On the use of multi-parameter free energy relationships: The rearrangement of (Z)-arylhydrazones of 5-amino-3-benzoyl-1,2,4-oxadiazoleinto(2-aryl-5-phenyl- 2H-1,2,3-triazol-4-yl)ureas

Article abstract of DOI:10.1016/j.tet.2010.05.025

By using a multi-parameter approach (a combination of Hammett/Ingold- Yukawa-Tsuno/Fujita-Nishioka free energy relationships) the mononuclear rearrangements of heterocycles (MRH) rates for five new ortho-substituted and ten new di-, tri-, or tetra-substituted (Z)-arylhydrazones of 5-amino-3-benzoyl-1,2,4-oxadiazole into the relevant (2-aryl-5-phenyl-2H-1,2,3- triazol-4-yl)ureas (in dioxane/water and in a large range of pS⁺ values) have been related to the electronic and proximity effects exerted by the present substituents, also considering previous results on some mono meta-and para-substituted (Z)-arylhydrazones.In every case, excellent correlation coefficients have been calculated (r² or R²>0.996).Once more the study of MRH has furnished an interesting panel of different reactivity (three pathways of reaction have been evidenced: general-base- catalyzed, uncatalyzed, and specific-acid-catalyzed) and this has been useful in enlightening how polysubstitution can differently affect the MRH rates.Moreover 2,6-disubstitution on the (Z)-arylhydrazono moiety causes a significant increase of the reactivity in all of the three studied pathways.All of the collected data appear useful for understanding structure-reactivity/activity relationships in polysubstituted compounds.

Full text of DOI:10.1016/j.tet.2010.05.025

Tetrahedron 66 (2010) 5442e5450
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
On the use of multi-parameter free energy relationships: the rearrangement of
(Z)-arylhydrazones of 5-amino-3-benzoyl-1,2,4-oxadiazole into (2-aryl-5-phenyl-
2H-1,2,3-triazol-4-yl)ureas
Francesca D’Anna a, Vincenzo Frenna a, Camilla Zaira Lanza b, Gabriella Macaluso a, Salvatore Marullo a,
,
c
d
Domenico Spinelli b , Raffaella Spisani , Giovanni Petrillo
*
a Dipartimento di Chimica Organica ‘E. Paternò’, Viale delle Scienze-Parco d’Orleans II, 90128 Palermo, Italy
b Dipartimento di Chimica ‘G. Ciamician’, University of Bologna, Via Selmi 2, 40126 Bologna, Italy
c Dipartimento di Chimica Organica ‘A. Mangini’, Via San Giacomo 11, 40126 Bologna, Italy
d Dipartimento di Chimica e Chimica Industriale, via Dodecaneso 31, 16146 Genova, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
By using a multi-parameter approach (a combination of Hammett/Ingold-Yukawa-Tsuno/Fujita-Nishioka
free energy relationships) the mononuclear rearrangements of heterocycles (MRH) rates for five new
ortho-substituted and ten new di-, tri-, or tetra-substituted (Z)-arylhydrazones of 5-amino-3-benzoyl-
1,2,4-oxadiazole into the relevant (2-aryl-5-phenyl-2H-1,2,3-triazol-4-yl)ureas (in dioxane/water and in
a large range of pSþ values) have been related to the electronic and proximity effects exerted by the
present substituents, also considering previous results on some mono meta- and para-substituted (Z)-
arylhydrazones. In every case, excellent correlation coefficients have been calculated (r2 or R2ꢀ0.996).
Once more the study of MRH has furnished an interesting panel of different reactivity (three pathways of
reaction have been evidenced: general-base-catalyzed, uncatalyzed, and specific-acid-catalyzed) and this
has been useful in enlightening how polysubstitution can differently affect the MRH rates. Moreover 2,6-
disubstitution on the (Z)-arylhydrazono moiety causes a significant increase of the reactivity in all of the
three studied pathways. All of the collected data appear useful for understanding structure-reactivity/
activity relationships in polysubstituted compounds.
Received 18 January 2010
Received in revised form 20 April 2010
Accepted 10 May 2010
Available online 13 May 2010
Keywords:
Ring-to-ring interconversions
Structure/reactivity relationships
Base-catalyzed, uncatalyzed, and
acid-catalyzed paths in MRH
Changeover of mechanisms
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
structure of some thiosemicarbazone derivatives with their ability
to inhibit the corrosion processes of metallic glasses.7
The study of free energy relationships (FERs) has represented in
the past, and still represents, one of the milestones in the chemistry
research area. This kind of study introduced by Burkhardt1 and
Hammett2 in the early part of the twentieth century has been
frequently used to investigate reaction mechanisms, allowing the
rationalization of the outcome of many classical organic reactions.3
However, on the years, they have had significant influence on very
different fields of chemistry, as testified by the large number of
papers published on this subject.4
Moreover, the basic role that FERs can play in medicinal
chemistry is well known:8 they have a predictive role in quantita-
tive structure/activity relationship (QSAR) studies allowing an ap-
propriate substituent choice to achieve the right balance between
a drug’s electronic, steric and lipophilic effects, able to enhance
their activity.
On the years, some of us have been involved in the use of FERs to
get information in different fields of organic chemistry (from re-
actions mechanisms9 to spectrometric properties,10 and so on).11
Particular attention has been devoted to the study of the mono-
nuclear rearrangement of heterocycles (MRH, as named by Boulton
and Katritzky),12 a reaction that plays a central role in the large field
of ring-to-ring interconversion.13 In this research line, we have inter
alia measured the rearrangement rates14 of several substituted (Z)-
arylhydrazones of 3-benzoyl-5-phenyl-1,2,4-oxadiazole (1ae38a;
see Scheme 1) into the relevant 2-aryl-4-benzoylamino-5-phenyl-
1,2,3-triazole (1be38b) in dioxane/water (D/W; 1:1; v:v) in a wide
range of pSþ (an operational scale of proton concentration in D/W).
Thus, recently FERs have been used to explain the solvent effect
on the formation of p
-stacks of functional dyes in solution5 and have
proven to be valuable tools for the estimation of binding constants of
complexes of Hamilton-receptor-connected merocyanine chromo-
phores.6 Inthe materials chemistryarea, FERallowedtocorrelatethe
* Corresponding author. E-mail address: domenico.spinelli@unibo.it (D. Spinelli).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.05.025

F. D’Anna et al. / Tetrahedron 66 (2010) 5442e5450
5443
N
N
N
Y
N H
O
+B
slow
C6H5
N
(X)n
H
N
1a-38a
H2O +
H2N
1c,3c,4c,8c-11c,13c,16c,17c,
19c,20c,22c,24c,26c-33c,
35c-38c
N
N H
O
C6H5
N
+
c.H
N
(X)n
slow
N N H B
Y
O
(X)n
C6H5
N
H
(TS)b-c;u
N
H
,
N
N H O
H2N
O
H
-B
(X)n
H
(TS)a-c
N
Y
N
N
O
N
(X)n
1b-38b
1d,3d,4d,8d-11d,13d,16d,17d,
19d,20d,22d,24d,26d-33d,35d-38d
a,b: Y = Ph
c,d: Y = NH2
29: Ar = 3-Br
30: Ar = 3-NO2
31: Ar = 4-CN
32: Ar = 4-NO2
33: Ar = 2-Me
34: Ar = 2-Et
35: Ar = 2-F
36: Ar = 2-Cl
37: Ar = 2-Br
38: Ar = 2-NO2
19: Ar = 4-OMe
1: Ar = 2,3-Me2
2: Ar = 2,4-Me2
3: Ar = 2,5-Me2
4: Ar = 3,4 -Me2
5: Ar = 2,4-F2
6: Ar = 2,5-F2
7: Ar = 3,5-F2
8: Ar = 2,3-Cl2
9: Ar = 2,4-Cl2
10: Ar = 2,5-Cl2
20: Ar = 4-Me
21: Ar = 4-Et
22: Ar = 3-Me
23: Ar = 3-Et
24: Ar = H
11: Ar = 2,6-Cl2
12: Ar = 3,4-Cl2
13: Ar = 3,5 -Cl2
14: Ar = 3-Cl-4-F
15: Ar = 2,4-(NO2)2
16: Ar = 2,4,6-Cl3
17: Ar = 2,3,5,6-F4
18: Ar = 2,3,4,5,6-F5
25: Ar = 4-F
26: Ar = 4-Cl
27: Ar = 4-Br
28: Ar = 3-Cl
Scheme 1. B¼Water or dioxane; hydroxide or borate ions. (TS)aec: transition state for the acid-catalysed pathway; (TS)bec;u transition state for the general-base-catalyzed as well as
for the uncatalyzed pathways.
