First observation of Chapman rearrangement of a pseudosaccharyl ether in the solid state: the thermal isomerization of 3-(methoxy)-1,2-benzisothiazole 1,1-dioxide revisited

Article abstract of DOI:10.1016/j.tet.2008.02.007

3-(Methoxy)-1,2-benzisothiazole 1,1-dioxide, a pseudosaccharyl ether, was long ago known to undergo a thermal Chapman-like [1,3′]-isomerization to the corresponding N-methyl pseudosaccharin at temperatures above its melting point (ca. 184 °C) [Hettler H., Tetrahedron Lett. 1968, 15, 1793]. In the present study, it is shown that this rearrangement can also take place in the solid state, at temperatures as low as 150 °C. This was the first observation of a Chapman-like [1,3′]-isomerization in pseudosaccharyl ethers in the solid state. The study has been carried out by a multidisciplinary approach using temperature dependent infrared spectroscopy, differential scanning calorimetry (DSC), and polarized light thermomicroscopy, complemented by theoretical methods.

Full text of DOI:10.1016/j.tet.2008.02.007

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 3296e3305
www.elsevier.com/locate/tet
First observation of Chapman rearrangement of a pseudosaccharyl
ether in the solid state: the thermal isomerization of 3-(methoxy)-
1,2-benzisothiazole 1,1-dioxide revisited
a,b
R. Almeida , A. Gomez-Zavaglia , A. Kaczor , M.L.S. Cristiano ,
a,c
a,d
b
´
M.E.S. Eusebio , T.M.R. Maria , R. Fausto
a
a
a,
*
´
a Department of Chemistry, University of Coimbra, P-3004-535 Coimbra, Portugal
b Department of Chemistry and Biochemistry, F.C.T. and CCMAR, University of Algarve, P-8005-039 Faro, Portugal
c Faculty of Pharmacy and Biochemistry, University of Buenos Aires, C.P. 1113 Buenos Aires, Argentina
d Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland
Received 24 May 2007; received in revised form 13 November 2007; accepted 5 February 2008
Available online 7 February 2008
Abstract
3-(Methoxy)-1,2-benzisothiazole 1,1-dioxide, a pseudosaccharyl ether, was long ago known to undergo a thermal Chapman-like [1,30]-iso-
merization to the corresponding N-methyl pseudosaccharin at temperatures above its melting point (ca. 184 ꢀC) [Hettler H., Tetrahedron Lett.
1968, 15, 1793]. In the present study, it is shown that this rearrangement can also take place in the solid state, at temperatures as low as 150 ꢀC.
This was the first observation of a Chapman-like [1,30]-isomerization in pseudosaccharyl ethers in the solid state. The study has been carried out
by a multidisciplinary approach using temperature dependent infrared spectroscopy, differential scanning calorimetry (DSC), and polarized light
thermomicroscopy, complemented by theoretical methods.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Pseudosaccharin; 3-(Methoxy)-1,2-benzisothiazole 1,1-dioxide; Chapman rearrangement; DFT calculations; Infrared spectroscopy; DSC;
Thermomicroscopy
1. Introduction
frequently used as a key structural element of industrially devel-
oped biologically active compounds5,8,9 and has long been es-
tablished as a cheap and versatile starting material for the
synthesis of related heterocyclic derivatives. By their side,
substituted 1,2-benzisothiazole 1,1-dioxides (pseudosacchar-
ins) have also been shown to be important intermediates in or-
ganic synthesis. For instance, their O-ethers provide efficient
intermediates for reductive cleavage of the CeO bond in phe-
nols,10 benzylic,11 and naphthylmethylic alcohols,12 through
heterogeneous catalytic transfer hydrogenolysis or through
cross-coupling with organometallic reagents.13,14 The structural
basis of the enhanced reactivity of pseudosaccharyl ethers
toward transition metal-catalyzed ipso-replacement lies in the
unusual geometry of their CReOeCA linkage (where
R¼heteroaromatic ring and A¼aliphatic or aryl group). Indeed,
the strong withdrawing effect of the pseudosacharyl group
Benzisothiazoles are important heterocyclic compounds
due to their major applications in crucial areas. Saccharin
(1,2-benzisothiazol-3(2H)-one-1,1-dioxide) is a commonly
known substance as it is the oldest artificial sweetener. Isothi-
azolyl derivatives receive an increased attention as they show
herbicidal,1,2 antimicrobial, and antifungal activity3e5 or
potential in enzymatic inhibition.6 Also, the first non-benzoan-
nelated 4-amino-2,3-dihydroisothiazole 1,1-dioxide, lacking
a 3-oxo group, has recently been described and shows anti-
HIV-1 activity.7 Benzisothiazoles are also very important in
organic and bioorganic synthesis. Saccharin itself has been
* Corresponding author. Tel.: þ351 239 852080; fax: þ351 239 827703.
