Ald&KetoneII

Reactions of aldehydes and ketones:

oxidation

reduction

nucleophilic addition

1) Aldehydes are easily oxidized, ketones are not.

2) Aldehydes are more reactive in nucleophilic additions than ketones.

alkane alcohol

aldehydeketone

carboxylic acid

oxidation

reductionreduction

additionproduct

nucleophilicaddition

nucleophilic addition to carbonyl:

C

O+ Y Z C

Z

OY

Mechanism: nucleophilic addition to carbonyl

C

O+ Z

RDSC

O

Z

C

O

Z+ Y C

OY

Z

1)

2)

Mechanism: nucleophilic addition to carbonyl, acid catalyzed

C

O+ H C

OH

C

OH+ HZ

RDSC

OH

ZH

C

OH

ZH

C

OH

Z

+ H

1)

2)

3)

Aldehydes & ketones, reactions:

1) Oxidation

2) Reduction

3) Addition of cyanide

4) Addition of derivatives of ammonia

5) Addition of alcohols

6) Cannizzaro reaction

7) Addition of Grignard reagents

8) (Alpha-halogenation of ketones)

9) (Addition of carbanions)

1) Oxidation

a) Aldehydes (very easily oxidized!)

CH3CH2CH2CH=O + KMnO4, etc. CH3CH2CH2COOH

carboxylic acid

CH3CH2CH2CH=O + Ag+ CH3CH2CH2COO- + Ag

Tollen’s test for easily oxidized compounds like aldehydes.

(AgNO3, NH4OH(aq))

Silver mirror

Ketones only oxidize under vigorous conditions via the enol.

O

+ KMnO4 NR

O

Cyclohexanone

+ KMnO4, heat HOOCCH2CH2CH2CH2COOH

adipic acid

OH

enol

b) Methyl ketones:

RC

CH3

O+ OI-

RC

O-

O+ CHI3

iodoform

test for methyl ketonesYellow ppt

CH3CH2CH2CCH3 + (xs) NaOI CH3CH2CH2CO2- + CHI3

O

2-pentanone

2) Reduction:

a) To alcohols

H2, Ni

NaBH4 or LiAlH4

then H+

C

OC

OH

H

H2, Pt

1. NaBH4

2. H+

O

cyclopentanone

OHcyclopentanol

C CH3

OCHCH3

OH

acetophenone 1-phenylethanol

H

CO

H

H2, PtCH2OH

CH3CHCH=O

CH3 LiAlH4 H+

CH3CHCH2OH

CH3

benzaldehyde benzyl alcohol

isobutyraldehyde isobutyl alcohol

RDS1)

2)

mechanism: nucleophilic addition; nucleophile = hydride

hydride reduction

C

O+ H: C

H

O

C

H

O+ Al H C O Al

Al Al+

Then + H+ alcohol

Reduction

b) To hydrocarbons

NH2NH2, OH-

Zn(Hg), HCl

Clemmensen

Wolff-KishnerC

O

C

O

CH2

CH2

+ AlCl3

Zn(Hg), HCl

n-pentylbenzene

cannot be made by Friedel-Crafts alkylation due to rearrangement of carbocation

Cl

O O

3) Addition of cyanide

C

O 1. CN-

2. H+C

CN

OH

cyanohydrin

O + NaCN; then H+OH

CN

C

O

mechanism for addition of cyanidenucleophilic addition

RDSC

O

C

N

C

O

C

N

+ Na+ C

ONa

C

N

+ C N

then + H+

1)

2)

Cyanohydrins have two functional groups plus one additional carbon. Nitriles can be hydrolyzed to carboxylic acids in acid or base:

CH2CH

OHC N

H2O, OH-

heatCH2CH

OH

COO-

H2O, H+

heatCH

CH

COOHCH2CH

OHC N

4) Addition of derivatives of ammonia

O+

N+ H2OH2N G

(H+)

G

HN

phenylhydrazine

H2N NH2

hydrazine

H2N OH

hydroxylamine

HN NO2

O2N

2,4-dinitrophenylhydrazine

H2N NH

O

NH2

semicarbazide

H2NH2N

C

O+ H+

C

OH

C

OH+ H2N G

acid catalyzed nucleophilic addition mechanism followed by dehydration

C

NH2

OH

G

C

NH2

OH

G

C

NG

+ H2O + H+

RDS

1)

