Baeyer villiger oxidation

oxidation of menthone and tetrahydro carvone by monoperoxysulfuric acid.

1. BAEYER - VILLIGER OXIDATION Presented By: Gandham Malasree M Pharmacy Regd no: 620209502002 Dept of Pharmaceutical Chemistry Victor Villiger Adolf Von Baeyer

2. Baeyer - villiger oxidation The Baeyer- Villiger oxidation, also known as the Baeyer- Villiger rearrangement, was first reported on December 17, 1899 by Adolf Baeyer and Victor Villiger in Chemische Berichte . They referred to the oxidation of menthone and tetrahydro carvone by monoperoxysulfuric acid. It is a popular synthetic tool for the conversion of cyclic ketones to lactones and acyclic ketones to esters; lactones are precursors to hydroxy acids and acyclic diols.

3. The Baeyer Villiger reaction owes its name to the pioneering work of Adolf Baeyer and Victor Villiger who reported, almost a century ago, the possibility of converting cyclic ketones into lactones with a peroxy acid as oxidant. The reactions studied by Baeyer and Villiger in 1899 were the oxidations of menthone and tetrahydrocarvone to the corresponding lactones. For this purpose these authors used the most powerful oxidant known at that time, monopersulfuric acid, the synthesis of which had been accomplished the year before by Caro by mixing together equivalent amounts of potassium persulfate, concentrated sulfuric acid, and water. K2S2O8 + H2SO4 + H2O 2 KHSO4 + H2SO5 HISTORY

4. General Reaction

5. REAGENTS Peracids or peroxy acids (99% used) Hydrogen peroxide ( H2O2) ( rarely used) Bis trimethyl silyl peroxide ( rarely used) SOLVENTS Solvents used is CH2Cl2

6. Examples Of Peracids

7. MECHANISM Protonation Nucleophillic attack of peracid on carbonyl carbon. Abstraction of proton or removal of proton. Generation of electron deficient oxygen. Migration of alkyl group or attack of alkyl group on electron deficient oxygen. Neutralisation of carbonyl carbon. Deprotonation

8. MIGRATORY APTITUDE Order of migratory groups 3∘ alkyl > cyclo hexyl > 2∘ alkyl > benzyl= phenyl > vinyl > 1∘ alkyl> methyl Examples:

9. MODIFICATIONS

10. Asymmetric Baeyer- Villiger oxidation There have been attempts to use  organometallic catalysts  to perform enantioselective Baeyer– Villiger oxidations.  The first reported instance of one such oxidation of a prochiral ketone used dioxygen as the oxidant with a copper catalyst.  Other catalysts, including platinum and aluminum compounds, followed

11. Limitations The use of  peroxyacids  and  peroxides  when performing the Baeyer– Villiger oxidation can cause the undesirable  oxidation  of other  functional groups .   Alkenes  and  amines  are a few of the groups that can be  oxidized .  For instance, alkenes in the substrate, particularly when electron-rich, may be oxidized to  epoxides .  However, methods have been developed that will allow for the tolerance of these functional groups. In 1962, G. B. Payne reported that the use of hydrogen peroxide in the presence of a  selenium  catalyst will produce the epoxide from alkenyl ketones, while use of peroxyacetic acid will form the ester

12. APPLICATIONS RCO3H RCO3H

13. 6) ZOAPATANOL

14. 7) STEROIDS

15. Synthesis of 3-hydroxyindole-2-carboxylates. Conversion of non-activated [ 18 F] fluorobenzaldehydes to [ 18 F]fluorophenols with high radiochemical yield. Synthesis of dibenzo-18-crown-6, dibenzo-21-crown-7, and dihydroxydibenzo-18-crown-6. One-pot   chemoenzymatic synthesis of g-butyrolactones. Metal-free synthesis of vinyl acetates. Silica-supported tricobalt tetraoxide (Co 3 O 4 /SiO 2 ) catalysts have been employed for the Baeyer– Villiger oxidation of cyclohexanone under Mukaiyama conditions Chemoenzymatic Baeyer– Villiger oxidation of cyclic ketones catalyzed by  Candida antarctica  lipase B or Novozyme-435 suspended in an ionic liquid has been studied. Kinetic resolution of racemic 2-substituted cyclopentanones has been achieved via highly regio - and enantioselective Baeyer– Villiger oxidation.

16. Baeyer- Villiger monooxygenases In nature,  enzymes  called Baeyer- Villiger monooxygenases (BVMOs) perform the oxidation analogously to the chemical reaction.  To facilitate this chemistry, BVMOs contain a  flavin adenine dinucleotide  (FAD)  cofactor .

17. In the  catalytic cycle  the cellular  redox  equivalent  NADPH  first reduces the cofactor, which allows it subsequently to react with  molecular oxygen . The resulting peroxyflavin is the catalytic entity oxygenating the  substrate , and theoretical studies suggest that the reaction proceeds through the same Criegee intermediate as observed in the chemical reaction. After the rearrangement step forming the  ester  product, a hydroxyflavin remains, which spontaneously  eliminates  water to form oxidized flavin, thereby closing the catalytic cycle. BVMOs are closely related to the  flavin-containing monooxygenases  (FMOs), enzymes that also occur in the human body, functioning within the frontline metabolic  detoxification  system of the  liver  along the  cytochrome P450 monooxygenases .  Human FMOs was in fact shown to be able to catalyse Baeyer- Villiger reactions, indicating that the reaction may occur in the human body as well. BVMOs have been widely studied due to their potential as  biocatalysts , that is, for an application in organic synthesis.

18. BVMOs in particular are interesting for application because they fulfil a range of criteria typically sought for in biocatalysis : besides their ability to catalyse a synthetically useful reaction, some natural  homologs  were found to have a very large substrate scope (i.e. their reactivity was not restricted to a single compound, as often assumed in enzyme catalysis) they can be easily produced on a large scale, and because the  three-dimensional structure  of many BVMOs has been determined,  enzyme engineering  could be applied to produce variants with improved  thermostability  and/or reactivity. Another advantage of using enzymes for the reaction is their frequently observed regio - and enantioselectivity, owed to the steric control of substrate orientation during catalysis within the enzyme’s  active site . STEREOCHEMISTRY It is stereoretentive because the migration does not change the sterechemsitry of the migrating group.