Aldehydes & Ketones

Chapter 16

16-1 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)

16-2 16-

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.

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-

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 -enan- 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. carbaldehyde.

16-5 16-

B. Nomenclature: Aldehydes
O H 3-Methylbutanal O H
8

O
7 6 5 4 3 2 1

2-Propenal (2E)-3,7-Dimethyl-2,6-octadienal (Acrolein) (Geranial) CHO HO

4 1

CHO

Cyclopentanecarbaldehyde


trans-4-Hydroxycyclohexanecarbaldehyde

the IUPAC retains the common names benzaldehyde and cinnamaldehyde, as well formaldehyde and acetaldehyde.
CHO C6 H5 CHO

Benzaldehyde trans-3-Phenyl-2-propenal (Cinnamaldehyde)

16-6 16-

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.
O O O O

Propanone (Acetone)

Acetophenone

Benzophenone

1-Phenyl-1-pentanone

16-7 16-

Order of Precedence, Table 16.1

 For compounds that contain more than one functional group

indicated by a suffix.

16-8 16-

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.

O HCH Formaldehyde O

O HCOH Formic acid O

O CH3 CH Acetaldehyde

O CH3 COH Acetic acid O

Ethyl isopropyl ketone

Diethyl ketone

Dicyclohexyl ketone 16-9 16-

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.
16-10 16-

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.

O C R O Nu C R R Tetrahedral carbonyl addition compound
-

R Nu
-

16-11 16-

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.

R R C O
+

fast H-B

R
B +

R R O-H

C O H R

C O H

R B
+ H-Nu +

C O H R

slow

Nu

C R

H-B

R Tetrahedral carbonyl addition compound

16-12 16-

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.
Approach from the top face Nu O R R R' C O R' Approach from the bottom face Nu R'
+

Nu OH H3 O
+

R'
+

R O

R'

R OH

Nu A new chiral center is created

Nu A racemic mixture

16-13 16-

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.

RMgX A Grignard reagent

RC C RLi An organolithium An alkyne reagent anion

C N Cyanide ion

16-14 16-

A. Grignard Reagents
 Given the difference in electronegativity between carbon

and magnesium (2.5 - 1.3), the C-Mg bond is polar covalent, with CH- and MgH+.
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.

16-15 16-

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.
O CH3 CH2 -MgBr + H-C-H

ether

Formaldehyde O [ MgBr] CH3 CH2 -CH2 A magnesium alkoxide

+

HCl H2 O

OH CH3 CH2 -CH2 + Mg2 + 1-Propanol (a 1 alcohol) 16-16 16-

Grignard Reagents, 2o alcohols

addition to any other aldehyde, RCHO, gives a 2 alcohol (two steps).
MgBr O + ether

H Acetaldehyde (an aldehyde) O [ MgBr]

+

OH HCl H2 O + Mg2 +

A magnesium alkoxide

1-Cyclohexylethanol (a 2 alcohol; (racemic)

16-17 16-

Grignard Reagents, 3o alcohols

addition to a ketone gives a 3 alcohol (two steps).
O Ph-MgBr Phenylmagnesium bromide + Acetone (a ketone) O [ MgBr] Ph A magnesium alkoxide
+

ether

HCl H2 O

OH Ph

+ Mg2+

2-Phenyl-2-propanol (a 3 alcohol)

16-18 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

Work backwards to get starting materials.

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

Look at: Acetophenone + EtMgBr

Propiophenone + MeMgBe

2-butanone + PhMgBr
16-20 16-

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.
Li + Phenyl- 3,3-Dimethyl-2lithium butanone A lithium alkoxide (racemic) O O- Li+ HCl H2 O 3,3-Dimethyl-2-phenyl2-butanol (racemic) OH

16-21 16-

C. Salts of Terminal Alkynes

 Addition of an alkyne anion followed by H3O+

gives an E-

acetylenic alcohol.
O HC C: Na+ + Sodium acetylide Cyclohexanone A sodium alkoxide
-

HC C O - Na+ HCl H2 O

HC C OH

1-Ethynylcyclohexanol

16-22 16-

Salts of Terminal Alkynes

Addition of water or hydroboration/oxidation

of the product gives an enol which rearranges.

