organic syntheses collective volume 4

Organic Syntheses, Coll. Vol. 4, p.1 (1963); Vol. 32, p.1 (1952).

ABIETIC ACID

Submitted by G. C. Harris and T. F. Sanderson1. Checked by R. T. Arnold and K. L. Lindsay.

1. ProcedureIn a 2-l. round-bottomed flask fitted with a 35-cm. reflux condenser are placed 250 g. (0.74 mole) of N-grade wood rosin (Note 1), 740 ml. of 95% ethanol, and 42 ml. of hydrochloric acid (sp. gr. 1.19). A stream of carbon dioxide is passed over the surface of the solution by means of a glass tube which extends downward through the condenser during this reaction (Note 2). The mixture is boiled under reflux for 2 hours (Note 3). At the end of this time, the ethanol and acid are removed by steam distillation and the water is decanted. The residue is cooled to room temperature and dissolved in 1 l. of ether. The ether solution is extracted with water and dried over 200 g. of anhydrous sodium sulfate. The bulk of the ether is evaporated on the steam bath, and the last traces are removed by fusing the rosin over a free flame and under a vacuum furnished by a water aspirator. The molten rosin, blanketed continuously with carbon dioxide, is most conveniently handled by being poured into a paper boat; yield 24 245 g.; []D 35 (Note 4). The isomerized rosin, 245 g. (0.72 mole) (Note 1), is placed in a 1-l. Erlenmeyer flask and dissolved in 375 ml. of acetone by heating the mixture on a steam bath. To this solution, at incipient boiling, is added slowly and with vigorous agitation (Note 5) 127 g. (0.81 mole) of diamylamine2 (Note 6). Upon cooling to room temperature, crystals appear in the form of rosettes. The mass is agitated, cooled well in an ice bath, and filtered by suction. The crystalline salt is washed on a Bchner funnel with 150 ml. of 24 acetone and dried in a vacuum oven at 50 for 1 hour. The optical rotation of this material is []D 18 (Note 4). The solid is recrystallized four times from acetone. Each time a sufficient quantity (20 ml. per g.) of acetone is used to obtain complete solution, and the solvent is evaporated until incipient 24 precipitation of the salt occurs. The yield of product is 118 g.; []D 60 (Note 4). An additional 29 g. of product, having the same rotation, can be recovered from filtrates of the previous crystallizations. The amine salt (147 g.) is placed in a 4-l. Erlenmeyer flask and dissolved in 1 l. of 95% ethanol by heating the mixture on a steam bath. To the solution, which has been cooled to room temperature (Note 7), is added 39 g. (35.8 ml.) of glacial acetic acid, and the solution is stirred. Water (900 ml.) is added cautiously at first and with vigorous agitation until crystals of abietic acid begin to appear; the remainder of the water is then added more rapidly. The abietic acid is collected on a Bchner funnel (Note 8) and washed with water until the acetic acid has been removed completely as indicated by tests

with indicator paper. Recrystallization can be effected by dissolving the crude product in 700 ml. of 95% ethanol, adding 600 ml. of water as described above, and cooling the solution. The yield of abietic 24 acid is 98 g. (40% based on the weight of isomerized rosin; []D 106 (Note 4) and (Note 9). The ultraviolet absorption spectrum shows a maximum at 241 m; = 77.0 (Note 10).

2. Notes1. The calculation of molar quantities is based on an acid number of 166 for N-grade wood rosin as obtained from Hercules Powder Company, Wilmington, Delaware. Acid number is the number of milligrams of potassium hydroxide required to neutralize 1 g. of sample. 2. Blanketing the rosin in solution or in the molten state with carbon dioxide serves to keep it out of contact with air to avoid oxidation. 24 3. The maximum negative optical rotation, []D 35, is obtained with a minimum reflux time of 2 hours. 4. Rotations are reported as those of 1% solutions in absolute ethanol. 5. The addition of the amine to the hot solution is necessary for the formation of the salt. However, it must be done slowly and with rapid stirring because of the resulting vigorous exothermic reaction. 6. Commercial diamylamine, a mixture of isomers, purchased from Sharples Chemicals Company, Philadelphia, Pennsylvania, was employed. 7. The acid is added to a cooled solution of the salt in ethanol to minimize the chance for isomerization of the liberated abietic acid. 8. An early filtration is desirable for the purpose of removing the abietic acid from the acidic solution where isomerization can take place. Washing with a large volume of water and recrystallizing assures the complete removal of acetic acid. 9. The pure acid is dried in a vacuum desiccator over sodium hydroxide or calcium sulfate and stored in an oxygen-free atmosphere. Undue exposure to higher temperatures will result in isomerization, and contact with oxygen will result in oxidation. 10. The absorption spectrum data were obtained from measurements made with a Beckman Ultraviolet Spectrophotometer. The formulas employed in making the calculations use the term , specific absorption coefficient. = log10 I0/I/cl where I0 = intensity of radiation transmitted by the solvent; I = intensity of radiation transmitted by the solution; c = concentration of solute in grams per liter; l = length in centimeters of solution through which the radiation passes.

3. DiscussionAbietic acid has usually been prepared2 from rosin through the acid sodium salt (3C20H30O2C19H29CO2Na) with the subsequent formation and recrystallization of the diamylamine salt. The acid is regenerated from the pure salt by decomposition of the latter with a weak acid such as acetic acid. In addition, it has been purified3 through the potassium, piperidine, and brucine salts, as well as through abietic anhydride and trityl abietate. The acid is regenerated from the pure salts by decomposition of the latter with a weak acid such as acetic acid, and from the pure acid derivatives by treatment with potassium hydroxide. Two improvements have been introduced in the first method2 by the procedure described above: (1) the abietic content of the rosin is increased by isomerization, and (2) a much better recovery of acid is obtained by applying the amine salt technique directly to the isomerized rosin, thus eliminating the step involving the acid sodium salt.

References and Notes1. Hercules Powder Company, Wilmington, Delaware. 2. Palkin and Harris, J. Am. Chem. Soc., 56, 1935 (1934). 3. Lombard and Frey, Bull. soc. chim. France, 1948, 1194.

Appendix Chemical Abstracts Nomenclature (Collective Index Number); (Registry Number)ethanol (64-17-5) hydrochloric acid (7647-01-0) acetic acid (64-19-7) ether (60-29-7) sodium hydroxide (1310-73-2) sodium sulfate (7757-82-6) oxygen (7782-44-7) carbon dioxide (124-38-9) calcium sulfate (7778-18-9) acetone (67-64-1) potassium hydroxide (1310-58-3) piperidine (110-89-4) potassium (7440-09-7) brucine ABIETIC ACID (514-10-3) diamylamine (2050-92-2) abietic anhydride trityl abietateCopyright 1921-2005, Organic Syntheses, Inc. All Rights Reserved


3-ACETAMIDO-2-BUTANONE[2-Butanone, 3-acetamido-]

Submitted by Richard H. Wiley and O. H. Borum1. Checked by R. S. Schreiber and B. D. Aspergren.

1. ProcedureA mixture of 156.6 g. (159 ml., 1.98 moles) of pyridine (Note 1), 239.9 g. (224 ml., 2.35 moles) of acetic anhydride (Note 2), and 35.1 g. (0.39 mole) of vacuum-dried alanine (Note 3) and (Note 4) is heated with stirring (Note 5) on the steam bath for 6 hours after solution is complete (Note 6). The excess pyridine and acetic anhydride, and the acetic acid, are removed at reduced pressure. The residue is distilled through a 15-cm. column, packed with glass helices, to give 41.547.5 g. of crude product, boiling at 110125/3 mm. Refractionation gives 4145 g. (8188%) of 3-acetamido-2-butanone; b.p. 25 102106/2 mm.; nD 1.45581.4561 (Note 7).

2. Notes1. A commercial C.P. grade can be used. The checkers used Merck A.R. grade. 2. A commercial grade, 95% minimum assay, can be used. The checkers used Merck A.R. grade. 3. Any good commercial grade material appears to be satisfactory. 4. Reducing the molar ratio of pyridine or anhydride to the amino acid reduces the yield. 5. Without stirring the yield is 46%. 6. With other amino acids, notably glycine and sarcosine, it is necessary to reflux the reactants 16 hours. 7. The checkers found it necessary to heat the column to obtain the maximum available product.

3. DiscussionThis method, an adaptation of a previously described procedure,2,3,4 has been used with a variety of amino acids and anhydrides to give the following products: 1-phenyl-1-propionamido-2-butanone (75%);5 acetamidoacetylacetone (60%);5 N-methylacetamidoacetone;6 1-phenyl-2-acetamido-3butanone (79%);7 1-phenyl-2-propionamido-3-pentanone (41%);7 1-phenyl-2-butyramido-3-hexanone (27%);7 -benzamidopropiophenone (42%);7 -benzamido--phenylpropiophenone (44%);7 1-phenyl-1acetamidoacetone (7290%);8,9 1-phenyl-1-benzamidoacetone (65%);8 1-phenyl-2-benzamido-3butanone (78%);8 3-benzamido-2-butanone (6588%);8 and 3-acetamido-5-methyl-2-hexanone (73%).10 This preparation is referenced from: Org. Syn. Coll. Vol. 5, 27

References and Notes1. University of Louisville, Louisville, Kentucky.

2. 3. 4. 5. 6. 7. 8. 9. 10.

Dakin and West, J. Biol. Chem., 78, 91, 757 (1928). Levene and Steiger, J. Biol. Chem., 74, 689 (1927); 79, 95 (1928). Wiley, J. Org. Chem., 12, 43 (1947). Wiley and Borum, J. Am. Chem. Soc., 70, 2005 (1948). Wiley and Borum, J. Am. Chem. Soc., 72, 1626 (1950). Cleland and Niemann, J. Am. Chem. Soc., 71, 841 (1949). Searles and Cvejanovich, J. Am. Chem. Soc., 72, 3200 (1950). Rondestvedt, Manning, and Tabibian, J. Am. Chem. Soc., 72, 3183 (1950). Borum, Ph.D. Thesis, University of North Carolina, 1949.

Appendix Chemical Abstracts Nomenclature (Collective Index Number); (Registry Number)acetic acid (64-19-7) acetic anhydride (108-24-7) alanine (56-41-7) pyridine (110-86-1) sarcosine (107-97-1) Glycine (513-29-1) 3-Acetamido-2-butanone, 2-Butanone, 3-acetamido- (6628-81-5) 1-phenyl-1-propionamido-2-butanone acetamidoacetylacetone N-methylacetamidoacetone 1-phenyl-2-acetamido-3-butanone 1-phenyl-2-propionamido-3-pentanone 1-phenyl-2-butyramido-3-hexanone -benzamidopropiophenone -benzamido--phenylpropiophenone 1-phenyl-1-acetamidoacetone 1-phenyl-1-benzamidoacetone 1-phenyl-2-benzamido-3-butanone

3-benzamido-2-butanone 3-acetamido-5-methyl-2-hexanoneCopyright 1921-2005, Organic Syntheses, Inc. All Rights Reserved


N-(p-ACETYLAMINOPHENYL)RHODANINE[Rhodanine, 3-(p-acetamidophenyl)-]

Submitted by R. E. Strube1 Checked by John D. Roberts and Stanley L. Manatt.

