Anisotropic and hydrogen bonding effects in phenylglyoxamides and mandelamides: Theoretical and NMR conformational evaluation

Article abstract of DOI:10.1002/mrc.2192

Interesting anisotropic effects were observed for phenylglyoxamides and their respective mandelamides. Such effects were observed in experimental ¹H and ¹³C NMR (in CDCl₃, CD₃OD, and DMSO-d₆ solvents)

Full text of DOI:10.1002/mrc.2192

Research Article
Received: 7 May 2007
Revised: 10 December 2007
Accepted: 19 December 2007
Published online in Wiley Interscience: 10 March 2008
(www.interscience.com) DOI 10.1002/mrc.2192
Anisotropic and hydrogen bonding effects in
phenylglyoxamides and mandelamides:
theoretical and NMR conformational
evaluation
Biank T. Gonc¸alves,a Pierre M. Esteves,a Angelo C. Pinto,a Carlos R. Kaiser,a
Fernanda L. da Silva,a Eduardo Miguezb and Joaquim F. M. da Silvaa∗
Interesting anisotropic effects were observed for phenylglyoxamides and their respective mandelamides. Such effects were
observed in experimental 1H and 13C NMR (in CDCl3, CD3OD, and DMSO-d6 solvents) and in some cases with good correlation to
theoretical 1H and 13C NMR DFT–GIAO (B3LYP/6-311++G∗∗//B3LYP/6-31G∗) calculations. A systematic conformational analysis
of these compounds was performed in a two-step methodology, using PM3 and DFT (B3LYP/6-31G∗) calculations; with good
accomplishment and computational time economy. It was observed that intramolecular hydrogen bonding plays a significant
role in the conformation of such compounds. Finally, a geminal nonequivalence of an N–CH2 moiety, in one of the alkyl side
c
chain (R1 = R2), was found for the tertiary mandelamides studied. Copyright ꢀ 2008 John Wiley & Sons, Ltd.
Supplementary electronic material for this paper is available in Wiley InterScience at http://www.interscience.wiley.com/
jpages/0749-1581/suppmat/
Keywords: NMR; PM3 calculations; DFT calculations; anisotropic effects; hydrogen bonding; 1H; 13C; phenylglyoxamides; mandelamides
Introduction
mandelamide moieties are present in pharmacologically inter-
esting compounds.[14–18] In many cases, a strict relation exists
between the biological activity and the freedom conformation
of these groups for hydrogen bonding interaction with enzyme
active site.[19–23] In fact, these interesting systems encouraged us
to perform a systematic conformational analysis of 1 and 2, in
order to evaluate direct and indirect effects of intra- and inter-
molecular hydrogen bonds in the amide moieties. Our work was
based on two valuables tools for conformational studies: NMR
and theoretical calculations.[24–26] This way, we performed a sys-
The importance of the amide group for living organisms can be
related to some of its chemical properties such as planarity,
relatively high barrier of rotation around the C–N bond,
and their hydrogen bonding donor and acceptor properties.
These are the key factors in determining the conformations
of peptides, enzymes, and proteins. A deep understanding of
these characteristics would lead to a better comprehension of
many of the chemical and physical processes that constitute
life. Due to such relevance, studies on amide derivatives have
led to many speculations by scientists.[1–5] A crucial point
involves the participation of amides in hydrogen bonds, which
continues to attract interest due to its extreme importance
in nature.[6–8] Such hydrogen bonds might be expected to
increase the C–N rotational barrier of a peptide bond over
that of the nonhydrogen bonded state by stabilizing the
charge separation in the planar ground state of amides.[9]
However, systems where H-bonds reduce the rotation barriers
of amides have been proposed.[10,11] Although these studies
represent a significant advance in the comprehension of these
peculiar effects, it is still difficult to reproduce experimental
conditions that report the characteristics of amides in biological
organisms.
1
tematic evaluation of H and 13C NMR chemical shifts of 1 and
2 in different solvents and correlated them to calculated ones.
Finally, in this article we report intense effects of diamagnetic
anisotropy susceptibility, which are in part due to amide hydrogen
bonding.
