A N
`
`A D V A N C ED
`
`L A B O R A T O RY
`
`M A N U AL
`
`or
`
`O R G A N IC
`
`C H E M I S T RY
`
`BY
`
`MICHAEL H E I D E L B E R G E R, B.S., A.M., P H . D.
`ASSOCIATE IX CItEMIBTnV, IIOCKEFEIJJ-n INSTITUTE
`TOIt MEDICAL IlEflEARCH
`
`BOOK
`
`DEPABTMENT
`
`The CHEMICAL CATALOG COMPANY,
`Inc.
`19 EAST 24TH STREET, NEW YORK, U. S. A.
`1923
`
`Liquidia's Exhibit 1036
`IPR2020-00770
`Page 1
`
`
`
`A D V A N C ED
`
`L A B O R A T O RY
`
`M A N U AL
`
`or
`
`O R G A N IC
`
`C H E M I S T RY
`
`BY
`
`MICHAEL H E I D E L B E R G E R, B.S., A.M., P H . D.
`ASSOCIATE IX CItEMIBTnV, IIOCKEFEIJJ-n INSTITUTE
`TOIt MEDICAL IlEflEARCH
`
`BOOK
`
`DEPABTMENT
`
`The CHEMICAL CATALOG COMPANY,
`Inc.
`19 EAST 24TH STREET, NEW YORK, U. S. A.
`1923
`
`Liquidia's Exhibit 1036
`IPR2020-00770
`Page 1
`
`
`
`COPYRIGHT, 1923, BY
`The CHEMICAL CATALOG COMPANY, Ino.
`
`All Bighta Reserved
`
`Press of
`J, J Uttte & Ivos Company
`HOT York, U. S. L.
`
`Liquidia's Exhibit 1036
`IPR2020-00770
`Page 2
`
`
`
`TO
`N. T. H.
`
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`IPR2020-00770
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`
`Liquidia's Exhibit 1036
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`
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`Liquidia's Exhibit 1036
`IPR2020-00770
`Page 4
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`Liquidia's Exhibit 1036
`IPR2020-00770
`Page 4
`
`
`
`P R E F A C E .
`
`In the field of organic chemistry there are a number
`of elementary laboratory manuals, any one of which
`may be used to the student's advantage. When
`it
`comes to the choice of a guide for an advanced course,
`however, there is a vast amount of material available
`from which a selection in the form of a laboratory
`manual has never been made. Hence the student is
`often permitted to follow some line in which he is
`interested, regardless of its practicability or its value
`from the standpoint of training, or else the planning
`of the experiments devolves entirely upon the instructor.
`With the object of providing a brief advanced course
`in manipulative organic chemistry embodying experi-
`ments scattered as widely as possible over the important
`types of substances and reactions, the author desires
`to present this little book in the hope of rendering
`simpler the task both of the advanced student and his
`instructor.
`It has been the writer's aim to select experiments of
`greater difficulty than those ordinarily included m ele-
`mentary manuals, but to avoid preparations of so diffi-
`cult or involved a nature as to become a source of dis-
`couragement rather than a stimulus to the student.
`In
`this connection a word of apology may be necessary
`for including as much as has been done of the work
`of Dr. Walter A. Jacobs of the Rockefeller Institute
`and the writer, but it is very strongly felt that the value
`of a volume such as the present one depends largely on
`the personal experience of its author, and for this rea-
`5
`
`Liquidia's Exhibit 1036
`IPR2020-00770
`Page 5
`
`
`
`6
`
`-PREFACE
`
`son the writer has drawn freely on his own work an
`that -of his colleagues.
`It has been attempted also 1
`preserve as just a balance as possible between the chen
`istry of aliphatic and aromatic compounds, and to u
`elude products of technical and biological, as well \
`theoretical importance, in order to provide as broad
`foundation as possible for the student in his futui
`work.
`In the selection of experiments, care has bee
`taken to exclude those involving great expense, and
`further economy is effected by the use of many of tl
`initial products as steps in the synthesis of others.
`Finally, the author takes great pleasure in acknow
`edging his indebtedness to his colleagues at the Rock
`feller Institute for Medical Research for the use <
`their records in individual experiments, to Prof Ma
`ston T Bogert of Columbia University for some ve
`pertinent suggestions, and to Prof John 'M Nelson <
`Columbia University, whose encouragement and hel
`ful advice stimulated the writer to the preparation <
`this manual
`
`MICHAEL HEIDELBERGER.
`New York City, December, 1922.
`
`Liquidia's Exhibit 1036
`IPR2020-00770
`Page 6
`
`
`
`TABLE OF CONTENTS
`
`PREFACE
`
`INTRODUCTORY WARNING
`
`CHAPTER I. NITRATION AND NITROSATION
`A. c^Nitraniline
`B.
`/>-Nitroso-0-cresol
`
`.
