Carboxylic acid derivatives with oxygen nucleophiles

The most common representatives of this group are the carboxylic acid derivatives with Y as oxygen. As we saw in Section 4.5, replacement of the leaving group is a two-step process First nucleophile addition occurs, then the leaving group is lost. The ratedetermining step is almost always the nucleophilic attack thus the rate depends on the ability of this electron sink to attract and accept electron density from a nucleophile. 

Phenylthio)nitroalkenes are also excellent intermediates for the synthesis of other heterocyclic ring systems. For example, tetrahydropyran carboxylic acid derivatives are formed by the intramolecular addition of oxygen nucleophile to l-(phenylthio)nitroalkene predominantly as the m-isomer (9.1 1) (see Eq. 4.40). The reaction may proceed via the chair-like transition state with two pseudo-equatorial substituents.50... 

Thiols undergo the same types of nucleophilic reaction with carboxylic acid derivatives as do alcohols. However, reactivity tends to be increased for two reasons. First, sulfur, because of its larger size, is a better nucleophile than oxygen (see... 

Note that the reaction at the phosphorus atom is postulated to occur by an SN2 (no intermediate formed) rather than by an addition mechanism such as we encountered with carboxylic acid derivatives (Kirby and Warren, 1967). As we learned in Section 13.2, for attack at a saturated carbon atom, OH- is a better nucleophile than H20 by about a factor of 104 (Table 13.2). Toward phosphorus, which is a harder electrophilic center (see Box 13.1), however, the relative nucleophilicity increases dramatically. For triphenyl phosphate, for example, OH- is about 108 times stronger than H20 as a nucleophile (Barnard et al., 1961). Note that in the case of triphenyl phosphate, no substitution may occur at the carbon bound to the oxygen of the alcohol moiety, and therefore, neutral hydrolysis is much less important as compared to the other cases (see /NB values in Table 13.12). Consequently, the base-catalyzed reaction generally occurs at the phosphorus atom leading to the dissociation of the alcohol moiety that is the best leaving group (P-0 cleavage), as is illustrated by the reaction of parathion with OH ... 

The methoxide ion uses of its lone pairs of electrons to form a bond to the electrophilic carbonyl carbon of the acid chloride. Simultaneously, the relatively weak n bond of the carbonyl group breaks and both of the n electrons move onto the carbonyl oxygen to give it a third lone pair of electrons and a negative charge. This is exactly the same first step involved in nucleophilic addition to aldehydes and ketones. However, with an aldehyde or a ketone, the tetrahedral structure is the final product. With carboxylic acid derivatives, the lone pair of electrons on oxygen return to reform the carbonyl n bond (Step 2). As this happens, the C-Cl o bond breaks with both electrons moving onto the chlorine to form a chloride ion that departs the molecule. 

Carboxylic amides, carboxylic esters, and carboxylic acids react with acid-stable heteroatom nucleophiles in a neutral solution much more slowly via the mechanism of Figure 6.2 than in an acidic solution via the mechanism of Figure 6.5. In an acidic solution, their car-boxonium ion derivatives, which result from the reversible protonation of the carboxyl oxygen, act as precursors of the tetrahedral intermediate. According to the discussion earlier in... 

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. 

Step 1 Reaction of the diphosphate oxygen of GDP with the phosphorus of the acyl phosphate to produce an intermediate similar to the intermediates formed in nucleophilic acyl substitutions of carboxylic acid derivatives. 

The thiolates, though less sensitive to basicity, are more reactive than oxygen anions over the total accessible range of basicity, but intersect the amine line at ca. pA 12. Other reactive nucleophiles which do not fall in the amine, thiolate, or oxygen anion categories are fluoride, thiosulfate, nitrite, azide, and sulfite. Halides other than fluoride, and also thiocyanate, nitrate, sulfate, and thiourea have no reactivity towards p-nitrophenyl acetate (Jencks and Carriuolo, 1960a). The total lack of reactivity of thiocyanate, iodide, bromide, and thiourea, all very polarizable nucleophiles which are reactive to sp carbon, rules out any possibility that polarizability is at all important in nucleophilic reactions at the carbonyl carbon. In general, the order of nucleophilic reactivity to p-nitrophenyl acetate correlates well with nucleophilic reactivity to other carboxylic acid derivatives (see later). Nitrite, however, shows... 

The best alternatives to enamines for conjugate addition of enols of aldehyde, ketone, and carboxylic acid derivatives are silyl enol ethers. These stable neutral nucleophiles react very well with Michael acceptors either spontaneously or with Lewis acid catalysts such as TiCl4 at low temperature. If the 1,5-dicarbonyl compound is required, then an aqueous work-up with either acid or base cleaves the silicon—oxygen bond in the product. 

The retrosynthesis of an ester TM typically begins with a disconnection at either C-O bond. Formation of this bond always involves a nucleophilic oxygen reacting with an electrophilic carbon that is either acyl (a carboxylic acid derivative such as acid chloride) or alkyl (RX), causing a substitution to take place. If the alkoxy group is highly substituted (or is a phenoxy derivative), the Sn2 approach is unsuitable so the TM must be prepared by acyl substitution or by peroxyacid oxidation of the corresponding ketone. 

A number of mechanistic pathways exist for nucleophilic acyl substitution. In the simplest of these, a negatively charged nucleophile, Nu , attacks the electrophilic acyl carbon atom of 3 to give the tetrahedral intermediate 4. This then collapses to regenerate the carbon-oxygen double bond with loss of the leaving group, Z, to provide a substitution product 5, which is also a carboxylic acid derivative (Eq. 20.2). The first step in this reaction may be considered to be a Lewis acid-Lewis base reaction in which the acyl carbon atom is the Lewis acid and the nucleophile is the Lewis base. 

Conversion to a more facile, sulfur-derived, leaving group can be achieved by treatment with sodium thiosulfate or salts of thio and dithio acids (75,87). Under anhydrous conditions, boron tribromide converts the 3 -acetoxy group to a bromide whereas trimethyl silyl iodide gives good yields of the 3 -iodide (87,171,172). These 3 -halides are much more reactive, even when the carboxyl group is esterified, and can be displaced readily by cyano and by oxygen nucleophiles (127). 

The dianions derived from furan- and thiophene-carboxylic acids by deprotonation with LDA have been reacted with various electrophiles (Scheme 64). The oxygen dianions reacted efficiently with aldehydes and ketones but not so efficiently with alkyl halides or epoxides. The sulfur dianions reacted with allyl bromide, a reaction which failed in the case of the dianions derived from furancarboxylic acids, and are therefore judged to be the softer nucleophiles (81JCS(Pl)1125,80TL505l). 

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