Aminophenols 1

Aminophenols
Stephen C. Mitchell, Imperail College, London, United Kingdom
Rosemary H. Waring, University of Birmingham, Birmingham, United Kingdom

1. Aminophenols . . . . . . . . . . . . . . 1 1.6. Environmental Aspects . . . . . . . . 6

1.1. Physical Properties . . . . . . . . . . . 1 1.7. Uses . . . . . . . . . . . . . . . . . . . . . 7
1.2. Chemical Properties . . . . . . . . . . 2 1.8. Toxicology . . . . . . . . . . . . . . . . . 7
1.3. Production . . . . . . . . . . . . . . . . 4 2. Aminophenol Derivatives . . . . . . . 7
1.3.1. Reduction . . . . . . . . . . . . . . . . . 4
2.1. Derivatives of 2-Aminophenol . . . . 8
1.3.2. Substitution . . . . . . . . . . . . . . . . 5
1.3.3. Purification . . . . . . . . . . . . . . . . . 6 2.2. Derivatives of 3-Aminophenol . . . . 12
1.4. Storage and Handling . . . . . . . . . 6 2.3. Derivatives of 4-Aminophenol . . . . 13
1.5. Analysis . . . . . . . . . . . . . . . . . . 6 3. References . . . . . . . . . . . . . . . . . 15

1. Aminophenols and 4-aminophenols being more susceptible to

this phenomenon than the 3-isomer. The solu-
Aminophenols and their derivatives are of bilities of these compounds in common solvents
steadily increasing commercial importance, and their spectral characteristics are given in Ta-
both in their own right and as intermediates in bles 1 and 2, respectively [3–12].
the chemical and dye industries. They are am-
Table 1. Solubility ∗ of aminophenols in common solvents
photeric and can behave either as weak acids or
weak bases, but the basic character usually pre- 2- 3- 4-
dominates. 2-Aminophenol (1) and 4-amino- Aminophenol Aminophenol Aminophenol
phenol (2) are oxidized easily. This is the ba- Acetone 3 3 2
sis for their main applications, for example, as Acetonitrile 3 3 2
Benzene 1 1 0
photographic developers. In contrast, 3-amino- Chloroform 1 1 0
phenol (3) is fairly stable in air and is not oxi- Diethyl ether 2 2 1
dized rapidly. Dimethylsulfoxide 3 3 3
Ethanol 3 3 1
Ethyl acetate 3 3 2
Toluene 1 1 1
Water
Cold 1 2 1
Hot 2 3 2

∗ 0, insoluble; 1, slightly soluble; 2, soluble; 3, very soluble

1 2 3

2-Aminophenol (1) [95-55-6], 2-hy-

droxyaniline, 2-amino-1-hydroxybenzene, C.I.
1.1. Physical Properties Oxidation Base 17, C.I. 76520, C6 H7 NO,
M r 109.13, forms white orthorhombic bipyra-
The simple aminophenols exist in three isomeric midal needles when crystallized from water or
forms depending on the relative positions of the benzene, mp 174 ◦ C. The crystals have eight
hydroxyl and amino groups around the benzene molecules to the elementary cell and a den-
ring. At room temperature they are solid crys- sity of 1.328 g/cm3 (1.29 also quoted) [13–16].
talline compounds. The commercial-grade com- At reduced pressure (1.47 kPa), 2-aminophenol
pounds are usually impure because of contam- sublimes rapidly at 153 ◦ C without decomposi-
ination with oxidation products and may take tion [17]. Acid – base dissociation constants are
on a yellow-brown or pink-purple hue, the 2- pK 1 4.72 (water at 21 ◦ C), 4.66 (1 vol % ethyl

c 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

10.1002/14356007.a02 099
2 Aminophenols
Table 2. Spectral characteristics of the aminophenol isomers

2-Aminophenol 3-Aminophenol 4-Aminophenol

a −1
IR , cm 3380, 3300, 1600, 1510, 1470, 1270, 3370, 3310, 1600, 1470, 1390, 1260, 3050 – 2580, 1500, 1470, 1240, 970,
900, 740 1180, 910 830, 750
b
UV , nm 233, 285 (methanol) 287 (methanol) 234, 301 (methanol)
229, 281 (water) 270 (0.1 M HCl) 229, 294 (water)
235, 288 (cyclohex.) 234, 284 (cyclohex.) 235, 304 (cyclohex.)
NMRc , ppm 6.9 – 7.5, 8.6 (TFA) 4.7, 6.0, 6.1, 6.8, 8.8 (DMSO) 7.1, 7.4, 8.7 (TFA)
a
Only IR absorption bands reported as very strong are included (accuracy: ± 10 cm−1 ) [4], [5].
b
UV spectra: cyclohex. = cyclohexane containing 2 vol % diethyl ether [6–8].
c
Proton chemical shift spectra over the range of 0 – 15 ppm (± 0.1 ppm); TFA, trifluoroacetic acid; DMSO, dimethylsulfoxide.
When complex spectra caused by second-order effects or overlapping resonances were encountered the range was recorded [10], [11].

alcohol in water at 25 ◦ C); pK 2 9.66 (water at pressures are as follows: 284 ◦ C (101.3 kPa),
15 ◦ C), 9.71 (water at 22 ◦ C) [18], [19]. Salts: 174 ◦ C (1.47 kPa), 167 ◦ C (1.07 kPa), 150 ◦ C
hydrochloride [51-19-4], needles, mp 207 ◦ C ; (0.4 kPa), 130.2 ◦ C (0.04 kPa), decomposition
formate, mp 120 ◦ C; oxalate, mp 167.5 ◦ C (de- usually occurring. Acid – base dissociation con-
comp.); acetate, mp 150 ◦ C. stants are: pK 1 5.50 (water at 21 ◦ C), 4.86 (water
at 30 ◦ C), 5.48 (1 vol % aqueous ethyl alcohol
3-Aminophenol (3) [591-27-5], 3-hy- at 25 ◦ C); pK 2 10.30 (water at 22 ◦ C), 10.60
droxyaniline, 3-amino-1-hydroxybenzene, (water at 30 ◦ C) [18], [21]. Salts: hydrochloride
C6 H7 NO, M r 109.13, forms white prisms [51-78-5], prisms, mp 306 ◦ C (decomp.); hy-
when crystallized from water or toluene, drosulfate [15658-52-3], needles, mp 272 ◦ C;
mp 122 – 123 ◦ C. The orthorhombic crystals oxalate, mp 183 ◦ C; acetate [13871-68-6],
have a tetramolecular unit and a density of mp 183 ◦ C; chloroacetate, needles, mp 148 ◦ C;
1.195 g/cm3 (1.206 and 1.269 also quoted) [14– trichloroacetate, needles, mp 166 ◦ C.
16]. 3-Aminophenol boils at 164 ◦ C at 1.47 kPa
with slight decomposition [17]. Acid – base
dissociation constants are: pK 1 4.17 (water at 1.2. Chemical Properties
21 ◦ C), 4.31 (1 vol % aqueous ethyl alcohol at
25 ◦ C); pK 2 9.87 (water at 22 ◦ C) [18]. Salts: The chemical properties and reactions of the
hydrochloride [51-81-0], prisms, mp 229 ◦ C; aminophenols are to be found in detail in many
hydrobromide, prisms, mp 224 ◦ C; hydroiodide, standard chemical texts and only a summary is
prisms, mp 209 ◦ C; sulfate [66671-80-5], plates given here [22].
or needles, mp 152 ◦ C; oxalate, mp 275 ◦ C. The acidity of the phenols is depressed by
the presence of an amino group on the benzene
4-Aminophenol (2) [123-30-8], 4-hy-
ring; this phenomenon is most pronounced with
droxyaniline, 4-amino-1-hydroxybenzene,
4-aminophenol. They also behave as weak bases,
C6 H7 NO, M r 109.13, forms white plates when
giving salts with both mineral and organic acids.
crystallized from water, mp 189 – 190 ◦ C (de-
The aminophenols are true ampholytes, with no
comp.). The crystals exist in two forms. The α
zwitterion structure; hence they exist either as
form (from alcohol, water, or ethyl acetate) is the
neutral molecules (4) or as ammonium cations
more stable and has an orthorhombic pyrami-
(5) or phenolate anions (6), depending on the pH
dal structure containing four molecules per unit
value of the solution.
cell. It has a density of 1.290 g/cm3 (1.305 also
quoted). The less stable β form (from acetone)
exists as acicular crystals that turn into the α
form on standing; they are orthorhombic bipyra-
midal or pyramidal and have a hexamolecular
unit [14], [15], [20]. At reduced pressure (40 Pa)
4-aminophenol sublimes at 110 ◦ C with slight
decomposition. Boiling points quoted at various
Aminophenols 3

