Introduction

Background

One of the most important tools the synthetic organic chemistry arsenal is the ability to form carbon–carbon bonds. In this experiment, you will perform a Grignard reaction, one of the most versatile carbon–carbon bond forming reactions in our synthesis tool box.

Grignard reagents were discovered in 1901 by Victor Grignard, who won the 1912 Nobel Prize in Chemistry. The reagents—and related reaction—bear his name. A Grignard reagent is any organomagnesium halide (RMgX) and is classified as an organometallic compound. In fact, Grignard reagents were the first organometallic compounds to be extensively studied. In the carbon–metal bond, the polarization of the bond is such that carbon is electron-rich and bears a partial negative charge (δ–). As a result of this polarization, the carbon atom acts as a nucleophile or Lewis base. In contrast, when a carbon atom is bonded to a more electronegative atom, such as a halogen (RX), the carbon atom is electron-deficient and acts as an electrophile or a Lewis acid in chemical reactions. In short, the presence of the magnesium effectively inverts the polarity of the bonded carbon atom (Figure 1).

Figure 1. Inversion of carbon polarity: organohalide versus Grignard reagent

The reactivity of an organometallic compound in highly dependent upon the nature of the carbon–metal bond, which can be ionic or covalent. Organosodium and organopotassium reagents are highly ionic; the carbon acts as a powerful base. These reagents react explosively with water and are pyrophoric (ignite on exposure to air). Organomagnesium (Grignard) and organolithium reagents are sufficiently ionic to be strong carbon nucleophiles and bases, yet covalent enough to be soluble in many organic solvents. These two reagents are widely used in organic synthesis.

As a result of the highly polarized C–Mg bond, Grignard reagents are reactive not only toward electrophilic carbonyl carbons (as a “hot” nucleophile), but also toward acidic hydrogens (as a very strong base)—This base behavior even extends to the proton of water! Grignard reagents (RMgX) react immediately with acidic protons, if present, to give the corresponding R–H group (where R = aryl or alkyl, depending on the identity of the Grignard reagent). Even weak acids such as water, alcohols, phenols, and terminal acetylenes will react with a Grignard reagent to give the corresponding hydrocarbon (R–H). Since this side reaction will only lower the yield of our desired product, it is important to work with rigorously dried glassware.

Experiment Overview

As a nucleophile, Grignard reagents will react with many electrophiles, including the carbonyl carbon of aldehydes, ketones, and esters. Similarly, these reagents will also react with the electrophilic carbon of solid carbon dioxide, aka dry ice. Nucleophilic addition of an aryl or alkyl magnesium bromide to carbon dioxide produces an intermediate carboxylate salt that is converted to a carboxylic acid upon acidification. Following addition to the Grignard reagent, the excess dry ice is allowed to sublime and the reaction mixture is treated with aqueous acid to yield the carboxylic acid. The aqueous mixture is extracted with organic solvent to remove any inorganic salts and yield a solution of the product benzoic acid derivative plus any byproducts that may be formed. The product (and byproducts) are will then be separated by extraction of the organic solution with a solution of aqueous sodium hydroxide. The base solution will deprotonate the carboxylic acid to yield the water-soluble carboxylate salt (i.e., the conjugate base of the acid). The byproducts, however, will remain in the organic solvent. Thus, this extraction serves as a purification of the carboxylic acid. After separation of the two phases, acidification of the basic, aqueous extract regenerates the carboxylic acid product which precipitates out of solution. This white solid will be saved and used in the next stage of our multistep synthesis.

Safety and Waste

As always, appropriate lab attire and PPE are expected. Goggles must be worn any time chemicals or glassware are out and in use anywhere in the lab.

Care must be taken when handling dry ice. Prolonged contact of dry ice with skin will freeze cells and can cause injury similar to a burn. You must wear the provided insulated gloves when handling dry ice. The chemical gloves (nitrile) do not provide sufficient protection.

The hydrochloric acid and sodium hydroxide solutions should be handled with care. If any chemicals come into contact with your skin, clothes, or eyes, immediately wash the affected area with running water for 15 minutes and notify your TA. Large spills may require the use of the safety shower.

Experimental Protocol

You will use 15.8 mmol of the aryl bromide, 4-bromoanisole. All calculations should be made relative to the aryl bromide, unless otherwise noted. 4-bromoanisole will be provided as a 4.6 M solution in anhydrous THF.

Preparation of the Grignard Reagent

A 50-mL round-bottom flask will be oven-dried prior to your arrival. Carefully examine the flask for star cracks. Obtain a replacement if a star crack is found.

To an oven-dried 50-mL round-bottom flask, add 0.68 equiv. magnesium turnings. Attach the Claisen head and “air” condenser to the flask (Figure 2). Lightly grease all ground-glass joints when assembling the condenser apparatus.

Figure 2. A Claisen head–”air” condenser apparatus

Clamp the flask/condenser about 1″ above a heating stir plate. Add approximately 1 mL (about half a long glass pipette) of the  4-bromoanisole solution  (4.6 M in THF) to the flask through the Claisen head. Set the hot plate to a moderate heat setting; the reaction mixture should reach a gentle reflux. When the reaction mixture turns cloudy gray, add another 1 mL of the  4-bromoanisole solution dropwise. Continue the moderate heating and rapid stirring until the mixture reaches a gentle reflux.

Once the 4-bromoanisole solution has been fully added (15.8 mmol), continue to heat the mixture under gentle reflux for 15 min. Then, cool the flask to room temperature.

The Grignard Reaction

To a 100-mL beaker, add a piece (~2 g, about the size of a sugar cube) of dry ice and a stir bar. The surface of the dry ice should be fresh and unexposed to the air. Once at room temperature, slowly pour the Grignard reagent solution over the dry ice. Allow the mixture to stir until the solution reaches room temperature. Then, place the beaker in an ice-water bath. Slowly add 5 mL HCl (6 M) to the reaction and let stir for 5 min.

Dilute the mixture with ~15 mL EtOAc. Extract the product (2 x 15 mL) with EtOAc. Then, extract the combined organic phases with ~5 mL NaOH (3 M). Do not combine the acid/base washes. Extract the product (2 x 5 mL) with NaOH. Combine the two basic aqueous extracts. To the combined basic aqueous extracts, add ~5 mL HCl (6 M). A precipitate should form. Verify a pH of about 2–3. If the solution is neutral or basic, slowly add HCl until the mixture is sufficiently acidic.

Place the now-acidic suspension into an ice-water bath. Collect the solid by vacuum filtration. Rinse the filter cake with ice-cold water. Pull air through the filter for ~5 min to further dry the product. Store the product (open to air) for ~48 hours to dry.

Once dry, characterize the product by ¹H NMR, ¹³C NMR, and IR.