~ ~~

Journal f . prakt. Chemie. Band 330, Heft 1, 1988, S. 44-50 VEB J. A. Barth, Leipzig

Nitration of the Acetanilide-type Compounds

€3. KYZIOL*
JANUSZ
ZDZISLAWDASZKIEWICZ,
Instytut Chemii, Wyisza Szkola Pedagogiczna, Opole, Poland

A b s t r a c t . Some aromatic compounds containing the imino group (NH) were nitrated in acetic
acid or anhydride, and the ortho/para ratios were measured. N-Methyl derivatives of the afoIemen-
tioned compounds are much less reactive when nitrated under comparable conditions and give signi-
ficantly lower o/p ratios. These results along with the literature data support the hypothesis
that the acetanilide-type compounds are nitrated via IS-nitro intermedia.tes.

Nitration of acetanilide has attracted much attention because of the way in which
the product composition depends on the reaction conditions, e.g. in 9814 sulphuric acid
mainly (9.io/,) 4-nitroacetanilide is produced while in acetic anhydride 2-nitroacetani-
lide predominates (7734,) [l, 2, 31. The variation in the ortholpara ratio is not limited
to acetanilide, it was also observed during nitration of several compounds including
anilides, diarylamines and some heterocyclic compounds containing an NH group [3].
All these compounds are referred to as ,,acetanilide-type compounds" i n this paper.
The dependence of the ortho/para ratio on the reaction conditions was explained
in many ways [4]. No explanation appears convincing, neither was experimentally
proved nor generally accepted. The mechanism proposed by T)E LA MARE and R I I ~
[3] was ruled out by SCIIOFIELD et al. [:',I. The influence of hydrogen bonding on isomer
distribution [3] seems to be rather obscure, moreover, it does not explain the signifi-
cant decrease of the o/p ratio (from 0.39 to 0.025) when the concentration of sulphuric
acid is increased from ti5.8n/, to 96"/, [ 11.
I n our opinion the variable ortho/para ratio, strongly influenced by the acidity
of the reaction mixture, is a result of two independent reaction paths operating during
nitration of acetanilide-type compounds. Direct attack of the nitroniuin ion on an aro-
matic ring favours formation of the para-nitro derivative while formation and rearrange-
msnt of N-nitro intermediates yields mainly ortho-nitro compounds. In most cases
it is not possible t o isolate mechanisms completely, although by varying the conditions
either can be made predominant. We have assumed that acetanilide-type compounds
when nitrated in acetic acid or anhydride solutions form C-nitro derivatives via N-
nitro intermediates.
This idea is neither new nor original. KAMDERGER postulated formation of N-phenyl-
nibramirie as an intermediate during nitration of aniline in sulphuric acid solution
"$1. However, it was shown that isomer distribution in N-phenylnitramine rearrangement
(9534) ortho) differs markedly from the orientation of substitution in nitration of aniline
(34:/, meta) carried out under comparable conditions [?I. In some cases a two-step
mechanism of nitration was proved beyond reasonable doubt,s.
It has been shown that nitration of 2,3-diriitroanilitie 181 and N-methyl-S74-dinitro-
aniline [9, 101 in mixed acids occurs by attack on the amino nitrogen atom followed
Z. DASZKIEWICZ,
J. B. KYZIOL,
Kitration of the Bcctanilido-type Compounds 45
by intramolecular rearrangement. Formation and rearrangement of N-nitro inter-
mediates has been also observed during nitrations of aminopyridines [I I] and carbazole
P21.
The common feature of all these compounds is low basicity of their amino (or ana-
logous) groups. It is well known that effectiveness of nitration of aliphatic secondary
amines is strongly dependent on the basicity of the substrate. High yields of correspond-
ing nitramines can be obtained only in the case of very weak bases [ 131. There is no
reason to exclude formation of such compounds during nitration of aromatic subst rates
although they are not stable under conditions required for their formation. Now we
wish to demonstrate that substitution of the imino hydrogen with the methyl group,
which makes formation of the N-nitro intermediate impossible, causes significant de-
crease in the ortho/para ratio.

Results
Acetanilide-type compounds and their N-methyl derivatives were nitrated with
stoichometric amounts of nitric acid in acetic acid solutions a t 50°C until complete
conversion. The progress of the reaction was controlled by TLC. Less reactive substrates
were nitrated in acetic anhydride a t 50°C or at higher temperature if necessary. Reac-
tion products were isolated by preparative layer chromatography and identified by
comparison (mixed mp., infra-red spectra, TLC) with authentic specimens.

