Organic Chemistry II  | Lecture | Laboratory

Organic Chemistry Laboratory II
Preparation of Triphenylmethanol (Grignard Reaction)
Background Reading

Generation of Grignard Reagents
The Grignard reaction, named after its inventor, Nobel-prize-winning chemist, Victor Grignard (1871-1935) is an extremely useful reaction that allows carbon/carbon bonds to be formed using an organometallic intermediate. These intermediates, commonly known as Grignard reagents, can be formed by reacting alkyl, alkenyl or aryl halides with magnesium metal. The organometallic complex is characterized by the carbon-metal bond, such as that of phenylmagnesium bromide (Figure 1).  Conversion of the alkyl or aryl halide to the Grignard reagent results in an inversion of polarity associated with the carbon atom.  The carbon atom of the alkyl/aryl halide has partial positive character, while the same carbon develops partial negative character in the Grignard reagent.  The reaction is typically carried out in dry, aprotic solvents like diethylether or THF (tetrahydrofuran).

Figure 1: Formation of the Grignard Reagent from an Aryl Halide

The Grignard reagent is a strong base and a strong nucleophile. Specifically, the carbon atom, with its negative character reacts with electrophilic speciies. In the presence of acidic protons, the Grignard reagent will break its organometallic bond and regenerate a hydrocarbon. Water and alcohols, for example, will have this effect (Figure 2).  For this reason, it is very important that reactions using a Grignard reagent must take place under very dry conditions.

Figure 2:  Reaction of the Grignard Reagent with Protons Derived from Water or Alcohols

Once a Grignard reagent has been prepared, it is a very versatile material. It’s strongly nucleophilic character will cause interaction with any electrophilic carbon. Reactants with a carbonyl-containing functional groups, alkyl halides or alcohols (i.e.electrophilic proton) are a few examples of functional groups that will react  with a Grignard reagent.

Figure 3:  Reactions of the Grignard Reagent with Other Functional Groups

Mechanism of the Reactions Involving Grignard Reagents:
Nucleophilic Acyl Addition and Nucleophilic Acyl Substitution
The mechanism of the reaction between the Grignard reagent and the alkyl halide is completely analogous to the reaction of the Grignard reagent with a proton from water or an alcohol.  The negative carbon of the Grignard reagent reacts with the electrophilic carbon of the alkyl halide, forming a new bond between the Grignard carbon and the alkyl halide carbon. The mechanism of the reaction between the Grignard reagent and a carbonyl-containing functional group is more complex.   The negative carbon of the Grignard reagent attacks the carbonyl carbon, breaking the C-O pi bond of the carbonyl-containing functional group to form a tetrahedral intermediate.  A new C-C bond forms between the Grignard carbon and the carbonyl carbon, and the oxygen atom takes on a negative charge. If the starting carbonyl-containig functional group is an aldehyde or ketone,  the negatively charged oxygen reacts with a proton to generate an alcohol product (This reaction is referred to as a nucleophilic acyl addition)(Figure 4).

Figure 4:  Mechanism of the Reaction of the Grignard Reagent with a Ketone
Nucleophilic Acyl Addition

If the starting carbonyl-containing functional group is a ester, amide or anhydride, the tetrahedral intermediate follows an alternative path.  The electrons on the negatively charged oxygen are used to reform the carbonyl pi bond, forcing the C-N or C-O bond of the amide, ester or anhydride to break off as a leaving group, generating a ketone intermediate.  Because ketones and aldehydes are more reactive in with the Grignard reagent (The carbonyl carbons of ketones and aldehydes are more electrophilic), the ketone intermediate continues to react with a second equivalent of the Grignard reagent to give a more highly substituted alcohol final product. This reaction is referred to as a nucleophilic acyl substitution. (Figure 5)

Figure 5: Reaction Mechanism for reaction of the Grignard reagent with an Ester
Nucleophilic Acyl Substitution

Carbon dioxide is a unique carbonyl-containing electrophilic reagent.  Its addition in a 1:1 ratio with phenylmagnesium bromide will yield a MgBr salt of benzoic acid. Protonation of the salt with hydrochloric acid will yield the desired benzoic acid product, and the water-soluble MgBrCl salt (Figure 6).

Figure 6:  Reaction mechanism for Reaction of Grignard reagent with Carbon Dioxide