Origin of enantioselectivity in the Ru(arene)(amino alcohol)-catalyzed transfer hydrogenation of ketones

Article abstract of DOI:10.1021/jo030378q

The origin of the enantioselectivity in the ruthenium-catalyzed transfer hydrogenation has been studied by means of experiment and density functional theory calculations. The results clearly show that electrostatic effects are of importance, not only in the T-shaped arene-aryl interaction in the favored transition state but also between the aryl of the substrate and the amine ligand in the disfavored TS. In addition, the electrostatic interaction between the alkyl substituent of the substrate and the catalyst is of importance to the enantioselectivity. The major cause of enantioselection is found to be of nonelectrostatic origin. This inherent property of the catalytic system is discussed in terms of dispersion forces and solvent effects. Finally, a minor but well-characterized steric effect was identified. The success of this class of catalysts in the reduction of alkyl aryl ketones is based on the fact that all factors work in the same direction.

Full text of DOI:10.1021/jo030378q

Or igin of En a n tioselectivity in th e Ru (a r en e)(a m in o
a lcoh ol)-Ca ta lyzed Tr a n sfer Hyd r ogen a tion of Keton es
Peter Brandt,*,† Peter Roth,‡ and Pher G. Andersson*,‡
Department of Structural Chemistry, Biovitrum AB, 112 76 Stockholm, Sweden, and
Department of Organic Chemistry, Uppsala University, Box 531, S-751 21 Uppsala, Sweden
peter.brandt@biovitrum.com; phera@kemi.uu.se
Received December 10, 2003
The origin of the enantioselectivity in the ruthenium-catalyzed transfer hydrogenation has been
studied by means of experiment and density functional theory calculations. The results clearly
show that electrostatic effects are of importance, not only in the T-shaped arene-aryl interaction
in the favored transition state but also between the aryl of the substrate and the amine ligand in
the disfavored TS. In addition, the electrostatic interaction between the alkyl substituent of the
substrate and the catalyst is of importance to the enantioselectivity. The major cause of
enantioselection is found to be of nonelectrostatic origin. This inherent property of the catalytic
system is discussed in terms of dispersion forces and solvent effects. Finally, a minor but well-
characterized steric effect was identified. The success of this class of catalysts in the reduction of
alkyl aryl ketones is based on the fact that all factors work in the same direction.
In tr od u ction
With this type of catalysts, aryl alkyl ketones are reduced
with high enantiomeric excess using i-PrOH as reduc-
tant. The reaction mechanism has been investigated by
quantum chemical methods by our group8 and by the
groups of Noyori9 and van Leeuwen.10 In addition,
intermediates in the catalytic cycle have been isolated,
and the kinetic isotope effects have been determined.7h,11,12
These investigations support a mechanism with a con-
certed delivery of an N-H proton from the ligand and a
hydride from ruthenium.
The reduction of organic compounds is a subject of
remarkable interest from both academic and industrial
perspectives. Several viable methodologies have been
established for this purpose, and most of them make use
of a metal, in either stoichiometric or catalytic amounts,
to promote the reaction between the reducing agent and
the substrate. Transfer hydrogenation is a further one
of these methodologies, and among the metal-catalyzed
processes it is second only to hydrogenation with molec-
ular hydrogen in its importance. Enantioselective trans-
fer hydrogenation has been intensely studied during the
past decade.1 Noyori and co-workers reported on the use
of monotosylated diamines as ligands (L) in the Ru-
(arene)(L)-catalyzed transfer hydrogenation of aromatic
ketones.2 This important discovery led to the develop-
ment of new chiral ligands by our group3 and by the
groups of Wills,4 van Leeuwen,5 Knochel,6 and others.7
Stereoselectivity could arise from either attractive or
repulsive forces between the substrate and the catalyst
or a combination thereof. Enzymes, also recognized as
excellent catalysts for enantioselective reactions, are
(6) Schwink, L.; Ireland, T.; Puntener, K.; Knochel, P. Tetrahedron:
Asymmetry 1998, 9, 1143.
(7) (a) Frost, C. G.; Mendoca, P. Tetrahedron: Asymmetry 2000, 11,
1845. (b) Henning, M.; Puntener, K.; Scalone, M. Tetrahedron: Asym-
metry 2000, 11, 1849. (c) Ohta, T.; Nakahara, S.; Shigemura, Y.;
Hattori, K.; Furukawa, I. Appl. Organomet. Chem. 2001, 15, 699. (d)
Aitali, M.; Allaoud, S.; Karim, A.; Meliet, C.; Mortreaux, A. Tetrahe-
dron: Asymmetry 2000, 11, 1367. (e) Rhyoo, H. Y.; Yoon, Y.-A.; Park,
H.-J .; Chung, Y. K. Tetrahedron Lett. 2001, 45, 5045. (f) Faller, J . W.;
Lavoie, A. R. Organometallics 2001, 20, 5245. (g) Brunner, H.;
Henning, F.; Weber, M. Tetrahedron: Asymmetry, 2001, 13, 37. (h)
Everaere, K.; Mortreux, M.; Bulliard, A.; Brusse, J .; van der Gen, A.;
Nowogrocki, G.; Carpentier, J .-F. Eur. J . Org. Chem. 2001, 275.
