NMR Spectroscopy: a Tool for Conformational Analysis

Ann. Magn. Reson. Vol. 10, Issue 1/2, 1-27, 2011 AUREMN

Cláudio F. Tormena, Rodrigo A. Cormanich, Roberto Rittner* Physical Organic Chemistry Laboratory, Chemistry Institute, State University of Campinas, C.P. 6154, 13083-370 Campinas, SP, Brazil [email protected]

Matheus P. Freitas Chemistry Department, Federal University of Lavras, C.P. 3037, 37200-000, Lavras, MG, Brazil

Keywords: NMR spectroscopy, conformational analysis, theoretical calculations, infrared spectroscopy.

Abstract: The present review deals with the application of NMR data to the conformational analysis of simple organic compounds, together with other experimental methods like infrared spectroscopy and with theoretical calculations. Each sub-section describes the results for a group of compounds which belong to a given organic function like ketones, esters, etc. Studies of a single compound, even of special relevance, were excluded since the main goal of this review is to compare the results for a given function, where different substituents were used or small structural changes were introduced in the substrate, in an attempt to disclose their effects in the conformational equilibrium. Moreover, the huge amount of data available in the literature, on this research field, imposed some limitations which will be detailed in the Introduction, but it can be reminded in advance that these limitations include mostly the period when these results were published.

1. Introduction This review will include only the results shift reagents, etc.1 the present work will published from 1994 onwards since this concentrate on the analysis of data from NMR subject was reviewed in depth at that time by and IR spectroscopies and from theoretical Eliel et. al.1 An earlier extensive review on the calculations. rotational isomerism about sp2-sp3 carbon- A few concepts are briefly presented to carbon single bonds was published by make the whole text useful for a beginner in Karabatsos and Fenoglio2 in 1970. Another this field. All these concepts are detailed and review was also written by Olivato and Rittner3 spread in a large number of books at different in 1996. levels.1,4,5 Most of the selected compounds follows the scope proposed by Karabatsos and Fenoglio,2 Conformation including only the rotational isomerism for Y- It is important to distinguish the terms C-C=O systems, where Y=heteroatom. configuration and conformation. Both involve a Despite the wide variety of physical 3D structure. The first refers to the attachment methods available for such studies like of an atom or a group of atoms to a given measurements of dipole moments, microwave center in a given fixed order. Thus, two spectroscopy, Raman spectroscopy, use of enantiomers differ in their configuration since

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they have an opposite order of the substituents a given dihedral angle, with bonds being attachment. This means that to change from neither made nor broken. one configuration to another configuration it is Ethane is the simplest example of a necessary to break bonds and to form new compound which exhibits two different bonds. However, the situation with conformations, usually called conformers (Fig. conformations is very different. For any given 1). They differ by ca. 2.93 kcal mol-1, the configuration, it is possible to have several staggered conformation being the only one conformations, which only differ in the value of stable, since the eclipsed conformation corresponds to a maximum in energy (Fig. 2).

Staggered conformation Eclipsed conformation

Figure 1. Stable conformers for ethane.

An energy diagram for this rotational several papers from the literature severely equilibrium is shown in Fig. 2. Although it was criticized such interpretation and showed that believed that the higher energy of the eclipsed the major contribution for ethane form was due to steric effects of each pair of conformational preferences comes from steric hydrogens facing each other, Weinhold6 and effects (two thirds of the ethane rotational Pophristic and Goodman7 showed that this barrier energy).8-10 Notwithstanding, due to the energy difference can be attributed to large amount of different interpretations, the

CH→ *CH hyperconjugative orbital interactions controversies remain and the debate will likely 11 stabilizing the staggered form. However, to keep on.

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Figure 2. Energy diagram for changes in the ethane conformations.

The first studies on the rotational isomerism in Here it is important to define the ethane and similar compounds appeared in the conformation according to the substituent last decade of the 19th century and probably arrangements around the selected bond. The the first paper where the “free” rotation about IUPAC specification of the torsion angles as single bonds was the subject of discussion is proposed by Klyne and Prelog,14 is not as attributed to Bischoff.12 This was followed by a widely used as the practical assignments of cis large number of papers and a first reliable (synperiplanar), gauche (+synclinal for +30 to value for rotational barrier in ethane (3.15 kcal +90 and +anticlinal for +90 to +150) and trans mol-1) was obtained by Kemp and Pitzer in or anti (antiperiplanar) (see the C-C-C-C 1936,13 in close agreement with recent dihedral angle of butane in Fig. 3 as an experimental values (2.89-2.93 kcal mol-1). example).

cis gauche gauche anti or trans

(synperiplanar) (synclinal) (anticlinal) (antiperiplanar)

Figure 3. Practical assignments of conformer arrangements due to rotation of a single bond, in the C-C-C-C butane dihedral angle.

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Conformations of cyclic compounds effects in classical terms as “steric” and Despite early attempts to understand the “electrostatic” interactions or in quantum conformational properties of cyclic compounds, mechanical terms. However, some specific mostly cyclohexane derivatives, it was the terms were also introduced such as “hockey- remarkable paper of Barton15 which sticks”, “gauche-effect”, “rabbit-ears”, established the correct stereochemistry of “anomeric”, etc. these compounds and granted him the Nobel The results presented in the present review Prize in 1969. In that paper he showed that it will be interpreted using mostly classical terms was possible to distinguish two types of CH- and/or orbital interactions obtained from bonds: those lying perpendicular to the plane theoretical calculations. containing the six carbon atoms called polar (axial) and those lying approximately in this 2. Methodology plane called equatorial. The spectroscopic detection of individual The main difference between the acyclic conformers depend on the following and cyclic compounds is the large barrier to conditions:17 convert an equatorial to an axial substituted I. The average lifetime of the species must cyclohexane, which is in the range of ca. 10 be larger than the inverse frequency (1/ ) of -1 1 kcal mol . the radiation it is absorbing (Table 1). II. Each conformer must possess different absorption Substituent Effects characteristics and must be present within the In order to interpret and to explain the detection limits of concentration. results of the large number of published papers The limitation for NMR spectroscopy can be an extensive review was presented by overcome by working at sufficiently low 16 Zefirov, which describes the substituent temperatures, whenever it is possible.

Table 1. Minimum lifetimes for detecting stable conformers in conformational equilibrium.

