Side-Chain Reactions of Substituted Pyridines: Videos & Practice Problems

In the study of substituted pyridines, understanding the side chain reactions is crucial, particularly regarding the acidity of benzylic hydrogens. The benzylic position refers to the carbon atom directly connected to an aromatic ring, such as benzene or pyridine. Benzylic hydrogens are acidic due to the stability of the resulting carbanions, which are intermediates formed when a hydrogen ion (H⁺) is removed.

When comparing ordinary benzylic carbanions, which are stabilized by resonance, to pyridine carbanions, it becomes evident that pyridine carbanions exhibit even greater acidity. This increased acidity is attributed to two factors: resonance stabilization and the inductive effect of the electronegative nitrogen atom present in pyridine. The presence of nitrogen allows for better stabilization of the negative charge formed during deprotonation.

The pKa values of these carbanions illustrate this difference. For ordinary benzylic carbanions, the pKa is approximately 41, indicating a relatively low acidity. In contrast, pyridine carbanions have a pKa ranging from 34 to 36, signifying a higher acidity due to the influence of the nitrogen atom. A lower pKa value correlates with increased acidity, meaning that pyridine carbanions are more readily formed when a strong base deprotonates the benzylic carbon.

Strong bases, such as organolithiums and sodium amide, can effectively deprotonate the benzylic position, leading to the formation of various carbanions. The unique properties of pyridine, particularly the resonance and inductive effects from the nitrogen atom, make its carbanions particularly noteworthy in organic chemistry.

When evaluating the acidity of various compounds, it is essential to consider the structural features that influence their ability to donate protons. In this case, we are arranging compounds based on their acidity from weakest to strongest. The key factors affecting acidity include resonance stabilization and inductive effects.

Starting with the compounds, we identify that compound B is the most acidic. This is due to the presence of a benzylic carbon that can stabilize the resulting carbanion through resonance. The resonance effect allows the negative charge to be delocalized, making it easier for the compound to lose a proton.

Next, we analyze compound D, which also has a benzylic position. While it can form a carbanion, the resonance stabilization is not as effective as in compound B because it lacks the electronegative nitrogen that can further stabilize the negative charge through induction.

Compound A is less acidic than D because it features a double bond, which complicates the formation of a stable carbanion. The presence of the double bond makes it more challenging to deprotonate the benzylic position effectively.

Finally, compound C is the least acidic. It does not have a benzylic position, which means it lacks the stabilizing resonance effects that enhance acidity in the other compounds.

In summary, the order of acidity from weakest to strongest is as follows: C (least acidic), A, D, and B (most acidic). Understanding these concepts of resonance and inductive effects is crucial for predicting the acidity of organic compounds.

In the study of alkylated pyridines, the acidity of certain side chain positions, particularly at the benzylic carbon, is influenced by the resonance structures that can form upon deprotonation. The positions at C2 and C4 exhibit greater acidity compared to C3 due to the ability of the electronegative nitrogen atom to stabilize the negative charge that results from deprotonation.

The pKa values for these alkylated pyridines range from approximately 34 to 36. Specifically, the pKa values for C2 and C4 are around 34, indicating they are more acidic, while C3 has a pKa closer to 36, making it less acidic. This difference in acidity can be attributed to the resonance stabilization of the negative charge on the nitrogen atom.

When the benzylic carbon is deprotonated at C2, the resulting negative charge can resonate through the structure, allowing the charge to be delocalized onto the nitrogen atom. This process involves several steps: first, the negative charge forms a double bond with the adjacent carbon, which then allows the nitrogen to acquire a negative charge as it forms two bonds and retains two lone pairs. This resonance can continue, moving the negative charge through the structure and ultimately stabilizing it on the nitrogen atom, which is more electronegative than carbon.

In contrast, when deprotonation occurs at C3, the resonance structures do not allow for the negative charge to stabilize on the nitrogen. Instead, the negative charge remains on the carbon atoms throughout the resonance cycle, which is less favorable since carbon is not as electronegative as nitrogen.

For C4, similar to C2, the deprotonation leads to a negative charge that can resonate onto the nitrogen atom, again stabilizing the charge in a more favorable position. The ability of the nitrogen atom to accommodate the negative charge makes C2 and C4 more preferred positions for deprotonation in alkylated pyridines compared to C3.

In summary, the resonance structures and the electronegativity of the nitrogen atom play crucial roles in determining the acidity of alkylated pyridines, with C2 and C4 being more acidic due to the favorable stabilization of the negative charge on the nitrogen atom.

When 4-ethylpyridine reacts with sodium amide, a series of resonance structures can be generated through the deprotonation of the benzylic position. Initially, sodium amide acts as a strong base, removing a hydrogen atom from the benzylic carbon, which retains the electrons, resulting in a negatively charged carbon.

