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Organic Chemistry. William H. Brown & Christopher S. Foote. Aldehydes & Ketones. Chapter 15. Chapter 16. The Carbonyl Group. In this and several following chapters we study the physical and chemical properties of classes of compounds containing the carbonyl group, C=O

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organic chemistry

Organic Chemistry

William H. Brown & Christopher S. Foote

aldehydes ketones
Aldehydes & Ketones

Chapter 15

Chapter 16

the carbonyl group
The Carbonyl Group
  • In this and several following chapters we study the physical and chemical properties of classes of compounds containing the carbonyl group, C=O
    • aldehydes and ketones (Chapter 16)
    • carboxylic acids (Chapter 17)
    • acid halides, acid anhydrides, esters, amides (Chapter 18)
    • enolate anions (Chapter 19)
the carbonyl group1
The Carbonyl Group
  • The carbonyl group consists of
    • one sigma bond formed by the overlap of sp2 hybrid orbitals, and
    • one pi bond formed by the overlap of parallel 2p orbitals
the carbonyl group2
The Carbonyl Group
  • pi bonding and pi antibonding MOs for formaldehyde.
structure
Structure
  • The functional group of an aldehyde is a carbonyl group bonded to a H atom and a carbon atom
  • The functional group of a ketone is a carbonyl group bonded to two carbon atoms
nomenclature
Nomenclature
  • IUPAC names:
    • the parent chain is the longest chain that contains the functional group
    • for an aldehyde, change the suffix from -e to -al
    • for an unsaturated aldehyde, show the carbon-carbon double bond by changing the infix from -an- to -en-; the location of the suffix determines the numbering pattern
    • for a cyclic molecule in which -CHO is bonded to the ring, name the compound by adding the suffix -carbaldehyde
nomenclature ketones
Nomenclature: Ketones
  • IUPAC names:
    • select as the parent alkane the longest chain that contains the carbonyl group
    • indicate its presence by changing the suffix -e to -one
    • number the chain to give C=O the smaller number
order of precedence
Order of Precedence
  • For compounds that contain more than one functional group indicated by a suffix
common names
Common Names
  • for an aldehyde, the common name is derived from the common name of the corresponding carboxylic acid
  • for a ketone, name the two alkyl or aryl groups bonded to the carbonyl carbon and add the word ketone
physical properties
Physical Properties
  • Oxygen is more electronegative than carbon (3.5 vs 2.5) and, therefore, a C=O group is polar
    • aldehydes and ketones are polar compounds and interact in the pure state by dipole-dipole interaction
    • they have higher boiling points and are more soluble in water than nonpolar compounds of comparable molecular weight
reaction themes
Reaction Themes
  • One of the most common reaction themes of a carbonyl group is addition of a nucleophile to form a tetrahedral carbonyl addition compound
reaction themes1
Reaction Themes
  • A second common theme is reaction with a proton or Lewis acid to form a resonance-stabilized cation
    • protonation in this manner increases the electron deficiency of the carbonyl carbon and makes it more reactive toward nucleophiles
add n of c nucleophiles
Add’n of C Nucleophiles
  • Addition of carbon nucleophiles is one of the most important types of nucleophilic additions to a C=O group; a new carbon-carbon bond is formed in the process
  • We study addition of these carbon nucleophiles
grignard reagents
Grignard Reagents
  • Given the difference in electronegativity between carbon and magnesium (2.5 - 1.3), the C-Mg bond is polar covalent, with C- and Mg+
    • in its reactions, a Grignard reagent behaves as a carbanion
  • Carbanion:an anion in which carbon has an unshared pair of electrons and bears a negative charge
    • a carbanion is a good nucleophile and adds to the carbonyl group of aldehydes and ketones
grignard reagents1
Grignard Reagents
  • Addition of a Grignard reagent to formaldehyde followed by H3O+ gives a 1° alcohol
grignard reagents2
Grignard Reagents
  • Addition to any other RCHO gives a 2° alcohol
grignard reagents3
Grignard Reagents
  • Addition to a ketone gives a 3° alcohol
grignard reagents4
Grignard Reagents

Problem:2-phenyl-2-butanol can be synthesized by three different combinations of a Grignard reagent and a ketone. Show each combination.

