Conformational preferences for some 2-substituted N-methoxy-N- methylacetamides through spectroscopic and theoretical studies

Article abstract of DOI:10.1016/j.molstruc.2010.05.021

The analysis of the IR carbonyl band of the 2-substituted N-methoxy-N-methylacetamides Y-CH₂C(O)N(OMe)Me (Y = F 1, OMe 2, OPh 3, Cl 4), supported by B3LYP/6-311++G(3df, 3pd) calculations along with the NBO analysis for 1-4, indicated the existence of cis-gauche conformers i.e. (c) and (g) for 1 and 3, (c₁, c₂) and (g₁, g ₂) for 2, and (c) and (g₁, g₂) for 4. In the gas phase, the g conformer population prevails over the c one, for 1 and 3, the (c₁ + c₂) population prevails over the (g₁ + g₂) one for 2, and the (g₁ + g₂) conformer population is more abundant than (c) one for 4. In n-hexane solution, the cis conformer is more abundant for 1-3. The occurrence of Fermi resonance in the ν_CO region, in n-hexane, precludes the estimative of relative populations of the (c, g₁, g₂) conformers for 4. The SCI-PCM calculations agree with the solvent effect on the ν_CO band component relative intensities for 1-3. NBO analysis showed that the n _N → π_co^* orbital interaction is the main factor which stabilizes the gauche (g, g₁, g₂) conformers for 1-4 into a larger extent relative to the cis (c, c₁, c₂) ones. The n_Y → π_co ^*, σ_C-Y → π_co^*, π_co → σ_C-Y^* and π_co^* → σ_C-Y^* orbital interactions still contribute, but into a minor extent for the stabilization of the gauche conformers relative to the cis ones. The existence of some pyramidalization at the nitrogen atom of the Weinreb amides 1-4 is responsible for the occurrence of Y^δ-(4)?O^δ-(9) and Y ^δ-(4)?N^δ-(7) short contacts in the gauche (g, g₁, g₂) conformers, which originates strong repulsive Coulombic interactions, acting in opposition to the large orbital stabilization of the gauche conformer with respect to the cis one. Therefore, a delicate balance of the Coulombic and orbital interactions seems to be responsible for the observed stabilization of the gauche (g, g₁, g₂) and cis (c, c₁, c₂) conformers, both in the gas phase and in the solution for 1-4. However, the cis conformer predominance, in non polar solvents, for the 2-substituted N-methoxy-N-methyl acetamides 1-3, bearing in α first raw (fluorine and oxygen) atoms, is in the opposite direction to the gauche conformer preference for the corresponding 2-substituted N,N-dialkyl-acetamides.

Full text of DOI:10.1016/j.molstruc.2010.05.021

Journal of Molecular Structure 977 (2010) 106–116
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Conformational preferences for some 2-substituted N-methoxy-N-methyl-
acetamides through spectroscopic and theoretical studies
a
a
b
Paulo R. Olivato a, , Roberto da Silva Gomes , Alessandro Rodrigues , Adriana K.C.A. Reis ,
*
Nelson L.C. Domingues c, Roberto Rittner d, Maurizio Dal Colle e
a Conformational Analysis and Electronic Interactions Laboratory, Institute of Chemistry, University of Sao Paulo, CP 26077, 05513-970 Sao Paulo, SP, Brazil
b Universidade Federal de São Paulo, UNIFESP, Diadema, SP, Brazil
c Faculdade de Ciências Exatas e Tecnologia, Universidade Federal da Grande Dourados, CP 533, 79.804-970 Dourados, MS, Brazil
d Physical Organic Chemistry Laboratory, Chemistry Institute, State University of Campinas, CP 6154, 13083-970 Campinas, SP, Brazil
e Dipartimento di Chimica, Università di Ferrara, Ferrara, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 April 2010
Received in revised form 12 May 2010
Accepted 13 May 2010
Available online 21 May 2010
The analysis of the IR carbonyl band of the 2-substituted N-methoxy-N-methylacetamides Y–CH2C(O)-
N(OMe)Me (Y = F 1, OMe 2, OPh 3, Cl 4), supported by B3LYP/6-311++G(3df, 3pd) calculations along with
the NBO analysis for 1–4, indicated the existence of cis–gauche conformers i.e. (c) and (g) for 1 and 3, (c1,
c2) and (g1, g2) for 2, and (c) and (g1, g2) for 4. In the gas phase, the g conformer population prevails over
the c one, for 1 and 3, the (c1 + c2) population prevails over the (g1 + g2) one for 2, and the (g1 + g2) con-
former population is more abundant than (c) one for 4. In n-hexane solution, the cis conformer is more
abundant for 1–3. The occurrence of Fermi resonance in the mCO region, in n-hexane, precludes the esti-
mative of relative populations of the (c, g1, g2) conformers for 4. The SCI-PCM calculations agree with the
solvent effect on the mCO band component relative intensities for 1–3. NBO analysis showed that the
Dedicated to Prof. Giuseppe Distefano for
his outstanding contribution in Theoretical
Physical Organic Chemistry
nN
into a larger extent relative to the cis (c, c1, c2) ones. The nY
rꢀCAY orbital interactions still contribute, but into a minor extent for the stabilization of the gauche
?
pꢀco orbital interaction is the main factor which stabilizes the gauche (g, g1, g2) conformers for 1–4
rꢀCAY and
Keywords:
?
pꢀco pꢀco
, rCAY ? , pco ?
Conformational analysis
Infrared spectroscopy
Theoretical calculations
2-Substituted N-methoxy-N-methyl
acetamides
pꢀco
?
conformers relative to the cis ones. The existence of some pyramidalization at the nitrogen atom of the
Weinreb amides 1–4 is responsible for the occurrence of Ydꢁ(4)ꢂꢂꢂOdꢁ(9) and Ydꢁ(4)ꢂꢂꢂNdꢁ(7) short contacts
in the gauche (g, g1, g2) conformers, which originates strong repulsive Coulombic interactions, acting in
opposition to the large orbital stabilization of the gauche conformer with respect to the cis one. Therefore,
a delicate balance of the Coulombic and orbital interactions seems to be responsible for the observed sta-
bilization of the gauche (g, g1, g2) and cis (c, c1, c2) conformers, both in the gas phase and in the solution for
1–4. However, the cis conformer predominance, in non polar solvents, for the 2-substituted N-methoxy-
N-methyl acetamides 1–3, bearing in
a first raw (fluorine and oxygen) atoms, is in the opposite direction
to the gauche conformer preference for the corresponding 2-substituted N,N-dialkyl-acetamides.
Ó 2010 Elsevier B.V. All rights reserved.
1. Introduction
bilization of gauche conformer of the 2-heterosubstituted N,N-dial-
kylacetamides compounds has been ascribed to the increasing
Previous infrared and theoretical studies of some 2-heterosub-
stituted N,N-dialkylacetamides [1–3] Y–CH2C(O)NR2 (R = Et, Me;
Y = F, OMe, NR2, Cl, Br, SEt and I) have shown that in the gas phase
and in solvent of low relative permittivity (CCl4) they prefer the
gauche conformation. However, going from fluorine to iodine sub-
stituent, the cis/gauche population ratio decreases progressively in
this direction, being the gauche conformer practically the only one
present for the iodine and bromine derivatives. The increasing sta-
contribution of the nX/pꢀco pcꢀo and pcꢀo rCꢀAX orbital
, rCAX/ /
interactions.
A comparison between the energies of some relevant orbitals
(computed at HF/6-31G(d,p) level) of N,N-diethylacetamide (a)
with those of the N-methoxy-N-methylacetamide (b) was per-
formed in our previous paper [4]. In the amide (b), containing
the electron attracting methoxy group bonded to the nitrogen
atom, the ionization energy of the nitrogen lone pair nN is in-
creased by 0.64 eV with respect to amide (a) and, simultaneously
the electron affinity of the pꢀco orbital increases in the same direc-
tion by 0.45 eV. The increased ionization energy of the nN lone pair
of (b) in relation to (a) is responsible for both the smaller nN/pcꢀo
* Corresponding author. Address: Instituto de Química, Universidade de São
Paulo-USP, Av. Prof. Lineu Prestes, 748, Caixa Postal 26077, 05513-970 São Paulo,
SP, Brazil. Tel.: +55 11 3091 2167; fax: +55 11 3815 5579.
