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CARBONYL COMPOUNDSALDEHYDES AND KETONES

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Aldehydes and Ketones

CH

RO C

R

RO

Aldehyde Ketone

C OH3C

H118o

121oC C

H

H

H

H118o

121o

C OH3C

HC O

H3C

H

δ−δ+

Resonance Structures

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Some naturally occurring aldehydes and ketones

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Formalin, 35-40% formadehyde in waterPreservative that reacts with proteins causing them to resist decay Coelacanth, “prehistoric fish”

OH

Acrolein (2-propenal)

- lachrymator and pleasant "odor" from barbacuing meat

HCO

H

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Preparation of Carbonyls

1. Oxidation of Alcohols

Primary alcohols can be oxidized with pyridinium chlorochromate(PCC) to aldehydes. Ketones can be obtained from secondary alcohols by oxidation with sodium dichromate/sulfuric acid or KMnO4.

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Preparation of Carbonyls

2. Friedel Crafts AcylationAromatic ketones (acyl benzenes) can be produced from the reaction of benzenoid compounds with acyl chlorides, which are derived from carboxylic acids.

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Preparation of Carbonyls

3. Ozonolysis of AlkenesThe cleavage of an alkene with ozone produces carbonyl compounds. Recall that disubstituted double-bonded carbons become ketones and monosubstituted double-bonded carbons become aldehydes through ozonolysis.

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Preparation of Carbonyls 4. Aldehydes from Acid ChloridesAldehydes are easily oxidized to carboxylic acids but carboxylic acids are difficult to reduce to aldehydes. This difficulty is circumvented by converting a carboxylic acid into the more reactive acid chloride, which can be readily reduced to an aldehyde. Lithium tri-t-butoxyaluminum hydride is a mild reducing agent that displaces chloride with hydride to produce an aldehyde.

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Preparation of Carbonyls 4. Ketones from Acid Chlorides

Alkyl groups can replace the chlorine to produce ketones.

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A Grignard (or organolithium) reagent would react with an acid chloride to produce a ketone, but then the ketone would react immediately with additional Grignard reagent in the solution to form a tertiary alcohol. This problem is circumvented by using the weakest of the organometallicreagents, an organocuprate, which is too weak a nucleophile to add to a ketone.

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Reactions of Aldehydes and Ketones

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Addition to Carbonyls: Simple Nucleophile

Carbonyls readily undergo Nucleophilic Attack

OC

δ−

δ+OCNuc

OCNuc

H

Nuc

H+

Alkoxide Alcohol

Aldehyde is more reactive than ketone

OC

R H

δ−

δ+OC

R R

δ−

δ+

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1. Reduction of CarbonylsThe most useful reagents for reducing aldehydes and ketones are the metal hydride reagents.The two most common metal hydride reagents are sodium borohydride (NaBH4) and lithium aluminum hydride (LiAlH4). These reagents contain a polar metal-hydrogen bond that serves as a source of the nucleophile hydride, H:-. LiAlH4 is a stronger reducing agent than NaBH4, because the Al-H bond is more polar than the B-H bond.

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MECHANISM LiAlH4 Reduction of RCHO and R2C=O

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2. Reaction of Carbonyls with Cyanide Ion• The reaction is conducted using sodium cyanide at pH 10 to yield

cyanohydrin.

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Addition to Carbonyls: Primary Amines and Alcohols1. Addition of primary amimes

Condensation Reaction – Elimination of water

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Reaction between an amine and a carbonyl compound

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General reactionGeneral reaction

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DNP test for aldehydes & ketones gives crystalline hydrazones

C OCH3

CH3

N NH H

H

O2N

O2NC N

CH3

CH3

NH

NO2

NO2

+

2,4-diphenylhydrazine

acetonehydrazone of acetone

- H2O

2,4-dinitrophenylhydrazine orange crystals

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Nucleophilic Addition of Hydrazine:The Wolff-Kishner Reduction

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Mechanism: The Wolff-Kishner Reduction

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Addition to Carbonyls: Primary Amines and Alcohols2. Addition of alcohols

Weak nucleophiles “Acid catalyzed”

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Mechanism ofhemiacetal formation

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Mechanism of acetal formation

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Addition to Carbonyls: Carbanions

Carbanion : strong Nucleophile- Grignard reagent : an organomagnesium bromide (RMgBr or ArMgBr). - Organolithium compounds (RLi and ArLi)

1. Addition of Grignard reagents

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Professor Victor Grignard (1912 Nobel Prize)Developed this chemistry with Professor P. A. Barbier

CR X

H

H

X = I or Br

δ+ δ−CH

HMgXR δ− δ+

Grignard Reagent

Ether

RCH2

MgXMg

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MgBr

C OH

H

EtherCH

HO MgBr C

H

HO H

Benzylalcohol

H3O+

C O MgBr1.

Ether

C OH

Triphenylmethanol

2. H3O+

Grignard reagent add to carbonyls to give alcohols

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OC

H H

OC

R HOC

R R

MgIPh MgIPh MgIPh

OCH H

H

Ph

OCR H

H

Ph

OCR R

H

Ph

+ + +

Primary alcohols Secondary alcohols tertiary alcohols

KetoneAldehydesFormaldehyde

Nucleophilic Addition Reactions

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CR X

H

H

X = I or Br

δ+ δ−CH

HLiR δ− δ+ RCH2

Li

Organolithium Reagent

Li

Ether

2. Addition of Organolithium compounds (RLi and ArLi)

C O

R Liδ+

δ−

δ−

δ+

CR OADDITION

Li

CR O

Protonation

H

Alcohol

H+

H2O

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Problems

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Problems

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Oxidation of AldehydesThe most common oxidation reaction of carbonyl compounds is the oxidation of aldehydes to carboxylic acids. A variety of oxidizing agents can be used, including CrO3, Na2Cr2O7, K2Cr2O7 and KMnO4. Aldehydes are also oxidized selectively in the presence of other functional groups using silver(I) oxide in aqueous ammonium hydroxide. This is called Tollens reagent. Because ketones have no H on the carbonyl carbon, they do not undergo this oxidation reaction.

