Configurational assignment and conformational study of methylglyoxal bisdimethylhydrazones derived from the 2-ethoxypropenal precursor

Article abstract of DOI:10.1071/CH05309

A configurational assignment of the isomeric methylglyoxal bisdimethylhydrazones derived from the 2-ethoxypropenal precursor has been performed based on experimental measurements and high-level ab initio calculations of ¹J(C,C) and ¹J(C,H) couplings. The results reveal the marked stereochemical dependence upon the orientation of the lone pairs of both nitrogen atoms in different isomers. Methylglyoxal bisdimethylhydrazone is shown to exist in a mixture of the EE and ZE isomers (ca. 75:25), both of which adopt predominant s-trans conformations with minor (up to 8°) out-of-plane deviations. CSIRO 2006.

Full text of DOI:10.1071/CH05309

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CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2006, 59, 211–217
Configurational Assignment and Conformational Study
of Methylglyoxal Bisdimethylhydrazones Derived
from the 2-Ethoxypropenal Precursor
Leonid B. Krivdin,A,B Lyudmila I. Larina,A Kirill A. Chernyshev,A and Natalia A. KeikoA
A A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences,
664033 Irkutsk, Russia.
B Corresponding author. Email: krivdin@irioch.irk.ru
A configurational assignment of the isomeric methylglyoxal bisdimethylhydrazones derived from the 2-
ethoxypropenal precursor has been performed based on experimental measurements and high-level ab initio
1
1
calculations of J(C,C) and J(C,H) couplings. The results reveal the marked stereochemical dependence upon
the orientation of the lone pairs of both nitrogen atoms in different isomers. Methylglyoxal bisdimethylhydrazone
is shown to exist in a mixture of the EE and ZE isomers (ca. 75:25), both of which adopt predominant s-trans
conformations with minor (up to 8◦) out-of-plane deviations.
Manuscript received: 16 November 2005.
Final version: 21 February 2006.
Introduction
3asaby-product.Theformationofthelattercanbeaccounted
for by the reversible hydrolysis of the bishydrazone 2 at
the ketoimine group. In order to exclude water, the methyl-
glyoxal is prepared in an anhydrous solvent (acetonitrile)
from 2-ethoxypropenal by a technique described elsewhere[2]
(Scheme 2). The water produced as a result of the con-
densation is adsorbed using MgSO4 and K2CO3. However,
even with a stoichiometric two-fold excess of N,N-
dimethylhydrazine, the yield of the bisdimethylhydrazone 2
is 65%, whereas the monohydrazone 3 is formed in 18%.
Another reaction product is 1-dimethylhydrazino-1-ethoxy-
2-oxopropane 5 (yield 16%) which seemingly appears as a
result of the ethanolysis of methylglyoxal monodimethyl-
hydrazone 3.
Methylglyoxal bishydrazones, in particular, substituted bis-
guanylhydrazone and bisthiosemicarbazone, show a clearly
expressed biological activity, which has led to molecules of
this type being used as drugs.[1] In a preliminary investigation
that involves the reaction of 2-ethoxyacrolein with an equi-
molar amount of N,N-dimethylhydrazine, a new methylgly-
oxal bishydrazone with potential biological action is obtained
in 8% yield. The reaction of the aqueous methylglyoxal 1
with a four-fold excess of N,N-dimethylhydrazine leads to
the formation of methylglyoxal bis-N,N-dimethylhydrazone
2 (Scheme 1) with methylglyoxal monodimethylhydrazone
NH2NMe2
CH3CCH
NNMe2
NNMe2
CH3CCH
O
NNMe2
A quite unexpected property of 2 is that, judging from
the 1H NMR and gas/liquid chromatography mass spectrom-
etry (GLC-MS) spectra, it is always obtained as a mixture of
two isomers (in an ratio of ca. 1:3) of unknown configuration
at the two C N bonds. In view of the prospective chemical
CH3COCHO
ϩ
3
1
2
Scheme 1.
NH2NMe2
Hϩ
CH3CCH
O
NNMe2
ϩ
ϩ
CH3CCH
NNMe2
CH2 C(OEt)CHO
4
NNMe2
2 (65%)
3 (18%)
CH3CCH(OEt)NNMe2
O
5 (16%)
Scheme 2.