organolithium compounds
Organolithium Compounds
  • Organolithium compounds are generally more reactive in C=O addition reactions than RMgX, and typically give higher yields
salts of terminal alkynes
Salts of Terminal Alkynes
  • Addition of an acetylide anion followed by H3O+ gives an -acetylenic alcohol
addition of hcn
Addition of HCN
  • HCN adds to the C=O group of an aldehyde or ketone to give a cyanohydrin
  • Cyanohydrin:a molecule containing an -OH group and a -CN group bonded to the same carbon
addition of hcn1
Addition of HCN
  • Mechanism of cyanohydrin formation
cyanohydrins
Cyanohydrins
  • The value of cyanohydrins
    • acid-catalyzed dehydration of the 2° or 3° alcohol
    • catalytic reduction of the cyano group gives a 1° amine
wittig reaction
Wittig Reaction
  • The Wittig reaction is a very versatile synthetic method for the synthesis of alkenes from aldehydes and ketones.
phosphonium ylides
Phosphonium Ylides
  • Phosphonium ylidesare formed in two steps:
wittig reaction1
Wittig Reaction
  • Phosphonium ylides react with the C=O group of an aldehyde or ketone to give an alkene
addition of h 2 o
Addition of H2O
  • Addition of water (hydration) to the carbonyl group of an aldehyde or ketone gives a gem-diol, commonly referred to as a hydrate
    • when formaldehyde is dissolved in water at 20°C, the carbonyl group is more than 99% hydrated
addition of h 2 o1
Addition of H2O
  • the equilibrium concentration of a hydrated ketone is considerably smaller
addition of alcohols
Addition of Alcohols
  • Addition of one molecule of alcohol to the C=O group of an aldehyde or ketone gives a hemiacetal
  • Hemiacetal:a molecule containing an -OH and an -OR or -OAr bonded to the same carbon
addition of alcohols1
Addition of Alcohols
  • Hemiacetals are only minor components of an equilibrium mixture, except where a five- or six-membered ring can form

(the model is of the trans isomer)

addition of alcohols2
Addition of Alcohols
  • Formation of a hemiacetal is base catalyzed
    • Step 1: proton transfer from HOR gives an alkoxide
    • Step 2: Attack of RO-on the carbonyl carbon
    • Step 3: proton transfer from the alcohol to O-gives the hemiacetal and generates a new base catalyst
addition of alcohols3
Addition of Alcohols
  • Formation of a hemiacetal is also acid catalyzed

Step 1: proton transfer to the carbonyl oxygen

Step 2: attack of ROH on the carbonyl carbon

Step 3: proton transfer from the oxonium ion to A- gives the hemiacetal and generates a new acid catalyst

addition of alcohols4
Addition of Alcohols
  • Hemiacetals react with alcohols to form acetals

Acetal:a molecule containing two -OR or -OAr groups bonded to the same carbon

addition of alcohols5
Addition of Alcohols

Step 1: proton transfer from HA gives an oxonium ion

Step 2: loss of water gives a resonance-stabilized cation

addition of alcohols6
Addition of Alcohols

Step 3: reaction of the cation (a Lewis acid) with methanol (a Lewis base) gives the conjugate acid of the acetal

Step 4: (not shown) proton transfer to A- gives the acetal and generates a new acid catalyst

addition of alcohols7
Addition of Alcohols
  • With ethylene glycol, the product is a five-membered cyclic acetal
acetals as protecting grps
Acetals as Protecting Grps
  • Suppose you wish to bring about a Grignard reaction between these compounds
acetals as protecting grps1
Acetals as Protecting Grps
  • If the Grignard reagent were prepared from 4-bromobutanal, it would self-destruct!
    • first protect the -CHO group as an acetal
    • then do the Grignard reaction
    • hydrolysis (not shown) gives the target molecule
acetals as protecting grps2
Acetals as Protecting Grps
  • Tetrahydropyranyl (THP) protecting group
    • the THP group is an acetal and, therefore, stable to neutral and basic solutions and to most oxidizing and reducting agents
    • it is removed by acid-catalyzed hydrolysis
add n of s nucleophiles
Add’n of S Nucleophiles
  • Thiols, like alcohols, add to the C=O of aldehydes and ketones to give tetrahedral carbonyl addition products
  • The sulfur atom of a thiol is a better nucleophile than the oxygen atom of an alcohol
  • A common sulfur nucleophile used for this purpose is 1,3-propanedithiol
    • the product is a 1,3-dithiane
add n of s nucleophiles1
Add’n of S Nucleophiles
  • The hydrogen on carbon 2 of the 1,3-dithiane ring is weakly acidic, pKa approximately 31
add n of s nucleophiles2
Add’n of S Nucleophiles
  • a 1,3-dithiane anion is a good nucleophile and undergoes SN2 reactions with methyl, 1° alkyl, allylic, and benzylic halides
  • hydrolysis gives a ketone
add n of s nucleophiles3
Add’n of S Nucleophiles
  • Treatment of the 1,3-dithiane anion with an aldehyde or ketone gives an -hydroxyketone
add n of n nucleophiles
Add’n of N Nucleophiles
  • Ammonia, 1° aliphatic amines, and 1° aromatic amines react with the C=O group of aldehydes and ketones to give imines (Schiff bases)
add n of n nucleophiles1
Add’n of N Nucleophiles
  • Formation of an imine occurs in two steps