Table 1 Reaction conditions of nitrations of the acctanilidc-type compounds and their N-methyl
derivatives
~ ~~

Substrate Reaction conditions Yields of Recovery

Solvent Temp. Time nitro of sub-
derivatives stratcs
("C) (h) (%) (%)
Carbazolc AcOH 50 3 95 -
9-Nethylcarbazole AcOH 50 3 90 -
Benzanilide AcOH 60 18 - 90
Benzanilide Ac,O 50 1 94 -

iT-Mcthylbcnzanilide Ac,O 50 5 7 77
Bcnzencsulphanilide Ac,O 95 1 90 -

N-Mcthylbenzcncsnlphanilide Ac,O 96 1 - 93
N-Dlcthylbenzcnesulphanilidc Ac,O b.p. 3 - 82
Acridone AcOH 50 7 97 -

N-Methylacridone AcOH 95 8 - 60
N-Mcthylacridone Ac,O 50 3 88 4
N-Methyldiphenylamine Bc,O 50 5 68 20
Triphenylamine Ac,O 50 6 90 3
Ethyl N-methyl-N-phenylrnrbamate Ac,O 50 (5 94 -

The data collected in Table 1 indicate that acetanilide-type compounds are more
reactive than their N-methyl derivatives. This difference was observed even in the case
of the very susceptible acridone which can be nitrated smoothly in acetic acid while
its 10-methyl derivative remains unchanged under the same conditions and must be
nitrated in acetic anhydride. The most significant example is benzenesulphanilide and
its N-methyl derivative. The first compound is nitrated quantitatively in acetic an-
hydride at 95"C, the second one seems to be resistant t o the action of nitric acid in
46 J. prakt. Chem. 330 (1988) 1

organic solvent solutions. Probably the electron withdrawing effect of the sulphonyl
group makes the direct attack of the nitronium ion on the aromatic ring impossible.
C-Nitro derivatives are formed in the intramolecular rearrangement of the N-nitro
intermediate.
Isomer distributions found i n nitrations of the acetanilide-type compounds in acetic
acid or anhydride media, completed with some literature data, are listed in Table 2 .

Table 2 Products of nitration of acetanilide-type compounds in acetic acid or anhydride solutions

Compound Isomers distribution Total O h

ortho para yield Ratio
(Yo) (%) (Yo)

Carbazole 28.5 71.5 95 0.40

Uenzanilide 49.5 50.5 94 0.49
Renzenesulphanilide 55.5 44.5 90 0.62
Methanesulphanilide [l] GO 40 0.76
Dihydroquinolone [3] 49.5 50.5 96 0.98
Acridone 53.0 47.0 97 1.13
Diphenylamine [18] 71.2 28.8 84 1.22
2-Methylacetanilide [3] 57.0 43.0 79 1.33
A-lcetanilide[l] 77 23 1.67
Methyl N-phenylcarbamate [3] 79.1 20.9 96 1.89
a-Chloroacetanilide [l] 80 20 85 2.00
10-Methyl-10,9-borazarophenanthrene 68 32 2.12
rl51

Half ortholpara ratios or corresponding quantitics for polycyclic or ring substituted

substrates are given in the last column (Table 3) contains analogous data of the N-
methyl derivatives.
In both cases the ortholpara ratios are dependent on the structure of the substrates
and vary in a broad range. A general conclusion can be drawn that ortholpara ratios
are significantly lower in the case of the tertiary substrates as compared with the
compounds containing an NH group. The change is moderate when two aryl groups
are bonded to the N H group (carbazole-4,4, diphenylamine-8.1, acridone-14.1 times)
hut in the case of carbamate and acetanilide very high ratios are observed.

Table 3 Products of nitration of N-methyl derivatives of some compounds from Table 2

Compound Isomers distribution Total OiP

ortho para yield Ratio
(%I (70) (%I
9-Meth ylcarbaiole 8.7 91.3 90 0.09
N-Methylbenzanilide resistant t o nitric acid in Ac,O
N-Methylbenzmesulphanilide resistant to nitric acid in Ac,O
N-Methyldipheny lamine 23.2 76.8 94 0.15
Triphenylamine 12.2 87.8 93 0.07
10-Methylacridone 7.7 9%.3 86 0.08
S-Methylacetanilide [3] 0 100 CH. 100 0
Ethyl N-methyl-N-phenyl-carbamate 0.4 99.6 94 0.002
Z. DASZKIEWICZ,
J. B. KYZIOL,
Nitration of the Acetanilide-type Compound? 47

