16

Aldehydes & Ketones

16-1

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

16-2

16 The Carbonyl Group

pi bonding and pi antibonding MOs for formaldehyde.

16-3

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 Methanal (Formaldehyde) O CH3 CH Ethanal (Acetaldehyde) O CH3 CCH3 Propanone (Acetone )

16-4

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-; 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

16-5

16 Nomenclature: Aldehydes
O H 3-Methylbutanal O H 2-Prope nal (Acrolein )
8 7 6 5 4 3 2 O 1 H

(2E)-3,7-Dimethyl-2,6-octadie nal (Ge ranial)

CHO CHO C6 H5

CHO

CH3 2 CH3

2,2-Dimethylcyclo- Benzaldehyde hexanecarbaldehyde

t rans-3-Phen yl-2-prope nal (Cinnamaldehyde)

16-6

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 O Propanone (Acetone) O
1 3 5 6 1 5

5-Methyl-3-hexan one

1-Phenyl-1-pentanone

16-7

16 Order of Precedence
For

compounds that contain more than one functional group indicated by a suffix
In creasing precedence
Functional Group - COOH - CH O C= O - OH - SH - NH2 Suffix I f Higher Pre fix I f Lower in Precede nce in Precede nce -oic acid -al -one -ol -thiol -amine oxooxohydroxy-s ulfanyl -amino

16-8

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 H H Formaldehyde O O H OH Formic acid O H Ace taldehyde O OH Acetic acid O O

Ethyl is opropyl k etone

Die thyl k e tone

Dicyclohexyl k eton e

16-9

16 Physical Properties
Oxygen

is more electronegative than carbon, therefore, a C=O group is polar

+ C O Polarity of a carbonyl group C O: C

: :

O:

More important contributing structure

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
16-10

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
R N u: + R C O: Nu :O : C R R Tetrahedral carbon yl addition compound

16-11

16 Reaction Themes
A

second common theme is reaction with a proton or Lewis acid to form a resonancestabilized cation
R C R 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

16-12

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 A Grignard re agent RLi An organolithium reagent RC C An anion of a te rminal alk yne
-

C N Cyanide ion

16-13

16 Grignard Reagents
Given

the difference in electronegativity between carbon and magnesium, 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

16-14

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 magn esium alk oxide

-

HCl H2 O

OH CH3 CH2 -CH2 + Mg 2+ 1-Propanol (a primary alcoh ol)

16-15

16 Grignard Reagents
Addition

to any other RCHO gives a 2 alcohol

O O [ Mg Br ] CHCH3 A magne sium alk oxide HCl H2 O OH 2+ CHCH3 + Mg
+

- + ether Mg Br + CH 3 - C-H + Acetaldehyde (an aldehyde)

1-Cyclohe xyle thanol (a se condary alcohol)

16-16

16 Grignard Reagents
Addition

to a ketone gives a 3 alcohol

O ether

C6 H5 Mg Br + CH3 -C- CH3 Acetone O - [ MgBr ] + C6 H5 CCH3 CH3 A magn esium alk oxide

HCl H2 O

OH C6 H5 CCH3 + Mg 2 + CH3

2-Phenyl-2-propanol (a tertiary alcohol)

16-17

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

16-18

16 Organolithium Compounds
Organolithium

compounds are generally more reactive in C=O addition reactions than RMgX, and typically give higher yields
Li + Phenyllithium 3,3-Dimethyl-2butanone A lithium alkoxide O O Li
+

OH HCl H2 O 3,3-Dimethyl-2-phenyl2-butanol

16-19

16 Salts of Terminal Alkynes

Addition

of an acetylide anion followed by H3O+ gives an -acetylenic alcohol

O
+ C: N a + HC

Cyclohexanol HC C O - N a+ HCl H2 O A s odium alk oxide 1-Ethyn ylcyclohexanol HC C OH

16-20

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 CH 3 C-C N H 2-Hydroxypropanenitrile (Acetaldehyde cyanohydrin)

16-21

16 Addition of HCN
Mechanism
H3 C C O + H3 C H3 C C H3 C C N O:+ -

of cyanohydrin formation
H3 C C N H3 C C C N H3 C H C N H3 C C C N O-H
+ - :C N

O:-

16-22

16 Cyanohydrins
The

value of cyanohydrins
OH CH3 CHC N acid catalyst

acid-catalyzed dehydration of the 2 or 3 alcohol

CH2 = CHC N + H2 O Propenenitrile (Acrylonitrile)

