Isomerization and rearrangement of (E)- and (Z)-phenylhydrazones of 3-benzoyl-5-phenyl-1,2,4-oxadiazole: Evidence for a 'new' type of acid-catalysis by copper(II) salts in mononuclear rearrangement of heterocycles

Article abstract of DOI:10.1002/poc.1327

A kinetic investigation in methanol of the title reaction has evidenced the occurrence of two processes: the 1 -E ? 1-Z isomerization and the rearrangement of the (Z)-isomer into the relevant 4-benzoylamino-2,5-diphenyl-1, 2,3-triazole (1-Z →T). The latter reaction is in line with the ability of the (Z)-phenylhydrazones of 3-benzoyl-1,2,4-oxadiazoles to undergo the so called mononuclear rearrangement of heterocycles (MRH). The occurrence of both the examined reactions is dependent on a Lewis-acid-catalysis. The obtained results have shown the possibility of a 'new' type of acid-catalysis (bifunctional catalysis by Lewis salts) in the MRH. This catalysis operates through a completely different mechanism with respect to the one recently observed, and deeply investigated, in the presence of protic acids for the (Z)-phenylhydrazone of 5-amino-3-benzoyl-1,2,4-oxadiazole, in both dioxane/water and toluene, for which the catalytic process was dependent on the protonation of N(4) ring-nitrogen of the 1,2,4-oxadiazole. As a matter of fact, the copper salts seem able to interact with the >C=N - NH - C₆H₅ moiety, yielding adducts which, in some cases, are prone to both isomerize and rearrange. Therefore, a similar behaviour in some manner parallel to that already observed in benzene in the presence of aliphatic amines (base-catalysis) has been evidenced. Copyright

Full text of DOI:10.1002/poc.1327

Research Article
Received: 8 October 2007,
Revised: 6 December 2007,
Accepted: 19 December 2007,
Published online in Wiley InterScience: 26 February 2008
(www.interscience.wiley.com) DOI 10.1002/poc.1327
Isomerization and rearrangement of (E)- and
Z)-phenylhydrazones of 3-benzoyl-5-phenyl-
,2,4-oxadiazole: evidence for a ‘new’ type
(
1
of acid-catalysis by copper(II) salts in
mononuclear rearrangement of heterocycles
a
a
b
Francesca D’Anna *, Vincenzo Frenna , Susanna Guernelli ,
a
a
b
Gabriella Macaluso , Salvatore Marullo and Domenico Spinelli **
A kinetic investigation in methanol of the title reaction has evidenced the occurrence of two processes: the 1-E !1-Z
isomerization and the rearrangement of the (Z)-isomer into the relevant 4-benzoylamino-2,5-diphenyl-1,2,3-triazole
(
1-Z !T). The latter reaction is in line with the ability of the (Z)-phenylhydrazones of 3-benzoyl-1,2,4-oxadiazoles to
undergo the so called mononuclear rearrangement of heterocycles (MRH). The occurrence of both the examined
reactions is dependent on a Lewis-acid-catalysis. The obtained results have shown the possibility of a ‘new’ type of
acid-catalysis (bifunctional catalysis by Lewis salts) in the MRH. This catalysis operates through a completely different
mechanism with respect to the one recently observed, and deeply investigated, in the presence of protic acids for the
(Z)-phenylhydrazone of 5-amino-3-benzoyl-1,2,4-oxadiazole, in both dioxane/water and toluene, for which the
catalytic process was dependent on the protonation of N(4) ring-nitrogen of the 1,2,4-oxadiazole. As a matter of
—
6 5
fact, the copper salts seem able to interact with the >C—N—NH—C H moiety, yielding adducts which, in some cases,
are prone to both isomerize and rearrange. Therefore, a similar behaviour in some manner parallel to that already
observed in benzene in the presence of aliphatic amines (base-catalysis) has been evidenced. Copyright ß 2008 John
Wiley & Sons, Ltd.
Supplementary electronic material for this paper is available in Wiley InterScience at http://www.mrw.interscience.wiley.com/
suppmat/0894-3230/suppmat/
Keywords: azole-to-azole interconversion; copper salts catalysis; E,Z-Isomerization; Lewis-acids-catalysis
study of synthesis and reactivity of the (E)- and (Z)-arylhydrazones
INTRODUCTION
[28–35]
of 3-benzoyl-5-X-1,2,4-oxadiazole.
In principle, these hydra-
Transition metal catalysis has attracted much attention in
zones might be able to show a dichotomic behaviour. On one
hand, in both polar and apolar solvents (acetonitrile, dioxane and
benzene), and in the presence of organic bases (e.g. piperidine)
the E !Z isomerization around the imino bond has been
[1–8]
chemistry.
This is not surprising as several examples of
efficient natural reactions catalyzed by metal enzymes are
known, and nature itself represents an ‘infinite’source of teaching
and inspiration for researchers.
[33]
observed.
This isomerization has been also investigated on a
In order to perform metal catalysis, it is important to consider
both the characteristics of the metal (or of the ion, if salts are
used) and the structure of the involved substrate. Several reports
in literature have shown that copper(II) salts are able to form
complexes with organic p- or p-donor ligands having both
series of meta- and para-substituted phenylhydrazones eviden-
*
*
Dipartimento di Chimica Organica ‘E. Patern o` ’, Universit a` di Palermo, Viale
delle Scienze, Parco d’Orleans 2, 90128 Palermo, Italy.
E-mail: fdanna@unipa.it
[9–17]
heterocyclic units
of nitrogen atoms.
(e.g. azoles, azines etc.) and various kinds
The interest in this area is also related to
[18–20]
*
Dipartimento di Chimica Organica ‘A. Mangini ’, Universit a` di Bologna, Via San
Giacomo 11, 40126 Bologna, Italy.
the biological importance of interactions of copper ions with the
imidazole of histidine in several biological molecules and metallo
[21–23]
[24–27]
E-mail: domenico.spinelli@unibo.it
proteins
as well as with pyrrole ring in porphyrins.
Indeed, these interactions represent the prerequisite for their
reactivity.
