In the Laboratory
Carbonyl and Conjugate Additions to Cyclohexenone Experiments Illustrating Reagent Selectivity Michael G. Organ* and Paul Anderson Department of Chemistry, Indiana University–Purdue University, 402 North Blackford St., Indianapolis, IN 46202
Organic chemistry is very challenging for most undergraduate students in that it is often perceived to be a subject unto itself, seemingly with its own language. Consequently, the focus of the curricula in most one-year organic chemistry courses is commonly on “the basics”, and issues that may serve to confuse are often glossed over or omitted completely. One such issue is the reagent selectivity, or chemoselectivity, observed when a reagent is added to starting materials that possess more than one reactive site or functional group. This is an issue commonly faced by a practicing synthetic chemist in the production of target molecules of industrial interest. Undergraduate students leaving an organic chemistry program should have exposure to these concepts and hands-on experience in dealing practically with the issue of selectivity. In this paper, selective addition of a nucleophile to either end of the enone moiety in cyclohexenone is examined. Background Grignard-type addition reactions to carbonyl substrates are one of the first and most important classes of carbon–carbon bond-forming reactions taught at the undergraduate level. The general reaction with enone substrates is shown in Figure 1. Typically, substrates are ketones or aldehydes and the nucleophilic partner is an organomagnesium halide (the “Grignard reagent” [1]) or an organolithium compound. If the carbonyl moiety is present by itself, reagent selectivity is not a consideration providing the carbonyl does not preferentially enolize or reduce for steric or other reasons (2, 3). Carbon–carbon double bonds are chemically unreactive towards these same reagents, so if they are present in another portion of the starting material, this offers no concern (4). However, if the carbonyl is present in conjugation with a double bond (i.e., forming an enone), the double bond is now receptive to the incoming nucleophile at the 4-position (5, 6). This increase in reactivity is the result of polarization created by the oxygen, which, through conjugation, makes the 4-position electrophilic. Thus, 1,4-addition is sometimes also referred to as conjugate addition. Selectivity now becomes an issue because if there were no selectivity in such additions, the nucleophile would add equally to the 2- and 4-positions and such a reaction would be of limited synthetic utility. A great deal of effort has been devoted to controlling the aforementioned problem with the result that 1,2-
and 1,4-additions to enones can be done with excellent selectivity. Grignard and organolithium reagents have a strong preference to deliver the alkyl group in a 1,2fashion. This result can be explained by the coordination of lithium or magnesium to oxygen, which delivers the alkyl fragment to the oxygen-bearing carbon. The reaction proceeds via a 4-centered cyclic transition state in the case of the lithium compound or a 6-centered transition state involving two molecules of the reagent in the case of Grignard additions (7). Although organolithium and organomagnesium halide reagents show preference for 1,2-addition, selectivity is rarely absolute. Steric considerations have been used to explain some variations in 1,2- and 1,4-selectivity in that the size of the substituents on the carbonyl group or the organometallic reagent has an impact on selectivity (8). Recent work has shown that the use of lanthanide-based reagents such as organocerium and organoytterbium species, derived from the corresponding lithio or magnesium reagent in situ, gives almost exclusive 1,2-selectivity in additions to enones (3, 9). In such reactions, the lanthanide is believed to substitute for lithium or the magnesium halide, producing an organolanthanide reagent and the corresponding metal halide, and it is the organolanthanide that actually adds to the enone (10). This point is still open to debate because the true identity of the species that adds in these reactions remains unknown. Important synthetic methodology has been developed also employing copper-based reagents in nucleo-
O
R
R-M ether
O 4
(A)
R-M ether
2
H
(B) R-M
R OH
(C) R-M
Figure 1. The general reaction with enone substrates where M is a metal, usually Li or MgBr. (B) reacts to form either the 1,4- or conjugate addition product (A) or the 1,2- or carbonyl addition product (C).
*Corresponding author.
