Ann. Magn. Reson. Vol. 10, Issue 1/2, 1-27, 2011 AUREMN NMR Spectroscopy: a Tool for Conformational Analysis 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 1 Ann. Magn. Reson. Vol. 10, Issue 1/2, 1-27, 2011 AUREMN 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. 2 Ann. Magn. Reson. Vol. 10, Issue 1/2, 1-27, 2011 AUREMN 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. 3 Ann. Magn. Reson. Vol. 10, Issue 1/2, 1-27, 2011 AUREMN 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 Ann. Magn. Reson. Vol. 10, Issue 1/2, 1-27, 2011 AUREMN 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.