(8) Alonso, D. A.; Brandt, P.; Nordin, S. J . M.; Andersson, P. G. J .
Am. Chem. Soc. 1999, 121, 9580.
(9) Yamakawa, M.; Ito, H.; Noyori, R. J . Am. Chem. Soc. 2000, 122,
1466.
(10) Petra, D. G. I.; Reek, J . N. H.; Handgraaf, J .-W.; Meijer, E. J .;
Dierkes, P.; Kamer, P. C.; Brusse, J .; Schoemaker, H. E.; van Leeuwen,
P. W. N. M. Chem. Eur. J . 2000, 6, 2818.
(11) (a) Haack, K.-A.; Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori,
R. Angew. Chem., Int. Ed. Engl. 1997, 36, 285. (b) Kenny, J . A.;
Versluis, K.; Heck, A. J . R.; Walsgrove, T.; Wills, M. Chem. Commun.
2000, 199.
† Biovitrum AB.
‡ Uppsala University.
(1) Reviews: (a) Palmer, M. J .; Wills, M. Tetrahedron: Asymmetry
1999, 10, 2045. (b) Zassinovich, G.; Mestroni, G.; Gladiali, S. Chem.
Rev. 1992, 92, 1051.
(2) (a) Hashiguchi, S.; Fujii, A.; Takehara, J .; Ikariya, T.; Noyori,
R. J . Am. Chem. Soc. 1995, 117, 7562. (b) Takerhara, J .; Hashiguchi,
S.; Fujii, A.; Inoue, S.; Ikariya, T.; Noyori, R. Chem. Commun. 1996,
233. (c) Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori, R.
J . Am. Chem. Soc. 1996, 118, 2521.
(3) (a) Nordin, S. J . M.; Roth, P.; Tarnai, T.; Alonso, D. A.; Brandt,
P.; Andersson, P. G. Chem. Eur. J . 2001, 7, 1431. (b) Alonso, D. A.;
Nordin, S. J . M.; Roth, P.; Tarnai, T.; Thommen, M.; Pittelkow, U.;
Andersson, P. G. J . Org. Chem. 2000, 65, 3116. (c) Alonso, D. A.;
Guijarro, D.; Pinho, P.; Temme, O.; Andersson, P. G. J . Org. Chem.
1998, 63, 2749.
(4) Palmer, M. J .; Walsgrove, T.; Wills, M. J . Org. Chem. 1997, 62,
5226.
(5) Petra, D. G. I.; Kamer, P. C. J .; van Leeuwen, P. W. N. M.;
Goubitz, K.; van Loon, A. M.; de Vries, J . G.; Schoemaker, H. E. Eur.
J . Inorg. Chem. 1999, 2335.
(12) Casey, C. P.; J ohnson J . B. J . Org. Chem. 2003, 68, 1998.
Nordin, S. J . M.; Andersson, P. G.; Ryberg, P. Manuscript in prepara-
tion. Casey, C. P.; J ohnson J . B. J . Org. Chem. 2003, 68, 1998.
10.1021/jo030378q CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/01/2004
J . Org. Chem. 2004, 69, 4885-4890
4885

Brandt et al.
known to use electrostatic interactions, hydrophobic
interactions, hydrogen bonds, and dispersion interactions
in combination with repulsive steric interactions to
specifically bind and transform a substrate.13 In asym-
metric catalysis a chiral ligand is commonly used in place
of a protein to differentiate between two prochiral faces
via repulsive steric interactions. In some cases though,
enantioselection is realized by stabilization of one of the
diastereomeric transition states by attractive inter-
actions. One such well-known example is the Sharpless
asymmetric dihydroxylation that partly relies on attrac-
tive interactions between aromatic moieties. This inter-
action could, according to the participating molecular
fragments and the geometry of the transition state, be
referred to as π-stacking.14 The importance of arene-arene
interactions as well as alkyl-arene interactions is still a
matter of debate.15
In the case of ruthenium-catalyzed asymmetric trans-
fer hydrogenation Van Leeuwen et al.10 suggest that
steric hindrance is the major factor determining the
enantioselectivity. To the contrary, Noyori et al. earlier
proposed that the selectivity is due to an attractive CH/π
interaction between the aryl of the substrate and the
arene in the catalyst.11,16 On the basis of MP2 and B3LYP
calculations, this interaction is suggested to be dominated
by electrostatic forces together with a nonnegligible
charge-transfer component. This proposal nicely rational-
izes why aliphatic ketones are poor substrates and that
electron-withdrawing substituents on acetophenone sub-
strates decrease the enantiomeric excess. For the catalyst
derived from an amino alcohol and [RuCl2(hexameth-
ylbenzene)]2, a stabilizing electrostatic attraction between
C(sp3)H/π is proposed. Again quantum chemical calcula-
tions show that the hydrogens of the methyl groups of
the hexamethylbenzene have net positive charge.
