J. Am. Chem. Soc. 1997, 119, 3383-3384
3383
13C Kinetic Isotope Effects for the Addition of
Lithium Dibutylcuprate to Cyclohexenone.
Reductive Elimination Is Rate-Determining
completion by the rapid addition of Bu2CuLi (prepared from
n-BuLi + CuBr‚SMe2) in THF to vigorously stirred solutions
of cyclohexenone in THF at -78 °C. The reactions were
9
quenched at -78 °C, and the unreacted cyclohexenone was
†
,†
Doug E. Frantz, Daniel A. Singleton,* and
James P. Snyder*,‡
recovered by an extractive workup followed by column chro-
matography. The recovered cyclohexenone was analyzed by
1
3
10
C NMR compared to a standard sample of cyclohexenone
Department of Chemistry, Texas A&M UniVersity
13
from the same commercial lot. The changes in C isotopic
composition were calculated using C6 as an “internal standard”11
assuming that its isotopic composition does not change during
the reaction. From the changes in isotopic composition, the
KIEs and errors were calculated by the previously reported
College Station, Texas 77843
Department of Chemistry, Emory UniVersity
Atlanta, Georgia 30329
ReceiVed October 18, 1996
8
method.
The conjugate addition of lithium dialkylcuprates to enones
is a vital tool in synthetic organic chemistry. Despite the broad
use of these reactions and abundant effort, a clear mechanistic
picture has yet to be delineated. Early studies by House
suggested a single-electron-transfer mechanism based on a
correlation between the reduction potentials of enones and their
The 13C KIEs for the butyl group were determined by analysis
of the product from reactions taken to low conversion, in a
simple novel manner. Reactions of ≈0.2 mol of natural-
abundance Bu2CuLi in THF at -78 °C were taken to ≈10%
conversion by the addition of 20 mmol of cyclohexenone. The
quantitatively-formed 3-butylcyclohexanone was isolated after
an extractive workup by chromatography. An NMR standard
sample of 3-butylcyclohexanone was prepared by the addition
of BuLi (from the same bottle as that used to form the Bu2-
CuLi) to excess 3-ethoxy-2-cylohexen-1-one followed by hy-
drolysis (1 N HCl) and hydrogenation (H2/Pd/C). The two
1
reactivity in conjugate additions. Later studies have tended to
2
focus on copper-olefin π-complexes as key intermediates,
3
although lithium-enone complexes, charge-transfer com-
4
5
3
6
plexes, R-cuprio ketones, and h -allyl complexes have all been
proposed to be important. Most mechanistic proposals finish
with the formation of a “Cu ” intermediate followed by
III
13
samples of 3-butylcyclohexanone were compared by C NMR,
reductive elimination to form the product enolate. Although
1
3
and the C KIEs were calculated directly from the change in
III
recent work has shown the plausibility of a ligated formal Cu
1
1
integrations relative to Cc as internal standard. The precision
of KIEs determined in this manner ((0.4-0.7%) is limited by
the reproducibility of NMR integrations but is sufficient for
chemical interpretability for the purpose at hand.
I
7
(
with a Cu -like electronic distribution), a weak point is a lack
of direct evidence for these normally high-energy species.
12
13
The resulting KIEs ( k/ k) are summarized in Table 1. The
appreciable KIE at C3 (1.020-1.026) is strongly indicative of
a substantial bonding change at C3 in the rate-limiting step. The
significant KIE at Ca of the butyl group (1.011-1.016), though
relatively small, suggests that Ca is also undergoing a bonding
change, i.e., the butyl group is being transferred in some fashion,
in the rate-limiting step. Taken together, these results implicate
1
2,13
For any reaction, knowledge of the rate-determining step is
key to an understanding of reactivity and selectivity. To gain
focused information on the rate-determining step for cuprate
conjugate additions, we have determined here a complete set
reductive elimination as the rate-determining step.
(
9) In a control reaction taken to completion, <1% cyclohexenone was
detected after quenching. This indicates that the recovery of cyclohexenone
from reactions taken to ≈90% conversion was not simply the result of
enolization.