O H2 O HO C CH H2 SO4 , HgSO4 An E-hydroxyketone HO 1 . (sia) 2 BH 2 . H2 O2 , NaOH F A F-hydroxyaldehyde
16-23 16-

HO E

CCH3

E CH2 CH

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 CH3 CH + HC N

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

16-24 16-

Addition of HCN
 Mechanism of cyanohydrin formation:

Step 1: nucleophilic addition of cyanide to the carbonyl carbon.

H3 C C O + C N H3 C

H3 C C H3 C

C N

Step 2: proton transfer from HCN gives the cyanohydrin and regenerates cyanide ion.
H3 C C H3 C C N O
-

H3 C
+ H C N

O-H C
+

C N

H3 C

C N
16-25 16-

Cyanohydrins
 The value of cyanohydrins:

1. acid-catalyzed dehydration of the alcohol gives an alkene.

OH CH 3 CHC N acid catalyst CH2 = CHC N + H2 O Propenenitrile (Acrylonitrile)

2. catalytic reduction of the cyano group gives a 1 amine.

OH CHC N + 2 H2 Benzaldehyde cyanohydrin (racemic) Ni OH CHCH2 NH2 2-Amino-1-phenylethanol (racemic)

2-Hydroxypropanenitrile (Acetaldehyde cyanohydrin)

16-26 16-

Cyanohydrins
 The value of cyanohydrins:

3. acid-catalyzed hydrolysis of the nitrile gives a carboxylic acid.

OH CH3 CHC N acid catalyst H2 O OH CH3 - CHCOOH 2-Hydroxypropanoic acid

2-Hydroxypropanenitrile (Acetaldehyde cyanohydrin)

16-27 16-

16.6 Wittig Reaction

 The Wittig reaction is

a very versatile synthetic method for the synthesis of alkenes from aldehydes and ketones.

O +

+ Ph3 P-CH2

CH2 +

Ph 3 P=O

Cyclohexanone A phosphonium ylide

MethyleneTriphenylcyclohexane phosphine oxide

16-28 16-

Phosphonium Ylides (Wittig reagent)

 Phosphonium ylides are formed in two steps:

Step 1: nucleophilic displacement of iodine by triphenylphosphine.

Ph 3 P + CH3 -I SN 2 + Ph3 P-CH3 I Triphenylphosphine

Methyltriphenylphosphonium iodide (an alkyltriphenylphosphine salt)

Step 2: treatment of the phosphonium salt with a very strong base, most commonly BuLi, NaH, or NaNH2.
CH3 CH 2 CH2 CH2 Li Butyllithium
+

+ + H-CH2 -PPh3 I+ CH3 CH 2 CH2 CH3 + CH2 -PPh3 + LiI Butane A phosphonium ylide 16-29 16-

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.
O CR2
+ -

:O
+

CR2 CH2

O Ph3 P

CR2 CH2

Ph3 P

CH2

Ph3 P

A betaine

An oxaphosphetane

Step 2: decomposition of the oxaphosphatane.

O CR2 Ph3 P CH2 Ph3 P=O
+

R2 C=CH2
16-30 16-

Triphenylphosphine An alkene oxide

Wittig Reaction
Examples:
O + Ph3 P Acetone
O + Ph3 P
+

Ph 3 P=O

2-Methyl-2-heptene

Ph

H Phenylacetaldehyde H Ph O + Ph3 P Phenylacetaldehyde O OEt

+ Ph + Ph P=O Ph 3 (Z)-1-Phenyl-2- (E)-1-Phenyl-2butene butene (87%) (13%)

O + Ph 3 P=O OEt Ethyl (E)-4-phenyl-2-butenoate (only the E isomer is formed) Ph

16-31 16-

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.
O Ph3 P OEt Ph3 P O OEt

Resonance contributing structures for an ylide stabilized by an adjacent carbonyl group

Wittig reagents without an anion-stabilizing group are generally Z selective.

16-32 16-

Wittig Reaction Modification

 Horner-Emmons-Wadsworth modification:

uses a phosphonoester. phosphonoester formation requires two steps (see next slide).
O Br-CH2 -C-OEt an E-bromoester ( MeO) 3 P Trimethylphosphite O Br-CH2 -C-R an E-bromoketone

O O ( MeO) 2 P-CH2 -C-OEt + MeBr An E-phosphonoester O O (MeO) 2 P-CH 2 -C-R + MeBr An E-phosphonoketone

16-33 16-

Wittig Reaction Modification

phosphonoesters are prepared by successive SN2 reactions: attack by the phosphite, then attack by BrO SN 2 + CH2 -C-OEt Br OMe O CH3 -O-P-CH2 -C-OEt Br OMe SN 2 O O ( MeO) 2 P-CH2 -C-OEt + MeBr An E-phosphonoester

( MeO) 3 P

16-34 16-

Wittig Reaction Modification

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.

