Hydrolysis of Thioesters: Videos & Practice Problems

Hydrolysis of thioesters involves two main pathways: acid-catalyzed and base-catalyzed (saponification). Acid-catalyzed hydrolysis yields a carboxylic acid and a thiol through a nucleophilic acyl substitution mechanism, comprising protonation, nucleophilic attack, proton transfer, leaving group departure, and deprotonation. In contrast, base-catalyzed hydrolysis produces a carboxylate anion and a thiol, with steps including nucleophilic attack, loss of the leaving group, and proton transfer. Understanding these mechanisms is crucial for grasping the reactivity of thioesters in organic synthesis.

Hydrolysis of Thioesters Concept 1

In the study of organic chemistry, the hydrolysis of thioesters is an important reaction to understand. Thioesters, which are sulfur analogs of regular esters, undergo acid-catalyzed hydrolysis to yield a carboxylic acid and a thiol. This reaction is characterized by a nucleophilic acyl substitution (NAS) mechanism, which consists of several key steps.

The first step involves protonation, where a proton (H⁺) is added to the thioester, enhancing its electrophilicity. In the second step, a nucleophile attacks the carbonyl carbon of the thioester, forming a tetrahedral intermediate. This is followed by a proton transfer in the third step, which facilitates the rearrangement of the intermediate. The fourth step involves the departure of the leaving group, which in this case is the thiolate ion. Finally, the fifth step is deprotonation, restoring the neutral charge and completing the formation of the products.

It is essential to note that steps one, three, and five all involve the movement of protons, highlighting the significance of proton transfer in the mechanism. Understanding this sequence of events is crucial for mastering the hydrolysis of thioesters and recognizing the broader implications of nucleophilic acyl substitution reactions in organic synthesis.

Hydrolysis of Thioesters Example 1

The acid-catalyzed hydrolysis of a thioester involves several key steps that lead to the formation of a carboxylic acid and a thiol. Initially, the carbonyl oxygen of the thioester is protonated by a hydronium ion (H₃O⁺). This protonation occurs as the oxygen uses its lone pair to bond with a hydrogen ion (H⁺), resulting in a positively charged oxygen and the release of a water molecule.

In the next step, a water molecule attacks the carbonyl carbon, breaking the bond between the carbon and the oxygen. This results in a neutral water molecule now attached to the carbonyl carbon. Following this, a proton transfer occurs from the positively charged oxygen to the sulfur atom of the thioester. This transfer converts the oxygen into a hydroxyl group (–OH), while the sulfur, now making three bonds, becomes positively charged, making it a better leaving group.

Subsequently, the oxygen atom pushes its lone pairs to form a double bond with the carbon, facilitating the departure of the thiol group. This step results in the reformation of a positively charged carbonyl oxygen and the presence of the hydroxyl group. Finally, the newly formed carbonyl oxygen is deprotonated by water, regenerating the hydronium ion and yielding the final products: a carboxylic acid and a thiol.

Throughout this mechanism, the movement of electrons and the formation of bonds are crucial, highlighting the importance of each step in organic chemistry. Understanding these transformations is essential for mastering reaction mechanisms.

Hydrolysis of Thioesters Concept 2

In the context of thioester chemistry, the process known as saponification refers to the basic hydrolysis of thioesters. This reaction results in the formation of a carboxylate anion and a thiol. It is important to note that in a basic environment, the carboxylic acid produced would be deprotonated, leading to the formation of the carboxylate anion instead of the acid itself.

The saponification of thioesters can be broken down into three key steps:

1. Nucleophilic Attack: A nucleophile attacks the carbonyl carbon of the thioester, initiating the reaction.
2. Loss of Leaving Group: The reaction proceeds with the departure of the leaving group, which in this case is the thiolate ion.
3. Proton Transfer: Finally, a proton transfer occurs, resulting in the formation of the thiol.

Overall, the basic hydrolysis of thioesters is a significant reaction in organic chemistry, illustrating the transformation of thioesters into useful products through a series of well-defined steps.

