© 2006 Thomson Higher Education Chapter 14 Aldehydes and Ketones: Nucleophilic Additions Reactions

Aldehydes and Ketones Aldehydes (RCHO) and Ketones (R 2 CO) are among the most widely occurring of all compounds Required by living organisms Pyridoxal phosphate (PLP) is common coenzyme Hydrocortisone is steroid hormone secreted by adrenal glands Solvents and starting materials in chemical industry 1.9 million tons of formaldehyde, H 2 C=O, produced each year for insulation materials and resins 1.5 million tons of acetone, ((CH 3 ) 2 C=O), produced each year for use as industrial solvent

14.1 Naming Aldehydes and Ketones Aldehydes named by replacing terminal –e of corresponding alkane name with –al Parent chain must contain the –CHO group see Appendix A Table A.2 for naming polyfunctional organic compounds containing an aldehyde – CHO carbon is numbered as C1

Naming Aldehydes and Ketones Carbaldehyde suffix is used for cyclic aldehydes

Naming Aldehydes and Ketones

Ketones named by replacing terminal –e of corresponding alkane name with –one Parent chain is longest chain containing ketone group Numbering begins at end of chain nearer the carbonyl carbon

Naming Aldehydes and Ketones Some common names accepted by IUPAC

Naming Aldehydes and Ketones If R-C=O is a substituent the name acyl (a-sil) group is used and name ending –yl is attached The prefix oxo- is used if ketone is not highest priority functional group and the carbonyl is considered a substituent on the parent chain See Appendix A Table A.2 for naming polyfunctional organic compounds containing a ketone

14.2 Preparation of Aldehydes and Ketones Aldehydes from oxidation of primary alcohols using pyridinium chlorochromate (PCC) Aldehydes from reduction of carboxylic esters using diisobutylaluminum hydride (DIBAH)

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

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

14.3 Oxidation of Aldehydes Aldehydes easily oxidized to carboxylic acids but ketones are relatively inert toward oxidation –CHO hydrogen abstracted during oxidation CrO 3 most common oxidizing agent KMnO 4 and hot HNO 3 occasionally used

Oxidation of Aldehydes Oxidation of aldehydes proceeds through intermediate 1,1-diols called hydrates Hydrates formed by reversible nucleophilic addition of water to carbonyl group (section 14.5)

14.4 Nucleophilic Addition Reactions of Aldehydes and Ketones Nucleophilic addition reaction :Nu – approaches C=O bond at 75° angle and adds to electrophilic C=O carbon Carbonyl carbon rehybridizes to sp 3 Electron pair moves from C=O bond to electronegative oxygen atom producing tetrahedral alkoxide ion intermediate Intermediate is protonated to give neutral alcohol product

Nucleophilic Addition Reactions of Aldehydes and Ketones Alternatively, the tetrahedral alkoxide ion intermediate (or neutral protonated tetrahedral intermediate) can eliminate H 2 O to give C=Nu bond

Nucleophilic Addition Reactions of Aldehydes and Ketones Aldehydes more reactive toward nucleophilic addition than ketones Aldehydes less sterically hindered than ketones

Nucleophilic Addition Reactions of Aldehydes and Ketones Aldehydes are more reactive than ketones due to electronic factors C=O of aldehyde more polarized than C=O of ketone

14.5 Nucleophilic Addition of H 2 O: Hydration Aldehydes and ketones react reversibly with water to give 1,1-diols, or geminal (gem) diols Equilibrium favors carbonyl compound for steric reasons with the exception of formaldehyde

Nucleophilic Addition of H 2 O: Hydration Nucleophilic addition of water to aldehyde or ketone is slow under neutral conditions but catalyzed by both acid and base Base-catalyzed hydration mechanism Hydroxide ion is good nucleophile

Nucleophilic Addition of H 2 O: Hydration Acid-catalyzed mechanism Protonated oxygen renders C=O carbon more electrophilic

Nucleophilic Addition of H 2 O: Hydration In general, equilibrium favors the carbonyl-containing aldehyde or ketone reactant for nucleophiles such as H 2 O, CH 3 OH, HCl, HBr, or H 2 SO 4

14.5 Nucleophilic Addition of Grignard and Hydride Reagents: Alcohol Formation Grignard reagent reacts with aldehyde or ketone C=O to give tetrahedral magnesium alkoxide intermediate Intermediate is hydrolyzed to produce neutral alcohol Grignard reagent reacts like a carbon anion, or carbanion Reaction mechanism involves radicals but can be represented as proceeding through a nucleophilic addition of a carbanion to the C=O carbon

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

14.7 Nucleophilic Addition of Amines: Imine and Enamine Formation Primary amines, RNH 2, add to aldehydes and ketones to yield imines, R 2 C=NR Imines are common biological intermediates

Nucleophilic Addition of Amines: Imine and Enamine Formation Secondary amines, R 2 NH, add to aldehydes and ketones to yield enamines, R 2 N-CR=CR 2 ene + amine = unsaturated amine

Nucleophilic Addition of Amines: Imine and Enamine Formation Mechanism of imine formation Nucleophilic addition of primary amine to give carbinolamine tetrahedral intermediate Elimination of water to form new C=Nu bond

