In the Laboratory
W
The Ethylene Ketal Protecting Group Revisited: The Synthesis of 4-Hydroxy-4,4-diphenyl-2-butanone Marsha R. Baar,* Charles E. Russell, and Kristin L. Wustholz Department of Chemistry, Muhlenberg College, Allentown, PA 18104; *
[email protected] Hazards
In 1973, Paulson, Hartwig, and Moran described a multistep synthesis of 4,4-diphenyl-3-buten-2-one (5, Figure 1) from ethyl acetoacetate that illustrated the use of a ketal protecting group (1). The ethylene glycol ketal (1) of ethyl acetoacetate was prepared with catalytic p-toluenesulfonic acid (p-TsOH) and a benzene azeotropic distillation utilizing a Dean–Stark apparatus. The ketal ester (1) was purified before use in a Grignard reaction with two equivalents of phenyl magnesium bromide followed by an aqueous workup to give the ketal alcohol (3). A separate step using aqueous HCl and acetone at reflux was required to remove the protecting group and restore the ketone (4), but a concurrent dehydration of the tertiary alcohol to an alkene occurred and the product isolated was the enone (5). This multistep sequence could easily consume five weeks to complete. In 1980, Rivett reported that the ketal alcohol (3) undergoes the removal of the ketal without the dehydration of the tertiary alcohol, producing 4-hydroxy-4,4-diphenyl-2butanone (4) by using more dilute acid in the deprotection step (2). We were intrigued by this, as it suggested that the procedure could be modified to obtain the hydroxyketone (4) directly from the Grignard workup, thereby shortening the synthetic sequence and avoiding an additional reflux procedure and the complication of the dehydration. Also, since the workup of the Grignard reaction could give any of three different products, it allowed us to present the students with the challenge of determining which product was obtained. However, if this experiment was to be currently employed, a different solvent was needed to replace carcinogenic benzene in the ketal formation. It is the purpose of this article to report that toluene can be substituted for benzene and that a change in the acid concentration in the Grignard workup directly produces 4.
O
O
C
C
H3C
p-TsOH
OEt
CH2
ⴙ
HO
Heating mantles–variacs and hotplates served as heat sources owing to the flammable nature of all reagents: ethyl acetoacetate, ethylene glycol, ketal ester (1), bromobenzene, and solvents: toluene, diethyl ether, tert-butyl methyl ether, and ligroin (60–90 ⬚C). These same materials and the products, 4-hydroxy-4,4-diphenyl-2-butanone and biphenyl, along with the aqueous washes, spectral solvents, and p-TsOH catalyst, are irritants or toxic, so students wore gloves and performed all operations in the hood. Generation of the Grignard reagent, phenylmagnesium bromide, requires anhydrous conditions and iodine initiation. Due to iodine’s toxic nature, the instructor dispensed it. The Grignard-forming reaction was exothermic and produced a corrosive organometallic reagent. An ice-water bath was kept handy and the Grignard reagent was never isolated but used directly. Additional specific cautions are provided in the Supplemental Material.W Results and Discussion We first investigated other solvents for the ketal formation. Paulson et al. reported a 64% yield of the ketal ester after one hour at reflux in benzene using a Dean–Stark apparatus and purification by distillation (1). Although toluene presents less of a health risk than benzene, we found the time required to collect the theoretical amount of water in the ketal formation was twice as long producing 76% crude yield of ketal ester.1 Decane was also tested, however it required a significantly longer time to collect the theoretical amount of water. As we did not have enough Dean–Stark apparatus for a lab section, we attempted a reflux period in toluene followed
O
benzene
OH
O C
H 3C
O
2 PhMgBr
C
ether
CH2
O H 3C
OEt
Ph
C H 3C
CH
C
C
C H 3C
CH2
Ph 5
Ph
Ph
H2O
O
ⴙ
H
CH2 C 2
OH
O
ⴙ
OMgBr
Ph
1
O
O C
Ph
H3O
acetone reflux
O
ice
OH
C H 3C
4
CH2 C 3
Ph
Ph
reacts further Figure 1. Original multistep sequence.
