In the Laboratory The Microscale Laboratory
A Multistep Synthesis of 4-Nitro-1-ethynylbenzene W Involving Palladium Catalysis, Conformational Analysis, Acetal Hydrolysis, and Oxidative Decarbonylation Thomas E. Goodwin,* Eva M. Hurst, and Ashley S. Ross Department of Chemistry, Hendrix College, Conway, AR 72032
Palladium-catalyzed reactions, particularly carbon– carbon bond formations, are rapidly becoming a mainstay of organic synthesis in industrial and academic laboratories (1). Although these important procedures are covered in advanced organic chemistry texts, they have rarely permeated into introductory organic texts or laboratory manuals. One of the more useful processes involves the coupling of a terminal alkyne to an aromatic bromide or iodide (2). Recently in this Journal, Brisbois and coworkers reported a new microscale laboratory synthesis of 4-nitro-1-pentynylbenzene from 1-pentyne and 1-bromo-4-nitrobenzene in the presence of bis(triphenylphosphine)palladium(II) chloride and copper(I) iodide (3). In this article, we will describe a complementary coupling procedure for the preparation of the tetrahydropyranyl ether of a propargyl alcohol derivative (3). This product can be easily hydrolyzed to the alcohol 4, then oxidatively decarbonylated to produce 4-nitro-1-ethynylbenzene (6). A Simplified Coupling Procedure A microscale experiment is described in which the tetrahydropyranyl ether of propargyl alcohol (Aldrich) (1) (4) and 4-iodo-1-nitrobenzene (93 mg) are coupled under quite different conditions from those mentioned above (3). This reaction is carried out rapidly (30 minutes) in refluxing 95% ethanol without a dry nitrogen atmosphere or addition of solubilizing ligands (commonly phosphines or arsines), while using solid piperazine hexahydrate as an easily weighed and non-malodorous base (5). This coupling gives a product (3) (6 ) that lends itself well to conformational analysis by 1H NMR spectroscopy and molecular modeling (see below). By this simple procedure, compound 3 can be prepared, isolated, and purified by students in one lab period. The yield is typically 80–90% after column chromatography in a Pasteur pipet, and 60–70% after subsequent recrystallization. O2N
I
+
HC
O
C
Discussion Two conformations (2 and 3) may be imagined for the coupling product. On the basis of cyclohexane conformational analysis, students normally predict that the more stable conformer is 2, with the equatorial substituent. However, 1H NMR spectroscopy (300 MHz) clearly shows that the product is in fact conformer 3, as evidenced by the observed coupling constants for Ha (dd, J = 3.2, 3.2 Hz), which shows up as an apparent triplet. There is a useful correlation between the experimental vicinal coupling constants for Ha and those calculated from energy-minimized conformations derived by molecular mechanics using PCMODEL (7). This analysis presents a good opportunity to discuss the variation of coupling constant with dihedral angle (the Karplus relationship), as well as the anomeric effect (8). In addition, the propargylic methylene hydrogens and those adjacent to H a are diastereotopic and easily observed independently in the 1H NMR spectrum (9). It is interesting to note that PCMODEL correctly predicts conformer 3 to be the more stable one. Acetal Hydrolysis and Oxidative Decarbonylation If a multistep synthesis experiment is desired, acetal 3 may be hydrolyzed to alcohol 4 by exposure of 3 to aqueous HCl in refluxing methanol for 45 minutes (6 ). Thus, a reaction that is often discussed in lecture but seldom demonstrated in the lab (10) can be illustrated. (Writing the mechanism for this hydrolysis is a useful heuristic exercise for the students.) The yield of solid product suitable for use in the next reaction is approximately 80% (11). This hydrolysis and the subsequent oxidative decarbonylation (see below) are easily accomplished in one lab period. O
NO2
∆, H3O
+
CH3OH
O
NO2 HO
4
3
Pd(OAc)2, CuI
O
MnO2
95% EtOH, piperazine, ∆
1
THF
H
KOH NO2
O
∆
5 H
Ha
Ha
O H
6
NO2
O
H
NO2
H
H
O
O
3
2 NO2
W Supplementary materials for this article are available on JCE Online at http://jchemed.chem.wisc.edu/Journal/issues/1999/ Jan/abs74.html.
*Corresponding author. Email:
[email protected].
