2012

Functional Group
Transformation
Notebook
M. Huffstickler, K. Syler, and H. Wayland
For Organic Chemistry I and II

Huffstickler, Syler, and Wayland

Henderson State University
8/3/2012

Table of Contents

Alkene and Alkyne Chemistry

p.5

Acid-Catalyzed Addition of an Alcohol to an Alkene

p.6

Addition of Halogen to an Alkyne

p.7

Addition of Peroxyacid to an Alkene

p.8

Addition of Halogen to an Alkene

p.9

Addition of Hydrogen Halide to an Alkyne

p.10

Addition of Hydrogen to an Alkene

p.11

Addition of Hydrogen to an Alkyne

p.12

Addition of Water to an Alkyne

p.13

Alkoxymercuration of an Alkene

p.14

Alkylation of Alkynes

p.15

Addition of Hydrogen Halide to an Alkene

p.16

Addition of Water to an Alkene

Benzene Chemistry
p.17

EAS Electrophiles

p.18

EAS

p.19

More Benzene Chemistry

Carbonyl Compounds I
p.20

Activating Carboxylic Acids

p.21

Ethers

p.22

Hydrolysis of Nitriles

p.23

Reactions of Acid Anhydrides

p.24

Reactions of Acyl halides

p.25

Reactions of Amides

p.26

Reactions of Carboxylic Acids

p.27

Reactions of Esters

Carbonyl Compounds II
p.28

Acetal or Ketal Formation

p.29

Alcohol Protecting Groups

p.30

Amino Protecting Groups

p.31

Carbonyl Compounds with Acetylide Ions

p.32

Carbonyl Compounds with Amines

p.33

Carbonyl Compounds with Hydride Ions

p.34

Carbonyl Compounds with Hydrogen Cyanide

p.35

Carbonyl Compounds with Water

p.36

Carbonyl Oxygen Protecting Groups

p.37

Wittig Reaction

Carbonyl Compounds III

p.38

Acid-Catalyzed Alpha-Carbon Halogenation

p.39

Aldol Condensation and Dehydration e1cB

p.40

Base-Catalyzed Alpha-Carbon Halogenation

p.41

Claisen Condensation

p.42

Dieckmann Condensation

p.43

Haloform Reaction

p.44

Hell-Volhard-Zelinski Reaction

p.45

Intramolecular Aldol Addition

p.46

Keto-Enol Interconversion

p.47

LDA to Form Enolates

p.48

Michael Reaction

p.49

Nucleophilic Addition to Unsaturated Ketones

Elimination Reactions
p.50

Alkyl Fluorides

p.51

Dehydration of Alcohols

p.52

E1

p.53

E2

Organometallic Chemistry
p.54

Carbonyl Compounds Grignard Reactions

p.55

Gilman Reaction

p.56

Grignardlithium

p.57

Palladium

p.58

Diels-Alder Ring Formation

Other

Oxidation
p.59

Hydroboration-Oxidation of an Alkene Part 1

p.60

Hydroboration-Oxidation of an Alkene Part 2

p.61

Hydroboration-Oxidation of an Alkyne

p.62

Oxidation of Alcohols

p.63

Oxidation of Aldehydes and Ketones

p.64

Oxidation of Alkenes to 1,2-Diols

p.65

Oxidative Cleavage of 1,2-Diols

p.66

Oxidative Cleavage of Alkenes

p.67

Addition of Radicals to an Alkene

p.68

Formation of Explosive Peroxides

p.69

Radical Halogenation of Alkanes

p.70

Radical Substitution of Benzylic and Allylic Hydrogens

Radicals

Reduction
p.71

Catalytic Hydrogenation

p.72

Dissolving Metal Reduction

p.73

Metal Hydride Reduction

p.74

Oxymercuration-Reduction of an Alkene

Substitution Reactions
p.75

Nucleophilic Substitution of Epoxides

p.76

Sn1

p.77

Sn2

p.78

Substitution of Alcohols

Acid catalyzed Addition of Alcohol to an Alkene

f unctional group transformation:
alkene
ether
general scheme:
OH
R

H2SO4

OH
2

Mechanism:
H2SO4

OH
H

H
O
H

OH
OH

Key Points:
O

alcohol quick to deprotonate the protonated

ether
- pH of solution is greater than pka of
protonated ether
regiospecific, Markovnikov
H

O
H

Addition of Halogen to an Alkyne

f unctional group transformation:
alkyne
halogenated alkane
general scheme:
R

X
X

R
R

X
X

mechanism:

Br

Br

Br

Br

Br

Br

Br

Br

Br

Br

Br

Br

Br

Br

Br

Br

Key Points:
solvent is typically CH2Cl2
anti addition

Addition of a Peroxyacid to an Alkene

f unctional group transformation:

alkene

epoxide + carboxylic acid

general scheme:

+1R

OOH

OH

mechanism:
epoxide

O
O
R

carboxylic acid

OO
OH
H

Key Points:
concerted reaction
syn addition

Addition of a Halogen to an Alkene

f unctional group transformation:

alkene
viscinal halogenated alkane

general scheme:
R

X
R

X2

"X" is any halogen

X

Mechanism:
Br

Br

Br

Br-

Br

Br

Key Points:
forms cyclic intermediate
stereospecific, anti-addition
racemic mix

Addition of Hydrogen Halide to an Alkyne

f unctional group transformation:
alkyne

geminal dihalide

general scheme:
R

R
R
X

mechanism:
Br
H

Br

Br
H

Br

Br
Br

Br

Br

Key Points:
anti addition
H+ adds to sp carbon bonded to the hydrogen
results in geminal (on same carbon) dihalide

The Addition of a Hydrogen to an Alkene

f unctional group transformation:
Alkene

Alkane

general scheme:
H2
R

Pd/C

mechanism:
H
H

R
H

R
R
H

Key Points:
don't know precise mechanism
concerted reaction
syn addition
reduction reaction

10

Addition of Hydrogen to an Alkyne

f unctional group transformation:
alkyne

alkane or alkene

general scheme:
R

H2

mechanism:
Lindler's catalyst

( cis)