`
`CHAPTER II. HALOGENATION
`A. Chloroacetone
`B. dZ-a-Bromopropionic acid
`C. 5-Iodo-2-toluidine
`
`.
`
`..
`
`SUBSTITUTIONS
`CHAPTER III.
`A. Ethylene cyanohydrin
`(3-Chloropropionic acid
`P-Bromopropionic acid
`B. Benzylamine
`C. w-Aminophenol
`D. 0-Nitrophenylarsonic acid
`
`.
`
`ESTERIFICATION, ETHERIFICA-
`IV.
`CHAPTER
`TION, DE-AUCYLATION, AND RELATED REAC-
`TIONS
`A. Methyl Anthranilate
`B. p-Nitrophenoxyacetic acid
`7
`
`..
`
`.
`
`.
`
`PAGE
`5
`
`n
`
`13
`13
`16
`
`18
`18
`20
`21
`
`23
`23
`23
`24
`24
`28
`29
`
`32
`32
`33
`
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`
`
`8
`
`TABLE OF
`
`CONTENTS
`
`C. w-Phenetidine
`D. Allyl Phenyl Ether and Its Molecular
`Rearrangements
`.
`.
`.
`.
`1. Allyl bromide .
`.
`2. Allyl phenyl ether
`.
`3. o-Allylphenol
`.
`.
`4. 0-Propenylpheftol
`.
`5
`a-Methylcoumarane
`.
`E. Dihydrocupreine
`.
`.
`..
`
`..
`.
`
`.
`
`..
`.
`
`.
`
`PAGE
`34
`
`36
`36
`37
`- 37
`•
`39
`39
`41
`
`- 45
`CHAPTER V
`REDUCTION
`.
`.
`..
`A. With stannous chloride-
`p-Ammodi-
`.
`.
`methylamline
`.
`.
`..
`B. With
`ferrous sulfate and ammonia-
`/>-Aminophenoxyacetic acid
`.
`.
`C. With sodium amalgam dl-1 -Phenyl-1-
`hydroxy-2-aminoethane
`.
`D. With palladium black. Dihydroqumine
`
`45
`
`46
`
`. 48
`50
`
`CHAPTER VI. OXIDATION
`
`.
`
`.
`
`..
`
`,
`
`.
`
`54
`
`54
`
`A. With potassium f erricyanide: jt»-Nitro-
`o-cresol
`.
`B. With nitrites: Isonitrosoc&gaphor and
`Campj^rqumone
`.
`.
`..
`C. With aft^ospherk oxygen: Camphoric
`58
`acid
`59
`.
`.
`D. With bromine • Calcium gluconate
`E. With hydrogen peroxide:
`rf-Arabinose 61
`
`55
`
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`
`
`
`TABLE OF CONTENTS'
`
`FORMATION OF HETEROCYCLES
`CHAPTER VII.
`.
`AND DYES
`.
`A. Diethylmalonic ester
`Diethylbarbitunc acid, "Veronal," "Bar-
`bital"
`.
`B. 9-Methylacndme
`C Quinicine (quinotoxine) hydrochloride
`D Meldola's blue
`E Rosindulme
`.
`Rosindone
`
`.
`
`.
`
`..
`
`.
`
`CHAPTER V I I I. SUGARS, PROTEINS, AND A M I N O-
`ACIDS
`A.
`
`..
`.
`[3-Glucose
`..
`.
`(3-Glucose penta-acetate
`B. Hydrolysis of a Biose- Galactose from
`lactose
`.
`.
`.
`..
`..
`C. Preparation of d/-alanine
`.
`D. Separation of dZ-alanine into its optical
`isomers
`.
`.
`1. Benzoylation of alanine
`2.
`/-Benzoylalanine
`.
`.
`3. Z-Alanine
`4. d-Alanine
`E. Crystalline egg albumin
`
`..
`
`.
`..
`
`PREPARATION AND REACTIONS OF
`CHAPTER IX.
`ORGANOMETALLIC COMPOUNDS
`.
`.
`..
`A, Direct arsenatipn of phenol. p-Hydroxy-
`pftenylarsonic acid
`
`g
`PJ.QH
`
`64
`64
`
`65
`66
`6j
`70
`71
`73
`
`74
`74
`75
`
`76
`78
`
`79
`80
`80
`81
`82
`83
`
`88
`
`88
`
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`
`
`
`i o
`
`TABLE OF
`
`CONTENTS
`
`(Arsphena-
`B. Synthesis of Salvarsan
`mme), 3,3'-diammo-4,4'-dihydroxyar-
`senobenzene dihydrochlonde
`.
`..
`1. 3-Nitro-4-hydroxyphenylarsomc
`acid
`.
`2 Reduction of the nitro acid .
`.
`C. Mercuric compounds of aniline .
`1. />-Aminophenylmercunc acetate
`2 />-Mercuri-&«-anilme
`.
`..