∗
Correspondence to: Joaquim F. M. da Silva, Departamento de Química
Organica, Instituto de Química, Bloco A, 6 a Andar do CT, Universidade Federal
ˆ
´
˜
do Rio de Janeiro, Cidade Universitaria, Ilha do Fundao, RJ, Brazil, 21949900.
E-mail: joaquim@iq.ufrj.br
a
Departamento de Química Organica, Instituto de Química, Bloco A, 6 a Andar
ˆ
As part of our research aiming the synthesis and pharmaco-
logical evaluation of α-functionalized amides, we prepared as
synthetic intermediates the phenylglyoxamides 1 and the man-
delamides 2 (Fig. 1).[12] These compounds present the possibility
of promoting intramolecular hydrogen bonds, which may exert
strong influence in their conformations.[13] The α-ketoamide and
´
do CT, Universidade Federal do Rio de Janeiro, Cidade Universitaria, Ilha do
˜
Fundao, RJ, Brazil, 21949900.
´
Instituto de Macromoleculas Profa Eloísa Mano, Universidade Federal do Rio
b
´
˜
de Janeiro, Cidade Universitaria, Ilha do Fundao, RJ, Brazil, 21945970.
c
Magn. Reson. Chem. 2008; 46: 418–426
Copyright ꢀ 2008 John Wiley & Sons, Ltd.

Anisotropic and hydrogen bonding in phenylglyoxamides and mandelamides
calculations. For the mandelamides, only the R enantiomer was
studied in the theoretical calculations. In the second step, the
conformations obtained during the molecular dynamics study
were submitted to density functional theory (DFT) analysis using
the B3LYP/6-31G∗ level of theory. Gaussian 98[29] was employed
for these geometry optimization calculations. Finally, the fully
optimized conformations at B3LYP/6-31G∗ were used to calculate
theoretical 1H and 13C NMR chemical shifts using DFT with B3LYP
hybrid functional and 6-311++G∗∗ basis set. The good reliability
of DFT calculations as a tool to predict 1H and 13C spectral
parameters has been well demonstrated in literature.[30–33] This
two-step methodology was employed in amide conformational
analysis with good accomplishment and feasible computational
time.[34]
Results and Discussion
Figure 1. Phenylglyoxamides (1) and mandelamides (2).
The geometry optimization of 1 by DFT revealed two favorable
conformations. The first one (1ꢁ) showed a six-membered in-
tramolecular hydrogen bonding between the ortho-acetamidic
hydrogen and the α-carbonyl oxygen. In the second conformation
(1ꢁꢁ), anintramolecularhydrogenbonding seven-memberring was
observed between the ortho-acetamidic hydrogen and the glyox-
amide oxygen carbonyl (Fig. 2). However, the conformation 1ꢁ is
about 3 Kcal/mol more stable than 1ꢁꢁ in all glyoxamides studied
here. In fact, the conformation adopted for 1ꢁ has been observed
for tertiary phenylglyoxamides by X-ray crystallography.[35] This
is reinforced by the observation of a substantial deshielding of
H-7 and H-a in CDCl3 1H NMR spectra (Table 1), and by nuclear
Overhauser effect (NOE) difference experiments in CDCl3 (Fig. 3)
and in DMSO-d6 (Fig. 4). The NOE difference experiments of 1G
in CDCl3 show a NOE between NH-a and –NCOCH3 (7.5% when
NH-a is irradiated) only, which is a confirmation for a conformation
like 1ꢁ (Fig. 3). However, in DMSO-d6 an NOE for H-7 (4.5%) is now
observed when the irradiation is over NH-a, indicating a polar
effect of this solvent (Fig. 4). A similar deshielding was observed
Experimental
The phenylglyoxamides 1A–G were synthesized following
methodology previously described.[12] The mandelamides 2A–F
were obtained from the reduction of the corresponding phenyl-
glyoxamides with NaBH4, except for 2G which was obtained from
the catalytic hydrogenation of 1G.[27]
The 1H and 13C NMR spectra were recorded on a Bruker DRX-300
at 300 and 75 MHz, respectively. Chemical shifts (δ) are expressed
in parts per million (ppm) from tetramethylsilane (TMS) as internal
standard. COSYandHMQCexperimentswererecordedonaBruker
DRX-300at300 MHz.CD3OD,DMSO-d6,andCDCl3 werepurchased
from FLUKA.
