Aromatic Heterocycles

• Aromatic heterocycles have six electrons within a cyclic conjugated system, making them exceptionally stable and chemically unique.
• Heterocycles cover approximately two-thirds of organic compounds.

Connections

• Reactions between enols and enolates.
• Reactions involving syntheses of aromatic heterocycles.
• Observing synthesis of saturated heterocycles.
• Studying biological chemistry.

Conceptual Derivation

• Aromatic heterocycles conceptually come from benzene through replacing CH with N to form pyridine.
• Aromatic heterocycles conceptually come from benzene through replacing CH=CH with N to form pyrrole.

Pyridine Reactions

• Pyridine derivatives help extend the reactivity of pyridine.
• Putting more nitrogens in five- and six-membered rings.
• Fused rings: Indole results from fused rings, as do quinoline, isoquinoline, and indolizine.

Heteroatoms

• Rings containing nitrogen and another heteroatom such as oxygen or sulfur

Introduction

• Aromaticity has a precise chemical definition, with benzene's reactions described in earlier chapters.
• Thousands of aromatic systems exist with heteroatoms like N, O, and S replacing benzene ring atoms.

Significance of Heterocycles

• Heterocycles define the history of medicine through various essential drugs.
• Quinine used to prevent/treat malaria.
• Antipyrine (1887) helped lower fevers.
• Sulfapyridine (1938) was the first antibiotic.
• Tagamet (1970s) treated ulcers.
• Viagra (1997) helped with male impotence.

Heterocyclic Ring Structures

• Heterocyclic aromatic rings have single rings, either five- or six-membered, and/or fused rings with varying nitrogen counts.

Nitrogen Replacement

• Nitrogen inserted into the benzene ring allows for maintained aromaticity, with nitrogen's trigonal shape and p orbital accommodating this.
• Replacing a CH group with a nitrogen atom forms pyridine.
• Pyridine lacks an NH bond. Its lone pair of electrons is in place of the C-H bond in benzene.

Evidence of Aromaticity

• Evidence of pyridine's aromatic qualities comes from the proton NMR spectrum, where protons resonate in the same region.
• Pyridine remains stable.
• Pyridine = aromatic.

New Aromatic Heterocycles

• Replacing more CH groups with nitrogen atoms yields new aromatic heterocycles: Pyridazine, pyrimidine, and pyrazine.
• Replacing a CH=CH unit with nitrogen allows use of its lone pair in the delocalized system if it is in a p orbital.
• With remaining double bonds and the nitrogen's lone pair, six electrons result.
• Nitrogen must remain trigonal, with the lone pair in a p orbital.
• The N-H bond is within the plane of the five-membered ring.
• Replacing a CH=CH unit with nitrogen results in pyrrole.

Chemical and Physical Properties of Pyrrole Compared to Benzene and Pyridine

• Pyrrole demonstrates less chemical shift in the proton NMR spectrum than benzene or pyridine, though, it still falls in the aromatic region.
• Pyrrole is also more reactive toward electrophiles, yet still favors aromatic substitution reactions.
• Pyrrole, too, is an aromatic compound.

Inventing Heterocycles

• Further CH group replacements in pyrrole form additional heterocycles. One CH replacement leads to pyrazole and imidazole; two form triazoles; three form tetrazole.

Common Traits

• The new heterocycles are broadly accepted as aromatic. They possess reactivities and NMR spectra matching aromatic norms.

Pyridine Compared to Pyrimidine

• The nitrogen is planar and trigonal, making it an imine.
• The nitrogen is very unreactive and aromatic.
• Pyridine's stable imines have a flat nitrogen and lone pair, differentiating them from carbonyl imines.

Pyridine as a Weak Base

• Pyridine's pKa for its conjugate acid is 5.5, making it a weak base.
• Pyridinium ions are as strong as carboxylic acids.
• Piperidine is a stronger base, possessing a pKa of 11.2.

