Substitution at the carbonyl group

Methods of synthesis for carboxylic acids include (1) oxidation of alkyl-benzenes, (2) oxidative cleavage of alkenes, (3) oxidation of primary alcohols or aldehydes, (4) hydrolysis of nitriles, and (5) reaction of Grignard reagents with CO2 (carboxylation). General reactions of carboxylic acids include (1) loss of the acidic proton, (2) nucleophilic acyl substitution at the carbonyl group, (3) substitution on the a carbon, and (4) reduction. 

CONTENTS OF SECTION III NUCLEOPHILIC SUBSTITUTION AT THE CARBONYL GROUP WITH COMPLETE REMOVAL OF CARBONYL OXYGEN... 

Section 2 Nucleophilic Substitution at the Carbonyl Group (frames 66-120)... 

V, /VCarbonyl di i m ida/.o e (CDI) 15 is another reagent to activate carboxylic acids for nucleophilic substitution at the carbonyl group.9... 

Aromatic chemistry is discussed earlier in this edition Chapter 16 covers aromaticity, and Chapter 17 presents aromatic substitution reactions. Chapters 18 and 19 discuss additions to and substitutions at the carbonyl group. To keep these chapters from being overwhelming, aldol and ester condensations are covered separately in Chapter 20, which deals with reactions of enolate and related nucleophiles. Chapter 21 presents the chemistry of radicals. 

Predict the success or failure of these attempted nucleophilic substitutions at the carbonyl group. You should use estimated pk"a or pXaH values in your answer and, of course, draw mechanisms. 

The formation of the acyl chloride with SOCl2 and the conversion of the a-bromoacyl chloride into the bromoester with MeOH are simple nucleophilic substitutions at the carbonyl group, just like the synthesis of esters from acyl chlorides in Chapter 12. The intermediate stage, the bromination of the very easily enolized acyl chloride, is a typical enol bromination. 

This is yet another synthesis in which almost every step is a reaction that you have already met in this book There are three nucleophilic substitutions at the carbonyl group, one S>j2 reaction, one electrophilic and one nucleophilic aromatic substitution (the latter being an S l reaction), and a reduction. The chemistry you already know is enough for a patented manufacture of a useful drug. 

Only now does something different happen, The aldehyde dimer simply captures a proton from the solvent to give an aldol product. The aldof from the ester (not, in fact, an aldol at all) has a leaving group, EtO-, instead of a hydrogen atom and is actually the tetrahedral intermediate in a nucleophilic substitution at the carbonyl group. Compare the two different steps again. 

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