Chapter 17: Chapter 17: Aldehydes and KetonesAldehydes and Ketones

R H

O

Functional Group: CarbonylFunctional Group: Carbonyl

Aldehyde: RCHO,Aldehyde: RCHO,

Ketone: Ketone: RCOR’, RCOR’,

R R'

O

Some 300 million sperm are released by the male during ejaculation, while the female usually produces one large egg at a time. Only one sperm cell can fertilize the egg. How does it find it?

Magnification: ~2,500

Sperm are selected for fertilization by their ability to “smell” a nearby egg. The 11-carbon aldehyde bourgeonal, above, activates this ability, whereas the straight-chain 11-carbon aldehyde, undecanal, shuts it down.

A little aldehyde at a A little aldehyde at a crucial moment.......crucial moment.......

O

H

NomenclatureNomenclature

The carbonyl group of aldehydes and ketones The carbonyl group of aldehydes and ketones has has priority priority over all other polar or functional over all other polar or functional groups used so far, namely groups used so far, namely

RX, ROH, , ,RX, ROH, , , (But not COOH)(But not COOH)

>>In addition:In addition:

Systematic Naming Systematic Naming (IUPAC)(IUPAC)

AldehydesAldehydes

AlkanAlkanee Alkan Alkanalal. Longest chain . Longest chain starts at carbonyl carbon, which is starts at carbonyl carbon, which is C1.C1.ExamplesExamples::

FormFormaldehydealdehyde AcetAcetaldehydealdehyde

IUPAC-accepted common namesIUPAC-accepted common names

Cyclic aldehydes have the endingCyclic aldehydes have the ending-carbaldehyde -carbaldehyde after cycloalkane after cycloalkane name.name.The carbon attached to -CHO is C1.The carbon attached to -CHO is C1.Examples:Examples:

TheThe unit as a substituent is calledunit as a substituent is calledformylformyl..

Cis-2-Cis-2-mercaptomercaptocyclo-cyclo-hexanehexanecarbaldehydcarbaldehydee

CHO

12

34

SH

KetonesKetones

AlkAlkaneane Alkan Alkanone. one. Longest chain Longest chain incorporates carbonyl carbon and is incorporates carbonyl carbon and is

numbered from terminus close numbered from terminus close to C=O.to C=O.

Cyclic ketones are Cyclic ketones are cycloalkanones; cycloalkanones; CC=O is =O is C1C1..Examples:Examples:

CisCis-2-ethenyl-3--2-ethenyl-3-methylcyclohexanonmethylcyclohexanone (if racemic) or e (if racemic) or 22SS,3,3S-.S-.

2-Pentanone

O

H

H

An aldehyde containing a An aldehyde containing a ketone C=O is called an ketone C=O is called an oxooxoalkanal.alkanal.Example:Example:

Substituent name: Substituent name: alkanoylalkanoyl

O

R

O

CH3acetylacetyl, but , but propanoylpropanoyl

(IUPAC accepted common name)(IUPAC accepted common name)

O

CH3CH2

O

O

HO

Complex Aldehydes and Complex Aldehydes and KetonesKetones

4-Acetylbenzenecarboxylic acid4-Acetylbenzenecarboxylic acid

Br

O

H

O

TransTrans-4-bromo-2-oxo-3-butenal-4-bromo-2-oxo-3-butenal

Structure Structure

OrbitalsOrbitals

The carbonyl group contains a The carbonyl group contains a shortshort, , strongstrong, and very , and very polarpolar bond.bond.

ResonanceResonance

PolarizationPolarization

Molecular structureMolecular structure

EPMEPM

175 kcal mol-1

Polarization affects the physical Polarization affects the physical constants of aldehydes and constants of aldehydes and

ketonesketones-- Boiling points relatively high-- Boiling points relatively high-- Smaller members (acetaldehyde, -- Smaller members (acetaldehyde, acetone) are completely miscible with acetone) are completely miscible with waterwater

11H NMR: Carbonyl group is H NMR: Carbonyl group is deshieldingdeshielding

Uniquely Uniquely deshieldeddeshielded by polarization and by polarization and double bond effectdouble bond effect