Technique 1/ /s Minimum lifetime/s NMR 10-8 10-5 IR 10-12 10-8

2.1. NMR Spectroscopy The NMR method involves the averaged The application of NMR spectroscopy in chemical shift or coupling constant conformational analysis was clearly determination for a given hydrogen atom of a established by Garbisch,18 based on the first compound in conformational equilibrium. 19 observations of Eliel. However, Garbisch’s The observed property value Pexp ( or J) is method required the use of models with a fixed related to the conformer populations by Eqns geometry, which are not available for aliphatic [1] and [2]: compounds. 4

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Pexp= nAPA + nBPB [1] moments to make the equilibrium sensitive to

nA + nB = 1 [2] changes in solvent polarity. However, the development of an increased Here, we have two equations and four precision in the calculation of J values unknowns. This system can be solved if more simplified this procedure, since it is possible to data are collected by changing the solvent, calculate these values for every conformer and since the populations may change with the to obtain straightway the population conformer solvent, while the coupling constant is almost ratios. This alternative procedure was invariant with the solvent. The other parameter, successfully used for the first time in a recent the chemical shift, is not suitable since A and paper on stereoelectronic interactions and their

B also change with the solvent. effects in the conformational preferences for 2- 26 Moreover, when one or more conformers substituted methylenecyclohexanes. exists in more than one optical isomer, the Detailed data for chloroacetone is given statistical weight of this conformer must be below (Section 3.1) as an example of the NMR considered. E.g. for n-butane (Fig. 3) the method’s application. population of the gauche vs. anti is given by: 2.2. IR Spectroscopy Most of the early work on conformational ng/na = 2 exp (- E/RT) [3] analysis published in the first half of the 20th E = Eg - Ea [4] century was performed by microwave The factor 2 arises due to the presence of two spectroscopy. The progress in the electronic equivalent gauche forms, i.e. for n-butane industry in the 1940 decade allowed the gauche/anti ratio is of 2:1. construction of commercial infrared This system can be solved using a method spectrometers, which became the preferred proposed by Abraham based on solvation technique for organic chemists, both for theory.20 In this procedure, the geometries are compound identification and for conformational obtained from theoretical calculations with a analysis. One of the first papers using the later suitable software like e.g. GAUSSIAN,21 technique in the conformational analysis of GAMESS22 or Dalton23 and the data are simple aliphatic compounds is due to Jones 27 transferred to CHARGE,24 which gives the Z- and Noack on diethyl ketone. matrix used as an input for MODELS,20 The main advantage of infrared allowing the determination of all necessary spectroscopy in comparison to NMR parameters to obtain the solvation energies. spectroscopy is the possibility of observing a Then, these energies are introduced in the single band for every conformer due to a BESTFIT program,25 which calculates the J functional group absorption. In general, these values for the individual rotamers and the bands are partially superimposed (Fig. 4) or in energies in every solvent. These data lead to an extreme case coincident. Now, they can be 21-23,28, the conformer ratios in every solvent. The easily separated using specific software conformers must have different dipole and can be assigned to each conformer using calculated frequencies obtained from such 5

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softwares. the geometries corresponding to these minima are optimized using a higher level of theory,

0,40 giving now the best values for bond lengths, A 0,35 bond angles, dihedral angles, dipole moments 0,30 and energies for every conformer. All these 0,25 calculations can be performed using a DFT or

0,20

0,15 ab initio method, with different basis set, Absorbancia CCl4 0,10 available in softwares for theoretical 0,05 calculation.21-23 The energy difference gives 0,00 the conformer population ratio in the gas 1820 1800 1780 1760 1740 1720 1700 1680 Número de onda (cm-1) phase.

Figure 4. Carbonyl stretching band from the IR 3. Compounds spectrum of 2-chlorocyclopentanone in CCl4, showing the deconvoluted bands for the two The results from the conformational conformers.29 equilibrium for some series of compounds will be described according to their organic functional groups. The results presented in Although an estimation of the conformer early reviews will not be discussed here.1-3 populations ratio can be done from the bands area, this may lead to an erroneous value, as 3.1. Ketones the area depends upon the molar absorptivity - for each conformer. This was demonstrated by haloacetones, where halo=Cl, Br and I. The a -bromocyclohexanone,30 which fluoro-derivative is not included here, and also has shown that the axial and equatorial for the other series of carbonyl compounds, conformers have molar absorptivities ( ) of -1 -1 since it presents a unique behavior and it will 417 and 8181 mol cm in CCl4, respectively, -1 be discussed separately. A detailed discussion while in CH3CN they were 664 and 2931 mol is given here, since it exemplifies the approach cm-1, respectively. used for almost all series of carbonyl 2.3. Theoretical Calculations compounds studied in our laboratory. Theoretical calculations are used in Theoretical calculations at B3LYP/6- conformational analysis for obtaining the 311++G(d,p) for chloroacetone (CA) and geometries and energies for the most stable bromoacetone (BA) and at B3LYP/6- conformers of a given compound. In the first 311++G(d,p)/LANL2DZ for iodoacetone (IA) step the Potential Energy Surface (PES) is showed that the isolated form energy constructed by changing a given dihedral angle difference (Ecis – Egauche) for CA, BA and IA is in steps of 10 degrees, from 0 to 180 degrees 1.4, 1.4 and 1.6 kcal mol-1, respectively (Fig. for symmetrical dihedral angles and from 0 to 5).31 It must be noted that there are two 360 degrees for nonsymmetrical dihedral equivalent gauche conformers and, thus, eqn angles. The minima in this PES correspond to [3] and [4] must be applied. the existing conformers. In the following step,

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cis gauche

Figure 5. Stable conformers for chloroacetone.

3 Experimental JCH couplings, obtained in The larger stability of the gauche solvents of different relative permittivities, were conformer, in the isolated form, may be used in conjunction with data from ab initio attributed not only to the strong C-X and C=O calculations and with the solvation theory, dipole repulsion in the cis form, but also to the giving energy differences (Ecis – Egauche) of 1.7 stabilising effect of the nx *C=O interaction -1 -1 kcal mol (CA), 1.8 kcal mol (BA) and 1.1 occurring in the gauche form.32 Some other -1 kcal mol (IA), in the vapor, which are in examples of haloacetones have also been reasonable agreement with the theoretical studied: the 1,1- and 1,3-dihaloacetones. In the values. The solvent effects in the case of the 1,1-dichloro- and 1,1-dibromo- conformational equilibrium of chloroacetone is acetone, the conformer presenting the shown by data in Table 2. Similar results were hydrogen atom eclipsing the carbonyl group obtained for BA and IA. and the two halogen atoms symmetrically The increased stability of the cis conformer arranged in a gauche orientation is the most in solution, for the three -haloacetones may stable in the gas phase and in non-polar be explained by a solvation effect, where the solvents. However, the equilibrium is partially solvent molecules gather around the shifted to the other isomer (halogen eclipsing compound, a dipole-dipole stabilisation. the carbonyl group) in polar solvents.32

Table 2. Energy differences (kcal mol-1), cis and gauche molar fractions, and calculated and observed 3 31 coupling constants ( JC,H/Hz) for chloroacetone.

