Discovery of internal rotation and conformers of 1,2-dichloroethane: the dawn of the concept of conformation

Abstract

In 1932, Mizushima and Higasi reported the dependence of the dipole moments of 1,2-dichloroethane on both temperature and solvent in the Proceedings of the Imperial Academy, Japan. This report was followed by their first proposal of the existence of conformers that exchanged by internal rotation about a C–C single bond based on experimental data. Their monumental work marked the beginning of the essential concept of conformation in modern stereochemistry. Their proposal was later confirmed by the direct observation of the anti and gauche conformers of 1,2-dichloroethane by Raman spectroscopy, and further supported by other experimental and theoretical methods. The relative stabilities of the anti and gauche conformers of 1,2-dichloroethane and other 1,2-disubstituted ethanes were discussed in terms of steric, electrostatic, and stereoelectronic effects based on analysis of calculated data. Those studies influenced the development of subsequent research in organic chemistry, such as the conformational analysis of cyclohexane derivatives and the isolation of chiral gauche conformers.

1. Introduction

“Conformation” is one of the most fundamental concepts in the stereochemistry of organic compounds when one considers organic molecules in a three-dimensional space.^1),2) In the International Union of Pure and Applied Chemistry (IUPAC) Recommendations, this term is defined as “the spatial arrangement of the atoms affording distinction between stereoisomers which can be interconverted by rotations about single bonds”.^3),4) Ethane H₃C–CH₃ is the smallest organic molecule whose conformation should be considered. The internal rotation about the C–C single bond connecting the two tetrahedral sp³ hybridized carbons generates two typical conformations (Fig. 1(a)). In the staggered conformation, the H atoms on one C atom are positioned at the maximum distance from the H atoms on the other C atom. This conformation is usually stable and located at an energy minimum during the internal rotation in ethane derivatives. The relative orientation of the H atoms is well visualized by the Newman projection, as shown in Fig. 1. The torsion angle defined by the dihedral angle formed by a H–C–C–H chain is an important parameter to specify the conformation: the torsion angle is 60° for the staggered ethane.⁴⁾ The conformation in which two H atoms on adjacent C atoms are in closest proximity is called eclipsed conformation, where the torsion angle is 0°. This conformation is usually unstable and located at an energy maximum.

Fig. 1.

(a) Projection formula of two typical conformations of ethane. Each conformation is represented as a sawhorse projection and a Newman projection. (b) Newman projections of three staggered conformations of 1,2-disubstituted ethanes. ap: antiperiplanar, sc: synclinal. Torsion angles are given in Newman projections.

This conformational arrangement becomes somewhat complicated for 1,2-disubstituted ethane derivatives, in which each tetrahedral carbon bears one non-hydrogen substituent. For XH₂C–CH₂Y, one can draw three staggered conformations that differ in the orientation of substituents X and Y during the rotation about the C–C bond by 360° (Fig. 1(b)). In A, substituents X and Y are anti (torsion angle 180°) relative to the C–C bond, and hence this achiral conformation is called anti or antiperiplanar (ap) conformation.⁵⁾ In contrast, the two substituents are +60° and −60° apart from the fully eclipsed conformation in B and C, respectively. These conformations are called gauche or synclinal (sc) conformation. These three forms are conformational isomers (conformers), which are stereoisomers that differ in conformations located at the energy minima.⁴⁾ Conformers B are C are chiral and mirror images of each other, namely, they are enantiomers. If necessary, B and C are distinguished into +sc and −sc forms, respectively, to specify the direction of the two substituents. In contrast, achiral conformer A is the diastereomer of B and C. Therefore, A should have different physical and chemical properties from the other two forms. These conformers interconvert rapidly via rotation about the C–C single bond under ordinary conditions, and their populations and exchange rates that determine the energy profile are dependent on the nature of the substituents and other conditions.

