1

A REVIEW OF ORGANIC REACTIONS

AND REAGENTS

FOR CHEMISTRY 551

January 2002

Dr. B.A. Keay Department of Chemistry

University of Calgary keay@ucalgary.ca

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The following schemes illustrate most of the reactions you were taught in Chemistry 351/353, 354 and/or 451/453. To do well in Chemistry 551 you need to know these reactions and the reagents necessary to effect various chemical reactions. This list is only a guide. You should consult textbooks and reference books for further information on each of these reactions. Links are provided for each entry. Table of Contents Chem 351/353 and 354 Reactions Page Preparation of Alkanes 3 Reactions of Alkanes 3 Preparation of Alkyl Halides 4 Reactions of Alkyl Halides 5 Preparation of Alcohols 6 Reactions of Alcohols 8 Preparation of Ethers 9 Preparation of Alkenes 10 Reactions of Alkenes 10 Preparation of Alkynes 13 Reactions of Alkynes 13 Preparation of Epoxides 14 Reactions of Epoxides 14 Preparation of Aldehydes 15 Preparation of Ketones 16 Reactions of Aldehydes and Ketones 16 Preparation of Carboxylic Acids 20 Reactions of Carboxylic Acids 21 Preparation of Acid Halides and Anhydrides 22 Reactions of Acid Halides and Anhydrides 22 Preparation of Esters 23 Reactions of Esters 23 Preparation of Amides 24 Reactions of Amides 24 Preparation of Lactones 25 Reactions of Lactones 25 Reactions Involving Carbanions 25 Preparation of Amines 28 Reactions of Amines 29 Reactions of Benzene 30 Reactions of Diazonium Salts 31 Changing Directing Ability of Groups on Benzene Rings 32 Diels-Alder Reactions 33 Chem 451/453 Reactions Pericyclic Reactions (Cope, Claisen, Oxy-Cope, etc.) 34 Other Sigmatropic Rearrangements 35 Dipolar Cycloadditons 36 Other Photochemical Reactions 37 Rearrangements 37

3

PREPARATION OF ALKANES 1. Hydrogenation of alkenes

H2

Pd, Pt, or Ni 2. Reduction of alkyl halides

a. Hydrolysis of Grignard reagent

R X R Mg X R H

X=Cl, Br, I

Mg

ether

H2O

(b) Reduction by metal and acid

R X R H

X=Cl, Br, I

Zn

HCl

3. Coupling of alkyl halides with organometallic compounds

R X R Li R CuLiR

R' X

R R'

X=Br or I

Li

may be 1o, 2o or 3o

CuI

should be 1o

REACTIONS OF ALKANES 1. Halogenation

R H R X

H

+ X2

hυ

Reactivity: X2: Cl2 > Br2

H: 3o > 2o > 1o > CH3

4

PREPARATION OF ALKYL HALIDES 1. From Alcohols

R OH R XHX or PX3

X=Cl, Br or I

2. Halogenation of certain hydrocarbons

R H R X

H

+ X2

hυ

Reactivity: X2: Cl2 > Br2

H: 3o > 2o > 1o > CH3 3. Addition of hydrogen halides to alkenes.

C11

C12

H XC16

C17

HX

X=Cl or Br

H usually attaches to least subsituted carbon atom in double bond (Markovnikovaddition) 4. Addition of halogens to alkenes or alkynes.

C CX X

C C C C C CX

X

X

XX=Cl or Br

X2

trans-addition across double bondsin rings

2 X2

5. Halide exchange

R X R I+ NaI (or NaBr)

X=Cl or Br1o >> 2o

(or Br)acetone

+ NaCl

NaCl ppt's fromacetone and drivethe reaction to completion

5

REACTIONS OF ALKYL HALIDES 1. Nucleophilic Substitution

R X R z

R X

R OH

R OH

R OR

R R'-C R'

R R'

R I

R CN

R COOR'

R NH2

R NHR'

R NR'R"

R PPh3

R X Ar R

OO

R R

OO

R RR'

O OR'

+ Z:

+ HO- alcohol

+ H2O alcohol

+ RO- ether(Williamsonether synthesis)

+ alkyne

+ R'-M alkane coupling

M=Li or Mg

+ I- alkyl iodide

+ nitrile-CN

+ R'COO- ester

+ primary amineNH3

+ secondary amineNH2R'

+ tetiary amineNHR'R"

+ phosphonium salt(for Wittig reaction)