E-mail address: rfausto@ci.uc.pt (R. Fausto).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.02.007

R. Almeida et al. / Tetrahedron 64 (2008) 3296e3305
3297
results in significant lengthening of the CAeO bond at the
expense of the CR-O bond, which gains partial double-bond
character.11,12,15e18 This characteristic structural feature of
pseudosaccharyl ethers, which is directly related to the potential
of the pseudosaccharyl-oxygen system as nucleofuge in transi-
tion metal-catalyzed reductive cleavage, is certainly also impor-
tant in other reactions that involve cleavage of the weak CAeO
bond, such as the Chapman-like thermal isomerization of 3-alk-
oxy-pseudosaccharins (Scheme 1).
observed by Hettler,36 in the course of an investigation on
the thermal reactivity of several derivatives of 5-chloro-1,2-
benzisothiazole 1,1-dioxide (pseudosaccharyl chloride).37e39
Four pseudosaccharyl ethers were found to undergo a Chap-
man isomerization, when heated above their melting points.36
In the case of MBID (mp w184 ꢀC), conversion was consid-
ered to be completed in 70 min, at 190 ꢀC. When this sac-
charyl derivative was rearranged in the presence of ethyl
iodide, a mixture of N-ethyl and N-methyl saccharin was
formed. This result is in agreement with the previously ob-
served catalytic effect of electrophilic reagents, via alkylation
on nitrogen, and also with the proposed intermolecular nature
of this Chapman isomerization.36
In the present study, the Chapman isomerization of 3-
(methoxy)-1,2-benzisothiazole 1,1-dioxide (MBID) was rein-
vestigated by a multidisciplinary approach, using temperature
dependent infrared spectroscopy, differential scanning calori-
metry (DSC), and polarized light thermomicroscopy, comple-
mented by theoretical methods. It is now demonstrated that
the Chapman isomerization of MBID occurs not only in the
melted phase, but it proceeds also very smoothly in the crystal-
line state, starting to take place at a clearly observable rate at
a temperature as low as 150 ꢀC. To the best of our knowledge,
this is the first observation of a Chapman-like [1,30]-isomeriza-
tion in pseudosaccharyl ethers in the solid state.
O
OR
N
Δ
NR
S
S
O
O
O
O
Scheme 1. Chapman rearrangement of alkyl pseudosaccharyl ethers
(R¼alkyl).
The thermal conversion of aryl iminoethers into N-aryl am-
ides is known generically as the Chapman rearrangement19,20
and represents a valuable synthetic strategy for N-arylation,
leading for instance to the preparation of amides.21e24 This
methodology has even been applied in polymer chemistry, en-
abling the easy preparation of thermally stable polyamides
from polyimidates.25 The intramolecularity of the aryl migra-
tion was postulated by Chapman, and further confirmed by
Rowland26 and Wheeler27 through cross-over and isotopic la-
beling studies, respectively. Aryl migration is thought to occur
via a four-membered cyclic transition state, and consists in
a nucleophilic ipso-replacement of O by N, at the arylic car-
bon. An investigation by Relles28 revealed that this migration
benefits from steric rate enhancement when the migrating aryl
bears substituents in ortho position, provided that these do not
lead to relevant steric compression. However, for alkyl imi-
dates, intramolecular Oe to Ne migration of the alkyl group
is not feasible on stereoelectronic grounds, and therefore the
mechanism is usually assumed to be intermolecular.29 Electro-
philic reagents such as alkyl iodide are often used to induce ini-
tial alkylation of the nitrogen, producing a quaternary salt from
which cleavage of the CeO bond is much easier. This strategy
has been widely applied for instance in the easy isomerization
of 5-(N-methylpyridinium-2-oxy)-1-phenyltetrazole to 4-(N-
methylpyridinium-2-yl)-1-phenyltetrazole-5-one, a key step in
the synthesis of 2-aminopyridines from 2(1H) pyridones.30 Un-
catalyzed migration of alkyl has been investigated, for instance,
in 2-alkoxypyridines,31 1-alkoxy-5-aryltetrazoles,32 2,4,6-tri-
methoxy-1,3,5-triazine,33 and 5-methoxy-2-aryl-1,3,4-oxadi-
azoles.34,35 In this last system, Chapman isomerization was
observed with the neat melted compounds and also in the crys-
talline phase, where it was found to be comparatively much eas-
ier.34,35 The observed ease of rearrangement in the solid state
was justified by solid-state analysis and ascribed to a suitable
arrangement of the molecules in the crystal, leading to an inter-
molecular ‘domino’ methyl transfer process.34
2. Experimental and computational methods
2.1. General
MBID (Fig. 1a) was synthesized from 3-chloro-1,2-benz-
isothiazole-1,1-dioxide (pseudosaccharyl chloride), through
solvolysis as described in Ref. 18 (62% yield; mp 184e
1
185 ꢀC). H NMR (300 MHz, CDCl3): d 4.20 (3H, s), 7.67e
7.80 (3H, m), 7.87e7.90 (1H, d); MS (EI): m/z 197 ([M]þ,
22%; see also Supplementary data). The N-methyl isomer of
MBID [2-methyl-1,2-benzisothiazol-3(2H)-one 1,1-dioxide
(MBIOD); Fig. 1b] was obtained from MBID, by heating
a neat sample at ca. 185 ꢀC and keeping the sample at this
temperature until all reactant has disappeared, as confirmed
(A)
O
O
N
H
H
H
H
S
H
O
H
H
H
(B)
O
O
H
H
S
H
H
N
H
O
H
The Chapman isomerization of 3-alkoxy-pseudosaccharins,
including the simplest member of this family, 3-(methoxy)-
1,2-benzisothiazole 1,1-dioxide (MBID), has been previously
Figure 1. Structures of (a) 3-methoxy-1,2-benzisothiazole 1,1-dioxide (MBID)
and (b) 2-methyl-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (MBIOD).

