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Stereospecific Reduction of Benzil with Sodium Borohydride; Determination of the Stereochemistry by NMR Spectroscopy Oxidation Compounds containing the

ketone or aldehyde functional group are important in organic chemistry. They are common in nature and are often key intermediates in organic synthesis. Useful methods for preparation of ketones include the coupling of acid chlorides with organocopper reagents and the hydration of alkynes. Aldehydes can be prepared by reduction of acid chlorides with certain metal hydrides or by catalytic hydrogenation. However, the most important method for preparation of both ketones and aldehydes is the oxidation of alcohols. Alcohols are among the most readily available organic compounds, and therefore, this method for preparation of aldehydes and ketones is extremely useful. Primary and secondary alcohols are oxidized to the corresponding aldehydes and ketones by various oxidizing agents, e.g., dichromates, t-butyl hypochlorite, hypochlorous acid, potassium permanganate, and nitric acid. The aldehydes derived from primary alcohols can be further oxidized to carboxylic acids by some of these oxidizing agents (including HOCl), while the ketones derived from secondary alcohols are stable to further oxidation.

Oxidation is a very common reaction in organic chemistry and chromium (VI) compounds are especially useful as oxidizing agents. At the end of the oxidation the chromium is usually reduced to chromium (III). Recall that primary alcohols will oxidize in two stages, firstly to aldehydes and then to carboxylic acids:

The second oxidation step is normally very facile and either special oxidants (e.g. pyridine chlorochromate, PCC), or special experimental conditions must be employed (eg rapid removal of the aldehyde from the oxidant by distillation) in order to obtain aldehydes in good yield. Secondary alcohols are more straightforward and, provided excessive heat is not used, they will oxidize smoothly to ketones:

Tertiary alcohols are stable to oxidizing agents at normal temperatures. However, heating in the presence of acidic oxidizing agents will cause elimination and the oxidation of the alkene. The most widely used oxidizing agent is chromic acid, which is prepared by mixing sodium dichromate with sulfuric acid. However, chromium salts are suspected mutagens and carcinogens, and strict EPA regulations exist for the handling and disposal of chromium compounds. The oxidizing agent used in this procedure is hypochlorous acid, the active component of household bleach. Replacing a harmful and polluting chemical reagent, such as chromic acid, with a relatively innocuous chemical, such as bleach, is an example of green chemistry at work. Green chemistry is the name given to modifications implemented in chemical manufacturing processes which ensure a safer and cleaner environment.

Hypochlorous acid (HOCl), an alternative oxidizing agent, is readily available, inexpensive, safe, and environmentally sound as compared to the dichromates. Although HOCl is unstable and decomposes slowly to upon storage, it can be prepared from a common household item: bleach. Household bleach contains sodium hypochlorite which, when treated with acetic acid*, produces the active oxidizing agent

Acetic acid is a component of another household item, namely, vinegar. Vinegar contains 4-5% acetic acid.

Reduction Sodium borohydride was discovered in 1943 by H. I. Schlesinger and H. C. Brown. Brown devoted his entire scientific career to this reagent, making it and other hydrides the most useful and versatile of reducing reagents. He received a Nobel Prize for his work. The reduction of carbonyl compounds is an important synthetic route to alcohols. Aldehydes and ketones can be reduced by a variety of reagents to yield their respective alcohol products. Among the most useful reagents for accomplishing these reductions are the complex metal hydrides such as lithium aluminum hydride (LiAlH4 or LAH) and sodium borohydride (NaBH4).

LAH and NaBH4 differ in their reactivities towards different classes of carbonyl,compounds. LAH is highly reactive and will reduce acid chlorides, esters, carboxylic acids, amides, and nitriles as well as aldehydes and ketones. NaBH4 is less reactive and therefore more selective than LAH: it reduces aldehydes and ketones, but not carboxylic acids and amides, and only slowly reduces esters. LAH reacts violently with water and other hydroxylic compounds, and reductions using this reagent must be carried out under non-protic, anhydrous conditions. Sodium borohydride, on the other hand, reacts only slowly with water and alcohols, and can be used in a wide range of solvents, including water and alcohols. The reaction is usually exothermic, but not violently so. NaBH4 is much safer to handle than is LAH, making it a good choice whenever the functional group to be reduced is an aldehyde or ketone. In an alcohol solution, NaBH4 ionizes to form Na+ and -BH4. The negativelycharged hydride complex, -BH4, reacts with the carbonyl as illustrated below. The alcohol facilitates the reduction by hydrogen bonding interactions between the carbonyl oxygen and the acidic hydroxyl group of the alcohol.

