Organic Reaction Mechanisms

Lecture Outline: Part 1

Context

Why bother with Organic Reaction Mechanisms?

What is a covalent bond?

What are curly reaction mechanism arrows and what is their physical meaning?

How do we form bonds with pairs of electrons (lone pairs or bonding electron pairs)?
 Lecture Outline: Part 2
Organic Reaction Mechanisms

Nucleophilic substitution with haloalkanes

Nucleophilic addition with aldehydes/ketones

Nucleophilic substitution (addition-elimination) with acid chlorides

Electrophilic aromatic substitution

Electrophilic addition to alkenes

Elimination of HX from haloalkanes (X = halogen)

Free radical chlorination of alkanes

 Why Are We Interested In Organic
Reaction Mechanisms
Paclitaxel was discovered beginning
in 1962 as a result of a U.S. National
Cancer Institute-funded screening
program.

It was isolated from the bark of the

Pacific yew tree, Taxus brevifolia,
thus its name "taxol".

It was shown to be active against

ovarian, breast, lung, pancreatic and
other cancers.

The supply from the Pacific yew tree

would not be enough.

A need to synthesise it….

https://en.wikipedia.org/wiki/Paclitaxel
 53 Step Synthesis!!

We need to bring understand at a molecular level (mechanism), in order to:

1. understand chemical transformations,

2. enabling the development of even more complex chemistry, and
3. to allow new drugs and materials to be designed and synthesised.
Molecules are 3D Objects
 What is a Covalent Bond?

2 electrons
Two atoms ‘equally’ shared
bonded by… by two atoms

…2 electrons
Reaction Mechanism ‘Curly’ Arrows

Two Electron Movement

Double headed arrow

Heterolytic Bond Cleavage

A—B A B:

A:B A B:

Electronegativty of atom A is less than atom B

 Lone Pairs Forming Bonds
H H
+ -
CH3 C Br CH3 C OH
H -
Br
H
OH- ethanol

Bonding Electrons Forming Bonds

H H H H
+ +
CH3 C C H C C

Br
+
H CH3 H
-
Br - H OH
OH -
 Nucleophilic
Substitution on a
Saturated Carbon
H
Electron rich Nucleophile + -
CH3 C X
(Nu)
Atom X is more
in search of an H electronegative
electron poor saturated than C
Nu
carbon centre

AS Level
Nucleophilic Substitution: 1 12

CH3CH2Br + OH- (aqueous) CH3CH2OH + Br-

ethanol

H H
+ -
CH3 C Br CH3 C OH
H -
Br
H

OH-
Nucleophilic Substitution: 2

CH3CH2I (ethanol) + CN-(aq) CH3CH2CN + I-

propanenitrile

H H
+ -
CH3 C Br CH3 C CN
H -
Br
H
CN-
Nucleophilic Substitution: 3

CH3CH2Br + 2 NH3 CH3CH2NH2 + NH4+Br-

aminoethane

H
+ -
CH3 C Br
-
Br
H H H
+
CH3 C NH2 CH3 C NH2
NH3
H H H
NH3
H NH3+Br -
Nothing is Black and White: 1

Stereochemistry
R R
Rate
Nu X Nu X
Equation
R' R'
"R "R

It is found that there are two possible stereochemical outcomes, each described
by a different rate equation, and different stereochemical outcomes.

Descriptor Rate Equation Stereochemical

Outcome

SN2 rate = k[R-Hal][Nu] Inversion

SN1 rate = k[R-Hal] Racemisation

Nucleophilic Substitution: SN2

Nucleophile can attacks from only

one side of the chloroalkane

1 R1
R Rate = k[R-Hal][Nu]

Nu Cl Nu Cl
3 R3
R
2 Bimolecular R2
R Process
Inversion
Rate of Configuration
Determinig
Step
http://chemistry.boisestate.edu/rbanks/organic/sn2.gif
 Nucleophilic Addition to
Acid Chlorides
(R(Cl)C=O) Followed by
Elimination
-
Electron rich Nucleophile (Nu)
+ O
in search of an CH3 C Then
electron poor unsaturated Cl elimination
of Cl-
carbon centre Nu

AS Level
Nucleophilic Substitution: SN1

Nucleophile attacks from either side

of the carbocation with equal
probability.

