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Chapter 1: Carbonyl Chemistry Aldehydes and Ketones

Organic Chemistry II Associate ProfessorPhan Minh Giang

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Aldehydes and Ketones

Organic Chemistry II

Classification of carbonyl compounds

Aldehydes and Ketones

IUPAC nomenclature of aldehydes and ketonesMolecular structure and Reactivity of carbonyl group

Nucleophil ic addition to teh carbonyl group

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Natural Aldehydes and Ketones


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Aldehydes-Ketones


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IUPAC Nomenclature


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IUPAC Nomenclature


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Common Names


common name(IUPAC name) ( )

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Radico-functional Names


Radico-functional names of ketones: alkyl alkyl ketone.

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Molecular Structure and Reactivi ty


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Molecular Structure and Reactivi ty


water solubili ty

solubilit y in alcohols

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Nucleophilic Additions


1) Nucleophilic addition to carbon-oxygen double bond

General mechanism

type 1: strong (ionic Nu ) nucleophiles

type 2: weak (neutral NuH, Nu2

H) nucleophiles

Nucleophiles in the addition reactions

O-nucleophiles (H2O, ROH)

N-nucleophiles (ammonia derivatives)

H-nucleophiles (metal hydrides)

C-nucleophiles (organometalic compounds)

2) Relative reactivity: aldehydes and ketones3) Reversibility of the nucleophilic addition

4) Irrevesible addition of hydride reducing agents (NaBH4 and

LiAlH4) and organometallic reagents (RMgX, RLi)

5) Subsequent reactions of the nucleophilic addition: water

elimination (N-nucleophiles)

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Nucleophilic Addition to >C=O Double Bond


sp2

sp2

Nuc: nucleophile (species with lone pair of electrons) _

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Nucleophilic Addition


1. Reversibility of the nucleophilic additions

2. Subsequent reactions of addit ion products

C

R

R'

Nu

OH

C

R

R'

C

R

R'

O C

R

R'

Nu

O

H+

H2O Nu

addition product

condensation product(addition-elimination)

Nu:

for O-, H-, or C-

nucleophiles

for N-nucleophiles

tetrahedralintermediatealdehydeketone

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C

R

R 1

O

Nu:

C

Nu

R

R 1

O

H Nu

Nu:

C

Nu

R

R 1

O H

Type 1: Strong nucleophiles

Nu = ions hydroxide or alkoxide

Irreversible addition reactions

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Type 2: Weak nucleophiles (Reversible nucleophiles)

C

R

R 1

OH C

Nu

R R 1

OH

H Nu:

C

Nu

R R 1

O H

C

R

R 1

O

H A

C

R

R 1

OH C

R

R 1

OH

H

:A

A:

HA

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Note: The role of lone pairs on oxygen. The oxygen atom is a strong Lewis base.

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(Metal hydride)

Summary of nucleophilic additions

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Relative Reactivity


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Relative Reactivity


Electronic

Steric Effects

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Relative Reactivity


Steric effect

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Synthesis of Aldehydes and Ketones


1. Ozonolysis of alkenes

2. Mercuric-catalyzed hydration of alkynes

3. Friedel-Crafts acylationC-C bond formation method

4. Oxidation of primary and secondary alcohols

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1) Ozonolysis of alkenes

Example

You can use in the second reduction step: Zn/H2O or Zn/H3O+ .

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2) Mercuric-catalyzed hydration of alkynes

Example

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Hydroboration-Oxidation

1. Sia BH2

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3) Friedel-Crafts acylation

Example

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4) Oxidation of pr imary and secondary alcohols

Example

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1) Hydration (addition of water) (O-nucleophile):

Formation of hydrates (gem-diols or 1,1-diols)2) Addition of alcohols (O-nucleophile):

Formation of semi-acetals (hemi-acetals) and acetals

3) Cyclic acetals as protecting group

4) Hydrocyanation (C-nucleophile):

Formation of cyanohydrins5) Addit ion of ammonia derivatives (N-nucleophiles):

Formation of imines

Reversible nucleophiles

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Hydrates, Semiacetals, and Acetals


