Research: Science and Education

The Michael Reaction W

Thomas Poon* W. M. Keck Science Center, Claremont McKenna, Pitzer, and Scripps Colleges, Claremont, CA 91711-5916; [email protected]

Bradford P. Mundy and Thomas W. Shattuck Department of Chemistry, Colby College, Waterville, ME 04901

Introduction to an α,β-unsaturated carbonyl compound. However, there is the obvious competitive reaction, where we see the 1,2- As chemical education has evolved, it has seen numerous addition reaction already familiar to us in carbonyl chemistry trends become mainstay modes of teaching in the classroom. (Scheme I). How can these two modes of attack be reconciled, The use of computational chemistry is one example. Until the and further, is it possible to predict products of a new reaction? turn of the 21st century, the use of computational chemistry As it turns out, this is easily rationalized by way of modern to explain phenomena in organic chemistry was reserved for computational methods. individuals or institutions with access to specialized software. The use of computations and the visually stunning three- O Nu dimensional output from these calculations is now available 1,2-addition to students in a growing number of textbooks (1). Two other O prevalent trends in chemistry education are the emphasis on Nu chemistry’s relationship to the fields of biology and medicine O (2), and the incorporation of research data and results into lectures and laboratory experiments (3). As students become 1,4-addition more accustomed to these methods of presenting chemical concepts, instructors will need to find more examples that Nu allow them to incorporate these modes of presentation into their daily lectures. Scheme I. The competition between 1,2 and 1,4 addition. While introductory organic chemistry possesses a fair number of topics that have already benefited from computa- Computational Approach tional treatments, biologically and medicinally relevant stories, Mendez and Gazquez (5) have discussed chemical reac- and significant research examples, there are many topics yet tivity in terms of hard–soft acid–base theory (6 ). They state, to be enriched by such approaches. We present herein a concise “the regions of a molecule where the Fukui function is large are review of a staple reaction in the organic chemistry curriculum, chemically softer than the regions where the Fukui function the Michael reaction. Included are examples of its use in is small, and by invoking the HSAB principle in a local sense, chemical research, an illustration of its biological and medicinal one may establish the behavior of the different sites with respect relevance, and detailed instructions for educators who wish to to hard or soft reagents.” They define, using a finite difference use a computational approach to present this reaction to their approximation, the Fukui function students. + ≈ ρ ρ f (r) N+1(r) – N(r) (1) Short Biography ρ for nucleophilic attack. In this analysis, N is the electron This reaction is named after Arthur Michael, born in density at a point r in space around the molecule. The N Buffalo, NY, in 1853. Although he was self-taught and never corresponds to the number of electrons in the molecule. Thus, formally took a degree, he had training with Bunsen N + 1 corresponds to an anion, with an electron added to the (Heidelburg), Hofmann (Berlin), Wurtz (Paris), and LUMO of the neutral molecule. All calculations are done at Mendeleyev (St. Petersburg). He took his first academic post the ground-state geometry. These functions can be condensed at Tufts, and in 1887 discovered the reaction for which he is to the nuclei by using an atomic charge partitioning scheme, remembered. After a short stint at Tufts, Michael took a three- such as Mulliken population analysis year break for private research on the Isle of Wight. He then f + = q (N + 1) – q (N )(2) returned to Tufts, where he eventually retired in 1907. After five Ak Ak A Ak A years of private research at Newton Center in Massachusetts, for nucleophilic attack, where qAk(NA) is the Mulliken charge he was appointed Professor of Chemistry at Harvard Uni- on atom k for NA total electrons. versity. Michael died in 1942, leaving a record of a highly While the user can obtain values for the condensed func- innovative and productive career (4). tions by hand, the difference plotting capabilities of Spartan1 for UNIX systems can be used to obtain 3-D grid represen- Overview of Reaction tations of the Fukui function. These are done by running the appropriate calculations of the (N + 1) state using the The broad view of the Michael reaction may be most same geometry and subtracting the resulting density readily summarized by “1,4 addition” or “conjugate addition” volumes.2,W