F IGURE 1. 2-Azanorbornyl-3-methanol ligands 1 and 2.
calculations using the polarized continuum model (PCM),17
a great improvement in the correlation between predicted
and experimental enantioselectivity was achieved. Thus,
we arrived at a conclusion very different from those of
Van Leeuwen and Noyori, namely, that electrostatics and
sterics, well taken care of by our DFT calculations, could
not be the main contributors to the enantioselectivity.
In this paper we have studied in detail the impact of
electrostatics and sterics on enantioselectivity, trying to
form a consensus picture of the origin of the enantio-
selectivity in the ruthenium-catalyzed transfer hydroge-
nation.
We have earlier reported that ligands 1 and 2 are
excellent ligands in the ruthenium-catalyzed asymmetric
transfer hydrogenation of aromatic ketones (Figure 1).
Here, we present our conclusions on the origin of the
enantioselectivities achieved in the reactions using these
ligands.
Com p u ta tion a l Meth od s
Geometries of all substrates were calculated using the
Gaussian electronic structure program,18 using B3LYP,19
a
density functional based on a hybrid functional, together with
the double-ú quality basis set LANL2DZ.20 The basis set
involve the use of d95 for C, N, O, and H. Atomic charge
distributions were thereafter fitted to the electrostatic poten-
tial at points selected according to the CHelpG21 scheme using
the procedure implemented in Gaussian 98. This was done
using the B3LYP/6-311+G(d,p) wave functions at the B3LYP/
LANL2DZ geometries. For the 3-substituted substrates, there
are two alternative conformations relating to the position of
the substituent relative to the acetyl group. In this work we
report data from the s-trans conformations. The s-cis confor-
mations were also investigated, but no significant differences
were detected. The sum of the calculated charges of the six
heavy atoms in the aromatic ring of the substrate were used
as a measure of the charge distribution of the aromatic ring.
To assess the performance of B3LYP in terms of predicting
relative enantioselectivities between substrates with different
charge distribution, we performed transition state calculations
using two different substrates, acetophenone and 2,3,4,5,6-
In the first published quantum chemical investigation
of the reaction,8 we concluded that gas-phase density
functional theory calculations (B3LYP) are not able to
reproduce the degree of enantioselection experienced in
the reaction. In this approach, two major forces are
neglected, namely, the dispersion interaction between
catalyst and substrate and the effect of the solvent.
Taking this latter effect into account by performing
(13) (a) Silverman, R. B. In The Organic Chemistry of Enzyme-
Catalyzed Reaction; Academic Press: San Diego, 2000. (b) Kirby, A.
J . Angew. Chem., Int. Ed. Engl. 1996, 35, 707.
(14) Kolb, H. C.; Andersson, P. G.; Bennani, Y. L.; Crispino, G. A.;
J eong, K. S.; Kwong, H. L.; Sharpless, K. B. J . Am. Chem. Soc. 1993,
115, 12226. (b) Norrby, P.-O.; Kolb, H. C.; Sharpless, K. B. J . Am.
Chem. Soc. 1994, 116, 8470. (c) Corey, E. J .; Noe, M. C. J . Am. Chem.
Soc. 1996, 118, 319. (d) Ujaque, G.; Maseras, F.; Lledos, A. J . Am.
Chem. Soc. 1999, 121, 1317. (e) Quan, R. W.; Li, Z.; J acobsen, E. N. J .
Am. Chem. Soc. 1996, 118, 8156. (f) For a review, see: J ones, G. B.;
Chapman, B. J . Synthesis 1995, 475. (g) For a detailed analysis of the
selectivity in the reaction, see: Norrby, P.-O.; Rasmussen, T.; Haller,
J .; Strassner, T.; Houk, K. N. J . Am. Chem. Soc. 1999, 121, 10186.
(15) (a) J orgensen, W. L.; Severance, D. L. J . Am. Chem. Soc. 1990,
112, 4768. (b) Kim, E.; Paliwal, S.; Wilcox, C. S. J . Am. Chem. Soc.
1998, 120, 11192. (c) Nakamura, K.; Houk, K. N. Org. Lett. 1999, 1,
2049. (d) Martin, C. B.; Mulla, H. R.; Willis, P. G.; Cammers-Goodwin,
A. J . Org. Chem. 1999, 64, 7802. (e) Mu¨ller-Dethlefs, K.; Hobza, P.
Chem. Rev. 2000, 100, 143. (f) Hunter, C. A.; Lawson, K. R.; Perkins,
J .; Urch, C. J . J . Chem. Soc., Perkin Trans. 2 2001, 651. (g) Ribas, J .;
Cubero, E.; Luque, F. J .; Orozco, M. J . Org. Chem. 2002, 67, 7057. (h)
Meyer, E. A.; Castellano, R. K.; Diedriech, F. Angew. Chem., Int. Ed.
