O-versus C-alkylation

Fig. 3.37. Differential reaction energy profiles for O versus C alkylation of enolates. (a) O-Alkylation is characterized by an early transition state, weak O-solvation, high anion reactivity, and relatively large electrostatic effects, (b) C-Alkylation is characterized by a later transition state with more C—C bond formation and more diffuse charge distribution.

Table 9.6. O versus C Alkylation for Phenyl Ketones in DMSO...

Figure 9.12. O- versus C-alkylation of isopropyl phenyl ketone. (See Jackman, L. M. Lange, B. C. J. Am. Chem. Soc., 1981,103, 4494.)...

Besitte the simple allylic N C transformation, which allows an allylation in the a-position of aldehydes avoiding completely the problem of O- versus C-alkylation (Scheme 74), the amino-Claisen rearrangement seems especially suited fw effecting asymmetric induction by employing optically active amine systems. - ... 

O- versus C-a kyIation product ratios in the methylation of desoxybenzoin by dimethyl sulphate can be varied between 0.75 and 63 by the choice of catalyst. The reaction can be steered towards enol-ether formation by large, sterically shielded ammonium ions, while C-alkylation is favoured by small ammonium ions (e.g. RMejN" ) and by crown ethers (Dehmlow and Schrader, 1990). 

As mentioned on p. 99, gas-phase reactions are under charge control and, therefore, almost by definition, FO theory is inappropriate for their study. Such a conclusion would be precipitous. Note to begin with that only the anion behaves in an unusual manner, the comportment of its partner being normal. An FO study of gas-phase SN2 reactions (X- + RY —> XR + Y ) is therefore perfectly possible. We can also study the competition of electrophilic sites. On the other hand, FO theory will give questionable conclusions for the regioselectivity of anions (e.g. O-alkylation versus C-alkylation of enolates). For these problems, a more thorough study, requiring in particular transition states determination, is necessary. 

In the first reaction (Table 8.6, item 23), alkylation of the anion of cyclohexanone is not reversible. Hence, the question of O-alkylation (Equation 8.35) versus C-alkylation (Equation 8.36) is a kinetic problem (AH° < 0 for both O- and C-alkylation, Table 1.1) and, in principle, the enolate anion of cyclohexanone could alkylate on carbon and/or oxygen. 

The leaving group in the alkylating reagent has a major effect on whether C- or O-alkylation occurs. In the case of the lithium enolate of acetophenone, for example, C-alkylation is predominant with methyl iodide, but C- and O-alkylation occur to approximately equal extents with dimethyl sulfate. The C- versus O-alkylation ratio has also been studied for the potassium salt of ethyl acetoacetate as a function of both solvent and leaving group. ... 

With secondary and tertiary alkyl halides an E2-elimination is often observed as a side-reaction. As the alkyl halide reactant an iodide is most often employed, since alkyl iodides are more reactive than the corresponding bromides or chlorides. With phenoxides as nucleophiles a C-aUcylation can take place as a competing reaction. The ratio of O-alkylation versus C-aUcylation strongly depends on the solvent used. For example reaction of benzylbromide 4 with /1-naphth-oxide 5 in iV,iV-dimethylformamide (DMF) as solvent yields almost exclusively the /1-naphthyl benzylether 6, while the reaction in water as solvent leads via intermediate 7 to formation of the C-benzylated product—l-benzyl-2-naphthol 8—as the major product ... 

C- versus D-alkylation of enolates is an old problem, with O-methylation of, for example, jS-ketoesters being difficult to achieve. Two new fluoromethylsulfoxonium salts (132) have been developed that exclusively give 0-monoflouromethylation in high yield, using DBU or a phosphorane base, via an 5 1 mechanism." This is in marked contrast to an earlier report that the corresponding trifluoromethylation occurs at carbon (apparently via an 5 n2 process)." ... 

As Mander and coworkers [101] have shown, methyl cyanoformate is the reagent of choice for C-alkylation in many cases. However, for ketone enolates with a hindered P-position increasing amounts of O-acylated product are observed. It has been demonstrated that the use of diethyl ether in place of TH F largely suppresses O-acylation. For instance, enolate 304 gave a 4 1-ratio of C- versus O-acylation in THF and 20 1 in ether [102]. Similarly, from enolate 307 enol carbonate 308 is predominantly formed in THF, whereas keto ester 309 is the main product in diethyl ether. The same phenomenon is observed if the enolate is generated from... 

Fig. 3. C,.o as a function of the number of carbons in the alcohol used to make the ester for poly(n-alkyl methacrylates) and poly (cycloalkyl methacrylates). C increases with increasing side group size in each family. For small rings is larger for cycloalkyl versus n-alkyl materials. Reprinted with permission from J. Macromol. Sd., Rev. Macromol. Cbem. Phys., C28(3 4) 393 (1988). Copyright 1988 Marcel Dekker, Inc.

Figure 9.24(a) Apparent viscosity, zeta potential, amount of adsorption, and pH in zinc oxide-water (50/50) suspensions versus initial concentration, c, curves for Na salt of polyacrylic acid (PA) (O), Na salt of formalin condensate of -naphthalene sulphonate acid (NSF) (C), and sodium tripolyphosphate ( ). The initial concentrations of PA and NSF refer to the mole concentrations expressed/monomer unit of them. A dotted line refers to the apparent viscosity versus c curve for PA at a controlled pH of 10.1. C = initial mole concentration of surfactant and polyphosphate, (b) Apparent viscosity, zeta potential, amount of adsorption, and pH in zinc oxide-water (50/50) suspensions versus initial concentration, c, curves for Na salt of formalin condensate of alkyl (C4) naphthalene sulphonic acid (Al-NSF) (Ci), sodium alkyl (C4) naphthalene sulphonate ( >), and sodium dodecyl benzene sulphonate (O). The initial concentrations of Al-NSF refer to the mole concentrations expressed/monomer unit. C = initial mole concentration of surfactant. From [61] with permission. 

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 fiequently increases the rate of enolate alkylation... 

Aluminum compounds such as AlMe3 are well known to be highly air and moisture sensitive due to the strength of the Al-O bond (—350kjmol-1) versus the Al-C bond (—255 kj mol-1). Complete oxidation of 1ml of A1Mc3 in ambient air can produce a fireball 3 ft in diameter. Recent studies under controlled conditions have produced a better understanding of the reactivity of aluminum alkyls. 

One of the factors directing the alkylation of an enolate is the Jt-facial selectivity. The differences in reactivity of the two diastereotopic faces of the enolate, due to steric and electronic features, contribute to the steric control of the alkylation (for extensive reviews, see refs 1, 4, and 30). Likewise, stereoelectronic features are important control elements for C- versus O-alkylation, as illustrated by the cyclization of enolates 1 and 3 via intramolecular nucleophilic substitution 39. 

The utility of global and local reactivity descriptors to predict chemical reactivity and C- versus O-alkylation has been investigated for the case of lithium enolates.298... 

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