1. ProcedureIn a 2-l. round-bottomed flask fitted with a mechanical stirrer and a reflux condenser are placed 30.0 g. (0.20 mole) of p-aminoacetanilide (Note 1) and 400 ml. of water. The mixture is heated on a steam bath with stirring, and to the clear solution is added at once a hot solution of 45.2 g. (0.20 mole) of trithiocarbodiglycolic acid (p. 967) in 500 ml. of water. Heating and stirring are continued for 5 hours (Note 2). The steam bath is then replaced by an ice bath, and the reaction mixture is cooled to 2025. The precipitate is removed by suction filtration. The solid is transferred to a 500-ml. Erlenmeyer flask containing 200 ml. of water. The mixture is heated on the steam bath to 7075 while the lumps are crushed by a glass rod to obtain a homogeneous mixture. The mixture is filtered with suction while hot, and the flask is cleaned by rinsing it with small amounts of hot water. The solid on the filter is sucked as dry as possible and then transferred to a 2-l. round-bottomed flask fitted with a reflux condenser. Glacial acetic acid (1.5 l.) is added and the mixture is heated in an oil bath to vigorous reflux for 5 minutes (Note 3). A small amount of solid does not dissolve, and this is removed by filtration while hot (Note 4). The filtrate is stirred mechanically and cooled to 1520 by an ice bath and kept at this temperature for 1 hour. The slightly yellow crystals are collected by suction filtration, washed successively with 25 ml. of glacial acetic acid, 100 ml. of ethanol, and 100 ml. of ether. The yield of air-dried material is 2628 g. (4953% yield). The compound decomposes on heating above 240 (Note 5).

2. Notes1. p-Aminoacetanilide (white label) supplied by Eastman Kodak Company was used. 2. Within 10 minutes a precipitate is formed; the greater part of the reaction product is present after 2 hours' heating. 3. The purification should be carried out in a hood, since gas escapes during the heating and hot acetic acid is irritating to the eyes. The checkers used a 2-l. heating mantle instead of an oil bath. 4. The filtration of the hot acetic acid solution should be done with care. The flask was surrounded by a towel and rubber gloves were worn. The filtration can best be done in two steps. Approximately half of the hot acetic acid solution is filtered through a large, fluted filter paper; the other half is heated again to reflux and then filtered through another fluted filter paper. Filtration through a steam-heated Bchner funnel may sometimes be troublesome, since the suction accelerates crystallization causing plugging of the funnel stem. 5. Analytical values: Calcd. for C11H10N2O2S2: C, 49.62; H, 3.78; N, 10.52; S, 24.08. Found: C, 49.76; H, 3.76; N, 10.36; S, 24.07.

3. DiscussionThis procedure is based on the method of Holmberg2 for preparing N-substituted rhodanines. The synthesis of N-(p-acetylaminophenyl)rhodanine has not yet been reported in the literature.

References and Notes1. The Upjohn Company, Kalamazoo, Michigan. 2. Holmberg, J. prakt. Chem., 81, 451 (1910).

Appendix Chemical Abstracts Nomenclature (Collective Index Number); (Registry Number)trithiocarbodiglycolic acid ethanol (64-17-5) acetic acid (64-19-7) ether (60-29-7) N-(p-ACETYLAMINOPHENYL)RHODANINE, Rhodanine, 3-(p-acetamidophenyl)- (53663-36-8) p-aminoacetanilide (122-80-5)Copyright 1921-2005, Organic Syntheses, Inc. All Rights Reserved


9-ACETYLANTHRACENE[Ketone, 9-anthryl methyl]

Submitted by Charles Merritt, Jr. and Charles E. Braun1. Checked by William S. Johnson and Ralph F. Hirschmann.

1. ProcedureFifty grams (0.28 mole) of purified anthracene (Note 1) is suspended in 320 ml. of anhydrous benzene and 120 ml. (1.68 moles) of reagent grade acetyl chloride contained in a 1-l. three-necked flask. The flask is fitted with a thermometer which is immersed in the suspension, a calcium chloride drying tube, an efficient motor-driven sealed stirrer, and a rubber addition tube to which a 125-ml. Erlenmeyer flask containing 75 g. (0.56 mole) of anhydrous aluminum chloride is attached.2 The flask is surrounded by an ice-calcium chloride cooling mixture, and the aluminum chloride is added in small portions from the Erlenmeyer flask at such a rate that the temperature is maintained between 5 and 0. After the addition is complete, the mixture is stirred for an additional 30 minutes, and the temperature is then allowed to rise slowly to 10. The red complex which forms is collected with suction on a sintered-glass funnel and washed thoroughly with dry benzene (Note 2). The complex is added in small portions by means of a spatula with stirring to a 600-ml. beaker nearly filled with a mixture of ice and concentrated hydrochloric acid. The mixture is then allowed to come to room temperature, and the crude ketone is collected on a suction filter. The product is digested under reflux for about 20 minutes with 100150 ml. of boiling 95% ethanol. The suspension (Note 3) is cooled quickly almost to room temperature and filtered rapidly with suction to remove any anthracene. The 9-acetylanthracene, which separates in the filtrate, is redissolved by heating and allowed to crystallize by slowly cooling the solution (finally to 05 in an icebox) (Note 4). A second recrystallization from 95% ethanol yields 3537 g. (5760%) of light-tan granules of 9acetylanthracene melting at 7576 (Note 5).

2. Notes1. The Eastman Kodak Company grade melting at 214215 is satisfactory. Technical grade anthracene can be purified by codistillation with ethylene glycol. (See Fieser, Experiments in Organic Chemistry, 2nd ed., p. 345, footnote 13, D. C. Heath and Company, 1941.) 2. A regular Bchner funnel fitted with a mat of glass wool can be employed successfully. The filtration should be carried out as rapidly as possible, and the hydrolysis should be performed immediately thereafter if the humidity is high to minimize reaction on the funnel. 3. Most of the unreacted anthracene remains undissolved as a brown fluffy residue. 4. If the product has a tendency to separate as an oil, the addition of more solvent followed by heating to redissolve the material and subsequent cooling will usually yield a crystalline product. 5. Lttringhaus and Kacer3 reported the melting point as ca. 80, but May and Mosettig4 have found it to be 7476.

3. DiscussionThe procedure described is essentially that of Lttringhaus and Kacer3 except for the method of

isolation of the product, which is due to May.5

References and Notes1. University of Vermont, Burlington, Vermont. 2. Fieser, Experiments in Organic Chemistry, 3rd ed., p. 265, Fig. 46.4, D. C. Heath and Company, 1955. 3. Lttringhaus and Kacer, Ger. pat. 493,688 [C. A., 24, 2757 (1930)]. 4. May and Mosettig, J. Am. Chem. Soc., 70, 686 (1948). 5. May, Private communication.

Appendix Chemical Abstracts Nomenclature (Collective Index Number); (Registry Number)ethanol (64-17-5) hydrochloric acid (7647-01-0) Benzene (71-43-2) acetyl chloride (75-36-5) aluminum chloride (3495-54-3) ethylene glycol (107-21-1) anthracene (120-12-7) 9-Acetylanthracene, Ketone, 9-anthryl methyl (784-04-3)Copyright 1921-2005, Organic Syntheses, Inc. All Rights Reserved


-ACETYL--CHLORO--VALEROLACTONE[Valeric acid, 2-acetyl-5-chloro-4-hydroxy-, -lactone]

Submitted by G. D. Zuidema, E. van Tamelen, and G. Van Zyl1. Checked by William S. Johnson and Herbert I. Hadler.

1. ProcedureA 1-l. three-necked round-bottomed flask is equipped with a sealed stirrer, a thermometer, a dropping funnel, and an efficient condenser, the upper end of which is protected with a calcium chloride drying tube. In this flask 23 g. (1 g. atom) of lustrous sodium (Note 1) is dissolved in 400 ml. of absolute ethanol (Note 2). The sodium is cut into about 25 pieces, and the entire amount is added at one time. It may be necessary to cool the flask in a cold-water bath if the reaction becomes violent. When all the sodium has dissolved, the solution is cooled to 50 and 130 g. (127 ml., 1 mole) of ethyl acetoacetate (Note 3) is added dropwise while the temperature is maintained between 45 and 50. The resulting solution is cooled to about 35, and 92.5 g. (78.4 ml., 1 mole) of epichlorohydrin (Note 4) is added dropwise with stirring over a period of 20 minutes. The temperature is then raised to 45 and is kept at 4550 for 18 hours. The clear red-orange solution is cooled to 15, and chilled glacial acetic acid (6065 ml.) is added with stirring until the solution is just acid to litmus; a mush of sodium acetate crystals precipitates. The dropping funnel is replaced by a capillary tube, and the condenser is set for distillation. About three-fourths of the ethanol is removed under reduced pressure while air is bubbled into the mixture through the capillary tube (Note 5). Care is taken that the internal temperature does not exceed 100. The mushy residue is shaken with 250300 ml. of water until the sodium acetate dissolves. The oily layer of lactone is separated, and the aqueous phase is extracted with two 100-ml. portions of ether. The combined oil and ether extracts are washed with 150 ml. of water and dried overnight over anhydrous sodium sulfate. The ether is removed under reduced pressure, and the product is distilled from a modified Claisen flask. The fraction boiling at 160170/11 mm. is collected; refractionation yields 25 107114 g. (6164%) of product boiling at 164168/11 mm. or 151156/8 mm.; nD 1.48151.4830 (Note 6) and (Note 7).

2. Notes1. The sodium must be present in an equivalent amount for best results. When 0.2 g. atom of sodium was used, the yield was only 10%. 2. It is necessary to maintain strictly anhydrous conditions in this reaction. The apparatus should be carefully predried and the absolute ethanol freshly prepared either by the diethyl phthalate method2 or

by the magnesium ethoxide method.3 3. Eastman Kodak Company white label quality ethyl acetoacetate (b.p. 7879/11 mm.) was used. 4. Epichlorohydrin may be prepared from glycerol-,-dichlorohydrin.4 It is also commercially available. 5. Unless this precaution is taken, there is considerable bumping due to the presence of the solid sodium acetate in the mixture. 6. The product may become slightly colored upon standing. 7. This reaction is typical of those between the following epoxides and ethyl acetoacetate: Epoxide Boiling Point of Product% Yield of Product 54 49 60 46 77

Butadiene monoxide 148151/32 mm. Propylene oxide 138141/26 mm. Styrene oxide 164167/3 mm. Ethyl glycidyl ether 160163/1415 mm. 195197/1 mm. Phenyl glycidyl ether

3. Discussion-Acetyl--chloro--valerolactone has been prepared only by the condensation of epichlorohydrin with ethyl acetoacetate. The preparation described is based on the method of Traube and Lehman.5

References and Notes1. Hope College, Holland, Michigan. 2. Manske, J. Am. Chem. Soc., 53, 1106 (1931), footnote 9. 3. Lund and Bjerrum, Ber., 64, 210 (1931). Fieser, Experiments in Organic Chemistry, 3rd ed., p. 286, D. C. Heath and Company, Boston, Massachusetts, 1955. 4. Org. Syntheses Coll. Vol. 1, 233 (1941). 5. Traube and Lehman, Ber., 34, 1980 (1901).

Appendix Chemical Abstracts Nomenclature (Collective Index Number); (Registry Number)glycerol-,-dichlorohydrin ethanol (64-17-5) acetic acid (64-19-7) ether (60-29-7) sodium acetate (127-09-3) Epichlorohydrin (106-89-8) sodium sulfate (7757-82-6) propylene oxide (75-56-9)

sodium (13966-32-0) Ethyl acetoacetate (141-97-9) Styrene oxide (96-09-3) -Acetyl--chloro--valerolactone, Valeric acid, 2-acetyl-5-chloro-4-hydroxy-, -lactone (3154-75-4) Butadiene monoxide (930-22-3) Ethyl glycidyl ether (4016-11-9) Phenyl glycidyl ether (122-60-1)Copyright 1921-2005, Organic Syntheses, Inc. All Rights Reserved


1-ACETYLCYCLOHEXANOL[Ketone, 1-hydroxycyclohexyl methyl]

Submitted by Gardner W. Stacy and Richard A. Mikulec1. Checked by John C. Sheehan, George A. Mortimer, and Norman A. Nelson.

