Summary of important

Undergraduate-level organic reactions

Dr. Stephen G. Boyes

Summer 2011

Synthesis of alkanes
Reactions of alkanes
Synthesis of alkenes
Reactions of alkenes
Synthesis of alkynes
Reactions of alkynes
Synthesis of alkyl halides
Reactions of alkyl halides
Synthesis of alcohols
Reactions of alcohols
Synthesis of ethers
Reactions of ethers
Synthesis of epoxides
Reactions of epoxides
Synthesis of ketones and aldehydes
Reactions of ketones and aldehydes
Synthesis of carboxylic acids
Reactions of carboxylic acids
Reactions of acid (acyl) chlorides
Synthesis and reactions of acid anhydrides
Synthesis and reactions of esters
Synthesis and reactions of amides
Synthesis and reaction of amines
Reactions of aromatic compounds

2
2
3
4
6
7
10
11
13
16
18
18
19
19
20
22
25
26
28
29
30
32
33
38

Summary of important, mainly single step, chemical reactions

PREPARATION OF ALKANES
2) Reduction of alkyl halides

1) Hydrogenation of alkenes

a. Hydrolysis of a Grignard reagent

H2

R-X

Pd, Pt, or Ni

Mg

R-Mg-X H2O

R-H

ether
b. Reduction by metal and acid
Zn
R-X

R-H

X = Cl, Br, I

HCl
3) Coupling of alkyl halides with organometallic cpds

R-X

Li

R-Li

CuI

R CuLi
R

maybe 10, 20 or 30
X = Br or I

R-R'

R'-X
should be 10

REACTIONS OF ALKANES
1) Halogenation

R H + X2

R X

Reactivity: X2: Cl2 > Br2

H: 30 > 20 > 10 > CH3-H
2

SYNTHESIS OF ALKENES
1) Dehydrohalogenation of alkyl halides
H

2) Dehydrohalogenation of vicinal dibromides

Br

base, heat
C C

C C

Br

3) Dehydration of alcohols
H OH

Zn, CH3COOH

4) Dehydrogenation of alkanes
H H

conc. H2SO4 or H3PO4

C C

C C

C C

C C

(loss of HX)

NaI or

heat

+ H2O

heat

C C

+ H2

C C

catalyst
useful only for small alkenes - often gives mixtures

5) Hofmann and Cope eliminations

H

H2, Pd/BaSO4

Ag2O, heat

C C
N(CH3)3
I

6) Reduction of alkynes

C C

+ N(CH3)3

R'
C C

R C C R'
quinoline

usually gives the least highly

substituted alkene

cis alkene
Na, NH3
R C C R'