2-Hydroxypropanenitrile (Acetaldehyde cyanohydrin)

catalytic reduction of the cyano group gives a 1 amine

OH CHC N + 2 H 2 Benzaldehyde cyanohydrin Ni OH CHCH 2 N H 2 2-Amino-1-phenylethanol

16-23

16 Wittig Reaction
The

Wittig reaction is a very versatile synthetic method for the synthesis of alkenes from aldehydes and ketones.
+ O + Ph 3 P- CH2 A phosphoniu m ylide CH2 Methylene cyclohexane + + Ph 3 P- O Triphe nylphos phine oxide

16-24

16 Phosphonium Ylides
Phosphonium Step 1:

ylides are formed in two steps:

SN 2

Ph 3 P : Triphen ylphosphine Step 2:

+ CH3 - I

+ Ph 3 P- CH3 I An alk yltriph enylphosphonium iodide

CH3 CH2 CH2 CH2 Li Butyllithiu m - + CH2 -PPh 3 + CH3 CH2 CH2 CH3 + LiI A phosph onium Butane ylide
:

+ + H- CH2 -PPh 3 I -

16-25

16 Wittig Reaction
Phosphonium

ylides react with the C=O group of an aldehyde or ketone to give an alkene
Step 1: O CR2
+ -

:O
+

CR2

O CR2 Ph 3 P CH2 An oxaphosphetane

Ph 3 P CH2

Ph 3 P CH2 A betaine

Step 2:

O CR2 Ph 3 P CH2 Ph 3 P= O
+

R2 C= CH2 An alk e ne

Triphenylphosphine oxide

16-26

16 Wittig Reaction
Examples:
O + PhCH2 CH + Ph 3 P- CHCH3 PhCH2 CH= CH CH 3 + Ph 3 P= O 1-Phenyl-2-butene (87% Z isomer, 13% E isomer O + PhCH2 CH + Ph 3 P- CHCH3 PhCH2 CH= CH CH 3 + Ph 3 P= O 1-Phenyl-2-butene (87% Z isomer, 13% E isomer

16-27

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%)

16-28

16 FORMALIN
Formalin adalah larutan formaldehida dalam air, dengan kadar antara 10%40%.
Tugas No 1: Apakah formalin berbahaya apabila dikonsumsi oleh manusia? Jelaskan! (4-03-2011) Tuliskan sumber pustaka yang saudara ambil. 16-29

16 Addition of H2O
the equilibrium concentration of a hydrated ketone is considerably smaller
H3 C C O + H2 O H3 C Acetone (99.9%) H3 C C H3 C OH 2,2-Propane diol (0.1%) OH

16-30

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 COCH 2 CH 3 CH3

A hemiacetal

16-31

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 he miace tal (major form present at equilibrium)

16-32

16 Addition of Alcohols
Formation

of a hemiacetal is base catalyzed

B H +
-

Step 1: proton transfer from HOR gives an alkoxide

B: - + H OR
: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: CH3 - C-CH3 + HOR OR OH CH3 - C-CH3 + OR

:O- R

16-33

16 Addition of Alcohols
Formation

of a hemiacetal is also acid catalyzed

+ H O CH3 - C-CH3 + :A
:OH CH3 - C-CH3 + O H R

Step 1: proton transfer to the carbonyl oxygen

O: CH3 - C-CH3 + H- A
+ H

Step 2: attack of ROH on the carbonyl carbon

O CH3 - C-CH3 + H- O-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

16-34

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 H
+

CH3 COCH 2 CH3 + CH3 CH2 OH CH3 OCH2 CH3 A h emiace tal CH3 COCH2 CH3 CH3 A diethyl acetal

+ H2 O

16-35

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 res onance-stabilized cation
:

16-36

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

16-37

16 Addition of Alcohols
With

ethylene glycol, the product is a fivemembered cyclic acetal

O + HOCH 2 CH 2 OH H
+

CH 2 O CH 2 A cyclic acetal

+ H2 O

16-38

16 Acetals as Protecting Grps

Suppose

you wish to bring about a Grignard reaction between these compounds

O H Benzaldehyde + Br O H ??

