)
Schrock-Osborn catalyst CO2H
CO2H
i-PrOH, H 2 (1 atm), rt NHAc
NHAc >99% yield
Knowles JACS 1975 (97) 2567. 93% ee
A variety of bidentate chiral phosphines have since been synthesized and used to effect the hydrogenation of aromatic enamides (important substrates for the efficient
generation of amino acids):
H
PPh2 PPh2 PPh2
O PPh2 NMe2
Fe PPh2
PPh2 O PPh2
PPh2
PPh2 PPh2
H
Chiraphos (99% ee) SKEWPHOS (92% ee) NORPHOS (95% ee) DIOP (85% ee) BPPFA (93% ee)
R We'll see these ligands again effecting asymmetry in
a wide assortment of mechanistically unrelated metal
P PPh 2 catalyzed reactions with prochiral substrates.
PPh2 H
R H PCy2 "Privileged ligand class": ligands that communicate
R Fe PPh2 asymmetry effectively with a transition state
PPh2 PPh 2 localized at the metal center, irrespective of the
P nature of the transition state.
PPh2 E.N. Jacobsen;
R personal communication
BINAP (100% ee) DuPHOS (99% ee) BICP (97% ee) JOSIPHOS (96% ee) E. N. Jacobsen. Chem 153 notes. Spring 2001.
For review on DuPhos: Burk Acc. Chem. Res. 2000 (33) 363.
M.C. White, Chem 153 Hydrogenation -153- Week of October 15, 2002

Origin of Asymmetric Induction

+

(ClO4-) It was concluded from kinetic measurements that

H 3C the minor diastereomer was 580 fold more reactive
P towards H2 oxidative addition (recall the RDS at rt).
Rh(I) This factor offsets its lower concentration in
H 3C P solution and results in a 60:1 product ratio in favor
of the R enantiomer.
(S,S-CHIRAPHOS)

(R) CO2Et
CO2H
H2 (1 atm), 25oC, MeOH NHAc
NHAc
N-acetyl-(R)-phenylalanine
>95% ee

stereospecific H migratory insertion /

stereospecific H/C reductive elimination
both to the olefin face bound to Rh

+ +

(ClO4-) (ClO4-)
CO 2Me CH3 H 3C MeO2 C NH
HN
P P olefin bound
Rh(I) Rh(I) to Rh via its
H 3C P O Ph si-face
Ph O P CH3
olefin bound
to Rh via its
re-face

major diastereomer formed minor diastereomer formed

in solution (identified by NMR none detected by NMR (must be
and x-ray crystallography) less than 5% present in solution)
Halpern Science 1982 (217) 401.
M.C. White/Q. Chen Chem 153 Hydrogenation -154- Week of October 15, 2002

Crystal structure of major diastereomer

(ClO4-)
CO 2Me CH3
HN
P
Rh(I)
Ph O P CH3
olefin bound
to Rh via its
re-face

major diastereomer formed

in solution (identified by NMR
and x-ray crystallography)

Major enantiomer observed upon Minor enantiomer observed upon

exposing crystal to H2: exposing crystal to H2.

(R) CO2Et (S) CO2Et

NHAc NHAc

N-acetyl-(R)-phenylalanine
>95% ee

Halpern Science 1982 (217) 401.

M.C. White/Q. Chen Chem 153 Hydrogenation -155- Week of October 15, 2002

Monohydride catalysts: RuClH(PPh3)3

Wilkinson's original report:
"In contrast to the rhodium system, ethanol plays an intimate part in the hydrogenation mechanism; in the
absence of such a co-solvent, hydrogenation is exceedingly slow." Wilkinson Nature 1965 (208) 1203.

