Reduc&on of Organic Compounds

Transcription

1 Reduc&on of Organic Compounds METAL HYDRIDE REDUCING AGENTS Reduc&on of Aldehydes and Ketones to Alcohols Reduc&on of Acids, Esters to Alcohols Reduc&on of Esters, Amides, etc. to Aldehydes Reduc&on of Imines and Amides to Amines BORANE Hydrobora&on of alkenes and alkynes Carbonyl reduc&on HYDROGENATION Alkene hydrogena&on Alkyne hydrogena&on Carbonyl hydrogena&on DISSOLVING METAL REDUCTION Alkyne reduc&on Selec&ve reduc&on of alkenes in cyclohexenones Birch reduc&on LOW VALENT METAL REDUCTIONS Forma&on of Grignard reagents N O, N N bond reduc&on Clemmensen reduc&on and Wolff Kishner reduc&on NADPH AND RELATED REDUCING AGENTS

2 Reduc&on is a process in which a chemical species gains electron(s). In most (but not all) organic reduc&ons, two electrons are transferred. ONen, the products contain one addi&onal proton (from the reac&on workup) for each electron transferred.

3 METAL HYDRIDE REDUCING AGENTS The more OR or R groups on the metal, the lower the ac&vity

4 Reduc&on of Aldehydes and Ketones to Alcohols Sodium borohydride (NaBH 4 ), lithium aluminum hydride LAH (LiAlH 4 ) can reduce aldehydes and ketones to alcohols. NaBH 4 is preferred due to its easy handling and gentle reac&vity compared to the more reac&ve LiAlH 4.

5 Meerwein- Pondorf- Verley reduc&on using Al(Oi- Pr) 3 in isopropanol (IPA)

6 Chemoselec&vity in reduc&on of aldehydes, ketones and enones

7 Esters to alcohols: LiAlH 4, LiBH 4 Reduc&on of Acids, Esters to Alcohols Although the aldehyde is an intermediate in the reduc&on of esters to alcohols, it is impossible to isolate it (even when using a sub- stoichiometric amount of reducing agent), as the aldehyde is much more reac&ve than the star&ng ester and gets reduced immediately. Acids to alcohols: Less reac&ve metal hydrides as NaBH 4 cannot reduce carboxylic acids due to the forma&on of carboxylates between carboxylic acids and counter ions. In this case only the much stronger LiAlH 4 or borane can be used. LiBH4 : The Li+ ca&on is a stronger Lewis acid than the Na+ ca&on. Li+ coordina&on with the carbonyl group enhances the electrophilicity of the carbonyl carbon, thereby facilita&ng hydride transfer. Lithium borohydride is a more powerful reducing agent than sodium borohydride: it reduces esters to primary alcohols but is unreac&ve towards a m ides.

8 Hydride consup&on in LiAlH 4 Reduc&ons

9 Reduc&on of Esters, Amides, etc. to Aldehydes Diisobutylaluminum hydride DIBAL or DIBAL- H Unlike other metal hydrides, DIBAL acts as a Lewis acid that coordinates to Lewis base (O of C=O) before it is ac&vated and transfers hydride. Choice of solvent is crucial (usually hexane, toluene), as coordina&ng solvents like THF destabilize the tetrahedral intermediate and cause over- reduc&on.

10 Reduc&on of esters/carboxylic acids to aldehydes via Weinreb s amide forma&on The formed tetrahedral intermediate is stabilized by chela&ng the metal center of the hydride reducing agent. This prevents further reduc&on un&l the aqueous workup, in which excess reducing agent is decomposed, and the aldehyde is revealed.

11 Reduc&on of Imines and Amides to Amines - Imines to amines: The C=N double bonds react with nucleophile in a same way as C=O double bonds. Therefore, reducing reagents that can reduce aldehydes or ketones to alcohols can be used in reducing imines to amines such as LiAlH 4, NaBH 4, NaCNBH 3 in acidic condi&ons. - The advantage of NaCNBH 3 as a selec&ve reducing agent for imines is that it tolerates other carbonyl groups which would be also reduced by LiAlH 4 or NaBH 4. - Amides to amines: Again, LiAlH 4 is a good reagent for this transforma&on. Borane (BH 3 ) is also a good alterna&ve to LiAlH 4 for reducing amides in the presence of esters (BH 3 does not reduce esters)

12 BORANE Boron has three electrons in the valence shell, which form three conven&onal bonds with other atoms in a planar structure leaving a vacant 2p orbital. This orbital is able to accept a lone pair from a Lewis base or from a nucleophile. Borane exists as a mixture of dimer (B 2 H 6 ) and monomer (BH 3 ). Diborane, B2H6, is a gas and is difficult to handle. However, borane complexed with donors such as THF or dimethylsulfide are commercially available and have become valuable reagents for the reduc&on of various func&onal groups. BH3 SMe, is soluble in and unreac&ve toward a wide variety of apro&c solvents such as THF, Et2O, CH2Cl2,and hydrocarbons.

