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Chapter 6 Reactions of Carbonyl Compounds 羰羰羰羰羰羰羰羰 6-1 Nucleophilic Addition Reacitions 羰羰羰羰羰 6-2 Nucleophilic Addition-Elimination Reac tions 羰羰羰羰羰羰羰羰 6-3 Condensation Reactions 羰羰羰羰 6-4 The Nucleophilic Substitutions of Carb onyl Acid and Their Derivatives 羰羰羰羰羰羰羰羰 羰羰羰羰

Chapter 6 Reactions of Carbonyl Compounds 羰基化合物的反应

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Chapter 6 Reactions of Carbonyl Compounds 羰基化合物的反应. 6-1 Nucleophilic Addition Reacitions 亲核加成反应 6-2 Nucleophilic Addition-Elimination Reactions 亲核加成消除反应 6-3 Condensation Reactions 缩合反应 6-4 The Nucleophilic Substitutions of Carbonyl Acid and Their Derivatives 羧酸及其衍生物的亲核取代. - PowerPoint PPT Presentation

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Page 1: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

Chapter 6 Reactions of Carbonyl Compounds

羰基化合物的反应

6-1 Nucleophilic Addition Reacitions 亲核加成反应

6-2 Nucleophilic Addition-Elimination Reactions 亲核加成消除反应

6-3 Condensation Reactions 缩合反应

6-4 The Nucleophilic Substitutions of Carbonyl Acid and Their Derivatives 羧酸及其衍生物的亲核取代

Page 2: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

Key Terms Involved in This Chapter

carbonyl ( 羰基 ) aldehyde( 醛 ) ketone ( 酮 )nucleophilic( 亲核的 ) nucleophile ( 亲核试剂 )electrophilic ( 亲电的 ) electrophile( 亲电试剂 )carbanion (碳负离子)diastereomer (非对映体)

Page 3: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

IntroductionSeveral functional groups contain the carbonyl group.

Structure of the Carbonyl GroupThe carbonyl carbon is sp2 hybridized and is trigonal planar. All three atoms attached to the carbonyl group lie in one plane.

Page 4: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

..:+

-..

::-

+electrophilic at carbon

nucleophilicat oxygen

Nu:

nucleophiles attack here

H+ or E+

electrophiles add here

O

C

O

C

Nu: nucleophile 亲核试剂

The carbonyl group is polarized.There is substantial + charge on the carbon.

Page 5: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

6-1 Nucleophilic Addition Reactions (亲核加成反应)

Carbonyl groups can undergo nucleophilic addition.The nucleophile adds to the + carbon.The electrons shift to the oxygen. The carbon becomes sp3 hybridized and therefore tetrahedral.

Page 6: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

O

CC

O

Nu

C

O

Nu

C

O

Nu

H

+ :Nuslow

::..

:_

:..

:

+

:..

fast

_

..

H2O

or adding acid

A strong nucleophile attacks the carbonyl carbon, forming an alkoxide ion that is then protonated.

An alkoxide ion

MechanismsMechanisms in Basic or Neutral Solutionsin Basic or Neutral Solutions

An alcohol

Page 7: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

Acid Catalyzed MechanismsAcid Catalyzed Mechanisms

Acid catalysis speeds the rate of addition of weak nucleophiles andweak bases (usually uncharged).

more reactive to addition than the un-protonated precursor

ACIDIC SOLUTION

+:Nu

slow:

..

O

C

H

C

O

Nu

H+

O

C

H:O

C+ H

+fast

+:..

..

pH 5-6 stronger acid protonates thenucleophile

Page 8: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

Typical Nucleophilies

Nu-: -CN, CC-, RMgX, RLi, RZnBr,Witting Reagents, H-, -OH, RO-, HSO3

-,

Nu: H2O, ROH, RNH2, NH2OH, H2NNHR

Page 9: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

+ CN_

R C R

O

R C R

O

CN

R C R

O

CN

+ R C R

O

CN

H

: : : :

: : :

..

..

_

_..

