FINAL Aromatic Heterocyclic Compounds

H3 Chem 1 Anglo-Chinese Junior College H3 Chemistry Aromatic Heterocyclic Compounds Lecture Notes Prepared by: Jun Kiat, Shanghong & Shi Shiun Section Content 1. Introduction 2. Nomenclature a. Common compounds under Trivial Method b. Common compounds under Systematic Method 3. Structure a. General Structure of Common Heterocyclic Compounds 4. Reactions _________________________________________________ References 1. https://chem.libretexts.org/Courses/Brevard_College/CHE_201%3A_Organic_Che mistry_I/04%3A_Aromatic_Compounds_(Arenes)/4.12%3A_Heterocyclic_Aromatic _Compounds 2. https://www.thermofisher.com/sg/en/home/chemicals/organic- chemistry/heterocyclic-compounds.html 3. https://uou.ac.in/lecturenotes/science/MSCCH- 17/CHEMISTRY%20LN.%203%20HETEROCYCLIC%20COMPOUNDS- converted%20(1).pdf

H3 Chem 2

H3 Chem 3 Introduction ● Heterocyclic compounds, or heterocycles, are cyclic compounds that have atoms of at least two different elements as members of the ring structure. ● Organic heterocycles contain one or more carbon atoms and, based on their electronic structure, are classified as saturated, unsaturated, and aromatic. ● When the heteroatom (any atom in the molecule that is not a carbon or hydrogen) is a part of an aromatic ring, the compound is called an aromatic heterocycle. ● Aromatic heterocycles can be single-ring heterocycles (e.g., pyrrole, furan, thiophene, pyridine) or fused-ring heterocycles (e.g., indole, quinoline, and isoquinoline). Some common examples of heterocycles containing common heteroatoms of O, N, and S

H3 Chem 4 Nomenclature ● The nomenclature is divided into Trivial Method and Systematic Method of nomenclature (additional info) ○ Trivial Method (Does not provide information on structure) Some common examples of heterocycles under the Trivial Method ○ Systematic Method (Provides information on structure) Some common examples of prefixes of atoms in aromatic heterocyclic compounds

H3 Chem 5 General Structure Huckel’s Rule: A cyclic, planar, fully conjugated molecule is aromatic if it contains 4𝑛+2 π-electrons, where 𝑛 is a non-negative integer (𝑛 = 0,1,2,…)

H3 Chem 6 Reactions Electrophilic Aromatic Substitution Overall Reaction: Fig.1 Alike the electrophilic substitution of benzene, a hydrogen atom on the ring is substituted for another substituent on it. The example shows the bromination of pyrrole, with Br+ being generated as the electrophile. As aromatic heterocyclic compounds are far more nucleophilic than benzene, this reaction does not require a Lewis Acid catalyst. Aromatic heterocyclic compounds are, in general, more nucleophilic than benzene, as their carbocation intermediates can stabilise the positive charge to a greater extent than a benzene ring. The positive charge can be ‘moved’, via resonance, to the electronegative atom (see fig. 4). Carbon atoms bearing positive charges are electron-deficient and will not obey the octet rule, making it unstable.

H3 Chem 7 Relative rates of electrophilic substitution in heterocyclics In decreasing reactivity of electrophilic aromatic substitution: Fig. 3 Pyrrole is more nucleophilic than Furan as nitrogen is less electronegative than oxygen, making the ring more nucleophilic. Electronegative atoms can withdraw electron density from the ring via an inductive effect. Furan is more nucleophilic than thiophene as the sulfur atom is relatively big compared to a carbon atom (3p in S vs 2p in C). Hence, the extent of effective orbital overlap between the 3p orbitals of sulfur and the 2p orbitals of carbon is low. Hence, thiophene is less nucleophilic than furan. This is despite sulfur being less electronegative than oxygen. Why is the product at the 2’ position the major product, while the product at the 3’ position is the minor product? It all ties back to the stability of the carbocation. The carbocation intermediate for the 2’ substituted product can have greater resonance stabilisation than that of the 3’ substituted product due to the presence of more resonance structures. The positive charge for the carbocation intermediate for the 2’ product is able to have its positive charge be dispersed over a greater number of carbon atoms. This stabilises the carbocation intermediate for the 2’ substituted product to a larger extent than that of the 3’ substituted product. Fig. 4 The resonance structures of the intermediate that gives the 2’ substituted product

H3 Chem 8 Fig. 5 The resonance structures of the intermediate that gives the 2’ substituted product

H3 Chem 9 The mechanism that forms the major product Fig. 6 Aromatic heterocyclic compounds are far more nucleophilic than the benzene ring, so they do not require a Lewis Acid catalyst (AlX3 or FeX3) when they undergo electrophilic substitution. Furthermore, the highly electronegative atom on the ring would coordinate strongly with the Lewis Acid catalyst, which will result in no reaction occurring. Relative reactivities of some aromatic heterocyclic compounds Fig 7

H3 Chem 10 Nucleophilic aromatic substitution, using pyridine as an example Why does substitution at the 2’ or 4’ position of pyridine give the major product instead of the 3’ position? Figure 8: The formation of the major 2’ substituted product of pyridine Figure 9: The formation of the very minor 3’ substituted product of pyridine