NMR Spectroscopy and Theoretical Calculations in the Conformational Analysis of 1-Methylpyrrolidin-2-one 3-Halo-derivatives

Article abstract of DOI:10.1021/jp512378g

This study reports the results of ab initio and density functional theory (DFT) electronic structure calculations as well as ³J_HH experimental and calculated coupling constant data obtained in the investigation of the conformational equilibrium of 3-halo-derivatives of 1-methylpyrrolidin-2-one. The five-membered ring assumes an envelope conformation owing to the plane of formation of the O=C-N-R bond, with C4 forming the "envelope lid". When the conformation changes, the "lid" alternates between positions above and below the amide plane. The α-carbonyl halogen assumes two positions: a pseudo-axial and a pseudo-equatorial. In the gaseous phase, the calculations indicate that the pseudo-axial conformer is more stable and preferable going down the halogen family. Natural bond orbital analysis showed that electronic delocalization is significant only for the iodo derivative. In the other derivatives, the electrostatic repulsion between oxygen and the halogen determines the conformational equilibrium. When the solvated molecule was taken into account, the pseudo-equatorial conformer population increased with the relative permittivity of the solvent. This variation was strong in the fluoro derivative, and the preference was inverted. In the chlorine derivative, the two populations became closer in methanol and acetonitrile. In the bromine and iodine derivatives, the percentage of pseudo-equatorial conformer increased only slightly owing to the dipole moment of the conformation: the pseudo-equatorial conformation has a greater dipole moment and thus is stable in media with high relative permittivity.

Full text of DOI:10.1021/jp512378g

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Article
NMR Spectroscopy and Theoretical Calculations in the Conformational
Analysis of 1-methylpyrrolidin-2-one 3-Halo-derivatives
Ulisses Zonta Melo, Rai Guilherme Monteiro Silva, Diego Alberto dos Santos Yamazaki, Rodrigo Meneghetti
Pontes, Gisele de Freitas Gauze, Fernanda Andeia Rosa, Roberto Rittner, and Ernani Abicht Basso
J. Phys. Chem. A, Just Accepted Manuscript • DOI: 10.1021/jp512378g • Publication Date (Web): 13 Feb 2015
Downloaded from http://pubs.acs.org on February 17, 2015
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NMR Spectroscopy and Theoretical Calculations in
the Conformational Analysis of 1ꢀmethylpyrrolidinꢀ2ꢀ
one 3ꢀHaloꢀderivatives
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Ulisses Z. Melo¹, Raí G.M. Silva¹, Diego A.S. Yamazaki¹, Rodrigo M. Pontes¹, Gisele F. Gauze¹,
Fernanda A. Rosa¹, Roberto Rittner²,, Ernani A. Basso¹*
¹ Chemistry Department, State University of Maringa, Avenida Colombo, 5790, 87020ꢀ900,
Maringa, PR, Brazil
² Physical Organic Chemistry Laboratory, Chemistry Institute, University of Campinas, 13083ꢀ970,
Campinas, SP, Brazil
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Abstract
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This study reports the results of ab initio and DFT electronic structure calculations as well as ³JHH
experimental and calculated coupling constant data obtained in the investigation of the
conformational equilibrium of 3ꢀhaloꢀderivatives of 1ꢀmethylpyrrolidinꢀ2ꢀone. The fiveꢀmembered
ring assumes an envelope conformation owing to the plane of formation of the O=C–N–R bond,
with C4 forming the "envelope lid". When the conformation changes, the "lid" alternates between
positions above and below the amide plane. The αꢀcarbonyl halogen assumes two positions: a
pseudoꢀaxial and a pseudoꢀequatorial. In the gaseous phase, the calculations indicate that the
pseudoꢀaxial conformer is more stable and preferable going down the halogen family. Natural bond
orbital analysis showed that electronic delocalization is significant only for the iodo derivative. In
the other derivatives, the electrostatic repulsion between oxygen and the halogen determines the
conformational equilibrium. When the solvated molecule was taken into account, the pseudoꢀ
equatorial conformer population increased with the relative permittivity of the solvent. This
variation was strong in the fluoro derivative and the preference inverted. In the chlorine derivative,
the two populations became closer in methanol and acetonitrile. In the bromine and iodine
derivatives, the percentage of pseudoꢀequatorial conformer increased only slightly owing to the
dipole moment of the conformation: the pseudoꢀequatorial conformation has a greater dipole
moment and thus is stable in media with high relative permittivity.
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Keywords: 1ꢀmethylpyrrolidinꢀ2ꢀone, steric and electronic substituent effects, solvent effect.
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1. Introduction
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Fiveꢀmembered rings, together with sixꢀmembered rings, are probably the most important
blocks present in the molecular structure of natural and synthetic organic compounds1 due to their
numerous applications. Because the stereochemistry of these compounds directly affects their
properties, the study of their threeꢀdimensional structure is necessary for understanding properties
such as reactivity and/or affinity for an enzyme, as well as clarifying their mechanisms of reaction
and planning and improving the corresponding synthesis methods.
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The number of studies in the literature on fiveꢀmembered rings, cyclopentanes, and their
derivatives is small compared to the number of studies on other compounds, especially sixꢀ
membered rings.1–3 However, it is important to note that fiveꢀmembered rings are present in the
structures of various natural products and synthetic derivatives, such as steroids, prostaglandins,
sugars and nucleotides.4
3
Recent studies on transꢀ2ꢀhalocyclopentanols5 using the JHH coupling constants and
theoretical calculations have shown that they present conformational equilibrium between diaxial
and diequatorial conformers with a slight predominance of the diequatorial conformer. This
proportion varies with the relative permittivity of the medium, which is attributed to
hyperconjugative interactions involving orbitals σCꢀC → σ*CꢀO, σCꢀC →σ*CꢀX and σCꢀH → σ*CꢀH
.
In a study of 2ꢀhalocyclopentanones using electronic structure calculations, Martins et al.2
determined that the cyclopentanone ring is in a halfꢀchair conformation (halfꢀchair, C2) and the
envelope conformation (Cs) was not observed. The conformer with the halogen in the pseudoꢀaxial
position predominates in the gaseous phase. The bromine derivative showed the greatest energy
difference between the conformers [ꢁE = 0.85 kcal molꢀ1 at theory level B3LYP/6ꢀ
311++G(2df,2p)]. The authors noted that the equilibrium reached depended on the solvent. In the
case of the chlorine derivative, for example, the population of the pseudoꢀequatorial conformer
increased from CCl4 to DMSO (from 70 to 88%). This variation was explained based on the dipole
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moments. Because the pseudoꢀequatorial conformer is more polar, it tends to be more stable in
media with high relative permittivity.
