Experimental NMR and MS study of benzoylguanidines. Investigation of E/Z isomerism

Article abstract of DOI:10.1002/poc.3088

Molecules containing the guanidinic nuclei possess several pharmacological applications, and knowing the preferred isomers of a potential drug is important to understand the way it operates pharmacologically. Benzoylguanidines were synthesized in satisfactory to good yields and characterized by NMR, Electrospray Ionization Mass Spectrometry (ESI-MS) and Fourrier Transform InfraRed Spectroscopy techniques (FTIR). E/Z isomerism of the guanidines was studied and confirmed by NMR analysis in solution (¹H-¹³C Heteronuclear Single Quantum Coherence (HSQC) and Heteronuclear Multiple-Bond Correlation (HMBC), ¹H-¹⁵N HMBC, ¹H- ¹H Correlation Spectroscopy (COSY) and Nuclear Overhauser Effect Spectroscopy (NOESY) experiments) at low temperatures. Compounds with p-Cl and p-Br aniline moiety exist mainly as Z isomer with a small proportion of E isomer, whereas compounds with p-NO2 moiety showed a decrease in proportion of isomer Z. The results are important for the application of these molecules as enzymatic inhibitors. Copyright

Full text of DOI:10.1002/poc.3088

Research Article
Received: 16 September 2012,
Revised: 10 December 2012,
Accepted: 24 December 2012,
Published online in Wiley Online Library: 20 February 2013
(wileyonlinelibrary.com) DOI: 10.1002/poc.3088
Experimental NMR and MS study of
benzoylguanidines. Investigation of E/Z
isomerism
Rafael Dias do Espírito Santoa,b, Rosineide Costa Simasc,
Alviclér Magalhãesd,e, Vanessa Gonçalves dos Santosc, Thais Regianic,
Ana Cristina Islerd,e, Natiza Graziele Martinsa, Marcos Nogueira Eberlinc and
Eduardo René Pérez Gonzáleza,b*
Molecules containing the guanidinic nuclei possess several pharmacological applications, and knowing the preferred iso-
mers of a potential drug is important to understand the way it operates pharmacologically. Benzoylguanidines were syn-
thesized in satisfactory to good yields and characterized by NMR, Electrospray Ionization Mass Spectrometry (ESI-MS) and
Fourrier Transform InfraRed Spectroscopy techniques (FTIR). E/Z isomerism of the guanidines was studied and confirmed
by NMR analysis in solution (1H-13C Heteronuclear Single Quantum Coherence (HSQC) and Heteronuclear Multiple-Bond
1
1
Correlation (HMBC), H-15N HMBC, H-1H Correlation Spectroscopy (COSY) and Nuclear Overhauser Effect Spectroscopy
(NOESY) experiments) at low temperatures. Compounds with p-Cl and p-Br aniline moiety exist mainly as Z isomer with
a small proportion of E isomer, whereas compounds with p-NO2 moiety showed a decrease in proportion of isomer Z.
The results are important for the application of these molecules as enzymatic inhibitors. Copyright © 2013 John Wiley &
Sons, Ltd.
Supporting information may be found in the online version of this paper.
Keywords: benzoylguanidines; E/Z isomerism; NMR experiments; ESI–MS characterization
Synthetic approaches toward substituted N-benzoylguanidines
INTRODUCTION
have described the formation of intramolecular hydrogen bond,
but few studies considered the possibility of these compounds
existing as E/Z isomers in solution.[2,11,34]
Guanidine derivatives have been synthesized from different
starting materials and reagents.[1] Thioureas have been widely
used as the starting materials for guanidine preparation in the
presence of different catalysts.[2–12]
Arylthioureas have attracted great attention owing to their
diverse biological activities as antiviral agents, herbicides,
pesticides, plant growth regulators and chelating agents.[13–17]
Guanidinium-based molecules also showed several biological
activities such as cardiovascular dilators,[18] antihistaminics,[19]
anti-inflammatory agents,[20,21] antidiabetics,[22] antibacterial,
antifungal,[23] antiprotozoal, antiparasitic[24] and antiviral.[25,26]
Lamy et al. have reported 1,3-di-o-tolyl guanidines blocking the
calcium and potassium channels in dopaminergic neurons.[27]
Zanamivir[28] and Peramivir[29] are bioactive guanidines that
have activities against all the influenza type A and B viruses.[30]
Benzoylguanidines also form intermolecular and intramolecu-
lar H bonds,[2] and this property seems relevant for a potential
anticonvulsant activity. Benzoylguanidines are also used as
strong and selective inhibitors of Na+/H+ exchangers that are
integral membrane proteins capable of exchanging intracellular
H+ for extracellular Na+ ions. Alterations in Na+/H+ exchange
have been implicated in pathophysiological processes such as
hypertension, postischemic dysfunction and cellular death. The
inhibition of the Na+/H+ exchanger during cardiac ischemia
and reperfusion has been shown to be beneficial for the preser-
vation of the cellular integrity and functional performance.[31–33]
* Correspondence to: Eduardo Gonzalez, Programa de Pós-Graduação em
Ciência e Tecnologia de Materiais (POSMAT), Universidade Estadual Paulista,
São Paulo, Brasil.