As shown in Scheme 1, besides m- and p-substituted (Z)-phe-
nylhydrazones, also ortho- and poly-substituted arylhydrazones
have been considered. The interest of polysubstitution in medicinal
chemistry has been already evidenced: in a drug skeleton causing
overcrowding could strongly influence the general effect of the
drug, decreasing or increasing the drug/receptor interactions. In
some cases this makes the use of a simple QSAR for the un-
derstanding of pharmacological activity quite difficult.8,15,16
‘asynchronous’ bond forming (NaeN2) and bond breaking (O1eN2),
as strongly supported by DFT calculations.18,19
According with the theory of the variable structure of the TS22,23
the transition state (TS)bec,u structure is not only pathway-de-
pendent, but also dependent on the substituent in the arylhy-
drazonic moiety, and different weights for ‘the formation of the
new NaeN2 bond’/‘the rupture of the relevant OeN2 bond’/‘the
loosening of the NaeH bond’ have been observed.17a,b
The above MRH (Scheme 1) usually occurs via two reaction
pathways (general-base-catalyzed and uncatalyzed at higher and at
lower pSþ values, respectively): an analysis of kinetic results by
means of FER17a,b has allowed an SNi mechanism to be proposed for
the studied reaction: the transition state of which [(TS)bec;u, see
Scheme 1], involving 10 electrons for the studied reaction, in a bi-
cyclic and quasi-aromatic structure, is characterized by a concerted
Thus, different FERs have been applied depending on the
number, position, and nature of the substituents. Indeed, while for
meta- and para-substituted (Z)-phenylhydrazones (19ae32a) sim-
ple FERs, such as Hammett (H),2 Yukawa-Tsuno (YT),24 and Ingold-
Yukawa-Tsuno (IYT)24,25 equations have been used; in the case of
ortho-substituted (33ae38a) and of several polysubstituted
(1ae18a) (Z)-arylhydrazones, the use of a multiparametric FER,

5444
F. D’Anna et al. / Tetrahedron 66 (2010) 5442e5450
such as the Fujita-Nishioka equation (FN, Eq. 1)26 (able to evaluate
also proximity and primary steric effects) has been proven neces-
sary (see later).14 All of the FER obtained (mono- or multi-
parametric) showed excellent statistical results (r2 or R2ꢀ0.998).
(4) to understand how the several electronic and steric effects of
the substituents can work in a multi-pathway process and how
the general picture obtained could be useful to get information
for studies concerning structure/reactivity or/activity re-
lationships. Some considerations on changeover between the
different mechanism pathways as a function of substituent
shall also be made.
h
i
X
ꢀ
ꢁ
ꢀ
ꢁ
log kA;R = kA;R
¼
r
so;m;p
þ
d
Es þ fFo þ i
(1)
X
H
It is noteworthy that the very particular kinetic behavior ob-
served in the instance of 2,6-dihalogeno (Z)-phenylhydrazones (11a,
16ae18a) has been rationalized on the grounds of a kinetic steric
acceleration which also depends on the bulkiness of the halogens.14
Recently we have addressed our attention to the research of
acidic catalysis in MRH processes: via a well-designed modification
of the structure of the 1,2,4-oxadiazole ring (an amino group in-
troduced at C-5 has strongly increased the basic character of N4)27
we have obtained (Z)-arylhydrazones able to rearrange ‘also’ via
a specific-acid-catalyzed pathway.
2. Results and discussion
2.1. A general examination of MRH reactivity data
In order to get a quick comparison among data previously
obtained14 and those we are now collecting, we are reporting in
Table 1 the most significant results of FER applied to the MRH of (Z)-
arylhydrazones of 3-benzoyl-5-phenyl-1,2,4-oxadiazole (1ae38a;
see Scheme 1) into the relevant 2-aryl-4-benzoylamino-5-phenyl-
1,2,3-triazole (1be38b).
Moreover by investigating the MRH of some meta- and para-
substituted (Z)-arylhydrazones of 5-amino-3-benzoyl-1,2,4-oxa-
Table 1
A summary of the FER application to the rearrangement of (Z)-arylhydrazones of 3-benzoyl-5-phenyl-1,2,4-oxadiazole (1ae38a) into the relevant 2-aryl-4-benzoylamino-5-
phenyl-1,2,3-triazole (1be38b)a
Substrate
FERb
Pathway
Substituents
r
or rꢂ
rþ
r-
rþ
f
d
24ae32a
YT
Base-catalyzed
Electron-withdrawing
2.22
0.60
n 9
19ae24a
YT
n 6
IYT
n 14
IYT/FN
n 23
YT/FN
n 12
IYT/FN
n 33
Base-catalyzed
Uncatalyzed
Electron-donating
All the substituents
Electron-withdrawing
Electron-donating
All the substituents
ꢂ0.33
19ae32a
ꢂ1.29
0.11
0.26
0.60
5ae10a, 12ae15a, 24ae32a, 35ae38a
1ae4a, 19ae24a, 33ae34a
1ae10a, 12ae14a, 19ae38a
Base-catalyzed
Base-catalyzed
Uncatalyzed
2.30
0.32
1.50
ꢂ0.33
2.33
0.62
ꢂ1.29
0.11
0.26
ꢂ0.92
ꢂ0.52
a
Data from Ref. 14.
b
YT, IYT, and FN refer to Yukawa-Tsuno, Ingold-Yukawa-Tsuno, and Fujita-Nishioka relationships, respectively.
diazole (19c, 20c, 22c, 24c, 26e32c)28 we have gained a general
FER-picture of meta- and para-substituents effects in the arylhy-
drazonic moiety on the different reaction pathways (general-base-
catalyzed, uncatalyzed, and specific-acid-catalyzed).
The course of the MRH of 1c, 3c, 4c, 8ce11c, 13c, 16c, 17c, 19c,
20c, 22c, 24c, 26ce33c, 35ce38c into the relevant (2-aryl-5-phe-
nyl-2H-1,2,3-triazol-4-yl)ureas 1d, 3d, 4d, 8de11d, 13d, 16c, 17d,
19d, 20d, 22d, 24d, 26de33d, 35de38d has been investigated in
the range 283e333 K in D/W over a wide range of pSþ values
(complete kinetic data and thermodynamic parameters are
reported in Tables AeQ, while Table R collects a summary of the
obtained data. See Supplementary data). The Apparent first-order
rate constants for the Rearrangements [kA,R; calculated at 313.1 K
from activation parameters] and the thermodynamic parameters
at pSþ 1.00, 3.80, and 11.50 have been collected in Table 2 together
with the different substituents constants used (scalcd, see notes of
Table 2).