RuCl2(PPh3) 2 cat.
H2 (1 atm), benzene:ethanol, rt
quantitative

The active species was identified as the monohydride, thought to form via heterolytic cleavage of
H2, with ethanol acting as a base. The monohydride can also be prepared in 100% benzene if an
equivalent of NEt3 is added. One mole of H 2 is absorbed with respect to Ru and amine
hydrochloride is quantitatively formed. Wilkinson J. Chem. Soc. (A) 1968 3143.
H

H2 (1 eq) PPh3
RuCl2(PPh3) 3 Ph3P Ru(II) + -
Cl +HNEt3
NEt3 (1 eq), benzene RuCl(H)(PPh3)3, highly distorted
PPh3 trigonal bipyramidal. Skapski Chem.
Cl Comm. 1968 1230.

Effect of base on conversion O O

RuCl2(PPh3) 2 cat.
H2 (126 atm), base (1 eq) + fully satuturated
benzene, 40oC, 6h products
O O

Base % Conversion
NEt3 95.4
Et2NH 95.4
BuNH2 86.5
aniline 88.1
Ca2CO3 95.2
Na 2CO3 73.0
none 76.0
Tsuneda Bull. Chem. Soc. Jpn. 1973 (46) 279.
M.C. White, Chem 153 Hydrogenation -156- Week of October 15, 2002

Base promoted heterolytic cleavage:

Mechanism of H2 Activation
H σ-donation>>
π-backbonding
Mn Mn H + BH+
heterolytic cleavage
note: there is no
H generally observed for electrophilic oxidation state
metals that are in their highest stable change at the
oxidation state within the context of metal
σ-complex their ligand framework.

Example:
Complexation of dihydrogen to the electrophilic, cationic
Ir(III) center is predominantly σ-donating in nature.
Donation of electron density from the H-H σ-bond to an
+ + empty Ir orbital leaves the H-H with a partial positive
(BF 4) - (BF4) - charge. The pendent NH2 group is thought to act as an
internal base effecting heterolytic cleavage of the acidified
dihydrogen σ-complex via deprotonation.When L = PPh3,
N NH2 N NH3+ the equilibrium lies far to the right and only the dihydride 2
L H δ+ L
is observed. When more basic alkyl phosphines are used
Ir(III) Ir(III) H (L= PBu3) the equilibrium lies to the left with the H2
H complex 1 being observed exclusively by NMR. It was
L L
H hypothesized that moving to a more basic phosphine
H
increases the electron density at the metal center. This
1 2 makes the metal a less effective σ-acceptor and attenuates
its ability to effectively acidify the dihydrogen complex.
Crabtree Chem. Commun. 1999 297.
σ-bond metathesis: the base is effectively one of the ligands on the metal
external amine base may still drive the rxn forward
by forming insoluble amine hydrochloride salts
δ−
Cl HCl
H2
RuCl2(PPh 3)3 δ+ H RuCl(PPh 3)3 RuHCl(PPh3)3

H
σ-bond metathesis
Crabtree The Organometallic Chemistry of the Transition Metals: 3rd Edition; Wiley: New York; 2001.
M.C. White, Chem 153 Hydrogenation -157- Week of October 15, 2002

BINAP-Ru complexes: Noyori increases the substrate scope

for asymmetric hydrogenations
The first report: asymmetric hydrogenation of (Z)-enamides
Interestingly, E-enamides are completely unreactive
towards these hydrogenation conditions. No
air-sensitive rationale for this has been presented.

O
Ph 2
H3CO P O H3CO HO
Ru(II)
NCOCH3 P O NCOCH3
AcO Ph 2 AcO
O O
HO
OAc (R)-1 (0.5-1 mol%) OAc

EtOH:CH2Cl2 (5:1), H2 (4 atm), 23oC NCH3

OCH3 OCH3 H
Noyori JACS 1986 (108) 7117. 92% yield
Noyori ACIEE 2002 (41) 2008. morphine
95% ee
Asymmetric hydrogenation of allylic and homoallylic alcohols:

