Modified from sides of William Tam & Phillis ChangCh. 16 - 1

Chapter 16Chapter 16

Aldehydes & Ketones:Aldehydes & Ketones:Nucleophilic AdditionNucleophilic Additionto the Carbonyl Groupto the Carbonyl Group

Ch. 16 - 2

About The AuthorsAbout The Authors

These PowerPoint Lecture Slides were created and prepared by Professor William Tam and his wife, Dr. Phillis Chang.

Professor William Tam received his B.Sc. at the University of Hong Kong in 1990 and his Ph.D. at the University of Toronto (Canada) in 1995. He was an NSERC postdoctoral fellow at the Imperial College (UK) and at Harvard University (USA). He joined the Department of Chemistry at the University of Guelph (Ontario, Canada) in 1998 and is currently a Full Professor and Associate Chair in the department. Professor Tam has received several awards in research and teaching, and according to Essential Science Indicators, he is currently ranked as the Top 1% most cited Chemists worldwide. He has published four books and over 80 scientific papers in top international journals such as J. Am. Chem. Soc., Angew. Chem., Org. Lett., and J. Org. Chem.

Dr. Phillis Chang received her B.Sc. at New York University (USA) in 1994, her M.Sc. and Ph.D. in 1997 and 2001 at the University of Guelph (Canada). She lives in Guelph with her husband, William, and their son, Matthew.

Ch. 16 - 3

1. Introduction

Carbonyl compounds

O

R R'ketone

O

R Haldehyde

O

R OR'ester

(R, R' = alkyl, alkenyl, alkynyl or aryl groups)

Ch. 16 - 4

2. Nomenclature of Aldehydes &Ketones

Rules● Aldehyde as parent (suffix)

Ending with “al”;● Ketone as parent (suffix)

Ending with “one”● Number the longest carbon chain

containing the carbonyl carbon and starting at the carbonyl carbon

Ch. 16 - 5

ExamplesCl

H

O

4-Chloro-2,2-dimethylpentanal

12345

O

Br

12 3 4 5 6

7

6-Bromo-4-ethyl-3-heptanone

Ch. 16 - 6

group as a prefix: methanoyl or

formyl group

O

H

group as a prefix: ethanoyl or

acetyl group (Ac)

O

groups as a prefix: alkanoyl or

acyl groups

O

R

Ch. 16 - 7

2-Methanoylbenzoic acid(o-formylbenzoic acid)

CO2H

H

O

4-Ethanoylbenzenesulfonic acid(p-acetylbenzenesulfonic acid)

SO3H

O

Ch. 16 - 8

3. Physical Properties

Butane

bp -0.5oC

(MW = 58)

H

O O

OH

Propanal

bp 49oC

(MW = 58)

Butane

bp 56.1oC

(MW = 58)

1-Propanol

bp 97.2oC

(MW = 60)

Ch. 16 - 9

4. Synthesis of Aldehydes

4A.4A. Aldehydes by Oxidation of 1Aldehydes by Oxidation of 1oo AlcoholsAlcohols

R OHR H

OPCC

Ch. 16 - 10

OH O

H

PCC

CH2Cl2(90%)

PCC

CH2Cl2

OH O

H(89%)

e.g.

Ch. 16 - 11

4B.4B. Aldehydes by Ozonolysis ofAldehydes by Ozonolysis ofAlkenesAlkenes

R'

R

H

R"

O

R'

R

O

H

R"1. O3

2. Me2S+

Ch. 16 - 12

O

O

H

1. O3, CH2Cl2, -78oC

2. Me2S

+

e.g.

H3C

1. O3, CH2Cl2, -78oC

2. Me2S

O

H3C

H

+

O

H H

Ch. 16 - 13

4C.4C. Aldehydes by Reduction of AcylAldehydes by Reduction of AcylChlorides, Esters, and NitrilesChlorides, Esters, and Nitriles

LiAlH4R OH

O

R HLiAlH4

O

R OH

O

R OR'

