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Organic Chemistry II

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Reducing Agents


Source: Vy M. Dong and Daniel Kim, Department of Chemistry, University of California, Irvine, CA

Controlling the reactivity and selectivity during the synthesis of a molecule is very important criteria for chemists. This has led to the development of many reagents that allow chemists to pick and choose reagents suitable for a given task. Quite often, a balance between reactivity and selectivity needs to be achieved. This experiment will use IR spectroscopy to monitor the reaction and to understand the reactivity of carbonyl compounds as well as the reactivity of hydride-reducing reagents.


Before understanding hydride-donor reagents, the reactivity of carbonyl compounds needs to be understood. Carbonyl compounds have a slight positive charge on the carbonyl-carbon giving it an electrophilic-character. Thus, carbonyl compounds that have a positive charge are more reactive to different nucleophiles such as a hydride donor. Acyl chlorides have a good leaving group (Cl-) making it also very electrophilic. Esters and amides are more stable because of the strong resonance structure from the second heteroatom on the carbonyl.

Most reductions of carbonyl compounds are done with reagents that transfer a hydride from boron or aluminum. Two common reagents of this type are sodium borohydride and lithium aluminum hydride. Sodium borohydride is a less reactive donor reagent but is efficient for reducing aldehydes and ketones to alcohols. However, lithium aluminum hydride is much more reactive and can reduce ketones and aldehydes to alcohols but also reduce esters, amides, and carboxylic acids.

To demonstrate the varying degree in reactivity, a reaction with two carbonyl functional groups will be subjected to two sets of conditions with hydride-donating reducing reagents.

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1. Measuring Properties of Ethyl Acetoacetate

  1. Take an IR of the starting material (ethyl acetoacetate).
  2. Take a TLC using 40% ethyl acetate in 60% hexanes.

2. Reduction of Ethyl Acetoacetate with Sodium Borohydride

  1. Add 1 mmol of ethyl acetoacetate to a round-bottom flask.
  2. Add 5 mL of ethanol and swirl to mix completely.
  3. Lower the beaker into an ice-water bath.
  4. Weigh 1 mmol of sodium borohydride and slowly add to the stirred solution of ethyl acetoacetate.
    1. Add in small portions. The reaction is exothermic and bubbles vigorously.
  5. Immediately after, monitor the reaction by TLC every few minutes until the reaction is complete.
  6. Once complete, add 10 mL of water to the reaction mixture.
  7. Transfer into a separatory funnel and extract with ethyl acetate (2x 30 mL).
  8. Dry with DI water (1x 30 mL) and with brine (1x 30 mL).
  9. Dry over sodium sulfate and filter into a round-bottom flask.
  10. Evaporate the solvent on a rotary evaporator.
  11. Take a TLC and IR of the reduction product.

3. Reduction of Ethyl Acetoacetate with Lithium Aluminum Hydride

  1. Add 1 mmol of lithium aluminum hydride into a dry round-bottom flask and cap it with a septum.
  2. Purge the flask with nitrogen gas using a nitrogen inlet line. Make sure to have an exit valve.
  3. Add 10 mL of dry THF.
  4. Place the round-bottom flask into an ice bath.
  5. Make a solution of 1 mmol of ethyl acetoacetate into 3 mL of dry THF and slowly add dropwise into the reaction flask.
  6. The reaction will vigorously bubble until all of the reagent is added.
  7. Immediately after, monitor the reaction by TLC every few minutes until the reaction is complete.
  8. Once complete, add 1 M HCl dropwise. The reaction will bubble vigorously until all of the LiAlH4 is consumed.
  9. Once consumed (no more bubbling), the septum can be removed and diluted with ethyl acetate (40 mL) and 1 M HCl (20 mL).
  10. Transfer to a separatory funnel.
  11. Extract with ethyl acetate (3x 50 mL).
  12. Dry with brine (1x 50 mL).
  13. Dry over sodium sulfate and filter into a round-bottom flask.
  14. Evaporate the solvent on a rotary evaporator.
  15. Take a TLC and IR of the reduction product.