3298
R. Almeida et al. / Tetrahedron 64 (2008) 3296e3305
by TLC analysis; mp 129e130 ꢀC. 1H NMR (300 MHz,
CDCl3): d 3.28 (3H, s), 7.80e7.90 (2H, m), 7.92e7.96 (1H,
d), 8.05e8.10 (1H, d). MS (EI): m/z 197 ([M]þ, 100%; see
also Supplementary data).
two conformers, differing in the relative position of the me-
thoxy and saccharyl moieties. However, the relative energy
of these two conformers is very large (ca. 47 kJ molꢁ1 18
)
and only the most stable conformer (depicted in Fig. 1a) is
of practical interest. In our previous study, the infrared spec-
trum of the monomer of this compound has also been obtained
theoretically at the DFT(B3LYP)/6-311þþG(3df,3pd) level
and compared with the experimental spectrum of the com-
pound isolated in cryogenic inert matrices (at 10 K). The
agreement between the experimental and calculated spectra
was found to be excellent, allowing a detailed analysis of
the experimental data and, simultaneously, showing that the
theoretical method selected is appropriate to be used in the
structural and vibrational study of pseudosaccharins.18
The infrared spectra, in the 500e4000 cmꢁ1 range, were re-
corded for the compound diluted in a KBr pellet, using a Bomem
MB104 FT-spectrometer, with 4 cmꢁ1 resolution, and a SPE-
CAC variable temperature infrared cell connected to a digital
controller (Shinho, MCD 530), which enables to attain an accu-
racy in the temperature of ca. ꢂ1 ꢀC. The temperature was mea-
sured directly at the sample holder by an iron/constantan
(copperenickel) J-type thermocouple. The sample compart-
ment of the spectrometer was purged during all experiments
by means of a constant flux of dry nitrogen, to avoid contamina-
tion from absorptions due to atmospheric water and CO2.
Thermal studies were carried out on a PerkineElmer
DSC7, a power compensation calorimeter with a CCA7 cool-
ing unit, over the temperature range 25e210 ꢀC, with scanning
rate 10 ꢀC minꢁ1. Data acquisition and determination of the
onset temperatures and transition enthalpies were performed
with the PerkineElmer 1020 Series Thermal Analysis System
Software. The samples were hermetically sealed in aluminum
pans and as reference an empty pan was used. No sample
weight loss occurred in any experiment. A 20 ml minꢁ1 nitro-
gen purge was employed. Temperature calibration40 was per-
formed with high grade standards namely biphenyl
(Tfus¼68.93ꢂ0.03 ꢀC) and zinc (Tfus¼419.53 ꢀC), and verified
In Figure 2a and b we compare the DFT(B3LYP)/
6-311þþG(3df,3pd) calculated infrared spectrum for the rele-
vant conformational state of MBID with the spectrum obtained
G
F
with naphthalene (Tfus¼80.20ꢂ0.04 ꢀC), benzoic acid (Tfus
¼
122.35ꢂ0.02 ꢀC), and indium (Tfus¼156.60 ꢀC). For heat
calibration, the enthalpy of fusion of indium was used
(DfusH¼3286ꢂ13 J molꢁ1).40
E
D
C
B
The hot stage/DSC video microscopy study was carried out
by means of a Linkam DSC600 system. The optical equipment
attached to the hot stage system consists of a DMRB Leica mi-
croscope fitted with polarized light facilities to which a Sony
CCD-IRIS/RGB video camera is attached. A Linkam system
software with Real Time Video Measurement was used for im-
age analysis. A small amount of the sample to be studied was
placed in a glass crucible used as a cell, which was covered
with a glass lid. Thermal cycles were followed by 200ꢃ mag-
nification and the images obtained by combined use of polar-
ized light and wave compensators. The thermal program for
the microscope examination was run at 10 ꢀC minꢁ1. Biphenyl
and benzoic acid were used to confirm temperature accuracy.
All geometry optimizations and calculations of the infrared
spectra were performed at the recommended18 level of theory
for pseudosaccharin compounds: DFT(B3LYP)/6-311þþG-
(3df,3pd),41,42 using the Gaussian 03 program package.43
A
600
800
1000 1200
Wavenumber/cm-1
1400
1600
1800
3. Results and discussion
3.1. Infrared spectroscopic experiments and results
of theoretical calculations
Figure 2. (a) Calculated [DFT(B3LYP)/6-311þþG(3df,3pd)] infrared spec-
trum for MBID; (b) room temperature (20 ꢀC) infrared spectrum of polycrys-
talline MBID in KBr pellet; (cef) infrared spectra at different temperatures
(150, 160, 170 and 210 ꢀC), obtained along the heating of MBID from room
temperature, showing the conversion of this compound into MBIOD via Chap-
man rearrangement; (g) calculated [DFT(B3LYP)/6-311þþG(3df,3pd)] infra-
red spectrum of MBIOD. (Displayed spectral range: 500e1800 cmꢁ1.)
