OC 2/e Ch 15

OC 2/e Ch 15

16 Organic Chemistry William H. Brown & Christopher S. Foote 16-1 16 Aldehydes & Ketones Chapter 16 Chapter 15 16-2 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) 16-3 16 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 C O 16-4 16 The Carbonyl Group pi bonding and pi antibonding MOs for formaldehyde. 16-5

16 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 HCH O CH3 CH Methanal Ethanal (Formaldehyde) (Acetaldehyde) O CH3 CCH3 Propanone (Acetone) 16-6 16 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-; -enthe 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 16-7 16 Nomenclature: Aldehydes O O H 5 7 H 8

6 O 1 3 4 2 H 3-Methylbutanal 2-Propenal (2E)-3,7-Dimethyl-2,6-octadiena (Acrolein) (Geranial) 1 CHO CH3 2 CH 3 CHO

2,2-DimethylcycloBenzaldehyde hexanecarbaldehyde C6 H5 CHO trans -3-Phenyl-2-propenal (Cinnamaldehyde) 16-8 16 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 O 1 O

3 O 1 5 5 6 Propanone 5-Methyl-3-hexanone 1-Phenyl-1-pentanone (Acetone) 16-9 16 Order of Precedence For compounds that contain more than one functional group indicated by a suffix FunctionalSuffix If Higher Prefix If Lower Group in Precedencein Precedence

-COOH -oic acid -CHO C=O -al -one oxooxo- -OH -ol hydroxy- -SH -thiol Increasing precedence -NH2 -amine -sulfanyl -amino

16-10 16 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 O O H H H OH FormaldehydeFormic acid O O O H OH

Acetaldehyde Acetic acid O O Ethyl isopropyl ketone Diethyl ketoneDicyclohexyl ketone 16-11 16 Physical Properties Oxygen is more electronegative than carbon (3.5 vs 2.5) and, therefore, a C=O group is polar + C O Polarity of a carbonyl group C O ::

+ : C O : : More imortant contributing tructure 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 16-12 16 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

: :O: R Nu:- + C R O :: Nu - C R R Tetrahedral carbonyl addition compound 16-13

16 Reaction Themes A second common theme is reaction with a proton or Lewis acid to form a resonancestabilized cation R R C O : : + H-B fast R R + C O : H + :B protonation in this manner increases the electron deficiency of the carbonyl carbon and makes it more reactive toward nucleophiles 16-14

16 Addn 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 RMgX RLi RC C C N A Grignard An organolithium An anion of a Cyanide reagent reagent terminal alkyne ion 16-15 16 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 16-16 16 Grignard Reagents Addition of a Grignard reagent to formaldehyde followed by H3O+ gives a 1 alcohol - O CH3 CH2 -MgBr + H- C-H -

+ ether + Formaldehyde - O [ Mg Br] CH3 CH2 -CH2 A magneium alkoxie + OH HCl H2 O CH3 CH2 -CH2 + Mg2+ 1-Propanol (a primary alcohol) 16-17

16 Grignard Reagents Addition to any other RCHO gives a 2 alcohol O - - + ether Mg Br + CH3 - C-H + Acetaldehyde (an aldehyde) HCl H2 O O [ Mg Br] + CHCH3 A magnesium alkoxide OH 2+

CHCH3 + Mg 1-Cyclohexylethanol (a secondary alcohol) 16-18 16 Grignard Reagents Addition to a ketone gives a 3 alcohol O + C6 H5 Mg Br + CH3 -C- CH3 + Acetone O - [ Mg Br] + C6 H5 CCH3 CH3 A magneium alkoxie ether

HCl H2 O OH C6 H5 CCH3 + Mg 2+ CH3 2-Phenyl-2-propanol (a tertiary alcohol) 16-19 16 Grignard Reagents Problem: 2-phenyl-2-butanol can be synthesized by three different combinations of a Grignard reagent and a ketone. Show each combination. OH C-CH2 CH3 CH3 16-20 16 Organolithium Compounds Organolithium compounds are generally more

reactive in C=O addition reactions than RMgX, and typically give higher yields - Li O OH HCl H2 O + Phenyl- 3,3-Dimethyl-2lithium butanone + O Li A lithium alkoxide 3,3-Dimethyl-2-phenyl2-butanol

