Reactions of hydroxypyridines with 1-chloro-2,4,6-trinitrobenzene - Product structure, kinetics, and tautomerism

Article abstract of DOI:10.1002/1099-0690(200103)2001:6<1175::AID-EJOC1175>3.0.CO;2-6

Reactions between 1-chloro-2,4,6-trinitrobenzene and 2-hydroxypyridine, 3-hydroxypyridine, and 4-hydroxypyridine are reported 4-Hydroxypyridine produces the product of attack at the nitrogen atom, while 3-hydroxypyridine reacts at the oxygen atom. 2-Hydroxypyridine reacts as an ambidentate nucleophile, providing a mixture of products arising from attack at both the oxygen and the nitrogen atom Reactions between X-substituted-3-hydroxypyridines (X = H, 5-Cl, 6-CH₃) and 1-chloro-2,4,6-trinitrobenzene provided 3-pyridinyl 2,4,6-trinitrophenyl ethers, analysed by ¹H and ¹³C NMR spectra and by X-ray diffraction. Moderate heating of methanolic solutions of 3-pyridinyl 2,4,6-trinitrophenyl ether and of 6-methyl-3-pyridinyl 2,4,6-trinitrophenyl ether caused a methylation reaction of the pyridine nitrogen ring through trinitroanisole, providing 3-hydroxy-1-methylpyridinium picrate and 1,2-dimethyl-5-hydroxypyridinium picrate Kinetic data are compared and discussed.

Full text of DOI:10.1002/1099-0690(200103)2001:6<1175::AID-EJOC1175>3.0.CO;2-6

FULL PAPER
Reactions of Hydroxypyridines with 1-Chloro-2,4,6-trinitrobenzene ؊ Product
Structure, Kinetics, and Tautomerism
Carla Boga,[a] Anna Corradi Bonamartini,[b] Luciano Forlani,*[a] Vincenzo Modarelli,[a]
Lara Righi,[c] Paolo Sgarabotto,[c] and Paolo Edgardo Todesco[a]
Keywords: Aromatic substitution / Kinetics / Nitrogen heterocycles / Tautomerism
Reactions between 1-chloro-2,4,6-trinitrobenzene and 2-hy- 2,4,6-trinitrophenyl ethers, analysed by 1H and 13C NMR
droxypyridine, 3-hydroxypyridine, and 4-hydroxypyridine
are reported. 4-Hydroxypyridine produces the product of at- anolic solutions of 3-pyridinyl 2,4,6-trinitrophenyl ether and
tack at the nitrogen atom, while 3-hydroxypyridine reacts at of 6-methyl-3-pyridinyl 2,4,6-trinitrophenyl ether caused a
the oxygen atom. 2-Hydroxypyridine reacts as an ambident- methylation reaction of the pyridine nitrogen ring through
spectra and by X-ray diffraction. Moderate heating of meth-
ate nucleophile, providing a mixture of products arising from
attack at both the oxygen and the nitrogen atom. Reactions
between X-substituted-3-hydroxypyridines (X = H, 5-Cl, 6-
CH3) and 1-chloro-2,4,6-trinitrobenzene provided 3-pyridinyl
trinitroanisole, providing 3-hydroxy-1-methylpyridinium pic-
rate and 1,2-dimethyl-5-hydroxypyridinium picrate. Kinetic
data are compared and discussed.
Introduction
3-Hydroxypyridine and its derivatives display an interest-
ing form of tautomerism[1,15] (the tautomer is a betaine
form), which is shown in Scheme 2. Cationic and anionic
forms 4 and 6[16] are clearly possible intermediates on the
tautomeric pathway. It is possible to depict 5 in a formally
neutral oxo form.[17]
The tautomerism of hydroxypyridines[1] receives constant
attention in both the theoretical[2Ϫ6] and experimental[7Ϫ9]
fields, with particular regard being paid to the solvent ef-
fect. It is interesting to note that hydroxypyridines may be
simple models for investigating mechanisms of some enzym-
atic reactions[10] or for discerning the behaviour of the bases
of nucleic acids in connection with mutation due to base
mispairing or other mistaken helices.[11] Tautomerism and
the presence of association by hydrogen bonds[12] are relev-
ant to the structure, properties and replication character-
istics of nucleic acids.[13]
While 2-hydroxypyridine (1) and 4-hydroxypyridine (2)
have been the subject of much theoretical and experimental
investigation, 3-hydroxypyridine (3) has been less extens-
ively studied (Scheme 1). Derivatives of 3-hydroxypyridine
are potential biocides.[14] In principle, polynitro derivatives
may be of interest as rodenticides.
Scheme 2. Tautomerism of 3-hydroxypyridine
In previous papers, we investigated the kinetic behaviour
of 2-hydroxypyridine as a nucleophilic reagent[18] towards
1-halo-2,4,6-trinitrobenzenes and as a catalyst (together
with some related compounds such as δ-valerolactam,
benzamides) in the SNAr reaction[19Ϫ21] of nitro-activated
substrates and amines, in apolar solvents. When 2-hydroxy-
pyridine reacts with nitro-activated halobenzenes it is an
ambidentate nucleophile, acting through both the oxygen
and the nitrogen atom.
To obtain more information on the kinetic behaviour of
hydroxy pyridines as nucleophiles in SNAr reactions, and in
particular to investigate the nucleophilic power of the differ-
ent nucleophilic centres of hydroxypyridines, we report data
on reactions between 1-chloro-2,4,6-trinitrobenzene (‘‘pic-
ryl chloride’’, 9) and the three isomers 2-hydroxypyridine
(1), 4-hydroxypyridine (2), and 3-hydroxypyridine (3), as
well as 5-chloro-3-hydroxypyridine (7) and 3-hydroxy-6-
methylpyridine (8).