The theoretical calculations were performed in two steps. In the
first one, the molecules were submitted to molecular dynamics
employing Hyperchem 5.0 at PM3 level[28] for exploring the
several conformational possibilities. The lower energy structures
from the dynamics were then picked up for higher level
Figure 2. Selected conformations of 1 (1Eꢁ, 1Eꢁꢁ) and 2 (2Eꢁ, 2Bꢁꢁ) obtained after optimization at DFT (B3LYP/6-31G∗) level.
c
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B. T. Gonc¸alves et al.
Table 1. Experimental 1H NMR chemical shifts (δ = ppm) for H-a and H-7 of phenylglyoxamides 1A–G and mandelamides 2A–G in CDCl3, DMSO-d6,
CD3OD, and corresponding calculated chemical shifts using DFT–GIAO/B3LYP/6-311++G∗∗//B3LYP/6-31G∗ level of theory (conformers 1ꢁ and 2ꢁ)
δ(H-a)
CDCl3
δ(H-a)
DMSO
δ(H-a)
δ(H-7)
CDCl3
δ(H-7)
DMSO
δ(H-7)
CD3OD
δ(H-7)
α-Ketoamide
B3LYP/6-31G∗
B3LYP/6-31G∗
1A
10.9
10.8
10.9
11.3
11.3
11.3
11.3
10.6
10.7
10.5
10.8
10.8
10.8
10.9
11.7
11.7
11.7
11.7
11.6
11.7
11.6
8.6
8.5
8.5
8.8
8.8
8.8
8.8
8.0
8.2
8.2
8.3
8.0
8.6
8.6
8.6
8.5
9.3
9.3
9.3
9.3
9.3
9.3
9.3
1B
1C
7.6–7.7
8.4
1D
1E
8.4
1F
8.3
1G
8.5
Mandelamide
a
a
2A
2B
2C
2D
2E
2F
2G
–
9.9
9.8
9.9
9.5
9.5
9.5
9.5
8.8
8.9
8.8
8.7
8.4
8.0
7.3
–
7.7
7.7
7.7
7.7
7.7
7.6
7.6
7.8
7.6
9.0
9.0
9.0
8.9
8.9
7.2
7.1
9.6
9.6
8.1
8.2
8.1
8.1
7.5
7.1–7.5
8.0
7.5–7.6
7.7
8.0
7.7
7.9
7.6
7.8
7.6
a Not soluble.
Figure 3. NOE difference experiments of 1G in CDCl3.
for acetanilides bearing hydrogen bond acceptor groups in ortho
position.[36] In this case, a planar conformation is assumed, which
forces the acetamidic carbonyl into a position able to deshield H-7.
This deshielding may be used as a diagnostic tool to estimate the
extent of coplanarity in such molecules and would not be found
in a conformation such as 1ꢁꢁ. Other fact favoring 1ꢁ is the large
deshielding effect observed for H-a (10.8–11.3 ppm in CDCl3).
The aim of studies have been the NH chemical shifts of amides
for the evaluation of conformational designs in hydrogen bond-
ing molecules.[37] In particular, these NH-a chemical shifts are in
accordance to the NH deshielding effect observed in acetanilides
carrying hydrogen bonding acceptors involved in an intramolec-
ular hydrogen bond six-member ring, such as 1ꢁ.[36] Also, the NH-a
deshielding of these phenylglyoxamides is consistent with the so-
called resonance assisted hydrogen bonds (RAHBs) due to planar
delocalization.[38,39]
In fact, the respective secondary phenylglyoxamides may adopt
a different conformation in the crystal structure, being associated
in intermolecular hydrogen bonding and due to the crystal
packing.[40]
The geometry optimization of 2 revealed the conformer 2ꢁ
as the most stable one, which presents the acetamide carbonyl
out of the plane of H-7 (Fig. 2). This is in accordance to the
NMR spectra, where these hydrogen atoms are shifted to a lower
frequency in relation to the phenylglyoxamides (Table 1). On the
other hand, DFT calculations yielded the conformer 2ꢁꢁ, but only
for the primary and secondary mandelamides (2A–C). For the
tertiary mandelamides, even when forcing the conformer 2ꢁꢁ in
c
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Magn. Reson. Chem. 2008; 46: 418–426

Anisotropic and hydrogen bonding in phenylglyoxamides and mandelamides
Figure 4. NOE difference experiments of 1G in DMSO-d6.
