Carboxylic acid derivatives hydride nucleophile reactions

Carboxylic acid derivatives undergo substitution reactions with nucleophiles, such as water, organometaUic compounds, and hydride reducing agents. These transformations proceed through the familiar (often acid- or base-catalyzed) addition-elimination sequence (Section 19-7). 

When a nucleophile containing a heteroatom reacts at a carboxyl carbon SN, reactions occur that convert carboxylic acid derivatives into other carboxylic acid derivatives, or they convert carbonic acid derivatives into other carbonic acid derivatives. When an organometallic compound is used as the nucleophile, SN reactions at the carboxyl carbon make it possible to synthesize aldehydes (from derivatives of formic acid), ketones (from derivatives of higher carboxylic acids), or—starting from carbonic acid derivatives—carboxylic acid derivatives. Similarly, when using a hydride transfer agent as the nucleophile, SN reactions at a carboxyl carbon allow the conversion of carboxylic acid derivatives into aldehydes. 

To make as much carboxylic acid derivative as possible available to the nucleophile at all stages of the reaction, the nucleophile is added dropwise to the carboxylic acid derivative and not the other way around. In Figure 6.41, the approach to chemoselective acylations of hydride donors and organometallic compounds, which we have just described, is labeled as strategy 2 and compared to two other strategies, which we will discuss in a moment. 

First, the general mechanisms for these reactions are presented. Then the reactivity of these carboxylic acid derivatives is discussed. As expected, the factors that control the reactivity are very similar to those that affect the addition reactions of Chapter 18. Next, reactions with nucleophiles that interconvert all of the members of the carboxylic acid family are presented. Finally, the reactions of hydride and organometallic nucleophiles with these electrophiles are discussed. 

By using the reactions described in Sections 19.2 through 19.6, it is possible to convert one carboxylic acid derivative to any other carboxylic acid derivative. Now let s examine the reactions of these compounds with hydride and organometallic nucleophiles. In these cases the products are no longer carboxylic acid derivatives. 

On the basis of what we have already learned about the reactions of lithium aluminum hydride with aldehydes and ketones (Chapter 18) and the mechanisms presented so far in this chapter, we can readily predict the product that results when hydride reacts with a carboxylic acid derivative. Consider, for example, the reaction of ethyl benzoate with lithium aluminum hydride. As with all of the reactions in this chapter, this reaction begins with attack of the nucleophile, hydride ion, at the carbon of the carbonyl group, displacing the pi electrons onto the oxygen (see Figure 19.7). Next, these electrons help displace ethoxide from the tetrahedral intermediate. The product of this step is an aldehyde. But recall from Chapter 18 that aldehydes also react with lithium aluminum hydride. Therefore, the product, after workup with acid, is a primary alcohol. 

Following strategy 2 from Figure 6.32, chemoselective SN reactions of hydride-donors with carboxylic acid derivatives also succeed starting from carboxylic chlorides. For the reasons mentioned further above, weakly nucleophilic hydride donors are used for this purpose preferentially and should be added dropwise to the acylating agent in order to achieve success ... 

Carboxylic acid derivatives can also undergo nucleophilic addition reactions. By a combination of nucleophilic acyl substitution and nucleophilic addition, all of the acid derivatives except amides can be reduced to primary alcohols using lithium aluminum hydride. The first hydride ion displaces the leaving group the resulting aldehyde is reduced to the primary alcohol. Reduction of amides produces amines. 

Let us now examine how substituent effects in reactants influence the rates of nucleophilic additions to carbonyl groups. The most common mechanism for substitution reactions at carbon centers is by an addition-elimination mechanism. The adduct formed by the nucleophilic addition step is tetrahedral and has sp hybridization. This adduct may be the product (as in hydride reduction) or an intermediate (as in nucleophilic substitution). For carboxylic acid derivatives, all of the steps can be reversible, but often one direction will be strongly favored by product stability. The addition step can be acid-catalyzed or base-catalyzed or can occur without specific catalysis. In protic solvents, proton transfer reactions can be an integral part of the mechanism. Solvent molecules, the nucleophile, and the carbonyl compound can interact in a concerted addition reaction that includes proton transfer. The overall rate of reaction depends on the reactivity of the nucleophile and the position of the equilibria involving intermediates. We therefore have to consider how the substituent might affect the energy of the tetrahedral intermediate. 