E-mail: eperez@fct.unesp.br
a R. D. E. Santo, N. G. Martins, E. R. P. González
Laboratório de Química Orgânica Fina, Departamento de Física, Química e
Biologia, Faculdade de Ciências e Tecnologia, Universidade Estadual Paulista
(UNESP), Campus de Presidente Prudente, 19060-900, São Paulo, Brazil
b R. D. E. Santo, E. R. P. González
Programa de Pós-Graduação em Ciência e Tecnologia de Materiais (POSMAT),
Universidade Estadual Paulista (UNESP), São Paulo, Brazil
c R. C. Simas, V. G. Santos, T. Regiani, M. N. Eberlin
Laboratório ThoMSon de Espectrometria de Massas, Instituto de Química, Uni-
versidade de Campinas (UNICAMP), Campinas 13083-970, São Paulo, Brazil
d A. Magalhães, A. C. Isler
Departamento de Química Inorgânica, Instituto de QuímicaUniversidade de
Campinas (UNICAMP), Campinas 13083-970, São Paulo, Brazil
e A. Magalhães, A. C. Isler
Instituto Nacional de Ciências e Tecnologia de Bioanalítica (INCT-BIOANALÍ-
TICA), São Paulo, Brazil
J. Phys. Org. Chem. 2013, 26 315–321
Copyright © 2013 John Wiley & Sons, Ltd.

R. D. E. SANTO ET AL.
removed with extraction with water (4 ꢂ 15 mL), and the organic phase
dried over anhydrous MgSO4 and evaporated. The crude residue was
crystallized from Et2O/petroleum ether.
The present work describes an E/Z isomeric study of new
benzoylguanidines using NMR spectroscopy in solution at low
temperature. All the guanidine compounds were fully character-
ized by electrospray ionization mass spectrometry (ESI–MS) and
Fourier transform infrared spectroscopy (FT-IR) techniques.
RESULTS AND DISCUSSION
Synthesis
EXPERIMENTAL
Thioureas 1–3 were synthesized following a reported procedure[35]
(Scheme 1) and used as intermediates for the subsequent
synthesis of guanidines 4–17 (Scheme 2), using the method
described by Cunha et al.[11] To form 4–17, thioureas were
reacted with N-benzylamine, N-furfurylamine, N-cyclohexylamine,
N-butylamine and N-(3-aminopropyl)-2-azepanone.
Materials and methods
Commercial benzoylchloride, ammonium isothiocyanate, 4-nitroaniline,
4-bromoaniline, 4-chloroaniline, benzylamine, furfurylamine, cyclohexyl-
amine, butylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine,
penta-hydrated bismuth nitrate and the solvents N,N-dimethylforma-
mide, acetonitrile and dichloromethane were used without previous
purification. Thin layer chromatography was performed on silica gel
plates and visualized using iodine reagent. 1H NMR spectra were
obtained at 400.13 MHz. 13C NMR spectra were obtained at 100.61 MHz.
15N NMR spectra were obtained at 40.54 MHz. Chemical shifts for 1H
NMR and 13C NMR were referenced to tetramethylsilane. Deuterated
dimethyl sulfoxide was assigned to d = 2.49 ppm for 1H NMR and
d = 39.5 ppm for 13C NMR; all NMR peaks were reported in ppm. Data
are presented as follows: chemical shift, multiplicity (s= singlet, d = doublet,
dd = doublet of doublet, t = triplet, qua = quadruplet, qu = quintuplet,
m = multiplet and br s = broad singlet), integration and coupling
constants (in Hertz). EI-MS data was obtained by direct infusion into
a GC-MS instrument. The energy used for electron ionization was
70 eV. ESI(+)–MS data were obtained by infusing directly into the
Nuclear magnetic resonance
Chemical shifts of 1H and 13C nuclei were unambiguously
assigned on the basis of the 1H–1H correlation spectroscopy
(COSY), one-bond 1H–13C heteronuclear single quantum co-
herence (HSQC) and long-range heteronuclear multiple bond
correlation (HMBC) NMR measurements. E/Z isomerism was
investigated by 1H–15N HMBC correlations and Nuclear
Overhauser effect spectroscopy (NOESY) experiments at low
temperatures. Tables 1–3 show representative chemical shifts
in the 1H, 13C and 15N NMR spectra, respectively, for 4–17.
