PAGE 1 OF 15
`
`SENJU EXHIBIT 2104
`LUPIN v SENJU
`IPR2015-01105
`
`

`
`
`
`Chemistry of Organic Compounds
`
`© 1965 by W. B. Saunders Company. Copyright 1951 and 1957 by W. B. Saunders Compa.ny.
`Copyright under the International Copyright Union. All rights reserved. This book is protected
`by copyright. No part of it may be duplicated or reproduced in any manner without written
`permission from the publisher. Made in the United States of America.
`Press of W. B. Saunders
`Company. Library of Congress catalog card number 65-10290.
`
`PAGE 2 OF 15
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`PAGE 2 OF 15
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`

`
`CHAPTER TWE.NTY-FOUR
`
`AROMATIC AMINES
`
`A‘ AND PHOSPHINES
`
`
`
`Compounds classed as aromatic amines have an amino group or an alkyl- or aryl-
`substituted amino group attached directly to an aromatic nucleus. Usually they are made
`by a procedure different from those for aliphatic amines and undergo additional reactions.
`Aromatic phosphines resemble the amines only in structure. Their methods of preparation
`and reactions are entirely different.
`
`Nomenclature
`
`AMINES
`
`Aromatic amines may be primary, secondary, or tertiary, and in the secondary or
`tertiary amines, the second or third hydrocarbon group may be alkyl or aryl. Usually the
`primary amines are named as amino derivatives of the aromatic hydrocarbon or as aryl
`derivatives of ammonia, but some are known best by common names such as aniline
`or toluidine.
`
`NH?
`
`(3
`
`Aniline
`(aminobenzene)
`
`CH3
`
`QNHZ
`
`o—To1uidine
`(0-aminoto luene)
`
`NH2
`
`QNH2
`
`m-Phenylenediamine
`(m—dz'amz'no benzene)
`
`Secondary and tertiary amines are named as derivatives of the primary amine, or as deriv-
`atives of ammonia.
`’
`
`N(CH3)2
`
`N,N—Dimethy1aniline
`(z1'i7m't/1ylmzz'[im')
`
`QNHO
`Diphenylamine
`
`Preparation
`
`1. By Reduction of More Highly Oxidized Nitrogen Compounds. Aromatic nitro
`compounds yield a series of reduction products, the final product being the primary amine
`(Fig. 23-1 , p. 519). Therefore primary aromatic amines may be prepared from nitro com-
`pounds or from the less highly oxidized nitroso, hydroxylamino, azoxy, azo, and hydrazo
`compounds, by reduction with alkaline hydrosulfite or with sodium and ethanol.
`2. By Ammonolysis of Halogen Compounds. Halogen attached to an aromatic
`nucleus usually is very stable to hydrolysis or ammonolysis, and rather drastic conditions
`are required to bring about reaction, which may occur with rearrangement (p. 495). If,
`however, electron-attracting groups are present in the art/20 and para positions, the halogen
`
`
`
`PAGE 3 OF 15
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`PAGE 3 OF 15
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`

`
`
`
`2 :
`
`-
`z.
`
`e.
`
`3‘
`
`524
`
`CHEMISTRY OF ORGANIC COMPOUNDS
`
`is more easily displaced. Thus 2,4,6—trinitrochlorobenzene (picryl c/zloride) reacts readily with
`ammonia to yield 2,4,6-trinitroaniline (picramzde) by an SIVATQ mechanism (p. 496).’
`
`Cl
`
`OZN
`
`N02
`
`,
`+ '2 NH; —>
`
`OQN
`
`NH;
`N02
`
`°
`+ NH4Cl
`
`N02
`2,4,6—Trinitrochlorobenzene
`( pier}! c}zlarz'dc)
`
`N02
`2,4-,6—Trinitroaniline
`( /Jz'cmmz'de)
`
`Physical Properties
`
`The physical properties of the aromatic amines are about what would be expected_
`just as benzene (b.p. 80°) boils at a higher temperature than n-hexane (b.p. 69°), so
`aniline (b.p. 184°) has a higher boiling point
`than n-hexylamine (b.p. 130°). The
`greater difference in the boiling points of the second pair may be ascribed to the fact that
`aniline has a higher dipole moment
`(p. : 1.6) than n-hexylamine (p. : 1.3). N-Methyl-
`aniline (b.p. 195°) boils at a higher temperature than aniline, but N,N-dimethylaniline
`(b.p. 193°) boils at a lower temperature than methylaniline despite the increase in the
`number of electrons because proton bonding is not possible for dimethylaniline.
`Aniline is considerably more soluble in water (3.6 g. per 100 g. of water) than n—hexyl~
`amine (0.4 g. per 100 g. of water). Water dissolves in aniline to the extent of about 5 per
`cent. Aniline is miscible with benzene but not with n-hexane.
`
`As is true for all of the disubstituted benzenes, the pam—substituted anilines, being the
`most symmetric, have the highest melting point. Thus /2-toluidine is a solid at room tem-
`perature whereas both the ortho and meta isomers are liquids.
