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

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  • Objectives

    After completing this section, you should be able to

    1. write the equation to describe the nucleophilic addition reaction between a Grignard reagent and a carbonyl group.
    2. 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

    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.

    metal hydrides can be ionic or covalent.svg
    (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.

    examples of covalent metal hydrides (sodium borohydride and lithium aluminum hydride) versus hydride nucleophile, H-.svg

    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 1o-alcohols and ketones produce 2o-alcohols. Both LiAlH4 and NaBH4 are capable of reducing aldehydes and ketones to the corresponding alcohol.

    general example of hydride reduction of an aldehyde to give a primary alcohol.svg

    general example of hydride reduction of a ketone to give a secondary alcohol.svg

    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).

    predicting the products of a hydride reduction.svg


    reduction of benzaldehyde with sodium borohydride in methanol to give benzyl alcohol.svg

    reduction of 2-butanone with 1. lithium aluminum hydride, followed by 2. water to give 2-butanol.svg

    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

    hydride reduction mechanism step 1.svg

    2) Protonation to form an alcohol

    hydride reduction mechanism step 2.svg

    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.


    Preferred Solvents

    Functions Reduced

    Reaction Work-up

    Sodium Borohydride

    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

    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

    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.

    Si and Re faces of hydride reduction.svg


    reduction of 2-butanone with 1. lithium aluminum hydride, followed by 2. water gives a mixture of enantiomers of 2-butanol.svg

    Organometallic Reactions

    Common Organometallic ReagentsEdit section

    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:

    examples of organolithium reagents.svg

    examples of grignard reagents.svg

    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

    organometallic carbonyl general reaction.svg

    Addition to Formaldehyde gives 1o Alcohols

    formaldehyde to primary alcohol using organometallic.svg

    Addition to Aldehydes gives 2o Alcohols

    aldehyde to secondary alcohol using a grignard.svg

    Addition to Ketones gives 3o Alcohols

    ketone to tertiary alcohol using a grignard.svg

    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".

    predicting the product of a grignard reaction.svg

    Example \(\PageIndex{2}\)

    example 19.svg

    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

    Mechanism, grignard step 1.svg

    2) Nucleophilic attack

    Mechanism, grignard step 2.svg

    3) Protonation

    grignard mechanism step 2.svg

    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, 1o amines, 2o amines, carboxylic acids, and terminal alkynes.

    limitations of ogranometallic reactions.svg

    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.


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

    Example 1 structure.svg


    Synthesis using a Grignard reaction.svg

    Something Extra

    As previously mentioned, a hydride reduction using LiAlH4 or NaBH4 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 which yield only one of the possible R and S stereocenters. Stereoselective hydride reductions can be accomplished by using the reagent Diisopinocampheylchloroborane (Ipc2BCl). The two versions of this reagent, (+)-Ipc2BCl & (−)-Ipc2BCl, allow for either an R or S stereocenter to be created during the hydride reduction. Ipc2BCl 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.

    something extra structure 1.svg

    Ipc2BCl 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 (RL) and a sterically small substituent (RS) will have a preferred orientation during this reaction causing a particular stereoisomer to be formed.

    something extra structure 2.svg

    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 were 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 Ipc2BCl versions to synthesis both the R and S enantiomers of Fluoxetine.

    something extra structure 3.svg


    1) Please draw the products of the following reactions:

    question 1 structures organometallic.svg

    2) Please draw the structure of the molecule which must be reacted to produce the product.

    question 2 structures.svg

    3) Deuterium oxide (D2O) is a form of water where the hydrogens have been replaced by deuteriums. For the following LiAlH4 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.

    question 3 structure.svg

    4) Please write the product of the following reactions.

    question 1 structures organometallic.svg

    5) Please indicate the starting material required to produce the product.

    question 5 structures organometallic.svg

    6) Please give a detailed mechanism and the final product of this reaction

    question 6 structures organometallic.svg

    7) Please show two sets of reactants which could be used to synthesize the following molecule using a Grignard reaction.




    answer 1 structures .svg


    answer 2 structures.svg


    answer 3 structures.svg


    answer 4 structures .svg


    answer 5 structures.svg


    Nucleophilic attack

    answer 6a structures organometallic .svg


    answer 6b structures organometallic .svg


    answer 7 structures organometallic .svg

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