Molecular hinge parade

24 May 2008 - Molecular machinery

MolecularHinges2008Small  Molecular machines are molecules that mimic life-size machines and can be found in abundance in the shape of molecular switches, molecular propellers, molecular tweezers or even molecular motors. They appear to exist solely for the entertainment of chemists.

In this field molecular hinges are molecules (as the name hinge implies) with a central axis connecting two molecular fragments. A certain degree of rotation around this axis allows variation of the angle between the two sections and in a smart system the hinging process can be controlled. The hinge motif features in many biochemical processes and synthetic hinges can potentially be applied as molecular sensor.

The variety in synthetic hinges is large with each rotation mechanism based on a specific physical chemistry concept. Light driven hinges exist with azobenzene groups as part of the hinge ( DOI ) . Other hinges rely on free rotation around the axis and special attractive forces between the adjoining molecular segments for instance pi stacking ( DOI) Bundled in a third group are hinges that can open or close when an additive breaks or forms a simultaneous bond with two actives sites on de side-group for instance a copper ion ( DOI) or a simple proton ( DOI DOI DOI) .

Two examples of the 2008 harvest of molecular hinges. In one novel system (Sankararaman et al. DOI), free rotation around the axis is provided by two alkyne groups and the two perylene side-groups can interact through pi-stacking. On crystallization from hexane two different crystals are obtained from each of the open or closed conformers.

In another system the side-groups do not only interact through pi-stacking but switching is also made possible by complexation of a metal ion between two pyridine units (Bosch et al. DOI). Surprisingly in light of the Sankararaman result, switching dynamics based on the stacking interaction alone were not investigated.

Metal-free hydrogenation update

21 May 2008 - FLP chemistry

MetalFreeImineHydrogenation  Hydrogenation in organic chemistry generally requires a metal such as palladium to work. Alternatives that do away with the metal are transfer hydrogenation (hydrogen donor is not hydrogen gas itself) and several true metal-free hydrogenation systems.

A novel system was introduced by Stephan et al. in 2007 ( DOI) for hydrogenation of imines with a amine-phosphine system called a frustrated Lewis pair. In a new 2008 report (DOI) Stephan replaces the catalyst by the much simpler tris(pentafluorophenyl)boron.

This work was in part inspired by older work (2000) by Piers et al. DOI who used the same catalyst in reduction of imines in combination with a silyl hydride as hydrogen donor.

Klankermayer et al. in 2008 ( DOI) were also motivated by the Piers work and produced very similar work as Stephan (only beaten by two months).

It is known that hydrogen can react with alkyl boranes to borane hydrides and compounds like 9-BBN are will known reducing agents. Is this reaction type therefore true hydrogenation ?. Stephan thinks so, he proposes an iminium ion / hydridoborate counterion as a key intermediate.

The missing-xenon problem

20 May 2008 - Gone!

The so-called missing-xenon problem is one worthy for inclusion into the Wikipedia list of unsolved problems in chemistry. Xenon's problem is that it is not very abundant in Earth's atmosphere compared to xenon concentrations in outer space or compared to the concentration of the other noble gases on Earth itself, so where has it all gone?

The problem was first identified in 1997 (DOI) by Caldwell et al. who tried in vain to form xenon-iron alloys at high pressures. If the xenon had disappeared so it seemed it was not in Earth's iron core at some point in Earth's evolution.

In 2005 Sanloup et al. ( DOI) discovered that xenon can substitute silicon in quartz at high temperatures and pressure but the gas escapes just as easily.

Although it is one of the noble gases, xenon can form chemical bonds with other elements for example in xenon hexafluoroplatinate. Most recently in 2008 Khriachtchev et al. ( DOI) have identified the compound HXeOXeH in a xenon matrix at 45 degrees kelvin by photolysis of xenon with plain water. The researchers think this finding gives a first clue towards polymeric Xe-O structures which may somehow be related to the missing-xenon problem.

Update February 2011: xenon dioxide is another contender (DOI)

Target tetra-tert-butylethylene

14 May 2008 - Organic chemistry

HinderedAlkeneIonkin2008  Still on the to-do list for organic chemists: the organic synthesis of the seemingly simple compound tetra-tert-butylethylene. It is strained because the 4 bulky
tert-butyl substituents crowd each other but at the same time it is predicted to be stable. Novel research from Du Pont researchers only indirectly aimed at this particular target is probing some properties of a related crowded alkene with just two t-Bu groups and one carboxylic acid group (DOI). Although this concerns 2008 chemistry, given the inventory of chemical reagents, the reactions presented may as well have been performed in 1908.

Step one is a Grignard reaction, joining acid chloride (1) and Grignard (2) to form the dineopentyl ketone (3). This compound is brominated to 4 and reacted to strained (E) - 5 with potassium hydroxide and DMSO in a Favorskii rearrangement.