However, deviations from theoretical curves nitrophenyl carboxylates, which is of particu-

observed during acid – base titrations have led to lar importance with the 4-aminophenol deriva-
postulation of the existence of half-salt complex tives. A migration of the acyl group from the
cations B+2 , formed by the association of an am- O to the N position is known to occur for
monium cation, B+ , with a neutral molecule, B. both 2- and 4-aminophenol acylated products.
This association phenomenon is most apparent 2-Aminophenyl ethyl carbonate (7) rearranges
with 4-aminophenol but is also displayed by the slowly in dilute acid to ethyl 2-hydroxyphenyl
other isomers [21]. carbamate (8); the corresponding 4 derivative
The aminophenols are chemically reactive, does not undergo this particular reaction [23].
undergoing reactions involving both the aro-
matic amino group and the phenolic hydroxyl
moiety, as well as substitution on the ben-
zene ring. Oxidation leads to the formation of
highly colored polymeric quinoid structures. 2-
Aminophenol undergoes a variety of cyclization
reactions.

Alkylation. All of the possible mono-, di-,

and trimethylated aminophenols are known. N- Diazonium Salt Formation. The aromatic
Monoalkylation occurs when the aminophenol amino group of aminophenols can be converted
is heated with the appropriate alkyl halide or to the diazonium salt with sodium nitrite in aque-
with an alcohol and Raney nickel; equal or even ous acid, although difficulties may be encoun-
better results can be achieved by using alde- tered when the aminophenol is oxidized easily
hydes or ketones in place of the alcohol. Spe- or of low solubility. Crystalline diazonium salts
cific alkylation of the hydroxyl group to form have been isolated by using the hydrochloride or
methoxyanilines (anisidines) or ethoxyanilines sulfate of the appropriate aminophenol under an-
(phenetidines) is difficult because of the reactiv- hydrous conditions. Such diazo derivatives find
ity of the amino group; mixed alkylated products extensive use in the dye [24], [25].
usually are obtained. 3-Methoxyaniline may be
prepared by methylation of 3-aminophenol un- Cyclization Reactions. Owing to the close
der alkaline conditions, but it is more usual to proximity of the amino and hydroxyl groups
protect the amino group and to methylate 3- in 2-aminophenol, this isomer is particularly
acetylaminophenol, followed by hydrolysis. The susceptible to cyclization and condensation re-
other anisidines and phenetidines are prepared actions. Oxidation by iron(III) chloride, en-
indirectly by reduction of the nitro analog: zymes, or light or autoxidation on silica thin-
layer plates gives 2-aminophenoxazin-3-one (9).
Further oxidation with iron(III) cyanide or heat-
ing with potassium hydroxide in ethanol gives a
five-ring structure, triphenoxdioxazine (benzox-
azinophenoxazine) (10). 2-Aminophenol and
its derivatives are useful starting materials for
the synthesis of phenoxazones, phenoxazines,
benzoxazoles, and thiobenzoxazoles. Most of
Acylation. Acylation of the aminophenol these condensation reactions involve heating at
(using acetic anhydride in alkali or pyridine, 200 – 300 ◦ C with a suitable catalyst [22].
acetyl chloride and pyridine in toluene, or ketene
in ethanol) usually leads to N-acylated prod-
ucts. If an excess of reagent is used, however,
especially with 2-aminophenol, O,N-diacylated
products are formed. Aminophenyl carboxyl-
9
ates (O-acylated aminophenols) normally are
prepared by the reduction of the corresponding
4 Aminophenols

complished with iron or with hydrogen in the

presence of a catalyst. The last mentioned is the
method of choice today for the production of 2-
and 4-aminophenol.
10

Condensation Reactions. Substituted 1.3.1. Reduction

diphenylamines or diphenyl ethers are obtained
from aminophenols and suitable reactants by Iron Reduction [26]. The reduction of ni-
elimination of ammonia or hydrogen chloride: trophenols with iron turnings takes place in
weakly acidic solution or suspension. Before
the iron – iron oxide sludge is separated from
the solution [27] the product aminophenol must
be made water soluble by adding sodium hy-
droxide. The resulting sodium aminophenolate
is very susceptible to oxidation in aqueous so-
lution; various methods are recommended for
its purification (see Section 1.3.3). Subsequent
to this, the aminophenols are precipitated from
acidic solution by neutralization with base and
in the absence of air; reducing agents usually
must be added during this procedure.
When 2-nitrophenol is reduced with iron, red
insoluble color lakes are formed as byproducts
that decrease the yield. Therefore, the iron re-
duction of 2-nitrophenol is of minor industrial
importance today.

Catalytic Reduction [28–30]. Catalytic re-

duction usually takes place in solution, emul-
sion, or suspension in autoclaves or pressurized
vessels; after the catalyst is added, the vessel
Reactions of the Benzene Ring. Both the
is pressurized with hydrogen. Water and metha-
amino and hydroxyl groups are electron-
nol are the preferred solvents; in water the addi-
donating moieties, and many substituted deriva-
tion of alkali hydroxide [31–34], alkali carbon-
tives are known. The controlled interaction
ate [31], [34], or acid [34], [35] has been recom-
of aminophenols with chlorine or bromine in
mended. Nickel [36] – preferably Raney nickel
glacial acetic acid can give a variety of mono-,
[32], [33], [37], [38] – or supported precious
di-, tri-, or tetra-halogenated products. The use
metals [31], [39], such as platinum or palladium
of concentrated sulfuric acid or oleum, with or
[34], [40] on activated carbon, or the oxides of
without heat, gives aromatic sulfonic acids. The
these metals [35], [41] are used as catalysts. The
sulfonic acid group enters the ortho or para
catalyst life can be extended, the catalyst con-
position relative to the hydroxyl group. Further
sumption decreased, and the product quality en-
treatment with oleum leads to the formation
hanced by adding organic solvents that are not
of disulfonated compounds. The carboxylation
miscible with water [32], [34]. The preferred hy-
of m-aminophenol leads to the formation of
drogen pressure is 2 MPa; the hydrogenation can
p-aminosalicylic acid.
also be performed at atmospheric pressure or at
higher pressure up to 6 MPa. The reaction tem-
1.3. Production perature does not exceed 100 – 110 ◦ C.