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philic additions to enones (11). It was found that the same Grignard or organolithium reagents when added to enones in the presence of copper(I) salts gave almost exclusive 1,4-addition. The reagent formed during the addition of such organometallics to copper(I) salts is thought to be R2CuLi, which is known as the “Gilman reagent” (12). This was a useful discovery for synthetic chemists, as it provided a routine and reliable approach to products of conjugate addition. The basis of the reversed selectivity from that of the Grignard reagent alone is another source of contention. Some researchers suggest that the reaction mechanism involves a single electron transfer process preceded by coordination of the reagent to the carbonyl oxygen. For geometric reasons, the copper atom is then delivered to the 4-position via a 6-centered transition state to form the copper(III) β adduct (13). The formation of this organocopper intermediate is widely accepted in all proposed mechanisms and the alkyl group is introduced by reductive elimination (14). More recently, it has been proposed that complexation does not take place with oxygen, but rather between the filled d-orbitals of copper and the LUMO of the enone at the carbon–carbon double bond (the socalled “π-d complex”) and this promotes delivery to the 4-position (14). The purpose of this communication is to illustrate 1,2- and 1,4-selectivity under the three different reaction conditions described above as detailed in the folloing reaction :
CeCl3
stir 2-4h
THF
1. -78 oC CeCl2-THF
CeCl3-(THF)n 2.
(23 oC)
Li
O
Li
O ether -78 oC
O HO +
1 1,2- or carbonyl addition product
2 1,4- or conjugate addition product
O
1. CuI, ether, 0oC
Experimental Methods and Results
General Glassware The 25-mL round-bottom flasks used in these experiments were oven-dried, equipped with a stir bar, flushed with nitrogen gas, and capped with a rubber septum. To ensure an inert atmosphere inside these flasks during reaction and to control pressure fluctuations during additions, a nitrogen-filled balloon equipped with a needle adapter was inserted through the rubber septum and kept there at all times during the reactions. Solvents Dried diethyl ether and tetrahydrofuran (THF) were obtained by distillation from sodium benzophenone ketyl and transferred by glass syringe. The same experimental results were obtained in this study by simply drying diethyl ether and THF in Erlenmeyer flasks over anhydrous magnesium sulfate (MgSO4) and anhydrous sodium sulfate (Na2SO4), respectively. Chemicals Copper(I) iodide and anhydrous cerium(III) chloride were purchased from Alfa/Aesar Chemicals and used as delivered. n-Butyllithium was purchased from Aldrich Chemical Co. and was titrated using diphenylacetic acid before use. Dry Ice Bath The {78 °C cooling bath was prepared by placing a few small pieces (2 to 3 cm across) of dry ice in a 100 mm × 50 mm crystallizing dish and slowly adding acetone to a depth of approximately 3 cm. In order to ensure a constant temperature of {78 °C during the reactions, dry ice was added to the bath if necessary so that some of the solid was always visible. Thin-Layer Chromatography (TLC) Thin-layer chromatography was performed using Merck kieselgel 60 F254 silica-gel plates (with fluorescent indicator). The solvent system used to elute the plates was 20% diethyl ether/pentane (vol/vol). After elution, the plates were placed under a UV lamp and spots that became visible were marked by circling them with a pencil. The plates were immersed briefly in the anisaldehyde developing stain, toweled off, and then placed on a hot plate until the spots appeared. Anisaldehyde developing stain is a mixture of 135 mL of ethanol, 5.0 mL of concentrated H2SO 4, 1.5 mL of acetic acid, and 0.37 mL of p-anisaldehyde.
Li 2. -78 oC
(
)2CuLi
The results will demonstrate that selectivity can be both absolute and opposing for the same substrate under similar reaction conditions by modifying the same basic nucleophilic reagent. At the same time, the experiments give second-semester organic chemistry students experience working with air-sensitive materials and subzero reaction temperature techniques. Furthermore, whereas cuprate chemistry has been studied for some time, the use of lanthanide reagents in addition reactions has only been developed during the last decade. As a result, to our knowledge, reagents such as cerium chloride have not been used in undergraduate laboratories in such a manner—if at all.
