ORGANIC
SYNTHESIS
KNOCKHARDY PUBLISHING
2015
SPECIFICATIONS
KNOCKHARDY PUBLISHING
ORGANIC SYNTHESIS
INTRODUCTION
This Powerpoint show is one of several produced to help students
understand selected topics at AS and A2 level Chemistry. It is based on the
requirements of the AQA and OCR specifications but is suitable for other
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ORGANIC SYNTHESIS
CONTENTS
• Introduction
• Functional groups
• Extending a carbon chain
• Chiral synthesis - introduction
• Nucleophilic addition
• Nucleophilic substitution
• Synthetic methods
ORGANIC SYNTHESIS
Involves the preparation of new compounds from others.
ORGANIC SYNTHESIS
Involves the preparation of new compounds from others.
Many industrial processes involve a multi stage process where functional
groups are converted into other functional groups.
ORGANIC SYNTHESIS
Involves the preparation of new compounds from others.
Many industrial processes involve a multi stage process where functional
groups are converted into other functional groups.
When planning a synthetic route, chemists must consider...
ORGANIC SYNTHESIS
Involves the preparation of new compounds from others.
Many industrial processes involve a multi stage process where functional
groups are converted into other functional groups.
When planning a synthetic route, chemists must consider...
• the reagents required to convert one functional group into another
• the presence of other functional groups - in case also they react
ORGANIC SYNTHESIS
Involves the preparation of new compounds from others.
Many industrial processes involve a multi stage process where functional
groups are converted into other functional groups.
When planning a synthetic route, chemists must consider...
•
•
•
•
•
•
the reagents required to convert one functional group into another
the presence of other functional groups - in case also they react
the conditions required - temperature, pressure, catalyst
the rate of the reaction
the yield - especially important for equilibrium reactions
atom economy
ORGANIC SYNTHESIS
Involves the preparation of new compounds from others.
Many industrial processes involve a multi stage process where functional
groups are converted into other functional groups.
When planning a synthetic route, chemists must consider...
•
•
•
•
•
•
•
•
•
•
the reagents required to convert one functional group into another
the presence of other functional groups - in case also they react
the conditions required - temperature, pressure, catalyst
the rate of the reaction
the yield - especially important for equilibrium reactions
atom economy
safety - toxicity and flammability of reactants and products
financial economy - cost of chemicals, demand for product
problems of purification
possibility of optically active products
ORGANIC SYNTHESIS
Involves the preparation of new compounds from others.
Many industrial processes involve a multi stage process where functional
groups are converted into other functional groups.
When planning a synthetic route, chemists must consider...
•
•
•
•
•
•
•
•
•
•
the reagents required to convert one functional group into another
the presence of other functional groups - in case also they react
the conditions required - temperature, pressure, catalyst
the rate of the reaction
the yield - especially important for equilibrium reactions
atom economy
safety - toxicity and flammability of reactants and products
financial economy - cost of chemicals, demand for product
problems of purification
possibility of optically active products
ORGANIC SYNTHESIS
Functional groups
Common functional groups found in organic molecules include...
alkene
hydroxyl
(alcohols)
haloalkane
carbonyl
(aldehydes & ketones)
amine
nitrile
carboxylic acid
ester
ORGANIC SYNTHESIS
Involves the preparation of new compounds from others, for example…
POLYMERS
ALKANES
DIBROMOALKANES
ALKENES
KETONES
ALCOHOLS
ALDEHYDES
HALOGENOALKANES
AMINES
ESTERS
NITRILES
CARBOXYLIC ACIDS
EXTENDING A CARBON CHAIN
Rationale
Methods
Haloalkanes
Carbonyl compounds (aldehydes and ketones)
Aromatic (benzene) rings
NUCLEOPHILIC SUBSTITUTION
POTASSIUM CYANIDE
Reagent
Conditions
Product
Nucleophile
Equation
Mechanism
Aqueous, alcoholic potassium (or sodium) cyanide
Reflux in aqueous , alcoholic solution
Nitrile (cyanide)
cyanide ion (CN¯)
e.g. C2H5Br +
KCN (aq/alc) ——> C2H5CN + KBr(aq)
NUCLEOPHILIC SUBSTITUTION
POTASSIUM CYANIDE
Reagent
Conditions
Product
Nucleophile
Equation
Aqueous, alcoholic potassium (or sodium) cyanide
Reflux in aqueous , alcoholic solution
Nitrile (cyanide)
cyanide ion (CN¯)
e.g. C2H5Br +
KCN (aq/alc) ——> C2H5CN + KBr(aq)
Mechanism
Importance
extends the carbon chain by one carbon atom
the CN group can be converted to carboxylic acids or amines.
