The role of aggregates in claisen acylation reactions of two lithium enolates in THF [8]

Full text of DOI:10.1021/ja982360g

J. Am. Chem. Soc. 1998, 120, 10557-10558
10557
Scheme 1
The Role of Aggregates in Claisen Acylation
Reactions of Two Lithium Enolates in THF1
Simon Shun-Wang Leung and Andrew Streitwieser*
Department of Chemistry
UniVersity of California
Berkeley, California 94720-1460
ReceiVed July 6, 1998
Lithium enolates are known to be generally aggregated in
ethereal solvents,2 and such aggregates have been assumed to be
involved in reaction.3 Several studies have provided some
evidence for this assumption.3c,e,j,4 Recent studies in our group
have involved quantitative measurements of the aggregation
equilibria of several lithium enolates in THF and their kinetic
role in reactions. Thus, the lithium enolate of p-phenylisobu-
tyrophenone, 1, forms a monomer-tetramer equilibrium with K1,4
) 5.0 × 108 M-3, but alkylation reactions involve dominantly
the monomer even when the tetramer is present in large excess.5
The lithium enolate of p-phenylsulfonylisobutyrophenone, 2,
Scheme 2
forms a monomer-dimer equilibrium with K1,2 ) 5.0 × 104 M-1
;
the monomer is 3000 times more reactive than the dimer toward
p-tert-butylbenzyl bromide.6 Similarly, the lithium enolate of
2-(p-biphenylyl)cyclohexanone forms a monomer-dimer equi-
librium with K1,2 ) 4.3 × 103 M-1 and again the monomer is the
sole reactive species in alkylation reactions.7 Clearly, in alkylation
reactions lithium enolate monomers are much more reactive than
aggregates; nevertheless, the extension of this generalization to
other reactions is not clear.
formation reactions in modern organic synthesis.8 Understanding
the role of enolate aggregates in this type of addition should have
synthetic significance. Initial attempts by our group to study aldol
additions of lithium enolates to aldehydes have been unsuccessful
because of high reaction rates and subsequent reactions.9 We
now report, however, that the kinetics of analogous Claisen
reactions of lithium enolates with phenyl esters can be studied
by our procedures and dissected into the relative reactivities of
monomers and aggregates. Ester carbonyls are more stable and
inherently less reactive than aldehyde carbonyls, but their reaction
mechanisms should be comparable.
The reactions of 1 and 2 with phenyl benzoate are irreversible
and proceed exclusively to the â-diketones (Scheme 1).10 Initial
rates (ca. 10% reaction) were measured by following the decrease
in the absorption at 385 nm of 1 and 390 nm of 2 after addition
of the esters in THF at 25 °C. Reactions were followed only in
the early stages of reaction to avoid possible complications and
interference from potential mixed aggregates between the lithium
enolate and lithium phenolate.
Kinetic studies with both enolates gave rate orders in the esters
of unity. For the reaction of 1 with 4-chlorophenyl benzoate, 4,
21 kinetic runs were carried out. In the concentration range
studied, (1.0-7.4) × 10-3 M in enolate, the equilibrium aggrega-
tion number ranges from 2.1 to 3.5 and the rate order of the
enolate changes from 0.67 to 0.63. These results lead to an
average kinetic aggregation number of 1.9 ( 0.3.11 Similarly,
for the reaction of 2 with 4-chlorophenyl benzoate, 4, 20 kinetic
Aldol-type additions of enolates to carbonyl compounds are
among the most important and common carbon-carbon bond
(1) Carbon Acidity. 104.
(2) (a) Novak, D. P.; Brown, T. L. J. Am. Chem. Soc. 1972, 94, 3793. (b)
Ion and Ion Pairs in Organic Reactions; Szwarc, M., Ed.; John Wiley and
Sons: New York, 1972. (c) Jackman, L. M.; Lange, B. C. Tetrahedron 1977,
33, 2737-69. (d) Smid, J. Ions and Ion Pairs and their role in Chemical
Reactions; Pergamon Press: Oxford, 1979. (e) Seebach, D. In Robert A. Welch
Foundation Conferences on Chemical Research XXVII; Houston, TX, 1983;
pp 93-145. (f) McGarrity, J. F.; Olge, C. A. J. Am. Chem. Soc. 1985, 107,
1805. (g) Kaufman, M. J.; Streitwieser, A., Jr. J. Am. Chem. Soc. 1987, 109,
6092-7. (h) Seebach, D. Angew. Chem., Int. Ed. Engl. 1988, 27, 1624-54.
