Chapter 16 1.Introduction - Konkukhome.konkuk.ac.kr/~parkyong/Classes/ch16.pdf · 4 © 2014 by John Wiley & Sons, Inc. All rights reserved. 4C.Aldehydes by Reduction of Acyl Chlorides,

1

Created byProfessor William Tam & Dr. Phillis Chang

Chapter 16

Aldehydes & Ketones:Nucleophilic Additionto the Carbonyl Group

Copyright © 2014 by John Wiley & Sons, Inc. All rights reserved.

1. Introduction

v Carbonyl compounds

O

R R'ketone

O

R Haldehyde

O

R OR'ester

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

© 2014 by John Wiley & Sons, Inc. All rights reserved.

v Rules● Aldehyde as parent (suffix)

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

t Ending with “one”● Number the longest carbon chain

containing the carbonyl carbon, starting at the carbonyl carbon

2. Nomenclature of Aldehydes &Ketones


v ExamplesCl

H

O4-Chloro-2,2-dimethylpentanal

12345

O

Br

12 3 4 5 6

7

6-Bromo-4-ethyl-3-heptanone© 2014 by John Wiley & Sons, Inc. All rights reserved.

2

v group as a prefix: methanoyl or formyl group

O

H

v group as a prefix: ethanoyl or acetyl group (Ac)

O

v groups as a prefix: alkanoyl or acyl groups

O

R


2-Methanoylbenzoic acid(o-formylbenzoic acid)

CO2H

H

O

4-Ethanoylbenzenesulfonic acid(p-acetylbenzenesulfonic acid)

SO3H

O


Butanebp -0.5oC(MW = 58)

H

O OOH

Propanalbp 49oC

(MW = 58)

Butanebp 56.1oC(MW = 58)

1-Propanolbp 97.2oC(MW = 60)

3. Physical Properties


4A. Aldehydes by Oxidation of 1o

Alcohols

4. Synthesis of Aldehydes


3

OH O

H

PCC

CH2Cl2 (90%)

PCC

CH2Cl2

OH O

H(89%)

v e.g.


4B. Aldehydes by Ozonolysis ofAlkenes



O

OH

1. O3, CH2Cl2, -78oC

2. Me2S

+

v e.g.

H3C

1. O3, CH2Cl2, -78oC

2. Me2S

O

H3C

H

+O

H H© 2014 by John Wiley & Sons, Inc. All rights reserved.

4


4C. Aldehydes by Reduction of AcylChlorides, and Esters


v 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

staget Not a good method to

synthesize aldehydes using LiAlH4

© 2014 by John Wiley & Sons, Inc. All rights reserved. © 2014 by John Wiley & Sons, Inc. All rights reserved.

5

v Two aluminum hydride derivatives that are less reactive than LAH:

Lithium tri-tert-butoxyaluminum hydride

AlR

OtBuAlLi+ H OtBuOtBu

-

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


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© 2014 by John Wiley & Sons, Inc. All rights reserved.


v Aldehydes from acyl chlorides: RCOCl ® RCHO

1.

2.

O

R Cl

O

R OH

O

R H

SOCl2LiAlH(OtBu)3,Et2O, -78oCH2O

v e.g.

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

2. H2O

Cl

O

CH3

H

O

CH3© 2014 by John Wiley & Sons, Inc. All rights reserved.

6

v Reduction of an Acyl Chloride to an AldehydeLiAlH(OtBu)3

R CCl

OR C

Cl

O Li+ Al(OtBu)3

H

R CCl

OH

Li

Al(OtBu)3R CCl

OHAl(OtBu)3

Li

R CH

O Al(OtBu)3-LiCl

R CH

OH2O


v Aldehydes from esters and nitriles: RCO2R’ ® RCHORC≡N ® RCHO● Both esters and nitriles can be

reduced to aldehydes by DIBAL-H


v Reduction of an ester to an aldehyde

R COR'

O

H

Al(i-Bu)2 R COR'

O Al(i-Bu)2H

R COR'