Carbocation
1
1 R
R Rate = k[R-Hal]

Cl Nu Nu
3
R
2 Unimolecular R3 2
R R
Process
Cl
Rate
Determining
State

1
R
1 R
One enantiomer Nu
Nu Racemisation
R 3 R3
2 2
R R
 QUIZ
• Predict the product for the following reactions and make their reaction
mechanism

CH3CH2Br NaOMe

Br H2O

(CH3)2CHI HCN

Cl

NaOH
 Nucleophilic
Addition to
Aldehydes/Ketones
(C=O)
-
Electron rich Nucleophile (Nu)
+ O
in search of an CH3 C
electron poor unsaturated CH3
carbon centre Nu

A2 Level
Nucleophilic Add’n to Aldehydes/Ketones 1

CH3COMe + HCN CH3C(OH)(CN)Me

2-hydroxy-2-methylpropanenitrile

- H+ +
O + O H
+ O H
CH3 C CH3 C
CH3 CH3 CH3 C CH3

CN CN
Nucleophilic Add’n to Acid Chlorides 1

CH3COCl + H 2O CH3COOH + HCl

- O
- O
+
O CH3 C
CH3 C CH3 C Cl OH
Cl OH - H +
H + Cl
H2O
O
CH3 C
HCl OH
Nucleophilic Add’n to Acid Chlorides 1

CH3COCl + CH3NH2 CH3CONHCH3 + HCl

N-methylethanamide

- O
- O
+
O CH3 C
CH3 C CH3 C Cl +
NHR
Cl + - H
NHR
H Cl
RNH2
An amide O
CH3 C
HCl NHR
 Electrophilic
Aromatic
Substitution

Electron rich aromatic unit +

in search of an E

electron poor electrophile (E)

A2 Level
Electrophilic Aromatic Substitution 1

C6H6 + HNO3/H2SO4 C6H5NO2 + H2 O

+
HNO3 + 2H2SO4 NO2 + 2HSO4- + H3O+
Electrophile
catalyst Nitronium Ion

+ NO2
O SO3H
-
NO2
H
+
NO2

H O SO3H
Electrophilic Aromatic Substitution 2
Lewis
C6H6 + (CH3)2CHCl acid C6H5CH(CH3)2 + HCl

+ -
AlCl3 Cl AlCl3
CH3 CH Cl CH3 CH -
Lewis Secondary + Cl AlCl3
CH3 Acid carbocation
CH3
catalyst
CH(CH3)2
+
HC CH3
+
H -
Cl AlCl3
CH3 + AlCl3

CH(CH3)2

+ HCl
Electrophilic Aromatic Substitution 3
Lewis
acid
C6H6 + RCOCl C6H5COR + HCl

O +
CH3C CH3C O -
Cl AlCl3 Acylium ion Cl AlCl3

+ O
CH3C O CH3
CH3C
C O
H
+
-
Cl AlCl3
H Cl
Not catalytic.
Why? AlCl3
 Electrophilic
Addition to Alkene

Electron rich p-bond H CH3

in search of an C C
electron poor electrophile (E) CH3 H
E

AS Level
Electrophilic Addition to an Alkene: 1

CH3CH=CHCH3+ HBr CH3CH2CHBrCH3

2-bromobutane

H CH3
carbocation
C C
H H
CH3 H
CH3 C C CH3
+ +
H
H
H H
Br Br-
- C C CH3
CH3
Permanent dipole
Br H
Electrophilic Addition to an Alkene: 2

