CHAPTER 1: ISOMERS

I. ISOMERS:
There are two types of isomers: constitutional isomer and stereoisomer.
The focus of the course is stereoisomer.
In stereoisomer, there are two types:
• Geometric isomer (cis trans)
• Isomer with chirality center (R, S)
II. Chirality:
Carbon has chirality only if it is connected to 4 different groups.

There is one chiral center since the C is connected to four different groups.
III. Cahn-Ingold-Prelog rule:
The priority depends on the molecular weight of the atoms that are connecting directly
to the carbon center. The higher the molecular weight, the higher priority the atom is.
Example: Br (80) > Cl (35.5) > T(3H) > D(2H) > H
In case the 1st direct atoms are the same, determine the order of atoms of the 2nd direct
atoms.
Example:

If there is double bond or triple bond, assume that it is connected to the atom twice or
three times.
Example:

1
This rule is applied for determining R,S as well as the Z,E structure:
For alkene:

Cis/trans is used when the comparing the relative position of two same groups.
Z/E may not always have similar result with cis/trans.

E but cis
IV. Representation of organic structure with chiral center:
1) Perspective formula:
CHIRAL CENTER must have perspective structure

Normal line: Within the plane

Dark line: In front of the plane, closer to you
Dash line: Behind the plane, farther from you
Determine R, S configuration:
There are two ways to examine configuration:
Step 1: Determine the order of functional groups.

2
TRADITIONAL METHOD:
Extend the line of the least prioritized group and look from the opposite direction. The
decreasing order of the remaining three functional groups will either be clockwise (R)
or counterclockwise (S).

CONVECTIONAL METHOD: This method does not require you to look directly
from the opposite side.
Step 2: If the least prioritized group is behind the plane (dash line), check if the
decreasing priority order of functional groups is clockwise (R) or counterclockwise
(S).
Step 3: If the least prioritized group is not behind the plane, switch that group
with the group that is currently behind the plane. Repeat step 2 to determine the
configuration of the new structure. The original configuration is the reverse of the new
configuration.

NOTE:
• The maximum number of normal lines is 2.
• The maximum number of dark line and dash line is 1 for each.
• When switching the groups, the number of times you switch determine the
relationship between new and old configurations:
➢ Number of times is even (2n): New = Original
➢ Number of times is odd (2n+1): New is the reverse of Original.
2) Newman projection:
When there are two chiral center, we can also display them in Newman projection:
Convert perspective formula to Newman projection: Look directly at the line with 2
chiral center from left to right.

3
For consistent result:
• All lines on the right side of the circle: In front of the plane, closer to you.
• All lines on the left side of the circle: Behind the plant, farther from you.
Examine configuration: It is best to convert them to either fisher or perspective and
determine the configuration.
NOTE: Check all the groups and lines are in the correct position with the correct
carbon center.
3) Fischer projection:
When display fisher projection, the cross section of all 4 groups must be a chiral
center.

Convert Newman projection to Fisher projection:

Step 1: Draw Fisher projection with the 1st cross section is the carbon center in
front of the circle and the 2nd cross section is the carbon center behind the circle.
Step 2: For the 1st carbon center, place the 3 functional groups in the same side
as the Newman projection.

4
 Step 3: For the second carbon, reverse the side of two functional groups on the
side of carbon center.
NOTE: Two functional groups on the same side of one projection (Newman or
Fisher) will be on the opposite side of the other projection (Fisher or Newman).
Convert perspective formula to Fisher:
Step 1: Determine R, S configuration of the perspective formula.
Step 2: Place the functional groups on Fisher corresponding to each carbon
center. Check chirality and switch place again until the configuration of Fisher is the
same as perspective formula.
To determine R, S configuration:
Step 1: Determine the priority order.
Step 2: Determine the decreasing order based on two cases:
a) If group 4 is on the vertical line: Clockwise is R, counterclockwise is S.
b) If group 4 is on the horizontal line: Clockwise is S, counterclockwise is R.
V. Types of stereoisomers:

NOTE: Meso isomers are compounds with chiral centers, but they are symmetrical.

CHAPTER 2: EFFECTS
I. INDUCTIVE EFFECT (I):
5
Inductive effect is an effect that occurs when the σ bond is polarized. The nature of
this effect is the difference in electronegativity between atoms.
There are two types of inductive effect:
a) Negative inductive effect (-I):

• X has higher electronegativity than C.

