Setliff, Frank L.

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UARK (University of Arkansas )

Journal of the Arkansas Academy of Science Volume 22 Article 17 1968 Heterocyclic Aromatic Fluorides by a Modified Schiemann Method (1) Frank L. Setliff University of Arkansas at Little Rock Follow this and additional works at: https://scholarworks.uark.edu/jaas  Part of the Organic Chemistry Commons Recommended Citation Setliff, Frank L. (1968) "Heterocyclic Aromatic Fluorides by a Modified Schiemann Method (1)," Journal of the Arkansas Academy of Science: Vol. 22 , Article 17. Available at: https://scholarworks.uark.edu/jaas/vol22/iss1/17 This article is available for use under the Creative Commons license: Attribution-NoDerivatives 4.0 International (CC BY-ND 4.0). Users are able to read, download, copy, print, distribute, search, link to the full texts of these articles, or use them for any other lawful purpose, without asking prior permission from the publisher or the author. This Article is brought to you for free and open access by ScholarWorks@UARK. It has been accepted for inclusion in Journal of the Arkansas Academy of Science by an authorized editor of ScholarWorks@UARK. For more information, please contact scholar@uark.edu. 88Arkansas Academy of Science Proceedings, Vol. 22, 1968HETEROCYCLIC AROMATIC FLUORIDES BYA MODIFIED SCHIEMANN METHOD (1)Frank L. SetliffLittle Rock UniversityINTRODUCTIONThe Schiemann Reaction (2) has long been employed byorganic chemists as the most efficient means of introducing flourineinto aromatic systems. The method is basically simple (equation 1)and involves diazotization of a primary aromatic amine in hydro-chloric acid followed by the addition of fluoboric acid (HBF4 ) tothe cold solution of the diazonium chloride. The precipitated dia-zonium fluborate is then filtered from the reaction mixture andthermally decomposed to yield the aromatic flouride. The success of(1) ArNH 2£i-» ArNa+Cl" -£££* ? ArN3+EF4-£ p ArF3 NaNO a 0° +Na + BF3the method lies in the fact that the diazonium fluborates are usuallyformed in good yields and their stability permits thorough wash-ing and purification before thermal decomposition. Furthermore, thesediazonium salts decompose smoothly without violence to generallygive good yields of the desired fluoride.Rutherford and co-workers have shown that replacement offluoboric acid with hexafluorophosphoric acid (HPF 6 ) in the Schie-mann Reaction (equation 2) results in much improved yields of aro-matic fluoride from aromatic amine (3). The following significantyield increases were realized over the classical Schiemann method:(2) ArNHa HC1 a) ArN3+Cl- HFFg » ArNa+PF s-heat > ArP +NaNO a ONa + PF Eo-fluorobenzoic acid from anthranilic acid (-(-52%) ;p-fluorobenzoicacid from p-aminobenzoic acid (-j- 49%); p-bromofluorobenzenefrom p-bromoaniline (-j-27%); and p-fluoroanisole from p-amino-anisole (-|-23%). Small yield increases were noted in numerousother cases. The success of the HPF 6 method was attributed to theincreased insolubility of the diazonium hexafluorophosphates(ArN2+PF 6~) which would permit more efficient isolation andpurification before decomposition. Furthermore, phosphorus penta-fluoride, a weaker Lewis acid than boron trifluoride, would be ex-pected to promote less polymerization during decomposition.RESULTS AND DISCUSSIONOur extension of this modified method to several aromaticamines in the heterocyclic series, i.e. pyridines and quinolines hassurprisingly revealed a predominant inferiority of HPF6 to HBF488Journal of the Arkansas Academy of Science, Vol. 22 [1968], Art. 17Published by Arkansas Academy of Science, 196889A Modified Schiemann Method(see Table I; the HBF 4 yield data are taken from the literature).The rather large differences in yields of fluorides from the 2-aminopyridines may be experimentally accounted for. In these in-stances it was necessary to diazotize the amines directly in thepresence of HPF 6 since the resulting diazonium hexafluorophosphatesare too unstable to be isolated before decomposition (8) (equation 3).