Nu Cleophilic Nature of Pyridine

• Pyridine functions as a carbonyl group nucleophile, which also makes it a nucleophilic catalyst for acylation reactions.
• Esters often result from pyridine solutions containing alcohols and acid chlorides.
• N,N-dimethylaminopyridine (DMAP) is more effective at catalyzing acylation than is pyridine alone due to reinforcing the nucleophilic properties of the nitrogen atom.
• Acylation catalyzed by pyridine typically occurs in pyridine solutions, whereas DMAP requires small amounts of other solvents.

Pyridine Disadvantages Despite Advantages

• Pyridine is toxic.
• Pyridine possess a foul odor.
• Pyridine continues to find use as a popular and cheap solvent.

Electron Delocalization

• Pyridine is nucleophilic at the nitrogen atom as its electrons cannot delocalize around the ring.
• The lone pair of electrons occupies an orthogonal sp2 orbital that permits no interaction because they are orthogonal.
• Attempts to delocalize lone electrons create absurd structures.

Nitrogen’s Effect on Reactivity

• Nitrogen lowers energy in all the orbitals.
• Lower-energy filled orbitals result in a less reactive nucleophile, whereas a lower-energy LUMO increases electrophilic reactivity.
• Nitrogen doesn't help attract electrophiles.

Impact of Nitrogen on Aromatic System

• Electrophilic attack becomes difficult when the orbitals of pyridine's aromatic system have lower energy.
• The nitrogen atom destabilizes the would-be intermediate cations, especially if delocalized onto nitrogen.

Drawbacks of Electrophilic Substitution

• The nitrogen lone pair's basicity results in normal reagents for electrophilic substitution reactions being acidic.
• Pyridine itself is not reactive toward electrophiles. In fact, pyridinium ions are entirely unreactive.
• Pyridine is a good ligand for metals like Al(III) or Sn(IV) leading to the complex with cationic nitrogen being inert to electrophiles.
• Aromatic electrophilic substitution on pyridine is not a useful reaction. Avoid nitration, sulfonation, halogenation, and Friedel-Crafts reactions on simple pyridines.

Nucleophilic Substitution

• The nitrogen atom prompts more reactive reactions toward nucleophilic substitution.
• Nucleophilic substitution notably occurs at the 2- and 4-positions by lowering pyridines LUMO energy of the π system.
• This has direct effects on halogen replacement through nucleophiles.

Pyridones

• Pyridones act as the starting materials in nucleophilic substitutions with 2- and 4-chloro or methoxypyridines, being created through nucleophilic substitution on the pyridones.

Tautomerization Structures

• 2- hydroxypyridine favors the amide structure because it is aromatic and possesses a strong C=O bond, with delocalization in amide style.
• 2-hydroxypyridine exists as 'amide'.
• 4-pyridone possesses similar delocalization.
• 3-hydroxypyridine exist in 'phenol' form.
• The pyridine nitrogen will not remove a proton from the hydroxyl group.

Electrophilic Aromatic Substitution

• Electrophilic substitutions only take place on pyridines if activated by electron-donating substituents. The reactions proceed in spite of the molecule's pyridine qualities.

Pyridine N-oxides

• Pyridine N-oxides undergo both electrophilic and nucleophilic substitutions on Carbon atoms (2, 4, and 6)

Acyl Group Migration

• Pyridine interactions with acid anhydrides prompts nucleophilic addition at distant sites when alkyl groups are present on the alpha positions.
• Acylation on oxygen occurs.
• A proton results being lost through the side chain which results in charge cancelling.
• This compound rearranges to restore aromaticity via acetate group migration to the side chain.

Reagent

• Pyridine acts as both a reagent and catalyst.
• Pyridine can also be a reagent in brominations.

Pyridine's Role in Brominations

• Another method puts it in stable crystalline form, simply a salt of pyridine w/ the anion Br3, such as pyridinium tribromide.
• Pyridine makes bromine interact through nitrogen only.
• Pyridine remains resistant to electrophiles (such as bromine).

