Honors Cup Synthetic Proposal Section: 220-2 Group Members: Justin Lomont, Koichi Murai, Lara Czabaniuk, Peter Horning Title: Three Step Synthesis of 11-cycloheptylundecanoic acid Introduction: Recently, a fatty acid mixture was isolated from the lipids of the thermoacidophile Alicyclobacillus cycloheptanicus. Subsequently, it was identified as a mixture of ω- cycloheptyl fatty acids which are unique in this organism. It has been suggested that these acids enable the organism to grow in acidic, hot media by providing a more dense cell membrane. This has led to the important understanding of their biosynthetic relations. However, owing to their very low natural abundance, it is necessary to synthesize these fatty acids in order to obtain them in sufficient amount both for their structural establishment and investigation of the involved biosynthetic pathway. ne such compound of this class is 11-cycloheptylundecanoic acid. (Reference 1) 11-cycloheptylundecanoic acid is a fascinating biological molecule. Its protective capabilities become more relevant in light of all the environmental concern over acid rain. Alicyclobacillus cycloheptanicus is a type of bacteria and due to its simple nature and quick reproduction, much research can be done on the acids in its membrane. In addition to its biological significance, this synthesis correlates with the material studied in organic chemistry. The first step is an oxidation of a ketone to an alcohol, a process studied in Chemistry 215. Cyclic compounds were studied in Chemistry 210, as were substitutions. Syntheses involving concepts studied in lecture will reinforce and solidify the concepts. verall synthetic reaction scheme: H Br NaS24 DMF, H2, NaHC3 Ph3P Br2 Pyridine Br(CH2)10C2Me Mg, THF, Li2CuCl4 H
Step 1 H NaS24 DMF, H2, NaHC3 Experimental 1 A solution of substrate (50 mmol) in dioxane (175 ml) or DMF for more difficultly reducible substrates is added to water (175 ml) containing NaHC03 (27.5 9). (When DMF was used as cosolvent, in some cases it was necessary to add some more water during the reduction to prevent gel formation.) When no cosolvent is used, the substrate is added neat. Sodium dithionite (12.5 g) is added and the reaction mixture refluxed for 4 h during which time three additional 12.5-g portions of Na2S204 are added. (A total of three 12.5-g portions of Na2S204 sufficed for the reductions of benzaldehyde, furfuraldehyde, 4-tert-b~-tylcyclohexanone, adamantanone, and norbornanone.) The reaction is carried out under an atmosphere of nitrogen. After the mixture cooled to room temperature, water is added until the solution becomes clear and thereafter the solution is extracted with ether (furfuryl alcohol and y-valerolactone were isolated by continuous extraction with ether for 7 and 72 h, respectively). When DMF is used as cosolvent the ether extracts are backwashed twice with water to remove traces of DMF. After the solution is dried (MgS04) and the ether is removed, the products are isolated by either distillation or recrystallization. Identification is based on melting or boiling points, infrared and 'H NMR spectra, and comparison with authentic materials. All reductions were carried out on a 2-mmol scale and for purposes of isolation were also done on a 50-mmol scale. The reaction is also done in nitrogen at a temperature of 85 degrees Celsius. Table I estimates 97% yield of cycloheptanol when reaction done in DMF. (48.5 mmol) (From Reference #2) Deviations from referenced experimental for 216: We will be using DMF as the solvent as it produces a higher yield and is more readily available. A four hour reflux is not feasible given the time we spend in lab. We propose a two and one half hour to three hour reflux in order to fit within the time constraints of 216. Due to the decreased reflux time and any experimental error, we estimate the yield to be 80% instead of 97%. The estimated yield is 48.5 mmol, which is 5.472 g. We need 1.316g for step two of the synthesis, so the materials used in this step need to be scaled down. After taking the new estimated yield into account, we found that scaling reagents and solvents down by a factor of 3.45 would produce an adequate amount of product. The new masses and volumes of reagents and solvents are as follows: 14.5 mmol of cycloheptanone (1.624 g) in 50.73 ml DMF and 50.73 ml water with 7.971 g NaHC3 dissolved in it 3.623 g Na2S24 added to the mixture four separate times. The times given for extraction are not feasible given the time constraints of Chem 216.