`
`Physiological Properties
`
`like the aromatic hydrocarbons and their halogen and nitro
`The aromatic amines,
`derivatives, are highly toxic. The liquids are absorbed readily through the skin, and low
`concentrations of the vapors produce symptoms of toxicity when inhaled for prolonged peri-
`ods. Aniline vapors may produce symptoms of poisoning after several hours of exposure to
`concentrations as low as 7 parts per million. Aniline affects both the blood and the nerv-
`ous system. Hemoglobin of the blood is converted into methemoglobin with reduction of
`the oxygen-carrying capacity of the blood and resultant cyanosis. A direct depressant action
`is exerted on heart muscle. Continued exposure leads to mental disturbances. Aromatic
`amines appear to be responsible also for bladder irritation and the formation of tumors in
`workers engaged in the manufacture of dye intermediates.
`The chloro and nitro nuclear—substituted amines, the N-alkylated and acylated amines,
`and the diamines all are highly toxic. The N-phenylamines are considerably less toxic than.
`the N-alkyl derivatives. The phenolic hydroxyl group also decreases the toxicity somewhat.
`Toxicity is greatly reduced by the presence of free carboxylic or sulfonic acid groups in the
`ring.
`
`Reactions of the Nucleus
`
`
`
`;.«.u._.~.<.;x...~,.~
`
`1. Hydrogen Exchange. Electrophilic substitution of deuterium for hydrogen of ben-
`zene takes place only with strong acids under anhydrous conditions (p. 469). The amino
`group is so strongly activating, however, that exchange with hydrogen in the ort/zo and para
`positions takes place readily in aqueous solutions, although less readily than with the amino
`hydrogen. As would be expected, these exchange reactions are catalyzed by acids.
`
`PAGE 4 OF 15
`
`
`
`
`
`ji-f,
`
`an
`
`
`
`77...-.::m._,\....t..-»:,v.:-:=.v:.zm::s,-:vx::r»~.=vc:v,‘;:;::.e.d;/—..r:=~z:-W»~~».-w..“:'-.-t::.,-1'.-_.»*.','=.?e"\"‘..~.«;l‘553’53‘5V?"*“'!*e-<1‘?<
`
`
`
`
`
`PAGE 4 OF 15
`
`

`
`
`
`
`
`
`
`CHAPTER 24. — AROMATIC AMINES AND PHOSPHINES
`
`525
`
`NH2
`
`ND2
`
`ND-2
`5+ H
`
`ND;
`
`D
`
`NDg
`H D
`
`H20
`
`‘OD 5+
`
`5+
`
`HDO
`
`‘OD 5+
`
`5+
`
`HDO
`
`H D
`
`ND2
`
`D
`
`D
`
`(D
`’OD
`
` / £39 DD /0]; D
`
`H ND2
`5+
`
`5+
`
`5+
`
`D
`
`‘L’
`HDO
`
`ND2
`
`D
`
`2. Oxidation. Aliphatic amines are fairly stable to oxidation, but many aromatic
`amines oxidize readily. Unless carefully purified, they soon darken on standing in air.
`Stronger oxidizing agents produce highly colored products. Even the simplest aromatic
`amine, aniline, can give rise to numerous and frequently complex oxidation products. It is
`not surprising that, depending on the oxidizing agent used, azobenzene, azoxybenzene,
`phenylhydroxylamine, nitrosobenzene, and nitrobenzene have been isolated (p. 519), since
`aniline is a reduction product of these compounds. In addition to the amino group, however,
`the hydrogen atoms of the benzene ring that are ortho and para to the amino group can be
`oxidized to hydroxyl groups because the amino group increases the electron density at the
`ortho and para positions. Thus when sodium hypochlorite solution is added to aniline,
`p-aminophenol is formed along with azobenzene and other products.
`NH2
`NH2
`
`E; + NaOCl 7> Ej + NaCl
`
`OH
`
`These hydroxy amines are oxidized very readily to quinones (p. 566), which undergo
`further oxidation and condensation reactions. For example, the violet color produced when
`aniline is mixed with a solution of bleaching powder is due to a series of reactions that form
`a blue compound known as indoaniline.
`
`NH;
`
`NC1
`
`E:m%,¢C6“5NH2>o
`
`on
`
`o
`
`/N/\NH2 <—> HO/\>N \NH
`
`Indoaniline
`
`Quinone
`chloroimine
`
`Some of the more complicated reactions are considered in the discussion of quinones
`(p. 567) and of the Aniline Blacks (p. 765).
`Amine salts are much less readily oxidized than the free amines because the positive
`charge makes the group electron-attracting rather than electron-donating. Similarly, electro-
`negative substituents such as the nitro group decrease the electron density of the ring and
`greatly reduce the ease of oxidation.
`3. Halogenation.