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Another class of cyclic compounds, lactams,6 is part of various molecules of chemical and
biological relevance. Among these compounds, ßꢀlactams have been examined in a large number of
studies7, whereas γꢀbutyrolactams remain significantly underinvestigated. The synthesis of certain
substituted ßꢀ and γꢀlactams was described by Chatterjee et al. and characterized by elemental
analysis and infrared spectroscopy as early as 1967.8
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Structural studies of certain alkaloidꢀanalogueꢀsubstituted δꢀlactams were conducted in 1994
by Boudreault et al.9 The authors determined the relationships between the substituents in carbons 5
and 6 based on ¹H and ¹³C NMR and Xꢀray crystallography. In 2009, ArizaꢀCastolo et al.10
published a conformational analysis of Nꢀaryl εꢀlactams substituted with alkyl groups based on the
analysis of coupling constants and chemical shift data from ¹H and ¹³C NMR spectra.
Recently, in a theoretical and experimental study, Esseffar et al.11 determined the main
parameters responsible for the solvent effect on the ¹H and ¹³C NMR chemical shifts of lactones and
lactams (including nonꢀsubstituted γꢀbutyrolactam). Another study on Nꢀmethylꢀγꢀbutyrolactams
involving theoretical calculations and NMR data has also been published recently,12 but with a
phenyl group at C4, as well as on other more complex bicyclic lactams.
The present work investigated the conformational equilibria of 3ꢀhaloꢀderivatives of 1ꢀ
methylpyrrolidinꢀ2ꢀone (Figure 1) by NMR and electronic structure calculations.
O
2
X
CH3
N
3
4
5
Figure 1. General structure of the compounds under study. X = F (1), Cl (2), Br (3) and I (4).
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2. Experimental and Computational Details
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2.1 Synthesis
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The compounds were prepared by reacting lithium enolate of 1ꢀmethylpyrrolidinꢀ2ꢀone with
a halogenation reagent (Nꢀfluorobenzenesulfonimide, mesyl chloride, bromine and iodine).13 The
Supporting Information details the synthesis procedure of each derivative as well its ¹H and ¹³C
NMR assignments. Compound 1, not previously described, could not be isolated from the substrate
(nonꢀsubstituted); therefore, its experimental data were analyzed as such.
2.2 Mass Spectrometry
A Micromass Quattro Micro API electrospray mass spectrometer was used with an
ionization source in positive mode. The samples were injected in a 1ꢀµmol Lꢀ1 methanol solution
with 0.1% (v/v) formic acid for protonation.
2.3 ¹H and ¹³C NMR Analyses
¹H and ¹³C NMR spectra were obtained on a Varian spectrometer, model Mercury Plus BB,
operating at 300 MHz for ¹H nuclei and 75 MHz for ¹³C nuclei. Approximately 10 mg of samples in
0.6 mL of solvent (carbon tetrachloride, chloroformꢀd, acetoneꢀd6, methanolꢀd4 and acetonitrileꢀd3)
were applied, by using tetramethylsilane as an internal reference. All analyses in carbon
tetrachloride were performed using a coaxial insert tube containing chloroformꢀd. The probe was
1
kept at room temperature, and for the H spectra, the spectral window was approximately 4000 Hz
and the number of points was 32k, resulting in a digital resolution of 0.12 Hz/point. The ¹³C spectra
were obtained with a spectral window of approximately 18115 Hz. The ¹H and ¹³C resonances were
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assigned based on the signal profile and bidimensional experiments (COSY and HSQC). To confirm
the chemical shifts and coupling constants assignments, the spectra were simulated in the software
MestreNova 10.0.0 (MestreLab Research, 2014) and compared with the experimental spectra.
Spectral data for compounds 1ꢀ4 in different solvents, ¹H and ¹³C NMR spectra in chloroformꢀd,
and the simulated spectra in chloroformꢀd are available in the Supporting Information.
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2.4 Theoretical Calculations
Electronic structure calculations were performed with the software package Gaussian 09,
revision B.01 (Gaussian Inc., Wallingford CT, 2010).14 Geometry optimizations were performed
using the M06ꢀ2X19 density functional together with the Pople 6ꢀ311++G(3df,3pd) basis set15 and
Dunning augꢀccꢀpVDZ basis set.16 For the iodine atom, the LanL2DZꢀECP basis set was used.17 In
addition to the gaseous phase optimization, all conformers were also optimized in the presence of
solvent (carbon tetrachloride, chloroform, acetone, acetonitrile and methanol) at theory level M06ꢀ
2X/6ꢀ311++G(3df,3pd) using model IEFꢀPCM,18 and the description of the molecular cavity was
optimized using Bondi radii. All of the optimized structures were submitted to frequency calculation
for characterization as stationary points or transition states and to obtain the thermodynamic
properties. In addition to the calculations performed using density functional theory, the secondꢀ
order MöllerꢀPlesset perturbation ab initio method19 was applied by combining the basis sets 6ꢀ
311+G(3df,3pd) and augꢀccꢀpVDZ for optimization and frequency calculations in the gaseous phase
and for calculation of the energy in the presence of the solvent. All optimization calculations were
performed with very tight convergence criteria using the keywords Tight for the selfꢀconsistent field
and Ultrafine, which increases the accuracy of the numerical integration grid. The coupling constant
values were calculated using the mPW1PW91 method with basis sets EPRꢀIII (for C and H), 6ꢀ
311++G(3df,3pd) (for N, O, F, Cl and Br) and LanL2DZꢀECP (for I).20,21 The structures optimized
at the M06ꢀ2X/6ꢀ311++G(3df,3pd) level were used in the gaseous phase. The calculations involving
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natural bond orbital theory were performed using the structures optimized in the gaseous phase at
theory level M06ꢀ2X/6ꢀ311++G(3fd,3pd) through module NBO 5.922 from Gaussian 09. Molecular
mechanics calculations were performed using method MMFF9423 in the software program
Avogadro 1.0.3.24
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3. Results and discussion
3.1 Molecular geometry optimization and determination of conformational equilibrium
Starting with the known conformations of cyclopentanone,1 halfꢀchair (C2) and envelope
(CS), and substituting one αꢀcarbonyl carbon atom by one nitrogen atom, we determined that, unlike
cyclopentanone, pyrrolidinꢀ2ꢀone has a single stable conformation: the envelope conformation. The
amide bond O=C–N–R and its resonance hybrids force the existence of a plane involving C3 and
C5 (Figure 2); thus the alternation of conformations occurs by pseudoꢀrotation of bonds C3ꢀC4 and
C4ꢀC5.
