E. Gary Nosh, Everett J. Nienhouse, I Thomas A. Silhavy,

Dale E. Humbert, and Mary Jo Mish

I Aromatic Nitro Musk Synthesis Ferris State College

Big Rapids, Michigan 49307 I The organic chemistry laboratory has

been the subject of an intensive review for the past few years (1-4). The goals and objectives of laboratory work have been discussed and, in general, most authors have advocated greater student involvement in the design and operation of laboratory experiments. Specifically, the newer laboratory curriculum involves "research" oriented sroblems and less of the traditional "cookbook" type experiments. However, this type of program, in a rapidly growing college or university, presents a challenge to the instructor in the most ef- fective use of staff time and facilities. Two main problems arise : (I) research equipment (primarily instrumentation) is expensive and of limited availabil- ity, and (2) laboratory space and/or time may be restricted. We have addressed ourselves to the former problem ( 5 ) ; however, the laboratory time/space factor is still very much present. Particularly, if chemistry classes are held in a multi-purpose building, difficulty is frequently encountered in scheduling "open" laboratory time.

Our organic laboratory has been designed around the following basic points: (1) laboratory worli is an extension of lecture material and hence should correlate as closely as possible with such lecture material, (2) modern methods of analysis should be introduced and used in subsequent experiments, (3) many laboratories can be "problem" oriented (I), and finally, (4) the pre- laboratory lecture with audio-visual instruction can be an effective learning aid in conjunction with item (I). The following is typical of the type of laboratory ex- periment which we feel fulfills the above goals.

Baur (6) in 1891 was the first to observe that certain nitro-aromatic compounds imitated the odor of natural musk. Since then, extensive research has been con- ducted into the synthesis of many "musk-like" sys- tems (6). We have adapted from t,his literature a multi-step synthesis involving electrophilic aromatic substitution which we wish to share with others.

The synthesis involves the preparation of the nitro- musks, musk xylene (111) and/or musk ketone (V), from the readily available m-xylene according to the scheme shown.

The preparation of 3,5-dimethyl-t-butylbenzene (I) involves a modified Friedel-Crafts alkylation using amalgamated aluminum wire. We have always en-

Presented in part, 157th National Meeting of the American Chemical Society, Minneapolis, Minn., April, 1969.

CCl +

I @I A l l Hg amalgam

rn-xylene

v IV I11

musk ketone musk xylene

countered some difficulty with student use of aluminum trichloride. Specifically, with large laboratory sections and semi-micro equipment, aluminum trichloride be- comes an inconvenient reagent. Rowever, a procedure described by Campbell and Kline (8) (based on the work of Diuguid (9)) for the preparation of an amal- gamated aluminum wire suitable for Friedel-Crafts alkylations, was adapted for the first reaction. This preparation presents the student with "research" type questions, i.e., (1) how does the aluminum amalgam function in this reaction? A number of studies have supported the idea of a carbonium ion intermediate (8) , but (2) how it is formed? (3) is surface area important? Students are assigned various modifications, e.g., aluminum foil is used instead of wire; or, the concen- tration of one of the reagents is increased. Students are encouraged to try their own modifications keeping complete notebook records of their procedure and ob- servations. Each student turns in his product for analysis and discussion of the results.

That the structure of the product is the symmetrical hydrocarbon (I) and not the unsymmetrical isomer (which would be predicted on the basis of o,p-orienta- tion) is clearly evident from both the infrared and nuclear magnetic resonance spectra. Specifically, the nmr spectra is particularly valuable in this case

NMR (neat): 6 6.68 (lH), 6.95 (2H), 2.17 (6H), 1.20 (9H)

Infrared and nmr spectra are posted in the laboratory for student examination. This reaction illustrates the fact that steric factors can and often do control the posi- tion of an incoming group in electrophilic aromatic sub- stitution.