2)

3)

CH2 CHO

phenylacetaldehyde

+ H2NOH CH2 CH NOH

an oxime

O + H2NHNCNH2

O H+

NHNCNH2

O

a semicarbazonecyclohexanone

CH3CH2CH2CH2CHO + NHNH2

phenylhydrazine

hydroxylamine

semicarbazide

pentanal

CH3CH2CH2CH2CH N NH

a phenylhydrazone

melting points of derivativesketones bp semi- 2,4-dinitro- oxime

carbazone phenylhydrazone

2-nonanone 195 119 56

acetophenone 202 199 240 60

menthone 209 189 146 59

2-methylacetophenone 214 205 159 61

1-phenyl-2-propanone 216 200 156 70

propiophenone 220 174 191 54

3-methylacetophenone 220 198 207 55

isobutyrophenone 222 181 16394

5) Addition of alcohols

C

O+ ROH, H+

C

OR

OR acetal

C

OH

OR hemiacetal

Mechanism = nucleophilic addition, acid catalyzed

1) C

O+ H C

OH

2)C

OH2 + ROH C

OH

HOR

3) C

OH

HOR

C

OH

OR

+ H

RDS

CH2CHO(xs) EtOH, H+

CH2 CHOEt

OEt

O (xs) CH3OH, dry HClOCH3

OCH3

acetal

ketal

CHO

OHH

HHO

OHH

OHH

CH2OH

O

H

HO

H

HO

H

OHOHH H

OH

O

H

HO

H

HO

H

HOHH OH

OH

nucleophilic addition of -OH on carbon 5 to the aldehyde functional group

CHO

OHH

HHO

OHH

OHH

CH2OH

CH

OHH

HHO

OHH

HHOH2C

OH

O

H

HO

H

HO

H

OHOHH H

OH

O

O

H

HO

H

HO

H

HOHH OH

OH

rotate C-5 OH to rear

6) Cannizzaro reaction. (self oxidation/reduction)

a reaction of aldehydes without α-hydrogens

CHO

Br

conc. NaOH

CH2OH COO-

Br Br

+

CH3OH + HCOO-H2C=Oconc. NaOH

Formaldehyde is the most easily oxidized aldehyde. When mixed with another aldehyde that doesn’t have any alpha-hydrogens and conc. NaOH, all of the formaldehyde is oxidized and all of the other aldehyde is reduced.

Crossed Cannizzaro:

CH=O

OCH3

OH

vanillin

+ H2C=Oconc. NaOH

CH2OH

OCH3

OH

+ HCOO-

7) Addition of Grignard reagents.

C

O+ RMgX C

O

R

MgBr

C

O

R

MgBr+ H2O C

OH

R

+ Mg(OH)Br

larger alcohol

C

ORMgBr+

RDSC

O

R

+ MgBr

C

O

R

+ MgBr C

OMgBr

R

mechanism = nucleophilic addition

1)

2)

#3 synthesis of alcohols. Used to build larger molecules from smaller organic compounds.

RMgX +H

CH

ORCH2OMgX

H+RCH2OH

formaldehyde 1o alcohol + 1 C

RMgX +R'

CH

OR'CHOMgX

R

H+R'CHOH

Rother aldehydes 2o alcohol + X C's

R-MgX +R'

CR"

OR-COMgX

R'

R"

H+

R-COH

ketone3o alcohol + X C's

RMgX +H2C CH2

ORCH2CH2OMgX

H+

RCH2CH2OH

ethylene oxide 1o alcohol + 2 C's

R'

R"

Aldehydes & ketones, reactions:

1) Oxidation

2) Reduction

3) Addition of cyanide

4) Addition of derivatives of ammonia

5) Addition of alcohols

6) Cannizzaro reaction

7) Addition of Grignard reagents

8) (Alpha-halogenation of ketones)

9) (Addition of carbanions)

Planning a Grignard synthesis of an alcohol:

a) The alcohol carbon comes from the carbonyl compound.

b) The new carbon-carbon bond is to the alcohol carbon.

C

O+ RMgX H+

C

OH

R

New carbon-carbon bond

“The Grignard Song” (sung to the tune of “America the Beautiful”)

Harry Wasserman

The carbonyl is polarized,

the carbon end is plus.

