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2302272 – Org Chem II – Part I

Lecture 4

Aldehydes & Ketones II

Instructor: Dr. Tanatorn Khotavivattana

E-mail: [email protected]

Recommended Textbook:

Chapter 18 and 22 in Organic Chemistry, 8th Edition, L. G. Wade, Jr.,

2010, Prentice Hall (Pearson Education)

Chapter 18 – Wade - Prentice Hall

1Synthesis of Aldehydes and Ketones

1) Oxidation of Alcohols

• Sodium dichromate in sulfuric acid (“chromic acid,” H2CrO4) is the traditional

laboratory reagent for oxidizing secondary alcohols to ketones

• Bleach (NaOCl) is an inexpensive, chromium-free alternative that also oxidizes

secondary alcohols to ketones.



1) Oxidation of Alcohols

• Pyridinium chlorochromate (PCC), a complex of chromium trioxide with

pyridine and HCl, provides good yields of aldehydes without over-oxidation.

• Swern oxidation (using DMSO as the oxidant)

• Dess–Martin periodinane (DMP) oxidation

Problem #1 3



2) Ozonolysis

• Ozonolysis, followed by a mild reduction, cleaves alkenes to give carbonyl

Example



3) Friedel–Crafts Acylation

• Excellent method for making alkyl aryl ketones or diaryl ketones

Example

• Cannot be used on strongly deactivated aromatic systems.



3) Friedel–Crafts Acylation

• Gatterman–Koch synthesis is a variant of the Friedel–Crafts acylation for the

synthesis of aryl aldehydes using carbon monoxide and HCl

• Gatterman–Koch formylation succeeds only with benzene and activated

benzene derivatives (electron-rich)


4) Hydration of Alkynes

• Hydration of a terminal alkyne is a convenient way of making methyl ketones

• Catalysed by a combination of sulfuric acid and mercuric ion

• Initial product of Markovnikov hydration is an enol, which quickly tautomerizes to

keto form

Example


5) Hydroboration–Oxidation of Alkynes

• Gives anti-Markovnikov addition of water across the triple bond

• Di(secondary isoamyl) borane (disiamylborane) is reagent; bulky borane cannot

add twice

• Unstable enol quickly tautomerizes to an aldehyde

Example



6) Synthesis of Ketones from Carboxylic Acid

• Organolithium reagents can be used to synthesise ketones from carboxylic acids

• Protonation of the dianion forms the hydrate of a ketone, which quickly loses water

to give the ketone


• It can attacks the lithium salts of carboxylate anions to give dianions.


6) Synthesis of Ketones from Carboxylic Acid

• If the organolithium reagent is inexpensive, we can simply add two equivalents to

the carboxylic acid. The first equivalent generates the carboxylate salt, and the

second attacks the carbonyl group


• Subsequent protonation gives the ketone

Problem #2 11


7) Synthesis of Aldehydes and Ketones from Nitriles

• A Grignard or organolithium reagent attacks a nitrile to give the magnesium salt

of an imine


• Acidic hydrolysis of the imine leads to the ketone.



• Aluminum hydrides can reduce nitriles to the corresponding aldehydes


• Diisobutylaluminum

hydride, abbreviated

(i-Bu)2AlH or DIBAL-H,

is commonly used for

the reduction of nitriles.

DIBAL-H




Examples

Problem #3 15


8) Synthesis of Aldehydes and Ketones from Acid Chlorides


• Reducing agents that are strong enough to reduce carboxylic acids also reduce

aldehydes even faster

• First, convert the carboxylic acids to a functional group that is easier to reduce than

an aldehyde: the acid chloride

• treatment of carboxylic acids with thionyl chloride, SOCl2




• Strong reducing agents like LiAlH4 reduce acid chlorides all the way to primary

alcohols

• Lithium tri-tert-butoxyaluminum hydride is a milder reducing agent

Example




• Grignard and organolithium reagents add to acid chlorides to give ketones, but they

add again to the ketones to give tertiary alcohols

• Lithium dialkylcuprates (R2CuLi) is a weaker organometallic reagent



9) Synthesis of Aldehydes and Ketones from Esters

• Diisobutylaluminum hydride (DIBAL-H) reduces esters directly to aldehydes at

dry ice temperature, about -78 °C

• Unlike LiAlH4 (which reduces esters to primary alcohols), cold DIBAL-H usually

does not reduce the aldehyde further

• The initial reaction forms an aluminum complex that is stable toward further

reduction, but hydrolyses to the aldehyde in the aqueous workup

Problem #4 20

21


Alpha Substitution

• Replacement of a hydrogen atom at the α carbon atom (the carbon next to the

carbonyl group) by some other group

• The α hydrogen is acidic because the enolate ion that results from its removal is

resonance-stabilized, with the negative charge delocalized over the carbon atom

and the carbonyl oxygen atom.

