chapter 19. aldehydes and ketones: nucleophilic addition ... · pdf...

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Chapter 19. Aldehydes andKetones: NucleophilicAddition Reactions

Based on McMurry’s Organic Chemistry, 6th

edition

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Aldehydes and Ketones

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

The compounds occur widely in nature asintermediates in metabolism and biosynthesis

They are also common as chemicals, as solvents,monomers, adhesives, agrichemicals andpharmaceuticals

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Naming Aldehydes and Ketones

Aldehydes are named by replacing the terminal -e ofthe 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 thesuffix 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 fora few ketones

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Ketones and Aldehydes as Substituents

The R–C=O as a substituent is an acyl group is usedwith 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 arepresent and the doubly bonded oxygen is labeled as asubstituent on a parent chain

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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 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

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Aryl Ketones by Acylation

Friedel–Crafts acylation of an aromatic ring with anacid chloride in the presence of AlCl3 catalyst

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Methyl Ketones by Hydrating Alkynes

Hydration of terminal alkynes in the presence of Hg2+

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Oxidation of Aldehydes and Ketones

CrO3 in aqueous acid oxidizes aldehydes tocarboxylic acids efficiently

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

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Nucleophilic Addition Reactions ofAldehydes and Ketones

Nu- approaches 45° to the plane of C=O and addsto 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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Relative Reactivity of Aldehydes andKetones 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 theC=O: ketones have two

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Electrophilicity of Aldehydes andKetones 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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Base-Catalyzed Addition of Water

Addition of water is catalyzed byboth acid and base

The base-catalyzed hydrationnucleophile is the hydroxide ion,which is a much strongernucleophile than water

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Acid-Catalyzed Addition of Water

Protonation of C=O makesit more electrophilic

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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 promotesaddition 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 toan oxonium ion, R2C=OR+ to which a second alcoholadds to form the acetal

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Uses of Acetals

Acetals can serve as protecting groups foraldehydes and ketones

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

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Addition of H-Y to C=O

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

Formation is readily reversible

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

to yield cyanohydrins, RCH(OH)C≡N

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Mechanism of Formation ofCyanohydrins 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 (C≡N) can be reduced with LiAlH4to yield a primary amine (RCH2NH2)

Can be hydrolyzed by hot acid to yield a carboxylicacid

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Nucleophilic Addition of Grignard Reagents andHydride Reagents: Alcohol Formation

Treatment of aldehydes or ketones with Grignardreagents yields an alcohol Nucleophilic addition of the equivalent of a carbon

anion, or carbanion. A carbon–magnesium bond isstrongly polarized, so a Grignard reagent reacts for allpractical purposes as R : − MgX +.

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Mechanism of Addition of GrignardReagents Complexation of C=O by Mg2+, Nucleophilic addition

of R : −, protonation by dilute acid yields the neutralalcohol

Grignard additions are irreversible because acarbanion 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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Nucleophilic Addition of Amines: Imine andEnamine Formation

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

R2NH yields enamines, R2NCR=CR2 (after loss ofHOH)

(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 veryreadily, 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

32http://en.wikipedia.org/wiki/2%2C4-dinitrophenylhydrazine

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Conjugate Nucleophilic Addition to α,b-Unsaturated Aldehydes and Ketones

A nucleophile canadd to the C=Cdouble bond of anα,b-unsaturatedaldehyde or ketone(conjugate addition,or 1,4 addition)

The initial productis a resonance-stabilized enolateion, which is thenprotonated

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Mechanism of Alkyl ConjugateAddition 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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Conjugate Addition of Alkyl Groups:Organocopper Reactions Reaction of an α, b-unsaturated ketone with a lithium

diorganocopper reagent Diorganocopper (Gilman) reagents from by reaction

of 1 equivalent of cuprous iodide and 2 equivalentsof organolithium

1°, 2°, 3° alkyl, aryl and alkenyl groups react but notalkynyl groups

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19.15 Biological NucleophilicAddition 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 carbonylgroup

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

1660 to 1770 cm−1

aldehydes show two characteristic C–H absorptionsin the 2720 to 2820 cm−1 range.

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C=O Peak Position in the IR Spectrum

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

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

distinctive spin–spin coupling with protons on theneighboring carbon, J ≈ 3 Hz

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Protons on Carbons Adjacent to C=O

Slightly deshielded and normally absorb near δ 2.0to δ2.3

Methyl ketones always show a sharp three-protonsinglet near δ 2.1

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

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Mass Spectrometry – McLaffertyRearrangement Aliphatic aldehydes and ketones that have

hydrogens on their gamma (γ) carbon atomsrearrange as shown

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Mass Spectroscopy: α-Cleavage

Cleavage of the bond between the carbonyl groupand the α carbon

Yields a neutral radical and an oxygen-containingcation

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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 mirrorimages and are equal in energy

However, if the reaction is subject to catalysis, a chiral catalystcan create a lower energy pathway for one enantiomer - calledan enantionselective synthesis

Reaction of benzaldehyde with diethylzinc with a chiral titanium-containing catalyst, gives 97% of the S product and only 3% ofthe 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) αβ-Unsaturated aldehydes and ketones are subject to conjugate

addition (1,4 addition)

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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 carboxylicacids

Reaction is practical for cleaving symmetrical ketones

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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 thecarbonyl 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 compoundover 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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Enamine Formation

After addition of R2NH, proton is lost from adjacentcarbon

CCOCCOH++ R2NHNHRCCHONRCCH2ONRCCNR+ H3O+RHHHHHHRRRHHH

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Nucleophilic Addition of Hydrazine: TheWolff–Kishner Reaction

Treatment of an aldehyde or ketone with hydrazine,H2NNH2 and KOH converts the compound to analkane

Originally carried out at high temperatures but withdimethyl sulfoxide as solvent takes place near roomtemperature

See Figure 19.11 fora mechanism

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19.12 Nucleophilic Addition of PhosphorusYlides: 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 andtriphenylphosphine 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) thatcannot 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 ithas 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 youwould 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 aletter in the Greek alphabet. There have been a lot of wagers on thisover the years.

RK

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Uses of the Wittig Reaction Can be used for monosubstituted, disubstituted, and

trisubstituted alkenes but not tetrasubstitutedalkenes The reaction yields a pure alkene of knownstructure

For comparison, addition of CH3MgBr tocyclohexanone and dehydration with, yields amixture 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 asimultaneous oxidation and reduction(disproportionation)

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The Biological Analogue of theCanizzaro 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 thecarbonyl of the acceptor is polarized by an acid from theenzyme, lowering the barrier

Enzymes are chiraland the reactionsare stereospecific.The stereochemistrydepends on theparticular enzymeinvolved.

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

unsaturated aldehydes and ketones to yield b-aminoaldehydes and ketones