Step 1: carbonyl addition followed by proton transfer

Step 2: loss of H2O and proton transfer to solvent

add n of n nucleophiles2
Add’n of N Nucleophiles
  • a value of imines is that the carbon-nitrogen double bond can be reduced to a carbon-nitrogen single bond
add n of n nucleophiles3
Add’n of N Nucleophiles
  • Rhodopsin (visual purple) is the imine formed between 11-cis-retinal (vitamin A aldehyde) and the protein opsin
add n of n nucleophiles4
Add’n of N Nucleophiles
  • Secondary amines react with the C=O group of aldehydes and ketones to form enamines
    • the mechanism of enamine formation involves formation of a tetrahedral carbonyl addition compound followed by its acid-catalyzed dehydration
    • we discuss the chemistry of enamines in more detail in Chapter 19
add n of n nucleophiles5
Add’n of N Nucleophiles
  • The carbonyl group of aldehydes and ketones reacts with hydrazine and its derivatives in a manner similar to its reactions with 1° amines
    • hydrazine derivatives include
acidity of hydrogens
Acidity of -Hydrogens
  • Hydrogens alpha to a carbonyl group are more acidic than hydrogens of alkanes, alkenes, and alkynes but less acidic than the hydroxyl hydrogen of alcohols
acidity of hydrogens1
Acidity of -Hydrogens
  • -Hydrogens are more acidic because the enolate anion is stabilized by

1. delocalization of its negative charge

2. the electron-withdrawing inductive effect of the adjacent electronegative oxygen

keto enol tautomerism
Keto-Enol Tautomerism
  • protonation of the enolate anion on oxygen gives the enol form; protonation on carbon gives the keto form
keto enol tautomerism1
Keto-Enol Tautomerism
  • acid-catalyzed equilibration of keto and enol tautomers occurs in two steps

Step 1: proton transfer to the carbonyl oxygen

Step 2: proton transfer to the base A-

keto enol tautomerism2
Keto-Enol Tautomerism
  • Keto-enol equilibria for simple aldehydes and ketones lie far toward the keto form
keto enol tautomerism3
Keto-Enol Tautomerism
  • For certain types of molecules, however, the enol is the major form present at equilibrium
    • for -diketones, the enol is stabilized by conjugation of the pi system of the carbon-carbon double bond and the carbonyl group
keto enol tautomerism4
Keto-Enol Tautomerism
  • Open-chain -diketones are further stabilized by intramolecular hydrogen bonding
racemization
Racemization
  • Racemization at an -carbon may be catalyzed by either acid or base
deuterium exchange
Deuterium Exchange
  • Deuterium exchange at an -carbon may be catalyzed by either acid or base
halogenation
-Halogenation
  • -Halogenation: aldehydes and ketones with at least one -hydrogen react at an  -carbon with Br2 and Cl2
    • reaction is catalyzed by both acid and base
halogenation1
-Halogenation
  • Acid-catalyzed -halogenation

Step 1: acid-catalyzed enolization

Step 2: nucleophilic attack of the enol on halogen

halogenation2
-Halogenation
  • Base-promoted -halogenation

Step 1: formation of an enolate anion

Step 2: nucleophilic attack of the enolate anion on halogen

halogenation3
-Halogenation
  • Acid-catalyzed halogenation:
    • introduction of a second halogen is slower than the first
    • introduction of the electronegative halogen on the -carbon decreases the basicity of the carbonyl oxygen toward protonation
  • Base-promoted -halogenation:
    • each successive halogenation is more rapid than the previous one
    • the introduction of the electronegative halogen on the -carbon increases the acidity of the remaining -hydrogens and, thus, each successive -hydrogen is removed more rapidly than the previous one
haloform reaction
Haloform Reaction
  • In the presence of base, a methyl ketone reacts with three equivalents of halogen to give a 1,1,1-trihaloketone, which then reacts with an additional mole of hydroxide ion to form a carboxylic salt and a trihalomethane
haloform reaction1
Haloform Reaction
  • The final stage is divided into two steps

