Structural characteristics of some mercaptoacetic acid hydrazides

Article abstract of DOI:10.1016/S0022-2860(03)00158-3

NMR and molecular modeling were used to analyze the conformational states of a series of mercaptoacetic acid hydrazides. A chemical exchange phenomenon was observed in the phase-sensitive NOESY spectrum of all derivatives in both CDCl₃ and DMSO-d6 solvents. Chemical shifts, temperature and solvent dependence as well as MonteCarlo conformational search suggest that two rotamers exist around the amide bond in solution in a slow, for the NMR time scale, interconversion at room temperature. The trans conformer is predominant in CDCl₃ and seems to be stabilized by the presence of hydrophobic interactions between the two aliphatic ends of the molecule. The relative population of the cis conformer increases tenfold in DMSO-d6 stabilized through the formation of hydrogen bonds.

Full text of DOI:10.1016/S0022-2860(03)00158-3

Journal of Molecular Structure 650 (2003) 213–221
www.elsevier.com/locate/molstruc
Structural characteristics of some mercaptoacetic acid hydrazides
Panagiotis Marakos, Nicole Pouli, Spyroula Papakonstantinou-Garoufalias,
*
Emmanuel Mikros
Department of Pharmaceutical Chemistry, University of Athens, Panepistimiopolis, 15771 Zografou, Greece
Received 9 January 2003; revised 14 February 2003; accepted 14 February 2003
Abstract
NMR and molecular modeling were used to analyze the conformational states of a series of mercaptoacetic acid hydrazides.
A chemical exchange phenomenon was observed in the phase-sensitive NOESY spectrum of all derivatives in both CDCl3 and
DMSO-d6 solvents. Chemical shifts, temperature and solvent dependence as well as MonteCarlo conformational search suggest
that two rotamers exist around the amide bond in solution in a slow, for the NMR time scale, interconversion at room
temperature. The trans conformer is predominant in CDCl3 and seems to be stabilized by the presence of hydrophobic
interactions between the two aliphatic ends of the molecule. The relative population of the cis conformer increases tenfold in
DMSO-d6 stabilized through the formation of hydrogen bonds.
q 2003 Elsevier Science B.V. All rights reserved.
Keywords: 1H NMR; 13C NMR; Molecular mechanics; Conformational analysis; Hydrazides; Amide rotation
1. Introduction
we have described the synthesis of some 5-adamantyl-
4-aryl-1,2,4-triazoles, bearing a 3-mercaptoacetic
acid substitution, which exhibit antifungal and anti-
microbial activity (Fig. 1, compounds 2, 3) [11]. The
1H NMR spectra revealed an interesting feature, since
two series of signals were observed. This phenom-
enon was previously been described only for the SCH2
protons in a series of related analogues [3–5,12],
however, a controversy still exists concerning this
observation. According to the authors these protons
resonated as two singlets, or as a doublet and this
pattern was attributed to the existence of two rotamers
around the sulfur bridge or to the presence of the
enolic form, or to hydrogen bond formation between
NH and S atom. On the other hand it has been
proposed that N-acyl hydrazones could undergo an
E=Z conformational isomerization as far as the NyN
The chemistry of hydrazones and their deriva-
tives has been extensively investigated in recent
years, since this group presents interesting chelating
properties and is a common structural feature in
many biologically active molecules [1,2]. More
specifically some mercaptoacetic acid hydrazones
and hydrazides have been reported to possess
interesting antimicrobial, antifugal and anticonvul-
sant activity [3–5].
In the course of our research efforts towards the
preparation of new compounds containing the 1,2,4-
triazole ring, a well known pharmacophore, [6–10]
*
Corresponding author. Tel: þ30-10-727-4813, fax: þ30-10-
727-4747.
E-mail address: mikros@pharm.uoa.gr (E. Mikros).
0022-2860/03/$ - see front matter q 2003 Elsevier Science B.V. All rights reserved.
doi:10.1016/S0022-2860(03)00158-3

214
P. Marakos et al. / Journal of Molecular Structure 650 (2003) 213–221
Fig. 1. Structure and numbering of compounds 1–7.
bond is concerned or a cis–trans isomerization
around the amide bond –C(O)NH– [13,14]. In an
attempt to study in detail this phenomenon we present
here the preparation of some new, structurally related
analogues (Fig. 1, compounds 1, 4–7), which together
with the previously reported derivatives were used for
the comprehensive spectral study of this class of
compounds on the basis of their 1H and 13C NMR data
in CDCl3 and DMSO-d6, EXSY spectra and molecu-
lar mechanics calculations.