Volume 47, Number 10, October 1970 / 705

The 3,5-dimethyl-t-butylbenzene, once prepared, can be converted into musk xylene (111) using either of the following methods: (I) direct conversion using vigor- ous nitration conditions, or (2) stepwise conversion using mild conditions to the mononitro compound I1 followed by more rigorous conditions to 111. Using this two track system, the student can readily appreciate the difficulty in introducing nitro groups into a system that is both sterically hindered and deactivated by the presence of a nitro group. As above, nmr and ir spectra can be used effectively in determining the structures of I1 and 111 (see experimental).

An alternate, more difficult sequence, is the two step conversion of I to musk ketone (V). This involves the facile Friedel-Crafts acylation of I to 4-t-butyl-2,6- dimethylacetophenone (IV) followed by careful nitra- tion to musk ketone (V). This sequence is suggested for students who have demonstrated superior laboratory technique.

At this point in the students' exposure to organic chemistry he has observed various colors and has noted the odors of various organic compounds. Many text- books discuss the basis for the color of organic com- pounds but mention little about the chimical and physiological basis of odor. In this connection, why does the musk xylene have an odor that imitates natural musk? An examination of the structures of the two compounds reveals little chemical similarity. How- ever, close examination of models of these two com- lsounds reveals similar dimensions. The students are asked to read a t least one theory of odor, e.g., that of Amoore ('7). This stereochemical "cavity" theory as a basis of odor is particularly attract,ive because of the importance placed on stereochemistry in modern organic chemistry texts. If the student is particularly interested in this area, he is referred to texts in physiol- ogy (1 0).

Experimental 3,6-dimethyl-t-butylbenzene (I). A solution of 6 g (0.056 mole)

of m-xylene and 6 g of t-butyl chloride is placed in a flask provided with a reflux condenser and gas trap. To this solution is added four 3-in. lengths of amalgamated aluminum wire (prepared by first cleaning the wire by immersion in 6 N sodium hydroxide solution, washing with water, dipping the cleaned wire into 0.2 M mercuric chloride solution until the mercury deposition is com- plete and then wiped dry). The evolution of hydrogen chloride gas begins immediately, becomes rapid, then finally slackens. At the same time, the solution becomes brown and dark spots appear on the metal. When reaction is complete (15-20 min) the liquid is cooled and transferred to a separatory funnel con- taining 5 ml of concentrated hydrochloric acid. The mixture is shaken until the organic layer becomes colorless. The layers are allowed to settle and the organic layer is washed once with cold water, then dried over anhydrous magnesium sulfate. Careful distillation of the dried product with a simple fractionating column gives 5-7 g (56-79%) of 3,5-dimethyl-t-butylbenzene, bp, 205-208°C: 99% pure by glpc on a 5-ft SE-30 column a t 145", vz:: 840,705 cm-I (1,3,5-trisubstituted benzene) A","."? 265 mu, e = 565, 6::; 1.20 (singlet, 9H), 2.17 (singlet 6II), 6.68 (singlet, IH), 6.97 (singlet, 2H). 4-t-Butyl-d,6-dimethylnitrobenzene (11). The reaction was car-

ried out according to a procedure similar to that of Powell and Johnson (11) for nitromesitylene (steam distillation is not re- quired for purification). The symmetrical product, 4-t-butyl-2,6- dimethylnitrobenzene, obtained by recrystallization from ethanol had mp 84-85°C (Id), yield: 30-60%. The liquid unsymmetrical isomer, 6-t-butyl-2,4-dimethylnitrobenzene can be isolated from the filtrates in approximately 25% yield.

vg:: 2967, 1508, 1361, 871, 714 cm-I

Musk Xylene (IIZ) (Route A). The solid mononitro derivative (above) was converted to the corresponding trinitro compound by the following procedure. Four ml of fuming nitric acid was added dropwise with stirring to a mixture of 1 g of the mononitro compound (11) in 6 ml of fuming sulfuric acid. The reaction mixture was warmed for 15 min on a steam bath, then poured onto cracked ice. The product, after recrystallization from ethanol in white platelets, had mp 112-113'. I t possesses a definite musky odor, especially when heated.

