Industrial Chemistry in the Organic Laboratory: C4 Alkylations David M. Teegarden,' Theresa C. Varco-Shea? Karen T. C ~ n k l i nCynthia ,~ A. Markle? and Scott D. Anderson5 St. John Fisher College, Rochester, NY 14618 For several years we have been interested in incorporating aspects of industrial chemistry in the undergraduate curriculum (I).The sophomore organic course presents ample o~oortunitvto illustrate discussions of svnthetic reactions or mechanisms with commercially important examples. A large number of industrial compounds are synthesized using chemistry covered in any contemporary organic course (2). Discussina some of these reactions helps students make important connections between "textbook" and industrial ("real") organic chemistry. Additional advantages may accrue. One has the opportunity to discuss key differences between laboratory- and large-scale synthetic options (e.g., batch vs. continuous processes, handling solids vs. pumping liquids, choice of starting materials and reagents, economics, etc.). Additionally, if the examples chosen include familiar commercial compounds, student interest may increase. We present a set of experiments to illustrate reactions of the tertiary-butyl group. The products are all compounds that occur in consumer ~ r o d u c t and s have received considerahleattenrion in the popular press. Ineach case,rhesynthetic ~rocedurewas adapted from that described in the patent literature. Although these compounds may in fact be produced commercially by a somewhat different (e.g., continuous) process, the procedures below accurately reflect the type of chemistry used. BHA, BHT, and TBHQ are common antioxidants added t o foods, plastics," and many other products. BHT, or butylated hydroxytoluene, is usually a single compound, 2,6-di-tbutyl-4-methylphenol. Synthesis by Friedel-Crafts alkylation with 2-methylpropene or 2-methyl-2-propanol, 4methylphenol (p-cresol), and strong acid is extremely straightforward (eq 1). .A
OH
H
more convenient and produces higher yields of dialkylated ~ r o d u c than t the alcohol method. which is a considerablv slower reaction. The dialkylated product WHT) is a solid, while monoalkylated 2-t-butyl-4-methylphenol is an oil. If the reaction proceeds far enough to produce a high concentration of BHT compared to the monoalkylated com~ound, the solid convenienily separates during workup, saving ex: traction, drying, and solvent stripping steps. Removal of any unreacted p-cresol from the crude product can be accomplished easily by washing with dilute base, since 2,6-di-tbutylphenols have very high pK. values and are insoluble in dilute base. The synthesis of BHA (butylated hydroxy anisole) is predictably more complicated than that for BHT. Students will recoenize that the rine in the preferred startine material. 4methoxyphenol, bears two substituents para to each other that activate the ring toward electrophilic aromatic suhstitution. Thus twomono- and fourdisuh,titutionproductsare expected on butvlation of this starrinz material. The commercial product is a mixture of 2- and 3-t-butyl-4-methoxyphenol (eq 2), both of which show antioxidant properties. An alternative synthesis of BHA involves the 0-methylation of TBHQ (eq 3) (4).
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,
0-methylation of TBHQ (eq 3) (4) In choosing the source of electrophilefor a bench-scale preparation, one's instinct would favor the t-butyl alcohol rather than the olefin, which is a gas at room temperature (bp -6.9 OC). Actually, experimental procedure 1 (below) in which isobutylene gas is bubbled into the reaction flask both is
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Author to whom correspondence should be addressed. Current address: Research Laboratories, Eastman Kodak Co., Rochestbr, NY 14850.
Current address: Anacon Corp.. Hopkinton. MA 01748. Current address: Oepattment of Chemistry, State University of New York College at Oswego. Oswego. NY 13126. Current address: E. I. DuPont de Nemours Company. Rochester, NY 14614.
Wilson Magnet High School. Rochester. NY. Current address: SUNY-Buffalo. Buffalo.NY 14260. "ee ref 3 for an Instrumental analysis laboratory experiment on the Is0 ation and determlnat~onof BHA and BHT In polymers.