Hydrolysis of Thioesters Example 2

In the basic hydrolysis of a thioester, such as propanethioate, the reaction begins with the attack of a hydroxide ion on the carbonyl carbon of the thioester. This interaction leads to the formation of an alkoxide ion, characterized by a negatively charged oxygen atom bonded to the carbon chain. The hydroxide ion donates its electrons, resulting in the breaking of the carbonyl bond and the creation of a negatively charged oxygen with three lone pairs.

In the subsequent step, the alkoxide ion facilitates the elimination of the thiol group, which transforms into a thiolate anion. This occurs as the alkoxide pushes its electrons to form a double bond with the carbonyl carbon, simultaneously expelling the thiol. The products of this step are a carboxylic acid and the thiolate anion.

Steps 3a and 3b involve proton transfer processes. In step 3a, the thiolate anion acts as a base and deprotonates the carboxylic acid, yielding a carboxylate anion. The carboxylic acid, being quite acidic, readily loses a proton (H⁺) to the thiolate, resulting in the formation of the carboxylate anion and a thiol. The thiol has a pK_a of approximately 10, indicating its acidity.

In step 3b, the thiol is further deprotonated by the hydroxide ion, which has a pK_a of around 15.7, making it a strong enough base to facilitate this reaction. The thiol donates its proton, leading to the formation of a negatively charged sulfur species and water. This series of reactions highlights the importance of the basic environment in promoting the deprotonation of acidic groups, making it easier for them to exist in their deprotonated forms.

Draw the structures of products A and B in the following reaction sequence.

• A.
• B.
• C.
• D.

Answer: (A)

Thioesters can react with nucleophiles to yield substitution products. Write a mechanism for the reaction of S-methyl ethanethioate with dimethylamine.

Thioesters are reactive compounds that can undergo nucleophilic substitution reactions. In this case, we will explore the reaction of S-Methylethane Thioate with Dimethylamine, where dimethylamine acts as a nucleophile due to the basic nature of nitrogen.

The mechanism begins with the nucleophilic attack of the nitrogen atom on the carbonyl carbon of the thioester. This results in the formation of a tetrahedral intermediate, where the nitrogen forms four bonds, leading to a positive charge on the nitrogen:

$$\text{R-S-C(=O)-R'} + \text{H}_2\text{N-R''} \rightarrow \text{R-S-C(OH)(N-R'')^+}$$

Next, a proton transfer occurs where a hydrogen atom from the nitrogen moves to the oxygen, converting the positively charged nitrogen back to a neutral state:

$$\text{R-S-C(OH)(N-R'')}^+ \rightarrow \text{R-S-C(OH)(N-R'')} + \text{H}^+$$

Following this, the leaving group, which is the sulfur atom, departs as the oxygen forms a double bond with the carbon, resulting in a positively charged oxygen and a negatively charged sulfur:

$$\text{R-S-C(OH)(N-R'')} \rightarrow \text{R-C(=O)(N-R'')} + \text{S}^-$$

In the next step, a second proton transfer occurs where the negatively charged sulfur deprotonates the hydroxyl group, yielding a neutral amide and a thiol:

$$\text{R-C(=O)(N-R'')} + \text{S}^- + \text{H}^+ \rightarrow \text{R-C(=O)(N-R'')} + \text{R-SH}$$

Due to the acidic nature of the thiol, it can exist in equilibrium with excess dimethylamine present in the solution. This equilibrium can be represented as:

$$\text{R-SH} + \text{H}_2\text{N-R''} \rightleftharpoons \text{R-S}^- + \text{H}_3\text{N-R''}^+$$

In summary, the reaction of S-Methylethane Thioate with Dimethylamine involves a series of nucleophilic attacks, proton transfers, and the formation of equilibrium between the thiol and the amine, illustrating the dynamic nature of these chemical species in solution.

Here’s what students ask on this topic:

What is the mechanism of acid-catalyzed hydrolysis of thioesters?

