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 functional groups in question.

### Step-by-Step Solution:

1. **Understanding Nucleophilic Substitution**:
- Nucleophilic substitution reactions occur when a nucleophile (an electron-rich species) attacks an electron-deficient carbon atom in a functional group. The carbon must have low electron density to allow for this attack.

2. **Identifying Functional Groups**:
- The functional groups given are amide (R-C(=O)-NH2), ester (R-C(=O)-O-R'), and acyl chloride (R-C(=O)-Cl).

3. **Analyzing Electron Density**:
- **Amide**: The nitrogen in amides has a lone pair of electrons that can donate electron density to the carbonyl carbon (C=O), reducing its electrophilicity. Therefore, the carbon in an amide is less electron-deficient.
- **Ester**: In esters, the oxygen atom has a partial negative charge, which can also withdraw electron density from the carbonyl carbon, but not as effectively as in acyl chlorides.
- **Acyl Chloride**: Chlorine is highly electronegative and withdraws electron density from the carbonyl carbon significantly, making it very electron-deficient and more reactive towards nucleophiles.

4. **Comparing Reactivity**:
- The order of reactivity towards nucleophilic substitution can be summarized as follows:
- Acyl Chloride > Ester > Amide
- Since amides have the least electron deficiency on the carbonyl carbon due to the electron-donating effect of the nitrogen, they are the least reactive towards nucleophilic substitution.

5. **Conclusion**:
- Therefore, the functional group that is generally least reactive towards nucleophilic substitution reactions is **Amide** (option 1).