OC II (FS 2013) Lecture 1 Prof. Bode. Oxidation

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1 C (F 2013) Lecture 1 Prof. Bode 1 xidation state of carbon xidation xidation is a process in which a chemical species loses electron. eduction is a process in which a chemical species gains electron. 3 C 3 C 2 C C methane methanol formaldehyde formic acid C carbon dioxide ther functional groups with equivalent oxidation state alkene thiol X X = halide,, or alkyne ' ' acetal epoxide ' C amide nitrile ' ' ' orthoester C isocyanate C cyanate C carbodiimide C carbon disulfide 2 Functional group interconversion Key to organic synthesis is the interconversion of functional groups. xidation and reduction allow for the change up and down the oxidantion ladder. Part of organic chemistry is learning how to master the manipulation of oxidation state and knowing the appropriate reagent for the desired transformation. For example: oxidant A oxidant B oxidant C oxidant D 3 xidizing agents xidizing agents increases the oxidation state of the substrate but itself undergoes a reduction. The net process is called a redox reaction. There are many oxidants available in the tool box. ere we are categorizing them based on their mode of action (). ome class of oxidizing agents: [tal] "X-Y" organic oxidant PCC: Cr Mn 2 u 4 KMn 4 Cr 3 2 a 2 Br BX: DMD: DDQ: TEMP: 1

2 C (F 2013) Lecture 1 Prof. Bode 3.1 xidation of alcohol to carbonyl compounds TEMP oxidation (catalytic) a [] base chanism oxidation a oxidation base base wern oxidation and other variants wern oxidation: (C) 2 DM 3 C o C chanism: less acidic C 2 base - + more acidic base - C 2 + C base C 2 C 2 ene-like ther varients Moffatt oxidation: DCC DM cat. + DCC acitivation C 2

3 C (F 2013) Lecture 1 Prof. Bode Corey-Kim oxidation: C 2 C acitivation TPAP oxidation Pr 4 u 4 (TPAP, 5 mol%) C 2 2, 4Å M (M, 1.5 eq.) chanism u u u u catalyst reoxidation u u 2 ther metal oxides oxidation (i.e. Cr or Mn) have similar. A special feature of Mn 2 oxidation is a mild and selective oxidation of unsaturated system. 20 equiv. Mn 2 C 2 2 room temp Dess-Martin and BX oxidation BX: Dess-Martin (DMP): Ac Ac Ac Bn DMP Bn 3

4 C (F 2013) Lecture 1 Prof. Bode chanism: Ac Ac Ac Ac Ac Ac AC 3.2 xidation of aldehyde (or equivalent) to carboxylic acid derivative Pinnick oxidation also sometime known as Lindgren oxidation a 2 a 2 P 4 tbu/ 2 or 2--Butene (as scavenger) chanism P xidation by -heterocyclic carbene (C) + Bn (5 mol %) 1.0 equiv [] 3 (7.5 mol %) Common oxidant: Bn + tbu Mn 2 tbu Bn + transfer [] ET? Bn Bn Breslow intermediate activated carboxylate tbu tbu xidative amidation This reaction is mechanistically similar to other metal oxides with the u cat performing two oxidations: first on the alcohol to aldehyde and second on the hemiaminal to the amide. t is a nice example of catalytic amidation reaction a problem with few satisfactory results (ee Milstein cience 2007, 317, 790). 1 P tbu u tbu C mol% 1 reflux-tol C 6 13 Bn 96% C % 99% 4

5 C (F 2013) Lecture 1 Prof. Bode chanism P tbu u tbu C 1 P tbu u tbu C 1-2 P tbu P tbu u tbu u tbu 2 2 C C hemiaminal Formal oxidation of aldehyde to nitrile This is technically an elimination reaction with the net outcome of oxidation of C= to CΞ bond 2 elimination oxime nitrile 3.3 C- oxidation adical halogenation : 2 hv Dehydrogenation: alkane to alkene Pt Δ Allylic C- oxidation β-pinene e 2, 2 2 tbu, o C trans-pinocarveol artshorn and Masamune rg. ynth., 1988, 6, 946. chanism e e e hydrolysis ' ' ' ' Benzylic C- oxidation Many strong oxidants such as KMn 4, BX or 2 2 may be used for benzylic oxidation KMn 4 / Mn 2 haabania Tetrahedron, 2004, 60, DM icolaou JAC 2002, 124,

6 C (F 2013) Lecture 1 Prof. Bode 3.4 Alkene oxidation Epoxidation by mcpba - This reaction is stereospecific m-cpba 24 h dr > 9:1 tereochemistry: Preferred reactive conformation 120 m-cpba A 1,3 -strain minimized dr = 95: Dihydroxylation - This reaction is also stereospecific 1 mol% s 4 M, 2 s s s s 2-2 M MM Wacker oxidation - This reaction generally follows Markovnikov selectivity 10% Pd(Ac) 2 Cu 2, 2 PdX 2 Cu Pd 0 X β-hydride elim. then tautomerization PdX 2 2 Markovnikov PdX PdX zonolysis 6

7 C (F 2013) Lecture 1 Prof. Bode 1) 3 C 2 2 2) P 3 or 2 primary ozonide = reduced secondary ozonide 3.5 Baeyer-Villiger oxidation This reaction is stereoretentive mcpba steps Taxol L L larger than L L migrates faster than L 4 eteroatom oxidation 4.1 Borane oxidation (in hydroboration sequence) MM 9-BB MM 2 2 MM Boc B 2 Boc a Boc B 2 B 2 B 2 B 2 + B() Fleming-Tamao oxidation i 1) BF 3 -Ac 2) 2 2, ac 3 i E-X X i i i base 5 ther functional groups and their oxidation state 7

8 C (F 2013) Lecture 1 Prof. Bode rganosulfur reagent thiol disulfide sulfoxide sulfone rganophosphorus reagent P phosphine P phosphonic acid P phosphate itro compound amine hydroxylamine nitroso nitrite nitro alogen hypochlorite chlorite chlorate perchlorate 6 xidation used in industrial setting xidation is commonly done in and industrial setting. Many of these processes have been performed in large scale. Examples include oxidation of p-xylene to terephthalic acid (44x 10 6 tons per year), oxidation of cyclohexane to cyclohexanol and cyclohexanone (6 x 10 6 tons per year), and the synthesis of ethylbenzene hydroperoxide (6 x 10 6 tons per year). A few examples are shown here: or 3 Cu( 3 ) 2 adipic acid air 44x 10 6 tons per year terephthalic acid BAF's methacrylic acid process: C C 2 aldol C 2 C Cavani ChemusChem 2009, 2, Biological oxidation 8

9 C (F 2013) Lecture 1 Prof. Bode imilar to organic chemists, biology utilizes many oxidation strategies (radical peroxide, metal oxide, etc) for synthesis of important metabolites and for regulation processes. 7.1 Cytochrome P-450 Cytochrome P-450 is a family of enzymes that catalyzes the oxidation of many metabolic intermediates: et reaction: ADP ADP + cytochrome P-450 oxidase progesterone deoxy-corticosterone chanism 2 eme Fe 3+ Cys 2 eme Fe 3+ Cys + 2e eme Fe Cys 2 eme Fe 3+ Cys 7.2 xidation of phenylalanine to tyrosine 2 2 biopterin C phenylalanine hydroxylase 2 C chanism 2 biopterin C -Enz 2 C 2 Enz-Base 2 2 C C C 7.3 ow does biology stores energy? Trapping energy released from oxidation in the form of ATP P glyceraldehyde- 3-phosphate P 4 2 oxidative phosphorylation AD AD P P dephosphorylation ADP ATP P 9