16-21 16 Salts of Terminal Alkynes Addition of an acetylide anion followed by H3O+ gives an a-acetylenic alcohol O + : + C Na HC Cyclohexanol HC C O-Na+ HC C OH HCl H2 O A sodium alkoxide 1-Ethynylcyclohexanol

16-22 16 Salts of Terminal Alkynes O HO H2 O HO C CH CCH3 a H2 SO4 , HgSO4 An a-hyroxyketone O CH2 CH a

HO 1. (sia) 2 BH b 2. H2 O2 , NaOH A b-hyroxyalehye 16-23 16 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 CH3 CH + HC N OH CH3 C-C N

H 2-Hydroxypropanenitrile (Acetaldehyde cyanohydrin) 16-24 16 Addition of HCN Mechanism of cyanohydrin formation H3 C - + C O C N H3 C O:+ HC N C C N O:C

H3 C H3 C H3 C H3 C C N H3 C H3 C O-H C + -:C N C N 16-25 16 Cyanohydrins The value of cyanohydrins acid-catalyzed dehydration of the 2 or 3 alcohol OH

CH3 CHC N acid catalyst CH2 =CHC N + H2 O 2-Hydroxypropanenitrile Propenenitrile (Acetaldehyde cyanohydrin) (Acrylonitrile) catalytic reduction of the cyano group gives a 1 amine OH CHC N + 2H2 Benzaldehyde cyanohydrin OH Ni CHCH2 NH2 2-Amino-1-phenylethanol 16-26

16 Wittig Reaction The Wittig reaction is a very versatile synthetic method for the synthesis of alkenes from aldehydes and ketones. + O + Ph3 P-CH2 A phosphonium ylide + CH2 + Ph3 P-O TriphenylMethylenecyclohexane phosphine oxide 16-27 16 Phosphonium Ylides Phosphonium ylides are formed in two steps: Step 1: Ph3 P : + CH3 -I SN2

Triphenylphosphine Step 2: + Ph3 P-CH3 I An alkyltriphenylphosphonium iodide : + + + H-CH2 -PPh3 I - CH3 CH2 CH2 CH2 Li Butyllithium :- + CH2 -PPh3 + CH3 CH2 CH2 CH3 + LiI A phosphonium Butane ylide 16-28 16 Wittig Reaction

Phosphonium ylides react with the C=O group of an aldehyde or ketone to give an alkene Step 1: O CR2 : Ph3 P CH2 + :O CR2 O CR2 Ph3 P CH2 Ph3 P CH2 - + An oxaphosphetane A betaine

Step 2: O CR2 Ph3 P CH2 Ph3 P=O + R2 C=CH2 TriphenylphosphineAn alkene oxide 16-29 16 Wittig Reaction Examples: O + PhCH2 CH + Ph3 P-CHCH3 PhCH2 CH=CHCH3 + Ph3 P=O 1-Phenyl-2-butene (87% Z isomer, 13% E isomer O + PhCH2 CH + Ph3 P-CHCH3

PhCH2 CH=CHCH3 + Ph3 P=O 1-Phenyl-2-butene (87% Z isomer, 13% E isomer 16-30 16 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 20C, the carbonyl group is more than 99% hydrated O HCH + H2 O Formaldehyde OH HCOH H Formaldehyde hydrate (>99%) 16-31

16 Addition of H2O the equilibrium concentration of a hydrated ketone is considerably smaller H3 C H3 C C O + H2 O H3 C Acetone (99.9%) OH C H3 C OH 2,2-Propanediol (0.1%) 16-32 16 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 H O CH3 CCH3 + OCH2 CH3 OH CH3 COCH2 CH3 CH3 A hemiacetal 16-33 16 Addition of Alcohols Hemiacetals are only minor components of an equilibrium mixture, except where a five- or sixmembered ring can form

(the model is of the trans isomer) O CH3 CHCH2 CH2 CH OH 4-Hydroxypentanal H3 C O OH A cyclic hemiacetal (major form present at equilibrium) 16-34 16 Addition of Alcohols Formation of a hemiacetal is base catalyzed Step 1: proton transfer from HOR gives an alkoxide B H + - :OR B: - + H OR

