NMR Spectroscopy and Theoretical Calculations in the

Subscriber access provided by University of Manitoba Libraries

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

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

The Journal of Physical Chemistry A is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 30

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Physical Chemistry

NMR Spectroscopy and Theoretical Calculations in the Conformational Analysis of 1-methylpyrrolidin-2one 3-Halo-derivatives 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, 87020-900, Maringa, PR, Brazil ² Physical Organic Chemistry Laboratory, Chemistry Institute, University of Campinas, 13083-970, Campinas, SP, Brazil

ACS Paragon Plus Environment

1


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 30

Abstract 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 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 pseudoequatorial 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 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.

Keywords: 1-methylpyrrolidin-2-one, steric and electronic substituent effects, solvent effect.


2

Page 3 of 30

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


1. Introduction

Five-membered rings, together with six-membered 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 three-dimensional 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. The number of studies in the literature on five-membered rings, cyclopentanes, and their derivatives is small compared to the number of studies on other compounds, especially sixmembered rings.1–3 However, it is important to note that five-membered rings are present in the structures of various natural products and synthetic derivatives, such as steroids, prostaglandins, sugars and nucleotides.4 Recent studies on trans-2-halocyclopentanols5 using the 3JHH 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 σC-C → σ*C-O, σC-C →σ*C-X and σC-H → σ*C-H. In a study of 2-halocyclopentanones using electronic structure calculations, Martins et al.2 determined that the cyclopentanone ring is in a half-chair conformation (half-chair, C2) and the envelope conformation (Cs) was not observed. The conformer with the halogen in the pseudo-axial position predominates in the gaseous phase. The bromine derivative showed the greatest energy difference between the conformers [∆E = 0.85 kcal mol-1 at theory level B3LYP/6311++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 pseudo-equatorial conformer increased from CCl4 to DMSO (from 70 to 88%). This variation was explained based on the dipole


3


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 4 of 30

moments. Because the pseudo-equatorial conformer is more polar, it tends to be more stable in media with high relative permittivity. Another class of cyclic compounds, lactams,6 is part of various molecules of chemical and biological relevance. Among these compounds, ß-lactams have been examined in a large number of studies7, whereas γ-butyrolactams remain significantly underinvestigated. The synthesis of certain substituted ß- and γ-lactams was described by Chatterjee et al. and characterized by elemental analysis and infrared spectroscopy as early as 1967.8 Structural studies of certain alkaloid-analogue-substituted δ-lactams 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 X-ray crystallography. In 2009, Ariza-Castolo et al.10 published a conformational analysis of N-aryl ε-lactams 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 non-substituted γ-butyrolactam). Another study on N-methyl-γ-butyrolactams 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 3-halo-derivatives of 1methylpyrrolidin-2-one (Figure 1) by NMR and electronic structure calculations.

O 2

X

N

3 4

CH3

5

Figure 1. General structure of the compounds under study. X = F (1), Cl (2), Br (3) and I (4).


4

Page 5 of 30

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


2. Experimental and Computational Details

2.1 Synthesis

The compounds were prepared by reacting lithium enolate of 1-methylpyrrolidin-2-one with a halogenation reagent (N-fluorobenzenesulfonimide, 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 (non-substituted); 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 1-µmol L-1 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, chloroform-d, acetone-d6, methanol-d4 and acetonitrile-d3) were applied, by using tetramethylsilane as an internal reference. All analyses in carbon tetrachloride were performed using a coaxial insert tube containing chloroform-d. The probe was kept at room temperature, and for the 1H 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


5


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 6 of 30

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 1-4 in different solvents, ¹H and ¹³C NMR spectra in chloroform-d, and the simulated spectra in chloroform-d are available in the Supporting Information.

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 M06-2X19 density functional together with the Pople 6-311++G(3df,3pd) basis set15 and Dunning aug-cc-pVDZ basis set.16 For the iodine atom, the LanL2DZ-ECP 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 M062X/6-311++G(3df,3pd) using model IEF-PCM,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 secondorder Möller-Plesset perturbation ab initio method19 was applied by combining the basis sets 6311+G(3df,3pd) and aug-cc-pVDZ 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 self-consistent 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 EPR-III (for C and H), 6311++G(3df,3pd) (for N, O, F, Cl and Br) and LanL2DZ-ECP (for I).20,21 The structures optimized at the M06-2X/6-311++G(3df,3pd) level were used in the gaseous phase. The calculations involving


6

Page 7 of 30

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


natural bond orbital theory were performed using the structures optimized in the gaseous phase at theory level M06-2X/6-311++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

3. Results and discussion

3.1 Molecular geometry optimization and determination of conformational equilibrium

Starting with the known conformations of cyclopentanone,1 half-chair (C2) and envelope (CS), and substituting one α-carbonyl carbon atom by one nitrogen atom, we determined that, unlike cyclopentanone, pyrrolidin-2-one 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 pseudo-rotation of bonds C3-C4 and C4-C5. (a)

(b)

-

O

O N

CH3

+

N

CH3

Figure 2. (a) Illustration of the amide plane, (b) resonance hybrids for 1-methylpyrrolidin-2-one.

