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11.7: Reduction of the Carbonyl Group - Synthesis of 1º and 2º Alcohols

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    182996
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    Reduction of Aldehydes and Ketones

    The most common sources of the hydride nucleophile are lithium aluminum hydride (LiAlH4) and sodium borohydride (NaBH4). Note! The hydride anion is not present during this reaction; rather, these reagents serve as a source of hydride due to the presence of a polar metal-hydrogen bond. Because aluminum is less electronegative than boron, the Al-H bond in LiAlH4 is more polar, thereby, making LiAlH4 a stronger reducing agent.

     

     

    Addition of a hydride anion (H:-) to an aldehyde or ketone gives an alkoxide anion, which upon protonation yields the corresponding alcohol. Aldehydes produce 1º-alcohols and ketones produce 2º-alcohols.  

    In metal hydrides reductions the resulting alkoxide salts are insoluble and need to be hydrolyzed (with care) before the alcohol product can be isolated. In the sodium borohydride reduction the methanol solvent system achieves this hydrolysis automatically. In the lithium aluminum hydride reduction water is usually added in a second step. The lithium, sodium, boron and aluminum end up as soluble inorganic salts at the end of either reaction. Note! LiAlH4 and NaBH4 are both capable of reducing aldehydes and ketones to the corresponding alcohol.

    Formally, that process is referred to as a reduction. Reduction generally means a reaction in which electrons are added to a compound; the compound that gains electrons is said to be reduced. Because hydride can be thought of as a proton plus two electrons, we can think of conversion of a ketone or an aldehyde to an alcohol as a two-electron reduction. A carbonyl (aldehyde or ketone) plus two electrons and two protons becomes an alcohol.

    Example 1

     

    Mechanism

    This mechanism is for a LiAlH4 reduction. The mechanism for a NaBH4 reduction is the same except methanol is the proton source used in the second step.

    1) Nucleopilic hydride anion reacts with the electrophilic carbonyl carbon forcing the pi electrons onto the electronegative oxygen atom.

    Fix1.jpg

    2) The alkoxide is protonated.

     

    Fix2.jpg

    Biological Reduction

    Addition to a carbonyl by a semi-anionic hydride, such as NaBH4, results in conversion of the carbonyl compound to an alcohol. The hydride from the BH4- anion acts as a nucleophile, adding H- to the carbonyl carbon. A proton source can then protonate the oxygen of the resulting alkoxide ion, forming an alcohol.

    CONADH2.png

    Aldehydes, ketones and alcohols are very common features in biological molecules. Converting between these compounds is a frequent event in many biological pathways. However, semi-anionic compounds like sodium borohydride don't exist in the cell. Instead, a number of biological hydride donors play a similar role.

    NADH is a common biological reducing agent. NADH is an acronym for nicotinamide adenine dinucleotide hydride. Insetad of an anionic donor that provides a hydride to a carbonyl, NADH is actually a neutral donor. It supplies a hydride to the carbonyl under very specific circumstances. In doing so, it forms a cation, NAD+. However, NAD+ is stabilized by the fact that its nicotinamide ring is aromatic; it was not aromatic in NADH.

    Reduction of Carboxylic Acids and Esters

    Carboxylic acids can be converted to 1o alcohols using Lithium aluminum hydride (LiAlH4). Note that NaBH4 is not strong enough to convert carboxylic acids or esters to alcohols. An aldehyde is produced as an intermediate during this reaction, but it cannot be isolated because it is more reactive than the original carboxylic acid.

    1.jpg

     

    Esters can be converted to 1o alcohols using LiAlH4, while sodium borohydride (\(NaBH_4\)) is not a strong enough reducing agent to perform this reaction.

     

    1.jpg

    Reduction Reaction Summary

    The table below summarize the reduction reactions covered so far in our text.  It is important to distinguish between functional group reactivity as we add more multiple-step synthetic pathways.

    ch 11 sect 6 summary table.png

    Exercise

    11.

    Give the aldehyde, ketone, or carboxyllic acid (there can be multiple answers) that could be reduced to form the following alcohols.

    (a) (b) (c) (d)

     

    12.

    Given the following alcohol, draw the structure from which it could be derived using only NaBH4

    (a) (b) (c) (d)

     

     

    Answer

    11.

    (a) (b) (c) (d)

     

    12.

    Note, NaBH4 is only a strong enough reducing agent to reduce ketones and aldehydes.

    (a) (b) (c) (d)