Scheme 1. Hydroxypyridines
[a]
`
Dipartimento di Chimica Organica ‘‘A. Mangini’’, Universita
di Bologna,
viale Risorgimento 4, 40136, Bologna, Italia
[b]
[c]
`
`
Dipartimento di Chimica, Facolta d’Ingegneria, Universita di
Modena,
via Campi 183, 41100 Modena, Italia
Dipartimento di Chimica Generale ed Inorganica, Chimica
Analitica, Chimica Fisica, Universita di Parma, Centro di
`
Studio per la Strutturistica Diffrattometrica del CNR
viale delle Scienze, 43100 Parma, Italia
Fax: (internat.) ϩ 39-51/209-3654
E-mail forlani@ms.fci.unibo.it
Eur. J. Org. Chem. 2001, 1175Ϫ1182
WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001
1434Ϫ193X/01/0306Ϫ1175 $ 17.50ϩ.50/0
1175

L. Forlani et al.
FULL PAPER
Results
shown in Scheme 4. Recently,[28] N-(4-nitrophenyl)-4-pyri-
done has been obtained not only from the direct attack of
the nitrogen atom of 2 onto 1-bromo-4-nitrobenzene, but
also (at high temperatures and in the presence of a base)
from the isomeric 4-nitrophenyl 4-pyridinyl ether. It is pos-
sible that 12 arises from 4-pyridinyl 2,4,6-trinitrophenyl
ether (13) by means of a rearrangement, as indicated by
pathway B of Scheme 4. This pathway B, under the experi-
mental conditions reported here (at low temperatures and
without a base in an inert solvent) is improbable. Further-
more, 12 was obtained in almost quantitative yields: in the
reaction mixtures, from low percentages of conversion right
up to high percentages of conversion, no evidence of the
presence of other isomers of 12 was obtained by TLC ana-
Reactions of 2-Hydroxypyridine
In agreement with our previous findings,[18] reactions, in
THF and in CH3CN, between 1 and 1-chloro-2,4,6-trinitro-
benzene (9) provided both isomers 10 and 11, as shown in
Scheme 3. Under our experimental conditions, no isomeriz-
ation from 10 to 11 (or vice versa) was observed.
1
lysis, by H NMR spectroscopic analysis of the crude reac-
tion product, or by UV/Vis spectroscopic analysis. The kN
value related to the reaction of Scheme 4 is reported in
Table 1.
Scheme 3. Reactions between 2-hydroxypyridine (1) and 1-chloro-
2,4,6-trinitrobenzene (9)
In principle, hydroxypyridines may also act as C-nucleo-
philes,[21,22] but we did not observe the presence of products
of C-attack in the reaction mixtures. Picryl chloride is also
a potentially ambidentate electrophile. Attack at C-3/C-5 of
9 is often found to be kinetically preferred,[22] but does not
lead to a stable product and hence we did not detect it in
this study. Kinetic constants of formation of 10 and 11,
kNobs and koObs, respectively (in sϪ1 molϪ1 dm3), were ob-
tained separately (see Exp. Sect.), and these data are shown
in Table 1.
Scheme 4. Reaction pathways to compound 12
Reactions of 3-Hydroxypyridines
Table 1 reports data concerning the reactions, in THF, of
3-hydroxypyridine (3) and 3-hydroxy-6-methylpyridine (8)
with 9 according to Scheme 5, with attack of the oxygen
atom on the substrate. Both nucleophilic centres, oxygen
and nitrogen, could react with 9. In principle, 3 may also
act as a C-nucleophile, although in practice this has not
been observed.
Even if 1 is considered to be strongly associated,[23Ϫ27]
under the reported experimental conditions both reactions
show regular kinetic behaviour: Both processes follow a se-
cond-order kinetic law, and the kobs (kNobs and koObs) values
are unaffected by any change in the initial concentration
value of 1.
The values of the [10]/[11] ratios of the two final products
calculated at ‘‘infinite’’ time (at about 100% of conversion)
are 2.4 and 4.0 in THF and in CH3CN, respectively. The
ratios obtained at the end of the reactions were also the
same at every percentage of conversion.
Alkylation of 3 with alkyl halides in CH3CN provides
betaines 17.[29] In the cases of 3-hydroxypyridine and 3-hy-
droxy-6-methylpyridine, the products of the attack on the
oxygen atom (14, 16) are unstable and react on simple heat-
ing of their methanolic solutions (see Scheme 5) to give 18
and 19 in almost quantitative yields. All attempts to crystal-
lize 14 and 16 from methanol provided 18 and 19. Attempts
Reactions of 4-Hydroxypyridine
The reaction between 9 and 2 (in acetonitrile) provides, to crystallize 14 and 16 from other solvents failed (see
in almost quantitative yield, the picramide derivative 12, as Exp. Sect.).
