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5-26-1947

Synthesis of

Jeanetta Reneberger

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Synthesis of Terpenes

Jeiinetta Reneberger Department Honors Ursinus College May, 1947

This paper is submitted in partial fulfillment of Department Honors.

Group Adviser Introdxiction

Terpenes are organic compounds having the empirical formula (Q.Hji) , They are the essential oils which early chemists extracted from the leaves, flowers, resins, bark, and roots of many plants. These volatile perfume materials were called the "essence". Isoprene, obtained by distillation of caoutchouc (india rubber), is the -narent hydrocarbon from which all terpenes are derived. Many plants produce isoprene and condense it through either linear or cyclic polymerization into compounds. These in turn oxidize, hydrolize, or reduce to form many familiar products. A few terpenes are solids, hut most are volatile liquids^having boiling points between 155** smd 1R5°. They are §^'^^Mft from their natural soiirces by steam distillation and by extraction with organic solvents. Terpenes incliide both open chain compounds and cyclic compounds having one and tvro rings. They are very active sub• stances, and have a complex chemistry. Addition react'-ons are common, for they are generally unsaturated; they polymerize readily. Terpenes are easily oxidized; they combine with ozone, and show the general characteristics of compounds containing double bonds. All terpenes are practically insoluble in water, but they are readily soluble in the ordinary organic solvents. Many industrial products are made from terpenes and their derivatives. They are used extensively in perfumes, flavors, paints, varnishes, plastics, and medicines. Terpenes are of great use in chemical study, for they form the link between simple organic structures and complex natural products. Classification

All terpenes have the empirical formxila CoHn- or some multiple of it, Hemiterpenes have the empirical formula G^Eg, They include the parent of all terpenes, Isoprene

C M,. = CM CH -Chi.

The true terpenes of formula C,^H,^are represented by

terpin

sylvestrene CM,

MC ^-«-^^..„3

Sesquiterpenes, having the formula C,^ H^,, inclixde

farnesol CH^CH^ T-'CH *H^CH^ T'CH^HX* »^

nerolidol CH, ^^H^^H^

Diterpenes, having the empirical formula, C ^.^fL ^j^, include among their representatives the common compovmd vitamin A -'^'^ i^^tMCH^cni^CMeH.oH H,C c Polyterpenes, which contain 25 or more carbons, are represented

crt '""^ "^"^ ^ • AH.H.C- CH CH, CH,.: = en JH.

«H C = CHCH^CH.C = t MCM^cHjC = cHcHi ^ cHj CH,

carotene ^M, ,CH,

^'^ . ,„e.= CHCH--CM e - tHCH=CMCH ^CCH=

\

alpha gerani«l "\H..H.C M J^HCH.^H myrcene CH^ e. -1 H c H^CH*. c CH = c H^. Examples of monocyclic terpenes are

soherol ^.H, • MC -'^"^ ' aril,

^ H; '^H>

paracymene «.iu nr*^^ ^ cM H C ,1 Ht V r SH^cHCHi The parent bicyclic terpenes are

CH. thui ane ^\L H,rC i u tHjCrtcH, carane in... Hit C rt;cm. Hit.,^1 ^'•I ^ H

pinane Hit — r>trA H^c , cHi "— t - H camphane C Hj Hit -"i^-trti Hic 3, t rt X 't' Tricyclic terpenes are represented by

cyclene ^rtj or tricyclene \ ,4 C Laboratory Preparations

1, a, Bornyl chloride b, Camphane c, Isobornylacetate d» Isoborneol e. Camphor

2. a. Paracymene b. Paranitrocymene c. Carvacrylamine d. Paracymene diazonium chloride e. Thymol Method for Preparation of Camphor

aH3 \ c e.

