Surfactant Technology: With New Rules, Designing New Sequences Is Required!

Abstract

With a growing toolbox of surfactantmediated chemistry in water and an increased number of scaled-up transformations has come tremendous learning [for example, see: Lipshutz, B. H.; et al. The Hydrophobic Effect Applied to Organic Synthesis: Recent Synthetic Chemistry "in Water". Chem. -Eur. J. 2018, 24 (26), 6672−6695]. These opportunities now reside within a few expert groups, and while all of the details are far from fully understood or still under development, substantial know-how has been gained in both reaction process and synthesis design. Herein we share some of the fundamental principles inherent to micellar catalysis and illustrate them on a particularly challenging case involving a Suzuki−Miyaura cross-coupling. The complete structures of the active pharmaceutical ingredient (API) and the intermediates are not fully disclosed for confidentiality reasons but can nevertheless serve as illustrative of the importance of factors that, unlike traditional chemistry in organic solvents, can be crucial to a successful outcome (e.g., lipophilicity). The API used as an example for this discussion bears significant commonality with a large number of other targets associated with the formation of a biphenyl array as well as the presence of an amide and products resulting from nucleophilic aromatic substitutions (S N Ar). Hence, we look to utilize these prior learnings and can now rapidly apply them to the design of optimal conditions for several other important transformations.

Metal–Micelle Cooperativity: Phosphine Ligand-Free Ultrasmall Palladium(II) Nanoparticles for Oxidative Mizoroki–Heck-type Couplings in Water at Room Temperature

“…This transformation is functional group tolerant and is compatible with nitro (10,12,17,19,31) and reactive fluoro groups (3,18). The trifluoromethyl group was also well-tolerated (6, 9, 14, 21), as were substrates containing heterocyclic moieties, including benzofuranyl (8,24) and thiophenyl (11). Alkyl styrene was also well-tolerated, and no isomerization or side products were observed when 4-phenylbutene was used as coupling partner (9).…”

“…Water is a safe, stable, inexpensive, and naturally abundant solvent. , However, in organic synthesis, it is predominantly used for reaction work-ups rather than as an alternative solvent. − Nonetheless, it has many exciting features to offer better and cleaner chemistry for green chemical synthesis. − The very forward-thinking statement by Sheldon more than a decade ago, “the best solvent is no solvent, but if a solvent is needed, then water has a lot to recommend it”, has experimentally been proven correct for many areas of chemistry. ,− For example, micellar catalysis, a significant enabler of chemistry in water, has been applied to many diverse classes of organic chemistry reactions, often with improved reactivity and/or selectivity compared to their organic solvent enabled counterparts. − …”

Nitro to amine reductions using aqueous flow catalysis under ambient conditions

“…The solvent is water or aqueous ethanol for all the experiments described here and the maximum concentration used was 0.1 M. Small amount of ethanol was used to facilitate solubilization at higher concentrations. Although surfactants have been reported to facilitate nitro compounds dissolution in water ( Lipshutz et al., 2018 ; Lippincott et al., 2020 ), the use of ethanol and acetonitrile minimizes product contamination.…”

HPMC: A Biomass-Based Semisynthetic Sustainable Additive Enabling Clean and Fast Chemistry in Water

“…Apart from nitrogen nucleophiles, a sulfur nucleophile was also found to be compatible (29). Nucleophiles containing spirocycles showed no side reactions (26,27). Substituted azasilanes (30) and a terminal-alkyne-bearing azapene (31) exhibited moderate to excellent reactivity.…”