ORGANICSYNTHESIS KNOCKHARDY PUBLISHING 2015 SPECIFICATIONS

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 examination boards. Individual students may use the material at home for revision purposes or it may be used for classroom teaching with an interactive white board. Accompanying notes on this, and the full range of AS and A2 topics, are available from the KNOCKHARDY SCIENCE WEBSITE at... Navigation is achieved by... either clicking on the grey arrows at the foot of each page orusing the left and right arrow keys on the keyboard KNOCKHARDY PUBLISHING 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… ESTERS ALKANES ALKENES HALOGENOALKANES ALCOHOLS AMINES ALDEHYDES KETONES CARBOXYLIC ACIDS POLYMERS NITRILES DIBROMOALKANES

EXTENDING A CARBON CHAIN Rationale MethodsHaloalkanes Carbonyl compounds (aldehydes and ketones) Aromatic (benzene) rings

POTASSIUM CYANIDE ReagentAqueous, alcoholic potassium (or sodium) cyanide ConditionsReflux in aqueous, alcoholic solution ProductNitrile (cyanide) Nucleophilecyanide ion (CN¯) Equation e.g. C 2 H 5 Br + KCN (aq/alc) ——> C 2 H 5 CN + KBr(aq) Mechanism NUCLEOPHILIC SUBSTITUTION

POTASSIUM CYANIDE ReagentAqueous, alcoholic potassium (or sodium) cyanide ConditionsReflux in aqueous, alcoholic solution ProductNitrile (cyanide) Nucleophilecyanide ion (CN¯) Equation e.g. C 2 H 5 Br + KCN (aq/alc) ——> C 2 H 5 CN + KBr(aq) Mechanism Importanceextends the carbon chain by one carbon atom the CN group can be converted to carboxylic acids or amines. Hydrolysis C 2 H 5 CN + 2H 2 O ———> C 2 H 5 COOH + NH 3 Reduction C 2 H 5 CN + 4[H] ———> C 2 H 5 CH 2 NH 2 NUCLEOPHILIC SUBSTITUTION

CARBONYL COMPOUNDS - NUCLEOPHILIC ADDITION Reagentpotassium cyanide – followed by dilute acid Conditionsreflux Nucleophilecyanide ion CN¯ Product(s)hydroxynitrile (cyanohydrin) Equation CH 3 CHO + HCN ——> CH 3 CH(OH)CN 2-hydroxypropanenitrile NotesHCN 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 TOXIC TAKE GREAT CARE HIGHLY TOXIC TAKE GREAT CARE

CARBONYL COMPOUNDS - NUCLEOPHILIC ADDITION MechanismNucleophilic addition Step 1CN¯ 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 1

CARBONYL COMPOUNDS - NUCLEOPHILIC ADDITION MechanismNucleophilic addition Step 1CN¯ 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 2A pair of electrons is used to form a bond with H + Overall, there has been addition of HCN STEP 2STEP 1

CARBONYL COMPOUNDS - NUCLEOPHILIC ADDITION MechanismNucleophilic addition Step 1CN¯ 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 2A pair of electrons is used to form a bond with H + Overall, there has been addition of HCN STEP 2STEP 1

CARBONYL COMPOUNDS - NUCLEOPHILIC ADDITION MechanismNucleophilic addition Step 1CN¯ 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 2A 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 - ALKYLATION OverviewAlkylation involves substituting an alkyl (methyl, ethyl) group Reagents a halogenoalkane (RX) and anhydrous aluminium chloride AlC l 3 Conditionsroom temperature; dry inert solvent (ether) Electrophilea carbocation ion R + (e.g. CH 3 + ) EquationC 6 H 6 + C 2 H 5 C l ———> C 6 H 5 C 2 H 5 + HC l Mechanism GeneralA catalyst is used to increase the positive nature of the electrophile and make it better at attacking benzene rings. AlCl 3 acts as a Lewis Acid and helps break the C—Cl bond.

FRIEDEL-CRAFTS REACTIONS OF BENZENE - ACYLATION OverviewAcylation involves substituting an acyl (methanoyl, ethanoyl) group Reagents an acyl chloride (RCOX) and anhydrous aluminium chloride AlC l 3 Conditionsreflux 50°C; dry inert solvent (ether) ElectrophileRC + = O ( e.g. CH 3 C + O ) EquationC 6 H 6 + CH 3 COC l ———> C 6 H 5 COCH 3 + HC l Mechanism ProductA carbonyl compound (aldehyde or ketone)

EXTENDING A CARBON CHAIN Rationale MethodsHaloalkanes 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 ExampleAldehydes and ketones undergo nucleophilic addition with cyanide (nitrile) ions; CH 3 CHO + HCN ——> CH 3 CH(OH)CN ethanal2-hydroxypropanenitrile

CHIRAL SYNTHESIS Example Aldehydes and ketones undergo nucleophilic addition with cyanide ions CH 3 CHO + HCN ——> CH 3 CH(OH)CN ethanal2-hydroxypropanenitrile

CHIRAL SYNTHESIS Example Aldehydes and ketones undergo nucleophilic addition with cyanide ions CH 3 CHO + HCN ——> CH 3 CH(OH)CN ethanal2-hydroxypropanenitrile 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

CHIRAL SYNTHESIS Example Aldehydes and ketones undergo nucleophilic addition with cyanide ions CH 3 CHO + HCN ——> CH 3 CH(OH)CN ethanal2-hydroxypropanenitrile 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 CN¯ attacks from above

CHIRAL SYNTHESIS Example Aldehydes and ketones undergo nucleophilic addition with cyanide ions CH 3 CHO + HCN ——> CH 3 CH(OH)CN ethanal2-hydroxypropanenitrile 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 CN¯ attacks from below

CHIRAL SYNTHESIS ExampleCH 3 CHO + HCN ——> CH 3 CH(OH)CN ethanal2-hydroxypropanenitrile CN¯ attacks from above CN¯ attacks from below MIRROR IMAGES

CHIRAL SYNTHESIS ExampleCH 3 CHO + HCN ——> CH 3 CH(OH)CN ethanal2-hydroxypropanenitrile CN¯ attacks from above CN¯ attacks from below

CHIRAL SYNTHESIS ExampleCH 3 CHO + HCN ——> CH 3 CH(OH)CN ethanal2-hydroxypropanenitrileANIMATION

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 ProblemsThere are two possible mechanisms S N 2 This produces just one optical isomer with reversed optical activity Called S N 2 because two species are involved in the rate determining step.

NUCLEOPHILIC SUBSTITUTION ProblemsThere are two possible mechanisms S N 1 This produces a racemic mixture of two optical isomers Called S N 1 because one species is involved in the rate determining step.

NUCLEOPHILIC SUBSTITUTION ProblemsThere are two possible mechanisms S N 2 This produces just one optical isomer with reversed optical activity Called S N 2 because two species are involved in the rate determining step. S N 1 This produces a racemic mixture of two optical isomers Called S N 1 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

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