OHAl(i-Bu)2

R CH

O H2O


v Reduction of a nitrile to an aldehyde

R C N

H

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

NCR

R CN

H

Al(i-Bu)2R C

H

O H2O


7

v Examples


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

v Ketones (and aldehydes) by ozonolysis of alkenes

5. Synthesis of Ketones


v Examples

1. O3

2. Me2S

O

O

(i)


v Ketones from arenes by Friedel–Crafts acylations

O

R Cl

AlCl3 R

O

+ HCl+

an alkyl arylketone


8

v Ketones from secondary alcohols by oxidation

OH

R R'

O

R R'

H2CrO4

or PCC


5B. Ketones from Nitriles

R C N1. R'-M, Et2O

N M

R'R

2. H3O+

O

R'R


v Examples


v Suggest synthesis ofO

from andBr

HO


9

v Retrosynthetic analysisO

HO

need to add one carbon

5 carbons here 4 carbons here

Þ


v Retrosynthetic analysis

NC

Br

+

HO

disconnection

disconnection


v Synthesis

O

HO Br

CN

PBr3

NaCNDMSO

1.

2. H3O+

Et2O

MgBr


v Suggest synthesis ofO

from andBr

HO


10

v Retrosynthetic analysisO

HO

no need to add carbon

5 carbons here

Þ

5 carbons here



MgBr+

H

O

HO

disconnection


v Synthesis


v Structure

● Carbonyl carbon: sp2 hybridized● Trigonal planar structure

Nu⊖

6. Nucleophilic Addition to theCarbon–Oxygen Double Bond


11

Nucleophilic Addition Reactions of Aldehydes and Ketones

Aldehydes more reactive toward nucleophilic addition than ketones

• Aldehydes less sterically hindered than ketones

v Polarization and resonance structure

CO

d+

OC

d-

● Nucleophiles will attack the electrophilic carbonyl carbon

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



v With a strong nucleophile:


12



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

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


13

+ A:C OHR

R'C OH

R

R'

v Mechanism

d+ d-C O

R

R'H A+(or a Lewis acid)


+ A:C O

RR'

NuH

H

C OHR

R':Nu H

v Mechanism

C O

RR'

:NuH

H A+


6B. Relative Reactivity: Aldehydes,Ketones, and Esters

O

R H

O

R R'

O

R OR'> >


large

small

O

R H

O

RNu

H

Nu

O

R R'

O

RNu

R'

Nu

v Steric factors


14

OC

R H

OC

R R'

d-

d+

d-

d+> >< <

v Electronic factors

(positive inductive effect from only one R group)

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


6C. Addition Products Can Undergo Further Reactions

v Butstable product: isolable

unstable© 2014 by John Wiley & Sons, Inc. All rights reserved.

v Hemiacetal & Acetal 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

7. The Addition of Alcohols:Hemiacetals and Acetals


Reactions with Alcohol

Elimination of water prevents O-alkylated intermediate from reverting to reactant

15

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

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


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

H+OR"R OR"

R'H2O

O

R R'+ + 2 R"OH


v Aldehyde hydrates: gem-diols

H2O+OH

H3C

H

H3C O

O

H

H

Acetaldehyde Hydrate(a gem-diol)


16


d+ d-C O

H

H3C OH2

v Mechanism

OH2H3C

O:H

OHH3C

OHH

OHHO

HR

O

R H+ H2O

distillation


HO

O

O

O

O

OH

H

Butanal-4-ol

A cyclichemiacetal

Hemiacetal: OH & OR groups bonded to the same carbon

7A. Hemiacetals


17

7B. Acetals


+O

R R'HO

OHH3O+

O O

R R'

+ H2O

Ketone (excess) Cyclic acetal

v 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


+

O

R R'

HOOH

H3O+O O

R R'

+ H2O

v This reaction, too, can be reversed by treating the acetal with lots of an aqueous acid


7C. Acetals Are Used as Protecting Groups

v Although acetals are hydrolyzed to aldehydes and ketones in aqueous acid, acetals are stable in basic solutions


18

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


O

OH

Br

O

Attempt to synthesize:

from:

v Example


O

O

OH

BrMg

O

+

● Synthetic plan

t This route will not work© 2014 by John Wiley & Sons, Inc. All rights reserved.

