Heterocycle Reactivity

Flashcards reviewing heterocycle reactivity, including pyridine, pyrrole, indole, imidazole, and pyrazole.

Describe the characteristics of Pyridine

The lone pair of N is in a sp2 orbital, perpendicular to the π plane and available for bonding, making pyridine basic and nucleophilic.

Describe the characteristics of Pyrrole

The lone pair of N is in a p orbital and is in resonance with other π electrons, making pyrrole not basic.

Where do electrophiles add on pyridine, and what type of substitution usually won't work?

Electrophiles add on N; electrophilic aromatic substitution usually won't work.

Why is electrophilic attack on the pyridine ring difficult?

Nitrogen lowers the orbital energy in pyridine’s π system, making electrophilic attack on the ring difficult.

What type of substitution is easy for pyridine?

Nucleophilic substitution is easy.

What type of substitution are five-membered heteroaromatics good for?

Good for electrophilic aromatic substitution

What is indole?

Benzene-fused pyrrole with pyrrole-type nitrogen and 10 π aromatic electrons.

List three characteristics of imidazole and pyrazole

Tautomerization, enhanced nucleophilicity and basicity, and slightly enhanced N–H acidity.

In general, what type of reagents react with electron-rich and electron-poor aromatics?

Electrophiles react with electron-rich aromatics, while nucleophiles react with electron-poor aromatics.

What can you do to pyridine for electrophilic aromatic substitution?

Activate pyridine.

What is required for halogenation in electrophilic reactions?

Requires an electrophilic halide source (F, Br, I, Cl).

What reaction does the Vilsmeier Haack reaction perform?

Formylation.

What reaction does the Mannich Reaction perform?

Dialkylaminomethylation.

What type of reaction occurs with nucleophiles and electron-poor aromatics?

Substitution of halogen (or “good leaving groups”) via Addition-Elimination Mechanism (SNAr Reaction).

What is the relationship between leaving groups and electron withdrawing groups in SNAr reactions?

Leaving groups ortho or para to the electron-withdrawing groups are activated toward SNAr reaction

What activates 5-membered heterocycles towards SNAr reactions?

EWG activates 5-membered heterocycles.

What occurs in the substitution of hydrogen with strong nucleophiles and forcing conditions?

Turning lousy leaving groups into good ones.

What conversion occurs to lousy leaving groups?

Substitution of hydrogen with strong Nu- and forcing conditions.

What role do C-Metallated Heterocycles play?

C-Metallated heterocycles act as nucleophiles.

What are two methods for the preparation of C-Metallated Heterocycles?

Metal-halide exchange or Grignard reagent.

Describe directed ortho metalation.

Driven by complexation, commonly ortho-directed, effectively a deprotonation reaction using a strong base.

What reaction often occurs with pyridine?

Often alkylated.