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Flash Column Chromatography Enough 230–400 mesh flash grade silica gel was placed into a 20 mm × 250 mm flash chromatography column to produce a bed of silica 150 mm deep. This was then transferred into a 150-mL Erlenmeyer flask and enough solvent (10% ethyl ether/pentane, vol/vol) was added to wet all of the silica gel. This slurry was then loaded back into the column and the solvent allowed to drain under slight air pressure until the liquid sat about 2 mm above the surface of the packed silica. The crude residues from the experiments were dissolved in 1 mL of 10% diethyl ether/pentane and the mixture was loaded on top of the column while the column was draining. The process was repeated once to get all of the product on the column. Two hundred milliliters of eluant was then loaded into the column reservoir and air pressure was used to maintain a flow rate of 10 mL/30 s. Ten-milliliter fractions were collected from the column, a spot from
Journal of Chemical Education • Vol. 73 No. 12 December 1996
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each was loaded onto a large TLC plate, and the plate was developed as described under “Thin Layer Chromatography” to identify fractions containing product(s). Fractions containing the same product were pooled into a preweighed round-bottom flask, the solvent was removed by rotary evaporation, and the flask reweighed to determine product yield.
Addition of n-Butyllithium to Cyclohexenone
1 H NMR (300 MHz, CDCl3) δ 5.81 (m, 1H), 5.62 (br d, J= 9.5 Hz, 1H), 1.98 (m, 2H), 1.75-1.25 (m, 11H), 0.91 (t, J=6.5 Hz, 3H);
C NMR (75 MHz, CDCl3) δ 132.83, 129.59, 69.62, 41.99, 35.31, 25.65, 25.17, 23.22, 18.98, 14.03; 13
IR (neat) 3369 (m, br), 3018 (w), 2953 (s) 2861 (m), 1466 (m).
Representative spectroscopic data for 2:
Five milliliters of dried diethyl ether was placed into a 25-mL round-bottom flask by syringe as described in the “Solvents” section; 200 mg (0.20 mL, 2.08 mmol) of cyclohexenone was added via syringe and the solution stirred at {78 °C for 10 min. At that time, 1.87 mL of nbutyllithium (titrated to be 1.67 molar in hexane, Aldrich, 3.12 mmol, 1.5 eq) was added dropwise using a plastic 2.5-mL syringe. CAUTION: n-Butyllithium is extremely reactive, particularly with water and acetone; therefore care must be taken while dispensing it and cleaning the needles. After 10 min, a small aliquot of reaction mixture was removed using a thin glass capillary tube that entered the reaction flask through the bore of a short 16-gauge needle. The needle was placed temporarily through the septum of the reaction flask, which was under positive nitrogen gas pressure from the balloon, in order to minimize exposure to moist air. One single drop of the above aliquot was spotted on a TLC plate beside a sample of cyclohexenone (one drop of a 5% solution in diethyl ether) and the plate developed to follow the reaction’s progress. Analysis of the TLC plate indicated that the reaction was complete (i.e., all cyclohexenone was gone) and that there were two principal products, of which both were less polar than the starting material. Compound 1 has an Rf of .25, coming just above cyclohexenone (Rf = .2); 2 has an R f of .5. The product of 1,2-addition (an alcohol) stains a characteristic blue using the anisaldehyde dip; the 1,4addition product (a ketone) stains reddish. Neither product is ultraviolet-active under 254-nm light, whereas the starting material, cyclohexenone, is very active. At that point, the reaction was quenched and worked up using the following general procedure, which was used for all experiments. After removing the rubber septum, 2.0 mL of aqueous saturated ammonium chloride (NH4Cl) was added dropwise and the cooling bath removed. After dilution with 10 mL of diethyl ether, the solution was loaded into a small separatory funnel, the mixture shaken, and the layers separated. The aqueous layer was extracted with 10 mL of diethyl ether and the organic layers were combined. After drying over anhydrous MgSO4 for 10 min, the organic fraction was filtered through Whatman 1 paper into a round-bottom flask and the solid rinsed with 10 mL of diethyl ether. Solvent was removed by rotary evaporation. 1H NMR spectroscopy of the crude mixture confirmed the presence of the two isomeric products. Although the aliphatic signals of 1 overlap with most of the resonances of 2, the signals from protons adjacent to the ketone of 2 (i.e., 2.5–2.2 ppm) are distinct from the aliphatic peaks of 1, which are all upfield of 2.0 ppm. The vinyl proton signals of 1 are clearly apparent downfield of 5.5 ppm. The crude material was then loaded onto a 20-mm column and flashed as described in the “Flash Column Chromatography” section, yielding 181 mg of the 1,2-adduct 1 (57% yield) and 39 mg of the 1,4-adduct 2 (12% yield). Both compounds were clear oils. Representative spectroscopic data for 1:
NMR (300 MHz, CDCl3) δ 2.48-2.20 (m, 2H), 2.081.02 (m, 13H), 0.90 (t, J=6.4 Hz, 3H); 1H
13C NMR (75 MHz, CDCl ) δ 199.07, 48.16, 41.43, 3 39.01, 36.23, 31.27, 28.79, 25.23, 22.65, 13.95;
IR (neat) 2928 (s), 2859 (s), 1714 (s).
