5378
J. Am. Chem. Soc. 2001, 123, 5378-5379
Because nonlinear effects are so easily detected,3 many
asymmetric catalysts have now been tested. However, we are
unaware of studies of nonlinear effects that focus on the substrate
dependency of this behavior. The substrate dependency of
nonlinear effects has important implications for two primary
reasons: (1) in the optimization of asymmetric processes it is
beneficial to determine the ee of the ligand necessary to obtain a
product of the desired ee and (2) substrate dependency of
nonlinear effects can be used to probe the mechanism of
asymmetric reactions. In this Communication we present a study
of the substrate dependency of nonlinear effects using the MIB
ligand of Nugent (eq 1).14 This ligand is closely related to the
DAIB ligand 1 that has been extensively studied by Noyori and
co-workers.9,15-18 We find that simply modifying the electronic
properties of benzaldehyde derivatives results in a change in the
product ee (eep) of over 30% in the asymmetric addition (eq 1)
with 10% ee of MIB. This effect is even more pronounced with
aliphatic aldehydes. Equally important, the current model for the
mechanism of the asymmetric addition reaction (eq 1) with DAIB
is not consistent with the observed substrate dependency of the
nonlinear effect with MIB.
We chose to employ the MIB ligand because of its ease of
synthesis and its stability on long-term storage.14 Asymmetric
addition reactions (eq 1) were conducted using 4 mol % MIB of
10, 20, and 100% ee of the ligand at 0 °C (Table 1). These
additions were performed by combining the ligand and aldehyde
followed by addition of the diethylzinc over 1 min (Method A).
Under these conditions, no precipitate formed over the course of
the reaction (Table 1). Reactions were also performed at room
temperature by mixing the ligand and diethylzinc (Method B,
Supporting Information). After 1 h the aldehyde was added and
the reactions were sampled between 10 and 20% conversion
except for m-trifluoromethyl benzaldehyde which was 96%
complete after 2 min (Table S2, Supporting Information). No
precipitate was present at these conversions; however, solid did
form in some reactions at later times. Importantly, both methods
exhibited the same trend in nonlinear behavior. A plot of the ee
of the MIB ligand versus the eep for the reaction conducted at 0
°C clearly shows that nonlinear effects are substrate dependent
in this system (Figure 1). The data in Figure 1 demonstrate that
benzaldehyde derivatives with electron-donating substituents
exhibit greater nonlinear behaVior than analogues with electron-
withdrawing substituents. Changing substrates form p-methyl-
benzaldehyde to o-methylbenzaldehyde resulted in no change in
the nonlinear behavior (compare entries 2 and 7, Table 1).
However, 2,4,6-trimethylbenzaldehyde exhibited a markedly
smaller nonlinear effect (entry 8). Aliphatic aldehydes were found
to show greater variation in nonlinear behavior than aromatic
aldehydes (Table 1). The linear chain nonal gave a stronger
nonlinear effect than cyclohexanecarboxaldehyde. Increasing the
steric hindrance around the carbonyl carbon leads to a decrease
in the nonlinear effect (entries 8 and 10).
Substrate Dependence of Nonlinear Effects:
Mechanistic Probe and Practical Applications
Young K. Chen, Anna M. Costa, and Patrick J. Walsh*
P. Roy and Diane T. Vagelos Laboratories
Department of Chemistry, UniVersity of PennsylVania
231 South 34th Street, Philadelphia, PennsylVania 19104-6323
ReceiVed March 12, 2001
ReVised Manuscript ReceiVed April 24, 2001
Enantioselective catalysis has witnessed explosive growth in
the last two decades as it has become the most versatile and
efficient method for the preparation of molecules of high
enantiomeric excess.1 Of the numerous contributions that have
shaped our understanding of catalytic asymmetric reactions, few
have had such a profound impact as the experimental and
theoretical description of nonlinear effects by Kagan and co-
workers.2-5 Before this seminal work,2 it was generally believed
that a strictly linear correlation existed between the ee of the
catalyst and the ee of the product. However, Kagan demonstrated
that this assumption was not valid2 and many systems have since
been shown to exhibit nonlinear behavior.3,4
The consequences of strong positive nonlinear effects are
remarkable.3,4,6-8 For example, Noyori used the DAIB ligand (eq
1) of only 15% ee in the asymmetric addition of alkyl groups to
aldehydes from which a product of 95% ee was generated. When
enantiopure DAIB was used in this reaction, the product was
generated in 98% ee.9 Soai has demonstrated that ligands with
very low ee, or even traces of chiral material, can be used in an
autocatalytic asymmetric process to generate product in high
ee.10-13 The only drawback to using partially resolved catalysts
exhibiting strong positive nonlinear behavior such as DAIB in
production of enantioenriched material is that they display a lower
overall rate than when they are enantiomerically pure.7
(1) Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. ComprehensiVe Asymmetric
Catalysis; Springer: Berlin, 1999; Vols. 1-3.
