Page 32 - Advanced Organic Chemistry Part B - Reactions & Synthesis

4 substituents with respect to their ability to stabilize carbanions. The order indicated
is NO > COR > CN ∼ CO R > SO R > SOR > Ph ∼ SR > H > R. Familiarity with
2 2 2
CHAPTER 1 the relative acidity and approximate pK values is important for an understanding of
Alkylation of Enolates the reactions discussed in this chapter.
and Other Carbon
Nucleophiles There is something of an historical division in synthetic procedures involving
2
carbanions as nucleophiles in alkylation reactions. As can be seen from Table 1.1, -
diketones, -ketoesters, malonates, and other compounds with two stabilizing groups
have pK values slightly below ethanol and the other common alcohols. As a result, these
compounds can be converted completely to enolates by sodium or potassium alkoxides.
These compounds were the usual reactants in carbanion alkylation reactions until about
1960. Often, the second EWG is extraneous to the overall purpose of the synthesis and its
removal requires an extra step. After 1960, procedures using aprotic solvents, especially
THF, and amide bases, such as lithium di-isopropylamide (LDA) were developed. The
dialkylamineshaveapK around35.Theseconditionspermittheconversionofmonofunc-
tional compounds with pK> 20, especially ketones, esters, and amides, completely to
their enolates. Other bases that are commonly used are the anions of hexaalkyldisilyl-
3
amines, especially hexamethyldisilazane. The lithium, sodium, and potassium salts are
abbreviated LiHMDS, NaHMDS, and KHMDS. The disilylamines have a pK around
4
30. The basicity of both dialkylamides and hexaalkyldisilylamides tends to increase
with branching in the alkyl groups. The more branched amides also exhibit greater
steric discrimination. An example is lithium tetramethylpiperidide, LiTMP, which is
5
sometimes used as a base for deprotonation. Other strong bases, such as amide anion
NH , the conjugate base of DMSO (sometimes referred to as the “dimsyl” anion), 6
−
2
and triphenylmethyl anion, are capable of effecting essentially complete conversion
of a ketone to its enolate. Sodium hydride and potassium hydride can also be used to
prepare enolates from ketones, although the reactivity of the metal hydrides is somewhat
dependent on the means of preparation and purification of the hydride. 7
By comparing the approximate pK values of the bases with those of the carbon
acid of interest, it is possible to estimate the position of the acid-base equilibrium for
a given reactant-base combination. For a carbon acid C−H and a base B−H,
+
−
C H B H
+
−
K = and K =
a C−H a B−H
C−H B−H
at equilibrium
K C−H K B−H
a C−H a B−H
=
C B
−
−
for the reaction
−
C−H+B B−H+C −
2
D. Seebach, Angew. Chem. Int. Ed. Engl., 27, 1624 (1988).
3 E. H. Amonoco-Neizer, R. A. Shaw, D. O. Skovlin, and B. C. Smith, J. Chem. Soc., 2997 (1965);
C. R. Kruger and E. G. Rochow, J. Organomet. Chem., 1, 476 (1964).
4
R. R. Fraser and T. S. Mansour, J. Org. Chem., 49, 3442 (1984).
5
M. W. Rathke and R. Kow, J. Am. Chem. Soc., 94, 6854 (1972); R. A. Olofson and C. M. Dougherty,
J. Am. Chem. Soc., 95, 581, 582 (1973).
6 E. J. Corey and M. Chaykovsky, J. Am. Chem. Soc., 87, 1345 (1965).
7
C. A. Brown, J. Org. Chem., 39, 1324 (1974); R. Pi, T. Friedl, P. v. R. Schleyer, P. Klusener, and
L. Brandsma, J. Org. Chem., 52, 4299 (1987); T. L. Macdonald, K. J. Natalie, Jr., G. Prasad, and
J. S. Sawyer, J. Org. Chem., 51, 1124 (1986).