Change of mechanism with a change of substituents for a Zincke reaction

Article abstract of DOI:10.1016/j.tetlet.2014.03.136

The reaction between N-(2,4-dinitrophenyl)-4-(4-pyridyl)pyridinium chloride and 4-aminothiophenol led to an unexpected displacement of the 2,4-dinitrophenyl group, in contrast with the normal Zincke product formed with other nucleophilic 4-substituted anilines. Evidence for a SET process was obtained from EPR spectra of the reaction mixture.

Full text of DOI:10.1016/j.tetlet.2014.03.136

Tetrahedron Letters 55 (2014) 3097–3099
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Tetrahedron Letters
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Change of mechanism with a change of substituents for a Zincke
reaction
⇑
Marcos Caroli Rezende , Ingrid Ponce, Rubén Oñate, Iriux Almodovar, Carolina Aliaga
Facultad de Química y Biología, Universidad de Santiago, Av. Bernardo O’Higgins 3363, Santiago, Chile
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction between N-(2,4-dinitrophenyl)-4-(4-pyridyl)pyridinium chloride and 4-aminothiophenol
led to an unexpected displacement of the 2,4-dinitrophenyl group, in contrast with the normal Zincke
product formed with other nucleophilic 4-substituted anilines. Evidence for a SET process was obtained
from EPR spectra of the reaction mixture.
Received 11 March 2014
Revised 26 March 2014
Accepted 31 March 2014
Available online 5 April 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Zincke reaction
4-Substituted anilines
Unexpected displacement product
SET process
The reaction of N-(2,4-dinitrophenyl)pyridinium chloride with
amines to form N-substituted pyridinium salts was described for
the first time by Theodor Zincke nearly a hundred years ago.1
The reaction proceeds via an ANRORC (Attack of Nucleophile
Ring-Opening Ring-Closure) mechanism, with the initial attack of
the pyridinium ring by the nucleophile, followed by ring opening
and subsequent ring closure, with the elimination of a molecule
of 2,4-dinitroaniline.2 The reaction thus provides a way of prepar-
ing N-substituted nitrogen heterocycles from the corresponding,
analogous N-(2,4-dinitrophenyl) salts. If secondary amines are
employed as nucleophiles in aqueous media, formation of the
ring-opened compounds leads to valuable synthetic intermediates
(Zincke aldehydes). Thus, Zincke reaction has found widespread
applications in organic synthesis. Recent reports employing the
reaction include the preparation of N,N0-diaryl-substituted 4,40-
bipyridinium salts,3 pyridinium derivatives of amino acids,4 N-ary-
lated pyridinium salts with reactive groups,5 4-aryl bispyridinium
salts,6 new photochromic dyes,7 and ionic polymers.8 Zincke alde-
hydes have been used as intermediates in a variety of applica-
tions.9 The ‘normal’ Zincke reaction is a formal replacement of
the 2,4-dinitrophenyl substituent by an alkyl or aryl group R
attached to the primary NH2 functionality. This may be called the
‘endocyclic’ pathway to distinguish it from the ‘exocyclic’ displace-
ment of the 2,4-dinitrophenyl substituent by the nucleophile. This
competing process may take place when the pyridinium ring is
substituted by electron-releasing groups.10 However, the reasons
for favoring such a process are still not entirely understood. Zincke
reactions that are anticipated to occur in a ‘normal’ way may turn
out to follow this competing pathway, leading to unexpected prod-
ucts. A dramatic example of this was the report of a ‘normal’ Zincke
reaction, in the preparation of imidazolium salts with a chiral N-
substituent.11 Reinvestigation of the reaction showed that the
formed products were not the reported salts, but resulted from
the displacement of the 2,4-dinitrophenyl substituent by the
nucleophile and the solvent.12 As part of our efforts to develop
organic spacers acting as self-assembled monolayers for modified
electrodes,13,14 we resorted to the Zincke reaction to prepare N-
substituted pyridinium salts 2.
The preparation of compounds 2 employing this procedure had
been described before, for a variety of substituted anilines.5 We
confirmed the formation of a ‘normal’ Zincke product (2a) by the
reaction of 4-aminophenol with the pyridinium salt (1).5 However,
by following the same procedure with 4-aminothiophenol, we
were surprised to obtain 4,40-bipyridyl and the sulfide (3) as the
sole products of the reaction (Scheme 1).
X-ray analysis of the obtained orange crystals confirmed its
unequivocal formation (Fig. 1).
Attempts to modify the reaction conditions, by employing sol-
vent-free conditions,15 led to the same products.
By applying the same reaction conditions with 4-methylthioan-
iline as nucleophile, we obtained the expected Zincke product (2b).
This observation suggested that the acidic proton present in thio-
phenol played a decisive role in diverting the course of the
reaction.
⇑
Corresponding author.
E-mail address: marcos.caroli@usach.cl (M.C. Rezende).
http://dx.doi.org/10.1016/j.tetlet.2014.03.136
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

