Q-24-45P There are many methods for activ... [FREE SOLUTION]

Chapter 24: Q-24-45P (page 1300)

There are many methods for activating a carboxylic acid in preparation for coupling with an amine. The following method converts the acid to an N-hydroxysuccinimide (NHS) ester.
(a) Explain why an NHS ester is much more reactive than a simple alkyl ester.
(b) Propose a mechanism for the reaction shown.
(c) Propose a mechanism for the reaction of the NHS ester with an amine, R-NH₂

Short Answer

Expert verified

(a) An NHS ester is much more reactive than an alkyl ester because the anion of NHS ester R₂NO^-has an electron withdrawing group on oxygen anion, thereby distributing the negative charge over two atoms instead of one and we know that delocalisation of charge brings stability.

Anion of NHS ester

(Stable)

(b)

(c)

Step by step solution

Step-1. Explanation of part (a):

Anion of NHS ester acts as a leaving group and stabilisation of anion is the major factor in determining the ability of leaving group. The anion of NHS is stable and hence NHS ester is more reactive than alkyl ester. R₂NO^-, anion of NHS ester, is stable due to presence of electron withdrawing group which is attached with oxygen anion and stabilises the negative charge. Also, the negative charge is distributed over two atoms instead of just one atom as in alkyl ester anion.

Anion of NHS ester

(Stable)

Step-2. Explanation of part (b):

The anion of NHS ester is abbreviated as O-succ. In the mechanism, the carboxylate ion acts as a nucleophile and attacks at the carbonyl carbon of the given reactant which leads to formation of an intermediate and anion of NHS ester is stable and acts as a good leaving group in next step. NHS trifluoroacetate activates the carboxylic acid through a mixed anhydride to form an ester under mild conditions. Also, anion of NHS ester acts as a nucleophile and attacks at carbonyl carbon of the anhydride which leads to formation of another intermediate and after that, when leaving group leaves, we get our required product.

Mechanism of the given reaction

Step-3. Explanation of part (c):

Amine acts as a nucleophile and attacks at the carbonyl carbon of the NHS ester which leads to the formation of an intermediate and NHS anion acts as a good leaving group in next step. Nitrogen stabilises the positive charge on itself by losing proton attached to it and we get our required product.