(3) ArNHa—2=^2 ». ArNa PP a~NaNO 3O°ArF + N3 + PF 6The amine hydrohexafluorophosphates (ArNH3+ PF 6~) which pre-cipitate at the low temperature required for diazotization requirerather large quantities of water for dissolution before diazotization.Thus, diazonium hexafluorophosphate hydrolysis would appear to bea probable competitive side reaction to normal diazonium salt de-composition. In addition, acid-catalyzed hydrolysis of the initiallyformed fluoroderivative could be operative to a large extent (9).Either of these side reactions would result in pyridol side productsas depicted in Scheme I.As indicated in Table Ipyridols were indeed observed in additionto the fluorides in the series of 2-aminopyridines studied. That acid-catalyzed fluoride hydrolysis could be at least partially responsiblefor the pyridol formation was established by independent experi-ment. Under the conditions of the formation of 2-fluoro-3-methylpyri-dine, pure 2-fluoro-3-methylpyridine was converted to 2-hydroxy-3-methylpyridine in 31% yield. Itis assumed that similar results wouldbe obtained in other specific cases. The pyridols were identified bymixed melting point determinatons with authentic samples preparedby diazotization (and subsequent hydrolysis) of the appropriate2-aminopyridine.In those cases (i.e., 3-aminopyridine and 3-aminoquinoline)where the stability of the diazonium hexafluorophosphate permittedtheir isolation before decomposition, the resulting yields of aromaticfluorides more nearly paralleled those obtainable by the HBF4 method,with no accompanying pyridol formation.EXPERIMENTAL SECTIONGeneral Information. Hexafluorophosphoric acid is available as a65% aqueous solution from the Ozark-Mahoning Co., Tulsa, Okla-89Journal of the Arkansas Academy of Science, Vol. 22 [1968], Art. 17https://scholarworks.uark.edu/jaas/vol22/iss1/1790Arkansas Academy of Science Proceedingshoma. All diazotizations were carried out in a polyethylene beakerand measured quantities of hexafluorophosphoric acid were addedfrom a polyethylene graduate cylinder. A positive qualitative testfor fluorine (10) was obtained on each fluoride, and a positiveferric chloride test (11) on each pyridol. Melting points and boilingpoints are uncorrected.The 2-fluoropyridinea.2-Aminopyridine or the appropriately substituted 2-amino-methylpyridine (aminopicoline) ; (0.28 mole) was dissolved in amixture of water (110 ml.) and 65% hexafluorophosphoric acid(125 ml.). The solution was cooled at -5°, and solid, finely-dividedsodium nitrite (0.281 mole) was added in small portions over aperiod of 1.5 hr. wifht efficient magnetic stirring and rigorous tem-perature control (-5 to 0°) being maintained. At the end of thenitrite addition the solution was stirred at room temperature for 30minutes followed by warming to 45° for 30 minutes to insure completedecomposition of the diazonium hexafluorophosphate. The crudefluoride was obtained by cooling the solution to 5-10°, followed bycareful neutralization with sodium carbonate and steam distillation.The oilwhich separated from the steam distillate was removed, andthe aqueous distillate was saturated with sodium sulfate and ex-tracted with ether (50 ml.). The oil and ether extract were com-bined and dried over anhydrous sodium sulfate. After removal ofthe ether the appropriate fluoropyridine was distilled at atmos-pheric pressure. Physical data are summarized in Table II.The 2-pyridols.The residues from the steam distillation of the fluoropyndineswere cooled and the solid material filtered and recrystallized frombenzene to yield the appropriate pyridols. Yield and physical dataare reported in Table III.Preparation of authentic pyridol samples:The appropriate aminopyridine (0.10 mole) was dissolved ina mixture of sulfuric acid (30 ml.) and water (50 ml.) and theresulting solution diazotized at 0° by the dropwise addition of a solu-tion of sodium nitrite (.11 mole) in water 25 ml.). The solution wasthen warmed to 70° for 1 hr., cooled to 10°, and made basic withaqueous ammonia. The crude pyridols which precipitated were re-crystallized from benzene.HPF6 Hydrolysis of 2-fluoro.3-methylpyridine.2-Fluoro-3-methylpyridine (5.0 g.) was dissolved in a mixtureof water (20 ml.) and 65% hexafluorophosphoric acid (20 ml.), andthe resulting solution warmed at 45° for 40 min. The solution wascooled to 10°, made basic with sodium carbonate, and the