OH2

1. Cyanides act as nucleophiles toward C=O1. Cyanides act as nucleophiles toward C=O

Buffered to pH 6-8

In acid solution there would be little CN-, and HCN (g) would be a problem (poison).

a cyanohydrin

Page 10: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

C OCH3

C O C O C OR

C O

H

H> >>>

H

CH3

CH3 CH3 CH3

Ar

(1) Reactivity of Aldehydes and Ketones

Aldehydes are generally more reactive than ketones in nucleophilic additions.

formaldehyde acetaldehyde acetone Methyl ketones

Page 11: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

Electronic effects of alkyl groups

HCNK

K=530

CHO

CHO

Br

=210

RC O

H

RC O

H

¦Ä ¦Ä+ +

Nu - Nu -

Electron-donating groupmakes C=O less electrophilicless reactive

Electron-withdrawing group makes C=O more electrophilicmore reactive

(2) Factors affecting the nucleophilic addition

HCN:hydrocyanic acid

Page 12: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

HCN

(CH3)3C

C O

C O >CH3

CH3CH2

(CH3)3C

K 1

K<< 1

Steric effect

C OR

R/(H)

Hybridization: sp2 sp3

The bond angle: 120° 109.5°

The crowding in the products is increased by the larger group

Page 13: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

Watch out for the possibility of optical isomerism in hydroxynitriles

CN¯ attacks from above

CN¯ attacks from below

(3) Sterochemistry

Enantiomers

Page 14: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

CN¯ attacksfrom below

CN¯ attacksfrom above

Enantiomers

Page 15: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

Cram’s Rule

How does this center control the

direction of attack at the trigonal carbon?

C X* diastereomeric X = C, O, N

Chiralcenter

非对映体

Page 16: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

RM

S

L

O

LRNu

OHMS

LNuR

OHMS

Nu:

Less steric

Major product

Nu:

Minor product

OMS

RL More steric

Perspective drawing

Page 17: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

2. Grignard reagents act as nucleophiles toward C=O2. Grignard reagents act as nucleophiles toward C=O

Grignard reagents are prepared by the reaction of organic halides with magnesium turnings

Page 18: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

Aldehydes and ketones react with Grignard reagents to yield different classes of alcohols depending on the starting carbonyl compound

Page 19: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

Esters react with two molar equivalents of a Grignard reagent to yield a tertiary alcohol

The final product contains two identical groups at the alcohol carbon that are both derived from the Grignard reagent.

A ketone is formed by the first molar equivalent of Grignard reagent and this immediately reacts with a second equivalent to produce the alcohol.

Page 20: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应
Page 21: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

Planning a Grignard SynthesisExample : Synthesis of 3-phenyl-3-pentanol

Page 22: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

Restrictions on the Use of Grignard Reagents

Grignard reagents are very powerful nucleophiles and bases.They react as if they were carbanions.Grignard reagents cannot be made from halides which contain acidic groups or electrophilic sites elsewhere in the molecule.

Page 23: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

The substrate for reaction with the Grignard reagent cannot contain any acidic hydrogen atoms.

Two equivalents of Grignard reagent could be used, so that the first equivalent is consumed by the acid-base reaction , while the second equivalent accomplishes carbon-carbon bond formation.

Page 24: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

1 RMgX

2 H2O

+

minor

R major minorCH3 2.5 : 1C6H5 > 4 : 1(CH3)2CH 5 : 1(CH3)3C 49 : 1

R major minorCH3 2.5 : 1C6H5 > 4 : 1(CH3)2CH 5 : 1(CH3)3C 49 : 1

major

H

Ph

C2H5

R

HO H

H

Ph

C2H5

R

H OH

H

Ph

C2H5

H O

H

R

Ph

OH

C2H5H

H R

Ph

OHC2H5H

O

H

C2H5H

Ph

Sterochemistry-Cram’s rule

Page 25: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

3. Organolithium act as nucleophiles toward C=OOrganolithium act as nucleophiles toward C=O

Organolithium reagents react with aldehydes and ketOrganolithium reagents react with aldehydes and ketones in the same way that Grignard reagents do.ones in the same way that Grignard reagents do.