The reduction of carbonyls is a common task in organic chemistry. Chemists use different reducing agents to carefully control the outcome of the procedure.

Carbonyls are functional groups with a carbon atom double-bonded to an oxygen. Carbonyl groups appear in many types of compounds. When carbonyls are reduced, the product will depend in part on the exact chemical composition of the compound. Additionally, a particular reactant may have different reduction products. By using different reducing agents, chemists can control these products, or whether the reaction takes place at all.

This video will illustrate the reaction of a carbonyl compound with two different reducing agents, and the different products that result.

Carbon is less electronegative than oxygen, so when they share a bond, as in a carbonyl, the carbon will have a partial positive charge, making it electrophilic. This in turn makes it susceptible to nucleophilic attack, like the hydride transfer that starts most carbonyl reductions. Increasing this positive charge increases the electrophilicity, increasing the reactivity of the carbon. Decreasing the charge will make the carbon less reactive

Acyl halides have another strongly electronegative atom, such as chlorine, bound to the carbon, increasing the positive charge on the carbon. Therefore, this group is more reactive than ketones or aldehydes. On the other hand, esters, amides, and carboxylic acids all have resonance structures that spread additional negative charge onto their carbons, making them less positive. Therefore, these compounds are less reactive than ketones and aldehydes.

Different hydride donors have different reactivities as well, affecting which carbonyl compounds they are able to reduce. Lithium aluminum hydride is highly reactive, and is able to reduce most carbonyl compounds. Meanwhile, sodium borohydride has a relatively low reactivity. It can reduce acyl halides, aldehydes, and ketones, but is unable to reduce the less reactive esters, amides, or carboxylic acids. Lithium tri-tert-butoxyaluminum hydride's reactivity is intermediate, and will also produce different reduction products

Chemists use these principles of reactivity to control which products result from a reduction reaction. For example, ethyl acetoacetate has 2 unique carbonyl groups: a ketone and an ester. If it is reduced with sodium borohydride, only the ketone will be affected, producing ethyl 3-hydroxybutarate. However, if it is reduced with lithium aluminum hydride, both carbonyls will be affected, producing 1,3-butanediol.

To demonstrate these principles of carbonyl reduction, we will carry out both reduction reactions with ethyl acetoacetate. We will also investigate the products with thin-layer chromatography and infrared spectroscopy, to carefully examine the fate of each carbonyl.

The first reaction will use the less reactive sodium borohydride. To begin, set up a round-bottom flask over a stirplate Add a stirbar and 0.127 mL of ethyl acetoacetate to this flask. Then, add 5 mL of ethanol and begin stirring.

Next, weigh out 74 mg of sodium borohydride. In small portions, add it to the flask. The reduction reaction will turn white and bubble. After adding all the borohydride, monitor the reaction every few minutes with thin layer chromatography, using 40% ethyl acetate and 60% hexane as the mobile phase. The expected product will have a slightly lower retention value than the starting ethyl acetoacetate.

Once the reaction has finished, add 10 mL of water to the mixture to quench the reaction. Extract the product from the water twice with 30 mL of ethyl acetate in a separatory funnel. For more information about this procedure, see our video on extraction

In a separatory funnel, mix 30 mL brine with the solution. Mix the solution, allowing it to separate into two layers, and collect the organic phase. To this, add sodium sulfate powder, which will absorb any remaining water, until it no longer clumps.

Filter the solution into a round-bottomed flask, then evaporate the solvent with a rotary evaporator, or rotovap.

Next, use TLC to check the purity of the product. Then, analyze the product with infrared spectroscopy. See our video on IR for more details. Use a similar procedure to analyze the starting ethyl acetoacetate for reference.

Next, let's see the reaction using the more reactive lithium aluminum hydride. Set up a round-bottom flask with a stirbar, septum, and nitrogen inlet and outlet lines. Add 76 mg of lithium aluminum hydride to the flask and quickly recap with the septum and purge the flask with the nitrogen for a few minutes. After purging, inject 10 mL of dry tetrahydrofuran and lower the flask into an ice bath

When the other preparations are complete, make a solution of 0.127 mL of ethyl acetoacetate and 3 mL of dry THF. Inject this solution dropwise into the flask. The reaction will bubble vigorously. As before, monitor the reaction with TLC. The expected product-1,3, butanediol-will also have a lower retention value than the original ethyl acetoacetate.