(a)
O
O-
(b)
N+
CH3
CH3
N
Figure 2. (a) Illustration of the amide plane, (b) resonance hybrids for 1ꢀmethylpyrrolidinꢀ2ꢀone.
The investigated lactams therefore have the two conformations in equilibrium because C4
behaves as the "envelope lid", turned either downward or upward, to the amide plane, with an N–
C2–C3–C4 dihedral angle close to 21º. Thus, the αꢀcarbonyl halogen can occupy two positions: a
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pseudoꢀaxial (labeled pꢀax) and a pseudoꢀequatorial (labeled pꢀeq) (Figure 3).
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Figure 3. Conformational equilibrium for 3ꢀchloroꢀ1ꢀmethylpyrrolidinꢀ2ꢀone (2).
Each conformation was submitted to optimization and frequency calculations in the gaseous
phase at theory levels M06ꢀ2X/6ꢀ311++G(3df,3pd) and M06ꢀ2X/augꢀccꢀpVDZ and with the
continuum solvation model IEFꢀPCM at the same levels. Thermal correction for the Gibbs free
energy was applied for each energy value. Based on the free energy variation, the K constant for the
conformational equilibrium was calculated for pꢀax ↔ pꢀeq using the equation ꢁGº = – RTlnK,
where R = 8.31447 J molꢀ1 Kꢀ1; T = 298.15 K and K = αpꢀeq / αpꢀax. The data are shown in Table 1. For
the relative energy, conformer pꢀax was defined as zero.
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Table 1. Dipole moment (Debye), energy difference (kJ molꢀ1), Gibbs free energy difference (kJ molꢀ1) and conformational equilibrium constant
calculated at the M06ꢀ2X/6ꢀ311++G(3df,3pd) and M06ꢀ2X/augꢀccꢀpVDZ (LanL2DZꢀECP for I) theory levels for derivatives 1 to 4 in the gaseous
phase and in solution.
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Gas phase
Carbon tetrachloride
Chloroform
Acetone
Methanol
Acetonitrile
Cpd. Subs. Conf.
ꢂ
ꢁE
ꢁGº
K
ꢁE
ꢁGº
K
ꢁE
ꢁGº
K
ꢁE
ꢁGº
K
ꢁE
ꢁGº
K
ꢁE
ꢁGº
K
M06ꢀ2X/6ꢀ311++G(3df,3pd)
pꢀax 4.65 0.00 0.00
pꢀeq 5.32 0.29 0.29
pꢀax 4.57 0.00 0.00
pꢀeq 5.23 3.54 3.15
pꢀax 4.54 0.00 0.00
pꢀeq 5.19 5.57 5.14
pꢀax 4.35 0.00 0.00
pꢀeq 4.84 8.06 7.45
0.00 0.00
ꢀ0.85 ꢀ0.58
0.00 0.00
2.54 2.36
0.00 0.00
4.62 4.16
0.00 0.00
7.36 6.82
0.00 0.00
ꢀ2.02 ꢀ1.58
0.00 0.00
1.46 1.48
0.00 0.00
3.58 3.10
0.00 0.00
6.57 6.14
0.00 0.00
ꢀ3.36 ꢀ2.73
0.00 0.00
0.12 0.23
0.00 0.00
2.34 1.89
0.00 0.00
5.56 5.15
0.00 0.00
ꢀ3.58 ꢀ3.05
0.00 0.00
0.03 0.09
0.00 0.00
2.47 1.73
0.00 0.00
5.64 5.10
0.00 0.00
ꢀ3.57 ꢀ2.92
0.00 0.00
ꢀ0.11 0.00
0.00 0.00
2.14 1.71
0.00 0.00
5.39 4.95
1
2
3
4
F
Cl
Br
I
0.89
0.28
0.13
0.05
1.26
0.39
0.19
0.06
1.89
0.55
0.29
0.08
3.00
0.91
0.47
0.13
3.43
0.96
0.50
0.13
3.25
1.00
0.50
0.14
M06ꢀ2X/augꢀccꢀpVDZ
pꢀax 4.70 0.00 0.00
pꢀeq 5.36 1.26 0.90
pꢀax 4.65 0.00 0.00
pꢀeq 5.31 4.23 3.63
pꢀax 4.61 0.00 0.00
pꢀeq 5.26 6.06 5.21
pꢀax 4.42 0.00 0.00
pꢀeq 4.92 7.88 6.83
0.00 0.00
ꢀ0.05 0.18
0.00 0.00
3.08 2.77
0.00 0.00
5.05 4.28
0.00 0.00
7.11 6.30
0.00 0.00
ꢀ1.28 ꢀ0.77
0.00 0.00
1.90 1.80
0.00 0.00
3.99 3.25
0.00 0.00
6.25 5.75
0.00 0.00
ꢀ2.62 ꢀ1.84
0.00 0.00
0.49 0.54
0.00 0.00
2.71 2.02
0.00 0.00
5.23 4.76
0.00 0.00
ꢀ2.80 ꢀ2.00
0.00 0.00
0.29 0.34
0.00 0.00
2.52 1.88
0.00 0.00
5.08 4.56
0.00 0.00
ꢀ2.83 ꢀ2.02
0.00 0.00
0.26 0.54
0.00 0.00
2.50 2.10
0.00 0.00
5.06 4.53
1
2
3
4
F
Cl
Br
I
0.69
0.23
0.12
0.06
0.93
0.33
0.18
0.08
1.36
0.48
0.27
0.10
2.10
0.80
0.44
0.15
2.24
0.87
0.47
0.16
2.26
0.80
0.43
0.16
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According to the data presented in Table 1, in the gaseous phase, the conformational
equilibrium shifted to conformer pꢀax. This preference became more expressive going down the
halogen family (from F to I). When the solvent was present, the preference for pꢀax decreased, and
for the fluorine derivative, the preference was inverted; that is, conformer pꢀeq was favored in
solvents with greater relative permittivity. In the chlorine derivative, the population of conformer pꢀ
eq also increased; in methanol and in acetonitrile, the populations of the two conformers were rather
similar.
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In the bromine and iodine derivatives, the pꢀax conformer still predominated, but the energy
decreased with the increase in the relative permittivity of the solvent. This tendency can be better
visualized by plotting the conformational equilibrium constant as a function of the relative
permittivity of the medium (Figure 4).
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4
3
2
1
0
0
5
10
15
20
25
30
35
40
Relative permittivity
Figure 4. Variation of K as a function of the relative permittivity of the medium (gaseous phase ε =
1.0, carbon tetrachloride ε = 2.22, chloroform ε = 4.90, acetone ε = 20.70, methanol ε = 32.63 and
acetonitrile ε = 36.64) calculated at the M06ꢀ2X/6ꢀ311++G(3df,3pd) level (LanL2DZꢀECP for I) for
derivatives 1 to 4.