J ~ 2Hz

1313C NMRC NMR

R R'

O

~ 200 ppm~ 200 ppm

IRIR υυC OC O~~

---- = 1690-1750 cm= 1690-1750 cm-1-1

Conjugation reduces , strain increases itConjugation reduces , strain increases itυυCOCO~~

H3C CH3

O

H

11H NMRH NMR 1313C NMRC NMR

IRIR

UVUV

The The ππππ* and n* and nππ* * transitions in acetonetransitions in acetone

λλmaxmax (n(nππ*)*) = 275-295 nm= 275-295 nm

Lone Lone electron electron pairspairs

:: ::

Synthesis Synthesis (A review of Chapter 8)(A review of Chapter 8)

1.1.OxidationOxidation of of AlcoholsAlcoholsPrimary Primary aldehydes aldehydes Secondary Secondary ketones ketonesUse Use chromium(VI)chromium(VI) reagents reagents Selective: Will not oxidize alkene or Selective: Will not oxidize alkene or alkyne units. Especially mild is PCC:alkyne units. Especially mild is PCC:

PyridinePyridinePyridinium chlorochromate :Pyridinium chlorochromate : “PCC” “PCC”

NNH H ++

NNCrOCrO33ClCl

--

Avoid water: Causes Avoid water: Causes overoxidationoveroxidation of primary of primary alcoholsalcohols

ExamplesExamples::

2.2.AllylicAllylic Oxidation: Oxidation: MnOMnO22

Selective: Will not attack ordinary alcoholsSelective: Will not attack ordinary alcohols

Allylic H is reactiveAllylic H is reactive

3. 3. Ozonolysis Ozonolysis ofof alkenes: alkenes: OO33, then reducing agent, then reducing agent

Oxidative cleavage of carbon-carbon double Oxidative cleavage of carbon-carbon double bondsbonds

4. 4. HydrationHydration of alkynes of alkynesHydration of the carbon–carbon triple bond Hydration of the carbon–carbon triple bond yields enols that tautomerize to carbonyl yields enols that tautomerize to carbonyl compoundscompoundsMarkovnikovMarkovnikov: Use Hg: Use Hg2+2+, H, H22O, O, HH++::

Anti-MarkovnikovAnti-Markovnikov: Use hydroboration-: Use hydroboration-oxidationoxidation

5. 5. Friedel-CraftsFriedel-Crafts alkanoylation alkanoylation ((Electrophilic Aromatic Substitution)Electrophilic Aromatic Substitution)

ReactionsReactions

E.g., NaBH4, RLi, RMgX

(H+)

There are three regions of reactivity There are three regions of reactivity in aldehydes and ketonesin aldehydes and ketones

ReviewReview

Nucleophilic additions to carbonyls Nucleophilic additions to carbonyls to give alcoholsto give alcohols

Addition reactions occur with Addition reactions occur with milder nucleophilesmilder nucleophiles, , such as water, alcohols, amines, etc. To speed them such as water, alcohols, amines, etc. To speed them up, up, acid or base catalysisacid or base catalysis is required. is required.

Catalyzed Ionic Catalyzed Ionic AdditionsAdditions

Base CatalyzedBase Catalyzed Mechanisms: Mechanisms:

Acid CatalyzedAcid Catalyzed Mechanisms:Mechanisms:

X―Y = H―Nu

X―Y = H―Nu

1. 1. Hydration:Hydration: Geminal Geminal Diols Diols (Carbonyl Hydrates)(Carbonyl Hydrates)

KK ~ 1 ~ 1

KK depends on “unhappiness” of C=O depends on “unhappiness” of C=O polarization: Electron-withdrawing polarization: Electron-withdrawing substituents activate, donors substituents activate, donors deactivate.deactivate.