Step 2: Attack of RO- on the carbonyl carbon O CH3 -C-CH3 + :O-R O: CH3 -C-CH3 OR Step 3: proton transfer from the alcohol to O- gives the hemiacetal and generates a new base catalyst O: CH 3 - C-CH 3 + HOR OR OH CH3 -C-CH3 + OR :O-R

16-35 16 Addition of Alcohols Formation of a hemiacetal is also acid catalyzed Step 1: proton transfer to the carbonyl oxygen + H O CH3 -C-CH3 + :A O: CH3 -C-CH3 + H-A Step 2: attack of ROH on the carbonyl carbon + H O :OH CH3 -C-CH3 + H-O-R : CH3 -C-CH3

+ O H R Step 3: proton transfer from the oxonium ion to A- gives the hemiacetal and generates a new acid catalyst OH CH3 -C-CH3 + O A: H R OH CH3 -C-CH3 : OR + H-A 16-36 16 Addition of Alcohols

Hemiacetals react with alcohols to form acetals Acetal: a molecule containing two -OR or -OAr groups bonded to the same carbon OH + CH3 COCH2 CH3 + CH3 CH2 OH CH3 A hemiacetal H OCH2 CH3 CH3 COCH2 CH3 + H2 O CH3 A diethyl acetal 16-37 16 Addition of Alcohols Step 1: proton transfer from HA gives an oxonium ion HO:

R-C-OCH3 + H A H H + H O R-C-OCH3 + A: H An oxonium ion Step 2: loss of water gives a resonance-stabilized cation H + H O R-C-OCH3 H + + : R-C-OCH3 + H2 O R-C OCH3 H H A resonance-stabilized cation 16-38 16 Addition of Alcohols

Step 3: reaction of the cation (a Lewis acid) with methanol (a Lewis base) gives the conjugate acid of the acetal H CH3 -O: + + R-C OCH3 H H + CH3 O R-C-OCH3 H A protonated acetal Step 4: (not shown) proton transfer to A- gives the acetal and generates a new acid catalyst 16-39 16 Addition of Alcohols With ethylene glycol, the product is a fivemembered cyclic acetal

O + HOCH2 CH2 OH + H O CH 2 O CH2 + H2 O A cyclic acetal 16-40 16 Dean-Stark Trap QuickTime and a Photo - JPEG decompressor are needed to see this picture. 16-41 16 Acetals as Protecting Grps

Suppose you wish to bring about a Grignard reaction between these compounds O O H + Br H Benzaldehyde 4-Bromobutanal ?? OH O H 5-Hydroxy-5-phenylpentanal 16-42

16 Acetals as Protecting Grps If the Grignard reagent were prepared from 4bromobutanal, it would self-destruct! first protect the -CHO group as an acetal O Br + HO H OH O + H Br + H2 O O A cyclic acetal

then do the Grignard reaction - O Br + O MgBr O 1. Mg, ether O 2. C6 H5 CHO A cyclic acetal O hydrolysis (not shown) gives the target molecule 16-43 16 Acetals as Protecting Grps Tetrahydropyranyl (THP) protecting group THP group RCH2 OH +

H+ O Dihydropyran RCH2 O O A tetrahydropyranyl ether 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 16-44 16 Addn 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 O RCH + + HS SH An aldehyde 1,3-Propanedithiol H R

S3 C2 + H2 O 1 H S A 1,3-dithiane (a cyclic thioacetal) 16-45 16 Addn of S Nucleophiles The hydrogen on carbon 2 of the 1,3-dithiane ring is weakly acidic, pKa approximately 31 S H S + Bu:- Li + C C: Li+ + BuH S R S R A 1,3-dithianeButyllithium A lithio-1,3-dithiane Butane (stronger acid) (stronger base) (weaker base) (weaker acid)

pKa 31 pKa 51 16-46 16 Addn 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 S SN2 C: Li+ + R' CH2 -Br S R Lithium salt of S CH2 R' H O, HgCl a 1,3-dithiane 2 2 C CH3 CN S R O R-C-CH2 R'

