Organometallic nucleophiles used for conjugate additions are most often prepared in situ. The use of anhydrous equipment and inert atmosphere is necessary. Because these factors are sometimes difficult to control and the strength of freshly prepared reagents can vary substantially, titration methods are necessary to verify the purity of reagents. A number of efficient titration methodologies exist.
Usually, vicinal difunctionalizations are carried out in one pot, without the intermediacy of a neutral protected enolate. However, in specific cases it may be necessary to protect the intermediate of β-addition. Before reaching this point, however, solvent and nucleophile screens, order of addition adjustments, and counterion adjustments can be made to optimize the one-pot process for a particular combination of carbonyl compound, nucleophile, and alkylating (or acylating) agent. Solvent adjustments between the two steps are common; if one solvent is used, tetrahydrofuran is the solvent of choice. Polar aprotic solvents should be avoided for the conjugate addition step. Concerning temperature, conjugate additions are usually carried out at low temperatures (-78 °C), while alkylations are carried out at slightly higher temperatures (0 to -30 °C). Less reactive alkylating agents may require room temperature.