Aldehydes & Ketones: Nucleophilic Addition to the Carbonyl Group Chapter 16 Aldehydes & Ketones: Nucleophilic Addition to the Carbonyl Group

Introduction Carbonyl compounds

Nomenclature of Aldehydes & Ketones Rules: Aldehyde as parent (suffix) Ending with “al”; Ketone as parent (suffix) Ending with “one”. Number the longest carbon chain containing the carbonyl carbon and starting at the carbonyl carbon.

Examples:

group as a prefix: methanoyl or formyl group group as a prefix: ethanoyl or acetyl group (Ac) groups as a prefix: alkanoyl or acyl groups

Physical Properties Comparison:

Synthesis of Aldehydes 4A. Aldehydes by Oxidation of 1o Alcohols:

e.g.

4B. Aldehydes by Ozonolysis of Alkenes:

e.g.

4C. Aldehydes by Reduction of Acyl Chlorides, Esters, and Nitriles: Not a good method for aldehydes. LiAlH4 is to reactive.

LiAlH4 is a very powerful reducing agent, and aldehydes are easily reduced. Usually reduced all the way to the corresponding 1o alcohol. Difficult to stop at the aldehyde stage. Using LiAlH4 is not a good method to synthesize aldehydes.

These are effective where LiAlH4 is not. Two derivatives of aluminum hydride that are less reactive than LiAlH4. These are effective where LiAlH4 is not. For acid chlorides For esters and nitriles

Aldehydes from acyl chlorides: RCOCl  RCHO: e.g.

Reduction of an Acyl Chloride to an Aldehyde

Aldehydes from esters and nitriles: RCO2R’  RCHO RC≡N  RCHO Both esters and nitriles can be reduced to aldehydes by DIBAL-H.

Reduction of an ester to an aldehyde:

Reduction of a nitrile to an aldehyde:

Examples:

Synthesis of Ketones 5A. Ketones from Alkenes, Arenes, and 2o Alcohols: Ketones (and aldehydes) by ozonolysis of alkenes.

Examples:

Ketones from arenes by Friedel–Crafts acylations.

Ketones from secondary alcohols by oxidation.

5B. Ketones from Nitriles:

Examples:

Suggest synthesis of: from and

Retrosynthetic analysis: 5 carbons here 4 carbons here  need to add one carbon

Retrosynthetic analysis: disconnection disconnection

Synthesis:

Suggest synthesis of: from and

Retrosynthetic analysis: 5 carbons here 5 carbons here  no need to add carbon

Retrosynthetic analysis: disconnection

Synthesis

Nucleophilic Addition to the Carbon–Oxygen Double Bond Structure: Nu⊖ Carbonyl carbon: sp2 hybridized Trigonal planar structure

Polarization and resonance structure: Nucleophiles will attack the nucleophilic carbonyl carbon. Note: nucleophiles usually do not attack non-polarized C=C bond.

With a strong nucleophile:

Also would expect nucleophilic addition reactions of carbonyl compounds to be catalyzed by acid (or Lewis acid). Note: full positive charge on the carbonyl carbon in one of the resonance forms. Nucleophiles readily attack.

Mechanism:

Mechanism:

6A. Reversibility of Nucleophilic Additions to the Carbon–Oxygen Double Bond Many nucleophilic additions to carbon–oxygen double bonds are reversible; the overall results of these reactions depend, therefore, on the position of an equilibrium.

6B. Relative Reactivity: Aldehydes vs. Ketones

Steric factors: small large

Electronic factors: (positive inductive effect from both R & R' groups)  carbonyl carbon less d+ (less nucleophilic) (positive inductive effect from only one R group)

The Addition of Alcohols: Hemiacetals and Acetals Acetal & Ketal Formation: Addition of Alcohols to Aldehydes: Catalyzed by acid

Mechanism:

Mechanism (Cont’d):

Mechanism (Cont’d):

Note:. All steps are reversible Note: All steps are reversible. In the presence of a large excess of anhydrous alcohol and catalytic amount of acid, the equilibrium strongly favors the formation of acetal (from aldehyde) or ketal (from ketone). On the other hand, in the presence of a large excess of H2O and a catalytic amount of acid, acetal or ketal will hydrolyze back to aldehyde or ketone. This process is called hydrolysis.

