Mononuclear rearrangements of heterocycles in water/β-CD: information on the real site of reaction from structural modifications of substrates and from proton concentration dependence of the reactivity

Article abstract of DOI:10.1016/j.tet.2007.07.084

The effect of β-cyclodextrin (β-CD) on the reactivity in the base-catalyzed pathway for the rearrangement in water of some (Z)-hydrazones of 3-benzoyl-1,2,4-oxadiazoles (1b-f) into the relevant triazoles (2b-f) was investigated, finding different behavior

Full text of DOI:10.1016/j.tet.2007.07.084

Tetrahedron 63 (2007) 10260–10268
Mononuclear rearrangements of heterocycles in water/b-CD:
information on the real site of reaction from structural
modifications of substrates and from proton
concentration dependence of the reactivity
a,
Susanna Guernelli,a Paolo Lo Meo,b Stefano Morganti,a Renato Notob, and Domenico Spinelli
*
*
aDipartimento di Chimica Organica ‘A. Mangini’, Universitaꢀ di Bologna, Via San Giacomo 11, 40126 Bologna, Italy
bDipartimento di Chimica Organica ‘E. Paternoꢀ’, Universitaꢀ di Palermo, Viale delle Scienze,
Parco d’Orleans II, pad. 17, 90128 Palermo, Italy
Received 8 May 2007; revised 10 July 2007; accepted 20 July 2007
Available online 31 July 2007
Abstract—The effect of b-cyclodextrin (b-CD) on the reactivity in the base-catalyzed pathway for the rearrangement in water of some (Z)-
hydrazones of 3-benzoyl-1,2,4-oxadiazoles (1b–f) into the relevant triazoles (2b–f) was investigated, finding different behavior as a function
of the proton concentration. ESIMS and 1H NMR data evidence the formation of host–guest complexes. The whole of the experimental and
calculated (MM2) data enabled us to draw some intriguing conclusions concerning the influence of the structures of the substrates and the
nature of the formed host–guest complexes on the real site of the reaction.
Ó 2007 Published by Elsevier Ltd.
1. Introduction
In the framework of a supramolecular study of the behavior
of some (Z)-hydrazones in the presence of b-CD we investi-
gated the rearrangement of the (Z)-phenylhydrazone of 3-
benzoyl-5-phenyl-1,2,4-oxadiazole (1a)4 into the relevant
triazole 2a (Scheme 1), examining, for the first time, the
course of the mononuclear rearrangement of heterocycles
(MRH) in a ‘confined environment’ and thus observing the
formation of host–guest inclusion complexes.
Cyclodextrins (CDs) represent interesting materials for the
study of organic reactions:1 their ability to form inclusion
complexes with several hydrophobic guest molecules2
makes it possible to use them as artificial enzyme systems.3
The effect of CDs on organic reactions can be of two types.
CDs and reagents can at first form an intermediate involving
a covalent bond, which then leads to the product; or the em-
ployed CD can act like a host able to solvate the reagents,
thus also making possible the occurrence of the reaction in
water.1b,4
H
N
C6H5
C6H5
C6H5
X
N
N
Nα
R
B
N
N
Nα
R
+
δ
O
N
N
N
H
N
H B
N
R
X
X
O
Oδ-
1a-f
TS
2a-f
As a matter of fact, the cavity of CDs represents a new reac-
tion environment, which is hydrophobic and significantly
different from the hydrophilic bulk solvent (water), hence
the reactivity of the substrates examined may change.3,5 In
this case, the role of CD can be defined as a catalyst, because
it can ‘organize’ reagents thus affecting also the entropic
contribution to activation energy of the organic reactions.1,2
a: X = C6H5; R = C6H5
c: X = H; R = C6H5
e: X = C6H13; R = H
b: X = C6H13; R = C6H5
d: X = C2H5; R = H
f: X = C6H5; R = H
Scheme 1.
The use of the b-CD causes the solubilization in water of 1a:
thus the kinetic process can be carried out in aqueous solu-
tion, avoiding the use of the operational pS+ scale,6 neces-
sary in the dioxane/water (D/W) mixture (see Section 4.5).
Keywords: Host–guest interactions; Reaction in b-CD; Azole rearrange-
ment; ESIMS.
* Corresponding authors. Tel.: +39 091 596919; fax: +39 091 596825
(R.N.); tel.: +39 051 2095689; fax: +39 051 2095688 (D.S.); e-mail
addresses: rnoto@unipa.it; domenico.spinelli@unibo.it
A further contribution to the understanding of the complex-
ation process is derived from MM2 calculations: reactive or
0040–4020/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tet.2007.07.084

S. Guernelli et al. / Tetrahedron 63 (2007) 10260–10268
10261
starting absorption spectrum
non-reactive complexes, which are unable to rearrange into
2a, are possible; they show different stabilities and can be in
equilibrium between one another.
1
0,8
0,6
0,4
0,2
0
For understanding the course of the reaction, it is essential to
estimate the effect of the structure of the guest molecules in
the formation of the inclusion complexes. In this paper, we
present the results of a kinetic study of the MRH, in the pres-
ence of b-CD using substrates (1b–f) with chosen different
structures: as a matter of fact they are variously substituted
at both the C(5) of the 1,2,4-oxadiazole ring and/or at the
Na of the hydrazono group (Scheme 1). Such structural
changes could influence the stability and the actual number
of the possible complexes between (Z)-hydrazones 1b–f and
b-CD. The binding properties of the guest molecules (1b–f)
in the presence of b-CD were also ascertained in gas phase
and in solution by ESIMS and 1H NMR spectrometry,
respectively.
after about 170 minutes
300
375
450
λ (nm)
Figure 1. Absorption spectra of 1b recorded in the first period of the process
(at pH 7.76, about 170 min).
9.60) as well as a fair isosbestic point. The time length of
this period progressively decreases on increasing the pH
value (at 313 K, from ca. 170 min at pH 7.76 down to ca.
