Heterocycles Part 2: Pyridine

Professor Dave Explains

8 Mar 202105:52

EducationalLearning

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TLDRThis script delves into the chemistry of pyridine, a six-membered heterocyclic aromatic compound resembling benzene with a nitrogen atom. It discusses pyridine's electronic structure, basicity, and reactivity, contrasting it with pyrrole. The tutorial covers the molecule's synthesis via the Hantzsch method and its involvement in nucleophilic aromatic substitution. It also touches on the existence of pyridine derivatives like pyridazine, pyrimidine, and pyrazine, highlighting their prevalence in natural products and their significance in compounds such as DNA bases, vitamin B6, nicotine, and quinine.

Takeaways

🔍 Pyridine is a six-membered aromatic heterocycle similar to benzene but with a nitrogen atom replacing one of the carbons.
🌀 Pyridine's aromaticity is slightly less than benzene due to the electron-withdrawing effect of the nitrogen atom, reducing the resonance energy from 36 kcal/mole to 28.
🧬 The nitrogen atom in pyridine has a lone pair in an sp2 orbital, which does not delocalize, making pyridine more basic than pyrrole but less than a regular amine.
🧪 Pyridine can undergo nucleophilic reactions, such as alkylation and acylation, to form reactive intermediates like N-acetyl pyridinium salts.
🔬 Oxidation of pyridine with peroxyacids is possible, leading to the formation of a stable pyridine oxide.
❌ Unlike benzene, pyridine does not readily undergo electrophilic aromatic substitution due to the coordinating effect of the nitrogen atom with Lewis acids.
✅ Nucleophilic aromatic substitution is feasible for pyridine, as nitrogen can stabilize negative charges more effectively than carbon.
🧪 The Hantzsch synthesis is a widely used method for pyridine synthesis, involving two beta-keto esters, formaldehyde, and ammonium acetate to yield dihydropyridine, which is then oxidized.
🔑 Pyridine derivatives with two nitrogen atoms, such as pyridazine, pyrimidine, and pyrazine, are structurally isomeric and exhibit weaker basicity compared to pyridine.
🌿 Heterocycles like pyridine are abundant in natural products and are key components in molecules such as adenine in DNA, vitamin B6 (pyridoxine), nicotine, and quinine.
📚 The script provides a foundational understanding of important heterocycles, their properties, reactions, and significance in biological systems and pharmaceuticals.

Q & A

What is the primary difference between pyridine and benzene in terms of molecular structure?
-The primary difference is that in pyridine, one of the carbon atoms in the benzene ring is replaced with a nitrogen atom.
How does the presence of nitrogen in pyridine affect the aromaticity compared to benzene?
-The nitrogen atom withdraws some electron density and reduces the symmetry of delocalization, which lowers the resonance energy from 36 kcal/mole in benzene to 28 kcal/mole in pyridine, making it almost as aromatic as benzene but not quite as stable.
Why does the lone pair on the nitrogen atom in pyridine not participate in the aromatic delocalization?
-The lone pair on nitrogen does not delocalize because it is not required for the molecule to be aromatic; the six pi electrons from the three pi bonds are sufficient for aromaticity.
How does the basicity of pyridine compare to pyrrole and regular amines?
-Pyridine is more basic than pyrrole because its lone pair is available to act as a proton acceptor. However, it is not as basic as a regular amine due to the sp2 hybridization, which holds the lone pair closer to the nucleus.
What type of chemical reactions can pyridine undergo as an N-based nucleophile?
-Pyridine can undergo alkylation with an alkyl halide, acylation with an acyl chloride to form an N-acetyl pyridinium salt, and oxidation with peroxyacids to yield a stable pyridine oxide.
Why does pyridine not readily undergo electrophilic aromatic substitution?
-Pyridine does not undergo electrophilic aromatic substitution because the nitrogen atom coordinates with Lewis acids, which would be required for such a reaction, making electrophilic attack highly unlikely due to the potential formation of a second formal positive charge.
What type of aromatic substitution is feasible for pyridine and why?
-Nucleophilic aromatic substitution is feasible for pyridine because nitrogen can stabilize negative charges more effectively than carbon, allowing the reaction to occur without the need for activation.
What is the Hantzsch synthesis and how is it used to produce pyridine?
-The Hantzsch synthesis is a method developed by Arthur Rudolph Hantzsch in 1881, which uses two beta-keto esters, formaldehyde, and ammonium acetate to produce a dihydropyridine under aqueous conditions, which is then oxidized to form the aromatic pyridine system.
Why are six-membered heterocycles with oxygen or sulfur instead of nitrogen not stable as neutral species?
-The script does not provide a specific reason, but it is generally known that the electronegativity and atomic size differences between oxygen or sulfur and carbon can lead to instability in the neutral form of such heterocycles.
What are some examples of naturally occurring compounds that contain pyridine rings?
-Examples include the nitrogenous bases in DNA such as adenine, pyridoxine (vitamin B6), nicotine from tobacco, and quinine, an anti-malarial drug.
What are the three structurally isomeric structures with two nitrogen atoms in place of one in pyridine?
-The three structurally isomeric structures are pyridazine (adjacent nitrogens), pyrimidine (nitrogens two apart), and pyrazine (nitrogens on opposite sides).

