Aldehydes and Ketones - Part 2 | Organic Chemistry 2

Additional reactions of aldehydes and ketones are studied in this chapter: addition of amines, synthesis of hydrazones, Wolff-Kishner reduction, deoxygenation of carbonyls, addition of cyanide, addition of hydrides and carbanions, Wittig reaction, Baeyer-Villiger oxidation, α,β-unsaturated aldehydes and ketones and their reactivities

Addition of Amines

Addition of 1o amines - Formation of imines:
 

Mechanism:

  1. Protonation of the carbonyl group, making it even more nucleophilic.
  2. Nucleophilic attack of the amine to form a tetrahedral intermediate.
  3. Deprotonation of the tetrahedral intermediate to form a carbinolamine.
  4. Protonation of the OH group to form a good leaving group.
  5. Loss of water to form a resonance-stabilized iminium ion.
  6. Deprotonation of the iminium ion to form the imine.

 

 

Mildly acidic conditions with a pH around 4.5 are required for protonation of the hydroxy group. Strongly acidic conditions, however, will reduce the reaction rate by protonating the amine nucleophile.

 

Addition of 2o amines - Formation of enamines:
 

Mechanism:

  1. Protonation of the carbonyl group, making it even more nucleophilic.
  2. Nucleophilic attack of the amine to form a tetrahedral intermediate.
  3. Deprotonation of the tetrahedral intermediate to form a carbinolamine.
  4. Protonation of the OH group to form a good leaving group.
  5. Loss of water to form a resonance-stabilized iminium ion.
  6. Removal of a proton from the adjacent C-H bonds to form an enamine.

 

 

The difference between the formation of imines and enamines is that, with a secondary amine, the iminium ion intermediate does not have a proton on the nitrogen ⇒ a proton must be removed from an adjacent C-H bond, forming a C=C.

Wolff-Kishner Reduction

Synthesis of hydrazones:
 

Mechanism:

Same as imine formation with hydrazine (NH2NH2) as nucleophile.

 

Wolff-Kishner reduction:
 

Mechanism:

  1. Deprotonation of the hydrazone to form a resonance-stabilized intermediate.
  2. Protonation of the intermediate.
  3. Deprotonation of the second hydrogen on the nitrogen to form a good leaving group.
  4. Loss of nitrogen gas N2, generating a carbanion.
  5. Protonation of the carbanion to form an alkane.
     

 

Reduction of a ketone to an alkane:
 

Mechanism:

  1. Synthesis of a hydrazone:


     
  2. Wolff-Kishner reduction:

Addition of Cyanide Ion

Cyanohydrin formation:
 

Mechanism:

Faster reaction under mildly basic conditions (e.g., mixture of HCN and cyanide ions).

  1. Nucleophilic attack of the cyanide ion to form a tetrahedral intermediate.
  2. Protonation of the tetrahedral intermediate to form a cyanohydrin.
     


This reaction extends the carbon chain and introduces a functional group that can be easily transformed into other functional groups, such as carboxylic acids, amides, and amino acids.

Addition of Hydrides and Carbanions

Addition of hydrides:
 


Mechanism:

  1. Nucleophilic attack of H- to form a tetrahedral intermediate.
  2. Protonation of the alkoxide to form an alcohol.

NaBH4 and LiAlH4 serve as sources of hydride H-.

 

Addition of alkyl groups:
 

Mechanism:

  1. Nucleophilic attack of carbanion R- to form a tetrahedral intermediate.
  2. Protonation of the alkoxide to form an alcohol.

Organolithium (RLi) or Grignard reagent (RMgX) serve as sources of R-.

Wittig Reaction

Phosphorus ylide (Wittig reagent):

A phosphorane belonging to a larger class of compounds called ylides. A ylide is a compound with two oppositely charged atoms adjacent to each other. The Wittig reagent has a negative charge on the carbon atom (making it a good nucleophile) and a positive charge on the phosphorus atom.

 

Preparation:

  1. SN2 reaction of triphenylphosphine with an alkyl halide to form a phosphonium salt.
  2. Deprotonation of the phosphonium salt with a very strong base (e.g., BuLi) to form the ylide. 
     

