"

3.4.2 – Grignard Reactions with Carbonyls

The Grignard reaction is an organic reaction used to form new carbon—carbon bonds by adding an alkyl or aryl group to an aldehyde or ketone carbon center. This results in an alcohol product.

3-methyl-butan-2-one first undergoes nucleophilic attack at electron deficient carbon center by a Grignard reagent, phenyl magnesium chloride (phenyl group bonded with a MgCl) in ether (Et2O). It is then followed by protonation from acid to give the product 3-methyl-2-phenylbutan-2-ol.
Figure 3.4.2.a. Reaction of a ketone and a Grignard reagent to produce a tertiary alcohol.

 

The Grignard Reagent

Before a Grignard reaction can be done, the Grignard reagent must first be synthesized. A Grignard reagent is made by treating an alkyl halide with elemental magnesium, Mg, using diethyl ether (Et2O) as a solvent. The halogen in the alkyl halide is often Cl or Br.  You do not need to know the exact mechanism of how this reaction occurs. However, it is important to understand that the Mg inserts itself between the carbon and halide, while donating its 3s electrons to carbon, reducing it to a carbanion. This reagent is often written as R–MgX.

The synthesis of a Grignard reagent involves an alkyl halide (R bonded to X, where X is Cl or Br) and Mg in ether (Et2O) to form R-MgX.
Figure 3.4.2.b. The reaction of an alkyl halide with magnesium to synthesize the Grignard reagent, R–MgX.

Magnesium is electropositive, with an electronegativity value of 1.31 on the Pauling scale. In comparison, carbon has an electronegativity of 2.02. As carbon is the more electronegative atom in the C–Mg bond, it exhibits a partial negative charge, whereas the Mg has a partial positive charge. Thus, this is one of the rare cases where the carbon acts as a nucleophile, rather than an electrophile. Another way to visualize this is with the carbon atom containing a lone pair of electrons and a formal negative charge, and write the Grignard reagent as an ionic salt, as shown below.

Butylmagnesium Chloride (butyl group bonded to MgCl) behaves as or can be envisioned as the butane’s C-Mg bond dissociated, with a negative charge on the carbon (a nucleophile) and Mg in MgCl as a positively charged counterion.
Figure 3.4.2.c. The R-MgX Grignard reagent contains a carbon atom with a partial negative charge, which can also be depicted as a lone pair of electrons and a formal negative charge on carbon. The carbon atom acts as a nucleophile.

Reacting Carbonyls With a Grignard reagent

Grignard reagents react with aldehydes and ketones to form alcohols. The carbonyl group in the aldehyde or ketone contains an electrophilic carbon center due to the electronegative oxygen. Meanwhile, the Grignard reagent contains a nucleophilic carbon center. The nucleophilic Grignard reagent attacks the electrophilic carbonyl carbon atom, forming a new C–C bond while breaking a π bond to oxygen. Subsequent treatment with an acid delivers a proton (H+) to the oxygen, forming a new O–H bond, to produce an alcohol. The net result is breaking the C=O π bond, and forming two new σ bonds (C–C and O–H).

Reacting aldehydes and ketones with a Grignard reagent will form secondary and tertiary alcohols respectively.

2 Grignard reactions leading to the formation of 2 separate alcohol products. The first reaction being butanal (an aldehyde) reacting first with a methyl Grignard in ether, followed by the second acid step (H3O+). This forms a secondary alcohol product pentan-2-ol. Similarly, propan-2-one reacts with a phenyl Grignard in ether, followed by the second step of acid work-up, to form a tertiary alcohol (2-phenylpropan-2-ol).
Figure 3.4.2.d. Grignard reactions using both an aldehyde and a ketone and their respective products.

(The full solution to this problem can be found in Chapter 5.2)

Mechanism of Grignard Reaction for Aldehydes and Ketones

The reaction consists of two individual mechanistic steps, which include the creation of the carbon—carbon σ bond and then the protonation of the alkoxide intermediate across the carbonyl π bond.

An aldehyde group where there are 2 lone pairs on the oxygen and a partially negative symbol. The oxygen is double bonded to a carbon underneath, which has the partially positive charge. The lone pair from the carbon in a charge separated grignard attacks the partially positive carbon in the aldehyde (tail of the curved arrow starting from the lone pair in the grignard and the head pointing towards the electrophilic aldehyde carbon). Another curved arrow starting from the double bond in the aldehyde points to the oxygen. A horizontal arrow shows the final product where the carbon attached to the oxygen is now bonded to a methyl group and singly bonded to oxygen. Oxygen now has 3 lone pairs, a negative charge or alkoxide, and is associated with the positively charged MgCl.
Figure 3.4.2.e. The first step in the Grignard reaction with an aldehyde. In this step, the Grignard reagent, which contains a nucleophilic carbon, attacks the electrophilic carbon carbonyl center, breaking the C=O π bond.