13
of C kinetic isotope effects (KIEs) for the prototypical reaction
of Bu2CuLi with cyclohexenone. The results implicate rate-
determining reductive elimination from Cu and have broad
implications for both synthetic and mechanistic studies of
(10) As described in the Supporting Information, a number of precautions
were taken to minimize both random and systematic errors in the NMR
analysis. See: Rabenstein, D. L.; Keire, D. A. In Modern NMR Techniques
and Their Application in Chemistry; Popov, A. I., Hallenga, K., Eds.; Marcel
Dekker: New York, 1991; pp 323-69. Samples from recovered and
standard material were prepared identically and a T1 determination was
cuprate conjugate additions.
The 13C KIEs for cyclohexenone in its reaction with Bu2-
13
carried out for each sample. C spectra were obtained with inverse-gated
CuLi were determined by recently reported methodology for
1H decoupling and a 120 s delay between calibrated 2π/9 pulses.
the combinatorial high-precision determination of small KIEs
(11) C6 of cyclohexenone and Cc of butylcyclohexanone were chosen
13
at natural abundance.8 Reactions of natural abundance cyclo-
as internal standards because their C peaks were most cleanly separated
from other peaks in the 13C NMR and potential impurities. Small deviations
from KIEs of 1.000 for these carbons will not affect the conclusions.
hexenone on a 0.2 mol scale were taken to 91.0, 92.1, and 81.1%
(12) Corroborative evidence for rate-limiting reductive elimination comes
†
Texas A&M University.
from the observation of enone Z-E isomerization (see ref 2b), although
other isomerization mechanisms are possible, and a linkage between the
isomerization and the reaction process had not been established. House had
earlier used the same evidence to support an electron-transfer mechanism:
House, H. O.; Weeks, P. D. J. Am. Chem. Soc. 1975, 97, 2778.
‡
Emory University.
(
1) House, H. O.; Umen, M. J. J. Am. Chem. Soc. 1972, 94, 5495-7.
(
2) (a) Hallnemo, G.; Olsson, T.; Ullenius, C. J. Organomet. Chem. 1985,
2
8
1
8
3
1
1
82, 133. (b) Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1985, 26, 6015-
. (c) Lipshutz, B. H.; Dimock, S. H.; James, B. J. Am. Chem. Soc. 1993,
15, 9283. (d) Bertz, S. H.; Smith, R. A. J. J. Am. Chem. Soc. 1989, 111,
276. (e) Alexakis, A.; Sedrani, R.; Mangeney, P. Tetrahedron Lett. 1990,
1, 345. (f) Krause, N.; Wagner, R.; Gerold, A. J. Am. Chem. Soc. 1994,
16, 381. (g) Vellekoop, A. S.; Smith, R. A. J. J. Am. Chem. Soc. 1994,
16, 2902.
(
13) A referee suggested that the butyl group KIEs could be the result
of an internal competition between butyl groups, after the rate-limiting step,
in a structure such as A.
(
3) Krauss, S. R.; Smith, S. G. J. Am. Chem. Soc. 1981, 103, 141-8.
House, H. O.; Chu, C.-Y. J. Org. Chem. 1976, 41, 3083.
(
4) Smith, R. A. J.; Hannah, D. J. Tetrahedron 1979, 101, 4236.
5) (a) Berlan, J.; Battioni, J.; Koosha, K. J. Organomet. Chem. 1978,
(
Such a competition would not be expected if the butyl groups were
diastereotopic in a square-planar structure such as 3 (see ref 7). However,
we have addressed this question experimentally by determining the KIEs
for the reaction of cyclohexenone with BuCuCNLi. The observed KIEs
were Ca 1.020(4); Cb 1.000(5); Cc 1.000 (assumed); Cd 1.005(4). In this
case no internal competition is possible, and the large Ca KIE must be the
result of the rate-limiting step.
1
1
52, 359-65. (b) Berlan, J.; Battioni, J.; Koosha, K. Bull. Soc. Chim. Fr.
979, 183-90.
(
6) (a) Corey, E. J.; Hannon, F. J. Tetrahedron Lett. 1990, 31, 1393-6.
(b) Corey, E. J.; Hannon, F. J.; Boaz, N. W. Tetrahedron 1989, 45, 545.
(
7) Snyder, J. P. J. Am. Chem. Soc. 1995, 117, 11025-6.
(
8) Singleton, D. A.; Thomas, A. A. J. Am. Chem. Soc. 1995, 117, 9357.
S0002-7863(96)03634-7 CCC: $14.00 © 1997 American Chemical Society