Nucleophilic strength with carbonyls

The facility of attack by a nucleophile on an electrophile depends on both the strength of the nucleophile (its ability to donate electrons to carbon) and the nature of the carbonyl substrate. An order of nucleophilic strength for reaction of representative nucleophiles with a carbonyl is2l2b... 

A complete discussion of nucleophilic strength will be delayed until sec. 2.7.A, in connection with reactions of nucleophiles and alkyl halides.21 This section will focus on nucleophilic reactions of carbonyl compounds. 

Nucleophilic strength for a given substituent can be measured in terms of the rate of the Sn2 reaction or in reactions with carbonyl derivatives. The relative rates of several nucleophiles were determined by reaction with iodomethane and are shown in Table 2.13. As mentioned previously, several factors contribute to nucleophilic strength. Electronic effects are important, as illustrated by the electron releasing methyl group, which should make methoxide more nucleophilic than hydroxide. The rate of the Sn2 reaction of sodium hydroxide with iodomethane is 1.3 x lO" M s whereas the rate with sodium methoxide with iodomethane is 2.51 x 1Q2 M- s-1.98... 

Slightly greater variations in the activation entropy are noted in ester than the halide thermolyses, but the A values again approximate to 10 and indicate the cyclic unimolecular nature of the transition states. With changing ester, the rate of pyrolysis and strength of the liberated acid qualitatively increase in the same direction" . The dichloroacetate, chloroacetate and acetate of t-butyl alcohol exemplify this relationship and at 250°C their rates of pyrolysis follow the order 18.6 4.4 1 (ref. 406). Nucleophilicity of the carbonyl function cannot be the dominating influence as a reverse order of reactivity would be predicted . 

The introduction to acyl addition in Chapter 16 avoided or minimized identification of the nucleophiles because nucleophiles of different strength react differently. Acyl addition is simply the reaction of a nucleophile with the carbonyl of an aldehyde or ketone. If nucleophiles of different electron-donating ability (differing nucleophilic strength) react differently, there should be a reasonable evaluation of the strength of different nucleophiles. One measure of nucleophilic strength is certainly whether or not a nucleophile reacts reversibly or irreversibly, at least in terms of product isolation. This discussion begins with the reaction of a weak nucleophile, the chloride ion, which adds to carbonyl compounds reversibly. 

In Section 18.5, water was a weak nucleophile that reacts with aldehydes or ketones to generate hydrates however, they are unstable and lose water to regenerate the ketone or aldehyde via an enol. Therefore, even if a reaction is devised that will overcome the weak nucleophilic strength of water and force the reaction, the product is unstable. An alcohol is ROH and, from a simple structural point of view, one H of HOH has been replaced by an alkyl group. Chemically, this will cause some differences, but there should be many similarities. The oxygen atom of an alcohol is a nucleophile when it reacts with carbonyls, and there is an obvious structural relationship to water. The nucleophilic strength of an alcohol, the reversibility of acyl addition, and the stability of the expected product lead to differences with the water reaction. 

The lone pair of electrons on the N atom of amines accounts for their base strength and nucleophilicity. They abstract protons from water, react with Lewis acids, and attack electrophilic sites such as carbonyl carbon. 

The methyl transfer reactions are envisoned as arising from SN2 displacement of a less nucleophilic metal carbonyl anion by a more nucleophilic carbonyl anion. CpFe(CO)2 is the more basic species (69) and therefore abstracts methyl from the less basic CpMo(Me)(CO)3. CpMo(CO)3 and Mn(CO)5 are bases of comparable strength, and, therefore, the reaction either of MnMe(CO)s with CpMo(CO)3" or of CpMo(Me)(CO)3 with Mn(CO)5 gave mixtures of CpMo(Me)(CO)3 and Mn(Me)(CO)s. 

It should also be emphasized that the metal counterions associated with the nucleophiles are active participants in carbonyl addition reactions. There are strong interactions between the carbonyl oxygen and the metal ions in the TSs and intermediates. This effect can be recognized, for example, in the reactivity of borohydrides, where the Li, Ca, and Zn + salts are more reactive than the standard NaBH4 reagent because of the greater Lewis acid strength of these cations. 

---