The first step of this reaction is the nucleophilic attack of the Grignard reagent at the electrophilic carbon centre of the carbonyl group. The lone pair of electrons on the Grignard reagent attack the carbon center of the aldehyde to form a new covalent bond. As a new bond is forming, another bond must break to ensure that the octet rule is not violated at carbon. The π bond preferentially breaks, with the electron pair from the π orbital of the C=O bond moving towards the electronegative oxygen. This step results in the formation of a new C–C bond and formation of an alkoxide intermediate with a formal negative charge at oxygen.

See caption for description.
Figure 3.4.2.f. The second step in the Grignard reaction with an aldehyde. In this step, the alkoxide is protonated by an acid, H3O+, resulting in the final products: a secondary alcohol and water, as well as MgCl+ remaining after the first step.

The second step of this reaction is the protonation of the negatively charged oxygen in the alkoxide intermediate. As the previous step ended with an anionic alkoxide as the intermediate, it must be protonated to stabilize the molecule and produce a neutral alcohol. This will occur by using acid, written as H3O+. The negatively charged oxygen uses a lone pair of electrons to abstract the proton on the acid. This is essentially an acid-base reaction between H3O+ (the acid) and the anionic alkoxide (the base). This second step results in our final product, a secondary alcohol.

The addition of a Grignard reaction to an aldehyde produces a secondary alcohol. Aldehydes only contain one carbon attached to the central carbonyl carbon, but reaction with the carbon-containing Grignard reagent will increase the number of carbons attached to the central carbon to two.

The mechanism for Grignard reaction with ketones is functionally identical to that of aldehydes. It follows the same pattern of an initial nucleophilic attack from the Grignard reagent, followed by protonation of the anionic oxygen. Reacting a ketone with a Grignard reagent produces a tertiary alcohol. Ketones contain two carbons attached to the central carbonyl carbon, so reacting with the carbon-containing Grignard reagent will increase the number of carbons attached to the central carbon to three.

Phenylmagnesium chloride (a phenyl Grignard reagent) attacks the electrophilic carbon in the ketone, pushing the electron density in the double bond between carbon and oxygen to the oxygen, generating an alkoxide. The alkoxide gets protonated by attacking H3O+ and forming a tertiary alcohol
Figure 3.4.2.g. The mechanism steps of the Grignard reaction with a ketone. It follows a similar two—step process that involves the nucleophilic attack of the alkyl chain, following by the protonation of the alkoxide.

The two-step reaction can be summarized in the following manner, showing the intermediate as well as the starting reactant and product.

In reference to figures 3.4.2.f and g, the same Grignard reactions of the aldehyde and ketone is shown to highlight how both form alkoxides then get reduced/protonated to secondary and tertiary alcohols respectively.
Figure 3.4.2.g. The reactants, intermediates and products in a Grignard reaction of carbonyls.

Energy Profile Diagram of Grignard Reactions

As this reaction follows a two-step process, we can draw an energy diagram to show the changes in energy and the intermediate formed in the reaction. The minimum of the energy profile represents the alkoxide intermediate that is synthesized in the first step after the addition of the C–C bond. The two maxima correspond to the two transition states where bond breaking and forming are occurring.

The energy profile diagram is similarly shaped as an Sn1. The first step being the nucleophilic carbon of the Grignard attacking the electrophilic carbon of the aldehyde leading to the formation of the alkoxide intermediate (indicated by the minimum in between the 2 maxima). The alkoxide reacts with acid to form the final secondary alcohol product.
Figure 3.4.2.h. An energy profile diagram of a Grignard reaction with an aldehyde. The two energy maxima correspond to the transition states for each step, while the energy minimum corresponds to the alkoxide intermediate.

(The full solution to this problem can be found in Chapter 5.2)

Key Takeaways

  • A Grignard reagent is a specific molecule which has a nucleophilic carbon. It has the general form R–MgX, where X is usually Br or Cl.
  • Grignard reagents are formed when alkyl halides react with elemental magnesium in Et2O solvent.
  • Grignard reagents can be used to form new carbon-carbon bonds when they are reacted with a carbonyl group containing reagent, as in an aldehyde or a ketone. This results in an alcohol product.
  • There are two steps involved in the Grignard reaction with carbonyls:
    1. The nucleophilic Grignard carbon attacks the electrophilic carbon centre of the carbonyl group, breaking a π bond to oxygen in the process. This results in an alkoxide intermediate.
    2. The alkoxide intermediate is protonated in the presence of an acid to produce an alcohol.
  • The degree of the alcohol product relies on how many carbons the carbonyl group was bound to initially.

Any feedback or comments on this chapter? You may either email chemoer@mcmaster.ca, access this MS Form, or provide a comment in the feedback box below.

License

Icon for the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License

Organic Chemistry and Chemical Biology for the Students by the Students! (and the Profs...) Copyright © 2023 by Emma Abreu; Anumta Amir; Anthony Chibba; Jim Ghoshdastidar; Sharonna Greenberg; Angela Liang; Layla Vulgan; and Shuoyang Wang is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License, except where otherwise noted.

Share This Book