2003, 42, 1210. (i) Hunter, C. A.; Low, C. M. R.; Vinter, J . G.; Zonta,
C. J . Am. Chem. Soc. 2003, 125, 9936.
(17) (a) Cossi, M.; Barone, V.; Cammi, R.; Tomasi, J . Chem. Phys.
Lett. 1996, 255, 327. (b) For a review, see also: Tomasi, J .; Persisco,
M. Chem. Rev. 1994, 94, 2027.
(18) Frisch, M. J .; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J . R.; Zakrzewski, V. G.; Montgomery, J . A.,
J r.; Stratmann, R. E.; Burant, J . C.; Dapprich, S.; Millam, J . M.;
Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J .;
Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo,
C.; Clifford, S.; Ochterski, J .; Petersson, G. A.; Ayala, P. Y.; Cui, Q.;
Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J . B.; Cioslowski, J .; Ortiz, J . V.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.;
Fox, D. J .; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Gonzalez, C.; Challacombe, M.; Gill, P. M. W.; J ohnson, B. G.; Chen,
W.; Wong, M. W.; Andres, J . L.; Head-Gordon, M.; Replogle, E. S.;
Pople, J . A. Gaussian 98, revision A.3; Gaussian, Inc.: Pittsburgh, PA,
1998.
(19) (a) Becke, A. D. J . Chem. Phys. 1993, 98, 5648. (b) Lee, C.; Yang,
W.; Parr, R. G. Phys. Rev. B 1988, 37, 785.
(20) Hay, P. J .; Wadt, W. R. J . Chem. Phys. 1985, 82, 299.
(21) Breneman, C. M.; Wiberg, K. B. J . Comput. Chem. 1990, 11,
361.
(16) Yamakawa, M.; Yamada, I.; Noyori, R. Angew. Chem., Int. Ed.
2001, 40, 2818.
4886 J . Org. Chem., Vol. 69, No. 15, 2004

Ru-Catalyzed Transfer Hydrogenation
TABLE 1. Tr a n sfer Hyd r ogen a tion of Su bstitu ted
Acetop h en on es w ith Ru (p-cym en e)(1) a s Ca ta lyst
TABLE 3. Va r ia tion of th e Ru (a r en e) in Tr a n sfer
Hyd r ogen a tion of Acetop h en on e Usin g Am in o Alcoh ol 1
time
(min)
conv
(%)a
ee
time
(min)
conv
(%)a
ee
entry
Ar
(%)b(config)c
Σ(q)d
entry
Ru(arene)
(%)b(config)
1
2
3
4
5
6
7
8
3-NH2-C6H4
3-MeO-C6H4
C6H5
3-Me-C6H4
4-Me-C6H4
4-Cl-C6H4
4-Br-C6H4
4-pyridyl
3-NO2-C6H4
4-CF3-C6H4
3-pyridyl
4
4
6
4
6
3
3
3
4
3
4
3
3
3
3
98
100
96
99
92
92
98
97
99
97
98
95
97
98
98
99(S)
98(S)
96(S)
96(S)
93(S)
93(S)
91(S)
91(S)
91(S)
89(S)
89(S)
88(S)
88(S)
82(S)
32(S)
-0.26
-0.29
-0.44
-0.39
-0.38
-0.29
-0.28
-0.26
-0.29
-0.35
-0.27
-0.31
-0.10
0.15
1
2
3
4
Ru(HMB)c
Ru(p-cymene)
Ru(PhCO2Et)
Ru(benzene)
60
10
6
92
90
96
94
97(S)
96(S)
88(S)
81(S)
4
Determined by 1H NMR. Determined by chiral GC. c HMB
) hexamethylbenzene.
a
b
9
TABLE 4. Tr a n sfer Hyd r ogen a tion of Keton es w ith
Va r ia tion of Alip h a tic Su bstitu en t Usin g
Ru (p-cym en e)(2) a s Ca ta lyst3b
10
11
12
13
14
15
4-NO2-C6H4
2,6-F2-C6H3
3,4,5-F3-C6H2
2,3,4,5,6-F5-C6
conv
(%)a
ee
STERIMOL B1
parameter
entry
R
(%)b(config)c
0.56
1
2
3
4
5
6
7
8
Me
Et
n-Pr
n-Bu
n-hexyl
i-Pr
91
81
90
78
85
76
93
46
94(S)
93(S)
92(S)
95(S)
95(S)
90(S)
90(S)
64(S)
1.52
1.52
1.55
1.52
1.52
1.90
1.90
2.60
a
b
Determined by 1H NMR. Determined by chiral GC. c Abso-
lute configuration determined by comparison with reported optical
rotation. Σ(q) refers to the sum of the electrostatic potential
derived atomic charges of the six heavy atoms in the aromatic ring
of the substrate.