E-mail address: prolivat@iq.usp.br (P.R. Olivato).
0022-2860/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2010.05.021

P.R. Olivato et al. / Journal of Molecular Structure 977 (2010) 106–116
107
interaction (O@CAN M ꢁOAC@N+ conjugation), which in turn orig-
inates some pyramidalization of the nitrogen atom in the
MeOAN(Me)AC(O) fragment for (b). Additionally, the higher elec-
tron affinity of the pꢀco orbital in the N-methoxy-N-methylamide
must also occur in the gauche conformer of the 2-heterosubstituted
N-methoxy-N-methyl-acetamides in comparison to the corre-
sponding gauche conformer of the 2-heterosubstituted N,N-diethy-
the nature of the 2-heteroatom, which in turn should influence
the stabilization of the referred conformers.
2. Experimental
2.1. Materials
lacetamides. This should originate strong nX/pꢀco and rCAX
orbital interactions for the 2-heterosubstituted N-methoxy-N-
methylacetamides, which leads to an increase of nX/pꢀco and rCAX
/
pꢀco
All solvents for IR measurements were spectrograde and were
used without further purification. The 2-substituted-N-methoxy-
N-methyl-acetamides [X-CH2C(O)N(OCH3)(CH3)] (X = F 1 [7], OMe
2 [8], OPh 3 [9], Cl 4 [10]) have already been described in the liter-
ature and were prepared as follows. Initially the 2-substituted ace-
tic acids were converted to the corresponding acyl chlorides
through their reaction with thionyl chloride. The 2-substituted-
N-methoxy-N-methylacetamides were obtained by the reaction
of the acyl chlorides with N,O-dimethylhydroxylamine hydrochlo-
ride in the presence of triethylamine, using dichloromethane as the
solvent. These compounds were obtained in 86–93% yield [11].
/
pꢀco orbital interactions and, thus, into a larger stabilization of the
gauche conformer relative to the cis one, in comparison to the
smaller stabilization of the gauche conformer relative to the cis
one for the 2-heterosubstituted N,N-diethylacetamides. Our recent
study on the N-methoxy-N-methyl-2-(40-substituted) phenylthio
propanamides [5] is in line with these predictions as only two
gauche conformers are present in the gas phase and in solution,
being stabilized by the rCAX/
pꢀco orbital interaction (ca.
6 kcal molꢁ1) into a larger extent than the corresponding interac-
tion (ca. 4 kcal molꢁ1) in the N,N-diethyl-2-(40-substituted)phenyl-
thio acetamides [6].
2.2. IR measurements
Therefore it became of interest to extend the study of 2-thio-
substituted N-methoxy-N-methyl-amides to the 2-substituted N-
methoxy-N-methyl-acetamides bearing as substituents F 1, OMe
2, OPh 3 and Cl 4 (Scheme 1), by means of IR spectra along with
density functional theory (DFT) and NBO calculations. These com-
pounds were selected taking into account that the orbital and elec-
trostatic interactions which could act to stabilize their cis and
gauche conformers, might be affected significantly by changing
The IR spectra were recorded with a FT-IR Nicolet Magna 550
spectrometer, with 1.0 cmꢁ1 resolution, at a concentration of
1.0 ꢃ 10ꢁ2 mol dmꢁ3 in n-hexane, carbon tetrachloride, chloroform,
dichloromethane and acetonitrile solutions, using a 0.519 mm so-
dium chloride cell, for the fundamental carbonyl region (1800–
1600 cmꢁ1). The spectra for the carbonyl first overtone region
(3600–3100 cmꢁ1) were recorded in carbon tetrachloride solution
(1.0 ꢃ 10ꢁ2 mol dmꢁ3), using a 1.00 cm quartz cell. The overlapped
O1
C 2
H12
23 H
O1
C 2
H12
18
H
11
10
11
10
H
H
H
H
4
4
Y
8 C
24 H
Y
8 C
17
3
17
3
18
21
C
C
7 N
O9
C
7 N
O9
19
19H
Y = O
20
22
H6
H6
H16
H15
H16
H15
H
H
H
5
5
20
13C
H
13C
H27
25
14
14
H
H26
H
O1
C 2
H12
5H
11
H
8 C
6H
10
C
7 N
O9
H
3
Y = F, Cl
H16
H15
4 Y
13
C
14H
O(1)-C(2)-C(3)-Y(4)
C(2)-C(3)-Y(4)-C(17)
α =
β =
γ =
δ =
δ’=
δ”=
C(3)- Y(4)-C(17)-C(18)
O(1)-C(2)-N(7)-C(8)
O(1)-C(2)-N(7)-O(9)
C(2)-N(7)-O(9)-C(13)
Scheme 1.

108
P.R. Olivato et al. / Journal of Molecular Structure 977 (2010) 106–116
carbonyl bands (fundamental and first overtone) were deconvo-
luted by means of the Grams/32 curve fitting program, version
4.04, Level II [12]. The populations of the cis and gauche conformers
were estimated from the maximum of each component of the re-
solved carbonyl doublet or triplet, expressed in percentage of
absorbance, assuming equal molar absorptivity coefficients for
the referred conformers.
components in the first overtone region, in carbon tetrachloride,
at frequencies twice those of the fundamental unless ca. 18 cmꢁ1
(which corresponds two times the mechanical anharmonicity
(veme) of the carbonyl oscillator [19]), and with practically the
same intensity ratios, strongly suggest that compounds 1–3 pres-
ent, in solution, two stable conformers [20–21]. The solvent effect
on the carbonyl band components for 2, taken as prototype of com-
pounds 1–3 [22] is illustrated in Fig. 1.
For compound 4 a carbonyl doublet is observed in n-hexane
(Table 1 and Fig. 2), being the higher frequency component of low-
er intensity. However, going to solvents of increasing polarity a
triplet is observed i.e. a new carbonyl band component appears
at the lower frequency region. Moreover as the solvent polarity in-
creases an abnormal behaviour is observed on the relative intensi-
ties of the carbonyl triplet component. In the first overtone region,
in carbon tetrachloride, a carbonyl triplet is also observed and the
relative intensities of the middle and lower frequency components
show opposite values relative to the corresponding components in
the fundamental region, except the higher frequency component
for which close relative intensities values are found in both first
overtone and fundamental regions. Furthermore, twice the fre-
quency of the middle and low carbonyl triplet components in the
fundamental region differs from those found in the first overtone
region by 8 and 1 cmꢁ1, respectively, which in turn is significantly
smaller than twice the expected mechanical anharmonicity of ca.
18 cmꢁ1 found in compounds 1–3. Therefore, it seems reasonable
to invoke that some combination band or first overtone of low ly-
ing vibrational modes of the low symmetry cis (c) or gauche (g1, g2)
conformers (Point Group C1 [19]) of 4 having frequency close to
2.3. Theoretical calculations
All calculations for 2-substituted N-methoxy-N-methyl-aceta-
mides 1–4 were carried out (at 298 K) using methods and basis sets
implemented in the Gaussian package of programs (G03.E01) [13].
The hybrid Hartree–Fock density functional B3LYP method [14]
with the 6-311++G(3df, 3pd) basis set was used [15]. Full geometry
optimizations and analytical vibrational frequency calculations
were performed on all the cis and gauche orientations of the a-het-
eroatom with respect to the carbonyl group resultant from a sys-
tematic conformational search, allowing complete relaxation of
all internal parameters. Frequency analyses were carried out to
verify the nature of the minimum state of all the stationary points
obtained and to calculate the zero-point vibrational energies
(ZPVE) corrections. To obtain an estimation of the solvation effects
on the relative stability of the most relevant minima, single-point
calculations were conducted on the optimized structures using a
SCRF model as implemented in the Gaussian 03. Specifically, the
Self-Consistent Isodensity PCM (SCI-PCM) model [16] was used
to describe the structures in n-heptane, carbon tetrachloride, chlo-
roform, dichloromethane and acetonitrile as solvents. The NBO 3.1
program [17] was used as implemented in the Gaussian 03 pack-
age, and the reported NBO delocalization energies (E2) are those
given by second-order perturbation theory.
that of the fundamental mCO mode, originates the Fermi resonance.
