Animated Solution for Chemistry - Organic Chemistry: The correct sequence of reagents used in the preparation of 4-bromo-2-nitroethyl benzene from benzene is

The synthesis of multi-substituted benzene rings is like a game of chess. Every move you make dictates the possibilities for your next move. In this problem, we are tasked with synthesizing 4-bromo-2-nitroethylbenzene from a simple benzene ring.

To win this game, we must carefully orchestrate the introduction of three distinct substituents: an ethyl group ($-{\text{CH}}_2{\text{CH}}_3$), a bromine atom ($-\text{Br}$), and a nitro group ($-{\text{NO}}_2$). The order in which we introduce these groups is the difference between a successful synthesis and a flask full of unwanted isomers.

Before we mix any chemicals, we must understand the directing nature of our target substituents.

The ethyl group is an electron-donating group (EDG) via hyperconjugation. It activates the benzene ring and directs incoming electrophiles to the ortho and para positions.

The bromine atom is a unique player. It is an electron-withdrawing group (EWG) due to its strong $-I$ effect, making it deactivating. However, because of its lone pairs, it directs incoming electrophiles to the ortho and para positions via resonance ($+M$ effect).

Finally, the nitro group is a powerful electron-withdrawing group. It strongly deactivates the ring and directs incoming electrophiles exclusively to the meta position.

If we were to introduce the nitro group first, its strong deactivating nature would make subsequent reactions incredibly difficult, and its meta-directing effect would force the next group into the wrong position. Therefore, nitration must be our final move.

The Acylation-Reduction Strategy

Our first goal is to attach the ethyl group. You might be tempted to use direct Friedel-Crafts alkylation with ethyl chloride (${\text{CH}}_3{\text{CH}}_2\text{Cl}$) and ${\text{AlCl}}_3$. However, alkyl groups activate the ring, meaning the product (ethylbenzene) is more reactive than the starting benzene. This often leads to uncontrollable polyalkylation.

To bypass this trap, we use a two-step strategy. First, we perform a Friedel-Crafts Acylation using acetyl chloride (${\text{CH}}_3\text{COCl}$) and ${\text{AlCl}}_3$. This introduces an acetyl group ($-{\text{COCH}}_3$), forming acetophenone. Because the acetyl group is deactivating, the reaction cleanly stops at mono-substitution.

Next, we must convert this ketone into an alkane. We employ the Clemmensen Reduction, treating the acetophenone with zinc amalgam ($\text{Zn-Hg}$) and concentrated $\text{HCl}$. This smoothly reduces the carbonyl group, yielding our desired ethylbenzene.

Directing the Halogen

With ethylbenzene in hand, we move to bromination using ${\text{Br}}_2$ and a Lewis acid catalyst like ${\text{AlBr}}_3$.

The ethyl group is ortho/para directing. However, the ethyl group is somewhat bulky, creating steric hindrance at the adjacent ortho positions. Consequently, the bulky bromine electrophile (${\text{Br}}^{+}$) prefers to attack the less hindered para position. This yields 4-bromoethylbenzene as the major product.

The Final Nitration Clash

We have reached the final stage: Nitration using a mixture of concentrated ${\text{HNO}}_3$ and ${\text{H}}_2{\text{SO}}_4$.

Our ring now hosts two substituents: the activating ethyl group and the deactivating bromo group. When an activating group and a deactivating group compete to direct an incoming electrophile, the activating group always wins.

The ethyl group directs the incoming nitronium ion (${\text{NO}}_2^{+}$) to its ortho and para positions. Since the para position is already occupied by the bromine atom, the nitro group has no choice but to attach at the ortho position.

This flawless sequence—Acylation, Reduction, Bromination, and Nitration—delivers our exact target: 4-bromo-2-nitroethylbenzene.