• Electrons of the bond will be attracted to X.
b) Positive inductive effect (+I):

• Z has lower electronegativity than C.

• Electrons of the bond will be attracted to C.
Negative The order of -I: NH3+ > NO2 > CN > SO3H > CHO > COR > COOH >
inductive effect COCl > CONH2 > F > Cl > Br >I > OH > OR > C≡CH > NH2 > C6H5 >
(-I) HC=CH2 > H

Positive The order of +I: CH- > NH- > COO- > C(CH3)3 > CH(CH3)2 > CH2CH3
inductive effect > CH3 > T > D > H
(+I)

Factor affecting the amplitude of the effect:

• Distance. As the distance increases, the effect reduces.

II. CONJUGATION EFFECT (C):

6
Conjugation effect (C) can only occur within a conjugation system.
As O is more electronegative than C, the electrons move through p-bond network
towards C=O.
Similar to inductive effect, there are two types of conjugation effect: +C and -C
Negative The order of -C: NO2 > CN > SO3H > CHO > C=O > COOCOR >
conjugation COOR > COOH > COCl > CONH2 > COO-
effect (-C)

Positive The order of +C: O- > NH2 > NHR > OH>OR > NHCOR > OCOR >
conjugation Ph (C6H5) > F > Cl > Br > I
effect (+C)

If both conjugation effect and inductive effect are present, conjugation effect is
stronger than inductive effect except for HALOGEN (-I > +C).
Factor affecting the amplitude of the effect:
• Relative position: No conjugation system => No conjugation effect.
Example:

7
Conjugation effect also explains why allylic and benzylic carbocation are very stable:

NOTE: FOR BENZENE, Ortho and Para position can have C but meta will not have
C effect.
III. HYPERCONJUGATION EFFECT (H):
Hyperconjugation effect involves the partial overlap of electron pairs in C-H bond of
CH3 and the empty p orbital of carbocation:

Since CH3 can rotate freely, all three C-H bonds have this effect.
The more CH3 groups directly connecting to carbocation present, the more
hyperconjugation effect there is.
The more C-H bonds , the stronger inductive effect is

The hyperconjugation effect is responsible for stability of carbocation and free radical.
IV. STERIC EFFECT:
Steric effect is responsible for relative reaction rates caused by the molecules
attaching at/near the reacting site:

8
V. ORTHO EFFECT:
Ortho-substituents on benzene rings have complicated effect.
IT IS BEST TO REMEMBER BY HEART
Case 1:

WHY ?

Case 2:

9
WHY ?

VI. HYBRIDIZATION
The relative electronegativity of hybridized orbitals is sp > sp2 > sp3.
VII. ACID BASE COMPARISION:
1) Acid comparison:
The following steps should be followed for arranging acid in decreasing order:
Step 1: Determine all groups in the following acid strength order: Sulfonic acid
(RSO3H) > Organic acid (RCOOH) > Phenol > Water > Alcohol.
Step 2: For each compound in each group, determine the main effect. Then arrange
them in this order: -C > -I > None > +I > +C
Example: Arrange these compounds in the decreasing strength of acid:
a)

10
b)

c)

2) Base comparison:
You can do acid comparison and flip the order.
NOTE: For amine, aromatic amine is more acidic than alkyl amine.

11
VIII. CARBOCATION STABILITY:
The following order is applied when comparing which carbocation is more stable:

CHAPTER 3: MECHANISM
I. NUCLEOPHILIC SUBSTITUTION (SN):

SN2 SN1
Procedure Just insert the nucleophile on Step 1: Remove original
the opposite side of the nucleophile. The carbon
original nucleophile. attached to that nucleophile
will become carbocation.
Step 2: Carbocation
rearrangement.
Step 3: Insert the nucleophile
on either si
+de of the carbocation.