Aminophenols are made either by reduction of

nitrophenols or by substitution. Reduction is ac-
Aminophenols 5

Reduction of Nitrobenzene. When reduc- performed below 100 ◦ C, either at atmospheric

ing nitrobenzene in acidic medium [42], the or at higher pressure. Hydrogen is added during
intermediate phenylhydroxylamine [43] rear- the reaction as consumed. The addition of inert
ranges to 2- and 4-aminophenol before it is fur- organic solvents further increases the yield of
ther reduced to aniline. The main product of this 4-aminophenol and the product quality [52].
reaction is 4-aminophenol; byproducts are 2- In another variant, only 88 % of the ni-
aminophenol, aniline, and 4,4 -diaminodiphenyl trobenzene is reduced [53]; after that, the re-
ether: action mixture consists of two phases with the
precious-metal catalyst (palladium on activated
carbon) remaining in the unreacted nitrobenzene
phase. Therefore, phase separation is sufficient
as workup, and the nitrobenzene phase can be
recycled directly to the next batch. The aqueous
sulfuric acid phase contains 4-aminophenol and
byproduct aniline. After neutralization, the ani-
line is stripped, and 4-aminophenol is obtained
by crystallization after the aqueous phase is pu-
rified with activated carbon.

Electrolytic reduction also is possible [44],

[54–57]; this method causes less concern over
pollution than metal – acid reduction systems,
but it has not yet found industrial applica-
tion. Electrolysis of nitrobenzene or phenylhy-
In the past, metals in dilute sulfuric acid droxylamine in the presence of sulfuric acid or
were used as reducing agents [44]. Today, the of azoxybenzene in acid solution yields specifi-
reducing agent is hydrogen in the presence of cally 4-aminophenol [58].
precious-metal catalysts [43], [45], [46], e.g.,
palladium or platinum. Other catalysts have been
suggested: molybdenum and platinum sulfide 1.3.2. Substitution
[47], [48], and a platinum – ruthenium mixed
catalyst [49]. Either the catalysts are used as their Substitution of various groups by amino or hy-
oxides, or they are supported on activated car- droxyl groups is industrially unimportant for the
bon. production of 2- and 4-aminophenol [59], but
Dilute aqueous mineral acid is used as reac- this type of reaction is used for the synthesis of
tion medium, for example, dilute sulfuric acid; 2- or 4-aminophenol derivatives.
acidic salts also can be added to the reduction However, 3-aminophenol cannot be obtained
medium [47]. easily by reduction. It is made mainly by the
In a two-step process, nitrobenzene first is se- reaction of 3-aminobenzenesulfonic acid with
lectively reduced to phenylhydroxylamine with sodium hydroxide or by the reaction of resorci-
hydrogen in the presence of Raney copper and nol with ammonia. Substitution of the sulfonic
in an organic solvent, such as 2-propanol [43]. acid group in 3-aminobenzenesulfonic acid is
The product rearranges to 4-aminophenol after accomplished by caustic soda fusion (5 – 6 h;
addition of dilute sulfuric acid [50]. 240 – 245 ◦ C). The product is purified by vac-
The addition of wetting agents increases the uum distillation [60].
aminophenol yield [51]; these agents must be Alternatively, resorcinol reacts with ammo-
water soluble and stable in the presence of sulfu- nia [61], for example, in the presence of di-
ric acid. Quaternary ammonium salts that con- ammonium phosphate and arsenic pentoxide
tain at least one alkyl group with at least ten [62] or ammonium sulfite to form 3-amino-
carbon atoms are suitable, e.g., dodecyltrimeth- phenol. The compound also may be made by
ylammonium chloride. The reaction usually is hydrolysis of 3-aminoaniline [63], [64].
6 Aminophenols

1.3.3. Purification and 275 nm [78] and also in parts per thousand
by using potentiometric titrations in a two-phase
Generally, aminophenols can be purified by sub- chloroform–water medium [79] or potentio-
limation at reduced pressure and higher tempera- argentometric titrations of liberated bromide af-
ture. 3-Aminophenol may be purified by vacuum ter reaction with bromine [80]. More specif-
distillation; to obtain a colorless product sulfur ically, 2-aminophenol can be identified using
dioxide is added during distillation [65] or the an iron(II) sulfate–hydrogen peroxide reagent
distillate is collected under a blanket of an un- [81] or dimerized in acidic solution to 2-hy-
reactive liquid of lower density, such as water droxyisophenoxazin-3-one, as intensively col-
[66]. ored dye [82]. 4-Aminophenol can be ana-
Another method for purifying aminophenols lyzed by voltammetry [83], [84]. A colorimetric
is the treatment of their aqueous solutions method using 3-cyano-N-methoxypyridinium
with activated carbon [67], [68]. During this perchlorate as reagent detects 4-aminophenol in
treatment, sodium sulfite, sodium dithionite, or the presence of N-acetyl-4-aminophenol [85].
disodium ethylenediaminotetraacetate [68] is 3-Aminophenol has been analyzed colorimetri-
added to increase the quality and stability of the cally by oxidation in base and subsequent ex-
products and to chelate heavy-metal ions that traction of a violet quinoneimide dye [86].
would catalyze oxidation. Addition of sodium Chromatographic methods for the separation
dithionite, hydrazine [68], or sodium hydrosul- and identification of aminophenols also have
fite [69] also is recommended during precipita- been described. Thin layer chromatography pro-
tion or crystallization of aminophenols. vides a rapid and convenient method of separat-
Contaminants, which are usually present in ing the isomers from many derivatives, and sub-
the 4-aminophenol made by catalytic reduction, sequent spraying with a variety of chromogenic
can be reduced or even removed completely by a reagents gives additional information [87], [88].
variety of procedures: treatment with 2-propanol Several gas–liquid [89] and high-pressure liquid
[70]; with aliphatic, cycloaliphatic or aromatic [90–92] chromatographic separation techniques
ketones [71]; with aromatic amines [72]; with have also been reported, and the use of selected-
toluene or low molecular mass alkyl acetates ion mass spectrometry greatly increases detec-
[73]; with phosphoric acid, hydroxyacetic acid, tion sensitivity [93], [94].
hydroxypropionic acid, or citric acid [74]; or by
extraction with methylene chloride, chloroform
[75], or nitrobenzene [76].
1.6. Environmental Aspects