Table 1. Reactions between hydroxypyridines and 1-chloro-2,4,6-trinitrobenzene (9)
104 ϫ kO
104 ϫ kN
obs
n[c]
104 ϫ kO[d]
kN [d]
[a]
[b]
[b]
Isomer
Solvent
[9]0
obs
1[e]
1[f]
3[g]
8[g]
2[h]
THF
CH3CN
THF
4.0
2.1
1.2
1.0
1.0
3.55 Ϯ 0.2
0.74 Ϯ 0.02
1.33 Ϯ 0.08
7.30 Ϯ 1
Յ 5
3.15 Ϯ 0.1
1.34 Ϯ 0.06
Ϫ
11
4
3.9
0.75
0.41
2.0
5
(1.3)
THF
Ϫ
3
5
(7.3)
Յ 0.06
CH3CN
541 Ϯ 10
30
[a]
[b]
[c]
[d]
ϫ 104 (in mol dmϪ3). Ϫ
In sϪ1molϪ1 dm3; error is standard deviation. Ϫ Number of determinations. Ϫ
In sϪ1molϪ1 dm3;
calculated from Equations (1) and (2). Ϫ [1]o from 8·10Ϫ4 to 5·10Ϫ2 [mol dmϪ3]. Ϫ [1]o from 7·10Ϫ4 to 3·10Ϫ3 [mol dmϪ3]. Ϫ [3]o
[e]
[f]
[g]
and [8]o from 5·10Ϫ4 to 1·10Ϫ3 [mol dmϪ3]. Ϫ [2]o from 5·10Ϫ4 to 1.0·10Ϫ3 [mol dmϪ3].
[h]
1176
Eur. J. Org. Chem. 2001, 1175Ϫ1182

Reactions of Hydroxypyridines with 1-Chloro-2,4,6-trinitrobenzene
FULL PAPER
tion.[33] Probably, for moieties sterically less hindered than
the trinitrophenyl group, a pathway similar to that in
Scheme 6 may explain the apparent migration from O to N
of alkyl or aryl groups of derivatives of hydroxypyridines.
The structure of 15 was ascertained by single-crystal X-ray
analysis (Figure 1).
Scheme 5. Reactions between 3-hydroxypyridines and 9 and trans-
formation of 14 and 16 in methanol
The structures of 14, 16, 18, and 19 were assigned on the
basis of H and 13C NMR spectral data.[30] The structures
1
of 18 and 19 agree with those found in 1H-1H NOE experi-
ments and shows considerable enhancement of both the 2-
H and 6-H (18% and 14%) signals of 18, and of 2-H (23%)
and 6-CH3 (6%) of 19. These values were obtained by irra-
diating the NϪCH3 signal of 18 and 19. An oil showing the
Figure 1. Perspective view and atom labelling of compound 15;
displacement ellipsoids are drawn at the 50% probability level and
H atoms are drawn as small circles of arbitrary radii
In solution, 15 is only moderately stable. This explains
the low yield (60%). In THF, in DMSO and in methanol,
15 does not show any particular trinitrophenyl group reac-
tion. On heating 15 to 50Ϫ60 °C in THF or in DMSO,
considerable amounts of picric acid and of 7 are obtained.
In 7, the presence of the chlorine atom in position 5 prob-
ably depresses (through the electron-withdrawing effect) the
nucleophilic power of the aza nitrogen atom and com-
pounds corresponding to 18 or 19 cannot be formed.
1
same H and 13C NMR spectral characteristics as 14 was
obtained from the treatment of the sodium salt of 3 with 9
(see Exp. Sect.).
During attempts to crystallize 14 and 16 from methanol,
it was interesting to note that when the isomerization reac-
tion was halted at about 50% of conversion, the presence
of a large quantity of 2,4,6-trinitroanisole (20) (ca. 20%)
was observed in the methanolic solutions. Compound 20
was present in small amounts (Ͻ 2%) at the end of the
transformations of 14 into 18 and of 16 into 19 (see
Scheme 6).
Discussion
In principle, one possible nucleophilic centre may be the
negative oxygen atom of the anion of hydroxypyridines,
arising from the equilibrium in Scheme 7, which may also
permit attack through ring carbon atoms. It is known that
the oxygen anion is a more powerful nucleophile than the
dicoordinated oxygen atom.[34] With the equilibrium in
Scheme 7 in operation, and the nucleophile being the
phenoxide ion, a strong autoinhibition of the substitution
reaction was observed.[35] Because of the absence of a kin-
etic effect from the released acid, as the reaction progresses,
the reactions of 1, 2, 3, and 8 cannot be attributed to the
anionic (or zwitterionic) form of the nucleophile. They may,
however, be attributed to the undissociated nucleophiles.[35]
HCl released during the reactions probably protonates the
hydroxypyridines.
Scheme 6. Mechanism of the reaction between 14 (and 16) and
methanol
In separate experiments, we observed that trinitroanisole
(20) (obtained as described in the literature[31]) reacts with
3 and 8, providing 18 and 19, respectively. These findings
suggest a two-step mechanism, the first step being the at-
tack of the methanol onto 14 or 16, yielding 3 or 8 and
trinitroanisole (20), and the second step being the attack of
3 or 8 on 20. The formation of 18 and 19 may be explained
by the attack of the aza nitrogen atom of 3 or 8 on the sp3
carbon atom of 20, causing a demethylation reaction of 20,
as in an SN2 reaction.[32]
Scheme 7. Dissociation of hydroxypyridines
In conclusion, the intervention of methanol produces the
trinitroanisole intermediate, which is demethylated by 3 or
8. It is a reaction different to a simple shift from O to N,
such as in the case of alkyl group migration derivatives of
Reactions of 2-Hydroxypyridine
It has been reported that the use of 1 in SNAr reactions
2-alkoxypyridines under acid catalysis or on heating in solu- produces a particular kinetic effect in two main ways. The
Eur. J. Org. Chem. 2001, 1175Ϫ1182
1177

L. Forlani et al.
FULL PAPER
observed kinetic effect depends on the kind of solvent used.