R
C C

7) Wittig reaction

R'
trans alkene

R'
C O + Ph3P=CHR''
R

R'
C CHR'' + Ph3P=O
R

REACTIONS OF ALKENES
ELECTROPHILIC ADDITIONS
1) Addition of hydrogen halides

C C

+ H-X

2) Acid-catalyzed hydration

C C

HX = HCl, HBr, HI

C C

H+

+ H2O

C C

H X

H OH

Markovnikov orientation

Markovnikov
orientation

Anti-Markovnikov in the
presence of HBr and peroxides

3) Oxymercuration-demercuration

C C

+ Hg(OAc)2

H2 O

NaBH4

C C
OHHgOAc

C C
OHH
Markovnikov
orientation

4) Alkoxymercuration-demercuration

C C

+ Hg(OAc)2

ROH

NaBH4

C C

C C

OR HgOAc

OR H
Markovnikov
orientation

5) Hydroboration-oxidation

C C

+ BH3-THF

H2O2, HOC C

C C

H BH2

H OH
Anti-Markovnikov
orientation

REDUCTION: CATALYTIC HYDROGENATION

Pt, Pd, or Ni
C C

+ H2
H H
syn addition

ADDITION OF CARBENES: CYCLOPROPANATION

X
C C

C C

X,Y = H, Cl, Br, I, or -CO2Et

OXIDATIVE ADDITIONS
1) Addition of halogens

2) Halohydrin formation
X

C C

+ X2

+ X2

C C

H2 O

X
X2 = Cl2, Br2, sometimes I2

X
OH

anti addition

X2 = Cl2, Br2, sometimes I2

anti addition
Markovnikov
orientation

3) Epoxidation
C C + R

OH

O
peroxyacid

+
C C
O
syn addition

OH
O

4) Anti hydroxlation
C C + R

OH

O
peroxyacid

H+, H2O
C C
O
syn addition

OH
OH
net anti
addition

5) Syn hydroxylation
C C +

KMnO4 + HO-, H2O

or OsO4, H2O2

OHOH
net syn
addition

OXIDATIVE CLEAVAGE OF ALKENES

1) Ozonolysis
R

R'

R
+ O3

(CH3)2S

R'

R'
O + O

C
C
H
O O

ketones and aldehydes

2) Potassium permanganate
R

R'

warm

R
O + O

+ KMnO4
R

R'

OH
ketones and acids
(aldehydes are oxidized)

SYNTHESIS OF ALKYNES
1) Alkylation of acetylide ions
R C C

+ R'-X

SN 2

R C C R' + X

R'-X must be an unhindered primary halide or tosylate

2) Additions to carbonyl groups

R'

R'
R C C

C O
R'

R C C

C O
R'

R'

H2O or
R C C
H3O+

C OH
R'

REACTIONS OF ALKYNES
ACETYLIDE CHEMISTRY
1) Formation of acetylide anions (alkynides)
a) Sodium, lithium, and magnesium acetylides
R C C H + NaNH2

R C C Na

+ NH3

R C C H + R'Li

R C C Li

+ R'H

R C C H + R'MgX

R C C [MgX]

+ R'

b) Heavy-metal acetylides
R C C H + Ag+

R C C Ag

R C C H + Cu+

R C C Cu

these reactions are used to test for the presence of a terminal alkyne

2) Alkylation of acetylide ions

R C C

+ R'-X

S N2

R C C R' + X

R'-X must be an unhindered primary halide or tosylate

3) Additions to carbonyl groups

R'

R'
R C C

C O
R'

R C C

C O
R'

R'

H2O or
R C C
H3O+

C OH
R'

ADDITIONS TO THE TRIPLE BOND

1) Reduction to alkanes
R C C R' + 2 H2

H H

Pt, Pd, or Ni

R C C R'
H H

2) Reduction to alkenes
R

Pd/BaSO4

C C

R C C R' + H2
quinoline

cis
H

Na/NH3

R C C R'

R'

C C
H

trans
R'

3) Addition of halogens (X2 = Cl2, Br2)

X2

R C C R'

X X

X2

R-CX=CX-R'

R C C R'
X X

4) Addition of hydrogen halides (HX = HCl, HBr, HI)

HX

R C C R'

H X

HX

R-CH=CX-R'

R C C R'
H X

Markovnikov
orientation

5) Addition of water
a) Catalyzed by HgSO4/H2SO4
HgSO4
R C C H
H2SO4
Markovnikov
orientation

R
HO

keto-enol

R C C H
tautomerism

O H
ketone
(stable)

vinyl alcohol
(unstable)

b) Hydroboration-oxidation
i) Sia2BH-THF

keto-enol

R C C R'

R C C H
ii) H2O2, NaOH

Anti-Markovnikov
orientation

OH

vinyl alcohol
(unstable)

tautomerism

H O
ketone or aldehyde
(stable)

OXIDATION OF ALKYNES
1) Oxidation to -diketones
KMnO4

O O
R C C R'

R C C R'
H2O, neutral

2) Oxidative cleavage
(1) KMnO4, HO(2) H+
R C C R'

O
R C OH +

O
HO C R'

(or O3 then H2O)

SYNTHESIS OF ALKYL HALIDES

1) From alkanes: free radical halogenation
synthetically useful only in certain cases
X2
R-H

