Carbonyl substitutes

07 June 2008 - Drug discovery

SpiroCycliOxetanesWuitschik2008
When 15 people get together writing a single 4 page article something must be going on (DOI). Researchers from Hoffmann-La Roche and ETH Zurich have noted the chemical similarities between carbonyl groups and oxetane groups. This is useful information: in drug discovery carbonyl groups are often too reactive while hydrogen bonding properties are similar and larger molecular volume of oxetanes may be an advantage. The researchers examined properties such as distribution coefficient, solubility and pKa for a large number of amines fitted with a carbonyl, oxetane or geminal dimethyl group. The latter group matches the carbonyl group in molecular volume

The idea is not entirely new: the same researchers already arrived at a similar conclusion in 2006 with a different set of amino oxetanes (DOI).

Hexacoordinated carbon update

06 June 2008 - Strange molecules

A new development in hypercoordinated carbon research as Kin-ya Akiba of Hiroshima University together with team from 5 other research institutions announced a novel organic compound with a hexacoordinated carbon atom (DOI). This work is basically an extension of earlier work published in 1999 featuring pentacoordinating carbon. The anthracene frames are identical and coordination partners are oxygen.

The earliest reported hypercoordinated (the phrase hypervalent is now discouraged) carbon compounds are the methanium ion (Olah 1972), an anthracene system (Martin et al. 1979 DOI), a fluorene system (Hojo et al. 1985 DOI) and a polyauriomethane system (Schmidbaur et al. 1988 DOI DOI DOI DOI ). It has also been found to exist in certain zirconium organometallic complexes (Schottek et al. 1998 DOI). Hypercoordination also occurs in carboranes and with agostic interactions.

Hexacoordinated carbon is also an accepted transition state for bimolecular nucleophilic substitution. Heavier hypercoordinated silicon compounds are also known. Prerequisits for true hypercoordinated bonding are acceptable bond lengths and symmetry, which can be revealed by X-ray crystallography.

In the novel Akiba work the central allene carbon atom has four neighboring oxygen atoms with nearly identical C-O bond lengths in between that of a true C-O bond and the sum of carbon and oxygen van der Waals radii. So far so good because al the previous Hojo and Martin systems, according to Akiba, fail to meet this mark. On the other hand, the electron density between carbon and oxygen as determined by X-ray analysis with synchrotron radiation is very low. Although not referred to in the article, this research is tied in with bonding in anthracene itself as discussed in Bader's Atoms in molecules theory.

The allene was synthesised in a Grignard reaction followed by methylation with iodomethane and a carborane superacid.

Unhappy molecules

04 June 2008 - Philosophy

In the Angewandte Chemie this week two heavy-hitters in chemistry Roald Hoffmann and Henning Hopf attempt to answer a fundamental question: why bother with unhappy molecules (DOI). These molecules are afflicted with unusual bond angles or bond lengths and therefore too energetic, requiring very little to decompose or engage in reactions. Many strained molecules have been synthesised by organic chemists for example cubane, dodecahedrane and cyclophanes but others still await the light of day (for example hexaprismane).

In their essay titled Learning from molecules in distress the authors arrive at a somewhat predictable but candid answer. Yes, abnormal molecules are alluring just because they are there (compare George Mallory's because it is there), yes chemists are curious by nature, they enjoy the praise they receive for doing something not done before and yes they want to publish and they want to be quoted.

On the other hand they rule out molecular sadism as a driving force for chemical research. They investigate at length the founding father of sadism Marquis de Sade (must be his first mention in chemical literature) praise him for his libertine thinking out of the box but deplore his overall sick (sic) philosophy.

Aside from psychological considerations, strained molecules should be studied for their philosophical appeal. The authors argue that in science generalizations will only hold up to scrutiny when limits and limitations are explored. To make their case the authors offer comparisons to several famous philosophical gedanken experiments such as the Twin Earth, Swamp man or the Trolley problem (for that article Wikipedia gets a favorable mention although curiously not in the citations).

In short, research and innovation is driven by explorations of the extreme or in the words of Hoffmann & Hopf it is the rim from which we understand the center better.



Memory of chirality

31 May 2008 - Stereochemistry

Enantiopure synthesis is a big research topic in organic chemistry and any racemization taking place in the course of a synthesis is usually a showstopper. For example a nucleophilic substitution at a saturated carbon atom in the SN2 regime results in inversion of stereochemistry. In the SN1 regime on the other hand the carbon center is racemized which is due to the nature of the carbocation intermediate involved. Its structure is planar and an incoming nucleophile can approach unhindered from each of the two sides. Other intermediates notable for messing up stereochemistry are free radicals and in particular enolates.

Memory of chirality (MOC) is a concept introduced in 1991 by Kawabata and Fuji where a given substrate reacts with retention of central chirality by passing through an intermediate displaying axial chirality or planar chirality (DOI DOI)

They showed how chirality was retained in an alkylation (iodomethane) of the enolate of an arylketone.

A group of French chemists have recently devised a way to synthesise new derivatives of valine also using the concept of memory of chirality ( DOI).


They induce temporary axial chirality in the valine enolate by converting it first to a oxazolidinone with a bulky naphthalene group. The enolate is then alkylated with MeTf and after acid hydrolysis, methylated valine is obtained with 94% enantiomeric excess.

Open-access chemistry

30 May 2008 - Freedom of information

Open-access publication has a long way to go in chemistry land. The basic idea behind open-access is that authors and not readers pay a fee for having a scientific article published. For a number of reasons this is a great idea. Scientific papers should be freely accessible because access to knowledge should be free in the first place and because a large portion of scientific research is paid by the public anyway through taxes. As an added bonus researchers will be expected to show some constraint when publishing their results when it costs them money, increasing the quality of published content.

Many publishers of chemistry content now have an open-access platform where you can expect to see some open-access content among the subscription based content. Problem though is that the open-access content is usually not properly labeled in the table of contents.

Current fully open-access organic chemistry sources: the venerable organic Syntheses @ orgsynth.org are now in their 86th volume. Example: two ways to synthesise diphenyldiazomethane here (1944) and here (2008). Interestingly its inorganic cousin Inorganic Syntheses is again subscription based. A recent initiative is the Beilstein Journal of Organic Chemistry and then there are Molecules and The Open Organic Chemistry Journal . An extensive list of open-access publications can be found here.

The most recent addition to the list is called JACSbeta which is a web-based collection of JACS articles around a specific theme (currently total synthesis). Free access is granted until the next edition of this publication.