Chapter 19. Aldehydes and Ketones: Nucleophilic Addition Reactions

Based on McMurry’s Organic Chemistry, 6th edition

Aldehydes and Ketones

• Aldehydes and ketones are characterized by the the carbonyl functional group (C=O)

• The compounds occur widely in nature as intermediates in metabolism and biosynthesis

• They are also common as chemicals, as solvents, monomers, adhesives, agrichemicals and pharmaceuticals

19.1 Naming Aldehydes and Ketones

• Aldehydes are named by replacing the terminal -e of the corresponding alkane name with –al

• The parent chain must contain the CHO group– The CHO carbon is numbered as C1

• If the CHO group is attached to a ring, use the suffix See Table 19.1 for common names

19.2 Preparation of Aldehydes and Ketones

• Preparing Aldehydes

• Oxidize primary alcohols using pyridinium chlorochromate

• Reduce an ester with diisobutylaluminum hydride (DIBAH)

Preparing Ketones

• Oxidize a 2° alcohol (see Section 17.8)

• Many reagents possible: choose for the specific situation (scale, cost, and acid/base sensitivity)

Ketones from Ozonolysis

• Ozonolysis of alkenes yields ketones if one of the unsaturated carbon atoms is disubstituted (see Section 7.8)

Aryl Ketones by Acylation

• Friedel–Crafts acylation of an aromatic ring with an acid chloride in the presence of AlCl3 catalyst (see Section 16.4)

Methyl Ketones by Hydrating Alkynes

• Hydration of terminal alkynes in the presence of Hg2+ (catalyst: Section 8.5)

19.3 Oxidation of Aldehydes and Ketones

• CrO3 in aqueous acid oxidizes aldehydes to carboxylic acids efficiently

• Silver oxide, Ag2O, in aqueous ammonia (Tollens’ reagent) oxidizes aldehydes (no acid)

Hydration of Aldehydes

• Aldehyde oxidations occur through 1,1-diols (“hydrates”)

• Reversible addition of water to the carbonyl group• Aldehyde hydrate is oxidized to a carboxylic acid by

usual reagents for alcohols

Ketones Oxidize with Difficulty

• Undergo slow cleavage with hot, alkaline KMnO4

• C–C bond next to C=O is broken to give carboxylic acids

• Reaction is practical for cleaving symmetrical ketones

19.4 Nucleophilic Addition Reactions of Aldehydes and Ketones

• Nu- approaches 45° to the plane of C=O and adds to C

• A tetrahedral alkoxide ion intermediate is produced

Nucleophiles

• Nucleophiles can be negatively charged ( : Nu) or neutral ( : Nu) at the reaction site

• The overall charge on the nucleophilic species is not considered

19.5 Relative Reactivity of Aldehydes and Ketones

• Aldehydes are generally more reactive than ketones in nucleophilic addition reactions

• The transition state for addition is less crowded and lower in energy for an aldehyde (a) than for a ketone (b)

• Aldehydes have one large substituent bonded to the C=O: ketones have two

Electrophilicity of Aldehydes and Ketones

• Aldehyde C=O is more polarized than ketone C=O• As in carbocations, more alkyl groups stabilize +

character• Ketone has more alkyl groups, stabilizing the C=O

carbon inductively

Reactivity of Aromatic Aldehydes

• Less reactive in nucleophilic addition reactions than aliphatic aldehydes

• Electron-donating resonance effect of aromatic ring makes C=O less reactive electrophilic than the carbonyl group of an aliphatic aldehyde

19.6 Nucleophilic Addition of H2O: Hydration

• Aldehydes and ketones react with water to yield 1,1-diols (geminal (gem) diols)

• Hyrdation is reversible: a gem diol can eliminate water

Relative Energies

• Equilibrium generally favors the carbonyl compound over hydrate for steric reasons