The studied reactant molecule, 3-(methoxy)-1,2-benziso-
thiazole 1,1-dioxide (MBID) has been recently characterized
structurally in our laboratories.18 It has been shown to have

R. Almeida et al. / Tetrahedron 64 (2008) 3296e3305
3299
Table 1
Assignment of experimental IR spectra of polycrystalline MBID in KBr pellet
for the compound in the crystalline phase at room temperature.
The close agreement between the two spectra is clearly evident
from this figure, indicating that intermolecular interactions in
the crystal are not strong enough to disturb significantly the in-
tramolecular vibrational modes. Based on the theoretical data
(and also on the previously reported data for the matrix-isolated
compound18), the infrared spectrum of the crystalline phase of
MBID could be easily assigned (Table 1).
Upon temperature increase, the spectrum of MBID loses in-
tensity whereas new bands emerge. Traces c to f in Figure 2
correspond to spectra registered at different temperatures
(150, 160, 170 and 210 ꢀC), during the heating of MBID up
till the bands due to this compound completely disappear
from the spectrum. These spectra were obtained using a temper-
ature-raising program in which the temperature was increased
as fast as possible (starting from room temperature) in incre-
ments of 10 ꢀC and letting the sample to equilibrate at each
temperature during ca. 5 min. The new bands start to be clearly
visible in the spectrum obtained at 150 ꢀC, which is rather far
from the melting temperature of MBID (ca. 184 ꢀC), indicating
that the observed process starts taking place in the solid phase.
The spectrum shown in trace f corresponds to a temperature of
210 ꢀC, i.e., clearly above the melting point of MBID, and does
not exhibit signs of presence of this compound. So, it can be
concluded that at that point the observed process was already
completed and the observed spectrum corresponds to the reac-
tion product.
According to the expectations, the obtained product should
be the N-methyl isomer of MBID [2-methyl-1,2-benzisothi-
azol-3(2H)-one 1,1-dioxide (MBIOD); Fig. 1b], resulting
from the Chapman rearrangement of the methyl pseudosac-
charin ether. In order to check this, we performed several
experiments.
The first one consisted in predicting theoretically the in-
frared spectrum of MBIOD (which is a molecule possessing
only one conformer) and then comparing it with the exper-
imental spectrum obtained after the observed thermal pro-
cess was completed. This theoretical spectrum is shown as
trace g in Figure 2. As can be observed, the theoretical spec-
trum matches closely the experimental one, confirming
MBIOD as the product resulting from the observed thermal
process.
(500e4000 cmꢁ1 spectral range)
Calculateda
Experimental
(polycrystalline;
KBr pellet)
Approximate
assignmentb
B3LYP/6-311
þþG(3df,3pd)
n/cmꢁ1
I/km molꢁ1
n/cmꢁ1
Ic
3167
3164
3152
3139
3127
3095
3019
1634
1610
1583
1478
1476
1466
1465
1457
1371
1355
1328
1284
1211
1177
1172
1160
1150
1129
1049
1025
1005
972
5.4
2.2
3092
3078
w
nCeH6R
nCeH6R
nCeH6R
nCeH6R
nCeHM
w
4.6
1.2
3060
3044
w
w
10.3
8.9
3028/3020
3008/2994
2958
w/sh
w/w
w
nCeHM
nCeHM
24.8
150.4
3.6
1619
1591
S
nC]N, nCeC6R
nCeC6R
nCeC6R, nC]N
dCeCeH6R
dM
w
164.7
11.1
10.8
2.7
1564
1471
S
w
1454
w
dM
11.3
33.6
340.8
210.6
70.8
1.5
dM
1434/1425
1384
1323
1314
1273
1202
1174
1163
1155
1146
1121
1053
1015
1000
954
m/sh
S
dM
nC5ReO, nCeC5R
nS]O
S
sh
w
nCeC6R
dCeCeH6R
dM
3.6
w
270.7
52.9
0.9
S
nS]O
dCeCeH6R
dM
sh
sh
sh
w
25.1
0.2
dCeCeH6R, nCeC6R
dCeCeH6R, nCeC6R
dCeCeC6R
nCeC6R
g6R
18.9
0.9
m
w
0.0
w
29.1
0.6
m
nCMeO
970
896
g6R, g5R
nNeS, dXeCeO
g6R
63.5
0.0
916
908
784
771
754
702
669
621
m
m
m
m
m
m
m
m
891
787
13.6
41.3
32.3
10.2
20.8
39.4
g6R
762
754
dCeCeC6R
g6R, t6R
dCeCeC6R
t6R
700
672
617
dCeCeC6R
dXeS]O
,
588
538
90.0
15.5
597
539
S
gCeS(]O)eN,
dCeXeX5R
gCeS(]O)eN,
dCeXeX5R, t6R
dXeS]O
m
A second and even more conclusive experiment was under-
taken, where the spectrum shown in trace f of Figure 2 was com-
pared with the spectrum of the independently synthesized and
duly characterized crystalline MBIOD. These two spectra are
shown in Figure 3 (a and b, black lines). As seen in this figure,
though being similar and easily ascribed to the same chemical
species, the two spectra do not match perfectly. Indeed, the spec-
trum obtained at the end of the experiment whose progress is
shown in Figure 2 (trace f in that figure, which is now repeated
in Fig. 3a) appears to be identical to the one obtained directly
from the MBIOD sample at temperatures above the melting
point of this compound (ca. 129 ꢀC), i.e., identical to the spectra
drawn in blue and violet in Figure 3b. Such result can easily be
explained if we notice that MBIOD is produced from MBID at
temperatures above its melting point. However, after leaving
529
501
a
20.1
7.5
532
505
sh
m
dCeXeX5R
Frequencies scaled uniformly by the factor of 0.987.18
Notation used in this table follows that of Ref. 18; 6R and 5R refer to the
b
six- and five-membered ring, respectively; M stands for methyl group; n, d, g,
and t indicate stretching, bending, rocking, and torsion modes, respectively; X
designates either a C, S or N atom.