A nucleophile will thus attack

the carbon nucleus.

The Grignard yields an alcohol

of types there are but three.

It makes a bond that corresponds

from “C” to shining “C.”

CH3CH2CH2CH2 C CH3

CH3

OH

2-Methyl-2-hexanol

CH3CH2CH2CH2MgBr + CH3CCH3

OH2O

CH3CH2CH2CH2 C CH3

CH3

OH

2-Methyl-2-hexanol

CH3CH2CH2CH2CCH3 + CH3MgBrH2O

O

or

ROH RX

-C=O

RMgX

R´OH

HX Mg

ox.

H2O larger alcohol

Stockroom:

alcohols of four-carbons or less:

(methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-2-propanol, 2-methyl-1-propanol.)

benzene

cyclohexanol

any needed inorganic reagents or solvents.

Grignard synthesis of 4-methyl-2-pentanol from alcohols of four-carbons or less:

Step one: determine the carbonyl compound and Grignard reagent that you would use:

CH3

CH3CHCH2CHCH3

OH

H2O CH3

CH3CHCH2MgBr + CH3CH=O

Step two: show the syntheses of the Grignard reagent and the carbonyl compound from alcohols…

CH3 HBr CH3 Mg CH3

CH3CHCH2OH CH3CHCH2Br CH3CHCH2MgBr

H+

K2Cr2O7 CH3

CH3CH2OH CH3CH=O CH3CHCH2CHCH3

special cond. OH

4-methyl-2-pentanol

Br2,FeBr

MgMgBr

CH3CHCH3

OH CrO3

CH3CCH3

O

H2OC CH3

CH3

OH

2-phenyl-2-propanol

2-phenyl-2-propanol

H3C OH

1-Methylcyclohexanol

OHH

Cyclohexanol

NaOCl

O

Cyclohexanone

CH3OHHBr

CH3BrMg

CH3MgBr

H2O

1-methylcyclohexanol

CH2OHH

Cyclohexylmethanol

OHH BrH MgBrH

CH3OH H2C=O

HBr Mg

K2Cr2O7

special cond.

H2O

cyclohexylmethanol

aldehyde RCOOHketone

ROR

alkyne

alkene

RH

RX

ROH

Alcohols are central to organic syntheses

ROH RX

-C=O

RMgX

R´OH

HX Mg

ox.

H2O larger alcohol

Using the Grignard synthesis of alcohols we can make any alcohol that we need from a few simple alcohols. From those alcohols we can synthesize alkanes, alkenes, alkynes, alkyl halides, ethers, aldehydes, ketones, carboxylic acids…

eg. Outline all steps in a possible laboratory synthesis of 3-methyl-1-butene from alcohols of four carbons or less.

CH3

CH3CHCH=CH2

Retrosynthesis:

alkenes, syntheses:

1. Dehydrohalogenation of an alkyl halide

2. Dehydration of an alcohol

3. Dehalogenation of a vicinal dihalide

4. Reduction of an alkyne

Methods 3 & 4 start with compounds that are in turn made from alkenes.

Dehydration of an alcohol?

CH3 H+

CH3CHCHCH3 yields a mixture of alkenes OH

CH3 H+

CH3CHCH2CH2-OH yields a mixture of alkenes

E1 mechanism via carbocation!

Dehydrohalogenation of an alkyl halide?

CH3 KOH(alc)CH3CHCHCH3 yields a mixture of alkenes Br

CH3 KOH(alc) CH3

CH3CHCH2CH2-Br CH3CHCH=CH2

only product E2 mechanism, no carbocation, no rearrangement

CH3 HBr CH3

CH3CHCH2CH2-OH CH3CHCH2CH2-Br

1o alcohol, SN2 mechanism, no rearrangement!

CH3 KOH(alc) CH3

CH3CHCH2CH2-Br CH3CHCH=CH2

Use the Grignard synthesis to synthesize the intermediate alcohol from the starting materials.

CH3 PBr3 CH3 Mg CH3 CH3CHCH2-OH CH3CHCH2Br CH3CHCH2MgBr

K2Cr2O7

CH3OH H2C=O special cond. H2O

CH3

CH3CHCH2CH2-OH

HBr

CH3 KOH(alco) CH3

CH3CHCH=CH2 CH3CHCH2CH2-Br