BrMg

Od+ d-

Reason:(a) Intramolecular nucleophilic addition

(b) Homodimerization or polymerization

BrMg

O

BrMg

O

BrMg

O


19

t Thus, need to “protect” carbonyl group first

Br

O O

HOOH

, H+

(ketal)

BrMg

O O

MgEt2O d+

d- O

OMgBr

O O


7D. Thioacetalsv Aldehydes & ketones react with thiols

to form thioacetalsEtS SEt

R H

O

R H

2 EtSH

HA+ H2O

Thioacetal

O

R R' BF3+ H2O

S S

R R'

HSSH

Cyclicthioacetal


v 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

SHR R'

H H+


20


DesulfurizationofthioacetalusingRaneyNiv Aldehydes & ketones react with 1o

amines to form imines and with 2o

amines to form enaminesFrom a 1o amine From a 2o amine

8. The Addition of Primary andSecondary Amines


8A. Iminesv Addition of 1o amines to aldehydes &

ketones


H2NR"

v 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"

H2O


21

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

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


8B. Oximes and Hydrazonesv 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

v Oxime formation – reaction with hydroxylamine


There are some special amines thatyield insoluble products (imines) that are easy to crystallize …..

CRYSTALLINE IMINES

:NH2OH

R-NH-NH2

hydroxylamine

varioushydrazinecompounds

NHNH2

NO2

O2N2,4-dinitrophenyl-

hydrazine

C NHNH2

ONH2 semicarbazine

..

....

shownbelow

v 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. HAOC

CH R

H

RR

enamine

v Enamine formation – reaction with a 2o

amine


22

8C. The Wolff-Kishner Reduction


v Mechanism

N

R'R

NH

H

- N2

H

R R'

OH


8D. Enamines


N R+

OC

CH R

H

v Mechanism

C CH

ONR

RH


23

C CH

ON RR

H

A H +

v Mechanism (Cont’d)

C CH

ON RR

HH

iminium ionintermediate

CH

CNR

R:A + H2O +


CH

CNR

R

A:

v Mechanism (Cont’d)

enamine

CH

CN

R

R

+ H A


C

R

R

N G

O H

H

..R C C R

H

R

OH

NR2

imine enamine

..

PRIMARY AMINES SECONDARY AMINES

-H2O -H2O no hydrogenon nitrogenhydrogen

on thenitrogen

COMPARISON

hydrogen on theadjacent carbon

When there is no hydrogen onnitrogen, one is lost from carbon.

carbinolamine intermediates

Quiz 1

24

Quiz 2 Quiz 3

Quiz 4 Quiz 5

25

v Addition of HCN to aldehydes & ketones

R R'

O HCN OH

RR'

CN

O

RR'

CNH+CN

(cyanohydrin)

9. The Addition of HydrogenCyanide: Cyanohydrins


R R'

O CN

v Mechanism

O

RR'

CN(slow)

NC H

OH

RR'

CN


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

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

R R'

O

NaCN

O Na

RCN

R'

OH

RR'

CNH2SO4


R'

O HCNR

R'R

HO CN

R'R

COOH95% H2SO4

heat

HCl, H2O

heat R'R

HO COOH

1. LiAlH4

2. H2O R'R

HO NH2

(a-hydroxy acid)

(a,b-unsaturated acid)

(b-aminoalcohol)

v Synthetic applications


26

R

R'O

aldehydeor ketone

+ (C6H5)3P CR"

R"C C

R'

R

R"

R"

O P(C6H5)3+

phosphorus ylide(or phosphorane)

alkene[(E) & (Z) isomers]

triphenyl-phosphine

oxide

10. The Addition of Ylides:The Wittig Reaction


YlideA compound or intermediate with both a positive and a negative charge on adjacent atoms.