The borate, H-BH2OEt-, formed from the acid-base reaction of -:OEt and BH3, has three remaining BH bonds, each of which, in turn, reduces another molecule of the starting ketone:

Note that the stoichiometry of the overall reaction is the following: One mole of NaBH4 reduces four moles of aldehyde or ketone

Stereospecific Reduction of Benzil with Sodium Borohydride; Determination of the Stereochemistry by NMR Spectroscopy
The stereochemistry of the reduction of cyclic ketones with sodium borohydride is reasonably well understood with various torsional and steric effects playing important roles determining the relative energies of transition states. The stereochemical course of ketone reductions can be influenced by the presence of hydroxyl groups close to the carbonyl function. This experiment illustrates the stereoselective reduction of benzil using sodium borohydride as a reducing agent to the 1,2-diol. The reduction of a carbonyl group in an organic compound can be readily accomplished with a metal hydride, such as lithium aluminum hydride or sodium borohydride. While LiAlH4 is the more powerful of the two, capable of reducing aldehydes, ketones, carboxylic acids, esters and amides, NaBH4 is easier to handle and more selective, reducing only aldehydes and ketones. Sodium borohydride can be utilized under non-anhydrous conditions and in alcoholic solutions, in contrast to lithium aluminum hydride which reacts violently with both water and alcohol. Every mole of NaBH4 reduces four moles of carbonyl groups, however, a stoichiometric excess of the reducing agent is usually used since impurities may be present in the reagent or a small amount may react with the solvent.
O NaBH4 O ethanol O OH NaBH4 ethanol OH OH

benzil

benzoin

hydrobenzoin

Each mole of NaBH4 provides 4 moles of hydride (H-) therefore: 2 Benzil + NaBH4 2 Hydrobenzoin The mechanism for the reduction of a carbonyl group with sodium borohydride is shown:

In the last step of the experimental procedure for week 1, water is added followed by heating which results in hydrolysis of the boron complex and formation of the desired alcohol.

Excess reducing agent is also eliminated during this step since sodium borohydride decomposes in water at elevated temperatures. In todays experiment, you will use sodium borohydride to reduce the compound benzil, thus producing hydrobenzoin:

Three possible stereoisomers of hydrobenzoin can form from this reaction, as shown above. The melting point of your product should give you some indication as to which isomer(s) are formed. Week II: The second step involves the conversion of the resulting 1,2-diol into its acetonide (isopropylidene/acetal) derivative catalyzed by anhydrous iron(III) chloride, a reaction commonly used for the protection of 1,2-diols during a synthetic sequence when strong bases are used as reagents. Nuclear magnetic resonance (NMR) spectroscopic analysis of the acetonide permits the determination of its relative stereochemistry and hence that of the diol. The purpose of this

experiment is to carry out this reaction and determine the identity of the product. The stereochemistry of the product will be determined by preparing the acetal derivative with acetone. The cyclic acetal produced from the meso isomer has two non-identical methyl groups that will produce different NMR signals.

The derivative produced from the racemic mixture has equivalent methyl groups that produce a single NMR signal.

Construct models of the acetals to convince yourself that the statements made are accurate. Materials 1. Preparation of 1,2-diphenylethane-1,2-diol benzil 10mmol sodium borohydride 10mmol ethanol light petroleum (bp 6080C) hydrochloric acid (6 M) 2. Preparation of acetonide derivate acetone (pure) iron(III) chloride (anhydrous) 0.30g dichloromethane light petroleum (bp 4060C) potassium carbonate solution (10%)

irritant corrosive, flammable flammable, toxic flammable corrosive

flammable corrosive, hygroscopic irritant, toxic flammable corrosive

Procedure First, check that the sodium borohydride is good by placing a small amount in a few drops of methanol and heating gently. Remove from heat, and if H2 gas bubbles are vigorously forming on the NaBH4, the material is still good. An appreciable amount of NaBH4 will react slowly (and exothermically) with water or alcohol to form sodium borate and hydrogen gas:

1. Preparation of 1,2-diphenylethane-1,2-diol Dissolve 2g benzil in 20 mL of ethanol in a 100 mL Erlenmeyer flask. Record the exact weight, and use this for your calculation of theoretical and percent yield. Swirl the flask in a beaker of hot water for 2 minutes then swirl the flask under cool running water to produce a fine suspension. Add 0.4 g of sodium borohydride and swirl. Add the sodium borohydride in small portions over 5 min using a spatula. If necessary, rinse in the last traces of sodium borohydride with 5mL of ethanol. Allow the solution to sit for 10 minutes (the solution should clear and the yellow color should fade in 2-3 minutes). Add 30mL of water followed by 1 mL of 6 M hydrochloric acid. Place in a beaker of hot water for 5 minutes with swirling. Stir the mixture at room temperature for a further 20 min, and then cool it in an ice bath. If the solution is not clear at this point, filter it by gravity (hot) through fluted filter paper. Add a further 10 mL of water, and set it aside to crystallize for about 20 min. Collect the product by suction. Dry with suction for 30 min. Weigh the product and record the yield. This material is sufficiently pure to be used, so set aside 1.00 g of the product to be left drying until the next period for use in the Preparation of acetonide derivative. Recrystallize the remainder (ca.0.50 g) from petroleum (bp 6080C). record the mp and IR spectrum of the product after one recrystallization. Record an IR spectrum of benzil for comparison. 2. Preparation of acetonide derivative (2,2-dimethyl-4,5-diphenyl-1,3-dioxolane) Dissolve 1.00 g of the diol in 30 mL of pure acetone, and add the anhydrous iron(III) chloride. Heat the mixture under reflux with a calcium chloride guard tube for 20 min, and then allow it to cool to room temperature. Pour the mixture into a 100 mL beaker containing 40 mL water, and add 10 mL potassium carbonate solution. Transfer the mixture to a 250 mL separatory funnel and extract with 3 x 20 mL portions of dichloromethane. Wash the combined organic extracts with 25 mL water, and then dry them over MgSO4. Evaporate the solvent on the rotary evaporator, and purify the crude acetonide by dissolving it in 15 mL boiling petroleum (bp 4060C), and filtering whilst hot to remove any unreacted diol. Concentrate the filtrate to a volume of 35 mL, and then cool the solution in ice, whereupon the acetonide crystallizes out. Collect the product by suction filtration, and wash it with a little ice-cold petroleum. Dry the product by suction at the filter pump for 10 min. Record the yield, mp and IR spectrum of the product. Record the NMR spectrum (CDCl3) of your purified material for assignment of stereochemistry.

Data Analysis 1. Based on your proton NMR spectrum draw a 3-D structure of the acetonide formed in your experiment. 2. Based on the identity of the acetonide formed what was the stereochemistry of the hydrobenzoin produced by the reduction reaction? Draw its structure. 3. The melting point of meso-hydrobenzoin is 137-9oC and the melting point of the racemic mixture is 122-3oC. Is your melting point data consistent with the conclusions based on the NMR spectrum? 4. Discuss the mechanism and stereochemistry of the reduction; propose a transition state for the reduction which accounts for the stereochemistry. 5. Compare and contrast the IR spectra of benzil, the diol and the acetonide; Assign peaks to the important group frequencies of the functional groups. Questions. 1) What two product alcohols would be produced if (R)-3-methylcyclohexanone were treated with sodium borohydride? 2) Give the products of the following reactions:

3) Each of the compounds below is treated with hypochlorous acid (HOCl). For each compound, give the structure of the product of the reaction or, if no reaction occurs, write No Reaction.

4) The IR spectra of benzophenone and benzhydrol are shown in Figure 1. Determine which spectrum represents which compound and designate which bands substantiate your assignment. 5) The 1H-NMR spectra of benzhydrol and benzophenone are given in Figure 2. Identify which spectrum belongs to which compound and assign the peaks in each spectrum that substantiate your decision.

Fig. 1. IR spectra of benzophenone and benzhydrol. Which is which?

Fig. 2. The 1H-NMR spectra of benzhydrol and benzophenone.

http://orgchem.colorado.edu/courses/3341LMS06/OxAlcoholsLM41S06.pdf http://chemserv.bc.edu/ugrad/lab/org/RednOxid.pdf http://www2.bc.edu/~oconnell/Org/RednOxid.pdf