4-Bromobutanal

OH

O H

5-Hydroxy-5-phen ylpentan al

16-39

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 H
+

O Br O A cyclic acetal + H2 O

then do the Grignard reaction

O Mg Br O O Br 1 . Mg, e t he r O O 2 . C H CHO 6 5 A cyclic acetal
+

hydrolysis (not shown) gives the target molecule 16-40

16 Acetals as Protecting Grps

Tetrahydropyranyl

(THP) protecting group

THP group H+ RCH2 O O

RCH2 OH + O Dihydropyran

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

16-41

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 H
+

S3

An alde hyde

1,3-Propane dithiol

C2 + H2 O H S1 A 1,3-dithian e (a cyclic thioacetal)

16-42

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-dithiane Butyllithium A lithio-1,3-dithiane Butane (s tronger acid) (s tronger bas e) (we ak er bas e) (we ak er acid) pK a 31 pK a 51

16-43

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
SN 2 C: Li + + R' CH2 - Br S R Lithium salt of S CH2 R' H O, Hg Cl a 1,3-dithiane 2 2 C CH3 CN S R S

O R- C-CH2 R'

16-44

16 Addn of S Nucleophiles
Treatment

of the 1,3-dithiane anion with an aldehyde or ketone gives an -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, HgCl 2 CH3 CN
+

O OH R C CH-R' An -h ydroxyk etone

16-45

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 Acetaldehyde Aniline
+

CH3 CH=N An imine (a Schiff base )

+ H2 O

N H3

N H + H2 O An imine (a Schiff base )

Cyclohexanone Ammonia

16-46

16 Addn of N Nucleophiles
Formation

of an imine occurs in two steps

O:- H + C N -R H O H C N -R H A tetrahedral carbonyl addition compound

Step 1: carbonyl addition followed by proton transfer

O C + H2 N- R
:

Step 2: loss of H2O and proton transfer to solvent

H H + O H + :O H H + H O C N -R H C N -R H :O H C N -R + H2 O H An imine

16-47

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 + H2N H+ - H2 O

Cyclohexanone Cyclohe xylamine H N (An imine) H2 / N i N Dicyclohexylamine

16-48

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 5 12

+ H2 N- OPSIN O

11-cis- Retinal

Rhodopsin (Visual purple) H

N -OPSIN

16-49

16 Addn of N Nucleophiles
Secondary

amines react with the C=O group of aldehydes and ketones to form enamines
O Cyclohexanone
+

H-N

N An enamine

H2 O

Piperidine (a s econdary 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

16-50

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 Hydrazine NNH2 A hydrazone + H2 O

hydrazine derivatives include

H 2 N-OH Hydroxylamine H 2 N-NH Phenylhydrazine

16-51

16 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

Type of Bond pK a CH 3 CH 2 O-H O CH 3 CCH 2 -H CH 3 C C-H CH 2 = CH- H CH 3 CH 2 -H 16 20 25 44 51

16-52

16 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
O CH3 - C-CH2 -H + :A-

O CH3 - C CH2

O-

:
CH3 - C= CH2 + H- A Enolate anion

16-53

16 Keto-Enol Tautomerism
protonation of the enolate anion on oxygen gives the enol form; protonation on carbon gives the keto form
O CH3 - C-CH2 H- A OCH3 - C= CH2 H- A

Enolate an ion O A + CH3 - C-CH3 Keto form OH +A CH3 - C= CH2 Enol form

16-54

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 O H + A:CH3 - C-CH3 The conjugate acid of the ke tone

Step 2: proton transfer to the base A+ O H + :Aslow : OH CH3 - C= CH2 Enol form + H- A

CH3 - C-CH2 - H

16-55

16 Keto-Enol Tautomerism
Keto-enol

equilibria for simple aldehydes and ketones lie far toward the keto form

Keto form
O CH3 CH O CH3 CCH3 O

Enol form
OH CH2 = CH OH CH3 C= CH2 OH

% Enol at Equilibrium

6 x 10-5 6 x 10-7 1 x 10-6

OH

4 x 10-5

16-56

16 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 conjugated
O O

system H H H HO

H O H

O OH 1,3-Cycloh exanedione

16-57

16 Keto-Enol Tautomerism
Open-chain

-diketones are further stabilized by intramolecular hydrogen bonding

hydrogen bon ding O O O + H

20% 2,4-Pentan edione (Acetylacetone)