Due to our interest in the study of the reactivity of
five-membered heterocyclic compounds, we decided to inves-
tigate the effect of metal catalysis on heterocyclic rearrange-
ments. In particular, for a long time we have been involved in the
a
F. D’Anna, V. Frenna, G. Macaluso, S. Marullo
Dipartimento di Chimica Organica ‘E. Patern o` ’, Universit a` di Palermo, Viale
delle Scienze, Parco d’Orleans 2, 90128 Palermo, Italy
b
S. Guernelli, D. Spinelli
Dipartimento di Chimica Organica ‘A. Mangini ’, Universit a` di Bologna, Via San
Giacomo 11, 40126 Bologna, Italy
J. Phys. Org. Chem. 2008, 21 306–314
Copyright ß 2008 John Wiley & Sons, Ltd.

HYDRAZONE ISOMERIZATION AND REARRANGEMENT
Scheme 1. Isomerization of 1-E and rearrangement of 1-Z.
[
33]
cing the occurrence of an unusual substituent effect.
other hand, the (Z)-arylhydrazones of 3-benzoyl-5-phenyl-
,2,4-oxadiazole, under the same experimental conditions used
On the
1,2,4-oxadiazole (1-E and 1-Z) give both the 1-E ! 1-Z
isomerization and the 1-Z !T rearrangement into the relevant
4-benzoylamino-2,5-diphenyl-1,2,3-triazole. Considering all these
information and particularly the last intriguing behaviour (see
above the stability of 1-E in benzene in the presence of acetic
acid ), we started with a quantitative examination of the
reactivity of 1-E and 1-Z in methanol in the presence of some
Cu(II) salts to gain mechanistic information. Thus, we carried out a
1
for the isomerization, rearrange into the relevant 2-aryl-4-
benzoylamino-5-phenyl-1,2,3-triazoles by means of a mono-
nuclear rearrangement of heterocycles (MRH; as named by
[33]
[29,36–39]
Boulton and Katritzky; Scheme 1).
In contrast, the (E)-
phenylhydrazone of 3-benzoyl-5-phenyl-1,2,4-oxadiazole (1-E)
remains unchanged in benzene either at room temperature or by
heating in the presence of an excess of acetic acid (48 h at
study by using several Cu(II) salts [CuSO
4
ꢀ5H
2
O, Cu(ClO
4
)
2
ꢀ6H
2
O,
CuCl , CuBr and Cu(OAc) ꢀH O] having different characteristics,
2
2
2
2
[33]
333 K).
that is, anions showing different coordinating ability as well as
different basic and nucleophilic aptitude.
MRHs are intramolecular nucleophilic substitutions (S
N
i). They
and show
[40]
proceed via a ‘quasi-aromatic’ transition state (TS)
reaction rates largely influenced by both the acidity of the
hydrogen of the N —H on the arylhydrazonic nitrogen and the
nucleophilicity of the Na.
Usually this ring-to-ring interconversion can occur via a
a
[29,34]
RESULTS AND DISCUSSION
A qualitative approach
[28,30]
general-base-catalyzed and/or a uncatalyzed pathway.
Moreover, a specific-acid-catalyzed pathway has been observed
if an amino group is present at the C-5 of the 1,2,4-oxadiazole
ring, thus rendering the N-4 atom so basic to undergo a
protonation: an example is given by the behaviour of the
In order to verify the ability of the above Cu(II) salts to induce the
isomerization and/or the rearrangement, we have checked the
reactivity of 1-E and 1-Z in methanol in the presence of
equimolar amounts of the salt. All the reactions were monitored
for 8 h (refer to Experimental section).
(
Z)-phenylhydrazone of 5-amino-3-benzoyl-1,2,4-oxadiazole in
[41–43]
water/dioxane or in toluene in the presence of protic acids.
Moreover, for comparison, we have carried out a blank test on a
methanol solution of 1-Z since its rearrangement into the
relevant triazole can significantly proceed via an uncatalyzed
Also in non-aqueous solvents the MRHs can occur by
base-catalyzed or uncatalyzed pathways. They have been studied
in conventional solvents (acetonitrile, benzene, dioxane, ethyl
[30,31]
pathway in a protic solvent.
The same blank reaction has
[
31,32]
acetate and methanol),
and in organized and pre-organized
been carried out also with 1-E which appeared to remain
unchanged. The results are reported in Table 1.
[44]
[45]
systems (micelles and b-cyclodextrin ) and recently in room
temperature ionic liquids.
However, it has been qualitatively outlined that in methanol
[46–48]
An analysis of data evidenced that the outcome of the
reactions is affected by the nature of the anion of the copper
salts. In particular, CuCl , CuBr and Cu(OAc) ꢀH O were able to
[49]
and in the presence of copper acetate (Lewis acids),
the (E)-
2
2
2
2
and the (Z)-phenylhydrazones of the 3-benzoyl-5-phenyl-
promote both the 1-E !1-Z isomerization and the 1-Z !T
rearrangement. With these salts, increasingly higher yields in
triazole (from 24 ꢁ3% to 91 ꢁ3%), with respect to the blank test
(
17 ꢁ3%), were obtained showing the occurrence of catalysis.
At first sight some results concerning the yields in T from 1-E
and 1-Z (comparable or higher yields from 1-E, which gives the
MRH only after the isomerization into 1-Z) could appear
unexpected, but they can be easily related to the different
solubility in methanol of the two isomers (refer to Experimental
section).
In contrast, CuSO
4
ꢀ5H
2
O and Cu(ClO
4
)
2
ꢀ6H
2
O seem able to
induce only the 1-E !1-Z isomerization as indicated by yields in
triazole strictly comparable to that observed in pure methanol
[
(17.5–18.0) ꢁ3% vs. 17 ꢁ3%].
Data in Table 1 indicate that the nature of the anion in the
salts affects the reactivity. Among acetate, bromide and chloride
the former is the best catalyst for the 1-Z !T rearrangement,
while the chloride anion seems to be the worst. In contrast,
sulphate and perchlorate did not favour any rearrangement.
