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17.5 Alcohols from Reaction of Carbonyl Compounds - Grignard Reagents

  • Page ID
    90942
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    Objectives

    After completing this section, you should be able to

    1. write an equation to illustrate the formation of a Grignard reagent.
    2. write a general equation to represent the reaction of an aldehyde or ketone with a Grignard reagent.
    3. write the detailed mechanism for the reaction of an aldehyde or ketone with a Grignard reagent. 
    4. identify the product formed from the reaction of a given aldehyde or ketone with a given Grignard reagent. 
    5. identify the carbonyl compound, the Grignard reagent, or both, needed to prepare a given alcohol. 
    6. write the equation to describe the reaction of an ester with a Grignard reagent. 
    7. identify the product formed from the reaction of a given ester with a given Grignard reagent. 
    8. discuss the limitations of Grignard reagent formation, and determine whether a given compound can be used to form such a reagent. 
    Study Notes

    Before you begin this section, you may wish to review Section 10.6 which discusses the formation of Grignard reagents.

    Grignard reagents are among the most frequently used reagents in organic synthesis. They react with a wide variety of substrates; however, in this section, we are concerned only with those reactions that produce alcohols. Notice that in a reaction involving a Grignard reagent, not only does the functional group get changed, but the number of carbon atoms present also changes. This fact provides us with a useful method for ascending a homologous series. For example:

    Reaction diagram. Methanol reacts with thionyl chloride forming methyl chloride. Methyl chloride reacts with magnesium in ether forming methylmagnesium chloride. Methylmagnesium chloride reacts first with formaldehyde, then with hydronium to form ethanol.

    One important route for producing an alcohol from a Grignard reagent has been omitted from the discussion in the reading. It involves the reaction of the Grignard reagent with ethylene oxide to produce a primary alcohol containing two more carbon atoms than the original Grignard reagent.

    Reaction diagram. A Grignard Reagent reacts with ethylene oxide. The R group of the Grignard reagent attacks a carbon of ethylene oxide, breaking the carbon-oxygen bond. A bond forms between the oxygen and magnesium halide; another bond forms between the carbon and the R group. This then reacts with hydronium resulting in an alcohol and Mg(OH)X.

    As mentioned in the reading, both organolithium and Grignard reagents are good nucleophiles. They also act as strong bases in the presence of acidic protons such as −CO2H, −OH, −SH, −NH and terminal alkyne groups. Not only do acidic protons interfere with the nucleophilic attack on the carbonyl of these organometallic reagents, if the starting materials possess any acidic protons, reagents cannot be generated in the first place. They are also the reason these reactions must be carried out in a water‑free environment.

    Another limitation of preparing Grignard and organolithium reagents is that they cannot already contain a carbonyl group (or other electrophilic multiple bonds like C$\ce{=}$N C$\ce{#}$N, N$\ce{=}$O S$\ce{=}$O) because it would simply react with itself.

    A summary of the methods used to prepare alcohols from Grignard reagents is provided below.

    Because organometallic reagents react as their corresponding carbanion, they are excellent nucleophiles. The basic reaction involves the nucleophilic attack of the carbanionic carbon in the organometallic reagent with the electrophilic carbon in the carbonyl to form alcohols.

    Reaction diagram. A carbonyl reacts first with R-MgX and ether, or R-Li and hexane; then hydronium. This results in an alcohol and addition of the R group.

    Both Grignard and Organolithium Reagents will perform these reactions

    Addition to formaldehyde gives 1o alcohols

    Reaction diagram. Formaldehyde reacts first with a grignard reagent then with hydronium forming a primary alcohol.

    Addition to aldehydes gives 2o alcohols

    Addition to ketones gives 3o alcohols

    Example 17.5.1

    Mechanism for the Addition to Carbonyls

    The mechanism for a Grignard agent is shown. The mechanism for an organometallic reagent is the same.

    1) Nucleophilic attack

    2) Protonation

    Grignard reagents convert esters to 3o alcohols

    In effect, the Grignard reagent adds twice.

    Example 17.5.2

    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 are: alcohols, amides, 1o amines, 2o amines, carboxylic acids, and terminal alkynes.

     

    Worked Example 17.5.1

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

    Example 1 structure.svg
    Answer
    Analysis: Because the target molecule is a 1o alcohol there is only one C-C bond which can be cleaved to generate possible starting materials. The only possible reagents which would provide the target molecule would be formaldehyde and phenylmagnesium bromide.
    Synthesis using a Grignard reaction.svg
    Worked Example 17.5.2

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

    Answer

    Analysis: Because the target molecule is an asymmetrical 2o alcohol there are two different C-C bond cleavage points. Each of these will provide a unique set of reagents which should be considered in terms of their reactivity and availability.

    Pathway 1)

    Synthesis using a Grignard reaction2.svg

    Pathway 1 synthesis)

    Pathway 1 shows that propanal and propylmagnesium bromide can be reacted to create the target molecule.

    Synthesis using a Grignard reaction2 Pathway 1.svg

    Pathway 2)

    Synthesis using a Grignard reaction Retro 2.svg

    Pathway 2 synthesis)

    Pathway 2 shows that butanal and ethylmagnesium bromide can be reacted to create the target molecule.

    Synthesis using a Grignard reaction2 Pathway 2.svg

    Exercises

    Exercise 17.5.1

    If allylmagnesium chloride were added to a solution of the following compound and then worked-up with acid, the product would contain a chiral center. Would the product be a racemic mixture or an enatiomerically pure product? Draw both enantiomers.

    17_5_1.svg

    Answer

    The result would be a racemic mixture of the following.

    17_5_1_Answer.svg

    Exercise 17.5.2

    What combination of carbonyl compound and grignard (use MgBr) reagent would yield the following alcohols (after workup)?

    17_5_2.svg

    Answer

    17_5_2_Answer.svg

    Exercise 17.5.3

    Fill in the blanks of the following reaction scheme.

    17_5_3.svg

    Answer

    17_5_3_Answer.svg

    Contributors and Attributions


    17.5 Alcohols from Reaction of Carbonyl Compounds - Grignard Reagents is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by LibreTexts.

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