R-X + H-X
heat or light

2) From alkenes and alkynes

2 HX

HX

C C

C C

C C

C C

H X

H X
X2

C C

C C

C C
X X

C C

Br
N

2 X2

X X
C C
X X

(NBS)

H X

C C

allylic bromination
C

Br

light

3) From alcohols

R-OH

HX, PX3
R-X

4) From other halides (the Finkelstein reaction)

acetone
R-X + I

R-I + X

18-crown-6
R-Cl + KF

R-F
CH3CN

10

REACTIONS OF ALKYL HALIDES

works for other halides
as well under
specific conditions

1) Nucleophilic substitutions
Halide exchange
(the Finkelstein reaction)

Alcohol formation

R-OH + X

R-I + X

Alkyne
synthesis

R'

OH

C C R

ether

R-O-R' synthesis

R'-O
R'

C C

R-X

NaNH2

synthesis

R'-S
excess

C N
R'

R-S-R' thioether

Williamson
ether
synthesis

C CH

NH3
R-NH3+X-

R C N
Nitrile
synthesis

NH3

R-NH2 + NH4+BrAmine
synthesis

2) Elimination reactions
Dehydrohalogenation

base
C C

C C
X

e.g. KOH or NaOCH3

Dehalogenation

Br

KI

C C

C C

+ I-Br + KBr

Br

11

3) Formation of organometallic reagents

a. Grignard reagents

diethyl ether
R-Mg-X

R-X + Mg

behaves like R-[MgBr] +

or THF
X = Cl, Br, I
b. Organolithium reagents

R-Li + Li+X-

R-X + 2Li
X = Cl, Br, I
4) Coupling or organocopper reagents

2 R-Li + CuI

R2CuLi + LiI

R2CuLi + R'-X

R-R' + R-Cu + LiX

5) Reduction

(1) Mg or Li
R-X

R-H
(2) H2O

12

SYNTHESIS OF ALCOHOLS
FROM ALKENES
1) Hydration
a. Acid catalyzed: forms Markovnikov alcohols
b. Oxymercuration-demercuration: forms Markovnikov alcohols
H2SO4, H2O, or
(1) Hg(OAc)2, H2O
(2) NaBH4

OH

c. Hydroboration-oxidation: forms anti-Markovnikov alcohols

(1) BH3-THF

HO

(2) H2O2, NaOH

2) Hydroxylation: forms vicinal diols (glycols)

a. Syn hydroxylation using KMnO4/NaOH or using OsO4/H2O2
KMnO4/NaOH

H
OH
OH

or OsO4/H2O2

cis product

H
b. Anti hydroxylation, using peracids
+

RCO3H, H
H2O

OH
H

trans product, + enantiomer

OH

13

FROM ALKYL HALIDES: NUCLEOPHILIC SUBSTITUTION

1) Second-order substitution: primary (and some secondary) halides
KOH
Br

OH
H2O

1) First-order substitution: tertiary (and some secondary) halides

acetone/water
+
heat

Cl

OH

FROM CARBONYL COMPOUNDS: NUCLEOPHILIC ADDITION TO THE CARBONYL GROUP

1) Addition of a Grignard or organolithium reagent
O

OMgX

ether

+ RMgX

H3O+

OH
R

a. Addition to formaldehyde gives a primary alcohol

O
MgBr

(1) ether solvent

H

OH

1-propanol

(2) H3O+

b. Addition to an aldehyde gives a secondary alcohol

(1) ether solvent

O
MgBr

+
H

OH
+

(2) H3O

c. Addition to a ketone gives a tertiary alcohol

O
MgCl

(1) ether solvent

OH

+
(2) H3O+

14

d. Addition to an acid halide or an ester gives a tertiary alcohol

O
MgBr

(1) 2

Cl
O

OH

(2) H3O+
O

e. Addition to ethylene oxide gives a primary alcohol with two carbons added
MgBr

(1)

OH

(2) H3O+
2) Reduction of carbonyl compounds
a. Catalytic hydrogenation of aldehydes and ketones
O
+ H2