v::: 2994, 1527, 1348, 881, 741 cm-l b CC14 1.35 (singlet, 9H), 2.09 (singlet, 6H)

Must Xylene (111) (Route B). Alternatively, the trinitro compound may be prepared directly from hydrocarbon I by the following procedures. A solution of 10 ml of fuming nitric acid and 14 ml of sulfuric acid was added to 4 g of I while the reaction flask was agitated. After addition, the contents of the flask were heated on a steam bath for one half hour, then poured onto cracked ice. The product after recrystallization from ethanol had mp 111-113°C and was identical in all respects with that prepared above. 4-t-Butyl-d,6-dimethylacetophenone (IV). Anhydrous aluminum

chloride, 14.1 g was added, with vigorous stirring and over a period of 1 hour, to a mixture of 7.5 g of I, 19.5 g of freshly distilled acetyl chloride, and 35 ml of carbon disulfide. The mixture was allowed to stand for 1 hr (no longer). The reaction mixture was quenched in diluted, iced hydrochloric acid and extracted with two 30-ml portions of benzene. After neutralization with bicar- bonate solution and drying, the solvent was evaporated by means of a stream of air in the hood. The crude ketone, which crystal- lized on cooling, may be used directly in the next step or may be purified by vacuum distillation, bp 107-110°C (2.5 mm). I t may also be recrystallized with diflculty from methanol in large glistening plates, mp 46-47OC

vc;; 2267, 1690, 1253, 870 cm-I

4-t-Butyl-2,6-dimethyI-S,6-dinitroacetophenone (Musk Ketone) ( V ) . One gram of ketone (above) was added slowly, with stirring, to 20 ml of fuming nitric acid maintained below 5°C. The mix- ture was allowed to stand a t room temperature for 1 hr, then quenched with ice water. The dinitro compound, Musk Ketone, when removed by filtration and recrystallized repeatedly from methanol, had mp 134-136OC. Nitration a t higher temperatures leads to the formation of increasing amounts of 4-t-butyl-2,6- dimethyl-3,5-dinitrobenzoic acid (VI).

Literature Cited (1) SMITH. R. B., J. CHEM. EDUC., 44, 148 (1967). (2) FIFE, W. K., J. CHEM. EDUC., 45. 417 (1968). (3) SILBERMAN, R. , AND MCCONNELL, J., J. CHEM. EDUC., 45, 267 (1968). (4) Y o u ~ a , J. A,, J. CHEM. EDUC., 45, 798 (1968). (5) NASH. E. G.. AND NIENHOUSE. E. J.. Abstracts of the 158th National

Meeting of the American chemical Society, New York, Sept., 1969, CHED 049.

(6) WOOD. T. F. , i n Giuaudanian, publication of Givaudan Corp., Jan., 1969, and references cited therein.

(7) A M ~ ~ R E , J. E., JOHNSON, J. W., AND RUBIN, M., "The Stereochemical Theory of Odor." Scientific American, February, 1964.

( 8 ) CAMPBELL, B., AND KLINE, E. R., "Semimicro Experiments in Organic Chemistry,'' Heath and Co., Boston, 1964, p. 108.

(9) DIUGUID, L. I., J . Amer. Chem. Soc., 63,3527 (1941). (10) For example, GUYTON, A. C., "Textbook of Medical Physiology" (3rd

ed.), W. B. Saunders Co., Philadelphia, 1966, pp. 765-768. (11) POWELL, G. , AND JOHNSON, F. R. , Org. Syntheses, Coll. Vol. 11, p. 449

1943. (12) F u s o ~ , R. C., MILLS, J., KLOSE, T. G., AND CARPENTER, M. S., J . Org.

Chem., 12, 587 (1947).

706 / Journal o f Chemical Education