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CIP rewrite

26 December 2011 - Chirality

point chirality by photoisomerisation  The well-known CIP system perhaps needs a footnote added in order to be able to incorporate the novel molecule constructed by Hashim & Kamaoki. They report (DOI) the conversion of prochiral A - a quarternary carbon atom with a methyl, a phenyl and two azobenzene groups to chiral compound B with one of the azobenzene groups photoisomerized from the trans to the cis configuration. Because the central carbon atom now has 4 different substituents it is an asymmetric carbon and now has point chirality.
However please note that the new compound is still racemic. The enantiomers could only be detected individually and isolated by chiral column chromatography. Synthesis is also transient because a second isomerization step will produce the achiral double Z,Z isomer.
And is this truly "the first example of the induction of point chirality in which two of the substituents around an sp3 carbon atom are geometric isomers."? Surely in the huge CAS database there must be countless of compounds with a quaternary carbon atom and two isomeric substituents except that then the researchers did not bother to mention it. Did Hashim & Kamaoki look hard enough or exactly how do you search for such a compound in a database? In any event, as Hashim & Kamaoki are now pushing towards synthesis of the enantiopure compounds via asymmetric synthesis, the rest of the world can decide which one to call the S and which one the R. To be continued.

Update: Reader S comments the comments are not on! He is right. Still needs to be coded into the application. But here is his comment: CIP takes care of such questions - I'm pretty sure Z beats E. And also, R beats S if you have two mirror-image substituents on a chiral carbon that only differ based on the R or S configuration of the chiral centre in them - from the Wikipedia page you cite: "It is possible in rare cases that two substituents on an atom differ only in their absolute configuration (R or S). If the relative priorities of these substituents need to be established, R takes priority over S. When this happens, the descriptor of the stereocenter is a lowercase letter (r or s) instead of the uppercase letter normally used". It's an oversight that the same situation with E/Z is not mentioned.

Engineered serendipity

23 December 2011 - Lazy chemistry II

Serendipity McMillan 2011  McNally, Prier & MacMillan are also on the trail of high-throughput organic reaction discovery in what this blog likes to call lazy chemistry (DOI). The main theme is serendipity and the quotes are fantastic: "Recently, we questioned whether serendipity could be forced or simulated to occur on a predictable basis in the realm of reaction discovery, thereby providing a reliable platform to access valuable transformations or unexpected pathways" and "assuming that serendipity is governed by probability...".
The research protocol looks very similar to the one described by Hartwig (DOI) just 4 months ago and features a 96-well plate that was filled horizontally and vertically with up to 19 different simple organic substrates such as benzaldehyde or pyridine. A known reaction type between any two reaction partners should not be obvious. A solvent containing transition-metal catalysts / ligands was then added and after exposure to a 26 watt fluorescent lamp and a certain reaction time the reaction product was analysed by GC-MS and a MS library. The article boasts up to a thousand reactions per day can be screened in this semi automatic way.
The main find was a novel carbon-carbon coupling reaction between 1,4-dicyanobenzene and N-phenyl-pyrrolidine using photoredox catalyst iridium tris(2-phenylpyridine).

Exit 18 electron rule

16 December 2011 - Unsolved problems in chemistry

The 18 electron rule in chemistry is a useful tool in predicting the stability of metal complexes. For example in ferrocene the iron core provides 8 electrons and 2 cyclopentadienyl ligands add 2 x 5 making a total of 18: hence the compound is stable. Likewise in tetrakis(triphenylphosphine)palladium(0) Pd(P(Ph)3)4 palladium owns 10 electrons all by itself and as the four phosphine ligands each donate 2 electrons the grand total again is 18.
But what when said Pd(P(Ph)3)4 is the catalyst in one of those typical coupling reactions such as the Heck reaction?. All reaction schemes assume that the catalyst will willingly surrender two ligands to an electron-poor and reactive 14e compound before it can engage in actual business. On the other hand it is well known that the p-orbital in general is too high in energy for any electron sharing and the 18e rule falls apart.
In a recent publication Ahlquist & Norrby have some further doubts DOI and discuss a new computational model. Experimental evidence collected thus far suggests 4-coordinated Pd (P4) is in chemical equilibrium with tri-coordinated Pd (P3) and further dissociation to P2 is unfavourable. The popular theoretical modelling tool B3LYP is unable to replicate these dynamics (P3 formation too favourable) but Ahlquist & Norrby throw in London dispersion for a quick fix. In another find the d-orbital occupancy was found to decrease on going from P1 (9.72 electrons) to P4 (9.61 electrons). This means the driving force for the formation of P3 and P4 is back donation from the electron-rich Pd center to the ligands. This is a departure from the established driving force featuring an electron-deficient Pd center. Ahlquist & Norrby also offer an explanation for the formation of P2. They invoke ps orbital hybridisation which makes the molecule linear with long metal to ligand sigma bonds.

Comments? #NNNS_chemistry

Target: taxadiene

10 December 2011 - En route to Taxol

taxadiene Baran 2011  Target: (+)-taxadiene
Who: Mendoza / Ishihara / Baran
Publication: Nature Chemistry (DOI)
Relevance: possible alternative route to Paclitaxel
Strategies: Redox economy
Advantages: gram-scale, few steps
Disadvantages: poor diastereomeric control
How: starting from achiral enone 1 Copper(I)-thiophene-2-carboxylate , chiral catalyst 2, trimethylaluminum heptane / THF then chlorotrimethylsilane to silyl enol ether 3 ( asymmetric conjugate addition), acrolein 4 (20 eq.), Gd(OTf)3 (toluene, water/EtOH) to 5 Mukaiyama aldol reaction (not isolated), then Jones reagent to diketone 6 as diastereomeric mixture, boron trifluoride etherate to tricycle 7 as diastereomeric mixture (Diels-Alder reaction) , N-phenylbis(trifluoromethanesulfonimide), KHMDS, THF to the enol triflate, then tetrakis, dimethylzinc to ketone 8 (Negishi coupling), then LiAlH4 / Et2O to alcohol 9, then KH / THF, then AcCl to acetate, then sodium, HMPA and tBuOK to taxadiene 10
Main competition: biosynthetic taxadiene by Escherichia coli starting from glucose ,Stephanopoulos 2010 ( DOI)

Moerdijk redux

08 December 2011 - The Law of the Land

This blog has been commenting on a particular ferocious fire that consumed chemical packaging company Chemie-Pack on January 5 2011 here and here. The aftermath of this disaster (nobody was hurt though) proved just as exhilarating as the initial fireworks. The company went bankrupt but not before a lot of quarrelling with regards to the damage to the environment and clean-up costs. And now the public prosecutor has stepped in.

We know what caused the fire. An employee was tasked with the job of transferring a resin from one container to another with the aid of a pneumatic pump (source: NOS). The day was cold, the pump refused to work and the employee decided to defrost it with a gas burner. The pump caught fire.

The employee was experienced (13 years on the job), survived the first round of job redundancies and kept his mouth shut until finally confessing to the police after multiple interrogations. And guess who stands trial as of this week? Not the employee who was granted immunity in exchange for his confession but three members of the former senior management (NOS BNdeStem). In addition to procedural offences they are charged with arson (!). According to the public prosecutor the employee is not to blame because his action were inspired by company culture.

Regardless of the outcome of this trial (this blog will keep you posted) micromanagers around the country must feel vindicated. Of course ordinary employees are nothing but dumb zombies incapable of original thought and (safe) creative solutions. As a micromanager you cannot possibly transfer any responsibility and you have to well.. huh micromanage them. Dumb Chemie-Pack management.