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Problems

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Reactivity of Enolate Ions

CO

CH

α Base

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Reactivity of Enolate Ions

Reaction on carbon is more common.

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1. Haloform reactionIf excess base and halogen are used, a methyl ketone is triply halogenated and then cleaved by base in the haloform reaction. The product are carboxylic and haloform.

+ -CX3

+CHX3

haloform

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2. Alkylation of Enolate Ionsเกิดขึ้นไดกับ ketone ที่มี α-hydrogen โดยทําปฏิกิริยากับเบสจะให enolate ion ซึ่งสามารถทําปฏิกิริยาไดอยางรวดเร็วกับ alkyl halide เกิดสารผลิตภัณฑคือ α- alkylketone

LDA = lithium diisopropylamide

C CH

O 1) LDA, THF2) R-X

ketone

C CR

O

α-alkylketone

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3. Aldol Condensationเกิดเมื่อ aldehyde หรือ ketone ที่มี α-hydrogen เปลี่ยนเปน enolate ion และทําหนาที่เปน nucleophile เพิ่มเขาไปที่ aldehyde หรือ ketone อีกโมเลกุลหนึ่ง เกิดสารผลิตภัณฑคือ β-hydroxy carbonyl หรือที่เรียกกันวา aldol (aldehyde + alcohol)

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Mechanism: Aldol Condensation

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สาร β-hydroxy aldehyde หรือ ketone ที่เกิดขึ้น ถายังมี α-hydrogen เหลืออยูจะสูญเสียโมเลกุลของน้ําไดงายโดยเกิดเปนสารที่ไมอิ่มตัวโดยมีพันธะที่ตําแหนง α,β เรียกวา α,β-unsaturated aldehyde หรือ ketone ซึง่สารที่เกิดขึ้นนี้เปนสารที่เสถียรมีการเคลื่อนที่ของ electron ไปไดทั่วทั้ง 4 atom

+ H2O

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Crossed Aldol Condensationเกิดระหวาง aldehyde หรือ ketone ตางชนิดกัน สวนใหญมักเลือกใหสารหนึ่งมี α-hydrogen และอีกสารหนึ่งไมมี α-hydrogen เพือ่ปองกันการเกิดผลิตภัณฑหลายชนิดผสมกัน

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Problem : จงเลือกสารตั้งตนที่ใชสําหรับสังเคราะหสารในแตละขอตอไปนี้

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CARBOXYLIC ACIDS

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Carboxylic Acids

OC

O H H2O+

OC

O H3O+

pKa = 4 - 5 , water = 16

OC

O H NaOH+

OC

OH2O

Na

Benzoic acid Sodium Benzoate

ClCClCl

COH

O HCClCl

COH

OHCClH

COH

O HCHH

COH

O

pKa = 0.7 1.48 2.86 4.76

Carboxylic acids are strong organic acids

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Highly PolarLow molecular weight acids show Appreciable Solubility in Water

High B.p.– Extensive H-bonds to themselves and water

Carboxylic Acids

Methanoic acid

Ethanoic acid

4-Bromo-2-ethylpentanoic acidrhubarbRed ants

O

H OH

Vinegar

O

H3C OH

Acetic acid

O

OH

OCH3

OAspirin

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Reactions of Carboxylic Acids

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Conversion of RCOOH to RCOClCarboxylic acids can't be converted to acid chlorides by using Cl- as a nucleophile, because the attacking nucleophile Cl- is a weaker base than the departing leaving group, -OH. But carboxylic acids can be converted to acid chlorides using thionyl chloride, SOCl2.

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Mechanism

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Conversion of RCOOH to (RCO)2OCarboxylic acids cannot be readily converted to anhydrides, but dicarboxylic acid can be converted to cyclic anhydrides by heating to high temperatures. This is a dehydration reaction because a water molecule is lost from the diacid.

OHOH

O

O

O

O

O

+ H2O

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Conversion of RCOOH to RCOORTreatment of a carboxylic acid with an alcohol in the presence of an acid catalyst forms an ester. This reaction is called a Fischer esterification.

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Mechanism

R OH

O

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Esterification of a carboxylic acid occurs in the presence of acid but not in the presence of base. Base removes a proton from the carboxylic acid, forming a carboxylate anion, which does not react with an electron-rich nucleophile.

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Intramolecular esterification of γ- and δ-hydroxy carboxylic acids forms five- and six-lactones.

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Draw the products of each reaction

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Conversion of RCOOH to RCONR’2The direct conversion of a carboxylic acid to an amide with NH3 or an amine is very difficult. The problem is that carboxylic acids are strong organic acids and NH3 and amines are bases, so they undergo an acid-base reaction to form an ammonium salt before any nucleophilic substitution occurs.

The overall conversion of RCOOH to RCONH2 requires two steps:[1] Acid-base reaction of RCOOH with NH3 to form an ammonium salt [2] Dehydration at high temperature (>100 oC)

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A carboxylic acid and an amine readily react to form an amide in the presence of an additional reagent, dicyclohexylcarbodiimide (DCC), which is converted to the by-product dicyclohexylurea in the course of the reaction.

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Mechanism

R OH

O

R'NH2

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Cleaning Action of Soaps