H2
Pd/C
Na or

Li

( trans)

NH3 (liquid)

Na or

NH 2

Li

+ NH2

NH3 (liquid)
Na

+ Na
Na
H

NH 2
H
H
H

+ NH2

Na

Key Points:
Linder's catalyst causes syn addition
cis alkene
Na or Li in NH3 cause trans alkene
because is most stable radical
f ormation

11

Addition of Water to an Alkyne

f unctional group transformation:
alkyne

ketone

general scheme:
R

H2O

R
R

H2SO4

R
O

mechanism:
O

H2SO4
H

enol

H
O

OH

keto-enol
tautomerization
O
H

ketone

H
H

Key Points:
an enol is unstable and will tautomerize
most, if not all, of the product will be a ketone

12

Alkoxy-Mercuration Reduction of an Alkene

f unctional group transformation:
Alkene

Ether

general scheme:

OCH 3
R1

1.) Hg(O2CCF3)2 , CH3OH

R
R

2.) NaBH4

Mechanism:

O2 CCF3

1.) Hg(O2CCF3)2 , CH3OH

Hg
CH 3

2.) NaBH4
HO

Hg
F3 CCO2

O2 CCF3

CH 3
HO
H 3C

H 3C
O

O2 CCF3

Hg

NaBH4
H 3C

H
O2 CCF3
Hg

Key Points:
regiospecific, anti-Markovinikov
syn addition

+ Hg + CF3CO2-

13

Alkylation of Alkynes
Functional Group Transf ormation: terminal alkyne to internal alkyne

General Scheme:
R

NaNH2

CH

RX

C-

CR

Reaction Mechanism:

CH 3C

CH

NaNH2

CH 3 C

CCH3

CH 3 C

Br

Br

+ NH2

CH3

H3 CC

NH3

Notes:
-an alkylation reaction is the attachment of an alkyl group to a species by selection of an alkyl halide of
the appropriate structure
-actual alkylation is second step, f irst step is the removal of a hydrogen f rom the terminal sp2 carbon by
NaNH2
-negatively charged acetylide ion (nucleophile) is attracted to the partially positively charged carbon
(electrophile) of the alkyl halide, represented as RX in General Scheme

14

Addition of Hydrogen Halide to an Alkene

f unctional group transformation:
alkene
alkyl halide

general scheme:

HX

(Z)

R1

"X" is any halogen

R
1

Mechanism:

Cl

( E)

+ Cl

Cl

+ Cl

Key Points:
regiospecific, Markovnikov addition
racemic mixture
carbocation intermediate subject to 1,2 hydride/methyl shifts

15

Acid Catalyzed addition of Water to an Alkene

f unctional group transformation:

alkene

alcohol

general scheme:
R

H2SO4

H2O

R
OH

Mechanism:
H2SO4
O
O
H

OH
O
H
H

H
O

O
H

Key Points:
regiospecif ic, Markovnikov
carbocation intermediate subject to 1,2 hydride/methyl shifts

16

Electrophilic Aromatic Substitution

Functional Group Transf ormation:

Benzene

Substituted Benzene

General Reaction Mechanism:

E+

Notes:
Benzene does not undergo nucleophilic substitution due to its cloud of pi electrons repelling any
incoming nucleophiles
The intermediate carbocation is stabilized by resonance
The hydrogen attached to the same carbon as the incoming electrophile is eliminated to restore
aromaticity to the benzene ring
Where multiple electrophiles will be directed onto a benzene ring depends on the substituents already
on the ring
Activating substituents have electrons pairs to push into the benzene ring and stabilize the
intermediate carbocation, these substituents are ortho-para directors; alkyl chains and halogens do
not push electrons into the benzene ring, but they still ortho-para direct
Deactivating substituents draw electron density f rom the benzene ring and they direct electrophiles to
the electron dense meta positions
Benzene can only be reduced with Nickel at 225 degrees celsius and 25 atmospheres of pressure

17

Generation of EAS Electrophiles

Halogenation:
Br

FeBr3

Br

Br

Br

FeBr3

Also works with chlorine. The reagents are Br2 and FeBr3
Iodination:

I2

H2O2
H2SO4

2I

Nitration:

HO

NO2 + H

OSO3 H

HOH

NO2

NO2

Reagents are HNO3 and H2SO4

Sulfonation:

HO

SO3H

OSO3H

HOH

SO3H

SO3 H

Reagents are Sulfuric acid and heat, reversible

Friedel-Crafts Acylation:
O

AlCl3
Cl

Friedel-Crafts Reagents are the acyl chloride, or haloalkane and AlCl3

Friedel-Crafts Alkylation:

Cl

AlCl 3

Notes:
Friedel-Crafts chemistry can not be done on deactivated rings or aniline
Aniline can not be nitrated safely

18

More Benzene Chemistry

To remove the carbonyl group af ter acylation the Wolf f -Kishner or Clemmensen reductions can be
used.
H2NNH2

Wolff-Kishner Reagents:

-OH,

Clemmenson Reagents:

Heat

Zn(Hg), HCl
Heat

Conditions for the Clemmenson reduction will react with double bonds.

Arenediazonium Salts:

NH2

NaNO2

HCl, 0oC

X=Br, Cl, CN
N

CuX

Also works with KI for X=I, H3O+ for X=OH, HBF4 for X=F, and H3PO2 for X=H
Arenediazonium salts can also act as electrophiles with benzene to form azo linkages that consist of two
benzene rings conected by
N
N

Mechanism f or Nucleophilic Aromatic Substitution:

Cl

Cl

O2 N

NO 2

O 2N

NO2

O 2N

NO2

For substitution to take place the benzene ring must be highly deactivated

19

Activation of Carboxylic Acids

Functional Group Transf ormation: Carboxylic Acid to Acyl Halide or Acid Anhydride
General Scheme:
O

or
R

OH

Cl

Reactions:
O

SOCl2

OH

HCl

OH

H3PO3

Cl

P 2O 5
R

Cl

PCl3
R

SO2

OH

+
R

H 2O

Notes:
-Converting a carboxylic acid into an acyl halide or an acid anhydride is a priceless tool in the laboratory,
as carboxylic acids are the most used type of compound and changing them into something more reactive
increases the number of things that they can be used f or.