Products 1 product (inverse 2 products (both

configuration) configuration)

12
 How to determine which SN Step 1: Determine carbon structure.
• Primary carbon: SN2
• Tertiary carbon: SN1
• Secondary carbon: follow step 2.
Step 2: Determine nature of solvent:
• Polar aprotic solvent (DMSO, DMF, acetonitrile):
SN2
• Polar protic solvent (alcohol, water): SN1

II. ELIMINATION (E): MUST HAVE TEMPERATURE

E2 E1
Procedure Case 1: C2 no stereochemistry Step 1: Remove
• Simple base (KOH, NaOH, original nucleophile.
RONa): Zaitsev rule, more The carbon attached
substituted alkene is to that nucleophile
obtained. will become
• Bulky base (R3CONa): carbocation.
Hofmann rule, opposite of Step 2: Carbocation
Zaitsev. rearrangement.
• Usually, trans is favored. Step 3: Form alkene
Case 2: Stereochemistry with the most stable
• Periplanar geometry. carbon next to it that
• Anti-positions. has H.
Products 1 product (Zaitsev or Hofmann) 1 product (usually
trans)
How to determine which Step 1: Determine carbon structure.
E • Primary carbon: E2
• Secondary and tertiary carbon: Follow step 2

13
 Step 2: Determine nature of solvent and base.
• Strong base (OH-,OR-): and polar aprotic
solvent (DMSO, DMF, acetonitrile): E2
• Weak base and polar protic solvent (H2O,
ROH): E1

III. ELECTROPHILIC SUBSTITUTION (SE), NUCLEOPHILIC ADDITION

(AN), ELECTROPHILIC ADDITION (AE):

CHAPTER 4: ALKANE
I. SYNTHESIS:
1) Hydrogenation of unsaturated hydrocarbon

This reaction is syn addition => Add two H on the same side.
With this catalyst, only alkane is obtained.
2) Hydrogenation of carbonyl compounds (Aldehyde and Ketone only)

14
 3) Corey-House reaction from alkyl halides (R-X)

II. CHEMICAL REACTION:

Halogenation of alkane based on radical reactions (must have light, heat is optional):

Hv (light) and heat

Mechanism:

15
This reaction is selective based on radical stability:

Product stereochemistry: We can obtain R and S configurations due to the electron

can move to both orbitals.

CHAPTER 5: ALKENE
I. SYNTHESIS:
1) Hydrogenation of alkyne:
DO NOT USE Raney catalyst as the final product will be alkane, not alkene.
Instead, use these two catalysts:
a) + H2 Lindlar catalyst (Pd/CaCO3/Pb(OAc)2/quinoline)
Syn addition: 2 H are added to the same side of C=C

b) Na/NH3 (liquid)/-78 oC
Anti addition: 2 H are added to opposite side of C=C

16
2) Wittig reaction: applied to carbonyl

3) Dehydration of alcohol: Acid condition

This reaction follows the E1 mechanism. This reaction must be proceeded with
acid catalyst (SHOULD USE H2SO4) and heat:

Mechanism:

17
NOTE:
• Carbocation rearrangement can occur via H-shift. If no H exists, CH3-shift
will take place.
• You can only rearrange to the adjacent carbons.

18
Example:

19
 4) Elimination of alkyl halide: Basic condition
This reaction follows E2 mechanism. This reaction can only occur with base and
heat.
Case 1: Simple base (-OH, -OR) => Still follow Zaitsev’s rule

Case 2: Bulky base (R3CO-) => Hofmann product (less substituted)

Example:

20
II. CHEMICAL REACTION:
The majority reactions of alkene will be addition. For alkene, this addition works
based on Electrophilic addition mechanism (AE) due to the high electron density of
alkene:

NOTE: The reaction is caused by the high electron density. Therefore:

• A1, A2, A3, A4: Electron donating groups will increase the reactivity.
• A1, A2, A3, A4: Electron withdrawing groups will decrease the reactivity.
1) Addition of H-X (X: Cl, Br, I, OH):
a) Markovnikov’rule case and carbocation rearrangement:
Step 1: Add H (of H-X) to the carbon with more H atoms (Markovnikov’ rule). In
case both sides have the same number of H atoms, check which side has smaller
hyperconjugation effect.

H
H

Step 2: Consider carbocation rearrangement:

H

21
Step 3: Add X to the carbocation center. Since X is added to carbocation center,
both configurations R, S are obtained.

Example:

For H-OH addition, MUST HAVE ACID CATALYST:

Since water itself is not acidic enough to allow H to act as an electrophile, this
reaction itself cannot occur.