The first resonance structure shows the formation of a double bond between the benzylic carbon and the nitrogen atom, while the nitrogen carries a negative charge due to the addition of electrons. This can be represented as:

1. Initial structure:
C₆H₄(C₂H₅)N^- (where the nitrogen has a negative charge)

Next, the electrons can shift to create a double bond between the nitrogen and the adjacent carbon, resulting in a new resonance form where the nitrogen now has two lone pairs and a negative charge:

2. Resonance structure:
C₆H₄(C₂H₅)=N^- (with nitrogen holding two lone pairs)

Continuing this process, the nitrogen can utilize one of its lone pairs to form a pi bond with the adjacent carbon, which leads to another resonance structure. This results in the nitrogen becoming positively charged while the adjacent carbon becomes negatively charged:

3. Resonance structure:
C₆H₄(C₂H₅)N⁺ (where nitrogen has a positive charge)

Finally, the electrons can shift back to the benzylic carbon, restoring the negative charge to it while forming a pi bond with the nitrogen, leading to the last resonance structure:

4. Final resonance structure:
C₆H₄(C₂H₅)=N^- (with the negative charge back on the benzylic carbon)

These resonance structures illustrate the delocalization of electrons in the reaction of 4-ethylpyridine with sodium amide, highlighting the stability and reactivity of the resulting anion.

In the study of addition reactions involving alkylated pyridines, it is essential to understand the behavior of the conjugate base of pyridine, which acts similarly to the enolate anion found in carbonyl chemistry. This relationship can be illustrated through the aldol reaction, a key process where aldehydes and ketones interact with enolate anions.

To begin, consider the carbonyl group, where the carbon adjacent to it is referred to as the alpha carbon. When a base is introduced, it can deprotonate the alpha carbon, resulting in a negatively charged species that holds onto the electrons. This negatively charged alpha carbon can then perform a nucleophilic attack on another aldehyde or ketone, leading to the formation of a beta-hydroxy carbonyl compound. The reaction can be summarized as follows:

1. Deprotonation of the alpha carbon:
\[ \text{R}_2\text{C}(\text{OH})\text{C}(\text{O})\text{R} \rightarrow \text{R}_2\text{C}^-(\text{C}(\text{O})\text{R}) \]

2. Nucleophilic attack on another carbonyl:
\[ \text{R}_2\text{C}^-(\text{C}(\text{O})\text{R}) + \text{R}'\text{C}(\text{O}) \rightarrow \text{R}_2\text{C}(\text{OH})\text{C}(\text{R}')\text{C}(\text{O})\text{R} \]

3. Protonation of the negative oxygen by water, yielding a beta-hydroxy carbonyl compound.

These reactions often progress to form an alpha-beta unsaturated product through dehydration, where a pi bond is established, and water is lost:

4. Formation of the alpha-beta unsaturated compound:
\[ \text{R}_2\text{C}(\text{C}(\text{R}')\text{C}(\text{O})\text{R}) \rightarrow \text{R}_2\text{C}=\text{C}(\text{R}') + \text{H}_2\text{O} \]

In the context of benzylic carbon compounds, these alpha-beta unsaturated products are readily formed due to their stability. This behavior is mirrored in pyridine chemistry, where the deprotonation of the benzylic carbon allows for similar reactions with aldehydes or ketones. The resulting structures are not only analogous to those formed in carbonyl chemistry but also exhibit enhanced stability due to increased conjugation.

In summary, the interplay between the conjugate base of pyridine and carbonyl compounds highlights the versatility of these reactions, showcasing how foundational concepts in organic chemistry can be applied to more complex molecular systems.

In this synthesis, starting with 2-methylpyridine, the process involves several key steps to predict the final product. Initially, a strong base, butyllithium, is used to deprotonate a benzylic carbon, resulting in a negatively charged carbon. This negatively charged carbon then reacts with an aldehyde, leading to the formation of a new bond while displacing a bond to oxygen, which is subsequently protonated by water.

Typically, this intermediate would undergo condensation to form an α,β-unsaturated carbonyl compound. However, the reaction is quickly followed by the addition of pyridinium chlorochromate (PCC) in methylene chloride. PCC acts as a mild oxidizing agent, converting the alcohol formed in the previous step into a carbonyl group instead of retaining the alcohol functionality.

Finally, the synthesis concludes with a Wolff-Kishner reduction, a method used to completely remove the carbonyl group, resulting in the formation of a fully saturated carbon chain. The end product of this sequence is an ortho-alkylated pyridine ring, showcasing the transformation of the starting material through strategic reactions and the application of specific reagents.