The reaction indicated by k1 is not very significant, be-
i) Compound 1 is the nucleophile. Reactions between 1- cause in 1 the nucleophilic power of the dicoordinated oxy-
fluoro-2,4,6-trinitrobenzene and 1, in solvents less polar gen atom is weak.[34,35] The electron-withdrawing effect of
than those used here, show[18] (for the attack of the nitrogen the aza group depresses the nucleophilic power of the dico-
atom, i.e. for formation of 10 alone) autocatalytic behavi- ordinated oxygen atom of the OH group. Compound 21 is
our: kobs (in sϪ1 molϪ1 dm3) increases as [1]o values in- an amido form; its most nucleophilic centre should be the
crease, without reaching a constant value (as in ‘‘satura- oxygen atom (protonation also occurs at the oxygen atom),
tion’’ phenomena). We attribute this kinetic behaviour to and reaction k2 is unlikely. Consequently, pathways A and
the presence of molecular complexes between the substrate B of Scheme 8 should be the preferred reaction pathways.
and 2-hydroxypyridine on the reaction pathway.[18] 1H This conclusion is in accord with the literature concerning
NMR investigations show that these complexes mainly in- alkylation of 1.[43] From Scheme 8, assuming that 10 and 11
volve hydrogen bonding interactions.[36,37] In the more po- are from tautomers 1 and 21 respectively, if the tautomeric
lar THF, no evidence for autocatalysis is observed.
constant KT is known, then kN and kO may be calculated
ii) Compound 1 is the catalyst. SNAr reactions between by Equation (1) and Equation (2).[44]
1-fluoro-2,4-dinitrobenzene and amines (in apolar solvents)
kO ϭ koObs (1 ϩ KT)/KT
(1)
(2)
are catalysed by 1 (1 is a well-known[38] ‘‘polyfunctional
kN ϭ kNobs (1 ϩ KT)
catalyst’’): kobs values increase as the concentration of the
catalyst increases, until a constant value is reached. The
The KT value of 2-hydroxypyridine in acetonitrile is
plot of kobs vs. [1]o shows a saturation plateau. Some au-
thors explain[39,40] the saturation by self association of 2-
hydroxypyridine. However, our previous evidence (obtained
using 2-hydroxypyridine and related compounds) strongly
indicates[20] that the catalytic kinetic behaviour may be ex-
plained by the presence of an equilibrium involving all the
reagents (substrate and amine) and the catalyst. The level-
ling off of kobs values mainly arises from the obvious inter-
action (resembling acidϪbase interaction) between 1 and
amines.[20]
The kinetic feature reported here (in poorly associating
solvents THF and CH3CN) agrees (as well as the reactions
of 2, 3, and 8) with the conclusions discussed above. The
reactions of Scheme 2 to Scheme 4 are free of complications
and they follow the simple second-order kinetic law. In the
solvents used here, dimerization is probably low and virtu-
ally negligible.[41] No kinetic effects arising from association
between 9 and hydroxypyridines are observed, probably be-
cause the chloro derivatives are less prone to associate with
hydroxypyridines than the fluoro derivatives are.[36]
Of the isomers considered, only 2-hydroxypyridine be-
haves as a bidentate nucleophile; the possible reactions are
shown in Scheme 8. No evidence for isomerization from 10
to 11 (or vice versa) was obtained. It is known that the
migration of alkyl groups of 2-alkoxypyridines occurs
through acid catalysis.[42]
150,[43,45] and in THF (see Exp. Sect.) it is 12. Similar equa-
tions can be obtained for reactions of 2; in CH3CN, KT
ϭ
4.6.[45] The kN and kO values are reported in Table 1.
The KT value of 2-hydroxypyridine in THF indicates that
both tautomers are present (in THF) at the same time. The
KT values reported here agree with those reported in the
literature.[8,9,45] In particular, the tautomeric forms of 5-
chloro-2-hydroxypyridine are present in approximately
equal amounts in dioxane,[46] and both tautomers should
be detectable. In [D8]THF, however, low-temperature 1H
NMR unfortunately does not provide evidence for the sim-
ultaneous presence of both tautomers.[27]
In the solvent used here, the rate of formation of 10 is
close to that of 11, in agreement with the [11]/[10] ratios
reported in the Results Section. The dicoordinated oxygen
atom displays nucleophilicity similar to that of the neutral
nitrogen atom. However, the kN/kO ratios Ϫ of 11 in THF
and 267 in CH3CN Ϫ favour the nitrogen atom, as is to be
expected, considering the difference in basicity and nucleo-
philicity of the two neutral heteroatoms. Probably, the re-
activity at the oxygen atom of 21 arises from the structure
22, with charge separation as conventionally accepted for
the amido group (see Scheme 9).
Scheme 9. Charge separation of 2-hydroxypyridine
The reactivity at the nitrogen atom of 1 may arise from
the mesomeric effect of the hydroxy group, as depicted in
23. In position 2 of the pyridine ring, this mesomeric elec-
tronic effect is strongly balanced by the electron-with-
drawing inductive effect.[47] When the hydroxy group is far
from the aza nitrogen atom (2), the mesomeric electron-
donating effect of the OH group produces a reactivity at
the nitrogen atom higher than that in 1 (kN2 /k1N ϭ 15). Reac-
tion through the O centre of 2 is not competitive with N-
attack, and so no product of O-reaction is found. In ap-
Scheme 8. Reaction pathways of 2-hydroxypyridine with 9
1178
Eur. J. Org. Chem. 2001, 1175Ϫ1182

Reactions of Hydroxypyridines with 1-Chloro-2,4,6-trinitrobenzene
FULL PAPER
rotic, poorly polar solvents, the mechanism for the tauto- atom is enhanced by the electron-releasing effect of the
meric equilibrium of 1 involves the dimeric form of 1, which methyl group in position 6: k8O/k3O ϭ 5.5.
may be the intermediate for both tautomers as in
Scheme 10.[8,25,48] The current data show that the rate of
Conclusion
the studied reactions is unaffected by the presence of self as-
sociation.