Today, the presence of such conformers is well established and considered fundamental stereochemical knowledge. The concept of conformation is essential to understanding the structures of organic compounds ranging from small molecules to macromolecules, which govern their properties and functions. For example, characteristic coiled or folded structures of proteins express specific enzyme activities depending on their conformation relative to C–C and C–N single bonds. Therefore, the discovery of conformers was a milestone in the history of organic chemistry to fully understand organic compounds. It was in 1932 when Mizushima and Higasi published a pioneering article on the physical properties of 1,2-dichloroethane (DCE) in the Proceedings of the Imperial Academy, Japan, the predecessor journal of the Proceedings of the Japan Academy.⁶⁾ This article signaled the beginning of a series of studies on “Structure of molecules and internal rotation” by Mizushima and co-workers, and related works were comprehensively compiled in his famous book.⁷⁾ For other related literature, Mizushima reviewed research on internal rotation in Japan,⁸⁾ and Morino described the history of their work in a review entitled “Discovery of the gauche form in dichloroethane”.⁹⁾ These studies have been widely accepted by a broad range of academic fields, and are regarded as one of the most important discoveries in modern molecular science and technology. In this memorial review, the author would like to revisit the contributions of their work on conformation starting from their pioneering article mentioned above.

2. Dipole moment measurements

In 1869, Paternò first predicted a tetrahedral carbon structure and the presence of three structures for 1,2-dibromoethane.¹⁰⁾ Later, van’t Hoff^11),12) and Le Bel¹³⁾ independently proposed the theory of tetrahedral carbon in 1874, which is widely considered as the beginning of the stereochemistry. After these proposals, it was assumed for the longest time that the rotation about a C–C single bond was free, namely, no rotational barrier existed. However, in the 1930s, some chemists began to report evidence against the free rotation about C–C single bonds in ethane and related compounds. In the case of ethane, Kemp and Pitzer proposed the hindered rotation of the methyl groups on the basis of thermodynamic analysis of entropy values.¹⁴⁾ Much later, the rotational barrier, namely, the energy difference between staggered and eclipsed conformations, was determined by spectroscopic analysis¹⁵⁾ and calculated by computational chemistry,¹⁶⁾ and the value of 12 kJ mol⁻¹ was established as described in general organic chemistry textbooks. Because the three staggered forms of ethane are identical, namely, degenerated, further experimental approaches to tackle this problem were hardly possible at that time.

The situation changes when nonhydrogen atoms or groups are attached to the carbons in ethane. As mentioned above, 1,2-disubstituted ethanes are suitable target molecules to reveal the relationship between conformation and properties. In particular, the polarized bonds of polar substituents can influence the properties of such molecules. Mizushima and Higasi disclosed the dipole moments of DCE measured under various conditions in a report in 1932⁶⁾ and a full paper in 1933.¹⁷⁾ Their measurements revealed that DCE had nonzero dipole moment, and the dipole moment increased with increasing temperature in the gas phase and the solution state (Fig. 2). For example, the dipole moment of DCE in heptane increased from 1.16 D (D (Debye) = 3.33564 × 10⁻³⁰ C·m) to 1.42 D as the temperature was increased from 223 K to 323 K. They explained this phenomenon by the large amplitude motion of two Cl groups relative to the C–C bond assuming rotation with a barrier rather than the free rotation that had been believed by previous researchers.^18),19) Therefore, they were the first chemists to recognize the existence of conformers on the basis of experimental data.

Fig. 2.

Newman projections of three conformers of 1,2-dichloroethane (DCE). The dipole moment of each C–Cl bond is shown as a blue arrow. Molecular dipole moments are indicated by μ.

This finding is now understood as follows. The dipole moments of two polar C^δ+–Cl^δ− bonds cancel each other out in the anti form, resulting in the zero molecular dipole moment. In contrast, the two bond dipole moments do not cancel each other out in the gauche forms, resulting in the nonzero molecular dipole moment. The observed dipole moment is a weighted average of the two forms (three forms including the enantiomeric gauche forms), and the populations are influenced by the temperature according to the Boltzmann distribution. Because the gauche forms are less stable than the anti form, the ratio of the two forms, gauche/anti, should be smaller than 2. The higher the temperature, the larger the population of the polar gauche forms owing to the increased entropic contribution. In addition, polar solvents tend to stabilize the polar gauche forms by solvation. The authors of early works named the gauche form the cis form because they had no concrete information on the orientation of the two Cl atoms on the same side, namely, staggered, eclipsed, or others. Subsequent spectroscopic studies revealed structural details.