1. ProcedureIn a 1-l. three-necked round-bottomed flask, equipped with a sealed stirrer, a reflux condenser, a thermometer, and a dropping funnel, is dissolved 5 g. of mercuric oxide (Note 1) in a solution of 8 ml. of concentrated sulfuric acid and 190 ml. of water. The solution is warmed to 60, and 49.7 g. (0.40 mole) of 1-ethynylcyclohexanol (Note 2) is added dropwise over a period of 1.5 hours. After the addition has been completed, the reaction mixture is stirred at 60 for an additional 10 minutes and allowed to cool. The green organic layer which settles is taken up in 150 ml. of ether, and the aqueous layer is extracted with four 50-ml. portions of ether (Note 3). The combined ethereal extracts are washed with 100 ml. of saturated sodium chloride solution (Note 4) and dried over anhydrous sodium sulfate. The drying agent is removed, the ether is evaporated, and the residue is distilled under reduced pressure through a 15-cm. column packed with glass helices. The 1-acetylcyclohexanol is collected at 25 25 9294/15 mm. as a colorless liquid, nD 1.4670, d4 1.0248 (Note 5). The yield is 3738 g. (6567%).

2. Notes1. Mallinckrodt mercuric oxide red (analytical reagent or N.F. 1x grade) was used. 2. 1-Ethynylcyclohexanol is available commercially. It may be prepared as reported by Saunders.2 3. To facilitate subsequent extractions, the solid material remaining after separation of as much of the aqueous phase as possible should be removed by gentle suction filtration and washed with 25 ml. of ether. 4. The sodium chloride solution removes the green color from the ether extract, leaving a yellow solution. 25 5. The checkers found b.p. 100/21 mm., nD 1.46621.4665, d25 1.02351.0238. Others have reported 4 20 11 b.p. 9294/12 mm., d0 1.0256;3 b.p. 91/11 mm., nD 1.4726, d11 1.1033;4 b.p. 88.088.6/12 mm., 4 28 nD 1.4712.5 Establishing a criterion for the purity of the product is of particular importance because of the known tendency of ethynylcarbinols to undergo rearrangement.5,6 The authors have reported that consecutive small fractions of the distillate possess a constant boiling point and refractive index. Furthermore, representative fractions, treated with periodic acid and subsequently with 2,4-dinitrophenylhydrazine, give cyclohexanone 2,4-dinitrophenylhydrazone in 83% over-all yield in a high state of purity.

3. Discussion1-Acetylcyclohexanol has been prepared by the hydrolysis of 1-bromo-1-acetylcyclohexane3 and of 1-acetoxy-1-acetylcyclohexane oxime,7 by the hydration of 1-ethynylcyclohexanol,4,5,8,9,10,11,12 by the treatment of 1-hydroxycyclohexanecarboxylic acid with methyllithium13,14 and by the hydrolysis of 1(isopropoxyethoxy)-1-(1-iminoethyl)cyclohexane.15 and 1-(2-tetrahydropyranoxy)-1-(1-iminoethyl) cyclohexane.16 The present procedure is based upon that of Stacy and Mikulec for the preparation of 1acetylcyclopentanol.6

References and Notes1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. State College of Washington, Pullman, Washington. Org. Syntheses Coll. Vol. 3, 416 (1955). Favorskii, J. Russ. Phys. Chem. Soc., 44, 1339 (1912) [C. A., 7, 984 (1913)]. Locquin and Wouseng, Compt. rend., 176, 516 (1923). Newman, J. Am. Chem. Soc., 75, 4740 (1953). Stacy and Mikulec, J. Am. Chem. Soc., 76, 524 (1954). Wallach, Ann., 389, 191 (1912). Bergmann, Brit. pat. 640,477 [C. A., 45, 1622 (1951)]; U. S. pat. 2,560,921 [C. A., 46, 3072 (1952)]. Stacy and Hainley, J. Am. Chem. Soc., 73, 5911 (1951). Newman (to Ohio State University Research Foundation), U. S. pat. 2,853,520 [C. A., 54, 345 (1960)]. Papa, Ginsberg, and Villani, J. Am. Chem. Soc., 76, 4441 (1954). Hennion and Watson, J. Org. Chem., 23, 656 (1958). Billimoria and MacLagan, Nature, 167, 81 (1951); J. Chem. Soc., 1951, 3067. MacLagan and Billimoria, Brit. pat. 742,571 [C. A., 50, 16845 (1956)]. Tchoubar, Compt. rend., 237, 1006 (1953). Elphimoff-Felkin, Bull. soc. chim. France, 1955, 784.

Appendix Chemical Abstracts Nomenclature (Collective Index Number); (Registry Number)sulfuric acid (7664-93-9) ether (60-29-7) sodium chloride (7647-14-5) sodium sulfate (7757-82-6) mercuric oxide (21908-53-2) 2,4-Dinitrophenylhydrazine (119-26-6) 1-Ethynylcyclohexanol (78-27-3) 1-Acetylcyclohexanol, Ketone, 1-hydroxycyclohexyl methyl (1123-27-9) periodic acid cyclohexanone 2,4-dinitrophenylhydrazone (1589-62-4) 1-bromo-1-acetylcyclohexane 1-acetoxy-1-acetylcyclohexane oxime

1-hydroxycyclohexanecarboxylic acid Methyllithium (917-54-4) 1-(isopropoxyethoxy)-1-(1-iminoethyl)cyclohexane 1-(2-tetrahydropyranoxy)-1-(1-iminoethyl)cyclohexane 1-acetylcyclopentanolCopyright 1921-2005, Organic Syntheses, Inc. All Rights Reserved


2-p-ACETYLPHENYLHYDROQUINONE[Acetophenone, 4'-(2,5-dihydroxyphenyl)-]

Submitted by George A. Reynolds and J. A. VanAllan1. Checked by R. S. Schreiber and A. H. Nathan.

1. ProcedureIn a 500-ml. beaker equipped with a mechanical stirrer are placed 27 g. (0.2 mole) of paminoacetophenone (Note 1), 100 g. of chopped ice, and 53 ml. of concentrated hydrochloric acid (sp. gr. 1.19). To the stirred mixture is added, over a period of 5 minutes, a solution of 13.8 g. (0.2 mole) of sodium nitrite dissolved in 75 ml. of water. The stirring is continued for 15 minutes, during which all the insoluble amine hydrochloride reacts to form the soluble diazonium compound (Note 2). In a 4-l. beaker, equipped with a high-speed stirrer (Note 3), are placed 20 g. (0.185 mole) of quinone (Note 4), 34 g. (0.4 mole) of sodium bicarbonate, 50 g. of chopped ice, and 500 ml. of water. About 10 ml. of the above diazonium salt solution is added (Note 5). After the frothing has subsided (Note 6), the diazonium salt solution is added in 10- to 20-ml. portions over a period of about an hour (Note 7). The temperature of the reaction mixture is kept below 15 during this period by the addition of ice. After the diazonium salt solution has been added, the mixture is allowed to warm to room temperature, and the stirring is continued for an additional hour. The precipitate of 2-pacetylphenylquinone is collected on a Bchner funnel and washed thoroughly with approximately 1 l. of water. The yield of crude yellow-brown solid is 4041 g. (9698%). The melting point ranges from 125135 to 134136 (Note 8).

The crude quinone is dissolved in 250 ml. of chloroform (Note 9) and added to a solution of 40 g. of sodium hydrosulfite in 300 ml. of water. The mixture is shaken for 10 minutes, and the light-tan 2-pacetylphenylhydroquinone which precipitates from solution is collected on a Bchner funnel and dried. The yield of crude hydroquinone is 3237 g. (7892%). The melting point ranges from 175180 to 184194 (Note 10). A suspension of 35 g. (0.153 mole) of 2-p-acetylphenylhydroquinone in 77 ml. of acetic anhydride is treated with 0.5 ml. of concentrated sulfuric acid (sp. gr. 1.84). The hydroquinone goes into solution immediately with the evolution of much heat. The dark-colored solution is allowed to stand at room temperature overnight; then it is poured into 400 ml. of water. The acetylated material is collected by suction filtration and dried. The crude 2-p-acetylphenylhydroquinone diacetate is distilled at reduced pressure (b.p. 236241/1 mm. or 182190/0.1 mm.), and the hot distillate is poured into 20 ml. of nbutyl alcohol (Note 11). The product immediately separates as a colorless, crystalline mass, which is collected by suction filtration and dried. The yield is 3235 g. (6773%), m.p. 104105. To a 300-ml. three-necked round-bottomed flask, equipped with a sealed stirrer, a condenser, and a gas inlet tube, is added a solution of 34 g. (0.11 mole) of 2-p-acetylphenylhydroquinone diacetate in 140 ml. of hot methanol. The solution is cooled to room temperature, causing some of the hydroquinone diacetate to crystallize. A slow stream of nitrogen is passed through the suspension, and 70 ml. of methanol containing 6.1 g. of anhydrous hydrogen chloride is added. The reaction mixture is stirred at room temperature for 2 hours under nitrogen, during which period the hydroquinone diacetate gradually dissolves. The pale yellow solution is poured onto 500 g. of chopped ice, and the colorless or faintly yellowish solid is collected by suction filtration and dried. The yield of p-acetylphenylhydroquinone melting at 193194 is 24.8 g. (quantitative). The over-all yield of product based on quinone is 5066%.

2. Notes1. The purest grade of p-aminoacetophenone supplied by the Eastman Kodak Company was used without further purification. 2. This reaction has been successfully carried out on a 3-mole scale. 3. A "Lightnin" mixer (manufactured by the Mixing Equipment Company, Rochester, N. Y.) equipped with a propeller stirrer was used. If rapid stirring is not maintained, the reaction does not go to completion. 4. The checkers used a practical grade of quinone obtainable from the Eastman Kodak Company. 5. If nitrogen is not evolved immediately, the reaction may be initiated by the addition of a small amount of hydroquinone. 6. If the foaming becomes too violent, a few drops of octyl alcohol are added. 7. The checkers found it convenient to add the diazonium salt solution slowly from a dropping funnel. The time of addition was 2545 minutes. 8. Recrystallization from butanol gives material melting at 139140. The pure substance is reported to melt at 152153.2 9. Ethanol can also be used as a solvent but has the disadvantage of more readily dissolving the hydroquinone, thus making it necessary to evaporate the solution nearly to dryness. 10. It is difficult to purify the crude hydroquinone by recrystallization; therefore the remainder of the procedure is recommended in order to obtain a highly purified product. 11. The checkers found it convenient to crystallize the viscous distillate from 125 ml. of methanol by chilling a hot solution in the refrigerator overnight. A small second crop amounting to about 2 g. may also be obtained by concentration of the mother liquors.

3. DiscussionThis procedure is a modification of the method described for the preparation of 2chlorophenylhydroquinone.3 2-p-Acetylphenylquinone has been prepared by carrying out the coupling in alcohol solution in the presence of sodium acetate instead of sodium bicarbonate.2 Reduction by zinc, acetic acid, and a small amount of concentrated hydrochloric acid yielded 2-pacetylphenylhydroquinone.2

References and Notes1. Eastman Kodak Company, Rochester, New York. 2. Kvalnes, J. Am. Chem. Soc., 56, 2478 (1934). 3. B.I.O.S., Report 1146 (1946). [Reports obtainable from British Intelligence Objectives Subcommittee, 32 Bryanston Sq., London, W. 1.]