`
`PAGE
`
`92
`
`92
`93
`96
`gt
`9^
`
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`
`
`I N T R O D U C T O R Y W A R N I N G.
`
`The student will remember from his elementary
`course that many organic reactions, harmless under con-
`trolled conditions, may gather speed and violence if not
`carefully watched. Every experiment should therefore
`be considered as a whole from the point of view of its
`potential sources of danger, and a plan of procedure
`mapped out accordingly.
`If the reaction is accompanied by a rise of tempera-
`ture, even if no minimum is specified m the directions,
`accidents may often be prevented by keeping a pot of
`ice water or freezing mixture at hand, into which the
`vessel may be plunged in time to prevent boiling over or
`decomposition.
`If gases such as hydrobromic acid, for
`example, are evolved, the reaction should be carried out
`under the hood, and the vapors led into a flask of water
`by a tube terminating above the surface.
`Many a weary repetition may also be avoided by
`keeping in pots as much as possible large flasks or
`beakers containing material on which much time has
`been expended.
`It should also be kept in mind that most organic
`compounds are more or less toxic and many are ex-
`tremely dangerous. Distillations other
`than under
`diminished pressure should therefore be carried out
`under the hood, and care should be taken to avoid con-
`tact of the substances handled with the skin, or inhala-
`tion of their vapors or dusts. The writer still has vivid
`ii
`
`Liquidia's Exhibit 1036
`IPR2020-00770
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`
`
`
`
`
`12 INTRODUCTORY WARNING
`
`recollectl.ons of several extremely uncomfortable days
`
`
`
`
`
`
`
`many years ago as a result of getting minute traces of
`
`O CHBr2
`CHBr2
`
`, on his fing er tips
`ro-tetrabromo-o-xylene,
`
`and thence indirectly on lus face and into his eyes.
`
`
`
`
`which are When worlang therefore with substances
`ng the student
`known to be irritati
`will find it advisable
`
`
`
`to wear rubber gloves. Dried crystalline material or
`
`
`
`
`powders should also be transferred under the hood, a
`
`
`
`precaution which it is particularly unsafe to overlook in
`
`
`the case of the alkaloid, arsenic, and mercury deriva
`
`
`tlves of which the preparation is described in the fol
`
`lowing pages.
`The student will also frequently handle highly in
`
`
`
`
`
`
`
`
`flammable solvents, and must therefore remember that
`
`
`many painful and even fatal accidents have resulted
`
`
`
`from working with these near a flame or electric switch.
`
`
`While there need be no occasion for timidity, it must
`
`
`be borne i'h mind that constant vigilance and concen
`
`tration are the price that must be paid for the joys, the
`
`
`sahsfaction, and the thrills that come to those who work
`
`in organic chemistry.
`
`Liquidia's Exhibit 1036
`IPR2020-00770
`Page 12
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`
`
`L A B O R A T O RY
`A N A D V A N C ED
`M A N U AL OF O R G A N IC
`C H E M I S T RY
`
`I. N I T R A T I ON A ND NITROSATION.
`(See also p. 92)
`
`A. Nitration.
`
`o-Nitraniline, o-O2NCaH4NHfl.
`In the nitration of benzene, it will be remembered,
`only one mononitro compound was capable of forma-
`tion, and the by-product occurring in the reaction was
`w-dinitrobenzene:
`
`NO2
`
`NO2
`
`If one substituent ia already present in the benzene
`nucleus,1 however, the case becomes more complicated,
`and using aniline or its acetyl derivative as an example,
`three fsotineric monotiitro derivatives are theoretically
`possible c
`
`13
`
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`
`
`14 ADVANCED
`
`LABORATORY
`
`MANUAL
`
`NHCOCH3
`
`|NO2
`
`NHCOCH3
`
`o-Nitro-acetamlide.
`
`w-Nitro-acetamlide.
`
`J N O,
`
`NHCOCHa
`
`NO2
`
`p-Nitro-acetanilide.
`
`The relative amounts of the position isomers formed
`vary within wide limits according to the conditions
`used, for if one nitrates aniline itself in cold, concen-
`trated sulfunc acid a relatively large proportion of
`metQr and para- mtranilines are the chief products,
`while if acetanilide is nitrated in the same solvent the
`para- nitro derivative is obtained almost exclusively.
`If the nitration is carried out in an excess of
`fuming
`nitric acid the main product is again the para- com-
`pound, with only 6 to 8 per cent of o-nitramline. Witt
`and Utermann1 found, however, that by carrying out
`the nitration in glacial acetic acid in the presence of
`acetic anhydride as dehydrating agent, about 75 per
`cent of the acetanilide nitrated was converted into the
`ortho- compound, the remainder being p-nitro-acetan-
`llide. By this method
`large amounts of o-nitran-
`1Ber. 39, 3901 (1906), 41, 3090 (1908).
