Preparation and Use of (+)-p-2,8-menthadien-1-ol
According to (Reference 182) the following photo-catalyzed oxidation of (+)-Limonene is the best method of preparing the (+)-p-2,8-menthadien-1-ols. The starting, material is readily available and the two operations are easily carried out. In a later paper (Reference 183) the cis- isomer is prepared by peracetic acid oxidation of (+)-delta4-Carene, but it is not clear whether this is a practical method of preparation.
It is likely that certain simplifications are possible on the method used in (Reference 182), and described here as the basis for experiment. For example, although oxygen gas was used in the original work for the catalytic oxidation, it is probable that it would be satisfactory to use air, simply sucking it through the reaction liquid by means of a water-pump, or using an ordinary vacuum-cleaner to blow it through. It is best to use a sintered glass gas distributor to provide small, readily absorbed bubbles. Some methanol may be lost by vaporization and if necessary this can be replaced by fresh, dry methanol as needed.
The oxidation occurs only when the mixture is illuminated by ultraviolet light. Schenck used an Osram high-pressure mercury lamp (HgH; 5000) , but it is possible to use other ultraviolet lamps, and it even might be possible to employ bright sunlight.
When air is used instead of pure oxygen, and when lower intensity ultraviolet sources are employed, it should be expected that the time required for the oxidation will be extended by a considerable amount.
(1). Catalytic Oxidation.
136 grams (+)-Limonene and 2 grams Rose Bengal in two liters of anhydrous methyl alcohol are treated with oxygen while continuously illuminated with ultraviolet light from a high-pressure mercury lamp. The light must fall directly on the liquid, or a special ultraviolet transmitting vessel must be used. Within 14 hours 1.05 moles of oxygen are absorbed and the oxidation is stopped. (In the original work this point was detected by monitoring the absorption of oxygen. While it is obvious that too little absorption would lower the yield, it is not clear whether extending the reaction time beyond this point would cause the production of by-products, or otherwise lower the yield. If continuing the reaction beyond this point did prove to lower the yield it would be necessary to monitor the absorption of oxygen or to standardize the reaction conditions such that the reaction could be stopped in each case close to the optimum point.)
(2). Reduction.
The product of the above catalytic oxidation is a complex mixture of hydroperoxides which must be reduced to give the desired (+)-p-2,8-menthadien-1-ol, together with other products from which they are separated. The reaction product from the catalytic oxidation of 136 grams (+)-Limonene in two liters methanol is reduced in volume to about 500 ml. (Schenck accomplished this by distilling at a temperature no higher than 10 deg C., using a high vacuum Since hydroperoxide mixtures have been known to be explosive, it is not safe to distil at a higher temperature, but the same effect can be obtained by using a fan to blow a stream of air over a basin of the liquid until it has evaporated to the desired extent. This should be done where the toxic methanol vapors can do no harm. Possibly this reduction in volume could be omitted). With good stirring and continuous cooling by means of an ice-bath, the solution is gradually added to an ice-cold solution of 250 grams sodium sulfite (Na2SO3) in 1.5 liters of water. The whole is stirred for 12 hours, then warmed at 70 deg. C. for another 2 hours. After cooling the product is extracted with several portions of ether, the ether solutions dried with anhydrous potassium carbonate and sodium sulphate, and the ether distilled off. The liquid residue is a mixture of alcohols weighing about 112 grams. From this mixture the desired trans- and cis-(+)-2,8-menthadien-1-ols must be separated by fractional distillation. (The appropriate chapters in References186 or 185 should be consulted).
Schenck has carried out the separation at reduced pressure (4 mm.), but for the present purpose it may be possible to use only the reduced pressure of a water-pump aspirator or perhaps even ordinary pressure. Distillation is simplified as the two products of interest are also the two lowest-boiling components of the mixture. (If the oxidation is stopped before a full mole of oxygen has been absorbed then the un-oxidized (+)-Limonene is also present in the product mixture. In this case the two desired products are preceeded during distillation by whatever (+)-Limonene there is present). The following chart shows the sequence of distillation of an 85.2 gram sample in which some (-)-Limonene is present due to having stopped the oxidation at the point where 0.9 moles oxygen had been absorbed (Reference 182).
Compound I: 35-65 deg. C./ 4 mm. 1.8% 1.6 grams
Compound II: 66-68 deg. C./ 4 mm. 28% 24 grams
Compound III: 69-75 deg. C./ 4 mm. 9% 7.7 grams
Compound IV: 75-92 deg. C./ 4 mm. 61.2% 51.9 grams
(Note: I is (-)-limonene; II is (+)-trans-p-2,8-menthadien-1-ol, III is (+)-cis-p-2,8-menthadiene-1-ol, IV is higher alcohol by-products).
For the present purposes the distillation would be stopped after all the Compound III has passed over, and the undistilled higher boiling residue discarded. The yield of Compound II and Compound III (which need not be separated but can be used as a mixture) is about 28%of theoretical, based on (+)-Limonene used.
The boiling range at water-pump reduced pressure (25 mm. Hg) corresponding to 66-75 deg. C. at 4 mm. is about 100-110 deg. C. at atmospheric pressure it is 210-220 deg. C. Note: It is essential whatever the pressure used to add a quantity of sodium carbonate to the mixture before distilling in order to avoid decomposition.
The best guide to the fractional distillation is to watch the thermometer measuring the temperature of the vapor in the distillation flask. The temperature remains stationary for most of the period during which each of the first three fractions distil over, then toward the end when most of the particular material has passed over, it begins again to rise. Observation of the volume of distillate collected is also a helpful guide.
The mixture of cis- and trans- (-)-2,8-p-menthadien-1-ols obtained as described above is reacted with olivetol as described by Petrzilka (Reference 181) in the presence of p-toluene sulphonic acid monohydrate;
"A mixture of 2,5 mMoles olivetol, 2,5 mMoles (+)-(cis or trans)-2,8-p-menthadien-l-ol, and 0.3 mMoles p-toluene sulphonic acid monohydrate in 25 ml. benzene are refluxed for two hours. After the usual working up and chromatography on silica gel the yield of THC is about 50%."
On a larger scale the amounts of reactants are (1 mole each) 180 grams olivetol, 152 grams (+)-2,8-p-menthadien-1-ol, and 23 grams (0.12 mole) p-toluene sulphonic acid monohydrate, with the amount of benzene required to be determined by experiment.
Petrzilka notes that with more than 2.5 mMole quantities there is visible darkening of the reaction mixture during reflux, indicating partial decomposition of the product. It is likely (and preferable) that this can be avoided by allowing the reaction mixture to stand for an extended time at room temperature rather than using a short period of reflux. (A week or two may be sufficient).
A suitable ultraviolet source is the Hanau laboratory immersion lamp, S81. Caution: The operator must be protected against exposure to the UV light. Although no immediate effect will be felt, serious delayed damage can occur to the eyes and skin through even comparatively short exposures.
Preparation and Use of (-)-2-Carbethoxy 5-Methylcyclohexane
Appendix One