(1.15 mmol) [11] in absolute ethanol (20 ml). The
mixture was refluxed for 24 h and then, allowed to
stand overnight. The solvent was vacuum-evaporated
and the residue was purified by column chromatog-
raphy (silica gel), using mixtures of dichloromethane/
cyclohexane: 1/2–1/3 (v/v) as the eluent to give 68–
77% yield of the target compounds. Mp: 1:
128–130 8C (EtOH), 2: 225–228 8C (EtOH), [11]
3: 134–136 8C (EtOH), [11] 4: 119–121 8C (EtOH),
5: 123–125 8C (EtOH), 6: 196–198 8C (EtOH), 7:
162–164 8C (EtOH).
2. Experimental
2.3. NMR methods
2.1. Synthesis
NMR spectra were recorded on a Bruker DRX 400
spectrometer at 400.13 and 100.6 MHz for 1H and 13
C
All reagents used were purchased from Aldrich
Chemical Company. Melting points were taken in
glass capillary tubes on a Bu¨chi 530 apparatus and are
uncorrected. Silica gel TLC was performed on 60F-254
precoated sheets and column chromatography was
carried out on silica gel (60–120 mesh). The elemental
analyses (C, H, N) of all compounds were performed
by the Service Centrale de Microanalyses (CNRS,
Vernaison, France) and are within the range of
experimental error (^0.4% of the calculated values).
experiments, respectively, equipped with a direct and
an inverse 5 mm broadband probe and B0 gradients.
All spectra were recorded using 5 mg of each product
dissolved in 0.6 ml of CDCl3 or DMSO-d6 in a 5 mm
tube at ambient temperature (20 8C). Standard Bruker
pulse programs were used throughout.
The 2D experiments were carried out with the
following parameters (a) COSY were recorded with
gradient pulses for selection, spectral width 12.5 ppm
in both dimensions, 16 transients for each FID; 512 t2
points, 256 t1 increments; recycling delay 2 s; (b) the
phase-sensitive NOESY were obtained with time-
proportional phase incrementation (TPPI), tm ¼ 1:0 s;
a recycling delay of 2 s; spectral with of 5000 Hz in
both dimensions, 256 t1 increments, 2048 points in the
t2 dimension and 16 transients for each FID; a p/2
shifted sine-squared weighting function was applied
2.2. General method for the preparation
of the hydrazides 1–7
The appropriate ketone (1.2 mmol) was added to a
solution of [5-adamantyl-4-(2,4-dichlorophenyl)-4H-
1,2,4-triazol-3-yl]mercaptoacetic acid hydrazide

P. Marakos et al. / Journal of Molecular Structure 650 (2003) 213–221
215
prior to Fourier transformation and zero filled along f1
to 512 points. (c) C–H correlation spectra (HSQC)
were obtained using sensitivity improvement Echo–
Antiecho, phase-sensitive (TPPI) with B0 gradient
pulses for selection of 1H coupled to carbons. A sweep
width of 15 ppm for 1H and 240 ppm for 13C was used
with 128 FIDs in the t1 domain and 1 K data points in
the t2 domain, 48 transients for each t1 increment and
recycling delay 1.5 s. Data were processed using a
shifted sine-square bell and zero filled along f1 to 1024
points. The HMBC experiments were performed
using a low pass J-filter (3.4 ms) and a delay in
order to observe the long-range couplings (65 ms). As
in the HSQC experiments, B0 gradient pulses were
This hydrazide was finally treated with a number of
ketones (acetone, cyclopentanone, cyclohexanone,
cycloheptanone, cyclooctanone, cyclododecanone
and adamantanone) to result in the substituted
hydrazides 1–7.
The assignment of 1H and 13C signals in the NMR
spectra was achieved by the concerted application of
1
COSY, NOESY, HSQC and HMBC experiments. H
and 13C NMR spectra of all compounds in both
solvents show two series of signals.
The 1H NMR data for compounds 1–7 in DMSO-d6
and CDCl3 are provided, for the most relevant protons,
in Table 1 and for the rest Section 4. The alkylidene
protons of the NyCr substituent appear upfield and are
severely overlapped, consequently they are not men-
tioned, except of the deshielded Ha and Hb neighboring
to the imine bond. 13C chemical shifts are summarized
in Table 2 for the most relevant carbons, other
assignments are given in Section 4 (Table S1).