O

R Cl

R C N

or

or

or

Ch. 16 - 14

LiAlH4 is a very powerful reducing agent, and aldehydes are easily reduced● Usually reduced all the way to the

corresponding 1o alcohol● Difficult to stop at the aldehyde

stage Not a good method to

synthesize aldehydes using LiAlH4

Ch. 16 - 15

Two derivatives of aluminum hydride that are less reactive than LAH

Lithium tri-tert-butoxyaluminum hydride

AlR

OtBu

AlLi+ H OtBu

OtBu

−

Diisobutylaluminum hydride(abbreviated i-Bu2AlH or DIBAL-H)

Ch. 16 - 16

1. LiAlH(OtBu)3, -78oC

2. H2O

O

R Cl

O

R OR'

R C N

O

R H

1. DIBAL-H, hexane, -78oC

2. H2O

1. DIBAL-H, hexane

2. H2O

Acyl chloride

Ester

Nitrile

Ch. 16 - 17

Aldehydes from acyl chlorides: RCOCl RCHO

1.

2.

O

R Cl

O

R OH

O

R H

SOCl2

LiAlH(OtBu)3,

Et2O, -78oC

H2O

e.g.

1. LiAlH(OtBu)3, Et2O, -78oC

2. H2O

Cl

O

CH3

H

O

CH3

Ch. 16 - 18

Reduction of an Acyl Chloride to an Aldehyde

LiAlH(OtBu)3R C

Cl

O

R C

Cl

O Li+ Al(OtBu)3

H

R C

Cl

O

H

Li

Al(OtBu)3R C

Cl

O

H

Al(OtBu)3

Li

R C

H

O Al(OtBu)3-LiCl

R C

H

OH2O

Ch. 16 - 19

Aldehydes from esters and nitriles: RCO2R’ RCHO

RC≡N RCHO● Both esters and nitriles can be

reduced to aldehydes by DIBAL-H

Ch. 16 - 20

Reduction of an ester to an aldehyde

R C

OR'

O

H

Al(i-Bu)2 R C

OR'

O Al(i-Bu)2

H

R C

OR'

O

H

Al(i-Bu)2

R C

H

O H2O

Ch. 16 - 21

Reduction of a nitrile to an aldehyde

R C N

H

Al(i-Bu)2 Al(i-Bu)2

H

NCR

R C

N

H

Al(i-Bu)2R C

H

O H2O

Ch. 16 - 22

Examples

1. DIBAL-H, hexane, -78oC

2. H2O(1)

O

O

OH

H

O

1. DIBAL-H, hexane, -78oC

2. H2O

(2) C

H

O

N

Ch. 16 - 23

5. Synthesis of Ketones

5A.5A. Ketones from Alkenes, Arenes,Ketones from Alkenes, Arenes,and 2and 2oo Alcohols Alcohols

Ketones (and aldehydes) by ozonolysis of alkenes

R'

R

H

R"

O

R'

R

O

H

R"1. O3

2. Me2S+

Ch. 16 - 24

Examples

1. O3

2. Me2S

O

O

(i)

OO

H

+

(ii)1. O3

2. Me2S

Ch. 16 - 25

Ketones from arenes by Friedel–Crafts acylations

O

R Cl

AlCl3 R

O

+ HCl+

an alkyl arylketone

Ch. 16 - 26

Ketones from secondary alcohols by oxidation

OH

R R'

O

R R'

H2CrO4

or PCC

Ch. 16 - 27

5B.5B. Ketones from NitrilesKetones from Nitriles

R C N1. R'−M, Et2O

N M

R'R

2. H3O+

Ch. 16 - 28

Examples

C N

O

Me1. MeLi, Et2O

2. H3O+

C N1. , Et2O

2. H3O+

MgBr

O

Ch. 16 - 29

Suggest synthesis of

O

from andBr

HO

Ch. 16 - 30

Retrosynthetic analysis

O

HO

need to add one carbon

5 carbons here 4 carbons here

Ch. 16 - 31

Retrosynthetic analysisO

C

MgBr

N+

NC

Br

+

HO

disconnection

disconnection

Ch. 16 - 32

Synthesis

O

HO Br

CN

PBr3

NaCNDMSO

1.