This effect precludes suggesting the number of the conformers
present in solution of the referred compound.
Aiming to determine the geometries for the stable conforma-
tions of series 1–4, computations at the B3LYP/6-311++G(3df,
3pd) level of theory for the 2-substituted-N-methoxy-N-methylac-
etamides were performed. Table 2 shows the relevant data for
compounds 1–4. The results from theoretical calculations for 1
and 3 derivatives, indicate the existence of two stable cis (c) and
gauche (g) conformations, the former being the slightly less stable
and the more polar one. It should be pointed out that this trend is
in the opposite direction relative to that found in n-hexane solu-
tion. In fact, the estimated IR populations for the cis (c) and gauche
(g) conformers for 1 and 3 derivatives are of ca. 65% and 35%,
respectively. Additionally, the computed carbonyl frequencies for
the c and g conformers match well the experimental values, in n-
hexane (Table 1). Actually, the carbonyl frequencies of the less
abundant c conformers (1725 and 1714 cmꢁ1) and of g conformers
(1688 and 1683 cmꢁ1), in the gas phase for 1 and 3, respectively,
correspond to the higher and lower doublet carbonyl frequency
3. Results and discussion
Table 1 collects the stretching frequencies and the absorbance
percentage of the analytically resolved carbonyl band for the 2-
substituted N-methoxy-N-methylacetamides (1–4) in solvents of
increasing relative permittivity [18] i.e. n-hexane (
tetrachloride = 2.2), chloroform = 4.8), dichloromethane
= 9.1) and acetonitrile ( = 38). A doublet is shown for com-
e = 1.9), carbon
(e
(e
(e
e
pounds 1–3 in all solvents, being the higher frequency component
the more intense one, whose intensity increases with the respect to
that of the lower frequency component, as the solvent polarity in-
creases. The intensity of the lower doublet frequency component
for compounds 1 and 2 almost vanishes, while it disappears for
3, in the most polar solvent acetonitrile. These noticed solvent ef-
fects on the carbonyl band components for compounds 1–3 (Ta-
ble 1), along with the existence of two carbonyl band
Table 1
Frequencies (
m
, cmꢁ1) and intensities of the carbonyl stretching bands in the IR spectra of 2-substituted-N-methoxy-N-methylacetamides, YCH2C(O)N[OMe][Me] 1–4.
Comp.
Y
n-C6H14
CCl4
CHCl3
CH2Cl2
CH3CN
m
Pa
m
P
mb
P
m
P
m
P
m
P
1
2
3
4
F
1725
1694
69.0
31.0
1713
1682
69.0
31.0
3405
3344
73.3
26.7
1691
1674
69.9
30.1
1694
1673
80.2
19.8
1694
1670
94.0
6.0
OMe
OPh
Cl
1708
1686
71.3
28.7
1696
1670
71.1
28.9
3373
3327
69.7
30.3
1678
1653
88.2
11.8
1681
1657
89.6
10.4
1682
1660
91.6
8.4
1718
1683
59.7
40.3
1704
1675
60.9
39.1
3389
3334
62.9
37.1
1684
1656
88.0
22.0
1687
1663
90.4
9.6
1687
–
100
–
1717
1694
–
26.0
74.0
–
1707
1687
1671
28.5
53.0
18.5
3391
3366
3341
20.9
22.4
56.7
1702
1681
1660
6.2
59.2
34.6
1701
1683
1665
15.8
49.7
34.5
1704
1684
1666
7.6
66.8
25.6
a
Intensity of each component of the carbonyl doublet, expressed in percentage of absorbance.
First overtone.
b

P.R. Olivato et al. / Journal of Molecular Structure 977 (2010) 106–116
109
.45
.4
.025
(b)
(a)
(c)
.2
.35
.3
.02
.15
.25
.2
.015
.1
.15
.1
.01
.05
.05
0
.005
0
1740
1720
1700
1680
1660
1640
3420 3400 3380 3360 3340 3320 3300 3280
Wavenumber (cm-1)
1740 1720 1700 1680 1660 1640 1620
Wavenumber (cm-1)
Wavenumber (cm-1)
.5
.4
.3
.2
.1
0
.35
.4
.3
.25
(d)
(e)
(f)
.3
.2
.2
.1
0
.15
.1
.05
0
1720 1710 1700 1690 1680 1670 1660 1650 1640
Wavenumber (cm-1)
1740 1720 1700 1680 1660 1640 1620
Wavenumber (cm-1)
1730 1720 1710 1700 1690 1680 1670 1660 1650 1640 1630
Wavenumber (cm-1)
Fig. 1. IR spectra of N-methoxy-N-methyl-2-methoxyacetamide (2) showing the carbonyl stretching band, in n-hexane (a), carbon tetrachloride [fundamental (b) and first
overtone (c)], chloroform (d), dichloromethane (e) and acetonitrile (f).
components, respectively, in n-hexane solution for these com-
pounds (Table 1).
the solvation effects on the relative stability of the obtained cis
and gauche minimum energies in the gas phase conformations,
for compounds 1–4. Table 3 presents the computed SCI-PCM rela-
tive c and g conformer populations in n-heptane, carbon tetrachlo-
ride, chloroform, dichloromethane and acetonitrile solvents.
It is worth of noting that a good agreement has been found be-
tween the computed c and g or (c1 + c2) and (g1 + g2) conformer
populations for compounds 1 and 3, and for compound 2, respec-
tively, with the corresponding IR experimental values for each sol-
vent (Table 1). In fact, there is a progressive increase population of
the more polar (c or c1 and c2) cis conformers with respect to the
less polar (g or g1 and g2) gauche conformers for compounds 1–3,
whose population values are very close to those found for the same
solvent in solution (Table 1). As for compound 4 there is a progres-
sive increase of the population of the more polar c conformer with
the simultaneous decrease of the intensity of the less polar g1 con-
former, while the population of the g2 conformer, which is slightly
more polar than g1, remains practically constant going from n-hex-
ane to acetonitrile. Additionally, except in carbon tetrachloride, for
which there is a matching between the computed and experimen-
tal populations of the c, g1 and g2 conformers, in the remaining sol-
vents a strong divergence is found between the computed and
experimental population of the referred conformers. This trend is
in line with the occurrence of the Fermi resonance in the carbonyl
band fundamental region in solution.
For compound 2, two pairs of cis (c1, c2) and gauche (g1, g2) con-
formers were found, in the gas phase, being the former pair the
more stable and more polar ones. Moreover, each pair of conform-
ers presents almost degenerated computed carbonyl frequencies,
whose values are ca. 1705 cmꢁ1 for (c1, c2) conformers and ca.
1684 cmꢁ1 for (g1, g2) conformers, which are in good agreement
to the higher (1708 cmꢁ1) and lower (1686 cmꢁ1) doublet carbonyl
frequencies in n-hexane solution (Table 1). Besides the summing
up of the computed c1 and c2 and g1 and g2 conformer population
which are of ca. 68% and 32%, respectively, matches well the esti-
mated IR populations for the doublet carbonyl frequency compo-
nents, in n-hexane, whose values are of ca. 71% and 29%,
respectively.
Theoretical calculations for compound 4 indicate the existence
of one cis (c) and two gauche (g1, g2) conformers, being the g1 the
most stable and least polar conformer, while the second stable c
conformer is the most polar one. As stated above, the occurrence
of Fermi resonance on the fundamental mCO stretching mode of 4
in solution, precludes practically any comparison between the
computed populations of the three (c, g1, g2) conformers with the
IR relative intensities of the doublet or triplet carbonyl band com-
ponents found in solution (Tables 1 and 2, Fig. 2).