In the 1H spectra in DMSO-d6 solution the chemical
shift difference between the corresponding resonances
in the two series of signals concerning the CH2 and NH
protons are ,0.3 and ,0.1 ppm, respectively.
In the majority of the compounds the two SCH2
protons are almost equivalent and their resonances
exhibit a second order AB system for both series of
signals with the Dn=J ratio ranging from 0.9 to 0.0
(Table 1).
1
applied in order to select H coupled to 13C nuclei,
256 transients with 128 increments in the t1 domain
and 1 K data points in the t2 domain. Data were
processed using a shifted sine-square bell and zero
filled along f1 to 1024 points.
2.4. Molecular calculations
Molecular calculations were performed using
Macromodel 6.5 (Schrondinger) [15] running on
a Silicon Graphics O2 R5000 computer under IRIX
6.3. The MMFF force field was used [16] as
implemented in the Macromodel software. The
Polak–Ribiere (conjugate gradient) minimization
method with an energy convergence criterion of
0.01 kJ/mol was used for geometry optimization.
A 2000 steps conformational search was performed
using MonteCarlo/Low Mode (MC/LMOD) [17]
mixed mode strategy involving systematic search of
low frequency modes (LMOD) or torsional Monte-
Carlo mode (as implemented in the MonteCarlo
Multiple Minimum command in Macromodel/Batch-
min). Volume of the NyCr substituent was calculated
using the VOL mode implemented in Macromodel.
In the phase-sensitive NOESY spectrum cross-
peaks appear, relating the two AB second order
systems of the two different series of signals attributed
to the SCH2 protons (Fig. 2). These cross-peaks exhibit
the same phase as the diagonal peaks characteristic for
a chemical exchange phenomenon. The same type
cross-peaks are observed connecting the two NH
peaks. These signals also present ‘chemical exchange’
cross-peaks with the residual water resonance signal
existing in the DMSO solution.
Moreover, in DMSO-d6 two additional resonances
appear in the spectra at 4.03 and 3.31 ppm when the
samples were prepared in relatively anhydrous
conditions. These signals should originate from
mobile hydrogens as they exhibit chemical exchange
cross-peaks in the EXSY spectrum with the NH and
the residual water peak. They are also shifted together
with the water residual peak when the temperature
increases and vanish when the spectra are recorded in
solutions with more residual water.
3. Results and discussion
For the preparation of the compounds 5-adamantyl-
4-(2,4-dichlorophenyl)-3-mercapto-4H-1,2,4-triazole
[10] reacted with ethyl bromoacetate in alkaline
medium, to give the corresponding mercaptoacetic
acid ethyl ester, which was readily converted to
the hydrazide after treatment with hydrazine hydrate.

216
P. Marakos et al. / Journal of Molecular Structure 650 (2003) 213–221
Table 1
1H-NMR data of compounds 1–7. Chemical shifts (ppm) of the mercaptoacetic acid hydrazide moiety in CDCl3 and DMSO-d6 for both
conformers together with the Dn=J ratio concerning the AB second order system of two geminal SCH2 protons. II=III is the integral ratio
3
˚
presenting the population ratio of the two conformers. V is the volume of the NyCr substituent in A
3
V (A )
˚
Compound
Conformer I
Conformer II
II=III
d (ppm)
Dn=J
d (ppm)
Dn=J
NH
Ha
Hb
SCH2
NH
Ha
Hb
SCH2
CDCl3
11.13
10.94
11.16
10.94
11.02
11.13
11.12
1
2
3
4
5
6
7
2.04
2.44
2.41
2.49
2.41
2.38
2.80
2.00
2.52
2.47
2.58
2.49
2.38
3.31