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The data obtained with the basis functional 6ꢀ311++G(3df,3pd) agree with the tendency
observed with augꢀccꢀpVDZ. However, it can be observed that the K values are closer for iodine
than for fluorine.
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Ab initio calculations were performed for these compounds by method MP2 associated with
the two previously mentioned bases; the results are shown in Table 2. It can be noted that the data
agree with the tendency observed by method M06ꢀ2X. However, for derivatives 1 and 2 in
particular, constant K presented smaller values; that is, the relative energy of conformer pꢀax
increased. The difference between bases 6ꢀ311++G(3df,3pd) and augꢀccꢀpVDZ mentioned in the
previous paragraph was also observed for the fluorine derivative.
Table 2. Dipole moment (Debye), energy difference (kJ molꢀ1), Gibbs free energy variation in the
gaseous phase (kJ molꢀ1), and conformational equilibrium constant based on the total energy (Ke)
calculated at the MP2/6ꢀ311++G(3df,3pd) and MP2/augꢀccꢀpVDZ (LanL2DZꢀECP for I) theory
levels for derivatives 1 to 4 in the gaseous phase and in solution.
Carbon
tetrachloride
Gas phase
Chloroform
Acetone
Methanol
Acetonitrile
Cpd. Subs. Conf.
ꢂ
ꢁGº
K
ꢁE
Ke
ꢁE
Ke
ꢁE
Ke
ꢁE
Ke
ꢁE
Ke
MP2/6ꢀ311++G(3df,3pd)
pꢀax 4.95 0.00
pꢀeq 5.74 1.84
pꢀax 4.82 0.00
pꢀeq 5.55 4.44
pꢀax 4.80 0.00
pꢀeq 5.51 5.99
pꢀax 4.00 0.00
pꢀeq 4.63 6.77
0.00
0.54
0.00
3.93
0.00
5.86
0.00
6.20
0.00
ꢀ0.81
0.00
2.72
0.00
4.81
0.00
5.56
0.00
ꢀ2.35
0.00
1.27
0.00
3.51
0.00
4.74
0.00
ꢀ2.57
0.00
1.06
0.00
3.32
0.00
4.62
0.00
ꢀ2.60
0.00
1.03
0.00
3.29
0.00
4.60
1
2
3
4
F
Cl
Br
I
0.48
0.17
0.09
0.07
0.80
0.20
0.09
0.08
1.39
0.33
0.14
0.11
2.58
0.60
0.24
0.15
2.82
0.65
0.26
0.15
2.86
0.66
0.26
0.16
MP2/augꢀccꢀpVDZ
pꢀax 5.07 0.00
pꢀeq 5.87 3.02
pꢀax 4.95 0.00
pꢀeq 5.70 5.01
pꢀax 4.89 0.00
pꢀeq 5.62 6.68
pꢀax 4.70 0.00
pꢀeq 5.26 6.64
0.00
1.70
0.00
4.33
0.00
6.31
0.00
6.22
0.00
0.33
0.00
3.08
0.00
5.22
0.00
5.51
0.00
ꢀ1.24
0.00
1.57
0.00
3.86
0.00
4.61
0.00
ꢀ1.46
0.00
1.35
0.00
3.66
0.00
4.49
0.00
ꢀ1.50
0.00
1.32
0.00
3.63
0.00
4.47
1
2
3
4
F
Cl
Br
I
0.30
0.13
0.07
0.07
0.50
0.17
0.08
0.08
0.88
0.29
0.12
0.11
1.65
0.53
0.21
0.16
1.80
0.58
0.23
0.16
1.83
0.59
0.23
0.17
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3.2 Analysis of the natural bond orbitals
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9
It has been proposed that the ηX → π*C=O orbital interaction is important for the
conformational preference of 2ꢀhaloꢀcyclohexanones1,25,26 and that the overlap of these orbitals
increases with the increase in the halogen volume and with the proximity of their energy values. For
cyclohexanones, this interaction is greater for the axial than for the equatorial conformer and
increases in the order F < Cl < Br < I, as does the difference in axial ꢀ equatorial energy in the
gaseous phase, which is 0.45, 1.05, 1.50 and 1.90 kcal molꢀ1 for F, Cl, Br and I, respectively. 27 A
study by Rozada et al.28 (2012) showed that in addition to the abovementioned interaction, for
cycloheptanone 2ꢀhalo derivatives, the σCꢀX → π*C=O delocalization also plays a major role in
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determining their conformational equilibrium.
In a more recent study, Rozada et al.29 added
that in addition to the σCꢀX → π*C=O interaction, the σCαꢀH → π*C=O interaction must also be closely
investigated. This study provided evidence of the importance of other forms of intermolecular
interactions, such as steric repulsion, exchange energy and electrostatic repulsion, which are
sometimes overlooked in studies of natural bond orbitals.
Table 3 presents the stabilization energy values (Eij) for these interactions, as well as the
difference in energy (Ei – Ej) between the orbitals and the Fock matrix elements (F(i;j)).
Table 3. Main hyperconjugative interactions that affect the conformational equilibrium. Eij in kJ
molꢀ1, Ei – Ej in atomic units. Calculated at the M06ꢀ2X/6ꢀ311++G(3df,3pd) level (LanL2DZꢀECP
for I).
σCꢀX → π*C=O
σCꢀH → π*C=O
ηX → π*C=O
Cpd. Subs. Conf.
Eij
Ei – Ej
F(i;j)
Eij
Ei – Ej
F(i;j)
Eij
Ei – Ej
F(i;j)
pꢀax
7.06
1.68
1.12
1.15
0.80
0.83
0.74
0.75
0.042
0.021
0.057
0.028
0.062
0.032
5.12
25.20
6.97
0.68
0.67
0.68
0.67
0.69
0.67
0.028
0.061
0.032
0.062
0.033
0.062
7.31
ꢀa
0.57
0.030
1
2
3
F
pꢀeq
ꢀ
0.45
ꢀ
ꢀ
pꢀax 18.27
pꢀeq 4.28
pꢀax 24.19
pꢀeq 6.13
8.74
ꢀa
0.029
Cl
Br
25.96
7.10
ꢀ
0.028
ꢀ
8.11
ꢀa
0.43
ꢀ
25.96
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pꢀax 36.37
pꢀeq 11.13
0.60
0.60
0.069
0.038
7.52
0.70
0.68
0.034
0.061
6.51
ꢀa
0.39
ꢀ
0.024
ꢀ
4
I
25.66
(a) interaction smaller than 2.1 kJ molꢀ1.