OH

Raney Ni

This method is usually not as selective or as effective

as the use of the hydride reagents

H
b. Use of hydride reagents
(1) Reduction of an aldehyde gives a primary alcohol
O
Ph

NaBH4
H

Ph-CH2-OH

(2) Reduction of a ketone gives a secondary alcohol

O

NaBH4

OH
(3) Reduction of an acid or an ester gives a primary alcohol
O
R

OH

R-CH2-OH
(2) H3O

O
R

(1) LiAlH4
+

15

REACTIONS OF ALCOHOLS
1) Oxidation-reduction reactions
a. Oxidation of secondary alcohols to ketones
OH
R

Na2Cr2O7, H2SO4
R'

R'

b. Oxidation of primary alcohols to carboxylic acids

O

Na2Cr2O7, H2SO4
R-CH2-OH

OH

c. Oxidation of primary alcohols to aldehydes

O

PCC
R-CH2-OH

PCC: pyridinium chlorochromate

(pyH+CrO3Cl-)

d. Reduction of alcohols to alkanes

(1) TsCl/pyridine
R-H

R-OH
(2) LiAlH4

2) Cleavage of the alcohol hydroxyl group

a. Conversion of alcohols to alkyl halides
HCl or SOCl2/pyridine

R-OH

HBr or PBr3
HI or P/I2

R-Cl
R-Br
R-I
16

b. Dehydration of alcohols to form alkenes

H OH

H2SO4 or H3PO4
+ H2O

C C
3) Cleavage of the hydroxyl proton
a. Tosylation
O
R-OH + Cl

pyridine

RO S

tosyl chloride (TsCl)

alkyl tosylate

b. Acylation to form esters

O
R'

Cl

R-OH

R'

O-R

+ HCl

c. Williamson ether synthesis

R-O

R'-X

R-O-R' + X

R' must be primary

d. Deprotonation to form an alkoxide

R-OH + Na (or K)

R-O-Na+ + 1/2 H2

R-OH + NaH

R-O-Na+ + 1/2 H2

17

SYNTHESIS OF ETHERS
1) The Williamson ether synthesis
R O

R-O-R' + X

R'-X

X = Cl, Br, I, OTS, etc

R' must be primary

2) Addition of an alcohol across a double bond: alkoxymercuration-demurcuration

+ Hg(OAc)2

C C

ROH

NaBH4

C C
OR HgOAc

C C
OR H
Markovnikov
orientation

3) Bimolecular dehydration of alcohols: industrial synthesis

H+

2 R-OH

R-O-R + H2O

R must be primary

REACTIONS OF ETHERS
1) Cleavage by HBr and HI
excess HX
R-X + R'-X

R-O-R'
(X = Br, I)
excess HX

Ar-OH + R'-X

Ar-O-R
(X = Br, I)
Ar : aromatic ring

2) Autoxidation
excess O2
R-O-CH2-R'

OOH
R O

slow

R'

R O O CH2 R'

H
hydroperoxide

dialkyl
peroxide

18

SYNTHESIS OF EPOXIDES
1) Peroxyacid epoxidation
O
+

O
+

OH

2) Base-promoted cyclization of halohydrins

X

base

C C
OH

X = Cl, Br, I, OTs, etc

REACTIONS OF EPOXIDES
1) Acid-catalyzed opening
a. In water
H+

OH
C C

H2O

anti stereochemistry

OH

b. In alcohols
H+

OH
C C

R-OH

OR

the alkoxy group bonds to the more

highly substituted carbon

c. Using hydrohalic acids (X = Cl, Br, I)

OH

H-X
O

H-X

C C

C C

2) Base-catalyzed opening
a. With alkoxides
CH2
O

R-O
R-OH

C CH2 OR
OH

b. With organometallics
CH2
O

(1) R-M
(2) H3O+

C CH2 R
OH

R bound to less substituted carbon

19

SYNTHESIS OF KETONES AND ALDEHYDES

1. Oxidation of alcohols
a. Secondary alcohols to ketones
OH

Na2Cr2O7/H2SO4

R'
R
2o alcohol

R
R'
ketone

b. Primary alcohols to aldehydes

C5H5NH+CrO3Cl-

R-CH2OH

(PCC)

aldehyde
2. Ozonolysis of alkenes
R

1) O3

R'