The lack of matching between the theoretical (gas phase) pop-
ulation values for the cis (c) and gauche (g) conformers with the
estimated IR relative populations in n-hexane solution for com-
pounds 1 and 3 prompted us to perform single point Self-Consis-
tent Isodensity PCM (SCI-PCM) calculations in order to estimate
Table 2 shows that for compound 1 the slightly more stable
(Erel. = 0 kJ molꢁ1
;
l
= 2.84D) g conformer displays the fluorine
= +129.4°) substituent in an anti-clinal or gauche geometry with
respect to the carbonyl group. For the slightly less stable
(a

110
P.R. Olivato et al. / Journal of Molecular Structure 977 (2010) 106–116
.04
.25
.2
(a)
.2
(c)
(b)
.035
.15
.15
.1
.03
.1
.025
.05
.05
0
.
.02
0
3420
3400
3380
3360
3340
)
3320
3300
1740
1720
1700
1680
1660
)
1640
1740
1720
1700
1680
1660
1640
1620
Wavenumber (cm-1
Wavenumber (cm-1
)
Wavenumber (cm-1
.2
.2
.2
(d)
(e)
(f)
.15
.1
.15
.15
.1
.1
.05
0
.05
.05
0
0
1720
1700
1680
1660
1640
1620
1740
1720
1700
1680
1660
1640
1740
1720
1700
1680
1660
)
1640
1620
Wavenumber (cm-1
)
Wavenumber (cm-1
)
Wavenumber (cm-1
Fig. 2. IR spectra of N-methoxy-N-methyl-2-chloroacetamide (4) showing the carbonyl stretching band, in n-hexane (a), carbon tetrachloride [fundamental (b) and first
overtone (c)], chloroform (d), dichloromethane (e) and acetonitrile (f).
Table 2
Relative energy (kJ molꢁ1), dipole moments (
l
, D), selected dihedral angles (°), carbonyl frequencies (
m
, cmꢁ1) for the minimum energy conformations of 2-substituted-N-
methoxy-N-methylacetamides YCH2C(O)N[OMe][Me] 1–4, at the B3LYP/6–311++G(3df, 3pd).
Comp.
Y
Conf.a
Eb
P (%)c
l
mCO
Dihedral anglesd
a
b
c
d
d0
d00
1
2
F
c
g
0.37
0.0
46.3
53.7
5.25
2.84
1725e
1688
1706e
1704
1680
1687
1714f
1683
1725g
1693
1699
7.3
129.4
–
–
–
–
21.9
13.4
164.4
159.3
120.3
119.0
OMe
c1
c2
g1
g2
0.0
35.5
33.5
15.8
15.2
4.21
3.69
2.58
3.37
3.3
9.5
113.8
120.8
74.2
–77.9
ꢁ70.5
–
–
–
–
21.1
20.9
15.2
14.3
163.7
164.8
162.2
161.2
119.4
118.1
115.2
117.3
0.14
2.00
2.07
ꢁ178.6
ꢁ177.3
ꢁ179.2
–
–
–
3
4
OPh
Cl
c
g
0.98
0.0
40.2
59.8
4.5
3.1
9.5
118.8
180.0
178.0
21.5
14.2
163.8
161.5
120.2
118.9
c
g1
g2
2.21
0.0
3.02
24
58.7
17.3
5.14
3.43
4.31
9.5
105.7
ꢁ94.9
–
–
–
20.8
15.5
19.7
163.4
164.3
166.8
120.0
120.9
116.7
a
b
c
d
e
f
C and g means cis and gauche conformers, respectively.
Relative energy.
Molar fraction in percentage.
See Scheme 1.
Scaling factor: 0.972.
Scaling factor: 0.967.
g
Scaling factor: 0.975.

P.R. Olivato et al. / Journal of Molecular Structure 977 (2010) 106–116
111
Table 3
Single point SCI-PCM solvent effect on the minimum energy gas phase conformations of 2-substituted-N-methoxy-N-methylacetamides YCH2C(O)N[OMe][Me] 1–4 at the B3LYP/
6-311++G(3df, 3pd) level.
Comp.
Y
F
Conf.a
Gas phase
n-C7H16
CCl4
CHCl3
CH2Cl2
CH3CN
1
c
g
43.9b/1725c,d/5.25g
56.1/1688/2.85
67.7b
32.3
72.8b
27.2
88.2b
11.8
92.5b
7.5
95.5b
4.5
2
OMe
c1
c2
g1
g2
35.5/1706d/4.21
33.5/1704/3.69
15.8 1680/2.59
15.2 1687/3.38
37.8
34.5
14.9
12.6
39.2
35.1
13.6
12.0
45.2
37.0
9.0
48.0
37.2
7.4
49.3
39.5
5.6
8.8
7.3
5.5
3
4
OPh
Cl
c
g
40.2/1714e/4.50
59.8/1683/3.11
24.0/1725f/5.15
58.7/1693/3.43
17.3/1699/4.31
43.4
48.6
63.8
27.7
71.0
20.7
71.0
20.7
77.4
14.5
c
g1
g2
26.4
51.4
21.7
29.1
47.8
22.5
39.5
33.6
26.0
46.5
27.3
25.3
52.7
20.6
25.8
a
b
c
d
e
f
C and g mean cis and gauche conformers, respectively.
Molar fraction in percentage.
Carbonyl stretching frequency (cmꢁ1).
Scaling factor: 0.972 (see Table 1).
Scaling factor: 0967 (see Table 1).
Scaling factor: 0.975 (see Table 1).
Dipole moment (Debye).
g
(Erel. = 0.37 kJ molꢁ1
substituent presents a syn-periplanar or cis geometry relative to the
;
l
= 5.25D) c conformer the fluorine (
a
= +7.3°)
3.37D) g2 conformers the methoxy oxygen (
a
ffi +117°) substituent
is in a anti-clinal or gauche geometry with respect to the carbonyl
group. Additionally, the b dihedral angle for the c1, c2 and g1 con-
formers is of ca. 74° while the same dihedral angle for g1 conformer
is of ca. 121° (Fig. 3b).
carbonyl group (Fig. 3a).
Compound
= 4.21D) c1 and (Erel. = 0.14 kJ molꢁ1; 3.69D) c2 conformers, which
present the methoxy oxygen (
ffi +5°) substituent in a syn-peripla-
nar or cis geometry relative to the carbonyl group. For the less sta-
ble (Erel. = 2.00 kJ molꢁ1 = 2.58D) g1 and (Erel. = 2.70 kJ molꢁ1
2 ;
shows two more stable (Erel. = 0 kJ molꢁ1
l
a
Similarly to 1, compound
(Erel. = 0 kJ molꢁ1
= 3.11D) g conformer which displays the phen-
oxy oxygen ( = +118.8°) substituent in an anti-clinal or gauche
3
presents
a
more stable
;
l
;
l
;
a
Fig. 3. Cis (c, c1, c2) and gauche (g, g1, g2) conformers for 1 (a), 2 (b), 3 (c) and 4 (d) obtained at B3LYP/6–311++G(3df,3pd) level.

112
P.R. Olivato et al. / Journal of Molecular Structure 977 (2010) 106–116
geometry with respect to the carbonyl group. For the less stable
(Erel. = 0.98 kJ molꢁ1
= 4.5D) c conformer the phenoxy oxygen
= +9.5°) substituent presents a syn-periplanar or cis geometry
relative to the carbonyl group. It should be pointed out that b
and
(
D
l mean value of ca. ꢁ0.76 Å), being responsible for the stabiliza-
tion of the gauche conformers through the rCAY
rꢀCAY, nS/
pcꢀo and pꢀco rCꢀAY orbital interactions (see below).
;
l
/ , pCO/
pꢀco
(a
/
As expected for the cis conformers, of the title compounds, there
is a very short intramolecular contact between the negatively
charged Ydꢁ(4)ꢂꢂꢂOdꢁ(1) atoms (see Table 5) with respect to the
sum of their van der Waals radii for compounds 1–4, whose dis-
c
dihedral angles which are of ca. ꢁ178° and ca. +180°, respec-
tively, keep the phenyl ring away from the carbonyl group for both
conformers (Fig. 3c).