O

HO

HO

OH

OH

Sucrose

OR

OR

O

OH

OH

O

CH2OH

OH

O

HO

HO

OH

OH

OH

(+)-GlucoseOH

OR

Carbohydrates: Natural semi-acetals and acetals

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Hydration of Aldehydes and Ketones


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Hydration of Aldehydes and Ketones


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Formation of Semiacetals (Hemiacetals)


semiacetal

Most stable semiacetals are from aldehydes or cyclic ketones

acetal (IUPAC)

(common)

acid-catalyzed (L.A. = Lewis Acid) and

base-catalyzed reactions

RO-

RO -

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Acid-catalyzed Formation of Semiacetals


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Stable Cyclic Semiacetals


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Carbohydrates (Sugars)


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Formation of Acetals


Problem: Explain why semiacetals, but not acetals, are formed under basic conditions?

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Mechanism of Formation of Acetals


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Formation of Acetals from Semiacetals


From semiacetal to acetal: acid-catalyzed step

resonance-

stabilized

cation

semiacetal

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Synthetic Strategy: Acetals as Protecting Groups


Cyclic acetals are stable in basic medium.

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Ethylene glycol is a common reagent for the protection of aldehydes and

ketones. Carbonyl groups can be protected by converting them into their

acetal forms, and then regenerating them as needed.

O

excess ROHacid catalysis

X

O

Y

OR

X

OR

reagent Y inbase-catalyzed reaction OR

Y

OR

excess wateracid catalysis

Cyclic acetals:- Easy to be formed

- Easy to be removed

- Stable with basic and nucleophilic reagents

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Draw mechanism of the formation of the cyclic acetal.

lone-pair assisted ionization

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Synthetic Strategy: Protecting Groups


Example Carbonyl compounds can be protected by converting them into

their acetal forms, and then regenerating them as needed.

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Example

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Hydrolysis of Acetals


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Hydrolysis of Acetals


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Formation of Cyanohydrin


-hydroxycarboxylic acid

-hydroxyamine

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Cyanohydrin Formation


Example

steric hindrancepoor electrophilicicty

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Formation of Imines


Example

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Formation of Imines


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Mechanism of Imine Formation


Mechanism


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Formation of Imines



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Condensation with Amine Derivatives


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Oximes and Hydrazones


Wolff-Kishner Reduction

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Wolff-Kishner Reduction


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Mechanistic Problems


Problem: Write a mechanism for the following reaction.

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Mechanistic Problems


Problem: Write a mechanism for the following reaction.

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Reduction and Oxidation


1) Metal hydride reduction (H-nucleophiles)

NaBH4LiAlH4

2) Oxidation of aldehydes and ketones

Irreversible nucleophiles

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Metal Hydride Reduction


Hydride reducing agents (Metal hydrides)

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Reduct ion mechanism with NaBH4

O i Ch i t II

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Reduct ion mechanism with LiAlH4

O i Ch i t II

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Clemmensen and Wolff-Kishner Reduction


Clemmensen

reduction Wolff-Kishner

reduction

one step reduction

two step reduction

Example: Complete the reductions by filling in your products.

O i Ch i t II

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Selectivity

O i Ch i t II

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Oxidation of Aldehydes


General

strong oxidant

weak oxidant


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Reducing and Nonreducing Sugars


D-Glucose: Semiacetal formationby the intramolecular reaction

Reducing sugars:

positive tests with

Tollens reagent

(aqueous solution of

silver nitrate andammonia) and

Benedict’s reagent

(aqueous solution of

copper (II) hydroxide and

sodium citrate)

reducing sugar


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Oxidation of Ketones


heat

strong oxidant

C-C bond break

Baeyer-Villiger

rearrangement


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Reactions of Multi-functional Compounds


Problem: Give the structures of the major products formed when citronellal is

treated with each of the following reagents.


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Reactions of Multi-functional Compounds



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Organometallic Reactions (C-nucleophiles)


Carbanions (C-nucleophiles)

The nature of carbon-metal bond: ionic/covalent.

The carbon can be sp3

, sp2

or sp.1) Grignard reagents

Alkylmagnesium halide: R-MgX

Alkenyl and aryl Grignard reagents: C=CH-MgX, Ar-MgX

Alkynyl Grignard reagents: CC-MgX

2) Organolithium compounds

Alkyllithium: R-Li

Alkenyl lithium: C=CH-Li

Alkynyl lithium: CC-Li

Irreversible nucleophiles


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Organometallic Reactions


• The Grignard reaction is an organometallic chemical reaction in which

alkyl, vinyl, or aryl magnesium halides (Grignard reagents) add to a

carbonyl group in an aldehyde or ketone.