30 min at pH 9.60). During the second phase (‘regular
period’),4 lmax remains nearly constant and the absorption
decays exponentially as expected for a simple pseudo-first-
order process, in line with the triazole optical densities being
much lower than those of the starting (Z)-hydrazones.
The overall results obtained support the previous hypothesis
about the nature of the b-CD/1a interactions4 and provide
new and interesting information about the MRH in confined
environment.
2. Results and discussion
Firstly the obtained results (kinetic, UV–vis, MM2, ESIMS
as well as H NMR data) will be separately examined. Fi-
nally the results will be globally discussed.
Using a suitable non-linear-regression-analysis, we ob-
served that the trend of the absorption versus time plots at
given wavelengths (curves registered at 285, 290, and
295 nm, in the region of appearance of the final product
2b, and at 360, 370, 380, 390, 400, and 410 nm, in the region
of disappearance of the starting 1b) are conveniently fitted
by a sum of three exponential functions, and therefore may
be rationalized assuming the existence of at least three dis-
tinct consecutive processes. The values of the apparent con-
stants k1 and k2 for the first two processes (Table 1), which
could be calculated only at the lowest pH values, showed
only minor variations with pH and at times large
uncertainties; in contrast, the apparent rate constants k3 for
the last process reveal a large dependence on pH.
1
The kinetic behavior of some (Z)-phenylhydrazones (1b,c)
and (Z)-hydrazones (1d–f) of 3-benzoyl-1,2,4-oxadiazoles,
containing at the C(5) of the 1,2,4-oxadiazole ring one
hydrogen atom (1c), alkyl chains (1b,e: X¼C6H13; 1d:
X¼C2H5) or a phenyl ring (1f), that is, substituents with dif-
ferent electronic and steric requirements, has been investi-
gated at various pH values and at different temperatures.
All the kinetic measurements were performed at [b-CD]¼
1.0ꢀ10ꢁ4 M and [1b–f]¼5.0ꢀ10ꢁ5 M in aqueous borate
buffer solution ([borate]¼1.25ꢀ10ꢁ2; pseudo-first-order
conditions with respect to the base). Under these experimen-
tal conditions, b-CD was effectively able to dissolve 1b–f,
otherwise almost insoluble in water.
Within the range of the pHs examined, it is known that the
reaction is generally base-catalyzed,6 thus the increase of
k3 values with pH suggests that the calculated k3 is the one
(kA,R) that actually measures the rate of the rearrangement.
By analogy with the behavior of 1a,4 we suppose that k1
and k2 are related to some quite rapid complexation equilib-
ria between 1b and b-CD, which result in the formation of
different host–guest complexes, some of which are ‘non-
reactive’. It was not possible to calculate the k1 and k2 for
the reactions at pH 9.60, probably because the rearrange-
ment becomes so fast as to conceal the occurrence of the
complex formation processes.
The data collected for the MRH of the above substrates can
be compared with those obtained by the rearrangement of
the (Z)-phenylhydrazone 1a in the presence of b-CD4 or in
the dioxane/water mixture (D/W; 1:1, v/v).6a
2.1. The rearrangement of the (Z)-phenylhydrazone of
3-benzoyl-5-hexyl-1,2,4-oxadiazole (1b)
The conversion of 1b into 2b was studied in aqueous solution
(borate buffer, at pH 7.76, 8.96, and 9.60) at different tem-
peratures (293–313 K) in the presence of b-CD. A typical
set of UV–vis absorption spectra, recorded at different times
during the conversion, is shown in Figure 1.
It is possible to compare these kA,R values with some kinetic
data concerning the rearrangement of 1b in D/W (1:1, v/v).
For the reaction in the mixed solvent and at the values of pS+
11.35 and 11.80 (corresponding about to pH 8.96 and 9.60 in
aqueous solution) apparent rate constants of 9.36ꢀ10ꢁ4 sꢁ1
and 2.30ꢀ10ꢁ3 sꢁ1, respectively, were determined. The
lower value of kA,R, measured in the presence of b-CD
(e.g., at pH 9.60 and at 313 K, rate ratio¼ca. 31), suggests
As observed for the MRH of 1a,5 two distinct periods can be
identified during the course of the reaction. Initially, spectra
show a significant bathochromic shift of the absorption max-
imum (from 368 nm to 405ꢂ3 nm at pHs 7.76, 8.96, and

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S. Guernelli et al. / Tetrahedron 63 (2007) 10260–10268
Table 1. Calculated rate constantsa in the 293–313 K temperature range and activation parameters for the rearrangement of 1b into 2b in b-CD at different pH
103 k1 (sꢁ1
)
104 k2 (sꢁ1
)
105 k3 (sꢁ1
)
DHsc,d (kJ molꢁ1
)
DSsc,e (J K molꢁ1
ꢁ33.8
)
b
T (K)
pH
293
303
313
313
313
9.60
9.60
9.60
8.96
7.76
1.10 (ꢂ0.50)
2.10 (ꢂ0.12)
2.00 (ꢂ0.30)
2.16 (ꢂ0.06)
0.65 (ꢂ0.10)
2.46 (ꢂ0.19)
7.50 (ꢂ0.30)
3.82 (ꢂ0.27)
1.97 (ꢂ0.20)
90.9
2.00 (ꢂ0.14)
1.69 (ꢂ0.11)
1.50 (ꢂ0.10)
1.62 (ꢂ0.07)
a
Data are mean values on at least two independent runs. Uncertainty in parenthesis represents the standard deviation of least square treatment.
k3 represents the apparent rate constants (kA,R) for the rearrangement (see text).
Thermodynamic data refer to k3, measured at pH 9.60.
b
c
d
e
The maximum error is 4 kJ molꢁ1
.
The maximum error is 8 J K molꢁ1
.
that the reaction always occurs with the base-catalyzed
mechanism but now the substrate experiences a more hydro-
phobic environment, i.e., the cavity of host (b-CD). As a con-
sequence, because the reaction goes through a transition
state more polar (TS, Scheme 1) than the reagents, it is dis-
favored by a non-polar reaction medium such as the cavity of
the b-CD.4,6
complexes in the gas phase are also reported in Figure. 2.