Page 26: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

4. Sodium alkynidesSodium alkynides act as nucleophiles toward act as nucleophiles toward C=O

NaNH2: sodium amide

propine Sodium alkynide

Page 27: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

5. Reformatskii Reactions (Organozinc Addition to C=O )

CH3

+ CH3-CH-CO2C2H5+ Zn H3O+OH

C2H5CHCHO

C4H9(n)

Br

C2H5CHCH

C4H9(n)

-CH-CO2C2H5

C+ Br-C-CO2R(R)H

+ Zn

OZnBr

C-CO2RR

(R)H

H3O+

C

OH

C-CO2RR

(R)H

¦Á-bromoester

¦Â-hydroxyester

C=OR

BrZn-C-CO2R

Organozinc is not as reactive as Grignard reagent,Grignard reagent, so it will not reactive with estersso it will not reactive with esters

Page 28: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

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

X Y..- +

Betaine or ZwitterionBetaine or Zwitterion

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

X-

Y+

:

BOND

MOLECULE

内铵盐 两性离子

6. Wittig reaction (Ylides addition to C=O )Synthetic method for preparing alkenes.

Page 29: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

(C(C66HH55))33PP CC++

AA

BB

••••––++

++CC CC

RR

R'R'

AA

BB

(C(C66HH55))33PP OO++

••••––••••

••••

CC OO

RR

R'R'

••••

••••

triphenyl phosphine oxide(三苯基氧膦)An alkene

Page 30: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

+ (C6H5)3P+

R1 C

R2

X

H

(C6H5)3P C R2

R1

H

X_

(C6H5)3P C

R2

R1

Preparation of a Phosphorous YlidePreparation of a Phosphorous Ylide

strong base

:

O-CH3

-

P Ph

Ph

Ph..

Triphenylphosphine( Ph = C6H5 )

:....

( WITTIG REAGENT )

+ ..-

an ylide

benzene

phosphonium salt

ether

SN2 reaction

Substrates: 1°, 2°Alkyl halides

Page 31: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

..

INSOLUBLE

very thermodynamicallystable molecule

ylide betaine

+ -

The Wittig ReactionThe Wittig ReactionMECHANISM

synthesis ofan alkene

+

:..

:_ +

C O

R1

R2

(C6H5)3P C

R4

R3

R2 C

R1

O

C R4

R3

P(C6H5)3

+C

R1

R2

C

R4

R3

O P(C6H5)3

:..

R2 C

R1

O

C R4

R3

P(C6H5)3

oxaphosphetane(UNSTABLE)

内磷盐

Page 32: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

H

CH3

CH3

CH2CH3 CH3

CH3

O

H

CH2CH3Br

H

H

CH2CH3(C6H5)3P

H

:P(C6H5)3

+

H

CH2CH3(C6H5)3P

:

+

CH3ONa-ylide

CH3

CH3

O

SYNTHESIS OF AN ALKENE - WITTIG REACTIONSYNTHESIS OF AN ALKENE - WITTIG REACTION

Page 33: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

ANOTHER WITTIG ALKENE SYNTHESISANOTHER WITTIG ALKENE SYNTHESIS

C

H

Br

HO

CH2Br

:P(C6H5)3

C P(C6H5)3

H

HBr-

+

PhLi

..C P(C6H5)3

H

- +

ylide

: ..

+

+-

triphenylphosphineoxide (insoluble)

P(C6H5)3O

O

..

C

H

Page 34: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

Georg F. K. Wittig received the Nobel Prize in Chemistry in 1979.Georg F. K. Wittig received the Nobel Prize in Chemistry in 1979.

CH P(C6H5)3+2 O CH CHO

Synthesis of β-Carotene ( β- 胡萝卜素)

Page 35: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

Georg Wittig 1/2 of the prize

University of Heidelberg Heidelberg, Federal

Republic of Germany b. 1897d. 1987

German chemist whose method of synthesizing olefins (alkenes) from carbonyl compounds is a reaction often termed the Wittig synthesis. For this achievement he shared the 1979 Nobel Prize for Chemistry.