Discussion
In our opinion the isomer distribution given in table 3 reflects the susceptibility of
the ortho and para positions to the electrophilic attack. In the case of acetanilide-type
compounds the isomer distribution is dependent on the equilibrium state between
the N-nitro derivatives and the intermediates occuring in the nitramine rearrangement.
X-N-NO,
I
/'\
1) ~ + o-intermediate + p-intermediate

i i
NHX NHX

/I I
\/
,
Schemn 1 NO,
I t is well known that a mixture of C-nitro cornpourids produced in the nitramirie
rearrangement contains variable, dependent on the structure and reaction conditions,
but usually high amounts of an ortho-nitro isomer [ 141.
Such an assumption makes some surprissing results of nitrations easily explainable,
e. g. isomer distributions observed in nitrations of 2-methylacetanilide [O]. I n acetic
anhydride only 4-nitro- and A-nitro derivatives are formed (o/p ratio 1.33) while in
concent rated (li4.0 - 83.70/,) sulphuric acid significant amounts of 3-nitro (ca. loo/?)
and 5-nitro-2-methylacetanilide (52.7 - 22.2"d) are also produced ; the ortho/para ratio
(0.14) is significantly lower. Hence, there must be a special mechanism operating only
in acetic: anhydride which prevents formation of the meta-substituted 2-methylacet-
anilides. Another example is the nitration of 10-methyl-10,9-borazarophenanthrene
in acetic anhydride which yields 0-nitro and 8-nitro derivatives only [15]. Considering
the state of valence of nitrogen atom and its positive charge, the result is rather surpri-
sing because this is the only example of a strongly activating and ortho/para directing
effect of the ammonium substituent. The mechanism involving formation and rearrange-
ment of N-nitro compounds seems to be the only possible explanation of both examples.
When a substrate yields two different cornpourids (e. g. isomers) in variable ratios
dependent on the reaction conditions, the possibility of two competing reaction mecha-
nisms must, be considered. Nitration of acetanilide and analogous compounds is such
a case. Competition of direct attack of the nitronium ion on the aromatic ring and forma-
tion of the N-nitro intermediates accounts for the variable isomer distribution.
H
lo

In strongly acidic media these equilibria are strongly shifted to the left and forma-
tion of the N-nitro compounds is restricted, hence in e.g. concentrated sulphuric acid
the one-step mechanism predominates. Decrease of sulphuric acid concentration facili-
tates formation of N-nitroacotanilide, consequently the lower the acid concentration
the greater the ortho/para ratio. In organic solvents nitration follows only the two-step
mechanism. The charige of the reaction mechanism causes significant changes in both :
48 J. prakt. Chem. 330 (1988) 1

reactivity and isomer distribution. I n sulphuric acid the order of reactivity is acetariilide
< benzene < toluene while in acetic anhydride acetanilide reacts diffusion.-controlled
[ 161, because the N-nitro intermediate is formed and rearranges easily. Nitration of
N-methylacetanilide in acetic anhydride gave only the 4-nitro derivative. Analogously
nitration of acetanilide in 987', sulphuric acid gave almost exclusively 4-nitroacetanilide
[3]. Despite different reaction conditions the results are similar because the same one-
step mechanism is operating in both cases. The hT-methylsubstituent in the first case,
and high acidity in the second make formation of the N-nitro intermediate impossible.
Nitration of acridorie in the presence of sulphuric acid [17] gives also an o/p ratio (0.18)
similar to that observed in nitration of N-methylacridone (0.08) and significantly lower
than that of nitration of acridone (1.13) in acetic anhydride.

Experimental
The substrates and their nitro derivatives were obtained according t o the literature data. The
methods of preparation of reference compounds were selected to avoid any doubts about their
structure. All the compounds were purified by crystallization and, if necessary, by column chromato-
graphy. The purity and structure were confirmed by TLC, elemental analyses and mass spectrometry
methods. The substrates and reference compounds which were not commercial samples are listed
in Table 4.

