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有機化學乙 蔡蘊明 教授

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Chapter 12 Alcohols from carbonyl compounds

※ Carbonyl compounds

C O A carbonyl functional group (羰基)

C OH

RC O

R'

RC O

HO

RC O

R'O

R

aldehyde ketone carboxylic acid ester

醛 酮 酸 酯

◎ Structure C O

p for π bonding

sp2

for σbonding

planar

C O C O C Oδ+ δ−

two resonance structures electrophilic

nucleophilc

Real structure: hybrid of the two resonance structures

Polar in nature: C O

H

H

formaldehydeµ = 2.27 D

C OH3C

H3C

acetoneµ = 2.88 D

※ Oxidation and reduction of organic compounds.

RCH3

[O]

[H]RCH2OH

[O]

[H]RCH

O [O]

[H]RCOH

O

A simple guideline: Oxidation − # of O ↑, # of H ↓ Reduction − # of O ↓, # of H ↑

※ Preparation of alcohols from carbonyl compounds

RCOHO [H]

RCHO

RCOR'O [H]

[H]

RCH2OH

RCH2OH

RCH2OH (+ R'OH) 1o

RCR'O [H]

RCHOHR'

2o

◎ Lithium aluminum hydride (LAH)

Li+ AlH

HH

HA highly reactive reducing agent Reacts violently with H2O and ROH and releases H2

Solvents often used:

OTHF

Diethyl ether (Et2O)

Good ligands for aluminum

R CO

H RCH2OH1) LAH, Et2O

2) H2O

C OHR

H Al

C OHR

H Al

work up

H2OC OHH

R

H

Mechanism:

R CO

R'1) LAH, Et2O

2) H2OR C

OHR'

H

R CO

OH1) LAH, Et2O

2) H2OR C

OHH

H

R CO

O Al

+H2

R CO

O AlH

Al

R CO

H

◎ Sodium borohydride (NaBH4)

Na+ BH

HH

H

• Less reactive than LAH • Reacts slowly with H2O • Alcohols or H2O are often used as solv. • Does not reduce acid or ester

CH3CH2CH2CHO NaBH4

H2OCH3CH2CH2CH2OH

85%

C OHR

H B

C OHR

H BC OHH

R

H

R'OH + R'O B

Mechanism:

HO CH2OH OOCH3

ONaBH4

CH3OHHO

OCH3

O1) LAH

2) H2O

CH3CH2CH2CCH3

O NaBH4

H2OCH3CH2CH2CHCH3

OH

87%

racemic

※ Oxidation of alcohols

RCH2OH[O]

RCHO [O]

RCOHO

◎ Jones reagent: CrO3∕aq. H2SO4 ∕acetone

Cr

O

OO

H+

CrO

OOH

OHH2O

(H2CrO4)

CrO

OOH

O CrO

OOH

(H2Cr2O7)

−1/2 H2O 12

chromiumtrioxide chromic acid dichromic acid

All are Cr(VI)

RCH2OH Jones reagent

RCOOH

Mechanism:

CO

RH

HJones

reagent CO

RH

H

CrO

O OH

(blood red)

H

a chromic ester

CO

R H+ Cr

OH

O OH

Cr(VI) Cr(IV)2 e− oxidation

Cr(III)green

CO

R HH+

H2OCO

ROH

HH

a carbonyl hydrate

Jonesreagent C

OR OH

CO

RR'

HJonesreagent

H

CO

R R'

2o alcohol

CO

RR''

R'Jonesreagent

H

3o alcohol

NR (no reaction)

No removable H, can not be oxidized further

Chemical test: 1o, 2o alcohol + CrO3∕aq. H2SO4 Cr3+ orange red greenish opaque 3o alcohol + CrO3∕aq. H2SO4 no change

Q: Can we stop at aldehyde?

Solution 1: remove aldehyde as is formed by distillation (aldehyde has lower bp than alcohol) Limitation: aldehyde must have lower bp (<100 oC) for practical reason

Solution 2: use PCC or PDC

NH O CrO

ClO

NH Cr2O72−

2

PCC: pyridinium chlorochromate

PDC: pyridinium dichromate

*They are soluble in CH2Cl2 and weakly acidic

(C2H5)2C CH2OHCH3 PCC

CH2Cl2(C2H5)2C C

CH3H

O

例

Reason for the success: non-aqueous condition is used no carbonyl hydrate formation (no H2O) no further oxidation

◎ KMnO4

RCH2OHKMnO4

∆MnO2

R CO

O−K+H+

R CO

OHOH−, H2O+

purple brown ppt.