`
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`
`
`OF ORGANIC CHEMISTRY
`
`15
`
`ihne can readily be prepared. Batches of the size
`given below may be conveniently handled in the labora-
`tory.
`Nitration.
`90 g. of acetanihde are dissolved by warming
`gently in a mixture of 80 g of acetic anhydride and
`44 g. of glacial acetic acid, and the solution is then
`chilled
`in
`ice-water. 50 g. of fummg nitric acid
`(d 1.52) are mixed with 46 g. of glacial acetic acid,
`also cooled, and added in small portions to the chilled
`acetanilide solution, from which a portion of
`the
`acetanihde may separate. The mixture is stirred well
`with a thermometer, adding the nitric acid solution
`slowly enough to prevent the temperature from rising
`above that of the room, and controlling the speed of the
`reaction by immersing in ice-water when necessary.
`When the tendency of the temperature to rise becomes
`very slight the reaction mixture should be removed
`from the ice-water and allowed to stand 24 hours at
`room temperature. Care should be taken by cooling
`occasionally if necessary during the first hour or two
`that the reaction does not become too vigorous. The
`next day the mixture is poured on to ice, stirred well,
`and the crude crystalline o-nitro-acetamhde filtered off,
`washed well with ice-cold water, and sucked as dry as
`possible.
`Separation of Isomers.
`In the meantime a mixture of one volume, of 50 per
`cent aqueous potassium hydroxide, 4 volumes of water,
`and one volume of alcohol is prepared, cooled to o°,
`and the nitration product thoroughly rubbed up (in
`portions) in a chilled mortar with about 600 cc. of the
`solution. The onitro-acetanilide dissolves, while the
`bare*- compound remains insoluble in the cold mixture
`ind is sucked off and washed with a little of the cold
`
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`
`
`
`16 ADVANCED
`
`LABORATORY
`
`MANUAL
`
`solution, then with a little ice-cold water. After re-
`crystalhzation from water the yield is 20 g, melting at
`207 °.
`Saponification.
`The filtrate and washings from the crude paro nitro
`derivative are now allowed to come to room tempera-
`ture, and on letting stand for 24 hours saponification
`occurs and pure o-nitraniline separates in long, orange
`red needles, the reaction being as follows:
`o-CH8CONHC6H4NO2 -f H2O
`> CH8COOH +
`H N C H NO
`just as acetamide, CH8CONH2, when warmed with
`dilute alkali, splits into acetic acid and ammonia. After
`washing with ice-cold water the yield of o-nitraniline is
`30-40 g., melting at 71 50.
`
`B. Nitrosation.
`OH
`
`p-Nitroso-o-cresol, 1
`
`j CHa.
`
`NO
`
`While the nitrosation of phenols occurs at least as
`readily as that of tertiary aromatic amines -such as
`dimethylanilme, the conditions must be very carefully
`controlled owing to the ease with which most phenols
`oxidize. For this reason a higher proportion of tarry
`by-products is formed and the yields are smaller than
`in the case of the dialkylanilines. Taking o-cresol as
`a typical example of a phenol with an unsubstituted
`para- position, the main product of the reaction is
`^-nitroso-o-cresol«
`
`Liquidia's Exhibit 1036
`IPR2020-00770
`Page 16
`
`
`
`OF ORGANIC CHEMISTRY
`
`17
`
`54 g. of o-cresol are dissolved in 4 liters of ice-water
`in a battery jar provided with an adequate mechanical
`stirrer, and 34 5 g of 100 per cent sodium nitrite (or an
`equivalent amount of a less pure salt) are then added.
`Since nitrosation is effected by means of free nitrous
`acid and not its salts no reaction takes place at this
`point A solution of 18.5 cc. of concentrated sulfuric
`acid in 500 cc. of water is then added through a
`dropping funnel during one-half to three-quarters of
`an hour, keeping the temperature between 50 and io°
`by means of additional ice, and stirring continually.
`In this way the nitrous acid reacts with the cresol as
`fast as liberated to yield the ^-nitroso compound, and
`since any local excess of nitrous acid is largely avoided
`by the slow addition of the sulfuric acid and the efficient
`stirring, the formation of tarry by-products is reduced
`to a minimum While the nitroso compound may
`separate oily at first, it soon crystallizes. After stand-
`ing in the cold for one to two hours after the addition
`of the sulfuric acid the mixture is filtered on a large
`Buchner funnel and washed with ice-cold water. The
`resulting brown solid is purified by dissolving in 10
`per cent sodium carbonate solution, stirring with bone-
`black to collect insoluble tar, and filtering into an excess
`of dilute sulfuric acid. 40-45 g. of the nitroso com->
`pound should be obtained in this way as glistening,
`orange-brown scales melting at 1340.
`
`Liquidia's Exhibit 1036
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`
`
`18 ADVANCED
`
`LABORATORY
`
`MANUAL
`
`I I. H A L O G E N A T I O N.
`
`A. Chlorination.