R'
O

2) (CH3)2S

R"

H
aldehyde

O
R"
ketone

3. Friedel-Crafts acylation
O
AlCl3

Cl

+ HCl

O
aryl ketone
Gatterman-Koch synthesis
+ CO, HCl

O
AlCl3/CuCl

H
benzaldehyde derivative

4. Hydration of alkynes
a. Catalyzed by acid and mercuric salts
HgSO4
R C C H
H2SO4
Markovnikov
orientation

R
HO

H
H

vinyl alcohol
(unstable)

keto-enol

H
R C C H

tautomerism

O H
ketone
(stable)

20

b. Hydroboration-oxidation
i) Sia2BH-THF

keto-enol

R C C R'

R C C H
ii) H2O2, NaOH

tautomerism

OH

H O
ketone or aldehyde
(stable)

vinyl alcohol
(unstable)

Anti-Markovnikov
orientation

5. Alkylation of 1,3-dithianes
1) BuLi
S

2) 1o R-X
alkylation

1) BuLi
S

2) 1o R'-X
alkylation

thioacetal

R'

thioketal

H3O+, HgCl2

H3O+, HgCl2

O
H

O
R

R'

aldehyde

R
ketone

6. Synthesis of ketones using organolithium reagents with carboxylic acids

O

OH

OLi

2 R'-Li

H3O+

OLi

R'

R'

R
ketone

7. Synthesis of ketones from nitriles

N MgX
R-CN + R'-Mg-X
R'
or R'-Li

H3O+
R'

R
ketone

Mg salt
of imine

8. Aldehyde synthesis by reduction of acid chlorides

O
R

Li+-AlH(O-t-Bu)3
Cl

H
(or H2, Pd, BaSO4, S)

aldehyde

21

9. Ketone synthesis from acid chlorides

O
R

R2CuLi
R'

Cl

REACTIONS OF KETONES AND ALDEHYDES

1. Addition of organometallic reagents
O
R'

metal

O
R

+ R"-metal

metal = MgX, Li, Na etc

OH

H3O+

R'

R'

R"

R"

alkoxide

alcohol

2. Reduction
O

O
R'

+ NaBH4 (or LiAlH4)

(or H2/Raney Ni)

aldehyde
or
ketone

R'

H+

OH
R

R'

alkoxide

alcohol

3. The Wittig reaction

O
R'

R'

PPh3

R'
+ Ph3P=O

aldehyde
or
ketone

R'

4. Hydration
OH

O
R

R'

aldehyde
or
ketone

H2 O

OH
R'
22

5. Formation of cyanohydrins
O
R

OH

CNR'

HCN

CN
R'

aldehyde
or
ketone
6. Formation of imines
O

H+

N R"

R' + R"-NH2

aldehyde
or
ketone

R'

imine
(Schiff base)

7. Formation of oximes and hydrazones

O
R

H+
R'

aldehyde
or
ketone

N OH

+ H2N-OH
R

hydroxylamine

oxime

N NH-R"

H+
R' + H2N-NH-R"

aldehyde
or
ketone

R'

hydrazine
reagent

R'

hydrazone

8. Formation of acetals
O
R

OR"

H+
R'

+ 2 R"-OH

OR" + H2O

R
R'

aldehyde
or
ketone
9. Oxidation of aldehydes
O
R

chromic acid, permanganate, Ag+, etc

H

23

OH

10. Deoxygenation reactions

a. Clemmensen reduction
O
R' + Zn(Hg)

b. Wolff-Kishner reduction
O
R

N NH2

H+
R' + H2N-NH2

aldehyde
or
ketone

hydrazine

R'

KOH
heat

H
R'