Step 1: addition of OH- to the carbonyl group gives a tetrahedral carbonyl addition intermediate and is followed by its collapse

Step 2: proton transfer from the carbonyl group to the haloform anion

oxidation of aldehydes
Oxidation of Aldehydes
  • Aldehydes are oxidized to carboxylic acids by a variety of oxidizing agents, including H2CrO4
  • They are also oxidized by Ag(I)
    • in one method, a solution of the aldehyde in aqueous ethanol or THF is shaken with a slurry of silver oxide
oxidation of aldehydes1
Oxidation of Aldehydes
  • Aldehydes are oxidized by O2 in a radical chain reaction
    • liquid aldehydes are so sensitive to air that they must be stored under N2
oxidation of ketones
Oxidation of Ketones
  • ketones are not normally oxidized by chromic acid
  • they are oxidized by powerful oxidants at high temperature and high concentrations of acid or base
reduction
Reduction
  • aldehydes can be reduced to 1° alcohols
  • ketones can be reduced to 2° alcohols
  • the C=O group of an aldehyde or ketone can be reduced to a -CH2- group
catalytic reduction
Catalytic Reduction
  • Catalytic reductions are generally carried out at from 25° to 100°C and 1 to 5 atm H2
catalytic reduction1
Catalytic Reduction
  • A carbon-carbon double bond may also be reduced under these conditions
    • by careful choice of experimental conditions, it is often possible to selectively reduce a carbon-carbon double in the presence of an aldehyde or ketone
metal hydride reduction
Metal Hydride Reduction
  • The most common laboratory reagents for the reduction of aldehydes and ketones are NaBH4 and LiAlH4
    • both reagents are sources of hydride ion, H:-, a very powerful nucleophile
nabh 4 reduction
NaBH4 Reduction
  • reductions with NaBH4 are most commonly carried out in aqueous methanol, in pure methanol, or in ethanol
  • one mole of NaBH4 reduces four moles of aldehyde or ketone
nabh 4 reduction1
NaBH4 Reduction
  • The key step in metal hydride reduction is transfer of a hydride ion to the C=O group to form a tetrahedral carbonyl addition compound
lialh 4 reduction
LiAlH4 Reduction
  • unlike NaBH4, LiAlH4 reacts violently with water, methanol, and other protic solvents
  • reductions using it are carried out in diethyl ether or tetrahydrofuran (THF)
metal hydride reduction1
Metal Hydride Reduction
  • metal hydride reducing agents do not normally reduce carbon-carbon double bonds, and selective reduction of C=O or C=C is often possible
clemmensen reduction
Clemmensen Reduction
  • refluxing an aldehyde or ketone with amalgamated zinc in concentrated HCl converts the carbonyl group to a methylene group
wolff kishner reduction
Wolff-Kishner Reduction
  • in the original procedure, the aldehyde or ketone and hydrazine are refluxed with KOH in a high-boiling solvent
  • the same reaction can be brought about using hydrazine and potassium tert-butoxide in DMSO
prob 16 19
Prob 16.19

Draw a structural formula for the product formed by treating each compound with propylmagnesium bromide followed by aqueous HCl.

prob 16 20
Prob 16.20

Suggest a synthesis of each alcohol from an aldehyde or ketone and a Grignard reagent. Under each is the number of combinations of Grignard reagents and aldehyde or ketone that might be used.

prob 16 21
Prob 16.21

Show how to prepare this alcohol from the three given starting materials.

prob 16 22
Prob 16.22

Show how to synthesize 1-phenyl-2-butanol from these starting materials.

prob 16 24
Prob 16.24

Draw the Wittig reagent formed from each haloalkane, and for the alkene formed by treating the Wittig reagent with acetone.

prob 16 25
Prob 16.25

Show how to bring about each conversion using a Wittig reaction.

prob 16 26
Prob 16.26

Show two sets of reagents that might be combined in a Wittig reaction to give this conjugated diene.

