organicsynthesis knockhardy publishing 2015 specifications

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SYNTHESISSYNTHESIS

KNOCKHARDY PUBLISHINGKNOCKHARDY PUBLISHING20152015

SPECIFICATIONSSPECIFICATIONS

INTRODUCTION

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ORGANIC SYNTHESISORGANIC SYNTHESIS

CONTENTS• Introduction

• Functional groups

• Extending a carbon chain

• Chiral synthesis - introduction

• Nucleophilic addition

• Nucleophilic substitution

• Synthetic methods



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







• 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


Functional groupsFunctional groups

Common functional groups found in organic molecules include...

alkene

hydroxyl (alcohols)

haloalkane

carbonyl (aldehydes & ketones)

amine

nitrile

carboxylic acid

ester


Involves the preparation of new compounds from others, for example…

ESTERSESTERS

ALKANESALKANES ALKENESALKENES

HALOGENOALKANESHALOGENOALKANES

ALCOHOLSALCOHOLS

AMINESAMINES

ALDEHYDESALDEHYDES

KETONESKETONES

CARBOXYLIC ACIDSCARBOXYLIC ACIDS

POLYMERSPOLYMERS

NITRILESNITRILES

DIBROMOALKANESDIBROMOALKANES

EXTENDING A CARBON CHAINEXTENDING A CARBON CHAIN

Rationale

Methods HaloalkanesCarbonyl compounds (aldehydes and ketones)Aromatic (benzene) rings

POTASSIUM CYANIDE

Reagent Aqueous, alcoholic potassium (or sodium) cyanideConditions Reflux in aqueous , alcoholic solutionProduct Nitrile (cyanide)Nucleophile cyanide ion (CN¯)

Equation e.g. C2H5Br + KCN (aq/alc) ——> C2H5CN + KBr(aq)

Mechanism

NUCLEOPHILIC SUBSTITUTIONNUCLEOPHILIC SUBSTITUTION

POTASSIUM CYANIDE

Reagent Aqueous, alcoholic potassium (or sodium) cyanideConditions Reflux in aqueous , alcoholic solutionProduct Nitrile (cyanide)Nucleophile cyanide ion (CN¯)

Equation e.g. C2H5Br + KCN (aq/alc) ——> C2H5CN + KBr(aq)

Mechanism

Importance extends the carbon chain by one carbon atomthe CN group can be converted to carboxylic acids or amines.

Hydrolysis C2H5CN + 2H2O ———> C2H5COOH + NH3

Reduction C2H5CN + 4[H] ———> C2H5CH2NH2


CARBONYL COMPOUNDS - NUCLEOPHILIC ADDITIONCARBONYL COMPOUNDS - NUCLEOPHILIC ADDITION

Reagent potassium cyanide – followed by dilute acid

Conditions reflux

Nucleophile cyanide ion CN¯

Product(s) hydroxynitrile (cyanohydrin)

Equation CH3CHO + HCN ——> CH3CH(OH)CN

2-hydroxypropanenitrile

Notes HCN is a weak acid and has difficulty dissociating into ions

HCN 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¯

HIGHLY TOXICTAKE GREAT CARE

HIGHLY TOXICTAKE GREAT CARE


Mechanism Nucleophilic addition

Step 1 CN¯ acts as a nucleophile and attacks the slightly positive COne of the C=O bonds breaks; a pair of electrons goes onto the O

STEP 1


Mechanism Nucleophilic addition

Step 1 CN¯ acts as a nucleophile and attacks the slightly positive COne 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

STEP 2STEP 1

FRIEDEL-CRAFTS REACTIONS OF BENZENE - FRIEDEL-CRAFTS REACTIONS OF BENZENE - ALKYLATIONALKYLATION

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 - FRIEDEL-CRAFTS REACTIONS OF BENZENE - ACYLATIONACYLATION

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 ( e.g. CH3C+O )

Equation C6H6 + CH3COCl ———> C6H5COCH3 + HCl

Mechanism

Product A carbonyl compound (aldehyde or ketone)

EXTENDING A CARBON CHAINEXTENDING A CARBON CHAIN

Rationale

Methods HaloalkanesCarbonyl compounds (aldehydes and ketones)Aromatic (benzene) rings

CHIRAL SYNTHESISCHIRAL SYNTHESIS

Rationale

Pharmaceutical synthesis often requires the production of just one optical isomer. This is because...


Rationale


• 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


Rationale


• 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 + HCN ——> CH3CH(OH)CNethanal 2-hydroxypropanenitrile


Example

Aldehydes and ketones undergo nucleophilic addition with cyanide ions



Example



Problem - 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


Example







CN¯ attacksfrom above


Example







CN¯ attacksfrom below


Example CH3CHO + HCN ——> CH3CH(OH)CNethanal 2-hydroxypropanenitrile



MIRROR IMAGES



ANIMATIONANIMATION


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





larger doses needed



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





larger doses needed



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


Problems There are two possible mechanisms

SN2

This produces just one optical isomer with reversed optical activityCalled SN2 because two species are involved in the rate determining step.



SN1

This produces a racemic mixture of two optical isomersCalled SN1 because one species is involved in the rate determining step.



SN2

This produces just one optical isomer with reversed optical activityCalled SN2 because two species are involved in the rate determining step.

SN1

This produces a racemic mixture of two optical isomersCalled SN1 because one species is involved in the rate determining step.

MODERN SYNTHETIC METHODSMODERN SYNTHETIC METHODS

The following methods can be used to synthesise a single optical isomer

Enzymes / bacteriaEnzymes / bacteria

Chiral chemicalsChiral chemicals

Chiral catalystsChiral catalysts

Natural chiral moleculesNatural chiral molecules

©2015 JONATHAN HOPTON & KNOCKHARDY PUBLISHING©2015 JONATHAN HOPTON & KNOCKHARDY PUBLISHING

THE ENDTHE END

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organicsynthesis knockhardy publishing 2015 specifications

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