resultingmixture subjected to steam distillation. The steam distillate yieldedi t i till tion ri90Journal of the Arkansas Academy of Science, Vol. 22 [1968], Art. 17Published by Arkansas Academy of Science, 1968911A Modified Schiemann Method2.7 g. (54% recovery) of starting material. The pot residue fromthe steam distillation deposited 1.52 g. (31%) of 2-hydroxy-3-methylpyridine, m.p. 138°.S-Fluoropyridine.3-Aminopyridine (18.8 g.; 0.2 mole) was dissolved in a mixtureof water (100 ml.) and concentrated hydrochloric acid (75 ml.) andcooled to 0° with stirring. Sodium nitrite (15.4 g.; 0.22 mole) dis-solved in water (30 ml.) was added slowly to the cold, acid solu-tion over a period of twenty minutes, maintaining the temperaturebelow 5°. Hexafluorophosphoric acid (70 ml.) was then added to thecold solution causing instant precipitation of the diazonium hexa-fluorophosphate. Complete precipitation of the diazo compound wasinsured by added a few pieces of ice to the suspension and allowingthe mixture to stand in an ice bath for thirty minutes. The salt wasfiltered and washed with, 50 ml. portions of ice-cold water, methanol,and ether respectively. A small portion of the slightly moist salt wasfound to decompose at 45°. If this diazonium salt is allowed to be-come dry, it willdecompose spontaneously at room temperature. Thus,it is necessary to proceed directly to the decomposition step withoutdrying and weighing the salt.The slightly moist salt was transferred to a three-necked,round-bottomed flask equipped with two condensers and covered withpetroleum ether (150 ml.; b.p. 60-90°). Decomposition began atroom temperature, and the flask was heated gently in order to facil-itate smooth decomposition. When gas evolution subsided, the mix-ture was refluxed gently for one hour to insure complete decompo-sition. The solution was then cooled, concentrated hydrochloric acid(10 ml.) was added, followed by removal of petroleum ether at re-duced pressure. The petroleum ether distillate was extracted with25% hydrochloric acid (25 ml.) and the acid extract returned tothe residue in the boiler. The acid solution was cooled to 10°, madebasic with sodium hydroxide solution, and the alkaline solution steamdistilled. Solid sodium hydroxide was added to the steam distillateand the oil which separated removed. Ether extraction at this pointis not desirable since the product azeotropes with ether (4). The oilwas dried over sodium hydroxide and distilled to give 7.5 g. (38.5%)of clear, colorless 3-fluoropyridine, b.p. 107-108° (763 mm.), njj"1.4689 (lit. (4) b.p. 105-107° at 752 mm.; nD"1.4700).S.Fluoroquinoline.3-Aminoquinoline (28.8 g.;0.20 mole) was dissolved in a mixtureof water (250 ml.) and concentrated hydrochloric acid (85 ml.) andcooled to 0° with stirring. Diazotization of the cold solution wasperformed by the dropwise addition of sodium nitrite (15.4 g.; 0.22mole) in water (35 ml.). The amine hydrochloride, which began toseparate, disappeared as the diazotization proceeded. Precipitation ofthe yellow 3-quinoline-diazonium hexafluorophosphate was accom-91Journal of the Arkansas Academy of Science, Vol. 22 [1968], Art. 17https://scholarworks.uark.edu/jaas/vol22/iss1/1792>Arkansas Academy of Science Proceedingsplished by addition of 65% hexafluorophosphoric acid (90 ml.), tothe cold, diazotized solution. After allowing the slurry to stand inthe ice bath for one hour, the yellow salt was filtered and washedwith cold 100 ml. portions of water, methanol, and ether respectively.The air-dried salt weighed 58.7 g. (97.5% from the amine). The de-composition point was found to be 96°.The dry salt (30 g.) was transferred to a round-bottomed flaskand covered with dry toluene (150 ml.). A spiral condenser wasattached, and the flask was heated gently under the hood to facil-itate smooth decomposition. Once decomposition began, it was rapid,as evidenced by expulsion of white phosphorous pentafluoride fumes.After gas evolution had moderated, the solution was gently refluxedfor one hour. The toluene was decanted and extracted with 50 ml.portions of 30% hydrochloric acid, with the acid extracts being re-turned to the decomposition flask. The acid solution was steam dis-tilled to remove a small amount of