Compound 4 shows a more stable (Erel. = 0 kJ molꢁ1
;
l
= 3.43D)
= +105.7°) substituent
in an anti-clinal or gauche geometry with respect to the carbonyl
group. The second stable (Erel. = 2.20 kJ molꢁ1
= 5.14D) is the c
conformer which displays the chlorine ( = 9.5°) substituent in a
tances are shorter than the
inates strong Repulsive Effect between the
d+@Odꢁ dipoles which destabilizes significantly the cis conformers
R
vdW radii by
D
l ffi -0.33 Å. This orig-
g1 conformer which displays the chlorine (
a
a
C
d+AYdꢁ and
C
;
l
relative to the gauche conformer in the series. It should be pointed
out that in 2-hetero-substituted amides there is an expressive in-
crease of the carbonyl oxygen negative charge due to the
[O@CAN M ꢁOAC@N+] conjugation in comparison to other classes
of carbonyl compounds. This originates a strong Cd+AYdꢁ and
a
syn-periplanar or cis geometry. The g2 conformer which is the least
stable (Erel. = 3.02 kJ molꢁ1; 4.31D) and slightly less polar than the c
conformer presents the chlorine (
si-anti-clinal or gauche geometry (Fig. 3d).
a
= ꢁ94.7°) substituent in a qua-
C
d+@Odꢁ repulsion which leads to a significant destabilization of
As expected for the N-methoxy-N-methyl amides 1–4 [4–5,23]
the d, d0 and d00 dihedral angles of the MeOAN(Me)AC@O moiety
are almost the same for the cis (c, c1, c2) and gauche (g, g1, g2) con-
formers, and the O@CANAOMe fragment (d0 ffi 163°) assumes an
anti geometry for all conformers. It is noteworthy that in the series
1–4 the summing up of the internal angles of the [MeO–N(Me)-
C@O] fragment which is ca. 350° for the cis (c, c1, c2) and gauche
(g, g1, g2) conformers indicates the occurrence of some pyramidal-
ization at the nitrogen atom as currently found in the Weinreb
amides [4–5,23].
the cis conformer with respect to the most stable gauche con-
former, both in the gas phase and in the solution of solvent of
low polarity [1–3]. It is worth of commenting that differently from
the 2-substituted amides, for which the RN(R)C@O fragment is pla-
nar, in the corresponding 2-substituted N-methoxy-N-methyl
acetamides (Weinreb amides), an unexpected behaviour occurs
in their gauche conformers due to some pyramidalization at the
amidic nitrogen atom. In fact, in the g, g1, g2 conformers of 2-
substituted N-methoxy-N-methyl acetamides 1–4 a close contact
between the negatively charged a-heteroatom and both negatively
Table 4 shows the CHELPG charges at the selected atoms at
B3LYP/6-311++G(3df, 3pd) level for compounds 1–4 and Table 5
displays the interatomic distances between some selected atoms
charged methoxy oxygen and nitrogen atoms in the MeO–
N(Me)C@O moiety takes place (see Fig. 3).
Table 5 also shows that for the gauche conformers of 1–4 the
Y(4)ꢂꢂꢂO(9) and Y(4)ꢂꢂꢂN(7) contacts are smaller or close to the
and the difference between these contacts (
Dl) and the sum of
the van der Waals radii ( vdW radii) for the same compound. The
R
RvdW radii, and as a consequence, a significant Coulombic repul-
geometries of the cis (c, c1 or c2) conformers for 1–4 compounds al-
sion between the Ydꢁ(4)ꢂꢂꢂOdꢁ(9) and Ydꢁ(4)ꢂꢂꢂNdꢁ(7) arises, which
act destabilizing the gauche conformers for the 2-substituted
methoxy-N-methyl acetamides 1–4.
lows the following short intramolecular contacts between the
oppositely charged Odꢁ(9)[OMe]ꢂꢂꢂHd+
(for both H(5) and H(6)
[aACH2]
atoms) and Odꢁ(1)[CO]ꢂꢂꢂHd+(12)[NMe], atoms whose distances are
Table 6 presents selected computed bond lengths and the corre-
sponding IR vibrational stretching frequencies along with the dif-
ference between bond lengths (Dl) and frequency (Dm) values for
shorter than the
R
vdW radii by
D
l ffi ꢁ0.14 Å and
D
l ffi ꢁ0.30 Å,
respectively. As for the gauche (g, g1 or g2) conformers of the title
compounds, the following short contacts between the oppositely
the cis and gauche conformers and it gives support to the above
short contact analysis. In fact, it may be seen that the strong Repul-
sive Effect between the Cd+AYdꢁ and Cd+@Odꢁ dipoles for the cis (c,
c1 and c2) conformers of 1–4 act decreasing the bond order, the
bond length and consequently increases the C@O and the CAY
stretching frequencies of the cis conformer with respect to the
charged
O
tances are shorter than the
O
dꢁ(9)[OMe]ꢂꢂꢂHd+(5)[
,
O
dꢁ(1)[CO]ꢂꢂꢂHd+(12)[NMe]
,
a
ACH2]
dꢁ(1)[CO]ꢂꢂꢂHd+(6)[
and Y(4)ꢂꢂꢂHd+(15)[OMe] atoms, whose dis-
a
ACH2]
RvdW radii by (Dl which varies from
ꢁ0.04 for 1 to ꢁ0.27 Å for 4), (
D
l ffi ꢁ0.30 Å), ( l ffi ꢁ0.25 Å) and
D
(D
l which varies from ca. ꢁ0.20 Å for 1–3, to ꢁ0.06 Å for 4), respec-
tively. These short contacts originate attractive electrostatic inter-
actions (hydrogen bond), which contribute for the stabilization of
the referred cis and gauche conformers into different extents. Addi-
tionally, the gauche (g, g1 or g2) conformers of 1–4 display very short
gauche one. Actually, the negative
D
l values (which vary from
values (which vary from
ꢁ0.007 Å to ꢁ0.025 Å) and the positive
Dm
+22.6 to +139 cmꢁ1) corroborate well this behaviour. Moreover, it
seems reasonable to suggest that the repulsive electrostatic inter-
action between Ydꢁ(4)ꢂꢂꢂOdꢁ(9) and Ydꢁ(4)ꢂꢂꢂNdꢁ(7) atoms, which
contacts between the a-heteroatom and the carbonyl carbon atom
Table 4
CHELPG charges (e) at selected atoms obtained at B3LYP/6-311++G(3df, 3pd) level for 2-substituted-N-methoxy-N-methylacetamides, YCH2C(O)N[OMe][Me] 1–4.
Comp
Y
F
Conf.a
O(1)
C(2)
C(19)
Y(4)
N(7)
O(9)
H(12)b
H(15)
H(24)
C(3)
0.141
1
c
g
ꢁ0.527
ꢁ0.558
0.621
0.577
–
–
ꢁ0.272
ꢁ0.232
ꢁ0.223
ꢁ0.088
ꢁ0.240
ꢁ0.245
0.057
0.108
0.061
0.043
–
–
0.097
2
OMe
c1
c2
g1
g2
ꢁ0.509
ꢁ0.505
ꢁ0.574
ꢁ0.563
0.603
0.581
0.595
0.595
–
–
–
–
ꢁ0.392
ꢁ0.429
ꢁ0.318
ꢁ0.315
ꢁ0.242
ꢁ0.195
ꢁ0.038
ꢁ0.089
ꢁ0.225
ꢁ0.243
ꢁ0.256
ꢁ0.247
0.048
0.050
0.112
0.102
0.049
0.061
0.039
0.025
–
–
–
–
0.070
0.114
0.039
0.002
3
4
OPh
Cl
c
g
ꢁ0.524
ꢁ0.565
ꢁ0.562
ꢁ0.563
ꢁ0.560
0.620
0.603
ꢁ0.276
ꢁ0.295
–
–
–
ꢁ0.479
ꢁ0.432
ꢁ0.131
ꢁ0.139
ꢁ0.118
ꢁ0.237
ꢁ0.091
ꢁ0.281
ꢁ0.144
ꢁ0.192
ꢁ0.232
ꢁ0.244
ꢁ0.216
ꢁ0.238
ꢁ0.223
0.051
0.099
0.051
0.036
0.141
0.141
0.244
0.152
c
g1
g2
0.825
0.674
0.721
0.072
0.081
0.065
0.052
0.044
0.034
–
–
–
ꢁ0.342
–0.205
ꢁ0.328
a
Refers to the cis and gauche conformers.
