A new leaving group in nucleophilic aromatic substitution reactions (S NAr)

Article abstract of DOI:10.3184/030823408X338693

Nucleophilic aromatic substitution of a 2,4-dinitrophenyl substituted pyrazole 1 with primary amines leads to substitution of the pyrazolo substituent. In these nucleophilic aromatic substitution reactions (S _NAr), 5-amino-1H-4- pyrazolecarbonitrile (3) acts as a new leaving group.

Full text of DOI:10.3184/030823408X338693

432 RESEARCH PAPER
AUGUST, 432–433
JOURNAL OF CHEMICAL RESEARCH 2008
A new leaving group in nucleophilic aromatic substitution reactions (SNAr)
Mehdi Bakavoli*, Mehdi Pordel, Mohammad Rahimizadeh and Pooneh Jahandari
Department of Chemistry, School of Sciences, Ferdowsi University, Mashhad 91775-1436, Iran
Nucleophilic aromatic substitution of a 2,4-dinitrophenyl substituted pyrazole 1 with primary amines leads to
substitution of the pyrazolo substituent. In these nucleophilic aromatic substitution reactions (SNAr), 5-amino-1H-4-
pyrazolecarbonitrile (3) acts as a new leaving group.
Keywords: nucleophilic aromatic substitution, leaving group, pyrazole, primary amines
While studying the cyclocondensation reaction of 5-amino-1-
(2,4-dinitrophenyl)-1H-pyrazole-4-carbonitrile 1 with ethylene-
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imidazole ring 4, we observed that the pyrazolo substituent
was fairly easily substituted by the diamine (Scheme 1),
reminiscent of the nucleophilic aromatic substitution
reactions (SNAr)1 of 2,4-dinitrochlorobenzene with amines.2
The success of SNAr reactions is mainly dependent upon
the presence of strongly electron-withdrawing groups in the
substrate to stabilise the negative charge in the intermediate
anion formed along the reaction path. The stabilising power
FDQꢀEHꢀHVWLPDWHGꢀIURPꢀWKHꢀįp values of the different groups.3
In the presence of mild electron-withdrawing groups, harsh
conditions like high pressure (up to 103 M Pa)4 or long reaction
times and high temperatures in dipolar aprotic solvents like
DMSO or DMF are needed.5-6 The greater reactivity of the
aryl halides containing strong electron-withdrawing groups
UHÀHFWVꢀ DQꢀ ipso-substitution in which the attachment of the
nucleophile to the aromatic ring is the rate determining step.7
In nucleophilic aromatic substitution the common leaving
groups are halides (X) and the leaving group order F >> Cl >
Br is commonly observed when activated aromatic derivatives
such as 1-X-2,4-dinitrobenzene or 1-X-4-nitrobenzene are
subjected to nucleophilic substitution.7
Apart from halides, other potential leaving groups such as
amine derivatives8-9 have been used in SNAr reactions. Also
aminotriazoles10 have been used as leaving groups in some
vicarious nucleophilic substitution (VNS) reactions. We now
report on pyrazole as a new leaving group in SNAr reactions.
In order to study further the leaving potential of the pyrazolo
substituent towards nucleophiles, we examined the reaction of
2,4-dinitrophenyl substituted pyrazole 1 with primary amines
LQꢀUHÀX[LQJꢀHWKDQROꢁꢀ$OOꢀWKHVHꢀUHDFWLRQVꢀRFFXUUHGꢀWRꢀJLYHꢀWKHꢀ
corresponding substituted products 2a–j. The compounds 2g–
j are derivatives formed (Scheme 2).
In contrast, weaker nucleophiles such as aryl amines as well
as bulkier nucleophiles, like secondary amines e.g. morpholine
or pyrrolidine, failed to replace the pyrazolo substituent.
A rough estimation based on TLC testing indicated that the
pyrazolo substituent possibly has a similar leaving ability to
chloride ion in SNAr reactions.
The intrinsic leaving potential of the pyrazolo substituent
is attributable to the electron-withdrawing inductive and
mesomeric effects exerted by the nitrogen atoms and the nitrile
moiety.