Scheme 2. 1-E (* 1-Z isomerization and 1-Z !1-T rearrangement
J. Phys. Org. Chem. 2008, 21 306–314
Copyright ß 2008 John Wiley & Sons, Ltd.
www.interscience.wiley.com/journal/poc

F. D’ANNA ET AL.
Table 1. Data concerning the isomerization (1-E !1-Z) and the rearrangement (1-Z !T) in methanol at 313 K and in the presence
a
of some copper salts
Substrate
Copper salt
None
Reaction time
Substrate unchanged (%)
Yield in 1-E(%)
Yield in 1-Z(%)
Yield in (T)(%)
17.0
1-Z
1-E
1-Z
1-E
1-Z
1-E
1-Z
1-E
1-Z
1-E
1-Z
1-E
8 h
8 h
8 h
8 h
8 h
8 h
8 h
8 h
8 h
8 h
8 h
8 h
83.0
100
54.7
12.5
21.7
1
CuCl
2
11.9
17.3
23.8
27.0
52.1
66.7
88.4
91.0
17.5
18.0
18.0
18.0
56.2
26.7
CuBr
2
Cu(OAc) ꢀH O
4.7
2
2
CuSO
4
ꢀ5H
2
O
65.0
20.0
51.2
26.4
12.5
23.2
60.0
54.5
Cu(ClO4)2
a
The yields are reproducible within ꢁ3%.
A quantitative approach: the mechanism of the
conversion processes
(K
formation of the adducts between 1-E and 1-Z and Cu(II) and
) , and (k the rate constants for the isomerization,
E Z
[ )Cu and (K )Cu are the binding equilibrium constants for the
(k
)
Z,E Cu
To better interpret the above results we have measured the
reactivity in methanol as a function of copper salts concentration.
As the hydrazones 1-E and 1-Z and the relevant triazole T are
active in different region of UV–Vis spectrum, the kinetic
investigation was carried out at 313.1 K by means of UV–Vis
measurements. At the used kinetic concentrations, 1-E and 1-Z
E,Z Cu
respectively] gave the results in Table 2.
Data in Table 2 show that all of the copper salts tested are able
to promote the 1-E !1-Z isomerization. For both isomers, two
parallel pathways furnishing the same TS can be depicted as
shown in Scheme 4.
In both cases the coordination of the Cu(II) cation must occur
(as well as T) are soluble in methanol and we have ascertained
at the imino nitrogen in order to cause the isomerization: it
that the presence of a small quantity of water (crystallization
water of used salts, always lower than 1%) does not affect the
nature of the solvent. The overall reactivity of hydrazones 1 is
illustrated in Scheme 2:
where kE,Z and kZ,E are the rate constants related to the
reversible isomerization and kZ,T is the rate constant for the
rearrangement, respectively. Details concerning the reaction
mixture analysis and the determination of the rate constants have
been reported in the Experimental section.
0
lowers the carbon-nitrogen [C(3 )
a
—N
b
] double bond character
and allows the occurrence of the rotation around the ‘ex-
double bond’ in the TS. In the TS the imino nitrogen would
have a trigonal structure with Cu(II) and NH —Ph substituents
a
orthogonal to the plane individuated by N(2)
a
—C(3)
a
—
0
C(3 ) —N .
a
b
[50]
This hypothesis appears in line with literature data
about
the ability of ions of transition metals, for example Zn(II), to
—
catalyze the isomerization around a >C—N—. Furthermore, a
similar function of Cu(II) salts was previously suggested also by
The 1-E !1-Z isomerization
[51]
[49]
Gokhale et al.
and by some of us.
In all of the cases considered, the plot of the observed rate
constants (kE,Z or kZ,E) versus Cu(II) concentration showed an
hyperbolic trend: in Fig. 1 data concerning the isomerization in
the presence of Cu(ClO4)2 are shown. Data at different
concentrations of all the copper salts are reported in Supple-
mentary Material (Tables 4–8 and Figures 7–14). Collected data
indicate that, in the presence of copper salts, the reaction
proceeds via a two steps mechanism: a first fast equilibrium [the
coordination between the substrate and Cu(II)], followed by the
rate determining step (the isomerization around the imino bond),
as reported in Scheme 3 considering 1-E as substrate.
Analogous equilibria apply to 1-Z as starting material. The fit of
experimental data by means of equations such as:
ðkE;ZÞ ðKEÞ ½CuðIIÞꢂ
Cu
Cu
kE;Z ¼
kZ;E ¼
1
þðKEÞCu½CuðIIÞꢂ
(1)
ðkZ;EÞ ðKZÞ ½CuðIIÞꢂ
Cu
Cu
Cu
Figure 1. Observed rate constant (kE,Z) versus [Cu(ClO
1-E !1-Z isomerization in methanol at 313.1 K
4
)
2
2
ꢀ6H O] for the
1
þðKZÞ ½CuðIIÞꢂ
www.interscience.wiley.com/journal/poc
Copyright ß 2008 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2008, 21 306–314

HYDRAZONE ISOMERIZATION AND REARRANGEMENT
2
ꢃ
ꢃ
4
Moreover, both SO and ClO in the HSAB are hard anion,
4
[
64,65]
ꢃ
while Cu(II) is a borderline cation,
give more loose ion-pairs with respect to SO . Thus, data in
and ClO4 was reported to
2
4
ꢃ
Table 2 show that the more intimate ion-pair gives the more
stable complex.
Looking at the rate constants, the (kE,Z
the order: CuSO O < CuCl < Cu(OAc)
ꢀ5H
H O < CuBr [a parallel trend has been observed for (k ) ]
)
Cu smoothly increases in
Scheme 3. 1-E/Cu(II) complexation equilibrium and 1-E (* 1-Z copper
assisted isomerization
4
2
2
2
ꢀH O < Cu(ClO
2
4
)
2
ꢀ
6
2
2
Z,E Cu
E
showing an opposite trend to that observed for (K )Cu. Indeed,
with the exception of acetate (see above), the reactivity follows
an inverse trend with respect to the adduct stability, that is, the
reaction proceeds faster when the substrate is more loosely
bonded to the cation.
Moreover, since the formation of chelated adducts can occur
in organic systems containing several donor atoms with the
[52–56]
correct arrangement,
we have taken into account this
possibility. For both of the isomers, the formation of chelated
adducts with a stable five- or six-membered ring [e.g. refer to
In line with the higher stability of 1-Z with respect to 1-E the
(kE,Z)Cu is higher than the (kZ,E)Cu, the relevant ratios being only
moderately affected by the anion (from 1.7 with CuBr up to 3.6
2
0
0
(1-E/Cu ) and (1-Z/Cu ) in Scheme 4] could be hypothesized, but
these species could be considered kinetically ‘inactive’ versus the
isomerization.
with CuSO ꢀ5H O).