Outlines

00:00

🔬 Pyridine: Structure, Properties, and Reactivity

This paragraph introduces pyridine, a six-membered aromatic heterocycle with one nitrogen atom replacing a carbon in benzene. It explains pyridine's aromaticity, which is slightly less stable than benzene due to the electron-withdrawing nature of nitrogen. The nitrogen atom's lone pair is localized, making pyridine more basic than pyrrole but less so than typical amines due to the sp2 hybridization. Pyridine's reactivity is discussed, including its ability to undergo nucleophilic substitution and form N-acetyl pyridinium salts and pyridine oxides. The paragraph also touches on pyridine's reluctance to undergo electrophilic aromatic substitution due to the nitrogen's nucleophilic effect. Finally, it mentions the Hantzsch synthesis as a common method for pyridine production and briefly notes the existence of pyridine derivatives with two nitrogen atoms, such as pyridazine, pyrimidine, and pyrazine, which are weaker bases but share similar reactivity.

05:04

📚 Historical and Biological Significance of Pyridine Derivatives

The second paragraph concludes the discussion on pyridine by highlighting its historical and biological importance. It mentions the role of pyridine derivatives in the history of drugs, referencing a tutorial focused on quinine, an anti-malarial drug. The paragraph also underscores the prevalence of these heterocycles in natural products, exemplified by adenine in DNA, pyridoxine (vitamin B6), nicotine in tobacco, and quinine. This summary underscores the fundamental role of pyridine and its derivatives in both the history of medicinal chemistry and their presence in essential biological molecules.

Mindmap

Keywords

💡Heteroaromatic systems

Heteroaromatic systems are organic compounds that contain a ring of atoms with at least one atom being different from carbon, typically nitrogen, oxygen, or sulfur. In the script, this term is used to describe the structure of pyridine and its comparison to other five-membered rings like furan and thiophene, as well as pyrrole. The concept is central to the theme of the video, which is to explore the characteristics and reactions of these systems.

💡Pyridine

Pyridine is a heterocyclic aromatic compound with the chemical formula C5H5N, which resembles benzene but with one carbon atom replaced by nitrogen. It is described in the script as being almost as aromatic as benzene, with a slight reduction in resonance energy due to the electron-withdrawing nature of nitrogen. Pyridine is a key compound in the video, illustrating the electronic structure and reactivity of six-membered heteroaromatic systems.

💡Aromaticity

Aromaticity refers to a property of cyclic (ring-shaped), planar structures with delocalized π-electrons in conjugation, which gives them increased stability and distinctive physical and chemical properties. In the script, pyridine is noted as being aromatic, with its aromaticity being slightly less than that of benzene due to the presence of nitrogen, which withdraws electron density.

💡sp2 hybridization

sp2 hybridization is a type of atomic orbital hybridization that occurs in atoms with three electron orbitals (s, p), resulting in three sp2 hybrid orbitals. In the context of the script, all atoms in the pyridine ring are sp2 hybridized, which allows for the delocalization of the π-electron cloud and contributes to its aromaticity.

💡Lone pair

A lone pair in chemistry refers to a pair of electrons that are not involved in bonding. In the script, the nitrogen atom in pyridine has a lone pair of electrons that resides in an sp2 orbital. Unlike in pyrrole, this lone pair does not participate in the aromatic system's resonance, and it is localized on the nitrogen atom, making pyridine more basic than pyrrole.

💡Basicity

Basicity is the ability of a substance to accept protons (H+) or to donate pairs of electrons. The script explains that pyridine is more basic than pyrrole due to the availability of its nitrogen's lone pair to act as a proton acceptor. However, it is not as basic as a regular amine because the sp2 orbitals have more s character, which holds the lone pair closer to the nucleus.

💡Nucleophile

A nucleophile is a chemical species that donates an electron pair to an electrophile in a reaction. In the script, pyridine is described as an N-based nucleophile, capable of undergoing reactions such as alkylation with alkyl halides or acylation with acyl chlorides, leading to the formation of reactive intermediates.