toluene, then cooled to 15° andneutralized with a 50% sodium carbonate solution. The steam dis-tillation was continued whereupon white solid collected in the con-denser and receiving flask. The solid, evidently a hydrae of 3-fluoro-quinoline (7), was separated and the aqueous dstillate saturated withsodium sulfate and extracted twice with ether (75 ml.). The whitesolid was added to the ether extracts and dissolved; the resultingsolution was dried over anhydrous sodium sulfate. After removal ofether at atmospheric pressure, 3-fluoroquinoline (7.0 g.; 45% fromthe amine) dstilled, b.p. 96-97° (10 mm.), nD*5 1.5900 (lit. (7) b.p.102° at 15 mm.; nD"1.5902).In another experiment, the diazonium salt (58.7 g.) was de-composed in heavy mineral oil (350 ml.) preheated to 100°. The pro-duct, which was isolated by steam distillation and worked up asabove, weighed 14.1 grams (48%), b.p. 96-97° (10 mm.).92Journal of the Arkansas Academy of Science, Vol. 22 [1968], Art. 17Published by Arkansas Academy of Science, 1968Aromatic Aromatic % 7^- kit. % 7^ % 7^' PyridolAmine Fluoride (HBF4 method) Ref. (HPF6 method) (HPF6 method)2-aminopyridine 2-fluoropyridine 34 (4) 20 392-amino-3-methyl- 2-fluoro-3-methyl- 48 (5) 32 28pyridine pyridine2-amino-4-methyl- 2-fluoro-4-methyl- 36 (6) 24 27pyridine pyridine2-amino-5-methyl- 2-fluoro-5-methyl- 46 (5) 39 22pyridine pyridine2-amino-6-methyl- 2-fluoro-6-methyl- 34 (6) 25 33pyridine pyridine3-aminopyridine 3-fluoropyridine 50 (4) 39—3-aminoquinoline 3-fluoroquinoline 53 (7) 48—93Journal of the Arkansas Academy of Science, Vol. 22 [1968], Art. 17https://scholarworks.uark.edu/jaas/vol22/iss1/17yld. obs. obs. rept'd rept'd lit.Fluoropyridine grams (%) b.p. ref. ind. b.p. ref. ind. ref.2-fluoropyridine 5.4 (20) 126° nD"1.4706 125° nD"1.4700 (4)2-fluoro-3-methyl- 9.9 (32) 149-150° nD261.4686 150-151° not rept'd (5)pyridine2-fluoro-4-methyl- 8.4 (24) 155* nD*51.4692 157° nD251.4690 (6)pyridine2-fluoro-5-methyl- 12.0 (39) 156° nD"1.4680 155-156° not rept'd (5)pyridine2-fluoro-6-methyl- 7.7 (25) 142-144° nD*51.4675 142° nD"1.4673 (6)pyridine94Journal of the Arkansas Academy of Science, Vol. 22 [1968], Art. 17Published by Arkansas Academy of Science, 1968yld. obs. reported litPyridol gms. (%) m.p. m.p. reference2-hydroxypyridine 2.7 (39) 104-106* 106° (12)2-hydroxy-3-methyl- 3.0 (28) 138* 140* (13)pyridine2-hydroxy-4-methyl- 2.9 (27) 127-128° 130f (14)pyridine2-hydroxy-5-methyl- 2.4 (22) 18? 183-184* (15)pyridine2-hydroxy-6-methyl- 3.6 (33) 159* 158» (16)pyridine95Journal of the Arkansas Academy of Science, Vol. 22 [1968], Art. 17https://scholarworks.uark.edu/jaas/vol22/iss1/1796Arkansas Academy of Science ProceedingsREFERENCES AND LITERATURE CITED(1) Abstracted in part from the M.S. Thesis of F.L.S., TulaneUniversity, August, 1962.(2) For an excellent review of the Schiemann Reaction, see A.Roe in "Organic Reactions," vol. V, J. Wiley and Sons,Inc., New York, N.Y., 1949, p. 193.(3) K.Rutherford, W. Redmond, and J. Rigamonti, J. Org. Chem.,26, 5149 (1961).(4) A. Roe and G. Hawkins, J. Am. Chem. Soc, 69, 2443 (1947).(5) A. Roe, G. Hawkins, J. Minor, and C. Vanderwerf, J. Am.Chem. Soc, 71, 1125 (1949).(6) A. Roe, P. Cheek, and G. Hawkins, J. Am. Chem. Soc, 71,4152 (1949).(7) A. Roe and G. Hawkins, J. Am. Chem. Soc, 71, 1985 (1949).(8) This technique was employed by A. Roe et. al with HBF4 insuch cases.(9) The facile acid-catalyzed hydrolysis of 2-fluoropyridines hasbeen reported previously, c.f. G. C. Finger, L. D. Starr,A Roe, and W. J. Link, J. Org. Chem., 27, 3965 (1962).(10) R. Shriner and R. Fuson, "The Systematic Identification ofOrganic Compounds," 3rd edition, J. Wiley and Sons, Inc.,New York, N.Y., 1948, p. 27.(11) ibid., p. 98.(12) Handbook of Chemistry and Physics, 38th edition, ChemicalRubber Publishing Co., Cleveland, Ohio, 1957, p. 1134.(13) O. Siede, Chem. Ber., 57B, 1802 (1924).(14) O. Seide, ibid., 57B, 791 (1924).(16) H. Bradlow and C. Vanderwerf, J. Org. Chem., 14, 509 (1948).(16) E. Ochiai and Y. Ito, Chem. Ber., 74B, 1111 (1941).96Journal of the Arkansas Academy of Science, Vol. 22 [1968], Art. 17Published by Arkansas Academy of Science, 1968

Heterocyclic Aromatic Fluorides by a Modified Schiemann Method (1)