A first examination of the results reported in Table 2 [log kA,R
versus pSþ plots for some representative derivatives (1c, 13c, 24c,
37c, and 38c) are summarized in Figure 1] shows that all of the
examined compounds can rearrange via the general-base-cata-
lyzed and the uncatalyzed pathways. Looking at the specific-acid-
catalyzed pathway, only 38c does not rearrange at low pSþ values.
Once more the log kA,R versus pSþ plots display quasi-unitary
slopes over a wide pSþ range (see data in Table R of Supplementary
data; average values: 0.912ꢁ0.004 and ꢂ0.930ꢁ0.009 in the base-
and in the acid-catalyzed ranges, respectively, as expected for this
kind of process carried out in water-like solvents), thus replicating
the situations observed in the instances of 1ae38a (0.913, in the
base-catalyzed range)14 and of the meta- and para-substituted (Z)-
arylhydrazones 19c, 20c, 22c, 24c, 26ce32c in both base- and acid-
catalyzed paths.28
We have been able also to evidence some interesting relation-
ships between the break points (i.e., the pSþ at which the switch from
one mechanism to the other occurs) or the width of the uncatalyzed
pathway and the electronic effects of the present substituents.29
Starting from the above results we have now synthesized five
new ortho-substituted (X¼2-Me, 2-F, 2-Cl, 2-Br, and 2-NO2: 33c,
35ce38c) and ten new polysubstituted (di-, tri-, and four-
substituted: X2¼2,3-Me2, 2,5-Me2, 3,4-Me2, 2,3-Cl2, 2,4-Cl2, 2,5-Cl2,
2,6-Cl2, 3,5-Cl2; X3¼2,4,6-Cl3; X4¼2,3,5,6-F4: 1c, 3c, 4c, 8ce11c, 13c,
16c, 17c) (Z)-arylhydrazones of 5-amino-3-benzoyl-1,2,4-oxadia-
zole and studied their MRH into the relevant (2-aryl-5-phenyl-2H-
1,2,3-triazol-4-yl)ureas with the following aims:
(1) to compare the ‘classical’ electronic effects and the ‘proximity
polar’ and‘primarysteric’effectsinthisseriesofcompoundswith
those previously observed in the rearrangement of 1ae38a14
(2) to gain information on the ‘global’ effects of ortho and multiple
substituents on the course of the acid-catalyzed path;
(3) to ascertain if the kinetic steric acceleration observed in
2,6-dihalogeno (Z)-phenylhydrazones of 3-benzoyl-5-phenyl-1,
2,4-oxadiazole (11a, 16ae18a)14 represents a general behavior
in the MRH of (Z)-arylhydrazones of 3-benzoyl-1,2,4-oxadiazoles
and in that case, looking if it also works in the acid-catalyzed
pathway;

Table 2
Kinetic and thermodynamic dataa and parameters used in FER treatments for the rearrangement of 1c, 3c, 4c, 8ce11c, 16c, 17c, 19c, 20c, 22c, 24c, 26ce33c, 35ce38c into 1d, 3d, 4d, 8de11d, 16d, 17d, 19d, 20d, 22d, 24d, 26de33d,
35de38d at various pSþ and at 313.1 K in D/W (1:1, v/v)
Comp. Subst.b (Es, F)
kA,R (sꢂ1) at pSþ 11.50c
(
D
H#,
D
S#)
(
scalcd
)
kA,R (sꢂ1) at pSþ 3.80c
(
D
H#,
D
S#)
(
scalcd
)
kA,R (sꢂ1) at pSþ 1.00c
(
scalcd)
kH (L molꢂ1 sꢂ1) (
D
H#,
D
S#) K (L molꢂ1
)
d,e
e,f
e,g
11.50
3.80
1.00
1c
3c
4c
8c
2,3-Me2 (ꢂ1.24, ꢂ0.04) 6.62ꢃ10ꢂ4 (89.8, ꢂ19.4)
ꢂ0.379
ꢂ0.379
ꢂ0.379
0.626
0.506
0.626
0.506
0.746
0.759
0.948
ꢂ0.78i
ꢂ0.31i
ꢂ0.069j
0.000j
0.253
0.300
0.373j
0.391j
0.71j
4.53ꢃ10ꢂ6 (99.9, ꢂ29.0)
4.67ꢃ10ꢂ6 (99.4, ꢂ30.3)
1.40ꢃ10ꢂ5 (99.8, ꢂ19.6)
2.52ꢃ10ꢂ7 (98.7, ꢂ55.8)
3.17ꢃ10ꢂ7 (97.8, ꢂ57.7)
2.45ꢃ10ꢂ7 (98.5, ꢂ56.4)
1.41ꢃ10ꢂ6 (99.3, ꢂ42.5)
9.31ꢃ10ꢂ7 (97.2, ꢂ50.7)
7.89ꢃ10ꢂ7 (98.4, ꢂ48.1)
2.22ꢃ10ꢂ6 (98.9, ꢂ36.7)
1.24ꢃ10ꢂ5 (97.4, ꢂ28.0)
1.19ꢃ10ꢂ5 (99.6, ꢂ22.2)
9.18ꢃ10ꢂ6 (97.5, ꢂ31.0)
7.94ꢃ10ꢂ6 (94.8, ꢂ37.8)
3.99ꢃ10ꢂ6 (99.2, ꢂ31.4)
3.44ꢃ10ꢂ6 (98.7, ꢂ35.6)
2.71ꢃ10ꢂ6 (99.2, ꢂ34.7)
ꢂ0.190
ꢂ0.190
ꢂ0.190
0.645
0.544
0.645
0.544
0.746
0.816
0.986
ꢂ0.158
ꢂ0.121
ꢂ0.069j
0.000j
0.272
0.285
0.373j
0.391j
0.71j
1.59ꢃ10ꢂ4 (82.8, ꢂ54.3) ꢂ0.187