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Simplified Computational Approach (Fig. 2) provides the necessary insight for the preferential conjugate addition. In general we note that soft nucleophiles An easy graphical display technique based on the Fukui will add in the Michael sense, whereas hard nucleophiles will functions can also be achieved. Instead of calculating the add 1,2. A soft nucleophile can be considered one that is more molecular orbitals for the neutral species, cation, and anion, diffused in its electrons. In the chemistry of the S 2 reaction one can just add or subtract electrons from the molecular N we readily appreciated that these nucleophiles include sulfide orbitals of the neutral species. This procedure isn’t as good and iodide ion. We can expand this to include many enolate- as the one described above, but it does give a quick graphical type nucleophiles such as cyanide ion and Gilman reagents. display of the susceptibility of the molecule to different kinds Literature examples will show that hard nucleophiles such as of attack. So rather than being a definitive calculation of a alkyl lithium reagents and Grignard reagents tend to undergo molecular property, freezing the molecular orbitals to those for chemistry at the carbonyl carbon, as do LiAlH and NaBH . the neutral molecule gives a useful graphical technique that 4 4 can be rapidly applied. To use the frozen orbitals approach for nucleophilic attack: The Michael Reaction in Organic Synthesis 1. Build and minimize your molecule. Only the neutral The Michael reaction has been used widely in organic molecule is needed for this approach. synthesis for its C–C bond-forming ability. It is employed 2. Enter the Expert mode of the Volumes setup. Define in the traditional sense where an enolate reacts with an α,β- the following volume in the Volume setup dialog box: unsaturated carbonyl as seen in the work of Rubio et al. (7) α volume=density[EADD=LUMO].-.density for the synthesis of (᎑)- -kainic acid (Scheme II). 3. Use resolution=med and submit your job with a single TBDMSO point MO calculation. CO2Et You can then set up slices or isosurfaces to display the results. CO2Et These results provide a very clear understanding for the course of the reaction. If we had simply looked at the elec- CO2Et tronic structure associated with the LUMO of methyl vinyl N ketone (MVK), we would predict that the carbonyl carbon is O O Boc most receptive to attack (Fig. 1). However, a Fukui analysis EtOC CH2 C OEt

NaH/THF 65% TBDMSO CO2Et

CO Et CO Et N 2 N 2 Boc Boc Kainic Acid Scheme II. Synthesis of (᎑)-α-kainic acid. The Michael reaction is also used in tandem with other re- actions. Perhaps the best known of these is the Robinson an- nulation where the Michael addition occurs as the first step. This sequence of Michael addition followed by intramolecular Aldol condensation proved extremely important early on in the area of steroid chemistry as illustrated in Woodward’s syn- Figure 1. LUMO of MVK mapped onto an electron density surface thesis of cortisone (Scheme III) (8). calculation. (Shown in color on page 140.) Me

NaOH dioxane O O

O Me Et Me O OH Me Me

O Figure 2. Volume plots of the Fukui functions for MVK using the O (left) standard and (right) simplified computational approaches. Cortisone (Shown in color on page 140.) Scheme III. Synthesis of cortisone.

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OMOM OMOM O O O 2 CO Et O LDA, THF, 2 3 O

-78° C 1 4 OEt O 5 O O

6 OMOM

O O 5 O O 4 3 O

H 6 2 MOMO CO2Et 1 Claenone (82%, racemic)

Scheme IV. Synthesis of claenone.

O H3C O O 7 O H3C 6 5 95% 1 Et3N Ph O 2 O S 7 2 10-20% 1 4 6 5 3 3 4 S H3C Ph CH3 Scheme VI. Michael reaction employing non-enolic Scheme V. Example of an intramolecular Michael addition. carbon nucleophile.

Ac Ac Ac TBSO N O N O N O MOMO MOMO HO Me O 1) TASF O OTf Me O OTf 2) PhNTf2, O TEA (95%) O O TBSO H HO OTBS H (±)-Batrachotoxinin A Scheme VII. Example of nucleophilic oxygen used in the Michael reaction.

CO2t-Bu CO2t-Bu S 2 CO2t-Bu S 3 S 3 CO2t-Bu 1 2 S N O O O H N H 1 N 2 N H S Me S N O N 1 O HO H Me O Me O OH CH OH H 2 Gliotoxin

Scheme VIII. Example of nucleophilic nitrogen used in the Michael reaction.