In the 13C NMR spectra of 1–3, the chemical shifts of carbonyl
and thioureic carbon atoms were observed around 168 and
179 ppm, respectively. The chemical shifts of guanidinic and
carbonyl carbon atoms for guanidines were observed around
158 and 177 ppm, respectively. Moreover, the signals for all alkyl
(R) groups in 4–17 were observed in the 1H and 13C NMR spectra.
The assignment of carbonyl carbon was confirmed through corre-
lation with benzoyl ortho protons in the 1H–13C HMBC NMR spec-
trum. The other 1H and 13C nuclei were unambiguously confirmed
by 1H–1H COSY, 1H–13C HSQC and 1H–13C HMBC NMR spectra.
ESI source by means of a syringe pump at a flow rate of 10 mL minꢀ1
.
The molecules display rather clean tandem mass spectra with predom-
inance of their protonated molecules. The ESI–MS/MS experiments
show fragment ions formed upon collisions with argon that are fully
compatible with their proposed structures. ESI–MS and ESI–MS/MS were
acquired using a Quadrupole Time-Of-Flight Mass Spectrometer in the
positive ion mode from acetonitrile solutions with 0.1% of formic acid
and using the following basic operation conditions: Capillary and cone
voltages were set to 3.500 and 45 V, respectively, with a desolvation
temperature of 100 ꢁC. FT-IR measurements were performed at 23 ꢁC
with 124 scans and 4 cmꢀ1 spectral resolution in the form of KBr pellets.
E/Z isomeric study
General procedure for the synthesis of 1-benzoyl-3-(4-aryl-substituted)
The chemical shifts of NH hydrogens at room temperature were
observed at ~5 and 12 ppm as broad lines with low intensity,
which is in agreement with proton exchange and/or substituent
motion effects.
The assignment of these hydrogen atoms was performed
through 1H and the 1H–15N HMBC NMR experiments at low
temperatures (see as example 1H–15N HMBC NMR experiment
thioureas 1–3[35]
To a solution of ammonium isothiocyanate (0.76 g, 10 mmol) in acetonitrile
(20 mL) was added benzoyl chloride (1.40 g, 10 mmol), and the resulting mix-
ture was refluxed for 1 h. After that, the reaction solution was filtered off (for
removal of ammonium chloride), and 10 mmol of (4-nitro, 4-bromo or 4-cloro)
aniline was added. Then, the reaction mixture was refluxed for an additional
2 h. The crude product was filtered off and washed with ice acetonitrile.
General procedure for the synthesis of N-(3-aminopropyl)-2-
azepanone[36]
1,8-Diazabicyclo[5.4.0]undec-7-ene (2.28 g, 15 mmol) and water (0.27 g,
15 mmol) were mixed in a round flask coupled to a reflux condenser,
and the mixture was heated for 12 h at 85 ꢁC. The corresponding
amino-lactam was obtained in the form of a colorless oil and analyzed
by gas chromatography–MS.