5
It can be observed that the σCꢀX → π*C=O hyperconjugation is visibly stronger in conformer
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9
pꢀax and that this preference increases going down in the halogen family, from F → I. The pꢀax
preference over pꢀeq can be understood relative to the overlap: in pꢀax, the overlap is nearly twice
the value of pꢀeq, as shown in the orbital representation in Figure 5. Because the maximum overlap
occurs when the orbitals are periplanar or antiꢀperiplanar, it is clear that this parameter favors
conformer pꢀax.
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πC*=O
σCꢀCl
pꢀax σCꢀH
pꢀax π
pꢀax σCꢀCl
*
pꢀax
C=O
πC*=O
σCꢀCl
pꢀeq σCꢀH
pꢀeq π
pꢀeq σCꢀCl
*
pꢀeq
C=O
Figure 5. Representation of natural bond orbitals σCꢀX and π*C=O for conformers pꢀeq and pꢀax of
the chlorine derivative.
Another relevant parameter is the energy difference between the orbitals involved in the
electronic delocalization (Ei – Ej): the smaller this difference is, the more effective the donation of
electron density becomes. This relationship explains the tendency observed in the halogen family:
whereas the energy difference between orbitals σCꢀX and π*C=O in fluorine derivatives is 1.15 a.u.
(atomic unit or Hartree), in iodine derivatives it is approximately 0.60 a.u.
In contrast, the σCꢀH → π*C=O donation is more significant in conformer pꢀeq, and it hardly
varies when the halogen is varied. This variation is likely related to the electronegativity of the
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substituent. As in the previous interaction, the dihedral angle H–C–C=O favors conformer pꢀeq.
Naturally, the difference in energy between the orbitals is nearly constant. Another interaction of
importance for the conformational equilibrium is ηX → π*C=O, which also favors conformer pꢀax
with high Eij values, whereas the values for pꢀeq are less than 2.1 kJ molꢀ1 in all cases.
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The equilibrium between these interactions agrees with the tendency observed in the
calculations: the preference of the fluorine derivative for the pꢀeq conformer is greater. Its σCꢀH
→
π*C=O interaction is greater than that of σCꢀX → π*C=O; the opposite occurs for iodine derivatives,
which have a stronger preference for the pꢀax conformer.
To confirm the importance of these interactions, we calculated the effects of specific
deletion. We deleted orbital π*C=O; that is, the occupancy of this antiꢀligand orbital was considered
to be zero. Therefore, there was no possibility of any delocalization to this orbital. The energy
verification data, together with their respective conformational equilibrium constants, are presented
in Table 4.
Table 4. Energy variation (kJ molꢀ1) and conformational equilibrium constant for the deletion of
orbital π*C=O. Calculated at the M06ꢀ2X/6ꢀ311++G(3df,3pd) level (LanL2DZꢀECP for I).
Before deletion Deletion π*C=O
Cpd. Subs. Conf.
ꢁE
K
ꢁE
K
pꢀax
0.00
0.29
0.00
3.54
0.00
5.57
0.00
8.06
0.00
0.24
6.38
0.00
6.98
0.00
1.20
0.00
1
2
3
4
F
Cl
Br
I
0.89
0.91
pꢀeq
pꢀax
pꢀeq
pꢀax
pꢀeq
pꢀax
pꢀeq
0.24
0.11
0.04
13.12
16.72
1.62
It can be observed that when π*C=O was deleted, the conformational preference of all
derivatives inverted, except for the fluorine derivative. The reduction of the effect on 1 was
expected (in this case, the deletion favored conformer pꢀax even more) because the interactions
involving fluorine were less intense. Because fluorine is very electronegative, the electron density
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donation tends to be smaller. Furthermore, because the delocalizations presented in Table 3 are no
longer possible, conformer pꢀeq prevails, which demonstrates the relevance of interactions
involving π*C=O, such as σCꢀX → π*C=O, σCꢀH → π*C=O and ηX → π*C=O, and other less significant
ones for the relative stability of conformer pꢀax.
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However, although these tendencies agree with each other, these interactions alone are not
sufficient for fully understanding the conformational equilibrium of these compounds. No other
interaction energy variation that could be associated with the alternation of conformations was
found.
A means of qualifying the importance of the delocalization for a conformation as a whole is
to calculate the total deletion, which yields the deletion energy. Table 5 presents this parameter,
together with the energy difference for conformers pꢀax and pꢀeq without electronic delocalization.
Table 5. Deletion energy (kJ molꢀ1) and conformer equilibrium constant variation for total deletion
and total steric exchange energy (Eex) and its variations for the conformers (kJ molꢀ1) calculated at
the M06ꢀ2X/6ꢀ311++G(3df,3pd) level (LanL2DZꢀECP for I).
Total steric exchange
Total deletion
energy
Cpd. Subs. Conf.
E(a)
ꢁE (b)
K
ꢁE(hip) (c)
Eex
ꢁEex
pꢀax ꢀ1114094.43
pꢀeq ꢀ1114058.13
pꢀax ꢀ2060232.75
pꢀeq ꢀ2060216.41
pꢀax ꢀ7610482.37
pꢀeq ꢀ7610477.41
pꢀax ꢀ881800.80
pꢀeq ꢀ881809.22
2160.59
2196.57
2153.37
2166.03
2136.09
2134.80
2094.85
2077.54
463.41
460.03
485.97
481.74
495.67
490.44
478.81
470.42
3.38
0.00
4.23
0.00
5.23
0.00
8.39
0.00
0.00
36.30
0.00
1
2
3
4
F
Cl
Br
I
0.00
0.00
0.14
16.33
0.00
4.96
8.42
29.87
0.00
(a) Energy after deletion: energy of the conformer without electronic delocalization, (b) energy variation for the two
conformers without electronic delocalization, (c) energy variations corresponding to the electronic delocalization.
Because orbital interactions have a stabilizing character due to the electronic delocalization,
destabilizing interactions also exist and are equally important in conformational analysis. Table 5
also compiles values of the steric exchange total energy, a parameter that allows for the evaluation
of the repulsion between electron clouds.
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When the total deletion is applied, it can be observed that the preference for pꢀax is strongly
enhanced for the fluorine derivative and that it decreases for the chlorine and bromine derivatives,
reaching an inversion for the iodine derivative. This behavior suggests that hyperconjugation exerts
a significant effect only in the iodine derivative.
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The steric exchange energy data indicate that conformer pꢀeq has lower indicators than does
pꢀax; thus, pꢀeq steric features are favored.
Therefore, what drives fluorine, chlorine and bromine derivatives to prefer the pꢀax
conformation?