On paper, the synthesis of t-butylhydroquinone (TBHQ) is very similar to the two preceding ones, involving in this instance the monobutylation of hydroquinone (eq 4). Because only one possible ring monosubstitution product exists, the synthesis and isolation of TBHQ would appear to be almost as straightforward as the B H T case. However, the reaction must somehow be stopped a t the monosubstitution stage. One approach is to carry out the reaction in a twophase system such as toluene/HsPOa, with hydroquinone dissolving preferentially in the phosphoric acid. Dialkylation is minimized by taking advantage of the fact that the monoalkylation product (TBHQ) is much more soluble in toluene than in the acid and is therefore removed from the catalyst phase as it is formed (4). The workupof the reaction is also a hit more comolicated than that for BHA or BHT. Since hydroquinone, ?BHQ, and the di-t-hutylhydroquinone side reaction products are solids with similar pK.'s, isolation of TBHQ from the crude reaction mixture requires Volume 67
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a little thought. T h e workup in t h e synthesis we outline below calls for a n easv steam distillation t o remove unreacted hydroquinone and toluene. As the pot residue becomes more concentrated, t h e dihutyl products precipitate and are filtered. Then, T B H Q precipitates a s the filtrate is cooled. Methyl tertiary-hutylether (MTBE) is usedprincipally as a blending agent in unleaded gasoline t o boost octane ( 5 , 6 ) and t o reduce carbon monoxide emissions (7). It has also found utility a s an alkylating agent (a), including the thutylation of p-cresol t o form BHT (9). M T B E is synthesized readily by t h e acid-catalyzed addition of methanol t o isohutylene (eq 5).
Although any of a number of acids can h e used, we chose methanesulfonic acid because the reaction ~ r o c e e d auicklv s t o give a high yield of product. Sulfuric acid'can also d e used; although a t higher acid concentrations polyisohutylene forms in a side reaction. T o isolate M T B E at the end of the reaction, t h e mixture is diluted with a n excess of methanol and t h e M T B E distilled a s a n azeotrope with methanol and then chased with methanol. After the a z e o t r o ~ eis washed with water t o remove t h e alcohol, t h e product {s purified by distillation. These experiments a s written require minimal technical skills and assume a n introductory understanding of chromatography, refluxing, extraction, recrystallization, and distillation. T h e TBHQ synthesis calls for a n extremely simple direct steam distillation. I R a n d NMR sDectroscoDv .-h e l ~ determine isomer composition in products; however, if students have not vet studied these techniaues. . . little sacrifice in impact resulis. Although some of the procedures require reaction times in excess of t h e normal 3- or 4-h lahoratory periods, constant monitoring of t h e reactions is not necessary. In many cases, shortening of reaction times is n o more detrimental than causing lower product yields. Clearly these experimental suggestions can serve a s ideas for a variety of additional studies. For example, students might explore alternative synthetic pathways to t h e compounds above or plan the syntheses of different target molecules utilizing some of these alkylations.
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Experimental Reagents were obtained from general laboratory supply companies with the exception of isohutylene, which was purchased in lecture bottles from Matheson Gas Products. Thin-laver ehromatographic separations were accomplished on comme~cialsilica gel dates with either toluene or ethvl etber-hexane (1:9) (BHT). or kthvl ether-toluene (2:8) TBHQI. ehrbma&a. ~.(BHA. . ,. G-liauih phtwa.3 performed on a parked;atainlcssstrel column !I,.( in. X 10 fr) eonmming n 69, SF 9fi on 80. 100 GasChrom 1'. 60-75 mL,min helium flow nt R0 OC IMTBEJor 200-220 OC WIT, HHA, TBHQ,. Quantitative analysis of product mixtures was carried out either from integration of gas chromatograms or of 60-MHz 'H NMR spectra. ~~
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2,5D/4-b~I-4-methylphenol (BH7) 1. From Zsobutylene. (Note: The fint parts of this experiment should he conducted in the hood.) In a 1W-mL, three-necked, round-bottomed flask fitted with a magnetic spin bar, a thermometer, a gas dispersion tuhe, and a gas outlet adapter, add 0.2 mol of pcresol (caution: use gloves). Position the thermometer and dispersion tuhe so that the hulh and outlet are beneath the liquid level but not touching the spin har. With dry rubber or Tygon tuhingconnect the gas dispersion tuhe to the valve on an isohutylene lecture bottle (clamped in an upright position). Connect the outlet adapter to agas bubbler. Position a mametic heatedstirrer beneath the reaction flask in such a manner &at warm water and ice baths can he interchanged readilv. Dissolve 10-15 drops of concentrated sulfuric acid in thep-cresol, and heat the reaction mixture to 60-65 OC with the hot water hath. ~