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 α-carbonyl halogen can occupy two positions: a


7


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 8 of 30

pseudo-axial (labeled p-ax) and a pseudo-equatorial (labeled p-eq) (Figure 3).

Figure 3. Conformational equilibrium for 3-chloro-1-methylpyrrolidin-2-one (2).

Each conformation was submitted to optimization and frequency calculations in the gaseous phase at theory levels M06-2X/6-311++G(3df,3pd) and M06-2X/aug-cc-pVDZ and with the continuum solvation model IEF-PCM 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 p-ax ↔ p-eq using the equation ∆Gº = – RTlnK, where R = 8.31447 J mol-1 K-1; T = 298.15 K and K = αp-eq / αp-ax. The data are shown in Table 1. For the relative energy, conformer p-ax was defined as zero.


8

Page 9 of 30

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48


Table 1. Dipole moment (Debye), energy difference (kJ mol-1), Gibbs free energy difference (kJ mol-1) and conformational equilibrium constant calculated at the M06-2X/6-311++G(3df,3pd) and M06-2X/aug-cc-pVDZ (LanL2DZ-ECP for I) theory levels for derivatives 1 to 4 in the gaseous phase and in solution. Gas phase Cpd. Subs. Conf.

µ

M06-2X/6-311++G(3df,3pd) p-ax 4.65 1 F p-eq 5.32 p-ax 4.57 2 Cl p-eq 5.23 p-ax 4.54 3 Br p-eq 5.19 p-ax 4.35 4 I p-eq 4.84 M06-2X/aug-cc-pVDZ p-ax 4.70 1 F p-eq 5.36 p-ax 4.65 2 Cl p-eq 5.31 p-ax 4.61 3 Br p-eq 5.26 p-ax 4.42 4 I p-eq 4.92

∆E

∆Gº

0.00 0.29 0.00 3.54 0.00 5.57 0.00 8.06

0.00 0.29 0.00 3.15 0.00 5.14 0.00 7.45

0.00 1.26 0.00 4.23 0.00 6.06 0.00 7.88

0.00 0.90 0.00 3.63 0.00 5.21 0.00 6.83

Carbon tetrachloride K

0.89 0.28 0.13 0.05

0.69 0.23 0.12 0.06

∆E

∆Gº

0.00 -0.85 0.00 2.54 0.00 4.62 0.00 7.36

0.00 -0.58 0.00 2.36 0.00 4.16 0.00 6.82

0.00 -0.05 0.00 3.08 0.00 5.05 0.00 7.11

0.00 0.18 0.00 2.77 0.00 4.28 0.00 6.30

K

1.26 0.39 0.19 0.06

0.93 0.33 0.18 0.08

Chloroform ∆E

∆Gº

0.00 -2.02 0.00 1.46 0.00 3.58 0.00 6.57

0.00 -1.58 0.00 1.48 0.00 3.10 0.00 6.14

0.00 -1.28 0.00 1.90 0.00 3.99 0.00 6.25

0.00 -0.77 0.00 1.80 0.00 3.25 0.00 5.75

Acetone K

1.89 0.55 0.29 0.08

1.36 0.48 0.27 0.10

∆E

∆Gº

0.00 -3.36 0.00 0.12 0.00 2.34 0.00 5.56

0.00 -2.73 0.00 0.23 0.00 1.89 0.00 5.15

0.00 -2.62 0.00 0.49 0.00 2.71 0.00 5.23

0.00 -1.84 0.00 0.54 0.00 2.02 0.00 4.76

Methanol K

3.00 0.91 0.47 0.13

2.10 0.80 0.44 0.15

∆E

∆Gº

0.00 -3.58 0.00 0.03 0.00 2.47 0.00 5.64

0.00 -3.05 0.00 0.09 0.00 1.73 0.00 5.10

0.00 -2.80 0.00 0.29 0.00 2.52 0.00 5.08

0.00 -2.00 0.00 0.34 0.00 1.88 0.00 4.56

Acetonitrile K

3.43 0.96 0.50 0.13

2.24 0.87 0.47 0.16

∆E

∆Gº

0.00 -3.57 0.00 -0.11 0.00 2.14 0.00 5.39

0.00 -2.92 0.00 0.00 0.00 1.71 0.00 4.95

0.00 -2.83 0.00 0.26 0.00 2.50 0.00 5.06

0.00 -2.02 0.00 0.54 0.00 2.10 0.00 4.53

K

3.25 1.00 0.50 0.14

2.26 0.80 0.43 0.16

9 ACS Paragon Plus Environment


According to the data presented in Table 1, in the gaseous phase, the conformational equilibrium shifted to conformer p-ax. This preference became more expressive going down the halogen family (from F to I). When the solvent was present, the preference for p-ax decreased, and for the fluorine derivative, the preference was inverted; that is, conformer p-eq was favored in solvents with greater relative permittivity. In the chlorine derivative, the population of conformer peq also increased; in methanol and in acetonitrile, the populations of the two conformers were rather similar. In the bromine and iodine derivatives, the p-ax 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). 5 1 2 Conformational equilibrium constant

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 10 of 30

3

4

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 M06-2X/6-311++G(3df,3pd) level (LanL2DZ-ECP for I) for derivatives 1 to 4.


