Materi Pertemuan 1

Part 1 Introduction
Part 2 Functionalization

1
Part 1 Introduction

2
 Why study Organic Synthesis?

 Heart of Chemistry  Broad applications

• Petrochemicals
“Chemists make new things and we • Pharmaceuticals
study reactions. That’s the core of • Agrochemicals
this profession” - D.G. Nocera (MIT)
• (Bio) polymers
in C&EN (Jan. 1998)
• Dyes & Pigments
• Cosmetics
• Food (Additives)
• Household products
• Electrochemicals
• Display materials
• Semiconductors
• Organic electronics
• and many more
3
 Petrochemicals

H+
+
cat.

cumene

O2
OH
O OOH
H3O+
+

phenol acetone cumene hydroperoxide

4
Pharmaceuticals & Medicinal Chemistry

OH OH OH

1. HNO3 Ac2O

2. Pd, H2

NH2 NHAc
Tylenol

RCONH
S R = PhCH2; Pen G
N R = PhCH(NH2); ampicillin
O R = (4-OH)-PhCH(CH2);
CO2H amoxycillin

5
 Agrochemicals

OH O O Me
1. Lindlar, H2 1. mCPBA
HO 2. acetone, H+ 2. Me2CuLi OH
O O
Aldrich, $20.0/500g
1. HCl
2. TsCl, py
3. NaI
H H H H
Me
H+ 3-pentanone I
O
O H
O O LDA
O
O
multistriatin: a pheromone O
of the elm bark beetle

• mCPBA = m-ChloroPeroxyBenzoic Acid

• LDA = Lithium Di-isopropyl Amide (Reagent Friday)
6
 Polymers & Biopolymers

CO2Me CO2CH2CH2
- MeOH
+ HOCH2CH2OH
MeO2C O2C
n
polyester (Dacron)

HO HO HO
O O
O O O
HO O O chitin (chitosan)
NH HO NH HO NH
Ac(H) Ac(H) Ac(H)

7
 Biology & Biochemistry

11
H2N opsin
-H2O

CHO opsin
11-cis-retinal h nerve +
N
retinal H2O pulse
H
isomerase

retinol CHO
vitamin A dehydrogenase
(retinol)
all-trans-retinal

8
 Electrochemicals

O
O
O O

ethylene carbonate THF

(better electrolyte) (poor electrolyte)

9
 Display Materials

* * n *
n * * N n *
H
polyacetylene PPP polypyrrole

*
* S n *
n *

PPV polythiophene
 Poly[1,4-phenylenevinylene]

10
 Components of Organic Synthesis

 Synthetic work
experimental
procedures

TARGET

 Retrosynthetic analysis  Synthetic design

‘disconnection 1. C-C bond formation
approach’ 2. functional group
interconversion (FGI)
11
 Disconnection Approach: An Example

alkylation -
HO + HO synthons
O HO O HO

LiN(iPr)2

acetal H+ (-H2O) X
HO synthetic
O equivalents
HO
O
O
OsO4 oxidation
multistriatin: a pheromone
of the elm bark beetle
X
?

14
 A Stereorandom Synthesis of Multistriatin

TsCl, py LiN(iPr)2
HO TsO
2
Aldrich, $31.50/g
O

O SnCl4 mCPBA

O O O O
1 4 3

15
 A Stereoselective Synthesis of Multistriatin

OH O O Me
1. Lindlar, H2 1. mCPBA
HO 2. acetone, H+ 2. Me2CuLi OH
O O
Aldrich, $20.0/500g 5 6
AcO

AcO 1. HCl
2. TsCl, py
$42.9/25mL 3. NaI
H H H H
Me
O H+ 3-pentanone I
O H
O O LDA
O
1 8 O
O
(85:15) 7

16
 Design and Synthesis
 Retrosynthetic Analysis
1. recognise the functional groups in the target molecule
2. disconnect by known methods and reliable reactions
3. repeat 1 and 2 until the readily available starting materials are
obtained
4. design as many alternative retrosynthetic routes as possible
 Synthesis
1. write down the synthetic schemes containing the detailed
reaction conditions according to the analyses
2. compare the pros and cons between the syntheses designed;
the number of steps, availability of reagents/starting materials,
selectivity (chemo-/regio-/stereo-), economy, process, etc
3. modify the selected synthetic plan whenever unexpected
problems are encountered

18
-Functionalization
 Part 2 Functionalization

Functionalization means the introduction of functional

groups in particular compounds

20
 Functionalization of Alkanes

 functionalization of alkanes: unreactive

 radical reaction

21
 Halogenation of Alkanes => Radical reaction
• In the presence of heat or light, alkanes react with halogens to form
alkyl halides.
• Halogenation of alkanes is a radical substitution reaction.
• Halogenation of alkanes is only useful with Cl2 or Br2. Reaction with F2
is too violent, and reaction with I2 is too slow to be useful.
• With an alkane that has more than one type of hydrogen atom, a
mixture of alkyl halides may result.