3 3 Solvent Ecis-Egauche JCH (calc.) JCH (obs.) % cis % gauche

CCl4 0.76 1.5 1.5 10.3 89.7

CDCl3 0.00 1.7 1.8 39.9 60.1

CD2Cl2 -0.47 1.9 1.9 49.8 50.2 Pure liq. -0.95 2.1 2.1 69.6 30.4 Acetone -0.93 2.1 2.1 69.6 30.4

CD3CN -1.27 2.2 2.2 79.4 20.6 DMSO -1.40 2.3 2.3 89.3 10.7 7

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For the 1,3-dihaloacetones, there is a of three conformers (4 – 6) in solution (Fig. 6) predominance of the gauche-gauche’ isomer whose populations depend on the solvent (5) in the gas phase for the dichloro- and polarity, as observed from their infrared dibromo-derivative, which turns into a mixture spectra.33

cis / cis (1) cis/gauche (2) cis/trans (3)

gauche/gauche (4) gauche/gauche’ (5) trans/trans (6)

Figure 6. Possible rotamers for 1,3-dihaloacetones.33

Aminoacetone34 presents an interesting electronic-density region. However, the main case since its cis isomer is far more stable effects which stabilize the cis arrangement are than the gauche isomer (Egauche -Ecis = 3.00 the hyperconjugative effects obtained from kcal mol-1). In the cis isomer there is a NBO calculations.35 stabilizing electrostatic attraction between the The geometries for the corresponding N,N- amino hydrogens and the non-bonding dimethylaminoacetone can only be obtained electron pairs of oxygen, but there is also a from 3D potential energy surfaces, varying the destabilizing repulsion between the nitrogen (N-CH2-C=O) and (LP-N-CH2-C=O) lone pair and the carbonyl-oxygen high dihedral angles (Fig. 7).

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-0.048

-0.05

-0.052

-0.054

-0.056

-0.058

Energia(u.a.) -0.06

-0.062

-0.064

-0.066 -200 400 -150 350 -100 300 -50 250 0 200 50 150 LP-N-CH2-C=O 100 100 N-CH2-C=O 150 50 200 0

Figure 7. 3D Potential energy surface obtained by rotating (N-CH2-C=O) and [LP-N-CH2-C(=O)] dihedral angles. The energy levels (AM-1 method) contour plot is showed in the x-y plane.

The removal of equivalent geometries ESc-Sc). It is noteworthy that despite the large (specular relationship) leads to two main stabilization energies, due to orbital isomers: synperiplanar-antiperiplanar ( =0°, interactions, for the Sp-Ap in relation to the Sc- =-180°) (Sp-Ap) and synclinal-synclinal Sc conformer, there is still a predominance of ( =135°, =-52°) (Sc-Sc), which are rather stereo-electronic repulsive effects making the 34 similar to the cis and gauche isomers. Here, later the most stable conformer (Fig. 8). -1 the energy difference is 0.81 kcal mol (ESp-Ap-

Sp-Ap Sc-Sc

Figure 8. Sp-Ap and Sc-Sc conformers for N,N-dimethylaminoacetone.

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3.2. Esters energy difference for the unsubstituted methyl -1 A series of methyl -haloacetates, similar to acetate is ca. 7.8 kcal mol , which is too high acetones, was also studied.36 Here, there are and means that only the s-cis must be two possible dihedral angles to be analysed considered. Considering only the most stable [O=C-O-R and X-C-C=O). The first would lead s-cis geometry, now the other dihedral angle to the s-cis and s-trans isomers (Fig. 9), whose gives two main isomers (Fig. 10).

O O

R1 R2 R1 O O

R2 s-cis s-trans

Figure 9. s-cis and s-trans isomers for aliphatic esters.

cis gauche

Figure 10. cis and gauche conformers for -substituted aliphatic esters.

Here, the conformational preferences for a polar solvent [(Ecis – Egauche) = 0.53 to 0.66 -1 methyl chloroacetate (MCA), methyl kcal mol , from CD2Cl2 to DMSO]. For MBA bromoacetate (MBA) and methyl iodoacetate the gauche form is more stable than the cis, in (MIA) were analyzed using experimental both the vapor and in solution, but for infrared data, theoretical calculations and NBO compound MIA only the gauche form was analyses. The conformational equilibria of observed both in isolated form as in solution. these three compounds can be represented by These conformational preferences were their cis and gauche rotamers. The gauche attributed to an unexpected orbital interaction, form of MCA is stable in the isolated form by not yet reported in the literature, between two -1 only 0.1 kcal mol (Ecis – Egauche), and also in a antibonding orbitals, *C=O *C-X, which non-polar solvent, but the cis is predominant in occurs only in the gauche rotamer. The iodo-

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derivative (MIA) presents the highest energy around 0.2, for the three compounds, obtained - for this *C=O *C-X interaction (19.2 kcal mol for *C=O orbital are too high for an antibonding 1), followed by bromo-derivative (MBA) (11.9 orbital, but they can be justified by the high kcal mol-1), then by chloro-derivative (MCA) energy (48 kcal mol-1) of the LP * O2 C=O -1 (5.0 kcal mol ). The occupancy and energy for interaction, which increases the electron the antibonding orbitals *C=O and *C-X are density at the *C=O orbital. presented in Table 3. The occupancy values

Table 3. NBO occupancy and energies (eV) for the antibonding orbitals calculated at the B3LYP/aug-cc-pVTZ level for the gauche conformer of the methyl haloacetates (halo= Cl, Br and I).36

Occupancy Orbital Energy Orbital Cl Br I Cl Br I

*C=O 0.220 0.225 0.232 -0.00728 -0.00457 -0.00296

*C-X 0.014 0.016 0.017 0.08484 0.03331 0.01904 E - - - 0.09212 0.03788 0.02200

were done using the DFT/B3LYP method with 3.3. Amides different basis set [cc-pVDZ, 6-31g(d,p) and Here, we will discuss separately the aug-cc-pVDZ] in the isolated form to identify results obtained for the -haloacetamides and the energy minima corresponding to each N,N-dimethyl -haloacetamides. rotamer and including the Polarizable

Continuum Model (PCM) to take into account 3.3.1. -Haloacetamides the solvents effects on the rotational 2 3 NMR data for JC-H and for J -H for the isomerism. Subsequent optimizations of the two studied amides – the -chloroacetamide most stable rotamers were performed at the (CA) and -bromoacetamide (BA),37 did not B3LYP/aug-cc-pVTZ in the isolated form and in show any changes on varying the solvent different solvents (CH3CN, DMSO and H2O). polarity, precluding the use of the NMR It was observed only the trans conformer method. The next step was to check for the for BA, while for CA a cis and a trans occurrence of possible conformers from the conformer were present, despite the very large potential energy surfaces (PES), using energy difference between them [ E(cis-trans) theoretical calculations. These calculations = 4.2 kcal mol-1] (Fig. 11).

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cis gauche trans

Figure 11. cis and trans stable conformers for chloro- (X=Cl) and trans and gauche conformers for bromoacetamide (X=Br).