d
i-Bu
t-Bu
TABLE 2. Tr a n sfer Hyd r ogen a tion of Su bstitu ted
Acetop h en on es w ith Ru (HMB)(1) a s Ca ta lyst
a
b
Determined by 1H NMR. Determined by chiral GC. c Abso-
lute configuration determined by comparison with reported optical
rotations.
time
(min)
conv
(%)a
ee
entry
Ar
(%)b(config)c
1
2
3
4
5
6
C6H5
2,6-F2-C6H3
4-Br-C6H4
4-CF3-C6H4
3,4,5-F3-C6H2
2,3,4,5,6-F5-C6
60
60
60
60
60
93
98
98
97
92
99
97(S)
94(S)
92(S)
91(S)
84(S)
78(S)
TABLE 5. Tr a n sfer Hyd r ogen a tion of Keton es w ith
Va r ia tion of th e Alip h a tic Su bstitu en t Usin g
Ru (p-cym en e)(1) a s Ca ta lyst
time
(min)
conv
(%)a
eeb
STERIMOL B1
parameter
entry
R
(%)(config)c
120
1
2
3
4
5
Me
6
20
30
30
30
96
91
92
93
83
96(S)
93(S)
90(S)
90(S)
85(S)
1.52
1.55
1.90
1.90
2.60
a
b
Determined by 1H NMR. Determined by chiral GC. c Abso-
lute configuration determined by comparison with reported optical
rotations.
n-Pr
i-Pr
i-Bu
t-Bu
a
b
Determined by 1H NMR. Determined by chiral GC. c Abso-
lute configuration determined by comparison with reported optical
rotations.
pentafluoroacetophenone. These calculations were performed
in the J aguar program.22 The transition state structures were
located using the quadratic synchronous transit (QST) method
and the B3LYP functional together with the LACVP ECP and
basis set. Normal-mode analysis revealed one imaginary
frequency for each structure. LACVP in J aguar defines a
combination of the LANL2DZ basis set for ruthenium20 and
the 6-31G basis set for other atoms. LACVP implies the use
of an effective core potential for 28 core electrons of ruthenium
and a (5s,6p,4d) primitive basis contracted to [3s,3p,2d]. Final
energies were retrieved from single point calculations at
B3LYP/LACV3p+**. LACV3p+** differs from LACVP by
using the 6-311+G** basis set in place of 6-31G.
Discu ssion
We have earlier discovered that electrostatics is im-
portant for the overall rate of the ruthenium-catalyzed
transfer hydrogenation of aromatic ketones.3a Therefore,
it is not far-fetched that electrostatics could be of
importance also for the enantioselectivity. However, the
interaction that was found to increase the rate was a
dipole-dipole stabilization of the transition state, whereas
the interaction that is expected to influence the enantio-
selectivity is a quadrupole-quadrupole interaction. This
latter interaction is generally weaker and more depend-
ent on the distance between the interacting partners.
Fortunately, the arene of the catalyst is in direct contact
with the aryl of the reacting substrate. Thus, a significant
contribution could be expected as suggested by Noyori
et al.11,16
However, could this agreeably weak interaction really
be the main contributor to the enantioselectivity as
suggested by the same authors? This skepticism is based
on several publications of studies of T-shaped arene-arene
interactions, claiming that, at least for the generic system
consisting of two interacting benzene rings, the main
contribution to the stability of the molecular complex is
Resu lts
Four different studies were performed to obtain an
understanding of what is important for the enantiofacial
discrimination observed in the reduction of alkyl aryl
ketones. The variations studied were (1) substituents on
the aryl of the substrate using Ru(p-cymene)(1) as
catalyst, (2) substituents on the aryl of the substrate
using Ru(hexamethylbenzene)(1) as catalyst, (3) changes
of the substituents of the arene in the catalyst using
acetophenone as substrate and finally, (4) a study of how
the alkyl part of the substrate influences the enantio-
selectivity. The results are summarized in Tables 1-5.
(22) J aguar 4.2; Schro¨dinger, Inc., Portland, OR, 1991-2000.
J . Org. Chem, Vol. 69, No. 15, 2004 4887

Brandt et al.
F IGURE 2. Favored TS showing a close contact between the
methyl of the substrate and the amino alcohol oxygen and a
tilted T-shaped arene-aryl interaction between catalyst and
the phenyl group of the substrate (stereoimage).
the dispersion energy.15a-c,23 The consensus that can be
extracted from the literature is that dispersion inter-
actions dominate the interaction energy, whereas the
electrostatic interactions generally determine the geo-
metrical preference. To shed light on the origin of the
enantioselectivity, we decided to reinvestigate the current
reaction with a combination of experiments and calcula-
tions.
F IGURE 3. Linear correlation between the sum of charges
of the atoms in the aromatic ring and the difference in
transition state energy ∆∆GqExp(R - S) (kcal/mol) using Ru-
(p-cymene)(1) as catalyst. Excluding the m-substituted sub-
strates ()) gives slope ) -1.60, intercept ) 1.39, R2 ) 0.883.
