Reactions that form a C–C bond make up a foundational pillar of synthetic organic chemistry. In addition, organocatalysis has emerged as an easy, environmentally-friendly way to promote this type of bond formation. Since around 2000, organocatalysts have been used in a variety of C–C bond-forming reactions including Michael and aldol additions, Mannich-type reactions, and Diels–Alder reactions, to name a few. Many of these methodologies have been refined and further developed to include cascade and domino processes. This review will focus on recent advances in this area with an emphasis on methodologies having applications in the synthesis of biologically-significant compounds.

There has recently been greater appreciation for the impact that n → π* interactions have on the conformational preferences of molecules in the gas phase, solution, and crystalline form. Earlier studies, both experimental and computational, have demonstrated that suitably placed substituents can affect the extent of these interactions. A thorough understanding of how substituents affect these interactions is necessary for these forces to be potentially utilized as a means of crystal engineering. We synthesized a series of 2-(dimethylamino)­biphenyl-2′-carboxaldehydes substituted at the position para to the aldehyde group with substituents ranging in electronic properties from strong electron-withdrawing to strong electron-donating and determined their structures via X-ray crystallography. In all cases, evidence suggests that the conformations adopted in the crystals retained n → π* interactions. However, contrary to computational studies conducted in vacuo, the geometries varied not according to the substituents’ electronic properties (as described by Hammett σp values) as expected but instead according to their steric properties (using Sotomatsu and Fujita’s steric parameters; J. Org. Chem.1989544443; Bull. Chem. Soc. Jpn.1992652343). Calculations on representative molecular clusters demonstrate that the geometries adopted in the crystal form are such that they minimize destabilizing intermolecular steric interactions, while maximizing stabilizing intermolecular dispersive and electrostatic forces. This comes at fairly low energetic cost to the molecules relative to their optimized theoretical in vacuo geometries (generally less than 0.5 kcal/mol) even though it stresses, but does not overwhelm, the intramolecular n → π* interactions.

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