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Lorillard

Heliotropin

Date: 19670000/PE
Length: 7 pages
88699491-88699497
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Bedoukian
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LIBRARY/LITERATURE SEARCHES
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PUBL, OTHER PUBLICATION
BIBL, BIBLIOGRAPHY
CHAR, CHART/GRAPH/MAPS
DRAW, DRAWING
SPEC, SPECIFICATION
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G33
Request
R1-037
Named Person
Babo
Barth
Ciamician
Eykman
Fittig
Keller
Mielch
Poleck
Remsen
Silber
Date Loaded
20 Dec 2001
Document File
88699486/88699619/Literature Search No. 408 Toxicity and
Pyrolysis of Heliotropin
Named Organization
Essential Oil Assn of US
Organic Syntheses
US Tariff Commission
Characteristic
EXTR, EXTRA
MARG, MARGINALIA
Litigation
Feda/Produced
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88699487/9544

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176 tILLIOTROPIN removal of the active aldehydic group either by acctal formation or reduction to the alcohol considerably reduces the odor intensity- As a crystallized material, the commercial product has a high degree of purity. A containcr of heliotropin of good quality always suggests cherry-vanilla. Any traces of solvents or chemical impurities cloud this impression. Adulteration, if present, may be in the form of addition of a solid material which is odorless and comparatively c heap. Its presence can be detected by taking a mixed melting point with an authentic sample of heliotropin. to' Occurrence. - Small quantities of heliotropin have been detected in a few essential prn oils obtained from Spiraca ufmari R., Itabiaia pseudoacacia L., Monarda fistulosa L., ~ da cta. Heliotropin has been reported to form during the curing process of vanillons (Va¢illa planifolia). ' ah History and Chemistry. - Ileliotropin is one of the few perfumery chemicals to ( yi, be discovered as a result of investigations in fields not connected with the perfume i ri( indastry. In the early part of the 19th century, considerable research was being carried out on the structure of alkaloids. During the course of a study on the degradation re- i W. actions of piperine, the main flavor component of black pepper, it was noticed that m nitric acid oxidation gave a product possessing an almond odor2. Five years later, in , ta 1857, Babo and Keller similarly reported the formation of an odorous compound on sa the oxidation of piperineY is These reports led to numerous investigations on the problem of piperine. It was pi found that hydrolysis of piperine yielded piperidine and piperic acid. On heating the tt latter with potassium hydroxide, protocatechuic acid was formed. The benzenoid nature of the compound was thusestablished. The next serious study of piperine and a product obtained from it, piperonal, was made by Fittig and Mielch" who described in detail the production of piperonal from piperic acid by means of permanganate and I ;. a dichromate oxidation. They noted the pleasant odor of piperonal, established its cor- iii p rect chemical composition as being CaHsO3, and its physical constants. They also reported methods for its identification by oxidation to piperonylic acid. Further studies on piperonal were made by Fittig and Remsene with a view to elucidating its structure. After examination of numerous reactions of piperonal, they concluded that it was a niethylenedioxybenzaldehyde, but were unable to determine the position of the methy- lenedioxy lenedioxy grouping. A clarification of the structure of piperonal was finally brought aboui by Barth' when he noted, during a study unrelated to piperonal, that in pyrocatechol the two hydroxyl groups were adjacent and that in protocatechuic acid the substituents were ~ in position 1, 3, 4. Since both protocatechuic aldehyde and protocatechuic acid were 0) obtained from piperonal, this discovery led to the elucidation of the structure of piper- onal (heliotropin). Preparation of Heliotropin. - As mentioned above, Fittig and Mielch° obtained ~. piperonal by first hydrolyzing piperine to piperidine and piperic acid (1) and then oxidizing the latter to piperonal (II). Since black pepper, Piper nigrum L., contains 5