Another parameter that must be evaluated is the electrostatic repulsion energy, presented in
Table 6. These values were approximated by the molecular mechanics method MMFF94.23
Table 6 shows that the electrostatic energy data agree with the optimization results. In all the
derivatives, conformer pꢀax suffers less electrostatic repulsion, as demonstrated by both the EEO–X
parameter, which indicates a greater O–X repulsion in pꢀeq, and EETOTAL, which shows that
conformer pꢀeq in general is destabilized by electrostatic interactions.
Table 6. O–Xꢀray (in Angström), electrostatic energy values and total energy (kJ molꢀ1) calculated
at the MMFF94 level.
Electrostatic energy
Total energy
(a)
(b)
Cpd. Subs. Conf.
rO–X
EEO–X
EETOTAL
ꢁEETOTAL
E (c)
ꢁE
pꢀax
3.089
2.918
3.355
3.173
3.466
3.282
3.619
3.437
65.63
69.48
51.53
54.49
39.57
41.78
31.31
32.96
ꢀ4.05
0.42
0.00
4.47
0.00
3.70
0.00
2.81
0.00
2.11
52.90
54.08
32.10
37.70
15.37
22.89
7.49
0.00
1.18
0.00
5.60
0.00
7.51
0.00
4.03
1
2
3
4
F
Cl
Br
I
pꢀeq
pꢀax
pꢀeq
pꢀax
pꢀeq
pꢀax
pꢀeq
ꢀ25.37
ꢀ21.67
ꢀ43.83
ꢀ41.03
ꢀ56.58
ꢀ54.47
11.52
(a) Electrostatic energy relative to the oxygenꢀhalogen repulsion interaction, (b) total electrostatic energy of the
conformation, (c) total energy calculated by molecular mechanics method MMFF94.
The analysis of the total energy data shows that this parameter also indicates that the
conformation pꢀax is more stable. However, ꢁE is greater for iodine derivatives than for fluorine
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derivatives, a tendency opposite to that demonstrated by ab initio and density functional theory
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calculations. However, the molecular mechanics methods do not take electronic delocalization into
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account. As observed in the deletion calculations, this effect is more pronounced in iodine
derivatives. Thus, we can qualitatively state that these effects set each other off. Going from F → I,
the effect of electronic delocalization increases in the opposite direction, with the predominance of
electrostatic repulsion. Although the iodine atom is bulkier than the fluorine atom, fluorine has a
more concentrated charge due to its high electronegativity. Because iodine is bulkier, its charge is
dispersed, which significantly reduces the electrostatic repulsion of the carbonyl oxygen atom.
Although the tendency of the data is consistent, there are some disagreements between the
sets of data. For example, the variation in the deletion energy for derivative 1 is 36.30 kJ molꢀ1, and
this parameter is set off by the electrostatic repulsion in favor of the pꢀax conformer by 4.47 kJ molꢀ
1. Apparently, 4.47 kJ molꢀ1 would not be sufficient to set off the 36.30 kJ molꢀ1 from electronic
delocalization. Nevertheless, we did not decompose the energy difference obtained from
optimization calculations into its various components but rather applied different independent
methods to explain a tendency that had been observed. Therefore, numerical data agreement is not
relevant in this case.
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5.4 Association of NMR measurements with the calculated data
Because the value of the spinꢀspin coupling constant is strongly dependent on molecular
geometry, this measure can provide valuable information regarding conformational equilibrium.
The dihedral angle between hydrogen atoms in the trans orientation is an extremely relevant
parameter, especially in the case of 3JHH.
In the equilibrium between pꢀax and pꢀeq, Jpꢀax and Jpꢀeq are J values for these conformers,
and the coupling constant will be as follows:
3J34exp = αpꢀax Jpꢀax + αpꢀeq Jpꢀeq
(1)
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where αpꢀax and αpꢀeq are the molar fractions of conformers pꢀax and pꢀeq, respectively. The observed
JAB value corresponds to a conformational equilibrium weighted average because under these
conditions conformer interconversion is much faster than the rate of spectrum acquisition.26
Using the electronic structure methods, we calculated the coupling constants Jpꢀax and Jpꢀeq
for each of the conformers, and the ¹H NMR spectra yielded approximate values for Jexp (firstꢀorder
analysis). The aboveꢀdescribed equation estimated the molar fraction of each conformer.1 By
varying the ¹H NMR solvent, we evaluated how the relative permittivity of the medium affected the
conformational equilibrium.
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Among the six hydrogen signals, that of H3 (αꢀcarbonyl) was the most sensitive to solvent
variation, as shown in Figure 6d for derivative 2. This hydrogen signal appeared as a double duplet
of quartets. The first two were related to the H3ꢀH4 and H3ꢀH4' couplings, whereas the quartet was
due to the coupling of approximately 0.5ꢀ0.6 Hz via the five bonds with the methyl. This finding
was corroborated by a homonuclear decoupling experiment. Upon irradiation at the methyl
frequency (2.92 ppm), the double duplet of the quartets became only a double duplet (Figure 6c).
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Figure 6. (a) The structure of 2; (b) expansion of the H3 signal in CD3CN showing coupling
constants 3JH3H4, 3JH3H4’ and 5JH3CH3; (c) homonuclear decoupling experiment with irradiation at
2.92 ppm in CDCl3; (d) overlapping of ¹H NMR spectra at 300 MHz for derivative 2 in carbon
tetrachloride, chloroformꢀd, acetoneꢀd6, methanolꢀd4 and acetonitrileꢀd3.
The variation of the coupling constant as a function of the solvent variation of the αꢀ
carbonyl hydrogen in the 4.2 ~ 4.5 ppm region was outstanding. In these compounds, the variation
3
of the JH3H4 coupling constant may have been directly associated with the interconversion of the
two conformations, as shown in Figure 7.
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X
4H
4H
3H
X
C2
C5
C5
C2
4H'
H3
4H'
9
pꢀax
pꢀeq
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11
12
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Figure 7. Variation of the dihedral angle θ(H3ꢀC3ꢀC4ꢀH4) in the pꢀax and pꢀeq conformers.
The values of the 3JH3H4 coupling constant were calculated by the mPW1PW91 method with
the EPRꢀIII basis set for carbon and hydrogen, the 6ꢀ311++G(3df,3pd) basis set for oxygen,
nitrogen, fluorine, chlorine, and bromine and the LanL2DZꢀECP basis set for iodine on the
structures previously optimized at the M06ꢀ2X/6ꢀ311++G(3df,3pd) level. The inclusion of the
solvation model did not affect the calculated values significantly. The variations were 0.02 Hz of the
value of the gaseous phase at most. Therefore, the gaseous phase data were used as a reference.
Table 7 presents the calculated data and the θ(H3ꢀC3ꢀC4ꢀH4) dihedral angles.
