In the Laboratory edited by
The Microscale Laboratory
R. David Crouch Dickinson College Carlisle, PA 17013-2896
Synthesis of Unsymmetrical Alkynes via the Alkylation of Sodium Acetylides
An Introduction to Synthetic Design for Organic Chemistry Students
W
Jennifer N. Shepherd* and Jason R. Stenzel Department of Chemistry, Gonzaga University, Spokane, WA 99258; *
[email protected] The transition from cookbook verification experiments to inquiry-based experiments in the undergraduate organic chemistry laboratory has been the topic of many recent articles in this Journal (1–6). As part of our efforts to modernize our first-semester organic laboratory, we developed this experiment with several common goals in mind. First, we wanted to explore and strengthen students’ understanding of lecture concepts. Second, we wanted students to apply their previous knowledge of laboratory techniques toward solving a new problem. Most importantly, we wanted our students to learn about the process of science through critical interpretation of experimental results. We found the following experiment to be effective in achieving these goals. The use of acetylides as nucleophiles is introduced in Paula Yourkanis Bruice’s Organic Chemistry text in Chapter 6; it also appears reasonably early in a number of other texts (7–11). Very often the reaction of an acetylide with an alkyl halide is used as an introduction to multistep synthesis and retrosynthetic analysis (Scheme I). It is also reinforced in the study of bimolecular substitution reactions. Even though these reactions are commonplace in the organic texts, we have not found an undergraduate organic chemistry laboratory in the literature that utilizes such a reaction. To bridge this apparent gap, we have developed an alkylation experiment for the microscale organic laboratory. Several unsymmetrical alkynes (A–G) were chosen as synthetic targets for this experiment (Figure 1). The students were assigned a partner and a target. Several considerations were made when choosing these targets: (i) Each target has two possible C⫺C bond disconnections; (ii) The target and at least one reactant are UV active or stain with vanillin for TLC visualization; (iii) The reactants and products have protons that are clearly distinguishable by 1H NMR; and (iv) The cost and availability of starting materials are reasonable. Of course, many other synthetic targets could be envisioned for this experiment.
Because a certain freedom of choice is present in this experiment, students must plan ahead carefully. Important concepts from the lecture must be considered in the synthetic design of a target, as well as simple reaction stoichiometry. The results that students expect are not necessarily obtained, particularly if a poor choice of electrophile was made and if elimination effectively competes with substitution. Based on the characterization data obtained, students are expected to critically interpret their results and propose explanations for low yielding or unsuccessful reactions. We are more interested in the process of learning that takes place than the actual success of these experiments.
Scheme I. Retrosynthetic analysis of an unsymmetrical alkyne.
Figure 1. Unsymmetrical alkynes chosen as synthetic targets.
www.JCE.DivCHED.org
•
Vol. 83 No. 3 March 2006
•
Journal of Chemical Education
425
In the Laboratory
This experiment ties together many of the laboratory techniques that students have learned earlier in the semester (extraction, TLC, IR, and 1H NMR). Several new techniques are also introduced, such as the handling of air-sensitive reagents, preparation of a dry ice–isopropanol bath, and syringe technique. We have prepared a video demonstration of these techniques that students have found extremely useful.W Classic reaction conditions were adopted for the preparation of sodium acetylides (12–13) that utilize sodium amide in liquid ammonia, followed by the addition of an alkyl halide at temperatures below ᎑33 ⬚C (Scheme II). The starting materials (available from Aldrich) provided for students and the possible combinations of each are shown in Table 1. Our reaction setup involved a rudimentary nitrogen-handling system that consisted of Tygon tubing, T-joints, disposable syringes and needles, and an oil bubbler. Insulated cooling baths were prepared from crystallization dishes and packing material. General Experimental Procedure
Week 1 The oven-dried reaction apparatus (10-mL round-bottom flask, magnetic stir bar, and Claisen head) was assembled, capped with septa, and placed under nitrogen gas. The roundbottom flask was briefly removed and charged with NaNH2 (3.2 mmol) before the apparatus was placed into a cooling bath containing 2-propanol and dry ice (between ᎑60 and ᎑65 ⬚C). Instructors or TAs dispensed liquid ammonia (4–5 mL) into the reaction apparatus and the resulting gray slurry was allowed to stir for 5 minutes. The alkyne (2.8 mmol) was then added dropwise to the flask using a 1-mL ovendried syringe and the mixture was stirred vigorously for 20 minutes. Next, the alkyl bromide (2.8 mmol) was added to
Scheme II. General synthetic scheme for preparation of unsymmetrical alkynes via alkylation of an acetylide anion.