Note that unlike aryl halides, 2, 4-dinitrophenyl substituted
pyrazole 1 on subjection to non-anionic polarisable nucleophiles
in SNAr reactions does not produce hydrogen halide in the
NO2
NO2
NO2
NC
NH2
NO2
NO2
H2N
ethylendiamine
N
H2N
NH2
NH
N
N
H2N
NO2
N
N
NH(CH2)2NH2
HN
NC
N
2a
3
4
1
Scheme 1
NO2
NO2
2a, R= NH2-C2H4
2b, R= C2H5
NC
NH2
2c, R= C3H7
NO2
RNH2
EtOH, 2 h reflux
2d, R= (CH3)2CH
2e, R= C4H9
2f, R= C6H5-CH2
2g, R= 4-Cl-C6H4-CH2
2h, R= 4-Br-C6H4-CH2
2i, R= 4-CH3-C6H4-CH2
2j, R= Cyclo-Pr
NH
N
H2N
NO2
N
N
NHR
NC
3
2a–j
1
Scheme 2
* Correspondent. E-mail: mbakavoli@yahoo.com

JOURNAL OF CHEMICAL RESEARCH 2008 433
N-benzyl-N-(2,4-dinitrophenyl)amine (2f): Yellow crystals (EtOH),
yield (90%), m.p. 109–111°C (Lit. m.p. 107–109°C)14; 1H NMR
(100 MHz, acetone-d6ꢆꢀ įꢀ ꢊꢁꢈꢈꢀ ꢃGꢉ Jꢀ ꢀ ꢅꢁꢋꢀ +]ꢉꢀ ꢇ+ꢆꢉꢀ ꢏꢁꢌꢈꢀ ꢃGꢉꢀ
Jꢀ ꢀꢌꢍꢁꢍꢀ+]ꢉꢀꢌ+ꢆꢉꢀꢏꢁꢇꢄ±ꢏꢁꢋꢇꢀꢃPꢉꢀꢋ+ꢆꢉꢀꢈꢁꢌꢊꢀꢃGGꢉꢀJꢀ ꢀꢌꢍꢁꢍꢉꢀꢊꢁꢋꢀ+]ꢉꢀꢌ+ꢆꢉꢀ
8.93(d, Jꢀ ꢀꢊꢁꢋꢀ+]ꢉꢀꢌ+ꢆꢉꢀꢅꢁꢌꢅꢀꢃEUꢀVꢉꢀꢌ+ꢆꢉꢁꢀ06ꢀꢃm/z) 273 (M+). Found:
C, 57.35; H, 4.2; N, 23.7. Calcd. for C13H11N3O4 (273.2): C, 57.14;
H, 4.06; N, 23.42.
N-(4-chlorobenzyl)-N-(2,4-dinitrophenyl)amine (2g): Yellow
crystals (EtOH), yield (81%), m.p. 135–137°C; 1H NMR (100 MHz,
acetone-d6ꢆꢀįꢀꢊꢁꢅꢌꢀꢃGꢉ Jꢀ ꢀꢅꢁꢋꢀ+]ꢉꢀꢇ+ꢆꢉꢀꢏꢁꢌꢎꢀꢃGꢉꢀJꢀ ꢀꢌꢍꢁꢍꢀ+]ꢉꢀꢌ+ꢆꢉꢀ
7.25 (d, Jꢀ ꢀꢅꢁꢋꢍꢀ+]ꢉꢀꢇ+ꢆꢉꢀꢏꢁꢄꢌꢀꢃGꢉꢀJꢀ ꢀꢅꢁꢋꢍꢀ+]ꢉꢀꢇ+ꢆꢉꢀꢈꢁꢌꢏꢀꢃGGꢉꢀJꢀ ꢀ
10.0, 4.5 Hz, 1H), 8.95(d, Jꢀ ꢀꢊꢁꢋꢀ+]ꢉꢀꢌ+ꢆꢉꢀꢅꢁꢌꢏꢀꢃEUꢀVꢉꢀꢌ+ꢆꢉꢁꢀ06ꢀꢃm/z)
307 (M+). Found: C, 50.55; H, 3.3; N, 13.8. Calcd. for C13H10ClN3O4
(307.7): C, 50.75; H, 3.28; N, 13.66.