In this section, we will focus primarily on nucleophilic additions to carbonyl groups. The carbonyl substrate may be an aldehyde or ketone, as well as various carboxylic acid derivatives such acid halides and esters. Among the variety of nucleophiles that can participate in these reactions are hydride, hydroxide, alkoxide, and a variety of carbon-based nucleophiles. For carbonyl substrates, attack by a nucleophile typically results in an opening up of the C-O ar-bond, leading to a tetrahedral intermediate, as shown below for the addition of cyanide to a ketone in the presence of water. 

Metal hydride reductions occur by nucleophilic attack at the carbonyl carbon atom of acyl derivatives. Reduction of carboxylic acids with hydride reagents occurs slowly, but reduction by diborane occurs rapidly. Based on the structure of BH3, the active reagent in diborane reductions, suggest the structure of the first intermediate formed in the reaction. 

Hydrogen atom donors such as non-nucleophilic tertiary thiols or tri-n-butyltin hydride are extremely efficient traps for the capture of the alkyl radical R derived from O-acyl thiohydroxamates, thus providing a very efficient method for reductive decarboxylation (Scheme 3). In practical terms, the use of the mercaptan is preferred since the tertiary alkyl pyridyl disulfide can be easily removed during work up by a simple acid extraction. The reaction has been successfully applied to a very wide range of complex substrates [8] possessing primary, secondary, or tertiary aliphatic carboxylic acids, and reactions at room temperature or below require only photolysis from a simple tungsten lamp and often involve in situ O-acyl thiohy-droxamate derivatization. 

Acylimidazoles and Nucleophiles. Acylimidazoles are readily prepared from the parent carboxylic acids by reaction of the derived acid chloride with imidazole or directly using N,N -Carbonyldiimidazole. These intermediates react smoothly with a variety of nucleophiles including Grignard reagents (eq 3), Lithium Aluminum Hydride (eq 4), and nitronates (eq 5). At —20 ""C, aroylimidazoles can be reduced to the corresponding aldehydes in the presence of an ester function. ... 

Nucleophilic addition to C=0 (contd.) ammonia derivs., 219 base catalysis, 204, 207, 212, 216, 226 benzoin condensation, 231 bisulphite anion, 207, 213 Cannizzaro reaction, 216 carbanions, 221-234 Claisen ester condensation, 229 Claisen-Schmidt reaction, 226 conjugate, 200, 213 cyanide ion, 212 Dieckmann reaction, 230 electronic effects in, 205, 208, 226 electrons, 217 Grignard reagents, 221, 235 halide ion, 214 hydration, 207 hydride ion, 214 hydrogen bonding in, 204, 209 in carboxylic derivs., 236-244 intermediates in, 50, 219 intramolecular, 217, 232 irreversible, 215, 222 Knoevenagel reaction, 228 Lewis acids in, 204, 222 Meerwein-Ponndorf reaction, 215 MejSiCN, 213 nitroalkanes, 226 Perkin reaction, 227 pH and, 204, 208, 219 protection, 211... 

Camphor-10-sulfonic acid (1) is available in large quantities in both enantiomeric forms. In only 3 steps the cyclic sulfonamide 2 (sultam) can be synthesized, which can be acylated with acid chlorides after deprotonation with sodium hydride (Scheme 1) [1, 2]. The resulting amides 3 are considerable more reactive towards nucleophiles than the corresponding carboxylic esters and the a,/ -unsaturated derivatives undergo, with excellent selectivities, Diels-Alder reactions or Michael additions under mild conditions. Al-... 

---