16-47 16 Addn of S Nucleophiles Treatment of the 1,3-dithiane anion with an aldehyde or ketone gives an a-hydroxyketone O C: Li+ + H-C-R' S R Lithium salt of a 1,3-dithiane S O:- Li S CH-R' C S R H2 O, HgCl2 CH3 CN + O OH R C CH-R'

An a-hyroxyketone 16-48 16 Addn 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) O CH3 CH + H2 N + H Acetaldehyde Aniline CH3 CH=N + H2 O An imine (a Schiff base) +

O + NH3 H Cyclohexanone Ammonia NH + H2 O An imine (a Schiff base) 16-49 16 Addn of N Nucleophiles Formation of an imine occurs in two steps Step 1: carbonyl addition followed by proton transfer O C

H O C N-R O:- H + C N-R : + H2 N-R H H A tetrahedral carbonyl addition compound Step 2: loss of H2O and proton transfer to solvent H + O H + H

:O H C N-R H H + H O C N-R H H :O H C N-R + H2 O An imine 16-50 16 Addn of N Nucleophiles a value of imines is that the carbon-nitrogen double

bond can be reduced to a carbon-nitrogen single bond O + H+ -H2 O H2N Cyclohexanone Cyclohexylamine N (An imine) H2 / Ni H N Dicyclohexylamine 16-51 16 Addn of N Nucleophiles Rhodopsin (visual purple) is the imine formed

between 11-cis-retinal (vitamin A aldehyde) and the protein opsin 11 1 12 5 11-cis-Retinal H + H2 N-OPSIN O Rhodopsin H (Visual purple) N-OPSIN 16-52 16 Addn of N Nucleophiles Secondary amines react with the C=O group of aldehydes and ketones to form enamines

+ O + H-N H N + H2 O Cyclohexanone Piperidine An enamine (a secondary amine) 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

16-53 16 Addn 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 O + H2 NNH2 NNH2 Hydrazine + H2 O A hydrazone hydrazine derivatives include H2 N-OH Hydroxylamine H2 N-NH Phenylhydrazine 16-54

16 Acidity of a-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 Type of Bond pKa CH3 CH2 O-H 16 O CH3 CCH2 -H 20 CH3 C C-H 25 CH2 =CH-H 44 CH3 CH2 -H

51 16-55 16 Acidity of a-Hydrogens a-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 O CH3 -C-CH2 -H + :AO : CH3 -C CH2 : OCH3 -C=CH2 + H-A Enolate anion 16-56 16 Keto-Enol Tautomerism protonation of the enolate anion on oxygen gives the

enol form; protonation on carbon gives the keto form O - O- CH3 -C-CH2 CH3 -C=CH2 Enolate anion A - O H-A + CH3 -C-CH3 Keto form H-A

OH CH3 -C=CH2 - +A Enol form 16-57 16 Keto-Enol Tautomerism acid-catalyzed equilibration of keto and enol tautomers occurs in two steps Step 1: proton transfer to the carbonyl oxygen O: CH3 -C-CH3 + H-A Keto form fast + H O A:The conjugate acid of the ketone

CH3 -C-CH3 + Step 2: proton transfer to the base A+ H O CH3 -C-CH2 -H + :A- slow :OH CH3 -C=CH2 + H-A Enol form 16-58 16 Keto-Enol Tautomerism Keto-enol equilibria for simple aldehydes and ketones

lie far toward the keto form Keto form O CH3 CH % Enol at Enol form Equilibrium OH CH2 =CH O OH CH3 CCH3 CH3 C=CH2 O OH O

OH -5 6 x 10 -7 6 x 10 -6 1 x 10 -5 4 x 10 16-59 16 Keto-Enol Tautomerism For certain types of molecules, however, the enol is the major form present at equilibrium for b-diketones, the enol is stabilized by conjugation of the pi system of the carbon-carbon double bond and the carbonyl group conjugated O

O O OH 1,3-Cyclohexanedione system H H H O H HO H 16-60 16 Keto-Enol Tautomerism Open-chain b-diketones are further stabilized by intramolecular hydrogen bonding hydrogen

bonding O O 20% O + H O 80% 2,4-Pentanedione (Acetylacetone) 16-61 16 Racemization Racemization at an a-carbon may be catalyzed by either acid or base Ph