3. Raman effect

To obtain further evidence of the existence of such conformers, they adopted Raman spectroscopy for studies of the internal rotation of ethane derivatives. In 1934, Mizushima and coworkers reported a series of articles under the title “Raman effect and dipole moment in relation to free rotation”.^20)–23) They found a characteristic Raman effect in the spectrum of DCE in the liquid state or the solution state. The two lines at 752 and 653 cm⁻¹ were assigned to the trans and cis forms, respectively, by theoretical vibrational analysis: they used these terms instead of anti and gauche forms, respectively, at that time (Fig. 3). The ratio of the intensities of the two lines, I₇₅₂/I₆₅₃, increased with decreasing dielectric constants of the solvents and with increasing population of the trans form. They rationally explained the spectroscopic feature on the basis of the internal rotation and criticized an earlier work by Kohlrausch, who had misinterpreted the observed phenomenon.^24),25) In the solid state and at a low temperature, the line at 653 cm⁻¹ disappeared completely, meaning that almost all the molecules existed in the trans form.^26),27) These results were communicated as a Letter in Nature in 1936 as an influential work in structural organic chemistry.²⁸⁾

Fig. 3.

Observed Raman lines of pure 1,2-dichloroethane (DCE). ω₁ = 653 cm⁻¹, ω₂ = 752 cm⁻¹. Reproduced from Ref. 20. Raman lines ω₁ and ω₂ were assigned to the cis and trans forms, respectively. Both Stokes lines and anti-Stokes lines are shown.

They also reported the Raman effects of other substituted ethanes including 1,2-dibromoethane and 1,2-diiodoethane in the above-mentioned references to find other examples of such observations. Mizushima and Higasi compared the Raman spectra of 1,2-dibromoethane and 1,2-dibromoethane-d₂ in another report published in the Proceedings in 1938.²⁹⁾ The observed isotope effect on the Raman frequencies was in good agreement with that expected from the vibration model. This was another confirmation of their conclusion on the molecular structures of 1,2-dihaloethanes. The Raman effects of ethanol and paraffins were also reported in 1940 and 1944, respectively, in the Proceedings.^30),31) In a paper published in 1941, they represented the conformations of 1,2-disubstituted ethanes by using two triangles based on the van’t Hoff’s tetrahedral molecular model, as shown in Fig. 4, where the term “gauche”, originated from a French word, was used instead of “cis” for the two conformers for the first time.^32),33) The authors commented that the gauche forms differ by approximately 120° (but not exactly) from the trans (hereinafter referred to as anti) form and each one is the mirror image of the other.

Fig. 4.

Representations and terms of conformations of 1,2-disubstituted ethanes as originally illustrated in Ref. 32. A triangular framework indicates a perspective view of each tetrahedron showing the arrangement of a carbon atom based on the van’t Hoff’s tetrahedral molecular model (Ref. 33).

4. Other experimental studies

Thermodynamic data offered additional evidence for the existence of conformational isomers and the barrier between them. Mizushima et al. calculated the entropy values of DCE from the thermochemical data for the anti and gauche forms.³⁴⁾ These data were consistent with the data observed in the Raman spectra. Later, Pitzer et al. measured the gas heat capacity of DCE as they had measured that for ethane earlier.³⁵⁾ They estimated the barrier to internal rotation from the experimental data and other entropy and dipole moment data to be approximately 12 kJ mol⁻¹ for the anti→gauche process.