Scheme 1. Synthesis of thioureas 1–3
General procedure for the synthesis of guanidines 4–17[11]
To a solution of 1 mmol of thioureas 1–3 dissolved in 5 mL of N,N-
dimethylformamide, 2 mmol of amine, 4 mmol of triethylamine and then
1 mmol of Bi(NO3)3.5H2O were added. The solution became black after a
few minutes, and the mixture was heated for 24 h at ~100 ꢁC. After this
time, the suspension was filtered off through a pad of Celite, and the
pad washed with 20 mL of dichlorometane. The impurity of filtrate was
Scheme 2. Synthesis of benzoylguanidines 4–17
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NMR OF E/Z ISOMERISM IN BENZOYLGUANIDINES
1
Table 1. Representative H chemical shifts (ppm) at ꢀ60 ꢁC for compounds 4–17
Compound
H1
H2
H4
H5
H10
H11
H12
H13
H14
H15
4
5
6
7
8
9
10
11
12
13
14
15
16
17
5.99
5.94
5.50
5.76
5.45
5.43
4.84
4.99
7.00
5.44
5.45
4.82
5.01
6.92
12.63
12.62
12.54
12.51
12.15
12.14
12.12
12.09
12.29
12.16
12.12
12.13
12.05
12.27
7.36
7.39
7.36
7.37
7.14
7.16
7.17
7.16
7.24
7.21
7.20
7.23
7.20
7.29
8.23
8.32
8.32
8.31
7.53
7.56
7.59
7.58
7.58
7.42
7.38
7.45
7.42
7.43
8.29
8.27
8.27
8.28
8.29
8.31
8.27
8.29
8.28
8.29
8.31
8.27
8.27
8.28
7.47
7.54
7.51
7.50
7.48
7.48
7.52
7.50
7.49
7.48
7.49
7.51
7.48
7.47
7.50
7.58
7.58
7.58
7.56
7.52
7.56
7.54
7.54
7.56
7.56
7.57
7.53
7.54
4.92
4.88
3.63
3.68
4.85
4.80
4.13
3.58
3.53
4.85
4.80
4.12
3.56
3.53
—
—
7.42
6.43
1.07-2.18a
1.67
1.43
7.41
6.36
—
—
2.12–1.04a
1.59
1.38
3.43
7.40
6.36
1.84
—
—
2.13–1.07a
1.58
1.37
3.42
1.83
aHydrogens H14, H15 and H16.
Table 2. Representative 13C chemical shifts (ppm) for compounds 4–17
Compound
C4
C5
C6
C7
C8
C10
C12
C13
C16
4a
123.6
123.5
123.0
123.2
127.4
127.2
126.9
127.2
125.9
127.1
126.9
126.7
126.9
125.4
125.8
125.9
125.8
125.6
133.1
133.1
133.2
133.1
132.8
131.5
130.1
130.3
130.1
131.2
144.1
143.1
144.4
—
120.6
120.4
120.1
120.3
119.5
—
156.9
157.8
156.3
—
177.7
177.6
177.5
—
129.0
129.0
128.8
128.8
128.9
128.9
129.2
128.8
128.9
130.1
128.9
129.2
129.1
128.7
132.0
132.0
131.9
nm
45.1
38.3
50.6
42.4
44.8
37.9
50.4
41.1
37.8
44.8
37.9
50.4
41.4
37.0
127.9
110.6
24.7
5a
6a
7
13.8
8a
158.1
157.6
157.7
158.0
158.0
158.2
157.7
157.8
158.6
157.4
177.5
177.4
177.8
177.3
177.3
177.5
177.4
177.8
177.8
177.2
131.6
131.6
131.4
131.4
131.1
132.5
131.5
131.4
131.4
129.8
128.8
110.4
25.7
9a
10
11a
12
13
14a
15
16
17a
14.0
176.8
128.9
110.4
25.7
13.9
176.9
132.5
132.1
128.6
—
aMeasured at ꢀ60 ꢁC.
for 11 in Figure 1). The (Na) nitrogen of 11 at 90 ppm shows
a doublet correlation indicating 1J coupling correlation with
hydrogen H1 at 5.0 ppm and long-range cross-peak with methy-
corresponding to the ortho protons of the p-substituted aromatic
ring and was assigned to aryl-NH. Nitrogen at 173 ppm (Nc) did not
show 1J coupling, therefore was attributed to amide sp2 nitrogen.
1H NMR spectrum at low temperatures (ꢀ60 ꢁC) of the
compounds allowed observation of another signal attributed
to alkyl-NH proton (H10) as a triplet at ~11 ppm (doublet when
R = cyclohexyl) suggesting the existence of E/Z isomers. Figures
2 and 3.
3
lene protons H13 and H14 (2J and J coupling, respectively) of
the butyl substituent and therefore was assigned to alkyl-NH
nitrogen. The nitrogen at 107 ppm (Nb) shows a doublet correla-
tion indicating 1J couplings with hydrogen H2 in the 12 ppm
3
region and J coupling with aromatic hydrogen H4 at 7.2 ppm
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R. D. E. SANTO ET AL.