PPh3

+

+ ArHAlCl3 Friedel-Crafts reaction

3o halide is best otherwise carbocation rearrangements can occur

R=alkyl and/or OR

-

R'-Xalkylation of 1,3-dicarbonyl systems

R'-Xalkylation of ketone enolates

6

2. Dehydrohalogenation: Elimination

C CH X

C Cbase

3. Preparation of Grignard reagent

R-X + Mgether

R-Mg-X 4. Reduction

R-HR-X + M + H+ + M+ + X-

M=Mg, Na, Zn

e.g. Mg followed by water, Na/EtOH, Zn/HCl, PREPARATION OF ALCOHOLS 1. Oxymercuration-demercuration

C11

C12

HO HgOAcC16

C17

C27

C28

HO H+ Hg(OAc)2

H2O NaBH4

Markovnikov addition 2. Hydroboration-Oxidation

C11

C12

H BR2

C16

C17

C27

C28

H OH+

anti-Markovnikov addition

B2H6

diborane

H2O2

3 x

3. Grignard synthesis

O OMgXR

OHR

etherR-Mg-X+

H2O

ketones or aldehydes 4. Hydrolysis of alkyl halides R-X + -OH R-OH + X-

usually requires a silver salt so can bevery expensive

7

5. Aldol condensation

H

OR

H

OR

OHR

H

OR

R

base

3-hydroxyaldehydemay eliminate uponworkup

-usually restricted to a condensation between the same aldehyde-crossed Aldol reactions provide complex mixtures of products

2 x

6. Reduction of ketones and aldehydes

R

H

OH

ROH

H

R

R'

OR'

ROH

H

1) H-

2) acid workup

1) H-

2) acid workup

1o alcohols

2o alcohols

aldehydes

ketones

-many sources of hydride-most common are: NaBH4, LiAlH4, DIBAL-H 7. Reductions of acids and esters

R

OH

OH

ROH

H

R

R'O

OH

ROH

H

1) LiAlH4

2) acid workup

1) LiAlH4

2) acid workup

1o alcohols

1o alcohols

+ R'-OH

esters

-NaBH4 will not reduce acids and esters-reductions with LiAlH4 cannot be stopped at the aldehyde

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8. Hydroxylation of alkenes

C CHO OH

C C

C CO

C CHO OH

O

O

OH

Cl

+KMnO4 orNaIO4

cis-addition

MCPBA

epoxide

H2O

H+

anti-addition

MCPBA = meta-chloroperoxybenzoic acid

9. Hydrolysis of Esters

R OR'

O

R OH

OOH

R'+

H3O+ or

NaOH, H2O 10. Misc.

C CX OH

C C +

anti-addition

X2, H2O

X=Cl, Br or I

REACTIONS OF ALCOHOLS 1. Reaction with hydrogen halides

R OH R X

R OH R OTs R X

+ HX

reactivityof HX: HI > HBr > HCl

reactivity of ROH: allyl, benzyl > 3o > 2o > 1o

-poor yielding, rearrangements and eliminationscan occur

BETTER IS:

+ TsClpyridine NaX

X=Cl, Br or I1o alcohol is best

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2. Reaction with phosphorus trihalides

R OH R X+ PX3

X= Br or I 3. Dehydration

C CH OH

C Cacid

3o > 2o > 1o

rearrangements may occur

4. Reactions as acids: reaction with active metals.

R OH R OM+ M

M = Na, K, Mg, Al, etc.

Reactivity: MeOH > 1o > 2o > 3o

5. Ester formation

R OH R' OH

O

R' OR

O+

H+

6. Oxidation

OHR

HH

RH

O

ROH

OOH

RH

H

RR'

OOH

RH

R'

OHR

R"R'

PDC

aldehyde

carboxylic acid

KMnO4

or Swernoxidation

ketone

KMnO4

KMnO4no reaction

or K2Cr2O7

PREPARATION OF ETHERS 1. Williamson Synthesis

R X R OR+ RO-

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PREPARATION OF ALKENES 1. Dehydrohalogenation of alkyl halides

C CX X

C C

X=Cl, Br or I

Zn

2. Reduction of Alkynes

C CR RR R

HHC CR R

R H

RH

H2

Lindlar catalyst

Na or Li

NH3

REACTIONS OF ALKENES 1. Addition of hydrogen. Catalytic hydrogenation

C C C CHH

H2

Pt. Pd, or Ni

syn addition 2. Addition of halogens

C C C CXX

X2

anti additionX=Cl or Br 3. Addition of hydrogen halides

H X

Br

Br

HX

X=Cl or Br

HBr

no peroxides

HBr

with peroxides

Markovnikovaddition

E.g.