20

Nucleophilic Substitution Reactions of Ethers

Functional Group Transf ormation:

Ether

Alkyl Nucleophile

General Scheme:
O
R

HX
Heat

Reaction Mechanism:

Br

+O

Br-

Heat

Br

Heat

+
OH

Notes:

Ethers can only undergo nucleophilic substitution with HBr and HI

If a secondary or tertiary carbocation would be f ormed, the reaction will proceed through the SN1
mechanism
If an unstable carbocation would be f ormed the reaction will proceed through the SN2 mechanism
(methyl, vinyl, aryl, primary)
Only substitution occurs, because any elimination product would react with HBr or HI to f orm the
substitution product
Ethers can also be activated by tosyl chlorides, SOCl 2, and PCl 3 in the same way as alcohols to f orm
an alkyl chloride

21

Hydrolysis of Nitriles
Functional Group Transf ormation: Nitrile to Carboxylic Acid
General Scheme:
O
R

H2O

+
R

NH4Cl

OH

Reaction Mechanism:
NH
H
R

B
R

NH

H2O
R

OH

NH 2

NH 2

NH

H2O
R

H
R

OH

OH

B
R

OH

Notes:
-Nitriles are harder to hydrolyze than amides, but it can be done by the above mechanism when water, acid,
and heat are used.

22

Reactions of Acid Anhdrides

Functional Group Transf ormation: Acid Anhydride to Ester and Carboxylic Acid via Alcohol
Acid Anhydride to Amide and Carboxylate Ion via Amine
General Scheme:
O

+
R

R1

OR/OH/N

Reaction Mechanism:
O
O
O

+
R

OH

OR
H

B
O

+
R

HO

OR
OR

Notes:
-Acid anhydrides do not react with sodium chloride or bromide because the incoming halide is a weaker base
than the departing carboxylate ion.
-All of the mechanisms f ollow the general mechanistic scheme of the nucleophilic addition-elimination
reaction with a neutral nucleophile.

23

Reactions of Acyl Halides

Functional Group Transformation: Acyl Halide to Anhydride via Carboxylate Ion
Acyl Halide to Ester via Alcohol
Acyl Halide to Carboxylic Acid via Water
Acyl Halide to Amide via Amine
General Scheme:
O

+
R

Cl

Cl

Reaction Mechanism:
O
O

O
R

Cl

+
R

Cl

O
R

O
OH

Cl

+
R

OH

Cl

Cl
OR

Cl
R

OR

+ B

OR

+ Cl

Notes:
-The mechanisms shown are f or the conversions of acyl chlorides to anhydride and ester, respectively.
-The reaction of an acyl chloride with an amine to f orm an amide calls f or twice as much amine as acyl
chloride because the HCl f ormed as a byproduct will protonate any amine that has not reacted yet.
-In each mechanism, the incoming nucleophile is a stronger base than the departing chloride ion, so the
reaction is a nucleophilic substitution.

24

Reactions of Amides
Functional Group Transf ormation: Amide to Carboxylic Acid
Amide to Nitrile
General Scheme:
O

NH2

OH

R2CN
R

NH2

Reaction Mechanism:
OH

OH

H2O
R

NH2

NH 2

NH2

O
H

OH

NH4

OH

OH

OH
R

NH 3

NH 2

OH

NH3

OH

OH

Notes:
-Amides cannot be hydrolyzed without catalysts.
-The mechanism is similar to that of the acid catalyzed hydrolysis of an ester.

25

Reactions of Carboxylic Acids

Functional Group Transf ormation: Carboxylic Acid to Ester via Alcohol

General Scheme:
O

+
R

OH

OH

H 2O

OR'

Reaction Mechanism:
H
O

B
OH

CH3OH

+
R

OH

OH

OCH 2

OH

OH

H
O

OH

OH

R
R

OCH 3

OCH3

H2O

O
H

OCH 3
OH

Notes:
-The mechanism is the exact reverse of the acid catalyzed ester hydrolysis.
-Carboxylic acids have approximately the same reactivity as esters, theref ore they do not react with halide
ions or carboxylate ions either.

26

Reactions of Esters
Functional Group Transf ormation: Ester to Carboxylic Acid and Alcohol via Water
Ester to New Ester and New Alcohol via Alcohol
Ester to Amide via Amine
General Scheme:
O

+
R

H
R

OR

OH

Reaction Mechanism:
Acid Catalyzed Ester Hydrolosis:
H
O
H
R

OH

OCH3

H2O

OCH3

OCH 3
OH

B
H

OH

B
OH
R

OH

OH
OCH 4

OCH 3

OH

CH3OH

OH

OH

Notes:
-Curiously enough, this mechanism is the exact reverse of the mechanism f or the acid catalyzed reaction
of a carboxylic acid and an alcohol to f orm an ester.
-The reaction of an ester with an amine is not as slow as the reaction of an ester with water or alcohol
because amine is a better nucleophile.
-Transesterif ication is also acid catalyzed.

27

Acid-Catalyzed Acetal or Ketal Formation

Functional Group Transf ormation:
aldehyde

hemiacetal

acetal

ketone

hemiketal

ketal

Reaction Scheme:
O

HCl

CH3OH, HCl

+ CH3OH
R

H
O

OH

HCl

CH3OH

OH

CH3OH, HCl

Reaction Mechanism:
H
OH

CH3OH

H
R

OH

R
H

O
O

O
O
R
R

CH3OH

OHH
O

Notes:
acid catalyst is required
one equivalence of alcohol is added to the aldehyde or ketone, goes to hemiacetal
or hemiketal
two equivalence of alcohol takes aldehyde or ketone all the way to acetal or ketal

28

Alcohol Protecting Groups

Functional Group Transf ormation:
OH of an alcohol

triethylsilyl ether

OH of carboxylic acid

OH of an alcohol

ester

OH of carboxylic acid

Reaction Scheme:
OH

Cl

(CH3CH2)3N

OSi(CH 2 CH 3) 3

Si

Br

alcohol

H3O

OH

Br

Br

O
excess OH
HO
OH

HCl

HO
O

carboxylic acid
HCl, H2O
heat
O
HO
OH

29

Amino Protecting Group

Functional Group Transf ormation:
amino

amide

amino

Reaction Scheme:
O
NH 2

HN
Cl

1. HCl, H2O, heat

2. HO

30

Reactions of Carbonyl Compounds with Acetylide Ions

Functional Group Transf ormation: Aldehyde or Ketone to Alkoxide
General Scheme:
OH

1. acetylide ion
2. H3O+
R

R
R

Reaction Mechanism:
O

OH

H+

+
R

R
R

Notes:
-As a method of making carbon-carbon double bonds, this reaction is extremely important to chemists.
-The acetylide ion f orms a nucleophilic addition product.