`Because of the strong activating effect of the amino group, no
`catalyst is required in the halogenation of the nucleus. Furthermore, halogenation takes
`place in aqueous solution and is so rapid that the only product readily isolated is 2,4,6-tri-
`chloro- or 2,4,6-tribromoaniline. Thethree halogen atoms in the art/20 and para positions
`reduce the basicity of the amino group, and the salt does not form in aqueous solution.
`
`' P
`
`AGE 5 OF 15
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`PAGE 5 OF 15
`
`

`
`
`
`526
`
`.
`
`CHEMISTRY OF ORGANIC COMPOUNDS
`
`NH2
`
`+ 3 BF2 ?>
`
`NH2
`Br
`
`. Br
`
`+ 3 HBr
`
`Br
`
`2,4,6-Tribromo—
`aniline
`
`_
`
`"
`
`Actually trichloroaniline or tribromoaniline is formed even when chlorine or bromine
`
`is added to an aqueous solution of an aniline salt. This behavior seems anomalous at first,
`since salt formation should lead to deactivation and meta orientation. The experimental re-
`sults can be explained by the presence of free amine in equilibrium with the salt in aqueous
`solution. This view is confirmed by the fact that aniline dissolved in concentrated sulfuric
`acid is not chlorinated or brominated at room temperature. At higher temperatures the
`meta substitution product is formed.
`
`KIH3-sO4H
`
`KIH3-sO4H
`
`+ C12 —>
`
`+ HCl
`
`Cl
`m—Chloroaniline
`acid sulfate
`
`Aniline acid
`sulfate
`
`Even the less reactive iodine substitutes aniline directly, the hydrogen iodide combin-
`ing with unreacted aniline.
`
`NH2
`
`NH2
`
`KIH3-1
`
`2© + 12 -» Q +
`
`I
`
`[7—Iodo-
`aniline
`
`Aniline hydroiodide
`([7/zenylammomium iodide)
`
`If the activating effect of the amino group is reduced by conversion to the acetamino group,
`monochloro or monobromo derivatives can be obtained.
`
`NHCOCH3
`
`NHCOCH3
`
`+ BF2 ?>
`
`+ HBr
`
`Br
`
`Acetanilide
`
`p—Bromoacetanil ide
`
`Usually monohalogenated anilines are prepared by reduction of the halogenated nitro
`compounds.
`4. Nitration. Because of the ease of oxidation of free aniline (p. 525), only the salt
`can be nitrated efficiently, and nitration is carried out in concentrated sulfuric acid solu-
`tion. Hence the chief product is m-nitroaniline.
`
`KIH3-OsO3H
`
`HONOz
`->
`
`KIH3-OsO3H
`
`NaOH
`->
`
`NH2
`
`NO2
`
`NO2
`m—Nitroaniline
`
`Some 0- and p-nitroaniline also are formed, probably by nitration of the small amount of
`free amine in equilibrium with its salt, since the amount of meta increases with the concen-
`tration of the sulfuric acid (cf. p. 527). The three nitroanilines differ in basicity (p. 528)
`and can be separated by fractional precipitation from their salts with alkali. The order of
`precipitation is art/zo, then para, then meta. m—Nitroaniline usually is made by the partial
`reduction of m-dinitrobenzene (p. 517).
`
`;,,;;'’
`
`,-,.........==.~.~,-..-« . —.,_....._...,,.__..~-.._..-.._...._.-
`
`PAGE 6 OF 15
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`PAGE 6 OF 15
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`

`
`
`
`
`
`
`‘'“Mhupa:av—e..;~u:«x.ac':..s;s.—j./..ai:.'¢%:.;.:.:x.w:v.w.a9wa.;2s.ni
`
`CHAPTER 24. — AROMATIC AMINES AND PHOSPHINES
`
`527
`
`Ifsalt formation is prevented by the conversion of the basic amino group to the neutral
`acetamido group, nitration in acetic acid takes place almost exclusively in the para position.
`If the nitration is carried out in acetic anhydride, the ortho isomer is the chief product.
`
`HNO3 in
`acetic acid
`
`NHCOCH3
`
`NHCOCH3
`
`N02
`p-Nitroacetanilide
`
`Acetanilide
`
`HNO3 l“
`acetic anhydride
`
`NHCOCH3
`N02
`
`0-Nitroacetanilide
`
`Saponification of the nitroacetanilides with sodium hydroxide solution gives the nitro-
`anilines. p-Nitroaniline is an intermediate for the manufacture of Para Red (p. 744).
`5. Sulfonation.
`Sulfonation of aniline at room temperature with fuming sulfuric acid
`gives a mixture of 0-, m-, and p-aminobenzenesulfonic acids. Since the. effect of the +NH3
`group should be comparable to that of the +NR3 group, it should lead to pure meta substi-
`tution. Hence, as in nitration (p. 526), the ortho and para isomers probably arise from the
`sulfonation of the small amount of free amine in equilibrium with the salt. When aniline
`is heated with concentrated sulfuric acid for several hours at 180° (baking process), the sole
`product is the para isomer, sulfanilic acid. There is some evidence that here the initial
`product is the sulfamic acid, which should be ort}zo,para-directing.