anti-Markovnikovaddition

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4. Addition of Water

H OH

H2O

H+

Markovnikov addition 5. Halohydrin formation

C CX OH

C C +

anti-addition

X2, H2O

X=Cl, Br or I

6. Oxymercuration-demercuration

C11

C12

HO HgOAcC16

C17

C27

C28

HO H+ Hg(OAc)2

H2O NaBH4

Markovnikov addition 7. Hydroboration-Oxidation

C CH BR2

C C C CH OH

+

anti-Markovnikov addition

B2H6

diborane

H2O2

3 x

8. Addition of carbenes

C C + ":CH2"

HCCl3 + NaOH :CCl2

dichlorocarbene(neutral electron defficientspecies-very reactive)

E.g.formed "in situ"

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9. Epoxidation

C C C CO

O

O

OH

Cl

MCPBA

epoxide

MCPBA = meta-chloroperoxybenzoic acid

10. Hydroxylation

C CHO OH

C C +KMnO4 orNaIO4

cis-addition 11. Polymerization -not useful in synthesis 12. Allylic Halogenation

C CH C CBr N OO

Br

low conc.

NBSNBS=N-bromosuccinimide=

13. Ozonolysis

C CO O

OO O

O OOH

+ O3

ozonide

Me2S

orZn

+

aldehydes and ketones

reductive workup

H2O2 oxidative workup

+

ketones andcarboxylic acids

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PREPARATION OF ALKYNES 1. Dehydrohalogenation of alkyl dihalides

XX

H

X

X2

anti additionX=Cl or Br

KOH NaNH2

2. Reaction of metal acetylides with primary alkyl halides

H C RNaNH2

Na+RX

R must be primaryX = Br or I

REACTIONS OF ALKYNES 1. Addition of hydrogen

C CR RR R

HHC CR R

R H

RH

R R

HH HH

H2

Lindlar catalyst

Na or Li

NH3

H2H2

Pd, Pt or Ni Pd, Pt or Ni

2 x H2

Pd, Pt or Ni 2. Addition of halogens

C CR RR X

RX

R R

XX XX

X2 X2

X2 = Cl2 or Br2 3. Addition of hydrogen halides

C CR RR X

RH

R R

XH HXHX HX

HX = HCl, HBr, HI

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4. Addition of water

C CR RR OH

RH

R O

RH+ H2O

H2SO4

HgSO4

enol tautomerizes to ketone immediately 5. Formation of metal acetylides

H C NaNH2

Na+

PREPARATION OF EPOXIDES 1. From alkenes

C16

C17

C27

C28O

O

O

OH

ClO O

O

epoxide

MCPBA = meta-chloroperoxybenzoic acid

MCPBA

H2O2

NaOH

-only with conjugated enones, i.e. electron poor double bonds

-the more electron rich the double bondthe better the yield

2. From halohydrins

C CX OH

C C CCO

+

anti-addition

X2, H2O

X=Cl, Br or I

NaOH

X and OH must beanti-periplanar for epoxide to form

REACTIONS OF EPOXIDES 1. Acid-catalyzed opening

C11

C12OH

ZC

12C

11 OC

38C

39 OH

H+ Z:

+

anti-opening

15

2. Base opening

C COH

ZCC

O

anti-opening

Z:- +

Z:- can be: RO-, RS-, R2NH, etc. 3. Reaction with Grignard reagents

C COH

RCC

O

anti-opening

+R-Mg-XH+ workup

PREPARATION OF ALDEHYDES 1. Oxidation of primary alcohols

OHR

HH

RH

O

PDC

aldehyde

or Swernoxidation

2. Oxidation of methylbenzenes

HH

H HO

XH

X

benzaldehyde

Cl2, heat

orBr2, benzoylperoxide

water

3. Reduction of acid chlorides

RH

O

R

Cl O

aldehydeacid chloride

LiAlH(OBu-t)3

4. Reimer-Tiemann reaction

OH OH

H

OCHCl3, NaOH

70 oC

-must have a phenol and aldehyde is always introduced into the ortho position to the hydroxygroup

16

PREPARATION OF KETONES 1. Oxidation of secondary alcohols

RR'