31

Reactions of Carbonyl Compounds with Amines

Functional Group Transf ormation: Aldehyde or Ketone to Imine
General Scheme:
O

H+

+
R

NR"

H2NR"

H 2O

Reaction Mechanism:
O

+
R

R"NH2

OH

B
R

NH 2 R"

R
NHR"

H
H
NR"

B
R
R

H
O

NR"

OH

H
R

R'
NHR"

NHR"

Notes:
-Imine f ormation is reversible, with equilibrium f avoring the nitrogen protonated tetrahedral intermediate.
-Overall the addition of an amine to an aldehyde or ketone is nucleophilic addition-elimination.
-Other amine reactions are possible, which are not mentioned here, but which include f ormation of
derivatives such as oxime, semicarbazone, and Wolf f -Kishner reduction.

32

Reactions of Carbonyl Compounds with Hydride Ions

Functional Group Transf ormation: Aldehyde, Ketone, Acyl Chloride, or Carboxylic Acid to Alcohol
Ester to Aldehyde
Amide to Amine
General Scheme:
O

OH

1. NaBH4
2. H3O+
R

Reaction Mechanism:

+
R

OH

O
H

BH3

R
H

H3O+

R
H

Notes:
-The mechanism shown above is specif ically f or a ketone or aldehyde, but the other reactions f ollow the
same pathway.
-Sodium borohydride will reduce aldehydes, ketones, and acyl chlorides.
-Lithium aluminum hydride is required to reduce carboxylic acids, esters, and amides.

33

Reactions of Carbonyl Compounds with Hydrogen Cyanide

Functional Group Transf ormation: Aldehyde or Ketone to Cyanohydrin
General Scheme:
OH

CN
HCl
R

Reaction Mechanism:
OH

O
O

+
R

N
R

N
R

Notes:
-The hydrogen cyanide is generated in situ by adding copius amounts of HCl to a mixture of the aldehyde
or ketone in excess sodium cyanide.
-Only ketones and aldehydes react with hydrogen cyanide.
-The catalytic addition of hydrogen to the cyanohydrin will f orm a primary amine.

34

Carbonyl Compounds with Water

Functional Group Transf ormation: Aldehyde or Ketone to Hydrate
General Scheme:
OH

HCl

H 2O

OH

Reaction Mechanism:
OH
OH

O
H

OH

+
R

H
1

H 2O

O
H

H 2O
OH
R

+
OH

H 3O +

Notes:
-Water is a poor nucleophile, so addition is sped up by addition of an acid catalyst.
-The hydrate product is also known as a geminal-diol.

35

Ketone or Aldehyde Protecting Groups

Functional Group Transf ormation:
Ketone or Aldehyde

5 or 6-membered ring ketal or acetal

ketone or aldehyde

Reaction Scheme:
OH
HO

O
O

, HCl
R

HO
R

OH

R
O

, HCl

R
R

HS

SH

, BF3

R
O

H3O

HgSO4
S

H3O

H3O

Notes:
aldeydes and ketones can be protected by being converted into acetals
can be brought back by use of aq acid or mercury sulfate in aq acid
thioketal can be reduced to an alkyl group through Raney Nickel

36

Wittig Reaction
Functional Group Transf ormation:
aldehyde or ketone

alkene

Reaction Scheme:
O

R'
R'

(C6 H5 )3 P

(C6 H5 )3 P

Phosphonium
ylide

Reaction Mechanism:
P(C6 H 5) 3
O

P(C 6H 5) 3

P(C 6H 5) 3

H 2C
R

CH 2

CH 2

R
R

R
R

Notes:
concerted cycloaddition reaction
O

Horner-Wittig Reaction uses

but gives same product

P
R

37

Acid- Catalyzed Halogenation of Alpha Carbon

f uncitonal group transformation
aldehyde or ketone

halogenated aldehyde or ketone

Reaction Scheme:

H3O

O + HCl

Cl2
Cl

Reaction Mechanism:
H
O
H

OH

H
R

R
R

R
H

H
O

H
Br

H
Br

O
H

R
R

H
R

Br
Br

Notes:
can add to either alpha carbon
each successive halogenation is slower than the previous
-basicity of carbonyl oxygen is decreased, making protonation of O less favorable

38

Aldol Condensation and Dehydration, E1cB

Functional Group Transf ormation:
Aldehydes or Ketones

Beta-hydroxyaldehydes or Beta-hydroxyketones

Reaction Scheme:
condensation:

OH

H3O

OH, H2O
R

heat

R
H

dehydration:

OH

OH

OH, H2O

heat

Reaction Mechanism: E1cB mechanism

OH

OH

B
H

OH

H
R

R
H

B
O

Notes:
heating the aldol addition product leads to dehydration which produces an enone
base catalyzed deyhdration reaction represents E1cB reaction

39

Base-Catalyzed Halogenation of an Alpha

Carbon
f unctional group transformation:
aldehyde or ketone

halogenated aldehyde or ketone

Reaction Scheme:
O

Br
Br

OH
Br2

Br

Br

Br

Br

Reaction Mechanism:
O

Br

Br

+ H20

H
O

O
Repeat first 2 steps

Br

R
Br

+ Br

Br

Notes:
each successive halogenation is more rapid than the previous
-acidity of remaining H's is increased