2. H3O+

Et2O

MgBr

Ch. 16 - 33

Suggest synthesis of

O

from andBr

HO

Ch. 16 - 34

Retrosynthetic analysis

O

HO

no need to add carbon

5 carbons here

5 carbons here

Ch. 16 - 35

Retrosynthetic analysis

O

MgBr

+H

O

disconnection

Ch. 16 - 36

Synthesis

O

PCC

2. H3O+

1. , Et 2O

MgBr

HO O

OH

PCC

Ch. 16 - 37

6. Nucleophilic Addition to theCarbon–Oxygen Double Bond

StructureO

C

~ 120o

~ 120o

~ 120o

δ−

● Carbonyl carbon: sp2 hybridized● Trigonal planar structure

Nu⊖

Ch. 16 - 38

Polarization and resonance structure

C

O

δ+

O

C

δ−

● Nucleophiles will attack the nucleophilic carbonyl carbon

● Note: nucleophiles usually do not attack non-polarized C=C bond

Ch. 16 - 39

With a strong nucleophile:

δ+ δ−C O

R

R'

Nu: C O:

R

R'

Nu

H Nu

C O

R

R'

Nu

HNu: +

Ch. 16 - 40

Also would expect nucleophilic addition reactions of carbonyl compounds to be catalyzed by acid (or Lewis acid)

O

C H+O

C

HO

C

H

(protonated carbonyl group)

+

● Note: full positive charge on the carbonyl carbon in one of the resonance forms Nucleophiles readily attack

Ch. 16 - 41

+ A:C OH

R

R'

C OH

R

R'

Mechanism

δ+ δ−C O

R

R'

H A+

(or a Lewis acid)

Ch. 16 - 42

+ A:C O

R

R'

Nu

H

H

C OH

R

R'

:Nu H

Mechanism

C O

R

R'

:Nu

H

H A+

Ch. 16 - 43

6A.6A. Reversibility of NucleophilicReversibility of NucleophilicAdditions to the CarbonAdditions to the Carbon––OxygenOxygenDouble BondDouble Bond

Many nucleophilic additions to carbon–oxygen double bonds are reversible; the overall results of these reactions depend, therefore, on the position of an equilibrium

Ch. 16 - 44

6B.6B. Relative Reactivity: AldehydesRelative Reactivity: Aldehydesvs. Ketonesvs. Ketones

O

R H

O

R R'

O

R OR'> >

Ch. 16 - 45

large

small

O

R H

O

RNu

H

Nu

O

R R'

O

RNu

R'

Nu

Steric factors

Ch. 16 - 46

O

CR H

O

CR R'

δ−

δ+

δ−

δ+> >< <

Electronic factors

(positive inductive effect from only one R group)

(positive inductive effect from both R & R' groups) carbonyl carbon less δ+ (less nucleophilic)

Ch. 16 - 47

7. The Addition of Alcohols:Hemiacetals and Acetals

Acetal & Ketal Formation: Addition of Alcohols to Aldehydes

R R'

O

R R'

R"O OHH+

R R'

R"O OR"

+ R"OH

H+

R"OH

hemi-acetal (R' = H)hemi-ketal (R' = alkyl)

acetal (R' = H)ketal (R' = alkyl)

Catalyzed by acid

Ch. 16 - 48

O

CR R'

H+

+ R"OH

Mechanism

RC

R'

O:H

OR"

H

+

RC

R'

OH

+ R"OH

OH

R O

R' R"

H

Ch. 16 - 49

Mechanism (Cont’d)

OH

R O

R' R"

H R"OHOH

R OR"

R'

R"O

HH

hemi-acetal (R' = H) or

hemi-ketal (R' = alkyl)

+

OH2

R OR"

R'RC

R'

OR"

H2O +

Ch. 16 - 50

RC

R'

OR"

R"OH

Mechanism (Cont’d)

OR"

R O

R' R"

H

R"OH

OR"

R OR"

R'

acetal (R' = H) orketal (R' = alkyl)

Ch. 16 - 51

Note: All steps are reversible. In the presence of a large excess of anhydrous alcohol and catalytic amount of acid, the equilibrium strongly favors the formation of acetal (from aldehyde) or ketal (from ketone)

On the other hand, in the presence of a large excess of H2O and a catalytic amount of acid, acetal or ketal will hydrolyze back to aldehyde or ketone. This process is called hydrolysis

