Stuart Warren, in an article in Accounts of Chemical Research 11 (11) 401 (1978), wrote that almost all diphenylphosphine oxide-containing compounds are highly crystalline white solids. KiloMentor is, therefore, proposing the use of compounds containing the diphenylphosphine oxide substructure as one of the preferred intermediate types in ‘paper’ syntheses.
It is well known that the reaction of a primary alkyl halide with triphenylphosphine produces a quaternary phosphonium salt that is both an ionic salt and crystalline. Hydrolysis of such a compound in aqueous base liberates benzene and provides the phosphine oxides. These compounds in turn can be alkylated with other alkyl halides using butyllithium and TMEDA as co-solvent. [J. Chem. Soc. Perkin Trans. I, 550 (1977)] Warren predicts that these also will be highly crystalline solids.
The KiloMentor strategy for paper synthesis route design emphasizes the advantages of selecting a route that can easily be scaled up. To be preferred, intermediates need to have an increased likelihood of being easily separated and purified, preferably by acid-base extraction. This is proposed to be an overarching advantage over competing routes, whose intermediates almost always have to be purified by crystallization. The problem with these competing routes is that the crystallizability of an intermediate from a paper synthesis cannot be dependably predicted.
Besides those intermediates, purifiable by extraction, other intermediates would also be preferred if, even when still unknown and existing only ‘on paper’, they contained a functional group that could pretty well guarantee they would be found to be crystalline. There are not many of these and they are not celebrated for this property. Usually, the ease of crystallization for a compound depends upon the entire molecular structure and cannot be predicted, but diphenylphosphine oxide appears to be one that should come with a guarantee.
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