40

Claisen Condensation
Functional Group Transf ormation:
Ester
Beta-keto ester
Reaction Scheme:
O

1. CH3CH2O

2. HCl

HO

O
O

Reaction Mechanism:
O

O
H

CH3O

R
O

R
O

O
R

R
O
R
O

Notes:
nucleophilic addition-elimination reaction
crossed claisen condensation reaction is between two different esters, will form a
mixture of products

41

Dieckmann Condensation
Functional Group Transf ormation:
1,6- Diester

5-membered ring beta-keto ester

1,7- Diester

6-membered ring beta-keto ester

Reaction Scheme:
O
O

1.CH3O

2.HCl

O
1,6-diester

beta-keto ester

O
O

1. CH3O
O

2. HCl
O

beta-keto ester

1.7-diester

Reaction Mechanism:
O

O
O

OCH3

O
O

Notes:
intramolecular Claisen condensation

42

Halof orm Reaction

Functional Group Transf ormation:
methyl ketone

carboxylate ion + halof orm

Reaction Scheme:
O
O

+ Br2
excess
R

Br

OH

Br

H
C

CH 3

Br

Reaction Mechanism:
O

R
O

HO
R

CH 3

I2 excess

CI3

HO

CI 3

H
O

O
O

I
O

H
C

I
C

I
R

OH

Notes:
only works with methyl ketone

43

Hell-Volhard-Zelinski Reaction
Functional Group Transf ormation:
Carboxylic Acid

Alpha-brominated carboxylic acid

Reaction Scheme:
O
O

1. PBr3 (or P), Br2

R
OH

OH

2. H2O
Br

Reaction Mechanism:
O

PBr3

OH

R
Br

R
Br

OH

Br
Br

H2O

Br

Br

OH
Br

OH

Br

Br

Notes:
Alpha substitution occurs because acyl bromide is undergoing the substitution,
not the carboxylic acid

44

Intramolecular Aldol Addition

Functional Group Transf ormation:
1,4- diketone or 1,6-diketone

f ive membered ring

1,5-diketone or 1,7-diketone

six membered ring

Reaction Scheme:
OH
O

1,4-diketone

OH, H2O

OH
O

1,5-diketone

Reaction Mechanism:
O

OH, H2O

OH

H2O, HO

O
O

Notes:
can potentially f orm a different numbered ring but most stable ring will form

45

Keto-Enol Interconversion
functional group transformation:
keto tautomer
enolate ion

enol tautomer

Mechansim: (acid -catalyzed interconversion)

O

OH

O
R

OH

R
R

H
O
H

Mechanism: (base-catalyzed interconversion)

O
O

H
O

R
R

R
R

OH
H

OH
R
R

+ OH

Key Points:

46

Using LDA to f orm an Enolate Ion

Functional Group Transformation:

carbonyl compound

enolate ion

Reaction Scheme:
O
O

LDA/THF

Notes:
LDA is a very strong base so all of carbonyl compound is converted to the enolate ion

47

The Micheal Reaction

Functional Group Transf ormation:
alpha, beta-unsaturated carboxylic acid derivative
or conjugate addition product

nucleophilic addition product

Reaction Scheme:

Nu

1. Nu
2. H3O
R

Nu

OH

direct addition

an alpha, beta-unsaturated
aldehyde or ketone

conjugate addition

Reaction Mechanism:
O
O

HO
H2O

R
O
H

Notes:
if either of reactants has an ester group, the base used to remove the alpha proton
must be same as leaving group of the ester
form 1,5-dicarbonyl compounds
use enolate ions of : beta-diketones, beta-diester, beta-keto esters, beta-keto nitriles

48

Nucleophilic Addition to Alpha, BetaUnsaturated Ketones and Aldehydes

Direct Addition:
Y

Y
R

H3O

Y
OH

alpha, beta-unsaturated carbonyl compound

Conjugate Addition:
R

H3O

Y
O

alpha, beta-unsaturated carbonyl compound

keto
tautomer

OH

enol
tautomer

Usually direct addition:

R-MgX
R-Li
C

Usually Conjugate addition:

(R)2CuLi
HO-R, H
H2N-R
H-X
CN

49

Reactivity of Alkyl Fluorides

Functional Group Transf ormation:

Anti-Zaitsev Elimination Product

Alkyl Fluoride
General Scheme:
F

Heat / Conc. Base

Polar Protic Solvent

Reaction Mechanism:

Conc. NaOEt
H

Heat/EtOH

Notes:

Anti-Zaitsev product is f ormed because the reaction mechanism goes through a carbanion like
transition state *
The mechanism f or this reaction is E2
Reaction conditions are E2 conditions

* The carbanion like transition state occurs because f luorine is a relatively strong base and a very poor leaving
group; the reason the product is anti-Zaitsev is because the carbanion transition state does not want to
hyperconjugate with the neighboring carbon-hydrogen bonds. It wants to avoid additional electron density due
to its partial negative charge.

50

Dehydration of Alcohols
Functional Group Transf ormation:
Alcohol

Alkene

General Scheme:
OH

H 2SO4
Heat
Reaction Mechanism:

OSO3H

Heat

Heat
OH2

OH

H2O

Heat

Notes:
Secondary and Teriary alcohols react through the E1 mechanism, and Primary alcohols react
through the E2 mechanism
To prevent ref ormation of the alcohol f rom the product and H2O, the alkene is distilled f rom the
reaction mixture because it boils at a lower temperature than the alcohol
The reagents POCl3/pyridine, 0 degrees celsius also convert an alcohol to an alkene through the
E2 reaction mechanism

51

Elimination Unimolecular Reactions, E1

Functional Group Transf ormation:

Alkyl Halide

Alkene

General Scheme:

Low conc. Base

Polar Protic Solv.
Heat

Reaction Mechanism:

Low conc.
NaOEt

Low conc.
NaOEt

EtOH
Heat
X

EtOH
Heat
H

Notes:
Two step mechanism, Rate=k[alkyl halide][Base]
Mechanism involves f ormation of a carbocation, rearrangement can occur
E2 can go through a syn-periplanar or anti-periplanar mechanism, the major product will have the
most stable stereochemistry (E or trans/Zaitsev product)
If a bulky enough base or substrate is used an anti-Zaitsev product will be the major product
Reactivity of Alkyl Halides: Benzyl, Allyl, Tertiary, Secondary, [Primary] (Only when a bulky
base/substrate is used)
Bases: NaOEt, NaOR, NaOH
Protic Polar Solvents: H2O, EtOH, ROH
Elimination is f avored by heat, EtOH, conjugation, and a good base

52

Elimination Bimolecular Reactions, E2

Functional Group Transf ormation:

Alkene

Alkyl Halide

General Scheme:

Strong Base, conc.