Ch. 16 - 52

Acetals and ketals are stable in neutral or basic solution, but are readily hydrolyzed in aqueous acid

H+OR"

R OR"

R'

H2OO

R R'+ + 2 R"OH

Ch. 16 - 53

Aldehyde hydrates: gem-diols

H2O+O

H

H3C

H

H3C O

O

H

H

Acetaldehyde Hydrate(a gem-diol)

Ch. 16 - 54

δ+ δ−C O

H

H3C OH2

Mechanism

OH2H3C

O:H

OHH3C

OHH

OHHO

HR

O

R H+ H2O

distillation

Ch. 16 - 55

HO

O

O

O

O

OH

H

Butanal-4-ol

A cyclichemiacetal

Hemiacetal: OH & OR groups bonded to the same carbon

7A.7A. HemiacetalsHemiacetals

Ch. 16 - 56

(+)-Glucose(A cyclic hemiacetal)

OHO

HO OH

OH

OH Hemiacetal: OH & OR groups bonded to the same carbon

Ch. 16 - 57

Sucrose(table sugar)

O

O

OHO

OH

HOHO

OHHO

OH

OHAn acetal

A ketal

7B.7B. AcetalsAcetals

Ch. 16 - 58

+O

R R'

HOOH

H3O+

O O

R R'

+ H2O

Ketone (excess) Cyclic acetal

Cyclic acetal formation is favored when a ketone or an aldehyde is treated with an excess of a 1,2-diol and a trace of acid

Ch. 16 - 59

+

O

R R'

HOOH

H3O+

O O

R R'

+ H2O

This reaction, too, can be reversed by treating the acetal with aqueous acid

Ch. 16 - 60

7C.7C. Acetals Are Used as Protecting GroupsAcetals Are Used as Protecting Groups Although acetals are hydrolyzed to

aldehydes and ketones in aqueous acid, acetals are stable in basic solutions

R'O OR"

R H H2O

OH−

No Reaction

O O

R R'H2O

OH−

No Reaction

Acetals are used to protect aldehydes and ketones from undesired reactions in basic solutions

Ch. 16 - 61

O

OH

Br

O

Attempt to synthesize:

from:

Example

Ch. 16 - 62

O

O

OH

BrMg

O

+

● Synthetic plan

This route will not work

Ch. 16 - 63

BrMg

O

δ+ δ−

Reason:

(a) Intramolecular nucleophilic addition

(b) Homodimerization or polymerization

BrMg

O

BrMg

O

BrMg

O

Ch. 16 - 64

Br

O O

HO

Thus, need to “protect” carbonyl group first

Br

O O

HOOH

, H+

(ketal)

BrMg

O O

MgEt2O δ+

δ− O

OMgBr

O O

aqueous H+

Ch. 16 - 65

7D.7D. ThioacetalsThioacetals

Aldehydes & ketones react with thiols to form thioacetals

EtS SEt

R H

O

R H

2 EtSH

HA+ H2O

Thioacetal

O

R R' BF3

+ H2OS S

R R'

HSSH

Cyclicthioacetal

Ch. 16 - 66

Thioacetal formation with subsequent “desulfurization” with hydrogen and Raney nickel gives us an additional method for converting carbonyl groups of aldehydes and ketones to –CH2– groups

H2, Raney Ni

+ NiS

S S

R R'HS

SH

R R'

H H+

Ch. 16 - 67

8. The Addition of Primary andSecondary Amines

Aldehydes & ketones react with 1o amines to form imines and with 2o amines to form enamines

From a 1o amine From a 2o amine

N

R1 R2

R3

Imine

R1

NR5

R2

R3

R4

Enamine

R1, R2, R3 = C or H;R4, R5 = C

Ch. 16 - 68

8A.8A. IminesImines

Addition of 1o amines to aldehydes & ketones

R

R'

O H2N R"

R

R'

NR"

H++

(1o amines) (imines)

[(E) & (Z) isomers]

+ H2O

Ch. 16 - 69

H2NR"

Mechanism

R R'

O H3O+

R R'

OH O

RR'

H

N R"

H

H

-H+

O

RR'

H

NHR"

(amino alcohol)

H+OH2

RR'

NHR"N

R'

R

R"

H

H2O

N

R'