`
`Chloroacetone, C1CH2COCH8
`If acetone be treated with a chlorinating agent such
`as phosphorus pentachloride, the keto group is at-
`tacked and 2,2-dichloro-propane, CH8CClaCH8, results.
`If, however, elementary chlorine is used, the hydrogen
`atoms of the methyl groups are successively replaced.
`Not only is a mixture of mono- and poly-chlorinated
`acetones formed, but the hydrochloric acid liberated
`condenses the acetone to products of higher molecular
`weight, of which mesityl oxide may be taken as an
`example.
`
`CH8
`
`CH8
`
`> CO + H8CCOCH8
`
`CH8
`=>
`CH8
`
`>C .CHCOCHa.
`
`Thus, unless some substance is at hand to bind the
`hydrochloric acid as fast as formed, exceedingly com-
`plex mixtures are obtained from which it is virtually
`impossible to isolate pure products; mesityl oxide, for
`instance, boiling at practically the same point as mono-
`chloroacetone. Fritsch1 found that small pieces of
`marble were very satisfactory, as these reacted at once
`with the hydrochloric acid liberated, and his method
`is accordingly the basis of that given below.
`
`M«« 279, 313 (1894).
`
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`IPR2020-00770
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`
`
`
`19
`
`OF ORGANIC CHEMISTRY
`Chlorination.
`21 g. of marble, broken into small pieces, and 84 g.
`of acetone are placed in a flask provided with an inlet
`tube, dropping funnel, and reflux condenser, and
`warmed to 400 in a water bath. A slow stream of
`chlorine is then passed in and enough water (a total
`of 50 to 60 cc. slowly dripped in to keep in solu-
`tion the calcium chloride formed by interaction of
`the marble and hydrochloric acid This is also aided
`by frequent agitation of the flask. The reaction must
`be very carefully watched, for if a yellow color develops
`(and according to Khng2 this usually happens at the
`lower reaction temperature originally given by Fritsch)
`it indicates the formation of hypochlorous acid, and
`this, if it accumulates, may react explosively with the
`acetone
`In the event, then, that the solution turns
`yellow the stream of chlorine is at once interrupted
`until the coloration disappears. When only a little
`marble is left, the reaction is discontinued, for although
`a large excess of acetone is present the main product
`would
`be
`the
`symmetrical
`dichloro
`derivative,
`C1CH2COCH2C1, if this excess were not maintained.
`The mixture is allowed to stand at 400 until the evolu-
`tion of carbon dioxide ceases, making sure that an ex-
`cess of marble is present, and is then poured off from the
`marble into a separatory funnel. The two layers formed
`are separated and the lower, consisting of a strong
`aqueous solution of calcium chloride, is discarded.
`Fractionation.
`The upper layer of acetone and its chlorination
`products is fractionated with the aid of a good distill-
`ing column, the monochloroacetone boiling at 118-200.
`The yield is 16.8 g., plus an additional 5 g. on refrac-
`tionation of the lower and upper fractions.
`
`'Bull, soc chvm. [3] 33, 32a (1905).
`
`Liquidia's Exhibit 1036
`IPR2020-00770
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`
`
`
`20 ADVANCED
`
`LABORATORY
`
`MANUAL
`
`The chloro-acetones are extremely irritating, both in
`vapor form and if dropped on the skin. Gloves should
`be worn and all operations conducted under the hood.
`This applies to the next experiment as well.
`
`B. Bromination.
`
`di-a-Bromopropionic Acid, CH8CHBrCO2H.
`The method used depends upon the fact that although
`acetic acid and its homologs react with difficulty with
`bromine, the anhydrides and acid bromides readily
`yield bromo substitution products.8
`Acid Bromide.
`To 50 g. of propionic acid and 7.6 g. of dry amor-
`phous phosphorus are added, drop by drop, 66 7 g. of
`bromine, at about which point evolution of hydro-
`bromic acid ceases. Through the intermediate forma-
`tion of phosphorus bromides the acid is converted into
`the bromide according to the equation (Zehnsky):
`>
`4CH8CH2COaH + P + 5Br
`4CH8CHsCOBr + P O ( O H )8 + HBr.
`Bromo Acid Bromide.
`In order now that substitution should take place it is
`unnecessary to isolate the acid bromide—-the mixture
`is simply warmed to 40-50 ° on the water bath, using
`a reflux condenser, and an additional ip$ & ef bromine
`is added drop by drop, the reaction b e | %:
`CHaCH3COBr + BrB —» CH8CHBrCGBr + HBr.
`Bromination proceeds rapidly and may be considered
`complete two Ijoursi after all of the bromine has been
`added, Bromoprogiony! 'bromide boils at 154° under
`
`, Ber. 14, api (1881); VbiSiard, Arm 242, 141 (1887);
`, Ber. 20. 2036 (18S7) ; We&fe, Ann. 280, 247 (1894).
