Organic Chemistry, 5th ed. Marc Loudon Chapter 19 The Chemistry of Aldehydes and Ketones. Carbonyl-Addition Reactions Eric J. Kantorowski California Polytechnic State University San Luis Obispo, CA

Chapter 19 Overview 19.1 Nomenclature of Aldehydes and Ketones 19.2 Physical Properties of Aldehydes and Ketones 19.3 Spectroscopy of Aldehydes and Ketones 19.4 Synthesis of Aldehydes and Ketones 19.5 Introduction to Aldehyde and Ketone Reactions 19.6 Basicity of Aldehydes and Ketones 19.7 Reversible Addition Reactions of Aldehydes and Ketones 19.8 Reduction of Aldehydes and Ketones to Alcohols 19.9 Reactions of Aldehydes and Ketones with Grignard and Related Reagents 19.10 Acetals and Their Use of Protecting Groups

Chapter 19 Overview 19.11 Reactions of Aldehydes and Ketones with Amines 19.12 Reduction of Carbonyl Groups to Methylene Groups 19.13 The Wittig Alkene Synthesis 19.14 Oxidation of Aldehydes to Carboxylic Acids 19.15 Manufacture and Use of Aldehydes and Ketones

Aldehydes and ketones have the following general structure Carbonyl Compounds Aldehydes and ketones have the following general structure 19.1 Nomenclature of Aldehydes and Ketones

Carbonyl Compounds 19.1 Nomenclature of Aldehydes and Ketones

Common Nomenclature 19.1 Nomenclature of Aldehydes and Ketones

Prefixes Used in Common Nomenclature 19.1 Nomenclature of Aldehydes and Ketones

Common Nomenclature 19.1 Nomenclature of Aldehydes and Ketones

Substitutive Nomenclature 19.1 Nomenclature of Aldehydes and Ketones

Substitutive Nomenclature 19.1 Nomenclature of Aldehydes and Ketones

Most simple aldehydes and ketones are liquids Physical Properties Most simple aldehydes and ketones are liquids 19.2 Physical Properties of Aldehydes and Ketones

Strong C=O stretch: 1700 cm-1 IR Spectroscopy Strong C=O stretch: 1700 cm-1 19.3 Spectroscopy of Aldehydes and Ketones

Conjugation with a p bond lowers the absorption frequency IR Spectroscopy Conjugation with a p bond lowers the absorption frequency 19.3 Spectroscopy of Aldehydes and Ketones

IR Spectroscopy The C=O stretching frequency in small-ring ketones is affected by ring size 19.3 Spectroscopy of Aldehydes and Ketones

However, the electronegative O increases this shift farther downfield 1H NMR Spectroscopy The reason for the large d value for aldehydic protons is similar to that for vinylic protons However, the electronegative O increases this shift farther downfield 19.3 Spectroscopy of Aldehydes and Ketones

Aldehyde and ketone C=O: d 190-220 a-Carbons: d 30-50 13C NMR Spectroscopy Aldehyde and ketone C=O: d 190-220 a-Carbons: d 30-50 19.3 Spectroscopy of Aldehydes and Ketones

p → p*: 150 nm (out of the operating range) UV/Vis Spectroscopy p → p*: 150 nm (out of the operating range) n → p*: 260-290 nm (much weaker) 19.3 Spectroscopy of Aldehydes and Ketones

UV/Vis Spectroscopy 19.3 Spectroscopy of Aldehydes and Ketones

Mass Spectrometry 19.3 Spectroscopy of Aldehydes and Ketones

What accounts for the m/z = 58 peak? Mass Spectrometry What accounts for the m/z = 58 peak? 19.3 Spectroscopy of Aldehydes and Ketones

There must be an available g-H Mass Spectrometry The McLafferty rearrangement involves a hydrogen transfer via a transient six-membered ring There must be an available g-H 19.3 Spectroscopy of Aldehydes and Ketones

Summary of Aldehyde and Ketone Preparation 1. Oxidation of alcohols 2. Friedel-Crafts acylation 3. Hydration of alkynes 4. Hydroboration-oxidation of alkynes 5. Ozonolysis of alkenes 6. Periodate cleavage of glycols 19.4 Synthesis of Aldehydes and Ketones

Carbonyl-Group Reactions Reactions with acids Addition reactions Oxidation of aldehydes 19.5 Introduction to Aldehyde and Ketone Reactions

Basicity of Aldehydes and Ketones The carbonyl oxygen is weakly basic One resonance contributor reveals that carbocation character exists The conjugate acids of aldehydes and ketones may be viewed as a-hydroxy carbocations 19.6 Basicity of Aldehydes and Ketones

Basicity of Aldehydes and Ketones a-hydroxy and a-alkoxy carbocations are significantly more stable than ordinary carbocations (by ~100 kJ mol-1) 19.6 Basicity of Aldehydes and Ketones