© CSIRO 2006
10.1071/CH05309
0004-9425/06/030211

212
L. B. Krivdin et al.
interest of 2 for use as a potential precursor in a stereoselec-
tive heterocyclic synthesis, it is highly desirable to establish
the configuration of both isomers once and for all.
The goal of the present communication is to establish the
isomeric composition of methylglyoxal bisdimethylhydra-
zone 2 (Scheme 2) including the configurational assignment
of the observed isomers as well as to carry out a confor-
mational study of all possible isomers of 2 using high-level
ab initio calculations.
of the two isomers of 2 is performed unambiguously based
1
1
on the J(C,C) and J(C,H) constants measured from the
INADEQUATE and the proton-coupled 13C NMR spectra,
respectively (see below).
It has been well established in our early[3] and more
recent[4] publications that 1J(C,C) couplings in azomethines
demonstrate a profound stereochemical dependence on the
orientation of the nitrogen lone pair. Indeed, the difference
between Jcis and Jtrans (Fig. 2) amounts to 20% of their total
values and provides an unambiguous guide to the configura-
tional assignment at the C N bond in several azomethines,
RRꢀC N X (X = OH, OCH CH2, Alk, Ar, SO2Ar).[3,4]
The same is true for the 1J(C,H) couplings involving the α-
imino carbon, however, this remarkable feature of 1J(C,H) is
much less known and is much less exploited in the stereo-
chemical analysis. Apart from the main goal of the present
study lying in the configurational assignment of the isomers
of 2, another interesting aspect that is dealt with is the poten-
tial applicability of the 1J(C,H) involving the α-imino carbon
used for the same purposes, namely for the configurational
analysis of azomethines.
Results and Discussion
The signal assignment in the 13C NMR spectrum of 2
(obtained from 2-ethoxypropenal as shown in Scheme 2) is
mostly straightforward, and is in accord with the existence
of two isomeric forms of 2 in a ratio of ca. 1:3. Additional
proofisgainedfromthe1J(C,C)couplingconstantsmeasured
from the 13C satellites in the proton-decoupled 13C NMR
spectra, as exemplified in Fig. 1. Spectroscopic assignment
of the 13C resonances of the two different NNMe2 groups
(attached to either C2 or C3) in both isomers are performed
by means of the combined application of 2D NOESY, HSQC,
and HMBC 15N–1H techniques. Configurational assignment
What is most remarkable in the present object of this study,
methylglyoxal bisdimethylhydrazone 2, is the presence of
1
1
H3C
N
H
NMe2
2
3
H3C
N
H
NMe2
2
3
C
C
C
C
N
N
Me2N
NMe2
EE (ca. 75%)
ZE (ca. 25%)
C2
C2
1J(C2,C3)
1J(C1,C2)
1J(C2,C3)
1J(C1,C2)
ppm
Fig. 1. 13C satellites in the low-field region of the 13C NMR spectra of 2 in CDCl3 (101.61 MHz).
163.0 162.8 162.6 162.4 162.2 162.0 161.8 161.6 161.4 161.2
13C
Jcis
13C
1H
1H
Jcis
R
R
R
R
X
13C
N
13C
13C
N
13C
Jtrans
Jtrans
N
N
X
X
X
Fig. 2. Orientation of the N lone pair for Jcis and Jtrans
.

Configurational Assignment and Conformational Study of Methylglyoxal Bisdimethylhydrazones
213
two azomethine functions, both of which impart a nitrogen
lone pair effect (LPE) upon the values of 1J(C,C) and 1J(C,H)
of the neighbouring C C and C H bonds.
Jcis (+LPE) and negatively to Jtrans (−LPE) of the adjacent
C C or C H bond.
Thus the marked difference between Jcis and Jtrans is con-
tributed to by three different factors, namely the effects of
(a) the nitrogen lone pair, (b) the carbon–carbon bonds con-
taining coupled carbons, and (c) the carbon inner core
orbitals.[5] The first one relates to the direct nitrogen lone
pair participation in the transmission of 13C–13C spin–spin
coupling to give a positive contribution to Jcis and a negative
contribution to Jtrans (primary lone pair effect). On the other
hand, the second and the third contributions originate mainly
in the charge transfer from the nitrogen lone pair to the anti-
bonding orbital of the adjacent carbon–carbon bond in trans
orientation to the nitrogen lone pair as explained in detail by
Juaristi et al.[6] This charge transfer interaction, which is very
similartotheanomericeffect, resultsinthesubstantiallength-
ening of the transoid carbon–carbon bond and, hence, in the
negative contribution to Jtrans (secondary lone pair effect).