O C C acid or OH Ph C C acid or Ph O C C

H3 C H CH3 base CH3 CH3 base H3 C H H3 C (R)-3-Phenyl-2An achiral enol (S)-3-Phenyl-2butanone butanone 16-62 16 Deuterium Exchange Deuterium exchange at an a-carbon may be catalyzed by either acid or base O CH3 CCH3 + 6D2 O Acetone O +

D - or OD CD3 CCD3 + 6HOD Acetone-d 6 16-63 16 a-Halogenation a-Halogenation: aldehydes and ketones with at least one a-hydrogen react at an a -carbon with Br2 and Cl2 O CCH3 + Br2 CH3 COOH O CCH2 Br + HBr

Acetophenone reaction is catalyzed by both acid and base 16-64 16 a-Halogenation Acid-catalyzed a-halogenation Step 1: acid-catalyzed enolization OH R' -C-C-R H-O C slow R R' R C R

Step 2: nucleophilic attack of the enol on halogen H-O R C C + Br R' R Br fast O Br C C R + H+ + Br: R' R 16-65 16 a-Halogenation Base-promoted a-halogenation

Step 1: formation of an enolate anion OH R' -C-C-R + :OH O slow C O: : R C C R C + H2 O R' R' R

R Resonance-stabilized enolate anion R Step 2: nucleophilic attack of the enolate anion on halogen O:C R' R C R + Br Br fast O R' Br C C R + :BrR

16-66 16 a-Halogenation Acid-catalyzed halogenation: introduction of a second halogen is slower than the first introduction of the electronegative halogen on the acarbon decreases the basicity of the carbonyl oxygen toward protonation Base-promoted a-halogenation: each successive halogenation is more rapid than the previous one the introduction of the electronegative halogen on the a-carbon increases the acidity of the remaining ahydrogens and, thus, each successive a-hydrogen is removed more rapidly than the previous one 16-67 16 Haloform Reaction In the presence of base, a methyl ketone reacts with three equivalents of halogen to give a 1,1,1trihaloketone, which then reacts with an

additional mole of hydroxide ion to form a carboxylic salt and a trihalomethane O RCCH3 3Br2 3NaOH O O NaOH + RCCBr3 RCO Na + CHBr3 Tribromomethane (Bromoform) O O 1. Cl2 / NaOH 2. HCl/ H2 O 5-Methyl-3-hexen-2-one OH

+ CHCl3 4-Methyl-2-pentenoic Trichloromethane acid (Chloroform) 16-68 16 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 : O- O RC-CBr3 + -:OH O

RC-CBr3 RC + - :CBr3 OH Conjugate base of bromoform OH Step 2: proton transfer from the carbonyl group to the haloform anion O RC-O-H + -:CBr3 O RC-O:- + H-CBr3 Bromoform 16-69

16 Oxidation of Aldehydes Aldehydes are oxidized to carboxylic acids by a variety of oxidizing agents, including H2CrO4 CHO H2 CrO4 Hexanal COOH Hexanoic acid 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 CH3 O O CH + Ag2 O

HO Vanillin THF, H2 O NaOH HCl H2 O CH3 O O COH + Ag HO Vanillic acid 16-70 16 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 2 CH O + O2 Benzaldehyde 2 COH Benzoic acid 16-71 16 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

OH O HNO3 HO CyclohexanoneCyclohexanone (keto form) (enol form) OH O Hexanedioic acid (Adipic acid) 16-72 16 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 Aldehydes O RCH

Can Be Reduced to RCH2 OH RCH3 Ketones O RCR' Can Be Reduced to OH RCHR' RCH2 R' 16-73 16 Catalytic Reduction Catalytic reductions are generally carried out at from 25 to 100C and 1 to 5 atm H2 OH O + H2

Pt 25 oC, 2 atm Cyclohexanone O Cyclohexanol 2H2 H Ni trans2-Butenal (Crotonaldehyde) OH 1-Butanol 16-74 16 Catalytic Reduction A carbon-carbon double bond may also be

reduced under these conditions O 2H2 H Ni trans2-Butenal (Crotonaldehyde) OH 1-Butanol 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 16-75 16 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 + Na H-B-H H Li + H-Al-H H: H H Sodium Lithium aluminumHydride ion borohydride hydride (LAH) 16-76 16 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 O 4RCH + NaBH4 methanol - + (RCH2O) 4B Na A tetraalkyl borate H2O 4RCH2OH + borate salts 16-77 16 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