Addition Reactions One of the most typical reactions of aldehydes and ketones is addition across the C=O 19.7 Reversible Addition Reactions of Aldehydes and Ketones

Mechanism of Carbonyl-Addition Reactions 19.7 Reversible Addition Reactions of Aldehydes and Ketones

Addition Reactions The addition of a nucleophile to the carbonyl carbon is driven by the ability of oxygen to accept the unshared electron pair 19.7 Reversible Addition Reactions of Aldehydes and Ketones

The nucleophile attacks the unoccupied p* MO (LUMO) of the C=O Addition Reactions The nucleophile attacks the unoccupied p* MO (LUMO) of the C=O 19.7 Reversible Addition Reactions of Aldehydes and Ketones

Addition Reactions The second mechanism for carbonyl addition takes place under acidic conditions 19.7 Reversible Addition Reactions of Aldehydes and Ketones

Equilibria in Carbonyl-Addition Reactions The equilibrium for a reversible addition depends strongly on the structure of the carbonyl compound 1. Addition is more favorable for aldehydes 2. Addition is more favorable if EN groups are near the C=O 3. Addition is less favorable when groups that donate electrons by resonance to the C=O are present 19.7 Reversible Addition Reactions of Aldehydes and Ketones

Equilibrium Constants for Hydration 19.7 Reversible Addition Reactions of Aldehydes and Ketones

Relative Carbonyl Stability 19.7 Reversible Addition Reactions of Aldehydes and Ketones

For example, alkyl groups stabilize carbocations more than hydrogens Carbonyl Stability Any feature that stabilizes carbocations will impart greater stability to the carbonyl group For example, alkyl groups stabilize carbocations more than hydrogens Hence, alkyl groups will discourage addition reactions to the carbonyl group 19.7 Reversible Addition Reactions of Aldehydes and Ketones

Resonance can also add stability to the carbonyl group Carbonyl Stability Resonance can also add stability to the carbonyl group However, EN groups make the addition reaction more favorable 19.7 Reversible Addition Reactions of Aldehydes and Ketones

Rates of Carbonyl-Addition Reactions Relative rates can be predicted from equilibrium constants Compounds with the most favorable addition equilibria tends to react most rapidly General reactivity: formaldehyde > aldehydes > ketones 19.7 Reversible Addition Reactions of Aldehydes and Ketones

Reduction with LiAlH4 and NaBH4 19.8 Reduction of Aldehydes and Ketones to Alcohols

LiAlH4 serves as a source of hydride ion (H:-) Reduction with LiAlH4 LiAlH4 serves as a source of hydride ion (H:-) LiAlH4 is very basic and reacts violently with water; anhydrous solvents are required 19.8 Reduction of Aldehydes and Ketones to Alcohols

Like other strong bases, LiAlH4 is also a good nucleophile Reduction with LiAlH4 Like other strong bases, LiAlH4 is also a good nucleophile Additionally, the Li+ ion is a built-in Lewis-acid 19.8 Reduction of Aldehydes and Ketones to Alcohols

Each of the remaining hydrides become activated during the reaction Reduction with LiAlH4 Each of the remaining hydrides become activated during the reaction 19.8 Reduction of Aldehydes and Ketones to Alcohols

Hydrogen bonding then serves to activate the carbonyl group Reduction with NaBH4 Na+ is a weaker Lewis acid than Li+ requiring the use of protic solvents Hydrogen bonding then serves to activate the carbonyl group 19.8 Reduction of Aldehydes and Ketones to Alcohols

Reduction with LiAlH4 and NaBH4 Reactions by these and related reagents are referred to as hydride reductions These reactions are further examples of nucleophilic addition 19.8 Reduction of Aldehydes and Ketones to Alcohols

Selectivity with LiAlH4 and NaBH4 NaBH4 is less reactive and hence more selective than LiAlH4 LiAlH4 reacts with alkyl halides, alkyl tosylates, and nitro groups, but NaBH4 does not 19.8 Reduction of Aldehydes and Ketones to Alcohols

Reduction by Catalytic Hydrogenation Hydride reagents are more commonly used However, catalytic hydrogenation is useful for selective reduction of alkenes 19.8 Reduction of Aldehydes and Ketones to Alcohols

Grignard Addition Grignard reagents with carbonyl groups is the most important application of the Grignard reagent in organic chemistry 19.9 Reactions of Aldehydes and Ketones with Grignard and Related Reagents

The addition is irreversible due to this basicity Grignard Addition R-MgX reacts as a nucleophile; this group is also strongly basic behaving like a carbanion The addition is irreversible due to this basicity 19.9 Reactions of Aldehydes and Ketones with Grignard and Related Reagents