In all cases, inclusion appears to occur through the side of
the secondary rim.13
As discussed elsewhere for the corresponding complexes of
1a,4 we may reasonably presume that only A is the actual
precursor of the rearranged 2b, because in model C the Na
of the hydrazono group seems to be too deeply inserted
into the host cavity and then it does not seem able to interact
effectively with the base. Moreover, dynamic simulations
show that E quickly collapses into F. However, A has the
highest energy and is separated from F and B by nearly
16.8 and 12.7 kJ molꢁ1. Models C and D are very close in
energy, and the dynamic simulations show that they very
rapidly interconvert into each other. In contrast, mutual con-
formational interconversions between A and B do not seem
to occur rapidly. Therefore the overall computational data
seem to suggest that B and F (which are not reactive as
such) could be the first formed complexes in solution.
They probably afford the truly ‘reactive’ complex A via D
and C according to the scheme in Figure 2.13
This finding is consistent with the behavior observed previ-
ously for 1a:4 in that case, the MRH process in b-CD occurs
more slowly than in D/W (rate ratio¼ca. 300) and at reaction
rates intermediate between those observed in benzene and in
D/W. The results agree with the hydrophobic character of the
cavity of b-CD that appears intermediate between those of the
two solvents and with the stabilization of the substrate by
means ofits inclusion, due to hydrogen bonding, hydrophobic
interactions, and so on. Moreover, in D/W for all of the (Z)-
hydrazones of 3-benzoyl-1,2,4-oxadiazoles studied we ob-
served a linear increase of the log kA,R versus pS+ with slopes
near to unity (s 0.89–0.93)6,7 as expected for a base-catalyzed
reactionoccurringinawater-likemedium;8 onthecontrary, in
the presence of b-CD the plot of log kA,R versus pH for 1b
shows a slope of 0.31 clearly demonstrating that the rear-
rangement does not occur in the aqueous medium.
To gain further information about the influence of the chem-
ical structure of the substrates involved in the MRH, we
investigated the behavior of 1c–f, substrates less substituted
in their skeleton: 1c is the (Z)-phenylhydrazone of 3-benzo-
yl-1,2,4-oxadiazole (i.e., unsubstituted at C(5) of the
1,2,4-oxadiazole ring), while 1d–f are (Z)-hydrazones of
3-benzoyl-5-X-1,2,4-oxadiazoles (X¼C2H5, C6H13, C6H5;
i.e., unsubstituted at the Na of the hydrazono group:
R¼H), but with different substituents at C(5). Thus we
have examined a set of substrates, which would presumably
show different ability to complex with b-CD.
With regard to the red shifts of lmax, the presence of b-CD
causes both a chromophore displacement because of
a more hydrophobic environment upon host binding9,10
and the occurrence of specific constraints/interaction effects.
Considering that in D/W the absorption maximum of 1b was
at 361 nm, the large shift toward longer wavelengths (from
the initial value, 368 nm, to 408 nm) observed during the re-
action in the presence of b-CD was likely related to specific
interactions of 1b with the hydrophobic cavity of the host,
rather than to a simple ‘solvent effect’. As a matter of fact,
the absorption maximum of 1b in different mixtures of
D/W (from 20:80 to 100:0) remains almost unchanged
(361ꢂ2 nm) and shifts ‘only’ to 367 nm in benzene,11 how-
ever, to 408 nm in b-CD.4,9,10
2.2. The rearrangement of the (Z)-phenylhydrazone of
3-benzoyl-1,2,4-oxadiazole (1c)
The conversion of 1c into 2c in the presence of b-CD was
studied in aqueous solution (borate buffer, at pH 7.76,
8.53, 8.99, and 9.60) at 313 K. Interestingly, 1c showed
a kinetic behavior different from that observed for the
(Z)-phenylhydrazones substituted at C(5) with a phenyl
group (1a) or with a long alkyl chain (1b). Compound
1c does not show an isosbestic point during the recording
of the spectra. After a short initial period (about 100 s or
less up to pH 8.99, but not observed at pH 9.60), the
UV–vis absorption decays exponentially as expected for
a simple pseudo-first-order process, with the absorption
maximum wavelength nearly constant during the
A computational (MM2/QD)12 approach can provide useful
insights. Simple models in the gas phase suggest that at least
six different host–guest complexes might be formed between
1b and b-CD (Fig. 2, models A–F), bearing n-hexyl (A, B),
the phenylhydrazone moiety (C, D) or 3-benzoyl group (E,
F) within the cavity. Moreover, the 1,2,4-oxadiazole ring
could be either in the correct ‘ready-to-close’ conformation
(A, C, E) with respect to the Na of the hydrazono group or
not (B, D, F). Steric energies for the models of the

S. Guernelli et al. / Tetrahedron 63 (2007) 10260–10268
10263
N
O
N
N
N
O
N
HN
N
HN
N
N
HN
N
O
A
C
E
N
N
N
N
HN
N
HN
N
HN
O
O
O
N
N
N
B
D
F
k1
-CD
k2
-CD
+
+
fast
k3
B
F
2b . -CD
fast
1b + -CD
D
C
A
-
-CD
-
-CD
Figure 2. Different host–guest complexes between 1b and b-CD. Steric energies for the complexes: A: 247.1 kJ molꢁ1; B: 234.4 kJ molꢁ1; C: 243.9 kJ molꢁ1
;
D: 244.0 kJ molꢁ1; F: 230.3 kJ molꢁ1. Model E collapses to F. Structures are not intended to give a correct picture of the actual minimized structures (or of how
deeply the guest moieties are included) and only indicate the host–guest interaction mode.
rearrangement. The kA,Rs at the four different pHs exam-
ined are reported in Table 2.
