Ch16 Aldehyde Keton

8/9/2019 Ch16 Aldehyde Keton

1/52

Created byProfessor William Tam & Dr. Phillis Chang

Ch. 16 - 1

Chapter 16

Aldehydes & Ketones:Nucleophilic Additionto the Carbonyl Group

Ch. 16 - 2

About The Authors

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

Professor William Tam received his B.Sc. at the University of Hong Kong in1990 and his Ph.D. at the University of Toronto (Canada) in 1995. He was anNSERC postdoctoral fellow at the Imperial College (UK) and at HarvardUniversity (USA). He joined the Department of Chemistry at the University ofGuelph (Ontario, Canada) in 1998 and is currently a Full Professor and

Associate Chair in the department. Professor Tam has received several awardsin research and teaching, and according to Essential Science Indicators , he iscurrently ranked as the Top 1% most cited Chemists worldwide. He haspublished four books and over 80 scientific papers in top international journalssuch 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, herM.Sc. and Ph.D. in 1997 and 2001 at the University of Guelph (Canada). Shelives in Guelph with her husband, William, and their son, Matthew.


2/52

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 andstarting at the carbonyl carbon


3/52

Ch. 16 - 5

ExamplesCl

H

O4-Chloro-2,2-dimethylpentan al

12345

O

Br

1

2 3 4 5 6

7

6-Bromo-4-ethyl-3-heptan one

Ch. 16 - 6

group as a prefix: methanoylor formyl group

O

H

group as a prefix: ethanoyl or

acetyl group (Ac)

O

groups as a prefix: alkanoyl or

acyl groups

O

R


4/52

Ch. 16 - 7

2-Methanoyl benzoic acid(o- formyl benzoic acid)

CO2H

H

O

4-Ethanoylbenzenesulfonic acid( p- acetyl benzenesulfonic acid)

SO3H

O

Ch. 16 - 8

3. Physical Properties

Butane

bp -0.5 oC

(MW = 58)

H

O O

OH

Propanal

bp 49 oC

(MW = 58)

Butane

bp 56.1 oC

(MW = 58)

1-Propanol

bp 97.2 oC

(MW = 60)


5/52

Ch. 16 - 9

4. Synthesis of Aldehydes

4A. Aldehydes by Oxidation of 1o

Alcohols

R OHR H

OPCC

Ch. 16 - 10

OH O

H

PCC

CH2Cl2(90%)

PCC

CH2Cl2

OH O

H(89%)

e.g.


6/52

Ch. 16 - 11

4B. Aldehydes by Ozonolysis of Alkenes

R'

R

H

R"

OR'

R O

H

R"1. O 3

2. Me 2S+

Ch. 16 - 12

O

OH

1. O 3, CH2Cl2, -78oC

2. Me 2S

+

e.g.

H3C

1. O 3, CH2Cl2, -78oC

2. Me 2S

O

H3C

H

+O

H H


7/52

Ch. 16 - 13

4C. Aldehydes by Reduction of AcylChlorides, 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 easilyreduced

● Usually reduced all the way to thecorresponding 1 o alcohol

● Difficult to stop at the aldehydestage

Not a good method tosynthesize aldehydes usingLiAlH4


8/52

Ch. 16 - 15

Two derivatives of aluminum hydridethat are less reactive than LAH

Lithium tri- tert -butoxy

aluminum hydride

AlR

OtBu

AlLi+ H OtBu

OtBu

Diisobutylaluminum hydride

(abbreviated i- Bu2 AlH or DIBAL-H)

Ch. 16 - 16

1. LiAlH(OtBu)3, -78oC

2. H 2O

O

R Cl

O

R OR'

