Type of Reaction for Peptide Bond Formation

[OrangeMed]

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Hey guys,

What is the reaction that makes peptide bond called? I know that it is dehydration reaction, but EK Chemistry calls it a "typical nucleophilic substitution reaction." How so?

EK calls the phosphodiester bond formation a nucleophilic substitution reaction as well. Both the reactions form water as product. Are dehydration reactions inherently nucleophilic substitution reactions?

Thanks!

 

[Summerlax2016]

Out of all the practice questions I have done, dehydration reaction would suffice as the answer. My thinking is that it is a nucleophilic substitution because the n-terminus has the free electrons on the nitrogen that are capable of attacking the c-terminus, and -OH is a nucleophile bonded to carbon that is being replaced with a nitrogen bonded to the carbon it is a substitution. (I feel like that sounded convoluted hope it helped)

 

[aldol16]

Try not to compartmentalize information. Just because something is a dehydration reaction doesn't mean it can't also be labeled as something else. Dehydration just means water is released as a product, so many reactions are dehydrations - fatty acid biosynthesis involves a key dehydration reaction, for instance. In most chemical reactions you learn, there is usually a nucleophile. Nucleophilic attack is especially important with carbonyls and forms the basis of biochemistry. So almost all carbonyl-based reactions are nucleophilic in nature, with the carbonyl carbon acting as the electrophile.

So what happens in a peptide bond formation? The carboxylic acid is first phosphorylated to yield a phosphodiester bond, thus activating the peptide for nucleophilic attack. The second step involves nucleophilic attack by the lone pair of a nitrogen atom that's on the amino group of the amino acid. This is the typical carbonyl nucleophilic substitution step. The electrons attack the pi antibonding orbital of the carbonyl, thereby breaking the pi bond between the carbon and oxygen, putting the negative charge on the oxygen. Finally, since the C=O double bond is so thermodynamically favorable, the electrons on the oxygen collapse back down to reform the carbonyl, kicking out either the amine or the phosphate. Since kicking out the amine would be unproductive and the phosphate is such a good leaving group, it's usually shown that the phosphate leaves as inorganic phosphate to complete the peptide bond formation.