1.4. Storage and Handling As the aminophenols are oxidized easily they
tend to remove oxygen from solutions. Hence,
Under atmospheric conditions, 3-aminophenol if they are released from industrial waste waters
is the most stable of the three isomers. Both 2- into streams and rivers they will deplete the ca-
and 4-aminophenol are unstable; they darken on pacity of these environments to sustain aquatic
exposure to air and light and should be stored life. The adsorption of aminophenols onto metal
in brown glass containers, preferably in an at- ferrocyanides and activated carbons from bitu-
mosphere of nitrogen. The use of activated iron minous coal has met with limited success but
oxide in a separate cellophane bag inside the may provide a possible means of removal [95],
storage container inhibits the discoloration of 4- [96]. Biological degradation of 3-aminophenol
aminophenol [77]. The salts, especially the hy- has been carried out in aeration tanks with
drochlorides, are more resistant to oxidation and adapted microflora from active sludge; the pro-
should be used where possible. cess took 4 months [97]. An enzymatic method
for removing aminophenols from waste wa-
ters has been described using horseradish per-
1.5. Analysis oxidase to cross-link and precipitate the com-
pounds as insoluble polymers [98]. Degradative
Aminophenols have been detected in waste wa- metabolism by bacteria [99–101] and the im-
ter by investigating UV absorptions at 220, 254,
Aminophenols 7

mobilization of microbial cells onto Ca-alginate skin sensitization, dermatitis, and allergic reac-
beads [102] may open up a new approach. tions [108], [109]. Immunogenic conjugates are
spontaneously produced on exposure to 2- and 4-
aminophenol [110]. Methemoglobin formation
1.7. Uses with subsequent cyanosis is another possible
complication. Inhalation of 4-aminophenol may
Both 2- and 4-aminophenols are strong reducing precipitate this event and also cause bronchial
agents and are employed as photographic devel- asthma, [111]. 3-Aminophenol is less hazardous
opers under the trade names of Atomal and Ortol than the others. The sulfonated derivatives are
(2-aminophenol); Activol, Azol, Certinal, Citol, less irritating than the unsulfonated compounds.
Paranol, Rodinal, Unal, and Ursol P (4-amino- 2-Aminophenol is neuroactive, inducing
phenol); they may be used alone or in combi- spike discharges when instilled into the cere-
nation with hydroquinone. The oxalate salt of broventricle of the rat [112]. 4-Aminophenol
4-aminophenol is marketed under the name of is nephrotoxic and strongly inhibits proximal
Kodelon. tubular function [113–115]. Respiration, oxida-
The aminophenols are versatile intermedi- tive phosphorylation, and ATPase activity are
ates and are employed in the synthesis of vir- inhibited in rat kidney mitochondria [116]. 2-
tually every class of stain and dye. In addition, Aminophenol and 4-aminophenol, but not 3-
2-aminophenol (Oxidation Base 17; C.I. 76520) aminophenol, are teratogenic in the hamster
is specifically used for shading leather, fur, and [117]. 4-Aminophenol is known to inhibit DNA
hair from grays and browns to yellowish brown. synthesis and alter DNA structure in human lym-
3-Aminophenol has found application as a hair phoblasts [118]. The aminophenols also have
colorant and as a coupler molecule in hair dyes been shown to be genotoxic, as evidenced by
[103], [104]. 4-Aminophenol is used as an inter- the induction of sister chromatid exchanges and
mediate in the synthesis of pharmaceuticals, as micronucleus tests [119–122].
a wood stain imparting a roselike color to timber Obviously, care should be taken in handling
[105], and as a dyeing agent for fur and feathers. these compounds; prolonged exposure should
As a result of the close proximity of the be avoided. Contaminated clothing should be
amino and hydroxyl groups on the benzene removed immediately and the affected area
ring and their ease of condensation with suit- washed thoroughly with running water for at
able reagents, 2-aminophenol is a principal in- least 10 min.
termediate in the synthesis of such heterocyclic
systems as oxyquinolines, phenoxamines, and
benzoxazoles. The last-named compounds have 2. Aminophenol Derivatives
been used as inflammation inhibitors [106].
3-Aminophenol has found use as a stabilizer The derivatives of the aminophenols have im-
of chlorine-containing thermoplastics [107], al- portant uses in both the photographic and the
though its major use is as an intermediate in the pharmaceutical industries. They are also ex-
production of 4-amino-2-hydroxybenzoic acid, tensively applied as precursors and interme-
a tuberculostat. Similarly, nitrogen-substituted diates in the synthesis of more complicated
4-aminophenols have long been known as an- molecules, especially those used in the stain-
tipyretics and analgesics, and the production of ing and dye industry. All of the major classes of
these derivatives is a major use of 4-amino- dyes have representatives that incorporate sub-
phenol. stituted aminophenols. The varying degrees of
ease with which the aminophenols can be di-
azotized and coupled has led to their use in
the manufacture of azo compounds. The sul-
1.8. Toxicology
fonated aminophenols also are employed in this
context; these compounds, however, are treated
In general, aminophenols are irritants. Their
elsewhere (→ Benzenesulfonic Acids and Their
toxic hazard rating is slight to moderate, but re-
Derivatives). Details concerning which amino-
peated contamination may cause general itching,
phenol derivatives and sulfonated compounds
8 Aminophenols

are produced commercially as dye intermedi- or of Raney nickel [129] (solvent: methanol or
ates have been reviewed and are given in the 2-propanol).
publications listed in reference [123]. The more
commonly encountered simple derivatives of the
aminophenols can be found in the review articles
cited in the references and also in standard or-
ganic chemistry texts [124]. A few examples,
which have specific uses or are manufactured in 12 13 14

large quantities, have been selected for detailed

discussion.
2-Ethoxyaniline (13) [94-70-2], o-
phenetidine, C8 H11 NO, M r 137.18, d 20
20 1.0513,
bp 232.5 ◦ C (101.3 kPa), is produced from 2-
2.1. Derivatives of 2-Aminophenol
ethoxynitrobenzene by reduction with iron or
by catalytic hydrogenation in the presence of
2-(N-Methylamino)phenol (11) [611-24-5],
precious-metal catalysts or Raney nickel [130].
C7 H9 NO, M r 123.15, mp 99 ◦ C, forms colorless
plates; the aqueous hydrochloric acid solution 2-Acetamidophenol (14) [614-80-2], 2-hy-
turns reddish brown when FeCl3 solution is droxyacetanilide, C8 H9 NO2 , M r 151.16, forms
added. colorless crystals, mp 209 ◦ C, that are quite sol-
Compound 11 is synthesized by reaction uble in ethanol and hot water. Production is by
of 2-aminophenol with phosgene, alkylation of acetylation of 2-aminophenol with acetic anhy-
the intermediate benzoxazolone, and cleavage dride [131].
of N-methylbenzoxazolone with hydrochloric
acid [125]. Alternatively, 2-N-acetyl-N-meth- 2-Amino-5-nitrophenol (15) [121-88-0],
ylaminophenol is heated at 140 ◦ C in the pres- C6 H6 N2 O3 , M r 154.13, forms orange nee-
ence of hydrochloric acid [126]: dles, mp 207 – 208 ◦ C, that are sparingly sol-
uble in water. Production is by nitration of
benzoxazolone (16) and separation from the
2-amino-4-nitrophenol isomer after treatment
with hydrochloric acid [132]. It induces Cu(II)-
dependent DNA cleavage, presumably via the
generation of active oxygen species [133].