Addition of n -Butyllithium to Cyclohexenone with Copper(I) Iodide Copper(I) iodide (792 mg, 4.16 mmol, 2 eq) was placed into a 25-mL round-bottom flask and 5.0 mL of dried diethyl ether was added. The grayish suspension was stirred in an ice bath for 10 min, after which 4.98 mL of n-butyllithium (titrated to be 1.67 molar in hexane, Aldrich, 8.32 mmol, 4 eq) was added dropwise using a plastic 5-mL syringe. During the addition the solution darkened, becoming almost black. After addition, the mixture was cooled to {78 °C. After stirring for 10 min, 200 mg of cyclohexenone were added (0.2 mL, 2.08 mmol) via syringe and the solution was stirred for 20 min. At that time, TLC analysis (as above) indicated that the reaction was complete and the solution was worked up. Analysis of this TLC plate indicated the presence of only the 1,4-adduct; this was confirmed by evaluation of the crude 1H NMR spectrum, as no vinylic proton signals were evident. After flash chromatography, 268 mg of 2 (84% yield) was obtained. Addition of n -Butyllithium to Cyclohexenone with Cerium(III) Chloride Anhydrous cerium(III) chloride (230 mg, 0.94 mmol, 3 eq) was placed into a 25-mL round-bottom flask and 5.0 mL of dried THF was added. The chalky-white suspension was stirred for 2 h, cooled to {78 °C, and held at that temperature for 10 min. It is crucial to ensure that the cerium chloride is well solvated by THF before adding the lithium reagent. The most reproducible results were obtained by stirring for 4 h before adding alkyllithium or by sonicating the suspension for 30 min. n-Butyllithium (0.56 mL, titrated to be 1.67 molar in hexane, Aldrich, 0.94 mmol, 3 eq) was then added dropwise using a 1-mL plastic syringe. After the addition, the mixture was stirred for 30 min, 30 mg of cyclohexenone was added (0.030 mL, 0.31 mmol) via syringe, and the solution was stirred for an additional 20 min. At that time, TLC analysis (as above) showed that the reaction was complete and the solution was worked up. TLC and 1H NMR spectroscopic analysis indicated the presence of only the 1,2-adduct. After flash chromatography, 44 mg of 1 (92% yield) was obtained. Discussion Addition of the copper and cerium derivatives of nbutyllithium to cyclohexenone under similar reaction conditions demonstrated absolute but opposing selectivity. Addition of the cuprate derivative showed complete selectivity for the 1,4-addition product, while the organocerium species displayed complete 1,2-addition selectiv-
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ity. In the absence of either transition metal additive, nbutyllithium exhibited a preference for 1,2-addition (83:17, 1,2-add:1,4-add). This work has shown that chemoselectivity in additions to enones can be rigorously controlled. In the case of the organocerium reagent, the metal is very highly “oxophilic” meaning that it binds to oxygen centers very tightly. This strong coordination has been proposed to “soften” the carbonyl carbon, making it more susceptible to nucleophilic attack (9). This additional electronic effect, relative to the lithium case, could be the cause of the increased 1,2-selectivity. In the case of the cuprate reagent, strong complexation of copper with the π orbitals of the double bond of the enone moiety is most likely the cause of the pronounced 1,4-selectivity. This hypothesis has been supported by recent spectroscopic studies of the “π-d complex” (15). Thus, it delivers the alkyl group to the 4-position of the double bond to which it is coordinated rather than the 2-position, even though both sites are highly electrophilic. Acknowledgments MGO acknowledges financial assistance from Eli Lilly, the Purdue Research Foundation, and Indiana University–Purdue University at Indianapolis.