In acid-catalyzed hydrolysis of thioesters, the reaction proceeds via a nucleophilic acyl substitution mechanism. The steps are as follows:

1. Protonation: The carbonyl oxygen of the thioester is protonated, increasing its electrophilicity.
2. Nucleophilic Attack: A water molecule attacks the carbonyl carbon, forming a tetrahedral intermediate.
3. Proton Transfer: A proton is transferred within the intermediate to facilitate the next step.
4. Leaving Group Departure: The thiol group (R-SH) leaves, forming a protonated carboxylic acid.
5. Deprotonation: The protonated carboxylic acid loses a proton to yield the final carboxylic acid product.

The overall reaction produces a carboxylic acid and a thiol.

What are the products of base-catalyzed hydrolysis (saponification) of thioesters?

In base-catalyzed hydrolysis, also known as saponification, of thioesters, the products are a carboxylate anion and a thiol. The reaction steps are:

1. Nucleophilic Attack: A hydroxide ion (OH⁻) attacks the carbonyl carbon of the thioester, forming a tetrahedral intermediate.
2. Leaving Group Departure: The thiol group (R-SH) leaves, resulting in a carboxylate anion.
3. Proton Transfer: The thiol group is protonated to form the final thiol product.

Because the reaction occurs in a basic medium, the carboxylic acid formed is immediately deprotonated to yield the carboxylate anion.

How does the nucleophilic acyl substitution mechanism work in thioester hydrolysis?

The nucleophilic acyl substitution mechanism in thioester hydrolysis involves several key steps:

1. Protonation (acid-catalyzed) or Nucleophilic Attack (base-catalyzed): The carbonyl oxygen is protonated in acid-catalyzed hydrolysis, or a nucleophile (e.g., OH⁻) attacks the carbonyl carbon in base-catalyzed hydrolysis.
2. Nucleophilic Attack: A nucleophile (e.g., H₂O or OH⁻) attacks the carbonyl carbon, forming a tetrahedral intermediate.
3. Proton Transfer: A proton is transferred within the intermediate to facilitate the departure of the leaving group.
4. Leaving Group Departure: The thiol group (R-SH) leaves, forming a carboxylic acid or carboxylate anion.
5. Deprotonation (acid-catalyzed): The protonated carboxylic acid loses a proton to yield the final carboxylic acid product.

This mechanism is crucial for understanding the reactivity of thioesters in organic synthesis.

What is the difference between acid-catalyzed and base-catalyzed hydrolysis of thioesters?

The main difference between acid-catalyzed and base-catalyzed hydrolysis of thioesters lies in the reaction conditions and products:

• Acid-Catalyzed Hydrolysis: This reaction occurs in an acidic medium and produces a carboxylic acid and a thiol. The mechanism involves protonation, nucleophilic attack, proton transfer, leaving group departure, and deprotonation.
• Base-Catalyzed Hydrolysis (Saponification): This reaction occurs in a basic medium and produces a carboxylate anion and a thiol. The mechanism involves nucleophilic attack, leaving group departure, and proton transfer. The carboxylic acid formed is immediately deprotonated to yield the carboxylate anion due to the basic environment.

Understanding these differences is essential for predicting the outcomes of thioester hydrolysis under different conditions.

Why is the carboxylate anion formed in base-catalyzed hydrolysis of thioesters?

In base-catalyzed hydrolysis (saponification) of thioesters, the carboxylate anion is formed because the reaction occurs in a basic medium. The steps are:

1. Nucleophilic Attack: A hydroxide ion (OH⁻) attacks the carbonyl carbon of the thioester, forming a tetrahedral intermediate.
2. Leaving Group Departure: The thiol group (R-SH) leaves, resulting in a carboxylic acid.
3. Proton Transfer: The basic environment causes the carboxylic acid to lose a proton, forming a carboxylate anion (R-COO⁻).

The basic medium is too alkaline for the carboxylic acid to remain protonated, leading to the formation of the carboxylate anion.