1.63ꢃ10ꢂ4 (82.7, ꢂ55.4) ꢂ0.187
5.18ꢃ10ꢂ4 (82.7, ꢂ45.6) ꢂ0.187
7.89ꢃ10ꢂ4 (79.9, ꢂ49.8)
7.97ꢃ10ꢂ4 (79.0, ꢂ52.7)
2.55ꢃ10ꢂ3 (79.1, ꢂ42.4)
4.66ꢃ10ꢂ5 (85.7, ꢂ55.0)
5.33ꢃ10ꢂ5 (82.4, ꢂ64.2)
4.35ꢃ10ꢂ5 (82.5, ꢂ65.6)
2.89ꢃ10ꢂ4 (79.6, ꢂ62.2)
1.80ꢃ10ꢂ4 (83.3, ꢂ51.2)
1.58ꢃ10ꢂ4 (76.0, ꢂ75.6)
3.33ꢃ10ꢂ4 (80.4, ꢂ55.3)
2.13ꢃ10ꢂ3 (77.0, ꢂ51.5)
1.88ꢃ10ꢂ3 (78.2, ꢂ46.7)
1.77ꢃ10ꢂ3 (79.1, ꢂ46.4)
1.58ꢃ10ꢂ3 (85.4, ꢂ26.8)
7.26ꢃ10ꢂ4 (80.8, ꢂ48.5)
6.52ꢃ10ꢂ4 (83.7, ꢂ39.7)
5.33ꢃ10ꢂ4 (79.5, ꢂ54.0)
4.95ꢃ10ꢂ4 (77.0, ꢂ62.8)
1.80ꢃ10ꢂ4 (76.7, ꢂ73.6)
1.55ꢃ10ꢂ4 (82.0, ꢂ57.3)
1.78ꢃ10ꢂ4 (77.0, ꢂ71.1)
5.81ꢃ10ꢂ4 (81.5, ꢂ47.2)
2.82ꢃ10ꢂ4 (82.1, ꢂ51.3)
1.18ꢃ10ꢂ4 (82.0, ꢂ59.5)
7.48ꢃ10ꢂ5 (85.2, ꢂ52.4)
1.34
1.37
1.31
0.90
0.956
0.895
0.984
0.807
0.870
0.901
1.40
2,5-Me2 (ꢂ1.24, ꢂ0.04) 7.24ꢃ10ꢂ4 (88.8, ꢂ22.4)
3,4-Me2
4.83ꢃ10ꢂ3 (89.7, ꢂ3.8)
5.70ꢃ10ꢂ3 (86.2, ꢂ13.2)
3.52ꢃ10ꢂ3 (85.4, ꢂ20.5)
6.27ꢃ10ꢂ3 (85.5, ꢂ15.0)
1.48ꢃ10ꢂ2 (83.0, ꢂ15.2)
0.172 (84.2, þ8.4)
2,3-Cl2 (ꢂ0.97, 0.41)
2,4-Cl2 (ꢂ0.97, 0.41)
2,5-Cl2 (ꢂ0.97, 0.41)
2,6-Cl2 (ꢂ1.94, 0.82)
3,5-Cl2
6.36ꢃ10ꢂ6 (82.9, ꢂ80.2)
7.80ꢃ10ꢂ6 (85.0, ꢂ72.1)
6.14ꢃ10ꢂ6 (83.4, ꢂ79.5)
4.36ꢃ10ꢂ5 (84.9, ꢂ57.2)
2.34ꢃ10ꢂ5 (83.2, ꢂ68.4)
2.19ꢃ10ꢂ5 (84.2, ꢂ66.4)
4.67ꢃ10ꢂ5 (83.2, ꢂ62.7)
0.648
0.550
0.648
0.550
0.746
0.825
0.992
9c
10c
11c
13c
16c
17c
19ch
20ch
22ch
24ch
26ch
27ch
28ch
29ch
30ch
31ch
32ch
33c
35c
36c
37c
38c
2,4,6-Cl3 (ꢂ1.94, 0.82)
0.0836 (85.3, þ5.2)
2,3,5,6-F4 (ꢂ0.92, 0.86) 3.65 (80.2, þ20.4)
4-OMe
4-Me
3-Me
H
4-Cl
4-Br
3-Cl
3-Br
6.41ꢃ10ꢂ3 (85.5, ꢂ16.7)
4.22ꢃ10ꢂ4 (84.9, ꢂ37.7) ꢂ0.147
3.71ꢃ10ꢂ4 (86.6, ꢂ34.7) ꢂ0.118
3.16ꢃ10ꢂ4 (83.7, ꢂ45.6) ꢂ0.069j
4.67ꢃ10ꢂ3 (88.3, ꢂ6.7)
3.95ꢃ10ꢂ3 (85.7, ꢂ17.4)
3.68ꢃ10ꢂ3 (88.2, ꢂ12.4)
1.61ꢃ10ꢂ2 (89.5, þ6.7)
2.00ꢃ10ꢂ2 (84.1, ꢂ10.2)
2.69ꢃ10ꢂ2 (87.6, ꢂ12.1)
3.12ꢃ10ꢂ2 (87.0, þ4.6)
1.58ꢃ10ꢂ1 (85.9, þ13.2)
3.21ꢃ10ꢂ1 (87.2, þ24.3)
1.19 (83.1, þ21.3)
1.34
1.23
1.23
1.08
2.86ꢃ10ꢂ4 (84.9, ꢂ40.2)
1.19ꢃ10ꢂ4 (84.9, ꢂ50.2)
1.05ꢃ10ꢂ4 (83.3, ꢂ54.5)
7.83ꢃ10ꢂ4 (81.2, ꢂ63.6)
7.46ꢃ10ꢂ5 (83.3, ꢂ60.2)
2.43ꢃ10ꢂ5 (83.7, ꢂ66.5)
2.22ꢃ10ꢂ5 (82.8, ꢂ70.5)
1.24ꢃ10ꢂ5 (82.4, ꢂ78.3)
0.000j
0.275
0.287
0.373j
0.391j
0.71j
1.06
0.976
0.983
0.868
0.880
0.414
1.31
1.15
1.08
1.04
2.64ꢃ10ꢂ6 (100.0, ꢂ33.1)
9.95ꢃ10ꢂ7 (98.7, ꢂ46.0)
9.50ꢃ10ꢂ7 (98.7, ꢂ45.2)
6.10ꢃ10ꢂ7 (98.7, ꢂ49.4)
3.20ꢃ10ꢂ6 (96.7, ꢂ41.2)
1.49ꢃ10ꢂ6 (98.7, ꢂ41.8)
6.76ꢃ10ꢂ7 (96.5, ꢂ55.6)
4.30ꢃ10ꢂ7 (99.1, ꢂ50.8)
1.25ꢃ10ꢂ8 (97.8, ꢂ84.5)
3-NO2
4-CN
4-NO2
2-Me (ꢂ1.24, ꢂ0.04)
2-F (ꢂ0.46, 0.43)
2-Cl (ꢂ0.97, 0.41)
2-Br (ꢂ1.16, 0.44)
2-NO2 (ꢂ2.52, 0.67)
0.846
1.07
0.770
0.886
ꢂ0.121
0.155
0.272
0.285
0.886
0.784
0.909
6.89ꢃ10ꢂ4 (88.7, ꢂ23.4)
2.33ꢃ10ꢂ3 (89.2, ꢂ12.1)
7.80ꢃ10ꢂ4 (89.8, ꢂ20.2)
4.56ꢃ10ꢂ4 (90.9, ꢂ19.4)
2.43ꢃ10ꢂ4 (94.1, ꢂ15.4)
ꢂ0.31i
0.137
0.253
0.300
1.07
1.07ꢃ10ꢂ4 (82.0, ꢂ60.2) ꢂ0.118
4.57ꢃ10ꢂ5 (85.7, ꢂ55.2)
1.97ꢃ10ꢂ5 (82.6, ꢂ72.1)
1.17ꢃ10ꢂ5 (85.8, ꢂ65.8)
0.159
0.275
0.287
a
D
H#: kJ molꢂ1, the maximum error is 2 kJ molꢂ1
; D .
S#: J Kꢂ1 molꢂ1, the maximum error is 5 J Kꢂ1 molꢂ1
b
c
Es and F values from Ref. 26 are reported.
Values calculated from activation parameters. The experimental first-order rate constants were measured in the range 283e333 K and were reproducible within ꢁ3% (see Tables AeQ in the Supplementary data).
scalcd¼S(sHþ0.64 Dsꢂ).
d
e
Calculated sigma values (notes d, f, and g) come from YT or IYT treatment concerning kinetic data for the rearrangement of meta- and para-substituted (Z)-arylhydrazones of 5-amino-3-benzoyl-1,2,4-oxadiazoles in D/W at pSþ
11.50, 3.80, and 1.00, respectively. Values from Ref. 28.
f
scalcd¼S(snþ0.10 DsRþþ0.24 DsꢂR ).
g
scalcd¼S(snþ0.08 DsRþþ0.29 DsꢂR ).
h
Values from Ref. 28 and references therein.
i
Values of s
þ from Ref. 2d.
j
s
values defined by Hammett from Ref. 2c.