What happens next is interesting: for no particular reason the Du Pont researchers add thionyl chloride in order to convert (5) into the acid chloride (possibly to fit the molecule with a nice ester tail and then polymerize it) which works just fine but an unexpected cis-trans isomerisation yields the (Z)-isomer (the authors suspect involvement of hydrochloric acid).

The final reaction step to the (Z)-carboxylic acid by hydrolysis from ambient air and subsequent crystallization while dissolved in methylene chloride is either an carefully planned reaction protocol or the researchers initially discarded the acid chloride as a failed project.

In any event the final outcome allows an interesting direct comparison between two hindered alkene isomers. Both alkenes are reported to have have shortened carbon-carbon bonds and experience some serious torsional strain.

Prostratin total synthesis

12 May 2008 - Total synthesis

ProstratinSynthesisWender2008  A new total synthesis from the lab of Paul Wender converts phobol to prostratin in 5 easy steps (DOI).

Prostratin is in the picture as a potential drug in the battle against HIV. The diterpene is very efficient in luring the virus out of those places in the hman body where the regular HIV destroyers cannot reach. One of the natural sources for prostratin is the plant Homalanthus nutans which has been known in traditional Samoan medicine for its healing powers for a long time for example in the treatment of hepatitis.

Problem is that the isolable yield is low (up to 50 mg/g). On the other hand, phorbol, the new precursor to prostratin is isolated from widely available croton oil.

The main difference between the two compounds is a hydroxyl group at C12 but all deoxygenation attempts fail without opening the cyclopropane ring next-door to a propenyl group. Rather than resorting to protective groups (increasingly criticized) the researchers opted for restoring the cycloprane ring instead.

Acid hydrolysis of phorbol A gives crotophorbolone B. Addition of hydrazine and acetic acid first gives the hydrazone and then after addition of base (pyridine, DIPEA) the pyrazoline C. Oxidation to the diazene D with lead tetraacetate is accompanied with placement of the acetate group. This step is followed by photolysis with extrusion of nitrogen to prostratin E.

Chemspider relaunch

09 May 2008 - cheminformatics

This week the journal Nature reported on the latest chemistry open-access initiative called chemspider at www.chemspider.com (DOI). This database aims to be the chemical counterpart of biology PubChem and already contains over 20 million chemical compounds. Both free-access initiatives intent to make life miserable for the Chemical Abstracts run by the American Chemical Society. The chemspider venture is privately funded and attracts revenues with online advertising.

A basic search for a chemical gives an extensive list of synonyms, chemical structure, SMILES, InChI, and a section on predicted properties. A promising tool is the semi-graphical substructure search like the one implemented in the online Aldrich catalogue. The chemical elements search allows you to select any compound with nitrogen, oxygen and sulfur but not containing carbon or phosphorous (74 hits).

There is a downside. The application depends on aggregating information from many other databases which introduces the risk that a single mistake in one database is perpetuated in many others. The application also relies on contributions made by members of the chemical community and active user contributions are always a bottleneck in any Internet venture.

The system is not yet flawless.

When searching for compounds with chemical formula C6H6, chemspider comes up with 24 isomers of benzene, not only the classic isomers such as Dewar benzene, benzvalene, prismane and fulvene but also many linear polyenes and polyynes. So far so good. But 4 structures are actually ions such as the dianion of cyclohexadiene which should not count as a discrete compound. The cyclohexane hexaanion C6H6 is highly esoteric.

A Simple search for formula C47H51NO14 (Taxol) results in 53 hits but all compounds listed are in fact taxol. In the datasheet there is no indication given that the relevant taxol molecule is in fact chiral and although the boiling point is listed as 957 °C it will probably decompose well before that temperature.


Periodic table, new and improved

08 May 2008 - General chemistry

leftStepTableScerri2008  The Mendeleev periodic table is over 140 years old but is not the only periodic table in existence and new representations regularly appear.

The so-called left step table (Charles Janet 1929) demonstrates more clearly than the Mendeleev table how blocks form from the first two quantum numbers n and l.

Another classic is Timmothy Stowe's physicists periodic table. This is a three-dimensional representation with three axes for each of the first three quantum numbers.

In both tables helium is placed with elements in period 2 (the one with sodium, magnesium etc) with which it has very little in common chemically and this presents a problem.

In a new (2008) periodic table modification (Link), Eric Scerri is repositioning some of the elements in the left-step table based on the re-examination of so-called periodic table triads, a phenomenon already studied by the early chemistry pioneers.

In these triads the atomic weight of an element is the average of that of the element above and the one below. This relationship is exact for atomic numbers. For example the atomic number for arsenic is 33 which is the mean of 15 (phosphorus) and 51 (antimony). The reason is the long periodicity of 18 in the periodic table.