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.10?xfl} HELIOTROPIN Ptperonal;. 3,414Methylenedioxytlenealtlehyde Ptotocatechuic aldehydee methylene ether C:.H,O: REoLwt..15D.13 The popular garden variety of heliotrope, Neliotropms arborescens, is.sometimes referred to~as "cherry pie" because of its highlyfragrant cherry aroma. Although the so-calledwinter heliotrope, Petasitesfragrarrs, hasa somewhat similarodbr, it belongs to a.different.family. The odor of 3;4-metbylenedioxybenzaldehydeis.strongly re- miniscent.of theflower,.hencethe.name heliolropin. The presence of thischemical in either variety'oC heliotrope, ti.owever,, has ye[ to be provemIn the'19th, century, this.compound.s was prepared! . from piperineandl waseonse- quently also knowm.as piperonal. Heliotropin impartsa warm, floral, spicy sweetness to perfumes,andi is used exr t'ensively in compositions where.floral odors such as heliotrope, lilac and violet are desired. Ithasapersistent:odor which makes.it valuable in formulations where stability andlhsting.characterare important. Contrary to,a widespread! beliefthathelio[ropin as an aldehyde causes discoloration in soaps,it has been reported' thatithe pure material can be.used in soapswitlloutfear of discoloratiun: In general,, the use of heliotropio presents nospecial problems, although in some.media discoloration canoccur.. As would be expected from a highly oxygenatedicompound, heliotropin is.freely soluble in.alcoholl . and to a considerable degree,. in. dilutealcohol..It isalso freely soluble in esters such as benzyl henzoate,.diethyl, phthalate, and fixed oils. It has a higbdegree of.soluliility in: propyl6ne glycol; less in: glycerol,, and onlyslig8t solubility in mineral oils. Its solubiSity in fluorinated hyd rocarbons of the types used inaerosol spray compo- siitions issufncient for most..purposcs.. In additiomtoits use in the perfume and flavor industry,large quantities of helio- tropinare.used.in unrefated fields. Technical.grade heliotropin.isused in the electro= plating of inetals. Many derivatives of heliotropin.hpve;been investigirtedfor possible use asfungicides and insecticides. Hleliotropinis used.to a..limitedexlent.in flavors such as van'rlla and cherry where its fragrance and bitter-sweet taste are.desirable. It isfound.ons the GRAS1istS and is thgreforeconsidered suitable for flavor applications. .. Theacetalsand.thealcohol and its.esters have been prepared but their value.in perfumery is limited~ becausetheir odors lack intensity. Uhlikee anisic aldehyde, the Iteliotropimmolecule.is apparently near iits limit in. molecular weight and structure, and ReltrsrtcexF. 181 Gn fib CD fD rA ~
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IIII31,I0 'PaOPLN F;OpI"' I reducing agents can be employed forr this purpose. The final product, heliotropin, mustt be completely free from peroxygenated impuritiess since.even traeeamounrtse of lhese. materials will cause discoloration withina short time. High yields of alilehyde can beobtained~ by rapidly steam distilling the freshly' prepared ozonide: Yields of 87 per cent helibtropin from isosafrole tiave been report'edrs A.metbod of separating thecarbonyLeompound from peroxides,., both, of whichh ave:formed' during ozonolysis, involves fractional extraction?°:, Ezperimental conditions forthe oxidation of isosafrole with,dichromate-sulfurioh acidd have been criticallY studiedr'. v Heliotropin hasbeeo-synthesized from pyrocatechol (V). The steps consist of ~ -+.- somo . potass conversion to 3~,4'-methylenedioxybenzene: (VI), then to piperonyl chloride (\f1I)~ whichli on treatment with hexamiire,.gives the altlehyde..An over-a1lyield of'20-28Iper cent based on.pyrocatechol was obtained's. It isreported that hellotropin. can be prepared directlijfrom methylenedioxy-benzene by. reacting it withHormaldehydein: the.presenceof ineta nitrobenzenesulfonic . acid. Treatment of 3;4-methylenedioxybenzene.witttp-nilrosoe dimethyl'aniline in thee presence of hydrochlbric acid and catalysts gave good yjeldsof heliotropin". Physicall Constants. - Heliotropin ismarketedl as a colbrless, crystalline solid. possessing the characteristic mildd heliotrope odor.. Its physical constants are: ~ Melting:point °C' 37 , . 