the flask (between ᎑50 and ᎑55 ⬚C). The temperature of the bath was allowed to slowly increase to ᎑33 ⬚C over about 45 minutes. The reaction apparatus was then removed from the cooling bath and the mixture was allowed to warm to room temperature. After all of the ammonia evaporated, the reaction was quenched with saturated ammonium chloride (2 mL). The reaction flask was then sealed and stored until the following week.
Week 2 The aqueous ammonium chloride mixture was transferred into a 5-mL conical vial and CH2Cl2 (2 mL) was added. After thorough shaking, the CH2Cl2 layer was removed and placed into a new conical vial, to which water (1 mL) was added. Next, 1.0 M HCl was added dropwise until the aqueous layer tested acidic. The CH2Cl2 layer was removed, washed with H2O (2 mL) and dried over Na2SO4. A TLC of the crude product mixture was performed using the starting materials for co-spotting. Plates were eluted in hexanes containing 1% ethyl acetate and visualized under UV and with vanillin stain. Several drops of the crude mixture were set aside for IR and the remaining CH2Cl2 and other low-boiling components of the mixture were removed by evaporation using a hotplate. IR spectra were measured before and after evaporation, and a 1H NMR spectrum was acquired after evaporation.
Table 1. Available Starting Materials and Possible Synthetic Routes to Targets A–G Starting Materials: Alkyl Bromides Starting Materials: Alkynes
----
----
----
D*
I (No F)
----
----
----
E*
I (No G)
C*
----
----
A*
----
D*
NR (No E)
NR (No A)
----
I (No B)
F*
NR (No G)
----
B*
----
*Representative yields (based on recovered starting materials) for the most successful route to each target are: A (20%); B (20%); C (93%); D (74%); E (19%); F (18%). No G or H were obtained.
426
Journal of Chemical Education
•
Vol. 83 No. 3 March 2006
•
www.JCE.DivCHED.org
In the Laboratory
Hazards Sodium amide is flammable and reacts vigorously with water. It must be stored in a desiccator or kept under nitrogen gas. Ammonia can cause respiratory tract, skin, eye, and mucous membrane burns. It must be kept in the hood at all times and distribution should be left to the instructor. The safety and handling procedures for the various alkyne and alkyl halide starting materials are discussed in the Supplementary Material.W Discussion and Results To begin the data analysis, students were provided spectra of pure starting materials and asked to predict the spectra of the desired product. In the IR spectrum, the absorbance of the terminal alkyne (νCH = 3300 ± 10 cm-1) was expected to disappear. The difference in frequency between internal (νC≡C = 2225 ± 35 cm-1) and terminal (νC≡C = 2120 ± 20 cm-1) alkyne C⬅C bonds is not as useful because of the vanishing intensity of the former. While many of the 1H NMR spectral peaks were predicted to be coincidental, signals such as the α-methylene signal of the halide (3.5–4.0 ppm), the acetylenic proton of the terminal alkyne (2.0 ppm if aliphatic, 3.0 ppm for phenylacetylene), and the methylene adjacent to the newly-formed C⫺C bond (2.15 ppm) made percent composition analysis possible. This last signal is distinctive due to coupling between protons on either side of the triple bond, resulting in a splitting pattern of a triplet of triplets. Students performed this experiment prior to covering elimination reactions in the lecture, so many were able to “discover” the conditions required for this reaction type by analyzing “unexpected” side-products formed. For example, products H and I (Figure 2) may be observed when cyclohexyl bromide and (2-bromoethyl)benzene are used as electrophiles, respectively. Both of these compounds are readily characterized by 1H NMR. It is not surprising that the reaction of an acetylide with cyclohexyl bromide can result in an elimination product because it is a secondary halide and the acetylides are reasonably strong bases. However, because (2bromoethyl)benzene is a primary halide, even the best students predicted that it should preferably undergo a SN2 reaction, when in fact styrene was the major product observed (see Appendix on page 428 for sample data). In order to justify their results, students were required to investigate the E2 mechanism and consider steric and basicity effects, as well as the stabilities of the transition states leading to both the substitution and elimination products. Conclusion This experiment illustrates two aspects of synthesis well. The issue of design was logically developed from a section of text covered concurrently in lecture, and then a limited selection of potential synthons were presented to construct an internal alkyne. Judicious selection of targets allowed students two possible approaches in all cases, with one synthesis predicted to be superior to the other based on critical evaluation of parameters guiding S N2 mechanisms. Through independent planning and data interpretation, students were exposed to the scientific process. Overall we have found this experiment to be effective in training the students to think www.JCE.DivCHED.org
•
Figure 2. Elimination products.