`
`KIH3-so4H
`
`NHSO3H
`
`NHSO3H
`
`NH2
`
`KIH3
`
`Phenylsul-
`famic acid
`
`SO3H
`
`SO3H
`Sulfanilic acid
`
`SO3-
`
`N,N-Dimethylaniline, however, behaves in the same way as aniline, and since it cannot
`form a sulfamic acid, para substitution is assumed to result from sulfonation of the free
`amine at both low and high temperatures.
`Although the formulasfor the sulfonated amines frequently are written as amino-
`sulfonic acids, they actually are inner salts or dipolar ions (cf. p. 441). Thus sulfanilic acid
`decomposes at 280-300° without melting, whereas aniline is a liquid, benzenesulfonic acid
`is a low melting solid, and both can be distilled. Whereas the amino carboxylic acids are
`more soluble in either strong base or strong acid than in water, sulfanilic acid is more
`soluble only in strong bases because the sulfonic acid group is as strong as any of the min-
`eral acids in aqueous solution.
`The common names for 0-, m-, and p-aminobenzenesulfonic acids are art/zanilic, metanzilic,
`and sulfanilic acids respectively. Metanilic acid is prepared by the reduction of m-nitroben-
`zenesulfonic acid. Orthanilic acid is not readily available but can be obtained by removal
`of the bromine atom in 2-amino-5-bromobenzenesulfonic acid by reduction, or by reduc-
`tion of 0-nitrobenzenesulfonic acid made from 0-nitrophenyl disulfide (p. 496) by oxidation.
`
`
`
`I Reactions of the Amino Group
`
`1. Basicity. When an amino group is attached to an aromatic nucleus, the unshared
`i pair of electrons on nitrogen interacts with the 77 orbital system of the nucleus (p. 474) and
`makes the unshared pair less available for bonding with other groups. Moreover the elec-
`tronegativity of the phenyl group is greater than that of an alkyl group because the greater:
`
`PAGE 7 OF 15
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`PAGE 7 OF 15
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`

`
`
`
`528
`
`CHEMISTRY or ORGANIC COMPOUNDS
`
`character of the aryl 5102 orbital pulls the electrons closer to the nucleus. Hence the basicity
`of aromatic amines is less than that of aliphatic amines, although it is still greater than that
`of amides. Thus the acidity constants (pKa’s) of methylamine, aniline, and acetamide are
`10.6, 4.6, and -1.5 respectively. The introduction of a second aromatic nucleus on the
`nitrogen atom decreases the basicity still further, the pKa for diphenylamine being 0.9. On
`the other hand the introduction of alkyl groups increases the basicity, the pKa’s for N-meth-
`ylaniline and N,N—dimethylaniline being 4.8 and 5.1 respectively.
`The effects of substituents in the aromatic nucleus depend both on their inductive and
`resonance effects. The inductive effects depend on the distance separating the groups con-
`cerned, and hence the order of effectiveness when in the various positions is 0 > m > p_
`Resonance effects, however, are transmitted through conjugated systems and therefore are
`effective in the art/zoiand para positions but not in the meta positions.
`
`+
`NH-2
`
`O
`/_
`N
`
`(3 L
`
`O
`
`NH2
`
`CL //
`
`O
`
`N<_
`o
`
`Resonance strong
`and induction strong
`
`Resonance weak
`and induction fair
`
`+
`NH2
`
`p
`N\
`of f _o
`Resonance strong
`and induction weak
`
`For the nitro group the inductive and resonance effects are in the same direction. The pKa’s
`for 0-, m-, and p-nitroaniline are 0.3, 2.4, and 1.1 respectively. Although the inductive effect
`in the para position is less than that in the meta position, p-nitroaniline is a weaker base
`than m-nitroaniline because the resonance effect is added to the inductive effect. 0-Nitro-
`
`aniline is the weakest base because the resonance effect is operative and the inductive effect
`is at a maximum.
`
`the primary aromatic
`Like the aliphatic amines,
`2. Alkylation and Arylation.
`amines react with alkyl halides to give secondary and tertiary amines and quaternary
`ammonium salts.
`
`_ NaOH
`+
`C5H5NH2 -- RX Y) [C5H5NH2R]X ma“) C5H5NHR + NaX + H20
`N-Alkylaniline
`
`C6H5NHR —— RX ‘) [CGH5-,ItIHR2]X‘ EL C5H5NR-2 + NaX + H20
`N,N-Di»
`alkylaniline
`
`C.,~H5NR2 __ RX *» [C6H5KIR3]X-
`Phenyltrialkyl»
`ammonium halide
`
`Simple aryl halides react with difficulty. Although diphenylamine is a minor coproduct of
`the commercial production of aniline from chlorobenzene (p. 533), it is made best by heat-
`ing aniline with aniline hydrochloride.
