CHEM 191 Module 4 Lecture 2 Summary: Reactions of Carbonyl Compounds

Reactions of Carbonyl Compounds

Learning Objectives:

• Understand the structure and reactivity of carbonyl compounds.
• Draw mechanisms for the reactions of nucleophiles (weak and strong) with carbonyl compounds.
• Understand the chemistry of vision.
• Draw mechanisms for the formation of hemiacetals, acetals, and imines.

Carbonyl Compounds

• Contain a carbonyl $(C=O)$ functional group.
• Carbon and oxygen are $sp^2$ hybridized and planar.
• The $(C=O)$ bond is polarized due to the difference in electronegativity between carbon and oxygen.
• Examples include aldehydes and ketones.
• Comparison to the $\pi$-bond in an alkene (Module 3).

Reactivity of Aldehydes and Ketones

• Aldehydes and ketones commonly undergo addition reactions.
• The carbonyl carbon is electrophilic (partially positive, $\delta^+$) and susceptible to nucleophilic attack.
• Mechanism depends on the strength of the nucleophile $(Nu)$.
  • Strong nucleophiles (e.g., amines $(R-NH_2)$) attack in the first step.
  • Weak nucleophiles (e.g., water $(H-OH)$, alcohol $(R-OH)$) require activation of the carbonyl via an electrophile in the first step.

Addition with Stronger Nucleophiles (Amines)

• An amine $(R-NH_2)$ is a stronger nucleophile than an alcohol $(R-OH)$ because the lone pair of electrons on nitrogen is more readily shared.
• The amine directly attacks the carbonyl carbon.

Mechanism

1. Nucleophilic attack (rate-determining step, slow).
2. Deprotonation.
3. $O^-$ attacks an electrophile $(H^+)$.

• This results in the addition of the nucleophile $(R-NH_2)$ and electrophile $(H^+)$ across the $(C=O)$ bond, forming a nucleophilic addition product (unstable).

Imine Formation

• The unstable addition product forms an imine via the loss of water $(H_2O)$.
• The reaction of an aldehyde/ketone with an amine to form an imine is a reversible covalent bond used in the body.

$C=O + H<em>2N-R \rightleftharpoons C=N-R + H</em>2O$

• Where R = alkyl (e.g., $CH_3$)

Chemistry of Vision

• Reversible imine formation is a key part of vision.
• Retinol is oxidized to retinal.
• The aldehyde of retinal reacts with an amine of the protein (opsin) to form an imine.

$11-cis-retinal + H_2N-OPSIN \rightleftharpoons N-OPSIN (imine)$

• Different opsins are optimized for different colors, which gives color vision.
• The small 11-cis-retinal 'fits well' and is recognized by the much larger protein.
• Formation of the trans alkene changes the shape of the bound retinal, which changes the shape of the protein, which sends a signal from the eye to the brain.
• 11-trans-retinal is isomerized by enzymes and recycled back into the 11-cis isomer.
• A photon of light induces a rotation around the C11-C12 single bond in the 11-trans-retinal imine.

Addition with Weaker Nucleophiles (Water, Alcohols)

• The nucleophile is too weak to attack $(C=O)$ directly in the first step.
• The reactivity of the carbonyl carbon is increased by first reacting with an electrophile, often $H^+$ (acid catalysis).

Mechanism

1. The $\pi$-bond reacts with an electrophile $(E^+)$, often $H^+$ (acid-catalyzed).
2. The nucleophile attacks (rate-determining step, slow).
3. Deprotonation.

• This results in the addition of the nucleophile $(R-OH)$ and electrophile $(H^+)$ across the $(C=O)$ bond.
• An alcohol acts as the weak nucleophile, and the reaction is acid-catalyzed, forming a hemiacetal.

Hemiacetal and Acetal Formation

• Hemiacetal reacts further with an alcohol to form an acetal.

$hemiacetal + alcohol \rightleftharpoons acetal + H_2O$

• Acetals have two $O$-alkyl bonds and no $O-H$ bonds.
• The '$OH$' cannot leave directly as a hydroxide ion because hydroxide is a bad leaving group.
• Hemiacetals and acetals are important in carbohydrate chemistry (e.g., glucose, galactose, starch, cellulose).

Aldehydes vs. Ketones

• Both can undergo addition reactions with strong and weak nucleophiles.
• Aldehydes are more reactive than ketones due to:
  • Sterics: Aldehydes are less sterically hindered because one substituent is $H$.
  • Electronics: Electron-donating alkyl groups reduce $\delta^+$ on $C$ of $(C=O)$.

Summary

• Aldehydes and ketones undergo addition reactions.
• The reaction mechanism depends on the strength of the nucleophile.
• Aldehyde/ketone + amine $\rightarrow$ addition then dehydration $\rightarrow$ imine.

$C=O + H<em>2N-R \rightleftharpoons C=N-R + H</em>2O$

• Aldehyde/ketone + alcohol $\rightarrow$ addition $\rightarrow$ hemiacetal $\rightarrow$ reaction with another alcohol $\rightarrow$ acetal.
• Imines are used as reversible covalent bonds in the body (e.g., vision).

$H_2N-OPSIN + retinal \rightleftharpoons N-OPSIN$

Homework

• Sample Exercise 28.4, page 1306
• Page 1330, exercise 28.45 (imines, some harder examples), 28.46
• Page 1368, exercise 29.48