However, acid catalyst (H2SO4, H3PO4) helps protonate water to form electrophile:

22
 b) Anti-Markovnikov rule:
There are two cases that does not follow Markovnikov rule:
Case 1: One of the attaching groups to alkene is EWG:
Since carbocation is electron-poor, any electron withdrawing group will destabilize it.

Case 2: Addition of HBr in peroxide (ROOR, H2O2):

This reaction does not have to be rearranged.

WHY?
This reaction is radical addition:

23
Like stereochemistry of carbocation, we can obtain both configuration R, S.
2) Addition of halogens:
This reaction follows:
• Markovnikov rule
• No rearrangement due to formation of cyclic halonium ion, which is more
stable than carbocation.
• Anti addition

SPECIAL CASE: In the presence of other anions (RCOO-, RO-, -OH,etc), these
anions will replace the role of Br-.
Example: Determine the final products and its stereochemistry:

24
 3) Formation of alcohol via oxymercuration-reduction:
This reaction follows:
• No rearrangement
• Markovnikov addition
• Anti addition

4) Formation of alcohol via hydroboration-oxidation:

This reaction follows:
• No rearrangement
• Anti-Markovnikov addition

25
• Syn addition

5) Formation of diols:
a) Epoxidation of alkene – Ring opening with acid:
Anti addition:

b) Oxidation of alkene in presence of OsO4:

Syn addition

6) Oxidation of alkene in the presence of KMnO4 (temperature dependent):

Case 1: In cold aqueous base:

26
Case 2: In heated acid or basic solution:
The product varies based on the attaching group to each carbon of double bond:

7) Ozonolysis of alkene:

The workup can break down ozonide into different products:

• Reductive workup: (CH3)2S (DMS) or Zn/acid => Ketone and aldehyde
• Oxidative workup: H2O2 => Ketone and carboxylic acid

27
 CHAPTER 6: ALKADIENE
This chapter will focus primarily on conjugated diene.
I. SYNTHESIS:
Elimination of R-OH or R-X:
This part is similar to alkene. The main difference is one of the attaching groups is
also an alkene, creating the final product a conjugated diene.

II. CHEMICAL REACTION:

1) Addition of X2 and HX:

28
High temperature favors 1,4 additions while low temperature favors 1,2 additions.
2) Diels-Alder reaction:
• Syn addition
• Alkadiene must be in cis form.
• Z alkene => Both high priority groups are on the same side.
• E alkene => Both high priority groups are on the opposite side.
• Alkene with no Z/E => Racemic mixture (R and S)

29
 CHAPTER 7: ALKYNE

I. PROPERTIES:

To separate a proton of acid, we need to use a base that is stronger than the formed
conjugated base.
Due to alkyne acidic property, it can react with Na, NaNH2 to form acetylide
anions:

HOWEVER, alkyne cannot react with NaOH:

II. SYNTHESIS:
1) Elimination of dihalides: Under strong base at high temperatures, H-X
elimination occurs. However base selection can affect the outcome:
• KOH/EtOH: Internal alkyne
• NaNH2: Terminal alkyne.

30
III. CHEMICAL REACTION:
1) Substitution reaction with primary alkyl halide (RCH2X):
Acetylide anion as a nucleophile can react with RCH2X via SN2 to form an alkyne
with longer carbon chain:

NOTE: For acetylene, ratio should be noted to ensure substitution occurs on one
side, not both sides.

2) Elimination with secondary and tertiary alkyl halide:

• Products: Terminal alkyne + Alkene
• Mechanism: E2

3) Addition with HX and X2 (X: Halogen):

• Anti addition
• Markovnikov rule
• If alkene is also present, prioritize double bond addition.

31
4) Addition of H2O in acid:
• Markovnikov rule, no rearrangement.
• For terminal alkyne: Hg2+ is required.
• Product: Ketone (R-CO-R) except for C2H2

5) Hydroboration – oxidation reaction:

• Anti-Markovnikov rule, no rearrangement.
• Product: Aldehyde (for terminal alkyne only) and ketone

32
 6) Oxidation of alkyne:
• Product: carboxylic acid (COOH) and CO2 (terminal alkyne only)

CHAPTER 8: ARENES
I. CRITERIA FOR AROMATICITY
A molecule is aromatic if and if only:
• It is cyclic.
• The molecule is planar.
• Conjugated (no sp3)
• Have 4n+2 p electrons.
Example:

33
Example: Determine which compound is aromatic

34
II. CHEMICAL REACTION
1) Main mechanism:
For aromatic compounds, the main mechanism is electrophilic aromatic
substitution (SEAr):

2) Halogenation of benzene:

35
 • Catalyst (must have): Lewis’s acid (Fe3+, Al3+)

3) Nitration of benzene:
• Catalyst: Concentrated H2SO4

4) Sulfonication of benzene:

More specifically:

Benzenesulfonic acid is the key ingredient in synthesizing:

a) Ether with phenyl branch:

b) Phenol:

36
5) Friedel-Crafts alkylation of benzene:
• Carbocation formation and rearrangement.

Alkylation reagent Catalyst

RCl Lewis acid: AlCl3, FeCl3
Alkene H ( 1st step of H-X addition)
+

Alcohol H+ (1st step of dehydration)

a) RCl:

b) Alkene:

37
c) Alcohol:

Disadvantage of Friedel-Crafts alkylation:

38
How to synthesize:

6) Friedel-Crafts acylation of benzene:

• Carbonyl formation.
• No carbocation formation, no rearrangement.

But how to synthesize:

7) Halogenation of branched alkyl benzene:

• Radical mechanism
39
 • Carbon that has at least 1H that is connecting to phenyl will be prioritized
due to formation of a very stable radical:

8) Oxidation of branched alkyl benzene with KMnO4:

• Condition: Carbon connecting directly with benzene must have at least 1H.
• Products: The carbon connecting directly to benzene will become COOH.

9) Nucleophilic substitution of aryl halide:

At normal condition, SN reaction is unlikely to happen.
HOWEVER, by increasing the number of EWG on the benzene, substitution
reaction can occur.

40
 10) GENERAL RULE FOR SYNTHESIZING BENZENE WITH MULTIPLE
GROUPS:

EDG (Electron-donating
groups)

41
42
 EWG (Electron-
withdrawing groups)

• If the 1st group is EDG (positive effect), the next group will be attached to ortho, para
position. Usually, para is favored due to no steric effect in ortho

• If the 1st group is EWG (negative effect), the next group will be attached to meta
position.

• If there are multiple groups, determine the most positive group and attach the group
following the directing position of that group.

43
• If there are two or more benzene connecting to each other, determine which one has
the most positive substituents and attach the group to the position following the
directing order of the substituents.

• DO NOT add the group between two groups due to high steric effect.

• ALKYLATION AND ACYLATION does not occur when strong EWG is present. To
make sure no problem occurs, try to avoid alkylation and acylation when weak or
strong EWG groups are present.
Example: Synthesis:

• ALKYLATION AND ACYLATION cannot be performed when NH2, NHR, NR2 are
present.

CHAPTER 9: ETHER & ALKYL MAGNESIUM

HALIDES
I. ETHER SYNTHESIS:
• SN2 mechanism

44
Example:

To synthesize Alkoxide:

Example: Synthesize:

II. ALKYL MAGNESIUM HALIDES (GRIGNARD REAGENT)

1) Synthesize:

45
2) Chemical reaction:
a) Protonation reaction
• RMgX are strong base:

• React with proton donor to gain H

• Proton donors: Alkyne, Amine, NH3, ROH, H2O, Phenol, RCOOH,…
Example: Write down the product(s) of the following reactions:

46
b) Reaction with carbonyl groups (Ketone and Aldehyde):
• Product: Alcohol with addition R from RMgX
• Must have protonation reaction in the 2nd step to obtain alcohol

47
 Mechanism:

Example: Determine the main product(s):

48
 c) Reaction with ester:
• Product: Alcohol with 2 R from RMgX
• Must have protonation reaction in the 2nd step to obtain alcohol.