2-Methoxyaniline (12) [90-04-0], o-

anisidine, C7 H9 NO, M r 123.15, mp 6.22 ◦ C,
bp 224 ◦ C (102.1 kPa), bp 105 – 106 ◦ C
(1.85 kPa), d 4 1.0923, d 4 1.0263, n20
20 98.7
D 1.5738,
dynamic viscosity η 2.211 mPa · s (55 ◦ C),
η 1.051 mPa · s (98.7 ◦ C), dipole moment 1.62 D
(vapor), is slightly soluble in water (1.38 wt %
at 25 ◦ C).
The compound is produced from 2-
methoxynitrobenzene by reduction with iron 2-Amino-4-nitrophenol (17) [99-57-0],
[127] or by hydrogenation in the presence of C 6 H6 N2 O3 , M r 154.13, 2-hydroxy-5-
precious-metal catalysts [128] (platinum or pal- nitroaniline, forms orange prisms from water
ladium on activated carbon; solvent: toluene) that are hydrated with one molecule of water
of crystallization, mp 80 – 90 ◦ C. They can be
Aminophenols 9

dehydrated over sulfuric acid to the anhydrous pound suggest potential health hazards [143],
form, mp 143 – 145 ◦ C, soluble in alcohol, ether, [144].
acetic acid, and warm benzene and slightly sol-
uble in water.
Compound 17 is produced commercially by
the partial reduction of 2,4-dinitrophenol; this
may be achieved electrolytically with vanadium
[134] or chemically with polysulfide, sodium
18 19
hydrosulfide, or hydrazine and copper [135–
137]. Alternatively, 2-acetamidophenol or 2-
methylbenzoxazole may be nitrated in sulfuric
acid to yield a mixture of 4- and 5-nitro deriva- 2,4-Diaminophenol (19) [95-86-3], 4-
tives that are then separated and hydrolyzed with hydroxy-m-phenylenediamine, C6 H8 NO2 ,
sodium hydroxide [138]. M r 124.14, forms leaflets that darken on ex-
The major use of this compound is in the pro- posure to air and melt at 78 – 80 ◦ C with decom-
duction of mordant and acid dyes. 2-Amino-4- position. The compound is soluble in acid, al-
nitrophenol also has found limited use as an an- kali, alcohol, and acetone and sparingly sol-
tioxidant and light stabilizer in butyl rubbers and uble in chloroform, ether, and ligroin. 2,4-
as a catalyst in the manufacture of hexadiene. Diaminophenol usually is sold as the sulfate
2-Amino-4-nitrophenol has been shown to be [72556-58-2] (Diamol) or dihydrochloride salt
a skin irritant and continuous exposure should be [137-09-7] (Acrol, Amidol).
avoided. Toxicologic studies have shown it to be 2,4-Diaminophenol can be prepared from
nonaccumulative [139] but suggest it is carcino- 2,4-dinitrophenol by catalytic hydrogenation
genic [133]. or, less conveniently, by metal reduction in
acid solution (Béchamp method) [145–150].
2-Amino-4,6-dinitrophenol (18) [96-91-3], Alternatively, electrolytic reduction and subse-
C6 H5 N3 O5 , M r 199.13, 4,6-dinitro-2-amino- quent hydroxylation of 1,3-dinitrobenzene or 3-
phenol, picramic acid, forms dark red nee- nitroaniline in sulfuric acid can be undertaken
dles from alcohol and prisms from chloro- [151–153].
form, mp 169 – 170 ◦ C. The compound flashes The dihydrochloride salt is used as a photo-
at 210 ◦ C in contact with an open flame, ignites graphic developer. It also is applied as an inter-
rapidly, and burns relatively fast. 2-Amino-4,6- mediate in the manufacture of fur dyes, in hair
dinitrophenol is soluble in glacial acetic acid, dyeing, as a reagent in testing for ammonia and
water, alcohol, benzene, and aniline and spar- formaldehyde, and as an oxygen scavenger in
ingly soluble in ether and chloroform. water to prevent boiler corrosion [154].
The compound can be prepared from 2,4,6-
trinitrophenol (picric acid) by reduction with 2-Amino-4-chlorophenol [95-85-2],
sodium hydrosulfide [140], with ammonia – hy- C6 H6 ClNO, M r 143.58, forms colorless plates,
drogen sulfide followed by acetic acid neu- mp 139 – 140 ◦ C, that are extremely sensitive
tralization of the ammonium salt [141], with to oxidation when wet. For its production 2,5-
ethanolic hydrazine and copper [137], or elec- dichloronitrobenzene is converted to 4-chloro-
trolytically with vanadium sulfate in alco- 2-nitrophenol by reaction with sodium hydrox-
holic sulfuric acid [134]. Heating 4,6-dinitro-2- ide; this product is then reduced either with iron
benzamidophenol in concentrated HCl at 140 ◦ C [155], with hydrazine, or with hydrogen [156]
also yields picramic acid [142]. It is a major in- in the presence of Raney nickel or platinum
termediate in the manufacture of colorants, espe- catalysts.
cially mordant dyes. It has also been used as an
indicator dye in titrations (yellow with acid, red 2-Amino-4-methylphenol [95-84-1],
with alkali) and as a reagent for albumin deter- C7 H9 NO, M r 123.15, forms crystals, mp 135 ◦ C
mination. The induction of sister chromatid ex- (decomp.), that are almost insoluble in cold wa-
change and micronuclei formation by this com- ter. The compound is quite soluble in ethanol,
diethyl ether, and chloroform but is almost in-
10 Aminophenols

soluble in benzene. 2-Amino-4-methylphenol 2-Amino-4,6-dichlorophenol (23)

is obtained by reduction of 2-nitro-4-meth- [527-62-8], C6 H5 Cl2 NO, M r 178.03, is spar-
ylphenol either with hydrazine or catalytically ingly soluble in water and ethanol and decom-
[157]. poses when heated above 109 ◦ C. Industrial pro-
duction is by reduction of the corresponding ni-
2-Methoxy-5-methylaniline (20) [120-71-8], tro compound with iron [160] or with hydrazine.
2-amino-4-methylanisole, 3-amino-4-
methoxytoluene, C8 H11 NO, M r 137.18, forms 2-Methoxy-4-nitroaniline (24) [97-52-9],
needles or plates, mp 52 ◦ C, bp 235 ◦ C C7 H8 N2 O3 , M r 168.15, mp 140 – 142 ◦ C, is pre-
(101.3 kPa), that can be steam distilled. The pared by acetylation and subsequent nitration
compound is quite soluble in ethanol, diethyl of 2-methoxyaniline to form intermediate 33 ,
ether, and benzene, but not very soluble in cold which is then deacetylated to 24.
water. Production is by alkylation of 4-meth-
yl-2-nitrophenol and subsequent reduction with 2-Methoxy-5-nitroaniline (25) [99-59-2],
iron [158]. C7 H8 N2 O3 , M r 168.15, mp 118.5 – 119 ◦ C, is
prepared either by partial reduction of 2,4-
dinitroanisole (26) with ammonium or sodium
sulfide [161] or by nitration of 2-methoxyaniline
(27) [162].