This relationship also holds for atomic weights, an observation first made by chemist Döbereiner in 1829 with the chlorine (35.47) , bromine (80.97 = ( Cl + I ) / 2) and iodine (126.47) triad. In fact the study of triads gave chemists the first clue about periodicity in the first place. This relationship is not obvious as the exact atomic weight depends on isotopic distribution and geological history.

Helium is also part of a triad, together with neon and argon and for this reason Scerri favors placement of helium with the noble gases. To restore order, he also positions hydrogen with the halogens which also makes sense chemically. For instance hydrogen like the halogens can form negatively charged ions.

Update: 31 May Tom emails that there are in fact four quantum numbers, so noted!

Direct C-H bond arylation

06 May 2008 - Organic chemistry

CHbondArylationKawai2008  C-H bond activation is a hot topic in current chemistry potentially converting cheap and abundant alkanes into valuable fine chemicals. Breakthroughs in this field were made in 1982 by Bergman and Graham in 1982 with humble cyclohexane.

The functionalization of certain aromatic compounds is also considered C-H activation but the question is if this is rightly so. These reactions used to be called aromatic substitution but the label C-H bond activation makes them all the more trendy. Case at hand the arylation of naphthalene by palladium as investigated by a group of Japanese researchers (DOI) .

The reagents are phenyltintrichloride, a catalytic amount palladium(II) chloride and oxidant copper chloride and the optimised product distribution shows this reaction type has a long way to go.

The researchers propose that copper chloride (the sacrificial catalyst) oxidizes Pd(II) to Pd(IV) which after accepting a phenyl ligand in transmetallation acts as a strong electrophile in plain old fashioned electrophilic substitution with the arene.
They have plenty of evidence in support for this reaction mechanism: no reaction takes place without the copper chloride and a radical scavenger does not exactly spoil it.

But if there is nothing new here then where is it?

What makes this mechanism so interesting is that involvement of organopalladium (IV) complexes in organic reactions is of of those other hot topics with those arguing they exist and those who see a multitude of alternative mechanisms. To be continued!

Palladium cycle in Suzuki reaction made visible

01 May 2008 - Catalysis

SuzukiMacQuarrie2008  The Suzuki reaction is a coupling reaction between an aryl halide and an aryl boronic acid catalyzed by palladium metal. The first step in this reaction is insertion of palladium(0) into the aryl halide bond forming an oxidized ArPd(II)X intermediate and in the final step Pd(0) reforms from a diaryl palladium species.

This sequence implies that in a suitable heterogeneous system palladium first dissolves and then redeposits. This is where the details get sketchy.

Researchers from Queen's University in Canada have now been able to observe the palladium cycle by heating a tiny section of palladium foil in presence of both reactants and examining the metal surface by scanning electron microscopy (DOI) . They found that palladium disappears at the center of the hot zone and re-deposits in the cooler sections. The aryl halide alone also does the trick emphasizing the similarities with dissolving magnesium metal when forming a Grignard reagent.

In this type of reaction the catalyst is separated from the reaction product by filtration and a better understanding of metal redeposition will certainly help cleaning it up.

Handle with care: pi - pi stacking

30 April 2008 - Physical chemistry

pistackingGrimme2008  Pi - pi stacking is a popular chemistry concept describing how aromatic molecules are stabilized when oriented face-to-face as in a stack of coins. It explains how certain supramolecular structures are formed and especially in biology it explains the finer points of base pairing in DNA.

The origins of pi stacking are unclear. In a simple bonding model the interaction results from favorable overlap of the aromatic pi-orbitals. But in a recent article (DOI) Stephan Grimme points out this is a widely held misconception. As one of the offenders he cites the November 2007 wikipedia pi stacking article which must be the first time Wikipedia gets a mention in the scientific literature but for the wrong reasons.

In his article Grimme investigates the true origin of pi stacking and questions if it really exists. After all, many intermolecular interactions can equally well be explained with conventional dispersion forces which arise from statistical fluctuations in electron density.

In a series of computations Grimme compares a group of aromatic compounds (benzene, anthracene and the two higher acenes) with their saturated all-trans counterparts (e.q. cyclohexane, decaline etc.) with respect to intermolecular separation and stabilization energy. Sure enough, in the aromatic series this distance decreases as the stabilization energy increases but interestingly for the first two members the stabilization energy is similar be it unsaturated or saturated. So no special pi effect there. On the other hand for the higher members genuine pi stacking is a reality and is dominated by dispersion.

Therefore handle with care, with less than 11 atoms all a molecule experiences are plain old-fashioned van der Waals forces. Biomolecules such as purines still stack but without the pi pi.

