Reduction reactions

Reduction reactions in Organic Chemistry, Mechanism and reagents.

1. Reduction reactions (paper iii- organic) -Jaiswal Priyanka Balister MSc- I

2. Contents Introduction General mechanism Metal hydride reduction Boron reagents Aluminium reagents Diimide reduction Bibliography

3. Introduction Reduction can be defined as conversion of an atom in a higher oxidation stage to a lower one (III → II, IV → II or II → I), as in the transformation RCH=NH → RCH2NH2 A reduction reaction proceeds with a decrease in oxidation state and a gain of electrons . Reduction potential can be used to assess the ability of a reagent to reduce molecules. Example:

4. Classification of reduction reactions Catalytic hyrdogenation (H 2 with metals) Hydride transfer reactions, using hydride sources such as LiAlH 4 , NaBH 4 ,etc. Dissolving metal reductions (Na, Li in ammonia solution) (Birch reduction) Replacement of oxygen by hydrogen Removing oxygen from the substrate Reduction with cleavage Reductive coupling

5. Metal hydride reduction: Metal hydride reductions are probably the most widely used, followed by catalytic hydrogenation. BORON REAGENTS Boron Based Reagents Sodium Borohydride - NaBH 4 Sodium Cyanoborohydride - NaCNBH 3 Sodium Triacetoxyborohydride - Na(OAc) 3 BH Lithium Borohydride  - LiBH 4 Potassium Borohydride - KBH 4 Tetramethylammonium Borohydride

6. Sodium Borohydride - NaBH 4 Sodium borohydride was first prepared by reaction of sodium hydride (NaH) with trimethylborate, B(OMe) 3 . NaBH 4  is less reactive than LiAlH 4. It is only powerful enough to reduce aldehydes, ketones and acid chlorides to alcohols. Esters, amides, acids and nitriles are largely untouched. An aldehyde is reduced to 1 o & ketone to a 2 o alcohol respectively. Selective (chemoselectivity) reagent

7. NaBH 4 - Mechanism Selectivity:

8. Sodium Borohydride - NaBH 4 Aqueous and alcohol solvents are preferred due to the excellent solubility of NaBH 4 . NaBH 4 reacts with water to form hydroxyborohydride intermediates, but these are also mild reducing agents. It is relatively insoluble in ether solvents , so these are rarely used for borohydride reductions. In most cases aqueous ammonium chloride, aqueous acetic acid, or dilute mineral acids are used for hydrolysis . An important use of NaBH 4 is reduction of enamines, imines or iminium salts, which is particularly useful in alkaloid and amino acid syntheses. In a synthesis of (+)-majvinine,134 Cook and co-workers converted the amine unit in 99 to the imine (100) by reaction with benzaldehyde. Subsequent reduction with NaBH4 gave a 92% overall yield of the N-benzylamine, 101.

9. Sodium Cyanoborohydride - NaCNBH 3 Reaction of NaBH 4 with HCN gives sodium cyanoborohydride (NaBH 3 CN). A remarkably stable reagent that it is very selective, and does not decompose in acid solution (the pH should be less acidic than pH 3). It is soluble in THF, MeOH, H 2 O, HMPA, DMF and sulfolane and they do not react. Ketones and aldehydes are reduced in acidic media but not at neutral pH. At pH 3-4, It reduces aldehydes & ketones At pH 6-8, It reduces iminium ions Less reactive than NaBH 4 . Used predominantly in reductive aminations (Borsch Reduction). Electron withdrawing cyano group decreases the ease of hydrogen transfer. NaBH 3 CN reduced iminium ions much more quickly than ketone or aldehyde.

10. NaCNBH 3 Uses: Reduction of oximes:

11. NaCNBH 3 α,β- Unsaturated ketones: Epoxide openings: Drawback: Sometimes strong acids can release HCN from NaCNBH 3

12. Sodium Triacetoxyborohydride - Na(OAc) 3 BH The preparation of triacetoxyborohydride was first performed by Wartik and Pearson through the reaction of NaBH 4  and CO 2  . It can be also generated in situ from NaBH 4  and acetic acid. It is a milder and more selective reducing agent than NaBH 4 . The mild nature may be attributed both to the bulky nature of the reagent and to the inductive electron-withdrawing ability of the three acetoxy groups which stabilize the B-H bond. It is effective in reductive amination of aldehydes and ketones, it can reduce N-heterocycles (indoles, quinolines, and isoquinolines), imines, enamines, oximes, amides, aryl ketones, acetals, and other substrates.

13. Aluminum-based reagents Lithium aluminum hydride (LiAlH4) Lithium tri-tert-butoxyaluminumhydride [Li(OtBu) 3 AlH] Diisobutylaluminum hydride ([(CH 3 ) 2 CHCH 2 ] 2 AlH, Dibal or Dibal-H) Sodium bis(2-methoxyethoxy)aluminium hydride (Red-Al) L and K selectrides

14. Lithium aluminum hydride (LiAlH4) Very powerful reducing reagent Available as either powder or pallet Used as a suspension in ether or THF Reacts violently with water, alcohol Reduces carbonyl, carboxylic acid & ester Reduces nitrile, amide & aryl nitro group to amine Reduces acetylene to olefin Reduces C-X bond, opens epoxide LiAlH 4 is a stronger reducing agent than NaBH 4 due to weaker Al-H bond LiAlH 4 is used to reduce compounds that are nonreactive toward NaBH 4 Mechanism:

15. LiAlH4

16. Diisobutylaluminum hydride ([(CH 3 ) 2 CHCH 2 ] 2 AlH, Dibal or Dibal-H) Prepared by refluxing triisobutylaluminum in the solvent heptane. Highly pyrophoric Dibal-H is a strong reducing reagent, reducing most functional . Selective reagent (alkyne to alkene, ester or ketone to aldehyde). Specialist reductant of nitrile to aldehyde

17. Dibal-H Under carefully controlled conditions, will partially reduce an ester to an aldehyde. Direct conversion of acids to aldehydes: Acid chloride to aldehyde using Weinreb’s amide:

18. Lithium tri-tert-butoxy aluminumhydride [Li(OtBu) 3 AlH]

19. Sodium bis(2-methoxyethoxy) aluminum hydride (Red-Al)

20. The Selectrides Very reactive hydride donors due to inductive effect Bulk makes them very good at diastereoselective reactions (substrate control)

21. Reduction with Diimide Diimide (NH=NH) is a transient species generated by reaction of acids with potassium azodicarboxylate by thermolysis of anthracene-9,10-diimine. Diimide gives primarily cis reduction of alkenes Reduces symmetrical π bonds faster than polarized π bonds.

22. Bibliography Advanced Organic Chemistry: Part B: Reaction and Synthesis, By Francis A. Carey, Richard J. Sundberg Reaction Mechanisms in Organic Chemistry , Dr. Mukul C Ray Organic Synthesis ,   By Michael Smith Advanced Organic Chemistry, 4th Edition , Jerry March, Wiley India A Guidebook to Mechanism In Organic Chemistry, 6 th ed. By   Peter Sykes . Reaction Mechanism in Organic Chemistry,   By S. M. Mukherji, S. P. Singh Organic Reaction Mechanism, 3rd Edition, V.K. Ahluwalia and R.K. Parashar, Narosa Publishers Organic Chemistry: Vol 2, 5th Edition , I.L. Finar, Pearson Education