I cw3C-

I c xC I C.-^"A oC-fcH,

CH3 HiO Hi

CH3 ^^3

C ^ c_ ^ HxC' I ^CHoH Coic. jx

^ h~^-^ """^ H.e^ \ c Bornyl Chloride

a, chemicals: pinene 200 grams concentrated HCl concentrated H^SC^ ethyl alcohol 50 grams h. procedxire: Dry hydrochloric acid gas Is generated by dropping concentrated sulfuric acid into a flask containing concentrated hydrochloric acid. The gas is le«d through an empty gas bottle into two large containers of concentrated sulfi-ric acid, to insure perfect drying, and thence through an empty bottle into the pinene, which is embedded in an ice salt mixture and kept at 12?,After a steady stream of gas is lead into the mixture for tv/o hours, the pinene ceases to absorb the hydrochloric acid. The pinene is allowed to stand overnight, packed in ice. The next day it is repacked for two hours, the temperature lowered to -10*?, White crystals form. The crystals are filtered with suction. The filtrate, on cooling, yields more crystals. This bornyl chloride is dissolved in hot ethyl alcohol; the solution is filtered to free it from impurities, and the filtrafce is cooled to -5t. The crystals reform. The yield is 110 grams. c, properties: Bornyl chloride is a snow;;^ white crystalline pov/der with a distinct odor of camphor. Its melting point is 148^, It is very volatile; it dissolves in alcohol and ether. Camphene

a, chemicals: ortho cresol 200 grams potassium hydroxide 75 grams bornyl chloride 100 grams anhydrous calcium chloride b. procedure: Into a 500 cc. roundbottom flask is placed 200 grams of melted ortho cresol, and 75 grams of crushed potassium hydroxide are added. The mixture is warmed, and then the water is distilled off, using a water cooled condenser. At 150% this condenser is exchanged for an air condenser. The mixttxre is heated to 180%, The flask is cooled, and 100 grams of bornyl chloride are added in three portions, with vigorous shaking of the mixture. Then a very long air condenser is attached upright, and the mixture refluxed for three hours. The camphene is then distilled, the portion boiling from 150c.-160% is collected and shaken with dilute sodium hydroxide, and then cooled in an ice salt mixture. The camphene solidifies into crystalline Iximps, The camphene is filtered and washed with ice water. It is then melted and the vrater contained in 5.t is decanted from it. The camphene is remelted, this time with a bit ofi anhydrous calcium chloride added. Again it is decanted, and then fractionally distilled. The portion boiling between 155^-160H.is cellected. This is tested for chlorine by dipping a copper wire into it, and then placing the v/ire into the flame, A green chlorine color appears in the flame. The camphene is redistilled. This time it is chlorine free. The yield is 49 grams.

c, properties: Camphene is a colorless, crystalline mass which melts at 52% and boils at 160cf. It is insoluble in water, but dissolves readily in alcohol and ether. Isobornylacetate'

a. chemicals: camphene 48 grams glacial 125 grams concentrated H^^se^ powdered sodium carbonate crystals 300 grams b, procedure: To a solution of 48 grams of camphene in 125 cc. of glacial acetic acid contained in a flask, is added a mixture of 2cc. of concentrated HASO^ and 3cc. of water. This is warmed on a steam bath at 50d.-60%..for two sind one half hours with frequent shaking. Two layers, which form at first, disappear after heating. The reddish solution of ester is placed in a large beaker, 100 cc, of water is added,and then it is neutralized with 300 grams of powdered sodium carbonate crystald. The ester is separated and dried with anhydrous calcixm chloride. The isobornylacetate is then fractioned in vacuo. The portion boiling at 95c-105 c.is collected, A pressure of 12 millimeters is obtained for the distilling by means of a vacuum pump, and measured with a manometer. The yield is 35 grams, c. properties: Isobornylacetate ia a colorless liquid that smslls like valerian. It boils at 102tat 12 millimeters pressure. Isoborneol a, chemicals: isobornylacetate 30 grams ethyl acetate 60 grams potassium hydroxide 12 grams b. procedure: In a 250 cc, flask 30 grams of isobornylacetate are dissolved in a solution of 60cc, of ethyl alcohol and 12 grams of potassium hydroxide, and heated to boiling for three hours under a reflux condenser on the steam bath. The solution is then poured into cold water, and the isoborneol separates as a light yellow semi-solid mass. The beaker is placed into ice and stirred mechanically for two hours. The isoborneol becomes solid. The crystals are filtered with suction, and washed with cold water; then pressed dry. xhe yield is 23 grams. c. properties: Isoborneol is a white crystalline solid, which is very volatile. Its melting point is 212c°, Camphor a, chemicals: concentrated HNOa 40 grains red fuming HNO^ (s.g. 1.6) 12 grams isoborneol 20 grams sodium hydroxide 3 grams potassium permanganate 5 grams h, procedure: A mixture of 40 grams of concentrated nitric acid (s, g, 142) and 12 grams of red fuming nitric acid (s.g,1,6) is made in a 200 cc. flask and cooled to 20"-25t, In small amounts, 20 grams of isoborneol are added cautiously, keeping the temperature at 20''-252, A compound of camphor and nitrogen pentoxlde separates as an oily, slightly colored mass. The mixture is stirred for 30 miniites, and then poured upon cracked ice. The camphor separates out into white lumps. It is filtered with suction and washed with ice water. It is purified by mixing it withia dilute solixtion of 3 grams of sodium hydroxide and 5 grams of potassium permanganate, and then distilled with steam through an air cooled condenser into a wide mouthed bottle, which is cooled in cold running water. The final product is dried on a porous tile. The yield is 12 grams. c. properties: Camphor is a white crystalline solid with a distinctive odor. It is very volatile. Its melting point is 1^2"-1730J its boiling point is 205c, It is very slightly soluble in water, and quite soluble in alcohol and ether. Method for Preparation of Thymol