Mechanism:

Example:

49
d) Reaction with Nitrile (CN):
• Product: Imine.
• Imine can be used to synthesize ketone via hydrolyzation in acidic
environments

e) Reaction with CO2:

• Product: Carboxylic acid (attach COOH to the R of RMgX)

f) Reaction with epoxide:

• Product:
o Symmetrical epoxide: Alcohol with 1 R attach to one C of epoxide

o Asymmetrical epoxide: Alcohol with 1 R attach to C less hindered of

epoxide

CHAPTER 10: ALCOHOL & PHENOL

50
I. ALCOHOL SYNTHESIS:
1) From alkene:

2) From alkyl halide:

3) From reduction reaction:
a) Reducing agent:
Three commonly used reducing agent:

b) From ketone and aldehyde:

• Reducing agent: NaBH4, LiAlH4, H2/Raney
• Product: Alcohol

51
 c) Carboxylic acids and its derivatives:
• Reducing agent: LiAlH4 only
• Product: Primary alcohol

Example: Select the most suitable reagent:

52
II. CHEMICAL REACTION OF ALCOHOL:
1) Dehydration of alcohol:

53
2) Conversion of alcohols to alkyl halide:
Two new reagents for SN2 reaction of 1o, 2o alcohols:
• SOCl2 (solvent: Pyridine): Cl substitution
• PX3, PX5 (X: Cl, Br): X substitution

Pyridine

3) Ether synthesis:
a) Dehydration of primary alcohols:
• Williamson synthesis (RONa + RX): Useful for all cases
• Dehydration of primary alcohol ONLY: To synthesize symmetrical ether
• SHOULD NOT BE USED
o Temperature can cause side effects: Alkene formation
o Only applied to primary alcohols: Higher degree tends to form
carbocation easily, promoting formation of alkene.

b) Intramolecular ether:
• Dehydration of diols can produce intramolecular ether containing 5 or 6
members rings:

4) Esterification:

54
5) Oxidation of alcohols:
• Oxidizing agents: CrO3 or Na2Cr2O7 in H2SO4, H2CrO4, KmnO4
• Note: Cr does not cleavage alkene
• Products:
o Tertiary alcohol: No reaction

o Secondary alcohol: Ketone

o Primary alcohol: Carboxylic acid

▪ While it does form aldehyde, the aldehyde will be oxidated
immediately to form carboxylic acid
▪ To form aldehyde: Use mild oxidizing agent such as PCC.
PCC can still be used to oxidize secondary alcohol to ketone.

55
III. CHEMICAL REACTION OF PHENOL:
1) Alkoxide formation:
• While alcohol CANNOT react with NaOH, phenol can due to its acidity
higher than alcohol and water.
• In adittion, K2CO3 and Na2CO3 can also be used.

2) Esterification reaction:
• Phenol DOES NOT react with Carboxylic acid
• Can react with annhydride (RCO)2O and acyl chloride
3) Halogenation reaction of phenol
• Due to OH group, halogenation reaction can occur without the usage of
Lewis acid
• The final product of halogenation reaction of phenol depends on solvent:
o Non-polar solvent (trans ClCH2CH2Cl): Halogen is substituted one
time only
o Polar solvent (H2O): Halogen is substituted three times. Cannot
obtain one halogen substituted.

56
 4) Nitration reaction:
• Unlike benzene, phenol does not require catalyst H2SO4
Example:

57
 CHAPTER 11: ALDEHYDE AND KETONE
I. Aldehyde/Ketone synthesis
1) From alkene:
• Oxidizing agent:
o KmnO4, heat or K2Cr2O7, H+: Ketone and carboxylic acid
o 1. O3 2. H2O2: Ketone and carboxylic acid
o 1. O3 2. Zn/CH3COOH: Ketone and aldehyde

2) From alkyne:

3) From alcohols:
• Mn(VII), Cr(VI): Ketone and acid
• PCC: Ketone and aldehyde

58
II. Chemical reactions
1) Nucleophilic addition with HCN
• Product: Cyanohydrin (=O convert to OH and addition of CN as well)
• CN of cyanohydrin can conver to
o CH2NH2 via LiAlH4 or H2/Metal
o COOH via hydrolysis in acidic enviroment
Mechanism:

2) Nucleophilic addition with acetylide ions

• Product: =O convert to OH and attach acetylide ion to the carbon

59
3) Nucleophilic addition with amine
• Product: Imine (for ammonia, primary amine) and enamine (for secondary
amine)
• Reaction can only happen when N still have at least 1H
• Reaction is reversible and occurs in acidic environment

Example:

60
4) Nucleophilic addition with H2O
• Product: Geminal diol
• Can occur in either acidic environment or basic environment

5) Acetalization/ Ketalization with alcohols

• Reagent: Alcohol or Diol
• Products: Hemiacetal or acetal

61
 Example: Synthesis the following compounds

6) Aldol reaction:
• Base environment.
• Only aldehyde/ ketone with Calpha-H can react.
• Aldol products will be the sum of both reactants.
• Aldol products: Calpha will connect with C of C=O bonds and C=O will
become C-OH.

