Retrosynthesis: Principles and Analysis of Phenacetin in Organic Chemistry

Retrosynthesis Theory

Retrosynthesis / Retrosynthetic Analysis E.J. Corey, b. 1928 American Chemist Nobel Prize for Retrosynthetic Analysis 1990

1. Work backwards, from the target molecule, to progressively simpler molecules.
2. Use a 'special' arrow symbol to show that we are 'working backwards'.
3. Simplify as much as possible until we arrive at recognisable building blocks. This is called 'a disconnection'.

https://en.wikipedia.org/wiki/Elias_James_Corey#/media/File:E.J.Coreyx240.jpg

Retrosynthesis Examples

Wittig Reaction Example 1

Wittig Reaction O H2C 3 I H I H Me + CH CH,-P Ph2 Br + Me H Starting materials Target molecule CH3CH2-Br + PPh3 Disconnection line(s)

Wittig Reaction Example 2

H Et Et Target molecule + O Et Et Wittig Reaction H -H p+ Ph3 Br H H L Br + PPh3 Starting materials Disconnection line(s)

Compound Retrosynthesis Question

Q: Complete the retrosynthesis of the following compound: HO 2 Et OH Et-OMgBr 1 Et-MgBr + O Et-Br + Mg

Retrosynthesis of Phenacetin

Phenacetin Overview

Phenacetin is an analgesic (carcinogenic, withdrawn 1983).

First Step in Retrosynthesis of Phenacetin

First Step in retrosynthesis is to: identify the functional groups. Ether + amide

Second Step in Retrosynthesis of Phenacetin

Second step is to: identify how these are synthesised.

Phenacetin Synthesis Pathway

O O O + Cl N CH3 NH2 H I + - Na lo + Na + NH2 NH2 H2 with Pd/C catalyst (reduction) HO EAS Nitration (& separation of isomers) HO NO 2 O H3C HO Cl I

Phenacetin 1st Chemical Step: Acetylation

1st chemical step: Acetylation 8- O O Cl H 8+ 8- + N CH3 Cl H O .. N CH3 + + N CH 3 H + HCl O H H CH3 NH2 –

Retrosynthesis of Benzocaine

Benzocaine Overview

Benzocaine is a local anaesthetic O O HON 2

Benzocaine Functional Groups

What functional groups are present? Ester + amine NPN 0022 1561 HURRY CAINE Topical Anesthetic Spray Pulvérisation anesthésique topique Benzocaine Topical Aerosol 20% w/w For Oral Mucosal Application Aérosol pique à la benzocaïne 20% p/p À appliquer sur le muqueuses buccales. Original Wild Cherry Gout original cerise douce CAUTION/AT ENTION CONTAINER MAY EXPLODE IF HEATED. LE RÉCIPIENT PEUT EXPLOSER S'IL EST CHAUFFE tel: (005) 676-4400 1; (900) 876-5044 Net Weight Poids Net 59,7 g (2 oz) DOT20 MY M5655 https://commons.wikimedia.org/wiki/File:Benzocainespray.JPG

Benzocaine Synthesis Pathway

O EtOH/H+ I O I HON 2 O OH H2N Pd/C/H 2 O KMNO4 CH3 OH ON O2N CH3 HNO3 / c.H2SO4

Retrosynthesis of Paracetamol

Paracetamol Overview

HO O N CH. 3 H Paracetamol (UK) Acetaminophen (US) Note structural similarity to phenacetin

Paracetamol Functional Groups

Q: Always start with "What functional groups are present?" Amide + alcohol/hydroxyl (phenol) https://commons.wikimedia.org/wiki/File:Paracetamol_acetaminophen_500_mg_pills.jpg

Paracetamol Synthesis Pathway

HO O N CH3 H HO O + H3C Cl NH2 Pd/C/H 2 HO HNO3 / c.H2SO4 HO I NO2