4
2
In the presence of CuCl
also to give the rearrangement (see later). For these salts, with the
2
, CuBr
2
and Cu(OAc)
2
ꢀH
2
O 1-Z was able
The 1-Z ! T rearrangement
As above reported, copper acetate, bromide and chloride were
able to induce the isomerization as well as the MRH. In Fig. 2a–c,
the plots of kZ,T as a function of copper salt concentration are
reported (details are in Tables 4–6 of Supplementary Material):
they point out the occurrence of a ‘new’ kind of acid-catalysis
exception of CuBr , the isomerization reaction was studied only
2
considering as starting material 1-E. Indeed, in the case of 1-Z,
the rearrangement proceeded too fast to allow the determination
of the 1-E isomer concentration, with an acceptable degree of
precision and therefore the relevant (K
A comparison between data obtained in the presence of CuCl
or of CuBr2 shows that the latter displays a lower ability to
coordinate the substrate [(K
CuBr2 ¼3.2 ꢁ0.2], but, in
contrast, a higher efficiency in catalyzing the 1-E ! 1-Z
isomerization [(kE,Z
CuBr2 ¼0.2 ꢁ0.1]. In line with the
qualitative data of Table 1, we observed that the (K )
Z
)Cu and (kZ,E)Cu constants.
(Lewis-acid-catalysis, see after) in the MRH.
2
As can be seen, with copper acetate, the kZ,T follows a
hyperbolic trend as a function of salt concentration. In contrast,
with copper halides, it follows a parabolic trend suggesting that
the ‘real’ course of the two reactions is different. For this reason,
we shall discuss separately the 1-Z !T MRH catalyzed by copper
acetate from that catalyzed by halides.
E E
)CuCl2/(K )
)CuCl2/(kE,Z)
E CuBr2
E,Z E
(k )CuBr2/(K )CuCl2 (kE,Z)CuCl2 ratio is higher than 1.
As can be seen from data in Table 2 the adducts stability from
1-E or 1-Z and Cu(II) depends on the present anion. Indeed, for
Rearrangement in the presence of copper acetate
1
-E it increases in the order: CuBr
ꢀ5H O < Cu(OAc) ꢀH O and a parallel trend has been
observed for 1-Z.
2
< CuCl
2
< Cu(ClO
4
)
2
ꢀ6H
2
O <
The trend observed for the MRH of 1-Z in the presence of copper
acetate (Fig. 2a) agrees with a reaction following a two steps
mechanism (Scheme 5).
CuSO
4
2
2
2
This trend is related to the fact that the salts tested individuate
two classes of copper Lewis salts: the former with highly
coordinating (Cl or CuCl ; Br or CuBr ; AcO ) and the latter
The observed rate constant kZ,T can be expressed as
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
3
3
ðK Þ ðk
Þ
½CuðIIÞꢂ
Z
Cu
Z;T Cu
ꢃ
2ꢃ
with loosely coordinating anions (ClO , SO ) able, respectively,
kZ;T ¼
(2)
4
4
1
þðKZÞ ½CuðIIÞꢂ
[57–63]
Cu
‘to live in’ or ‘to live out’ the cation sphere.
In the first class, (K Cu increases with the anion electro-
E
)
Z Cu
(K ) being the binding constant between 1-Z and Cu(II) and
negativity: the high value with Cu(OAc) ꢀH O can also depend on
(k
)
the relevant rate constant for its rearrangement. The
2
2
Z,T Cu
ꢃ
[59]
ꢃ1
the ability of AcO to act as a bidentate ligand. In contrast, in
methanol the second class salts would exist as loose ion-pairs.
The stability constants concerning 1-E are a little higher than
those for 1-Z, with a negligible effect of the anions.
analysis of experimental data gives: (K ) ¼1293 ꢁ80 M
Z Cu
;
ꢃ3 ꢃ1
(k
)
Z,T Cu
¼(4.77 ꢁ0.17) 10
s
(R ¼0.999).
The course of the reaction can be depicted as in Scheme 6
(refer to 1): the adduct formation makes the hydrazonic hydrogen
Table 2. Binding equilibrium constants and rate constants concerning the 1-E !1-Z isomerization in methanol at 313.1 K and in the
presence of different copper salts
ꢃ1
ꢃ1
ꢃ1
ꢃ1
Cu (s )
Copper salt
(K
E
)
Cu (M
)
(K
Z
)Cu (M
)
(kE,Z
)
Cu (s
)
(kZ,E
)
ꢃ3
ꢃ2
ꢃ3
ꢃ3
ꢃ3
CuCl
CuBr
2
620 ꢁ50
195 ꢁ20
(2.11 ꢁ0.06)10
(1.10 ꢁ0.07)10
(2.47 ꢁ0.03)10
(3.16 ꢁ0.08)10
(1.12 ꢁ0.01)10
140 ꢁ25
920 ꢁ50
(6.44 ꢁ0.95)10ꢃ3
2
Cu(OAc) ꢀH O
21100 ꢁ1170
1130 ꢁ110
7400 ꢁ250
2
2
ꢃ4
Cu(ClO
CuSO
4
)
2
ꢀ6H
2
O
(7.69 ꢁ0.12)10
ꢃ4
4
ꢀ5H
2
O
5500 ꢁ280
(3.13 ꢁ0.04)10
J. Phys. Org. Chem. 2008, 21 306–314
Copyright ß 2008 John Wiley & Sons, Ltd.
www.interscience.wiley.com/journal/poc

F. D’ANNA ET AL.
Scheme 4. General scheme for 1-E (* 1-Z isomerization in the presence of copper salts.
more acidic and then prone to interact with feeble bases, such as
acetate ion, methanol and so on.
matter of facts, the rearrangement rate is the result of a subtle
[28–35,40]
balance between these effects.
Also the occurrence of a bifunctional catalysis
[69–71]
can be
supposed as proposed for other nucleophilic substitutions:
the Cu(II) acting as a Lewis acid, the relevant anion [in this case,
the acetate ion present in the coordination sphere of Cu(II)]
acting as a Lewis base.
To confirm the importance of the acetate anion, we have
ꢃ4
ꢃ3
carried kinetic measurements at [Cu(ClO
and [NaOAc] variable from 1.8 ꢄ10
4
ꢃ4
)
2
ꢀ6H
2
O] ¼1 ꢄ10
M
up to 5 ꢄ10 M.