Appendix Chemical Abstracts Nomenclature (Collective Index Number); (Registry Number)ethanol (64-17-5) sulfuric acid (7664-93-9) hydrogen chloride, hydrochloric acid (7647-01-0) acetic acid (64-19-7) methanol (67-56-1) acetic anhydride (108-24-7) sodium acetate (127-09-3) chloroform (67-66-3) hydroquinone (123-31-9) sodium bicarbonate (144-55-8) nitrogen (7727-37-9) sodium nitrite (7632-00-0) sodium hydrosulfite (7775-14-6) butanol, n-butyl alcohol (71-36-3) zinc (7440-66-6) Quinone (106-51-4) octyl alcohol (111-87-5) Hydroquinone diacetate (1205-91-0)

2-chlorophenylhydroquinone (117-71-5) 2-p-Acetylphenylhydroquinone, p-acetylphenylhydroquinone, Acetophenone, 4'-(2,5-dihydroxyphenyl)- (3948-13-8) p-aminoacetophenone (99-92-3) 2-p-acetylphenylquinone 2-p-acetylphenylhydroquinone diacetateCopyright 1921-2005, Organic Syntheses, Inc. All Rights Reserved


-ACETYL-n-VALERIC ACID[Heptanoic acid, 6-oxo-]

Submitted by J. R. Schaeffer and A. O. Snoddy1. Checked by Richard T. Arnold and H. W. Turner.

1. ProcedureA solution of 368 g. of 96% sulfuric acid in 664 ml. of water is cooled to room temperature and placed in a 3-l. three-necked flask provided with a mechanical stirrer, a thermometer, and a dropping funnel. To this acid solution is added 114 g. (1 mole) of 2-methylcyclohexanol (Note 1). A mixture of 220 g. (2.2 moles) of chromic oxide (Note 2) in 368 g. of 96% sulfuric acid and 664 ml. of water is added from the dropping funnel to the 2-methylcyclohexanol suspension at such a rate that the temperature of the mixture remains at 30 2 (Note 3). Good agitation and an ice bath are necessary to control the temperature in this range. The mixture is stirred at 30 2 for 1 hour and then at room temperature until all the chromic oxide is consumed (Note 4). The sulfuric acid solution is extracted with ether until the returns from the ether extractions fall to an insignificant amount. Approximately 10 extractions with 200-ml. portions of ether are required (Note 5). The ether extracts are combined, and the ether is removed by distillation on the steam bath. The resulting crude -acetyl-n-valeric acid is a yellow liquid with a sharp odor and amounts to about 130 g. The crude acid is purified by distillation through a 30-in. Vigreux column, using a variable take-off, a reflux ratio of 3:1, and a pressure of 1 mm. A fore-run of approximately 30 g. of material distilling up to 122/1 mm. is obtained. The main fraction which distils at 122123/1 mm. is pure -acetyl-n-valeric acid and amounts to 6679 g. (4655%). The pure acid is a colorless crystalline hygroscopic solid which melts (sealed capillary) at 3435 and is miscible with water in all proportions. The literature records the melting point of -acetyl-n-valeric acid as ranging from 31 to 42.2,3,4

2. Notes1. Eastman Kodak Company practical grade 2-methylcyclohexanol was used in this preparation. 2. Technical grade chromic oxide (99.5% CrO3) in flake form was used. 3. An alcohol-Dry Ice bath is very convenient for this purpose; with this bath only about 45 minutes is needed for the addition of the chromic oxide solution. A water-ice bath can be used, but a longer time will be required for the addition of the chromic oxide solution. 4. The chromic oxide content of the mixture at any time may be determined by titrating a test portion against standard ferrous ammonium sulfate solution. If the mixture is allowed to stand overnight at room temperature without stirring, it will be free from chromic oxide. A convenient procedure is to perform the oxidation in the afternoon and the extraction the next day. 5. A liquid-liquid continuous extractor is convenient for extracting the crude acid from the aqueous solution. With such apparatus, it is possible to extract all the crude -acetyl-n-valeric acid from the aqueous acid in 68 hours. 6. The fore-run and the still residue contain some -acetyl-n-valeric acid. These fractions may be combined and redistilled to yield an additional 510% of -acetyl-n-valeric acid, but the low cost of the starting materials and the ease of preparing the crude -acetyl-n-valeric acid scarcely justify the labor unless a considerable number of batches are being prepared.

3. Discussion

-Acetyl-n-valeric acid has been prepared by the oxidation of 1-methylcyclohexene with potassium permanganate;5 by the oxidation of 2-methylcyclohexanone with chromic oxide and sulfuric acid,6,7 with neutral potassium permanganate,8 and by air in the presence of adipic acid and manganese nitrate;9 by the reaction of methylzinc iodide on the ethyl ester of adipic acid chloride, followed by saponification of the ester so obtained;10 by the saponification of the ethyl ester of diacetylvaleric acid;2 by the hydrolysis of ethyl -acetyl--cyanovalerate with boiling 20% hydrochloric acid;3 by the permanganate oxidation of 1-methyl-1,2-cyclopentanediol;11 and by the alkaline cleavage of 2-acetylcyclopentanone.12

References and Notes1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. Procter and Gamble Company, Ivorydale, Ohio. Perkin, J. Chem. Soc., 57, 229 (1890). Derick and Hess, J. Am. Chem. Soc., 40, 551 (1918). Blaise and Kohler, Compt. rend., 148, 490 (1909). Wallach, Ann., 329, 371, 376 (1903). Wallach, Ann., 359, 300 (1908). Ruzicka, Seidel, Schinz, and Pfeiffer, Helv. Chim. Acta, 31, 422 (1948). Acheson, J. Chem. Soc., 1956, 4232. Badische Anilin- und Soda-Fabrik, Ger. pat. 812,073 [C. A., 47, 2769 (1953)]. Blaise and Koehler, Bull. soc. chim., [4] 7, 222 (1910). Adkins and Roebuck, J. Am. Chem. Soc., 70, 4041 (1948). Hauser, Swamer, and Ringler, J. Am. Chem. Soc., 70, 4023 (1948).

Appendix Chemical Abstracts Nomenclature (Collective Index Number); (Registry Number)ethyl ester of adipic acid chloride sulfuric acid (7664-93-9) hydrochloric acid (7647-01-0) ether (60-29-7) Adipic acid (124-04-9) potassium permanganate (7722-64-7) ferrous ammonium sulfate (10045-89-3) 2-methylcyclohexanone (583-60-8) Heptanoic acid, 6-oxo-, -ACETYL-n-VALERIC ACID (3128-07-2) 2-methylcyclohexanol (583-59-5) chromic oxide (1308-38-9)

1-methylcyclohexene manganese nitrate (10377-66-9) methylzinc iodide ethyl -acetyl--cyanovalerate 1-methyl-1,2-cyclopentanediol 2-acetylcyclopentanone (1670-46-8) ethyl ester of diacetylvaleric acidCopyright 1921-2005, Organic Syntheses, Inc. All Rights Reserved


ACROLEIN ACETAL[Acrolein diethyl acetal]

Submitted by J. A. VanAllan1 Checked by T. L. Cairns and R. E. Benson.

1. ProcedureA warm solution of 3 g. of ammonium nitrate in 50 ml. of anhydrous ethanol is added to a mixture of 44 g. (52.4 ml., 0.79 mole) of acrolein and 144 g. (160 ml., 0.97 mole) of ethyl orthoformate, and the mixture is allowed to react at room temperature for 68 hours (Note 1). The light-red solution is filtered, 4 g. of sodium carbonate is added, and the reaction mixture is distilled from the sodium carbonate through a good column (Note 2). The fraction boiling at 120125 is acrolein acetal and weighs 7381 25 g. (7280%); nD 1.3981.407 (Note 3).

2. Notes1. Refluxing causes the formation of some resinous material. The solution remains warm for about 1.5 hours after mixing. 2. The column described by Pingert2 is suggested. 3. This reaction appears to be of general application; crotonaldehyde diethyl acetal is formed in 68% 25 yield; b.p. 145147; nD 1.409. (In this preparation the amount of ethyl orthoformate used is reduced to exactly one equivalent since it distils at 142143. For this particular acetal, it is preferable to use ethyl orthosilicate according to Helferich.3) Tiglylaldehyde diethyl acetal is formed in 79% yield; b.p. 25 158160; nD 1.419.

3. DiscussionThese have been reviewed previously.2,4 The procedure described above is an adaptation of a method reported in a German patent.5 It has been claimed that the reaction of acrolein with ethanol in the presence of hydrochloric acid2 produces a mixture of substances from which no acrolein acetal can be isolated.6 More recently it has been reported7 that acrolein acetal is formed in 62% yield from acrolein and ethanol in the presence of p-toluenesulfonic acid.

References and Notes1. 2. 3. 4. 5. 6. 7. Eastman Kodak Company, Rochester, New York. Org. Syntheses, 25, 1 (1945). Helferich, Ger. pat. 404,256 (1924) [Frdl., 14, 228 (19211925)]. Org. Syntheses Coll. Vol. 2, 17 (1943). Schmidt, Ger. pat. 553,177 (1932) [Frdl., 19, 229 (1932)]. Hall and Stern, Chem. & Ind. (London), 1950, 775. Weisblat, Magerlein, Myers, Hanze, Fairburn, and Rolfson, J. Am. Chem. Soc., 75, 5893 (1953).

Appendix

Chemical Abstracts Nomenclature (Collective Index Number); (Registry Number)ethanol (64-17-5) hydrochloric acid (7647-01-0) Acrolein (107-02-8) sodium carbonate (497-19-8) ammonium nitrate Ethyl orthoformate Acrolein acetal Acrolein diethyl acetal (3054-95-3) crotonaldehyde diethyl acetal ethyl orthosilicate Tiglylaldehyde diethyl acetal (51786-74-4) p-toluenesulfonic acid (104-15-4)Copyright 1921-2005, Organic Syntheses, Inc. All Rights Reserved


ALLOXAN MONOHYDRATE[Barbituric acid, 5,5-dihydroxy-]

Submitted by A. V. Holmgren and Wilhelm Wenner1. Checked by T. L. Cairns and R. W. Upson.

1. ProcedureIn a 2-l. three-necked, round-bottomed flask with glass joints are placed 850 g. of commercial glacial acetic acid and 100 ml. of water. The flask is fitted with a stirrer. One of the side necks carries a reflux condenser and a thermometer reaching to the bottom of the flask; the other is provided with a stopper which can be replaced by a powder funnel. The flask is surrounded by a water bath. At room temperature 156 g. (1.53 moles) of 9899% chromium trioxide (Note 1) is added, and the mixture is stirred for about 15 minutes to effect solution of the oxidizing agent. One hundred and twenty-eight grams (1 mole) of barbituric acid is added in the course of about 25 minutes in portions approximating 1520 g. The temperature of the mixture rises from about 2530 at the beginning of the reaction to 50 and is held at that value until all the barbituric acid has been added (Note 2). During the addition, alloxan monohydrate begins to crystallize. The temperature of the solution is held at 50 for 2530 minutes after completion of the addition of barbituric acid. Then the reaction slurry, which contains the major amount of alloxan monohydrate in crystalline form, is cooled to 510 and filtered through a 5-in. Bchner funnel fitted with a piece of filter cloth. The product is washed while still on the funnel with cold glacial acetic acid until the washings are practically colorless. In order to effect rapid drying, the acetic acid is finally washed out of the filter cake by means of 100 200 ml. of ether. The yellow alloxan monohydrate weighs 120125 g. (7578%) after drying; m.p. 254 (dec.). It is pure enough for most purposes (Note 3).

