CHM 252 Organic Chemistry II

Experiment #2, Spring 2008

The Aldol Condensation

Introduction

The aldol condensation is a term used to describe any number of reactions involving an enolate and a carbonyl compound. Other examples of reactions involving similar types of chemistry include:

(a) the Claisen condensation

(b) the Claisen-Schmidt condensation

(d) the Dieckmann condensation

(e) the malonic ester synthesis

(f) the acetoacetic ester synthesis

(g) the Michael reaction

The general reaction involves: (a) the removal of an acidic a-hydrogen from one carbonyl containing molecule generating the enolate; (b) attack of the slightly positive carbon of a second carbonyl containing molecule by the carbanion of the enolate; (c) eventual loss of water by the b-hydroxy carbonyl compound to yield the ultimate a,b-unsaturated carbonyl product. The general reaction scheme is shown below.

This type of chemistry has been exploited extensively by both the synthetic chemist and by enzymes in biological systems. In synthetic organic chemistry, these types of reactions have been shown to be highly useful in the synthesis of complex natural products. Within the last twenty years, much has been discovered about the synthetic utility of enolates. The primary utility comes from the fact that given certain reagents and reaction conditions, the synthetic chemist can utilize the reaction to form carbon-carbon bonds (here it is again!). In addition, these reactions generally occur with a high degree of stereoselectivity. The stereoselective nature of these reactions allows chemists to create various complex natural products that contain multiple stereocenters. We can actually introduce those stereocenters into the molecule using enolate-type chemistry! Therefore, enolate chemistry has a high degree of synthetic utility.

There are also many biological examples of "aldol-type" reactions. For example, collagen, the most abundant protein in many vertebrates and invertebrates, provides strength to bones, tendons, cartilage, and skin. This strength has been attributed to the extensive cross-linking of lysine residues. The first step in the cross-linking process is the conversion of two lysine residues to aldehydes by an enzyme called lysyl oxidase. Once converted, the two aldehydes undergo an aldol condensation to provide a covalent cross-link (new carbon-carbon bond). Further cross-linking may occur (Michael reaction) in order to link together up to four residues.

A second example of the involvement of aldol chemistry in biological systems occurs during the second stage of glycolysis (metabolic pathway in living systems used to produce modest amounts of ATP). During this stage, the six carbon sugar (fructose-1,6-diphosphate) is split into two three carbon units (dihydroxyacetone phosphate and glyceraldehyde 3-phosphate) by the enzyme aldolase (Refer to Biochemistry, Fourth Edition by Lubert Stryer, Chapter 19). Basically what happens here is the REVERSE of an aldol condensation (a retro-aldol condensation). Without this step the six carbon sugar could not be reduced to the necessary three carbon unit for the production of ATP.

A final example can be found in the citric acid cycle. Citric acid is formed by a Claisen-type condensation between oxaloacetate and acetyl coenzyme A. The acidic a-hydrogen on acetyl CoA is removed by the enzyme citrate synthetase. Once removed, the enolate can attack the carbonyl of oxaloacetate to yield citryl CoA. Hydrolysis of this compound yields citric acid.

Objective

In this week's experiment, you will be synthesizing an addition product from the aldol condensation of an unknown aldehyde and an unknown ketone. The product of the reaction is an a,b-unsaturated ketone. You will have considerable control over how you go about performing this experiment. I will give you general guidelines. The goal here is for you to determine the identity of your product from proton and carbon NMR. Once you have identified your product, you will need to determine both the reaction mechanism and the identities of your starting ketone and aldehyde. You will be assigned ONE of the procedures shown below.

Procedure A (Monday Laboratory Students)

In a 125 mL Erlenmeyer flask, dissolve 50 mmol of the unknown ketone A in 25 mL of diethyl ether. Add 45 mL of 0.1 M NaOH and cool the mixture in an ice bath for 5 minutes. Add 50 mmol of freshly distilled unknown aldehyde A. Cork the flask loosely and stir the solution vigorously in a cold water bath for 45 minutes.

Filter the reaction mixture by vacuum filtration and thoroughly wash any solid on the filter paper with 10 mL of ether. Save the solid and weigh it when it is dry. Shake the filtrate in a separatory funnel in order to extract any residual product from the aqueous layer. Save the ether layer and extract the remaining aqueous layer with an additional 15 mL portion of ether. Combine ether layers and wash with saturated NaCl solution (25 mL). Dry the ether layer over magnesium sulfate and evaporate the solvent in the hood under low heat.

Purify the residue by short path vacuum distillation with no cooling bath. Any unreacted starting material and residual ether should distill below 100 ºC. The forerun should be disposed of in the hood waste containers. Collect the distillate boiling above 100 ºC and cool until it solidifies. Purify by recrystallization from ethanol-water. Once you have isolated the solid product let it dry. Measure the mass for the final product you recrystallized. Prepare a sample for NMR analysis in the usual fashion. You should acquire the 1H-NMR and I will collect the following: 13C NMR, 13C DEPT-135, 1H-1H COSY, HMQC 1H-13C correlation.

Procedure B (Tuesday Laboratory Students)

In a 125 mL Erlenmeyer flask, dissolve 10 mmol of the unknown ketone A in 10 mL of diethyl ether. Add 12 mL of 0.1 M NaOH and 6 drops of the phase-transfer catalyst, tricaprylmethylammonium chloride (Aliquat 336). Cool the mixture in an ice bath for 5 minutes. Add 2.0 mL of freshly distilledunknown aldehyde A. Cork the flask and shake the solution vigorously for 15 minutes. Swirl it frequently in the ice bath to prevent pressure buildup. Let the reaction stand at room temperature for 10-20 minutes.

Collect the product by vacuum filtration and wash it on the filter with diethyl ether. Pull the vacuum for about 10 minutes to assist in drying. Recrystallize the product from 2-butanone, using about 12 mL of solvent per gram of crude product. Wash the product on the filter with ether. Measure the mass for the final product you recrystallized. Prepare a sample for NMR analysis in the usual fashion. You should acquire the 1H-NMR and I will collect the following: 13C NMR, 13C DEPT-135, 1H-1H COSY, HMQC 1H-13C correlation.

Laboratory Follow-up (LFU)

Due: Tuesday, April 22, 2008 by 5:00 pm

You should compose a short RESULTS/DISCUSSION-style report (limit 4 pages) in which you summarize/discuss the outcomes from your aldol condensation experiment. The report should include all spectra (attached) and a ChemDraw representation of the proposed product structure (fully labeled). Be sure to label all of the protons and carbons and correlate them with the appropriate peaks in your NMR spectra. Be sure to discuss how your data is consistent with your proposed structure (story of elucidation). In addition, you should compare/contrast your product with that of the other lab section (you’ll need to work up their data as well). You’ll likely want to provide the complete mechanism of reaction that outlines the steps in the conversion of the two carbonyl starting materials into your proposed products.