H + O Na H-B-H + R-C-R' H + O BH3 Na R-C-R' H H2 O OH from water from the hydride reducing agent R-C-R' H 16-78

16 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) O ether 4RCR + LiAlH4 (R 2CHO)4Al- Li+ H 2O OH 4RCHR + aluminum salts A tetraalkyl aluminate 16-79 16 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 O RCH=CHCR'

1. NaBH4 2. H2 O O RCH=CHCR' + H2 Rh OH RCH=CHCHR' O RCH2 CH2 CR' 16-80 16 Clemmensen Reduction refluxing an aldehyde or ketone with amalgamated zinc in concentrated HCl converts the carbonyl group to a methylene group OH O OH Zn(Hg), HCl

16-81 16 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 O + H2 NNH2 Hydrazine KOH diethylene glycol (reflux) + N2 + H2 O 16-82 16 Prob 16.19 Draw a structural formula for the product formed by treating each compound with propylmagnesium bromide followed by aqueous HCl. (a)CH2 O

(c) O (b) (d) O O 16-83 16 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. OH OH (a) OH (b)

(c) 3 Combinations 2 Combinations OCH3 2 Combinations 16-84 16 Prob 16.21 Show how to prepare this alcohol from the three given starting materials. Br + CHO + O several steps OH 16-85

16 Prob 16.22 Show how to synthesize 1-phenyl-2-butanol from these starting materials. Br + Bromobenzene 1-Butene several steps OH 1-Phenyl-2-butanol 16-86 16 Prob 16.24 Draw the Wittig reagent formed from each haloalkane, and for the alkene formed by treating the Wittig reagent with acetone. (a) (c) (e)

Br (b) Br Cl Br O (d)Cl (f) Ph O Cl 16-87 16 Prob 16.25 Show how to bring about each conversion using a Wittig reaction. O (a) O (b)

(c) O CH OCH3 OCH3 16-88 16 Prob 16.26 Show two sets of reagents that might be combined in a Wittig reaction to give this conjugated diene. CH=CHCH=CHCH3 1-Phenyl-1,3-pentadiene 16-89 16 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.

CH3 ClCH2 OCH3 ClCHOCH3 (A) (B) 16-90 16 Prob 16.28 Suggest a mechanism for the reaction of a sulfur ylide with a ketone to give an epoxide. Ph CH3 + S CH - Br

strong base Ph CH3 A sulfonium bromide salt Ph CH3 +O + S C: Ph CH3 Ph CH3 + S C: Ph CH3 A sulfur ylide O CH3 + (Ph)2 S

16-91 16 Prob 16.29 Propose a structural formula for compound D and for the product C9H14O. + S C6 H5 Br C6 H5 - BuLi O D C9 H14 O 16-92 16 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. OH O + H H 5-Hydroxyhexanal a cyclic hemiacetal 16-93 16 Prob 16.31 Draw structural formulas for the hemiacetal and acetal formed from each pair of reagents in the presence of an acid catalyst. O (a) + CH3 CH2 OH

OH (b) OH O + CH3 CCH3 O (c) CH3 CH2 CH2 CH + CH3 OH 16-94 16 Prob 16.32 Draw structural formulas for the products of hydrolysis of each acetal in aqueous acid. CH3 O (a) O (b) (c) OCH3

OCH3 O H CHO O 16-95 16 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? O + H + CH3 OH H OH 4-Hydroxypentanal O

OCH3+ H2 O A cyclic acetal 16-96 16 Prob 16.34 Propose a mechanism for this acid-catalyzed reaction. OCH3 + H2 O + H O + CH3 OH 16-97 16 Prob 16.35 Propose a mechanism for this acid-catalyzed

rearrangement. OOH CCH3 H2 SO4 O OH + CH3 CCH3 CH3 Cumene hydroperoxide Phenol Acetone 16-98 16 Prob 16.37 Show how to bring about this conversion. O O H