10

Page 11 of 30

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


The data obtained with the basis functional 6-311++G(3df,3pd) agree with the tendency observed with aug-cc-pVDZ. However, it can be observed that the K values are closer for iodine than for fluorine. 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 M06-2X. However, for derivatives 1 and 2 in particular, constant K presented smaller values; that is, the relative energy of conformer p-ax increased. The difference between bases 6-311++G(3df,3pd) and aug-cc-pVDZ mentioned in the previous paragraph was also observed for the fluorine derivative.

Table 2. Dipole moment (Debye), energy difference (kJ mol-1), Gibbs free energy variation in the gaseous phase (kJ mol-1), and conformational equilibrium constant based on the total energy (Ke) calculated at the MP2/6-311++G(3df,3pd) and MP2/aug-cc-pVDZ (LanL2DZ-ECP for I) theory levels for derivatives 1 to 4 in the gaseous phase and in solution. Gas phase Cpd. Subs. Conf.

µ

MP2/6-311++G(3df,3pd) p-ax 4.95 1 F p-eq 5.74 p-ax 4.82 2 Cl p-eq 5.55 p-ax 4.80 3 Br p-eq 5.51 p-ax 4.00 4 I p-eq 4.63 MP2/aug-cc-pVDZ p-ax 5.07 1 F p-eq 5.87 p-ax 4.95 2 Cl p-eq 5.70 p-ax 4.89 3 Br p-eq 5.62 p-ax 4.70 4 I p-eq 5.26

∆Gº 0.00 1.84 0.00 4.44 0.00 5.99 0.00 6.77 0.00 3.02 0.00 5.01 0.00 6.68 0.00 6.64

K

0.48 0.17 0.09 0.07

0.30 0.13 0.07 0.07

Carbon tetrachloride ∆E Ke 0.00 0.54 0.00 3.93 0.00 5.86 0.00 6.20 0.00 1.70 0.00 4.33 0.00 6.31 0.00 6.22

0.80 0.20 0.09 0.08

0.50 0.17 0.08 0.08

Chloroform ∆E 0.00 -0.81 0.00 2.72 0.00 4.81 0.00 5.56 0.00 0.33 0.00 3.08 0.00 5.22 0.00 5.51

K

e

1.39 0.33 0.14 0.11

0.88 0.29 0.12 0.11

Acetone ∆E 0.00 -2.35 0.00 1.27 0.00 3.51 0.00 4.74 0.00 -1.24 0.00 1.57 0.00 3.86 0.00 4.61


K

Methanol e

2.58 0.60 0.24 0.15

1.65 0.53 0.21 0.16

∆E 0.00 -2.57 0.00 1.06 0.00 3.32 0.00 4.62 0.00 -1.46 0.00 1.35 0.00 3.66 0.00 4.49

K

e

2.82 0.65 0.26 0.15

1.80 0.58 0.23 0.16

Acetonitrile ∆E 0.00 -2.60 0.00 1.03 0.00 3.29 0.00 4.60 0.00 -1.50 0.00 1.32 0.00 3.63 0.00 4.47

Ke

2.86 0.66 0.26 0.16

1.83 0.59 0.23 0.17

11


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 12 of 30

3.2 Analysis of the natural bond orbitals

It has been proposed that the ηX → π*C=O orbital interaction is important for the conformational preference of 2-halo-cyclohexanones1,25,26 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 mol-1 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 2-halo derivatives, the σC-X → π*C=O delocalization also plays a major role in determining their conformational equilibrium.

In a more recent study, Rozada et al.29 added

that in addition to the σC-X → π*C=O interaction, the σCα-H → 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 mol-1, Ei – Ej in atomic units. Calculated at the M06-2X/6-311++G(3df,3pd) level (LanL2DZ-ECP for I). σC-X → π*C=O Cpd. Subs. Conf. 1

F

2

Cl

3

Br

p-ax p-eq p-ax p-eq p-ax p-eq

σC-H → π*C=O

ηX → π*C=O

Eij

Ei – Ej

F(i;j)

Eij

Ei – Ej

F(i;j)

Eij

Ei – Ej

F(i;j)

7.06 1.68 18.27 4.28 24.19 6.13

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 25.96 7.10 25.96

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 8.74 -a 8.11 -a

0.57 0.45 0.43 -

0.030 0.029 0.028 -


12

Page 13 of 30

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


4

I

p-ax p-eq

36.37 11.13

0.60 0.60

0.069 7.52 0.70 0.034 6.51 0.038 25.66 0.68 0.061 -a -1 (a) interaction smaller than 2.1 kJ mol .