In the Wittig reaction, he first demonstrated 1954, a carbonyl compound (aldehyde or ketone) reacts with an organic phosphorus compound, an alkylidene-triphenylphosphorane, (C6H5)3P=CR2, where R is a hydrogen atom or an organic radical. The alkylidene group (=CR2) of the reagent reacts with the oxygen atom of the carbonyl group to form a hydrocarbon with a double bond, an olefin (alkene). The reaction is widely used in organic synthesis, for example to make squalene (the synthetic precursor of cholesterol) and vitamin D3

German chemist whose method of synthesizing olefins (alkenes) from carbonyl compounds is a reaction often termed the Wittig synthesis. For this achievement he shared the 1979 Nobel Prize for Chemistry.

In the Wittig reaction, he first demonstrated 1954, a carbonyl compound (aldehyde or ketone) reacts with an organic phosphorus compound, an alkylidene-triphenylphosphorane, (C6H5)3P=CR2, where R is a hydrogen atom or an organic radical. The alkylidene group (=CR2) of the reagent reacts with the oxygen atom of the carbonyl group to form a hydrocarbon with a double bond, an olefin (alkene). The reaction is widely used in organic synthesis, for example to make squalene (the synthetic precursor of cholesterol) and vitamin D3

Page 36: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

7. Hydride Addition to C=O

Sources of hydride ("H-"), such as NaBH4, LiAlH4, all convert aldehydes and ketones to the corresponding alcohols by nucleophilic addition of hydride to C=O, followed or concurrently with protonation of the oxygen

R

O

H or R'

R

O

H or R'

"H "R

OH

H or R'

H

1)

2) H

LiAlH4, NaBH4, AlH3

"H " HOH orHORNaBH4, NADH (with dehydrogenase)

Page 37: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

Ethyl ether

LiAlH4 H2O

+

75% 25%

C C

C2H5H

C6H5 CH3

OHH

C C

C2H5H

C6H5 CH3

OHH

C C

C2H5H

C6H5 CH3

O

Page 38: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

20%20%

CHCH33HH33CC

OO

80%80%

OOHH

HH

CHCH33HH33CC

OOHH

HH

CHCH33HH33CCNaBHNaBH44

Page 39: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

this methyl group hindersthis methyl group hindersapproach of nucleophileapproach of nucleophilefrom topfrom top

this methyl group hindersthis methyl group hindersapproach of nucleophileapproach of nucleophilefrom topfrom top

HH33B—HB—H––

preferred direction ofapproach is to less hindered(bottom) face of carbonyl group

preferred direction ofapproach is to less hindered(bottom) face of carbonyl group

Steric Hindrance to Approach of Reagent

Page 40: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

Biological reductions are highly stereoselective

pyruvic acid S-(+)-lactic acid

OO

CHCH33CCOCCO22HHNADHNADH

HH++

enzyme is lactate dehydrogenaseenzyme is lactate dehydrogenase

COCO22HH

HOHO HH

CHCH33

Page 41: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

One face of the One face of the substrate can bind to substrate can bind to the enzyme better the enzyme better than the other.than the other.

Page 42: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

Change in geometry from trigonal to tetrahedral is stChange in geometry from trigonal to tetrahedral is stereoselective. Bond formation occurs preferentially ereoselective. Bond formation occurs preferentially from one side rather than the other.from one side rather than the other.

Page 43: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

8. Hydration of C=O

hydrates or gem-diols

R

O

H or R' HOHR

OH

H or R'

OH

H or OH(catalyst)

Page 44: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

H

O

H HOHH

OH

H

OH

H or OH(catalyst)

H3C

O

H HOH H3C

OH

H

OH

H or OH(catalyst)

(100%)

(58%)

steric hindrance in the product

Page 45: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

R

O

H or R' HOHR

OH

H or R'

OH

H or OH(catalyst)

R = CH2X, CHX2, CX3 (X = F, Cl, Br); R = R' = CH2X

Very electrophilic C=O carbon because of nearby highly electronegative atoms

favorable

Page 46: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

C=O + H-OH..

COHOH

HHCl3C Cl3C

Knock out drops

O

O

O + H2O

O

O

O

O

H

H

Page 47: Chapter 6  Reactions of Carbonyl Compounds 羰基化合物的反应

O

HOH

H or OH(catalyst)

OHHO

Hydrate formation relieves some ring strain by decreasing bond angles