R C N

O

R H

1. DIBAL-H, hexane, -78 oC

2. H 2O

1. DIBAL-H, hexane

2. H 2O

Acyl chloride

Ester

Nitrile


9/52

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, Et 2O, -78oC

2. H 2O

Cl

O

CH3

H

O

CH3

Ch. 16 - 18

Reduction of an Acyl Chloride to an Aldehyde

LiAlH(O tBu)3R C

Cl

O

R CCl

O Li+ Al(O tBu)3

H

R C

Cl

O

H

Li

Al(OtBu)3R C

Cl

O

H

Al(OtBu)3

Li

R CH

O Al(OtBu)3-LiCl

R CH

OH2O


10/52

Ch. 16 - 19

Aldehydes from esters and nitriles :RCO 2R’ RCHORC≡ N RCHO

● Both esters and nitriles can bereduced to aldehydes by DIBAL-H

Ch. 16 - 20

Reduction of an ester to an aldehyde

R COR'

O

H

Al(i -Bu)2 R COR'

O Al(i -Bu)2

H

R C

OR'

OH

Al(i -Bu)2R C

H

O H2O


11/52

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 CN

H

Al(i -Bu)2R C

H

O H2O

Ch. 16 - 22

Examples


2. H 2O(1)

O

O

OH

H

O


2. H 2O

(2) C

H

O

N


12/52


13/52

Ch. 16 - 25

Ketones from arenes by Friedel–Craftsacylations

O

R Cl

AlCl3 R

O

+ HCl+

an alkyl aryl

ketone

Ch. 16 - 26

Ketones from secondary alcohols byoxidation

OH

R R'

O

R R'

H2CrO4

or PCC


14/52

Ch. 16 - 27

5B. Ketones from Nitriles

R C N1. R' M, Et2O

N M

R'R

2. H 3O+

O

R'R

Ch. 16 - 28

Examples

C N

O

Me1. MeLi, Et2O

2. H 3O+

C N1. , Et 2O2. H 3O

+MgBr

O


15/52

Ch. 16 - 29

Suggest synthesis of

O

from andBr

HO

Ch. 16 - 30

Retrosynthetic analysis

O

HO

need to addone carbon

5 carbons here 4 carbons here


16/52


17/52

Ch. 16 - 33

Suggest synthesis of

O

from andBr

HO

Ch. 16 - 34


O

HO

no need toadd carbon

5 carbons here

5 carbons here


18/52

Ch. 16 - 35


O

MgBr

+H

O

HO

disconnection

Ch. 16 - 36

Synthesis

O

PCC

2. H 3O+

1. , Et 2O

MgBr

HO O

OH

PCC


19/52

Ch. 16 - 37

6. Nucleophilic Addition to the

Carbon–Oxygen Double BondStructureO

C

~ 120 o

~ 120 o

~ 120 o

● Carbonyl carbon: sp 2 hybridized● Trigonal planar structure

Nu⊖

Ch. 16 - 38

Polarization and resonance structure

C

O O

C

● Nucleophiles will attack thenucleophilic carbonyl carbon

● Note: nucleophiles usually do notattack non-polarized C=C bond


20/52

Ch. 16 - 39

With a strong nucleophile:

C OR

R'Nu: C O:

R

R'

Nu

H Nu

C O

R

R'

Nu

HNu: +

Ch. 16 - 40

Also would expect nucleophilic additionreactions of carbonyl compounds to becatalyzed by acid (or Lewis acid)

O

C H+

O

C

HO

C

H

(protonated carbonyl group)

+

● Note: full positive charge on thecarbonyl carbon in one of theresonance forms

Nucleophiles readily attack


21/52

Ch. 16 - 41

+ A:C OHR

R'

C OHR

R'

Mechanism

C OR

R'H A +

(or a Lewis acid)

Ch. 16 - 42

+ A:C O

R

R'

NuH

H

C OHR

R':Nu H

Mechanism

C O

R

R'

:NuH

H A +


22/52

Ch. 16 - 43

6A. Reversibility of Nucleophilic Additions to the Carbon – OxygenDouble Bond

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

Ch. 16 - 44

6B. Relative Reactivity: Aldehydesvs. Ketones

O

R H

O

R R'

O

R OR'> >


23/52

Ch. 16 - 45

large

small

O

R H

O

R Nu

H

Nu

O

R R'