2-Methoxyacetanilide (21) [93-26-5],

C9 H11 NO2 , M r 165.19, crystallizes as needles,
mp 86.5 ◦ C, bp 303 – 305 ◦ C (101.3 kPa). The
compound is quite soluble in acetic acid and
hot water. Production is by acetylation of 2-
methoxyaniline with acetic anhydride.

2-Methoxy-5-chloroaniline (22) [2401-24-3],

C7 H8 ClNO, M r 157.61, mp 84 ◦ C, is quite sol-
uble in ethanol and can be steam distilled. Pro-
duction is by reduction of the corresponding
nitro compound with iron [159]. 2-Amino-4-chloro-5-nitrophenol (28)
[6358-07-2], C6 H5 ClN2 O3 , M r 188.58, forms
yellow needles that darken when heated above
200 ◦ C and decompose above 225 ◦ C. The com-
pound is scarcely soluble in hot water but
quite soluble in ethanol. Industrial produc-
21 22 tion is by reaction of 2-amino-4-chlorophenol
with phosgene, nitration of the product 5-
chlorobenzoxazolone (29) with nitric acid to
form 5-chloro-4-nitrobenzoxazolone (30), and
subsequent hydrolysis with sodium hydroxide
[163].

23 24
Aminophenols 11

2-Amino-6-chloro-4-nitrophenol (31)
[6358-09-4], C6 H5 ClN2 O3 , M r 188.58, crystal-
lizes from water in yellow needles that contain 2-Methylbenzoxazole (35) [95-21-6],
1 mol of water. Dehydration occurs when the C8 H7 NO, M r 133.16, mp 8.5 – 10 ◦ C,
needles are heated above 100 ◦ C; the crystals bp 178 ◦ C, n20
D 1.5497, is made by cyclization
turn scarlet and finally melt at 160 ◦ C. The com- of 2-acetamidophenol. Its chief use is for the
pound is sparingly soluble in water and quite production of 2-amino-5-nitrophenol (15).
soluble in ethanol and diethyl ether. Industrial
production is by partial reduction of 6-chloro-
2,4-dinitrophenol with sodium hydrosulfide or
ammonium sulfide [164]. 35

Orthocaine [536-25-4], 3-amino-4-hy-

droxybenzoic acid methyl ester, methyl 3-
amino-4-hydroxybenzoate, Orthoform New,
C8 H9 NO3 , M r 167.16, mp 143 ◦ C, is almost
31 32 insoluble in cold, but soluble in hot water, and
very soluble in alcohol, ether, and dilute alkali.
For preparation, see [167], [168].
3-Amino-4-methoxybenzoic acid (32)
[2840-26-8], C8 H9 NO3 , M r 167.16, mp
204 – 205 ◦ C, forms needles or prisms that are
sparingly soluble in cold water and also in boil-
ing water (0.12 wt %). The crystals are sparingly
soluble in diethyl ether and quite soluble in hot
ethanol. Production is by reduction of the cor-
responding nitro compound. The compound is used as a topical anesthetic.
4-Amino-2-methoxy-acetanilide (34) Acetarsone [97-44-9], 3-acetamido-4-hy-
[5329-15-7], 4-acetamido-3-methoxyaniline, droxyphenylarsonic acid, acetarsol, stovarsol,
C9 H12 N2 O2 , M r 180.2, mp 120 – 121 ◦ C, is C8 H10 AsNO5 , M r 275.08, mp 240 – 250 ◦ C (de-
quite soluble in ethanol, ethyl acetate, ace- comp.), is practically insoluble in alcohols or
tone, and chloroform. The solubility in diethyl dilute acids, slightly soluble in water, and freely
ether is low. Production is by acetylation of 2- soluble in dilute aqueous alkali. For its prepara-
methoxyaniline and subsequent nitration with tion, see [169], [170].
nitric acid [165]. Nitro compound 33 is then
reduced with iron in dilute acetic acid [166].
12 Aminophenols

3-(N-Methylamino)phenol (37)
[14703-69-6], C7 H9 NO, M r 123.15, bp 170 ◦ C
(1.6 kPa), is easily soluble in ethyl acetate,
ethanol, diethyl ether, and benzene; it is spar-
ingly soluble in cold water, better in hot wa-
ter. Industrial synthesis is by heating 3-(N-meth-
ylamino)benzenesulfonic acid with sodium hy-
Salts of acetarsone are used in the treat- droxide at 200 – 220 ◦ C [176] or by the reaction
ment of intestinal amoebiasis, trade name Ac- of resorcinol with methylamine in the presence
etarsol, of vaginal trichomoniasis, trade name of aqueous phosphoric acid at 200 ◦ C [177].
S.V.C. (May and Baker), and as a constituent of
a mouthwash, trade name Pyrex (Bengué). Be- 3-(N,N-Diethylamino)phenol (38)
cause of acetarsone’s toxicity, safer drugs have [91-68-9], C10 H15 NO, M r 165.23, forms
been developed; lethal dose LD50 150 mg/kg rhombic bipyramidal crystals, mp 78 ◦ C,
(rabbit, oral). bp 276 – 280 ◦ C (101.3 kPa), bp 209 – 211 ◦ C
(1.6 kPa). Industrial synthesis is analogous
to the previously described synthesis of 3-
2.2. Derivatives of 3-Aminophenol (N,N-dimethylamino)phenol: from resorci-
nol and diethylamine, by reaction of 3-(N,N-
3-(N,N-Dimethylamino)phenol (36) diethylamino)benzenesulfonic acid with sodium
[99-07-0], 3-hydroxydimethylaniline, hydroxide, or by alkylation of 3-aminophenol
C8 H11 NO, M r 137.18, forms white needles, hydrochloride with ethanol.
mp 87 ◦ C. Boiling points quoted at various
pressures are 265 – 268 ◦ C (101.3 kPa), 206 ◦ C
(13.3 kPa), 194 ◦ C (6.7 kPa), 153 ◦ C (0.7 kPa).
The compound is soluble in alkali, mineral acid,
ethanol, ether, acetone, and benzene and practi-
cally insoluble in water.
37 38

39
36

3-(N,N-Dimethylamino)phenol can be pre-

pared by heating resorcinol with an aqueous so- 3-(N-Phenylamino)phenol (39) [101-18-8],
lution of dimethylamine and its hydrochloride C12 H11 NO, M r 185.22, mp 81.5 – 82 ◦ C, bp
at 200 ◦ C under pressure for 12 h [171], [172]. 340 ◦ C (101.3 kPa), is slightly soluble in
Alternatively, the treatment of dimethylaniline ethanol, diethyl ether, acetone, benzene, and
with oleum at 55 – 60 ◦ C, followed by fusion water. The compound is made by heating re-
with sodium hydroxide at 270 – 300 ◦ C, gives sorcinol and aniline at 200 ◦ C in the presence
3-(N,N-dimethylamino)phenol [173]. In addi- of aqueous phosphoric acid [62] or calcium
tion, 3-aminophenol may be methylated with di- chloride [178]. In another process, 3-amino-
methyl sulfate under neutral conditions [174] or phenol is heated with aniline hydrochloride at
its hydrochloride salt heated with methanol at 210 – 215 ◦ C [179].
170 ◦ C under pressure for 8 h to give the desired
product [175]. The compound is used primar- 4-Amino-2-hydroxybenzoic acid (40)
ily as an intermediate in the production of basic [65-49-6], 4-aminosalicylic acid (PAS),
(Red 3 and Red 11) and mordant (Red 77) dyes. C7 H7 NO3 , M r 153.13, white crystals from al-
cohol, melts at 150 – 151 ◦ C with effervescence
Aminophenols 13