80%

16-58

16 Racemization
Racemization
Ph C C O

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

acid or Ph C C OH acid or Ph C C O H3 C CH3 bas e CH3 bas e H3 C H (R)-3-Phenyl-2An achiral enol butanone H CH3 H3 C (S )-3-Phenyl-2butanone

16-59

16 Deuterium Exchange
Deuterium
O CH 3 CCH 3 Acetone

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

+ 6 D2 O D
+ -

O CD 3 CCD 3 + 6 HOD Acetone-d 6

or OD

16-60

16 -Halogenation
-Halogenation:

aldehydes and ketones with at least one -hydrogen react at an -carbon with Br2 and Cl2
O CCH 3 + Br2 CH3 COOH Acetophenone O CCH 2 Br + HBr

reaction is catalyzed by both acid and base

16-61

16 -Halogenation
Acid-catalyzed

-halogenation
slow H-O C R' C R R

Step 1: acid-catalyzed enolization

OH R' -C- C-R R

Step 2: nucleophilic attack of the enol on halogen

H-O R' R C C + Br R Br
fast

Br C C R + H+ + Br: R' R

16-62

16 -Halogenation
Base-promoted

-halogenation
slow O R O: C C R + H2 O

Step 1: formation of an enolate anion

OH
R' -C- C-R + :OH

:
C C

R' R' R R Resonance-stabilized enolate anion

Step 2: nucleophilic attack of the enolate anion on halogen

O:C R' R C + Br R Br O fast R' Br C C R + :Br R

16-63

16 -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 16-64

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 3 Br2 3 NaOH O O NaOH + RCCBr3 RCO Na + CHBr3 Tribromomethane (Bromoform)
O 1 . Cl 2 / N aOH 2 . HCl/ H2 O O OH + CHCl 3

5-Methyl-3-hexen -2-one

4-Methyl-2-pentenoic Trichloromethane acid (Chloroform)

16-65

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 RC- CBr 3 +
-

: O:OH RC- CBr 3 OH

O RC + - :CBr 3 OH Conjugate base of bromoform

Step 2: proton transfer from the carbonyl group to the haloform anion
O RC- O- H +
-

O :CBr 3 RC- O: - + H- CBr 3 Bromoform

16-66

16 Oxidation of Aldehydes
Aldehydes

are oxidized to carboxylic acids by a variety of oxidizing agents, including H2CrO4

CHO Hexanal H2 Cr O4 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 HO Vanillin O CH + A g2 O CH3 O O COH + Ag HO Vanillic acid

T HF, H 2 O N aOH

HCl H2 O

16-67

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 Benzaldehyde + O2 2 O COH Benzoic acid

16-68

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 HN O 3 HO Cyclohexanone (k e to form) Cyclohexanone (e nol form) O OH O Hexanedioic acid (Adipic acid)

16-69

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 RCH3 Can Be Reduced to RCH2 OH Ketones O RCR' RCH2 R' Can Be Reduced to OH RCHR'

16-70

16 Catalytic Reduction
Catalytic

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

O + Cyclohe xanone H2 Pt 25 o C, 2 atm Cyclohe xanol OH

2 H2 OH 1-Butanol

H Ni trans- 2-Butenal (Crotonalde hyde)

16-71

16 Catalytic Reduction
A

carbon-carbon double bond may also be reduced under these conditions

O 2 H2 OH 1-Butanol H Ni trans- 2-Butenal (Crotonalde hyde)

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

16-72

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 Li
+

H- B- H

H- A l- H

H: Hydride ion

H Sodium borohydride

H Lithium aluminum hydride (LAH)

16-73

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 4 RCH + NaBH4 methanol ( RCH2 O) 4 B Na A tetraalkyl borate
+

H2 O

4 RCH2 OH + borate salts

16-74

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 H O
+ N a H- B- H + R- C-R'