OOH

RH

R'ketone

KMnO4

or K2Cr2O7

2. Friedel-Crafts acylation

RCl

O

RAr

O+AlCl3

Ar-H

3. Reaction of acid chlorides with organocopper compounds

R'Cl

O R'R

OR-Li

CuXR2CuLi

4. Ethyl acetoacetate synthesis

CH3EtO

O

CH3EtO

O

O

OEt

O

+1. NaOMe, MeOH

2. 10% HCl workup ethyl acetoacetate REACTIONS OF ALDEHYDES AND KETONES 1. Oxidation

R

O

Ar

O

R-CHO or Ar-CHOKMnO4 or

K2Cr2O7

R-CO2H or Ar-CO2H

Aldehydes

Methyl Ketones-haloform reaction

orKOCl

acidic workup

R-CO2H or Ar-CO2H + CHCl3

acidic workup

17

2. Reduction to alcohols

R R'

O

Ar R'

O

R R'

OH

Ar R'

OH

R-CHO or Ar-CHO R-CH2OH or Ar-CH2OH

Aldehydes

Ketones

or

acidic workup

NaBH4, MeOH

or LiAlH4

NaBH4, MeOH

or LiAlH4

or

3. Reduction to hydrocarbons

Ar R'

O

Ar R'Ar H

O

Ar H

R R'

O

R R'

or orZn(Hg)

conc. HCl

Clemmensen reduction-must be an aromatic aldehyde or ketone

H2NNH2

NaOH, heat

Wolff-Kishner reduction 4. Reductive amination

R R'

O

R R'

NHRH2NR

NaCNBH3

pH 5 5. Addition of cyanide

R R'

O

R R'

HO CN+ -CN

H+

cyanohydrin

18

6. Addition of derivatives of ammonia

R R'

O

R R'

HO NHG

R R'

NG

NOH

NNH2

NNHAr

NNHCONH2

NR

+ H2N-G

H2N-G Product

H2N-OH oxime

H2N-NH2 hydrazone

H2N-NHAr phenylhydrazone

H2N-NHCONH2 semicarbazone

H2N-R imine

7. Addition of alcohols

R R'

O

R R'

R"O OR"+

H+

acetal or ketal

2 R"OH

aldehyde or ketone 8. Addition of Grignard reagents

R R'

O

R R'

HO R"+

H+ workupR"-Mg-X

9. Halogenation of ketones

R

O

H

R

O

X

H+ workup+ X2

X2 = Cl2, Br2, or I2 10. Addition of carbanions a) Aldol condensation

CH3H

O

CH3

HO H

O

+1% HCl

or -OH

19

b) Reactions related to aldol condensation O O

Ar+ Ar-CHONaOH

c) Alkylation of Ketones

O O

O

ONH

N N

O

1) LDA, -78oC, THF

2) MeI

1) KOtBu, HOtBu

2) MeI

Enamine Formation Followed by Alkylation

MeI

enamine

H3O+

20

d) Wittig reaction

R' H

O

R' H

R H

R' H

O O

R' H

H R

O HH

+ Ph3P=CHR

Ph3P+-CH2RX-

phosphonium salt

n-BuLi

X-CH2R + Ph3P

mainly Z-isomernonstabilized ylid

EtO2P=CHR+

stabilized ylid mainly E-isomer

Wittig reactions can be done with unhindered ketones

+ Ph3P=CH2

PREPARATION OF CARBOXYLIC ACIDS 1. Oxidation of primary alcohols

ROH

OOH

RH

Hcarboxylic acid

KMnO4

NaOH0 oC

2. Hydrolysis of Esters

R OR'

O

R OH

OOH

R'+

H3O+ or

NaOH, H2O 3. Oxidation of alkylbenzenes

R CO2H -length and nature of R group does not matter-sidechain is cleaved to leave one carbon atom at the oxidation level of an acid

KMnO4

NaOHheat

21

4. Carbonation of Grignard reagents

R-Mg-X + CO2 R-CO2-

HClR-CO2H

5. Hydrolysis of nitriles

R-CN + 2 H2OH+ or

baseR-CO2H + NH3

REACTIONS OF CARBOXYLIC ACIDS 1. Acidity. Salt formation R-COOH + R-COO- Na+ +NaOH H2O 2. Conversion into functional derivatives a) Conversion into acid chlorides

R OH

O

R Cl

OSOCl2

PCl5or PCl3

b) Conversion into esters

R OH

O

R OR'

