Ankur organic presentation

Arndt Eistert homologation

1. Arndt Eistert Homologation Submitted by: Ankur Submitted to : Mrs Priyanka

2. ARNDT EISTERT HOMOLOGATION □ General Information □ Historical Perspective □ Mechanistic Details □ Important Points □ Applications & Synthetic Utility □ Variations □ References

3. # General Information :- The conversion of carboxylic acid to its homologous ( one CH 2 group longer ) in three stages via α – Diazo Methylketone is known as Arndt Eistert Homologation . Its is best preparative method for the chain elongation of carboxylic acids.

4. # Historical Perspective :- Ludwig Wolff made the discovery that diazo ketone can be converted into derivative of an acid in 1915 . For e.g. :- the treatment of ω - diazophenone ( PhCOCHN 2 ) with ethanolic solution and a silver catalyst give phenylacetamide ( PhCH 2 CONH 2 ) . Following Staudinger’s seminal work on ketene , a revised mechanism was publish by Wolff . In 1935 , Arndt- Eistert publish their seminal paper on the homologation of carboxylic acids . The first review on the homologation appeared a mere 7 year later and included 76 examples of its use . The Arndt- Eistert homologation is now best preparative method for the chain elongation of carboxylic acid derivatives , having proved itself as a flexible and scalable synthetic method .

5. Exposure of carboxylic acids to thionyl chloride ( or analogous reagent ) produces acid chloride and also produce sulfur dioxide and hydrochloric acid . Displacement of the chloride moiety by diazomethane furnishes diazo ketone . Since HCl is a by product of this reaction , two equivalents of diazomethane must be used to prevent side products ( Chloroketones ) . The HCl reacts with second equivalent of diazomethane to form methyl chloride and nitrogen . Newmann and Beal reported a modification whereby triethylamine is added to capture one the released HCl . In these processes one equivalent of diazomethane is sufficient. Classically , a silver catalyst was employed to mediate the Wolff rearrangement , although the role is catalyst to decrease the activation energy . Loss of nitrogen from diazoketone gives a carbene which can interconvert to ketene which further reacts readily with nucleophiles to give homologated acid derivatives . # Mechanism of Arndt Eistert Homolagation :-

6. R = alkyl , aryl , hetrocyclic , alicyclic .

7. # Important Points :- □ The key step of this reaction is wolf rearrangement of the diazo ketone to ketene . □ The used of Ag 2 O is just to lowering the activation energy. We can used colloidal Pt , Ag , Au etc . □ We have take excess amount of diazomethane . It consume liberated HCl .

8. □ The isotope labelling experiment has shown that the carbonyl carbon of diazoketone is present in the resulting acid as the carboxyl carbon . □ The R group migrates with retention of configuration . , □ If we not used excess diazomethane , diazoketone is loss in reacting with HCl to form chloromethyl ketone as follow

9. □ If we use alcohal , ammonia , amine in place of water then ester , amide , subsituted amide respectively formed . The reaction as follows □ In the absence of the catalyst , the carbene act as carbocation and combine with nucleophlie like H 2 O to hydroxy ketone .

10. # Application & Synthetic Utility :- 1. Synthesis of Homoveratroyl chloride , an intermediate for Papeverine synthesis . Papeverine is vasodilator drug that relaxes blood muscle in our blood vessel . This lower blood pressure and allows blood vessel to flow more easily in our blood vessel .

11. Double bond present in the substrate reamain unaffected . The reason behind this is that diazomethane is a methylating agent and act as a sources of CH 2 group . We can use this reaction in case of hetro cyclic compound .

12. 5. Synthesis of Mescaline :- By use of this reaction , we can prepare the Mescaline . Mescaline produces Euphoria . Euphoria has various medical usage like treatment of alcohalism and depression and also a side effect that is a neurological disorder which cause intense felling of happiness .

13. 6. Natural Product Synthesis :- The oligomers of β -amino acids shown remarkable properties to fold into well defined secondary properties in solution as well as in the solid state . The β -amino acids building block were synthesized from α -amino acids using Arndt Eistert homologation in the laboratory of D. Seebach . Where Boc = ( tert-butoxycarbonyl protecting group)

14. # Variation in Arndt Eistert homologation :- Only slight modification have been reported . Classically , two equivalents diazomethane are required due to production of HCl upon reaction of diazomethane with acid chloride . Newmann and Beal reported modification whereby triethylamine is added to capture the released HCl and therefore only one equivalent of diazomethane is required . The reaction given below explain the above behaviour . □ Another variation in the Arndt Eistert homologation an in the activation of the carboxylic acid . While thionyl chloride is classically used , other reagent that mediate the conversion of a carboxylic acid to acid chloride are suitable . The reagents are oxalyl chloride ( ClCOCOCl ) , PCl 5 , PCl 3 , Cyanuric chloride (C 3 N 3 Cl 3 ) etc.

15. □ Another variation in this reaction are alternative of diazomethane . Diazomethane is a toxic and violent exposure , so its alternative procedure being developed . Like the usage of Ynolates ( Kowalski Ester Homolagation ) or use of Diazo ( trimethylsilylmethane ) . □ It is a organosilicon compound that is also a methylating agent for carboxylic acids and work as alternative of diazomethane and less explosive as compared to dizomethane .

16. □ Kowaski Ester Homologation is chemical reaction for the homologation of ester . This reaction was designed as safer alternatives to the Arndt Eistert Homologation avioding the need for diazomethane .

17. # Reference :- 1. ^ Sanyal , S.N. (2003). Reactions Rearrangements and Reagents ( 4 ed.) . pp. 86 , 87 . ISBN: 978-81-7709-605-7 . 2. ^ Jie Jack Lie (2009). Name Reactions for Homologation – Part 1 ( 1 ed.) . pp. 336, 337,338. ISBN: 978-0-470-08507-3(pt. 1 : cloth) . 3. ^ https://en.wikipedia.org/wiki/Kowalski_ester_homologation 4.^ https://en.wikipedia.org/wiki/Trimethylsilyldiazomethane

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