c
Experimental intensities are provided as qualitative: S, strong; m, medium;
w, weak; sh, shoulder.
the resulting sample cooling to room temperature, its infrared
spectrum became equal to that of crystalline MBIOD (Fig. 3a,
red line), fully confirming the nature of the product of the
observed thermal process of MBID.

3300
R. Almeida et al. / Tetrahedron 64 (2008) 3296e3305
Figure 3 corresponds to the one where these changes are the
A
most relevant. The most prominent band shift occurs for the
band observed at 1276 cmꢁ1 in the crystal spectrum, which
moves to 1264 cmꢁ1 in the spectrum of the melt. This band is
ascribable to the all-in-phase in-plane bending of hydrogen
atoms of the phenyl ring. The higher frequency observed for
this mode in the spectrum of the crystal is then an indication
of the steric restrictions imposed to the movement of the phenyl
hydrogen atoms by the crystal environment. A significant shift
to lower frequency upon melting is also observed for the band
observed at 1316 cmꢁ1, which has also a large contribution of
the phenyl all-in-phase in-plane H-bending coordinate (see
Table 2). On the contrary, the characteristic intensive band as-
signed to the nS]O antisymmetric stretching mode shifts to
higher frequency upon melting of the compound (from 1328
to 1337 cmꢁ1), which can be correlated with a greater polariza-
tion of the S]O bonds (i.e., larger contribution of the dipolar
SþeOꢁ structure) in the crystal. This interpretation is also sup-
ported by the considerable decrease of intensity experienced by
this band upon melting (see Fig. 3b).
B
C
The infrared spectroscopic experiments carried out in this
study also include kinetic studies on the observed Chapman re-
arrangement. In order to do this, diluted KBr pellets (MBID/
KBr ca. 1:100 in weight) were prepared, heated quickly to
the desired temperature and then the consumption of the reac-
tant followed by measuring the area under its characteristic
and well isolated band at ca. 1619 cmꢁ1. The results are sum-
marized in Figure 4.
1150
1200
1250
1300
Wavenumber/ cm-1
1350
1400
Figure 3. (a) Black trace: infrared spectrum obtained at the final of the heating
process of the MBID sample (the same spectrum as in trace f in Fig. 2); red
trace: infrared spectrum of the same sample after letting the sample to cool
to room temperature. (b) Black trace: infrared spectrum of the polycrystalline
MBIOD sample (KBr pellet) at room temperature (20 ꢀC); color spectra: infra-
red spectra of the MBIOD sample subjected to heating (red: 90 ꢀC, orange:
120 ꢀC, green: 135 ꢀC, blue: 138 ꢀC, violet: 147 ꢀC); in agreement with the
known melting point of MBIOD (129 ꢀC), the spectral changes associated
with melting of the compound can be clearly noticed by comparing the spectra
obtained at 120 and 147 ꢀC, whereas those obtained at intermediate tempera-
tures indicate the ongoing melting process. (c) Calculated [DFT(B3LYP)/6-
311þþG(3df,3pd)] infrared spectrum of MBIOD. (Displayed spectral range:
1150e1400 cmꢁ1.)
The results shown in Figure 4 clearly demonstrate that the
Chapman reaction increases with the temperature and follows
a sigmoidal kinetics. At the temperature of 190 ꢀC, i.e.,
slightly above the melting point of the reactant, the reaction
is clearly faster, and in 10 min the amount of the reactant is
below the detection limit of the experimental procedure
used. When the sample was kept at a temperature below the
melting point of the reactant but still close to it the rearrange-
ment still occurred at a relatively fast rate. For example, at 180
and 170 ꢀC, the amount of unreacted MBID became smaller
than the detection limit of the method in ca. 24 and 32 min,
respectively. However, for lower temperatures the process
was found to slow down considerably: at 160 ꢀC it took ca.
1 h and at 150 ꢀC ca. 3 h to reduce the quantity of the reactant
to below the experimental limit of detection. Hence, the first
conclusion that can be extracted is that, contrarily to what
was observed before by Dessolin and co-workers34,35 for 5-
methoxy-2-aryl-1,3,4-oxadiazoles, the Chapman rearrange-
ment in MBID is faster in the melt than in the solid state. In
addition, the sigmoid profile of the isotherms clearly reveals
that the process is intermolecular in nature as suggested before
for alkyl imidates.29
Both the DSC and thermomicroscopy experiments, de-
scribed in the following section, were also unequivocal proofs
of MBIOD being the product of the observed thermal process
of MBID, as it will be shown in detail below.