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Journal of Chemical Education • Vol. 76 No. 1 January 1999 • JChemEd.chem.wisc.edu
In the Laboratory
A convenient procedure for oxidative decarbonylation of substituted propargylic alcohols to provide the corresponding terminal alkynes has been reported (11a). Using this procedure but substituting THF for the original solvent (benzene), alcohol 4 can be oxidized with activated manganese dioxide to the aldehyde 5, which is not isolated but is reacted in situ with hydroxide ion to provide 4-nitro-1ethynylbenzene (6) in a total reaction time of 30 minutes. The latter step (5 to 6) provides an unusual example of the familiar nucleophilic acyl substitution reaction. The yield is typically 70–80% after column chromatography in a Pasteur pipet and 60–70% after subsequent recrystallization (12). Conclusion Several important topics may be illustrated and discussed in conjunction with the multistep microscale reaction series discussed above. These experiments have been carried out successfully by approximately 60 students. Spectral data and complete experimental procedures are available upon request from the corresponding author, or on JCE Online. W Acknowledgments Appreciation is expressed to the National Science Foundation-Instrumentation Laboratory Improvement Program, Research Corporation, and The Roy and Christine Sturgis Charitable and Educational Trust for funding the purchase of an NMR spectrometer, and to The Camille and Henry Dreyfus Foundation and Research Corporation for supporting the purchase of an FTIR spectrometer. Literature Cited 1. Heck, R. F. Palladium Reagents in Organic Synthesis; Academic: New York, 1985. Tsuji, J. Palladium Reagents and Catalysts: Innovations in Organic Synthesis; Wiley: New York, 1995. 2. Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 19, 4467. Alami, M.; Ferri, F.; Linstrumelle, G. Tetrahedron Lett. 1993, 34, 6403. Bleicher, L.; Cosford, N. D. P. Synlett 1995, 1115. Nguefack, J-F.; Bolitt, V.; Sinou, D. Tetrahedron Lett. 1996, 37, 5527.
3. Brisbois, R. G.; Batterman, W. G.; Kragerud, S. R. J. Chem. Educ. 1997, 74, 832. 4. A previous report details the copper-catalyzed coupling of the same alkyne with iodobenzene: Okuro, K.; Furuune, M.; Enna, M.; Miura, M.; Nomura, M. J. Org. Chem. 1993, 58, 4716. 5. We have also carried out this reaction in 100 proof vodka, using a commercial animal deworming medication as the base: Chem. Eng. News 1996, 74(April 15), 34. 6. Alkynes 3 and 4 have previously been prepared via the copper acetylide of compound 1: Harris, M. A.; McMillan, I.; Nayler, J. H. C.; Osborne, N. F.; Pearson, M. J.; Southgate, R. J. Chem. Soc., Perkin Trans. I 1976, 1612. 7. Structures were minimized using MMX as implemented in PCMODEL (Serena Software). PCMODEL’s 1H NMR calculation is based on a modified Karplus algorithm of Haasnoot, C. A. G.; de Leeuw, F. A. A. M.; Altona, C. Tetrahedron 1980, 36, 2783. Calculated J values for Ha are 10.7 and 3.3 Hz for conformer 2; for conformer 3 they are 3.8 and 2.3 Hz. 8. Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of Organic Compounds; Wiley-Interscience: New York, 1994; pp 749– 752. 9. A microscale synthesis of alkyne 1 has recently been reported in which 1H NMR analysis of diastereotopic hydrogens is also discussed: Brisbois, R. G.; Batterman, W. G.; Kragerud, S. R. J. Chem. Educ. 1997, 74, 834. 10. For a clever experiment involving acetal formation on D-galactose with subsequent conformational analysis by 1H NMR spectroscopy and molecular modeling, see Midland, M. M.; Beck, J. J.; Peters, J. L.; Rennels, R. A.; Asirwatham, G. J. Chem. Educ. 1994, 71, 897. 11. For alternative preparations of alcohol 4 via Pd-catalyzed alkyne coupling, see (a) Bumagin, N. A.; Ponomaryov, A. B.; Beletskaya, I. P. Synthesis 1984, 728. (b) Bumagin, N. A.; Bykov, V. V.; Beletskaya, I. P. Russ. J. Org. Chem. 1995, 31, 348. 12. For a shorter, alternative synthesis of alkyne 6 via Pd-catalyzed alkyne coupling, see Takahashi, S.; Kuroyama, Y.; Sonogashira, K.; Hagihara, N. Synthesis 1980, 627.
JChemEd.chem.wisc.edu • Vol. 76 No. 1 January 1999 • Journal of Chemical Education
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