SMALL-SCALE EXPERIMENTS FOR THE ORGANIC CHEMICAL LABORATORY Preparation and Isornerization of Levo-Menthanone GEORGE F. WRIGHT University of Toronto, Toronto, Canada
LImTATIoN of laboratory space and facilities has in the past made it necessary that experiments in the elementary organic chemical laboratory of this university be carried out on a small scale. Advantage has been taken of this limitation by introduction of experiments which accentuate principles rather than techniques. A wide variety of such experiments is possible when small-scale procedures are used because cost of chemicals becomes less of a factor in choice of the experiment.' A typical example is presented here as the oxidation of levo-menthol to levo-menthanone and its isomeriza-
tion to a diastereomeric mixture of levo-menthanone and dutro-isomenthanone. This has been adapted from a known procedure2 with little modification. The physical constants of leva-menthanone (m. p.-7' C.; h. p. 210°C.; l a ] ~ - 2 5 . 5 5 ~ ;n2r: 1.4495; dii 0.8937) and dextro-isomenthanoue (m. p. ea.-35"; b. p. 212O; [ a ] ~+85.1°; : n 1.4530; dig 0.902) have been reported3 and the recent opinion expressed4 that menthanone has the methyl and isopropyl in trans relationship with respect to the ring while isomethanone has these groups in the cis relationship. This has been used in the present paper. The con-
4
sdmi$afba.ide Mixture 11 and M menthanone semioilrbazones m. p. 11, 189 m. p. Id, 164" (Ip = Isopropyl)
I ~=NNHCON& L"
H&
/"'..
H IP leuc-(11) mentha none semicarbazone
1 ~h~ does not mean to imply that laboratory based entirely an s m a ~ s c a l eexperiments is superior or even as good as one wherein larger amounts of material are manipulated. Indeed the unavoidable use of small-scale procedures over 12 years in this laboratory has shown that the student does not gain the skill in the organic chemical laboratory that 0.1-1 mol preparations will give him.
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figurational designations are entirely arbitrary but were chosen on the basis of enantiom& superposition.
' BECKMANN, E., Ann., 250, 322 (1889).
a MEYER,V., AND P. JACOBSON, "Lehrbnch der Orgsnischen Chemie," 3rd ed., Vol. 2, 1902, Part I, p. 891. Ber., 59, 2298 (1926). ZEITSCHE~ O., AND H. SCHMIDT,
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423
In the experimental procedure which is outlined here the recognition of the diastereomeric forms does not arise from a consideration of these physical constants. Indeed (perhaps fortuitously from the pedagogical point of view) they are misleading since the specific optical rotation of the equilibrated isomers in ethanol a t 20°C. is almost exactly (+28") the opposite of that for an ethanol solution of pure leuo-menthanone a t the same temperature (-28'). The oil ~ r i t hpositive rotation does, however, form a mixture of semicarbazones. This is shown by the wide range and the lowering of the melting point as contrasted to that of the relatively pure semicarbasone which is obtained from the leuorotatory menthanone.
aqueous suspension with one 20-ml. port,ion and t,wo 10-ml. portions of ethyl ether. Combine the et.her extracts in a separat.ory funnel and wash once with 10 ml. of 5% aqueous sodium hydroxide and twice with 5-ml. portions of nrat,er. Transfer t,o a clean dry 50-ml. Erlenmeyer flask and add a threefold excess (considering solubilit,y of wat,er in et,her) of anhydrous sodium sulfate. 1,et stand in refrigerator overnight, or stopper, chill, and shake vigorously for 10 minut,es. Equip the microdi.;t,illation t u b e 7 F i g u r e I) by means of a No. 0 rubher stopper, nit11 a tube, B, 4 to 5 mm. in diamet,er, 100 mm. in length. This tube should he drawn a t one m d to a capillary so fine that one can just blow a t,l~inslow &ream of air through it when the tip is immersed in ether. The tip should reach to the PROCEDURE FOR THE STUDENT bottom of t,lle distillation tube. The opening C should Weigh into a 125-ml. Erlenmeyer flask 4.9 g. of be equipped alt,ernatively with a small dropping funpotassium dichromste and add to this a solution of 2.2 nel iIy ;L cork stopperol. a thermometer a rubber ml. (not more) of concentrated sulfuric acid in 24 ml. of (Xo. 00) stopper. A rubber tube and pine11 clamp, A, water. To this chromic acid solution a t 42% add with ellould the upper of R. strong agitation 3.6 g. of finely groun@ levo-menth~l Add a chip of porous t,ile to the distillation tube and over a five-minute period. During this period the then filter the menthanone solut,ion into the dropping temperature should be increased to 47'-4S°C. with a funnel. rmmerse t,he bottom of the distillat,ion tube hot \rater bath. Continue shaking or swirling, observe into a. beaker containing satllrat,ed aqueous sodium color and phase changes, and raise the temperature to cllloride solution, lleat to 5 0 0 ~ and . "flash off" dlle 55"-57°C. After some.time, depending on the vigor of ether by dripping in the solut,ion from the s e p a r a t , ~ ~ agitation, the precipitate liquefies completely to an oil. funnel a t such a rate that the addition and distillation This marks the end of the reaction. After the mixture are equivalent in liquid volume so that the ether does has cooled to 3OoC. pour it into a'separatory funnel, not accumulate in the still. Cool the side arm by hmgrinse the flask with ether, and successively extract the ing on it a filter paper on whicll a stream of \vat,er is played, hut attach a rubber tube to the receiver outlet In view of the cost of levo-menthol it is advisable to grind this material prior to use or else to leave a. common mortar close to the balance.
