Nucleophilic substitution at the carbonyl group

Drawing mechanisms chS Nucleophilic attack followed by loss of Loss of carbonyl oxygen chll 

Nucleophilic attack on carbonyl groups leaving group Kinetics and mechanism chi 2 

In this chapter and Chapter 11 we shall look at some more reactions of the carbonyl group— and revisit some of the ones we touched on in Chapter 6. It is a tribute to the importance of this functional group for organic chemistry that we have devoted four chapters of this book to its reactions. Just like the reactions in Chapters 6 and 9, the reactions in Chapters 10 and 11 all involve attack of a nucleophile on a carbonyl group. The difference is that this step is followed by other mechanistic steps, which means that the overall reactions are not just additions but also substitutions. 

The product of nucleophilic addition to a carbonyl group is not always a stable compound 

Addition of a Grignard reagent to an aldehyde or ketone gives a stable alkoxide, which can be protonated with acid to produce an alcohol (you met this reaction in Chapter 9). The same is not true for addition of an alcohol to a carbonyl group in the presence of base—in Chapter 6 we drew a reversible, equilibrium arrow for this transformation and said that the product, a hemiacetal, is formed to a significant extent only if it is cyclic. 

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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... 

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. 

Drawing mechanisms for nucleophilic substitution at the carbonyl group with important compounds. 

The second reaction starts with nucleophilic attack by the amine on the more electrophilic carbonyl group - the ketone. Imine formation is followed by cyclization and this second step is i normal nucleophilic substitution at the carbonyl group of an ester (Chapter 12). The imine double bond moves into the ring to secure conjugation with the ester. 

The acylation is a straightforward nucleophilic substitution at the carbonyl group and the CFj>. group is chosen to make the anion at nitrogen more stable. Alkylation can occur only once wherea direct alkylation with Mel could occur several times. Hydrolysis of the amide is also easier with .. CF3CO group. 

Revision of conjugate addition (Chapter 10 and this chapter), nucleophilic substitution at the carbonyl group (Chapter 14), and decarboxylation of malonates (Chapter 21). 

Ozonolysis of the alkene frees the carboxylic acid, which reacts with carbonyl diimidazole (GDI) n a nucleophilic substitution at the carbonyl group. The relatively stable imidazole anion is the ea ing group. The anion of nitromethane displaces the second imidazole anion and completes the uence. 

Substitution is the replacement of one group by another. In Chapter 12 we discussed nucleophilic substitution at the carbonyl group, this sort of thing. 

Problems for Chapter 10 - Nucleophilic substitution at the carbonyl group... 

Reaction with acid chlorides.2 The adduct reacts with aliphatic and aromatic acid chlorides to give phosphate esters of a-hydroxy /3-diketones (1) in yields of 70-90%. The reaction is considered to involve nucleophilic substitution at the carbonyl group of the acid chloride. The esters are hydrolyzed to a-hydroxy-/3-di-ketones readily by refluxing aqueous benzene (12 hrs.). 

We need an Sn2 reaction at a primary carbon and a nucleophilic substitution at the carbonyl group with the amino group as the nucleophile in both cases. The carbonyl group reaction probably happens first. Don t worry if you didn t deprotonate the amide before the Sn2 reaction. The stereochemistry is the same as that of the starting material (C02Et up as drawn) as no change has occurred at the chiral centre. 

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