Aldehydes and Ketones II. NUCLEOPHILIC

ADDITIONS TO THE CARBONYL GROUP

OBJECTIVES

1. Describe the reactivity of carbonyl group towards the nucleophilic

addition (PAGE : 741)

2. Predict the products of cyanohydrin from synthesis of α-hydroxy acids

and hydrolysis of nitriles (PAGE : 755)

3. Predict the products from the addition of Organometallic Reagents

Grignard and alkyl lithium reagents) to aldehydes and ketones. (PAGE

: 566-568, 776)

4. Predict the products from the addition of water (hydration) to aldehydes

and ketones (PAGE : 746)

5.. Predict the products of acetals and hemiacetal from the addition of

Alcohols and describe the formation of cyclic acetals (PAGE : 748) and

its uses as protecting group. (PAGE : 749)

6. Predict the products from the addition of amines to aldehydes and

ketones which produce Imines from 1o Amines (PAGE : 751), Enamines

from 2o Amines (PAGE : 754), Enamines for Alkylation of Ketones

(PAGE : 755)

7. Predict the products from Wittig Reaction (PAGE : 757-760)

1. Describe the reactivity of carbonyl group towards the

nucleophilic addition (PAGE : 741)

Chapter 16 3

Chapter 16 4

Nucleophilic Addition to the Carbonyl

Groups o Addition of a nucleophile to a carbonyl carbon occurs because

of the d+ charge at the carbon

o Addition of strong nucleophiles such as hydride or Grignard

reagents result in formation of a tetrahedral alkoxide

intermediate H The carbonyl p electrons shift to oxygen to give the alkoxide

H The carbonyl carbon changes from trigonal planar to tetrahedral

Chapter 16 5

6

o acid catalyst is used to facilitate reaction of weak nucleophiles

with carbonyl groups Protonating the carbonyl oxygen enhances the electrophilicity of the carbon

REACTIVITY OF ALDEHYDE AND

KETONE

Chapter 16 7

Chapter 16 8

Relative Reactivity: Aldehydes versus Ketones

o Aldehydes are generally more reactive than ketones The tetrahedral carbon resulting from addition to an aldehyde is less

sterically hindered than the tetrahedral carbon resulting from addition

to a ketone

Aldehyde carbonyl groups are more electron deficient because they

have only one electron-donating group attached to the carbonyl

carbon

2. Predict the products of cyanohydrin from synthesis of

α-hydroxy acids and hydrolysis of nitriles (PAGE :

755)

Chapter 16 9

Chapter 16 10

The Addition of Hydrogen Cyanide (PAGE : 755)

Aldehydes and ketone react with HCN to form a

cyanohydrin

• A catalytic amount of cyanide helps to speed

the reaction

The cyano group can be hydrolyzed or reduced

• Hydrolysis of a cyanohydrin produces an a-

hydroxycarboxylic acid (Sec. 18.8H)

Chapter 16 11

Reduction of a cyanohydrin produces α b-

aminoalcohol

Chapter 16 12

3. Predict the products from the addition of

Organometallic Reagents Grignard and alkyl lithium

reagents) to aldehydes and ketones. (PAGE : 566-

568, 776)

Chapter 16 13

Chapter 12 14

Reaction of Grignard Reagents with Carbonyl Compounds

Nucleophilic attack of Grignard reagents at carbonyl carbons is the

most important reaction of Grignard reagents

Reaction of Grignard reagents with aldehydes and ketones

yields a new carbon-carbon bond and an alcohol

Chapter 16 15

Chapter 12 16

Alcohols from Grignard Reagents

Chapter 12 17

Alkyl Lithium Reagents

Organolithium reagents react similarly to Grignard

reagents

4. . Predict the products from the addition of water

(hydration) to aldehydes and ketones (PAGE : 746)

Chapter 16 18

Nucleophilic Addition of H2O:

Hydration Aldehydes and ketones react with water to yield

1,1-diols (geminal (gem) diols) :the term geminal refers to the relationship between two atoms or functional groups that are attached to the same atom.

Hyrdation is reversible: a gem diol can eliminate water

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

Acid-Catalyzed Addition of Water

Protonation of C=O makes

it more electrophilic

5. Predict the products of acetals and hemiacetal from

the addition of Alcohols and describe the formation of

cyclic acetals (PAGE : 748) and its uses as protecting

group. (PAGE : 749)

Chapter 16 22

• the addition of an alcohol nucleophile to a ketone or aldehyde.