In conclusion, while 2-hydroxypyridine is found to react
as an ambidentate nucleophile, 3-hydroxypyridines react es-
sentially as oxygen nucleophiles and 4-hydroxypyridine as a
nitrogen nucleophile. In agreement with literature re-
ports,[47] the ratio k1O/k3O ϭ 3 confirms that the electronic
interaction between the endocyclic nitrogen atom and the
hydroxy group in position 2 is mainly inductive in character.
There is a moderate superposition of the conjugative elec-
tron-releasing effect of the OH group in position 2, which
is less relevant in position 3. Probably, in 2 structure 25 is
so dominant that the oxygen atom cannot act as nucleo-
philic centre.
Scheme 10. Tautomerism of 2-hydroxypyridine by dimer formation
4-Hydroxypyridine
For 2, it is possible to draw a scheme similar to Scheme 8
for 1. However, 12 is the only product recovered, even if the
more populated form of 2 is the oxo form 24.[49]
The high reactivity of 2 may be explained by considering
that the nitrogen atom of 2, of the four nucleophilic centres
of the tautomers of Scheme 11, is clearly the centre most
prone to make the nucleophilic attack, because of the
strongly electron-donating mesomeric effect of the OH
group (without the electron-withdrawing inductive effect
present in isomer 1).
In agreement with our previous findings,[18,20] these data
show that the rates of the studied reactions are unaffected
by the presence or otherwise of self association of 1 or of
other hydroxypyridines. A tentative explanation may be the
possibility that the monomer and the dimer (which may be
also in a linear, noncyclic form) of 1 react with 9 at the
same rate. An alternative explanation is that the self associ-
ation and homoconjugation in solvents used here are not
important.[41,51]
Finally, attack by the nitrogen atom of hydroxypyridines
1 and 2 is faster than attack by the oxygen atom, as ex-
pected on the basis of the difference in nucleophilicity. The
kN/kO ratios arise from electronic interaction between the
aza nitrogen atom and the hydroxy group. The electronic
interaction is relevant to the rate of reactions, and to the
regioselectivity of the reactions.
Scheme 11. Tautomerism of 4-hydroxypyridine
Experimental Section
In conclusion, tautomer 2 is the form of 4-hydroxypyrid-
ine reactive towards 9. This is an example of the possibility
that the product can arise from the less prevalent tautomer
2, in agreement with the CurtinϪHammett principle.
General: The 1H and 13C NMR spectra were recorded at 200 or
300 MHz and 50.3 or 75.46 MHz, respectively, using Gemini 200
and 300 instruments. Chemical shifts were measured in δ (ppm)
with reference to TMS or to the solvent ([D6]DMSO: δ ϭ 2.6 and
1
39.5 for H and 13C spectra, respectively). Ϫ Melting points were
3-Hydroxypyridines
measured with a Büchi apparatus and are uncorrected. Ϫ UV/Vis
spectra were recorded with PerkinϪElmer Lambda 5 and Lambda
12 spectrophotometers.
In principle, the ethers 14, 15, and 16, may arise from
attack on picryl chloride either by the neutral oxygen atom
of 3, or from the charged oxygen atom of forms 5 and 6.
When the charged oxygen atom of the sodium salt of 3 is
the reacting centre, the reaction is very fast (see Exp. Sect.).
Thus, 5 should also be more reactive than 3. The fact that
the HCl generation did not affect the reaction rate as the
reaction progressed clearly indicates that very basic centres
are not involved in the reaction pathway. These reactions
may be associated with the formally neutral hydroxypyrid-
ines without intervention of the other forms of Scheme 1.
This conclusion agrees with those of von Philipsborn[30] and
of Albert and Phillips[50] regarding the phenolic form of 3
in apolar solvents. As a consequence, kO is identical with
Materials: Hydroxypyridines were commercial samples (Fluka)
purified by conventional procedures.[30] 1-Chloro-2,4,6-trinitroben-
zene (9) was a commercial sample (Carlo Erba), purified by crystal-
lization from chloroform, m.p. 82Ϫ83 °C. THF (Carlo Erba) was
dried with sodium, distilled, and then redistilled from LiAlH4 un-
der nitrogen immediately before use.[52] Trinitroanisole (20) was
prepared as described in the literature.[31]
General Procedure: A solution of 1 mmol of 9 was added to a solu-
tion of 2 mmol of the hydroxypyridine in THF (or CH3CN), with
vigorous stirring. After the disappearance of 9 (TLC, silica gel,
eluent dichloromethane), the solvent was removed under vacuum
(12 mm/Hg) and the reaction product was separated using a chro-
koObs for 3 in Table 1. In 8 the nucleophilicity of the oxygen matographic column (silica gel, eluent dichloromethane). The 1H
Eur. J. Org. Chem. 2001, 1175Ϫ1182 1179

L. Forlani et al.
FULL PAPER
2-Pyridinyl 2,4,6-Trinitrophenyl Ether (11):[18] M.p. 129Ϫ130 °C
(from methanol). Ϫ 13C NMR (75.46 MHz, [D6]DMSO): δ ϭ
111.2, 121.2, 125.1, 141.9, 143.5, 143.8, 144.2, 147.0, 160.6;
(CDCl3): δ ϭ 111.3, 120.8, 124.3, 141.0, 143.1, 144.9, 145.4,
146.8, 160.7.