+ H2O + N2

hydrazone

24

SYNTHESIS OF CARBOXYLIC ACIDS

1) Oxidation of primary alcohols and aldehydes
O

H2CrO4

R-CH2-OH
primary
alcohol

or KMnO4

H2CrO4
H

or KMnO4

aldehyde

OH

carboxylic
acid

2) Oxidative cleavage of alkenes and alkynes

R

R'

conc. KMnO4

R'
R-COOH +

O
R''

R''
conc. KMnO4

R'

R-COOH + HOOC-R'
or (1) O3
(2) H2O

3) Oxidation of alkylbenzenes

R(alkyl)

COOH

Na2Cr2O7, H2SO4
or KMnO4, H2O

a benzoic acid

Z must be oxidant resistant

4) Carboxylation of Grignard reagents

R-X

Mg

R-MgX

O=C=O
R

alkyl or
ether
aryl halide

H+
OMgX

OH

5) Formation and hydrolysis of nitriles

H+, H 2 O

NaCN
R-CH2-CN

R-CH2-X
acetone

O
R CH2 C

or -OH, H2O

OH 25

6) The haloform reaction

O
R

X2
CH3

O-

HO

+ HCX3
(haloform)

X = Cl, Br, I

7) Malonic ester synthesis

O

EtO

(1) NaOEt
(2) R-X

OEt

(1) HO-

EtO

OEt

O
R

(2) H , heat

OH

R
REACTIONS OF CARBOXYLIC ACIDS
O
R
O
R

deprotonation

O
OH

nucleophilic acyl substitution

R-CH2-OH

reduction

R-Y + CO2

decarboxylation

1) Salt formation
O
R

O
OH

+ M+-OH

strong
base

O-+M + H2O

2) Conversion to acid chlorides

O
OH

Cl

Cl

Cl

SO2

HCl

thionyl
chloride

26

3) Conversion to esters
O
C

H+
OH

+ R'-OH

O
C

O
Cl

+ R'-OH

O
C

+ H2O

OR'

+ HCl

OR'

O
OH

+ CH2N2

OCH3 + N2

4) Conversion to amides
O
C

O
OH

+ R'-NH2
R

O
C

Cl

+ R'-NH2

heat
O-H3N+-R

NH-R'

+ H2O

NaOH
R

+ NaCl + H2O

NH-R'

5) Conversion to anhydrides
O
R

O
OH

R'

Cl

O
O

+ HCl

R'

6) Reduction to primary alcohols

O
R

(1) LiAlH4

OH

(2) H3O+
(or use BH3-THF)

R-CH2-OH

6) Reduction to aldehydes
O
R

LiAl[OC(CH3)3]3H

Cl

lithium aluminium tri(t-butoxy)hydride

7) Alkylation to form ketones

O
R

(1) R'-Li (an alkyl lithium)

O-Li+

(2) H2O

O
R

R'

27

REACTIONS OF ACID (ACYL) CHLORIDES

O

H2O
R
O
R

Cl

R'OH
R

+ HCl

ACID

OR'

+ HCl

ESTER

+ HCl

AMIDE

+ HCl

ANHYDRIDE

O
R'NH2
R
R'CO2H
R

2) H2O

NHR'

R'

OH

1) 2R'MgX

R'
R'

O
C

OH

acid chloride

3o ALCOHOL

O
Cl

R2'CuLi
R

R'

KETONE

acid chloride
1) LiAlH4

R-CH2OH

1o ALCOHOL

2) H2O

O
Li(t-BuO)3AlH

ALDEHYDE

28

SYNTHESIS AND REACTIONS OF ANHYDRIDES

1. Synthesis
O

O
R

+
HO

Cl

R'

O
O

R'

+ pyr.HCl

(or carboxylate
salt)

O
OH
OH

this is general for cyclic anhydride formation

heat
O

dehydrating agents are also sometimes employed

O

O
2. Reactions of anhydrides
O

H2O
R

O
R

OH

+ RCO2H

ACID

OR'

+ RCO2H

ESTER

NHR'

+ RCO2H

AMIDE

O
R'OH, H
R'

