Chapter 16

Aldehydes & Ketones: Nucleophilic Addition to the Carbonyl Group

Ch. 16 - 1

1. Introduction
Carbonyl compounds y p
O R H aldehyde O R R' ketone R O OR' ester

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

Ch. 16 - 2

2. Nomenclature of Aldehydes & Ketones

Rules Aldehyde as parent (suffix) Ending with al; d h l Ketone as parent (suffix) p ( ) Ending with one Number the longest carbon chain containing the carbonyl carbon and starting at the carbonyl carbon
Ch. 16 - 3

Examples
Cl
5 4 3 2 1

O 4-Chloro-2,2-dimethylpentanal

Br
1 2 3 4 5 6 7

O 6-Bromo-4-ethyl-3-heptanone
Ch. 16 - 4

O H

group as a prefix: methanoyl

or formyl group
O

group as a prefix: ethanoyl or

acetyl group (A ) t l (Ac)

O R

groups as a prefix: alkanoyl or

Ch. 16 - 5

acyl groups

CO2H O H

2-Methanoylbenzoic acid (o-formylbenzoic acid)

SO3H

O 4-Ethanoylbenzenesulfonic acid (p acetylbenzenesulfonic acid) pCh. 16 - 6

3. Physical Properties
O H Butane bp -0.5 C (MW = 58)
o

O OH Butane bp 56.1 C (MW = 58)

o

Propanal bp 49 C (MW = 58)

o

1-Propanol bp 97.2 C (MW = 60)

o

Ch. 16 - 7

4. Synthesis of Aldehydes
4A. Aldehydes by Oxidation of 1 Alcohols
PCC R OH R O H
o

Ch. 16 - 8

e.g.
OH PCC CH2Cl2 (90%) H O

OH

PCC CH2Cl2 (89%) H

Ch. 16 - 9

4B. Aldehydes by Ozonolysis of Alkenes

R R' R" H 1. O3 2. Me2S R O R' + O H R"

Ch. 16 - 10

e.g.
1. O3, CH2Cl2, -78oC 2. 2 Me2S + O H O

H 1. O3, CH2Cl2, -78oC H3C 2. Me2S H3C + H O H O

Ch. 16 - 11

4C. Aldehydes by Reduction of Acyl Chlorides, Esters Chlorides Esters, and Nitriles
O R or O R or O R or R C N
Ch. 16 - 12

OH O OR' LiAlH4 R H LiAlH4 R OH

Cl

LiAlH4 is a very powerful reducing agent, and aldehydes are easily t d ld h d il reduced Usually reduced all the way to the o corresponding 1 alcohol p g Difficult to stop at the aldehyde stage Not a good method to synthesize aldehydes using th i ld h d i LiAlH4
Ch. 16 - 13

Two derivatives of aluminum hydride that are less reactive than LAH
OtBu Li+ H Al OtBu R Al OtBu Lithium t i t t-butoxy Lithi tri-tert b t aluminum hydride

Diisobutylaluminum h d id Dii b t l l i hydride (abbreviated i-Bu2AlH or DIBAL-H)

Ch. 16 - 14

O R Cl

1. LiAlH(OtBu)3, -78oC 2. H2O

Acyl chloride O R Ester 1. DIBAL-H, hexane R C N Nitrile 2. H2O

Ch. 16 - 15

1. DIBAL-H, hexane, -78 C OR OR' 2. 2 H2O R

O H

Aldehydes from acyl chlorides: RCOCl RCHO

O R OH SOCl2 R O 1. LiAlH(OtBu)3, Et2O -78 C O, 78 Cl 2. H2O R
o

O H

e.g.
O Cl 1. 1 LiAlH(OtBu)3, Et2O -78oC O, 78 2. H2O CH3 CH3
Ch. 16 - 16

O H

Reduction of an Acyl Chloride to an Aldehyde

O R C Cl LiAlH(OtBu)3

O R C Cl

Li

+ Al(OtBu)3 H

Li
O R C Cl Al(OtBu)3 H Li

O R C Cl H Al(OtBu)3 ( )

-LiCl R C

O
H

Al(OtBu)3

H2O

O R C
Ch. 16 - 17

Aldehydes from esters and nitriles: y RCO2R RCHO RCN RCHO Both esters and nitriles can be reduced to aldehydes by DIBAL-H d d t ld h d b DIBAL H

Ch. 16 - 18

Reduction of an ester to an aldehyde

O R C OR' Al(i-Bu)2 H

O R C OR'

