Aldehydes & Ketones Chapter 16 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. aldehydes and ketones (Chapter 16) carboxylic acids (Chapter 17) acid halides, acid anhydrides, esters, amides (Chapter 18) enolate anions (Chapter 19)

16.1 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. 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. O O O H C C H 3 C H 3 Methanal (Formaldehyde) Ethanal (Acetaldehyde) Propanone (Acetone)

16.2 A. 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, change 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, add the suffix –carbaldehyde.

B. Nomenclature: Aldehydes the IUPAC retains the common names benzaldehyde and cinnamaldehyde, as well formaldehyde and acetaldehyde.

Nomenclature: Ketones IUPAC names the parent alkane is the longest chain that contains the carbonyl group. indicate the ketone by changing the suffix -e to -one. number the chain to give C=O the smaller number. the IUPAC retains the common names acetone, acetophenone, and benzophenone.

Order of Precedence, Table 16.1 For compounds that contain more than one functional group indicated by a suffix.

C. 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.

16.3 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.

Preparation of aldehydes and ketones Review of methods previously seen in 3010. Oxidation of alkenes with conc. KMnO4 Oxidation of alkenes with O3 Oxidation of 1o alcohols with PCC Oxidation of 2o alcohols with Na2Cr2O4 + H2SO4 Oxidation of glycols with HIO4 Hydroysis of alkynes Hydroboration/oxidation of alkynes

16.4 Reaction Themes , Nu attack at C 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 , O attack at H A second common theme is reaction with a proton or other Lewis acid to form a resonance-stabilized cation. protonation increases the electron deficiency of the carbonyl carbon and makes it more reactive toward nucleophiles.

Reaction Themes, stereochemistry often the tetrahedral product of addition to a carbonyl is a new chiral center. if none of the starting materials is chiral and the reaction takes place in an achiral environment, then enantiomers will be formed as a racemic mixture.

16.5 Addition 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.

A. 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, 1o alcohols addition of a Grignard reagent to formaldehyde followed by H3O+ gives a 1° alcohol. Note that these reactions require two steps.

Grignard Reagents, 2o alcohols addition to any other aldehyde, RCHO, gives a 2° alcohol (two steps).

Grignard Reagents, 3o alcohols addition to a ketone gives a 3° alcohol (two steps).

Grignard Reagents Work backwards to get starting materials. Problem: 2-phenyl-2-butanol can be synthesized by three different combinations of a Grignard reagent and a ketone. Show each combination. Work backwards to get starting materials.

Grignard Reagents Look at: Acetophenone Propiophenone 2-butanone Problem: 2-phenyl-2-butanol can be synthesized by three different combinations of a Grignard reagent and a ketone. Show each combination. Look at: Acetophenone Propiophenone 2-butanone + EtMgBr + MeMgBr + PhMgBr

B. Organolithium Compounds Organolithium compounds, RLi, give the same C=O addition reactions as RMgX but generally are more reactive and usually give higher yields. Lithium is monovalent and does not insert between C and X like Mg. Like the Grignard this requires two steps.

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

Salts of Terminal Alkynes Addition of water or hydroboration/oxidation of the product gives an enol which rearranges.

D. 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. O O H C H 3 + H C N C H 3 - N H 2-Hydroxypropanenitrile (Acetaldehyde cyanohydrin)

Addition of HCN Mechanism of cyanohydrin formation: Step 1: nucleophilic addition of cyanide to the carbonyl carbon. Step 2: proton transfer from HCN gives the cyanohydrin and regenerates cyanide ion.

Cyanohydrins The value of cyanohydrins: 1. acid-catalyzed dehydration of the alcohol gives an alkene. 2. catalytic reduction of the cyano group gives a 1° amine.

Cyanohydrins The value of cyanohydrins: 3. acid-catalyzed hydrolysis of the nitrile gives a carboxylic acid. O H acid catalyst O H C H 3 N C H 3 - COOH H 2 O 2-Hydroxypropanenitrile (Acetaldehyde cyanohydrin) 2-Hydroxypropanoic acid

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

Phosphonium Ylides (Wittig reagent) Phosphonium ylides are formed in two steps: Step 1: nucleophilic displacement of iodine by triphenylphosphine. Step 2: treatment of the phosphonium salt with a very strong base, most commonly BuLi, NaH, or NaNH2.

Wittig Reaction Phosphonium ylides react with the C=O group of an aldehyde or ketone to give an alkene. Step 1: nucleophilic addition of the ylide to the electrophilic carbonyl carbon. Step 2: decomposition of the oxaphosphatane.

Wittig Reaction Examples:

Wittig Reaction some Wittig reactions are Z selective, others are E selective. Wittig reagents with an anion-stabilizing group, such as a carbonyl group, adjacent to the negative charge are generally E selective. Wittig reagents without an anion-stabilizing group are generally Z selective.

Wittig Reaction Modification - Omit Horner-Emmons-Wadsworth modification: uses a phosphonoester. phosphonoester formation requires two steps (see next slide).

Wittig Reaction Modification - Omit phosphonoesters are prepared by successive SN2 reactions: attack by the phosphite, then attack by Br-

Wittig Reaction Modification - Omit treatment of a phosphonoester with a strong base produces the modified Wittig reagent, an aldehyde or ketone is then added to give an alkene. a particular value of using a phosphonoester-stabilized anion is that they are almost exclusively E selective.