– Acetone in water is 99.9% ketone form

• Exception: simple aldehydes– In water, formaldehyde consists is 99.9% hydrate

Base-Catalyzed Addition of Water

• Addition of water is catalyzed by both acid and base

• The base-catalyzed hydration nucleophile is the hydroxide ion, which is a much stronger nucleophile than water

Acid-Catalyzed Addition of Water

• Protonation of C=O makes it more electrophilic

Addition of H-Y to C=O

• Reaction of C=O with H-Y, where Y is electronegative, gives an addition product (“adduct”)

• Formation is readily reversible

19.7 Nucleophilic Addition of HCN: Cyanohydrin Formation

• Aldehydes and unhindered ketones react with HCN to yield cyanohydrins, RCH(OH)CN

Mechanism of Formation of Cyanohydrins

• Addition of HCN is reversible and base-catalyzed, generating nucleophilic cyanide ion, CN

• Addition of CN to C=O yields a tetrahedral intermediate, which is then protonated

• Equilibrium favors adduct

Uses of Cyanohydrins

• The nitrile group (CN) can be reduced with LiAlH4 to yield a primary amine (RCH2NH2)

• Can be hydrolyzed by hot acid to yield a carboxylic acid

19.8 Nucleophilic Addition of Grignard Reagents and Hydride Reagents: Alcohol Formation

• Treatment of aldehydes or ketones with Grignard reagents yields an alcohol

– Nucleophilic addition of the equivalent of a carbon anion, or carbanion. A carbon–magnesium bond is strongly polarized, so a Grignard reagent reacts for all practical purposes as R : MgX +.

Mechanism of Addition of Grignard Reagents

• Complexation of C=O by Mg2+, Nucleophilic addition of R : ,

protonation by dilute acid yields the neutral alcohol• Grignard additions are irreversible because a carbanion is

not a leaving group

Hydride Addition

• Convert C=O to CH-OH• LiAlH4 and NaBH4 react as donors of hydride ion• Protonation after addition yields the alcohol

19.9 Nucleophilic Addition of Amines: Imine and Enamine Formation

RNH2 adds to C=O to form imines, R2C=NR (after loss of HOH)

R2NH yields enamines, R2NCR=CR2 (after loss of HOH)

(ene + amine = unsaturated amine)

Mechanism of Formation of Imines

• Primary amine adds to C=O• Proton is lost from N and adds to O to yield a neutral

amino alcohol (carbinolamine)• Protonation of OH converts into water as the leaving

group• Result is iminium ion, which loses proton• Acid is required for loss of OH – too much acid blocks

RNH2

Note that overall reaction is substitution of RN for O

Imine Derivatives

• Addition of amines with an atom containing a lone pair of electrons on the adjacent atom occurs very readily, giving useful, stable imines

• For example, hydroxylamine forms oximes and 2,4-dinitrophenylhydrazine readily forms 2,4-dinitrophenylhydrazones

– These are usually solids and help in characterizing liquid ketones or aldehydes by melting points

Enamine Formation

• After addition of R2NH, proton is lost from adjacent carbon

CC

O

C

C

O

H++ R2NH

NH

R

C

C

HON

R

C

C

H2ON

R

C

CN

R

+ H3O+

R

H

H HH

H H

R R R

H H H

19.11 Nucleophilic Addition of Alcohols: Acetal Formation

• Two equivalents of ROH in the presence of an acid catalyst add to C=O to yield acetals, R2C(OR)2

• These can be called ketals if derived from a ketone

Formation of Acetals

• Alcohols are weak nucleophiles but acid promotes addition forming the conjugate acid of C=O

• Addition yields a hydroxy ether, called a hemiacetal (reversible); further reaction can occur

• Protonation of the OH and loss of water leads to an oxonium ion, R2C=OR+ to which a second alcohol adds to form the acetal

Uses of Acetals

• Acetals can serve as protecting groups for aldehydes and ketones

• It is convenient to use a diol, to form a cyclic acetal (the reaction goes even more readily)