* Now avi~ilr~hle from John's Glass Co., Toronto, 0nt:trio.
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so t,liat vapors which may escape this inefficient condensation may be led safely toward the floor. Collect t,he et.her distillate from the receiver with a pipette until no more distills when the bath has reached 90°C. Connect the exit side arm, via a manometer, to a trap wit,h stopcock release and thence to the aspirator pump. Under a vacuum of 10 t,o 20 mm. the menthanone mill distill as the bath is heated to the boilingpoint. Record distillation temperature and pressure and weigh thc dist.illate, for determination of ha-menthanone yield, in a tared 25ml. volumetric flask. Note odor and tast~e as compared with menthol. Dilute to 25 ml. wit,h ethanol and determine the specific rotation of your ment.hanonein a 20-mm. polarimeter tube. Dilute 5 ml. of the solution which has been examined for optical rotation with ethanol to a menthanone concentration of 4 g. per 100 ml. of solution. Add to this a solution consisting of 2 equivalents of semicarbazide hydrochloride and 2 equivalents of 5% aqueous sodium hydroxide. Adjust the p H of the resulting solution t,o 5.2 t,o 5.4 (bromcresol green paper) and let stand overnight. Filter the semicarbazone by suction and wash w%h water. When coagulation i n ~ t h efiltrate is complet,e filter separately the remainder precipitated by the wash water. Dry in air,, weigh for yield of semicarbazone, and det,ermine melting points of both fractions. Dilute the remainder of the ethanol solution used for rotation measureme~~ts with 80 ml. of water. Extract this diluate with one 20-ml. and two 10-ml. portions of ether. Combine the ether solutions, wash with 15 ml. of saturated aquecus calcium chloride solution, dry with solid anhydrous calcium chloride, and flash off the ether as before, but do not distill the residue. This recovered menthanone is isomerized as follo~vs: make up a solution of 10 g. cone. sulfuric acid and 1g. of water in a 25-ml. Erlenmeyer flask. Freeze by immersion in a mixture of salt and finely ground ice (or with dry ice if available). Now pour from the weighed distillation flask all of the recovered menthanone. The isomerization flask is agitated in order to dissolve the menthanone in the slowly melting &id. After complete solution the temperature is raised to 30°C. An equal weight of ice is added slowly. The resulting aqueous suspension is extracted twice with 10-ml. port,ions of ether. The combined ether extracts are dried by shaking several minutes with a threefold excess of anhydrous magnesium sulfate. After "flashing off" Lhe ether the isomerized menthanone is vacuum distilled as before. Judge the volume of your distillate to decide the approximate magnitude of your yield. Keep in mind the requirement that this distillate must yield its semicarbazone under exactly the same conditions of concentration which were used for the original levo-menthanone. On this basis you must decide whether to transfer this distillate into a 15-ml. or a 25-ml. volumetric flask. Determine the yield; then dilute with ethanol to the appropriate volume and determine the specific optical rotation. Withdraw a 5-ml. aliquot and
JOURNAL OF CHEMICAL EDUCATION
prepare the semicarbazone exactly as before. Transfer the remainder of the-ethanol solution to the laboratory accumulation bottle. Compare the yields and melting points of the fractions of semicarbazones from the original and isomerized menthanones. Crystallize the combined semicarbazone fractions from each of the original and isomerized menthanones using boiling ethanol (20 ml. per gram) as the solvent. Compare recovery and melting point. Turn in these purified semicarbazones to the supervisor. QUESTIONS FOR THE STUDENT 1. Why was an excess of oxidizing agent used over that required stoiehiometrically for conversion? 2. Describe an experimental procedure for evaluation of the amount of oxidizing agent to be used with n compound which has not been reported as having previously been oxidized. 3. Why was not sufficient sulfuric acid used to farm chromic sulfate a t the end of the oxidation? 4. Write a configurational flowsheet describing the oxidation, isomerizitt,ion, snd semicarbaaone formation, 5. The rotstion of id-menthanone (i~omenthnnone)is [OF: 4 9 6 in ethanol, while that of 11-menthanone (leuo-menthanone) is -28". On the basis that optical rotatory power is an additive function calculate the ratio of diastereomers in your isomerization mixture. Compare this ratio with that which you can evaluate on the basis of your yields of crude and purified lbmenthanone scmicarbaeones. 6. If vour isomerization u+th sulfuric acid were not eomnlst,~ (to equilibrium) a rotation of zero. might have been obtained. Explain the significance of this rotation. 7. If you had isomerieed with hot aqueous alkali rather than with cold sulfuric acid your observed rotation would have been zero. What relative amounts of the two diastereomers would you have obtained? 8. Explain the construction and operation of the polarimeter and name five factors which influence the observed rotation of a solution of a given pure optically active compound.