the starting geometries, the final optimized geometry is similar
to conformer 2ꢁ. It seems that the restrained conformation of 2ꢁ
is quite favorable for the tertiary mandelamides 2D–G. Figure 2
shows the conformers for the phenylglyoxamide 1E (1Eꢁ and 1Eꢁꢁ)
and for the mandelamide 2Eꢁ and 2Bꢁꢁ, obtained by this calculation
methodology.
The chemical shifts for H-7 and H-a were obtained from
the NMR experiments in CDCl3, CD3OD, and DMSO-d6 of
phenylglyoxamides 1A–G and mandelamides 2A–G (Table 1).
The tertiary phenylglyoxamides 1D–G showed a higher NH-
a deshielding (11.2–11.3 ppm) than the primary 1A (10.9 ppm)
and secondary 1B–C (10.8 ppm) amides in CDCl3, which sug-
gest a more effective intramolecular hydrogen bond for these
α-ketoamides in comparison to 1A–C. In addition, the presence
of a polar aprotic solvent such as DMSO seems to decrease the
deshielding effect over the NH-a in all the phenylglyoxamides
studied. This observation may be due to the hydrogen bonding
competition for acetamidic NH-a proton between DMSO and the
ketone carbonyl. The H-7 atom is shifted to a higher frequency
in 1D–G in relation to 1A–C. It seems that acetamidic NH-a in-
tramolecularhydrogenbondsandthedeshieldingdegreeoverH-7
are related, which reinforces conformation 1ꢁ as the preferential
one for these amides. However, the minor NH-a and H-7 deshield-
ing degree observed for 1A–C suggest that in these compounds
the1ꢁ conformationisnotsoeffectiveasin1D–Gandotherconfor-
mations may be contributing to these molecules. One reasonable
possibility is about intermolecular hydrogen bonding interactions,
which favor primary and secondary amides to form dimeric (or
higher) associations. Black et al. demonstrated the importance of
dimeric associations in several secondary phenylglyoxamides.[35]
Moreover, cooperative interactions involving primary and sec-
ondary amides have been reported as an important component of
intermolecular interactions, particularly those involving hydrogen
bonding.[41] However, thetertiaryamides1D–Gand2D–Garenot
expected to be associated as dimers in solution, due to high steric
hindrance and lack of NH hydrogen donor around the glyoxamide
and mandelamide moiety, respectively.[35] Thus, the H-a and H-7
chemical shifts observed for 1A–C may be due to a difference in
Table 2. Experimental 13C NMR chemical shifts (δ = ppm) for the ketonic CO and glyoxamidic CON of phenylglyoxamides (1A–G), and for
alcoholic COH and mandelamidic CON of mandelamides (2A–G) in CDCl3 and corresponding calculated chemical shifts using DFT–GIAO/B3LYP/6-
311++G∗∗//B3LYP/6-31G∗ level of theory
Ketonic
CO
CDCl3
Ketonic
CO
Glyoxamidic
CON
Glyoxamidic
CON
Alcoholic
COH
CDCl3
Alcoholic
COH
Mandelamidic
CON
Mandelamidic
CON
1
B3LYP/6-31G∗
CDCl3
B3LYP/6-31G∗
2
B3LYP/6-31G∗
CDCl3
B3LYP/6-31G∗
a
a
a
a
A
B
C
D
E
–
190.5
191.7
191.4
199.0
199.8
199.2
198.1
–
163.6
162.5
163.1
170.1
172.0
170.2
167.6
A
B
C
D
E
–
60.4
60.7
60.5
54.3
54.1
53.6
58.9
–
177.9
176.7
178.5
176.7
179.0
175.3
175.8
192.8
191.6
195.8
196.0
196.3
195.5
169.3
169.6
169.5
169.7
169.7
169.7
73.5
70.5
70.8
70.8
70.3
70.2
174.3
172.7
171.2
171.5
F
F
170.1
G
G
169.2–170.8
a Not soluble.