Manifestation of these LPE contributions to 1J(C,C) and
1J(C,H) in the four possible isomers of 2, namely EE, EZ,
ZE, and ZZ, is shown in Fig. 3. Statistical treatment of the cal-
culated 1J(C,C) and 1J(C,H) values in each conformation of
each isomer of 2 (Table 1) leads to the following average
values of +LPE and −LPE: 5.3 1.2 and −5.3 1.2 Hz
for J(C1,C2), 6.4 1.5 and −6.9 2.4 Hz for J(C2,C3), and
6.9 3.5 and −6.9 2.4 Hz for J(C3,H), respectively. These
values are more than enough to perform the required config-
urational assignment of the two isolated isomers of 2. What
According to our earlier theoretical results,[5] the nitrogen
lone pair of the azomethine moiety contributes positively to
NMe2
Me2N
ϪLPE
N
C
N
C
ϪLPE
ϩLPE
H3C
ϩLPE
H3C
C
N
H
C
N
H
ϩLPE
ϩLPE
ϪLPE
ϪLPE
Me2N
Me2N
EE
EZ
NMe2
ϪLPE
Me2N
N
C
N
C
ϪLPE
H3C
ϩLPE
H3C
ϩLPE
C
N
H
C
N
H
ϩLPE
ϩLPE
ϪLPE
ϪLPE
NMe2
NMe2
ZE
ZZ
Fig. 3. LPE contributions to 1J(C,C) and 1J(C,H) in the four possible
isomers of 2.
Table 1. Spin–spin coupling constants 1J(C,C) and 1J(C,H) of the isomers of methylglyoxal bisdimethyl-
hydrazone 2 calculated at the SOPPA(CCSD) level in comparison with experimental resultsA
Isomer
Coupled nuclei
C1,C2
Conformation
JDSO
JPSO
JSD
JFC
J
Experiment
41.5
EE
s-cis
s-trans
s-cis
s-trans
s-cis
s-trans
s-cis
s-trans
s-cis
s-trans
s-cis
s-trans
s-cis
s-trans
s-cis
s-trans
s-cis
s-trans
s-cis
s-trans
s-cis
s-trans
s-cis
0.3
0.3
0.3
0.3
1.2
1.2
0.3
0.3
0.3
0.3
1.1
1.1
0.3
0.3
0.3
0.3
1.2
1.3
0.3
0.3
0.3
0.3
1.1
1.1
−1.2
−1.3
−1.7
−2.1
0.1
−0.2
−1.1
−1.3
−1.8
−1.3
0.2
−0.4
−0.9
−1.1
−1.9
−2.0
0.1
−0.2
−0.8
−0.9
−1.8
−1.2
0.0
0.7
0.7
0.9
0.9
0.1
0.1
0.7
0.7
0.9
0.9
0.1
0.1
0.7
0.7
0.9
0.9
0.1
0.1
0.7
0.7
0.9
0.9
0.1
0.1
41.9
42.1
75.3
41.7
41.8
74.8
C2,C3
C3,H
C1,C2
C2,C3
C3,H
C1,C2
C2,C3
C3,H
C1,C2
C2,C3
C3,H
75.3
75.4
74.5
152.7
161.0
40.9
39.6
62.9
154.1
162.1
40.8
39.3
62.3
162.7
EZ
ZE
ZZ
57.4
57.3
168.4
177.8
51.0
50.3
64.6
169.8
178.6
51.1
50.2
63.9
50.3
64.8
65.1
64.3
152.6
165.2
52.8
51.7
52.3
44.5
170.2
170.7
154.0
166.4
53.0
51.8
51.7
44.5
171.4
171.4
166.8
s-trans
−0.5
A All couplings and their contributions are in Hz. In the calculations of 1J(C,C) and 1J(C,H) the coupled
carbonsandcoupled hydrogenswere specified with the cc-pVDZ-Cs and aug-cc-pVTZ-Jbasis sets, respectively,
while the rest of the elements were assigned with cc-pVDZ with no polarization p-functions on hydrogens.