3.88, 3.74
3.86, 3.72
3.88, 3.75
3.87, 3.80
3.88, 3.84
3.86, 3.82
3.87, 3.79
3.9
3.8
3.4
1.8
0.7
0.7
2.0
8.27
2.10
2.40
2.28
2.45
2.35
2.31
2.60
1.81
2.17
2.18
2.26
2.27
2.16
2.79
4.59, 4.70
4.57, 4.37
4.60, 4.42
4.60, 4.42
4.57, 4.45
4.54, 4.43
4.63, 4.46
4.5
4.6
4.4
4.1
2.9
2.5
3.8
1/0.07
1/0.07
1/0.08
1/0.11
1/0.10
1/0.25
1/0.07
8.05
8.02
8.30
8.39
8.52
8.38
90
106
123
140
210
153
DMSO
10.41
10.29
10.53
10.28
10.41
10.53
10.52
1
2
3
4
5
6
7
1.90
2.30
2.33
2.38
2.37
2.29
3.28
1.83
2.24
2.20
2.34
2.37
2.24
3.21
3.99, 3.95
3.98, 3.93
3.95, 3.95
3.97, 3.97
3.98
0.8
0.9
0.0
0.0
0.0
0.0
0.0
10.48
10.38
10.62
10.37
10.50
10.69
10.59
1.92
2.3
1.85
2.24
2.20
2.34
2.23
2.24
2.50
4.32, 4.26
4.30, 4.25
4.31, 4.26
4.29, 4.25
4.23
0.8
0.7
0.6
0.5
0.0
0.4
0.4
1/1.12
1/1.12
1/1.08
1/1.20
1/1.20
1/2.60
1/0.80
2.33
2.38
2.28
2.29
2.45
4.00, 3.96
2.95
4.26, 4.22
4.31, 4.27
In the 13C spectra in DMSO-d6 solution two
series of signals are clearly observed for all carbon
atoms. Quaternary carbon assignment for both
series of signals was derived unambiguously from
HMBC experiments. The three- and two-bond
connectivity with the NH proton provides
the assignment of NyC and CyO carbon atoms
in all cases, verified by the connectivities with the
CHa(b) and SCH2 protons, respectively. The assign-
ment of the carbon atoms Ca and Cb attached to
Table 2
13C-NMR data of compounds 1–7
Compound Conformer I
Conformer II
SCH2 CyO
NyC
C-3
NyC–Ca NyC–Cb SCH2 CyO
NyC
C-3
NyC–Ca NyC–Cb
CDCl3
1
2
3
4
5
6
7
33.87 164.90 156.10 153.50 25.46
33.99 164.83 168.66 153.63 33.62
33.59 165.13 162.40 153.92 35.56
33.75 165.03 164.50 153.63 36.88
33.65 165.05 164.82 153.81 36.54
33.76 164.95 162.30 153.89 32.94
33.67 165.18 168.78 153.55 39.25
17.97
27.83
28.00
31.14
28.42
27.59
32.14
35.94 168.70 149.95 151.70 25.60
36.15 168.92 163.12 151.95 33.19
15.75
26.92
25.28
29.96
27.12
27.99
30.05
36.18 169.09
152.22 35.39
36.13 168.97 158.74 151.79 35.98
36.09 169.11 159.21 151.81 36.35
36.05 169.35 155.65 152.00 31.87
36.24 168.93 163.19 151.86 39.34
DMSO
1
2
3
4
5
6
7
35.07 163.50 156.30 151.50 25.51
35.06 162.91 167.10 151.03 32.98
34.92 164.22 163.21 151.15 35.12
35.08 163.08 163.28 151.15 36.56
35.07 163.25 163.30 151.24 35.85
35.18 163.51 163.75 151.64 31.14
36.11 163.76 167.59 151.11 38.81
17.60
28.40
27.24
30.19
27.67
28.37
38.57
36.04 169.00 152.00
35.90 168.66 163.83 151.05 32.76
36.03 168.69 151.07 35.10
25.30
17.90
28.29
26.90
30.51
36.01 168.71 159.72 151.12 36.34
36.04 168.82 159.84 151.32 35.80
35.77 169.41 155.76 151.77 31.97
35.10 168.69 163.34 151.19 38.96
28.00
38.60

P. Marakos et al. / Journal of Molecular Structure 650 (2003) 213–221
217
Fig. 2. Part of the phase-sensitive NOESY spectrum of derivative 2 in DMSO-d6 containing the SCH2 resonances of the two rotamers. In f1
direction is presented the corresponding part of the 1D 1H NMR spectrum showing the two second-order AB system resonances. In f2 direction
is presented the row extracted from the spectrum showing the relative phase of the cross and diagonal peaks demonstrating the chemical
exchange phenomenon existing between these protons.
the NyC bond is effectively accomplished from the
HSQC spectra as the associated protons are down-
field shifted. Differences between the chemical
shifts of the corresponding carbon atoms in the
two series of signals are more pronounced in the
case of S–C, CyO and NyC carbon atoms
being ,1, ,5 and ,6 ppm, respectively.