15
Table 3. N chemical shifts (ppm) at ꢀ60 ꢁC for compounds
9–17
Compound
R
Na
Nb
Nc
9
Furfuryl
Cyclohexyl
Butyl
86.87
105.80
90.35
89.08
91.63
86.75
105.84
90.29
89.10
104.95
103.72
103.92
105.24
104.21
104.74
103.58
103.74
105.09
172.87
—
10
11
12
13
14
15
16
17
172.94
173.18
172.62
173.01
173.22
172.90
172.83
APA
Benzyl
Furfuryl
Cyclohexyl
Butyl
APA
APA, N-(3-aminopropyl)-2-azepanone.
1
Figure 2. H NMR spectrum showing signals of isomers 7 and 70 at
ꢀ60 ꢁC
Figure 1. 1H–15N heteronuclear multiple bond correlation NMR
experiment at ꢀ60 ꢁC for 11
The uncommon chemical shift at ~11 and 12 ppm attributed
to respective alkyl-NH (H10) and aniline (H2) protons (at ꢀ60 ꢁC)
can be explained as due to intramolecular H-bond formation
with carbonyl oxygen atom forming a pseudo six-member ring
that could stabilize the E and Z isomers in solution (Scheme 3).
The (Na0) nucleus of the isomer E was observed for some
compounds at ~115 ppm in the 1H–15N HMBC NMR experiments
Figure 3. 1H–1H correlation spectroscopy NMR spectrum showing
correlations between isomers 7 and 70at ꢀ60 ꢁC
1
(Supplementary material) and showed J coupling (Na0) with
hydrogen H10. The NOESY NMR agrees with the presence of Z
as a main isomer for 8–17 and E for 4–7. Figure 4 shows an
example of dipolar couplings observed in NOESY spectrum.
Broad lines were also observed for hydrogens H4 and H10 in
all 1H NMR spectra at room temperature, which indicate the
occurrence of dynamic process probably caused by an atropiso-
meric mechanism. Sharp lines were observed at lower tempera-
tures because molecular motion decreases with diminution
of temperature, which promotes changes in overall rate of
dynamics process as could be expected for atropoisomerism
effect. The signal-to-noise ratio increases in the NMR NOESY
experiments at lower temperatures because of this restriction
in the range of the average motions, making it possible to
observe more dipolar couplings with slow protons exchange
and molecular motion which support an E/Z isomerism.
Scheme 3. Proposed structures for Z and E isomers
shows signals for H4 and H10 as broad lines at room tempera-
tures and sharp lines at lower ones.
Despite a number of works reporting tautomerism as a main
mechanism responsible for broad NMR lines in guanidine
Figure 5(a) shows 1H NMR spectra for 12 at different tempera-
tures. Figure 5(b) represents an expansion of spectral region that
contains the signals of –NH-protons for isomer E. Figure 5(c)
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NMR OF E/Z ISOMERISM IN BENZOYLGUANIDINES
1
Figure 6. H NMR spectra at ꢀ60 ꢁC for 7, 11 and 16. H2 and H10 are
hydrogen atoms involved in the formation of intramolecular hydrogen
bond for isomers Z and E, respectively
allows the proposal of
a zwitterionic resonant structure
(Scheme 4). The mesomeric form in Scheme 4 shows an increase
of spatial distance between aniline hydrogen atom and carbonyl
oxygen. This effect could make the formation of intramolecular
hydrogen bond difficult and consequently reduces the Z isomers
stabilization. E/Z isomers proportion was calculated by areas
Figure 4. Nuclear Overhauser effect spectroscopy (NOESY) experiment
at ꢀ60 ꢁC for compound 13
1
of NH signals in H NMR spectra at – 60 ꢁC and is shown in
Table 4.
Electrospray ionization mass spectrometry
Benzoylthioureas 1–3 were investigated by ESI(+)–MS, which
allowed their detection as intact protonated molecules with
corresponding patterns of isotopologue ions. Characterization
by tandem mass spectrometry (ESI(+)–MS/MS) showed, as
expected from their structures, a major dissociation route
leading to the benzoyl cation of m/z 105 (main product ion
for 1). The product ion of m/z 122 corresponds to neutral loss
of p-substituted phenyl isothiocyanate and was observed for
the protonated molecules of 1–3, being the main fragment for
2 and 3. Ions formed by loss of neutral benzoylisothiocyanate
moiety (m/z 139, 173 and 128, respectively) were also observed
for 1–3, and the product ions of m/z 215 and 169 corresponding
to neutral loss of benzamide moiety were also observed for 2
and 3, respectively.