266 Journal of Chemical Education • Vol. 79 No. 2 February 2002 • JChemEd.chem.wisc.edu Research: Science and Education

Another useful application of a tandem Michael addi- Summary tion is seen in the total synthesis of the antimicrobial com- In this short account we have provided computational pound Claenone (Scheme IV) (9). In this instance, Yamada insight for the observed conjugate addition associated with and coworkers are able to construct a norbornane ring using the Michael reaction, presented significant examples of the two sequential Michael additions. In fact, the second step of reaction in synthesis, and shown its relevance in the activity Yamada’s synthesis, an intramolecular Michael addition, is fre- of a new type of drug. quently used to build complex ring systems. An interesting example is seen in Little’s use of the Michael reaction to form WSupplemental Material a tricyclic diketone (Scheme V) (10). Instructions for performing these calculations in various Although a majority of syntheses that utilize the title versions of Spartan for UNIX and other applications of Fukui reaction involve an enolate as the attacking nucleophile, other surfaces are available in this issue of JCE Online. This article types of nucleophiles have been effectively used in Michael is also available with color figures in JCE Online. reactions. Binns and coworkers (11) studied additions of phenyl- thioallyl anions to cyclopentenones and found the addition Note to be highly regioselective (Scheme VI). Kishi et al. used 1. Wavefunction, Inc., 18401 Von Karman, Suite 370, Irvine, heteronucleophiles extensively in Michael reactions to syn- CA 92612. thesize complex natural products. In one example, Kishi used 2. The Mac and PC versions of SpartanPro do not currently an oxygen anion to form a bridging ring in the steroid-like allow for Fukui function calculations. Detailed instructions for per- natural product (±)-batrachotoxinin (Scheme VII) (12). In forming these calculations in various versions of Spartan for UNIX another example, Fukuyama and Kishi use the negatively are available in this issue of JCE Online.W charged nitrogen of a thioacetal-bridged 3,5-piperazinedione to synthesize the antibiotic Gliotoxin (Scheme VIII) (13). Literature Cited 1. For examples, see: Brown, W. H.; Foote, C. S. Organic Chemis- The Michael Reaction in Nature try, 3rd ed.; Harcourt College Publishers: Fort Worth, TX, 2002. The Michael reaction was found to play a crucial part Carey, F. A. Organic Chemistry, 4th ed.; McGraw-Hill: Boston, in the mechanism for reactivity of the biomolecule, 2000. Bruice, P. Y. Organic Chemistry, 3rd ed.; Prentice Hall: Calicheamicin (Scheme IX). Calicheamicin, a naturally oc- Upper Saddle River, NJ, 2001. McMurry, J. Organic Chemistry, curring compound from the bacterium Micromonospora 5th ed.; Brooks/Cole: Pacific Grove, CA, 2000. Solomons, G.; echinospora, is a novel antibiotic containing an enediyne func- Fryhle, C. Organic Chemistry, 7th ed.; Wiley: New York, 2000. tional group as the active part of its structure. Nicolaou and 2. Barreto, J. C. J. Chem. Educ. 2000, 77, 1548. Meinwald, J. Sorensen, in their excellent book Classics in Total Synthesis J. Chem. Educ. 1994, 71, 506. Wolfson, A. J.; Hall, M. L.; (14), provide an intriguing story of the discovery and syn- Allen, M. M. J. Chem. Educ. 1998, 75, 737. thesis of this unique natural product. 3. Dunn, J. G.; Phillips, D. N. J. Chem. Educ. 1998, 75, 866. Kharas, G. B. J. Chem. Educ. 1997, 74, 829. Zafran, R. J. Chem. Educ. 1996, 73, 78. O O 4. Morris, P. Biographies of Chemists; Moss, G., Web presentation; http://www.chem.qmw.ac.uk/rschg/biog.html (accessed Oct 2001). NHCO2Me NHCO2Me Brock, W. H. The Chemical Tree—A History of Chemistry; HO Redn. of HO Norton: London, 1992; pp 517–518. trisulfide 5. Mendez, F.; Gazquez, J. L. J. Am. Chem. Soc. 1994, 116, 9298. 6. For discussions of HSAB theory, see: Pearson, R. G. Inorg. O O Sugar Sugar Chim. Acta 1995, 240, 93. Ho, T.-L. Tetrahedron 1985, 41, MeSSS S 3–86. Ho, T.-L. Chem. Rev. 1975, 75, 1. Michael 7. Rubio, A.; Ezquerra, J.; Escribano, A.; Remuiñán, M. J.; Va- addition quero, J. J. Tetrahedron Lett. 1998, 39, 2171. O O 8. Woodward, R. B.; Sondheimer, F.; Taub, D. J. Am. Chem. Soc. 1951, 73, 4057. NHCO2Me NHCO2Me 9. Miyaoka, H.; Isaji, Y.; Kajiwara, Y.; Kunimune, I.; Yamada, Y. Tet- rahedron Lett. 1998, 39, 6503. HO HO 10. Little, R. D.; Masjedizadeh, M. R.; Wallquist, O.; McLoughlin, J. I. Org. React. 1995, 47, 315. S O S O 11. Binns, M.; Haynes, R.; Houston, T.; Jackson, W. Tetrahedron Sugar Sugar Lett. 1980, 21, 573. Benzene diradical (DNA cleaving agent) 12. Kurosu, M.; Marcin, L. R.; Grinsteiner, T. J.; Kishi, Y. J. Am. Chem. Soc. 1998, 120, 6627. Scheme IX. Calicheamicin and site of Michael addition. 13. Fukuyama, T.; Kishi, Y. J. Am. Chem. Soc. 1976, 98, 6723. 14. Nicolaou, K. C.; Sorensen, E. J. Classics in Total Synthesis; VCH: We provide a short computer animation (15), based on Weinheim, 1995; Chapter 30. the strategies developed in the text, to show this biological 15. Mundy, B. P.; Poon, T. Computer Animations and Tutorials activity and the role played by a Michael reaction. One notes for Organic Chemistry; http://www.OCHeM.com (accessed that sulfur is generally considered a soft nucleophile and it is Oct 2001); the animation can be accessed by first clicking on not surprising that conjugate addition is observed. “Tutorials” and then “The Michael Reaction”.

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