Concerning the other carbon atoms these differ-
ences, when they exist, are of maximum 0.2 ppm
(Section 4).
or the amide bond. Giving the existing symmetry
around the NyC bond for compounds 1–7 the
inversion of the nitrogen atom or NyC rotation, will
not affect the spectra. Thus, these differences can be
explained only by the existence of two rotameric
structures around the C(O)–N amide bond. This is in
agreement with the results of the NMR study of 2,4-
dichlorophenoxyacetyl hydrazide derivatives [18],
where the authors observed the existence of rotamers
resulting only from the amide bond rotation, although
an E/Z-isomerism relative to the NyC bond is also
possible [18,19].
The two series of proton and carbon atom
resonances, as well as the chemical exchange cross-
peaks in the NOESY spectra reveal the existence of
two structures in equilibrium slowly interconverting
to each other in the NMR time scale. Chemical shift
differences between the two series of signals suggest
that the isomerization should concern the CyN bond
Temperature dependence of the spectra supports
also the existence of two isomers in equilibrium.
Spectra recorded in a temperature range between 290
and 370 K, in DMSO-d6 solution, showed that increas-
ing the temperature the two series of peaks broadens

218
P. Marakos et al. / Journal of Molecular Structure 650 (2003) 213–221
and finally, each couple of corresponding signals,
coalesces to one resonance. From the separation of the
SCH2 signals and their coalescence temperature ðTc ¼
360 KÞ;thefreeenergyofactivationofthisinterconver-
sion was found to be DG–ð360Þ ¼ 17:1 kcal=mol [20],
which is in agreement with the amide rotation barrier
described in Refs. [20,21].
to the trans orientation correspondingly. Furthermore,
the heteronuclear geminal coupling constant between
the carbonyl carbon and NH was also found to be
7.4 Hz in the trans rotamers and 3.0 Hz in the cis
rotamers, in agreement with the corresponding coup-
ling constants proposed by Himmelreich et al. [19].
Interestingly the spectra of the compounds in
CDCl3 exhibit differences comparing to those in
DMSO-d6 solutions concerning mainly the rotamer’s
population ratio and NH chemical shifts.
The integral ratio of the corresponding CH2 signals
show that the two rotamers are of almost equal
populations with one of them being somehow
predominant in compounds 1–5 and 7. An increase
of the major rotamer’s population as the volume of the
NyCr substituent increases is also observed (Table 1).
In the case of compound 6, where the volume of the
cyclododecyl substituent is clearly bigger, the popu-
lation of the major rotamer is more than 2-fold higher.
The same trend is observed for the Dn=J ratio
concerning the two SCH2 signals, which tend to be
equivalent as the volume of the substituent increases.
In order to identify the two conformers the NOEs
observed between the NH and the neighboring protons
were used. In trans amide orientation a NOE exists
between NH and CH2, while in the cis amide
orientation this NOE is very weak when it exists. A
verification of this assignment could be done using the
criteria proposed by Himmelreich et al. [17], based on
the heteronuclear coupling constant between the CH2
carbon and the NH proton. They proposed that this
vicinal coupling constant is close to zero for the trans
conformation. Indeed the proton coupled 13C
Spectra recorded in DMSO–CDCl3 mixture at
different solvent ratio’s (1/1, 1/2, 1/4, 1/5 v/v
DMSO/CDCl3, respectively) reveal that the rotamer
II which predominates in DMSO-d6 becomes, by 10-
fold, the minor rotamer in CDCl3 solution. In analogy
to the observations made in DMSO solution, the
relative population of rotamer I decreases as
the volume of the NyCr substituent increases and
the population ratio in CDCl3 changes from 1/0.07 in
compound 1 to 1/0.25 in compound 6 (Table 1).
Moreover, the NH proton of this rotamer exhibits an
upfield shift of ,2.2 ppm in CDCl3.
In order to better understand the rotameric equili-
brium proposed from the NMR data a theoretical study
has been undertaken using molecular mechanics
calculations. The conformational space of compound
2 was explored by applying a MonteCarlo–Low Mode
search. All single bonds were allowed to rotate
resulting in several low energy conformers. The two
lower energy conformer are presented in Fig. 3, since
the relative energy of all other conformers showed to
be more than 2 kcal/mol suggesting that those
structures are less probable in solution.