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Journal of the Arkansas Academy of ScienceVolume 22 Article 171968Heterocyclic Aromatic Fluorides by a ModifiedSchiemann Method (1)Frank L. SetliffUniversity of Arkansas at Little RockFollow this and additional works at: http://scholarworks.uark.edu/jaasPart of the Organic Chemistry CommonsThis article is available for use under the Creative Commons license: Attribution-NoDerivatives 4.0 International (CC BY-ND 4.0). Users are able toread, download, copy, print, distribute, search, link to the full texts of these articles, or use them for any other lawful purpose, without asking priorpermission from the publisher or the author.This Article is brought to you for free and open access by ScholarWorks@UARK. It has been accepted for inclusion in Journal of the Arkansas Academyof Science by an authorized editor of ScholarWorks@UARK. For more information, please contact scholar@uark.edu, ccmiddle@uark.edu.Recommended CitationSetliff, Frank L. (1968) "Heterocyclic Aromatic Fluorides by a Modified Schiemann Method (1)," Journal of the Arkansas Academy ofScience: Vol. 22 , Article 17.Available at: http://scholarworks.uark.edu/jaas/vol22/iss1/1788Arkansas Academy of Science Proceedings, Vol. 22, 1968HETEROCYCLIC AROMATIC FLUORIDES BYA MODIFIED SCHIEMANN METHOD (1)Frank L. SetliffLittle Rock UniversityINTRODUCTIONThe Schiemann Reaction (2) has long been employed byorganic chemists as the most efficient means of introducing flourineinto aromatic systems. The method is basically simple (equation 1)and involves diazotization of a primary aromatic amine in hydro-chloric acid followed by the addition of fluoboric acid (HBF4 ) tothe cold solution of the diazonium chloride. The precipitated dia-zonium fluborate is then filtered from the reaction mixture andthermally decomposed to yield the aromatic flouride. The success of(1) ArNH 2£i-» ArNa+Cl" -£££* ? ArN3+EF4-£ p ArF3 NaNO a 0° +Na + BF3the method lies in the fact that the diazonium fluborates are usuallyformed in good yields and their stability permits thorough wash-ing and purification before thermal decomposition. Furthermore, thesediazonium salts decompose smoothly without violence to generallygive good yields of the desired fluoride.Rutherford and co-workers have shown that replacement offluoboric acid with hexafluorophosphoric acid (HPF 6 ) in the Schie-mann Reaction (equation 2) results in much improved yields of aro-matic fluoride from aromatic amine (3). The following significantyield increases were realized over the classical Schiemann method:(2) ArNHa HC1 a) ArN3+Cl- HFFg » ArNa+PF s-heat > ArP +NaNO a ONa + PF Eo-fluorobenzoic acid from anthranilic acid (-(-52%) ;p-fluorobenzoicacid from p-aminobenzoic acid (-j- 49%); p-bromofluorobenzenefrom p-bromoaniline (-j-27%); and p-fluoroanisole from p-amino-anisole (-|-23%). Small yield increases were noted in numerousother cases. The success of the HPF 6 method was attributed to theincreased insolubility of the diazonium hexafluorophosphates(ArN2+PF 6~) which would permit more efficient isolation andpurification before decomposition. Furthermore, phosphorus penta-fluoride, a weaker Lewis acid than boron trifluoride, would be ex-pected to promote less polymerization during decomposition.RESULTS AND DISCUSSIONOur extension of this modified method to several aromaticamines in the heterocyclic series, i.e. pyridines and quinolines hassurprisingly revealed a predominant inferiority of HPF6 to HBF488Journal of the Arkansas Academy of Science, Vol. 22 [1968], Art. 17Published by Arkansas Academy of Science, 196889A Modified Schiemann Method(see Table I; the HBF 4 yield data are taken from the literature).The rather large differences in yields of fluorides from the 2-aminopyridines may be experimentally accounted for. In these in-stances it was necessary to diazotize the amines directly in thepresence of HPF 6 since the resulting diazonium hexafluorophosphatesare too unstable to be isolated before decomposition (8) (equation 3).