Carbonyl reduction

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Synthesis of an alcohol by ester reduction.

Carbonyl reduction in organic chemistry is the organic reduction of any carbonyl group containing compound by a reducing agent.

Typical carbonyl compounds are ketones, aldehydes, carboxylic acids and esters. A carbonyl group can be reduced to the alcohol or the oxygen atom can be removed altogether, a process called deoxygenation. Many reducing agents are metal hydrides based on boron and aluminum. A second important method is catalytic hydrogenation.[1][2]Carbonyl reductions are important to the pharmaceutical Industry. [3]

Mechanism[edit]

The reaction mechanism for metal hydride reduction is based on nucleophilic addition of hydride to the carbonyl carbon. In some cases, the alkali metal cation, especially Li+, participates by coordination to the carbonyl oxygen, thereby enhancing the electrophilicity of the carbonyl. Thus, LiAlH4 is more reactive than NaAlH4 because the smaller lithium cation is a better Lewis acid. A crown ether lowers its reactivity. Alkoxide substitution in metal hydrides increases solubility and selectivity. An example is Red-Al. Replacement of H- by electrongative

Aldehydes and ketones[edit]

Aldehydes reduce more easily than ketones and require milder reagents and milder conditions. The product of the reduction of an aldehyde is a primary alcohol and that of a ketone a secondary alcohol. Sodium borohydride is the typical reagent for these transformations. This salt tolerates more functional groups (nitro group, nitrile, ester) than LiAlH4 and can also be used with water or ethanol as a solvent. Sodium cyanoborohydride, 9-BBN-pyridine and tributyltin hydride are selective for aldehydes. A method for selective ketone reduction in presence of an aldehyde is the Luche reduction (NaBH4/cerium chloride). Aldehydes and ketones can also be reduced by stronger hydride sources such as lithium aluminium hydride,[4][5][6] diisobutylaluminium hydride, L-selectride, diborane, diazene, and aluminum hydride. These reagents however are considered overkill, since they often require greater handling skill and can present hazards. For example, LiAlH4 reacts with protic solvents, sometimes violently.

In hydrogenation platinum and ruthenium are preferred catalysts. Specific methods are the Meerwein–Ponndorf–Verley reduction (aluminumisopropylate/isopropanol), the Bouveault–Blanc reduction (sodium metal/ethanol) and the Cannizzaro reaction (KOH induced aldehyde disproportionation). Aldehydes can also be reduced to the alkane. An example is the reduction of an aromatic aldehyde to the methyl group using H2/Pd/C. Ketones and aldehydes can also be reduced to alkanes using a zinc amalgam and hydrochloric acid via the Clemmensen reduction.

Carboxylic acids[edit]

Typical reagents for the reduction of carboxylic acids or carboxylate salts to alcohols are lithium aluminium hydride, diborane, DIBAL and aluminum hydride. Catalytic hydrogenation and NaBH4 are usually ineffective. Benzoic acid and its derivativess reduced to the benzyl alcohols via electrosynthesis.[7]

Esters[edit]

Esters (R(CO)OR') are usually reduced to alcohols (RCH2OH and R'OH) by lithium aluminium hydride. Before the invention of soluble hydride reagents, esters were reduced by the Bouveault–Blanc reduction, employing a mixture of sodium metal in the presence of alcohols.[8][9] Diisobutylaluminium hydride and lithium tri-t-butoxyaluminum hydride are selective for the formation of the aldehyde. Catalytic hydrogenations over copper chromite[10] or W-6 grade Raney nickel[11] have been reported.

α,β-unsaturated carbonyls[edit]

In α,β-reduction (also called conjugate reduction), the substrate is an unsaturated carbonyl compound, an enone or enal. 1,2-Reduction, producing an allyl alcohol, competes with the 1,4-reduction to the saturated ketone or aldehyde. In 1,4-reduction the first step is conjugate addition of the hydride to the enolate ion followed by acidic workup forming the ketone. 1,2-reduction is found with DIBAL and 9-BBN and alane. 1,4-reduction can be accomplished with catalytic hydrogenation and by alkylmetal hydrides.

An example is the reduction of chalcone by tributyltin hydride:[12]

Conjugate reduction chalcone
Conjugate reduction chalcone

An asymmetric version of this reaction has also been developed.[13]

Asymmetric synthesis[edit]

Well known carbonyl reductions in asymmetric synthesis are the Noyori asymmetric hydrogenation (beta-ketoester reduction /Ru/BINAP) and the CBS reduction (BH3, proline derived chiral catalyst).

References[edit]

  1. ^ Advanced organic chemistry: Structure and mechanisms Francis A. Carey, Richard J. Sundberg 2nd Ed.
  2. ^ March, Jerry (1985), Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (3rd ed.), New York: Wiley, ISBN 0-471-85472-7 
  3. ^ Magano, J.; Dunetz, J. R. (2012). "Large-Scale Carbonyl Reductions in the Pharmaceutical Industry". Organic Process Research & Development 16 (6): 1156–1184. doi:10.1021/op2003826.  edit
  4. ^ Organic Syntheses, Coll. Vol. 7, p.129 (1990); Vol. 60, p.25 (1981). Link
  5. ^ Organic Syntheses, Coll. Vol. 6, p.887 (1988); Vol. 58, p.12 (1978). Link
  6. ^ Organic Syntheses, Coll. Vol. 6, p.769 (1988); Vol. 56, p.101 (1977). Link
  7. ^ Coleman, George H.; Johnson, Herbert L. (1955). "o-Aminobenzyl alcohol". Organic Syntheses 3: 60. doi:10.15227/orgsyn.021.0010. 
  8. ^ Organic Syntheses, Coll. Vol. 6, p.781 (1988); Vol. 53, p.70 (1973). Link
  9. ^ Organic Syntheses, Coll. Vol. 4, p.834 (1963); Vol. 33, p.82 (1953). link
  10. ^ Shriner, R. L.; Kaplan, J. F.; Lazier, W. A. (1943). "1,6-Hexanediol". Organic Syntheses 2: 325. doi:10.15227/orgsyn.019.0048. 
  11. ^ Adams, Rodger (1955). "Organic Reactions Volume VIII". Journal of the American Pharmaceutical Association 44 (2): 128. doi:10.1002/jps.3030440228. 
  12. ^ Leusink, A.J.; Noltes, J.G. (1966). "Reaction of organotin hydrides with α,β-unsaturated ketones". Tetrahedron Letters 7 (20): 2221. doi:10.1016/S0040-4039(00)72405-1. 
  13. ^ Moritani, Yasunori; Appella, Daniel H.; Jurkauskas, Valdas; Buchwald, Stephen L. (2000). "Synthesis of β-Alkyl Cyclopentanones in High Enantiomeric Excess via Copper-Catalyzed Asymmetric Conjugate Reduction". Journal of the American Chemical Society 122 (28): 6797. doi:10.1021/ja0009525.