As analytical techniques advanced, other spectroscopic methods were used by structural chemists. Mizushima and coworkers reported the infrared (IR) spectra of DCE in the liquid and gas phases.^36),37) The strong absorption observed at 710 cm⁻¹ was assignable to the antisymmetric C–Cl bond stretching of the anti form, which was inactive in the Raman spectrum. They determined the energy difference between the anti and gauche forms to be 4.3 kJ mol⁻¹ from the absorption intensities of the two forms. All observed frequencies in the IR and Raman spectra of DCE were then fully assigned by using modern instruments.³⁸⁾

The electron diffraction experiment for DCE vapor performed by the Mizushima group also supported the presence of the two forms.^37),39) Analysis of high-quality electron diffraction data gave detailed structural information of the molecular structures of the anti and gauche forms.^40),41) For example, the torsion angle of the two Cl atoms (Cl–C–C–Cl) in the gauche form was estimated to be 76.4°. In 1997, Takeo et al. reported the microwave spectrum of DCE.⁴²⁾ The torsion angle of the gauche form was determined from the observed rotational constants to be 68.1°. The photoelectron spectra of DCE were reported by Peel et al. in 1977.⁴³⁾ The observed HeI photoelectron spectra supported the presence of two kinds of stable conformers.

Nuclear magnetic resonance (NMR) spectroscopy, widely applied as an essential analytical tool, gives valuable structural information on organic compounds. For example, the Karplus equation rationalizes the relationship between the vicinal spin-spin coupling constant (³J_HH: H–C–C–H) and the torsion angle.^44),45) Abraham et al. measured the vicinal coupling constants of DCE in various solvents and analyzed the solvent effect to estimate the energy difference between the two forms according to the Karplus equation.⁴⁶⁾ It is generally difficult to observe conformers separately by the NMR spectroscopy because of the facile exchange relative to the spectroscopic time scale. However, the rotation about a C–C single bond can be restricted by the introduction of several or bulky substituents. For example, the rotational barrier of 2,2,3,3-tetrachlorobutane CH₃CCl₂–CCl₂CH₃, which was symmetrically analogous to DCE, was determined by the lineshape analysis of the NMR spectra observed at low temperatures.⁴⁷⁾ The rotation of a methyl groups can be restricted when it is bonded to a considerably bulky 9-triptycyl group on the NMR time scale.⁴⁸⁾ Hence, the NMR spectroscopy is one of the powerful techniques for the conformational analysis mentioned below.

5. Theoretical studies

Computational chemistry is a valuable approach to obtain further knowledge of the conformational analysis of organic molecules. The structures and conformations of DCE have been investigated by various theoretical methods by a large number of researchers as the first important molecule in the history of structural chemistry. The structural optimization gave two kinds of energy-minimum structures, anti (ap) and gauche (sc), and two kinds of energy-maximum structures, sp and ac, as the transition states, the energy profile of which is shown in Fig. 5. Theoretical studies in the 1980s using the molecular orbital (MO) theory at the Hartree-Fock (HF) or the Møller-Plesset (MP) level suggested that the energy difference between the anti and gauche forms (ΔE_a–g) was 6.4 kJ mol⁻¹ and the activation energy for the anti→gauche process (ΔE^≠_a–g) was 20.8 kJ mol⁻¹.^49),50) The calculated energy difference is comparable to the experimental values determined by the various methods mentioned above (4.6–6.3 kJ mol⁻¹). Dixon et al. compared the calculated structural and thermochemical data of DCE and other 1,2-dihaloethanes by various methods with the experimental data.⁵¹⁾ Recently, Raiteri et al. reported systematic computational data of DCE conformers obtained by the density functional theory (DFT) method at various levels and by the molecular dynamics (MD) method.⁵²⁾

Fig. 5.

(Color online) Energy profile during internal rotation about the C–C bond in 1,2-dichloroethane (DCE) based on data calculated at the MP3(fc)/6-31++G(d,p) level in Ref. 44. sp: synperiplanar, ac: anticlinal, and see Fig. 1 for other stereochemical symbols.

6. Gauche effect

The populations of the anti and gauche forms were affected not only by the states or conditions of samples but also by the kinds of substituents on the tetrahedral carbons. As knowledge of the conformation of various compounds accumulated, chemists became interested in factors influencing the stability of conformers. Such an effect is known as the “gauche effect”, a specific case of the stereoelectronic effect.⁵³⁾ The gauche effect is defined by the IUPAC Recommendations as follows: the stabilization (or destabilization) of the gauche conformation in a two-carbon unit bonded vicinally to various atoms or atomic groups (substituents).⁴⁾ This effect, which originated from the discovery of the conformers of 1,2-disubstituted ethanes, has been a key topic in organic chemistry for a long time. Many researchers have tackled this problem mainly by theoretical calculations such as MO analysis.