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I n this labo~atorythe experiment requires four threehour laboratory periods for its completion. It is designed to teach a knowledge of oxidation, tautomeric isomerization, diastereomeric and enantiomeric stereochemistry, and polarimetry to students majoring in science in their third year of college chemistry. The data are compiled from the records of 250 students over five years. When the experiment is carried out properly the leva-menthanone yield is 85%; a few students obtain an 80% yield but the average is 53.5%. The boiling point varies between 80' and 90°C. under ordinary waterpump vacuum. The specific-opticalleva-rotation of this material averages 24.2' with a high value of 31° and a low value of 10". The high yield of isomerized menthanones is 80% but low values d o m to 14% reduce the average to 63.5%. The specific optical dextro-rotation of this diastereomeric mixture averages 22.6' with a high value of 34' and a low value of 4".. The yield of crystallized semicarbazone from leuomenthanone averages 60% (high 98%, low 20%) with an average melting point of 184.3'C. (high, 189"; low, 180°), while the melting point of the crude material averages at 175'. On the other hand, the oncecrystallized yield of semicarbazones from the isomerized mixture of diastereomers averages 36.5% (high, 98; low
AUGUST, 1949
3) and the average melting point 170.5O, hut the average melting point of the crude is 153O. Each semicarhazone has been isolated in two fractions to illustrate to the student that the derivative of dextro isomenthanone is more soluble in ethanol and ethanol-water than that of the leuo menthanone. The true melting point of 11-menthanone semicarhazone is 189' while that of &(iso) menthanone semicarhazone is 164". The student is personally examined over about 30 minutes on the basis of the questions which occur a t the end of the experiment. He is expected to show the examiner the stereochemical changes which occur by means of structural models consisting of multicolored halls, ' / a inch in diameter drilled symmetrically with 1, 2,3, or 4 holes and which may he connected by means of flexible spring^.^ The student frequently does not at first appreciate the reluctance on the part of organic chemists to write stoichiometric equations to describe organic chemical phenomena. Question 1 is suggested to make him realize that the amount of oxidizing agent required for maximum yield must not only include that stoichiometrically required for the simple main reaction hut also that considerable and unavoidable amount consumed in oxidation of by-products to small fragments. On this basis he should then realize, through question 2, that employment of the stoichiometric amount of oxidizing agent will usually necessitate a separation from unchanged starting material. The minimal use of acid, which the student explains in question 3 as a device for reducing the tendency toward isomerization of the leuo-menthanone which is formed during the oxidation, should make clear to him that valence change (or electron loss) in the oxidizing agent is more significant than the inorganic end product of the reaction. Questions 4 and 5 are reviewed with the structural models while the concept of optical rotation as an approximately additive property is impressed so that the
student should realize from his demonstration that the isomerization and racemization cannot be expressed specifically in terms of one molecular model. The concept of additivity is, of course, also expressed in a description of the incomplete isomerization described from question 6. The distinction between enantiomeric and diastereomeric stereoisomers can he expressed in question 7 in comparing the acid isomerization (which affects only the hydrogen on the isopropylmethylene group adjacent to the carhonyl group) with the alkaline isomerization which affects both asymmetric centers. The greater effectiveness of alkali over acid in isomerization of C-C=C allylic systems as contrasted with C-C=O methylenecarbonyl systems is likewise expressed here. The student will find during his model demonstration of the alkaline saponification that a Walden Inversion must occur, and this can he related to the comparison between acid and alkali as isomerizing agents. Many textbooks describe racemization of a compound such as menthanone, with two asymmetric centers as "leading to four optical isomers." It has been found that the student implies from this statement that the four stereoisomeric forms in such a racemized mixture are present in equal amounts. Since this is obviously untrue from the thermodynamic standpoint and is contrary to practical experience reference to "four optical isomers" is discouraged. The student is persuaded to say that racemization results in a diastereomeric mixture (necessarily not in equal amounts since the energy contents of the diastereomers are different) in which each diastereomer comprises equal amounts of its enantiomeric forms. Question 8 is obviously a revjew of knowledge passed to the student in his prerequisite courses in physics, but it has been used here, together with the structural models, to give the student the qualitative significance of the theol:es of optical rotatorY~power.l ' NOLLER,C. R.,J. CHEM.EDUC.,24, 600 (1947).
