n-Butyllithium Titration

Organic Chemistry II

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Overview

Source: Vy M. Dong and Diane Le, Department of Chemistry, University of California, Irvine, CA

This experiment will demonstrate a simple technique to titrate and obtain an accurate concentration of the organolithium reagent, n-butyllithium (n-BuLi). Organolithium reagents are extremely air- and moisture-sensitive and proper care must be taken to maintain the quality of the reagent so that it may be used successfully in a reaction. The n-BuLi titration experiments should be performed regularly to obtain accurate concentrations prior to use in a chemical reaction. Subsequently, we will demonstrate the addition of the titrated n-BuLi to benzaldehyde.

Cite this Video

JoVE Science Education Database. Organic Chemistry II. n-Butyllithium Titration. JoVE, Cambridge, MA, (2017).

Principles

Organolithium reagents are compounds containing a C−Li bond and are very strong bases. Because organolithiums are extremely air- and moisture-sensitive, proper care must be taken to handle these reagents. They are sensitive to acids, corrosive, and often pyrophoric. n-BuLi, an alkyllithium, is typically stored at low temperatures (less than 0 °C) and stored as a solution in hydrocarbons such as hexanes. N-BuLi can be used as a base or nucleophile depending on the reaction conditions. Furthermore, it can be used in halogen-lithium exchange reactions to generate aryl or vinyl lithium reagents, which can immediately react with an electrophile. In addition, n-BuLi is commonly used as an initiator in the polymerization of dienes used in elastomers.

Titration is a common quantitative analytical technique used to determine an unknown concentration of an analyte by adding a known concentration of a titrant until the reaction reaches completion, which is indicated by a color change. In this experiment, we will demonstrate the titration of n-BuLi and calculate its concentration with diphenylacetic acid as the titrant, which is a stable solid and can be easily weighed. Upon reaction of the n-BuLi with diphenylacetic acid, the solution turns a deep yellow color at the end point of the titration, and so an indicator is not needed (Figure 1). By measuring the precise volume of n-BuLi used to consume the diphenylacetic acid, we can calculate the molarity of the reaction. This experiment should be repeated three times to obtain an average measurement.

Figure 1
Figure 1. Reaction of n-BuLi with diphenylacetic acid.

Procedure

1. Preparation of Titrant

  1. To a flame-dried round bottom flask equipped with a stir bar under N2, add diphenylacetic acid (250 mg, 1.18 mmol) and anhydrous THF (5 mL).

2. Titration of n-BuLi

  1. Calculate the approximate amount of n-BuLi solution (in hexanes) needed to consume the diphenylacetic acid. Using a syringe, slowly adda solution of n-BuLi dropwise. The reaction mixture will turn temporarily yellow and back to a colorless solution with each drop.
  2. Continue adding the solution of n-BuLi dropwise until the reaction mixture continues to stay a deep yellow color. This will be the end point of the reaction.
  3. Repeat the titration 3x to obtain an average volume of the n-BuLi used.

3. Calculation of Molarity

  1. The moles of n-BuLi used in the titration are equivalent to the moles of diphenylacetic acid used in the reaction. Since the moles of diphenylacetic acid used is known, the calculation of concentration of n-BuLi is given by the following equation: mmol diphenylacetic acid/mL n-BuLi = molarity of n-BuLi solution.

4. Addition of n-BuLi to Benzaldehyde (Figure 2)

  1. To a flame-dried round bottom flask equipped with a stir bar under N2, add anhydrous THF (30 mL) and benzaldehyde (3 mmol, 1 equiv.). Cool the solution to −78 °C.
  2. Add n-BuLi (1.1 equiv.) and let the reaction warm to room temperature.
  3. Add saturated NH4Cl (aq., 10 mL) to quench the reaction and extract the aqueous layer with diethyl ether (2 x 25 mL).
  4. Wash the combined organic layers with water (2 x 15 mL) and brine (1 x 20 mL).
  5. Dry with Na2SO4, filter, and concentrate the combined organic layers under reduced pressure to afford the product.

