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Methylhydroxycarbene

26 June 2011 - Quantum mechanics

methylhydroxycarbene  After hydroxymethylene (2008) and phenylhydoxymethylene (2010, DOI), Peter Schreiner and group now present methylhydroxycarbene. The method of generation is roughly similar: heat a precursor molecule to really high temperatures in Flash vacuum thermolysis and then trap the reaction products in solid argon at really low temperatures. In the case of methylhydroxycarbene the variables are pyruvic acid, 900°C and 11 K. The carbene yield is 2 to 5%. When irradiated at 435 nm, the carbene rearranges in a hydrogen 1,2-rearrangement to vinyl alcohol and acetaldehyde as can be observed by infrared spectroscopy. Acetaldehyde is formed predominantly with a chemical half-life of 1 hour. This is fast compared to a half-life of 10 hours for the isomerization of oxygen-hydrogen bond in pyruvic acid. The computed activation energies on the other hand are very high: 28 kcal/mole for the transition to acetaldehyde and 26 kcal/mole for the one to vinyl alcohol. If this reaction was simply ruled by Thermodynamic versus kinetic reaction control with kinetic control prevailing the reaction product would be vinyl alcohol and not acetaldehyde.
According to Schreiner the reaction proves that besides thermodynamic / kinetic control we can now add a third reaction driver: quantum tunneling It is the same tunneling also appearing in the kinetic isotope effect and it means that a reaction along a reaction coordinate does not bother to scale the barrier height but simple tunnels its way through the barrier itself. In this event the barrier width takes on some significance and as it happens this width is relatively narrow in the conversion to acetaldehyde.

Retire hybrid atomic orbitals? Not yet!

19 June 2011 - Conceptual tools

In the latest edition of the Journal of Chemical Education, Alexander Grushow bans orbital hybridisation to the scrapheap that is obsolete theories (DOI). Students have to get used to MO theory and hybridisation can join the ranks of phlogiston theory. Hybridisation proponents argue that the theory is very useful in explaining things like molecular geometry and bond energies but according to Grushow MO theory can do the job as well. Take for example methane. In orbital hybridisation 2 2s electrons and 2 2p electrons on carbon mix to form 4 identical sp3 atomic orbitals available for bonding to 4 hydrogen atomic orbitals. This explains why in methane the 4 C-H bonds are identical.

The assumption that the theory also makes sure a tetrahedral orientation of the 4 sp3 orbitals is incorrect according to Grushow because that can already be derived from VSEPR theory. According to this theory the 4 valence electrons on carbon simply stay out of each others way as far as possible in a tetrahedral configuration but Grushow is quick to remark this is another localized electron model albeit less harmful.

In MO theory Grushow continues, the C-H bonds may be identical but with different bonding energies. This is a difficult concept to grasp but Grushow thinks this matter should rest until students get to somewhat more advanced quantum mechanics which is much simpler if students do not have incorrect notions of localized bonding orbitals already stuck in their heads.

Does this blog agree? For starters, MO theory does not have a qualitative and didactic recipe for the explanation of relative MO energies. Calculations are laborious and require extensive mathematical background. Computer models are black boxes with no didactic value at all. Grushow proposes to ban orbital hybridization in university textbooks when the chemical literature is rife with it. Perhaps as a more ambitious plan the science journal editors and referees should be persuaded to take the first step.

Target: (+)-mefloquine

10 June 2011 - Total synthesis

Mefloquine coltart  Mefloquine hydrochloride a.k.a. Lariam is an important antimalarial drug (quinine analogue). It is sold as a racemate but uncertainty exists about the effectiveness of the individual enantiomers (R,S) and (S,R). Adding a long list of clinical side effect , an investigation is in order. Knight, Sauer & Coltart did their bit and have reported a new asymmetric synthesis for the compound (DOI).
Step 1 is a Darzens reaction of hydrazone 1 with ketone 2 forming chiral epoxide 3 thanks to the presence of an chiral auxiliary on 1. This auxiliary was then removed to form ketone 4 (TsOH), a Baeyer-Villiger oxidation (m-CPBA) then formed ester 5, ester reduction (lithium aluminum hydride) gave alcohol 6 and then oxidation via the Dess-Martin periodinane gave aldehyde 7.
Wittig reaction with ylide 8 then gave alkene 9, reaction with triphenylphosphine gave a Staudinger reaction to the amine and in-situ reaction with the epoxy group then gave the N-BOC alcohol 10 after protection with di-tert-butyl dicarbonate. The alkene group was reduced (H2, Pd-alumina) to 11 and the BOC group was then removed using trifluoroacetic acid and after adding HCl mefloquine hydrochloride 11 was obtained.

The mystery of the missing methane part II

03 June 2011 - Deepwater Horizon

Back in January Kessler et al. were sure most of the methane released by a faulty vent in the Gulf of Mexico was gobbled up by bacteria (See earlier blog) but Joye et al. in a recent comment in Science are not convinced (DOI). Here is what they think:

  • The new estimate for the amount of methane released is 10 times the number used in the Kessler model
  • The Kessler team only looked for methane where they thought it had gone to (south-west of the well-head) but other areas are also affected
  • Methanol was distributed at the disaster location as part of the relief effort adding more carbon for the bacteria to chew on. One of the bacteria found (Methylophaga) that showed the largest increase in numbers is known to consumer methanol but not methane
  • You can find midwater oxygen-depleted areas all over the place if you look for them, for example in the Mississippi Canyon
  • Kessler should have considered other techniques to back up his claim for example relative abundance of carbon-13 in the remaining methane

  • Luckily the same issue of Science also contains the Kessler rebuttal (DOI) so here we go:
  • No, even when new higher but unconfirmed estimates of total carbon output are accepted the new value is at the most 3 times higher but not 10 times higher
  • No, Kessler did hunt for methane in other directions than just that of the plume
  • No, some bacteria consume methane and release methanol, which is then consumed by other bacteria such as Methylophaga. Industrial methanol has nothing to do with it.
  • Kessler did collect data on oxygen depletion in the Mississippi Canyon but trends were not revealed
  • 13C measurements of residual methane proved difficult because most methane had disappeared


  • So who is right here? Of course, when the total amount of methane released gets a new higher figure the Kessler model has a problem. On the other hand if Joye still thinks there is a lot of methane still out there she should get on a boat and start doing measurements. The matter of the methanol is intriguing: where does it come from? An earlier blog here took a closer look at the nature of the surfactant used in vast amounts by BP with the purpose of dispersing the oil. No methanol there but another alcohol. Could 2-butoxyethanol have messed things up?