1 Boiling point, °C 263 (760 ~mm);, 135 (10'~0 mm)~. Solubility I voll. in 3~vols~~3 of 70%: alcohol ~ Oxime, m. p.. °C 110 Phenylhydrazone„m.p..°C 103' E Semioarlbazone„m.p.. °C 234 2,4- Dinitrophenylhydrazone, m.p. °C 265 17teEssential Oil. Association of U.S.A. has adopted the following.standards for Helrotrapin: Qa Colbr,.Odor, and'..Appearance: White lustrous crystals.having a sweet, 0oweryy odor ~ resembling heliotrope and free of safrole odors.. (0 Congealing Pcint:. At least. 35° C ~ Alda'byde Content: At least 99% calculatedlas heliotropin... ~. Solhbility in Alcohol: 1 gram is soluble in 4 ml. of 70% alcohol. ~A perma Synrh/ dilute be car phosp tures, R wlth li C methy Ir and.el MI found camph tions c safrole T' isosafr with al ing, 60 to reFlt mixtur group. determ which safrole determ and lmdistille• can be O~ Firstth in 1130 increas safrode oftecht to emff good rt Rejtremc -
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HELIOTROPIN I to 9 per cent of piperine, a considerable amount of piperonal could be produced by this process. It is cf interest to mention that this method was used commercially in the early days, and piperonal was marketed back in 1879 at fabulous prices'. One of the first methods reported involved its synthesis from protocatechuic aldehyde which was heated with potassium hydroxide and methylene iodide". The yields were very poor, and the method offered no practical advantage. Ethylene chlo- ride can be used instead of methylene iodide to form the dioxymethylene ring°. A revolutionary advance toward a practical commercial synthesis of heliotropin was made by Eykman10 in 1885 when on oxidizing a Japanese compound called shiki- mol with permanganate, he noted the resultant odor of heliotropin with which he was familiar. Thre following year, Poleck" found that by permanganate oxidation of iso- safrole and steam distillation of the product, an aromatic aldchyde is obtained which is identical with piperonal. This led to the realization that shikimol, a by-product in the production of camphor, and safrole, the main constituent of sassafras oil, are one and the same. It was also discovered, by Eykman's and by Ciamician and Silber", that oxidation of safrole (1V) produces larger yields of piperonal (iI) and piperonylic acid if the safrole is first rearranged to isosafrole (III) by alkali treatment and then oxidized. This is analogous to the oxidation of eugenol to vanillin where the allyl group is shifted to the propenyl group (isoeugenol) prior to oxidation. 177 [I ` Ho Ho-CH=CHrz CH=CH-CHy (. %oH _ ll -l .JOI -0 T I o~CHZ 0CH2 ]V IH H Isosafiole has been oxidized to heliotropin by ozonolysis1d. Several patents were taken out, but the method was not commercially successful in the past. In recent years, ozonolysis has been applied industrially in the manufacture of heliotropin with good results. Ttle exact technique and procedure are trade secrets. It is known, however, that reaction conditions such as temperature, solvents, and the manner of introducing ozone into the reaction mixture must be closely controlled for -a successful operation. The ozonide has to be decomposed in order to liberate the heliotropin. Various ReJerexea p. 181