Acetals and ketals are stable in neutral or basic solution, but are readily hydrolyzed in aqueous acid.

Aldehyde hydrates: gem-diols

Mechanism:

7A. Hemiacetals: Hemiacetal: OH & OR groups bonded to the same carbon

Example: Hemiacetal: OH & OR groups bonded to the same carbon

7B. Acetals: A ketal An acetal

Cyclic acetal formation is favored when a ketone or an aldehyde is treated with an excess of a 1,2-diol and a trace of acid. Protective group for aldehydes and ketones.

This reaction, too, can be reversed by treating the acetal with aqueous acid. Cyclic acetals and thioacetals are good protecting groups for aldehydes and ketones.

7C. Acetals Are Used as Protecting Groups Although acetals are hydrolyzed to aldehydes and ketones in aqueous acid, acetals are stable in basic solutions. Acetals are used to protect aldehydes and ketones from undesired reactions in basic solutions.

Example:

Synthetic plan: This route will not work

Reason: (a) Intramolecular nucleophilic addition. (b) Homodimerization or polymerization.

Thus, need to “protect” carbonyl group first:

7D. Thioacetals Aldehydes & ketones react with thiols to form thioacetals.

Thioacetal formation with subsequent “desulfurization” with hydrogen and Raney nickel gives us an additional method for converting carbonyl groups of aldehydes and ketones to –CH2– groups.

The Addition of Primary and Secondary Amines Aldehydes & ketones react with 1o amines to form imines and with 2o amines to form enamines. From a 1o amine From a 2o amine

8A. Imines Addition of 1o amines to aldehydes & ketones.

Mechanism:

Similar to the formation of acetals and ketals, all the steps in the formation of imine are reversible. Using a large excess of the amine will drive the equilibrium to the imine side. Hydrolysis of imines is also possible by adding excess water in the presence of catalytic amount of acid.

8B. Oximes and Hydrazones Imine formation – reaction with a 1o amine. Oxime formation – reaction with hydroxylamine.

Hydrazone formation – reaction with hydrazine. Enamine formation – reaction with a 2o amine.

8C. Enamines

Mechanism:

Mechanism (Cont’d):

Mechanism (Cont’d):

The Addition of Hydrogen Cyanide: Cyanohydrins Addition of HCN to aldehydes & ketones

Mechanism:

Slow reaction using HCN since HCN is a weak acid and a poor source of nucleophile. Can accelerate reaction by using NaCN or KCN and slow addition of H2SO4.

Synthetic applications of cyanaohydrin:

The Addition of Ylides: The Wittig Reaction

Phosphorus ylides: Ylide preparation:

Example:

Mechanism of the Wittig reaction

10A. How to Plan a Witting Synthesis Synthesis of using a Wittig reaction.

Retrosynthetic analysis:

Synthesis – Route 1:

Synthesis – Route 2:

Oxidation of Aldehydes

Chemical Analyses for Aldehydes and Ketones 12A. Derivatives of Aldehydes & Ketones:

12B. Tollens’ Test (Silver Mirror Test)

12C. Fehlings’ Test (Red precipitate) Ch. 16 - 91 91

Spectroscopic Properties of Aldehydes and Ketones 13A. IR Spectra of Aldehydes and Ketones

Conjugation of the carbonyl group with a double bond or a benzene ring shifts the C=O absorption to lower frequencies by about 40 cm-1.

Infra-red:

13B. NMR Spectra of Aldehydes and Ketones 13C NMR spectra: The carbonyl carbon of an aldehyde or ketone gives characteristic NMR signals in the d 180–220 ppm region of 13C spectra.

1H NMR spectra: An aldehyde proton gives a distinct 1H NMR signal downfield in the d 9–12 ppm region where almost no other protons absorb; therefore, it is easily identified. Protons on the a carbon are deshielded by the carbonyl group, and their signals generally appear in the d 2.0–2.3 ppm region. Methyl ketones show a characteristic (3H) singlet near d 2.1 ppm.

Proton (H1) NMR:

Broadband C13 NMR:

Summary of Aldehyde and Ketone Addition Reactions

 END OF CHAPTER 16 