13 Hydrobora&on of alkenes and alkynes Hydrobora&on is regioselec)ve (an&- Markovnikov) and stereoselec)ve (syn- addi&on across the alkenes)

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15 Carbonyl reduc&on Unlike borohydrides, borane is not an ion. It behaves as a Lewis acid and reacts best with the most electrophilic carbonyl groups. Consequently, it reduces electron- rich carbonyl groups such as carboxylic acid and amide fastest. Electron- poor carbonyl groups such as acyl chlorides and esters will not be affected.

16 Selec&vity in BH3 THF Reduc&ons

17 HYDROGENATION Cataly&c hydrogena&on is chemoselec&ve for the C=C double bonds over C=O double bonds. Alkene hydrogena&on The mechanism of the hydrogena&on of C=C double bonds starts with the coordina&on of the double bonds on to the catalyst surface.

18 Alkyne hydrogena&on - Reduc&on of alkynes to Z- alkenes: Lindlar s catalyst (Pd, CaCO 3, Pb(OAc) 2 ) is a palladium catalyst (Pd/CaCO 3 ) poisoned by lead. The lead lowers the ac&vity of the catalyst. Consequently, it will hydrogenate alkynes to alkenes rather than alkenes to alkanes. - Reduc&on of alkynes to E- alkenes: Na in NH 3 (liquid) (discussed below)

19 Carbonyl hydrogena&on - Cataly&c asymmetric hydrogena&on (Noyori Nobel prize in Chemistry 2001)

20 Concept of asymmetric catalysis - Enan&omeric ra&o is directly propor&onal to the rela&ve rate of the enan&omeric products. - Enan&omeric ra&o is governed by differen&al ac&va&on parameters ( G, H and S ). - R and S are chosen below arbitrarily. Some useful number to think about in enan&oselec&ve catalysis: - G of 1.38 kcal/mol is needed to achieve 80% ee at room temp - G of ~2.0 kcal/mol is needed to achieve 90% ee at room temp - G of 2.60 kcal/mol is needed to achieve 98% ee at room temp - G of 2.73 kcal/mol is needed to achieve 99% ee at room temp - G of 1.80 kcal/mol is needed to achieve 98% ee at - 78 C

21 DISSOLVING METAL REDUCTION Alkyne reduc&on Stereoselec&ve trans product is favored

22 Selec&ve reduc&on of alkenes in cyclohexenones Similar to reduc&ons of alkynes, also stereoselec&ve Birch reduc&on

23 Changing the workup in a reduc&on of anisole can lead to cyclohexenones. Dependent on subs&tu&on of anisole, different substa&on pamerns obtained

24 Forma&on of Grignard reagents Very basic and strong nucleophile LOW VALENT METAL REDUCTIONS

25 N O, N N bond reduc&on Reduc&on of the N O bond onen proceeds to the free amine under strong acidic condi&ons This is not always the case and the reac&on can be stopped at an intermediate stage by using neutralcondi&on. Nitro compounds with α hydrogen can be reduced to the corresponding oximes in ace&c acid. Similarly N N bonds can be reduced.

26 Clemmensen reduc&on Does not tolerate acid sensi&ve func&onali&es A related reac&on to Clemmensen reduc&on is called the Wolff Kishner reduc&on

27 NADPH AND RELATED REDUCING AGENTS Similar to hydride reducing agents we have covered. Coupled with enzymes, have the added benefit of absolute stereoselec&vity NADH and NADPH

28 FAD Reduc&on of molecular oxygen reduc&on leads to forma&on of epoxides

29 Ascorbic acid as hydride donor Mild reducing reagent. Used biologically to protect against stray oxidants and reducing important intermediates (peroxides and Fe3+)

30 CO 2 reduc&on Biological CO 2 reduc&ons (CO 2 fixa&on) Conversion of CO 2 to small organic compounds is achieved in the Calvin cycle, an important step in photosynthesis. The enzyme RuBisCo (Ribulose- 1,5- bisphosphate carboxylase oxygenase) catalyzes the CO 2 fixa&on. Industrial/Cataly&c CO 2 fixa&on Synthesis of hydrobenzoic acid by Kolbe- Schmidt reac&on Similarly other carbon nucleophiles can be used