Cr(VI) Compounds

• Cr(VI) uses the pyridinium ion (pKa 5) as the only acid.
• Pyridinium dichromate (PDC) and pyridinium chlorochromate (PCC) are the most well-known.
• Pyridine + CrO3 + HCl combine to give PCC

Bipyridyls

• Pyridine metal complexes demonstrate increased ability in their enhanced dimer, either as 'bipy' or 2,2'-bipyridyl.

Oxygen and Rings

• Although pyridine is important among six-membered aromatic heterocycles, pyrones are essential oxygen heterocycles that resemble pyridones. Alpha-pyrone is rather unstable.

Five-Membered Aromatic Heterocycles

• Five-membered aromatic heterocycles are good at electrophilic substitution.

Pyrrole Chemistry

• What is true of pyridine is the opposite of pyrrole.
• Reactions occur more readily in reactions akin to benzene.
• Pyrrole isn’t a base or convertible to an N-oxide.

Nitrogen Differences

• Nitrogen's lone pair is delocalized around the ring.
• Ring positions become equally electron-rich.
• Chemical shifts also appear smaller than those of benzene.

Delocalization

• As a base, pyrrole has a pKa of about -4, with protonation on carbon at that pH level.
• The NH proton (pKa 16.5) can be removed by bases stronger than normal secondary amines.

Electrophiles

• Nitrogen in pyrrole attacks readily
• Bromine leads to substitution at all four free positions.

Side Effects

• One can't use strong acids, though protonation won't occur at nitrogen.

Vilsmeier Reaction

• Reactions are controllable to make monosubstituted products, like the Vilsmeier reaction.
• N,N-dimethylamide and POCl3 help make carbon electrophiles with no strong acids or Lewis acids.

Indole Synthesis

• One mechanism utilizes a substrate, E+, which reacts with generalized electrophile, occurring smoothly. Reaction in the 2-position appears better than in the 3-position.
• Calculations suggest a stronger HOMO of pyrrole that's larger in a 2-position, to explain that result through assessment of intermediate structures.

Heterocycles in the System

• Furan and thiaphene are oxygen and sulfur analogues of pyrrole.
• Furan and thiaphene also support electrophilic aromatic substitution, although not as easily as pyrrole. Nitrogen is a large electron donor, with oxygen and sulfur being lesser.

Oxygen and Sulfur

• Furan, thiophene' and benzene are conjugated

Blocking

• If blocking substitution with a removable substituent, ester groups are often used.
• The reactions may end up on carbonyl.
• The ketone compounds lessens reactivity toward electrophiles.

Four and Thiophenes

• 1,4 addition
• Br atoms gets pushed out (to stabilize)

Furans Being Reactive

• If the prospect of stable bonds as C-O, from additions
• A bromide of methanol helps in these reactions

Lithiation

• This helps when there's metallation
• the heteroatom in the ring is what provides the necessary activation.

Five-Memmbered Reactions

• Five-membered ring molecules act as dienes in Diels-Alder
• A good example is using oxidized thiophene
• The molecules are pretty unstable, resulting in benzene derivative

Pyrrole Acidity

• Nitrogen anions can easily be created
• new groups are added to the Carbon atoms of the Ring

N-Acylated Derivatives

• One can generally make the nitrogen. This occurs though reactions with electrophiles
• To act w/ the the right, it needs a pi orbital

Imidazole

• There are more rings w/ more Nitrogen
• There are also 2 molecules with ring and Nitrogen atoms,
• there were good results w/ the 1-3 relationship w/ two nitrogen
• Atoms do this by using both, one has to grab a proton.
• It always will help out using delocalizer e-
• Histrydine plays a role in this also

CDI Compounds

• It's pretty important the Carbonly diimodazlde as well. It will be safe in use because,
• it can be a leaving group
• There is an intermerdiate to help w/ the reaction as well.
• The tauntermism is interesting as well. You have the isomerism and other properties.
• Tetrazoles are very good when added also which has been seen

Nitrogen Compounds

• They contain 2 -3 added nitro atoms together with other materials
• The limit has also been made as well