Hydrolysis
C2H5CN
+
2H2O
Reduction
C2H5CN + 4[H]
———>
C2H5COOH +
———> C2H5CH2NH2
NH3
CARBONYL COMPOUNDS - NUCLEOPHILIC ADDITION
HIGHLY TOXIC
TAKE GREAT CARE
Reagent
potassium cyanide – followed by dilute acid
Conditions
reflux
Nucleophile
cyanide ion CN¯
Product(s)
hydroxynitrile (cyanohydrin)
Equation
CH3CHO
Notes
HCN is a weak acid and has difficulty dissociating into ions
+
HCN
HCN
——> CH3CH(OH)CN
2-hydroxypropanenitrile
H+
+
CN¯
Using ionic KCN produces more of the nucleophilic CN¯
Alternative reagent: HCN catalysed by alkali which shifts
the above equilibrium in favour of CN¯
CARBONYL COMPOUNDS - NUCLEOPHILIC ADDITION
Mechanism
Nucleophilic addition
STEP 1
Step 1
CN¯ acts as a nucleophile and attacks the slightly positive C
One of the C=O bonds breaks; a pair of electrons goes onto the O
CARBONYL COMPOUNDS - NUCLEOPHILIC ADDITION
Mechanism
Nucleophilic addition
STEP 1
STEP 2
Step 1
CN¯ acts as a nucleophile and attacks the slightly positive C
One of the C=O bonds breaks; a pair of electrons goes onto the O
Step 2
A pair of electrons is used to form a bond with H+
Overall, there has been addition of HCN
CARBONYL COMPOUNDS - NUCLEOPHILIC ADDITION
Mechanism
Nucleophilic addition
STEP 1
STEP 2
Step 1
CN¯ acts as a nucleophile and attacks the slightly positive C
One of the C=O bonds breaks; a pair of electrons goes onto the O
Step 2
A pair of electrons is used to form a bond with H+
Overall, there has been addition of HCN
CARBONYL COMPOUNDS - NUCLEOPHILIC ADDITION
Mechanism
Nucleophilic addition
STEP 1
STEP 2
Step 1
CN¯ acts as a nucleophile and attacks the slightly positive C
One of the C=O bonds breaks; a pair of electrons goes onto the O
Step 2
A pair of electrons is used to form a bond with H+
Overall, there has been addition of HCN
FRIEDEL-CRAFTS REACTIONS OF BENZENE - ALKYLATION
Overview
Alkylation involves substituting an alkyl (methyl, ethyl) group
Reagents
a halogenoalkane (RX) and anhydrous aluminium chloride AlCl3
Conditions
room temperature; dry inert solvent (ether)
Electrophile
a carbocation ion R+ (e.g. CH3+)
Equation
C6H6 + C2H5Cl
———>
C6H5C2H5 + HCl
Mechanism
General
A catalyst is used to increase the positive nature of the electrophile
and make it better at attacking benzene rings.
AlCl3 acts as a Lewis Acid and helps break the C—Cl bond.
FRIEDEL-CRAFTS REACTIONS OF BENZENE - ACYLATION
Overview
Acylation involves substituting an acyl (methanoyl, ethanoyl) group
Reagents
an acyl chloride (RCOX) and anhydrous aluminium chloride AlCl3
Conditions
reflux 50°C; dry inert solvent (ether)
Electrophile
RC+= O
Equation
C6H6 + CH3COCl
( e.g. CH3C+O )
———>
C6H5COCH3 + HCl
Mechanism
Product
A carbonyl compound (aldehyde or ketone)
EXTENDING A CARBON CHAIN
Rationale
Methods
Haloalkanes
Carbonyl compounds (aldehydes and ketones)
Aromatic (benzene) rings
CHIRAL SYNTHESIS
Rationale
Pharmaceutical synthesis often requires the production of just one optical
isomer. This is because...
CHIRAL SYNTHESIS
Rationale
Pharmaceutical synthesis often requires the production of just one optical
isomer. This is because...
• one optical isomer usually works better than the other
• the other optical isomer may cause dangerous side effects
• laboratory reactions usually produce both optical isomers
• naturally occurring reactions usually produce just one optical isomer
CHIRAL SYNTHESIS
Rationale
Pharmaceutical synthesis often requires the production of just one optical
isomer. This is because...