3
spectrum showed that heteronuclear JCH2–NH was
found to be 3.5 Hz for CH2 of Conformer II, while it
was too weak to be measured for CH2 carbon of
Conformer I. Using both criteria resonances attributed
to Conformer II (Tables 1 and 2) were assigned to the
cis orientation and resonances assigned to Conformer I
As expected from the experimental data the two
most probable structures resulted from the calcu-
lations, differ mainly in the relative conformation of
Fig. 3. Representation of the low-energy conformations for derivative 2 derived from MonteCarlo–Low Mode conformational search along
with their relative energies (kcal/mol).

P. Marakos et al. / Journal of Molecular Structure 650 (2003) 213–221
219
the amide bond. Conformer I is the global minimum
and the NH bond is trans relatively to the CyO
carbonyl bond. In Conformer II the NH bond has a cis
orientation and exhibits a relative energy of 1 kcal/-
mol. The energy difference between conformers I and
II predicted from the calculations, is quite important
and can explain the concentration ratio observed
between the two rotameric structures in CDCl3.
It is interesting to notice that Conformer I seems
to be stabilized through the intramolecular hydro-
phobic interaction between the adamantyl moiety
attached to the triazole ring and the cycloalkyl
NyCr substituent, forcing the S–CH2 bond to a 908
conformation. This interaction is not easy to be
investigated because of the severe overlap between
adamantyl and cycloalkyl proton signals in the NMR
spectrum, but could explain the observed population
decrease of Conformer I as the bulk of the
cycloalkyl substituent increases and the steric
hindrance augments.
mercaptoacetic acid hydrazides under study exist in
two rotameric conformations around the amide bond.
The trans conformer is predominant in CDCl3 and
seems to be stabilized by the presence of hydrophobic
interactions between the two aliphatic ends of the
molecule. The cis conformer is stabilized in DMSO
solution probably through the formation of hydrogen
bonds.
4. Supporting material
1H-NMR chemical shifts (ppm) of compounds 1–7
in (A) CDCl3 and (B) DMSO-d6. Chemical shifts in
parentheses concern Conformer II.
An interesting feature concerning the differences
between DMSO and CDCl3 is the dramatic influence
of the solvent on the cis/trans equilibrium. In early
studies on the conformational behavior of N-acylhy-
drazones it has been observed that the cis isomer is
predominant in CDCl3, probably stabilized as dimmer
through the formation of pairs of hydrogen bonds
[13,14]. More recent studies showed that the trans
isomer is predominant in CDCl3 and the cis/trans ratio
is inversed in DMSO, in agreement to our results
[19,22].
Protons of the 4-(2,4-dichlorophenyl) and 5-
adamantyl groups were resonated in almost the same
frequency (^0.02 ppm) for all compounds. The
chemical shift values of these protons (in ppm) are
as follows:
A.
The stabilization of the cis conformer together with
the downfield shift of the NH resonance in DMSO-d6
should be explained by the formation of a hydrogen
bond with the surrounding solvent. Furthermore, the
existence of the two additional resonances in DMSO-
d6 could provide evidence that this hydrogen bond is
probably formed with the residual water molecules
existing in solution. The possibility of a hydrogen
bond with water molecules is supported by recent
crystallographic studies of aroylhydrazones derived
from the nicotinic acid hydrazide [23,24] and crystal-
lized from alcohol. In both cases the amide bond was
found to adopt a trans orientation linked with water
molecules via the carbonyl oxygen and/or the NH
hydrogen.
Phenyl 30-H: 7.62 (7.59),
Phenyl 50-H: 7.46 (7.42),
Phenyl 60-H:007.34 (7.36),
Adamantyl 2 -H: 1.98, 1.82,
Adamantyl 300-H: 1.98,
Adamantyl 400-H: 1.70, 1.59, and concerning
DMSO-d6.
B.
Phenyl 30-H: 8.02 (7.99),
Phenyl 50-H: 7.68 (7.70),
Phenyl 60-H:007.76 (7.78),
Adamantyl 2 -H: 1.89, 1.75,
Adamantyl 300-H: 1.88,
In conclusion, experimental NMR data and
molecular mechanics calculations consent that the
Adamantyl 400-H: 1.62, 1.51.