We suggest extraction with ether 3 times and then recrystallization or distillation for further isolation. The possible impurity of the product was also taken into account when the new yield was estimated. Expected yield: 80% 1.322g Safety, disposal and green issues 1: Though this experimental uses a large amount of Na2S24, the material is much safer to use than metal hydrides to reduce ketones. It will not explode. Using water as a solvent enables us to reduce use of toxic solvents. The experiment will of course need t o be done under a fume hood, especially since sodium dithionite will emit a toxic gas if it comes into contact with an acid. Sodium dithionite is sensitive to the air, and we must perform the transformation in nitrogen. DMF is a skin irritant and direct contact with it should be avoided. Step 2 H Br Ph3P Br2 Pyridine Experimental 2 To a cooled ( 0C) and stirred solution of triphenylphosphine ( 7.86 g, 0.03 mol) in CH2Cl2 (50 ml) was added Br2 (1.6 ml) in CH2Cl2 (50 ml) dropwise over a period of 30 min. To the resulting white suspension was added a solution of cycloheptanol (3.42 g, 0.03 mol) in pyridine (2.6 ml) over a period of 1 h while cooling was maintained externally. After stirring the mixture for 3 h, the solvent was removed under reduced pressure. The residue was chromatographed on a silica gel column, eluting with petroleum ether. The evaporation of the solvent furnished Cycloheptyl bromide (3.7 g, 69.8%): b.p. 82C/10 mm; IR: 2928, 1458 cm-1; 1H-NMR: δ 1.5 (m,12h, 6 x CH2), 3.4 (m, 1H, CHBr). (From reference #1) Deviations from referenced experimental for 216: The 3 hour stirring time is very hard to accomplish within one lab period. We propose stirring the mixture for two hours in order to complete the synthetic step within one fourhour lab period. Due to the decreased stirring time and any experimental error, we estimate a 55% yield instead of 69.8% yield. We will want to adjust the scale of the experimental step to produce the amount of product we need for the third step. We calculated the yield given the new estimated yield of 55% and then found that we would need to reduce everything by a factor of 2.6 to get the 1.122 grams of product, enough for step three. The new masses and volumes of reagents and solvents are as follows:
3.023 g triphenylphosphine in 19.2 ml CH2Cl2 0.62 ml Br2 in 19.2 ml CH2Cl2 1.316 g cycloheptanol in 1mL pyridine Reduce drop wise adding times to 15 and 30 minutes respectively due to scaling down of the experimental. Expected yield: 55% 1.122 g Safety, disposal and green issues 2: Triphenylphosphine is harmful if inhaled so the experimental step must be done under a fume hood. It is also harmful to the environment, especially to aquatic animals. Special care must be taken to ensure that this chemical is disposed of correctly. It is not compatible with acids. Bromine causes severe burns and is very toxic by inhalation. Any container containing bromine must be covered at all times and contact with skin must be avoided. Pyridine is harmful if inhaled or absorbed through the skin. Step 3 Br Br(CH2)10C2Me H Mg, THF, Li2CuCl4 Experimental 3 To a stirred suspension of Mg (1.44 g, 0.06 mol) in THF (15 ml) was added Cycloheptyl bromide (8.85 g 0.05 mol) in THF (50 ml) at room temperature over a period of 1 h. The mixture was cooled to -78C, Li2CuCl4 (3.5 ml, 0.1 M, prepared by dissolving 85 mg of LiCl and 43 mg of CuCl2 in 10 ml THF) added and the mixture stirred over a period of 30 min. A solution of methyl 11-bromoundecanoate (12.6 g, 0.045 mol) in THF (50 ml) was then added drop wise over a period of 1 h. Stirring was continued overnight at room temperature. Saturated aqueous NH4Cl solution was added to decompose the Grignard complex. The mixture was filtered and extracted with ether. The usual workup and removal of solvent, followed by column chromatography of the residue, furnished Methyl 11-Cycloheptylundecanoate (6.68 g, 50 %): IR: 2942, 1745 cm-1; 1H-NMR: δ 1.3 (m,18 H, 9 x CH2), 1.4-1.7 (m,13h, 6 x CH2 and CH), 2.3 (t, J = 6 Hz, 2H), 3.7 (s, 3H, CH3). MS: 296 (19), 200 (M-C7H12) (23), 171 (2), 157 (9), 143 (22), 129 (8), 111 (12), 97 (C7H13) (68), 87 ( 90), 74 (C3H62) (100). (From reference #1) Deviations from referenced materials for 216: Stirring overnight is a time issue that needs to be addressed. We suggest stirring the
mixture for two hours after the addition of the methyl 11-bromoundecoate and then waiting until the next lab session (1 week later) to add the saturated NH4Cl. Due to reduced stirring time and any experimental error, we estimate a 30% yield. Scale will need to be altered because we only need 0.5 grams of the product, instead of the 6.68 reported in the experimental. We calculated out new masses and volumes of chemicals by assuming the 30% yield mentioned previously and then dividing by a factor to get the goal of 0.5 grams. This factor turned out to be 8, and we scaled down all other reagents and solvents appropriately. The new masses and volumes are as follows:.18 g Mg in 1.9 ml THF 1.106 g cycloheptyl bromide in 6.25 ml THF.44 ml of the Li2CuCl4 solution (prepare it the same way as the experimental due to the already small scale) 1.575g Methyl 11-bromoundecanoate in 6.25 ml THF When adding cycloheptyl bromide and methyl 11-bromoundecanoate drop wise, reduce the time needed to add it from 1 hour to 15 minutes due to the scaling down of the experiment. Stirring times will not be altered. Expected yield: 30% 0.5g Safety, disposal and green issues 3: Magnesium and THF are highly flammable so extra care should be taken with them. Lithium Chloride needs to be protected from moisture. If inhaled, fumes from cooper (II) chloride are harmful. Keep samples covered and work under a fume hood. verall budget: Chemical Supplier Cost Amt. Needed Total cycloheptanone pfaltz & Bauer $1.04/g 1.624 g $1.69 Na2S24 Alfa Aesar $0.04/g 14.492g $0.60 NaHC3 pfaltz & Bauer $0.03/g 7.971g $0.24 Ph3P Alfa Aesar $1.55/g 3.023g $4.69 Mg (powder) Alfa Aesar $0.15/g 0.18g $0.03 Br2 pfaltz & Bauer $0.29/g 0.62 ml/.1.934g $0.56 LiCl Alfa Aesar $2.13/g 0.085g $0.18 CuCl2 pfaltz & Bauer $0.21/g 0.043g $0.01 Br(CH2)10C2Me pfaltz & Bauer $3.84/g 1.575g $6.05 *Chemicals also available through Aldrich s References 1. Hassarajani, S.; Mamdapur, V. Molecules. 1998, 3, 41-43. 2. Vries, J.G,; Kellog, R.M. J rg. Chem. 1980, 45, 4126-2129. Total costs per synthesis: $14.05