`
`Liquidia's Exhibit 1036
`IPR2020-00770
`Page 20
`
`
`
`OF ORGANIC CHEMISTRY
`
`2\
`
`atmospheric pressure, but distillation of the mixture is
`then difficult, and it is accordingly purified by distilla-
`tion in a moderate vacuum. The yield is 75-80 per
`cent of the theory.
`Bromo Acid.
`If an ester of a-bromopropionic acid were desired
`the appropriate alcohol would now be used, but as the
`acid itself is required, the bromide is decomposed by
`addition of one and one-third equivalents of water, the
`mixture being shaken under a reflux condenser, with a
`pot of ice close at hand, until homogeneous, and finally
`warmed for one-half hour on the water-bath. The
`solution is then cooled, treated with several volumes
`of ether, dried over sodium sulfate, and concentrated.
`When fractionated in vacuo the residue boils mainly at
`124 ° under a pressure of 18-19 mm. and solidifies in
`a freezing mixture, then melting at about 25 °. The
`acid should be protected from the moisture of the air,
`as it is quite hygroscopic.
`It is also a powerful skin
`irritant. The yield should be 60 per cent of the bro-
`mide used.
`
`C.
`
`Iodination.
`
`5-Iodo-2-toluidine,
`
`CH8
`
`NH <0
`
`In general the introduction of iodine into the aro-
`matic nucleus is not as readily effected as in the case of
`chlonne or bromine, butarornaticamines unsubstitutedin
`the paro- position nevertheless react easily with iodme.
`* Wheeler and Liddle, Am. Chem. I. 4a, 501 (igog).
`
`Liquidia's Exhibit 1036
`IPR2020-00770
`Page 21
`
`
`
`22 ADVANCED LABORATORY
`
`MANUAL
`
`An equimolecular amount of iodine is dissolved in
`o-toluidine, substitution taking place with evolution of
`heat and conversion of one-half of the base into the
`hydnodide, according to the equation:
`2CH8CaH4NH2 + I2
`>
`I(CH8)CaH8NH2 + CH8C6H,NHa.HI.
`In order to utilize the remainder of the o-toluidine and
`iodine the reaction is completed by heating the mixture
`under a reflux condenser with an equal volume of
`water, 2 molecular equivalents of powdered calcium
`carbonate, and 2 volumes of ether to take up the iodo
`base formed, the entire reaction being represented by
`2 + 2l2 + CaCO8
`>
`2l(CH3)CeH8NH2 + Cala + CO2 + HaO.
`After one hour's heating the ether is allowed to boil off
`and the mixture is distilled with steam, the iodo com-
`pound passing over slowly m a yield of 75 per cent of
`the theory. The practically pure product is dried and
`recrystallized from ligroin, forming prisms which melt
`at 90-1 °.
`
`Liquidia's Exhibit 1036
`IPR2020-00770
`Page 22
`
`
`
`OF ORGANIC CHEMISTRY
`
`23
`
`I I I.
`
`S U B S T I T U T I O N S.
`
`A. (3-Chloropropionic Acid.
`
`aa
`1. Ethylene Cyanohydrin,
`32 g of ethylene chlorohydnn, C1CH2CH2OH, are
`dissolved in 160 cc of absolute alcohol and boiled under
`a reflux condenser To the boiling liquid is added,
`drop by drop, a solution of 27.2 g. of potassium cyanide
`in 42 cc of water, and the boiling continued for 8-10
`hours. A precipitate of potassium chloride forms, and
`at the end this is filtered off, washed with a little alcohol,
`and the filtrate concentrated to a syrup and fractionated
`m vacuo. The yield of cyanohydrin should be 20 g.,
`boiling at u o° under 15 mm pressure.
`2. p-Chloropropionic Acid, C1CH2CH2CO2H.
`10 g. of ethylene cyanohydrin are heated in sealed
`tubes at ioo° with 75 cc. of concentrated hydrochloric
`acid for three hours
`If the cyanohydrin is boiled with
`dilute sodium hydroxide2 or warmed with acid in
`dilute alcohol,8 hydrolysis of the mtnle or CN group
`occurs,
`
`»
`HOCHaCH8CN -f 3H2O
`HOCH2CH2COOH + NH<OH,
`and the so-called hydracrylic acid is formed, among
`other products.
`If, on the other hand, the cyanohydrin
`aMoureu, Bull, soc chim [3] g, 426 (1893); Jacobs and
`Heidelberger, J. Am. Chem Soc 39, 1465 (1917),
`•Wislicenus, Ann 128, 6 (1863)
`•Erlenmeyer, Ann. 191, 268 (1878),
`
`Liquidia's Exhibit 1036
`IPR2020-00770
`Page 23
`
`
`
`24 ADVANCED
`
`LABORATORY
`
`MANUAL
`
`is heated in a sealed tube with concentrated hydro-
`chloric acid, not only is the nitrile group saponified to
`carboxyl, but chlorine replaces the hydroxyl group,*
`the end result being
`HOCH2CH2CN + 2HCI + H2O
`>
`C1CH2CH2COOH + NH<C1.