c
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B. T. Gonc¸alves et al.
c
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Anisotropic and hydrogen bonding in phenylglyoxamides and mandelamides
the extent of aggregation of these molecules, which might be in
equilibrium with the monomeric form in solution, as compared to
1D–G.
alkyl chains are magnetically nonequivalents, in the related
mandelamides 2D–G these anisotropic effects are extended to
the geminal hydrogens of the methylene directly bonded to
the amidic nitrogen. Magnetically nonequivalence of geminal
hydrogens was observed for esters of mandelic acid.[46] In
this case, the chirality of the benzylic carbon atom seems
to magnetically differentiate surrounding geminal hydrogens.
Although a similar differentiation should be occurring in the
mandelamides studied, the difference of the chemical shifts
(Table 3) of these geminal hydrogens (0.2–0.4 ppm to 2D–F
compared to <0.1 ppm to esters of mandelic acid) can be also
attributed to a structurally hindered conformation of 2D–G.
This fact is clearly observed in the respective Hαꢁ chemical
shifts, where in 1D–G they appear as two signals (2H each),
while in 2D–G mandelamides one of these signals is separated
into distinct multiple signals of 1H each. The nonequivalence
of geminal methylene protons of hindered N, N-substituted
amides was already described in literature.[47–50] However, they
described anisotropic effects in very simple models of amides
and, especially, in N-aryl amides with ortho-attached groups
in the benzene ring. Despite that, important insights involving
steric interferences, molecular asymmetry, and slow rotations
were reported. Therefore, peculiar conformational designs in
the mandelamides 2D–G must be implicated in a characteristic
magnetic resonance in the mandelamide moiety, since the
theoretical calculations furnished the minimal conformer 2ꢁ for the
tertiary mandelamides series (Fig. 2), and as this conformer shows
the oxygen carbonyl of the mandelamide side chain involved in
hydrogen bonding.
Conformation 2ꢁ adopts a rigid structural design with two fused
hydrogen bonding rings of six and five members (Fig. 2), which
restricts the conformational freedom of these mandelamides
in comparison to the related phenylglyoxamides. The higher
frequency chemical shifts of nonequivalents Hαꢁ1 and Hαꢁ2 in
comparison to lower frequency chemical shifts of equivalents Hα1
and Hα2 is an indication of a different deshielding degree in which
the geminal nonequivalence seems reasonable to occur as cis to
carbonyl. The conformer 2ꢁ for the tertiary mandelamides shows
Hαꢁ1 and Hαꢁ2 in distinct positions of magnetic susceptibility
of the mandelamide carbonyl group. According to Paulsen and
Todt,[48] Hαꢁ1 occupies position b of the model and must be more
With regard to the mandelamides 2A–G, there occurs an
inversion in the degree of deshielding over H-a. The primary
and secondary mandelamides 2A–C show NH-a chemical shift
at 9.6 ppm, while the tertiary ones range from 8.1–8.2 ppm in
CDCl3. These δ values are in lower frequency in comparison to
the respective phenylglyoxamides. The H-7 chemical shifts are
shifted to a lower frequency and it may be due to conformations
2ꢁ and 2ꢁꢁ, where the acetamidic carbonyl is out of the H-7
plane. In fact, the alcoholic hydroxyl group constitutes a further
site for intra- and intermolecular hydrogen bonds. Intermolecular
interactions in 2A–C seem to involve the acetamidic NH-a, which
may be associated in more effective hydrogen bonding than the
intramolecular hydrogen bonds proposed in conformations 2ꢁ and
2ꢁꢁ. It seems reasonable that in these cases the hydrogen bonds
are driving the acetamidic carbonyl to a position out of the plane
of H-7, and in this case this effect is more pronounced in the
secondary mandelamides. The polar aprotic DMSO-d6 and polar
protic CD3OD seem not to exert different effects in the solvation
of primary, secondary, and tertiary amides studied here, although
the H-7 phenylglyoxamide protons are slightly shifted to a higher
field in comparison to the mandelamide ones.
