Group Research

Some of the areas in which we currently have active programs include:

Green Chemistry

Organic Synthesis and Sustainability

Among the many challenges to sustainability, the yearly generation of huge amounts of organic waste in the form of organic solvents is one of the most onerous.  Organic solvents represent the vast majority of organic waste created by the chemical enterprise (over 70%); hence, our foremost goal is to provide the community with compelling alternatives to organic solvents; i.e., to get organic solvents out of organic reactions.

Our research in green chemistry, therefore, is highly focused on developing new technologies that offer such alternatives, with special emphasis on the use of water as the gross reaction medium (and not the solvent). To solve the insolubility issues associated with organic substrates, reagents, additives, and catalysts, small amounts of a nonionic amphiphile are added to the water.  These surfactants, with both polar and nonpolar termini, undergo self-assembly in water to form nanomicelles when available in amounts above their critical micelle concentrations (CMC), which tend to be very low (typically 10-4 M).  But since the nonpolar (interior) portions of these micelles are serving as the reaction “solvent”, their make up is very important, just as the choice of solvent in any traditional organic reaction must be chosen with care.  Hence, we have introduced the concept of a “designer” surfactant, where the composition and resulting size and shape of these nanoparticles are controlled.  And very importantly, each amphiphile in its composition must be environmentally  “benign by design.”

 

Designer surfactants

Our first- and second-generation surfactants, PTS and TPGS-750-M (illustrated below), respectively, continue to enable a growing library of transition metal-catalyzed cross-coupling reactions to be performed in water at room temperature.  In other words, in the absence of any organic co-solvent, and without heating (or cooling), many of the most commonly used C-C, C-H, and C-heteroatom bond-forming reactions (shown below) can now be done under these very mild, environmentally friendly conditions.

These methodologies have been reviewed in two separate accounts:  the first appeared in Aldrichimica Acta in 2008, summarizing the initial work with PTS; the second appeared in 2012 in the same journal, discussing additional reactions in PTS but with the updated, less expensive, and equally or more effective surfactant TPGS-750-M.  For an overview of published work from the group, download a pdf containing Abstracts from these papers. (download a Summary of Group Publications)

Aldrichimica Acta 2008, 41, 59.     Aldrichimica Acta 2012, 45, 3.

Ongoing Projects in Green Chemistry

Several new technologies are currently under development.  Some of these include:  (1) organocopper chemistry; (2) amidations; (3) Stille couplings; (4) numerous oxidation and reduction reactions; and (5) tandem processes, all in water at room temperature.

(1) Organocopper Chemistry. In previous work from the group, it has been shown, contrary to all intuition and textbook teachings, that water-intolerant organozinc halides can be generated and used in Pd-catalyzed Negishi-like cross-couplings with aryl and alkenyl halides in a medium of just water.  For the latest publication (and references therein) on this aspect of our work, see Organometallics 2011, 30, 6090

The rationale for the success associated with this process lies in the likelihood that the sensitive RZnX is being generated as nanomicelles containing high concentrations of the alkyl halide collide on the metal’s surface (see cover above).  The resulting, water-sensitive RZnX, buffered by the surrounding micellar exterior, enters the lipophilic interior where water is not present.  The otherwise high concentrations of the coupling partner and catalyst encourage the desired cross-coupling.  The overall process, therefore, consists of combining two starting halides, zinc powder or dust, and a palladium catalyst in water, and simply stirring well at room temperature.

    

Although the transmetalation from zinc to palladium that ultimately results in a net Negishi-like coupling goes through a water-insensitive Pd(II) intermediate, any transmetalation from zinc to copper leads to yet another water-sensitive species.  Thus, organocopper chemistry in water could be even more challenging.  Fortunately, this has been documented with conjugate additions to unsaturated ketones (see below).  Other types of organocopper chemistry are currently being pursued utilizing this unprecedented green chemistry. For example, new inroads to ketones are being developed via the combination of an in situ generated organocopper reagent (from a precursor alkyl halide), and a suitable acylation partner, all taking place within nanoreactors in water.

(2) Amidations. Considerable emphasis is being placed today on the introduction of an NH2 residue, or its equivalent, onto aromatic or heteroaromatic rings.  Whereas previously we had developed an amination route to unsymmetrical di- and tri-arylamines, we have devised a new entry to such targets using ammonia equivalents such as Boc or Cbz derivatives, as illustrated below.

(3) Stille Couplings. This name reaction is still quite popular in synthesis, presumably due to the stability and tolerance to functionality of organostannane intermediates.  On the other hand, with stability comes lower reactivity (e.g., relative to RZnX), in which case most Stille couplings require heating. The lipophilicity associated with tin reagents makes them ideal partners for such cross-couplings occurring within the lipophilic core of nanomicelles.  Indeed, these reactions under development appear to go well in water at ambient temperatures.

(4) Oxidation & Reduction Reactions. In addition to cross-couplings, we are studying a variety of transformations within nanomicelles that result in a net oxidation (or reduction).  For example, oxidation of alcohols to aldehydes can be accomplished in water at room temperature using air as the oxidant.  Reductions are focused on alkynes and other functionality that are subject to hydrogenation or SET events.

(5) Tandem Processes.  Many opportunities exist to conduct tandem reactions within aqueous nanomicelles, where the surfactant plays host to an initial metal-catalyzed coupling, and then enables a second bond-forming event, all in water at room temperature.  Our first representative coupling partners under study are shown below.  Several combinations of cross-couplings are under development on both alkenyl bromide lynchpins, and others are planned using aromatic/heteroaromatic substrates.

“Nok”:  A Third Generation Surfactant

As we look towards new surfactants that are both benign and less expensive, a next generation amphiphile under development now focuses on the use of b-sitosterol as the interior component of the new amphiphile called “Nok.”   A systematic study on a variety of cross-coupling reactions is currently being done to evaluate the enabling properties of this surfactant relative to TPGS-750-M.

Additional Research Projects

Total Synthesis

The development of new approaches to the formation of nonracemic, unsymmetrical biaryls that contain an element of axial chirality remains as an area of considerable interest in the group.  Previously we have shown that naphthylisoquinoline alkaloids, in particular the korupensamines (A and B) represent a class of natural products that are a good testing ground for new methodologies in asymmetric biaryl construction.  More recently, we continue to test our newly introduced use of intramolecular p-stacking as a stereocontrol element, which worked well en route to korupensamine B (shown below; see J. Am. Chem. Soc. 2010, 132, 14021).  Targets of current interest the approaches to which make use of this technology, include 4'-O-demethylhamatine and O,N-dimethylancistrocladine, both being antimalarials.

Organocopper Chemistry

Our interest in copper hydride chemistry continues, with a current focus on reactions of this species with allylic electrophiles.  Thus, the question of regiochemistry arises, notwithstanding the expected (albeit challenging) SN2’ mode of addition, which we have already shown can be altered in reactions of ligated CuH with variously substituted enones from the typical 1,4- to the uncommon 1,2-mode of addition (see J. Am. Chem. Soc. 2010, 132, 7852).