0.39 -

0.024 -

It can be observed that the σC-X → π*C=O hyperconjugation is visibly stronger in conformer p-ax and that this preference increases going down in the halogen family, from F → I. The p-ax preference over p-eq can be understood relative to the overlap: in p-ax, the overlap is nearly twice the value of p-eq, as shown in the orbital representation in Figure 5. Because the maximum overlap occurs when the orbitals are periplanar or anti-periplanar, it is clear that this parameter favors conformer p-ax. πC=O *

σC-Cl

p-ax σC-H

p-ax π*C=O

p-ax σC-Cl

p-ax πC=O *

σC-Cl

p-eq σC-H

p-eq π*C=O

p-eq σC-Cl

p-eq

Figure 5. Representation of natural bond orbitals σC-X and π*C=O for conformers p-eq and p-ax 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 σC-X 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 σC-H → π*C=O donation is more significant in conformer p-eq, and it hardly varies when the halogen is varied. This variation is likely related to the electronegativity of the ACS Paragon Plus Environment

13


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 14 of 30

substituent. As in the previous interaction, the dihedral angle H–C–C=O favors conformer p-eq. 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 p-ax with high Eij values, whereas the values for p-eq are less than 2.1 kJ mol-1 in all cases. The equilibrium between these interactions agrees with the tendency observed in the calculations: the preference of the fluorine derivative for the p-eq conformer is greater. Its σC-H → π*C=O interaction is greater than that of σC-X → π*C=O; the opposite occurs for iodine derivatives, which have a stronger preference for the p-ax 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 anti-ligand 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 mol-1) and conformational equilibrium constant for the deletion of orbital π*C=O. Calculated at the M06-2X/6-311++G(3df,3pd) level (LanL2DZ-ECP for I). Before deletion Cpd. Subs. Conf.

∆E

p-ax p-eq p-ax p-eq p-ax p-eq p-ax p-eq

0.00 0.29 0.00 3.54 0.00 5.57 0.00 8.06

1

F

2

Cl

3

Br

4

I

K 0.89 0.24 0.11 0.04

Deletion π*C=O ∆E 0.00 0.24 6.38 0.00 6.98 0.00 1.20 0.00

K 0.91 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 p-ax even more) because the interactions involving fluorine were less intense. Because fluorine is very electronegative, the electron density ACS Paragon Plus Environment

14

Page 15 of 30

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


donation tends to be smaller. Furthermore, because the delocalizations presented in Table 3 are no longer possible, conformer p-eq prevails, which demonstrates the relevance of interactions involving π*C=O, such as σC-X → π*C=O, σC-H → π*C=O and ηX → π*C=O, and other less significant ones for the relative stability of conformer p-ax. 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 p-ax and p-eq without electronic delocalization.

Table 5. Deletion energy (kJ mol-1) and conformer equilibrium constant variation for total deletion and total steric exchange energy (Eex) and its variations for the conformers (kJ mol-1) calculated at the M06-2X/6-311++G(3df,3pd) level (LanL2DZ-ECP for I). Total deletion Cpd. Subs. Conf.

E(a)

∆E (b)

K

∆E(hip) (c)

Total steric exchange energy ex E ∆Eex

p-ax -1114094.43 2160.59 463.41 3.38 0.00 0.00 p-eq -1114058.13 36.30 2196.57 460.03 0.00 p-ax -2060232.75 0.00 2153.37 485.97 4.23 2 Cl 0.00 p-eq -2060216.41 16.33 2166.03 481.74 0.00 p-ax -7610482.37 0.00 2136.09 495.67 5.23 3 Br 0.14 p-eq -7610477.41 4.96 2134.80 490.44 0.00 p-ax -881800.80 8.42 2094.85 478.81 8.39 4 I 29.87 p-eq -881809.22 0.00 2077.54 470.42 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. 1

F

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. ACS Paragon Plus Environment

15


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 16 of 30

When the total deletion is applied, it can be observed that the preference for p-ax 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. The steric exchange energy data indicate that conformer p-eq has lower indicators than does p-ax; thus, p-eq steric features are favored. Therefore, what drives fluorine, chlorine and bromine derivatives to prefer the p-ax 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 p-ax suffers less electrostatic repulsion, as demonstrated by both the EEO–X parameter, which indicates a greater O–X repulsion in p-eq, and EETOTAL, which shows that conformer p-eq in general is destabilized by electrostatic interactions.