Moreover a comparison between the kA,Rs in the presence of
b-CD and that relative to the rearrangement of 1c in D/W
shows that the reactivity observed in aqueous solution of
b-CD is not significantly different from that observed in
the mixed solvent. In D/W at 313 K and at pS+ 10.10 or
pS+ 11.25 (corresponding to about pH 7.76 or pH 8.99 in
aqueous solution, respectively) the kA,Rs are 7.50ꢀ10ꢁ3
The plot of log kA,R for 1c versus pH shows a linear trend
(base-catalysis) with a slope much closer to unity (0.88)7,8
than that for 1b (0.31), evidencing the occurrence of differ-
ent situations. Provided that some interaction between the
substrate and b-CD cavity is required for the solubilization
in water, the observation of a slope value much higher for
1c than for 1b, clearly indicates that the reaction site (i.e.,
the region of the CD where the TS is located) for 1c is in
a more ‘water-like’ environment.
sꢁ1 and 1.00ꢀ10ꢁ2 sꢁ1 6b
:
the reactivity observed in D/W
was only slightly higher (rate ratio¼1.3) than that in the
presence of b-CD, thus confirming that the rearrangement
of 1c into 2c proceeds in a ‘water-like’ environment. None-
theless, the importance of the medium effect on the MRH re-
activity of 1c can be confirmed by looking at the low kinetic
constants, in contrast measured for the same rearrangement
(1c into 2c) in benzene.6c
Substrates with different structures may penetrate into the
CD cavity to different extents, giving inclusion complexes
that are able to affect the reaction pathways. Thus, at pH
9.6 and 313 K, 1c rearranges much faster than 1a4 (reactivity
ratio>1750) enforcing the hypothesis that for 1c and 1a the
rearrangements occur in very different media (water-like and
hydrophobic). In contrast, 1c and 1a in D/W show quite sim-
ilar reactivity (reactivity ratio<9).6b
MM2 calculations indicate that the lack of a substituent at
C(5) of the 1,2,4-oxadiazole ring does not allow, in the
case of 1c, the formation of low-energy inclusion complexes
similar to A and B of Figure 2. Among the remaining
models, the complex with a structure similar to C is pre-
dicted to be the most stable; but it could hardly be the precur-
sor of the rearranged product 2c, as the reacting hydrazone
group appears too deeply buried in the CD cavity. However,
the most likely precursor of the product (E) is predicted to be
only 10.5 kJ molꢁ1 higher in energy; therefore interconver-
sion could now be a fast process.
Table 2. Apparent rate constantsa at 313 K for the rearrangement of 1c into
2c in b-CD
pH
103 kA,R (sꢁ1
)
7.76
8.53
8.99
9.60
0.603 (ꢂ0.012)
3.66 (ꢂ0.080)
7.50 (ꢂ0.50)
26.0 (ꢂ0.10)
2.3. The rearrangement of the (Z)-hydrazones of some
3-benzoyl-5-X-1,2,4-oxadiazoles (1d–f)
a
Data were obtained as mean values at least on two independent runs.
Moreover, for each experiment the kA,R was calculated as mean values
at different wavelengths (curves registered at 280, 290, and 300 nm, in
the region of appearance of the rearrangement product 2c, and at 345,
355, 365, and 375 nm, in the region of disappearance of the starting
1c). Uncertainty in parenthesis represents the standard deviation of least
square treatment.
The MRHs of 1d–f into 2d–f were carried out in aqueous
(borate buffer, at pH 10.20 or 10.60 and in the 313–333 K
range) solution of b-CD (Table 3). The kinetic behavior re-
sembles that observed for the 1c into 2c rearrangement:

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S. Guernelli et al. / Tetrahedron 63 (2007) 10260–10268
Table 3. Apparent rate constantsa in the 313–333 K temperature range and activation parameters for the rearrangement of 1d–f into 2d–f in b-CD at different pH
c
Substrates
T (K)
pH
105 kA,R (sꢁ1
)
DHsb
DSsb
ꢁ20.5
106 kA,R (sꢁ1
)
1d
313
323
333
333
333
333
333
313
323
333
313
323
333
10.20
10.20
10.20
9.96
9.64
9.27
1.45 (ꢂ0.08)
4.85 (ꢂ0.04)
15.20 (ꢂ0.50)
10.0 (ꢂ0.25)
5.93 (ꢂ0.12)
3.50 (ꢂ0.20)
2.30 (ꢂ0.10)
2.20 (ꢂ0.08)
8.00 (ꢂ0.08)
23.00 (ꢂ0.40)
5.22 (ꢂ0.02)
16.40 (ꢂ0.20)
51.00 (ꢂ0.20)
99.4
1.00
8.92
1e
1f
10.60
10.60
10.60
10.60
10.60
10.60
99.3
96.3
ꢁ16.7
ꢁ19.7
1.57
3.88
a
Data were obtained as mean values at least on two independent runs. Moreover, for each experiment the kA,R was calculated as mean value at different wave-
lengths (curves registered at 230, 240, 250, 255, 260, and 265 nm). Uncertainty in parenthesis represents the standard deviation of least square treatment.
DHs: kJ molꢁ1, the maximum error is 4 kJ molꢁ1; DSs: J Kꢁ1molꢁ1, the maximum error is 8 J Kꢁ1molꢁ1
Apparent kinetic constants (at 293 K) calculated by activation parameters.
.
b
c
a ‘regular period’ attributable to a pseudo-first-order process
was observed without shifts of the wavelength of maximum
absorption or occurrence of isosbestic points.
proton concentration). Indeed, the rearrangement in the pres-
ence of b-CD is accompanied by similar enthalpy factors,
but by less favorable entropy factors. Such fact clearly indi-
cates that the parameters for the reaction in b-CD are little
affected by some contribution ascribable to a feeble com-
plexation equilibrium. This result is also in line with the ob-
servation that in the instance of 1f there is some difference
between the reactivity in D/W and in the presence of b-CD
(calculated reactivity ratio¼4.3) and at the same time sug-
gests a role to the presence or not of a phenyl linked to the
hydrazono nitrogen.