R

R"

Ch. 16 - 70

Similar to the formation of acetals and ketals, all the steps in the formation of imine are reversible. Using a large excess of the amine will drive the equilibrium to the imine side

Hydrolysis of imines is also possible by adding excess water in the presence of catalytic amount of acid

N

R'

R

R"H2O

H+

O

R'

R

+ + H2NR"

Ch. 16 - 71

8B.8B. Oximes and HydrazonesOximes and Hydrazones Imine formation – reaction with a 1o amine

C O H2N R C N+

R

+ H2O

a 1o amine an imine

[(E) & (Z) isomers]aldehydeor ketone

C O H2N OH C N+

OH

+ H2O

hydroxylamine

an oxime

[(E) & (Z) isomers]

aldehydeor ketone

Oxime formation – reaction with hydroxylamine

Ch. 16 - 72

Hydrazone formation – reaction with hydrazine

C O H2NNH2 C N+NH2

+ H2O

hydrazine a hydrazonealdehydeor ketone

N R C C+

N

+ H2O

2o amine

cat. HA

O

CC

H R

H

RR

enamine

Enamine formation – reaction with a 2o amine

Ch. 16 - 73

8C.8C. EnaminesEnamines

N R5+

N

+ H2O

2o amine

cat. HAO

C R3

R2H

R1

R4

H

R4 R5

enamine

R3R1

R2

Ch. 16 - 74

N R+

O

CC

H R

H

Mechanism

C C

H

O

N

R

R

H

aminoalcoholintermediate

C C

H

O

N R

R

H

Ch. 16 - 75

C C

H

O

N R

R

H

A H +

Mechanism (Cont’d)

C C

H

O

N R

R

HH

iminium ionintermediate

C

H

C

N

R

R:A + H2O +

Ch. 16 - 76

C

H

C

N

R

R

A:

Mechanism (Cont’d)

enamine

C

H

CN

R

R

+ H A

Ch. 16 - 77

9. The Addition of HydrogenCyanide: Cyanohydrins

Addition of HCN to aldehydes & ketones

R R'

OHCN

OH

RR'

CN

O

RR'

CN

H+CN

(cyanohydrin)

Ch. 16 - 78

R R'

OCN

Mechanism

O

RR'

CN(slow)

NC H

OH

RR'

CN

Ch. 16 - 79

Slow reaction using HCN since HCN is a weak acid and a poor source of nucleophile

Can accelerate reaction by using NaCN or KCN and slow addition of H2SO4

R R'

O

NaCN

O Na

RCN

R'

OH

RR'

CNH2SO4

Ch. 16 - 80

R'

OHCN

RR'

RHO CN

R'R

COOH95% H2SO4

heat

HCl, H2O

heat R'R

HO COOH

1. LiAlH4

2. H2O R'R

HO NH2

(α-hydroxy acid)

(α,β-unsaturated acid)

(β-aminoalcohol)

Synthetic applications

Ch. 16 - 81

10. The Addition of Ylides: TheWittig Reaction

R

R'

O

aldehydeor ketone

+ (C6H5)3P C

R"

R"

C C

R'

R

R"

R"

O P(C6H5)3

+

phosphorus ylide(or phosphorane)

alkene[(E) & (Z) isomers]

triphenyl-phosphine

oxide

Ch. 16 - 82

Phosphorus ylides

(C6H5)3P C

R"

R"

(C6H5)3P C

R"

R"

(C6H5)3P CH

R"'

R"

(C6H5)3P: XXCH

R"'

R"

+

triphenyl-phosphine

an alkyltriphenylphos-phonium halide

(C6H5)3P C

R"'

R"

H :B + H:B(C6H5)3P C

R"'

R"

a phosphorusylide

Ch. 16 - 83

Example

(C6H5)3P CH3(C6H5)3P: Br+

Methyltriphenylphos-phonium bromide

(89%)

CH3BrC6H6

(C6H5)3P CH3

Br

+ C6H5Li (C6H5)3P CH2:

+ + LiBrC6H6

Ch. 16 - 84

Mechanism of the Wittig reaction

+C

O

R R'R"

:C R"'

P(C6H5)3: :

aldehydeor ketone

ylide

R'