O

+ HOR'H+

+ H2O

c) Conversion into amides

R OH

O

R Cl

O

R NH2

OSOCl2 NH3

3. Reduction

R OH

O

R OHLiAlH4

1o alcohol 4. Reaction with X2

OH

OR OH

OR

X

Br2 or Cl2

red phosphorus

Hell-Volhard-Zelinsky reaction

22

PREPARATION OF ACID HALIDES AND ANHYDRIDES From Carboxylic Acids

R OH

O

R Cl

O

R OH

O

R OH

O

R O

O

R

O

R Cl

O

R OH

O

R O

O

R

O

Cl

O

O

ClSOCl2

oroxalyl chloride

Acid Chlorides

Acid Anhydrides

+P2O5

+

oxalyl chloride

REACTIONS OF ACID CHLORIDES AND ANHYDRIDES Acid Chlorides

R OH

O

R Cl

O

R Cl

O

R OH

O

R O

O

R

O

R OR'

O

R NR2

O

R R

O

R H

O

R H

OH

+

water

HOR'

H2NR2

R2Cd

ketone

amide

ester

acid

anhydride

aldehyde

LiAlH(OiPr)3

alcohol

LiAlH4

Acid Anhydrides

R OH

O

R O

O

R

O

R OR'

O

R NR2

O water

HOR'

H2NR2

amide

ester

acid2

+ acid

+ acid

23

PREPARATION OF ESTERS 1. From acids

R OH

O

R OR'

O

+ HOR'H+

+ H2O

2. From acid chlorides or anhydrides

R Cl

O

R OR'

O

R O R

OO

R OR'

O

R OH

O

+ HOR' + HCl

+ HOR' +

anhydride 3. From esters: Transesterification

R OR'

O

R OR"

O

HOR'+H+

+HOR" REACTIONS OF ESTERS 1. Conversion into acids and acid derivatives a) Conversion into acids. Hydrolysis

R OH

O

R OR'

O+ HOR'

H+

+ H2O

or HO-

b) Conversion into amides

R NR2

O

R OR'

O+ HOR'H+

+ NR2heat

c) Conversion into esters. Transesterification

R OR'

O

R OR"

O

HOR'+H+

+HOR" 2. Reaction with Grignard reagents

R OR'

O

R R"

R"

OH+ 2 R"MgX

3o alcohol

24

3. Reduction to alcohols

R OR'

O

R OHLiAlH4

1o alcohol

+ HOR'

4. Reaction with carbanions. Claisen condensation

OR'

OR OR'

OO

R

R2

3-keto esters

NaOR'

heat

PREPARATION OF AMIDES 1. From acid chlorides

R OH

O

R Cl

O

R NR2

OSOCl2 HNR2

2. From nitriles

RN

R NH2

O

H2O

HCl

heat REACTIONS OF AMIDES 1. Preparation of acids

R NH2

O

R OH

O

H2O

heat

H2SO4

2. Reduction to amines

R NR2

O

R NR2

LiAlH4

an amine

25

PREPARATION OF LACTONES

OO O

O OOOHOH

MCPBA

-ring expansion and formation of lactone-oxygen atom introduced to side of ketone thatis most substituted

Baeyer-Villiger Reaction

P2O5

remove water

-5 and 6 membered lactones are easest to form REACTIONS OF LACTONES

O O

O O

OHOH

O OH

LiAlH4

diol

DIBAL-H

lactol

-78 oC, DCM

REACTIONS INVOLVING CARBANIONS 1. Halogenation of ketones

R'

OR R'

OR

X

Br2 or Cl2

H+ or HO-

2. Nucleophilic addition to carbonyl compounds a) Aldol condensation

H

OR H

OOH

RR

H

O

RR

2NaOR'

heat

H+ or

H+

26

b) Reactions related to aldol condensation

R'

OR R'

OOH

RR'

RR'

O

R

R'

R

2NaOR'

heat

H+ or

H+

ketone c) Addition of Grignard and organolithium reagents

R H

O

R H

OH

R'

R R"

O

R R"

OH

R'

R OR''

O

R R'

OH

R'

HOR''

+R'MgXorR'Li

aldehyde

R'MgXorR'Li

+

ketone

+R'MgXorR'Li

+esters

d) Wittig reaction

R H

O

R H

R'R"

R R"

O

R R"

R'R"

R3P R'

R"

R3P R'

R"