CH3

e.

H.xo, c. CHoa Cm«. l*<-ft.

CH3 C H3 ' I

.-ie'''^''''H C^c. H^ _^ H c."'^ ^^^^ ' C HHx ^'^^)o, , »« fee- H C u P C

e H CH

d Hj I

I I Hd d-oH

cH H>c' "*^H3 Paracymene

a, chemicals: concentrated H^SOH 572 grams isopropyl alcohol 168 grams sodium bromide dihydrate 187 grams tolemne 294 grams anhydrous aluminium chloride 24 grams concentrated HCl 35 cc. b, procedure: To 572 grams of concentrated HaSOs is added quickly with shaking, without cooling, 168 grams of isopropyl alcohol. After cxj...:.ig to room temperature, 108 grams of ice water are added, the cooling being continued. Then 167 grams of finely pulverized sodium bromide dihydrate are added. The mixture is subject to rapid distillation, the flask being heated on a water bath. The receiver is filled with svifficient water to allow the end of the adapter to dip below its surface. The distillation is continued as long as oily drops pass over. The lower layer of the distillate is washed with water, and then dried with anhydrous calcium chloride, and finally distilled. The isopropyl bromide boils at 59"-602, The yield is 150 grams. Seventy five grams of the isojjropyl bromide are mixed with 294 grams of tolaene in a one liter flask. To this are added 24 grams of anhydrous aluminium chloride, A water cooled condenser is set upright in the flask, and a tube lead from the top (3>f the condenser to a funnel inverted over a beaker of water. The reaction proceeds in the cold for about an hotxr, with occasional shaking. Then it is placed on the steam bath. After three-f oxrrths of an hour of - very slight ref luxing, a low flame is applied directly for about an hour,There is slow constant refItixing, Then the mixture is cooled and poured into 350 grams of ice, 100 grsms of water, and 35 cc, of concentrated HCl, The mixture, previously red, turns green. The paracymene layer is separated and dried with anhydrous calcium chloride. This mixture is fractionally distilled, and the portion boiling from 1T5*'-176,5£ is collected. The yield is 5 grams. Failure is attributed to insufficient refluxing and a too low concentration of tol««ne. The above preparation is repeated, the concentration of the tolaine is increased from nine to sixteen moles. The refluxing is continued for four hours, the mixture being heated in an oil bath. The yield this time is 35 grams, c, properties: Paracymene is a colorless liquid that melts at -73,5''e.and boils at Y^&i^, It is insolxxble in water, very soluble in alcohol and ether, and soluble in chloroform.

