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Home , Anomeric effect, A value, Conformational isomerism, Dihedral angle, Strain (chemistry)

UNIT-2

CONFORMATIONAL ISOMERISM

In , is a form of in which the can be interconverted exclusively by rotations about formally single bonds. Such isomers are generally referred to as conformational isomers or conformers and specifically as rotamers when the rotation leading to different conformations is restricted (hindered) rotation, in the sense that there exists a rotational barrier that needs to be overcome to convert one conformer to another. Conformational isomers are thus distinct from the other classes of stereoisomers for which interconversion necessarily involves breaking and reforming of chemical bonds. The rotational barrier, or barrier to rotation, is the activation energy required to interconvert rotamers.

Conformers of , shown in Newman projection. The two gauche as well as the anti form are staggered conformations

Types of conformational isomerism

Butane has three rotamers: two gauche conformers, which are enantiomeric and an anti conformer, where the four carbon centres are coplanar. The three eclipsed conformations with dihedral of 0°,120° and 240° are not considered to be rotamers, but are instead transition states.

Some important examples of conformational isomerism include: 1. Linear conformations with staggered, eclipsed and gauche conformers, and 2. Ring conformation o conformations with chair and boat conformers. o conformation 3. Atropisomerism- due to restricted rotation about a bond, a can become chiral 4. Folding of , where some shapes are stable and functional, but others are not.

Conformations of

While there are an infinite number of conformations about any sigma bond, in ethane two particular conformers are noteworthy and have special names. In the eclipsed conformation, the C-H bonds on the front and back carbons are aligned with each other with dihedral angles of 0 degrees. In the staggered conformation, the C-H bonds on the rear carbon lie between those on the front carbon with dihedral angles of 60 degrees.

Energetically, not all conformations are equally favored. The eclipsed conformation of ethane is less stable than the staggered conformation by 3 kcal/mol. The staggered conformation is the most stable of all possible conformations of ethane, since the angles between C-H bonds on the front and rear carbons are maximized at 60 degrees. In the eclipsed form, the electron densities on the C-H bonds are closer together than they are in the staggered form. When two C-H bonds are brought into a dihedral of zero degrees, their electron clouds experience repulsion, which raises the energy of the molecule. The eclipsed conformation of ethane has three such C-H eclipsing interactions, so we can infer that each eclipsed C-H "costs" roughly 1 kcal/mol.

Figure %: Eclipsing interactions in ethane.

Steric Hindrance

Eclipsing interactions are an example of a general phenomenon called steric hindrance, which occurs whenever bulky portions of a molecule repel other molecules or other parts of the same molecule. Because such hindrance causes resistance to rotation, it is also called torsional . The 3 kcal/mol needed to overcome this resistance is the torsional energy. Note that this figure is very small compared to the energy required to rotate around double bonds, which is 60 kcal/mol (the bond energy of a C-C $\pi$ bond). At room , ethane molecules have enough energy to be in a constant state of rotation. Because of this rapid rotation, it is impossible to isolate any particular conformation in the way that cis- and trans- can be individually isolated. Although the term "conformational " is sometimes used as a synonym for conformations, conformations of a molecule are not considered true isomers because of their rapid interconversion.

Figure %: Energy diagram for rotation about the C‐C bond in ethane.

Conformations of n-butane

The illustration of butane above is represented by the Newman Projections below by designating the two middle carbons, one as the "front" and one as the "behind" carbon, and connecting the two end methyl groups accordingly.

Conformations of cyclohexane

A is any of several three-dimensional shapes that a cyclohexane molecule can assume while maintaining the integrity of its chemical bonds.

The internal angles of a flat regular hexagon are 120°, while the preferred angle between successive bonds in a carbon chain is about 109°, the tetrahedral angle. Therefore the cyclohexane ring tends to assume certain non-planar (warped) conformations, which have all angles closer to 109° and therefore a lower strain energy than the flat hexagonal shape. The most important shapes are called chair, half-chair, boat, and twist-boat.[1] The molecule can easily switch between these conformations, and only two of them — chair and twist-boat — can be isolated in pure form.