`There is no evidence at hand as to whether the inter-
`mediate product is hydracrylic acid or ClCHjCH2CN,
`or both, although it is known that [3-chloropropionic
`acid can be prepared from the former."
`just
`The contents of the tubes are diluted with
`enough water
`to dissolve
`the ammonium chloride
`which has separated and extracted repeatedly with
`ether, thorough extraction being necessary, as
`the
`chloropropionic acid is also quite soluble in water.
`After drying the ethereal extracts over anhydrous
`sodium sulfate and concentrating, a syrupy residue is
`left, which crystallizes readily on cooling and rubbing
`with a rod The yield should be 10.5 g. Recrystallized
`from ligroin, it melts at 38.5-9 50 (corr.).
`Similarly 10 g. of ethylene cyanohydrin, boiled three
`hours with 100 cc. of hydrobromic acid (d 1.49) and
`worked up in the same way, yield 17 g. of (3-bromo-
`propionic acid, melting at 60-1 ° (corr.) after recrys-
`tallization from ligroin.
`
`B. Benzylamine, C6H5CH2NH8.
`Benzylhexamethylenetetraminium Chloride.
`70 g. of benzyl chloride are added to a suspension
`of 70 g. of finely powdered hexamethylenetetr«»mine in
`4 parts of chloroform, heated to boiling under ^ reflux
`condenser on the water bath, and removed if necessary
`* Jacobs and Heidelberger, loc. cit.
`"Beckurts and Otto, Ber, 18, 236 (1885).
`
`Liquidia's Exhibit 1036
`IPR2020-00770
`Page 24
`
`
`
`OF ORGANIC CHEMISTRY
`
`25
`
`until the initially often vigorous reaction is over. The
`mixture is then heated one-half hour longer, placing
`the flask on a cork or rubber ring to protect it from
`the bumping which usually occurs
`This method, of course, is an indirect one for replac-
`ing the halogen of benzyl chloride by ammonia.
`If
`ammonia itself is used, the usual mixture of primary,
`secondary, and tertiary bases is formed, and the yield
`of primary benzylamine is poor. Dele"pine6 found,
`however, that the primary amme was the main product
`if benzyl chloride was first combined with hexameth-
`ylenetetramine and the resulting compound suitably
`decomposed As the method is of wide application for
`the preparation of primary amines it is given here.
`As is well known, formaldehyde and ammonia com-
`bine to yield hexamethylenetetramine, C0HiaN4. Duden
`and Scharff7 found that most of the reactions of this
`substance could be explained on the basis of the three
`dimensional formula.
`
`Among its other properties, hexamethylenetetramine
`combines with one molecular equivalent of an aliphatic
`8 Del6piri«, Bull soc. chim. [3] 17, 393 (1897).
`TPydc8 and Scharff, Am. a88, 218 (1895).
`
`Liquidia's Exhibit 1036
`IPR2020-00770
`Page 25
`
`
`
`26 ADVANCED
`
`LABORATORY
`
`MANUAL
`
`halide, RX, such as methyl iodide or benzyl chloride,
`to yield quaternary ammonium salts of
`the
`type
`CeH12N4.RX,8 just as trimethylamine forms quaternary
`salts of the type (CH8)8N.RX. The chief objection
`to the Duden and Scharff formula is that the reaction
`stops when one equivalent of halide has reacted, while
`according to the formula, which postulates four tertiary
`nitrogen atoms, four molecules of halide should com-
`bine with one of hexamethylenetetramme. However,
`only one enters into reaction, and for our present pur-
`pose the equation is:
`^TT ^ „
`
`> CeH12N4 <
`
`C6H8CHaCl + CaHl aN4
`C1
`Isolation of the Salt
`The reaction mixture is cooled, filtered, and the
`salt washed with a little chloroform and sucked dry
`The yield should be 90 per cent of the theory. The
`salt darkens above 1800 and melts at 1920
`If some of the salt is dissolved in a little water and
`boiled, formaldehyde is evolved, and the solution sud-
`denly becomes turbid, owing to the decomposition of
`the quaternary salt to yield methylene-benzylamine,
`CaHBCH2N CHa, and as this product is fairly stable,
`vigorous treatment is necessary for its hydrolysis, as
`will be seen below.
`Decomposition.
`The salt is transferred to a distilling flask provided
`with a condenser and treated with the theoretical
`amounts of 95 per cent alcohol and concentrated hydro-
`chloric acid according to the equation:
`CflHiaN4.CeHBCH2Cl + 3HC1 + i2C2H8OH
`>
`6CH2(OCaHB)3 + 3NH.C1 + C6HBCHaNHa.HCl,
`"An indication of the extent to which RX may be varied
`may be obtained by glancing through / Bxol Chetn, 20, 659,
`685; ax, 103, 145, 439, 455, 4^5 (1915).