The calculated NH-a chemical shifts presented a good cor-
relation with NH-a experimental chemical shifts in CDCl3 and
especially with tertiary phenylglyoxamides whose deviation var-
ied from 0.3 to 0.4 ppm. The calculated H-7 protons showed
a higher frequency deviation from 0.5 to 0.8 ppm in com-
parison to experimental H-7 chemical shifts in CDCl3. The
experimental and calculated 13C NMR chemical shifts for ke-
tonic CO (phenylglyoxamides), COH (mandelamides) and the
amidic CON of the glyoxamide and mandelamide side chains
were performed to evaluate the deshielding effect over these
atoms. These data are expressed in Table 2, where we ob-
served a good correlation between the 13C NMR calculated
chemical shifts (DFT–GIAO/B3LYP/6-311++G∗∗//B3LYP/6-31G∗)
and experimental ones (CDCl3), for the ketonic and amidic sp2
carbons. Especially, the tertiary amides presented the best cor-
relation for the glyoxamidic CON moiety of 1D–G (average =
δtheoretical − δexperimental = 1.3 ppm) and for the mandelamide
CON of 2D–G (δtheoretical − δexperimental = 6.0 ppm). The alcoholic
sp3 COH chemical shifts of 2B–G presented a poor correlation
between the theoretical and experimental spectra, while the re-
lated phenylglyoxamides presented a good one for the respective
ketonic CO carbons.
Interesting anisotropic effects of diamagnetic susceptibility
of the carbonyl group were found for the alkyl chains of
the glyoxamides (1D–G) and mandelamides (2D–G). It is well
known that the high rotational barrier due to the partial
double-bond character of tertiary amides leads to the geometric
and magnetic nonequivalence of the nitrogen-attached groups
even when R1 = R2.[42] The first account of an experimental
approach describing anisotropic effects on amides was given by
Paulsen and Todt[43,44]; which described a model of shielding H
atoms out-of-plane and deshielding protons in-plane of carbonyl
amides. Since then, qualitative and quantitative evaluations
of the effects of anisotropy on amide chemical shifts were
published.[45] In the present work, an intriguing difference in
the anisotropic effects between the 1D–G and 2D–G amides
was found in the 1H spectra in CDCl3 (Table 3). While in the
tertiary phenylglyoxamides 1D–G the R1 and R2 (R1 = R2)
Figure 5. Model for the anisotropic effect of the mandelamide carbonyl
group over Hαꢁ1 and Hαꢁ2 of 2Eꢁ.
c
Magn. Reson. Chem. 2008; 46: 418–426
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B. T. Gonc¸alves et al.
shielded than Hαꢁ2, which occupies a position between c and
d. Although Hαꢁ2 is more distant of the mandelamide carbonyl
group, its occupation is nearer of the plane region and then more
deshielded (Fig. 5).
methylene protons of one side of the morpholine ring and thus
the signal at 3.7 ppm refers to the other two methylenes on the
other side of the morpholine ring (Fig. 6). The HMQC spectrum
of 1G reveals the coupling of the methylene protons at 3.7 ppm
with a higher frequency carbon at 66.7 ppm and with a lower
frequency one at 41.8 ppm. In fact, the 13C NMR spectra show
three distinct signals for the morpholine moiety at 41.8, 46.5, and
66.7 ppm, respectively. The signal at 66.7 ppm refers to the β car-
bons (–C–O–C–) of the morpholinic ring, while the signals at 41.8
and 46.5 ppm refer to the splitting of the α carbons (–C–N–C–)
of the same ring. The triplet at 3.3 ppm couples with the carbon at
During our study, we came across a surprising 1H NMR (CDCl3)
spectra for 1G. This spectra reveals, for the morpholine moiety,
a signal (similar to a ‘singlet’) at 3.7 ppm with integration of four
hydrogens and two triplets at 3.3 and 3.6 ppm with integration
1
of two hydrogens each. The H–1H COSY of 1G shows that the
lower frequency chemical shift protons at 3.3 and 3.6 ppm are
strongly coupled, which indicates that the two triplets are the
Figure 6. 1H–1H COSY spectrum of 1G in CDCl3.
