Unit 25: Organic Synthesis — Long Questions

Aliphatic FGI flow sheet (Fig. 25.3):
Alkene --HBr--> Halogenoalkane --NH3--> Amine
Halogenoalkane --KOH (alcoholic), heat--> Alkene (reverse, elimination)
Alcohol --PBr3 or SOCl2--> Halogenoalkane
Alcohol --K2Cr2O7/H2SO4 (controlled)--> Aldehyde --NaBH4--> Alcohol (reverse)
Aldehyde --K2Cr2O7/H2SO4 (excess)--> Carboxylic acid --LiAlH4--> Alcohol (reverse)
Carboxylic acid --SOCl2--> Acid chloride
Acid chloride --C2H5OH, H+--> Ester
Acid chloride --NH3--> Amide --LiAlH4--> Amine

Aromatic FGI flow sheet (Fig. 25.4):
Toluene --KMnO4/H2SO4--> Benzoic acid
Toluene --(i) Cl2, light; (ii) KOH(aq)--> Benzyl alcohol
Benzene --HNO3/H2SO4--> Nitrobenzene --Sn/HCl--> Aniline
Benzene --H2SO4 (fuming)--> Benzene sulphonic acid
Benzene --CH3COCl, AlCl3--> Acetophenone
Phenol --(i) NaOH (ii) CH3COCl--> Phenyl ester (acetylation)

The important reagents highlighted throughout are: HBr/PBr3/SOCl2 (introduce halogen), NH3 (introduce amine), KOH alcoholic (elimination to alkene)/aqueous (hydrolysis), K2Cr2O7-H2SO4 or KMnO4-H2SO4 (oxidation), NaBH4/LiAlH4 (reduction), and acid/AlCl3 catalysts (esterification/Friedel-Crafts).

Retrosynthesis is a systematic planning technique used to design the synthetic route of a target molecule, instead of relying on trial and error. Its importance includes:
1) Breaking down complexity: Complex-looking molecules (e.g. drugs) are disconnected step by step into simpler, readily/commercially available starting materials (e.g. aspirin and paracetamol are both reduced back to phenol).
2) Identifying synthons and synthetic equivalents: It reveals the ionic fragments (synthons) needed and the real, stable reagents (synthetic equivalents) that can be used to achieve the same bond formation.
3) Guiding use of FGI: It shows where a functional group must be temporarily changed into another (FGI) to make a disconnection/reaction feasible, e.g. converting -NH2 to -NO2 because nitro groups are easy to install by electrophilic substitution.
4) Choosing the best route: Since a target molecule may be made by several routes, retrosynthesis helps select the route with the fewest steps, cheapest and most available starting materials, and the highest overall yield.
5) Essential in pharmaceutical synthesis: Most valuable but structurally complex medicinal compounds can be traced back, through efficient retrosynthetic steps, to very simple starting materials, making seemingly difficult target molecules achievable in practice.

Halogenoalkanes act as versatile intermediates/synthetic equivalents that link several other functional groups during retrosynthetic planning. Since halogenoalkanes are themselves obtained from the very common and easily available alcohols (using PBr3 or SOCl2), they serve as a convenient 'hub': from a halogenoalkane one can, in the forward direction, reach an amine (by reaction with NH3), an alkene (by elimination with alcoholic KOH), an alcohol back again (by aqueous KOH hydrolysis), or a nitrile. In retrosynthesis, therefore, when a target molecule is disconnected to give a synthon equivalent to an alkyl group bonded to a leaving group, the halogenoalkane is usually chosen as its synthetic equivalent, because the C–X bond is reactive towards both nucleophilic substitution and elimination, giving the chemist flexibility in choosing the final functional group of the target molecule. This is illustrated by the two-step synthesis of a primary amine from an alcohol: alcohol → halogenoalkane (SOCl2) → amine (NH3), chosen over the direct one-step route because the alcohol starting material is more easily available than the halogenoalkane.

Retrosynthetic tree of aspirin (TM = acetylsalicylic acid):
Step I – Disconnection-I: Disconnect the C–O bond of the ester linkage to give synthon (A) [the acyl part, CH3CO+] and synthon (B) [the aryl-O– part bearing the -COOH group].
Step II – Synthetic equivalents: Synthon A ≡ acetic anhydride, (CH3CO)2O; synthon B ≡ salicylic acid (2-hydroxybenzoic acid).
Step III – Disconnection-II: Disconnect the C–C bond of the carboxylic (-COOH) group of salicylic acid to give synthon (A) [aryl anion bearing -OH] and synthon (B) [carboxyl cation, +COOH].
Step IV – Synthetic equivalents: Synthon A ≡ phenol; synthon B ≡ carbon dioxide (CO2).

Synthesis of aspirin (forward route):
1) Phenol + CO2 --(i) High temperature & pressure; (ii) H2SO4--> Salicylic acid (Kolbe's synthesis)
2) Salicylic acid + (CH3CO)2O --H3PO4, heat--> Aspirin (acetylsalicylic acid) + CH3COOH

Benzene is nitrated and the nitro group is then reduced to the amino group.
Step 1: C6H6 + HNO3 --H2SO4--> C6H5NO2 (nitrobenzene) + H2O
Step 2: C6H5NO2 --Sn + HCl--> C6H5NH2 (aniline)

Toluene is made by Friedel-Crafts alkylation of benzene with methyl chloride.
C6H6 + CH3Cl --anhyd. AlCl3--> C6H5CH3 (toluene) + HCl

Benzene is first alkylated to toluene, and the methyl side chain is then oxidized to -COOH.
Step 1: C6H6 + CH3Cl --anhyd. AlCl3--> C6H5CH3 (toluene) + HCl
Step 2: C6H5CH3 --KMnO4/H2SO4--> C6H5COOH (benzoic acid)

Benzene is alkylated to toluene, the methyl group is chlorinated at the side chain, and the resulting benzyl chloride is hydrolyzed.
Step 1: C6H6 + CH3Cl --anhyd. AlCl3--> C6H5CH3 (toluene) + HCl
Step 2: C6H5CH3 + Cl2 --light--> C6H5CH2Cl (benzyl chloride) + HCl
Step 3: C6H5CH2Cl + KOH(aq) --> C6H5CH2OH (benzyl alcohol) + KCl