more critically in the laboratory and to take more ownership of their learning. Acknowledgments The authors would like to thank Jeff Hazen, Pete Black, and Gonzaga University’s spring and summer 2004 organic chemistry students for helping with the preparation and testing of this lab. Support was received by the National Science Foundation Awards CHE-0077972 and CHE-0135091. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the National Science Foundation. W
Supplemental Material
Instructions for students, notes for the instructor, safety and hazards, video link, and sample data are available in this issue of JCE Online. Literature Cited 1. Mohrig, J. R. J. Chem. Educ. 2004, 81, 1083–1084. 2. Stocksdale, M. G.; Fletcher, S. E. S.; Henry, I.; Ogren, P. J.; Berg, M. A. G.; Pointer, R. D.; Benson, B. W. J. Chem. Educ. 2004, 81, 388–399. 3. Moroz, J. S.; Pellino, J. L.; Field, K. W. J. Chem. Educ. 2003, 80, 1319–1321. 4. Horowitz, G. J. Chem. Educ. 2003, 80, 1039–1041. 5. Centko, R. S.; Mohan, R. S. J. Chem. Educ. 2001, 78, 77– 79. 6. Cabay, M. E.; Ettlie, B. J.; Tuite, A. J.; Welday, K. A.; Mohan, R. S. J. Chem. Educ. 2001, 78, 79–81. 7. Bruice, P. Y. Organic Chemistry, 4th ed.; Prentice Hall: Upper Saddle River, NJ, 2004; Chapter 6. 8. Solomon, G.; Fryhle, C. Organic Chemistry, 8th ed.; John Wiley and Sons, Inc.: Hoboken, NJ, 2004; Chapter 7. 9. Ege, S. Organic Chemistry: Structure and Reactivity, 5th ed.; Houghton Mifflin: Boston, MA, 2004; Chapter 9. 10. McMurry, J. C. Organic Chemistry, 6th ed.; Brooks/Cole: Pacific Grove, CA, 2003; Chapter 8. 11. Wade, L. G. Organic Chemistry, 4th ed.; Prentice Hall: Upper Saddle River, NJ, 1999; Chapter 8. 12. Vaughn, T. H.; Hennion, G. F.; Vogt, R. R.; Nieuwland, J. A. J. Org. Chem. 1937, 2, 1–22. 13. Examples of other synthetic methods in the literature are: (a) Trost, B. M.; Rudd, M. T. Org. Lett. 2003, 5, 1467–1470. (b) Bleicher, L. S.; Cosford, N. D. P.; Herbaut, A.; McCallum, J. S.; McDonald, I. A. J. Org. Chem. 1998, 63, 1109–1118. (c) Touchard, D.; Morice, C.; Cadierno, V.; Haquette, P.; Toupet, L.; Dixneuf, P. H. J. Chem. Soc., Chem. Comm. 1994, 7, 859–60.
Vol. 83 No. 3 March 2006
•
Journal of Chemical Education
427
In the Laboratory
Appendix
Proton NMR spectra for starting materials and products for two possible routes to alkyne target F (CDCl3, Bruker Avance, 300 MHz). Route 1: (I) 4-phenyl-1-butyne; (II) 1-bromobutane; (III) major product, 1-phenyl-3-octyne, F, after evaporation of CH2Cl2 and unreacted 1bromobutane. Route 2: (IV) 1-hexyne; (V) (2-bromoethyl)benzene; (VI) major product, styrene, I, after evaporation of CH2Cl2 and unreacted 1-hexyne.
428
Journal of Chemical Education
•
Vol. 83 No. 3 March 2006
•
www.JCE.DivCHED.org