N-(4-bromobenzyl)-N-(2,4-dinitrophenyl)amine (2h): Yellow
crystals (EtOH), yield (83%), m.p. 137–139°C; 1H NMR (100 MHz,
acetone-d6ꢆꢀįꢀꢊꢁꢅꢇꢀꢃGꢉ Jꢀ ꢀꢅꢁꢋꢀ+]ꢉꢀꢇ+ꢆꢉꢀꢏꢁꢌꢏꢀꢃGꢉꢀJꢀ ꢀꢌꢍꢁꢍꢀ+]ꢉꢀꢌ+ꢆꢉꢀꢏꢁꢇꢎꢀ
(d, Jꢀ ꢀꢅꢁꢋꢍꢀ+]ꢉꢀꢇ+ꢆꢉꢀꢏꢁꢄꢇꢀꢃGꢉꢀJꢀ ꢀꢅꢁꢋꢍꢀ+]ꢉꢀꢇ+ꢆꢉꢀꢈꢁꢌꢋꢀꢃGGꢉꢀJꢀ ꢀꢌꢍꢁꢍꢉꢀ
4.5 Hz, 1H), 8.93(d, Jꢀ ꢀꢊꢁꢋꢀ+]ꢉꢀꢌ+ꢆꢉꢀꢅꢁꢌꢅꢀꢃEUꢀVꢉꢀꢌ+ꢆꢉꢁꢀ06ꢀꢃm/z) 287
(M+). Found: C, 43.95; H, 2.7; N, 12.2. Calcd. for C13H10BrN3O4
(287.3): C, 44.34; H, 2.86; N, 11.93.
N-(2,4-dinitrophenyl)-N-(4-methylbenzyl)amine (2i): Yellow
crystals (EtOH), yield (89%), m.p. 125–127°C; 1H NMR (100
MHz, acetone-d6ꢆꢀįꢀꢇꢁꢎꢈꢀꢃVꢉꢀꢄ+ꢆꢉꢀꢊꢁꢅꢍꢀꢃGꢉ Jꢀ ꢀꢅꢁꢋꢀ+]ꢉꢀꢇ+ꢆꢉꢀꢏꢁꢌꢅꢀꢃGꢉꢀ
Jꢀ ꢀꢌꢍꢁꢍꢀ+]ꢉꢀꢌ+ꢆꢉꢀꢏꢁꢇꢄꢀꢃGꢉꢀJꢀ ꢀꢅꢁꢋꢍꢀ+]ꢉꢀꢇ+ꢆꢉꢀꢏꢁꢇꢈꢀꢃGꢉꢀJꢀ ꢀꢅꢁꢋꢍꢀ+]ꢉꢀꢇ+ꢆꢉꢀ
8.18 (dd, Jꢀ ꢀꢌꢍꢁꢍꢉꢀꢊꢁꢋꢀ+]ꢉꢀꢌ+ꢆꢉꢀꢈꢁꢅꢏꢃGꢉꢀJꢀ ꢀꢊꢁꢋꢀ+]ꢉꢀꢌ+ꢆꢉꢀꢅꢁꢌꢋꢀꢃEUꢀVꢉꢀ
1H),. MS (m/z) 352 (M+). Found: C, 58.3; H, 4.4; N, 14.9. Calcd. for
C14H13N3O4 (352.1): C, 58.53; H, 4.56; N, 14.63.
course of the reaction. Therefore the pH value of the reaction
mixture is not altered and the protonation of the nucleophile
does not occur. Another feature of this reaction is the high
solubility in ethanol of the separated pyrazole 3 which allows
the easy work-up of the reaction mixture.
In summary, we have introduced a new leaving group in
SNAr reactions with relatively high leaving potential and no
impact on the pH value of the reaction mixture, therefore
leaving the nucleophile free from protonation so that it can
function effectively.
Experimental
Melting points were recorded on an Electrothermal type 9100 melting
1
point apparatus. The H NMR (100 MHz) spectra were recorded on
a Bruker AC 100 spectrometer. Chemical shifts are reported in ppm
GRZQ¿HOGꢀIURPꢀ706ꢀDVꢀLQWHUQDOꢀVWDQGDUGꢂꢀFRXSOLQJꢀFRQVWDQWVꢀJ are
given in Hertz. The mass spectra were scanned on a Varian. Mat CH-
7 at 70 eV. Elemental analysis was performed on a Thermo Finnigan
Flash EA microanalyser.
Compound 1 was obtained according to the published method.11
Other reagents were commercially available.
General procedure for the synthesis of 2a–j
To a solution of 1 (3.65 mmol) in EtOH (20 ml), ethylendiamine
ꢃꢄꢁꢅꢀPPROꢆꢀZDVꢀDGGHGꢁꢀ7KHꢀVROXWLRQꢀZDVꢀUHÀX[HGꢀIRUꢀꢇꢀKꢀDQGꢀWKHQꢀ
SRXUHGꢀ LQWRꢀ ZDWHUꢁꢀ 7KHꢀ SUHFLSLWDWHꢀ ZDVꢀ FROOHFWHGꢀ E\ꢀ ¿OWUDWLRQꢀ DQGꢀ
recrystallised from EtOH to give 2a.
