Exp't 13 (Adapted by Modi, Monarch, Perriello, Pohland, Minard and Walton (PSU '91-'92) from D Thompson and P. Reeves, "Phase-transfer-catalyzed Alkylation of Ethyl Acetoacetate and Diethyl Malonate", J. Chem. Ed., 62, 1985, 907-908.) Revised 10/5/00 Introduction: Practical synthetic methods for the construction of molecules through carbon-carbon bond formation are of obvious importance. f the somewhat limited number of methods available, the alkylation of an enolate anion with an alkyl halide is used quite often. In the past, the formation of the enolate anion required using a strong base such as sodium ethoxide (made by reacting sodium metal with ethanol) to remove a proton a to the carbonyl group. C 2 H 5 H (strong CH 2 X CH 2 R + X base) R enolate anion new C-C bond There are several problems with this method: 1) the handling of highly reactive sodium metal; 2) the necessity of preparing absolutely anhydrous ethanol; 3) the large amount of E2 elimination of the alkyl halide. While carbonate anion (C 3 2- )is not a very strong base in aqueous medium (pka=8.5), in an organic medium it is basic enough to remove a proton from an active methylene compound. Active methylene compounds contain two electron withdrawing groups, such as carbonyl groups, adjacent to a C-H bond, making the hydrogen relatively acidic. (The pk a =13 for the active methylene compound, diethyl malonate, shown below 1 ). B - CH H Diethyl malonate acidic hydrogen Base CH - C 2 H 5 - in C 2 H 5 H or C 3 2- in organic phase - CH Unfortunately, one cannot normally dissolve a carbonate salt, for example potassium carbonate, in organic solvents. However, the addition of a phase transfer catalyst such as (2) (1) CH 3 + N Cl - 18-crown-6, a cyclic polyether tricaprylmethylammonium chloride a cyclic polyether or a tetraalkylammonium salts will allow dissolution of carbonates in organic solvents. A liquidsolid two phase system using anhydrous K 2 C 3 or Na 2 C 3 has the added advantage of absorbing the water formed in the reaction, thus minimizing ester hydrolysis. Since diethylmalonate has two acidic a hydrogens, it can be dialkylated (a minor product of this reaction) by reaction with two equivalents of an alkyl halide. This double alkylation can be cleverly used to prepare cycloalkanecarboxylic acids starting with the appropriate alkyl dihalide. An example is the malonic ester synthesis of cyclopentanoic acid from 1,4-dibromobutane.
Exp't 13 CH 2 + Br Br base C Na + - C - Na + NaH H +, -C 2 H C H CH 2 CH 2 (3) In this experiment solid K 2 C 3 is used as the base and the cyclic polyether, 18-crown-6, is used as the phase transfer catalyst to prepare 2-(n-butyl)-diethyl malonate from diethyl malonate and 1-bromobutane (syn: n-bromobutane or n-butyl bromide): K 2 C 3 CH 2 CH 3 + -Br CH 2 18-crown-6 CH Diethyl malonate (4) Prelaboratory Exercise: 1. The use of phase transfer catalysts with hydroxide instead of carbonate as a base works with 2,4-pentanedione (acetylacetone), but not with diethyl malonate. What side reaction occurs with hydroxide and the ester to subvert the desired reaction? 2. When carbonate is used as a base (reaction 4 above), water and C 2 are formed. Using an equation or equations, explain why. Cautions: The cyclic polyether 18-crown-6 ether is toxic and induces sterility in male rats at high oral doses. Wear gloves when handling. 1-Bromobutane, like all alkylating reagents is toxic and a potential carcinogen because it can react with physiological nucleophiles in the body. Wear gloves when handling with care and work in a hood. Synthesis: In a 5-mL long-necked round-bottom flask, place about 0.4 g of anhydrous potassium carbonate, 0.30 ml of 1- bromobutane (0.38 g, 2.8 mmol), 0.38 ml of diethyl malonate (0.40 g, 2.5 mmol) and 0.25 ml of 18-crown-6 phase transfer catalyst solution (5% in acetonitrile). Add a 1/2-inch magnetic stir bar and cap the flask with a rubber septum and needle. Gently heat the mixture on the top of a shallow sand bath for 2 hr with constant vigorous stirring. Isolation and Purification: Remove the 1/2-inch stir bar by drawing it up and out magnetically with your 1-inch stir bar held on the outside. Add one ml of CH 2 Cl 2 and 2 ml of distilled water. Mix vigorously with pipet mixing to effect extraction into the organic layer. Remove the CH 2 Cl 2 layer with a pipet, placing it into a reaction tube, and repeat the extraction with another 1 ml of CH 2 Cl 2, combining the organic layers. Wash the CH 2 Cl 2 extracts with 2 ml sat'd. aqueous NaCl, and dry over anhydrous Na 2 S 4, adding the drying agent until it no longer clumps together and then letting the solution stand for about 10 minutes. Remove the CH 2 Cl 2 to a clean, dry, pre-weighed 10-mL Erlenmeyer flask and let the bulk of the CH 2 Cl 2 evaporate in your locker. In the next lab period, remove the last traces of CH 2 Cl 2 until a constant product weigh is obtained by aspirating the flask in a bell jar. The product is a viscous yellow liquid (typical yield is approx. 400 mg). Check product purity and identity by gas chromatography, followed by GC-MS if your GC results are equivocal. * If you are unsure about which layer is which, carefully add extra ether and note which layer becomes larger. Cleaning-up: The aqueous layer contains crown ether and should be placed in the non-halogenated solvents container. The sat. NaCl used for washing can be flushed down the sink. Place the dried Na 2 S 4 in the non-hazardous solid waste container.
