Interlude 2: Shapes of Cyclic Molecules Recall from 2nd year: - Rotation around C—C single bonds is generally fast. - This leads to a variety of different conformers for any given molecule. - To evaluate the energy of each conformer, we need to consider three basic types of strain: Torsional strain: caused by repulsions between bonding electrons. ~ 4 kJ/mol for each eclipsing bond. Steric strain: caused by repulsions between electrons in atoms that are not bound to one another. ~ 10 kJ/mol for methyl groups in eclipsing butane ~ 3 kJ/mol for methyl groups in gauche butane Angle strain: caused by deformation of a bond angle away from its lowest energy value (e.g. 109.5° for sp3 carbons). total strain energy for cyclopropane = 115 kJ/mol 1 Chemistry 335 Supplemental Slides: Interlude 2

Potential Energy (kJ/mol) Energies of Butane Conformers Potential Energy (kJ/mol) Dihedral Angle Between CH3 groups Figure adapted from Solomons & Fryhle, 10th Ed. 2 Chemistry 335 Supplemental Slides: Interlude 2

Shapes of Simple Cyclic Molecules (Review from 2nd Year) Three-membered rings (cyclopropanes) are flat! To reduce angle strain, the carbon atoms in the ring are actually not sp3 hybridized, but are technically sp5 (i.e.  1⁄6 s density and  5⁄6 p density). The result is that the bonds have somewhat more p character than a normal C—C single bond. Cyclopropane bonds are often described as ‘banana bonds’. 3 Chemistry 335 Supplemental Slides: Interlude 2

Shapes of Simple Cyclic Molecules (Review from 2nd Year) Cyclobutanes are not flat because this would require bond angles of 90°. Instead the ring puckers by about 25° out of the plane (i.e. each carbon atom in the ring is 25° off the plane described by the other three atoms). Technically speaking, the substituents on a cyclobutane can be in two different environments, but these are much less distinct than the familiar axial/equatorial orientations in a cyclohexane, and in any case are rapidly interconvertible. 4 Chemistry 335 Supplemental Slides: Interlude 2

Shapes of Simple Cyclic Molecules (Review from 2nd Year) While saturated 4-membered rings are puckered, unsaturated 4-membered rings are essentially flat. This facilitates good control in the addition of nucleophiles / electrophiles:

Shapes of Simple Cyclic Molecules (Review from 2nd Year) Cyclopentanes adopt envelope shapes so that each bond angle can be nearly 109°. Even fairly simple substituted cyclopentanes can have many accessible conformations. 6 Chemistry 335 Supplemental Slides: Interlude 2

This can be important in medicinal chemistry! Richards, Brant, Boulanger, Cairo & Wulff, MedChemComm, 2014, 5, 1483-1488.

Shapes of Simple Cyclic Molecules (Review from 2nd Year) While saturated 5-membered rings are puckered, unsaturated 5-membered rings are essentially flat. This facilitates good control in the addition of nucleophiles / electrophiles:

Shapes of Simple Cyclic Molecules (Review from 2nd Year) Cyclohexanes adopt chair shapes to minimize torsional and angle strain. There is still some steric strain, however, due to 1,3-diaxial interactions. This will be larger for some chair conformations than others. Two chair conformations are interconvertible though a process called ring-flip. 9 Chemistry 335 Supplemental Slides: Interlude 2

Potential Energy (kJ/mol) Cyclohexane Ring Flip Half-Chair Half-Chair Boat Potential Energy (kJ/mol) Twist-Boat Twist-Boat 45 kJ/mol 45 kJ/mol 23 kJ/mol 30 kJ/mol 23 kJ/mol Chair Chair 10 Figure adapted from masterorganicchemistry.com Chemistry 335 Supplemental Slides: Interlude 2

A-Values: a measure of energy that tells you about sterics! Consider a cyclohexane bearing a single substituent. The difference in kcal/mol in Gibbs free energy (DG) between the lower energy conformation (equatorial) and the higher energy conformation (axial) is the A-value for that substituent. For example, when R = CH3, the difference in energy between the equatorial and axial conformations shown above is 1.74 kcal/mol (7.28 kJ/mol). CH3 is therefore assigned an A-Value of 1.74. A-Values are a measure of the steric bulk of a substituent. 11 Chemistry 335 Supplemental Slides: Interlude 2

Substituent A-Value Substituent A-Value A-Values: a measure of energy that tells you about sterics! Substituent A-Value H 0.000 D 0.006 F 0.15 Cl 0.43 Br 0.38 I CN 0.2 CO2H 1.4 CO2– 1.9 CO2Et 1.2 SOPh SO2Ph 2.5 Substituent A-Value Me 1.74 Et 1.75 i-Pr 2.1 t-Bu 4.5 CF3 OMe 0.6 Ph 2.9 CH=CH2 1.35 NH2 1.6 NH3+ 1.9 N(CH3)3 Si(CH3)3 2.5 12 Chemistry 335 Supplemental Slides: Interlude 2

Conformational Locking in Cyclohexanes By virtue of bulky substituents or ring fusion, some cyclohexanes are “locked” and cannot engage in ring flip: 13 Chemistry 335 Supplemental Slides: Interlude 2

Conformational Locking in Cyclohexanes Note that while trans-decalin is not capable of ring flipping, cis-decalin can readily engage in ring flipping operations. 14 Chemistry 335 Supplemental Slides: Interlude 2

Putting It All Together: Conformations, Orbitals and Reactions! Consider a nucleophile attacking the p* orbital of a cyclohexanone at the Bürgi–Dunitz angle. The nucleophile can approach either axially or equatorially, but either way it suffers some degree interaction with the axial substituents on the ring, and with the electrons in the bonds. 15 Chemistry 335 Supplemental Slides: Interlude 2