Figure 2. Addition of n -BuLi to benzaldehyde.

Figure 2

N-butyllithium, abbreviated n-BuLi, is an organolithium reagent that is frequently used as a strong base or as a nucleophile.

N-butyllithium is commercially available as a solution in alkanes such as hexane or heptane. These solutions are stable when properly stored, but still degrade upon aging and exposure to water or oxygen.

When using an n-butyllithium solution to prepare lithium di-isopropylamide, another type of strong base, it is essential that a precise amount is used in the reaction. For this reason, titration experiments must be performed prior to each use.

This video will illustrate the principles of n-butyllithium, a procedure for the titration of an n-butyllithiumsolution and its use in a chemical reaction, and several applications.

N-butyllithium, a four-carbon chain with a carbon-lithium bond at one end, is used as a strong Brønsted base and in lithium-halogen exchange reactions, but can also be used as a nucleophile or as a polymerization initiator in the production of elastomers.

For most experiments, only a slight molar excess of n-butyllithium must be added to the reaction mixture. Adding too little reagent will result in an incomplete reaction, and adding too large an excess may result in unwanted side products. The precise amount of n-butyllithium solution to be added is calculated by performing a titration experiment with diphenylacetic acid.

Now that we have discussed the principles of n-butyllithium, let's look at a procedure for titration of an n-butyllithium solution, and for its use in a chemical reaction.

First, cool to room temperature a flame-dried 20-mL round-bottomed flask and stir bar under a nitrogen atmosphere, then add diphenylacetic acid and 5 mL anhydrous tetrahydrofuran.

Using a 2-mL graduated glass syringe fitted with a needle, draw up 2 mL 1.6 molar solution of n-butyllithium in hexanes, which is under a nitrogen atmosphere. Then insert the needle into the flask containing diphenylacetic acid. While stirring, add the n-butyllithium solution dropwise to the contents of the flask, which should turn yellow and then back to colorless.

Continue adding n-butyllithium solution until the deep yellow color persists, indicating the endpoint has been reached. Note how much n-butyllithium has been added, and divide 1.18, which is the number of millimoles of diphenylacetic acid, by this number to calculate the actual molar concentration.

Now that we have calculated the actual concentration of n-butyllithium solution, we are ready to use it in an experiment. Cool to room temperature a flame-dried 100-mL round-bottomed flask and stir bar under a nitrogen atmosphere, then add benzaldehyde in 20 mL anhydrous tetrahydrofuran. Stir the contents at -78 degrees Celsius in a dry ice/acetone bath.

Add n-butyllithium dropwise to the flask.

Then using thin-layer chromatography, monitor benzaldehyde consumption. Once the reaction is complete, remove the flask from the chilled bath and allow it to reach room temperature. Next, add 10 mL saturated aqueous ammonium chloride to quench the reaction. Then extract the aqueous layer twice with 25 mL diethyl ether. Combine the organic layers and wash twice with 15 mL water then once with 15 mL saturated sodium chloride solution.

Remove traces of water from the combined organic layers by adding approximately 1 g of sodium sulfate, then filter off the solid and rinse with additional diethyl ether. Concentrate the mixture under reduced pressure to obtain the product. It should be a colorless liquid in appearance.

Now that we have seen an example laboratory procedure, let's see some useful applications of n-butyllithium.

Elastomers are a type of polymer having rubberlike properties, and are useful for many types of products, including dielectric actuators. A catalytic amount of n-butyllithium is important in the production of polybutadiene, for instance, by a Michael addition to one of the two vinyl groups of 1,4-butadiene, and the resulting anion adding to a second molecule of 1,4-butadiene, forming three possible addition products.

Vinyl and aromatic groups in natural products and pharmaceutical drugs are very common. Vinyl and aryl halides react with a molar equivalent of n-butyllithium in a lithium-halogen exchange to generate vinyl- and aryllithiums, which can displace a leaving group in an electrophile and form a new carbon-carbon bond.