The relative stability between conformers is governed by several kinds of interactions in each conformer: steric (Pauli) repulsion, electrostatic interactions, orbital interactions, and so on.⁵⁴⁾ In general, the gauche form is destabilized by the steric repulsion between the substituents relative to the anti form. In contrast, electronegative substituents tend to stabilize the gauche form by the hyperconjugative orbital interaction, as shown in Fig. 6. The interaction between the bonding σ_CH orbital and the antibonding σ*_CX orbital in the gauche form is more effective than that between the bonding σ_CX orbital and the antibonding σ*_CX orbital in the anti form. In particular, this stereoelectronic effect is significant for highly electronegative F groups because of the preferred orbital requirement. The steric repulsion is weak in the gauche form for relatively small F atoms. As a result, the gauche form is more stable by approximately 2–4 kJ mol⁻¹ than the anti form for 1,2-difluoroethane, as studied by various methods.^{49),51),55)–57)} Along this discussion, several research groups revisited the conformational isomerism of DCE and other 1,2-dihaloethanes by high-level calculations.^52),54),57) For large Cl atoms, steric repulsion becomes sufficiently large to destabilize the gauche form of DCE. Discussions on the origin of the gauche effect, which are based on various theories and interpretations, are ongoing.

Fig. 6.

Newman projections and hyperconjugative orbital interactions in gauche and anti forms in 1,2-disubstituted ethanes to explain the gauche effect.

7. Subsequent influence and impact

In this last section, the influence and impact of the discovery of internal rotation and conformers on subsequent research are briefly summarized. The concept of conformation can be applied to various organic compounds that have multiple single bonds. The number of possible conformers rapidly increases with an increase in the number of single bonds that can rotate. For example, Mizushima et al. applied their approaches to linear saturated hydrocarbons.^31),58) Their early measurements of Raman frequencies revealed that these molecules existed as zigzag-shaped all-anti conformers in the solid state and as several conformers in the liquid state. Conformational studies of acyclic molecules with alkyl groups and polar groups have provided valuable information on the steric effects and the intramolecular interactions, as exemplified by the gauche effect mentioned above.

The conformational behavior of organic molecules is significantly affected by the ring formation, which decreases the degree of freedom. Cyclohexane having six C–C single bonds has been a prominent molecule in the history of organic chemistry. Before Mizushima’s work, Sachse⁵⁹⁾ and Mohr⁶⁰⁾ proposed nonplanar structures, known today as chair and boat forms, for a cyclohexane molecule, which used to be considered a planar molecule (Fig. 7). Mizushima mentioned that only the chair conformer was observed in the Raman and IR spectra of cyclohexane in a communication published in 1942.⁶¹⁾ Later, the conformations of cyclohexane and its derivatives were systematically investigated by Hassel in the 1940s⁶²⁾ and Barton in the 1950s,⁶³⁾ who shared the Nobel Prize in Chemistry1969 for their contributions to the development of the concept of conformation and its application in chemistry. They established the chair form as the most stable conformation of cyclohexane, where all C–C single bonds took the gauche conformation. One chair form undergoes interconversion to another chair form by internal rotation about C–C single bonds, and this dynamic process is called chair-to-chair ring inversion. These studies were valuable in understanding the structures, reactivities, and properties of cyclic compounds involving natural compounds based on the concept of conformation. Thus, the principle of conformational analysis, which originated from the work of Mizushima et al., was established in modern chemistry.^64),65)

Fig. 7.

Perspective structures and Newman projections of chair and boat forms of cyclohexane.