New AkzoNobel logo

25 April 2008

AkzoNobelNew
On April 25 2008 Chemical company AkzoNobel presented a new company logo very similar to the previous one designed by Wolff Olins in 1988. That one was inspired by an ancient Greek sculpture and caused big commotion at its launch in the Arabic world because it was said Islam forbids graphical depictions of humans.

According to a company press release the new logo ' has been made more relevant for the 21st century and now has a greater sense of power and energy ' and that was just one of the empty public relation slogans.

Chemrefer dissapeared?

20 April 2008 - Internet

For a moment there it seemed www.chemrefer.com had disappeared. The url now links to chemspider.com. Turns out chemspider is doing a good job hiding chemrefer. The new (or temporary) link is this one

The nice thing about this search engine is that it only indexes from open access chemistry journals for example Pure Applied Chemistry or journals with open access content such as Chemical Communications. Remember that search engines like google index all journals but when you hit a promising link you will still get an access prohibited page unless you have a subscription.

Update: May 23. Now even this link throws a 404. Chemrefer is now officially M.I.A.

Vista / pdf trouble

29 March 2008 - IT

My library recently installed Vista on all their computers with some unexpected consequences. All of a sudden pdf files are unable to simply open in a browser, instead you have to explicitly open the file by clicking a bar located just below the address bar. Apparently according to Vista opening any pdf file constitutes a serious security risk. This is just a nuisance but there is more.

For some reason the library Vista browser is unable to open any pdf file from Wiley publishers (for instance any Angewandte Chemie article), possibly because it is unable to recognise the mime files types. Well then, simply access the html file instead, problem solved. Other problem solved: save html file as a .mht file (Mime HTML), the Microsoft pdf killer. This application (just like a pdf) includes any image inside the single html file making the pdf format obsolete. The only issues to solve then are the image sizes in the .mht file which for Wiley publications are tiny and the general remark that standard issue FireFox does not support Mime HTML (the browser wars continue).

The library helpdesk too is surprised the pdf files do not load properly and suggest renaming the file with a token name and a pdf extension. At first this trick seems to work but by the time the article has arrived on my own server the article is still unreadable.

Update 27 May: The Adobe help desk thus far did not send a reply to my inquiry sent in 18 May..
Update 1 June: Problem solved! All pdf files readable as before.

Computational chemist runs out of disk space

16 February 2008 - Bad luck

Computational chemistry requires big computers. A researcher from Trinity University, San Antonio was just barely able to complete his calculations on a gem-dimethyl effect problem.

A quote from his 2008 research paper in the Journal of Organic Chemistry DOI : Unfortunately, we lack sufficient disk space, but we were able to complete the computations at CCSD(T)/6-311+G(2d,p)//PBE1PBE/6-311+G(2df,2pd) with the PBE1PBE ZPVEs . Donations are welcome.

Oseltamivir total synthesis latest

18 May 2008 - Total synthesis

OseltamivirTrost3  Oseltamivir is an important antiviral drug used in the treatment of influenza. It is currently produced commercially in a semisynthesis starting from shikimic acid which is sourced from the Chinese star anise. Problem is that in the event of a influenza pandemic there might not be enough of this particular plant and that is why chemists are trying to find alternative ways to synthesise oseltamivir. The Barry Trost lab recently published oseltamivir total synthesis number 6 ( DOI).

The molecule in question has a 6-carbon cyclohexane frame with one carboxylic acid group, a hydroxyl group and two amino groups (the actual drug called Tamiflu is a phosphate salt). The starting material, bicyclic lactone 1 already has several components in place but is achiral while the target molecule has 3 stereocenters.

Step one therefore introduces the first of the two amino groups in an AAA reaction (Trost's own invention of 30 years ago) with allylpalladium chloride dimer, the DACH ligand and trimethylsilyl protected Phthalimide as the nucleophile. The lactone ring is opened and carbocylic acid group esterified in one go.

Thioester 4 is formed by application of a strong base (KHMDS) and PhSSO2Ph. Grieco elimination to diene 5 is then induced by mCPBA. This compound is almost identical to the diene in Corey's version which his lab synthesised in about 7 steps from butadiene and acrylic acid. Trost claims his version is the shortest yet from a commercially available compound but Coreys starting materials are more easily recognized as simple raw materials you could buy everywhere.

Much research effort was spent on the aziridation step. SESNH2 (2-(trimethylsilyl)ethanesulfonylamine)) is a nitrene precursor with a protective group rolled in one. Added reagents are a catalyst based on rhodium with two esp ligands, base magnesium oxide and an oxidizing reagent (Iodobenzene diacetate).

The final steps are ring-opening of the aziridine with 3-pentanol and boron trifluoride, Acylation of the amino group and its deprotection with TBAF and finally removal of the phthalimide group with hydrazine.