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ChemWiki: The Dynamic Chemistry Hypertext > Core > Organic Chemistry > Organic Chemistry With a Biological Emphasis > Chapter 12: Acyl substitution reactions

Chapter 12: Acyl substitution reactions

Section 12.1: Introduction to carboxylic acid derivatives and the nucleophilic acyl substitution reaction

A. Carboxylic acid derivatives and acyl groups
B. The nucleophilic acyl substitution reaction
C. The relative reactivity of carboxylic acid derivatives

Section 12.2: Acyl phosphates as activated carboxylic acids

A. Glutamine synthetase 
B. Asparagine synthetase 
C. Glycinamide ribonucleotide synthetase
D. Synthetic parallel - activated carboxylic acids in the lab

Section 12.3: Thioesters

A. Introduction to thioesters and Coenzyme A
B. Activation of fatty acids by coenzyme A - a thioesterification reaction
C. Transfer of fatty acyl groups to glycerol: a thioester to ester substitution
D. More transthioesterification reactions
E. Hydrolysis of thioesters

Section 12.4: Esters

A. Nonenzymatic esterification: synthesis of ‘banana oil’
B. Nonenzymatic ester hydrolysis and the soap-making process
C. Enzymatic ester hydrolysis: acetylcholinesterase and sarin nerve gas
D. More enzymatic ester hydrolysis: lipase, the resolution of enantiomers, and dehalogenation 
E. Transesterification: the chemistry of aspirin and biodeisel 

Section 12.5: Nucleophilic acyl substitution reactions involving peptide bonds 

A. Formation of peptide bonds on the ribosome 
B. Hydrolysis of peptide bonds: HIV protease
C. The chemical mechanism of penicillin

Section 12.P: Problems for Chapter 12


In chapter 11, we learned about the chemistry of aldehydes and ketones. We saw several variations on a single overarching theme – the attack by a nucleophile on the electrophilic carbonyl carbon.


In this chapter, we will see many variations of a reaction type known as nucleophilic acyl substitution,  the substrates for which are not aldehydes and ketones but carboxylic acid derivatives, such as acyl phosphates, thioesters, esters, and amides.


In nucleophilic acyl substitutions, the first step is again the attack of a nucleophile on an electrophilic carbonyl carbon.  Because the carbonyl carbon is bonded directly to a leaving group, however, the tetrahedral intermediate quickly collapses, expelling the leaving group (X in the figure below) and re-forming the trigonal planar, sp2-hybridized carbonyl. 


It is difficult to overemphasize how widespread nucleophilic acyl substitution reactions are in biochemical pathways: you will see them again and again when you take a course in biochemistry.  As we shall soon see, these reactions are especially important in the metabolism of lipids (fats and oils) and in the formation and breakdown of peptide bonds in proteins.



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13:20, 25 Jan 2015



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This material is based upon work supported by the National Science Foundation under Grant Numbers 1246120, 1525057, and 1413739.

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