O

R

Nu

R'

Nu

Steric factors

Ch. 16 - 46

O

CR H

O

CR R' > >< <

Electronic factors

(positive inductiveeffect from onlyone R group)

(positive inductive effect fromboth R & R' groups) carbonylcarbon less + (lessnucleophilic)


24/52

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

R C

R'

O:H

OR"

H+

R C

R'

O H

+ R"OH

OH

R O

R' R"

H


25/52

Ch. 16 - 49

Mechanism (Cont’d)

OH

R O

R' R"

H R"OHOH

R OR"

R'R"

OH

H

hemi-acetal (R' = H) or

hemi-ketal (R' = alkyl)

+

OH2

R OR"

R'R C

R'

O

R"

H2O +

Ch. 16 - 50

R C

R'

OR"

R"OH


OR"

R O

R' R"

H

R"OH

OR"

R OR"

R'

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


26/52

Ch. 16 - 51

Note: All steps are reversible. In thepresence of a large excess ofanhydrous alcohol and catalyticamount of acid, the equilibriumstrongly favors the formation of acetal(from aldehyde) or ketal (from ketone)On the other hand, in the presence ofa large excess of H 2O and a catalyticamount of acid, acetal or ketal willhydrolyze back to aldehyde or ketone.This process is called hydrolysis

Ch. 16 - 52

Acetals and ketals are stable in neutralor basic solution, but are readilyhydrolyzed in aqueous acid

H+OR"

R OR"

R'

H2OO

R R'+ + 2 R"OH


27/52

Ch. 16 - 53

Aldehyde hydrates: gem-diols

H2O+OH

H3C

H

H3C O

O

H

H

Acetaldehyde Hydrate(a gem -diol)

Ch. 16 - 54

C OH

H3C OH2

Mechanism

OH2H3C

O:H

OHH3C

OHH

OHHO

HR

O

R H+ H 2Odistillation


28/52

Ch. 16 - 55

HO

OO

O

O

OH

H

Butanal-4-ol

A cyclichemiacetal

Hemiacetal: OH & OR groupsbonded to the same carbon

7A. Hemiacetals

Ch. 16 - 56

(+)-Glucose(A cyclic hemiacetal)

OHO

HO OHOH

OH Hemiacetal: OH & ORgroups bonded to thesame carbon


29/52

Ch. 16 - 57

Sucrose(table sugar)

O

O

OHO

OH

HOHO

OHHO

OH

OH An acetal

A ketal

7B. Acetals

Ch. 16 - 58

+O

R R'

HOOH

H3O+

O O

R R'

+ H2O

Ketone (excess) Cyclic acetal

Cyclic acetal formation is favored whena ketone or an aldehyde is treated withan excess of a 1,2-diol and a trace ofacid


30/52

Ch. 16 - 59

+

O

R R'

HOOH

H3O+

O O

R R'

+ H2O

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

Ch. 16 - 60

7C. Acetals Are Used as Protecting Groups Although acetals are hydrolyzed toaldehydes and ketones in aqueous acid,acetals are stable in basic solutions

R'O OR"

R H H2O

OHNo Reaction

O O

R R'H2O

OHNo Reaction

Acetals are used to protect aldehydes andketones from undesired reactions in basicsolutions


31/52

Ch. 16 - 61

O

OH

Br

O

Attempt tosynthesize:

from:

Example

Ch. 16 - 62

O

O

OH

BrMg

O

+

● Synthetic plan

This route will not work


32/52

Ch. 16 - 63

BrMg

O

Reason:(a) Intramolecular nucleophilic addition

(b) Homodimerization or polymerization

BrMg

O

BrMg

O

BrMg

O

Ch. 16 - 64

Br

O O

HOThus, need to “protect” carbonyl group first

Br

O O

HOOH

, H+

(ketal)

BrMg

O O

MgEt2O

O

OMgBr

O O

aqueous H +


33/52

Ch. 16 - 65

7D. Thioacetals

Aldehydes & ketones react with thiolsto form thioacetalsEtS SEt

R H

O

R H

2 EtSH

HA + H2O

Thioacetal

O

R R' BF3 + H2O

S S

R R'