Mechanisms:Mechanisms:

ΔΔH H ° = ° = -3.09-3.09 kcal mol kcal mol-1-1, , ΔΔS S ° = ° = -22.9-22.9 eu, eu, ΔΔG G ° = ° = +3.74+3.74 kcal mol kcal mol-1-1

ΔΔH H ° = ° = -5.30-5.30 kcal mol kcal mol-1-1, , ΔΔS S ° = ° = -17.2-17.2 eu, eu, ΔΔG G ° = ° = -0.18-0.18 kcal mol kcal mol-1-1

2. Addition of 2. Addition of AlcoholsAlcohols

(Not (Not hemiketal: hemiketal: IUPAC)IUPAC)

Same as water, initially, to form Same as water, initially, to form hemiacetalshemiacetals

K

K

K varies from < 1 to > 1, as with water. Depends on R.

H+ or HO-

H+ or HO-

IntramolecularIntramolecular variant variant (important for (important for sugars, Chapter 24): sugars, Chapter 24): Best for 5- and Best for 5- and

6-membered rings.6-membered rings.

Favored by entropyFavored by entropy relative relative to intermolecular addition; to intermolecular addition;

ΔΔG G ° = ° = ΔΔH H ° - T° - TΔΔS S °°

ΔΔS S ° is ° is less negativeless negative for for intramolecular reaction.intramolecular reaction.

K >1!

We can drive the hemiacetal step We can drive the hemiacetal step furtherfurther with with more alcohol and with more alcohol and with HH++ catalysis: catalysis:

AcetalsAcetals

Acetals are stable to: Acetals are stable to: Base Base Oxidizing agents Oxidizing agents Nucleophiles (Grignards, Nucleophiles (Grignards,

alkyllithiums, hydrides)alkyllithiums, hydrides)

Acetals are Acetals are NOT NOT stable to: stable to: AcidAcid

(A geminal diether)(A geminal diether)

K >1!

(isolated)

Mechanism:Mechanism:

AcetalAcetal

Cyclic Acetals: Cyclic Acetals: Protecting Protecting GroupsGroups

o

o

CHCH33OHOH

IntramolecularIntramolecular variant variant (important for (important for sugars, Chapter 24). sugars, Chapter 24). Best for 5- and 6-Best for 5- and 6-membered rings.membered rings.

HO

O

H

H+, H2O

Hydrolysis = Deprotection

O

OH

O

Br

1.1. HOOH

2. 2. MgMg

3.3.

4. 4. HH++, H, H22OO

O

H

This is also a method to This is also a method to protect diols:protect diols:

OBr

OH

OH

+H+

Br

O

O

Mg

BrMg

O

O

O H+

OH

OH

HO

Thioacetals: Stable to Thioacetals: Stable to acid! acid!

Application of Application of thioacetals: thioacetals: DesulfurizationDesulfurization

Deprotection:Deprotection:

Thioacetalization uses Lewis acid catalysis, e.g., ZnClThioacetalization uses Lewis acid catalysis, e.g., ZnCl22. Again, . Again, cyclic version particularly favorable.cyclic version particularly favorable.

More applications: Chapter 23.More applications: Chapter 23.

3. 3. Amine AdditionsAmine Additions

Example:Example:

Ammonia and primary Ammonia and primary aminesamines add to the add to the carbonyl function and then carbonyl function and then dehydrate: A dehydrate: A ““condensationcondensation” reaction.” reaction.

Mechanism:Mechanism:

Hemiaminal Hemiaminal DehydrationDehydration

Imine FormationImine Formation

A condensation A condensation product (-Hproduct (-H22O)O)

LipshutzLipshutz

BBoysBBoys

IntramolecularIntramolecular reaction: reaction: Best for 5- Best for 5- and 6-membered rings.and 6-membered rings.

ONH2 N

Cat. Cat. HH++

Teaser: An Teaser: An 11H NMR H NMR spectrum of an spectrum of an imine (downfield imine (downfield region)region)

Special IminesSpecial Imines

+ H+ H22N-OHN-OH(as H(as H33NN++-OH -OH ClCl--))

An An oximeoxime

++

SemicarbazidSemicarbazidee

SemicarbazonSemicarbazonee

R R'

O

R R'

NOH

-H-H22OO

R R'

O

NH

NH2

O

H2N

R R'

N

HN

O

NH2

-H-H22OO

R R'

O

++ -H-H22OO

HydrazoneHydrazone

HydroxylaminHydroxylaminee

Reaction of the carbonyl function Reaction of the carbonyl function with with secondary aminessecondary amines gives gives hemiaminals in which normal hemiaminals in which normal condensation is not possible: No H condensation is not possible: No H left on N. Therefore, water loss left on N. Therefore, water loss occurs to the “carbon side” to form occurs to the “carbon side” to form an an enamineenamine..