(i) Boche, G. Angew. Chem., Int. Ed. Engl. 1989, 28, 277. (j) Arnett, E. M.;
Fisher, F. J.; Nichols, M. A.; Ribeiro, A. A. J. Am. Chem. Soc. 1990, 112,
801-8. (k) Arnett, E. M.; Palmer, C. A. J. Am. Chem. Soc. 1990, 112, 7354-
60. (l) Arnett, E. M.; Moe, K. D. J. Am. Chem. Soc. 1991, 113, 7288-93.
(m) Ciula, J. C.; Streitwieser, A. J. Org. Chem. 1992, 57, 431-2; correction
p 6686. (n) Seebach, D., Beck, A. K., Studer, A. Modern Synthetic Methods;
VCH: Weinheim, 1995; Vol. 7, pp 1-178.
(3) (a) Amstutz, R.; Schweizer, W. B.; Seebach, D.; Dunitz, J. D. HelV.
Chim. Acta 1981, 64, 2617-21. (b) Seebach, D.; Amstutz, R.; Dunitz, J. D.
HelV. Chim. Acta 1981, 64, 2622-6. (c) Jackman, L. M.; Lange, B. C. J. Am.
Chem. Soc. 1981, 103, 4494-9. (d) Heathcock, C. H.; Lampe, J. J. Org. Chem.
1983, 48, 4330. (e) Jackman, L. M.; Dunne, T. S. J. Am. Chem. Soc. 1985,
107, 2805-6. (f) Williard, P. G.; Hintze, M. J. J. Am. Chem. Soc. 1987, 109,
5539-41. (g) Williard, P. G.; MacEwan, G. J. J. Am. Chem. Soc. 1989, 111,
7671-2. (h) Hall, P. L.; Gilchrist, J. H.; Harrison, A. T.; Fuller, D. J.; Collum,
D. B. J. Am. Chem. Soc. 1991, 113, 9575-85. (i) Bach, R. D.; Andres, J. L.;
Davis, F. A. J. Org. Chem. 1992, 57, 613-8. (j) Palmer, C. A.; Ogle, C. A.;
Arnett, E. M. J. Am. Chem. Soc. 1992, 114, 5619-25. (k) Juaristi, E.; Beck,
A. K.; Hansen, J.; Matt, T.; Mukhopadhyay, T.; Simson, M.; Seebach, D.
Synthesis 1993, 1271-90. (l) Wei, Y.; Bakthavatchalam, R.; Jin, X. M.;
Murphy, C. K.; Davis, F. A. Tetrahedron Lett. 1993, 34, 3715-8. (m) Solladie´-
Cavallo, A.; Csaky, A. G.; Gantz, I.; Suffert, J. J. Org. Chem. 1994, 59, 5343-
6.
(8) For reviews, see: (a) Heathcock, C. H. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991;
Vol. 2; pp 181-238. (b) Heathcock, C. H. Mod. Synth. Methods 1992, 6,
1-102. (c) Braun, M. In AdVances in Carbanion Chemistry; Snieckus, V.,
Ed.; Jai Press Inc.: Greenwich, CT, 1992; Vol. 1, pp 177-247. (d) Davis, B.
H.; Garratt, P. J. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon Press: Oxford, 1991; Vol. 2, pp 795-863.
(4) Thompson, A.; Corley, E. G.; Huntington, M. F.; Grabowski, E. J. J.;
Remenar, J. F.; Collum, D. B. J. Am. Chem. Soc. 1998, 120, 2028-38.
(5) (a) Abbotto, A.; Streitwieser, A. J. Am. Chem. Soc. 1995, 117, 6358-
9. (b) Abbotto, A.; Leung, S. S. W.; Streitwieser, A.; Kilway, K. V. J. Am.
Chem. Soc. In press.
(9) Abu-Hasanayn, F.; Streitwieser, A. J. Org. Chem. 1998, 63, 2954-60.
(10) 1 was prepared in THF solution with the lithium salt of 9,9,10-
trimethyldihydroanthracene as a base; 2 was prepared in THF solution with
the lithium salt of 9-benzylfluorene as a base. Both bases were obtained from
the corresponding neutrals and sublimed LDA.
(11) The slope of a plot of log(rate/[ester]) vs log{enolate} is nagg/nk where
nagg is the average aggregation number of the enolate and nk is the
corresponding number of the kinetically active species. Krom, J. A.;
Streitwieser, A. J. Am. Chem. Soc. 1992, 114, 8747-8.
(6) (a) Abu-Hasanayn, F.; Stratakis, M.; Streitwieser, A. J. Org. Chem.
1995, 60, 4688-9. (c) Abu-Hasanayn, F.; Streitwieser, A. J. Am. Chem. Soc.
1996, 118, 8136-7.
(7) Wang, D. Z.; Streitwieser, A. Manuscript in preparation.