Nucleophilic Addition of Amines: Imine and Enamine Formation Mechanism of enamine formation: Nucleophilic addition of secondary amine to give carbinolamine tetrahedral intermediate Elimination of water yields iminium ion Loss of proton from  -carbon atom yields enamine

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

Worked Example 14.1 Predicting the Product of Reaction between a Ketone and an Amine Show the products you would obtain by acid-catalyzed reaction of pentan-3-one with methylamine, CH 3 NH 2, and with dimethylamine, (CH 3 ) 2 NH

Worked Example 14.1 Predicting the Product of Reaction between a Ketone and an Amine Strategy An aldehyde or ketone reacts with a primary amine, RNH 2, to yield an imine, in which the carbonyl oxygen atom has been replaced by the =N-R group of the amine Reaction of the same aldehyde or ketone with a secondary amine, R 2 NH, yields an enamine, in which the oxygen atom has been replaced by the –NR 2 group of the amine and the double bond has moved to a position between the former carbonyl carbon and the neighboring carbon

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

14.8 Nucleophilic Addition of Alcohols: Acetal Formation Aldehydes and ketones react reversibly with two equivalents of an alcohol in the presence of an acid catalyst to yield acetals, R 2 C(OR′) 2, sometimes called ketals if derived from a ketone

Nucleophilic Addition of Alcohols: Acetal Formation Mechanism of acetal formation: Acetal formation is acid-catalyzed Reversible nucleophilic addition of alcohol to the carbonyl group yields a hemiacetal Hemiacetal is a hydroxy ether analogous to gem diol formed by water addition Acid catalyst protonates hydroxyl group forming better leaving group, – OH 2 + Loss of – OH 2 + leads to an oxonium ion, R 2 C=OR + Nucleophilic addition of second alcohol gives protonated acetal Deprotonation of protonated acetal yields neutral acetal

Nucleophilic Addition of Alcohols: Acetal Formation One equivalent of diol such as ethylene glycol yields a cyclic acetal Intramolecular nucleophilic additions are common in carbohydrates (sugars) and give cyclic hemiacetals

Worked Example 14.2 Predicting the Product of Reaction between a Ketone and an Alcohol Show the structure of the acetal you would obtain by acid-catalyzed reaction of pentan-2-one with propane-1,3-diol

Worked Example 14.2 Predicting the Product of Reaction between a Ketone and an Alcohol Strategy Acid-catalyzed reaction of an aldehyde or ketone with 2 equivalents of a monoalcohol or 1 equivalent of a diol yields an acetal, in which the carbonyl oxygen atom is replaced by two –OR groups from the alcohol

Worked Example 14.2 Predicting the Product of Reaction between a Ketone and an Alcohol Solution

14.9 Nucleophilic Addition of Phosphorus Ylides: The Wittig Reaction 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 reaction yields a single, pure alkene of defined structure

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

Worked Example 14.3 Synthesizing an Alkene Using a 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 Strategy An aldehyde or ketone reacts with a phosphorus ylide to yield an alkene in which the oxygen atom of the carbonyl reactant is replaced by the =CR 2 of the ylide Preparation of the phosphorus ylide itself usually involves S N 2 reaction of a primary alkyl halide with triphenylphosphine, so the ylide is typically primary, RCH=P(Ph) 3 Disubstituted alkene carbon in product comes from carbonyl reactant, while the monosubstituted alkene carbon comes from the ylide

Worked Example 14.3 Synthesizing an Alkene Using a Wittig Reaction Solution

14.10 Biological Reductions Nucleophilic addition reactions are characteristic of aldehydes and ketones Tetrahedral intermediate produced by addition of nucleophile cannot expel a stable leaving group

Biological Reductions Cannizzaro reaction Exception to characteristic aldehyde and ketone reactions OH ¯ adds to aldehyde to give tetrahedral intermediate H: ¯ ion is expelled as leaving group

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

14.11 Conjugate Nucleophilic Addition to  - Unsaturated Aldehydes and Ketones Nucleophiles can add directly to carbonyl group of aldehydes and ketones, called 1,2-addition Nucleophiles can also add to conjugated C=C bond adjacent to carbonyl group of aldehydes and ketones, called conjugate addition or 1,4- addition Carbon atom adjacent to carbonyl carbon is the  carbon atom and the next one is the  carbon atom Initial product of conjugate addition is a resonance- stabilized enolate ion

Conjugate Nucleophilic Addition to  - Unsaturated Aldehydes and Ketones

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  - 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  - 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  - Unsaturated Aldehydes and Ketones Related biological addition of water to an ,  -unsaturated carboxylic acid in citric acid cycle Cis-aconitate is converted to isocitrate

14.12Spectroscopy of Aldehydes and Ketones - FTIR C=O bond absorption in IR region from 1660 to 1770 cm -1 is diagnostic of the nature of the carbonyl group Aldehydes show two characteristic C-H absorptions in the range 2720 to 2820 cm -1

Spectroscopy of Aldehydes and Ketones - FTIR

Spectroscopy of Aldehydes and Ketones - NMR 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 - NMR 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 – Mass Spectrometry Aldehydes and ketones with (  carbon atoms undergo McLafferty rearrangement Aldehydes and ketones also fragment by  cleavage

Spectroscopy of Aldehydes and Ketones – Mass Spectrometry