16.7 A. Addition of H2O, hydrates Addition of water (hydration) to the carbonyl group of an aldehyde or ketone gives a geminal diol, commonly referred to a gem-diol. gem-diols are also referred to as hydrates.

Addition of H2O, hydrates when formaldehyde is dissolved in water at 20°C, the carbonyl group is more than 99% hydrated. the equilibrium concentration of a hydrated ketone is considerably smaller.

B. Addition of Alcohol, hemiacetals 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, in base Formation of a hemiacetal can be base catalyzed. Step 1: proton transfer 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, in acid Formation of a hemiacetal can be 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 Alcohol, cyclic hemiacetals hemiacetals are only minor components of an equilibrium mixture, except where a five- or six-membered ring can form.

Addition of Alcohol, cyclic hemiacetals at equilibrium, the b anomer of glucose predominates because the -OH group on the anomeric carbon is equatorial.

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

Addition of Alcohols, acetals Step 1: proton transfer from HA gives an oxonium ion. Step 2: loss of water gives a resonance-stabilized cation.

Addition of Alcohols, acetals Step 3: reaction of the cation (an electrophile) with methanol (a nucleophile) gives the conjugate acid of the acetal. Step 4: proton transfer to A- gives the acetal and generates a new acid catalyst.

Addition of Alcohols, cyclic acetals with ethylene glycol and other glycols, the product is a five-membered cyclic acetal. these are used as carbonyl protective groups.

Dean-Stark Trap, Fig. 16.1

C. Acetals as Protecting Grps Suppose you wish to bring about a Grignard reaction between these compounds. But a Grignard reagent prepared from 4-bromobutanal will self-destruct! (react with C=O)

Acetals as Protecting Groups So, first protect the -CHO group as an acetal, then do the Grignard reaction. Hydrolysis in H+, HOH (not shown) removes the acetal to give the target molecule.

D. Acetals as Protecting Groups Tetrahydropyranyl (THP), as a protecting group for an alcohol. 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. THP group H + R C H 2 O + O R C H 2 O O Dihydropyran A tetrahydropyranyl acetal

16.8 A. Addition of Nitrogen Nucleophiles Ammonia, 1° aliphatic amines, and 1° aromatic amines react with the C=O group of aldehydes and ketones to give imines (Schiff bases). An imine has a CH=N bond.

Addition of Nitrogen 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.

Addition of Nitrogen Nucleophiles a value of imines is that the carbon-nitrogen double bond can be reduced to a carbon-nitrogen single bond. imine formation: reduction: H + N O + H 2 N - H 2 O (An imine) Cyclohexanone C yclohexylamine H H 2 / N i N N (An imine) Dicyclohexylamine

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

Addition of Nitrogen 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.

B. Addition of Nitrogen Nucleophiles the carbonyl group of aldehydes and ketones reacts with hydrazine and its derivatives in a manner similar to its reactions with 1° amines. Table 16.4

16.9 A. 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-.

B. Keto-Enol Tautomerism, Table 16.5 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. for acyclic -diketones, the enol is further stabilized by hydrogen bonding.

16.10 A. 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. O O 2 CH + O 2 2 COH Benzaldehyde Benzoic acid

B. 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. O O H O H N O 3 H O O H O Cyclohexanone (keto form) Cyclohexanone (enol form) H exanedioic acid (Adipic acid)

16.11 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 also be reduced to a -CH2- group. Can Be Reduced to Can Be Reduced to Aldehydes Ketones O H O O R C H 2 O R C H ' R C H R C ' R C H 3 R C H 2 '

A. 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. H H N a + H - B L i + H : H - A l H H Sodium borohydride H ydride ion L ithium aluminum hydride (LAH)

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).

B. Catalytic Reduction Catalytic reductions are generally carried out at from 25° to 100°C and 1 to 5 atm H2. O O H Pt + H 2 25 o C, 2 atm C yclohexanone C yclohexanol O 2 H H O H N i trans- 2-Butenal (Crotonaldehyde) 1-Butanol

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. O 2 H H O H N i trans- 2-Butenal (Crotonaldehyde) 1-Butanol

C. Clemmensen Reduction, in acid refluxing an aldehyde or ketone with amalgamated zinc in concentrated HCl converts the carbonyl group to a methylene group.

Wolff-Kishner Reduction, in base 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.

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

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

C. -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, in acid Acid-catalyzed -halogenation. Step 1: acid-catalyzed enolization. Step 2: nucleophilic attack of the enol on halogen. Step 3: (not shown) proton transfer to solvent completes the reaction.

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

-Halogenation, in acid 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.

-Halogenation, in base 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.

Review of Spectroscopy IR Spectroscopy Very strong C=O stretch around 1710 cm-1. Conjugation lowers frequency. Ring strain raises frequency. Additional C-H stretch for aldehyde: two absorptions ~ 2720 cm-1 and 2820 cm-1.

H1 NMR of butanal

C13 NMR of 2-heptanone

MS of butanal

McLafferty Rearrangement of butanal Loss of alkene (even mass number) Must have -hydrogen

Aldehydes & Ketones End Chapter 16