3
Table 7. JH3H4 coupling constants (in Hertz) and θ(H3ꢀC3ꢀC4ꢀH4) dihedral angle (in degrees)
calculated at the mPW1PW91/EPRꢀIII/6ꢀ311++G(3df,3pd) level on the structures previously
optimized at the M06ꢀ2X/6ꢀ311++G(3df,3pd) level.
pꢀax
pꢀeq
Cpd. Subs. 3JH3H4
θ
3JH3H4
θ
1
2
3
4
F
Cl
Br
I
0.27
0.43
0.72
0.41
ꢀ86.5
ꢀ85.0
ꢀ83.7
ꢀ82.9
9.99
11.44
11.79
11.65
ꢀ154.9
ꢀ156.6
ꢀ155.4
ꢀ153.5
3
Based on the experimental value of JH3H4 and the calculated constant values of each
conformer, we calculated the molar fractions using Equation 1. With the values of αpꢀax and αpꢀeq, we
determined the conformational equilibrium constant K. To evaluate the agreement between these
two parameters obtained via electronic structure methods, we used these data to estimate αpꢀax and
αpꢀeq. Applying these values to Equation 1, together with the calculated constants, we can propose a
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mean 3JH3H4 value, i.e., one that would appear in the spectrum, as shown in Table 8. The calculated
K value at the four levels of theory, M06ꢀ2X/6ꢀ311++G(3df,3pd), M06ꢀ2X/augꢀccꢀpVDZ, MP2/6ꢀ
311++G(3df,3pd) and MP2/augꢀccꢀpVDZ, follows the experimental value and the mean absolute
deviation (MAD).
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Table 8. ³JH3H4 constant (in Hertz), molar fraction, experimental and calculated conformational
equilibrium constant at different levels of theory and mean absolute error between experimental and
calculated values
8
9
3JH3H4
Exp.(a) Calc.(b) Exp.(c) Calc.(d) Exp.(e) Calc.(f) Exp.(a) Calc.(b) Exp.(c) Calc.(d) Exp.(e) Calc.(f)
M06ꢀ2X/6ꢀ311++g(3df,3pd) M06ꢀ2X/augꢀccꢀpVDZ
αpꢀax
K
3JH3H4
αpꢀax
K
10
11
12
13
14
15
16
17
18
19
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Cpd.
Solvent
Carb. Tetrachlor. 5.06
Chloroform
Acetone
5.69
6.63
7.56
7.80
7.70
3.52
4.34
5.68
5.82
5.94
2.49
3.21
4.26
4.41
4.41
1.05
1.24
1.70
1.70
1.79
0.87
0.51
0.45
0.43
0.40
0.40
0.67
0.64
0.59
0.60
0.57
0.84
0.81
0.77
0.78
0.75
0.86
0.85
0.81
0.84
0.80
0.44
0.35
0.25
0.23
0.24
0.72
0.65
0.52
0.51
0.50
0.84
0.78
0.68
0.67
0.67
0.94
0.93
0.88
0.88
0.88
0.08
0.97
1.24
1.35
1.50
1.49
0.49
0.56
0.68
0.68
0.75
0.19
0.23
0.30
0.28
0.33
0.16
0.18
0.24
0.20
0.25
1.26
1.89
3.00
3.43
3.25
0.39
0.55
0.91
0.96
1.00
0.19
0.29
0.47
0.50
0.50
0.06
0.08
0.13
0.13
0.14
0.41
5.06
5.66
5.85
6.11
6.09
4.04
4.36
4.90
4.88
5.15
2.49
2.80
3.27
3.17
3.44
2.00
2.15
2.60
2.26
2.69
4.95
5.87
6.85
6.99
7.01
3.16
4.00
5.32
5.55
5.32
2.41
3.07
4.10
4.26
4.05
1.24
1.43
1.88
1.96
1.96
0.59
0.97
0.45
0.43
0.40
0.40
0.67
0.64
0.59
0.60
0.57
0.84
0.81
0.77
0.78
0.75
0.86
0.85
0.81
0.84
0.80
0.52
0.42
0.32
0.31
0.31
0.75
0.68
0.56
0.53
0.56
0.85
0.79
0.69
0.68
0.70
0.93
0.91
0.87
0.86
0.86
0.05
0.97
1.24
1.35
1.50
1.49
0.49
0.56
0.68
0.68
0.75
0.19
0.23
0.30
0.28
0.33
0.16
0.18
0.24
0.20
0.25
0.93
1.36
2.10
2.24
2.26
0.33
0.48
0.80
0.87
0.80
0.18
0.27
0.44
0.47
0.43
0.08
0.10
0.15
0.16
0.16
0.19
5.66
5.85
6.11
6.09
1
Methanol
Acetonitrile
Carb. Tetrachlor. 4.04
Chloroform
Acetone
Methanol
Acetonitrile
4.36
4.90
4.88
5.15
2
3
4
Carb. Tetrachlor. 2.49
Chloroform
Acetone
Methanol
Acetonitrile
2.80
3.27
3.17
3.44
Carb. Tetrachlor. 2.00
Chloroform
Acetone
Methanol
Acetonitrile
MAD
2.15
2.60
2.26
2.69
MP2/6ꢀ311++g(3df,3pd)
Carb. Tetrachlor. 5.06
MP2/augꢀccꢀpVDZ
4.59
5.92
7.27
7.45
7.47
2.27
3.16
4.56
4.77
4.81
1.63
2.08
2.86
3.00
3.00
1.24
1.52
1.88
1.88
1.96
0.72
0.51
0.45
0.43
0.40
0.40
0.67
0.64
0.59
0.60
0.57
0.84
0.81
0.77
0.78
0.75
0.86
0.85
0.81
0.84
0.80
0.56
0.42
0.28
0.26
0.26
0.83
0.75
0.63
0.61
0.60
0.92
0.88
0.81
0.79
0.79
0.93
0.90
0.87
0.87
0.86
0.07
0.97
1.24
1.35
1.50
1.49
0.49
0.56
0.68
0.68
0.75
0.19
0.23
0.30
0.28
0.33
0.16
0.18
0.24
0.20
0.25
0.80
1.39
2.58
2.82
2.86
0.20
0.33
0.60
0.65
0.66
0.09
0.14
0.24
0.26
0.26
0.08
0.11
0.15
0.15
0.16
0.28
5.06
5.66
5.85
6.11
6.09
4.04
4.36
4.90
4.88
5.15
2.49
2.80
3.27
3.17
3.44
2.00
2.15
2.60
2.26
2.69
3.51
4.82
6.32
6.52
6.56
2.03
2.91
4.24
4.47
4.52
1.54
1.91
2.64
2.79
2.79
1.24
1.52
1.96
1.96
2.04
0.77
0.51
0.45
0.43
0.40
0.40
0.67
0.64
0.59
0.60
0.57
0.84
0.81
0.77
0.78
0.75
0.86
0.85
0.81
0.84
0.80
0.67
0.53
0.38
0.36
0.35
0.85
0.78
0.65
0.63
0.63
0.93
0.89
0.83
0.81
0.81
0.93
0.90
0.86
0.86
0.85
0.07
0.97
1.24
1.35
1.50
1.49
0.49
0.56
0.68
0.68
0.75
0.19
0.23
0.30
0.28
0.33
0.16
0.18
0.24
0.20
0.25
0.50
0.88
1.65
1.80
1.83
0.17
0.29
0.53
0.58
0.59
0.08
0.12
0.21
0.23
0.23
0.08
0.11
0.16
0.16
0.17
0.18
Chloroform
Acetone
Methanol
Acetonitrile
5.66
5.85
6.11
6.09
1
2
3
4
Carb. Tetrachlor. 4.04
Chloroform
Acetone
Methanol
Acetonitrile
4.36
4.90
4.88
5.15
Carb. Tetrachlor. 2.49
Chloroform
Acetone
Methanol
Acetonitrile
2.80
3.27
3.17
3.44
Carb. Tetrachlor. 2.00
Chloroform
Acetone
Methanol
Acetonitrile
MAD
2.15
2.60
2.26
2.69
(a) Observed coupling constant, (b) coupling constant calculated with Eqn. 1 based on the molar fraction and K values
obtained from electronic structure calculation, (c) molar fraction calculated with Eqn. 1 using the observed J value and
the calculated constants of each conformer, (d) molar fraction calculated based on the K constant obtained by electronic
structure calculation, (e) conformational equilibrium constant K based on the molar fractions of item (c), (f)
conformational equilibrium constant obtained by electronic structure calculation.