Al(i-Bu)2 Bu) H

O R C H

H2O

O R C OR OR'

Al(i-Bu)2 ( ) H

Ch. 16 - 19

Reduction of a nitrile to an aldehyde

Al(i-Bu)2 H

Al(i-Bu)2 H

O R C H

H2O

N R C H

Al(i-Bu)2

Ch. 16 - 20

Examples
O (1) O 1. DIBAL-H, hexane, -78oC 1 DIBAL H h 78 2. H2O O H OH

(2)

1. DIBAL-H, hexane, -78oC 2. H2O

O H
Ch. 16 - 21

5. Synthesis of Ketones
5A. Ketones from Alkenes, Arenes, o and 2 Alcohols Ketones (and aldehydes) by ozonolysis of alkenes
R R' R" H 1. O3 2. Me2S R O R' + O H
Ch. 16 - 22

R"

Examples
() (i) 1. O3 2. Me2S

O
(ii) 1. O3 2. Me2S O H

+ O
Ch. 16 - 23

Ketones from arenes by FriedelCrafts acylations

O O + R Cl l an alkyl aryl y y ketone AlCl3 R + HCl

Ch. 16 - 24

Ketones from secondary alcohols by oxidation

OH R R' O R R'

H2CrO4 or PCC

Ch. 16 - 25

5B. Ketones from Nitriles

1. R'M, Et2O '
O R R'

2. 2 H3O+

N R

M R'

Ch. 16 - 26

Examples
1. MeLi, Et2O C N 2. H3O+ O Me

O C N 1. 2. H3O+ MgBr , Et2O

Ch. 16 - 27

Suggest synthesis of
O

Br

from

and

HO

Ch. 16 - 28

Retrosynthetic analysis
O HO

5 carbons here b h

4 carbons here need to add one carbon

Ch. 16 - 29

Retrosynthetic analysis
O
MgBr + N

disconnection
C

disconnection
NC + Br

HO
Ch. 16 - 30

Synthesis
HO PBr3 Br

MgBr 1. 1 O Et2O 2. H3O+ N C

NaCN DMSO

Ch. 16 - 31

Suggest synthesis of
O

Br

from

and

HO

Ch. 16 - 32

Retrosynthetic analysis
O HO

5 carbons here b h

5 carbons here no need to add carbon

Ch. 16 - 33

Retrosynthetic analysis
O

MgBr + H

disconnection
HO

Ch. 16 - 34

Synthesis
PCC HO O MgBr 1. 2. H3O+ O PCC OH , Et 2O

Ch. 16 - 35

6. Nucleophilic Addition to the CarbonOxygen D bl B d C b O Double Bond

Structure
~ 120o C ~ 120o O

~ 120o

Nu

Carbonyl carbon: sp2 hybridized Trigonal planar structure

Ch. 16 - 36

Polarization and resonance structure

O O C

C +

Nucleophiles will attack the nucleophilic carbonyl carbon Note: nucleophiles usually do not attack non-polarized C=C bond tt k l i dC Cb d
Ch. 16 - 37

With a strong nucleophile:

R' Nu: N R C O
+

Nu R' R
H Nu

O: O

Nu Nu: + R' R
Ch. 16 - 38

Also would expect nucleophilic addition reactions of carbonyl compounds to be ti f b l d t b catalyzed by acid (or Lewis acid)
O C + H+ O C H O C H

(protonated carbonyl group)

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

Ch. 16 - 39

Mechanism
R' R + + H C O A

(or a Lewis acid)

R' C R OH

R' C R
Ch. 16 - 40

OH

+ A:

Mechanism
R' C R OH :Nu N H

H Nu R'
R :Nu

+ H

A H

+ A:

R' R

Ch. 16 - 41

6A. Reversibility of Nucleophilic Additions to the CarbonOxygen Carbon Double Bond Many nucleophilic additions to carbon oxygen double bonds are reversible; the overall results of these reactions depend, therefore, on the position of d d th f th iti f an equilibrium

Ch. 16 - 42

6B. Relative Reactivity: Aldehydes vs. Ketones vs

O > R H R R' O > R OR' O

Ch. 16 - 43

Steric factors
O R H Nu R O Nu N H

smal l
O R R' Nu R

O Nu R'

large
Ch. 16 - 44

Electronic factors
(positive inductive effect from g p ) y both R & R' groups) carbonyl carbon less + (less nucleophilic) p )
O C< > + R' R

C< > + H R

(positive inductive effect from only y one R group)