• Grignard reagents are similar to organolithium reagents because both

are strong nucleophiles that can form new carbon–carbon bonds.

Grignard reactions and reagents were

discovered by the French chemist Francois

Auguste Victor Grignard (University of Nancy,

France), Nobel Prize in Chemistry in 1912.


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Organometallic Reactions


Preparation of Grignard reagents


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Organometallic Reactions (C-nucleophiles)


Alcohols f rom Grignard reagents

1) Primary alcohols from formaldehyde

2) Secondary alcohols from aldehydes

3) Tertiary alcohols from ketones4) Carboxylic acids from carbon dioxide


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Retrosynthetic Analysis


Retrosynthetic analysis (Disconnection approach):

sequentially break bonds (i.e. diconnect atoms) within

a target structure to reveal the simpler structures.


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Wittig Reaction: Synthesis of Alkenes

g y

The Wittig reaction was discovered in 1954

by George Wittig, for which he was awarded

the Nobel Prize in Chemistry in 1979.

The Witt ig reaction or Wittig olefination is a chemical reaction of an

aldehyde or ketone with a triphenylphosphonium ylide (often called a

Wittig reagent) to give an alkene and triphenylphosphine oxide.


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g y

Retrosynthetic analysis

target molecule


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Wittig Reaction

g y


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Mechanism of Wittig Reaction

g y

R

R

Phosphonium ylides


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Retrosynthetic analysis


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Stereoselectivity of the Nucleophilic Addition

• Stereoselectivity: the preferential formation of one (or more)

products that differ only in their configuration.

• Stereoselectivity can be subdivided into enantioselectivity and

diastereoselectivity.

• Diastereoselectivity occurs when the products which can beformed are diastereomers.

Diastereoselectivity of the Addition of Hydride and

Organometallic Reagents to -Chiral Carbonyl Group


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Stereoselectivity of the Nucleophilic Addition

When an achiral nucleophilic reagent adds to an achiral aldehyde or

simple acyclic unsymmetrical ketone, a chiral center is formed, but the

two enantiomers are formed in equal amounts.


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Diastereoselectivity of the Nucleophilic Addition

If a chiral center already exists near the carbonyl group, there are

two possible diastereomeric products, and these are in general not

formed in equal amounts.


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If the substrate is chiral then two diastereomeric transition states occur with

the result that two diastereomeric products are formed in unequal amounts.



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• Kinetic nucleophiles (rate control, irriversible): metal hydrides and

organometallic compounds.

• -Chiral carbonyl compounds: carbonyl compounds that contain a

stereocenter in the position to the carbonyl group.

• Cram rule (steric factor): the carbonyl group and the largest substituent

L are placed anti in Newman projection. Group M is of intermediate size

and group S is smallest size.

• Cram chelate model: an -substituent (O or N) and the carbonyl oxygen

chelate a metal cation.

• Felkin-Ahn model: L distances equally from R group and the carbonylgroup, S is close to the trajectory of the nucleophile.

Diastereoselectivity of the Nulceophilic Addition


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Cram model: hydrocarbon groups or hydrogen at C

Cram chelate model: O- or N-atom at C

and carbonyl group chelate ametal cation

Felkin-Ahn model: O- or N-atom attached to C, non-chelated state



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The group containing a heteroatom on the adjacent carbon

atom is held syn coplanar to the carbonyl group


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Diastereoselectivity of the Addition of Organometallic


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Diastereoselectivity of the Addition of Hydride


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Chapter Test: Review 2

Topics

1) IUPAC nomenclature of aldehydes and ketones

2) Synthesis of aldehydes and ketones3) Nucleophilic addition reactions of aldehydes and ketones

4) Synthesis of alcohols and alkenes from aldehydes and ketones

5) Carbon-carbon bond formation: Retrosynthetic analysis of target

products (methods using organometallic reagents and Wittig reaction)

6) Oxidation-reduction reactions of aldehydes and ketones.

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