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Novel envirofriendly difluoromethylation

29 February 2013 - CRD 109

What : difluoromethylation
Reagent: difluoromethyltriflate, air stable liquid
Source: DOI (Fier & Hartwig)
Rationale: current methods require ozone depleting Freon 22 (gas) Relevant to pharma (example Pantoprazole)
Substrates: Phenols, aryl boronic acids
Mechanism: proceeds via difluorocarbene. Isotope labeling evidence
difluoromethyl ethers Hartwig 2013.PNG

Visitors by country

28 February 2013 - Web statistics

visitors by country NNNS chemistry blog.PNGAnd why not. Just a sampling of visitors to this blog and their origin by country.

Scientists discover homeopathic palladium

22 February 2013 - CRD 108

Murray et al of AstraZeneca Process R&D in the UK report on their optimization of the Mizoroki-Heck reaction because they feel the world needs an ubiquitous HM protocol which consistently delivers good yields of coupled product. Number of substrates covered: around 30. Number of catalysts covered: 15. Base: methyldicyclohexylamine, solvent: N,N-dimethylacetamide. Main conclusion: of all the catalysts tried only three stand out, bis(tri-ter-butylphospine)palladium on of them.
But what is tetrabutylammonium chloride doing here? The article only mentions in the footnotes that it increases catalyst activity and conversions. For all catalysts tried? and how does it work then? Are all reactions homogeneous?
Equally intriguing is the presence of "homeopathic palladium" as one of the catalysts tried. Palladium acetate is listed twice as catalyst in one of the main tables, one them the homeopathic version. With substrate methyl-4-bromobenzoate against styrene the yield is zero and with the non-homeopathic palladium the yield is 100%. With 4-cyanobromobenze the homeopathic yield is 30% versus 100%. The contrast could not be more stark. The text and supporting info remain silent on the details but the Mighty Google informs us homeopathic palladium may have something to do with successful Pd catalysed reactions at very low loading (review here). Not here.
Heck reaction Murray 2013.PNG

Amide reduction latest

21 February 2013 - CRD 107

The latest in amide reduction. Stein & Breit (DOI) really emptied their chemicals store for this one, with 43 potential catalysts screened. Winner: palladium / rhenium on carbon with metal particles 2 to 6 nanometer. Then 20 reaction optimizations (sieves help) and then 80 substrates screening. Drawback: attempts to selectively reduce amides in presence of alkenes or aromatics were futile. Added bonus: catalyst can be recycled by simple filtration.
Amide reduction Stein Breit 2013.PNG

Life? Really?

04 February 2013 - Making it Move XI

In entry XI of Making it Move Pallaci et al. treat us to "living crystals" (DOI). What are they? And alive by what definition?
The crystals in question are hematite cubes coated to some extent with polymerized 3-methacryloxypropyl trimethoxysilane. They are suspended in water containing a surfactant and hydrogen peroxide where they display regular Brownian motion. Under the influence of a bright blue light, hematite on exposed parts of the cube catalyses the decomposition of the hydrogen peroxide, creating an osmotic gradient and a surfing opportunity. From then on things get complicated.
Added colloid particles made of silica and acting as tracers can be seen to migrate towards the hematite cubes when illuminated in a process called phoretic migration which travels in the opposite direction as the osmotic migration of a regular surface. Phoretic migration is also the reason why the cubes themselves migrate to the bottom of the sample cell, attracted by the silica surface and shielding the exposed hematite layer. Due to imperfections in their geometry cubes can still take off again by peroxide induced self-propulsion.
The nett effect on display is a process of random assembly and disassembly of clusters of cubes as long as the light is on and complete disorder when the light is switched off. The similarity is with swarm behaviour as seen in flocks of birds and that is where the "living" in "living crystals" comes from. But was exactly is life? Do not bother to check Wikipedia for an answer. In the current life article, life is any object that displays biological processes but in the biological process article, a biological process is a process of a living organism. Movie!

DOS out fragment-based lead discovery in

02 February 2013 - Drug discovery

Some alarming news (at least to this blog) is hidden in the editorial by Brian Shoichet in a recent Nature Chemistry on developments in drug discovery: the pharmaceutical companies are no longer interested in natural products as lead compounds as they are often only active as mixtures, and (...) not amenable to rapid synthetic optimization. This must be bad news for rainforest proprietors who are now stuck with their merchandise of medicinal flowers, plants , roots and whatever. Diversity oriented synthesis according to Shoichet also has its setbacks: the molecules this strategy spawns simple do not have any biological track record. Enter fragment-based lead discovery: decompose a large biomolecule into fragments and in one or more of them biological activity (binding to proteins) should be retained. For example, fragment analysis of the natural alkaloid cytisine led to the development of the artificial drug Varenicline.
The Shoichet editorial was only an appetizer for some actual fragment analysis by Over et al. (DOI) in the same issue. Here are the numbers. The initial population was about 1800,000 biomolecules who had their chains pruned, their fused ring decoupled and their spacers cleaved. This resulted in an initial set of 750,000 fragments and after eliminating the weak, toxic and feeble a set of 160,000. These fragments had 18,000 so-called Murcko fragments in common of which about 1500 were not already known in the ZINC database. After compensating for similarity (Tanimoto treatment) the final set was about 2000 clusters of fragments. These fragments were then analysed as MAP kinase inhibitors. Effective molecules were indeed found to fill up key protein voids.
Interesting thought: what would happen if you administer the complete set of fragments of a single biomolecule as a cocktail?