and darkens on exposure to light and air. A droquinone at 200 – 250 ◦ C in alcoholic solution
reddish-brown crystalline powder is obtained on [185], [186].
recrystallization from ethanol – ether. 4-Amino- Its chief use is as a component in photo-
2-hydroxybenzoic acid is soluble in dilute so- graphic developers. Because the free compound
lutions of nitric acid and sodium hydroxide, is unstable in air and light, it usually is marketed
alcohol, and acetone; slightly soluble in water as the sulfate salt [55-55-0], Metol, mp 260 ◦ C
and ether; and virtually insoluble in benzene, (decomp.). It also finds application as an in-
chloroform, or carbon tetrachloride. It is un- termediate for fur and hair dyes and, under
stable in aqueous solution and decarboxylates certain circumstances, as a corrosion inhibitor
to form 3-aminophenol. Because of the insta- for steel. Prolonged exposure to 4-(N-meth-
bility of the free acid it is usually prepared as ylamino)phenol has been associated with the de-
the hydrochloride salt, mp 224 ◦ C (decomp.), velopment of dermatitis and allergies.
dissociation constant pKa 3.25.
4-(N,N-Dimethylamino)phenol (42)
[619-60-3], 4-hydroxydimethylaniline,
C8 H11 NO, M r 137.18, forms large rhombic
crystals from ether – hexane or ether – ligroin
that melt at 75 – 76 ◦ C, bp 101 – 103 ◦ C
40 (66.7 Pa). The compound forms a salt with sul-
furic acid, mp 208 – 210 ◦ C [187], [188].
4-Amino-2-hydroxybenzoic acid is manufac- Methylation of 4-aminophenol with a methyl
tured by carboxylation of 3-aminophenol under halide under pressure produces 4-(N,Ndimeth-
pressure with ammonium carbonate at 110 ◦ C ylamino)phenol. The major competing product,
[180] or with potassium bicarbonate and carbon 4-hydroxyphenyltrimethyl ammonium halide
dioxide at 85 – 90 ◦ C [181] and subsequent acid- (or the corresponding base), also yields 4-
ification. (N,N-dimethylamino)phenol on distillation. Al-
The major use of this compound is as a bacte- ternatively, it can be synthesized by dealky-
riostatic agent against tubercle bacilli. The com- lation of 4-methoxydimethylaniline with hy-
pound also is used as an adjunct to streptomycin droiodic acid at reflux temperature for 10 h
and isoniazid. The free acid and its sodium, [189] or by the photodecomposition of 4-
potassium, and calcium salts are marketed under dimethylaminobenzenediazonium tetrafluorob-
many trade names. Up to 10 – 15 g of the sodium orate [187].
salt may be administered each day, although pro- The compound is an intermediate in several
longed use may give rise to toxic symptoms. Oral synthetic reactions and recently has found ex-
LD50 of the free acid in mice is 4 g/kg. tensive use in experimental toxicity studies in
animals. It has been shown to cause methe-
moglobinemia; its metabolism in humans has
2.3. Derivatives of 4-Aminophenol been discussed in [190–195].

4-(N-Methylamino)phenol (41) [150-75-4],

4-hydroxy-N-methylaniline, C7 H9 NO,
M r 123.15, forms needles from benzene,
mp 87 ◦ C, bp 168 – 169 ◦ C (2 kPa); it is slightly
soluble in alcohol and insoluble in ether.
Industrial synthesis involves the decar- 41 42
boxylation of N-(4-hydroxyphenyl)glycine (47)
at elevated temperature in such solvents as
chlorobenzene – cyclohexanone [182]. It also
can be prepared by the methylation of 4-amino-
phenol [183] or from methylamine by heat-
ing with 4-chlorophenol and copper sulfate at
135 ◦ C in aqueous solution [184] or with hy- 43
14 Aminophenols

4-Hydroxyacetanilide (43) [103-90-2], 4- Industrial production of 4-ethoxyaniline is by

acetamidophenol, acetaminophen, paracetamol, reduction of 4-nitrophenetole with iron [207] or
forms large white monoclinic prisms from water with hydrogen under pressure in the presence
that melt at 169 – 171 ◦ C. The compound is odor- of a catalyst. Alternatively, 4-chlorophenetole
less and has a bitter taste. 4-Hydroxyacetanilide is heated with aqueous ammonia in the pres-
is insoluble in petroleum ether, pentane, and ence of copper(I) oxide at 225 ◦ C; the yield of
benzene; slightly soluble in ether and cold wa- 4-ethoxyaniline is 85 % [208].
ter; and soluble in hot water, alcohols, dimeth-
ylformamide, 1,2-dichloroethane, acetone, and 4-Ethoxyacetanilide (44) [62-44-2],
ethyl acetate. The dissociation constant, pK a , is phenacetin, p-acetophenetidine, 4-acetamido-
9.5 (25 ◦ C). phenetole, C10 H13 NO2 , M r 179.21, is a white
Production is by the acetylation of 4-amino- crystalline powder, mp 134 – 135 ◦ C. The com-
phenol. This can be achieved with acetic pound is odorless and has a slightly bitter taste;
acid and acetic anhydride at 80 ◦ C [196], it is sparingly soluble in cold water and more
[197], with acetic anhydride in pyridine at soluble in hot water, alcohol, ether, and chlo-
100 ◦ C [198], with acetyl chloride and pyri- roform. At relative humidities between 15 and
dine in toluene at 60 ◦ C [199], or by the ac- 90 % the equilibrium moisture content is about
tion of ketene in alcoholic suspension [200]. 2 % (25 ◦ C).
4-Hydroxyacetanilide also may be synthe-
sized directly from 4-nitrophenol. The available
reduction – acetylation systems include tin with
acetic acid [201], hydrogenation over Pd – C in
acetic anhydride [202], and hydrogenation over
platinum in acetic acid [203]. Other routes in-
clude rearrangement of 4-hydroxyacetophenone
hydrazone with sodium nitrite in sulfuric acid
44
[204] and the electrolytic hydroxylation of ac-
etanilide [205]. The main production route to 4-
4-Hydroxyacetanilide is used as an interme- ethoxyacetanilide is by catalytic reduction of
diate in the manufacture of azo dyes and pho- 4-nitrophenetole with hydrogen and subsequent
tographic chemicals. The compound possesses acetylation using acetic anhydride. The com-
antipyretic and analgesic properties and is used pound also can be synthesized by ethylating
widely in this context. The oral LD50 in rats is 4-nitrophenol with ethyl sulfate in alkali, re-
3.7 g/kg. ducing the nitro group to an amino group with
iron in acid, and then acetylating by boiling
4-Methoxyaniline [104-94-9], C7 H9 NO, with glacial acetic acid [209]. Alternatively, 4-
has M r 123.55, mp 58.5 ◦ C, bp 123.2 – 123.5 ◦ C aminophenol may be ethylated with ethyl iodide
(1.9 kPa), dipole moment 1.8 D (benzene), in alcoholic alkali; the resulting 4-phenetidine
d 55 67
4 1.092, nD 1.5559, viscosity η 3.215 mPa · s is then acetylated. The acetylation also may be
◦
(55 C). For its industrial production 4- carried out first, followed by the ethylation.
nitroanisole is reduced either with sodium sul- 4-Ethoxyacetanilide possesses both an-
fide [206] or with hydrogen in the presence of tipyretic and analgesic properties but is of little
precious-metal catalysts or Raney nickel. value for the relief of severe pain. Its use for pro-
longed periods should be avoided because one
4-Ethoxyaniline [156-43-4], C8 H11 NO, of its minor metabolites (2-hydroxyphenetidine)
M r 137.18, mp 2.4 ◦ C, bp 249.9 ◦ C (101.3 kPa), is nephrotoxic and may be involved in the for-
d 14.9
4 1.0652, n15.9 α 1.5572, is a colorless com- mation of methemoglobinemia. The oral LD50
pound at room temperature when pure; in the in rats is 1.65 g/kg [210].
light or in the presence of air, the liquid turns
brown. 4-Ethoxyaniline is slightly soluble in 5-Aminosalicylic acid (45) [89-57-6], 5-
water. amino-2-hydroxybenzoic acid, C7 H7 NO3 ,
M r 153.13, forms colorless crystals that turn
Aminophenols 15