HSSH

Cyclicthioacetal

Ch. 16 - 66

Thioacetal formation with subsequent “desulfurization” with hydrogen andRaney nickel gives us an additionalmethod for converting carbonyl groupsof aldehydes and ketones to –CH 2 –groups

H2, Raney Ni

+ NiS

S S

R R'HS SH

R R'

H H+


34/52

Ch. 16 - 67

8. The Addition of Primary and

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

From a 1 o amine From a 2 o amine

N

R 1 R 2

R 3

Imine

R 1

NR 5

R 2

R 3

R 4

Enamine

R 1, R 2, R 3 = C or H;R 4, R 5 = C

Ch. 16 - 68

8A. Imines

Addition of 1 o amines to aldehydes &ketones

R

R'O H2N R"

R

R'N

R"

H++

(1o amines) (imines)

[(E ) & ( Z ) isomers]

+ H2O


35/52

Ch. 16 - 69

H2NR"

Mechanism

R R'

O H3O+

R R'

OH O

R R'

H

N R"

H

H

-H+

O

R R'

H

NHR"

(amino alcohol)

H+OH2

R R'

NHR"NR'

R

R"

H

H2O

NR'

R

R"

Ch. 16 - 70

Similar to the formation of acetals andketals, all the steps in the formation ofimine are reversible. Using a largeexcess of the amine will drive theequilibrium to the imine sideHydrolysis of imines is also possible byadding excess water in the presence ofcatalytic amount of acid

NR'

R

R"H2O

H+O

R'

R + + H2NR"


36/52

Ch. 16 - 71

8B. Oximes and Hydrazones

Imine formation – reaction with a 1o

amineC O H2N R C N+

R + H2O

a 1 o 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 withhydroxylamine

Ch. 16 - 72

Hydrazone formation – reaction withhydrazine

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

R R

enamine

Enamine formation – reaction with a 2 o amine


37/52

Ch. 16 - 73

8C. Enamines

N R 5+

N

+ H2O

2o amine

cat. HA O

C R 3

R 2H

R 1

R 4H

R 4 R 5

enamine

R 3R 1

R 2

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


38/52

Ch. 16 - 75

C C

H

O

N R

R

H

A H +


C C

H

O

N R

R

HH

iminium ionintermediate

C

H

CN

R

R :A + H 2O +

Ch. 16 - 76

C

H

CN

R

R

A:



39/52

Ch. 16 - 77

9. The Addition of Hydrogen

Cyanide: Cyanohydrins Addition of HCN to aldehydes & ketones

R R'

OHCN

OH

R R'

CN

O

R R'

CNH+

CN

(cyanohydrin)

Ch. 16 - 78

R R'

O CN

Mechanism

O

R R'

CN(slow)

NC H

OH

R R'

CN


40/52

Ch. 16 - 79

Slow reaction using HCN since HCN is aweak acid and a poor source ofnucleophileCan accelerate reaction by using NaCNor KCN and slow addition of H 2SO4

R R'

O

NaCN

O Na

R

CN

R'

OH

R

R'

CNH2SO4

Ch. 16 - 80

R'

OHCN

R R'

R HO CN

R'R

COOH95% H 2SO4

heat

HCl, H2O

heat R'R

HO COOH

1. LiAlH4

2. H 2O R'R

HO NH2

( -hydroxy acid)

( , -unsaturated acid)

( -aminoalcohol)

Synthetic applications


41/52

Ch. 16 - 81

10. The Addition of Ylides: The

Wittig ReactionR

R'O

aldehydeor ketone

+ (C6 H5 )3 P CR"

R"

C CR'

R

R"

R"

O P(C6 H5 )3+

phosphorus ylide(or phosphorane)

alkene[(E) & (Z) isomers]

triphenyl-phosphine

oxide

Ch. 16 - 82

Phosphorus ylides

(C6H5)3P CR"