S0002-7863(98)02360-9 CCC: $15.00 © 1998 American Chemical Society
Published on Web 09/23/1998

10558 J. Am. Chem. Soc., Vol. 120, No. 40, 1998
Communications to the Editor
Scheme 3
Table 2. Bimolecular Rate Constants of the Claisen Acylation
Reactions
enolate 1
enolate 2
103kM,
103kT,
103kM,
103kD,
ester
M-1 s-1
M-1 s-1
M-1 s-1
M-1 s-1
3
4
5
6
10.1 ( 0.8
35.5 ( 1.4
33.1 ( 1.6
146 ( 5
13 ( 3
33 ( 4.3
41 ( 4
19.6 ( 0. 9
91.1 ( 3.9
68.3 ( 5.3
329 ( 14
1.7 ( 0.2
5.3 ( 0.8
8.3 ( 0. 9
34 ( 2
Figure 1. Plot for determining the bimolecular rate constants for the
reaction of monomeric and tetrameric lithium enolate of 1 with 4-chlo-
rophenyl benzoate 4. The equation of the least-squares line shown is y )
(0.033 ( 0.0043) + (0.0355 ( 0.0014)x.
105 ( 17
experiments led to the average kinetic aggregation number of 1.27
( 0.02 (Table S1, Supporting Information). These results clearly
indicate that monomer is not the only reactive species and that
higher order aggregates of the lithium enolates are involved in
the rate-determining addition process.
For the reactions formulated as in Schemes 2 and 3, the total
rate of reaction can be written as eq 1 or 3 and rearranged to eq
2 or 4, respectively. Plotting the kinetic results as in eq 2 or 4
gives straight lines in which the slopes are kM and the intercepts
are kT and kD, respectively (Figures 1 and 2). The kinetic rate
constants for several reactions of the two enolates with several
substituted phenyl benzoates are summarized in Table 2 (Figures
S3-S8, Tables S3 and S4, Supporting Information).12
In general, monomers are still more reactive than higher order
aggregates. After statistical correction, for 1, the monomer is
about 4 times faster than the tetramer with all of the phenyl esters
studied. In the case of 2, the monomer is about 20 times faster
than the dimer. Compared with alkylation reactions, in which
monomer is at least 1000 times more reactive than higher order
aggregates,5-7 the difference in reactivities of the monomer and
aggregates toward ester carbonyls is surprisingly small. In
particular, under synthesis conditions of several tenths molar, in
which monomer is present to the extent of only about 1% of the
total enolate concentration, addition of enolate to the ester
carbonyl occurs dominantly via the aggregates, a conclusion that
is just the reverse of that for alkylation reactions. Clearly, the
relative roles of aggregates can change for different reactions.
Positive Hammett F values of about 2-3 are found in both
benzoate and phenolate rings for both monomer and aggregates.
Considering that the reactions were carried out in a solvent of
low polarity, these values are quite reasonable.13 Moreover, the
substituent effects for both monomer and aggregates appear to
be additive. For example, in the case of the monomer of 2,
Figure 2. Plot for determining the bimolecular rate constants for the
reaction of monomeric and dimeric lithium enolate of 2 with 4-chlo-
rophenyl benzoate 4. The equation of the line shown is y ) (0.0053 (
0.0008) + (0.0911 ( 0.0039)x.
4-chlorophenyl benzoate 4 is about 4.65 times as reactive as
phenyl benzoate 3 and phenyl 4-chlorobenzoate 5 is about 3.49
times as reactive as phenyl benzoate 3. The combined effect
should make 4-chlorophenyl 4-chlorobenzoate 6 about 16.2 times
as reactive as phenyl benzoate 3; the observed factor is 16.8. These
studies are being continued with additional enolates and esters;
preliminary results, for example, show that the same types of
kinetic studies can be applied to thioesters.
Acknowledgment. This work was supported in part by NIH Grant
No. GM-30369.
(12) Phenyl benzoate 3 and 4-chlorophenyl benzoate 4 were obtained from
Aldrich and Lancaster, respectively. Phenyl 4-chlorobenzoate 5 and 4-chlo-
rophenyl 4-chlorobenzoate 6 were prepared from the reaction of 4-chloroben-
zoyl chloride and the corresponding phenols with triethylamine as a base.
(13) For the alkaline hydrolyses of substituted phenyl benzoates in 33%
acetonitrile-water at 25 °C, Hammett F values of 2.0 and 1.3 were found in
benzoate and phenolate rings, respectively. See: Kirsch, J. F.; Clewell, W.;
Simon, A. J. Org. Chem. 1968, 33, 127-132.
Supporting Information Available: Tables S1, S3, and S4 and
Figures S3-S8 of kinetic data (8 pages, print/PDF). See any current
masthead page for ordering information and Web access instructions.
JA982360G