5446
F. D’Anna et al. / Tetrahedron 66 (2010) 5442e5450
accelerationfromthe‘primarysteric’effectsobservedintheMRH
-1
-2
-3
-4
-5
-6
-7
-8
-9
of 2,6-dihalogeno (Z)-phenylhydrazones of series a14 does work
also in those of series c, giving a general significance to this effect.
This observation induced us to exclude these three substrates in
all of the following FERs. As a matter of fact we calculated (see
Figs. A, B, and C of Supplementary data) that they are much more
reactive than foreseen (by factors of 103, 153, and 53 in the base-
catalyzed path, 27, 33, and 59 in the uncatalyzed path, and 23, 25,
and 33 in the acid-catalyzed path, respectively).
13c
24c
1c
37c
Moreover the nice linear relationship clearly indicates that
similar ‘classical’ electronic, ‘proximity polar’, and ‘primary steric’
effects are operating in the two series of compounds (a and c) in
both pathways and this induces us to use the previous substituent
38c
constants (sm, sp, sn, , s
sþ ꢂ, as well as the relevant rþ and re pa-
rameters, Es, and Fo) in all of the following FERs. Of course, the
additivity rule of the substituents’ effects has also been applied (for
details see Supplementary data);
0
2
4
6
8
10
12
14
pS+
Figure 1. Plot of log kA,R at 313.1 K for the rearrangement of 1c, 13c, 24c, 37c, and 38c
into the relevant triazoles 1d, 13d, 24d, 37c, and 38d in D/W versus pSþ
(2) the calculated slopes are quite near to unity (see Fig. 2), even if
some difference between the two reaction pathways seems to
occur: in fact, in the uncatalyzed path the slope calculated (s
0.903ꢁ0.012) appears to be lower then unity, out of the sta-
tistical error (this agrees with the observation30 that for similar
reactions the relationship higher reactivity¼lower selectivity
does work. See after at point 3) while in the base-catalyzed
path, the slope calculated appears to be unitary in the range of
the statistical uncertainty (s 1.03ꢁ0.01); the calculated values
of intercepts are only a little different from zero;
(3) looking at the differences in reactivity between (Z)-arylhy-
drazones of series a and c we have observed that (Z)-arylhy-
drazones of series c are on average more reactive than those of
series a.14,31 Thus, in the presence of the same substituents the
reactivity ratios [(kA,R)c/(kA,R)a] in the base-catalyzed can range
between 1.4 (for 1c) and 3.0 (for 17c) (1.7 represents the av-
erage value) and in the uncatalyzed pathways between 6.4 (for
24c) and 14.3 (for 38c), with 8.3 as the average value. This
observation can be responsible for the unexpected result that
the (Z)-arylhydrazone 17c also rearranges via the uncatalyzed
pathway while in contrast 17a is not able to do it;
.
2.2. ‘Classical’ electronic, ‘proximity polar’, and ‘primary
steric’ effects in MRH of (Z)-arylhydrazones of series c:
a comparison with the reactivity of the relevant (Z)-
arylhydrazones of series a
(Z)-Arylhydrazones of series a (at C-5 a phenyl group is present)
can rearrange via the general-base-catalyzed and the uncatalyzed
pathways,14,17 while those of series c (at C-5 an amino group is
present) can rearrange also via the pSþ-dependent specific-acid-
catalyzed pathway.27,28
Thus the comparison between the effect of substituents in the
MRH of (Z)-arylhydrazones of series a and c can be carried out for the
first two pathways. To get initial information, we plotted the log kA,R
(the logarithms of the rearrangement rate constants for the MRH) of
compoundsof series c versusthose of the relevantones of series a for
both general-base-catalyzed and uncatalyzed paths (Fig. 2).
3
(4) this difference in the reactivity between the two series of (Z)-
arylhydrazones appears of some interest: it can be related to
the different effects of 5-amino (series c) and 5-phenyl (series
a) groups. In turn they could affect (a) the electrophilic char-
acter of N2, (b) the leaving group ability of the N4eC5eO1 sys-
tem, and (c) the stability of both starting and final products.
2
2
1
0
1
Interestingly, the differences of reactivity observed between
compounds of series a and c can berationalized, probablyconsidering
theterms bandc asthemostimportant:inbothpathways theprocess
overall is a SNi reaction, but the weaker the nucleophile, the more the
leaving group ability becomes important [in MRH the nucleophile
(the >NH of the arylhydrazono moiety) is very weak]. Accordingly, an
examination of the thermodynamic parameters concerning the
rearrangement in the uncatalyzed pathway (for which the reactivity
differences are higher and the discussion of thermodynamic param-
eters is ‘correct’),14,28 shows that the higher reactivity of (Z)-arylhy-
drazones of series c with respect to those of series a is essentially
entropy-dependent (see after data under Section 2.3.2 and in Ref.14).
-1
-2
-4
-3
-2
-1
0
1
2
3
log[(k ) /(kA,R)H]Ph
A,R X
Figure 2. Cross-correlations of log½ðkA;R
Þ
X=ðkA;R
Þ
HꢄNH at pSþ 11.50 (B) [s 1.03ꢁ0.01;
2
i
0.04ꢁ0.01;
n
26;
r
0.998] or f1 þ log½ðkA;R
Þ
X=ðkA;R
Þ
HꢄNH gat pSþ 3.80 (C)
[s 0.903ꢁ0.012; i 1.02ꢁ0.01; n 25; r 0.998] concerning 1c, 3c, 4c,28ce11c, 13c, 16c, 17c,
19c, 20c, 22c, 24c, 26ce33c, 35ce38c versus the relevant log[(kA,R)X/(kA,R)H]Ph for 1a,
3a, 4a, 8ae11a, 13a, 16a, 17a, 19a, 20a, 22a, 24a, 26ae33a, 35ae38a at 313.1 K.
Looking at Figure 2 the following comments appear evident at
a first sight:
2.3. On the MRH of (Z)-arylhydrazones of series c in the base-
catalyzed, in the uncatalyzed, and in the acid-catalyzed
pathways
(1) in both cases excellent relationships have been observed
(rꢀ0.998), interestingly also including the 2,6-dihalogeno (Z)-
arylhydrazones (11c, 16c, and 17c) in the correlation: thus, the
2.3.1. FERs in the general-base-catalyzed pathway. At high pSþ
valuesall of theexamined(Z)-arylhydrazones rearrangeviathis path

F. D’Anna et al. / Tetrahedron 66 (2010) 5442e5450
5447
showing the pSþ-dependent reactivity typical of a general-base-
catalyzed pathway (no limiting reactivity was observed and more-
over kinetic tests with different buffers17c,27 indicate the occurrence
of a buffer-dependent reactivity).15,32 An attempt to apply the FER
has again evidenced the presence of two separate relationships (by
using the Yukawa-Tsuno approach): the former for electron-with-
drawing and the latter for electron-donating substituents.
Looking at all of the (Z)-arylhydrazones containing electron-
withdrawing substituents (8ce10c, 13c, 24c, 26ce32c, 35ce38c)
and by using the calculation procedures previously followed14 (see
details in Supplementary data, complete computational results for
all of the three examined pathways are collected in Tables S, T, and
U) we obtained the results reported in line 1 of Table 3, showing an
excellent correlation coefficient for the YT/FN (Yukawa-Tsuno/
Fujita-Nishioka) equation (R2>0.998).