A primary study investigated the efficiency of the
catalyst Ru(p-cymene)(1) in the enantioselective reduc-
tion of a wide range of substituted acetophenones. To
describe the electrostatic properties of the aromatic rings
of the substrates, the electrostatic potential based atomic
charges of the substrates were calculated using the
hybrid density functional method B3LYP and the ChelpG
method. The results are summarized in Table 1.
For simplicity, we used the sum of the atomic charges
of the atoms in the aromatic ring of the substrate (Σ(q))
as an electrostatic measure. Plotting the observed dif-
ference in transition state energies (∆∆GqExp(R - S) kcal/
mol) against Σ(q), Figure 3, a reasonable correlation is
found. This crude model, neglecting conformational ef-
fects as well as the effect of the relative orientation of
the substrate and the catalyst, indeed supports the
conclusion made by Noyori that the electrostatic inter-
actions are important. Apart from two obvious outliers
(m-MeO and m-NH2, both substituents interacting di-
rectly with the arene ligand), the correlation is fair for
such a rudimentary model.24
F IGURE 4. (S)-Transition state for reduction of 2,3,4,5,6-
pentafluoroacetophenone showing a close contact between the
methyl of the substrate and the arene ligand and a possible
electrostatic interaction between the phenyl group of the
substrate and the amino alcohol oxygen of the ligand (stereo-
image).
SCHEME 1. Tr a n sfer Hyd r ogen a tion of
Acetop h en on e w ith Noyor i’s Ca ta lyst
If the columbic attraction between the hydrogens of the
arene ligand and the aryl carbons of the substrate (Figure
2) would be the main contributor to the selectivity, then
reverting the charge distribution of the aryl should lead
to the opposite enantiomer of the product. The best way
to do this is to replace the hydrogens by fluorines, as in
2,3,4,5,6-pentafluoroacetophenone. Using Ru(p-cymene)-
(1) as catalyst, this substrate is reduced in 32% ee with
the same asymmetric induction as observed with the
other acetophenone derivatives. Evidently, there is more
to the enantioface discrimination than simply the charge
distribution in the aromatic ring.
The energetic contribution of this nonelectrostatic
contributor to the enantioselection could be estimated to
ca. 1.4 kcal/mol for this catalyst, as calculated from the
intercept in Figure 3. This is slightly more than the
electrostatic contribution to the enantioselectivity in, for
example, acetophenone where the electrostatic contribu-
tion of the arene-phenyl interaction could be estimated
to ca. 1 kcal/mol.
Although we have discussed the electrostatic effects
in terms of an arene-aryl interaction, it is far from certain
at this point that the interaction is only attractive.
Another plausible explanation could be that there is an
electrostatic repulsion (Figure 4) between the aryl of the
substrate and the alkoxy substituent (or sulfonamide
with the amino sulfonamide ligands) of the ligand in the
disfavored diastereomer of the transition state. Accord-
ingly, reduction of acetophenone with Noyori’s mono-
tosylated diamine gives 95% ee (S), whereas 2,3,4,5,6-
pentafluoroacetophenone is reduced in 12% ee with the
opposite absolute configuration (R) (Scheme 1). Thus, this
system is slightly more sensitive to changes in the
electrostatics of the substrate and is also expected to be
(23) (a) Hobza, P.; Selzle, H. L.; Schlag, E. W. J . Phys. Chem. 1996,
100, 18790. (b) Tsuzuki, S.; Honda, K.; Uchimaru, T.; Mikami, M.;
Tanabe, K. J . Am. Chem. Soc. 2002, 124, 104.
4888 J . Org. Chem., Vol. 69, No. 15, 2004

Ru-Catalyzed Transfer Hydrogenation
F IGURE 5. Linear correlation between the sum of charges
of the heavy atoms in the aromatic ring and the difference in
transition state energy ∆∆GqExp(R - S) (kcal/mol) using Ru-
(HMB)(1) as catalyst; slope ) -1.0, intercept ) 1.74, R2 ) 0.74.
F IGURE 6. Correlation between ∆∆GqExp(R - S) (kcal/mol)
and the STERIMOL B1 parameter of the alkyl group of the
alkyl phenyl ketones Ru(p-cymene)(L). (L ) 1: slope ) -0.6,
R2 ) 0.77. L ) 2: slope ) -1.05, R2 ) 0.94).
less dependent on nonelectrostatic contributions to the
enantioselectivity.