X Y..- +

Betaine or Zwitterion

A compound or intermediate with both a positive and a negative charge, not on adjacent atoms, but in differentparts of the molecule. X

-Y

+

:

BOND

MOLECULE

v Phosphorus ylides(C6H5)3P C

R"

R"(C6H5)3P C

R"

R"

(C6H5)3P CR"'

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

R"'

R"

a phosphorusylide© 2014 by John Wiley & Sons, Inc. All rights reserved.

C

(C6H5)3P C

R

R(C6H5)3P C

R

R+ _ ..

Resonance in Ylides

..

3d 2p

dp-pp BACKBONDING

Remember that Phosphorousis a Period III element (d orbitals).

Backbonding to phosphorousreduces the formal chargesand stabilizes the negativecharge on carbon.

P

27

v Example

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

Methyltriphenylphos-phonium bromide

(89%)

CH3BrC6H6

(C6H5)3P CH3

Br

+ C6H5Li (C6H5)3P CH2:

+ + LiBrC6H6


v Mechanism of the Wittig reaction

+CO

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

aldehydeor ketone

ylide

R'C CR

:O

R"R"'

P(C6H5)3oxaphosphetane

:

C CR

R'

R"

R"O P(C6H5)3 +

alkene(+ diastereomer)

triphenylphosphineoxide

::


10A. How to Plan a Wittig Synthesis

v Synthesis of

using a Wittig reaction



disconnection

O

Ph3P+route 1

BrPh3P: +route 2

PPh3

O+

Br+ :PPh3


28

v Synthesis – Route 1

O

Ph3PBr:PPh3 Br

nBuLi

Ph3P


v Synthesis – Route 2


10B. The Horner–Wadsworth–Emmons Reaction: A Modification of the Wittig Reaction

P OEt

O

OEt

NaH

+ H2

P OEt

O

OEt

a phosphonateester


29

P OEt

O

OEt

X

OEtP

EtO OEt+

EtX +

Triethyl phosphite

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


Arbuzov reaction

11. Oxidation of Aldehydes


12. The Baeyer-Villiger Oxidation

O

+

O

OOH

O

R OH

(a peroxy-carboxylic acid)

Acetophenone Phenyl acetate

O

O


30

v Mechanism

O

O ArO

O

R'R

H


13A. Derivatives of Aldehydes & Ketones

13. Chemical Analyses for Aldehydes and Ketones


R H

O O

R O-

Ag(NH3)2+

H2O+ Ag

silvermirror

13B. Tollens’ Test (Silver Mirror Test)


31


14A. IR Spectra of Aldehydes and Ketones

Range (cm-1)R CHOAr CHO

C CCHO

C CCOR

RCORArCOR

Compound Range (cm-1)Compound

CyclohexanoneCyclopentanoneCyclobutanone

171517511785

1720 - 17401695 - 1715

1680 - 1690

1705 - 17201680 - 1700

1665 - 1680

C=O Stretching Frequencies

14. Spectroscopic Properties of Aldehydes and Ketones

Table 16.3



32

v 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


14B. NMR Spectra of Aldehydes andKetones

v 13C NMR spectra● The carbonyl carbon of an aldehyde

or ketone gives characteristic NMR signals in the d 180–220 ppmregion of 13C spectra


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

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

● Protons on the a carbon are deshielded by the carbonyl group, and their signals generally appear in the d 2.0–2.3 ppmregion

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


33


O

OHR1. RM

2. H3O+

OHH

1. LiAlH4 or NaBH42. H3O+

OHCN

1. NaCN2. H3O+

RR PPh3

RO OR

2 ROH, H+

NR

R-NH2, H+

R2NHH+

NR2

15. Summary of Aldehyde and Ketone Addition Reactions



Documents

Chapter 16 1.Introduction - Konkukhome.konkuk.ac.kr/~parkyong/Classes/ch16.pdf · 4 © 2014 by John Wiley & Sons, Inc. All rights reserved. 4C.Aldehydes by Reduction of Acyl Chlorides,