(2) Puchot, C.; Samuel, O.; Dunach, E.; Zhao, S. H.; Agami, C.; Kagan,
H. B. J. Am. Chem. Soc. 1986, 108, 2353-2357.
(3) Girard, C.; Kagan, H. B. Angew. Chem., Int. Ed. Engl. 1998, 37, 2922-
Variation of the substituent on benzaldehyde also affects the
overall rate using nonenantiopure MIB in eq 1. With 10% ee MIB,
the reaction of the m-(trifluoromethyl)benzaldehyde was complete
in under 30 min while the p-methoxybenzaldehyde was only 23%
complete after 2 h. The higher overall rate with electron-
withdrawing aldehydes is consistent with the proposed rate
determining addition of the alkyl group to the carbonyl.16 Control
experiments were conducted to estimate the rate of the background
2959.
(4) Avalos, M.; Babiano, R.; Cintas, P.; Jime´nez, J. L.; Palacios, J. C.
Tetrahedron: Asymmetry 1997, 8, 2997-3017.
(5) Mikami, K.; Terada, M.; Korenaga, T.; Matsumoto, Y.; Ueki, M.;
Angelaud, R. Angew. Chem., Int. Ed. 2000, 39, 3532-3556.
(6) Blackmond, D. G. Acc. Chem. Res. 2000, 33, 402-411.
(7) Blackmond, D. G. J. Am. Chem. Soc. 1997, 119, 12934-12939.
(8) Blackmond, D. G. J. Am. Chem. Soc. 1998, 120, 13349-13353.
(9) Kitamura, M.; Okada, S.; Suga, S.; Noyori, R. J. Am. Chem. Soc. 1989,
111, 4028-4036.
(10) Soai, K.; Shibata, T.; Morioka, H.; Choji, K. Nature 1995, 378, 767-
768.
(14) Nugent, W. A. J. Chem. Soc., Chem. Commun. 1999, 1369-1370.
(15) Noyori, R.; Suga, S.; Kawai, K.; Okada, S.; Kitamura, M. Pure Appl.
Chem. 1988, 60, 1597-1606.
(11) Shibata, T.; Morioka, H.; Hayase, T.; Choji, K.; Soai, K. J. Am. Chem.
Soc. 1996, 118, 471-472.
(12) Shibata, T.; Yamamoto, J.; Matsumoto, N.; Yonekubo, S.; Osanai,
S.; Soai, K. J. Am. Chem. Soc. 1998, 120, 12157-12158.
(13) Soai, K.; Osanai, S.; Kadowaki, K.; Yonekubo, S.; Shibata, T.; Sato,
I. J. Am. Chem. Soc. 1999, 121, 11235-11236.
(16) Kitamura, M.; Suga, S.; Oka, H.; Noyori, R. J. Am. Chem. Soc. 1998,
120, 9800-9809.
(17) Kitamura, M.; Oka, H.; Noyori, R. Tetrahedron 1999, 55, 3605-3614.
(18) Yamakawa, M.; Noyori, R. Organometallics 1999, 18, 128-133.
10.1021/ja0158004 CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/10/2001