A comparison of the kA,Rs calculated at 293 K from activa-
tion parameters for MRH of 1d–f into 2d–f with those for
the rearrangement in D/W is of some interest. On going
from an aqueous solution of b-CD to D/W only a small in-
crease in the reactivity is observed [(for 1d reactivity ratio
is 1.6 at pH 10.20; kA,R¼2.33ꢀ10ꢁ5 sꢁ1 at pS+ 12.50 in D/W,
data now collected, for 1e reactivity ratio is again 1.6 at
pH 10.60; kA,R¼3.50ꢀ10ꢁ5 sꢁ1 at pS+ 12.90, data now col-
lected, for 1f calculated reactivity ratio is 4.3 at pH 10.60;
kA,R¼1.67ꢀ10ꢁ5 sꢁ1 at pS+ 12.85 in D/W)].15 The small ki-
netic effect observed for the rearrangement of 1d–f studied in
confined environments supports the idea that the formation of
the transition state for the rearrangement occurs in a water-
like environment rather than in the hydrophobic cavity of
the host. By contrast, for the rearrangement of 1a and 1b in
b-CD the calculated rate ratios were ca. 300 and 31, respec-
tively. Moreover, the plot of log kA,R versus pH for the MRH
of 1d into 2d shows a linear increase versus the pH and the
slopevalue (0.64) is intermediate between those of 1b and 1c.
Owing to the lack of a phenyl group on the hydrazono moi-
ety, computations for 1d—f predict the absence of stable
complexes similar to C and D of Figure 2. This means
that, upon complexation, the hydrazone group is never bur-
ied into the CD cavity and it can interact more or less freely
with the aqueous buffer solvent pool, in agreement with the
observed dependence of the kA,Rs on the pH value.
2.4. ESIMS and 1H NMR evidences for the formation of
host–guest complexes
In order to find stronger evidence of the formation of host–
guest complexes between 1b–f and b-CD, we examined their
behavior by means of ESIMS analysis in gas phase and H
The kinetic data collected at different temperatures show
that the kA,Rs increase with temperature (as for 1b): then,
the analysis of the Arrhenius plot leads to ‘normal’ positive
values for the activation enthalpy (Table 3). By contrast, in
the instance of the MRH of 1a in the presence of b-CD4
an anomalous behavior was observed (negative value of ac-
tivation enthalpy), which was explained considering that the
calculated activation parameters were composite values, af-
fected by the contribution of complexation, where DHs
values are usually large and negative.14
1
NMR measurements in solution (see Supplementary data).
The ESIMS experiments were carried out in water/methanol
solution (1:1, v/v), using for b-CD and 1b–f the same con-
centrations of the kinetic investigations and recording the
spectra in positive mode. They are characterized by intense
peaks corresponding to the 1:1 host–guest complexes (Figs.
4–8, Supplementary data). Moreover, no signals for 2:1
complexes were observed, even in the presence of a large
excess of b-CD.
A comparison among activation parameters for the MRH of
1d–f evidences that they show almost the same activation en-
thalpy and entropy in line with the comparable kA,Rs mea-
sured. Similar results were observed studying the behavior
of the relevant (Z)-phenylhydrazones in D/W.6
1H NMR measurements also give evidences for the host–
guest complexes formation in solution.9,16 The binding af-
finity was evaluated by monitoring the chemical shift
changes of the protons of the guest in the presence of b-
CD. The low solubility in water of 1b,c and 1e,f induced
us to examine only the H NMR behavior of 1d. The H
NMR spectrum of a 5.5ꢀ10ꢁ2 M solution of 1d, containing
12% CD3OD to ensure the sample dissolution, showed at
1
1
It is interesting to compare the activation parameters for the
MRH of 1f in b-CD and in D/W15 (DHs¼100 kJ molꢁ1 and
DSs¼ꢁ7.9 J molꢁ1 Kꢁ1 in D/W mixture at the comparable

S. Guernelli et al. / Tetrahedron 63 (2007) 10260–10268
10265
-1
-2
-3
-4
-5
298 K shifts of aliphatic protons toward lower frequencies
after addition of the b-CD (1.1ꢀ10ꢁ2 M). The detected sig-
nals represent averaged peaks relative to the free molecule in
rapid equilibrium (compared to the NMR timescale) with its
host–guest complex. The higher shifts of aliphatic signals
(Dd 0.02–0.07 ppm) in comparison to those of the aromatic
ones, suggest that the part of the molecule located inside the
hydrophobic cavity is the small alkyl chain (C2) linked to the
C(5) of the heterocyclic ring.
1c s = 0.88
From the collected data some interesting remarks can be
drawn.
s = 0.64
1d
In the instance of (Z)-phenylhydrazone of 3-benzoyl-5-hexyl-
1,2,4-oxadiazole 1b the rearrangement, as for the 5-phenyl
derivative 1a,4 is largely affected by the presence of b-CD,
showing the occurrence of a large shift of lmax and of isosbes-
tic points. Moreover, the kA,Rs of 1b in water in the presence
1b s = 0.31
of b-CD are lower than in D/W [(kA,R D/W
)
/(kA,R b-CD
)
¼ca.
7
8
9
pH
10
11
31] and the plot of log kA,R versus pH shows a slope much
lower than unity (0.31; i.e., it does not occur in water or in
a water-like medium).8 Finally the activation parameters
show the normal positive value for the activation enthalpy
and the expected negative value for the activation entropy.6
Figure 3. Plot of log kA,R in presence of b-CD for the rearrangement of
1b–d into the relevant triazoles 2b–d versus pH. Near each line the value
of the slopes is reported.