O
R'NH2

29

SYNTHESIS AND REACTIONS OF ESTERS

1. Synthesis
O
R

H+
OH

+ R'-OH

O
R

O
+ R'-OH

Cl

O
R

+ H2O

OR'

OR'
O

+ HCl

+ R'-OH

OR'

+ RCO2H

O
+

OR''

+ R'-OH

or R'O

+ R''OH

O
R

OR'

OH

+ CH2N2

OCH3

+ N2

30

2. Reactions
H2O
H+ or HO-

O
R

OH

+ R'-OH

ACID

OR''

+ R'-OH

ESTER

NHR''

+ R'-OH

AMIDE

+ R'-OH

1o ALCOHOL

+ R'-OH

3o ALCOHOL

O
R"OH

O
R

H+ or R"O-

OR'
O
R"NH2

1) LiAlH4
2) H2O

R-CH2OH

OH

1) 2R"MgX
2) H2O

R"
R"

Lactone formation
H+
OH

CO2H

O
O

31

SYNTHESIS AND REACTIONS OF AMIDES

1. Synthesis
O

heat
R

+ R'-NH2

OH

O
R
O

+ 2 R'2NH

NHR'2

+ R'2NH2+Cl-

NHR'2

+ RCO2H

O
O

+ R'2NH

O
R

+ H2 O

O
Cl

NHR'

O
+ R'-NH2

OR"

+ R"OH

NH2

1o amide

H+ or HOR C N

NHR'

+ H2 O

2. Reactions
O

H2O
H+ or HO-

+ R'-NH2

OH

1) LiAlH4

O
R

2) H2O

NHR'

Br2, HO-

POCl3

R-CH2NHR'

R-NH2

R-CN

+ CO32-

ACID

AMINE

AMINE

NITRILE
32

SYNTHESIS AND REACTIONS OF AMINES

1) Reductive amination
a. Primary amines
O
R

N OH

H2N-OH
R'

H+

aldehyde
or
ketone

NH2

reduction

R'

R'

oxime

b. Secondary amines
O
R

N R"

R"-NH2
R'

H+

aldehyde
or
ketone

NHR"

reduction

R'

R'

oxime

c. Tertiary amines
O
R'

R N R

R-NH-R
R"

R'

H+

aldehyde
or
ketone

NR2

Na(CH3COO)3BH
R'

R"

R"

iminium salt

2) Acylation-reduction of amines
O
R-NH2

R'

acylation
R'

Cl

reduction

NHR

amide
(acylated amine)

R-CH2-NH-R
1) LiAlH4
2) H2O

alkylated amine

3) Alkylation of ammonia
R-CH2-NH2 + HX

R-CH2-X + excess NH3

4) The Gabriel Synthesis of primary amines

O
N K

R-X
alkyl
halide

N R
phthalimide
anion

H2NNH2
heat

O
N-alkyl phthalimide

R-NH2
33

5) Reduction of azides
LiAlH4
R-NH2

R N N N
or H2/Pd
6) Reduction of nitriles
LiAlH4

R-CH2-NH2

R-CN
or H2/Pd

7) Reduction of nitro compounds

H2/catalyst

R-NO2

R-NH2

8) The Hofmann rearrangement

O
R

NH2

+ X2 + 4 NaOH

R-NH2 + 2 NaX + Na2CO3 + 2 H2O

X2 = Cl2 or Br2

9) Nucleophilic aromatic substitution

R-NH2

+ Ar-X

R-NH-Ar + HX

the aromatic ring should be activated towards nucleophilic attack

34

1) Reaction as a proton base

H

2) Reactions with ketones and aldehydes

O
N
H+

+ Y-NH2
+ H2O
R
R'
R
R'

imine

3) Alkylation

R-NH2 + R'-CH2-Br
R-NH2-CH2-R' Br

4) Acylation to form amides

O
pyridine

R-NH2 +
R
Cl
R
NHR

5) Reaction with sulfonyl chlorides to give sulfonamides

O
O

RHN S R' + HCl

R-NH2 + Cl S R'