2. Notes1. This amount was found to give best yields. 2. It is very important that the temperature does not rise above 50. If the addition of barbituric acid is carried out too rapidly, the temperature rise cannot be checked satisfactorily and the yield may drop considerably. 3. If entirely pure alloxan monohydrate is desired, this material is recrystallized according to the directions in an earlier volume of this series.2

3. DiscussionThe methods for the preparation of alloxan have been reviewed earlier.2 The present method is essentially that of Wenner.3 This preparation is referenced from: Org. Syn. Coll. Vol. 4, 25

References and Notes1. Hoffmann-La Roche, Inc., Nutley, New Jersey. 2. Org. Syntheses Coll. Vol. 3, 37, 39 (1955). 3. Wenner, U. S. pat. 2,445,898 [C. A., 43, 2227 (1949)].

Appendix Chemical Abstracts Nomenclature (Collective Index Number); (Registry Number)acetic acid (64-19-7) ether (60-29-7) Barbituric acid (67-52-7) chromium trioxide (1333-82-0) Alloxan monohydrate (2244-11-3) Alloxan (50-71-5) Barbituric acid, 5,5-dihydroxy- (3237-50-1)Copyright 1921-2005, Organic Syntheses, Inc. All Rights Reserved


ALLOXANTIN DIHYDRATE

Submitted by R. Stuart Tipson1 Checked by T. L. Cairns and F. S. Fawcett.

1. ProcedureAn apparatus is assembled in the hood, as shown in Fig. 1. In the 2-l. globe-shaped separatory funnel H (stopcock J closed) is placed 1.3 l. of deaerated water (Note 1). Three-holed rubber stopper G (bearing the stem of a 125-ml. separatory funnel C with stopcock D closed, a long inlet tube E, and a short outlet tube F) is inserted in the neck of H. In the neck of C, a rubber stopper B, provided with an inlet tube A, is inserted. H is flushed with nitrogen (Note 2) admitted at E. To the water is added 16.0 g. (0.1 mole) of alloxan monohydrate (Note 3), and the mixture is stirred by the flow of nitrogen through E until the alloxan monohydrate has dissolved. The nitrogen flow is discontinued, and hydrogen sulfide (Note 4) is passed in at E until the mixture is saturated with this gas and the aqueous solution is free from opalescence (about 2 hours). Carbon disulfide (100 ml.) is now added, and the mixture is agitated for 5 minutes by means of the hydrogen sulfide gas stream. The carbon disulfide layer is then cautiously withdrawn through J and discarded, and the aqueous solution is washed once more with 100 ml. of carbon disulfide which is separated and discarded. The hydrogen sulfide flow is discontinued, and nitrogen is passed in at E for about 2 hours or until the gas emerging at F gives no more than a faint test for hydrogen sulfide with lead acetate paper. Fig. 1. Apparatus for preparation of alloxantin dihydrate.

Tubes E and F are now closed, stopper B is loosened, and C is flushed out with nitrogen admitted through tube A. Deaerated water (100 ml.) is placed in C, which is then flushed with nitrogen. To this water is added alloxan monohydrate (16.0 g.; 0.1 mole), and the mixture is stirred with A, while the nitrogen stream is continued, until the solid has dissolved. B is now pushed down to give a tight fit, a slight pressure of nitrogen is applied (at A), F and D are opened, and the solution is allowed to pass from C into H. To wash out traces of alloxan, a further 10 ml. of water is placed in C and run into H. D is closed, and nitrogen is passed in at E and out of F until the solutions are thoroughly mixed. E and F are now closed, and the mixture in H is allowed to stand until crystallization is complete (overnight). In the meantime, the stem of funnel H is inserted in one hole of the two-holed rubber stopper L (also bearing inlet tube K); L is inserted in the mouth of M (a 150-ml., Pyrex Bchner funnel with coarse, fritted-glass septum); and the stem of M is inserted in the rubber stopper N placed in the neck of a 2-liter Bchner flask P (side arm, Q). To flush out M and P, nitrogen is passed in at K and out of Q. K and Q are now closed, F is opened, and a slight pressure of nitrogen is applied at F. Q and J are opened, and, if necessary, slight suction is applied at Q. When all the suspension has passed out of H, the nitrogen stream is continued for a few minutes, to remove as much as possible of the liquid clinging to the precipitate in M. Then F, J, and Q are closed. The Bchner funnel M and its contents are quickly removed, placed in a vacuum desiccator (preflushed with nitrogen), and dried to constant weight, at room temperature, over phosphorus pentoxide and soda-lime. The yield is 2727.5 g. (8485%) (Note 5), (Note 6), and (Note 7).

2. Notes1. Deaerated water is prepared as follows. A boiling stone is added to distilled water which is then boiled under reflux for at least 5 minutes; it is cooled in ice to room temperature under an atmosphere of oxygen-free nitrogen. 2. For preparation of moist, oxygen-free nitrogen, the commercial gas is passed through (a) a 500-ml. Drechsel bottle containing a fresh solution of 25 g. of sodium hydroxide plus 5 g. of pyrogallol in 250 ml. of deaerated water, (b) a reversed, empty 500-ml. bottle, and (c) a 500-ml. bottle containing 250 ml. of deaerated water. 3. Alloxan monohydrate from Eastman Kodak Company is satisfactory. It is dried to constant weight over soda-lime and phosphorus pentoxide in the vacuum desiccator at room temperature. It should be colorless, and readily and completely soluble in 5 volumes of cold water. The sample employed assayed 99100% alloxan monohydrate (p. 23) by Tipson and Cretcher's method.2 4. Commercial hydrogen sulfide is passed through a (reversed) empty 500-ml. Drechsel gas-washing bottle and then through 250 ml. of deaerated water in a similar bottle (not reversed). 5. The solubility of alloxantin dihydrate in water at room temperature is about 0.29 g. per 100 ml. of solution.3 An additional 4 g. of product may be obtained by evaporation of the mother liquor to dryness at 25 under reduced pressure (nitrogen atmosphere). 6. The yield is slightly less if traces of crystals are left adhering to the inner walls of funnel H. The alloxantin obtained by dehydration of the product at 120150 under reduced pressure for 2 hours melts with decomposition in 0.5 to 1 minute when placed in a block heated to 245.4 7. The submitter reports that with minor modification the above hydrogen sulfide reduction procedure can be applied to the preparation of the dialuric acid monohydrate intermediate. The apparatus is assembled as in Fig. 1 with the exception that funnel C and its accessories are deleted. The above reduction procedure is followed initially, employing 500 ml. of deaerated water and 50 g. of alloxan monohydrate instead of the quantities shown above. After the saturation with hydrogen sulfide (determined by weighing) and the first agitation with carbon disulfide have been conducted as above, the funnel is assembled for filtration in an atmosphere of hydrogen sulfide (rather than nitrogen), and the suspension in H is filtered through M by manipulations analogous to those described. The colorless crystals of dialuric acid monohydrate are washed on the filter with an additional 100 ml. of carbon disulfide added portionwise via H, and, while wet with carbon disulfide and hydrogen sulfide, the crystals and funnel M are transferred to a shielded vacuum desiccator and dried over soda-lime and phosphorus pentoxide under high vacuum (Dry Ice-cooled trap). The yield is 4444.5 g. (8788%). Even at 300, the compound exhibits no true melting or gas evolution. Heated at 2 per minute in an aluminum block (initial temperature, 150) it appears unchanged at 200, turns faintly pink at 203206, and gradually becomes reddish brown (229232) and then purplish black at about 270.

3. DiscussionMethods of Preparation are reviewed in Org. Syntheses Coll. Vol. 3, 42 (1955). This preparation is referenced from: Org. Syn. Coll. Vol. 3, 42

References and Notes1. Mellon Institute of Industrial Research, Pittsburg, Pennsylvania. 2. Tipson and Cretcher, Anal. Chem., 22, 822 (1950). 3. Thunberg, Skand. Arch. Physiol., 33, 217 (1916) [C. A., 11, 456 (1917)]; Biilmann and Bentzon, Ber., 51, 522 (1918). 4. Org. Syntheses Coll. Vol. 3, 42 (1955).

Appendix Chemical Abstracts Nomenclature (Collective Index Number); (Registry Number)soda-lime sodium hydroxide (1310-73-2) hydrogen sulfide (7783-06-4) nitrogen (7727-37-9) carbon disulfide (75-15-0) pyrogallol (87-66-1) alloxantin (76-24-4) Alloxan monohydrate (2244-11-3) Alloxan (50-71-5) Alloxantin dihydrate (6011-27-4) phosphorus pentoxide (1314-56-3) dialuric acid monohydrate (444-15-5)Copyright 1921-2005, Organic Syntheses, Inc. All Rights Reserved


2-AMINO-4-ANILINO-6-(CHLOROMETHYL)-s-TRIAZINE[s-Triazine, 2-amino-4-anilino-6-(chloromethyl)-]

Submitted by C. G. Overberger and Francis W. Michelotti1. Checked by B. C. McKusick and F. W. Stacey.

1. ProcedureMethanol (225 ml.) is placed in a 500-ml. two-necked flask equipped with a mechanical stirrer and a reflux condenser. Sodium (6.8 g., 0.30 g. atom) in small pieces is dropped down the condenser into the stirred methanol. The resultant solution is cooled to room temperature, and 64 g. (0.30 mole) of 1phenylbiguanide hydrochloride (Note 1) is added. The mixture is stirred at room temperature for 20 minutes. The sodium chloride that precipitates is separated on a Bchner funnel and washed with 25 ml. of methanol. The combined filtrates, which contain 1-phenylbiguanide as the free base, are placed in a 500-ml. three-necked flask equipped with a mechanical stirrer, a drying tube containing calcium chloride, and a dropping funnel, and 36.8 g. (0.30 mole) of ethyl chloroacetate (Note 2) is added at room temperature with stirring. The mixture is stirred at room temperature for 14 hours, during which time 2-amino-4anilino-6-(chloromethyl)-s-triazine precipitates as a white solid. After being separated by filtration and air-dried, the triazine weighs 3740 g. and melts at 138140. The methanol filtrate is added to 500 ml. of cold water. The mixture is cooled in an ice bath with stirring for 2 hours and filtered to remove an additional 1012 g. of gray triazine, m.p. 140142. The total yield of crude product is 4752 g. The triazine is purified by recrystallizing it from 250 ml. of dioxane, using 2 g. of decolorizing carbon and filtering hot. The recrystallized triazine is dried for 5 hours at 60 (15 mm. pressure) in a vacuum oven (Note 3). It then weighs 3133 g. (4447%) (Note 4), m.p. 142143 (Note 5).

2. Notes1. 1-Phenylbiguanide hydrochloride can be obtained from American Cyanamid Company. If 1phenylbiguanide itself is available, the triazine can be prepared in the same way by dissolving 53 g. (0.30 mole) of 1-phenylbiguanide in 250 ml. of methanol, adding 36.8 g. of ethyl chloroacetate, and proceeding as before. The same yield is obtained whether one starts with the free base or its hydrochloride. 2. Ethyl chloroacetate from Fisher Scientific Company was used. 3. The checkers found that less rigorous drying failed to remove all the dioxane. 4. An additional 35 g. of the triazine, m.p. 141143, can be obtained by concentrating the dioxane filtrate to about 60 ml. and cooling the concentrate. 5. 2-Chloromethyl-4,6-diamino-s-triazine can be prepared in 82% yield by stirring a mixture of biguanide and ethyl chloroacetate in methanol in the same way.