 

Wittig reaction:
 

Mechanism:

  1. Nucleophilic attack of the Wittig reagent to form a tetrahedral intermediate called betaine.
  2. The alkoxide attacks the phosphorus atom in an intramolecular attack to form an oxaphosphetane.
  3. Rearrangement of the oxaphosphetane to produce an alkene and triphenylphosphine oxide.
     

 

Baeyer-Villiger Oxidation

Baeyer-Villiger oxidation:
 

Mechanism:

Oxidation with a peroxy acid to convert ketones to esters via insertion of an oxygen.

  1. Nucleophilic attack of the peroxy acid to form a tetrahedral intermediate.
  2. Intramolecular proton transfer.
  3. Reformation of the carbonyl by migration of an alkyl group to form an ester.
     

 

Regioselectivity:

When an asymmetric ketone is treated with a peroxy acid, the formation of the ester is regioselective due to the difference in migration rates, or migratory aptitude, between the alkyl groups.

The migration rates in the Baeyer-Villiger reaction are: Methyl < Primary alkyl < Phenyl, Secondary alkyl < Tertiary alkyl < H.
 

The tert-butyl group migrates more rapidly than the methyl group during the rearrangement step:

α,β-Unsaturated Aldehydes and Ketones

α,β-unsaturated carbonyl compounds:

Conjugated molecules containing a carbonyl group and a C=C bond, separated by a single σ bond. α,β-unsaturated aldehydes and ketones are stabilized by resonance.

 

Reactivity:

α,β-unsaturated carbonyls can react with nucleophiles at 2 different sites:

  • On the carbonyl carbon resulting in the formation of an allylic alcohol ⇒ 1,2-addition.
  • On the β carbon resulting in the formation of a carbonyl compound ⇒ 1,4-addition.

 

1,2-addition to an α,β-unsaturated carbonyls:

Mechanism:

  1. Nucleophlic attack on the carbonyl atom to form a tetrahedral intermediate.
  2. Protonation of the alkoxide to form an allylic alcohol.

 

1,4-addition to an α,β-unsaturated carbonyls:
 

Mechanism:

  1. Nucleophlic attack on the β carbon to form a resonance-stabilized enolate anion.
  2. Protonation and tautomerization to form a carbonyl compound.

 

Nu = Nucleophile; E = Electrophile

 

Reaction with organometallic reagents:
 


The identity of the metal in an organometallic reagent determines whether it will react with an α,β-unsaturated aldehyde or ketone by 1,2-addition or 1,4-addition:

  • 1,2-addition: organolithium (RLi) and Grignard (RMgBr) reagents.
  • 1,4-addition: organocuprate (R2CuLi) reagents.

Check your knowledge about this Chapter

Addition of amines to aldehydes and ketones typically leads to the formation of imines when a primary amine reacts with the carbonyl compound. In the presence of secondary amines, enamines are formed. These reactions proceed via nucleophilic attack of the amine's nitrogen atom on the carbonyl carbon, followed by the loss of water. Imines and enamines are useful intermediates in organic synthesis, as they can be further manipulated to create new carbon-nitrogen bonds or be reduced to amines.

The Wolff-Kishner reduction mechanism occurs in several steps to convert a carbonyl group into a methylene group. Initially, the carbonyl compound reacts with hydrazine (N2H4) to form a hydrazone, which is then treated with a strong base, commonly potassium or sodium hydroxide. This deprotonates the hydrazone, generating a nitrogen anion that undergoes a [1,2]-elimination to give a diimide intermediate. Subsequent heating causes the elimination of nitrogen gas (N2), leading to the formation of a carbanion, which quickly picks up a proton from the solvent or the surrounding medium, to form the final methylene group.

Cyanohydrin formation is an important reaction for aldehydes and ketones because it extends the carbon chain and introduces a functional group that can be easily transformed into other functional groups, such as carboxylic acids, amides, and amino acids. The reaction is favored under mildly basic conditions, where the hydrogen cyanide is converted to cyanide ion, facilitating nucleophilic attack. The produced cyanohydrin possesses both a nitrile group, which can be hydrolyzed or reduced, and an alcohol group, offering diverse options for subsequent chemical modifications.