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B C-PFcwktHh. HaGIOTR'OPCN' 179 Chemical Bfoperties.-Because of its peculiar structure, heliotropin undergoes some interestingreactions,.it is oxidi¢edto piperonylihacid.on boilingwith alcoli.olio potassium, hyd'roxide'r. Directions for, the oxidation. of piperonal withi potassiumpermanganale giving 90-96 per cent yi¢lds of piperonylioacid.are found'ia Organic SynrhesesY'~ Helfotropih produces protocatechuic aldehyde when Neated to 200° Cwith dilute hydr.ochlbric acid inn a sealed tube". Splitling.of the methylenedioxy groupca~n be.carried out more conveniently by meansof aluminum chlorid'e°6...Treatment.with. phosphorus: pentachloride'in the cold gives pigeronal.ehlorider°:, At highertempera- tures,r substitution takes plhceib thee benzenenueleus:. Reduction with sodium amalgam yields pi peronyl alcoholl and a dimer'i". Reduction with lithium aluminum hydrides" results in good.yields: of the alcoholi. Condensation of heliotropin with acetone yields piperonylidene acetone, and with methyl ethyl ketone,.piperonylidene.methyll ethyl' ketonem.. In.commom with.other aromatic aldehydes, heliotropin.readilly gives the methylP°and etlhylf' acetals. Manufacture. -The. onlyy practical souree' of.heliotropintoday issafrole which isfound~in a.number of oil9,noGably,.sassafras and.¢amphor:,Verylarge quantities of camphor are normally produced and the safrole is crystallized out from certainn frac- tions of this oi1L.BrAzilian.sassafras:oili(Oco(ea cymbanrm)isalso~used, as asource of safrole since it contains:over 92 per centt of'this:compound. The first step in, thee preparation of heliotropin is~ thee conversionn of saFroleinrto isosafrole.. This is dbne by heating safrole with, alcoholicpotlassium hydroxide orwith alkohoiatesunder pressure'r. A simple commercial procedure consists.of dissolv-ing 60 parts of potassiumhyd'roxide in 100: parts of alcohol bystirring and heating to re8trx.. Abour60.partsof pure safrole are'.tlhen adde& tothe alkali solution and thee mixture gentlyre8uxed to bring about the.conMersion of theallyi group to the propenp+l g'roup.. The.reaction.takes15-20 hours and iss follo!wed''bytaking periodic samples too determine the degree of conversion by noting the: index of refraction:of the samples which have been washed free of alcohol and dried. Sincee the index.x of refraction of safrole at 20° CC is 1.5360, ,, and ithat of isosaf[ole, ll.5780;the end.of the reaction is eas'ily determined. Wkiemthe reaction.iscomplete, the mixture is cooled, diluted with water, and most of ihe alcohoi' distilled off: The separatedierude isosafroPe is[ractionalL)< distilled to.remove impurities,., and.usedfor oxidation.to.piperonaf. The alkali solution can,be re-used in a~follbwingbatch.operation. l7xidation.is best carriedl out, by. means ofa diehramate-sulfuric acid mixture. First the dichromate solutionis prepared by dissolving 58 pound'sofsod'ium dichromate in 1130 pound's of water., Addition of small.quant~itiesof sulfanilic acid is reported to increase the yields appreciabl'y: To this miaturee iss added 33'3 pounds of the crude iso- safrole obtained as above. The mixture is stirred at room temperatureand 180 pounds of technical sulfuricacid(36'Baume) added slowl)y with.constantstirringh ltis necessary to employ a vessel.with, a cooling jacket lxcausethe.reaction' is.exothermic„ and for good,results a.elose control of temperature is.imperative. The temperature.is gradually . _A~ Referencet p. 131 '
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allbwed to rise attheeateof5°C'.for everyfifteen minutes and the rate of addition of sulfuric acid~ so regulated that all of its is ad'ded.within three.hours. Stirring is:continned for a fUrtherr half hour.r and'then IO0.pounds of benzeneor toluene areadded'e in order toextract the crude reaction product ffomt.themixture..The mixture is.stirred for half an hour andiallbwed.tostand until the benzene: or toluene layer is clearly separated. It is thendrainediolf, the aei.dmixture extracted once more at:4'0° C with.a further 46pounds of bcnzene,, and the extract: combined with the previous benzene or toluene: Psyer:.The:benzene solution is.washed with water and.neutralized.with cold sodium carbonate solution, then distilled too remove the solventl. The erude.heliotropinremainingas.aresidheimthe.stilAis subjected to.a vacuum fractiottal distillation and' heliotropin is. obtained as a semi-solidd product in.yields of about, 85 per cent. The lasrstep involvescrystal'lization ttom a suitable solvent sueh as an equal weight of 95 per cent alcohol. The miirture is:heated to