2
Kinetic data have shown that with Cu(ClO ) /NaOAc mixtures,
4
4 2
differently from what happens in the presence of Cu(ClO )
Indeed, the kinetically active adduct is the one having the
alone, also 1-E gives the MRH. As can be seen from Fig. 3 (details
in Table 9 of Supplementary Material), the kZ,T increases with
[NaOAc], furtherly supporting the hypothesis of a bifunctional
catalysis.
imino nitrogen (N
b
) coordinated by the cation. The coordination
of the imino nitrogen induces an electronic shift causing an
[
66,67]
acidity increase.
This kind of coordination has been recently
[68]
evidenced in substrates bearing also an amino nitrogen.
On
Rate constants in the presence of mixed salts are lower than
those observed in solution of pure Cu(OAc) ꢀH O of similar
the other hand, the coordination at the phenylhydrazonic amino
2
72]
2
[
nitrogen could give chelated ‘inactive’ adducts (refer to e.g. 1-Z/
concentration, well in line with observations
that the ‘real’
0
Cu in Scheme 4) unable to evolve into the triazole.
concentration of copper acetate deriving from mixtures of Cu(II)
ꢃ
In summary, the kinetically active adduct should show a higher
[e.g. from a solution of Cu(ClO ) ] and AcO (from a solution of
4
2
acidity of the of N —H proton, favouring the reaction and a lower
nucleophilicity of N nitrogen, disfavouring the reaction. As a
a
NaOAc) are lower than those from a solution of Cu(OAc)2 of
comparable concentration.
a
www.interscience.wiley.com/journal/poc
Copyright ß 2008 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2008, 21 306–314

HYDRAZONE ISOMERIZATION AND REARRANGEMENT
Figure 2. Rate constants (kZ,T) versus [Cu(II)] concerning the 1-Z !T rearrangement in methanol at 313.1 K and in the presence of: (a) Cu(OAc)
2
ꢀH
2
O,
2 2
(b) CuCl , (c) CuBr
ꢃ3
M the calculated rate ratio is 4.5. Refer to
Supplementary Material, Tables 4–5).
Rearrangement in the presence of copper halides
1.11 ꢄ10
As evidenced in Fig. 2b,c in the presence of copper chloride or
bromide, kZ,T as a function of salt concentration shows a parabolic
trend. The fit of experimental data agrees with Eqn (3), where ku
and kII represent the first-order and the third-order rate constants
concerning the uncatalyzed and trimolecular pathways, respect-
ively.
Furthermore, the main course of the reaction can be
determined by a species having two CuX ‘units ’. The kinetically
2
active species could be a halo-bridge dinuclear copper complex
such as 2.
2
kZ;T ¼ku þkII ½CuX2ꢂ
(3)
In Table 3 the relevant results of kinetic data fit are reported.
Looking at data in Table 3 the following considerations can be
done. The rearrangement (refer also to data of Table 1) proceeds
faster in the presence of CuBr than in the presence of CuCl . Rate
2
2
constants of Table 3 depend also on the stability constants that
our experimental data do not allow to determine being included
in the calculated rate constants. The higher reactivity in the
The formation of binuclear complexes with CuHalg
well documented.
2
has been
Their higher efficiency in catalyzing the
MRH, respect to mononuclear complex, can indicate a higher
ability of Cu complex to induce the electronic shift from
[19,20]
presence of CuBr
2
than in the presence of CuCl
2
can be confirmed
by comparing the various kZ,T values determined at the same
concentration of the two copper salts (e.g. at [CuX ] ¼
X
2 4
2
hydrazonic moiety to metal centre or can be related to the
occurrence of a bifunctional catalysis.
The contribution of the uncatalyzed pathway that is physically
meaningful in the presence of CuCl
2
, appears in line with some
ꢃ5
[31]
our previous results [k
u
¼(1.67 ꢁ0.18) 10 in methanol].
To confirm the importance of the nature of the anion in the
Lewis acids, we have carried out kinetic measurements for the
Scheme 5. 1-Z/Cu(II) complexation equilibrium and 1-Z !1-T re-
ꢃ3
arrangement
1-Z !T reaction at [Cu(ClO
4
)
2
ꢀ6H
2
O] ¼3 ꢄ10 M and [LiCl]
J. Phys. Org. Chem. 2008, 21 306–314
Copyright ß 2008 John Wiley & Sons, Ltd.
www.interscience.wiley.com/journal/poc

F. D’ANNA ET AL.
Scheme 6. Details on the 1-Z/copper acetate complexation equilibrium and the relevant 1-Z !1-T rearrangement
Figure 4. Observed rate constants (kZ,T) versus [LiCl] concerning the
Figure 3. Observed rate constants (kZ,T) versus [NaOAc] concerning the
1
-Z !T rearrangement in methanol at 313.1 K and at a fixed concen-
1
-Z !T rearrangement in methanol at 313.1 K and in the presence of a
ꢃ3
tration of Cu(ClO
4
)
2
ꢀ6H
2
O (3 ꢄ10 M)
ꢃ4
fixed concentration of Cu(ClO
4
)
2
ꢀ6H
2
O (1 ꢄ10 M)
ꢃ3
ꢃ3
variable from 6 ꢄ10 M up to 16 ꢄ10 M. As can be seen from
necessary the presence of salts with anions able to furnish a
bifunctional catalysis or else, a base-assistance on proton
Fig. 4 (details in Table 10 of Supplementary Material), unlike what
ꢃ
ꢃ
happens in the presence of the only Cu(ClO
-Z !T occurs, confirming the role of particular anions in the
MRH.
In such a kind of conditions the formation of various complexes
4
)
2
ꢀ6H
2
O, also the
abstraction from the N —H bond (e.g. by AcO , CuHalg and
a
3
1
so on). As a matter of fact the (k
)
increases linearly
Z,T Cu
ꢃ5
ꢃ2
[i ¼(6.55 ꢁ1.24) ꢄ10 , s ¼(2.87 ꢁ0.11) ꢄ10 , r ¼0.997] with
[LiCl] (refer to Fig. 4).