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Then open the lecture bottle valve slowly until a gentle stream of bubbles rises from the dispersion tube into the stirring mixture. Monitor the temperature and gas flow carefully such that the temperature of the reaction mixture is maintained at 65-70 "C and the gas is being added as rapidly as possible without bubbles emerging from the huhhler. The reaction, which is exothermic, is essentially complete when the reaction mixture no longer takes up gas at an appreciable rate (total time 1-1.5 h). The consumption of isohutylene can he followedby either weighing the lecture bottle or condensing the gas and measuring the volume of liquid (10). Note: The crude reaction product has a noxious odor that is difficult to remove from clothing or hands. Continue to work in the hood and to wear gloves. Workup. Transfer the still-warm reaction mixture to an Erlenmeyer flask, cool, and wash with 10%aq NaOH solritian until the aqueous layer remains basic. Eventually a solid should appear from the organic layer. Filter and wash the precipitate well with water. When the product is dry, weigh it, and calculate the crude percent yield. Set aside a smallsample of the crude product for chromatographic orspectroscopieanalysis. Recrystallizethe remainder of the product (alcohol-water) until a constant melting point is reached (lit. mp 70 OC). The pure product is colorless and odorless. Calculate the percent yield. 2. From t-Butyl Alcohol. Combine 30 mL of cone H3POnwith 0.1 mol ofp-cresol (caution: wear gloves) in a 100-mL,round-bottomed flask containing a magnetic spin bar. Fit the flask with a Claisen head, dropping funnel, and reflux condenser. Heat the contents of the flask in a water bath to approximately 60 'C with stirring. Add 0.22 mol of t-butyl alcohol slowly from the dropping funnel, maintaining the temperature of the water hath between 65 and 70 %. Continue heating and stirring the reaction mixture far a period of 23 h, longer as time permits. If it is desired to follow the progress of the reaction, periodically allow the two lavers to seoarate and remove 0.5-1 mL of the uowr .. layer.~sampleoftheali&otcan bespottedonathin-layerchn,matography plat? as is, or it can be neurrali~edfor injectiun into a g a i ~hromatograph.~ Note: The crude reaction pioduct has a noxious odor that is difficult to remove from clothing or hands. Continue to work in the hood and wear gloves. Workup. Cool the reaction mixture, and allow the layers to separate. Wash the organic layer with 10%aq NaOH until the aqueous laver remains basic. then seoarate the lavers. If a solid farms. filter tdremove the aquebus solu;ion, and wa;h the prmpitate ueil w i r h water. If no w i d iorms during the washing steps, add 60 mL of dichloromethane, separate the .ayers, and dry the organic layer over anhydrous sodium sultate. Hemow the dr).ing ageut, and evaporate the dichloromethane. Weigh the product, and characterize tr). CLC and NMR. Calculate the relatrve amounts oimono- and di-I-buts1 product. 2- and 3-t-Butyl-4-methoxyphenol (BHA) In a 250-mL round-bottomed flask, combine 0.2 mol ofp-methoxyphenol (caution: wear gloves) and 55 mL of cone H3P04. Fit the flask with a thermometer adjusted so that the bulb is below the level of the liquid hut ahove the magnetic spin bar. Stir the contents of the flask and warm to 60-10 'C to effect solution. Reduce the temperature to 45-50 'C, and add to the stirring reaction mixture 0.23 mol of t-hutyl alcohol at a rate such that the temperature does not increase (apprar 30 min). Stir the mixture at approximately 50 OC for an additional 2 h. Allow the mixture to cool, remove the inorganic layer in a separatory funnel, and dilute the organic layer with 20 mL of CHC12. Wash this solution once with 20 mL of 10%aq NaHC03, and then dry the solution over anhydrous NazS04.Remove the CH2Clrby evaporation, weigh the crude product, and recrystallize with 60-90 petroleum ether. The product should consist primarily of a mixture of 2- and3-t-hutyl-4-methoxyphenolwithameltingpoint of49.5-50 'C. The 2-isomer has a chemicalshift for the t-butyl methyl protons of 1.39 ppm 6 (CCb), and elutes hefore the 3-isomer on a Carhowax GLC column (11). The corresponding chemical shift for the 3-isomer is 1.28 ppm 6.