The spectra collected as a function of the temperature for
the MBIOD sample (Fig. 3b) was also used, together with
the DFT(B3LYP)/6-311þþG(3df,3pd) calculated spectrum
for this compound (Fig. 3c), to undertake the vibrational as-
signments for this species in both the crystalline and melted
phases that are presented in Table 2. Like for MBID, the
calculated spectrum for the isolated molecule fits nicely those
obtained in the condensed phases, indicating that in this mol-
ecule intermolecular interactions are also weak enough to let
the intramolecular modes almost unaffected. On the other
hand, besides the usual band broadening associated with melt-
ing, the spectrum of the melted phase exhibits some relatively
important frequency shifts when compared to that correspond-
ing to the crystalline phase. The spectral range shown in
Bawn44 has long ago proposed a kinetic model to consider
processes where the reaction occurs both in solid and liquid
states and where, as in the present case, the reactant is soluble
in the product. This model predicts sigmoidal kinetic iso-
therms and has been used successfully many times in pharma-
ceutical sciences to explain decomposition of organic solids.
Recently, the model was re-evaluated by Brown and Glass.45

R. Almeida et al. / Tetrahedron 64 (2008) 3296e3305
3301
Table 2
Assignment of experimental IR spectra of polycrystalline and melted MBIOD in KBr pellet (500e4000 cmꢁ1 spectral range)
Calculateda B3LYP/6-311þþG(3df,3pd)
Experimental
Polycrystalline
n/cmꢁ1
Approximate assignmentb
Melt
n/cmꢁ1
I/km molꢁ1
Ic
n/cmꢁ1
Ic
3169
3166
3154
3141
3106
3073
3008
1757
1612
1606
1494
1477
1474
1469
1431
1346
1343
1322
1278
1217
1186
1172
1169
1142
1129
1058
1028
1009
976
5.4
0.4
3095
3084
3072
3035
3016
2952
2925
1739
1595
m
sh
w
w
w
w
w
S
3095
3084
3074
3030
w
w
w
w
nCeH6R
nCeH6R
3.5
1.5
nCeH6R
nCeH6R
0.1
7.1
nCeHM
nCeHM
2950
2925
1737
1593
w
sh
S
28.6
367.4
5.1
nCeHM
nC]O
w
w
nCeC6R
nCeC6R
dM
5.3
18.0
6.6
1469
1460
m
m
1464
1456
m
sh
dCeCeH6R
dM
6.7
8.3
dCeCeH6R
dM
21.2
208.0
28.4
257.2
41.5
41.5
118.7
5.4
1422
1328
m
S
1422/1417
1337
w/sh
S
nS]O
nCeC6R
1315
1276
S
1308
1264
S
nC9eN, nC17eN
dCeCeH6R
dM, nCeC5R
nS]O
m
m
1221/1214
1187
1174/1160
m/sh
S
1223/1213
1183
1176/1162
m/sh
S
S/sh
sh/sh
dCeCeH6R
nS]O
dM
131.8
0.6
7.3
1132
1127
1057
1022
999
sh
w
m
w
w
m
sh
d
m
w
S
1137
1125
1059
1019
999
sh
w
m
w
w
m
sh
d
m
w
S
dCeCeH6R, nCeC6R
dCeCeC6R
nCeC6R
15.7
0.8
0.0
0.6
g6R
978
968
971
960
g6R
970
896
65.7
0.1
nC17eN, nC9eN
g6R
not obsd
890
785
not obsd
882
787
879
793
31.4
9.5
nNeS, dM, dXeC]O
gCeC(]O)eN, g6R
t6R, g6R
757
743
36.3
18.6
4.3
751
749
dCeCeC6R
dCeCeC6R
t6R
686
676
685
675
609
591
528
512
m
m
m
S
685
675
610
587
532
508
w
m
m
S
20.8
31.5
62.7
14.8
25.6
606
579
dXeS]O, dXeC]O
gCeS(]O)eN
gCeS(]O)eN, t6R
dCeXeX5R
533
505
m
m
m
m
Frequencies scaled uniformly by the factor of 0.987.18
Notation used in this table closely follows that of Ref. 18; 6R and 5R refer to the six- and five-membered ring, respectively; M stands for methyl group; n, d, g,
a
b
and t indicate stretching, bending, rocking, and torsion modes, respectively; X designates either a C, S or N atom.
c
Experimental intensities are provided as qualitative: S, strong; m, medium; w, weak; sh, shoulder.
The Bawn kinetical parameters obtained for the studied pro-
cess at different temperatures are summarized in Table 3. The or-
dinate of the inflexion point in the isothermal curves shown in
Figure 4, which allows obtaining the Bawn’s solubility parame-
ter (s; see Table 3), is about 0.5e0.6 for all the isotherms (i.e., the
a* parameter in the Bawn model is within the 0.4e0.5 range),
which is a result compatible with the adequacy of the Bawn
model to the description of the system under study.45 The
most important kinetical parameter extracted from the Bawn
model is the ratio between the rate coefficients for reactions in
the solid (ks) and liquid phases (kl). In the present case, for the
highest temperatures investigated, besides the product of
reaction, the reactant is also partially melted and the ratio of
the effective rate coefficients is high. Note that both the forma-
tion of the product and the presence of the ionic matrix media
contribute to reduce the melting point of the reactant, which ex-
plains the fact that the reactions at temperatures slightly below
the melting point of the pristine reactant (ca. 184 ꢀC) are still
considerably fast. On the other hand, for the lowest temperatures
investigated, the reaction in the liquid phase is strongly limited
by the availability of the product resulting from the initial reac-
tion in the solid phase (MBIOD melting point is ca. 129 ꢀC, so
this happens for all temperatures considered); accordingly, the
kl/ks ratio becomes much smaller.