3. Discussion2-Amino-4-anilino-6-(chloromethyl)-s-triazine has been prepared from 1-phenylbiguanide and ethyl chloroacetate in the presence of methanol2 or sodium methoxide at 40.3

References and Notes1. Polytechnic Institute of Brooklyn, Brooklyn, New York. 2. Schuller, U. S. pats. 2,822,364 and 2,848,452 [C. A., 52, 6807, 19169 (1958)]. 3. Shapiro and Overberger, J. Am. Chem. Soc., 76, 97 (1954).

Appendix Chemical Abstracts Nomenclature (Collective Index Number); (Registry Number)methanol (67-56-1) sodium chloride (7647-14-5) sodium methoxide (124-41-4) carbon (7782-42-5) sodium (13966-32-0) Ethyl chloroacetate (105-39-5) dioxane (5703-46-8) 1-phenylbiguanide hydrochloride 1-phenylbiguanide (102-02-3) triazine (289-96-3) 2-Amino-4-anilino-6-(chloromethyl)-s-triazine, s-Triazine, 2-amino-4-anilino-6-(chloromethyl)- (30355-60-3) 2-Chloromethyl-4,6-diamino-s-triazineCopyright 1921-2005, Organic Syntheses, Inc. All Rights Reserved


p-AMINOBENZALDEHYDE[Benzaldehyde, p-amino-]

Submitted by E. Campaigne, W. M. Budde, and G. F. Schaefer1. Checked by Cliff S. Hamilton and R. C. Rupert.

1. ProcedureTo 600 ml. of distilled water in a 1-l. beaker are added 30 g. (0.125 mole) of crystalline sodium sulfide nonahydrate (Note 1), 15 g. (0.47 g. atom) of flowers of sulfur, and 27 g. (0.67 mole) of sodium hydroxide pellets. The mixture is heated on a steam bath for 1520 minutes with occasional stirring and then poured into a 2-l. round-bottomed flask containing a hot solution of 50 g. (0.36 mole) of pnitrotoluene (Note 2) in 300 ml. of 95% ethanol. A reflux condenser is attached, and the mixture is heated under reflux for 3 hours. The resulting clear but deep red solution is rapidly steam-distilled until about 1.52 l. of condensate has been collected (Note 3). The distillate should be clear when the distillation is stopped. The residue in the 2-l. flask should have a volume of 500600 ml.; if less, it should be diluted to this volume with boiling water. The solution is rapidly chilled in an ice bath with occasional vigorous shaking and stirring to induce crystallization. After 2 hours in the ice bath the golden yellow crystals of p-aminobenzaldehyde are collected on a Bchner funnel and washed with 500 ml. of ice water to remove sodium hydroxide (Note 4). The product is immediately placed in a vacuum desiccator over solid potassium hydroxide pellets for 24 hours. The yield of p-aminobenzaldehyde, m.p. 6870, amounts to 1822 g. (4050%). The product contains some impurities but is pure enough for most purposes (Note 5). It should be stored in a sealed bottle (Note 6).

2. Notes1. Merck's reagent grade of sodium sulfide nonahydrate was used. Since sodium sulfide decomposes on contact with air, a freshly opened bottle should be employed. "Sodium Sulfhydrate" (Hooker Electrochemical Company hydrated sodium hydrosulfide) is also satisfactory; the amount should be based upon the formula NaHS2H2O, and an equivalent amount of sodium hydroxide in excess of the 27 g. is required. 2. The p-nitrotoluene used was Eastman Kodak Company practical grade. 3. The steam distillation should be carried out as rapidly as possible. The distillate contains ethanol, ptoluidine, and some unchanged p-nitrotoluene. It has been reported2 that a large amount of a dark oily tar may be present at this stage. Presumably it consists of Schiff's base polymers which have formed during the time necessary for reflux and steam distillation. The clear solution may be decanted from the oil, and the expected orange-yellow crystals of p-aminobenzaldehyde are obtained on cooling the solution. The oily tar may be dissolved in boiling acetic anhydride, and upon dilution of the reaction mixture with water and partial concentration, crude p-acetamidobenzaldehyde separates. The latter may be purified by dissolving it in hot sodium bisulfite solution and fractionally precipitating the aldehyde by the addition of sodium hydroxide solution. From 12.3 g. of intractable tars there were obtained a first fraction which consisted of a dark sludge which was discarded, a second fraction which weighed 5.2 g., m.p. 150, and a third which weighed 1.9 g., m.p. 147. The melting point of p-acetamidobenzaldehyde is recorded3 as 153. 4. It is sometimes necessary to suspend the precipitate in about 200 ml. of ice water, stir it vigorously,

and filter again to remove all traces of alkali. 5. The chief impurities are the polymeric condensation products of p-aminobenzaldehyde with itself. No satisfactory method for recrystallization has been found. If the melting point is high and a pure product is desired, it is best to extract with boiling water until the filtrate is clear, and extract the monomer from the water with ether. This procedure gives recoveries of 2530%. Readily purified aldehyde derivatives may be prepared in good yields from the crude polymer mixture. The oxime melts at 124, the azine at 245, and the phenylhydrazone at 175.4 If these derivatives are hydrolyzed, the same crude p-aminobenzaldehyde of broad melting range results. 6. Care must be taken to exclude all traces of acid fumes from p-aminobenzaldehyde, since they catalyze its self-condensation.

3. Discussionp-Aminobenzaldehyde has been prepared by the action of sodium polysulfide upon pnitrotoluene5,6,7,8 on which the method described is based. It can be prepared also from p-nitrobenzyl alcohol and sodium sulfide,6 by heating p-nitrobenzaldehyde with sodium bisulfite and decomposing the addition product with hydrochloric acid,9 by the reduction of p-nitrobenzaldoxime with ammonium sulfide3,10 and subsequent hydrolysis of the amino oxime, and by the decomposition of the benzenesulfonyl-hydrazide of p-aminobenzoic acid in the presence of powdered glass and sodium carbonate.11 This preparation is referenced from: Org. Syn. Coll. Vol. 3, 88

References and Notes1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. Indiana University, Bloomington, Indiana. Overberger, Private communication. Gabriel and Herzberg, Ber., 16, 2003 (1883). Walther and Kausch, J. prakt. Chem., [2] 56, 97 (1897). Geigy, Ger. pat. 86,874 (1895) [Frdl., 4, 136 (18941897)]; Friedlnder and Lenk, Ber., 45, 2087 (1912). Beard and Hodgson, J. Chem. Soc., 1944, 4. Mukherjee, Indian pat. 43,527 [C. A., 46, 7121 (1952)]. DeGarmo and McMullen (to Monsanto Chemical Co.) U. S. pat. 2,795,614 [C. A., 51, 16542 (1957)]. Meister Lucius and Brning, Ger. pat. 106,590 (1898) [Chem. Zentr., I 71, 1084 (1900)]. Cohn and Springer, Monatsh., 24, 87 (1903). Newman and Caflish, J. Am. Chem. Soc., 80, 862 (1958).

Appendix Chemical Abstracts Nomenclature (Collective Index Number); (Registry Number)sodium polysulfide ethanol (64-17-5) hydrochloric acid (7647-01-0)

ether (60-29-7) acetic anhydride (108-24-7) sodium hydroxide (1310-73-2) sodium carbonate (497-19-8) sulfur (7704-34-9) sodium bisulfite (7631-90-5) potassium hydroxide (1310-58-3) sodium sulfide (1313-82-2) ammonium sulfide p-Nitrobenzaldehyde (555-16-8) sodium hydrosulfide, Sodium Sulfhydrate sodium sulfide nonahydrate (1313-84-4) p-toluidine (106-49-0) benzenesulfonyl-hydrazide (80-17-1) p-Nitrobenzyl alcohol (619-73-8) p-aminobenzoic acid (150-13-0) p-nitrotoluene (99-99-0) p-Aminobenzaldehyde, Benzaldehyde, p-amino- (17625-83-1) p-nitrobenzaldoxime p-acetamidobenzaldehyde (122-85-0)Copyright 1921-2005, Organic Syntheses, Inc. All Rights Reserved


2-AMINOBENZOPHENONE[Benzophenone, 2-amino-]

Submitted by H. J. Scheifele, Jr. and D. F. DeTar1. Checked by R. T. Arnold and John D. Jones.

1. Procedure

A. p-Toluenesulfonylanthranilic acid. In a 5-l. three-necked flask equipped with a stirrer and a thermometer extending to the bottom of the flask are placed 1.5 l. of water and 260 g. (2.4 moles) of technical grade dry sodium carbonate (Note 1). While the mixture is warmed, 137 g. (1 mole) of anthranilic acid is added in three portions, and the temperature is raised to 70 to effect complete solution. The solution is allowed to cool to about 60, and 230 g. (1.2 moles) of technical ptoluenesulfonyl chloride is added in 5 portions over a period of about 20 minutes (Note 2). When all the p-toluenesulfonyl chloride has been added, the reaction mixture is maintained at 6070 for an additional 20 minutes. The temperature is raised to about 85, 10 g. of Norit is added cautiously, and the solution is filtered by suction through a previously heated Bchner funnel. In a 4-l. beaker equipped with a stirrer which can be operated above the liquid level to break the foam are placed 250 ml. of 12N hydrochloric acid and 250 ml. of water. The filtrate obtained above is cooled to about 50 and is added to the hydrochloric acid in small portions and at such a rate that the mixture does not foam over. If efficient stirring is used in the foam layer, this addition can be carried out in 5 minutes. The product is isolated by filtration through a Bchner funnel and is washed on the filter, first with a 250-ml. portion of dilute hydrochloric acid (prepared by diluting 50 ml. of 12N hydrochloric acid to about 250 ml.) to remove anthranilic acid, and then with 500 ml. of water. The product is sucked as dry as possible and is then spread in a thin layer and allowed to air dry for about 15 hours. When easily pulverizable, the material is transferred to an oven and dried for 3 hours at 100120. There is obtained 257265 g. (8891%) of p-toluenesulfonylanthranilic acid as a pale lavender powder with a neutral equivalent of 294300, which indicates a purity of 9799% (Note 3). This product is suitable for conversion to 2-aminobenzophenone, but it may be recrystallized by dissolving in hot 95% ethanol (10 ml. per g.) and then adding water (4 ml. per g.). The recovery in the first crop is about 75% of material melting at 229230 and having a neutral equivalent of 295. B. 2-Aminobenzophenone. In a dry 3-l. three-necked flask equipped with a stirrer, a reflux condenser connected to a hydrogen chloride trap, and a thermometer extending to the bottom of the flask are placed 146 g. (0.5 mole) of dry p-toluenesulfonylanthranilic acid, 1.5 l. of thiophene-free benzene, and 119 g. (0.57 mole) of phosphorus pentachloride. The mixture is stirred and heated at about 50 for 30 minutes. The murky solution (Note 4) is then cooled to 2025, and 290 g. (2.2 moles) of anhydrous aluminum chloride is added in 4 portions. When addition is complete, the dark mixture is heated with stirring at about 8090 for 4 hours. The mixture is cooled to room temperature and poured onto a mixture of 500 g. of ice and 40 ml. of 12N hydrochloric acid in a 5-l. round-bottomed flask. The benzene is best removed by vacuum distillation using a water aspirator (Note 5). The grainy, brown, crude product is separated by filtration on a Bchner funnel and washed thoroughly with dilute hydrochloric acid, with water, then with two 500-ml. portions of 5% sodium carbonate (to remove anthranilic acid and starting material), and finally with three 500-ml. portions of water (Note 6). The filter cake is sucked reasonably dry. The crude, moist sulfonamide is dissolved in 1.6 l. of concentrated sulfuric acid by warming on the steam bath for 15 minutes. The sulfuric acid solution is divided into two equal parts, each of which is placed in a 4-l. beaker. The beakers are cooled in ice baths while 1.6 kg. of ice is added slowly and with stirring to the contents of each beaker. During the addition of the ice, phenyl p-tolyl sulfone separates. A total of 50 g. of Norit is added, and the solution is filtered (Note 7) and (Note 8). The filtrates are best neutralized separately. Two 5-gal. crocks are half filled with crushed ice, and one-half of the total filtrate is poured into each. For neutralization, commercial 12N ammonium hydroxide is added slowly with stirring; a total of 4.8 l. is required. The solid is collected on a Bchner funnel, washed with water, and air-dried. The product is obtained in the form of bright yellow crystals, m.p. 103105. The yield is 6871 g. (6972% based on p-toluenesulfonylanthranilic acid). This material is dissolved in 1 l. of hot 95% ethanol, treated with 15 g. of Norit, and filtered. The hot solution is diluted with 700 ml. of hot water and cooled. After a second recrystallization, the yield of hexagonal yellow plates is 47 g.; m.p. 105 106. Another 6 g. of pure aminoketone can be recovered from the filtrate. The total yield of recrystallized 2-aminobenzophenone is 53 g. (54%) (Note 9).