Figure 7. The 1H–13C HMQC spectrum of 1G in CDCl3.
c
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Magn. Reson. Chem. 2008; 46: 418–426

Anisotropic and hydrogen bonding in phenylglyoxamides and mandelamides
consequence, four H atoms of two distinct methylenes in the same
4
side of the morpholine ring of 1G and 1H become magnetically
equivalents, this equivalence being disrupted in the MeOD and
DMSO-d6 polar media. Supplementary materials include synthetic
experimental conditions, spectral data and Cartesian coordinates
for calculated optimun geometries of compounds 1 and 2.
3
2
1
Conclusions
In summary, the present article reported interesting effects of
diamagnetic anisotropy susceptibility in phenylglyoxamides and
mandelamides. Such effects were evidenced in experimental
1H and 13C NMR and in some cases with good correlation
to DFT calculations. The systematic conformational evaluation
of 1 and 2, in a two-step methodology, using PM3 and DFT
(B3LYP/6-311++G∗∗//B3LYP/6-31G∗)calculations,providedagood
accomplishment and computational economy of time. The good
results obtained in the theoretical 1H (NH-a and H-7) and 13C NMR
chemical shifts for the tertiary α-ketoamides and mandelamides
suggest that this methodology may be an interesting tool
for predicting NMR spectra in similar systems. In addition, we
evidenced that in tertiary mandelamides, hydrogen bonding
seems to improve magnetic asymmetry in an amidic CONR1R2
methylene moiety.
Figure 8. Gradual increase of the concentration of DMSO-d6 in the 1H
NMR spectra of 1G in CDCl3. (1)100% CDCl3, (2) 30% DMSO-d6, (3) 60%
DMSO-d6, (4) 100% DMSO-d6.
46.5 ppm, and the triplet at 3.6 ppm couples with another one at
66.7 ppm. In summary, two isoelectronic carbons (at 66.7 ppm) are
coupled with two distinct methylene protons (3.6 and 3.7 ppm),
and two isoelectronic methylene protons (3.7 ppm) are coupled
with two distinct carbons (41.8 and 66.7 ppm) (Fig. 7). This peculiar
effect observed for 1G is quite atypical and not described, as far
as we know, for the morpholine moiety. This fact encouraged
us to evaluate other ortho groups in the aromatic ring of 1G.
Thus, we synthesized an analog of 1G with a p-chlorobenzamide
moiety replacing the acetamidic group (1H). The 1H NMR spectra
of 1H presents the same profile for the morpholine moiety, a
higher frequency signal (also similar a singlet) at 3.8 ppm (4H),
and two triplets at 3.7 ppm (2H) and 3.4 ppm (2H), respectively.
These data seem to reinforce that tertiary phenylglyoxamides
adopt a preferential conformation in CDCl3, while the oxygen in
the morpholine moiety seems to be responsible for this peculiar
effect, since it is not observed for 1F (piperidyl ring). In DMSO
and MeOD the signal at 3.7 ppm splits into two triplets, show-
ing that the polar media promotes direct effects in the chemical
shifts of these protons. In Fig. 8 we can see that the increase of
Supplementary material
Supplementary electronic material for this paper is available in
Wiley InterScience at http://www.interscience.wiley.com/
jpages/0749-1581/suppmat/
Acknowledgements
The authors wish to thanks CNPq, CAPES and FAPERJ for the
financial support for this work.
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Magn. Reson. Chem. 2008; 46: 418–426