Refers to the hydrogen atom nearest to the carbonyl oxygen atom.
b

P.R. Olivato et al. / Journal of Molecular Structure 977 (2010) 106–116
113
operates in the gauche (g, g1 and g2) conformers of 1–4, should in-
creases the NAO and C@N bond order which in turn decreases their
bond lengths, and consequently, increases the mNAO and mC=N
stretching frequencies of the gauche conformers relative to the cis
(c, c1 and c2) ones. In fact, the positive
and C@N groups (varies from +0.006 Å to +0.012 Å) and the nega-
tive values for both NAO and C@N oscillators (varies from
Dl values for both NAO
D
m
ꢁ10.6 to ꢁ69.7 cmꢁ1) agree with the referred proposition.
This behaviour explains quite well the decreased population of
the gauche conformers with respect to the cis ones for the 2-substi-
tuted N-methoxy-N-methylacetamides 1–3, in both gas phase and
in the solution of low polarity solvents (see Tables 1–3). The fact
that the population of the gauche conformers (g1 and g2) largely
predominates for 4 may be ascribed to the occurrence of orbital
interactions which overcomes the repulsive electrostatic interac-
tions between the Yd-(4)ꢂꢂꢂOdꢁ(9) and Ydꢁ(4)ꢂꢂꢂNdꢁ(7) atoms (see
below).
3.1. Orbital interactions
In order to understand the nature of the orbital interactions
which act stabilizing the cis and gauche conformers for the title
compounds, the Natural Bond Orbital (NBO) analysis [17] was
performed.
Tables 7 and 8 present selected NBO interactions and the donor
and acceptor orbitals occupancies for cis (c, c1 and c2) and gauche
(g, g1 and g2) conformers and the NBO energies of some selected
orbitals are displayed in Table 9.
The most important orbital interactions is the nN
?
pꢀco, which
corresponds to the [O@CAN M ꢁOAC@N+] conjugation, with ener-
gies of ca. 25 kcal molꢁ1 for cis (c, c1 and c2) conformers and ca.
45 kcal molꢁ1 for gauche (g, g1 and g2) conformers
[
D
E ffi
20 kcal molꢁ1
; DE corresponds to the value of E(c) or the mean va-
lue of E(c1 and c2) minus the E(g) or the mean value of E(g1 and g2)].
It is noteworthy that the [O@CAN M ꢁOAC@N+] conjugation en-
ergy for both cis and gauche conformers for 2-heterosubstituted
N,N-dialkyl-amides [3,5] is of ca. 64 kcal molꢁ1 which is signifi-
cantly higher than the mean value conjugation energy for the cis
and gauche conformers by ca. 35 kcal molꢁ1. As pointed out above,
the nN
?
pꢀco interaction is stronger for N,N-diethyl acetamide com-
pared with the same interaction for the N-methoxy-N-methylace-
tamide by ca. 0.2 eV (see Introduction). Moreover the occurrence
of some pyramidalization at the nitrogen atom for the N-meth-
oxy-N-methylamides 1–4 seems to be responsible for the smaller
nN
to the same interaction in the N,N-dialkylamides.
The larger nN
pꢀco orbital interaction value for the gauche (g, g1
?
pꢀco overlap (conjugation) in these compounds with respect
?
and g2) conformers with respect to the same interaction for the cis
(c, c1 and c2) conformers may be ascribed in the gauche (g, g1 and
g2) conformers to the close contact between the negatively charged
a-heteroatom and both negatively charged methoxy oxygen and
nitrogen atoms. This leads not only to a repulsive electrostatic
interaction between Ydꢁ(4)ꢂꢂꢂOdꢁ(9) and Ydꢁ(4)ꢂꢂꢂNdꢁ(7) atoms, but
also to a decreasing of the ionization energies of the nN and nO(OMe)
lone pair orbitals in the gauche conformers with respect to the cis
conformers, whose values are of ca. 7 and 5 kcal molꢁ1, respec-
tively (Table 9). Simultaneously, Table 9 shows that there is a large
increase of the electron affinity of the pꢀco orbital for the gauche
conformers relative to the cis ones, whose energy values are of
ca. 20 and 72 kcal molꢁ1, respectively. Therefore, both effects justi-
fies that the nN
?
pꢀco interaction is of ca. 20 kcal molꢁ1 stronger for
the gauche (g, g1 and g2) conformers in comparison with the cis (c,
c1 and c2) conformers.
This explanation is supported by the smaller nN
?
pꢀco interac-
tion for the g2 conformer with respect to the g1 conformer of 4,
whose values are of ca. 37 and 53 kcal molꢁ1, respectively. In fact

114
P.R. Olivato et al. / Journal of Molecular Structure 977 (2010) 106–116
Table 6
Calculated selected bond lengths (Å) and corresponding stretching IR vibrational frequencies (m
, cmꢁ1) for YCH2C(O)N(OMe)Me 1–4 at the B3LYP/6-311++G(3df, 3pd) level.
Comp.
Y
la
mb
D
lc
D
md
D
lc
D
md
AꢁB/A=B
AꢁB/A=B
A–B/A=B
c1
c2
g1
g2
c1
c2
g1
g2
1
F
C@O
CAF
NAO
C@N
1.209
1.374
1.408
1.379
–
–
–
–
1.217
1.391
1.401
1.369
–
–
–
–
1774.6
1137.7
1194.2
1348.4
–
–
–
–
1737.2
1053.0
1209
–
–
–
–
ꢁ0.008
ꢁ0.017
+0.007
+0.010
37.4
84.0
–
–
–
–
–
–
–
–
ꢁ15.0
1413.5
ꢁ65.1
2
3
4
OMe
OPh
Cl
C@O
1.213
1.396
1.407
1.381
1.213
1.397
1.406
1.380
1.219
1.415
1.401
1.373
1.217
1.413
1.400
1.371
1755.4
1165.3
1194.7
1343.3
1753.2
1166.5
1194.5
1344.7
1728.1
1158.9
1206.3
1403.7
1735.2
1134.8
1207.2
1416.3
ꢁ0.006f
ꢁ0.008f
0.006f
22.6g
19.1g
–
–
–
–
–
–
–
–
CAOAMee
NAO
ꢁ12.0g
C@N
0.009f
ꢁ28.0g
C@O
1.209
1.404
1.407
1.382
–
–
–
–
1.217
1.420
1.401
1.370
–
–
–
–
1772.8
1088.1
1194.3
1347.2
–
–
–
–
1739.4
1067.6
1204.9
1416.9
–
–
–
–
ꢁ0.009
ꢁ0.016
0.006
33.4
20.5
–
–
–
–
–
–
–
–
CAOAPhe
NAO
ꢁ10.6
C@N
0.012
ꢁ69.7
C@O
CACl
NAO
C@N
1.209
1.780
1.407
1.381
–
–
–
–
1.216
1.805
1.400
1.371
1.215
1.801
1.401
1.373
1768.6
790.2
1193.5
1380.7
–
–
–
–
1735.9
651.2
1217.9
1408.9
1742.8
651.7
1214.8
1402.9
ꢁ0.007h
ꢁ0.025h
0.007h
32.7i
139.0i
ꢁ24.4i
ꢁ28.2i
ꢁ0.006h
ꢁ0.021h
0.006h
25.8i
138.5i
ꢁ21.3i
ꢁ22.2i
0.010h
0.008h
a
b
c
d
e
f
Interatomic distance.
Stretching frequency.
Refers to the difference between the bond length values for the cis and gauche conformers.
Refers to the difference between the stretching frequency values for the cis and gauche conformers.
Refers to he asymmetric mCAOAC stretching vibration.
Refers to the difference between the mean bond length values for the cis (c1 and c2) and gauche (g1 and g2) conformers.
Refers to the difference between the mean stretching frequency values for the cis (c1 and c2) and gauche (g1 and g2) conformers.
Refers to the difference between the cis (c) and gauche (g1 and g2) bond lengths, respectively.
g
h
i
Refers to the difference between cis (c) and gauche (g1 and g2) stretching frequencies, respectively.
Table 7
Comparison of significant NBO interactions (kcal molꢁ1) of the corresponding interacting orbitals for the cis (c) and gauche (g) conformers of YCH2C(O)N(OMe)Me 1–4 at the
B3LYP/6-311++G(3df, 3pd) level.