This energy difference changes with solvent All structures for N,N-dimethylchloroacetamide and a value of 2.0 kcal mol-1 was obtained in (DMCA) and N,N-dimethylbromoacetamide DMSO. Thus, a comparison of the averaged (DMBA) were fully optimized at experimental couplings with theoretically DFT/B3LYP/aug-cc-pVTZ level, to give the calculated values, and taking into account the correct description of Cl and Br atoms, since it calculated energy difference between the two includes additional diffuse functions (prefix conformers, allowed the conclusion that both aug-), which take into account the relatively for CA as for BA the trans form was the most diffuse nature of the lone pairs. For the iodo- stable conformer in all solvents. Despite the derivative (DMIA) the geometry optimization occurrence of several orbital interactions, the was performed at DFT/B3LYP and aug-cc-

LPN/π*C=O interaction, presents in both pVTZ basis set for C, H, O and N atoms, while compounds, was 6.0 kcal mol-1 more energetic for the iodine atom a correlation consistent for the trans conformer, which explains its basis set aug-cc-pVTZ-PP,39 with small-core larger stabilization. For BA the gauche form relativistic pseudo-potential was applied. only occurs in polar solvents as 20% [from The calculated energy values showed that theoretical data in DMSO; E(gauche-trans) = the gauche was the only conformer in the 0.9 kcal mol-1] or as 40% (from the calculated isolated form [ E(cis-gauche) > 3.0 kcal mol-1], coupling constants values). These relative for these haloacetamides. Infrared data in larger populations for BA gauche conformer in different solvents are in agreement with these polar solvents, can be attributed to an results. Even in very polar solvents the gauche unexpected interaction, between two conformer largely predominates over the cis antibonding orbitals ( *C=O and *C-X), as conformer. The orbital interactions (NBO described for N,N-dimethylbromoacetamide analysis) can be invoked to explain why the (see Section 3.3.2).38 gauche conformer is the most stable form in the isolated form and condensed phase 3.3.2. N,N-Dimethyl- -haloacetamides (Fig.12).

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XO HO

H H H X N(CH3)2 N(CH3)2

Cis cis gaGaucheuch e

Figure12. The most stable rotamers cis and gauche, for N,N-dimethyl-2-haloacetamides (halo=F, Cl, Br and I).

The main orbital interaction in amides is the atom at the -carbon or ’-carbon, or one or -1 nN/ *C=O with energies around 66 kcal mol , more methyl groups also at both carbon atoms. which is very similar for both conformers. It is noteworthy that while most of the halo- Several other interactions also occur in the substituted carbonyl compounds (halo = Cl, Br three amides, but they are very similar for both and I) present cis and gauche isomers, the conformers. However, the unexpected monofluoro-derivatives present cis and trans interaction between two antibonding orbitals isomers, as it will be shown in the following

( *C=O and *C-X), due to the larger occupancy discussion. of the *C=O (~0.3), which is only present in the This series of compounds has a first study gauche conformer, can explain why it is more using the methodology proposed in Section 2.1 4 stable than the cis conformer. This interaction using experimental coupling constants ( JHF) decreases in the order Br>I>Cl, which is the and solvation theory in the conformational same as the gauche/cis population ratio (Table equilibrium of -fluoroacetone (FA) and , ’- 40 4).38 difluoroacetone (DFA). The solvation theory gave [ E(cis-trans) = 2.2 kcal mol-1] for FA in a 4. -Fluorcarbonyl compounds good agreement with theoretical calculations -1 (2.9 kcal mol ) at MP4/6-31G* level of theory.

4.1. Ketones That value changes from 1.0 in CCl4 to -1.3 -1 Fluoroacetones have been extensively kcal mol in DMSO. This corresponds to a investigated in the search of the possible change from 97% in the vapor to 85% in CCl4 effects of the introduction of a second fluorine to 11% in DMSO for the trans conformer.

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Table 4. NBO occupancy and energies (eV) for the antibonding orbitals calculated at the B3LYP/aug-cc-pVTZ level for the gauche conformer of the N,N-dimethyl-2-haloacetamides (halo= Cl, Br and I).38

Occupancy Orbital Energy Orbital Cl Br I Cl Br I

*C=O 0.309 0.313 0.315 0.02428 0.02836 0.02977

*C-X 0.019 0.023 0.023 0.09865 0.04532 0.05799 E - - - 0.07437 0.01696 0.02822 Gauche popul.(%)* - - - 56 93 80

-1 (*) In CH3CN solutions. In the gas phase E(cis-gauche) > 3 kcal mol for the three compounds.

NBO calculations showed that the orbital interactions predominate over those orbital interactions for the cis conformer amount to interactions leading to a higher stabilization for 6.56 kcal mol-1, while for the trans conformer the trans conformer. These results superseded they correspond to only 1.97 kcal mol-1 (Table the data from Durig et al.41 from Raman 5). However, steric and electrostatic spectroscopy.

Table 5. Orbital interactions for the cis and trans conformers of fluoroacetone

Trans cis Interaction E(kcal) Interaction E(kcal) → * 1.44 → * 5.07 C(1)-F C(2)-O C(1)-H C(2)-O → * 0.53 → * 1.49 C(2)-O C(1)-F C(2)-O C(1)-H E= 1.97 E= 6.56

For DFA the equilibrium between the cis (H- group which operates as a resulting dipole C-C=O 0°) and a gauche conformation (H-C- opposed to the carbonyl group, giving a C=O 104°) involves 0.8 kcal mol-1 [ E(gauche- system rather equivalent to the trans cis)] in the isolated form, decreasing to 0.1 in conformer of fluoroacetone. -1 4 CCl4 to -1.23 kcal mol in DMSO. These data It is also remarkable that the JHF follows an are in agreement with the infrared spectra approximate cos2 dependence , where is recorded as pure liquid, in CH2Cl2, CHCl3, CCl4 the F-C-C-C torsional angle. Thus, for equals and in isolated form. It is also interesting that 0 or 180° the coupling is large (5.0 and 3.4 Hz, its most stable conformer (cis) has two fluorine respectively) while for equals 60° the atoms in a gauche relationship to the carbonyl coupling is much smaller (0.6 Hz). 14

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Further work with two other fluoroketones, of a larger number of conformers in 3-fluorobutan-2-one (FB) and 3,3- comparison to fluoroacetone, NMR and IR difluorobutan-2-one (DFB) was performed, to experimental data as well as theoretical determine the methyl group effect on the calculations showed the presence of only two conformational behavior of this kind of conformers (cis and trans) for FB and a single compound.42 Despite the possible occurrence conformer (cis C-C-C=O 0°) for DFB (Fig. 13).

Cis trans cis

Figure13. Stable conformers for FB (cis and trans) and for DFB (cis).

4 Here, the JHF value, for FB, also shows calculations) in excellent agreement with 3.7 significant changes with the solvent (4.92 in kcal mol-1 from NMR data and solvation theory.