1
Figure 5. (a) H NMR spectra for 12 at different temperatures (25 ꢁC;
0 ꢁC; ꢀ30 ꢁC; ꢀ60 ꢁC; and ꢀ70 ꢁC); (b) Region of –NH hydrogen atoms
of isomer E; (c) H4 and H10 regions
In the ESI(+)–MS, all guanidines 4–17 were identified by the
detection of their protonated molecules, which were selected
and further fragmented via ESI(+)–MS/MS experiments. Frag-
mentation of the protonated guanidines 4–17 yielded mainly
the product ions of m/z 105 and m/z 122, corresponding to
benzoyl and benzamide cations, respectively. The ion of m/z
105 was the most abundant for 7 and m/z 122 for 4. Guanidines
4, 8 and 13 showed also the benzyl cation of m/z 91 as one of
the most abundant fragments. For 5, 9 and 14, the furfuryl cation
of m/z 81 was the most abundant fragment. Neutral loss of
cyclohexene generating the product ion of m/z 285 was observed
for 6, which also showed a major fragment ion of m/z 164
corresponding to p-nitrophenylcarbodiimide ion. For guanidines
10, 11, 15 and 16 (see example for compound 16 in the Figure 7),
the product ions of m/z 197 and m/z 153 were the most abundant
(m/z 197 for 10 and 11, and m/z 153 for 15 and 16). These
systems, the results described in the present manuscript indicate
the existence of other effects.
Influence of p-substitution on the E/Z ratio
1
When the H NMR spectra at ꢀ60 ꢁC of the three different
p-substituted guanidines (Figure 6) are compared, signals of
proton H10 corresponding to isomer E show lower intensities.
Isomer E could therefore be present in a small proportion and
was mainly identified by the multiplicity of the observed signal
at ~11 ppm in the 1H NMR spectra.
The compounds with p-NO2 aniline moiety showed a decrease
in the Z isomer population when compared with p-Br and p-Cl
compounds (Figure 6). This behavior could be explained by
strong p-electronic withdrawing effect of nitro group, which
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R. D. E. SANTO ET AL.
Scheme 4. Zwitterionic resonant structure for p-nitroaniline moiety in
compounds 4–7
Scheme 5. Mechanism proposed for the ion fragment of m/z 197
(X = Br, compounds 10 and 11) and m/z 153 (X = Cl, compounds 15
and 16)
Table 4. E/Z isomers proportion (%) calculated by 1H NMR at
ꢀ60 ꢁC
and thiocarbonyl (vC═S) groups appeared around 1680 and
1260 cmꢀ1, respectively.
Compound
p-group
Z isomer
E isomer
The FT-IR spectra of 4–17 showed, as expected, no absorbance
at ~1260 cmꢀ1(vC═S) and a characteristic band at ~1560 cmꢀ1
(vC═N). This supports the transformation of thiourea intermediates to
the corresponding guanidines. The bands observed at 3233–
3425 cmꢀ1 (vN–H) and 1110cmꢀ1 (vCꢀN) also confirm the formation
of the guanidines 4–17.
4
5
6
7
8
9
10
11
12
13
14
15
16
17
NO2
NO2
NO2
NO2
Br
Br
Br
Br
Br
Cl
Cl
Cl
Cl
53.2
55.2
38.8
22.4
90.1
67.6
90.0
84.7
91.7
91.7
93.5
93.5
84.0
91.7
46.8
44.8
61.2
77.6
9.9
32.4
9.1
15.3
8.3
8.3
6.5
6.5
16.0
8.3
CONCLUSION
A number of benzoylguanidines are synthesized in satisfactory
to good yields. All compounds are well characterized by NMR
1
and MS techniques. E/Z isomerism is present as probed by H
NMR at low temperatures. NMR studies at low temperatures
indicate ring rotation or the atropisomerism mechanism as likely
effects responsible for dynamic process in guanidine systems.
This affirmation was supported by the very small proportions
of the tautomeric forms detected at room and low temperature
and dipolar couplings observed by NOESY experiments, which
in some systems show dipolar connections between the
aromatic and aliphatic protons.
Cl
SUPPORTING INFORMATION
Synthesis and Isomeric NMR Study of Benzoylguanidines.
Acknowledgements
The authors would like to thank the Brazilian Research Founda-
tions FAPESP, CNPq and FINEP for their financial assistance. We
are also grateful to Nanobiotec-Brasil-CAPES Network and to
Post-graduation Program POSMAT at São Paulo State University
(UNESP) for the research fellowship and financial support.
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