19.12 Nucleophilic Addition of Phosphorus Ylides: The Wittig Reaction

• The sequence converts C=O is to C=C• A phosphorus ylide adds to an aldehyde or ketone to

yield a dipolar intermediate called a betaine • The intermediate spontaneously decomposes through

a four-membered ring to yield alkene and triphenylphosphine oxide, (Ph)3P=O

• Formation of the ylide is shown below

A Note on the Word “Betaines”

• The term “betaines” is an extension from a specific substance (betaine) that has permanent + and – charges (as in a zwitterion) that cannot be neutralized by proton transfers (as in normal amino acids). Webster's Revised Unabridged Dictionary lists: Betaine \Be"ta*ine\, n. [From beta, generic name of the beet.] (Chem.) A nitrogenous base, {C5H11NO2}, produced artificially, and also occurring naturally in beet-root molasses and its residues. The listed pronunciation indicates it has the exact same emphasis as “cocaine”.

• Cocaine \Co"ca*ine\, n. (Chem.) A powerful alkaloid, {C17H21NO4}, obtained from the leaves of coca

• So – if you say “co-ca-een” (as this dictionary suggests) then you would also say “bee-ta-een”. If you sat “co-cayn” then say “beet-ayn”.

• Whatever you say, the “beta” in “betaine” refers to beets and not a letter in the Greek alphabet. There have been a lot of wagers on this over the years.

RK

Uses of the Wittig Reaction

• Can be used for monosubstituted, disubstituted, and trisubstituted alkenes but not tetrasubstituted alkenes The reaction yields a pure alkene of known structure

• For comparison, addition of CH3MgBr to cyclohexanone and dehydration with, yields a mixture of two alkenes

Mechanism of the Wittig Reaction

19.14 Conjugate Nucleophilic Addition to -Unsaturated Aldehydes and Ketones

• A nucleophile can add to the C=C double bond of an ,-unsaturated aldehyde or ketone (conjugate addition, or 1,4 addition)

• The initial product is a resonance-stabilized enolate ion, which is then protonated

Conjugate Addition of Amines

• Primary and secondary amines add to , -unsaturated aldehydes and ketones to yield -amino aldehydes and ketones

Mechanism of Alkyl Conjugate Addition

• Conjugate nucleophilic addition of a diorganocopper anion, R2Cu, an enone

• Transfer of an R group and elimination of a neutral organocopper species, RCu

Conjugate Addition of Alkyl Groups: Organocopper Reactions

• Reaction of an , -unsaturated ketone with a lithium diorganocopper reagent

• Diorganocopper (Gilman) reagents from by reaction of 1 equivalent of cuprous iodide and 2 equivalents of organolithium

• 1, 2, 3 alkyl, aryl and alkenyl groups react but not alkynyl groups

Enantioselective Synthesis

• When a chiral product is formed achiral reagents, we get both enantiomers in equal amounts - the transition states are mirror images and are equal in energy

• However, if the reaction is subject to catalysis, a chiral catalyst can create a lower energy pathway for one enantiomer - called an enantionselective synthesis

• Reaction of benzaldehyde with diethylzinc with a chiral titanium-containing catalyst, gives 97% of the S product and only 3% of the R

Summary

• Aldehydes are from oxidative cleavage of alkenes, oxidation of 1° alcohols, or partial reduction of esters

• Ketones are from oxidative cleavage of alkenes, oxidation of 2° alcohols, or by addition of diorganocopper reagents to acid chlorides.

• Aldehydes and ketones are reduced to yield 1° and 2° alcohols , respectively

• Grignard reagents also gives alcohols • Addition of HCN yields cyanohydrins• 1° amines add to form imines, and 2° amines yield enamines• Reaction of an aldehyde or ketone with hydrazine and base yields an

alkane• Alcohols add to yield acetals• Phosphoranes add to aldehydes and ketones to give alkenes (the

Wittig reaction) -Unsaturated aldehydes and ketones are subject to conjugate

addition (1,4 addition)