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Organic Chemistry

17.4 Alcohols from Carbonyl Compounds: Reduction

Organic Chemistry17.4 Alcohols from Carbonyl Compounds: Reduction

17.4 • Alcohols from Carbonyl Compounds: Reduction

The most general method for preparing alcohols, both in the laboratory and in living organisms, is by reduction of a carbonyl compound. Just as reduction of an alkene adds hydrogen to a C=CC=C bond to give an alkane (Section 8.6), reduction of a carbonyl compound adds hydrogen to a C=OC=O bond to give an alcohol. All kinds of carbonyl compounds can be reduced, including aldehydes, ketones, carboxylic acids, and esters.

A carbonyl compound undergoes reduction to form an alcohol, where a bond to hydrogen is added to the carbonyl carbon.

Reduction of Aldehydes and Ketones

Aldehydes are easily reduced to give primary alcohols, and ketones are reduced to give secondary alcohols.

An aldehyde undergoes reduction to form a primary alcohol, a ketone undergoes reduction to form a secondary alcohol. In both cases, a bond to hydrogen is added to carbonyl carbon.

Dozens of reagents are used in the laboratory to reduce aldehydes and ketones, depending on the circumstances, but sodium borohydride, NaBH4, is usually chosen because of its safety and ease of handling. Sodium borohydride is a white, crystalline solid that can be weighed in the open atmosphere and used in either water or alcohol solution.

Two reductions. Butanal reacts first with sodium borohydride and ethanol, then hydronium to form 1-butanol. Dicyclohexyl ketone reacts first with sodium borohydride and ethanol, then hydronium to form dicyclohexylmethanol.

Lithium aluminum hydride, LiAlH4, is another reducing agent often used for reduction of aldehydes and ketones. A grayish powder that is soluble in ether and tetrahydrofuran, LiAlH4 is much more reactive than NaBH4 but also much more dangerous. It reacts violently with water and decomposes explosively when heated above 120 °C.

2-cyclohexenone reacts first with lithium aluminum hydride and ether, then hydronium ion to form 2-cyclohexenol with 94 percent yield.

We’ll defer a detailed discussion of these reductions until Chapter 19. For the moment, we’ll simply note that they involve the addition of a nucleophilic hydride ion (:H) to the positively polarized, electrophilic carbon atom of the carbonyl group. The initial product is an alkoxide ion, which is protonated by addition of H3O+ in a second step to yield the alcohol product.

A carbonyl compound reacts with hydrogen anion having an electron pair to form an alkoxide ion intermediate. This reacts with hydronium ion to form an alcohol.

In living organisms, aldehyde and ketone reductions are carried out by either of the coenzymes NADH (reduced nicotinamide adenine dinucleotide) or NADPH (reduced nicotinamide adenine dinucleotide phosphate). Although these biological “reagents” are much more complex structurally than NaBH4 or LiAlH4, the mechanisms of laboratory and biological reactions are similar. The coenzyme acts as a hydride-ion donor to give an alkoxide anion, and the intermediate anion is then protonated by acid. An example is the reduction of acetoacetyl ACP to β-hydroxybutyryl ACP, a step in the biological synthesis of fats (Figure 17.5). Note that the pro-R hydrogen of NADPH is the one transferred in this example. Enzyme-catalyzed reactions usually occur with high specificity, although it’s not usually possible to predict the stereochemical result before the fact.

Acetoacetyl A C P reacts with nicotinamide adenine dinucleotide phosphate hydrogen to form beta-hydroxybutyryl A C P and nicotinamide adenine dinucleotide plus cation.
Figure 17.5 The biological reduction of a ketone (acetoacetyl ACP) to an alcohol (β-hydroxybutyryl ACP) by NADPH.

Reduction of Carboxylic Acids and Esters

Carboxylic acids and esters are reduced to give primary alcohols.

A carboxylic acid or an ester undergoes reduction to form a primary alcohol. In each case, the carbonyl oxygen becomes a hydroxy, and the carbon gains two hydrogens.

These reactions aren’t as rapid as the reductions of aldehydes and ketones. NaBH4 reduces esters very slowly and does not reduce carboxylic acids at all. Instead, carboxylic acid and ester reductions are usually carried out with the more reactive reducing agent LiAlH4. All carbonyl groups, including acids, esters, ketones, and aldehydes, are reduced by LiAlH4. Note that one hydrogen atom is delivered to the carbonyl carbon atom during aldehyde and ketone reductions but that two hydrogens become bonded to the former carbonyl carbon during carboxylic acid and ester reductions. We’ll defer a discussion of the mechanisms of these reactions until Chapter 21.

9-octadecenoic acid reacts first with lithium aluminum hydride and ether, then hydronium to form 9-octadecen-1-ol. Methyl-2-pentenoate reacts first with lithium aluminum hydride and ether, then hydronium, forming 2-penten-1-ol and methanol.

Worked Example 17.2

Identifying a Reactant, Given the Product

What carbonyl compounds would you reduce to obtain the following alcohols?

Structure A is a condensed formula for 4-methylhexan-2-ol. Structure B is a condensed formula for trans-4-methylpent-2-en-1-ol.

Strategy

Identify the target alcohol as primary, secondary, or tertiary. A primary alcohol can be prepared by reduction of an aldehyde, an ester, or a carboxylic acid; a secondary alcohol can be prepared by reduction of a ketone; and a tertiary alcohol can’t be prepared by reduction.

Solution

(a) The target molecule is a secondary alcohol, which can be prepared only by reduction of a ketone. Either NaBH4 or LiAlH4 can be used.
4-methylhexan-2-one reacts first with sodium borohydride or lithium aluminum hydride, then with hydronium ion to form 4-methylhexan-2-ol.

(b) The target molecule is a primary alcohol, which can be prepared by reduction of an aldehyde, an ester, or a carboxylic acid. LiAlH4 is needed for the ester and carboxylic acid reductions.

Reactions of aldehyde, ester, and carboxylic acid derivatives of the same alkene. Each reacts with sodium borohydride or lithium aluminum hydride, then hydronium to form the same primary alcohol product.
Problem 17-7
What reagent would you use to accomplish each of the following reactions?
(a)
Methyl 4-oxopentanoate reacts with an unknown reagent represented by a question mark to form methyl 4-hydroxypentanoate.
(b)
Methyl 4-oxopentanoate reacts with an unknown reagent represented by a question mark to form pentane-1,4-diol.
(c)
2-methyl-5-(prop-1-en-2-yl)cyclohex-2-enone reacts with an unknown reagent represented by a question mark to form a product with unchanged carbon skeleton, where carbonyl oxygen is now a hydroxy group.
Problem 17-8
What carbonyl compounds give the following alcohols on reduction with LiAlH4? Show all possibilities.
(a)
The structure of a benzene ring linked to C H 2 O H at C 1 position.
(b)
The structure of benzyl alchol with a methyl substituent on the benzylic position.
(c)
The structure of cyclohexane with hydroxyl and hydrogen on C 1 position.
(d)
A condensed structure of 2-methylpropan-1-ol.
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