X
Polar Protic/Aprotic Solvent

Reaction Mechanism:

NaOt
Br

tOH, heat

Notes:
Concerted Mechanism, Rate=k[alkyl halide][Base]
H and X must be anti-periplanar to eliminate through E2
When reacting a cycloalkyl halide the H and X must be in axial positions
When two H's are present on the beta carbon two stereoisomers will be f ormed, but the more stable
trans or E isomer will be the major product (Zaitsev Product).
If only one H is present on the beta carbon the stereochemistry will be determined by the substrate's
configuration.
Strong Base: NaOH, NaNH2, NaOR
Ethanol as a solvent, heat, and conjugation f avor Elimination
If a bulky base or substrate is used Elimination is more likely to occur (anti-Zaitsev)
Reactivity of Alkyl Halides: Benzyl, Allyl, Tertiary, Secondary, [Primary] (f avors substitution
unless a bulky base or substrate is used)

53

Reactions of Carbonyl Compounds with Grignard Reagents

Functional Group Transf ormations: Aldehyde, Ketone, Ester, or Acyl Chloride to Alcohol
Carbon Dioxide to Carboxylic Acid
General Scheme:
O

OH

1. R'MgBr
(H) R

R (H)

2. H3O+
(H) R

R(H)
R(H)
1

Reaction Mechanism:
O

MgBr +

OH

+
R

MgBr

H3O

Notes:
-Although only the mechanism f or the reaction of a ketone with a Grignard reagent is shown, they all
react by the same pathway, f orming primary, secondary, or tertiary alcohols depending on the number of
hydrogens in place of the R groups and the number of potential leaving groups the compound has.

54

Gilman Coupling Reactions

Reaction Scheme:
Organolithium Reagent

Alkyl Chain

General Scheme:

THF
Li

CuI

) 2CuLi + LiI

Sample Reaction:

) 2CuLi

THF
Br

Notes:
Couples any two alkyl, aryl, or vinylic groups
Alkyl Fluorides will not undergo this reaction
The precise mechanism f or this reaction is not known
Gilman reagents, dialkyl lithium cuprates, react with primary secondary, vinylic, or aryl,
halides
This reaction works even if the halogenated compound contains other f unctional groups
(without acidic protons)
If a vinylic halide is reacted, it will maintain its E or Z conf iguration

55

Organolithium and Organomagnesium Reactions

Functional Group Transf ormation:

Haloalkane

Carbon Nucleophile

General Scheme:

Br

Li or MgBr

Li, Hexanes
or
Mg, THF

Reaction Mechanism:
Sample Reaction of Organolithiums and Grignard Reagents
O
MgBr +

THF

H+

OH

Notes:
Organolithiums and Grignard (Organomagnesium) reagents react in the same way, as a source of
carbon nucleophile
The solvent f or these reactions is important, an aqueous solvent, or any solvent with acidic
hydrogens, would destroy the reagent

56

Palladium Based Coupling Reactions: Heck, Suzuki

Functional Group Transf ormation:

Couples two alkyl pieces, at least one of them with a halogen attached to an aryl or vinyl position.

General Scheme:

OR
X + Ar

PdL2

OR

Ar

Suzuki

HO-

X
PdL2

Heck

TEA

Reaction Mechanism

PdL2

R
Ar

Pd

X
OR

Pd

R'

R'

Suzuki

B
OR

Pd
R

PdL 2

Pd

X
R

Heck

Z
Z

Notes:
The organopalladium compoud can not have beta hydrogens, or an elimination reaction will occur
instead of the coupling
The suzuki boron ester must have an aryl group
Triethyl amine is a necessary reagent f or the heck reaction; it reduces the Pd2 to Pd0

57

Diels-Alder Reactions
Functional Group Transf ormation:

Substituted Cylohexene, or Cyclohexadiene

Diene + Dienophile
General Scheme:

Heat

W-electron withdrawing group

Reaction Mechanism:
O

Heat

+
OH

OH

Notes:
The diene is the nucleophile and the dienophile is the electrophile
A six memebered ring is always f ormed
The reaction will not occur if the diene is locked in the s-trans configuration
[4+2] cycloaddition reaction: 4 pi electrons f rom the diene, and 2 f rom the dienophile
Concerted reaction mechanism
If a stereocenter is f ormed, the product will be a racemic mixture
Syn addition reaction, stereochemistry of substituents is conserved

58

Hydroboration-Oxidation of an Alkene
f unctional group transformation:
Alkene

Alcohol

general scheme:
1.) BH3 / THF
OH

2.) OH- , H2O , H2O2

partial positive

mechanism:

partial negative
H

BH

H
B

BH2

x3
R
R
R

OH- , H2O2 , H2O

R
B

HO

OH

OR

RO

OH

OR
RO

H
OH

OR
B

RO

R
B

OR

H
O

OR
OR

OH

59

Hydroboration-Oxidation of an Alkene Part 2

continuation of mechanism:

OH
R

OH

B(OH)4

OH
R

Key Points:
no carbocation rearrangement
concerted reaction
syn addition

60

Hydroboration-Oxidation of an Alkyne
f unctional group transformation:
alkyne
ketone or aldehyde
general scheme:
R
R

BH3/THF

aldehyde

OH-, H20, H2O2

R

BH3/THF
OH-, H20, H2O2

ketone
O

mechanism:

BH3

THF
R
H

HO- , H2O2

H2O

OH

3
O

Key Points:
mechanism basically same as hydroboration of alkene
electrophile (BH3) adds to C with most H's
product is ketone due to keto-enol tautomerization
if terminal alkyne then aldehyde is produced

61

Oxidation of Alcohols
Functional Group Transf ormation: Primary Alcohol to Aldehyde
Secondary Alcohol to Ketone
O

OH

General Scheme:

or
R

OH

Reaction Mechanism:
SWERN Oxidation:
R(H)

R(H)
R

OH
H

S+

Cl

R
S

Notes:
-Chromic acid (H2CrO4) is used to oxidize secondary alcohols to ketones, but it will oxidize primary
alcohols all the way to carboxylic acids.
-SWERN is CH3SCH3, ClCOCOCl, and TEA at 60 degrees Celcius

62

Oxidation of Aldehydes and Ketones

Functional Group Transf ormation: Aldehyde to Carboxylic Acid
Ketone to Ester
O

General Scheme:
R

R(H)

O/R(H)

Reaction Mechanism:
Baeyer-Villager Oxidation:
O

+
R

F
O

O
O

F
O

R
F

OR

Notes:
-Tollens reagent: oxidizes an aldehyde, too mild f or anything else, it is (1) Ag2O, NH3 (2) H3O+
-Any reagent used to oxidize primary alcohols to carboxylic acids can be used to oxidize aldehydes to
carboxylic acids.
-Ketones do not react with most of the reagents used to oxidize aldehydes, but both can be oxidized by
conjugate base of a peroxyacid, i.e. a Baeyer-Villager reaction.

63

Oxidation of Alkenes to 1,2-Diols

Functional Group Transf ormation: Alkene to 1,2-Diol (vicinal diol)
General Scheme:
OH

OH

Reaction Mechanism:
H
O

OH
H

H 2O 2

Os
O

O
O
O

Os
O

OH

OsO4

Notes:
-Syn addition
-Forms cyclic intermediate
-Hydrogen peroxide reoxidizes osmium reagent

64

Oxidative Clevage of 1,2-Diols

Functional Group Transf ormation: 1,2-Diol to Ketone or Aldehyde
General Scheme:
OH

+
H

OH

Reaction Mechanism:

HIO4
OH
OH

I
O

O H

H2O

HIO3

Notes:
-Periodic acid is used to f orm a cyclic intermediate f rom the diol, and when the intermediate breaks down,
the bond between the two carbons bonded to the oxygens breaks as well.
-It is called an oxidative clevage because it cuts a reactant into two pieces.

65

Oxidative Clevage of Alkenes

Functional Group Transf ormation: Alkene to Aldehyde or Ketone
General Scheme:
O

Reaction Mechanism:
O
H
O

O
O

Zn, H2O
or (CH3) 2S
O

H 2O 2

OH

Notes:
-When an alkene is treated with ozone at low temperatures, the double bond breaks and the carbons are
doubly bonded to oxygens instead of to each other, known as ozonolysis.
-The immediate reaction results in a molozonide, which is unstable and theref ore quickly rearranges into
an ozonide.
-Ozonide treated with reducing conditions yields ketones and aldehydes.
-Ozonide treated with oxidizing conditions yields ketones and carboxylic acids.

66

Addition of Radicals to an Alkene

Functional Group Transformation: alkene to alkyl halide
General Scheme:
R

C
H

C
H

peroxide

H Br

CH2 CH 2 R

Br

Reaction Mechanism:
light
H 3 CO

H 3C

Br

OCH 3

H 2C

BrCH 2CHCH 3

Br

2 CH 3O

or

Br

H3 C

BrCH2CH 2CH3

Br

Br

Br

BrCH 2CHCH 3

Br

Br

Br
Br

BrCH 2CHCH 3

Br

BrCH 2CHCH3

CHCH 3

OH

CH 2 CHCH 3
Br
CH3CH

CHCH 3

BrCH 2CHCH 3
Br

CH 2 H 2 C

Br

Notes:
-mechanism is divided into three groups of reactions: initiation, propagation, and termination
-this is known as a radical addition reaction
-in the presence of peroxide, Br becomes the electrophile which adds to the less substituted carbon, causing anti-Markovnikov
addition of the Br

67

Formation of Explosive Peroxides

Functional Group Transf ormation: ether to peroxide
General Scheme:
R

CH R

O2

CH R
O

Reaction Mechanism:

H 3C

CH

CH 3

H 3C

CH CH 3

HY

O2

H 3C

CH

CH 3

H 3C

H 3C

CH CH 3
O

CH

H 3C

CH 3

H 3C

CH CH 3

CH CH 3

OH

Notes:
-must have chain initiating radical (i.e., Y) to remove H f rom ether
-a peroxide is simply a compound with an O-O bond, which is easily cleaved homolytically to f orm
radicals that can propogate f urther radical production
-a peroxide is a radical initiator
-ethers contain stabilizers to trap chain-imitating radicals to prevent explosive situations

68

Radical Halogenation of Alkanes

Functional Group Transf ormation: alkane to alkyl halide

General Scheme:
heat
RCHn

X2

RCHn-1X

HX

or hv
Reaction Mechanism:
heat
Cl

2 Cl

Cl

or hv
HCl

CH3

CH3Cl

Cl

Cl

CH3

Cl

Cl

Cl

Cl2

Cl

CH3

CH3Cl

CH3

CH3

CH3CH3

H CH 3

Cl

Notes:
-heat or UV light supplies energy to break dihalide bond homolytically; that is, so that each atom
retains one of the two bonding electrons, f orming radicals
-the specif ic reaction above is called the monochlorination of methane, where the chlorine radical
removes a hydrogen atom from methane, the alkane, making HCl and a methyl radical
-in any radical reaction such as this, there are three types of steps: initiation (f irst above), propogation
(second and third above), and termination (f ourth through sixth above)
-any step that continues the radical cycle started in the initiation step(s) is a propogation step, while any
step that combines two radicals to f orm a product with all paired electrons is termination