N-1-(2,4-dinitrophenyl)-1,2-ethanediamine (2a): Yellow crystals
(EtOH), yield (90%), m.p. 146–148°C (Lit. m.p. 145–147°C);12
1H NMR (100 MHz, acetone-d6ꢆꢀ įꢀ ꢇꢁꢅꢈꢀ ꢃEUꢀ Vꢉꢀ ꢇ+ꢆꢉꢀ ꢄꢁꢊꢋ±ꢊꢁꢈꢋꢀ ꢃPꢉꢀ
4H), 7.35 (d, Jꢀ ꢀꢌꢍꢁꢍꢀ+]ꢉꢀꢌ+ꢆꢉꢀꢈꢁꢄꢋꢀꢃGGꢉꢀJꢀ ꢀꢌꢍꢁꢍꢉꢀꢊꢁꢋꢀ+]ꢉꢀꢌ+ꢆꢉꢀꢈꢁꢎꢋꢀ
(br s, 1H), 8.96 (d, Jꢀ ꢀꢊꢁꢋꢀ+]ꢉꢀꢌ+ꢆꢁꢀ06ꢀꢃm/z) 226 (M+). Found: C,
42.8; H, 4.5; N, 25.0. Calcd. for C8H10N4O4 (226.2): C, 42.48; H,
4.46; N, 24.77.
N-cyclopropyl-N-(2,4-dinitrophenyl)amine (2j): Yellow crystals
(EtOH), yield (71%), m.p. 115–117°C; 1H NMR (100 MHz, acetone-
d6ꢆꢀįꢀꢍꢁꢎꢋ±ꢍꢁꢏꢅꢀꢃPꢉꢀꢊ+ꢆꢉꢀꢍꢁꢅꢌ±ꢌꢁꢌꢇꢀꢃPꢉꢀꢌ+ꢆꢉꢀꢏꢁꢋꢋꢀꢃGꢉꢀJꢀ ꢀꢌꢍꢁꢍꢀ+]ꢉꢀ
1H), 8.35 (dd, Jꢀ ꢀ ꢌꢍꢁꢍꢉꢀ ꢊꢁꢋꢀ +]ꢉꢀ ꢌ+ꢆꢉꢀ ꢈꢁꢎꢋꢀ ꢃEUꢀ Vꢉꢀ ꢌ+ꢆꢉꢀ ꢈꢁꢅꢌꢀ ꢃGꢉꢀ
Jꢀ ꢀꢊꢁꢋꢀ+]ꢉꢀꢌ+ꢆꢁꢀ06ꢀꢃm/z) 223 (M+). Found: C, 48.2; H, 3.9; N, 19.1.
Calcd. for C9H9N3O4 (223.2): C, 48.43; H, 4.06; N, 18.83.