`
`CSHSNH2 + [C.—,H5$IH3]C1- L33 (CeH5)2NH + NH4C1
`Diphenylamine
`
`Reaction of the lithium salt ofa diarylamine with an aryl iodide in the presence ofcatalytic
`amounts of cuprous iodide yields the triarylamine. The lithium salt is prepared from the
`amine and phenyllithium.
`
`PAGE 8 OF 15
`
`PAGE 8 OF 15
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`

`
`
`
`CHAPTER 24. — AROMATIC AMINES AND PHOSPHINES
`
`529
`
`ATZNH —|—
`
`———~—> AF2N'+Li + CgHs
`
`ArgN‘+Li + IAr’ 53$» Ar2NAr’ + Lil
`
`3. Acylation. Acid anhydrides and acyl halides convert primary and secondary
`amines into the amides.
`
`C5H5NH2 +
`
`2
`N~Methylaniline
`
`+
`
`Acetanilide
`
`+
`
`-*9
`
`-*9
`
`N-Methylacetanilide
`
`+ [C5H5l+\'IH2CH3]Cl_
`N-Methylaniline
`hydrochloride
`
`Acylation can be brought about also by heating the amine salts of carboxylic acids (p. 186).
`
`CH3
`
`CH3
`
`(3 + CH3COOH 3% © + H20
`
`NH2
`p»Toluidine
`
`NHCOCH3
`p~Acetotoluidide
`
`Reaction of aniline with phosgene gives phenylcarbamyl chloride. When it is heated,
`hydrogen chloride is lost and phenyl isocyanate is produced.
`
`NH2
`
`NHCOCI
`
`=C=O
`
`® cocig ® Heat © +Hcl
`
`Phenyl isocyanate
`
`isocyanate is useful for the identification of alkyl halides. The latter can be
`Phenyl
`converted to Grignard reagents, which add to phenyl isocyanate. Hydrolysis of the addi-
`tion product gives a solid anilide.
`
`‘?“l
`W F
`C5H5N=C=O + RMgX —.» C¢~,H5N==CR
`_H_2Q—>
`lLC6H5N=CR
`
`at
`-4.) C6H5NHCR
`
`When phenyl isocyanate is used for the preparation of derivatives of alcohols and amines
`(p. 339), all moisture must‘ be excluded. Otherwise the phenylcarbamic acid that is formed
`loses carbon dioxide, and the resulting aniline reacts with more phenyl isocyanate to give
`insoluble diphenylurea.
`H20
`C6H5N=C—-0 ___> [C.3H5NHCOOH] —_» CO2 + CeH5NH2 £6l*i“‘f—9=—O» C5H5NI-ICONHC5-H5
`
`Diphenylurea is one of the substances in coconut milk that stimulates the growth of plant
`cells. Various 1-aryl-1,3-dialkylureas and alkyl N-arylcarbamates are made commercially
`from aryl
`isocyanates for use as selective herbicides. An 80:20 mixture of 2,4- and
`2,6-tolylene diisocyanate (so-called toluene diisocyanate) made from the mixed diamino-
`toluenes is of commercial importance for the manufacture of urethan plastics (p. 819).
`Production of isocyanates in 1962 was almost 94 million pounds.
`4. Reaction with Nitrous Acid.
`The behavior of aromatic amines toward nitrous
`
`acid, like that of the aliphatic amines, depends on whether the amine is primary, second-
`ary, or tertiary. The reactions of primary and tertiary aromatic amines, however, differ
`from those of primary and tertiary aliphatic amines (p. 261).
`(a) PRIMARY AMINES. At temperatures below 0° in strongly acid solution, nitrous acid
`reacts with the primary aromatic amine salts to give water—soluble compounds known as
`diazanium salts.
`
`
`
`PAGE 9 OF 15
`
`PAGE 9 OF 15
`
`

`
`530
`
`CHEMISTRY OF ORGANIC COMPOUNDS
`
`[c6H51§H3]c1- + HONO (NaNO2 + HC1) —» [C6H5N2]CI‘ + 2 H20
`Aniline
`'
`Benzenediazon-
`hydrochloride
`ium chloride
`
`‘
`
`The properties and uses of these important compounds are described in Chapter 25.
`(b) SECONDARY AMINES. Secondary aromatic amines behave like secondary aliphatic
`amines and yield N-nitroso derivatives.
`
`CsH5NHCH3 +
`N—methyl—
`amlme
`
`—) C5H5lTJCH3 + H20
`NO
`N-Nitroso—N—
`methylaniline
`
`(c) TERTIARY AMINES. Tertiary aromatic amines having an unsubstituted para position
`yield p-nitroso derivatives.