NMR spectra of crude products resulting from reactions between
all of the hydroxypyridines and 9 are identical to those of the eluted
products. However, the spectral data of 14, 15, and 16 are different
from those of the solid product crystallized from methanol or from
a THF/methanol mixture. All attempts to crystallize 14, 15, and 16
from a number of solvents (dichloromethane, diethyl ether, tetrahy-
drofuran, acetonitrile, light petroleum) failed. Ϫ The 1H NMR and
MS spectra of compounds 10 and 11 are as previously reported.[18]
The yield of 12 was 95%. Ϫ The structures of 12, 14, 15, 16, 18,
and 19 were assigned on the basis of 1H and 13C NMR spectral
data and by comparison with the data by von Philipsborn.[30] The
spectrum of the crude reaction product of 2 is identical to that of
the eluted product and to that after crystallization from MeOH. Ϫ
Under the experimental conditions used, compounds 10, 11, and
12 are stable. In particular, no conversion of 10 into 11 (or of 11
into 10) was observed, even after long reaction times, either in the
absence or in the presence of 1.
N-(2,4,6-Trinitrophenyl)-4-pyridone (12): M.p 174Ϫ176 °C (from
1
methanol). Ϫ H NMR (300 MHz, [D6]acetone): δ ϭ 6.47 (d, J ϭ
7.9 Hz, 2 H), 7.90 (d, J ϭ 7.9 Hz, 2 H), 9.51 (s, 2 H, Ph). Ϫ 13C
NMR (75.46 MHz, [D6]acetone): δ ϭ 119.9, 126.0, 135.2, 140.9,
149.1, 149.2, 178.7. Ϫ MS (EI); m/z (%): 306 [Mϩ] (1), 229 (5), 172
(54),144 (88), 117 (26), 90 (14), 78 (48), 51 (100).
3-Pyridinyl 2,4,6-Trinitrophenyl Ether (14): Oil. Ϫ 1H NMR
(300 MHz, [D6]DMSO): δ ϭ 7.58 (dd, J ϭ 4.3 Hz, J ϭ 4.9 Hz, 1
H, 5-H), 7.70Ϫ7.85 (m, 1 H, 4-H), 8.45Ϫ8.60 (m, 2 H, 2-H and 6-
H), 9.38 (s, 2 H, Ph). Ϫ 13C NMR (75.46 MHz, [D6]DMSO): δ ϭ
123.0, 124.7, 125.7, 137.8, 143.8, 144.3, 145.5 (2 signals overlap),
153.5. Ϫ MS (EI); m/z (%): 306 [Mϩ], 229 (100), 199 (10), 95 (31).
Reaction between the Sodium Salt of 3 and 9: NaH (0.060 g,
2.5 mmol) was added to a vigorously stirred solution of 3 (0.183 g,
1.9 mmol) in 10 mL of anhydrous THF. After 10 min, compound
9 (0.504 g, 1.9 mmol) was slowly added. After 10 min, the solvent
was removed under vacuum and after column chromatography an
oil was obtained. Addition of this oil to a solution of 14 did not
5-Chloro-3-pyridinyl 2,4,6-Trinitrophenyl Ether (15): M.p. 145Ϫ146
°C (from methanol). Ϫ 1H NMR (300 MHz, [D6]DMSO): δ ϭ
7.99Ϫ8.02 (m, 1 H, 4-H), 8.58Ϫ8.61 (m, 2 H, 2-H, 6-H), 9.40 (s, 2
H, Ph). Ϫ 13C NMR (75.46 MHz, [D6]DMSO): δ ϭ 107.37, 123.3,
126.3, 131.8, 136.9, 144.1, 144.2, 144.5, 154.0. Ϫ MS (EI); m/z (%):
342 (3), 340 (9), 139 (8), 128 (5), 112 (11), 102 (29), 100 (100). Ϫ
HRMS for C11H5ClN4O7: calcd. 339.9847; found 339.9853.
1
change its H NMR spectrum.
Kinetics: The choice of solvents was determined by the low solubil-
ity of hydroxypyridines in a number of solvents. Ϫ The reaction at
[9]o ϭ 10Ϫ4 mol dmϪ3 was carried out by monitoring the appear-
ance of the reaction products using UV/Vis spectrophotometry. In
the case of reactions of 1, the reactions were monitored at 3 differ-
ent λ values to determine the quantities of 9, 10, and 11 and to
check the analytical data, taking into account that [9] ϩ [10] ϩ
[11] ϭ [9]o. Ϫ λ values used in the spectrophotometric determina-
tions are as follows:
6-Methyl-3-pyridinyl 2,4,6-Trinitrophenyl Ether (16): M.p. 126Ϫ128
°C (crude product). Ϫ 1H NMR (300 MHz, [D6]DMSO): δ ϭ 2.55
(s, 3 H, Me), 7.39 (d, J ϭ 8.6 Hz, 1 H, 5-H), 7.57 (dd, J ϭ 8.6 Hz,
J ϭ 3.3 Hz, 1 H, 4-H), 8.39 (d, J ϭ3.3 Hz, 1 H, 2-H), 9.36 (s, 2 H,
Ph). Ϫ 13C NMR (75.46 MHz, [D6]DMSO): δ ϭ 23.1, 123.6, 124.1,
125.7, 136.7, 143.6, 143.8, 144.6, 151.7, 154.0. Ϫ MS (EI); m/z (%):
320 (5) [Mϩ], 229 (8), 109 (42), 108 (12), 91 (14), 80 (100). Ϫ
HRMS for C12H8N4O7: calcd. 320.0393; found 320.0387.
