JNTU Pharm. D I Year PHARMACEUTICAL ORGANIC CHEMISTRY Previous Question Paper (October/November - 2019 - R08)

Cycloalkanes are prepared through several key synthetic methods:

• Freund Reaction: Dihalides react with sodium or zinc to form cycloalkanes. For example, 1,3-dibromopropane reacts with sodium to yield cyclopropane.
• Dieckmann Condensation: This involves the intramolecular Claisen condensation of dicarboxylic acid esters in the presence of a strong base (like sodium ethoxide) to form cyclic beta-keto esters, which can subsequently be reduced to cycloalkanes.
• Reduction of Cyclic Ketones: Cyclic ketones can be reduced to cycloalkanes using Clemmensen reduction (Zn-Hg/HCl) or Wolff-Kishner reduction (NH2NH2/KOH).
• Catalytic Hydrogenation: Aromatic compounds like benzene can be hydrogenated under high pressure and temperature with a nickel catalyst to produce cyclohexane.
• Pyrolysis of Calcium Salts of Dicarboxylic Acids: Heating the calcium or barium salts of dicarboxylic acids (like adipic acid) leads to the formation of cyclic ketones, which are then reduced to cycloalkanes.

Bayer’s Strain Theory proposes that the stability of cycloalkanes depends on the deviation of their bond angles from the ideal tetrahedral angle of 109.5°. The theory suggests that any deviation creates 'angle strain,' making the ring unstable and reactive.

The strain is calculated as: Angle Strain = 1/2(109.5° - Internal Angle). According to this theory, cyclopropane (60°) is highly strained and unstable, cyclobutane (90°) is less strained, and cyclopentane (108°) is the most stable as its angle is closest to 109.5°.

Orbital pictures of angle strain reveal that in small rings, the carbon-carbon bonds cannot achieve maximum overlap due to the geometric constraints. Instead of forming strong sp3-sp3 sigma bonds through direct head-on overlap, the orbitals overlap at an angle, resulting in 'bent' or 'banana' bonds. These bonds possess higher energy and increased p-character compared to standard alkanes, which accounts for the inherent instability and high reactivity of cyclopropane and cyclobutane rings.