3302
R. Almeida et al. / Tetrahedron 64 (2008) 3296e3305
190 °C
180 °C
1.0
170 °C
endo
160 °C
150 °C
0.8
0.6
0.4
0.2
0.0
2mW
e
d
c
b
a
0
10
20
Time / min.
30
40
50
40
60
80
100
120
T / ºC
140
160
180
200
Figure 4. Plot of the integrated absorbance of the MBID band at ca. 1619 cmꢁ1
as a function of time, for various temperatures. The absorbances of the spectra
registered at t¼0 min at each temperature considered were normalized to unity.
Initial concentrations of the reactant species in the KBr pellet are equal (all
KBr pellets were prepared from the same MBID/KBr mixture, with a weight
ratio of 1:100).
Figure 5. DSC heating curves: (a) MBIOD (m¼1.83 mg); (b) MBID
(m¼2.26 mg) 1st heating scan; (c) the liquid obtained in the first heating
scan of a MBID (m¼1.59 mg) sample was immediately cooled to 25 ꢀC. Ther-
mogram (c) reports the subsequent heating scan; (d) the melt obtained in (b)
was kept for 15 min at 210 ꢀC and then cooled to 25 ꢀC. Thermogram (d)
was obtained in the subsequent heating run; (e) the liquid obtained in (d)
stayed at 210 ꢀC for 30 min before the cooling process. Thermogram (e)
was registered in the subsequent heating scan. All scanning steps were per-
Table 3
Kinetic parameters obtained from the Bawn model for the isotherms shown in
Figure 4
formed at 10 ꢀC minꢁ1
.
T/ꢀC
t*
4.44
1ꢁa*
a*
s
kl
ks
kl/ks
The large baseline change that is observed between the begin-
ning and the end of the melting peak is indicative of thermal
conversion of the starting compound. The thermomicroscopy
study (Fig. 6b and movie provided as Supplementary data), al-
lowed to recognize the first transition as a solid/solid one (not
detectable by IR), and to confirm that, under the used experi-
mental conditions, no other modifications occur until fusion,
that is, to say MBID is stable in the solid state, when heated
190
180
170
160
150
0.58
0.54
0.55
0.55
0.59
0.42
0.46
0.45
0.45
0.41
1.39
1.18
1.23
1.22
1.43
0.484
0.207
0.146
0.062
0.016
0.017
0.014
0.011
0.013
0.007
28.44
14.81
13.15
4.72
9.40
12.72
20.85
52.78
2.29
t* is the time corresponding to the inflection point of the isotherms shown in
Figure 4, whose ordinate is 1ꢁa*. s¼(1ꢁa*)/a* is the Bawn solubility para-
meter. k1 and k2 are the rate coefficients for the liquid and solid state reaction
phases reaction, respectively, and were obtained, accordingly to the Bawn
model, by non-linear fitting of the following two equations to the kinetical
data [(1ꢁa)¼f(t)]: (1ꢁa)¼(1ꢁa*) exp[ꢁkl(tꢁt*)], for 0<t<t*, to obtain kl;
(1ꢁa)¼1-ks/(sklꢁsksꢁks){exp[(sklꢁsksꢁks)t]ꢁ1}, for t>t*, to obtain ks.
at 10 ꢀC minꢁ1
.
The cooling experiments, performed at 10 ꢀC minꢁ1, gave
rise to crystallization of the liquid at temperatures between
80 and 65 ꢀC, and no conclusions can be drawn from the
obtained curves. On the other hand, the thermogram profiles
obtained in the heating runs performed after cooling the liquid
from 210 to 25 ꢀC were found to be particularly informative.
They depend on the time the liquid was left at the higher tem-
perature and, therefore, on the extent of MBID to MBIOD
conversion: if the liquid is cooled at once, the result shown
in Figure 5c is obtained; annealing for 15 min or for 15 plus
additional 30 min at 210 ꢀC give rise to the thermograms pre-
sented in Figure 5d and e, respectively. Thermomicroscopy
images obtained in the conditions of Figure 5c and e are
presented in Figure 6c and d, correspondingly. In Figure 5e
a narrow peak is observed, as expected when a pure substance
melts, and the peak onset temperature and transition enthalpy
match those obtained for MBIOD fusion process, clearly tes-
tifying conversion of MBID into this compound. A 15þ
30 min annealing at 210 ꢀC allows the complete conversion
of MBID into MBIOD, while the other thermal treatments
lead to incomplete conversion, resulting in the lowering of
MBIOD melting point.
