SLE214 - Arndt-Eistert Synthesis: Mechanism, Applications & Synthesis

The Arndt-Eistert Synthesis is a chemical reaction sequence used to homologate carboxylic acids, increasing the carbon chain length by one methylene group. It involves the acylation of diazomethane to form α-diazoketones, followed by the Wolff rearrangement to ketenes, typically under thermal, photochemical, or silver (I) catalysis. The reaction is conducted in the presence of nucleophiles like water, amines, or alcohols to trap the ketene intermediate and yield carboxylic acids, amides, or esters, respectively. Mild conditions are crucial to avoid interference with reducible or complex groups in the substrates, ensuring high yield. Applications include the synthesis of β-amino acids, mescaline, and homoveratroyl chloride, highlighting its significance in various chemical fields. Desklib provides solved assignments and past papers for students.

Arndt-Eistert Synthesis
Submitted XX/XX/20XX
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Arndt-Eistert Synthesis is a series of chemical reactions used in the formation of homologated
carboxylic acids. It has widely been applied in various fields including the synthesis of
β−amino acids, mescaline and homoveratroyl chloride.
Biographical Section
There were two German chemists: Fritz Arndt and Bernd Eistert
who were behind the Arndt-Eistert Synthesis. Fritz Arndt was
born on July 6 1985 in Hamburg but began his studies in
chemistry at the University of Geneva before proceeding to the
University of Bern. He was awarded his PhD from the University
of Freiburg. He began his academic career with a brief term work
at the University of Greifswald, University if Breslau and
University if Kiel (Carrié et al., 2018). He was appointed to serve
in the newly created position of Chair in Chemistry at the
University of Istanbul during which he managed to create close
contacts with the Turkish chemists. He got back to the University
of Breslau.
Bernd Eistert lived between November 1902 and May 1978. He
was born in Ohlau. Upon receiving is PhD in Breslau in 1927 in
recognition of his work with Fritz Arndt he served for the BASF
Company. He also served at the Technical University of
Darmstadt up to 1957 after which he shifted to the University of
Saarbrucken (Haugeberg et al., 2017).
Description of the Reaction
The Arndt-Eistert Synthesis defines a series of chemical reactions
that enable the formation of homologated carboxylic acids or
even their derivative by reacting the activated carboxylic acids
with diazomethane and the preceding Wolff-Rearrangement of the
very intermediate diazomethane (Fuse et al., 2017). The Arndt-
Eistert involves increasing the length of the carbon chain through
the addition of one methylene group in the carboxylic acids. This
takes place in the presence of nucleophiles including amines,
water and alcohols.
The initial step f of this single carbon homologation involves
acylation of the diazomethane carbon using acid chloride or
mixed anhydride to produce ∝−diazonketone. The surplus
diazomethane is destroyed through stirring or the addition of little
amount of acetic acid. Most of the ∝−diazonketone formed
in this process tend to be of high stability and hence isolatable
and purifiable through column chromatography (Carrié et al.,
2018).
The Wolff-Rearrangement of the diazoketones to ketenes is a
chief step of the Arndt-Eistert Homologation and may be
achieved through thermal heating over a range of room
temperature and pressure of 750⁰C (Haugeberg et al., 2017). It
can as well be achieved photochemical or by the use of silver (I)
catalysis. The reaction is normally carried out in the presence of
nucleophiles for example water (to produce carboxylic acids),
amines (to generate amides) or alcohols (to produces esters), to
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trap the ketene intermediate and avoid formation of diketenes in a
competing manner.
Mild conditions are needed for the reaction so as allow the
synthesis process without interfering with the reducible or
complex groups that are in the substrates (Smith et al., 2017).
This ensures a high yield and hence having numerous substrates
without interfering with the reducible to complex groups that are
found in the substrate.
Equipment required
 Column chromatography
 Water/ alcohol/amines
Current applications
3. It is used in the synthesis of mescaline
4. Used in the synthesis of homoveratroyl chloride that is used as
an intermediate for papaverine synthesis substrates (Smith et al.,
2017)
5. Diazoketones when treated with aqueous formic acid provides
hydroxyl ketones
6. Synthesis of β−amino acids. Peptides that are containing
β−amino acids have a characteristic lower metabolic
degradation rates and hence of special interest especially in the
pharmaceutical applications
Figure 1-3: Various Reaction Steps in Arndt-Eistert Synthesis
Conclusions
References
Carrié, D., Roisnel, T. and Simonneaux, G., 2018. Synthesis,
crystal structure, catalytic dimerization and SH insertion of new
porphyrin diazoketones. Journal of Molecular Structure, 1165,
pp.101-105
Fuse, S., Otake, Y. and Nakamura, H., 2017. Integrated Micro‐
Flow Synthesis Based on Photochemical Wolff
Rearrangement. European Journal of Organic
Chemistry, 2017(44), pp.6466-6473
Haugeberg, B.J., Phan, J.H., Liu, X., O'Connor, T.J. and Clift,
M.D., 2017. Homologation of α-aryl amino acids through
quinone-catalyzed decarboxylation/Mukaiyama–Mannich
addition. Chemical Communications, 53(21), pp.3062-3065
Smith, J.M., Qin, T., Merchant, R.R., Edwards, J.T., Malins,
L.R., Liu, Z., Che, G., Shen, Z., Shaw, S.A., Eastgate, M.D. and
Baran, P.S., 2017. Decarboxylative alkynylation. Angewandte
Chemie, 129(39), pp.12068-12072
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