Organocataytic Povarov

27 February 2010 - Asymmetric synthesis

Xu et al. of the Jacobsen laboratory have extended the application of Brønsted acid cooperative catalysis (more specifically enantioselective organocatalysis) using chiral thiourea's to the Povarov reaction (DOI). Cooperative acid catalysis using achiral urea's resulting in racemic products was already introduced by Weil et a. in 2008 (DOI) and Jacobsen had already tackled another asymmetric reaction - the Pictet-Spengler reaction - in 2009 using a very similar protocol (DOI). Also applied in asymmetric reductive amination (Li et al. 2009 DOI) , asymmetric alkynylation of Imines (DOI) .

In this Povarov reaction benzylidene aniline (the imine product of aniline and benzaldehyde) is reacted with 2,3-dihydrofuran to a tetrahydroquinoline with the Brønsted acid triflic acid. The product forms as an exo and endo mixture with the endo isomer (phenyl group and pentacycle on opposite faces of the piperidine ring) favored by 2 to 1. As the reaction is achiral both isomers are present as a 1:1 mixture of enantiomers bringing the total to 4 different isomers.

The goal in asymmetric synthesis is the formation of just one isomer and in one particular strategy chirality present in the catalyst drives the formation of just one enantiomer through asymmetric induction. Simple acids such as the proton cannot be placed on a chiral scaffold and that is where the cooperative catalyst comes in. With the chiral urea present at 10% loading the reaction slows down to a trickle but the exo:endo ratio is now 4:1 with the exo isomer present in 95% enantiomeric excess (endo isomer 37%).


The transition state picture shows that the urea has a firm grip on the acid-iminium ion complex through hydrogen bonding at the urea site and the sulfoxide site leaving only one avenue for attack of the furan molecule. The alternative furan approach from the right (flip the reactants but not the urea 180 °) that creates the minor enantiomer is less attractive because pi-pi interactions (in green) between the urea aryl group and the imine phenyl group are lost.

The Chemotactic Droplet

19 February 2010 - Making It Move II



This blog has a longstanding interest in a peculiar branch of chemistry dedicated to making small objects physically move in response to chemicals in their environment (synthetic chemotaxis), previous episodes here and here. In their latest entry Lagzi et al. (DOI) (inspired by Hanczyc et al. DOI 2007 is not recent!) have come up with a practical solution to a nonexistent problem how to send a droplet of oil through a maze using the shortest possible path.

A PDMS maze was constructed with channels 1 mm wide and filled with a KOH solution. One entrance was filled with agarose soaked in a HCl solution and the other entrance was the starting point for a droplet of oil (mineral oil/2-hexyldecanoic acid). In this system the droplet moves along a gradient of lower pH (1 mm/s). The fatty acid component in the oil drop diffuses into the water more rapidly facing the region with lower pH due to protonation, resulting in a surface tension gradient fuelling the motion.

The concept needs refining but this blog is confident that in the future it is be possible to toss oil into the ocean somewhere in the Middle East and collect it again close to shore anywhere in Europe without having to bother with oil tankers.

Chemistry goes solar

08 February 2010 - green chemistry?

Organic photochemists are taking the next logical step and venture out of their laboratory and into the sunshine. Obviously all photochemists require light do to their work but some of them shun artificial light bulbs and insist on the natural thing: solar light! And that all on account of greenness. Does this sound like some lame excuse for northern-hemisphere chemists to relocate to a sunnier climate?
Italian chemists have recently invented the word solarylation for their solar powered aryl SN1 reactions that turn out to work just as well in sunlight as with artificial light sources (Dichiarante et al. DOI). All they had to do was switch to greener solvents and increase concentration. Besides mesitylene other suitable nucleophiles for this particular reaction are alkenes.

