4.2: Nucleophilic Addition of Hydride and Grignard Reagents- Alcohol Formation

Reduction of Carbonyls to Alcohols Using Metal Hydrides

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.

(M = metal)

The most common sources of the hydride anion (^-:H) 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. 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 LiAlH₄ is more polar, thereby, making LiAlH₄ a stronger reducing agent.

General Reaction

Nucleophilic addition of a hydride anion (^-:H) to an aldehyde or a ketone gives a tetrahedral alkoxide anion intermediate, which on protonation yields the corresponding alcohol. Aldehydes produce 1^o-alcohols and ketones produce 2^o-alcohols. Both LiAlH₄ and NaBH₄ are capable of reducing aldehydes and ketones to the corresponding alcohol.

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.

Predicting the Product of a Hydride Addition to a Carbonyl

During the reduction, the C=O double bond in the reactant becomes a C-O single bond in the product. The breaking of the C=O double bond allows for the formation of two new single bonds in the product. One will be attached to the oxygen (O-H) and one to the carbon (C-H).

Example

Mechanism for the Reduction of Carbonyls using LiAlH₄

Both NaBH₄ and LiAlH₄ 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 LiAlH₄ 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.

1) Nucleophilic attack to form a tetrahedral alkoxide intermediate

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 NaBH4	ethanol; aqueous ethanol 15% NaOH; diglyme avoid strong acids	aldehydes to 1º-alcohols ketones to 2º-alcohols inert to most other functional groups	1) simple neutralization 2) extraction of product
Lithium Aluminum Hydride LiAlH4	ether; THF avoid alcohols and amines avoid halogenated compounds avoid strong acids	aldehydes to 1º-alcohols ketones to 2º-alcohols carboxylic acids to 1º-alcohols esters to alcohols epoxides to alcohols nitriles & amides to amines halides & tosylates to alkanes most functional groups react	1) careful addition of water 2) remove aluminum salts 3) extraction of product

Conversion of Amides into Amines: Reduction

 

Like other carboxylic acid derivatives, amides can be reduced by LiAlH₄. The product of the reduction, however, is an amine rather than an alcohol. The net effect of an amide reduction is thus the conversion of the amide carbonyl group into a methylene group (C=). This kind of reaction is specific to amides and does not occur with other carboxylic acid derivatives.

Amide reduction occurs by nucleophilic addition of hydride ion to the amide carbonyl group, followed by expulsion of the oxygen atom as an aluminate anion leaving group to give an iminium ion intermediate. The intermediate iminium ion is further reduced by LiAlH₄ to yield the amine.

The reaction is effective with both acyclic and cyclic amides, or lactams, and is a good method for preparing cyclic amines.

 

 

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

Organometallic Reactions

Common Organometallic Reagents

Lithium and magnesium metals reduce the carbon-halogen bonds of alkyl halides to form organolithium reagents and Grignard reagents respectively. In both cases, the carbon bonds to the metal and has characteristics similar to a carbanion (R:^-) nucleophile. Some common organometallic reagents are shown below:

Reaction of Organometallic Reagents with Carbonyls

Because organometallic reagents react as their corresponding carbanion, they are excellent nucleophiles. Aldehydes and ketones will undergo nucleophilic addition with organolithium and Grignard reagent nucleophiles. The nucleophilic carbon in the organometallic reagents forms a C-C single bond with the electrophilic carbonyl carbon. An alkoxide ion intermediate is formed which becomes an alcohol with subsequent protonation with an acid. Both Grignard and organolithium reagents will perform these reactions.

General Reaction

Addition to Formaldehyde gives 1^o Alcohols

Addition to Aldehydes gives 2^o Alcohols

Addition to Ketones gives 3^o Alcohols

Predicting the Product of Addition of Organometallic Reagents to Aldehydes and Ketones

During the reaction, the C=O double bond in the reactant forms a C-O single bond in the product. The breaking of the C=O double bond allows for the formation of two single bonds in the product. One will be attached to the oxygen and one to the carbon which was originally in the carbonyl. The carbon will gain whatever R group was part of the organometallic reagent and the oxygen will gain a "H".

Example \(\PageIndex{2}\)

Mechanism for the Addition of Grignard Reagents to Carbonyls

The mechanism starts with the formation of a acid-base complex between ⁺MgX and the carbonyl oxygen. The ⁺MgBr of the Grignard reagent acts as a Lewis acid and accepts a lone pair of electrons from the carbonyl oxygen. This gives the oxygen a positive charge which correspondingly increases the partial positive charge on the carbonyl carbon increasing it susceptibility to nucleophilic attack. The carbanion nucleophile from the Grignard reagent adds to the electrophilic carbon of the acid-base complex forming a C-C bond. The two electrons of the C=O are pushed toward the carbonyl oxygen atom forming a tetrahedral magnesium alkoxide intermediate. The alkoxide intermediate is converted to an alcohol through addition of a acidic aqueous solution. The ⁺MgX ion is also converted to HOMgX.

1) Lewis acid-base formation

2) Nucleophilic attack

3) Protonation

Limitation of Organometallic Reagents

As discussed above, Grignard and organolithium reagents are powerful bases. Because of this they cannot be used as nucleophiles on compounds which contain acidic hydrogens. If they are used they will act as a base and deprotonate the acidic hydrogen rather than act as a nucleophile and attack the carbonyl. A partial list of functional groups which cannot be used with organometallic reagents includes: alcohols, amides, 1^o amines, 2^o amines, carboxylic acids, and terminal alkynes.

Planning an Alcohol Synthesis Using a Grignard Reaction

The nucleophilic addition of a Grignard reagent to a carbonyl is a powerful tool in organic synthesis because if forms a C-C bond. Also, there is often more than one way to make a given target molecule. Primary alcohols have one C-C bond which can be retrosynthetically cleaved. Secondary alcohols have two and tertiary alcohols have three.

Example

What reagents are required to make the following molecule using a Grignard Reaction?

Answer

 

Contributors and Attributions

• Layne A. Morsch (University of Illinois Springfield)
• (1) Chemistry of Amides https://chem.libretexts.org/@go/page/448785 (accessed Mar 11, 2024)