Ch. 16 - 45

7. The Addition of Alcohols: Hemiacetals and A H i l d Acetals l

Acetal & Ketal Formation: Addition of Alcohols to Aldehydes
O + R"OH R R R' H+ R O R"O R hemi acetal OH hemi-acetal (R' = H) R R' hemi-ketal (R' = alkyl)

Catalyzed y by acid
acetal ( ' = H) l (R' ) ketal (R' = alkyl)

H+ R"OH R O R"O R

OR" R'
Ch. 16 - 46

Mechanism
O R C R' + R"OH H
+

O: R C R' +

R R" H

OH R R' O

H R" "
R

O C

H R R' + R"OH
Ch. 16 - 47

Mechanism (Contd)
O OH R R' ' O H R" R"OH "

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

R R'

OR"

R"

O H

H2O + R

O C

R R" R R'

OH2

OR" R'
Ch. 16 - 48

Mechanism (Contd)
O R C R" R"OH R'
R R R' OR" O H R" R OH R"OH

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

OR OR" R R'
Ch. 16 - 49

OR"

Note: All steps are reversible. In the presence of a l f large excess of f anhydrous alcohol and catalytic amount of acid, the equilibrium strongly favors the formation of acetal gy (from aldehyde) or ketal (from ketone) On the other hand in the presence of hand, a large excess of H2O and a catalytic amount of acid, acetal or ketal will acid hydrolyze back to aldehyde or ketone. This Thi process is called h d l i i ll d hydrolysis
Ch. 16 - 50

Acetals and ketals are stable in neutral or b i solution, but are readily basic l ti b t dil hydrolyzed in aqueous acid
OR" R R' OR" + H2O H+ R O R' + 2 R"OH

Ch. 16 - 51

Aldehyde hydrates: gem-diols

H3C O + H2O H Acetaldehyde H3C H O O H H

Hydrate (a gem-diol) diol)

Ch. 16 - 52

Mechanism
H3C
H
C+ O OH2

H3C H

OH2 O: O

H3C H

OH OH

HO R

OH H

distillation R

O H + H2O

Ch. 16 - 53

7A. Hemiacetals
H O Butanal-4-ol O O O H

O OH A cyclic hemiacetal
Ch. 16 - 54

Hemiacetal: OH & OR groups bonded to the same carbon

OH HO HO O OH OH

Hemiacetal: OH & OR groups bonded to the same carbon

(+)-Glucose (A cyclic hemiacetal)

Ch. 16 - 55

7B. Acetals
OH HO HO O OH HO O OH

A ketal

O HO OH

An acetal
Sucrose (table sugar)

Ch. 16 - 56

Cyclic acetal formation is favored when ak t ketone or an aldehyde is treated with ld h d i t t d ith an excess of a 1,2-diol and a trace of acid
O R R' (excess) + HO H3O+ OH O R O R'

Ketone

Cyclic acetal + H2O

Ch. 16 - 57

This reaction, too, can be reversed by treating the t ti th acetal with aqueous acid t l ith id
O R O R' HO + H2O H3O+ R + OH O R'

Ch. 16 - 58

7C. Acetals Are Used as Protecting Groups Although acetals are hydrolyzed to Alth h t l h d l dt aldehydes and ketones in aqueous acid,

acetals are stable in basic solutions t l t bl i b i l ti

R'O R OR" H OH H2O No Reaction

O R

O R'

OH H2O

No Reaction

Acetals are used to protect aldehydes and ketones from undesired reactions in basic solutions Ch. 16 - 59

Example
Attempt to synthesize: th i OH

O from: Br O

Ch. 16 - 60

 Synthetic plan
O + g BrMg O OH

This Thi route will not work ill k

Ch. 16 - 61

Reason: (a) Intramolecular nucleophilic addition

BrMg
+

(b) Homodimerization or polymerization

O BrMg BrMg BrMg O O

Ch. 16 - 62

Thus, need to protect carbonyl group first

HO Br O
HO Br O
Mg Et2O

O
OH , H
+

aqueous H+

OMgBr

( (ketal) )
O O + O O
O
Ch. 16 - 63

BrMg

7D. Thioacetals Aldehydes & ketones react with thiols to form thioacetals
O R H 2 EtSH HA EtS R SEt H + H2O

Thioacetal
O R R' HS BF3 SH S S

+ H2O

R R R' Cyclic thioacetal

Ch. 16 - 64

Thioacetal formation with subsequent desulfurization with hydrogen and d lf i ti ith h d d Raney nickel gives us an additional method for converting carbonyl groups of aldehydes and ketones to CH2 y groups
S R S R' H2, Raney Ni H R H R' + HS + NiS
Ch. 16 - 65