C CR

:O

R"

R"'

P(C6H5)3

oxaphosphetane

:

C C

R

R'

R"

R"

O P(C6H5)3 +

alkene(+ diastereomer)

triphenylphosphineoxide

::

Ch. 16 - 85

10A. 10A. How to Plan a Witting SynthesisHow to Plan a Witting Synthesis

Synthesis of

using a Wittig reaction

Ch. 16 - 86

Retrosynthetic analysis

disconnection

O

Ph3P+route 1

BrPh3P: +route 2

PPh3

O+

Br

+ :PPh3

Ch. 16 - 87

Synthesis – Route 1

O

Ph3PBr:PPh3

Br

nBuLi

Ph3P

Ch. 16 - 88

Synthesis – Route 2

PPh3 Br

O

:PPh3

nBuLi

Br

PPh3

Ch. 16 - 89

10B. 10B. The HornerThe Horner––WadsworthWadsworth––EmmonsEmmons ReactionReaction

P OEt

O

OEt

NaH

+ H2

P OEt

O

OEt

a phosphonateester

Ch. 16 - 90

+P OEt

O

OEt

H

O

EtO P O

O

EtONa+

84%

Ch. 16 - 91

P OEt

O

OEt

X

OEt

PEtO OEt

+

EtX +

Triethyl phosphite

The phosphonate ester is prepared by reaction of a trialkyl phosphite [(RO)3P] with an appropriate halide (a process called the Arbuzov reaction)

Ch. 16 - 92

11. Oxidation of Aldehydes

R H

O O

R O−

O

R OH

H3O+

KMnO4, OH−

or Ag2O, OH−

Ch. 16 - 93

12. Chemical Analyses for Aldehydes and Ketones

R

R'

O + NO2

O2N

N

H

H2N

R

R'

N

N

H

NO2

O2N

H+

hydrazine

hydrazone(orange ppt.)

12A. 12A. Derivatives of Aldehydes & KetonesDerivatives of Aldehydes & Ketones

Ch. 16 - 94

R H

O O

R O−

Ag(NH3)2+

H2O+ Ag

silvermirror

12B. 12B. TollensTollens’’ Test (Silver Mirror Test) Test (Silver Mirror Test)

Ch. 16 - 95

13. Spectroscopic Properties of Aldehydes and Ketones

13A. 13A. IR Spectra of Aldehydes and KetonesIR Spectra of Aldehydes and Ketones

Range (cm−1)

R CHO

Ar CHO

C C

CHO

C C

COR

RCOR

ArCOR

Compound Range (cm−1)Compound

Cyclohexanone

Cyclopentanone

Cyclobutanone

1715

1751

1785

1720 - 1740

1695 - 1715

1680 - 1690

1705 - 1720

1680 - 1700

1665 - 1680

C=O Stretching Frequencies

Ch. 16 - 96

Conjugation of the carbonyl group with a double bond or a benzene ring shifts the C=O absorption to lower frequencies by about 40 cm-1

O Osingle bond

Ch. 16 - 97

Ch. 16 - 98

13B. 13B. NMR Spectra of Aldehydes andNMR Spectra of Aldehydes and KetonesKetones

13C NMR spectra● The carbonyl carbon of an aldehyde

or ketone gives characteristic NMR signals in the δ 180–220 ppm region of 13C spectra

Ch. 16 - 99

1H NMR spectra● An aldehyde proton gives a distinct 1H

NMR signal downfield in the δ 9–12 ppm region where almost no other protons absorb; therefore, it is easily identified

● Protons on the α carbon are deshielded by the carbonyl group, and their signals generally appear in the δ 2.0–2.3 ppm region

● Methyl ketones show a characteristic (3H) singlet near δ 2.1 ppm

Ch. 16 - 100

Ch. 16 - 101

Ch. 16 - 102

14. Summary of Aldehyde and Ketone Addition Reactions

O

OH

R1. RM

2. H3O+

OH

H1. LiAlH4 or NaBH4

2. H3O+

OH

CN

1. NaCN

2. H3O+

RR PPh3

RO OR

2 ROH, H+

NR

R-NH2, H+

R2NH

H+

NR2

Ch. 16 - 103

END OF CHAPTER 16