As shown in Fig. 1, the gauche conformers of DCE and related compounds are chiral. However, the resolution of such enantiomers was difficult because of the facile racemization via the internal rotation. Although the presence of such chiral conformers was conceptually apparent, no direct evidence had been presented for the long time. In 1997, Kuroda, Toda, and a coworker succeeded in isolating an enantiopure gauche conformer of DCE by the formation of a host–guest compound. All DCE molecules were included in the crystal cavities formed by an enantiopure host in a nearly gauche form (torsion angle −36°, −sc).⁶⁶⁾ Later, both enantiopure gauche conformers of DCE (torsion angle +63° or −65°) were isolated as inclusion compounds in enantiopure metal complex hosts.⁶⁷⁾

Another approach was the restriction of the internal rotation by the steric effect for the actual isolation of conformers at room temperature: such isolable conformers are called atropisomers.^4),68) The rotation about the C–C single bond in 9,9′-bitriptycyl is extremely restricted because of the severe steric hindrance between the rigid moieties on both sides.^69),70) Ōki et al. designed a 9,9′-bitriptycyl derivative having methoxy groups at specific positions as a stereochemical analog of DCE (Fig. 8).⁷¹⁾ They isolated not only the ap form, which was achiral and optically inactive, but also a pair of enantiomers of the sc form. The resolved enantiomers were optically active as observed by their optical rotation and circular dichroism, and their absolute stereochemistry was determined by X-ray crystallographic analysis to be P-sc or M-sc, where P and M represent a right-handed helix and a left-handed helix, respectively.

Fig. 8.

(Color online) Structures of three conformers of 2,2′,3,3′-tetramethoxy-9,9′-bitriptycyl: achiral ap form and a pair of enantiomers of chiral sc form.

8. Summary

After Mizushima and Higasi published the first article on the dipole moment of DCE in 1932, the concept of conformation was proposed by the Mizushima group and then refined and established by them and other researchers over a long period close to a century. Today, the concept is essential in any academic field that treats molecules that change their shapes by internal rotation about single bonds. Without this concept, we could not have understood and predicted the structures, properties, and functions of molecules in a rational and accurate manner. Chemistry related to the conformation is still spreading accompanied by developments of theories, analytical techniques, and informational and artificial intelligence (AI) technologies. Even in the era of modern science and technology, it is not always easy to fully predict the conformation of target molecules, particularly large molecules having several possible conformers and assembled molecular systems including solutions, interfaces, and supramolecules. Hence, it is timely to revisit monumental original work performed by Mizushima’s group in the early days in Japan in anticipation of further progress in molecular sciences in the future.

Notes

Edited by Keisuke SUZUKI, M.J.A.

Correspondence should be addressed to: S. Toyota, Department of Chemistry, School of Science, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro-ku, Tokyo 152-8551, Japan (e-mail: [e-mail]).

Footnotes

This paper commemorates the 100th anniversary of this journal and introduces the following paper previously published in this journal. Mizushima, S.-i. and Higasi, K.-i. (1932) Abhängigkeit des Dipolmomentes von 1.2 Dichloräthan von der Temperatur und dem Lösungsmittel. Proc. Imp. Acad. 8 (10), 482–485 (https://doi.org/10.2183/pjab1912.8.482).

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Appendices

[From Proc. Imp. Acad., Vol. 8 No. 10, pp. 482–485 (1932)]

Profile

Shinji Toyota was born in Kagawa Prefecture in 1964 and graduated from Faculty of Science, The University of Tokyo in 1986. He received Master’s degree in 1988 under the supervision of Professor Michinori Ōki and then became a research assistant of Faculty of Science, Okayama University of Science in 1988. After he received Doctor’s degree in 1992 from The University of Tokyo, he promoted to lecturer in 1993, associate professor in 1998, and professor in 2002. During the period, he worked as a visiting researcher in the laboratory of Professor Jay. S. Siegel in University of California, San Diego in 1996–1997. Since 2015, he has been a professor of School of Science, Tokyo Institute of Technology. He is interested in physical organic chemistry, structural organic chemistry, aromatic chemistry, and supramolecular chemistry. He received the Nagase Science Technology Foundation Award (2019) and The Japanese Association for Organic π-Electron Systems Award (2021).