SH

8. The Addition of Primary and Secondary A i S d Amines

Aldehydes & ketones react with 1 o amines to form imines and with 2 amines to form enamines fo m
From a 1 amine
N R3 R3 R1 N R2 R4 Enamine R5 R1, R4, R2, R3 = C or H; R5 = C
Ch. 16 - 66

From a 2 amine

R2 R1 Imine

8A. Imines Addition of 1 amines to aldehydes & ketones

R O R' + H2N R" H
+

R N R' R" (imines) [(E) & (Z) isomers] + H2O

(1o amines)

Ch. 16 - 67

Mechanism
O R R' H3O
+

O R

H R'

H O H

H2NR"

R R'

N H

R"

-H+ H
R N R' R" H R R'

OH2
NHR"

H+

O
R R'

H
NHR"

H2O
R N R' R"

(amino l h l) ( i alcohol)

Ch. 16 - 68

Similar to the formation of acetals and ketals, ll th t k t l all the steps in the formation of i th f ti f imine are reversible. Using a large excess of the amine will drive the equilibrium to the imine side q Hydrolysis of imines is also possible by adding excess water in the presence of catalytic amount of acid
R N R' R" + H2O H
+

R O + H2NR" R'
Ch. 16 - 69

8B. Oximes and Hydrazones

Imine formation reaction with a 1 amine
R C O + H2N R C N + H2O
o

aldehyde y or ketone

a 1o amine

an imine [(E) & (Z) isomers]

Oxime formation reaction with hydroxylamine

OH C O + H2N OH C N + H2O

aldehyde or ketone

hydroxyl h d l amine

an oxime [(E) & (Z) isomers]

Ch. 16 - 70

Hydrazone formation reaction with hydrazine

C O + H2NNH2 NH2 C N + H2O

aldehyde hydrazine or ketone

a hydrazone

Enamine formation reaction with a 2 amine

O C H C + H N R cat. HA C R N C R

+ H2O

R 2o amine

enamine

Ch. 16 - 71

8C. Enamines
R1 H C R
2

O R
3

R + H N R4 2o amine R5 cat. HA R1

R5 R3

R2 enamine + H2O

Ch. 16 - 72

Mechanism
O C
H

R N H R

N
R

C H

O C H C

H N R R

aminoalcohol mino l ohol intermediate

Ch. 16 - 73

Mechanism (Contd)
O A H + C H C H N R R
H C H O C H N R R

R N :A + H2O + C C R

H iminium i i i i ion intermediate

Ch. 16 - 74

Mechanism (Contd)

R N

R R C H enamine C N R + H A

C H A:

Ch. 16 - 75

9. The Addition of Hydrogen Cyanide: C C id Cyanohydrins h d i

Addition of HCN to aldehydes & ketones
O R CN R R'
Ch. 16 - 76

HCN R R' O CN R

OH CN R' (cyanohydrin) H+

Mechanism
O R R' CN
(slow) R R R' NC H O CN

OH R R'
Ch. 16 - 77

CN

Slow reaction using HCN since HCN is a weak acid and a poor source of k id d f nucleophile Can accelerate reaction by using NaCN or KCN and slow addition of H2SO4
O R R' ' NaCN R CN O Na R R' H2SO4 R R' OH CN

Ch. 16 - 78

Synthetic applications
HCl, H2O heat HO R COOH R' (-hydroxy acid) COOH R

O R R'

HCN

HO R

CN R'

95% H2SO4 heat

R' (,-unsaturated ( -unsaturated acid) HO R NH2

1. LiAlH4 2. H2O

R' (-aminoalcohol)
Ch. 16 - 79

10. The Addition of Ylides: The Wittig R Wi i Reaction i

R O R R' aldehyde or ketone + (C6H5)3P C R R' R R" R R" phosphorus ylide (or phosphorane) R C C R R" R R"

alkene [(E) & (Z) isomers] + O P(C6H5)3 triphenylphosphine oxide

Ch. 16 - 80

Phosphorus ylides
R" (C6H5)3P C R" (C6H5)3P C R" R"

R" (C6H5)3P + P: R"' triphenylphosphine CH X (C6H5)3P

R" CH C X R"' an alkyltriphenylphosphonium halide

R" (C6H5)3P C R"' H :B (C6H5)3P C

R" + H:B R"' a phosphorus ylide

Ch. 16 - 81

Example
(C6H5)3P: + CH3Br C6H6 (C6H5)3P CH3 Br

Methyltriphenylphosp phonium bromide (89%)