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Literature Cited 1. Grignard, V. C. R. Acad. Sci. 1900, 130, 1322. 2. Kharasch, M. S.; Reinmuth, O. Grignard Reactions of Nonmetallic Substances, Prentice-Hall: New York, 1954; p 138. 3. (a) Dimitrov, V.; Bratovanov, S.; Simova, S.; Kostova, K. Tetrahedron Lett., 1994, 35, 6713; (b) Imamoto, T.; Takiyama, T.; Nakamura, K. Tetrahedron Lett. 1985, 26, 4763. 4. Chiara, J. L.; Cabri, W.; Hanessian, S. Tetrahedron Lett. 1991, 32, 1125. 5. Roush, W.R.; Michaelides, M. R.; Tai, D. F.; Chong, W. K. M. J. Am. Chem. Soc. 1987, 109, 7575. 6. For reviews in cuprate addition chemistry, see: (a) Normant, J. F. Synthesis 1972, 63; (b) Erdik, E. Tetrahedron 1984, 40, 641; (c) Yamamoto, Y. Angew. Chem. Int., Ed. Engl. 1986, 25, 947. 7. Ashby, E. C. Q. Rev. Chem. Soc. 1967, 21, 259. 8. (a) Park, O. S.; Grillasca, Y.; García, G. A.; Maldonado, L. A. Synth. Commun. 1977, 7, 345; (b) Hauser, F. M.; Hewawasam, P.; Rho, Y. S. J. Org. Chem. 1989, 54, 5110. 9. For reviews discussing the use of lanthanides in promoting 1,2-addition, see: (a) Kagan, H. B.; Namy, J. L. Tetrahedron 1986, 42, 6573; (b) Kagan, H. B.; Sasaki, M.; Collin, J. Pure Appl. Chem. 1988, 60, 1725; (c) Molander, G. A. Chem. Rev. 1992, 92, 29. 10. Imamoto, T.; Sugiura, Y.; Takiyama, N. Tetrahedron Lett. 1984, 25, 4233. 11. For discussion on cuprate additions, see: Posner, G. H. An Introduction to Synthesis Using Organocopper Reagents; Wiley: New York, 1980. 12. (a) Gilman, H.; Straley, J. M. Recl. Trav. Chim. Pays-Bas 1936, 55, 821; (b) Gilman, H.; Jones, R. G.; Woods, L. A. J. Org. Chem. 1952, 17, 1630; (c) Snyder, J. P.; Spangler, D. P.; Behling, J. R.; Rossiter, B. E. J. Org. Chem. 1994, 59, 2665. 13. (a) Bindra, J. S.; Brindra, R. Prostaglandin Synthesis; Academic: New York, 1973: p 111; (b) Bernady, K. F.; Weiss, M. J. Prostaglandins 1973, 3, 505. 14. (a) Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1985, 26, 6015; (b) Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1985, 26, 6019. 15. (a) Krauss, S. R.; Smith, S. G. J. Am. Chem. Soc. 1981, 103, 141; (b) Hallnemo, G.; Olsson, T.; Ullenius, C. J. Organomet. Chem. 1985, 282, 133; (c) Lipshutz, B. H.; James, B. Tetrahedron Lett. 1993, 34, 6689; d. Ullenius, C.; Christenson, B. Pure Appl. Chem. 1988, 60, 57.
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