Organolithium and Acetylide Reagents These reagents react with aldehydes and ketones analogous to Grignard reagents 19.9 Reactions of Aldehydes and Ketones with Grignard and Related Reagents

Importance of the Grignard Addition This reaction results in C-C bond formation The synthetic possibilities are almost endless 19.9 Reactions of Aldehydes and Ketones with Grignard and Related Reagents

Importance of the Grignard Addition 19.9 Reactions of Aldehydes and Ketones with Grignard and Related Reagents

Preparation and Hydrolysis of Acetals Acetal: A compound in which two ether oxygens are bound to the same carbon 19.10 Acetals and Their Use of Protecting Groups

Preparation and Hydrolysis of Acetals Use of a 1,2- or 1,3-diol leads to cyclic acetals Only one equivalent of the diol is required 19.10 Acetals and Their Use of Protecting Groups

Preparation and Hydrolysis of Acetals 19.10 Acetals and Their Use of Protecting Groups

Preparation and Hydrolysis of Acetals Acetal formation is reversible The presence of acid and excess water allows acetals to revert to their carbonyl form Acetals are stable in basic and neutral solution 19.10 Acetals and Their Use of Protecting Groups

Hemiacetals normally cannot be isolated Exceptions include simple aldehydes and compounds than can form 5- and 6-membered rings 19.10 Acetals and Their Use of Protecting Groups

Hemiacetals 19.10 Acetals and Their Use of Protecting Groups

Protecting Groups A protecting group is a temporary chemical disguise for a functional group preventing it from reacting with certain reagents 19.10 Acetals and Their Use of Protecting Groups

Protecting Groups 19.10 Acetals and Their Use of Protecting Groups

Reactions with Primary Amines Imines are sometimes called Schiff bases 19.11 Reactions of Aldehydes and Ketones with Amines

Reactions with Primary Amines The dehydration of water is typically the rate-limiting step 19.11 Reactions of Aldehydes and Ketones with Amines

Derivatives Before the advent of spectroscopy, aldehydes and ketones were characterized as derivatives 19.11 Reactions of Aldehydes and Ketones with Amines

Some Imine Derivatives 19.11 Reactions of Aldehydes and Ketones with Amines

Reactions with Secondary Amines Like imine formation, enamine formation is reversible 19.11 Reactions of Aldehydes and Ketones with Amines

Reactions with Secondary Amines 19.11 Reactions of Aldehydes and Ketones with Amines

Reactions with Tertiary Amines Tertiary amines do not react with aldehydes or ketones to form stable derivatives They are good nucleophiles, but the lack of an N-H prevents conversion to a stable compound 19.11 Reactions of Aldehydes and Ketones with Amines

Reduction of Aldehydes and Ketones Complete reduction to a methylene (-CH2-) group is possible by two different methods Wolff-Kishner reduction: 19.12 Reduction of Carbonyl Groups to Methylene Groups

Reduction of Aldehydes and Ketones The Wolff-Kishner reduction takes place under highly basic conditions It is an extension of imine formation 19.12 Reduction of Carbonyl Groups to Methylene Groups

Reduction of Aldehydes and Ketones Clemmensen reduction: This reduction occurs under acidic conditions The mechanism is uncertain 19.12 Reduction of Carbonyl Groups to Methylene Groups

The Wittig Alkene Synthesis This reaction is completely regioselective, assuring the location of the alkene 19.13 The Wittig Alkene Synthesis

The Wittig Alkene Synthesis Occurs via an addition-elimination sequence using a phosphorous ylide An ylid (or ylide) is any compound with opposite charges on adjacent, covalently bound atoms 19.13 The Wittig Alkene Synthesis

The Wittig Alkene Synthesis

Preparation of the Wittig Reagent Any alkyl halide that readily participates in SN2 reactions can be used 19.13 The Wittig Alkene Synthesis

The Wittig Alkene Synthesis Retrosynthetically Stereochemistry 19.13 The Wittig Alkene Synthesis

Carboxylic Acids from Aldehydes The hydrate is the species oxidized 19.14 Oxidation of Aldehydes to Carboxylic Acids

Carboxylic Acids from Aldehydes This is known as the Tollen’s test A positive indicator for an aldehyde is the deposition of a metallic silver mirror on the walls of the reaction flask 19.14 Oxidation of Aldehydes to Carboxylic Acids

Production and Use of Aldehydes The most important commercial aldehyde is formaldehyde Its most important use is in the synthesis of phenol-formaldehyde resins 19.15 Manufacture and Use of Aldehydes and Ketones

Production and Use of Ketones The most important commercial ketone is acetone It is co-produced with phenol by the autoxidation-rearrangement of cumene 19.15 Manufacture and Use of Aldehydes and Ketones