3098
M. C. Rezende et al. / Tetrahedron Letters 55 (2014) 3097–3099
N
N
N
NH2
NH2
S
+
Cl-
NO2
0
10 20 30 40 50 60
Time, minutes
(if X= SH)
Cl-
N
X
NO2
X
NO2
10 gauss
NO2
1
3
2, X = OH (a)
X = SMe (b)
Scheme 1. Reaction of Zincke salt (1) with different 4-substituted anilines.
Figure 2. Epr spectrum of the reaction mixture in ethanol (g value = 2.00802). In
the inset, decay of the recorded signal with time.
N
S-
N
N
+
NH3
3
Cl-
NO2
+
N
Cl-
NO2
N
.
.
S
N
Figure 1. Ortep projection of compound (3).
NO2
NO2
1
Both 4-amino-phenol and -thiophenol are amphiphilic nucleo-
philes, resulting from the equilibria below (Scheme 2).
+
NH3
In the case of 4-aminophenol, the reaction products suggest
that the amino group behaves as a better, or more efficient nucle-
ophile than the phenolate. The opposite, however, occurs with 4-
aminothiophenol, a result which may be explained in terms of
the greater nucleophilicity of ArSꢀ in aromatic nucleophilic substi-
tutions, when compared with ArOꢀ.16 This argument might be
invoked if the reaction mechanism was in fact an SNAr process.
Scheme 3. A possible SET mechanism for the reaction.
been described nearly fifty years ago,17,18 and such a process would
have to circumvent a smaller steric hindrance.
In order to decide between the two mechanistic pathways, we
recorded epr spectra of an equimolar (25 mM) mixture of 1 and
4-aminothiophenol in ethanol. It was evident from the spectra that
a radical intermediate was formed, which collapsed to products
within 10–15 min (Fig. 2).
A possible mechanism for the reaction, compatible with the
above observation, is shown in Scheme 3. A single-electron transfer
from the thiophenolate anion to the N-dinitrophenyl ring leads to
an intermediate radical pair, which collapses to the observed prod-
uct by the elimination of 4,40-dipyridyl.
Another mechanistic possibility involved
a single-electron
transfer (SET) process. This process would be easier for the softer,
and better reducing agent ArSꢀ, than for the harder phenolate mol-
ecule. In addition, a direct nucleophilic attack by the thiophenolate
would have to overcome a significant steric barrier, and would lead
to a highly congested Meisenheimer intermediate. Intermolecular
charge-transfer from thiophenolates to 2,4-dinitrobenzene has
In conclusion, in the present communication we report the
unexpected change of pathways for Zincke salt (1) when reacting
with different 4-substituted anilines. Instead of the normal nucle-
ophilic attack at the 2-position of the pyridinium ring by the
amine, first step of the ANRORC mechanism, a 4-aminothiophenol,
in equilibrium with a zwitterionic thiophenolate, transferred one
electron to the pyridinium group. The resulting radical pair inter-
mediate rapidly collapsed to 4,40-dipiridyl and 2,4-dinitro-40-amin-
odiphenylsulfide (3). The postulated mechanism suggests that
other Zincke salts may undergo the same SET process when react-
ing with aminothiols.
NH3
NH2
X
XH
X = O,S
Scheme 2. Equilibria of 4-amino-phenol and -thiophenol with zwitterionic forms.

M. C. Rezende et al. / Tetrahedron Letters 55 (2014) 3097–3099
3099
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This work was financed by FONDECYT projects 1100022,
1110736 and PB0807. I.P. thanks Becas Chile and Conicyt for a doc-
toral fellowship and a postdoctoral Grant (#3140104). We thank
Profs. Gerard Parkin and Luis Campos of Columbia University and
the National Science Foundation (CHE-0619638) for the acquisition
of the X-ray diffractometer employed in confirming the structure
of 3.
Supplementary data
14. Ponce, I.; Silva, J. F.; Oñate, R.; Rezende, M. C.; Paez, M.; Zagal, J. H.; Pavez, J.;
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