※ Organometallic compounds

C M+ C M

M+ = Na+, K+ M = Li, Mg

C M

M = Pd, Pb, Sn, Hg....

ionic covalent in between 例 butyllithium CH3CH2CH2CH2Li

soluble in hexane but still a very strong base

(water sensitive)

weakly basic (water insensitive)

very polar

◎ Organolithium compounds

CH3CH2CH2CH2Br + 2 Li −10 oC

Et2O CH3CH2CH2CH2Li + LiBr

Solvent: Et2O or THF or hexane

Ethereal solvent: coordinates with BuLi

Bu−Li+OEt2

OEt2

OEt2 helps formation and more stable

Reactivity: RI > RBr > RCl

CH3CH2CH2CH2 Br CH3CH2CH2CH2

CH3CH2CH2CH2

e−

+ Br−

e−

Mechanism:

◎ Grignard reagents

Et2O

Et2O

R-MgX

Ar-MgX

R-X + Mgor

THF

Ar-X + Mgor

THF

Grignard reagents

(also for vinyl halides)

例 Br

Mg

Et2O, 35 oCMgBr

phenylmagnesium bromide

*Ethereal solvent complexes with Grignard reagent

★ Reactions with acids

RMgX and RLi are strong bases reacts with H2O, ROH, R-C≡C-H

例 R-MgX + H-OR' R-H + R'OMgBr

RLi + D2O R-D + LiODOverall reduction of halides:

R-MgXH2O

R-HR-X + Mg

HRLiR

MgXR+ R'MgX (R'Li)

+ R'H

Preparation of acetylides:

◎ Reactions of Grignard reagents

*R-MgX is more covalent and less basic than R-Li R-MgX used more often as nucleophile R-Li used more often as base

Opening of epoxides

R−Mg2+X−O

ROMgX+

H+R

OH

another way to prepare alcohols

C6H5MgBrO

C6H5CH2CH2OH1)

2) H3O+

C6H5MgBrO

CH3

C6H5CH2CHCH3OH

1)

2) H3O+

例

attack less hindered carbon

◎ Reaction with carbonyl compounds

R−Mg2+X− C O CROMgX

+δ+ δ−

H+

CROH

CO

HR'

CO

HHH+

H+

CO

R"R'H+

RCH2OH

CRH

R'OH

CRR'

R"OH

RMgX +

RMgX +

RMgX +

1o alcohol

2o alcohol

3o alcohol

★ This is a very useful way to prepare alcohols

Reaction with esters

R−Mg2+X−R' C

OOR" CR'

O

ROR"

MgX

+

an ester

R' CO

R

+ R"OMgX

a ketonemore reactive than esterRMgX

CR'O

RR

MgXH+

CR'OH

RR

H3C CO

OC2H5CH3COH

EtEt

1) EtMgBr

2) H3O+

67%

例

◎ Planning a Grignard synthesis

Q: Synthesis of CCH3CH2

OHCH2CH3

Retrosynthetic analysis:

CCH3CH2

OHCH2CH3

O

EtEt+ PhMgBr

Ph

Et O+ EtMgBr

O

OEtPh+ 2 EtMgBr

Q: Synthesis of

O

using alcohols with less than 4 carbons

Retrosynthetic analysis:

OH

BrOH

Ans:

O OH O

O

HPCC

OH PBr3

CH2Cl2Br

Br

OH

OH

PCC

CH2Cl2

1) Mg, Et2O

2)

3) H+

O

Q: Synthesis of OH

OH

OHO

H

H

OH

HBrOBr

Rretrosynthetic analysis:

Ans:

BrO

CH2CH2OHPCCCH2Cl2 CH2CH

O1) Mg, Et2O

2)

3) H3O+

★ Limitations

RMgX is still a strong base can not tolerate the presence of: -OH, -NH2, -NHR, -CO2H, -SO3H, -SH, -C≡C-H

Reactive FGs can not coexist:

CO

HCO

RCO

ORCO

NH2

NO2 C N O, , , , , ,

例 X

OCCH3

HOCH2CH2OH

CH3CH3MgBr + HOCH2CH2CCH3

CH4 + BrMgOCH2CH2CCH3

O

A solution: HOCH2CH2CCH3

OBrMgOCH2CH2CCH3

O2 CH3MgBr +

BrMgOCH2CH2CCH3

CH3

OMgBr

H+

HOCH2CH2CCH3

CH3

OH

Other strategy: protect -OH

HOCH2CH2CCH3O H+ O

O

CH3MgBr

O

OMgBrH3O+

HO

OH

◎ The use of alkyllithium

Similar to Grignard reagents More reactive but more basic More side-reaction

◎ Sodium alkynide

R HNaNH2

R COH

R"R'

H3O+

R Na

R CONa

R"R'

O

R"R'+