2. Notes1. If sodium hydroxide is used, the main product is the p-toluenesulfonic acid salt of anthranilic acid. This salt has properties quite similar to those of the desired p-toluenesulfonylanthranilic acid but is useless for the preparation of 2-aminobenzophenone. 2. It is advisable to have sodium hydroxide solution available in case carbon dioxide is evolved indicating that the amount of sodium carbonate used was insufficient. There is a tendency for salts to precipitate from the mixture and for some foaming to occur if much less water is used. 3. The melting point of the p-toluenesulfonylanthranilic acid is not a good criterion of purity because the p-toluenesulfonic acid salt of anthranilic acid has about the same value. The neutral equivalents are widely different: 154 for the salt and 291 for p-toluenesulfonylanthranilic acid. The compound obtained in this preparation gives a negative test for anthranilic acid on diazotization and treatment with alkaline -naphthol solution. The probable impurity is the sodium salt of p-toluenesulfonylanthranilic acid. 4. When recrystallized p-toluenesulfonylanthranilic acid is used, the solution is clear at this point. The crude acid gives rise to a dark solution containing a small amount of suspended solid. The yield of 2aminobenzophenone is the same in either case. 5. Steam distillation may also be used but should not be prolonged. If the contents of the flask are kept below 80, the crude product is obtained as a fine powder. If the temperature becomes too high, the material melts and anthranilic acid is not easily removed from the solid mass obtained on cooling. 6. It is convenient to keep the wash solutions at 7580, but the temperature should not exceed 85 or part of the organic material will melt and clog the filter. It is advisable to transfer the solid to a 2-l. beaker to permit thorough washing. Most of the wash solution can be separated by decantation. 7. Phenyl p-tolyl sulfone may be isolated at this point by filtering the acid solution before using Norit. It can be purified by recrystallization from 95% ethanol; m.p. 125. 8. The temperature of the solution should be 3035. If too cold some of the product will be retained on the filter, and if too hot the filter paper will be attacked by the acidic solution. 2-Aminobenzophenone is a weak base and separates as the free base from sulfuric acid solutions below about 4N. 9. 4'-Methyl-2-aminobenzophenone can be prepared similarly by substituting toluene for benzene. The yield of crude material, m.p. 8588, is 70%. On recrystallization from 95% ethanol, using 5 ml. per g., there is obtained, in two crops, a 70% recovery of 4'-methyl-2-aminobenzophenone, m.p. 9293. Because of the higher temperature required in the steam distillation (Note 5), the sulfonamide is obtained in a form difficult to purify. As a result the crude aminoketone usually contains 12 g. of aluminum oxide.

3. DiscussionThe above procedure is essentially that of Ullmann and Bleier.2 2-Aminobenzophenone has also been prepared by reduction of 2-nitrobenzophenone,3 by the Hofmann reaction of the amide of obenzoylbenzoic acid with sodium hypobromite,4 by the action of an excess of benzoyl chloride on aniline at 220,5 and by hydrolysis of the acetyl derivative which is obtained by the action of phenylmagnesium bromide on 2-methyl-3,1,4-benzoxaz-4-one (from anthranilic acid and acetic anhydride).6 Various methods for the preparation of 2-aminobenzophenones have been summarized critically by Simpson, Atkinson, Schofield, and Stephenson.7

References and Notes1. Cornell University, Ithaca, New York. 2. Ullmann and Bleier, Ber., 35, 4273 (1902); Stoermer and Finche, Ber., 42, 3118 (1909). 3. Geigy and Koenigs, Ber., 18, 2400 (1885); Tatschaloff, J. prakt. Chem., [2] 65, 308 (1902); Gabriel and Stelzner, Ber., 29, 1300 (1896). 4. Graebe and Ullmann, Ann., 291, 8 (1896); Hewett, Lermit, Openshaw, Todd, Williams, and Woodward, J. Chem. Soc., 1948, 292. (The submitters have found that the Curtius procedure gives better results than the method of Hofmann; cf. P. A. S. Smith, in Adams, Organic

Reactions, Vol. 3, p. 337, John Wiley & Sons, New York, 1946.) 5. Chattaway, J. Chem. Soc., 85, 386 (1904). 6. Lothrop and Goodwin, J. Am. Chem. Soc., 65, 363 (1943). 7. Simpson, Atkinson, Schofield, and Stephenson, J. Chem. Soc., 1945, 646.

Appendix Chemical Abstracts Nomenclature (Collective Index Number); (Registry Number)p-toluenesulfonic acid salt of anthranilic acid 2-methyl-3,1,4-benzoxaz-4-one ethanol (64-17-5) sulfuric acid (7664-93-9) hydrochloric acid (7647-01-0) Benzene (71-43-2) acetic anhydride (108-24-7) aniline (62-53-3) sodium hydroxide (1310-73-2) phosphorus pentachloride (10026-13-8) sodium carbonate (497-19-8) -naphthol (135-19-3) carbon dioxide (124-38-9) Norit (7782-42-5) benzoyl chloride (98-88-4) aluminum chloride (3495-54-3) toluene (108-88-3) ammonium hydroxide (1336-21-6) Anthranilic Acid (118-92-3) Phenylmagnesium bromide (100-58-3)

sodium hypobromite aluminum oxide (1344-28-1) 2-Aminobenzophenone, Benzophenone, 2-amino- (2835-77-0) 2-nitrobenzophenone (2243-79-0) p-Toluenesulfonyl chloride (98-59-9) o-benzoylbenzoic acid (85-52-9) p-Toluenesulfonylanthranilic acid (6311-23-5) phenyl p-tolyl sulfone (640-57-3) sodium salt of p-toluenesulfonylanthranilic acid 4'-Methyl-2-aminobenzophenoneCopyright 1921-2005, Organic Syntheses, Inc. All Rights Reserved


-AMINOCAPROIC ACID[Hexanoic acid, 6-amino-]

Submitted by Cal Y. Meyers and Leonard E. Miller1. Checked by Richard T. Arnold and William R. Hasek.

1. ProcedureInto a 500-ml. round-bottomed flask containing 50 g. (0.44 mole) of 2-ketohexamethylenimine (caprolactam) is poured a solution containing 45 ml. of concentrated hydrochloric acid (sp. gr. 1.19) dissolved in 150 ml. of water. The mixture is boiled for 1 hour, and the resulting yellow solution is decolorized with Norit and evaporated to dryness under reduced pressure on a steam bath (Note 1). The resulting -aminocaproic acid hydrochloride is converted into the amino acid by means of a column containing Amberlite IR-4B resin (Note 2): 1. Construct the column as shown in Fig. 2. 2. Exhaustion. Pass a 1% aqueous hydrochloric acid solution through the column (downflow) until the pH of the solution leaving the column decreases from 5.56.5 to about 2. 3. Regeneration. Now pass a 1% aqueous sodium hydroxide solution through the column (downflow) until the solution leaving the column is strongly alkaline. 4. Classification. Wash the resin (upflow) with 10 l. of distilled water. 5. Wash the resin with distilled water (downflow) (Note 3) until the salts are all washed out and the pH of the washings is 5.66.5. The column is now ready for use (Note 4). Fig. 2.

The solid -aminocaproic acid hydrochloride is dissolved in 1 l. of distilled water. This solution is passed through the column (downflow) and followed by at least 2 l. of distilled water (Note 5). The collected solution (pink) is concentrated by distillation, under reduced pressure, to a volume of about 100 ml. (Note 6), and the resulting orange-colored solution is decolorized with Norit. After the addition of 300 ml. of absolute ethanol and 500 ml. of ether, followed by vigorous shaking, a white solid forms within a few minutes. The -aminocaproic acid is collected on a Bchner funnel and dried in a vacuum desiccator until no more ether-alcohol odor is detected. A yield of 52 g. (90%) is obtained; m.p. 202203.

2. Notes1. This hydrolysis is similar to that utilized previously.2 2. Obtained from the Resinous Products Division, Rohm and Haas Company, Philadelphia, Pennsylvania. The checkers found that this resin sometimes liberates carbon dioxide when treated with 1% hydrochloric acid. In such cases the total resin sample may be pretreated in a beaker with 1% hydrochloric acid until no more gas is evolved, and then a 30-in. (rather than 25-in.) column containing 1% hydrochloric acid is packed with resin. Further treatment of the resin is continued as described by the submitters. 3. Intermittent silver nitrate tests will indicate whether the solution is free of salts. 4. The liquid level of the column should always be above the resin when the column is not in use. 5. To assure the user that the resin is functioning, the eluant should be tested frequently for pH and the presence of salts. If the test for chloride ion becomes positive, or if the pH falls below 5.6, regeneration procedures are necessary; generally the column is good for two runs. 6. Excessive heating and excessive evaporation may result in peptide formation.

3. Discussion-Aminocaproic acid has been prepared by the hydrolysis of -benzoylaminocapronitrile,3 by the hydrolysis of diethyl -phthalimidobutylmalonate,4 from cyclohexanone oxime by rearrangement and hydrolysis,5 by hydrochloric acid hydrolysis of -caprolactam and removal of the acid by the use of

litharge, silver oxide, etc.,2 by alkaline hydrolysis of -caprolactam6 or by hydrolysis of caprolactam in the presence of a cation exchange resin,7 by the reduction of -cyanovaleric acid8 or the corresponding ethyl ester,9 and by the hydrogenation of -oximinocaproic acid.10

References and Notes1. University of Illinois, Urbana, Illinois. 2. Org. Syntheses Coll. Vol. 2, 28 (1943). 3. von Braun and Steindorff, Ber., 38, 117 (1905); von Braun, Ber., 40, 1839 (1907); Ruzicka and Hugoson, Helv. Chim. Acta, 4, 479 (1921); Marvel, MacCorquodale, Kendall, and Lazier, J. Am. Chem. Soc., 46, 2838 (1924); Sumitomo and Hachihama, Chem. High Polymers (Japan), 8, 332 (1951) [C. A., 48, 593 (1954)]. 4. Gabriel and Maass, Ber., 32, 1266 (1899). 5. Wallach, Ann., 312, 188 (1900); Eck and Marvel, J. Biol. Chem., 106, 387 (1934); Algemeene Kunstzijde Unie N.V., Ger. pat. 812,076 [C. A., 48, 6464 (1954)]; Nagasawa et al., Jap. pat. 7577 (1954) [C. A., 50, 10764 (1956)]. 6. Shpital'nyi, Shpital'nyi, and Yablochnik, Zhur. Priklad. Khim., 32, 617 (1959) [C. A., 53, 16005 (1959)]. 7. Itin and Kahr (to Inventa A.-G. fr Forschung und Patentverwertung), Brit. pat. 774,468 [C. A., 52, 2056 (1958)]. Shono and Hachihama, Chem. High Polymers (Japan), 8, 504 (1951) [C. A.,48, 10581 (1954)]. 8. 9. Chrtien, Ann. chim. (Paris), [13] 2, 682 (1957). 10. Chiusoli and Minisci, Gazz. chim. ital., 88, 261 (1958).