💡Electrophilic aromatic substitution

Electrophilic aromatic substitution is a type of chemical reaction where an electrophile reacts with an aromatic ring, resulting in the substitution of a hydrogen atom on the ring. The script notes that pyridine does not readily undergo this type of reaction due to the electron-withdrawing effect of nitrogen, which would lead to an unfavorable positive charge on the nitrogen if such a substitution were to occur.

💡Nucleophilic aromatic substitution

Nucleophilic aromatic substitution is a reaction where a nucleophile replaces a substituent on an aromatic ring. The script explains that this type of reaction is feasible for pyridine because nitrogen can stabilize negative charges more effectively than carbon, allowing the reaction to proceed without additional activation.

💡Hantzsch synthesis

The Hantzsch synthesis is a method for the preparation of dihydropyridines, which can be oxidized to form pyridine derivatives. The script mentions this synthesis as the most widely used method for pyridine synthesis, involving two beta-keto esters, formaldehyde, and ammonium acetate to yield a dihydropyridine under aqueous conditions.

💡Isomeric structures

Isomeric structures refer to compounds with the same molecular formula but different arrangements of atoms. The script discusses pyridazine, pyrimidine, and pyrazine, which are structurally isomeric to pyridine but with two nitrogen atoms in different positions within the six-membered ring. These compounds are weaker bases than pyridine and share similar reactivities.

Highlights

Pyridine is the most relevant six-membered heterocyclic aromatic compound, resembling benzene with one carbon atom replaced by nitrogen.

Pyridine is aromatic, almost as aromatic as benzene, with a resonance energy of 28 kcal/mole, slightly lower than benzene's 36 kcal/mole, due to nitrogen withdrawing electron density and reducing symmetry.

In pyridine, all ring atoms are sp2 hybridized with unhybridized p orbitals contributing to the pi-electron cloud, except for nitrogen's lone pair which remains localized in an sp2 orbital and does not delocalize.

Pyridine is more basic than pyrrole due to the availability of its lone pair to act as a proton acceptor, though not as basic as regular amines due to sp2 orbitals having more s character.

Pyridine can undergo nucleophilic reactions similar to other amines, such as alkylation with alkyl halides or acylation with acyl chlorides, forming reactive N-acetyl pyridinium salts.

Oxidation of pyridine with peroxyacids is possible, yielding stable pyridine oxides.

Pyridine does not readily undergo electrophilic aromatic substitution due to the nitrogen atom coordinating with Lewis acids and hindering electrophilic attack.

Nucleophilic aromatic substitution is feasible for pyridine, as nitrogen can stabilize negative charges more effectively than carbon.

The Hantzsch synthesis, developed in 1881, is a widely used method for synthesizing pyridine, involving two beta-keto esters, formaldehyde, and ammonium acetate under aqueous conditions.

The Hantzsch synthesis yields dihydropyridines, which can be readily oxidized to form aromatic pyridine systems.

Non-symmetrical pyridines can be produced using a variety of esters in the Hantzsch synthesis.

Replacing nitrogen with oxygen or sulfur in six-membered rings does not result in stable neutral species, unlike five-membered heterocycles.

Pyridine derivatives with two nitrogen atoms, such as pyridazine, pyrimidine, and pyrazine, are weaker bases than pyridine but share similar reactivities.

Heterocycles like pyridine and its derivatives are prevalent in natural products, including the nitrogenous bases in DNA, such as adenine.

Pyridoxine, also known as vitamin B6, is an example of a pyridine derivative with important biological functions.

Nicotine, the addictive component of tobacco, is another example of a pyridine derivative.

Quinine, an anti-malarial drug, is a pyridine derivative that has been a focus in the study of the history of drugs.

The transcript provides a preliminary understanding of some important heterocycles and their significance in chemistry and biology.

Transcripts

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Takeaways

Q & A

What is the primary difference between pyridine and benzene in terms of molecular structure?

How does the presence of nitrogen in pyridine affect the aromaticity compared to benzene?

Why does the lone pair on the nitrogen atom in pyridine not participate in the aromatic delocalization?

How does the basicity of pyridine compare to pyrrole and regular amines?

What type of chemical reactions can pyridine undergo as an N-based nucleophile?

Why does pyridine not readily undergo electrophilic aromatic substitution?

What type of aromatic substitution is feasible for pyridine and why?

What is the Hantzsch synthesis and how is it used to produce pyridine?

Why are six-membered heterocycles with oxygen or sulfur instead of nitrogen not stable as neutral species?

What are some examples of naturally occurring compounds that contain pyridine rings?

What are the three structurally isomeric structures with two nitrogen atoms in place of one in pyridine?