(3) ArNHa—2=^2 ». ArNa PP a~NaNO 3O°ArF + N3 + PF 6The amine hydrohexafluorophosphates (ArNH3+ PF 6~) which pre-cipitate at the low temperature required for diazotization requirerather large quantities of water for dissolution before diazotization.Thus, diazonium hexafluorophosphate hydrolysis would appear to bea probable competitive side reaction to normal diazonium salt de-composition. In addition, acid-catalyzed hydrolysis of the initiallyformed fluoroderivative could be operative to a large extent (9).Either of these side reactions would result in pyridol side productsas depicted in Scheme I.As indicated in Table Ipyridols were indeed observed in additionto the fluorides in the series of 2-aminopyridines studied. That acid-catalyzed fluoride hydrolysis could be at least partially responsiblefor the pyridol formation was established by independent experi-ment. Under the conditions of the formation of 2-fluoro-3-methylpyri-dine, pure 2-fluoro-3-methylpyridine was converted to 2-hydroxy-3-methylpyridine in 31% yield. Itis assumed that similar results wouldbe obtained in other specific cases. The pyridols were identified bymixed melting point determinatons with authentic samples preparedby diazotization (and subsequent hydrolysis) of the appropriate2-aminopyridine.In those cases (i.e., 3-aminopyridine and 3-aminoquinoline)where the stability of the diazonium hexafluorophosphate permittedtheir isolation before decomposition, the resulting yields of aromaticfluorides more nearly paralleled those obtainable by the HBF4 method,with no accompanying pyridol formation.EXPERIMENTAL SECTIONGeneral Information. Hexafluorophosphoric acid is available as a65% aqueous solution from the Ozark-Mahoning Co., Tulsa, Okla-89Journal of the Arkansas Academy of Science, Vol. 22 [1968], Art. 17http://scholarworks.uark.edu/jaas/vol22/iss1/1790Arkansas Academy of Science Proceedingshoma. All diazotizations were carried out in a polyethylene beakerand measured quantities of hexafluorophosphoric acid were addedfrom a polyethylene graduate cylinder. A positive qualitative testfor fluorine (10) was obtained on each fluoride, and a positiveferric chloride test (11) on each pyridol. Melting points and boilingpoints are uncorrected.The 2-fluoropyridinea.2-Aminopyridine or the appropriately substituted 2-amino-methylpyridine (aminopicoline) ; (0.28 mole) was dissolved in amixture of water (110 ml.) and 65% hexafluorophosphoric acid(125 ml.). The solution was cooled at -5°, and solid, finely-dividedsodium nitrite (0.281 mole) was added in small portions over aperiod of 1.5 hr. wifht efficient magnetic stirring and rigorous tem-perature control (-5 to 0°) being maintained. At the end of thenitrite addition the solution was stirred at room temperature for 30minutes followed by warming to 45° for 30 minutes to insure completedecomposition of the diazonium hexafluorophosphate. The crudefluoride was obtained by cooling the solution to 5-10°, followed bycareful neutralization with sodium carbonate and steam distillation.The oilwhich separated from the steam distillate was removed, andthe aqueous distillate was saturated with sodium sulfate and ex-tracted with ether (50 ml.). The oil and ether extract were com-bined and dried over anhydrous sodium sulfate. After removal ofthe ether the appropriate fluoropyridine was distilled at atmos-pheric pressure. Physical data are summarized in Table II.The 2-pyridols.The residues from the steam distillation of the fluoropyndineswere cooled and the solid material filtered and recrystallized frombenzene to yield the appropriate pyridols. Yield and physical dataare reported in Table III.Preparation of authentic pyridol samples:The appropriate aminopyridine (0.10 mole) was dissolved ina mixture of sulfuric acid (30 ml.) and water (50 ml.) and theresulting solution diazotized at 0° by the dropwise addition of a solu-tion of sodium nitrite (.11 mole) in water 25 ml.). The solution wasthen warmed to 70° for 1 hr., cooled to 10°, and made basic withaqueous ammonia. The crude pyridols which precipitated were re-crystallized from benzene.HPF6 Hydrolysis of 2-fluoro.3-methylpyridine.2-Fluoro-3-methylpyridine (5.0 g.) was dissolved in a mixtureof water (20 ml.) and 65% hexafluorophosphoric acid (20 ml.), andthe resulting solution warmed at 45° for 40 min. The solution wascooled to 10°, made basic with sodium carbonate, and the resultingmixture subjected to steam distillation. The steam distillate yieldedi