reaction, mechanism and synthetic application

1. Arndt-Eistert homologation
Presented to:
Dr. Uzma Rasheed
Presented by:
Muhammad Samiullah Shah
Roll# 980
Department:
chemistry
Class:
M.Sc (4th)
1

2. Definition:
The conversion of carboxylic acid to homolog (one CH2 group
longer) in three stages is called Arndt-Eistert synthesis or
homologation.
This homologation is best preparative method for chain elongation
of carboxylic acid.
2

3. 1st stage:
The acid is converted into corresponding acid
chloride.
R OH
O
S
O
ClCl
R Cl
O
3

4. 2nd stage:
It involves the formation of an α-
diazomethyl ketone, following by wolf rearrangement
R Cl
O
R
O
N
N
CH2N2
α-diazo methyl ketone
4

5. 3rd stage:
It conducted either in the presence of solid silver
oxide/water or silver benzoate/ triethyl amine solution
and give homologated carboxylic acid.
R
O
N
N
Ag2O/H2O
OH
O
R
5

6. Reaction conditions:
If reaction conducted in the presence of alcohol or amine, the
corresponding ester or amide is formed.
Other metals also catalyze the decomposition of diazomethyl
ketone.
6

7. The alternate method is to heat or photolysis the diazoalkyle ketone in
the presence of Nucleophilic solvent e.g. H2O, ROH, RNH2
In these cases no catalyst is required.
7

8. Mechanism:
• since HCl is the by-product of the reaction between the acid
chloride and diazomethane, 2 equivalents of diazomethane are
needed so that the presence of HCl does not give side products
(e.g. chloroketone).
• the HCl reacts with the 2nd equivalent of diazomethane to form
methyl chloride and nitrogen.
8

9. the role of catalyst is not well understood.
Diazoketone can exist in two conformations, namely the s-(E) and
s-(Z) conformations, which arise from the rotation about the C-C
single bond.
It has been shown that the wolf rearrangement takes place
preferentially from s-(Z) conformation.
9

10. With loss of a molecule of nitrogen, the decomposition of the
diazoketone involves the formation of a carbene, followed by a carbene
rearrangement with the intermediacy of an oxirene.
Carbene undergoes a rapid [1,2] shift to afford a ketene that reacts
with the Nucleophilic solvent to give the homologated acid derivative.
10

11. Mechanism:
R OH
O S
O
Cl
Cl
-Cl
R
O
O
S
Cl
O
H
Cl
R
O
O
S
Cl
O
-HCl
Cl
R
O
O
Cl
S
Cl
O
11

12. R
O
O
Cl
S
Cl
O
-Cl
R
O
Cl
N
N
H2C
R Cl
O
N H
H
N
S OO
12

13. R Cl
O
N H
H
N
-Cl
R
O
N
N
H
H
Cl
R
O
H
N
N
-HCl
13

14. R
O
H
N
N
R
O
N
H
N
R
O
N
H
N
The resonance structures of diazomethyl ketone,
the s-(Z) conformation
14

15. R
O
N
H
N
Ag2O
wolf rearrangement R C
H
O
carbene
O
H
R
oxirene
R
O
Hcarbene
Carbene rearrangement with the intermediacy oxirene
15

16. R
O
Hcarbene
1,2
C
O
C
ketene
NuH
HR
R
O
Nu
H
H
homologated
derivative
Carbene converted into homologated derivative with the intermediacy
of ketene
NuH= H2O, ROH, RNH2
16

17. Examples:
Cl
O
H2C
N
N
(i)
(ii)
H3C
OH
O
O
(1)
(2)
O
O
Cl H2C
N
N
(i)
(ii)
H3C OH O
O
O
17

18. 3. α- Naphthoic acid to α- naphthyl acetic acid
(ii)
O O
S
O
Cl Cl
O Cl
O Cl
H2C
N
N
(i)
Ag2O / Na2S2O3
O
O
H
H
18

19. Synthetic application
1. The oligomers of β-amino acids as opposed to α-peptides, show a
remarkable ability to fold into well-defined secondary stryctures in
solution as well as in the solid state. The β-amino acid building
blocks were synthesized from α-amino acids using the Arndt- Eistert
homologation reaction in the laboratory of D.Seebach.
19

20. O
Cl O
N
O
O
O
O
R
HN
Boc
O
O
R
HN
Boc
H
O
O
O
O
R
HN
Boc
CH2N2
Et2O
O
H
N
N
R
HN
Boc
α-aminoacid
20

21. O
H
N
N
R
HN
Boc
CF3COOAg (cat.)
ET3N, THF, ROH
O
R
HN
Boc
O
R
H
H
Β-amino acid
21

22. 2. C.P molecules are also synthesized by
using Arndt-Eistert mechanism.
In this case, a sterically hindered carboxylic
acid is formed, which was advanced
intermediate. Due to this reason, diazoketone
was prepared by acyl mesylate rather than
acid chloride.
It is further dissolved in DMF and heated to
120oC in the presence of excess Ag2O for one
minute to generate the homologated acid.
22

23. O
O
O O
O
OH
O
OHH
H
C8H15
HO
H O
C5H9
CP molecule-225,917 formed by Arndt-Eistert homologation
23

24. (R)-(-)-homocitric acid-γ-lactone in multigram
quantities starting from citric acid by using Arndt-
Eistert homologation.
O
O
O
O
O
O
H
H
HH
(R)-(-)-homocitric acid-γ-lactone
2.
24

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