1 Mononitroparacymene a, chemicals: paracymene 30 grams glacial acetic acid 4cc. concentrated Hi^SOs 82 grams concentrated HNO3 21 grams b, procedure: A mixture of 30 grams of paracymene and 4 cc. of glacial acetic acid is treated with 30 grams of concentrated H^SOH, added in drops. The mixture is kept in an ice-salt bath and agitated, A mixture of 21 grams of concentrated HNO^ and 52 grams of concentrated Ha^SO^is added, the temperature being kept below OX-After two hours of mechanical stirring, it is poured into an ice-salt mixture, and the nitro compotuad is extended with benzene. The layers are separated and dried. The benzene is distilled off and the nitro comp6und fractionated. The portion boiling from 148''-162%.is collected. The yield is 20 grams, c, properties: 2 nitroparacymene is an aromatic oil with a boiling point of 152 5, It is insoluble in water, very soluble in alcohol and ether. Carvacrylamine a, chemicals: mononitroparacymene 18 grams granxilated tin 24 grams concentrated HCl 50 grams sodium hydroxide 35 grams solvent ether lOOcc. b. procedure: In a 500 cc. round-bottom flask provided with an air-cooled reflujc condenser,is placed 18 grams of mononitro• paracymene and 24 grams of granxxlated tin. The mixture is thoroughly shaken v/hile 50 grams of concentrated HCl is added in small portions through the condenser tube. After all the acid is added, the mixture is heated on the steam-bath for about an hour. The reaction mixture is then cooled to room temperature, and a solution of 35 grams of sodium hydroxide in 50 cc, of water is added, with further cooling. The reaction mixture is very alkaline at this point, and the carvacrylamine separates as an oil. The mixture is steam distilled through a v/ater-cooled condenser, until the distillate ceases to be turbid. The distillate is saturated with sodium chloride. Then the carvacryl• amine is extracted with ether, using first 50cc, and then two portions of 25cc, each. The combined ethereal solutions are dried v/ith cru.shed sodium hydroxide over-night. The next day the solution is decanted from the sodium hydroxide into a small distilling flask. The ether is distilled off, using a water bath. Then a direct flame is applied, and the carvacryl-> amine boiling at 241V1S collected. The yield isB grams, c. properties: carvacrylamine is a colorless liquid with a boiling point of 241c.. It is insoluble in water, but dissolves readily in alcohol and.'ether, , Paracymene diazoniumchloride

a, chemicals: carvacrylamine 8 grams , ~ concentrated HCl 30 grams sodium nitrite 5 grams h, procedure: To 8 grams of carvacrylamine in a small beaker are added 30 grams of concentrated HCl and 110 grams of water. The mixture is stirred and cooled to 0*'-2*'C.in an ice-salt bath. Into a separatory funnel is placed 5 grams of sodium nitrite dissolved in 16cc, of water. The funnel is arranged so that the stem dips below the surface of the liquid. The nitrite solxxtion is dropped in slowly, while the mixture^ is constantly agitated, and the temperature is kept at Ot, This diazonium compound is not isolated before it is hydrolyzed into thymol. Thymol

a, chemicals: paracymene diazonitunchloride solvent ether lOOcc anhydrous calcixim chloride 6 grams b, procedure: The |>aracymene diazoniumchloride solution obtained in the last step is placed into a small distilling tube connected with a reflux condenser and heated in a water hath to 60%until the evolution of nitrogen gases ceases. The mixture is the distilled oh a wire gauze. The thymol is extracted from the distillate with 100 cc, of solvent ether. The thymol-ether mixture is dried with anhydrous calcium chloride, and then distilled in a water hath until all the ether is removed, A few grams of thymol remained in the distillation flask. Heating failed to drive the thymol vapor through the- distillation tube. The thymol was salvaged by dissolving it in a little ether. The thymol yield was approximately 5 grams,

c, properties! thymol is a colorless compound with a boiling point of SSe^-BSSc, It is slightly soluble in water, very soluble in alcohol and ether. Bibliography

Adams, fioger and Johnson, John, Elementary Laboratory Experiments in Organic Chemistry New York, Macmillan Company, 1945,

Crane, E,J., Editor, Chemical Abstracts Columbus, Ohio, American Chemical Society, 1936-1947,

Fisher, Harry, Laboratory Manual of Organic Chemistry New York, John Wiley and Sons7~T9^,

Gatterman, L,, The Practical Method of Organic Chemistry New York, Macmillan Company, 1918,

Lowyy, Alexander and Baldwin, Wilmer, Laboratory Book of Elementary Organic Chemistry New York, John Wiley and SonsJ 1934,

Richter, George, Textbook of Organic Chemistry New York, John Wiley and Sons, 1943,

Wertheim, E., Organic Chemistry Eaboratdry Guide Philadelphia, P. Blakiston'T Son and Company, 1^3v,

Wertheim, E,, Texthook of Organic Ohemistry Philadelphia, P.Blakiston's Son and Company, 1939,