'Add a 10% NaHC03 solution dropwise to the aliquot until the mixture is slightly basic. Add several drops of toluene to the mixture. and stir. Remove the toluene layer 10 a Clean, dry test tuoe, and add a smal amount of anhydrous Na,S04. The dried solution can then oe Injected into a gas chromatograph
t-Botylhydr~quiin~ne (TBHQ (4, 12) In a 250-mL, round-bottomed, three-necked flask combine 0.1 mol of hvdroauinone. 30 mL of toluene. and 40 mL of 85% H3POc Fit the flask'with a'magnetic spin bar (or better, a mechanical stirrer), Clsisen bead, reflux condenser, and addition funnel. Heat thestirring reactionmixture to90-95 "C, thenaddO.l mol of t-butyl alcohol from the funnel over approximately 45 min. After all of the solid has dissolved (approximately 1 h), separate the hot toluene layer from the H:,P04layer, add 100 mL of H20to the toluene layer, and steam distill to remove the toluene and unreacted hydroquinone. Filter the hot distillation pot residue to remove any di-thutyl-hydroquinone, then isolate the t-butylhydroquinone, which crystallizes from the cooled filtrate. The product isolated in this way should melt a t 125-128 *C (lit mp 129 'C) and is tan. The product can be recrystallized from water if further purification is desired. Yield 20-30%. Also determine the yield of di-t-butylbydroquinone (mp 219 'C).
methanol; bp 51.2 "C (14). Wash the distillate with 3 X 50 mL of water, dry the organic layer over NazSOd, and distill (lit. bp 55 'C); yield approximately 75%.
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Methyl t-Butyl Ether (MTBO (13) Fit a 100-mL,round-bottomed, three-necked flask with amagnetic spin bar, thermometer, gas inlet tube, and gas outlet adapter connected to a bubbler. Combine 0.4 mol of absolute methanol and 0.25 mol of methanesulfonic acid in the flask, and adjust the tbermometer and inlet tube such that they are submerged in the liquid but do not interfere with stirring. After cooling the mixture to approximately 20 'C, bubble isobutylene gas into the rapidly stirring mixture as fast as possible without gas exiting through the bubbler. The temperature of the reaction mixture will gradually rise over the period of addition ( 6 6 b). Stop the reaction when approximately 0.3 mol of isobutylene bas been added, and allow the mixture to stand at room temperature overnight. Next. add 0.5 mol of methanol. fit the flask with a short Vigreaux column, and distill, collecting distillate until the still head reaches approximately 65 "C.The azeotrope consists of 85 wt% MTBE, 15% ~~
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Acknowledgment Support from Project S E E D and from t h e Rochester Section of the American Chemical Society enabled one of u s (SDA) t o complete a portion of this work, for which we a r e grateful. We acknowledge t h e many helpful comments of organic students who tried these experiments in preliminary form. We are also grateful t o Eastman Chemicals Products, Subsidiary of Eastman Kodak Co., a n d t o t h e Uniroyal Chemical Division for generously providing authentic samples of BHA, B H T , a n d TBHQ. Literature Clted Teegarden. D.M."Symposium on InduatrialChemirtry and College ChernirfryTeaching: 186th Nations1 Meeting. American Chemical Society. Washington. OC. S e p ~ temher 1989. 2. Wilteoff. H. A,: Reuben, B. G, lnduslriol O r ~ o n i cCh~rnirolrin Prrspocfiur: Wile).: New York, 1980; Parts 1 and 2. 3. Chan.W.H.:Lam.K.S.:Yu. W . K . J.Cham.Educ. 1989,66.17?-173. 4. Young.De W. S.; Rudgers, G. F. U S Patent 2,722,656. November 1,1955. 5 . Iborra, M.: Irquierdo, J. F.; Tejero. .I.: Cunill. F. CHEMTECH 1988, hhruary. 120122.and referencancited. 6. Pmzelj. M. Hydromrbon Procers.. I I . Ed. 1987.66.68-70. 7. Anon. Chern. Eng.Neus 1987, June 29.8. s; NewYork, 1974 Vol I . 8. Fieser. M.: Fierer. L. F.R ~ o g e n l s i o r O ~ p a n i c S y n t h e r iWile): p 853. 9. Haubold, W.;Seiffsrfh, K.; Gladigau. U. Ger. (East) Patent DD 221.960. 1985; Chem. ~ b d r1986,105.6309r. . lo. Rshjohn, N.,Ed. D~gonicSynlhrsrs:Wiley: New York. 1963:Coll. Vol. 4, p. 261. 11. Boughton,O.O.; Bryant, R.:Combs,C. M. J . Abr. FoodChrm. 1967,15,751-752. 12. Stroh. R.; Seydel, R.: Hahn. W. Angev. Chem. 1957.68.699-705. 13. Wulff. W. F.; Juhnr0n.C. E. U S . Patent 2,7?0.547.ORober 11. 1955. 14. Cottie. D.I.: Vanderbilt. B. M.: Smith, B. I. U.S. Patent 2,721,222, October 18, 1955. example 6. 1.
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