62
 Aldol produts are easy to be eliminated H-OH in basic or acidic
environments
 Creating double bond
There are three types of aldol reaction:
• Aldol reaction with itself:

• Crossed aldol reaction:

63
 • Intramolecular aldol reaction

7) Cannizzaro reaction:
• Only aldehyde without Calpha – H can react
• React in basic conditions
• Products: Primary alcohol and carboxylic acid

64
8) Halogenation at Calpha-H:
• Acidic enviroment: Replace 1H
• Basic enviroment: If Halogen is exceed, replace all H of C alpha

• Special case: COCH3 group

CHAPTER 11: CARBOXYLIC ACID

I. Carboxylic acid synthesis:
1) From RMgX
2) From nitrile compounds:
• Hydrolysed in acid condition

• How to add CN ?

65
3) From primary alcohol and aldehyde
• Oxidizing agent:
4) From alkyl benzene:
• Carbon connecting to benzene must have at least…… to create COOH
II. Chemical reaction:
1) Acyl halide formation:
• Halogenation with SOCl2, PX3, PX5 (X: Cl, Br)

2) Esterification:
Example: Determine the missing reactant

• Beside normal esterification, esterification in the presence of alkyl halides can

be used
• Applied to methyl or primary halide

3) Bromination at Calpha:

66
 • Reagent: P + Br2 or PBr3 + Br2
• Product: Convert H of Calpha to Br

• Alpha-Br can be replaced easily with other functional groups:

o OH: K2CO3, H2O, heat
o NH2: NH3, H2O
o CN: KCN
III. Ester chemical reaction:
1) Hydrolysis of ester:
• Acidic condition: Reversible reaction, form acid and alcohol

• Basic condition: Irreversible reaction, form carboxylate ion and alcohol

2) Transesterification:
• Reversible reaction in acidic and basic conditions
• Reagents: Ester and a different alcohol
• Products: Exchange the OR of the original ester with OR of the alcohol

IV. Anhydrides synthesis:

1) From carboxylate ions and acyl chloride:

67
V. Anhydrides chemical reaction:
1) Amide formation:
2) Carboxylic acid formation:
VI. Acyl halides chemical reaction:
1) Corey House reaction:
2) Amide formation:
3) Hydrolysis of acyl halides:
VII. Amide synthesis:
• Must have temperature

VIII. Amide chemical reaction:

1) Esterification:

2) Carboxylic acid formation:

• Hydrolysis in acid condition

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3) Reduction:
• Product: Amine
• Can only use LiAlH4

CHAPTER 13: AMINES & DIAZONIUM SALTS

I. Amine synthesis:
1) From alkyl halides:
• Case 1: Alkyl halides exceed: Obtain quaternary ammonium.
• Case 2: Ammonia exceed: Obtain primary amine

2) From amides:
• Using LiAlH4 to produce …. amine
3) From nitrile and imine

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4) From nitrobenzene:
• Method 1: H2/ metal
o Function:
o Disadvantages:

• Method 2: 1. Sn/Fe/Zn in HCl or SnCl2 2. NaOH

o Function: Reduce NO2 only to NH2
o Disadvantages:

• Method 3: (NH4)2S
o Function: Reduce only 1 NO2 to NH2

II. Amine chemical reaction:

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1) Reaction with aldehyde and ketone:

2) Amidation reaction:
3) Unwanted reaction:
a. Oxidizing reaction:
• Amine can be oxidized easily by strong oxidizing agent
• Product: Convert NH2 to NO2-

b. Electrophilic substitution of aromatic amines

• DO NOT APPLY LEWIS ACID to aromatic amine => Will form strong
EWG group => No further reaction
• Adding Br2 in polar protic solvent: Easily reach tribromo.

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c. Protection method
• Create amide first then convert back to amine via hydrolysis in acid
condition.
Example:

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4) Reaction of amine with HNO2
• Only applied to aromatic amine.

• The diazonium can be converted to the following groups:

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5) Diazonium coupling reaction:

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