The equilibrium MP2/6-311G* geometries were used throughout. All calculations were performed without
symmetry constraints assuming the C1 symmetry point group.

214
L. B. Krivdin et al.
30.1Њ
1.7Њ
s-cis (7.6 kcal molϪ1
)
EE
EZ
ZE
s-trans (0.0 kcal molϪ1
)
)
)
25.4Њ
40.3Њ
s-cis (10.8 kcal molϪ1
)
s-trans (9.7 kcal molϪ1
27.3Њ
8.3Њ
s-cis (7.8 kcal molϪ1
)
s-trans (0.6 kcal molϪ1
41.1Њ
77.3Њ
s-cis (7.7 kcal molϪ1
)
ZZ
s-trans (10.6 kcal molϪ1
)
Fig. 4. MP2/6-311G* optimized equilibrium structures of EE, EZ, ZE and ZZ isomers of methylglyoxal
bisdimethylhydrazone 2. Element/color: hydrogen/gray, carbon/yellow, and nitrogen/cyan.
is still needed to solve this problem is to carry out the calcu-
lations of 1J(C,C) and 1J(C,H) in the four possible isomers of
2 and to compare the results with the experimental data keep-
ing in mind the expected LPE contributions in each isomer
depicted in Fig. 3.
Calculations of J(C,C) and J(C,H) for the four possi-
ble isomers of 2 are performed at the most sophisticated
SOPPA (second-order polarization propagator approach)[7]
level in combination with the CCSD (coupled cluster sin-
gles and doubles)[8] computational scheme, the so-called
SOPPA(CCSD), which is approved for the calculation of
spin–spin coupling constants by Sauer and coworkers.[9]
The correlation-consistent basis set cc-pVDZ[10] augmented
with two core s-functions of Woon and Dunning[11] on cou-
pled carbons, cc-pVDZ-Cs, and a basis set of Sauer and
coworkers[12] with four tight s-functions on coupled hydro-
gens, aug-cc-pVTZ-J, are applied to calculate Fermi contact,
JFC, spin–dipolar, JSD, diamagnetic spin–orbital, JDSO, and
paramagnetic spin–orbital, JPSO, contributions of 1J(C,C)
1
and J(C,H), as described elsewhere.[13] It is worth noting
that augmentation of the standard Dunning’s correlation-
consistent basis sets with either core or tight s-functions to
account for the correlation effects of inner electrons and to
improve the description of the cusp of the wave function at
the position of the nucleus (which is crucial for the Fermi
contact contribution) plays a key role in the accuracy of the
SOPPA-based calculations of 1J(C,C) and 1J(C,H), as shown
in several of the publications cited above.
Equilibrium structures of the four possible isomers of 2
used for the calculations of 1J(C,C) and 1J(C,H) are located
at the MP2/6-311G* level and are shown in Fig. 4. Each
of the four possible isomers of 2 is established to pos-
sess two conformers, s-cis and s-trans. Here and further on,
these notations are used keeping in mind that in fact actual
1
1

Configurational Assignment and Conformational Study of Methylglyoxal Bisdimethylhydrazones
215
Table 2. Calculated versus experimental spin–spin coupling constants 1J(C,C) and 1J(C,H) used for
the configurational assignment of the isomeric mixture of methylglyoxal bisdimethylhydrazone 2A
Isomer
Predominant
conformation
Relative energy
1J(C1,C2)
1J(C2,C3)
1J(C3,H)
[kcal mol−1
]
Calc.
Exp.
Calc.
Exp.
Calc.
Exp.
EEB
EZ
ZEC
ZZ
s-trans
s-trans
s-trans
s-cis
0.0
9.7
0.6
7.7
41.8
39.3
50.2
53.0
41.5
74.5
57.3
64.3
51.7
75.3
162.1
178.6
166.4
171.4
162.7
50.3
64.8
166.8
A See footnote to Table 1. All couplings and their contributions are in Hz.
B Major component (ca. 75%).
C Minor component (ca. 25%).
1
conformations possess considerable out-of-plane deviations
N
N(CH3)2
H3C
(see below) while planar s-cis and s-trans forms are just the
starting points to yield the non-planar systems after geometry
optimization.