( MeO) 2 P-CH2 -C-OEt

1. strong base O

O OEt

O MeO-P-O

2.
H

OMe Only the E isomer Dimethylphosphate is formed anion

16-35 16-

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.
acid or base H2 O OH C OH A hydrate (a gem-diol)

C O + Carbonyl group of an aldehyde or ketone

16-36 16-

Addition of H2O, hydrates

when formaldehyde is dissolved in water at 20C, the carbonyl group is more than 99% hydrated.
H O + H2 O H Formaldehyde H OH OH H Formaldehyde hydrate (>99%)

the equilibrium concentration of a hydrated ketone is considerably smaller.

O + H2 O Acetone (99.9%) OH OH 2,2-Propanediol (0.1%)
16-37 16-

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.

O + H-OEt

acid or base

OH OEt A hemiacetal

16-38 16-

Addition of Alcohol, cyclic hemiacetals

hemiacetals are only minor components of an equilibrium mixture, except where a five- or six-membered ring can form.
O
4 1

OH (S)-4-Hydroxypentanal

OH

OH

Cyclic hemiacetals (major forms present at equilibrium)

6

OH OH O HO
6 5 4 3 2 1

CH2 OH HO + OH HO

CH2 OH anomeric carbon OH

HO H HO

OH OH
D-Glucose

4 5 O 3 2 1

4 5 O 3 2 1

(open chain form)

OH F Anomer of D -glucose cyclic hemiacetal (predominates at equilibrium)

OH E Anomer of D -glucose cyclic hemiacetal

16-39 16-

Addition of Alcohol, cyclic hemiacetals

at equilibrium, the F anomer of glucose predominates because the -OH group on the anomeric carbon is equatorial.
6

CH2 OH

HO HO

4 5 O 3 2 1

redraw as anomeric a chair carbon conformation HO

OH
4 6 5 2

O OH
1

anomeric carbon OH (equatorial)

OH

HO
3

OH F Anomer

CH2 OH

HO HO

4 5 O 3 2 1

redraw as a chair anomeric conformation HO carbon

OH
4 6 5 2

O
1

anomeric carbon

OH

HO
3

OH E Anomer of

HO OH (axial)

16-40 16-

Addition of Alcohols, in base

 Formation of a

hemiacetal can be base catalyzed.

fast and reversible

Step 1: proton transfer gives an alkoxide.

B
-

+ H OR

B H +

OR

Step 2: attack of RO- on the carbonyl carbon.

O CH3 -C-CH3 + O:

:O-R

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 + H OR OR

OH CH3 -C-CH3 + OR

OR

16-41 16-

Addition of Alcohols, in acid

 Formation of a
O CH3 -C-CH3 + H-A
H

hemiacetal can be acid catalyzed.

fast and reversible + O H A
-

Step 1: proton transfer to the carbonyl oxygen.

CH3 -C-CH3 +

Step 2: attack of ROH on the carbonyl carbon.. +

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

16-42 16-

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.
+

OH

OEt A hemiacetal

+ H-OEt

OEt

OEt A diethyl acetal

+ H2 O

16-43 16-

Addition of Alcohols, acetals

Step 1: proton transfer from HA gives an oxonium ion.
HO R-C-OCH 3 + H A H H + H O R-C-OCH 3 H An oxonium ion + A:-

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

+H O H

R-C OCH3

+ R-C OCH3

+ R-C OCH3

+ H2 O

H H A resonance-stabilized cation
16-44 16-

Addition of Alcohols, acetals

Step 3: reaction of the cation (an electrophile) with methanol (a nucleophile) gives the conjugate acid of the acetal.
H + CH3 -OH + R-C OCH3 H + CH 3 O

Step 4: proton transfer to A- gives the acetal and generates a new acid catalyst.
H + CH3 O A: + R-C OCH3 H OCH3 R-C-OCH3 + H-A H An acetal
16-45 16-

R-C OCH3 H A protonated acetal

(4)

Addition of Alcohols, cyclic acetals

with ethylene glycol and other glycols, the product is a fivemembered cyclic acetal. these are used as protective groups.
HO O + OH H
+

O O Cyclic acetal + H2 O

16-46 16-

DeanDean-Stark Trap, Fig. 16.1

16-47 16-

C. Acetals as Protecting Grps

 Suppose you wish to bring about a Grignard reaction

between these compounds.