`'
`N(CH3)2
`
`N(CH3)2
`
`+ HONO —>
`
`+ H20
`
`N,N—Dimethyl-
`aniline
`
`NO
`
`p—Nitroso-N,N—di-
`rncthylaniline
`
`I
`
`This reaction takes place because of the strong activating effect of the dimethylamino
`group. Although most of the dimethylaniline is present as the salt in the acid solution, and
`the dimethylammonium group is deactivating and meta-directing, sufficient free dimethyl-
`aniline is in equilibrium with the salt to react with nitrous acid, and the equilibrium shifts
`until nitrosation is complete. Nitrous acid does not bring about the nitrosation of benzene
`or even of toluene or mesitylene.
`
`H
`":
`‘
`
`Activation by the dimethylamino group depends on the resonance effect (p. 474), which re-
`quires that the dimethylamino group must be able to take up a position coplanar with the benzene
`ring.
`
`
`
`\~~
`/CH;,
`N
`
`HHC
`
`
`
`H3C\+/CH
`‘
`N
`
`;;
`
`H3C\+/CH3
`N
`
`|
`
`/
`
`<—.
`
`4:.
`
`.—.
`
`\ /
`N
`H,-3C if CH3
`
`If groups larger than hydrogen occupy the ortho positions, coplanarity cannot be attained, and
`activation of the ring is not possible. Thus 2,6, N,N-tetramethylaniline does not undergo reactions
`that require strong activation of the nucleus such as nitrosation and coupling with diazonium salts
`(p. 543).
`
`The diazonium salts from primary amines can be detected readily by reaction with
`aromatic amines or phenols to give highly colored azo compounds (p. 543). Although both
`secondary and tertiary aromatic amines yield nitroso derivatives, the reaction still can be
`used to distinguish between them, because the N-nitroso derivatives are amides of nitrous
`acid. Hence they are not basic and do not dissolve in dilute acids. The p-nitroso derivatives,
`however, form yellow salts with mineral acids. It appears that salt formation does not take
`place with the tertiary amino group, but with the nitroso group, stabilization being brought
`about by resonance with the quinonoid structure (p. 738).
`
`N(CH3)z
`
`N(CH3)2
`
`N(CH3)2
`
`t:
`
`N
`
`\%
`
`(f—)
`
`Q
`
`N
`
`H
`
`\OH
`
`T)
`
`W
`
`PAGE 10 OF 15
`
`PAGE 10 OF 15
`
`

`
`CHAPTER 24. — AROMATIC AMINES AND PHOSPHINES
`
`531
`
`5. Hydrolysis. As in the aliphatic series, an aromatic amino group usually is not dis-
`placed readily by hydroxide ion, although in the presence of water at high temperatures
`equilibrium exists between the aromatic amine and the phenol.
`
`C3H5NH2 + H20 £1’! C6H5OH + NH3
`
`This reaction is of little importance in the benzene series but finds commercial application
`in the naphthalene series (pp. 634, 637).
`If, however, a strongly electron-attracting group is present in the para position, the
`amino group can be displaced by a strong base under relatively mild conditions by
`an SNM2 reaction (p. 496). The reaction is useful for the preparation of pure primary and
`pure secondary aliphatic amines. For primary amines the starting point is the N-alkylaniline,
`which is acetylated and nitrated and then hydrolyzed with sodium hydroxide solution.
`RNH
`RNCOCH3
`RNCOCH3
`ONa
`
`@ + (CH3CO)2O —.> @ $39.3.) [Z
`
`N02
`
`LMQPIA RNH2 + CH3COONa +
`
`NO2
`Sodium p-nitro-
`phenoxide
`
`Secondary amines are obtained from p-nitrosodialkylanilines.
`NR2
`ONa
`
`@ + NaOH ——> RZNH + ®
`
`NO
`
`NO
`
`6. Oxidation. Primary aromatic amines are oxidized to azo compounds by iodoso-
`benzene acetate (p. 502) in benzene solution.
`
`2 ArNH2 + 2 CeH5I(OCOCH3)2 ——> ArN==NAr + 2C3H5I + 4CH3COOH
`
`Trifluoroperoxyacetic acid (hydrogen peroxide and trifluoroacetie acid ) oxidizes the amino group
`to the nitro group. The reaction is particularly useful for the preparation of compounds that
`cannot be obtained by direct substitution, such as p~dinitrobenzene.
`
`O2N©NH2 + 3 F3CCO3H ———~> O2N©NO2 + 3 F3CCO2H + H20
`
`7. Other Reactions. Aromatic amines undergo most of the reactions described for
`aliphatic amines. Thus they give condensation products with aldehydes and ketones. Inter-
`mediate condensation products frequently are more stable than those of the aliphatic
`amines. For example,
`the products of reaction of an aldehyde with one or two moles
`of aniline can be isolated.
`
`C6H5NH2 —— OCHR ——> CeH5N=CHR + H20
`
`2C6H5NH2 —— OCHR ——>
`
`(C6H5NH)2CHR + H20
`
`The products from one mole each of amine and aldehyde are known as Sc/zzfi" bases or arzilx.
`These intermediates undergo further polymerization and condensation. The condensation
`products have been used as rubber accelerators and antioxidants (p. 782). [7-Toluidine
`reacts with formaldehyde in acid solution to give a cyclic condensation product known as
`Troeger’s base, which is of stereochemical interest (p. 370).