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In the Laboratory
by a distillation to force the equilibrium. In the hands of our students, the theoretical amount of water was collected after one hour at reflux and a half hour of distillation. The following period, after extraction and solvent removal by rotary evaporation, the crude ketal ester was obtained with a typical yield of ∼30%. Each student obtained IR, 1H, and 13 C NMR spectra and refractive index of their product. GC–MS analysis of a composite sample indicated that the composition of the crude product was > 80% ketal ester, contaminated with small quantities of toluene, unreacted ethyl acetoacetate, and other trace impurities. The mass spectrum of the product matched the library spectrum. 1H NMR spectra of typical student samples were consistent with the data reported by Paulson (1). The spectra also showed the presence of toluene, but not the ethyl acetoacetate. This impure ketal ester was used without further purification in the subsequent Grignard reaction. The nature of the workup following the Grignard reaction with the ketal ester is key for controlling which product is isolated. Paulson et al. used an ice-water quench and only water during their extraction to produce the ketal alcohol (3), which was then refluxed in HCl兾acetone to produce enone (5) (1). Rivett’s treatment of (3) with more dilute HCl produced hydroxyketone (4) (2). We adjusted the workup of the Grignard reaction to obtain the hydroxyketone directly without having to isolate the ketal alcohol. Our Grignard reaction mixture was quenched in ice cold 10% H2SO4 and was then left to sit for one week.2 Our extraction procedure included washes with 10% aqueous H2SO4, not plain water, to help dissolve magnesium salts. Following drying and rotary evaporation, the crude product was obtained as an orangey oil. Recrystallization from ligroin (60–90 ⬚C) gave a light beige solid in ∼40% yield, which melted in the low 80’s (lit. 84–85 ⬚C) (3). The 1H NMR spectra matched the data reported by Rivett (2). Prior to their isolation of the product we devoted lab time to discuss with the students how the workup conditions might affect which compound is formed and how to identify it. The techniques used to identify the product included a consideration of physical properties, IR, 1H, and 13C NMR spectra. Physical property information could be provided for the students or they could be given the assignment of finding it in the literature.
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Conclusions Our modifications demonstrate the use of a protecting group in a shorter experimental sequence, one that can be completed in four lab periods. The switch from benzene to toluene in the ketal formation allows the sequence to be utilized with current safety guidelines. Sufficient yield of the ketal ester is obtained from a reflux–distillation procedure, making the use of the Dean–Stark apparatus unnecessary. The crude ketal ester can be used without further purification by distillation and can be identified by IR and 1H NMR. The hydroxyketone can be obtained directly from the Grignard workup, thus avoiding an additional reflux. The range of possible compounds obtained from this step allows for discussion before the fact about how to characterize the product, and discussion after the fact about the effect of reaction conditions on the results. The hydroxy ketone can be identified by its melting point, IR, and 1H NMR. The ketal ester and hydroxy ketone can be further characterized by 13 C NMR. W
Supplemental Material
A student handout, report sheets, instructor notes, CAS numbers with specific hazard information, and tabulated spectral data for the ketal ester and hydroxy ketone are available in this issue of JCE Online. Notes 1. The toluene兾water azeotrope initially boils at 85 ⬚C as compared to benzene兾water at 80 ⬚C. 2. We performed the experiment on 1兾3 the scale of Paulson et al.
Literature Cited 1. Paulson, D. R.; Hartwig, A. L.; Moran, G. F. J. Chem. Educ. 1973, 50, 216–217. 2. Rivett, D. E. A. J. Chem. Educ. 1980, 57, 751. 3. Within Rivett’s note he gave the following reference for the melting point of the hydroxyketone: Wittig, G.; Suchanek, P. Tetrahedron 1966, Suppl. No. 8, Part 1, 347.
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