þ
ꢃ
2ꢃ
[57]
(
CuCl , CuCl , CuCl , CuCl etc.) can occur:
thus, it can be
2
3
4
Table 3. Rate constants concerning the 1-Z !T rearrange-
ment in methanol at 313.1 K and in the presence of copper
halides according to Eqn (3)
CONCLUSIONS
The results of a thermodynamic and kinetic study of the
behaviour in methanol of 1-E and of 1-Z in the presence of
different copper salts [CuSO ꢀ5H O, Cu(ClO ) ꢀ6H O, CuCl , CuBr
ꢃ1
ꢃ1 ꢃ2
M )
Copper salt
k
u
(s
)
k
II (s
R
4
2
4 2
2
2
2
and Cu(OAc)
2
ꢀH
2
O] have been discussed, giving a role to both
a
ꢃ5
ꢃ5
CuCl2
(5.41 ꢁ0.84) 10
14.15 ꢁ0.38
326 ꢁ15
0.996
0.987
copper cation and present anions on the occurring processes. In
CuBr
2
(ꢃ6.22 ꢁ2.64) 10
fact CuSO ꢀ5H O and Cu(ClO ) ꢀ6H O are able to cause only the
4
2
4 2
2
a
1-E !1-Z isomerization. In contrast Cu(OAc)
ꢀH
2 2
O, CuBr and
In an attempt to correlate kinetic data by using three-
2
CuCl
2
are also able to determine the subsequent 1-Z !T MRH, as
parametric equation we found a k
times lower than k value (k ¼0.0301 M
I
value about 500
ꢃ1 ꢃ1
well as the global 1-E !1-Z !T process.
s
and k ¼
II
I
II
ꢃ1 ꢃ1
s ).
The different course of the rearrangement in the presence of
copper acetate or of copper halides has been examined.
14.15 M
www.interscience.wiley.com/journal/poc
Copyright ß 2008 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2008, 21 306–314

HYDRAZONE ISOMERIZATION AND REARRANGEMENT
To confirm the role of the anion we have studied the reaction in
sample for a typical kinetic run was prepared by mixing in a
quartz cuvette (light path 1 cm) 2 ml of a solution of the substrate
in methanol with 1 ml of the appropriate copper salt solution.
Both the solutions were thermostated at 313.1 K. The concen-
the presence of mixed salts [such as Cu(ClO
4
)
2
ꢀ6H O þNaOAc, or
2
þ LiCl], observing in such conditions also the 1-Z !T
rearrangement.
ꢃ5
The whole of the obtained results has evidenced the
occurrence of a ‘new’ kind of Lewis-acid-catalysis in MRH,
completely different from that recently discovered in the case of
the (Z)-arylhydrazones of 5-amino-3-benzoyl-1,2,4-oxadiazole in
tration of the substrates was 5 ꢄ10 M. The copper salt
ꢃ4
ꢃ3
concentration ranged from 2 ꢄ10 up to 8 ꢄ10 M. All kinetic
data were analysed by means of Kaleidagraph 3.0.1 software.
Supplementary Material associated with this article can be
found in the online version.
[41–43]
the presence of protic acids.
In that case the basic centre
protonated by the added acids was the N-4 of the 1,2,4-
oxadiazole ring.
In contrast, in the instance now examined the basic centre
appears to be the imino nitrogen of the phenylhydrazone moiety
able to interact with Lewis acids giving the relevant adducts. The
Acknowledgements
We thank MIUR (Rome) for financial support [PRIN 2005,
(2005034305)]. Investigations supported by the Universities of
Bologna and Palermo (ex-60%, funds for selected research
topics). Prof. Renato Noto is gratefully acknowledged for useful
discussion.
—
!
weakening of the >C—N— bond makes possible the 1-E 1-Z
isomerization and in case the 1-Z !T MRH (increasing the acidity
of the N —H proton). As a matter of fact this acidity increase
a
ꢃ
ꢃ
makes the proton able to interact with bases (AcO , CuBr ,
3
methanol and so on). This fact causes the occurrence of a sort of
[69–71]
bifunctional catalysis,
whose course can be easily realized
looking at the structure of the intermediates 1 and 2.
REFERENCES
In the whole the present study has enlightened a new aspect of
the possible reactivity of 1,2,4-oxadiazole derivatives in MRH
showing how azoles, particularly 1,2,4-oxadiazoles characterized
[
[
1] J. Tsuji, in Transition Metal Reagents and Catalysts: Innovations in
Organic Synthesis, Wiley-VCH, Chichester, 2000.
2] A. J. Fletcher, S. D. R. Christie, J. Chem. Soc. Perkin Trans. 1 2001, 1–13.
[73–76]
by a very low heteroaromaticity,
kinds of reactivity.
can offer new and new
[3] I. P. Beletskaya, Pure App. Chem. 2002, 74, 1327–1337.
[
4] W. N. M. Piet, in Homogeneous Catalysis: Understanding the Art,
Kluwer Academic Publishers, Dordrecht, Boston, London, 2004.
5] C.-H. Jun, Chem. Soc. Rev. 2004, 33, 610–618.
[
[
[
EXPERIMENTAL
6] I. Nakamura, Y. Yamamoto, Chem. Rev. 2004, 104, 2127–2198.
7] M. J. Wilkinson, P. W. N. M. van Leeuwen, J. N. H. Reek, Org. Biomol.
Chem. 2005, 3, 2371–2383.
Materials
[
8] I. Fairlamb, J. Ann. Rep. Prog. Chem. Sect. B: Org. Chem. 2006, 102,
Commercial methanol was distilled before use. Commercial
CuSO O, Cu(ClO ꢀ6H O, CuCl CuBr and Cu(OAc)
ꢀ5H
O were dried in a muffle at 608C over phosphorous pentoxide.
Then they were stored in a dryer over CaCl . 1-Z, 1-E and (T) were
50–80.
4
2
4
)
2
2
2
,
2
2
ꢀ
[9] H. Adams, N. A. Bajley, D. E. Fenton, S. Moss, C. O. Rodriguez de
H
2
Barbarin, J. Chem. Soc. Dalton Trans. 1986, 693–699.
[10] F. B. Hulsbergen, R. W. M. ten Hoedt, G. C. Versechoor, J. Reedijk, A. K.
2
[77,78]
Spek, E. J. Gabe, F. L. Lee, J. Chem. Soc. Dalton Trans. 1983, 539–545.
prepared according to procedure previously reported.