O
O

6) Hofmann and Cope eliminations

a. Hofmann elimination

3 CH3I
R-CH2-CH2-NH2
R-CH2-CH2-N(CH3)3 I

Ag2O
R-CH2-CH2-N(CH3)3 I
R-CH2-CH2-N(CH3)3

HO

R-NH2 + HX

R N H
H X

H H
R

H
H N(CH3)3

H2O + N(CH3)3 +
35

a. Cope elimination of a tertiary amine oxide

H H
R

H H

peracid
H

H N(CH3)2

heat

R'
+ HO-N(CH3)2

or H2O2

H N(CH3)2

O
7) Oxidation
a. Secondary amines
R2N-OH + H2O

R2N-H + H2O2
b. Tertiary amines
R3N + H2O2

R3N-O + H2O

or ArCO3H

or ArCOOH

8) Diazotization
R-NH2

NaNO2, HCl

R N N Cl

primary
alkyl amine
Ar-NH2

alkanediazonium salt
NaNO2, HCl

Ar

N N Cl

aryldiazonium salt

primary
aryl amine
a. Reactions of diazonium salts
I. Hydrolysis
H2SO4, heat
Ar N N Cl
H2O

Ar-OH + N2 + HCl

II. The Sandmeyer reaction

CuX
Ar N N Cl
(X = Cl, Br, CN)

Ar-X + N2

III. Replacement by fluoride or iodide

Ar

N N Cl

Ar

N N Cl

HBF4

KI

heat
Ar

N N BF4

Ar-I + N2 + KCl

Ar-F + N2 + BF3

36

IV. Reduction to hydrogen

Ar

N N Cl

H3PO2

Ar-H + N2

V. Diazo coupling
Ar

N N

+ H-Ar'

Ar

N N Ar' + H+

37

REACTIONS OF AROMATIC COMPOUNDS

1. Electrophilic aromatic substitution
a. Halogenation
+ Br2

Br

FeBr3

+ HBr

b. Nitration
NO2

H2SO4

+ HNO3

+ H2O

c. Sulfonation
H2SO4

SO3H

+ SO3
H3O+, heat
d. Friedel-Crafts alkylation
+ (CH3)3C-Cl

AlCl3

C(CH3)3
+ HCl

e. Friedel-Crafts acylation
O
Cl

AlCl3

+ HCl

O
f. Gatterman-Koch synthesis
+ CO, HCl

O
AlCl3/CuCl

g. Substituent effects
Activating, ortho, para-directing: -R, -OR, -OH, -O-, -NR2 (amines, amides)
Deactivating, ortho, para-directing: -Cl, -Br, -I
Deactivating, meta-directing: -NO2, -SO3H, -NR3+, -C=O(-), -CN

38

2. Nucleophilic aromatic substitution

X

Nuc
+ X

+ Nuc
G

a halobenzene
(G = strong withdrawing
group)

strong
nucleophile

If G is not a strong electron-withdrawing group, severe conditions are required,

and a benzyne mechanism is involved
3. Addition reactions
a. Chlorination
heat and pressure
+ 3 Cl2

or light

Cl

Cl
H
Cl

Cl
H
Cl
H

H Cl
b. Catalytic hydrogenation
H

Ru or Rh catalyst
+ 3 H2

100oC, 1000 psi

mixture of cis and trans

c. Birch reduction
Na or Li
NH3(l), R-OH
4. Side-chain reactions
a. The Clemmensen reduction (converts acyl benzenes to alkyl benzenes)
O
Zn(Hg)
R

R
dilute HCl
39

b. Permanganate oxidation

hot, conc. KMnO4

R

O K
H2O

c. Side-chain halogenation
Br
R

Br2

hv

d. Nucleophilic substitution at the benzylic position

The benzylic position is activated towards both SN1 and SN2 displacements
X

Nuc
R

+ Nuc

5. Oxidation of phenols to quinones

OH

O
Cl

Na2Cr2O7

Cl

H2SO4
O

40