Enamine Enamine FormationFormation

Mechanism:Mechanism:

Enamines are useful, can be alkylated (Chapter Enamines are useful, can be alkylated (Chapter 18-4).18-4).

Wolff-Kishner Reduction Wolff-Kishner Reduction An Application of An Application of HydrazonesHydrazones

Synthesis of a Synthesis of a HydrazoneHydrazone

Wolff-Kishner ReductionWolff-Kishner Reduction

Mechanism:Mechanism: Nitrogen elimination Nitrogen elimination

In practice, the reaction is carried out without isolating the intermediate hydrazone.

A diazaallylic anion

Use in alkylbenzene synthesis:Use in alkylbenzene synthesis:

Br

Br

Br

Br

The Wolff-Kishner reduction is an alternative to The Wolff-Kishner reduction is an alternative to the Clemmensen (rough, conc. acid) and thioacetal desulfurization methods (incompatible with cat. H2- sensitive groups) of deoxygenating aldehydes and ketones.

4. Addition of 4. Addition of Non-Non-organometallic organometallic Carbon Carbon

NucleophilesNucleophilesa. Cyanide makes a. Cyanide makes cyanohydrinscyanohydrins

To make HCN,but keep pH slightly basic

MechanismMechanism

NaNaOHOH

Usefulness: A C-C bond formation and -CN is a versatile functional Usefulness: A C-C bond formation and -CN is a versatile functional groupgroup

b. The b. The Wittig ReactionWittig Reaction

Phosphonium salt Phosphonium salt synthesissynthesis

Georg Wittig (1897–1987) NP 1979

Discovered during an investigation of Discovered during an investigation of SSNN2 reactions of phosphines with 2 reactions of phosphines with haloalkanes.haloalkanes.

The charge on P The charge on P acidifies the adjacent acidifies the adjacent C-H: Deprotonation C-H: Deprotonation gives a so-called gives a so-called ylideylide

Other (weaker) bases OK, such as CHOther (weaker) bases OK, such as CH33OO--, CH, CH33OH, generate the OH, generate the ylide in equilibrium concentrations sufficient for the next step: ylide in equilibrium concentrations sufficient for the next step: Attack on carbonyl carbon and formation of alkenes.Attack on carbonyl carbon and formation of alkenes.

NucleophilicNucleophilic Valence shell Valence shell expandedexpanded

WittigWittig

Driving force: Very strong Driving force: Very strong bondbond

CompareCompare::

CHCH22=P(C=P(C66HH55))

33

Can be made cis or trans selective.Can be made cis or trans selective.

Steroid modificationSteroid modification

O

CH2

H

H

H

O

O

H

H

H

Resonance-stabilized, trans-selective

5. Addition of Hydroxy Groups 5. Addition of Hydroxy Groups Revisited: Revisited: Baeyer-Villiger Baeyer-Villiger

OxidationOxidationOxidation of ketones by peroxycarboxylic Oxidation of ketones by peroxycarboxylic acids gives acids gives esters:esters:

MechanismMechanism::

Adolf von Adolf von Baeyer Baeyer (1835-1917) (1835-1917) NP 1905. NP 1905.

Victor VilligerVictor Villiger

LipshutzLipshutzCarusoCaruso

Familiar? Recall: Chapter 9-Familiar? Recall: Chapter 9-33

And Chapter 12-8And Chapter 12-8

The transition state of the Baeyer-The transition state of the Baeyer-Villiger oxidation involves migration Villiger oxidation involves migration of of R’ R’ through a push-pull electronic through a push-pull electronic relay:relay:

Examples:Examples:

O

Regioselective!Regioselective!

O

O

OHH33CCOOHCCOOH

O

OO

OOH

OO

RegioselectivRegioselective!e!