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It is well known that peptides are synthesized by a so called "condensation" reaction between an amine and a carboxylic acid group to form the final amide moiety (because it releases water). In its general form, it resembles the picture below.

Depicted here

However, what is the actual chemical mechanism behind this reaction? My thoughts are that the amine can deprotonate the carboxylic acid and form a carboxylate - which is a very bad electrophile - so how would it form the amide from nucleophilic attack? I am aware that in the body, it is possible that this reaction is mediated by biochemical catalysts but I am still not sure of the overall mechanism. If this reaction does indeed involve biochemical catalysts, is it possible to complete the synthesis without them?

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    $\begingroup$ Getting a carboxylic acid to react directly with an amine is very difficult, that's why the body uses a huge ribosome to facilitate it. In a lab these couplings are also very complex, everything is protected apart from your target carb. acid and amine, which are then joined with coupling agents like DCC or HATU. Either way you need to activate your carboxylic acid for anything to happen. $\endgroup$
    – Jabbamanga
    Apr 1, 2021 at 21:13

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Here is a proposed mechanism in a 2005 paper. One thing to point out is that this is a proposed mechanism but it is all I could find:

enter image description here

link to pdf: https://www.pnas.org/content/pnas/102/35/12395.full.pdf

Typically, these reactions involve the nitrogen attacking the partially positive carbonyl carbon as a form of nucleophilic substitution. However, OH is a bad leaving group so often, reagents such as DCC can be used to make the OH into a good leaving group before reacting. This is why it is easier to make nylon using a diacid chloride instead of a diacid.

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  • $\begingroup$ In addition to this being a proposed mechanism, this reaction is slighly different from the one asked in the question, in that the leaving group is -O-H rather than -O-tRNA (correspondingly, the by-product is H2O instead of HO-tRNA). Nevertheless, I agree with your answer - the reaction goes by a mechanism where the nitrogen attacks the partially positive carbonyl carbon. $\endgroup$
    – Josiah_H
    Jan 1, 2022 at 15:18
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    $\begingroup$ @Quantum I believe the reason why I chose this example/proposed mechanism was that the t-RNA acts like DCC. Usually, I believe, you don't see carboxylic acid reacting with an amine spontaneously since OH is a bad leaving group. You often would use some sort of reagent to make OH a good leaving group before proceeding in the reaction. $\endgroup$
    – M.L
    Jan 1, 2022 at 19:24

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