Substitution of one metal catalyst for another is not as straightforward as simply justifying this change based on the availability and/or cost of the metals. Methodologies to properly assess options for reaction design, including multiple factors like a metals availability, cost, or environmental indicators have not advanced at the pace needed, leaving decisions to be made along these lines more challenging. Isolated indicators can lead to conclusions being made in too hasty a fashion. Therefore, an extensive life cycle-like assessment was performed documenting that the commonly held view that methods using earth-abundant metals (and in this case study, Ni) are inherently green replacements for methods using palladium in cross-coupling reactions, and Suzuki-Miyaura couplings, in particular, is an incomplete analysis of the entire picture. This notion can be misleading, and unfortunately derives mainly from the standpoint of price, and to some degree, relative natural abundance associated with the impact of mining of each metal. A more accurate picture emerges when several additional reaction parameters involved in the compared couplings are considered. The analysis points to the major impact that use of organic solvents has in these couplings, while the metals themselves actually play subordinate roles in terms of CO2-release into the environment and hence, the overall carbon footprint (i.e., climate change). The conclusion is that a far more detailed analysis is required than that typically being utilized.

A new catalyst that derives from commercially available precursors for copper-free, Pd-catalyzed Sonogashira reactions at the sustainable ppm level of precious metal palladium under mild aqueous micellar conditions has been developed. Both the palladium pre-catalyst and ligand are commercially available, bench stable, and highly cost-effective. The catalyst is applicable to both aryl- and heteroaryl-bromides as educts. A wide range of functional groups are tolerated and the aqueous reaction medium can be recycled. An application to a key intermediate associated with an active pharmaceutical ingredient (ponatinib) is discussed.

A 1 : 1 Pd : ligand complex, [t-BuXPhos(Pd-π-cinnamyl)]OTf, has been identified as a highly robust pre-catalyst for amination reactions leading to diarylamines, where loadings of metal are typically at 1000 ppm Pd, run in water at temperatures between rt and 45 °C. The protocol is exceptionally simple, is readily scaled, and compares very favorably vs. traditional amination conditions. It has also been shown to successfully lead to key intermediates associated with several physiologically active compounds.

The new monophosphine ligand HandaPhos has been identified such that when complexed in a 1:1 ratio with Pd(OAc)2, enables Pd-catalyzed cross-couplings to be run using ≤1000 ppm of this pre-catalyst. Applications to Suzuki-Miyaura reactions involving highly funtionalized reaction partners are demonstrated, all run using environmentally benign nanoreactors in water at ambient temperatures. Comparisons with existing state-of-the-art ligands and catalysts are discussed herein.

Several ppm level gold-catalyzed reactions enabled by the ligand HandaPhos can be performed at room temperature in aqueous nanoreactors composed of the surfactant Nok. Variously substituted allenes undergo cycloisomerization leading to heterocyclic products in good yields. Likewise, cyclodehydration is also illustrated under similar conditions, as is an intermolecular variant, hydration of terminal alkynes. Recycling of the catalyst and reaction medium is also illustrated. A low E factor associated with limited solvent use and therefore, waste generation, documents the greenness of this process.

A newly engineered palladacycle that contains substituents on the biphenyl rings along with the ligand HandaPhos is especially well-matched to an aqueous micellar medium, enabling valued Suzuki-Miyaura couplings to be run not only in water under mild conditions, but at 300 ppm of Pd catalyst. This general methodology has been applied to several targets in the pharmaceutical area. Multiple recyclings of the aqueous reaction mixture involving both the same as well as different coupling partners is demonstrated. Low temperature microscopy (cryo-TEM) indicates the nature and size of the particles acting as nanoreactors. Importantly, given the low loadings of Pd invested per reaction, ICP-MS analyses of residual palladium in the products shows levels to be expected that are well within FDA allowable limits.

A new biaryl phosphine-containing ligand from an active palladium catalyst for ppm level Suzuki-Miyaura couplings, enabled by an aqueous micellar reaction medium. A wide array of functionalized substrates including aryl/heteroaryl bromides are amenable, as are, notably, chlorides. The catalytic system is both general and highly effective at low palladium loadings (1000-2500 ppm or 0.10-0.25 mol%). Density functional theory calculations suggest that greater steric congestion in N₂Phos induces increased steric crowding around the Pd center, helping to destabilize the 2 : 1 ligand-Pd(0) complex more for N₂Phos than for EvanPhos (and less bulky ligands), and thereby favoring formation of the 1 : 1 ligand-Pd^o complex that is more reactive in oxidative addition to aryl chlorides.

Esterification in an aqueous micellar medium is catalyzed by a commercially available lipase in the absence of any co-factors. The presence of only 2 wt% designer surfactant, TPGS-750-M, assists in a 100% selective enzymatic process in which only primary alcohols participate (in a 1 : 1 ratio with carboxylic acid). An unexpected finding is also disclosed where the simple additive, PhCF₃ (1 equiv. vs. substrate), appears to significantly extend the scope of usable acid/alcohol combinations. Taken together, several chemo- and bio-catalyzed 1-pot, multi-step reactions can now be performed in water.