Table 6. O–X-ray (in Angström), electrostatic energy values and total energy (kJ mol-1) calculated at the MMFF94 level. Electrostatic energy Cpd. Subs. Conf.

rO–X

EEO–X

(a)

EETOTAL

(b)

∆EETOTAL

Total energy E (c)

∆E

p-ax 3.089 65.63 -4.05 0.00 52.90 0.00 p-eq 2.918 69.48 0.42 4.47 54.08 1.18 p-ax 3.355 51.53 -25.37 0.00 32.10 0.00 2 Cl p-eq 3.173 54.49 -21.67 3.70 37.70 5.60 p-ax 3.466 39.57 -43.83 0.00 15.37 0.00 3 Br p-eq 3.282 41.78 -41.03 2.81 22.89 7.51 p-ax 3.619 31.31 -56.58 0.00 7.49 0.00 4 I p-eq 3.437 32.96 -54.47 2.11 11.52 4.03 (a) Electrostatic energy relative to the oxygen-halogen repulsion interaction, (b) total electrostatic energy of the conformation, (c) total energy calculated by molecular mechanics method MMFF94. 1

F

The analysis of the total energy data shows that this parameter also indicates that the conformation p-ax is more stable. However, ∆E is greater for iodine derivatives than for fluorine


16

Page 17 of 30

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


derivatives, a tendency opposite to that demonstrated by ab initio and density functional theory calculations. However, the molecular mechanics methods do not take electronic delocalization into 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 mol-1, and this parameter is set off by the electrostatic repulsion in favor of the p-ax conformer by 4.47 kJ mol. Apparently, 4.47 kJ mol-1 would not be sufficient to set off the 36.30 kJ mol-1 from electronic

1

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.

5.4 Association of NMR measurements with the calculated data

Because the value of the spin-spin 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 p-ax and p-eq, Jp-ax and Jp-eq are J values for these conformers, and the coupling constant will be as follows: 3

J34exp = αp-ax Jp-ax + αp-eq Jp-eq


(1) 17


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 18 of 30

where αp-ax and αp-eq are the molar fractions of conformers p-ax and p-eq, 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 Jp-ax and Jp-eq for each of the conformers, and the ¹H NMR spectra yielded approximate values for Jexp (first-order analysis). The above-described 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. Among the six hydrogen signals, that of H3 (α-carbonyl) 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 H3-H4 and H3-H4' couplings, whereas the quartet was due to the coupling of approximately 0.5-0.6 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).


18

Page 19 of 30

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


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, chloroform-d, acetone-d6, methanol-d4 and acetonitrile-d3.

The variation of the coupling constant as a function of the solvent variation of the αcarbonyl hydrogen in the 4.2 ~ 4.5 ppm region was outstanding. In these compounds, the variation of the 3JH3H4 coupling constant may have been directly associated with the interconversion of the two conformations, as shown in Figure 7.


19


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

X

4H

4H

3H

Page 20 of 30

X C5

C2

C2

C5 4H'

4H'

H3

p-ax

p-eq

Figure 7. Variation of the dihedral angle θ(H3-C3-C4-H4) in the p-ax and p-eq conformers.

The values of the 3JH3H4 coupling constant were calculated by the mPW1PW91 method with the EPR-III basis set for carbon and hydrogen, the 6-311++G(3df,3pd) basis set for oxygen, nitrogen, fluorine, chlorine, and bromine and the LanL2DZ-ECP basis set for iodine on the structures previously optimized at the M06-2X/6-311++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(H3-C3-C4-H4) dihedral angles.

Table 7. 3JH3H4 coupling constants (in Hertz) and θ(H3-C3-C4-H4) dihedral angle (in degrees) calculated at the mPW1PW91/EPR-III/6-311++G(3df,3pd) level on the structures previously optimized at the M06-2X/6-311++G(3df,3pd) level. p-ax Cpd. Subs. 1 2 3 4

F Cl Br I

3

p-eq

JH3H4

θ

0.27 0.43 0.72 0.41

-86.5 -85.0 -83.7 -82.9

3

JH3H4

θ

9.99 11.44 11.79 11.65

-154.9 -156.6 -155.4 -153.5

Based on the experimental value of 3JH3H4 and the calculated constant values of each conformer, we calculated the molar fractions using Equation 1. With the values of αp-ax and αp-eq, 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 αp-ax and αp-eq. Applying these values to Equation 1, together with the calculated constants, we can propose a ACS Paragon Plus Environment

20

Page 21 of 30

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


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, M06-2X/6-311++G(3df,3pd), M06-2X/aug-cc-pVDZ, MP2/6311++G(3df,3pd) and MP2/aug-cc-pVDZ, follows the experimental value and the mean absolute deviation (MAD).


21


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 22 of 30

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 3

JH3H4

Solvent

(b)

(c)

3

K (d)

(e)

(f)

JH3H4

(a)

αp-ax (b)

(c)