Chair conformation

The two chair conformations have the lowest total energy, and are therefore the most stable. In the basic chair conformation, the carbons C1 through C6 alternate between two parallel planes, one with C1, C3 and C5, the other with C2, C4, and C6. The molecule has a symmetry axis to these two planes, and is congruent to itself after a rotation of 120° about that axis. The two chair conformations have the same shape; one is congruent to the other after 60° rotation about that axis, or after being mirrored across the mean . The perpendicular projection of the ring onto its mean plane is a regular hexagon. All C-C bonds are tilted relative to the mean plane, but opposite bonds (such as C1-C2 and C4-C5) are parallel to each other.

As a consequence of the ring warping, six of the 12 carbon-hydrogen bonds end up almost perpendicular to the mean plane and almost parallel to the symmetry axis, with alternating directions, and are said to be axial. The other six C-H bonds lie almost parallel to the mean plane, and are said to be equatorial.

The precise angles are such that the two C-H bonds in each carbon, one axial and one equatorial, point in opposite senses relative to the symmetry axis. Thus, in a chair conformation, there are three C-H bonds of each kind --- axial "up", axial "down", equatorial "up", and equatorial "down"; and each carbon has one "up" and one "down", and one axial and one equatorial. The hydrogens in successive carbons are thus staggered so that there is little torsional strain. This geometry is often preserved when the hydrogen are replaced by halogens or other simple groups.

The conversion from one chair shape to the other is called ring flipping or chair-flipping. Carbon-hydrogen bonds that are axial in one configuration become equatorial in the other, and vice-versa; but their "up" or "down" character remains the same.

In cyclohexane, the two chair conformations have the same energy. At 25°C, 99.99% of all molecules in a cyclohexane solution will be in a chair conformation.

In cyclohexane derivatives, the two chair conformations may have different , depending upon the identity and location of the . For example, in methylcyclohexane the lowest energy conformation is a chair one where the is in equatorial position. This configuration reduces interaction between the methyl group (on carbon number 1) and the hydrogens at carbons 3 and 5; more importantly, it avoids two gauche butane interactions (of the C1-CH3 bond with the C2-C3 and C5-C6 ring bonds). Similarly, cis-1,3-dimethylcyclohexane usually has both methyls in the equatorial position so as to avoid interaction between them. In six-membered heterocycles such as pyran, a next to an heteroatom may prefer the axial position due to the .

The preference of a substituent towards the equatorial conformation is measured in terms of its , which is the difference between the two chair conformations, with the substituent in equatorial or in axial position. A positive A value indicates preference towards the equatorial position. The magnitude of the A values ranges from nearly zero for very small substituents such as deuterium, to about 5 kcal/mol for very bulky substituents such as the tert- .

Boat conformation

In the basic boat conformation (C2v symmetry), carbons C2, C3, C5 and C6 are coplanar, while C1 and C4 are displaced away from that plane in the same direction. Bonds C2-C3 and C5-C6 are therefore parallel. In this form, the molecule has two perpendicular planes of symmetry as well as a C2 axis. The boat conformations have higher energy than the chair conformations. The interaction between the two flagpole hydrogens, in particular, generates steric strain. There is also torsional strain involving the C2-C3 and C5-C6 bonds, which are eclipsed. Because of this strain, the boat configuration is unstable (not a local minimum of the energy function).

Twist-boat conformation [1] The twist-boat conformation, sometimes called twist (D2 symmetry) can be derived from the boat conformation by applying a slight twist to the molecule about the axes connecting the two unique carbons. The result is a structure that has three C2 axes and no plane of symmetry.

The concentration of the twist-boat conformation at room temperature is very low (less than 0.1%) but at 1073 Kelvin it can reach 30%. Rapid cooling from 1073 K to 40 K will freeze in a large concentration of twist-boat conformation, which will then slowly convert to the chair conformation upon heating

Half-chair conformation

The half-chair conformation is a transition state with C2 symmetry generally considered to be on the pathway between chair and twist-boat. It involves rotating one of the dihedrals to zero such that four adjacent atoms are coplanar and the other two atoms are out of plane (one above and one below).

K.Anita priyadharshini,

Lecturer,

Dept.of Pharmaceutical Chemistry,

SRM College of Pharmacy