CCl4 to 3.86 Hz in DMSO) and was used for Despite the large solvent effect in the the analysis of its conformational behavior. Its equilibrium, even in DMSO the trans is still IR spectra correlate well with the NMR data more stable than the cis ( E = 0.14 kcal mol-1). showing either a shoulder or two partially It is noteworthy that the trans conformer was resolved carbonyl bands (Fig. 14). not considered by Shapiro et al.,43 in a paper on solvent effects in the NMR spectra of FB. A different behavior was observed for DFB. Theoretical calculations just show a single

conformer (cis) (Fig. 13), which is agreement with NMR data since no changes were observed, on changing the solvent polarity, for 3 4 1 2 all couplings [ JHF, JHF, JCF, JCF(F-C-C=O) and 2J ) and its IR spectra exhibited a very CF(F-C-CH3) sharp carbonyl band confirming the occurrence Figure 14. Carbonyl stretching band for FB in 42 of the single conformer. Its geometry is similar CH3CN solution. 41 to the cis conformer of , ’-difluoroacetone

The energy difference ( Ecis-trans) for FB was and its stability was explained by similar 3.67 kcal mol-1 in isolated form (theoretical reasons.

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More crowded fluoroketones, i.e. 3-fluoro-3- Fig. 6) ( E = 1.30 kcal mol-1, in the isolated methyl-2-butanone (FMB) and 1-fluoro-3,3- form). This is true even in different solvents, dimethyl-2-butanone (FDMB), were also although in acetonitrile there is a significant 44 analysed. These compounds allowed the amount (34%) of the cis/cis conformer. study of two methyl groups effect attached at All these results show that in the isolated the same carbon atom bearing the fluorine form the fluorine atom is always trans to the atom and the three methyl groups (a t-butyl carbonyl oxygen atom indicating a strong group) effect away of the fluorine atom. The electrostatic repulsion between them corresponding conformers are presented in reinforced by a nF → *CO orbital interaction Fig. 15. and by an electrostatic attractive interaction, The large predominance of the trans form such as hydrogen bonding, involving the -1 for FMB ( E = 3.20 kcal mol , in the vapour methyl hydrogen and the fluorine atom. The phase) was attributed to the steric effect latter interaction is in agreement with the between the two methyl groups, one attached calculated distance (H…F) of 2.63 Å in to the carbon and the acetyl methyl group. comparison with the sum of van der Waals However, it is noteworthy that for FDMB there radii which is 2.67 Å. Moreover, in more polar is no significant steric effect ( E = 1.70 kcal solvents the equilibria are shifted towards a mol-1, in the isolated form), which is even conformer which has the fluorine atom cis to smaller than the energy difference observed the carbonyl oxygen due to the solvent cage. for fluoroacetone ( E = 2.20 kcal mol-1, in the Then, the electrostatic interaction between vapour phase). The solvent effects were solute and solvent become the main factor, similar to the other fluoroketones here which leads to the stabilization of the more described. A comparison of the conformational polar rotamer (cis) with increasing the solvent behavior of 1,3-difluoroacetone with all polarity. fluoroketones described above showed a It is noticeable that all compounds bearing similar behavior.45 The conformer presenting a a single fluorine atom present only cis and/or fluorine atom trans to the carbonyl oxygen trans conformers, but none has a gauche predominates in the equilibrium, which is the conformer. This reinforces our conclusions cis/trans form (structure 3, X=F, Fig. 6), in about the factors which determine the relation to the second more stable conformer stabilities. gauche/gauche’ conformer (structure 5, X=F,

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trans cis b)

trans cis

Figure 15. a) trans and cis conformers for FMB; b) trans and cis conformers for FDMB.

4.2. Esters the cis (F-C-C=O 0o) and trans (F-C-C=O 180o) Despite the significant importance of conformers, while the gauche conformer was fluoroesters, a single paper reported the study not a minimum in the energy surface. The of methyl fluoroacetate (MFA) and methyl observed coupling constants, when analysed difluoroacetate (MDFA), but using Raman and by solvation theory lead to an energy -1 infrared spectroscopy and ab initio calculations difference (Ecis – Etrans) of 0.90 kcal mol in the at 4-21G and 6-31G level of theory.46 However, vapour phase, decreasing to 0.41 kcal mol-1 in -1 it is well known that larger basis sets and CCl4 and –0.71 kcal mol in DMSO. In MDFA, correction for electron correlation may lead to the DFT calculations gave two minima for the enormous difference in the results. cis (H-C-C=O 0o) and gauche (H-C-C=O Thus, a later study on these compounds 141.9o) conformers, with an energy difference 1 -1 (MFA and MDFA) using NMR data ( JCF) and (Ecis – Egauche) of 0.2 kcal mol . The FTIR infrared spectroscopy ( C=O) in several spectrum of MDFA in a non polar solvent solvents, and also theoretical calculations at (CCl4) showed the presence of two resolved B3LYP/6-311+G(d,p) have given more bands, but in the other solvents of medium and accurate data for their conformational high polarity the carbonyl absorption appears equilibria.47 Theoretical calculations for MFA as a single sharp band (Fig. 16). gave only two energy minima corresponding to

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a) b)

0.7 0.8

0.7 0.6

0.6 0.5 0.5

0.4

0.3 0.3

Absorbance Absorbance 0.2 0.2

0.1 0.1

0.0 0.0 1890 1860 1830 1800 1770 1740 1710 1680 1650 1620

1890 1860 1830 1800 1770 1740 1710 1680 1650 1620 -1 Wavenumber/cm -1 Wavenumber/cm c) d)

1.0 1.3 1.2 0.9 1.1 0.8 1.0 0.7 0.9

0.6 0.8 0.7

0.5

0.6

0.4 0.5

Absorbance Absorbance 0.3 0.4 0.3 0.2 0.2 0.1 0.1 0.0 0.0 1890 1860 1830 1800 1770 1740 1710 1680 1650 1620 1890 1860 1830 1800 1770 1740 1710 1680

-1 -1 Wavenumber/cm Wavenumber/cm

Figure 16. The carbonyl absorption band in the IR spectrum of MDFA in: a) CCl4; b) CH2Cl2; c) CH3CN and d) DMSO.47

The NMR data do not show significant fluorophenylacetate (MFPA) (Fig. 17) the changes with solvent, confirming that there is potential energy surfaces (PES) were obtained only one stable conformer in the latter solvents at the B3LYP/6-31g(d,p) level, which showed for MDFA. The conformational behavior of two stable rotamers: cis and trans. Their some other fluoroesters was also reported.48 geometries were optimized at B3LYP/6- For methyl 2-fluoropropionate (MFP), methyl 2- 311++g(d,p) level of theory giving very similar fluorobutyrate (MFB), methyl 2-fluoro-tert- energies for both rotamers of the four studied butylacetate (MBA) and methyl 2- compounds, in the isolated form.

MFP MFB MBA MFPA

Figure 17. Structures of -fluoroesters: methyl 2-fluoropropionate (MFP), methyl 2-fluorobutyrate (MFB), methyl 2-fluoro-tert-butylacetate (MBA).