Orbitals
Fluorine (1)
Methoxy (2)
Phenoxy (3)
Chloro (4)
c
g
c1
c2
g1
g2
c
g
c
g1
g2
LPN7
LPO1
LPO1
LPY4
LPY4
LPY4
LPO9
LPY4
?
?
?
?
?
?
?
?
pꢀC2@O1
rꢀC2AN7
rꢀC2AC3
rꢀC2AC3
rꢀC3AH6
rꢀC3AH5
rꢀC3AH6
pꢀC2@O1
24.0
26.4
22.5
7.0
48.0
25.4
20.4
6.2
3.5
6.1
0.5
0.5
1.2
0.5
23.7
25.9
20.9
9.0
2.8
5.4
–
–
–
–
–
21.3
25.7
20.7
9.3
2.1
2.7
–
–
–
–
–
41.5
25.6
19.6
7.8
4.6
2.5
0.6
0.8
1.2
1.9
41.6
25.4
19.4
1.9
6.6
6.5
0.6
–
23.4
26.3
22.0
2.5
6.1
6.5
–
–
–
–
–
43.6
25.5
19.7
2.3
5.6
5.9
0.6
–
0.5
2.0
1.7
29.2
27.0
26.9
22.3
5.5
53.3
25.7
20.0
4.1
2.5
3.8
0.6
1.2
2.4
2.6
37
26.1
20.3
4.1
3.4
3.2
0.7
1.3
4.0
2.7
16.4
6.1
4.0
4.9
3.4
a
a
–
–
–
–
–
–
–
–
–
–
rC3AY4
pC2@O1
pꢀC2@O1
?
?
?
pꢀC2@O1
1.4
1.8
1.5
rꢀC3AY4
rꢀC3AY4
2.0
2.0
5.9
LPY4
?
pꢀC17AC18½PhŠ
30.2
a
Interaction energy smaller than 0.5 kcal molꢁ1
.
Table 8
NBO occupancy of selected orbitals calculated at the B3LYP/6-311++G(3df, 3pd) level for the cis and gauche conformers of 2-substituted N-methoxy-N-methylacetamides Y–
CH2C(O)N[OMe][Me] 1–4.
Orbital
Occupancy
F (1)
OMe (2)
OPh (3)
Cl (4)
ca
ga
c1
c2
g1
g2
c
g
ca
g1
g2
a
a
LPN7
LPO9
LPO1
1.754
1.939
1.848
1.970
0.207
–
1.724
1.942
1.865
1.968
1.983
–
1.752
1.940
1.854
1.915
0.207
–
1.749
1.940
1.854
1.916
0.198
–
1.723
1.943
1.868
1.918
0.258
–
1.724
1.942
1.867
1.924
0.258
–
1.755
1.940
1.849
1.844
0.204
0.387
1.723
1.943
1.865
1.851
0.262
0.390
1.751
1.938
1.851
1.966
0.217
–
1.721
1.943
1.861
1.969
0.286
–
1.726
1.940
1.859
1.967
0.254
–
LPY4
pꢀC2@O1
pꢀC17@
C18ðPhÞ
a
c and g refer to the cis and gauche conformations, respectively.

P.R. Olivato et al. / Journal of Molecular Structure 977 (2010) 106–116
115
Table 9
NBO energies (kcal molꢁ1
) of selected orbitals calculated at the B3LYP/6-311++G(3df, 3pd) level for the cis and gauche conformers of 2-substituted N-methoxy-N-
methylacetamides Y–CH2C(O)N[OMe][Me] 1–4.
Orbital
Energy
F (1)
ca
OMe (2)
OPh (3)
Cl (4)
ga
c1
c2
g1
g2
c
g
c
g1
g2
LPN7
LPO9
LPO1
LPY4
ꢁ198.9
ꢁ217.6
ꢁ163.6
ꢁ252.5
86.9
ꢁ192.3
ꢁ212.5
ꢁ166.6
ꢁ260.0
9.4
ꢁ193.0
ꢁ213.1
ꢁ160.9
ꢁ183.6
91.5
ꢁ191.4
ꢁ213.2
ꢁ160.8
ꢁ183.3
52.3
ꢁ184.7
ꢁ208.5
ꢁ161.6
ꢁ191.8
30.2
ꢁ185.1
ꢁ207.4
ꢁ159.9
ꢁ192.0
31.1
ꢁ196.2
ꢁ216.1
ꢁ161.4
ꢁ199.3
90.2
ꢁ189.1
ꢁ211.0
ꢁ166.6
ꢁ204.5
22.8
ꢁ198.8
ꢁ218.4
ꢁ165.6
ꢁ196.0
70.2
ꢁ191.5
ꢁ215.3
ꢁ166.3
ꢁ206.6
1.9
ꢁ194.1
ꢁ215.6
ꢁ165.9
ꢁ205.4
43.0
pꢀC2@O1
a
c and g refer to the cis and gauche conformations, respectively.
the larger
a
dihedral angle for the g1 conformer (106°) compared
(E ffi 0.6 kcal molꢁ1) interaction, which takes place only in the
gauche conformers of 1–4 due to the favourable quasi-anti geome-
try of the oxygen lone pair orbital with respect to the antibonding
rꢀC3AH6 orbital. Therefore, the Od-(Ydꢁ)ꢂꢂꢂHd+ short contacts above
mentioned should stabilize the cis and gauche conformers by elec-
trostatic interactions only.
with that of the g2 conformer (95°) brings closer the Ydꢁ(4)ꢂꢂꢂOdꢁ(9)
and Ydꢁ(4)ꢂꢂꢂNdꢁ(7) atoms, which in turn originates strong Coulom-
bic repulsions for the former conformer in comparison with the
latter one. This trend gives rise to a smaller ionization energy for
nN lone pair orbital in the g1 conformer with respect to the c con-
former by ca. 2.5 kcal molꢁ1 (without any variation in the ioniza-
tion energy for the g2 conformer relative to that of the g1
conformer). Moreover, there is a large electron affinity of the pcꢀo
orbital for the g1 conformer (ca. 2 kcal molꢁ1) with respect to g2
In the O@CACAY fragment there are four orbital interactions
which have been ascribed to the gauche conformer preference i.e.
nY ? pꢀco pcꢀo rCꢀAY and pꢀco rCꢀAY [1–2,5]. This last
, rCAY ? , pco ? ?
interaction, which has already been reported in the literature
[2,5], corresponds to the unusual delocalization interaction, be-
tween two antibonding orbitals which is only possible due to the
high occupancy of pꢀco antibonding orbital of ca. 0.27 for the gauche
(g, g1 and g2) conformers. Table 7 shows that, in general, the above
referred interactions present lower delocalization energies for the
conformer (ca. 43 kcal molꢁ1). Finally, a stronger nN
tion for the g2 conformer with respect to the g1 conformer of 4
should occur.
?
pꢀco interac-
The stronger nN
?
pꢀco delocalization energy for the gauche (g, g1
and g2) conformers than that of the cis (c, c1 and c2) conformers for
1–4, is in line with the higher occupancy of the pꢀco orbital for the
former conformers relative to the latter ones by ca. 0.266 and ca.
0.208, respectively, along with the lower occupancy of the nN7 orbi-
tal for the gauche conformers relative to the cis ones by ca. 1.725
and ca. 1.752, respectively (Table 8). This trend is responsible for
a smaller carbonyl bond order and thus to lower mCO frequency
for the gauche conformers with respect to the cis ones, as found
both theoretically for 1–4 (Table 2) and experimentally, for 1–3
(Table 1) (see above).
a
-fluoro 1,
pared to the
calization energy values for nY ? pcꢀo
rꢀCAY are of 0.7, 1.0, 1.6 and 1.8 kcal molꢁ1, respectively. On
a
a
-methoxy 2 and
-chlorine 4 derivative. In fact for 1–3, the mean delo-
a-phenoxy 3 derivatives when com-
,
rC-Y ? , pco ? ,
pꢀco rꢀCAY
pꢀco
?
the other hand, slightly higher mean delocalization energy values
were found for the same interactions for 4 i.e. 1.2, 3.2, 2.7 and
11.2 kcal molꢁ1, respectively. Additionally, Table 7 shows that the
low delocalization energy values for nO4
? ?
pꢀco and rC3AO4 pcꢀo
interactions for the gauche (g) conformer of the phenoxy derivative
3 (E 6 0.5 kcal molꢁ1) compared with the higher delocalization val-
ues for the gauche (g1) conformer of the methoxy derivative 2
In the carboxamide group, there are two other interactions
(through bond coupling) with high energies i.e. LPO1
?
rꢀC2AN7
and LPO1
?
rC2AC3 whose energy values are of ca. 26 and ca.