HO H OH 16-99 16 Prob 16.39 Which compound will cyclize to give the insect pheromone frontalin? O O Frontalin O O O OH O A HO O O

OH B C 16-100 16 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. (a) O CH O (b)CH2 CH (c)ClCH2 CH=CH2 16-101 16 Prob 16.42 Show how to bring about each conversion using a 1,3dithiane. O

(a) O H O O H (b) O (c) OH Ph Ph O H OH 16-102

16 Prob 16.44 Show how each compound can be synthesized by reductive amination of an aldehyde or ketone and an amine. (a) H N NH2 (b) Amphetamine Methamphetamine 16-103 16 Prob 16.45 Show how to bring about this final step in the synthesis of the antiviral drug rimantadine. O NH2 16-104

16 Prob 16.46 Draw a structural formula for the a-hydroxyaldehyde and a-hydroxyketone with which this enediol is in equilibrium. CH-OH -Hydroxyaldehyde C-OH a-Hydroxyketone CH3 An enediol 16-105 16 Prob 16.47 Propose a mechanism for the isomerism of (R)glyceraldehyde to (R,S)-glyceraldehyde and dihydroxyacetone. CHO CHOH NaOH CH2OH

(R)-Glyceraldehyde CHO CHOH CH2OH (R,S)-Glyceraldehyde CH2OH + C=O CH2OH Dihydroxyacetone 16-106 16 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. H H HCl

HO cis-2-Decalone HO trans2-Decalone 16-107 16 Prob 16.49 When this bicyclic ketone is treated with D2O in the presence of an acid catalyst, only two of the three ahydrogens exchange. Propose a mechanism for the exchange and account for the fact that the bridgehead hydrogen does not exchange. Thi a-hyrogen oe not exchange H H H These two a-hyrogen exchange O

16-108 16 Prob 16.51 Propose a mechanism for the formation of the bracketed intermediate and for the formation of the sodium salt of cyclopentanecarboxylic acid. O O Cl NaOH THF NaOH THF A proposed intermediate O O CO-Na+ HCl H2 O COH

16-109 16 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. O Cl O CH3 CH2 O-Na+ COCH2 CH3 CH3 CH2 OH 16-110 16 Prob 16.53 Propose a mechanism for each step in this transformation, and account for the regioselectivity of the HCl addition. Cl O O

HCl 1. NaOH 2. HCl (R)-(+)-Pulegone C OH O (R)-3,7-Dimethyl-6-octenoic acid (R)-Citronellic acid 16-111 16 Prob 16.57 Show how to convert cyclopentanone to each compound. (a) OH (b) Cl

OH (c) CH-CH=CH2 (d) 16-112 16 Prob 16.59 Propose structural formulas for A, B, and C. Show how C can also be prepared by a Wittig reaction. O 1. HC CH, NaNH2 C7 H1 0 O 2. H2 O A C7 H1 2 O B H2 Lindlar catalyst

KHSO4 heat C7 H1 0 C 16-113 16 Prob 16.60 Given this retrosynthetic analysis, show how to synthesize cis-3-penten-2-ol from the three given starting materials. OH OH O + HCCH3 CH3 I + HC CH 16-114 16 Prob 16.61 Propose a synthesis for Oblivon from acetylene and a ketone. HO

Oblivon 16-115 16 Prob 16.62 Propose a synthesis for Surfynol from acetylene and a ketone. OH OH Surfynol 16-116 16 Prob 16.63 Propose a mechanism for this acid-catalyzed rearrangement. OH C CH + H

CHO C H 16-117 16 Prob 16.64 Propose a mechanism for this acid-catalyzed rearrangement. O O ArSO3 H 16-118 16 Prob 16.66 Propose mechanisms for Steps (1) and (4) and reagents for Steps (2), (3), and (5). O H2 SO 4 O (1)

Peuoionone (2 ) b-Ionone Ph 3 P, HBr (3) OH (4) O - Br + PPh 3 OH (5) O CCH 3

Vitamin A acetate 16-119 16 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. O H 1. SnCl4, CH2 Cl2 2. NH4 Cl (S)-Citronellal (C10H18O) OH Isopulegol (C10H18O) 16-120 16 Aldehydes

& Ketones End Chapter 16 16-121

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