By contrast, in the instance of (Z)-phenylhydrazone of 3-ben-
zoyl-1,2,4-oxadiazole 1c and (Z)-hydrazones of 3-benzoyl-
1,2,4-oxadiazole 5-ethyl, -hexyl and -phenyl substituted
1d–f, the kA,Rs are scarcely affected by the presence of b-
CD, although the occurrence of inclusion complexes was as-
certained both in gas phase and in solution by means ESIMS
and 1H NMR data. Thus, for the rearrangement of 1c–f nei-
ther a significant shift of lmax nor the occurrence of isobestic
points were evidenced and their kA,Rs in water in the presence
substrate/b-CD interactions occur at the level of the substit-
uent at C(5) of the 1,2,4-oxadiazole ring as we ascertained
by studying the rearrangement of 1a.4 Perhaps R could
play some role (by interacting with two units of b-CD or,
more probably, by determining an increase of the lypophilic
character of the substrate, which augments its ability to inter-
act with b-CD), as evidenced by the different behavior of 1a
and 1f. The above considerations gain support from the
MM2 calculations.
of b-CD are comparable to those in D/W [(kA,R D/W
(kA,R)b-CD
)
/
¼1.3, 1.6, 1.6, and 4.3]. The slopes of the plots
As previously pointed out (see also under Section 2.1),4 we
observed an interesting dichotomy in the rearrangement of
1a in D/W and in water in the presence of b-CD. Indeed 1a
of log kA,R versus pH are linear and for 1c and 1d higher
(0.88 and 0.64) than that for 1b (0.31) (Fig. 2). In the case
of 1c the MRH ‘occurs’ in water or in a water-like medium,
while in the case of 1d a situation intermediate between that
of 1b and 1c occurs. These results confirm the importance of
the substituent at the C(5) of the 1,2,4-oxadiazole ring for the
host–guest interaction and in determining the real site of the
reaction. Accordingly, shortening the linear chain from C6
(1b) to C2 (1d) causes a weakening of these interactions
and then an increase of the relevant slopes of the log kA,R ver-
sus pH from 0.31 to 0.64. Interestingly enough, in the case of
1c, where no substituent is present at C(5), the slope of this
plot rises up to 0.88 (Fig. 3).
is much more reactive in D/W [(kA,R D/W
)
/(kA,R b-CD
)
¼300];
moreover, it shows in D/W a positive DHs, whereas large
negative apparent DHs is found in the presence of b-CD.
In contrast, examining the reactivity of 1c–f in the presence
of b-CD we observed reactivity similar to those measured
in D/W [(kA,R D/W/(kA,R)b-CD: 1.3, 1.6, 1.6, and 4.3]; and
)
the observed reactivity trend seems to be affected by small
and unfavorable variations on DSs values rather than on
DHs. The decrease of DSs accounts for the fact that also
in these instances some weak complexation phenomena
between b-CD and the substrates 1c–f could occur.
The most striking evidence concerning the influence of the
site of reaction on the reactivity comes from a comparison
of the reactivity ratios concerning 1a and 1c in b-CD and
in D/W. In b-CD and at comparable proton concentration
1c rearranges much faster than 1a (reactivity ratio>1750),
in line with the hypothesis that 1c and 1a rearrange in a
hydrophilic (water-like) and in a hydrophobic environment,
respectively. This is confirmed by the observation that in
contrast the same couple of (Z)-phenylhydrazones shows
in D/W quite similar reactivity (reactivity ratio<9).
3. Conclusions
Interestingly, the results indicate that quite different behav-
iors are at work in the rearrangement of (Z)-hydrazones
1a–f. In the instance of 1a and 1b the rearrangement occurs
more or less deeply in the b-CD cavity, whereas in the in-
stances of 1c–f the rearrangement occurs in the border region
between b-CD and water pool. Thus, the kinetic and thermo-
dynamic data, and the reactivity plots versus pH for the rear-
rangement of a set of (Z)-hydrazones with well-chosen
structure differences indicated that the presence of b-CD
always causes their solubilization in water. However, this
The substituent at Na of the hydrazone moiety (Ph or H)
plays a minor role, confirming that the most important

10266
S. Guernelli et al. / Tetrahedron 63 (2007) 10260–10268
phenomenon depends on different kinds of (Z)-hydrazone/b-
CD interactions that can occur at the external shell (still hy-
drophilic) of b-CD or, by contrast, at the internal core (quite
hydrophobic) of b-CD, differently affecting the interaction
of the substrate with the basic catalyst and the formation
of the transition state.
4.3. Synthesis and characterization of the (E)- and (Z)-
isomer of the 5-ethyl and 5-hexyl-1,2,4-oxadiazol-3-yl-
(phenyl)methanone N-hydrazones (1d–e) and of the
relevant triazoles 2d–e
These compounds were prepared according to methods
reported for other Z-hydrazones.15
4. Experimental
4.3.1. (Z)-(5-Ethyl-1,2,4-oxadiazol-3-yl)-(phenyl)metha-
none N-hydrazone (Z-1d). White solid mp 64.2–65.4 ꢃC
(yield 19%). 1H NMR (200 MHz, DMSO) d 1.32 (t,
J¼7.6 Hz, 3H), 3.02 (q, J¼7.6 Hz, 2H), 7.21–7.41 (m,
3H), 7.52–7.61 (m, 2H), 8.45 (br s, 2H). 13C NMR
(200 MHz, DMSO) d 10.5, 19.7, 126.7, 126.9, 127.3,
128.0, 137.3, 162.4, 180.2. ESI–MS m/z¼238.9 [M+Na]+.
Anal. Calcd for C11H12N4O: C, 61.10; H, 5.59; N, 25.91.
Found: C, 61.19; H, 5.64; N, 25.86. HRMS calcd for
C11H12N4O: 216.1011; found 216.1009.
4.1. General synthesis procedure
Compounds (1c, 2c)6a and (1f, 2f)15 were prepared following
known procedures.
4.2. Synthesis and characterization of the (E)- and (Z)-
isomer of the phenylhydrazone of 3-benzoyl-5-hexyl-
1,2,4-oxadiazole (1b) and of the relevant triazole 1d
The (E-1b) and (Z-1b) were synthesized according to known
methods.6a,17 Together with the phenylhydrazones (or the
hydrazones) also a certain amount of the rearranged relevant
triazoles was obtained. In this paper we have examined only
the kinetic behavior of the (Z)-isomers. Concerning the gen-
eral reactivity of the (E)-isomers see Ref. 6c.