The interpretation of the data presented in Table 8 confirms the tendency observed in the
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electronic structure calculations: conformer pꢀax prevails in less polar media, and this preference
decreases with the increase in the relative solvent permittivity. This behavior is more expressive in
fluorine and chlorine derivatives than in bromine and iodine derivatives.
8
9
The values calculated based on the coupling constant and the values obtained by electronic
structure calculations are distinct, which was expected because the model employed is relatively
simple. Nevertheless, the agreement between the techniques was rather satisfactory.
Among the theory levels used, the DFT method M06ꢀ2X associated with the augꢀccꢀpVDZ
basis set produced the smallest mean absolute deviation in the coupling constant and molar fraction
values. Although the MP2/augꢀccꢀpVDZ level provided a smaller deviation in the K value than did
the M06ꢀ2X/augꢀccꢀpVDZ level, the difference was minimal. Therefore, the best theory level was
M06ꢀ2X/augꢀccꢀpVDZ. At this level, the greatest deviation was 1.09 Hz for the bromine derivative
coupling constant in methanolꢀd4, which correlated to the deviation of 0.10 of the molar fraction
and 0.19 of the equilibrium constant. The values presented in this discussion were obtained at this
level.
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The fluoro derivative also showed a less sharp population variation relative to the theoretical
calculation. For compound 1, for example, the observed variation ranged from 51% to 40%, from
carbon tetrachloride to acetonitrile, whereas the calculation pointed to a variation ranging from 52%
to 31%.
Derivative 2 is a good example of the population variation as a function of the relative
permittivity of the medium and how it relates to the dipole moment of each conformer. Conformer
pꢀax has a dipole moment of 4.6 D, whereas the dipole moment of pꢀeq is 5.2 D. The population of
67% observed for pꢀax in carbon tetrachloride fell to 57% in acetonitrile. This decrease was also
predicted by the calculation, which indicated a variation ranging from 75 to 56%. This variation is
illustrated in the graph in Figure 8 and agrees with the calculated dipole moments. In general, there
was better agreement between solvents of high relative permittivity and for bromine and iodine
derivatives.
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Figure 8. Molar fraction of conformer pꢀax of derivative 2 as a function of the relative medium
permittivity (carbon tetrachloride ε = 2.22, chloroform ε = 4.90, acetone ε = 20.70, methanol ε =
32.63 and acetonitrile ε = 36.64). Population calculated at the M06ꢀ2X/augꢀccꢀpVDZ level.
4. Conclusions
Electronic structure calculations correctly described the tendencies observed experimentally.
The different levels agreed for the most stable conformer: in the gaseous phase, the conformer pꢀax
prevailed for all substituents, and the iodine derivative population was more significant than that of
the fluorine derivative.
This tendency can be explained considering an equilibrium between electrostatic repulsion
and electronic delocalization. The first favors conformer pꢀax and is stronger in the fluorine
derivative, which would have its conformational preference inverted if delocalization predominated.
Because O – F repulsion is stronger in conformer pꢀeq, pꢀax is favored. In the iodine derivative,
electronic delocalization exerts a stronger effect on the relative stability of conformer pꢀax, i.e., the
hyperconjugative interactions that favor this conformer are energetically favorable. Additionally,
this conformation is less affected by electrostatic repulsion.
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In the solvated structure, the conformational preference varied. As the relative permittivity
of the solvent increased, conformer pꢀeq became progressively more stable, mainly in fluorine and
chlorine derivatives, which presented a conformational inversion. Bromine and iodine derivatives
did not suffer a significant variation. This tendency agrees with the dipole moment of each
conformer: pꢀeq is more polar and more stable in solvents with high relative permittivity. We can
infer in this case that the interactions with the solvent become more significant than the electrostatic
repulsion.
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Although the iodine derivative presented the same correlation between the dipole moments,
this compound was significantly affected by electronic delocalization, which is less influenced by
the relative permittivity of the solvent than by electrostatic forces; consequently, only a slight
increase in the percentage of conformer pꢀeq occurred.
5. Author information
* E.A.B. Eꢀmail: eabasso@uem.br. Tel: +55 44 3011 3662
6. Acknowledgements
The authors would like to thank the Brazilian Council for Scientific and Technological
Development (CNPq) for fellowships for (E.A.B. and R.R.) and to Coordination for the
Improvement of Higher Education Personal (CAPES) for scholarships for (U.Z.M. and D.A.S.Y). A
grant (#2012/03933ꢀ5) from São Paulo Research Foundation (FAPESP) for this work is also
gratefully acknowledged.
7. Supporting Information
Experimental procedure (synthesis) for each derivative, Cartesian coordinates for the
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optimized conformers, ¹H and ¹³C NMR spectra in CDCl3 and NMR spectral data in different
solvents. This material is available free of charge via the Internet at http://pubs.acs.org.
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8. References
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