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Thus, MFP was synthesized for the study of -fluoracetamide its behavior in solution, and its NMR and IR in the gas phase and in solution was also spectra recorded, and its results extrapolated recently published.37 All theoretical calculations to the other esters. The significant changes in were performed as described in Section 3.3.1. 1 JCF (184.1 to 177.8 Hz), corroborated by the for other -haloacetamides. changes in the infrared spectra, showed that The trans conformer is far more stable than -1 the trans conformer population varies from the cis ( Ecis-trans = 3.4 kcal mol ), in the

56% in the vapor to 49% in CCl4, to 19.8% in isolated form, but this energy difference DMSO. The trans form shows distinct effects: a decreases to ~2.0 kcal mol-1 in solution (Fig. - - repulsive dipolar F / OCH3 effect and an 18). However, no significant changes were 2 3 attractive nF/ *C=O interaction observed for JC-H and for JC -H which (hyperconjugation). For the cis rotamer the F - precluded the use of the classical NMR / -O=C repulsive interaction is progressively method, as described in the introduction to decreased with the increase in the solvent determine the conformers ratio. However, the polarity. energy differences and theoretically calculated A comparison with the corresponding - coupling constants allowed us to conclude that fluoroketones shows that again the fluorine fluoroacetamide adopts the trans conformation atom prefers the trans arrangement in relation in the isolated form (~100%) and it largely to the carbonyl group. predominates in solution (97%). Besides the steric and electronic interactions, there is a 4.3. Amides very favourable interaction between the C-F Here, it will discussed separately the results and N-H dipoles in the trans isomer. Additional obtained for the -fluoroacetamide, N-methyl stabilization comes from the LPN/ *CO -1 -fluoro-N-methylacetamides and - fluoro- interaction which is 6.0 kcal mol more N,N-dimethylacetamides. energetic for the trans conformer, both in the isolated form as in solution, as shown by NBO 4.3.1. -Fluoroacetamide calculations.

cis trans

Figure 18. Stable conformers for cis and trans fluoracetamides.

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4.3.2. -Fluoro-N-methylamides initio calculations at the CBS-Q level yielded Theoretical calculations plus the solvent only two stable rotamers, the cis and trans, dependence of the 13C NMR and IR spectra with E(cis-trans) = 4.71 kcal mol-1. The were used for the analysis of the presence of two conformers, in solution, was conformational equilibrium in N-methyl- - confirmed by the FTIR spectra. Assuming fluoroacetamide (MFA) and N-methyl- - these forms, the observed couplings when fluoropropionamide (MFP).49 Ab initio analysed by solvation theory gave E = 5.09 -1 calculations were used to identify the stable kcal mol in the isolated form, decreasing to -1 -1 rotamers and obtain their geometries and the 2.13 kcal mol in CHCl3 and to 0.19 kcal mol 1 1 application of solvation theory on the JCF in DMSO (Fig. 19). The corresponding JCF coupling constant gave the rotamer couplings changed from 185.4 (in CDCl3) to populations in the solvents studied. In MFA ab 180.2 Hz (in DMSO).

a) b)

0.6

1.5

0.4

1.0

Absorbance 0.2 Absorbance 0.5

0.0 0.0 1750 1700 1650 1600 1720 1690 1660 1630

-1 cm cm-1

Figure 19. The carbonyl absorption band in the IR spectrum of MFA in: 49 a) CHCl3, b) DMSO.

For MFP, the B3LYP calculations at the 6- theoretical calculations were performed using 311++g(2df,2p) level gave only the trans as a the SCRF (self consistent reaction field) stable rotamer, while the gauche form was a routine, which allowed the identification of a plateau in the potential energy surface. minimum for the gauche rotamer, in DMSO However the FTIR spectra clearly showed the solution (Fig. 20). presence of two conformers. Therefore, new

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-387,070 B3LYP/6-31g(d,p) isolated form B3LYP/6-31g(d,p) =4.81 -387,072 B3LYP/6-31g(d,p) =20.7 B3LYP/6-31g(d,p) =46.7 -387,074

-387,076

-387,078

-387,080

-387,082 Energy / hartrees

-387,084

-387,086

0 30 60 90 120 150 180 210 240 270 300 330 360 Dihedral angle / o (F-C-C=O)

Figure 20. PES for N-methylfluoropropionamide at B3LYP/6-31g(d,p) level at different values of medium relative 49 permittivity (CHCl3, = 4.81; acetone, = 20.7; DMSO, = 46.7).

The equilibrium in MFP was therefore analysed NH(CH3) group, which are too close when the by solvation theory in terms of the trans and F is cis to the C=O group. gauche rotamers to give E(gauche-trans) = 3.80 kcal mol-1 in the isolated form, decreasing 4.3.3. -Fluoro-N,N-dimethylamides -1 1 to 2.58 kcal mol in CCl4 ( JCF = 182.9 Hz) and Two -fluoro-N,N-dimethylamides were -1 to 0.12 kcal mol in DMSO (179.2 Hz). The studied: the acetamide (DMFA) and trans form of both compounds is stabilized, in propionamide (DMFP) derivatives.50 Two the isolated form and in solution, by the natural rotamers: gauche (97%) and cis (3%), in the repulsion between the F atom and the carbonyl isolated form, were found for DMFA, with an -1 group in the cis conformer, and also by the energy difference ( Ecis-gauche = 4.71 kcal mol ). possible formation of a hydrogen bond This equilibrium is shifted to the cis conformer between the NH hydrogen and the F atom, in polar solvents, as confirmed by the large 1 since they are apart by only 2.18 Å in the trans changes in the JCF experimental values (180.2 conformer (Fig. 21). to 170.3 Hz) on increasing the solvent relative It is also important to note that the cis permittivity, leading to 90% of the cis in conformer does not occur due to the strong DMSO). steric repulsion between the 2-methyl and the

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cis trans b)

gauche trans

Figure 21. Possible conformers for: a) NMFA and b) NMFP.

The interpretation is similar to the other The equilibrium for the DMFP, in the isolated amides. The predominance of the gauche form, is similar. But, here, there are two conformer in the isolated form is due to the gauche rotamers (Fig. 23) of very similar -1 strong repulsion between the F and the C=O energies [(Egauche1 – Egauche2) = 0.3 kcal mol ], group, which is stronger than the repulsion and the energy difference for the two main -1 between the F and the N(CH3)2 group. conformers (Ecis – Egauche2) was 2.5 kcal mol , However, in a polar solvent the cis form is corresponding to 97 % of the gauche stabilized by the interaction with the solvent conformers, in the isolated form. The solvent 1 and, then, the repulsion between the N(CH3)2 effect was also similar to DMFA, with JCF group and the F atom predominates. experimental values varying from 178.4 to

This was confirmed in a further work on 170.1 Hz, from CCl4 to DMSO, respectively, several fluoro-derivatives of N,N- giving 86% of the cis in DMSO solution, dimethylacetamides,51 through infrared resulting in a similar interpretation. spectroscopy, whose spectra clearly show the Difluoroamides were also studied,51 but they population changes with the solvent polarity are out of the scope of the present review. (Fig. 22).

