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Chapter 16

Aldehydes & Ketones:

Nucleophilic Addition

to the Carbonyl Group

Created by

Professor William Tam & Dr. Phillis Chang

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1. Introduction

Carbonyl compounds

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Rules

Aldehyde as parent (suffix)

Ending with “al”;

Ketone as parent (suffix)

Ending with “one”

Number the longest carbon chain containing the carbonyl carbon, starting at the carbonyl carbon

2. Nomenclature of Aldehydes &�Ketones

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Examples

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group as a prefix: methanoyl or formyl group

group as a prefix: ethanoyl or acetyl group (Ac)

groups as a prefix: alkanoyl or acyl groups

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3. Physical Properties

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4A. Aldehydes by Oxidation of 1^o �Alcohols

4. Synthesis of Aldehydes

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e.g.

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4B. Aldehydes by Ozonolysis of�Alkenes

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e.g.

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4C. Aldehydes by Reduction of Acyl�Chlorides, and Esters

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LiAlH₄ is a very powerful reducing agent and aldehydes are easily reduced

Usually reduced all the way to the corresponding 1^o alcohol
Difficult to stop at the aldehyde stage

Not a good method to synthesize aldehydes using LiAlH₄

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Two aluminum hydride derivatives that are less reactive than LAH:

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Aldehydes from acyl chlorides: RCOCl → RCHO

e.g.

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Reduction of an Acyl Chloride to an Aldehyde

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Aldehydes from esters and nitriles: RCO₂R’ → RCHO

RC≡N → RCHO

Both esters and nitriles can be reduced to aldehydes by DIBAL-H

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Reduction of an ester to an aldehyde

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Reduction of a nitrile to an aldehyde

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Examples

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5A. Ketones from Alkenes, Arenes,�and 2^o Alcohols

Ketones (and aldehydes) by ozonolysis of alkenes

5. Synthesis of Ketones

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Examples

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Ketones from arenes by Friedel–Crafts acylations

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Ketones from secondary alcohols by oxidation

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5B. Ketones from Nitriles

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Examples

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Suggest synthesis of

from and

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Retrosynthetic analysis

need to add one carbon

5 carbons here

4 carbons here

⇒

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Retrosynthetic analysis

disconnection

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Synthesis

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Suggest synthesis of

from and

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Retrosynthetic analysis

no need to add carbon

5 carbons here

⇒

5 carbons here

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Retrosynthetic analysis

disconnection

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Synthesis

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Structure

Carbonyl carbon: sp² hybridized
Trigonal planar structure

Nu^⊖

6. Nucleophilic Addition to the�Carbon–Oxygen Double Bond

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Polarization and resonance structure

Nucleophiles will attack the electrophilic carbonyl carbon

Note: nucleophiles usually do not attack a non-polarized C=C bond

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With a strong nucleophile:

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Also would expect nucleophilic addition reactions of carbonyl compounds to be catalyzed by an acid (or Lewis acid)

Note: full positive charge on the carbonyl carbon in one of the resonance forms

Nucleophiles readily attack

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Mechanism

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Mechanism

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6A. Reversibility of Nucleophilic�Additions to the Carbon–Oxygen�Double Bond

Many nucleophilic additions to carbon–oxygen double bonds are reversible; the overall results of these reactions depend, therefore, on the position of an equilibrium

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6B. Relative Reactivity: Aldehydes,�Ketones, and Esters

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large

small

Steric factors

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Electronic factors

(positive inductive effect from only one R group)

(positive inductive effect from both R & R' groups) ⇒ carbonyl carbon less δ⁺ (less nucleophilic)

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6C. Addition Products Can Undergo Further Reactions

But

stable product: isolable

unstable

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Hemiacetal & Acetal Formation: Addition of Alcohols to Aldehydes

Catalyzed by acid

7. The Addition of Alcohols:�Hemiacetals and Acetals

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Mechanism

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Mechanism (Cont’d)

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Mechanism (Cont’d)

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Note: All steps are reversible. In the presence of a large excess of anhydrous alcohol and a catalytic amount of acid, the equilibrium strongly favors the formation of acetal (from aldehyde) or ketal (from ketone).
On the other hand, in the presence of a large excess of H₂O and a catalytic amount of acid, the acetal or ketal will hydrolyze back to aldehyde or ketone. This process is called hydrolysis.

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Acetals and ketals are stable in neutral or basic solution, but are readily hydrolyzed in aqueous acid

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Aldehyde hydrates: gem-diols

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Mechanism

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Hemiacetal: OH & OR groups bonded to the same carbon

7A. Hemiacetals

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Hemiacetal: OH & OR groups bonded to the same carbon

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An acetal

A ketal

7B. Acetals

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Cyclic acetal formation is favored when a ketone or an aldehyde is treated with an excess of a 1,2-diol and a trace of acid

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This reaction, too, can be reversed by treating the acetal with lots of an aqueous acid

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7C. Acetals Are Used as Protecting Groups

Although acetals are hydrolyzed to aldehydes and ketones in aqueous acid, acetals are stable in basic solutions

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Acetals are used to protect aldehydes and ketones from undesired reactions in basic solutions

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Example

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Synthetic plan

This route will not work

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Reason:

(a) Intramolecular nucleophilic addition

(b) Homodimerization or polymerization

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Thus, need to “protect” carbonyl group first

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7D. Thioacetals

Aldehydes & ketones react with thiols to form thioacetals

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Thioacetal formation with subsequent “desulfurization” with hydrogen and Raney nickel gives us an additional method for converting carbonyl groups of aldehydes and ketones to –CH₂– groups

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Aldehydes & ketones react with 1^o amines to form imines and with 2^o amines to form enamines

From a 1^o amine

From a 2^o amine

8. The Addition of Primary and�Secondary Amines

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8A. Imines

Addition of 1^o amines to aldehydes & ketones

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Mechanism

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Similar to the formation of acetals and ketals, all the steps in the formation of imines are reversible. Using a large excess of the amine will drive the equilibrium to the imine side
Hydrolysis of imines is also possible by adding excess water in the presence of catalytic amount of acid

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8B. Oximes and Hydrazones

Imine formation – reaction with a 1^o amine

Oxime formation – reaction with hydroxylamine

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Hydrazone formation – reaction with hydrazine

Enamine formation – reaction with a 2^o amine

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8C. The Wolff-Kishner Reduction

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Mechanism

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8D. Enamines

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Mechanism

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Mechanism (Cont’d)

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Mechanism (Cont’d)

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Addition of HCN to aldehydes & ketones

9. The Addition of Hydrogen�Cyanide: Cyanohydrins

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Mechanism

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Slow reaction using HCN since HCN is a weak acid and a poor source of nucleophile
Can accelerate reaction by using NaCN or KCN and slow addition of H₂SO₄

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Synthetic applications

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10. The Addition of Ylides:�The Wittig Reaction

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Phosphorus ylides

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Example

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Mechanism of the Wittig reaction

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10A. How to Plan a Wittig Synthesis

Synthesis of

using a Wittig reaction

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Retrosynthetic analysis

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Synthesis – Route 1

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Synthesis – Route 2

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10B. The Horner–Wadsworth–Emmons Reaction: A Modification of the Wittig Reaction

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The phosphonate ester is prepared by reaction of a trialkyl phosphite [(RO)₃P] with an appropriate halide (a process called the Arbuzov reaction)

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11. Oxidation of Aldehydes

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12. The Baeyer-Villiger Oxidation

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Mechanism

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13A. Derivatives of Aldehydes & Ketones

13. Chemical Analyses for Aldehydes and Ketones

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13B. Tollens’ Test (Silver Mirror Test)