K

Exp. Calc. Exp. Calc. Exp. Calc. Exp. Calc. Exp. Calc. Exp. Calc.(f) M06-2X/6-311++g(3df,3pd) M06-2X/aug-cc-pVDZ Carb. Tetrachlor. 5.06 5.69 0.51 0.44 0.97 1.26 5.06 4.95 0.97 0.52 0.97 0.93 Chloroform 5.66 6.63 0.45 0.35 1.24 1.89 5.66 5.87 0.45 0.42 1.24 1.36 Acetone 5.85 7.56 0.43 0.25 1.35 3.00 5.85 6.85 0.43 0.32 1.35 2.10 1 Methanol 6.11 7.80 0.40 0.23 1.50 3.43 6.11 6.99 0.40 0.31 1.50 2.24 Acetonitrile 6.09 7.70 0.40 0.24 1.49 3.25 6.09 7.01 0.40 0.31 1.49 2.26 Carb. Tetrachlor. 4.04 3.52 0.67 0.72 0.49 0.39 4.04 3.16 0.67 0.75 0.49 0.33 Chloroform 4.36 4.34 0.64 0.65 0.56 0.55 4.36 4.00 0.64 0.68 0.56 0.48 Acetone 4.90 5.68 0.59 0.52 0.68 0.91 4.90 5.32 0.59 0.56 0.68 0.80 2 Methanol 4.88 5.82 0.60 0.51 0.68 0.96 4.88 5.55 0.60 0.53 0.68 0.87 Acetonitrile 5.15 5.94 0.57 0.50 0.75 1.00 5.15 5.32 0.57 0.56 0.75 0.80 Carb. Tetrachlor. 2.49 2.49 0.84 0.84 0.19 0.19 2.49 2.41 0.84 0.85 0.19 0.18 Chloroform 2.80 3.21 0.81 0.78 0.23 0.29 2.80 3.07 0.81 0.79 0.23 0.27 Acetone 3.27 4.26 0.77 0.68 0.30 0.47 3.27 4.10 0.77 0.69 0.30 0.44 3 Methanol 3.17 4.41 0.78 0.67 0.28 0.50 3.17 4.26 0.78 0.68 0.28 0.47 Acetonitrile 3.44 4.41 0.75 0.67 0.33 0.50 3.44 4.05 0.75 0.70 0.33 0.43 Carb. Tetrachlor. 2.00 1.05 0.86 0.94 0.16 0.06 2.00 1.24 0.86 0.93 0.16 0.08 Chloroform 2.15 1.24 0.85 0.93 0.18 0.08 2.15 1.43 0.85 0.91 0.18 0.10 Acetone 2.60 1.70 0.81 0.88 0.24 0.13 2.60 1.88 0.81 0.87 0.24 0.15 4 Methanol 2.26 1.70 0.84 0.88 0.20 0.13 2.26 1.96 0.84 0.86 0.20 0.16 Acetonitrile 2.69 1.79 0.80 0.88 0.25 0.14 2.69 1.96 0.80 0.86 0.25 0.16 0.87 0.08 0.41 0.59 0.05 0.19 MAD MP2/6-311++g(3df,3pd) MP2/aug-cc-pVDZ Carb. Tetrachlor. 5.06 4.59 0.51 0.56 0.97 0.80 5.06 3.51 0.51 0.67 0.97 0.50 Chloroform 5.66 5.92 0.45 0.42 1.24 1.39 5.66 4.82 0.45 0.53 1.24 0.88 Acetone 5.85 7.27 0.43 0.28 1.35 2.58 5.85 6.32 0.43 0.38 1.35 1.65 1 Methanol 6.11 7.45 0.40 0.26 1.50 2.82 6.11 6.52 0.40 0.36 1.50 1.80 Acetonitrile 6.09 7.47 0.40 0.26 1.49 2.86 6.09 6.56 0.40 0.35 1.49 1.83 Carb. Tetrachlor. 4.04 2.27 0.67 0.83 0.49 0.20 4.04 2.03 0.67 0.85 0.49 0.17 Chloroform 4.36 3.16 0.64 0.75 0.56 0.33 4.36 2.91 0.64 0.78 0.56 0.29 Acetone 4.90 4.56 0.59 0.63 0.68 0.60 4.90 4.24 0.59 0.65 0.68 0.53 2 Methanol 4.88 4.77 0.60 0.61 0.68 0.65 4.88 4.47 0.60 0.63 0.68 0.58 Acetonitrile 5.15 4.81 0.57 0.60 0.75 0.66 5.15 4.52 0.57 0.63 0.75 0.59 Carb. Tetrachlor. 2.49 1.63 0.84 0.92 0.19 0.09 2.49 1.54 0.84 0.93 0.19 0.08 Chloroform 2.80 2.08 0.81 0.88 0.23 0.14 2.80 1.91 0.81 0.89 0.23 0.12 Acetone 3.27 2.86 0.77 0.81 0.30 0.24 3.27 2.64 0.77 0.83 0.30 0.21 3 Methanol 3.17 3.00 0.78 0.79 0.28 0.26 3.17 2.79 0.78 0.81 0.28 0.23 Acetonitrile 3.44 3.00 0.75 0.79 0.33 0.26 3.44 2.79 0.75 0.81 0.33 0.23 Carb. Tetrachlor. 2.00 1.24 0.86 0.93 0.16 0.08 2.00 1.24 0.86 0.93 0.16 0.08 Chloroform 2.15 1.52 0.85 0.90 0.18 0.11 2.15 1.52 0.85 0.90 0.18 0.11 Acetone 2.60 1.88 0.81 0.87 0.24 0.15 2.60 1.96 0.81 0.86 0.24 0.16 4 Methanol 2.26 1.88 0.84 0.87 0.20 0.15 2.26 1.96 0.84 0.86 0.20 0.16 Acetonitrile 2.69 1.96 0.80 0.86 0.25 0.16 2.69 2.04 0.80 0.85 0.25 0.17 0.72 0.07 0.28 0.77 0.07 0.18 MAD (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. Cpd.