Table 4 Acetanilide type compounds and their derivatives

Compound Melting point "3 c %H

("C) Calcd. Found Calcd. Found

9-hlethylcarbazole 88-89 (EtOH) 8G.15 86.24 6.12 6.15

3-Xtrocarbazole 212-214 (aq. EtOH) 67.92 68.00 3.80 3.99
1-Xtrocarbazole 190-191 (ELOH) 67.92 68.07 3.80 3.89
:~-Pu'itro-9-methylcllrbazole 172-173 (AcEt) 69.06 69.12 4.46 4.50
l-Xitro-9-methylc~rbazole 92-93 (MeOH) 69.02 69.20 4.46 4.55
Acridone 357--358(DMF) 79.98 80.03 4.65 4.70
10-Methylacridone 207-208 (DMF) 80.36 80.41 5.30 5.89
2-Nitroncridone 3GO (DMF) 66.00 65.13 3.36 3.40
4-Sitroacridonc 271-272 (AeEt) (i5.00 65.01 3.36 3.51
2-Kitro-l O-methylacridone 284-285 (DMF) 66.14 66.17 3.96 4.07
~-~itro-lO-methylacridone 167-168 (CHCI,) 66.14 66.24 3.96 4.11
S-Methyldiphenylamine -5 (distilled)") 85.21 85.29 7.13 7.14
4-Kitro-~-methyldiphenylamine 67 -68 (MeOH) 68.41 G8.55 5.30 5.40
b-P;itro-S-methyldiphenylamine non-volat. oil 68.41 68.50 5.30 ;,.50
Triphenylamine 126-128 (hexane) 88.13 88.26 6.16 t121
4-~itrotriphenylamine 1.23- 144 (hexane) 74.47 74.56 4.86 4.99
2-Nitrotriphenylamine red oil 74.47 74.60 4.86 4.80
S-Methylbenzanilide 57-59 (MeOH) 79.59 79.67 6.20 (1.31
4'-Pu'itrobenzanilide 200-201 (AcEt) 64.46 64.57 4.16 4.33
2'-Kitrobenzanilide 93-94 (EtOH) 64.46 64.61 4.16 4.30
4'-Nitro-N-methylbenzanilide 112-113 (EtOH) 65.6% 65.70 4.76 4.88
:!'-Witro-hT-mcthylbenzanilide 83-84 (CIICI,) 65.62 66.77 4.76 4.81
Benzenesulphanilide 108-110 (hexane) 61.78 61.80 4.75 4.91
?;-Methyl benzensulphanilide 77-78 (aq. MeOH) G3.13 63.27 5.30 5.30
 J. B. Kyzroe, Nitration of the Acztmilide-typ? CwnpmndY
Z. DASZKIEWICZ, 49
Table 4 (continued)

Compound Melting point %C 76 H

("C) Chlrtl. Found Calcd. Pound

4'-R'itrobenzenesulphanilide 139-140 (PhlCle) 51.79 51.85 3.62 3.70

2'-Nitrobenzenesulphanilide 101-102 (EtOH) 51.79 51.90 3.62 3.69
Ethyl N-phenyl-N- visc. oiIb) 67.02 67.13 7.31 7.50
methylcarbamate
Ethyl N-(4-nitrophenyl)- 47-48 (EtOH) 33.57 53.69 3.39 6.42
N-methyl car barnate
Ethyl N-(2-nitropheny1)- yellow oil 53 5 7 63.70 j.39 6.40
N-methylcarbamate

") b.p. 138-141"C/1000 Pa, b, b.p. 94-96"C/1000 Pa, ni" = 1.5164

X i t r i c a c i d s o l u t i o n . Fuming nitric acid (loo"& HNO,, d = 1.56) was mixed with an equal
amount of concentrated sulphuric acid and dist'illed in vacuum. A stream of carbon dioxide was
passed through the distillate until nitrogen oxides were removed. The liquid was cooled in a dry-ice
bath until colourless needles of nitric acid separated. The slightly yellow liquid was decanted and the
crystals were melted in carbon dioxide atmosphere. Nitric acid was dissolved in purified acetic acid,
a small amount (ca. @(, mol) of urea was added, the solution WBS left, for 1hour a t room temperature
and the concentration (1-2 mol/l) of nitric acid was measured conductomet~rically.
N i t r a t i o n p r o c e d u r e . d solution of a subst,rate (1.0mmol) in 100 ml of acetic acid or anhydride
was warmed to 50°C and the stoichiometric amount of nitric acid dissolved in acetic acid was added
with stirring. The mixture was maintained a t 50°C for 3-18 11 and evapomted in vacuum a t a
temperature not exceeding 50°C. The residue was chromnt,ographed on 30 plates 20 x 20 em covered
with 1mm layer of silicagel/Kieselgel G, E. RIerck/using benzene - n-hexane 2 : l mixture as the
developing system. The zones were collected, ext,ratted with acetone, the extracts were evaporated
and the residues dried in vacuum t o constant weight. The products were crystallized and compared
with the previously preparated specimens.

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Received March, loth, t987 resp. June 6th, 1987.

Address of the authors: Dr. ZDZISLAW DASZKIEWICZ, Dr. JANUSZ KYZIOE,Instytut Chemii,
IVgisza Szkola Pedagogiczna, PL-45-052 Opole, Poland