86.2ꢁ1.0 kJ molꢂ1 and in contrast the activation entropies range
from ꢂ45.1 to þ5.9 J Kꢂ1 molꢂ1, respectively.
2.3.2. FERs in the uncatalyzed pathway. All of the examined (Z)-
arylhydrazones rearrange via an uncatalyzed path. Starting from
the results of the IYT relationship applied to meta- and para-
substituted (Z)-arylhydrazones (19c, 20c, 22c, 24c, and 26e32c)28
we have enlarged the FN treatment to all of the examined ortho-
and poly-substituted (Z)-arylhydrazones (1c, 3c, 4c, 8ce10c, 13c,
33c, 35ce38c), obtaining an excellent correlation (see line 3 of
Table 3, R2>0.998).
Looking at the values of the various contributing susceptibility
constants one can observe that the low (on this point see some our
previous comments)17a calculated
comparable to those previously obtained for both the relevant (Z)-
r
value (ꢂ1.25ꢁ0.02) is strictly
Table 3
FER application to the rearrangement of (Z)-arylhydrazones of 5-amino-3-benzoyl-1,2,4-oxadiazole (1c, 3c, 4c, 8ce10c, 13c, 19c, 20c, 22c, 24c, 26ce33c, 35ce38c) into the
relevant (2-aryl-5-phenyl-2H-1,2,3-triazol-4-yl)ureas (1d, 3d, 4d, 8de10d, 13d, 19d, 20d, 22d, 24d, 26de33d, 35de38d)
Substrate
FERa
Pathway
Substituents
r
or re rþ
re
rþ
f
d
8ce10c, 13c, 24c, 26ce32c, 35ce38c
YT-FN
n 16
YT-FN
n 8
Base-catalyzed (kA,R
)
)
Electron-withdrawing 2.30
0.64
0.67
1.61
1c, 3c, 4c, 19c, 20c, 22c, 24c, 33c
Base-catalyzed (kA,R
Electron-donating
ꢂ0.30
0.68
1c, 3c, 4c, 8ce10c, 13c, 19c, 20c, 22c, 24c, 26ce33c, 35ce38c IYT/FN Uncatalyzed (kA,R
n 23
1c, 3c, 4c, 8ce10c, 13c, 19c, 20c, 22c, 24c, 26ce33c, 35ce37c IYT/FN Acid-catalyzed (kH)
n 22
)
All the substituent
All the substituents
All the substituents
All the substituents
ꢂ1.25
0.10 0.24
0.08 0.29
ꢂ0.79 0.45
ꢂ0.79 0.44
ꢂ1.23
ꢂ0.218
ꢂ1.42
1c, 3c, 4c, 8ce10c, 13c, 19c, 20c, 22c, 24c, 26ce33c, 35ce37c
H
Acid-catalyzed (K)
n 22
1c, 3c, 4c, 8ce10c, 13c, 19c, 20c, 22c, 24c, 26ce33c, 35ce37c IYT/FN Acid-catalyzed (kA,R
n 22
)
0.08 0.29
ꢂ0.83 0.43
a
H, YT, IYT, and FN refer to Hammett, Yukawa-Tsuno, Ingold-Yukawa-Tsuno, and Fujita-Nishioka relationships, respectively.
After we looked at (Z)-arylhydrazones containing electron-
donating substituents (1c, 3c, 4c, 19c, 20c, 22c, 24c, 33c). Con-
sidering some our previous results14,17,28 and because of their
limited number and nature (in the instance of disubstituted (Z)-
arylhydrazones only methyl substituents are present) we di-
rectly correlated reactivity data by using sþ values and by
neglecting the proximity polar effect (its susceptibility constant
was calculated near to zero) and obtained the results reported in
line 2 of Table 3 again with an excellent correlation coefficient
(R2>0.999).
arylhydrazones of series a (ꢂ1.29ꢁ0.02)14 and the meta- and para-
substituted (Z)-arylhydrazones of series c (ꢂ1.24ꢁ0.02).29
Of course a negative proximity polar constant (f ꢂ0.79ꢁ0.05)
and a positive proximity steric effect (
d
0.45ꢁ0.01) have been cal-
culated: they are not very different from that obtained for the rel-
evant (Z)-arylhydrazones of series
a
(f: ꢂ0.92ꢁ0.05 and
d:
0.52ꢁ0.01, respectively).14
In the uncatalyzed pathway the values of thermodynamic pa-
rameters can be appropriately discussed, as rate constants are not
composite values. Once more the kA,R values variations are essen-
tially entropy-dependent. E.g., at pSþ 3.80 the activation enthalpy is
practically substituent-independent (
in contrast the activation entropy (
Overall, the results with (Z)-arylhydrazones containing electron-
withdrawing as well as electron-donating substituents compare
well with the previous ones collected with meta- and para-
substituted (Z)-arylhydrazones of series c28 and with the relevant
mono- and poly-substituted (Z)-arylhydrazones of series a,14 con-
D
Hþ 98.4ꢁ1.0 kJ molꢂ1) and
D
Sþ) varies from ꢂ84.5 to
ꢂ19.6 J K molꢂ1. Of course for all of the studied (Z)-arylhydrazones
in the pSþ range of the uncatalyzed pathway the values of enthalpy
and entropy activation stay practically unchanged: for example in
the instance of 13c in the pSþ interval 2.90e5.45 (see Table H of
Supplementary data) its average values are in the field of
97.5ꢁ1.0 kJ molꢂ1 and of e49.1 ꢁ 1.0 J K molꢂ1, respectively.
sidering both resonance contributions (
effects ( and f): compare results in Tables 1 and 3.
r
, rþ, rꢂ) and proximity
d
Because of their composite nature (the base-catalysis is general,
therefore depending on the concentration of all of the bases pres-
ent)14,28 a discussion on thermodynamic parameters is not strictly
correct. Anyway we have observed that the reactivity variations are
essentially entropy-dependent, the enthalpy values staying prac-
tically unchanged. For example looking at the MRH at pSþ 11.50 (see
data in Table 2) we can observe that the average value of their ac-
tivation enthalpies is 87.6ꢁ1.5 kJ molꢂ1 and in contrast the activa-
tion entropies range from ꢂ23.4 to þ24.3 J Kꢂ1, as a function of the
present substituent, thus determining the reactivity fluctuations.
Moreover looking at the reactivity of a single (Z)-arylhydrazone
in the base-catalyzed pathway as a function of the pSþ we have
observed that the activation enthalpies at different pSþ values again
stay practically unchanged and in contrast the activation entropies
change significantly. E.g., for 10c in the pSþ interval 9.40e12.60 (see
data in Table F of SD) the average value of activation enthalpy is
2.3.3. FERs in the specific-acid-catalyzed pathway. At low pSþ values
(2.4e2.7) all of the examined (Z)-arylhydrazones, except 38c, rear-
range via a specific-acid-catalyzed pathway.27,28 As a matter of fact,
looking at data reported in Figure 1 and in Table 2 one can observe
that after an increase of the reactivity with the increase of proton
concentration at the lowest pSþ values, the reactivity tends to
a limiting value: moreover kinetic tests with different buffers in-
dicate the occurrence of a buffer-independent reactivity27,28 (sug-
gesting an Arrhenius complex formation,15,32 see Scheme 1), thus
replicating the situation previously evidenced in some meta- and
para-substituted (Z)-arylhydrazones (19c, 20c, 22c, 24c, 26ce32c).28
The application of steady state treatment to this pathway of the
MRH gives Eq. 2

5448
F. D’Anna et al. / Tetrahedron 66 (2010) 5442e5450
enthalpy
is
practically
substituent-independent
(D
D
H#
S#)
ꢂ
ꢃꢄꢀ
ꢂ
ꢃꢁ
logkA;R ¼ ku þ KkH H3Oþ 1 þ K H3Oþ
(2)
83.7ꢁ1.0 kJ molꢂ1) and in contrast the activation entropy (
ranges from ꢂ34.7 to ꢂ80.2 J K molꢂ1
.