(C6H5)3P Br

CH3

C6H5Li

(C6H5)3P

CH2:

+ C6H6 + LiBr

Ch. 16 - 82

Mechanism of the Wittig reaction

R C :O: aldehyde or ketone R' R" + :C R R"'

R' R" R C :O
:

R R"'

P(C6H5)3 ylide

P(C6H5)3

oxaphosphetane

R' : : O P(C6H5)3 + R triphenylphosphine oxide C C

R" R"
Ch. 16 - 83

alkene (+ diastereomer)

10A. How to Plan a Witting Synthesis

Synthesis of y using a Wittig reaction

Ch. 16 - 84

Retrosynthetic analysis
route 1 O + Ph3P

d sco ect o disconnection

route 2 oute PPh3 + O

Ph3P: + Br

Br + :PPh3
Ch. 16 - 85

Synthesis Route 1
:PPh3

Br

Ph3P
n

Br

BuLi

Ph3P

Ch. 16 - 86

Synthesis Route 2
Br PPh3 Br

:PPh3

BuLi B Li PPh3

Ch. 16 - 87

10B. The HornerWadsworthEmmons HornerWadsworth Reaction

O P OEt OEt + H2 NaH O P OEt OEt

a phosphonate ester

Ch. 16 - 88

O O P OEt OEt + H

O + 84%
Ch. 16 - 89

EtO P EtO

Na

The phosphonate ester is prepared by reaction of a t i lk l phosphite [(RO)3P] ti f trialkyl h hit with an appropriate halide (a process called the Arbuzov reaction)
OEt X + EtO P OEt

Triethyl phosphite EtX + O P OEt OEt

Ch. 16 - 90

11. Oxidation of Aldehydes

O R H KMnO4, OH or Ag2O, OH R O O H3O O R OH
Ch. 16 - 91

12. Chemical Analyses for Aldehydes and Ketones

12A. Derivatives of Aldehydes & Ketones
R O + H2N R' O2N H
+

H N NO2 hydrazine R N R' hydrazone (orange ppt.) H O2N

Ch. 16 - 92

NO2

12B. Tollens Test (Silver Mirror Test) Tollens

O R H

Ag(NH3)2+ H2O R

O O + Ag silver mirror

Ch. 16 - 93

13. Spectroscopic Properties of Aldehydes Ald h d and K d Ketones

13A. IR Spectra of Aldehydes and Ketones
C=O Stretching Frequencies Compound R Ar C CHO CHO C CHO Range (cm1) 1720 - 1740 1695 - 1715 1680 - 1690 Compound RCOR ArCOR C C COR Cyclohexanone Cyclobutanone 1715 1785 Cyclopentanone 1751
Ch. 16 - 94

Range (cm1) 1705 - 1720 1680 - 1700 1665 - 1680

Conjugation of the carbonyl group with a d bl bond or a benzene ring shifts double b d b i hift the C=O absorption to lower frequencies by about 40 cm-1
O O s g e bo d single bond

Ch. 16 - 95

Ch. 16 - 96

13B. NMR Spectra of Aldehydes and Ketones

13C

NMR spectra p The carbonyl carbon of an aldehyde or ketone gives characteristic NMR signals in the 180220 ppm region of 13C spectra egion pe t

Ch. 16 - 97

1H

NMR spectra

A aldehyde proton gives a distinct 1H An ld h d t i di ti t NMR signal downfield in the 912 ppm region where almost no other protons i h l t th t absorb; therefore, it is easily identified P t Protons on th carbon are d hi ld d the b deshielded by the carbonyl group, and their signals generally appear in the 2 0 2 3 ppm ll i th 2.02.3 region M th l ketones show a characteristic Methyl k t h h t i ti (3H) singlet near 2.1 ppm
Ch. 16 - 98

Ch. 16 - 99

Ch. 16 - 100

14. Summary of Aldehyde and Ketone Addi i K Addition R Reactions i

NR2

R
R2NH H

OH

1. RM 2. H3O+
O

R
OH H

RO

OR

R-NH2, H+ 2 ROH, H
R
+

1. LiAlH4 or NaBH4 2. H3O+

1. NaCN OH

PPh3

2. H3O+

CN
Ch. 16 - 101

END OF CHAPTER 16

Ch. 16 - 102