2
3
C
C
H
As determined from the calculated relative energies
(Fig. 4), the predominant conformation of the EE, EZ, and
ZE isomers is s-trans, which is more favourable for π,π-
conjugation, while that of the ZZ isomer is s-cis. This con-
formational effect should account for the very strong steric
interactions in the s-trans conformer of the latter which gives
rise to the enormous out-of-plane deviation (almost 90◦!)
and results in the ca. 3 kcal mol−1 preference of the diverse
s-cis conformer. It is worth noting that considerable out-of-
plane deviations of ca. 25–40◦ are also observed in most of
the structures depicted in Fig. 4, except for the s-trans con-
former of the EE isomer (ca. 2◦) and s-trans conformer of
the ZE isomer (ca. 8◦), which possess remarkably lower total
energies as compared to the rest in the series. Thus, it seems
very likely that the two unknown isomers of 2 are EE (major)
and ZE (minor), provided the reaction shown in Scheme 2 is
basically under thermodynamic control.
As was pointed out by one of the referees, some conclu-
sions drawn on the basis of the quite involved calculations
(see above) are in full agreement with purely qualitative con-
siderations. For instance, the ZZ isomer is obviously the least
stable and assumes a non-planar conformation because of the
hugestericrepulsionofthemethylanddimethylaminogroups
together with the repulsion of the latter with the proton of the
N CH moiety. For similar reasons, the slightly higher sta-
bility of the EZ isomer can be assumed. Following the same
reasoning one can say that EE and ZE are more stable with
the former prevailing.
(H3C)2N
N
Fig. 5. Numbering of atoms in 2.
taken into account in the calculation of 1J(C,C) and 1J(C,H).
However, it follows from the data in Table 1 that total values
1
1
of J(C,C) and J(C,H) and, accordingly, the orientational
nitrogen lone pair effect that results in a dramatic difference
between Jcis and Jtrans of both types of couplings, are almost
solely governed by the dominant Fermi contact mechanism
while the non-contact contributions are essentially negligible,
in line with our previous results for the related oximes.[4a]
Comparison of the calculated total values of 1J(C,C) and
1J(C,H) in all four possible isomers of 2 (Table 2) demon-
strates the marked stereochemical dependence of both types
of couplings upon the orientation of the lone pairs of both
nitrogen atoms in the different isomers in accord with our
expectations (Fig. 3). Indeed, 1J(C1,C2) in EE and EZ are ca.
39–42 Hz (−LPE) while they are ca. 50–53 Hz in ZE and ZZ
(+LPE). On the other hand, J(C2,C3) in ZZ are ca. 52 Hz
1
(−2LPE), ca. 75 Hz in EE (+2LPE), and ca. 57–64 Hz in EZ
and ZE (−LPE of one azomethine nitrogen and +LPE of the
1
other). In much the same manner, J(C3,H) in EE and ZE
are ca. 162–166 Hz (−LPE) while they are ca. 171–178 Hz
in EZ and ZZ (+LPE). The established manifestation of the
LPE in the values of 1J(C1,C2), 1J(C2,C3), and 1J(C3,H) of
the four different isomers of 2 leaves no doubt that the major
isomer is EE and the minor isomer is ZE, with both adopting
predominant s-trans conformations with minor out-of-plane
deviations.
However, the unambiguous evidence of their formation
1
1
could be gained only from the J(C,C) and J(C,H) data
discussed below. Results of the present SOPPA(CCSD) cal-
culations of 1J(C,C) and 1J(C,H) in all possible forms of 2
are compiled in Tables 1 and 2, and the numbering of atoms
is given in Fig. 5.
In conclusion, the most encouraging result of the present
study is that experimental differences between Jcis and Jtrans
1
1
for both J(C,C) and J(C,H) induced by the nitrogen lone
pair effects of two azomethine functions in methylglyoxal
bishydrazones are large and essentially additive, and are very
well reproduced in the SOPPA calculations, which provides
a straightforward guide to the configurational assignment of
the C N bond in related systems based on the experimental
First, it should be noted that the calculated total values of
both 1J(C,C) and 1J(C,H) of the predominant conformations
of EE and ZE isomers are in exceptionally good agreement
(<1 Hz)withthosemeasuredforthemajorandminorisomers
of 2 (Table 1), respectively, in line with the thermodynamic
arguments above. All four coupling contributions have been
1
measurements and theoretical calculations of their J(C,C)
and/or 1J(C,H) couplings.