N-(2,4-dinitrophenyl)-N-ethylamine (2b): Yellow crystals (EtOH),
yield (82%), m.p. 110–112°C (Lit. m.p. 114–115°C)13; 1H NMR (100
MHz, acetone-d6ꢆꢀįꢀꢌꢁꢄꢋꢀꢃWꢉꢀJꢀ ꢀꢅꢁꢍꢀ+]ꢉꢀꢄ+ꢆꢉꢀꢄꢁꢋꢋ±ꢄꢁꢏꢋꢀꢃPꢉꢀꢇ+ꢆꢉꢀꢏꢁꢄꢏꢀ
(d, Jꢀ ꢀꢌꢍꢁꢍꢀ+]ꢉꢀꢌ+ꢆꢉꢀꢈꢁꢇꢅꢀꢃGGꢉꢀJꢀ ꢀꢌꢍꢁꢍꢉꢀꢊꢁꢋꢀ+]ꢉꢀꢌ+ꢆꢉꢀꢈꢁꢏꢋꢀꢃEUꢀVꢉꢀꢌ+ꢆꢉꢀ
8.92 (d, Jꢀ ꢀꢊꢁꢋꢀ+]ꢉꢀꢌ+ꢆꢁꢀ06ꢀꢃm/z) 211 (M+). Found: C, 45.3; H, 4.3; N,
20.1. Calcd. for C8H9N3O4 (211.2): C, 45.50; H, 4.30; N, 19.90.
N-(2,4-dinitrophenyl)-N-propylamine (2c): Yellow crystals (EtOH),
yield (86%), m.p. 101–103°C (Lit. m.p. 99–101°C)14; 1H NMR
(100 MHz, acetone-d6ꢆꢀįꢀꢌꢁꢇꢌꢀꢃWꢉꢀJꢀ ꢀꢅꢁꢍꢀ+]ꢉꢀꢄ+ꢆꢉꢀꢌꢁꢊꢋ±ꢌꢁꢏꢏꢀꢃPꢉꢀꢇ+ꢆꢉꢀ
3.45–3.65 (m, 2H), 7.38 (d, Jꢀ ꢀꢌꢍꢁꢍꢀ+]ꢉꢀꢌ+ꢆꢉꢀꢈꢁꢇꢈꢀꢃGGꢉꢀJꢀ ꢀꢌꢍꢁꢍꢉꢀꢊꢁꢋꢀ+]ꢉꢀ
1H), 8.75 (br s, 1H), 8.91(d, Jꢀ ꢀ ꢊꢁꢋꢀ +]ꢉꢀ ꢌ+ꢆꢁꢀ 06ꢀ ꢃm/z) 225 (M+).
Found: C, 47.6; H, 4.8; N, 18.90. Calcd. for C9H11N3O4 (225.2): C,
48.00; H, 4.92; N, 18.66.
Received 26 May 2008; accepted 25 June 2008
Paper 08/5291 doi: 10.3184/030823408X338693
Published online: 26 August 2008
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F. Terrier, Nucleophilic aromatic displacement, VCH, NY, 1991.
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N-(2,4-dinitrophenyl)-N-isopropylamine (2d): Yellow crystals
1
(EtOH), yield (71%), m.p. 92–94°C (Lit. m.p. 94–95°C)14; H NMR
(100 MHz, acetone-d6ꢆꢀįꢀꢌꢁꢌꢊꢀꢃGꢉ Jꢀ ꢀꢅꢁꢍꢉꢀꢎ+ꢆꢉꢀꢄꢁꢋꢄ±ꢄꢁꢏꢌꢀꢃPꢉꢀꢌ+ꢆꢉꢀꢏꢁꢄꢏꢀ
(d, Jꢀ ꢀꢌꢍꢁꢍꢀ+]ꢉꢀꢌ+ꢆꢉꢀꢈꢁꢇꢅꢀꢃGGꢉꢀJꢀ ꢀꢌꢍꢁꢍꢉꢀꢊꢁꢋꢀ+]ꢉꢀꢌ+ꢆꢉꢀꢈꢁꢏꢋꢀꢃEUꢀVꢉꢀꢌ+ꢆꢉꢀ
8.92 (d, Jꢀ ꢀꢊꢁꢋꢀ+]ꢉꢀꢌ+ꢆꢁꢀ06ꢀꢃm/z) 225 (M+). Found: C, 47.9; H, 4.9; N,
18.9. Calcd. for C9H11N3O4 (225.2): C, 48.00; H, 4.92; N, 18.66.
N-butyl-N-(2,4-dinitrophenyl)amine (2e): Yellow crystals (EtOH),
yield (83%), m.p. 87–90°C (Lit. m.p. 89–90°C)15; 1H NMR
(100 MHz, acetone-d6ꢆꢀįꢀꢍꢁꢅꢈꢀꢃWꢉꢀJꢀ ꢀꢅꢁꢍꢀ+]ꢉꢀꢄ+ꢆꢉꢀꢌꢁꢄꢋ±ꢌꢁꢈꢎꢀꢃPꢉꢀꢊ+ꢆꢉꢀ
3.47–3.67 (m, 2H), 7.35 (d, Jꢀ ꢀꢌꢍꢁꢍꢀ+]ꢉꢀꢌ+ꢆꢉꢀꢈꢁꢄꢊꢀꢃGGꢉꢀJꢀ ꢀꢌꢍꢁꢍꢉꢀ
4.5 Hz, 1H), 8.74 (br s, 1H), 8.95(d, Jꢀ ꢀꢊꢁꢋꢀ+]ꢉꢀꢌ+ꢆꢁꢀ06ꢀꢃm/z) 239
(M+). Found: C, 49.9; H, 5.4; N, 17.7. Calcd. for C10H13N3O4 (239.2):
C, 50.21; H, 5.48; N, 17.56.
9
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