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19.2: Overview of common redox reactions

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    225881
  • Redox reactions in synthesis

    Synthetic organic chemists have a wide range of reagents at their disposal for the reduction or oxidation of functional groups in organic compounds.  The reagent to be used for any given transformation must be chosen carefully in order to ensure that only the desired functional group or groups is affected: some reducing agents, for example, will act on ketones and aldehydes but leave alkenes and carboxylic acid derivatives untouched, while other will reduce all of these functional groups. Different redox reagents will also transform groups to different extents: we will soon see oxidizing agents, for example, that will transform a primary alcohol to a carboxylic acid, and others that, given the same primary alcohol, will produce an aldehyde.  Similarly, reduction of an alkyne can produce a cis-alkene, a trans-alkene, or an alkane, depending on the reducing agent used. In this section, we will take a look at the action of some of the most important redox reactions – those that are used most frequently in the laboratory, and those which, perhaps more importantly for some of you, tend to make their appearance on standardized tests such as the MCAT. A much more complete discussion of redox reagents can be found in advanced organic synthesis textbooks and reference sources. It also important to bear in mind that increasingly, synthetic organic chemists are figuring out how to use redox enzymes as tools to catalyze the reactions that they wish to carry out in the lab (Curr. Opin. Biotechnol. 2003, 14, 427; Adv. Biochem. Eng. Biotechnol. 2005, 92, 261).

    A: Metal hydride reducing agents

    In the organic synthesis laboratory, carbonyl groups can be reduced using hydride transfer reactions that are mechanistically similar to biochemical reactions with NAD(P)H. Three common reducing agents are sodium borohydride (NaBH4), lithium aluminum hydride (LiAlH4), and diisobutyl aluminum hydride (DIBAH).

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    For example, when sodium borohydride is stirred in solution with an aldehyde or ketone, a hydride ion adds to the carbonyl  carbon to form a 2o alcohol (from a ketone) or a 1o alcohol (from an aldehyde).

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    Sodium borohydride is a relatively mild reducing agent, and reactions are typically run in water or ethanol solvent.  One mole of NaBH4 is capable of reducing four moles of ketone or aldehyde.  Carboxylic acid derivatives and alkene double bounds are not affected.

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    LiAlH4 works in a manner similar to NaBH4, but is much more reactive.  It will react violently with protic solvents (like water or methanol), and so an organic solvent such as diethyl ether must be used.  LiAlH4 will not affect alkene double bonds, but unlike NaBH4 it will reduce carboxylic acids and esters (to 1o alcohols), amides (to amines), nitriles (to 1oamines), and can even be used in reductive ring-opening reactions with epoxides to form alcohols.

    DIBAH has the formula i-Bu2AlH (where i-Bu represents isobutyl), so it has only one hydride to deliver (as opposed to four for NABH4 and LiAlH4).  If only one molar equivalent is used it can reduce an ester to an aldehyde. Using LiAlH4 would reduce the ester to a primary alcohol, as would using two molar equivalents of DIBAH.

    B: Catalytic hydrogenation

    In synthetic organic chemistry, hydrogenation of alkenes is generally carried out with hydrogen gas on the surface of a metal catalyst such as platinum, palladium, or nickel.  This process is usually referred to as catalytic hydrogenation.

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    It is not only alkene double bonds that are reduced by catalytic hydrogenation: alkynes are reduced to alkanes, aldehydes and ketones are reduced to their corresponding alcohols, and nitro groups are reduced to amines.  Carboxylic acid derivatives, however, are not affected, and aromatic double bonds are also left untouched.

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    Alkynes can also be selectively reduced to alkenes, by using Lindlar’s catalyst.

    C: Reduction of carbonyl carbons to methylene

    There are two principle methods for reducing the carbonyl group of a ketone to a simple methylene (CH2) carbon.  The mechanism for the Clemmensen reduction is not well understood, but you will be asked to propose a mechanism for the Wolff-Kishner reduction in the end-of-chapter problems.

    The Clemmensen reduction:

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    The Wolff-Kishner reduction:

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    D: Oxidation reactions

    The oxidation of an alcohol to form an aldehyde or ketone is very important in synthesis. A common method for oxidizing secondary alcohols to ketones uses chromic acid (H2CrO4) as the oxidizing agent. Other methods can be used, such as PCC or the Swern oxidation.

    The PCC and Swern oxidation conditions can both also be used to oxidize secondary alcohols to ketones.  Silver ion, Ag(I), is often used to oxidize aldehydes to ketones.

    The set of reagents in the latter reaction conditions are commonly known as ‘Tollens’ reagent’.

    Alkenes are oxidized to cis-1,2-diols by osmium tetroxide (OsO4).  The stereospecificity is due to the formation of a cyclic osmate ester intermediate.  Osmium tetroxide is used in catalytic amounts, and is regenerated by N-methylmorpholine-N-oxide.

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    cis-1,2-diol compounds can be oxidized to dialdehydes (or diketones, depending on the substitution of the starting diol) using periodic acid:

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    Alkenes can also be oxidized by treatment with ozone, O3. In ozonolysis, the carbon-carbon double bond is cleaved, and the alkene carbons are converted to aldehydes:

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    Dimethyl sulfide or zinc is added in the work-up stage of the reaction in order to reduce hydrogen peroxide, which is formed in the reaction, to water.

    Potassium permanganate (KMnO4) is another very powerful oxidizing agent that will oxidize primary alcohols and aldehydes to carboxylic acids. KMnO4 is also useful for oxidative cleavage of alkenes to ketones and carboxylic acids:

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    Finally, alkenes can be oxidized to epoxides using a ‘peroxyacid‘ such as m-chloroperoxybenzoic acid (MCPBA). Notice the presence of a third oxygen in the peroxyacid functional group.

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    Epoxides are very useful intermediates in organic synthesis, as we learnt in section 9.6.

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