When the reaction is complete, add 1 M hydrochloric acid dropwise, until all the lithium aluminum hydride is consumed and the solution stops bubbling. Remove the septum, then add 40 mL of ethyl acetate and 20 mL of 1 M hydrochloric acid.

Now, purify the product using the same steps as before. Extract the product three times with 50 mL of ethyl acetate. Dry the ethyl acetate solution with 30 mL of saline and sodium sulfate, filter, and evaporate the solvent with a rotovap.

Now that we have a product, we can analyze it with TLC and IR as before.

First, let's take a look at the TLC results. Ethyl acetoacetate is highly non-polar, and will travel close to the solvent front on a TLC plate. Its product with sodium borohydride, ethyl 3-hydroxybutarate, is slightly more polar, and won't travel as far. Meanwhile, the product with lithium aluminum hydride, 1,3-butanediol, is even more polar, causing it to travel the least up the plate

Now, let's examine the IR results. Ethyl acetoacetate has two peaks that correspond to the stretching of the carbonyl bond. One, around 1,650 wavenumbers, is the ketone and the other, around 1,730, is the ester. The spectrum of the first product is similar, however it has only one carbonyl peak and has gained a broad alcohol O-H stretching peak at around 3,200 wavenumbers. The second product shows a loss of both carbonyl peaks, illustrating the higher reactivity of the lithium aluminum hydride

The control of selectivity and reactivity are important and must be balanced in many organic reactions. Let's look a few ways in which this is done.

In addition to selectively reducing functional groups, reducing agents may react stereospecifically, leading to products with different three-dimensional structures. For example, the reduction of 4-tert-butyl-cyclohexanoneto 4-tert-butyl-cyclohexanol produces two different stereoisomers, depending on which direction the hydride attacks the carbonyl from. Lithium aluminum hydride attacks from the axial side, producing the trans product. Another reducing agent, L-selectride, attacks from the equatorial side, producing the cis product.

Lastly, we can selectively modify other types of molecules, such as proteins. For instance, maleimides specifically form bonds with thiol groups, but not other nucleophiles. In a protein, the only thiol groups present are in the amino acid cysteine, so maleimides will only form bonds with those parts of the molecule. Biochemists can use these compounds with dyes attached to illuminate specific regions of a protein

You've just watched JoVE's introduction to chemoselectivity in reduction reactions. You should now understand how different reducing agents can produce different products when reacting with carbonyls. Thanks for watching!

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Figure 1
Figure 1. Representative IR results for ethyl 3-hydroxybutyrate.

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Applications and Summary

The trends of carbonyl reactivity and hydride donor ability have been reviewed and demonstrated. The visual reactiveness of the two commonly used reagents is apparent and can be appreciated.

The understanding of the reactivity of reagents and functional groups is of high importance when developing new methods for reductions or any other kind of reaction. Controlling the selectivity and reactivity of any reaction is an important factor to consider when deciding on the reagents used for a chemical step. This drives chemists to develop new reagents and new methods.

The review of periodic trends is still important in organic chemistry. For example, when adding potassium metal to water, there is a more violent explosion than when sodium metal is added to water. For that reason, we could extend this analogy to the comparison and reasoning to why LiAlH4 is more reactive than NaBH4.

On the entire spectrum of nucleophiles and electrophiles, reactivity matters. A weak nucleophile will not react with a weak electrophile; but a more reactive electrophile might react with the same weak nucleophile. It all depends on their reactivity and the conditions.

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Reducing Agents Carbonyls Organic Chemistry Reactants Reduction Products Chemical Composition Electrophilic Nucleophilic Attack Hydride Transfer Acyl Halides Ketones Aldehydes Esters Amides Carboxylic Acids

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