+

aldehyde

+

ketone

ylidmixture of E and Z

ylidmixture of E and Z

3. Nucleophilic acyl substitution a) Claisen condensation

OR'

OR OR'

OO

R

R2

3-keto esters

NaOR'

heat

27

4. Nucleophilic aliphatic substitution a) Coupling of alkyl halides with organometallic compounds

R X R Li R CuLiR

R' X

R R'

X=Br or I

Li

may be 1o, 2o or 3o

CuI

should be 1o

b) Synthesis of acetylides

H C RNaNH2

Na+RX

R must be primaryX = Br or I

c) Alkylation of malonic ester and acetoacetic ester

OR'

OO

R OR'

OO

RR"

OR'

OO

R'OR"

OR'

OO

R'O

acetoacetic esters

NaOR'

heat+ R"X

NaOR'

heat+ R"X

malonic ester

d) Alkylation of ketones

RO

RO

R'

RO

ROR'

1) LDA, -78 oC, THF

2) R'X

kinetic control

1) KOtBu, HOtBu, heat

2) R'X

thermodynamic control

28

5. Addition to conjugated carbonyl compounds. Michael addition

O OCuLi

R

R

O

R

O OCuLi

R

R

O

R

R'

O

O O O

O

R2CuLi

enolate

water

R2CuLi

enolate

R'X

trans-stereochemistry

Micheal addition orconjugate addition

Robinson Annelation

+ NaOMe

MeOH 6. Reformansky Reaction

R R'

OOMe

OR''

BrOMe

OR''

RR'

OH

+Zn

PREPARATION OF AMINES 1. Reduction of nitro compounds Ar-NO2

or

R-NO2

Zn, HCl

H2, Pd/C

Ar-NH2

or

R-NH2 2. Reaction of halides with ammonia or amines

NH3

RXRNH2

RXR2NH

RXR3N

RXR4N+ X-

1o amine 2o amine 3o amine quaternaryammoniumsalt

29

3. Reductive amination

R R'

O

R R'

NHRH2NR

NaCNBH3

pH 5 4. Reduction of Nitriles

RN

R NH2

LiAlH4

or2H2, Pd/C

5. Hofmann degradation of amides

R NH2

O

RNH2

NH2

ONH2

KOBr

+ CO3-

chain loses one carbonatom in length

KOBr

rearrangement withretention of stereochemistry

REACTIONS OF AMINES 1. Basicity. Salt Formation

R2N+H2

2o amine

HClR2NH

ammonium salt

Cl-

2. Alkylation

NH3

RXRNH2

RXR2NH

RXR3N

RXR4N+ X-

1o amine 2o amine 3o amine quaternaryammoniumsalt

3. Conversion into Amides

R' Cl

O

R' NR2

O

R2NH +

amide

30

4. Hofmann Elimination from Quaternary Ammonium Salts

NR2NR3RI+

NaOH, heat

REACTIONS OF BENZENE

BrCl

NO2SO3H

R

X

R

R Cl

O

R

O

Electrophilic Aromatic Substitution of Benzene

Br2, FeBr3

Cl2, FeCl3

HNO3, H2SO4

SO3, H2SO4

AlCl3

rearrangements can occur with primary halides

Friedel-Crafts AcylationFriedel-Crafts Alkylation

AlCl3

Na, NH3(l)

Birch Reduction

BrCl

SO3H

NH2

Reactions to Remove Groups to give Benzene

KOH, heat

Mg, etherthen H2O 1) NaNO2, HCl

2) H3PO2

Mg, etherthen H2O

31

Eelectrophilic Aromatic Substitution on Substituted Aromatic Systems

Ortho/para Directors Meta Directors

-NR2 -NH2 -OH-OR-NHCOMe-OCOMe-R-H

-NR3 -NO2 -CN-SO3H-CHO-COMe-CO2H-CO2Me-CONH2 -NH3

+strong

weak

strong

weak+

Activators-make benzene ring electron richer

Deactivators-make benzene ring electron poor

Halides are deactivating but ortho/para directors!!