R"(C6H5)3P C

R"

R"

(C6H5)3P CHR"'

R"(C6H5)3P: XXCH

R"'

R"+

triphenyl-phosphine

an alkyltriphenylphos-phonium halide

(C6H5)3P C

R"'

R"

H :B + H:B(C6H5)3P CR"'

R"

a phosphorusylide


42/52

Ch. 16 - 83

Example

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

Methyltriphenylphos-phonium bromide

(89%)

CH3Br C6H6

(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 CR

R'

R"

R"O P(C6H5)3 +

alkene(+ diastereomer)

triphenylphosphineoxide

: :


43/52

Ch. 16 - 85

10A. How to Plan a Witting Synthesis

Synthesis of

using a Wittig reaction

Ch. 16 - 86


disconnection

O

Ph3P+route 1

BrPh3P: +route 2

PPh3

O+

Br

+ :PPh 3


44/52

Ch. 16 - 87

Synthesis – Route 1

O

Ph3PBr:PPh 3

Br

nBuLi

Ph3P

Ch. 16 - 88

Synthesis – Route 2

PPh3 Br

O

:PPh 3

nBuLi

Br

PPh3


45/52

Ch. 16 - 89

10B. The Horner – Wadsworth – EmmonsReaction

P OEt

O

OEt

NaH

+ H 2

P OEt

O

OEt

a phosphonateester

Ch. 16 - 90

+P OEt

O

OEt

H

O

EtO P O

O

EtONa+

84%


46/52

Ch. 16 - 91

P OEtO

OEt

X

OEt

PEtO OEt

+

EtX +

Triethyl phosphite

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

Ch. 16 - 92

11. Oxidation of Aldehydes

R H

O O

R O

O

R OH

H3O+

KMnO4, OH

or Ag 2O, OH


47/52

Ch. 16 - 93

12. Chemical Analyses for Aldehydesand Ketones

R

R'O + NO2

O2N

N

H

H2N

R

R'

N

NH

NO2

O2N

H

hydrazine

hydrazone(orange ppt.)

12A. Derivatives of Aldehydes & Ketones

Ch. 16 - 94

R H

O O

R O

Ag(NH3)2

H2O+ Ag

silvermirror

12B. Tollens ’ Test (Silver Mirror Test)


48/52

Ch. 16 - 95

13. Spectroscopic Properties of

Aldehydes and Ketones13A. IR Spectra of Aldehydes and Ketones

Range (cm )

R CHO Ar CHO

C CCHO

C CCOR

RCOR ArCOR

Compound Range (cm )Compound

Cyclohexanone

Cyclopentanone

Cyclobutanone

1715

1751

1785

1720 - 17401695 - 1715

1680 - 1690

1705 - 17201680 - 1700

1665 - 1680

C=O Stretching Frequencies

Ch. 16 - 96

Conjugation of the carbonyl group witha double bond or a benzene ring shiftsthe C=O absorption to lowerfrequencies by about 40 cm -1

O Osingle bond


49/52

Ch. 16 - 97

Ch. 16 - 98

13B. NMR Spectra of Aldehydes andKetones

13C NMR spectra● The carbonyl carbon of an aldehyde

or ketone gives characteristic NMRsignals in the 180–220 ppm region of 13C spectra


50/52

Ch. 16 - 99

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

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

● Protons on the carbon are deshieldedby the carbonyl group, and their signalsgenerally appear in the 2.0–2.3 ppm region

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

Ch. 16 - 100


51/52

Ch. 16 - 101

Ch. 16 - 102

14. Summary of Aldehyde andKetone Addition Reactions

O

OH

R 1. RM

2. H 3O+

OH

H1. LiAlH4 or NaBH 4

2. H 3O+

OH

CN

1. NaCN

2. H 3O+

R R PPh3

RO OR

2 ROH, H +

NR

R-NH2, H+

R 2NH

H+

NR 2


52/52

Ch. 16 - 103

END OF CHAPTER 16

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Ch16 Aldehyde Keton