O regioselectivity: allylic and homoallylic alcohols are

Tol2 hydrogenated whereas bis homoallylic and higher
P O
analogues are left untouched.
Ru(II)
P O
Tol2
E-olefin O
(S)-1 0.01 mol%
OH OH
MeOH, H2, 18-20oC (R)-citronellol allylic olefin geometry may dictate the
geraniol
96% ee stereochemical outcome of the
97 to >99% yields hydrogenation. Practical consequence:
to obtain high ee's must start with
Z-olefin
stereochemically pure olefins.
(S)-1 0.2 mol%
MeOH, H2, 18-20oC OH

(S)-citronellol Noyori JACS 1987 (109) 1596.

nerol OH
98% ee
M.C. White, Chem 153 Hydrogenation -158- Week of October 15, 2002

BINAP-Ru complexes: Noyori increases the substrate scope

for asymmetric hydrogenations
The first demonstration of high asymmetric induction in the hydrogenation of substrates lacking an acylamino group:
asymmetric hydrogenation of α,β-unsaturated carboxylic acids

CO2H O CO2H
Ph 2
P O (S)
(II) The degree of asymmetric induction is significantly
H 3C CH3 Ru H3C CH3
O affected by the H 2 pressure in a substrate specific
P H2 (4 atm): 91% ee manner. The implication of this is that a range of H2
Ph 2
O H2 (101 atm): 50% ee pressures must be screened to achieve optimal
CO2H asymmetric induction on a substrate by substrate basis.
(S)-1 (0.5-1 mol%)
CO2H No trend was observed and no rationale for the
MeOH, H2, 15-30oC emperical observation was given.
(S)
Ph
H2 (4 atm): 48% ee
H2 (112 atm): 92% ee

Asymmetric Synthesis of (S)-Naproxen:

CO2H (S)-1 (0.5 mol%) CO2H

MeOH, H2 (135 atm), 15-30oC
H3CO 92% yield H 3CO
97% ee (S)-Naproxen Noyori JOC 1987 (52) 3174.
M.C. White, Chem 153 Hydrogenation -159- Week of October 15, 2002
Mechanism of BINAP-Ru hydrogenation of α,β-unsaturated acids
O
Ph 2
P O
Ru (II)
P O
Ph 2
O

1 CO 2H note: mechanism is valid for both enantiomers of

BINAP. No rationalization for the enantiofacial
AcOH
selectivity is given.

O
CO 2H Ph 2
P O
Ru (II)
P O
Ph 2 H2 Heterolytic cleavage of H2
O
CO 2H RDS

H+

O O
Ph 2 Ph 2
P O P O
Ru (II) Ru (II) O
P O P O
Ph 2 Ph 2
O H

note: no oxidation
O
Ph 2 state change to the
P O metal
protonolysis Ru (II)
cis-migratory
P O
H+ Ph 2 H insertion
O

Reactions in MeOD Experiment indicates that the hydrogen α to the acid comes from H2 whereas the β-hydrogen
CO2H D H comes from MeOH. Regio- and stereospecific deuterium incorporation indicates that cis-migratory
insertion of the Ru-H is stereospecific as is cleavage of the Ru-C bond via protonolysis. The lack of
(S)-1
D incorporation into the α position indicates that the rate of H/D exchange between the Ru-H and
H2, MeOD H 3C CH3 solvent is slow.
H 3C CH3 H CO2H
Halpern JACS 1991 (113) 589.
M.C. White, Chem 153 Hydrogenation -160- Week of October 15, 2002

Question of the Week

Ru(CH3CO2) 2-[(S)-BINAP] catalyzes the hydrogenation of α-(acylamino)acrylic esters to give the (S) saturated product in >90% ee's.
Propose a mechanism that accounts for the observed mixture of hydrogenation products when the reaction is run in MeOD. Note: your
mechanism need not rationalize the absolute stereochemistry obtained.

O
Ph 2
CH3 P O CH3 CH3 CH3
Ru (II)
O P O O O O
Ph 2
Ph NH O Ph NH Ph NH Ph NH
(S)-1
H O H2 (1 atm), MeOD H H O H H O H D H O
H D
MeO OMe OMe OMe

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