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Pyrazole based frustrated Lewis pair

27 November 2010 - FLP chemistry VII

FLP theuergarten 2010 replacement  More and more frustrated Lewis pairs (FLP, see part 6) see the light of day. The ultimate aim is reversible hydrogen storage but creating a metal-free hydrogenation catalyst is also worth the effort. Theuergarten et al. (DOI) have prepared pyrazolium-borate 3 from pyrazole 1 and bis(pentafluorophenyl)borane 2 as the trans isomer. Dehydrogenation with another FLP 4 forms pyrazolylborane 5 which easily takes up hydrogen again now to the cis-isomer. The trans isomer is a metal-free hydrogenation catalyst for N-(benzylidene)benzylamine 6 to dibenzylamine 7.

Update 22-02-2011: added missing bonds in image. Thanks to reader K. for spotting the error.

Enantioselective fluvastatin synthesis

20 November 2010 - Organic chemistry

Fluvastatin is a type of statin and a drug for the treatment of high cholesterol. The commercial drug is racemic but what about the effectiveness of the enantiomeric forms? Zacharia et al. have argued that as the compound has two chiral centers they might as well synthesize all 4 stereoisomers (DOI). Indole 1 was reacted with 3-(N-methyl-N-phenyl amino)-acrolein 2 to acrolein 3. Enantioselective addition of ketene 4 to diketone 6 was made possible with titanium isopropoxide and chiral catalyst 5, the Schiff base of 3-tert-butylsalicylaldehyde and chiral (S)-valinol. Carbonyl reduction was next: sodium borohydride / diethyl methoxyborane produced the (S,R) syn-adduct and triacetoxyborohydride the (S,S) anti diol 7. By switching the valinol enantiomer and repeating the process the other isomers were obtained.
Fluvastatin synthesis Zacharia 2010

The zinc macroswimmers

20 November 2010 - Making It Move IV

macroswimmers Loget 2010.gifLoget & Kuhn of the University of Bordeaux treat us to another episode of Making it Move (See part III), the popular chemistry parlour trick venture (DOI). This time the macroobjects are dendritic particles of zinc, the medium is plain zinc sulfate solution at pH = 5 , the arena a glass tube , the external force an electric field and the scientific principle : bipolar electrochemistry. In a nutshell the zinc particle tends to dissolve on the cathode part and zinc is deposited on its anodic side. Top speed: 60 micrometer per second.
See the movie

More reaction predictions

19 November 2010 - Computational chemistry

CSI chemistry Shellhammer 2010  And staying on the topic of computational chemistry (see previous topic) Shellhamer et al. (DOI) have run the electrophilic addition of chlorosulfonyl isocyanate (CSI) with a monofluoroalkene through the computer, again confirming the experimental result. CSI cycloaddition is stereospecific as the E-isomer gives the E-lactam and the Z-isomer the Z-lactam which is taken as evidence for a concerted reaction. A dipolar intermediate would produce a cis/trans mixture as a result of freed-up bond rotation (given the opportunity). Are we happy then with the results?. Not really. It would have been nicer if the methodology would have been able to distinguish between concerted and dipolar by tweaking the nature of the alkene substituent (not just fluorine). And something more disturbing: the computer can reproduce a concerted transition state (B in diagram) but (we recommend the Shellhammer team with their honesty) the obvious dipolar intermediate C (electrophilic CSI at carbon) is nowhere to be found and instead the computer coughs up intermediate A featuring a seemingly secondary carbocation. The supplementary info does not provide details on charge distribution so the negative charge at nitrogen is an uneducated guess. Who is going to sort out this mess?

Predicting organogold reactions

11 November 2010 - in-silico chemistry

cyclopropenylGoldChemistrySeraya2010  In an ideal world organic chemists set about synthesising a new molecule only after doing the proper calculations. In computational chemistry you can not only calculate the stability of the desired molecule (can it exist or will it fall apart?) but also the feasibility of the chemical reactions leading up to this molecule (competing reactions more likely? fast enough?). It would safe them a lot of time. Unfortunately in the real world bench chemists and computational chemists are not on speaking terms and live in their own bubbles. Organic chemists synthesise on a hunch with mixed results and computational chemists make a lot of predictions that are not followed up.

A global collective from California, Tasmania and Iran do the right thing and combine experimental chemistry and in-silico chemistry in a single article (Seraya et al. 2010 DOI). They react cyclopropenyl compound 1 with metal triflimidate P(Ph)3AuN(Tf)2 , observe what comes out of the reaction experimentally (cis-diene 2) and rationalize in terms of DFT. It turns out that all competing avenues for this reaction set are blocked by kinetics as judged from activation energy values. The first intermediate, the organogold gold-alkene complex 2 is noncontroversial. The acetate group can then attack the cyclopropenyl group via carbon atom a to 4 (forming cyclopropane 7) or via carbon atom b to 5 but in fact does nothing with the ring breaking up by itself to 6 powered by relief of ring strain. In this intermediate the oxygen atom in the acetate group again has options but avoids carbon atom c (forming allene 8) in favor of carbon atom d, with a approach that leaves the alkene group and the phenyl group in 9 in a trans configuration (steric repulsion minimized) leading stereospecifically to Z-1.

Perylene synthesis makeover

04 November 2010 - Organic chemistry

perylene synthesis Rickhaus 2010  In organic reaction makeovers, ugly and badly performing reactions are metamorphosed into clean happy synthetic procedures with general utility. A recent ugly duckling getting the makeover is the conversion of 1,1-binaphthyl to perylene using an alkali metal as reported by Rickhaus et al (DOI). This variation of the Scholl reaction was discovered by Solodovnikov in 1967 and quickly forgotten about because the publication was in Russian. The authors complain that they had to do the translation themselves because of the poor Chemical Abstracts summary which makes you wonder exactly how much decent Soviet-era chemical research is hidden away. In the new and improved synthesis (quantitative yield!) the solvent dimethoxyethane was replaced by tetrahydrofuran with an optimum 3 equivalents of potassium metal. The temperature was increased from room temperature to 80°C. As always the devil is in the details: note 20 specifies that "Not cleanly cutting all sides of the potassium piece generally leads to a significant drop in yield."

That leaves the reaction mechanism. Curiously in this reaction and eagerly pointed out by the authors, both binaphthyl and potassium are being oxidized, so what exactly is the reduced product? A clue was already provided by Solodovnikov: he detected hydrogen gas. In a new proposal the biphenyl is first reduced to the radical anion (as in a Birch reduction) and then again to the di-anion and at some point a new carbon carbon bond is formed. Related research had already established that the hydrogen atoms in the new bond have a trans relationship and therefore direct formation of hydrogen is unlikely. More plausible is the involvement of a free radical reaction with a hydrogen radical abstracting one of the hydrogen atoms to form H-H and then rearomatisation and expulsion of a new hydrogen radical. The solvent THF is also a radical acceptor but merely shuttles the electrons around.