CH3CH=CHCH3+ HOSO3H CH3CH2CH(OSO3H)CH3

2-butylhydrogensulphate

H H H H
carbocation
C C
CH3 C C CH3
CH3 CH3 +
H -
+ OSO3H
H H H
OSO3H CH3 C C CH3
-
H OSO3H
Electrophilic Addition to an Alkene: 3

CH3CH=CH2 + Br2 CH3CHBrCH2Br

1,2-dibromopropane

H H
carbocation
C C
H H
CH3 H
CH3 C C H
+ +
Br
Br
H H
Br
- Br-
Br CH3 C C H
Induced Dipole
Br Br Br
 Elimination of HX
from Alkanes to
form an alkene
H H
Lone Pair of Electrons on Base + +
CH3 C C H
(B:)in search of an +

electron poor hydrogen centre X H

-
Atom X is more B
electronegative
than C

AS Level
Elimination of HX: 1

CH3CHBrCH3 + OH- CH3CH=CH2 + H2O + Br-

(in ethanol) propene

H H H H
+ +
CH3 C C H C C

Br
+
H CH3 H
-
Br - H OH
OH -
acting as a base
this time….
Nothing is Black and White! 2
Nucleophilic
Substitution H H

CH3 C C Nu
-Nu
H H
Cl-
H H
+ + -
CH3 C C Cl
+
H H

- H H
B
C C Cl-
CH3 H
Elimination of HX

BH
 Free Radical
Substitution of
Alkanes
Light Induced Radical CH3 Cl Cl
Formation and
Subsequent
Replacement Cl
H3C Cl
Reactions

AS Level
Reaction Mechanism ‘Curly’ Arrows

One Electron Movement

Single ‘fish hook’ headed arrow

 Homolytic Bond Cleavage

C—D C• D•

C:D C• D•

Electronegativty of atom A is usually similar to atom B

Initiation

the formation of chlorine radicals by the homolytic

bond cleavage of diatomic chlorine, induced by light.

Light
Cl Cl Cl Cl

Radicals
Formed
Propagation reaction of the chlorine radicals with
methane, which generates methyl radicals
and HCl. Followed by the methyl radicals
reacting with diatomic chlorine, to afford
chloromethane and a chlorine radical.
Radicals
Consumed

H3C H Cl CH3 HCl

Cl Cl H3C Cl Cl

Chlorine Radical
Reformed
Termination

reaction of two radical species leading

to nonradical products.

Radicals
Consumed

CH3 Cl H3C Cl

CH3 CH3 H3C CH3

Radicals
Not Reformed
Further Free Radical Chlorination Reactions

CH3Cl + Cl2 CH2Cl2 + HCl

CH2Cl2 + Cl2 CHCl3 + HCl

CHCl3 + Cl2 CCl4 + HCl

 Nucleophilic Nucleophilic Nucleophilic
Substitution Addition Addition-Elimination

H - -
CH3 C X + O + O
CH3 C CH3 C Then
H CH3 Cl elimination
of Cl-
Nu Nu Nu

Electrophilic Electrophilic
Substitution Addition

Summary of the
H CH3
Chemistry Looked at
E C C
CH3 H
E
Free Radical Substitution Elimination of HX

H H
CH3 Cl Cl + +
CH3 C C H
+
X H
-
H3C Cl Cl B
Chemistry at Birmingham
www.chem.bham.ac.uk

Chemistry at Birmingham Ranked in the first

quartile of the 22 Russell Group Schools of
Supporting women in Science Chemistry for student satisfaction and
graduate employability
 Concluding Comments
Is the reaction light induced?
Yes No

Look for a bond with little Identify bonds with large

or no electronegativity differences in
difference in a bonded electronegativity in a
pair of atoms bonded pair of atoms.

Identify polarity to
Initiate: Cleave bond identify electrophilc
homolytically centre

Propagate: generate new Identify nucleophilic

radicals centre in other reagent
(lone pair of electrons) or
terminate: react radicals bonded pair of electrons
together to donate to electrophilic
centre