Appendix Chemical Abstracts Nomenclature (Collective Index Number); (Registry Number)alcohol, ethanol (64-17-5) hydrochloric acid (7647-01-0) ether (60-29-7) sodium hydroxide (1310-73-2) silver oxide (20667-12-3) silver nitrate (7761-88-8) carbon dioxide (124-38-9) Norit (7782-42-5) -AMINOCAPROIC ACID, Hexanoic acid, 6-amino- (60-32-2) 2-Ketohexamethylenimine, -caprolactam (105-60-2)

-aminocaproic acid hydrochloride -benzoylaminocapronitrile Cyclohexanone oxime (100-64-1) diethyl -phthalimidobutylmalonate -cyanovaleric acid (5264-33-5) -oximinocaproic acidCopyright 1921-2005, Organic Syntheses, Inc. All Rights Reserved


2-AMINO-3-NITROTOLUENE[o-Toluidine, 6-nitro-]

Submitted by John C. Howard1 Checked by Charles C. Price and Joseph D. Berman.

1. ProcedureA 1-l. three-necked flask is fitted with a sealed Hershberg stirrer, a reflux condenser, and a dropping funnel. The flask is charged with 650 ml. of acetic anhydride, and 107 g. (107 ml., 1 mole) of otoluidine (Note 1) is introduced from the dropping funnel. The mixture becomes very warm. After the amine has been completely added, the solution is cooled to 1213 in an ice-salt bath (Note 2). During the cooling, the dropping funnel and condenser are replaced by another dropping funnel containing 126 ml. (2 moles) of 70% nitric acid and a thermometer which can be read to within 0.5 in the range from 10 to 20 (Note 3). The nitric acid is added drop by drop to the cold slurry at a rate which maintains the temperature carefully within the limits of 1012 (Note 4). If the temperature persists in dropping, the addition is stopped after about 5 minutes. The ice bath is removed until the temperature rises 0.5, the ice-salt bath is replaced, and addition is continued. As the reaction progresses, the acetotoluide which may have precipitated redissolves, and the solution becomes deeply colored. The addition is complete in 12 hours, and the nitro compounds may start to separate. The solution is poured, with stirring, into 3 l. of ice water. The mixture of 4- and 6nitroacetotoluides precipitates as a creamcolored solid which is collected on a large Bchner funnel. After thorough washing with four 500-ml. portions of ice water, the precipitate is partly dried by suction (Note 5). The moist product is then placed in a steam-distillation apparatus (Note 6), covered with 300 ml. of concentrated hydrochloric acid, and heated until the mixture boils. The acetotoluides are rapidly hydrolyzed, and the solution becomes dark red. Steam is then introduced, and the distillation is thus continued until 36 l. of distillate has been collected (Note 7) and (Note 8). The 2-amino-3-nitrotoluene,

which separates as bright orange needles when the distillate is cooled, is collected on a large Bchner funnel. The dried product amounts to 7584 g. (4955%), m.p. 9294. The product may be further purified by a second steam distillation. Ten grams of the amine is distilled from 150 ml. of water, and 3 l. of distillate is collected, yielding 8.7 g. of 2-amino-3-nitrotoluene, m.p. 9596 (cor.).

2. Notes1. Commercially available o-toluidine, b.p. 7577/10 mm., is suitable. Redistillation of this material gave no significantly better results. The checkers obtained a 42% yield of 2-amino-3-nitrotoluene using practical grade o-toluidine directly, and a 57% yield after redistillation. 2. The flask should be immersed up to the neck in the slurry of ice and salt. During the cooling, the acetotoluide may suddenly precipitate, immobilizing the stirrer; a few turns manually break up the mass of crystals and allow the stirring to be continued. 3. A low-temperature thermometer with a range from 15 to +50 is suitable. 4. If the temperature is allowed to rise above 18, violent if not explosive decomposition may ensue. 5. The precipitate can be air-dried to a constant weight of 150160 g. 6. An efficient steam-distillation apparatus such as that described by Fieser2 is recommended. A 12-l. round-bottomed flask cooled in a tub of ice serves as the receiver, which is equipped with an auxiliary vertical condenser attached to a gas absorption trap3 to accommodate the hydrogen chloride which distils first. 7. The third 12-l. portion yields about 20 g. of 2-amino-3-nitrotoluene. The residue in the steamdistillation flask, about 20 g. of crude 2-amino-5-nitrotoluene, solidifies when cooled and may be separated by filtration. It can be recrystallized from 2 l. of hot water, yielding 1415 g. of yellow plates, m.p. 130131 (cor.). 8. Instead of separating the mixture of isomers by the slow steam distillation, one may employ the procedure of Wepster and Verkade.4 In the latter, the product from the nitration of o-methylacetanilide is treated with the Witt-Utermann solution,5 which consists of a water-alcohol solution of potassium hydroxide. 2-Acetylamino-5-nitrotoluene is insoluble in this solution, while the 3-nitro isomer is soluble and may be recovered in high yield and a good state of purity by acidification of the red filtrate. Hydrolysis of the acetyl derivatives affords 2-amino-5-nitro-and 2-amino-3-nitrotoluene.

3. Discussion2-Amino-3-nitrotoluene has been prepared by the nitration of oxalotoluide6 and by the nitration of o-acetotoluide in acetic acid with fuming nitric acid,7 with a mixture of nitric and sulfuric acid,8 or with metal nitrates.9 This preparation is referenced from: Org. Syn. Coll. Vol. 4, 291 Org. Syn. Coll. Vol. 9, 573

References and Notes1. Cornell University, Ithaca, New York. 2. Fieser, Experiments in Organic Chemistry, 3rd ed., p 257 (Figs. 45.4 and 45.5), D. C. Health and Company, Boston, Massachusetts, 1955. 3. Org. Syntheses Coll. Vol. 2, 4 (1943). 4. Wepster and Verkade, Rec. trav. chim., 68, 77 (1949). 5. Witt and Utermann, Ber., 39, 3901 (1906). 6. Hadfield and Kenner, Proc. Chem. Soc., 30, 253 (1914). 7. Cohen and Dakin, J. Chem. Soc., 79, 1127 (1901). 8. McGookin and Swift, J. Soc. Chem. Ind., 58, 152 (1939). 9. Kyryacos and Schultz, J. Am. Chem. Soc., 75, 3597 (1953).

Appendix Chemical Abstracts Nomenclature (Collective Index Number); (Registry Number)4- and 6-nitroacetotoluides 2-amino-5-nitro-and 2-amino-3-nitrotoluene nitric and sulfuric acid hydrogen chloride, hydrochloric acid (7647-01-0) acetic acid (64-19-7) acetic anhydride (108-24-7) nitric acid (7697-37-2) potassium hydroxide (1310-58-3) 2-amino-5-nitrotoluene (99-52-5) 2-Amino-3-nitrotoluene, o-Toluidine, 6-nitro- (570-24-1) acetotoluide (103-89-9) water-alcohol 2-Acetylamino-5-nitrotoluene o-toluidine (95-53-4) o-methylacetanilide, o-acetotoluide (120-66-1)Copyright 1921-2005, Organic Syntheses, Inc. All Rights Reserved


3-AMINOPYRIDINE[Pyridine, 3-amino-]

Submitted by C. F. H. Allen and Calvin N. Wolf1. Checked by Cliff S. Hamilton and Marjorie Debrunner.

1. ProcedureIn a 2-l. beaker equipped with a mechanical stirrer and immersed in an ice-salt bath is placed a solution of 75 g. (1.87 moles) of sodium hydroxide in 800 ml. of water. To the solution is added, with stirring, 95.8 g. (30.7 ml., 0.6 mole) of bromine. When the temperature of the solution reaches 0, 60 g. (0.49 mole) of nicotinamide (Note 1) is added all at once with vigorous stirring. After being stirred for 15 minutes, the solution is clear. The ice-salt bath is replaced by a bath containing water at 75, and the solution is stirred and heated at 7075 for 45 minutes. The solution is cooled to room temperature, saturated with sodium chloride (about 170 g. is required), and extracted with ether in a continuous extractor (Note 2). The extraction time is 1520 hours. The ether extract is adjusted to a volume of 1 l., dried over 45 g. of sodium hydroxide pellets, and filtered, and the ether is removed by distillation from a steam bath. The residue crystallizes on cooling. The yield of dark red crystals melting at 6163 is 3941 g. (8589%). The crude product is dissolved in a mixture of 320 ml. of benzene and 80 ml. of ligroin (b.p. 60 90) and heated on a steam bath with 5 g. of Norit and 2 g. of sodium hydrosulfite for 20 minutes. The hot solution is filtered by gravity, allowed to cool slowly to room temperature, and then chilled overnight in a refrigerator. The product is isolated by gravity filtration (Note 3), washed on the filter with 25 ml. of ligroin, and dried in a vacuum desiccator. The yield of white crystals melting at 6364 amounts to 2830 g. (6165%). By concentrating the combined filtrate and washings to a volume of 150 ml., an additional 23g. of pale yellow crystals melting at 6264 can be obtained. The total yield of 3aminopyridine is 3033 g. (6571%).

2. Notes1. The nicotinamide should be finely powdered to facilitate rapid solution. 2. The continuous extractor described by Pearl2 was used. If the material is extracted in a separatory funnel, four 800-ml. portions and ten 500-ml. portions of ether are required to give the above yield. 3. Since 3-aminopyridine is somewhat hygroscopic, it tends to liquefy if collected on a suction filter.

3. Discussion3-Aminopyridine has been prepared by heating nicotinamide in an alkaline potassium hypobromite solution at 70;3,4 by hydrolysis of -pyridylurethane with oleum;5 by heating 3-aminopyridine-2carboxylic acid at 250;6 by reduction of 3-nitropyridine with zinc and hydrochloric acid;7 by heating 3bromopyridine with ammonia and copper sulfate in a sealed tube,8,9 and by the hydrolysis of benzyl 3pyridylcarbamate, prepared from nicotinic acid hydrazide through the corresponding azide.10 This preparation is referenced from:

Org. Syn. Coll. Vol. 7, 27

References and Notes1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Eastman Kodak Company, Rochester, New York. Pearl, Ind. Eng. Chem., Anal. Ed., 16, 62 (1944). Camps, Arch. Pharm., 240, 354 (1902). Philips, Ann., 288, 263 (1895). Curtius and Mohr, Ber., 31, 2494 (1898). Gabriel and Colman, Ber., 35, 2833 (1902). Binz and Rth, Ann., 486, 95 (1931). Maier-Bode, Ber., 69, 1534 (1936). Gitsels and Wibaut, Rec. trav. chim., 60, 176 (1941). Sugasawa, Akahoshi, Toda, and Tomisawa, J. Pharm. Soc. Japan, 72, 192 (1952) [C. A., 47, 6418 (1953)].

Appendix Chemical Abstracts Nomenclature (Collective Index Number); (Registry Number)ligroin -pyridylurethane hydrochloric acid (7647-01-0) ammonia (7664-41-7) Benzene (