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P. Marakos et al. / Journal of Molecular Structure 650 (2003) 213–221
Table S1
13C-NMR chemical shifts (ppm) of compounds 1–7. (A) in CDCl3, (B) in DMSO. Chemical shifts in parentheses concern Conformer II
1
2
3
4
5
6
7
A. CDCl3
C-500
162.28
35.74
40.09
27.76
36.03
130.7
134.14
131.0
137.70
128.34
131.12
–
162.2
35.73
162.34
35.82
40.20
27.84
36.12
130.84
134.34
162.2
35.74
40.11
27.75
36.03
130.75
134.22
162.15
35.74
40.11
27.74
36.03
130.73
161.68
35.81
162.0
35.72
40.11
27.74
36.03
130.71
C-100
C-2
40.01
27.75
40.16 (40.13)
27.82 (27.91)
36.11 (36.20)
130.78
C-300
C-400
36.02
130.78
134.32 (134.6)
C-10
C-20
134.21 (134.38) 134.35 (134.62) 134.26
C-30
130.97 (130.71) 131.07
137.8 (137.0) 137.79
130.98 (130.70) 131.00 (130.68) 131.08 (130.74) 130.97 (128.65)
137.7 (137.04) 137.71 (137.02) 137.83 (137.20) 137.68
128.41 (128.06) 128.42 (128.04) 128.54 (128.11) 128.40
C-40
C-50
128.39 (128.10) 128.48
131.11 (131.53) 131.19
C-60
131.10 (131.53) 131.08 (131.36) 131.16 (131.70) 131.08 (131.56)
27.37 (27.05)
NyCr
substituent
25.0 (24.71)
27.10
29.98 (30.11)
22.17 (22.10)
38.83 (37.60)
24.77 (24.57)
26.21
25.68
24.51 (24.21)
27.20 (27.36)
30.22 (30.08)
25.18 (25.11)
23.98 (24.23)
24.72 (24.38)
26.06 (26.12)
22.27 (22.58)
22.71 (22.87)
22.95 (23.10)
23.22 (23.16)
23.48 (24.21)
24.64 (24.45)
24.81 (25.69)
24.88 (25.75)
37.89 (37.49)
37.64 (37.46)
36.27 (33.04)
27.62 (29.60)
27.62 (27.58)
39.04 (38.87)
B. DMSO
C-500
161.0 (161.2) 160.64 (160.83) 160.83 (160.55) 160.63 (160.84) 160.86 (160.64) 161.08 (160.93) 160.82 (160.63)
C-100
35.12
35.11
39.78
27.28
35.7
35.11
39.77
27.30
35.71
35.12
39.77
27.31
35.72
35.52
40.17
27.70
36.11
35.13
39.78
27.33
35.74
C-2
39.78
27.32
35.73
C-300
C-400
C-10
131.46 (131.28) 131.48 (131.31) 131.47 (131.26) 131.45 (131.22) 131.78 (131.57) 131.30 (131.50)
133.50 (133.41) 133.55 (133.47) 133.53 (133.43) 133.52 (133.42) 133.79 (133.77) 133.48 (133.56)
C-20
C-30
130.21
130.28 (130.26) 130.24 (130.28) 130.21 (130.30) 130.56 (130.66) 130.29 (130.25)
C-40
136.23 (136.14) 136.28 (136.20) 136.28 (136.17) 136.17 (136.33) 136.51 (136.72) 136.30 (136.21)
128.78 (128.76) 128.84 (128.80) 128.78 (128.84) 128.74 (128.86) 129.07 (129.22) 128.84 (128.79)
C-50
C-60
132.54
24.43 (24.36)
132.59 (132.59) 132.57
26.88 (26.67)
132.55 (132.55) 132.90 (132.84) 132.56 (132.56)
38.56 (38.48)
NyCr
substituent
29.55 (29.61)
26.88 (26.88)
23.71 (25.29)
24.29 (24.21)
25.71 (25.61)
25.07 (25.07)
26.98 (26.94)
23.90 (23.69)
29.74 (29.88)
25.99 (26.02)
24.70 (24.79)
24.31 (24.31)
23.94 (23.81)
23.59 (25.08)
23.37 (24.25)
28.95 (23.00)
22.81 (22.81)
22.77
37.21 (37.17)
37.10
31.06 (30.55)
27.11 (27.09)
27.11 (27.09)
22.50
22.05 (22.20)
25.96 (25.96)

P. Marakos et al. / Journal of Molecular Structure 650 (2003) 213–221
221
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