λ ϭ 360, ε ϭ 300, 1000, 700 for 9, 10, and 11, respectively;
λ ϭ 380, ε ϭ 130, 1000, 230 for 9, 10, and 11, respectively;
λ ϭ 400, ε ϭ 30, 850, 70 for 9, 10, and 11, respectively;
λ ϭ 360, ε ϭ 13.000 for 12.
3-Hydroxypyridinium Picrate: M.p. 202Ϫ203 °C. This product was
made by mixing a saturated (methanol) solution of picric acid with
a
solution of 3-hydroxypyridine. Ϫ
1H NMR (300 MHz,
[D6]DMSO): δ ϭ 7.90Ϫ8.10 (m, 2 H, 4-H and 5-H), 8.40Ϫ8.55 (m,
2 H, 2-H and 6-H), 8.70 (s, 2 H, Ph), 11.40Ϫ11.70 (br. s, 2 H, OH
and NH).
From the analytical data, kobs values were calculated, as an initial
rate, by using conventional procedures. Table 2 reports some se-
lected experimental data.
3-Hydroxy-1-methylpyridinium Picrate (18): M.p. 197Ϫ199 °C
(from methanol) ref.[53] 202Ϫ203.
Ϫ
1H NMR (300 MHz,
[D6]DMSO): δ ϭ 4.38 (s, 3 H, NϪCH3), 7.90Ϫ8.10 (m, 2 H, 4-H
and 5-H), 8.45Ϫ8.60 (m, 2 H, 2-H and 6-H), 8.68 (s, 2 H, Ph),
11.00Ϫ12.00 (br. s,
Table 2. Reactions between 1-chloro-2,4,6-trinitrobenzene (9) and
hydroxypyridines at 30 °C
1 H, OH). Ϫ
13C NMR (75.46 MHz,
[D6]DMSO): δ ϭ 47.8, 124.1, 125.1, 128.2, 130.8, 133.7, 136.4,
141.8, 156.6, 160.8. Ϫ C12H10N4O8 (338.2): calcd. C 42.61, H 2.98,
N 16.56; found C 42.55, H 3.02, N 16.50. Ϫ λ ϭ 360, ε ϭ 13.000.
[2P]o ϫ 103 [mol dmϪ3 [a]
]
0.841 1.12 1.40 1.73 2.37 3.15
3.00 3.21 3.28 3.30 3.10 3.02
3.60 3.25 3.37 3.72 3.40 3.68
koNbs ϫ 104 [sϪ1 mol dmϪ3
koObs ϫ 104 [sϪ1 mol dmϪ3
]
]
[2P]o ϫ 103 [mol dmϪ3 [a]
]
5.05 6.31 7.15 26.1 52.2
3.02 3.00 3.24 3.20 3.35
3.58 3.77 3.68 3.41 3.54
5-Hydroxy-1,2-dimethylpyridinium Picrate (19): M.p. 190 °C (from
methanol). Ϫ H NMR (300 MHz, [D6]DMSO): δ ϭ 2.65 (s, 3 H,
koNbs ϫ 104 [sϪ1 mol dmϪ3
koObs ϫ 104 [sϪ1 mol dmϪ3
]
]
1
CϪCH3), 4.25 (s, 3 H, NϪCH3), 7.85Ϫ7.96 (m, 2 H, 3-H and 4-
H), 8.55Ϫ8.60 (m, 1 H, 6-H), 8.69 (s, 2 H, Ph), 11.45Ϫ11.65 (br. s,
1 H, OH). Ϫ 13C NMR (75.46 MHz, [D6]DMSO): δ ϭ 18.5, 45.5,
124.1, 125.1, 129.4, 131.7, 133.6, 141.8, 146.0, 154.6, 160.7. Ϫ
C13H12N4O8 (352.3): calcd. C 44.33, H 3.43, N 15.90; found C
44.45, H 3.47, N 15.80.
[a]
Solvent ϭ tetrahydrofuran; [9]o ϭ 4.0·10Ϫ4 [mol dmϪ3].
The KT value related to 1, in THF, was calculated by described
procedures.[45,48] Values of [1] ranged from 7·10Ϫ4 to 1·10Ϫ5 mol
dmϪ3. Compound 1: λmax ϭ 306 (ε ϭ 4.0·103); 2-methoxypyridine:
λ ϭ 306 (ε ϭ 1); 1-methyl-2-pyridone: λmax ϭ 306 (ε ϭ 4.45·103).
2,4,6-Trinitroanisole (20): M.p. 68 °C.[31]
Ϫ
1H NMR (300 MHz,
N-(2,4,6-Trinitrophenyl)-2-pyridone (10):[18] M.p. 194Ϫ195 °C (from
[D6]DMSO): δ ϭ 4.15 (s, 3 H, OCH3), 9.18 (s, 2 H, Ph). Ϫ 13C
methanol). Ϫ 13C NMR (75.46 MHz, [D6]DMSO): δ ϭ 107.5, NMR (75.46 MHz, [D6]DMSO): δ ϭ 64.8, 124.6, 141.4, 143.8,
120.3, 124.6, 131.5, 136.9, 142.8, 147.0, 147.2, 160.3.
1180
150.7.