prob 16 27
Prob 16.27

Wittig reactions with an a-haloether can be used for the synthesis of aldehydes and ketones. To see this, convert each a-haloether to a Wittig reagent, and react the Wittig reagent with cyclopentanone followed by hydrolysis in aqueous acid.

prob 16 28
Prob 16.28

Suggest a mechanism for the reaction of a sulfur ylide with a ketone to give an epoxide.

prob 16 29
Prob 16.29

Propose a structural formula for compound D and for the product C9H14O.

prob 16 30
Prob 16.30

Draw a structural formula for the cyclic hemiacetal. How many stereoisomers are possible for it? Draw alternative chair conformations for each possible stereoisomer.

prob 16 31
Prob 16.31

Draw structural formulas for the hemiacetal and acetal formed from each pair of reagents in the presence of an acid catalyst.

prob 16 32
Prob 16.32

Draw structural formulas for the products of hydrolysis of each acetal in aqueous acid.

prob 16 33
Prob 16.33

Propose a mechanism for this reaction. If the carbonyl oxygen is enriched with oxygen-18, will the oxygen label appear in the cyclic acetal or in the water?

prob 16 34
Prob 16.34

Propose a mechanism for this acid-catalyzed reaction.

prob 16 35
Prob 16.35

Propose a mechanism for this acid-catalyzed rearrangement.

prob 16 37
Prob 16.37

Show how to bring about this conversion.

prob 16 39
Prob 16.39

Which compound will cyclize to give the insect pheromone frontalin?

prob 16 41
Prob 16.41

Draw a structural formula for the product formed by treating each compound with (1) the lithium salt of the 1,3-dithiane derived from acetaldehyde and then (2) H2O, HgCl2.

prob 16 42
Prob 16.42

Show how to bring about each conversion using a 1,3-dithiane.

prob 16 44
Prob 16.44

Show how each compound can be synthesized by reductive amination of an aldehyde or ketone and an amine.

prob 16 45
Prob 16.45

Show how to bring about this final step in the synthesis of the antiviral drug rimantadine.

prob 16 46
Prob 16.46

Draw a structural formula for the a-hydroxyaldehyde and a-hydroxyketone with which this enediol is in equilibrium.

prob 16 47
Prob 16.47

Propose a mechanism for the isomerism of (R)-glyceraldehyde to (R,S)-glyceraldehyde and dihydroxyacetone.

prob 16 48
Prob 16.48

When cis-a-decalone is dissolved in ether containing a trace of HCl, the following equilibrium is established. Propose a mechanism for the isomerization and account for the fact that the trans isomer predominates.

prob 16 49
Prob 16.49

When this bicyclic ketone is treated with D2O in the presence of an acid catalyst, only two of the three a-hydrogens exchange. Propose a mechanism for the exchange and account for the fact that the bridgehead hydrogen does not exchange.

prob 16 51
Prob 16.51

Propose a mechanism for the formation of the bracketed intermediate and for the formation of the sodium salt of cyclopentanecarboxylic acid.

prob 16 52
Prob 16.52

If the Favorskii rearrangement is carried out using sodium ethoxide in ethanol, the product is an ethyl ester. Propose a mechanism for this reaction.

prob 16 53
Prob 16.53

Propose a mechanism for each step in this transformation, and account for the regioselectivity of the HCl addition.

prob 16 57
Prob 16.57

Show how to convert cyclopentanone to each compound.

prob 16 59
Prob 16.59

Propose structural formulas for A, B, and C. Show how C can also be prepared by a Wittig reaction.

prob 16 60
Prob 16.60

Given this retrosynthetic analysis, show how to synthesize cis-3-penten-2-ol from the three given starting materials.

prob 16 61
Prob 16.61

Propose a synthesis for Oblivon from acetylene and a ketone.

prob 16 62
Prob 16.62

Propose a synthesis for Surfynol from acetylene and a ketone.

prob 16 63
Prob 16.63

Propose a mechanism for this acid-catalyzed rearrangement.

prob 16 64
Prob 16.64

Propose a mechanism for this acid-catalyzed rearrangement.

prob 16 66
Prob 16.66

Propose mechanisms for Steps (1) and (4) and reagents for Steps (2), (3), and (5).

prob 16 68
Prob 16.68

Propose a mechanism for this Lewis acid catalyzed isomerization. Account for the fact that only a single stereoisomer of isopulegol is formed.

aldehydes ketones1
Aldehydes & Ketones

End Chapter 16

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