Another common application of n-butyllithium is as a strong Brønsted base to generate a carbon nucleophile. In the synthesis of clarinex, an antihistamine drug, two equivalents of n-butyllithium are used to remove a proton from a picoline derivative, generating a carbon nucleophile, which displaces the leaving group in a benzyl chloride to create a new carbon-carbon bond. The resulting species is then converted to clarinex in four steps.

You've just watched JoVE's introduction to n-Butyllithium Titration and Addition of n-Butyllithium to Benzaldehyde. You should now understand the principles of n-butyllithium, how to perform an experiment, and some of its applications. Thanks for watching!

Results

Representative results for the titration of n-BuLi for Procedures 1-3

Procedure Step Color of reaction mixture
1.1 Colorless
2.1 Yellow, then colorless
2.2 Deep yellow
3.1 1.18 mmol diphenylacetic acid/1 mL n-BuLi = 1.18 M n-BuLi in hexanes

Table 1. Representative results for Procedures 1-3.

Applications and Summary

In this experiment, we have demonstrated how to determine the concentration of an n-BuLi solution by using diphenylacetic acid. We have also performed a reaction by adding n-BuLi to benzaldehyde.

Accurate concentrations of n-BuLi are important for its successful application in a number of reactions. n-BuLi is commonly used in lithium-halogen exchange reactions to prepare aryllithium or vinyllithium reagents, which can be subsequently used in C-C bond forming reactions. Furthermore, it can be used as a base or nucleophile, depending on the reaction conditions.

1. Preparation of Titrant

  1. To a flame-dried round bottom flask equipped with a stir bar under N2, add diphenylacetic acid (250 mg, 1.18 mmol) and anhydrous THF (5 mL).

2. Titration of n-BuLi

  1. Calculate the approximate amount of n-BuLi solution (in hexanes) needed to consume the diphenylacetic acid. Using a syringe, slowly adda solution of n-BuLi dropwise. The reaction mixture will turn temporarily yellow and back to a colorless solution with each drop.
  2. Continue adding the solution of n-BuLi dropwise until the reaction mixture continues to stay a deep yellow color. This will be the end point of the reaction.
  3. Repeat the titration 3x to obtain an average volume of the n-BuLi used.

3. Calculation of Molarity

  1. The moles of n-BuLi used in the titration are equivalent to the moles of diphenylacetic acid used in the reaction. Since the moles of diphenylacetic acid used is known, the calculation of concentration of n-BuLi is given by the following equation: mmol diphenylacetic acid/mL n-BuLi = molarity of n-BuLi solution.

4. Addition of n-BuLi to Benzaldehyde (Figure 2)

  1. To a flame-dried round bottom flask equipped with a stir bar under N2, add anhydrous THF (30 mL) and benzaldehyde (3 mmol, 1 equiv.). Cool the solution to −78 °C.
  2. Add n-BuLi (1.1 equiv.) and let the reaction warm to room temperature.
  3. Add saturated NH4Cl (aq., 10 mL) to quench the reaction and extract the aqueous layer with diethyl ether (2 x 25 mL).
  4. Wash the combined organic layers with water (2 x 15 mL) and brine (1 x 20 mL).
  5. Dry with Na2SO4, filter, and concentrate the combined organic layers under reduced pressure to afford the product.

Figure 2. Addition of n -BuLi to benzaldehyde.

Figure 2

N-butyllithium, abbreviated n-BuLi, is an organolithium reagent that is frequently used as a strong base or as a nucleophile.

N-butyllithium is commercially available as a solution in alkanes such as hexane or heptane. These solutions are stable when properly stored, but still degrade upon aging and exposure to water or oxygen.

When using an n-butyllithium solution to prepare lithium di-isopropylamide, another type of strong base, it is essential that a precise amount is used in the reaction. For this reason, titration experiments must be performed prior to each use.