O H Benzaldehyde + Br O H ?? OH O H 5-Hydroxy-5-phenylpentanal (racemic)

4-Bromobutanal

 But a

Grignard reagent prepared from 4-bromobutanal will self-destruct! (react with C=O)
16-48 16-

Acetals as Protecting Groups

So, first protect the -CHO group as an acetal,
O Br H + HO OH H
+

O Br O A cyclic acetal + H2 O

then do the Grignard reaction.

O Br O 1 . Mg, ether 2 . C6 H5 CHO

O- MgBr+ O O

A chiral magnesium alkoxide (produced as a racemic mixture)

hydrolysis (not shown) gives the target molecule.

16-49 16-

D. Acetals as Protecting Groups

 Tetrahydropyranyl (THP), as a

protecting group for an

THP group

alcohol.
RCH 2 OH + H+ RCH2 O O

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.
16-50 16-

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.
O CH3 CH + H 2 N Acetaldehyde Aniline
+

CH3 CH =N An imine (a Schiff base)

+ H2 O

N H3

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

16-51 16-

Cyclohexanone Ammonia

Addition of Nitrogen Nucleophiles

 Formation of an imine occurs in two steps.

Step 1: carbonyl addition followed by proton transfer.

O C + H2 N-R O: C
-

H + N-R H

O C

H N-R H

Step 2: loss of H2O and proton transfer to solvent.

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

+ O H +

C N-R H

16-52 16-

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:
O + H 2N H+ - H2 O N (An imine)

reduction:

Cyclohexanone Cyclohexylamine

H N (An imine) H2 / Ni N Dicyclohexylamine 16-53 16-

Addition of Nitrogen Nucleophiles

 Rhodopsin (visual purple) is the imine formed between 11-

cis-retinal (vitamin A aldehyde) and the protein opsin.

11 12

+ H2 N-opsin O Rhodopsin (Visual purple) H N-opsin

11-cis-Retinal

16-54 16-

Addition of Nitrogen 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 secondary amine)

the mechanism of enamine formation involves formation of a tetrahedral carbonyl addition compound followed by its acidcatalyzed dehydration. we discuss the chemistry of enamines in more detail in Chapter 19.
16-55 16-

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.
O + H2 NNH2 Hydrazine NNH2 + H2 O A hydrazone
Name of Derivative Formed Oxime Phenylhydrazone

Table 16.4

Reagent, H2N-R H2 N-OH H2 N-NH H2 N-NH O2 N O H2 N-NHCNH2 NO2

Name of Reagent Hydroxylamine Phenylhydrazine

2,4-Dinitrophenyl- 2,4-Dinitrophenylhydrazone hydrazine

Semicarbazide

Semicarbazone

16-56 16-

16.9 A. Acidity of E-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.

T ype of Bond

pK a 16 20 25 44 51

CH3 CH2 O-H O CH3 CCH 2 -H CH3 C C-H CH2 =CH-H CH3 CH2 -H

16-57 16-

Acidity of E-Hydrogens
 E-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=CH 2 + H-A

Resonance-stabilized enolate anion

16-58 16-

KetoKeto-Enol Tautomerism
protonation of the enolate anion on oxygen gives the enol form; protonation on carbon gives the keto form.
OCH3 - C= CH2 H- A

CH3 - C-CH2 H- A

Enolate anion O OH
-

+ CH3 - C-CH3
Keto form

CH3 - C= CH2 + A Enol form

16-59 16-

KetoKeto-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 and reversible + O H

CH3 -C-CH3 + AThe conjugate acid of the ketone

Step 2: proton transfer to the base A-.

+ O H
-

CH3 -C-CH2 -H + :A

slow

OH CH3 -C=CH2 + H-A Enol form

16-60 16-

B. Keto-Enol Tautomerism, Table 16.5 Keto Keto-enol

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

Keto form
O CH3 CH O CH3 CCH 3 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

16-61 16-

KetoKeto-Enol Tautomerism
 For certain types of molecules, however, the enol is

the

major form present at equilibrium.

for F-diketones, the enol is stabilized by conjugation of the pi system of the carbon-carbon double bond and the carbonyl group. for acyclic F-diketones, the enol is further stabilized by hydrogen bonding.