Analysis: Inject 1 ml of a CH 2 Cl 2 solution (see the Lab Guide, Chap. 11) of your product into the GC, determine the retention times, peak identities and peak areas. If gas chromatogram is reasonable, (i.e. has more than 30% product, by peak areas) reanalyze by GC-MS. Final Report: Label chromatographic peaks corresponding to C-alkylated, C-dialkylated, starting materials, solvents, and - alkylated products (if any),. Calculate the approx. percentage yield of butylated products based on peak areas from the GC analysis printout. Make a table of the major peaks, their retention times, areas, and assignments. Questions : 1. Why do 2 and 3 alkyl halides give low/no yields in this and similar carbanion (enolate) alkylations? What is the predominant product? Do you expect benzyl bromide to be reactive toward enolate anions? 2. Why might someone running this experiment detect, by GC-MS analysis, a product with a molecular weight of 272? Draw a structure for this product. 3. Use resonance structures to explain why diethylmalonate may be easily deprotonated. References: 1. Thompson Douglas L.; Reeves Perry C. Phase-Transfer-Catalyzed Alkylation of Ethyl Acetoacetate and Diethyl Malonate Journal of Chemical Education, volume 62, number 10, 1985. pp907-8. 2. Williamson Kenneth L. Macroscale and Microscale rganic Experiments D. C. Heath and Co. Mass, 1989. pg. 533. 3. Mackay, K. M.; Mackay R. A. Introduction to Modern Inorganic Chemistry 4th ed. Prentice Hall, Englewood cliffs, NJ 1989. pp 157-62. 4. Miller, James M. Chromatography Concepts and Contrasts : John Wiley and sons, New York, 1988, pp. 109-153. 5. M c Murry, John rganic Chemistry Brooks/Cole Co. 1984 pp. 832-7, 617-18. 6. Brandstrom, Arne; Junggren, Ulf Tetrahedron Letters no. 6, pp 473-474, 1972.
Synthetic Experiment PreLab Grading Sheet Name(s): TA: Date: PreLab For Exp't # 13 Date, Name, Desk #, Experiment # & Title(abbreviated after 1 st pg), Section & TA Name Possible 4 Missed Summary 8 Goals 8 Reactions, structures, conditions, diagrams 14 Completeness of Chemical Data Table(s) 14 Chromatographic Behavior Comparison 16 Spectral Features Comparison 12 Work-up - Explanation of the product isolation and purification process 12 PreLab Questions 12 TTAL FR PRELAB 100 Date Handed in: General Comments: Total :
Synthetic Experiment Final Report Grading Sheet Name: TA: Date: Final Report For Exp't # 13 Name, Date, Experiment Title (abbreviated after 1st page) and every page numbered Possible 4 Missed BSERVATINS and DATA - verall organization, readability, completeness 8 Data: Weighing data, molecular weights, moles, density, volumes, refractive index, Product analysis conditions i.e. gas chromatographic analysis conditions sheet for GC and/or GC-MS, weight of sample and KBr for IR; solvent and field strength for NMR; ionization mode for MS; Yield: Show % yield calculations with limiting reagent clearly stated. Indicators of product purity such as gas chromatograms or TLC, boiling point or refractive index. 12 12 RESULTS AND DISCUSSIN - verall organization, readability, completeness 8 Results; Achievement of goals 16 Product Analysis Data: Quality and Interpretation Structures assigned to all gas chromatogram peaks and structures written on the corresponding mass spectra from GC-MS. Structure(s) drawn and interpreted on the product spectrum. Calculate relative % s of isomers, by-products or starting materials from GC peak areas. Interpret major MS or IR peaks or all NMR peaks (including impurities). Explain how spectra confirm product identity. See Lab Guide Chapter 3, Section 3.4 for guidelines in annotating spectra and Ch 11 for help with interpretation. PSTLAB QUESTINS 16 TTAL PINTS 100 24 Date Handed in: General Comments: Total :