4.3.2. (E)-(5-Ethyl-1,2,4-oxadiazol-3-yl)-(phenyl)metha-
none N-hydrazone (E-1d). White solid mp 88.9–90.0 ꢃC
(yield 20%). 1H NMR (200 MHz, DMSO) d 1.28 (t,
J¼7.5 Hz, 3H), 2.89 (q, J¼7.6 Hz, 2H), 7.23–7.59 (m,
7H). 13C NMR (200 MHz, CDCl3) d 10.6, 20.1, 128.6,
129.2, 129.4, 129.5, 135.3, 167.8, 180.3. ESIMS m/z¼
238.9 [M+Na]+. Anal. Calcd for C11H12N4O: C, 61.10; H,
5.59; N, 25.91. Found: C, 61.20; H, 5.68; N, 25.83. HRMS
calcd for C11H12N4O: 216.1011; found 216.1010.
4.2.1. (Z)-Phenylhydrazones of 3-benzoyl-5-hexyl-1,2,4-
oxadiazole (Z-1b). Yellow oil (yield 53%). 1H NMR
(300 MHz, CDCl3) d 0.92 (br t, 3H), 1.32–1.54 (m, 6H),
1.90 (m, 2H), 3.02 (t, J¼7.5 Hz, 2H), 6.94–7.02 (m, 1H),
7.26–7.35 (m, 4H), 7.35–7.48 (m, 3H), 7.86–7.92 (m, 2H),
11.37 (s, 1H). 13C NMR (300 MHz, CDCl3) d 13.9, 22.3,
26.2, 26.3, 28.5, 31.1, 113.8, 121.5, 126.2, 127.8, 127.9,
128.2, 129.1, 136.6, 143.8, 163.2, 178.6. ESIMS
m/z¼347.2 [MꢁH]ꢁ, 371.3 [M+Na]+. Anal. Calcd for
C21H24N4O: C, 72.39; H, 6.94; N, 16.08. Found: C, 72.60;
H, 7.03; N, 16.15. HRMS calcd for C21H24N4O: 348.1950;
found 348.1955.
4.3.3. (Z)-(5-Hexyl-1,2,4-oxadiazol-3-yl)-(phenyl)metha-
none N-hydrazone (Z-1e). White solid mp 57.0–58.5 ꢃC
(yield 39%). H NMR (200 MHz, DMSO) d 0.86 (br t,
1
J¼6.4 Hz, 3H), 1.20–1.48 (m, 6H), 1.76 (m, 2H), 3.00 (t,
J¼7.6 Hz, 2H), 7.22–7.44 (m, 3H), 7.52–7.64 (m, 2H),
8.46 (s, 2H). 13C NMR (200 MHz, DMSO) d 14.0, 22.0,
25.8, 26.0, 28.1, 30.8, 126.6, 127.0, 127.3, 128.0, 137.3,
162.4, 179.4. ESIMS m/z¼295.0 [M+Na]+. Anal. Calcd
for C15H20N4O: C, 66.15; H, 7.41; N, 20.57. Found: C,
66.23; H, 7.34; N, 20.46. HRMS calcd for C15H20N4O:
272.1637; found 272.1642.
4.2.2. (E)-Phenylhydrazone of 3-benzoyl-5-hexyl-1,2,4-
oxadiazole (E-1b). Traces as yellow oil. 1H NMR
(300 MHz, CDCl3) d 0.91 (br t, 3H), 1.28–1.50 (m, 6H),
1.87 (m, 2H), 2.96 (t, J¼7.7 Hz, 2H), 6.90–6.98 (m, 1H),
7.12–7.64 (m, 9H), 8.10 (s, 1H). 13C NMR (75.5 MHz,
CDCl3) d 13.9, 22.3, 26.5, 26.6, 28.7, 31.2, 113.7, 121.5,
128.9, 129.1, 129.6, 129.9, 132.2, 143.0, 168.0, 179.9.
ESIMS m/z¼347.2 [MꢁH]ꢁ, 371.3 [M+Na]+.
4.3.4. (E)-(5-Hexyl-1,2,4-oxadiazol-3-yl)-(phenyl)metha-
none N-hydrazone (E-1e). White solid mp 91.0–93.0 ꢃC
(yield 28%). H NMR (200 MHz, DMSO) d 0.86 (br t,
1
J¼6.6 Hz, 3H), 1.20–1.47 (m, 6H), 1.72 (m, 2H), 2.87 (t,
J¼7.5 Hz, 2H), 7.20–7.57 (m, 7H). 13C NMR (200 MHz,
DMSO) d 14.0, 22.0, 25.8, 26.0, 28.1, 30.8, 129.0, 129.2,
130.9, 131.0, 168.3, 179.0. ESIMS m/z¼295.0 [M+Na]+.
Anal. Calcd for C15H20N4O: C, 66.15; H, 7.41; N, 20.57.
Found: C, 66.21; H, 7.46; N, 20.59. HRMS calcd for
C15H20N4O: 272.1637; found 272.1639.
4.2.3. 4-Heptanoylamino-2,5-diphenyl-1,2,3-triazole
(2b). Thermal rearrangement of 1b gave 2b by heating the
sample (0.2 g) in a preheated oil bath (150 ꢃC) for few min-
utes. By purification on a silica gel column (petroleum ether/
ethyl acetate 85:15) the triazole 2b was obtained in practi-
cally quantitative yields. White solid mp 132.2–132.8 ꢃC.
1H NMR (300 MHz, CDCl3) d 0.89 (broad band, 3H),
1.20–1.44 (broad band, 6H), 1.73 (broad band, 2H), 2.45
(t, J¼7.5 Hz, 2H), 7.30–7.56 (m, 7H), 7.80 (broad band,
2H), 8.04–8.13 (br d, 2H). 13C NMR (75.5 MHz, CDCl3)
d 14.0, 22.4, 25.2, 28.8, 31.4, 36.4, 36.2, 118.4, 126.9,
127.4, 128.6, 129.1, 139.4, 140.1, 142.4, 172.8. ESIMS
m/z¼347.2 [MꢁH]ꢁ, 371.3 [M+Na]+. Anal. Calcd for
C21H24N4O: C, 72.39; H, 6.94; N, 16.08. Found: C, 72.30;
H, 7.10; N, 16.16. HRMS calcd for C21H24N4O: 348.1950;
found 348.1950.