(E ffi 1 kcal molꢁ1) is in line with the strong LPO4
?
pꢀC17@C18ðPhÞ con-
ꢀ
21 kcal molꢁ1, respectively, for both cis (c, c1 and c2) and gauche
jugative interaction (above described), which compete with
(g, g1 and g2) conformers (Table 7). The LPY4
?
rꢀC2AC3 through bond
nO4 ? , rC3AO4 ?
pꢀco pꢀco interactions. This O-Ph conjugation leads
coupling interaction presents energy mean values for both cis and
gauche conformers of 7.9 kcal molꢁ1 (for 1 and 2), 2.4 kcal molꢁ1
(for 3) and 4.6 kcal molꢁ1 (for 4). The lowest delocalization energy
found for 2-phenoxy derivative (3) (2.4 kcal molꢁ1) may be as-
to an increase of the orbital nO4 and rC3AO4 ionization energies of
the gauche conformer of 3 compared to that of 2 by 13.2 and
10 kcal molꢁ1 (Table 9), respectively, which in turn makes difficult
the nO4
? ?
pꢀco and rC3AO4 pcꢀo interactions.
cribed to the strong LPO4
?
pꢀC17@C18 conjugative interaction of ca.
Therefore the overall balance of the orbital interactions energies
(Table 7) for the cis (c, c1, c2) and gauche (g, g1, g2) conformers
clearly indicates that the gauche conformer is largely more stable
by ca. 23 kcal molꢁ1 than the cis one for 1–4. However as pointed
30 kcal molꢁ1 (for both c and g conformers), which takes place be-
tween the 2p lone pair of the phenoxy oxygen atom and the pPꢀh
p
(LUMO). The nO(Ph)
tion energy of the 2p lone pair of the phenoxy oxygen atom which
?
pꢀPh conjugation should increase the ioniza-
r
out above, the summing up of both
Y
gauche conformers (which is larger for 1–3 derivatives than for
4) act in opposition to the orbital stabilization of the gauche con-
former with respect to the cis one. In fact, in the gas phase (Tables
Y
dꢁ(4)ꢂꢂꢂOdꢁ(9) and
in turn makes difficult the LPO4
dence for the nO
?
rꢀC2AC3 interaction. Further evi-
dꢁ(4)ꢂꢂꢂNdꢁ(7) repulsive Coulombic interactions present in the
?
pꢀPh comes from the large occupancy of the
pꢀC17@C18ðPhÞ antibonding orbital (0.390), which takes place for both
cis and gauche conformers. Additionally two anomeric
LPY4
?
rꢀC3AH5 and LPY4
?
rꢀC3AH6 interactions stabilize both the
2 and 3) for the
tion of the gauche conformer slightly prevails over the cis one. As
for the -methoxy 2 derivative the summing up of the population
of the cis conformers prevails over that for the gauche ones, while
for the -chloro 4 derivative the summing up of the populations of
a-fluor 1 and a-phenoxy 3 derivatives, the popula-
cis and gauche conformers for 1–4 by 2.1–6.6 kcal molꢁ1
.
It should be pointed out that the delocalization energies of the
a
above reported result in Odꢁ(9)[OMe]ꢂꢂꢂHd+
[for H(5) and H(6)
[aACH2]
O
atoms],
O
dꢁ(1)[CO]ꢂꢂꢂHd+(12)[NMe]
,
dꢁ(9)[OMe]ꢂꢂꢂHd+(5)[
,
ACH2]
a
a
O
dꢁ(1)[CO]ꢂꢂꢂHd+(12)[NMe], Odꢁ(1)[CO]ꢂꢂꢂHd+(6)[
and Ydꢁ(4)ꢂꢂꢂH-
gauche conformers is significantly more abundant than the cis one.
Finally, it seems reasonable to admit that the balance of the
orbital interaction energies for the gauche (g1 and g2) conformers
of the previously studied N-methoxy-N-methyl-2-(40-substi-
tuted)phenylthio propanamides [5] should prevail significantly
a
ACH2]
d+(15)[OMe] short contacts for the cis and gauche conformers (Ta-
ble 5), which are lower than 0.5 kcal molꢁ1, probably due to the
unfavourable geometry for the overlap of the appropriate orbitals.
However, Table
7
presents only
a
weak LPO9 ?
rꢀC3AH6

116
P.R. Olivato et al. / Journal of Molecular Structure 977 (2010) 106–116
over the summing up of both the repulsive electrostatic interac-
tions between the SdꢁꢂꢂꢂOdꢁ and SdꢁꢂꢂꢂNdꢁ atoms, into a lager extent
than compound 4 of the present work, as the cis conformer is ab-
sent in the N-methoxy-N-methyl-thiopropanamides.
Acknowledgments
The Brazilian authors thank the Fundação de Amparo à Pesquisa
do Estado de São Paulo (FAPESP) for financial support of this re-
search and for a fellowship to A.R., the Conselho Nacional de
Desenvolvimento Científico e Tecnológico (CNPq) for fellowships
to P.R.O. and R.R. and for a scholarship to R.S.G. The LCCA-Labora-
tory of Advanced Scientific Computation of the University of São
Paulo is acknowledged for access to resources. The Italian author
thanks the University of Ferrara (Nano & Nano Project) for financial
support.
4. Conclusions
The conformational preference of some 2-substituted N-meth-
oxy-N-methyl-acetamides, bearing as substituents F 1, OMe 2,
OPh 3, Cl 4 was determined by mCO IR analysis for 1–3 supported
by B3LYP/6–311++G(3df,3pd) calculations along with the NBO
analysis for 1–4. Theoretical data indicated the existence of cis–
gauche conformers i.e. (c) and (g) for 1 and 3, (c1, c2) and (g1, g2)
for 2, and (c) and (g1, g2) for 4. In the gas phase, the g conformer
population prevails over the c one, for 1 and 3, the (c1 + c2)
population prevails over the (g1 + g2) one for 2, and the (g1 + g2)
conformer population is more abundant than (c) one for 4. In
n-hexane solution, the cis conformer is more abundant for 1–3.
The occurrence of Fermi resonance in the mCO region, in n-hexane,
precludes the estimative of relative populations of the (c, g1, g2)
conformers for 4. The SCI-PCM calculations agree with the
solvent effect on the mCO band component relative intensities for
1–3.
Appendix A. Supplementary material
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.molstruc.2010.05.021.
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?
pꢀco
,
pco
?
?
contribute, but into a minor extent for the stabilization of the
gauche conformers relative to the cis ones. The existence of some
pyramidalization at the nitrogen atom of these Weinreb amides
is responsible for the occurrence of
Y
dꢁ(4)ꢂꢂꢂOdꢁ(9) and
Y
dꢁ(4)ꢂꢂꢂNdꢁ(7) short contacts in the gauche (g, g1, g2) conformers,
which originates strong repulsive Coulombic interactions, acting
in opposition to the large orbital stabilization of the gauche con-
former with respect to the cis one. Therefore a delicate balance of
the Coulombic and orbital interactions seems to be responsible
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the gauche (g, g1, g2) conformers, both in the gas phase as in solu-
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atives gauche conformer population slightly prevails over the cis
one. As for the -methoxy 2 derivative the summing up of the pop-
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while for the -chloro 4 derivative the summing up of the popula-
a-fluor 1 and a-phenoxy 3 deriv-
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a
a
tions of gauche conformers is larger relative to that of the cis one.
On the other hand, in non polar solvents solution the cis conformer
prevails significantly with respect to the gauche one for 1–3. Con-
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Supplementary materials session.
1 and 3 are shown in the
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