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0.40 a d 0.35 0.20

0.30

0.15 0.25

0.20 0.10

0.15

Absorbance Absorbance

0.10 0.05

0.05

0.00 0.00

1720 1700 1680 1660 1640 1620 1720 1700 1680 1660 1640

cm-1 cm-1

1.00

0.60 b e 0.50 0.80

0.40 0.60

0.30

0.40

0.20

Absorbance Absorbance

0.20 0.10

0.00 0.00

1760 1720 1680 1640 1600 1560 1720 1700 1680 1660 1640 1620 1600

cm-1 cm-1

0.14 c 1.20 f

0.12 1.00

0.10 0.80

0.60 0.08

Absorbance 0.40 0.06

0.20 Absorbance

0.04 0.00

1720 1700 1680 1660 1640 1620 3400 3380 3360 3340 3320 3300 3280 3260 cm-1 cm-1 Figure 22. IR spectra of DMFA showing the analytically resolved carbonyl stretching bands, in n-hexane (a), carbon tetrachloride [fundamental (b) and 1st overtone (c)], toluene (d), chloroform (e) and acetonitrile (f).51

cis gauche-1 gauche-2

Figure 23. cis and gauche rotamers for -fluor-N,N-dimethylpropionamide [gauche-1 (F-C-C=O, 144.7°); gauche-2 (F-C-C=O, -124.1°)]

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5. Conclusions der Waals radii (F=1.47; Cl=1.75; Br=1.85 and The systems described in this review I=1.98 Å). Thus, the strong field effect of the involved mostly simple carbonyl compounds, fluorine atom,52 results in a strong repulsion in i.e. aliphatic ketones, esters and amides, the cis isomer driving the fluorine atom as far presenting a single halogen atom at the as possible from the carbonyl group, i.e., to a position in relation of the carbonyl group. Very trans arrangement. All fluor-ketones present few examples presented two or more halogen the trans conformer as the most stable form in atoms. the isolated state and in non-polar solvents. The conformational equilibrium displayed However, the high polar cis conformer (e.g. for the selected compounds was analysed =4.18 D, for fluoroacetone) is stabilized in using data from NMR and infrared polar solvents becoming the prevalent spectroscopy experiments, complemented by conformer in DMSO. The same occurs in the data from theoretical calculations. fluoro-esters, and also in the amides. In the The results for the three series of mono- amides, there is an additional steric effect substituted compounds bearing Cl, Br and I between the amino group and the fluorine presented a very similar behavior in the atom, but this interaction is smaller than isolated state and in non-polar solvents. The between the fluorine and the carbonyl group. gauche conformer largely predominates over Several orbital interactions occur in these the cis conformer for the ketones and esters systems, but in most cases they are not strong and the trans is more populated for the enough to change the conformational amides. However, this is reversed in solution of preferences. polar solvents like acetonitrile and dimethylsulfoxide, when the cis population Acknowledgements increases and in most cases supersedes the population of the other conformer, due to a The authors thank the Fundação de dipole-dipole interaction with the solvent. Amparo à Pesquisa do Estado de São Paulo The predominance of the gauche was (FAPESP) for financial support of this research attributed to stereoelectronic effects, i.e., there (mostly: 2000/07692-5; 2005/59649-0; is a steric repulsion between the halogen atom 2008/06282-0 and 2009/16987-3) and for a and the carbonyl oxygen atom. scholarship (to R.A.C.), and the Conselho

Hyperconjugative interactions (nx *C=O) also Nacional de Desenvolvimento e Tecnológico contribute to stabilize the gauche conformer for (CNPq) for fellowships (to C.F.T. and R.R.). the ketones, esters and amides. For these two The authors record their sincere thanks to latter series and additional interaction the various authors and publishers for their ( *C=O *C-X) plays an important stabilizing kind permission to reproduce figures, schemes effect in the gauche conformer. and tables from their work, as follows: Fluor-derivatives display a specific behavior Fig. 4. Spectrochim. Acta A 72, 1089 since the fluorine atom is much more (2009); Fig. 7. J. Mol. Struct. (THEOCHEM) electronegative than the other halogen atoms 2006, 766, 177; Fig. 22. J. Mol. Struct. 2002, and a very small volume, as shown by the van 607, 87; Table 2. Spectrochim Acta, Part A 24

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2005, 61, 2221; Table 3. Spectrochim. Acta 8. Bickelhaupt, F. M.; Baerends, E. Part A 2006, 63, 511; Table 4. J. Mol. Struct. Angew. Chem. 42 (2003) 4183. (THEOCHEM) 2005, 728, 79; were published 9. Song, L.; Lin, Y.; Wu, W.; Zhang, Q.; by this review’s authors in Elsevier journals. Mo, Y. J. Phys. Chem. 109 (2005) Figs. 14, 16, 19 and 20 were also taken 2310. from author papers published by The Royal 10. Mo, Y.; Gao, J. Acc. Chem. Res. 40 Society of Chemistry in The Journal of (2007) 113. Chemical Society, Perkin Transactions 2. 11. Liu, S.; Govind, N., J. Phys. Chem. A It must be mentioned our gratitude to 112 (2008) 6690. Professor Raymond J. Abraham (The 12. Bischoff, C. A. Ber. Dtsch. Chem. Ges. University of Liverpool) for his generous 1890, 23, 623. hospitality during our stays in his laboratory, for 13. Kemp, J. D.; Pitzer, K. S. J. Chem. giving access to his programs and for his Phys. 1936, 4, 749. collaboration in a large number of our 14. Klyne, W.; Prelog, V. Experientia 1960, published papers in this field. 16, 521. We are also especially appreciative of the 15. Barton, D. R. H. Experientia 1950, 6, many graduate students who contributed some 316. of the important research discussed in this 16. Zefirov, N. S. Tetrahedron 1977, 33, review; and Professor Paulo R. Olivato and 3193. Professor Ernani A. Basso for decades of 17. Isaacs, N. S. Physical Organic fruitful collaboration. Chemistry, 2nd. ed.; Longman, 1995. 18. Garbisch, W. J. Am. Chem. Soc. 1964, References 86, 1780. 1. Eliel, E. L.; Wilen, S. H.; Mander, L. N. 19. Eliel, E. L. Chem. Ind. (London) 1959, Stereochemistry of Organic 18, 568. Compounds; Wiley: New York, 1994. 20. Abraham, R. J. J. Phys. Chem., 1969, 2. Karabatsos, G. J.; Fenoglio, D. J. Top. 73, 1192. Stereochem. 5 (1970) 167. 21. Frisch, M. J.; Trucks, G. W.; Schlegel, 3. Olivato, P. R.; Rittner, R. Rev. H. B.; Scuseria, G. E.; Robb, M. A.; Heteroatom Chem. 15 (1996) 115. Cheeseman, J. R.; Montgomery, J. A.; 4. Testa, B. Principles of Organic Vreven, T.; Kudin, K. N.; Burant, J. C.; Stereochemistry; Marcel Dekker: New Millam, J. M.; Iyengar, S. S.; Tomasi, York, 1979. J.; Barone, V.; Mennucci, B.; Cossi, 5. Morris, D. G. Stereochemistry; The M.; Scalmani, G.; N. Rega; Petersson, Royal Society of Chemistry: G. A.; Nakatsuji, H.; Hada, M.; Ehara, Cambridge, 2001. M.; Toyota, K.; Fukuda, R.; Hasegawa, 6. Weinhold, F. Nature 411 (2001) 539. J.; Ishida, M.; Nakajima, T.; Honda, Y.; 7. Pophristic, V.; Goodman, L. Nature Kitao, O.; Nakai, H.; Klene, M.; Li, X.; 411 (2001) 565. Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, 25