As mentioned earlier, dispersion forces and solvation
and steric effects could, in addition to the electrostatic
effects, be of importance to the enantioselectivity. Gas-
phase B3LYP calculations that only take steric and
electrostatic effects25 into account are in agreement with
the drop in enantioselectivity of 2,3,4,5,6-pentafluoro-
acetophenone compared to acetophenone using Ru(ben-
zene)(1) as model for the real catalyst Ru(p-cymene)(2),
To examine the enantioselection further, we changed
the arene of the catalyst from p-cymene to the less polar
and more lipophilic hexamethylbenzene ligand. This
change is known to be beneficial for the enantioselectivity
in many cases. Thus, if electrostatics would be the major
cause of the enantioselectivity, the plot of ∆∆GqExp(R -
S) versus the sum of the charges of the atoms in the
aromatic rings of the substrates tested would reveal a
steeper slope. If, on the other hand, the electrostatic
repulsion between the amino alcohol ligand and the aryl
of the substrate would be dominating (Figure 4) the slope
should probably be as steep or even steeper as the result
of a tighter substrate-catalyst interaction in the transi-
tion state. As a third alternative, the electrostatic con-
tribution to the enantioselectivity will be decreased as a
result of the less polar arene of the catalyst, and some
other property such as dispersion or solvation effects give
rise to the increased enantioselectivtiy. This last alterna-
tive should result in an enantioselectivity that is less
sensitive to the electrostatic properties of the substrate.
Figure 5 depicts the calculated results, with the
gradient dramatically reduced and the intercept in-
creased slightly. This indicates that the relative contribu-
tion from the electrostatics is reduced and that what
could be called the intrinsic selectivity is increased. To
conclude, the interaction between the arene of the
catalyst and the aryl of the substrate seems to be the
major electrostatic interaction present in the amino
alcohol system.
Having identified this difference between p-cymene
and hexamethylbenzene, it was of interest to expand this
study to other arenes. To get some reference data points,
we determined the enantiomeric excess by using benzene
and ethylbenzoate as ligands to ruthenium in the reduc-
tion of acetophenone. Ru(benzene)(1) gave only 81% ee,
and the corresponding ethylbenzoate catalyst gave 88%
ee. These results can be rationalized by means of a
decreased dispersion/solvophobic effect rather of suggest-
ing that these two arenes have less positively charged
hydrogens. Any rationalization based on steric inter-
actions would give the opposite result because of the
smaller size of benzene compared to hexamethylbenzene.
∆∆∆Eq
) 1.3, ∆∆∆Eq
) 2.0 kcal/mol. Thus, the
Calc
Exp
decreased enantioselectivity is probably, to a large extent,
governed by the change in the electrostatic potential of
the substrate. Conversely, these gas-phase calculations
are not able to reproduce the extent of enantioselection
displayed experimentally; instead, the enantiomeric ex-
cess is underestimated.8 This result is in agreement with
the conclusions drawn above. Thus, there are clear
indications that some additional parameters are involved,
such as dispersion forces and solvation effects.
As a final part of the investigation, we examined how
steric effects influence the enantioselectivity. As noted
above, Ru(benzene) catalysts generally give rise to lower
selectivities when compared to the sterically more de-
manding Ru(HMB) catalysts. Considering the larger size
of the phenyl group compared to the methyl group in
acetophenone derivatives, it would be logic to state that
steric factors therefore must be of minor importance.
Otherwise, the enantioselectivity should increase instead
of decrease. However, Because in this example the cause
of the reduction in enantioselectivity is more likely to be
the result of a reduction in dispersion forces or a decrease
in the solvation effect, there is still room for steric
impacts on the enantioselectivity.
Figure 6 displays the plot of ∆∆Eq(R - S)Exp in
experiments using Ru(p-cymene)(2) as catalyst versus a
steric descriptor of the width of the alkyl substituent of
the substrate. The parameter used to describe this
(24) More elaborate methods such as cross validated partial least
squares (PLS) using the individual electrostatic potential fitted atomic
charges gave improved results. However, as the purpose of this study
is to illustrate the relative contribution of different forces rather than
developing predictive models, we did not include these models.
(25) Charge transfer is also included but not likely to be of
importance for these systems.
J . Org. Chem, Vol. 69, No. 15, 2004 4889

Brandt et al.
property is the STERIMOL B1 parameter.26 As il-
lustrated by the plot, the enantiomeric excess is nicely
correlated with B1, and bulkier alkyl groups tend to
decrease the enantioselectivity. Thus, as B1 of a phenyl
group is slightly larger than that of a methyl group, there
is an intrinsic steric factor that enhances the enantio-
selectivity in the reduction of acetophenone and other
linear chain aliphatic phenyl ketones. A limited study
using the Ru(p-cymene)(1) indicates slightly weaker
steric effects for this catalyst (Table 5).
To conclude, the enantioselectivity in the ruthenium-
catalyzed transfer hydrogenation of ketones is governed
by the cooperative action of steric, electrostatic, disper-
sion, and solvent effects. The understanding of the
delicate balance between different effects can be used in
the design of new, even more selective catalysts, not only
in the field of hydrogenation but also for all other types
of catalysts where the selectivity is determined by an
interaction between the substrate and the organic part
of the catalyst.
