CHE 3332 – Organic Chemistry 2 – Spring 2021 Week 9 Resource Hello everyone! Virtual group tutoring for this class will be every Tuesday from 6-7 pm, and you can reserve your spot by making an appointment at www.Baylor.edu/Tutoring. This week, we’ll

cover Chapter 19: Aromatic Substitution Reactions. Keywords: aromatic substitutions, Friedel-crafts, activators, deactivators, benzyne

Electrophilic Aromatic Substitution (EAS) The aromatic ring is the nucleophile and the reagent should be a good electrophile. The ring attacks, a sigma complex (3 structures) occurs, and then a proton transfer happens at the end. There are three different reagents that can add halogens to a ring:

Sulfonation The SO3H is a blocking group and it replaces a hydrogen on the ring. It can be added and removed from the aromatic ring in a reversible reaction.

Nitration A nitro group can be added or removed from the ring, but that reaction is not reversible–different reagents are needed. HNO3 adds the nitro group to the ring. Removing the nitro group reduces it to an amine group and it can be done by either Fe/HCl or Zn/HCl.

Friedel-Crafts Alkylation This reaction adds an alkyl group to the aromatic ring. The reagents include AlCl3 and any alkyl halide. A carbocation is created on the alkyl halide group after the halide leaves and then the rind attacks the carbocation to bond. Secondary and tertiary carbon with carbocations don’t rearrange so only one product is made. A primary carbon with a carbocation can rearrange so that the charge is on a more favorable; thus, a mix of products is made. The major product is the one made from the rearrangement and the minor product is made if the carbocation does not rearrange.

major product minor product

Friedel-Crafts Acylation This reaction adds an acyl group to the aromatic ring. The reagents include AlCl3 and any acyl halide. The process works the same as an alkylation.

Clemmensen Reduction This reaction reduces the Friedel-craft acyl group with Zn(Hg)/HCl. The carbonyl group gets reduced to hydrogen bonds.

Adding Activating vs Deactivating Groups to the Aromatic Ring Activating groups favor adding to the ortho and para position on an aromatic ring. Deactivating groups favor adding to the meta position. These groups are already on the ring and direct which position a new group will be added to. These groups have different levels of strength; this matters when you’re trying to add both activators and deactivators to the ring because you’ll want to favor whichever group is stronger. Table to memorize:

Acyl group:

Activators

(add ortho & para) Strong

Moderate

Weak (alkyl group)

Deactivators (add meta)

Weak*

Moderate

Strong

*exception – halogens are deactivators but favor adding ortho and para If multiple substituents are already on the ring, favor the adding position of the strongest groups:

Bulky alkyl substituents favor adding new groups to the less hindered position. Alkyl groups favor both the ortho and para position so choose the position that doesn’t sterically hinder the big alkyl group–usually go para.

Use the SO3H blocking group to block a particular para, ortho, or meta position. Add it to the ring, do an EAS reaction, and then remove the blocking group. Without the blocking group, the bromine would have added to the para position because it’s sterically favored. With the blocking group on the ring, the bromine must add at the ortho position:

If there’s a moderate/strong deactivator on the ring, such as a nitro group, you cannot do a Friedel-crafts addition; even if the Friedel-crafts reagents are present, no reaction will happen:

The nitro group produced after step #1 is a strong deactivator; therefore, step #2 of Friedel-crafts acylation cannot happen.

In this case, Friedel-crafts acylation can happen: Nucleophilic Aromatic Substitution (NAS) The ring is the electrophile and gets attacked by the reagent. The following 3 conditions must be met for NAS to happen: the ring needs an electron withdrawing group, the ring needs a leaving group, and the withdrawing group & leaving group must be ortho or para to each other. The reagent attacks the ring, a meisenheimer complex (4 structurees) occurs, the leaving group leaves, and the nucleophile is put in place of the leaving group.

Benzyne Reaction This reaction occurs if the 3 conditions of the NAS are not met. Usually, no electron withdrawing group is present so when the reagent attacks the ring, a benzyne intermediate is made. The end product still includes the nucleophile put in place of the leaving group.

Benzyne structure:

Quiz: 1. What’s the most favored adding position on this structure?

2. Predict the product:

3. Propose a synthesis: Answers: All questions sourced from the Wiley Organic Chemistry Second Semester textbook.

1. 2.

3.