Not all carboxylic acid derivatives are equally reactive

Strength of nucleophile and leaving group ability are reiated and pKg is a guide to both 

But just a moment—we ve overlooked an important point. We have sometimes used anions as nucleophiles (for example when we made acid anhydrides from acid chlorides plus car-boxylate salts, we used an anionic nucleophile RCO2) but on other occasions we have used neutral nucleophiles (for example when we made amides from acid chlorides plus amines, we used a neutral nucleophile NH3). Anions are better nucleophiles for carbonyl groups than are neutral compounds so we can choose our nucleophilic reagent accordingly. 

For proper comparisons, we should use the pK of NH4 (about 10) if we are using neutral ammonia, but the pX of RCO2H (about 5) if we re using the carboxylate anion. Ammonia is a good nucleophile and we don t usually need its anion but carboxylic acids are very weak nucleophiles and we often use their anions. You will see later in this chapter that we can alter this with acid catalysts. So this reaction works badly in either direction. We don t make or hydrolyse esters this way. 

MeOH poor nucleophile, HO poor leaving group- 

While amines react with acetic anhydride quite rapidly at room temperature (reaction complete in a few hours), alcohols react extremely slowly in the absence of a base. On the other hand, an alkoxide anion reacts with acetic anhydride extremely rapidly—the reactions are often complete within seconds at 0 °C. We don t have to deprotonate an alcohol completely to increase its reactivity just a catalytic quantity of a weak base can do this job. All the piC s you need are in Chapter 8. 

We can list the common carboxylic acid derivatives in a hierarchy of reactivity, with the most reactive at the top and the least reactive at the bottom. Transformations are always possible moving do wn 

All of these derivatives will react with water to form carboxylic acids, but at very different rates. 

The greater the degree of delocalization, the weaker the C=0 bond becomes. This is most clearly 

Amides react as electrophiles only with powerful nucleophiles such as HO-. Acid chlorides, on the other hand, react with even quite weak nucleophiles neutral ROH, for example. They are more reactive because the electron-withdrawing effect of the chlorine atom increases the electrophilicity of the carbonyl carbon atom. 

You may think that a weaker C=0 bond should be more reactive. This is not so because the partial positive charge on carbon is also lessened by delocalization and because the molecule as a-whole is stabilized by the delocalization. Bond strength is not always a good guide to reactivity  

0 11 slow at 20 C R XH 0 X - HaO 0 only on prolonged heating with strong acid or base catalyst 

We trea hisin ifione detaiMn Chfa er f uencles fdr th tte carbo lata because and anti ayitirnetric  

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