William H. Brown & Christopher S. Foote Organic Chemistry William H. Brown & Christopher S. Foote

Aldehydes & Ketones Chapter 16 Chapter 15

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 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 Group pi bonding and pi antibonding MOs for formaldehyde.

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 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: Aldehydes

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 For compounds that contain more than one functional group indicated by a suffix

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 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 One of the most common reaction themes of a carbonyl group is addition of a nucleophile to form a tetrahedral carbonyl addition compound

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 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 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 Reagents Addition of a Grignard reagent to formaldehyde followed by H3O+ gives a 1° alcohol

Grignard Reagents Addition to any other RCHO gives a 2° alcohol

Grignard Reagents Addition to a ketone gives a 3° alcohol

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 are generally more reactive in C=O addition reactions than RMgX, and typically give higher yields

Salts of Terminal Alkynes Addition of an acetylide anion followed by H3O+ gives an -acetylenic alcohol

Salts of Terminal Alkynes

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 HCN Mechanism of cyanohydrin formation

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 The Wittig reaction is a very versatile synthetic method for the synthesis of alkenes from aldehydes and ketones.

Phosphonium Ylides Phosphonium ylides are formed in two steps:

Wittig Reaction Phosphonium ylides react with the C=O group of an aldehyde or ketone to give an alkene

Wittig Reaction Examples:

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 H2O the equilibrium concentration of a hydrated ketone is considerably smaller

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 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 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 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 Alcohols Hemiacetals react with alcohols to form acetals Acetal: a molecule containing two -OR or -OAr groups bonded to the same carbon

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 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 Alcohols With ethylene glycol, the product is a five-membered cyclic acetal

Dean-Stark Trap

Acetals as Protecting Grps Suppose you wish to bring about a Grignard reaction between these compounds

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 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 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 Nucleophiles The hydrogen on carbon 2 of the 1,3-dithiane ring is weakly acidic, pKa approximately 31

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 Nucleophiles Treatment of the 1,3-dithiane anion with an aldehyde or ketone gives an -hydroxyketone

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 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 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 Nucleophiles Rhodopsin (visual purple) is the imine formed between 11-cis-retinal (vitamin A aldehyde) and the protein opsin

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 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 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 -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 protonation of the enolate anion on oxygen gives the enol form; protonation on carbon gives the keto form

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 Tautomerism Keto-enol equilibria for simple aldehydes and ketones lie far toward the keto form

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 Tautomerism Open-chain -diketones are further stabilized by intramolecular hydrogen bonding

Racemization Racemization at an -carbon may be catalyzed by either acid or base

Deuterium Exchange Deuterium exchange at an -carbon may be catalyzed by either acid or base

-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

-Halogenation Acid-catalyzed -halogenation Step 1: acid-catalyzed enolization Step 2: nucleophilic attack of the enol on halogen

-Halogenation Base-promoted -halogenation Step 1: formation of an enolate anion Step 2: nucleophilic attack of the enolate anion on halogen

-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 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 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 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 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 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 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 reductions are generally carried out at from 25° to 100°C and 1 to 5 atm H2

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 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

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

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

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 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 refluxing an aldehyde or ketone with amalgamated zinc in concentrated HCl converts the carbonyl group to a methylene group

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

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

Prob 16.22 Show how to synthesize 1-phenyl-2-butanol from these starting materials.

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

Prob 16.26 Show two sets of reagents that might be combined in a Wittig reaction to give this conjugated diene.

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

Prob 16.29 Propose a structural formula for compound D and for the product C9H14O.

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

Prob 16.32 Draw structural formulas for the products of hydrolysis of each acetal in aqueous acid.

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 Propose a mechanism for this acid-catalyzed reaction.

Prob 16.35 Propose a mechanism for this acid-catalyzed rearrangement.

Prob 16.37 Show how to bring about this conversion.

Prob 16.39 Which compound will cyclize to give the insect pheromone frontalin?

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

Prob 16.44 Show how each compound can be synthesized by reductive amination of an aldehyde or ketone and an amine.

Prob 16.45 Show how to bring about this final step in the synthesis of the antiviral drug rimantadine.

Prob 16.46 Draw a structural formula for the a-hydroxyaldehyde and a-hydroxyketone with which this enediol is in equilibrium.

Prob 16.47 Propose a mechanism for the isomerism of (R)-glyceraldehyde to (R,S)-glyceraldehyde and dihydroxyacetone.

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

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

Prob 16.57 Show how to convert cyclopentanone to each compound.

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

Prob 16.61 Propose a synthesis for Oblivon from acetylene and a ketone.

Prob 16.62 Propose a synthesis for Surfynol from acetylene and a ketone.

Prob 16.63 Propose a mechanism for this acid-catalyzed rearrangement.

Prob 16.64 Propose a mechanism for this acid-catalyzed rearrangement.

Prob 16.66 Propose mechanisms for Steps (1) and (4) and reagents for Steps (2), (3), and (5).

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 & Ketones End Chapter 16