O BH3 N a R- C-R' H

H2 O OH R- C-R' H from water

from the hydride re ducing agent

16-75

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 (R2CHO)4Al- Li+ A tetraalkyl aluminate H 2O OH 4RCHR + aluminum s alts

16-76

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'
O RCH= CHCR' + H2

1 . NaBH 4 2 . H2 O
Rh

OH RCH= CHCHR'
O RCH2 CH 2 CR'

16-77

16 Clemmensen Reduction
refluxing an aldehyde or ketone with amalgamated zinc in concentrated HCl converts the carbonyl group to a methylene group
OH O Zn( Hg) , HCl OH

16-78

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 NN H2 Hydrazine KOH diethylen e glycol (reflux)

+ N 2 + H2 O

16-79

16 Prob 1
Draw a structural formula for the product formed by treating each compound with propylmagnesium bromide followed by aqueous HCl.
(a) CH2 O (b) O

(c)

(d)

16-80

16 Prob 2
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 (a) 3 Combinations (b) 2 Combinations OH OH (c) OCH3 2 Combinations

16-81

16 Prob 3
Show how to prepare this alcohol from the three given starting materials.
Br + CHO + O several s teps OH

16-82

16 Prob 4
Show how to synthesize 1-phenyl-2-butanol from these starting materials.
Br + Bromobenzene 1-Butene se veral steps OH

1-Phenyl-2-butanol

16-83

16 Prob 5
Draw the Wittig reagent formed from each haloalkane, and for the alkene formed by treating the Wittig reagent with acetone.
(a) Br (b) O (d) Cl O Br

Cl (c)

(e )

Br

(f) Ph

Cl

16-84

16 Prob 6
Show how to bring about each conversion using a Wittig reaction.
O (a) O (b)

(c)

CH

OCH3 OCH3

16-85

16 Prob 7
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

16-86

16 Prob 8
Wittig reactions with an -haloether can be used for the synthesis of aldehydes and ketones. To see this, convert each -haloether to a Wittig reagent, and react the Wittig reagent with cyclopentanone followed by hydrolysis in aqueous acid.
CH3 ClCH 2 OCH3 ( A) ClCH OCH 3 ( B)

16-87

16 Prob 9
Suggest a mechanism for the reaction of a sulfur ylide with a ketone to give an epoxide.
Ph + S CH CH3 Br
-

strong base

Ph

CH3 + S C:

Ph CH3 A sulfonium bromide s alt CH3 + O + S C: Ph CH 3 Ph

Ph CH3 A sulfur ylide O + CH 3 ( Ph) 2 S

16-88

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 H1 4 O

16-89

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

16-90

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

16-91

16 Prob 16.32
Draw structural formulas for the products of hydrolysis of each acetal in aqueous acid.
CH 3 O (a) OCH 3

O (b) OCH 3 O (c) O H CHO

16-92

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 OH 4-Hydroxypentanal O OCH3 + H
+

H2 O

A cyclic acetal

16-93

16 Prob 16.34
Propose a mechanism for this acid-catalyzed reaction.
OCH3 + H2 O H
+

O + CH3 OH

16-94

16 Prob 16.35
Propose a mechanism for this acid-catalyzed rearrangement.
OOH CCH3 CH3 Cumene hydroperoxide Phenol Acetone H2 SO 4 O OH + CH3 CCH3

16-95

16 Prob 16.37
Show how to bring about this conversion.
O H HO OH O H

16-96

16 Prob 16.39
Which compound will cyclize to give the insect pheromone frontalin?
O O Frontalin O O A B O O OH OH C HO O O

16-97

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) ClCH 2 CH= CH2

16-98

16 Prob 16.42
Show how to bring about each conversion using a 1,3dithiane.
O (a) H O (b) O (c) H H O OH Ph Ph O

O OH

16-99

16 Prob 16.44
Show how each compound can be synthesized by reductive amination of an aldehyde or ketone and an amine.
N H2 (a) Amphetamine (b) Methamphe tamine H N

16-100

16 Prob 16.57
Show how to convert cyclopentanone to each compound.
(a) OH (b) Cl OH (c) CH- CH = CH2 (d)

16-101

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, Na NH 2 2 . H2 O C7 H1 0 O A H2 Lindlar catalyst KHSO4 heat C7 H1 0 C

C7 H1 2 O B

16-102

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

16-103