22


Alpha Substitution – Keto-Enol Tautomerism

• Since the negative charge spreads over a carbon atom and an oxygen atom;

reprotonation can occur either on the carbon (returning to the keto form) or on

the oxygen, giving a vinyl alcohol, the enol form

• This type of isomerization, occurring by the migration of a proton and the

movement of a double bond, is called tautomerism

• The isomers that interconvert are called tautomers

23



• Keto-Enol Tautomerism can be catalysed by either base or acid

25


• For simple ketones and aldehydes, the equilibrium favours the keto form

• For β-dicarbonyl compounds, the equilibrium favours the enol form; the enol has

a conjugated p system and stabilisation from hydrogen bonding


Problem #5 25

• The alpha protons of typical aldehydes or ketones (pKa = 20) are much more

acidic than alkanes, alkenes (>40) or even alkyne (25) but less acidic than H2O

(15.7) or alcohol (16-18)

Formation of and Stability of Enolates

• When a simple ketone or aldehyde is treated with –OH ion or –OR, the

equilibrium mixture contains only a small fraction of deprotonated enolate form


26

• Even with small equilibrium concentration of enolate, when it reacts with E+ the

equilibrium shifts to the right



27

Problem #6 28

• Sometimes this equilibrium mixture of enolate and base won’t work, usually

because the base reacts with the electrophile faster than the enolate does



29

• Solution: use the base that completely converts the carbonyl compound to its

enolate before adding the electrophile (base never meets the electrophile)

• The most effective base for this purpose is lithium diisopropylamide (LDA),

made by using an alkyllithium reagent to deprotonate diisopropylamine

(pKa ~ 36)

• Diisopropylamine (pKa ~ 36): much less acidic than typical C=O compounds

• LDA: bulky reagent so it doesn’t attack C=O easily (powerful base but not a

strong nucleophile)

• LDA reacts with aldehyde or ketone by abstracting a-proton to give Lithium

Enolate (lithium salt of the enolate) which is very useful in synthesis



30

31


1) Racemisation

• An optically active aldehyde or ketone with a stereocenter at the α-carbon will

racemise in the presence of catalytic acid or base

Reactions of Enols and Enolates

32


2) Alpha Halogenation: Reaction of ketone with a halogen and base


33


2.1) Base-Catalysed Alpha Halogenation: Multiple halogenation


• Product (α-haloketone) is more reactive toward further halogenation than the

starting ketone because the electron withdrawing X stabilises the enolate ion

• Base-promoted halogenation is rarely used for preparation of monohalo ketones;

acid-catalysed method is more preferred

34

2.1) Base-Catalysed Alpha Halogenation: Haloform Reaction


• Methyl ketones have three protons on the methyl carbon, and they undergo

halogenation three times to give trihalomethyl ketones

• With three electron-withdrawing halogen atoms, the trihalomethyl group can serve

as a reluctant leaving group for nucleophilic acyl substitution.

• Substitution of the trihalomethyl group with hydroxide followed by a fast proton

exchange gives a carboxylate ion and a haloform (chloroform, bromoform, or

iodoform)

35

2.1) Base-Catalysed Alpha Halogenation: Haloform Reaction


• Overall Reaction

• Iodoform Test

• Iodoform is a solid that separates out as a yellow precipitate. This iodoform test

identifies methyl ketones


36


2.2) Acid-Catalysed Alpha Halogenation:


• In contrast with basic conditions, acidic halogenation can selectively replace just

one hydrogen or more than one, depending on the amount of the halogen added

• Attack of the enol form on the electrophilic halogen molecule

Problem #6 37

Problem #7 38

39


3) Alkylation: An enolate ion can serve as the nucleophile attacking an unhindered

alkyl halides and tosylates by the SN2 mechanism


• The reaction usually takes place at the α carbon, forming a new C—C bond

• Typical bases such as sodium hydroxide or an alkoxide ion cannot be used

because they can reacts with the alkyl halide or tosylate, giving side products

• Lithium diisopropylamide (LDA) avoids these side reactions.

40


3) Alkylation:


• LDA converts the ketone entirely to its enolate. All the LDA is consumed in

forming the enolate, leaving the enolate to react without interference from the LDA

Problem #7 41

42


4) Aldol Condensation: one of the most important enolate reactions


• Condensations combine two or more molecules, often with the loss of a small

molecule such as water or an alcohol

• Overall Reaction

• The product, a β-hydroxy ketone or aldehyde, is called an aldol because it contains

both an aldehyde group and the hydroxy group of an alcohol.

• The aldol product may dehydrate to an α,β-unsaturated carbonyl compound

43


4.1) Base-Catalysed Aldol Condensation:


• Nucleophilic addition of the enolate ion (a strong nucleophile) to a carbonyl group

• The aldol condensation is reversible, establishing an equilibrium between

reactants and products

444.2) Acid-Catalysed Aldol Condensation:

• Nucleophilic addition of an enol to a protonated carbonyl group


45


4.3) Dehydration of the Aldol Product: Heating a basic or acidic mixture of an

aldol product leads to dehydration of the alcohol


• The product is a conjugated α,β-unsaturated aldehyde or ketone

Problem #8 46

Problem #9 47

48


4.3) Crossed Aldol Condensations: the enolate of one aldehyde (or ketone) adds

to the carbonyl group of a different aldehyde or ketone


• Drawback: Selectivity! Consider the aldol condensation between ethanal

(acetaldehyde) and propanal, four possible products result

49


4.3) Crossed Aldol Condensations:


• Solution:

A) Only one of the reactants has an α-hydrogen, only one enolate will be

present in the solution

B) If the other reactant is present in excess or contains a particularly

electrophilic carbonyl group, it is more likely to be attacked by the enolate

Problem #10 50

51


Homework – 1

52


Homework – 2

Homework – 3 53


Homework – 4 54


Homework – 5 55


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