Scale-up of sun-powered reactions does not need to be an issue. Chemists from Ireland and Germany enthusiastically described the merits of solar light driven reactions in a 2007 article (DOI). Near Cologne, at the German Aerospace Center the Parabolic Trough Facility for Organic Photochemical Synthesis (PROPHIS) equipped with solar tracker has converted citronellol in an photooxygenation to an industrially important intermediate of rose oxide on a 8 liter scale with 70 liter of isopropanol with 2.5 hours exposure time (32 square meters surface area) and 133 moles of photons.

But is this really a viable contribution to green chemistry? From an economics point of view it is still smarter to use green solar electricity to power that light bulb. On the other hand in one particular branch of organic reactions - degradation - the merit is certainly there. Solar detoxification would be an interesting low-cost option for cleaning up remote but sunny contaminated water systems.
Solarylations dichiarante 2010

Wikibooks: Organic reactions

07 February 2010 - Part II

In the second part of Wikibooks (see part I on isomerism) again hundreds of Wikipedia editors have contributed to bring you the ultimate wikibook on organic reactions:

Open here: Wikibooks/Organic_Reactions.pdf (10 MB, 184 pages)

This wikibook contains all the organic reaction types (largely Jerry March classification) and a selection of organic reaction such as Wittig reaction and Aldol reaction. If the timestamp for the first edit in the organic reaction article is a measure, this project started almost 7 years ago at 4 minutes past 10 A.M. January 22 2003 by an anon user possibly associated with the University of Munich.

Menger & Karaman on singularity

02 February 2010 - transition state theory

NGP Hutchins 1975
In an example of a nucleophilic substitution reaction a nucleophile (Nu) reacts with an organohalide R3C-X to form the substituted product Nu-CR3. In conventional transition state theory this takes place with simultaneous bond making and bond breaking and on the reaction coordinate with decreasing nucleophile to carbon distance the intermediate structure Nu-C-X called the transition state lies at the top of an energy hill.

As a function of time the approach of the nucleophile is a smooth process but in a new model for chemical reactivity Menger & Karaman (DOI) introduce a singularity or catastrophic event along this reaction coordinate

In an analogy with simple stapler action (the staple will only start piercing the paper when the force needed to bend the metal is overcome), the hill commanded by Nu-C-X is now replaced by a plateau with Nu//C-X as one extreme (Nu has reached critical distance to C) and Nu-C//X as the other extreme with a barrier less and extremely fast interconversion. With catastrophic events comparisons are made with melting and micelle formation. It can be added that in modelling chemical reactions the cooperative actions of several dozens of molecules need to been involved for a plausible result.

But are there practical consequences to this theory? M&K think so when certain intramolecular substitution reactions are considered with the reactants in close proximity and beyond the critical Nu/C-X distance. For this type of reaction the singularity concept predicts faster than usual reaction kinetics. This is especially relevant to the so-called better-than perfect enzymes ,one of those unsolved problems in chemistry.

But is it all entirely new? Many theories already exist that have different wording but boiled-down possibly mean the same. In the classic organic chemistry textbooks a fast reaction is characterized by a so-called early transition state that resembles the reactant (Hammond's postulate). In another theory enzyme reactions are fast because for instance protons tunnel themselves a way through an energy barrier. To add to the confusion Menger himself introduced the so-called spatiotemporal effect (not just close proximity but sustained close proximity) in 1985 (DOI) that is just one of several theories that Menger again summarized in 1998 (DOI). One of the reactions that according to M&K exemplifies the new singularity concept is the strikingly fast solvolysis of an 6-aza-4-chloro-2.2.2-octane compared to that of N,N-dimethylamino-2-chloroethane first observed by Hutchins and Rue in 1975 (DOI). In their analysis the general effect introduced with nitrogen can be attributed to Neighbouring group participation when the nitrogen atom helps pushing out the chlorine atom. In addition in the bicyclo compound the orientation of nitrogen is much more favorable and reaction is faster in spite of unfavorable steric strain effects. No singularities there either.