• an alcohol adds to an aldehyde, the result is called a hemiacetal;

when an alcohol adds to a ketone the resulting product is

a hemiketal.

Chapter 16 23

Chapter 16 24

The Addition of Alcohols: Hemiacetals and

Acetals

Hemiacetals

An aldehyde or ketone dissolved in an alcohol will form an

equilibrium mixture containing the corresponding hemiacetal A hemiacetal has a hydroxyl and alkoxyl group on the same carbon

Acylic hemiacetals are generally not stable, however, cyclic five- and six-

membered ring hemiacetals are

Chapter 16 25

Hemiacetal formation is catalyzed by either acid or base

Chapter 16 26

Dissolving aldehydes (or ketones) in water causes formation of an

equilibrium between the carbonyl compound and its hydrate The hydrate is also called a gem-diol (gem i.e. geminal, indicates the presence of

two identical substituents on the same carbon)

The equilibrum favors a ketone over its hydrate because the tetrahedral ketone

hydrate is sterically crowded

Chapter 16 27

Acetals

è An aldehyde (or ketone) in the presence of excess alcohol and an

acid catalyst will form an acetal H Formation of the acetal proceeds via the corresponding hemiacetal

H An acetal has two alkoxyl groups bonded to the same carbon

Chapter 16 28

è Acetals are stable when isolated and purified

è Acetal formation is reversible H An excess of water in the presence of an acid catalyst will hydrolyze an acetal to

the corresponding aldehyde (or ketone)

Chapter 16 29

è Acetal formation from ketones and simple alcohols is less

favorable than formation from aldehydes H Formation of cyclic 5- and 6- membered ring acetals from ketones is, however,

favorable

H Such cyclic acetals are often used as protecting groups for aldehydes and

ketones

H These protecting groups can be removed using dilute aqueous acid

Chapter 16 30

Acetals as Protecting Groups

è Acetal protecting groups are stable to most reagents except

aqueous acid

è Example: An ester can be reduced in the presence of a ketone

protected as an acetal

6. Predict the products from the addition of amines to

aldehydes and ketones which produce Imines from 1o

Amines (PAGE : 751), Enamines from 2o Amines

(PAGE : 754), Enamines for Alkylation of Ketones

(PAGE : 755)

Chapter 16 31

Chapter 16 32

The Addition of Primary and Secondary Amines

Aldehydes and ketones react with primary amines

(and ammonia) to yield imines

• They react with secondary amines to yield

enamines

Chapter 16 33

Imines

These reactions occur fastest at pH 4-5

• Mild acid facilitates departure of the hydroxyl

group from the aminoalcohol intermediate

without also protonating the nitrogen of the

amine starting compound

Chapter 16 34

Chapter 16 35

Enamines

Secondary amines cannot form a neutral imine

by loss of a second proton on nitrogen

• An enamine is formed instead

Chapter 16 36

7. Predict the products from Wittig Reaction (PAGE :

757-760)

Chapter 16 37

Chapter 16 38

The Addition of Ylides: The Wittig Reaction

Aldehydes and ketones react with phosphorous

triphenyl phosphonium ylide to produce alkenes

• An ylide is a neutral molecule with adjacent

positive and negative charges

Chapter 16 39

Reaction of triphenylphosphine with a primary or

secondary alkyl halide produces a phosphonium salt

The phosphonium salt is deprotonated by a strong base to form

the ylide

Chapter 16 40

Addition of the ylide to the carbonyl leads to formation of a four-

membered ring oxaphosphetane

The oxaphophetane rearranges to the alkene and triphenylphosphine oxide

The driving force for the last reaction is formation of the very strong

phosphorus-oxygen double bond in triphenylphosphine oxide

Chapter 16 41

è Solved Problem: Make 2-Methyl-1-phenylprop-1-ene by a Wittig

reaction

Unlike elimination reactions (such as

dehydrohalogenation of alkyl halides), which

produce mixtures of alkene regioisomers

determined by Saytzeff's rule, the Wittig reaction

forms the double bond in one position with no

ambiguity.

Chapter 16 42