Aldehydes from oxidation of primary alcohols using the Dess- Martin periodinane reagent 14.2 Preparing Aldehydes and Ketones

Aldehydes from reduction of carboxylic esters using diisobutylaluminum hydride (DIBAH) Preparing Aldehydes and Ketones

Secondary alcohols are oxidized by variety of chromium-based reagents to give ketones Aryl ketones from Friedel-Crafts acylation reactions Preparing Aldehydes and Ketones

Mechanism of Grignard Reaction Nucleophilic Addition of Grignard and Hydride Reagents: Alcohol Formation

In an analogous manner the reaction of aldehydes and ketones with hydride reagents may be represented as proceeding through a nucleophilic addition of a hydride ion (:H – ) to the C=O carbon LiAlH 4 and NaBH 4 act as if they are donors of hydride ion Nucleophilic Addition of Grignard and Hydride Reagents: Alcohol Formation

Primary amines, RNH 2, add to aldehydes and ketones to yield imines, R 2 C=NR Secondary amines, R 2 NH, add similarly to yield enamines, R 2 N-CR=CR Nucleophilic Addition of Amines: Imine and Enamine Formation

Imines are common biological intermediates where they are often called Schiff bases Nucleophilic Addition of Amines: Imine and Enamine Formation

Imine and enamine formations reach maximum rate around pH = 4 to 5 Slow at pH > 5 because there is insufficient H + present in solution to protonate intermediate carbinolamine –OH to yield the better leaving group –OH 2 + Slow at pH < 4 because the basic amine nucleophile is protonated and initial nucleophilic addition cannot occur Nucleophilic Addition of Amines: Imine and Enamine Formation

Worked Example 14.1 Predicting the Product of Reaction between a Ketone and an Amine

Acetal and hemiacetal groups are common in carbohydrate chemistry Glucose, a polyhydroxy aldehyde, undergoes intramolecular nucleophilic addition Exists primarily as a cyclic hemiacetal Nucleophilic Addition of Alcohols: Acetal Formation

Wittig reaction Converts aldehydes and ketones into alkenes Phosphorus ylide, R 2 C–P(C 6 H 5 ) 3, adds to aldehyde or ketone to yield dipolar, alkoxide ion intermediate Ylide (pronounced ill-id) is a neutral, dipolar compound with adjacent positive and negative charges Also called a phosphorane and written in the resonance form R 2 C=P(C 6 H 5 ) 3 Dipolar intermediate spontaneously decomposes through a four-membered ring to yield alkene and triphenylphosphine oxide, (Ph) 3 P=O Wittig reaction results in replacement of carbonyl oxygen with R 2 C= group of original phosphorane Nucleophilic Addition of Phosphorus Ylides: The Wittig Reaction

Wittig reaction mechanism Nucleophilic Addition of Phosphorus Ylides: The Wittig Reaction

Phosphorus ylides are prepared by S N 2 reaction of primary and some secondary alkyl halides with triphenylphosphine, (Ph) 3 P, followed by treatment with base Nucleophilic Addition of Phosphorus Ylides: The Wittig Reaction

Wittig reactions used commercially to synthesize numerous pharmaceuticals Nucleophilic Addition of Phosphorus Ylides: The Wittig Reaction

What carbonyl compound and what phosphorus ylide might you use to prepare 3-ethylpent-2-ene? Worked Example 14.3 Synthesizing an Alkene Using a Wittig Reaction

Solution Worked Example 14.3 Synthesizing an Alkene Using a Wittig Reaction

Cannizzaro reaction is a nucleophilic acyl substitution reaction of aldehydes and ketones OH ¯ adds to aldehyde to give tetrahedral intermediate H: ¯ ion is transferred to a second aldehyde The aldehyde accepting the H: ¯ ion is reduced and the aldehyde transferring the H: ¯ is oxidized Biological Reductions

Cannizzaro reaction mechanism is analogous to biological reduction in living organisms by nicotinamide adenine dinucleotide, NADH NADH donates H: ¯ to aldehydes and ketones, similar to tetrahedral alkoxide intermediate in Cannizzaro reaction Biological Reductions

Conjugate addition occurs because the nucleophile can add to either one of two electrophilic carbons of the ,  -unsaturated aldehyde or ketone Conjugate Nucleophilic Addition to α,β- Unsaturated Aldehydes and Ketones

Conjugated double bond of ,  -unsaturated carbonyl is activated by carbonyl group of the aldehyde or ketone C=C double bond is not activated for addition in absence of carbonyl group Conjugate Nucleophilic Addition to α,β- Unsaturated Aldehydes and Ketones

Primary and secondary amines add to ,  -unsaturated aldehydes and ketones to yield  -amino aldehydes and ketones Both 1,2- and 1,4-addition occur Additions are reversible More stable conjugate addition product accumulates Conjugate Nucleophilic Addition to α,β- Unsaturated Aldehydes and Ketones

Conjugate addition of an alkyl or other organic group to an  - unsaturated ketone (but not aldehyde) is a useful 1,4- addition reaction Conjugate Nucleophilic Addition to α,β- Unsaturated Aldehydes and Ketones

Conjugate addition of alkyl groups to an  -unsaturated ketone (not aldehyde) is accomplished with a lithium diorganocopper reagent, R 2 CuLi (Gilman reagent) Lithium diorganocopper reagent is prepared by reaction of 1 equivalent of copper(I) iodide and 2 equivalents of an organolithium reagent, RLi Organolithium reagent is prepared by reaction of lithium metal with an organohalide Conjugate Nucleophilic Addition to α,β- Unsaturated Aldehydes and Ketones

Primary, secondary, and even tertiary alkyl groups undergo conjugate addition Alkynyl groups react poorly Grignard reagents and organolithium reagents normally give direct carbonyl addition to  -unsaturated ketones Conjugate Nucleophilic Addition to α,β- Unsaturated Aldehydes and Ketones

How might you use a conjugate addition reaction to prepare 2-methyl-3-propylcyclopentanone? Worked Example 14.4 Using a Conjugate Addition Reaction

Solution Worked Example 14.4 Using a Conjugate Addition Reaction

Spectroscopy of Aldehydes and Ketones

Aldehyde protons (RCHO) absorb near 10  in the 1 H NMR Aldehyde proton shows spin-spin coupling with protons on the neighboring carbon, with coupling constant J ≈ 3 Hz Hydrogens on carbon next to a carbonyl group are slightly deshielded and absorb near to 2.0 to 2.3  Spectroscopy of Aldehydes and Ketones

Carbonyl-group carbon atoms of aldehydes and ketones have characteristic 13 C NMR resonances in the range of 190 to 215  Spectroscopy of Aldehydes and Ketones