22
 Functionalization of Alkenes

 functionalization of alkenes: addition & substitution

 addition to double bonds
 allylic substitution: radical (oxidation)

23
Addition reaction

24
5

Addition reaction => Markovnikov’s Rule

• With an unsymmetrical alkene, HX can add to the double bond to
give two constitutional isomers, but only one is actually formed:

• Markovnikov’s rule states that in the addition of HX to an

unsymmetrical alkene, the H atom adds to the less substituted
carbon atom—that is, the carbon that has the greater number of H
atoms to begin with.
26
OCFC-Intro-Chap2 27
 Functionalization of Alkynes

 addition / substitution reactions:

 reduction to alkenes
 C-C bond formation
 electrophilic addition: largely anti addition
a mixture of products: syn addition & participation of the
reaction solvent
 ketones with oxymercuration

28
9

Addition Reactions of Alkynes (Reduction to Alkene)

• Alkynes undergo addition reactions because they contain relatively

weak  bonds.
• Two sequential reactions can take place: addition of one equivalent
of reagent forms an alkene, which can then add a second
equivalent of reagent to yield a product having four new bonds.
OCFC-Intro-Chap2 30
1

Formation of Acetylide Ions => C-C bond formation

• Sp hybridized C − H bonds are considerably more acidic than sp2

and sp3 hybridized C − H bonds.
• Therefore, terminal alkynes are readily deprotonated with strong
base in a Brønsted-Lowry acid-base reaction.
• The resulting ion is called the acetylide ion.
OCFC-Intro-Chap2 32
3

Hydration of Internal vs. Terminal Alkynes

• Internal alkynes undergo hydration with concentrated acid to form

ketones.
• Terminal alkynes require the presence of an additional Hg2+
catalyst (usually HgSO4) to yield methyl ketones by Markovnikov
addition of water.
 Functionalization of Aromatic Hydrocarbons

 electrophilic substitution: the ring

 substituted benzenes: depending on the substituents
 the rate & the orientation
 lower selectivity with a radical substitution

 nucleophilic substitution: p-chloronitrobenzene

 benzyne intermediate

 benzylic oxidation: the side chain

 Oxidation
 chlorination/bromination: radical mechanism
OCFC-Intro-Chap2 34
5

Functionalization of Substituted Benzene

Aromatic Electrophilic Substitution

or
Electrophilic
substitution
Electron donating Electron
group Withdrawing
group
Directing the electrophiles (o,p- directors) (meta- directors)
and influrencing the
reaction rate
Faster

Slower

36
7

Limitations in Electrophilic Aromatic Substitutions

• Benzene rings activated by strong electron-donating groups—OH,
NH2, and their derivatives (OR, NHR, and NR2)—undergo
polyhalogenation when treated with X2 and FeX3.
8

Another strategy: convert amino group into acetanilide

to avoid polyhalogenation

Aniline Acetanilide Monobromination

9

Rules for disubstituted benzene

1. When the directing effects of two groups reinforce, the new

substituent is located on the position directed by both
groups.
0

2. If the directing effects of two groups oppose each other, the

more powerful activator “wins out.”
1

3. No substitution occurs between two meta substituents

because of crowding.
 Aromatic Nucleophilic Substitution

 The introduction of electron withdrawing group (EWG)

on the aromatic nucleus makes the system susceptible
to nucleophilic attack.

OCFC-Intro-Chap2 42
 Benzyne Mechanism

Aryl halides that have no activating groups proceed reactions with

strong base to give benzyne intermediate which undergoes
reaction with nucleophile to give a mixture of regioisomers

OCFC-Intro-Chap2 43
2

Side-Chain Oxidation
Arenes containing at least one benzylic C—H bond are oxidized with
KMnO4 to benzoic acid.

Substrates with more than one alkyl group are oxidized to dicarboxylic
acids. Compounds without a benzylic hydrogen are inert to oxidation.

Chapt
er 17
3

Side-Chain Halogenation => Radical reaction

 Benzylic position is the most reactive.
 Chlorination is not as selective as bromination, results
in mixtures.
 Br2 reacts only at the benzylic position.

Br
CH2CH2CH3 CHCH2CH3
Br2, h
 Functionalization of Aromatic Heterocycles

 pyridine: weak base & e--poor ring

 electrophilic substitution: difficult but higher e--density at C-3
 nucleophilic substitution at C-2: ‘Chichibabin’

 pyrrole, furan, thiophene: e--rich

 substitution at C-2 / C-5: resonance-stabilized

OCFC-Intro-Chap2 46
Functionalization of Heterocyclic Compounds

Electrophilic substitution of pyridine

47
8

 Notes:
1. Pyridine is aromatic.
2. Pyridine does not undergo Friedel Crafts alkylation or asylation
or coupling with diazonium
3. The highest electron density is at position 3 (MO calculation).
The value is lower than benzene
4. Electrophilic substitution on pyridine needs a strong condition
Nucleophilic substitution of pyridine

The reaction takes place at position 2

49
 The Chichibabin Reaction

A substitution in which an amide anion (-NH2) attacks carbon 2 or

carbon 4 of a pyridine ring, and a hydride ion (H-), is the leaving group.
Occurs via the nucleophilic aromatic substitution reaction mechanism.

50
Electrophilic substitution: furan, pyrrole,thiophene

The molecules are electron rich

Electrophile will attack carbon at the position number 2
and 3
2

Functionalization of Pyrrole
3

Functionalization of Furan
4

Functionalization of Thiophene
 Exercises

1. Starting from 1-hexene and any reagent needed, please

synthesise:

2. Starting from 1-butyne and any reagent needed, please

synthesise:

OCFC-Intro-Chap2 55
 Exercises

3. Starting from ethylcyclopentane and any other

reagent, please synthesise:

4. Starting from toluene and any other reagent, please

synthesise:

OCFC-Intro-Chap2 56
 Exercises

5. Propose a synthetic scheme for the following compound,

starting from benzene.

6. Predict the major product for the reaction of pyrrole with Br2,
FeBr3. Hint: use resonance analysis of the intermediate to
determine the preferred regioselectivity of the reaction.

OCFC-Intro-Chap2 57