Hydride donors such as NaBH4 and LiAlH4 are sources of hydride ions (H-), which are nucleophiles that attack the electrophilic carbonyl carbon of aldehydes and ketones. This nucleophilic addition results in cleavage of the π bond and the formation of an alkoxide intermediate. Upon subsequent protonation, usually by adding water or an acid, the alkoxide is converted to an alcohol, thus reducing the carbonyl compound to its corresponding alcohol.

Carbanions are negatively charged carbon species that serve as nucleophiles in organic reactions. Their significance lies in the fact they can readily attack electrophilic centers, such as carbonyl carbons in aldehydes and ketones, to form new carbon-carbon bonds. This attack leads to the formation of alcohols after subsequent protonation, making carbanions a key player in synthesizing more complex organic molecules.

The Wittig reaction is important for forming carbon-carbon double bonds because it allows for the synthesis of alkenes from aldehydes or ketones in a very controlled and predictable manner. The reaction involves the use of a phosphonium ylide, which is a neutral molecule with a positively charged phosphorus atom and a negatively charged carbon atom. This ylide reacts with the carbonyl carbon of an aldehyde or ketone to form a new carbon-carbon double bond while expelling triphenylphosphine oxide as a byproduct. The Wittig reaction affords alkenes with a high degree of stereochemical control, making it a valuable tool for organic synthesis.

The outcome of the Baeyer-Villiger oxidation depends on the structure of the carbonyl compound and the migratory aptitude of its substituents. In general, the more electron-donating the substituent, the more likely it is to migrate in this reaction. Therefore, tertiary substituents migrate better than secondary ones, which in turn migrate better than primary substituents. This process transforms ketones into esters and aldehydes into carboxylic acids, involving an insertion of an oxygen atom adjacent to the carbonyl group.

Stereochemistry plays a critical role in both the Wittig and Baeyer-Villiger reactions:

  • In the Wittig reaction, the geometry of the alkene product (cis or trans) is influenced by the nature of the phosphonium ylide used. Stabilized ylides tend to give predominantly E (trans) alkenes, while non-stabilized ylides favor Z (cis) alkenes.
  • On the other hand, the Baeyer-Villiger reaction involves the migration of a substituent from the carbonyl carbon to the adjacent oxygen, and the migratory aptitude that generally follows is tertiary > secondary > primary. In addition, when the substituents have different migratory aptitudes, the stereochemical outcome can be predicted as the group with the higher propensity to migrate does so, leading to the formation of a particular stereoisomer of the lactone or ester product.

α,β-Unsaturated aldehydes and ketones contain a double bond that is conjugated with the carbonyl group, creating a region of electron density between the α- and β-carbon atoms. This arrangement allows these compounds to undergo 1,4-addition (conjugate addition), in which a nucleophile adds to the β-carbon, while a proton is gained by the α-carbon. The addition takes place at the β-carbon due to the stabilization of the intermediate enolate by resonance with the carbonyl group.

The presence of α,β-unsaturation in aldehydes and ketones increases their reactivity due to the stabilization of potential intermediates by conjugation. In these compounds, the carbon-carbon double bond is conjugated with the carbonyl group, which not only stabilizes the molecule but also provides two distinct sites for nucleophilic addition: the carbonyl carbon (C=O) for 1,2-addition and the β-carbon of the double bond for 1,4-addition (also known as conjugate addition). The choice between 1,2- and 1,4-addition can often be controlled by the choice of reagents and reaction conditions, allowing for selective synthesis of different products.

The selectivity of nucleophilic additions to α,β-unsaturated carbonyl compounds, often encountered with aldehydes and ketones, is determined by the type of nucleophile and reaction conditions. Soft nucleophiles, such as organometallic reagents, preferentially add to the carbonyl carbon (1,2-addition) due to electronic factors, forming an alcohol after aqueous workup. In contrast, hard nucleophiles, such as hydrides, will often add to the β-carbon (1,4-addition or conjugate addition) influenced by steric hindrance and the stability of the resulting enolate ion intermediate. Reaction conditions like temperature, solvent, and catalysts can also sway the pathway towards 1,2- or 1,4-addition.