Benzilic acid rearrangement

The benzilic acid rearrangement is the rearrangement reaction of benzil with potassium hydroxide to benzilic acid. First performed by Justus Liebig in 1838 [cite journal | author = Liebig, J.|title=Ueber Laurent's Theorie der organischen Verbindungen|journal = Annalen der Chemie |year = 1838|volume = 25| pages = 1–31|doi=10.1002/jlac.18380250102] this reaction type is displayed by 1,2-diketones in general. The reaction product is an α-hydroxy-carboxylic acid.

Certain acyloins also rearrange in this fashion.

This diketone reaction is related to other rearrangements: the corresponding keto-aldehyde (one alkyl group replaced by hydrogen) rearranges in a Cannizzaro reaction, the corresponding 1,2-diol reacts in a pinacol rearrangement.

Reaction mechanism

The reaction is a representative of 1,2-rearrangements. These rearrangements usually have migrating carbocations but this reaction is unusual because it involves a migrating carbanion. The long established reaction mechanism updated with in silico data [cite journal | title = A FMO-Controlled Reaction Path in the Benzil-Benzilic Acid Rearrangement | author = Shinichi Yamabe, Noriko Tsuchida, and Shoko Yamazaki | journal = J. Org. Chem. | year = 2006 | volume = 71 | issue = 5 | pages = 1777–1783 | doi = 10.1021/jo051862r] is outlined in "scheme 2".

A hydroxide anion attacks one of the ketone groups in 1 in a nucleophilic addition to the hydroxyl anion 2. The next step requires a bond rotation to conformer 3 which places the migrating group R in position for attack on the second carbonyl group in a concerted step with reversion of the hydroxyl group back to the carbonyl group. This sequence resembles a nucleophilic acyl substitution. Calculations show that when R is methyl the charge build-up on this group in the transition state can be as high as 0.22 and that the methyl group is positioned between the central carbon carbon at a separation of 209 pm.

The carboxylic acid in intermediate 4 is less basic than the hydroxyl anion and therefore proton transfer takes place to intermediate 5 which can be protonated in acidic workup to the final α-hydroxy-carboxylic acid 6. Calculations show that an accurate description of the reaction sequence is possible with the participation of 4 water molecules taking responsibility for the stabilization of charge buildup. They also provide a shuttle for the efficient transfer of one proton in the formation of intermediate 5.

From a molecular orbital point of view this rearrangement may at a first glance not obvious. Contrary to a carbocationic rearrangement as in the Wagner-Meerwein rearrangement in which the empty carbocationic orbital interacts positively and symmetry allowed with the filled pi orbital HOMO of the central C-C bond (situation A in "scheme 3"), a filled carbanionic orbital should not be able to escape a symmetry forbidden MO overlap with the LUMO which is the empty antibonding pi orbital having one node (situation B).

In reality a 1,2-diketone LUMO is a 4 electron system without any nodes in the central C-C bond and a symmetry allowed transition is possible (Situation C). In other words the transition states of both a carbocationic rearrangement and the benzilic rearrangement obey the Woodward-Hoffmann rules because the involves respectively 2 electrons and 6 electrons (n=0 and 1 in the 4n+2 Hückel's rule).

Variations

A variation of this reaction occurs in certain steroids. In the so-called D-Homo Rearrangement of Steroids a cyclopentane ring expands to a cyclohexane ring with added base ["Über Steroide und Sexualhormone. 48. Mitteilung. Die Überführung von 17-Äthinyl-androsten-Derivaten in Pregnenon-Derivate. Herstellung des 17-Oxy-progesterons" Helvetica Chimica Acta Volume 21, Issue 1, Date: 1938, Pages: 1760-1770 L. Ruzicka, H. F. Meldahl DOI|10.1002/hlca.193802101214] ["Über Steroide und Sexualhormone. (51. Mitteilung). Die Herstellung von Neo-pregnenolon aus 5-3, 17-Dioxypregnenon-(20)" Helvetica Chimica Acta Volume 22, Issue 1, Date: 1939, Pages: 421-424 L. Ruzicka, H. F. Meldahl DOI|10.1002/hlca.19390220155] .

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References

Further reading

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External links

* [http://www.intech.mnsu.edu/groh/WebLabs/BenzilicAcid/PDF/BenzilicAcidSynth.pdf Lab procedure I]
* [http://www.miracosta.edu/home/dlr/211exp10.htm Lab procedure II]
* [http://student.augie.edu/~kjbetsch/mcl5.htm Lab procedure III]