Reaction Prediction using Density Functional Theory Calculations: A Study into the Synthesis of Safranal via Diels-Alder Reactions

Abstract

Two pathways for the synthesis of safranal (2,6,6-trimethyl-cyclohexa-1,3-diene-1-carbaldehyde) via a Diels-Alder reaction are proposed and analyzed for their feasibility by Density Functional Theory (DFT) calculations on a B3LYP/6-31G* level of theory. Pathway A involving the reaction of 3-methyl-2-butenal with 4-methoxypenta-1,3-diene is predicted to produce the desired regioisomers, although with low stereoselectivity. Due to the high activation barrier (23 kcal mol−1), the reaction will require harsher conditions than the related known reaction of Z-2-butenal and 1-methoxy-1,3- butadiene with a calculated ΔEa of 17 kcal mol−1. Replacement of the methoxy group at the diene by OAc, OSiMe3 or pyrrolidinyl does not enhance the reactivity any further. Preliminary experiments confirm these results, although the reaction conditions need to be improved for the reaction to be of synthetic use. In the reaction of methoxyethene with 3-formyl-2,4-dimethylpenta-1,3-diene (pathway B), the homo- and hetero-Diels-Alder pathways were compared. The desired homo-Diels-Alder reaction is predicted to give the correct regioisomer in an exothermic reaction. However, the activation barrier is high (30 kcal mol−1) and the reaction unlikely to proceed. The hetero-Diels-Alder reaction requires less activation energy (23 kcal mol−1) and is expected to dominate, although the thermodynamic driving force is low. The preferred regioisomeric product is the 2-methoxy-3,4-dihydropyran, in agreement with related reactions studied experimentally