From the experimental kA,R values (Tables AeQ) the relevant K and
kH values could be calculated.33 The obtained values are well in line
with an Arrhenius complex formation: in fact at 313.1 K the K
values range between 0.4 and 1.4 L molꢂ1 and the kH ones between
0.47ꢃ10ꢂ4 and 25.5ꢃ10ꢂ4 L molꢂ1 sꢂ1. Therefore we have a true
acid-base equilibrium followed by a slow rearrangement of the
protonated (Z)-arylhydrazones according with the occurrence of
a specific-acid-catalysis (see Scheme 1).
2.4. The effects of substituents on the break-points and on
the widths of the uncatalyzed pathway
Results collected in Figure 1 provide evidence that the switchfrom
one mechanism to the other (named ‘break-point’) is substituent-
dependent, in turn rendering also the width of the uncatalyzed
pathway substituent-dependent.28,29 We shall call (pSþ)1 and (pSþ)2,
respectively, thepSþ values atwhichthechangesfrombase-catalyzed
to uncatalyzed and then from uncatalyzed to acid-catalyzed path-
ways occur. They represent the pSþ-values at which the substrate
shows the same reactivity in the two adjacent paths. Table V (see
Supplementary data) collects (pSþ)1 and (pSþ)2 values as well as the
The three series of calculated values (kA,R, K, and kH) can be related
to the substituent effects, electronic as well as steric. We shall firstly
examine the effects on the constants concerning the two simple
component steps (kH and K) and then on the composite one (kA,R).
Again by enlarging the treatment from meta and para to all of the
examined ortho- and poly-substituted (Z)-arylhydrazones showing
the specific-acid-catalyzed pathway(1c, 3c, 4c, 8ce10c,13c, 33c, and
35ce37c), that is, applying a IYT/FN treatment, an excellent corre-
lation can be obtained for kH values (see line 4 of Table 3, R2>0.997).
Moreover a logarithmic plot of kH versus kA,R at pSþ 3.80 and at
313.1 K gave an excellent cross-correlation (Eq. 3; R2>0.996) with
a unitary slope showing that in the two cases similar electronic and
steric effects are operating.
width values indicated as
D
pSþ [i.e.,
D
pSþ¼(pSþ)1ꢂ(pSþ)2].
We already carried out a deep discussion on these points in the
instance of meta- and para-substituted (Z)-arylhydrazones,29 for
this here we will give only some short comments.
(pSþ)1 values ranges between 4.75 and 9.1 showing a strong de-
pendenceon the substituent: the lowest values (4.75 and 4.8) concern
(Z)-arylhydrazones containing electron-withdrawing substituents
(32c: X¼4-NO2; 17c: X¼2,3,5,6-F4), and in contrast the highest values
(8.8 and 9.1) concern (Z)-arylhydrazones containing electron-donat-
ing substituents (19c: X¼4-OMe; 3c: X¼2,5-Me2; 1c: X¼2,3-Me2).
This behavior is well in line with the fact that electron-with-
drawing and -donating substituents in the (Z)-arylhydrazones de-
crease and increasethe nucleophilicityof Na, affecting theuncatalyzed
pathway, which in turn starts at lower or at higher pSþ values.
A comparison between the (pSþ)1 values concerning the rear-
rangement of the (Z)-arylhydrazones of series a and c shows that
their values are strictly correlated. Therefore a plot of [(pSþ)1]c ver-
sus [(pSþ)1]a gives an excellent (r 0.997) linear plot with a unitary
slope (s 1.01ꢁ0.02; i 0.65ꢁ0.11; n 25; see Fig. D in Supplementary
data). A short comment on the intercept value: the effectively high
value clearly indicates that the shift from the base-catalyzed to the
uncatalyzed pathway occurs in the instance of (Z)-arylhydrazones of
series c at higher pSþ values than for those of series a (i.e.,, it is fa-
vored in series c). This appears well in line with the higher reactivity
of compounds c, probably linked to their higher ability to undergo
the SNi process (see above under Section 2.2).
h
i
ꢀ
ꢁ
ꢀ
ꢁ
log ðkHÞX=ðkHÞH ¼ ð0:999 ꢁ 0:013Þlog kA;R = kA;R
i ꢂ 0:04 ꢁ 0:01; n 24; R 0:998; CL > 99:9%
þi
X
H
3:80
(3)
Considering the substituent effects on K an excellent correlation
versus Hammett constants (see line 5 of Table 3; R2>0.990) has
been evidenced.
Finally in the instance of the apparent rate constants for the
acid-catalyzed path at pSþ 1.00 the data treatment enlarged to all of
the ortho- and poly-substituted (Z)-arylhydrazones gives an ex-
cellent relationship (see line 6 of Table 3; R2>0.996).
The results of the above correlations allow some interesting
considerations. The susceptibility constant concerning the re-
lationship involving kH (line 4 of Table 3) is strictly comparable to
that calculated for the uncatalyzed path at pSþ 3.80 (line 3 of Table
3) as indicated by Eq. 3 clearly showing that the same kind of
substituent effects are operating.
Concerning the K values (measuring the degree of protonation at
N4 determined by the conjugative effect of the amino group at C5),
they give an excellent simple Hammett FER with a low and negative
susceptibility constant. This agrees with: (a) the absence of through-
conjugation, (b) the large distance between the substituents and the
site of protonation, and (c) the electronic effects of the substituents
able to increase and decrease, respectively, the basicity of N4.
As concerns the FERs for kA,R values at pSþ 1.00 the obtained results
(seeline 6 of Table 3)parallelthosediscussedforthekH values. The only
furthercomment that can be attached regardsthe higher susceptibility
(pSþ)2 values range between 2.35 and 2.82 showing a very small
dependence on the effect of the present substituent: the lowest
values (2.35e2.44) concern (Z)-arylhydrazones with electron-
withdrawing substituents (32c: X¼4-NO2; 31c: X¼4-CN; 17c:
X¼2,3,5,6-F4; and 30c: X¼3-NO2, respectively), and in contrast the
highest values (2.70e2.82) concern (Z)-arylhydrazones unsub-
stituted or containing electron-donating substituents (3c: X¼2,5-
Me2; 24c: X¼H; 22c: X¼3-Me; 21c: X¼4-Me; 19c: X¼4-OMe). The
above considerations are valid also in this instance.
constant calculated for the electronic effects (
appears in line with the composite nature of the involved kA,R values at
pSþ 1.00 [see Scheme 1 and Eq. 2: from which: rkA,R
rkH rK, in fact
ꢂ1.42yꢂ1.23þ(ꢂ0.22); see a discussion on this point in Ref. 28].
