1The Aldol Condensation Puzzle Revised January 2002 The Aldol Condensation is an extremely useful carbon-carbon bond forming reaction in organic chemistry. In this experiment, a mixed Aldol Condensation will be performed. This means that two different carbonyl compounds will be used, but only one, the ketone, will have α-hydrogens: the aldehyde will not have α-hydrogens. The overall reaction is shown below. H H O O 2 G Aldehyde + H H C C C R R Ketone H NaOH, H2O H ethanol O C H C C C C R R G G Aldol Condensation Product Some of these aldol products show cytotoxic and anti-tumor activities (see Dimmock, J. R., et al, J. Pharm. Sci. 1994, 83(6), 852-858). If the aldehyde has acidic α-hydrogens, then it could react with itself. By choosing aldehydes without α-hydrogens, the aldehyde will react with the ketone. Although the ketone could do an Aldol Condensation with itself as well, it usually reacts much faster with the aldehyde (why?). The carbon-carbon double bonds that are formed are usually in the configuration shown, the socalled "trans, trans" form. Trace amounts of the "cis, trans" and "cis, cis" probably also form, but these isomers are less likely to be solids, so they do not crystallize out of solution. To make this lab a little more challenging, you will not know the identity of the aldehyde or ketone you are using. Instead, you will be assigned a coded aldehyde and ketone to react together. You will purify a small portion of the product by recrystallization, and determine the melting point. You will demonstrate the purity of your product by TLC, and then obtain the NMR spectrum of your product. From the NMR and melting point data, you should be able to deduce what aldehyde and ketone you started with. The reaction produces several intermediates before the final product is produced. These are shown below. You can draw the arrows and supply the missing steps. The reaction is catalytic in hydroxide. The ethanol solvent serves to keep the intermediate structures in solution so that the final product can be formed. 5 mL portions of: 1. and 2M aqueous sodium hydroxide (10 mL). Check the purity of your crude and recrystallized products by TLC. and then collect the product by suction filtration. 2. If no precipitate has formed after 15 minutes. When you have demonstrated that your recrystallized product is pure. 95% ethanol. Dissolve tiny amounts of each in ethyl acetate in separate small test tubes. the aldehyde (2. Once crystallization is complete at room temperature. The physical constants you might want are given below. others require several hours. 3. then allow the reaction to cool. .0 mL).2 O H C Ar O H + H H C C C R R H H OH C Ar O H C H C C R R H O C Ar H C C C R R H H H H O C Ar H H C C C C C R R O Ar Ar HO C H C O C C C R R H Ar Ar 4-ethylbenzaldehyde is not in the CRC Handbook or in the Merck Index.18 0. Recrystallize a small portion of your product from either 95% ethanol or toluene (whichever solvent works the best). Some reactions form precipitate almost immediately. 95% ethanol. and see if crystals form.5 mL). Stir or shake the reaction mixture until no more precipitate is observed to form. Magnetically stirring the reaction mixture also speeds up the rate of reaction. Wash the product consecutively with ice-cold. you have a slow-reacting mixture. Molecular weight: Density: Boiling Point: 134. 95% ethanol (12 mL). 5% acetic acid in 95% ethanol. and visualize the plate with UV light to see the spots if needed. Use toluene as a developing solvent. You can either allow this sit until the next lab period. or heat the reaction mixture on the steam bath for about 15 minutes.979 221 General Procedure In a 50 mL Erlenmeyer flask place in this order the ketone (0. and spot each solution on a small silica gel TLC plate. you can obtain the NMR spectrum of your product from your lab instructor. cool the reaction in an ice bath. Hints on interpreting your NMR spectrum. This is due to the C=C being conjugated to the C=O. These peaks often appear as lumps. around 7. If G = H.3 ppm. If G = CH3 or OCH3. then it should appear as a single peak in the appropriate region of the spectrum. If your ketone was 4-methylcyclohexanone. The alkene hydrogens. so the apparent coupling patterns may appear distorted. If your ketone is acetone. it will couple with Ha with a large coupling constant. if Hb and Hc are very close to one another in chemical shift. The CH and the CH2’s are coupled to each other. then it will appear in the aromatic region of the spectrum.7 and 7.3 ppm. You should see a peak for each type of CH2. 4. Hb Hc Ha O C G Hb Hc Ha C Hb C C C R R Hc Hb G Hc 1. usually show up in the aromatic region of the spectrum. Hc. especially if the peak looks distorted or unusual. However. the R = H. 5. appear about 7. 3. on the other hand. Hb and Hc usually couple with each other. the coupling patterns may be severely distorted. If R = H.3 A general structure of the Aldol product is shown below.2-7. If you started with a cyclopentanone or cyclohexanone. and could complicate that region of the spectrum somewhat. then you should see a triplet and a quartet at appropriate places in the spectrum. because coupling in cyclic compounds is more complex. so be sure to use the integration values to check the number of H's in each set of peaks. due to the peak(s) for Ha. so the N + 1 rule may not apply. then the R's are some number of CH2 groups. Ha. The aromatic hydrogens.6 ppm. Hb. 2. so each appears as a doublet. due to the CH2’s not being free to rotate. then the methyl group will be split by the adjacent CH into a doublet. Ha may show up in the same region these peaks. about 15-18 Hz. . If G = CH2CH3. The peaks for the G groups may overlap the peaks for the CH2's. and these hydrogens usually show up close to 7 ppm. and may form some complex patterns. may appear between 6. depending upon what G is. the product derived from the reaction of benzaldehyde with cyclohexanone is reported to melt at 118C. Aldehydes O O H O C H O C H C C H CH 3 H 3C CH 2 O H 3C Benzaldehyde p-tolualdehyde (4-methyl benzaldehyde) 4-ethyl benzaldehyde p-anisaldehyde (4-methoxy benzaldehyde) 113 175 125-127 129-130 189 235-236 147-148 212 118 170 124-125 159 98-99 133-135 115-116 141-2 Ketones O C H3C CH3 Acetone O Cyclopentanone O Cyclohexanone O H3C 4-methyl cyclohexanone For example.4 The following table gives the reported melting points of the Aldol condensation products derived from each combination of aldehyde and ketone. . Tape your TLC plate to the bottom of the page. C. labeled clearly so I know what is what. . (colors of solutions & solids. Interpret your NMR spectrum by drawing the structure of your product on the spectrum. and showing which H's in your structure give rise to which peaks in your spectrum. How did you distinguish between close choices? Did all of your data point to the same structure? If not. 3. Your name. What impurities are removed by the ethanol and acetic acid in ethanol washes? Explain your reasoning. length of time until precipitate formed.) Weight of crude product. Melting points of both crude and recrystallized products. identity of starting aldehyde and ketone). B. Title Page 1. 6. 2. how did you decide which structure was correct? Include your NMR spectrum with your report. 7. Body of the report. 2. TLC data. Identify the limiting reagent. melting point. Balanced chemical equation. Explain in detail how you used all of the data you obtained to determine the structure of your product.5 Report Format A. Explain the coupling patterns and any unexpected peaks. and their interpretations. Calculations of theoretical and percent yields. 4. Questions 1. Important observations. 5. 3. Show calculations for the moles of all reactants. A 2-3 sentence summary of your results (amount of product. and calculations of Rf values for all spots. A descriptive title with between 10 & 20 words. 1. etc. 2. What do your melting points tell you about the purity of your products? What do your TLC data tell you about the purity of your products? How accurate do you think these data are? Explain. using the actual structures you used. if possible. 3. 4. Dates that the experiment was performed. Course and section number.