Eur. J. Org. Chem. 2001, 1175Ϫ1182

Reactions of Hydroxypyridines with 1-Chloro-2,4,6-trinitrobenzene
˚
FULL PAPER
Table 3. Selected bond lengths [A], angles [°] and torsion angles [°] with e.s.d. values in brackets for compound 15
C(1)ϪC(2)
1.388(6)
C(3)ϪC(4)
1.376(6)
C(1)ϪC(6)
C(1)ϪO(1)
C(2)ϪC(3)
C(3)ϪCl(3)
1.364(6)
1.393(4)
1.380(5)
1.724(5)
C(4)ϪN(5)
N(5)ϪC(6)
O(1)ϪC(11)
1.331(6)
1.341(5)
1.362(5)
O(1)ϪC(1)ϪC(6)
O(1)ϪC(1)ϪC(2)
C(2)ϪC(1)ϪC(6)
C(1)ϪC(2)ϪC(3)
C(2)CϪC(3)ϪC(4)
116.4(3)
123.3(3)
120.3(4)
116.2(4)
121.1(3)
C(3)ϪC(4)ϪN(5)
C(4)ϪN(5)ϪC(6)
C(1)ϪC(6)ϪN(5)
C(1)ϪO(1)ϪC(11)
21.7(4)
118.1(4)
122.6(4)
118.7(2)
C(2)ϪC(1)ϪO(1)ϪC(11)
C(1)ϪO(1)ϪC(11)ϪC(12)
21.8(5)
76.8(4)
O(1)ϪC(1)ϪC(6)ϪN(5)
Ϫ178.2(4)
Molecular Geometry of 5-Chloro-3-pyridinyl 2,4,6-Trinitrophenyl
Ether (15): Selected bond lengths, angles, and torsion angles are
given in Table 3. The structure is shown in Figure 1. The intramole-
cular bond lengths and angles, in line with the hybridization ex-
pected for the atoms involved, are similar to those of analogous
ethers reported in the literature.[54]
Table 4. Experimental data for the X-ray diffraction studies on
crystalline compound 15
Empirical formula
Crystal habit
C11H5ClN4O7
prism
Crystal colour
Molecular mass
F(000)
pale brown
340.6
688
monoclinic
P21/c
The out-of-plane distortion of the oxygen atom from the mean pyr-
Crystal system
Space group
˚
idine plane [0.040(3) A] as well as the value of the
Cell parameters at 295 K[a]
O(1)ϪC(1)ϪC(6)ϪC(5) torsion angle [Ϫ178.2(4)°] and the dihedral
angle between the two mean planes of the six-membered rings
(87.9(1)°) are indicative of a possible conjugative interaction solely
of the oxygen p orbitals in the direction of the pyridine ring. The
nitro groups are not equivalently oriented with respect to the
phenyl ring, the dihedral angles between the planes involving
N(12), N(14), and N(16) and that of the benzene ring being 41.4(2),
5.6(2), and 25.5(3)°, respectively. Ϫ Packing is consistent with van
der Waals interactions.
˚
a [A]
9.505(2)
13.029(3)
11.299(3)
110.6(1)
1309.8(10)
4
˚
b [A]
˚
c [A]
β [°]
3
˚
V [A ]
Z
dcalcd. [g cmϪ3
]
1.72
Crystal dimensions [mm]
Linear absoption coefficient [cmϪ1
hkl range
0.32 ϫ 0.25 ϫ 0.45
30.7
]
Ϯh,k,l
272
Unique total data
Criterion of observation
Unique observed data (NO)
I Ͼ 2σ(I)
1577
Crystal Structure of (5-Chloro-3-pyridinyl) 2,4,6-Trinitrophenyl
Ether (15): Table 4 shows the experimental and crystallographic
data for 15. X-ray measurements were performed using a Siemens
AED single-crystal diffractometer in the range 3° Ͻ θ Ͻ 70° using
Number of refined parameters (NV)
228
Overdetermination ratio (NO/NV)
6.9
R
0.056
Rw
0.062
˚
Ni-filtered Cu-Kα radiation (λ ϭ 1.54178 A). The diffraction angle
GOF
0.840
θ for every reflection was determined on the basis of the orientation
matrix and the outline of the diffraction peak was collected in the
ω-2θ step scanning mode, using a scan width from (θ Ϫ 0.60)° to
(θ ϩ 0.60 ϩ ∆λ/λτγθ)°. The intensities Ihkl were determined by
analysing the reflection profiles using the Lehmann and Larsen[58]
procedure. Corrections for Lorentz and polarization effects were
performed. There were no corrections for absorption effects. The
structure was solved by direct methods and refined with cycles of
full-matrix, anisotropic least squares. All hydrogen atoms were loc-
ated in the difference Fourier map and refined isotropically.
Largest shift/esd
0.043
Ϫ3
˚
Largest peak [eA
Programs
]
0.39
[b]
[a]
Unit cell parameters were obtained by least-squares analysis of
the setting angles of 30 carefully centred reflections chosen from
[b]
various regions of the reciprocal space. Ϫ
SHELXS86,[55]
SHELX76,[56] PARST,[57] R ϭ |DF|/|Fo|, Rw ϭ [w(DF2)2/w(Fo ) ]
,
2 2 1/2
GOF ϭ [w|DF|2/(NO Ϫ NV)]1/2
.
Acknowledgments
`
The authors thank the Ministero dell’Universita e della Ricerca
Scientifica e Tecnologica, the Consiglio Nazionale delle Ricerche
(CNR, Roma) and the University of Bologna (Funds for Selected
Research Topics, 1997Ϫ1999).
Atomic scattering factors were taken from the International Tables
for X-ray Crystallography.[59] Bibliographic searches were carried
out using the Cambridge Structural Database Files through the
Servizio Italiano di Diffusione Dati Cristallografici, Parma, Italy.
Ϫ Crystallographic data (excluding structure factors) for the struc-
ture reported in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
no. CCDC-1220-154937. Copies of the data can be obtained
free of charge by writing to CCDC, 12 Union Road, Cambridge
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[O00223]
1182
Eur. J. Org. Chem. 2001, 1175Ϫ1182