-F-Cl-Br-I

REACTIONS OF DIAZONIUM SALTS

NO2 NH2

N2

Cl

Br

I

F

CNOH

NN

NO2

N2

CO2H

Formation of and Reaction of Diazonium Salts

Zn, HCl

NaNO2,HCl

+Cl-

CuCl

KI

HBF4

CuCNH2O,H2SO4

H3PO2 or NaBH4

Diazo dyes

heat

Cu, NaNO2 (aq)

warm+ Cl-

Benzyne

32

CHANGING DIRECTING ABILITY OF GROUPS ON BENZENE RINGS

CO2H

NH2 R

NO2 NH2

CHO

O

Changing Activators into Deactivators

KMnO4

NaNO2, HCl

see diazonium wagonwheel

Changing Deactivators into Activators

H2NNH2, KOH

heat

Zn, HCl

33

DIELS-ALDER REACTION

O

OH

H

O

REWG

REWG

R

EWG

R

EWG

+

diene dienophile

Normal electron demand Diels-Alder reaction requires the dienophile have at least one electron withdrawing group attached and the diene should be electron rich.

Reverse electron demand Diels-Alder reaction requires the diene have at least one electron withdrawing group attached and the dienophile should be electron rich.

Endo vs Exo Products

+ +

exo product-thermodynamic product

endo product-kinetic product

Endo product forms the fastest due to secondary orbital overlap and is the kinetic product.Exo product forms if the reaction proceeds for a longer period of time (i.e. and is reversible).The exo product is thermodynamically more stable due to less steric crowding.

Regiochemistry

+

Diels-Alder reactions with unsymmetrical electron rich dienes and electron poor dienophiles give mainly cyclohexenes with the substituents in either a 1,2- or 1,4- orientation.

+

1,2-product

1,4-product

34

PERICYCLIC REACTIONS

R'

R R

R'

OR'

R

H

O

R

R'H

R'

R

OH

R

R'OH

R

R'OH

OR'

R

OR

O

R

R'OR

OR'

R

NR2

O

R

R'NR2

R'

R

R2N

R

R'R2N

R

R'OH

Cope Reaction

Claisen Reaction

4-enal

Oxy-Cope Reaction

4-enoate

Ortho-ester Claisen Reaction

4-enamide

Ortho-amide Claisen Reaction

Aza-Cope Reaction

H3O+

enamine

These are examples of [3,3] Sigmatropic Rearrangements

35

OTHER SIGMATROPIC REARRANGEMENTS

O OH

O OH

S+ S

S+

S

You have been shown[1,3] and [1,5]-H and alkyl shifts with heat or light. These will not be shown here.

[1,2] Wittig Rearrangement

n-BuLi

[2,3] Wittig Rearrangement

n-BuLi

[1,2] StevensRearrangement

base

Sommelet-Hauser Rearrangements ([2,3] Rearrangement)

base

36

DIPOLAR CYCLOADDITIONS

AB

C 3

D E D EC 8B

A A BC 13

D ED E

C 18BA

N+

NMeO

O

CO2Me

NN

CO2Me

MeO2C

-O O+

O OOO

-+

-+

e.g.

-

ozonide

a)

b)

O

R R'

OR

R'

Electrocyclic Reactions

[2 + 2] Cycloadditions

+light

Follow the Woodward-Hoffman Rules (Chem 453)

heat

not all permutations are shown

+ light

Paterno-Buchi reaction

37

OTHER PHOTOCHEMICAL REACTIONS

O

OHR

O

ORNO

O

OHRON

O

OHRN

OH

O

OHRO H

NOCl

nitrite ester

light

oximealdehyde

-conversion of a delta methyl group to an OH into an aldehyde

Barton Reaction

REARRANGEMENTS

R Cl

O

R CHN2

O OR

R

O

OH

R2R1

R3OH

H

R5

R2

R3

R1

R5

ArAr

O

O

ArOH

O

OHAr

R2

OH

R1OH

R3R4 R2

O

R1

R3R4

O NOH

N OH

Wolff Rearrangement

+ CH2N2

ketene

+N2-chain lengthened by one carbon atom

Arndt-Eistert Synthesis

H2O

Ag2O

H2O

Wagner-Meerwin Migrations

+ H+

-formation of carbocations followed by migration of alkyl, H, or aryl groups

Benzil-Benzilic Acid Rearrangement

NaOH

Pinacol Rearrangement

H+

Beckmann Rearrangement

HONH2

oxime

H+

lactam

38

NH2

OC17

ONNH2

Cl

O O

N3

C53

ON

OH

O

Hofmann Rearrangement

NaOBr hydrolysis

retention of stereochemistry

Curtius Rearrangement

NaN3 heat

hydrolysis

acyl azide

isocyanate

isocyanate

Schmidt Reaction

+ HN3