The relevant triazoles (2d–e) were isolated from the reaction
mixture and purified by chromatography; the above com-
pounds could also be obtained from 1d–e by thermally
induced rearrangement (see before).
4.3.5. 5-Phenyl-4-propanoylamino-2H-1,2,3-triazole
(2d). Yellow solid mp 145.8–147.5 ꢃC (yield 14%). 1H
NMR (200 MHz, DMSO) d 1.19 (t, J¼7.6 Hz, 3H), 2.38
(q, J¼7.6 Hz, 2H), 7.35–7.46 (m, 3H), 7.77–7.86 (m, 2H),
9.68 (s, 1H), 12.17 (s, 1H). 13C NMR (200 MHz, CDCl3)
d 10.3, 26.4, 128.1, 128.6, 130.4, 132.2, 145.1, 146.4,

S. Guernelli et al. / Tetrahedron 63 (2007) 10260–10268
10267
159.1. ESIMS m/z¼238.9 [M+Na]+. Anal. Calcd for
C11H12N4O: C, 61.10; H, 5.59; N, 25.91. Found: C, 61.15;
H, 5.91; N, 25.95. HRMS calcd for C11H12N4O: 216.1011;
found 216.1010.
allowed to undergo geometry optimization by simulated an-
nealing. In this way only a limited amount of energy minima
are found. An energy cutoff of 0.05 kcal molꢁ1 was used for
calculations.
4.3.6. 4-Heptanoylamino-5-phenyl-2H-1,2,3-triazole
(2e). Yellow solid mp 116.8–118.0 ꢃC (yield 5%). 1H
NMR (200 MHz, DMSO) d 0.87 (br t, J¼6.6 Hz, 3H),
1.18–1.40 (m, 6H), 1.58 (m, 2H), 2.33 (t, J¼7.1 Hz, 2H),
7.30–7.52 (m, 3H), 7.62–7.78 (m, 2H), 9.84 (br s, 2H). 13C
NMR (200 MHz, CDCl3) d 14.0, 22.4, 26.3, 28.7, 31.4,
33.1, 128.1, 128.6, 130.4, 132.3, 145.3, 146.3, 158.6. ESIMS
m/z¼294.9 [M+Na]+. Anal. Calcd for C15H20N4O: C, 66.15;
H, 7.41; N, 20.57. Found: C, 66.30; H, 7.50; N, 20.61.
HRMS calcd for C15H20N4O: 272.1637; found 272.1640.
4.7. ESIMS measurements
ESIMS spectra were acquired with a ZMD Micromass single
quadrupole mass spectrometer operating at m/z 4000. A
Hamilton syringe driven by a Harvard pump was used for
the injection of the sample into the instrument. To minimize
the influence of variations in instrumental conditions on the
reliability of spectra, the ESIMS parameters (pressure of gas,
desolvation temperature, capillary cone voltages, etc.) were
kept rigorously constant from run to run in each series of
experiments. In particular a capillary voltage of 3.00 kV
and a cone voltage of 30 V were applied; and a desolvation
temperature of 423 K was used. The solutions of 1b–f with
b-CD in water/methanol (1:1, v/v) were introduced at
a flow-rate of 15 ml minꢁ1. For all of the mass spectra the
measurements were averaged over typically 50 scans.
4.4. Kinetic measurements in water in the presence of
b-CD
For the reaction of 1b–f in the presence of b-CD the solution
was prepared by introducing the suitable amount of a mother
solution of the substrate in dioxane into a buffered and ther-
mostated solution of b-CD (1.00ꢀ10ꢁ4 M); in the reaction
mixture the dioxane concentration was about 1% (v/v) and
the concentration of 1 was 5.00ꢀ10ꢁ5 M. Pseudo-first-order
conditions were assured by the large excess of borate buffer
(1.25ꢀ10ꢁ2 M). The kinetics were followed recording the
spectra at due times in the 200–500 nm range and at 293–
333 K. All the kinetic measurements were collected with
a double-beam spectrophotometer (Varian Cary 1E). The ab-
sorbances at various wavelengths were plotted versus time,
the curves were processed both by the Guggenheim method18
and by fitting them directly into the equation Abs¼a+beꢁkt
keeping a, b, and t as fitting parameters. The values calcu-
lated for the kinetic constant with the two different methods
and for the absorbance curves were all in excellent agree-
ment. The KaleidaGraphÔ 3.0.1 software delivered by Abel-
beck Software was used to perform data processing.
4.8. 1H NMR measurements
1H NMR spectra were recorded on a Varian Inova spectrom-
eter operating at 300 MHz. 1H NMR experiments were per-
formed in mixed solutions of D2O/CD3OD using residual
1
HOD as an internal standard (4.76 ppm at 298 K). H and
13C NMR spectra of all the synthesized compounds were
carried out on a Varian Inova spectrometer operating at
200 MHz (proton) and 50 MHz (carbon) using the solvent
peak as internal reference. Chemical shifts are reported in
parts per million (d scale).
Acknowledgements
We thank M.I.U.R. (Rome) [PRIN 2005 (2005034305) and
PRIN 2006 (20066034372)] for financial support. Investiga-
tions supported by the Universities of Bologna and Palermo
(ex-60%, funds for selected research topics).
4.5. pSD and kinetic measurements in water/dioxane
The kinetics in water/dioxane mixture (1:1, v/v) were fol-
lowed spectrophotometrically as described6,15,17 by measur-
ing the disappearance of 1b, 1d, and 1e at the wavelengths of
their absorption maxima, where the absorption of the rele-
vant triazoles 2 was minimal. An operational pH scale,
pS+,17,19 was established in aqueous dioxane by employing
the pKa values of acids determined by interpolation from
the data reported by Harned and Owen.19b For dioxane/water
(1:1, v/v) the meter reading after calibration against buffers
was not significantly different from pS+, requiring a correc-
tion of only +0.16.
Supplementary data
ESIMS spectra of the host–guest complexes between 1b–f
and b-CD are provided. Supplementary data associated
with this article can be found in the online version, at
doi:10.1016/j.tet.2007.07.084.
References and notes
4.6. MM2 calculations
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