t i till tion ri90Journal of the Arkansas Academy of Science, Vol. 22 [1968], Art. 17Published by Arkansas Academy of Science, 1968911A Modified Schiemann Method2.7 g. (54% recovery) of starting material. The pot residue fromthe steam distillation deposited 1.52 g. (31%) of 2-hydroxy-3-methylpyridine, m.p. 138°.S-Fluoropyridine.3-Aminopyridine (18.8 g.; 0.2 mole) was dissolved in a mixtureof water (100 ml.) and concentrated hydrochloric acid (75 ml.) andcooled to 0° with stirring. Sodium nitrite (15.4 g.; 0.22 mole) dis-solved in water (30 ml.) was added slowly to the cold, acid solu-tion over a period of twenty minutes, maintaining the temperaturebelow 5°. Hexafluorophosphoric acid (70 ml.) was then added to thecold solution causing instant precipitation of the diazonium hexa-fluorophosphate. Complete precipitation of the diazo compound wasinsured by added a few pieces of ice to the suspension and allowingthe mixture to stand in an ice bath for thirty minutes. The salt wasfiltered and washed with, 50 ml. portions of ice-cold water, methanol,and ether respectively. A small portion of the slightly moist salt wasfound to decompose at 45°. If this diazonium salt is allowed to be-come dry, it willdecompose spontaneously at room temperature. Thus,it is necessary to proceed directly to the decomposition step withoutdrying and weighing the salt.The slightly moist salt was transferred to a three-necked,round-bottomed flask equipped with two condensers and covered withpetroleum ether (150 ml.; b.p. 60-90°). Decomposition began atroom temperature, and the flask was heated gently in order to facil-itate smooth decomposition. When gas evolution subsided, the mix-ture was refluxed gently for one hour to insure complete decompo-sition. The solution was then cooled, concentrated hydrochloric acid(10 ml.) was added, followed by removal of petroleum ether at re-duced pressure. The petroleum ether distillate was extracted with25% hydrochloric acid (25 ml.) and the acid extract returned tothe residue in the boiler. The acid solution was cooled to 10°, madebasic with sodium hydroxide solution, and the alkaline solution steamdistilled. Solid sodium hydroxide was added to the steam distillateand the oil which separated removed. Ether extraction at this pointis not desirable since the product azeotropes with ether (4). The oilwas dried over sodium hydroxide and distilled to give 7.5 g. (38.5%)of clear, colorless 3-fluoropyridine, b.p. 107-108° (763 mm.), njj"1.4689 (lit. (4) b.p. 105-107° at 752 mm.; nD"1.4700).S.Fluoroquinoline.3-Aminoquinoline (28.8 g.;0.20 mole) was dissolved in a mixtureof water (250 ml.) and concentrated hydrochloric acid (85 ml.) andcooled to 0° with stirring. Diazotization of the cold solution wasperformed by the dropwise addition of sodium nitrite (15.4 g.; 0.22mole) in water (35 ml.). The amine hydrochloride, which began toseparate, disappeared as the diazotization proceeded. Precipitation ofthe yellow 3-quinoline-diazonium hexafluorophosphate was accom-91Journal of the Arkansas Academy of Science, Vol. 22 [1968], Art. 17http://scholarworks.uark.edu/jaas/vol22/iss1/1792>Arkansas Academy of Science Proceedingsplished by addition of 65% hexafluorophosphoric acid (90 ml.), tothe cold, diazotized solution. After allowing the slurry to stand inthe ice bath for one hour, the yellow salt was filtered and washedwith cold 100 ml. portions of water, methanol, and ether respectively.The air-dried salt weighed 58.7 g. (97.5% from the amine). The de-composition point was found to be 96°.The dry salt (30 g.) was transferred to a round-bottomed flaskand covered with dry toluene (150 ml.). A spiral condenser wasattached, and the flask was heated gently under the hood to facil-itate smooth decomposition. Once decomposition began, it was rapid,as evidenced by expulsion of white phosphorous pentafluoride fumes.After gas evolution had moderated, the solution was gently refluxedfor one hour. The toluene was decanted and extracted with 50 ml.portions of 30% hydrochloric acid, with the acid extracts being re-turned to the decomposition flask. The acid solution was steam dis-tilled to remove a small amount of toluene, then cooled to 15° andneutralized with a 50% sodium carbonate solution. The