• one optical isomer usually works better than the other
• the other optical isomer may cause dangerous side effects
• laboratory reactions usually produce both optical isomers
• naturally occurring reactions usually produce just one optical isomer
Example
Aldehydes and ketones undergo nucleophilic addition
with cyanide (nitrile) ions;
CH3CHO
ethanal
+
HCN
——> CH3CH(OH)CN
2-hydroxypropanenitrile
CHIRAL SYNTHESIS
Example
Aldehydes and ketones undergo nucleophilic addition with cyanide ions
CH3CHO
ethanal
+
HCN
——> CH3CH(OH)CN
2-hydroxypropanenitrile
CHIRAL SYNTHESIS
Example
Aldehydes and ketones undergo nucleophilic addition with cyanide ions
CH3CHO
ethanal
Problem
-
+
HCN
——> CH3CH(OH)CN
2-hydroxypropanenitrile
the C=O bond is planar
the nucleophile can attack from above and below
there is an equal chance of each possibility
a mixture of optically active isomers is produced
only occurs if different groups are attached to the C=O
CHIRAL SYNTHESIS
Example
Aldehydes and ketones undergo nucleophilic addition with cyanide ions
CH3CHO
ethanal
Problem
CN¯ attacks
from above
-
+
HCN
——> CH3CH(OH)CN
2-hydroxypropanenitrile
the C=O bond is planar
the nucleophile can attack from above and below
there is an equal chance of each possibility
a mixture of optically active isomers is produced
only occurs if different groups are attached to the C=O
CHIRAL SYNTHESIS
Example
Aldehydes and ketones undergo nucleophilic addition with cyanide ions
CH3CHO
ethanal
Problem
CN¯ attacks
from below
-
+
HCN
——> CH3CH(OH)CN
2-hydroxypropanenitrile
the C=O bond is planar
the nucleophile can attack from above and below
there is an equal chance of each possibility
a mixture of optically active isomers is produced
only occurs if different groups are attached to the C=O
CHIRAL SYNTHESIS
Example
CH3CHO
ethanal
+
HCN
——> CH3CH(OH)CN
2-hydroxypropanenitrile
CN¯ attacks
from above
MIRROR
IMAGES
CN¯ attacks
from below
CHIRAL SYNTHESIS
Example
CN¯ attacks
from above
CN¯ attacks
from below
CH3CHO
ethanal
+
HCN
——> CH3CH(OH)CN
2-hydroxypropanenitrile
CHIRAL SYNTHESIS
Example
CH3CHO
ethanal
+
HCN
——> CH3CH(OH)CN
2-hydroxypropanenitrile
ANIMATION
CHIRAL SYNTHESIS
Consequences • isomers have to be separated to obtain the effective one
• separation can be expensive and complicated
• non-separation leads to
CHIRAL SYNTHESIS
Consequences • isomers have to be separated to obtain the effective one
• separation can be expensive and complicated
• non-separation leads to
larger doses needed
possible dangerous side effects
possible legal action
CHIRAL SYNTHESIS
Consequences • isomers have to be separated to obtain the effective one
• separation can be expensive and complicated
• non-separation leads to
larger doses needed
possible dangerous side effects
possible legal action
Solution
• use natural chiral molecules as starting materials
• use stereoselective reactions which give one isomer
• use catalysts which give a specific isomer
• use enzymes or bacteria which are stereoselective
CHIRAL SYNTHESIS
Consequences • isomers have to be separated to obtain the effective one
• separation can be expensive and complicated
• non-separation leads to
larger doses needed
possible dangerous side effects
possible legal action
Solution
• use natural chiral molecules as starting materials
• use stereoselective reactions which give one isomer
• use catalysts which give a specific isomer
• use enzymes or bacteria which are stereoselective
Other examples
Nucleophilic substitution of haloalkanes
NUCLEOPHILIC SUBSTITUTION
Problems
There are two possible mechanisms
SN2
This produces just one optical isomer with reversed optical activity
Called SN2 because two species are involved in the rate determining step.
NUCLEOPHILIC SUBSTITUTION
Problems
There are two possible mechanisms
SN1
This produces a racemic mixture of two optical isomers
Called SN1 because one species is involved in the rate determining step.
NUCLEOPHILIC SUBSTITUTION
Problems
There are two possible mechanisms
SN2
This produces just one optical isomer with reversed optical activity
Called SN2 because two species are involved in the rate determining step.
SN1
This produces a racemic mixture of two optical isomers
Called SN1 because one species is involved in the rate determining step.
MODERN SYNTHETIC METHODS
The following methods can be used to synthesise a single optical isomer
Enzymes / bacteria
Chiral chemicals
Chiral catalysts
Natural chiral molecules
ORGANIC
SYNTHESIS
THE END
©2015 JONATHAN HOPTON & KNOCKHARDY PUBLISHING