5.6: Nucleophilic Addition of Hydride - Alcohol Formation
After completing this section, you should be able to
- write the general mechanism of nucleophilic addition of the “hydride ion” in the reduction of a carbonyl group.
Reduction of Carbonyls to Alcohols Using Metal Hydrides
We saw in Alcohol's Chapter that the most common method for preparing alcohols, both in the laboratory and in living organisms, is by the reduction of carbonyl compounds. Like carbon, hydrogen can be used as a nucleophile if it is bonded to a metal in such a way that the electron density balance favors the hydrogen side. A hydrogen atom that carries a net negative charge and bears a pair of unshared electrons is called a hydride ion. How much negative charge density resides on hydrogen depends on the difference in electronegativity between hydrogen and the metal it’s bonded to.
The most common sources of the hydride anion ( - :H) are lithium aluminum hydride (LiAlH 4 ) and sodium borohydride (NaBH 4 ) . 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. Also, each are capable of delivering up to 4 hydride equivalents. The reaction equation of hydride reductions are not typically balanced ( i.e. it does not specify the stoichiometry of the reagent). Because aluminum is less electronegative than boron, the Al-H bond in LiAlH 4 is more polar, thereby, making LiAlH 4 a stronger reducing agent.
Aldehydes are reduced with sodium borohydride (NaBH 4 ) to give primary alcohols, and ketones are reduced similarly to give secondary alcohols.
Carbonyl reduction occurs by a typical nucleophilic addition mechanism under basic conditions. Although the details of carbonyl-group reductions are complex, LiAlH 4 and NaBH 4 act as if they were donors of hydride ion nucleophile, : H – , and the initially formed alkoxide ion intermediate is then protonated by addition of aqueous acid. The lithium, sodium, boron and aluminum end up as soluble inorganic salts at the end of either reaction.
The reaction is effectively irreversible because the reverse process would require the expulsion of a very poor leaving group.
Mechanism for the Reduction of Carbonyls using LiAlH 4
Both NaBH 4 and LiAlH 4 act as if they were a source of hydride. The hydride anion undergoes nucleophilic addition to the carbonyl carbon to form a C-H single bond and forming a tetrahedral alkoxide ion intermediate. The alkoxide ion is subsequently converted to an alcohol by reaction with a proton source (such as water). In the LiAlH 4 reduction, the resulting alkoxide salts are insoluble and need to be hydrolyzed (with care) before the alcohol product can be isolated. In the borohydride reduction the hydroxylic solvent system achieves this hydrolysis automatically. The lithium, sodium, boron and aluminum end up as soluble inorganic salts.
Note! The reaction and the corresponding mechanism of hydride reductions of carbonyls is fairly complicated. The following mechanism has been simplified for easier understanding.
Step 1: Nucleophilic attack to form a tetrahedral alkoxide intermediate
Step 2: Protonation to form an alcohol
Properties of Hydride Sources
Two practical sources of hydride-like reactivity are the complex metal hydrides lithium aluminum hydride (LiAlH4) and sodium borohydride (NaBH4). These are both white (or near white) solids, which are prepared from lithium or sodium hydrides by reaction with aluminum or boron halides and esters. Lithium aluminum hydride is by far the most reactive of the two compounds, reacting violently with water, alcohols and other acidic groups with the evolution of hydrogen gas. The following table summarizes some important characteristics of these useful reagents.
|
Reagent |
Preferred Solvents |
Functions Reduced |
Reaction Work-up |
|---|---|---|---|
|
Sodium Borohydride
|
ethanol; aqueous ethanol
|
aldehydes to 1º-alcohols
inert to most other functional groups |
1)
simple neutralization
|
|
Lithium Aluminum Hydride
|
ether; THF
|
aldehydes to 1º-alcohols
most functional groups react |
1)
careful addition of water
|
Limitations of Hydride Reductions
A hydride addition to an asymmetric ketone has the possibility of forming a chiral carbon that is not stereospecific. Attack by the hydride can occur from either the re or the si face of an asymmetrical carbonyl, leading to a mixture of the ( S ) and ( R ) alcohols. These reactions can be made to have stereochemical control by using several different methods including stereospecific reagents, sterics, and by the affect of an enzyme during a biological reduction.
Example
As previously mentioned, a hydride reduction using LiAlH 4 or NaBH 4 has the possibility of forming R or S stereoisomers of a chiral carbon in the product. An important area of organic synthesis is developing stereoselective methods that yield only one of the possible R and S stereocenters. Stereoselective hydride reductions can be accomplished by using the reagent Diisopinocampheylchloroborane (Ipc 2 BCl). The two versions of this reagent, (+)-Ipc 2 BCl & (−)-Ipc 2 BCl, allow for either an R or S stereocenter to be created during the hydride reduction. Ipc 2 BCl was first reported in 1961 by Zweifel and Brown and is considered a pioneering work in stereoselective synthesis using boranes. Herbert Charles Brown (1912-2004) was an American chemist who received the Nobel Prize in Chemistry in 1979 for his work with organoboranes.
Ipc 2 BCl allows for stereoselectivity by changing the mechanism of the hydride reduction and introducing sterics to the reaction. Asymmertric carbonyls which have a sterically large substituent (R L ) and a sterically small substituent (R S ) will have a preferred orientation during this reaction causing a particular stereoisomer to be formed.
Stereochemical control during a synthesis is important because a particular stereoisomer is usually the target molecular. This is particularly true in the synthesis of pharmaceuticals, where one stereoisomer often has different biological properties and another. An example of this is the drug Fluoxetine (Prozac), which was shown to have superior biological properties when the R isomer of its single chiral carbon was tested. Fluoxetine is an antidepressant given FDA approval in 1987. in 2010, over 24.4 million prescriptions for fluoxetine were filled in the United States alone. Currently, there are many different synthesis pathways to Fluoxetine. A fragment of one pathway is shown below which uses the two Ipc 2 BCl versions to synthesis both the R and S enantiomers of Fluoxetine.
Please draw the products of the reaction of the following substrates with LAH:
a- 2-butanone b-butanal
- Answer
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Draw the structure of the molecule which must be reacted to produce the product.
- Answer
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Deuterium oxide (D 2 O) is a form of water where the hydrogens have been replaced by deuteriums. For the following LiAlH 4 reduction the water typically used has been replaced by deuterium oxide. Please draw the product of the reaction and place the deuterium in the proper location. Hint! Look at the mechanism of the reaction.
- Answer
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