brown on heating above 250 – 260 ◦ C and melt bacteriology. Prolonged use of this compound
at 283 ◦ C (decomp.). The crystals are insoluble may result in kidney damage [216].
in ethanol and cold water and sparingly soluble
in hot water.

47 48

4-Amino-2,6-dichlorophenol (48)
[5930-28-9], C6 H5 Cl2 NO, M r 178.03, can be
sublimed and melts at 167 ◦ C. The compound
is soluble in ethanol, diethyl ether, acetone, and
acetic acid; it is sparingly soluble in benzene and
almost insoluble in water.

The compound is made by reduction of 3-

nitrobenzoic acid at 115 – 145 ◦ C and 3.5 MPa 3. References
in dilute sulfuric acid and in the presence of plat-
inum catalyst. The intermediate hydroxylamine General References
derivative (46) rearranges to 45 under these 1. K.-F. Wedemeyer, in “Phenole,”Houben-Weyl
conditions [211]. Alternatively, 5-nitrosalicyclic Teil 1 and 2 (1976).
acid is reduced, for example, with zinc in hy- 2. Beilstein, 13, 354 – 549; 13 (2), 164 – 308.
drochloric acid [212].
Specific References
N-(4-Hydroxyphenyl)glycine (47) 3. E. G. Smith: The Wiswesser Line-Formula
[122-87-2], 4-hydroxyphenylaminoacetic Chemical Notation, McGraw-Hill, New York
acid, 4-oxyanilinoacetic acid, photoglycine, 1968.
C8 H9 NO3 , M r 167.16, forms aggregate spheres 4. G. Varsanyi: Assignment for Vibrational
or shiny leaflets from water; it turns brown at Spectra of Seven Hundred Benzene
200 ◦ C, begins to melt at 220 ◦ C, and melts com- Derivatives, Akademiai Kiado,
pletely with decomposition at 245 – 247 ◦ C. The Budapest – Adam Hilger, London 1974,
compound is soluble in alkali and mineral acid pp. 136, 206, 253, 473, 476, 478.
and sparingly soluble in water, glacial acetic 5. C. J Pouchert (ed.): The Aldrich Library of
acid, ethyl acetate, alcohol, ether, acetone, chlo- Infrared Spectra, 3rd ed., vol. 3, Aldrich
roform, and benzene. Chemical Co., Milwaukee, Wisc. 1981,
N-(4-Hydroxyphenyl)glycine can be pre- pp. 718 B, 720 D, 725 D.
pared from 4-aminophenol and chloroacetic acid 6. W. F. Forbes, I. R. Leckie, Can. J. Chem. 36
(1958) 1371 – 1380.
[213], [214] or by alkaline hydrolysis of the cor-
7. J. C. Dearden, W. F. Forbes, Can. J. Chem. 37
responding nitrile with subsequent elimination
(1959) 1294 – 1304.
of ammonia [215]. 8. Sadtler Catalog of Ultraviolet Spectra, The
N-(4-Hydroxyphenyl)glycine is used as a Sadtler Research Co., Philadelphia, Pa., SAD
photographic developer under the trade names of no. 236, 1894, 3509.
Glycine, Iconyl, and Monazol. It also is applied 9. Aldermaston Eight-peak Index of Mass
as a photoresist in the dye industry and serves as Spectra, Imperial Chemical Industries,
an intermediate in the production of 4-(N-meth- Organics Division, Manchester, & Mass
ylamino)phenol (Metol) by liberation of CO2 . Spectrometry Data Centre, Atomic Weapons
N-(4-Hydroxyphenyl)glycine is used in analyti- Research Establishment (AWRE),
cal chemistry for the determination of iron, phos- Aldermaston, U.K., p. 46.
phorus, and silicon and as an acid indicator in
16 Aminophenols

10. C. J. Pouchert, J. R. Campbell (eds): The 29. Mallinckrodt Inc., EP 41837, 1980 (W. R.
Aldrich Library of NMR Spectra, vol. 5., Clingan, E. L. Derrenbacker, T. J. Dunn).
Aldrich Chemical Company, Milwaukee, 30. Mallinckrodt Inc., US 4264529, 1975 (T. J.
Wisc., 1974 – 75, pp. 45 C, 51 B, 57 A. Dunn).
11. Sadtler Catalog of NMR Spectra, The Sadtler 31. Universal Oil, FR 1354430, 1964.
Research Co., Philadelphia, Pa., SAD no. 717, 32. BASF, DE 1244196, 1967.
1176, 10220. 33. Du Pont, US 2183019, 1939.
12. J. G. Grasselli (ed.): CRC Atlas of Spectral 34. Seiko Chem. Ind. Co. Ltd., JP 75135042, 1975.
Data and Physical Constants for Organic 35. Abbott Lab., US 3079435, 1963.
Compounds, CRC Press, Cleveland, Ohio, 36. Sumitomo, JP 30294/68, 1968.
1973, p. B 754. 37. Monsanto, US 2035292, 1933.
13. S. Ashfaquzzaman, A. K. Pant: Acta 38. P. Sidheswaran, V. Krishnan, A. N. Bhat:
Crystallogr., Sect. B. B 35 (1979) no. 6, “Catalytic Reduction of p-Nitrophenol to
1394 – 1399; Chem. Abstr. 91 (1979) 66707. p-Aminophenol,.” Indian J. Chem. Sect. A.
14. W. A. Caspari, Phil. Mag. 4, 1927, no. 7, 36A (1997) 149 – 152.
1276 – 1285. 39. Sumitomo, JP 2701/69, 1969.
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Aminoplastics → Amino Resins