[
[
[
[
11] L. Rosenberg, L. K. Thompson, E. J. Gabe, F. L. Lee, J. Chem. Soc. Dalton
Trans. 1986, 625–631.
12] T. Kamiusuki, H. Okawa, M. Matsumoto, S. Kida, J. Chem. Soc. Dalton
Trans. 1989, 2077–2081.
13] J. C. Bay o´ n, P. Esteban, G. Net, P. G. Rasmussen, K. N. Baker, C. W. Hahn,
M. M. Gumz, Inorg. Chem. 1991, 30, 2572–2574.
14] P. M. Slangen, P. J. van Koningsbruggen, K. Goubitz, J. G. Haasnoot, J.
Reedijk, Inorg. Chem. 1994, 33, 1121–1126.
[15] D. M. Dawson, D. A. Walker, M. Thornton Pett, M. Bochmann, J. Chem.
Soc. Dalton Trans. 2000, 459–466.
General procedure for qualitative studies
Each experiment was carried out at 313 K suspending 0.1 g of
substrate in 40 ml of anhydrous methanol and adding the copper
salt dissolved in 10 ml of solvent. Different behaviours were
observed depending on the isomer used as starting material:
thus, with 1-E, a clear solution was immediately obtained; while
with 1-Z [excluding the reaction in the presence of
[
16] C. Incarvito, A. L. Rheingold, C. J. Qin, A. L. Gavrilova, B. Bosnich, Inorg.
Chem. 2001, 40, 1386–1390.
17] M. Du, Z. Huang, S.-T. Chen, Y.-M. Guo, C. Diaz, J. Ribas, Inorg. Chem.
Cu(OAc)
in the time (ca. 3 h).
2
ꢀH
2
O] a suspension was observed, which became clear
[
2003, 42, 552–559.
The composition of the reaction mixture was examined by TLC
time by time and the reaction was monitored for 8 h. Then the
solvent was eliminated at reduced pressure and the obtained
residue was extracted several times with ethyl ether. After the
ethyl ether elimination the residues were separated by flash
chromatography on silica gel. In the presence of copper
perchlorate, in order to avoid the decomposition of the reaction
products during the solvent elimination, the reaction mixture was
poured in water and then extracted with ethyl ether.
[18] P. J. van Koningsbruggen, E. M u˝ ller, J. G. Haasnoot, J. Reedijk, Inorg.
Chim. Acta 1993, 208, 37–42.
19] A. Vi sˇ njevac, L. Tu sˇ ek-Bo zˇ i c´ , M. Majeri c´ -Elenkov, V. Sunjic, B. Kojic-
ˇ
´
´
[
Prodi c´ , Eur. J. Inorg. Chem. 2001, 2647–2654.
[
20] P. N. Gaponik, M. M. Gegtyarik, A. S. Lyakhov, V. E. Matulis, O. A.
Ivashkevich, M. Quesada, J. Reedijk, Inorg. Chim. Acta 2005, 358,
3949–3957.
[21] T. G. Spiro (ed.), Copper Proteins, John-Wiley, New York, 1981.
[22] N. Kitajima, Y. Moro-oka, Chem. Rev. 1974, 74, 471–517.
[23] E. I. Solomon, M. J. Baldwin, M. D. Lowery, Chem. Rev. 1992, 92,
521–542.
[24] G. B. Guseva, E. V. Antina, A. S. Semeikin, M. B. Berezin, A. I. V’yugin,
Russ. J. Gen. Chem. 2000, 72, 1306–1310.
Kinetic measurements
[
[
25] G. Szintay, A. Horv a´ th, Inorg. Chim. Acta 2001, 324, 278–285.
26] Q. H. Huang, Z. Pan, P. Wang, Z. Chen, X. Zhang, H. Xu, Bioorg. Med.
Chem. Lett. 2006, 16, 3030–3033.
UV–Vis spectra for kinetic measurements were carried out by
using a spectrophotometer equipped with a Peltier temperature
controller, to keep the temperature constant within 0.1 K. The
[
27] L. Jiao, B. H. Courtney, F. R. Fronczek, K. M. Smith, Tetrahedron Lett.
2006, 47, 501–504.
J. Phys. Org. Chem. 2008, 21 306–314
Copyright ß 2008 John Wiley & Sons, Ltd.
www.interscience.wiley.com/journal/poc

F. D’ANNA ET AL.
[
[
[
[
[
[
[
[
[
28] D. Spinelli, A. Corrao, V. Frenna, N. Vivona, M. Ruccia, G. Cusmano,
J. Heterocycl. Chem. 1976, 13, 357–360.
29] M. Ruccia, N. Vivona, D. Spinelli, Adv. Heterocycl. Chem. 1981, 29,
[52] T. C. Woon, P. Thompson, P. Robichaud, Inorg. Chim. Acta 1984, 90,
201–208.
[53] P. Bisiacchi, A. Corsico Coda, G. Desimoni, P. P. Righetti, G. Tacconi,
Gazz. Chim. Ital. 1985, 115, 119–123.
[54] A. Corsico Coda, G. Desimoni, P. Quadrelli, P. P. Righetti, G. Tacconi,
Gazz. Chim. Ital. 1987, 117, 301–305.
[55] V. Y. Kukushkin, A. J. L. Pombeiro, Coord. Chem. Rev. 1999, 181,
147–175.
[56] K. Mashima, H. Tsurugi, J. Organometallic Chem. 2005, 690,
4414–4423.
[57] M. A. Khan, J. Meullemeestre, M. J. Schwing, F. Vierling, Inorg. Chem.
1989, 28, 3306–3309.
[58] H. Grasdalen, J. Chem. Soc. Faraday Trans. II 1973, 69, 462–470.
[59] P. O’Brien, Coord. Chem. Rev. 1984, 58, 169–244.
[60] K.-S. B u¨ rger, P. Chaudhuri, K. Wieghardt, Inorg. Chem. 1996, 35,
2704–2707.
[61] T. K. Lal, R. Gupta, S. Mahapatra, R. Murkherjee, Polyhedron 1999, 18,
1743–1750.
141–169.
30] V. Frenna, N. Vivona, G. Consiglio, A. Corrao, D. Spinelli, J. Chem. Soc.