`
`NH2
`A
` # H2
`2®+3HcHo—> £1 I
`'
`2
`H3C
`
`CH3
`
`+3H2O
`
`CH3
`
`
`
`PAGE 11' OF 15
`
`PAGE 11 OF 15
`
`

`
`
`
`
`
`'.‘.
`
`‘
`
`1'“-.'i~.a.."2;...~“»;és
`
`532
`
`CHEMISTRY or ORGANIC COMPOUNDS
`
`Unlike the aliphatic amines, aniline does not react with carbon disulfide at room tem.
`perature _to give the dithiocarbamate (p. 347). When a solution of aniline and carbon di-
`sulfide in alcohol is refluxed, hydrogen sulfide is evolved with the formation of thiocarbanilide.
`2C6H5NH2 + CS2 ~:>
`+ H25
`
`Thiocarbanilide
`(dzgb/zezzylt/ziourea)
`
`Thiocarbanilide at one time was an important rubber accelerator. It now is used chiefly for
`the preparation of 2-mercaptobenzothiazole, which has supplanted it (p. 688).
`When thiocarbanilide is boiled with strong hydrochloric acid, phenyl isothiocyanate
`( p/zen}! mustard oil), a very pungent compound, is produced.
`+
`T)
`
`+ C6H5NH3+_Cl
`
`Phenyl isothiocyanate reacts readily with primary and secondary amines to give thioureas,
`which are useful for the identification of amines.
`
`C5H5N=C=S + HZNR {> C5H5NHCSNHR
`
`Reaction“ with ammonia gives phenylthiourea, C3H5NHCSNH2, which is of interest in that it
`is extremely bitter to some persons and tasteless to others. The ability to taste the compound has
`been shown to be hereditary. p-Ethoxyphenylurea (Dulcin), p—C2H5OC6H4NHCONH2, on
`the other hand, is about 100 times sweeter than sucrose. Its toxicity is too great for use
`in foods.
`
`In the presence of ammonia, aniline reacts with carbon disulfide to give ammonium
`phenyldithiocarbamate.
`
`C6H5NH2 + CS2 + NH3 ~:> C6H5NHCSS_+NH4
`
`Removal of hydrogen sulfide from the salt by reaction with lead nitrate (p. 348) gives
`phenyl isothiocyanate.
`
`C6H5NHCSS‘+NH4 + Pb(NO3)2 «—> C6H5N=C=S + PbS + NH4NO3 + HNO3
`
`Primary aromatic amines when heated with chloroform and alkali give the isocyanides or
`carbylamines (p. 260).
`
`Technically Important Aromatic Amines and Their Derivatives
`
`Aniline is by far the most important amine from the technical viewpoint. Over 154 million
`pounds were produced in the United States in 1963, the selling price being about 14 cents per
`pound. Aniline was discovered in 1826 in the products of the destructive distillation of indigo
`(p. 753) and given the name /crystallin because it readily formed crystalline salts. It was detected in
`coal tar in 1834 and called kyanol, because it gave a blue color with bleaching powder. It was redis-
`covered in the distillation products of indigo in 1841 and called aniline from afiil, the Spanish word
`for indigo. In the same year it was produced by the reduction of nitrobenzene with ammonium sul-
`fide and called benzidam. In 1843 Hofmann (p. 253) proved that all four substances are identical.
`Both the reduction of nitrobenzene and the ammonolysis of chlorobenzene are used in the
`commercial production of aniline. In the reduction process scrap cast-iron turnings and water are
`placed in a cast-iron vessel fitted with a stirrer and a reflux condenser. A small amount of hydro-
`chloric acid or ferric chloride is added, and the mixture is heated to remove oxides from the surface
`of the iron, the hydrochloric acid or ferric chloride being converted to ferrous chloride. Nitroben—
`zene then is added with vigorous stirring. The iron is converted to black iron oxide, Fe_-304, which
`is recovered and used as a pigment (p. 517). The aniline is distilled with steam, and the mixed
`vapors are condensed. The aniline layer of the distillate is separated from the water layer and puri-
`fied by distillation at reduced pressure. Since aniline is soluble in water to the extent of about 3'
`per cent, it must be ‘recovered from the aqueous layer of the distillate. In order to avoid extraction
`with a solvent and recovery of the solvent, the aniline-saturated aqueous layer is returned to the
`steam generator for processing a subsequent batch. In another procedure the aniline is extracted
`from the water with nitrobenzene, and the extract put through the reduction process. Operation of
`a continuous vapor phase hydrogenation process using a fluidized catalyst bed began in 1956.
`
`’
`
`
`
`
`
`PAGE 12 OF 15
`
`PAGE 12 OF 15
`
`

`
`CHAPTER 24..—- AROMATIC AMINES AND PHOSPHINES
`
`533
`
`Since 1926 aniline has been prepared on a large scale by the reaction of chlorobenzene with
`ammonia. The chlorobenzene is heated in a pressure system with 28 per cent aqueous ammonia
`(mole ratio 1:6) in the presence of cuprous chloride (introduced as cuprous oxide) at 190-210”.