steam dis-tillation was continued whereupon white solid collected in the con-denser and receiving flask. The solid, evidently a hydrae of 3-fluoro-quinoline (7), was separated and the aqueous dstillate saturated withsodium sulfate and extracted twice with ether (75 ml.). The whitesolid was added to the ether extracts and dissolved; the resultingsolution was dried over anhydrous sodium sulfate. After removal ofether at atmospheric pressure, 3-fluoroquinoline (7.0 g.; 45% fromthe amine) dstilled, b.p. 96-97° (10 mm.), nD*5 1.5900 (lit. (7) b.p.102° at 15 mm.; nD"1.5902).In another experiment, the diazonium salt (58.7 g.) was de-composed in heavy mineral oil (350 ml.) preheated to 100°. The pro-duct, which was isolated by steam distillation and worked up asabove, weighed 14.1 grams (48%), b.p. 96-97° (10 mm.).92Journal of the Arkansas Academy of Science, Vol. 22 [1968], Art. 17Published by Arkansas Academy of Science, 1968Aromatic Aromatic % 7^- kit. % 7^ % 7^' PyridolAmine Fluoride (HBF4 method) Ref. (HPF6 method) (HPF6 method)2-aminopyridine 2-fluoropyridine 34 (4) 20 392-amino-3-methyl- 2-fluoro-3-methyl- 48 (5) 32 28pyridine pyridine2-amino-4-methyl- 2-fluoro-4-methyl- 36 (6) 24 27pyridine pyridine2-amino-5-methyl- 2-fluoro-5-methyl- 46 (5) 39 22pyridine pyridine2-amino-6-methyl- 2-fluoro-6-methyl- 34 (6) 25 33pyridine pyridine3-aminopyridine 3-fluoropyridine 50 (4) 39—3-aminoquinoline 3-fluoroquinoline 53 (7) 48—93Journal of the Arkansas Academy of Science, Vol. 22 [1968], Art. 17http://scholarworks.uark.edu/jaas/vol22/iss1/17yld. obs. obs. rept'd rept'd lit.Fluoropyridine grams (%) b.p. ref. ind. b.p. ref. ind. ref.2-fluoropyridine 5.4 (20) 126° nD"1.4706 125° nD"1.4700 (4)2-fluoro-3-methyl- 9.9 (32) 149-150° nD261.4686 150-151° not rept'd (5)pyridine2-fluoro-4-methyl- 8.4 (24) 155* nD*51.4692 157° nD251.4690 (6)pyridine2-fluoro-5-methyl- 12.0 (39) 156° nD"1.4680 155-156° not rept'd (5)pyridine2-fluoro-6-methyl- 7.7 (25) 142-144° nD*51.4675 142° nD"1.4673 (6)pyridine94Journal of the Arkansas Academy of Science, Vol. 22 [1968], Art. 17Published by Arkansas Academy of Science, 1968yld. obs. reported litPyridol gms. (%) m.p. m.p. reference2-hydroxypyridine 2.7 (39) 104-106* 106° (12)2-hydroxy-3-methyl- 3.0 (28) 138* 140* (13)pyridine2-hydroxy-4-methyl- 2.9 (27) 127-128° 130f (14)pyridine2-hydroxy-5-methyl- 2.4 (22) 18? 183-184* (15)pyridine2-hydroxy-6-methyl- 3.6 (33) 159* 158» (16)pyridine95Journal of the Arkansas Academy of Science, Vol. 22 [1968], Art. 17http://scholarworks.uark.edu/jaas/vol22/iss1/1796Arkansas Academy of Science ProceedingsREFERENCES AND LITERATURE CITED(1) Abstracted in part from the M.S. Thesis of F.L.S., TulaneUniversity, August, 1962.(2) For an excellent review of the Schiemann Reaction, see A.Roe in "Organic Reactions," vol. V, J. Wiley and Sons,Inc., New York, N.Y., 1949, p. 193.(3) K.Rutherford, W. Redmond, and J. Rigamonti, J. Org. Chem.,26, 5149 (1961).(4) A. Roe and G. Hawkins, J. Am. Chem. Soc, 69, 2443 (1947).(5) A. Roe, G. Hawkins, J. Minor, and C. Vanderwerf, J. Am.Chem. Soc, 71, 1125 (1949).(6) A. Roe, P. Cheek, and G. Hawkins, J. Am. Chem. Soc, 71,4152 (1949).(7) A. Roe and G. Hawkins, J. Am. Chem. Soc, 71, 1985 (1949).(8) This technique was employed by A. Roe et. al with HBF4 insuch cases.(9) The facile acid-catalyzed hydrolysis of 2-fluoropyridines hasbeen reported previously, c.f. G. C. Finger, L. D. Starr,A Roe, and W. J. Link, J. Org. Chem., 27, 3965 (1962).(10) R. Shriner and R. Fuson, "The Systematic Identification ofOrganic Compounds," 3rd edition, J. Wiley and Sons, Inc.,New York, N.Y., 1948, p. 27.(11) ibid., p. 98.(12) Handbook of Chemistry and Physics, 38th edition, ChemicalRubber Publishing Co., Cleveland, Ohio, 1957, p. 1134.(13) O. Siede, Chem. Ber., 57B, 1802 (1924).(14) O. Seide, ibid., 57B, 791 (1924).(16) H. Bradlow and C. Vanderwerf, J. Org. Chem., 14, 509 (1948).(16) E. Ochiai and Y. Ito, Chem. Ber., 74B, 1111 (1941).96Journal of the Arkansas Academy of Science, Vol. 22 [1968], Art. 17Published by Arkansas Academy of Science, 1968

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Heterocyclic Aromatic Fluorides by a Modified Schiemann Method (1)

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