Which of the following functional groups is generally least reactive towards nucleophilic substitution reaction?

Options

A. Amide
B. Ester
C. Acid chloride
D. Acid Anhydride

Answer

To determine which functional group is generally least reactive towards nucleophilic substitution reactions, we need to analyze the electron density around the carbonyl carbon in each functional group. Here's a step-by-step breakdown:

### Step 1: Identify the Functional Groups
The functional groups mentioned in the question are:
- Amide (RCO-NH2)
- Ester (RCO-O-R)
- Acid Chloride (RCO-Cl)
- Acid Anhydride (RCO-O-CO)

### Step 2: Understand Nucleophilic Substitution
Nucleophilic substitution reactions involve nucleophiles (electron-rich species) attacking electron-deficient centers (typically carbonyl carbons). The more electron-deficient the carbonyl carbon, the more reactive the functional group will be towards nucleophilic attack.

### Step 3: Analyze Each Functional Group
1. **Acid Chloride (RCO-Cl)**: The chlorine atom is a strong electron-withdrawing group due to its electronegativity and -I (inductive) effect. This makes the carbonyl carbon highly electron-deficient, making acid chlorides very reactive towards nucleophiles.

2. **Acid Anhydride (RCO-O-CO)**: The presence of the carbonyl groups and the oxygen atom allows for some electron withdrawal, but it is less reactive than acid chlorides.

3. **Ester (RCO-O-R)**: Esters are less reactive than acid anhydrides because the alkoxy group (O-R) has a slight electron-donating effect, which reduces the electron deficiency of the carbonyl carbon compared to acid chlorides and anhydrides.

4. **Amide (RCO-NH2)**: The amine group (NH2) has a lone pair of electrons that can donate electron density to the carbonyl carbon, making it less electron-deficient. This electron-donating behavior significantly decreases the reactivity of amides towards nucleophilic substitution.

### Step 4: Conclusion
Based on the analysis, the functional group that is least reactive towards nucleophilic substitution reactions is the **Amide (RCO-NH2)**.

### Final Answer
The correct answer is **Amide (RCO-NH2)**.

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