The variations of thermodynamic parameters can be appropri-
ately discussed in the instance of kH. Once more, the activation
r
ꢂ1.42ꢁ0.02), which
Accordingly with previous analyses the smallest and largest
D
pSþ values have been calculated for (Z)-arylhydrazones contain-
¼
þ
ing electron-withdrawing substituents (32c: X¼4-NO2; 17c:
X¼2,3,5,6-F4), or electron-donating substituents (19c: X¼4-OMe;
3c: X¼2,5-Me2; 1c: X¼2,3-Me2), respectively.29
enthalpies are practically substituent-independent
(
D
D
H#
S#)
3. Conclusions
80.8ꢁ3.0 kJ molꢂ1) and in contrast the activation entropies (
vary from ꢂ75.6 to e26.8 J K molꢂ1. In the instance of K the sub-
stituent-dependent variations of K are very low and the thermo-
dynamic data are affected by a large uncertainty (for this reason
their values are not reported in Table 2), so that a discussion on
thermodynamic parameters is not allowed.
The whole of the obtained results allow the following final
considerations.
The kinetic study in D/W of the MRH of the 26 considered (Z)-
arylhydrazones (1c, 3c, 4c, 8ce11c, 13c, 16c, 17c, 19c, 20c, 22c, 24c,
26ce33c, 35ce38c) into the relevant triazoles across a large range of
temperatures and of pSþ has furnished the instruments for a wide
application of the extended Fujita-Nishioka equation together with
Vice-versa the kA,R values are composite values (see Eq. 2): they
are essentially entropy-dependent. Again at pSþ 1.00 the activation

F. D’Anna et al. / Tetrahedron 66 (2010) 5442e5450
5449
different FER of Hammett, YT, and IYT types. This has allowed a fur-
References and notes
ther comparison of electronic and proximity effects in the instance of
ortho-, meta-, and para-substituted and of polysubstituted (Z)-aryl-
hydrazones of series c in the different reaction pathways. In-
terestingly enough, these new collected data, strictly comparable to
those previously collected in the instance of (Z)-arylhydrazones of
series a,14 well confirm the general applicability of a multi-parameter
approach combining H/IYT/FN FERs. We are confident that, collecting
new data, a better and better knowledge of factors affecting FER will
help not only the understanding of the structure/reactivity re-
lationships but also of the structure/activity ones, allowing applica-
tions in different fields of chemistry (material, medicinal, and so on).
Comparing susceptibility constants collected in Table 3 some
interesting comments can be carried on:
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(a) in the instance of the general-base-catalyzed path, a positive
and high rꢂ value has been observed for (Z)-arylhydrazones
containing electron-withdrawing substituents (line 1 of Table
3) according with a large effect of the substituents able to in-
crease the acidity of the NaeH and in turn to make the general-
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substituents (line 2 of Table 3) has been calculated;
8. Hansch, C. In Correlation Analysis in Chemistry; Chapman, N. B., Shorter, J., Eds.;
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a positive medium proximity polar effect and a large primary
steric effect (line 1 of Table 3: f¼0.67, and ¼1.61) have been
d
observed; in contrast, in the uncatalyzed and acid-catalyzed
paths (lines 3, 4, and 6 of Table 3) similar values of the sus-
ceptibility constants for the proximity polar effects (negative,
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(d) the kinetic acceleration observed in the rearrangement of 2,6-
disubstituted (Z)-arylhydrazones is present in all of the three
pathways, thus it appears to be a general event in MRH pro-
cesses of (Z)-arylhydrazones in line with its interpretation;14
(e) both break-points [(pSþ)1 and (pSþ)2] and widths of the
uncatalyzed path appear substituent-dependent. Interestingly
enough the (pSþ)1 values now determined for the (Z)-arylhy-
drazones of series c correlate well with the values measured for
the relevant compounds of series a. These shifts of reaction
mechanism caused by small proton concentration changes
could help to enlighten the behavior of some enzymes whose
activity can be affected by small proton concentration changes
(e.g., disease-dependent).34
4. Experimental
18. Bottoni, A.; Frenna, V.; Lanza, C. Z.; Macaluso, G.; Spinelli, D. J. Phys. Chem. A
2004, 108, 1731e1740.
19. Looking at the MRH of some (Z)-hydrazones of 3-benzoyl-5-phenyl 1,2,4-ox-
adiazoles we have been recently able to evidence the occurrence of a specific-
Chemistry; syntheses, purification, and characterization of
compounds; pSþ and kinetic measurements; and calculation
methods are collected in Supplementary data.
base-catalyzed path by introducing at Na electron-withdrawing groups such as
eCOeNHeC6H5 or eCOeCH3.20 Now, as indicated by some preliminary DFT
calculations, the timing of the bond-breaking and bond-forming processes ap-
pears quite synchronous. This appears in line with very recent DFT results from
the fully degenerate rearrangement of the anion of 3-acetylamino-5-methyl-
1,2,4-oxadiazole for which the two processes are completely synchronous.21
20. D’Anna, F.; Frenna, V.; Guernelli, S.; Lanza, C. Z.; Macaluso, G.; Marullo, S.;
Spinelli, D. ARKIVOC 2009, 125e144.
Acknowledgements
We thank MIUR (PRIN 20078J9L2A_005, 20085E2LXC_001,
20085E2LXC_004) as well as Universities of Bologna and Palermo
for financial support.
21. Mugnoli, A.; Barone, G.; Buscemi, S.; Lanza, C. Z.; Pace, A.; Pani, M.; Spinelli, D.
J. Phys. Org. Chem. 2009, 22, 1086e1093.
22. (a) Schreck, O. J. Chem. Educ. 1971, 48, 103e107; (b) Exner, O. Correlation Analysis
of Chemical Data; Plenum: New York, NY and London, 1988; Chapter 2.5.
23. See Ref. 15, Chapters 3 and 7.
24. Yukawa, Y.; Tsuno, Y.; Sawada, M. Bull. Chem. Soc. Jpn. 1972, 45, 1198e1205 and
refs therein.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2020.05.025.
25. Ingold, C. K. Structure and Mechanism in Organic Chemistry, 2nd ed.; Cornell
University Press: Ithaca, 1969; pp 1217e1218.

5450
F. D’Anna et al. / Tetrahedron 66 (2010) 5442e5450
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28. D’Anna, F.; Frenna, V.; Macaluso, G.; Marullo, S.; Morganti, S.; Pace, V.; Spinelli,
D.; Spisani, R.; Tavani, C. J. Org. Chem. 2006, 71, 5616e5624.
29. D’Anna, F.; Frenna, V.; Guernelli, S.; Macaluso, G.; Petrillo, G.; Rizzato, E.;
Spinelli, D. ARKIVOC 2009, 15e29.
32. (a) See Ref. 2c, Chapter 10. (b) See Ref. 22b, Chapter 7.4. (c) Laidler, K. J. Chemical
Kinetics; McGraw-Hill: London, 1965, pp 450e463; (d) Laidler, K. J.; Bunting, P.
S. The Chemical Kinetics of Enzyme Action; Clarendon: Oxford, 1973, pp 60e62.
33. The intercepts of the regression function (ku), calculated from Eq. 2, would in
principle be equal (or at least comparable) to the kA, R values measured at pSþ 3.
80, but because of their very low absolute values and of the quite complex
nature of Eq. 2 they are affected by a too large inherent uncertainty to be
significant.
30. About the reactivity-selectivity principle (RSP) and its criticism see: Mayr, H.;
Ofial, A. R. Angew. Chem., Int. Ed. 2006, 45, 1844e1854.
31. Similar results had been previously observed comparing only meta and para-
substituted (Z)-arylhydrazones of series a and c.28
34. (a) Sikora, A. L.; Frankel, B. A.; Blanchard, J. S. Biochemistry 2008, 47,
10781e10789; (b) Ando, C.; Ichikawa, N. J. Biochem. 2008, 144, 547e553; (c)
Hermann, P.; Lee, J. C. Biochemistry 2009, 48, 9466e9470.