`
`Liquidia's Exhibit 1036
`IPR2020-00770
`Page 26
`
`
`
`OF ORGANIC CHEMISTRY
`
`27
`
`the formaldehyde split off combining at once with the
`alcohol
`to form methylal." The flask is rotated
`gently until the salt is dissolved and then warmed care-
`fully until crystals of ammonium chloride begin to
`separate, removing the source of heat until certain that
`the reaction does not become violent. The liquid sepa-
`rates into two layers, of which the upper is mainly
`methylal. When this no longer increases it is distilled
`off, and the residue in the flask cooled and filtered.
`The mixture of ammonium chloride and benzyl-
`amine hydrochloride on the filter is washed with some
`of the hydrochloric acid-alcohol mixture, the filtrate
`returned to the flask, and treated with one-third of the
`original amount of acid-alcohol mixture. A volume
`of liquid equal to that added is now distilled off, and
`the process again repeated, by which time the distillate
`should be free from methylal. As stated above, a
`methylene compound is initially formed, the equation
`being:
`
`CflHiaN4.CeHBCH2Cl + 3HCI + ioCaH6OH
`>
`5CHa(OC2H6)a + 3NH4C1 + CeH8CH8N:CH2.HCl,
`and the prolonged treatment described is necessary in
`order to decompose this completely.
`Benzylaminc.
`The final residue in the flask and the crystals already
`filtered off are dissolved in water, chilled, and the solu-
`tion made alkaline with strong sodium hydroxide solu-
`tion or solid sodium carbonate. The amine layer is
`separated, dried over a few sticks of sodium hydroxide,
`and distilled.
`A representative run started with 70 g. of hexa-
`methylenetetramine and 70 g. of benzyl chloride gave
`129 g. of the quaternary salt, which in turn yielded 45 g.
`of pure benzylamine, boiling at 1840.
`
`Liquidia's Exhibit 1036
`IPR2020-00770
`Page 27
`
`
`
`28 ADVANCED
`
`LABORATORY
`
`MANUAL
`
`C. rn-Aminophenol,
`
`OH
`
`*
`
`INH.
`
`Of the methods for the preparation of this substance
`two would seem best suited for laboratory use
`In
`the first place, one can start with w-nitranilme, diazo-
`tize this, and decompose the diazo compound by boil-
`ing with dilute acid, forming m-nitrophenol, but as the
`yield is not very good and the nitrophenol must sub-
`sequently be reduced to the ammo compound, the
`method is scarcely suited for the preparation of con-
`siderable amounts of this material. On the other hand,
`the method involving the direct replacement of one of
`the hydroxyl groups of resorcinol, w-CeH4(OH)a by
`ammonia, was found to be very satisfactory.
`The direct replacement of a phenolic hydroxyl group
`by the ammo group is relatively difficult in the benzene
`series, requiring high temperatures, although it takes
`place somewhat more readily m the case of the naph-
`thols.
`If, for example, resorcinol and ammonia alone
`are heated under pressure, a high reaction temperature
`is required, and the yield of m-ammophenol is poor.
`If, however, ammonium chloride is present,9 the reac-
`tion may be carried out at a lower temperature and
`the yield is more satisfactory.
`200 g. of resorcinol, 120 g. of ammonium chloride,
`and 400 cc of 10 per cent aqueous ammonia are heated
`in an autoclave in a bath the temperature of which is
`2200, the heating being continued for 14 hours after
`the pressure reaches a constant value The yields are
`smaller if the heating is earned out at a lower tem-
`perature or for a shorter period and are not improved
`"Ger pat 49,060.
`
`Liquidia's Exhibit 1036
`IPR2020-00770
`Page 28
`
`
`
`OF ORGANIC CHEMISTRY
`
`29
`
`by longer heating. After the autoclave and contents
`have cooled, the mixture is concentrated to dryness in
`vacuo, taken up in 650-750 cc. of hot water, and allowed
`to cool. 90-100 g. of crude m-aminophenol separate
`on standing in the cold. The filtrate is acidified strongly
`with concentrated hydrochloric acid and shaken out
`several times with ether to remove unchanged resor-
`cinol. The aqueous liquor is then treated with an
`excess of ammonia and again shaken out with ether,
`an additional 30-35 g. of aminophenol being recovered.
`The crude product is recrystallized from 2-3 parts of
`water, about 115 g. separating as sandy crystals melt-
`ing at 1230.
`
`AsO8Ha
`
`D. o-Nitrophenylarsonic Acid, ]
`
`J NO2.
`
`The student is already familiar with the replacement
`of the aromatic ammo group by the cyano- and halogen
`residues by means of the Sandmeyer reaction, and its
`conversion into the phenol group through the diazo
`rea
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