Perkin Trans. II 1981, 1325–1328.
31] V. Frenna, N. Vivona, G. Consiglio, D. Spinelli, J. Chem. Soc. Perkin
Trans II 1983, 1199–1202.
32] V. Frenna, N. Vivona, G. Consiglio, D. Spinelli, J. Chem. Soc. Perkin
Trans. II 1984, 541–545.
33] V. Frenna, S. Buscemi, D. Spinelli, G. Consiglio, J. Chem. Soc. Perkin
Trans. 2 1990, 215–221.
34] N. Vivona, S. Buscemi, V. Frenna, G. Cusmano, Adv. Heterocycl. Chem.
1993, 56, 49–154.
35] F. D’Anna, F. Ferroni, V. Frenna, S. Guernelli, C. Z. Lanza, G. Macaluso, V.
Pace, G. Petrillo, D. Spinelli, R. Spisani, Tetrahedron 2005, 61, 167–178.
36] A. R. Katritzky, C. W. Rees (Eds.), in Comprehensive Heterocyclic
Chemistry I, (Eds: A. R. Katritzky, C. W. Rees, E. F. V. Scriven ) Pergamon,
New York, 1982–1985.
[62] S. Yo u´ ngme, K. Poopasit, K. Chinnakali, S. Chantrapromma, H.-K. Fun,
Inorg. Chim. Acta 1999, 292, 57–63.
[37] A. J. Boulton, A. R. Katritzky, A. Hamid, J. Chem. Soc. C 1967,
2
005–2007.
[63] N. G. Tsierkenos, I. E. Molinou, J. Chem. Eng. Data 2000, 45, 819–
822.
[64] R. G. Pearson, J. Am. Chem. Soc. 1963, 85, 3533–3539.
[65] R. G. Pearson, J. Chem. Educ. 1987, 64, 561–567.
[66] M. Baiocchi, L. Fabbrizzi, F. Foti, E. Monzani, A. Poggi, Org. Lett. 2005,
7, 3417–3420.
[
38] A. J. Boulton, Lectures in Heterocyclic Chemistry, Hetero Corporation,
Provo, Utah, 1973.
39] A. R. Katritzky, M. F. Gordev, Heterocycles 1993, 35, 483–518.
40] A. Bottoni, V. Frenna, C. Z. Lanza, G. Macaluso, D. Spinelli, J. Phys.
Chem. A 2004, 108, 1731–1740.
[
[
[
[
[
[
[
[
[
[
[
41] B. Cosimelli, V. Frenna, S. Guernelli, C. Z. Lanza, G. Macaluso, G.
Petrillo, D. Spinelli, J. Org. Chem. 2002, 67, 8010–8018.
42] B. Cosimelli, F. D’Anna, V. Frenna, G. Macaluso, S. Morganti, P. Nitti, V.
Pace, D. Spinelli, R. Spisani, J. Org. Chem. 2004, 69, 8718–8722.
43] F. D’Anna, V. Frenna, G. Macaluso, S. Marullo, S. Morganti, V. Pace, D.
Spinelli, R. Spisani, C. Tavani, J. Org. Chem. 2006, 71, 5616–5624.
44] S. Guernelli, R. Noto, C. Sbriziolo, D. Spinelli, M. L. Turco Liveri,
J. Colloid Interface Sci. 2002, 239, 217–221.
[67] Z. Zhong, B. J. Postnikova, R. E. Hanes, V. M. Lynch, E. V. Anslyn, Chem.
Eur. J. 2005, 11, 2385–2394.
[68] E. Amadei, M. Carcelli, S. Ianelli, P. Cozzini, P. Pelagatti, C. Pelizzi,
J. Chem. Soc. Dalton Trans. 1998, 1025–1029.
[69] C. F. Bernasconi, MTP International Reviews of Science: Organic Chem-
istry, Series 1, Vol. 3, Butterworths, London, 1973, 33 p.
[70] F. Terrier, Nucleophilic Aromatic Displacement, The Influence of the
Nitro Group, VCH Publ., New York, 1991, 53 p.
[71] B. Cornils, W. A. Herrmann, R. Schlogl, C.-H. Wong (Eds.), Catalysis from
A to Z, A Concise Encyclopedia, Wiley-VCH, Weinheim, II Ed., 2003,
84 p.
[72] K. J. Kochi, R. V. Subramanian, Inorg. Chem. 1965, 11, 1527–1533.
[73] C. W. Bird, Tetrahedron 1985, 41, 1409–1414.
[74] C. W. Bird, Tetrahedron 1992, 48, 335–340.
[75] A. R. Katritzky, K. Jug, D. C. Oniciu, Chem. Rev. 2001, 101, 1421–
1449.
45] S. Guernelli, M. F. Lagan a` , D. Spinelli, P. Lo Meo, R. Noto, S. Riela, J. Org.
Chem. 2002, 67, 2948–2953.
46] F. D’Anna, V. Frenna, R. Noto, V. Pace, D. Spinelli, J. Org. Chem. 2005,
7
0, 2828–2831.
47] F. D’Anna, V. Frenna, R. Noto, V. Pace, D. Spinelli, J. Org. Chem. 2006,
1, 9637–9642.
7
48] F. D’Anna, V. Frenna, S. La Marca, R. Noto, V. Pace, D. Spinelli,
Tetrahedron 2008, 64, 672–680.
49] S. Buscemi, V. Frenna, N. Vivona, D. Spinelli, J. Chem. Soc. Perkin
Trans. 1 1993, 2491–2493.
[76] A. T. Balaban, D. C. Oniciu, A. R. Katritzky, Chem. Rev. 2004, 104,
2777–2812.
[
[
50] D. R. Eaton, J. P. K. Tong, Inorg. Chem. 1980, 19, 740–744.
51] N. Gokhale, S. Padhye, D. Rathbone, D. Billington, P. Lowe, C.
Schwalbe, C. Newton, Inorg. Chem. Commun. 2001, 4, 26–29.
[77] M. Ruccia, D. Spinelli, Gazz. Chim. Ital. 1959, 89, 1654–1669.
[78] N. Vivona, M. Ruccia, V. Frenna, D. Spinelli, J. Heterocycl. Chem. 1980,
17, 401–402.
www.interscience.wiley.com/journal/poc
Copyright ß 2008 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2008, 21 306–314