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J.; Gomperts, R.; Stratmann, R. E.; 28. Galactic. Industries Corporation, Yazyev, O.; Austin, A. J.; Cammi, R.; Grams/32 curve fitting program, Pomelli, C.; Ochterski, J. W.; Ayala, P. version 4.04, Level II 1991–1998. Y.; Morokuma, K.; Voth, G. A.; 29. C. R. Martins, L. C. Ducati, C. F. Salvador, P.; Dannenberg, J. J.; Tormena and R. Rittner, Spectrochim. Zakrzewski, V. G.; Dapprich, S.; Acta A 72, 1089 (2009). Daniels, A. D.; Strain, M. C.; Farkas, 30. Freitas, M. P.; Tormena, C. F.; Rittner, O.; Malick, D. K.; Rabuck, A. D.; R.; Abraham, R. J. Spectrochim. Acta, Raghavachavi, K.; Foresman, J. B.; Part A 2003, 59, 1783. Ortiz, J. V.; Cui, Q.; Baboul, A. G.; 31. Doi, T. R.; Yoshinaga, F.; Tormena, C. Clifford, S.; Cioslowski, J.; Stefanov, B. F.; Rittner, R.; Abraham, R. J. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Spectrochim Acta, Part A 2005, 61, Komaromi, I.; Martin, R. L.; Fox, D. J.; 2221. Keith, T.; Al-Laham, M. A.; Peng, C. 32. Doi, T. R. Ph D Thesis, State Y.; Nanayakkara, A.; Challacombe, M.; University of Campinas, 2005. Gill, P. M. W.; Johnson, B. G.; Chen, 33. Tormena, C. F.; Freitas, M. P.; Rittner, W.; Wong, M. W.; Gonzalez, C.; Pople, R.; Abraham, R. J. J. Phys. Chem. A J. A. GAUSSIAN 03 (Revision D.02); 2004, 108, 5161. Gaussian: Pittsburgh, 2004. 34. Ducati, L. C.; Rittner, R.; Custodio, R. 22. Schmidt, M. W.; Baldridge, K. K.; J. Mol. Struct. (THEOCHEM) 2006, Boatz, J. A.; Elbert, S. T.; Gordon, M. 766, 177. S., Jensen, J. H., Koseki, S., 35. Glendening, E. D.; Badenhoop, J. K.; Matsunaga, N., Nguyen, K. A., Su, S. Reed, A. E.; Carpenter, J. E.; J., Windus, T. L., Dupuis, M., Bohmann, J. A.; Morales, C. M.; Montgomery J. A. J. Comput. Chem. Weinhold, F. NBO version 5.0 G; 1993, 14, 1347. University of Wisconsin: Madison, 23. DALTON2011, a molecular electronic 2001. structure program (2011), see 36. Tormena, C. F.;Yoshinaga, F.; Doi, T. http://www.daltonprogram.org R.; Rittner, R. Spectrochim. Acta Part 24. Abraham, R. J.; Grant, G.; Haworth, I. A 2006, 63, 511. S.; Smith, P. E. J. Comp. Aided Mol. 37. Pedersoli, S.; Tormena, C. F.; Rittner, Design 1991, 5, 21. R. J. Mol. Struct. 2008, 875, 235. 25. Abraham, R. J.; Leonard, P.; Smith, T. 38. Martins, C. R.; Rittner, R.; Tormena, C. A. D.; Thomas, W. A. Magn. Reson. F. J. Mol. Struct. (THEOCHEM) 2005, Chem. 1996, 34, 71. 728, 79. 26. Anizelli, P. R.; Vilcachagua, J. D.; 39. Peterson, K. A.; Figgen, D.; Goll, E.; Neto, A. C.; Tormena, C. F. J. Phys. Stoll, H.; Dolg, M. J. Chem. Phys. Chem. A 2008, 112, 8785. 2003, 119, 11113. 27. Jones, R. N.; Noack, K. Can. J. Chem. 1961, 39, 2214. 26

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40. Abraham, R. J.; Jones, A. D.; Warne, 47. Abraham, R. J.; Tormena, C. F.; M.; Rittner, R.; Tormena, C. F. J. Rittner, R. J. Chem. Soc. Perkin Trans Chem. Soc. Perkin 2 1996, 533. 2 2001, 815. 41. Durig, J. R.; Hardin, J. A.; Phan, H. V.; 48. Tormena, C. F.; Freitas, M. P.; Rittner, Little, T. S. Spectrochim. Acta A 1989, R.; Abraham, R. J. Phys. Chem. 45, 1239. Chem. Phys. 2004, 1152. 42. Abraham, R. J.; Tormena, C. F.; 49. Tormena, C. F.; Amadeu, N. S.; Rittner, R. J. Chem. Soc. Perkin 2 Rittner, R.; Abraham, R. J. J. Chem. 1999, 1663. Soc. Perkin Trans 2 2002, 773. 43. Shapiro, B. L.; Lin, H. L.; Johnston, M. 50. Tormena, C. F.; Rittner, R.; Abraham, D. J. Magn. Reson. 1973, 9, 305. R. J.; Basso, E. A.; Pontes, R. M. J. 44. Tormena, C. F.; Rittner, R.; Abraham, Chem. Soc. Perkin 2 2000, 2054. R. J. J. Phys. Org. Chem. 2002, 15, 51. Olivato, P. R.; Guerrero, S. A.; Yreijo, 211-217. M. H.; Rittner, R.; Tormena, C. F. J. 45. Tormena, C. F.; Freitas, M. P.; Rittner, Mol. Struct. 2002, 607, 87. R.; Abraham, R. J. J. Phys. Chem. A 52. Hansch, C.; Leo, A.; Taft, R. W. Chem. 2004, 108, 5161. Rev. 1991, 91, 165. 46. Veken, B. J. v. d.; Truyen, S.; Herrebout, Q. A.; Watkins, G. J. Mol. Struct. 1993, 293, 55.