Page 632 - Advanced Organic Chemistry Part A - Structure and Mechanisms, 5th ed (2007) - Carey _ Sundberg

614 Because of the delocalized nature of enolates, an electrophile can attack either at
oxygen or at carbon. Soft electrophiles prefer carbon and it is found experimentally
CHAPTER 6
that most alkyl halides react to give C-alkylation. Because of the character of the
Carbanions and Other
Carbon Nucleophiles HOMO of the anion, there is a stereoelectronic preference for attack of the electrophile
approximately perpendicular to the plane of the enolate. The frontier orbital is with
2
electron density mainly at O and C(2). The TS for an S 2 alkylation of an enolate can
N
be represented as below.

X –
X
O – O O
– O
O

One of the general features of the reactivity of enolate anions is the sensitivity
of both the reaction rate and the ratio of C versus O alkylation to the degree of
aggregation of the enolate. For example, addition of HMPA frequently increases the
90
rate of enolate alkylation reactions. Use of a dipolar aprotic solvent such as DMF or
DMSO in place of THF also leads to rate acceleration. 91 These effects are attributed,
at least in part, to dissociation of the enolate aggregates. Similar effects are observed
when crown ethers or other cation-complexing agents are added to reaction mixtures. 92
The order of enolate reactivity also depends on the metal cation that is present. The
general order is BrMg < Li < Na < K, which is also in the order of greater disso-
ciation of the enolate-cation ion pairs and ion aggregates. Carbon-13 chemical shift
data provide an indication of electron density at the nucleophilic carbon in enolates.
These shifts have been found to be both cation and solvent dependent. Apparent
+
+
+
electron density is in the order K > Na > Li and THF/HMPA > DME > THF >
ether. 93 There is a good correlation with observed reactivity under the corresponding
conditions.
The leaving group in the alkylating reagent has a major effect on whether
C- or O-alkylation occurs. The C- versus O-alkylation ratio has been studied for
the potassium salt of ethyl acetoacetate as a function of both solvent and leaving
group. 94

90
L. M. Jackman and B. C. Lange, J. Am. Chem. Soc., 103, 4494 (1981); C. L. Liotta and T. C. Caruso,
Tetrahedron Lett., 26, 1599 (1985).
91 H. D. Zook and J. A. Miller, J. Org. Chem., 36, 1112 (1971); H. E. Zaugg, J. F. Ratajczyk, J. E. Leonard,
and A. D. Schaeffer, J. Org. Chem., 37, 2249 (1972); H. E. Zaugg, J. Am. Chem. Soc., 83, 837 (1961).
92
A. L. Kurts, S. M. Sakembaeva, J. P. Beletskaya, and O. A. Reutov, Zh. Org. Khim. SSSR, (Engl.
Transl.), 10, 1588 (1974).
93 H. O. House, A. V. Prabhu, and W. V. Phillips, J. Org. Chem., 41, 1209 (1976).
94
A. L. Kurts, A. Macias, N. K. Genkina, I. P. Beletskaya, and O. A. Reutov, Dokl. Akad. Nauk,
SSSR (Engl. Trans.), 187, 595 (1969); A. L. Kurts, N. K. Genkina, A. Macias, I. P. Beletskaya, and
O. A. Reutov, Tetrahedron, 27, 4777 (1971).