3.2. DSC and polarized light thermomicroscopy experiments
The thermal behavior of pure MBIOD was characterized by
differential scanning calorimetry between 25 and 210 ꢀC and
a typical heating run thermogram is shown in Figure 5a. A sin-
gle peak is observed, corresponding to the melting process,
which occurs at Tfus¼129.3ꢂ0.2 ꢀC (n¼4). The corresponding
enthalpy, DHfus is 19.5ꢂ0.3 kJ molꢁ1 (n¼4). Images obtained
by thermomicroscopy for the phase transition observed in pure
MBIOD are shown in Figure 6a, where the starting of the fu-
sion can be clearly noticed in the image obtained at 129.3 ꢀC.
Below this temperature no changes in the sample were
observed.
MBID samples were studied in the same temperature range
and a characteristic first heating thermogram is shown in Fig-
ure 5b. A low enthalpic endothermic transition [DHtrs¼1.6ꢂ
0.3 kJ molꢁ1 (n¼5)] is observed at Ttrs¼120.3ꢂ0.2 ꢀC (n¼5)
and the melting process occurs at Tfus¼183.7ꢂ0.2 ꢀC (n¼5).

R. Almeida et al. / Tetrahedron 64 (2008) 3296e3305
3303
(a)
25 ºC
129.3 ºC
131.2 ºC
(b)
25 °C
118.1 °C
123.2 °C
182.3 °C
184.1 °C
185.5 °C
(c)
25 °C
110.5 °C
111.9 °C
(d)
129.5 °C
132.0 °C
25 °C
Figure 6. Phase transitions observed by thermomicroscopy: (a) MBIOD fusion. (b) MBID 1st heating scan: solid/solid transition and melting. (c) The liquid ob-
tained in a MBID first heating run was immediately cooled to 25 ꢀC. The images report the subsequent heating scan. (d) Images for a heating process of a MBID
sample treated as in Figure 5e. All scanning steps performed at 10 ꢀC minꢁ1
.

3304
R. Almeida et al. / Tetrahedron 64 (2008) 3296e3305
In the preceding experiments conversion of MBID to
which occurs at 129.3ꢂ0.2 ꢀC (DH¼19.5ꢂ0.3 kJ molꢁ1).
The infrared spectrum of crystalline MBID and those of
MBIOD in both crystalline and liquid phases were fully as-
signed on the basis of comparison with results of theoretical
calculations and, for MBID, also taking into account previous
experimental data obtained for the compound isolated in cryo-
genic inert matrices.18
MBIOD by annealing of the melt at 210 ꢀC was achieved.
An additional DSC experiment was also made, in order to fur-
ther confirm, by an independent method, the likelihood of the
isomerization in the solid state. In this experiment, a MBID
sample was heated until 160 ꢀC at 10 ꢀC minꢁ1 and left at
that temperature for 3 h. The sample was then rapidly cooled
to room temperature and reheated to 210 ꢀC. As expected, the
thermogram corresponding to this latter heating run was found
to closely match that presented in Figure 5c, indicating that
partial conversion of MBID to MBIOD took place.
Acknowledgements
~
The research was supported by the Portuguese Fundac¸ao
para a Ciencia e a Tecnologia (Grant FCT #SFRH/BPD/
A final note concerning the kinetics of the process must be
considered here, since apparently the DSC experiments do not
fit exactly the kinetical results as determined by infrared spec-
troscopy in what concerns the time required to complete the
rearrangement reaction, which appear to be longer by the for-
mer methods. In spite of the fact that the experimental condi-
tions in the two experiments were not exactly the same and
this might have influenced somewhat the results (in the infra-
red experiments the size of the MBID crystals was reduced
before usedduring preparation of the KBr pelletsdthus in-
creasing the accessible area of the reactant and eventually
led to increase the reaction rate), the main cause for this appar-
ent discrepancy is certainly a result of the lower sensibility of
the infrared experiments to detect trace amounts of unreacted
MBID when compared to DSC. Indeed, in the DSC experi-
ments, the presence of such low amounts produces an easily
noticeable decrease in the melting point of MBIOD, which
is then a highly sensitive indirect way to detect trace amounts
of unreacted MBID in the sample after thermal treatment. On
the other hand, in the infrared experiments the amount of
MBID had to be estimated from band intensity measurements,
which necessarily implies a higher detection limit, since the
bands are relatively broad and, for very low intensities, they
might easily be concealed within the baseline.
ˆ
17081/2004 and projects POCI/QUI/59019/2004 and POCI/
~
QUI/58937/2004) and Instituto de Investigac¸ao Interdiscipli-
nar, Universidade de Coimbra, Portugal III/BIO/40/2005. Cal-
culations were partially done at the Academic Computer
Center ‘Cyfronet’, Krakow, Poland (Grant KBN/SGI_ORI-
GIN_2000/UJ/044/1999), which is acknowledged for comput-
ing time. A.G.Z. is member of the research career Conicet
(National Research Council, Argentina).
Supplementary data
1
It consists of (a) NMR and mass spectra for MBID and
MBIOD, and (b) movie with the changes in the MBID sample
in the solid/solid phase transition region (110e130 ꢀC) as ob-
served in the thermomicroscopy experiments. Supplementary
data associated with this article can be found in the online ver-
sion, at doi:10.1016/j.tet.2008.02.007.
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