An example where steric discrimination could be of
importance to the enantioselectivity is the dialkyl sub-
strate cyclohexylmethyl ketone, which is reduced in 23%
ee with the expected absolute configuration of the product
alcohol (S) and 90% conversion after 2 h with the Ru(p-
cymene)(1) catalyst. On the other hand, transfer hydro-
genation effected by the Ru(HMB)(1) catalyst is slightly
more selective and yields (S)-1-cyclohexylethanol in 30%
ee and 66% conversion after 2 h. Thus, again the steric
effect is less important than other factors.
Exp er im en ta l Section
Commercially available ketones were used without further
purification. The [RuCl2(HMB)]2 and [RuCl2(p-cymene)]2 com-
plexes were prepared according to the literature.27 All transfer
hydrogenations were performed in a 0.1 M solution of the
substrate in i-PrOH (freshly distilled over CaH2). H and 13C
1
NMR spectra were measured in CDCl3 (400 MHz for proton
and 100.4 MHz for carbon). The residual solvent peak of CDCl3
was used as reference (7.26 and 77.0 ppm). The absolute
configuration of the products was determined from the sign
1
Con clu sion s
of the optical rotation, and all products were identified by H
NMR analysis and by comparison with literature data.28
Gen er a l P r oced u r e for Red u ction of Keton es. To a dry
25-mL Schlenk flask was added amino alcohol 1 (4.3 mg, 0.02
mmol) and [RuCl2(p-cymene)]2 (1.5 mg, 0.0025 mmol) followed
by 2 mL of i-PrOH, and the reaction was stirred for 15 min.
i-PrOH (8 mL) and the ketone (1.0 mmol) were added followed
by i-PrOK (0.025 mmol, 25 µL, from a 1 M solution in i-PrOH),
and the solution was stirred at room temperature until
completion according to GC. The reaction was quenched by
the addition of 10 µL of 1 M HCl, and the solvent was
evaporated under reduced pressure. The crude product was
flashed through a short column of SiO2 (1 g) with pentane/
Et2O as eluent to yield the pure alcohol. The enantiomeric
excess was determined with chiral GC (CP-Chirasil-DEX CB)
25 m × 0.25 mm i.d. with N2 (12 psi) as carrier gas. [RuCl2-
(HMB)]2, [RuCl2(benzene)]2, and [RuCl2(PhCO2Et)]2 were stirred
with the amino alcohol 1 at 80 °C for 30 min in 2 mL of i-PrOH
to form the corresponding precatalysts.
Our results can be summarized as follows. Aliphatic
substrates are reduced with low enantioselectivity com-
pared to aromatic substrates, indicating that interactions
between the substrate phenyl ring and the catalyst are
important. The correlation between the sum of charges
on the atoms in the aryl ring of the substrate and the
enantiomeric excess of the product alcohol is to some
extent due to an electrostatic interaction. Most likely,
there is a similar but smaller contribution from the alkyl
substituent of the substrate since electron-withdrawing
substituents on the aryl of the substrate effect a change
in net charge flux in the substrates. However, the
electrostatic interaction between the substrate and cata-
lyst is not the major contributor to the enantioselectivity
for the Ru(p-cymene)(1)-catalyzed transfer hydrogena-
tion.
(S)-(-)-1-(3,4,5-Tr iflu or o-p h en yl)-eth a n ol: 1H NMR (400
MHz, CDCl3) δ 1.44 (3H, d, J ) 6.4 Hz,), 2.19 (1H, bs), 4.82 (1
H, q, J ) 6.4 Hz) and 6.94-7.01 (2H, m); IR (neat) (cm-1) 3350,
2981, 1620, 1532 and 1042; (EI) m/z (rel intensity) 176 (8),
159 (100) and 133 (13). The absolute configuration was
determined after MTPA ester formation.29
Another, more important contribution originates from
a mixture of solvation effects and dispersion interactions.
The balance between these two factors and the former
was found to be affected both by the choice of arene ligand
on the catalyst and by the amine ligand.
A final smaller contribution was identified as a steric
effect that, in the case of acetophenone, works in the
same direction as the more significant factors described
above.
J O030378Q
(27) Bennet, M. A.; Smith, A. K. J . Chem. Soc., Dalton Trans. 1974,
233.
(28) (a) Doucet, H.; Fernandez, E.; Layzell, T. P.; Brown, J . M. Chem.
Eur. J . 1999, 5, 1320. (b) Nakamura, K.; Matsuda, T. J . Org. Chem.
1998, 63, 8957. (c) Blake, A. J .; Cunningham, A.; Ford, A.; Teat, S. J .;
Woodward, S. Chem. Eur. J . 2000, 6, 3586.
(26) For use of STERIMOL parameters in QSAR, see: Ho¨gberg, T.;
Norinder, U. In A Textbook of Drug Design and Development, 2nd ed.;
Krogsgaard-Larsen, P.; Liljefors, T.; Madsen, U., Eds.; Harwood
Academic Publichers, Amsterdam, 1996.
(29) Dale, J . A.; Mosher, H. S. J . Am. Chem. Soc. 1973, 95, 512.
4890 J . Org. Chem., Vol. 69, No. 15, 2004