(a)

αp-ax

(d)

(e)

The interpretation of the data presented in Table 8 confirms the tendency observed in the ACS Paragon Plus Environment

22

Page 23 of 30

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


electronic structure calculations: conformer p-ax 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. 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 M06-2X associated with the aug-cc-pVDZ basis set produced the smallest mean absolute deviation in the coupling constant and molar fraction values. Although the MP2/aug-cc-pVDZ level provided a smaller deviation in the K value than did the M06-2X/aug-cc-pVDZ level, the difference was minimal. Therefore, the best theory level was M06-2X/aug-cc-pVDZ. At this level, the greatest deviation was 1.09 Hz for the bromine derivative coupling constant in methanol-d4, 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. 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 p-ax has a dipole moment of 4.6 D, whereas the dipole moment of p-eq is 5.2 D. The population of 67% observed for p-ax 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.


23


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 24 of 30

Figure 8. Molar fraction of conformer p-ax 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 M06-2X/aug-cc-pVDZ 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 p-ax 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 p-ax 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 p-eq, p-ax is favored. In the iodine derivative, electronic delocalization exerts a stronger effect on the relative stability of conformer p-ax, i.e., the hyperconjugative interactions that favor this conformer are energetically favorable. Additionally, this conformation is less affected by electrostatic repulsion.


24

Page 25 of 30

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


In the solvated structure, the conformational preference varied. As the relative permittivity of the solvent increased, conformer p-eq 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: p-eq 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. 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 p-eq occurred.

5. Author information

* E.A.B. E-mail: [email protected]. 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 (#2012/03933-5) 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 ACS Paragon Plus Environment

25


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 26 of 30

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.

8. References

(1)

Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds; Wiley Interscience: New York, 1994.

(2)

Martins, C. R.; Ducati, L. C.; Tormena, C. F.; Rittner, R. Conformational Analysis of 2Halocyclopentanones by NMR and IR Spectroscopies and Theoretical Calculations. Spectrochim. Acta. A. Mol. Biomol. Spectrosc. 2009, 72, 1089–1096.

(3)

Braga, C. B.; Ducati, L. C.; Tormena, C. F.; Rittner, R. Conformational Analysis and Intramolecular Interactions of L-Proline Methyl Ester and Its N-Acetylated Derivative through Spectroscopic and Theoretical Studies. J. Phys. Chem. A 2014, 118, 1748–1758.

(4)

Biamonte, M. A.; Vasella, A. Glycosylidene Carbenes Part 26. The Intramolecular F?HO Hydrogen Bond of 1,3-Diaxial 3-Fluorocyclohexanols. Helv. Chim. Acta 1998, 81, 695–717.

(5)

Tormena, C. F.; Santos, F. P. Dos; Neto, A. C.; Rittner, R.; Yoshinaga, F.; Temistocles, J. C. T. Electronic Interactions and Their Influence on the Conformational Stability of Trans-2Halocyclopentanol. J. Phys. Chem. A 2007, 111, 295–298.

(6)

Orchin, M.; Macomber, R. S.; Pinhas, A. R.; Wilson, R. M. The Vocabulary and Concepts of Organic Chemistry; 2a ed.; Wiley Interscience: New Jersey, 2005.

(7)

Bose, A. K.; Manhas, M. S.; Srinivasan, P. R.; Chawla, H. P. S.; Dayal, B.; Foley, D. A. NMR Spectral Studies: XIII—Titanium Tetrachloride-Induced and Lanthanide-Induced Shifts in the Proton NMR Spectra of β-Lactams. Org. Magn. Reson. 1976, 8, 151–154.

(8)

Chatterjee, B. G.; Venkateswara Rao, V.; Roy, S. K.; Chawla, H. P. S. Synthesis of Substituted β- and γ-Lactams. Tetrahedron 1967, 23, 493–498.

(9)

Boudreault, N.; G. Ball, R.; Bayly, C.; A. Bernstein, M.; Leblanc, Y. Conformational Analysis of δ-Lactams. Tetrahedron 1994, 50, 7947–7956.

(10)

Montalvo-González, R.; Ariza-Castolo, A. Structural Determination of Epsilon-Lactams by 1H and 13C NMR. Magn. Reson. Chem. 2009, 47, 1013–1018.

(11)

El Firdoussi, A.; Esseffar, M.; Bouab, W.; Abboud, J.-L. M.; Mó, O.; Yáñez, M.; Ruasse, M. F. Density Functional Theory Study of the Hydrogen Bond Interaction between Lactones, Lactams, and Methanol. J. Phys. Chem. A 2005, 109, 9141–9148.