69

Radical Substitution of Benzylic and Allylic Hydrogens

Functional Group Transf ormation: alkene to halogenated alkene
General Scheme:
X

CH 2R

CHR

X2

X2

Reaction Mechanism:
Br
CH 3

CH 3

hv or

H 2O 2

CH 3

Br

CH 2

Br

CH2

HBr

Br

CH 2Br

Br 2

CH2

CH 2Br

Br

Notes:
-Bromine radical f rom NBS removes allylic H, but bromine radical f rom HBr + H2O2 adds to double
bond

70

Catalytic Hydrogenation
Functional Group Transf ormation:
Alkene or Alkyne to Alkane
Aldehyde to Primary Alcohol
Ester to Secondary Alcohol
Acyl Halide to Aldehyde
General Scheme:
or
Reaction Mechanism:

Pd/C
or PtO2

Lindlar
Catalyst

O-

H
C+
R

Raney Ni

OH
H

Raney Ni
R

OH
C+

OH

OC+

Cl

Cl

Partially
Deactivated
Pd

71

Dissolving Metal Reductions

Functional Group Transf ormation: Alkyne to Trans Alkene
General Scheme:

Reaction Mechanism:
C-

Na

Na
H

H2 N

NH 2

C-

Na
H

Notes:
-Na or Li in liquid NH3 cannot reduce double bonds
-Na and Li have a strong tendency to lose single electron in outer shell s-orbital
-Radical anion is strong enough base to deprotonate NH3, as is vinylic anion

72

Metal Hydride Reduction

Functional Group Transf ormation: Carbonyl group to Alcohol
Acyl chloride to Aldehyde or Alcohol
Amide to Amine (*doesn't use H3O+)
General Scheme:
O

OH

Reaction Mechanism:
OO

NaBH4

H3
R

H
R

OH

O+

H+

R
H

Notes:
-metal hydrides: sodium borohydride (NaBH4) or lithium aluminum hydride (LiAlH4) in H3O+
-metal-hydrogen bonds in LiAlH4 are more polar than NaBH4, making LiAlH4 a stronger reducing agent
-both NaBH4 and LiAlH4 reduce aldehydes, ketones, and acyl halides, but NaBH4 is a saf er choice
-LiAlH4 used to reduce carboxylic acids, esters, and amides
-replacing some hydrogens of LiAlH4 with alkoxy groups decreases reactivity of metal hydrides; lithium
tri-tert-butoxyaluminum hydroxide reduces acyl chlorides to aldehydes
-metal hydride reduction will not reduce alkynes or alkenes

73

Oxymercuration- Reduction of an Alkene

functional group transformation:
alkene
alcohol
general scheme:
R

1.) Hg(O2CCH3)2 , H2O, THF

R

2.) NaBH4

OH

Mechanism:

O2CH 3

1.) Hg(O2CCH3)2 , H2O, THF

Hg

2.) NaBH4
O
H

Hg
H3 CO2

O2CH 3

OH

O 2CH3

H
O

O 2CH3

Hg
H

Hg

NaBH4
OH

+ Hg + CH3CO2-

Key Points:
regiospecific, anti-Markovnikov
syn addition

74

Nucleophilic Substitution of Epoxides

Functional Group Transf ormation:
Epoxide

Vicinal Alcohol/Nucleophile

General Scheme:
Nu
O
R

Acidic Conditions
Or Neutral/Basic Conditions

OH
OH

Nu

or

Acidic
Neutral/Basic
Racemic Mixture of Conditional Product
Reaction Mechanism:

H+

+
OH

OCH 3

CH3OH

CH3OH

OH

Notes:
If the conditions are acidic, the nucleophile will attack the more substituted carbon; if conditions are
neutral or basic the nucleophile will attack the less substituted carbon because of reduced steric
hindrance
This reaction is an anti-addition because the epoxide blocks one face of the reactive site
Stereochemistry is a racemic mixture if a stereocenter is f ormed
Epoxides can be f ormed f rom the addition of a peroxy acid (RCO3H) to a double bond, or through the
addition of Cl2 and H2O to a double bond f ollowed by HO-

75

Substitution Nucleophilic Unimolecular Reactions, SN1

Functional Group Transf ormation:

Alkyl Halide

Alkyl Nucleophile

General Scheme:

Nu

Weak Nucleophile

Enantiomer

Polar Protic Solvent

Reaction Mechanism:

Cl

EtOH

EtOH
OEt

Notes:
Two step mechanism, Rate=k[alkyl halide]
Carbocation f ormation, carbocation rearrangement is possible
Racemic mixture, due to Sp2 carbocation intermediate
Alkyl Halide Reactivity: Tertiary, Secondary, Primary and Methyl do not react
Weak Nucleophile: EtOH, MeOH, H2O
Protic Polar Solvent: H2O, Acetic Acid, EtOH

76

Substition Nucleophilic Bimolecular Reactions-SN2

Functional Group Transf ormation:

Alkyl Halide

Alkyl Nucleophile

General Scheme:
Good Nucleophile

R
X

Polar Aprotic Solvent

NH 2

Reaction Mechanism:

NaOEt
+

DMSO
Br

Br -

OEt

Notes:
100% Inversion of Stereochemistry through Back Side Attack
Reactivity of Alky Halides: Methyl, Primary, Secondary, Tertiary will not react
Concerted Mechanism, Rate=k[alkyl halide][nucleophile]
Polar Aprotic Solvents: DMSO, DMF, Acetone
Strong Nucleophiles: NaOEt, NaOMe

77

Nucleophilic Substitution of Alcohols

Functional Group Transf ormation:
Alcohol

Alkyl Nucleophile

General Scheme:
HX
R

OH

Heat
Reaction Mechanism:

OH

Br

Heat

OH2

Br -

HBr

Br

Heat

Notes:
This reaction can proceed through either an SN2 or SN1 mechanism, depending on the degree of
the alcohol
Primary goes through SN2, Secondary and Tertiary go through SN1
The same reaction can also proceed using PX3/Pyridine as reagents
Alcohols can also be made into good leaving groups by reacting them with pyridine/tosCl, and
then a good nucleophile (ex. NaCN, SMe)

78