effect complete solution of crude .lielio- tropinn inn the solvent.It is then fil'tered, if necessary througp: decolorizingcharcoal istn order to remove impurities:which may affect the color of the finished product. The so- lhtion.is cooled and'the crystals formed',are centrifugedd and driedd at low temperatures in special drying~ shelves. To obtain.heliotropin of.the highest.purity, free from by-odors, each step must be carried oub.under rigid control. Many variatlons.ofthis method can be.employed, depending.upon, the.equipment used and the:experience oflthe operators': Sinceoxidation.of isosafrole to.heliotropin issimill<r ian nature to, the oxidation of anethol to anisic aldehyde,mostproceduresaresuitable for the.preparation of both aldehydes. Thus, thediscl'osures made in a patenfit coveringchromic acid oxidation" resultedd in a.yield' of 87 per cent heliotropin when appliedi too isosal'rolb (see Anisic aldehyde), Trad'e.and Commerce. - The Ulnited States Tari$'.Commission has published.tlhe following;figures on the production of beliotropin: Year Production Pounds Unit Wslue. Dollara Nwnbcr of Ptoduccn I.isted 1937. 198,000 7..50 4 1960. 276,000 2.45. 5 1962 209;000 2.19 4 1964' 210J(100 201 4 ~ : Heliotropin is shipped in glass, plastic or paper-lihed containers, or, woodbmbar 'A Srels.:It is quite stable undernormal conditions. of'storage, but becomes colored on ~ JM prolonged exposure to.light: Because of iicarelativelylowmeltingpoint,.it should be ~, stored.in a cool place to prevent.liquefaction.. I 15 16 17 18 19 20 21 22 2i
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E~r-DoL,-Kc r1N'. BIOL1IpiROPIN' 181 Add9tion.l Literature ~I A..WAmwert.,,DieAldeh)de, Val: 3;.pp• 980-1018, Wien 1930. Givaudhnian,. August 1945, New York (Reprinted imSoap;PerfumerPr & Cosmetics;, 677; 1947), andi December, 1953. Re(erences I GMuudantan, New Tfork,. August.1945 and'Decemhen 1953.. 2 Armexwn, Comyt:.Rend:,.34 (1852).664. 3 BArw eNa Keum;..R: Prakt Chem.,,117, 72 (1857) 53, 4 Ftrno AND MreccH;:Ann.,152 (1869).25.. 6 FYmic ANU RemseN;,Ann.,,159(1871) 129:. 6 B.uavrtl;. Ber., 4 (1871')'633': 7 hlwnce,. Ind.. CMm; Purit„ 16 (1929) 422. 8 WeescMteen;,Munarsh.,,14(1893)388. 9 Et>reevwANDD~YA, Trudy Vresenyuz: Nauchn.-lnled: Inrt.. SintetI Nmaral: Dushlahrykh Veshchestv., No. 4'.(1958)'31;.C,A.,.54 (1960) 1391. 10 Hvxntqn; Rec, Traa Chim„ 4(1 885) 32. 11 Porscx, Ber.,.19 (1886):1094., 12 Evr.r.rAta; Ber.,, 23r(1890),855. 13 C7et.neuN taca Sn.e¢R, Rer., 23' (1890).1159: 14 Gnn tate VeRter;, Ger, Pat 97;620;, Apri1.20,.1895. Nwo.v,:Jl Chem. Sac. Japan, Ind Chem. Sect., 25(1922) 631.. Hwnmst;.Ger. Pat. 321,567, lune 13„19181 15 HARws; Sver.usc¢netaF., Advancesin Chem., Su. No. 21 (1959) 11491. 16 Btwrn; U. S. Pat..2,916;499, Dec. 8;.1959. 17 Hlaeq, J. Chem. Soc. Japan, Ind. CAem..Seer., 29 (1926) 504- KuwoK.Arro,Sutm; Fnrmamn,Sci:,.5 (11951) 36;. C: A., 49 (1955) 5367: 1'8 Srtonrcm, SmuNOVSfurA .ervD.BOODAROVA, J:.Gen. Chem. USSR, 8(1938)975. 19 LnstuNA, DmmsrzwwA at nL„TiudyYsesoyuz. Nauclrn: fssled:Inrr. Sintel. iNarurol.. Dushishrykh Peshchestr.,, No. 5(1961) 21; C. A:,, 57 (9714) 1963... U.S.S.R. Pat..142;302, Dec. 14„ 1961;C.. A., 56(1962)', 7176.. 20 P,uztxv.t Awu~ DmrtrS~Y.t, Zh. PrikC Khhn., 29'. (1956)'. 1894; C: A., 51 (1957) 73261' 21 Flrno:nrm. Mmcx;, Ann:, 152 (1869)49,. _ 22 Osganic Syntheses„ Vol: 10 (1930)„P, .82: 23 WECsnumaq Manatsh.,.14 (1893) 388.. HematmceR, Get Pa1..339,945;, M'ap13;.1916 (ADpI.):, 24 C.tnPerrea etm Kct+z,. U. & Pat..2',027„148, Jan. 7,.1936:.Seealso Ger. Pat;.591',888, 25 Etrne~ Rieta+, Ann., 159'(1879) 144! 26 Ohm,..Ronvuort ~ Wt1~MS;.J: Chem;,Soa.,,111 (1917)946. 27 L~x, 7Yans. Chalmers UMv. Technol: Gothenhurg;.No,:94 (11950)15. 28 RrAra ANDC.Vnr;y.Prar- Rolti.Irhh:Arnd.',.36B~ (1924) 334. 29 tYsatert ~, Gmee, Ber., 30 (1897) 3058:. 306t~, Ben, 31'. (1898).1016, 31 N'ncµ J- Soc. Chem..lnd., 29' (1926) 364. 32 McLAlvo, Chem. 2kade.J„ 79 (1926) 359;. WAot+eR, RlechsYOf/lnd:,.1 (1926),65. 33 FAatNUm„ U. S. Pat: 2'„794,813, June 4„ 1957.

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