16-62 16-

16.10 A. 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.
CH 3 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

16-63 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

16-64 16-

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.

OH HNO 3 HO

O OH O Hexanedioic acid (Adipic acid)

Cyclohexanone Cyclohexanone (keto form) (enol form)

16-65 16-

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 RCH2 OH RCH3

Aldehydes O RCH

Ketones O RCR'

Can Be Reduced to OH RCHR' RCH2 R'

16-66 16-

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 Na
+

H Li
+

H- B- H

H- Al- H

H: Hydride ion

H Sodium borohydride

H Lithium aluminum hydride (LAH)

16-67 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

16-68 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.
This H comes from water during hydrolysis H
+

O BH3 Na R-C-R' H

Na H-B-H + R-C-R' H

H2 O

O-H R-C-R' H

This H comes from the hydride reducing agent

16-69 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 4 RCR + LiAlH4 ( R2 CHO) 4 Al Li A tetraalkyl aluminate
+

H2 O H+ or OH-

OH 4 RCHR + aluminum salts

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B. Catalytic Reduction
 Catalytic reductions are generally carried out at from 25

to

100C and 1 to 5 atm H2.

O + H2 Pt 25 oC, 2 atm Cyclohexanol 2 H2 OH

Cyclohexanone O

H Ni trans-2-Butenal (Crotonaldehyde)

OH 1-Butanol

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Catalytic Reduction
 A carbon-carbon double bond may also be reduced under

these conditions.
O 2 H2 H Ni trans-2-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.
O 1 . NaBH4 RCH=CHCR' 2 . H2 O
O RCH=CHCR' + H2 Rh

OH RCH=CHCHR'
O RCH2 CH 2 CR'

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C. Clemmensen Reduction, in acid

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

OH O Zn( H g) , HCl

OH

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WolffWolff-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.
O + H 2 NN H 2 Hydrazine KOH diethylene glycol (reflux)

+ N 2 + H2 O

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16.12 A. Racemization
 Racemization at an E-carbon may be catalyzed by either

acid or base.
O OH Ph An achiral enol O

Ph (R)-3-Phenyl-2butanone

Ph (S)-3-Phenyl-2butanone

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B. Deuterium Exchange
 Deuterium exchange at an E-carbon may be catalyzed by

either acid or base.

O CH 3 CCH 3 + 6 D 2 O Acetone O D CD 3 CCD 3 + 6 HOD or OD Acetone-d6
+

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C. E-Halogenation
 E-Halogenation: aldehydes and ketones with at least one E-

hydrogen react at an E-carbon with Br2 and Cl2.

O + Br2 Acetophenone CH3 COOH E-Bromoacetophenone O Br + HBr

reaction is catalyzed by both acid and base.

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E-Halogenation, in acid
 Acid-catalyzed E-halogenation.

Step 1: acid-catalyzed enolization.

OH R'-C-C-R R slow H-O C R' C R R

Step 2: nucleophilic attack of the enol on halogen.

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

Step 3: (not shown) proton transfer to solvent completes the reaction.

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E-Halogenation, in base
 Base-promoted E-halogenation.

Step 1: formation of an enolate anion.

OH R'-C-C-R + - :OH R slow O C - R C O: C C R + H2 O

R' R' R R Resonance-stabilized enolate anion

Step 2: nucleophilic attack of the enolate anion on halogen.

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

Br

E-Halogenation, in acid

 Acid-catalyzed halogenation:

introduction of a second halogen is slower than the first. introduction of the electronegative halogen on the E-carbon decreases the basicity of the carbonyl oxygen toward protonation.

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E-Halogenation, in base
 Base-promoted E-halogenation:

each successive halogenation is more rapid than the previous one. the introduction of the electronegative halogen on the Ecarbon increases the acidity of the remaining E-hydrogens and, thus, each successive E-hydrogen is removed more rapidly than the previous one.

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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 at 2710 cm-1 and 2810 cm-1.
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H1 NMR of butanal

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C13 NMR of 2-heptanone 2-

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MS of butanal

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McLafferty Rearrangement of butanal

 Loss of alkene (even mass number)  Must have K-hydrogen

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Aldehydes & Ketones

End Chapter 16
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