216
L. B. Krivdin et al.
Experimental
[4] (a) L. B. Krivdin, N. A. Scherbina, N. V. Istomina, Magn. Reson.
Chem. 2005, 43, 435. doi:10.1002/MRC.1572
Synthesis
(b)L. B. Krivdin, L. I. Larina, K.A. Chernyshev, I. B. Rozentsveig,
Magn. Reson. Chem. 2005, 43, 937. doi:10.1002/MRC.1645
(c) L. B. Krivdin, N.A. Nedolya,Tetrahedron Lett. 2005, 46, 7367.
doi:10.1016/J.TETLET.2005.08.118
Methylglyoxal bis-N,N-dimethylhydrazone 2 was prepared by adding
0.36 g (0.02 M) of water, 0.002 g of hydroxyquinone, and 0.12 g of
a catalyst to 2 g (0.02 M) of 2-ethoxypropenal dissolved in 65 mL of
acetonitrile (pH 2). The catalyst was prepared by dissolving 0.5 mL of
concentrated HCl in 1 mL of acetonitrile. The mixture was heated at
60◦C for 50 min and then cooled. Freshly calcined 4 Å molecular sieves
(1.5 mL) and 4.58 g (0.078 M) of dimethylhydrazine were added and the
mixture was stirred for 2 h and allowed to stand overnight.After distilla-
tion under argon flow, compound 2 was obtained in 65% yield, bp 55◦C
(1 mmHg). δC (100.61 MHz, CDCl3) isomer EE (major, ca. 75%): 12.24
(C1), 41.88 (NNMe2 at C3), 46.71 (NNMe2 at C2), 132.21 (C3), 162.56
(C2); isomer ZE (minor, ca. 25%): 18.77 (C1), 41.71 (NNMe2 at C3),
47.26 (NNMe2 at C2), 132.65 (C3), 161.36 (C2). The assignment of C1,
C2, and C3 are shown in Fig. 1.
[5] (a) V. Barone, J. E. Peralta, R. H. Contreras, A. V. Sosnin,
L. B. Krivdin, Magn. Reson. Chem. 2001, 39, 600. doi:10.1002/
MRC.901
(b) L. B. Krivdin, S. V. Zinchenko, V. V. Shcherbakov,
G. A. Kalabin, R. H. Contreras, M. F. Tufro, M. C. Ruiz de Azua,
C. G. Giribet, J. Magn. Reson. 1989, 84, 1.
(c) R. H. Contreras, C. G. Giribet, M. C. Ruiz de Azua,
C. N. Cavasotto, L. B. Krivdin, J. Mol. Struct. Theochem. 1990,
210, 175. doi:10.1016/0166-1280(90)80039-Q
(d) L. B. Krivdin, S. V. Zinchenko, G. A. Kalabin,
M. F. Tufro, R. H. Contreras, A. Yu. Denisov, O. A. Gavrilyuk,
V. I. Mamatyuk, J. Chem. Soc., Faraday Trans. 1992, 88, 2459.
doi:10.1039/FT9928802459
NMR Measurements
[6] (a) E. Juaristi, G. Cuevas, A. Vela, J. Am. Chem. Soc. 1994, 116,
5796. doi:10.1021/JA00092A034
13C NMR spectra were recorded on a Bruker AVANCE 400 MHz spec-
trometer in a 10 mm broadband probe at 300 K in CDCl3 with HMDS
as an internal standard. Carbon–carbon coupling constants were mea-
sured at 25◦C in CDCl3 from the 13C satellites in the proton-decoupled
13C NMR spectra and also using the INADEQUATE[14] pulse sequence
adjusted for J 45 and 70 Hz. Settings for the INADEQUATE experi-
ments were as follows: 90◦ pulse length: 12–14 µs, spectroscopic width:
10–15 kHz, acquisition time: 4–6 s, relaxation delay: 6–10 s, character-
istic delay τ 1/4J: 5.6 and 3.6 ms, digital resolution: 0.05–0.1 Hz per
point, accumulation time: 12 h. Carbon–hydrogen coupling constants
were measured from the proton-coupled 13C NMR spectra using the
same spectroscopic widths, acquisition times, relaxation delays, and
digital resolutions as in the INADEQUATE experiments.
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