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Chapter 19. Aldehydes and Ketones: Nucleophilic Addition Reactions

Based on McMurry’s Organic Chemistry, 6th edition

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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

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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

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Naming Ketones Replace the terminal -e of the alkane name with –one Parent chain is the longest one that contains the

ketone group Numbering begins at the end nearer the carbonyl

carbon

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Ketones with Common Names IUPAC retains well-used but unsystematic names for

a few ketones

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Ketones and Aldehydes as Substituents The R–C=O as a substituent is an acyl group is used

with the suffix -yl from the root of the carboxylic acid CH3CO: acetyl; CHO: formyl; C6H5CO: benzoyl

The prefix oxo- is used if other functional groups are present and the doubly bonded oxygen is labeled as a substituent on a parent chain

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19.2 Preparation of Aldehydes and Ketones

Preparing Aldehydes Oxidize primary alcohols using pyridinium

chlorochromate Reduce an ester with diisobutylaluminum

hydride (DIBAH)

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Preparing Ketones Oxidize a 2° alcohol (see Section 17.8) Many reagents possible: choose for the specific

situation (scale, cost, and acid/base sensitivity)

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Ketones from Ozonolysis Ozonolysis of alkenes yields ketones if one of the

unsaturated carbon atoms is disubstituted (see Section 7.8)

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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)

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Methyl Ketones by Hydrating Alkynes

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

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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)

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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

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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

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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

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Nucleophiles Nucleophiles can be negatively charged ( : Nu) or

neutral ( : Nu) at the reaction site The overall charge on the nucleophilic species is not

considered

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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

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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

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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

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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

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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

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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

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Acid-Catalyzed Addition of Water Protonation of C=O makes it

more electrophilic

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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

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19.7 Nucleophilic Addition of HCN: Cyanohydrin Formation Aldehydes and unhindered ketones react with HCN to

yield cyanohydrins, RCH(OH)CN

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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

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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

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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 +.

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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

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

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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)

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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

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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

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Enamine Formation

After addition of R2NH, proton is lost from adjacent carbon

CCOCCOH++ R2NHNHRCCHONRCCH2ONRCCNR+ H3O+RHHHHHHRRRHHH

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19.10 Nucleophilic Addition of Hydrazine: The Wolff–Kishner Reaction Treatment of an aldehyde or ketone with hydrazine,

H2NNH2 and KOH converts the compound to an alkane

Originally carried out at high temperatures but with dimethyl sulfoxide as solvent takes place near room temperature

See Figure 19.11 for a mechanism

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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

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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

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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)

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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

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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

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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

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Mechanism of the Wittig Reaction

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19.13 The Cannizzaro Reaction: Biological Reductions The adduct of an aldehyde and OH can transfer

hydride ion to another aldehyde C=O resulting in a simultaneous oxidation and reduction (disproportionation)

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The Biological Analogue of the Canizzaro Reaction Enzymes catalyze the reduction of aldehydes and ketones

using NADH as the source of the equivalent of H-

The transfer resembles that in the Cannizzaro reaction but the carbonyl of the acceptor is polarized by an acid from the enzyme, lowering the barrier

Enzymes are chiral and the reactions are stereospecific. The stereochemistry depends on the particular enzyme involved.

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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

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Conjugate Addition of Amines Primary and secondary amines add to , -

unsaturated aldehydes and ketones to yield -amino aldehydes and ketones

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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

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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

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19.15 Biological Nucleophilic Addition Reactions Example: Many enzyme reactions involve pyridoxal phosphate

(PLP), a derivative of vitamin B6, as a co-catalyst PLP is an aldehyde that readily forms imines from amino groups

of substrates, such as amino acids The imine undergoes a proton shift that leads to the net

conversion of the amino group of the substrate into a carbonyl group

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19.16 Spectroscopy of Aldehydes and Ketones Infrared Spectroscopy Aldehydes and ketones show a strong C=O peak

1660 to 1770 cm1

aldehydes show two characteristic C–H absorptions in the 2720 to 2820 cm1 range.

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C=O Peak Position in the IR Spectrum

The precise position of the peak reveals the exact nature of the carbonyl group

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NMR Spectra of Aldehydes Aldehyde proton signals are at 10 in 1H NMR -

distinctive spin–spin coupling with protons on the neighboring carbon, J 3 Hz

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Protons on Carbons Adjacent to C=O

Slightly deshielded and normally absorb near 2.0 to 2.3

Methyl ketones always show a sharp three-proton singlet near 2.1

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13C NMR of C=O C=O signal is at 190 to 215 No other kinds of carbons absorb in this range

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Mass Spectrometry – McLafferty Rearrangement Aliphatic aldehydes and ketones that have hydrogens

on their gamma () carbon atoms rearrange as shown

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Mass Spectroscopy: -Cleavage Cleavage of the bond between the carbonyl group

and the carbon Yields a neutral radical and an oxygen-containing

cation

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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

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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)