Reduction reactions in Organic Chemistry, Mechanism and reagents.

1. REDUCTION REACTIONS
(PAPER III- ORGANIC)
-Jaiswal Priyanka Balister
MSc- I

2. CONTENTS
1. Introduction
2. General mechanism
3. Metal hydride reduction
 Boron reagents
 Aluminium reagents
 Diimide reduction
4. 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
1. Catalytic hyrdogenation (H2 with metals)
2. Hydride transfer reactions, using hydride sources
such as LiAlH4, NaBH4,etc.
3. Dissolving metal reductions (Na, Li in ammonia
solution) (Birch reduction)
4. Replacement of oxygen by hydrogen
5. Removing oxygen from the substrate
6. Reduction with cleavage
7. 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 - NaBH4
• Sodium Cyanoborohydride - NaCNBH3
• Sodium Triacetoxyborohydride - Na(OAc)3BH
• Lithium Borohydride - LiBH4
• Potassium Borohydride - KBH4
• Tetramethylammonium Borohydride

6. SODIUM BOROHYDRIDE - NABH4
 Sodium borohydride was first prepared by reaction of sodium hydride
(NaH) with trimethylborate, B(OMe)3.
 NaBH4 is less reactive than LiAlH4.
 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 1O & ketone to a 2O alcohol respectively.
 Selective (chemoselectivity) reagent

7. NABH4 - MECHANISM
Selectivity:

8. SODIUM BOROHYDRIDE - NABH4
 Aqueous and alcohol solvents are preferred due to the excellent
solubility of NaBH4.
 NaBH4 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 NaBH4 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 - NACNBH3
 Reaction of NaBH4 with HCN gives sodium cyanoborohydride (NaBH3CN).
 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, H2O, 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 NaBH4. Used predominantly in reductive aminations
(Borsch Reduction).
 Electron withdrawing cyano group decreases the ease of hydrogen transfer.
 NaBH3CN reduced iminium ions much more quickly than ketone or
aldehyde.

10. NACNBH3
 Uses:
Reduction of oximes:

11. NACNBH3
α,β-Unsaturated ketones:
Epoxide openings:
Drawback:
Sometimes strong acids can release HCN from NaCNBH3

12. SODIUM TRIACETOXYBOROHYDRIDE - NA(OAC)3BH
 The preparation of triacetoxyborohydride was first performed by Wartik
and Pearson through the reaction of NaBH4 and CO2 .
 It can be also generated in situ from NaBH4 and acetic acid.
 It is a milder and more selective reducing agent than NaBH4. 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)3AlH]
 Diisobutylaluminum hydride ([(CH3)2CHCH2]2AlH, 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
 LiAlH4 is a stronger reducing agent than NaBH4 due to weaker Al-H bond
 LiAlH4 is used to reduce compounds that are nonreactive toward NaBH4
 Mechanism:

15. LIALH4

16. DIISOBUTYLALUMINUM HYDRIDE
([(CH3)2CHCH2]2ALH, 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)3ALH]

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