(12)

Nazarski, R. B.; Pasternak, B.; Leśniak, S. Three-Component Conformational Equilibria of Some Flexible Pyrrolidin-2-(thi)ones in Solution by NMR Data (δC, δH, and nJHH) and Their DFT Predictions: A Confrontation of Different Approaches. Tetrahedron 2011, 67, 6901–6916.


26

Page 27 of 30

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(13)

Beard, M. J.; Bailey, J. H.; Cherry, D. T.; Moloney, M. G.; Shim, S. B.; Statham, K. A.; Bamford, M. J.; Brian Lamont, R. Functionalised Pyrrolidinones Derived from (S)Pyroglutamic Acid. Tetrahedron 1996, 52, 3719–3740.

(14)

Frisch, M. J. et al. Gaussian 09, Revision B.01, 2009.

(15)

Krishnan, R.; Binkley, J. S.; Seeger, R.; Pople, J. A. Self-Consistent Molecular Orbital Methods. XX. A Basis Set for Correlated Wave Functions. J. Chem. Phys. 1980, 72, 650– 654.

(16)

Dunning, T. H. Gaussian Basis Sets for Use in Correlated Molecular Calculations. I. The Atoms Boron through Neon and Hydrogen. J. Chem. Phys. 1989, 90, 1007–1023.

(17)

Hay, P. J.; Wadt, W. R. Ab Initio Effective Core Potentials for Molecular Calculations. Potentials for the Transition Metal Atoms Sc to Hg. J. Chem. Phys. 1985, 82, 270–283.

(18)

Cancès, E.; Mennucci, B.; Tomasi, J. A New Integral Equation Formalism for the Polarizable Continuum Model: Theoretical Background and Applications to Isotropic and Anisotropic Dielectrics. J. Chem. Phys. 1997, 107, 3032–3041.

(19)

Head-Gordon, M.; Pople, J. A.; Frisch, M. J. MP2 Energy Evaluation by Direct Methods. Chem. Phys. Lett. 1988, 153, 503–506.

(20)

Richter, W. E.; Pontes, R. M.; Abiko, L. A.; Gauze, G. F.; Basso, E. A. Computation of 3JHH Coupling Constants with a Combination of Density Functional Theory and Semiempirical Calculations. Application to Complex Molecules. Comput. Theor. Chem. 2012, 1001, 7–14.

(21)

Richter, W. E.; Rozada, T. C.; Basso, E. A.; Pontes, R. M.; Gauze, G. F. Levels of Theory Modifications and Their Effects on 1JCH SSCCs Calculations: A Factorial Design Analysis. Comput. Theor. Chem. 2011, 964, 116–120.

(22)

Glendening, E. D.; Badenhoop, J. K.; Reed, A. E.; Carpenter, J. E.; Bohmann, J. A.; Morales, C. M.; Weinhold, F. NBO 5.G, 2001.

(23)

Halgren, T. A. Merck Molecular Force Field. I. Basis, Form, Scope, Parameterization, and Performance of MMFF94. J. Comput. Chem. 1996, 17, 490–519.

(24)

Hanwell, M. D.; Curtis, D. E.; Lonie, D. C.; Vandermeersch, T.; Zurek, E.; Hutchison, G. R. Avogadro: An Advanced Semantic Chemical Editor, Visualization, and Analysis Platform. J. Cheminform. 2012, 4, 17.

(25)

Eisenstein, O.; Anh, N. T.; Jean, Y.; Devaquet, A.; Cantacuzène, J.; Salem, L. Lone Pairs in Organic Molecules: Energetic and Orientational Non-Equivalence. Tetrahedron 1974, 30, 1717–1723.

(26)

Basso, E. A.; Kaiser, C.; Rittner, R.; Lambert, J. B. Axial/equatorial Proportions for 2Substituted Cyclohexanones. J. Org. Chem. 1993, 58, 7865–7869.

(27)

Yoshinaga, F.; Tormena, C. F.; Freitas, M. P.; Rittner, R.; Abraham, R. J. Conformational Analysis of 2-Halocyclohexanones: An NMR, Theoretical and Solvation Study. J. Chem. Soc. Perkin Trans. 2 2002, 1494–1498. ACS Paragon Plus Environment

27


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 28 of 30

(28)

Rozada, T. C.; Gauze, G. F.; Favaro, D. C.; Rittner, R.; Basso, E. A. Infrared and Theoretical Calculations in 2-Halocycloheptanones Conformational Analysis. Spectrochim. Acta. A. Mol. Biomol. Spectrosc. 2012, 94, 277–287.

(29)

Rozada, T. C.; Gauze, G. F.; Rosa, F. A; Favaro, D. C.; Rittner, R.; Pontes, R. M.; Basso, E. A. The Conformational Analysis of 2-Halocyclooctanones. Spectrochim. Acta. A. Mol. Biomol. Spectrosc. 2014, 137C, 176–184.


28

Page 29 of 30

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


TOC


29


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Page 30 of 30

NMR Spectroscopy and Theoretical Calculations in the

Recommend Documents