This video will illustrate the principles of n-butyllithium, a procedure for the titration of an n-butyllithiumsolution and its use in a chemical reaction, and several applications.

N-butyllithium, a four-carbon chain with a carbon-lithium bond at one end, is used as a strong Brønsted base and in lithium-halogen exchange reactions, but can also be used as a nucleophile or as a polymerization initiator in the production of elastomers.

For most experiments, only a slight molar excess of n-butyllithium must be added to the reaction mixture. Adding too little reagent will result in an incomplete reaction, and adding too large an excess may result in unwanted side products. The precise amount of n-butyllithium solution to be added is calculated by performing a titration experiment with diphenylacetic acid.

Now that we have discussed the principles of n-butyllithium, let's look at a procedure for titration of an n-butyllithium solution, and for its use in a chemical reaction.

First, cool to room temperature a flame-dried 20-mL round-bottomed flask and stir bar under a nitrogen atmosphere, then add diphenylacetic acid and 5 mL anhydrous tetrahydrofuran.

Using a 2-mL graduated glass syringe fitted with a needle, draw up 2 mL 1.6 molar solution of n-butyllithium in hexanes, which is under a nitrogen atmosphere. Then insert the needle into the flask containing diphenylacetic acid. While stirring, add the n-butyllithium solution dropwise to the contents of the flask, which should turn yellow and then back to colorless.

Continue adding n-butyllithium solution until the deep yellow color persists, indicating the endpoint has been reached. Note how much n-butyllithium has been added, and divide 1.18, which is the number of millimoles of diphenylacetic acid, by this number to calculate the actual molar concentration.

Now that we have calculated the actual concentration of n-butyllithium solution, we are ready to use it in an experiment. Cool to room temperature a flame-dried 100-mL round-bottomed flask and stir bar under a nitrogen atmosphere, then add benzaldehyde in 20 mL anhydrous tetrahydrofuran. Stir the contents at -78 degrees Celsius in a dry ice/acetone bath.

Add n-butyllithium dropwise to the flask.

Then using thin-layer chromatography, monitor benzaldehyde consumption. Once the reaction is complete, remove the flask from the chilled bath and allow it to reach room temperature. Next, add 10 mL saturated aqueous ammonium chloride to quench the reaction. Then extract the aqueous layer twice with 25 mL diethyl ether. Combine the organic layers and wash twice with 15 mL water then once with 15 mL saturated sodium chloride solution.

Remove traces of water from the combined organic layers by adding approximately 1 g of sodium sulfate, then filter off the solid and rinse with additional diethyl ether. Concentrate the mixture under reduced pressure to obtain the product. It should be a colorless liquid in appearance.

Now that we have seen an example laboratory procedure, let's see some useful applications of n-butyllithium.

Elastomers are a type of polymer having rubberlike properties, and are useful for many types of products, including dielectric actuators. A catalytic amount of n-butyllithium is important in the production of polybutadiene, for instance, by a Michael addition to one of the two vinyl groups of 1,4-butadiene, and the resulting anion adding to a second molecule of 1,4-butadiene, forming three possible addition products.

Vinyl and aromatic groups in natural products and pharmaceutical drugs are very common. Vinyl and aryl halides react with a molar equivalent of n-butyllithium in a lithium-halogen exchange to generate vinyl- and aryllithiums, which can displace a leaving group in an electrophile and form a new carbon-carbon bond.

Another common application of n-butyllithium is as a strong Brønsted base to generate a carbon nucleophile. In the synthesis of clarinex, an antihistamine drug, two equivalents of n-butyllithium are used to remove a proton from a picoline derivative, generating a carbon nucleophile, which displaces the leaving group in a benzyl chloride to create a new carbon-carbon bond. The resulting species is then converted to clarinex in four steps.

You've just watched JoVE's introduction to n-Butyllithium Titration and Addition of n-Butyllithium to Benzaldehyde. You should now understand the principles of n-butyllithium, how to perform an experiment, and some of its applications. Thanks for watching!

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