`
`C‘,-H5Cl + 2 Nu».
`
`l9g:*2°1‘0,> C(,»H5NHg + NH.ci
`
`A pressure of around 900 p.s.i. develops. The process is continuous, the reactants entering at one end
`of the system. and the products leaving the other end, About 5 per cent of phenol and 1 to 2 per cent
`of diphenylamine are formed as coproducts.
`
`C5H5Cl + H20 + NH; ——> C31-I5OH + NI-I4C1
`Phenol
`c,,H5c1 + H2NCgl-I5 + NH; _—» C5H5NHC5H5 + NI-I401
`Diphenylamine
`
`These side reactions would take place to a greater extent were it not for the presence of the large
`excess of ammonia. At the end of the reaction the liquid is blown into a column. The free ammonia
`and aniline vaporize and are condensed. Caustic soda is added to the residue to liberate ammonia
`and aniline from their hydrochlorides, convert the phenol into its sodium salt, and precipitate the
`copper salts.
`The first technical use for aniline was in 1856 for the production of mauve, the first commer-
`cial synthetic dye (p. 765). Aniline still is used almost exclusively as an intermediate in the produc-
`tion of other compounds. About 65 per cent of the total production is used in the manufacture of
`rubber accelerators and antioxidants (p. 782), 15 per cent for dyes and dye intermediates, 6 per
`cent for drug manufacture and 2 per cent for photographic developers (p. 566).
`The toluidines, xylidines, phenylenediamines, and most other primary aromatic amines are
`prepared by similar procedures involving reduction of the nitro compounds. m-Nitroaniline is pre-
`pared commercially by the partial reduction of m-dinitrobenzene using sodium sulfide as the reduc-
`ing agent (p. 517). 0- or p-Nitroaniline may be prepared by the ammonolysis of 0- or _17-nitrochloro-
`benzene. This reaction takes place more readily than the ammonolysis of chlorobenzene because of
`the activating effect of nitro groups in the artho or para position (p. 496).
`Acetanilide was produced to the extent of about 13 million pounds in 1943, but output has
`fallen to about one fourth of this amount since 1948 because of the decrease in the production of
`sulfa drugs (p. 534). A small amount is used as a dye intermediate. Acetanilide was introduced
`as an antipyretic in 1886 under the name antzfebnine, and at one time it was used widely for this
`purpose and as an analgesic. It is highly toxic, however, being similar to aniline in its action, and
`it has been displaced largely by the relatively safer salicylates (p. 600), especially aspirin, which
`was introduced in 1899. Because acetanilide is cheap, it still is used in some proprietary headache
`and pain-killing remedies.
`Lidocaine (lgzlocaine), a local anesthetic (p. 162) that now is used widely instead of Novocaine
`(p. 600), is the hydrochloride of 2,6-dimethyl—a-diethylaminoacetanilide and is prepared by the
`following series of reactions.
`
`
`
`
`
`CI-I3 .
`if
`CH3
`QNHZ clcocmcl ©NHCOCH2Cl ~LH(C"lH")‘=,
`CH3
`CH3
`
`cu.
`\)NHcoCH21:1H(C2H5)‘2 Cl"
`"CH3
`
`</
`
`.
`
`I
`
`i
`
`About 10 million pounds of N,N-dimethylaniline was produced in 1963. It is made from
`aniline and methyl alcohol in the presence of hydrochloric or sulfuric acid in a pressure reactor
`at 220°.
`
`It can be made also from aniline and methyl ether over activated alumina at 260°.
`
`C.gH,-,NHg + 2 canon
`
`C61-I5N(CH3)-3 + 2 H20
`
`CgH5NH2 + (CH3)2O
`
`CtiH.5NlCH.1)2 + H20
`
`Dimethylaniline is used as a dye intermediate (pp. 749, 751, 765) and in the manufacture of tetryl
`(p. 534). Nitrosation of N—methylaniline gives N,4-dinitroso-N-methylaniline (N,4-DNMA), which
`is used in the compounding of rubber (p. 782).
`'N,N’-Di-s-butyl-p-phenylenediamine,
`_t7—(5—
`C4HgNH)2C5H4, is one of the more widely used antioxidants (p. 77) for preventing the polymer-
`ization of the unsaturated components of cracked gasoline. Long—chain alkyl derivatives, such as
`N,N'-di-2-octyl-p-phenylenediamine, are used as antioxidants for synthetic rubber.
`Diphenylamine is the principal stabilizer for smokeless powder (p. 427), being added in
`amounts of 1 to 8 per cent of the finished product. Its function is to combine with any oxides of
`nitrogen that are liberated, which otherwise would catalyze further decomposition. Large quantities
`of diphenylamine are used also in the manufacture of phenothiazine (p. 695),